Heterocyclic compounds and methods of use

Abstract

The present disclosure provides compounds useful for inhibiting KRAS G12D. The compounds have the general formula (I): TIFF2024532734000485.tif26170, where the variables of formula I are defined herein. The disclosure also provides pharmaceutical compositions comprising the compounds, for example, uses of the compounds and compositions for the treatment of cancer.

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 / 289,579, filed December 14, 2021, each of which is incorporated by reference herein in its entirety.

[0002] The present disclosure provides compounds that have activity as inhibitors of G12D mutant KRAS proteins. The present disclosure also provides pharmaceutical compositions comprising the compounds, uses, and methods for treating certain diseases, such as cancer, including, but not limited to, non-small cell lung cancer (NSCLC), colorectal cancer, and / or pancreatic cancer. [Background technology]

[0003] Since its identification in 1982 as one of the first human oncogenes (Der et al., 1982), KRAS (Kirsten rat sarcoma viral oncogene homolog) has been the 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 acts 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, leading to cell proliferation. Normally, growth-promoting signaling is regulated by the action of GTPase-activating proteins (GAPs), which revert KRAS to its GDP-bound, non-proliferative state. KRAS mutations impair the regulated cycling of KRAS between these GDP- and GTP-bound states, resulting in 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 frustrated by the absence of a druggable pocket on the surface of the protein (Cox et al., 2014). In 2013, Shokat et al. identified a covalent inhibitor of a common (O'Bryan, 2019) oncogenic mutant of KRAS, KRAS G12C, that bound to a previously unrecognized allosteric pocket on GDP-KRAS G12C and prevented its subsequent activation (Ostream et al., 2013). This discovery led to significant new efforts in KRAS inhibitor research and 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 or G12S. Thus, there is a need to develop new inhibitors of KRAS G12D, G12V, G12A, G12S or G12C for the treatment of disorders such as cancer. [Means for solving the problem]

[0008] In one aspect, the present application provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: [ka] is a single or double bond, W is C, CH or N, and when W is CH or N, [ka] is a single bond, X is CH2 or CH=CH; n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1, 2, 3 or 4; 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, -TR y or two R x together with the adjacent carbon atom, C 3~7 cycloalkyl, 5- to 7-membered heterocycloalkyl, each C 3~7 Cycloalkyl or 5- to 7-membered heterocycloalkyl is R y or two R x can be taken together to form a bridged ring, the bridge being one of the following:-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 R y is further replaced by 0 to 2 occurrences of L is C 1~6 Alkylene, -OC 1~6 Alkylene, -SC 1~6 Alkylene, NR z , O or S, and each C 1~6 Alkylene, -OC 1~6 Alkylene and -SC 1~6 The alkylene chain is R 2 is replaced by 0 to 2 occurrences of R 1 is hydroxyl, aryl, heteroaryl, R 5 C replaced with 0-3 occurrences of3~8 is cycloalkyl or heterocycloalkyl; R 2 is halogen, hydroxyl, C 1~4 alkyl, or two R on the same or adjacent carbon atoms 2 Together, C 3~7 can form a cycloalkyl, R 3 is R 6 is an aryl or heteroaryl substituted with 0 to 3 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 is cycloalkyl or cyano; Each R 5 is halogen, oxo, hydroxyl, amino 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)-, -N(H)-C(O)-, -N(H)-S(O)2-, C 1~4 alkylene -S(O)2- or -S-; R y is a halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, hydroxyl, cyano or -N(R z )2, R z is hydrogen or C 1~4It is alkyl.

[0009] In a second aspect, provided herein is a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt of said compound, and a pharmaceutically acceptable excipient.

[0010] In a third aspect, there is provided herein a compound of Formula I, or a pharmaceutically acceptable salt of said compound, or a pharmaceutical composition as described herein, for use in treating cancer (e.g., NSCLC, colorectal cancer, or pancreatic cancer).

[0011] Reference will now be made in detail to the embodiments of the present disclosure. While particular 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 cover alternatives, modifications, and equivalents, as may be included within the spirit and scope of the embodiments of the present disclosure, as defined by the appended claims. DETAILED DESCRIPTION OF THE INVENTION

[0012] In embodiment 1, provided herein is a compound of formula (I): [ka] or a pharmaceutically acceptable salt of said compound, wherein: [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 CH2 or CH=CH; n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1, 2, 3 or 4; 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, -TR y or two R x together with the adjacent carbon atom, C 3~7 cycloalkyl, 5- to 7-membered heterocycloalkyl, each C 3~7 Cycloalkyl or 5- to 7-membered heterocycloalkyl is R y or two R x can be taken together to form a bridged ring, and this bridge is 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 R y is further replaced by 0 to 2 occurrences of L is C 1~6 Alkylene, -OC 1~6 Alkylene, -SC 1~6 Alkylene, NR z , O or S, and each C 1~6 Alkylene, -OC 1~6 Alkylene and -SC 1~6 The alkylene chain is R 2 is replaced by 0 to 2 occurrences of R 1 is hydroxyl, aryl, heteroaryl, R 5 C replaced with 0-3 occurrences of 3~8 is cycloalkyl or heterocycloalkyl; R 2 But halogen, hydroxyl, C 1~4 alkyl, or two R on the same or adjacent carbon atoms 2Together, C 3~7 can form a cycloalkyl, R 3 But R 6 is an aryl or heteroaryl substituted with 0 to 3 occurrences of R 4 But 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 is cycloalkyl or cyano; Each R 5 is halogen, oxo, hydroxyl, amino or C 1~4 is alkyl, Each R 6 However, 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)-, -N(H)-C(O)-, -N(H)-S(O)2-, C 1~4 alkylene -S(O)2- or -S-; R y But halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, hydroxyl, cyano or -N(R z )2, R z is hydrogen or C 1~4 It is alkyl.

[0013] In embodiment 2, the present invention provides a method for treating a hydroxyl group containing L, R 2 C replaced with 0-2 occurrences of 1~6Compounds according to embodiment 1, wherein L is alkylene (e.g., methylene or ethylene). 2 -OC substituted with 0 to 2 occurrences of 1~6 Compounds according to embodiment 1 are provided wherein L is alkylene (e.g., -O-methylene-, -O-ethylene-, or -O-propylene). 2 As an embodiment 5, provided herein is a compound according to embodiment 3, wherein L is -O-ethylene or -On-propylene substituted with 0 to 2 occurrences of R 2 Compounds according to embodiment 4 are provided wherein the aryl group is -O-ethylene substituted with 0 occurrences of

[0014] As a sixth embodiment, the present invention provides a compound represented by the formula: 1 But R 5 As an embodiment 7, provided herein is a compound according to any one of embodiments 1 to 5, wherein R is heterocycloalkyl substituted with 0 to 3 occurrences of 1 But R 5 As an embodiment 8, provided herein is a compound according to embodiment 6, wherein the compound is 7-(hexahydro-1H-pyrrolidine) substituted with 0 to 3 occurrences of R 1 But R 5 As an embodiment 9, there is provided herein a compound according to embodiment 7, wherein the compound is 7-(hexahydro-1H-pyrrolidine) substituted with 0 occurrences of R 1 But R 5 As an embodiment 10, there is provided herein a compound according to embodiment 7, wherein the compound is 7-(hexahydro-1H-pyrrolidine) substituted with one occurrence of R 5 Compounds according to embodiment 9 are provided, wherein is a halogen (eg, fluorine).

[0015] In embodiment 11, the present invention provides a compound represented by the formula: 1 But R 5 As an embodiment 12, compounds according to embodiment 6 are provided herein that are 2-pyrrolidine or 3-pyrrolidine substituted with 0 to 3 occurrences of R1 But R 5 As an embodiment 13, there is provided herein a compound according to embodiment 11, which is a 3-pyrrolidine substituted with one occurrence of R 5 is cyano. 1 But R 5 As an embodiment 15, there is provided herein a compound according to embodiment 11, which is a 3-pyrrolidine substituted with two occurrences of 5 is methyl and other R 5 Compounds according to embodiment 14 are provided, wherein is cyano.

[0016] As embodiment 16, the present invention provides a compound represented by the formula: R 1 But R 5 As an embodiment 17, there is provided herein a compound according to embodiment 11, which is a 2-pyrrolidine substituted with two occurrences of R 5 But C 1~4 Compounds according to embodiment 16 are provided, wherein one R is alkyl (e.g., methyl), oxo, cyano, or halogen (e.g., fluorine). 5 is methyl and other R 5 is fluorine. As embodiment 19, compounds according to embodiment 16 are provided herein in which one R 5 is methyl and other R 5 Compounds according to embodiment 16, wherein is oxo.

[0017] As embodiment 20, the present disclosure provides a compound in which L is R 2 As embodiment 21, provided herein is a compound according to embodiment 3, wherein the compound is -On-propylene substituted with two occurrences of R 2 But together with the same carbon atom, C 3~7 Compounds according to embodiment 20 are provided that form a cycloalkyl (e.g., cyclopropyl). 1 But R 5Compounds according to embodiment 21 are provided herein in which R is heterocycloalkyl (e.g., N-morpholinyl) substituted with 0 to 3 occurrences of 1 is hydroxyl.

[0018] As embodiment 24, the present invention provides -LR 1 but, [ka] There is provided a compound according to any one of embodiments 1 to 23, wherein:

[0019] As embodiment 25, the present invention provides -LR 1 but, [ka] 25. A compound according to embodiment 24, wherein:

[0020] As embodiment 26, the present invention provides -LR 1 but, [ka] 25. A compound according to embodiment 24, wherein: As embodiment 27, the present invention provides -LR 1 but, [ka] 25. A compound according to embodiment 24, wherein: As embodiment 28, the present invention provides -LR 1 but, [ka] 25. A compound according to embodiment 24, wherein: As embodiment 29, the present invention provides -LR 1 but, [ka] 25. A compound according to embodiment 24, wherein: As embodiment 30, the present disclosure provides -LR 1 but, [ka] 25. A compound according to embodiment 24, wherein: As embodiment 31, the present specification provides -LR 1 but, [ka] 25. A compound according to embodiment 24, wherein: As embodiment 32, the present invention provides -LR 1 but, [ka] 25. A compound according to embodiment 24, wherein: As embodiment 33, the present specification provides -LR 1 but, [ka] 25. A compound according to embodiment 24, wherein: As embodiment 34, the present invention provides -LR 1 but, [ka] 25. A compound according to embodiment 24, wherein: As embodiment 35, the present invention provides -LR 1 but, [ka] 25. A compound according to embodiment 24, wherein: As embodiment 36, the present invention provides -LR 1 but, [ka] 25. A compound according to embodiment 24, wherein: As embodiment 37, the present specification provides -LR 1 but, [ka] 25. A compound according to embodiment 24, wherein:

[0021] As embodiment 38, the present invention provides a compound comprising R 3 But R 6 is aryl (eg, phenyl or naphthyl) substituted with 0 to 3 occurrences of.

[0022] As embodiment 39, the present invention provides a compound comprising R 3 But R 6 As embodiment 40, provided herein is a compound according to any one of embodiments 1 to 37, wherein R is naphthyl substituted with one 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 41 are compounds according to embodiment 39, wherein R is alkynyl (e.g., ethynyl). 6 Compounds according to embodiment 40 are provided, wherein is hydroxyl.

[0023] As embodiment 42, the present invention provides a compound comprising R 3 But R 6 As embodiment 43, provided herein is a compound according to embodiment 38, wherein R is naphthyl substituted with two occurrences of 6 But C 1~4 Alkyl, C 2~4 Alkynyl, C 3~6 Cycloalkyl, halogen, hydroxyl or -N(R z )2. As embodiment 44, compounds according to embodiment 42 are provided herein, wherein R6 is ethyl, ethynyl, cyclopropyl, fluorine, chlorine, hydroxyl, or —NH. 6 is ethynyl, other R 6 is hydroxyl. As embodiment 46, compounds according to embodiment 43 are provided herein in which one R 6 is ethyl, other R 6 is hydroxyl. As embodiment 47, compounds according to embodiment 43 are provided herein in which one R 6 is ethyl, other R 6 is fluorine. As embodiment 48, compounds according to embodiment 43 are provided herein in which both R 6 Compounds according to embodiment 43, wherein is fluorine. As embodiment 49, compounds according to embodiment 43, wherein is fluorine. 6 is cyclopropyl, other R 6 is hydroxyl. As embodiment 50, compounds according to embodiment 43 are provided herein in which one R 6 is fluorine, other R 6 is hydroxyl. As embodiment 51, compounds according to embodiment 43 are provided herein in which one R 6 is chlorine, other R 6 is -NH2. As embodiment 52, compounds according to embodiment 43 are provided herein in which one R 6 is ethynyl, other R 6 Compounds according to embodiment 43 are provided, wherein is fluorine.

[0024] As embodiment 53, the present invention provides a compound comprising R 3 But R 6 As embodiment 54, provided herein is a compound according to embodiment 38, wherein R is naphthyl substituted with 3 occurrences of 6 But C 1~4 Alkyl, C 2~4 Provided herein as embodiment 55 are compounds according to embodiment 53, wherein R is alkynyl, halogen, or hydroxyl.6 is ethyl, ethynyl, fluorine or hydroxyl. 6 is hydroxyl and another R 6 is ethyl, and the final compound is provided herein, wherein R 6 is fluorine. As embodiment 57, compounds according to embodiment 54 are provided herein in which one R 6 is hydroxyl, another R 6 is ethynyl and the last R 6 is fluorine. As embodiment 58, compounds according to embodiment 54 are provided herein, wherein two R 6 is a halogen (e.g., fluorine or chlorine) and other R 6 Compounds according to embodiment 54 are provided, wherein is hydroxy.

[0025] As embodiment 59, the present specification provides a compound represented by the formula: R 3 But R 6 As embodiment 60, provided herein is a compound according to embodiment 38, wherein R is phenyl substituted with 3 occurrences of 6 is hydroxyl and another R 6 is cyclopropyl and the last R 6 Compounds according to embodiment 59 are provided, wherein is chlorine.

[0026] As embodiment 61, the present invention provides a method for treating a steroid hormone comprising administering to a subject a subject, comprising administering to 3 But R 6

[0037] Provided herein as embodiment 62 are compounds according to any one of embodiments 1 to 37, wherein R is heteroaryl (e.g., 4-(1H-indazole) or 4-benzo[d]thiazolyl) substituted with 0 to 3 occurrences of 3 But R 6 As embodiment 63, provided herein is a compound according to embodiment 61, which is a 4-(1H-indazole) substituted with two occurrences of 6 is methyl and other R 6Compounds according to embodiment 62, wherein R is chlorine are provided herein as embodiment 64. 3 But R 6

[0072] Provided herein as embodiment 65 is a compound according to embodiment 61, which is 4-benzo[d]thiazolyl substituted with two occurrences of 6 is fluorine and other R 6 65. Compounds according to embodiment 64 are provided, wherein is —NH 2 .

[0027] As embodiment 66, the present specification provides a method for producing a compound comprising: 3 but, [ka] Embodiment 66. Provided is a compound according to any one of embodiments 1 to 65, wherein:

[0028] As embodiment 67, the present specification provides a method for producing a compound comprising: 3 but, [ka] 67. A compound according to embodiment 66, wherein: As embodiment 68, the present specification provides a method for producing a compound comprising: 3 but, [ka] 67. A compound according to embodiment 66, wherein: As embodiment 69, the present specification provides a compound represented by the formula: R 3 but, [ka] 67. A compound according to embodiment 66, wherein: As embodiment 70, the present disclosure provides R 3 but, [ka] 67. A compound according to embodiment 66, wherein: As embodiment 71, the present invention provides a compound represented by the formula: 3 but, [ka] 67. A compound according to embodiment 66, wherein: As embodiment 72, the present invention provides a compound comprising R 3 but, [ka] 67. A compound according to embodiment 66, wherein: As embodiment 73, the present invention provides a compound comprising R 3 but, [ka] 67. A compound according to embodiment 66, wherein: As embodiment 74, the present invention provides a compound comprising R 3 but, [ka] 67. A compound according to embodiment 66, wherein: As embodiment 75, the present invention provides a compound comprising R 3 but, [ka] 67. A compound according to embodiment 66, wherein: As embodiment 76, the present invention provides a compound comprising R 3 but, [ka] 67. A compound according to embodiment 66, wherein: As embodiment 77, the present invention provides a compound comprising R 3 but, [ka] 67. A compound according to embodiment 66, wherein: As embodiment 78, the present invention provides a compound comprising R 3 but, [ka] 67. A compound according to embodiment 66, wherein: As embodiment 79, the present invention provides a compound comprising R 3 but, [ka] 67. A compound according to embodiment 66, wherein: As embodiment 80, the present disclosure provides a compound comprising R 3 but, [ka] 67. A compound according to embodiment 66, wherein: As an embodiment 81, the present invention provides a compound represented by the formula: 3 but, [ka] 67. A compound according to embodiment 66, wherein: As embodiment 82, the present invention provides a compound comprising R 3 but, [ka] 67. A compound according to embodiment 66, wherein: As an embodiment 83, the present invention provides a compound comprising R 3 but, [ka] 67. A compound according to embodiment 66, wherein:

[0029] As embodiment 84, the present specification relates to a compound wherein W is N; [ka] Compounds according to any one of embodiments 1-83 are provided, wherein is a single bond.

[0030] As embodiment 85, provided herein is a compound according to any one of embodiments 1 to 84, wherein X is CH2.

[0031] As embodiment 86, provided herein is a compound according to embodiment 85, wherein n is 0 and m is 0. As embodiment 87, provided herein is a compound according to embodiment 86, wherein p is 1. As embodiment 88, provided herein is a compound according to embodiment 87, wherein R x is 5- to 7-membered heteroaryl or -TR y As an embodiment 89, compounds according to embodiment 87 are provided herein, wherein R x But R y Provided herein as embodiment 90 are compounds according to embodiment 87, wherein R is a 5-7 membered heteroaryl substituted with 0-3 occurrences of x But R y Provided herein as embodiment 91 is a compound according to embodiment 89, which is 1-imidazolyl substituted with 0 occurrences of -TR y is —CH 2 OH, —C(O)NH 2 , —CH 2 C(O)NH 2 , —CH 2 S(O) 2 NH 2 , or —S(O) 2 NH 2 .

[0032] As embodiment 92, provided herein is a compound according to embodiment 86, wherein p is 2. As embodiment 93, provided herein is a compound according to embodiment 86, wherein each R x But hydroxyl, C 1~4 Alkyl, -TR y or two R x together with the adjacent carbon atom, R y

[0082] Provided herein as embodiment 94 are compounds according to embodiment 92, wherein 0 to 3 occurrences of R form a 5 to 7 membered cycloalkyl substituted. x is methyl and other R x is hydroxyl. As embodiment 95, compounds according to embodiment 93 are provided herein in which one R x is -C(O)NH2 and other R x is hydroxyl. As embodiment 96, compounds according to embodiment 93 are provided herein in which two R xtogether with the adjacent carbon atom, R y Compounds according to embodiment 92 are provided, wherein 0 occurrences of form a substituted 1-hydrofuranyl or 2-tetrahydrofuranyl.

[0033] As embodiment 97, provided herein is a compound according to embodiment 86, wherein n is 1 and m is 0, or when n is 0, m is 1. As embodiment 98, provided herein is a compound according to embodiment 97, wherein p is 0. As embodiment 99, provided herein is a compound according to embodiment 97, wherein p is 1. As embodiment 100, provided herein is a compound according to embodiment 86, wherein n is 1 and m is 0, or when n is 0, m is 1. x but hydroxyl or -TR y As embodiment 101, compounds according to embodiment 99 are provided herein, wherein R x -TR y is —CH 2 OH, —CH 2 S(O) 2 NH 2 , —C(O)NH 2 , or —S(O) 2 NH 2 .

[0034] As embodiment 102, provided herein is a compound according to embodiment 97, wherein p is 2. As embodiment 103, provided herein is a compound according to embodiment 97, wherein R x But hydroxyl, halogen, -TR y or two R x together with the adjacent carbon atom, C 3~7 cycloalkyl or 5- to 7-membered heterocycloalkyl, and each cycloalkyl or heterocycloalkyl is R y Provided herein as embodiment 104 are compounds according to embodiment 102, wherein both R x is hydroxyl. As embodiment 105, compounds according to embodiment 103 are provided herein in which one R x

[0072] Provided herein as embodiment 106 are compounds according to embodiment 103, wherein one R is fluorine and the other is -CHOH. x together with the adjacent carbon atom, R yC replaced with 0-3 occurrences of 3~7 Compounds according to embodiment 102 are provided herein in which two R form a cycloalkyl or a 5- to 7-membered heterocycloalkyl. x together with the adjacent carbon atom, R y

[0047] Provided herein as embodiment 108 are compounds according to embodiment 106, wherein one occurrence of R forms a substituted cyclobutyl. y is hydroxyl. As embodiment 109, compounds according to embodiment 107 are provided herein in which two R x together with the adjacent carbon atom, R y Compounds according to embodiment 106 are provided, wherein 0 occurrences of form a substituted 1-hydrofuranyl or 2-tetrahydrofuranyl.

[0035] As an embodiment 110, the present specification provides: [ka] but, [ka] Embodiment 84. Provided is a compound according to any one of embodiments 1 to 83, wherein:

[0036] As an embodiment 111, the present specification provides: [ka] but, [ka] 110. A compound according to embodiment 110, wherein: As an embodiment 112, the present specification provides: [ka] but, [ka] 110. A compound according to embodiment 110, wherein: As embodiment 113, the present specification provides: [ka] but, [ka] 110. A compound according to embodiment 110, wherein: As embodiment 114, the present specification provides: [ka] but, [ka] 110. A compound according to embodiment 110, wherein: As embodiment 115, the present specification provides: [ka] but, [ka] 110. A compound according to embodiment 110, wherein: As embodiment 116, the present specification provides: [ka] but, [ka] 110. A compound according to embodiment 110, wherein: As embodiment 117, the present specification provides: [ka] but, [ka] 110. A compound according to embodiment 110, wherein: As embodiment 118, the present specification provides: [ka] but, [ka] 110. A compound according to embodiment 110, wherein: As embodiment 119, the present specification provides: [ka] but, [ka] 110. A compound according to embodiment 110, wherein: As an embodiment 120, the present specification provides: [ka] but, [ka] 110. A compound according to embodiment 110, wherein: As an embodiment 121, the present specification provides: [ka] but, [ka] 110. A compound according to embodiment 110, wherein: As embodiment 122, the present specification provides: [ka] but, [ka] 110. A compound according to embodiment 110, wherein: As embodiment 123, the present specification provides: [ka] but, [ka] 110. A compound according to embodiment 110, wherein: As embodiment 124, the present specification provides: [ka] but, [ka] 110. A compound according to embodiment 110, wherein: As embodiment 125, the present specification provides: [ka] but, [ka] 110. A compound according to embodiment 110, wherein: As embodiment 126, the present specification provides: [ka] but, [ka] 110. A compound according to embodiment 110, wherein: As embodiment 127, the present specification provides: [ka] but, [ka] 110. A compound according to embodiment 110, wherein: As embodiment 128, the present specification provides: [ka] but, [ka] 110. A compound according to embodiment 110, wherein: As embodiment 129, the present specification provides: [ka] but, [ka] 110. A compound according to embodiment 110, wherein: As an embodiment 130, the present specification provides: [ka] but, [ka] 110. A compound according to embodiment 110, wherein: As an embodiment 131, the present specification provides: [ka] but, [ka] 110. A compound according to embodiment 110, wherein: As embodiment 132, the present specification provides: [ka] but, [ka] 110. A compound according to embodiment 110, wherein: As embodiment 133, the present specification provides: [ka] but, [ka] 110. A compound according to embodiment 110, wherein:

[0037] As embodiment 134, provided herein is a compound according to embodiment 85, wherein n is 1 and m is 1. As embodiment 135, provided herein is a compound according to embodiment 134, wherein p is 0. As embodiment 136, provided herein is a compound according to embodiment 134, wherein p is 1. As embodiment 137, provided herein is a compound according to embodiment 85, wherein n is 1 and m is 1. x But hydroxyl, cyano, C 1~4 Alkoxy, -N(R z ) 2, 5- to 7-membered heteroaryl or -TR y As embodiment 138, compounds according to embodiment 136, wherein R x is hydroxyl, cyano, methoxy, —NH 2 , 5-oxazolyl, 4-imidazolyl, or 3-pyrazolyl. y is —NHC(O)OMe, —S(O)Me, —NHC(O)Me, —NHC(O)—N(H)CHCHOMe, —CHOH, —NHS(O)Me, —COH, —C(O)Me, 1-isopropanol, —S(O)NH, —C(O)NH, —S(O)N(H)Me, or —C(O)N(H)Me.

[0038] As embodiment 140, provided herein is a compound according to embodiment 134, wherein p is 2. As embodiment 141, provided herein is a compound according to embodiment 134, wherein R x But halogen, hydroxyl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 3~7 Cycloalkyl, -N(Rz)2 or -TR y or two R x together with the same carbon atom, Ry Compounds according to embodiment 140 are provided herein, wherein one R x is fluorine and one R x Compounds according to embodiment 141, wherein is hydroxyl. As embodiment 143, compounds according to embodiment 142, wherein one R x is methyl and one R x Compounds according to embodiment 141, wherein is hydroxyl. As embodiment 144, compounds according to embodiment 142, wherein one R x is -NHS(O)2Me and one R x is methyl. As embodiment 145, compounds according to embodiment 141 are provided herein in which one R x is -C(O)NH2 and one R x is hydroxyl. As embodiment 146, compounds according to embodiment 141 are provided herein in which one R x is methoxy and one R x is methyl. As embodiment 147, compounds according to embodiment 141 are provided herein in which one R x is -NH2 and one R x is methyl. As embodiment 148, compounds according to embodiment 141 are provided herein in which one R x is -NHC(O)OMe and one R x is methyl. As embodiment 149, compounds according to embodiment 141 are provided herein in which one R x is cyclopropyl and one R x is hydroxyl. As embodiment 150, compounds according to embodiment 141 are provided herein in which one R x is trifluoromethyl and one R x Compounds according to embodiment 141, wherein is hydroxyl. As embodiment 151, compounds according to embodiment 141, wherein one R x is difluoromethyl and one R xis hydroxyl. As embodiment 152, compounds according to embodiment 141 are provided herein in which one R x is -C(O)NH2 and one R x Provided herein as embodiment 153 is a compound according to embodiment 141, wherein one R x is -CHOH and one R x Provided herein as embodiment 154 is a compound according to embodiment 141, wherein both R x Compounds according to embodiment 141 are provided, wherein is hydroxyl.

[0039] As embodiment 155, the present invention provides a method for treating a cyclohexyl group comprising administering to a patient a compound having two R x together with the adjacent carbon atom, R y Compounds according to embodiment 140 are provided herein, wherein the heterocycloalkyl is substituted with 0 to 3 occurrences of R x together with the adjacent carbon atom, R y Provided herein as embodiment 157 are compounds according to embodiment 155, wherein two R x together with the adjacent carbon atom, R y

[0082] Provided herein as embodiment 158 ​​are compounds according to embodiment 155, wherein one occurrence of R forms a substituted 1-pyrrolidinyl or 2-pyrrolidinyl. y Compounds according to embodiment 157, wherein is oxo.

[0040] As embodiment 159, provided herein is a compound of embodiment 134, wherein p is 3. As embodiment 160, provided herein is a compound of embodiment 134, wherein one R x is hydroxyl, halogen, oxo, C 1~4 alkyl or two R x together with the adjacent carbon atom, R y C replaced with 0-3 occurrences of 3~7Two R can form a cycloalkyl group. x But R y Compounds according to embodiment 159 are provided herein, wherein 0 to 2 occurrences of R can form a bridged ring that is further substituted. x is hydroxyl and the other two R x is methyl. As embodiment 162, compounds according to embodiment 160 are provided herein in which one R x is hydroxyl, and the other two R x Compounds according to embodiment 160, wherein is fluorine. As embodiment 163, compounds according to embodiment 160, wherein is fluorine. x is -C(O)NH2, and the other two R x is methyl. As embodiment 164, compounds according to embodiment 160 are provided herein in which one R x is oxo and the other two R x Compounds according to embodiment 160, wherein is fluorine. As embodiment 165, compounds according to embodiment 160, wherein is fluorine. x is hydroxyl and the other two R x together with the adjacent carbon atom, R y Provided herein as embodiment 166 are compounds according to embodiment 160, wherein 0 occurrences of R form a substituted cyclopropyl. x is hydroxyl and the other two R x Together, R y Provided herein as embodiment 167 are compounds according to embodiment 160, wherein 0 occurrences of R form a substituted ethylene or methylene bridge. x is C(O)NH2, and the other two R x Together, R y Compounds according to embodiment 160 are provided in which 0 occurrences of form a substituted ethylene.

[0041] As embodiment 168, the present specification provides: [ka] but, [ka] [ka] [ka] Embodiment 84. Provided is a compound according to any one of embodiments 1 to 83, wherein:

[0042] As embodiment 169, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 170, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 171, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 172, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 173, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 174, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 175, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 176, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 177, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 178, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 179, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 180, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 181, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 182, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 183, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 184, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 185, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 186, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 187, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 188, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 189, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 190, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 191, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 192, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 193, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 194, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 195, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 196, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 197, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 198, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 199, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 200, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 201, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 202, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 203, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 204, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 205, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 206, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 207, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 208, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 209, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 210, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 211, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 212, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 213, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 214, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 215, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 216, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 217, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 218, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 219, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 220, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 221, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 222, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 223, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 224, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 225, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 226, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 227, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 228, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 229, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 230, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 231, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 232, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As an embodiment 233, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 234, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 235, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 236, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 237, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 238, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein: As embodiment 239, the present specification provides: [ka] but, [ka] 168. A compound according to embodiment 168, wherein:

[0043] As embodiment 240, provided herein is a compound according to embodiment 85, wherein n is 1 and m is 2, or n is 2 and m is 1. As embodiment 241, provided herein is a compound according to embodiment 240, wherein p is 0. As embodiment 242, provided herein is a compound according to embodiment 420, wherein p is 1. As embodiment 243, provided herein is a compound according to embodiment 420, wherein R x But C 1~4 Alkyl, C 1~4 Alkenyl, cyano, hydroxyl, oxo, -N(R z )2 or -TR y As embodiment 244, compounds according to embodiment 242 are provided herein, wherein R x is cyano, methyl, oxo, hydroxyl, -NH2, methenyl, -SO2NH2, -NHC(O)Me, or -NHC(O)CF2H.

[0044] As embodiment 245, provided herein is a compound according to embodiment 240, wherein p is 2. As embodiment 246, provided herein is a compound according to embodiment 240, wherein R x But hydroxy, C 1~4 alkyl, halogen, or two R x Together, R y C further substituted with 0-2 occurrences of 1~4 Compounds according to embodiment 245 are provided herein in which both R x Compounds according to embodiment 246, wherein is fluorine. As embodiment 248, compounds according to embodiment 248, wherein one R x is hydroxyl and other R x is methyl. As embodiment 249, compounds according to embodiment 246, wherein R x together form a bridged ring, and this bridge is y Provided herein as embodiment 250 are compounds according to embodiment 246, wherein R is methylene further substituted with 0 occurrences ofx together form a bridged ring, and this bridge is y Provided herein as embodiment 251 are compounds according to embodiment 246, wherein one occurrence of R is methylene further substituted. y is hydroxyl. As embodiment 252, compounds according to embodiment 250 are provided herein in which two R x together form a bridged ring, and this bridge is y Provided herein as embodiment 253 are compounds according to embodiment 246, wherein each R y 253. Compounds according to embodiment 252 are provided, wherein is methyl or hydroxyl.

[0045] As embodiment 254, provided herein is a compound according to embodiment 240, wherein p is 3. As embodiment 255, provided herein is a compound according to embodiment 240, wherein R x is hydroxy, oxo, halogen, or two R x Together, R y C further substituted with 0-2 occurrences of 1~4 Compounds according to embodiment 254 are provided herein, in which one R x is oxo and the other two R x Compounds according to embodiment 255, wherein is fluorine. As embodiment 257, compounds according to embodiment 256, wherein one R x is hydroxyl and the other two R x Compounds according to embodiment 255, wherein is fluorine. As embodiment 258, compounds according to embodiment 259, wherein one R x is hydroxy and the other two R x together form a bridged ring, and this bridge is y Compounds according to embodiment 255 are provided wherein R is methylene further substituted with 0 occurrences of

[0046] As embodiment 259, provided herein is a compound according to embodiment 85, wherein n is 2 and m is 2. As embodiment 260, provided herein is a compound according to embodiment 259, wherein p is 0. As embodiment 261, provided herein is a compound according to embodiment 259, wherein p is 2. As embodiment 262, provided herein is a compound according to embodiment 259, wherein two R x Compounds according to embodiment 261 are provided, wherein: are taken together to form a bridged ring, and the bridge is —O—.

[0047] As an embodiment 263, the present specification provides: [ka] but, [ka] Embodiment 84. Provided is a compound according to any one of embodiments 1 to 83, wherein:

[0048] As an embodiment 264, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As an embodiment 265, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As embodiment 266, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As embodiment 267, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As embodiment 268, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As embodiment 269, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As an embodiment 270, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As an embodiment 271, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As embodiment 272, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As embodiment 273, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As embodiment 274, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As embodiment 275, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As embodiment 276, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As embodiment 277, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As embodiment 278, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As embodiment 279, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As an embodiment 280, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As an embodiment 281, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As an embodiment 282, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As an embodiment 283, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As an embodiment 284, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As an embodiment 285, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As embodiment 286, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As embodiment 287, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As embodiment 288, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As embodiment 289, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As an embodiment 290, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As an embodiment 291, the present specification provides [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As embodiment 292, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As embodiment 293, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein: As embodiment 294, the present specification provides: [ka] but, [ka] 264. A compound according to embodiment 263, wherein:

[0049] As embodiment 295, provided herein is a compound according to any one of embodiments 1 to 84, wherein X is CH═CH.

[0050] As embodiment 296, provided herein is a compound according to embodiment 295, wherein n is 0 and m is 1. As embodiment 297, provided herein is a compound according to embodiment 296, wherein p is 1. As embodiment 298, provided herein is a compound according to embodiment 298, wherein R x 297. Compounds according to embodiment 297 are provided, wherein is hydroxyl.

[0051] As embodiment 299, provided herein is a compound according to embodiment 295, wherein n is 1 and m is 1. As embodiment 300, provided herein is a compound according to embodiment 299, wherein p is 0. As embodiment 301, provided herein is a compound according to embodiment 299, wherein p is 1. As embodiment 302, provided herein is a compound according to embodiment 299, wherein R xCompounds according to embodiment 301 are provided, wherein is oxo or hydroxyl.

[0052] As an embodiment 303, the present specification provides: [ka] but, [ka] Embodiment 84. Provided is a compound according to any one of embodiments 1 to 83, wherein:

[0053] As an embodiment 304, the present specification provides 4 But C 1~4 Alkyl, C 1~4 Alkoxy, hydroxyl, halogen or C 1~4 Provided herein as embodiment 305 are compounds according to any one of embodiments 1 to 303, wherein R is haloalkyl. 4 But C 1~4 Compounds according to embodiment 304 are provided, wherein R is alkyl or halogen. 4 306. Compounds according to embodiment 305 are provided, wherein is fluorine.

[0054] As embodiment 307, the compound herein is a compound of formula (II): [ka] A compound according to embodiment 1 is provided.

[0055] As embodiment 308, the compound herein is a compound of formula (III): [ka] A compound according to embodiment 1 is provided.

[0056] As embodiment 309, the compound herein is a compound of formula (IV): [ka] A compound according to embodiment 1 is provided.

[0057] As an embodiment 310, the compound herein is a compound of formula (V): [ka] A compound according to embodiment 1 is provided.

[0058] In embodiment 311, the compound described herein is 1-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (S)-1-(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)-3-methylpiperidin-3-ol; (R)-1-(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)-3-methylpiperidin-3-ol; (3R,5S)-5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidin-3-ol; (2R,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolidin-2-ol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-ol; [(3R,5S)-5-[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-4-[(3S)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1-methyl-pyrrolidin-3-yl]N-methylcarbamate; (S)-1-(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)-3-methylpiperidin-3-ol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-ol; (3R,5S)-5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidin-3-ylmethylcarbamate; (R)-1-(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)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(6-(8-ethyl-7-fluoronaphthalen-1-yl)-5-fluoro-3-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-1-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-((1R,5S)-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 8-Fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidine; 8-Fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidine; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; 1-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((hexahydro-lH-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol; 4-(3-(1H-1,2,4-triazol-3-yl)piperidin-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 4-(2-azabicyclo[4.1.0]heptan-2-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 8-Fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(octahydro-1H-cyclopenta[b]pyridin-1-yl)pyrido[4,3-d]pyrimidine; (3R,5S)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-methylpiperidin-3-ol; 1-(7-(2-amino-5,6-dimethylbenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(2-amino-5,6-dimethylbenzo[d]thiazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(Azocan-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-ol; (R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(3,3-dimethylpiperidin-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 1-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 8-(8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthonitrile; 6-(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-azabicyclo[3.2.1]octan-3-ol; (3R,5R)-1-(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)piperidine-3,5-diol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazepan-3-ol; 1-(8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-7-(quinolin-8-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(2-aminobenzo[d]thiazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(benzo[d]thiazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-7-(naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(3-(1H-imidazol-1-yl)azetidin-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 6-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azabicyclo[3.2.1]octan-3-ol; 3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-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)-3-azabicyclo[3.2.1]octan-6-ol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxamide; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-carbonitrile; (3S,5R)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3,5-diol; 4-(3-(1H-imidazol-1-yl)azetidin-1-yl)-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; 4-(2-(1H-pyrazol-4-yl)pyrrolidin-1-yl)-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; 6-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azabicyclo[3.2.1]octan-3-ol; 4-(3-(1H-1,2,3-triazol-4-yl)piperidin-1-yl)-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; 4-(3-(1H-pyrazol-1-yl)piperidin-1-yl)-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; (3R,5R)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-methylpiperidin-3-ol; (1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methylazepan-4-ol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(hydroxymethyl)piperidin-4-ol; 2-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)isoindolin-4-ol; 4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-ol; (1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-yl)methanol; 4-(3-(1H-pyrazol-3-yl)piperidin-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; 1-(7-(3-chloro-5-hydroxy-2-((lS,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(4-(3-(1H-imidazol-1-yl)azetidin-1-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; 4-(4-(3-(1H-1,2,4-triazol-5-yl)piperidin-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(3-(3-methyl-1H-1,2,4-triazol-5-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-(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)-3-azabicyclo[3.2.1]octan-6-ol; 1-(7-(5-cyclopropyl-6-methyl-1H-indazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(4-(3-(1H-1,2,4-triazol-5-yl)piperidin-1-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; 1-(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)piperidine-3-carboxamide; 1-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(7-(6-chloro-5-(2-methylcyclopropyl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(7-(1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(1-(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)piperidin-3-yl)methanesulfonamide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(3-(pyridin-4-yl)azetidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(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)azepane-4-carbonitrile; (3R,5R)-1-(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)-5-fluoropiperidin-3-ol; (3S,4S)-1-(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)-4-fluoropiperidin-3-ol; (3R,5S)-1-(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)-5-methylpiperidin-3-ol; (2R,3R)-1-(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-methylpiperidin-3-ol; (3R,6R)-1-(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-methylpiperidin-3-ol; 1-(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)-3-(trifluoromethyl)piperidin-3-ol; 3-(difluoromethyl)-1-(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)piperidin-3-ol; (2S,3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[1,3-d]pyrimidin-4-yl)-2-methylpiperidin-3-ol; (3R,6S)-1-(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-methylpiperidin-3-ol; (3R,5R)-1-(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)-5-methylpiperidin-3-ol; (3R,4S)-1-(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)-4-methylpiperidin-3-ol; (3R,4R)-1-(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)-4-methylpiperidin-3-ol; 1-(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)-5,5-difluoropiperidin-3-ol; 1-(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)-4,4-difluoropiperidin-3-ol; (3R,5S)-1-(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)-5-fluoropiperidin-3-ol; (R)-1-(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)piperidin-3-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)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione; (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[1-(pyrrolidin-1-ylmethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol; 1-(1-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide; 8-Fluoro-7-(8-fluoronaphthalen-1-yl)-4-(3-(pyridin-4-yl)azetidin-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; 1-(1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide; 5-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methylpiperidine-3-sulfonamide; 2-(1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)isothiazolidine-1,1-dioxide; 8-Fluoro-7-(8-fluoronaphthalen-1-yl)-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-4-[3-(sulfamoylamino)piperidin-1-yl]pyrido[4,3-d]pyrimidine; 1-(1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)urea; N-(1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)formamide; 1-(1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)urea; N-(1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)formamide; 6-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ylsulfamate; 8-Fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(3-(methylsulfonyl)azepan-1-yl)pyrido[4,3-d]pyrimidine; 8-Fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(3-(methylsulfonyl)azocan-1-yl)pyrido[1,3d]pyrimidine; 4-(3-(1H-1,2,4-triazol-1-yl)azetidin-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-7-(8-fluoronaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyrido[1,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-(1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol; (S)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxamide; 5-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2(4H)-carboxamide; 1-(1-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide; 1-(1-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide; 3-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol; 5-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione; 4-(3-(1H-1,2,4-triazol-3-yl)piperidin-1-yl)-7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; (3R,5R)-1-(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)piperidine-3,5-diol; 1-(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)piperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3R,7aS)-3-(hydroxymethyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,7aR)-3-(hydroxymethyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3R,7aR)-3-(hydroxymethyl)hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,7aS)-3-(hydroxymethyl)hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(3-(hydroxymethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(3-(methylsulfonyl)azepan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(3-(methylsulfonyl)azocan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (2R,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolidin-2-ol; N-(1-(dimethylamino)propan-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-1-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[1,3-d]pyrimidine-2-carboxamide; ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methyl dimethylcarbamate; ((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methyl dimethylcarbamate; (R)-1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(4-(azepan-1-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; (1R,5R,6R)-3-(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)-3-azabicyclo[3.2.1]octan-6-ol; 4-(4-(azocan-1-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; (3RS,5RS)-1-(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)-5-(hydroxymethyl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-(piperidin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 7-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)hexahydro-2,7-naphthyridine-1,3(2H,4H)-dione; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-((4-methylpiperazin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(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)azepan-4-ol; 1-(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)azepan-3-ol; 2-(1-(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)piperidin-3-yl)isothiazolidine-1,1-dioxide; 4-(4-(3-azabicyclo[3.2.1]octan-3-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; 7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-[3-(sulfamoylamino)-1-piperidyl]pyrido[4,3-d]pyrimidine; 5-(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)-N,N-dimethyl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2(4H)-carboxamide; (1R,5R,6R)-3-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol; ((3R,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methyl dimethylcarbamate; (4aR,7aS)-6-(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)hexahydro-1H-pyrrolo[3,4-d]pyridazine-1,4(4aH)-dione; (R)-1-(2-(3-(dimethylamino)-2,2-dimethylpropoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(2-(2-(dimethylamino)ethoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; (1R,5R,6R)-3-(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)-3-azabicyclo[3.2.1]octan-6-ol; 5-(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)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione; 6-(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-azabicyclo[3.2.1]octan-3-ol; (R)-1-(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)-3-methylpiperidin-3-ol; 3-(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)-3-azabicyclo[3.2.1]octan-6-ol; 6-(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-azabicyclo[3.2.1]octan-3-ol; 5-(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)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione; 1-(1-(7-(8-chloro-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)piperidin-3-yl)methanesulfonamide; (R)-1-(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)-3-methylpiperidin-3-ol; 3-(7-(8-chloro-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-azabicyclo[3.2.1]octan-6-ol; 6-(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-azabicyclo[3.2.1]octan-3-ol; 5-(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)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione; 1-(8-fluoro-7-(2-fluoro-5-hydroxyphenyl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-7-(5-methyl-1H-indazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(8-fluoro-7-(6-methyl-1H-indazol-4-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-7-(5-hydroxy-2-methylphenyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (1-(8-fluoro-7-(naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide; 1-(1-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide; 1-(1-(8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-7-(8-methylnaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide; 1-(1-(8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-7-(8-(hydroxymethyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide; 1-(7-(8-cyclopropylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyridine[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(3-(1H-1,2,4-triazol-3-yl)piperidin-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-7-(8-methylnaphthalen-1-yl)pyrido[4,3-d]pyrimidine; 8-(4-(3-(1H-1,2,4-triazol-3-yl)piperidin-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthonitrile; (3aR,6aS)-5-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione; 1-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(1-(8-fluoro-7-(8-(fluoromethyl)naphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide; 1-(1-(8-fluoro-7-(7-fluoro-3-hydroxy-8-methylnaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide; 1-(1-(7-(8-(difluoromethyl)naphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide; 1-(1-(8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-7-(8-(trifluoromethyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide; 1-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(7-(8-ethyl-2-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(7-(5-ethyl-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 5-(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)-N-isopropyl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepine-2(4H)-carboxamide; 5-(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)-3a-methyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione; (1R,5R,6S,7R)-3-(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)-7-(hydroxymethyl)-3-azabicyclo[3.2.1]octan-6-ol; 5-(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)hexahydro-1H-pyrrolo[3,4-c]pyridine e-1,3(2H)-dione; (3R,3aR,6aS)-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)-3-(hydroxymethyl)hexahydropyrrolo[3,4-c]pyrrol-1(2H)-one; (3R,6R)-1-(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)azepane-3,6-diol; (3R,6S)-1-(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)azepane-3,6-diol; ((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methylmorpholine-4-carboxylate; ((3R,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methyl dimethylcarbamate; (R)-1-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-2-((l-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 5-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione; or There is provided a compound according to embodiment 1 which is not (3R)-1-(7-(5,6-dimethyl-1H-indazol-4-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol.

[0059] As embodiment 312, the present specification provides a compound comprising: 1-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (S)-1-(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)-3-methylpiperidin-3-ol; (R)-1-(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)-3-methylpiperidin-3-ol; (3R,5S)-5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidin-3-ol; (2R,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolidin-2-ol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-ol; [(3R,5S)-5-[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-4-[(3S)-3-hydroxy-3-methyl-1-piperidyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1-methyl-pyrrolidin-3-yl]N-methylcarbamate; (S)-1-(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)-3-methylpiperidin-3-ol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-ol; (3R,5S)-5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidin-3-ylmethylcarbamate; (R)-1-(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)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(6-(8-ethyl-7-fluoronaphthalen-1-yl)-5-fluoro-3-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-1-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-((1R,5S)-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 8-Fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidine; 8-Fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidine; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; 1-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((hexahydro-lH-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol; 4-(3-(1H-1,2,4-triazol-3-yl)piperidin-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 4-(2-azabicyclo[4.1.0]heptan-2-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 8-Fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(octahydro-1H-cyclopenta[b]pyridin-1-yl)pyrido[4,3-d]pyrimidine; (3R,5S)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-methylpiperidin-3-ol; 1-(7-(2-amino-5,6-dimethylbenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(2-amino-5,6-dimethylbenzo[d]thiazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(Azocan-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-ol; (R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(3,3-dimethylpiperidin-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 1-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 8-(8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthonitrile; 6-(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-azabicyclo[3.2.1]octan-3-ol; (3R,5R)-1-(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)piperidine-3,5-diol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazepan-3-ol; 1-(8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-7-(quinolin-8-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(2-aminobenzo[d]thiazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(benzo[d]thiazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-7-(naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(3-(1H-imidazol-1-yl)azetidin-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 6-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azabicyclo[3.2.1]octan-3-ol; 3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-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)-3-azabicyclo[3.2.1]octan-6-ol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxamide; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-carbonitrile; (3S,5R)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3,5-diol; 4-(3-(1H-imidazol-1-yl)azetidin-1-yl)-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; 4-(2-(1H-pyrazol-4-yl)pyrrolidin-1-yl)-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; 6-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azabicyclo[3.2.1]octan-3-ol; 4-(3-(1H-1,2,3-triazol-4-yl)piperidin-1-yl)-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; 4-(3-(1H-pyrazol-1-yl)piperidin-1-yl)-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; (3R,5R)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-methylpiperidin-3-ol; (1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methylazepan-4-ol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(hydroxymethyl)piperidin-4-ol; 2-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)isoindolin-4-ol; 4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-ol; (1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-yl)methanol; 4-(3-(1H-pyrazol-3-yl)piperidin-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; 1-(7-(3-chloro-5-hydroxy-2-((lS,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(4-(3-(1H-imidazol-1-yl)azetidin-1-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; 4-(4-(3-(1H-1,2,4-triazol-5-yl)piperidin-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(3-(3-methyl-1H-1,2,4-triazol-5-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-(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)-3-azabicyclo[3.2.1]octan-6-ol; 1-(7-(5-cyclopropyl-6-methyl-1H-indazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(4-(3-(1H-1,2,4-triazol-5-yl)piperidin-1-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; 1-(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)piperidine-3-carboxamide; 1-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(7-(6-chloro-5-(2-methylcyclopropyl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(7-(1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(1-(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)piperidin-3-yl)methanesulfonamide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(3-(pyridin-4-yl)azetidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(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)azepane-4-carbonitrile; (3R,5R)-1-(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)-5-fluoropiperidin-3-ol; (3S,4S)-1-(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)-4-fluoropiperidin-3-ol; (3R,5S)-1-(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)-5-methylpiperidin-3-ol; (2R,3R)-1-(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-methylpiperidin-3-ol; (3R,6R)-1-(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-methylpiperidin-3-ol; 1-(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)-3-(trifluoromethyl)piperidin-3-ol; 3-(difluoromethyl)-1-(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)piperidin-3-ol; (2S,3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[1,3-d]pyrimidin-4-yl)-2-methylpiperidin-3-ol; (3R,6S)-1-(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-methylpiperidin-3-ol; (3R,5R)-1-(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)-5-methylpiperidin-3-ol; (3R,4S)-1-(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)-4-methylpiperidin-3-ol; (3R,4R)-1-(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)-4-methylpiperidin-3-ol; 1-(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)-5,5-difluoropiperidin-3-ol; 1-(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)-4,4-difluoropiperidin-3-ol; (3R,5S)-1-(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)-5-fluoropiperidin-3-ol; (R)-1-(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)piperidin-3-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)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione; (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[1-(pyrrolidin-1-ylmethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol; 1-(1-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide; or There is provided a compound according to embodiment 1 which is not 8-fluoro-7-(8-fluoronaphthalen-1-yl)-4-(3-(pyridin-4-yl)azetidin-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine.

[0060] As an embodiment 313, the compound is described herein as follows: 1-(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)azepan-3-one; (R)-1-(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)-3-methylpiperidin-3-ol; (R)-1-(7-(8-cyclopropyl-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-methylpiperidin-3-ol; 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 1); (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 1); (1R,5R,6R)-3-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 1); (1R,5R,6R)-3-(7-(8-ethynyl-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-azabicyclo[3.2.1]octan-6-ol (isomer 1); (R)-1-(7-(8-chloro-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-methylpiperidin-3-ol; (R)-1-(7-(7,8-difluoro-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-methylpiperidin-3-ol; 3-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 2); 1-(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-methylazepan-3-ol (isomer 2); (R)-1-(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)azepan-3-ol; 1-(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)azepan-4-one; 1-(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)-2,3,6,7-tetrahydro-1H-azepin-3-ol; 4-(4-((R)-5-amino-3,3-difluoropiperidin-1-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; rac-(3S,5R)-1-(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)-5-fluoropiperidin-3-ol; 4-(4-(azepan-1-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; 4-(4-(azocan-1-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; 1-(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)-5,5-difluoropiperidin-3-ol; (R)-1-(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)piperidin-3-ol; 4-(4-(azepan-1-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; (R)-1-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(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)azepane-4-carbonitrile (isomer 1); 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; rac-(3R,5S)-1-(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)-5-methylpiperidin-3-ol; N-((R)-1-(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)azepan-3-yl)-2,2-difluoroacetamide; 3-ethyl-1-(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)piperidin-3-ol; (R)-1-(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)piperidine-3-sulfonamide; or 1-(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-(trifluoromethyl)piperidin-3-ol.

[0061] As embodiment 314, the compound is described herein as follows: 1-(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)azepan-3-one; (R)-1-(7-(8-cyclopropyl-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-methylpiperidin-3-ol; 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 1); (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 1); (1R,5R,6R)-3-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 1); (1R,5R,6R)-3-(7-(8-ethynyl-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-azabicyclo[3.2.1]octan-6-ol (isomer 1); (R)-1-(7-(8-chloro-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-methylpiperidin-3-ol; (R)-1-(7-(7,8-difluoro-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-methylpiperidin-3-ol; 3-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 2); 1-(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-methylazepan-3-ol (isomer 2); (R)-1-(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)azepan-3-ol; 1-(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)azepan-4-one; 1-(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)-2,3,6,7-tetrahydro-1H-azepin-3-ol; 4-(4-((R)-5-amino-3,3-difluoropiperidin-1-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; rac-(3S,5R)-1-(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)-5-fluoropiperidin-3-ol; 4-(4-(azepan-1-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; 4-(4-(azocan-1-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; 1-(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)-5,5-difluoropiperidin-3-ol; (R)-1-(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)piperidin-3-ol; 4-(4-(azepan-1-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; (R)-1-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(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)azepane-4-carbonitrile (isomer 1); 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; rac-(3R,5S)-1-(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)-5-methylpiperidin-3-ol; N-((R)-1-(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)azepan-3-yl)-2,2-difluoroacetamide; 3-ethyl-1-(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)piperidin-3-ol; (R)-1-(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)piperidine-3-sulfonamide; or 1-(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-(trifluoromethyl)piperidin-3-ol.

[0062] As an embodiment 315, the present specification provides a compound selected from the group consisting of: (R)-1-(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)piperidine-3-sulfonamide; 4-(4-(azepan-1-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; 1-(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)pyrrolidine-3-carboxamide; (S)-1-(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)pyrrolidine-2-carboxamide; 1-(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)azetidine-2-carboxamide; 1-(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)piperidine-4-carboxamide; (S)-1-(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)piperidine-3-sulfonamide; 2-(1-(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)azetidin-3-yl)acetamide; 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)-3-azabicyclo[3.2.0]heptan-6-ol; (R)-1-(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)piperidin-3-ol; (3S,4R)-1-(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)pyrrolidine-3,4-diol; (R)-1-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; (R)-1-(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)piperidin-3-ol; (S)-1-(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)piperidin-3-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-methoxypiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(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)pyrrolidin-3-ol; (1R,4S)-2-(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-azabicyclo[2.2.2]octan-6-ol; 3-(7-(7,8-difluoro-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-azabicyclo[3.2.1]octan-6-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-2-(hydroxymethyl)azetidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-((1S,5R)-3-oxa-6-azabicyclo[3.2.0]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; rel-4-(4-((1R,5R)-2-oxa-6-azabicyclo[3.2.0]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; 4-(4-(3-(chloromethyl)-3-(hydroxymethyl)piperidin-1-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-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 1); 3-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 2); (1R,5R,6R)-3-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 1); (1R,5R,6R)-3-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (isomer 1); (1R,5R,6R)-3-(7-(8-ethynyl-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-azabicyclo[3.2.1]octan-6-ol (isomer 1); 1-(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)-5,5-dimethylpiperidin-3-ol; (3R,6S)-1-(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-methylpiperidin-3-ol; 8-(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)-8-azabicyclo[3.2.1]octan-2-ol 2,2,2-trifluoroacetate; (3R,6R)-1-(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-methylpiperidin-3-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(hexahydro-5H-furo[2,3-c]pyrrol-5-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 1); 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 2); 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 1); rel-5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((3aR,7aR)-hexahydrofuro[3,2-b]pyridin-4(2H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (R)-1-(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)-3-methylpiperidin-3-ol; 1-(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-(fluoromethyl)piperidin-3-ol (isomer 1); 1-(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-(fluoromethyl)piperidin-3-ol (isomer 2); (3R)-1-(7-(8-ethyl-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (isomer 2); (3R)-1-(7-(8-ethyl-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (isomer 1); (3R)-1-(7-(8-allyl-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(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)-5,5-dimethylpiperidine-3-carboxamide; 4-(4-((R)-3-aminopiperidin-1-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-((S)-3-amino-3-methylpiperidin-1-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-((R)-3-amino-3-methylpiperidin-1-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; (3R,4S)-1-(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)-4-fluoropyridin-3-ol; (R)-1-(7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 2-(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-azabicyclo[2.2.1]heptan-6-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-chloro-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-methylpiperidin-3-ol; (R)-1-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(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)-3-methylpiperidin-3-ol; (R)-1-(7-(7,8-difluoro-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-methylpiperidin-3-ol; (R)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; rel-(3aR,6aS)-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)hexahydropyrrolo[3,4-c]pyrrol-1(2H)-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-rel-((3aR,7aS)-hexahydrofuro[3,2-c]pyridin-5(4H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; rel-(3aR,7aR)-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)octahydro-2H-pyrrolo[3,2-b]pyridin-2-one; rel-(3S,6R)-1-(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-methylpiperidine-3-carboxamide; 3-ethyl-1-(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)piperidin-3-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-3-(hydroxymethyl)-3-methylpiperidin-1-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-((R)-3-(hydroxymethyl)-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(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-methylpiperidine-3-carboxamide; 8-(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)-2-methyl-8-azabicyclo[3.2.1]octan-2-ol; 8-(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-methyl-8-azabicyclo[3.2.1]octan-2-ol; 2-(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-2-azabicyclo[2.2.1]heptan-6-ol; 2-(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-azabicyclo[2.2.1]heptan-6-one; N-((R)-1-(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)piperidin-3-yl)acetamide; 1-((R)-1-(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)piperidin-3-yl)-3-(2-methoxyethyl)thiourea; N-((R)-1-(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-methylpiperidin-3-yl)methanesulfonamide; N-((R)-1-(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-methylpiperidin-3-yl)acetamide; Methyl ((R)-1-(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-methylpiperidin-3-yl)carbamate; Methyl ((R)-1-(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)piperidin-3-yl)carbamate; 1-(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-methylpiperidine-3-sulfonamide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-2-methylazepan-1-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)-2-methylazepan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (1-(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)azetidin-3-yl)methanesulfonamide; 1-(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-hydroxyazetidine-3-carboxamide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-(methylsulfonyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(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)piperidine-4-sulfonamide; 1-(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)pyrrolidine-3-sulfonamide; 1-(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)azetidine-3-sulfonamide; 1-(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)azetidine-3-carboxamide; 1-(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-methylpiperidine-3-carboxamide; (S)-1-(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)piperidine-3-carboxamide; 4-(4-(3-(1H-imidazol-1-yl)azetidin-1-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; 1-(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-methylazetidin-3-ol; 4-(4-(azocan-1-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; 1-(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)azepan-4-one; rac-(3R,5S)-1-(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)-5-methylpiperidin-3-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)-3-azabicyclo[3.2.1]octan-8-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)-8-methyl-3-azabicyclo[3.2.1]octan-8-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)-3-azabicyclo[4.1.0]heptan-1-ol; rel-(3R,4S)-1-(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)piperidine-3,4-diol; rel-(3S,4S)-1-(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)piperidine-3,4-diol; rel-(3aR,7aR)-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)octahydro-3H-pyrrolo[3,4-c]pyridin-3-one; 4-(4-((S)-3-aminopiperidin-1-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-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-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(3-(1H-imidazol-4-yl)piperidin-1-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-(1H-pyrazol-5-yl)piperidin-1-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-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-(oxazol-5-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(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)-1,2,3,6-tetrahydropyridin-3-ol; N-(1-(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)piperidin-3-yl)methanesulfonamide; 5-ethyl-6-fluoro-4-(8-fluoro-4-((2S,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (3R,4R)-1-(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)-4-fluoropyridin-3-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; rac-(3S,5R)-1-(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)-5-fluoropiperidin-3-ol; (3S,4S)-1-(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)pyrrolidine-3,4-diol; 1-(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)-5,5-difluoropiperidin-3-ol; ((S)-1-(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)pyrrolidin-2-yl)methanesulfonamide; 1-(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)-5,5-difluoroazepan-4-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)-3-azabicyclo[3.2.1]octane-1-carboxamide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; rac-(1S,5S)-8-(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)-8-azabicyclo[3.2.1]octane-2-carboxamide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-(2-hydroxypropan-2-yl)piperidin-1-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)-3-(hydroxymethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; Methyl (R)-1-(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)piperidine-3-carboxylate; 1-(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)azepan-3-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-3-(hydroxymethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (R)-1-(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)azepan-3-ol; (S)-1-(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)azepan-3-ol; 4-(4-((R)-3-aminoazepan-1-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; N-((R)-1-(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)azepan-3-yl)-2,2-difluoroacetamide; N-((R)-1-(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)azepan-3-yl)acetamide; 1-(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)-1,2,6,7-tetrahydro-3H-azepin-3-one; 1-(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)-2,3,6,7-tetrahydro-1H-azepin-3-ol; 1-(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-methylazepan-3-ol (isomer 1); 1-(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-methylazepan-3-ol (isomer 2); (R)-1-(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)piperidine-3-carboxylic acid; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-((R)-5-amino-3,3-difluoropiperidin-1-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; 1-(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)azepan-4-ol; 1-(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)-4-methylazepan-4-ol; 4-(4-(4-aminoazepan-1-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-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(4-methyleneazepan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-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)-3-azabicyclo[3.2.1]octane-6-carbonitrile (isomer mixture 1); 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)-3-azabicyclo[3.2.1]octane-6-carbonitrile (isomer mixture 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)-3-azabicyclo[3.2.2]nonane-6-carbonitrile; (R)-1-(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-(methyl-d3)piperidin-3-ol; (S)-1-(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-(methyl-d3)piperidin-3-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-methoxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-(4,4-difluoroazepan-1-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; 1-(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)-5,5-difluoroazepan-4-one; 1-(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)piperidine-3-carbonitrile; 1-(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)-3,3-difluoropiperidin-4-one; 1-(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)piperidin-4-ol; (3R,5S)-1-(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)-5-(trifluoromethyl)piperidin-3-ol; 6-(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-azabicyclo[3.2.1]octan-2-ol; 1-(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-(trifluoromethyl)piperidin-3-ol; 3-cyclopropyl-1-(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)piperidin-3-ol; 1-(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)azepane-3-sulfonamide; 1-(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-hydroxypiperidine-3-carboxamide; 4-(4-(3-((difluoromethyl)sulfonyl)piperidin-1-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; 1-(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)-5-methylpiperidine-3-carboxamide; (R)-1-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide; 4-(4-(azepan-1-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; (R)-1-(7-(8-cyclopropyl-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-methylpiperidin-3-ol; (R)-1-(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)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-methylpyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine-3-ol bis(2,2,2-trifluoroacetate); (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; or (R)-1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol.

[0063] As embodiment 316, the compound is described herein as follows: 1-(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)azepan-3-one; (R)-1-(7-(8-cyclopropyl-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-methylpiperidin-3-ol; 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 1); (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 1); (1R,5R,6R)-3-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 1); (1R,5R,6R)-3-(7-(8-ethynyl-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-azabicyclo[3.2.1]octan-6-ol (isomer 1); (R)-1-(7-(8-chloro-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-methylpiperidin-3-ol; (R)-1-(7-(7,8-difluoro-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-methylpiperidin-3-ol; 3-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 2); 1-(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-methylazepan-3-ol (isomer 2); (R)-1-(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)azepan-3-ol; 1-(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)azepan-4-one; 1-(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)-2,3,6,7-tetrahydro-1H-azepin-3-ol; 4-(4-((R)-5-amino-3,3-difluoropiperidin-1-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; rac-(3S,5R)-1-(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)-5-fluoropiperidin-3-ol; 4-(4-(azepan-1-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; 4-(4-(azocan-1-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; 1-(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)-5,5-difluoropiperidin-3-ol; or (R)-1-(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)piperidin-3-ol.

[0064] As embodiment 317, the compound is described herein as follows: 1-(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)azepan-3-one; (R)-1-(7-(8-cyclopropyl-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-methylpiperidin-3-ol; 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 1); (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 1); (1R,5R,6R)-3-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 1); (1R,5R,6R)-3-(7-(8-ethynyl-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-azabicyclo[3.2.1]octan-6-ol (isomer 1); (R)-1-(7-(8-chloro-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-methylpiperidin-3-ol; (R)-1-(7-(7,8-difluoro-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-methylpiperidin-3-ol; or 3-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 2).

[0065] As embodiment 318, the compound is described herein as follows: 1-(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)azepan-3-one; (R)-1-(7-(8-cyclopropyl-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-methylpiperidin-3-ol; 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 1); (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; or 3-(difluoromethyl)-1-(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)piperidin-3-ol (Isomer 1).

[0066] As an embodiment 319, the compound is described herein as follows: 1-(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-(fluoromethyl)piperidin-3-ol (isomer 1); (R)-1-(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)-3-methylpiperidin-3-ol; (3R)-1-(7-(8-allyl-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-cyclopropyl-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-methylpiperidin-3-ol; (R)-1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 1); (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(7-(8-ethyl-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (isomer 2); 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 1); (1R,5R,6R)-3-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 1); (1R,5R,6R)-3-(7-(8-ethynyl-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-azabicyclo[3.2.1]octan-6-ol (isomer 1); (R)-1-(7-(8-chloro-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-methylpiperidin-3-ol; (R)-1-(7-(7,8-difluoro-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-methylpiperidin-3-ol; (R)-1-(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)-3-methylpiperidin-3-ol; 3-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 2); 1-(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-methylazepan-3-ol (isomer 2); (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-methylpyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(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)azepan-3-ol; 4-(4-((R)-5-amino-3,3-difluoropiperidin-1-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; rac-(3S,5R)-1-(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)-5-fluoropiperidin-3-ol; 1-(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)-5,5-difluoropiperidin-3-ol; 4-(4-(azepan-1-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; rac-(3R,5S)-1-(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)-5-methylpiperidin-3-ol; or N—((R)-1-(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)azepan-3-yl)-2,2-difluoroacetamide.

[0067] As an embodiment 320, the present specification provides a compound selected from the group consisting of: (R)-1-(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)-3-methylpiperidin-3-ol; (R)-1-(7-(8-cyclopropyl-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-methylpiperidin-3-ol; 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 1); 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 1); (1R,5R,6R)-3-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 1); (R)-1-(7-(8-chloro-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-methylpiperidin-3-ol; (R)-1-(7-(7,8-difluoro-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-methylpiperidin-3-ol; (R)-1-(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)-3-methylpiperidin-3-ol; 3-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 2); 1-(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-methylazepan-3-ol (isomer 2); (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-methylpyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(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)azepan-3-ol; 4-(4-((R)-5-amino-3,3-difluoropiperidin-1-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; rac-(3S,5R)-1-(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)-5-fluoropiperidin-3-ol; 1-(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)-5,5-difluoropiperidin-3-ol; 4-(4-(azepan-1-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; rac-(3R,5S)-1-(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)-5-methylpiperidin-3-ol; or N—((R)-1-(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)azepan-3-yl)-2,2-difluoroacetamide.

[0068] As embodiment 321, provided herein is a compound selected from the group consisting of Examples 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 21, 22, 23, 25, 27, 28, 30, 31, 32, 33, 39, 40, 41, 44, 51, 53, 54, 55, 56, 58, 59, 65, 66, 67, 68, 69, 71, 75, 76, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 138, 139, 144, 145, 14 82, 86, 87, 89, 101, 104, 106, 108, 109, 112, 113, 116, 117, 120, 123, 129, 130, 131, 132, 134, 137, 138, 140, 144, 145, 147, 151, 153, 154, 170, 172, 173, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 197, 202, 203, 213, 221, 228, 2 37, 239, 240, 241, 242, 243, 244, 246, 248, 250, 251, 253, 256, 257, 268, 273, 274, 281, 285, 290, 292, 295, 296, 299, 301, 302, 303, 304, 306, 308, 309, 311, 312, 313, 314, 316, 317, 320, 325, 327, 331, 332, 335, 336, 346, 347, 348, 350, 352, 353, 360, 362, 363, 364 6, 387, 388, 389, 390, 399, 402, 403, 404, 414, 418, 421, 422, 423, 429, 430, 431, 432, 435, 436, 437, 438, 439, 440, 455, 456, 458, 459, 460, 461, 463, 465, 471, 472, 473, 479, 482, 486, 487, 488, 490, 491, 511, 512, 514, 517, 519 or 520.

[0069] As embodiment 322, herein provided is a compound selected from the group consisting of Examples 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 21, 22, 23, 25, 27, 28, 30, 31, 32, 33, 39, 40, 41, 44, 51, 53, 54, 55, 56, 58, 59, 65, 66, 67, 68, 69, 71, 75, 76, 81, 82, 86, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 138, 139, 144, 145, 146, 147, 148, 149, 150 , 87, 89, 101, 104, 106, 108, 109, 112, 113, 116, 117, 120, 123, 129, 130, 131, 132, 134, 137, 138, 140, 144, 145, 147, 151, 153, 154, 170, 172, 173, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 197, 202 or 203.

[0070] The foregoing merely summarizes certain aspects of the disclosure and is not intended, nor should it be construed, as limiting the disclosure in any way.

[0071] Formulation and route of administration In the described uses, although it may be possible to administer the compound disclosed herein alone, the administered compound will usually be present as an active ingredient in a pharmaceutical composition.Thus, in one embodiment, provided herein is a pharmaceutical composition comprising the compound disclosed herein in combination with one or more pharmaceutically acceptable excipients, such as diluents, carriers, adjuvants, etc., and optionally other active ingredients. See, for example, Remington: The Science and Practice of Pharmacy, Volume I and Volume II, twenty-second edition, edited by Loyd V. Allen Jr., Philadelphia, PA, Pharmaceutical Press, 2012; Pharmaceutical Dosage Forms (Vol. 1-3), Liberman et al., Eds., Marcel Dekker, New York, NY, 1992; Handbook of Pharmaceutical Excipients (3rd Ed.), edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, 2000; Pharmaceutical Formulation: The Science and Technology of Dosage Forms (Drug Discovery), 1st Edition, Royal Society of Chemistry, 2018. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein.

[0072] The compounds disclosed herein can be administered by any suitable route of administration in the form of a pharmaceutical composition adapted to such route and in a dose effective for the intended treatment. The compounds and compositions provided herein can be administered, for example, orally, mucosally, topically, transdermally, rectally, pulmonary, parenterally, intranasally, intravascularly, intravenously, intraarterially, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, intravaginally, or by infusion techniques in dosage unit formulations containing conventional pharmaceutically acceptable excipients.

[0073] 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, drops, 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.

[0074] As embodiment 323, provided herein is a pharmaceutical composition comprising a compound according to any one of embodiments 1 to 322, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, and a pharmaceutically acceptable excipient.

[0075] As embodiment 324, provided herein is a compound according to any one of embodiments 1 to 322 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 323, for use as a medicament.

[0076] How to use As discussed herein (see the section entitled "Definitions"), the compounds described herein should be understood to include all stereoisomers, tautomers, or pharmaceutically acceptable salts of any of the foregoing, or solvates of any of the foregoing. Accordingly, the scope of methods and uses provided in this disclosure should be understood to encompass methods and uses employing all such forms.

[0077] 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.

[0078] In one embodiment, the present disclosure provides methods of using a compound or pharmaceutical composition of the present disclosure to treat a disease state, including, but not limited to, a condition associated with a KRAS G12D, G12V, G12A, G12S, or G12C mutation (e.g., cancer), where the cancer type 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, sinus cancer, cholangiocarcinoma, or melanoma.

[0079] KRAS G12D mutations occur at the alteration frequencies shown in the table below (TCGA dataset; 1~3 For example, this table shows that 32.4% of subjects with pancreatic cancer have cancers in which one or more cells express the KRAS G12D mutant protein. G12D Compounds provided herein that bind to (see the section below entitled "Biological Evaluation") are useful for treating subjects with cancers, including, but not limited to, those listed in the table below.

[0080] [Table 1]

[0081] As embodiment 325, provided herein is a compound according to any one of embodiments 1 to 322, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 323, for use in treating cancer.

[0082] As embodiment 326, provided herein is a compound according to any one of embodiments 1 to 322, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 323, for use in treating a cancer in which one or more cells express a KRAS G12D, G12V, G12A, G12S, or G12C mutant protein.

[0083] As embodiment 327, provided herein is a compound or pharmaceutical composition for use in embodiment 325 or 326, 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 cancer of unknown primary site, 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.

[0084] As embodiment 328, provided herein is the use of a compound according to any one of embodiments 1 to 322, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 323, in the preparation of a medicament for treating cancer.

[0085] As embodiment 329, provided herein is the use of a compound according to any one of embodiments 1 to 322 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 323, 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.

[0086] As embodiment 330, the present specification provides a use according to embodiment 328 or 329, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine carcinoma, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia or melanoma.

[0087] As embodiment 331, 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 according to any one of embodiments 1 to 322, or a pharmaceutically acceptable salt thereof.

[0088] As embodiment 332, provided herein is a method of treating a cancer in which one or more cells express a KRAS G12D, G12V, G12A, G12S, or G12C mutant protein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 322, or a pharmaceutically acceptable salt thereof.

[0089] As embodiment 333, provided herein is a method according to embodiment 331 or 332, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine carcinoma, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

[0090] As embodiment 334, the present specification provides a method according to embodiment 332 or 333, 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.

[0091] As embodiment 335, provided herein is a method according to embodiment 334, wherein the cancer is non-small cell lung cancer.

[0092] As embodiment 336, provided herein is a method according to embodiment 334, wherein the cancer is colorectal cancer.

[0093] As embodiment 337, provided herein is a method according to embodiment 334, wherein the cancer is pancreatic cancer.

[0094] As embodiment 338, provided herein is a method according to any one of embodiments 331 to 337, wherein the subject has 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 pharmaceutically acceptable salt thereof.

[0095] Combination therapy The present disclosure provides combination treatment methods in which agents known to regulate other pathways or other components of the same pathway, or even overlapping sets of target enzymes, are used in combination with compounds of the present disclosure or pharmaceutically acceptable salts thereof. In one aspect, such treatments include, but are not limited to, the combination of one or more compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation therapy to provide synergistic or additive therapeutic effects. See, for example, U.S. Patent No. 10,519,146 B2, issued December 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.

[0096] As embodiment 339, provided herein is a method according to any one of embodiments 331 to 338, further comprising the 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, an SOS1 inhibitor, a Src kinase inhibitor, or one or more chemotherapeutic agents.

[0097] In one embodiment, the second compound is administered as a pharmaceutically acceptable salt, hi another embodiment, the second compound is administered as a pharmaceutical composition comprising the second compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0098] Aurora kinase A inhibitors Provided herein are methods according to any one of embodiments 331-338, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an Aurora kinase A inhibitor.

[0099] Exemplary Aurora kinase A inhibitors for use in the methods provided herein include alisertib, cenisertib, danusertib, tozasertib, LY3295668 ((2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyridin-2-yl]methyl]-2-methylpiperidine-4-carboxylic acid), ENMD-2076 (6-(4-methylpiperazine -1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[(E)-2-phenylethenyl]pyrimidin-4-amine), TAK-901 (5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide), TT-00420 (4-[9-(2-chlorophenyl)-6-methyl-2,4,5,8,12-pentazatricyclo[8.4.0.03,7]tetradeca-1(14),3,6,8,10,12-hexaen-13-yl]morpholine), AMG 900 (N-[4-[3-(2-aminopyrimidin-4-yl)pyridin-2-yl]oxyphenyl]-4-(4-methylthiophen-2-yl)phthalazin-1-amine), MLN 8054 (4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid), PF-03814735 (N-[2-[(1R,8S)-4-[[4-(cyclobutylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-11-azatricyclo[6.2.1.02,7]undec-2(7),3,5-trimethyl-2-pyrimidin-2-yl]amino)

[0033] 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.

[0100] AKT inhibitors Provided herein are methods according to any one of embodiments 331 to 338, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an AKT inhibitor.

[0101] Exemplary AKT inhibitors for use in the methods provided herein include afuresertib, capivasertib, ipatasertib, uprosertib, BAY1125976 (2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide), ARQ 092 (3-[3-[4-(1-aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2-amine), MK2206 (8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one), SR13668 (indolo[2,3-b]carbazole-2,10-dicarboxylic acid, 5,7-dihydro-6-methoxy-2,10-diethyl ester), ONC201 (11-benzyl-7-[2-methylphenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one), ARQ 751 (N-(3-aminopropyl)-N-[(1R)-1-(3-anilino-7-chloro-4-oxoquinazolin-2-yl)but-3-ynyl]-3-chloro-2-fluorobenzamide), RX-0201, and LY2780301.

[0102] Arginase inhibitors Provided herein are methods according to any one of embodiments 331-338, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an arginase inhibitor.

[0103] Exemplary arginase inhibitors for use in the methods provided herein include, but are not limited to, numidardistat and CB 280.

[0104] CDK4 / 6 inhibitors Provided herein are methods according to any one of embodiments 331-338, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a CDK4 / 6 inhibitor.

[0105] The term "CDK4 / 6" as used herein refers to cyclin-dependent kinases ("CDKs") 4 and 6, which are members of the mammalian serine / threonine protein kinases.

[0106] The term "CDK4 / 6 inhibitor" as used herein refers to a compound that is capable of negatively regulating or inhibiting all or part of the enzymatic activity of CDK4 and / or 6.

[0107] 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]).

[0108] In one embodiment, the CDK4 / 6 inhibitor is palbociclib.

[0109] ErbB family inhibitors Provided herein are methods according to any one of embodiments 331-338, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an ErbB family inhibitor.

[0110] The term "ErbB family" as used herein refers to members of the mammalian transmembrane protein tyrosine kinase family that includes ErbB1 (EGFR HER1), ErbB2 (HER2), ErbB3 (HER3) and ErbB4 (HER4).

[0111] The term "ErbB family inhibitor" as used herein refers to an agent, e.g., a compound or antibody, that can negatively regulate or inhibit 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 modulating or inhibiting the kinase enzymatic activity of one or more ErbB family members, or by preventing homodimerization or heterodimerization of ErbB family members.

[0112] In one embodiment, the ErbB family inhibitor is an EGFR inhibitor, for example, an anti-EGFR antibody. Exemplary anti-EGFR antibodies for use in the methods provided herein include, but are not limited to, zalutumumab, nimotuzumab, matuzumab, necitumumab, panitumumab, and cetuximab. In one embodiment, the anti-EGFR antibody is cetuximab. In one embodiment, the anti-EGFR antibody is panitumumab.

[0113] In another embodiment, the ErbB family inhibitor is a HER2 inhibitor, e.g., an anti-HER2 antibody. Exemplary anti-HER2 antibodies for use in the methods provided herein include, but are not limited to, pertuzumab, trastuzumab, and trastuzumab emtansine.

[0114] In yet another embodiment, the ErbB family inhibitor is a HER3 inhibitor such as an anti-HER3 antibody, for example, HMBD-001 (Hummingbird Bioscience).

[0115] In one embodiment, the ErbB family inhibitor is a combination of an anti-EGFR antibody and an anti-HER2 antibody.

[0116] In one embodiment, the ErbB family inhibitor is an irreversible inhibitor. Exemplary irreversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to, afatinib, dacomitinib, canertinib, poziotinib, AV 412 ((N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butyn-1-yl]-6-quinazolinyl]-2-propenamide), PF 6274484 (N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-2-propenamide), and HKI 357 ((E)-N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide).

[0117] In one embodiment, the irreversible ErbB family inhibitor is afatinib. In one embodiment, the irreversible ErbB family inhibitor is dacomitinib.

[0118] 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, vallitinib, talloxotinib, TAK-285 (N-(2-(4-((3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl)-3-hydroxy-3-methylbutanamide), AEE788 ((S)-6-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-N-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine), BMS Examples of compounds that may be used include, but are not limited to, 599626 ((3S)-3-morpholinylmethyl-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamate) and GW 583340 (N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[2-[(2-methylsulfonylethylamino)methyl]-1,3-thiazol-4-yl]quinazolin-4-amine).

[0119] In one embodiment, the reversible ErbB family inhibitor is sapitinib. In one embodiment, the reversible ErbB family inhibitor is tarloxotinib.

[0120] ERK inhibitors Provided herein are methods according to any one of embodiments 331-338, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an ERK inhibitor.

[0121] Exemplary ERK inhibitors for use in the methods provided herein include ulixertinib, lavoxertinib, CC-90003 (N-[2-[[2-[(2-methoxy-5-methylpyridin-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]-5-methylphenyl]prop-2-enamide), LY3214996 (6,6-dimethyl-2-[2-[(2-methyl-

[0037] 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.

[0122] FAK inhibitors Provided herein are methods according to any one of embodiments 331-338, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a FAK inhibitor.

[0123] 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.

[0124] FGFR inhibitors Provided herein are methods according to any one of embodiments 331-338, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an FGFR inhibitor.

[0125] 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), Debio 1347 ([5-amino]pyrazol-3-yl), and AZD4547 (N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]benzamide).

[0037] These compounds include, but are not limited to, N-(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.

[0126] glutaminase inhibitors Provided herein are methods according to any one of embodiments 331-338, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a glutaminase inhibitor.

[0127] Exemplary glutaminase inhibitors for use in the methods provided herein include, but are not limited to, telaglenastat, IPN60090, and OP 330.

[0128] IGF-1R inhibitors Provided herein are methods according to any one of embodiments 331-338, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an IGF-1R inhibitor.

[0129] Exemplary IGF-1R inhibitors for use in the methods provided herein include, but are not limited to, cixutumumab, dalotuzumab, linsitinib, ganitumab, lobatumumab, 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.

[0130] KIF18A inhibitors Provided herein is a method according to any one of embodiments 331 to 338, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a KIF18A inhibitor.

[0131] 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.

[0132] MCL-1 inhibitors Provided herein are methods according to any one of embodiments 331-338, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an MCL-1 inhibitor.

[0133] Exemplary MEK inhibitors for use in the methods provided herein include murizatoclax, tapotoclax, AZD 5991 ((3aR)-5-chloro-2,11,12,24,27,29 hexahydro-2,3,24,33-tetramethyl-22H-9,4,8-(metheniminomethino)-14,20:26,23-dimetheno-10H,20H-pyrazolo[4,3-l][2,15,22,18,19]benzoxadithiadiazacyclohexacosine-32-carboxylic acid), and MEK inhibitors. 665 ((αR)-α-[[(5S)-5-[3-chloro-2-methyl-4-[2-(4-methyl-1-piperazinyl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy]-2-[[2-(2-methoxyphenyl)-4-pyrimidinyl]methoxy]benzenepropanoic acid) and ABBV-467.

[0134] In one embodiment, the MCL-1 inhibitor is murizatoclax. In another embodiment, the MCL-1 inhibitor is tapotoclax.

[0135] MEK inhibitors Provided herein are methods according to any one of embodiments 331-338, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a MEK inhibitor.

[0136] Exemplary MEK inhibitors for use in the methods provided herein include trametinib, cobimetinib, selumetinib, pimasertib, refametinib, PD-325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), AZD8330 (2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxopyridine-3- carboxamide), GDC-0623 (5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide), RO4987655 (3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-5-[(3-oxooxazinan-2-yl)methyl]benzamide), TAK-733 (3-[(2R)-2,3-dihydroxypropyl]-6-fluoro-5 -(2-Fluoro-4-iodoanilino)-8-methylpyrido[2,3-d]pyrimidine-4,7-dione), PD0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), CI-1040 (2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide), PD318088 (5-bromo-N-(2,3-dihydroxypropoxy)-3,4-difluorobenzamide),

[0033] Examples of compounds that may be used 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.

[0137] In one embodiment, the MEK inhibitor is trametinib.

[0138] mTOR inhibitors Provided herein are methods according to any one of embodiments 331-338, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an mTOR inhibitor.

[0139] Exemplary mTOR inhibitors for use in the methods provided herein include everolimus, rapamycin, zotarolimus (ABT-578), ridaforolimus (deforolimus, MK-8669), sapanisertib, buparlisib, pictilisib, bistosertib, dactolisib, torin-1(1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)cyclohexyl)-9-(quinolin-3-yl)benzo[h][1, 6]naphthyridin-2(1H)-one), GDC-0349 ((S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-7-(oxetan-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea), and VS-5584 (SB2343, (5-(8-methyl-2-morpholin-4-yl-9-propan-2-ylpurin-6-yl)pyrimidin-2-amine).

[0140] In one embodiment, the mTOR inhibitor is everolimus.

[0141] PD-1 inhibitors Provided herein are methods according to any one of embodiments 331-338, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a PD-1 inhibitor.

[0142] 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), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, and anti-PD-1 antibodies such as those described in U.S. Pat. No. 10,640,504 B2 ("Anti-PD-1 Antibody A," column 66, lines 56 to 67, line 24 and column 67, lines 54-57), which are incorporated herein by reference.

[0143] In one embodiment, the PD-1 inhibitor is pembrolizumab. In another embodiment, the PD-1 inhibitor is anti-PD-1 antibody A.

[0144] PD-L1 inhibitors Provided herein are methods according to any one of embodiments 331-338, 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.

[0145] 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.

[0146] In one embodiment, the PD-L1 inhibitor is atezolizumab.

[0147] PI3K inhibitors Provided herein are methods according to any one of embodiments 331-338, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a PI3K inhibitor.

[0148] Exemplary PI3K inhibitors for use in the methods provided herein include idelalisib, copanlisib, duvelisib, alpelisib, taselisib, perifosine, buparlisib, ambralisib, pictilisib, dactolisib, voxtalisib, sonolisib, tenalisib, selavelsib, acalisib, CUDC-907 (N-hydroxy-2-[[2-(6-methoxypyridin-3-yl)-4-morpholin-4-ylthieno[ 3,2-d]pyrimidin-6-yl]methyl-methylamino]pyrimidine-5-carboxamide), ME-401 (N-[2-methyl-1-[2-(1-methylpiperidin-4-yl)phenyl]propan-2-yl]-4-(2-methylsulfonylbenzimidazol-1-yl)-6-morpholin-4-yl-1,3,5-triazin-2-amine), IPI-549 (2-amino-N-[(1S)-1-[8-[2-(1-methyl pyrazol-4-yl)ethynyl]-1-oxo-2-phenylisoquinolin-3-yl]ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide), SF1126 (((2S)-2-[[(2S)-3-carboxy-2-[[2-[[(2S)-5-(diaminomethylideneamino)-2-[[4-oxo-4-[[4-(4-oxo-8-phenylchromen-2-yl)morpholin-4-ium-4-yl]methoxy]butadiene

[0033] Examples of compounds useful for the treatment of rhodium include, but are not limited to, N-[(1S)-1-(7-fluoro-2-pyridin-2-ylquinolin-3-yl)ethyl]-7H-purin-6-amine ...

[0149] Raf kinase inhibitors Provided herein are methods according to any one of embodiments 331-338, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a Raf kinase inhibitor.

[0150] The term "RAF kinase" as used herein 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 and heterodimers between isoforms, e.g., C-Raf / B-Raf heterodimers.

[0151] The term "Raf kinase inhibitor" as used herein refers to a compound that is capable of negatively regulating or inhibiting all or part of the enzymatic activity of one or more members of the Raf family kinases, or that is capable of disrupting Raf homodimer or heterodimer formation, thereby inhibiting activity.

[0152] In one embodiment, Raf kinase inhibitors include encorafenib, sorafenib, lifirafenib, vemurafenib, dabrafenib, PLX-8394 (N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-3a,7a-dihydro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide), Raf-709 (N-(2-methyl-5-morpholino-6'-((tetrahydro-2H -pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide), LXH254 (N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide), LY3009120 (1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidine-6-yl)-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide), yl)phenyl)urea), Tak-632 (N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide), CEP-32496 (1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea), CCT19696 9 (1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-((3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yl)oxy)phenyl)urea) and RO5126766 (N-[3-fluoro-4-[[4-methyl-2-oxo-7-(2-pyrimidinyloxy)-2H-1-benzopyran-3-yl]methyl]-2-pyridinyl]-N'-methyl-sulfamide).

[0153] 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.

[0154] SHP2 inhibitors Provided herein are methods according to any one of embodiments 331-338, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an SHP2 inhibitor.

[0155] 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).

[0156] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include 3-[(1R,3R)-1-amino-3-methoxy-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyrazinemethanol (CAS 2172651-08-8), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2-pyrazinemethanol (CAS 2172652-13-8), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-[[3-chloro-2-(3-hydroxy-1-azetidinyl)-4-pyridinyl]thio]-5-methyl-2-pyrazinemethanol (CAS 2172652-38-7) and 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-methyl-2-pyrazinemethanol (CAS 2172652-48-9).

[0157] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include 1-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-4-methyl-4-piperidinamine (CAS 2240981-75-1), (1R)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine (CAS 2240981-78-4), (3S,4S)-8-[7-(2,3-dichlorophenyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-45-8), (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]pyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-57-2), 4-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-7-(2,3-dichlorophenyl)-6-methyl-pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-69-6), 7-[(2-amino-3-chloro-4-pyridinyl)thio]-4-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-methyl-pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-73-2) and (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-77-6).

[0158] In one embodiment, the SHP inhibitor for use in the methods provided herein is (1R)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine (CAS 2240981-78-4).

[0159] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-54-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56-5), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-(2,3-dichlorophenyl)-3-pyridinol (CAS 2238840-58-7), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-60-1), (1R)-8-[6-(2,3-dichlorophenyl)-5-methyl-3-pyridinyl]-8-azaspiro[4.5]decan-1-amine (CAS 2238840-62-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2-pyridinemethanol (CAS 2238840-63-4), (1R)-8-[6-[(2,3-dichlorophenyl)thio]-5-methyl-3-pyridinyl]-8-azaspiro[4.5]decan-1-amine (CAS 2238840-64-5), 5-(4-amino-4-methyl-1-piperidinyl)-2-[(2,3-dichlorophenyl)thio]-3-pyridinol (CAS 2238840-65-6), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-[[(2,3-dichlorophenyl)thio]-3-pyridinol (CAS 2238840-66-7), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-hydroxy-2-pyridinemethanol (CAS 2238840-67-8), 3-(4-amino-4-methyl-1-piperidinyl)-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-68-9), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-69-0), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-methyl-2-pyridinemethanol (CAS 2238840-70-3), 3-(4-amino-4-methyl-1-piperidinyl)-6-[(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-71-4), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-(4-amino-4-methyl-1-piperidinyl)-2-pyridinemethanol (CAS 2238840-72-5), 5-[(2-amino-3-chloro-4-pyridinyl)thio]-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-methyl-3-pyridinemethanol (CAS 2238840-73-6), 2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-(2,3-dichlorophenyl)-6-methyl-3-pyridinemethanol (CAS 2238840-74-7), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-75-8) and 2-[(2-amino-3-chloro-4-pyridyl)sulfanyl]-5-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(hydroxymethyl)pyridin-3-ol.

[0160] In one embodiment, the SHP inhibitor for use in the methods provided herein is 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56-5).

[0161] 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.

[0162] SOS1 inhibitors Provided herein are methods according to any one of embodiments 331-338, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an SOS1 inhibitor.

[0163] Exemplary SOS1 inhibitors for use in the methods provided herein include, but are not limited to, BI 3406 (N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-7-methoxy-2-methyl-6-[(3S)-oxolan-3-yl]oxyquinazolin-4-amine) and BI 1701963.

[0164] Src kinase inhibitors Provided herein are methods according to any one of embodiments 331-338, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a Src kinase inhibitor.

[0165] The term "Src kinase" as used herein 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.

[0166] The term "Src kinase inhibitor" as used herein refers to a compound that is capable of negatively regulating or inhibiting all or part of the enzymatic activity of one or more members of the Src kinases.

[0167] Exemplary Src kinase inhibitors for use in the methods provided herein include dasatinib, ponatinib, vandetanib, bosutinib, saracatinib, KX2-391 (N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide), SU6656 ((Z)-N,N-dimethyl-2-oxo-3-((4,5,6,7-tetrahydro-1H-indol-2-yl)methylene)indoline-5-sulfonamide), PP 1 (1-(tert-butyl)-3-(p-tolyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), WH-4-023 (2,6-dimethylphenyl(2,4-dimethoxyphenyl)(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)carbamate), and KX-01 (N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide).

[0168] 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.

[0169] chemotherapy drugs Provided herein are methods according to any one of embodiments 331-338, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is one or more chemotherapeutic agents.

[0170] 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.

[0171] definition The following definitions are provided to facilitate understanding of the scope of the present disclosure.

[0172] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending on the standard deviation found in their respective testing measurements.

[0173] As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. When the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

[0174] stereoisomer 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 (in whole or in part) disclosed herein, unless the stereochemistry is otherwise specified.

[0175]

[0013] When the stereochemistry of a structure or portion of a structure is not indicated, for example, with a bold or dashed line, the structure or portion of a structure is to be interpreted as encompassing all stereoisomers thereof. When the stereochemistry of a structure or portion of a structure is not indicated, for example, with a bold or dashed line, 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 rest of the molecule).

[0176] As used herein, the term "stereoisomer" or "stereoisomerically pure" compound refers to one stereoisomer (e.g., geometric isomer, enantiomer, diastereomer, and atropisomer) of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the mirror-image enantiomer of that compound, and a stereoisomerically pure compound having two chiral centers will be substantially free of other enantiomers or diastereomers of that compound. A typical stereoisomerically pure compound contains greater than about 80% by weight of one stereoisomer of the compound and about 20% by weight or less of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and about 10% by weight or less of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and about 5% by weight or less of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and about 3% by weight or less of other stereoisomers of the compound.

[0177] The present disclosure also encompasses pharmaceutical compositions comprising stereoisomerically pure forms and the use of stereoisomerically pure forms of any compound disclosed herein. Additionally, the present disclosure also encompasses pharmaceutical compositions comprising mixtures of stereoisomers of any compound disclosed herein and the use of said pharmaceutical compositions or mixtures of stereoisomers. These stereoisomers or mixtures thereof can be synthesized according to methods known in the art and disclosed herein. Mixtures of stereoisomers can be resolved using standard techniques, such as chiral columns or chiral resolving agents. Additionally, the present disclosure encompasses pharmaceutical compositions comprising mixtures of any of the compounds disclosed herein with one or more other active agents disclosed herein. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725; Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (Eliel, Ed., University of Notre Dame Press, Notre Dame, IN, 1972).

[0178] tautomers As known to those skilled in the art, certain compounds disclosed herein can exist in one or more tautomeric forms.Since one chemical structure can only be used to represent one tautomeric form, for convenience, it will be understood that reference to a compound of a given structural formula includes other tautomeric forms of said structural formula.Therefore, the scope of the present disclosure should be understood to encompass all tautomeric forms of the compounds disclosed herein.

[0179] isotope labeled compounds Additionally, the scope of the present disclosure includes all pharmaceutically 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 and 35 Certain isotopically labeled compounds of Formula I, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 ( 14 C) are particularly useful for this purpose given their ease of incorporation and ready means of detection. 2 Substitution with isotopes such as H or D may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be advantageous in some circumstances. 11 C. 18 F, 15 O and 13 Substitution with positron-emitting isotopes, such as N, can be useful, for example, in positron emission tomography (PET) studies for examining target occupancy. Isotopically labeled compounds of the compounds disclosed herein can generally be prepared by conventional techniques known to those of skill in the art or by processes analogous to those described in the accompanying general synthetic schemes and examples, in which the appropriate isotopically labeled reagent is substituted for a previously used non-labeled reagent.

[0180] solvate As noted above, the compounds disclosed herein, as well as the stereoisomers, tautomers, and isotopically labeled forms thereof, or pharmaceutically acceptable salts of any of the foregoing, can exist in solvated or unsolvated forms.

[0181] As used herein, the term "solvate" refers to a molecular complex comprising a compound described herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable solvent molecules, in a stoichiometric or non-stoichiometric amount. When the solvent is water, the solvate is referred to as a "hydrate."

[0182] Accordingly, the scope of the present disclosure should be understood to encompass all solvates of the compounds disclosed herein and their stereoisomers, tautomers, and isotopically labeled forms, or pharmaceutically acceptable salts of any of the foregoing.

[0183] Various definitions This section defines additional terms used to describe the scope of the compounds, compositions and uses disclosed herein.

[0184] The term "aryl" refers to an aromatic hydrocarbon group having 6 to 20 carbon atoms in the ring portion. Typically, aryl is a monocyclic, bicyclic, or tricyclic aryl having 6 to 20 carbon atoms. Furthermore, as used herein, the term "aryl" refers to an aromatic substituent which may be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl, each of which may be optionally substituted with 1 to 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.

[0185] 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.

[0186] 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.

[0187] As used herein, the term "C 2~4 "Alkenyl" refers to a saturated hydrocarbon containing 2 to 4 carbon atoms with 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.

[0188] As used herein, the term "C 2~4 "Alkynyl" refers to a saturated hydrocarbon containing 2 to 4 carbon atoms with at least one carbon-carbon triple bond. The term includes both straight and branched chain moieties. 3~6 Representative examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, and 3-butynyl.

[0189] As used herein, the term "C 1~4 Alkoxy" or "C 1~6 "Alkoxy" is -OR # refers to R # are C as defined herein, respectively. 1~4 Alkyl group or C 1~6 Represents an alkyl group. 1~4 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy, and butoxy. 1~6 Representative examples of alkoxy include, but are not limited to, ethoxy, propoxy, iso-propoxy, and butoxy.

[0190] 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.

[0191] The term "deuterium," as used herein as a prefix of another term for a chemical group, refers to a group in which one or more hydrogen atoms have been replaced with deuterium ("D" or " 2 For example, the term "C 1~4 "Deuteroalkyl" refers to a C alkyl group, as defined herein, in which one or more hydrogen atoms are replaced with D. 1~4 Refers to alkyl. C 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).

[0192] The term "halogen" as used herein refers to -F, -CI, -Br or -I.

[0193] The term "halo," as used herein as a prefix of another term for a chemical group, refers to a modification of the 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, the term "C 1~4 "Haloalkyl" refers to a C alkyl group, as defined herein, in which one or more hydrogen atoms are replaced with halogen. 1~4 Refers to alkyl. C 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).

[0194] As used herein, the term "heteroaryl" refers to a 5- to 20-membered monocyclic, bicyclic, or tricyclic aromatic ring system having 1 to 8 heteroatoms selected from N, O, and S. In certain preferred embodiments, the heteroaryl is a 5- to 10-membered ring system (e.g., a 5- to 7-membered monocyclic, an 8- to 10-membered bicyclic, or an 11- to 14-membered tricyclic) or a 5- to 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.

[0195] The term "heteroaryl" also refers to groups in which a heteroaromatic ring is fused to one or more aryl, aliphatic, or heterocycloalkyl rings.

[0196] As used herein, the term "heterocycle," "heterocycloalkyl," or "heterocyclo" refers to a saturated or unsaturated non-aromatic ring or ring system, e.g., 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 can be optionally oxidized to various oxidation states. The heterocyclic group can be attached at a heteroatom or a carbon atom. Heterocycloalkyl can include fused or bridged rings and 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.

[0197] As used herein, the term "pharmaceutically acceptable" generally refers to something that is recognized for use in subjects, particularly humans.

[0198] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, etc., or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine, etc. Additional examples of such salts can be found in Berge et al., J. Pharm. Sci. 66(1):1-19 (1977). Stahl et al., Pharmaceutical Salts: Properties, Selection, and Use, 2 nd See also Revised Edition (2011).

[0199] As used herein, the term "pharmaceutically acceptable excipient" refers to a wide variety of ingredients that can be combined with the compounds or salts disclosed herein to prepare pharmaceutical compositions or formulations. Typically, excipients include, but are not limited to, diluents, colorants, vehicles, anti-adherents, glidants, disintegrants, flavoring agents, coating agents, binders, sweeteners, lubricants, adsorbents, and preservatives.

[0200] As used herein, the term "subject" refers to humans and animals, including, but not limited to, primates, cows, sheep, goats, horses, dogs, cats, rabbits, rats, and mice. In one embodiment, the subject is a human.

[0201] The term "therapeutically effective amount" as used herein refers to an amount of a compound disclosed herein that will elicit the biological or medical response of a tissue, system, or subject desired by a researcher, veterinarian, medical doctor, or other clinician.

[0202] General synthetic procedure The compounds provided herein can be synthesized according to the procedures described in this section and the following sections. The synthetic methods described herein are merely exemplary, and the compounds disclosed herein can also be synthesized by alternative routes utilizing alternative synthetic strategies, as will be appreciated by those skilled in the art. It should be understood that the general synthetic procedures and specific examples provided herein are merely exemplary and should not be construed as limiting the scope of the present disclosure in any way.

[0203] In general, compounds of Formula I can be synthesized according to the following schemes. Any variables used in the following schemes are as defined for Formula I unless otherwise specified. All starting materials are either commercially available from, for example, Merck Sigma-Aldrich Inc., Fluorochem Ltd., and Enamine Ltd., or known in the art, and can be synthesized by using known procedures using conventional techniques. The starting materials can also be synthesized by the procedures disclosed herein. Suitable reaction conditions, such as solvents, reaction temperatures, and reagents, for the schemes discussed in this section can be found in the examples provided herein. [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 converted into a compound of formula R in a solvent, such as acetonitrile, in the presence of a base, such as Hunig's base.1 -LH with nucleophiles and S N The compound (I-4) undergoes an Ar reaction to give compound (I-3). In step C, compound (I-3) is coupled with an organometallic reagent or a boronic acid (ester) to give compound (I-4). This coupling reaction proceeds in a solvent or solvent mixture such as 1,4-dioxane and water, with or without a base such as potassium phosphate, and in a catalyst such as cataCXium A Pd G3. In step D, compound (I-4) is treated with a suitable reagent such as Pd / C and 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 may contain protecting groups which may be removed in step D or after step E in the synthetic sequence. [ka] Compounds of formula (I) can also be prepared according to Scheme II. In Step A, compound (I-1) is treated with sodium thiomethoxide in a solvent such as tetrahydrofuran to give compound (I-6). In Step B, compound (I-6) is reacted with a nucleophile having the formula R1-LH in a solvent such as acetonitrile in the presence of a base such as Hunig's base to give compound (I-6). N The compound (I-7) undergoes an Ar reaction to give compound (I-7). In step C, compound (I-7) is coupled with an organometallic reagent or a boronic acid (ester) to provide compound (I-8). This coupling reaction proceeds in a solvent or solvent mixture such as 1,4-dioxane and water, with or without a base such as potassium phosphate, and in a catalyst such as cataCXium A Pd G3. In step D, compound (I-8) is coupled with an optionally substituted cyclic amine in the presence of a palladium catalyst such as Pd(PPh3)4 or a copper catalyst such as CuTC in a solvent such as 1,4-dioxane to give a compound of formula (I). Optionally, R3 The species contains protecting groups, which can be removed after step D in the synthetic sequence. [ka] Compounds of formula (I) can also be prepared according to Scheme III. In Step A, compound (I-8) is treated with sulfuryl chloride in a solvent such as dichloromethane to give compound (I-9). In Step B, compound (I-9) is reacted with an optionally substituted cyclic amine in the presence of a base such as Hunig's base in a solvent such as acetonitrile to give compound (I-9). N Ar reaction to give compounds of formula (I). 3 The species contains protecting groups, which can be removed after step B in the synthetic sequence. [ka] Compounds of formula (I) can also be prepared according to Scheme IV. In Step A, compound (1) is reacted with an optionally substituted cyclic amine in a solvent such as dichloromethane in the presence of a base such as Hunig's base. N In step B, compound (I-10) is reacted with a compound of formula R in the presence of a base such as Hunig's base in a solvent such as acetonitrile to give compound (I-10). 1 -LH with nucleophiles and S N In step C, compound (I-11) is coupled with an organometallic reagent or a boronic acid (ester) to provide a compound of formula (I). This coupling reaction proceeds with or without a base such as potassium phosphate, in a solvent or solvent mixture such as 1,4-dioxane and water, and in a catalyst such as cataCXium A Pd G3. Optionally, R 3 The species contains protecting groups, which can be removed after step C in the synthetic sequence. [Example]

[0204] This section provides specific examples of compounds of Formula I and methods for their preparation.

[0205] List of abbreviations

[0206] [Table 2]

[0207] [Table 3]

[0208] [Table 4]

[0209] 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.

[0210] 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 (SiO), and eluting the product from the column with a solvent gradient as indicated.

[0211] Preparative HPLC Methods: Where indicated, compounds described herein were purified by reverse-phase HPLC using a Waters FractionLynx or Gilospn semi-preparative HPLC-MS system utilizing one of the following two HPLC columns: (a) a Phenomenex Gemini column (5 micron, C18, 150 x 30 mm) or (b) a Waters X-select CSH column (5 micron, C18, 100 x 30 mm). A typical run through the instrument involved eluting with a linear gradient of 10% (v / v) to 100% MeCN (0.1% v / v formic acid) in water (0.1% formic acid) over 10 minutes at 45 mL / min; conditions can be varied to achieve optimal separation.

[0212] 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 the reference. Some protons may be present due to exchange with D from MeOD or due to signal suppression. 1 The H signal may be absent.

[0213] Mass Spectrum (MS): Unless otherwise indicated, all mass spectral data for starting materials, intermediates, and / or exemplary compounds are reported as mass / charge (m / z) with the [M+H]+ molecular ion. The 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.

[0214] Preparation of intermediates ((5,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)oxy)triisopropylsilane (Intermediate A) [ka] Step 1: Methyl 2-(2-bromo-3,4-difluorophenyl)acetate. To a 100 mL round-bottom flask were added 2-(2-bromo-3,4-difluorophenyl)acetic acid (2.00 g, 7.97 mmol), DBU (1.21 g, 1.20 mL, 7.97 mmol), and toluene (40 mL). To the mixture was added MeI (2.26 g, 1.0 mL, 15.93 mmol), and the mixture was stirred at rt for 4 h. Upon completion, the reaction was diluted with water and extracted with EtOAc. The organic layers were combined, dried, concentrated, and chromatographed using 0-50% EtOAc in heptane to give methyl 2-(2-bromo-3,4-difluorophenyl)acetate (1.62 g, 6.11 mmol, 77% yield) as a colorless oil. m / z (ESI): 265.0 (M+H). + . Step 2: Methyl 2-(2-acetyl-3,4-difluorophenyl)acetate. A microwave vial was charged with methyl 2-(2-bromo-3,4-difluorophenyl)acetate (1.62 g, 6.11 mmol), trifluorotoluene (15 mL), tributyl(1-ethoxyvinyl)stannane (4.41 g, 12.22 mmol), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.86 g, 1.22 mmol). The vial was purged with nitrogen for 2 minutes, sealed, and placed in a microwave reactor at 150 °C for 12 hours. Upon completion, the mixture was filtered through a Celite / silica plug and concentrated. The resulting yellow oil was dissolved in THF (10 mL) and 5 mL of 5 N HCl was added. The reaction was stirred at rt for 30 minutes. Upon completion, the reaction was slowly poured into a separatory funnel containing saturated NaHCO3. The mixture was extracted with EtOAc, dried, concentrated, and chromatographed with 0-30% EtOAc in heptane to give methyl 2-(2-acetyl-3,4-difluorophenyl)acetate (1.21 g, 5.30 mmol, 87% yield) as a colorless oil. m / z (ESI): 229.1 (M+H). + . Step 3: 7,8-Difluoronaphthalene-1,3-diol. To a 250 mL round-bottom flask was added methyl 2-(2-acetyl-3,4-difluorophenyl)acetate (1.21 g, 5.30 mmol), KOtBu (1.79 g, 15.91 mmol), and THF (40 mL). The flask was capped, placed in a preheated aluminum block, and maintained at 80 °C for 3 h. Upon completion, the reaction was diluted with 1 M HCl, extracted with DCM, and dried to give 7,8-difluoronaphthalene-1,3-diol (1.04 g, 5.30 mmol, 100% yield) as a red oil. 197.0 (M+H) + . Step 4: 7,8-Difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-ol. To a 100 mL round-bottom flask was added 7,8-difluoronaphthalene-1,3-diol (0.75 g, 3.82 mmol), DIPEA (2.00 mL, 11.47 mmol), and DCM (38 mL). The solution was cooled to 0 °C, and TIPS-Cl (0.66 g, 0.73 mL, 3.44 mmol) was added. The reaction was allowed to warm to room temperature. Upon completion, the reaction was concentrated and chromatographed with 0 to 30% EtOAc in heptane. The isomers were separated on a silica gel column with 0-30% EtOAc in heptane to give 7,8-difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-ol (0.88 g, 2.51 mmol, 66% yield) (first eluting isomer) as the major product and 5,6-difluoro-4-((triisopropylsilyl)oxy)naphthalen-2-ol (0.18 g, 0.50 mmol, 13% yield) (second eluting isomer) as the minor product. m / z (ESI): 353.2 (M+H). + . Step 5: 7,8-Difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl trifluoromethanesulfonate To a 100 mL round-bottom flask was added 7,8-difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-ol (0.88 g, 2.50 mmol), DIPEA (1.31 mL, 7.51 mmol), and DCM (25 mL). The solution was cooled to 0 °C, and TfO (1 M in DCM, 2.76 mL, 2.76 mmol) was added. The reaction was allowed to warm to rt and stirred for 1 h. Upon completion, the reaction was poured into a separatory funnel containing saturated NaHCO and extracted with DCM. The organics were dried and concentrated to give 7,8-difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl trifluoromethanesulfonate (1.21 g, 2.51 mmol, 100% yield) as an orange oil, which was used in the next step without further purification. m / z (ESI): 485.1 (M+H). + . Step 6: ((5,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)oxy)triisopropylsilane. A 100 mL round-bottom flask was charged with 7,8-difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl trifluoromethanesulfonate (1.21 g, 2.50 mmol), bis(pinacolato)diboron (1.27 g, 4.99 mmol), potassium acetate (0.86 g, 8.74 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.37 g, 0.499 mmol), and toluene (25 mL). The reaction was purged with nitrogen for 5 minutes and then stirred at 80° C. for 12 hours. Upon completion, the reaction was concentrated and chromatographed with a gradient of 0-40% EtOAc in hexanes to give ((5,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)oxy)triisopropylsilane (0.97 g, 2.09 mmol, 84% yield). m / z (ESI): 463.3 (M+H). + .

[0215] 2-(8-ethyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate B) [ka] Step 1: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol. A pressure-release vial was charged with potassium acetate (1.21 g, 12.3 mmol, Sigma Aldrich), 7-fluoro-1-naphthol (1.00 g, 6.17 mmol, Enamine), and dichloro(p-cymene)ruthenium(II) dimer (0.38 g, 0.62 mmol, Alfa Aesar) and then purged with nitrogen gas for 5 minutes. The solid was then suspended in 1,4-dioxane (12 mL) and (bromoethynyl)triisopropylsilane (1.77 g, 1.63 mL, 6.78 mmol, Enamine) was added. The reaction was then stirred at 110 °C for 18 hours, followed by room temperature for 2 days. The volatiles were removed under vacuum, and the crude material was absorbed onto silica gel. The crude product was purified by column chromatography on silica gel, eluting with a gradient of 0-20% EtOAc in heptane to afford 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (1.90 g, 5.55 mmol, 90% yield) as a yellow oil. m / z (ESL, +ve ion: 343.0 (M+H) + . Step 2: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl pivalate. 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (1.00 g, 2.92 mmol) was dissolved in dichloromethane (11 mL) and cooled to 0 °C. DMAP (0.07 g, 0.58 mmol, Sigma-Aldrich Corporation) and TEA (0.89 g, 1.23 mL, 8.76 mmol, Sigma-Aldrich Corporation) were added, followed by the dropwise addition of pivaloyl chloride (1.06 g, 1.08 mL, 8.76 mmol, Sigma-Aldrich Corporation). The mixture was warmed to room temperature and stirred for 45 min. Water (10 mL) was added, and the aqueous layer was extracted with DCM (2 × 10 mL). The combined organic phase was dried over Na2SO4. The volatiles were removed in vacuo and the crude material was purified by column chromatography on silica gel eluting with a gradient of 0-10% EtOAc in heptane to afford 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl pivalate (1.13 g, 2.65 mmol, 91% yield) as a yellow crystalline solid. m / z (ESI, +ve ion): 427.4 (M+H). + . Step 3: 8-Ethyl-7-fluoronaphthalen-1-ol. A centrifugal vial was charged with 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl pivalate (1.13 g, 2.65 mmol) and dissolved in DMF (12 mL). Cesium fluoride (4.02 g, 26.5 mmol, Sigma-Aldrich Corporation) was added, and the mixture was stirred at rt for 30 min. Water (100 mL) was added, and the aqueous phase was extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over NaSO, and the volatiles were then removed in vacuo to yield 8-ethynyl-7-fluoronaphthalen-1-yl pivalate (0.72 g, 2.65 mmol, quantitative yield) as a crude yellow oil, which was used without further purification. 8-Ethynyl-7-fluoronaphthalen-1-yl pivalate (0.72 g, 2.65 mmol) was dissolved in MeOH (9 mL), and palladium on activated carbon (85 mg, 0.795 mmol, Sigma-Aldrich Corporation) was added. The reaction vessel was purged with H and then stirred at room temperature under an H atmosphere (15 psi) for 2 hours. The mixture was filtered over Celite, washed with EtOAc until the filtrate was clear, and the volatiles were removed in vacuo. The crude material was then dissolved in MeOH (10 mL), and potassium hydroxide (0.45 g, 7.95 mmol, VWR International, LLC) was added. After stirring at room temperature for 2 hours, the pH of the solution was adjusted to pH = 3 using 1 M aqueous HCl. Water (20 mL) was added, and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over NaSO, and the volatiles were removed in vacuo. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-20% EtOAc in heptane over three steps to afford 8-ethyl-7-fluoronaphthalen-1-ol (0.35 g, 1.84 mmol, 70% yield) as a yellow oil. m / z (ESI, +ve ion): 191.2 (M+H). + . Step 4: 8-Ethyl-7-fluoronaphthalen-1-yl trifluoromethanesulfonate. 8-Ethyl-7-fluoronaphthalen-1-ol (0.35 g, 1.84 mmol) was dissolved in DCM and cooled to 0 °C. TEA (0.28 g, 0.39 mL, 2.76 mmol, Sigma-Aldrich Corporation) was added, followed by the dropwise addition of 1 M TfO solution (2.02 mL, 2.02 mmol, Sigma-Aldrich Corporation). The mixture was stirred at rt for 20 min and poured into ice-water (20 mL). The aqueous phase was extracted with DCM (2 × 10 mL), and the combined organic layers were dried over NaSO, and the volatiles were removed in vacuo. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0 to 5% EtOAc in heptane to afford 8-ethyl-7-fluoronaphthalen-1-yl trifluoromethanesulfonate (0.47 g, 1.47 mmol, 80% yield) as a colorless oil. 1 H NMR(400MHz,chloroform-d)δ ppm 7.86(dd,J=8.3,0.9Hz,1H),7.79(dd,J=9.4,6.5Hz,1H),7.59(dt,J=7.7,0.8Hz,1H),7.44 (t,J=8.2Hz,1H),7.36(t,J=9.4Hz,1H),3.32(qd,J=7.5,2.9Hz,2H),1.29(t,J=7.4Hz,3H). Step 5: 2-(8-ethyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Potassium acetate (0.43 g, 4.38 mmol, Sigma-Aldrich Corporation) was placed in a pressure-release vial and dried under vacuum. 8-Ethyl-7-fluoronaphthalen-1-yl trifluoromethanesulfonate (0.47 g, 1.46 mmol), bis(pinacolato)diboron (0.74 g, 2.92 mmol, Combi-Blocks Inc.), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.11 g, 0.15 mmol, Sigma-Aldrich Corporation) were then added, and the mixture was stirred at 90 °C for 3 hours and then at room temperature for 12 hours. The volatiles were removed in vacuo and the crude mixture was purified by column chromatography on silica gel, eluting with a gradient of 0-15% EtOAc in heptane to afford 2-(8-ethyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.15 g, 0.50 mmol, 34% yield) as a yellow wax. m / z (ESI, +ve ion): 301.0 (M+H). + .

[0216] 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 C) [ka] Step 1: 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine. To a 250 mL round-bottom flask charged with activated 3 Å 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 blend in heptane to yield 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). + . 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 hour. 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 containing 2% triethylamine additive to yield 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). + . 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 a 0-50% 3:1 EtOAc / EtOH blend in heptane containing 2% triethylamine additive, to yield 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). + . 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)-2-(((2R,7aS)-8-fluoro-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 overnight at rt under an atmosphere of H. 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 brown foam, which was used without further purification. m / z (ESI): 555.0 (M+H). + .

[0217] 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 D) [ka] Step 1: 4-(tert-butoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine. To a stirred mixture of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (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 over 0.5 h. Additional potassium tert-butoxide (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, saturated ammonium hydroxide was added, and the mixture was extracted with 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) + . 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). The 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 afford 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). + . 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 irradiated in a microwave 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 to 50% MeOH in DCM (20% MeOH 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). + . 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 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 rt. The resulting mixture was stirred at rt for 0.5 h. The volatiles were removed under reduced pressure. The crude residue was dissolved in MeOH / DCM, cooled in an ice bath, neutralized with ammonium hydroxide, loaded onto a silica gel precolumn, and purified by column chromatography on silica gel eluting with a gradient of 0-50% MeOH 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). + .

[0218] 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(methylthio)pyrido[4,3-d]pyrimidine (Intermediate E1) [ka] Step 1: 2,7-Dichloro-8-fluoro-4-(methylthio)pyrido[4,3-d]pyrimidine. To a stirred solution of 2,4,7-trichloro-8-fluoropyrido[4.3-d]pyrimidine (3.50 g, 13.86 mmol) in tetrahydrofuran (40 mL) at 0 °C was added sodium methanethiolate (0.97 g, 13.9 mmol) in water (6 mL). The reaction was stirred at 0 °C for 0.5 h, at which time a precipitate formed. The precipitate was collected by filtration to provide 2,7-dichloro-8-fluoro-4-(methylthio)pyrido[4,3-d]pyrimidine (2.10 g, 7.95 mmol, 57% yield) as a white solid. m / z (ESI): 264.0 (M+H). + . Step 2: 7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(methylthio)pyrido[4.3-d]pyrimidine. A mixture of 2,7-dichloro-8-fluoro-4-(methylthio)pyrido[4,3-d]pyrimidine (2.10 g, 7.95 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (1.90 g, 11.93 mmol), and Hunig's base (4.11 g, 5.6 mL, 31.8 mmol) in acetonitrile (25 mL) was stirred at 70° C. for 1.5 hours. The reaction mixture was cooled to rt. The precipitate was collected by filtration and washed with heptane to provide a portion of the desired product. The filtrate was concentrated and purified by column chromatography on silica gel eluting with a gradient of 0-50% (20% MeOH in DCM) in DCM to give another portion of the desired product. The two portions were combined to give 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(methylthio)pyrido[4.3-d]pyrimidine (2.34 g, 6.05 mmol, 76% yield) as an orange solid. m / z (ESI): 387.0 (M+H). + . Step 3: 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(methylthio)pyrido[4.3-d]pyrimidine. A mixture of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(methylthio)pyrido[4,3-d]pyrimidine (2.34 g, 6.05 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborolane (3.27 g, 9.07 mmol), cataCXium A Pd G3 (0.88 g, 1.21 mmol), and tribasic potassium phosphate (3.85 g, 18.15 mmol) was suspended in degassed water (4 mL) and 1,4-dioxane (30 mL). The reaction was stirred at 85 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure and purified twice by column chromatography, eluting first with a gradient of 0-50% (20% MeOH in DCM) in DCM, then with 0-50% 3:1 EtOAc / EtOH in heptane containing 2% triethylamine additive, to provide 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(methylthio)pyrido[4.3-d]pyrimidine (1.50 g, 2.57 mmol, 42% yield) as a yellow solid. m / z (ESI): 585.0 (M+H). + .

[0219] 7-(7,8-Difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(methylthio)pyrido[4,3-d]pyrimidine (Intermediate E2) [ka] Synthesized in a similar manner to intermediate E1. m / z (ESI): 687.0 (M+H) + .

[0220] (2S,4S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluoropyrrolidine (Intermediate F1) [ka] ((2S,4S)-4-Fluoropyrrolidin-2-yl)methanol hydrochloride (0.50 g, 3.20 mmol) was dissolved in DCM (16 mL) followed by the addition of triethylamine (0.49 g, 0.67 mL, 4.80 mmol). The solution was cooled to 0° C. Then, tert-butylchlorodimethylsilane (0.53 g, 3.50 mmol) was added in one portion. The reaction was allowed to warm to rt and subsequently stirred overnight. The crude product was purified by column chromatography on silica gel eluting with a gradient of 0-35% EtOAc in heptane to afford (2S,4S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluoropyrrolidine (0.38 g, 1.60 mmol, 50% yield). m / z (ESI): 234.2 (M+H). + .

[0221] (R)-2-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine (Intermediate F2) [ka] Synthesized from D-prolinol in a manner similar to that of intermediate F1. m / z (ESI): 216.2 (M+H) + .

[0222] 5,5-Dimethylpiperidine-3-carboxamide hydrochloride (Intermediate G1) [ka] Step 1: tert-Butyl 5-carbamoyl-3,3-dimethylpiperidine-1-carboxylate. A solution of 1,1'-carbonyldiimidazole (0.14 g, 0.87 mmol, Acros Organics) in acetonitrile (2.3 mL) was added dropwise to a stirred solution of 1-[(tert-butoxy)carbonyl]-5,5-dimethylpiperidine-3-carboxylic acid (0.21 g, 0.83 mmol, Enamine) in acetonitrile (3.2 mL). The reaction mixture was allowed to stir at rt. After 1 h, ammonium hydroxide (4.20 g, 4.6 mL, 0.12 mol, Fisher Scientific) was added, and the reaction was stirred at the same temperature overnight. The organic solvent was removed under reduced pressure. The remaining solution was then diluted with EtOAc (10 mL), and the organic layer was washed with 10% aqueous citric acid (10 mL), saturated aqueous sodium bicarbonate (10 mL), and brine (10 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide tert-butyl 5-carbamoyl-3,3-dimethylpiperidine-1-carboxylate (0.20 g, 0.77 mmol, 92% yield), which was used directly in the next step without further purification. m / z (ESI): 201.2 (M+H-Bu). + . Step 2: 5,5-Dimethylpiperidine-3-carboxamide hydrochloride. A vial was charged with tert-butyl 5-carbamoyl-3,3-dimethylpiperidine-1-carboxylate (0.20 g, 0.77 mmol) and acetonitrile (20 mL). HCl (4 M in dioxane, 4.8 mL, 19 mmol, Sigma-Aldrich Corporation) was then added, and the reaction was stirred at rt. After 1 h, the reaction was concentrated under reduced pressure to provide 5,5-dimethylpiperidine-3-carboxamide hydrochloride (0.14 g, 0.75 mmol, 97% yield) as a white solid. m / z (ESI): 157.2 (M+H). + .

[0223] rel-(1S,5S)-8-Azabicyclo[3.2.1]octane-2-carboxamide hydrochloride (Intermediate G2) [ka] Synthesized in a manner similar to that of Intermediate G1 using 8-[(tert-butoxy)carbonyl]-8-azabicyclo[3.2.1]octane-2-carboxylic acid (Pharmablock, Inc.). m / z (ESI): 155.2 (M+H). + .

[0224] rel-(1R,5R)-3-azabicyclo[3.2.1]octane-1-carboxamide hydrochloride (Intermediate G3) [ka] Synthesized in a manner similar to Intermediate G1 using 3-[(tert-butoxy)carbonyl]-3-azabicyclo[3.2.1]octane-1-carboxylic acid (Enamine). m / z (ESI): 155.2 (M+H). + .

[0225] 3-Methylazepan-3-ol hydrochloride isomer 1 (intermediate H1) and isomer 2 (intermediate H2) [ka] Step 1: Benzyl 3-hydroxy-3-methylazepane-1-carboxylate. To a 100 mL round-bottom flask were added 3-methylazepan-3-ol hydrochloride (0.25 g, 1.51 mmol, Asta-tech), benzyl chloroformate (0.28 g, 0.24 mL, 1.66 mmol, Oakwood Products, Inc.), DIPEA (0.59 g, 0.8 mL, 4.53 mmol, Sigma-Aldrich Corporation), and THF (5.0 mL). The reaction mixture was stirred at rt overnight. The solution was concentrated in vacuo. The crude material was purified by column chromatography on a silica gel column eluting with a gradient of 0 to 100% EtOAc in hexanes to provide benzyl 3-hydroxy-3-methylazepane-1-carboxylate (0.33 g, 1.25 mmol, 83% yield). m / z (ESI): 264.2 (M+H). + . Step 2: Chiral separation. Benzyl 3-hydroxy-3-methylazepane-1-carboxylate (0.24 g) was purified by SFC using a Chiralpak IG, 21 x 250 mm 5 μm column, with a mobile phase of 20% methanol containing 0.2% triethylamine, at a flow rate of 80 mL / min, to yield 89 mg of peak 1 (ee >99%) and 91 mg of peak 2 (ee >99%). Step 3: 3-Methylazepan-3-ol hydrochloride. Benzyl 3-hydroxy-3-methylazepan-1-carboxylate (89 mg, 0.34 mmol, Peak 1) was dissolved in ethanol (1.7 mL). Palladium on activated carbon (74 mg, 0.07 mmol, Sigma-Aldrich Corporation) and aqueous HCl (1 N, 0.2 mL, 0.42 mmol, Sigma-Aldrich Corporation) were added, and the mixture was stirred at rt under an atmosphere of H2 for 10 h. The catalyst was removed, and the solution was concentrated to provide 3-methylazepan-3-ol hydrochloride (Isomer 1, Intermediate H1, 60 mg, 0.36 mmol). Isomer 2, Intermediate H2, was obtained by the same method. m / z (ESI): 130.2 (M+H). + .

[0226] 1,2,6,7-Tetrahydro-3H-azepin-3-one hydrochloride (Intermediate I) [ka] To a 25 mL round-bottom flask was added tert-butyl 3-oxo-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (0.10 g, 0.47 mmol, AstaTech, Inc.) in acetonitrile (2.4 mL) and HCl in 1,4-dioxane (4 M, 1.2 mL, 4.73 mmol, Sigma-Aldrich). The reaction mixture was stirred at rt overnight. The material was concentrated in vacuo to give a brown oil, which was used in the next step without purification.

[0227] 2,3,6,7-Tetrahydro-1H-azepin-3-ol hydrochloride (Intermediate J) [ka] To a 25 mL round-bottom flask was added tert-butyl 3-oxo-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (75 mg, 0.36 mmol, AstaTech, Inc.) and sodium borohydride (40 mg, 1.07 mmol, Sigma-Aldrich Corporation) in THF (1.8 mL). A small amount of MeOH was added, and the reaction was stirred at rt for 1 h. The reaction mixture was diluted with saturated NH4Cl solution (10 mL) and extracted with EtOAc (2 x 10 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material, which was dissolved in 2 mL of DCM. At 0 °C, 2 mL of TFA was added. The reaction was stirred at rt for 1 h. The mixture was concentrated in vacuo. To the residue, 1 mL of 1 N HCl was added. The mixture was lyophilized to give 2,3,6,7-tetrahydro-1H-azepin-3-ol hydrochloride (60 mg, 0.40 mmol).

[0228] 2,3,6,7-Tetrahydro-1H-azepine hydrochloride (Intermediate K) [ka] To a 25 mL round-bottom flask was added tert-butyl 2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (0.25 g, 1.27 mmol, AstaTech, Inc.) in acetonitrile (3.6 mL). TFA (0.74 g, 0.5 mL, 6.49 mmol, Sigma-Aldrich) was added at 0 °C. The reaction was then stirred at rt for 3 hours and then concentrated in vacuo. To the crude product was added HCl solution (1 N, 2.5 mL, 2.53 mmol, Sigma-Aldrich). The material was lyophilized to give 2,3,6,7-tetrahydro-1H-azepine hydrochloride as an off-white solid, which was used in the next step without any further purification.

[0229] 8-Oxa-3-azabicyclo[3.2.1]octane-6-carbonitrile hydrochloride (Intermediate L1) [ka] Step 1: tert-Butyl 6-carbamoyl-3-azabicyclo[3.2.2]nonane-3-carboxylate. A solution of 1,1'-carbonyldiimidazole e (0.25 g, 1.56 mmol, Acros Organics) in acetonitrile (4.1 mL) was added dropwise to a stirred solution of 3-[(tert-butoxy)carbonyl]-3-azabicyclo[3.2.2]nonane-6-carboxylic acid (0.40 g, 1.49 mmol, Enamine) in acetonitrile (5.8 mL). The reaction mixture was allowed to stir at rt. After 1 h, ammonium hydroxide (7.50 g, 0.22 mol, Fisher Scientific) was added, and the reaction was stirred at the same temperature. After stirring overnight, the organic solvent was removed under reduced pressure, and the reaction mixture was then diluted with EtOAc (10 mL), and the organic layer was washed with 10% aqueous citric acid (10 mL), saturated aqueous sodium bicarbonate (10 mL), and brine (10 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide tert-butyl 6-carbamoyl-3-azabicyclo[3.2.2]nonane-3-carboxylate (0.34 g, 1.26 mmol, 85% yield). m / z (ESI): 213.2 (M+H). + The product was then carried forward without further purification. Step 2: tert-Butyl 6-cyano-3-azabicyclo[3.2.2]nonane-3-carboxylate. To a stirred solution of tert-butyl 6-carbamoyl-3-azabicyclo[3.2.2]nonane-3-carboxylate (0.13 g, 0.47 mmol) in pyridine (1.2 mL) was added 1H-imidazole (63 mg, 0.93 mmol, Sigma-Aldrich). The resulting mixture was cooled to 0 °C, and phosphorus oxychloride (0.29 g, 0.17 mL, 1.86 mmol, Sigma-Aldrich Corporation) was added dropwise slowly, maintaining the mixture at the same temperature. After 1.2 h, the reaction was quenched by adding saturated aqueous ammonium chloride (2 mL), and the aqueous layer was extracted with EtOAc (3 × 3 mL). The combined organic layers were then washed with 10% copper sulfate (2 × 10 mL) and dried over sodium sulfate to provide tert-butyl 6-cyano-3-azabicyclo[3.2.2]nonane-3-carboxylate (94 mg, 0.38 mmol, 81% yield). m / z (ESI): 151.2 (M+H-Boc). + The product was then carried forward without further purification. Step 3: 8-Oxa-3-azabicyclo[3.2.1]octane-6-carbonitrile hydrochloride. tert-Butyl 6-cyano-3-azabicyclo[3.2.2]nonane-3-carboxylate (94 mg, 0.38 mmol) was then dissolved in MeCN (3.5 mL) and HCl in 1,4-dioxane (4 M, 0.47 mL, 1.86 mmol, Sigma-Aldrich Corporation) was added. The reaction was then stirred at rt for 15 minutes. The reaction was then concentrated under reduced pressure to provide 3-azabicyclo[3.2.2]nonane-6-carbonitrile hydrochloride (71 mg, 0.38 mmol, 82% yield) as an off-white solid. The product was carried forward without further purification. m / z (ESI): 151.2 (M+H). + .

[0230] 3-Azabicyclo[3.2.1]octane-6-carbonitrile hydrochloride (intermediate L2) [ka] Synthesized in a manner similar to intermediate L1 using 3-[(tert-butoxy)carbonyl]-3-azabicyclo[3.2.1]octane-6-carboxylic acid (CAS#: 2287288-75-7, Enamine). m / z (ESI): 137.1 (M+H). + .

[0231] (1S,5R)-2-Methyl-8-azabicyclo[3.2.1]octan-2-ol 2,2,2-trifluoroacetate (Intermediate M1) [ka] A round-bottom flask was charged with tert-butyl (1S,5R)-2-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (0.50 g, 2.22 mmol, PharmaBlock) and THF (12 mL). The mixture was cooled to -78 °C and MeMgBr (1.5 mL, 4.44 mmol) was added. The mixture was allowed to warm to rt. Upon completion, the reaction was quenched with brine and extracted with EtOAc. The organic layer was dried and concentrated to give tert-butyl (1S,5R)-2-hydroxy-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate as a colorless oil, which was dissolved in DCM (3 mL) and TFA (0.5 mL, 6.67 mmol). The mixture was stirred at rt. Upon completion, the reaction was concentrated in vacuo to give (1S,5R)-2-methyl-8-azabicyclo[3.2.1]octan-2-ol 2,2,2-trifluoroacetate (0.31 g, 2.22 mmol, 100% yield), which was used in the next step without further manipulation. m / z (ESI): 142.1 (M+H). + .

[0232] 6-Methyl-2-azabicyclo[2.2.1]heptan-6-ol 2,2,2-trifluoroacetate (Intermediate M2) [ka] Synthesized in a manner similar to intermediate M1 using tert-butyl 6-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate (Enamine). m / z (ESI): 128.1 (M+H). + .

[0233] 2-Azabicyclo[2.2.1]heptan-6-one hydrochloride (Intermediate N) [ka] A round-bottom flask was charged with tert-butyl 6-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate (0.50 g, 2.37 mmol, Enamine) and 1,4-dioxane (11 mL). The mixture was cooled to -78 °C, and HCl (4 M in dioxane, 1.78 mL, 7.10 mmol) was added. The mixture was allowed to stir at rt. Upon completion, the reaction was concentrated in vacuo to afford 2-azabicyclo[2.2.1]heptan-6-one hydrochloride (0.26 g, 2.37 mmol, 100% yield) as a white solid, which was used in the next step without further purification. m / z (ESI): 112.1 (M+H). +

[0234] 2-(8-chloro-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate O) [ka] Step 1: (E)-5-chloro-6-fluoro-3,4-dihydronaphthalen-1(2H)-one oxime. To a solution of 5-chloro-6-fluoro-3,4-dihydronaphthalen-1(2H)-one (0.40 kg, 2.01 mol) in EtOH (2.4 L) and HO (0.8 L) was added NaOAc (0.25 kg, 3.02 mol) and NHOH·HCl (0.21 kg, 3.02 mol). The reaction was stirred at 25 °C for 12 h. Four reactions were run in parallel and combined. The mixture was poured onto ice and then extracted with EtOAc (3 L × 3). The combined organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (E)-5-chloro-6-fluoro-3,4-dihydronaphthalen-1(2H)-one oxime (1.60 kg, 83% yield, 88.9% purity) as a yellow solid. 1 H NMR:(400MHz,CDCl3)δ 7.81-7.78(m,1H),7.01(t,J=8.4Hz,1H),2.89-2.86(m,2H),2.82-2.79(m,2H),1.94-1.87(m,1H). Step 2: 5-Chloro-6-fluoronaphthalen-1-amine. To a solution of E)-5-chloro-6-fluoro-3,4-dihydronaphthalen-1(2H)-one oxime (0.26 kg, 1.22 mol) in AcOH (1.6 L) was added H2SO4 (0.36 kg, 3.65 mol, 0.2 L) and AcO (0.25 kg, 2.43 mol, 0.2 mL). The mixture was stirred at 90 °C for 2 h. Six reactions were run in parallel and combined. The mixture was then acidified with aqueous NaOH (15 L) to pH = 13 and extracted with EtOAc (5 L × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (0.1% HCl condition) to give 5-chloro-6-fluoronaphthalen-1-amine (0.35 kg, 24% yield, 99.5% purity) as a red solid. 1H NMR:(400MHz,CDCl3)δ 7.69-7.66(m,1H),7.61(d,J=8.4Hz,1H),7.37-7.33(m,1H),7.21-7.17(m,1H),6.72(d,J=7.6Hz,1H),4.11(s,2H). Step 3: 2,4-Dibromo-5-chloro-6-fluoronaphthalen-1-amine hydrobromide. A solution of 5-chloro-6-fluoronaphthalen-1-amine (93 g, 0.48 mol) in AcOH (0.65 L) was cooled to 0 °C, and then Br2 (0.30 kg, 1.90 mol, 98 mL) was added. The mixture was stirred at 25 °C for 12 h. Three reactions were run in parallel and combined. The mixture was filtered, and the filter cake was washed with MTBE / MeCN (3 / 1) (800 mL) to give 2,4-dibromo-5-chloro-6-fluoronaphthalen-1-amine hydrobromide (0.27 kg, 54% yield) as a brown solid. Step 4: 5-Bromo-6-chloro-7-fluoronaphtho[1,2-d][1,2,3]oxadiazole. A solution of 2,4-dibromo-5-chloro-6-fluoronaphthalen-1-amine hydrobromide (0.15 kg, 0.34 mol) in AcOH (0.90 L) and propionic acid (0.37 L) was cooled to 0 °C, and then NaNO (27 g, 0.39 mol) was added. The mixture was stirred at 25 °C for 2 h. Two reactions were run in parallel and combined. The reaction mixture was quenched at 20 °C by the addition of HO (2.0 L), then filtered, and the filter cake was concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE (500 mL x 2) at 25°C for 30 minutes to give 5-bromo-6-chloro-7-fluoronaphtho[1,2-d][1,2,3]oxadiazole (0.16 kg, 65% yield, 84% purity) as a brown solid. 1 H NMR:(400MHz DMSO-d6)δ 7.76-7.72(m,2H),7.34(s,1H). Step 5: 4-Bromo-5-chloro-6-fluoronaphthalen-2-ol. A solution of 5-bromo-6-chloro-7-fluoronaphtho[1,2-d][1,2,3]oxadiazole (80 g, 0.27 mol) in EtOH (0.40 L) and THF (0.16 L) was cooled to 0 °C, and then NaBH (20 g, 0.53 mol) was added. The mixture was stirred at 0 °C for 1.5 h. Two reactions were run in parallel and combined. The reaction mixture was quenched by adding NH Cl (1.0 L) at 0 °C and then extracted with EtOAc (0.5 mL × 2). The combined organic layers were washed with brine (0.5 L), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel eluting with a gradient of 1:0 to 0:1 petroleum ether / EtOAc to give 4-bromo-5-chloro-6-fluoronaphthalen-2-ol (61 g, 42% yield) as a brown solid. 1 H NMR:(400MHz DMSO-d6)δ 10.34(s,1H),7.88-7.84(m,1H),7.61(s,1H),7.57(t,J=9.2Hz,1H),7.31(s,1H). Step 6: 8-Bromo-1-chloro-2-fluoro-6-(methoxymethoxy)naphthalene. A solution of 4-bromo-5-chloro-6-fluoronaphthalen-2-ol (55 g, 0.20 mol) and DIPEA (77 g, 0.10 L, 0.60 mol) in DCM (0.33 L) was cooled to 0 °C, and then MOMCl (32 g, 30 mL, 0.40 mol) was added dropwise to the mixture. The solution was warmed to 25 °C and stirred for 12 h. The reaction mixture was quenched at 25 °C by adding saturated NaHCHO (100 mL aqueous solution), then diluted with DCM (500 mL), washed with HO (200 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with a gradient of 20:1 to 1:1 petroleum ether / EtOAc to give 8-bromo-1-chloro-2-fluoro-6-(methoxymethoxy)naphthalene (50 g, 73% yield, 93% purity) as a brown solid. Step 7: 2-(8-chloro-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A mixture of B2pin2 (62 g, 0.24 mol), 8-bromo-1-chloro-2-fluoro-6-(methoxymethoxy)naphthalene (26 g, 81 mmol), Pd(dppf)Cl2 (6.0 g, 8.14 mmol), and KOAc (20 g, 0.20 mol) in DMF (0.15 L) was degassed and purged with N2 three times, and then the mixture was stirred at 110 °C under a N2 atmosphere for 8 h. Two reactions were run in parallel and combined. The reaction mixture was diluted with EtOAc (500 mL) and washed with brine (500 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of 100:1 to 1:1 petroleum ether / EtOAc. The crude product was repurified by reverse-phase HPLC (neutral) to give 2-(8-chloro-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50.0 g) as a white solid (38 g, 76% yield, 99% purity). 1 H NMR:(400MHz CDCl3)δ 7.57-7.54(m,1H),7.32(s,2H),7.28-7.22(m,1H),5.20(s,2H),3.42(s,3H),1.37(s,12H).

[0235] (3R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (Intermediate P) [ka] Step 1. (R)-1-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol. To a mixture of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (25 g, 99 mmol, Wu Xi) in acetonitrile (500 mL) was added DIPEA (86 mL, 495 mmol) and (R)-3-methylpiperidin-3-ol hydrochloride (15 g, 99 mmol). The mixture was stirred at 0 °C under N for 0.5 h. The reaction mixture was diluted with water (1 L) and extracted with EtOAc (0.9 L × 3). The combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (28 g, 85 mmol, 85% yield) as a yellow solid. Step 2: (R)-1-(7-chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol. To a solution of (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (20 g, 60.4 mmol) in dimethyl sulfoxide (300 mL) was added potassium fluoride (35 g, 604 mmol). The mixture was stirred at 80° C. for 12 hours. The reaction mixture was partitioned between EtOAc (2000 mL) and water (500 mL). The mixture was extracted with EtOAc (500 mL × 3). The organic phase was separated, washed with brine (500 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was diluted with the mixture (petroleum ether: EtOAc = 20:1, 150 mL). The suspension was stirred at 20 °C for 1 hour. Then, the mixture was filtered through a fixed funnel. The filter cake was washed with MTBE (50 mL × 2) and concentrated under reduced pressure to give (R)-1-(7-chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (15 g, 47.8 mmol, 79% yield) as a yellow solid. m / z (ESI): 315.1, 317.1 (M+H). + . Step 3: (R)-1-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol. To a mixture of (R)-1-(7-chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (15 g, 47.7 mmol) in tetrahydrofuran (200 mL) was added sodium thiomethoxide (17 g, 47.7 mmol, 20% in HO) dropwise at 0° C. The mixture was stirred at 20° C. for 2 hours, diluted with HO (100 mL) and EtOAc (200 mL), and extracted with EtOAc (200 mL × 2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was triturated with a mixed solvent (petroleum ether: EtOAc = 20:1, 500 mL) at 20 °C for 1 hour. The suspension was filtered through a stationary funnel, and the filter cake was washed with petroleum ether: EtOAc = 20:1, 15 mL × 2. The filtrate was concentrated under reduced pressure to give (R)-1-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (15 g, 43 mmol, 90% yield) as a yellow solid. Step 4: (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol. A mixture of (R)-1-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (9.0 g, 26.3 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11 g, 31.5 mmol, Wu Xi), and cesium carbonate (17 g, 52.5 mmol) in 1,4-dioxane (170 mL) and water (15 mL) was degassed and purged with N three times. CataCXium A Pd G (1.8 g, 2.63 mmol) was then added to the mixture, and the reaction was stirred at 100 °C under N for 8 h. The reaction mixture was diluted with EtOAc (200 mL) and water (200 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (400 mL × 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (7.7 g, 14.3 mmol, 54% yield) as a white solid. (ESI): 541.3, 542.3 (M+H) + . Step 5: (3R)-1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol. To a mixture of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (7.0 g, 13.0 mmol) in dichloromethane (100 mL) was added m-CPBA (2.6 g, 13.0 mmol, 85% purity) in several portions at 0° C. The mixture was then stirred at 0° C. for 1 hour. The crude product was directly purified by column chromatography (SiO, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give (3R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (5.0 g, 8.99 mmol, 69% yield) as a yellow solid. m / z (ESI): 557.1 (M+H). + .

[0236] (R)-3-(methyl-d3)piperidin-3-ol and (S)-3-(methyl-d3)piperidin-3-ol (Intermediates Q1 and Q2) [ka] Step 1. (R)-3-(methyl-d3)piperidin-3-ol and (S)-3-(methyl-d3)piperidin-3-ol. A solution of 1-benzylpiperidin-3-one hydrochloride (3.0 g, 13.3 mmol, AA Blocks) in water (20 mL) was neutralized with potassium carbonate and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was redissolved in tetrahydrofuran (66 mL) and cooled to −78° C. To the reaction was added dropwise a solution of methyl-d3-magnesium iodide (14.6 mL, 14.6 mmol, Sigma-Aldrich Corporation). The reaction was stirred at −78° C. After 30 minutes, the reaction was quenched with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, and the organic layer was concentrated. The crude product was purified by RP-MPLC chromatography eluting with 0–50% (ACN / 0.1% TFA) in (water / 0.1% TFA). Product fractions were combined, frozen, and lyophilized. The residue was redissolved in ethyl acetate, washed with aqueous potassium carbonate, and concentrated to provide 1-benzyl-3-(methyl-d3)piperidin-3-ol (1.6 g, 7.44 mmol, 56% yield) as a colorless oil. The racemic mixture was purified by SFC using a Chiralpak AD (21 × 250 mm 5 μm) column with a mobile phase of 10% methanol containing 2% diethylamine at a flow rate of 120 mL / min to provide two products. The first eluted product (242 mg, 1.16 mmol, 8.7% yield, ee: >99%) was assigned to the R stereochemistry. The second eluting product (227 mg, 1.09 mmol, 8.2% yield, ee: >90%) was assigned to S stereochemistry. Step 2. (R)-3-(methyl-d3)piperidin-3-ol and (S)-3-(methyl-d3)piperidin-3-ol. A solution of either (R)-1-benzyl-3-(methyl-d3)piperidin-3-ol (0.24 g, 1.16 mmol) or (S)-1-benzyl-3-(methyl-d3)piperidin-3-ol (0.23 g, 1.09 mmol) in ethanol (6.0 mL) was stirred under a hydrogen atmosphere (25 psi). After 2 hours, the reaction mixture was filtered through Celite and concentrated in vacuo to provide the title compound as a colorless oil. The isolated product was used in the next reaction without further purification, and quantitative yield was assumed.

[0237] 5-Ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydronaphthalen-2-yl pivalate (Intermediate R) [ka] Step 1. 8-Bromo-1-ethyl-1,2,3,4-tetrahydronaphthalen-1-ol. To a 50 mL round-bottom flask were added 8-bromo-3,4-dihydronaphthalen-1(2H)-one (0.72 g, 3.20 mmol, Ambeed, Inc.) and lanthanum(III) chloride bis(lithium chloride) complex solution, 0.6 M in THF (5.3 mL, 3.2 mmol, Sigma-Aldrich Corporation) in THF (13 mL). At 0 °C, 3.0 M ethylmagnesium bromide in diethyl ether (1.3 mL, 3.84 mmol) was added, and the reaction mixture was stirred for 1 h. The reaction mixture was then diluted with saturated NH4Cl solution (10 mL) and extracted with EtOAc (2 × 10 mL). The organic extract was washed with saturated NaCl solution (20 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material, which was absorbed onto a plug of silica gel and purified by column chromatography on silica gel eluting with a gradient of 0 to 50% EtOAc in heptane to provide 8-bromo-1-ethyl-1,2,3,4-tetrahydronaphthalen-1-ol (0.71 g, 2.78 mmol, 87% yield) as a yellow oil. m / z (ESI): 237.2 (M+H-HO). + . Step 2. 8-Bromo-1-ethyl-1,2,3,4-tetrahydronaphthalene. To a 25 mL round-bottom flask was added 8-bromo-1-ethyl-1,2,3,4-tetrahydronaphthalen-1-ol (0.48 g, 1.88 mmol) in DCM (7.5 mL). After cooling to -30 °C, triethylsilane (1.09 g, 9.41 mmol) was added, followed by the dropwise addition of TFA (0.64 g, 0.44 mL, 5.6 mmol). The reaction mixture was stirred for 3 h while slowly warming to rt. The reaction mixture was diluted with water (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, which was absorbed onto a plug of silica gel and purified by column chromatography on silica gel eluting with a gradient of 0-20% EtOAc in heptane to provide 8-bromo-1-ethyl-1,2,3,4-tetrahydronaphthalene (0.39 g, 1.63 mmol, 87% yield) as a colorless oil. m / z (ESI): 237.2 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ ppm 7.35-7.48(m,1H),7.29-7.58(m,2H),2.64-2.89(m,3H),1.84-2.04(m,1H),1.52-1.85(m,4H),1.30-1.45(m,1H),0.95 - 1.05(m,3H). Step 3. 2-(4-Bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A 20 mL vial was charged with 8-bromo-1-ethyl-1,2,3,4-tetrahydronaphthalene (0.21 g, 0.88 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.28 g, 319 µL, 2.2 mmol, Sigma-Aldrich Corporation), 4,4'-di-tert-butyl-2,2'-dipyridyl (28 mg, 0.11 mmol), and di-µ-methoxobis(1,5-cyclooctadiene)diiridium(I) (58 mg, 0.088 mmol, Sigma-Aldrich Corporation). The reaction was purged with nitrogen for 5 minutes and then stirred for 3 hours at 65° C. The reaction mixture was concentrated, and the crude material was absorbed onto a plug of silica gel and purified by column chromatography on silica gel eluting with a gradient of 0 to 70% EtOAc in hexanes to provide 2-(4-bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.20 g, 0.55 mmol, 62% yield) as a colorless oil. Step 4. 4-Bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol. To a 50 mL round-bottom flask was added 2-(4-bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.20 g, 0.55 mmol) in tetrahydrofuran (1.6 mL) and water (0.6 mL). After cooling to 0 °C, hydrogen peroxide (0.56 g, 0.5 mL, 4.93 mmol) was added slowly, followed by the dropwise addition of acetic acid (1.65 g, 1.6 mL, 27.4 mmol). The reaction mixture was stirred for 3 h, then diluted with saturated NaSO solution (15 mL) and extracted with EtOAc (2 × 15 mL). The combined organic layers were dried (NaSO) and concentrated. The crude material was absorbed onto a plug of silica gel and purified by column chromatography on silica gel eluting with a gradient of 0-50% EtOAc in hexanes to provide 4-bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol as an oil (0.120 g, 0.47 mmol, 86% yield). m / z (ESI): 255.0 (M+H). + . Step 5. 4-Bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-yl pivalate. To a 50 mL round-bottom flask were added 4-bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol (0.12 g, 0.47 mmol) and triethylamine (0.16 mL, 0.94 mmol) in tetrahydrofuran (2.4 mL). After cooling to 0 °C, 2,2-dimethylpropionyl chloride (87 μL, 0.71 mmol) was slowly added. The reaction mixture was stirred for 1 h, and the crude material was absorbed onto a plug of silica gel and purified by column chromatography on silica gel, eluting with a gradient of 0 to 25% EtOAc in hexanes, to provide 4-bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-yl pivalate (0.12 g, 0.35 mmol, 75% yield) as an oil. Step 6. 5-Ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydronaphthalen-2-yl pivalate. A 20 mL vial was charged with 4-bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-yl pivalate (0.12 g, 0.35 mmol), bis(pinacarato)diboron (54 mg, 0.21 mmol), potassium acetate (0.10 g, 1.06 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride (26 mg, 0.035 mmol) in toluene (2.4 mL). The reaction mixture was purged with nitrogen for 5 minutes and then stirred at 90 °C for 3 hours. The crude material was absorbed onto a plug of silica gel and purified by column chromatography on silica gel eluting with a gradient of 0-60% EtOAc in hexanes to provide 5-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydronaphthalen-2-yl pivalate as an oil. m / z (ESI): 387.1 (M+H). + .

[0238] 5-Allyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydronaphthalen-2-yl pivalate (Intermediate S) [ka] The intermediate was synthesized in a similar manner to intermediate R, using 8-bromo-3,4-dihydro-2h-naphthalen-1-one (CAS#: 651735-60-3, Aurum Pharmatech LLC), performing steps 3, 4, and 5 before step 1 (using allylzinc bromide at 0.5 M in THF), and performing step 2. 5-Allyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydronaphthalen-2-yl pivalate was purified as an oil. m / z (ESI): 399.2 (M+H). + .

[0239] (R)-1-(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)piperidine-3-sulfonamide (Example 1) [ka] Step 1: (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide. To a 40 mL vial was added 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (0.10 g, 0.40 mmol, WuXi) and DCM (4.0 mL). The mixture was cooled to -40 °C, and then DIPEA (0.21 g, 0.28 mL, 1.58 mmol, Sigma-Aldrich) and (3R)-piperidine-3-sulfonamide hydrochloride (87 mg, 0.44 mmol, Enamine) were added. The reaction was then stirred at this temperature for 2 hours. The reaction was then diluted with water (10 mL) and DCM (10 mL). The mixture was transferred to a separatory funnel. The layers were separated, and the aqueous layer was extracted with DCM (3 x 10 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a crude orange oil. The crude residue was purified by column chromatography using a gradient of 0-50% 3:1 EtOAc / EtOH (containing 2% triethylamine) in heptane to provide (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide (95 mg, 0.25 mmol, 63% yield) as a white solid. m / z (ESI): 379.8 (M+H). + . Step 2: (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide. To a 20 mL vial was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (52 mg, 0.32 mmol, LabNetwork), DIPEA (0.13 g, 0.17 mL, 1.00 mmol, Sigma-Aldrich), 4 Å molecular sieves (100 mg), (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide (95 mg, 0.25 mmol), and acetonitrile (0.8 mL). The reaction was stirred at 75 °C overnight. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-75% 3:1 EtOAc / EtOH (containing 2% triethylamine) in heptane to provide (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide (71 mg, 0.14 mmol, 57% yield) as a yellow solid. m / z (ESI): 503.0 (M+H). + . Step 3: (R)-1-(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)piperidine-3-sulfonamide. A 1-dram vial was charged with (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide (50 mg, 0.10 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (54 mg, 0.15 mmol, WuXi), potassium phosphate (63 mg, 0.30 mmol, Sigma Aldrich Corporation), and cataCXium A Pd G3 (15 mg, 0.02 mmol, Sigma Aldrich Corporation). The vial was purged with nitrogen, and the reaction was suspended in degassed tetrahydrofuran (0.9 mL) and water (90 μL). The reaction was then sealed and heated to 70° C. for 12 hours. The reaction was concentrated under reduced pressure to provide a black oil. The black oil was then purified by column chromatography on silica gel, eluting with a gradient of 0 to 100% 3:1 EtOAc / EtOH (containing 2% triethylamine) in heptane to provide (R)-1-(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)piperidine-3-sulfonamide (33 mg, 0.05 mmol, 48% yield) as a gray solid. m / z(ESI):701.0(M+H) + . Step 4: (R)-1-(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)piperidine-3-sulfonamide. A vial was charged with R)-1-(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)piperidine-3-sulfonamide (33 mg, 0.05 mmol) and acetonitrile (1.5 mL). HCl (4 M in 1,4-dioxane, 0.3 mL, 1.18 mmol, Sigma-Aldrich Corporation) was added, and the reaction was stirred at room temperature for 15 minutes. The reaction was then concentrated under reduced pressure and purified by reverse-phase HPLC to provide (R)-1-(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)piperidine-3-sulfonamide as the bis(2,2,2-trifluoroacetate) and as a yellow solid (20 mg, 0.02 mmol, 47% yield). m / z (ESI): 657.2 (M+H). + . 1 H NMR (400MHz, methanol-d4) δ ppm 9.20(s,1H)7.66-7.75(m,1H)7.34(d,J=2.49Hz,1H)7.28(s,1H)7.07(s,1H)5.51-5.72(m,1H)5.01(br s,2H)4.67-4.82(m,1H)4.51-4.65(m,1H)3.75-4.16(m,5H)3.43-3.59(m,2H)2 .55-2.86(m,2H)2.33-2.55(m,5H)2.01-2.27(m,4H)1.78-1.91(m,1H)0.82(br d, J = 10.16 Hz, 3H).

[0240] [Table 5]

[0241]

Table 6

[0242]

Table 7

[0243]

Table 8

[0244]

Table 9

[0245] Table 10

[0246] Table 11

[0247] Table 12

[0248] Table 13

[0249]

Table 14

[0250]

Table 15

[0251] Table 16

[0252] Table 17

[0253] Table 18

[0254] Table 19

[0255] Table 20

[0256] Table 21

[0257] Table 22

[0258] Table 23

[0259] Table 24

[0260] Table 25

[0261] [Table 26]

[0262] Additional steps for Example 15 [ka] To a 20 mL vial was added 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (0.10 g, 0.16 mmol, synthesized in a manner similar to Example 1) and sodium hydride (19 mg, 0.47 mmol, TCI America) in tetrahydrofuran (1.6 mL) at 0 °C. The reaction was stirred at 0 °C for 20 min. Iodomethane (45 mg, 0.02 mL, 0.31 mmol, Sigma-Aldrich Corporation) was then added and the reaction was allowed to warm to rt for 2 h. The reaction mixture was diluted with water and extracted with CHCl. ​​The organic extract was dried over MgSO. The solution was filtered and concentrated in vacuo to give the crude material as a pale yellow solid. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0 to 100% EtOAc in heptane to provide 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-methoxypiperidin-1-yl)pyrido[4,3-d]pyrimidine as a pale yellow solid. m / z(ESI): 652.3 (M+H) + .

[0263] Additional steps for Example 27 [ka] To a solution of 3-(8-fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (0.15 g, 0.19 mmol) in N,N-dimethylformamide (1.9 mL) was added cesium fluoride (0.25 g, 1.61 mmol, Sigma-Aldrich Corporation). The reaction mixture was stirred at rt for 2 days. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was back-extracted with EtOAc, and the combined organics were dried over NaSO and concentrated under reduced pressure. The crude material was purified by reverse-phase HPLC to provide 3-(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)-3-azabicyclo[3.2.1]octan-6-ol as the 2,2,2-trifluoroacetate and as an off-white solid (70 mg, 0.10 mmol, 50% yield).

[0264] [Table 27]

[0265] [Table 28]

[0266] [Table 29]

[0267] [Table 30]

[0268] [Table 31]

[0269] [Table 32]

[0270] [Table 33]

[0271] [Table 34]

[0272] 1-(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)-5,5-dimethylpiperidine-3-carboxamide (Example 43) [ka] Step 1: 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-dimethylpiperidine-3-carboxamide. To a suspension of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (0.10 g, 0.40 mmol, LabNetwork) in acetonitrile (2.0 mL) at 0 °C, 5,5-dimethylpiperidine-3-carboxamide hydrochloride (80 mg, 0.42 mmol, Intermediate G1) and DIPEA (0.21 mg, 0.28 mL, 1.58 mmol, Aldrich) were added. The reaction was stirred at 0 °C. Separately, a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (0.11 g, 0.71 mmol, Labnetwork) in acetonitrile (1.0 mL) was dried over anhydrous magnesium sulfate. The mixture was stirred at rt for 5 minutes and then filtered through Celite to remove the magnesium sulfate. After 20 minutes, (1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-5,5-dimethylpiperidine-3-carboxamide) was observed. The two mixtures were combined and the reaction was stirred at 80° C. overnight. The reaction was cooled to rt and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0 to 100% 3:1 EtOAc / EtOH (containing 2% triethylamine) in heptane to provide 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-dimethylpiperidine-3-carboxamide (0.12 g, 0.24 mmol, 61% yield) as an orange solid. m / z (ESI): 495.0 (M+H). + . Step 2: 1-(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)-5,5-dimethylpiperidine-3-carboxamide. A 1-dram vial was charged with 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-dimethylpiperidine-3-carboxamide (50 mg, 0.10 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (55 mg, 0.15 mmol, PharmaBlock), potassium phosphate (64 mg, 0.30 mmol, Sigma Aldrich Corporation), and cataCXium A Pd G3 (15 mg, 0.02 mmol, Sigma Aldrich Corporation). The vial was purged with nitrogen and the reaction was suspended in degassed tetrahydrofuran (0.9 mL) and water (0.09 mL). The reaction was then sealed and stirred at 65° C. overnight. The reaction was then cooled to rt and concentrated under reduced pressure to provide a crude black oil. The oil was then purified by column chromatography on silica gel eluting with a gradient of 0 to 100% 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane to provide 1-(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)-5,5-dimethylpiperidine-3-carboxamide (60 mg, 0.09 mmol, 85% yield) as an off-white solid. m / z (ESI): 693.2 (M+H). + . Step 3: 1-(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)-5,5-dimethylpiperidine-3-carboxamide. 1-(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)-5,5-dimethylpiperidine-3-carboxamide (60 mg, 0.09 mmol) was dissolved in MeCN (3.1 mL) and HCl (4 M in 1,4-dioxane, 0.6 mL, 2.53 mmol, Sigma-Aldrich Corporation). The reaction was stirred at rt for 3 h, then cooled to rt and concentrated under reduced pressure to provide a crude orange oil. The oil was then purified by reverse-phase HPLC to provide the 2,2,2-trifluoroacetate of 1-(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)-5,5-dimethylpiperidine-3-carboxamide (38 mg, 0.05 mmol, 49% yield) as a pale yellow solid. m / z (ESI): 649.2 (M+H). + . 1H NMR(400MHz,メタノール-d4)δ ppm 9.19(s,1H),7.65-7.75(m,1H),7.31-7.36(m,1H),7.23-7.30(m,1H),7.04-7.13(m, 1H),5.49-5.71(m,1H),4.65-4.77(m,3H),4.36-4.49(m,1H),3.82-4.12(m,3H),3.35 -3.54(m,3H),2.98-3.14(m,1H),2.54-2.86(m,2H),2.32-2.53(m,4H),2.14-2.30(m ,2H),1.73-1.95(m,2H),1.12(d,J=4.0Hz,3H),0.96-1.09(m,3H),0.73-0.87(m,3H).

[0273] Table 35

[0274] Table 36

[0275] Table 37

[0276] Table 38

[0277] Table 39

[0278] Table 40

[0279] Table 41

[0280] [Table 42]

[0281] [Table 43]

[0282] [Table 44]

[0283] [Table 45]

[0284] [Table 46]

[0285] [Table 47]

[0286] [Table 48]

[0287] Additional steps for Example 44 [ka] To a stirred solution of tert-butyl ((R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)carbamate (0.27 g, 0.50 mmol, synthesized in a manner similar to Example 1) in DCM (2.0 mL) was added trifluoroacetic acid (1.50 g, 1.0 mL, 13.42 mmol, Sigma-Aldrich Corporation). The resulting mixture was stirred at rt for 1 h and then concentrated under reduced pressure. The residue was diluted with DCM and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over Na2SO4 and evaporated to afford the product, which was used directly in the next step. m / z (ESI, +ve ion): 439.0 (M+H). + .

[0288] N-((R)-1-(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)piperidin-3-yl)acetamide (Example 73) [ka] Step 1: N-((R)-1-(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)piperidin-3-yl)acetamide. To a solution of (R)-1-(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)piperidin-3-amine (35 mg, 0.06 mmol, prepared according to Example 44) in DCM (0.5 mL) was added DIPEA (21 mg, 0.03 mL, 0.17 mmol, Sigma-Aldrich Corporation), followed by acetyl chloride (5.2 mg, 4.7 μL, 0.07 mmol, Sigma-Aldrich Corporation). The reaction mixture was stirred at rt for 15 minutes. The reaction mixture was concentrated under reduced pressure and purified by reverse-phase HPLC to provide N-((R)-1-(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)piperidin-3-yl)acetamide (25 mg, 0.04 mmol, 67% yield) as a yellow solid. m / z (ESI, +ve ion) 679.2 (M+H) + . Step 2: N-((R)-1-(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)piperidin-3-yl)acetamide. N-((R)-1-(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)piperidin-3-yl)acetamide (25 mg, 0.04 mmol) was dissolved in acetonitrile (0.5 mL), HCl (4 M in dioxane, 13 mg, 0.01 mL, 0.37 mmol, Sigma-Aldrich Corporation) was added, and the reaction mixture was stirred at rt for 0.5 h. The reaction mixture was purified by reverse-phase HPLC to provide the bis(2,2,2-trifluoroacetate) of N-((R)-1-(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)piperidin-3-yl)acetamide (18 mg, 0.02 mmol, 38% yield) as a yellow solid. m / z (ESI, +ve ion): 635.2 (M+H). + . 1H NMR(400MHz,メタノール-d4)δ ppm 9.25(d,J=2.7Hz,1H),7.70(dd,J=9.0,5.9Hz,1H),7.34(d,J=2.7Hz,1H),7.28(t,J=9.4Hz,1H),7.09(dd ,J=7.6,2.6Hz,1H),5.46-5.72(m,1H),4.81-4.91(m,1H),4.69-4.77(m,2H),4.61-4.68(m,1H),4.55(br d,J=13.0Hz,1H),3.85-4.12(m,4H),3.67-3.76(m,1H),3.35-3.53(m,2H),2.55-2.85(m,2H), 2.32-2.53(m,4H),2.16-2.28(m,2H),1.95-2.13(m,4H),1.72-1.88(m,2H),0.78-0.86(m,3H).

[0289] Table 49

[0290]

Table 50

[0291] Table 51

[0292] Table 52

[0293] Table 53

[0294] Table 54

[0295] Table 55

[0296] [Table 56]

[0297] [Table 57]

[0298] [Table 58]

[0299] [Table 59]

[0300] 1-(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-methylpiperidine-3-sulfonamide (Example 79) [ka] Step 1: 1-(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)-N-methylpiperidine-3-sulfonamide. An 8 mL vial was charged with 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 (40 mg, 0.072 mmol), N,N-diisopropylethylamine (46 mg, 0.06 mL, 0.36 mmol), and N,N-dimethylacetamide (0.4 mL). The solution was stirred at rt for 10 min, after which HATU (0.11 g, 0.29 mmol) was added. After 10 min, a solution of N-methylpiperidine-3-sulfonamide (13 mg, 0.072 mmol, Enamine) in DMA was added to the vial, and the reaction was stirred at rt for 30 min. The mixture was purified by column chromatography on silica gel eluting with 0-50% 3:1 EtOAc / EtOH blend in heptane containing 2% triethylamine additive to yield 1-(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)-N-methylpiperidine-3-sulfonamide (47 mg, 0.066 mmol, 91% yield). m / z (ESI): 715.2 (M+H). + . Step 2: 1-(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-methylpiperidine-3-sulfonamide. 1-(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)-N-methylpiperidine-3-sulfonamide (47 mg, 0.066 mmol) was stirred in methanol (0.3 mL) and hydrogen chloride (4.0 M in dioxane, 0.3 mL, 1.32 mmol) at rt for 1 h. The volatiles were removed under reduced pressure. The crude product was purified by reverse-phase HPLC to yield 1-(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-methylpiperidine-3-sulfonamide as its TFA salt (16 mg, 0.020 mmol, 30% yield). m / z (ESI): 671.0 (M+H). + . 1 H NMR (400 MHz, methanol-d4) δ ppm 9.19 (s, 1H), 7.66-7.75 (m, 1H), 7.32-7.36 (m, 1H), 7.23-7.31 (m, 1H), 7.05-7.11 (m, 1H), 5.50-5.70 (m, 1H), 4.85-4.99 (m, 1H), 4.78-4.83 (m, 1H), 4.68-4.74 (m, 1H), 4.44-4.6 0(m,1H),3.74-4.13(m,5H),3.55-3.65(m,1H),3.46-3.55(m,1H),2.80(s,3H),2.56-2 .78(m,2H),2.31-2.53(m,5H),2.02-2.29(m,4H),1.76-1.96(m,1H),0.76-0.88(m,3H).

[0301] [Table 60]

[0302] Table 61

[0303] Table 62

[0304] Table 63...

Claims

1. Compounds of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt of said compound, wherein: 【Chemistry 2】 is a single bond or a double bond, W is C, CH or N, and when W is CH or N, 【Chemistry 3】 is a single bond, X is CH ２ or CH═CH, n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1, 2, 3 or 4; 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, C ３～７ cycloalkyl, 5- to 7-membered heterocycloalkyl, and each C ３～７ Cycloalkyl or 5- to 7-membered heterocycloalkyl is R ｙ or two R ｘ can be taken together to form a bridged ring, said bridge being one of the following: １～４ Alkylene, -C １～４ Alkylene -O-C １～４ Alkylene-, —O—, —S— or —C １～４ Alkylene -S-C １～４ alkylene-, and each C １～４ The alkylene is R ｙ further substituted with 0 to 2 occurrences of L is C １～６ Alkylene, —O—C １～６ Alkylene, —S—C １～６ Alkylene, NR ｚ , O or S, and each C １～６ Alkylene, —O—C １～６ Alkylene and —S—C １～６ The alkylene chain is R ２ is replaced by 0 to 2 occurrences of R １ is hydroxyl, aryl, heteroaryl, R ５ C substituted with 0-3 occurrences of ３～８ is cycloalkyl or heterocycloalkyl; R ２ However, halogen, hydroxyl, C １～４ alkyl, or two R on the same or adjacent carbon atoms ２ Together, C ３～７ can form a cycloalkyl, R ３ But, R ６ is an aryl or heteroaryl substituted with 0 to 3 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 is cycloalkyl or cyano; Each R ５ is halogen, oxo, hydroxyl, amino 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)-, -N(H)-C(O)-, -N(H)-S(O) ２ -, C １～４ Alkylene-S(O) ２ - or -S-, R ｙ But halogen, C １～４ Alkyl, C １～４ Alkoxy, C １～４ haloalkyl, hydroxyl, cyano or —N(R ｚ ) ２ and R ｚ is hydrogen or C １～４ A compound that is alkyl.

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

3. L is R ２ The compound of any one of claims 1 to 2, which is -O-ethylene or -On-propylene substituted with 0 to 2 occurrences of:

4. R １ is hydroxyl or R ５ 2. The compound of claim 1, wherein the compound is heterocycloalkyl substituted with 0 to 3 occurrences of:

5. R ５ But halogen, cyano, C １～４ The compound of claim 1 which is alkyl or oxo.

6. -L-R １ but, 【Chemistry 4】 2. The compound of claim 1, wherein:

7. -L-R １ but, 【Chemistry 5】 7. The compound of claim 6, wherein:

8. R ３ But, R ６ 2. The compound of claim 1, wherein the aryl is substituted with 0 to 3 occurrences of:

9. R ３ But, R ６ 9. The compound of claim 8, wherein the compound is phenyl or naphthyl substituted with 0 to 3 occurrences of:

10. R ３ But, R ６ 2. The compound of claim 1, wherein the heteroaryl is substituted with 0 to 3 occurrences of:

11. 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 9. The compound of claim 8, wherein:

12. R ６ is hydroxyl, methyl, ethyl, trifluoromethyl, difluoromethyl, ethynyl, fluorine, chlorine, cyclopropyl or -NH ２ 12. The compound of claim 11, wherein:

13. R ３ but, 【Chemistry 6】 2. The compound of claim 1, wherein:

14. R ３ but, 【Chemistry 7】 14. The compound of claim 13, wherein:

15. W is N, 【Chemistry 8】 The compound of claim 1 , wherein is a single bond.

16. X is CH ２ 2. The compound of claim 1, wherein:

17. 17. The compound of claim 16, wherein n is 0 and m is 0, or n is 1 and m is 0, or n is 0 and m is 1.

18. 18. The compound of claim 17, wherein p is 0, 1 or 2.

19. Each R ｘ However, hydroxyl, halogen, C １～４ Alkyl, 5- to 7-membered heteroaryl, -T-R ｙ or two R ｘ together with the adjacent carbon atom, R ｙ C substituted with 0-3 occurrences of ３～７ The compound of claim 18, which forms a cycloalkyl or a 5- to 7-membered heterocycloalkyl.

20. Each R ｘ is hydroxyl, methyl, fluorine, -CH ２ OH, -C(O)NH ２ , -CH ２ C(O)NH ２ , -CH ２ S (O) ２ NH ２ , -S(O)NH ２ , 1-imidazolyl, or two R ｘ together with the adjacent carbon atom, cyclobutyl, 1-tetrahydrofuranyl, or 2-tetrahydrofuranyl (each of which is R ｙ 19. The compound of claim 18, wherein the compound forms a ring structure of which the ring is substituted with 0 to 3 occurrences of

21. [Chemical 9] but, 【Chemistry 10】 19. The compound of claim 18, wherein:

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

23. 23. The compound of claim 22, wherein p is 0, 1, 2, or 3.

24. Each R ｘ is hydroxyl, cyano, oxo, halogen, C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, C ３～７ cycloalkyl, 5- to 7-membered heteroaryl, —N(R ｚ ) ２ , -T-R ｙ or two R ｘ together with the adjacent carbon atom, R ｙ C substituted with 0-3 occurrences of ３～７ cycloalkyl or 5- to 7-membered heterocycloalkyl, or two R ｘ Together, R ｙ C substituted with 0-2 occurrences of １～４ 24. The compound of claim 23, capable of forming an alkylene bridge ring.

25. Each R ｘ is hydroxyl, cyano, oxo, fluorine, methyl, methoxy, trifluoromethyl, difluoromethyl, chloromethyl, cyclopropyl, -NH ２ , 5-oxazolyl, 4-imidazolyl, -pyrazolyl, -NHC(O)OMe, -S(O) ２ Me, -NHC(O)Me, -NHC(O)-N(H)CH ２ CH ２ OMe, -CH ２ OH, -NHS(O) ２ Me, -CO ２ H, —C(O) ２ Me, 1-isopropanol, -S(O) ２ NH ２ , —C(O)NH ２ , -S(O) ２ -N(H)Me, -C(O)N(H)Me, or two R ｘ together with the adjacent carbon atom, R ｙ or two R ｘ Together, R ｙ 25. The compound of claim 24, wherein 0 to 2 occurrences of can form a substituted methylene or ethylene bridged ring.

26. [Chemical 11] but, 【Chemistry 12】 【Chemistry 13】 25. The compound of claim 24, wherein:

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

28. 28. The compound of claim 27, wherein p is 0, 1, 2, or 3.

29. R ｘ But C １～４ Alkyl, C １～４ Alkenyl, cyano, hydroxy, halogen, oxo, -N(R ｚ ) ２ , -T-R ｙ or two R ｘ together to form -O- or R ｙ C substituted with 0-2 occurrences of １～４ 29. The compound of claim 28, capable of forming an alkylene bridge ring.

30. R ｘ is hydroxy, cyano, oxo, fluorine, methyl, methenyl, -SO ２ NH ２ , -NHC(O)Me, -NHC(O)CF ２ H or two R ｘ together to form -O- or R ｙ 30. The compound of claim 29, wherein 0 to 2 occurrences of can form a substituted methylene bridged ring.

31. [Catalog 14] but, 【Chemistry 15】 30. The compound of claim 29, wherein:

32. 2. The compound of claim 1, wherein X is CH=CH.

33. 33. The compound of claim 32, wherein n is 0 and m is 1, or n is 1 and m is 1.

34. 34. The compound of claim 33, wherein p is 0 or 1.

35. Each R ｘ is hydroxyl or oxo.

36. [Catalog 16] but, 【Chemistry 17】 36. The compound of claim 35, wherein:

37. The compound is the following compound: (R)-1-(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)piperidine-3-sulfonamide; 4-(4-(azepan-1-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; 1-(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)pyrrolidine-3-carboxamide; (S)-1-(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)pyrrolidine-2-carboxamide; 1-(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)azetidine-2-carboxamide; 1-(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)piperidine-4-carboxamide; (S)-1-(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)piperidine-3-sulfonamide; 2-(1-(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)azetidin-3-yl)acetamide; 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)-3-azabicyclo[3.2.0]heptan-6-ol; (R)-1-(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)piperidin-3-ol; (3S,4R)-1-(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)pyrrolidine-3,4-diol; (R)-1-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; (R)-1-(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)piperidin-3-ol; (S)-1-(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)piperidin-3-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-methoxypiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(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)pyrrolidin-3-ol; (1R,4S)-2-(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-azabicyclo[2.2.2]octan-6-ol; 3-(7-(7,8-difluoro-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-azabicyclo[3.2.1]octan-6-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-2-(hydroxymethyl)azetidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-((1S,5R)-3-oxa-6-azabicyclo[3.2.0]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; rel-4-(4-((1R,5R)-2-oxa-6-azabicyclo[3.2.0]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; 4-(4-(3-(chloromethyl)-3-(hydroxymethyl)piperidin-1-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-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 1); 3-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 2); (1R,5R,6R)-3-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 1); (1R,5R,6R)-3-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (isomer 1); (1R,5R,6R)-3-(7-(8-ethynyl-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-azabicyclo[3.2.1]octan-6-ol (isomer 1); 1-(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)-5,5-dimethylpiperidin-3-ol; (3R,6S)-1-(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-methylpiperidin-3-ol; 8-(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)-8-azabicyclo[3.2.1]octan-2-ol 2,2,2-trifluoroacetate; (3R,6R)-1-(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-methylpiperidin-3-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(hexahydro-5H-furo[2,3-c]pyrrol-5-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 1); 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 2); 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 1); rel-5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((3aR,7aR)-hexahydrofuro[3,2-b]pyridin-4(2H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (R)-1-(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)-3-methylpiperidin-3-ol; 1-(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-(fluoromethyl)piperidin-3-ol (isomer 1); 1-(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-(fluoromethyl)piperidin-3-ol (isomer 2); (3R)-1-(7-(8-ethyl-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (isomer 2); (3R)-1-(7-(8-ethyl-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (isomer 1); (3R)-1-(7-(8-allyl-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(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)-5,5-dimethylpiperidine-3-carboxamide; 4-(4-((R)-3-aminopiperidin-1-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-((S)-3-amino-3-methylpiperidin-1-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-((R)-3-amino-3-methylpiperidin-1-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; (3R,4S)-1-(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)-4-fluoropyridin-3-ol; (R)-1-(7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 2-(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-azabicyclo[2.2.1]heptan-6-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-chloro-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-methylpiperidin-3-ol; (R)-1-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(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)-3-methylpiperidin-3-ol; (R)-1-(7-(7,8-difluoro-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-methylpiperidin-3-ol; (R)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; rel-(3aR,6aS)-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)hexahydropyrrolo[3,4-c]pyrrol-1(2H)-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-rel-((3aR,7aS)-hexahydrofuro[3,2-c]pyridin-5(4H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; rel-(3aR,7aR)-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)octahydro-2H-pyrrolo[3,2-b]pyridin-2-one; rel-(3S,6R)-1-(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-methylpiperidine-3-carboxamide; 3-ethyl-1-(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)piperidin-3-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-3-(hydroxymethyl)-3-methylpiperidin-1-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-((R)-3-(hydroxymethyl)-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(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-methylpiperidine-3-carboxamide; 8-(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)-2-methyl-8-azabicyclo[3.2.1]octan-2-ol; 8-(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-methyl-8-azabicyclo[3.2.1]octan-2-ol; 2-(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-2-azabicyclo[2.2.1]heptan-6-ol; 2-(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-azabicyclo[2.2.1]heptan-6-one; N-((R)-1-(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)piperidin-3-yl)acetamide; 1-((R)-1-(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)piperidin-3-yl)-3-(2-methoxyethyl)thiourea; N-((R)-1-(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-methylpiperidin-3-yl)methanesulfonamide; N-((R)-1-(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-methylpiperidin-3-yl)acetamide; Methyl ((R)-1-(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-methylpiperidin-3-yl)carbamate; Methyl ((R)-1-(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)piperidin-3-yl)carbamate; 1-(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-methylpiperidine-3-sulfonamide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-2-methylazepan-1-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)-2-methylazepan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (1-(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)azetidin-3-yl)methanesulfonamide; 1-(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-hydroxyazetidine-3-carboxamide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-(methylsulfonyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(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)piperidine-4-sulfonamide; 1-(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)pyrrolidine-3-sulfonamide; 1-(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)azetidine-3-sulfonamide; 1-(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)azetidine-3-carboxamide; 1-(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-methylpiperidine-3-carboxamide; (S)-1-(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)piperidine-3-carboxamide; 4-(4-(3-(1H-imidazol-1-yl)azetidin-1-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; 1-(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-methylazetidin-3-ol; 4-(4-(azocan-1-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; 1-(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)azepan-4-one; rac-(3R,5S)-1-(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)-5-methylpiperidin-3-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)-3-azabicyclo[3.2.1]octan-8-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)-8-methyl-3-azabicyclo[3.2.1]octan-8-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)-3-azabicyclo[4.1.0]heptan-1-ol; rel-(3R,4S)-1-(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)piperidine-3,4-diol; rel-(3S,4S)-1-(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)piperidine-3,4-diol; rel-(3aR,7aR)-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)octahydro-3H-pyrrolo[3,4-c]pyridin-3-one; 4-(4-((S)-3-aminopiperidin-1-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-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-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(3-(1H-imidazol-4-yl)piperidin-1-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-(1H-pyrazol-5-yl)piperidin-1-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-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-(oxazol-5-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(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)-1,2,3,6-tetrahydropyridin-3-ol; N-(1-(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)piperidin-3-yl)methanesulfonamide; 5-ethyl-6-fluoro-4-(8-fluoro-4-((2S,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (3R,4R)-1-(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)-4-fluoropyridin-3-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; rac-(3S,5R)-1-(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)-5-fluoropiperidin-3-ol; (3S,4S)-1-(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)pyrrolidine-3,4-diol; 1-(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)-5,5-difluoropiperidin-3-ol; ((S)-1-(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)pyrrolidin-2-yl)methanesulfonamide; 1-(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)-5,5-difluoroazepan-4-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)-3-azabicyclo[3.2.1]octane-1-carboxamide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; rac-(1S,5S)-8-(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)-8-azabicyclo[3.2.1]octane-2-carboxamide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-(2-hydroxypropan-2-yl)piperidin-1-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)-3-(hydroxymethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; Methyl (R)-1-(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)piperidine-3-carboxylate; 1-(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)azepan-3-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-3-(hydroxymethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (R)-1-(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)azepan-3-ol; (S)-1-(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)azepan-3-ol; 4-(4-((R)-3-aminoazepan-1-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; N-((R)-1-(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)azepan-3-yl)-2,2-difluoroacetamide; N-((R)-1-(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)azepan-3-yl)acetamide; 1-(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)-1,2,6,7-tetrahydro-3H-azepin-3-one; 1-(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)-2,3,6,7-tetrahydro-1H-azepin-3-ol; 1-(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-methylazepan-3-ol (isomer 1); 1-(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-methylazepan-3-ol (isomer 2); (R)-1-(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)piperidine-3-carboxylic acid; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-((R)-5-amino-3,3-difluoropiperidin-1-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; 1-(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)azepan-4-ol; 1-(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)-4-methylazepan-4-ol; 4-(4-(4-aminoazepan-1-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-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(4-methyleneazepan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-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)-3-azabicyclo[3.2.1]octane-6-carbonitrile (isomer mixture 1); 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)-3-azabicyclo[3.2.1]octane-6-carbonitrile (isomer mixture 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)-3-azabicyclo[3.2.2]nonane-6-carbonitrile; (R)-1-(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-(methyl-d3)piperidin-3-ol; (S)-1-(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-(methyl-d3)piperidin-3-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-methoxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-(4,4-difluoroazepan-1-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; 1-(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)-5,5-difluoroazepan-4-one; 1-(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)piperidine-3-carbonitrile; 1-(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)-3,3-difluoropiperidin-4-one; 1-(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)piperidin-4-ol; (3R,5S)-1-(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)-5-(trifluoromethyl)piperidin-3-ol; 6-(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-azabicyclo[3.2.1]octan-2-ol; 1-(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-(trifluoromethyl)piperidin-3-ol; 3-cyclopropyl-1-(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)piperidin-3-ol; 1-(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)azepane-3-sulfonamide; 1-(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-hydroxypiperidine-3-carboxamide; 4-(4-(3-((difluoromethyl)sulfonyl)piperidin-1-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; 1-(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)-5-methylpiperidine-3-carboxamide; (R)-1-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide; 4-(4-(azepan-1-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; (R)-1-(7-(8-cyclopropyl-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-methylpiperidin-3-ol; (R)-1-(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)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-methylpyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine-3-ol bis(2,2,2-trifluoroacetate); (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; or 2. The compound of claim 1, wherein the compound is selected from one of: (R)-1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol.

38. The compound is the following compound: (R)-1-(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)piperidine-3-sulfonamide; 4-(4-(azepan-1-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; 1-(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)pyrrolidine-3-carboxamide; (S)-1-(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)pyrrolidine-2-carboxamide; 1-(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)azetidine-2-carboxamide; 1-(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)piperidine-4-carboxamide; (S)-1-(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)piperidine-3-sulfonamide; 2-(1-(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)azetidin-3-yl)acetamide; 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)-3-azabicyclo[3.2.0]heptan-6-ol; (R)-1-(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)piperidin-3-ol; (3S,4R)-1-(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)pyrrolidine-3,4-diol; (R)-1-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; (R)-1-(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)piperidin-3-ol; (S)-1-(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)piperidin-3-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-methoxypiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(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)pyrrolidin-3-ol; (1R,4S)-2-(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-azabicyclo[2.2.2]octan-6-ol; 3-(7-(7,8-difluoro-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-azabicyclo[3.2.1]octan-6-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-2-(hydroxymethyl)azetidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-((1S,5R)-3-oxa-6-azabicyclo[3.2.0]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; rel-4-(4-((1R,5R)-2-oxa-6-azabicyclo[3.2.0]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; 4-(4-(3-(chloromethyl)-3-(hydroxymethyl)piperidin-1-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-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 1); 3-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 2); (1R,5R,6R)-3-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 1); (1R,5R,6R)-3-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (isomer 1); (1R,5R,6R)-3-(7-(8-ethynyl-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-azabicyclo[3.2.1]octan-6-ol (isomer 1); 1-(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)-5,5-dimethylpiperidin-3-ol; (3R,6S)-1-(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-methylpiperidin-3-ol; 8-(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)-8-azabicyclo[3.2.1]octan-2-ol 2,2,2-trifluoroacetate; (3R,6R)-1-(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-methylpiperidin-3-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(hexahydro-5H-furo[2,3-c]pyrrol-5-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 1); 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 2); 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 1); rel-5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((3aR,7aR)-hexahydrofuro[3,2-b]pyridin-4(2H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(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)-5,5-dimethylpiperidine-3-carboxamide; 4-(4-((R)-3-aminopiperidin-1-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-((S)-3-amino-3-methylpiperidin-1-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-((R)-3-amino-3-methylpiperidin-1-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; (3R,4S)-1-(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)-4-fluoropyridin-3-ol; (R)-1-(7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 2-(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-azabicyclo[2.2.1]heptan-6-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-chloro-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-methylpiperidin-3-ol; (R)-1-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(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)-3-methylpiperidin-3-ol; (R)-1-(7-(7,8-difluoro-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-methylpiperidin-3-ol; (R)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; rel-(3aR,6aS)-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)hexahydropyrrolo[3,4-c]pyrrol-1(2H)-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-rel-((3aR,7aS)-hexahydrofuro[3,2-c]pyridin-5(4H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; rel-(3aR,7aR)-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)octahydro-2H-pyrrolo[3,2-b]pyridin-2-one; rel-(3S,6R)-1-(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-methylpiperidine-3-carboxamide; 3-ethyl-1-(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)piperidin-3-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-3-(hydroxymethyl)-3-methylpiperidin-1-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-((R)-3-(hydroxymethyl)-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(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-methylpiperidine-3-carboxamide; 8-(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)-2-methyl-8-azabicyclo[3.2.1]octan-2-ol; 8-(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-methyl-8-azabicyclo[3.2.1]octan-2-ol; 2-(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-2-azabicyclo[2.2.1]heptan-6-ol; 2-(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-azabicyclo[2.2.1]heptan-6-one; N-((R)-1-(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)piperidin-3-yl)acetamide; 1-((R)-1-(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)piperidin-3-yl)-3-(2-methoxyethyl)thiourea; N-((R)-1-(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-methylpiperidin-3-yl)methanesulfonamide; N-((R)-1-(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-methylpiperidin-3-yl)acetamide; Methyl ((R)-1-(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-methylpiperidin-3-yl)carbamate; Methyl ((R)-1-(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)piperidin-3-yl)carbamate; 1-(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-methylpiperidine-3-sulfonamide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-2-methylazepan-1-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)-2-methylazepan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (1-(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)azetidin-3-yl)methanesulfonamide; 1-(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-hydroxyazetidine-3-carboxamide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-(methylsulfonyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(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)piperidine-4-sulfonamide; 1-(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)pyrrolidine-3-sulfonamide; 1-(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)azetidine-3-sulfonamide; 1-(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)azetidine-3-carboxamide; 1-(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-methylpiperidine-3-carboxamide; (S)-1-(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)piperidine-3-carboxamide; 4-(4-(3-(1H-imidazol-1-yl)azetidin-1-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; 1-(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-methylazetidin-3-ol; 4-(4-(azocan-1-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; 1-(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)azepan-4-one; rac-(3R,5S)-1-(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)-5-methylpiperidin-3-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)-3-azabicyclo[3.2.1]octan-8-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)-8-methyl-3-azabicyclo[3.2.1]octan-8-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)-3-azabicyclo[4.1.0]heptan-1-ol; rel-(3R,4S)-1-(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)piperidine-3,4-diol; rel-(3S,4S)-1-(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)piperidine-3,4-diol; rel-(3aR,7aR)-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)octahydro-3H-pyrrolo[3,4-c]pyridin-3-one; 4-(4-((S)-3-aminopiperidin-1-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-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-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(3-(1H-imidazol-4-yl)piperidin-1-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-(1H-pyrazol-5-yl)piperidin-1-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-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-(oxazol-5-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(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)-1,2,3,6-tetrahydropyridin-3-ol; N-(1-(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)piperidin-3-yl)methanesulfonamide; 5-ethyl-6-fluoro-4-(8-fluoro-4-((2S,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (3R,4R)-1-(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)-4-fluoropyridin-3-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; rac-(3S,5R)-1-(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)-5-fluoropiperidin-3-ol; (3S,4S)-1-(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)pyrrolidine-3,4-diol; 1-(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)-5,5-difluoropiperidin-3-ol; ((S)-1-(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)pyrrolidin-2-yl)methanesulfonamide; 1-(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)-5,5-difluoroazepan-4-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)-3-azabicyclo[3.2.1]octane-1-carboxamide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; rac-(1S,5S)-8-(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)-8-azabicyclo[3.2.1]octane-2-carboxamide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-(2-hydroxypropan-2-yl)piperidin-1-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)-3-(hydroxymethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; Methyl (R)-1-(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)piperidine-3-carboxylate; 1-(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)azepan-3-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-3-(hydroxymethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (R)-1-(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)azepan-3-ol; (S)-1-(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)azepan-3-ol; 4-(4-((R)-3-aminoazepan-1-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; N-((R)-1-(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)azepan-3-yl)-2,2-difluoroacetamide; N-((R)-1-(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)azepan-3-yl)acetamide; 1-(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)-1,2,6,7-tetrahydro-3H-azepin-3-one; 1-(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)-2,3,6,7-tetrahydro-1H-azepin-3-ol; 1-(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-methylazepan-3-ol (isomer 1); 1-(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-methylazepan-3-ol (isomer 2); (R)-1-(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)piperidine-3-carboxylic acid; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-((R)-5-amino-3,3-difluoropiperidin-1-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; 1-(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)azepan-4-ol; 1-(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)-4-methylazepan-4-ol; 4-(4-(4-aminoazepan-1-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-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(4-methyleneazepan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-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)-3-azabicyclo[3.2.1]octane-6-carbonitrile (isomer mixture 1); 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)-3-azabicyclo[3.2.1]octane-6-carbonitrile (isomer mixture 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)-3-azabicyclo[3.2.2]nonane-6-carbonitrile; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-methoxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-(4,4-difluoroazepan-1-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; 1-(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)-5,5-difluoroazepan-4-one; 1-(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)piperidine-3-carbonitrile; 1-(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)-3,3-difluoropiperidin-4-one; 1-(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)piperidin-4-ol; (3R,5S)-1-(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)-5-(trifluoromethyl)piperidin-3-ol; 6-(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-azabicyclo[3.2.1]octan-2-ol; 1-(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-(trifluoromethyl)piperidin-3-ol; 3-cyclopropyl-1-(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)piperidin-3-ol; 1-(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)azepane-3-sulfonamide; 1-(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-hydroxypiperidine-3-carboxamide; 4-(4-(3-((difluoromethyl)sulfonyl)piperidin-1-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; 1-(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)-5-methylpiperidine-3-carboxamide; (R)-1-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide; 4-(4-(azepan-1-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; (R)-1-(7-(8-cyclopropyl-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-methylpiperidin-3-ol; (R)-1-(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)-3-methylpiperidin-3-ol; or 2. The compound of claim 1, wherein the compound is selected from one of the following: (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-methylpyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol.

39. The compound is the following compound: 1-(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)pyrrolidine-3-carboxamide; (S)-1-(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)pyrrolidine-2-carboxamide; 1-(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)azetidine-2-carboxamide; 1-(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)piperidine-4-carboxamide; 2-(1-(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)azetidin-3-yl)acetamide; 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)-3-azabicyclo[3.2.0]heptan-6-ol; (R)-1-(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)piperidin-3-ol; (3S,4R)-1-(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)pyrrolidine-3,4-diol; (R)-1-(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)piperidin-3-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-methoxypiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(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)pyrrolidin-3-ol; (1R,4S)-2-(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-azabicyclo[2.2.2]octan-6-ol; 3-(7-(7,8-difluoro-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-azabicyclo[3.2.1]octan-6-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-2-(hydroxymethyl)azetidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-((1S,5R)-3-oxa-6-azabicyclo[3.2.0]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; rel-4-(4-((1R,5R)-2-oxa-6-azabicyclo[3.2.0]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; 4-(4-(3-(chloromethyl)-3-(hydroxymethyl)piperidin-1-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-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 1); 3-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 2); (1R,5R,6R)-3-(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)-3-azabicyclo[3.2.1]octan-6-ol (isomer 1); (1R,5R,6R)-3-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (isomer 1); 1-(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)-5,5-dimethylpiperidin-3-ol; (3R,6S)-1-(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-methylpiperidin-3-ol; 8-(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)-8-azabicyclo[3.2.1]octan-2-ol 2,2,2-trifluoroacetate; (3R,6R)-1-(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-methylpiperidin-3-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(hexahydro-5H-furo[2,3-c]pyrrol-5-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 1); 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 2); 3-(difluoromethyl)-1-(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)piperidin-3-ol (isomer 1); rel-5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((3aR,7aR)-hexahydrofuro[3,2-b]pyridin-4(2H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(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)-5,5-dimethylpiperidine-3-carboxamide; 4-(4-((R)-3-aminopiperidin-1-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-((S)-3-amino-3-methylpiperidin-1-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-((R)-3-amino-3-methylpiperidin-1-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; (3R,4S)-1-(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)-4-fluoropyridin-3-ol; (R)-1-(7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 2-(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-azabicyclo[2.2.1]heptan-6-ol; (R)-1-(7-(8-chloro-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-methylpiperidin-3-ol; (R)-1-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(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)-3-methylpiperidin-3-ol; (R)-1-(7-(7,8-difluoro-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-methylpiperidin-3-ol; (R)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; rel-(3aR,6aS)-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)hexahydropyrrolo[3,4-c]pyrrol-1(2H)-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-rel-((3aR,7aS)-hexahydrofuro[3,2-c]pyridin-5(4H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; rel-(3aR,7aR)-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)octahydro-2H-pyrrolo[3,2-b]pyridin-2-one; rel-(3S,6R)-1-(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-methylpiperidine-3-carboxamide; 3-ethyl-1-(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)piperidin-3-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-3-(hydroxymethyl)-3-methylpiperidin-1-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-((R)-3-(hydroxymethyl)-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(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-methylpiperidine-3-carboxamide; 8-(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)-2-methyl-8-azabicyclo[3.2.1]octan-2-ol; 8-(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-methyl-8-azabicyclo[3.2.1]octan-2-ol; 2-(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-2-azabicyclo[2.2.1]heptan-6-ol; 2-(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-azabicyclo[2.2.1]heptan-6-one; N-((R)-1-(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)piperidin-3-yl)acetamide; 1-((R)-1-(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)piperidin-3-yl)-3-(2-methoxyethyl)thiourea; N-((R)-1-(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-methylpiperidin-3-yl)acetamide; Methyl ((R)-1-(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-methylpiperidin-3-yl)carbamate; Methyl ((R)-1-(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)piperidin-3-yl)carbamate; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-2-methylazepan-1-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)-2-methylazepan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (1-(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)azetidin-3-yl)methanesulfonamide; 1-(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-hydroxyazetidine-3-carboxamide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-(methylsulfonyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(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)pyrrolidine-3-sulfonamide; 1-(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)azetidine-3-sulfonamide; 1-(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)azetidine-3-carboxamide; 1-(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-methylpiperidine-3-carboxamide; 1-(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-methylazetidin-3-ol; 1-(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)azepan-4-one; 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)-3-azabicyclo[3.2.1]octan-8-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)-8-methyl-3-azabicyclo[3.2.1]octan-8-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)-3-azabicyclo[4.1.0]heptan-1-ol; rel-(3R,4S)-1-(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)piperidine-3,4-diol; rel-(3S,4S)-1-(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)piperidine-3,4-diol; rel-(3aR,7aR)-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)octahydro-3H-pyrrolo[3,4-c]pyridin-3-one; 4-(4-((S)-3-aminopiperidin-1-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-(1H-imidazol-4-yl)piperidin-1-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-(1H-pyrazol-5-yl)piperidin-1-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-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-(oxazol-5-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; N-(1-(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)piperidin-3-yl)methanesulfonamide; 5-ethyl-6-fluoro-4-(8-fluoro-4-((2S,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (3R,4R)-1-(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)-4-fluoropyridin-3-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; rac-(3S,5R)-1-(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)-5-fluoropiperidin-3-ol; (3S,4S)-1-(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)pyrrolidine-3,4-diol; 1-(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)-5,5-difluoropiperidin-3-ol; ((S)-1-(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)pyrrolidin-2-yl)methanesulfonamide; 1-(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)-5,5-difluoroazepan-4-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)-3-azabicyclo[3.2.1]octane-1-carboxamide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; rac-(1S,5S)-8-(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)-8-azabicyclo[3.2.1]octane-2-carboxamide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-(2-hydroxypropan-2-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; Methyl (R)-1-(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)piperidine-3-carboxylate; 1-(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)azepan-3-one; 4-(4-((R)-3-aminoazepan-1-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; N-((R)-1-(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)azepan-3-yl)-2,2-difluoroacetamide; N-((R)-1-(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)azepan-3-yl)acetamide; 1-(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)-1,2,6,7-tetrahydro-3H-azepin-3-one; 1-(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)-2,3,6,7-tetrahydro-1H-azepin-3-ol; 1-(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-methylazepan-3-ol (isomer 1); 1-(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-methylazepan-3-ol (isomer 2); (R)-1-(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)piperidine-3-carboxylic acid; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-((R)-5-amino-3,3-difluoropiperidin-1-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; 1-(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)azepan-4-ol; 1-(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)-4-methylazepan-4-ol; 4-(4-(4-aminoazepan-1-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-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(4-methyleneazepan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-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)-3-azabicyclo[3.2.1]octane-6-carbonitrile (isomer mixture 1); 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)-3-azabicyclo[3.2.1]octane-6-carbonitrile (isomer mixture 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)-3-azabicyclo[3.2.2]nonane-6-carbonitrile; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-methoxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-(4,4-difluoroazepan-1-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; 1-(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)-5,5-difluoroazepan-4-one; 1-(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)piperidine-3-carbonitrile; 1-(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)-3,3-difluoropiperidin-4-one; (3R,5S)-1-(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)-5-(trifluoromethyl)piperidin-3-ol; 1-(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-(trifluoromethyl)piperidin-3-ol; 3-cyclopropyl-1-(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)piperidin-3-ol; 1-(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-hydroxypiperidine-3-carboxamide; 4-(4-(3-((difluoromethyl)sulfonyl)piperidin-1-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; 1-(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)-5-methylpiperidine-3-carboxamide; (R)-1-(7-(8-cyclopropyl-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-methylpiperidin-3-ol; (R)-1-(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)-3-methylpiperidin-3-ol; or 2. The compound of claim 1, wherein the compound is selected from one of the following: (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-methylpyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol.

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

41. 41. 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 40, for use as a medicament.

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

43. 41. The compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 40, for use in treating cancer, wherein one or more cells express a KRAS G12D mutant protein.

44. 43. The compound or pharmaceutical composition for use according to claim 42, 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 cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

45. 41. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 40, in the preparation of a medicament for treating cancer.

46. 41. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 40, in the preparation of a medicament for treating cancer, wherein one or more cells express a KRAS G12D mutant protein.

47. 46. The use of claim 45, 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, 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.

48. 41. 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 40, said method comprising administering said medicament to said subject.

49. 41. 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 40, the method comprising administering the compound to the subject, wherein one or more cells express a KRAS G12D mutant protein.

50. The drug of claim 48, 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.

51. 49. The method of claim 48, 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.

52. 52. The method of claim 51, wherein the cancer is non-small cell lung cancer.

53. 52. The method of claim 51, wherein the cancer is colorectal cancer.

54. The method of claim 51, wherein the cancer is pancreatic cancer.

55. 49. The method of claim 48, 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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