Heterocyclic compounds and methods of use

Abstract

The present disclosure provides compounds useful for inhibiting KRAS G12D. The compounds have the general formula I: TIFF2024532733000233.tif32170, The variables of formula I are defined herein.The disclosure also provides pharmaceutical compositions comprising the compounds, such as the use of the compounds and compositions for the treatment of cancer.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 231,543, filed August 10, 2021, U.S. Provisional Patent Application No. 63 / 289,578, filed December 14, 2021, and U.S. Provisional Patent Application No. 63 / 299,667, filed January 14, 2022, each of which is incorporated by reference in its entirety herein.

[0002] The present disclosure provides compounds that have activity as inhibitors of G12D mutant KRAS protein. The present disclosure also provides pharmaceutical compositions containing the compounds, uses, and methods for treating certain diseases, such as cancer, including, but not limited to, non-small cell lung cancer (NSCLC), 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 return KRAS to its GDP-bound, non-proliferative state. Mutations in KRAS impair the regulated cycling of KRAS between these GDP-bound and GTP-bound states, leading to the accumulation of the GTP-bound active state and dysregulated cell proliferation (Simanshu et al., 2017).

[0005] Attempts to develop inhibitors of mutant KRAS proteins have historically been hampered by the absence of a druggable pocket on the protein surface (Cox et al., 2014). In 2013, Shokat et al. identified a covalent inhibitor of KRAS G12C, a common (O'Bryan, 2019) oncogenic mutant of KRAS. This mutant bound to a previously unrecognized allosteric pocket on GDP-KRAS G12C and inhibited its subsequent activation (Ostream et al., 2013). This discovery provided an important new frontier in KRAS inhibitor research and has led to the entry of KRAS inhibitors in human clinical trials in recent years.

[0006] While some progress has been made with respect to KRAS G12C inhibitors, there is continuing 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 against KRAS G12D, G12V, G12A, G12S or G12C for the treatment of diseases such as cancer. [Prior art documents] [Non-patent literature]

[0007] [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 [Means for solving the problem]

[0008] In one aspect, the present application provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt of said compound, wherein [ka] is a single bond or a double bond; W is C, CH or N. When W is CH or N, [ka] is a single bond; X is O, S, S(O), S(O)(NR z ), S(O)2, CH2 or CH=CH; n is 0, 1 or 2; m is 0, 1 or 2; p is 2, 3, or 4; The Two R's x With the same carbon atom, C 3~7 cycloalkyl or 4- to 7-membered heterocycloalkyl, 3~7 Cycloalkyl or 4-7 membered heterocycloalkyl is 0-3 R y When p is 3 or 4, each remaining R x is hydroxyl, halogen, oxo, cyano, -N(R z )2, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 3~6 cycloalkyl, 5-7 membered heteroaryl; L is for 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 consists of 0 to 2 R 2 is replaced by; R 1 is hydroxyl, aryl, heteroaryl, C 3~8 Cycloalkyl or 0 to 3 R 5 is a heterocycloalkyl substituted with; R 2 is halogen, hydroxyl, C 1~4 alkyl, or two R on the same or adjacent carbon atoms 2 Both are C 3~7 Can form a cycloalkyl; R 3 is 0 to 3 R 6 is an aryl or heteroaryl substituted with; R 4 is hydrogen, hydroxyl, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~7 cycloalkyl or cyano; Each R 5 is halogen, oxo, hydroxyl, cyano, 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 for 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)- or -S-; R y is halogen, oxo, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, hydroxyl, cyano, -S(O)2-C 1~4 Alkyl, =NR z Or -N(R z ) 2; and R z is hydrogen or C 1~4 It is an alkyl.

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

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

[0011] Reference will now be made in detail to the embodiments of the present disclosure. Although 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 encompass such alternatives, modifications, and equivalents as may be encompassed within the spirit and scope of the embodiments of the present disclosure as defined by the appended claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] As an embodiment, the present specification provides a compound represented by formula (I): [ka] or a pharma- ceutically 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 O, S, S(O), S(O)(NR z ), S(O)2, CH2 or CH=CH; n is 0, 1 or 2; m is 0, 1 or 2; p is 2, 3, or 4; The Two R's x With the same carbon atom, C 3~7 cycloalkyl or 4- to 7-membered heterocycloalkyl, 3~7Cycloalkyl or 4-7 membered heterocycloalkyl is 0-3 R y When p is 3 or 4, each remaining R x is hydroxyl, halogen, oxo, cyano, -N(R z )2, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 3~6 cycloalkyl, 5-7 membered heteroaryl; L is for 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 consists of 0 to 2 R 2 is replaced by; R 1 is hydroxyl, aryl, heteroaryl, C 3~8 Cycloalkyl or 0 to 3 R 5 is a heterocycloalkyl substituted with; R 2 is halogen, hydroxyl, C 1~4 alkyl, or two R on the same or adjacent carbon atoms 2 Both are C 3~7 Can form a cycloalkyl; R 3 is 0 to 3 R 6 is an aryl or heteroaryl substituted with; R 4 is hydrogen, hydroxyl, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~7 cycloalkyl or cyano; Each R 5 is halogen, oxo, hydroxyl, cyano, amino or C1~4 is alkyl; Each R 6 is halogen, hydroxyl, cyano, -N(R z )2, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 2~4 Alkynyl or C 3~6 is cycloalkyl; T is for C 1~4 Alkylene, -S(O)2-, -C(O)-, -C 1~4 Alkylene-C(O)-, -N(H)-C(O)-, -N(H)-S(O)2-, C 1~4 alkylene -S(O)- or -S-; R y is halogen, oxo, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, hydroxyl, cyano, -S(O)2-C 1~4 Alkyl, =NR z Or -N(R z ) 2; and R z is hydrogen or C 1~4 It is an alkyl.

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

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

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

[0016] As embodiment 14, the present specification provides 1 There are two R 5 As embodiment 15, the compound of embodiment 11 is provided herein, wherein one R is substituted 3-pyrrolidine. 5 is methyl, and the other R 5 is cyano.

[0017] As an embodiment 16, R 1 There are two R 5 As embodiment 17, the compound of embodiment 11 is provided herein, which is 2-pyrrolidine substituted with 5 C 1~4 Compounds of embodiment 16 are provided where one R is alkyl (e.g., methyl), oxo, cyano, or halogen (e.g., fluorine). 5 is methyl, and the other R 5 Compounds of embodiment 17, wherein is fluorine. As embodiment 19, compounds of embodiment 17, wherein is fluorine, 5 is methyl, and the other R 5

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

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

[0019] As embodiment 24, the present specification provides -LR 1 but, [ka] Compounds according to embodiments 1-23 are provided, wherein

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

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

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

[0039] There is provided a compound of any one of embodiments 1-37, wherein R is aryl substituted with R (eg, phenyl or naphthyl).

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

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

[0024] As embodiment 42, the present invention relates to a compound comprising R 3 There are two R 6 As embodiment 43, provided herein is a compound of embodiment 40, wherein R is naphthyl substituted with 6 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 R 6 is ethyl, ethynyl, cyclopropyl, fluorine, chlorine, hydroxyl, or -NH. 6 is ethynyl, and the other R 6 Compounds according to embodiment 42, wherein R is hydroxyl. 6 is ethyl, and the other R 6 Compounds of embodiment 42 are provided herein, in which one R is hydroxyl. 6 is ethyl, and the other R 6 Compounds of embodiment 42 are provided in which R is fluorine. 6 and R are fluorine. 6 is cyclopropyl, and the other R 6 is hydroxyl. As embodiment 50, provided herein is a compound of embodiment 42, wherein one R 6 is fluorine, and the other R 6 is hydroxyl. As embodiment 51, compounds according to embodiment 42 are provided herein in which one R 6 is chlorine, and the other R 6As embodiment 52, the compound of embodiment 42 is provided herein, wherein one R 6 is ethynyl, and the other R 6

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

[0025] As embodiment 53, the present invention relates to a compound comprising R 3 There are three R 6 As embodiment 54, provided herein is a compound of embodiment 40, wherein R is naphthyl substituted with 6 C 1~4 Alkyl, C 2~4 Compounds of embodiment 53 are provided herein, where R is alkynyl, halogen, or hydroxyl. 6 Compounds according to embodiment 54, wherein R is ethyl, ethynyl, fluorine or hydroxyl are provided herein as embodiment 56. 6 is hydroxyl and another R 6 is ethyl, and the last R 6 Compounds according to embodiment 53, wherein R is fluorine. 6 is hydroxyl and another R 6 is ethynyl and the last R 6 Compounds according to embodiment 53, wherein R is fluorine. 6 is a halogen (e.g., fluorine or chlorine), and the other R 6

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

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

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

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

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

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

[0031] As embodiment 85, provided herein is a compound of any one of embodiments 1 to 84, wherein X is O.

[0032] As embodiment 86, provided herein is a compound of embodiment 85, wherein n is 1 and m is 1. As embodiment 87, provided herein is a compound of embodiment 86, wherein p is 2. As embodiment 88, provided herein is a compound of embodiment 86, wherein two R x With the same carbon atom, 0 to 3 R y Further substituted C 3~7 Compounds of embodiment 87 are provided herein in which two R x with the same carbon atom and 0 R y As embodiment 90, provided herein is a compound of embodiment 88, wherein the cyclopropyl group is substituted with two R x with the same carbon atom and 0 R y Compounds of embodiment 88 are provided in which the cyclobutyl is further substituted with

[0033] As embodiment 91, provided herein is a compound of embodiment 85, wherein n is 1 and m is 2, or n is 2 and m is 1. As embodiment 92, provided herein is a compound of embodiment 91, wherein p is 2. As embodiment 93, provided herein is a compound of embodiment 91, wherein two R x With the same carbon atom, 0 to 3 R y As embodiment 94, provided herein is a compound of embodiment 92, wherein two R x with the same carbon atom and 0 R y As embodiment 95, provided herein is a compound of embodiment 93, wherein the compound forms a 3-oxetanyl further substituted with two R x with the same carbon atom and one R y As embodiment 96, provided herein is a compound of embodiment 93, further substituted 2-azetidinyl with y96. Compounds according to embodiment 95, wherein is oxo.

[0034] As embodiment 97, the present specification provides [ka] but, [ka] The compound of any one of embodiments 1-83 is provided, wherein

[0035] As embodiment 98, the present specification provides [ka] but, [ka] As embodiment 99, provided herein is a compound of embodiment 97, wherein [ka] but, [ka] Provided herein as embodiment 97 is a compound of embodiment 97, wherein: [ka] but, [ka] As embodiment 101, provided herein is a compound of embodiment 97, wherein [ka] but, [ka] 98. The compound of embodiment 97, wherein

[0036] As embodiment 102, provided herein is a compound of any one of embodiments 1-84, wherein X is CH2.

[0037] As embodiment 103, provided herein is a compound of embodiment 102, wherein n is 0 and m is 1, or m is 0 and n is 1. As embodiment 104, provided herein is a compound of embodiment 103, wherein p is 2. As embodiment 105, provided herein is a compound of embodiment 102, wherein n is 0 and m is 1, or m is 0 and n is 1. x With the same carbon atom, 0 to 3 R y Further substituted C 3~7 Compounds according to embodiment 104 are provided herein in which two R x with the same carbon atom and one R y As embodiment 107, provided herein is a compound of embodiment 105, wherein R y Compounds of embodiment 106 are provided, wherein is hydroxyl.

[0038] As embodiment 108, the present specification provides a method for producing a compound comprising the steps of: x With the same carbon atom, two R y As embodiment 109, provided herein is a compound of embodiment 105, wherein both R y

[0046] Provided herein is a compound of embodiment 108, wherein is oxo.

[0039] As embodiment 110, provided herein is a compound of embodiment 102, where n is 1 and m is 1. As embodiment 111, provided herein is a compound of embodiment 110, where p is 2.

[0040] As embodiment 112, the present invention relates to a compound having two R x With the same carbon atom, 0 to 3 R y Further substituted C3~7 Compounds of embodiment 111 are provided herein in which two R x with the same carbon atom and one R y As embodiment 114, compounds of embodiment 112 are provided herein, wherein R y Compounds according to embodiment 113, wherein R is hydroxyl. x With the same carbon atom, two R y As embodiment 116, provided herein is a compound of embodiment 112, wherein one R x is methyl, and the other R x Compounds according to embodiment 115, wherein R is hydroxyl. x With the same carbon atom, two R y As embodiment 118, provided herein are compounds of embodiment 112, in which both R y Compounds of embodiment 117 are provided, wherein is fluorine.

[0041] As embodiment 119, the present disclosure provides a method for the preparation of a compound having two R x With the same carbon atom, 0 to 3 R y Compounds according to embodiment 111 are provided in which the compound forms a 4-7 membered heterocycloalkyl further substituted with

[0042] As embodiment 120, the present specification provides a method for producing a compound having two R x with the same carbon atom and 0 R y As embodiment 121, provided herein is a compound of embodiment 119, wherein the compound forms a 2-azetidinyl further substituted with two R x with the same carbon atom and one R y As embodiment 122, provided herein is a compound of embodiment 119, which forms a 2-azetidinyl further substituted with yCompounds according to embodiment 121, wherein R is oxo. x With the same carbon atom, two R y As provided herein as embodiment 124, a compound of embodiment 119 is provided, wherein each R y Compounds according to embodiment 123, wherein R is oxo or methyl are provided herein as embodiment 125. x with the same carbon atom and 0 R y As embodiment 126, provided herein is a compound of embodiment 119, wherein the compound forms a 3-azetidinyl further substituted with two R x with the same carbon atom and one R y As embodiment 127, compounds of embodiment 119 are provided herein that form a 3-azetidinyl further substituted with y

[0046] 127. Compounds according to embodiment 126 are provided, wherein is oxo, -S(O)2Me, or methyl.

[0043] As embodiment 128, the present disclosure provides a method for the preparation of a compound having two R x with the same carbon atom and one R y As embodiment 129, compounds of embodiment 119 are provided herein that form 2-pyrrolidinyl further substituted with y Provided herein as embodiment 128 is a compound in which R is oxo. Provided herein as embodiment 130 is a compound in which two R x with the same carbon atom and one R y As embodiment 131, provided herein is a compound of embodiment 119, which forms a 3-pyrrolidinyl further substituted with y

[0046] Provided herein is a compound of embodiment 130, wherein is oxo.

[0044] As embodiment 132, the present invention relates to a compound having two R x With the same carbon atom, two R yAs embodiment 133, provided herein is a compound of embodiment 119, wherein both R y

[0046] Provided herein is a compound of embodiment 132, wherein is oxo.

[0045] As embodiment 134, the present invention relates to a compound having two R x With the same carbon atom, two R y As embodiment 135, provided herein is a compound of embodiment 119, wherein both R y Compounds according to embodiment 134, wherein R is oxo. y is oxo, and the other R y =NR z (In the formula, R z and R is hydrogen.

[0046] As embodiment 137, the present disclosure provides a method for the preparation of a compound having two R x with the same carbon atom and 0 R y As embodiment 138, provided herein is a compound of embodiment 119, wherein the compound forms a 2-oxetanyl further substituted with two R x with the same carbon atom and 0 R y Compounds of embodiment 119 are provided, which form 3-oxetanyl further substituted with.

[0047] As embodiment 139, the present specification provides a method for the preparation of a compound having two R x with the same carbon atom and 0 R y As embodiment 140, provided herein is a compound of embodiment 119, wherein the compound is a 2-tetrahydrofuranyl further substituted with x with the same carbon atom and 0 R y Compounds according to embodiment 119 are provided, wherein the 3-tetrahydrofuranyl is further substituted with

[0048] As an embodiment 141, the present invention relates to a compound having two R x with the same carbon atom and one R y As embodiment 142, provided herein is a compound of embodiment 119, which forms a 4-oxazolidinyl further substituted with y Compounds according to embodiment 141, wherein R is oxo. x with the same carbon atom and one R y As embodiment 144, there is provided herein a compound of embodiment 119, which forms a 5-oxazolidinyl further substituted with y Compounds of embodiment 143 are provided, wherein is oxo.

[0049] As embodiment 145, provided herein is a compound of embodiment 110, wherein p is 3.

[0050] As embodiment 146, the present invention relates to a compound comprising one R x is hydroxyl, and the remaining two R x With the same carbon atom, 0 to 3 R y Further substituted C 3~7 Compounds of embodiment 145 are provided herein in which one R x is hydroxyl, and the remaining two R x with the same carbon atom and 0 R y As embodiment 148, compounds according to embodiment 146 are provided herein, wherein one R x is hydroxyl, and the remaining two R x with the same carbon atom and 0 R y Compounds of embodiment 146 are provided in which the cyclopropyl is further substituted with

[0051] As embodiment 149, provided herein is a compound of embodiment 110, wherein p is 4.

[0052] As embodiment 150, the present specification provides a method for the preparation of a compound comprising the steps of: x is hydroxyl and the second R x C 1~4 alkyl, and the remaining two R x With the same carbon atom, 0 to 3 R y Further substituted C 3~7 Compounds of embodiment 149 are provided herein in which one R x is hydroxyl and the second R x is methyl, and the remaining two R x with the same carbon atom and 0 R y As embodiment 152, provided herein is a compound of embodiment 150, wherein one R x is hydroxyl and the second R x is methyl, and the remaining two R x with the same carbon atom and 0 R y Compounds of embodiment 150 are provided in which the cyclopropyl is further substituted with

[0053] As embodiment 153, the present specification provides [ka] but, [ka] [ka] The compound of any one of embodiments 1-83 is provided, wherein

[0054] As embodiment 154, the present specification provides [ka] but, [ka] Provided herein as embodiment 155 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 156 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 157 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 158 ​​is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 159 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 160 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 161 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 162 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 163 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 164 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 165 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 166 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 167 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 168 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 169 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 170 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 171 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 172 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 173 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 174 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 175 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 176 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 177 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 178 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 179 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 153 is a compound, wherein: [ka] but, [ka] Provided herein as embodiment 181 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 182 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 183 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 184 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 153 is a compound of embodiment 185, [ka] but, [ka] Provided herein as embodiment 153 is a compound of embodiment 186, [ka] but, [ka] Provided herein as embodiment 153 is a compound of embodiment 187, [ka] but, [ka] Provided herein as embodiment 153 is a compound of embodiment 188, [ka] but, [ka] Provided herein as embodiment 153 is a compound of embodiment 189, [ka] but, [ka] Provided herein as embodiment 190 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 191 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 192 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 193 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 194 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 195 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 196 is a compound of embodiment 153, wherein [ka] but, [ka] Provided herein as embodiment 197 is a compound of embodiment 153, wherein [ka] but, [ka] The compound of embodiment 153 is provided, wherein

[0055] As embodiment 198, the present specification provides a method for producing a compound comprising the steps of: 4 C 1~4 Alkyl, C 1~4 Alkoxy, hydroxyl, halogen or C 1~4 As embodiment 199, provided herein is a compound of any one of embodiments 1 to 197, wherein R is haloalkyl. 4 C 1~4 Provided herein as embodiment 198 is a compound, wherein R is alkyl or halogen. 4199. Compounds according to embodiment 199 are provided, wherein is fluorine.

[0056] As embodiment 201, the present specification relates to a compound having formula (II): [ka] The compound of embodiment 1 is provided, which is a compound of

[0057] As embodiment 202, the present specification relates to a compound having formula (III): [ka] The compound of embodiment 1 is provided, which is a compound of

[0058] As embodiment 203, the present specification relates to a compound having formula (IV): [ka] The compound of embodiment 1 is provided, which is a compound of

[0059] As embodiment 204, the present specification relates to a compound having formula (V): [ka] The compound of embodiment 1 is provided, which is a compound of

[0060] As embodiment 205, provided herein is a compound of embodiment 1, wherein the compound is not: 7-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one; 7-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one; 7-(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)-2,7-diazaspiro[4.5]decan-3-one; 7-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one; 7-(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)-2,7-diazaspiro[4.5]decan-3-one; 7-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one; 7-(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)-2,7-diazaspiro[4.5]decan-3-one; 7-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one; 7-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7-azaspiro[4.5]decan-2-one; 7-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7-azaspiro[4.5]decan-2-ol; 8-Fluoro-4-(2-fluoro-7-azaspiro[4.5]decan-7-yl)-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 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)-1,6-diazaspiro[3.5]nonan-2-one; 8-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,8-triazaspiro[5.5]undecan-2-one; 7-(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)-1,7-diazaspiro[3.5]nonan-2-one; 7-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,7-diazaspiro[3.5]nonan-2-one; 6-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one; 6-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonan-1-one; 8-Fluoro-7-(8-fluoronaphthalen-1-yl)-4-(5-azaspiro[2.5]octan-5-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-fluoro-2-((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one; 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)-2,6-diazaspiro[3.5]nonan-1-one; 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)-1,6-diazaspiro[3.5]nonan-2-one; 7-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione; (S)-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)-1,6-diazaspiro[3.5]nonan-2-one; 7-(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)-1,3,7-triazaspiro[4.5]decane-2,4-dione; (S)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-hydroxyhexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one; 8-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,8-triazaspiro[4.5]decan-2-one; 6-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-oxa-6-azaspiro[3.5]nonane; 8-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxa-1,8-diazaspiro[4.5]decan-2-one; 7-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxa-1,7-diazaspiro[1.5]decan-2-one; 8-Fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidine; 6-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-1-ol; 8-Fluoro-4-(2-fluoro-6-azaspiro[3.5]nonan-6-yl)-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-azaspiro[3.5]nonan-2-ol; 8-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,8-triazaspiro[5.5]undecane 2,2-dioxide; 7-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide; 6-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-6-azaspiro[3.5]nonane; 7-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[1,3d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decane-1,3-dione; 6-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.6]decan-2-one; 7-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.6]undecane-2,4-dione; 10-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7-oxa-1,3,10-triazaspiro[4.6]undecane-2,4-dione; (S)-7-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-3-one; 7-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione; 6-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one; 7-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one; 7-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one; 6-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one; 7-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione; 7-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one; (R)-7-(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)-1,3,7 triazaspiro[4.5]decan-2-one; (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-hydroxytetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one; (R)-7-(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)-1,3,7-triazaspiro[4.5]decane-2,4-dione; 7-(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)-2,7-diazaspiro[4.5]decane-1,3-dione; (S)-6-(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)-1,6-diazaspiro[3.5]nonan-2-one; (R)-7-(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)-1,3,7-triazaspiro[4.5]decane-2,4-dione; trans-(2R,4r)-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-azaspiro[3.5]nonan-2-ol; cis-(2S,4s)-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-azaspiro[3.5]nonan-2-ol; trans-6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-methyl-6-azaspiro[3.5]nonan-2-ol; cis-6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-methyl-6-azaspiro[3.5]nonan-2-ol; 7-(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-thia-1,3,7-triazaspiro[4.5]decane-2,2-dioxide; 10-(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-oxa-1,3,10-triazaspiro[4.6]undecane-2,4-dione; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.6]undecane-2,4-dione; 5-ethyl-6-fluoro-4-(8-fluoro-4-(2-fluoro-6-azaspiro[3.5]nonan-6-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 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-azaspiro[3.5]nonan-1-ol; 7-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione; 7-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane-2,2-dioxide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2-thia-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 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)-2,6-diazaspiro[3.5]nonan-1-one; 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-azaspiro[3.5]nonan-2-ol; 7-(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)-1,3,7-triazaspiro[4.5]decan-2-one; 7-(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)-2-thia-1,3,7-triazaspiro[4.5]decane-2,2-dioxide; 7-(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)-1,3,7-triazaspiro[4.5]decane-2,4-dione; 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)-1,6-diazaspiro[3.5]nonan-2-one; 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)-2,6-diazaspiro[3.5]nonan-1-one; 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-azaspiro[3.5]nonan-2-ol; 7-(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)-1,3,7-triazaspiro[4.5]decan-2-one; 7-(7-(8-bromo-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2.R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione; 7-(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)-2-thia-1,3,7-triazaspiro[4.5]decane-2,2-dioxide; (R)-7-(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)-1,3,7-triazaspiro[4.5]decane-2,4-dione; (S)-7-(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)-1,3,7-triazaspiro[4.5]decan-2-one; (S)-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)-1,6-diazaspiro[3.5]nonan-2-one; 7-(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)-2-thia-1,3,7-triazaspiro[4.5]decane-2,2-dioxide; 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)-2,6-diazaspiro[3.5]nonan-1-one; 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-azaspiro[3.5]nonan-2-ol; 7-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide; 6-(8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-7-(8-(hydroxymethyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one; 2-(8-(8-fluoro-2-((hexahydro-1H'-pyrrolidin-7a-yl)methoxy)-4-(2-oxo-1,6-diazaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-1-yl)acetonitrile; trans-6-(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)-6-azaspiro[3.5]nonan-2-ol; cis-6-(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)-6-azaspiro[3.5]nonan-2-ol; 7-(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)-1,3,7-triazaspiro[4.5]decane-2,4-dione; 7-(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)-1,3,7-triazaspiro[4.5]decan-2-one; 7-(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)-2,7-diazaspiro[4.5]decan-3-one; 7-(8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-7-(8-(hydroxymethyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione; 7-(8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-7-(8-methylnaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione; 8-(4-(2,4-dioxo-1,3,7-triazaspiro[4.5]decan-7-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthonitrile; 6-(8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-7-(8-methylnaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one; 8-(8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2-oxo-1,6-diazaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthonitrile; 6-(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)-1,6-diazaspiro[3.5]nonan-2-one; 7-(8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-7-(8-(hydroxymethyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one; 7-(8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-7-(8-methylnaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one; 7-(8-fluoro-7-(8-(fluoromethyl)naphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione; 7-(7-(8-(difluoromethyl)naphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione; 6-(7-(8-(difluoromethyl)naphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one; 6-(8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-7-(8-(trifluoromethyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one; 6-(8-fluoro-7-(8-(fluoromethyl)naphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one; 6-(8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-7-(8-(methylthio)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one; 6-(8-fluoro-7-(8-(2-fluoromethyl)naphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-thia-7-azaspiro[4.5]decan-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxa-1,7-diazaspiro[4.5]decan-2-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,6-dioxa-9-azaspiro[3.6]decan-9-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 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)-2-thia-6-azaspiro[3.5]nonane-2,2-dioxide; 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)-2-thia-6-azaspiro[3.5]nonane-2-oxide; 4-(4-((S)-1,1-difluoro-5-oxa-8-azaspiro[2.6]nonan-8-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; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(3,8-dioxa-11-azaspiro[5.6]dodecan-11-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-9-thia-4-azaspiro[5.5]undecane-9,9-dioxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-9-imino-1-oxa-9-thia-4-azaspiro[5.5]undecane 9-oxide; 7-(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-thia-7-azaspiro[4.5]decane 2,2-dioxide; 7-(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-imino-2-thia-7-azaspiro[4.5]decane 2-oxide; 4-(4-(2,2-difluoro-7-azaspiro[4.5]decan-7-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-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7-azaspiro[4.5]decan-2-ol; 6-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one; (R)-7-(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)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide; (S)-7-(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)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide; 6-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one; 7-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide; or 6-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one.

[0061] As embodiment 206, provided herein is a compound of embodiment 1, wherein the compound is not: 7-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one; 7-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one; 7-(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)-2,7-diazaspiro[4.5]decan-3-one; 7-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one; 7-(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)-2,7-diazaspiro[4.5]decan-3-one; 7-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one; 7-(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)-2,7-diazaspiro[4.5]decan-3-one; 7-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one; 7-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7-azaspiro[4.5]decan-2-one; 7-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7-azaspiro[4.5]decan-2-ol; 8-Fluoro-4-(2-fluoro-7-azaspiro[4.5]decan-7-yl)-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 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)-1,6-diazaspiro[3.5]nonan-2-one; 8-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,8-triazaspiro[5.5]undecan-2-one; 7-(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)-1,7-diazaspiro[3.5]nonan-2-one; 7-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,7-diazaspiro[3.5]nonan-2-one; 6-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one; 6-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonan-1-one; 8-Fluoro-7-(8-fluoronaphthalen-1-yl)-4-(5-azaspiro[2.5]octan-5-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-fluoro-2-((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one; 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)-2,6-diazaspiro[3.5]nonan-1-one; 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)-1,6-diazaspiro[3.5]nonan-2-one; 7-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione; (S)-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)-1,6-diazaspiro[3.5]nonan-2-one; 7-(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)-1,3,7-triazaspiro[4.5]decane-2,4-dione; or (S)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-hydroxyhexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one.

[0062] As embodiment 207, provided herein is a compound of embodiment 1, wherein the compound is selected from: 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 6-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol (isomer 1); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 2); 3-Chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol (isomer 1); 6-(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)-6-azaspiro[3.5]nonan-2-ol (isomer 1); 6-(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)-6-azaspiro[3.5]nonan-2-ol (isomer 2); 7-(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)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); 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)-2-methyl-6-azaspiro[3.5]nonan-2-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)-2,6-diazaspiro[3.5]nonan-1-one (isomer 1); 6-(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)-6-azaspiro[3.5]nonan-2-ol (isomer 1); 9-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-1,9-diazaspiro[3.6]decan-2-one; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 7-(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)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,7-diazaspiro[4.5]decan-2-one; 7-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one; or 7-(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)-2,7-diazaspiro[4.5]decan-3-one.

[0063] As embodiment 208, provided herein is a compound of embodiment 1, wherein the compound is selected from: 5-Chloro-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-Ethyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-methyl-4-((R)-1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 7-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-7-azaspiro[4.5]decan-2-one (isomer 2); (S)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-dioxa-7-azaspiro[4.5]decan-2-one (isomer 1); 3-Chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol (isomer 1); 7-(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)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); 9-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-1,9-diazaspiro[3.6]decan-2-one; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 7-(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)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,7-diazaspiro[4.5]decan-2-one; or (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-dioxa-7-azaspiro[4.5]decan-2-one (isomer 2).

[0064] As embodiment 209, provided herein is a compound of embodiment 1, wherein the compound is selected from: 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 3-Chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol (isomer 1); 7-(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)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); 9-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-1,9-diazaspiro[3.6]decan-2-one; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 7-(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)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); or 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,7-diazaspiro[4.5]decan-2-one.

[0065] As embodiment 210, provided herein is a compound of embodiment 1, wherein the compound is selected from: 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-8-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-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)-5-azaspiro[2.5]octan-7-ol (isomer 1); 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)-5-azaspiro[2.5]octan-7-ol (isomer 2); 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,6-diazaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-methyl-1,6-diazaspiro[3.5]nonan-2-one; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one (isomer 1); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one (isomer 2); 6-(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)-6-azaspiro[3.5]nonan-2-ol (isomer 1); 6-(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)-6-azaspiro[3.5]nonan-2-ol (isomer 2); 6-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol (isomer 1); 6-(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)-6-azaspiro[3.5]nonan-2-ol (isomer 1); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 2); 7-(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)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); 7-(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)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7-methyl-5-azaspiro[2.5]octan-7-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-oxa-6-azaspiro[3.5]nonan-6-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-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 5-Ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 3-Chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol (isomer 1); 5-Chloro-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-Ethyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-methyl-4-((R)-1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-Ethyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-methyl-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-7-azaspiro[4.5]decan-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,7-diazaspiro[4.5]decan-2-one; 7-(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)-2,7-diazaspiro[4.5]decan-3-one; 7-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(5-oxa-8-azaspiro[3.5]nonan-8-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 6-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonan-1-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-oxa-7-azaspiro[4.5]decan-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide (isomer 1); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide (isomer 2); 7-(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)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide (isomer 1); 7-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); 7-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 2); 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-azaspiro[3.4]octan-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,6-diazaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-imino-2l6-thia-7-azaspiro[4.5]decane 2-oxide; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxa-1,7-diazaspiro[4.5]decan-2-one; 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)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 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)-3-oxa-1,8-diazaspiro[4.5]decan-2-one; 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)-1-thia-6-azaspiro[3.5]nonane-1,1-dioxide; (S)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-7-azaspiro[4.5]decan-2-one (isomer 1); (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-7-azaspiro[4.5]decan-2-one (isomer 2); (S)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-dioxa-7-azaspiro[4.5]decan-2-one (isomer 1); (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-dioxa-7-azaspiro[4.5]decan-2-one (isomer 2); 4-(4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 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)-2,6-diazaspiro[3.5]nonan-1-one (isomer 1); 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)-2,6-diazaspiro[3.5]nonan-1-one (isomer 2); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-1-one; 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-azaspiro[3.5]nonan-1-ol (isomer 1); 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-azaspiro[3.5]nonan-1-ol (isomer 2); 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,6-dioxa-9-azaspiro[3.6]decan-9-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-thia-7-azaspiro[4.4]nonane-1,1-dioxide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 9-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-1,9-diazaspiro[3.6]decan-2-one; 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)-2-methyl-6-azaspiro[3.5]nonan-2-ol; 9-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-1,9-diazaspiro[3.6]decan-2-one; 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol; or 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)-2-methyl-6-azaspiro[3.5]nonan-2-ol.

[0066] As embodiment 211, provided herein is a compound of embodiment 1, wherein the compound is selected from: 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-8-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-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)-5-azaspiro[2.5]octan-7-ol (isomer 1); 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)-5-azaspiro[2.5]octan-7-ol (isomer 2); 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,6-diazaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-methyl-1,6-diazaspiro[3.5]nonan-2-one; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one (isomer 1); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one (isomer 2); 6-(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)-6-azaspiro[3.5]nonan-2-ol (isomer 1); 6-(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)-6-azaspiro[3.5]nonan-2-ol (isomer 2); 6-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol (isomer 1); 6-(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)-6-azaspiro[3.5]nonan-2-ol (isomer 1); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 2); 7-(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)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); 7-(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)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7-methyl-5-azaspiro[2.5]octan-7-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-oxa-6-azaspiro[3.5]nonan-6-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-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 5-Ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 3-Chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol (isomer 1); 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-7-azaspiro[4.5]decan-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,7-diazaspiro[4.5]decan-2-one; 7-(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)-2,7-diazaspiro[4.5]decan-3-one; 7-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(5-oxa-8-azaspiro[3.5]nonan-8-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 6-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonan-1-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-oxa-7-azaspiro[4.5]decan-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide (isomer 1); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide (isomer 2); 7-(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)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide (isomer 1); 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-azaspiro[3.4]octan-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,6-diazaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-imino-2l6-thia-7-azaspiro[4.5]decane 2-oxide; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxa-1,7-diazaspiro[4.5]decan-2-one; 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)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 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)-3-oxa-1,8-diazaspiro[4.5]decan-2-one; 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)-1-thia-6-azaspiro[3.5]nonane-1,1-dioxide; 4-(4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 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)-2,6-diazaspiro[3.5]nonan-1-one (isomer 1); 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)-2,6-diazaspiro[3.5]nonan-1-one (isomer 2); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-1-one; 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-azaspiro[3.5]nonan-1-ol (isomer 1); 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-azaspiro[3.5]nonan-1-ol (isomer 2); 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,6-dioxa-9-azaspiro[3.6]decan-9-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-thia-7-azaspiro[4.4]nonane-1,1-dioxide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 9-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-1,9-diazaspiro[3.6]decan-2-one; 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)-2-methyl-6-azaspiro[3.5]nonan-2-ol; 9-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-1,9-diazaspiro[3.6]decan-2-one; 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol; or 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)-2-methyl-6-azaspiro[3.5]nonan-2-ol.

[0067] As embodiment 212, provided herein is a compound of embodiment 1, wherein the compound is selected from: 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-8-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-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)-5-azaspiro[2.5]octan-7-ol (isomer 1); 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)-5-azaspiro[2.5]octan-7-ol (isomer 2); 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,6-diazaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 7-(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)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); 7-(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)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7-methyl-5-azaspiro[2.5]octan-7-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 5-Ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 3-Chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol (isomer 1); 5-Chloro-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-Ethyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-methyl-4-((R)-1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-Ethyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-methyl-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-7-azaspiro[4.5]decan-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,7-diazaspiro[4.5]decan-2-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(5-oxa-8-azaspiro[3.5]nonan-8-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-oxa-7-azaspiro[4.5]decan-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide (isomer 1); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide (isomer 2); 7-(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)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide (isomer 1); 7-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); 7-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 2); 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-azaspiro[3.4]octan-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,6-diazaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-imino-2l6-thia-7-azaspiro[4.5]decane 2-oxide; 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)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 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)-3-oxa-1,8-diazaspiro[4.5]decan-2-one; 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)-1-thia-6-azaspiro[3.5]nonane-1,1-dioxide; (S)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-7-azaspiro[4.5]decan-2-one (isomer 1); (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-7-azaspiro[4.5]decan-2-one (isomer 2); (S)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-dioxa-7-azaspiro[4.5]decan-2-one (isomer 1); (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-dioxa-7-azaspiro[4.5]decan-2-one (isomer 2); 4-(4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-1-one; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-thia-7-azaspiro[4.4]nonane-1,1-dioxide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; or 9-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-1,9-diazaspiro[3.6]decan-2-one.

[0068] As embodiment 213, provided herein is a compound of embodiment 1, wherein the compound is selected from: 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-8-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-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)-5-azaspiro[2.5]octan-7-ol (isomer 1); 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)-5-azaspiro[2.5]octan-7-ol (isomer 2); 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,6-diazaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 7-(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)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); 7-(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)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7-methyl-5-azaspiro[2.5]octan-7-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 5-Ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 3-Chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol (isomer 1); 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-7-azaspiro[4.5]decan-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,7-diazaspiro[4.5]decan-2-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(5-oxa-8-azaspiro[3.5]nonan-8-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-oxa-7-azaspiro[4.5]decan-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide (isomer 1); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide (isomer 2); 7-(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)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide (isomer 1); 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-azaspiro[3.4]octan-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,6-diazaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-imino-2l6-thia-7-azaspiro[4.5]decane 2-oxide; 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)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 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)-3-oxa-1,8-diazaspiro[4.5]decan-2-one; 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)-1-thia-6-azaspiro[3.5]nonane-1,1-dioxide; 4-(4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-1-one; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-thia-7-azaspiro[4.4]nonane-1,1-dioxide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; or 9-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-1,9-diazaspiro[3.6]decan-2-one.

[0069] As embodiment 214, provided herein is a compound of embodiment 1, wherein the compound is selected from: 5-Chloro-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-Ethyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-methyl-4-((R)-1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 6-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol (isomer 1); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 2); 7-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-7-azaspiro[4.5]decan-2-one (isomer 2); or 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)-1,6-diazaspiro[3.5]nonan-2-one (isomer 2).

[0070] As embodiment 215, provided herein is a compound of embodiment 1, selected from one of the following compounds: 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 6-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol (isomer 1); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 2); 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)-1,6-diazaspiro[3.5]nonan-2-one (isomer 2); 3-chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 6-(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)-6-azaspiro[3.5]nonan-2-ol (isomer 1); 6-(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)-6-azaspiro[3.5]nonan-2-ol (isomer 2); 7-(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)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); 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)-2-methyl-6-azaspiro[3.5]nonan-2-ol (isomer 2); 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)-2,6-diazaspiro[3.5]nonan-1-one (isomer 1); 6-(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)-6-azaspiro[3.5]nonan-2-ol (isomer 1); 9-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-1,9-diazaspiro[3.6]decan-2-one; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 7-(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)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,7-diazaspiro[4.5]decan-2-one; 7-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one; 7-(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)-2,7-diazaspiro[4.5]decan-3-one; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide (isomer 1); 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-methyl-1,6-diazaspiro[3.5]nonan-2-one; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-imino-2l6-thia-7-azaspiro[4.5]decane 2-oxide; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxa-1,7-diazaspiro[4.5]decan-2-one; 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)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 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-azaspiro[3.5]nonan-2-ol (isomer 1); or 5-Ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1).

[0071] As embodiment 216, provided herein is a compound of embodiment 1, selected from one of the following compounds: 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 6-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol (isomer 1); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 2); 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)-1,6-diazaspiro[3.5]nonan-2-one (isomer 2); 3-chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 6-(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)-6-azaspiro[3.5]nonan-2-ol (isomer 1); 6-(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)-6-azaspiro[3.5]nonan-2-ol (isomer 2); 7-(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)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); 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)-2-methyl-6-azaspiro[3.5]nonan-2-ol (isomer 2); or 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)-2,6-diazaspiro[3.5]nonan-1-one (isomer 1).

[0072] As embodiment 217, provided herein is a compound of embodiment 1, selected from one of the following compounds: 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 6-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol (isomer 1); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 2); 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)-1,6-diazaspiro[3.5]nonan-2-one (isomer 2); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 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-azaspiro[3.5]nonan-2-ol (isomer 1); 5-Ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 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)-5-azaspiro[2.5]octan-7-ol (isomer 1); 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); or 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide (isomer 2).

[0073] As embodiment 218, the present specification relates to a compound selected from the group consisting of Examples 2, 20, 24, 26, 36, 37, 38, 45, 46, 47, 48, 57, 72, 73, 77, 97, 98, 114, 133, 146, 148, 158, 160, 170, 172, 174, 176, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 232, 236, 237, 238, 240, 242, 244, 246, 248, 250, 252, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 30 194, 196, 206, 217, 220, 224, 227, 232, 233, 234, 235, 247, 252, 262, 265, 266, 267, 272, 280, 282, 283, 284, 286, 288, 293, 294, 300, 305, 307, 318, 319, 322, 323, 324, 328, 329, 330, 337, 338, 344, 351, 359, 364, 365, 392, 393, 395, 396, 397, 405, 406, 407, 409, 410, 411, 413, 415, 416, 417, 424, 425, 428, 433, 434, 441, 442, 444, 445, 446, 447, 448, 449, Provided is a compound of embodiment 1 which is not 450, 451, 452, 453, 454, 462, 464, 466, 467, 468, 469, 470, 476, 478, 480, 481, 484, 498, 500, 502, 503, 507, 508, 509, 510, 513, 515, 516, 518, 521 or 523.

[0074] As embodiment 219, provided herein is a compound of embodiment 1, wherein the compound is not Example 2, 20, 24, 26, 36, 37, 38, 45, 46, 47, 48, 57, 72, 73, 77, 97, 98, 114, 133, 146, 148, 158, 194, 196 or 206 of WO 2022 / 132200 (International Application No. PCT / US2021 / 010065).

[0075] The foregoing description merely summarizes certain aspects of the disclosure and is not intended, nor should it be construed, as limiting the disclosure in any way.

[0076] Formulation and Route of Administration In the described use, the compound disclosed herein can be administered alone, but the compound administered is usually present as an active ingredient in pharmaceutical composition.Therefore, in one embodiment, the pharmaceutical composition provided herein comprises the compound disclosed herein in combination with one or more pharma- ceutically acceptable excipients such as diluent, carrier, adjuvant, and other active ingredients as necessary. 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), first edition, edited by GD Tovey, Royal Society of Chemistry, 2018. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein.

[0077] The compounds disclosed herein may be administered by any suitable route, in the form of a pharmaceutical composition adapted for such route, and in a dose effective for the intended treatment. The compounds and compositions provided herein may be administered, for example, orally, mucosally, topically, transdermally, rectally, pulmonary, parenterally, intranasally, intravascularly, intravenously, intraarterially, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, intravaginally, or by injection techniques, in unit dosage forms containing conventional pharma- ceutically acceptable excipients.

[0078] 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, troche, patch, cream, gel, sachet, microneedle array, syrup, flavored syrup, juice, drop, injection, 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.

[0079] As embodiment 220, provided herein is a pharmaceutical composition comprising a compound of any one of embodiments 1-219, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, and a pharma- ceutically acceptable excipient.

[0080] As embodiment 221, there is provided herein a compound of any one of embodiments 1 to 219, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition of embodiment 220, for use as a medicament.

[0081] How to use As discussed herein (see the section entitled "Definitions"), the compounds described herein should be understood to include all stereoisomers, tautomers, or pharma- ceutically acceptable salts of any of the foregoing, or solvates of any of the foregoing. Accordingly, the scope of methods and uses provided in this disclosure should be understood to encompass methods and uses using all such forms.

[0082] 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.

[0083] In one embodiment, the present disclosure provides a method of using a compound or pharmaceutical composition of the present disclosure to treat a disease state including, but not limited to, a condition (e.g., cancer) in which KRAS G12D, G12V, G12A, G12S, or G12C mutation is implicated. The type of cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendix cancer, endometrial cancer, esophageal cancer, cancer of unknown primary site, ampullary cancer, gastric cancer, small intestine cancer, paranasal sinus cancer, cholangiocarcinoma, or melanoma.

[0084] KRAS G12D mutations occur with the mutation frequencies shown in the table below (TCGA dataset; 1~3 For example, this table shows that 32.4% of subjects with pancreatic cancer have cancer in which one or more cells express the KRAS G12D mutant protein. G12D Compounds provided herein that bind to (see the section entitled "Biological Evaluation" below) are useful for treating subjects with cancer, including but not limited to those listed in the table below.

[0085] [Table 1]

[0086] As embodiment 222, there is provided herein a compound of any one of embodiments 1-219, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 220, for use in treating cancer.

[0087] As embodiment 223, there is provided herein a compound of any one of embodiments 1 to 219, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 220, for use in treating a cancer in which one or more cells express a KRAS G12D, G12V, G12A, G12S, or G12C mutant protein.

[0088] As embodiment 224, there is provided herein a compound or pharmaceutical composition for use in embodiment 222 or 223, 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 type, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia or melanoma.

[0089] As embodiment 225, provided herein is the use of a compound of any one of embodiments 1 to 219 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 220, in the preparation of a medicament for treating cancer.

[0090] As embodiment 226, there is provided herein the use of a compound of any one of embodiments 1 to 219 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 220, 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.

[0091] As embodiment 227, the present specification provides the use of embodiment 225 or 226, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary site, endometrial cancer, mixed cancer type, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia or melanoma.

[0092] As embodiment 228, provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1 to 219, or a pharma- ceutically acceptable salt thereof.

[0093] As embodiment 229, provided herein is a method of treating cancer in a subject in need thereof, wherein one or more cells express a KRAS G12D, G12V, G12A, G12S, or G12C mutant protein, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-219, or a pharma- ceutically acceptable salt thereof.

[0094] As embodiment 230, the present specification provides the method of embodiment 228 or 229, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary site, endometrial cancer, mixed cancer type, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophageal gastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia or melanoma.

[0095] As embodiment 231, the present specification provides the method of embodiment 228 or 229, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendix cancer, endometrial cancer, esophageal cancer, cancer of unknown primary site, ampullary cancer, gastric cancer, small intestine cancer, paranasal sinus cancer, bile duct cancer or melanoma.

[0096] As embodiment 232, provided herein is the method of embodiment 231, wherein the cancer is non-small cell lung cancer.

[0097] As embodiment 233, provided herein is the method of embodiment 231, wherein the cancer is colorectal cancer.

[0098] As embodiment 234, provided herein is the method of embodiment 231, wherein the cancer is pancreatic cancer.

[0099] As embodiment 235, provided herein is the method of any one of embodiments 228 to 234, 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 pharma- ceutically acceptable salt thereof.

[0100] Combination therapy The present disclosure also provides methods for combination therapy using agents known to regulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes, in combination with the compounds of the present disclosure or pharma- ceutically acceptable salts thereof. In one embodiment, such therapy includes, but is not limited to, the combination of one or more compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation therapy to provide synergistic or additive therapeutic effects. See, for example, U.S. Patent No. 10,519,146 B2, issued Dec. 31, 2019, specifically sections 201 (line 37) to 212 (line 46) and 219 (line 64) to 220 (line 39), which are incorporated herein by reference.

[0101] As embodiment 236, provided herein is the method of any one of embodiments 228-235, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an Aurora kinase A inhibitor, an AKT inhibitor, an arginase inhibitor, a CDK4 / 6 inhibitor, an ErbB family inhibitor, an ERK inhibitor, a FAK inhibitor, an FGFR inhibitor, a glutaminase inhibitor, an IGF-1R inhibitor, a KIF18A inhibitor, an MCL-1 inhibitor, a MEK inhibitor, an mTOR inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a PI3K inhibitor, a Raf kinase inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Src kinase inhibitor, or one or more chemotherapeutic agents.

[0102] In one embodiment, the second compound is administered as a pharma- ceutically acceptable salt, hi another embodiment, the second compound is administered as a pharmaceutical composition comprising the second compound or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient.

[0103] Aurora kinase A inhibitors Provided herein is the method of any one of embodiments 228-235, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an Aurora kinase A inhibitor.

[0104] 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-methylpiperazin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl]methyl)-2-methylpiperidine-4-carboxylic acid), (3-phenylethenyl)-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]molybdenum fluoroline), AMG900 (N-[4-[3-(2-aminopyrimidin-4-yl)pyridin-2-yl]oxyphenyl]-4-(4-methylthiophen-2-yl)phthalazin-1-amine), MLN8054 (4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid), PF-03814735 (N-[2-[(1R,8S)-4-[[4-(cyclobutylamino)-5-(trifluoromethyl)pyrimidine-2

[0036] Examples of suitable 5-[2-(4-methyl-5-[2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]-1,3-thiazol-2-amine (TPA-1,3-dihydro-1H-pyrimidin-4-yl)-1,3-thiazol-2-amine) are disclosed herein, but are not limited to, 5-[2-(4-methyl-5-[2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]-1,3-thiazol-2-amine), ...

[0105] AKT inhibitors Provided herein is the method of any one of embodiments 228-235, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an AKT inhibitor.

[0106] 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.

[0107] Arginase inhibitors Provided herein is any one of the methods of embodiments 228-235, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an arginase inhibitor.

[0108] Exemplary arginase inhibitors for use in the methods provided herein include, but are not limited to, numidardistat and CB 280.

[0109] CDK4 / 6 inhibitors Provided herein is any one of the methods of embodiments 228-235, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a CDK4 / 6 inhibitor.

[0110] As used herein, the term "CDK4 / 6" refers to cyclin-dependent kinases ("CDKs") 4 and 6, which are members of the mammalian serine / threonine protein kinases.

[0111] As used herein, the term "CDK4 / 6 inhibitor" refers to a compound capable of negatively regulating or inhibiting all or part of the enzymatic activity of CDK4 and / or 6.

[0112] 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]).

[0113] In one embodiment, the CDK4 / 6 inhibitor is palbociclib.

[0114] ErbB family inhibitors Provided herein is the method of any one of embodiments 228-235, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an ErbB family inhibitor.

[0115] As used herein, the term "ErbB family" refers to members of the mammalian transmembrane protein tyrosine kinase family that includes ErbB1 (EGFR HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4).

[0116] As used herein, the term "ErbB family inhibitor" refers to an agent, e.g., a compound or an antibody, capable of negatively regulating or inhibiting all or part of the activity of at least one member of the ErbB family. This regulation or inhibition of one or more ErbB tyrosine kinases can occur by regulating or inhibiting the kinase enzymatic activity of one or more ErbB family members, or by preventing homodimerization or heterodimerization of ErbB family members.

[0117] In one embodiment, the ErbB family inhibitor is an EGFR inhibitor, such as an anti-EGFR antibody. Exemplary anti-EGFR antibodies used in the methods provided herein include, but are not limited to, zalutumumab, nimotuzumab, matuzumab, necitumumab, panitumumab and cetuximab. In one embodiment, the anti-EGFR antibody is cetuximab. In one embodiment, the anti-EGFR antibody is panitumumab.

[0118] In another embodiment, the ErbB family inhibitor is a HER2 inhibitor, such as an anti-HER2 antibody. Exemplary anti-HER-2 antibodies for use in the methods provided herein include, but are not limited to, pertuzumab, trastuzumab, and trastuzumab emtansine.

[0119] In yet another embodiment, the ErbB family inhibitor is a HER3 inhibitor, for example, an anti-HER3 antibody such as HMBD-001 (Hummingbird Bioscience).

[0120] In one embodiment, the ErbB family inhibitor is a combination of an anti-EGFR antibody and an anti-HER2 antibody.

[0121] 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).

[0122] In one embodiment, the irreversible ErbB family inhibitor is afatinib.In one embodiment, the irreversible ErbB family inhibitor is dacomitinib.

[0123] In one embodiment, the ErbB family inhibitor is a reversible inhibitor. Exemplary reversible ErbB family inhibitors for use in the methods provided herein include erlotinib, gefitinib, sapitinib, varlitinib, tarloxotinib, TAK-285 (N-(2-(4-((3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl)-3-hydroxy-3-methylbutanamide), AEE788 ((S)-6-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-N-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine), BMS Examples of suitable amines 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).

[0124] In one embodiment, the reversible ErbB family inhibitor is sapitinib.In one embodiment, the reversible ErbB family inhibitor is tarloxotinib.

[0125] ERK inhibitors Provided herein is the method of any one of embodiments 228-235, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an ERK inhibitor.

[0126] Exemplary ERK inhibitors for use in the methods provided herein include ulixertinib, lavoxertinib, CC-90003 (N-[2-[[2-[(2-methoxy-5-methylpyridin-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]-5-methylphenyl]prop-2-enamide), LY3214996 (6,6-dimethyl-2-[2-[(2-methyl

[0113] Examples of suitable amine analogs include, but are not limited to, 1,5,6,8-tetrahydro-6-(phenylmethyl)-3-(4-pyridinyl)-7H-pyrazolo[4,3-g]quinazolin-7-one ...

[0127] FAK inhibitors Provided herein is the method of any one of embodiments 228-235, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a FAK inhibitor.

[0128] 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.

[0129] FGFR inhibitors Provided herein is the method of any one of embodiments 228-235, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an FGFR inhibitor.

[0130] 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), debiotin, and rivaroxaban. These include, but are not limited to, 1347 ([5-amino-1-(2-methyl-3H-benzimidazol-5-yl)pyrazol-4-yl]-(1H-indol-2-yl)methanone), INCB062079, H3B-6527 (N-[2-[[6-[(2,6-dichloro-3,5-dimethoxyphenyl)carbamoyl-methylamino]pyrimidin-4-yl]amino]-5-(4-ethylpiperazin-1-yl)phenyl]prop-2-enamide), ICP-105, CPL304110, HMPL-453 and HGS1036.

[0131] Glutaminase Inhibitors Provided herein is the method of any one of embodiments 228-235, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a glutaminase inhibitor.

[0132] Exemplary glutaminase inhibitors for use in the methods provided herein include, but are not limited to, telaglenastat, IPN60090, and OP 330.

[0133] IGF-1R inhibitors Provided herein is any one of the methods of embodiments 228-235, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an IGF-1R inhibitor.

[0134] Exemplary IGF-1R inhibitors for use in the methods provided herein include, but are not limited to, cixutumumab, dalotuzumab, linsitinib, ganitumab, lovatumumab, BMS-754807 ((2S)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide), KW-2450 (N-[5-[[4-(2-hydroxyacetyl)piperazin-1-yl]methyl]-2-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-3-methylthiophene-2-carboxamide), PL225B, AVE1642, and BIIB022.

[0135] KIF18A inhibitors Provided herein is any one of the methods of embodiments 228-235, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a KIF18A inhibitor.

[0136] 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.

[0137] MCL-1 inhibitors Provided herein is any one of the methods of embodiments 228-235, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an MCL-1 inhibitor.

[0138] Exemplary MEK inhibitors for use in the methods provided herein include murizatoclax, topotoclax, AZD 5991 ((3aR)-5-chloro-2,11,12,24,27,29-hexahydro-2,3,24,33-tetramethyl-22H-9,4,8-(methenylaminomethino)-14,20:26,23-dimetheno-10H,20H-pyrazolo[4,3-l][2,15,22,18,19]benzoxadithiadiazacyclohexacosine-32-carboxylic acid), MIK 665 ((αR)-α-[[(5S)-5-[3-chloro-2-methyl-4-[2-(4-methyl-1-piperazinyl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy]-2-[[2-(2-methoxyphenyl)-4-pyrimidinyl]methoxy]benzenepropanoic acid) and ABBV-467.

[0139] In one embodiment, the MCL-1 inhibitor is murizatoclax. In another embodiment, the MCL-1 inhibitor is topotoclax.

[0140] MEK inhibitors Provided herein is the method of any one of embodiments 228-235, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a MEK inhibitor.

[0141] 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), and AZD8330 (2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxopyridine-3-carboxamide). boxamide), GDC-0623 (5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide), RO4987655 (3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-5-[(3-oxooxazinan-2-yl)methyl]benzamide), TAK-733 (3-[(2R)-2,3-dihydroxypropyl]-6-fluoro-5-( 2-Fluoro-4-iodoanilino)-8-methylpyrido[2,3-d]pyrimidine-4,7-dione), PD0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), CI-1040 (2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide), PD318088 (5-bromo-N-(2,3-dihydro

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

[0142] In one embodiment, the MEK inhibitor is trametinib.

[0143] mTOR inhibitors Provided herein is the method of any one of embodiments 228-235, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an mTOR inhibitor.

[0144] Exemplary mTOR inhibitors for use in the methods provided herein include everolimus, rapamycin, zotarolimus (ABT-578), ridaforolimus (deforolimus, MK-8669), sapanisertib, buparlisib, pictilisib, bistusertib, dactolisib, trilin-1 (1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)cyclohexyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthalene ... tilidin-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).

[0145] In one embodiment, the mTOR inhibitor is everolimus.

[0146] PD-1 inhibitors Provided herein is the method of any one of embodiments 228-235, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a PD-1 inhibitor.

[0147] Exemplary PD-1 inhibitors for use in the methods provided herein include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostallimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, and anti-PD-1 antibodies as described in U.S. Pat. No. 10,640,504 B2 ("Anti-PD-1 Antibody A", col. 66, lines 56-67, lines 24 and col. 67, lines 54-57), which are incorporated herein by reference.

[0148] In one embodiment, the PD-1 inhibitor is pembrolizumab. In another embodiment, the PD-1 inhibitor is anti-PD-1 antibody A.

[0149] PD-L1 inhibitors Provided herein is the method of any one of embodiments 228-235, 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.

[0150] 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.

[0151] In one embodiment, the PD-L1 inhibitor is atezolizumab.

[0152] PI3K inhibitors Provided herein is the method of any one of embodiments 228-235, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a PI3K inhibitor.

[0153] Exemplary PI3K inhibitors for use in the methods provided herein include idelalisib, copanlisib, duvelisib, alpelisib, taselisib, perifosine, buparlisib, umbralisib, pictilisib, dactolisib, voxtalisib, sonolicisib, tenalisib, selavelisib, acalisib, CUDC-907 (N-hydroxy-2-[[2-(6-methoxypyridin-3-yl)-4-morpholin-4-ylthieno[3 ,2-d]pyrimidin-6-yl]methyl-methylamino]pyrimidine-5-carboxamide), ME-401 (N-[2-methyl-1-[2-(1-methylpiperidin-4-yl)phenyl]propan-2-yl]-4-(2-methylsulfonylbenzimidazol-1-yl)-6-morpholin-4-yl-1,3,5-triazin-2-amine), IPI-549 (2-amino-N-[(1S)-1-[8-[2-(1-methylpiperidin-4-yl)phenyl]propan-2-yl]-4-(2-methylsulfonylbenzimidazol-1-yl)-6-morpholin-4-yl-1,3,5-triazin-2-amine), 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-2-yl)ethyl)

[0113] Examples of suitable benzothiadiazol-5-ylamino]quinoxalin-2-yl]-4-methylbenzenesulfonamide include, but are not limited to, N-[(1S)-1-(7-fluoro-2-pyridin-2-ylquinolin-3-yl)ethyl]-7H-purin-6-amine, N-[(1H)-1-(7-fluoro-2-pyridin-2-ylquinolin-3-yl)ethyl]-7H-purin-6-amine, N-[(1S)-1-(7-fluoro-2-pyridin-2-ylquinolin-3-yl)ethyl]-7H-purin-6-amine, and N-[(1H)-1-(7-fluoro-2-pyridin-2-ylquinolin-3-yl)ethyl]-7H-purin-6-amine.

[0154] Raf kinase inhibitors Provided herein is the method of any one of embodiments 228-235, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a Raf kinase inhibitor.

[0155] As used herein, the term "RAF kinase" refers to a member of the mammalian serine / threonine kinases that are composed of three isoforms (C-Raf, B-Raf and A-Raf) and includes homodimers of each isoform as well as heterodimers between the isoforms, e.g., C-Raf / B-Raf heterodimers.

[0156] As used herein, the term "Raf kinase inhibitor" refers to a compound capable of negatively regulating or inhibiting all or part of the enzymatic activity of one or more members of the Raf family kinases, or capable of inhibiting activity by preventing the formation of Raf homodimers or heterodimers.

[0157] In one embodiment, the Raf kinase inhibitors include encorafenib, sorafenib, lifirafenib, vemurafenib, dabrafenib, PLX-8394 (N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-3a,7a-dihydro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide), Raf-709 (N-(2-methyl-5-morpholino-6'-((tetrahydro- 2H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide), LXH254 (N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide), LY3009120 (1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidine-6-yl)- (1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)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).

[0158] 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.

[0159] SHP2 inhibitors Provided herein is the method of any one of embodiments 228-235, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a SHP2 inhibitor.

[0160] 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 used in the methods provided herein is RMC-4630 (Revolution Medicine).

[0161] 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).

[0162] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include 1-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-4-methyl-4-piperidinamine (CAS 2240981-75-1), (1R)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine (CAS 2240981-78-4), (3S,4S)-8-[7-(2,3-dichlorophenyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-45-8), (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]pyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine (CAS 2240982-57-2), 4-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-7-(2,3-dichlorophenyl)-6-methyl-pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-69-6), 7-[(2-amino-3-chloro-4-pyridinyl)thio]-4-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-methyl-pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-73-2) and (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-77-6).

[0163] In one embodiment, the SHP inhibitor used 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).

[0164] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-54-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56-5), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-(2,3-dichlorophenyl)-3-pyridinol (CAS 2238840-58-7), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-60-1), (1R)-8-[6-(2,3-dichlorophenyl)-5-methyl-3-pyridinyl]-8-azaspiro[4.5]decane-1-amine (CAS 2238840-62-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2-pyridinemethanol (CAS 2238840-63-4), (1R)-8-[6-[(2,3-dichlorophenyl)thio]-5-methyl-3-pyridinyl]-8-azaspiro[4.5]dec-1-amine (CAS 2238840-64-5), 5-(4-amino-4-methyl-1-piperidinyl)-2-[(2,3-dichlorophenyl)thio]-3-pyridinol (CAS 2238840-65-6), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-[(2,3-dichlorophenyl)thio]-3-pyridinol (CAS 2238840-66-7), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-hydroxy-2-pyridinemethanol (CAS 2238840-67-8), 3-(4-amino-4-methyl-1-piperidinyl)-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-68-9), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-69-0), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-methyl-2-pyridinemethanol (CAS 2238840-70-3), 3-(4-amino-4-methyl-1-piperidinyl)-6-[(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-71-4), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-(4-amino-4-methyl-1-piperidinyl)-2-pyridinemethanol (CAS 2238840-72-5), 5-[(2-amino-3-chloro-4-pyridinyl)thio]-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-methyl-3-pyridinemethanol (CAS 2238840-73-6), 2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-(2,3-dichlorophenyl)-6-methyl-3-pyridinemethanol (CAS 2238840-74-7), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-75-8) and 2-[(2-amino-3-chloro-4-pyridyl)sulfanyl]-5-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(hydroxymethyl)pyridin-3-ol.

[0165] In one embodiment, the SHP inhibitor used 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).

[0166] In one embodiment, the SHP2 inhibitor used 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 herein in its entirety.

[0167] SOS1 inhibitors Provided herein is the method of any one of embodiments 228-235, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an SOS1 inhibitor.

[0168] 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.

[0169] Src kinase inhibitors Provided herein is the method of any one of embodiments 228-235, 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.

[0170] As used herein, the term "Src kinase" refers to members of the mammalian non-receptor tyrosine kinase family that includes Src, Yes, Fyn and Fgr (SrcA subfamily); Lck, Hck, Blk and Lyn (SrcB subfamily) and the Frk subfamily.

[0171] As used herein, the term "Src kinase inhibitor" refers to a compound capable of negatively regulating or inhibiting all or part of the enzymatic activity of one or more members of the Src kinases.

[0172] 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).

[0173] 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.

[0174] Chemotherapeutic agents Provided herein is any one of the methods of embodiments 228-235, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is one or more chemotherapeutic agents.

[0175] Exemplary chemotherapeutic agents for use in the methods provided herein include, but are not limited to, leucovorin calcium (calcium folinate), 5-fluorouracil, irinotecan, oxaliplatin, cisplatin, carboplatin, pemetrexed, docetaxel, paclitaxel, gemcitabine, vinorelbine, chlorambucil, cyclophosphamide, and methotrexate.

[0176] definition The following definitions are provided to aid in understanding the scope of the present disclosure.

[0177] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless otherwise indicated, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending on the standard deviation found in their respective testing measurements.

[0178] As used herein, when any variable occurs more than one time in a chemical formula, its definition at each occurrence is independent of its definition at every other occurrence. In the case of conflict between the chemical structure and the chemical name, the chemical structure is determining the identity of the compound.

[0179] stereoisomer The compounds of the present disclosure may contain, for example, double bonds, one or more asymmetric carbon atoms, and bonds with rotational hindrance, and therefore may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers (E / Z)), enantiomers, diastereomers, and atropisomers. Accordingly, the scope of the present disclosure should be understood to encompass all possible stereoisomers of the exemplified compounds, including stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, diastereomerically pure, and atropisomerically pure), as well as mixtures of stereoisomers (e.g., mixtures of geometric isomers, enantiomers, diastereomers, and atropisomers, or mixtures of any of the foregoing) of any chemical structure (all or part) disclosed herein, unless the stereochemistry is specifically specified.

[0180] If the stereochemistry of a structure or portion of a structure is not shown, e.g., with bold or dashed lines, then the structure or portion of a structure should be interpreted as encompassing all stereoisomers thereof. If the stereochemistry of a structure or portion of a structure is shown, e.g., with bold or dashed lines, then the structure or portion of a structure should be interpreted as encompassing only the stereoisomer shown. A bond drawn with a wavy line indicates that both stereoisomers are encompassed. This wavy line should not be confused with a wavy line drawn perpendicular to a bond, which indicates where a group is attached to the remainder of the molecule.

[0181] As used herein, the term "stereoisomer" or "stereoisomerically pure" compound refers to one stereoisomer of a compound (e.g., geometric isomer, enantiomer, diastereomer, and atropisomer) that is substantially free of other stereoisomers of the compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of that compound, and a stereoisomerically pure compound having two chiral centers will be substantially free of other enantiomers or diastereomers of that compound. Typical stereoisomerically pure compounds comprise greater than about 80% by weight of the compound of one stereoisomer and about 20% or less by weight of the compound of the other stereoisomer, greater than about 90% by weight of the compound of one stereoisomer and about 10% or less by weight of the compound of the other stereoisomer, greater than about 95% by weight of the compound of one stereoisomer and about 5% or less by weight of the compound of the other stereoisomer, or greater than about 97% by weight of the compound of one stereoisomer and about 3% or less by weight of the compound of the other stereoisomer.

[0182] The present disclosure also encompasses pharmaceutical compositions comprising stereoisomerically pure forms and the use of any of the compounds disclosed herein in stereoisomerically pure form. Additionally, the present disclosure also encompasses pharmaceutical compositions comprising mixtures of stereoisomers of any of the compounds disclosed herein and the use of said pharmaceutical compositions or mixtures of stereoisomers. These stereoisomers or mixtures thereof can be synthesized according to methods well known in the art and disclosed herein. Mixtures of stereoisomers can be resolved using standard techniques, such as chiral columns or chiral resolving agents. Additionally, the present disclosure encompasses pharmaceutical compositions comprising mixtures of any of the compounds disclosed herein with one or more other active agents disclosed herein. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725; Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0183] Tautomers As known to those skilled in the art, certain compounds disclosed herein may exist in one or more tautomeric forms.Since one chemical structure can only be used to represent one tautomeric form, for convenience, it will be understood that reference to a compound of a given structural formula includes other tautomeric forms of said structural formula.Therefore, the scope of the present disclosure should be understood to include all tautomeric forms of the compounds disclosed herein.

[0184] isotope labeled compounds Additionally, the scope of the present disclosure includes all pharma- ceutically acceptable isotopically labeled compounds of the compounds disclosed herein, such as compounds of Formula I, in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds disclosed herein include: 2 H and 3 Hydrogen such as H 11 C. 13 C and 14 Carbon, such as C 36 Chlorine such as Cl, 18 Fluorine such as F 123 I and 125 Iodine, such as I 13 N and 15 Nitrogen such as N 15 O. 17 O and 18 Oxygen, such as O 32 Phosphorus such as P 35 Certain isotopically labeled compounds of formula I, for example those incorporating a radioactive isotope, are useful for studying the tissue distribution of drugs and / or substrates. 3 H) and carbon-14 ( 14 C) is particularly useful for this purpose given its ease of incorporation and ready means of detection. 2 Substitution with isotopes such as H or D may be preferred in some circumstances since they may afford certain therapeutic advantages resulting from increased metabolic stability, such as increased in vivo half-life or reduced dosage requirements. 11 C. 18 F, 15 O and 13 Substitution with positron-emitting isotopes such as N may be useful, for example, in positron emission tomography (PET) studies to determine target occupancy. Isotopically labeled compounds of the compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the accompanying general synthetic schemes and examples, using appropriate isotopically labeled reagents in place of conventionally used non-labeled reagents.

[0185] solvate As mentioned above, the compounds disclosed herein as well as the stereoisomers, tautomers, and isotopically labeled forms thereof, or pharma- ceutically acceptable salts of any of the foregoing, can exist in solvated or unsolvated forms.

[0186] As used herein, the term "solvate" refers to a molecular complex comprising a compound described herein or a pharma- ceutically acceptable salt thereof and a stoichiometric or non-stoichiometric amount of one or more pharma- ceutical acceptable solvent molecules. When the solvent is water, the solvate is referred to as a "hydrate."

[0187] Accordingly, the scope of the present disclosure should be understood to encompass all solvates of the compounds disclosed herein and their stereoisomers, tautomers, and isotopically labeled forms or pharma- ceutically acceptable salts of any of the foregoing.

[0188] Various definitions This section defines additional terms used to describe the scope of the compounds, compositions and uses disclosed herein.

[0189] The term "aryl" refers to an aromatic hydrocarbon group having 6-20 carbon atoms in the ring portion. Typically, aryl is a monocyclic, bicyclic or tricyclic aryl having 6-20 carbon atoms. Furthermore, the term "aryl" as used herein refers to an aromatic substituent which may be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl, each of which may be optionally substituted with 1-4 substituents such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(O)-O-, aryl-O-, heteroaryl-O-, amino, thiol, alkyl-S-, aryl-S-, nitro, cyano, carboxy, alkyl-OC(O)-, carbamoyl, alkyl-S(O)-, sulfonyl, sulfonamido, phenyl and heterocycloalkyl.

[0190] 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.

[0191] 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.

[0192] As used herein, the term "C 2~4 "Alkenyl" refers to a saturated hydrocarbon containing 2 to 4 carbon atoms having at least one carbon-carbon double bond. Alkenyl groups include both straight-chain and branched-chain moieties. 2~4 Representative examples of alkenyl include, but are not limited to, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, and butenyl.

[0193] 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.

[0194] As used herein, the term "C 1~4 Alkoxy" or "C 1~6 "Alkoxy" is -OR # As defined herein, R # are C 1~4 Alkyl group or C 1~6 Represents an alkyl group. 1~4 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy, and butoxy. 1~6 Representative examples of alkoxy include, but are not limited to, ethoxy, propoxy, iso-propoxy, and butoxy.

[0195] 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.

[0196] When used herein as a prefix for another term in reference to a chemical group, the term "deuterium" refers to an atom or atoms in which one or more hydrogen atoms have been replaced with a heavy atom ("D" or " 2 For example, the term "C 1~4 "Deuteroalkyl" refers to a C alkyl group, as defined herein, in which one or more hydrogen atoms have been replaced with D. 1~4 Refers to alkyl. 1~4 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).

[0197] As used herein, the term "halogen" refers to -F, -Cl, -Br, or -I.

[0198] The term "halo," as used herein as a prefix of another term for a chemical group, refers to a modification of a chemical group in which one or more hydrogen atoms have been replaced with a halogen, as defined herein. 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. 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).

[0199] As used herein, the term "heteroaryl" refers to a 5-20 membered monocyclic, bicyclic or tricyclic aromatic ring system having 1-8 heteroatoms selected from N, O and S. In certain preferred embodiments, the heteroaryl is a 5-10 membered ring system (e.g., a 5-7 membered monocyclic, an 8-10 membered bicyclic or an 11-14 membered tricyclic) or a 5-7 membered ring system. Exemplary monocyclic heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4- or 5-pyrazinyl, 2-pyrazinyl, and 2-, 4- and 5-pyrimidinyl. Exemplary bicyclic heteroaryl groups include 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 2-, 4-, 5-, 6-, 7- or 8-benzimidazolyl, and 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-indolyl.

[0200] The term "heteroaryl" also refers to groups in which a heteroaromatic ring is fused to one or more aryl, aliphatic, or heterocycloalkyl rings.

[0201] As used herein, the term "heterocycle", "heterocycloalkyl" or "heterocyclo" refers to a saturated or unsaturated non-aromatic ring or ring system, such as a 4-, 5-, 6- or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic or 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system, and containing at least one heteroatom selected from O, S and N, which may also be optionally oxidized to various oxidation states. The heterocyclic group may be attached at a heteroatom or a carbon atom. Heterocycloalkyl may 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.

[0202] As used herein, the term "pharmaceutical acceptable" generally refers to something that is recognized for use in subjects, particularly humans.

[0203] As used herein, the term "pharmaceutical acceptable salt" refers to a salt of a compound that is pharmaceutical acceptable and has the desired pharmacological activity of the parent compound. Such salts include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, etc.; or (2) salts formed when the acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth ions, or aluminum ions; or salts formed when coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine, etc. Further examples of such salts can be found in Berge et al., J. Pharm. Sci. 66(1):1-19 (1977). Also, Stahl et al., Pharmaceutical Salts: Properties, Selection, and Use, 2 nd See also the Revised Edition (2011).

[0204] As used herein, the term "pharmaceutical acceptable excipient" refers to a wide range of ingredients that can be combined with the compounds or salts disclosed herein to prepare pharmaceutical compositions or formulations.Typically, excipients include, but are not limited to, diluents, colorants, vehicles, anti-adhesive agents, glidants, disintegrants, flavoring agents, coating agents, binders, sweeteners, lubricants, adsorbents, preservatives, etc.

[0205] 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.

[0206] As used herein, the term "therapeutically effective amount" refers to an amount of a compound disclosed herein that elicits the biological or medical response in a tissue, system, or subject desired by a researcher, veterinarian, medical doctor, or other clinician.

[0207] 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 illustrative, and the compounds disclosed herein can also be synthesized by alternative routes using alternative synthetic strategies, as will be appreciated by those skilled in the art. It will be understood that the general synthetic procedures and specific examples provided herein are merely illustrative and should not be construed as limiting the scope of the present disclosure in any way.

[0208] 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 stated. All starting materials are commercially available, for example from Merck Sigma-Aldrich Inc., Fluorochem Ltd, and Enamine Ltd., or are known in the art and may be synthesized by using known procedures using routine techniques. Starting materials may also be synthesized by the procedures disclosed herein. Suitable reaction conditions, such as solvents, reaction temperatures, and reagents for the schemes described in this section can be found in the examples provided herein. [ka]

[0209] 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, a compound of formula R is reacted with an aliphatic alcohol, such as benzyl alcohol, and a base, such as Hunig's base, in a solvent, such as acetonitrile, to give compound (I-3). 1 The compound (I-2) is reacted with a nucleophile having -LH to form S N In step C, compound (I-3) is coupled with an organometallic reagent or a boronic acid (ester) to provide compound (I-4). The coupling reaction proceeds in a solvent or mixture of solvents, such as 1,4-dioxane and water, with or without a base, such as potassium phosphate, and a catalyst, such as cataCXium A Pd G3. In step D, compound (I-4) is treated with a suitable set of reagents, such as Pd / C with H2 to remove the alkyl group R to provide 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 provide a compound of formula (I). In some cases, the species R 3 contains a protecting group, which can be removed during step D or after step E of the synthetic sequence. [ka]

[0210] Compounds of formula (I) can also be prepared according to Scheme II. In step A, an optionally substituted cyclic amine and compound (1) are reacted with S to afford compound (1) in the presence of a base such as Hunig's base in a solvent such as dichloromethane. N In step B, a compound of formula R is reacted with 1,2-dichlorophenyl ether in a solvent such as acetonitrile in the presence of a base such as Hunig's base to obtain compound (I-10). 1 The compound (I-10) is reacted with a nucleophile having -LH to form S NIn 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 in a solvent or mixture of solvents such as 1,4-dioxane and water, with or without a base such as potassium phosphate, and a catalyst such as cataCXium A Pd G3. In some cases, the species R 3 contains a protecting group, which can be removed after step C of the synthetic sequence. EXAMPLES

[0211] This section provides specific examples of compounds of Formula I and methods for their preparation.

[0212] List of abbreviations

[0213] [Table 2]

[0214] [Table 3]

[0215] [Table 4]

[0216] General analytical and purification methods This section provides a description of the general analytical and purification methods used to prepare the specific examples provided herein.

[0217] Chromatography: Unless otherwise indicated, residues containing crude product were purified by passing the crude material or concentrate through a Biotage or ISCO brand silica gel column pre-packed with flash silica (SiO2) and eluting the product from the column with a solvent gradient as indicated.

[0218] Preparative HPLC Methods: Where indicated, compounds described herein were purified by reverse-phase HPLC using a Waters Fractionlynx or Gilson semi-preparative HPLC-MS system using one of the following two HPLC columns: (a) a Phenomenex Gemini column (5 micron, C18, 150 x 30 mm) or (b) a Waters X-select CSH column (5 micron, C18, 100 x 30 mm). A typical run through the instrument involves eluting with a linear gradient of 10% (v / v) to 100% MeCN (0.1% v / v formic acid) in water (0.1% formic acid) at 45 mL / min over 10 minutes; conditions may be varied to achieve optimal separation.

[0219] 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. 1 Some of the H signals may be missing due to exchange with D from MeOD or signal suppression.

[0220] Mass Spectrum (MS): Unless otherwise indicated, all mass spectral data for starting materials, intermediates and / or example 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 generally reported according to the detected isotopic pattern.

[0221] Preparation of intermediates 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (Intermediate A) [ka] Step 1: 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine. To a 250 mL round bottom flask charged with activated 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 give 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (3.30 g, 10.18 mmol, 43% yield). m / z (ESI): 325.9 (M+H). + .

[0222] Step 2: 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine. To a solution of 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (3.30 g, 10.18 mmol) in acetonitrile (20 mL) was added ((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (1.78 g, 11.20 mmol) and DIPEA (5.26 g, 7.1 mL, 40.7 mmol). The reaction was stirred at 80° C. for 1 h. The volatiles were removed under reduced pressure and the mixture was purified by column chromatography on silica gel eluting with 0-100% 3:1 EtOAc / EtOH blend in heptane with 2% triethylamine to give 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (2.60 g, 5.82 mmol, 57% yield): m / z (ESI): 447.0 (M+H). + .

[0223] Step 3: 4-(benzyloxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine. To a solution of 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (2.60 g, 5.82 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.14 g, 8.73 mmol) in tetrahydrofuran (17 mL) and water (1.7 mL) was added potassium phosphate (3.70 g, 17.45 mmol) and cataCXium A Pd G3 (0.85 g, 1.16 mmol). The reaction mixture was stirred at 70° C. for 2 hours. The reaction mixture was purified by column chromatography on silica gel eluting with 0-50% 3:1 EtOAc / EtOH blend in heptane containing 2% triethylamine additive to give 4-(benzyloxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (2.42 g, 3.75 mmol, 65% yield). m / z (ESI): 645.0 (M+H) + .

[0224] Step 4: 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol. 4-(benzyloxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (2.42 g, 3.75 mmol) was dissolved in ethyl acetate (75 mL). Palladium on carbon (0.80 g, 0.75 mmol) was added and the mixture was stirred at room temperature under H2 atmosphere overnight. The mixture was filtered through Celite and the cake was washed with DCM:MeOH (2:1) until the filtrate was clear. The volatiles were removed in vacuo to give 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol as a slightly brownish foam which was used without further purification. m / z (ESI): 555.0 (M+H) + .

[0225] 7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (Intermediate B) [ka] Step 1: 4-(tert-butoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine. To a stirred 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 slowly over 0.5 h. After 1 h, additional potassium tert-butoxide (1.0 M in THF, 2.5 mL) was added. The resulting mixture was stirred at -40°C for 10 min, then poured into ice and saturated aqueous ammonium hydroxide solution, and then 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) + .

[0226] 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% in DCM (20% MeOH in DCM) to give 4-(tert-butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (0.66 g, 1.60 mmol, 80% yield) as an off-white solid. m / z (ESI): 413.2 (M+H). + .

[0227] 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 min, then sealed and irradiated under microwave at 85 °C for 3 h. Volatiles were removed under reduced pressure and the crude residue was purified by column chromatography on silica gel eluting with a gradient of 0-50% 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) + .

[0228] Step 4: 7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol. To a stirred solution of 4-(tert-butoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (0.84 g, 1.38 mmol) in MeCN (2.0 mL) was added HCl (4M in dioxane, 12 mL, 48.1 mmol) at room temperature. The resulting mixture was stirred at room temperature for 0.5 h. Volatiles were removed under reduced pressure. The crude residue was dissolved in MeOH / DCM, cooled in a water bath and neutralized with ammonium hydroxide before being loaded onto a silica gel precolumn and purified by column chromatography on silica gel eluting with a gradient of 0-50% in DCM (20% MeOH in DCM) to give 7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (0.39 g, 0.76 mmol, 56% yield) as an off-white solid. m / z (ESI): 511.0 (M+H) + .

[0229] 1-Methyl-1,6-diazaspiro[3.5]nonan-2-one (Intermediate C) [ka] Step 1: Benzyl 2-oxo-1,6-diazaspiro[3.5]nonane-6-carboxylate. 1,6-Diazaspiro[3.5]nonane-2-one (0.30 g, 2.14 mmol) was dissolved in THF (5.0 mL) and water (1.0 mL). The mixture was cooled to 0° C. and DIPEA (0.83 mg, 1.1 mL, 6.42 mmol) was added, followed by dropwise addition of Cbz-Cl (0.44 g, 0.37 mL, 2.57 mmol). The mixture was allowed to warm to room temperature and then stirred for 3 h. Water (5 mL) was added and the mixture was extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified by column chromatography on silica gel eluting with a gradient of 0-70% 3:1 EtOAc / EtOH in heptane to give benzyl 2-oxo-1,6-diazaspiro[3.5]nonane-6-carboxylate (0.47 g, 1.7 mmol, 79% yield) as a colorless oil. m / z (ESI): 275.0 (M+H). + .

[0230] Step 2: Benzyl 1-methyl-2-oxo-1,6-diazaspiro[3.5]nonane-6-carboxylate. Benzyl 2-oxo-1,6-diazaspiro[3.5]nonane-6-carboxylate (0.26 g, 0.95 mmol) was dissolved in THF (9.5 mL). The mixture was cooled to 0° C. and sodium hydride (46 mg, 1.14 mmol) was added. The mixture was stirred at 0° C. for 45 minutes, after which iodomethane (0.16 g, 0.07 mL, 1.14 mmol) was added dropwise. The mixture was allowed to warm to room temperature and then stirred for 3 hours. The mixture was then cooled to 0° C. before a saturated NH4Cl solution (5 mL) was slowly added. The reaction was then stirred and extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4, filtered, and the volatiles were removed in vacuo. The crude mixture was purified by column chromatography on silica gel eluting with a gradient of 0-100% 3:1 EtOAc / EtOH in heptane to give benzyl 1-methyl-2-oxo-1,6-diazaspiro[3.5]nonane-6-carboxylate (98 mg, 0.34 mmol, 36% yield) as a brown oil. m / z (ESI): 289.0 (M+H). + .

[0231] Step 3: 1-Methyl-1,6-diazaspiro[3.5]nonan-2-one. Benzyl 1-methyl-2-oxo-1,6-diazaspiro[3.5]nonane-6-carboxylate (98 mg, 0.34 mmol), ammonium formate (0.11 g, 1.7 mmol) and Pd / C (0.11 g, 0.10 mmol) were mixed in ethanol (4.0 mL) and the reaction was stirred at 40° C. for 2 h. The mixture was filtered through Celite and washed with EtOH (10 mL). The volatiles were removed in vacuo to give 1-methyl-1,6-diazaspiro[3.5]nonan-2-one (51 mg, 0.33 mmol, 97% yield) as a colorless oil which was used without further purification. m / z (ESI): 155.2 (M+H) + .

[0232] 7-Methyl-5-azaspiro[2.5]octan-7-ol 2,2,2-trifluoroacetate (Intermediate D) [ka] tert-Butyl 7-oxo-5-azaspiro[2.5]octane-5-carboxylate (0.10 g, 0.44 mmol) was dissolved in THF (2.2 mL). The solution was cooled to 0° C. Methylmagnesium bromide (3.0 M in diethyl ether, 0.18 mL, 0.53 mmol) was added dropwise and the mixture was stirred at 0° C. for 2 h. Saturated NH4Cl (5 mL) was added dropwise to the solution. The layers were separated and the aqueous phase was washed with EtOAc (3×5 mL). The combined organic phase was dried over Na2SO4, filtered and the volatiles were removed in vacuo. The residue was then dissolved in DCM (4.0 mL) and TFA (1.0 mL). The reaction was stirred at room temperature for 3 h. The volatiles were removed in vacuo to give 7-methyl-5-azaspiro[2.5]octan-7-ol 2,2,2-trifluoroacetate, which was used in the next step without further manipulation. m / z (ESI): 142.2 (M+H). + .

[0233] 6-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (Intermediate E1) [ka] ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.00 g, 1.95 mmol, LabNetwork) was dissolved in tetrahydrofuran (4 mL). HCl (4 M in dioxane, 0.71 g, 0.71 mL, 19.51 mmol, Sigma-Aldrich Corporation) was added. The reaction mixture was stirred at room temperature for 5 h and then the volatiles were removed in vacuo. The residue was purified by column chromatography on silica gel eluting with a gradient of 0-50% EtOAc / heptane to give 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (0.89 g, 1.90 mmol, 97% yield). m / z (ESI): 469.0 (M+H) + .

[0234] [Table 5]

[0235] 2-(8-ethyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate F) [ka] Step 1: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol. A pressure relief vial was charged with potassium acetate (1.21 g, 12.3 mmol, Sigma Aldrich), 7-fluoro-1-naphthol (1.00 g, 6.17 mmol, Enamine), dichloro(p-cymene)ruthenium(II) dimer (0.38 g, 0.62 mmol, Alfa Aesar) and then purged with nitrogen 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 stirring at room temperature for 2 days. The volatiles were removed in vacuo and the crude material was absorbed onto silica gel. The crude product was purified by column chromatography on silica gel eluting with a gradient of 0-20% EtOAc in heptane to give 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (1.90 g, 5.55 mmol, 90% yield) as a yellow oil. m / z (ESI, +ve ion): 343.0 (M+H). + .

[0236] 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 dropwise addition of pivaloyl chloride (1.06 g, 1.08 mL, 8.76 mmol, Sigma-Aldrich Corporation). The mixture was allowed to warm to room temperature and stirred for 45 min. Water (10 mL) was added and the aqueous layer was extracted with DCM (2×10 mL). The combined organic phase was dried over anhydrous 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 give 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). + .

[0237] Step 3: 8-Ethyl-7-fluoronaphthalen-1-ol. A scintillation vial was charged with 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl pivalate (1.13 g, 2.65 mmol) and dissolved in DMF (12 mL). Cesium fluoride (4.02 g, 26.5 mmol, Sigma-Aldrich Corporation) was added and the mixture was stirred at room temperature for 30 min. Water (100 mL) was added and the aqueous phase was extracted with EtOAc (2×20 mL). The combined organic layers were dried over Na2SO4 and then the volatiles were removed in vacuo to give 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.

[0238] 8-Ethynyl-7-fluoronaphthalen-1-yl pivalate (0.72 mg, 2.65 mmol) was dissolved in MeOH (9 mL) and palladium on carbon (85 mg, 0.795 mmol, Sigma-Aldrich Corporation) was added. The reaction vessel was purged with H2 and then stirred under H2 atmosphere (15 psi) at room temperature for 2 h. The mixture was filtered through Celite, washed with EtOAc until the filtrate was clear, and the volatiles were removed in vacuum. 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 h, 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 Na2SO4 and the volatiles were removed in vacuum. 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 give 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). + .

[0239] 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 dropwise addition of 1 M Tf2O solution (2.02 mL, 2.02 mmol, Sigma-Aldrich Corporation). The mixture was stirred at room temperature for 20 min and poured into ice water (20 mL). The aqueous phase was extracted with DCM (2×10 mL), the combined organic layers were dried over Na2SO4, and the volatiles were removed in vacuo. The crude mixture was purified by column chromatography on silica gel eluting with a gradient of 0 to 5% EtOAc in heptane to give 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).

[0240] 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 relief vial and dried under vacuum. Then 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 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 give 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). + .

[0241] 1,3-Dioxa-7-azaspiro[4.5]decan-2-one hydrochloride (Intermediate G) [ka] Step 1: tert-Butyl 2-oxo-1,3-dioxa-7-azaspiro[4.5]decane-7-carboxylate. A 40 mL vial was charged with tert-butyl 3-hydroxy-3-(hydroxymethyl)piperidine-1-carboxylate (0.75 g, 3.24 mmol, Combi-Blocks Inc.), 1,1'-carbonyldiimidazole (0.63 g, 3.89 mmol, Acros Organics), and triethylamine (0.39 g, 0.55 mL, 3.90 mmol). Dichloromethane (16 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction was concentrated under reduced pressure to give a crude oil which was then purified by column chromatography on silica gel using a gradient of 0-100% EtOAc (with 2% triethylamine) in heptane to give tert-butyl 2-oxo-1,3-dioxa-7-azaspiro[4.5]decane-7-carboxylate (0.83 g, 3.21 mmol, 99% yield) as a colorless oil. m / z (ESI): 202.2 (M+H-Bu). + .

[0242] Step 2: 1,3-Dioxa-7-azaspiro[4.5]decan-2-one hydrochloride. A 40 mL vial was charged with tert-butyl 2-oxo-1,3-dioxa-7-azaspiro[4.5]decane-7-carboxylate (0.65 g, 2.53 mmol) and diluted with acetonitrile (25 mL). 4 M HCl in 1,4-dioxane (6.3 mL, 25.2 mmol) was then added and the reaction was stirred at room temperature. After 1.5 h, the reaction was concentrated under reduced pressure to give 1,3-dioxa-7-azaspiro[4.5]decan-2-one hydrochloride (0.41 g, 2.13 mmol, 84% yield) as a white solid. m / z (ESI): 158.2 (M+H) + .

[0243] 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-azaspiro[3.5]nonan-8-ol (Example 1) [ka] Step 1: 6-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-8-ol. A mixture of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (0.20 g, 0.79 mmol, LabNetwork) in DCM (4.0 mL) was cooled to 0° C. Then 6-azaspiro[3.5]nonan-8-ol (0.13 g, 0.95 mmol, Enamine) was added followed by DIPEA (0.12 g, 0.17 mL, 0.95 mmol, Sigma-Aldrich Corporation). The reaction mixture was stirred at 0° C. for 1 h. The solvent was removed in vacuo and the crude material was used in the next step without further purification. m / z (ESI): 357.1 (M+H) + .

[0244] Step 2: 6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-8-ol. The crude 6-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-8-ol from above was then dissolved in N,N-dimethylformamide (1.3 mL) and tetrahydrofuran (2.6 mL). Cesium carbonate (0.77 g, 2.38 mmol, Sigma-Aldrich Corporation), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (0.25 g, 1.59 mmol, LabNetwork) and 1,4-diazabicyclo[2.2.2]octane (18 mg, 0.16 mmol, Sigma-Aldrich Corporation) were added and the mixture was stirred at 60° C. overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic extracts were dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material as a pale yellow oil. The crude material was purified by column chromatography on a silica gel column eluting with a gradient of 0-100% 3:1 EtOAc / EtOH in heptane to give 6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-8-ol (98 mg, 0.20 mmol, 26% yield) as an orange solid. m / z (ESI): 480.3 (M+H). + .

[0245] Step 3: 6-(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)-6-azaspiro[3.5]nonan-8-ol. A 20 mL vial was charged with cataCXium A Pd G3 (74 mg, 0.10 mmol, Sigma-Aldrich Corporation), potassium phosphate (0.13 g, 0.61 mmol, Acros Organics), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.15 g, 0.41 mmol, LabNetwork), 6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-8-ol (98 mg, 0.20 mmol), water (0.2 mL) and tetrahydrofuran (1.9 mL). The reaction was stirred at 60° C. for 1 h. After cooling, the crude mixture was purified by column chromatography on silica gel eluting with a gradient of 0-100% 3:1 EtOAc / EtOH in heptane with 2% triethylamine to give 6-(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)-6-azaspiro[3.5]nonan-8-ol (0.13 g, 0.19 mmol, 92% yield). m / z (ESI): 678.4 (M+H) + .

[0246] Step 4: 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-azaspiro[3.5]nonan-8-ol. In a 20 mL vial, 6-(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)-6-azaspiro[3.5]nonan-8-ol (0.13 g, 0.19 mmol), HCl (4 M in dioxane, 1.2 mL, 4.68 mmol, Sigma-Aldrich Corporation) and acetonitrile (3.5 mL) were added at 0° C. The reaction was stirred at the same temperature for 30 min. The volatiles were removed under reduced pressure. The crude material was purified by reverse phase HPLC to give 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-azaspiro[3.5]nonan-8-ol (73 mg, 0.10 mmol, 52% yield) as the 2,2,2-trifluoroacetate as a pale yellow solid. m / z (ESI): 634.3 (M+H). + . 1H NMR(400MHz,メタノール-d4)δ ppm 9.30(dd,J=12.9,2.2Hz,1H),7.71(dd,J=9.0,5.9Hz,1H),7.34(d,J=2.7Hz,1H),7.28(t,J=9.4Hz,1H),7.10(dd,J=7.7,2. 5Hz,1H),5.48-5.71(m,1H),4.72(m,J=7.9Hz,2H),4.48-4.59(m,1H),4.33-4.44(m,1H),4.05-4.12(m,1H),3.85-4.03(m, 4H),3.77(dd,J=13.3,3.4Hz,1H),3.59-3.67(m,1H),3.47-3.55(m,1H),3.42(ddd,J=12.7,9.1,3.4Hz,1H),2.55-2.63(m, 1H),2.32-2.54(m,4H),2.14-2.24(m,2H),1.96-2.03(m,3H),1.80-1.93(m,2H),1.61-1.79(m,2H),0.82(t,J=7.3Hz,3H).

[0247]

Table 6

[0248]

Table 7

[0249]

Table 8

[0250]

Table 9

[0251]

Table 10

[0252]

Table 11

[0253]

Table 12

[0254]

Table 13

[0255]

Table 14

[0256]

Table 15

[0257]

Table 16

[0258]

Table 17

[0259]

Table 18

[0260]

Table 19

[0261]

Table 20

[0262]

Table 21

[0263] [Table 22]

[0264] Further steps of Example 11 [ka] 6-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-one (0.60 g, 1.26 mmol) was dissolved in methanol (5.0 mL) and the solution was cooled to 0° C. Sodium borohydride (71 mg, 1.88 mmol, Sigma-Aldrich Corporation) was added dropwise and the mixture was stirred at 0° C. for 90 min. The volatiles were removed in vacuo and the residue was redissolved in DCM (20 mL) and extracted with saturated NH4Cl (20 mL). The aqueous layer was extracted with DCM (2×20 mL). The combined organic layers were dried over Na2SO4 and the volatiles removed in vacuo to afford 6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol (0.47 g, 0.98 mmol, 78% yield) as a yellow solid which was used in the next step without further purification. m / z (ESI): 480.0 (M+H). + .

[0265] Further steps of Example 17 [ka] 7-(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)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (0.16 g, 0.20 mmol) was dissolved in DMF (2.0 mL). Cesium fluoride (0.31 g, 2.02 mmol, Sigma-Aldrich Corporation) was added. The mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate was purified by reverse phase HPLC to give the bis(2,2,2-trifluoroacetate) 7-(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)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (55 mg, 0.06 mmol, 31% yield) as a yellow solid.

[0266] [Table 23]

[0267] [Table 24]

[0268] [Table 25]

[0269] [Table 26]

[0270] [Table 27]

[0271] [Table 28]

[0272] [Table 29]

[0273] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-7-azaspiro[4.5]decan-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Example 27) [ka] Step 1: 7-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-7-azaspiro[4.5]decane. To a suspension of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (0.15 g, 0.59 mmol, LabNetwork) in acetonitrile (3.0 mL) at 0° C. was added 1-oxa-7-azaspiro[4.5]decane (84 mg, 0.59 mmol, Enamine) and DIEA (0.31 g, 0.4 mL, 2.38 mmol, Sigma Aldrich). The reaction was stirred at 0° C. Separately, a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (0.17 g, 1.07 mmol, LabNetwork) in acetonitrile (1.0 mL) was dried over anhydrous magnesium sulfate. The mixture was stirred at ambient temperature for 5 min and then filtered through Celite to remove magnesium sulfate. After 15 min, the two solutions were mixed together and stirred at 80° C. overnight. The reaction was cooled to room temperature and concentrated under reduced pressure. The crude material was purified by column chromatography on a silica gel column eluting with a gradient of 0-75% 3:1 EtOAc / EtOH (containing 2% triethylamine) in heptane to give 7-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-7-azaspiro[4.5]decane (0.24 g, 0.50 mmol, 85% yield) as an orange solid. m / z (ESI): 480.0 (M+H). + .

[0274] Step 2: 7-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-7-azaspiro[4.5]decane. A vial was charged with 7-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-7-azaspiro[4.5]decane (50 mg, 0.10 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (56 mg, 0.16 mmol, PharmaBlock), potassium phosphate (66 mg, 0.31 mmol, Sigma Aldrich Corporation) and cataCXium A Pd G3 (15 mg, 0.02 mmol, Sigma Aldrich Corporation). The vial was purged with nitrogen and then the reactants were suspended in degassed tetrahydrofuran (0.9 mL) and water (0.1 mL). The reaction was then sealed and stirred at 65° C. for 4.5 hours. The reaction was then cooled to room temperature and concentrated under reduced pressure to give a crude black oil. This oil was then purified by column chromatography on silica gel eluting with a gradient of 0-75% 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane to give 7-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-7-azaspiro[4.5]decane as an off-white solid, which was used directly in the next step. m / z (ESI): 678.2 (M+H) + .

[0275] Step 3: 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-7-azaspiro[4.5]decan-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol. The above 7-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-7-azaspiro[4.5]decane was then dissolved in MeCN (3.0 mL) and HCl (4M in 1,4-dioxane, 0.5 mL, 2.08 mmol, Sigma-Aldrich Corporation) was added. The reaction was stirred at room temperature for 20 minutes. The reaction was cooled to room temperature and concentrated under reduced pressure to give a crude yellow solid. This oil was then purified by reverse phase HPLC to give 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-7-azaspiro[4.5]decan-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (44 mg, 0.06 mmol, 57% yield) as the 2,2,2-trifluoroacetate as a pale yellow solid. m / z (ESI): 634.2 (M+H). + . 1 H NMR(400MHz, methanol-d4)δ ppm 9.25(d,J=11.4Hz,1H),7.65-7.75(m,1H),7.34(d,J=2.5Hz,1H),7.24- 7.32(m,1H),7.04-7.12(m,1H),5.47-5.70(m,1H),4.57-4.78(m,3H),4. 32-4.46(m,1H),3.63-4.14(m,6H),3.40-3.60(m,2H),2.55-2.85(m,2H) ),2.32-2.54(m,4H),2.08-2.28(m,3H),1.76-2.08(m,7H),0.82(m,3H).

[0276] [Table 30]

[0277] [Table 31]

[0278] [Table 32]

[0279] [Table 33]

[0280] [Table 34]

[0281] [Table 35]

[0282] [Table 36]

[0283] [Table 37]

[0284] 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-azaspiro[3.4]octan-2-ol (Example 37) [ka] Step 1: 6-(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)-6-azaspiro[3.4]octan-2-ol. A 4 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 (26 mg, 0.05 mmol), DIPEA (30 mg, 41 μL, 0.23 mmol, Sigma-Aldrich Corporation) and N,N-dimethylacetamide (0.2 mL). The solution was stirred at room temperature for 10 min, after which HATU (71 mg, 0.19 mmol, Combi-Blocks Inc.) was added. After 10 min, a solution of 6-azaspiro[3.4]octan-2-ol hydrochloride (9.2 mg, 0.06 mmol, CAS number 2027496-49-5, Synax) in DMA (0.2 mL) was added and the reaction was stirred at room temperature for 20 min. The mixture was then purified by column chromatography on silica gel eluting with a gradient of 0-100% 3:1 EtOAc / EtOH in heptane to give 6-(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)-6-azaspiro[3.4]octan-2-ol as a tan solid, which was used directly in the next step without determining the yield. m / z (ESI): 664.3 (M+H) + .

[0285] Step 2: 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-azaspiro[3.4]octan-2-ol. To a solution of 6-(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)-6-azaspiro[3.4]octan-2-ol (31 mg, 0.05 mmol) in acetonitrile (0.5 mL) cooled to 0° C. was added HCl (4 M in 1,4-dioxane, 0.6 mL, 2.34 mmol, Sigma-Aldrich Corporation) dropwise. The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was concentrated under reduced pressure. The crude material was purified by reverse phase HPLC to give 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-azaspiro[3.4]octan-2-ol (11 mg, 0.02 mmol, 32% yield) as the 2,2,2-trifluoroacetate as an off-white solid. (m / z(ESI): 620.3 (M+H) + . 1 H NMR (methanol-d4,400MHz)δ 9.33(s,1H),7.70(dd,1H,J=5.9,9.0Hz),7.34(d,1H,J=2.5Hz),7.28(t, 1H,J=9.4Hz),7.07(d,1H,J=2.7Hz),5.5-5.7(m,1H),4.6-4.7(m,3H),4.3 -4.5(m,1H),3.8-4.1(m,6H),3.4-3.6(m,1H),3.15(td,1H,J=1.6,3.2Hz) ,2.6-2.8(m,2H),2.3-2.6(m,6H),2.1-2.3(m,6H),0.82(t,3H,J=6.9Hz).

[0286]

Table 38

[0287]

Table 39

[0288]

Table 40

[0289]

Table 41

[0290]

Table 42

[0291]

Table 43

[0292]

Table 44

[0293]

Table 45

[0294]

Table 46

[0295] 4-(4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 44) [ka] An 8 mL vial was charged with 7-(8-ethyl-7-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 (80 mg, 0.16 mmol, intermediate B), DIPEA (0.10 g, 0.14 mL, 0.78 mmol, Sigma-Aldrich Corporation), N,N-dimethylacetamide (1.3 mL), HATU (0.24 mg, 0.63 mmol, Combi-Blocks Inc.) and 1,1-difluoro-5-azaspiro[2.5]octane hydrochloride (58 mg, 0.31 mmol, Enamine). The reaction was stirred at room temperature overnight. Water and TEA were then added and the reaction was stirred at room temperature for 1 h. The crude mixture was purified by reverse phase HPLC to give 4-(4-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (21 mg, 0.03 mmol, 18% yield) as the 2,2,2-trifluoroacetate as an off-white solid. m / z (ESI): 640.2 (M+H). + . 1H NMR(400MHz,メタノール-d4)δ ppm 9.14(s,1H),7.66-7.75(m,1H),7.32-7.37(m,1H),7.22-7.32(m,1H),7.03-7. 14(m,1H),5.48-5.71(m,1H),4.63-4.77(m,2H),4.31-4.61(m,1H),4.20-4.31( m,1H),3.73-4.18(m,5H),3.44-3.57(m,1H),2.54-2.82(m,2H),2.30-2.52(m,4 H),2.07-2.29(m,2H),1.87-2.08(m,4H),1.26-1.52(m,2H),0.74-0.86(m,3H).

[0296]

Table 47

[0297]

Table 48

[0298]

Table 49

[0299]

Table 50

[0300]

Table 51

[0301]

Table 52

[0302] 9-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-1,9-diazaspiro[3.6]decan-2-one (Example 53) [ka] Step 1: tert-Butyl 6-(2-ethoxy-2-oxoethylidene)-1,4-oxazepane-4-carboxylate. Sodium hydride (60% in mineral oil, 0.67 g, 17 mmol) was suspended in THF (70 mL) and the mixture was cooled to 0° C. (Diethoxyphosphinyl)acetic acid ethyl ester (3.80 g, 3.3 mL, 17 mmol) was added dropwise and the reaction was stirred at the same temperature for 30 min. Then tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate (3.00 g, 14 mmol, CAS number: 748805-97-2, Combi-Blocks Inc.) dissolved in 5 mL of THF was added to the mixture and the reaction was allowed to warm to room temperature. After stirring at room temperature for 2 h, water (50 mL) was added and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4, filtered and the volatiles were removed in vacuo. The crude mixture was purified by column chromatography on silica gel eluting with a gradient of 0-20% EtOAc in heptane to give tert-butyl 6-(2-ethoxy-2-oxoethylidene)-1,4-oxazepane-4-carboxylate (2.50 g, 8.80 mmol, 63% yield). m / z (ESI): = 230.2 (M-Bu+H). + .

[0303] Step 2: tert-Butyl 6-(benzylamino)-6-(2-ethoxy-2-oxoethyl)-1,4-oxazepane-4-carboxylate. tert-Butyl 6-(2-ethoxy-2-oxoethylidene)-1,4-oxazepane-4-carboxylate (0.50 g, 1.75 mmol) was dissolved in methanol (4.0 mL). Benzylamine (0.19 g, 0.2 mL, 1.75 mmol) was added and the mixture was stirred at 85° C. for 16 h in a microwave reactor. The volatiles were removed in vacuo and the crude mixture was purified by column chromatography on silica gel eluting with a gradient of 0-60% EtOAc in heptane to give tert-butyl 6-(benzylamino)-6-(2-ethoxy-2-oxoethyl)-1,4-oxazepane-4-carboxylate (0.23 g, 0.59 mmol, 34% yield) as a pale yellow oil. m / z (ESI): 393.2 (M+H). + .

[0304] Step 3: tert-Butyl 6-amino-6-(2-ethoxy-2-oxoethyl)-1,4-oxazepane-4-carboxylate. tert-Butyl 6-(benzylamino)-6-(2-ethoxy-2-oxoethyl)-1,4-oxazepane-4-carboxylate (0.16 g, 0.41 mmol) was dissolved in ethyl acetate (1.5 mL) and Pd / C (10 wt% on carbon, 0.13 g, 0.12 mmol) was added. The mixture was stirred overnight under 40 psi H2 atmosphere. The mixture was filtered through Celite and the volatiles were removed in vacuo to give tert-butyl 6-amino-6-(2-ethoxy-2-oxoethyl)-1,4-oxazepane-4-carboxylate (0.12 g, 0.39 mmol, 96% yield) as a colorless oil. m / z (ESI): 303.2 (M+H) + .

[0305] Step 4: 2-(6-amino-4-(tert-butoxycarbonyl)-1,4-oxazepan-6-yl)acetic acid. tert-Butyl 6-amino-6-(2-ethoxy-2-oxoethyl)-1,4-oxazepan-4-carboxylate (0.12 g, 0.39 mmol) was dissolved in MeOH (2.0 mL). Lithium hydroxide (24 mg, 0.61 mmol) and water (1.0 mL) were added and the mixture was stirred at room temperature overnight. The mixture was then neutralized using 1 M HCl. The volatiles were removed in vacuo to give 2-(6-amino-4-(tert-butoxycarbonyl)-1,4-oxazepan-6-yl)acetic acid (0.11 g, 0.4 mmol, quantitative yield). m / z (ESI): 275.2 (M+H) + .

[0306] Step 5: tert-Butyl 2-oxo-6-oxa-1,9-diazaspiro[3.6]decane-9-carboxylate. 2-Benzoxazolinone (1.30 g, 9.80 mmol, Combi-Blocks Inc.) was dissolved in tetrahydrofuran (2.5 mL). Triethylamine (1.00 g, 1.4 mL, 9.78 mmol, Sigma-Aldrich Corporation) was added and the mixture was cooled to 0° C. Phosphorus oxychloride (0.50 g, 0.30 mL, 3.26 mmol, Sigma-Aldrich Corporation) was added slowly and the reaction was stirred at room temperature overnight. The mixture was filtered. The filtrate was concentrated under reduced pressure and the resulting residue was treated with iPrOH (20 mL). The precipitated solid was collected by filtration, washed with iPrOH, and then dried in vacuum to give 3,3',3''-(oxo-15-phosphanetriyl)tris(benzo[d]oxazol-2(3H)-one) (0.50 g, 1.11 mmol, 34% yield) as a white solid.

[0307] 2-(6-amino-4-(tert-butoxycarbonyl)-1,4-oxazepan-6-yl)acetic acid (50 mg, 0.18 mmol) was dissolved in acetonitrile (18 mL). 3,3',3''-(oxo-15-phosphantriyl)tris(benzo[d]oxazol-2(3H)-one) (82 mg, 0.18 mmol) was added to the mixture. The reaction was stirred at 100 °C for 1 h. The reaction was cooled to room temperature. The volatiles were removed in vacuo and the crude mixture was purified by column chromatography on silica gel eluting with a gradient of 0-10% DCM in MeOH to give tert-butyl 2-oxo-6-oxa-1,9-diazaspiro[3.6]decane-9-carboxylate (23 mg, 0.09 mmol, 49% yield) as a colorless oil. m / z (ESI): 201.2 (M+H) + .

[0308] Step 6: 9-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-1,9-diazaspiro[3.6]decane-2-one. tert-Butyl 2-oxo-6-oxa-1,9-diazaspiro[3.6]decane-9-carboxylate (40 mg, 0.16 mmol) was dissolved in DCM (0.8 mL). 1,1,1-trifluoroacetic acid (0.32 g, 0.2 mL, 2.8 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was neutralized with TEA, the volatiles were removed in vacuo and MeCN (1 mL) was added. The solution was cooled to 0° C., and then 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (39 mg, 0.16 mmol, LabNetwork) was added. The mixture was stirred at the same temperature for 2 h, and then ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (30 mg, 0.19 mmol, LabNetwork) and TEA (32 mg, 44 μL, 0.31 mmol) were added. The solution was stirred at 80° C. for 24 h. The crude mixture was purified by reverse phase HPLC to give 9-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-1,9-diazaspiro[3.6]decan-2-one (20 mg, 0.04 mmol, 26% yield). m / z (ESI): 495.0 (M+H) + .

[0309] Step 7: 9-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-1,9-diazaspiro[3.6]decan-2-one. 9-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-1,9-diazaspiro[3.6]decan-2-one (20 mg, 0.04 mmol), cataCXium A Pd G3 (5.9 mg, 8.0 μmol), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (26 mg, 0.08 mmol, PharmaBlock) and potassium phosphate monohydrate (28 mg, 0.12 mmol) were mixed in tetrahydrofuran (0.4 mL) and water (0.04 mL). The mixture was degassed for 10 minutes and then stirred at 70° C. overnight. The volatiles were removed in vacuo and the crude mixture was purified by reverse phase HPLC to give the bis(2,2,2-trifluoroacetate) 9-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-1,9-diazaspiro[3.6]decan-2-one (4.0 mg, 4.56 μmol, 11% yield) as a pale yellow solid. m / z (ESI): 649.0 (M+H). + . 1H NMR (400MHz, methanol-d4) δ ppm 9.31-9.33 (m, 1H), 7.71 (dd, J = 9.0, 5.9Hz, 1H), 7.34 (d, J = 2.5Hz, 1H), 7.28 (t, J = 9.4Hz, 1H), 7.05-7.09 (m, 1H), 5.53-5.70 (m, 1H), 5.02 (dd, J = 14.0, 11.3Hz, 1H), 4.60-4.77 (m, 3H), 4.27 -4.42(m,4H),4.04-4.18(m,2H),3.87-4.03(m,4H),3.47-3.55(m,1H),3.01-3.10(m,1H),2. 85-2.92(m,1H),2.59-2.81(m,2H),2.32-2.55(m,4H),2.18-2.31(m,2H),0.78-0.87(m,3H).

[0310] 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-azaspiro[3.5]nonan-2-ol (Examples 54 and 55) [ka] Step 1: 6-(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)-6-azaspiro[3.5]nonan-2-one. 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 (75 mg, 0.14 mmol, intermediate A) was dissolved in N,N-dimethylformamide (0.4 mL), followed by addition of HATU (0.10 g, 0.27 mmol) and DIPEA (70 mg, 0.10 mL, 0.54 mmol). The mixture was stirred at room temperature for 10 minutes. Then, 6-azaspiro[3.5]nonan-2-one hydrochloride (24 mg, 0.14 mmol, CAS number: 1359704-57-6, Pharmablock, Inc.) was added, and the mixture was stirred at room temperature overnight. Water (0.4 mL) was added and the aqueous phase was extracted with EtOAc (3×0.5 mL). The combined organic layers were dried over Na2SO4 and the volatiles were removed in vacuo to give crude 6-(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)-6-azaspiro[3.5]nonan-2-one (60 mg, 0.09 mmol, 66% yield). m / z (ESI): 676.2 (M+H) + .

[0311] Step 2: 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-azaspiro[3.5]nonan-2-ol. 6-(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)-6-azaspiro[3.5]nonan-2-one (30 mg, 0.05 mmol) was dissolved in MeOH (0.5 mL) and the solution was cooled to 0 ° C. Sodium borohydride (5.0 mg, 0.14 mmol) was added. The mixture was stirred at room temperature for 1 h and the volatiles were removed in vacuo. The crude mixture was dissolved in THF (1.5 mL) and HCl (4 M in dioxane, 0.5 mL) was added. The mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo. The crude product was purified by reverse phase HPLC to give the diastereomeric 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-azaspiro[3.5]nonan-2-ol isomer 1 (Example 54) (3 mg, 3.5 μmol, 3% yield), m / z (ESI): 634.2 (M+H) as bis(2,2,2-trifluoroacetate). + ; 1H NMR (400MHz, methanol-d4) δ ppm 9.14-9.15(m,1H),7.70(dd,J=9.1,5.7Hz,1H),7.34(d,J=2.5Hz,1H),7.27(t ,J=9.4Hz,1H),7.09(d,J=2.5Hz,1H),5.52-5.69(m,1H),4.71(dd,J=10.9,4.0 Hz,2H),4.29(quin,J=7.4Hz,1H),4.09-4.22(m,2H),3.89-4.07(m,4H),3.46- 3.55(m,1H),2.57-2.82(m,2H),2.14-2.54(m,8H),1.83-1.89(m,3H),1.74(br d, J = 10.7 Hz, 2H), 0.82 (t, J = 7.3 Hz, 3H), and isomer 2 (Example 55) was obtained as the 2,2,2-trifluoroacetate (2 mg, 2.7 μmol, 2% yield), m / z (ESI): 634.0 (M+H). + ; 1 H NMR(400MHz, methanol-d4)δ ppm 9.16(s,1H),7.70(dd,J=9.0,5.9Hz,1H),7.34(d,J=2.5Hz,1H),7.27(t,J=9.4H z,1H),7.08(d,J=2.5Hz,1H),5.48-5.71(m,1H),4.66-4.75(m,2H),4.27-4.39( m,1H),3.81-4.23(m,7H),3.46-3.57(m,1H),2.58-2.83(m,2H),2.44-2.55(m,2 H),2.34-2.42(m,2H),2.18-2.29(m,4H),1.76-1.92(m,6H),0.79-0.89(m,3H).

[0312] 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)-2-methyl-6-azaspiro[3.5]nonan-2-ol (Example 56 and Example 57) [ka] 6-(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)-6-azaspiro[3.5]nonan-2-one (30 mg, 0.04 mmol) was dissolved in THF (0.5 mL). After the solution was cooled to 0° C., methylmagnesium bromide (3 M in diethyl ether, 22 μL, 0.07 mmol) was added dropwise. The mixture was stirred at room temperature for 1 h before being cooled again to 0° C. Saturated NH4Cl (5 mL) was added slowly, the aqueous layer was extracted with EtOAc (3×5 mL), and the combined organic phases were dried over Na2SO4 and concentrated in vacuo. The crude residue was then dissolved in THF (1.5 mL) followed by the addition of TFA (0.5 mL). The reaction was stirred at room temperature for 3 h. The volatiles were removed in vacuo. The crude residue was purified by reverse phase HPLC to give 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)-2-methyl-6-azaspiro[3.5]nonan-2-ol isomer 1 (Example 56) (2.3 mg, 2.6 μmol, 6% yield) as the bis(2,2,2-trifluoroacetate); m / z (ESI): 648.2 (M+H). + ; 1H NMR(400MHz, methanol-d4)δ ppm 9.16(s,1H),7.71(dd,J=9.1,6.0Hz,1H),7.34(d,J=2.5Hz,1H),7.28(t,J=9.4Hz,1H),7.08(d,J=2.5Hz,1H),5. 47-5.70(m,1H),4.71(dd,J=12.2,4.3Hz,2H),4.16-4.27(m,2H),3.99-4.12(m,2H),3.88-3.99(m,3H),3.46-3. Isomer 2 (Example 57) (3.0 mg, 3.4 μmol, 8% yield) was obtained as 56 (m, 1H), 2.60-2.81 (m, 2H), 2.35-2.58 (m, 4H), 2.14-2.28 (m, 2H), 1.81-2.12 (m, 9H), 1.37-1.40 (m, 3H), 0.82 (t, J=7.3 Hz, 3H), and bis(2,2,2-trifluoroacetate); m / z (ESI): 648.2 (M+H). + ; 1 H NMR(400MHz, methanol-d4)δ ppm 9.19(s,1H),7.70(dd,J=9.0,5.9Hz,1H),7.34(d,J=2.7Hz,1H),7.27(t,J=9.4Hz,1H),7.09(d,J=2.5Hz,1H),5.50- 5.69(m,1H),4.23-4.32(m,2H),4.05-4.14(m,2H),3.84-4.01(m,3H),3.45-3.57(m,1H),2.74-3.01(m,1H),2.66(br d,J=3.6Hz,1H),2.55-2.63(m,1H),2.33-2.54(m,4H),2.17-2.29(m,2H),1.98-2.0 5(m,2H),1.89-1.97(m,2H),1.84(s,3H),1.37(s,3H),0.83(td,J=7.3,1.9Hz,3H).

[0313] Biological evaluation In this section, a biological evaluation of the embodiments provided herein is provided.

[0314] KRAS G12D TR-FRET assay Compounds of interest were prepared in dose-response titrations in DMSO and 80 nL was added to each well of a 384-well plate (Perkin Elmer 6008280) from a Labcyte Echo. His-tagged KRAS G12D protein (Amgen) was diluted to 20 nM in assay buffer (20 mM HEPES, pH 7.4, 10 mM MgCl2, 50 mM NaCl, 0.1% BSA, 0.01% Tween-20, 10 μM GDP) and 2 μL was added to the appropriate wells of the 384-well plate. Plates were incubated at room temperature for 30 minutes. Biotinylated KRPep-2d substrate (Amgen) was diluted to 20 nM in assay buffer and 2 μL was added to all wells and incubated at room temperature for 1 hour. Detection reagents (0.4 nM LANCE Eu-W1024 Anti-6xHis (Perkin Elmer AD0401), 5 nM streptavidin-d2 (Cisbio 610SADLA)) were prepared in assay buffer, then 4 μL was added to the plate and incubated for 1 h at room temperature. Plates were read using a PerkinElmer EnVision (ex: 320 nm, em1: 665 nm, em2: 615 nm) and the em1 / em2 data was used to generate a curve fit using a four-parameter logistic model to calculate IC 50 values ​​were calculated.

[0315] KRAS G12D-binding nucleotide exchange assay Purified GDP-bound KRAS protein (aa1-169) containing both G12D and C118A amino acid substitutions and an N-terminal His tag was pre-incubated with a dose-response titration of compound in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCl2 and 0.01% Triton X-100) for 2 hours. After compound pre-incubation, purified SOS protein (aa564-1049) and GTP (Roche 10106399001) were added to the assay wells and incubated for an additional 30 minutes. To determine the extent of inhibition of SOS-mediated nucleotide exchange, purified GST-tagged cRAF (aa1-149), nickel-chelating AlphaLISA acceptor beads (PerkinElmer AL108R) and AlphaScreen glutathione donor beads (PerkinElmer 6765302) were added to the assay wells and incubated for 10 minutes. The assay plates were then read on a PerkinElmer EnVision Multilabel Reader using AlphaScreen® technology and the data was analyzed using a four-parameter logistic model to determine IC 50 The value was calculated.

[0316] Phospho-ERK1 / 2 MSD assay AsPC-1 (ATCC® CRL-1682™) cells were cultured in RPMI 1640 medium (ThermoFisher Scientific 11875093) containing 10% fetal bovine serum (ThermoFisher Scientific 16000044) and 1× penicillin-streptomycin-glutamine (ThermoFisher Scientific 10378016). 16 hours prior to compound treatment, AsPC-1 cells were seeded into 96-well cell culture plates at a density of 25,000 cells / well and incubated at 37° C., 5% CO2. Dose-response titrations of compounds were diluted in growth medium and added to the appropriate wells of the cell culture plate, then incubated for 2 hours at 37° C., 5% CO2. After compound treatment, cells were incubated for 2 hours at 37° C. ... 2+ or Mg 2+Cells were washed with ice-cold Dulbecco's Phosphate Buffered Saline (ThermoFisher Scientific 14190144) without riboflavin and then lysed in RIPA buffer (50 mM Tris-HCl pH 7.5, 1% Igepal, 0.5% sodium deoxycholate, 150 mM NaCl and 0.5% sodium dodecyl sulfate) containing protease inhibitors (Roche 4693132001) and phosphatase inhibitors (Roche 4906837001). Phosphorylation of ERK1 / 2 in compound-treated lysates was assayed using the Phospho-ERK1 / 2 Whole Cell Lysate kit (Meso Scale Discovery K151DWD) according to the manufacturer's protocol. Assay plates were read on a Meso Scale Discovery Sector Imager 6000 and data were analyzed using a 4-parameter logistic model to determine IC 50 The value was calculated.

[0317] [Table 53]

[0318] [Table 54]

[0319] [Table 55]

[0320] [Table 56]

[0321] References All references cited in this specification, e.g., scientific publications or published patent applications, are hereby incorporated by reference in their entirety for all purposes to the same extent as if each reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

Claims

1. Compounds of formula (I): [Chemical Formula 1] or a pharmaceutically acceptable salt of said compound, wherein: 【Chemistry 2】 is a single or double bond; W is C, CH or N, and when W is CH or N, 【Chemistry 3】 is a single bond; X is O, S, S(O), S(O)(NR ｚ ), S(O) ２ , C.H. ２ or CH═CH; n is 0, 1 or 2; m is 0, 1 or 2; p is 2, 3, or 4; Two R's ｘ With the same carbon atom, C ３～７ forming a cycloalkyl or a 4- to 7-membered heterocycloalkyl, and each C ３～７ The cycloalkyl or 4- to 7-membered heterocycloalkyl is selected from 0 to 3 R ｙ and when p is 3 or 4, each remaining R ｘ is hydroxyl, halogen, oxo, cyano, -N(R ｚ ) ２ , C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, C １～４ Haloalkoxy, C ３～６ cycloalkyl, 5-7 membered heteroaryl; 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 a chain consisting of 0 to 2 R ２ is substituted with; R １ is hydroxyl, aryl, heteroaryl, C ３～８ cycloalkyl or 0 to 3 R ５ is a heterocycloalkyl substituted with R ２ is a halogen, hydroxyl, C １～４ alkyl, or two R on the same or adjacent carbon atoms ２ Both are C ３～７ can form a cycloalkyl; R ３ is 0 to 3 R ６ is an aryl or heteroaryl substituted with R ４ is hydrogen, hydroxyl, halogen, C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, C ２～４ Alkenyl, C ２～４ Alkynyl, C ３～７ cycloalkyl or cyano; Each R ５ is halogen, oxo, hydroxyl, cyano, 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 halogen, oxo, C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, hydroxyl, cyano, -S(O) ２ -C １～４ Alkyl, =NR ｚ or -N(R ｚ ) ２ and R ｚ is hydrogen or C １～４ A compound that is alkyl.

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

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

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

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 0 to 3 R ６ 2. The compound of claim 1, wherein the compound is an aryl substituted with

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

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

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. The compound of claim 1 , wherein X is O.

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

18. Two R's ｘ with the same carbon atom, 0 to 3 R ｙ C further substituted with ３～７ The compound of claim 17, which forms a cycloalkyl or a 4- to 7-membered heterocycloalkyl.

19. Two R's ｘ with the same carbon atom, 0 to 3 R ｙ 19. The compound of claim 18, wherein the cyclopropyl, cyclobutyl, 3-oxetanyl, or 2-azetidinyl is further substituted with

20. 【Chemical 9】 but, 【Chemistry 10】 17. The compound of claim 16, wherein:

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

22. 22. The compound of claim 21, wherein n is 0 and m is 1; m is 0 and n is 1, or n is 1 and m is 1.

23. Each R ｘ is hydroxyl or C １～４ alkyl, and two R ｘ with the same carbon atom, 0 to 3 R ｙ C further substituted with ３～７ The compound of claim 22, which forms a cycloalkyl or a 4- to 7-membered heterocycloalkyl.

24. Each R ｘ is hydroxyl or methyl, and two R ｘ with the same carbon atom, 0 to 3 R ｙ 24. The compound of claim 23, wherein the aryl group is cyclopropyl, cyclobutyl, 2-tetrahydrothiophene, 2-azetidinyl, 3-azetidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-thietanyl, 3-tetrahydrothiophenyl, 2-oxetanyl, 3-oxetanyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 4-oxazolidinyl, 5-oxazolidinyl, which are further substituted by

25. [Catalog 11] but, 【Chemistry 12】 【Chemistry 13】 22. The compound of claim 21, wherein:

26. R ４ But C １～４ Alkyl, C １～４ Alkoxy, hydroxyl, halogen or C １～４ The compound of claim 1 which is a haloalkyl.

27. R ４ But C １～４ 27. The compound of claim 26, wherein the alkyl, hydroxyl, or halogen is hydroxyl.

28. The compound is the following compound: 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 6-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol (isomer 1); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 2); 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)-1,6-diazaspiro[3.5]nonan-2-one (isomer 2); 3-chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 6-(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)-6-azaspiro[3.5]nonan-2-ol (isomer 1); 6-(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)-6-azaspiro[3.5]nonan-2-ol (isomer 2); 7-(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)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); 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)-2-methyl-6-azaspiro[3.5]nonan-2-ol (isomer 2); 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)-2,6-diazaspiro[3.5]nonan-1-one (isomer 1); 6-(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)-6-azaspiro[3.5]nonan-2-ol (isomer 1); 9-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-1,9-diazaspiro[3.6]decan-2-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 7-(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)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 1); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,7-diazaspiro[4.5]decan-2-one; 7-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-3-one; 7-(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)-2,7-diazaspiro[4.5]decan-3-one; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide (isomer 1); 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-methyl-1,6-diazaspiro[3.5]nonan-2-one; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-imino-216-thia-7-azaspiro[4.5]decane 2-oxide; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxa-1,7-diazaspiro[4.5]decan-2-one; 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)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 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-azaspiro[3.5]nonan-2-ol (isomer 1); or 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Isomer 1).

29. The compound is the following compound: 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 6-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azaspiro[3.5]nonan-2-ol (isomer 1); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (isomer 2); 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)-1,6-diazaspiro[3.5]nonan-2-one (isomer 2); 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 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-azaspiro[3.5]nonan-2-ol (isomer 1); 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 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)-5-azaspiro[2.5]octan-7-ol (isomer 1); 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); or 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide (isomer 2).

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

31. 31. 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 30, for use as a medicament.

32. 31. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 30, for use in the treatment of cancer.

33. 31. The compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 30, for use in treating cancer in which one or more cells express a KRAS G12D mutant protein.

34. 33. The compound or pharmaceutical composition for use according to claim 32, 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 types, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia or melanoma.

35. 31. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 30, in the preparation of a medicament for treating cancer.

36. 31. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 30, in the preparation of a medicament for treating cancer in which one or more cells express a KRAS G12D mutant protein.

37. 37. The use of claim 36, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

38. A drug for use in a method for treating cancer in a subject in need thereof, said drug comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 30, said method comprising administering said drug to the subject.

39. A drug for use in a method of treating cancer in a subject in need thereof, said drug comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 30, said method comprising administering said drug to a subject, wherein one or more cells express a KRAS G12D mutant protein.

40. The drug of claim 38, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, mixed cancer type, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

41. 39. The method of claim 38, 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.

42. The method of claim 41, wherein the cancer is non-small cell lung cancer.

43. 42. The method of claim 41, wherein the cancer is colorectal cancer.

44. The method of claim 41, wherein the cancer is pancreatic cancer.

45. 39. The method of claim 38, wherein the subject has a cancer determined to have one or more cells that express the KRAS G12D mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof.

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