Macrocyclic KRAS inhibitors and methods of use

Abstract

To provide macrocyclic KRAS inhibitors and methods of use.SOLUTION: The present disclosure provides compounds useful for the inhibition of KRAS G12D, G12V, G12A, G12S, G13D, Q61H, Q61L or G12C. The compounds have the general Formula I' in the figure, where the variables in the Formula I' are defined herein. This disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions for treatment of, e.g., cancer.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO PRIOR APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 383,674, filed November 14, 2022, U.S. Provisional Patent Application No. 63 / 497,978, filed April 24, 2023, and U.S. Provisional Patent Application No. 63 / 582,751, filed September 14, 2023, each of which is incorporated by reference in its entirety.

[0002] The present disclosure provides compounds that have activity as inhibitors of mutant KRAS proteins. The disclosure also provides pharmaceutical compositions containing the compounds, uses, and methods for treating certain disorders such as cancer, including, but not limited to, non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendix cancer, endometrial cancer, esophageal cancer, cancer of unknown primary site, ampullary cancer, gastric cancer, small intestine cancer, sinus cancer, bile duct cancer, or melanoma. [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, a transforming factor in a network of parallel effector pathways (e.g., PI3K / AKT) (Vojtek et al., 1998), and 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 MEK (Caunt et al., 2015), the KRAS protein has historically proven resistant to direct inhibition.

[0004] KRAS is a G protein that couples extracellular mitogenic signaling to intracellular growth-promoting responses. KRAS acts as an intracellular "on / off" switch. Mitogen stimulation induces the binding of GTP to KRAS, resulting in a conformational change that allows KRAS to interact with downstream effector proteins, leading to cell proliferation. Normally, growth-promoting signaling is regulated by the action of GTPase-activating proteins (GAPs), which revert KRAS to its GDP-bound, non-proliferative state. KRAS mutations impair the regulated cycling of KRAS between these GDP-bound and GDP-bound states, resulting in the accumulation of the active GDP-bound state and impaired cell proliferation (Simanshu et al., 2017).

[0005] Attempts to develop inhibitors of mutant KRAS proteins have historically been hampered by the absence of a druggable pocket on the protein surface (Cox et al., 2014). In 2013, Shokat and colleagues identified a covalent inhibitor of KRASG12, a common (O'Bryan, 2019) oncogenic mutant of KRAS, that bound to a previously unrecognized allosteric pocket on GDP-KRASG12C and prevented its subsequent activation (Ostrem et al., 2013). This discovery marked an important new milestone in KRAS inhibitor research, leading to the recent entry of KRAS inhibitors into human clinical trials. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] U.S. Patent No. 10,519,146B2 [Patent Document 2] US Patent Application Publication No. 2020 / 0239441 [Patent Document 3] International Publication No. 2020 / 132649 Brochure [Patent Document 4] International Publication No. 2020 / 132651 Brochure [Patent Document 5] International Publication No. 2020 / 132653 Brochure [Patent Document 6] U.S. Patent No. 10,590,090B2 [Patent Document 7] U.S. Patent Application Publication No. 2020 / 017517A1 [Patent Document 8] US Patent Application Publication No. 2020 / 017511A1 [Patent Document 9] International Publication No. 2019 / 075265A1 Brochure [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] Ostrem et al., 2013 [Non-Patent Document 11] Remington:The Science and Practice of Pharmacy,Volume I and Volume II,twenty-second edition,Philadelphia,PA,Pharmaceutical Press,2012 [Non-Patent Document 12] Pharmaceutical Dosage Forms (Vol.1-3), Liberman et al., Eds., Marcel Dekker, New York, NY, 1992 [Non-Patent Document 13] Handbook of Pharmaceutical Excipients (3rd Ed.), edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, 2000 [Non-Patent Document 14] Pharmaceutical Formulation:The Science and Technology of Dosage Forms(Drug Discovery),first edition,edited by GD Tovey,Royal Society of Chemistry,2018 [Non-Patent Document 15] Jacques et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); [Non-Patent Document 16] Wilen et al., Tetrahedron 33:2725; Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962) [Non-Patent Document 17] Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972) [Non-Patent Document 18] Berge et al., J.Pharm.Sci.66(1):1-19(1977) [Non-Patent Document 19] Stahl et al.,Pharmaceutical Salts:Properties,Selection,and Use,2nd Revised Edition(2011) Summary of the Invention [Problem to be solved by the invention]

[0008] While some progress has been made with KRAS G12C inhibitors, there is continued interest and effort to develop inhibitors of KRAS, particularly inhibitors of other KRAS such as KRAS G12D, G12V, G12A, G12S, G13D, Q61H, Q61L or G12C. Thus, there is a need to develop new inhibitors of KRAS G12D, G12V, G12A, G12S, G13D, Q61H, Q61L or G12C for the treatment of disorders such as cancer. [Means for solving the problem]

[0009] In a first aspect, the present application provides a compound of formula (I'): [ka] (In the formula, Z is CH, C-halogen, C-CN, CC 1~4 Alkyl, CC 1~4 Haloalkyl, CC 1~4 Alkoxy, CC 1~4 Haloalkoxy, CC 3~7 cycloalkyl or N; Q is CH, C-halogen, CC1~4 Alkyl, CC 1~4 haloalkyl or N; B is a 4-15 membered heterocycloalkyl having 0-3 additional ring heteroatoms independently selected from O, S, and N; p is 0, 1, 2, 3 or 4; q is 0, 1, 2 or 3; Each R x are independently hydroxyl, halogen, oxo, cyano, -N(R z )2, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 1~4 Hydroxyalkyl, 5-7 membered heteroaryl, -S(O)2-C 1~4 Alkyl, -S(O)N(R z )2, -C(O)R z , -C(O)OR z , -C(O)N(R z )2, -C 1~4 Alkylene-C(O)-C 1~4 Alkyl, -C 1~4 Alkylene-C(O)N(R z )2, C 1~4 Alkylene-S(O)2-C 1~4 Alkyl or -SC 1~4 is alkyl; L is a bond, C 1~6 Alkylene, -OC 1~6 Alkylene, -SC 1~6 Alkylene, NR z , O or S, and each C 1~6 Alkylene, -OC 1~6 Alkylene and -SC 1~6 The alkylene chain is R 2 Replaced by 0-2 occurrences of; -L 1 -L 2 -L 2 , -N(R z )C(O)-L 2 , -C(O)-L 2-, -OC(O)-L 2 , -C(O)OL 2 , -OC(O)-OL 2 , -OC(S)-OL 2 , -OL 2 , -N(R z )C(O)OL 2 , -OC(O)N(R z )-L 2 , -N(R z )-L 2 , -S(O)2-L 2 , -SL 2 , -S(O)-L 2 , C 1~4 Alkylene-C(O)-L 2 , C 1~4 Alkylene-C(O)OL 2 , -C 1~4 Alkylene-OC(O)OL 2 , -C 1~4 Alkylene-OC(O)-L 2 , -C 1~4 Alkylene-OL 2 , -C 1~4 Alkylene-S(O)2-L 2 , -C 1~4 Alkylene-SL 2 , -C 1~4 Alkylene-S(O)-L 2 , -O-5 to 6-membered heteroaryl-L 2 , -C 1~4 Alkylene-5-6-membered heteroaryl-L 2 , -C 1~4 Hydroxyalkylene-5-6-membered heteroaryl-L 2 or 5-6 membered heteroaryl-L 2 and; L 2 is C 1~6 Alkylene, C 1~6 Alkylene-O-, C 1~6 Alkylene-OC 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 3~7 Cycloalkylene, C 1~4 Alkylene-C 3~7 Cycloalkylene, C1~4 Haloalkylene-C 3~7 Cycloalkylene, C 3~7 Cycloalkylene-C 1~4 Alkylene, C 1~6 Hydroxyalkylene or C 1~6 haloalkylene; R 1 is hydrogen, hydroxyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 cycloalkyl or 4- to 15-membered heterocycloalkyl, and each aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is R 5 Replaced by 0-3 occurrences of; R 2 is halogen, hydroxyl, C 1~4 alkyl, or two R on the same or adjacent carbon atoms 2 Let's get together and C 3~7 can form a cycloalkyl; A is C 6~10 aryl or 5- to 10-membered heteroaryl, and R 6 is replaced by q occurrences of; R 4 is hydrogen, hydroxyl, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~7 is cycloalkyl or cyano; Each R 5 are independently halogen, cyano, oxo, -TR y , hydroxyl, -N(R z )2, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy or -OC 2~4 is alkynyl; Each R 6 are independently halogen, hydroxyl, cyano, -N(R z )2, -C(O)R z , -C(O)OR z , C1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 2~4 Alkynyl or C 3~6 cycloalkyl or two R 6 are joined together on adjacent carbon atoms, C 3~7 Forming a cycloalkyl; T is C 1~4 Alkylene, -S(O)2-, -C(O)-, -C 1~4 Alkylene-C(O)-, C 1~4 alkylene -S(O)2- or -S-; R y is C 1~4 Alkyl, C 1~4 Haloalkyl, hydroxyl, cyano or -N(R z )2; and Each R z is hydrogen or C 1~4 alkyl) or a pharmaceutically acceptable salt of said compound.

[0010] In a second aspect, provided herein is a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable excipient.

[0011] In a third aspect, provided herein is a compound as described herein or a pharmaceutically acceptable salt of said compound, or a pharmaceutical composition as described herein, for use in treating cancer (e.g., non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendix cancer, endometrial cancer, esophageal cancer, cancer of unknown primary site, ampullary cancer, gastric cancer, small intestine cancer, sinus cancer, bile duct cancer, or melanoma).

[0012] Reference will now be made in detail to the embodiments of the present disclosure. While particular embodiments of the present disclosure will be described, it will be understood that they are not intended to limit the embodiments of the present disclosure to those described embodiments. On the contrary, reference to the embodiments of the present disclosure is intended to cover alternatives, modifications, and equivalents, which may be included within the spirit and scope of the embodiments of the present disclosure as defined by the appended claims. DETAILED DESCRIPTION OF THE INVENTION

[0013] In embodiment 1, the present specification provides a compound of formula (I'): [ka] (In the formula, Z is CH, C-halogen, C-CN, CC 1~4 Alkyl, CC 1~4 Haloalkyl, CC 1~4 Alkoxy, CC 1~4 Haloalkoxy, CC 3~7 cycloalkyl or N; Q is CH, C-halogen, CC 1~4 Alkyl, CC 1~4 haloalkyl or N; B is a 4-15 membered heterocycloalkyl having 0-3 additional ring heteroatoms independently selected from O, S, and N; p is 0, 1, 2, 3 or 4; q is 0, 1, 2 or 3; Each R x are independently hydroxyl, halogen, oxo, cyano, -N(R z )2, C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 1~4 Hydroxyalkyl, 5-7 membered heteroaryl, -S(O)2-C 1~4 Alkyl, -S(O)N(R z )2, -C(O)R z, -C(O)OR z , -C(O)N(R z )2, -C 1~4 Alkylene-C(O)-C 1~4 Alkyl, -C 1~4 Alkylene-C(O)N(R z )2, C 1~4 Alkylene-S(O)2-C 1~4 Alkyl or -SC 1~4 is alkyl; L is a bond, C 1~6 Alkylene, -OC 1~6 Alkylene, -SC 1~6 Alkylene, NR z , O or S, and each C 1~6 Alkylene, -OC 1~6 Alkylene and -SC 1~6 The alkylene chain is R 2 Replaced by 0-2 occurrences of; -L 1 -L 2 -L 2 , -N(R z )C(O)-L 2 , -C(O)-L 2 -, -OC(O)-L 2 , -C(O)OL 2 , -OC(O)-OL 2 , -OC(S)-OL 2 , -OL 2 , -N(R z )C(O)OL 2 , -OC(O)N(R z )-L 2 , -N(R z )-L 2 , -S(O)2-L 2 , -SL 2 , -S(O)-L 2 , C 1~4 Alkylene-C(O)-L 2 , C 1~4 Alkylene-C(O)OL 2 , -C 1~4 Alkylene-OC(O)OL 2 , -C 1~4 Alkylene-OC(O)-L 2 , -C 1~4Alkylene-OL 2 , -C 1~4 Alkylene-S(O)2-L 2 , -C 1~4 Alkylene-SL 2 , -C 1~4 Alkylene-S(O)-L 2 , -O-5 to 6-membered heteroaryl-L 2 , -C 1~4 Alkylene-5-6-membered heteroaryl-L 2 , -C 1~4 Hydroxyalkylene-5-6-membered heteroaryl-L 2 or 5-6 membered heteroaryl-L 2 and; L 2 is C 1~6 Alkylene, C 1~6 Alkylene-O-, C 1~6 Alkylene-OC 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 3~7 Cycloalkylene, C 1~4 Alkylene-C 3~7 Cycloalkylene, C 1~4 Haloalkylene-C 3~7 Cycloalkylene, C 3~7 Cycloalkylene-C 1~4 Alkylene, C 1~6 Hydroxyalkylene or C 1~6 haloalkylene; R 1 is hydrogen, hydroxyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 cycloalkyl or 4- to 15-membered heterocycloalkyl, and each aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is R 5 Replaced by 0-3 occurrences of; R 2 is halogen, hydroxyl, C 1~4 alkyl, or two R on the same or adjacent carbon atoms 2 Let's get together and C 3~7 can form a cycloalkyl; A is C6~10 aryl or 5- to 10-membered heteroaryl, and R 6 is replaced by q occurrences of; R 4 is hydrogen, hydroxyl, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~7 is cycloalkyl or cyano; Each R 5 are independently halogen, cyano, oxo, -TR y , hydroxyl, -N(R z )2, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy or -OC 2~4 is alkynyl; Each R 6 are independently halogen, hydroxyl, cyano, -N(R z )2, -C(O)R z , -C(O)OR z , C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 2~4 Alkynyl or C 3~6 cycloalkyl or two R 6 are joined together on adjacent carbon atoms, C 3~7 Forming a cycloalkyl; T is C 1~4 Alkylene, -S(O)2-, -C(O)-, -C 1~4 Alkylene-C(O)-, C 1~4 alkylene -S(O)2- or -S-; R y is halogen, oxo, C 1~4 Alkyl, C 1~4 Haloalkyl, hydroxyl, cyano or -N(R z )2; and Each R z is hydrogen or C 1~4alkyl) or a pharmaceutically acceptable salt of said compound.

[0014] As embodiment 2, provided herein is a compound or salt according to embodiment 1, wherein B is a 4-10 membered heterocycloalkyl having one additional oxygen heteroatom. As embodiment 3, provided herein is a compound or salt according to embodiment 2, wherein p is 0. As embodiment 4, provided herein is a compound or salt according to embodiment 3, wherein BL 1 teeth, [ka] As embodiment 5, there is provided herein a compound or salt according to embodiment 4, wherein BL 1 teeth, [ka] As embodiment 6, there is provided herein a compound or salt according to embodiment 5, wherein BL 1 teeth, [ka] teeth, [ka] As embodiment 7, there is provided herein a compound or salt according to embodiment 6, wherein: [ka] teeth, [ka] As an embodiment 8, there is provided herein a compound or salt according to embodiment 6, wherein: [ka] teeth, [ka] As embodiment 9, there is provided herein a compound or salt according to embodiment 6, wherein: [ka] teeth, [ka] is.

[0015] As embodiment 10, provided herein is a compound or salt according to embodiment 1, wherein B is a 4-10 membered heterocycloalkyl having one additional nitrogen heteroatom. As embodiment 11, provided herein is a compound or salt according to embodiment 10, wherein p is 0. As embodiment 12, provided herein is a compound or salt according to embodiment 11, wherein BL 1 teeth, [ka] As embodiment 13, there is provided herein a compound or salt according to embodiment 12, wherein BL 1 teeth, [ka] As embodiment 14, there is provided herein a compound or salt according to embodiment 13, wherein BL 1 teeth, [ka] is.

[0016] As embodiment 15, provided herein is a compound or salt according to embodiment 1, wherein B is a 4-10 membered heterocycloalkyl having 0 additional heteroatoms. As embodiment 16, provided herein is a compound or salt according to embodiment 15, wherein p is 0. As embodiment 17, provided herein is a compound or salt according to embodiment 16, wherein BL1 teeth, [ka] As embodiment 18, there is provided herein a compound or salt according to embodiment 17, wherein BL 1 teeth, [ka] As embodiment 19, there is provided herein a compound or salt according to embodiment 18, wherein BL 1 teeth, [ka] As embodiment 20, there is provided herein a compound or salt according to embodiment 18, wherein BL 1 teeth, [ka] As embodiment 21, there is provided herein a compound or salt according to embodiment 18, wherein BL 1 teeth, [ka] As embodiment 22, there is provided herein a compound or salt according to embodiment 18, wherein BL 1 teeth, [ka] is.

[0017] As embodiment 23, provided herein is a compound or salt according to embodiment 1, wherein B is a 4-10 membered heterocycloalkyl having one additional oxygen heteroatom. As embodiment 24, provided herein is a compound or salt according to embodiment 23, wherein p is 1. As embodiment 25, provided herein is a compound or salt according to embodiment 24, wherein BL 1 teeth, [ka] As embodiment 26, there is provided herein a compound or salt according to embodiment 24 or 25, wherein R x is C 1~4 Alkyl, C 1~4 Haloalkyl or C 1~4 As embodiment 27, provided herein are compounds or salts according to embodiment 26, wherein R x is methyl, CD3 or monofluoromethyl.

[0018] As embodiment 28, there is provided herein a compound or salt according to embodiment 27, wherein BL 1 teeth, [ka] As embodiment 29, there is provided herein a compound or salt according to embodiment 28, wherein BL 1 teeth, [ka] As embodiment 30, there is provided herein a compound or salt according to embodiment 29, wherein BL 1 teeth, [ka] As embodiment 31, there is provided herein a compound or salt according to embodiment 29, wherein BL 1 teeth, [ka] As embodiment 32, there is provided herein a compound or salt according to embodiment 29, wherein BL 1 teeth, [ka] is.

[0019] As embodiment 33, provided herein is a compound or salt according to embodiment 1, wherein B is a 4-10 membered heterocycloalkyl having 0 additional heteroatoms. As embodiment 34, provided herein is a compound or salt according to embodiment 33, wherein p is 1. As embodiment 35, provided herein is a compound or salt according to embodiment 34, wherein BL 1 teeth, [ka] As embodiment 36, there is provided herein a compound or salt according to embodiment 35, wherein R x is halogen, hydroxyl, C 1~4 Haloalkyl or C 1~4 As embodiment 37, provided herein are compounds or salts according to embodiment 36, wherein R x is fluorine, hydroxyl, methyl or monofluoromethyl.

[0020] As embodiment 38, there is provided herein a compound or salt according to embodiment 37, wherein BL 1 teeth, [ka] As embodiment 39, there is provided herein a compound or salt according to embodiment 38, wherein BL 1 teeth, [ka] As embodiment 40, there is provided herein a compound or salt according to embodiment 39, wherein BL 1 teeth, [ka] As embodiment 41, there is provided herein a compound or salt according to any one of embodiments 40, wherein BL 1 teeth, [ka] As embodiment 42, there is provided herein a compound or salt according to embodiment 40, wherein BL 1 teeth, [ka] As embodiment 43, there is provided herein a compound or salt according to embodiment 40, wherein BL 1 teeth, [ka] As embodiment 44, there is provided herein a compound or salt according to embodiment 40, wherein BL 1 teeth, [ka] is.

[0021] As embodiment 45, provided herein is a compound or salt according to embodiment 1, wherein B is a 4-10 membered heterocycloalkyl having 0 additional heteroatoms. As embodiment 46, provided herein is a compound or salt according to embodiment 45, wherein p is 2. As embodiment 47, provided herein is a compound or salt according to embodiment 46, wherein BL 1 teeth, [ka] is.

[0022] As embodiment 48, there is provided herein a compound or salt according to embodiment 47, wherein each R x is independently halogen. As embodiment 49, provided herein is a compound or salt according to embodiment 48, wherein both R x As embodiment 50, there is provided herein a compound or salt according to embodiment 49, wherein BL 1 teeth, [ka] is.

[0023] As embodiment 51, provided herein is a compound or salt according to embodiment 1, wherein B is a 4-10 membered heterocycloalkyl having one additional nitrogen heteroatom. As embodiment 52, provided herein is a compound or salt according to embodiment 51, wherein p is 2. As embodiment 53, provided herein is a compound or salt according to embodiment 52, wherein BL 1 teeth, [ka] is.

[0024] As embodiment 54, there is provided herein a compound or salt according to embodiment 53, wherein each R x is independently halogen. As embodiment 55, there are provided herein compounds or salts according to embodiment 54, wherein both R x As embodiment 56, there is provided herein a compound or salt according to embodiment 55, wherein BL 1 teeth, [ka] is.

[0025] In embodiment 57, a compound or salt according to embodiment 1 and a compound of formula (I): [ka] (In the formula, X is N, CH2, O, S, S(O), S(O)(NR z ) or S(O)2; Z is CH, C-halogen, C-CN, CC 1~4 Alkyl, CC 1~4 Haloalkyl, CC 1~4 Alkoxy, CC 1~4 Haloalkoxy, CC 3~7cycloalkyl or N; Q is CH, C-halogen, CC 1~4 Alkyl, CC 1~4 haloalkyl or N; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3; Each R x is haloalkyl, C 1~4 Haloalkoxy, 5-7 membered heteroaryl, -TR y or two R x together with the same or adjacent carbon atom, C 3~7 cycloalkyl, 3- to 7-membered heterocycloalkyl, each C 3~7 Cycloalkyl or 3- to 7-membered heterocycloalkyl is R y or two R x can be joined together to form a bridged ring, and the bridge is -C 1~4 Alkylene, -C 1~4 Alkylene-OC 1~4 Alkylene-, -O-, -S- or -C 1~4 Alkylene-SC 1~4 alkylene-, wherein each C 1~4 Alkylene is R y further substituted with 0-2 occurrences of; L is a bond, C 1~6 Alkylene, -OC 1~6 Alkylene, -SC 1~6 Alkylene, NR z , O or S, and each C 1~6 Alkylene, -OC 1~6 Alkylene and -SC 1~6 The alkylene chain is R 2 Replaced by 0-2 occurrences of; -L 1 -L 2 -L 2 , -N(R z )C(O)-L 2, -C(O)-L 2 -, -OC(O)-L 2 , -C(O)OL 2 , -OC(O)-OL 2 , -OC(S)-OL 2 , -OL 2 , -N(R z )C(O)OL 2 , -OC(O)N(R z )-L 2 , -N(R z )-L 2 , -S(O)2-L 2 , -SL 2 , -S(O)-L 2 , C 1~4 Alkylene-C(O)-L 2 , C 1~4 Alkylene-C(O)OL 2 , -C 1~4 Alkylene-OC(O)OL 2 , -C 1~4 Alkylene-OC(O)-L 2 , -C 1~4 Alkylene-OL 2 , -C 1~4 Alkylene-S(O)2-L 2 , -C 1~4 Alkylene-SL 2 , -C 1~4 Alkylene-S(O)-L 2 , -O-5 to 6-membered heteroaryl-L 2 , -C 1~4 Alkylene-5-6-membered heteroaryl-L 2 , -C 1~4 Hydroxyalkylene-5-6-membered heteroaryl-L 2 or 5-6 membered heteroaryl-L 2 and; L 2 is C 1~6 Alkylene, C 1~6 Alkylene-O-, C 1~6 Alkylene-OC 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 3~7 Cycloalkylene, C 1~4 Alkylene-C3~7 Cycloalkylene, C 1~4 Haloalkylene-C 3~7 Cycloalkylene, C 3~7 Cycloalkylene-C 1~4 Alkylene, C 1~6 Hydroxyalkylene or C 1~6 haloalkylene; R 1 is hydrogen, hydroxyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 cycloalkyl or 4- to 15-membered heterocycloalkyl, and each aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is R 5 Replaced by 0-3 occurrences of; R 2 is halogen, hydroxyl, C 1~4 alkyl, or two R on the same or adjacent carbon atoms 2 Let's get together and C 3~7 can form a cycloalkyl; A is C 6~10 aryl or 5- to 10-membered heteroaryl, and R 6 is replaced by q occurrences of; R 4 is hydrogen, hydroxyl, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~7 is cycloalkyl or cyano; Each R 5 are independently halogen, cyano, oxo, -TR y , hydroxyl, -N(R z )2, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy or -OC 2~4 is alkynyl; Each R 6 are independently halogen, hydroxyl, cyano, -N(R z )2, -C(O)R z, -C(O)OR z , C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 2~4 Alkynyl or C 3~6 cycloalkyl or two R 6 are joined together on adjacent carbon atoms, C 3~7 Forming a cycloalkyl; T is C 1~4 Alkylene, -S(O)2-, -C(O)-, -C 1~4 Alkylene-C(O)-, C 1~4 alkylene -S(O)2- or -S-; R y is halogen, oxo, C 1~4 Alkyl, C 1~4 Haloalkyl, hydroxyl, cyano or -N(R z )2; and Each R z is hydrogen or C 1~4 alkyl) or a pharmaceutically acceptable salt of said compound.

[0026] As embodiment 58, provided herein is a compound or salt according to any one of embodiments 1 to 57, wherein Z is CH, CF, C—CN, C—CH 3 , C—CF 3 , C—OMe, C—Cl, or N. As embodiment 59, provided herein is a compound or salt according to any one of embodiments 1 to 57, wherein Z is N. As embodiment 60, provided herein is a compound or salt according to any one of embodiments 1 to 57, wherein Z is CH. As embodiment 61, provided herein is a compound or salt according to any one of embodiments 1 to 57, wherein Z is CF.

[0027] As embodiment 62, provided herein is a compound or salt according to any one of embodiments 1 to 57, wherein Q is CH or N. As embodiment 63, provided herein is a compound or salt according to any one of embodiments 1 to 57, wherein Q is CH. As embodiment 64, provided herein is a compound or salt according to any one of embodiments 1 to 57, wherein Q is N. As embodiment 65, provided herein is a compound or salt according to any one of embodiments 1 to 57, wherein Z is N and Q is CH. As embodiment 66, provided herein is a compound or salt according to any one of embodiments 1 to 57, wherein Z is CH and Q is CH. As embodiment 67, provided herein is a compound or salt according to any one of embodiments 1 to 57, wherein Z is CF and Q is CH. As embodiment 68, there is provided herein a compound or salt according to any one of embodiments 1 to 57, wherein Z is N and Q is N.

[0028] As embodiment 69, there is provided herein a compound or salt according to any one of embodiments 1 to 68, wherein L is R 2 As embodiment 70, provided herein are compounds or salts according to embodiment 69, wherein L is -O-methylene or -O-ethylene substituted with 0 to 2 occurrences of R 2 is -O-methylene substituted with 0 occurrences of

[0029] As embodiment 71, there is provided herein a compound or salt according to any one of embodiments 69-70, wherein R 1 is R 5 As embodiment 72, provided herein are compounds or salts according to embodiment 71, wherein R 1 is R 5As embodiment 73, provided herein is a compound or salt according to embodiment 71, wherein R is substituted with 0 to 3 occurrences of 7a-(hexahydro-1H-pyrrolidinine), 6-(hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl), 2-pyrrolidinyl, 1-(7-oxabicyclo[2.2.1]heptanyl), 2-morpholinyl, 1-(2-azabicyclo[2.2.2]octanyl), or 3-(2-azabicyclo[3.1.0]hexanyl). 1 is R 5 As embodiment 74, provided herein is a compound or salt according to embodiment 73, wherein R 1 is R 5 It is 7a-(hexahydro-1H-pyrrolidinine) substituted with 0 occurrences of

[0030] As embodiment 75, there is provided herein a compound or salt according to embodiment 71, wherein R 1 is R 5 As embodiment 76, provided herein is a compound or salt according to embodiment 75, wherein R is substituted with one occurrence of 7a-(hexahydro-1H-pyrrolidinine), 6-(hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl), 2-pyrrolidinyl, 1-(7-oxabicyclo[2.2.1]heptanyl), 2-morpholinyl, 1-(2-azabicyclo[2.2.2]octanyl), or 3-(2-azabicyclo[3.1.0]hexanyl). 5 is independently halogen, oxo, methyl, methoxy, or -O-(2-propynyl). As embodiment 77, provided herein are compounds or salts according to embodiment 75, wherein R 1 is R 5 As embodiment 78, there are provided herein compounds or salts according to embodiment 77, wherein R 5is independently fluoro or -O-(2-propynyl). As embodiment 79, provided herein are compounds or salts according to embodiment 78, wherein R 5 As embodiment 80, there are provided herein compounds or salts according to embodiment 75, wherein R 1 is R 5 As embodiment 81, provided herein are compounds or salts according to embodiment 80, wherein R 5 is methyl.

[0031] As embodiment 82, there is provided herein a compound or salt according to embodiment 71, wherein R 1 is R 5 As embodiment 83, provided herein are compounds or salts according to embodiment 82, wherein each R 5 is independently methyl, fluoro or methoxy.

[0032] As embodiment 84, there is provided herein a compound or salt according to embodiment 69, wherein L is R 2 As embodiment 85, provided herein are compounds or salts according to embodiment 84, wherein R 2 is C 1~4 It is alkyl (eg, methyl).

[0033] As embodiment 86, there is provided herein a compound or salt according to embodiment 85, wherein R 1 is R 5 As embodiment 87, provided herein are compounds or salts according to embodiment 86, wherein R 1 is R 5 As embodiment 88, provided herein are compounds or salts according to embodiment 87, wherein R 5 is C 1~4It is alkyl (eg, methyl).

[0034] As embodiment 89, provided herein is a compound or salt according to embodiment 69, wherein L is R 2 As embodiment 90, provided herein is a compound or salt according to embodiment 89, wherein both R 2 C 1~4 As embodiment 91, provided herein are compounds or salts according to embodiment 90, wherein R 1 is a hydroxyl.

[0035] As embodiment 92, provided herein is a compound or salt according to embodiment 69, wherein L is R 2 As embodiment 93, there is provided herein a compound or salt according to embodiment 92, wherein two R 2 is combined with the same carbon atom as C 3~7 Forms a cycloalkyl (eg, cyclopropyl).

[0036] As embodiment 94, there is provided herein a compound or salt according to any one of embodiments 92-93, wherein R 1 is R 5 N-azetidinyl or -N(R z As embodiment 95, there is provided herein a compound or salt according to embodiment 94, wherein R 1 is R 5 As embodiment 96, provided herein are compounds or salts according to embodiment 95, wherein R 5 As embodiment 97, there are provided herein compounds or salts according to any one of embodiments 92-93, wherein R 1 is -N(R z )2, and R z is methyl.

[0037] As embodiment 98, there is provided herein a compound or salt according to any one of embodiments 1 to 68, wherein L is O.

[0038] As embodiment 99, there is provided herein a compound or salt according to embodiment 98, wherein R 1 is R 5 As embodiment 100, provided herein is a compound or salt according to embodiment 99, wherein R 1 is R 5 As embodiment 101, provided herein are compounds or salts according to embodiment 100, wherein R 1 is R 5 As embodiment 102, provided herein are compounds or salts according to embodiment 101, wherein R 1 is R 5 As embodiment 103, provided herein are compounds or salts according to embodiment 102, wherein R 5 is methyl.

[0039] As embodiment 104, there is provided herein a compound or salt according to any one of embodiments 1 to 68, wherein L is C 1~6 Alkylene or -OC 1~6 As embodiment 105, provided herein are compounds or salts according to embodiment 104, wherein L is methylene or -O-methylene. As embodiment 106, provided herein are compounds or salts according to embodiment 105, wherein R 1 is hydrogen.

[0040] As embodiment 107, provided herein is a compound or salt according to any one of embodiments 1 to 68, wherein L is a bond. As embodiment 108, provided herein is a compound or salt according to embodiment 107, wherein R 1 is R 5 As embodiment 109, provided herein are compounds or salts according to embodiment 108, wherein R 5 is methyl.

[0041] As embodiment 110, there is provided herein a compound or salt according to any one of embodiments 1 to 68, wherein -LR 1 teeth, [ka] , methoxy or methyl.

[0042] As embodiment 111, provided herein is a compound or salt according to embodiment 110, wherein -LR 1 teeth, [ka] , methoxy or methyl.

[0043] As embodiment 112, provided herein is a compound or salt according to embodiment 111, wherein -LR 1 teeth, [ka] As embodiment 113, provided herein is a compound or salt according to embodiment 112, wherein -LR 1 teeth, [ka] As embodiment 114, there is provided herein a compound or salt according to embodiment 112, wherein -LR 1 teeth, [ka] As embodiment 115, provided herein is a compound or salt according to embodiment 112, wherein -LR 1 teeth, [ka] As embodiment 116, provided herein is a compound or salt according to embodiment 112, wherein -LR 1 teeth, [ka] As embodiment 117, provided herein is a compound or salt according to embodiment 112, wherein -LR 1 teeth, [ka] is.

[0044] As embodiment 118, provided herein is a compound or salt according to any one of embodiments 57-117, wherein X is O. As embodiment 119, provided herein is a compound or salt according to embodiment 118, wherein n is 1 and m is 1. As embodiment 120, provided herein is a compound or salt according to embodiment 119, wherein p is 0.

[0045] As embodiment 121, provided herein is a compound or salt according to embodiment 119, wherein p is 1. As embodiment 122, provided herein is a compound or salt according to embodiment 121, wherein R x As embodiment 123, there are provided herein compounds or salts according to embodiment 122, wherein R x As embodiment 124, there are provided herein compounds or salts according to embodiment 122, wherein R x is methyl.

[0046] As embodiment 125, provided herein is a compound or salt according to embodiment 119, wherein p is 2. As embodiment 126, provided herein is a compound or salt according to embodiment 125, wherein two R x is combined with the same carbon atom and y As embodiment 127, provided herein are compounds or salts according to embodiment 125, wherein two R x is combined with the same carbon atom and y As embodiment 128, provided herein are compounds or salts according to embodiment 127, wherein R y is methyl.

[0047] As embodiment 129, provided herein is a compound or salt according to embodiment 118, wherein n is 1 and m is 2, or n is 2 and m is 1. As embodiment 130, provided herein is a compound or salt according to embodiment 129, wherein p is 0.

[0048] As embodiment 131, provided herein is a compound or salt according to embodiment 129, wherein p is 1. As embodiment 132, provided herein is a compound or salt according to embodiment 131, wherein R x is C 1~4 Alkyl, C 1~4 Deuteroalkyl, C 1~4 Haloalkyl, C 1~4 As embodiment 133, provided herein are compounds or salts according to embodiment 132, wherein R x As embodiment 134, there are provided herein compounds or salts according to embodiment 132, wherein R x As embodiment 135, provided herein are compounds or salts according to embodiment 132, wherein R x is -CD3.

[0049] As embodiment 136, provided herein is a compound or salt according to embodiment 129, wherein p is 2. As embodiment 137, provided herein is a compound or salt according to embodiment 136, wherein two R x is combined with the same carbon atom and y 0 occurrences of to form a further substituted cyclobutyl.

[0050] As embodiment 138, there is provided herein a compound or salt according to any one of embodiments 118 to 137, wherein: [ka] teeth, [ka] is.

[0051] As embodiment 139, there is provided herein a compound or salt according to embodiment 138, wherein: [ka] teeth, [ka] As embodiment 140, there is provided herein a compound or salt according to embodiment 139, wherein [ka] teeth, [ka] As embodiment 141, there is provided herein a compound or salt according to embodiment 140, wherein [ka] teeth, [ka] As embodiment 142, there is provided herein a compound or salt according to embodiment 140, wherein [ka] teeth, [ka] As embodiment 143, there is provided herein a compound or salt according to embodiment 140, wherein [ka] teeth, [ka] As embodiment 144, there is provided herein a compound or salt according to embodiment 140, wherein [ka] teeth, [ka] As embodiment 145, there is provided herein a compound or salt according to embodiment 140, wherein [ka] teeth, [ka] As embodiment 146, there is provided herein a compound or salt according to embodiment 140, wherein [ka] teeth, [ka] is.

[0052] As embodiment 147, provided herein is a compound or salt according to any one of embodiments 57 to 117, wherein X is N. As embodiment 148, provided herein is a compound or salt according to embodiment 147, wherein n is 1 and m is 2. As embodiment 149, provided herein is a compound or salt according to embodiment 148, wherein p is 0.

[0053] As embodiment 150, there is provided herein a compound or salt according to any one of embodiments 147 to 149, wherein: [ka] teeth, [ka] is.

[0054] As embodiment 151, provided herein is a compound or salt according to embodiment 147, wherein n is 3 and m is 1. As embodiment 152, provided herein is a compound or salt according to embodiment 151, wherein p is 2. As embodiment 153, provided herein is a compound or salt according to embodiment 152, wherein two R x together form a methylene-bridged ring.

[0055] As embodiment 154, there is provided herein a compound or salt according to any one of embodiments 151 to 153, wherein: [ka] teeth, [ka] As embodiment 155, there is provided herein a compound or salt according to embodiment 154, wherein [ka] teeth, [ka] is.

[0056] As embodiment 156, provided herein is a compound or salt according to any one of embodiments 57 to 117, wherein X is CH. As embodiment 157, provided herein is a compound or salt according to embodiment 156, wherein n is 0 and m is 1, or n is 1 and m is 0. As embodiment 158, provided herein is a compound or salt according to embodiment 157, wherein p is 0.

[0057] As embodiment 159, provided herein is a compound or salt according to embodiment 157, wherein p is 1. As embodiment 160, provided herein is a compound or salt according to embodiment 159, wherein R x is C 1~4 It is alkyl (eg, methyl).

[0058] As embodiment 161, provided herein is a compound or salt according to embodiment 156, wherein n is 1 and m is 1. As embodiment 162, provided herein is a compound or salt according to embodiment 161, wherein p is 0.

[0059] As embodiment 163, provided herein is a compound or salt according to embodiment 161, wherein p is 1. As embodiment 164, provided herein is a compound or salt according to embodiment 163, wherein R x is methyl, methoxy, hydroxyl, monofluoromethyl, or fluorine. As embodiment 165, there are provided herein compounds or salts according to embodiment 164, wherein R x As embodiment 166, there are provided herein compounds or salts according to embodiment 164, wherein R xAs embodiment 167, provided herein is a compound or salt according to embodiment 164, wherein R x is monofluoromethyl.

[0060] As embodiment 168, provided herein is a compound or salt according to embodiment 161, wherein p is 2. As embodiment 169, provided herein is a compound or salt according to embodiment 168, wherein both R x is a halogen (e.g., fluorine).

[0061] As embodiment 170, provided herein is a compound or salt according to embodiment 156, wherein n is 1 and m is 2, or n is 2 and m is 1. As embodiment 171, provided herein is a compound or salt according to embodiment 170, wherein p is 0.

[0062] As embodiment 172, provided herein is a compound or salt according to embodiment 170, wherein p is 1. As embodiment 173, provided herein is a compound or salt according to embodiment 172, wherein R x is methyl, methoxy, monofluoromethyl, hydroxyl, or fluorine. As embodiment 174, there are provided herein compounds or salts according to embodiment 173, wherein R x As embodiment 175, provided herein are compounds or salts according to embodiment 173, wherein R x As embodiment 175, provided herein are compounds or salts according to embodiment 173, wherein R x is monofluoromethyl.

[0063] As embodiment 177, there is provided herein a compound or salt according to any one of embodiments 161 to 176, wherein: [ka] teeth, [ka] is.

[0064] As embodiment 178, provided herein is a compound or salt according to embodiment 177, wherein: [ka] teeth, [ka] is.

[0065] As embodiment 179, there is provided herein a compound or salt according to embodiment 178, wherein: [ka] teeth, [ka] As embodiment 180, there is provided herein a compound or salt according to embodiment 179, wherein [ka] teeth, [ka] As embodiment 181, there is provided herein a compound or salt according to embodiment 180, wherein [ka] teeth, [ka] As embodiment 182, there is provided herein a compound or salt according to embodiment 180, wherein [ka] teeth, [ka] As embodiment 183, there is provided herein a compound or salt according to embodiment 180, wherein [ka] teeth, [ka] As embodiment 184, there is provided herein a compound or salt according to embodiment 180, wherein [ka] teeth, [ka] As embodiment 185, there is provided herein a compound or salt according to embodiment 180, wherein [ka] teeth, [ka] As embodiment 186, there is provided herein a compound or salt according to embodiment 180, wherein [ka] teeth, [ka] is.

[0066] As embodiment 187, provided herein is a compound or salt according to any one of embodiments 57 to 117, wherein X is CH. As embodiment 188, provided herein is a compound or salt according to embodiment 187, wherein n is 1 and m is 0, or m is 0 and n is 1. As embodiment 189, provided herein is a compound or salt according to embodiment 188, wherein two R x is combined with the same carbon atom and y to form a 3- to 7-membered heterocycloalkyl (e.g., 2-azetidinyl) further substituted with 0 occurrences of

[0067] As embodiment 190, provided herein is a compound or salt according to embodiment 187, wherein n is 1 and m is 1. As embodiment 191, provided herein is a compound or salt according to embodiment 190, wherein p is 2. As embodiment 192, provided herein is a compound or salt according to embodiment 191, wherein two R x is combined with the same carbon atom, C 3~7 Forming a cycloalkyl or 3- to 7-membered heterocycloalkyl, each C 3~7 Cycloalkyl or 3- to 7-membered heterocycloalkyl is R y As embodiment 193, provided herein are compounds or salts according to embodiment 192, wherein two R x is combined with the same carbon atom and y As embodiment 194, provided herein are compounds or salts according to embodiment 192, wherein two R x is combined with the same carbon atom and y As embodiment 195, provided herein are compounds or salts according to embodiment 192, wherein two R x is combined with the same carbon atom and yAs embodiment 196, provided herein are compounds or salts according to embodiment 192, wherein two R x is combined with the same carbon atom and y As embodiment 197, provided herein are compounds or salts according to embodiment 196, wherein R y is methyl or hydroxyl.

[0068] As embodiment 198, provided herein is a compound or salt according to embodiment 192, wherein two R x is combined with the same carbon atom and y 0 occurrences of to form a 3- to 7-membered heterocycloalkyl (e.g., 2-azetidinyl or 2-tetrahydrofuranyl) further substituted.

[0069] As embodiment 199, provided herein is a compound or salt according to embodiment 191, wherein two R x together with the adjacent carbon atom, C 3~7 Forming a cycloalkyl or 3- to 7-membered heterocycloalkyl, each C 3~7 Cycloalkyl or 3- to 7-membered heterocycloalkyl is R y As embodiment 200, provided herein is a compound or salt according to embodiment 199, wherein two R x together with the adjacent carbon atom, R y C further replaced with 0 occurrences of 3~7 As embodiment 201, provided herein are compounds or salts according to embodiment 199, wherein two R x together with the adjacent carbon atom, R yAs embodiment 202, provided herein are compounds or salts according to embodiment 201, wherein two R x together with the adjacent carbon atom, R y 0 occurrences of to form a further substituted 2-pyrrolidinyl.

[0070] As embodiment 203, there is provided herein a compound or salt according to embodiment 191, wherein two R x can be joined together to form a bridged ring, and the bridge is -C 1~4 Alkylene, -C 1~4 Alkylene-OC 1~4 Alkylene-, -O-, -S- or -C 1~4 Alkylene-SC 1~4 alkylene-, wherein each C 1~4 Alkylene is R y As embodiment 204, provided herein are compounds or salts according to embodiment 203, wherein two R x Together, R y C further replaced with 0 occurrences of 1~4 Alkylene (eg, ethylene) forms a bridged ring.

[0071] As embodiment 205, there is provided herein a compound or salt according to any one of embodiments 187 to 204, wherein: [ka] teeth, [ka] is.

[0072] As embodiment 206, there is provided herein a compound or salt according to embodiment 205, wherein: [ka] teeth, [ka] As embodiment 207, there is provided herein a compound or salt according to embodiment 206, wherein [ka] teeth, [ka] As embodiment 208, there is provided herein a compound or salt according to embodiment 207, wherein [ka] teeth, [ka] As embodiment 209, there is provided herein a compound or salt according to embodiment 207, wherein: [ka] teeth, [ka] As embodiment 210, there is provided herein a compound or salt according to embodiment 207, wherein: [ka] teeth, [ka] is.

[0073] As embodiment 211, provided herein is a compound or salt according to any one of embodiments 1 to 210, wherein A is C 6~10aryl (e.g., phenyl, naphthyl, 8-(1,2,3,4-tetrahydroquinolinyl), or 5-(1,2,3,4-tetrahydronaphthalyl). As embodiment 212, provided herein are compounds or salts according to embodiment 211, wherein A is phenyl. As embodiment 213, provided herein are compounds or salts according to embodiment 212, wherein q is 0.

[0074] As embodiment 214, provided herein is a compound or salt according to embodiment 212, wherein q is 1. As embodiment 215, provided herein is a compound or salt according to embodiment 214, wherein R 6 is halo (e.g., chlorine).

[0075] As embodiment 216, provided herein is a compound or salt according to embodiment 212, wherein q is 2. As embodiment 217, provided herein is a compound or salt according to embodiment 216, wherein each R 6 is halo (e.g., chloro or fluoro), hydroxyl, or cyano. As embodiment 218, provided herein are compounds or salts according to embodiment 217, wherein one R 6 is chloro, and the other R 6 As embodiment 219, provided herein are compounds or salts according to embodiment 217, wherein one R 6 is chloro, and the other R 6 As embodiment 220, provided herein are compounds or salts according to embodiment 217, wherein one R 6 is chloro, and the other R 6 is hydroxyl.

[0076] As embodiment 221, provided herein is a compound or salt according to embodiment 212, wherein q is 3. As embodiment 222, provided herein is a compound or salt according to embodiment 221, wherein one R 6 is halo (e.g., fluoro), and another R6 C 1~4 alkyl (e.g., methyl), and the final R 6 -N(R z )2 (e.g., -NH2).

[0077] As embodiment 223, provided herein is a compound or salt according to embodiment 211, wherein A is 5-(1,2,3,4-tetrahydronaphthalyl). As embodiment 224, provided herein is a compound or salt according to embodiment 223, wherein q is 0. As embodiment 225, provided herein is a compound or salt according to embodiment 224, wherein q is 1. As embodiment 226, provided herein is a compound or salt according to embodiment 225, wherein R 6 is hydroxy.

[0078] As embodiment 227, provided herein is a compound or salt according to embodiment 211, wherein A is 8-(1,2,3,4-tetrahydroquinolinyl). As embodiment 228, provided herein is a compound or salt according to embodiment 227, wherein q is 0.

[0079] As embodiment 229, provided herein is a compound or salt according to embodiment 211, wherein A is naphthyl. As embodiment 230, provided herein is a compound or salt according to embodiment 229, wherein q is 0.

[0080] As embodiment 231, provided herein is a compound or salt according to embodiment 229, wherein q is 1. As embodiment 232, provided herein is a compound or salt according to embodiment 231, wherein R 6 are hydroxyl, halo, C 1~4 Alkoxy or C 1~4 As embodiment 233, provided herein are compounds or salts according to embodiment 232, wherein R 6As embodiment 234, there are provided herein compounds or salts according to embodiment 232, wherein R 6 is halo (e.g., fluorine or chlorine). As embodiment 235, provided herein are compounds or salts according to embodiment 232, wherein R 6 is C 1~4 As embodiment 236, provided herein are compounds or salts according to embodiment 232, wherein R 6 is C 1~4 It is alkyl (eg, methyl).

[0081] As embodiment 237, provided herein is a compound or salt according to embodiment 229, wherein q is 2. As embodiment 238, provided herein is a compound or salt according to embodiment 237, wherein R 6 Each occurrence of is a halogen, hydroxyl, cyano, C 1~4 Alkoxy or C 1~4 As embodiment 239, provided herein are compounds or salts according to embodiment 238, wherein R 6 Each occurrence of is fluorine, chlorine, cyano, hydroxyl, or methoxy.

[0082] As embodiment 240, there is provided herein a compound or salt according to any one of embodiments 211 to 239, wherein AL 2 teeth, [ka] As embodiment 241, provided herein is a compound or salt according to embodiment 240, wherein AL 2 teeth, [ka] As embodiment 242, provided herein is a compound or salt according to embodiment 240, wherein AL 2 teeth, [ka] As embodiment 243, provided herein is a compound or salt according to embodiment 240, wherein AL 2 teeth, [ka] As embodiment 244, provided herein is a compound or salt according to embodiment 240, wherein AL 2 teeth, [ka] As embodiment 245, provided herein is a compound or salt according to embodiment 240, wherein AL 2 teeth, [ka] As embodiment 246, provided herein is a compound or salt according to embodiment 240, wherein AL 2 teeth, [ka] As embodiment 247, provided herein is a compound or salt according to embodiment 240, wherein AL 2 teeth, [ka] As embodiment 248, provided herein is a compound or salt according to embodiment 240, wherein AL 2 teeth, [ka] As embodiment 249, provided herein is a compound or salt according to embodiment 248, wherein AL 2 teeth, [ka] is.

[0083] As embodiment 250, provided herein is a compound or salt according to any one of embodiments 1 to 210, wherein A is a 5- to 10-membered heteroaryl (e.g., 3-pyrimidinyl, 4-indazolyl, 4-isoquinolinyl, 4-(5,6,7,8)-tetrahydroisoquinolinyl, or 7-indazolyl).

[0084] As embodiment 251, provided herein is a compound or salt according to embodiment 250, wherein A is 3-pyrimidinyl. As embodiment 252, provided herein is a compound or salt according to embodiment 251, wherein q is 1. As embodiment 253, provided herein is a compound or salt according to embodiment 252, wherein R 6 is halo (e.g., chlorine).

[0085] As embodiment 254, provided herein is a compound or salt according to embodiment 250, wherein A is 4-isoquinolinyl. As embodiment 255, provided herein is a compound or salt according to embodiment 252, wherein q is 0.

[0086] As embodiment 256, provided herein is a compound or salt according to embodiment 250, wherein A is 4-(5,6,7,8)-tetrahydroisoquinolinyl. As embodiment 257, provided herein is a compound or salt according to embodiment 256, wherein q is 0.

[0087] As embodiment 258, provided herein are compounds or salts according to embodiment 250, wherein A is 4-indazolyl. As embodiment 259, provided herein are compounds or salts according to embodiment 258, wherein q is 0.

[0088] As embodiment 260, provided herein is a compound or salt according to embodiment 258, wherein q is 1. As embodiment 261, provided herein is a compound or salt according to embodiment 260, wherein R 6 Halo is C1~4 Alkyl, Halo, C 1~4 Haloalkyl or -C(O)OR z As embodiment 262, provided herein is a compound or salt according to embodiment 261, wherein R 6 is halo (e.g., fluorine or chlorine). As embodiment 263, provided herein are compounds or salts according to embodiment 261, wherein R 6 is C 1~4 As embodiment 264, provided herein are compounds or salts according to embodiment 261, wherein R 6 is C 1~4 haloalkyl (e.g., trifluoromethyl. As embodiment 265, provided herein are compounds or salts according to embodiment 261, wherein R 6 is -C(O)OR z (For example, -C(O)OtBu.

[0089] As embodiment 266, provided herein is a compound or salt according to embodiment 258, wherein q is 2. As embodiment 267, provided herein is a compound or salt according to embodiment 266, wherein one R 6 is halo (e.g., chloro), and the other R 6 -C(O)R z (e.g., —C(O)CH 3 ). As embodiment 268, provided herein are compounds or salts according to embodiment 266, wherein two R 6 together with the adjacent carbon atom to form C 3~7 Forms a cycloalkyl (eg, cyclopentyl).

[0090] As embodiment 269, provided herein are compounds or salts according to embodiment 250, wherein A is 7-indazolyl. As embodiment 270, provided herein are compounds or salts according to embodiment 269, wherein q is 2. As embodiment 271, provided herein are compounds or salts according to embodiment 270, wherein one R 6 is chloro, and the other R6 is methyl.

[0091] As embodiment 272, provided herein is a compound or salt according to any one of embodiments 250 to 271, wherein AL 2 teeth, [ka] As embodiment 273, provided herein is a compound or salt according to embodiment 272, wherein AL 2 teeth, [ka] As embodiment 274, provided herein is a compound or salt according to embodiment 273, wherein AL 2 teeth, [ka] As embodiment 275, provided herein is a compound or salt according to embodiment 273, wherein AL 2 teeth, [ka] As embodiment 276, provided herein is a compound or salt according to embodiment 273, wherein AL 2 teeth, [ka] As embodiment 277, provided herein is a compound or salt according to embodiment 273, wherein AL 2 teeth, [ka] is.

[0092] As embodiment 278, provided herein is a compound or salt according to any one of embodiments 1 to 277, wherein -L 1 -L 2- is -N(R z )-C(O)-L 2 As embodiment 279, provided herein is a compound or salt according to embodiment 278, wherein R z As embodiment 280, provided herein is a compound or salt according to embodiment 279, wherein L 2 is n-propylene, 1-fluoro-n-propylene, n-butylene, 1-fluoro-n-butylene, 1-fluoro-n-pentylene, n-pentylene, methylene-O-ethylene, methylene-On-propylene, -CHF-CH2-cyclopropylene- or -CH2CH2-cyclopropylene-.

[0093] As embodiment 281, provided herein is a compound or salt according to embodiment 278, wherein R z As embodiment 282, provided herein is a compound or salt according to embodiment 281, wherein L 2 is n-propylene, n-butylene, 1-fluoro-n-butylene, -CHF-CH2-cyclopropylene-, methylene-O-ethylene, or -CH2CH2-cyclopropylene-. As embodiment 283, provided herein are compounds or salts according to embodiment 278, wherein -L 1 -L 2 -teeth, [ka] is.

[0094] As embodiment 284, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L 1 -L 2 - is -OC(O)-L 2 As embodiment 285, provided herein is a compound or salt according to embodiment 284, wherein L 2is methylene-On-propylene, n-propylene-O-, n-butylene, 1-methyl-n-butylene, trans-n-propenylene, cis-n-butenylene, n-pentylene, -CHF-CH2-cyclopropylene-, methylene-O-ethylene, -ethylene-cyclopropylene-, or n-propylene. As embodiment 286, provided herein are compounds or salts according to embodiment 284, wherein -L 1 -L 2 -teeth, [ka] is.

[0095] As embodiment 287, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L 1 -L 2 - is -OC(O)-L 2 As embodiment 288, provided herein is a compound or salt according to embodiment 287, wherein L 2 is ethylene, n-propylene, n-butylene, 2-methyl-n-propylene, cis-2-propenylene, trans-2-propenylene, or -CH2-cyclopropylene. As embodiment 289, provided herein are compounds or salts according to embodiment 287, wherein -L 1 -L 2 -teeth, [ka] As embodiment 290, provided herein is a compound or salt according to embodiment 289, wherein -L 1 -L 2 -teeth, [ka] As embodiment 291, provided herein is a compound or salt according to embodiment 290, wherein -L 1 -L 2 -teeth, [ka] is.

[0096] As embodiment 292, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L 1 -L 2 - is -C 1~4 Alkylene-S(O)2-L 2 As embodiment 293, provided herein is a compound or salt according to embodiment 292, wherein -L 1 -L 2 - is -methylene-S(O)2-L 2 As embodiment 294, provided herein is a compound or salt according to embodiment 293, wherein L 2 As embodiment 295, provided herein is a compound or salt according to embodiment 292, wherein -L 1 -L 2 -teeth, [ka] is.

[0097] As embodiment 296, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L 1 -L 2 - is -C 1~4 Alkylene-S(O)-L 2 As embodiment 297, provided herein is a compound or salt according to embodiment 296, wherein -L 1 -L 2 - is -methylene-S(O)-L 2 As embodiment 298, provided herein is a compound or salt according to embodiment 297, wherein L 2 As embodiment 299, provided herein are compounds or salts according to embodiment 296, wherein -L 1 -L 2 -teeth, [ka] is.

[0098] As embodiment 300, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L 1 -L 2 - is -C 1~4 Alkylene-SL 2 As embodiment 301, provided herein is a compound or salt according to embodiment 300, wherein -L 1 -L 2 -, -methylene-SL 2 As embodiment 302, provided herein is a compound or salt according to embodiment 301, wherein L 2 As embodiment 303, provided herein are compounds or salts according to embodiment 300, wherein -L 1 -L 2 -teeth, [ka] is.

[0099] As embodiment 304, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L 1 -L 2 -, -OL 2 As embodiment 305, provided herein is a compound or salt according to embodiment 304, wherein L 2 is n-butylene, n-pentylene, cis-2-pentenylene, or trans-2-pentenylene. As embodiment 306, provided herein are compounds or salts according to embodiment 304, wherein -L 1 -L 2 -teeth, [ka] is.

[0100] As embodiment 307, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L1 -L 2 As embodiment 308, provided herein are compounds or salts according to embodiment 307, wherein L 2 As embodiment 309, provided herein are compounds or salts according to embodiment 307, wherein -L 1 -L 2 -teeth, [ka] is.

[0101] As embodiment 310, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L 1 -L 2 As embodiment 311, provided herein is a compound or salt according to embodiment 310, wherein L 2 is C 2~6 As embodiment 312, provided herein are compounds or salts according to embodiment 311, wherein L is alkenylene. 2 As embodiment 313, provided herein are compounds or salts according to embodiment 310, wherein -L 1 -L 2 -teeth, [ka] is.

[0102] As embodiment 314, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L 1 -L 2 -, -NR z -C(O)-OL 2 As embodiment 315, provided herein is a compound or salt according to embodiment 314, wherein R z is hydrogen or methyl. As embodiment 316, provided herein are compounds or salts according to embodiment 315, wherein L 2is n-propylene, ethylene, n-butylene, -CH2-cyclopropylene. As embodiment 317, provided herein are compounds or salts according to embodiment 314, wherein -L 1 -L 2 -teeth, [ka] As embodiment 318, provided herein is a compound or salt according to embodiment 317, wherein -L 1 -L 2 -teeth, [ka] is.

[0103] As embodiment 319, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L 1 -L 2 - is -OC(O)-L 2 As embodiment 320, provided herein is a compound or salt according to embodiment 319, wherein L 2 is n-propylene or n-butylene. As embodiment 321, provided herein are compounds or salts according to embodiment 319, wherein -L 1 -L 2 -teeth, [ka] is.

[0104] As embodiment 322, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L 1 -L 2 - is -OC(O)-NR z -L 2 As embodiment 323, provided herein is a compound or salt according to embodiment 322, wherein R z is hydrogen or methyl. As embodiment 324, provided herein is a compound or salt according to embodiment 323, wherein L2 is n-propylene or -methylene-cyclopropylene. As embodiment 325, provided herein are compounds or salts according to embodiment 322, wherein -L 1 -L 2 -teeth, [ka] is.

[0105] As embodiment 326, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L 1 -L 2 - is a 5- to 6-membered heteroaryl-L 2 As embodiment 327, provided herein is a compound or salt according to embodiment 326, wherein -L 1 -L 2 -teeth, [ka] As embodiment 328, provided herein is a compound or salt according to embodiment 327, wherein L 2 is n-propylene, ethylene, cis-2-propenylene, or trans-2-propenylene. As embodiment 329, provided herein are compounds or salts according to embodiment 326, wherein -L 1 -L 2 -teeth, [ka] As embodiment 330, provided herein is a compound or salt according to embodiment 329, wherein -L 1 -L 2 -teeth, [ka] is.

[0106] As embodiment 331, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L 1-L 2 - is -C 1~4 Alkylene-5-6-membered heteroaryl-L 2 As embodiment 332, provided herein is a compound or salt according to embodiment 331, wherein -L 1 -L 2 - is -methylene-5-6 membered heteroaryl-L 2 As embodiment 333, provided herein is a compound or salt according to embodiment 332, wherein -L 1 -L 2 -teeth, [ka] As embodiment 334, provided herein is a compound or salt according to embodiment 333, wherein L 2 is ethylene, n-propylene, cyclopropylene, cis-2-propenylene, or trans-2-propenylene. As embodiment 335, provided herein are compounds or salts according to embodiment 331, wherein -L 1 -L 2 -teeth, [ka] is.

[0107] As embodiment 336, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L 1 -L 2 - is -C 1~4 Hydroxyalkylene-5-6-membered heteroaryl-L 2 As embodiment 337, provided herein is a compound or salt according to embodiment 336, wherein -L 1 -L 2 - is -hydroxymethylene-5-6-membered heteroaryl-L 2 As embodiment 338, provided herein is a compound or salt according to embodiment 337, wherein -L 1 -L 2 -teeth, [ka] As embodiment 339, provided herein is a compound or salt according to embodiment 338, wherein L 2 As embodiment 340, provided herein is a compound or salt according to embodiment 336, wherein -L 1 -L 2 -teeth, [ka] is.

[0108] As embodiment 341, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L 1 -L 2 -O-5-6 membered heteroaryl-L 2 As embodiment 342, provided herein is a compound or salt according to embodiment 341, wherein -L 1 -L 2 -teeth, [ka] As embodiment 343, provided herein is a compound or salt according to embodiment 342, wherein L 2 As embodiment 344, provided herein is a compound or salt according to embodiment 341, wherein -L 1 -L 2 -teeth, [ka] is.

[0109] As embodiment 345, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L 1 -L 2 As embodiment 346, provided herein are compounds or salts according to embodiment 345, wherein L 2is n-propylene, -methylene-O-ethylene, -methylene-On-propylene, or n-butylene. As embodiment 347, provided herein are compounds or salts according to embodiment 346, wherein -L 1 -L 2 -teeth, [ka] As embodiment 348, provided herein is a compound or salt according to embodiment 347, wherein -L 1 -L 2 -teeth, [ka] is.

[0110] As embodiment 349, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L 1 -L 2 -C 1~4 Alkylene-C(O)-L 2 As embodiment 350, provided herein is a compound or salt according to embodiment 349, wherein -L 1 -L 2 - is -methylene-C(O)-L 2 As embodiment 351, provided herein is a compound or salt according to embodiment 350, wherein L 2 is n-propylene or n-butylene. As embodiment 352, provided herein are compounds or salts according to embodiment 349, wherein -L 1 -L 2 -teeth, [ka] As embodiment 353, provided herein is a compound or salt according to embodiment 349, wherein -L 1 -L 2 - is -ethylene-C(O)-L 2 As embodiment 354, provided herein is a compound or salt according to embodiment 353, wherein L2 As embodiment 355, provided herein is a compound or salt according to embodiment 349, wherein -L 1 -L 2 -teeth, [ka] is.

[0111] As embodiment 356, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L 1 -L 2 - is -C 1~4 Alkylene-OC(O)OL 2 As embodiment 357, provided herein is a compound or salt according to embodiment 356, wherein -L 1 -L 2 - is -methylene-OC(O)OL 2 As embodiment 358, provided herein is a compound or salt according to embodiment 357, wherein L 2 As embodiment 359, provided herein are compounds or salts according to embodiment 356, wherein -L 1 -L 2 -teeth, [ka] is.

[0112] As embodiment 360, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L 1 -L 2 -C 1~4 Hydroxyalkylene-C(O)-L 2 As embodiment 361, provided herein is a compound or salt according to embodiment 360, wherein -L 1 -L 2 - is -hydroxymethylene-C(O)-L 2 As embodiment 362, provided herein is a compound or salt according to embodiment 361, wherein L2 As embodiment 363, provided herein are compounds or salts according to embodiment 360, wherein -L 1 -L 2 -teeth, [ka] is.

[0113] As embodiment 364, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L 1 -L 2 - is -C 1~4 Alkylene-OL 2 As embodiment 365, provided herein is a compound or salt according to embodiment 364, wherein -L 1 -L 2 -, -methylene-OL 2 As embodiment 366, provided herein is a compound or salt according to embodiment 365, wherein L 2 is n-butylene, 2,2-difluoro-n-butylene, trans-2-butenylene, cis-2-butenylene, 3-methyl-n-butylene, -ethylene-cyclopropylene-, or ethylene-O-methylene. As embodiment 367, provided herein are compounds or salts according to embodiment 364, wherein -L 1 -L 2 -teeth, [ka] As embodiment 368, provided herein is a compound or salt according to embodiment 367, wherein -L 1 -L 2 -teeth, [ka] As embodiment 369, provided herein is a compound or salt according to embodiment 364, wherein -L 1 -L 2 - is methylmethylene-OL 2As embodiment 370, provided herein is a compound or salt according to embodiment 369, wherein L 2 As embodiment 371, provided herein are compounds or salts according to embodiment 364, wherein -L 1 -L 2 -teeth, [ka] As embodiment 372, provided herein is a compound or salt according to embodiment 364, wherein -L 1 -L 2 - is ethylene-OL 2 As embodiment 373, provided herein is a compound or salt according to embodiment 372, wherein L 2 is ethylene, n-propylene, or methylenecyclopropylene. As embodiment 374, provided herein are compounds or salts according to embodiment 364, wherein -L 1 -L 2 -teeth, [ka] As embodiment 375, provided herein is a compound or salt according to embodiment 374, wherein -L 1 -L 2 -teeth, [ka] is.

[0114] As embodiment 376, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L 1 -L 2 - is -C 1~4 Alkylene-C(O)OL 2 As embodiment 377, provided herein is a compound or salt according to embodiment 376, wherein -L 1 -L 2 - is -methylene-C(O)OL 2As embodiment 378, provided herein is a compound or salt according to embodiment 377, wherein L 2 is ethylene, n-propylene, or 2-methyl-n-propylene. As embodiment 379, provided herein are compounds or salts according to embodiment 376, wherein -L 1 -L 2 -teeth, [ka] is.

[0115] As embodiment 380, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L 1 -L 2 - is -C 1~4 Alkylene-OC(O)-L 2 As embodiment 381, provided herein is a compound or salt according to embodiment 380, wherein -L 1 -L 2 - is -methylene-OC(O)OL 2 As embodiment 382, ​​provided herein is a compound or salt according to embodiment 381, wherein L 2 As embodiment 383, provided herein are compounds or salts according to embodiment 380, wherein -L 1 -L 2 - is -ethylene-OC(O)-L 2 As embodiment 384, provided herein is a compound or salt according to embodiment 383, wherein L 2 As embodiment 385, provided herein is a compound or salt according to embodiment 380, wherein -L 1 -L 2 -teeth, [ka] is.

[0116] As embodiment 386, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L 1 -L 2 As embodiment 387, provided herein is a compound or salt according to embodiment 386, wherein L 2 is 2-hydroxy-n-hexylene or 3-hydroxy-n-hexylene. As embodiment 388, provided herein are compounds or salts according to embodiment 386, wherein -L 1 -L 2 -teeth, [ka] is.

[0117] As embodiment 389, there is provided herein a compound or salt according to any one of embodiments 1 to 277, wherein -L 1 -L 2 - is -OC(S)-OL 2 As embodiment 390, provided herein is a compound or salt according to embodiment 389, wherein L 2 As embodiment 391, provided herein is a compound or salt according to embodiment 389, wherein -L 1 -L 2 -teeth, [ka] is.

[0118] As embodiment 392, provided herein is a compound or salt according to any one of embodiments 1 to 391, wherein R 4 is C 1~4 Alkyl, C 1~4 Alkoxy, hydroxyl, halogen or C 1~4 As embodiment 393, provided herein are compounds or salts according to embodiment 392, wherein R 4 is C 1~4As embodiment 394, provided herein are compounds or salts according to embodiment 393, wherein R 4 is C 1~4 As embodiment 395, provided herein is a compound or salt according to embodiment 394, wherein R 4 As embodiment 396, provided herein are compounds or salts according to embodiment 395, wherein R 4 is fluorine.

[0119] As embodiment 397, there is provided a compound or salt according to embodiment 1, wherein the compound has formula (II): [ka] is a compound of

[0120] As embodiment 398, there is provided a compound or salt according to embodiment 1, wherein the compound has formula (III): [ka] is a compound of

[0121] As embodiment 399, there is provided a compound or salt according to embodiment 1, wherein the compound has formula (IV): [ka] is a compound of

[0122] As embodiment 400, there is provided a compound or salt according to embodiment 1, wherein the compound has formula (V): [ka] is a compound of

[0123] As embodiment 401, there is provided a compound or salt according to embodiment 1, wherein the compound is selected from the compounds of Table 1.

[0124] [Table 1]

[0125] [Table 2]

[0126] [Table 3]

[0127] As embodiment 402, there is provided a compound or salt according to embodiment 1, wherein the compound is selected from the compounds of Table 2.

[0128] [Table 4]

[0129] [Table 5]

[0130] As embodiment 403, there is provided herein a compound or salt according to embodiment 1, wherein the compound is [ka] As embodiment 404, provided herein is a compound or salt according to embodiment 1, wherein the compound is [ka] As embodiment 405, provided herein is a compound or salt according to embodiment 1, wherein the compound is [ka] As embodiment 406, provided herein is a compound or salt according to embodiment 1, wherein the compound is [ka] As embodiment 407, provided herein is a compound or salt according to embodiment 1, wherein the compound is [ka] As embodiment 408, provided herein is a compound or salt according to embodiment 1, wherein the compound is [ka] As embodiment 409, provided herein is a compound or salt according to embodiment 1, wherein the compound is [ka] As embodiment 410, provided herein is a compound or salt according to embodiment 1, wherein the compound is [ka] As embodiment 411, provided herein is a compound or salt according to embodiment 1, wherein the compound is [ka] As embodiment 412, provided herein is a compound or salt according to embodiment 1, wherein the compound is [ka] is.

[0131] As embodiment 413, there is provided a compound or salt according to embodiment 1, wherein the compound is selected from the compounds of Table 3.

[0132] [Table 6]

[0133] [Table 7]

[0134] [Table 8]

[0135] As embodiment 414, there is provided a compound or salt according to embodiment 1, wherein the compound is selected from the compounds of Table 4.

[0136] [Table 9]

[0137] [Table 10]

[0138] As embodiment 415, there is provided herein a compound or salt according to embodiment 1, wherein the compound is [ka] As embodiment 416, provided herein is a compound or salt according to embodiment 1, wherein the compound is [ka] As embodiment 417, provided herein is a compound or salt according to embodiment 1, wherein the compound is [ka] As embodiment 418, provided herein is a compound or salt according to embodiment 1, wherein the compound is [ka] As embodiment 419, provided herein is a compound or salt according to embodiment 1, wherein the compound is [ka] As embodiment 420, provided herein is a compound or salt according to embodiment 1, wherein the compound is [ka] As embodiment 421, provided herein is a compound or salt according to embodiment 1, wherein the compound is [ka] As embodiment 422, provided herein is a compound or salt according to embodiment 1, wherein the compound is [ka] As embodiment 423, provided herein is a compound or salt according to embodiment 1, wherein the compound is [ka] As embodiment 424, provided herein is a compound or salt according to embodiment 1, wherein the compound is [ka] is.

[0139] Further embodiments As a further embodiment B1, provided herein is a compound of formula (BI): [ka] (In the formula, X is N, CH2, O, S, S(O), S(O)(NR z ) or S(O)2; Z is CH, CF, C—CN, C—OMe, C—Cl or N; Q is CH or N; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3; Each R x is hydroxyl, halogen, oxo, cyano, -N(R z )2, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, 5-7 membered heteroaryl, -TR y or two R x together with the same or adjacent carbon atom, C 3~7 cycloalkyl, 3- to 7-membered heterocycloalkyl, each C 3~7 Cycloalkyl or 3- to 7-membered heterocycloalkyl is R y or two R x can be joined together to form a bridged ring, and the bridge is -C 1~4 Alkylene, -C 1~4 Alkylene-OC 1~4 Alkylene-, -O-, -S- or -C 1~4 Alkylene-SC 1~4 alkylene-, wherein each C 1~4 Alkylene is R y Further substituted with 0-2 occurrences of; L is C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylene, -OC 1~6 Alkylene, -SC 1~6 Alkylene, NR z , O or S, and each C 1~6 Alkylene, -OC 1~6 Alkylene and -SC 1~6 The alkylene chain is R 2 Replaced by 0-2 occurrences of; L 1 is a bond, -N(Rz )C(O)-L 2 , -C(O)-L 2 -, -OC(O)-L 2 , -C(O)OL 2 , -C 1~4 Alkylene -C(O)O-, -OC(O)-OL 2 , -OL 2 , -N(R z )-L 2 , -C 1~4 Alkylene-C(O)OL 2 , -C 1~4 Alkylene-OC(O)-L 2 or 5-6 membered heteroaryl; L 2 is C 1~6 Alkylene, C 1~6 Alkylene-O-, C 1~6 Alkylene-OC 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 3~7 Cycloalkylene, C 1~4 Alkylene-C 3~7 Cycloalkylene, C 1~4 Haloalkylene-C 3~7 Cycloalkylene, C 3~7 Cycloalkylene-C 1~4 Alkylene or C 1~6 haloalkylene; R 1 is hydrogen, hydroxyl, aryl, heteroaryl, C 3~8 Cycloalkyl or R 5 is heterocycloalkyl substituted with 0-3 occurrences of; R 2 is halogen, hydroxyl, C 1~4 alkyl, or two R on the same or adjacent carbon atoms 2 Let's get together and C 3~7 can form a cycloalkyl; A is q R 6 is an aryl or heteroaryl substituted with the presence of R 4 is hydrogen, hydroxyl, halogen, C1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~7 is cycloalkyl or cyano; Each R 5 are independently halogen, cyano, oxo, -TR y , hydroxyl, amino or C 1~4 is alkyl; Each R 6 are independently halogen, hydroxyl, cyano, -N(R z )2, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 2~4 Alkynyl or C 3~6 is cycloalkyl; T is C 1~4 Alkylene, -S(O)2-, -C(O)-, -C 1~4 Alkylene-C(O)-, C 1~4 alkylene -S(O)2- or -S-; R y is halogen, oxo, C 1~4 Alkyl, C 1~4 Haloalkyl, hydroxyl, cyano or -N(R z )2; and R z is hydrogen or C 1~4 alkyl) or a pharmaceutically acceptable salt of said compound.

[0140] As Embodiment B2, provided herein is a compound of Embodiment B1, wherein Z is N and Q is CH.

[0141] As Embodiment B3, provided herein is a compound of Embodiment B1, wherein L is R 2 is -O-methylene-, -O-ethylene-, -O-propylene, or -O-isopentanylene substituted with 0 to 2 occurrences of As embodiment B4, provided herein is a compound of embodiment B1, wherein -LR 1 teeth, [ka] , methoxy, or methyl. As embodiment B5, provided herein is a compound of embodiment B4, wherein -LR 1 teeth, [ka] is.

[0142] As embodiment B6, provided herein is a compound of embodiment B1, wherein X is O. As embodiment B7, provided herein is a compound of embodiment B6, wherein n is 0 and m is 1, or n is 1 and m is 1. As embodiment B8, provided herein is a compound of embodiment B7, wherein [ka] teeth, [ka] is.

[0143] As embodiment B9, provided herein is a compound of embodiment B1, wherein X is S. As embodiment B10, provided herein is a compound of embodiment B9, wherein n is 0 and m is 1, or n is 1 and m is 1. As embodiment B11, provided herein is a compound of embodiment B10, wherein [ka] teeth, [ka] is.

[0144] As embodiment B12, provided herein is a compound of embodiment B1, wherein X is N. As embodiment B13, provided herein is a compound of embodiment B12, wherein n is 1 and m is 2. As embodiment B14, provided herein is a compound of embodiment B13, wherein [ka] teeth, [ka] is.

[0145] As embodiment B15, provided herein is a compound of embodiment B1, wherein X is CH. As embodiment B16, provided herein is a compound of embodiment B15, wherein n is 0 and m is 1; n is 1 and m is 0; n is 1 and m is 1; n is 1 and m is 2, or n is 2 and m is 1. As embodiment B17, provided herein is a compound of embodiment B16, wherein [ka] teeth, [ka] is.

[0146] As embodiment B18, provided herein is a compound of embodiment 366, wherein B1 is aryl (e.g., phenyl, naphthyl, or 5-(1,2,3,4-tetrahydronaphthalyl). As embodiment B19, provided herein is a compound of embodiment B18, wherein AL 2 teeth, [ka] is.

[0147] As embodiment B20, provided herein is a compound of embodiment B1, wherein AL 2 is heteroaryl (e.g., 4-indazolyl or 8-(1,2,3,4-tetrahydroquinolinyl). As embodiment B21, provided herein is a compound of embodiment B20, wherein AL 2 teeth, [ka] is.

[0148] As embodiment B22, provided herein is a compound of embodiment B1, wherein -L 1 -L 2 - is -N(R z )-C(O)-L 2 As embodiment B23, provided herein is a compound of embodiment B22, wherein R z is hydrogen. As embodiment B24, provided herein is a compound of embodiment B23, wherein L 2 is n-propylene, n-butylene, 1-fluoro-n-pentylene, n-pentylene, or -CH2-cyclopropylene-. As embodiment B25, provided herein is a compound of embodiment B22, wherein -L 1 -L 2 -teeth, [ka] is.

[0149] As embodiment B26, provided herein is a compound of embodiment B1, wherein -L 1 -L 2 - is -OC(O)-L 2 As embodiment B27, provided herein is a compound of embodiment B26, wherein L 2 is n-propylene-O-, n-butylene, n-butenylene, n-pentylene, or n-propylene. As embodiment B28, provided herein is a compound of embodiment B26, wherein -L 1 -L2 -teeth, [ka] is.

[0150] As embodiment B29, provided herein is a compound of embodiment B1, wherein -L 1 -L 2 - is -OC(O)-OL 2 As embodiment B30, provided herein is a compound of embodiment B29, wherein L 2 is n-propylene or -CH2-cyclopropylene. As embodiment B31, provided herein is a compound of embodiment B29, wherein -L 1 -L 2 -teeth, [ka] is.

[0151] As embodiment B32, provided herein is a compound of embodiment B1, wherein -L 1 -L 2 -, -OL 2 As embodiment B33, provided herein is a compound of embodiment B32, wherein L 2 is n-pentylene. As embodiment B34, provided herein is a compound of embodiment B32, wherein -L 1 -L 2 -teeth, [ka] is.

[0152] As embodiment B35, provided herein is a compound of embodiment B1, wherein -L 1 -L 2 -, -NR z -C(O)-OL 2 As embodiment B36, provided herein is a compound of embodiment B35, wherein R zAs embodiment B37, provided herein is a compound of embodiment B36, wherein L 2 is n-propylene or -CH2-cyclopropylene. As embodiment B38, provided herein is a compound of embodiment B35, wherein -L 1 -L 2 -teeth, [ka] is.

[0153] As embodiment B39, provided herein is a compound of embodiment B1, wherein -L 1 -L 2 - is -OC(O)-NR z -L 2 As embodiment B40, provided herein is a compound of embodiment B39, wherein L 2 is n-propylene or -CH2-cyclopropylene. As embodiment B41, provided herein is a compound of embodiment B39, wherein -L 1 -L 2 -teeth, [ka] is.

[0154] As embodiment B42, provided herein is a compound of embodiment B1, wherein -L 1 -L 2 - is 5-6 membered heteroaryl. As embodiment B43, provided herein is a compound of embodiment B42, wherein -L 1 -L 2 -teeth, [ka] As embodiment B44, provided herein is a compound of embodiment B42, wherein -L 1 -L 2 -teeth, [ka] is.

[0155] As embodiment B45, provided herein is a compound of embodiment B1, wherein -L 1 -L 2 As embodiment B46, provided herein is a compound of embodiment B45, wherein L 2 is n-hexylene.

[0156] As embodiment B47, provided herein is a compound of embodiment B1, wherein -L 1 -L 2 - is -C(O)-. As embodiment B48, provided herein is a compound of embodiment B47, wherein L 2 is n-butylene. As embodiment B49, provided herein is a compound of embodiment B47, wherein -L 1 -L 2 -teeth, [ka] is.

[0157] As embodiment B50, provided herein is a compound of embodiment B1, wherein R 4 is C 1~4 As embodiment B51, provided herein is a compound of embodiment B1, wherein R 4 is fluorine.

[0158] As embodiment C1, provided herein is a compound of formula (CI): [ka] (In the formula, X is N, CH2, O, S, S(O), S(O)(NR z ) or S(O)2; Z is CH, CF, C—CN, C—OMe, C—Cl or N; Q is CH or N; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3; Each R x is hydroxyl, halogen, oxo, cyano, -N(R z )2, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, 5-7 membered heteroaryl, -TR y or two R x together with the same or adjacent carbon atom, C 3~7 cycloalkyl, 3- to 7-membered heterocycloalkyl, each C 3~7 Cycloalkyl or 3- to 7-membered heterocycloalkyl is R y or two R x can be joined together to form a bridged ring, and the bridge is -C 1~4 Alkylene, -C 1~4 Alkylene-OC 1~4 Alkylene-, -O-, -S- or -C 1~4 Alkylene-SC 1~4 alkylene-, wherein each C 1~4 Alkylene is R y Further substituted with 0-2 occurrences of; L is C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylene, -OC 1~6 Alkylene, -SC 1~6 Alkylene, NR z , O or S, and each C 1~6 Alkylene, -OC 1~6 Alkylene and -SC 1~6 The alkylene chain is R 2 Replaced by 0-2 occurrences of; L 1 is a bond, -N(R z )C(O)-L 2 , -C(O)-L2 -, -OC(O)-L 2 , -C(O)OL 2 , -OC(O)-OL 2 , -OC(S)-OL 2 , -OL 2 , -N(R z )C(O)OL 2 , -OC(O)N(R z )-L 2 , -N(R z )-L 2 , -S(O)2-L 2 , -SL 2 , -S(O)-L 2 , C 1~4 Alkylene-C(O)-L 2 , C 1~4 Alkylene-C(O)OL 2 , -C 1~4 Alkylene-OC(O)OL 2 , -C 1~4 Alkylene-OC(O)-L 2 , -C 1~4 Alkylene-OL 2 , -C 1~4 Alkylene-S(O)2-L 2 , -C 1~4 Alkylene-SL 2 , -C 1~4 Alkylene-S(O)-L 2 , -O-5 to 6-membered heteroaryl-L 2 , -C 1~4 Alkylene-5-6-membered heteroaryl-L 2 , -C 1~4 Hydroxyalkylene-5-6-membered heteroaryl-L 2 or 5-6 membered heteroaryl-L 2 and; L 2 is C 1~6 Alkylene, C 1~6 Alkylene-O-, C 1~6 Alkylene-OC 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 3~7 Cycloalkylene, C 1~4 Alkylene-C 3~7Cycloalkylene, C 1~4 Haloalkylene-C 3~7 Cycloalkylene, C 3~7 Cycloalkylene-C 1~4 Alkylene, C 1~6 Hydroxyalkylene or C 1~6 haloalkylene; R 1 is absent, hydroxyl, aryl, heteroaryl, C 3~8 Cycloalkyl or R 5 is heterocycloalkyl substituted with 0-3 occurrences of; R 2 is halogen, hydroxyl, C 1~4 alkyl, or two R on the same or adjacent carbon atoms 2 Let's get together and C 3~7 can form a cycloalkyl; A is q R 6 is an aryl or heteroaryl substituted with the presence of R 4 is hydrogen, hydroxyl, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~7 is cycloalkyl or cyano; Each R 5 are independently halogen, cyano, oxo, -TR y , hydroxyl, amino or C 1~4 is alkyl; Each R 6 are independently halogen, hydroxyl, cyano, -N(R z )2, -C(O)R z , -C(O)OR z , C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 2~4 Alkynyl or C 3~6 cycloalkyl or two R 6are joined together on adjacent carbon atoms, C 3~7 Forming a cycloalkyl; T is C 1~4 Alkylene, -S(O)2-, -C(O)-, -C 1~4 Alkylene-C(O)-, C 1~4 alkylene -S(O)2- or -S-; R y is halogen, oxo, C 1~4 Alkyl, C 1~4 Haloalkyl, hydroxyl, cyano or -N(R z )2; and R z is hydrogen or C 1~4 alkyl) or a pharmaceutically acceptable salt of said compound.

[0159] As embodiment C2, provided herein is a compound according to embodiment C1, wherein Z is N and Q is CH.

[0160] As embodiment C3, provided herein is a compound according to embodiment C2, wherein L is R 2 As embodiment C4, provided herein is a compound of embodiment C3, wherein -LR- is substituted with 0 to 2 occurrences of -LR-. 1 teeth, [ka] , methoxy, or methyl. As embodiment C5, provided herein is a compound of embodiment C4, wherein -LR 1 teeth, [ka] is.

[0161] As embodiment C6, provided herein is a compound according to embodiment C1, wherein n is 1 and m is 1, or n is 1 and m is 2, or n is 2 and m is 1. As embodiment C7, provided herein is a compound according to embodiment C6, wherein [ka] teeth, [ka] As embodiment C8, provided herein is a compound according to embodiment C7, wherein: [ka] teeth, [ka] is.

[0162] As embodiment C9, provided herein is a compound according to embodiment C1, wherein X is O. As embodiment C10, provided herein is a compound according to embodiment C9, wherein [ka] teeth, [ka] is.

[0163] As embodiment C11, provided herein is a compound according to embodiment C1, wherein X is CH. As embodiment C12, provided herein is a compound according to embodiment C11, wherein n is 0 and m is 1; n is 1 and m is 0; n is 1 and m is 1; n is 1 and m is 2, or n is 2 and m is 1. As embodiment C13, provided herein is a compound according to embodiment C12, wherein [ka] teeth, [ka] is.

[0164] As embodiment C13, provided herein are compounds according to embodiment C1, wherein A is aryl. As embodiment C14, provided herein are compounds according to embodiment C13, wherein AL 2 teeth, [ka] is.

[0165] As embodiment C15, provided herein is a compound according to embodiment C1, wherein A is heteroaryl. As embodiment C16, provided herein is a compound according to embodiment C15, wherein AL 2 teeth, [ka] As embodiment C17, provided herein is a compound according to embodiment C16, wherein AL 2 teeth, [ka] is.

[0166] As embodiment C18, provided herein is a compound according to embodiment C1, wherein -L 1 -L 2 - is -OC(O)-OL 2 As embodiment C19, provided herein is a compound according to embodiment C18, wherein L 2is ethylene, n-propylene, 2-methyl-n-propylene, cis-2-propenylene, trans-2-propenylene, or -CH2-cyclopropylene. As embodiment C20, provided herein are compounds according to embodiment C19, wherein -L 1 -L 2 -teeth, [ka] As embodiment C21, provided herein is a compound according to embodiment C20, wherein -L 1 -L 2 -teeth, [ka] As embodiment C22, provided herein is a compound according to embodiment C21, wherein -L 1 -L 2 -teeth, [ka] is.

[0167] As embodiment C23, provided herein is a compound according to embodiment C1, wherein -L 1 -L 2 -, -OL 2 As embodiment C24, provided herein is a compound according to embodiment C23, wherein L 2 is n-butylene, n-pentylene, cis-2-pentenylene, or trans-2-pentenylene. As embodiment C25, provided herein are compounds according to embodiment C23, wherein -L 1 -L 2 -teeth, [ka] As embodiment C26, provided herein is a compound according to embodiment C25, wherein -L 1 -L 2 -teeth, [ka] is.

[0168] As embodiment C27, provided herein is a compound according to embodiment C1, wherein -L 1 -L 2 - is -C 1~4 Alkylene-OC(O)OL 2 As embodiment C28, provided herein is a compound according to embodiment C27, wherein L 2 As embodiment C29, provided herein is a compound according to embodiment C27, wherein -L 1 -L 2 -teeth, [ka] is.

[0169] As embodiment C30, provided herein is a compound according to embodiment C1, wherein -L 1 -L 2 - is -C 1~4 Hydroxyalkylene-5-6-membered heteroaryl-L 2 As embodiment C31, provided herein is a compound according to embodiment C30, wherein -L 1 -L 2 -teeth, [ka] As embodiment C32, provided herein is a compound according to embodiment C31, wherein L 2 As embodiment C33, provided herein is a compound according to embodiment C30, wherein -L 1 -L 2 -teeth, [ka] is.

[0170] As embodiment C34, provided herein is a compound according to embodiment C1, wherein -L 1 -L 2 - is -C 1~4 As embodiment C35, provided herein is a compound according to embodiment C34, wherein -L 1 -L 2 -, -methylene-OL 2 As embodiment C36, provided herein is a compound according to embodiment C35, wherein L 2 is n-butylene, 2,2-difluoro-n-butylene, trans-2-butenylene, cis-2-butenylene, 3-methyl-n-butylene, -ethylene-cyclopropylene-, or ethylene-O-methylene. As embodiment C37, provided herein are compounds according to embodiment C34, wherein -L 1 -L 2 -teeth, [ka] As embodiment C38, provided herein is a compound according to embodiment C37, wherein -L 1 -L 2 -teeth, [ka] is.

[0171] As embodiment C39, provided herein is a compound according to embodiment C1, wherein -L 1 -L 2 - is ethylene-OL 2 As embodiment C40, provided herein is a compound according to embodiment C39, wherein L 2 is ethylene, n-propylene, or methylenecyclopropylene. As embodiment C41, provided herein are compounds according to embodiment C39, wherein -L 1 -L 2 -teeth, [ka] As embodiment C42, provided herein is a compound according to embodiment C41, wherein -L 1 -L 2 -teeth, [ka] is.

[0172] As embodiment C43, provided herein is a compound according to embodiment C1, wherein -L 1 -L 2 -, -NR z -C(O)-OL 2 As embodiment C44, provided herein is a compound according to embodiment C43, wherein R z is hydrogen or methyl. As embodiment C45, provided herein is a compound according to embodiment C44, wherein L 2 is n-propylene, ethylene, -CH2-cyclopropylene. As embodiment C46, ​​provided herein is a compound according to embodiment C43, wherein -L 1 -L 2 -teeth, [ka] As embodiment C47, provided herein is a compound according to embodiment C46, ​​wherein -L 1 -L 2 -teeth, [ka] is.

[0173] As embodiment C48, provided herein is a compound according to embodiment C1, wherein -L 1 -L 2 - is 5-6 membered heteroaryl. As embodiment C49, provided herein are compounds according to embodiment C48, wherein -L 1 -L 2 -teeth, [ka] As embodiment C50, provided herein is a compound according to embodiment C48, wherein -L 1 -L 2 -teeth, [ka] As embodiment C51, provided herein is a compound according to embodiment C50, wherein -L 1 -L 2 -teeth, [ka] is.

[0174] As embodiment C52, provided herein is a compound according to embodiment C1, wherein -L 1 -L 2 - is -C(O)-. As embodiment C53, provided herein is a compound according to embodiment C52, wherein L 2 is n-propylene, -methylene-On-propylene, or n-butylene. As embodiment C54, provided herein are compounds according to embodiment C52, wherein -L 1 -L 2 -teeth, [ka] As embodiment C55, provided herein is a compound according to embodiment C54, wherein -L 1 -L 2 -teeth, [ka] is.

[0175] As embodiment C56, provided herein is a compound according to embodiment C1, wherein -L 1 -L 2 - is -C 1~4 Alkylene-5-6-membered heteroaryl-L 2As embodiment C57, provided herein is a compound according to embodiment C56, wherein -L 1 -L 2 -teeth, [ka] As embodiment C58, provided herein is a compound according to embodiment C56, wherein -L 1 -L 2 -teeth, [ka] As embodiment C59, provided herein is a compound according to embodiment C58, wherein -L 1 -L 2 -teeth, [ka] is.

[0176] As embodiment C60, provided herein is a compound according to embodiment C1, wherein R 4 is C 1~4 As embodiment C61, provided herein is a compound of embodiment C1, wherein R 4 is fluorine.

[0177] As embodiment C62, there is provided a compound according to embodiment C1, wherein the compound is selected from the compounds of Table 5.

[0178] [Table 11]

[0179] [Table 12]

[0180] [Table 13]

[0181] [Table 14]

[0182] As embodiment C63, there is provided a compound according to embodiment C1, wherein the compound is selected from the compounds of Table 6.

[0183] [Table 15]

[0184] [Table 16]

[0185] The foregoing description merely summarizes certain aspects of the disclosure and is not intended, nor should it be construed, to limit the disclosure in any way.

[0186] Formulation and Route of Administration In the described use, although the compound disclosed herein can be administered alone, the compound administered will usually be present as an active ingredient in a pharmaceutical composition.Therefore, in one embodiment, the present invention provides a pharmaceutical composition comprising the compound disclosed herein in combination with one or more pharmaceutically acceptable excipients such as diluents, carriers, adjuvants, and optionally other active ingredients. See, for example, Remington: The Science and Practice of Pharmacy, Volume I and Volume II, twenty-second edition, Philadelphia, PA, Pharmaceutical Press, 2012; Pharmaceutical Dosage Forms (Vol. 1-3), Liberman et al., Eds., Marcel Dekker, New York, NY, 1992; Handbook of Pharmaceutical Excipients (3rd Ed.), edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, 2000; Pharmaceutical Formulation: The Science and Technology of Dosage Forms (Drug Discovery), first edition, edited by G. D. Tovey, Royal Society of Chemistry, 2018. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein.

[0187] The compounds disclosed herein can be administered by any suitable route of administration in the form of a pharmaceutical composition adapted to such route and in a dose effective for the intended treatment. The compounds and compositions provided herein can be administered, for example, orally, mucosally, topically, transdermally, rectally, pulmonary, parenterally, intranasally, intravascularly, intravenously, intraarterially, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, intravaginally, or by infusion techniques in dosage unit formulations containing conventional pharmaceutically acceptable excipients.

[0188] The pharmaceutical composition may be in the form of, for example, a tablet, chewable tablet, mini-tablet, caplet, pill, bead, hard capsule, soft capsule, gelatin capsule, granule, powder, lozenge, patch, cream, gel, sachet, microneedle array, syrup, flavored syrup, juice, drop, injectable solution, emulsion, microemulsion, ointment, aerosol, aqueous suspension or oily suspension. Pharmaceutical compositions are usually made in the form of a dosage unit containing a particular amount of the active ingredient.

[0189] As embodiment 425, provided herein is a pharmaceutical composition comprising a compound or salt according to any one of embodiments 1 to 424, B1 to B51, or C1 to C63, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable excipient.

[0190] As embodiment 426, provided herein is a compound according to any one of embodiments 1 to 424, B1 to B51, or C1 to C63, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 423, for use as a pharmaceutical.

[0191] How to use As described herein (see the section entitled "Definitions"), the compounds described herein are understood to include all stereoisomers, tautomers, or pharmaceutically acceptable salts of any of the above, or solvates of any of the above. Accordingly, the scope of methods and uses provided in this disclosure should be understood to encompass methods and uses employing all such forms.

[0192] 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 can be treated with the compounds provided herein.

[0193] 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) implicated by a KRAS G12D, G12V, G12A, G12S, G13D, Q61H, Q61L, or G12C mutation, where the cancer type is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendix cancer, endometrial cancer, esophageal cancer, cancer of unknown primary site, ampullary cancer, gastric cancer, small intestine cancer, sinus cancer, cholangiocarcinoma, or melanoma.

[0194] The KRAS G12D mutation occurs at the alteration frequency shown in the table below (TCGA dataset). For example, the table shows that 32.4% of subjects with pancreatic cancer have cancer in which one or more cells express the KRAS G12D mutant protein. Therefore, KRAS G12D Compounds provided herein that bind to (see the section below entitled "Biological Evaluation") are useful for treating subjects with cancers, including, but not limited to, those listed in the table below.

[0195] [Table 17]

[0196] As embodiment 427, provided herein is a compound according to any one of embodiments 1 to 424, B1 to B51, or C1 to C63, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 425, for use in treating cancer.

[0197] As embodiment 428, provided herein is a compound according to any one of embodiments 1 to 424, B1 to B51, or C1 to C63, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 425, for use in treating a cancer in which one or more cells express a KRAS G12D mutant protein.

[0198] As embodiment 429, provided herein is a compound according to any one of embodiments 1 to 424, B1 to B51, or C1 to C63, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 425, for use in treating a cancer in which one or more cells express a KRAS G12V mutant protein.

[0199] As embodiment 430, provided herein is a compound according to any one of embodiments 1 to 424, B1 to B51, or C1 to C63, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 425, for use in treating a cancer in which one or more cells express a KRAS G12A mutant protein.

[0200] As embodiment 431, provided herein is a compound according to any one of embodiments 1 to 424, B1 to B51, or C1 to C63, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 425, for use in treating a cancer in which one or more cells express a KRAS G12S mutant protein.

[0201] As embodiment 432, provided herein is a compound according to any one of embodiments 1 to 424, B1 to B51, or C1 to C63, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 425, for use in treating a cancer in which one or more cells express a KRAS G13D mutant protein.

[0202] As embodiment 433, provided herein is a compound according to any one of embodiments 1 to 424, B1 to B51, or C1 to C63, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 425, for use in treating a cancer in which one or more cells express KRAS Q61H mutant protein.

[0203] As embodiment 434, provided herein is a compound according to any one of embodiments 1 to 424, B1 to B51, or C1 to C63, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 425, for use in treating a cancer in which one or more cells express KRAS Q61L mutant protein.

[0204] As embodiment 435, provided herein is a compound according to any one of embodiments 1 to 424, B1 to B51, or C1 to C63, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 425, for use in treating a cancer in which one or more cells express a KRAS G12C mutant protein.

[0205] As embodiment 436, there is provided herein a compound or pharmaceutical composition for use in any one of embodiments 427 to 435, 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 neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

[0206] As embodiment 437, provided herein is the use of a compound according to any one of embodiments 1 to 424, B1 to B51, or C1 to C63, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 425, in the preparation of a medicament for treating cancer.

[0207] As embodiment 438, provided herein is the use of a compound according to any one of embodiments 1 to 424, B1 to B51, or C1 to C63, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 425, in the preparation of a medicament for treating a cancer in which one or more cells express a KRAS G12D mutant protein.

[0208] As embodiment 439, provided herein is the use of a compound according to any one of embodiments 1 to 424, B1 to B51, or C1 to C63, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 425, in the preparation of a medicament for treating a cancer in which one or more cells express a KRAS G12V mutant protein.

[0209] As embodiment 440, provided herein is the use of a compound according to any one of embodiments 1 to 424, B1 to B51, or C1 to C63, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 425, in the preparation of a medicament for treating a cancer in which one or more cells express a KRAS G12A mutant protein.

[0210] As embodiment 441, provided herein is the use of a compound according to any one of embodiments 1 to 424, B1 to B51, or C1 to C63, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 425, in the preparation of a medicament for treating a cancer in which one or more cells express a KRAS G12S mutant protein.

[0211] As embodiment 442, provided herein is the use of a compound according to any one of embodiments 1 to 424, B1 to B51, or C1 to C63, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 425, in the preparation of a medicament for treating a cancer in which one or more cells express a KRAS G13D mutant protein.

[0212] As embodiment 443, provided herein is the use of a compound according to any one of embodiments 1 to 424, B1 to B51, or C1 to C63, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 425, in the preparation of a medicament for treating a cancer in which one or more cells express a KRAS Q61H mutant protein.

[0213] As embodiment 444, provided herein is the use of a compound according to any one of embodiments 1 to 424, B1 to B51, or C1 to C63, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 425, in the preparation of a medicament for treating a cancer in which one or more cells express KRAS Q61L mutant protein.

[0214] As embodiment 445, provided herein is the use of a compound according to any one of embodiments 1 to 424, B1 to B51, or C1 to C63, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 425, in the preparation of a medicament for treating a cancer in which one or more cells express a KRAS G12C mutant protein.

[0215] As embodiment 446, the present specification provides a use according to any one of embodiments 437 to 445, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine carcinoma, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

[0216] Provided herein, as embodiment 447, is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1-424, B1-B51, or C1-C63, or a pharmaceutically acceptable salt thereof.

[0217] Provided herein as embodiment 448 is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1-424, B1-B51, or C1-C63, or a pharmaceutically acceptable salt thereof, wherein one or more cells express KRAS G12D mutant protein.

[0218] Provided herein as embodiment 449 is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1-424, B1-B51, or C1-C63, or a pharmaceutically acceptable salt thereof, wherein one or more cells express a KRAS G12V mutant protein.

[0219] Provided herein as embodiment 450 is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1-424, B1-B51, or C1-C63, or a pharmaceutically acceptable salt thereof, wherein one or more cells express KRAS G12A mutant protein.

[0220] Provided herein as embodiment 451 is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1-424, B1-B51, or C1-C63, or a pharmaceutically acceptable salt thereof, wherein one or more cells express a KRAS G12S mutant protein.

[0221] Provided herein as embodiment 452 is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1-424, B1-B51, or C1-C63, or a pharmaceutically acceptable salt thereof, wherein one or more cells express KRAS G13D mutant protein.

[0222] Provided herein as embodiment 453 is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1-424, B1-B51, or C1-C63, or a pharmaceutically acceptable salt thereof, wherein one or more cells express KRAS Q61H mutant protein.

[0223] Provided herein as embodiment 454 is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1-424, B1-B51, or C1-C63, or a pharmaceutically acceptable salt thereof, wherein one or more cells express KRAS Q61L mutant protein.

[0224] Provided herein as embodiment 455 is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1-424, B1-B51, or C1-C63, or a pharmaceutically acceptable salt thereof, wherein one or more cells express a KRAS G12C mutant protein.

[0225] As embodiment 456, the present specification provides a method according to any one of embodiments 447 to 455, 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 neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

[0226] As embodiment 457, the present specification provides a method according to any one of embodiments 457 to 455, 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.

[0227] As embodiment 458, provided herein is a method according to embodiment 457, wherein the cancer is non-small cell lung cancer.

[0228] As embodiment 459, provided herein is a method according to embodiment 457, wherein the cancer is colorectal cancer.

[0229] As embodiment 460, provided herein is the method according to embodiment 457, wherein the lung cancer is pancreatic cancer.

[0230] Combination therapy The present disclosure also provides methods for combination therapy in which overlapping sets of agents known to regulate other pathways or other components of the same pathway, or even target enzymes, are used in combination with the compounds of the present disclosure or pharmaceutically acceptable salts thereof. In one embodiment, such therapy includes, but is not limited to, the combination of one or more compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation therapy to produce synergistic or additive therapeutic effects. See, for example, U.S. Patent No. 10,519,146 B2, issued December 31, 2019, specifically sections 201 (line 37) to 212 (line 46) and sections 219 (line 64) to 220 (line 39), which are incorporated herein by reference.

[0231] As embodiment 461, provided herein is a method according to any one of embodiments 447 to 460, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an Aurora kinase A inhibitor, an AKT inhibitor, an arginase inhibitor, a CDK4 / 6 inhibitor, an ErbB family inhibitor, an ERK inhibitor, a FAK inhibitor, an FGFR inhibitor, a glutaminase inhibitor, an IGF-1R inhibitor, a KIF18A inhibitor, an MCL-1 inhibitor, a MEK inhibitor, an mTOR inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a PI3K inhibitor, a Raf kinase inhibitor, a SHP2 inhibitor, an SOS1 inhibitor, a Src kinase inhibitor, or one or more chemotherapeutic agents.

[0232] In one embodiment, the second compound is administered as a pharmaceutically acceptable salt, hi another embodiment, the second compound is administered as a pharmaceutical composition comprising the second compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0233] Aurora kinase A inhibitors Provided herein are methods according to any one of embodiments 447-460, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an Aurora kinase A inhibitor.

[0234] 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)-2-[(E)-2-phenylethenyl]pyrimidin-4-amine), TAK-901 (5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide), TT-00420 (4-[9-(2-chlorophenyl)-6-methyl-2,4,5,8,12-pentazatricyclo[8.4.0.03,7]tetradeca-1(14),3,6,8,10,12-hexaen-13-yl ]morpholine), AMG900 (N-[4-[3-(2-aminopyrimidin-4-yl)pyridin-2-yl]oxyphenyl]-4-(4-methylthiophen-2-yl)phthalazin-1-amine), MLN8054 (4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid), PF-03814735 (N-[2-[(1R,8S)-4-[[4-(cyclobutylamino)-5-(trifluoromethyl)pyrimidine-

[0023] Examples of compounds that may be used include, but are not limited to, 1-(3-chlorophenyl)-3-[5-[2-(thieno[3,2-d]pyrimidin-4-ylamino)ethyl]-1,3-thiazol-2-amine), TAS-119, BI 811283, and TTP607.

[0235] AKT inhibitors Provided herein are methods according to any one of embodiments 447-460, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an AKT inhibitor.

[0236] Exemplary AKT inhibitors for use in the methods provided herein include afarestib, capivasertib, ipatasertib, uprosertib, BAY1125976 (2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide), ARQ 092 (3-[3-[4-(1-aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2-amine), MK2206 (8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one), SR13668 (indolo[2,3-b]carbazole-2,10-dicarboxylic acid, 5,7-dihydro-6-methoxy-, 2,10-diethyl ester) ter), ONC201 (11 benzyl-7-[2-methylphenyl)methyl]-2,5,7,11 tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one), ARQ751 (N-(3-aminopropyl)-N-[(1R)-1-(3-anilino-7-chloro-4-oxoquinazolin-2-yl)but-3-ynyl]-3-chloro-2-fluorobenzamide), RX-0201, and LY2780301.

[0237] Arginase inhibitors Provided herein are methods according to any one of embodiments 447-460, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an arginase inhibitor.

[0238] Exemplary arginase inhibitors for use in the methods provided herein include, but are not limited to, numidardistat and CB280.

[0239] CDK4 / 6 inhibitors Provided herein are methods according to any one of embodiments 447-460, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a CDK4 / 6 inhibitor.

[0240] 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.

[0241] 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.

[0242] 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]).

[0243] In one embodiment, the CDK4 / 6 inhibitor is palbociclib.

[0244] ErbB family inhibitors Provided herein is a method according to any one of embodiments 447-460, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an ErbB family inhibitor.

[0245] 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).

[0246] As used herein, the term "ErbB family inhibitor" refers to an agent, e.g., a compound or antibody, capable of negatively modulating or inhibiting all or part of the activity of at least one member of the ErbB family. Modulation or inhibition of one or more ErbB tyrosine kinases can occur through modulation or inhibition of the kinase enzymatic activity of one or more ErbB family members or by blocking homodimerization or heterodimerization of ErbB family members.

[0247] In one embodiment, the ErbB family inhibitor is an EGFR inhibitor, for example, an anti-EGFR antibody. Exemplary anti-EGFR antibodies for use in the methods provided herein include, but are not limited to, zalutumumab, nimotuzumab, matuzumab, necitumumab, panitumumab, and cetuximab. In one embodiment, the anti-EGFR antibody is cetuximab. In one embodiment, the anti-EGFR antibody is panitumumab.

[0248] In another embodiment, the ErbB family inhibitor is a HER2 inhibitor, e.g., an anti-HER2 antibody. Exemplary anti-HER2 antibodies for use in the methods provided herein include, but are not limited to, pertuzumab, trastuzumab, and trastuzumab emtansine.

[0249] In yet another embodiment, the ErbB family inhibitor is a HER3 inhibitor, for example, an anti-HER3 antibody, for example, HMBD-001 (Hummingbird Bioscience).

[0250] In one embodiment, the ErbB family inhibitor is a combination of an anti-EGFR antibody and an anti-HER2 antibody.

[0251] In one embodiment, the ErbB family inhibitor is an irreversible inhibitor. Exemplary irreversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to, afatinib, dacomitinib, canertinib, poziotinib, AV412 ((N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butyn-1-yl]-6-quinazolinyl]-2-propenamide), PF6274484 (N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-2-propenamide), and HKI357 ((E)-N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide).

[0252] In one embodiment, the irreversible ErbB family inhibitor is afatinib. In one embodiment, the irreversible ErbB family inhibitor is dacomitinib.

[0253] In one embodiment, the ErbB family inhibitor is a reversible inhibitor. Exemplary reversible ErbB family inhibitors for use in the methods provided herein include erlotinib, gefitinib, sapitinib, valitinib, taloxotinib, TAK-285 (N-(2-(4-((3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl)-3-hydroxy-3-methylbutanamide), AEE788 ((S)-6-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-N-(1-phenylethyl)-7H-pyrrolo[ 2,3-d]pyrimidin-4-amine), BMS599626 ((3S)-3-morpholinylmethyl-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamate) and GW583340 (N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[2-[(2-methylsulfonylethylamino)methyl]-1,3-thiazol-4-yl]quinazolin-4-amine).

[0254] In one embodiment, the reversible ErbB family inhibitor is sapitinib. In one embodiment, the reversible ErbB family inhibitor is tarloxotinib.

[0255] ERK inhibitors Provided herein are methods according to any one of embodiments 447-460, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an ERK inhibitor.

[0256] 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-methylpyrimidin-4-yl) ...

[0037] These include, but are not limited to, [1,5,6,8-tetrahydro-6-(phenylmethyl)-3-(4-pyridinyl)-7H-pyrazolo[4,3-g]quinazolin-7-one], ASTX029, LTT462, and JSI-1187.

[0257] FAK inhibitors Provided herein are methods according to any one of embodiments 447-460, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a FAK inhibitor.

[0258] 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.

[0259] FGFR inhibitors Provided herein are methods according to any one of embodiments 447-460, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an FGFR inhibitor.

[0260] Exemplary FGFR inhibitors for use in the methods provided herein include futibatinib, pemigatinib, ASP5878 (2-[4-[[5-[(2,6-difluoro-3,5-dimethoxyphenyl)methoxy]pyrimidin-2-yl]amino]pyrazol-1-yl]ethanol), AZD4547 (N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]benzamide), Debio 1347 ([5-amino]pyrazol-3-yl), AZD4547 (N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]benzamide), and AZD4547 (N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]benzamide).

[0037] These include, but are not limited to, 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.

[0261] glutaminase inhibitors Provided herein are methods according to any one of embodiments 447-460, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a glutaminase inhibitor.

[0262] Exemplary glutaminase inhibitors for use in the methods provided herein include, but are not limited to, telaglenastat, IPN60090, and OP330.

[0263] IGF-1R inhibitors Provided herein are methods according to any one of embodiments 447-460, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an IGF-1R inhibitor.

[0264] Exemplary IGF-1R inhibitors for use in the methods provided herein include cixutumumab, dalotuzumab, linsitinib, ganitumab, lobatumumab, BMS-754807 ((2S)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]-N-(6-fluoropyridin-3-yl)amino). Examples of such compounds include, but are not limited to, N-[5-[[4-(2-hydroxyacetyl)piperazin-1-yl]methyl]-2-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-3-methylthiophene-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.

[0265] KIF18A inhibitors Provided herein is a method according to any one of embodiments 447-460, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a KIF18A inhibitor.

[0266] 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.

[0267] MLC-1 inhibitors Provided herein are methods according to any one of embodiments 447-460, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an MLC-1 inhibitor.

[0268] Exemplary MEK inhibitors for use in the methods provided herein include murizatoclax, topotoclax, AZD5991 ((3aR)-5-chloro-2,11,12,24,27,29-hexahydro-2,3,24,33-tetramethyl-22H-9,4,8-(metheniminomethino)-14,20:26,23-dimetheno-10H,20H-pyrazolo[4,3-l][2,15,22,18,19]benzoxadithiadiaza), cyclohexacosine-32-carboxylic acid), MIK665 ((αR)-α-[[(5S)-5-[3-chloro-2-methyl-4-[2-(4-methyl-1-piperazinyl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy]-2-[[2-(2-methoxyphenyl)-4-pyrimidinyl]methoxy]benzenepropanoic acid), and ABBV-467.

[0269] In one embodiment, the MCL-1 inhibitor is murizatoclax. In another embodiment, the MCL-1 inhibitor is tapotoclax.

[0270] MEK inhibitors Provided herein are methods according to any one of embodiments 447-460, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a MEK inhibitor.

[0271] Exemplary MEK inhibitors for use in the methods provided herein include trametinib, cobimetinib, selumetinib, pimasertib, refametinib, PD-325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), AZD8330 (2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxopyridine-3 -carboxamide), GDC-0623 (5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide), RO4987655 (3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-5-[(3-oxooxazinan-2-yl)methyl]benzamide), TAK-733 (3-[(2R)-2,3-dihydroxypropyl]-6-fluoro-5 -(2-Fluoro-4-iodoanilino)-8-methylpyrido[2,3-d]pyrimidine-4,7-dione), PD0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), CI-1040 (2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide), PD318088 (5-bromo-N-(2,3-dihydroxypropoxy)-3,4-difluorobenzamide),

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

[0272] In one embodiment, the MEK inhibitor is trametinib.

[0273] mTOR inhibitors Provided herein is a method according to any one of embodiments 447-460, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an mTOR inhibitor.

[0274] 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, Torin-1(1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)cyclohexyl)-9-(quinolin-3-yl)benzo[h][1, 6]naphthyridin-2(1H)-one), GDC-0349 ((S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-7-(oxetan-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea), and VS-5584 (SB2343, (5-(8-methyl-2-morpholin-4-yl-9-propan-2-ylpurin-6-yl)pyrimidin-2-amine).

[0275] In one embodiment, the mTOR inhibitor is everolimus.

[0276] PD-1 inhibitors Provided herein are methods according to any one of embodiments 447-460, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a PD-1 inhibitor.

[0277] Exemplary PD-1 inhibitors for use in the methods provided herein include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS001), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, and the anti-PD-1 antibodies described in U.S. Pat. No. 10,640,504 B2 ("Anti-PD-1 Antibody A," column 66, line 56 to column 67, line 24 and column 67, lines 54-57), which are incorporated herein by reference.

[0278] In one embodiment, the PD-1 inhibitor is pembrolizumab. In another embodiment, the PD-1 inhibitor is anti-PD-1 antibody A.

[0279] PD-L1 inhibitors Provided herein are methods according to any one of embodiments 447-460, 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.

[0280] 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.

[0281] In one embodiment, the PD-L1 inhibitor is atezolizumab.

[0282] PI3K inhibitors Provided herein are methods according to any one of embodiments 447-460, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a PI3K inhibitor.

[0283] Exemplary PI3K inhibitors for use in the methods provided herein include idelalisib, copanlisib, duvelisib, alpelisib, taselisib, perifosine, buparlisib, umbralisib, pictilisib, dactolisib, voxtalisib, sonolisib), 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-methylpyrazol-4-yl)ethynyl]-1-oxo-2-phenylisoquinoline-3- yl]ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide), SF1126 ((2S)-2-[[(2S)-3-carboxy-2-[[2-[[(2S)-5-(diaminomethylideneamino)-2-[[4-oxo-4-[[4-(4-oxo-8-phenylchromen-2-yl)morpholin-4-ium-4-yl]methoxy]butanoyl]amino]pentanoyl]amino]acetyl]amino]propanoyl]amino]-3-hydroxypropanoate), XL1 These include, but are not limited to, 47 (N-[3-(2,1,3-benzothiadiazol-5-ylamino)quinoxalin-2-yl]-4-methylbenzenesulfonamide), GSK1059615 ((5Z)-5-[(4-pyridin-4-ylquinolin-6-yl)methylidene]-1,3-thiazolidine-2,4-dione), and AMG319 (N-[(1S)-1-(7-fluoro-2-pyridin-2-ylquinolin-3-yl)ethyl]-7H-purin-6-amine).

[0284] Raf kinase inhibitors Provided herein is a method according to any one of embodiments 447-460, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a Raf kinase inhibitor.

[0285] As used herein, the term "RAF kinase" refers to a member of the mammalian serine / threonine kinase family consisting of three isoforms (C-Raf, B-Raf, and A-Raf), including homodimers of each isoform and heterodimers between isoforms, such as C-Raf / B-Raf heterodimers.

[0286] 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 disrupting Raf homodimer or heterodimer formation, thereby inhibiting activity.

[0287] 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-2 H-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]pyrimidin-6-yl)-2-isonicotinamide), (phenyl)phenyl)urea), Tak-632 (N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide), CEP-32496 (1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea), CCT196969 (1-(3-(tert-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).

[0288] 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.

[0289] SHP2 inhibitors Provided herein are methods according to any one of embodiments 447-460, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an SHP2 inhibitor.

[0290] 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 vosiprotafib (RMC-4630—Revolution Medicine). In one embodiment, the SHP inhibitor for use in the methods provided herein is voshiprotafib (Revolution Medicine).

[0291] 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-hydroxyphenyl)-

[0037] 6-[(2-amino-3-chloro-4-pyridinyl)thio]-5-methyl-2-pyrazinemethanol (CAS 2172652-38-7) and 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-methyl-2-pyrazinemethanol (CAS 2172652-48-9).

[0292] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include 1-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-4-methyl-4-piperidinamine (CAS 2240981-75-1), (1R)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine (C AS2240981-78-4), (3S,4S)-8-[7-(2,3-dichlorophenyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS2240982-45-8), (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]pyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4 .5]decan-4-amine (CAS 2240982-57-2), 4-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-7-(2,3-dichlorophenyl)-6-methyl-pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-69-6), 7-[(2-amino-3-chloro-4-pyridinyl)thio]-4-[(3S,4S)-4-amino-3-methyl-2-oxa-8-yl]-7-(2,3-dichlorophenyl)-6-methyl-pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-69-6). -azaspiro[4.5]dec-8-yl]-6-methyl-pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-73-2) and (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-77-6).

[0293] In one embodiment, the SHP inhibitor for use in the methods provided herein is (1R)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine (CAS 2240981-78-4).

[0294] 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 22 38840-56-5), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-(2,3-dichlorophenyl)-3-pyridinol (CAS 2238840-58-7), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-60-1), (1R)-8-[6-(2,3-dichlorophenyl)-5-methyl-3-pyridinyl]- 8-Azaspiro[4.5]decane-1-amine (CAS 2238840-62-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2-pyridinemethanol (CAS 2238840-63-4), (1R)-8-[6-[(2,3-dichlorophenyl)thio]-5-methyl-3-pyridinyl]-8-azaspiro[4.5]decane-1-amine (CAS 2238840-64-5), 5-( 4-Amino-4-methyl-1-piperidinyl)-2-[(2,3-dichlorophenyl)thio]-3-pyridinol (CAS 2238840-65-6), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-[[(2,3-dichlorophenyl)thio]-3-pyridinol (CAS 2238840-66-7), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-3S, 4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-hydroxy-2-pyridinemethanol (CAS 2238840-67-8), 3-(4-amino-4-methyl-1-piperidinyl)-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-68-9), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-69-0), 6-[(2-azaspiro[4.5]dec-8-yl]-5-hydroxy-2-pyridinemethanol (CAS 2238840-69-0), 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 22388 40-74-7), 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.

[0295] In one embodiment, the SHP inhibitor for use in the methods provided herein is 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56-5).

[0296] In one embodiment, the SHP2 inhibitor for use in the methods provided herein is an inhibitor disclosed in U.S. Pat. No. 10,590,090 B2, U.S. Patent Application Publication No. 2020 / 017517 A1, U.S. Patent Application Publication No. 2020 / 017511 A1, or WO 2019 / 075265 A1, each of which is incorporated by reference in its entirety.

[0297] SOS1 inhibitors Provided herein is a method according to any one of embodiments 447-460, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an SOS1 inhibitor.

[0298] Exemplary SOS1 inhibitors for use in the methods provided herein include, but are not limited to, BI3406 (N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-7-methoxy-2-methyl-6-[(3S)-oxolan-3-yl]oxyquinazolin-4-amine) and BI1701963.

[0299] Src kinase inhibitors Provided herein is a method according to any one of embodiments 447-460, 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.

[0300] As used herein, the term "Src kinase" refers to members of the mammalian non-receptor tyrosine kinase family, including: Src, Yes, Fyn, and Fgr (SrcA subfamily); Lck, Hck, Blk, and Lyn (SrcB subfamily) and the Frk subfamily.

[0301] 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 kinase family.

[0302] 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).

[0303] 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.

[0304] chemotherapy drugs Provided herein are methods according to any one of embodiments 447-460, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is one or more chemotherapeutic agents.

[0305] 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.

[0306] definition The following definitions are provided to aid in understanding the scope of the present disclosure.

[0307] 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 specification and appended claims are approximations that may vary depending on the standard deviation found in their respective testing measurements.

[0308] 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. When the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

[0309] 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 thus may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers (E / Z)), enantiomers, diastereomers, and atropisomers. Accordingly, it should be understood that the scope of the present disclosure encompasses 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.

[0310]

[0013] When the stereochemistry of a structure or portion of a structure is not indicated, for example, with bold or dashed lines, the structure or portion of a structure is to be interpreted as encompassing all stereoisomers thereof. When the stereochemistry of a structure or portion of a structure is not indicated, for example, with bold or dashed lines, the structure or portion of a structure is to be interpreted as encompassing only the specified stereoisomer. A bond drawn with a wavy line indicates that both stereoisomers are encompassed. This wavy line should not be confused with a wavy line drawn perpendicular to a bond, which indicates where a group is attached to the rest of the molecule.

[0311] As used herein, the term "stereoisomer" or "stereoisomerically pure" compound refers to one stereoisomer (e.g., geometric isomer, enantiomer, diastereomer, and atropisomer) of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the mirror-image enantiomer of that compound, and a stereoisomerically pure compound having two chiral centers will be substantially free of other enantiomers or diastereomers of that compound. A typical stereoisomerically pure compound contains greater than about 80% by weight of one stereoisomer of the compound and about 20% by weight or less of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and about 10% by weight or less of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and about 5% by weight or less of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and about 3% by weight or less of other stereoisomers of the compound.

[0312] The present disclosure also encompasses pharmaceutical compositions containing stereoisomerically pure forms and the use of stereoisomerically pure forms of any compound disclosed herein. Additionally, the present disclosure also encompasses pharmaceutical compositions containing mixtures of stereoisomers of any compound disclosed herein and the use of such 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 containing mixtures of any of the compounds disclosed herein and one or more other active agents disclosed herein. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725; Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (Eliel, Ed., University of Notre Dame Press, Notre Dame, IN, 1972).

[0313] tautomers As known to those skilled in the art, certain compounds disclosed herein can exist in one or more tautomeric forms.Because one chemical structure can only be used to represent one tautomeric form, for convenience, reference to a compound of a given structural formula should be understood to include other tautomeric forms of said structural formula.Therefore, the scope of the present disclosure should be understood to encompass all tautomeric forms of the compounds disclosed herein.

[0314] isotope labeled compounds Additionally, the scope of the present disclosure includes all pharmaceutically acceptable isotopically labeled compounds of the compounds disclosed herein, such as compounds of Formula I, in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds disclosed herein include: 2 H and 3 Hydrogen such as H 11 C. 13 C and 14 Carbon, such as C 36 chlorine such as Cl, 18 Fluorine such as F, 123 I and 125 Iodine, such as I 13 N and 15 Nitrogen such as N 15 O. 17 O and 18 Oxygen, such as O 32 Phosphorus such as P and 35 Certain isotopically labeled compounds of Formula I, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 ( 14 Deuterium (C) is particularly useful for this purpose given its ease of incorporation and facile means of detection. 2 Substitution with isotopes such as H or D may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be advantageous in some cases. 11 C. 18 F, 15 O and 13 Substitution with positron-emitting isotopes, such as N, can be useful, for example, in positron emission tomography (PET) studies to 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, in which suitable isotopically labeled reagents are substituted for conventionally used non-labeled reagents.

[0315] solvate As mentioned above, the compounds disclosed herein and the stereoisomers, tautomers, and isotopically labeled forms thereof, or pharmaceutically acceptable salts of any of the foregoing, can exist in solvated or unsolvated forms.

[0316] As used herein, the term "solvate" refers to a molecular complex comprising a compound described herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable solvent molecules, in a stoichiometric or non-stoichiometric amount. When the solvent is water, the solvate is referred to as a "hydrate."

[0317] Accordingly, the scope of the present disclosure should be understood to encompass all solvates of the compounds disclosed herein and their stereoisomers, tautomers, and isotopically labeled forms or pharmaceutically acceptable salts of any of the foregoing.

[0318] Various definitions This section defines additional terms used to describe the scope of the compounds, compositions and uses disclosed herein.

[0319] The term "aryl" refers to an aromatic hydrocarbon group having 6 to 20 carbon atoms in the ring portion. Typically, aryl is a monocyclic, bicyclic, or tricyclic aryl having 6 to 20 carbon atoms. Furthermore, the term "aryl," as used herein, refers to an aromatic substituent that may be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl, each of which may be optionally substituted with 1 to 4 substituents such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(O)-O-, aryl-O-, heteroaryl-O-, amino, thiol, alkyl-S-, aryl-S-, nitro, cyano, carboxy, alkyl-OC(O)-, carbamoyl, alkyl-S(O)-, sulfonyl, sulfonamido, phenyl, and heterocycloalkyl.

[0320] The term "alkyl" refers to a saturated straight-chain or branched-chain hydrocarbon containing the specified number of carbon atoms. For example, C alkyl refers to an alkyl group having 3 carbon atoms (e.g., n-propyl or isopropyl). For example, C 1~6 Alkyl refers to an alkyl group having 1 to 6 carbon atoms. When a range is given, all members of that range and all subgroups within that range are contemplated. For example, C 1~6 Alkyl includes alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms (or any combination of the foregoing) and all subgroups in the specified range (e.g., 1-2, 1-3, 1-4, 1-5, 1-6, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, or 5-6 carbon atoms or any combination of the foregoing ranges). 1~4 "Alkyl" includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, and n-hexyl.

[0321] The term alkylene (e.g., "C 1~4 Alkylene" and "C 1~6 "Alkylene" refers to a straight-chain or branched divalent alkyl group, as defined herein, containing the specified number of carbon atoms (e.g., 1 to 4 or 1 to 6 carbon atoms). 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.

[0322] The term "alkenyl" refers to a straight or branched chain hydrocarbon containing the specified number of carbon atoms and having one or more carbon-carbon double bonds. For example, C3 alkenyl means that the alkenyl group has three carbon atoms (e.g., 1-propenyl or 2-propenyl). For example, C 2~6 Alkenyl refers to an alkenyl group having 2 to 6 carbon atoms. When a range is given, all members of that range and all subgroups within that range are contemplated. For example, C 2~6 Alkenyl includes alkenyl groups having 2, 3, 4, 5, or 6 carbon atoms (or any combination of the foregoing) and all subgroups in the specified range (e.g., 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, or 5-6 carbon atoms or any combination of the foregoing ranges). 2~4 Alkenyl includes, for example, ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or 3-butenyl. Non-limiting examples of alkenyl groups include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl.

[0323] The term "alkynyl" refers to a straight or branched chain hydrocarbon containing the specified number of carbon atoms and having one or more carbon-carbon triple bonds. For example, C3 alkynyl means that the alkynyl group has 3 carbon atoms. For example, C 2~6 Alkynyl refers to an alkynyl group having 2 to 6 carbon atoms. When a range is given, all members of that range and all subgroups within that range are contemplated. For example, C 2~6Alkynyl includes alkynyl groups having 2, 3, 4, 5, or 6 carbon atoms (or any combination of the foregoing) and all subgroups in the specified range (e.g., 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, or 5-6 carbon atoms or any combination of the foregoing ranges). 2~4 Alkynyl includes, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, or 3-butynyl. Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl.

[0324] The terms "alkoxy" and "alkoxyl" are interchangeable and refer to an -O-alkyl group, where the alkyl group is as defined elsewhere herein. For example, a C alkoxy group means that the alkoxy group has 3 carbon atoms (e.g., OCH CH CH). When a range is given, all members of that range and all subgroups within that range are contemplated. For example, C 1~6 Alkoxy includes alkoxy groups having 2, 3, 4, 5, or 6 carbon atoms, or any combination of the foregoing, and all subgroups in the specified range (e.g., 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, and 5-6 carbon atoms, or any combination of the foregoing ranges). Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, 1-methylethyloxy (iso-propoxy), n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0325] The term "cycloalkyl" refers to a saturated carbocyclic molecule containing the specified number of carbon atoms. 3~8 cycloalkyl" or "C 3~7"Cycloalkyl" refers to a saturated carbocyclic molecule whose ring structure has 3 to 8 carbons or 3 to 7 carbons. 3~8 Representative examples of cycloalkyl include, but are not limited to, cyclopropyl and cyclobutyl.

[0326] Cycloalkylene (e.g., "C 3~7 The term "cycloalkylene") refers to a saturated carbocyclic divalent group, as defined herein, containing the specified number of carbon atoms (e.g., 3 to 7 carbon atoms). Representative examples of cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and the like.

[0327] The term "cyano" refers to the group --CN.

[0328] When used herein as a prefix for another term for a chemical group, the term "deutero" refers to a group in which one or more hydrogen atoms are replaced with deuterium ("D" or " 2 For example, the term "C 1~4 "Deuteroalkyl" refers to a C, as defined herein, in which one or more hydrogen atoms are replaced by D. 1~4 Refers to alkyl. C 1~4 Representative examples of deuteroalkyl include, but are not limited to, -CH2D, -CHD2, -CD3, -CH2CD3, -CDHCD3, -CD2CD3, -CH(CD3)2, -CD(CHD2)2, and -CH(CH2D)(CD3).

[0329] As used herein, the term "halogen" refers to -F, -CI, -Br or -I.

[0330] The term "halo," when used herein as a prefix of another term for a chemical group, refers to a modification of the chemical group in which one or more hydrogen atoms have been replaced with a halogen, as defined herein. Each occurrence of a halogen is independently selected. For example, the term "C 1~4"Haloalkyl" refers to a C alkyl group, as defined herein, in which one or more hydrogen atoms are replaced with halogen. 1~4 Refers to alkyl. C 1~4 Representative examples of haloalkyl include, but are not limited to, -CH2F, -CHF2, -CF3, -CHFCl, -CH2CF3, -CFHCF3, -CF2CF3, -CH(CF3)2, -CF(CHF2)2, and -CH(CH2F)(CF3).

[0331] The term "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a halogen. Each occurrence of halogen is independently selected. This term includes, for example, monohaloalkyl (e.g., CHF, CH(CHF)CH), dihaloalkyl (e.g., CHF, CH(CHF)CH), trihaloalkyl (e.g., CF, CH(CF)CH), and polyhaloalkyl (e.g., CF(CF)CH). A haloalkyl group may or may not be perhalogenated (e.g., perfluorinated, such as CF(CF)CF). For example, the term "C 1~4 "Haloalkyl" refers to a C alkyl group in which one or more hydrogen atoms are replaced by halogen. 1~4 For illustration, C 1~4 Haloalkyls include, for example, CH2F, CHF2, CF3, CHFCl, CH2CF3, CFHCF3, CF2CF3, CH(CF3)2, CF(CHF2)2, CH(CH2F)(CF3), CH2Cl, CHCl2, CCl3, CHFCl, CH2CCl3, CClHCCl3, CCl2CCl3, CH(CCl3)2, CCl(CHCl2)2, CH(CH2Cl)CCl3 and CH2CF(CH3)2.

[0332] The term haloalkylene refers to a divalent haloalkyl group in which one or more of the hydrogen atoms has been replaced by a halogen (e.g., "C 1~4 haloalkylene" and "C 1~6Representative examples of haloalkylene include, but are not limited to, -CHF-, -CF2-, -CHCl-, -CH2CF2-, -CF2CF2-, -CHCl-, -CCl2-, -CFCl-, and the like.

[0333] The terms "haloalkoxy" and "haloalkoxyl" are interchangeable and refer to an alkoxy group in which one or more of the hydrogen atoms have been replaced by a halogen. The halogen is independently selected at each occurrence. This term includes monohaloalkoxy (e.g., OCHF, OCH(CHF)CH), dihaloalkoxy (e.g., OCHF, OCH(CHF)CH), trihaloalkoxy (e.g., OCF, OCH(CF)CH), and polyhaloalkoxy (e.g., OCF(CF)CH). The haloalkoxy group may or may not be perhalogenated (e.g., perfluorinated, such as OCF(CF)CF). For example, the term "C 1~4 "Haloalkoxy" refers to a C alkyl group, as defined herein, in which one or more hydrogen atoms are replaced with halogen. 1~4 Refers to alkoxy. 1~4 Representative examples of haloalkoxy include OCH2F, OCHF2, OCF3, OCHFCl, OCH2CF3, OCFHCF3, OCF2CF3, OCH(CF3)2, OCF(CHF2)2, OCH(CH2F)(CF3), OCH2Cl, OCHCl2, OCF3, OCHFCl, OCH2CCl3, OCClHCCl3, OCCl2CCl3, OCH(CCl3)2, OCCl(CHCl2)2, OCH(CH2Cl)CCl3 and OCH2CF(CH3)2.

[0334] 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-, or 7-indolyl.

[0335] The term "heteroaryl" also refers to groups in which an aromatic heterocycle is fused to one or more aryl, alicyclic, or heterocycloalkyl rings.

[0336] As used herein, the term "heterocycloalkyl" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6-, or 7-membered monocyclic, a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic, or a 10-, 11-, 12-, 13-, 14-, or 15-membered tricyclic ring system, and containing at least one heteroatom selected from O, S, and N, which can be optionally oxidized to various oxidation states. A heterocyclic group can be bonded at a heteroatom or a carbon atom. Heterocycloalkyl can include fused or bridged rings and spirocyclic rings. For example, a heterocycloalkyl group having five total atoms and two heteroatoms independently selected from N, O, and S refers to a ring having three carbon atoms and two heteroatoms, where each heteroatom in the ring is independently N, O, or S. When a range is specified, all members of that range and all subgroups within that range are contemplated. For example, a heterocycloalkyl group having 5 to 7 total ring atoms and 1 to 3 heteroatoms independently selected from N, O, and S includes rings having 5, 6, or 7 total atoms, or any combination of the foregoing, and all subgroups in the specified range (e.g., 5 to 6 or 6 to 7 total ring atoms, or any combination of the foregoing), where 1, 2, or 3 of the atoms in the ring are heteroatoms, and each heteroatom is independently selected from N, O, and S. Thus, a heterocycloalkyl group having 5 to 7 total ring atoms and 1 to 3 heteroatoms independently selected from N, O, and S includes rings containing, for example, 4 carbon atoms and 1 heteroatom, 3 carbon atoms and 2 heteroatoms, 2 carbon atoms and 3 heteroatoms, 5 carbon atoms and 1 heteroatom, 4 carbon atoms and 2 heteroatoms, 3 carbon atoms and 3 heteroatoms, 6 carbon atoms and 1 heteroatom, 5 carbon atoms and 2 heteroatoms, and 4 carbon atoms and 3 heteroatoms, where each heteroatom is independently selected from N, O, and S.Non-limiting examples of heterocycloalkyl groups include, but are not limited to, aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophen-yl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, oxathiolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, dioxanyl, dithianyl, morpholinyl, thiomorpholinyl, azepanyl, hexahydro-1H-pyrrolidinyl, and 1,4-diazepanyl.

[0337] The terms "hydroxy" and "hydroxyl" are interchangeable and refer to the --OH group.

[0338] The term "hydroxyalkyl" or "hydroxylalkyl" refers to a saturated straight-chain or branched-chain alkyl containing the specified number of carbon atoms substituted with one or two hydroxy groups in place of hydrogen, provided that if two hydroxy groups are present, they are both on the same carbon atom. Non-limiting examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and the like.

[0339] The term "hydroxyalkylene" or "hydroxylalkylene" refers to a saturated straight-chain or branched-chain alkylene containing the specified number of carbon atoms substituted with one or two hydroxy groups in place of hydrogen, provided that if two hydroxy groups are present, they are both on the same carbon atom. Non-limiting examples of hydroxyalkylenes include, but are not limited to, hydroxymethylene, 2-hydroxyethylene, 2-hydroxypropylene, 3-hydroxypropylene, 1-(hydroxymethyl)-2-methylpropylene, 2-hydroxybutylene, 3-hydroxybutylene, 4-hydroxybutylene, 2,3-dihydroxypropylene, 1-(hydroxymethyl)-2-hydroxyethylene, 2,3-dihydroxybutylene, 3,4-dihydroxybutylene, and the like.

[0340] The term "oxo" refers to a substituent oxygen atom that is attached to another atom by a double bond (e.g., =0). For example, an oxo substituent on a cyclopentyl ring is [ka] It can be depicted as:

[0341] As used herein, the term "pharmaceutically acceptable" generally refers to something that is recognized for use in subjects, particularly humans.

[0342] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; 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, and methanesulfonic acid; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion; or when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and dicyclohexylamine. Further examples of such salts can be found in Berge et al., J. Pharm. Sci. 66(1):1-19 (1977). Stahl et al., Pharmaceutical Salts: Properties, Selection, and Use, 2 nd See also Revised Edition (2011).

[0343] As used herein, the term "pharmaceutically acceptable excipient" refers to a wide variety of ingredients that can be combined with the compounds or salts disclosed herein to prepare pharmaceutical compositions or formulations. Typically, excipients include, but are not limited to, diluents, colorants, vehicles, anti-adherents, glidants, disintegrants, flavoring agents, coating agents, binders, sweeteners, lubricants, adsorbents, preservatives, etc.

[0344] 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.

[0345] As used herein, the term "therapeutically effective amount" refers to the amount of a compound disclosed herein that will elicit the biological or medical response of a tissue, system, or subject as desired by a researcher, veterinarian, medical doctor, or other clinician.

[0346] General synthetic procedure The compounds provided herein can be synthesized according to the procedures described in this section and the following sections. The synthetic methods described herein are merely exemplary, and the compounds disclosed herein can also be synthesized by alternative routes using alternative synthetic strategies as would be understood by one of ordinary skill in the art. It should be understood that the general synthetic procedures and specific examples provided herein are illustrative only and should not be construed as limiting the scope of the present disclosure in any way.

[0347] In general, compounds of Formula I can be synthesized according to the following schemes. Any variables used in the following schemes are those defined for Formula I unless otherwise noted. All starting materials are either commercially available from, for example, Merck Sigma-Aldrich Inc., Fluorochem Ltd., and Enamine Ltd., or known in the art, and can be synthesized by utilizing known procedures using conventional techniques. Starting materials can also be synthesized via the procedures disclosed herein. Suitable reaction conditions, such as solvents, reaction temperatures, and reagents for the schemes described in this section, can be found in the examples provided herein.

[0348] [ka] Compounds of formula (I) can be prepared according to Scheme I. In Step A, compound (I-1) is reacted with an aliphatic amine or protected amine bearing an optionally substituted cyclic amine or alcohol in a solvent such as acetonitrile and in the presence of a base such as Hunig's base. NIn step B, compound (I-2) is reacted with a compound of formula R in the presence of a base such as Hunig's base in a solvent such as acetonitrile. 1 -LH with nucleophiles and S N The Ar reaction affords compound (I-3). In step C, compound (I-3) is coupled with an organometallic reagent or a boronic acid (ester) linked to an aryl or heteroaryl having a terminal ester group to afford compound (I-4). This coupling reaction proceeds with or without a base such as potassium phosphate in a solvent or a mixture of solvents such as THF and water and a catalyst such as cataCXium A Pd G3. In step D, compound (I-4) is saponified to afford compound (I-5). This reaction proceeds in TFA in a solvent such as DCM or in LiOH in a mixture of solvents such as THF and water. In step E, compound (I-5) is cyclized under conditions such as HATU and DIPEA or DCC / DMAP in a solvent such as DMF or dichloromethane to afford compound (I).

[0349] [ka] The compound of formula (II) can also be prepared according to Scheme II. In Step A, compound (II-1) is reacted with an aliphatic amine or protected amine bearing an optionally substituted cyclic amine or alcohol in a solvent such as acetonitrile in the presence of a base such as Hunig's base. N In step B, compound (II-2) is obtained by reacting a compound of formula R 1 -LH with nucleophiles and S NCompound (II-3) is obtained via an Ar reaction. In step C, compound (II-3) is coupled with an organometallic reagent such as bis(tributyltin) to obtain compound (II-4). This coupling reaction proceeds in a solvent such as 1,4-dioxane and a catalyst such as chloro[(tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II), with or without an additive such as lithium chloride. In step D, compound (II-4) is coupled with an organometallic reagent or a boronic acid (ester) linked to an aryl or heteroaryl having a terminal ester group to obtain compound (II-5). This coupling reaction proceeds in a solvent or a mixture of solvents such as THF and water and a catalyst such as cataCXium A Pd G3, with or without a base such as potassium phosphate. In step E, compound (II-5) is saponified to obtain compound (II-6). The reaction proceeds in TFA in a solvent such as DCM or in LiOH in a mixture of solvents such as THF and water. In step F, compound (II-6) is cyclized under conditions such as HATU and DIPEA or DCC / DMAP in a solvent such as DMF or dichloromethane to give compound of formula (II).

[0350] [ka] The compound of formula (III) can also be prepared according to Scheme III. In Step A, compound (III-1) is reacted with an aliphatic amine or protected amine bearing an optionally substituted cyclic amine or alcohol in a solvent such as acetonitrile in the presence of a base such as Hunig's base. N In step B, compound (III-2) is reacted with a compound of formula R in the presence of a base such as Hunig's base in a solvent such as acetonitrile. 1 -LH with nucleophiles and S NThe compound (III-3) is obtained through an Ar reaction. In step C, compound (III-3) is coupled with an organometallic reagent or a boronic acid (ester) linked to an aryl or heteroaryl having a terminal TBS-protected alcohol to obtain compound (III-4). This coupling reaction proceeds in a solvent or a mixture of solvents such as THF and water and a catalyst such as cataCXium A Pd G3, with or without a base such as potassium phosphate. In step D, compound (III-4) is reacted with CDI, followed by treatment with a desilylation reagent such as TBAF in a solvent such as THF to obtain compound (III).

[0351] [ka] The compound of formula (IV) can also be prepared according to Scheme IV. In Step A, compound (IV-1) is reacted with an optionally substituted cyclic amine or an aliphatic amine having a terminal ester group in a solvent such as acetonitrile and in the presence of a base such as Hunig's base. N In step B, compound (IV-2) is reacted with a compound of formula R in the presence of a base such as Hunig's base in a solvent such as acetonitrile. 1 -LH with nucleophiles and S NThe Ar reaction affords compound (IV-3). In step C, compound (IV-3) is coupled with an organometallic reagent or a boronic acid (ester) linked to an aryl or heteroaryl having a terminal TBS-protected alcohol to afford compound (IV-4). This coupling reaction proceeds in a solvent or a mixture of solvents such as THF and water and a catalyst such as cataCXium A Pd G3, with or without a base such as potassium phosphate. In step D, compound (IV-4) is treated with a desilylation reagent such as TBAF in a solvent such as THF, followed by saponification using a reagent such as Me3SnOH in a solvent such as DCE to afford compound (IV-5). In step E, compound (IV-5) is cyclized using a reagent such as 2-chloro-1-methylpyridinium iodide in a solvent such as DCE in the presence of a base such as TEA to afford compound (IV).

[0352] [ka] The compound of formula (V) can be prepared according to Scheme V. In Step A, compound (V-1) is reacted with an aliphatic amine or protected amine bearing an optionally substituted cyclic amine or alcohol in a solvent such as acetonitrile and in the presence of a base such as Hunig's base. N In step B, compound (V-2) is reacted with a nucleophile such as sodium methanethiolate in a solvent such as THF to give compound (V-3). NCompound (V-3) is obtained via Ar reaction. In step C, compound (V-3) is coupled with an organometallic reagent or a boronic acid (ester) linked to an aryl or heteroaryl having a terminal ester group to obtain compound (V-4). This coupling reaction proceeds with or without a base such as potassium phosphate in a solvent or a mixture of solvents such as THF and water and a catalyst such as cataCXium A Pd G3. In step D, compound (V-4) is saponified to obtain compound (V-5). This reaction proceeds in TFA in a solvent such as DCM or in LiOH in a mixture of solvents such as THF and water. In step E, compound (V-5) is cyclized under conditions such as HATU and DIPEA or DCC / DMAP in a solvent such as DMF or dichloromethane to obtain compound (V-6). In step F, compound (V-6) is oxidized using a reagent such as m-CPBA in a solvent such as DCM to obtain compound (V-7). In step G, compound (V-7) can be prepared by reacting a compound of formula R 1 -LH with nucleophiles and S N Compound (V) is obtained via Ar reaction.

[0353] [ka] The compound of formula (VI) can also be prepared according to Scheme VI. In Step A, compound (VI-1) is reacted with an optionally substituted cyclic amine or an aliphatic amine having a terminal alkene in a solvent such as acetonitrile and in the presence of a base such as Hunig's base. N In step B, compound (VI-2) is converted to a compound of formula R in the presence of a base such as Hunig's base in a solvent such as acetonitrile. 1 -LH with nucleophiles and S NThe reaction proceeds via an Ar reaction to give compound (VI-3). In step C, compound (VI-3) is coupled with an organometallic reagent or a boronic acid (ester) linked to an aryl or heteroaryl having a terminal alkene to give compound (VI-4). This coupling reaction proceeds in a solvent or a mixture of solvents such as THF and water and a catalyst such as cataCXium A Pd G3, with or without a base such as potassium phosphate. In step D, compound (VI-4) undergoes ring-closing metathesis to give compound (VI-5). This reaction proceeds in a solvent such as DCE and with a Hoveyda-Grubbs second-generation catalyst in the presence of an acid such as TsOH. In step E, compound (VI-5) is hydrogenated under conditions such as Pd on carbon in a hydrogen atmosphere in a solvent such as ethanol to give compound of formula (VI). [Example]

[0354] This section provides specific examples of compounds of Formula I and methods for making them.

[0355] List of abbreviations

[0356] [Table 18]

[0357] [Table 19]

[0358] [Table 20]

[0359] [Table 21]

[0360] [Table 22]

[0361] 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.

[0362] Chromatography: Unless otherwise indicated, the crude product-containing residue was purified by passing the crude material or concentrate through either a Biotage or Isco brand silica gel column pre-packed with flash silica (SiO) and eluting the product from the column with a solvent gradient as specified.

[0363] Preparative HPLC Method: 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 two HPLC columns: (a) a Phenomenex Gemini column (5 micron, C18, 150x30mm) or (b) a Waters X-select CSH column (5 micron, C18, 100x30mm). A typical run through the instrument involved elution with a linear gradient of 10% (v / v) to 100% MeCN (0.1% v / v formic acid) in water (0.1% formic acid) over 10 minutes at 45 mL / min; conditions may be varied to achieve optimal separation.

[0364] 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 a reference. 1 The H signal may be missing due to exchange of MeOD with D or due to signal suppression.

[0365] Mass Spectrum (MS): Unless otherwise indicated, all mass spectral data for starting materials, intermediates, and / or exemplary compounds are reported as mass / charge (m / z) with the [M+H]+ molecular ion. The reported molecular ions were obtained by electrospray detection (commonly referred to as ESI MS) using a Waters Acquity UPLC / MS system. As will be appreciated by those skilled in the art, compounds with isotopic atoms such as bromine are typically reported according to the detected isotopic pattern.

[0366] Preparation of intermediates Intermediate A: tert-butyl 4-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate. [ka] Step 1. 2-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. To a mixture of triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (1.00 g, 2.00 mmol, LabNetwork Inc.) in N,N-dimethylformamide (4.0 mL) was added cesium fluoride (4.61 g, 30.3 mmol) and stirred at room temperature overnight. Water was added to the reaction mixture, and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and the volatiles were removed in vacuo. The crude residue was purified by column chromatography on silica gel eluting with a gradient of 0-30% EtOAc in heptane to give 2-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.60 g, 1.77 mmol, 88% yield) as a white solid. m / z (ESI): 339.2 (M+H). + .

[0367] Step 2. tert-Butyl 4-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)but-3-ynoate. 2-(8-Ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.18 g, 0.52 mmol), copper(I) iodide (9.9 mg, 0.05 mmol) were dissolved in acetonitrile (1.5 mL), and tert-butyl diazoacetate (0.15 g, 0.14 mL, 1.04 mmol, Sigma-Aldrich Corporation) was added dropwise. The mixture was stirred at room temperature for 5 hours. Water was added, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and the volatiles were removed in vacuo. The residue was purified by column chromatography on silica gel eluting with a gradient of 0-30% EtOAc in heptane to give tert-butyl 4-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)but-3-inoate (0.14 g, 0.30 mmol, 58% yield) as a clear oil. m / z (ESI): 397.0 (Mt-Bu+H). + .

[0368] Step 3. tert-Butyl 4-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate. tert-Butyl 4-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)but-3-inoate (0.11 g, 0.24 mmol) was dissolved in ethyl acetate (3.0 mL) and 5% Pd / C (52 mg, 0.024 mmol, Alfa Aesar) was added. The mixture was placed under an atmosphere of hydrogen (15 psi) and stirred at room temperature for 4 hours. The reaction mixture was filtered through Celite and the filter cake was washed with EtOAc. The volatiles were removed in vacuo and the residue was purified by column chromatography on silica gel eluting with a gradient of 0 to 50% EtOAc in heptane to give tert-butyl 4-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate (94 mg, 0.21 mmol, 85% yield) as a colorless oil. 1 H NMR(400MHz,chloroform-d)δ ppm 7.62(d,J=7.5Hz,1H),7.43(d,J=2.7Hz,1H),7.35-7.41(m,2H),7.26(d,J=6.7Hz,1H),5.30-5.31 (m,2H),3.53(s,3H),3.18-3.27(m,2H),2.22-2.29(m,2H),2.04-2.12(m,2H),1.45-1.48(m,21H).

[0369] Intermediate B: Ethyl 4-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate. [ka] Step 1. Ethyl 4-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)but-3-ynoate. 2-(8-Ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.00 g, 2.96 mmol, Intermediate A Step 1), copper(I) iodide (0.08 g, 0.44 mmol) were dissolved in acetonitrile (7.0 mL), and a 15% solution of ethyl diazoacetate in toluene (4.50 g, 4.17 mL, 5.91 mmol, Sigma-Aldrich Corporation) was added. The mixture was stirred at room temperature for 3 hours. Saturated NH4Cl was added, and the aqueous layer was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and the volatiles were removed in vacuo. The mixture was then purified by column chromatography on silica gel eluting with a gradient of 0-30% EtOAc in heptane to give ethyl 4-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)but-3-inoate (1.10 g, 2.59 mmol, 88% yield) as a clear oil. m / z (ESI): 425.0 (M+2H). + .

[0370] Step 2. Ethyl 4-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate. Ethyl 4-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)but-3-inoate (1.03 g, 2.43 mmol) was dissolved in ethyl acetate (25 mL) and 5% Pd / C (0.52 g, 0.24 mmol, Alfa Aesar) was added. The mixture was placed under an atmosphere of hydrogen (15 psi) and stirred at room temperature for 4 hours. The reaction mixture was filtered through Celite and the filter cake was washed with EtOAc. The volatiles were removed in vacuo and the residue was purified by column chromatography on silica gel eluting with a gradient of 0 to 50% EtOAc in heptane to give ethyl 4-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate (0.80 g, 1.87 mmol, 77% yield) as a colorless oil. 1 H NMR(400MHz,chloroform-d)δ ppm 7.61-7.65(m,1H),7.43(d,J=2.7Hz,1H),7.40(d,J=2.7Hz,1H),7.37(d,J=7.9Hz,1H),7.24-7.28(m,1H),5.30-5.31(m,2H),4.13(q ,J=7.1Hz,2H),3.53(s,3H),3.23(t,J=7.3Hz,2H),2.32(d,J=7.7Hz,2H),2.12(t,J=7.4Hz,2H),1.46(s,12H),1.25(t,J=7.2Hz,3H).

[0371] Intermediate C: tert-butyl 4-(2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate. [ka] Step 1. 2-(8-ethynyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. ((2-Fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.00 g, 4.42 mmol, LabNetwork Inc.) and cesium fluoride (13.4 g, 88 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the mixture was stirred at 50 °C for 3 h. Water was added, and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over NaSO, filtered, and the volatiles were removed in vacuo. The residue was then purified by column chromatography on silica gel eluting with a gradient of 0-30% EtOAc in heptane to give 2-(8-ethynyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.80 g, 2.70 mmol, 61% yield) as a white solid. m / z (ESI): 297.2 (M+H). +

[0372] Step 2. tert-Butyl 4-(2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)but-3-ynoate. 2-(8-Ethynyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.86 g, 2.90 mmol) was dissolved in acetonitrile (10 mL) and tert-butyl diazoacetate (0.83 mg, 5.81 mmol, Sigma-Aldrich Corporation) was added, followed by copper(I) iodide (0.11 g, 0.58 mmol). The reaction mixture was stirred at room temperature for 16 hours. Saturated NH4Cl and water were added, and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and the volatiles were removed in vacuo. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0-25% EtOAc in heptane to give tert-butyl 4-(2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)but-3-inoate (0.52 g, 1.27 mmol, 44% yield) as a colorless oil. m / z (ESI): 355.0 (Mt-Bu+H). +

[0373] Step 3. tert-Butyl 4-(2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate. tert-Butyl 4-(2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)but-3-inoate (0.52 g, 1.27 mmol) was dissolved in ethyl acetate (10 mL) and 5% Pd / C (0.27 g, 0.13 mmol) was added. The mixture was placed under an atmosphere of hydrogen (15 psi) and stirred at room temperature for 6 hours. The reaction mixture was filtered through Celite and the filter cake was washed with EtOAc. The volatiles were removed in vacuo and the residue was purified by column chromatography on silica gel eluting with a gradient of 0-30% EtOAc in heptane to give tert-butyl 4-(2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate (0.25 g, 0.60 mmol, 48% yield) as a colorless oil. m / z (ESI): 359.2 (Mt-Bu+H). + .

[0374] Intermediate D: Ethyl 4-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate. [ka] In a 100 mL round-bottom flask, 2-(8-chloro-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.10 g, 5.70 mmol, Labnetwork), PEPPSI-IPr catalyst (0.39 g, 0.57 mmol, Sigma-Aldrich Corporation), and anhydrous DMF (45 mL) were charged under nitrogen. Lithium bromide (4 M in THF, 4.6 mL, 18.4 mmol) was added, followed by the dropwise addition of (4-ethoxy-4-oxobutyl)zinc(II) bromide (0.5 M solution in THF, 23 mL, 11.5 mmol, Rieke Metal). The reaction mixture was stirred at 60 °C for 5 h. After cooling to room temperature, the reaction mixture was quenched with aqueous NH4Cl and extracted with EtOAc. The combined organics were dried (NaSO) and concentrated. The crude material was purified by column chromatography on silica gel eluting with a gradient of 5-20% ethyl acetate in heptane to give ethyl 4-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate as a colorless oil. m / z (ESI): 464.4 (M+Na). + . 1 H NMR(400MHz,chloroform-d)δ ppm 7.51-7.67(m,1H),7.35-7.47(m,2H),7.18-7.26(m,1H),5.11-5.31(m,2H),3.95-4.18(m,2H),3.44-3.6 0(m,3H),3.04-3.34(m,2H),2.14-2.31(m,2H),1.86-2.07(m,2H),1.41-1.53(m,12H),1.17-1.27(m,3H).

[0375] Intermediate E: Methyl 5-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)pentanoate. [ka] Step 1. Methyl 5-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)pent-4-ynoate. A vial was charged with bis(triphenylphosphoranylidene)ammonium chloride (0.22 g, 0.39 mmol), triruthenium dodecacarbonyl (39 mg, 0.061 mmol), and NMP (0.7 mL). The reaction mixture was aerated with argon and stirred at 60 °C. After 15 min, methyl acrylate (0.63 mL, 6.95 mmol) and 2-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.47 g, 1.39 mmol, Intermediate A, Step 1) were added to the mixture. The reaction was stirred at 65 °C. After 5 days, the reaction mixture was partitioned between water and ethyl acetate; the organic layer was concentrated. The crude product was purified by column chromatography on silica gel eluting with 0 to 100% ethyl acetate in heptane to give methyl 5-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)pent-4-ynoate (0.42 g, 0.99 mmol, 71% yield) as a pale yellow solid. m / z (ESI): 425.2 (M+H). + .

[0376] Step-2: Methyl 5-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)pentanoate. A solution of methyl 5-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)pent-4-ynoate (0.84 g, 1.98 mmol) in ethyl acetate (10 mL) was transferred to a hydrogenation flask, flushed with argon, and 5% Pd / C (0.42 g, 0.20 mmol) was added. The mixture was placed under an atmosphere of hydrogen (20 psi) and stirred at room temperature. After 2 hours, the reaction mixture was filtered through Celite; the filtrate was concentrated. The crude product was purified by column chromatography on silica gel eluting with 0-50% ethyl acetate in heptane to give methyl 5-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)pentanoate (0.41 g, 0.96 mmol, 49% yield) as a colorless oil. m / z (ESI): 450.1 (M+Na). + .

[0377] Intermediate F: Ethyl 2-fluoro-4-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate. [ka] A round-bottom flask was charged with NaHMDS (1 M in THF, 0.32 mL, 0.32 mmol) and the contents were cooled to −78° C. Ethyl 4-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate (0.12 g, 0.27 mmol, Intermediate D) dissolved in 1.0 mL of THF was added dropwise to the solution. The reaction mixture was stirred at −78° C. for 30 minutes, followed by the slow addition of N-fluorobenzenesulfonimide (0.10 g, 0.32 mmol) dissolved in 1.0 mL of THF over 15 minutes. The mixture was allowed to slowly warm to room temperature with stirring for 16 hours. The reaction was then cooled to −78° C. and quenched by the addition of MeOH (3 mL). After warming to room temperature, the volatiles were removed in vacuo and the residue was purified by reverse phase chromatography to give ethyl 2-fluoro-4-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate (40 mg, 0.086 mmol, 32% yield). 1 H NMR(400MHz,chloroform-d)δ ppm 7.63(dd,J=9.0,5.9Hz,1H),7.48(d,J=2.5Hz,1H),7.43(d,J=2.7Hz,1H),7.23(t,J=9.2Hz,1H),5.28-5.31(m,2H),4.82-4.98(m,1H),4.22(qd ,J=7.1,1.2Hz,2H),3.52-3.54(m,3H),3.30-3.38(m,2H),2.24-2.31(m ,1H),2.17-2.23(m,1H),1.46(d,J=1.9Hz,12H),1.27(t,J=7.2Hz,3H). 19 F NMR (377 MHz, chloroform-d) δ ppm -76.59 - -74.96 (m, 3F), -117.11 (br s, 1F), -192.09 - -191.74 (m, 1F).

[0378] Intermediate G: Ethyl 4-(2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate. [ka] Step 1. Ethyl 4-(2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)but-3-ynoate. A vial was charged with 2-(8-ethynyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.76 g, 5.94 mmol, Intermediate C, Step 1) and copper(I) iodide (0.11 g, 0.59 mmol) in acetonitrile (15 mL). Ethyl diazoacetate solution (15% in toluene, 6.1 mL, 7.1 mmol) was added slowly, and the reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with saturated aqueous NH4Cl and water and extracted with EtOAc. The combined organics were dried over MgSO4, filtered, and concentrated. The crude residue was purified by column chromatography on silica gel eluting with a gradient of 25 to 100% EtOAc in heptane to give ethyl 4-(2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)but-3-inoate (1.11 g, 2.90 mmol, 49% yield). 1 H NMR (400 MHz, chloroform-d) δ ppm 7.77-7.89 (m, 3H), 7.41-7.47 (m, 1H), 7.28-7.32 (m, 1H), 4.27 (d, J = 7.1 Hz, 2H), 3.66 (s, 2H), 1.44 (s, 12H), 1.32-1.37 (m, 3H).

[0379] Step 2: Ethyl 4-(2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate. A 250 mL pressure tube was charged with ethyl 4-(2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)but-3-inoate (1.00 g, 2.62 mmol), palladium hydroxide on carbon (0.18 g, 0.26 mmol), and ethyl acetate (6.5 mL). The system was purged with nitrogen and then pressurized with H (25 psi). The reaction was stirred vigorously for 2.5 h. The reaction mixture was filtered through SiO, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel eluting with a gradient of 10 to 100% EtOAc in heptane to give ethyl 4-(2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate (0.81 g, 2.07 mmol, 79% yield) as a white solid. 1 H NMR(500MHz,chloroform-d)δ ppm 7.87(dd,J=8.2,1.3Hz,1H),7.68-7.75(m,2H),7.38-7.46(m,1H),7.26(s,1H),4.06-4.12(m,2H),3.29(br d,J=2.5Hz,2H),2.21-2.30(m,2H),1.98-2.07(m,2H),1.47(s,12H),1.20-1.23(m,3H).

[0380] Intermediate H: Ethyl 2-fluoro-4-(2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate. [ka] A round-bottom flask was charged with NaHMDS (1 M in THF, 1.55 mL, 1.55 mmol) and the contents were cooled to −78° C. Next, ethyl 4-(2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate (0.50 g, 1.30 mmol, Intermediate G) dissolved in 1.0 mL of THF was added to the solution. The reaction mixture was stirred at −78° C. for 30 minutes, followed by the slow addition of N-fluorobenzenesulfonimide (0.57 g, 1.81 mmol) dissolved in THF (1 mL) over 15 minutes. The mixture was allowed to slowly warm to room temperature with stirring for 16 hours. The reaction was then cooled to −78° C. and MeOH (3 mL) was added to quench the reaction. After warming to room temperature, the volatiles were removed in vacuo and the residue was purified by reverse phase chromatography to give ethyl 2-fluoro-4-(2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate (0.35 g, 0.87 mmol, 67% yield). m / z (ESI): (M+H) + 405.1.

[0381] Intermediate I: tert-Butyl 6-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)hexanoate. [ka] A 100 mL RBF was charged with 5-chloro-6-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (1.00 g, 2.65 mmol, Advanced ChemBlocks Inc.) in tetrahydropyran (26.5 mL), PEPPSI-IPr catalyst (0.18 g, 0.27 mmol, Sigma-Aldrich Corporation). 6-tert-Butoxy-6-oxohexylzinc bromide (0.5 M in THF, 10.6 mL, 5.3 mmol, Rieke Metals, Inc.) was added. The reaction was stirred at room temperature for 16 hours. The reaction mixture was then quenched with saturated aqueous ammonium chloride and extracted with DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with a gradient of 0-20% EtOAc in heptane to give tert-butyl 6-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)hexanoate (0.60 g, 1.18 mmol, 44% yield). m / z (ESI): 513.2 (M+H).

[0382] Intermediate J: Ethyl 5-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)pentanoate. [ka] An oven-dried round-bottom flask was charged with 5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (3.90 g, 10.40 mmol, Ambeed, Inc.) and tetrahydrofuran (52 mL). 5-Ethoxy-5-oxopentylzinc bromide (0.5 M in THF, 52 mL, 25.5 mmol) was added. To this stirred solution, PEPPSI-IPr catalyst (2.05 g, 2.59 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography on silica gel eluting with 0-25% EtOAc in heptane to give ethyl 5-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)pentanoate (1.21 g, 2.57 mmol, 25% yield) as a yellow oil. m / z (ESI): 471.2 (M+H). + .

[0383] Intermediate K: 5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. [ka] A 250 mL round-bottom flask was charged with 5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (5.00 g, 13.30 mmol, Ambeed, Inc.) and the flask was loaded into a nitrogen box. PEPPSI-IPr (1.05 g, 1.33 mmol, Labnetwork) was then added, followed by THF (1.5 mL). (3-((tert-butyldimethylsilyl)oxy)propyl)zinc(II) bromide (66.5 mL, 33.2 mmol, Rieke metals) was then slowly added while swirling the flask. The reaction flask was then removed from the nitrogen box and stirred under nitrogen at room temperature for 3 hours. The reaction was quenched by the addition of saturated NH4Cl solution with vigorous stirring for 10 min. The mixture was then diluted with water and extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified sequentially by column chromatography on silica gel with a gradient of 0-10% EtOAc in heptane and reverse-phase chromatography with a gradient of 0-80% MeCN (0.1% formic acid) in water (0.1% formic acid) to give 5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1.24 g, 2.40 mmol, 18% yield) as a pale yellow oil. m / z (ESI): 515.2 (M+H). + .

[0384] Intermediate L: ethyl 4-(6-(pivaloyloxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)butanoate. [ka] Step 1. 4-Bromo-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl pivalate. To a 250 mL round-bottom flask was added 8-bromo-6-hydroxy-tetralin-1-one (5.00 g, 20.70 mmol, PharmaBlock, Inc.) and DIEA (9.1 mL, 51.8 mmol) in 2-MeTHF (104 mL). The mixture was cooled to 0 °C, and 2,2-dimethyl-propanoyl chloride (2.88 g, 23.9 mmol) was added slowly. The reaction was stirred at 0 °C for 1 hour, diluted with saturated NH Cl solution, and extracted with EtOAc. The organic extract was washed with saturated NaCl solution, dried over MgSO , filtered, and concentrated in vacuo. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0-50% EtOAc in hexanes to give 4-bromo-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl pivalate (6.30 g, 18 mmol, 93% yield) as a brown oil. m / z (ESI): 324.8 / 326.8 (M+H). + .

[0385] Step 2. 5-Allyl-4-bromo-5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl pivalate. To a 250 mL round-bottom flask was added 4-bromo-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl pivalate (4.20 g, 12.90 mmol) in THF (52 mL). The mixture was cooled to 0 °C, and allylzinc bromide (0.5 M in THF, 33.6 mL, 16.7 mmol) was added. The reaction was stirred for 1 h, then diluted with saturated NH4Cl solution and extracted with EtOAc. The organic extract was concentrated and the crude material was purified by column chromatography on silica gel eluting with a gradient of 0-50% EtOAc in hexanes to give 5-allyl-4-bromo-5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl pivalate (4.20 g, 11.4 mmol, 89% yield) as a colorless oil. m / z (ESI): 388.8 / 390.8 (M+Na). + .

[0386] Step 3: 5-Allyl-4-bromo-5,6,7,8-tetrahydronaphthalen-2-yl pivalate. To a 25 mL round-bottom flask was added 5-allyl-4-bromo-5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl pivalate (4.20 g, 11.4 mmol) in DCM (57 mL). The mixture was cooled to 0 °C, and triethylsilane (3.99 g, 34.3 mmol) was added, followed by TFA (1.8 mL, 23 mmol). The reaction was stirred from 0 °C to room temperature for 3 h, then diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0-60% EtOAc in heptane to give 5-allyl-4-bromo-5,6,7,8-tetrahydronaphthalen-2-yl pivalate (3.00 g, 8.54 mmol, 75% yield) as a colorless oil. m / z (ESI): 373.0 / 375.0 (M+Na). + .

[0387] Step 4. 4-Bromo-5-(2-oxoethyl)-5,6,7,8-tetrahydronaphthalen-2-yl pivalate. A 25 mL round-bottom flask was charged with 5-allyl-4-bromo-5,6,7,8-tetrahydronaphthalen-2-yl pivalate (0.20 g, 0.57 mmol) and 4-methylmorpholine 4-oxide (0.10 g, 0.85 mmol) in acetone (2.1 mL) and water (0.7 mL). Potassium dioxide dioxoosmium dihydrate (2.1 mg, 5.7 μmol, Oakwood Products, Inc.) was added, and the reaction mixture was stirred at room temperature for 2 hours. Sodium (meta)periodate (0.24 g, 1.14 mmol) was added, and stirring was continued for an additional hour. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with saturated NaCl solution, dried over MgSO, filtered, and concentrated in vacuo. The crude material was purified by column chromatography eluting with a gradient of 0-45% EtOAc in heptane to give 4-bromo-5-(2-oxoethyl)-5,6,7,8-tetrahydronaphthalen-2-yl pivalate (0.10 g, 0.28 mmol, 50% yield) as a colorless oil. m / z (ESI): 374.8 / 376.8 (M+Na). + . 1 H NMR (400 MHz, chloroform-d) δ ppm 9.85 (m, 1H), 7.04-7.22 (m, 1H), 6.57-6.89 (m, 1H), 3.61-3.82 (m, 1H), 2.76-2.98 (m, 3H), 2.51-2.68 (m, 1H), 1.70-1.94 (m, 4H), 1.36 (s, 9H).

[0388] Step 5. Ethyl (E / Z)-4-(8-bromo-6-(pivaloyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)but-2-enoate. To a 25 mL round-bottom flask was added (carbethoxymethyl)triphenylphosphonium bromide (0.24 g, 0.57 mmol) in THF (1.4 mL). The mixture was cooled to 0° C., and lithium bis(trimethylsilyl)amide solution (1 M in THF, 0.50 mL, 0.5 mmol) was added. The reaction mixture was stirred for 30 minutes, followed by the addition of 4-bromo-5-(2-oxoethyl)-5,6,7,8-tetrahydronaphthalen-2-yl pivalate (0.10 g, 0.28 mmol). The reaction mixture was stirred at room temperature for 16 hours. The crude material was purified by column chromatography eluting with a gradient of 0-25% EtOAc in heptane to give (E / Z)-ethyl 4-(8-bromo-6-(pivaloyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)but-2-enoate as a colorless oil. m / z (ESI): 422.8 / 424.8 (M+H). + NMR showed a mixture of cis / trans isomers (approximately 1:2 ratio).

[0389] Step 6. Ethyl 4-(8-bromo-6-(pivaloyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)butanoate. To a 25 mL round-bottom flask was added (E / Z)-ethyl 4-(8-bromo-6-(pivaloyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)but-2-enoate (0.28 g, 0.66 mmol) in THF (1.6 mL) and methanol (1.6 mL). The mixture was cooled to 0 °C and nickel(II) bromide (0.17 g, 0.79 mmol) was added. After stirring at 0 °C for 15 min, sodium borohydride (63 mg, 1.65 mmol) was added. The mixture was stirred for 1 h, quenched with water, and extracted with EtOAc. The organic layer was separated, dried (Na2SO4), and concentrated. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0-45% EtOAc in heptane to give ethyl 4-(8-bromo-6-(pivaloyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)butanoate. m / z (ESI): 446.8 / 448.8 (M+Na). + .

[0390] Step 7. Ethyl 4-(6-(pivaloyloxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)butanoate. To a 20 mL vial was added ethyl 4-(8-bromo-6-(pivaloyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)butanoate (0.25 g, 0.59 mmol), bis(pinacolato)diboron (0.15 g, 0.59 mmol), potassium acetate (0.17 g, 1.76 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (43 mg, 0.059 mmol) in toluene (2.9 mL). The reaction mixture was purged with nitrogen and then stirred at 90° C. for 3 hours. After cooling to room temperature, the crude material was purified by column chromatography on silica gel eluting with a gradient of 0-45% EtOAc in heptane to give ethyl 4-(6-(pivaloyloxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)butanoate (0.20 g, 0.42 mmol, 50% yield). m / z (ESI): 473.1 (M+H). + .

[0391] Intermediate M: 5-(but-3-en-1-yl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. [ka] A flask was charged with 5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1.00 g, 2.65 mmol, Ambeed, Inc.) and PEPPSI-IPr (0.42 g, 0.53 mmol, LabNetwork). Next, but-3-en-1-ylzinc(II) bromide (0.5 M in THF, 10.6 mL, 5.3 mmol) and LiCl (0.5 M in THF, 5.3 mL, 2.6 mmol) were added. The mixture was purged with nitrogen for 10 minutes and then heated to 40 °C for 16 hours. Upon completion, the reaction was quenched with water and extracted with EtOAc. The organic layer was concentrated and purified by reverse phase chromatography to give 5-(but-3-en-1-yl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (0.59 g, 1.49 mmol, 56% yield) as a pale yellow solid. m / z (ESI): 397.2 (M+H). + .

[0392] Intermediate N: 2-(8-allylnaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. [ka] A 250 mL round-bottom flask was charged with 1-allyl-8-bromonaphthalene (2.33 g, 9.43 mmol, CombiBlocks) and dry THF (100 mL). The mixture was cooled to -78 °C, and n-BuLi (2.5 M in hexanes, 4.9 mL, 12.3 mmol) was added dropwise. The resulting mixture was stirred at -78 °C for 30 minutes. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.6 mL, 14.1 mmol, Sigma-Aldrich Corporation) was then added, and the reaction mixture was allowed to warm to room temperature over 1 hour. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried and concentrated. The crude mixture was purified by column chromatography on silica gel eluting with a gradient of 0 to 50% EtOAc in heptane to give 2-(8-allylnaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.70 g, 9.18 mmol, 97% yield), which was contaminated with the des-allyl impurity. 1 H NMR(400MHz, methanol-d4)δ ppm 7.92(d,J=8.2Hz,1H),7.76(d,J=7.9Hz,1H),7.64(d,J=6.7Hz,1H),7.37-7.48(m,3H),6.14 (ddt,J=16.9,10.2,6.7,6.7Hz,1H),5.08-5.24(m,2H),3.97(d,J=6.7Hz,2H),1.45(s,12H).

[0393] Intermediate O: (Z)-5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pent-4-enoate methyl ester and Intermediate P: 5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoate methyl ester. [ka] Step 1. Methyl 5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pent-4-ynoate. A 40 mL vial was charged with methyl pent-4-ynoate (1.52 g, 13.6 mmol), 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (3.00 g, 6.80 mmol, Lab Network), triethylamine (9.5 mL, 68 mmol), and N,N-dimethylformamide (14 mL). The solution was aerated with nitrogen for 20 minutes, and copper iodide (39 mg, 0.20 mmol) and bis(triphenylphosphine)palladium dichloride (0.24 g, 0.34 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours and then heated to 35°C for 6 hours. The reaction was diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The aqueous layer was extracted with EtOAc and washed with brine, and the organics were dried over sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel eluting with 0 to 30% EtOAc in heptane to give methyl 5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pent-4-inoate (2.23 g, 5.24 mmol, 77% yield) as an off-white solid.

[0394] Step 2. (Z)-Methyl 5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pent-4-enoate and methyl 5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoate. A 60 mL hydrogenation reactor was charged with methyl 5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pent-4-inoate (0.60 g, 1.41 mmol) and platinum(IV) oxide (6.4 mg, 0.028 mmol). The reactor was purged with nitrogen and then charged with EtOH (7 mL). The reaction vessel was charged with hydrogen (20 psi) and the reaction was stirred at room temperature for 18 hours. Upon completion, the reaction mixture was diluted with EtOAc, filtered through Celite, and the filtrate was concentrated. The crude material was purified by column chromatography on silica gel eluting with 0–30% EtOAc in heptane to afford methyl (Z)-5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pent-4-enoate (0.22 g, 0.51 mmol, 36% yield, Intermediate O) as a colorless oil. m / z (ESI): 427.8 (M+H)+. Methyl 5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoate (0.28 g, 0.65 mmol, 46% yield, Intermediate P) was also isolated. m / z(ESI):429.0(M+H) +

[0395] Intermediate Q: ethyl 2-(3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propoxy)acetate. [ka] Step 1. Ethyl 2-(prop-2-yn-1-yloxy)acetate. An oven-dried three-neck flask under nitrogen was charged with ethyl glycolate (3.49 mL, 33.6 mmol) and THF (96 mL). Sodium hydride, 60% dispersion in mineral oil (1.61 g, 40.3 mmol) was added in small portions, and the reaction mixture was stirred at room temperature for 1 h. Next, propargyl bromide (5.0 mL, 33.6 mmol) was added dropwise, and the reaction was stirred at room temperature for 48 h. The mixture was diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography on silica gel eluting with 0–20% ethyl acetate in heptane to give ethyl 2-(prop-2-yn-1-yloxy)acetate (1.90 g, 13.40 mmol, 40% yield) as a pale yellow solid. 1 H NMR (400 MHz, chloroform-d) δ ppm 4.34 (d, J = 2.5 Hz, 2H), 4.20-4.29 (m, 4H), 2.49 (t, J = 2.4 Hz, 1H), 1.32 (t, J = 7.2 Hz, 3H).

[0396] Step 2. Ethyl 2-(3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propoxy)acetate. A 40 mL vial was charged with 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.00 g, 4.53 mmol, LabNetwork), DMF (9.06 mL), and triethylamine (6.4 mL, 45.3 mmol). The solution was aerated with nitrogen, and bis(triphenylphosphine)palladium(II) dichloride (0.16 g, 0.23 mmol) and copper iodide (26 mg, 0.14 mmol) were added. The solution was stirred at 35° C. for 24 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The organics were dried over sodium sulfate, concentrated, and the crude material was purified by column chromatography on silica gel eluting with 0-40% EtOAc in heptane to give ethyl 2-((3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)prop-2-yn-1-yl)oxy)acetate (0.86 g, 1.89 mmol, 42% yield) as an orange oil. m / z (ESI): 455.0 (M+H). + .

[0397] A 60 mL ChemGlass reactor tube was charged with ethyl 2-((3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)prop-2-yn-1-yl)oxy)acetate (0.86 g, 1.89 mmol) and platinum(IV) oxide (21 mg, 0.094 mmol). The tube was purged with nitrogen and then charged with ethanol (9.5 mL). The reaction vessel was charged with hydrogen (30 psi) and stirred at room temperature for 14 h. The reaction mixture was filtered through Celite, washing with EtOAc. The crude material was purified by column chromatography on silica gel eluting with 0-30% EtOAc in heptane to give ethyl 2-(3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propoxy)acetate (0.26 g, 0.57 mmol, 30% yield) as a colorless oil. m / z (ESI): 459.0 (M+H). + .

[0398] Intermediate R. 3-(but-3-en-1-yl)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol. [ka] Step 1. 2,2,2-Trifluoroacetic acid 3-(but-3-en-1-yl)piperidin-3-ol. To a 250 mL round-bottom flask were added magnesium turnings (0.73 g, 30.1 mmol), THF (150 mL), and 4-bromobut-1-ene (4.07 g, 30.1 mmol, CombiBlocks). The mixture was heated to 80 °C. After 2 h, the mixture was cooled to -78 °C, and a solution of tert-butyl 3-oxopiperidine-1-carboxylate (3.00 g, 15.1 mmol, CombiBlocks) in THF (10 mL) was added. The mixture was allowed to warm slowly to room temperature. After 1 h, the mixture was quenched with saturated NH4Cl, extracted with EtOAc, and concentrated. The resulting red oil was dissolved in DCM (100 mL), and TFA (11.6 mL, 151 mmol) was added. The mixture was stirred at 35° C. for 16 hours. Upon completion, the mixture was concentrated and purified by reverse phase chromatography to give 3-(but-3-en-1-yl)piperidin-3-ol 2,2,2-trifluoroacetate (1.24 g, 4.61 mmol, 31% yield) as an orange oil. m / z (ESI): 156.3 (M+H). + .

[0399] Step 2. 3-(But-3-en-1-yl)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol. To a round-bottom flask was added 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1.20 g, 4.75 mmol, Enamine) in acetonitrile (30 mL). The mixture was cooled to 0 °C, and 3-(but-3-en-1-yl)piperidin-3-ol 2,2,2-trifluoroacetate (1.28 g, 4.75 mmol) in MeCN (10 mL) was added, followed by N-ethyl-N-isopropylpropan-2-amine (2.48 mL, 14.3 mmol). The mixture was allowed to warm to room temperature over 20 minutes. ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (1.14 g, 7.13 mmol, LabNetwork) was added, and the mixture was heated to 80 °C for 16 hours. After cooling to room temperature, the mixture was concentrated, and the residue was purified by column chromatography on silica gel eluting with a gradient of 0 to 50% (3:1 EtOAc:EtOH, 2% TEA) in heptane to give 3-(but-3-en-1-yl)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (0.76 g, 1.54 mmol, 32% yield) as an orange solid. m / z(ESI):494.2(M+H) + .

[0400] Intermediate S: Methyl 4-(8-bromo-3,4-dihydroquinolin-1(2H)-yl)butanoate. [ka] A solution of 8-bromo-1,2,3,4-tetrahydroquinoline (1.25 mL, 5.89 mmol, Aurum Pharmatech LLC), 4-oxobutanoic acid methyl ester (1.37 g, 11.8 mmol, CombiBlocks Inc.), and acetic acid (0.14 mL, 2.36 mmol) in DCE (10 mL) was stirred at room temperature for 20 minutes. Sodium triacetoxyborohydride (1.50 g, 7.10 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 3.5 hours, then at 50° C. for 20 hours. The crude mixture was poured into ice-cold saturated sodium carbonate solution and extracted with 20% MeOH / DCM. The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0 to 50% EtOAc in heptane to give methyl 4-(8-bromo-3,4-dihydroquinolin-1(2H)-yl)butanoate (0.64 g, 2.03 mmol, 35% yield) as a colorless oil. 1 H NMR(chloroform-d,400MHz)δ 7.3-7.4(m,1H),6.98(dd,1H,J=1.0,7.5Hz),6.75(t,1H,J=7.6Hz),3.70(s,3H),3.1-3.2(m,2H),3.0-3.0(m,2H) ),2.79(t,2H,J=6.7Hz),2.42(t,2H,J=7.5Hz),2.1-2.2(m,2H),1.8-1.9(m,2H).m / z(ESI):312.2 and 314.2(M+H) + .

[0401] Intermediate T: tert-butyl 5-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate. [ka] Step 1: tert-Butyl 4-bromo-5-hydroxy-1H-indazole-1-carboxylate. To a 250 mL round-bottom flask was added 4-bromo-1H-indazol-5-ol (6.30 g, 29.6 mmol, Enamine) and triethylamine (12.5 mL, 89 mmol) in tetrahydrofuran (70 mL). A solution of di-tert-butyl dicarbonate (14.2 g, 65.1 mmol) in tetrahydrofuran (70 mL) was added slowly via syringe. After the addition was complete, 4-dimethylaminopyridine (0.18 g, 1.48 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and then cooled to 0° C. Lithium hydroxide monohydrate (7.45 g, 177 mmol) in water (30 mL) was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was slowly diluted with 2 M HCl (90 mL) at 0 °C to pH 6 and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0 to 40% [3:1 EtOAc:EtOH] in heptane to give tert-butyl 4-bromo-5-hydroxy-1H-indazole-1-carboxylate (3.80 g, 12.10 mmol, 41% yield) as an off-white solid. m / z (ESI): 257.1 (M- t Bu) + . 1 H NMR(400MHz,DMSO-d6)δ ppm 9.98-10.84(m,1H),8.21(d,J=0.6Hz,1H),7.91(d,J=8.9Hz,1H),7.27(d,J=8.8Hz,1H),1.65(s,9H).

[0402] Step 2: tert-Butyl 5-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate. A 20 mL vial was charged with tert-butyl 4-bromo-5-hydroxy-1H-indazole-1-carboxylate (0.86 g, 2.75 mmol), potassium acetate (0.54 mg, 5.49 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.98 g, 3.84 mmol), and Pd(dppf)Cl (0.16 g, 0.22 mmol) in 1,4-dioxane (10 mL). The reaction mixture was heated to 80 °C for 6 h. The crude mixture was cooled to room temperature and filtered through a Whatman PTFE 0.45 μm filter. The crude material was used directly in the next step without further purification.

[0403] Intermediate U: (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol. [ka] A 100 mL round-bottom flask was charged with 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (2.10 g, 5.90 mmol, Intermediate Z) and N-ethyl-N-isopropylpropan-2-amine (3.1 mL, 18 mmol) in DMF (29 mL). HATU (3.36 g, 8.8 mmol) was added in one portion, and the reaction mixture was stirred at room temperature for 30 minutes. Next, (R)-3-methylpiperidin-3-ol hydrochloride (0.98 g, 6.5 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride. The aqueous layer was extracted with EtOAc, and the combined organics were washed with brine, dried, and concentrated. The crude material was purified by column chromatography on silica gel eluting with 0-100% 3:1 (EtOAc:EtOH with 2% triethylamine) in heptane to give (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (2.60 g, 5.80 mmol, 98% yield) as a brown solid. m / z (ESI): 455.0 (M+H). + .

[0404] Intermediate V: (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(fluoromethyl)piperidin-3-ol. [ka] A 100 mL round-bottom flask was charged with 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (3.00 g, 8.41 mmol, Intermediate Z) and N-ethyl-N-isopropylpropan-2-amine (4.4 mL, 25.2 mmol) in DMF (34 mL). HATU (4.80 g, 12.60 mmol) was added, and the reaction mixture was stirred at room temperature for 20 minutes. Next, (R)-3-(fluoromethyl)piperidin-3-ol (1.23 g, 9.25 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 16 hours. The mixture was partitioned between acetic acid and brine. The aqueous layer was extracted with EtOAc, and the combined organics were washed with brine, dried, and concentrated. The crude material was purified by column chromatography on silica gel eluting with 0-100% 3:1 (EtOAc:EtOH with 2% triethylamine) in heptane to give (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(fluoromethyl)piperidin-3-ol (2.71 g, 5.74 mmol, 68% yield) as an orange solid. m / z (ESI): 472.0 (M+H). + .

[0405] Intermediate W: (R)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(tributylstannyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol. [ka] Step 1. (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol. To a suspension of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.00 g, 7.92 mmol, Enamine) in acetonitrile (22.5 mL) was added (3R)-piperidin-3-ol (0.80 g, 7.92 mmol, CombiBlocks Inc.) and DIPED (6.9 mL, 39.6 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 40 minutes. The desired intermediate (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol was observed via LDMS (m / z(ESI): 317.2 (M+H) + ). A solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (2.27 g, 14.3 mmol, BLD Pharmatech) in acetonitrile (2 mL) was added, and the reaction mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0 to 75% (3:1 EtOAc:EtOH with 2% triethylamine) in heptane to give (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (2.45 g, 5.57 mmol, 70% yield) as a yellow solid. m / z(ESI):440.0(M+H) + .

[0406] Step 2. (R)-1-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(tributylstannyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol. A 40 mL vial was charged with (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (1.00 g, 2.27 mmol), LiCl (0.48 g, 11.4 mmol), and 1,4-dioxane (8.5 mL). The solution was degassed by bubbling with nitrogen for 15 minutes. [2-(2-aminophenyl)phenyl]-chloro-palladium tricyclohexylphosphane (0.54 g, 0.91 mmol) and bis(tributyltin) (3.4 mL, 6.82 mmol) were added and the reaction was sealed and heated to 100° C. for 15 h. After cooling to room temperature, the mixture was filtered through Celite and washed with EtOAc. The filtrate was concentrated and the crude material was purified by column chromatography on silica gel eluting with a gradient of 0-100% (3:1 EtOAc:EtOH with 2% triethylamine) in heptane to give (R)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(tributylstannyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (0.85 g, 1.22 mmol, 54% yield) as a yellow semi-solid. m / z (ESI): 696.0 (M+H). + .

[0407] Intermediate X: 7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-ol. [ka] Step 1. 7-Bromo-2-chloro-6,8-difluoro-4-(piperidin-1-yl)quinazoline. To a solution of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (50.0 g, 159 mmol) in acetonitrile (800 mL) was added piperidine (15.8 mL, 159 mmol) and DIPED (55.6 mL, 319 mmol) in small portions at 0° C. The mixture was stirred at 0° C. for 30 minutes and then concentrated under reduced pressure. The crude product was triturated with petroleum ether (100 mL) at 20° C. for 1 hour. The suspension was filtered, and the filter cake was washed with petroleum ether and dried under vacuum to give 7-bromo-2-chloro-6,8-difluoro-4-(piperidin-1-yl)quinazoline (52.6 g, 145 mmol, 91% yield) as a yellow solid. m / z(ESI):362.1 / 364.1(M+H) + .

[0408] Step 2. 7-Bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperidin-1-yl)quinazoline. To a solution of 7-bromo-2-chloro-6,8-difluoro-4-(piperidin-1-yl)quinazoline (55.0 g, 152 mmol) in THF (550 mL) and DMF (550 mL) was added, in sequence, ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (29.0 g, 182 mmol, LabNetwork), CsCO (59.3 g, 182 mmol), and DABCO (5.10 g, 45.5 mmol). The reaction mixture was stirred at 25° C. for 10 hours, then diluted with HO and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The crude product was triturated with MTBE (80 mL) at 20° C. for 1 hour. The suspension was filtered, and the filter cake was washed with MTBE and dried in vacuo to give 7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperidin-1-yl)quinazoline (41.3 g, 85 mmol, 56% yield) as a white solid. m / z (ESI): 485.1 / 487.1 (M+H). + .

[0409] Step 3. 7-Bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-ol. To a solution of 7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperidin-1-yl)quinazoline (50.0 g, 103 mmol) in methanol (1 L) and water (500 mL) was added LiOH hydrate (15.14 g, 361 mmol). The reaction mixture was stirred at 100° C. for 10 hours. This procedure was repeated three more times on this scale.

[0410] After cooling to room temperature, the reaction mixtures were combined and concentrated under reduced pressure, and the residue was then diluted with HO and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The crude product was triturated with a mixture of petroleum ether and EtOAc (1:1, 200 mL) at room temperature for 30 minutes. The suspension was filtered, and the filter cake was washed with a mixture of petroleum ether and EtOAc (1:1) and dried under vacuum to give 7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-ol (150 g, 358 mmol, 87% yield) as a white solid. m / z (ESI): 418.0 / 420.0 (M+H). + .

[0411] Intermediate Y: 7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-ol hydrobromide. [ka] Step 1. 4-(Benzyloxy)-7-bromo-2-chloro-8-fluoroquinazoline. A solution of 7-bromo-2,4-dichloro-8-fluoroquinazoline (50.0 g, 169 mmol) in tetrahydrofuran (2 L) was treated with 4 Å molecular sieves (30 g) and then cooled to −60° C. A solution of t-BuOK (1 M in THF, 161 mL, 161 mmol) and phenylmethanol (16.6 mL, 161 mmol) pre-reacted at −60° C. was added dropwise. The mixture was stirred at −60° C. for 2 h. This procedure was repeated three more times on this scale.

[0412] The reaction mixtures were combined and poured into water, followed by extraction with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was triturated with petroleum ether (800 mL) at 20°C for 50 minutes. The suspension was filtered, and the filter cake was washed with petroleum ether and dried under vacuum to give 4-(benzyloxy)-7-bromo-2-chloro-8-fluoroquinazoline (220 g, 589 mmol, 88% yield) as a yellow solid. m / z (ESI): 367.1 / 369.1 (M+H). + .

[0413] Step 2. 4-(Benzyloxy)-7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline. To a solution of 4-(benzyloxy)-7-bromo-2-chloro-8-fluoroquinazoline (70 g, 190 mmol) and 4 Å molecular sieves (30 g) in 1,4-dioxane (700 mL) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (42.4 g, 267 mmol) and DIPED (700 mL) in sequence. The mixture was stirred at 120 °C for 12 h. This procedure was repeated two more times on a similar scale.

[0414] After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was triturated with MTBE (800 mL) at 20 °C for 30 min. The suspension was filtered, and the filter cake was washed with MTBE and dried under vacuum to give 4-(benzyloxy)-7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline (115 g, 235 mmol, 41% yield) as a yellow solid. m / z (ESI): 490.3 / 492.2 (M+H). + .

[0415] Step 3. 7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-ol hydrobromide. 4-(benzyloxy)-7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline (35.0 g, 71.4 mmol) in 33% HBr in AcOH (33% solution, 250 mL, 71.4 mmol) was stirred at room temperature for 4 hours. This procedure was repeated two more times on a similar scale.

[0416] The reaction mixture was diluted with EtOAc, and the suspension was filtered. The filter cake was triturated with EtOAc (100 mL) at room temperature for 20 minutes. The suspension was filtered, and the filter cake was washed with EtOAc and dried under vacuum to give 7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-ol hydrobromide (105 g, 219 mmol, HBr salt) as a white solid. m / z (ESI): 400.1 / 402.1 (M+H). + .

[0417] Intermediate Z: 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol hydrobromide. [ka] The title compound was synthesized in a similar manner to intermediate Y using 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (CAS#: 2454396-80-4, Enamine) in step 1. m / z(ESI):357.2(M+H) + .

[0418] Intermediate AA: ethyl 4-(2-fluoro-8-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-(methoxymethoxy)naphthalen-1-yl)butanoate. [ka] Step 1. 2,7-Dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine. To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (50.0 g, 198 mmol, Enamine) in tetrahydrofuran (750 mL) cooled to −60° C., 2,2,2-trifluoroethan-1-ol (18.82 g, 188 mmol) was added, followed by dropwise addition of t-BuOK (1 M in THF, 188 mL, 188 mmol). The mixture was stirred at −60° C. for 2 hours. The reaction mixture was quenched by the addition of HO (1 L) at 20° C. and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was washed with petroleum ether (50 mL) and subsequently filtered. The filter cake was concentrated under reduced pressure to give 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (50 g, 158 mmol, 84% yield) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ ppm 9.18 (s, 1H), 5.06-5.12 (m, 2H).

[0419] Step 2. 7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine. To a solution of 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (28 g, 89 mmol) in 1,4-dioxane (280 mL) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (16.93 g, 106 mmol) and DIPEA (46.4 mL, 266 mmol) in sequence. The mixture was then stirred at 80° C. for 10 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with a gradient of 5-100% EtOAc in petroleum ether to give 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (28 g, 63.8 mmol, 72% yield) as a yellow solid. m / z (ESI): 439.1 / 441.1 (M+H). + .

[0420] Step 3. Ethyl 4-(2-fluoro-8-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-(methoxymethoxy)naphthalen-1-yl)butanoate. A mixture of ethyl 4-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate (1.12 g, 2.51 mmol, Intermediate D), 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.00 g, 2.28 mmol), cataCXium A Pd G (0.15 g, 0.23 mmol), and CsCO (1.86 g, 5.70 mmol) in 1,2-dimethoxyethane (10 mL) and water (2 mL) was degassed and purged with nitrogen. The reaction mixture was heated at 100 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with a gradient of 5 to 100% ethyl acetate in petroleum ether to give ethyl 4-(2-fluoro-8-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-(methoxymethoxy)naphthalen-1-yl)butanoate (0.56 g, 0.77 mmol, 34% yield) as a yellow solid. m / z (ESI): 725.3 / 723.2 (M+H). + .

[0421] Intermediate BB: ethyl 4-(2-fluoro-8-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-1-yl)butanoate. [ka] Synthesized in a similar manner to Intermediate AA using ethyl 4-(2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate (Intermediate G) as the boronic acid in step 3. m / z (ESI): 663.2 (M+H) + .

[0422] Intermediate CC: Methyl 5-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)pentanoate. [ka] Step 1. 5-(2-Fluoro-8-iodo-6-(methoxymethoxy)naphthalen-1-yl)pent-4-yn-1-ol. To a solution of 1-ethynyl-2-fluoro-8-iodo-6-(methoxymethoxy)naphthalene (5.5 g, 15.4 mmol, Lab Network) in tetrahydrofuran (60 mL) was added lithium bis(trimethylsilyl)amide (1 M in THF, 46.5 mL, 46.5 mmol), and the reaction mixture was stirred at −78° C. for 30 minutes under N. BF OEt (3.0 mL, 24 mmol) was added and stirred for 30 minutes. After stirring, oxetane (2.5 g, 43 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with aqueous NH Cl and extracted with EtOAc. The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 1–20% EtOAc in petroleum ether to give 5-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-1-yl)pent-4-yn-1-ol (1.80 g, 4.40 mmol, 28% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.05(d,J=2.3Hz,1H),7.89(dd,J=6.1,9.0Hz,1H),7.62(d,J=2.5Hz,1H),7.51(t,J=8.8Hz,1H),5.31( s,2H),4.56(t,J=5.2Hz,1H),3.50-3.65(m,3H),3.42(s,3H),2.62(t,J=7.1Hz,2H),1.70-1.90(m,3H).

[0423] Step 2. 5-(2-Fluoro-8-iodo-6-(methoxymethoxy)naphthalen-1-yl)pent-4-ynal. To a solution of 5-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-1-yl)pent-4-yn-1-ol (1.70 g, 4.10 mmol) in acetonitrile (20 mL) was added 2-iodoxybenzoic acid (5.75 g, 20.5 mmol). The reaction mixture was stirred at 70° C. for 0.5 h. Water was added and the mixture was extracted with EtOAc. The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with 0–10% EtOAc in petroleum ether to give 5-(2-fluoro-8-iod-6-(methoxymethoxy)naphthalen-1-yl)pent-4-ynal (1.70 g, 4.10 mmol, 100% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 9.75-9.78(m,1H),8.04(d,J=2.5Hz,1H),7.80-7.90(m,1H),7.61(d,J=2.6 Hz,1H),7.50(t,J=8.8Hz,1H),5.30(s,2H),3.42(s,3H),2.80-2.91(m,4H).

[0424] Step 3. Methyl 5-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-1-yl)pent-4-ynoate. To a solution of 5-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-1-yl)pent-4-ynal (1.70 g, 4.10 mmol) in methanol (20 mL) was added K2CO3 (1.43 g, 10.3 mmol) and NIS (2.32 g, 10.3 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 0–20% EtOAc in petroleum ether to give methyl 5-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-1-yl)pent-4-ynoate (1.70 g, 3.10 mmol, 75% yield) as a pale yellow solid.1 H NMR(400MHz,DMSO-d6)δ ppm 8.03(s,1H),7.89(dd,J=6.3,9.0Hz,1H),7.61(d,J=2.5Hz,1H),7.50(t,J=8.9Hz, 1H),5.30(s,2H),3.64(s,3H),3.41(s,3H),2.80-2.85(m,2H),2.70-2.76(m,2H).

[0425] Step 4. Methyl 5-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)pent-4-ynoate. To a solution of methyl 5-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-1-yl)pent-4-ynoate (1.40 g, 3.20 mmol) in tetrahydrofuran (15 mL) was added isopropylmagnesium chloride / lithium chloride (4.9 mL, 6.3 mmol) dropwise at −78° C. The reaction mixture was stirred at −78° C. for 0.5 hours. Then, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.95 g, 15.8 mmol) was added. The mixture was stirred at 0° C. for 1 hour. The reaction mixture was quenched at 0 °C by the addition of aqueous NH4Cl and subsequently diluted with EtOAc. The mixture was extracted with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with 0–10% EtOAc in petroleum ether to give methyl 5-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)pent-4-ynoate (0.70 g, 1.58 mmol, 50% yield) as a yellow solid.

[0426] Step 5. Methyl 5-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)pentanoate. To a solution of methyl 5-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)pent-4-ynoate (0.70 g, 1.58 mmol) in methanol (10 mL) was added Pd / C (0.40 g, 3.17 mmol) under argon. The suspension was degassed and purged with H twice. The mixture was stirred under H (15 psi) at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 0–20% EtOAc in petroleum ether to give methyl 5-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)pentanoate (0.65 g, 1.46 mmol, 92% yield) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ ppm 7.77(dd,J=6.1,8.9Hz,1H),7.53(d,J=2.5Hz,1H),7.37(t,J=9.3Hz,1H),7.29(d,J=2.5Hz,1H),5.30(s, 2H),3.53(s,3H),3.41(s,3H),3.02-3.11(m,2H),2.25(t,J=6.9Hz,2H),1.44-1.56(m,4H),1.38(s,12H).

[0427] Intermediate DD: Ethyl 2-fluoro-5-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)pentanoate. [ka] A solution of NaHMDS (1 M in THF, 2.5 mL, 2.5 mmol) was cooled to −78° C. Next, ethyl 5-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)pentanoate (0.99 g, 2.10 mmol, Intermediate J) dissolved in 3 mL of THF was added to the solution. The solution was stirred at −78° C. for 30 minutes, followed by the slow addition of NFSI (0.93 g, 2.94 mmol) dissolved in 2 mL of THF over 15 minutes. The mixture was allowed to slowly warm to room temperature with stirring for 16 hours. The reaction was then cooled to −78° C., and MeOH (3 mL) was added. The volatiles were removed in vacuo and the residue was purified by reverse-phase column chromatography (10-100% MeCN / HO + 0.1% TFA) to give ethyl 2-fluoro-5-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)pentanoate (0.49 g, 0.99 mmol, 47% yield). m / z (ESI): (M+H) + 489.2.

[0428] Intermediate EE: tert-butyl ((S)-4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)carbamate. [ka] A 40 mL vial was charged with 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (2.00 g, 4.56 mmol, Intermediate AA, Step 2), tert-butyl (S)-(1,4-oxazepan-6-yl)carbamate (1.7 mL, 9.12 mmol, Enamine), DIPEA (3.2 mL, 18 mmol), and N,N-dimethylformamide (20 mL). The reaction was stirred at room temperature for 1 h. Water and DCM were then added. The organic layer was separated, dried (NaSO), and concentrated. The residue was purified by column chromatography on silica gel eluting with 0-85% 3:1 EtOAc / EtOH in heptane (with 2% triethylamine) to give tert-butyl ((S)-4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)carbamate (1.40 g, 3.10 mmol, 68% yield). m / z (ESI): 456.0 (M+H). + .

[0429] Intermediate FF: tert-butyl ((R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-yl)carbamate. [ka] Synthesized in a similar manner to Intermediate EE using (R)-tert-butyl azepan-3-ylcarbamate (CAS#: 1354351-56-6, Ambeed, Inc.). 553.0 (M+H) + .

[0430] Intermediate GG: tert-butyl 6-(7-chloro-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]nonane-2-carboxylate. [ka] Synthesized in a similar manner to Intermediate V using tert-butyl 2,6-diazaspiro[3.5]nonane-2-carboxylate (CAS#: 1086394-57-1, Enamine). m / z (ESI): 564.9 (M+H). + .

[0431] Intermediate HH: tert-butyl 5-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)octahydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate. [ka] Synthesized in a similar manner to Intermediate EE using tert-butyl hexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate hydrochloride (CAS#: 236406-56-7, eNovation Chemicals LLC). m / z (ESI): 565.0 (M+H). + .

[0432] Intermediate II: Ethyl 5-(2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pentanoate. [ka] Step 1. Ethyl (2E,4E)-5-(2-bromo-6-chlorophenyl)penta-2,4-dienoate. To a solution of LDA (2 M in THF, 8.8 mL, 17.7 mmol) in THF (80 mL) was added ethyl (E)-4-(diethoxyphosphoryl)but-2-enoate (4.79 g, 19.1 mmol) in tetrahydrofuran (50 mL) at −78° C. under N. The mixture was stirred at −78° C. for 0.5 h, followed by the addition of a solution of 2-bromo-6-chlorobenzaldehyde (3.23 g, 14.7 mmol) in THF (30 mL) via syringe. The mixture was stirred at 0° C. for 2 h, followed by quenching with HO and extraction with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 0-100% EtOAc in petroleum ether to give ethyl (2E,4E)-5-(2-bromo-6-chlorophenyl)penta-2,4-dienoate (3.93 g, 12.5 mmol, 85% yield) as a yellow solid. 1 H NMR((400MHz,CDCl3)δ ppm 7.54(d,J=8.40Hz,1H),7.42-7.50(m,1H),7.35-7.40(m,1H),7.02-7.10(m,1H),6.85-6.95(m,2H) ,6.05(d,J=8.40Hz,1H),4.20-4.30(m,2H),1.30-1.35(t,J=7.20Hz,3H).m / z(ESI):315 / 317(M+H) + .

[0433] Step 2. Ethyl (2E,4E)-5-(2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)penta-2,4-dienoate. To a solution of ethyl (2E,4E)-5-(2-bromo-6-chlorophenyl)penta-2,4-dienoate (3.93 g, 12.5 mmol) in 1,4-dioxane (40 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (9.49 g, 37.4 mmol), KOAc (4.28 g, 43.6 mmol), and Pd(dppf)Cl (91 mg, 0.13 mmol). The mixture was stirred at 120 °C for 12 h and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 5-20% EtOAc in petroleum ether to give ethyl (2E,4E)-5-(2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)penta-2,4-dienoate (2.36 g, 10 mmol, 83% yield) as a colorless oil. m / z (ESI): 236.2 (M-BPin). + .

[0434] Step 3. Ethyl 5-(2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pentanoate. To a solution of platinum(IV) oxide (0.19 g, 0.83 mmol) in ethanol (30 mL) was added ethyl (2E,4E)-5-(2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)penta-2,4-dienoate (1.95 g, 8.27 mmol) under argon. The suspension was purged with H and then stirred under H (15 psi) at room temperature for 2 h. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 5-20% EtOAc in petroleum ether to give ethyl 5-(2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pentanoate (0.78 g, 3.3 mmol, 40% yield) as a colorless oil. m / z (ESI): 240.2 (M-BPin).+ .

[0435] Intermediate JJ: 4-(tert-butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)yl)methoxy)pyrido[4,3-d]pyrimidine. [ka] Step 1. To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (50.0 g, 198 mmol, Enamine) in tetrahydrofuran (1.5 L) was added dropwise t-BuOK (1 M in THF, 190 mL, 190 mmol) at −60° C., and the reaction mixture was stirred at −60° C. for 2 hours. The mixture was diluted with EtOAc and water and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The crude product was triturated with petroleum ether at room temperature for 1 hour. The suspension was filtered, and the mass was concentrated under reduced pressure to give 4-(tert-butoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (30 g, 103 mmol, 54% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm 9.08(s,1H),1.74(s,9H).

[0436] 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. To a solution of 4-(tert-butoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (50.0 g, 172 mmol) and 4Å MS (10 g) in 1,4-dioxane (1 L) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (30.2 g, 190 mmol) and DIPEA (60.0 g, 431 mmol) in sequence. The mixture was then stirred at 80 °C for 5 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was triturated with MTBE at room temperature for 1 hour. The suspension was filtered, and the mass was concentrated under reduced pressure 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 (40 g, 97 mmol, 56% yield) as a yellow solid. m / z (ESI): 413.2 / 415.2 (M+H) + .

[0437] Intermediate KK: 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(tributylstannyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine. [ka] Step 1. 2,7-Dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine. To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (40.0 g, 158 mmol, Enamine) in tetrahydrofuran (600 mL) was added dropwise a mixture of 2,2,2-trifluoroethan-1-ol (15.1 g, 151 mmol) and t-BuOK (1 M in THF, 151 mL, 151 mmol) at −60° C. The reaction mixture was stirred at −60° C. for 2 hours, then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The crude product was triturated with petroleum ether at room temperature for 30 minutes. The suspension was filtered and the filter cake was concentrated under reduced pressure to give 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (46 g, 145 mmol, 96% yield) as a white solid.

[0438] Step 2. 7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine. To a solution of 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (40 g, 127 mmol) in 1,4-dioxane (400 mL) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (24.2 g, 152 mmol) and DIPEA (55.3 mL, 316 mmol) in sequence. The reaction mixture was stirred at 65° C. for 1.5 hours. After cooling to room temperature, the mixture was diluted with water and subsequently extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was triturated with a mixed solvent (petroleum ether / EtOAc = 2 / 1) at room temperature for 3 hours. The suspension was filtered, and the filter cake was concentrated under reduced pressure to give 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (41 g, 93.4 mmol, 74% yield) as a white solid.

[0439] Step 3: 8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(tributylstannyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine. To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (10.0 g, 22.8 mmol) in 1,4-dioxane (200 mL) was added PCyPd G (5.38 g, 9.12 mmol) and LiCl (4.83 g, 114 mmol), followed by bis(tri-n-butyltin) (39.7 g, 68.4 mmol) in one portion under N. The mixture was stirred at 80 °C under a nitrogen atmosphere for 12 h. The suspension was filtered, and the filter cake was washed with EtOAc. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of 0-100% EtOAc in petroleum ether. The crude product was triturated with DMSO at room temperature for 1 hour. The suspension was filtered, and the filter cake was concentrated under reduced pressure to give 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(tributylstannyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (2.68 g, 3.87 mmol, 17% yield) as a white solid. m / z (ESI): 695.3 / 693.3 (M+H). + .

[0440] Intermediate LL: methyl 5-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)pentanoate. [ka] Step 1. Methyl (E)-4-(diethoxyphosphoryl)but-2-enoate. A 3 L round-bottom flask was charged with methyl (E)-4-bromobut-2-enoate (150 g, 838 mmol). The contents were heated to 120 °C, and triethyl phosphite (167 g, 1.00 mol) was added dropwise. The resulting mixture was stirred at 120 °C for 4 hours under a N atmosphere. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure. The crude product, methyl (E)-4-(diethoxyphosphoryl)but-2-enoate (150 g), as a yellow oil, was used in the next step without further purification.

[0441] Step 2. Methyl (2E,4E)-5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)penta-2,4-dienoate. To a solution of LDA (2 M in THF, 175 mL, 350 mmol) in tetrahydrofuran (360 mL) was added dropwise a solution of methyl (E)-4-(diethoxyphosphoryl)but-2-enoate (82.0 g, 349 mmol) in tetrahydrofuran (600 mL) at −78° C. under N. The reaction mixture was stirred at −78° C. for 30 minutes, followed by the dropwise addition of a solution of 4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carbaldehyde (100 g, 291 mmol, Intermediate ZZZ) in tetrahydrofuran (600 mL) at −78° C. The mixture was then stirred at 0° C. for 1.5 hours. The mixture was quenched at 0° C. by the addition of water, followed by extraction with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of 0 to 100% EtOAc in petroleum ether to give methyl (2E,4E)-5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)penta-2,4-dienoate (91 g, 214 mmol, 73% yield) as a white solid.

[0442] Step 3. Methyl 5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoate. In a hydrogenation reactor, PtO (7.47 g, 32.9 mmol) in tetrahydrofuran (1.4 L) was charged. Methyl (2E,4E)-5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)penta-2,4-dienoate (70 g, 164 mmol) was added under argon, and the suspension was degassed and purged with H three times. The mixture was hydrogenated under H (15 psi) at room temperature for 72 hours. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of 2-100% EtOAc in petroleum ether to give methyl 5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoate (37.5 g, 87 mmol, 53% yield) as a white solid. m / z (ESI): 429.1 / 431.1 (M+H). + .

[0443] Step 4. Methyl 5-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)pentanoate. To a solution of methyl 5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoate (25 g, 58.2 mmol) in 1,4-dioxane (250 mL) was added bis(pinacolato)diboron (44.3 g, 175 mmol) and CsCO (56.9 g, 175 mmol) under nitrogen. Pd(dppf)Cl (4.26 g, 5.82 mmol) was added and the reaction mixture was stirred at 120 °C for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of 10-35% EtOAc in petroleum ether to give methyl 5-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)pentanoate (12 g, 25 mmol, 43% yield) as a white solid. m / z (ESI): 477.2 (M+H). + .

[0444] Intermediate MM: 5-(6-chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoic acid. [ka] Step 1. Methyl 5-(6-chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoate. To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (0.50 g, 1.14 mmol, Step 2 in Intermediate AA) and methyl 5-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)pentanoate (0.56 g, 1.17 mmol, Intermediate LL) in THF (8 mL) and water (1 mL) was added KPO (0.73 g, 3.42 mmol) and CataCXium A Pd G3 (83 mg, 0.13 mmol) was added in turn under N. The mixture was then stirred at 80 °C for 3 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with a gradient of 0–50% EtOAc in petroleum ether to give methyl 5-(6-chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoate (0.47 g, 0.63 mmol, 55% yield) as a colorless oil.

[0445] Step 2. 5-(6-chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoic acid. To a solution of methyl 5-(6-chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoate (0.47 g, 0.62 mmol) in THF (8 mL) and water (1.6 mL) was added LiOH.HO (0.26 g, 2.45 mmol). The mixture was stirred at 60 °C for 5 h. After cooling to room temperature, the reaction was adjusted to pH 5 with 1 N HCl, and the mixture was then extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The crude product was triturated with a mixed solvent (EtOAc / EtOH=5:1) at room temperature for 30 minutes. The suspension was filtered, and the filter cake was concentrated under reduced pressure to give 5-(6-chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoic acid (0.15 g, 0.23 mmol, 37% yield) as a yellow solid. m / z (ESI): 657.2 / 659.2 (M+H). + .

[0446] Intermediate NN: 5-(4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin7a(5H)-yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoic acid. [ka] Step 1. Ethyl 5-(4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoate. To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (20 g, 45.6 mmol, Intermediate AA, Step 2) and ethyl 5-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)pentanoate (23.6 g, 50.1 mmol, Intermediate J) in tetrahydrofuran (400 mL) and water (10 mL) was added KPO (29.0 g, 137 mmol) and cataCXium A Pd G3 (3.32 g, 4.56 mmol) was added under N. The reaction mixture was stirred at 80 °C for 10 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of 10 to 100% EtOAc in petroleum ether to give ethyl 5-(4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoate (20 g, 26.8 mmol, 59% yield) as a yellow solid. m / z(ESI):747.4(M+H) + .

[0447] Step 2. 5-(4-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoic acid. To a solution of ethyl 5-(4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoate (11.0 g, 14.7 mmol) in tetrahydrofuran (220 mL) and water (44 mL) was added LiOH.HO (2.48 g, 58.9 mmol). The reaction mixture was stirred at 60 °C for 5 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The aqueous layer was neutralized to pH 5 using 1 M HCl, and the resulting suspension was filtered. The filter cake was washed with HO and concentrated under reduced pressure to give 5-(4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoic acid (5.00 g, 7.85 mmol, 53% yield) as a yellow solid. m / z (ESI): 637.4 (M+H). + .

[0448] Intermediate OO: 3,6,8-trichloropyrimido[5,4-c]pyridazine. [ka] Step 1. 4-Amino-6-chloro-pyridazine-3-carboxamide. A solution of methyl 4,6-dichloropyridazine-3-carboxylate (50.0 g, 242 mmol) in NH3-MeOH (7 M, 500 mL, 14.5 equiv.) was stirred at 100 °C for 12 hours in a 2 L sealed tube. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was triturated with a mixed solvent (petroleum ether: ethyl acetate = 3:1) at room temperature for 1 hour. The suspension was filtered, and the filter cake was washed with petroleum ether and dried to give 4-amino-6-chloro-pyridazine-3-carboxamide (50 g, crude) as a yellow solid. m / z (ESI): 173.0 / 175.0 (M+H). + .

[0449] Step 2. 3-Chloro-5H-pyrimido[5,4-c]pyridazine-6,8-dione. To a mixture of 4-amino-6-chloro-pyridazine-3-carboxamide (55.0 g, 319 mmol) in EtOH (660 mL) was added dimethyl carbonate (143.5 g, 1.59 mol) and EtONa (108 g, 1.59 mol). The reaction mixture was stirred at 80 °C for 5 h. After cooling to room temperature, the reaction mixture was adjusted to pH 6 by the addition of 1 M HCl to give a suspension. It was filtered, and the filter cake was concentrated under reduced pressure. The crude product was triturated with EtOAc at room temperature for 1 h. The mixture was then filtered, and the filter cake was washed with EtOAc and dried to give 3-chloro-5H-pyrimido[5,4-c]pyridazine-6,8-dione (40.0 g, 201 mmol, 63% yield) as a yellow solid. m / z(ESI):196.9(M+H) + .

[0450] Step 3. 3,6,8-Trichloropyrimido[5,4-c]pyridazine. To a mixture of 3-chloro-5H-pyrimido[5,4-c]pyridazine-6,8-dione (34.5 g, 174 mmol) in dioxane (350 mL), POCl3 (81 mL, 869 mmol) was added dropwise, followed by DIPEA (91 mL, 521 mmol). The reaction mixture was stirred at 100 °C for 3 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of 0 to 100% EtOAc in petroleum ether to give 3,6,8-trichloropyrimido[5,4-c]pyridazine (8.50 g, 36.2 mmol, 21% yield) as a white solid. m / z (ESI): 337.0 / 339.0 (quenched with morpholine, M+2 morpholine + H) + .

[0451] Intermediate PP: 1-(3-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)propyl)(3aS,7aR)-hexahydro-1H-pyrrolo[2,3-c]pyridine-1,6(2H)-dicarboxylate rac-6-(tert-butyl). [ka] To a 100 mL round-bottom flask was added 5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (0.33 g, 0.65 mmol, Intermediate K) in a mixture of water (5 mL) and 2,2,2-trifluoroacetic acid (0.1% in acetonitrile) (22.5 mL, 0.197 mmol). The mixture was stirred at room temperature for 1 h and immediately quenched with saturated NaHCO solution under vigorous stirring. The mixture was stirred at room temperature for an additional 10 min, then diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated NaCl solution, dried over NaSO, and concentrated. To the crude material was added dichloromethane (3 mL), followed by triethylamine (0.17 mL, 1.3 mmol). The mixture was cooled to 0° C., 4-nitrophenyl carbonochloridate (0.13 g, 0.65 mmol) was added, and the mixture was stirred at room temperature for 2 hours. cis-1,2,3,3a,4,5,7,7a-octahydropyrrolo[2,3-c]pyridine-6-carboxylate rac-tert-butyl ester (0.44 g, 1.95 mmol, Angel Pharmatech Ltd.) in N,N-dimethylformamide (0.5 mL) was added, and the mixture was warmed to 40° C. for 1 hour. After cooling to room temperature, the crude material was concentrated and purified by column chromatography on silica gel eluting with 0-50% EtOAc in heptane to give rac-6-(tert-butyl) 1-(3-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)propyl)(3aS,7aR)-hexahydro-1H-pyrrolo[2,3-c]pyridine-1,6(2H)-dicarboxylate (0.27 g, 0.42 mmol, 64% yield) as a white solid. m / z (ESI): 653.2 (M+H). + .

[0452] Intermediate QQ: (R)-tert-butyl 3-(((2-(2-fluoro-8-iodonaphthalen-1-yl)ethoxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate. [ka] Step 1. 1-Ethynyl-2-fluoro-8-iodonaphthalene. To a solution of ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (15.0 g, 33.1 mmol, LabNetwork Inc.) in DMF (200 mL) and toluene (100 mL) was added CuI (9.47 g, 49.7 mmol), followed by NIS (8.95 g, 39.8 mmol). The reaction mixture was stirred at 110 °C for 4 h, cooled to room temperature, and then quenched with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give ((2-fluoro-8-iodonaphthalen-1-yl)ethynyl)trimethylsilane (20 g) as a brown solid, which was used in the next step without purification. To the above crude brown solid dissolved in N,N-dimethylacetamide (100 mL) was added CsF (30.0 g, 197 mmol). The mixture was stirred at 80 °C for 2 hours and then cooled to room temperature. Water was added, and the mixture was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with 100% petroleum ether to give 1-ethynyl-2-fluoro-8-iodonaphthalene (5.90 g, 19.9 mmol, 45% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.35(d,J=7.4Hz,1H),8.03-8.12(m,2H),7.61(t,J=8.8Hz,1H),7.23(t,J=8.0Hz,1H),5.07(d,J=1.2Hz,1H).m / z(ESI):296.6(M+H) + .

[0453] Step 2. 2-Fluoro-8-iodo-1-vinylnaphthalene. To a suspension of bis(cyclopentadienyl)zirconium chloride hydride (5.23 g, 20.3 mmol) in dichloromethane (60 mL) was added dropwise 1-ethynyl-2-fluoro-8-iodonaphthalene (3.00 g, 10.1 mmol) in dichloromethane (2 mL) with stirring at 0 °C. The reaction mixture was then stirred at 15 °C for 20 h. The reaction was quenched with water and extracted with EtOAc. The combined organic phase was washed with brine, dried (Na SO ), filtered, and concentrated. The reaction was repeated twice. The residue was purified by column chromatography on silica gel eluting with 100% petroleum ether to give 2-fluoro-8-iodo-1-vinylnaphthalene (3.53 g, 11.8 mmol, 58% yield) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.32(d,J=7.2Hz,1H),8.00-8.05(m,2H),7.50-7.55(m,2H),7.18(t,J=8.0Hz, 1H),5.73(d,J=1.2Hz,1H),5.40-5.50(t,J=17.6Hz,1H).m / z(ESI):298.6(M+H) + .

[0454] Step 3. 2-(2-Fluoro-8-iodonaphthalen-1-yl)ethan-1-ol. To a solution of 2-fluoro-8-iodo-1-vinylnaphthalene (7.20 g, 24.2 mmol) in THF (60 mL) was added BH3-Me2S (10 M in THF solution, 12.1 mL, 121 mmol) at room temperature. The mixture was stirred for 12 h and then treated with HO (24.7 mL, 242 mmol) and NaOH (121 mL of a 1 M solution). After stirring for 12 h, the reaction mixture was diluted with saturated Na2SO3 and extracted with EtOAc. The combined organic phase was washed with brine, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with 20-50% EtOAc in petroleum ether to give 2-(2-fluoro-8-iodonaphthalen-1-yl)ethan-1-ol (1.44 g, 4.56 mmol, 19% yield) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ ppm 8.36(d,J=7.3Hz,1H),8.01(d,J=8.0Hz,1H),7.90-7.95(m,1H),7.49(t,J=9.20Hz,1H ),7.13(t,J=7.60Hz,1H),4.79-4.85(m,1H),3.76-3.67(m,4H).m / z(ESI):316.6(M+H) + .

[0455] Step 4. 2-(2-Fluoro-8-iodonaphthalen-1-yl)ethyl(4-nitrophenyl)carbonate. To a solution of 4-nitrophenyl carbonochloridate (0.61 g, 3.04 mmol) and 2-(2-fluoro-8-iodonaphthalen-1-yl)ethan-1-ol (0.96 g, 3.04 mmol) in dichloromethane (10 mL) was added TEA (0.85 mL, 6.1 mmol) at 0 °C. The mixture was stirred at room temperature for 2 h, then diluted with DCM and washed with water. The organic phase was dried over Na SO , filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with 40-80% EtOAc in petroleum ether to give 2-(2-fluoro-8-iodonaphthalen-1-yl)ethyl(4-nitrophenyl)carbonate (1.31 g, 1.97 mmol, 65% yield) as a yellow oil. m / z(ESI):481.5(M+H) + .

[0456] Step 5. (R)-tert-butyl 3-(((2-(2-fluoro-8-iodonaphthalen-1-yl)ethoxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate. To a solution of 2-(2-fluoro-8-iodonaphthalen-1-yl)ethyl(4-nitrophenyl)carbonate (1.31 g, 1.97 mmol) and (R)-tert-butyl 3-amino-3-methylpiperidine-1-carboxylate (1.16 g, 5.4 mmol) in dichloromethane (15 mL) and N,N-dimethylformamide (1.5 mL) was added TEA (1.3 mL, 9.33 mmol). The mixture was stirred at 80° C. for 12 hours and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 50-80% EtOAc in petroleum ether to give tert-butyl (R)-3-(((2-(2-fluoro-8-iodonaphthalen-1-yl)ethoxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate (1.38 g, 2.48 mmol, 91% yield) as a colorless oil. m / z (ESI): 579.0 (M+Na). + .

[0457] Intermediate RR: (R)-1-(7-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-ol. [ka] To a suspension of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (0.50 g, 1.98 mmol, Enamine) in acetonitrile (8 mL) at 0° C. was added (3R)-azepan-3-ol (0.23 g, 1.98 mmol, PharmaBlock) and DIPEA (1.7 mL, 9.9 mmol). The reaction mixture was stirred at 0° C. for 15 minutes. Separately, a solution of [(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methanol (0.48 mL, 3.6 mmol, Synnovator, Inc.) in acetonitrile (2 mL) was dried over anhydrous magnesium sulfate. The mixture was stirred at room temperature for 15 minutes and then filtered through Celite to remove the magnesium sulfate. The filtrate of the solution containing [(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methanol was added, and the reaction mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the crude material was purified by column chromatography on silica gel eluting with a 0-75% gradient of 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane to give (R)-1-(7-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-ol (0.48 g, 1.10 mmol, 57% yield) as a yellow solid. m / z (ESI): 428.1 (M+H). + .

[0458] Intermediate SS: (1R,2S,5S)-8-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-2-ol and (1S,2R,5R)-8-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-2-ol. [ka] A 40 mL vial was charged with 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (0.20 g, 0.56 mmol, Intermediate Z), 1,1'-dimethyltriethylamine (0.39 mL, 2.2 mmol), and N,N-dimethylacetamide (5.5 mL). The solution was stirred at room temperature for 10 minutes, after which HATU (0.26 g, 0.67 mmol) was added. After stirring for 50 minutes, exo-azabicyclo[3.2.1]octan-2-ol hydrochloride (0.12 g, 0.73 mmol, PharmaBlock, Inc.) was added, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with 0-80% 3:1 HCl in heptane. Purification by column chromatography on silica gel eluting with EtOAc / EtOH with 2% triethylamine gave (1R,2S,5S)-8-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-2-ol and (1S,2R,5R)-8-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-2-ol (0.15 g, 0.33 mmol, 58% yield) as a yellow solid. m / z(ESI):466.0(M+H) + .

[0459] Intermediate TT: Ethyl 5-(1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1H-indazol-5-yl)pentanoate. [ka] A vial was charged with palladium(II) acetate (52 mg, 0.23 mmol), CPhos (0.20 g, 0.46 mmol, Strem Chemicals), and 5-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1H-indazole (1.00 g, 2.32 mmol, PharmaBlock). 5-Ethoxy-5-oxopentylzinc bromide (0.5 M in THF, 14 mL, 7 mmol, Rieke Metals) was added dropwise with vigorous stirring, and the mixture was stirred at room temperature for 3 h. The reaction was quenched with half-saturated aqueous ammonium chloride solution. The aqueous layer was extracted with EtOAc, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was dissolved in MeOH (2 mL) and loaded onto a C18 column (50 g) eluting with a gradient of 5-80% (0.1% formic acid MeCN) / (0.1% formic acid water). The desired fractions were concentrated under reduced pressure to give ethyl 5-(1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1H-indazol-5-yl)pentanoate (0.33 g, 0.63 mmol, 27% yield) as an orange oil.

[0460] Intermediate UU: (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-ol. [ka] The title compound was synthesized in a similar manner to Intermediate V using (3R)-azepan-3-ol (CAS#: 1573085-99-0, PharmaBlock, Inc.). m / z (ESI): 454.0 (M+H) + .

[0461] Intermediate VV: (S)-4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol. [ka] The title compound was synthesized in a similar manner to Intermediate EE using (S)-[1,4]oxazepan-6-ol (CAS#: 1373232-31-5, J&W Pharmlab). m / z (ESI): 456.0 (M+H) + .

[0462] Intermediate WW: methyl 5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-methylpentanoate. [ka] An oven-dried round-bottom flask was charged with methyl 5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoate (0.80 g, 1.90 mmol, Intermediate P) in tetrahydrofuran (9 mL). The contents were cooled to −78° C. and LiHMDS (1 M in THF, 2.0 mL, 2.0 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 15 minutes, then iodomethane (0.14 mL, 2.2 mmol) was added and the reaction was stirred at −78° C. for 1 hour. After warming, the reaction was diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The organics were dried (Na2SO4) and concentrated, and the residue was purified by column chromatography on silica gel eluting with 0-35% EtOAc in heptane to give methyl 5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-methylpentanoate (0.15 g, 0.33 mmol, 18% yield) as a colorless oil. m / z (ESI): 443.0 (M+H). + .

[0463] Intermediate XX: 2-(2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethoxy)ethyl acetate. [ka] Step 1. 2-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethan-1-ol. A vial was charged with (E)-1-ethoxyethene-2-boronic acid pinacol ester (2.02 g, 10.2 mmol, Aurum Pharmatech), 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (3.00 g, 6.80 mmol, LabNetwork), potassium phosphate tripotassium (5.05 g, 23.8 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.50 g, 0.68 mmol), water (4 mL), and 1,4-dioxane (19 mL). The reaction mixture was heated to 100° C. for 1.5 hours. After cooling to room temperature, the crude material was diluted with EtOAc and saturated aqueous ammonium bicarbonate. The aqueous layer was extracted with EtOAc, and the combined organics were dried (NaSO) and concentrated. The crude product was then diluted with 1,4-dioxane (18 mL) and water (1 mL), to which trifluoroacetic acid (7.8 mL, 102 mmol) was added dropwise. The reaction mixture was stirred at 40 °C for 6 hours. After cooling to room temperature, the reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel eluting with 0 to 100% (3:1 EtOAc:EtOH + 2% triethylamine) in heptane to give 2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)acetaldehyde (2.40 g, 6.71 mmol, 99% yield) as an impure brown oil, which was treated with triethylamine and filtered to neutralize residual TFA. m / z(ESI):357.0(M+H) +A 250 mL round-bottom flask was charged with the above aldehyde (2.40 g, 6.71 mmol) and ethanol (70 mL). The reaction mixture was cooled to 0 °C, and sodium borohydride (0.53 g, 14 mmol) was added portionwise. The solution was warmed to room temperature and stirred for 30 minutes. The reaction was then carefully quenched by the addition of methanol, water, and saturated aqueous ammonium chloride. The resulting solution was extracted with EtOAc. The combined organics were dried (Na2SO4) and concentrated. The residue was purified by reverse-phase chromatography using a 50 g C18 column eluting with 0–100% acetonitrile + 0.1% TFA in water + 0.1% TFA to give 2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethan-1-ol (0.20 g, 0.56 mmol, 8% yield). m / z(ESI):359.0(M+H) + .

[0464] Step 2. Ethyl 2-(2-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethoxy)acetate. An oven-dried 100 mL round-bottom flask was charged with 2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethan-1-ol (0.34 g, 0.95 mmol) in tetrahydrofuran (9.5 mL). The contents were cooled to 0° C. and sodium hydride, 60% dispersion in mineral oil (0.12 g, 3.0 mmol) was added. The reaction mixture was stirred at 0° C. for 20 minutes, followed by the dropwise addition of ethyl bromoacetate (0.42 mL, 3.8 mmol) and the reaction was allowed to warm to room temperature and stir for 4.5 hours. The reaction mixture was carefully quenched by the addition of saturated aqueous ammonium chloride, followed by extraction with EtOAc. The combined organics were dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel eluting with 0-40% EtOAc in heptane to give ethyl 2-(2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethoxy)acetate (0.20 g, 0.45 mmol, 48% yield) as a colorless oil. m / z (ESI): 445.8 (M+H). + .

[0465] Intermediate YY: 2-((S)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(tributylstannyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methyl acetate. [ka] Step 1. Methyl 2-((S)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)acetate. A 250 mL round-bottom flask was charged with 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (4.00 g, 11 mmol, Intermediate Z), N-ethyl-N-isopropylpropan-2-amine (7.8 mL, 45 mmol), and HATU (6.39 g, 16.8 mmol) in N,N-dimethylformamide (45 mL). The solution was stirred at room temperature for 10 minutes, followed by the addition of methyl 2-[(3S)-piperidin-3-yl]acetate hydrochloride (2.82 g, 14.6 mmol, Enamine). The reaction mixture was stirred at room temperature for 16 hours, diluted with saturated NH4Cl, and extracted with EtOAc. The organic extract was washed with saturated NaCl, dried over MgSO4, and concentrated. The crude material was purified by column chromatography on a silica gel column eluting with a gradient of 0 to 100% EtOAc / EtOH with 1% TEA in heptane (3:1) to give methyl 2-((S)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)acetate (5.00 g, 10 mmol, 90% yield) as an orange solid. m / z(ESI):496.0(M+H) + .

[0466] Step 2. Methyl 2-((S)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(tributylstannyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)acetate. To a 40 mL vial was added methyl 2-((S)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)acetate (0.80 g, 1.6 mmol) and lithium chloride (0.34 g, 8.07 mmol) in 1,4-dioxane (8 mL). The reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of 1,1,1,2,2,2-hexabutyl-distannane (2.5 mL, 4.8 mmol) and chloro[(tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II) (0.38 g, 0.65 mmol), and the reaction mixture was stirred at 100°C for 16 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a 0-75% gradient of 3:1 EtOAc / EtOH (containing 2% triethylamine) in heptane to give methyl 2-((S)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(tributylstannyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)acetate (0.60 g, 0.80 mmol, 50% yield) as a clear oil. m / z (ESI): 751.8 (M+H). + .

[0467] Intermediate ZZ: 4-bromo-5-(3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. [ka] Step 1. 3-(4-Bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-methylpropanal. A 40 mL vial was charged with 4-bromo-5-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.50 g, 3.56 mmol, Advanced ChemBlocks), sodium bicarbonate (0.75 g, 8.91 mmol), TBACl (0.99 g, 3.56 mmol), and palladium(II) acetate (40 mg, 0.18 mmol). The vial was purged with nitrogen, followed by the addition of N,N-dimethylformamide (7 mL) and methallyl alcohol (0.45 mL, 5.3 mmol, Combi-Blocks), and the reaction mixture was stirred at 65 °C for 2 days. After cooling to room temperature, the reaction was diluted with 10% aqueous LiCl and EtOAc. The layers were separated, and the organic layer was washed once more with 10% aqueous LiCl. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography on silica gel eluting with 0-35% EtOAc in heptane to give 3-(4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-methylpropanal (0.99 g, 2.7 mmol, 76% yield) as a colorless oil. m / z (ESI): 365.1 / 367.0 (M+H). + .

[0468] Step 2. 3-(4-Bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-methylpropan-1-ol. A solution of 3-(4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-methylpropanal (0.99 g, 2.70 mmol) in methanol (27 mL) was cooled to 0° C., followed by the addition of sodium borohydride (0.13 g, 3.38 mmol). The reaction was stirred at 0° C. for 15 minutes and then quenched by the addition of saturated aqueous ammonium chloride solution. The mixture was diluted with EtOAc and allowed to warm to room temperature. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica gel eluting with a gradient of 0-40% EtOAc in heptane to give 3-(4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-methylpropan-1-ol (0.90 g, 2.40 mmol, 91% yield) as a colorless oil. m / z (ESI): 367.0 / 368.95 (M+H). + .

[0469] Step 3. 4-Bromo-5-(3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. A mixture of 3-(4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-methylpropan-1-ol (0.9 g, 2.4 mmol), tert-butyldimethylsilyl chloride (0.44 g, 2.94 mmol), imidazole (0.42 g, 6.12 mmol), and DMAP (30 mg, 0.25 mmol) in dichloromethane (16 mL) was stirred at room temperature for 16 hours. The reaction was then quenched by the addition of saturated aqueous sodium bicarbonate, and the aqueous layer was extracted with CHCl. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography eluting with a gradient of 0-20% EtOAc / heptane to give 4-bromo-5-(3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.20 g, 2.40 mmol, 99% yield) as a colorless oil. m / z (ESI, +ve ion): 481.0 / 483.0 (M+H). + .

[0470] Intermediate AAA: 3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-methylpropan-1-ol. [ka] This compound was prepared in a similar manner to intermediate ZZ in step 1 using 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Lab Network). m / z (ESI): 408.8 / 410.8 (M+Na). + .

[0471] Intermediate BBB: rac-(3S,4R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-fluoropiperidin-3-ol. [ka] A vial was charged with 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (0.75 g, 1.71 mmol, Intermediate AA, Step 2), rel-(3R,4S)-4-fluoropiperidin-3-ol hydrochloride (0.29 g, 1.88 mmol, Advanced ChemBlocks Inc.), and acetonitrile (7 mL). N-Ethyl-N-isopropylpropan-2-amine (1.0 mL, 6.0 mmol) was added, and the reaction was heated to 50° C. for 5 h. After cooling to room temperature, the reaction was concentrated and the crude product was purified by column chromatography on silica gel eluting with a 0-75% gradient of 3:1 EtOAc / EtOH (containing 2% triethylamine) in heptane to give rac-(3S,4R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-fluoropiperidin-3-ol (0.57 g, 1.24 mmol, 72% yield) as an orange solid. m / z (ESI): 458.0 (M+H). + .

[0472] Intermediate CCC: (3R,4R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-3-ol. [ka] A 40 mL vial was charged with 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (0.28 g, 0.77 mmol, Intermediate Z), 1,1′-dimethyltriethylamine (0.67 mL, 3.9 mmol), and N,N-dimethylacetamide (5 mL). The solution was stirred at room temperature for 10 minutes, after which HATU (0.35 g, 0.93 mmol) was added. After 50 minutes, (3R,4R)-4-methylpiperidin-3-ol hydrochloride (0.15 g, 1.00 mmol, Enamine) was added, and the reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with CHCl, and the organic layer was washed with water, dried (NaSO), filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with a 0-75% 3:1 blend of EtOAc / EtOH in heptane with 2% triethylamine as an additive to give (3R,4R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-3-ol (0.18 g, 0.39 mmol, 50% yield) as an orange solid. m / z (ESI): 454.0 (M+H). + .

[0473] Intermediate DDD: rac-(3R,5S)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-fluoropiperidin-3-ol. [ka] A 40 mL vial was charged with 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (0.20 g, 0.56 mmol, Intermediate Z), 1,1′-dimethyltriethylamine (0.39 mL, 2.2 mmol), and N,N-dimethylacetamide (5.5 mL). The solution was stirred at room temperature for 10 minutes, after which HATU (0.26 g, 0.67 mmol) was added. After 50 minutes, rel-(3R,5S)-5-fluoropiperidin-3-ol hydrochloride (0.11 g, 0.73 mmol, AK scientific) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction was diluted with CHCl, and the organic layer was washed with water, dried (NaSO), filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with a 0-80% 3:1 blend of EtOAc / EtOH in heptane with 2% triethylamine additive to give rac-(3R,5S)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-fluoropiperidin-3-ol (89 mg, 0.20 mmol, 35% yield) as a yellow solid. m / z (ESI): 458.0 (M+H). + .

[0474] Intermediate EEE: (3R)-1-(7-(5-((E)-3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol. [ka] Step 1. 7-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine. To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (8.50 g, 19.4 mmol, Intermediate AA, Step 2) in 1,4-dioxane (170 mL) and water (21 mL) was added 5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (8.76 g, 23.3 mmol, Ambeed, Inc.), KPO (18.9 g, 58.1 mmol), and cataCXium A Pd G2 (1.30 g, 1.90 mmol) was added under N2. The mixture was then stirred at 100 °C for 5 h. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of 30 to 100% EtOAc in petroleum ether to give 7-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (5 g, 7.67 mmol, 39% yield) as a yellow solid. m / z(ESI):653.2(M+H) + .

[0475] Step 2. (3R)-1-(7-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol. A vial was charged with 7-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (0.50 g, 0.77 mmol), (R)-piperidin-3-ol hydrochloride (0.11 g, 0.77 mmol), and N,N-dimethylformamide (2.5 mL). N-Ethyl-N-isopropylpropan-2-amine (0.3 mL, 1.7 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 3 hours, diluted with water, and extracted with DCM. The combined organic phases were washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was dissolved in MeOH (2 mL) and loaded onto a pre-packed C18 column (50 g) eluted with a gradient of 5 to 100% (0.1% formic acid MeCN) / (0.1% formic acid water) over 10 min. The desired fractions were basified with saturated aqueous sodium bicarbonate and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (3R)-1-(7-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (0.30 g, 0.46 mmol, 60% yield) as an off-white solid. m / z (ESI): 653.8 (M+H). + .

[0476] Step 3. (3R)-1-(7-(5-((E)-3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol. A vial was charged with (3R)-1-(7-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (0.30 g, 0.46 mmol), (E)-tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane (0.68 g, 2.29 mmol, Enamine), cataCXium A Pd G3 (50 mg, 0.069 mmol), potassium phosphate tribasic (0.34 g, 1.61 mmol), water (0.8 mL), and 2-methyltetrahydrofuran (3.8 mL) were charged. The reaction mixture was heated to 100 °C for 3 h, cooled, diluted with water, and extracted with DCM. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was dissolved in a minimal amount of MeOH and loaded onto a pre-packed C18 column (50 g), eluting with a gradient of 5–80% (0.1% formic acid MeCN) / (0.1% formic acid water) over 20 min.The desired fractions were basified with saturated aqueous sodium bicarbonate, extracted with DCM, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (3R)-1-(7-(5-((E)-3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (58 mg, 0.073 mmol, 16% yield) as an off-white solid. m / z (ESI): 789.9 (M+H). + .

[0477] Intermediate FFF: 5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. [ka] Step 1. 3-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propanal. A 40 mL vial was charged with 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (3.00 g, 6.80 mmol, Lab Network), sodium bicarbonate (1.43 g, 17.0 mmol), TBACl (1.95 g, 6.82 mmol), and N,N-dimethylformamide (14 mL). The solution was degassed by bubbling nitrogen through for 10 minutes. Then, palladium(II) acetate (77 mg, 0.34 mmol) and allyl alcohol (0.7 mL, 10 mmol) were added at 50° C. The reaction mixture was stirred at 50° C. for 18 hours. After cooling to room temperature, the reaction was diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0-50% 3:1 EtOAc / EtOH in heptane to give 3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propanal (2.12 g, 5.70 mmol, 84% yield) as a pale orange oil. m / z (ESI): 371.0 (M+H). + .

[0478] Step 2: 3-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propan-1-ol. To a 100 mL round-bottom flask was added 3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propanal (1.06 g, 2.86 mmol) in tetrahydrofuran (5 mL) / methanol (5 mL). The reaction mixture was cooled to 0° C. Then, sodium borohydride (0.11 g, 2.86 mmol) was added slowly in small portions. The reaction mixture was stirred at 0° C. for 30 minutes, then slowly quenched with saturated NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. 3-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propan-1-ol (1.03 g, 2.76 mmol, 97% yield) was obtained as a pale yellow oil without further purification. m / z (ESI): 289.0 (M-THP+H) + .

[0479] Step 3: 4-Bromo-5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. To a stirred solution of 3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propan-1-ol (1.03 g, 2.76 mmol) and 1,1′-dimethyltriethylamine (0.53 mL, 3.0 mmol) in dichloromethane (10 mL) in a 40 mL vial was added tert-butyldimethylsilyl chloride (0.46 g, 3.03 mmol) and 4-(dimethylamino)pyridine (34 mg, 0.28 mmol) at 0° C. After stirring at 0 °C for 2 h, the crude material was purified by column chromatography on silica gel eluting with a gradient of 0-30% 3:1 EtOAc / EtOH in heptane to give 4-bromo-5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.12 g, 2.3 mmol, 83% yield) as a colorless oil. m / z (ESI): 487.1 (M+H). + .

[0480] Step 4. 5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. To a solution of 4-bromo-5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (3.4 g, 7.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (8.85 g, 34.8 mmol) in 1,4-dioxane (80 mL) and water (10 mL) was added Pd(dppf)Cl (0.51 g, 0.7 mmol) and CsCO (6.81 g, 20.9 mmol) under N. The reaction mixture was heated at 120 °C for 5 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with a gradient of 10-100% EtOAc in petroleum ether to give 5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (3.3 g, 6.2 mmol, 88% yield) as a yello...

Claims

1. Formula (I'): 【Chemistry 1】 (In the formula, Z is C—H, C-halogen, C—CN, C—C １～４ Alkyl, C-C １～４ Haloalkyl, C-C １～４ Alkoxy, C-C １～４ Haloalkoxy, C-C ３～７ cycloalkyl or N; Q is CH, C-halogen, C-C １～４ Alkyl, C-C １～４ haloalkyl or N; B is a 4-15 membered heterocycloalkyl having 0-3 additional ring heteroatoms independently selected from O, S, and N; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3; Each R ｘ are independently hydroxyl, halogen, oxo, cyano, -N(R ｚ ) ２ , C １～４ Alkyl, C １～４ Deuteroalkyl, C １～４ Alkoxy, C １～４ Haloalkyl, C １～４ Haloalkoxy, C １～４ Hydroxyalkyl, 5- to 7-membered heteroaryl, —S(O) ２ -C １～４ Alkyl, —S(O) ２ N (R ｚ ) ２ , -C(O)R ｚ , -C(O)OR ｚ , -C(O)N(R ｚ ) ２ , -C １～４ Alkylene-C(O)-C １～４ Alkyl, —C １～４ Alkylene -C(O)N(R ｚ ) ２ , C １～４ Alkylene-S(O) ２ -C １～４ Alkyl or -S-C １～４ is alkyl; L is a bond, C １～６ Alkylene, —O—C １～６ Alkylene, —S—C １～６ Alkylene, NR ｚ , O or S, and each C １～６ Alkylene, —O—C １～６ Alkylene and —S—C １～６ The alkylene chain is R ２ substituted with 0 to 2 occurrences of; -L １ -L ２ - is -L ２ , -N(R ｚ ) C(O)-L ２ , -C(O)-L ２ -, -OC(O)-L ２ , -C(O)O-L ２ , -OC(O)-OL ２ , -OC(S)-OL ２ , -O-L ２ , -N(R ｚ ) C(O)O-L ２ , -OC(O)N(R ｚ )-L ２ , -N(R ｚ )-L ２ , -S(O) ２ -L ２ , -S-L ２ , -S(O)-L ２ , C １～４ Alkylene-C(O)-L ２ , C １～４ Alkylene-C(O)O-L ２ , -C １～４ Alkylene-OC(O)O-L ２ , -C １～４ Alkylene-OC(O)-L ２ , -C １～４ Alkylene-O-L ２ , -C １～４ Alkylene-S(O) ２ -L ２ , -C １～４ Alkylene-SL ２ , -C １～４ Alkylene-S(O)-L ２ , —O-5- to 6-membered heteroaryl-L ２ , -C １～４ Alkylene-5-6-membered heteroaryl-L ２ , -C １～４ Hydroxyalkylene-5-6-membered heteroaryl-L ２ or 5- to 6-membered heteroaryl-L ２ and L ２ is C １～６ Alkylene, C １～６ Alkylene-O-, C １～６ Alkylene -O-C １～６ Alkylene, C ２～６ Alkenylene, C ２～６ Alkynylene, C ３～７ Cycloalkylene, C １～４ Alkylene-C ３～７ Cycloalkylene, C １～４ Haloalkylene-C ３～７ Cycloalkylene, C ３～７ Cycloalkylene-C １～４ Alkylene, C １～６ Hydroxyalkylene or C １～６ haloalkylene; R １ is hydrogen, hydroxyl, C ６～１０ Aryl, 5- to 10-membered heteroaryl, C ３～８ cycloalkyl or 4- to 15-membered heterocycloalkyl, and each aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is R ５ substituted with 0 to 3 occurrences of; R ２ is a halogen, hydroxyl, C １～４ alkyl, or two R on the same or adjacent carbon atoms ２ Let's join together and ３～７ can form a cycloalkyl; A is C ６～１０ aryl or 5- to 10-membered heteroaryl, and R ６ is replaced by q occurrences of; R ４ is hydrogen, hydroxyl, halogen, C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, C ２～４ Alkenyl, C ２～４ Alkynyl, C ３～７ cycloalkyl or cyano; Each R ５ are independently halogen, cyano, oxo, -T-R ｙ , hydroxyl, -N(R ｚ ) ２ , C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy or —O—C ２～４ is alkynyl; Each R ６ are independently selected from halogen, hydroxyl, cyano, -N(R ｚ ) ２ , -C(O)R ｚ , -C(O)OR ｚ , C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, C １～４ Haloalkoxy, C ２～４ Alkynyl or C ３～６ cycloalkyl or two R ６ are taken together on adjacent carbon atoms to form C ３～７ Forming a cycloalkyl; T is C １～４ Alkylene, —S(O) ２ -, -C(O)-, -C １～４ Alkylene-C(O)-, C １～４ Alkylene-S(O) ２ - or -S-; R ｙ is halogen, oxo, C １～４ Alkyl, C １～４ haloalkyl, hydroxyl, cyano or —N(R ｚ ) ２ and Each R ｚ is hydrogen or C １～４ alkyl) or a pharmaceutically acceptable salt of said compound.

2. The compound has the formula (I): 【Chemistry 2】 (In the formula, X is N, CH ２ , O, S, S(O), S(O)(NR ｚ ) or S(O) ２ and Z is C—H, C-halogen, C—CN, C—C １～４ Alkyl, C-C １～４ Haloalkyl, C-C １～４ Alkoxy, C-C １～４ Haloalkoxy, C-C ３～７ cycloalkyl or N; Q is CH, C-halogen, C-C １～４ Alkyl, C-C １～４ haloalkyl or N; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3; Each R ｘ is hydroxyl, halogen, oxo, cyano, -N(R ｚ ) ２ , C １～４ Alkyl, C １～４ Deuteroalkyl, C １～４ Alkoxy, C １～４ Haloalkyl, C １～４ haloalkoxy, 5- to 7-membered heteroaryl, -T-R ｙ or two R ｘ together with the same carbon atom or an adjacent carbon atom, C ３～７ cycloalkyl, 3- to 7-membered heterocycloalkyl, and each C ３～７ Cycloalkyl or 3- to 7-membered heterocycloalkyl is R ｙ or two R ｘ can be taken together to form a bridged ring, said bridge being -C １～４ Alkylene, -C １～４ Alkylene -O-C １～４ Alkylene-, —O—, —S— or —C １～４ Alkylene -S-C １～４ alkylene-, and each C １～４ Alkylene is R ｙ further substituted with 0-2 occurrences of; L is a bond, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylene, —O—C １～６ Alkylene, —S—C １～６ Alkylene, NR ｚ , O or S, and each C １～６ Alkylene, —O—C １～６ Alkylene and —S—C １～６ The alkylene chain is R ２ substituted with 0 to 2 occurrences of; -L １ -L ２ - is -L ２ , -N(R ｚ ) C(O)-L ２ , -C(O)-L ２ -, -OC(O)-L ２ , -C(O)O-L ２ , -OC(O)-OL ２ , -OC(S)-OL ２ , -O-L ２ , -N(R ｚ ) C(O)O-L ２ , -OC(O)N(R ｚ )-L ２ , -N(R ｚ )-L ２ , -S(O) ２ -L ２ , -SL ２ , -S(O)-L ２ , C １～４ Alkylene-C(O)-L ２ , C １～４ Alkylene-C(O)O-L ２ , -C １～４ Alkylene-OC(O)O-L ２ , -C １～４ Alkylene-OC(O)-L ２ , -C １～４ Alkylene-O-L ２ , -C １～４ Alkylene-S(O) ２ -L ２ , -C １～４ Alkylene-SL ２ , -C １～４ Alkylene-S(O)-L ２ , —O-5- to 6-membered heteroaryl-L ２ , -C １～４ Alkylene-5-6-membered heteroaryl-L ２ , -C １～４ Hydroxyalkylene-5-6-membered heteroaryl-L ２ or 5- to 6-membered heteroaryl-L ２ and L ２ is C １～６ Alkylene, C １～６ Alkylene-O-, C １～６ Alkylene -O-C １～６ Alkylene, C ２～６ Alkenylene, C ２～６ Alkynylene, C ３～７ Cycloalkylene, C １～４ Alkylene-C ３～７ Cycloalkylene, C １～４ Haloalkylene-C ３～７ Cycloalkylene, C ３～７ Cycloalkylene-C １～４ Alkylene, C １～６ Hydroxyalkylene or C １～６ haloalkylene; R １ is hydrogen, hydroxyl, C ６～１０ Aryl, 5- to 10-membered heteroaryl, C ３～８ cycloalkyl or 4- to 15-membered heterocycloalkyl, and each aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is R ５ substituted with 0 to 3 occurrences of; R ２ is a halogen, hydroxyl, C １～４ alkyl, or two R on the same or adjacent carbon atoms ２ Let's join together and ３～７ can form a cycloalkyl; A is C ６～１０ aryl or 5- to 10-membered heteroaryl, and R ６ is replaced by q occurrences of; R ４ is hydrogen, hydroxyl, halogen, C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, C ２～４ Alkenyl, C ２～４ Alkynyl, C ３～７ cycloalkyl or cyano; Each R ５ are independently halogen, cyano, oxo, -T-R ｙ , hydroxyl, -N(R ｚ ) ２ , C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy or —O—C ２～４ is alkynyl; Each R ６ are independently selected from halogen, hydroxyl, cyano, -N(R ｚ ) ２ , -C(O)R ｚ , -C(O)OR ｚ , C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, C １～４ Haloalkoxy, C ２～４ Alkynyl or C ３～６ cycloalkyl or two R ６ are taken together on adjacent carbon atoms to form C ３～７ Forming a cycloalkyl; T is C １～４ Alkylene, —S(O) ２ -, -C(O)-, -C １～４ Alkylene-C(O)-, C １～４ Alkylene-S(O) ２ - or -S-; R ｙ is halogen, oxo, C １～４ Alkyl, C １～４ haloalkyl, hydroxyl, cyano or —N(R ｚ ) ２ and Each R ｚ is hydrogen or C １～４ alkyl) 2. The compound or salt of claim 1, wherein the compound or salt is:

3. 3. The compound or salt of claim 2, wherein Z is N and Q is CH, or Z is C--F and Q is CH.

4. L is —O-methylene-, —O-ethylene-, —On-propylene, or —O-isopentanylene, and L is R ２ 3. The compound or salt of claim 2, substituted with 0 to 2 occurrences of:

5. -L-R １ teeth, 【Transformation 3】 , methoxy or methyl.

6. -L-R １ teeth, 【Chemistry 4】 6. The compound or salt of claim 5, wherein:

7. -L-R １ teeth, 【Transformation 5】 7. The compound or salt of claim 6, wherein:

8. -L-R １ teeth, 【Transformation 6】 7. The compound or salt of claim 6, wherein:

9. 9. The compound or salt according to any one of claims 2 to 8, wherein n is 1 and m is 1, or n is 1 and m is 2, or n is 2 and m is 1.

10. 10. The compound or salt of claim 9, wherein X is O.

11. B-L １ teeth, 【Transformation 7】 The compound or salt according to any one of claims 1 to 10,

12. B-L １ teeth, 【Transformation 8】 12. The compound or salt of claim 11, wherein:

13. X is CH ２ 10. The compound or salt of any one of embodiments 2-9, wherein

14. 14. The compound or salt of claim 13, wherein n is 0 and m is 1; n is 1 and m is 0; n is 1 and m is 1; n is 1 and m is 2, or n is 2 and m is 1. 【Request Item 15】 【Chemistry 9】 teeth, 【Chemistry 10】 15. The compound or salt of claim 14, wherein:

16. B-L １ teeth, 【Chemistry 11】 16. The compound or salt of claim 15, wherein:

17. B-L １ teeth, 【Chemistry 12】 2. The compound or salt of claim 1, wherein:

18. B-L １ teeth, 【Chemistry 13】 18. The compound or salt of claim 17, wherein:

19. A is C ６～１０ 18. The compound or salt of any one of claims 1 to 17, which is aryl.

20. A-L ２ teeth, 【Chemistry 14】 20. The compound or salt of claim 19, wherein:

21. A-L ２ teeth, 【Chemistry 15】 21. The compound or salt of claim 20, wherein:

22. A-L ２ The compound or salt of any one of claims 1 to 18, wherein is 5-10 membered heteroaryl.

23. A-L ２ teeth, 【Chemistry 16】 23. The compound or salt of claim 22, wherein:

24. A-L ２ teeth, 【Chemistry 17】 24. The compound or salt of claim 23, wherein:

25. -L １ -L ２ - is -OC(O)-OL ２ The compound or salt according to any one of claims 1 to 24,

26. L ２ is ethylene, n-propylene, 2-methyl-n-propylene, cis-2-propenylene, trans-2-propenylene, or —CH ２ 26. The compound or salt of claim 25, wherein the compound or salt is -cyclopropylene.

27. -L １ -L ２ -teeth, [Chemistry 18] 27. The compound or salt of claim 26, wherein:

28. -L １ -L ２ -teeth, 【Chemistry 19】 28. The compound or salt of claim 27, wherein:

29. -L １ -L ２ -teeth, 【Chemistry 20】 29. The compound or salt of claim 28, wherein:

30. -L １ -L ２ - is -C １～４ Hydroxyalkylene-5-6-membered heteroaryl-L ２ The compound or salt according to any one of claims 1 to 24,

31. -L １ -L ２ -teeth, 【Chemistry 21】 31. The compound or salt of claim 30, wherein:

32. L ２ 32. The compound or salt of claim 31 , wherein is ethylene.

33. -L １ -L ２ -teeth, 【Chemistry 22】 33. The compound or salt of claim 32, wherein:

34. -L １ -L ２ - is -C １～４ Alkylene-O-L ２ The compound or salt according to any one of claims 1 to 24,

35. -L １ -L ２ - is -methylene-OL ２ 35. The compound or salt of claim 34, wherein:

36. L ２ is n-butylene, 2,2-difluoro-n-butylene, trans-2-butenylene, cis-2-butenylene, 3-methyl-n-butylene, -ethylene-cyclopropylene-, or ethylene-O-methylene.

37. -L １ -L ２ -teeth, 【Chemistry 23】 37. The compound or salt of claim 36, wherein:

38. -L １ -L ２ -teeth, 【Chemistry 24】 38. The compound or salt of claim 37, wherein:

39. -L １ -L ２ - is ethylene -OL ２ 35. The compound or salt of claim 34, wherein:

40. L ２ 40. The compound or salt of claim 39, wherein is ethylene, n-propylene, or methylene-cyclopropylene.

41. -L １ -L ２ -teeth, 【Chemistry 25】 41. The compound or salt of claim 40, wherein:

42. -L １ -L ２ -teeth, 【Chemistry 26】 42. The compound or salt of claim 41, wherein:

43. -L １ -L ２ - is -NR ｚ -C(O)-O-L ２ The compound or salt according to any one of claims 1 to 24,

44. R ｚ 44. The compound or salt of claim 43, wherein is hydrogen or methyl.

45. L ２ represents n-propylene, ethylene, -CH ２ 45. The compound or salt of claim 43 or 44, wherein the compound or salt is -cyclopropylene.

46. -L １ -L ２ -teeth, 【Chemistry 27】 46. ​​The compound or salt of claim 45, wherein:

47. -L １ -L ２ -teeth, 【Chemistry 28】 47. The compound or salt of claim 46, wherein:

48. -L １ -L ２ 25. The compound or salt of any one of claims 1 to 24, wherein - is a 5- to 6-membered heteroaryl.

49. -L １ -L ２ -teeth, 【Chemistry 29】 49. The compound or salt of claim 48, wherein:

50. -L １ -L ２ -teeth, 【Transformation 30】 50. The compound or salt of claim 49, wherein:

51. -L １ -L ２ -teeth, 【Chemistry 31】 51. The compound or salt of claim 50, wherein:

52. -L １ -L ２ The compound or salt according to any one of claims 1 to 24, wherein - is -C(O)-.

53. L ２ 53. The compound or salt of claim 52, wherein - is n-propylene, -methylene-On-propylene, or n-butylene.

54. -L １ -L ２ -teeth, 【Chemistry 32】 54. The compound or salt of claim 53, wherein:

55. -L １ -L ２ -teeth, 【Transformation 33】 55. The compound or salt of claim 54, wherein:

56. R ４ is C １～４ 56. The compound or salt of any one of claims 1 to 55, which is alkyl or halogen.

57. R ４ 57. The compound or salt of claim 56, wherein is fluorine.

58. The compound is Table 1 Table 2 Table 3 3. The compound or salt according to claim 1 or 2, wherein:

59. The compound is Table 4 Table 5 3. The compound or salt according to claim 1 or 2, wherein:

60. The compound is Table 6 Table 7 Table 8 3. The compound or salt according to claim 1 or 2, wherein:

61. The compound is Table 9 Table 10 3. The compound or salt according to claim 1 or 2, wherein:

62. 62. A pharmaceutical composition comprising a compound or salt according to any one of claims 1 to 61 and a pharmaceutically acceptable excipient.

63. A compound or salt according to any one of claims 1 to 61 or a pharmaceutical composition according to claim 62 for use as a medicament.

64. A compound or salt according to any one of claims 1 to 61 or a pharmaceutical composition according to claim 62 for use in the treatment of cancer.

65. 63. A compound or salt according to any one of claims 1 to 61 or a pharmaceutical composition according to claim 62 for use in the treatment of cancer, wherein one or more cells of the cancer express a KRAS G12D mutant protein.

66. 66. The compound, salt or pharmaceutical composition for use according to claim 64 or 65, 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 neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia or melanoma.

67. 63. Use of a compound or salt according to any one of claims 1 to 61 or a pharmaceutical composition according to claim 62 in the preparation of a medicament for treating cancer.

68. 63. Use of a compound or salt according to any one of claims 1 to 61 or a pharmaceutical composition according to claim 62 in the preparation of a medicament for treating cancer, wherein one or more cells of the cancer express a KRAS G12D mutant protein.

69. 69. The use of claim 67 or 68, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine carcinoma, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia or melanoma.

70. 63. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or salt of any one of claims 1 to 61 or a pharmaceutical composition of claim 62.

71. 63. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or salt of any one of claims 1 to 61 or a pharmaceutical composition of claim 62, wherein one or more cells of the cancer express a KRAS G12D mutant protein.

72. 72. The method of claim 70 or 71, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine carcinoma, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

73. 72. The method of claim 70 or 71, 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.

74. 74. The method of claim 73, wherein the cancer is non-small cell lung cancer.

75. 74. The method of claim 73, wherein the cancer is colorectal cancer.

76. 74. The method of claim 73, wherein the cancer is pancreatic cancer.

77. 77. The method of any one of claims 70-76, 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, salt or composition.

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