Macrocyclic KRAS inhibitors and methods of use

Abstract

The present disclosure provides compounds useful for the inhibition of KRAS G12D, G12V, G12A, G12S, G13D, Q61H, Q61L, or G12C. These compounds have the general formula I '(I') wherein the variables of formula I 'are defined herein. The disclosure also provides pharmaceutical compositions comprising these compounds, the use of these compounds and compositions for the treatment of e.g. Cancer. # imgabs0 #

Description

[0001] Cross-reference to prior applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 383,674 filed on November 14, 2022, U.S. Provisional Patent Application No. 63 / 497,978 filed on April 24, 2023, and U.S. Provisional Patent Application No. 63 / 582,751 filed on September 14, 2023, each of which is incorporated by reference in its entirety. Technical Field

[0003] The present disclosure provides compounds that are active as inhibitors of mutant KRAS proteins. The present disclosure also provides pharmaceutical compositions comprising these 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, paranasal sinus cancer, bile duct cancer or melanoma. Background Art

[0004] Since it was identified as one of the first human oncogenes in 1982 (Der et al., 1982), KRAS ( K KRAS (Krasten rat sarcoma viral oncogene homolog) has been the focus of extensive academic and industrial research as a key node in the MAPK signaling pathway, as a transforming factor in a network of parallel effector pathways (e.g., PI3K / AKT) (Vojtek et al., 1998), and as a potential target for anticancer agents (Malumbres et al., 2003). Despite progress in the development of inhibitors of upstream and downstream nodes in 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.

[0005] KRAS is a G protein that couples extracellular pro-mitogenic signaling with intracellular pro-proliferative responses. KRAS acts as an “on / off” switch within the cell. Mitogen stimulation induces GTP binding to KRAS, causing conformational changes that enable KRAS to interact with downstream effector proteins, leading to cell proliferation. Normally, pro-proliferative signaling is regulated by the action of GTPase-activating proteins (GAPs) to return KRAS to its GDP-bound, non-proliferative state. Mutations in KRAS impair the regulatory cycling of KRAS between these GDP-bound and GTP-bound states, leading to accumulation of the GTP-bound active state and dysregulated cell proliferation (Simanshu et al., 2017).

[0006] Attempts to develop inhibitors of mutant KRAS proteins have historically been hampered by the lack of druggable pockets on the protein's surface (Cox et al., 2014). In 2013, Shokat and colleagues identified a covalent inhibitor of KRAS G12C, a common oncogenic mutant of KRAS (O'Bryan, 2019), which binds to a previously unrecognized allosteric pocket on GDP-KRAS G12C and prevents its subsequent activation (Ostream et al., 2013). This discovery spurred significant new efforts in KRAS inhibitor research, culminating recently in the entry of several KRAS inhibitors into human clinical trials.

[0007] Despite some progress in KRAS G12C inhibitors, there is ongoing interest and effort in developing KRAS inhibitors, particularly inhibitors of other KRAS such as KRAS G12D, G12V, G12A, G12S, G13D, Q61H, Q61L, or G12C. Therefore, 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. Summary of the Invention

[0008] In a first aspect, the present application relates to compounds having formula (I'):

[0009]

[0010] or a pharmaceutically acceptable salt of said compound, wherein:

[0011] 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;

[0012] Q is CH, C-halogen, CC 1-4 Alkyl, CC 1-4 Haloalkyl or N;

[0013] B is a 4-15 membered heterocycloalkyl group having 0-3 additional ring heteroatoms independently selected from O, S and N;

[0014] p is 0, 1, 2, 3, or 4;

[0015] q is 0, 1, 2, or 3;

[0016] Each R x are independently hydroxy, halogen, oxo, cyano, -N(R z)2、C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, 5-7 membered heteroaryl, -S(O)2-C 1-4 Alkyl, -S(O)2N(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 alkyl;

[0017] L is a key, C 1-6 Alkylene, -OC 1-6 Alkylene, -SC 1-6 Alkylene, NR z , O or S, where C 1-6 Alkylene, -OC 1-6 Alkylene and -SC 1-6 The alkylene chains are each replaced by 0-2 occurrences of R 2 replace;

[0018] -L 1 -L 2 -Yes-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 、C1-4 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-5-6 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 ;

[0019] L 2 It 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 Alkynylidene, C 3-7 Cycloalkylene, C 1-4 Alkylene-C 3-7 Cycloalkylene, C 1-4 Halogenated alkylene-C 3-7 Cycloalkylene, C 3-7 Cycloalkylene-C 1-4 Alkylene, C 1-6 Hydroxyalkylene or C 1-6 alkylene halide;

[0020] R 1 It is hydrogen, hydroxyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl or 4-15 membered heterocycloalkyl, wherein aryl, heteroaryl, cycloalkyl or heterocycloalkyl is each replaced by 0-3 occurrences of R 5 replace;

[0021] R 2 Halogen, hydroxyl, C 1-4 Alkyl, or two R on the same or adjacent carbon atoms 2Can form C together 3-7 Cycloalkyl;

[0022] A is C 6-10 Aryl or 5-10 membered heteroaryl and q occurrences of R 6 replace;

[0023] R 4 It is hydrogen, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-7 Cycloalkyl or cyano;

[0024] Each R 5 are independently halogen, cyano, oxo, -TR y , hydroxyl, -N(R z )2、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or -OC 2-4 Alkynyl;

[0025] Each R 6 are independently halogen, hydroxy, cyano, -N(R z )2、-C(O)R z 、-C(O)OR z 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 2-4 Alkynyl or C 3-6 Cycloalkyl, or two R on adjacent carbon atoms 6 Together they form C 3-7 Cycloalkyl;

[0026] 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-;

[0027] R y It is C 1-4 Alkyl, C 1-4 Haloalkyl, hydroxy, cyano or -N(R z )2; and

[0028] Each R z is hydrogen or C 1-4 alkyl.

[0029] In a second aspect, provided herein is a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt of the compound, and a pharmaceutically acceptable excipient.

[0030] In a third aspect, provided herein are compounds described herein or pharmaceutically acceptable salts of the compounds, or pharmaceutical compositions 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).

[0031] Reference will now be made in detail to the embodiments of the present disclosure. Although certain embodiments of the present disclosure will be described, it will be understood that it is not intended to limit the embodiments of the present disclosure to those described embodiments. On the contrary, reference to the embodiments of the present disclosure is intended to cover alternatives, modifications, and equivalents that may be included within the spirit and scope of the embodiments of the present disclosure as defined by the appended claims. DETAILED DESCRIPTION

[0032] Provided herein as Example 1 is a compound having formula (I'):

[0033]

[0034] or a pharmaceutically acceptable salt of said compound, wherein:

[0035] 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;

[0036] Q is CH, C-halogen, CC 1-4 Alkyl, CC 1-4 Haloalkyl or N;

[0037] B is a 4-15 membered heterocycloalkyl group having 0-3 additional ring heteroatoms independently selected from O, S and N;

[0038] p is 0, 1, 2, 3, or 4;

[0039] q is 0, 1, 2, or 3;

[0040] Each R x are independently hydroxy, halogen, oxo, cyano, -N(R z )2、C 1-4 Alkyl, C 1-4 Deuterated alkyl, C1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, 5-7 membered heteroaryl, -S(O)2-C 1-4 Alkyl, -S(O)2N(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 alkyl;

[0041] L is a key, C 1-6 Alkylene, -OC 1-6 Alkylene, -SC 1-6 Alkylene, NR z , O or S, where C 1-6 Alkylene, -OC 1-6 Alkylene and -SC 1-6 The alkylene chains are each replaced by 0-2 occurrences of R 2 replace;

[0042] -L 1 -L 2 -Yes-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 、C1-4 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-5-6 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 ;

[0043] L 2 It 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 Alkynylidene, C 3-7 Cycloalkylene, C 1-4 Alkylene-C 3-7 Cycloalkylene, C 1-4 Halogenated alkylene-C 3-7 Cycloalkylene, C 3-7 Cycloalkylene-C 1-4 Alkylene, C 1-6 Hydroxyalkylene or C 1-6 alkylene halide;

[0044] R 1 It is hydrogen, hydroxyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl or 4-15 membered heterocycloalkyl, wherein aryl, heteroaryl, cycloalkyl or heterocycloalkyl is each replaced by 0-3 occurrences of R 5 replace;

[0045] R 2 Halogen, hydroxyl, C 1-4 Alkyl, or two R on the same or adjacent carbon atoms 2 Can form C together 3-7 Cycloalkyl;

[0046] A is C 6-10 Aryl or 5-10 membered heteroaryl and q occurrences of R 6 replace;

[0047] R 4 It is hydrogen, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-7 Cycloalkyl or cyano;

[0048] Each R 5 are independently halogen, cyano, oxo, -TR y , hydroxyl, -N(R z )2、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or -OC 2-4 Alkynyl;

[0049] Each R 6 are independently halogen, hydroxy, cyano, -N(R z )2、-C(O)R z 、-C(O)OR z 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 2-4 Alkynyl or C 3-6 Cycloalkyl, or two R on adjacent carbon atoms 6 Together they form C 3-7 Cycloalkyl;

[0050] 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-;

[0051] R y Is halogen, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, hydroxy, cyano or -N(R z )2; and

[0052] Each R z is hydrogen or C 1-4 alkyl.

[0053] Provided herein as embodiment 2 are compounds or salts as described in embodiment 1, wherein B is a 4-10 membered heterocycloalkyl group having one additional oxygen heteroatom. Provided herein as embodiment 3 are compounds or salts as described in embodiment 2, wherein p is 0. Provided herein as embodiment 4 are compounds or salts as described in embodiment 3, wherein BL 1 yes Provided herein as embodiment 5 is a compound or salt as described in embodiment 4, wherein BL 1 yes Provided herein as embodiment 6 is a compound or salt as described in embodiment 5, wherein BL 1 yes yes Provided herein as embodiment 7 is a compound or salt as described in embodiment 6, wherein yes Provided herein as embodiment 8 is a compound or salt as described in embodiment 6, wherein yes Provided herein as embodiment 9 is a compound or salt as described in embodiment 6, wherein yes

[0054] Provided herein as embodiment 10 are compounds or salts as described in embodiment 1, wherein B is a 4-10 membered heterocycloalkyl group having one additional nitrogen heteroatom. Provided herein as embodiment 11 are compounds or salts as described in embodiment 10, wherein p is 0. Provided herein as embodiment 12 are compounds or salts as described in embodiment 11, wherein BL 1 yes Provided herein as embodiment 13 is a compound or salt as described in embodiment 12, wherein BL 1 yes Provided herein as embodiment 14 is a compound or salt as described in embodiment 13, wherein BL 1 yes

[0055] Provided herein as embodiment 15 are compounds or salts as described in embodiment 1, wherein B is a 4-10 membered heterocycloalkyl group having 0 additional heteroatoms. Provided herein as embodiment 16 are compounds or salts as described in embodiment 15, wherein p is 0. Provided herein as embodiment 17 are compounds or salts as described in embodiment 16, wherein BL 1 yes Provided herein as embodiment 18 is a compound or salt as described in embodiment 17, wherein BL 1 yes Provided herein as embodiment 19 is a compound or salt as described in embodiment 18, wherein BL 1 yes Provided herein as embodiment 20 is a compound or salt as described in embodiment 18, wherein BL 1 yes Provided herein as embodiment 21 is a compound or salt as described in embodiment 18, wherein BL 1 yes Provided herein as embodiment 22 is a compound or salt as described in embodiment 18, wherein BL 1 yes

[0056] Provided herein as embodiment 23 are compounds or salts as described in embodiment 1, wherein B is a 4-10 membered heterocycloalkyl group with one additional oxygen heteroatom. Provided herein as embodiment 24 are compounds or salts as described in embodiment 23, wherein p is 1. Provided herein as embodiment 25 are compounds or salts as described in embodiment 24, wherein BL 1 yes Provided herein as embodiment 26 are compounds or salts as described in embodiments 24 or 25, wherein R x It is C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Deuterated alkyl. Provided herein as embodiment 27 is a compound or salt as described in embodiment 26, wherein R x is methyl, CD3 or monofluoromethyl.

[0057] Provided herein as embodiment 28 is a compound or salt as described in embodiment 27, wherein BL 1 yes Provided herein as embodiment 29 is a compound or salt as described in embodiment 28, wherein BL 1 yes Provided herein as embodiment 30 is a compound or salt as described in embodiment 29, wherein BL 1 yes Provided herein as embodiment 31 is a compound or salt as described in embodiment 29, wherein BL 1 yes Provided herein as embodiment 32 is a compound or salt as described in embodiment 29, wherein BL1 yes

[0058] Provided herein as embodiment 33 are compounds or salts as described in embodiment 1, wherein B is a 4-10 membered heterocycloalkyl group having 0 additional heteroatoms. Provided herein as embodiment 34 are compounds or salts as described in embodiment 33, wherein p is 1. Provided herein as embodiment 35 are compounds or salts as described in embodiment 34, wherein BL 1 yes Provided herein as embodiment 36 is a compound or salt as described in embodiment 35, wherein R x Halogen, hydroxyl, C 1-4 Haloalkyl or C 1-4 Alkyl. Provided herein as embodiment 37 is a compound or salt as described in embodiment 36, wherein R x is fluorine, hydroxy, methyl or monofluoromethyl.

[0059] Provided herein as embodiment 38 is a compound or salt as described in embodiment 37, wherein BL 1 yes Provided herein as embodiment 39 is a compound or salt as described in embodiment 38, wherein BL 1 yes Provided herein as embodiment 40 is a compound or salt as described in embodiment 39, wherein BL 1 yes Provided herein as embodiment 41 is a compound or salt as described in any one of embodiment 40, wherein BL 1 yes Provided herein as embodiment 42 is a compound or salt as described in embodiment 40, wherein BL 1 yes Provided herein as embodiment 43 is a compound or salt as described in embodiment 40, wherein BL 1 yes Provided herein as embodiment 44 is a compound or salt as described in embodiment 40, wherein BL 1 yes

[0060] Provided herein as embodiment 45 are compounds or salts as described in embodiment 1, wherein B is a 4-10 membered heterocycloalkyl group having 0 additional heteroatoms. Provided herein as embodiment 46 are compounds or salts as described in embodiment 45, wherein p is 2. Provided herein as embodiment 47 are compounds or salts as described in embodiment 46, wherein BL 1 yes

[0061] Provided herein as embodiment 48 is a compound or salt as described in embodiment 47, wherein each R x are independently halogen. Provided herein as embodiment 49 are compounds or salts as described in embodiment 48, wherein both R x Provided herein as embodiment 50 is a compound or salt as described in embodiment 49, wherein BL 1 yes

[0062] Provided herein as embodiment 51 are compounds or salts as described in embodiment 1, wherein B is a 4-10 membered heterocycloalkyl group having one additional nitrogen heteroatom. Provided herein as embodiment 52 are compounds or salts as described in embodiment 51, wherein p is 2. Provided herein as embodiment 53 are compounds or salts as described in embodiment 52, wherein BL 1 yes

[0063] Provided herein as embodiment 54 is a compound or salt as described in embodiment 53, wherein each R x are independently halogen. Provided herein as embodiment 55 are compounds or salts as described in embodiment 54, wherein both R x Provided herein as embodiment 56 is a compound or salt as described in embodiment 55, wherein BL 1 yes

[0064] Provided herein as Example 57 is a compound or salt as described in Example 1 and is a compound of Formula (I):

[0065]

[0066] or a pharmaceutically acceptable salt of said compound, wherein:

[0067] X is N, CH2, O, S, S(O), S(O)(NR z ) or S(O)2;

[0068] Z is CH, C-halogen, C-CN, CC 1-4Alkyl, CC 1-4 Haloalkyl, CC 1-4 Alkoxy, CC 1-4 Haloalkoxy, CC 3-7 Cycloalkyl or N;

[0069] Q is CH, C-halogen, CC 1-4 Alkyl, CC 1-4 Haloalkyl or N;

[0070] n is 0, 1, 2, or 3;

[0071] m is 0, 1, 2, or 3;

[0072] p is 0, 1, 2, or 3;

[0073] q is 0, 1, 2, or 3;

[0074] x haloalkyl, C 1-4 Halogenated alkoxy, 5-7 membered heteroaryl, -TR y , or two R x Together with the same carbon atom or adjacent carbon atoms, they can form C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, wherein C 3-7 The cycloalkyl or 3-7 membered heterocycloalkyl groups are each further separated by 0-3 occurrences of R y Replace, or two R x can together form a bridged ring, wherein the bridge is selected from one of the following: -C 1-4 Alkylene, -C 1-4 Alkylene-OC 1-4 Alkylene-, -O-, -S- or -C 1-4 Alkylene-SC 1-4 Alkylene-, and each C 1-4 The alkylene group is further replaced by 0-2 occurrences of R y replace;

[0075] L is a key, C 1-6 Alkylene, -OC 1-6 Alkylene, -SC 1-6 Alkylene, NR z , O or S, where C 1-6 Alkylene, -OC 1-6 Alkylene and -SC 1-6 The alkylene chains are each replaced by 0-2 occurrences of R 2 replace;

[0076] -L 1 -L 2 -Yes-L 2 、-N(R z )C(O)-L2 、-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-5-6 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 ;

[0077] L 2 It 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 Alkynylidene, C 3-7 Cycloalkylene, C 1-4 Alkylene-C 3-7 Cycloalkylene, C 1-4 Halogenated alkylene-C3-7 Cycloalkylene, C 3-7 Cycloalkylene-C 1-4 Alkylene, C 1-6 Hydroxyalkylene or C 1-6 alkylene halide;

[0078] R 1 It is hydrogen, hydroxyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl or 4-15 membered heterocycloalkyl, wherein aryl, heteroaryl, cycloalkyl or heterocycloalkyl is each replaced by 0-3 occurrences of R 5 replace;

[0079] R 2 Halogen, hydroxyl, C 1-4 Alkyl, or two R on the same or adjacent carbon atoms 2 Can form C together 3-7 Cycloalkyl;

[0080] A is C 6-10 Aryl or 5-10 membered heteroaryl and q occurrences of R 6 replace;

[0081] R 4 It is hydrogen, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-7 Cycloalkyl or cyano;

[0082] Each R 5 are independently halogen, cyano, oxo, -TR y , hydroxyl, -N(R z )2、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or -OC 2-4 Alkynyl;

[0083] Each R 6 are independently halogen, hydroxy, cyano, -N(R z )2、-C(O)R z 、-C(O)OR z 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 2-4 Alkynyl or C 3-6 Cycloalkyl, or two R on adjacent carbon atoms6 Together they form C 3-7 Cycloalkyl;

[0084] 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-;

[0085] R y Is halogen, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, hydroxy, cyano or -N(R z )2; and

[0086] Each R z is hydrogen or C 1-4 alkyl.

[0087] Provided herein as embodiment 58 is a compound or salt as described in any one of embodiments 1-57, wherein Z is CH, CF, C-CN, C-CH3, C-CF3, C-OMe, C-Cl or N. Provided herein as embodiment 59 is a compound or salt as described in any one of embodiments 1-57, wherein Z is N. Provided herein as embodiment 60 is a compound or salt as described in any one of embodiments 1-57, wherein Z is CH. Provided herein as embodiment 61 is a compound or salt as described in any one of embodiments 1-57, wherein Z is CF.

[0088] Provided herein as embodiment 62 is a compound or salt as described in any of embodiments 1-57, wherein Q is CH or N. Provided herein as embodiment 63 is a compound or salt as described in any of embodiments 1-57, wherein Q is CH. Provided herein as embodiment 64 is a compound or salt as described in any of embodiments 1-57, wherein Q is N. Provided herein as embodiment 65 is a compound or salt as described in any of embodiments 1-57, wherein Z is N and Q is CH. Provided herein as embodiment 66 is a compound or salt as described in any of embodiments 1-57, wherein Z is CH and Q is CH. Provided herein as embodiment 67 is a compound or salt as described in any of embodiments 1-57, wherein Z is CF and Q is CH. Provided herein as embodiment 68 is a compound or salt as described in any of embodiments 1-57, wherein Z is N and Q is N.

[0089] Provided herein as embodiment 69 is a compound or salt as described in any one of embodiments 1-68, wherein L is replaced by 0-2 occurrences of R 2substituted -O-methylene or -O-ethylene. Provided herein as embodiment 70 is a compound or salt as described in embodiment 69, wherein L is R 2 Substituted-O-methylene.

[0090] Provided herein as embodiment 71 is a compound or salt as described in any one of embodiments 69-70, wherein R 1 It is R that appears 0-3 times 5 Substituted heterocycloalkyl. Provided herein as embodiment 72 is a compound or salt as described in embodiment 71, wherein R 1 It is R that appears 0-3 times 5 substituted 7a-(hexahydro-1H-pyrrolazine), 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). Provided herein as embodiment 73 is a compound or salt as described in embodiment 71, wherein R 1 is R that appears 0 times 5 substituted 7a-(hexahydro-1H-pyrrolazine), 6-(hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl) or 1-(7-oxabicyclo[2.2.1]heptanyl). Provided herein as embodiment 74 is a compound or salt as described in embodiment 73, wherein R 1 is R that appears 0 times 5 Substituted 7a-(hexahydro-1H-pyrrolizine).

[0091] Provided herein as embodiment 75 is a compound or salt as described in embodiment 71, wherein R 1 It is the one-time occurrence of R 5 substituted 7a-(hexahydro-1H-pyrrolazine), 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). Provided herein as embodiment 76 is a compound or salt as described in embodiment 75, wherein R 5 is independently halogen, oxo, methyl, methoxy or -O-(2-propynyl). Provided herein as embodiment 77 is a compound or salt as described in embodiment 75, wherein R 1 It is the one-time occurrence of R 5Substituted 7a-(hexahydro-1H-pyrrolizine). Provided herein as embodiment 78 is a compound or salt as described in embodiment 77, wherein R 5 is independently fluoro or -O-(2-propynyl). Provided herein as embodiment 79 is a compound or salt as described in embodiment 78, wherein R 5 is fluoro. Provided herein as embodiment 80 is a compound or salt as described in embodiment 75, wherein R 1 It is the one-time occurrence of R 5 Substituted 2-pyridinyl. Provided herein as embodiment 81 is a compound or salt as described in embodiment 80, wherein R 5 It's methyl.

[0092] Provided herein as embodiment 82 is a compound or salt as described in embodiment 71, wherein R 1 It is the R that appears twice 5 Substituted 2-pyrrolidinyl. Provided herein as embodiment 83 is a compound or salt as described in embodiment 82, wherein each R 5 is independently methyl, fluoro or methoxy.

[0093] Provided herein as embodiment 84 is a compound or salt as described in embodiment 69, wherein L is replaced by 1 occurrence of R 2 Substituted-O-methylene. Provided herein as embodiment 85 is a compound or salt as described in embodiment 84, wherein R 2 It is C 1-4 Alkyl (eg, methyl).

[0094] Provided herein as embodiment 86 is a compound or salt as described in embodiment 85, wherein R 1 It is R that appears 0-3 times 5 Substituted 2-pyrrolidines. Provided herein as embodiment 87 are compounds or salts as described in embodiment 86, wherein R 1 It is R that appears once 5 Substituted 2-pyrrolidine. Provided herein as embodiment 88 is a compound or salt as described in embodiment 87, wherein R 5 It is C 1-4 Alkyl (eg, methyl).

[0095] Provided herein as embodiment 89 is a compound or salt as described in embodiment 69, wherein L is replaced by two occurrences of R 2 Substituted-O-ethylene. Provided herein as embodiment 90 is a compound or salt as described in embodiment 89, wherein both R 2 All C 1-4Alkyl (eg, methyl). Provided herein as embodiment 91 is a compound or salt as described in embodiment 90, wherein R 1 It is a hydroxyl group.

[0096] Provided herein as embodiment 92 is a compound or salt as described in embodiment 69, wherein L is replaced by two occurrences of R 2 Provided herein as embodiment 93 is a compound or salt as described in embodiment 92, wherein the two R 2 Together with the same carbon atom, it forms C 3-7 Cycloalkyl (eg, cyclopropyl).

[0097] Provided herein as embodiment 94 is a compound or salt as described in any one of embodiments 92-93, wherein R 1 It is R that appears 0-3 times 5 Substituted N-azetidinyl or -N(R z ) 2. Provided herein as embodiment 95 is a compound or salt as described in embodiment 94, wherein R 1 It is the one-time occurrence of R 5 Substituted N-azetidinyl. Provided herein as embodiment 96 is a compound or salt as described in embodiment 95, wherein R 5 is fluoro. Provided herein as embodiment 97 is a compound or salt as described in any one of embodiments 92-93, wherein R 1 Yes-N(R z )2 and R z It's methyl.

[0098] Provided herein as embodiment 98 is the compound or salt of any one of embodiments 1-68, wherein L is O.

[0099] Provided herein as embodiment 99 is a compound or salt as described in embodiment 98, wherein R 1 It is R that appears 0-3 times 5 Substituted heterocycloalkyl. Provided herein as embodiment 100 is a compound or salt as described in embodiment 99, wherein R 1 It is R that appears 0-3 times 5 substituted 3-tetrahydrofuranyl or 4-piperidinyl. Provided herein as embodiment 101 is a compound or salt as described in embodiment 100, wherein R 1 is R that appears 0 times 5 Substituted 3-tetrahydrofuranyl. Provided herein as embodiment 102 is a compound or salt as described in embodiment 101, wherein R 1 It is the one-time occurrence of R 5Substituted 4-piperidinyl. Provided herein as embodiment 103 is a compound or salt as described in embodiment 102, wherein R 5 It's methyl.

[0100] Provided herein as embodiment 104 is a compound or salt as described in any one of embodiments 1-68, wherein L is C 1-6 Alkylene or -OC 1-6 Alkylene. Provided herein as embodiment 105 is a compound or salt as described in embodiment 104, wherein L is methylene or -O-methylene. Provided herein as embodiment 106 is a compound or salt as described in embodiment 105, wherein R 1 It's hydrogen.

[0101] Provided herein as embodiment 107 is a compound or salt as described in any one of embodiments 1-68, wherein L is a bond. Provided herein as embodiment 108 is a compound or salt as described in embodiment 107, wherein R 1 It is the one-time occurrence of R 5 Substituted N-piperazinyl. Provided herein as embodiment 109 is a compound or salt as described in embodiment 108, wherein R 5 It's methyl.

[0102] Provided herein as embodiment 110 is a compound or salt as described in any one of embodiments 1-68, wherein -LR 1 yes Methoxy or methyl.

[0103] Provided herein as embodiment 111 is a compound or salt as described in embodiment 110, wherein -LR 1 yes Methoxy or methyl.

[0104] Provided herein as embodiment 112 is a compound or salt as described in embodiment 111, wherein -LR 1 yes Provided herein as embodiment 113 is a compound or salt as described in embodiment 112, wherein -LR 1 yes Provided herein as embodiment 114 is a compound or salt as described in embodiment 112, wherein -LR 1 yes Provided herein as embodiment 115 is a compound or salt as described in embodiment 112, wherein -LR 1 yes Provided herein as embodiment 116 is a compound or salt as described in embodiment 112, wherein -LR 1 yes Provided herein as embodiment 117 is a compound or salt as described in embodiment 112, wherein -LR 1 yes

[0105] Provided herein as embodiment 118 is a compound or salt as described in any of embodiments 57-117, wherein X is O. Provided herein as embodiment 119 is a compound or salt as described in embodiment 118, wherein n is 1 and m is 1. Provided herein as embodiment 120 is a compound or salt as described in embodiment 119, wherein p is 0.

[0106] Provided herein as embodiment 121 are compounds or salts as described in embodiment 119, wherein p is 1. Provided herein as embodiment 122 are compounds or salts as described in embodiment 121, wherein R x is methyl, methoxy or hydroxy. Provided herein as embodiment 123 is a compound or salt as described in embodiment 122, wherein R x is hydroxy. Provided herein as embodiment 124 is a compound or salt as described in embodiment 122, wherein R x It's methyl.

[0107] Provided herein as embodiment 125 is a compound or salt as described in embodiment 119, wherein p is 2. Provided herein as embodiment 126 is a compound or salt as described in embodiment 125, wherein both R x Together with the same carbon atom, it forms a further 0 occurrence of R y Substituted cyclobutyl. Provided herein as embodiment 127 is a compound or salt as described in embodiment 125, wherein both R x Together with the same carbon atom, it forms a further R y Substituted cyclobutyl. Provided herein as embodiment 128 is a compound or salt as described in embodiment 127, wherein R y It's methyl.

[0108] Provided herein as embodiment 129 is a compound or salt as described in embodiment 118, wherein n is 1 and m is 2, or n is 2 and m is 1. Provided herein as embodiment 130 is a compound or salt as described in embodiment 129, wherein p is 0.

[0109] Provided herein as embodiment 131 are compounds or salts as described in embodiment 129, wherein p is 1. Provided herein as embodiment 132 are compounds or salts as described in embodiment 131, wherein Rx It is C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or hydroxy. Provided herein as embodiment 133 is a compound or salt as described in embodiment 132, wherein R x is methyl. Provided herein as embodiment 134 is a compound or salt as described in embodiment 132, wherein R x is monofluoromethyl. Provided herein as embodiment 135 is a compound or salt as described in embodiment 132, wherein R x Yes - CD3.

[0110] Provided herein as embodiment 136 is a compound or salt as described in embodiment 129, wherein p is 2. Provided herein as embodiment 137 is a compound or salt as described in embodiment 136, wherein both R x Together with the same carbon atom, it forms a further 0 occurrence of R y Substituted cyclobutyl.

[0111] Provided herein as embodiment 138 is a compound or salt as described in any one of embodiments 118-137, wherein yes

[0112] Provided herein as embodiment 139 is a compound or salt as described in embodiment 138, wherein yes Provided herein as embodiment 140 is a compound or salt as described in embodiment 139, wherein yes Provided herein as embodiment 141 is a compound or salt as described in embodiment 140, wherein yes Provided herein as embodiment 142 is a compound or salt as described in embodiment 140, wherein yes Provided herein as embodiment 143 is a compound or salt as described in embodiment 140, wherein yes Provided herein as embodiment 144 is a compound or salt as described in embodiment 140, wherein yes Provided herein as embodiment 145 is a compound or salt as described in embodiment 140, wherein yes Provided herein as embodiment 146 is a compound or salt as described in embodiment 140, wherein yes

[0113] Provided herein as embodiment 147 is a compound or salt as described in any of embodiments 57-117, wherein X is N. Provided herein as embodiment 148 is a compound or salt as described in embodiment 147, wherein n is 1 and m is 2. Provided herein as embodiment 149 is a compound or salt as described in embodiment 148, wherein p is 0.

[0114] Provided herein as embodiment 150 is a compound or salt as described in any one of embodiments 147-149, wherein yes

[0115] Provided herein as embodiment 151 is a compound or salt as described in embodiment 147, wherein n is 3 and m is 1. Provided herein as embodiment 152 is a compound or salt as described in embodiment 151, wherein p is 2. Provided herein as embodiment 153 is a compound or salt as described in embodiment 152, wherein both R x Together they form a methylene-bridged ring.

[0116] Provided herein as embodiment 154 is a compound or salt as described in any one of embodiments 151-153, wherein yes Provided herein as embodiment 155 is a compound or salt as described in embodiment 154, wherein yes

[0117] Provided herein as embodiment 156 is a compound or salt as described in any of embodiments 57-117, wherein X is CH. Provided herein as embodiment 157 is a compound or salt as described in embodiment 156, wherein n is 0 and m is 1, or n is 1 and m is 0. Provided herein as embodiment 158 is a compound or salt as described in embodiment 157, wherein p is 0.

[0118] Provided herein as embodiment 159 is a compound or salt as described in embodiment 157, wherein p is 1. Provided herein as embodiment 160 is a compound or salt as described in embodiment 159, wherein R x It is C 1-4 Alkyl (eg, methyl).

[0119] Provided herein as embodiment 161 is a compound or salt as described in embodiment 156, wherein n is 1 and m is 1. Provided herein as embodiment 162 is a compound or salt as described in embodiment 161, wherein p is 0.

[0120] Provided herein as embodiment 163 are compounds or salts as described in embodiment 161, wherein p is 1. Provided herein as embodiment 164 are compounds or salts as described in embodiment 163, wherein R x is methyl, methoxy, hydroxy, monofluoromethyl or fluoro. Provided herein as embodiment 165 is a compound or salt as described in embodiment 164, wherein R x is hydroxy. Provided herein as embodiment 166 is a compound or salt as described in embodiment 164, wherein R x is methyl. Provided herein as embodiment 167 is a compound or salt as described in embodiment 164, wherein R x It is a monofluoromethyl group.

[0121] Provided herein as embodiment 168 is a compound or salt as described in embodiment 161, wherein p is 2. Provided herein as embodiment 169 is a compound or salt as described in embodiment 168, wherein both R x All are halogens (eg, fluorine).

[0122] Provided herein as embodiment 170 is a compound or salt as described in embodiment 156, wherein n is 1 and m is 2, or n is 2 and m is 1. Provided herein as embodiment 171 is a compound or salt as described in embodiment 170, wherein p is 0.

[0123] Provided herein as embodiment 172 is a compound or salt as described in embodiment 170, wherein p is 1. Provided herein as embodiment 173 is a compound or salt as described in embodiment 172, wherein R x is methyl, methoxy, monofluoromethyl, hydroxy or fluoro. Provided herein as embodiment 174 is a compound or salt as described in embodiment 173, wherein R x is methyl. Provided herein as embodiment 175 is a compound or salt as described in embodiment 173, wherein R x is hydroxy. Provided herein as embodiment 175 is a compound or salt as described in embodiment 173, wherein R x It is a monofluoromethyl group.

[0124] Provided herein as embodiment 177 is a compound or salt as described in any one of embodiments 161-176, wherein yes

[0125] Provided herein as embodiment 178 is a compound or salt as described in embodiment 177, wherein yes

[0126] Provided herein as embodiment 179 is a compound or salt as described in embodiment 178, wherein yes Provided herein as embodiment 180 is a compound or salt as described in embodiment 179, wherein yes Provided herein as embodiment 181 is a compound or salt as described in embodiment 180, wherein yes Provided herein as embodiment 182 is a compound or salt as described in embodiment 180, wherein yes Provided herein as embodiment 183 is a compound or salt as described in embodiment 180, wherein yes Provided herein as embodiment 184 is a compound or salt as described in embodiment 180, wherein yes Provided herein as embodiment 185 is a compound or salt as described in embodiment 180, wherein yes Provided herein as embodiment 186 is a compound or salt as described in embodiment 180, wherein yes

[0127] Provided herein as embodiment 187 are compounds or salts as described in any of embodiments 57-117, wherein X is CH2. Provided herein as embodiment 188 are compounds or salts as described in embodiment 187, wherein n is 1 and m is 0, or m is 0 and n is 1. Provided herein as embodiment 189 are compounds or salts as described in embodiment 188, wherein both R x Together with the same carbon atom, it forms a further 0 occurrence of R y Substituted 3-7 membered heterocycloalkyl (eg, 2-azetidinyl).

[0128] Provided herein as embodiment 190 is a compound or salt as described in embodiment 187, wherein n is 1 and m is 1. Provided herein as embodiment 191 is a compound or salt as described in embodiment 190, wherein p is 2. Provided herein as embodiment 192 is a compound or salt as described in embodiment 191, wherein both Rx Together with the same carbon atom, it forms C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl, wherein C 3-7 The cycloalkyl or 3-7 membered heterocycloalkyl groups are each further separated by 0-3 occurrences of R y Substitution. Provided herein as embodiment 193 is a compound or salt as described in embodiment 192, wherein both R x Together with the same carbon atom, it forms a further 0 occurrence of R y substituted cyclopropyl or cyclobutyl. Provided herein as embodiment 194 is a compound or salt as described in embodiment 192, wherein both R x Together with the same carbon atom, it forms a further 0 occurrence of R y Substituted cyclopropyl. Provided herein as embodiment 195 is a compound or salt as described in embodiment 192, wherein both R x Together with the same carbon atom, it forms a further 0 occurrence of R y Substituted cyclobutyl. Provided herein as embodiment 196 is a compound or salt as described in embodiment 192, wherein both R x Together with the same carbon atom, it forms a further R y Substituted cyclobutyl. Provided herein as embodiment 197 is a compound or salt as described in embodiment 196, wherein R y is a methyl group or a hydroxy group.

[0129] Provided herein as embodiment 198 is a compound or salt as described in embodiment 192, wherein both R x Together with the same carbon atom, it forms a further 0 occurrence of R y Substituted 3-7 membered heterocycloalkyl (eg, 2-azetidinyl or 2-tetrahydrofuranyl).

[0130] Provided herein as embodiment 199 is a compound or salt as described in embodiment 191, wherein both R x Together with the adjacent carbon atoms, it forms C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl, wherein C 3-7 The cycloalkyl or 3-7 membered heterocycloalkyl groups are each further separated by 0-3 occurrences of R y Substitution. Provided herein as embodiment 200 is a compound or salt as described in embodiment 199, wherein both R x Together with the adjacent carbon atoms, it forms a further 0 occurrences of R y Substituted C 3-7 Cycloalkyl (eg, cyclopropyl). Provided herein as embodiment 201 is a compound or salt as described in embodiment 199, wherein both R xTogether with the adjacent carbon atoms, it forms a further 0 occurrences of R y Substituted 3-7 membered heterocycloalkyl (eg, azetidinyl, 2-tetrahydrofuranyl, 2-pyrrolidinyl or 3-pyrrolidinyl). Provided herein as embodiment 202 is a compound or salt as described in embodiment 201, wherein both R x Together with the adjacent carbon atoms, it forms a further 0 occurrences of R y Substituted 2-pyrrolidinyl.

[0131] Provided herein as embodiment 203 is a compound or salt as described in embodiment 191, wherein both R x together to form a bridged ring, wherein the bridge is selected from one of the following: -C 1-4 Alkylene, -C 1-4 Alkylene-OC 1-4 Alkylene-, -O-, -S- or -C 1-4 Alkylene-SC 1-4 Alkylene-, and each C 1-4 The alkylene group is further replaced by 0-2 occurrences of R y Substitution. Provided herein as embodiment 204 is a compound or salt as described in embodiment 203, wherein both R x Together they form R which is further represented by 0 occurrences y Substituted C 1-4 Alkylene groups (eg, ethylene) bridge the rings.

[0132] Provided herein as embodiment 205 is a compound or salt as described in any one of embodiments 187-204, wherein yes

[0133] Provided herein as embodiment 206 is a compound or salt as described in embodiment 205, wherein yes Provided herein as embodiment 207 is a compound or salt as described in embodiment 206, wherein yes Provided herein as embodiment 208 is a compound or salt as described in embodiment 207, wherein yes Provided herein as embodiment 209 is a compound or salt as described in embodiment 207, wherein yes Provided herein as embodiment 210 is a compound or salt as described in embodiment 207, wherein yes

[0134] Provided herein as embodiment 211 is a compound or salt as described in any one of embodiments 1-210, wherein A is C 6-10 aryl (e.g., phenyl, naphthyl, 8-(1,2,3,4-tetrahydroquinolinyl) or 5-(1,2,3,4-tetrahydronaphthyl)). Provided herein as embodiment 212 is a compound or salt as described in embodiment 211, wherein A is phenyl. Provided herein as embodiment 213 is a compound or salt as described in embodiment 212, wherein q is 0.

[0135] Provided herein as embodiment 214 are compounds or salts as described in embodiment 212, wherein q is 1. Provided herein as embodiment 215 are compounds or salts as described in embodiment 214, wherein R 6 is halogenated (eg, chloro).

[0136] Provided herein as embodiment 216 is a compound or salt as described in embodiment 212, wherein q is 2. Provided herein as embodiment 217 is a compound or salt as described in embodiment 216, wherein each R 6 is halo (eg, chloro or fluoro), hydroxy, or cyano. Provided herein as embodiment 218 is a compound or salt as described in embodiment 217, wherein one R 6 It's chlorine, another R 6 is cyano. Provided herein as embodiment 219 is a compound or salt as described in embodiment 217, wherein one R 6 It's chlorine, another R 6 is fluoro. Provided herein as embodiment 220 is a compound or salt as described in embodiment 217, wherein one R 6 It's chlorine, another R 6 It is a hydroxyl group.

[0137] Provided herein as embodiment 221 are compounds or salts as described in embodiment 212, wherein q is 3. Provided herein as embodiment 222 are compounds or salts as described in embodiment 221, wherein one R 6 is halogenated (eg, fluoro), another R 6 It is C 1-4 Alkyl (e.g., methyl), the last R 6 Yes-N(R z )2 (e.g., -NH2).

[0138] Provided herein as embodiment 223 are compounds or salts as described in embodiment 211, wherein A is 5-(1,2,3,4-tetrahydronaphthyl). Provided herein as embodiment 224 are compounds or salts as described in embodiment 223, wherein q is 0. Provided herein as embodiment 225 are compounds or salts as described in embodiment 224, wherein q is 1. Provided herein as embodiment 226 are compounds or salts as described in embodiment 225, wherein R 6 It is a hydroxyl group.

[0139] Provided herein as embodiment 227 is a compound or salt as described in embodiment 211, wherein A is 8-(1,2,3,4-tetrahydroquinolinyl). Provided herein as embodiment 228 is a compound or salt as described in embodiment 227, wherein q is 0.

[0140] Provided herein as embodiment 229 is a compound or salt as described in embodiment 211, wherein A is naphthyl. Provided herein as embodiment 230 is a compound or salt as described in embodiment 229, wherein q is 0.

[0141] Provided herein as embodiment 231 is a compound or salt as described in embodiment 229, wherein q is 1. Provided herein as embodiment 232 is a compound or salt as described in embodiment 231, wherein R 6 Is hydroxyl, halogen, C 1-4 Alkoxy or C 1-4 Alkyl. Provided herein as embodiment 233 is a compound or salt as described in embodiment 232, wherein R 6 is hydroxy. Provided herein as embodiment 234 is a compound or salt as described in embodiment 232, wherein R 6 is halo (eg, fluoro or chloro). Provided herein as embodiment 235 is a compound or salt as described in embodiment 232, wherein R 6 It is C 1-4 Alkoxy (eg, methoxy). Provided herein as embodiment 236 is a compound or salt as described in embodiment 232, wherein R 6 It is C 1-4 Alkyl (eg, methyl).

[0142] Provided herein as embodiment 237 is a compound or salt as described in embodiment 229, wherein q is 2. Provided herein as embodiment 238 is a compound or salt as described in embodiment 237, wherein each occurrence of R 6 Halogen, hydroxyl, cyano, C 1-4 Alkoxy or C 1-4 Alkyl. Provided herein as embodiment 239 is a compound or salt as described in embodiment 238, wherein each occurrence of R6 is fluorine, chlorine, cyano, hydroxy or methoxy.

[0143] Provided herein as embodiment 240 is a compound or salt as described in any one of embodiments 211-239, wherein AL 2 yes Provided herein as embodiment 241 is a compound or salt as described in embodiment 240, wherein AL 2 yes Provided herein as embodiment 242 is a compound or salt as described in embodiment 240, wherein AL 2 yes Provided herein as embodiment 243 is a compound or salt as described in embodiment 240, wherein AL 2 yes Provided herein as embodiment 244 is the compound or salt of embodiment 240, wherein AL 2 yes Provided herein as embodiment 245 is a compound or salt as described in embodiment 240, wherein AL 2 yes Provided herein as embodiment 246 is a compound or salt as described in embodiment 240, wherein AL 2 yes Provided herein as embodiment 247 is a compound or salt as described in embodiment 240, wherein AL 2 yes Provided herein as embodiment 248 is a compound or salt as described in embodiment 240, wherein AL 2 yes Provided herein as embodiment 249 is a compound or salt as described in embodiment 248, wherein AL 2 yes

[0144] Provided herein as embodiment 250 is a compound or salt as described in any of embodiments 1-210, wherein A is a 5-10 membered heteroaryl (e.g., 3-pyrimidinyl, 4-indazolyl, 4-isoquinolinyl, 4-(5,6,7,8)-tetrahydroisoquinolinyl, or 7-indazolyl).

[0145] Provided herein as embodiment 251 are compounds or salts as described in embodiment 250, wherein A is 3-pyrimidinyl. Provided herein as embodiment 252 are compounds or salts as described in embodiment 251, wherein q is 1. Provided herein as embodiment 253 are compounds or salts as described in embodiment 252, wherein R 6 is halogenated (eg, chloro).

[0146] Provided herein as embodiment 254 is a compound or salt as described in embodiment 250, wherein A is 4-isoquinolinyl. Provided herein as embodiment 255 is a compound or salt as described in embodiment 252, wherein q is 0.

[0147] Provided herein as embodiment 256 is a compound or salt as described in embodiment 250, wherein A is 4-(5,6,7,8)-tetrahydroisoquinolinyl. Provided herein as embodiment 257 is a compound or salt as described in embodiment 256, wherein q is 0.

[0148] Provided herein as embodiment 258 is a compound or salt as described in embodiment 250, wherein A is 4-indazolyl. Provided herein as embodiment 259 is a compound or salt as described in embodiment 258, wherein q is 0.

[0149] Provided herein as embodiment 260 is a compound or salt as described in embodiment 258, wherein q is 1. Provided herein as embodiment 261 is a compound or salt as described in embodiment 260, wherein R 6 Halogenated is C 1-4 Alkyl, halo, C 1-4 Haloalkyl or -C(O)OR z Provided herein as embodiment 262 is a compound or salt as described in embodiment 261, wherein R 6 is halo (eg, fluoro or chloro). Provided herein as embodiment 263 is a compound or salt as described in embodiment 261, wherein R 6 It is C 1-4 Alkyl (eg, methyl). Provided herein as embodiment 264 is a compound or salt as described in embodiment 261, wherein R 6 It is C 1-4 Halogenated alkyl (eg, trifluoromethyl). Provided herein as embodiment 265 is a compound or salt as described in embodiment 261, wherein R 6 Yes-C(O)OR z (e.g., -C(O)OtBu).

[0150] Provided herein as embodiment 266 is a compound or salt as described in embodiment 258, wherein q is 2. Provided herein as embodiment 267 is a compound or salt as described in embodiment 266, wherein one R 6 is halogenated (e.g., chloro), the other R 6 Yes-C(O)R z(eg, -C(O)CH3). Provided herein as embodiment 268 is a compound or salt as described in embodiment 266, wherein two R on adjacent carbon atoms are 6 Together they form C 3-7 Cycloalkyl (eg, cyclopentyl).

[0151] Provided herein as embodiment 269 are compounds or salts as described in embodiment 250, wherein A is 7-indazolyl. Provided herein as embodiment 270 are compounds or salts as described in embodiment 269, wherein q is 2. Provided herein as embodiment 271 are compounds or salts as described in embodiment 270, wherein one R 6 It's chlorine, another R 6 It's methyl.

[0152] Provided herein as embodiment 272 is a compound or salt as described in any one of embodiments 250-271, wherein AL 2 yes Provided herein as embodiment 273 is a compound or salt as described in embodiment 272, wherein AL 2 yes Provided herein as embodiment 274 is a compound or salt as described in embodiment 273, wherein AL 2 yes Provided herein as embodiment 275 is a compound or salt as described in embodiment 273, wherein AL 2 yes Provided herein as embodiment 276 is a compound or salt as described in embodiment 273, wherein AL 2 yes Provided herein as embodiment 277 is a compound or salt as described in embodiment 273, wherein AL 2 yes

[0153] Provided herein as embodiment 278 is a compound or salt as described in any one of embodiments 1-277, wherein -L 1 -L 2 -Yes-N(R z )-C(O)-L 2 Provided herein as embodiment 279 is a compound or salt as described in embodiment 278, wherein R z Is hydrogen. Provided herein as embodiment 280 is a compound or salt as described in embodiment 279, wherein L 2It is n-propylene, 1-fluoro-n-propylene, n-butylene, 1-fluoro-n-butylene, 1-fluoro-n-pentylene, n-pentylene, methylene-O-ethylene, methylene-O-n-propylene, -CHF-CH2-cyclopropylene- or -CH2CH2-cyclopropylene-.

[0154] Provided herein as embodiment 281 is a compound or salt as described in embodiment 278, wherein R z is methyl. Provided herein as embodiment 282 is a compound or salt as described in embodiment 281, wherein L 2 Is n-propylene, n-butylene, 1-fluoro-n-butylene, -CHF-CH2-cyclopropylene-, methylene-O-ethylene or -CH2CH2-cyclopropylene-. Provided herein as embodiment 283 is a compound or salt as described in embodiment 278, wherein -L 1 -L 2 -yes

[0155] Provided herein as embodiment 284 is a compound or salt as described in any one of embodiments 1-277, wherein -L 1 -L 2 -Yes-OC(O)-L 2 Provided herein as embodiment 285 is a compound or salt as described in embodiment 284, wherein L 2 Is methylene-O-n-propylene, n-propylene-O-, n-butylene, 1-methyl-n-butylene, trans-n-propylene, cis-n-butylene, n-pentylene, -CHF-CH2-cyclopropylene-, -methylene-O-ethylene, -ethylene-cyclopropylene- or n-propylene. Provided herein as Example 286 are compounds or salts as described in Example 284, wherein -L 1 -L 2 -yes

[0156] Provided herein as embodiment 287 is a compound or salt as described in any one of embodiments 1-277, wherein -L 1 -L 2 -Yes-OC(O)-OL 2 Provided herein as embodiment 288 is a compound or salt as described in embodiment 287, wherein L 2 Is ethylene, n-propylene, n-butylene, 2-methyl-n-propylene, cis-2-propylene, trans-2-propylene or -CH2-cyclopropylene. Provided herein as embodiment 289 is a compound or salt as described in embodiment 287, wherein -L1 -L 2 -yes Provided herein as embodiment 290 is a compound or salt as described in embodiment 289, wherein -L 1 -L 2 -yes Provided herein as embodiment 291 is a compound or salt as described in embodiment 290, wherein -L 1 -L 2 -yes

[0157] Provided herein as embodiment 292 is a compound or salt as described in any one of embodiments 1-277, wherein -L 1 -L 2 -Yes-C 1-4 Alkylene-S(O)2-L 2 Provided herein as embodiment 293 is a compound or salt as described in embodiment 292, wherein -L 1 -L 2 - is - methylene-S(O)2-L 2 Provided herein as embodiment 294 is a compound or salt as described in embodiment 293, wherein L 2 Provided herein as embodiment 295 is a compound or salt as described in embodiment 292, wherein -L 1 -L 2 -yes

[0158] Provided herein as embodiment 296 is a compound or salt as described in any one of embodiments 1-277, wherein -L 1 -L 2 -Yes-C 1-4 Alkylene-S(O)-L 2 Provided herein as embodiment 297 is a compound or salt as described in embodiment 296, wherein -L 1 -L 2 -Yes-Methylene-S(O)-L 2 Provided herein as embodiment 298 is a compound or salt as described in embodiment 297, wherein L 2 Provided herein as embodiment 299 is a compound or salt as described in embodiment 296, wherein -L 1 -L 2 -yes

[0159] Provided herein as embodiment 300 is a compound or salt as described in any one of embodiments 1-277, wherein -L 1 -L 2 -Yes-C 1-4 Alkylene-SL 2 Provided herein as embodiment 301 is a compound or salt as described in embodiment 300, wherein -L 1 -L 2 -Yes-Methylene-SL 2 Provided herein as embodiment 302 is a compound or salt as described in embodiment 301, wherein L 2 Provided herein as embodiment 303 is a compound or salt as described in embodiment 300, wherein -L 1 -L 2 -yes

[0160] Provided herein as embodiment 304 is a compound or salt as described in any one of embodiments 1-277, wherein -L 1 -L 2 -Yes-OL 2 Provided herein as embodiment 305 is a compound or salt as described in embodiment 304, wherein L 2 Is n-butylene, n-pentylene, cis-2-pentenylene or trans-2-pentenylene. Provided herein as embodiment 306 is a compound or salt as described in embodiment 304, wherein -L 1 -L 2 -yes

[0161] Provided herein as embodiment 307 is a compound or salt as described in any one of embodiments 1-277, wherein -L 1 -L 2 - is a single bond. Provided herein as embodiment 308 is a compound or salt as described in embodiment 307, wherein L 2 Provided herein as embodiment 309 is a compound or salt as described in embodiment 307, wherein -L 1 -L 2 -yes

[0162] Provided herein as embodiment 310 is a compound or salt as described in any one of embodiments 1-277, wherein -L 1 -L 2 - is a single bond. Provided herein as embodiment 311 is a compound or salt as described in embodiment 310, wherein L 2 It is C 2-6Provided herein as embodiment 312 is a compound or salt as described in embodiment 311, wherein L 2 Is trans-3-hexenylene. Provided herein as embodiment 313 is a compound or salt as described in embodiment 310, wherein -L 1 -L 2 -yes

[0163] Provided herein as embodiment 314 is a compound or salt as described in any one of embodiments 1-277, wherein -L 1 -L 2 -Yes-NR z -C(O)-OL 2 Provided herein as embodiment 315 is a compound or salt as described in embodiment 314, wherein R z is hydrogen or methyl. Provided herein as embodiment 316 is a compound or salt as described in embodiment 315, wherein L 2 Is n-propylene, ethylene, n-butylene, -CH2-cyclopropylene. Provided herein as embodiment 317 is a compound or salt as described in embodiment 314, wherein -L 1 -L 2 -yes Provided herein as embodiment 318 is a compound or salt as described in embodiment 317, wherein -L 1 -L 2 -yes

[0164] Provided herein as embodiment 319 is a compound or salt as described in any one of embodiments 1-277, wherein -L 1 -L 2 -Yes-C(O)-OL 2 Provided herein as embodiment 320 is a compound or salt as described in embodiment 319, wherein L 2 Is n-propylene or n-butylene. Provided herein as embodiment 321 is a compound or salt as described in embodiment 319, wherein -L 1 -L 2 -yes

[0165] Provided herein as embodiment 322 is a compound or salt as described in any one of embodiments 1-277, wherein -L 1 -L 2 -Yes-OC(O)-NR z -L 2 Provided herein as embodiment 323 is a compound or salt as described in embodiment 322, wherein Rz Is hydrogen or methyl. Provided herein as embodiment 324 is a compound or salt as described in embodiment 323, wherein L 2 Is n-propylene or -methylene-cyclopropylene. Provided herein as embodiment 325 is a compound or salt as described in embodiment 322, wherein -L 1 -L 2 -yes

[0166] Provided herein as embodiment 326 is a compound or salt as described in any one of embodiments 1-277, wherein -L 1 -L 2 - is a 5-6 membered heteroaryl-L 2 Provided herein as embodiment 327 is a compound or salt as described in embodiment 326, wherein -L 1 -L 2 -yes Provided herein as embodiment 328 is a compound or salt as described in embodiment 327, wherein L 2 Is n-propylene, ethylene, cis-2-propylene or trans-2-propylene. Provided herein as embodiment 329 is a compound or salt as described in embodiment 326, wherein -L 1 -L 2 -yes Provided herein as embodiment 330 is a compound or salt as described in embodiment 329, wherein -L 1 -L 2 -yes

[0167] Provided herein as embodiment 331 is a compound or salt as described in any one of embodiments 1-277, wherein -L 1 -L 2 -Yes-C 1-4 Alkylene-5-6 membered heteroaryl-L 2 Provided herein as embodiment 332 is a compound or salt as described in embodiment 331, wherein -L 1 -L 2 -is-methylene-5-6 membered heteroaryl-L 2 Provided herein as embodiment 333 is a compound or salt as described in embodiment 332, wherein -L 1 -L 2 -yes Provided herein as embodiment 334 is a compound or salt as described in embodiment 333, wherein L 2 Is ethylene, n-propylene, cyclopropylene, cis-2-propylene or trans-2-propylene. Provided herein as embodiment 335 is a compound or salt as described in embodiment 331, wherein -L 1 -L 2 -yes

[0168] Provided herein as embodiment 336 is a compound or salt as described in any one of embodiments 1-277, wherein -L 1 -L 2 -Yes-C 1-4 Hydroxyalkylene-5-6 membered heteroaryl-L 2 Provided herein as embodiment 337 is a compound or salt as described in embodiment 336, wherein -L 1 -L 2 -is-hydroxymethylene-5-6 membered heteroaryl-L 2 Provided herein as embodiment 338 is a compound or salt as described in embodiment 337, wherein -L 1 -L 2 -yes Provided herein as embodiment 339 is a compound or salt as described in embodiment 338, wherein L 2 Provided herein as embodiment 340 is a compound or salt as described in embodiment 336, wherein -L 1 -L 2 -yes

[0169] Provided herein as embodiment 341 is a compound or salt as described in any one of embodiments 1-277, wherein -L 1 -L 2 -is-O-5-6 membered heteroaryl-L 2 Provided herein as embodiment 342 is a compound or salt as described in embodiment 341, wherein -L 1 -L 2 -yes Provided herein as embodiment 343 is a compound or salt as described in embodiment 342, wherein L 2 Provided herein as embodiment 344 is a compound or salt as described in embodiment 341, wherein -L 1 -L 2 -yes

[0170] Provided herein as embodiment 345 is a compound or salt as described in any one of embodiments 1-277, wherein -L 1 -L 2 - is -C(O)-. Provided herein as embodiment 346 is a compound or salt as described in embodiment 345, wherein L 2 Is n-propylene, -methylene-O-ethylene, -methylene-O-n-propylene or n-butylene. Provided herein as embodiment 347 is a compound or salt as described in embodiment 346, wherein -L 1 -L 2 -yes Provided herein as embodiment 348 is a compound or salt as described in embodiment 347, wherein -L 1 -L 2 -yes

[0171] Provided herein as embodiment 349 is a compound or salt as described in any one of embodiments 1-277, wherein -L 1 -L 2 -It's C 1-4 Alkylene-C(O)-L 2 Provided herein as embodiment 350 is a compound or salt as described in embodiment 349, wherein -L 1 -L 2 -is-methylene-C(O)-L 2 Provided herein as embodiment 351 is a compound or salt as described in embodiment 350, wherein L 2 Is n-propylene or n-butylene. Provided herein as embodiment 352 is a compound or salt as described in embodiment 349, wherein -L 1 -L 2 -yes Provided herein as embodiment 353 is a compound or salt as described in embodiment 349, wherein -L 1 -L 2 -is-ethylene-C(O)-L 2 Provided herein as embodiment 354 is a compound or salt as described in embodiment 353, wherein L 2 Is ethylene or n-propylene. Provided herein as embodiment 355 is a compound or salt as described in embodiment 349, wherein -L 1 -L 2 -yes

[0172] Provided herein as embodiment 356 is a compound or salt as described in any one of embodiments 1-277, wherein -L1 -L 2 -Yes-C 1-4 Alkylene-OC(O)OL 2 Provided herein as embodiment 357 is a compound or salt as described in embodiment 356, wherein -L 1 -L 2 - is - methylene-OC(O)OL 2 Provided herein as embodiment 358 is a compound or salt as described in embodiment 357, wherein L 2 Provided herein as embodiment 359 is a compound or salt as described in embodiment 356, wherein -L 1 -L 2 -yes

[0173] Provided herein as embodiment 360 is a compound or salt as described in any one of embodiments 1-277, wherein -L 1 -L 2 -It's C 1-4 Hydroxyalkylene-C(O)-L 2 Provided herein as embodiment 361 is a compound or salt as described in embodiment 360, wherein -L 1 -L 2 -is-hydroxymethylene-C(O)-L 2 Provided herein as embodiment 362 is a compound or salt as described in embodiment 361, wherein L 2 Provided herein as embodiment 363 is a compound or salt as described in embodiment 360, wherein -L 1 -L 2 -yes

[0174] Provided herein as embodiment 364 is a compound or salt as described in any one of embodiments 1-277, wherein -L 1 -L 2 -Yes-C 1-4 Alkylene-OL 2 Provided herein as embodiment 365 is a compound or salt as described in embodiment 364, wherein -L 1 -L 2 - is - methylene - OL 2 Provided herein as embodiment 366 is a compound or salt as described in embodiment 365, wherein L 2is n-butylene, 2,2-difluoro-n-butylene, trans-2-butylene, cis-2-butylene, 3-methyl-n-butylene, -ethylene-cyclopropylene- or ethylene-O-methylene. Provided herein as embodiment 367 is a compound or salt as described in embodiment 364, wherein -L 1 -L 2 -yes Provided herein as embodiment 368 is a compound or salt as described in embodiment 367, wherein -L 1 -L 2 -yes Provided herein as embodiment 369 is a compound or salt as described in embodiment 364, wherein -L 1 -L 2 - is methylmethylene-OL 2 Provided herein as embodiment 370 is a compound or salt as described in embodiment 369, wherein L 2 Provided herein as embodiment 371 is a compound or salt as described in embodiment 364, wherein -L 1 -L 2 -yes Provided herein as embodiment 372 is a compound or salt as described in embodiment 364, wherein -L 1 -L 2 - is ethylene-OL 2 Provided herein as embodiment 373 is a compound or salt as described in embodiment 372, wherein L 2 Is ethylene, n-propylene or methylenecyclopropylene. Provided herein as embodiment 374 is a compound or salt as described in embodiment 364, wherein -L 1 -L 2 -yes Provided herein as embodiment 375 is a compound or salt as described in embodiment 374, wherein -L 1 -L 2 -yes

[0175] Provided herein as embodiment 376 is a compound or salt as described in any one of embodiments 1-277, wherein -L 1 -L 2 -Yes-C 1-4 Alkylene-C(O)OL 2 Provided herein as embodiment 377 is a compound or salt as described in embodiment 376, wherein -L 1 -L 2 -is-methylene-C(O)OL 2Provided herein as embodiment 378 is a compound or salt as described in embodiment 377, wherein L 2 Is ethylene, n-propylene or 2-methyl-n-propylene. Provided herein as embodiment 379 is a compound or salt as described in embodiment 376, wherein -L 1 -L 2 -yes

[0176] Provided herein as embodiment 380 is a compound or salt as described in any one of embodiments 1-277, wherein -L 1 -L 2 -Yes-C 1-4 Alkylene-OC(O)-L 2 Provided herein as embodiment 381 is a compound or salt as described in embodiment 380, wherein -L 1 -L 2 - is - methylene-OC(O)OL 2 Provided herein as embodiment 382 is a compound or salt as described in embodiment 381, wherein L 2 Provided herein as embodiment 383 is a compound or salt as described in embodiment 380, wherein -L 1 -L 2 - is - ethylene-OC(O)-L 2 Provided herein as embodiment 384 is a compound or salt as described in embodiment 383, wherein L 2 Is ethylene or n-propylene. Provided herein as embodiment 385 is a compound or salt as described in embodiment 380, wherein -L 1 -L 2 -yes

[0177] Provided herein as embodiment 386 is a compound or salt as described in any one of embodiments 1-277, wherein -L 1 -L 2 - is a single bond. Provided herein as embodiment 387 is a compound or salt as described in embodiment 386, wherein L 2 Is 2-hydroxy-n-hexylene or 3-hydroxy-n-hexylene. Provided herein as embodiment 388 is a compound or salt as described in embodiment 386, wherein -L 1 -L 2 -yes

[0178] Provided herein as embodiment 389 is a compound or salt as described in any one of embodiments 1-277, wherein -L1 -L 2 -Yes-OC(S)-OL 2 Provided herein as embodiment 390 is a compound or salt as described in embodiment 389, wherein L 2 Provided herein as embodiment 391 is a compound or salt as described in embodiment 389, wherein -L 1 -L 2 -yes

[0179] Provided herein as embodiment 392 is a compound or salt as described in any one of embodiments 1-391, wherein R 4 It is C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy, halogen or C 1-4 Provided herein as embodiment 393 is a compound or salt as described in embodiment 392, wherein R 4 It is C 1-4 alkyl, hydroxy or halogen. Provided herein as embodiment 394 is a compound or salt as described in embodiment 393, wherein R 4 It is C 1-4 Alkyl or halogen. Provided herein as embodiment 395 is a compound or salt as described in embodiment 394, wherein R 4 is halogen (eg, fluorine or chlorine). Provided herein as embodiment 396 is a compound or salt as described in embodiment 395, wherein R 4 It's fluorine.

[0180] Provided herein as embodiment 397 is the compound or salt of embodiment 1, wherein the compound is a compound of formula (II):

[0181]

[0182] Provided herein as embodiment 398 is the compound or salt of embodiment 1, wherein the compound is a compound of formula (III):

[0183]

[0184] Provided herein as embodiment 399 is the compound or salt of embodiment 1, wherein the compound is a compound of formula (IV):

[0185]

[0186] Provided herein as embodiment 400 is a compound or salt as described in embodiment 1, wherein the compound is a compound of formula (V):

[0187]

[0188] Provided herein as Embodiment 401 is a compound or salt as described in Embodiment 1, wherein the compound is selected from the compounds of Table 1:

[0189] Table 1

[0190]

[0191]

[0192]

[0193] Provided herein as embodiment 402 is a compound or salt as described in embodiment 1, wherein the compound is selected from the compounds of Table 2:

[0194] Table 2

[0195]

[0196]

[0197] Provided herein as embodiment 403 is a compound or salt as described in embodiment 1, wherein the compound is Provided herein as embodiment 404 is a compound or salt as described in embodiment 1, wherein the compound is Provided herein as embodiment 405 is a compound or salt as described in embodiment 1, wherein the compound is Provided herein as embodiment 406 is a compound or salt as described in embodiment 1, wherein the compound is Provided herein as embodiment 407 is a compound or salt as described in embodiment 1, wherein the compound is Provided herein as embodiment 408 is a compound or salt as described in embodiment 1, wherein the compound is Provided herein as embodiment 409 is a compound or salt as described in embodiment 1, wherein the compound is Provided herein as embodiment 410 is a compound or salt as described in embodiment 1, wherein the compound is Provided herein as embodiment 411 is a compound or salt as described in embodiment 1, wherein the compound is Provided herein as embodiment 412 is a compound or salt as described in embodiment 1, wherein the compound is

[0198] Provided herein as embodiment 413 is a compound or salt as described in embodiment 1, wherein the compound is selected from the compounds of Table 3:

[0199] Table 3

[0200]

[0201]

[0202] Provided herein as embodiment 414 is a compound or salt as described in embodiment 1, wherein the compound is selected from the compounds of Table 4:

[0203] Table 4

[0204]

[0205]

[0206] Provided herein as embodiment 415 is a compound or salt as described in embodiment 1, wherein the compound is Provided herein as embodiment 416 is a compound or salt as described in embodiment 1, wherein the compound is Provided herein as embodiment 417 is a compound or salt as described in embodiment 1, wherein the compound is Provided herein as embodiment 418 is a compound or salt as described in embodiment 1, wherein the compound is Provided herein as embodiment 419 is a compound or salt as described in embodiment 1, wherein the compound is Provided herein as embodiment 420 is a compound or salt as described in embodiment 1, wherein the compound is Provided herein as embodiment 421 is a compound or salt as described in embodiment 1, wherein the compound is Provided herein as embodiment 422 is a compound or salt as described in embodiment 1, wherein the compound is Provided herein as embodiment 423 is a compound or salt as described in embodiment 1, wherein the compound is Provided herein as embodiment 424 is a compound or salt as described in embodiment 1, wherein the compound is

[0207] Additional embodiments

[0208] Provided herein as an additional Example B1 is a compound of formula (BI):

[0209]

[0210] or a pharmaceutically acceptable salt of said compound, wherein:

[0211] X is N, CH2, O, S, S(O), S(O)(NR z ) or S(O)2;

[0212] Z is CH, CF, C-CN, C-OMe, C-Cl, or N;

[0213] Q is CH or N;

[0214] n is 0, 1, 2, or 3;

[0215] m is 0, 1, 2, or 3;

[0216] p is 0, 1, 2, or 3;

[0217] q is 0, 1, 2, or 3;

[0218] Each R x is hydroxy, halogen, oxo, cyano, -N(R z )2、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, 5-7 membered heteroaryl, -TR y , or two R x Together with the same carbon atom or adjacent carbon atoms, they can form C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, wherein C 3-7 The cycloalkyl or 3-7 membered heterocycloalkyl groups are each further separated by 0-3 occurrences of R y Replace, or two R x can together form a bridged ring, wherein the bridge is selected from one of the following: -C 1-4 Alkylene, -C 1-4 Alkylene-OC 1-4 Alkylene-, -O-, -S- or -C 1-4 Alkylene-SC 1-4 Alkylene-, and each C 1-4 The alkylene group is further replaced by 0-2 occurrences of R y replace;

[0219] 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, where C 1-6 Alkylene, -OC 1-6 Alkylene and -SC 1-6 The alkylene chains are each replaced by 0-2 occurrences of R 2 replace;

[0220] L 1 is a bond, -N(R z )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 a 5-6 membered heteroaryl group;

[0221] L 2 It 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 Alkynylidene, C 3-7 Cycloalkylene, C 1-4 Alkylene-C 3-7 Cycloalkylene, C 1-4 Halogenated alkylene-C 3-7 Cycloalkylene, C 3-7 Cycloalkylene-C 1-4 Alkylene or C 1-6 alkylene halide;

[0222] R 1 It is R that appears 0-3 times 5 Substituted hydrogen, hydroxy, aryl, heteroaryl, C 3-8 cycloalkyl or heterocycloalkyl;

[0223] R 2 Halogen, hydroxyl, C 1-4 Alkyl, or two R on the same or adjacent carbon atoms 2 Can form C together 3-7 Cycloalkyl;

[0224] A is R that appears q times 6 substituted aryl or heteroaryl groups;

[0225] R 4 It is hydrogen, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-7 Cycloalkyl or cyano;

[0226] Each R 5 are independently halogen, cyano, oxo, -TR y , hydroxyl, amino or C 1-4 alkyl;

[0227] Each R 6 are independently halogen, hydroxy, cyano, -N(R z )2、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 2-4 Alkynyl or C 3-6 Cycloalkyl;

[0228] 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-;

[0229] R y Is halogen, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, hydroxy, cyano or -N(R z )2; and

[0230] R z is hydrogen or C 1-4 alkyl.

[0231] Provided herein as embodiment B2 is the compound as described in embodiment B1 wherein Z is N and Q is CH.

[0232] Provided herein as embodiment B3 is the compound of embodiment B1 wherein L is replaced by 0-2 occurrences of R 2 substituted -O-methylene-, -O-ethylene-, -O-n-propylene- or -O-isopentylene-.

[0233] Provided herein as embodiment B4 is the compound as described in embodiment B1, wherein -LR 1 yes Methoxy or methyl. Provided herein as embodiment B5 is the compound as described in embodiment B4, wherein -LR 1 yes

[0234] Provided herein as embodiment B6 are compounds as described in embodiment B1, wherein X is O. Provided herein as embodiment B7 are compounds as described in embodiment B6, wherein n is 0 and m is 1, or n is 1 and m is 1. Provided herein as embodiment B8 are compounds as described in embodiment B7, wherein yes

[0235] Provided herein as embodiment B9 are compounds as described in embodiment B1, wherein X is S. Provided herein as embodiment B10 are compounds as described in embodiment B9, wherein n is 0 and m is 1, or n is 1 and m is 1. Provided herein as embodiment B11 are compounds as described in embodiment B10, wherein yes

[0236] Provided herein as embodiment B12 are compounds as described in embodiment B1, wherein X is N. Provided herein as embodiment B13 are compounds as described in embodiment B12, wherein n is 1 and m is 2. Provided herein as embodiment B14 are compounds as described in embodiment B13, wherein yes

[0237] Provided herein as embodiment B15 are compounds as described in embodiment B1, wherein x is CH2. Provided herein as embodiment B16 are compounds as described in 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. Provided herein as embodiment B17 are compounds as described in embodiment B16, wherein yes

[0238] Provided herein as embodiment B18 is a compound as described in embodiment 366, wherein B1 is aryl (e.g., phenyl, naphthyl, or 5-(1,2,3,4-tetrahydronaphthyl)). Provided herein as embodiment B19 is a compound as described in embodiment B18, wherein AL 2 yes

[0239] Provided herein as embodiment B20 is the compound as described in embodiment B1, wherein AL 2 is heteroaryl (eg, 4-indazolyl or 8-(1,2,3,4-tetrahydroquinolinyl)). Provided herein as embodiment B21 are compounds as described in embodiment B20, wherein AL 2yes

[0240] Provided herein as embodiment B22 is the compound as described in embodiment B1, wherein -L 1 -L 2 -Yes-N(R z )-C(O)-L 2 Provided herein as embodiment B23 is the compound as described in embodiment B22, wherein R z Is hydrogen. Provided herein as embodiment B24 is the compound as described in embodiment B23, wherein L 2 Is n-propylene, n-butylene, 1-fluoro-n-pentylene, n-pentylene or -CH2-cyclopropylene-. Provided herein as embodiment B25 is the compound as described in embodiment B22, wherein -L 1 -L 2 -yes

[0241] Provided herein as embodiment B26 is the compound as described in embodiment B1, wherein -L 1 -L 2 -Yes-OC(O)-L 2 Provided herein as embodiment B27 is the compound as described in embodiment B26, wherein L 2 Is n-propylene-O-, n-butylene, n-butenyl, n-pentylene or n-propylene. Provided herein as embodiment B28 is the compound as described in embodiment B26, wherein -L 1 -L 2 -yes

[0242] Provided herein as embodiment B29 is the compound as described in embodiment B1, wherein -L 1 -L 2 -Yes-OC(O)-OL 2 Provided herein as embodiment B30 is the compound as described in embodiment B29, wherein L 2 Is n-propylene or -CH2-cyclopropylene. Provided herein as embodiment B31 is the compound as described in embodiment B29, wherein -L 1 -L 2 -yes

[0243] Provided herein as embodiment B32 is the compound as described in embodiment B1, wherein -L 1 -L 2 -Yes-OL 2Provided herein as embodiment B33 is the compound as described in embodiment B32, wherein L 2 Is n-pentylene. Provided herein as Embodiment B34 is the compound as described in Embodiment B32, wherein -L 1 -L 2 -yes

[0244] Provided herein as embodiment B35 is the compound as described in embodiment B1, wherein -L 1 -L 2 -Yes-NR z -C(O)-OL 2 Provided herein as embodiment B36 is the compound as described in embodiment B35, wherein R z Is hydrogen. Provided herein as embodiment B37 is the compound as described in embodiment B36, wherein L 2 Is n-propylene or -CH2-cyclopropylene. Provided herein as embodiment B38 is the compound as described in embodiment B35, wherein -L 1 -L 2 -yes

[0245] Provided herein as embodiment B39 is the compound as described in embodiment B1, wherein -L 1 -L 2 -Yes-OC(O)-NR z -L 2 Provided herein as embodiment B40 is the compound as described in embodiment B39, wherein L 2 Is n-propylene or -CH2-cyclopropylene. Provided herein as embodiment B41 is the compound as described in embodiment B39, wherein -L 1 -L 2 -yes

[0246] Provided herein as embodiment B42 is the compound as described in embodiment B1, wherein -L 1 -L 2 - is a 5-6 membered heteroaryl. Provided herein as embodiment B43 is a compound as described in embodiment B42, wherein -L 1 -L 2 -yes Provided herein as embodiment B44 is the compound as described in embodiment B42, wherein -L 1 -L 2 -yes

[0247] Provided herein as embodiment B45 is the compound as described in embodiment B1, wherein -L 1 -L 2 - is absent. Provided herein as embodiment B46 is the compound as described in embodiment B45, wherein L 2 It is n-hexamethylene.

[0248] Provided herein as embodiment B47 is the compound as described in embodiment B1, wherein -L 1 -L 2 - is -C(O)-. Provided herein as embodiment B48 is a compound as described in embodiment B47, wherein L 2 Is n-butylene. Provided herein as Embodiment B49 is the compound as described in Embodiment B47, wherein -L 1 -L 2 -yes

[0249] Provided herein as embodiment B50 is the compound as described in embodiment B1, wherein R 4 It is C 1-4 alkyl or halogen. Provided herein as embodiment B51 is a compound as described in embodiment B1, wherein R 4 It's fluorine.

[0250] Provided herein as Example C1 is a compound having formula (CI):

[0251]

[0252] or a pharmaceutically acceptable salt of said compound, wherein:

[0253] X is N, CH2, O, S, S(O), S(O)(NR z ) or S(O)2;

[0254] Z is CH, CF, C-CN, C-OMe, C-Cl, or N;

[0255] Q is CH or N;

[0256] n is 0, 1, 2, or 3;

[0257] m is 0, 1, 2, or 3;

[0258] p is 0, 1, 2, or 3;

[0259] q is 0, 1, 2, or 3;

[0260] Each R x is hydroxy, halogen, oxo, cyano, -N(R z )2、C1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, 5-7 membered heteroaryl, -TR y , or two R x Together with the same carbon atom or adjacent carbon atoms, they can form C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, wherein C 3-7 The cycloalkyl or 3-7 membered heterocycloalkyl groups are each further separated by 0-3 occurrences of R y Replace, or two R x can together form a bridged ring, wherein the bridge is selected from one of the following: -C 1-4 Alkylene, -C 1-4 Alkylene-OC 1-4 Alkylene-, -O-, -S- or -C 1-4 Alkylene-SC 1-4 Alkylene-, and each C 1-4 The alkylene group is further replaced by 0-2 occurrences of R y replace;

[0261] 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, where C 1-6 Alkylene, -OC 1-6 Alkylene and -SC 1-6 The alkylene chains are each replaced by 0-2 occurrences of R 2 replace;

[0262] L 1 is a bond, -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 、-SL2 、-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-5-6 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 ;

[0263] L 2 It 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 Alkynylidene, C 3-7 Cycloalkylene, C 1-4 Alkylene-C 3-7 Cycloalkylene, C 1-4 Halogenated alkylene-C 3-7 Cycloalkylene, C 3-7 Cycloalkylene-C 1-4 Alkylene, C 1-6 Hydroxyalkylene or C 1-6 alkylene halide;

[0264] R 1 R does not exist and appears 0-3 times 5 Substituted hydroxy, aryl, heteroaryl, C 3-8 cycloalkyl or heterocycloalkyl;

[0265] R 2 Halogen, hydroxyl, C 1-4 Alkyl, or two R on the same or adjacent carbon atoms 2Can form C together 3-7 Cycloalkyl;

[0266] A is R that appears q times 6 substituted aryl or heteroaryl groups;

[0267] R 4 It is hydrogen, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-7 Cycloalkyl or cyano;

[0268] Each R 5 are independently halogen, cyano, oxo, -TR y , hydroxyl, amino or C 1-4 alkyl;

[0269] Each R 6 are independently halogen, hydroxy, cyano, -N(R z )2、-C(O)R z 、-C(O)OR z 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 2-4 Alkynyl or C 3-6 Cycloalkyl, or two R on adjacent carbon atoms 6 Together they form C 3-7 Cycloalkyl;

[0270] 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-;

[0271] R y Is halogen, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, hydroxy, cyano or -N(R z )2; and

[0272] R z is hydrogen or C 1-4 alkyl.

[0273] Provided herein as embodiment C2 is the compound as described in embodiment C1 wherein Z is N and Q is CH.

[0274] Provided herein as embodiment C3 are compounds as described in embodiment C2, wherein L is replaced by 0-2 occurrences of R 2 substituted -O-methylene-, -O-ethylene-, -O-n-propylene-, or -O-isopentylene. Provided herein as embodiment C4 is a compound as described in embodiment C3, wherein -LR 1 yes Methoxy or methyl. Provided herein as embodiment C5 is the compound as described in embodiment C4, wherein -LR 1 yes

[0275] Provided herein as embodiment C6 are compounds as described in 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. Provided herein as embodiment C7 are compounds as described in embodiment C6, wherein yes Provided herein as Example C8 is the compound as described in Example C7, yes

[0276] Provided herein as embodiment C9 is a compound as described in embodiment C1, X is O. Provided herein as embodiment C10 is a compound as described in embodiment C9, wherein yes

[0277] Provided herein as an embodiment C11 is a compound as described in embodiment C1, wherein X is CH2. Provided herein as an embodiment C12 is a compound as described in 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. Provided herein as an embodiment C13 is a compound as described in embodiment C12, wherein yes

[0278] Provided herein as embodiment C13 are compounds as described in embodiment C1, wherein A is aryl. Provided herein as embodiment C14 are compounds as described in embodiment C13, wherein AL 2 yes

[0279] Provided herein as embodiment C15 are compounds as described in embodiment C1, wherein A is heteroaryl. Provided herein as embodiment C16 are compounds as described in embodiment C15, wherein AL 2 yes Provided herein as embodiment C17 is the compound as described in embodiment C16, wherein AL 2 yes

[0280] Provided herein as embodiment C18 is the compound as described in embodiment C1, wherein -L 1 -L 2 -Yes-OC(O)-OL 2 Provided herein as embodiment C19 is the compound as described in embodiment C18, wherein L 2 Is ethylene, n-propylene, 2-methyl-n-propylene, cis-2-propylene, trans-2-propylene or -CH2-cyclopropylene. Provided herein as embodiment C20 is the compound as described in embodiment C19, wherein -L 1 -L 2 -yes Provided herein as embodiment C21 is the compound as described in embodiment C20, wherein -L 1 -L 2 -yes Provided herein as embodiment C22 is the compound of embodiment C21, wherein -L 1 -L 2 -yes

[0281] Provided herein as embodiment C23 is the compound as described in embodiment C1, wherein -L 1 -L 2 -Yes-OL 2 Provided herein as embodiment C24 is the compound as described in embodiment C23, wherein L 2 Is n-butylene, n-pentylene, cis-2-pentenylene or trans-2-pentenylene. Provided herein as embodiment C25 is the compound as described in embodiment C23, wherein -L 1 -L 2 -yes Provided herein as embodiment C26 is the compound as described in embodiment C25, wherein -L 1 -L 2 -yes

[0282] Provided herein as embodiment C27 is the compound as described in embodiment C1, wherein -L 1 -L 2 -Yes-C 1-4 Alkylene-OC(O)OL 2 Provided herein as embodiment C28 is the compound as described in embodiment C27, wherein L 2 Is ethylene. Provided herein as embodiment C29 is the compound as described in embodiment C27, wherein -L 1 -L 2 -yes

[0283] Provided herein as embodiment C30 is the compound as described in embodiment C1, wherein -L 1 -L 2 -Yes-C 1-4 Hydroxyalkylene-5-6 membered heteroaryl-L 2 Provided herein as embodiment C31 is the compound as described in embodiment C30, wherein -L 1 -L 2 -yes Provided herein as embodiment C32 is the compound of embodiment C31, wherein L 2 Is ethylene. Provided herein as embodiment C33 is the compound as described in embodiment C30, wherein -L 1 -L 2 -yes

[0284] Provided herein as embodiment C34 is the compound of embodiment C1, wherein -L 1 -L 2 -Yes-C 1-4 Alkylene-OL 2 Provided herein as embodiment C35 is the compound as described in embodiment C34, wherein -L 1 -L 2 - is - methylene - OL 2 Provided herein as embodiment C36 is the compound as described in embodiment C35, wherein L 2 Is n-butylene, 2,2-difluoro-n-butylene, trans-2-butylene, cis-2-butylene, 3-methyl-n-butylene, -ethylene-cyclopropylene- or ethylene-O-methylene. Provided herein as embodiment C37 is a compound as described in embodiment C34, wherein -L 1 -L 2 -yes Provided herein as embodiment C38 is the compound as described in embodiment C37, wherein -L 1 -L 2 -yes

[0285] Provided herein as embodiment C39 is the compound as described in embodiment C1, wherein -L 1 -L 2 - is ethylene-OL 2 Provided herein as embodiment C40 is the compound as described in embodiment C39, wherein L 2 Is ethylene, n-propylene or methylenecyclopropylene. Provided herein as embodiment C41 is the compound as described in embodiment C39, wherein -L 1 -L 2 -yes Provided herein as embodiment C42 is the compound as described in embodiment C41, wherein -L 1 -L 2 -yes

[0286] Provided herein as embodiment C43 is the compound as described in embodiment C1, wherein -L 1 -L 2 -Yes-NR z -C(O)-OL 2 Provided herein as embodiment C44 is the compound as described in embodiment C43, wherein R z Is hydrogen or methyl. Provided herein as embodiment C45 is the compound as described in embodiment C44, wherein L 2 Is n-propylene, ethylene, -CH2-cyclopropylene. Provided herein as embodiment C46 is the compound as described in embodiment C43, wherein -L 1 -L 2 -yes Provided herein as embodiment C47 is the compound as described in embodiment C46, wherein -L 1 -L 2 -yes

[0287] Provided herein as embodiment C48 is the compound as described in embodiment C1, wherein -L 1 -L 2 - is a 5-6 membered heteroaryl. Provided herein as embodiment C49 is a compound as described in embodiment C48, wherein -L 1 -L 2 -yes Provided herein as embodiment C50 is the compound as described in embodiment C48, wherein -L 1 -L 2 -yes Provided herein as embodiment C51 is the compound as described in embodiment C50, wherein -L 1 -L 2 -yes

[0288] Provided herein as embodiment C52 is the compound as described in embodiment C1, wherein -L 1 -L 2 - is -C(O)-. Provided herein as embodiment C53 is the compound as described in embodiment C52, wherein L 2 Is n-propylene, -methylene-O-n-propylene or n-butylene. Provided herein as embodiment C54 is the compound as described in embodiment C52, wherein -L 1 -L 2 -yes Provided herein as embodiment C55 is the compound as described in embodiment C54, wherein -L 1 -L 2 -yes

[0289] Provided herein as embodiment C56 is the compound as described in embodiment C1, wherein -L 1 -L 2 -Yes-C 1-4 Alkylene-5-6 membered heteroaryl-L 2 Provided herein as embodiment C57 is the compound as described in embodiment C56, wherein -L 1 -L 2 -yes Provided herein as embodiment C58 is the compound as described in embodiment C56, wherein -L 1 -L 2 -yes Provided herein as embodiment C59 is the compound as described in embodiment C58, wherein -L 1 -L 2 -yes

[0290] Provided herein as embodiment C60 is the compound as described in embodiment C1, wherein R 4 It is C 1-4alkyl or halogen. Provided herein as embodiment C61 is the compound as described in embodiment C1, wherein R 4 It's fluorine.

[0291] Provided herein as embodiment C62 is the compound of embodiment C1, wherein the compound is selected from the compounds of Table 5:

[0292] Table 5

[0293]

[0294]

[0295]

[0296] Provided herein as embodiment C63 is the compound of embodiment C1, wherein the compound is selected from the compounds of Table 6:

[0297] Table 6

[0298]

[0299]

[0300] The foregoing merely summarizes certain aspects of the disclosure and is not intended to, and should not be construed to, limit the disclosure in any way.

[0301] Formulations and routes of administration

[0302] Although it is possible to administer the compounds disclosed herein alone for the purposes described, the compounds typically administered will be present in a pharmaceutical composition as an active ingredient. Thus, in one embodiment, provided herein are pharmaceutical compositions comprising the compounds disclosed herein in combination with one or more pharmaceutically acceptable excipients (e.g., diluents, carriers, adjuvants, etc.) and other active ingredients (if desired). See, e.g., Remington: The Science and Practice of Pharmacy, Volumes I and II, Twenty-Second Edition, edited by Loyd V. Allen Jr., Philadelphia, PA, Pharmaceutical Press, 2012; Pharmaceutical Dosage Forms (Volumes 1-3), Liberman et al., eds., Marcel Dekker, New York, NY, 1992; Handbook of Pharmaceutical Excipients (3rd Edition), edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, 2000; Pharmaceutical Formulation: The Science and Technology of Dosage Forms (Drug Discovery), First Edition, edited by GD Tovey, ed., Royal Society of Chemistry, 2018. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein.

[0303] One or more compounds disclosed herein can be administered by any suitable route, in the form of a pharmaceutical composition suitable for such route, and in a dose effective for the intended treatment. The compounds and compositions presented herein can be administered, for example, orally, mucosally, topically, transdermally, rectally, pulmonary, parenterally, intranasally, intravascularly, intravenously, intraarterially, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, intravaginally, or by infusion techniques in dosage unit formulations containing conventional pharmaceutically acceptable excipients.

[0304] The pharmaceutical composition can be in the form of, for example, tablets, chewable tablets, mini-tablets, caplets, pills, beads, hard capsules, soft capsules, gelatin capsules, granules, powders, lozenges, patches, creams, gels, sachets, microneedle arrays, syrups, flavored syrups, juices, drops, injectable solutions, emulsions, microemulsions, ointments, aerosols, aqueous suspensions, or oily suspensions. The pharmaceutical composition is typically prepared in dosage unit form containing a specific amount of the active ingredient.

[0305] Provided herein as Example 425 is a pharmaceutical composition comprising a compound or salt as described in any one of Examples 1-424, B1-B51 or C1-C63, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, and a pharmaceutically acceptable excipient.

[0306] Provided herein as Example 426 is a compound as described in any of Examples 1-424, B1-B51 or C1-C63, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition as described in Example 423, for use as a medicament.

[0307] How to use

[0308] As discussed herein (see the section entitled "Definitions"), the compounds described herein should be understood to include all stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates of any of the foregoing substances. Therefore, the scope of the methods and uses provided in this disclosure should be understood to also encompass methods and uses employing all such forms.

[0309] In addition to being useful for human therapy, the compounds provided herein can also be used in 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.

[0310] In one embodiment, the present disclosure provides methods of using the compounds or pharmaceutical compositions of the present disclosure to treat disease conditions, including but not limited to conditions (e.g., cancer) affected by KRAS G12D, G12V, G12A, G12S, G13D, Q61H, Q61L, or G12C mutations. These cancer types are non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendix cancer, endometrial cancer, esophageal cancer, cancer of unknown primary site, ampullary cancer, gastric cancer, small intestine cancer, paranasal sinus cancer, bile duct cancer, or melanoma.

[0311] KRAS G12D mutations occur with altered frequencies as shown in the table below (TCGA dataset). For example, the table shows that 32.4% of pancreatic cancer subjects have cancer in which one or more cells express KRAS G12D mutant protein. G12D The combined compounds (see the section entitled "Biological Evaluation" below) can be used to treat subjects suffering from cancer, including but not limited to the cancers listed in the table below.

[0312]

[0313]

[0314] Provided herein as Example 427 is a compound as described in any one of Examples 1-424, B1-B51 or C1-C63, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in Example 425, for use in treating cancer.

[0315] Provided herein as Example 428 is a compound as described in any one of Examples 1-424, B1-B51 or C1-C63, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in Example 425, for use in treating cancer wherein one or more cells express KRAS G12D mutant protein.

[0316] Provided herein as Example 429 is a compound as described in any one of Examples 1-424, B1-B51 or C1-C63, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in Example 425, for use in treating cancer wherein one or more cells express KRAS G12V mutant protein.

[0317] Provided herein as Example 430 is a compound as described in any one of Examples 1-424, B1-B51 or C1-C63, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in Example 425, for use in treating cancer wherein one or more cells express KRAS G12A mutant protein.

[0318] Provided herein as Example 431 is a compound as described in any one of Examples 1-424, B1-B51 or C1-C63, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in Example 425, for use in treating cancer wherein one or more cells express KRAS G12S mutant protein.

[0319] Provided herein as Example 432 is a compound as described in any one of Examples 1-424, B1-B51 or C1-C63, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in Example 425, for use in treating cancer wherein one or more cells express KRAS G13D mutant protein.

[0320] Provided herein as Example 433 is a compound as described in any one of Examples 1-424, B1-B51 or C1-C63, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in Example 425, for use in treating cancer wherein one or more cells express KRAS Q61H mutant protein.

[0321] Provided herein as Example 434 is a compound as described in any one of Examples 1-424, B1-B51 or C1-C63, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in Example 425, for use in treating cancer wherein one or more cells express KRAS Q61L mutant protein.

[0322] Provided herein as Example 435 is a compound as described in any one of Examples 1-424, B1-B51 or C1-C63, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in Example 425, for use in treating cancer wherein one or more cells express KRAS G12C mutant protein.

[0323] Provided herein as Example 436 is a compound or pharmaceutical composition for use as described in any one of Examples 427-435, 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 types, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

[0324] Provided herein as Example 437 is the use of a compound as described in any one of Examples 1-424, B1-B51 or C1-C63, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in Example 425, in the preparation of a medicament for treating cancer.

[0325] Provided herein as Example 438 is the use of a compound as described in any one of Examples 1-424, B1-B51 or C1-C63, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in Example 425, in the preparation of a medicament for treating cancer, wherein one or more cells express KRAS G12D mutant protein.

[0326] Provided herein as Example 439 is the use of a compound as described in any one of Examples 1-424, B1-B51 or C1-C63, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in Example 425, in the preparation of a medicament for treating cancer, wherein one or more cells express KRAS G12V mutant protein.

[0327] Provided herein as Example 440 is the use of a compound as described in any one of Examples 1-424, B1-B51 or C1-C63, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in Example 425, in the preparation of a medicament for treating cancer, wherein one or more cells express KRAS G12A mutant protein.

[0328] Provided herein as Example 441 is the use of a compound as described in any one of Examples 1-424, B1-B51 or C1-C63, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in Example 425, in the preparation of a medicament for treating cancer, wherein one or more cells express KRAS G12S mutant protein.

[0329] Provided herein as Example 442 is the use of a compound as described in any one of Examples 1-424, B1-B51 or C1-C63, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in Example 425, in the preparation of a medicament for treating cancer, wherein one or more cells express KRAS G13D mutant protein.

[0330] Provided herein as Example 443 is the use of a compound as described in any one of Examples 1-424, B1-B51 or C1-C63, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in Example 425, in the preparation of a medicament for treating cancer, wherein one or more cells express the KRAS Q61H mutant protein.

[0331] Provided herein as Example 444 is the use of a compound as described in any one of Examples 1-424, B1-B51 or C1-C63, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in Example 425, in the preparation of a medicament for treating cancer, wherein one or more cells express KRAS Q61L mutant protein.

[0332] Provided herein as Example 445 is the use of a compound as described in any one of Examples 1-424, B1-B51 or C1-C63, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in Example 425, in the preparation of a medicament for treating cancer, wherein one or more cells express KRAS G12C mutant protein.

[0333] Provided herein as Example 446 is the use of any one of Examples 437-445, 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 types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

[0334] Provided herein as Example 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 as described in any one of Examples 1-424, B1-B51, or C1-C63, or a pharmaceutically acceptable salt thereof.

[0335] Provided herein as Example 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 as described in any one of Examples 1-424, B1-B51, or C1-C63, or a pharmaceutically acceptable salt thereof, wherein one or more cells express KRAS G12D mutant protein.

[0336] Provided herein as Example 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 as described in any one of Examples 1-424, B1-B51, or C1-C63, or a pharmaceutically acceptable salt thereof, wherein one or more cells express KRAS G12V mutant protein.

[0337] Provided herein as Example 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 as described in any one of Examples 1-424, B1-B51, or C1-C63, or a pharmaceutically acceptable salt thereof, wherein one or more cells express KRAS G12A mutant protein.

[0338] Provided herein as Example 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 as described in any one of Examples 1-424, B1-B51, or C1-C63, or a pharmaceutically acceptable salt thereof, wherein one or more cells express a KRAS G12S mutant protein.

[0339] Provided herein as Example 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 as described in any one of Examples 1-424, B1-B51, or C1-C63, or a pharmaceutically acceptable salt thereof, wherein one or more cells express KRAS G13D mutant protein.

[0340] Provided herein as Example 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 as described in any one of Examples 1-424, B1-B51, or C1-C63, or a pharmaceutically acceptable salt thereof, wherein one or more cells express the KRAS Q61H mutant protein.

[0341] Provided herein as Example 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 as described in any one of Examples 1-424, B1-B51, or C1-C63, or a pharmaceutically acceptable salt thereof, wherein one or more cells express the KRAS Q61L mutant protein.

[0342] Provided herein as Example 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 as described in any one of Examples 1-424, B1-B51, or C1-C63, or a pharmaceutically acceptable salt thereof, wherein one or more cells express KRAS G12C mutant protein.

[0343] Provided herein as Example 456 is a method as described in any of Examples 447-455, 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 types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

[0344] Provided herein as Example 457 is a method as described in any of Examples 457-455, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendix cancer, endometrial cancer, esophageal cancer, cancer of unknown primary site, ampullary cancer, gastric cancer, small intestine cancer, paranasal sinus cancer, bile duct cancer, or melanoma.

[0345] Provided herein as embodiment 458 is the method of embodiment 457, wherein the cancer is non-small cell lung cancer.

[0346] Provided herein as embodiment 459 is the method of embodiment 457, wherein the cancer is colorectal cancer.

[0347] Provided herein as embodiment 460 is the method of embodiment 457, wherein the cancer is pancreatic cancer.

[0348] Combination therapy

[0349] The present disclosure also provides a method for combination therapy, wherein the medicament of the overlapping set of other components of other pathways or the same pathway or even target enzymes known to be adjustable is used in combination with the compound of the present disclosure or its pharmaceutically acceptable salt. On the one hand, this therapy includes but is not limited to the combination of one or more compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies and radiation therapy, to provide a synergistic or cumulative therapeutic effect. See, for example, U.S. Patent No. 10,519,146B2, issued on December 31, 2019; Specifically, from the 201st column (37th row) to the 212th column (46th row) and the 219th column (64th row) to the 220th column (39th row), which are incorporated herein by reference.

[0350] Provided herein as embodiment 461 is the method of any of embodiments 447-460, further comprising administering simultaneously, separately or sequentially an effective amount of a second compound, wherein the second compound is an Aurora kinase inhibitor, an AKT inhibitor, an arginase inhibitor, a CDK4 / 6 inhibitor, an ErbB family inhibitor, an ERK inhibitor, a FAK inhibitor, a FGFR inhibitor, a glutaminase inhibitor, an IGF-1R inhibitor, a KIF18A inhibitor, a MCL-1 inhibitor, a MEK inhibitor, an mTOR inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a PI3K inhibitor, a Raf kinase inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Src kinase inhibitor, or one or more chemotherapeutic agents.

[0351] In one embodiment, the second compound is administered as a pharmaceutically acceptable salt. In 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.

[0352] Aurora kinase A inhibitors

[0353] Provided herein is the method of any one of embodiments 447-460, further comprising administering simultaneously, separately or sequentially an effective amount of a second compound, wherein the second compound is an Aurora kinase A inhibitor.

[0354] Exemplary Aurora A inhibitors for use in the methods provided herein include, but are not limited to, alisertib, cenisertib, danusertib, tozasertib, LY3295668 ((2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyridin-2-yl]methyl]-2-methylpiperidine-4-carboxylic acid), ENMD-2076 (6-(4-methylpiperazine-1 -yl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[(E)-2-phenylvinyl]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-pentaazatricyclo[8.4.0.03,7]tetradec-1(14),3,6,8,10,12-hexen-13-yl]morpholine), AMG 900 (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)pyrimidin-2-yl]amino

[0015] The present invention also includes the following agents:

[0015] wherein the present invention comprises ...

[0355] AKT inhibitors

[0356] Provided herein is the method of any one of embodiments 447-460, further comprising administering simultaneously, separately or sequentially an effective amount of a second compound, wherein the second compound is an AKT inhibitor.

[0357] Exemplary AKT inhibitors for use in the methods provided herein include, but are not limited to, afuresertib, capivasertib, ipatasertib, uprosertib, BAY1125976 (2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide), ARQ 092 (3-[3-[4-(1-aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2-amine), MK2206 (8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one), SR13668 (indolo[2,3-b]carbazole-2,10-dicarboxylic acid, 5,7-dihydro-6-methoxy-, 2,10-diethyl ester), ONC201 (11-benzyl-7-[(2-methylphenyl)methyl]-2,5,7,11-tetraazatricyclo[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.

[0358] Arginase inhibitors

[0359] Provided herein is the method of any one of embodiments 447-460, further comprising administering simultaneously, separately, or sequentially an effective amount of a second compound, wherein the second compound is an arginase inhibitor.

[0360] Exemplary arginase inhibitors for use in the methods provided herein include, but are not limited to, numidargistat and CB 280.

[0361] CDK4 / 6 inhibitors

[0362] Provided herein is the method of any one of embodiments 447-460, further comprising administering simultaneously, separately or sequentially an effective amount of a second compound, wherein the second compound is a CDK4 / 6 inhibitor.

[0363] As used herein, the term "CDK 4 / 6" refers to cyclin-dependent kinases ("CDK") 4 and 6, which are members of the mammalian serine / threonine protein kinases.

[0364] As used herein, the term "CDK 4 / 6 inhibitor" refers to a compound that is capable of negatively regulating or inhibiting all or part of the enzymatic activity of CDK 4 and / or 6.

[0365] Exemplary CDK 4 / 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)-4-piperidinyl]amino]).

[0366] In one embodiment, the CDK4 / 6 inhibitor is palbociclib.

[0367] ErbB family inhibitors

[0368] Provided herein is the method of any one of embodiments 447-460, further comprising administering simultaneously, separately or sequentially an effective amount of a second compound, wherein the second compound is an ErbB family inhibitor.

[0369] As used herein, the term "ErbB family" refers to members of the mammalian transmembrane protein tyrosine kinase family, which includes: ErbB1 (EGFR HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4).

[0370] As used herein, the term "ErbB family inhibitor" refers to an agent, such as a compound or antibody, that is capable of negatively regulating or inhibiting all or part of the activity of at least one member of the ErbB family. Regulation or inhibition of one or more ErbB tyrosine kinases can be performed by regulating or inhibiting the kinase enzymatic activity of one or more ErbB family members or by blocking homodimerization or heterodimerization of ErbB family members.

[0371] In one embodiment, the ErbB family inhibitor is an EGFR inhibitor, such as an anti-EGFR antibody. Exemplary anti-EGFR antibodies for 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.

[0372] In another embodiment, the ErbB family inhibitor is a HER2 inhibitor, such as an anti-HER2 antibody. Exemplary anti-HER-2 antibodies for methods provided herein include but are not limited to pertuzumab, trastuzumab, and trastuzumab emtansine.

[0373] In yet another embodiment, the ErbB family inhibitor is a HER3 inhibitor, such as an anti-HER3 antibody, such as HMBD-001 (Hummingbird Bioscience).

[0374] In one embodiment, the ErbB family inhibitor is a combination of an anti-EGFR antibody and an anti-HER2 antibody.

[0375] In one embodiment, the ErbB family inhibitor is an irreversible inhibitor. Exemplary irreversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to, afatinib, dacomitinib, canertinib, poziotinib, AV 412 ((N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butyn-1-yl]-6-quinazolinyl]-2-acrylamide)), PF 6274484 ((N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-2-acrylamide), and HKI 357 ((E)-N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide).

[0376] In one embodiment, the irreversible ErbB family inhibitor is afatinib. In one embodiment, the irreversible ErbB family inhibitor is dacomitinib.

[0377] In one embodiment, the ErbB family inhibitor is a reversible inhibitor. Exemplary reversible ErbB family inhibitors for the methods provided herein include, but are not limited to, erlotinib, gefitinib, sapitinib, varlitinib, tarloxotinib, TAK-285 (N-(2-(4-((3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl)-3-hydroxy-3-methylbutanamide), AEE788 ((S)-6-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-N-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine), BMS 599626 ((3S)-3-morpholinylmethyl-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamate), and GW 583340 (N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[2-[(2-methylsulfonylethylamino)methyl]-1,3-thiazol-4-yl]quinazolin-4-amine).

[0378] In one embodiment, the reversible ErbB family inhibitor is sabutinib. In one embodiment, the reversible ErbB family inhibitor is tasotinib.

[0379] ERK inhibitors

[0380] Provided herein is the method of any one of embodiments 447-460, further comprising administering simultaneously, separately or sequentially an effective amount of a second compound, wherein the second compound is an ERK inhibitor.

[0381] Exemplary ERK inhibitors for use in the methods provided herein include, but are not limited to, ulixertinib, ravoxertinib, 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-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5-(2-morpholin-4-ylethyl)thieno[2,3-c]pyrrol-4-one), KO-947 (1,5,6,8-tetrahydro-6-(phenylmethyl)-3-(4-pyridinyl)-7H-pyrazolo[4,3-g]quinazolin-7-one), ASTX029, LTT462, and JSI-1187.

[0382] FAK inhibitors

[0383] Provided herein is the method of any one of embodiments 447-460, further comprising administering simultaneously, separately or sequentially an effective amount of a second compound, wherein the second compound is a FAK inhibitor.

[0384] 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-dihydroindolin-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.

[0385] FGFR inhibitors

[0386] Provided herein is the method of any one of embodiments 447-460, further comprising administering simultaneously, separately or sequentially an effective amount of a second compound, wherein the second compound is a FGFR inhibitor.

[0387] Exemplary FGFR inhibitors for use in the methods provided herein include, but are not limited to, 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), debiotinib, 1347 ([5-amino-1-(2-methyl-3H-benzimidazol-5-yl)pyrazol-4-yl]-(1H-indol-2-yl)methanone), INCB062079, H3B-6527 (N-[2-[[6-[(2,6-dichloro-3,5-dimethoxyphenyl)carbamoyl-methylamino]pyrimidin-4-yl]amino]-5-(4-ethylpiperazin-1-yl)phenyl]prop-2-enamide), ICP-105, CPL304110, HMPL-453, and HGS1036.

[0388] Glutaminease inhibitors

[0389] Provided herein is the method of any one of embodiments 447-460, further comprising administering simultaneously, separately, or sequentially an effective amount of a second compound, wherein the second compound is a glutaminase inhibitor.

[0390] Exemplary glutaminase inhibitors for use in the methods provided herein include, but are not limited to, telaglenastat, IPN60090, and OP 330.

[0391] IGF-1R inhibitors

[0392] Provided herein is the method of any one of embodiments 447-460, further comprising administering simultaneously, separately, or sequentially an effective amount of a second compound, wherein the second compound is an IGF-1R inhibitor.

[0393] Exemplary IGF-1R inhibitors for use in the methods provided herein include, but are not limited to, cixutumumab, dalotuzumab, linsitinib, ganitumab, robatumumab, BMS-754807 ((2S)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-1H-pyrazol-3-yl) ...

[0015] The products include:

[0015] N-[5-[[4-(2-hydroxyacetyl)piperazin-1-yl]methyl]-2-[(E)-2-(1H-indazol-3-yl)vinyl]phenyl]-3-methylthiophene-2-carboxamide, ....

[0394] KIF18A inhibitors

[0395] Provided herein is the method of any one of embodiments 447-460, further comprising administering simultaneously, separately or sequentially an effective amount of a second compound, wherein the second compound is a KIF18A inhibitor.

[0396] Exemplary KIF18A inhibitors for use in the methods provided herein include, but are not limited to, those disclosed in US 2020 / 0239441, WO 2020 / 132649, WO 2020 / 132651, and WO 2020 / 132653, each of which is incorporated herein by reference in its entirety.

[0397] MCL-1 inhibitors

[0398] Provided herein is the method of any one of embodiments 447-460, further comprising administering simultaneously, separately or sequentially an effective amount of a second compound, wherein the second compound is an MCL-1 inhibitor.

[0399] Exemplary MEK inhibitors for use in the methods provided herein include, but are not limited to, murizatoclax, tapotoclax, AZD 5991 ((3aR)-5-chloro-2,11,12,24,27,29-hexahydro-2,3,24,33-tetramethyl-22H-9,4,8-(metheniminomethyno)-14,20:26,23-dimetheno-10H,20H-pyrazolo[4,3-1][2,15,22,18,19]benzoxadithiadiazacyclohexacosane-32-carboxylic acid), MIK 665 ((αR)-α-[[(5S)-5-[3-chloro-2-methyl-4-[2-(4-methyl-1-piperazinyl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy]-2-[[2-(2-methoxyphenyl)-4-pyrimidinyl]methoxy]benzenepropanoic acid), and ABBV-467.

[0400] In one embodiment, the MCL-1 inhibitor is Muritox. In another embodiment, the MCL-1 inhibitor is Tapotox.

[0401] MEK inhibitors

[0402] Provided herein is the method of any one of embodiments 447-460, further comprising administering simultaneously, separately or sequentially an effective amount of a second compound, wherein the second compound is a MEK inhibitor.

[0403] Exemplary MEK inhibitors for use in the methods provided herein include, but are not limited to, 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-oxoxazinane-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-dihydroxypropyloxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), CI-1040 (2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide), PD318 088 (5-bromo-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide), 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-morpholinethanamine), FCN-159, CS3006, HL-085, SHR 7390, and WX-554.

[0404] In one embodiment, the MEK inhibitor is trametinib.

[0405] mTOR inhibitors

[0406] Provided herein is the method of any one of embodiments 447-460, further comprising administering simultaneously, separately or sequentially an effective amount of a second compound, wherein the second compound is an mTOR inhibitor.

[0407] Exemplary mTOR inhibitors for use in the methods provided herein include, but are not limited to, everolimus, rapamycin, zotarolimus (ABT-578), ridaforolimus (deforolimus, MK-8669), sapanisertib, buparlisib, pictilisib, vistusertib, dactolisib, and sirolimus. ib), 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).

[0408] In one embodiment, the mTOR inhibitor is everolimus.

[0409] PD-1 inhibitors

[0410] Provided herein is the method of any one of embodiments 447-460, further comprising administering simultaneously, separately or sequentially an effective amount of a second compound, wherein the second compound is a PD-1 inhibitor.

[0411] Exemplary PD-1 inhibitors for use in the methods provided herein include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, and anti-PD-1 antibodies as described in US 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.

[0412] In one embodiment, the PD-1 inhibitor is pembrolizumab. In another embodiment, the PD-1 inhibitor is anti-PD-1 antibody A.

[0413] PD-L1 inhibitors

[0414] Provided herein is the method of any one of embodiments 447-460, further comprising administering simultaneously, separately or sequentially an effective amount of a second compound, wherein the second compound is a PD-L1 inhibitor.

[0415] 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.

[0416] In one embodiment, the PD-L1 inhibitor is atezolizumab.

[0417] PI3K inhibitors

[0418] Provided herein is the method of any one of embodiments 447-460, further comprising administering simultaneously, separately or sequentially an effective amount of a second compound, wherein the second compound is a PI3K inhibitor.

[0419] Exemplary PI3K inhibitors for use in the methods provided herein include, but are not limited to, idelalisib, copanlisib, duvelisib, alpelisib, taselisib, perifosine, bupallisib, umbralisib, pitilisib, daclisib, voxtalisib, sonolisib, and selenisib. nolisib), tenalisib, serabelisib, 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-methyl)- (2-amino-N-[(1S)-1-[8-[2-(1-methylpyrazol-4-yl)ethynyl]-1-oxo-2-phenylisoquinolin-3-yl]ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide), SF1126 ((2S)-2-[[(2S)-3-carboxy-2-[[2-[[(2S)-5-(diaminomethyleneamino)-2-[[4-oxo-4-phenyl)-3-ol]-1-[1-methylpyrazol-4-yl)ethynyl]-1-oxo-2-phenylisoquinolin-3-yl]ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide),

[0015] The following are 1,2-dextrinsic acid compounds: -[[4-(4-oxo-8-phenylchromen-2-yl)morpholin-4-ium-4-yl]methoxy]butyryl]amino]pentanoyl]amino]acetyl]amino]propionyl]amino]-3-hydroxypropanoate), XL147 (N-[3-(2,1,3-benzothiadiazol-5-ylamino)quinoxalin-2-yl]-4-methylbenzenesulfonamide), GSK1059615 ((5Z)-5-[(4-pyridin-4-ylquinolin-6-yl)methylene]-1,3-thiazolidine-2,4-dione), and AMG 319 (N-[(1S)-1-(7-fluoro-2-pyridin-2-ylquinolin-3-yl)ethyl]-7H-purin-6-amine).

[0420] Raf kinase inhibitors

[0421] Provided herein is the method of any one of embodiments 447-460, further comprising administering simultaneously, separately or sequentially an effective amount of a second compound, wherein the second compound is a Raf kinase inhibitor.

[0422] 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), and includes homodimers of each isoform as well as heterodimers between isoforms (e.g., C-Raf / B-Raf heterodimers).

[0423] As used herein, the term "Raf kinase inhibitor" refers to a compound that can negatively regulate or inhibit all or part of the enzymatic activity of one or more members of the Raf family kinases, or can disrupt the inhibitory activity of Raf homodimer or heterodimer formation.

[0424] In one embodiment, Raf kinase inhibitors include but are not limited to 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)-1,4-difluorophenyl ... )-3-fluoropyrrolidine-1-sulfonamide), Raf-709 (N-(2-methyl-5,-morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridyl]-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)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-methylpropane-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-chromen-3-yl]methyl]-2-pyridinyl]-N′-methyl-sulfonamide).

[0425] In one embodiment, the Raf kinase inhibitor is connefenib. In one embodiment, the Raf kinase inhibitor is sorafenib. In one embodiment, the Raf kinase inhibitor is rifafenib.

[0426] SHP2 inhibitors

[0427] Provided herein is the method of any one of embodiments 447-460, further comprising administering simultaneously, separately or sequentially an effective amount of a second compound, wherein the second compound is a SHP2 inhibitor.

[0428] 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 vociprotafib (RMC-4630 - Revolution Medicine). In one embodiment, the SHP inhibitor used in the methods provided herein is worcesterol (Revolution Pharmaceuticals).

[0429] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 3-[(1R,3R)-1-amino-3-methoxy-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyrazinemethanol (CAS 2172651-08-8), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2-pyrazinemethanol (CAS 2172652-13-8), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-[[3-chloro-2-(3-hydroxy-1-azetidinyl)-4-pyridinyl]thio]-5-methyl-2-pyrazinemethanol (CAS 2172652-38-7), and 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-methyl-2-pyrazinemethanol (CAS 2172652-48-9).

[0430] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 1-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-4-methyl-4-piperidinamine (CAS 2240981-75-1), (1R)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine (CAS 22 40981-78-4), (3S,4S)-8-[7-(2,3-dichlorophenyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-45-8), (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]pyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine Spiro[4.5]decan-4-amine (CAS2240982-57-2), 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 (CAS2240982-69-6), 7-[(2-amino-3-chloro-4-pyridyl)thio]-4-[(3S,4S)-4-amino-3- Methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-methyl-pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-73-2), and (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-77-6).

[0431] In one embodiment, the SHP inhibitor used in the methods provided herein is (1R)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine (CAS 2240981-78-4).

[0432] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-54-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56-5), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-57-6), 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-pyridyl]-8-azaspiro[4.5]decan-1-amine (CAS 2238840-62-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2-pyridinemethanol (CAS2238840-63-4), (1R)-8-[6-[(2,3-dichlorophenyl)thio]-5-methyl-3-pyridinyl]-8-azaspiro[4.5]decan-1-amine (CAS2238840-64-5), 5-(4-amino-4-methyl-1-piperidinyl)-2-[(2,3-dichlorophenyl)thio]-3-pyridinol (CAS2238840-65-6), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-[(2,3-dichlorophenyl)thio]-3-pyridinol (CAS2238840-66-7), 6-[( 2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-hydroxy-2-pyridinemethanol (CAS 2238840-67-8), 3-(4-amino-4-methyl-1-piperidinyl)-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-68-9), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-69-0), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5-[(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 (CAS2238840-70-3), 3-(4-amino-4-methyl-1-piperidinyl)-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS2238840-71-4), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-(4-amino-4-methyl-1-piperidinyl)-2-pyridinemethanol (CAS2238840-72-5), 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 (CAS2238840-73 -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 (CAS2238840-74-7), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS2238840-75-8), and 2-[(2-amino-3-chloro-4-pyridyl)sulfanyl]-5-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(hydroxymethyl)pyridin-3-ol.

[0433] In one embodiment, the SHP inhibitor used in the methods provided herein is 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56-5).

[0434] In one embodiment, the SHP2 inhibitor used in the methods provided herein is an inhibitor disclosed in US 10,590,090 B2, US 2020 / 017517 A1, US 2020 / 017511 A1, or WO 2019 / 075265 A1, each of which is incorporated herein by reference in its entirety.

[0435] SOS1 inhibitors

[0436] Provided herein is the method of any one of embodiments 447-460, further comprising administering simultaneously, separately or sequentially an effective amount of a second compound, wherein the second compound is an SOS1 inhibitor.

[0437] Exemplary SOS1 inhibitors for use in the methods provided herein include, but are not limited to, BI 3406 (N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-7-methoxy-2-methyl-6-[(3S)-oxolan-3-yl]oxyquinazolin-4-amine) and BI 1701963.

[0438] Src kinase inhibitors

[0439] Provided herein is the method of any one of embodiments 447-460, further comprising administering simultaneously, separately or sequentially an effective amount of a second compound, wherein the second compound is a Src kinase inhibitor.

[0440] As used herein, the term "Src kinase" refers to members of the mammalian non-receptor tyrosine kinase family, which includes: Src, Yes, Fyn and Fgr (SrcA subfamily); Lck, Hck, Blk and Lyn (SrcB subfamily) and the Frk subfamily.

[0441] As used herein, the term "Src kinase inhibitor" refers to a compound that is capable of negatively regulating or inhibiting all or part of the enzymatic activity of one or more members of the Src kinase family.

[0442] Exemplary Src kinase inhibitors for use in the methods provided herein include, but are not limited to, 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).

[0443] In one embodiment, the Src kinase inhibitor is dasatinib. In one embodiment, the Src kinase inhibitor is saratinib. 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.

[0444] chemotherapeutic agents

[0445] Provided herein is the method of any one of embodiments 447-460, further comprising administering simultaneously, separately, or sequentially an effective amount of a second compound, wherein the second compound is one or more chemotherapeutic agents.

[0446] Exemplary chemotherapeutic agents for use in the methods provided herein include, but are not limited to, leucovorincalcium (calcium folinate), 5-fluorouracil, irinotecan, oxaliplatin, cisplatin, carboplatin, pemetrexed, docetaxel, paclitaxel, gemcitabine, vinorelbine, chlorambucil, cyclophosphamide, and methotrexate.

[0447] definition

[0448] The following definitions are provided to assist in understanding the scope of this disclosure.

[0449] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary according to the standard deviation found in their respective testing measurements.

[0450] As used herein, if any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. If a chemical structure and a chemical name conflict, the chemical structure will determine the identity of the compound.

[0451] Stereoisomers

[0452] The compounds of the present disclosure may contain, for example, double bonds, one or more asymmetric carbon atoms, and bonds with hindered rotation, and may therefore exist as stereoisomers such as double bond isomers (i.e., geometric isomers (E / Z)), enantiomers, diastereomers, and restricted configuration isomers. Therefore, unless stereochemistry is explicitly determined, the scope of the present disclosure should be understood to encompass all possible stereoisomers of the compounds shown, including stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, diastereomerically pure, and restricted configuration isomerically pure) and stereoisomer mixtures (e.g., mixtures of geometric isomers, enantiomers, diastereomers, and restricted configuration isomers, or mixtures of any of the foregoing) of any chemical structure (whole or in part) disclosed herein.

[0453] If the stereochemistry of a structure or portion of a structure is not indicated, for example, by bold or dashed lines, then that structure or portion of a structure should be interpreted as encompassing all stereoisomers thereof. If the stereochemistry of a structure or portion of a structure is indicated, for example, by bold or dashed lines, then that structure or portion of a structure should be interpreted as encompassing only the stereoisomer indicated. A bond drawn with a wavy line indicates that both stereoisomers are encompassed. This should not be confused with a wavy line drawn perpendicular to a bond, which indicates the point of attachment of a group to the rest of the molecule.

[0454] As used herein, the term "stereoisomer" or "stereomerically pure" compound refers to one stereoisomer (e.g., geometric isomers, enantiomers, diastereomers, and constrained configurational isomers) of a compound that is substantially free of other stereoisomers of the compound. For example, a stereomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound, and a stereomerically pure compound having two chiral centers will be substantially free of other enantiomers or diastereomers of the compound. A typical stereomerically pure compound contains greater than about 80% by weight of one stereoisomer of the compound and equal to or less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and equal to or less than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and equal to or less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and equal to or less than about 3% by weight of other stereoisomers of the compound.

[0455] This disclosure also encompasses pharmaceutical compositions comprising stereoisomer-pure forms and the purposes of the stereoisomer-pure forms of any compound disclosed herein. In addition, this disclosure also encompasses pharmaceutical compositions comprising a mixture of stereoisomers of any compound disclosed herein and the purposes of the pharmaceutical compositions or stereoisomer mixtures. These stereoisomers or their mixtures can be synthesized according to methods well known in the art and methods disclosed herein. Standard techniques (such as chiral columns or chiral resolving agents) can be used to split stereoisomer mixtures. In addition, this disclosure encompasses pharmaceutical compositions comprising a mixture of any compound disclosed herein and one or more other active agents disclosed herein. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725; Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, New York, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0456] Tautomers

[0457] As known to those skilled in the art, certain compounds disclosed herein may exist in one or more tautomeric forms. Because a chemical structure can only be used to represent one tautomeric form, it is understood for convenience that reference to a compound having a given structural formula includes other tautomers having that structural formula. Therefore, the scope of this disclosure should be understood to encompass all tautomeric forms of the compounds disclosed herein.

[0458] Isotope-labeled compounds

[0459] In addition, 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 suitable isotopes for inclusion in the compounds disclosed herein include isotopes of hydrogen, such as 2 H and 3 H; isotopes of carbon, e.g. 11 C. 13 C and 14 C; isotopes of chlorine, e.g. 36 CI; isotopes of fluorine, e.g. 18 F; isotopes of iodine, e.g. 123 I and 125 I; isotopes of nitrogen, e.g. 13 N and 15 N; isotopes of oxygen, e.g. 15 O. 17 O and 18 O; isotopes of phosphorus, e.g. 32 P; and isotopes of sulfur, e.g. 35 Certain isotopically labeled compounds of Formula I (e.g., those incorporating a radioactive isotope) are useful in drug and / or substrate tissue distribution studies. In view of the ease of incorporation and the ready-to-use detection format, the radioactive isotope tritium ( 3 H) and carbon-14 ( 14 C) are particularly useful for this purpose. 2 H or D) substitution may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and thus may be advantageous in some circumstances. For example, substitution with positron emitting isotopes (e.g., 11 C. 18 F. 15 O and 13 N) substitution can be used in positron emission tomography (PET) studies to examine target occupancy. Isotopically labeled compounds of the compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the accompanying general synthetic schemes and examples, using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.

[0460] Solvates

[0461] As discussed above, the compounds disclosed herein, and stereoisomers, tautomers, and isotopically labeled forms thereof, or pharmaceutically acceptable salts of any of the foregoing, may exist in solvated or unsolvated forms.

[0462] As used herein, the term "solvate" refers to a molecular complex comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and a stoichiometric or non-stoichiometric amount of one or more pharmaceutically acceptable solvent molecules. If the solvent is water, the solvate is referred to as a "hydrate."

[0463] Therefore, the scope of the present disclosure should be understood to encompass all solvents of the compounds disclosed herein and stereoisomers, tautomers, and isotopically labeled forms thereof, or pharmaceutically acceptable salts of any of the foregoing.

[0464] Other definitions

[0465] This section defines additional terminology used to describe the scope of the compounds, compositions, and uses disclosed herein.

[0466] The term "aryl" refers to an aromatic hydrocarbon radical having 6 to 20 carbon atoms in a ring moiety. Typically, an aryl radical is a monocyclic, bicyclic or tricyclic aromatic radical having 6 to 20 carbon atoms. In addition, as used herein, the term "aryl" refers to an aromatic substituent, which can be a single aromatic ring, or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl, each of which can optionally be substituted with 1 to 4 substituents, such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxyl, alkoxy, acyl, alkyl-C (O)-O-, aryl-O-, heteroaryl-O-, amino, thiol, alkyl-S-, aryl-S-- nitro, cyano, carboxyl, alkyl-OC (O)--, carbamoyl, alkyl-S (O)-, sulfonyl, sulfonamido, phenyl and heterocycloalkyl.

[0467] The term "alkyl" refers to a saturated straight-chain hydrocarbon or a saturated branched-chain hydrocarbon containing the specified number of carbon atoms. For example, C3 alkyl means an alkyl group having 3 carbon atoms (e.g., n-propyl or isopropyl). 1-6 Alkyl refers to an alkyl group having 1 to 6 carbon atoms. Where a range is indicated, all members of the range and all subgroups within the 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), as well as all subgroups within the specified ranges (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 tert-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.

[0468] The term alkylene (e.g., "C 1-4 Alkylene" and "C 1-6 "Alkylene" refers to a straight or branched chain 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, isopropylene, n-butylene, sec-butylene, isobutylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, and the like.

[0469] 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 an alkenyl group having 3 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. Where a range is indicated, 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), as well as all subgroups within the specified ranges (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, vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl or 3-butenyl. The limiting examples of alkenyl groups include vinyl (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.

[0470] 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 an alkynyl group having 3 carbon atoms. For example, C 2-6 Alkynyl refers to an alkynyl group having 2 to 6 carbon atoms. Where a range is indicated, all members of that range and all subgroups within that range are contemplated. For example, C 2-6Alkynyl includes any alkynyl group having 2, 3, 4, 5, or 6 carbon atoms (or any combination of the foregoing), as well as all subgroups within the specified ranges (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). For illustration, C 2-4 Alkynyl includes for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl or 3-butynyl. The 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.

[0471] The terms "alkoxy" and "alkoxyl" are interchangeable and refer to an -O-alkyl group, wherein the alkyl group is as defined elsewhere herein. For example, a C3 alkoxy group means an alkoxy group having 3 carbon atoms (e.g., OCH2CH2CH3). Where a range is indicated, all members of the range and all subgroups within the range are contemplated. For example, C 1-6 Alkoxy groups include alkoxy groups having 2, 3, 4, 5, or 6 carbon atoms (or any combination of the foregoing), as well as all subgroups within 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). Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, 1-methylethyloxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0472] 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 wherein the ring framework 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.

[0473] The term cycloalkylene (e.g., "C 3-7 "Cycloalkylene" refers to a saturated carbocyclic divalent radical 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.

[0474] The term "cyano" refers to a -CN group.

[0475] As used herein, the term "deuterated" as a prefix to another term for a chemical group refers to a modification of a chemical group in which one or more hydrogen atoms are replaced by deuterium ("D" or " 2 H”) substituted. For example, the term “C 1-4 "Deuterated alkyl" means a C 1-4 Alkyl, in which one or more hydrogen atoms are replaced by D. C 1-4 Representative examples of deuterated alkyl include, but are not limited to, -CH2D, -CHD2, -CD3, -CH2CD3, -CDHCD3, -CD2CD3, -CH(CD3)2, -CD(CHD2)2, and -CH(CH2D)(CD3).

[0476] As used herein, the term "halogen" refers to -F, -CI, -Br, or -I.

[0477] As used herein, the term "halo" as a prefix to another term for a chemical group refers to a modification of the chemical group wherein one or more hydrogen atoms are replaced by a halogen as defined herein. Halogen is independently selected at each occurrence. For example, as defined herein, the term "C 1-4 "Haloalkyl" refers to C 1-4 Alkyl groups in which one or more hydrogen atoms are replaced by halogen. 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).

[0478] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen. Halogen is independently selected at each occurrence. The term includes, for example, monohaloalkyl (e.g., CH2F, CH(CH2F)CH3), dihaloalkyl (e.g., CHF2, CH(CHF2)CH3), trihaloalkyl (e.g., CF3, CH(CF3)CH3), and polyhaloalkyl (e.g., CF(CF3)CH3). A haloalkyl group may or may not be perhalogenated (e.g., perfluorinated, such as CF(CF3)CF3). For example, the term "C 1-4 "Haloalkyl" refers to C 1-4 Alkyl, in which one or more hydrogen atoms are replaced by halogen. For illustration, C 1-4Haloalkyl groups 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.

[0479] The term haloalkylene refers to a divalent haloalkyl group in which one or more hydrogen atoms are replaced by a halogen (e.g., "C 1-4 "Haloalkylene" and "C 1-6 Representative examples of haloalkylene include, but are not limited to, -CHF-, -CF2-, -CHCl-, -CH2CF2-, -CF2CF 2- , -CHCl-, -CCl2-, -CFCl-, etc.

[0480] The terms "haloalkoxy" and "haloalkoxyl" are interchangeable and refer to an alkoxy group in which one or more hydrogen atoms are replaced by a halogen. Halogen is independently selected at each occurrence. The term includes monohaloalkoxy (e.g., OCH2F, OCH(CH2F)CH3), dihaloalkoxy (e.g., OCHF2, OCH(CHF2)CH3), trihaloalkoxy (e.g., OCF3, OCH(CF3)CH3), and polyhaloalkoxy (e.g., OCF(CF3)CH3). A haloalkoxy group may or may not be perhalogenated (e.g., perfluorinated, such as OCF(CF3)CF3). For example, the term "C 1-4 "Haloalkoxy" refers to a C 1-4 Alkoxy, in which one or more hydrogen atoms are replaced by halogen. 1-4 Representative examples of haloalkoxy groups 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.

[0481] As used herein, the term "heteroaryl" refers to a 5-20 membered monocyclic, bicyclic or tricyclic aromatic ring system having 1 to 8 heteroatoms selected from N, O and S. In certain preferred aspects, the heteroaryl is a 5-10 membered ring system (e.g., a 5-7 membered monocyclic, 8-10 membered bicyclic or 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-isoquinolyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 1-, 2-, 4-, 5-, 6-, 7-, or 8-benzimidazolyl, and 1-, 2-, 3-, 4-, 5-, 6-, or 7-indolyl.

[0482] The term "heteroaryl" also refers to groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocycloalkyl rings.

[0483] 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 ring system, a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring system, 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, wherein N and S may also be optionally oxidized to various oxidation states. The heterocyclyl group may be attached at a heteroatom or carbon atom. Heterocycloalkyl may include fused or bridged rings and spirocycles. For example, a heterocycloalkyl group having a total of 5 atoms and 2 heteroatoms independently selected from N, O, and S refers to a ring having 3 carbon atoms and 2 heteroatoms, wherein each heteroatom of the ring is independently N, O, or S. Where a range is indicated, all members of the range and all subgroups within the range are contemplated. For example, a heterocycloalkyl group having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S includes rings having 5, 6, or 7 total atoms (or any combination of the foregoing), as well as all subsets within the specified range (e.g., 5-6 or 6-7 total ring atoms, or any combination of the foregoing), wherein 1, 2, or 3 atoms in the ring are heteroatoms and each heteroatom is independently selected from N, O, and S. Thus, a heterocycloalkyl group having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S encompasses 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, wherein each heteroatom of the foregoing is independently selected from N, O, and S. Non-limiting examples of heterocycloalkyl groups include, but are not limited to, aziridinyl, oxiranyl, thiirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, oxathiolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, dioxanyl, dithianyl, morpholinyl, thiomorpholinyl, azepanyl, hexahydro-1H-pyrrolazinyl, and 1,4-diazepanyl.

[0484] The terms "hydroxy" and "hydroxyl" are interchangeable and refer to an -OH group.

[0485] The term "hydroxyalkyl" or "hydroxylalkyl" refers to a saturated straight-chain alkyl or saturated branched-chain alkyl containing the specified number of carbon atoms, substituted by one or two hydroxyl groups (instead of hydrogen), provided that if two hydroxyl groups are present, they are not located 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.

[0486] The term "hydroxyalkylene ( hydroxyalkyl "Ene or hydroxylalkylene)" refers to a saturated straight chain alkylene or saturated 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 not located on the same carbon atom. Non-limiting examples of hydroxyalkylene 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.

[0487] The term "oxo" refers to a substituent oxygen atom attached to another atom by a double bond (e.g., =0). For example, an oxo substituent on a cyclopentyl ring can be depicted as:

[0488] As used herein, the term "pharmaceutically acceptable" means generally accepted for use in subjects, particularly humans.

[0489] 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 (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.); or acid addition salts formed with organic acids (e.g., acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, etc.); or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion); or salts formed by coordination with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine, etc.). Further examples of such salts can be found in Berge et al., J. Pharm. Sci. 66(1): 1-19 (1977). See also Stahl et al., Pharmaceutical Salts: Properties, Selection, and Use, 2nd revised edition (2011).

[0490] As used herein, the term "pharmaceutically acceptable excipient" refers to various ingredients that can be combined with the compounds or salts disclosed herein to prepare pharmaceutical compositions or formulations. Typically, excipients include, but are not limited to, diluents, colorants, vehicles, anti-adherents, glidants, disintegrants, flavorings, coatings, binders, sweeteners, lubricants, adsorbents, preservatives, and the like.

[0491] As used herein, the term "subject" refers to humans and mammals, including but not limited to primates, cows, sheep, goats, horses, dogs, cats, rabbits, rats and mice. In one embodiment, the subject is a human.

[0492] As used herein, the term "therapeutically effective amount" refers to that amount of a compound disclosed herein that will elicit the biological or medical response of a tissue, system, or subject that is being sought by the researcher, veterinarian, medical doctor, or other clinician.

[0493] General synthetic procedure

[0494] The compounds provided herein can be synthesized according to the procedures described in this section and the following sections. As will be appreciated by those of ordinary skill in the art, the synthetic methods described herein are exemplary only, and the compounds disclosed herein can also be synthesized by alternative synthetic strategies using alternative pathways. It should be understood that the general synthetic procedures and specific examples provided herein are illustrative only and should not be construed in any way to limit the scope of this disclosure.

[0495] Typically, compounds of formula I can be synthesized according to the following scheme. Unless otherwise stated, any variables used in the following scheme are variables defined for formula I. All starting materials are commercially available (e.g., purchased from Merck Sigma-Aldrich Inc., Fluorochem Ltd, and Enamine Ltd); or are known in the art and can be synthesized using common techniques by employing known procedures. Starting materials can also be synthesized via procedures disclosed herein. For the schemes discussed in this section, suitable reaction conditions (e.g., solvents, reaction temperatures, and reagents) can be found in the examples provided herein.

[0496]

[0497] Compounds of formula (I) can be prepared according to Scheme 1. In step A, compound (I-1) is reacted with an optionally substituted cyclic amine or aliphatic amine bearing an alcohol or a protected amine in a solvent such as acetonitrile and in the presence of a base such as Hunig's base. N Ar is reacted to give compound (I-2). In step B, compound (I-2) is reacted with a compound having formula R 1 The nucleophile of -LH undergoes S in the presence of a base (such as Hunin's base) in a solvent (such as acetonitrile). N Ar reacts, to give compound (I-3). In step C, compound (I-3) and organometallic reagent or boronic acid (ester) (attached to aryl or heteroaryl, with terminal ester group) coupling, to give compound (I-4). This coupling reaction, containing or not containing alkali (such as potassium phosphate), in solvent or solvent mixture (such as THF and water) and catalyst (such as cataCXium A Pd G3) in carry out. In step D, compound (I-4) is saponified, to give compound (I-5). This reaction is carried out in the TFA in solvent (such as DCM) or in the LiOH in solvent mixture (such as THF and water). In step E, compound (I-5) is cyclized under the conditions of such as HATU and DIPEA or DCC / DMAP in solvent (such as DMF or dichloromethane), to give the compound with formula (I).

[0498]

[0499] Compounds of formula (II) can also be prepared according to Scheme II. In step A, compound (II-1) is reacted with an optionally substituted cyclic amine or aliphatic amine with an alcohol or protected amine in a solvent (e.g. acetonitrile) and in the presence of a base (e.g. Huning's base) by S- NAr is reacted to give compound (II-2). In step B, compound (II-2) is reacted with a compound having formula R 1 The nucleophile of -LH undergoes S in the presence of a base (such as Hunin's base) in a solvent (such as acetonitrile). N Ar reaction, to give compound (II-3). In step C, compound (II-3) is coupled with an organometallic reagent (such as bis(tributyltin)) to give compound (II-4). The coupling reaction is carried out 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 boric acid (ester) (attached to an aryl or heteroaryl group, with a terminal ester group) to give compound (II-5). The coupling reaction is carried out in a solvent or solvent mixture (such as THF and water) and a catalyst (such as cataCXium A Pd G3) with or without an alkali (such as potassium phosphate). In step E, compound (II-5) is saponified to give compound (II-6). The reaction is carried out in TFA in a solvent such as DCM or in LiOH in a solvent mixture 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 a compound of formula (II).

[0500]

[0501] Compounds of formula (III) can also be prepared according to Scheme III. In step A, compound (III-1) is reacted with an optionally substituted cyclic amine or aliphatic amine with an alcohol or protected amine in a solvent (e.g. acetonitrile) and in the presence of a base (e.g. Huning's base) by S-reaction. N Ar is reacted to give compound (III-2). In step B, compound (III-2) is reacted with a compound having formula R 1 The nucleophile of -LH undergoes S in the presence of a base (such as Hunin's base) in a solvent (such as acetonitrile). NAr reacts, to give compound (III-3). In step C, compound (III-3) and organometallic reagent or be attached to the aryl of the alcohol with terminal TBS protection or the boronic acid (ester) coupling of heteroaryl, to give compound (III-4). This coupling reaction is when containing or not containing alkali (such as potassium phosphate), in solvent or solvent mixture (such as THF and water) and catalyst (such as cataCXium A PdG3) carry out. In step D, compound (III-4) is reacted with CDI, then in solvent (such as THF), handle with desilylation reagent (such as TBAF), to give compound with formula (III).

[0502]

[0503] Compounds 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 aliphatic amine having a terminal ester group in a solvent (e.g. acetonitrile) and in the presence of a base (e.g. Huning's base) by S- N Ar is reacted to give compound (IV-2). In step B, compound (IV-2) is reacted with a compound having formula R 1 The nucleophile of -LH undergoes S in the presence of a base (such as Hunin's base) in a solvent (such as acetonitrile). N Ar reaction, to provide compound (IV-3).In step C, compound (IV-3) and organometallic reagent or be attached to the aryl of the alcohol with terminal TBS protection or the boric acid (ester) coupling of heteroaryl, to provide compound (IV-4).This coupling reaction, containing or not containing alkali (such as potassium phosphate), in solvent or solvent mixture (such as THF and water) and catalyst (such as cataCXium A Pd G3) in carry out.In step D, compound (IV-4) is processed with desilylation reagent (such as TBAF) in solvent (such as THF), subsequently use reagent (such as Me3SnOH) saponify in solvent (such as DCE), to provide compound (IV-5).In step E, use reagent (such as 2-chloro-1-picoline iodide) in solvent (such as DCE), under the existence of alkali (such as TEA) by compound (IV-5) cyclization, to provide the compound with formula (IV).

[0504]

[0505] Compounds of formula (V) can also be prepared according to Scheme V. In step A, compound (V-1) is reacted with an optionally substituted cyclic amine or aliphatic amine bearing an alcohol or a protected amine in a solvent such as acetonitrile and in the presence of a base such as Huning's base. NAr reaction to give compound (V-2). In step B, compound (V-2) is reacted with a nucleophile (such as sodium thiomethoxide) in a solvent (such as THF) by S N Ar reacts, to provide compound (V-3).In step C, compound (V-3) and organometallic reagent or boronic acid (ester) (attached to aryl or heteroaryl, with terminal ester group) coupling, to provide compound (V-4).This coupling reaction, containing or not containing alkali (such as potassium phosphate), in solvent or solvent mixture (such as THF and water) and catalyst (such as cataCXium A Pd G3) in carry out.In step D, compound (V-4) is saponified, to provide compound (V-5).This reaction is carried out in the TFA in solvent (such as DCM) or in the LiOH in solvent mixture (such as THF and water).In step E, compound (V-5) is cyclized in solvent (such as DMF or dichloromethane) under the conditions of such as HATU and DIPEA or DCC / DMAP, to provide compound (V-6).In step F, compound (V-6) is oxidized in solvent (such as DCM) using reagent (such as m-CPBA), to provide compound (V-7). In step G, compound (V-7) is reacted with a compound having formula R 1 The nucleophile of -LH undergoes S in a solvent (such as acetonitrile) and in the presence of a base (such as Hunin's base). N Ar reacts to give compounds of formula (V).

[0506]

[0507] Compounds 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 aliphatic amine having a terminal olefin in a solvent such as acetonitrile and in the presence of a base such as Huning's base. N Ar is reacted to give compound (VI-2). In step B, compound (VI-2) is reacted with a compound having formula R 1 The nucleophile of -LH undergoes S in the presence of a base (such as Hunin's base) in a solvent (such as acetonitrile). NAr reaction, to provide compound (VI-3).In step C, compound (VI-3) and organometallic reagent or be attached to the aryl with terminal olefin or the boric acid (ester) coupling of heteroaryl, to provide compound (VI-4).This coupling reaction, when containing or not containing alkali (such as potassium phosphate), in solvent or solvent mixture (such as THF and water) and catalyst (such as cataCXium A Pd G3), carries out.In step D, compound (VI-4) undergoes ring-closure metathesis, to provide compound (VI-5).This reaction uses Hoveyda-Grubbs second generation catalyst in solvent (such as DCE) and in the presence of acid (such as TsOH), to carry out.In step E, compound (VI-5) is hydrogenated in solvent (such as ethanol) under the conditions of such as palladium carbon in a hydrogen atmosphere, to provide the compound with formula (VI).

[0508] Examples

[0509] This section provides specific examples of compounds having Formula I and methods for their preparation.

[0510] List of abbreviations

[0511] Table 7.

[0512]

[0513]

[0514]

[0515]

[0516] General analytical and purification methods

[0517] This section provides a description of the general analytical and purification methods used to prepare the specific examples provided herein.

[0518] Chromatography: Unless otherwise indicated, the residue containing crude product was purified by passing the crude material or concentrate through a Biotage or ISCO brand silica gel column prepacked with flash silica (SiO2) and eluting the product from the column with the indicated solvent gradient.

[0519] Preparative HPLC Methods: Where indicated, compounds described herein were purified by reverse phase HPLC using a Waters FractionLynx or Gilson semi-preparative HPLC-MS system using one of two HPLC columns: (a) a Phenomenex Gemini column (5 micron, C18, 150 x 30 mm) or (b) a Waters X-select CSH column (5 micron, C18, 100 x 30 mm). A typical run on this instrument included elution at 45 mL / min with a linear gradient from 10% (v / v) to 100% MeCN (0.1% v / v formic acid) in water (0.1% formic acid) over 10 minutes; conditions can be varied to achieve optimal separation.

[0520] Proton NMR spectra: Unless otherwise indicated, all 1 H NMR spectra were collected on Bruker NMR instruments at 300, 400, or 500 MHz. All observed protons are reported in parts per million (ppm) downfield in tetramethylsilane (TMS) using the internal solvent peak as a reference. Some protons may be present due to exchange of MeOD with D or due to signal suppression. 1 The H signal may be lost.

[0521] Mass Spectrometry (MS): Unless otherwise indicated, all mass spectral data for starting materials, intermediates, and / or exemplary compounds are reported as having a mass / charge (m / z) of [M+H]+ molecular ions. The reported molecular ions were obtained using a Waters Acquity UPLC / MS system using electrospray detection (commonly referred to as ESIMS). As will be understood by those skilled in the art, compounds having isotopic atoms (e.g., bromine, etc.) are typically reported based on the isotopic pattern detected.

[0522] Preparation of intermediates

[0523] Intermediate A: tert-butyl 4-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate.

[0524]

[0525] 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 NaSO, filtered, and the volatiles removed in vacuo. The crude residue was purified by silica gel column chromatography (eluting with a gradient of 0-30% EtOAc in heptane) to provide 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) + .

[0526] 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-dioxaborolan (0.18 g, 0.52 mmol) and 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 h. Water was added and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and the volatiles were removed in vacuo. The residue was purified by silica gel column chromatography (eluting with a gradient of 0-30% EtOAc in heptane) to provide tert-butyl 4-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)but-3-ynoate (0.14 g, 0.30 mmol, 58% yield) as a clear oil. m / z (ESI): 397.0 (Mt-Bu+H) + .

[0527] 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-ynoate (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 a hydrogen atmosphere (15 psi) and stirred at room temperature for 4 h. 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 silica gel column chromatography (eluting with a gradient of 0-50% EtOAc in heptane) to provide 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 (400 MHz, CHLOROFORM-d) δ ppm 7.62 (d, J = 7.5 Hz, 1H), 7.43 (d, J = 2.7 Hz, 1H), 7.35–7.41 (m, 2H), 7.26 (d, J = 6.7 Hz, 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).

[0528] Intermediate B: ethyl 4-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate.

[0529]

[0530] 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-dioxaborolan (1.00 g, 2.96 mmol, Intermediate A, Step 1) and copper(I) iodide (0.08 g, 0.44 mmol) were dissolved in acetonitrile (7.0 mL) and a 15% solution of ethyl diazoacetate (4.50 g, 4.17 mL, 5.91 mmol, Sigma-Aldrich) in toluene was added. The mixture was stirred at room temperature for 3 h. 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 silica gel column chromatography (eluting with a gradient of 0-30% EtOAc in heptane) to provide ethyl 4-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)but-3-ynoate (1.10 g, 2.59 mmol, 88% yield) as a clear oil. m / z (ESI): 425.0 (M+2H) + .

[0531] 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-ynoate (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 a hydrogen atmosphere (15 psi) and stirred at room temperature for 4 h. 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 silica gel column chromatography (eluting with a gradient of 0-50% EtOAc in heptane) to provide 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. 1H NMR (400MHz, chloroform-d) δppm7.61–7.65(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).

[0532] Intermediate C: tert-butyl 4-(2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate.

[0533]

[0534] 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, Limbo Networks) 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 Na2SO4, filtered, and the volatiles removed in vacuo. The residue was then purified by silica gel column chromatography (eluting with a gradient of 0-30% EtOAc in heptane) to provide 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) +

[0535] 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-dioxaborolan (0.86 g, 2.90 mmol) was dissolved in acetonitrile (10 mL) and tert-butyl diazoacetate (0.83 mg, 5.81 mmol, Sigma-Aldrich) was added followed by copper(I) iodide (0.11 g, 0.58 mmol). The reaction mixture was stirred at room temperature for 16 h. 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 silica gel column chromatography (eluting with a gradient of 0-25% EtOAc in heptane) to provide tert-butyl 4-(2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)but-3-ynoate (0.52 g, 1.27 mmol, 44% yield) as a colorless oil. m / z (ESI): 355.0 (Mt-Bu+H) +

[0536] 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-ynoate (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 a hydrogen atmosphere (15 psi) and stirred at room temperature for 6 h. 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 silica gel column chromatography (eluting with a gradient of 0-30% EtOAc in heptane) to provide 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) + .

[0537] Intermediate D: ethyl 4-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate.

[0538]

[0539] Under nitrogen, a 100 mL round-bottom flask was charged with 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, Limpex Networks), PEPPSI-IPr catalyst (0.39 g, 0.57 mmol, Sigma-Aldrich), and anhydrous DMF (45 mL). 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 NHCl and extracted with EtOAc. The combined organics were dried (Na2SO4) and concentrated. The crude material was purified by silica gel column chromatography (eluting with a gradient of 5% to 20% ethyl acetate in heptane) to provide 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 (400 MHz, 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), 3.44–3.60 (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).

[0540] Intermediate E: methyl 5-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)pentanoate.

[0541]

[0542] 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 sparged with argon and stirred at 60°C. After 15 minutes, 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-dioxaborolan (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 silica gel column chromatography (eluting with 0-100% ethyl acetate in heptane) to provide 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) + .

[0543] 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 a hydrogen atmosphere (20 psi) and stirred at room temperature. After 2 h, the reaction mixture was filtered through celite; the filtrate was concentrated. The crude product was purified by silica gel column chromatography (eluting with 0-50% ethyl acetate in heptane) to provide 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) + .

[0544] 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.

[0545]

[0546] NaHMDS (1M in THF, 0.32mL, 0.32mmol) is loaded into a round-bottom flask and the contents are cooled to -78°C. 4-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)naphthalene-1-yl)butyric acid ethyl ester (0.12g, 0.27mmol, intermediate D) dissolved in 1.0mL THF is added dropwise to the solution. The reaction mixture is stirred at -78°C for 30 minutes, and then N-fluorobenzenesulfonimide (0.10g, 0.32mmol) dissolved in 1.0mL THF is slowly added over 15 minutes. The mixture is slowly heated to room temperature and stirred for 16h. The reaction is then cooled to -78°C and MeOH (3mL) is 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 provide 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) δppm7.63 (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,1 H),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 FNMR (377 MHz, chloroform-d) δ ppm -76.59–-74.96 (m, 3F), -117.11 (br s, 1F), -192.09–-191.74 (m, 1F).

[0547] Intermediate G: ethyl 4-(2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate.

[0548]

[0549] 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-dioxaborolan (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 slowly added and the reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with saturated aqueous NH4Cl solution and water and extracted with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (gradient elution with 25% - 100% EtOAc in heptane) to afford ethyl 4-(2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)but-3-ynoate (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).

[0550] Step 2. 4-(2-Fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoic acid ethyl ester. Into a 250 mL pressure tube was loaded 4-(2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)but-3-ynoic acid ethyl ester (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 sparged with nitrogen and then pressurized with H2 (25 psi). The reaction was stirred vigorously for 2.5 h. The reaction mixture was filtered through SiO2 and the filtrate was concentrated. The residue was purified by silica gel column chromatography (gradient elution with 10% - 100% EtOAc in heptane) to provide 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. 1H NMR (500MHz, chloroform-d) δppm 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).

[0551] Intermediate H: ethyl 2-fluoro-4-(2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)butanoate.

[0552]

[0553] NaHMDS (1M in THF, 1.55mL, 1.55mmol) is loaded into a round-bottom flask and the contents are cooled to -78 ° C. Then 4- (2- fluoro- 8- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- bases) naphthalene -1- bases) butyric acid ethyl ester (0.50g, 1.30mmol, intermediate G) dissolved in 1.0mL THF is added to the solution. The reaction mixture is stirred at -78 ° C for 30 minutes, and then N- fluorobenzenesulfonimide (0.57g, 1.81mmol) dissolved in THF (1mL) is slowly added over 15 minutes. The mixture is slowly heated to room temperature and stirred for 16h. The reaction is then cooled to -78 ° C and MeOH (3mL) is 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 provide 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.

[0554] 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.

[0555]

[0556] 5-chloro-6-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)indazole (1.00 g, 2.65 mmol, Advanced ChemBlocks Inc.), PEPPSI-IPr catalyst (0.18 g, 0.27 mmol, Sigma-Aldrich) in tetrahydrofuran (26.5 mL) were loaded into a 100 mL RBF. 6-tert-butoxy-6-oxohexylzinc bromide (0.5 M THF, 10.6 mL, 5.3 mmol, Reck Metals) was added. The reaction was stirred at room temperature for 16 h. 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 silica gel column chromatography (eluting with a gradient of 0-20% EtOAc in heptane) to provide 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).

[0557] 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.

[0558]

[0559] To a oven-dried round-bottom flask was charged 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. PEPPSI-IPr catalyst (2.05 g, 2.59 mmol) was added to the stirred solution and the reaction mixture was stirred at room temperature for 16 h. The reaction 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 silica gel column chromatography (eluting with 0-25% EtOAc in heptane) to provide 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) + .

[0560] 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.

[0561]

[0562] 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, Ambiden) and placed under a nitrogen box. PEPPSI-IPr (1.05 g, 1.33 mmol, Labo Networks) was then added, followed by THF (1.5 mL). (3-((tert-butyldimethylsilyl)oxy)propyl)zinc(II) bromide (66.5 mL, 33.2 mmol, Reich Metals) was then slowly added while swirling the flask. The reaction flask was then removed from the nitrogen box and stirred at room temperature under nitrogen for 3 h. The reaction was quenched by adding saturated NH4Cl solution and stirred vigorously for 10 minutes. 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 product was purified by silica gel column chromatography (gradient of 0-10% EtOAc in heptane) followed by reverse phase chromatography (gradient of 0-80% MeCN (0.1% formic acid) in water (0.1% formic acid)) to provide 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 light yellow oil. m / z (ESI): 515.2 (M+H) + .

[0563] 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.

[0564]

[0565] Step 1. 4-bromo-5-oxo-5,6,7,8-tetrahydronaphthalene-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-propionyl chloride (2.88 g, 23.9 mmol) was slowly added. The reaction was stirred at 0 ° C for 1 h and diluted with saturated NH4Cl solution and extracted with EtOAc. The organic extract was washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography (eluting with a gradient of 0-50% EtOAc in hexanes) to provide 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) + .

[0566] Step 2. 5-allyl-4-bromo-5-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl pivalate. To a 250-mL round-bottom flask was added 4-bromo-5-oxo-5,6,7,8-tetrahydronaphthalene-2-yl pivalate (4.20 g, 12.90 mmol) in THF (52 mL). The mixture was cooled to 0 ° C and allyl zinc 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 extracts were concentrated and the crude material was purified by silica gel column chromatography (eluting with a gradient of 0-50% EtOAc in hexanes) to provide 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) + .

[0567] Step 3. 5-allyl-4-bromo-5,6,7,8-tetrahydronaphthalene-2-yl pivalate. To a 25-mL round-bottom flask was added 5-allyl-4-bromo-5-hydroxy-5,6,7,8-tetrahydronaphthalene-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 at 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 silica gel column chromatography (eluting with a gradient of 0-60% EtOAc in heptane) to provide 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) + .

[0568] Step 4. 4-bromo-5-(2-oxoethyl)-5,6,7,8-tetrahydronaphthalene-2-yl pivalate. To a 25-mL round-bottom flask was added 5-allyl-4-bromo-5,6,7,8-tetrahydronaphthalene-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 osmium dioxide dihydrate (2.1 mg, 5.7 μmol, Oakwood Products, Inc.) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium (meta) periodate (0.24 g, 1.14 mmol) was added and continued to stir for another hour. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography (eluting with a gradient of 0-45% EtOAc in heptane) to provide 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 (400MHz, chloroform-d) δppm 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).

[0569] Step 5. (E / Z)-ethyl 4-(8-bromo-6-(pivaloyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)but-2-enoate. To a 25-mL round-bottom flask was added (ethoxycarbonylmethyl)triphenylphosphonium bromide (0.24 g, 0.57 mmol) in THF (1.4 mL). The mixture was cooled to 0 °C and a solution of lithium bis(trimethylsilyl)amide (1 M in THF, 0.50 mL, 0.5 mmol) was added. The reaction mixture was stirred for 30 minutes, and then 4-bromo-5-(2-oxoethyl)-5,6,7,8-tetrahydronaphthalen-2-yl pivalate (0.10 g, 0.28 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The crude material was purified by column chromatography (eluting with a gradient of 0-25% EtOAc in heptane) to provide (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 indicated a mixture of cis / trans (approximately 1:2 ratio) isomers.

[0570] 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 ethyl (E / Z)-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 and quenched with water and extracted with EtOAc. The organic layer was separated, dried (Na2SO4) and concentrated. The crude material was purified by silica gel column chromatography (eluting with a gradient of 0-45% EtOAc in heptane) to provide ethyl 4-(8-bromo-6-(pivaloyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)butanoate. m / z (ESI): 446.8 / 448.8 (M+Na) + .

[0571] 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 h. After cooling to room temperature, the crude material was purified by silica gel column chromatography (eluting with a gradient of 0-45% EtOAc in heptane) to provide 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) + .

[0572] 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.

[0573]

[0574] 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, Ambiden) and PEPPSI-IPr (0.42 g, 0.53 mmol, Limpex). 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 then added. The mixture was purged with nitrogen for 10 min and then heated to 40°C for 16 h. Upon completion, the reaction was quenched with water and extracted with EtOAc. The organic layer was concentrated and purified by reverse phase chromatography to provide 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 light yellow solid. m / z (ESI): 397.2 (M+H) + .

[0575] Intermediate N: 2-(8-allylnaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0576]

[0577] Into a 250mL round-bottom flask, 1-allyl-8-bromonaphthalene (2.33g, 9.43mmol, CombiBlocks) and dry THF (100mL) were charged. The mixture was cooled to -78°C and n-BuLi (2.5M in hexane, 4.9mL, 12.3mmol) was added dropwise. The resulting mixture was stirred at -78°C for 30min. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.6mL, 14.1mmol, Sigma-Aldrich) was then added and the reaction mixture was warmed to room temperature within 1h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layer was dried and concentrated. The crude mixture was purified by silica gel column chromatography (eluting with a gradient of 0-50% EtOAc in heptane) to provide 2-(8-allylnaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.70 g, 9.18 mmol, 97% yield) contaminated with a deallylated impurity. 1H NMR (400MHz, methanol-d4) δppm 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).

[0578] Intermediate O: (Z)-methyl 5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pent-4-enoate and Intermediate P: methyl 5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoate.

[0579]

[0580] 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, Labo Networks), triethylamine (9.5 mL, 68 mmol), and N,N-dimethylformamide (14 mL). The solution was sparged 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 h and then heated to 35° C. for 6 h. The reaction was diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The aqueous layer was extracted with EtOAc, washed with brine, and the organics were dried over sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography (eluting with 0-30% EtOAc in heptane) to provide methyl 5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pent-4-ynoate (2.23 g, 5.24 mmol, 77% yield) as an off-white solid.

[0581] 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-ynoate (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 h. After completion, the reaction mixture was diluted with EtOAc, filtered through celite, and the filtrate was concentrated. The crude material was purified by silica gel column chromatography (eluting with 0-30% EtOAc in heptane) to provide (Z)-methyl 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) +

[0582] Intermediate Q: ethyl 2-(3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propoxy)acetate.

[0583]

[0584] Step 1.2-(prop-2-yn-1-yloxy)ethyl acetate. Under nitrogen, ethyl glycolate (3.49 mL, 33.6 mmol) and THF (96 mL) were charged into a dried 3-necked flask. Sodium hydride (60% dispersion in mineral oil) (1.61 g, 40.3 mmol) was added in batches and the reaction mixture was stirred at room temperature for 1 h. Propargyl bromide (5.0 mL, 33.6 mmol) was then 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 silica gel column chromatography (eluted with 0–20% ethyl acetate in heptane) to provide 2-(prop-2-yn-1-yloxy)ethyl acetate (1.90 g, 13.40 mmol, 40% yield) as a light yellow oil. 1H 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).

[0585] 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, Limbo Networks), DMF (9.06 mL), and triethylamine (6.4 mL, 45.3 mmol). The solution was sparged with nitrogen and bis(triphenylphosphine)palladium(II) dichloride (0.16 g, 0.23 mmol) and cuprous iodide (26 mg, 0.14 mmol) were added. The solution was stirred at 35° C. for 24 h. 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 silica gel column chromatography (eluting with 0-40% EtOAc in heptane) to provide 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) + .

[0586] 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 silica gel column chromatography (eluting with 0-30% EtOAc in heptane) to provide 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) + .

[0587] Intermediate R. 3-(But-3-en-1-yl)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol.

[0588]

[0589] Step 1. 3-(But-3-en-1-yl)piperidin-3-ol 2,2,2-trifluoroacetate. 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, Blockchain). 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, Blockchain) in THF (10 mL) was added. The mixture was slowly warmed 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 h. After completion, the mixture was concentrated and purified by reverse phase chromatography to provide 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) + .

[0590] Step 2. 3-(But-3-en-1-yl)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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, Anemi) 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 warmed to room temperature over 20 minutes. ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (1.14 g, 7.13 mmol, Limbo Networks) 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 silica gel column chromatography (eluting with a 0–50% (3:1 EtOAc:EtOH, 2% TEA) gradient in heptane) to afford 3-(but-3-en-1-yl)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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) + .

[0591] Intermediate S: methyl 4-(8-bromo-3,4-dihydroquinolin-1(2H)-yl)butanoate.

[0592]

[0593] A solution of 8-bromo-1,2,3,4-tetrahydroquinoline (1.25 mL, 5.89 mmol, AurumPharmatech LLC), methyl 4-oxobutanoate (1.37 g, 11.8 mmol, Combination Block Co., Ltd.) and acetic acid (0.14 mL, 2.36 mmol) in DCE (10 mL) was stirred at room temperature for 20 min. Sodium triacetoxyborohydride (1.50 g, 7.10 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 3.5 h and then at 50 ° C for 20 h. The crude mixture was poured into an 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 silica gel column chromatography (gradient elution with 0-50% EtOAc in heptane) to provide 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, 400 MHz) δ 7.3–7.4 (m, 1H), 6.98 (dd, 1H, J = 1.0, 7.5 Hz), 6.75 (t, 1H, J = 7.6 Hz), 3.70 (s, 3H), 3.1–3.2 (m, 2H), 3.0–3.0 (m, 2H), 2.79 (t, 2H, J = 6.7 Hz), 2.42 (t, 2H, J = 7.5 Hz), 2.1–2.2 (m, 2H), 1.8–1.9 (m, 2H). m / z (ESI): 312.2 and 314.2 (M+H) + .

[0594] Intermediate T: tert-butyl 5-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate.

[0595]

[0596] Step 1: tert-Butyl 4-bromo-5-hydroxy-1H-indazole-1-carboxylate. To a 250-mL round-bottom flask was added 4-bromo-1H-indazole-5-ol (6.30 g, 29.6 mmol, Ainimei) 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 slowly added via a 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 h and then cooled to 0 ° C. Lithium hydroxide monohydrate (7.45 g, 177 mmol) in water (30 mL) was slowly added. The reaction mixture was warmed to room temperature and stirred for 2 days. The mixture was slowly diluted to about pH 6 with 2M HCl (90 mL) at 0 ° C and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO 4 , filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (eluting with a 0–40% [3:1 EtOAc:EtOH] gradient in heptane) to provide 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) δppm 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).

[0597] Step 2: tert-Butyl 5-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-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'-bis(1,3,2-dioxaborolane) (0.98 g, 3.84 mmol) and Pd(dppf)Cl2 (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 product was used directly in the next step without further purification.

[0598] Intermediate U: (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol.

[0599]

[0600] To a 100 mL round-bottom flask was charged 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (2.10 g, 5.90 mmol, Intermediate Z) and N-ethyl-N-isopropylpropane-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. (R)-3-methylpiperidin-3-ol hydrochloride (0.98 g, 6.5 mmol) was then added. The reaction mixture was stirred at room temperature for 2 h. The mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The aqueous layer was extracted with EtOAc and the combined organics were washed with brine, dried, and concentrated. The crude material was purified by silica gel column chromatography eluting with 0-100% 3:1 (EtOAc:EtOH with 2% triethylamine) in heptane to provide (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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) + .

[0601] Intermediate V: (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(fluoromethyl)piperidin-3-ol.

[0602]

[0603] To a 100 mL round-bottom flask was charged 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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. (R)-3-(Fluoromethyl)piperidin-3-ol (1.23 g, 9.25 mmol) was then added in one portion. The reaction mixture was stirred at room temperature for 16 h. The mixture was partitioned between ethyl acetate 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 silica gel column chromatography eluting with 0-100% 3:1 (EtOAc:EtOH with 2% triethylamine) in heptane to provide (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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) + .

[0604] Intermediate W: (R)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(tributylstannyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol.

[0605]

[0606] Step 1. (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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, Anemi) in acetonitrile (22.5 mL) at 0°C was added (3R)-piperidin-3-ol (0.80 g, 7.92 mmol, Combination Block) and DIPEA (6.9 mL, 39.6 mmol). The reaction mixture was stirred at 0°C for 40 min. The desired intermediate (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol was identified by LCMS (m / z (ESI): 317.2 (M+H) +) was observed. A solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 silica gel column chromatography (eluting with a 0–75% (3:1 EtOAc:EtOH in heptane, containing 2% triethylamine) gradient) to provide (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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) + .

[0607] Step 2. (R)-1-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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-pyrrolazin-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 min. [2-(2-Aminophenyl)phenyl]-chloro-palladium tricyclohexylphosphine (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 a silica gel column eluting with a gradient of 0-100% (3:1 EtOAc:EtOH with 2% triethylamine) in heptane to afford (R)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 semisolid. m / z (ESI): 696.0 (M+H) + .

[0608] Intermediate X: 7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-ol.

[0609]

[0610] Step 1.7-bromo-2-chloro-6,8-difluoro-4-(piperidin-1-yl)quinazoline. To a 0°C 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 DIPEA (55.6 mL, 319 mmol) in portions at 0°C. The mixture was stirred at 0°C for 30 min and then concentrated under reduced pressure. The crude product was triturated with petroleum ether (100 mL) at 20°C for 1 h. The suspension was filtered and the filter cake was washed with petroleum ether and dried in vacuo 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) + .

[0611] Step 2. 7-Bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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) were added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (29.0 g, 182 mmol, Labo Networks), CsCO (59.3 g, 182 mmol), and DABCO (5.10 g, 45.5 mmol). The reaction mixture was stirred at 25° C. for 10 h, then diluted with H O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was triturated with MTBE (80 mL) at 20 °C for 1 h. The suspension was filtered and the filter cake was washed with MTBE and dried under vacuum to give 7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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) + .

[0612] Step 3. 7-Bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-ol. To a solution of 7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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 h. This procedure was repeated three more times at this scale.

[0613] After cooling to room temperature, the reaction mixture is combined and concentrated under reduced pressure, and the residue is then diluted with H o and extracted with EtOAc. The combined organic layer is washed with brine, dried over Na sO , filtered and concentrated. The crude product is ground together with a mixed solvent of petroleum ether and EtOAc (1: 1, 200 mL) at room temperature for 30 min. The suspension is filtered and the filter cake is washed with a mixed solvent of petroleum ether and EtOAc (1: 1), dried in vacuo, to give 7- bromo -6,8- difluoro -2- (((2R, 7aS) -2- fluorotetrahydro -1H- pyrrolizine -7a (5H) -yl) methoxy) quinazoline -4- alcohol (150 g, 358 mmol, 87% yield) as a white solid. m / z (ESI): 418.0 / 420.0 (M+H) + .

[0614] Intermediate Y: 7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-ol hydrobromide.

[0615]

[0616] 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 stirred with The mixture was treated with 1% t-butyl ether (30 g) and then cooled to -60°C. A solution of phenylmethanol (16.6 mL, 161 mmol) pre-reacted with t-BuOK (1 M in THF, 161 mL, 161 mmol) was added dropwise at -60°C. The mixture was stirred at -60°C for 2 h. This procedure was repeated three more times on this scale.

[0617] The reaction mixture was combined and poured into water, then extracted with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was ground together with petroleum ether (800mL) at 20 ° C for 50min. The suspension was filtered and the filter cake was washed with petroleum ether and dried in vacuo to give 4- (benzyloxy) -7- bromo -2- chloro -8- fluoroquinazoline (220g, 589mmol, 88% yield) as a yellow solid. m / z (ESI): 367.1 / 369.1 (M+H) + .

[0618] Step 2. 4-(Benzyloxy)-7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazoline. To 4-(benzyloxy)-7-bromo-2-chloro-8-fluoroquinazoline (70 g, 190 mmol) and To a solution of molecular sieves (30 g) in 1,4-dioxane (700 mL) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (42.4 g, 267 mmol) and DIPEA (700 mL). The mixture was stirred at 120° C. for 12 h. This procedure was repeated two more times on a similar scale.

[0619] 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 ground with MTBE (800 mL) at 20 ° C for 30 min. The suspension was filtered and the filter cake was washed with MTBE and dried in vacuo to give 4- (benzyloxy) -7- bromo -8- fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro -1H- pyrrolizine -7a (5H) -yl) methoxy) quinazoline (115 g, 235 mmol, 41% yield) as a yellow solid. m / z (ESI): 490.3 / 492.2 (M + H) + .

[0620] 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 (33% solution in AcOH, 250 mL, 71.4 mmol) was stirred at room temperature for 4 h. This procedure was repeated two more times on a similar scale.

[0621] The reaction mixture was diluted with EtOAc and the suspension was filtered. The filter cake was ground together with EtOAc (100 mL) at room temperature for 20 min. The suspension was filtered and the filter cake was washed with EtOAc, dried under vacuum to give 7- bromo -8- fluoro -2- (((2R, 7aS) -2- fluorotetrahydro -1H- pyrrolizine -7a (5H) -yl) methoxy) quinazolin -4- alcohol hydrobromide (105 g, 219 mmol, HBr salt) as a white solid. m / z (ESI): 400.1 / 402.1 (M+H) + .

[0622] 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.

[0623]

[0624] The title compound was synthesized in a similar manner to Intermediate Y using 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (CAS No. 2454396-80-4, Anemi) in step 1.

[0625] m / z(ESI):357.2(M+H) + .

[0626] Intermediate AA: ethyl 4-(2-fluoro-8-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-(methoxymethoxy)naphthalen-1-yl)butanoate.

[0627]

[0628] 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, Aneme) in tetrahydrofuran (750 mL) cooled to -60 ° C was added 2,2,2-trifluoroethane-1-ol (18.82 g, 188 mmol) followed by dropwise addition of t-BuOK (1 M in THF, 188 mL, 188 mmol). The mixture was stirred at -60 ° C for 2 h. The reaction mixture was quenched at 20 ° C by addition of H2O (1 L) and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was washed with petroleum ether (50 mL) and then 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).

[0629] Step 2. 7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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-pyrrolazin-7a(5H)-yl)methanol (16.93 g, 106 mmol) and DIPEA (46.4 mL, 266 mmol). The mixture was then stirred at 80° C. for 10 h. 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 silica gel column chromatography (eluting with a gradient of 5% to 100% EtOAc in petroleum ether) to provide 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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) + .

[0630] 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-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.00 g, 2.28 mmol), cataCXium A Pd G2 (0.15 g, 0.23 mmol) and Cs2CO3 (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 silica gel column chromatography (eluting with a gradient of 5%–100% ethyl acetate in petroleum ether) to provide 4-(2-fluoro-8-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-(methoxymethoxy)naphthalene-1-yl)butanoic acid ethyl ester (0.56 g, 0.77 mmol, 34% yield) as a yellow solid. m / z(ESI): 725.3 / 723.2(M+H) + .

[0631] Intermediate BB: ethyl 4-(2-fluoro-8-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-1-yl)butanoate.

[0632]

[0633] 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) + .

[0634] Intermediate CC: methyl 5-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)pentanoate.

[0635]

[0636] 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, Limpex Networks) 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 under N2 for 30 min. BF3OEt2 (3.0 mL, 24 mmol) was added and after stirring for 30 min, oxetane (2.5 g, 43 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with aqueous NHCl and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1%-20% EtOAc in petroleum ether) to provide 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) δppm8.05(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).

[0637] 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-iodooxybenzoic 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 phases were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with 0-10% EtOAc in petroleum ether) to give 5-(2-fluoro-8-iodo-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)δppm 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).

[0638] Step 3. 5-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-1-yl)pent-4-ynoic acid methyl ester. 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 KCO (1.43 g, 10.3 mmol) and NIS (2.32 g, 10.3 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (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 light yellow solid. 1 HNMR(400MHz,DMSO-d6)δppm 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).

[0639] Step 4.5-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)naphthalen-1-yl)pent-4-ynoic acid methyl ester. To a solution of 5-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-1-yl)pent-4-ynoic acid methyl ester (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 h. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.95 g, 15.8 mmol) was then added. The mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by the addition of aqueous NHCl at 0 °C and then 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 silica gel column chromatography (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.

[0640] Step 5.5-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)pentanoic acid methyl ester. To a solution of 5-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)pent-4-ynoic acid methyl ester (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 H2 twice. The mixture was stirred at room temperature under H2 (15 psi) for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (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. 1H NMR(400MHz,DMSO-d6)δppm 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).

[0641] 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.

[0642]

[0643] A solution of NaHMDS (1M in THF, 2.5 mL, 2.5 mmol) was cooled to -78 ° C. 5-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-5-yl) ethyl 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 min, and then NFSI (0.93 g, 2.94 mmol) dissolved in 2 mL of THF was slowly added over 15 min. The mixture was slowly warmed to room temperature and stirred for 16 h. 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 yield 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.

[0644] Intermediate EE: tert-butyl ((S)-4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)carbamate.

[0645]

[0646] A 40-mL vial was charged with 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (2.00 g, 4.56 mmol, Intermediate AA, Step 2), (S)-tert-butyl(1,4-oxazepan-6-yl)carbamate (1.7 mL, 9.12 mmol, Anemi), 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 (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography eluting with 0-85% 3:1 EtOAc / EtOH in heptane with 2% triethylamine to yield 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) + .

[0647] Intermediate FF: tert-butyl ((R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-yl)carbamate.

[0648]

[0649] Synthesized in a similar manner to Intermediate EE using (R)-azepan-3-ylcarbamic acid tert-butyl ester (CAS No.: 1354351-56-6, Ambiden). m / z (ESI): 553.0 (M+H) + .

[0650] Intermediate GG: tert-butyl 6-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonane-2-carboxylate.

[0651]

[0652] Synthesized in a similar manner to Intermediate V using tert-butyl 2,6-diazaspiro[3.5]nonane-2-carboxylate (CAS No. 1086394-57-1, Anemi). m / z (ESI): 564.9 (M+H) + .

[0653] Intermediate HH: tert-butyl 5-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)octahydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate.

[0654]

[0655] Synthesized in a similar manner to Intermediate EE using tert-butyl hexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate hydrochloride (CAS No. 236406-56-7, eNovation Chemicals LLC). m / z (ESI): 565.0 (M+H) + .

[0656] Intermediate II: ethyl 5-(2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pentanoate.

[0657]

[0658] Step 1. Ethyl (2E,4E)-5-(2-bromo-6-chlorophenyl)penta-2,4-dienoate. To a solution of LDA (2M 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 N2. The mixture was stirred at -78 °C for 0.5 h, then a solution of 2-bromo-6-chlorobenzaldehyde (3.23 g, 14.7 mmol) in THF (30 mL) was added via syringe. The mixture was stirred at 0 °C for 2 h, then quenched with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (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. 1H NMR((400MHz, CDCl3)δppm7.54(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). + .

[0659] 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'-bis(1,3,2-dioxaborolan) (9.49 g, 37.4 mmol), KOAc (4.28 g, 43.6 mmol), and Pd(dppf)Cl2 (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 silica gel column chromatography (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) + .

[0660] 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 H2 and then stirred under H2 (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 silica gel column chromatography (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) + .

[0661] Intermediate JJ: 4-(tert-Butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)yl)methoxy)pyrido[4,3-d]pyrimidine.

[0662]

[0663] Step 1. To a solution of 2,4,7-trichloro-8-fluoropyrido [4,3-d] pyrimidine (50.0 g, 198 mmol, Ainimei) in tetrahydrofuran (1.5 L) was added t-BuOK (1 M in THF, 190 mL, 190 mmol) at -60 ° C, and the reaction mixture was stirred for 2 h at -60 ° C. The 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 ground together with petroleum ether at room temperature for 1 h. The suspension was filtered and the filter cake 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) δppm 9.08 (s, 1H), 1.74 (s, 9H).

[0664] Step 2. 4-(tert-Butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)yl)methoxy)pyrido[4,3-d]pyrimidine. To 4-(tert-Butoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (50.0 g, 172 mmol) and To a solution of MS (10 g) in 1,4-dioxane (1 L) were added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (30.2 g, 190 mmol) and DIPEA (60.0 g, 431 mmol). 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 h. The suspension was filtered and the filter cake was concentrated under reduced pressure to give 4-(tert-butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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) + .

[0665] Intermediate KK: 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(tributylstannyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine.

[0666]

[0667] 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, Anemi) in tetrahydrofuran (600 mL) was added dropwise a mixture of 2,2,2-trifluoroethane-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 h, then diluted with 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 petroleum ether at room temperature for 30 min. 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.

[0668] Step 2. 7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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-pyrrolazin-7a(5H)-yl)methanol (24.2 g, 152 mmol) and DIPEA (55.3 mL, 316 mmol). The reaction mixture was stirred at 65 °C for 1.5 h. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na SO , 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 h. 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-pyrrolazin-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.

[0669] 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-pyrrolazin-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 PCy3PdG2 (5.38 g, 9.12 mmol) and LiCl (4.83 g, 114 mmol) followed by the addition of bis(tri-n-butyltin) (39.7 g, 68.4 mmol) in one portion under N2. The mixture was stirred at 80 °C for 12 h under nitrogen. 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 Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with a 0-100% EtOAc gradient in petroleum ether). The crude product was triturated with DMSO at room temperature for 1 h. The suspension was filtered and the filter cake was concentrated under reduced pressure to give 8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-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) + .

[0670] 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.

[0671]

[0672] Step 1. (E) -4- (diethoxyphosphoryl) but-2-enoic acid methyl ester. Into a 3-L round-bottom flask, (E) -4- bromobut-2-enoic acid methyl ester (150g, 838mmol) was loaded. The contents were heated to 120 ° C and triethyl phosphite (167g, 1.00mol) was added dropwise. The resulting mixture was stirred at 120 ° C for 4h under N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product (E) -4- (diethoxyphosphoryl) but-2-enoic acid methyl ester (150g) in the form of a yellow oil was used in the next step without further purification.

[0673] 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 (2M 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 N2. The reaction mixture was stirred at -78°C for 30 min, then 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) was added dropwise at -78°C. The mixture was then stirred at 0 ° C for 1.5 h. The mixture was quenched by adding water at 0 ° C and then extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with a 0-100% EtOAc gradient in petroleum ether) to give (2E,4E)-5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)penta-2,4-dienoic acid methyl ester (91 g, 214 mmol, 73% yield) as a white solid.

[0674] Step 3. Methyl 5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoate. A hydrogenation reactor was charged with PtO2 (7.47 g, 32.9 mmol) in tetrahydrofuran (1.4 L). Under argon, (2E,4E)-methyl 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 and the suspension was degassed and purged with H2 three times. The mixture was hydrogenated under H2 (15 psi) at room temperature for 72 h. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with a gradient of 2% to 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) + .

[0675] 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 silica gel column chromatography (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) + .

[0676] Intermediate MM: 5-(6-chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoic acid.

[0677]

[0678] Step 1. Methyl 5-(6-chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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-pyrrolazin-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) under N2 were added K3PO4 (0.73 g, 3.42 mmol) followed by CataCXium A Pd G3 (83 mg, 0.13 mmol). The mixture was then stirred at 80 ° C for 3h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with 0-50% EtOAc gradient in petroleum ether) to give 5- (6- chloro-4- (8- fluoro-2- (((2R, 7aS) -2- fluorotetrahydro -1H- pyrrolizine -7a (5H) -yl) methoxy) -4- (2,2,2- trifluoroethoxy) pyrido [4,3-d] pyrimidin-7-yl) -1- (tetrahydro -2H- pyrans -2-yl) -1H- indazole -5-yl) pentanoic acid methyl ester (0.47 g, 0.63 mmol, 55% yield) as a colorless oil.

[0679] Step 2. 5-(6-Chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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-pyrrolazin-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 1N HCl, and the mixture was 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 min. 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-pyrrolazin-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) + .

[0680] Intermediate NN: 5-(4-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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.

[0681]

[0682] Step 1. Ethyl 5-(4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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-pyrrolazin-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) under N2 were added K3PO4 (29.0 g, 137 mmol) and cataCXium A Pd G3 (3.32 g, 4.56 mmol). 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 Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 10%–100% EtOAc gradient in petroleum ether) to give 5-(4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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)pentanoic acid ethyl ester (20 g, 26.8 mmol, 59% yield) as a yellow solid. m / z(ESI):747.4(M+H) + .

[0683] Step 2. 5-(4-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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-pyrrolazin-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 H2O and concentrated under reduced pressure to give 5-(4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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) + .

[0684] Intermediate OO: 3,6,8-trichloropyrimido[5,4-c]pyridazine.

[0685]

[0686] Step 1.4-amino-6-chloro-pyridazine-3-carboxamide. A solution of methyl 4,6-dichloropyridazine-3-carboxamide (50.0 g, 242 mmol) in NH3-MeOH (7 M, 500 mL, 14.5 equivalents) was stirred at 100 ° C for 12 h in a 2-L sealed tube. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was ground with a mixed solvent (petroleum ether: ethyl acetate = 3: 1) at room temperature for 1 h. 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 product) as a yellow solid. m / z (ESI): 173.0 / 175.0 (M+H) + .

[0687] 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 adding 1MHCl to give a suspension. It was filtered and the filter cake was concentrated under reduced pressure. The crude product was ground together with EtOAc at room temperature for 1 h. The mixture was then filtered and the filter cake was washed with EtOAc, 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) + .

[0688] 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) was added POCl3 (81 mL, 869 mmol) 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 silica gel column chromatography (eluted with 0–100% EtOAc gradient in petroleum ether) to give 3,6,8-trichloropyrimido [5,4-c] pyridazine (8.50 g, 36.2 mmol, 21% yield) as a green solid. m / z (ESI): 337.0 / 339.0 (quenched with morpholine, M+2 morpholine+H) + .

[0689] Intermediate PP: 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)rac-(3aS,7aR)-hexahydro-1H-pyrrolo[2,3-c]pyridine-1,6(2H)-dicarboxylate.

[0690]

[0691] 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 and 4-nitrophenyl chloroformate (0.13 g, 0.65 mmol) was added, and the mixture was stirred at room temperature for 2 h. Rac-cis-tert-butyl 1,2,3,3a,4,5,7,7a-octahydropyrrolo[2,3-c]pyridine-6-carboxylate (0.44 g, 1.95 mmol, Angel Pharmatech Ltd.) in N,N-dimethylformamide (0.5 mL) was added and the mixture was heated at 40°C for 1 h. After cooling to room temperature, the crude material was concentrated and purified by silica gel column chromatography (eluting with 0-50% EtOAc in heptane) to provide rac-(3aS,7aR)-hexahydro-1H-pyrrolo[2,3-c]pyridine-1,6(2H)-dicarboxylic acid 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) ester as a white solid (0.27 g, 0.42 mmol, 64% yield). m / z (ESI): 653.2 (M+H) + .

[0692] Intermediate QQ: (R)-tert-butyl 3-(((2-(2-fluoro-8-iodonaphthalen-1-yl)ethoxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate.

[0693]

[0694] 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, Limbo Networks) 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, then quenched with water and extracted with EtOAc. The combined organic phases were 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. CsF (30.0 g, 197 mmol) was added to the above-mentioned crude brown solid dissolved in N, N-dimethylacetamide (100 mL). The mixture was stirred at 80 ° C for 2 h and then cooled to room temperature. Water was added and the mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with 100% petroleum ether) to provide 1-ethynyl-2-fluoro-8-iodonaphthalene (5.90 g, 19.9 mmol, 45% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δppm 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) + .

[0695] Step 2.2-fluoro-8-iodo-1-vinylnaphthalene. To a suspension of bis(cyclopentadienyl)zirconium chloride hydride (5.23g, 20.3mmol) in dichloromethane (60mL), 1-ethynyl-2-fluoro-8-iodonaphthalene (3.00g, 10.1mmol) in dichloromethane (2mL) was added dropwise and stirred at 0°C, and the reaction mixture was then stirred at 15°C for 20h. The reaction was quenched with water and extracted with EtOAc. The combined organic phases were washed with salt water, dried (Na2SO4), filtered and concentrated. The reaction was repeated twice. The residue was purified by silica gel column chromatography (eluting with 100% petroleum ether), to provide 2-fluoro-8-iodo-1-vinylnaphthalene (3.53g, 11.8mmol, 58% yield) as a brown solid. 1H NMR(400MHz,DMSO-d6)δppm 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) + .

[0696] Step 3. 2-(2-fluoro-8-iodonaphthalen-1-yl)ethane-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, 12.1 mL, 121 mmol) at room temperature. The mixture was stirred for 12 h and then treated with H2O2 (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 phases were washed with brine, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with 20%-50% EtOAc in petroleum ether) to provide 2-(2-fluoro-8-iodonaphthalen-1-yl)ethan-1-ol (1.44 g, 4.56 mmol, 19% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 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) + .

[0697] Step 4. (4-nitrophenyl) 2-(2-fluoro-8-iodonaphthalene-1-yl) ethyl carbonate. At 0 ° C, TEA (0.85 mL, 6.1 mmol) was added to a solution of 4-nitrophenyl chloroformate (0.61 g, 3.04 mmol) and 2-(2-fluoro-8-iodonaphthalene-1-yl) ethane-1-ol (0.96 g, 3.04 mmol) in dichloromethane (10 mL). The mixture was stirred at room temperature for 2 h, then diluted with DCM and washed with water. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with 40%-80% EtOAc in petroleum ether) to provide 2-(2-fluoro-8-iodonaphthalene-1-yl) ethyl carbonate (1.31 g, 1.97 mmol, 65% yield) as a yellow oil. m / z(ESI):481.5(M+H) + .

[0698] 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 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 50%-80% EtOAc in petroleum ether) to provide (R)-tert-butyl 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) + .

[0699] 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.

[0700]

[0701] To a 0 ° C suspension of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (0.50 g, 1.98 mmol, Ainimei) in acetonitrile (8 mL) was added (3R)-azepan-3-ol (0.23 g, 1.98 mmol, Yaoshi) 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 magnesium sulfate. The filtrate containing a solution of [(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 silica gel column chromatography (eluting with a 0-75% 3:1 EtOAc / EtOH gradient in heptane (containing 2% triethylamine)) to provide (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) + .

[0702] Intermediate SS: (1R,2S,5S)-8-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-2-ol.

[0703]

[0704] A 40-mL vial was charged with 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 min, then HATU (0.26 g, 0.67 mmol) was added. After stirring for 50 min, exo-azabicyclo[3.2.1]octan-2-ol hydrochloride (0.12 g, 0.73 mmol, Yaoshi Company) was added and the reaction mixture was stirred at room temperature for 1 h. The mixture was purified by silica gel column chromatography eluting with 0-80% 3:1 EtOAc / EtOH in heptane with 2% triethylamine to afford (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 as a yellow solid. -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). m / z (ESI): 466.0 (M+H) + .

[0705] 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.

[0706]

[0707] 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-dioxaborolane-2-yl)-6-(trifluoromethyl)-1H-indazole (1.00 g, 2.32 mmol, Yaoshi). 5-ethoxy-5-oxopentylzinc bromide (0.5 M in THF, 14 mL, 7 mmol, Reck 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. 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 injected into a C18 column (50 g) eluted with a 5%-80% (0.1% formic acid in MeCN) / (0.1% formic acid in water) gradient. The desired fractions were concentrated under reduced pressure to provide 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.

[0708] Intermediate UU: (R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-ol.

[0709]

[0710] The title compound was synthesized using (3R)-azepan-3-ol (CAS No. 1573085-99-0, Yaoshi Company) in a similar manner to Intermediate V. m / z (ESI): 454.0 (M+H) + .

[0711] Intermediate VV: (S)-4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol.

[0712]

[0713] The title compound was synthesized in a similar manner to intermediate EE using (S)-[1,4]oxazepan-6-ol (CAS No. 1373232-31-5, J&W Pharmlab). m / z (ESI): 456.0 (M+H) + .

[0714] Intermediate WW: methyl 5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-methylpentanoate.

[0715]

[0716] To an oven-dried round-bottom flask was placed 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 min, then iodomethane (0.14 mL, 2.2 mmol) was added and the reaction was stirred at -78°C for 1 h. After heating, 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 silica gel column chromatography (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) + .

[0717] Intermediate XX: ethyl 2-(2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethoxy)acetate.

[0718]

[0719] 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-ethoxyethylene-2-boronic acid pinacol ester (2.02 g, 10.2 mmol, Jinyao Technology Co., Ltd.), 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (3.00 g, 6.80 mmol, Lanbo Networks), tripotassium phosphate (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 h. After cooling to room temperature, the crude material is diluted with EtOAc and saturated aqueous sodium bicarbonate. The water layer is extracted with EtOAc, and the combined organic matter is dried (Na2SO4) and concentrated. The crude product is then diluted with 1,4-dioxanes (18mL) and water (1mL) and trifluoroacetic acid (7.8mL, 102mmol) is added dropwise thereto. The reaction mixture is stirred at 40 ° C for 6h. After cooling to room temperature, the reaction mixture is concentrated and the residue is passed through silica gel column chromatography (eluted with 0-100% (3:1EtOAc:EtOH+2% triethylamine) in heptane) to provide 2- (4- bromo-6- chloro-1- (tetrahydro -2H- pyrans -2- bases) -1H- indazole -5- bases) acetaldehyde (2.40g, 6.71mmol, 99% yield) as an impure brown oil, which is treated with triethylamine and filtered to neutralize the remaining TFA. m / z(ESI):357.0(M+H) + .

[0720] Into a 250mL round-bottom flask, the above-mentioned aldehyde (2.40g, 6.71mmol) and ethanol (70mL) were charged. The reaction mixture was cooled to 0°C and sodium borohydride (0.53g, 14mmol) was added in batches. The solution was warmed to room temperature and stirred for 30min. The reaction was then carefully quenched by adding methanol, water and saturated aqueous ammonium chloride. The resulting solution was extracted with EtOAc. The combined organic matter was dried (Na2SO4) and concentrated. The residue was purified by reverse phase chromatography (eluting with 0–100% acetonitrile+0.1% TFA in water+0.1% TFA) using a 50g C18 column to give 2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)ethane-1-ol (0.20g, 0.56mmol, 8% yield). m / z(ESI):359.0(M+H) + .

[0721] Step 2. Ethyl 2-(2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethoxy)acetate. To an oven-dried 100 mL round-bottom flask was charged 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 min, then ethyl bromoacetate (0.42 mL, 3.8 mmol) was added dropwise and the reaction was warmed to room temperature and stirred for 4.5 h. The reaction mixture was carefully quenched by the addition of saturated aqueous ammonium chloride and then extracted with EtOAc. The combined organics were dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography (eluting with 0-40% EtOAc in heptane) to provide 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) + .

[0722] Intermediate YY: methyl 2-((S)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(tributylstannyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)acetate.

[0723]

[0724] Step 1. Methyl 2-((S)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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-pyrrolazin-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 min, and then 2-[(3S)-piperidin-3-yl]acetic acid methyl ester hydrochloride (2.82 g, 14.6 mmol, Anemi) was added. The reaction mixture was stirred at room temperature for 16 h and 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 (eluted with a gradient of 0-100% EtOAc / EtOH (3: 1) (containing 1% TEA) in heptane) to provide 2-((S)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)acetic acid methyl ester (5.00 g, 10 mmol, 90% yield) as an orange solid. m / z(ESI):496.0(M+H) + .

[0725] Step 2. Methyl 2-((S)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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-pyrrolazin-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 sparged with nitrogen for 15 min, then 1,1,1,2,2,2-hexabutyl-distannoe (2.5 mL, 4.8 mmol) and chloro[(tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II) (0.38 g, 0.65 mmol) were added. The reaction mixture was stirred at 100° C. for 16 h. After cooling to room temperature, the reaction was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with a 0-75% 3:1 EtOAc / EtOH gradient with 2% triethylamine in heptane to provide 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) + .

[0726] Intermediate ZZ: 4-bromo-5-(3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole.

[0727]

[0728] 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 Chemicals), 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, then N,N-dimethylformamide (7 mL) and methallyl alcohol (0.45 mL, 5.3 mmol, Combination Block) were added 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 again with 10% aqueous LiCl. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel column chromatography (eluted 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 clear oil. m / z(ESI): 365.1 / 367.0(M+H) + .

[0729] 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 and sodium borohydride (0.13 g, 3.38 mmol) was added. The reaction was stirred at 0 °C for 15 min and then quenched by the addition of saturated aqueous ammonium chloride. The mixture was diluted with EtOAc and warmed 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 silica gel column chromatography (eluting with a gradient of 0-40% EtOAc in heptane) to provide 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) + .

[0730] 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 h. 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 0-20% EtOAc / heptane gradient) 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) + .

[0731] Intermediate AAA: 3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-methylpropan-1-ol.

[0732]

[0733] This compound was prepared in a similar manner to Intermediate ZZ using 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Lampion Networks) in step 1. m / z (ESI): 408.8 / 410.8 (M+Na) + .

[0734] Intermediate BBB: rac-(3S,4R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-fluoropiperidin-3-ol.

[0735]

[0736] 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 Chemicals), 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 silica gel column chromatography eluting with a 0-75% 3:1 EtOAc / EtOH gradient (with 2% triethylamine) in heptane to provide rac-(3S,4R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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) + .

[0737] Intermediate CCC: (3R,4R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-3-ol.

[0738]

[0739] A 40 mL vial was charged with 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 min, then HATU (0.35 g, 0.93 mmol) was added. After 50 min, (3R,4R)-4-methylpiperidin-3-ol hydrochloride (0.15 g, 1.00 mmol, Anemi) was added and the reaction was stirred at room temperature for 16 h. 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 silica gel column chromatography, eluting with a 3:1 mixture of 0-75% EtOAc / EtOH in heptane with 2% triethylamine as an additive, to afford (3R,4R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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) + .

[0740] Intermediate DDD: rac-(3R,5S)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-fluoropiperidin-3-ol.

[0741]

[0742] A 40 mL vial was charged with 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-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 min, then HATU (0.26 g, 0.67 mmol) was added. After 50 min, 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 h. The reaction was diluted with CHCl, and the organic layer was washed with water, dried (NaSO), filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with a 3:1 mixture of 0-80% EtOAc / EtOH in heptane with 2% triethylamine additive, to afford rac-(3R,5S)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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) + .

[0743] 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-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol.

[0744]

[0745] 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-pyrrolazin-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, Ambed), K3PO4 (18.9 g, 58.1 mmol) and cataCXium A Pd G2 (1.30 g, 1.90 mmol) under N2. The mixture was then stirred at 100 ° C for 5h. 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 silica gel column chromatography (eluted with 30%–100% EtOAc gradient 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-pyrrolizine-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) + .

[0746] 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-pyrrolizin-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 h, 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 injected into a pre-packed C18 column (50 g) eluted with a gradient of 5% to 100% (0.1% formic acid in MeCN) / (0.1% formic acid in 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 afford (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-pyrrolazin-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) + .

[0747] 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-pyrrolazin-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, ANIMI), catalytic CXium A Pd G3 (50 mg, 0.069 mmol), potassium phosphate (0.34 g, 1.61 mmol), water (0.8 mL) and 2-methyltetrahydrofuran (3.8 mL). 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 minimum amount of MeOH and injected into a pre-packed C18 column (50 g) (eluted with a gradient of 5%-80% (0.1% formic acid MeCN) / (0.1% formic acid water) in 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 afford (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-pyrrolazin-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) + .

[0748] 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.

[0749]

[0750] 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, Labo Networks), 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 for 10 min. Palladium(II) acetate (77 mg, 0.34 mmol) and allyl alcohol (0.7 mL, 10 mmol) were then added at 50°C. The reaction mixture was stirred at 50°C for 18 h. 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 silica gel column chromatography (eluting with a 0-50% 3:1 EtOAc / EtOH gradient in heptane) to provide 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 light orange oil. m / z (ESI): 371.0 (M+H) + .

[0751] 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. Sodium borohydride (0.11 g, 2.86 mmol) was then slowly added portionwise. The reaction mixture was stirred at 0°C for 30 min, 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 light yellow oil without further purification. m / z (ESI): 289.0 (M-THP+H) + .

[0752] 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 at 0°C was added tert-butyldimethylsilyl chloride (0.46 g, 3.03 mmol) and 4-(dimethylamino)pyridine (34 mg, 0.28 mmol). After stirring at 0 °C for 2 h, the crude material was purified by silica gel column chromatography (eluting with a 0-30% 3:1 EtOAc / EtOH gradient in heptane) to provide 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) + .

[0753] 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'-bis(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 N2. 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 Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (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 yellow oil. m / z (ESI): 535.3 / 537.2 (M+H)+ .

[0754] Intermediate GGG: (S)-4-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-oxazepan-6-ol.

[0755]

[0756] Step 1.7-bromo-2-chloro-6,8-difluoro-4-(2,2,2-trifluoroethoxy)quinazoline. To a solution of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (20.0 g, 63.7 mmol) in tetrahydrofuran (300 mL) was added dropwise a mixture of 2,2,2-trifluoroethane-1-ol (6.06 g, 60.5 mmol) and t-BuOK (1 M in THF, 60.5 mL, 60.5 mmol) at -60 ° C. The mixture was stirred at -60 ° C for 2 h, then quenched by adding water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated with petroleum ether at room temperature for 30 min. The suspension was filtered and the filter cake was concentrated under reduced pressure to give 7-bromo-2-chloro-6,8-difluoro-4-(2,2,2-trifluoroethoxy)quinazoline (17 g, 45 mmol, 74% yield) as a yellow solid.

[0757] Step 2. 7-Bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline. 7-Bromo-2-chloro-6,8-difluoro-4-(2,2,2-trifluoroethoxy)quinazoline (5.00 g, 13.2 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (2.53 g, 15.9 mmol), DIPEA (6.9 mL, 40 mmol), A mixture of MS (5 g) in 1,4-dioxane (70 mL) was stirred at 100 ° C for 12 h under nitrogen. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure. The mixture was diluted by adding water and then extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 10%–100% EtOAc gradient in petroleum ether) to give 7- bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (1.50 g, 3.00 mmol, 23% yield) as a white solid.

[0758] m / z(ESI):500.0 / 502.1(M+H) + .

[0759] Step 3. (S)-4-(7-Bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-oxazepan-6-ol. A 40-mL vial was charged with (S)-[1,4]oxazepan-6-ol (0.94 g, 8.0 mmol, Jadawi Pharmaceutical Laboratories), 7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (2.00 g, 4.00 mmol), N,N-diisopropylethylamine (2.8 mL, 16 mmol), and DMF (20 mL). The reaction w...

Claims

1. A compound having formula (I'): or a pharmaceutically acceptable salt of said compound, wherein: 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 group 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 hydroxy, halogen, oxo, cyano, -N(R z )2、C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, 5-7 membered heteroaryl, -S(O)2-C 1-4 Alkyl, -S(O)2N(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 alkyl; L is a key, C 1-6 Alkylene, -OC 1-6 Alkylene, -SC 1-6 Alkylene, NR z , O or S, where C 1-6 Alkylene, -OC 1-6 Alkylene and -SC 1-6 The alkylene chains are each replaced by 0-2 occurrences of R 2 replace; -L 1 -L 2 -Yes-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-5-6 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 ; L 2 It 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 Alkynylidene, C 3-7 Cycloalkylene, C 1-4 Alkylene-C 3-7 Cycloalkylene, C 1-4 Halogenated alkylene-C 3-7 Cycloalkylene, C 3-7 Cycloalkylene-C 1-4 Alkylene, C 1-6 Hydroxyalkylene or C 1-6 alkylene halide; R 1 It is hydrogen, hydroxyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl or 4-15 membered heterocycloalkyl, wherein aryl, heteroaryl, cycloalkyl or heterocycloalkyl is each replaced by 0-3 occurrences of R 5 replace; R 2 Halogen, hydroxyl, C 1-4 Alkyl, or two R on the same or adjacent carbon atoms 2 Can form C together 3-7 Cycloalkyl; A is C 6-10 Aryl or 5-10 membered heteroaryl and q occurrences of R 6 replace; R 4 It is hydrogen, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-7 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 Halogenated alkyl, C 1-4 Alkoxy or -OC 2-4 Alkynyl; Each R 6 are independently halogen, hydroxy, cyano, -N(R z )2、-C(O)R z 、-C(O)OR z 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 2-4 Alkynyl or C 3-6 Cycloalkyl, or two R on adjacent carbon atoms 6 Together they form C 3-7 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, hydroxy, 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 is a compound having formula (I): or a pharmaceutically acceptable salt of said compound, wherein: 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 3-7 Cycloalkyl 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 hydroxy, halogen, oxo, cyano, -N(R z )2、C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, 5-7 membered heteroaryl, -TR y , or two R x Together with the same carbon atom or adjacent carbon atoms, they can form C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, wherein C 3-7 The cycloalkyl or 3-7 membered heterocycloalkyl groups are each further separated by 0-3 occurrences of R y Replace, or two R x can together form a bridged ring, wherein the bridge is selected from one of the following: -C 1-4 Alkylene, -C 1-4 Alkylene-OC 1-4 Alkylene-, -O-, -S- or -C 1-4 Alkylene-SC 1-4 Alkylene-, and each C 1-4 The alkylene group is further replaced by 0-2 occurrences of R y replace; L is a key, 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, where C 1-6 Alkylene, -OC 1-6 Alkylene and -SC 1-6 The alkylene chains are each replaced by 0-2 occurrences of R 2 replace; -L 1 -L 2 -Yes-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-5-6 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 ; L 2 It 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 Alkynylidene, C 3-7 Cycloalkylene, C 1-4 Alkylene-C 3-7 Cycloalkylene, C 1-4 Halogenated alkylene-C 3-7 Cycloalkylene, C 3-7 Cycloalkylene-C 1-4 Alkylene, C 1-6 Hydroxyalkylene or C 1-6 halogenated alkylene; R 1 It is hydrogen, hydroxyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl or 4-15 membered heterocycloalkyl, wherein aryl, heteroaryl, cycloalkyl or heterocycloalkyl is each replaced by 0-3 occurrences of R 5 replace; R 2 Halogen, hydroxyl, C 1-4 Alkyl, or two R on the same or adjacent carbon atoms 2 Can form C together 3-7 Cycloalkyl; A is C 6-10 Aryl or 5-10 membered heteroaryl and q occurrences of R 6 replace; R 4 It is hydrogen, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-7 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 Halogenated alkyl, C 1-4 Alkoxy or -OC 2-4 Alkynyl; Each R 6 are independently halogen, hydroxy, cyano, -N(R z )2、-C(O)R z 、-C(O)OR z 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 2-4 Alkynyl or C 3-6 Cycloalkyl, or two R on adjacent carbon atoms 6 Together they form C 3-7 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, hydroxy, cyano or -N(R z )2; and Each R z is hydrogen or C 1-4 alkyl.

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

4. The compound or salt of claim 2, wherein L is -O-methylene-, -O-ethylene-, -O-n-propylene-, or -O-isopentylene and L is replaced by 0-2 occurrences of R 2 replace.

5. The compound or salt of claim 2, wherein -LR 1 yes Methoxy or methyl.

6. The compound or salt of claim 5, wherein -LR 1 yes 7. The compound or salt of claim 6, wherein -LR 1 yes 8. The compound or salt of claim 6, wherein -LR 1 yes 9. The compound or salt of 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. The compound or salt of claim 9, wherein X is O.

11. The compound or salt of any one of claims 1 to 10, wherein BL 1 yes 12. The compound or salt of claim 11, wherein BL 1 yes 13. The compound or salt of any one of claims 2-9, wherein X is CH2.

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.

15. The compound or salt of claim 14, wherein yes 16. The compound or salt of claim 15, wherein BL 1 yes 17. The compound or salt of claim 1, wherein BL 1 yes 18. The compound or salt of claim 17, wherein BL 1 yes 19. The compound or salt of any one of claims 1 to 17, wherein A is C 6-10 Aryl.

20. The compound or salt of claim 19, wherein AL 2 yes 21. The compound or salt of claim 20, wherein AL 2 yes 22. The compound or salt of any one of claims 1 to 18, wherein AL 2 It is a 5-10 membered heteroaryl group.

23. The compound or salt of claim 22, wherein AL 2 yes 24. The compound or salt of claim 23, wherein AL 2 yes 25. The compound or salt of any one of claims 1 to 24, wherein -L 1 -L 2 -Yes-OC(O)-OL 2 .

26. The compound or salt of claim 25, wherein L 2 It is ethylene, n-propylene, 2-methyl-n-propylene, cis-2-propylene, trans-2-propylene or -CH2-cyclopropylene.

27. The compound or salt of claim 26, wherein -L 1 -L 2 -yes 28. The compound or salt of claim 27, wherein -L 1 -L 2 -yes 29. The compound or salt of claim 28, wherein -L 1 -L 2 -yes 30. The compound or salt of any one of claims 1 to 24, wherein -L 1 -L 2 -Yes-C 1-4 Hydroxyalkylene-5-6 membered heteroaryl-L 2 .

31. The compound or salt of claim 30, wherein -L 1 -L 2 -yes 32. The compound or salt of claim 31, wherein L 2 It is ethylene.

33. The compound or salt of claim 32, wherein -L 1 -L 2 -yes 34. The compound or salt of any one of claims 1 to 24, wherein -L 1 -L 2 -Yes-C 1-4 Alkylene-OL 2 .

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

36. The compound or salt of claim 35, wherein L 2 It is n-butylene, 2,2-difluoro-n-butylene, trans-2-butylene, cis-2-butylene, 3-methyl-n-butylene, -ethylene-cyclopropylene- or ethylene-O-methylene.

37. The compound or salt of claim 36, wherein -L 1 -L 2 -yes 38. The compound or salt of claim 37, wherein -L 1 -L 2 -yes 39. The compound or salt of claim 34, wherein -L 1 -L 2 - is ethylene-OL 2 .

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

41. The compound or salt of claim 40, wherein -L 1 -L 2 -yes 42. The compound or salt of claim 41, wherein -L 1 -L 2 -yes 43. A compound or salt as described in any one of claims 1-24, wherein -L 1 -L 2 -Yes-NR z -C(O)-OL 2 .

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

45. The compound or salt of claim 43 or 44, wherein L 2 It is n-propylene, ethylene, -CH2-cyclopropylene.

46. The compound or salt of claim 45, wherein -L 1 -L 2 -yes 47. The compound or salt of claim 46, wherein -L 1 -L 2 -yes 48. A compound or salt as described in any one of claims 1-24, wherein -L 1 -L 2 - is a 5-6 membered heteroaryl group.

49. The compound or salt of claim 48, wherein -L 1 -L 2 -yes 50. The compound or salt of claim 49, wherein -L 1 -L 2 -yes 51. The compound or salt of claim 50, wherein -L 1 -L 2 -yes 52. The compound or salt of any one of claims 1 to 24, wherein -L 1 -L 2 -is-C(O)-.

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

54. The compound or salt of claim 53, wherein -L 1 -L 2 -yes 55. The compound or salt of claim 54, wherein -L 1 -L 2 -yes 56. A compound or salt as described in any one of claims 1 to 55, wherein R 4 It is C 1-4 Alkyl or halogen.

57. The compound or salt of claim 56, wherein R 4 It's fluorine.

58. The compound or salt of claim 1 or 2, wherein the compound is:

59. The compound or salt of claim 1 or 2, wherein the compound is:

60. The compound or salt of claim 1 or 2, wherein the compound is:

61. The compound or salt of claim 1 or 2, wherein the compound is:

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. The compound or salt of any one of claims 1-61, or the pharmaceutical composition of claim 62, for use in treating cancer, wherein one or more cells of the cancer express KRAS G12D mutant protein.

66. The compound, salt, or pharmaceutical composition for use of 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 site, endometrial cancer, mixed cancer types, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

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

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

69. The method 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 site, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

70. 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 1-61, or a pharmaceutical composition of claim 62.

71. 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 1-61, or a pharmaceutical composition of claim 62, wherein one or more cells of the cancer express a KRAS G12D mutant protein.

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 site, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

73. 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 site, ampullary cancer, gastric cancer, small intestine cancer, paranasal sinus cancer, bile duct cancer, or melanoma.

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

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

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

77. The method of any one of claims 70-76, wherein the subject has a cancer determined to have one or more cells expressing the KRAS G12D mutant protein prior to administration of the compound, salt or composition.

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