Quinazoline compounds and their use as inhibitors of mutant KRAS proteins - Patents.com

Abstract

The present disclosure provides compounds useful for inhibiting KRAS G12D, G12V, G12A, G12S or G12C. The compounds have the general formula I TIFF2025508703000265.tif33170, and the variables of formula I are defined herein. The disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds and compositions, for example, to treat cancer.

Description

[Technical field]

[0001] The present disclosure provides compounds that have activity as inhibitors of mutant KRAS protein.The present disclosure also provides pharmaceutical compositions, uses and methods that include the compounds to treat 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 technology]

[0002] Since its identification in 1982 as one of the first human oncogenes (Der et al., 1982), KRAS (Kirsten rat sarcoma viral oncogene homolog) has been the subject of extensive academic and industrial research as a key node in the MAPK signaling pathway, as a transforming factor in a network of parallel effector pathways (e.g., PI3K / AKT) (Vojtek et al., 1998), and as a potential target for anticancer drugs (Malumbres et al., 2003). Despite advances in the development of inhibitors of upstream and downstream nodes of the MAPK pathway (e.g., EGFR (Sridhar et al., 2003), BRAF (Holderfield et al., 2014), and MOK (Caunt et al., 2015), the KRAS protein has historically proven resistant to direct inhibition.

[0003] KRAS is a G protein that couples extracellular mitogenic signaling to intracellular growth-promoting responses. KRAS acts as an intracellular "on / off" switch. Mitogen stimulation induces the binding of GTP to KRAS, resulting in a conformational change that allows KRAS to interact with downstream effector proteins, leading to cell proliferation. Normally, growth-promoting signaling is regulated by the action of GTPase-activating proteins (GAPs), which return KRAS to its GDP-bound, non-proliferative state. Mutations in KRAS impair the regulated cycling of KRAS between these GDP-bound and GTP-bound states, leading to the accumulation of the GTP-bound active state and dysregulated cell proliferation (Simanshu et al., 2017).

[0004] Attempts to develop inhibitors of mutant KRAS proteins have historically been hampered by the absence of a druggable pocket on the protein surface (Cox et al., 2014). In 2013, Shokat et al. identified a covalent inhibitor of KRAS G12C, a common (O'Bryan, 2019) oncogenic mutant of KRAS. This mutant bound to a previously unrecognized allosteric pocket on GDP-KRAS G12C and inhibited its subsequent activation (Ostream et al., 2013). This discovery provided an important new frontier in KRAS inhibitor research and has led to the entry of KRAS inhibitors in human clinical trials in recent years.

[0005] While some progress has been made with respect to KRAS G12C inhibitors, there is continuing interest and effort in developing inhibitors of KRAS, particularly other KRAS such as KRAS G12D, G12V, G12A or G12S. Thus, there is a need to develop new inhibitors of KRAS G12D, G12V, G12A, G12S or G12C for the treatment of disorders such as cancer. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Der et al., 1982 [Non-Patent Document 2] Vojtek et al., 1998 [Non-Patent Document 3] Malumbres et al., 2003 [Non-Patent Document 4] Sridhar et al., 2003 [Non-Patent Document 5] Holderfield et al., 2014 [Non-Patent Document 6] Caunt et al., 2015 [Non-Patent Document 7] Simanshu et al., 2017 [Non-Patent Document 8] Cox et al., 2014 [Non-Patent Document 9] O'Bryan, 2019 [Non-Patent Document 10] Ostream et al., 2013 Summary of the Invention [Means for solving the problem]

[0007] In one aspect, the present application relates to a compound of formula (I): [ka] or a pharma- ceutically acceptable salt of said compound, wherein [ka] is a single bond or a double bond; W is C, CH or N; X is CH2, O, S, S(O), S(O)(NR z ) or S(O)2; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; Each R x is hydroxyl, halogen, oxo, cyano, -N(R z )2, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, 5-7 membered heteroaryl, -TR y or two R x together with the same or adjacent carbon atom, C 3~7 cycloalkyl, 5- to 7-membered heterocycloalkyl, where each C 3~7 Cycloalkyl or 5- to 7-membered heterocycloalkyl is 0 to 3 R y or two R x can be joined together to form a bridged ring, the bridge being -C 1~4 Alkylene, -C 1~4 Alkylene-OC 1~4 Alkylene-, -O-, -S- or -C 1~4 Alkylene-SC 1~4 alkylene-, wherein each C 1~4 Alkylene is a group consisting of 0 to 2 R y is further replaced by the appearance of; Z is CH, CR', or N; R' is halogen, cyano, or C 1~4 is alkyl; L is a bond, C 1~6 Alkylene, C 1~6 Alkenylene, -OC 1~6 Alkylene, -SC 1~6 Alkylene, NR z , O or S, where each C 1~6 Alkylene, -OC 1~6 Alkylene and -SC 1~6 The alkylene chain consists of 0 to 2 R 2 has been replaced by occurrences of; R 1 is hydroxyl, aryl, heteroaryl, C3~8 Cycloalkyl or 0 to 3 R 5 is an optionally substituted heterocycloalkyl; R 2 is hydrogen, hydroxyl, halogen, amino, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~8 cycloalkyl, cyano, or two R on the same or adjacent carbon atoms. 2 Together, C 3~7 Can form a cycloalkyl; R 3 is 0 to 4 R 6 is an optionally substituted aryl or heteroaryl at each occurrence of R 4 is hydrogen, hydroxyl, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~8 cycloalkyl or cyano; Each R 5 is halogen, hydroxyl, oxo, amino, C 1~4 Alkyl or -TR y and; Each R 6 is halogen, hydroxyl, amino, cyano, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 1~4 Haloalkyl, C 3~7 Cycloalkyl or two R on adjacent carbon atoms 6 Using C 3~7 A cycloalkyl group can be formed, where each C 3~7 Cycloalkyl is 0 to 2 R 7 is further substituted with; R 7 is hydrogen, halogen or C 1~4is alkyl; T is for C 1~4 Alkylene, -O-, -S-, -C 1~4 Alkylene -C(O)- or -NR z -C(O)-; R y is halogen, hydroxyl, cyano, C 1~4 alkoxy or amino; R z is hydrogen or C 1~4 It is an alkyl.

[0008] In a second aspect, provided herein is a pharmaceutical composition comprising a compound of formula I, or a pharma- ceutically acceptable salt of said compound, and a pharma- ceutically acceptable excipient.

[0009] In a third aspect, there is provided herein a compound of formula I, or a pharma- ceutically acceptable salt of said compound, or a pharmaceutical composition as described herein, for use in the treatment of cancer (e.g., NSCLC, colorectal cancer, or pancreatic cancer).

[0010] Reference will now be made in detail to the embodiments of the present disclosure. Although specific embodiments of the present disclosure will be described, it will be understood that it is not intended to limit the embodiments of the present disclosure to those described embodiments. On the contrary, reference to the embodiments of the present disclosure is intended to encompass alternatives, modifications, and equivalents that may be encompassed within the spirit and scope of the embodiments of the present disclosure as defined by the appended claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] As an embodiment, the compound of formula (I): [ka] Provided herein is a compound of the formula: [ka] is a single bond or a double bond; W is C, CH or N; X is CH2, O, S, S(O), S(O)(NR z ) or S(O)2; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; Each R x is hydroxyl, halogen, oxo, cyano, -N(R z )2, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, 5-7 membered heteroaryl, -TR y or two R x together with the same or adjacent carbon atom, C 3~7 cycloalkyl, 5- to 7-membered heterocycloalkyl, where each C 3~7 Cycloalkyl or 5- to 7-membered heterocycloalkyl is 0 to 3 R y or two R x can be joined together to form a bridged ring, the bridge being -C 1~4 Alkylene, -C 1~4 Alkylene-OC 1~4 Alkylene-, -O-, -S- or -C 1~4 Alkylene-SC 1~4 alkylene-, wherein each C 1~4 Alkylene is a group consisting of 0 to 2 R y is further replaced by the appearance of; Z is CH, CR', or N; R' is halogen, cyano, or C 1~4 is alkyl; L is a bond, C 1~6 Alkylene, C 1~6 Alkenylene, -OC 1~6 Alkylene, -SC 1~6 Alkylene, NR z , O or S, where each C 1~6 Alkylene, -OC 1~6Alkylene and -SC 1~6 The alkylene chain consists of 0 to 2 R 2 has been replaced by occurrences of; R 1 is hydroxyl, aryl, heteroaryl, C 3~8 Cycloalkyl or 0 to 3 R 5 is an optionally substituted heterocycloalkyl; R 2 is hydrogen, hydroxyl, halogen, amino, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~8 cycloalkyl, cyano, or two R on the same or adjacent carbon atoms. 2 Together, C 3~7 Can form a cycloalkyl; R 3 is 0 to 4 R 6 is an optionally substituted aryl or heteroaryl at each occurrence of R 4 is hydrogen, hydroxyl, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~8 cycloalkyl or cyano; Each R 5 is halogen, hydroxyl, oxo, amino, C 1~4 Alkyl or -TR y and; Each R 6 is halogen, hydroxyl, amino, cyano, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 1~4 Haloalkyl, C 3~7 Cycloalkyl or two R on adjacent carbon atoms 6 Using C 3~7A cycloalkyl group can be formed, where each C 3~7 Cycloalkyl is 0 to 2 R 7 is further substituted with; R 7 is hydrogen, halogen or C 1~4 is alkyl; T is for C 1~4 Alkylene, -O-, -S-, -C 1~4 Alkylene -C(O)- or -NR z -C(O)-; R y is halogen, hydroxyl, cyano, C 1~4 alkoxy or amino; R z is hydrogen or C 1~4 It is an alkyl.

[0012] As embodiment 2, provided herein is a compound according to embodiment 1, wherein Z is N.

[0013] As a third embodiment, L is 0 to 2 R 2 Replaced by occurrence of -OC 1~6 Provided herein are compounds according to any one of embodiments 1-2, wherein L is an alkylene (e.g., -O-methylene-, -O-ethylene-, or -On-propylene-). 2 Provided herein are compounds according to embodiment 3, wherein the -O-methylene is substituted with occurrences of:

[0014] As a fifth embodiment, R 1 0 to 3 R 5 Provided herein is a compound according to any one of embodiments 1 to 4, wherein R is an optionally substituted heterocycloalkyl at each occurrence of R. 1 0 to 3 R 5 As embodiment 7, there is provided herein a compound according to embodiment 5, which is 7-(hexahydro-1H-pyrrolidine) substituted with occurrences of R 1 R with 0 5As an embodiment 8, there is provided herein a compound according to embodiment 6, which is 7-(hexahydro-1H-pyrrolidine) substituted with occurrences of R 1 There is one R 5 As an embodiment 9, there is provided herein a compound according to embodiment 6, which is 7-(hexahydro-1H-pyrrolidine) substituted with occurrences of R 5 Provided herein are compounds according to embodiment 8, wherein is halogen (e.g., fluorine).

[0015] As a tenth embodiment, R 1 0 to 3 R 5 As an embodiment 11, there is provided herein a compound according to any one of embodiments 1 to 4, which is 2-pyrrolidine substituted with an occurrence of R 1 There are two R 5 As an embodiment 12, there is provided herein a compound according to embodiment 10, which is a 2-pyrrolidine substituted with an occurrence of 5 C 1~4 alkyl (e.g., methyl) and other R 5 Provided herein are compounds according to embodiment 11, wherein is halogen (e.g., fluorine).

[0016] As a thirteenth embodiment, L is two R 2 As an embodiment 14, there is provided herein a compound according to embodiment 3, wherein the compound is -On-propylene substituted with occurrences of 2 Provided herein is a compound according to embodiment 13, wherein R are taken together on the same carbon atom to form a cyclopropyl. 1 Provided herein are compounds according to embodiment 14, wherein is hydroxyl.

[0017] As an embodiment 16, -LR 1 but [ka] Provided herein is a compound according to any one of embodiments 1-15, wherein

[0018] As an embodiment 17, -LR 1 but [ka] Provided herein is a compound according to embodiment 16, wherein As an eighteenth embodiment, -LR 1 but [ka] Provided herein is a compound according to embodiment 16, wherein As embodiment 19, -LR 1 but [ka] Provided herein is a compound according to embodiment 16, wherein As an embodiment 20, -LR 1 but [ka] Provided herein is a compound according to embodiment 16, wherein As an embodiment 21, -LR 1 but [ka] Provided herein is a compound according to embodiment 16, wherein

[0019] As embodiment 22, R 3 0 to 3 R 6 Provided herein are compounds according to any one of embodiments 1-21, wherein each occurrence of is substituted aryl (eg, phenyl or naphthyl).

[0020] As embodiment 23, R 3 There is one R 6 As an embodiment 24, there is provided herein a compound according to embodiment 22, wherein R is naphthyl substituted with an occurrence of 6Provided herein are compounds according to embodiment 23, wherein is hydroxyl.

[0021] As embodiment 25, R 3 There are two R 6 As an embodiment 26, there is provided herein a compound according to embodiment 22, wherein R is naphthyl substituted with an occurrence of 6 Each occurrence of halogen, hydroxyl, C 2~4 Alkynyl or C 1~4 Provided herein is a compound according to embodiment 25, wherein R is alkyl. 6 27. Provided herein are compounds according to embodiment 26, wherein each occurrence of is fluorine, hydroxyl, 2-ethynyl, or ethyl.

[0022] As embodiment 28, R 3 There are three R 6 As an embodiment 29, there is provided herein a compound according to embodiment 22, wherein R is naphthyl substituted with an occurrence of 6 Each occurrence of is hydroxyl, C 2~4 Alkynyl, C 1~4 Provided herein are compounds according to embodiment 28, wherein R is alkyl, halogen, or amino. 6 29. Provided herein are compounds according to embodiment 29, wherein each occurrence of is hydroxyl, 2-ethynyl, ethyl, fluorine, chlorine, or amino.

[0023] As an embodiment 31, R 3 There are three R 6 As an embodiment 32, there is provided herein a compound according to embodiment 22, wherein R is phenyl substituted with an occurrence of 6 Each occurrence of halogen, hydroxyl, C 1~4 Haloalkyl, C 3~7 cycloalkyl or amino, where each C 3~7 Cycloalkyl is 0 to 3 R 7 Provided herein is a compound according to embodiment 31, further substituted with occurrences of R 6is hydroxyl, chloro, cyclopropyl, trifluoromethyl, or amino, where each cyclopropyl is selected from zero R 7 Provided herein are compounds according to embodiment 32, further substituted with occurrences of:

[0024] As an embodiment 34, R 6 Each occurrence of R is a hydroxyl and the other two R 6 on adjacent carbon atoms, and C 3~7 Forms a cycloalkyl, where C 3~7 Cycloalkyl is 0 to 2 R 7 As an embodiment 35, there is provided herein a compound according to embodiment 31, further substituted with 6 Each occurrence of R is a hydroxyl and the other two R 6 are on adjacent carbon atoms and one R 7 As an embodiment 36, there is provided herein a compound according to embodiment 34, wherein R 7 C 1~4 Provided herein are compounds according to embodiment 35, wherein is alkyl (eg, methyl or ethyl).

[0025] As an embodiment 37, R 3 0 to 3 R 6 Provided herein are compounds according to any one of embodiments 1 to 21, wherein R is heteroaryl substituted with an occurrence of 3 However, 0 to 3 R 6 Provided herein are compounds according to embodiment 37, which are 4-(1H-indazolyl) or 7-(1H-indazolyl) substituted with occurrences of:

[0026] As an embodiment 39, R 3 0 to 3 R 6 As an embodiment 40, there is provided herein a compound according to embodiment 38, which is 4-(1H-indazolyl) substituted with an occurrence of R 3 There are two R 6Provided herein is a compound according to embodiment 39, which is 4-(1H-indazolyl) substituted with occurrences of 6 C 1~4 Alkyl, C 2~4 Provided herein are compounds according to embodiment 40, wherein each R is alkenyl or halogen. 6 is cyclopropyl, methylcyclopropyl, cis-prop-1-enyl, methyl or chloro, where cyclopropyl is selected from one R 7 Provided herein is a compound according to embodiment 41, further substituted with occurrences of R 7 C 1~4 Provided herein are compounds according to embodiment 42, wherein is alkyl (eg, methyl).

[0027] As embodiment 44, R 3 0 to 3 R 6 As an embodiment 45, there is provided herein a compound according to embodiment 38, which is 7-(1H-indazolyl) substituted with an occurrence of R 3 There are two R 6 Provided herein is a compound according to embodiment 44, which is 7-(1H-indazolyl) substituted with occurrences of 6 C 1~4 Provided herein are compounds according to embodiment 45, wherein each R is alkyl or halogen. 6 Provided herein are compounds according to embodiment 46, wherein is methyl or chloro.

[0028] As embodiment 48, R 3 but [ka] Provided herein is a compound according to any one of embodiments 1-47, wherein:

[0029] As an embodiment 49, R 3 but [ka] Provided herein is a compound according to embodiment 48, wherein As embodiment 50, R 3 but [ka] Provided herein is a compound according to embodiment 48, wherein As embodiment 51, R 3 but [ka] Provided herein is a compound according to embodiment 48, wherein As embodiment 52, R 3 but [ka] Provided herein is a compound according to embodiment 48, wherein As embodiment 53, R 3 but [ka] Provided herein is a compound according to embodiment 48, wherein As an embodiment 54, R 3 but [ka] Provided herein is a compound according to embodiment 48, wherein As embodiment 55, R 3 but [ka] Provided herein is a compound according to embodiment 48, wherein As embodiment 56, R 3 but [ka] Provided herein is a compound according to embodiment 48, wherein As an embodiment 57, R 3 but [ka] Provided herein is a compound according to embodiment 48, wherein As embodiment 58, R 3 but [ka] Provided herein is a compound according to embodiment 48, wherein As embodiment 59, R 3 but [ka] Provided herein is a compound according to embodiment 48, wherein As embodiment 60, R 3 but [ka] Provided herein is a compound according to embodiment 48, wherein As an embodiment 61, R 3 but [ka] Provided herein is a compound according to embodiment 48, wherein As embodiment 62, R 3 but [ka] Provided herein is a compound according to embodiment 48, wherein As embodiment 63, R 3 but [ka] Provided herein is a compound according to embodiment 48, wherein As an embodiment 64, R 3but [ka] Provided herein is a compound according to embodiment 48, wherein As embodiment 65, R 3 but [ka] Provided herein is a compound according to embodiment 48, wherein As embodiment 66, R 3 but [ka] Provided herein is a compound according to embodiment 48, wherein As an embodiment 67, R 3 but [ka] Provided herein is a compound according to embodiment 48, wherein As an embodiment 68, R 3 but [ka] Provided herein is a compound according to embodiment 48, wherein As embodiment 69, R 3 but [ka] Provided herein is a compound according to embodiment 48, wherein As an embodiment 70, R 3 but [ka] Provided herein is a compound according to embodiment 48, wherein As an embodiment 71, R 3 but [ka] Provided herein is a compound according to embodiment 48, wherein

[0030] As embodiment 72, provided herein is a compound according to any one of embodiments 1 to 71, wherein W is N.

[0031] As embodiment 73, provided herein is a compound according to embodiment 72, wherein X is CH2.

[0032] Provided herein as embodiment 74 is a compound according to embodiment 73, wherein n is 1 and m is 0, or m is 1 and n is 0. Provided herein as embodiment 75 is a compound according to embodiment 74, wherein p is 1.

[0033] As an embodiment 76, R x is hydroxy or -TR y As an embodiment 77, R x Provided herein are compounds according to embodiment 76, wherein is hydroxy or -C(O)NH2.

[0034] As embodiment 78, provided herein is a compound according to embodiment 73, wherein n is 1 and m is 1. As embodiment 79, provided herein is a compound according to embodiment 78, wherein p is 2.

[0035] As an embodiment 80, each R x independently, hydroxy, C 1~4 Alkyl, C 1~4 haloalkyl or two R x may be, together with the same carbon atom or adjacent carbon atoms, 0 to 3 R y Provided herein are compounds according to embodiment 79, in which each occurrence of R can form a 5-7 membered heterocycloalkyl, further substituted. xProvided herein are compounds according to embodiment 80, wherein R is independently hydroxy, methyl, fluoromethyl, or difluoromethyl. x With the same carbon, 0 to 3 R y Provided herein are compounds according to embodiment 80, further substituted with occurrences of R to form 1-oxetanyl, 1-azetidinyl, 2-azetidinyl, 2-pyrrolidinyl, cyclobutyl, 1,3-dioxolanyl, 3-tetrahydrothiophenyl, 2-tetrahydrofuranyl, or 5-oxazolidinyl. x With the same carbon, 0 R y Provided herein is a compound according to embodiment 82, in which the occurrence of two R forms a further substituted 1-oxetanyl. x is combined with the same carbon to form one R y Provided herein are compounds according to embodiment 82, further substituted with occurrences of R to form 1-azetidinyl, 2-azetidinyl, 2-pyrrolidinyl, 1,3-dioxolanyl, 2-tetrahydrofuranyl or 5-oxazolidinyl. y As an embodiment 86, there is provided herein a compound according to embodiment 84, wherein R is oxo. x is combined with the same carbon to form one R y Provided herein is a compound according to embodiment 82, in which occurrences of R form a further substituted cyclobutyl. y Provided herein is a compound according to embodiment 86, wherein R is hydroxyl. x With the same carbon, two R y Provided herein is a compound according to embodiment 82, wherein the occurrence of both R y Provided herein are compounds according to embodiment 88, wherein is oxo.

[0036] As an embodiment 90, there is provided herein a compound according to embodiment 78, wherein p is 3. As an embodiment 91, each R x are independently hydroxy, halogen, -N(R z )2, -TR y or two R x are taken together to form a bridged ring, and the bridge is y Further replaced by the appearance of C 1~4 Provided herein is a compound according to embodiment 90, wherein the compound is an alkylene. As embodiment 92, two R x is fluorine and other R x As an embodiment 93, there is provided herein a compound according to embodiment 91, wherein R is -NH2. x is fluorine and other R x Ga-TR y As an embodiment 94, there is provided herein a compound according to embodiment 91, wherein: x is fluorine and other R x As an embodiment 95, there is provided herein a compound according to embodiment 93, wherein R is -NH-C(O)-OMe. x is hydroxy and two R x are taken together to form a bridged ring, and the bridge is y Provided herein are compounds according to embodiment 91, wherein the occurrence of is ethylene further substituted.

[0037] Provided herein as embodiment 96 is a compound according to embodiment 73, wherein n is 1 and m is 2, or n is 2 and m is 1. Provided herein as embodiment 97 is a compound according to embodiment 96, wherein p is 3.

[0038] As an embodiment 98, one R x is hydroxyl and the other two R x are taken together to form a bridged ring, and the bridge is y Further replaced by the appearance of -C 1~4 Provided herein is a compound according to embodiment 97, wherein R is an alkylene.x is hydroxyl and the other two R x are taken together to form a bridged ring, and the bridge is y Provided herein are compounds according to embodiment 98, wherein the occurrence of is methylene further substituted.

[0039] As an embodiment 100, [ka] but, [ka] Provided herein is a compound according to embodiment 73, wherein

[0040] As embodiment 101, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein As embodiment 102, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein As an embodiment 103, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein As an embodiment 104, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein As embodiment 105, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein As an embodiment 106, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein As an embodiment 107, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein As an embodiment 108, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein As an embodiment 109, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein As an embodiment 110, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein As an embodiment 111, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein As an embodiment 112, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein As an embodiment 113, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein As an embodiment 114, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein As an embodiment 115, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein As an embodiment 116, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein As an embodiment 117, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein As an embodiment 118, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein As an embodiment 119, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein As an embodiment 120, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein As an embodiment 121, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein As an embodiment 122, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein As an embodiment 123, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein As an embodiment 124, [ka] but, [ka] Provided herein is a compound according to embodiment 100, wherein

[0041] As embodiment 125, there is provided herein a compound according to embodiment 72, wherein X is O.

[0042] As embodiment 126, provided herein is a compound according to embodiment 125, wherein n is 1 and m is 1. As embodiment 127, provided herein is a compound according to embodiment 126, wherein p is 2.

[0043] As an embodiment 128, two R x are taken together to form a bridged ring, and the bridge is y Further replaced by the appearance of C 1~4 Provided herein is a compound according to embodiment 127, wherein R is an alkylene. x are taken together to form a bridged ring, and the bridge is y Provided herein are compounds according to embodiment 128, wherein the ethylene is further substituted with an occurrence of:

[0044] Provided herein as embodiment 130 are compounds according to embodiment 125, wherein n is 1 and m is 2, or m is 1 and n is 2. Provided herein as embodiment 131 are compounds according to embodiment 130, wherein p is 0. Provided herein as embodiment 132 are compounds according to embodiment 130, wherein p is 2.

[0045] As an embodiment 133, each R x halogen, hydroxyl, C 1~4 Haloalkyl or C 1~4 alkyl or two R x are taken together to form a bridged ring, and the bridge is y Further replaced by the appearance of C 1~4 Provided herein is a compound according to embodiment 132, wherein R is an alkylene. x is hydroxyl and the other R x Provided herein is a compound according to embodiment 133, wherein R is methyl. xis hydroxyl and the other R x Provided herein is a compound according to embodiment 134, wherein R is fluoromethyl. x Provided herein is a compound according to embodiment 133, wherein R is fluorine. x are taken together to form a bridged ring, and the bridge is y Provided herein are compounds according to embodiment 133, wherein each occurrence of is methylene further substituted.

[0046] As embodiment 138, [ka] but, [ka] Provided herein is a compound according to embodiment 125, wherein

[0047] As an embodiment 139, [ka] but, [ka] Provided herein is a compound according to embodiment 138, wherein As an embodiment 140, [ka] but, [ka] Provided herein is a compound according to embodiment 138, wherein As an embodiment 141, [ka] but, [ka] Provided herein is a compound according to embodiment 138, wherein As embodiment 142, [ka] but, [ka] Provided herein is a compound according to embodiment 138, wherein As an embodiment 143, [ka] but, [ka] Provided herein is a compound according to embodiment 138, wherein As embodiment 144, [ka] but, [ka] Provided herein is a compound according to embodiment 138, wherein

[0048] As an embodiment 145, R 2 Provided herein are compounds according to any one of embodiments 1 to 144, wherein R is hydrogen. 2 Provided herein are compounds according to any one of embodiments 1 to 144, wherein R is halogen (e.g., fluorine). 2 Provided herein are compounds according to any one of embodiments 1 to 144, wherein R is cyano. 2 Provided herein are compounds according to any one of embodiments 1 to 144, wherein R is hydroxyl. 2Provided herein are compounds according to any one of embodiments 1-144, wherein is amino.

[0049] As an embodiment 150, R 4 Provided herein are compounds according to any one of embodiments 1 to 149, wherein R is halogen (e.g., fluorine). 2 C 1~4 Provided herein are compounds according to any one of embodiments 1-149, wherein is alkyl (eg, methyl).

[0050] As an embodiment 152, R 7 Provided herein are compounds according to any one of embodiments 1-151, wherein is hydrogen.

[0051] As an embodiment 153, the compound has formula (II): [ka] Provided herein is a compound according to embodiment 1, which is a compound of the formula:

[0052] As an embodiment 154, the compound has formula (III): [ka] Provided herein is a compound according to embodiment 1, which is a compound of the formula:

[0053] As an embodiment 155, the compound has formula (IV): [ka] Provided herein is a compound according to embodiment 1, which is a compound of the formula:

[0054] As embodiment 156, provided herein is a compound according to embodiment 1, selected from one of the following compounds: (6S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (3R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; (5S)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one; (6S)-4-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (3R)-1-(7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; (S)-4-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)quinazolin-6-ol; (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one; (6S)-4-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (S)-4-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (5S)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one; (S)-6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)naphthalen-2-ol; (3R)-3-(difluoromethyl)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperidin-3-ol; (3R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; (5R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one; (3R)-1-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; (1R,5R,6R)-3-(7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol; or (3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol.

[0055] As embodiment 157, provided herein is a compound according to embodiment 1, selected from one of the following compounds: (6S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (3R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; (5S)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one; (6S)-4-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (3R)-1-(7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; (S)-4-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; or 7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)quinazolin-6-ol.

[0056] As embodiment 158, provided herein is a compound according to embodiment 1, selected from one of the following compounds: 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (isomer 1); (3R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (isomer 2); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one; 4-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (isomer 1); (3R)-1-(7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (isomer 2); (5S)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one; 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (isomer 1); (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (isomer 1); 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)naphthalen-2-ol; 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (isomer 2); 4-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (isomer 1); (S)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one; (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (isomer 1); 5-chloro-4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-6-fluoronaphthalen-2-ol; (2S,4s)-6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-azaspiro[3.5]nonan-2-ol; 7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)quinazolin-6-ol (isomer 1); (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one; 4-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (isomer 1); 4-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (isomer 1); (5S)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide; or 4-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (isomer 1).

[0057] As embodiment 159, provided herein is a compound according to embodiment 1, selected from one of the following compounds: 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (isomer 1); (3R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (isomer 2); 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one; 4-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (isomer 1); (3R)-1-(7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (isomer 2); (5S)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one; 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (isomer 1); (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (isomer 1); or 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)naphthalen-2-ol.

[0058] The foregoing description merely summarizes certain aspects of the disclosure and is not intended, nor should it be construed, as limiting the disclosure in any way.

[0059] Formulation and Route of Administration In the described use, the compound disclosed herein can be administered alone, but the compound administered is usually present as an active ingredient in a pharmaceutical composition.Therefore, in one embodiment, the pharmaceutical composition provided herein comprises the compound disclosed herein in combination with one or more pharma- ceutically acceptable excipients such as diluent, carrier, adjuvant, and other active ingredients as necessary. See, e.g., Remington: The Science and Practice of Pharmacy, Volume I and Volume II, twenty-second edition, edited by Loyd V. Allen Jr., Philadelphia, PA, Pharmaceutical Press, 2012; Pharmaceutical Dosage Forms (Vol. 1-3), Liberman et al., Eds., Marcel Dekker, New York, NY, 1992; Handbook of Pharmaceutical Excipients (3rd Ed.), edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, 2000; Pharmaceutical Formulation: The Science and Technology of Dosage Forms (Drug Discovery), first edition, edited by GD Tovey, Royal Society of Chemistry, 2018. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein.

[0060] The compounds disclosed herein can be administered by any suitable route of administration in the form of a pharmaceutical composition adapted to such route, and in a dose effective for the intended treatment. The compounds and compositions provided herein can be administered, for example, orally, mucosally, topically, transdermally, rectally, pulmonary, parenterally, intranasally, intravascularly, intravenously, intraarterially, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, intravaginally, or by injection techniques, in dosage unit formulations containing conventional pharma- ceutically acceptable excipients.

[0061] The pharmaceutical composition may be in the form of, for example, a tablet, a chewable tablet, a mini-tablet, a caplet, a pill, a bead, a hard capsule, a soft capsule, a gelatin capsule, a granule, a powder, a troche, a patch, a cream, a gel, a sachet, a microneedle array, a syrup, a flavored syrup, a juice, a drop, an injection, an emulsion, a microemulsion, an ointment, an aerosol, an aqueous suspension, or an oily suspension. Pharmaceutical compositions are typically made in the form of a dosage unit containing a particular amount of the active ingredient.

[0062] As embodiment 160, provided herein is a pharmaceutical composition comprising a compound according to any one of embodiments 1 to 159, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, and a pharma- ceutically acceptable excipient.

[0063] As embodiment 161, provided herein is a compound according to any one of embodiments 1 to 159, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 160, for use as a medicament.

[0064] How to use As discussed herein (see the section entitled "Definitions"), the compounds described herein should be understood to include all stereoisomers, tautomers, or pharma- ceutically acceptable salts of any of the foregoing, or solvates of any of the foregoing. Accordingly, the scope of methods and uses provided in this disclosure should be understood to encompass methods and uses using all such forms.

[0065] In addition to being useful for human treatment, the compounds provided herein may be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, etc. For example, animals including horses, dogs and cats may be treated with the compounds provided herein.

[0066] In one embodiment, the present disclosure provides a method of using a compound or pharmaceutical composition of the present disclosure to treat a disease state, including but not limited to a condition involving KRAS G12D, G12V, G12A, G12S or G12C mutation (e.g., cancer), the type of cancer being non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendix cancer, endometrial cancer, esophageal cancer, cancer of unknown primary site, ampullary cancer, gastric cancer, small intestine cancer, paranasal sinus cancer, cholangiocarcinoma, or melanoma.

[0067] KRAS G12D mutations occur with the mutation frequencies shown in the table below (TCGA dataset; 1~3 For example, this table shows that 32.4% of subjects with pancreatic cancer have cancer in which one or more cells express the KRAS G12D mutant protein. G12D Compounds provided herein that bind to (see the section entitled "Biological Evaluation" below) are useful for treating subjects with cancer, including but not limited to those listed in the table below.

[0068] [Table 1]

[0069] As embodiment 162, there is provided herein a compound according to any one of embodiments 1 to 159, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 159, for use in treating cancer.

[0070] As embodiment 163, there is provided herein a compound according to any one of embodiments 1 to 159 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 159, for use in treating a cancer in which one or more cells express a KRAS G12D, G12V, G12A, G12S or G12C mutant protein.

[0071] As embodiment 164, there is provided herein a compound or pharmaceutical composition for use in embodiment 162 or 163, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small intestine cancer, appendix cancer, cancer of unknown primary site, endometrial cancer, mixed type cancer of unknown primary site, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia or melanoma.

[0072] As embodiment 165, there is provided herein the use of a compound according to any one of embodiments 1 to 159 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 160, in the preparation of a medicament for treating cancer.

[0073] As embodiment 166, there is provided herein the use of a compound according to any one of embodiments 1 to 159 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 160, in the preparation of a medicament for treating a cancer in which one or more cells express a KRAS G12D, G12V, G12A, G12S or G12C mutant protein.

[0074] As embodiment 167, the use according to embodiment 165 or 166 is provided herein, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed type cancer of unknown primary, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine carcinoma, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophageal and gastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia or melanoma.

[0075] As embodiment 168, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 159, or a pharma- ceutically acceptable salt thereof.

[0076] As embodiment 169, provided herein is a method of treating cancer in a subject in need thereof, wherein one or more cells express a KRAS G12D, G12V, G12A, G12S, or G12C mutant protein, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1-159, or a pharma- ceutically acceptable salt thereof.

[0077] As embodiment 170, there is provided herein a method according to embodiment 168 or 169, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed type cancer of unknown primary, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine carcinoma, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia or melanoma.

[0078] As embodiment 171, provided herein is a method according to embodiment 168 or 169, 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.

[0079] As embodiment 172, provided herein is a method according to embodiment 171, wherein the cancer is non-small cell lung cancer.

[0080] As embodiment 173, provided herein is a method according to embodiment 171, wherein the cancer is colorectal cancer.

[0081] As embodiment 174, provided herein is a method according to embodiment 171, wherein the cancer is pancreatic cancer.

[0082] As embodiment 175, provided herein is a method according to any one of embodiments 170 to 174, wherein the subject has cancer determined to have one or more cells expressing a KRAS G12D, G12V, G12A, G12S or G12C mutant protein prior to administration of the compound or a pharma- ceutically acceptable salt thereof.

[0083] Combination therapy The present disclosure also provides methods for combination therapy using agents known to regulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes, in combination with the compounds of the present disclosure or pharma- ceutically acceptable salts thereof. In one aspect, such therapy includes, but is not limited to, the combination of one or more compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation therapy to provide synergistic or additive therapeutic effects. See, for example, U.S. Patent No. 10,519,146 B2, issued Dec. 31, 2019, specifically sections 201 (line 37) to 212 (line 46) and 219 (line 64) to 220 (line 39), which are incorporated herein by reference.

[0084] Provided herein as embodiment 176 is a method according to any one of embodiments 168 to 175, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an Aurora kinase A inhibitor, an AKT inhibitor, an arginase inhibitor, a CDK4 / 6 inhibitor, an ErbB family inhibitor, an ERK inhibitor, a FAK inhibitor, an FGFR inhibitor, a glutaminase inhibitor, an IGF-1R inhibitor, a KIF18A inhibitor, an MCL-1 inhibitor, a MEK inhibitor, an mTOR inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a PI3K inhibitor, a Raf kinase inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Src kinase inhibitor, or one or more chemotherapeutic agents.

[0085] In one embodiment, the second compound is administered as a pharma- ceutically acceptable salt, hi another embodiment, the second compound is administered as a pharmaceutical composition comprising the second compound or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient.

[0086] Aurora kinase A inhibitors Provided herein are methods according to any one of embodiments 168-175, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an Aurora kinase A inhibitor.

[0087] Exemplary Aurora kinase A inhibitors for use in the methods provided herein include alisertib, cenisertib, danusertib, tozasertib, LY3295668 (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyridin-2-yl]methyl]-2-methylpiperidine-4-carboxylic acid), ENMD-2076 (6-(4-methylpiperazin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl]methyl)-2-methylpiperidine-4-carboxylic acid), (3-phenylethenyl)-2-[(E)-2-phenylethenyl]pyrimidin-4-amine), TAK-901 (5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide), TT-00420 (4-[9-(2-chlorophenyl)-6-methyl-2,4,5,8,12-pentazatricyclo[8.4.0.03,7]tetradeca-1(14),3,6,8,10,12-hexaen-13-yl]molybdenum fluoroline), AMG900 (N-[4-[3-(2-aminopyrimidin-4-yl)pyridin-2-yl]oxyphenyl]-4-(4-methylthiophen-2-yl)phthalazin-1-amine), MLN8054 (4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid), PF-03814735 (N-[2-[(1R,8S)-4-[[4-(cyclobutylamino)-5-(trifluoromethyl)pyrimidine-2

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

[0088] AKT inhibitors Provided herein are methods according to any one of embodiments 168-175, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an AKT inhibitor.

[0089] Exemplary AKT inhibitors for use in the methods provided herein include afuresertib, capivasertib, ipatasertib, uprosertib, BAY1125976 (2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide), ARQ 092 (3-[3-[4-(1-aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2-amine), MK2206 (8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one), SR13668 (indolo[2,3-b]carbazole-2,10-dicarboxylic acid, 5,7-dihydro-6-methoxy-2,10-diethyl ester), ONC201 (11-benzyl-7-[2-methylphenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one), ARQ 751 (N-(3-aminopropyl)-N-[(1R)-1-(3-anilino-7-chloro-4-oxoquinazolin-2-yl)but-3-ynyl]-3-chloro-2-fluorobenzamide), RX-0201, and LY2780301.

[0090] Arginase inhibitors Provided herein are methods according to any one of embodiments 168-175, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an arginase inhibitor.

[0091] Exemplary arginase inhibitors for use in the methods provided herein include, but are not limited to, numidardistat and CB 280.

[0092] CDK4 / 6 inhibitors Provided herein are methods according to any one of embodiments 168-175, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a CDK4 / 6 inhibitor.

[0093] As used herein, the term "CDK4 / 6" refers to cyclin-dependent kinases ("CDKs") 4 and 6, which are members of the mammalian serine / threonine protein kinases.

[0094] As used herein, the term "CDK4 / 6 inhibitor" refers to a compound capable of negatively regulating or inhibiting all or part of the enzymatic activity of CDK4 and / or 6.

[0095] Exemplary CDK4 / 6 inhibitors for use in the methods provided herein include, but are not limited to, abemaciclib, palbociclib, ribociclib, trilaciclib, and PF-06873600 ((pyrido[2,3-d]pyrimidin-7(8H)-one, 6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[[1-(methylsulfonyl-1)-4-piperidinyl]amino]).

[0096] In one embodiment, the CDK4 / 6 inhibitor is palbociclib.

[0097] ErbB family inhibitors Provided herein is a method according to any one of embodiments 168-175, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an ErbB family inhibitor.

[0098] As used herein, the term "ErbB family" refers to members of the mammalian transmembrane protein tyrosine kinase family that includes ErbB1 (EGFR HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4).

[0099] As used herein, the term "ErbB family inhibitor" refers to an agent, e.g., a compound or an antibody, capable of negatively regulating or inhibiting all or part of the activity of at least one member of the ErbB family. This regulation or inhibition of one or more ErbB tyrosine kinases can occur by regulating or inhibiting the kinase enzymatic activity of one or more ErbB family members, or by preventing homodimerization or heterodimerization of ErbB family members.

[0100] In one embodiment, the ErbB family inhibitor is an EGFR inhibitor, for example, an anti-EGFR antibody. Exemplary anti-EGFR antibodies used in the methods provided herein include, but are not limited to, zalutumumab, nimotuzumab, matuzumab, necitumumab, panitumumab and cetuximab. In one embodiment, the anti-EGFR antibody is cetuximab. In one embodiment, the anti-EGFR antibody is panitumumab.

[0101] In another embodiment, the ErbB family inhibitor is a HER2 inhibitor, such as an anti-HER2 antibody. Exemplary anti-HER-2 antibodies for use in the methods provided herein include, but are not limited to, pertuzumab, trastuzumab, and trastuzumab emtansine.

[0102] In yet another embodiment, the ErbB family inhibitor is a HER3 inhibitor, for example, an anti-HER3 antibody such as HMBD-001 (Hummingbird Bioscience).

[0103] In one embodiment, the ErbB family inhibitor is a combination of an anti-EGFR antibody and an anti-HER2 antibody.

[0104] In one embodiment, the ErbB family inhibitor is an irreversible inhibitor. Exemplary irreversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to, afatinib, dacomitinib, canertinib, poziotinib, AV 412 (N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butyn-1-yl]-6-quinazolinyl]-2-propenamide), PF 6274484 (N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-2-propenamide), and HKI 357 ((E)-N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide).

[0105] In one embodiment, the irreversible ErbB family inhibitor is afatinib.In one embodiment, the irreversible ErbB family inhibitor is dacomitinib.

[0106] In one embodiment, the ErbB family inhibitor is a reversible inhibitor. Exemplary reversible ErbB family inhibitors for use in the methods provided herein include erlotinib, gefitinib, sapitinib, varlitinib, tarloxotinib, TAK-285 (N-(2-(4-((3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl)-3-hydroxy-3-methylbutanamide), AEE788 ((S)-6-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-N-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine), BMS Examples of suitable amines include, but are not limited to, 599626 ((3S)-3-morpholinylmethyl-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamate) and GW 583340 (N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[2-[(2-methylsulfonylethylamino)methyl]-1,3-thiazol-4-yl]quinazolin-4-amine).

[0107] In one embodiment, the reversible ErbB family inhibitor is sapitinib.In one embodiment, the reversible ErbB family inhibitor is tarloxotinib.

[0108] ERK inhibitors Provided herein are methods according to any one of embodiments 168-175, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an ERK inhibitor.

[0109] Exemplary ERK inhibitors for use in the methods provided herein include ulixertinib, lavoxertinib, CC-90003 (N-[2-[[2-[(2-methoxy-5-methylpyridin-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]-5-methylphenyl]prop-2-enamide), LY3214996 (6,6-dimethyl-2-[2-[(2-methyl

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

[0110] FAK inhibitors Provided herein are methods according to any one of embodiments 168-175, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a FAK inhibitor.

[0111] Exemplary FAK inhibitors for use in the methods provided herein include, but are not limited to, GSK2256098 (2-[[5-chloro-2-[(5-methyl-2-propan-2-ylpyrazol-3-yl)amino]pyridin-4-yl]amino]-N-methoxybenzamide), PF-00562271 (N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]methyl]pyridin-2-yl]methanesulfonamide), VS-4718 (2-[[2-(2-methoxy-4-morpholin-4-ylanilino)-5-(trifluoromethyl)pyridin-4-yl]amino]-N-methylbenzamide), and APG-2449.

[0112] FGFR inhibitors Provided herein are methods according to any one of embodiments 168-175, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an FGFR inhibitor.

[0113] Exemplary FGFR inhibitors for use in the methods provided herein include futibatinib, pemigatinib, ASP5878 (2-[4-[[5-[(2,6-difluoro-3,5-dimethoxyphenyl)methoxy]pyrimidin-2-yl]amino]pyrazol-1-yl]ethanol), AZD4547 (N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]benzamide), Debio These include, but are not limited to, 1347 ([5-amino-1-(2-methyl-3H-benzimidazol-5-yl)pyrazol-4-yl]-(1H-indol-2-yl)methanone), INCB062079, H3B-6527 (N-[2-[[6-[(2,6-dichloro-3,5-dimethoxyphenyl)carbamoyl-methylamino]pyrimidin-4-yl]amino]-5-(4-ethylpiperazin-1-yl)phenyl]prop-2-enamide), ICP-105, CPL304110, HMPL-453 and HGS1036.

[0114] Glutaminase Inhibitors Provided herein are methods according to any one of embodiments 168-175, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a glutaminase inhibitor.

[0115] Exemplary glutaminase inhibitors for use in the methods provided herein include, but are not limited to, telaglenastat, IPN60090, and OP 330.

[0116] IGF-1R inhibitors Provided herein are methods according to any one of embodiments 168-175, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an IGF-1R inhibitor.

[0117] Exemplary IGF-1R inhibitors for use in the methods provided herein include, but are not limited to, cixutumumab, dalotuzumab, linsitinib, ganitumab, lovatumumab, BMS-754807 ((2S)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide), KW-2450 (N-[5-[[4-(2-hydroxyacetyl)piperazin-1-yl]methyl]-2-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-3-methylthiophene-2-carboxamide), PL225B, AVE1642, and BIIB022.

[0118] KIF18A inhibitors Provided herein is a method according to any one of embodiments 168-175, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a KIF18A inhibitor.

[0119] Exemplary KIF18A inhibitors for use in the methods provided herein include, but are not limited to, those disclosed in U.S. Patent Application Publication No. 2020 / 0239441, WO 2020 / 132649, WO 2020 / 132651, and WO 2020 / 132653, each of which is incorporated by reference in its entirety.

[0120] MCL-1 inhibitors Provided herein are methods according to any one of embodiments 168-175, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an MCL-1 inhibitor.

[0121] Exemplary MCL-1 inhibitors for use in the methods provided herein include murizatoclax, topotoclax, AZD 5991 ((3aR)-5-chloro-2,11,12,24,27,29-hexahydro-2,3,24,33-tetramethyl-22H-9,4,8-(methenylaminomethino)-14,20:26,23-dimetheno-10H,20H-pyrazolo[4,3-l][2,15,22,18,19]benzoxadithiadiazacyclohexacosine-32-carboxylic acid), MIK 665 ((αR)-α-[[(5S)-5-[3-chloro-2-methyl-4-[2-(4-methyl-1-piperazinyl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy]-2-[[2-(2-methoxyphenyl)-4-pyrimidinyl]methoxy]benzenepropanoic acid) and ABBV-467.

[0122] In one embodiment, the MCL-1 inhibitor is murizatoclax. In another embodiment, the MCL-1 inhibitor is topotoclax.

[0123] MEK inhibitors Provided herein are methods according to any one of embodiments 168-175, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a MEK inhibitor.

[0124] Exemplary MEK inhibitors for use in the methods provided herein include trametinib, cobimetinib, selumetinib, pimasertib, refametinib, PD-325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), AZD8330 (2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxopyridine-3-carboxamide), and AZD8330 (2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxopyridine-3-carboxamide). boxamide), GDC-0623 (5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide), RO4987655 (3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-5-[(3-oxooxazinan-2-yl)methyl]benzamide), TAK-733 (3-[(2R)-2,3-dihydroxypropyl]-6-fluoro-5-( 2-Fluoro-4-iodoanilino)-8-methylpyrido[2,3-d]pyrimidine-4,7-dione), PD0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), CI-1040 (2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide), PD318088 (5-bromo-N-(2,3-dihydro

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

[0125] In one embodiment, the MEK inhibitor is trametinib.

[0126] mTOR inhibitors Provided herein are methods according to any one of embodiments 168-175, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an mTOR inhibitor.

[0127] Exemplary mTOR inhibitors for use in the methods provided herein include everolimus, rapamycin, zotarolimus (ABT-578), ridaforolimus (deforolimus, MK-8669), sapanisertib, buparlisib, pictilisib, bistusertib, dactolisib, trilin-1 (1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)cyclohexyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthalene ... tilidin-2(1H)-one), GDC-0349 ((S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-7-(oxetan-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea) and VS-5584 (SB2343, (5-(8-methyl-2-morpholin-4-yl-9-propan-2-ylpurin-6-yl)pyrimidin-2-amine).

[0128] In one embodiment, the mTOR inhibitor is everolimus.

[0129] PD-1 inhibitors Provided herein are methods according to any one of embodiments 168-175, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a PD-1 inhibitor.

[0130] Exemplary PD-1 inhibitors for use in the methods provided herein include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostallimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, and anti-PD-1 antibodies as described in U.S. Pat. No. 10,640,504 B2 ("Anti-PD-1 Antibody A", col. 66, lines 56-67, lines 24 and col. 67, lines 54-57), which are incorporated herein by reference.

[0131] In one embodiment, the PD-1 inhibitor is pembrolizumab. In another embodiment, the PD-1 inhibitor is anti-PD-1 antibody A.

[0132] PD-L1 inhibitors Provided herein are methods according to any one of embodiments 168-175, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a PD-L1 inhibitor.

[0133] 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.

[0134] In one embodiment, the PD-L1 inhibitor is atezolizumab.

[0135] PI3K inhibitors Provided herein is a method according to any one of embodiments 168-175, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a PI3K inhibitor.

[0136] Exemplary PI3K inhibitors for use in the methods provided herein include idelalisib, copanlisib, duvelisib, alpelisib, taselisib, perifosine, buparlisib, umbralisib, pictilisib, dactolisib, voxtalisib, sonolicisib, tenalisib, selavelisib, acalisib, CUDC-907 (N-hydroxy-2-[[2-(6-methoxypyridin-3-yl)-4-morpholin-4-ylthieno[3 ,2-d]pyrimidin-6-yl]methyl-methylamino]pyrimidine-5-carboxamide), ME-401 (N-[2-methyl-1-[2-(1-methylpiperidin-4-yl)phenyl]propan-2-yl]-4-(2-methylsulfonylbenzimidazol-1-yl)-6-morpholin-4-yl-1,3,5-triazin-2-amine), IPI-549 (2-amino-N-[(1S)-1-[8-[2-(1-methylpiperidin-4-yl)phenyl]propan-2-yl]-4-(2-methylsulfonylbenzimidazol-1-yl)-6-morpholin-4-yl-1,3,5-triazin-2-amine), pyrazolo[1,5-a]pyrimidine-3-carboxamide), SF1126 (((2S)-2-[[(2S)-3-carboxy-2-[[2-[[(2S)-5-(diaminomethylideneamino)-2-[[4-oxo-4-[[4-(4-oxo-8-phenylchromen-2-yl)morpholin-4-ium-4-yl]methoxy]butadiene-2-yl)ethyl)

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

[0137] Raf kinase inhibitors Provided herein are methods according to any one of embodiments 168-175, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a Raf kinase inhibitor.

[0138] As used herein, the term "RAF kinase" refers to a member of the mammalian serine / threonine kinases that are composed of three isoforms (C-Raf, B-Raf and A-Raf) and includes homodimers of each isoform as well as heterodimers between the isoforms, e.g., C-Raf / B-Raf heterodimers.

[0139] As used herein, the term "Raf kinase inhibitor" refers to a compound capable of negatively regulating or inhibiting all or part of the enzymatic activity of one or more members of the Raf family kinases, or capable of inhibiting activity by preventing the formation of Raf homodimers or heterodimers.

[0140] In one embodiment, the Raf kinase inhibitors include encorafenib, sorafenib, lifirafenib, vemurafenib, dabrafenib, PLX-8394 (N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-3a,7a-dihydro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide), Raf-709 (N-(2-methyl-5-morpholino-6'-((tetrahydro-2 H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide), LXH254 (N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide), LY3009120 (1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)-2-(trifluoromethyl)isonicotinamide), (1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea), Tak-632 (N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide), CEP-32496 (1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea), CCT19696 9 (1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-((3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yl)oxy)phenyl)urea) and RO5126766 (N-[3-fluoro-4-[[4-methyl-2-oxo-7-(2-pyrimidinyloxy)-2H-1-benzopyran-3-yl]methyl]-2-pyridinyl]-N'-methyl-sulfamide).

[0141] In one embodiment, the Raf kinase inhibitor is encorafenib. In one embodiment, the Raf kinase inhibitor is sorafenib. In one embodiment, the Raf kinase inhibitor is lifirafenib.

[0142] SHP2 inhibitors Provided herein are methods according to any one of embodiments 168-175, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a SHP2 inhibitor.

[0143] Exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, SHP-099 (6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine dihydrochloride), RMC-4550 ([3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl]methanol), TNO155 ((3S,4S)-8-[6-amino-5-(2-amino-3-chloropyridin-4-yl)sulfanylpyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine), and RMC-4630 (Revolution Medicine). In one embodiment, the SHP inhibitor used in the methods provided herein is RMC-4630 (Revolution Medicine).

[0144] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include 3-[(1R,3R)-1-amino-3-methoxy-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyrazinemethanol (CAS 2172651-08-8), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2-pyrazinemethanol (CAS 2172652-13-8), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-[[3-chloro-2-(3-hydroxy-1-azetidinyl)-4-pyridinyl]thio]-5-methyl-2-pyrazinemethanol (CAS 2172652-38-7) and 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-methyl-2-pyrazinemethanol (CAS 2172652-48-9).

[0145] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include 1-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-4-methyl-4-piperidinamine (CAS 2240981-75-1), (1R)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine (CAS 2240981-78-4), (3S,4S)-8-[7-(2,3-dichlorophenyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-45-8), (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]pyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine (CAS 2240982-57-2), 4-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-7-(2,3-dichlorophenyl)-6-methyl-pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-69-6), 7-[(2-amino-3-chloro-4-pyridinyl)thio]-4-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-methyl-pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-73-2) and (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-77-6).

[0146] 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).

[0147] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-54-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56-5), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-(2,3-dichlorophenyl)-3-pyridinol (CAS 2238840-58-7), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-60-1), (1R)-8-[6-(2,3-dichlorophenyl)-5-methyl-3-pyridinyl]-8-azaspiro[4.5]decane-1-amine (CAS 2238840-62-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2-pyridinemethanol (CAS 2238840-63-4), (1R)-8-[6-[(2,3-dichlorophenyl)thio]-5-methyl-3-pyridinyl]-8-azaspiro[4.5]dec-1-amine (CAS 2238840-64-5), 5-(4-amino-4-methyl-1-piperidinyl)-2-[(2,3-dichlorophenyl)thio]-3-pyridinol (CAS 2238840-65-6), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-[(2,3-dichlorophenyl)thio]-3-pyridinol (CAS 2238840-66-7), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-hydroxy-2-pyridinemethanol (CAS 2238840-67-8), 3-(4-amino-4-methyl-1-piperidinyl)-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-68-9), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-69-0), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-methyl-2-pyridinemethanol (CAS 2238840-70-3), 3-(4-amino-4-methyl-1-piperidinyl)-6-[(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-71-4), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-(4-amino-4-methyl-1-piperidinyl)-2-pyridinemethanol (CAS 2238840-72-5), 5-[(2-amino-3-chloro-4-pyridinyl)thio]-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-methyl-3-pyridinemethanol (CAS 2238840-73-6), 2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-(2,3-dichlorophenyl)-6-methyl-3-pyridinemethanol (CAS 2238840-74-7), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-75-8) and 2-[(2-amino-3-chloro-4-pyridyl)sulfanyl]-5-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(hydroxymethyl)pyridin-3-ol.

[0148] 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).

[0149] In one embodiment, the SHP2 inhibitor used in the methods provided herein is an inhibitor disclosed in U.S. Pat. No. 10,590,090 B2, U.S. Patent Application Publication No. 2020 / 017517 A1, U.S. Patent Application Publication No. 2020 / 017511 A1, or WO 2019 / 075265 A1, each of which is incorporated by reference in its entirety.

[0150] SOS1 inhibitors Provided herein is a method according to any one of embodiments 168-175, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an SOS1 inhibitor.

[0151] 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.

[0152] Src kinase inhibitors Provided herein are methods according to any one of embodiments 168-175, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a Src kinase inhibitor.

[0153] As used herein, the term "Src kinase" refers to members of the mammalian non-receptor tyrosine kinase family that includes Src, Yes, Fyn and Fgr (SrcA subfamily); Lck, Hck, Blk and Lyn (SrcB subfamily) and the Frk subfamily.

[0154] As used herein, the term "Src kinase inhibitor" refers to a compound capable of negatively regulating or inhibiting all or part of the enzymatic activity of one or more members of the Src kinases.

[0155] Exemplary Src kinase inhibitors for use in the methods provided herein include dasatinib, ponatinib, vandetanib, bosutinib, saracatinib, KX2-391 (N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide), SU6656 ((Z)-N,N-dimethyl-2-oxo-3-((4,5,6,7-tetrahydro-1H-indol-2-yl)methylene)indoline-5-sulfonamide), PP 1 (1-(tert-butyl)-3-(p-tolyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), WH-4-023 (2,6-dimethylphenyl(2,4-dimethoxyphenyl)(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)carbamate) and KX-01 (N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide).

[0156] In one embodiment, the Src kinase inhibitor is dasatinib. In one embodiment, the Src kinase inhibitor is saracatinib. In one embodiment, the Src kinase inhibitor is ponatinib. In one embodiment, the Src kinase inhibitor is vandetanib. In one embodiment, the Src kinase inhibitor is KX-01.

[0157] Chemotherapeutic agents Provided herein are methods according to any one of embodiments 168-175, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is one or more chemotherapeutic agents.

[0158] Exemplary chemotherapeutic agents for use in the methods provided herein include, but are not limited to, leucovorin calcium (calcium folinate), 5-fluorouracil, irinotecan, oxaliplatin, cisplatin, carboplatin, pemetrexed, docetaxel, paclitaxel, gemcitabine, vinorelbine, chlorambucil, cyclophosphamide, and methotrexate.

[0159] definition The following definitions are provided to aid in understanding the scope of the present disclosure.

[0160] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless otherwise indicated, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending on the standard deviation found in their respective testing measurements.

[0161] As used herein, when any variable occurs more than one time in a chemical formula, its definition at each occurrence is independent of its definition at every other occurrence. In the case of conflict between the chemical structure and the chemical name, the chemical structure is determinative of the compound's identity.

[0162] stereoisomer The compounds of the present disclosure may contain, for example, double bonds, one or more asymmetric carbon atoms, and bonds with rotational hindrance, and therefore may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers (E / Z)), enantiomers, diastereomers, and atropisomers. Accordingly, the scope of the present disclosure should be understood to encompass all possible stereoisomers of the exemplified compounds, including stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, diastereomerically pure, and atropisomerically pure), as well as mixtures of stereoisomers (e.g., mixtures of geometric isomers, enantiomers, diastereomers, and atropisomers, or mixtures of any of the foregoing) of any chemical structure (all or part) disclosed herein, unless the stereochemistry is specifically specified.

[0163] If the stereochemistry of a structure or a portion of a structure is not shown, for example, with bold or dashed lines, then the structure or portion of the structure is to be interpreted as encompassing all stereoisomers thereof. If the stereochemistry of a structure or portion of a structure is shown, for example, with bold or dashed lines, then the structure or portion of the structure is to be interpreted as encompassing only the specified stereoisomer, unless otherwise stated.

[0164] for example, [ka] teeth, [ka] Represents. Similarly, for example, the chemical name (4R)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H-isoindole represents (4R,5R)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H-isoindole and (4R,5S)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H-isoindole.

[0165] Similarly, for example, the chemical name 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione represents (M)-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione and (P)-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

[0166] In certain cases, a bond drawn with a wavy line indicates that both stereoisomers are encompassed. This wavy line should not be confused with the wavy line drawn perpendicular to the bond, which indicates the point at which the group is attached to the remainder of the molecule.

[0167] As used herein, the term "stereoisomer" or "stereoisomerically pure" compound refers to one stereoisomer of a compound (e.g., geometric isomer, enantiomer, diastereomer, and atropisomer) that is substantially free of other stereoisomers of the compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of that compound, and a stereoisomerically pure compound having two chiral centers will be substantially free of other enantiomers or diastereomers of that compound. Typical stereoisomerically pure compounds comprise greater than about 80% by weight of the compound of one stereoisomer and about 20% or less by weight of the compound of the other stereoisomer, greater than about 90% by weight of the compound of one stereoisomer and about 10% or less by weight of the compound of the other stereoisomer, greater than about 95% by weight of the compound of one stereoisomer and about 5% or less by weight of the compound of the other stereoisomer, or greater than about 97% by weight of the compound of one stereoisomer and about 3% or less by weight of the compound of the other stereoisomer.

[0168] The present disclosure also encompasses pharmaceutical compositions comprising stereoisomerically pure forms and the use of any of the compounds disclosed herein in stereoisomerically pure form. Additionally, the present disclosure also encompasses pharmaceutical compositions comprising mixtures of stereoisomers of any of the compounds disclosed herein and the use of said pharmaceutical compositions or mixtures of stereoisomers. These stereoisomers or mixtures thereof can be synthesized according to methods well known in the art and disclosed herein. Mixtures of stereoisomers can be resolved using standard techniques, such as chiral columns or chiral resolving agents. Additionally, the present disclosure encompasses pharmaceutical compositions comprising mixtures of any of the compounds disclosed herein with one or more other active agents disclosed herein. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725; Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0169] Tautomers As known to those skilled in the art, certain compounds disclosed herein may exist in one or more tautomeric forms.Since one chemical structure can only be used to represent one tautomeric form, for convenience, it will be understood that reference to a compound of a given structural formula includes other tautomeric forms of said structural formula.Therefore, the scope of the present disclosure should be understood to include all tautomeric forms of the compounds disclosed herein.

[0170] isotope labeled compounds Additionally, the scope of the present disclosure includes all pharma- ceutically acceptable isotopically labeled compounds of the compounds disclosed herein, such as compounds of Formula I, in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds disclosed herein include: 2 H and 3 Hydrogen such as H 11 C. 13 C and 14 Carbon, such as C 36 Chlorine such as Cl, 18 Fluorine such as F 123 I and 125 Iodine, such as I 13 N and 15 Nitrogen such as N 15 O. 17 O and 18 Oxygen, such as O 32 Phosphorus such as P 35 Certain isotopically labeled compounds of formula I, for example those incorporating a radioactive isotope, are useful in studying the tissue distribution of drugs and / or substrates. 3 H) and carbon-14 ( 14 C) is particularly useful for this purpose given its ease of incorporation and ready means of detection. 2 Substitution with isotopes such as H or D may be preferred in some circumstances since they may afford certain therapeutic advantages resulting from increased metabolic stability, such as increased in vivo half-life or reduced dosage requirements. 11 C. 18 F, 15 O and 13 Substitution with positron-emitting isotopes such as N may be useful, for example, in positron emission tomography (PET) studies to determine target occupancy. Isotopically labeled compounds of the compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the accompanying general synthetic schemes and examples, using appropriate isotopically labeled reagents in place of conventionally used non-labeled reagents.

[0171] solvate As mentioned above, the compounds disclosed herein as well as the stereoisomers, tautomers, and isotopically labeled forms thereof, or pharma- ceutically acceptable salts of any of the foregoing, can exist in solvated or unsolvated forms.

[0172] As used herein, the term "solvate" refers to a molecular complex comprising a compound described herein or a pharma- ceutically acceptable salt thereof and a stoichiometric or non-stoichiometric amount of one or more pharma- ceutical acceptable solvent molecules. When the solvent is water, the solvate is referred to as a "hydrate."

[0173] Accordingly, the scope of the present disclosure should be understood to encompass all solvates of the compounds disclosed herein and their stereoisomers, tautomers, and isotopically labeled forms or pharma- ceutically acceptable salts of any of the foregoing.

[0174] Various definitions This section defines additional terms used to describe the scope of the compounds, compositions and uses disclosed herein.

[0175] The term "aryl" refers to an aromatic hydrocarbon group having 6-20 carbon atoms in the ring portion. Typically, aryl is a monocyclic, bicyclic or tricyclic aryl having 6-20 carbon atoms. Furthermore, the term "aryl" as used herein refers to an aromatic substituent which may be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl, each of which may be optionally substituted with 1-4 substituents such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(O)-O-, aryl-O-, heteroaryl-O-, amino, thiol, alkyl-S-, aryl-S-, nitro, cyano, carboxy, alkyl-OC(O)-, carbamoyl, alkyl-S(O)-, sulfonyl, sulfonamido, phenyl, and heterocyclyl.

[0176] As used herein, the term "C 1~4 Alkyl" and "C 1~6 "Alkyl" refers to a straight or branched chain hydrocarbon containing 1 to 4 and 1 to 6 carbon atoms, respectively. 1~4 Alkyl or C 1~6 Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, and hexyl.

[0177] The term “C 1~4 Alkylene" and "C 1~6 "Alkylene" refers to a straight or branched chain divalent alkyl group, as defined herein, containing 1 to 4 and 1 to 6 carbon atoms, respectively. Representative examples of alkylene include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, and the like.

[0178] As used herein, the term "C 2~4 "Alkenyl" refers to a saturated hydrocarbon containing 2 to 4 carbon atoms having at least one carbon-carbon double bond. Alkenyl groups include both straight-chain and branched-chain moieties. 2~4 Representative examples of alkenyl include, but are not limited to, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, and butenyl.

[0179] As used herein, "C 2~4 The term "alkynyl" refers to a saturated hydrocarbon containing 2 to 4 carbon atoms with at least one carbon-carbon triple bond. This term includes both straight and branched chain moieties. 3~6 Representative examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, and 3-butynyl.

[0180] As used herein, the term "C 1~4 Alkoxy" or "C 1~6 "Alkoxy" is -OR # As defined herein, R # are C 1~4 Alkyl group or C 1~6 Represents an alkyl group. 1~4 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy, and butoxy. 1~6 Representative examples of alkoxy include, but are not limited to, ethoxy, propoxy, iso-propoxy, and butoxy.

[0181] As used herein, the term "C 3~8 "Cycloalkyl" refers to a saturated carbocyclic molecule whose cyclic backbone has 3 to 8 carbons. 3~8 Representative examples of cycloalkyl include, but are not limited to, cyclopropyl and cyclobutyl.

[0182] When used herein as a prefix for another term in reference to a chemical group, the term "deuterium" refers to an atom or atoms in which one or more hydrogen atoms have been replaced with a heavy atom ("D" or " 2 For example, the term "C 1~4 "Deuteroalkyl" refers to a C alkyl group, as defined herein, in which one or more hydrogen atoms have been replaced with D. 1~4 Refers to alkyl. 1~4 Representative examples of deuterated alkyls include, but are not limited to, -CH2D, -CHD2, -CD3, -CH2CD3, -CDHCD3, -CD2CD3, -CH(CD3)2, -CD(CHD2)2, and -CH(CH2D)(CD3).

[0183] As used herein, the term "halogen" refers to -F, -Cl, -Br, or -I.

[0184] The term "halo," as used herein as a prefix of another term for a chemical group, refers to a modification of a chemical group in which one or more hydrogen atoms have been replaced with a halogen, as defined herein. The halogens are independently selected at each occurrence. For example, the term "C 1~4 "Haloalkyl" refers to a C alkyl group, as defined herein, in which one or more hydrogen atoms are replaced with halogen. 1~4 Refers to alkyl. 1~4 Representative examples of haloalkyl include, but are not limited to, -CH2F, -CHF2, -CF3, -CHFCl, -CH2CF3, -CFHCF3, -CF2CF3, -CH(CF3)2, -CF(CHF2)2, and -CH(CH2F)(CF3).

[0185] As used herein, the term "heteroaryl" refers to a 5-20 membered monocyclic, bicyclic or tricyclic aromatic ring system having 1-8 heteroatoms selected from N, O and S. In certain preferred embodiments, the heteroaryl is a 5-10 membered ring system (e.g., a 5-7 membered monocyclic, an 8-10 membered bicyclic or an 11-14 membered tricyclic) or a 5-7 membered ring system. Exemplary monocyclic heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4- or 5-pyrazinyl, 2-pyrazinyl, and 2-, 4- and 5-pyrimidinyl. Exemplary bicyclic heteroaryl groups include 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 2-, 4-, 5-, 6-, 7- or 8-benzimidazolyl, and 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-indolyl.

[0186] The term "heteroaryl" also refers to groups in which a heteroaromatic ring is fused to one or more aryl, aliphatic, or heterocyclyl rings.

[0187] As used herein, the term "heterocycle", "heterocycloalkyl" or "heterocyclo" refers to a saturated or unsaturated non-aromatic ring or ring system, such as a 4-, 5-, 6- or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic or 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system, and containing at least one heteroatom selected from O, S and N, which may also be optionally oxidized to various oxidation states. The heterocyclic group may be attached to a heteroatom or a carbon atom. Heterocyclyl may include fused or bridged rings as well as spirocyclic rings. Examples of heterocycles include tetrahydrofuran, dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, azetidine, thiazolidine, morpholine, and the like.

[0188] As used herein, the term "pharmaceutical acceptable" refers to something that is generally recognized for use in subjects, particularly humans.

[0189] As used herein, the term "pharmaceutical acceptable salt" refers to a salt of a compound that is pharmaceutical acceptable and has the desired pharmacological activity of the parent compound. Such salts include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, etc.; or (2) salts formed when the acidic protons present in the parent compound are replaced with metal ions, such as alkali metal ions, alkaline earth ions, or aluminum ions; or salts formed when coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine, etc. Further examples of such salts can be found in Berge et al., J. Pharm. Sci. 66(1):1-19 (1977). Stahl et al., Pharmaceutical Salts: Properties, Selection, and Use, 2 nd See also the Revised Edition (2011).

[0190] As used herein, the term "pharmaceutical acceptable excipient" refers to a wide range of ingredients that can be combined with the compounds or salts disclosed herein to prepare pharmaceutical compositions or formulations.Typically, excipients include, but are not limited to, diluents, colorants, vehicles, anti-adherents, glidants, disintegrants, flavorings, coatings, binders, sweeteners, lubricants, adsorbents, preservatives, etc.

[0191] As used herein, the term "subject" refers to humans and animals, including, but not limited to, primates, cows, sheep, goats, horses, dogs, cats, rabbits, rats, and mice. In one embodiment, the subject is a human.

[0192] As used herein, the term "therapeutically effective amount" refers to an amount of a compound disclosed herein that elicits the biological or medical response in a tissue, system, or subject desired by a researcher, veterinarian, medical doctor, or other clinician.

[0193] General synthetic procedure The compounds provided herein can be synthesized according to the procedures described in this section and the following sections. The synthetic methods described herein are merely illustrative, and the compounds disclosed herein can also be synthesized by alternative routes using alternative synthetic strategies, as will be appreciated by those skilled in the art. It will be understood that the general synthetic procedures and specific examples provided herein are merely illustrative and should not be construed as limiting the scope of the present disclosure in any way.

[0194] In general, the compound of formula I can be synthesized according to the following scheme. Any variables used in the following scheme are defined as for formula I unless otherwise noted. All starting materials are commercially available, for example, from Merck Sigma-Aldrich Inc., Fluorochem Ltd, and Enamine Ltd., or are known in the art and may be synthesized by using known procedures using routine techniques. Starting materials may also be synthesized by the procedures disclosed herein. Suitable reaction conditions, such as solvents, reaction temperatures, and reagents for the schemes described in this section can be found in the examples provided herein.

[0195] [ka] Compounds of formula (I) can be prepared according to Scheme I. In step A, compound (I-1) is treated with an aliphatic alcohol, such as benzyl alcohol, and a base, such as Hunig's base, or a metal alkoxide, such as potassium tert-butoxide, in a solvent, such as 1,4-dioxane, to give compound (I-2). In step B, a compound of formula R is reacted with an aliphatic alcohol, such as benzyl alcohol, and a base, such as Hunig's base, in a solvent, such as acetonitrile, to give compound (I-3).1 The compound (I-2) is reacted with a nucleophile having -LH to form S N In step C, compound (I-3) is coupled with an organometallic reagent or a boronic acid (ester) to provide compound (I-4). The coupling reaction proceeds in a solvent or mixture of solvents, such as 1,4-dioxane and water, with or without a base, such as potassium phosphate, and a catalyst, such as cataCXium A Pd G3. In step D, compound (I-4) is treated with a suitable set of reagents, such as Pd / C with H2 to remove the alkyl group R to provide compound (I-5). In step E, compound (I-5) is treated with an optionally substituted cyclic amine in the presence of a coupling reagent, such as HATU, and a base, such as Hunig's base, in a solvent, such as DMA, to provide a compound of formula (I). In some cases, the species R 3 contains a protecting group, which can be removed during step D or after step E of the synthetic sequence.

[0196] [ka] Compounds of formula (I) can also be prepared according to Scheme II. In step A, an optionally substituted cyclic amine and compound (1) are reacted with S to afford compound (1) in the presence of a base such as Hunig's base in a solvent such as dichloromethane. N In step B, a compound of formula R is reacted with 1,2-dichlorophenyl ether in a solvent such as acetonitrile in the presence of a base such as Hunig's base to obtain compound (I-10). 1 The compound (I-10) is reacted with a nucleophile having -LH to form S N In step C, compound (I-11) is coupled with an organometallic reagent or a boronic acid (ester) to provide a compound of formula (I). This coupling reaction proceeds in a solvent or mixture of solvents such as 1,4-dioxane and water, with or without a base such as potassium phosphate, and a catalyst such as cataCXium A Pd G3. In some cases, the group R 2 undergoes further transformation. In some cases, the species R 3contains a protecting group, which can be removed after step C of the synthetic sequence. EXAMPLES

[0197] This section provides specific examples of compounds of Formula I and methods for their preparation.

[0198] List of abbreviations

[0199] [Table 2]

[0200] [Table 3]

[0201] [Table 4]

[0202] [Table 5]

[0203] General analytical and purification methods This section provides a description of the general analytical and purification methods used to prepare the specific examples provided herein.

[0204] Chromatography: Unless otherwise indicated, crude product-containing residues were purified by passing the crude material or concentrate through either a Biotage or Isco brand silica gel column pre-packed with flash silica (SiO2) and eluting the product from the column with a solvent gradient as specified.

[0205] Preparative HPLC Methods: Where indicated, compounds described herein were purified by reverse-phase HPLC using a Waters Fractionlynx or Gilson semi-preparative HPLC-MS system using one of the following two HPLC columns: (a) a Phenomenex Gemini column (5 micron, C18, 150 x 30 mm) or (b) a Waters X-select CSH column (5 micron, C18, 100 x 30 mm). A typical run through the instrument involves eluting with a linear gradient of 10% (v / v) to 100% MeCN (0.1% v / v formic acid) in water (0.1% formic acid) at 45 mL / min over 10 minutes; conditions may be varied to achieve optimal separation.

[0206] Proton NMR spectra: All unless otherwise indicated. 1 H NMR spectra were collected at 300, 400 or 500 MHz on a Bruker NMR instrument. All observed protons are reported as parts per million (ppm) downfield from tetramethylsilane (TMS) using the internal solvent peak as the reference. 1 Some of the H signals may be missing due to exchange with D from MeOD or signal suppression.

[0207] Mass Spectrum (MS): Unless otherwise indicated, all mass spectral data for starting materials, intermediates and / or example compounds are reported as mass / charge (m / z) with [M+H]+ molecular ion. Reported molecular ions were obtained by electrospray detection (commonly referred to as ESI MS) using a Waters Acquity UPLC / MS system. As will be appreciated by those skilled in the art, compounds with isotopic atoms such as bromine are generally reported according to the detected isotopic pattern.

[0208] Preparation of intermediates 6-Methyl-1,4-oxazepan-6-ol hydrochloride isomer 1 (intermediate A1) and isomer 2 (intermediate A2) [ka] Step 1: 4-(4-Methoxybenzyl)-1,4-oxazepan-6-one. To a 20 mL vial was added 1,4-oxazepan-6-one hydrochloride (0.30 g, 1.98 mmol, AA BLOCKS LLC), 4-methoxybenzyl chloride (0.37 g, 0.32 mL, 2.38 mmol, TCI America), DIPEA (0.77 g, 1.0 mL, 5.94 mmol, Sigma-Aldrich Corporation), and DCM (10 mL). The reaction was stirred at room temperature overnight. The crude material was purified by column chromatography on a silica gel column eluting with a gradient of 0-80% 3:1 EtOAc / EtOH (with 1% TEA) in heptane to give 4-(4-methoxybenzyl)-1,4-oxazepan-6-one (0.43 g, 1.83 mmol, 92% yield) as a colorless oil. m / z(ESI):236.2(M+H) + .

[0209] Step 2: 4-(4-Methoxybenzyl)-6-methyl-1,4-oxazepan-6-ol. To a 100 mL round bottom flask was added 4-(4-methoxybenzyl)-1,4-oxazepan-6-one (0.87 g, 3.70 mmol) in THF (15 mL). The mixture was cooled to 0° C., then methylmagnesium bromide solution (3 M in Et2O, 3.7 mL, 11.09 mmol, Sigma-Aldrich Corporation) was added. The reaction was stirred for 1 h. The reaction mixture was diluted with saturated NH4Cl (15 mL) and extracted with EtOAc (2×15 mL). The organic extract was washed with saturated NaCl (15 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0-50% 3:1 EtOAc / EtOH in heptane to give 4-(4-methoxybenzyl)-6-methyl-1,4-oxazepan-6-ol (0.65 g, 2.59 mmol, 70% yield) as a yellow oil. m / z (ESI): 252.1 (M+H). + .

[0210] Step 3: Chiral separation. 4-(4-Methoxybenzyl)-6-methyl-1,4-oxazepan-6-ol (0.65 g, 2.59 mmol) was purified by SFC using a Chiralpak AD, 30×150 mm 5 μm column with a mobile phase of 20% methanol with 0.2% triethylamine using a flow rate of 200 mL / min to give 246 mg of peak 1 (ee>99%) and 292 mg of peak 2 (ee>99%).

[0211] Step 4: 6-Methyl-1,4-oxazepan-6-ol hydrochloride. 4-(4-Methoxybenzyl)-6-methyl-1,4-oxazepan-6-ol (0.24 g, 0.96 mmol, peak 1) was dissolved in ethanol (5.8 mL). Palladium on activated carbon (0.25 g, 0.23 mmol, Sigma-Aldrich Corporation) and aqueous HCl (2N, 0.7 mL, 1.33 mmol, Sigma-Aldrich Corporation) were added and the mixture was stirred at room temperature under H2 atmosphere for 5 h. The catalyst was removed and the solution was concentrated to give 6-methyl-1,4-oxazepan-6-ol hydrochloride (quantitative yield, isomer 1, intermediate A1). The same method was used to give isomer 2, intermediate A2.

[0212] 6-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (Intermediate B1) [ka] ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.00 g, 1.95 mmol, LabNetwork) was dissolved in tetrahydrofuran (4 mL). HCl (4 M in dioxane, 0.71 g, 0.71 mL, 19.51 mmol, Sigma-Aldrich Corporation) was added. The reaction mixture was stirred at room temperature for 5 h, then the volatiles were removed in vacuo. The residue was purified by column chromatography on silica gel eluting with a gradient of 0-50% EtOAc / heptane to give 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (0.89 g, 1.90 mmol, 97% yield). m / z(ESI):469.0(M+H) + .

[0213] [Table 6]

[0214] 7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-ol (Intermediate C) [ka] Step 1: 4-(Benzyloxy)-7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline. 7-Bromo-2,4-dichloro-8-fluoroquinazoline (92 mg, 0.31 mmol, PharmaBlock) was dissolved in acetonitrile (0.6 mL) and benzyl alcohol (0.34 g, 0.3 mL, 3.10 mmol) and DIPEA (0.12 g, 0.2 mL, 0.93 mmol) were added. The mixture was stirred at room temperature for 2 h. This crude mixture was directly purified by column chromatography on silica gel eluting with a gradient of 0-100% 3:1 EtOAc:EtOH in heptane. The product was dissolved in acetonitrile (0.6 mL) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (49 mg, 0.31 mmol, LabNetwork) and DIPEA (0.12 g, 0.2 mL, 0.93 mmol) were added. The mixture was stirred at 80° C. overnight. The crude mixture was purified by reverse phase HPLC to give 4-(benzyloxy)-7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline (0.13 g, 0.27 mmol, 85% yield) as a colorless oil. m / z (ESI): 491.0 (M+H). + .

[0215] Step 2: 4-(benzyloxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline. To a solution of 4-(benzyloxy)-7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline (0.14 g, 0.29 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.21 g, 0.59 mmol, PharmaBlock) in degassed tetrahydrofuran (2.7 mL) and water (0.3 mL) was added potassium phosphate (0.19 g, 0.88 mmol) and cataCXium A Pd G3 (43 mg, 0.06 mmol). The reaction mixture was stirred at 70° C. overnight. The crude mixture was purified by reverse phase HPLC to give 4-(benzyloxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline (0.20 g, 0.30 mmol, quantitative) as a yellow oil which was used in the next step without further manipulation. m / z (ESI): 644.0 (M+H). + .

[0216] Step 3: 7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-ol. 4-(Benzyloxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline (0.20 g, 0.30 mmol) was dissolved in EtOAc (3.0 mL) in a pressure tube containing palladium on activated carbon (63 mg, 0.06 mmol). The reaction was stirred at room temperature under 15 psi of H2 overnight. The mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was dissolved in THF (3.0 mL) and HCl solution (4M in 1,4-dioxane, 2.0 mL). The reaction was stirred at room temperature for 3 h. The volatiles were removed in vacuo and co-evaporated with DCM (3×5 mL) to give 7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-ol (0.14 g, 0.27 mmol, 90% yield) as a yellow solid which was used without further purification. m / z (ESI): 510.1 (M+H). + .

[0217] 7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-ol (Intermediate D) [ka] Step 1: 4-(benzyloxy)-7-bromo-2-chloro-6,8-difluoroquinazoline. 7-Bromo-2,4-dichloro-6,8-difluoroquinazoline (1.00 g, 3.19 mmol, PharmaBlock) was dissolved in acetonitrile (12 mL) and benzyl alcohol (3.44 g, 3.3 mL, 31.9 mmol) and DIPEA (1.24 g, 1.7 mL, 9.56 mmol) were added. The mixture was stirred at 35° C. for 2 h. The crude mixture was purified by column chromatography eluting with a gradient of 0-30% EtOAc in heptane to give 4-(benzyloxy)-7-bromo-2-chloro-6,8-difluoroquinazoline (0.30 g, 0.78 mmol, 24% yield). m / z (ESI): 384.8 (M+H). + .

[0218] Step 2: 4-(benzyloxy)-7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline. 4-(benzyloxy)-7-bromo-2-chloro-6,8-difluoroquinazoline (0.30 g, 0.77 mmol) was dissolved in acetonitrile (1.5 mL) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (0.12 g, 0.77 mmol) and DIPEA (0.30 g, 0.4 mL, 2.30 mmol) were added. The mixture was stirred at 80° C. for 24 hours. The mixture was purified by reverse phase HPLC to give 4-(benzyloxy)-7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline (25 mg, 0.05 mmol, 6% yield). m / z (ESI): 508.1 (M+H). + .

[0219] Step 3: 4-(4-(benzyloxy)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol. 4-(benzyloxy)-7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline (50 mg, 0.10 mmol), cataCXium A Pd G3 (14 mg, 0.02 mmol), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (62 mg, 0.20 mmol) and potassium phosphate monohydrate (68 mg, 0.30 mmol) were dissolved in tetrahydrofuran (0.9 mL) and water (90 μL) and degassed for 10 min. The mixture was stirred at 70 °C overnight. The crude mixture was then purified by reverse phase HPLC to give 4-(4-(benzyloxy)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (30 mg, 0.05 mmol, 49% yield). m / z (ESI) 618.0 (M+H). + .

[0220] Step 4: 7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-ol. 4-(4-(benzyloxy)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (30 mg, 0.05 mmol) was dissolved in EtOH (1.5 mL). Palladium on activated carbon (21 mg, 0.02 mmol) was added and the mixture was stirred under 50 psi of H2 for 16 hours. The reaction was filtered and the volatiles removed in vacuo to give 7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-ol (25 mg, 0.05 mmol, quant.) as a colorless oil which was used without further purification. m / z (ESI): 528.0 (M+H). + .

[0221] (R)-1-Oxa-3,7-diazaspiro[4.5]decan-2-one (intermediate H). [ka] Step 1: Benzyl (S)-2-oxo-1-oxa-3,7-diazaspiro[4.5]decane-7-carboxylate. A mixture of 1-oxa-3,7-diazaspiro[4.5]decane-2-one hydrochloride (1.48 g, 7.66 mmol, J&W Pharmlab), benzyl carbonochloridate (1.3 mL, 9.2 mmol), and sodium bicarbonate solution (1N, 23 mL, 23 mmol) in 2-methyltetrahydrofuran (22 mL) was stirred at room temperature for 16 hours. The reaction mixture was extracted with EtOAc, and the organic layer was washed with brine, separated, dried over anhydrous Na2SO4, and concentrated in vacuo to give benzyl 2-oxo-1-oxa-3,7-diazaspiro[4.5]decane-7-carboxylate (2.16 g, 7.44 mmol, 97% yield). Purification of 1.07 g by SFC using a ChiralPak IC, 2 x 15 cm, 5 μm column with a mobile phase of 40% MeOH with 0.2% DEA using a flow rate of 100 mL / min gave peak 1 of 484 mg as benzyl (R)-2-oxo-1-oxa-3,7-diazaspiro[4.5]decane-7-carboxylate with an ee of 99% and peak 2 of 536 mg as benzyl (S)-2-oxo-1-oxa-3,7-diazaspiro[4.5]decane-7-carboxylate with an ee of 99%.

[0222] Step 2: (R)-1-Oxa-3,7-diazaspiro[4.5]decane-2-one. A mixture of benzyl (S)-2-oxo-1-oxa-3,7-diazaspiro[4.5]decane-7-carboxylate (0.58 g, 1.99 mmol), formic acid, ammonium salt (0.63 g, 9.94 mmol), and palladium, 10%, wet (0.64 g, 0.60 mmol) in ethyl acetate (5 mL) was stirred at room temperature for 16 h. The reaction mixture was filtered through Celite and washed with EtOAc and EtOH. The filtrate was concentrated in vacuo to give (S)-1-Oxa-3,7-diazaspiro[4.5]decane-2-one (0.26 g, 1.66 mmol, 83% yield) as a white solid. m / z (ESI): 157.1 (M+H). + .

[0223] [Example] (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (Example 1) [ka] Step 1: (R)-1-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol. To a stirred solution of 7-bromo-2,4-dichloro-8-fluoroquinazoline (2.00 g, 6.76 mmol, Enamine) in acetonitrile (34 mL) was added (3R)-3-methylpiperidin-3-ol hydrochloride (1.08 g, 7.10 mmol, PharmaBlock) and DIPEA (2.62 g, 3.54 mL, 20.28 mmol, Sigma-Aldrich Corporation). The reaction was stirred overnight at room temperature. The reaction was then diluted with water (1.5 mL) and brine (1.5 mL) and the aqueous layer was extracted with CHCl. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (R)-1-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol as an orange solid. The product was used without further purification. m / z(ESI): 374.0(M+H). + .

[0224] Step 2: (R)-1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol. To a 250 mL vial was added 1,4-diazabicyclo[2.2.2]octane (0.16 g, 1.44 mmol, Sigma-Aldrich Corporation), cesium carbonate (7.04 g, 21.62 mmol, Sigma-Aldrich Corporation), (R)-1-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol from step 1, and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (2.30 g, 14.41 mmol, LabNetwork). The solid was then suspended in N,N-dimethylformamide (24 mL) and tetrahydrofuran (48 mL). The reaction mixture was stirred overnight at 40° C. The reaction was then diluted with water and transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude reaction mixture was then purified by column chromatography on silica gel eluting with a gradient of 0-50% 3:1 EtOAc / EtOH in heptane containing 2% triethylamine to give (R)-1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (2.48 g, 4.99 mmol, 69% combined yield over two steps). m / z (ESI): 498.0 (M+H). + .

[0225] Step 3: (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol. In an 8 mL vial, add cataCXium A Pd G4 (30 mg, 0.04 mmol, Sigma Aldrich), potassium phosphate tribasic (0.17 g, 0.80 mmol, Acros The reaction was charged with 1,3,2-dioxaborolane (0.15 g, 0.40 mmol, PharmaBlock), 1,3,2-dioxaborolane 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthalenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.15 g, 0.40 mmol, PharmaBlock), (R)-1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (0.10 g, 0.20 mmol), water (0.25 mL) and tetrahydrofuran (0.75 mL). The reaction was stirred at 70° C. for 1 h. The crude mixture was purified by column chromatography on silica gel eluting with a gradient of 0-50% 3:1 EtOAc / EtOH in heptane with 2% triethylamine additive to give (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (77 mg, 0.12 mmol, 59% yield). m / z (ESI): 651.2 (M+H). + .

[0226] Step 4: (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol. (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (77 mg, 0.12 mmol) was stirred in hydrogen chloride solution (4.0 M in dioxane, 0.59 mL, 2.37 mmol, Sigma-Aldrich Corporation) and methanol (0.6 mL) at room temperature for 1 h. Volatiles were removed under reduced pressure. The crude product was purified by reverse phase HPLC to give (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol as the 2,2,2-trifluoroacetate as an off-white solid (79 mg, 0.11 mmol, 93% yield). m / z (ESI): 607.0 (M+H). + . 1 H NMR (400MHz, methanol-d4) δ ppm 8.13-8.23 (m, 1H), 7.65-7.73 (m, 1H), 7.48-7.57 (m, 1H), 7.23-7.32 (m, 2H), 6.96-7.01 (m, 1H), 5.49-5.68 (m, 1H), 4.73-4.79 (m, 2H), 4.64-4.73 (m, 1H), 4.38-4.51 (m, 1H), 3.80-4.12(m,3H),3.61-3.73(m,1H),3.42-3.60(m,2H),2.55-2.84(m,2H),2.32-2.5 3(m,5H),2.13-2.29(m,2H),1.77-1.95(m,3H),1.26-1.40(m,3H),0.77-0.89(m,3H).

[0227]

Table 7

[0228]

Table 8

[0229]

Table 9

[0230]

Table 10

[0231]

Table 11

[0232]

Table 12

[0233]

Table 13

[0234]

Table 14

[0235]

Table 15

[0236]

Table 16

[0237]

Table 17

[0238]

Table 18

[0239]

Table 19

[0240]

Table 20

[0241]

Table 21

[0242]

Table 22

[0243]

Table 23

[0244]

Table 24

[0245]

Table 25

[0246]

Table 26

[0247]

Table 27

[0248]

Table 28

[0249]

Table 29

[0250]

Table 30

[0251]

Table 31

[0252]

Table 32

[0253]

Table 33

[0254]

Table 34

[0255]

Table 35

[0256]

Table 36

[0257]

Table 37

[0258]

Table 38

[0259] [Table 39]

[0260] Further steps of Example 4 [ka] To a stirred solution of tert-butyl ((R)-1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-5,5-difluoropiperidin-3-yl)carbamate (0.24 g, 0.39 mmol) in DCM (2 mL) was added trifluoroacetic acid (1.53 g, 1 mL, 13.42 mmol, Sigma-Aldrich Corporation). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated. The residue was diluted with DCM and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over Na2SO4 and evaporated in vacuo and the product was used as 100% yield. m / z (ESI): 519.0 (M+H) + .

[0261] Further steps of Example 5 [ka] To a solution of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-5,5-difluoropiperidin-3-amine (55 mg, 0.082 mmol) in DCM (0.5 mL) at 0° C. was added Hunig's base (32 mg, 0.043 mL, 0.25 mmol, Sigma-Aldrich Corporation), followed by methyl chloroformate (7.7 mg, 7.7 μL, 0.082 mmol, Sigma-Aldrich Corporation). The reaction mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated and purified by HPLC to give methyl ((R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-5,5-difluoropiperidin-3-yl)carbamate (28 mg, 0.038 mmol, 47% yield) as a yellow solid. m / z (ESI): 730.2 (M+H). + .

[0262] Further steps of Example 11 [ka] To a 10 mL round bottom flask was added (3R)-1-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol (0.20 g, 0.25 mmol) in N,N-dimethylformamide (2.5 mL) and cesium fluoride (76 mg, 0.50 mmol, Aldrich). The reaction was stirred at room temperature for 2 h 20 min and then at 45° C. for 1 h. The reaction was diluted with brine (10 mL), extracted with EtOAc (3×10 mL), dried over MgSO4, filtered and concentrated in vacuo to afford (3R)-1-(7-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol as a dark oil which was used directly in the next step without further purification. m / z (ESI): 647.2 (M+H). + .

[0263] Further steps of Example 26 [ka] A vial was charged with 4-(6-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-oxazepane (60 mg, 0.09 mmol), [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (14 mg, 0.02 mmol, Sigma-Aldrich Corporation), and potassium hydroxide (15 mg, 0.27 mmol, VWR International, LLC). This solid was then suspended in 1,4-dioxane (0.2 mL) and water (0.2 mL) and degassed. The reaction was sealed and heated to 100° C. After 1.5 h, the reaction was concentrated under reduced pressure to give a crude black oil. The crude residue was then purified by column chromatography on silica gel eluting with a gradient of 0-75% 3:1 EtOAc / EtOH (containing 2% triethylamine) to give 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)quinazolin-6-ol as a bright yellow solid which was carried on to the next step without further purification. m / z (ESI): 653.2 (M+H). + .

[0264] [Table 40]

[0265] [Table 41]

[0266] [Table 42]

[0267]

Table 43

[0268]

Table 44

[0269]

Table 45

[0270]

Table 46

[0271]

Table 47

[0272]

Table 48

[0273]

Table 49

[0274]

Table 50

[0275]

Table 51

[0276]

Table 52

[0277] [Table 53]

[0278] 8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-4-(1,4-oxazepan-4-yl)quinazoline-6-carbonitrile (Example 44) [ka] To a 10 mL round bottom flask was added 4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)quinazolin-7-yl)naphthalen-2-ol (0.11 g, 0.19 mmol), potassium ferrocyanide trihydrate (41 mg, 0.10 mmol, Toronto Research Chemicals), NaCO (2.6 mg, 0.02 mmol, Sigma-Aldrich Corporation), and 2-dicyclohexylphosphino-2',4',6',-triisopropylbiphenyl (18 mg, 0.04 mmol, Sigma-Aldrich Corporation) in dioxane (1.0 mL) and water (1.0 mL). Then, ((2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (16 mg, 0.02 mmol, Sigma-Aldrich A 100 mL aliquot of 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-4-(1,4-oxazepan-4-yl)quinazoline-6-carbonitrile was added. The vial was purged with argon and the reaction was stirred at 90° C. After 1 h, the reaction was diluted with NaHCO3 (5 mL), extracted with EtOAc (3×5 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by HPLC. The product-containing fractions were combined, diluted with saturated NaHCO3 (10 mL), extracted with EtOAc (3×10 mL), dried over MgSO4, filtered and concentrated in vacuo to give 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-4-(1,4-oxazepan-4-yl)quinazoline-6-carbonitrile (50 mg, 0.09 mmol, 45% yield) as a brown solid. m / z(ESI): 572.2 (M+H) + . 1H NMR(400MHz,DMSO-d6)δ ppm 10.03(s,1H),8.47(s,1H),7.84(d,J=8.2Hz,1H),7.48(ddd,J=8.2,6.4,1.7Hz,1H),7.34(d,J=2.3Hz,1H),7.24-7.32(m,2H) ,7.17(dd,J=2.3,0.6Hz,1H),5.16-5.41(m,1H),4.12-4.20(m,5H),4.07(dd,J=10.5,2.9Hz,1H),3.91-3.97(m,2H),3.75(br t,J=4.1Hz,2H),3.01-3.17(m,3H),2.79-2.90(m,1H),2.04-2.19(m,4H),1.93-2.04(m,1H),1.74-1.91(m,3H).

[0279] 7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)quinazoline-6-carbonitrile (Example 45) [ka] Synthesized in the same manner as in Example 44. m / z (ESI): 600.3 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ ppm 9.95(s,1H),8.44(s,1H),7.71(d,J=7.3Hz,1H),7.37-7.45(m,1H),7.34(d,J=2.5Hz,1H),7 .17(d,J=6.7Hz,1H),6.96(d,J=2.1Hz,1H),5.09-5.46(m,1H),4.11-4.22(m,5H),4.04-4.1 0(m,1H),3.90-3.98(m,2H),3.71-3.79(m,2H),2.96-3.17(m,3H),2.78-2.88(m,1H),2.24- 2.41(m,2H),2.03-2.20(m,4H),1.94-2.03(m,1H),1.72-1.90(m,3H),0.89(t,J=7.3Hz,3H).

[0280] 4-(6-amino-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 46) [ka] Step 1: 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N-(4-methoxybenzyl)-4-(1,4-oxazepan-4-yl)quinazolin-6-amine. A vial was charged with 4-methoxybenzylamine (20 mg, 20 μL, 0.15 mmol, Sigma-Aldrich Corporation), sodium tert-butoxide (21 mg, 0.22 mmol, Sigma-Aldrich Corporation), 4-(6-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-oxazepane (50 mg, 0.07 mmol), BrettPhos Pd G4 (14 mg, 0.02 mmol, Sigma-Aldrich Corporation) and 1,4-dioxane (0.75 mL). The reaction was then heated to 90° C. for 3 hours. The reaction was then cooled to room temperature and concentrated under reduced pressure to give a crude black oil. The crude residue was then purified by column chromatography on silica gel eluting with a gradient of 0-75% 3:1 EtOAc / EtOH (containing 2% triethylamine) in heptane to give 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N-(4-methoxybenzyl)-4-(1,4-oxazepan-4-yl)quinazolin-6-amine. m / z (ESI): 772.2 (M+H). + The product was then carried on to the next step without further purification.

[0281] Step 2: 4-(6-amino-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol. 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N-(4-methoxybenzyl)-4-(1,4-oxazepan-4-yl)quinazolin-6-amine was stirred in MeCN (2.3 mL) and HCl (4M in 1,4-dioxane, 0.5 mL, 1.86 mmol, Sigma-Aldrich Corporation). The reaction was stirred at room temperature. After 30 min, the reaction was concentrated under reduced pressure and the resulting solid was suspended in DCM (1.3 mL) and 1,1,1-trifluoroacetic acid (0.2 mL, 2.24 mmol, Apollo Scientific Ltd.). The reaction was stirred at room temperature for 5 h. The reaction was then concentrated under reduced pressure and subsequently purified by reverse phase HPLC followed by purification by XBridge column (19×100 mm, 5 μm) using 0.1% NH4OH in HO and MeCN as the mobile phase to give 4-(6-amino-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (6.1 mg, 0.01 mmol, 13% yield) as a yellow solid. m / z(ESI):607.8(M+H) + . 1H NMR(500MHz,DMSO-d6)δ ppm 7.71-7.78(m,1H),7.27-7.35(m,2H),7.10-7.14(m,1H),6.86-6.89(m,1H),5.14-5.36(m,1H),4.76-4.86(m,2H),3.84-4.14(m,9H),3.6 9-3.83(m,2H),2.98-3.15(m,3H),2.77-2.88(m,1H),2.50(d,J=1.8Hz,2H),1.95-2.17(m,5H),1.70-1.85(m,3H),0.75(t,J=7.4Hz,3H).

[0282] (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (Example 47) [ka] Step 1: (R)-1-(7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol. To a vial was added 2,4,7-trichloro-8-fluoroquinazoline (1.00 g, 3.98 mmol, Enamine) and DIPEA (2.06 g, 2.78 mL, 15.91 mmol, Sigma-Aldrich) in acetonitrile (20 mL). The solution was cooled to 0° C. and (R)-3-methylpiperidin-3-ol hydrochloride (0.60 g, 3.98 mmol, PharmaBlock) was added and the reaction was left to stir. After 40 min, ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (2M in MeCN, 2.1 mL, 4.18 mmol, LabNetwork), cesium carbonate (3.89 g, 11.93 mmol, Aldrich) and DABCO (89 mg, 0.80 mmol, Aldrich) were added. The reaction was left stirring at 40° C. for 20 h. The reaction was diluted with brine (15 mL), extracted with EtOAc (3×15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was adsorbed onto a plug of silica gel and purified by column chromatography on a silica gel column eluting with a gradient of 0-100% 3:1 EtOAc / EtOH in heptane to give (R)-1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (0.70 g, 1.40 mmol, 35% yield) as a yellow solid. m / z (ESI): 497.2 (M+H). + . 1H NMR(400MHz,クロロホルム-d)δ ppm 7.59(br d,J=9.0Hz,1H),7.36(dd,J=9.0,6.1Hz,1H),5.23-5.41(m,1H),4.34(d,J=10.5Hz,1H),4.22(s,1H),4.18(br d,J=4.6Hz,1H),3.29-3.39(m,2H),3.19-3.29(m,2H),3.13(br d,J=13.6Hz,1H),2.95-3.07(m,1H),2.26-2.41(m,1H),2.12-2.26(m,2H),1.92-2.03(m,4H),1.85-1.92(m,1H),1.52-1.80(m,7H).

[0283] Step 2: (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol. To a vial was added (R)-1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (0.24 g, 0.47 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (0.36 g, 0.71 mmol, Wu Xi) in 1,4-dioxane (4.3 mL) and water (0.4 mL). Potassium phosphate (0.33 g, 1.42 mmol, Sigma-Aldrich Corporation) and cataCXium A Pd G3 (69 mg, 0.09 mmol, Aldrich) were then added. The mixture was then stirred at 60° C. After 20 h, the reaction was concentrated, loaded onto a plug of silica gel, and purified by column chromatography on silica gel eluting with a gradient of 0-100% 3:1 EtOAc / EtOH in heptane to give (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (0.32 g, 0.40 mmol, 84% yield) as a brown solid. m / z(ESI):803.4(M+H) + .

[0284] Step 3: (R)-1-(8-fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol. To a vial was added (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (0.32 g, 0.40 mmol) in acetonitrile (4.0 mL) and HCl solution (4.0 M in dioxane, 1.0 mL, 3.96 mmol, Sigma-Aldrich Corporation). The mixture was stirred at 40° C. After 55 min, MeOH (3-5 mL) was added and the solution was concentrated in vacuo to give (R)-1-(8-fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (0.30 g, 0.40 mmol, 100% yield) as a light brown solid which was used in the next step without further purification. m / z (ESI): 759.3 (M+H). + .

[0285] Step 4: (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol. To a vial was added (R)-1-(8-fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (60 mg, 0.08 mmol) and cesium fluoride (36 mg, 0.24 mmol, Aldrich) in acetonitrile (0.8 mL) and N,N-dimethylformamide (0.2 mL). The mixture was stirred at 40° C. After 75 min, additional DMF (0.6 mL) and 3 equivalents of CsF were added and the temperature was increased to 60° C. After an additional 30 min, the reaction was diluted with saturated NaHCO3 (5 mL), extracted with EtOAc (3 x 5 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was adsorbed onto a plug of silica gel and purified by column chromatography on silica gel eluting with a gradient of 0-100% 3:1 EtOAc / EtOH (with 2% TEA) in heptane to give (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (30 mg, 0.05 mmol, 63% yield) as a bright yellow solid. m / z (ESI): 603.3 (M+H). + . 1H NMR(400MHz, methanol-d4)δ ppm 7.78-7.93(m,2H),7.27-7.36(m,2H),7.19-7.27(m,1H),7.11(dd,J=9. 2,2.4Hz,1H),5.17-5.45(m,1H),4.18-4.38(m,3H),4.03-4.17(m,1H),3 .51-3.63(m,1H),3.37-3.51(m,1H),3.14-3.29(m,3H),3.02(td,J=9.3, 5.7Hz,1H),2.11-2.45(m,4H),1.69-2.07(m,7H),1.27(d,J=8.1Hz,3H).

[0286] [Table 54]

[0287] [Table 55]

[0288] [Table 56]

[0289] 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one (Example 51) [ka] 7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-ol (30 mg, 0.06 mmol, intermediate C) was dissolved in N,N-dimethylformamide (0.4 mL), HATU (45 mg, 0.12 mmol, CombiBlocks Inc.), and DIPEA (30 mg, 41 μL, 0.24 mmol, Sigma-Aldrich Corporation) was added. The mixture was stirred at room temperature for 10 min. Then, 1,6-diazaspiro[3.5]nonan-2-one (8.3 mg, 0.06 mmol, Activate Scientific GmbH) was added, and the mixture was stirred at room temperature for 3 days. The crude mixture was purified by reverse phase HPLC to give 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one as its 2,2,2-trifluoroacetate salt (5.0 mg, 6.7 μmol, 11% yield). m / z(ESI): 632.2 (M+H). + . 1 H NMR(400MHz, methanol-d4)δ ppm 7.95(d,J=9.1Hz,1H),7.69(dd,J=9.0,6.1Hz,1H),7.45(t,J=7.8Hz,1H),7.28(d,J=2.5Hz,2H),6.97(d,J=1.9Hz,1H),5.64(br s,1H),4.70-4.78(m,1H),4.61-4.69(m,1H),4.15-4.31(m,2H),3.99-4.10(m,1H),3.86-3.98(m,3H),3.76-3.86(m,1H),3.50(br s,1H),2.87(d,J=14.9Hz,1H),2.75-2.83(m,1H),2.68(s,1H),2.59-2.64(m,1H),2.40-2. 50(m,3H),2.31-2.39(m,2H),2.09-2.24(m,2H),1.97-2.09(m,3H),0.79(t,J=7.4Hz,3H).

[0290] [Table 57]

[0291] [Table 58]

[0292] [Table 59]

[0293] [Table 60]

[0294] [Table 61]

[0295] [Table 62]

[0296] rac-(1S,5R)-8-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-8-azabicyclo[3.2.1]octan-2-ol (Example 55) [ka] Step 1: rac-(1R,2S,5S)-8-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-8-azabicyclo[3.2.1]octan-2-ol. To a solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-ol (0.10 g, 0.18 mmol, MOM-protected intermediate D) and DIPEA (57 mg, 76 μL, 0.44 mmol, Aldrich) in N,N-dimethylformamide (1.5 mL) was added HATU (67 mg, 0.18 mmol, CombiBlocks). The reaction was stirred at room temperature for 15 min and then exo-azabicyclo[3.2.1]octan-2-ol hydrochloride (24 mg, 0.15 mmol, PharmaBlock) was added. The reaction was stirred at room temperature for 16 h. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was separated and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a gradient of 0-100% 3:1 EtOAc / EtOH (with 2% TEA) in heptane to give rac-(1R,2S,5S)-8-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-8-azabicyclo[3.2.1]octan-2-ol as a colorless oil, which was used directly in the next step.

[0297] Step 2: rac-(1S,5R)-8-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-8-azabicyclo[3.2.1]octan-2-ol. To a solution of rac-(1R,2S,5S)-8-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-8-azabicyclo[3.2.1]octan-2-ol in acetonitrile (1.5 mL) was added HCl solution (4.0 M in dioxane, 0.4 mL, 1.47 mmol, Sigma-Aldrich Corporation). The reaction was stirred at room temperature. After 1 h, the reaction mixture was neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with a gradient of 0-100% 3:1 EtOAc / EtOH (with 2% TEA) in heptane to give rac-(1S,5R)-8-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-8-azabicyclo[3.2.1]octan-2-ol (69 mg, 0.11 mmol, 74% combined yield over two steps) as a white powder. m / z (ESI): 637.2 (M+H). + . 1H NMR(400MHz, methanol-d4)δ ppm 8.19(t,J=9.3Hz,1H),8.10(t,J=9.3Hz,1H),7.68(dd,J=9.1,6.0Hz,1H),7.22-7.31(m,2H),7.00(d,J=2.5Hz,1H),5.19-5.43(m,1H),5.07(br s,2H),4.29(dd,J=10.5,3.1Hz,1H),4.19-4.24(m,1H),3.91-3.95(m,1H),3.29-3.31(m,1H),3.16-3.27(m,3H),3.01(br d,J=5.2Hz,1H),2.58(br s,1H),2.37-2.50(m,3H),2.26(br s,1H),2.20(s,1H),1.96-2.16(m,6H),1.84-1.93(m,3H),1.68(br dd,J=15.4,5.1Hz,2H),0.82(td,J=7.4,1.9Hz,3H).

[0298] 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one (Examples 56, 57, 58, 59) [ka] Step 1: 7-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one. This compound was synthesized in a similar manner to Example 55 using 1-oxa-3,7-diazaspiro[4.5]decan-2-one (CAS number: 1308384-36-2, ChemSpace). m / z(ESI): 710.3(M+H) + .

[0299] Step 2: Chiral separation. 7-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one 2,2,2-trifluoroacetate (0.27 g, 0.33 mmol) was purified by SFC using a Chiralpak AD, 21×250 mm, 5 μm column with a mobile phase of 40% 2-propanol with 0.2% diethylamine using a flow rate of 80 mL / min to give 37 mg of peak 1 with an ee of >99%, 66 mg of peaks 2-3 with an ee of >90%, and 34 mg of peak 4. Purification of peaks 2–3 by SFC using an SS Whelk-O1, 21 × 250 mm, 5 μm column with a mobile phase of 40% methanol with 0.2% diethylamine using a flow rate of 80 mL / min yielded 25 mg of peak 2 with ee > 96% and 29 mg of peak 3 with ee > 96%.

[0300] Step 3: 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one. Isomers 1-4 were synthesized in a similar manner to Example 55 using peaks 1-4 from Step 2. Isomer 1, Example 56: Isolated as bis(2,2,2-trifluoroacetate). m / z(ESI): 666.0(M+H) + . 1H NMR(500MHz, methanol-d4)δ ppm 7.67-7.76(m,2H),7.33(d,J=2.5Hz,1H),7.28(t,J=9.3Hz,1H),7.01(d,J=2.2 Hz,1H),5.50-5.66(m,1H),4.74(d,J=12.5Hz,1H),4.59-4.67(m,2H),4.44(br d,J=13.4Hz,1H),3.83-4.10(m,3H),3.71(d,J=13.8Hz,1H),3.60-3.67(m,1H),3.42-3.56(m,3H),2.55-2.77(m,3H),2.45(br d, J = 7.8 Hz, 2H), 2.30-2.40 (m, 2H), 2.19 (br s, 3H), 2.00-2.08 (m, 1H), 1.87-1.96 (m, 1H), 0.83 (t, J = 7.4 Hz, 3H). Isolated as isomer 2, Example 57: bis(2,2,2-trifluoroacetate). m / z (ESI): 666.0 (M+H). + . 1 H NMR(500MHz, methanol-d4)δ ppm 7.66-7.77(m,2H),7.33(d,J=2.3Hz,1H),7.27(t,J=9.4Hz,1H),7.01(d, J=2.2Hz,1H),5.51-5.66(m,1H),4.72(s,1H),4.59-4.69(m,2H),4.48(br d,J=13.6Hz,1H),3.96-4.09(m,1H),3.89(br d, J = 15.1 Hz, 2H), 3.71 (d, J = 13.9 Hz, 1H), 3.54-3.64 (m, 1H), 3.39-3.52 (m, 3H), 2.58-2.77 (m, 2H), 2.32-2.57 (m, 5H), 2.15-2.28 (m, 3H), 1.99-2.08 (m, 1H), 1.85-1.94 (m, 1H), 0.82 (t, J = 7.4 Hz, 3H). Isomer 3, Example 58: Isolated as the bis(2,2,2-trifluoroacetate) salt. m / z (ESI): 666.0 (M+H) + . 1H NMR(500MHz, methanol-d4)δ ppm 7.66-7.80(m,2H),7.32(d,J=2.6Hz,1H),7.27(t,J=9.4Hz,1H),7.01(d,J=2.5Hz,1H),5.52-5.66(m,1H),4.67(s,3H),4.49(br d, J = 13.1 Hz, 1H), 3.97-4.11 (m, 1H), 3.82-3.96 (m, 2H), 3.70 (d, J = 13.9 Hz, 1H), 3.55-3.65 (m, 1H), 3.40-3.52 (m, 3H), 2.66-2.83 (m, 1H), 2.48-2.64 (m, 2H), 2.31-2.47 (m, 4H), 2.14-2.26 (m, 3H), 2.00-2.09 (m, 1H), 1.85-1.93 (m, 1H), 0.82 (t, J = 7.4 Hz, 3H). Isolated as isomer 4, Example 59: bis(2,2,2-trifluoroacetate). m / z (ESI): 666.0 (M+H). + . 1 H NMR(500MHz, methanol-d4)δ ppm 7.67-7.76(m,2H),7.32(d,J=2.6Hz,1H),7.27(t,J=9.3Hz,1H),7.00(d,J=2.5Hz,1H), 5.51-5.67(m,1H),4.66(s,3H),4.42-4.50(m,1H),3.97-4.12(m,1H),3.84-3.95(m,2H) ,3.60-3.75(m,2H),3.41-3.54(m,3H),2.66-2.82(m,1H),2.53-2.64(m,2H),2.32-2.48 (m,4H),2.12-2.26(m,3H),2.01-2.09(m,1H),1.86-1.94(m,1H),0.82(t,J=7.4Hz,3H).

[0301] 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 90). [ka] Step 1: Chiral SFC separation of MOM-protected intermediate D. 2.6 g of material was purified using a Chiralcel OD, 2×25 cm, 5 μm column with a mobile phase of 25% MeOH with 0.2% DEA using a flow rate of 120 mL / min to give peak 1 at 1.18 g with an ee of >99% and peak 2 at 1.34 g with an ee of 96%. Peak assignments were determined by SFC on a Chiralcel OD column using 25% MeOH with 0.2% DEA. m / z (ESI): 528.2 (M+H). + .

[0302] Step 2: 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol. To a mixture of peak 1 from above step (77 mg, 0.146 mmol) and N,N-diisopropylethylamine (0.13 mL, 0.73 mmol) in N,N-dimethylacetamide (0.7 mL) at room temperature was added HATU (0.11 g, 0.29 mmol). The solution was stirred for 10 min and then treated with (4S)-1-oxa-6-azaspiro[3.5]nonane (19 mg, 0.15 mmol, PharmaBlock) and stirred for 0.5 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried (Na2SO4), concentrated, and the residue was dissolved in THF (1.5 mL) and treated with 4M HCl / dioxane (1.5 mL). The mixture was stirred at room temperature for 4 h. The volatiles were removed in vacuo and the crude residue was purified on a silica gel column with 0-100% 2M NH3 in MeOH / DCM to give p-4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (40 mg, 0.062 mmol, 43% yield) as a light brown solid. 1H NMR(400MHz, methanol-d4)δ ppm 7.87-7.93(m,1H),7.68(dd,J=9.0,5.9Hz,1H),7.31(d,J=2.5Hz,1H),7.25(t,J=9.3Hz,1H ),7.01(d,J=2.7Hz,1H),5.41-5.61(m,1H),4.59-4.65(m,1H),4.49-4.59(m,4H),4.27(br d,J=13.5Hz,1H),3.82-3.94(m,1H),3.68-3.82(m,2H),3.62-3.68(m, 1H),3.34-3.43(m,2H),2.58-2.70(m,1H),2.45-2.58(m,4H),2.35-2.4 5(m,2H),2.22-2.33(m,3H),1.98-2.16(m,2H),1.85-1.95(m,1H),1.8 0(dt,J=13.4,3.6Hz,1H),0.81(t,J=7.4Hz,3H).m / z(ESI):637.1(M+H) + .

[0303] (2S,4s)-6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-azaspiro[3.5]nonan-2-ol (Example 91). [ka] To a solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-ol (MOM-protected intermediate D, 0.20 g, 0.35 mmol) in DMF (3.5 mL) was added HATU (0.20 g, 0.53 mmol) and DIPEA (0.18 mL, 1.1 mmol). The reaction mixture was stirred at room temperature for 10 min. 6-Azaspiro[3.5]-nonan-2-ol hydrochloride (75 mg, 0.42 mmol, Ambeed, Inc.) was added and the mixture was stirred at room temperature for 14 h. Water was 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 residue was dissolved in THF (1.5 mL) and treated dropwise with 4 M HCl / dioxane (1.5 mL). The mixture was stirred at room temperature for 4 h. The volatiles were removed in vacuo and the crude residue was purified by preparative HPLC (10%-90% MeCN / H2O with 0.1% TFA as modifier) ​​to give (2S,4S)-6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-azaspiro[3.5]nonane-2-ol bis(2,2,2-trifluoroacetate) (peak 1, 40 mg, 0.046 mmol, 13% yield). 1H NMR(400MHz, methanol-d4)δ ppm 7.79-7.86(m,1H),7.71(dd,J=8.9,5.8Hz,1H),7.34(d,J=2.5Hz,1H),7.28(t,J=9.3Hz,1H),7.03(d,J=2.3Hz,1H),5. 50-5.68(m,1H),4.72-4.83(m,2H),4.32(quin,J=6.4Hz,1H),3.82-4.19(m,8H),3.47(td,J=10.5,6.0Hz,1H),2.66(br s,3H),2.43-2.52(m,2H),2.33-2.42(m,2H),2.18-2.29(m,3H),1.84(br s,6H),0.85(t,J=7.3Hz,3H). 19 F NMR (376 MHz, methanol-d4) δ ppm -77.50 (s, 3 F), -116.53 (s, 1 F), -120.86 (s, 1 F), -125.80 (s, 1 F), -174.17 (s, 1 F). m / z (ESI): 651.3 (M+H) + .

[0304] 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-7-azaspiro[4.5]decan-2-one (Example 92). [ka] This compound was prepared in a similar manner as described for Example 91 using 1-oxa-7-azaspiro[4.5]decan-2-one (CAS number: 1315303-69-5, PharmaBlock). 1H NMR(500MHz, methanol-d4)δ ppm 7.70(br d,J=9.2Hz,2H),7.32(d,J=2.6Hz,1H),7.27(t,J=9.4Hz,1H),7.01(s,1H),5.50-5.64(m,1H),4.64- 4.70(m,1H),4.52-4.63(m,2H),4.42-4.52(m,1H),3.91-4.05(m,1H),3.79-3.90(m,2H),3.66-3.75( m,1H),3.55-3.63(m,1H),3.41-3.49(m,1H),2.66-2.79(m,3H),2.53-2.65(m,2H),2.29-2.48(m,4H) ),2.11-2.28(m,5H),1.96-2.07(m,2H),1.85-1.94(m,1H),0.79-0.86(m,3H).m / z(ESI):655.2(M+H) + .

[0305] (5R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3-dioxa-7-azaspiro[4.5]decan-2-one (Example 93). [ka] This compound was prepared using 1,3-dioxa-7-azaspiro[4.5]decan-2-one (CAS number: 2386032-05-7, Enamine) in a similar manner as described for Example 91. Chiral separation was performed before the deprotection step. The sample was purified by SFC on a Chiralpak IC, 2×25 cm, 5 μm column with a mobile phase of 50% IPrOH with 0.2% DEA using a flow rate of 80 mL / min, giving 46 mg of peaks 1 and 2 and 44 mg of peaks 3 and 4. Peak assignments were determined by SFC on a Chiralpak IC column using 50% iPrOH with 0.2% DEA. Step 2: The sample was purified by SFC using a (S,S)Whelk-O, 2 x 25 cm, 5 μm column with a mobile phase of 45% iPrOH with 0.2% DEA using a flow rate of 80 mL / min to give 20 mg of peak 1 with an ee of 99% and 20 mg of peak 2 with an ee of 99%. Peak 2 gave the desired product. 1 H NMR(400MHz, methanol-d4)δ ppm 7.68-7.75(m,2H),7.23-7.35(m,2H),7.01(d,J=2.30Hz,1H),5.51-5. 67(m,1H),4.67(s,3H),4.25-4.52(m,3H),3.75-4.12(m,4H),3.62-3. 73(m,1H),3.44-3.52(m,1H),2.48-2.86(m,3H),2.31-2.47(m,4H),2. 03-2.27(m,4H),1.86-1.99(m,1H),0.81(s,3H).m / z(ESI):667.2(M+H) + .

[0306] (5S)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide (Example 94). [ka] This compound was prepared using 21λ6-thia-7-azaspiro[4.5]decane-2,2-dione hydrochloride in a similar manner as described for Example 91. Chiral separation was performed prior to the deprotection step. The sample was purified by SFC using a Chiralcel OJ, 2×25 cm, 5 μm column with a mobile phase of 20% EtOH with 0.2% DEA using a flow rate of 80 mL / min to give peaks 1 and 2 at 164 mg with an ee of 91%, peak 3 at 31 mg with an ee of 91%, and peak 4 at 30 mg with an ee of 95%. Peak 4 gave the desired product. 1 H NMR (400MHz, methanol-d4) δ ppm 7.73-7.80(m,1H), 7.67-7.73(m,1H), 7.31-7.35(m,1H), 7.23-7.31(m,1H), 6.96-7.04(m,1H), 5.49-5.69(m,1H), 4.55-4.78(m,3H), 4.26-4.39(m,1H), 3.97-4.13(m,1H), 3 .76-3.96(m,3H),3.59-3.68(m,1H),3.40-3.54(m,2H),2.99-3.07(m,1H),2.53-2.83( m,3H),2.07-2.52(m,8H),1.75-2.06(m,5H),0.79-0.86(m,3H).m / z(ESI):699.2(M+H) + .

[0307] (R)-1-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (Example 60) [ka] Step 1. (8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)quinazolin-7-yl)boronic acid. A 40 mL vial was charged with (R)-1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (0.50 g, 1.01 mmol, from Example 1), bis(pinacolato)diboron (0.41 g, 1.61 mmol, Sigma-Aldrich Corporation), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.15 g, 0.20 mmol, Sigma-Aldrich Corporation), and potassium acetate (0.35 g, 3.52 mmol, Sigma-Aldrich Corporation), followed by toluene (10 mL). The resulting mixture was stirred at 90° C. for 1 hour. The crude mixture was filtered through a layer of Celite and the filter cake was washed with EtOAc. The filtrate was concentrated in vacuo to give crude (8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)quinazolin-7-yl)boronic acid, which was used directly in the next step without further purification. m / z(ESI): 463.0(M+H). + .

[0308] Step 2. (R)-1-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol. A vial was charged with SPhos Pd G3 (30 mg, 35 μmol, Strem Chemicals, Inc.), potassium carbonate (60 mg, 0.43 mmol), (8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)quinazolin-7-yl)boronic acid (80 mg, 0.17 mmol), 3,5-dichloro-4-(trifluoromethyl)benzenamine hydrochloride (69 mg, 0.26 mmol, CAS number: 1432795-16-8, AstaTech, Inc), water (0.7 mL) and 1,4-dioxane (3.6 mL). The reaction was stirred at 95° C. for 1 h. The crude mixture was filtered through a plug of Celite. The filtrate was concentrated under reduced pressure and purified by reverse phase HPLC to give (R)-1-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol as the bis(2,2,2-trifluoroacetate) (30 mg, 36 μmol, 21% yield) as an off-white solid. m / z(ESI): 612.0 (M+H). + . 1H NMR (400MHz, methanol-d4) δ ppm 8.04-8.13(m,1H),7.29-7.39(m,1H),6.92(d,J=1.7Hz,1H),6.40-6.47(m,1 H),5.49-5.69(m,1H),4.72-4.76(m,2H),4.54-4.65(m,1H),4.30-4.40(m,1H ),3.84-4.09(m,3H),3.59-3.67(m,1H),3.41-3.54(m,2H),2.56-2.80(m,2H) ,2.30-2.49(m,3H),2.10-2.26(m,2H),1.76-1.92(m,3H),1.27-1.35(m,3H).

[0309] 4-Bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-yl pivalate (Intermediate I) [ka] Step 1. 8-Bromo-1-ethyl-1,2,3,4-tetrahydronaphthalen-1-ol. To a 50 mL round bottom flask was added 8-Bromo-3,4-dihydronaphthalen-1(2H)-one (0.72 g, 3.2 mmol, Ambeed, Inc.) and lanthanum(III) chloride bis(lithium chloride) complex solution (0.6 M in THF, 5.3 mL, 3.2 mmol, Sigma-Aldrich Corporation) in THF (12.8 mL). Ethylmagnesium bromide (3.0 M in diethyl ether, 1.3 mL, 3.84 mmol) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 h, then diluted with saturated NH4Cl 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 chromatography through a silica gel column (12 g) eluting with a gradient of 0-50% EtOAc in heptane to give 8-bromo-1-ethyl-1,2,3,4-tetrahydronaphthalen-1-ol (0.71 g, 2.78 mmol, 87% yield) as a yellow oil. LC / MS: m / z (ESI): 237.2 (M+H-H2O). + .

[0310] Step 2. 8-Bromo-1-ethyl-1,2,3,4-tetrahydronaphthalene. To a 25 mL round bottom flask was added 8-Bromo-1-ethyl-1,2,3,4-tetrahydronaphthalen-1-ol (0.48 g, 1.89 mmol) in DCM (7.5 mL). Triethylsilane (1.1 g, 9.4 mmol) was added at -30°C, followed by TFA (0.44 mL, 5.64 mmol). The reaction mixture was stirred from -30°C to room temperature for 3 hours, then 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 chromatography through a silica gel column (12 g) eluting with a gradient of 0-20% EtOAc in heptane to give 8-bromo-1-ethyl-1,2,3,4-tetrahydronaphthalene (0.39 g, 1.63 mmol, 87% yield) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ ppm 7.35-7.48(m,1H),7.29-7.58(m,2H),2.64-2.89(m,3H),1.84-2.04(m,1H),1.52-1.85(m,4H),1.30-1.45(m,1H),0.95 - 1.05(m,3H)LC / MS:m / z(ESI):237.2(M+H) + .

[0311] Step 3. 2-(4-Bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A 20 mL vial was charged with 8-bromo-1-ethyl-1,2,3,4-tetrahydronaphthalene (0.21 g, 0.88 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.32 mL, 2.2 mmol), 4,4'-di-tert-butyl-2,2'-dipyridyl (28 mg, 0.11 mmol), and di-μ-methoxobis(1,5-cyclooctadiene)diiridium(I) (58 mg, 0.088 mmol, Sigma-Aldrich Corporation). The reaction mixture was purged with nitrogen for 5 minutes and then stirred at 65° C. for 3 hours. After cooling to room temperature, the reaction mixture was concentrated and the crude material was purified by chromatography through a silica gel column (12 g) eluting with a gradient of 0-70% EtOAc in hexanes to give 2-(4-bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.20 g, 0.55 mmol, 62% yield) as a colorless oil. LC / MS: m / z (ESI): 365.2 (M+H). + .

[0312] Step 4. 4-Bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol. A 50 mL round bottom flask was charged with 2-(4-bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.20 g, 0.55 mmol) in tetrahydrofuran (1.6 mL) and water (0.55 mL). Hydrogen peroxide (0.5 mL, 4.93 mmol) was added slowly at 0° C., followed by acetic acid (1.6 mL, 27.4 mmol). The reaction mixture was stirred for 3 h, then diluted with saturated Na2S2O3 and extracted with EtOAc. The organic layer was concentrated and the crude material was purified by chromatography through a silica gel column (12 g) eluting with a gradient of 0-50% EtOAc in hexanes to give 4-bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol (0.12 g, 0.47 mmol, 86% yield). LC / MS: m / z (ESI): 255.0 (M+H). + .

[0313] Step 5. 4-Bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-yl pivalate. To a 50 mL round bottom flask was added 4-bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol (0.12 g, 0.47 mmol) and triethylamine (0.16 mL, 0.94 mmol) in tetrahydrofuran (2.4 mL). 2,2-Dimethylpropionyl chloride (87 μL, 0.71 mmol) was added slowly at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The crude material was purified by chromatography through a silica gel column (12 g) eluting with a gradient of 0-25% EtOAc in hexanes to give 4-bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-yl pivalate (0.12 g, 0.35 mmol, 75% yield). LC / MS: m / z(ESI): 339.0(M+H) + .

[0314] 4-Bromo-5-methyl-5,6,7,8-tetrahydronaphthalen-2-yl pivalate (Intermediate J). [ka] This intermediate was made in a similar manner to intermediate I, using MeMgBr instead of EtMgBr in the first step. LC / MS: m / z (ESI): 325.0 (M+H). + .

[0315] (3R)-1-(7-(8-ethyl-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (Example 95). [ka] This compound was prepared in a similar manner as described for Example 60 using Intermediate I. 1 H NMR(400MHz, methanol-d4)δ ppm 7.97-8.23(m,1H),7.19-7.52(m,1H),6.58-6.73(m,1H),6.34-6.55(m,1H),5.51-5.81(m,1H),4.65-4.79(m,2H),4.48-4.60(m ,1H),4.20-4.45(m,1H),3.80-4.14(m,3H),3.42-3.69(m,3H),2.32-2.89(m,8H),2.07-2.27(m,2H),1.67-1.93(m,7H),1.30(br s,5H),0.35-0.57(m,3H).m / z(ESI):593.4(M+H) + .

[0316] (3R)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxy-8-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol (Example 96). [ka] This compound was prepared in a similar manner as described for Example 60 using Intermediate J. 1 H NMR(400MHz, methanol-d4)δ ppm 7.95-8.33(m,1H),7.16-7.44(m,1H),6.63(s,1H),6.33-6.51(m,1H),5.36-5.77(m,1H),4.65-4.76(m,2H) ),4.41-4.58(m,1H),4.21-4.34(m,1H),3.78-4.10(m,3H),3.57-3.71(m,1H),3.42-3.54(m,2H),2.82(br m / z(ESI):579.2(M+H) + .

[0317] (3R)-1-(7-(3-amino-8-ethyl-7-fluoronaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (Example 61 and Example 62) [ka] Step 1: 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-yl trifluoromethanesulfonate. A vial was charged with (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (0.83 g, 1.32 mmol, Example 2) and DIPEA (0.18 g, 0.24 mL, 1.39 mmol, Aldrich) in DCM (13 mL). The solution was then cooled to 0° C. and trifluoromethanesulfonic anhydride (1.32 mL, 1.32 mmol, Aldrich) was added dropwise. After 20 min, the reaction was quenched with saturated NH4Cl (15 mL), extracted with DCM (3×15 mL), dried over MgSO4, filtered and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by column chromatography on silica gel eluting with a gradient of 0-100% 3:1 EtOAc / EtOH in heptane to give 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-yl trifluoromethanesulfonate (0.45 g, 0.60 mmol, 45% yield) as a bright yellow solid. m / z (ESI): 757.2 (M+H). + .

[0318] Step 2: (3R)-1-(7-(3-amino-8-ethyl-7-fluoronaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol. To a vial was added 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-yl trifluoromethanesulfonate (0.45 g, 0.60 mmol) and benzophenone imine (0.16 g, 0.15 mL, 0.89 mmol, Sigma-Aldrich Corporation) in 1,4-dioxane (6.0 mL). To this mixture was then added cesium carbonate (0.39 g, 1.19 mmol, Aldrich), followed by methanesulfonato[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2'-amino-1,1'-biphenyl]palladium(II) DCM adduct (61 mg, 0.06 mmol, Strem Chemicals, Inc.). The reaction was then stirred at 60°C. After 1 h, the temperature was increased to 75°C. After an additional 1 h, the reaction was cooled to room temperature and hydrochloric acid (1N in water, 3.0 mL, 2.97 mmol, Fisher) was added. The mixture was left stirring at room temperature for 20 min. The reaction was poured into saturated NaHCO3 (20 mL), extracted with EtOAc (3 x 15 mL), dried over MgSO4, filtered and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by column chromatography on silica gel eluting with a gradient of 0-100% 3:1 EtOAc / EtOH (with 2% TEA) in heptane to give (3R)-1-(7-(3-amino-8-ethyl-7-fluoronaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (0.32 g, 0.52 mmol, 87% yield) as a yellow solid. m / z (ESI): 624.3 (M+H).+ .

[0319] Step 3: Chiral separation. A 70 mg sample was purified by SFC using a Chiralcel OJ, 21×250 mm, 5 μm column with a mobile phase of 20% MeOH using a flow rate of 100 mL / min to give 19 mg of peak 1 with an ee of >99% and 20 mg of peak 2 with an ee of >99%. Peak 1 (Example 61): m / z (ESI): 624.3 (M+H) + . 1 H NMR(400MHz, methanol-d4)δ ppm 7.76(dd,J=9.8,1.7Hz,1H),7.59(dd,J=9.0,5.9Hz,1H),7.15-7.24(m,2H),6.95(d,J=2.3Hz,1H),5.18-5.46(m,1H),4.17-4.36(m,3H),4.05(br d,J=13.2Hz,1H),3.39-3.58(m,2H),3.15-3.31(m,3H),3.02(td,J=9.4,5.7Hz,1H),2.47-2.64(m,1H),2.1 2-2.47(m,5H),1.72-2.05(m,6H),1.28(s,3H),0.81(t,J=7.3Hz,3H).Peak 2 (Example 62): m / z(ESI):624.3(M+H) + . 1 H NMR(400MHz, methanol-d4)δ ppm 7.79(dd,J=9.8,1.7Hz,1H),7.59(dd,J=9.2,5.9Hz,1H),7.15-7.22(m,2H),6.95(d, J=2.5Hz,1H),5.16-5.48(m,1H),4.27-4.35(m,1H),4.17-4.27(m,2H),4.05(d,J=13 .0Hz,1H),3.39-3.51(m,2H),3.16-3.31(m,3H),3.02(td,J=9.3,5.9Hz,1H),2.50-2 .63(m,1H),2.09-2.49(m,5H),1.70-2.07(m,6H),1.31(s,3H),0.82(t,J=7.4Hz,3H).

[0320] [Table 63]

[0321] [Table 64]

[0322] [Table 65]

[0323] (3R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (Examples 66 and 67) [ka] Step 1: (3R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol. To a 10 mL round bottom flask was added 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl trifluoromethanesulfonate (60 mg, 0.07 mmol, synthesized in a manner similar to that described in Example 61) and triethylsilane (15 mg, 21 μL, 0.13 mmol, Sigma-Aldrich Corporation) in N,N-dimethylformamide (0.7 mL). To this solution was then added methanesulfonato[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2'-amino-1,1'-biphenyl]palladium(II) DCM adduct (6.8 mg, 6.60 μmol, Strem Chemicals, Inc.) and the reaction was stirred at 60° C. After 20 minutes, the reaction was cooled to room temperature and cesium fluoride (70 mg, 0.46 mmol, Aldrich) was added and the reaction was stirred at 50° C. After 30 min, the reaction was loaded directly onto a plug of silica gel and purified by column chromatography on silica gel eluting with a gradient of 0-100% 3:1 EtOAc / EtOH in heptane to give (3R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (39 mg, 0.06 mmol, 96% yield) as a rust-colored solid. m / z (ESI): 605.2 (M+H). + .

[0324] Step 2: Chiral separation. (3R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (39 mg, 0.06 mmol) was purified by SFC using a ChiralPak IC, 2×25 cm, 5 μm column with a mobile phase of 45% MeOH with 0.2% DEA using a flow rate of 80 mL / min to give 11 mg of peak 1 with an ee of 99% and 11 mg of peak 2 with an ee of 98%. Peak 1 (isomer 1, Example 66): m / z (ESI): 605.2 (M+H) + . 1 H NMR(400MHz, methanol-d4)δ ppm 8.06-8.17(m,2H),7.62-7.73(m,2H),7.56(d,J=7.0Hz,1H),7.45(t,J=9.0Hz,1H),5.18-5.51( m,1H),4.18-4.41(m,3H),4.01-4.11(m,1H),3.52(d,J=13.5Hz,1H),3.35-3.47(m,2H),3.24(br dd. + . 1 H NMR(400MHz, methanol-d4)δ ppm 8.08-8.15(m,2H),7.62-7.70(m,2H),7.55-7.61(m,1H),7.45(t,J=8.9Hz,1H),5.19-5.45(m,1H),4.19-4.36(m,3H),4.10(br d,J=13.3Hz,1H),3.44-3.52(m,2H),3.30(br d,J=3.1Hz,1H),3.14-3.28(m,3H),3.02(td,J=9.2,5.6Hz,1H),2.11-2.45(m,4H),1.70-2.09(m,6H),1.27(s,3H).

[0325] 7-(3-amino-8-ethyl-7-fluoronaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-ol (Intermediate E) [ka] To a vial was added (3R)-1-(7-(3-amino-8-ethyl-7-fluoronaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (0.25 g, 0.40 mmol, Example 61) and lithium hydroxide (88 mg, 3.69 mmol, Aldrich) in water (2.5 mL) and MeOH (4.9 mL). The reaction was then stirred at 80° C. After 3 h, additional lithium hydroxide (88 mg, 3.69 mmol, Aldrich) was added and the reaction was stirred at 80° C. for an additional 1.5 h. The reaction was diluted with H2O (10 mL). The volatiles were removed in vacuo. The aqueous layer was extracted with EtOAc (3×10 mL), dried over MgSO4, filtered and concentrated to give crude 7-(3-amino-8-ethyl-7-fluoronaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-ol (0.21 g, 0.40 mmol, 99% yield) as a brown solid which was used in the next step without further purification. m / z (ESI): 527.2 (M+H). + .

[0326] 7-(3-amino-8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-ol (Intermediate F) [ka] Synthesized in a similar manner to intermediate E using 7-bromo-2,4-dichloro-8-fluoroquinazoline (Enamine). m / z (ESI): 509.1 (M+H) + .

[0327] 7-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-ol (Intermediate G) [ka] Synthesized in the same manner as intermediate E. m / z (ESI): 523.2 (M+H) + .

[0328] 1-(7-(3-amino-8-ethyl-7-fluoronaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-(difluoromethyl)piperidin-3-ol (Example 68) [ka] To a vial was added 7-(3-amino-8-ethyl-7-fluoronaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-ol (50 mg, 0.10 mmol, intermediate E), DIPEA (49 mg, 66 μL, 0.38 mmol, Sigma-Aldrich Corporation) and N,N-dimethylacetamide (1.0 mL). HATU (43 mg, 0.11 mmol, Combi-Blocks Inc.) was then added and the mixture was stirred at room temperature for 30 minutes before adding 3-(difluoromethyl)piperidin-3-ol hydrochloride (23 mg, 0.12 mmol, Enamine). The reaction was left stirring at room temperature overnight. The crude material was then loaded directly onto a plug of silica gel and purified by column chromatography on silica gel eluting with a gradient of 0-100% 3:1 EtOAc / EtOH in heptane to give 1-(7-(3-amino-8-ethyl-7-fluoronaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-(difluoromethyl)piperidin-3-ol (35 mg, 0.05 mmol, 56% yield) as a bright yellow solid. m / z (ESI): 660.1 (M+H). + . 1 H NMR (400MHz, methanol-d4) δ ppm 7.71-7.82 (m, 1H), 7.59 (dd, J=9.0, 5.9Hz, 1H), 7.14-7.23 (m, 2H), 6.90-6.98 (m, 1H), 5.59-5.96 (m, 1H), 5.17-5.44 (m, 1H), 4.35-4.44 (m, 1H), 4.19-4.35 (m, 3H), 3.48-3.63 (m, 1 H),3.34-3.40(m,1H),3.16-3.32(m,3H),2.97-3.05(m,1H),2.48-2.64(m,1H),2.35-2.4 8(m,1H),2.12-2.33(m,4H),1.95-2.06(m,2H),1.80-1.95(m,4H),0.81(q,J=7.1Hz,3H).

[0329] [Table 66]

[0330] [Table 67]

[0331] [Table 68]

[0332] [Table 69]

[0333] [Table 70]

[0334] [Table 71]

[0335] [Table 72]

[0336] 4-Bromo-6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Intermediate K). [ka] Step 1. 4-Bromo-6-chloro-1-(triisopropylsilyl)-1H-indazole. A vial was charged with 4-bromo-6-chloro-1H-indazole (2.00 g, 8.64 mmol, CombiBlocks Inc.) and tetrahydrofuran (3.0 mL). The reaction mixture was then cooled to -78°C. LiHMDS (1.0 M in THF, 10.4 mL, 10.4 mmol) was added dropwise and the mixture was stirred at -78°C for 20 minutes. Triisopropylchlorosilane (2.00 g, 2.2 mL, 10.4 mmol) was added dropwise and the mixture was stirred at -78°C for 20 minutes and then warmed to room temperature. Upon completion (as indicated by TLC), the reaction was carefully quenched by adding water. The aqueous layer was extracted with EtOAc and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0-2% (3:1 EtOAc / EtOH) in heptane to give 4-bromo-6-chloro-1-(triisopropylsilyl)-1H-indazole (2.75 g, 7.09 mmol, 82% yield) as an orange solid. m / z (ESI): 231.0 / 233.0 (M-TIPS+H). + . 1 H NMR(400MHz,DMSO-d6)δ ppm 8.34-8.39(m,1H),7.67-7.70(m,1H),7.51-7.55(m,1H),1.70-1.88(m,3H),1.08(d,J=7.46Hz,18H).

[0337] Step 2. 4-Bromo-6-chloro-5-iodo-1-(triisopropylsilyl)-1H-indazole. A vial was charged with 4-bromo-6-chloro-1-(triisopropylsilyl)-1H-indazole (2.00 g, 5.16 mmol) and tetrahydrofuran (26 mL) under nitrogen. The reaction mixture was then cooled to -78°C. LDA (1.0 M in THF, 6.7 mL, 6.7 mmol) was added dropwise and the reaction mixture was stirred at -78°C for 1 h. A solution of iodine (1.70 g, 6.70 mmol) in THF (1.0 mL) was then added dropwise and the reaction was allowed to warm to room temperature with stirring as monitored by LCMS. Upon completion, the reaction was quenched with 10% aqueous sodium thiosulfate solution. The aqueous layer was extracted with DCM and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. TFA (2.0 mL) was added dropwise to the DCM layer and the mixture was stirred until TIPS deprotection was complete as indicated by TLC. The organic layer was concentrated under reduced pressure and the crude material was purified by reverse phase chromatography to give 4-bromo-6-chloro-5-iodo-1H-indazole (0.81 g, 2.27 mmol, 44% yield) as an off-white solid. m / z (ESI): 356.8 / 358.8 (M+H). + .

[0338] Step 3. 4-Bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. A vial was charged with 4-bromo-6-chloro-5-iodo-1H-indazole (1.00 g, 2.80 mmol), 4-methylbenzenesulfonic acid (24 mg, 0.14 mmol), 3,4-dihydro-2H-pyran (0.71 g, 0.77 mL, 8.39 mmol) and dichloromethane (14 mL). The reaction mixture was monitored by LCMS while stirring at room temperature. Upon completion, the reaction was concentrated under reduced pressure. The crude residue was dissolved in DMSO (2×4.0 mL) and purified by reverse phase chromatography to give 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.10 g, 2.49 mmol, 89% yield) as an off-white solid. m / z (ESI): 440.8 / 442.8 (M+H). + .

[0339] Step 4. 4-Bromo-6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. A vial was charged with 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.50 g, 1.13 mmol), cyclopropylboronic acid (0.29 g, 3.40 mmol), potassium phosphate tribasic (0.87 g, 4.10 mmol, CombiBlocks), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride (83 mg, 0.11 mmol), 1,4-dioxane (4.7 mL) and water (1.0 mL) under nitrogen. The mixture was heated to 100° C. and monitored by LCMS. Upon completion, the crude reaction was purified by reverse phase chromatography to give 4-bromo-6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.16 g, 0.46 mmol, 40% yield) as an orange residue. LCMS m / z (ESI): 354.9 / 357.0 (M+H). + .

[0340] (Z)-4-Bromo-6-chloro-5-(prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Intermediate L). [ka] A vial was charged with (Z)-4,4,5,5-tetramethyl-2-(prop-1-en-1-yl)-1,3,2-dioxaborolane (0.25 g, 0.28 mL, 1.47 mmol, AstaTech), 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.50 g, 1.13 mmol, step 3 of intermediate K), potassium phosphate tribasic (0.84 g, 3.96 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride (83 mg, 0.11 mmol), water (0.8 mL) and 1,4-dioxane (3.8 mL). The reaction mixture was monitored by LCMS while heating to 100° C. Upon completion, the crude material was purified by reverse phase chromatography to give (Z)-4-bromo-6-chloro-5-(prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.23 g, 0.65 mmol, 57% yield) as an orange oil. m / z (ESI): 270.8 / 272.8 (M-THP+H). + .

[0341] (Z)-6-Chloro-5-(prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Intermediate M). [ka] Intermediate L (1.00 g, 2.81 mmol) was dissolved in THF (14 mL) in a flask and the solution was cooled to -78 °C. n-Butyl lithium (2.5 M in hexanes, 1.7 mL, 4.22 mmol) was added dropwise and the mixture was stirred at -78 °C for 10 min. Then, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.79 g, 0.86 mL, 4.22 mmol) was added dropwise and the mixture was stirred at -78 °C for 90 min. Saturated aqueous NH4Cl (10 mL) was added and the mixture was allowed to warm to room temperature. The aqueous layer was extracted with EtOAc (3 × 15 mL) and the combined organic layers were dried over Na2SO4, filtered and the volatiles were removed in vacuo. The residue was purified by reverse phase chromatography eluting with a gradient of 5-100% MeCN / H2O with 0.1% TFA. Saturated aqueous NaHCO3 (20 mL) was added to the product-containing fractions and the resulting aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4 and the volatiles removed in vacuo to give (Z)-6-chloro-5-(prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (0.55 g, 1.37 mmol, 49% yield). m / z (ESI): (M+H) + =403.0.

[0342] rel-((1R,2S)-2-Methylcyclopropyl)boronic acid (intermediate N). [ka] Step 1: rel-4,4,5,5-tetramethyl-2-((1R,2S)-2-methylcyclopropyl)-1,3,2-dioxaborolane. To a cooled solution of dichloromethane (19.8 mL) in a 100 mL round bottom flask was added diethylzinc (1.0 M in hexanes, 10.4 mL, 10.4 mmol). The mixture was stirred at 0° C. for 10 min, then diiodomethane (2.79 g, 0.84 mL, 10.41 mmol) was added dropwise. The reaction mixture was stirred at this temperature for 25 min, then a pre-cooled solution of (Z)-4,4,5,5-tetramethyl-2-(prop-1-en-1-yl)-1,3,2-dioxaborolane (0.50 g, 3.00 mmol, Advanced ChemBlocks Inc.) in dichloromethane (10 mL) was added via cannula transfer. The reaction was then stirred at 0° C. for 40 min and then at room temperature for 3.5 h. The reaction was quenched by the addition of a chilled solution of 1N HCl (50 mL). The mixture was then transferred to a separatory funnel using dichloromethane (50 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting orange oil was then filtered through a short plug of silica gel (eluting with DCM) to give rel-4,4,5,5-tetramethyl-2-((1R,2S)-2-methylcyclopropyl)-1,3,2-dioxaborolane (0.27 g, 1.46 mmol, 49% yield) as a clear oil. 1 H NMR (400 MHz, chloroform-d) δ ppm 1.26 (s, 6H), 1.25 (s, 6H), 1.13-1.18 (m, 3H), 1.04-1.13 (m, 1H), 0.74-0.83 (m, 1H), 0.38 (dt, J = 3.45, 1.62 Hz, 1H), -0.08 (d, J = 6.90 Hz, 1H).

[0343] Step 2: rel-((1R,2S)-2-methylcyclopropyl)boronic acid. Sodium (meta)periodite (0.91 g, 4.30 mmol, Sigma-Aldrich Corporation) was added to a solution of rel-4,4,5,5-tetramethyl-2-((1R,2S)-2-methylcyclopropyl)-1,3,2-dioxaborolane (0.26 g, 1.40 mmol) in tetrahydrofuran (10 mL) and water (2.6 mL) at room temperature. The reaction mixture was stirred for 30 min and then 2N HCl (0.47 mL, 0.94 mmol) was added. The mixture was stirred for 12 h and then diluted with water (15 mL). The aqueous layer was extracted with EtOAc (3×15 mL). The combined organic layers were then dried over sodium sulfate, filtered, and concentrated under reduced pressure to give rel-((1R,2S)-2-methylcyclopropyl)boronic acid (0.10 g, 1.04 mmol, 74% yield) as a light pink oil. 1 H NMR (400 MHz, methanol-d4) δ ppm 1.00-1.13 (m, 4H), 0.61-0.74 (m, 1H), 0.28-0.37 (m, 1H), -0.06-0.06 (m, 1H).

[0344] 6-Chloro-5-((1S,2R)-2-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (intermediate O). [ka] Step 1: rel-4-bromo-6-chloro-5-((1S,2R)-2-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. A vial was charged with 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.0 g, 2.3 mmol, intermediate K, step 3), rel-((1R,2S)-2-methylcyclopropyl)boronic acid (0.41 g, 4.10 mmol, intermediate N), potassium phosphate tribasic (1.70 g, 7.90 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride (0.17 g, 0.23 mmol), water (1.5 mL) and 1,4-dioxane (7.5 mL). The reaction mixture was heated to 100° C. Upon completion of the reaction, the crude material was purified by reverse phase chromatography to give rel-4-bromo-6-chloro-5-((1R,2S)-2-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.40 g, 1.10 mmol, 48% yield) as an orange oil. m / z (ESI): 369.0 (M+H). + .

[0345] Step 2: 6-chloro-5-((1S,2R)-2-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. rel-4-Bromo-6-chloro-5-((1R,2S)-2-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.20 g, 3.30 mmol) was dissolved in THF (16 mL) and cooled to -78°C. n-Butyl lithium (2.0 mL, 4.90 mmol) was added dropwise and the reaction mixture was stirred at -78°C for 10 minutes. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.90 g, 1.00 mL, 4.90 mmol) was then added dropwise and the reaction mixture was stirred for 90 min. The reaction was quenched with saturated aqueous NH4Cl (20 mL) and allowed to warm to room temperature. The aqueous phase was extracted with EtOAc (3 x 20 mL) and the combined organic layers were dried over Na2SO4, filtered and the volatiles removed in vacuo. The residue was purified by reverse phase column chromatography to give rel-6-chloro-5-((1R,2S)-2-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-indazole (0.74 g, 1.80 mmol, 55% yield). m / z (ESI): 417.2 (M+H) + .

[0346] The sample (9.5 g) was purified by SFC using a Chiralpak AD, 30 x 250 mm, 5 μm column with a mobile phase of 20% 2-propanol using a flow rate of 150 mL / min to give peak 1 at 3.58 g with an ee of >99% and peak 2 at 5.02 g with an ee of >99%. Peak 2 gave the desired isomer.

[0347] (Z)-6-Methyl-5-(prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Intermediate P). [ka] Step 1: (Z)-4-Bromo-6-methyl-5-(prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. A vial was charged with potassium phosphate tribasic (3.53 g, 16.6 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride (0.35 g, 0.48 mmol), 4,4,5,5-tetramethyl-2-[(z)-prop-1-enyl]-1,3,2-dioxaborolane (1.1 mL, 5.7 mmol, PharmaBlock), 4-bromo-5-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.00 g, 4.75 mmol), water (3.2 mL) and 1,4-dioxane (16 mL). The reaction mixture was then heated to 100° C. After 1 h, the reaction was concentrated under reduced pressure. The crude material was purified by chromatography through an 80 g silica gel column eluting with a gradient of 0-20% EtOAc in heptane to give (Z)-4-bromo-6-methyl-5-(prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.20 g, 3.59 mmol, 76% yield) as a clear oil. m / z (ESI): 335.0 (M+H). + .

[0348] Step 2: (Z)-6-Methyl-5-(prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. (Z)-4-Bromo-6-methyl-5-(prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.03 g, 3.08 mmol) was dissolved in tetrahydrofuran (40 mL) and cooled to −78° C. n-Butyl lithium (2.5 M in hexanes, 1.9 mL, 4.6 mmol) was added dropwise and the mixture was stirred at −78° C. for 12 minutes. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.1 mL, 5.6 mmol, Sigma-Aldrich Corporation) was then added dropwise and the mixture was stirred at -78 °C for 1.5 h when saturated aqueous NH4Cl was added. The mixture was allowed to warm to room temperature and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the volatiles removed in vacuo. The residue was purified by column chromatography on silica gel (40 g) using a gradient of 0-20% EtOAc in heptane to give (Z)-6-methyl-5-(prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (0.67 g, 1.75 mmol, 57% yield) as a white solid. m / z(ESI): 383.2(M+H) + .

[0349] (S)-6-(7-Bromo-2-chloro-8-fluoroquinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (Intermediate Q). [ka] To a suspension of 7-bromo-2,4-dichloro-8-fluoroquinazoline (3.71 g, 12.5 mmol, PharmaBlock) and 1-oxa-6-azaspiro[3.5]nonane hydrochloride (2.05 g, 12.5 mmol, Enamine) in acetonitrile (50 mL) at 0° C., 1,1′-dimethyltriethylamine (6.6 mL, 37.6 mmol) was added. The reaction mixture was stirred at 0° C. for 15 min. The solid formed was collected by filtration, washed with acetonitrile and dried to give pure 6-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (3.97 g, 10.3 mmol, 82% yield) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 7.93(dd,J=9.2,1.5Hz,1H),7.77(dd,J=9.0,6.7Hz,1H),4.35-4.43(m,2H),4.26(d,J=13.4Hz,1H),4.00-4.08(m,1H),3.76(d,J=13. 2Hz,1H),3.32-3.49(m,1H),2.30-2.39(m,2H),2.03-2.13(m,1H),1.79-1.90(m,2H),1.64-1.75(m,1H).m / z(ESI):385.9 / 387.9(M+H) + .

[0350] The sample was purified by SFC using a Chiralpak AS, 21 x 250 mm, 5 μm column with a mobile phase of 25% methanol with 0.2% diethylamine using a flow rate of 150 mL / min, giving peak 1 at 1.82 g with an ee of >99% and peak 2 at 1.83 g with an ee of >96%. Peak assignments were determined by SFC on a Chiralpak AS column with 20% methanol with 0.2% diethylamine. Peak 2 was the desired isomer, (S)-6-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane.

[0351] (R)-1-(6,8-Difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(tributylstannyl)quinazolin-4-yl)-3-methylpiperidin-3-ol (intermediate R). [ka] Step 1. (R)-1-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol. To a solution of 7-bromo-2,4-dichloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (5.00 g, 15.9 mmol) in acetonitrile (75 mL) was added (R)-3-methylpiperidin-3-ol hydrochloride (2.42 g, 15.9 mmol) and DIEA (8.3 mL g, 47.8 mmol) in sequence. The mixture was then stirred at 15° C. for 3 h. The reaction mixture was quenched by adding 80 mL of water and then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 100:1 to 10:1) to give (R)-1-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (4.1 g, 10.4 mmol, 66% yield) as a white solid. m / z (ESI): 394.0 / 392.0 (M+H). + .

[0352] Step 2. (R)-1-(7-Bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol. To a solution of (R)-1-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (50 g, 127 mmol) in tetrahydrofuran (750 mL) and N,N-dimethylformamide (750 mL) were added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (22.3 g, 140 mmol), Cs2CO3 (49.8 g, 153 mmol) and DABCO (4.29 g, 38.2 mmol) in sequence. The mixture was then stirred at 50° C. for 6 h. The reaction mixture was quenched by adding 1.5 L of water and then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10:1 to 0:1) to give (R)-1-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (26.0 g, 50.4 mmol, 40% yield) as a white solid.

[0353] Step 3. (R)-1-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(tributylstannyl)quinazolin-4-yl)-3-methylpiperidin-3-ol. To a 500 mL three-neck flask was added (R)-1-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (10.0 g, 19.4 mmol) in 1,4-dioxane (100 mL). To this mixture, PCy3PdG2 (1.15 g, 1.94 mmol) and lithium chloride (4.11 g, 97 mmol) were added in portions under N2, followed by dropwise addition of bis(tributyltin) (29.4 mL, 58.2 mmol) in 1,4-dioxane (50 mL) at 20°C under N2. The resulting mixture was stirred at 100°C for 10 h. The reaction mixture was quenched by adding 200 mL of water and then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10:1 to 0:1) to give (R)-1-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(tributylstannyl)quinazolin-4-yl)-3-methylpiperidin-3-ol (5.00 g, 6.90 mmol, 36% yield) as a yellow oil. m / z (ESI): 727.3 / 725.3 (M+H). + .

[0354] 4-Bromo-6-methyl-5-((1S,2R)-2-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Intermediate S). [ka] Step 1. 4-Bromo-6-methyl-5-((1S,2R)-2-methylcyclopropyl)-1H-indazole. A vial was charged with 4-bromo-5-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (10.0 g, 23.8 mmol, LabNetwork), rel-((1R,2S)-2-methylcyclopropyl)boronic acid (2.85 g, 28.5 mmol, Intermediate N), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride (1.74 g, 2.38 mmol), potassium phosphate tribasic (17.6 g, 83 mmol), water (15.83 mL) and toluene (79 mL). The mixture was degassed and then heated to 100° C. for 3 h. After cooling to room temperature, water was added and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the volatiles were removed in vacuo. The crude residue was purified by column chromatography eluting with 0-100% EtOAc:EtOH 3:1 with 2% NEt3 / heptane to give rel-4-bromo-6-methyl-5-((1S,2R)-2-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole as a colorless oil. The mixture was then dissolved in DCM (80 mL) and TFA (17.8 mL, 237 mmol) was added. The reaction mixture was stirred at room temperature for 6 h. The volatiles were removed under reduced pressure and the residue was neutralized with saturated NaHCO3 solution. The aqueous layer was extracted with DCM and the combined organic layers were dried over Na2SO4, filtered and concentrated. The crude mixture was purified by column chromatography eluting with 0-100% EtOAc:EtOH 3:1 with 2% NEt3 / heptane to give rel-4-bromo-6-methyl-5-((1S,2R)-2-methylcyclopropyl)-1H-indazole (5.5 g, 20.7 mmol, 87% yield). The sample was purified by SFC using a Chiralcel OD, 2 x 25 cm, 5 μm column with a mobile phase of 15% MeOH with 0.2% DEA using a flow rate of 100 mL / min to give peak 1 at 0.9 g with an ee of >99% and peak 2 at 2.88 g with an ee of >91.5%. Peak number 1 was the desired product and was used directly in the subsequent step.

[0355] Step 2. 4-Bromo-6-methyl-5-((1S,2R)-2-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. A mixture of 4-bromo-6-methyl-5-((1S,2R)-2-methylcyclopropyl)-1H-indazole-3-carbonitrile (0.28 g, 0.96 mmol), 3,4-dihydro-2H-pyran (0.24 mL, 0.29 mmol), and 4-methylbenzenesulfonic acid (8.3 mg, 0.048 mmol) in dichloromethane (5 mL) was stirred at room temperature overnight.

[0356] The reaction mixture was purified by column chromatography on silica gel (4 g column) eluting with 0-20% EtOAc / heptane to give 4-bromo-6-methyl-5-((1S,2R)-2-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbonitrile (0.25 g, 0.67 mmol, 69% yield) as a white solid. m / z (ESI): 395.8 (M+Na). + .

[0357] (S)-4-((S)-7-(6-chloro-5-((1S,2R)-2-methylcyclopropyl)-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (Example 98). [ka] Step 1. (S)-4-(7-Bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol. To a solution of 7-bromo-2,4-dichloro-6,8-difluoro-quinazoline (0.22 g, 0.69 mmol, PharmaBlock) in DCM (3 mL) was added (S)-6-methyl-1,4-oxazepan-6-ol hydrochloride (0.10 g, 0.60 mmol, Intermediate A1) followed by DIPEA (0.31 mL, 1.8 mmol). The reaction was stirred for 6 h. The reaction mixture was then diluted with saturated NH4Cl and extracted with EtOAc. The organic extract was washed with saturated NaCl solution and dried over MgSO4. The filtrate was concentrated in vacuo to give the desired product. m / z(ESI): 409.9(M+H). + .

[0358] To a vial was added ((2R,7aS)-2-fluorohexahydro-1H-pyrro-7a-yl)methanol (0.15 g, 0.92 mmol, LabNetwork), cesium carbonate (0.60 g, 1.84 mmol), and 1,4-diazabicyclo[2.2.2]octane (14 mg, 0.12 mmol). This solid was then suspended in N,N-dimethylformamide (1.0 mL) and tetrahydrofuran (2.0 mL) and (S)-4-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (0.25 g, 0.61 mmol) was added. The reaction mixture was then stirred at 35° C. for 9 hours. The reaction was then diluted with water and extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (12 g) using a gradient of 0-80% 3:1 EtOAc:EtOH (containing 2% triethylamine) in heptane to give (S)-4-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (0.23 g, 0.43 mmol, 71% yield) as a bright yellow solid. m / z (ESI): 531.0 (M+H). + .

[0359] Step 2. (6S)-4-((7S)-7-(6-chloro-5-((1S,2R)-2-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol. In a vial, 6-chloro-5-((1S,2R)-2-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (0.14 g, 0.34 mmol), intermediate M (0.14 g, 0.34 mmol), potassium phosphate tribasic (0.15 g, 0.71 mmol), palladium ( II) Acetate (13 mg, 0.056 mmol), (S)-(-)-2-(diphenylphosphino)-2-methoxy-1,1-binaphthyl (26 mg, 0.056 mmol), (R)-(+)-2-(diphenylphosphino)-2'-methoxy-1,1'-binaphthyl (26 mg, 0.056 mmol), 2-methyltetrahydrofuran (2.6 mL) and water (0.26 mL) were charged under nitrogen. The mixture was heated to 80 °C for 3 h. After cooling to room temperature, the crude reaction was loaded onto a pre-packed C18 column (50 g) eluting with a gradient of 5-80% (0.1% formic acid in MeCN) / (0.1% formic acid in water) over 10 min. The desired fraction was basified with saturated aqueous sodium bicarbonate and extracted with EtOAc. The combined organic phases were concentrated under reduced pressure to give (6S)-4-((7S)-7-(6-chloro-5-((1S,2R)-2-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (0.16 g, 0.21 mmol, 75% yield) as a brown solid. m / z(ESI): 741.2 (M+H). + .

[0360] Step 3. (S)-4-((S)-7-(6-chloro-5-((1S,2R)-2-methylcyclopropyl)-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol. A vial was charged with (6S)-4-((7S)-7-(6-chloro-5-((1S,2R)-2-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (0.16 g, 0.21 mmol) in DCM (2.0 mL). 2,2,2-Trifluoroacetic acid (0.7 mL, 25.0 equiv.) was added and the reaction mixture was monitored by LCMS while stirring at room temperature. Upon completion, the mixture was cooled to 0° C. and carefully neutralized with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with DCM and the combined organic phase was concentrated under reduced pressure. The crude material was dissolved in MeOH and loaded onto a pre-packed C18 column (30 g) eluting with a gradient of 5-100% (0.1% formic acid in MeCN) / (0.1% formic acid in water) over 10 min. The desired fraction was basified with saturated aqueous sodium bicarbonate and extracted with EtOAc. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (S)-4-((S)-7-(6-chloro-5-((1S,2R)-2-methylcyclopropyl)-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (84 mg, 0.13 mmol, 45% yield) as an off-white solid. 1H NMR (400MHz, methanol-d4) δ ppm 8.10-8.18 (m, 1H) 7.80 (s, 1H) 7.65 (br s,1H)5.22-5.42(m,1H)4.22-4.54(m,5H)3.98-4.16(m,3H)3.82-3.94(m,2H)3.63-3.75(m,2H)3.16-3.30(m,3H)3.00-3 .09(m,1H)2.10-2.14(m,1H)2.02(s,4H)1.84-1.95(m,1H)1.28(d,J=1.46Hz,3H)0.66-0.75(m,4H)-0.47--0.13(m,1H); 19 F NMR (376 MHz, methanol-d4) δ ppm -119.06--117.89 (m, 1 F) -124.43--123.12 (m, 1 F) -174.43--173.11 (m, 1 F).

[0361] The sample (60 mg) was purified by SFC using a Chiralpak IE column (21 x 250 mm, 5 μm) with a mobile phase of 65% methanol with 0.2% diethylamine using a flow rate of 80 mL / min to give 22 mg of peak 1 with an ee of >96% and 23 mg of peak 2 (Example 98) with an ee of >90%. 1 H NMR(600MHz,DMSO-d6)δ ppm 8.30-8.37(m,1H)7.85(s,1H)7.63-7.72(m,1H)7.28-7.34(m,1H)5.32(s,1H)4.29-4.37(m,1H)4. 22-4.27(m,1H)4.07-4.19(m,4H)3.99-4.03(m,1H)3.93-3.97(m,2H)3.78-3.82(m,1H)3.65-3.73 (m,1H)3.53-3.59(m,2H)2.79-2.86(m,1H)1.75-1.80(m,2H)1.63-1.72(m,1H)1.56-1.62(m,1H)1 .46-1.52(m,1H)1.39-1.45(m,1H)1.18-1.22(m,1H)1.15(s,3H)0.64(s,4H)-0.44--0.31(m,1H). m / z(ESI):657.2(M+H) + .

[0362]

Table 73

[0363]

Table 74

[0364]

Table 75

[0365]

Table 76

[0366]

Table 77

[0367]

Table 78

[0368]

Table 79

[0369]

Table 80

[0370]

Table 81

[0371]

Table 82

[0372]

Table 83

[0373]

Table 84

[0374]

Table 85

[0375]

Table 86

[0376]

Table 87

[0377]

Table 88

[0378]

Table 89

[0379]

Table 90

[0380]

Table 91

[0381]

Table 92

[0382] (3R)-1-(7-(6-chloro-5-((Z)-prop-1-en-1-yl)-1H-indazol-4-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (Example 115). [ka] Step 1. 7-Bromo-2-chloro-8-fluoro-4-(piperidin-1-yl)quinazoline. A vial was charged with 7-bromo-2,4-dichloro-8-fluoroquinazoline (0.75 g, 2.5 mmol, LabNetwork), piperidine (0.25 mL, 2.5 mmol) and acetonitrile (7 mL). The contents were cooled to 0° C. and then Hunig's base (1.3 mL, 7.6 mmol) was added dropwise. The reaction mixture was stirred at 0° C. and upon completion, it was diluted with water and extracted with DCM. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was dissolved in DMSO and loaded onto a pre-packed C18 column (50 g) eluting with a gradient of 5-80% (0.1% formic acid in MeCN) / (0.1% formic acid in water) over 10 min. The desired fractions were concentrated under reduced pressure to give 7-bromo-2-chloro-8-fluoro-4-(piperidin-1-yl)quinazoline as an off-white solid. m / z (ESI): 343.9 / 345.9 (M+H). + .

[0383] Step 2.1-(1-(((7-Bromo-8-fluoro-4-(piperidin-1-yl)quinazolin-2-yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethanamine. A vial was charged with crude 7-bromo-2-chloro-8-fluoro-4-(piperidin-1-yl)quinazoline, (1-((dimethylamino)methyl)cyclopropyl)methanol (0.59 g, 4.6 mmol, Enamine), catalyst DABCO (0.1 eq), cesium carbonate (2.48 g, 7.6 mmol) and THF / DMF (2:1, 0.2 M). The reaction mixture was monitored by LCMS while stirring at room temperature. Upon completion, the reaction was diluted with water and extracted with DCM. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-(1-(((7-bromo-8-fluoro-4-(piperidin-1-yl)quinazolin-2-yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethanamine (0.77 g, 1.76 mmol, 69% yield) as a brown solid. m / z (ESI): 436.8 / 438.8 (M+H). + .

[0384] Step 3. (2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-4-(piperidin-1-yl)quinazolin-7-yl)boronic acid. A vial was charged with 1-(1-(((7-bromo-8-fluoro-4-(piperidin-1-yl)quinazolin-2-yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethanamine (0.75 g, 1.72 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride (0.13 mg, 0.17 mmol), potassium acetate (0.34 g, 3.43 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.52 g, 2.06 mmol) and 1,4-dioxane (9 mL). The reaction mixture was heated to 100° C. and monitored by LCMS. Upon completion, the reaction mixture was cooled to room temperature, filtered, concentrated under reduced pressure and the crude product was used directly in the next step. m / z(ESI):403.0(M+H) + .

[0385] Step 4. (3R)-1-(7-(6-chloro-5-((Z)-prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol. A vial was charged with (2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-4-(piperidin-1-yl)quinazolin-7-yl)boronic acid (0.68 g, 1.69 mmol), (Z)-4-bromo-6-chloro-5-(prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.60 g, 1.69 mmol), potassium carbonate (0.70 g, 5.1 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride (0.12 g, 0.17 mmol), 1,4-dioxane (8.5 mL) and water (2.8 mL) under nitrogen. The mixture was heated to 100° C. for 1.5 h. After cooling to room temperature, the crude material was loaded onto a pre-packed C18 column (50 g) eluting with a gradient of 5-80% (0.1% formic acid in MeCN) / (0.1% formic acid in water) over 20 min. The desired fractions were concentrated under reduced pressure to give (Z)-1-(1-(((7-(6-chloro-5-(prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-4-(piperidin-1-yl)quinazolin-2-yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethanamine (0.28 g, 0.43 mmol, 26% yield) as a white solid. m / z (ESI): 633.0 (M+H) + .

[0386] Step 5. (Z)-7-(6-chloro-5-(prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-4-ol. A vial was charged with (Z)-1-(1-(((7-(6-chloro-5-(prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-4-(piperidin-1-yl)quinazolin-2-yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethanamine (0.28 g, 0.43 mmol), lithium hydroxide hydrate (0.18 g, 4.34 mmol), water (1.0 mL), ethanol (1.0 mL) and tetrahydrofuran (1.0 mL). The reaction mixture was monitored by LCMS while heating to 70° C. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (Z)-7-(6-chloro-5-(prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-4-ol (0.22 g, 0.39 mmol, 90% yield) as a brown solid. m / z (ESI): 565.9 (M+H). + .

[0387] Step 6. (3R)-1-(7-(6-chloro-5-((Z)-prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol. A vial was charged with (Z)-7-(6-chloro-5-(prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-4-ol (0.14 g, 0.25 mmol) and N,N-dimethylacetamide (2.5 mL). To this solution was then charged Hunig's base (0.22 mL, 1.27 mmol), HATU (0.39 g, 1.02 mmol), and (R)-3-methylpiperidin-3-ol hydrochloride (46 mg, 0.31 mmol, Synnovator). The resulting mixture was stirred at room temperature and monitored by LCMS.

[0388] Upon completion, the reaction mixture was loaded onto a pre-packed C18 column (50 g) eluting with a gradient of 5-80% (0.1% formic acid in MeCN) / (0.1% formic acid in water) over 10 min. The desired fraction was basified with saturated aqueous sodium bicarbonate and extracted with EtOAc. The combined organic phase was concentrated under reduced pressure to give (3R)-1-(7-(6-chloro-5-((Z)-prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (53 mg, 0.08 mmol, 31% yield) as an off-white solid. m / z(ESI): 662.8 (M+H) + .

[0389] Step 7. (3R)-1-(7-(6-chloro-5-((Z)-prop-1-en-1-yl)-1H-indazol-4-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol. A vial was charged with (3R)-1-(7-(6-chloro-5-((Z)-prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (53 mg, 0.08 mmol) and DCM (2 mL). 2,2,2-Trifluoroacetic acid (0.7 mL, ca. 25.0 equiv.) was then added and the reaction mixture was monitored by LCMS with stirring at room temperature. Upon completion, the mixture was concentrated and redissolved in MeOH. The crude material was loaded onto a pre-packed C18 column (50 g) eluting with a gradient of 5-80% (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 the aqueous layer was extracted with EtOAc. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The impure material was further purified by SFC / MS purification using MeOH as a co-solvent with a gradient of 10-40% to give (3R)-1-(7-(6-chloro-5-((Z)-prop-1-en-1-yl)-1H-indazol-4-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol as a bright yellow solid (8.2 mg, 0.014 mmol, 5.6% yield). 1H NMR(600MHz,DMSO-d6)δ ppm 7.92-8.01(m,1H)7.80-7.88(m,1H)7.66-7.74(m,1H)7.25-7.35(m,1H)6.36-6.43(m,1H)5.58-5.6 7(m,1H)4.30(s,2H)4.03-4.11(m,1H)3.82-3.92(m,1H)3.38-3.50(m,1H)3.13-3.25(m,1H)2.86(br s,6H)1.98-2.07(m,1H)1.63-1.76(m,3H)1.13-1.19(m,7H)0.87(br s,2H)0.77(br s,2H).m / z(ESI):579.2(M+H) + .

[0390] (4S)-6-(7-(6-chloro-5-((Z)-prop-1-en-1-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane. (Example 116). [ka] Step 1. (S)-6-(7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane. A mixture of (S)-6-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (1.83 g, 4.73 mmol, intermediate Q), ((2R,7aS)-2-fluorohexahydro-1H-pyrro-7a-yl)methanol (1.01 g, 6.63 mmol, BLD Pharmatech), 1,4-diazabicyclo[2.2.2]octane (0.11 g, 0.95 mmol), and cesium carbonate (3.08 g, 9.47 mmol) in tetrahydrofuran (14 mL) and N,N-dimethylformamide (7 mL) was stirred at 60° C. for 16 hours. The resulting reaction mixture was concentrated in vacuo to remove most of the THF. Water was added to the above solution and the precipitate was collected by filtration, washed with water, and dried. The crude product was purified by chromatography through a silica gel column (40 g) eluting with a gradient of 0-100% EtOAc in heptane (containing 10% 2M NH in MeOH) to give (S)-6-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (1.71 g, 3.35 mmol, 71% yield) as a white foam. 1H NMR(400MHz,DMSO-d6)δ ppm 7.82(dd,J=9.0,1.3Hz,1H),7.54(dd,J=9.0,6.7Hz,1H),5.13-5.44(m,1H),4.39(t,J=7.7Hz ,2H),4.07-4.16(m,2H),4.00-4.07(m,1H),3.86-3.95(m,1H),3.68(d,J=13.4Hz,1H),3.32-3 .41(m,1H),3.05-3.20(m,2H),3.03(s,1H),2.79-2.90(m,1H),2.30-2.40(m,2H),2.10-2.20( m,1H),1.98-2.09(m,3H),1.73-1.92(m,5H),1.62-1.73(m,1H).m / z(ESI):508.9 / 510.9(M+H) + .

[0391] Step 2. (8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)boronic acid. A vial was charged with (S)-6-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (0.11 g, 0.21 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (64 mg, 0.25 mmol), potassium acetate (41 mg, 0.42 mmol), and Pd(dppf)Cl2 (12 mg, 0.017 mmol) in 1,4-dioxane (2 mL). The reaction mixture was then heated to 90° C. for 1 h. After cooling to room temperature, the reaction mixture was filtered through a 0.45 μm PTFE Whatman filter and used in the subsequent step.

[0392] Step 3. (4S)-6-(7-(6-chloro-5-((Z)-prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane. A vial was charged with (8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)boronic acid (0.10 g, 0.21 mmol), CataCXium A Pd G3 (15 mg, 0.021 mmol), potassium phosphate (0.13 g, 0.63 mmol), (Z)-4-bromo-6-chloro-5-(prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.10 g, 0.29 mmol, intermediate L) and degassed 1,4-dioxane (1 mL). The reaction mixture was heated to 80° C. for 45 min. After cooling to room temperature, the reaction mixture was subjected to reverse phase column chromatography using a C18 column (50 g) with a gradient of 10-100% over 10 min of 0.1% formic acid in MeCN / H2O. The desired fractions were collected and neutralized with saturated NaHCO3 solution. The aqueous mixture was extracted with EtOAc and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give (4S)-6-(7-(6-chloro-5-((Z)-prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (32 mg, 0.045 mmol, 22% yield) as a bright yellow solid.

[0393] Step 4. (4S)-6-(7-(6-chloro-5-((Z)-prop-1-en-1-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane. A 6 mL vial was charged with (4S)-6-(7-(6-chloro-5-((Z)-prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (32 mg, 0.045 mmol) in dichloromethane (1.5 mL). Trifluoroacetic acid (0.4 mL, 5.3 mmol) was added and the reaction was stirred at room temperature for 1 h. The reaction mixture was quenched slowly with saturated NaHCO3 solution (3 mL) and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by reverse phase column chromatography using a C18 column (15 g) with a gradient of 5-100% over 10 min of 0.1% formic acid in MeCN / HO. The desired fraction was neutralized with saturated NaHCO3 solution and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give (4S)-6-(7-(6-chloro-5-((Z)-prop-1-en-1-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (9.5 mg, 0.015 mmol, 7.3% yield) as a white solid. 1H NMR(400MHz,メタノール-d4)δ ppm 7.99(t,J=8.8Hz,1H),7.73-7.80(m,2H),7.32(br s,1H),6.43(br d,J=11.1Hz,1H),5.65(dq,J=11.1,6.9Hz,1H),5.26-5.44(m,1H),4.57(td,J=7.8,1.8Hz,2H),4.38(br d,J=10.9Hz,2H),4.28-4.33(m,1H),4.12(br d,J=13.4Hz,1H),3.80(dd,J=13.4,9.4Hz,1H),3.38-3.55(m,2H),3.21-3.30(m,1H),3.08(td,J=9.4,6.1Hz,1H),2.50(t,J=7.7Hz,2H),2.44(br dd,J=15.3,4.8Hz,1H),2.32(br d,J=4.0Hz,1H),2.14-2.29(m,3H),1.91-2.10(m,6H),1.76-1.86(m,1H),1.25(d,J=6.9Hz,3H). 19 F NMR(376MHz,メタノール-d4)δ ppm -128.01(s,1 F),-173.68(s,1 F).m / z(ESI):621.0(M+H) + .

[0394]

Table 93

[0395]

Table 94

[0396]

Table 95

[0397]

Table 96

[0398] (3R)-1-(7-(6-chloro-5-((Z)-prop-1-en-1-yl)-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (Example 119). [ka] Step 1. (3R)-1-(7-(6-chloro-5-((Z)-prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol. In a vial, (R)-1-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(tributylstannyl)quinazolin-4-yl)-3-methylpiperidin-3-ol (0.31 mg, 0.42 mmol, Intermediate R), (Z)-4-bromo-6-chloro-5-(prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.10 g, 0.28 mmol, Intermediate L), cataCXium A Pd G3 (21 mg, 0.028 mmol), lithium chloride (24 mg, 0.56 mmol), copper(I) iodide (27 mg, 0.14 mmol) and degassed N,N-dimethylformamide (2 mL) were charged. The reaction mixture was heated to 100 °C and monitored by LCMS. Upon completion, the cooled reaction mixture was loaded onto a pre-packed C18 column (50 g) eluting with a gradient of 5-80% (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 phase was concentrated under reduced pressure to give (3R)-1-(7-(6-chloro-5-((Z)-prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (64 mg, 0.09 mmol, 32% yield) as a brown solid. m / z (ESI): 711.0 (M+H). + .

[0399] Step 2. (3R)-1-(7-(6-chloro-5-((Z)-prop-1-en-1-yl)-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol. A vial was charged with (3R)-1-(7-(6-chloro-5-((Z)-prop-1-en-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (64 mg, 0.09 mmol) in DCM (2.0 mL). 2,2,2-Trifluoroacetic acid (0.7 mL, 25.0 equiv.) was added and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated and redissolved in MeOH (1 mL). The crude material was loaded onto a pre-packed C18 column (50 g) eluting with a gradient of 5-100% (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 the aqueous layer was extracted with EtOAc. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (3R)-1-(7-(6-chloro-5-((Z)-prop-1-en-1-yl)-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (41 mg, 0.065 mmol, 23% yield) as a white solid. 1H NMR(400MHz, methanol-d4)δ ppm 7.83(s,3H)6.34-6.44(m,1H)5.62-5.77(m,1H)5.22-5.44(m,1H)4.18-4.37(m,3H)4.00-4.09(m,1H)3.36(br d,J=3.14Hz,3H)3.17-3.29(m,3H)2.98-3.08(m,1H)2.22-2.42(m,2H)1.74-2.06(m,8H)1.29(br d,J=7.94Hz,7H).m / z(ESI):627.0(M+H) + .

[0400] (3R)-1-(7-(6-chloro-5-((Z)-prop-1-en-1-yl)-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (Example 120) [ka] The sample (Example 119, 41 mg) was purified by SFC using a column with a mobile phase of 35% methanol with 0.2% diethylamine using a Chiralcel OD, 21×150 mm, 5 μm, flow rate of 125 mL / min to give 11.5 mg of peak 1 with an ee of >99% and 9.5 mg of peak 2 with an ee of >90%. Peak 2 gave Example 120.

[0401] (R)-1-((S)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(6-methyl-5-((1S,2R)-2-methylcyclopropyl)-1H-indazol-4-yl)quinazolin-4-yl)-3-methylpiperidine-3-ol bis(2,2,2-trifluoroacetate) (Example 121). [ka] Using a similar method as used in Example 119, (R)-1-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(tributylstannyl)quinazolin-4-yl)-3-methylpiperidin-3-ol (0.15 g, 0.21 mmol, Intermediate R) and 4-bromo-6-methyl-5-((1S,2R)-2-methylcyclopropyl)-1-(tetrahydro (R)-1-((S)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(6-methyl-5-((1S,2R)-2-methylcyclopropyl)-1H-indazol-4-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol was obtained with (R)-1-((S)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(6-methyl-5-((1S,2R)-2-methylcyclopropyl)-1H-indazol-4-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol. 1 H NMR(400MHz, methanol-d4)δ ppm 7.97(br d,J=10.03Hz,1H),7.50-7.67(m,2H),5.44-5.71(m,1H),4.66-4.80(m,3H),4.42-4.56(m, 1H),4.21-4.32(m,1H),3.83-4.09(m,3H),3.60(d,J=13.38Hz,1H),3.34-3.53(m,3H),2.6 4(d,J=2.51Hz,5H),2.31-2.50(m,3H),2.14-2.24(m,2H),2.00-2.14(m,1H),1.73-1.92(m ,3H),1.32(s,3H),1.17-1.29(m,1H),0.68-0.80(m,1H),0.65(d,J=6.06Hz,3H),-0.29(br dd,J=15.47,5.64Hz,1H).m / z(ESI):621.0(M+H) + .

[0402] Biological evaluation In this section, a biological evaluation of the embodiments provided herein is provided.

[0403] KRAS G12D TR-FRET assay Compounds of interest were prepared in dose-response titrations in DMSO and 80 nL was added to each well of a 384-well plate (Perkin Elmer 6008280) by Labcyte Echo. His-tagged KRAS G12D protein (Amgen) was diluted to 20 nM in assay buffer (20 mM HEPES, pH 7.4, 10 mM MgCl2, 50 mM NaCl, 0.1% BSA, 0.01% Tween-20, 10 μM GDP) and 2 μL was added to the appropriate wells of the 384-well plate. Plates were incubated at room temperature for 30 minutes. Biotinylated KRPep-2d substrate (Amgen) was diluted to 20 nM in assay buffer and 2 μL was added to all wells and incubated at room temperature for 1 hour. Detection reagents (0.4 nM LANCE Eu-W1024 Anti-6xHis (Perkin Elmer AD0401), 5 nM streptavidin-d2 (Cisbio 610SADLA)) were prepared in assay buffer, then 4 μL was added to the plate and incubated for 1 h at room temperature. Plates were read using a PerkinElmer EnVision (ex: 320 nm, em1: 665 nm, em2: 615 nm) and the em1 / em2 data was used to generate a curve fit using a four-parameter logistic model to calculate IC 50 values ​​were calculated.

[0404] KRAS G12D-binding nucleotide exchange assay Purified GDP-bound KRAS protein (aa 1-169) containing both G12D and C118A amino acid substitutions and an N-terminal His tag was pre-incubated with a dose-response titration of compound in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCl2 and 0.01% Triton X-100) for 2 hours. After compound pre-incubation, purified SOS protein (aa 564-1049) and GTP (Roche 10106399001) were added to the assay wells and incubated for an additional 30 minutes. To determine the extent of inhibition of SOS-mediated nucleotide exchange, purified GST-tagged cRAF (aa 1-149), nickel-chelating AlphaLISA acceptor beads (PerkinElmer AL108R) and AlphaScreen glutathione donor beads (PerkinElmer 6765302) were added to the assay wells and incubated for 10 minutes. The assay plates were then read on a PerkinElmer EnVision Multilabel Reader using AlphaScreen® technology and the data were analyzed using a four-parameter logistic model to determine IC 50 The value was calculated.

[0405] Phospho-ERK1 / 2 MSD assay AsPC-1 (ATCC® CRL-1682 (商標) ) cells were cultured in RPMI 1640 medium (ThermoFisher Scientific 11875093) containing 10% fetal bovine serum (ThermoFisher Scientific 16000044) and 1× penicillin-streptomycin-glutamine (ThermoFisher Scientific 10378016). 16 hours prior to compound treatment, AsPC-1 cells were seeded in 96-well cell culture plates at a density of 25,000 cells / well and incubated at 37°C, 5% CO2. Dose-response titrations of compounds were diluted in growth medium and added to the appropriate wells of the cell culture plate, then incubated for 2 hours at 37°C, 5% CO2. After compound treatment, cells were incubated for 2 hours at 37°C, 5% CO2, and then ... 2+or Mg 2+ Cells were washed with ice-cold Dulbecco's Phosphate Buffered Saline (ThermoFisher Scientific 14190144) without riboflavin and then lysed in RIPA buffer (50 mM Tris-HCl pH 7.5, 1% Igepal, 0.5% sodium deoxycholate, 150 mM NaCl and 0.5% sodium dodecyl sulfate) containing protease inhibitors (Roche 4693132001) and phosphatase inhibitors (Roche 4906837001). Phosphorylation of ERK1 / 2 in compound-treated lysates was assayed using the Phospho-ERK1 / 2 Whole Cell Lysate kit (Meso Scale Discovery K151DWD) according to the manufacturer's protocol. Assay plates were read on a Meso Scale Discovery Sector Imager 6000 and data was analyzed using a 4-parameter logistic model to determine IC 50 The value was calculated.

[0406] [Table 97]

[0407] [Table 98]

[0408] [Table 99]

[0409] [Table 100]

[0410] [Table 101]

[0411] [Table 102]

[0412] References All references cited in this specification, e.g., scientific publications or published patent applications, are hereby incorporated by reference in their entirety for all purposes to the same extent as if each reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

Claims

1. Formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein 【Chemistry 2】 is a single or double bond; W is C, CH or N; X is CH ２ , O, S, S(O), S(O)(NR ｚ ) or S(O) ２ and n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; Each R ｘ is hydroxyl, halogen, oxo, cyano, -N(R ｚ ) ２ , C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, C １～４ haloalkoxy, 5- to 7-membered heteroaryl, -T-R ｙ or two R ｘ together with the same carbon atom or adjacent carbon atoms to form C ３～７ cycloalkyl, 5- to 7-membered heterocycloalkyl, wherein each C ３～７ The cycloalkyl or 5- to 7-membered heterocycloalkyl is selected from 0 to 3 R ｙ or two R ｘ can be taken together to form a bridged ring, said bridge being -C １～４ Alkylene, -C １～４ Alkylene -O-C １～４ Alkylene-, —O—, —S— or —C １～４ Alkylene -S-C １～４ alkylene-, wherein each C １～４ Alkylene is 0 to 2 R ｙ is further replaced by the appearance of Z is CH, CR′, or N; R' is halogen, cyano, or C １～４ is alkyl; L is a bond, C １～６ Alkylene, C １～６ Alkenylene, —O—C １～６ Alkylene, —S—C １～６ Alkylene, NR ｚ , O or S, where each C １～６ Alkylene, —O—C １～６ Alkylene and —S—C １～６ The alkylene chain is a chain consisting of 0 to 2 R ２ is replaced by an occurrence of; R １ is hydroxyl, aryl, heteroaryl, C ３～８ cycloalkyl or 0 to 3 R ５ is an optionally substituted heterocycloalkyl; R ２ is hydrogen, hydroxyl, halogen, amino, C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, C ２～４ Alkenyl, C ２～４ Alkynyl, C ３～８ cycloalkyl, cyano, or two R on the same or adjacent carbon atoms ２ Together they form C ３～７ can form a cycloalkyl; R ３ is 0 to 4 R ６ is an optionally substituted aryl or heteroaryl at each occurrence of R ４ is hydrogen, hydroxyl, halogen, C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, C ２～４ Alkenyl, C ２～４ Alkynyl, C ３～８ cycloalkyl or cyano; Each R ５ is halogen, hydroxyl, oxo, amino, C １～４ Alkyl or -T-R ｙ and Each R ６ is halogen, hydroxyl, amino, cyano, C １～４ Alkyl, C ２～４ Alkenyl, C ２～４ Alkynyl, C １～４ Haloalkyl, C ３～７ cycloalkyl or two R on adjacent carbon atoms ６ Using C ３～７ A cycloalkyl can be formed, where each C ３～７ Cycloalkyl is 0 to 2 R ７ is further substituted with; R ７ is hydrogen, halogen or C １～４ is alkyl; T is C １～４ Alkylene, —O—, —S—, —C １～４ Alkylene -C(O)- or -NR ｚ -C(O)-; R ｙ is halogen, hydroxyl, cyano, C １～４ alkoxy or amino; R ｚ is hydrogen or C １～４ A compound that is alkyl.

2. The compound of claim 1 wherein Z is N.

3. L is 0 R ２ 2. The compound of claim 1, wherein the substituted -O-methylene is -O-methylene substituted with an occurrence of:

4. R １ But 0 to 3 R ５ 2. The compound of claim 1, which is 7-(hexahydro-1H-pyrrolidine) substituted with an occurrence of:

5. -L-R １ but, 【Transformation 3】 5. The compound of claim 4, wherein:

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

7. R ３ But 0 to 3 R ６ 7. The compound of claim 6, wherein the compound is phenyl or naphthyl substituted with an occurrence of:

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

9. R ３ But 0 to 3 R ６ 9. The compound of claim 8, which is 4-(1H-indazolyl) or 7-(1H-indazolyl) substituted with an occurrence of:

10. R ３ but, 【Chemistry 4】 2. The compound of claim 1, wherein:

11. The compound of claim 1 wherein W is N.

12. X is CH ２ 12. The compound of claim 11, wherein: 【Request Item 13】 【Chemistry 5】 but, 【Transformation 6】 13. The compound of claim 12, wherein:

14. 12. The compound of claim 11, wherein X is O. 【Request Item 15】 【Chemistry 7】 but, 【Transformation 8】 15. The compound of claim 14, wherein:

16. R ２ The compound of claim 1 , wherein is hydrogen, methyl, fluorine, cyano, hydroxyl, or amino.

17. R ４ The compound of claim 1 , wherein is fluorine or methyl.

18. R ７ The compound of claim 1 , wherein is hydrogen.

19. The following compounds: 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (3R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one; 4-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (3R)-1-(7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; (5S)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one; 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)naphthalen-2-ol; 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (S)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one; (R)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 5-chloro-4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-6-fluoronaphthalen-2-ol; (2S,4s)-6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-azaspiro[3.5]nonan-2-ol; 7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)quinazolin-6-ol; (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one; 4-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 4-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (5S)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-thia-7-azaspiro[4.5]decane 2,2-dioxide; or 4-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol.

20. The following compounds: 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (3R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one; 4-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (3R)-1-(7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; (5S)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-oxa-3,7-diazaspiro[4.5]decan-2-one; 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol; or 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)naphthalen-2-ol.

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

22. 22. A compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound, or a pharmaceutical composition according to claim 21, for use as a medicament.

23. 22. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, for use in the treatment of cancer.

24. 22. The compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 21, for use in treating cancer in which one or more cells express a KRAS G12D mutant protein.

25. 24. The compound or pharmaceutical composition for use according to claim 23, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small intestine cancer, appendix cancer, cancer of unknown primary origin, endometrial cancer, mixed cancer of unknown primary origin, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia or melanoma.

26. 22. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 21, in the preparation of a medicament for treating cancer.

27. 22. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 21, in the preparation of a medicament for treating cancer in which one or more cells express a KRAS G12D mutant protein.

28. 27. The use of claim 26, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, mixed cancer of unknown primary origin, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine carcinoma, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

29. 22. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 21.

30. 22. A method of treating cancer in a subject in need thereof, wherein one or more cells express a KRAS G12D mutant protein, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 21.

31. 30. The method of claim 29, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, mixed type cancer of unknown primary origin, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine carcinoma, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

32. 30. The method of claim 29, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendix cancer, endometrial cancer, esophageal cancer, cancer of unknown primary origin, ampullary cancer, gastric cancer, small intestine cancer, sinus cancer, bile duct cancer, or melanoma.

33. 33. The method of claim 32, wherein the cancer is non-small cell lung cancer.

34. 33. The method of claim 32, wherein the cancer is colorectal cancer.

35. 33. The method of claim 32, wherein the cancer is pancreatic cancer.

36. 30. The method of claim 29, wherein the subject has a cancer determined to have one or more cells that express the KRAS G12D mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof.

Images