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: TIFF2025508702000248.tif43170, where the variables of formula I are defined herein. The disclosure also provides pharmaceutical compositions comprising the compounds, such as uses of the compounds and compositions for the treatment of 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 progress 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, resulting in cell proliferation. Normally, growth-promoting signaling is regulated by the action of GTPase-activating proteins (GAPs), which revert KRAS to its GDP-bound, non-proliferative state. Mutations in KRAS impair the regulated cycling of KRAS between these GDP-bound and GTP-bound states, leading to the accumulation of the active GTP-bound state and impaired 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 a common (O'Bryan, 2019) oncogenic mutant of KRAS, KRAS G12C, that bound to a previously unrecognized allosteric pocket on GDP-KRAS G12C and prevented subsequent activation (Ostream et al., 2013). This discovery led to significant new efforts in the search for KRAS inhibitors, and has recently led to the entry of KRAS inhibitors into human clinical trials. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Der et al., 1982 [Non-Patent Document 2] Vojtek et al., 1998 [Non-Patent Document 3] Malumbres et al., 2003 [Non-Patent Document 4] Sridhar et al., 2003 [Non-Patent Document 5] Holderfield et al., 2014 [Non-Patent Document 6] Caunt et al., 2015 [Non-Patent Document 7] Simanshu et al., 2017 [Non-Patent Document 8] Cox et al., 2014 [Non-Patent Document 9] O'Bryan, 2019 [Non-Patent Document 10] Ostream et al., 2013 Summary of the Invention [Problem to be solved by the invention]

[0006] Although some progress has been made with respect to KRAS G12C inhibitors, there continues to be interest and effort in developing inhibitors of KRAS, particularly inhibitors of other KRAS, such as KRAS G12D, G12V, G12A, or G12S. Thus, there is a need to develop new inhibitors of KRAS G12D, G12V, G12A, G12S, or G12C for the treatment of disorders such as cancer. [Means for solving the problem]

[0007] In one aspect, the present application relates to a compound of formula (I): [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, During the ceremony, [ka] is a single bond or a double bond; W is C, CH, or N, and when W is N, [ka] is a single bond; X is a bond, 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, 3, or 4; Each R x is hydroxyl, halogen, oxo, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, -TR y or two R x C, together with the same or adjacent carbon atoms 3~7 cycloalkyl or 5-7 membered heterocycloalkyl, where each C 3~7 Cycloalkyl or 5- to 7-membered heterocycloalkyl is R y or 2 R x With the same carbon atom, R y C replaced with 0-3 occurrences of 3~8 cycloalkyl or 4- to 7-membered heterocycloalkyl, or two R x may, together with the carbon atoms to which they are attached, form a bridged ring, where the bridging atoms are as follows: -C 1~4 Alkylene, -C 1~4 Alkylene-O-, -C 1~4 Alkylene-OC 1~4 Alkylene-, -C 1~4 Alkylene-SC 1~4 Alkylene- or -C 1~4 alkylene-S-; Z is CH, CR', or N; R' is halogen, cyano, or C 1~4 is alkyl; L is a bond, -C 1~4 Alkylene, -OC 1~4 Alkylene, -SC 1~4 Alkylene, -NR z-, -O-, or -S-; R 1 is hydroxyl, aryl, heteroaryl, C 3~8 Cycloalkyl or R 5 is optionally substituted heterocycloalkyl with 0-3 occurrences of R 2 is hydrogen, halogen, C 1~4 Alkyl, C 2~4 alkenyl, or cyano; R 3 is hydrogen, halogen, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl or C 2~4 is alkynyl; R 4 is hydrogen or halogen; Each R 5 is halogen, oxo, hydroxyl, amino, or C 1~4 is alkyl, p is 0, 1, 2, or 3; R 8 is amino; R 9 is cyano; T is for C 1~4 alkylene, -C(O)-, -O-, -S(O)2-, or -S-; R q is hydrogen, halogen, or C 1~4 is alkyl; R y is halogen, hydroxyl, oxo, cyano, or amino; R z is hydrogen or C 1~4 is alkyl, The present invention relates to a compound, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

[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, provided herein is 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.

[0010] Reference will now be made in detail to the embodiments of the present disclosure. Although certain embodiments of the present disclosure will be described, it will be understood that it is not intended to limit the embodiments of the present disclosure to the described embodiments. On the contrary, reference to the embodiments of the present disclosure is intended to cover 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] Provided herein as embodiment 1 is a compound of formula (I): [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, During the ceremony, [ka] is a single bond or a double bond; W is C, CH, or N, and when W is N, [ka] is a single bond; X is a bond, CH 2、 O, S, S(O), S(O)(NR z ), or S(O)2; n is 0, 1, 2, or 3; m is 0, 1, 2, 3, or 4; Each R x is hydroxyl, halogen, oxo, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, -TRy or two R x C, together with the same or adjacent carbon atoms 3~7 cycloalkyl or 5-7 membered heterocycloalkyl, where each C 3~7 Cycloalkyl or 5- to 7-membered heterocycloalkyl is R y or 2 R x With the same carbon atom, R y C replaced with 0-3 occurrences of 3-8 cycloalkyl or 4- to 7-membered heterocycloalkyl, or two R x may, together with the carbon atoms to which they are attached, form a bridged ring, where the bridging atoms are as follows: -C 1~4 Alkylene, -C 1~4 Alkylene-O-, -C 1~4 Alkylene-OC 1~4 Alkylene-, -C 1~4 Alkylene-SC 1~4 Alkylene- or -C 1~4 alkylene-S-; Z is CH, CR', or N; R' is halogen, cyano, or C 1~4 is alkyl; L is a bond, -C 1~4 Alkylene, -OC 1~4 Alkylene, -SC 1~4 Alkylene, -NR z -, -O-, or -S-; R 1 is hydroxyl, aryl, heteroaryl, C 3~8 Cycloalkyl or R 5 is optionally substituted heterocycloalkyl with 0-3 occurrences of R 2 is hydrogen, halogen, C 1~4 Alkyl, C 2~4 alkenyl, or cyano; R 3 is hydrogen, halogen, cyano, C 1~4 Alkyl, C1~4 Haloalkyl or C 2~4 is alkynyl; R 4 is hydrogen or halogen; Each R 5 is halogen, oxo, hydroxyl, amino, or C 1~4 is alkyl, p is 0, 1, 2, or 3; R 8 is amino; R 9 is cyano; T is for C 1~4 alkylene, -C(O)-, -O-, -S(O)2-, or -S-; R q is hydrogen, halogen, or C 1~4 is alkyl; R y is halogen, hydroxyl, oxo, cyano, or amino; R z is hydrogen or C 1~4 is alkyl, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

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

[0013] Provided herein as embodiment 3 is a compound according to any one of embodiments 1 or 2, wherein L is -C 1~4 Alkylene or -OC 1~4 Provided herein as embodiment 4 is a compound according to embodiment 3, wherein L is -C 1~4 Provided herein as embodiment 5 is a compound according to embodiment 3, wherein L is -OC 1~4

[0023] Provided herein as embodiment 6 are compounds according to embodiment 5, wherein L is -O-methylene.

[0014] Provided herein as embodiment 7 is a compound according to embodiment 6, wherein R 1 is R 5 Provided herein as embodiment 8 is a compound according to embodiment 7, wherein R is 7-(hexahydro-1H-pyrrolidine) substituted with 0-3 occurrences of 1 is R 5 Provided herein as embodiment 9 is a compound according to embodiment 8, wherein R is 7-(hexahydro-1H-pyrrolidine) substituted with one occurrence of 5 Provided herein as embodiment 10 is a compound according to embodiment 7, wherein R 1 is R 5 Provided herein as embodiment 11 is a compound according to embodiment 10, wherein R is 7-(hexahydro-1H-pyrrolidine) substituted with two occurrences of 5 are compounds in which both are halogens (e.g., fluorine).

[0015] Provided herein as embodiment 12 is a compound according to embodiment 6, wherein R 1 is R 5 Provided herein as embodiment 13 is a compound according to embodiment 12, wherein R is 2-pyrrolidine substituted with 0-3 occurrences of 1 is R 5 Provided herein as embodiment 14 is a compound according to embodiment 13, wherein one R 5 is C 1~4 alkyl (e.g., methyl), and the other R 5is a compound in which is a halogen (e.g., fluorine).

[0016] Provided herein as embodiment 15 is a compound according to embodiment 5, wherein L is -O-isopentanylene (i.e., -O-2,2-dimethylethylene). Provided herein as embodiment 16 is a compound according to embodiment 15, wherein R 1 is a compound that is hydroxyl.

[0017] Provided herein as embodiment 17 is a compound according to embodiment 4, wherein L is -methylene. Provided herein as embodiment 18 is a compound according to embodiment 17, wherein R 1 is R 5 Provided herein as embodiment 19 is a compound according to embodiment 18, wherein R is N-morpholinyl substituted with 0-3 occurrences of 1 is R 5 The compound is N-morpholinyl substituted with 0 occurrences of

[0018] Provided herein as embodiment 20 is a compound according to embodiments 1-19, comprising LR 1 teeth, [ka] Provided herein as embodiment 21 is a compound according to embodiment 20, wherein the compound is LR 1 teeth, [ka] Provided herein as embodiment 22 is a compound according to embodiment 20, wherein the compound is LR 1 teeth, [ka] Provided herein as embodiment 23 is a compound according to embodiment 20, wherein the compound is LR 1 teeth, [ka] Provided herein as embodiment 24 is a compound according to embodiment 20, wherein the compound is LR 1 teeth, [ka] Provided herein as embodiment 25 is a compound according to embodiment 20, wherein 1 teeth, [ka] is a compound.

[0019] Provided herein as embodiment 26 is a compound according to any one of embodiments 1-25, wherein W is N.

[0020] Provided herein as embodiment 27 is a compound according to embodiment 26, wherein X is O. Provided herein as embodiment 28 is a compound according to embodiment 27, wherein n is 1 and m is 2, or m is 1 and n is 2. Provided herein as embodiment 29 is a compound according to embodiment 28, wherein p is 0.

[0021] Provided herein as embodiment 30 is a compound according to embodiment 28, wherein p is 1. Provided herein as embodiment 31 is a compound according to embodiment 30, wherein R x is hydroxyl, oxo, halogen, or -TR y Provided herein as embodiment 32 is a compound according to embodiment 31, wherein Rx R is hydroxyl, oxo, fluorine, or -SO2NH2. Provided herein as embodiment 33 are compounds according to embodiment 32, wherein R x is a compound which is hydroxyl, oxo, or fluorine.

[0022] Provided herein as embodiment 34 is a compound according to embodiment 28, wherein p is 2. Provided herein as embodiment 35 is a compound according to embodiment 34, wherein each R x is hydroxyl, halogen, C 1~4 Alkyl, C 1~4 haloalkyl or two R x are the bridging atoms, along with the carbon atoms to which they are attached, -C 1~4 Provided herein as embodiment 36 is a compound according to embodiment 35, wherein one R x is hydroxyl, and the other R x is C 1~4 Provided herein as embodiment 37 are compounds according to embodiment 35, wherein R is alkyl (e.g., methyl or ethyl). x and R are both halogen (e.g., fluorine). Provided herein as embodiment 38 are compounds according to embodiment 35, wherein one R x is hydroxyl, and the other R x is C 1~4 Provided herein as embodiment 39 are compounds according to embodiment 35, wherein two R are haloalkyl (e.g., difluoromethyl). x are compounds which, together with the carbon atoms to which they are attached, form a bridged ring, where the bridging atom is methylene or ethylene.

[0023] Provided herein as embodiment 40 is a compound described in embodiment 27, wherein n is 2 and m is 2. Provided herein as embodiment 41 is a compound described in embodiment 40, wherein p is 0. Provided herein as embodiment 42 is a compound described in embodiment 27, wherein m is 1 and n is 3. Provided herein as embodiment 43 is a compound described in embodiment 42, wherein p is 0.

[0024] Provided herein as embodiment 44 is a compound according to embodiment 26, wherein X is S(O)2. Provided herein as embodiment 45 is a compound according to embodiment 44, wherein n is 1 and m is 2, or m is 1 and n is 2. Provided herein as embodiment 46 is a compound according to embodiment 45, wherein p is 0.

[0025] Provided herein as embodiment 47 is a compound according to any one of embodiments 26-46, [ka] teeth, [ka] is a compound.

[0026] Provided herein as embodiment 48 is a compound according to embodiment 47, [ka] teeth, [ka] Provided herein as embodiment 49 is a compound according to embodiment 47, wherein [ka] teeth, [ka] Provided herein as embodiment 50 is a compound according to embodiment 47, wherein [ka] teeth, [ka] Provided herein as embodiment 51 is a compound according to embodiment 47, wherein [ka] teeth, [ka] Provided herein as embodiment 52 is a compound according to embodiment 47, wherein [ka] teeth, [ka] Provided herein as embodiment 53 is a compound according to embodiment 47, wherein [ka] teeth, [ka] Provided herein as embodiment 54 is a compound according to embodiment 47, wherein [ka] teeth, [ka] Provided herein as embodiment 55 is a compound according to embodiment 47, wherein [ka] teeth, [ka] Provided herein as embodiment 56 is a compound according to embodiment 47, wherein [ka] teeth, [ka] Provided herein as embodiment 57 is a compound according to embodiment 47, wherein [ka] teeth, [ka] Provided herein as embodiment 58 is a compound according to embodiment 47, wherein [ka] teeth, [ka] Provided herein as embodiment 59 is a compound according to embodiment 47, wherein [ka] teeth, [ka] Provided herein as embodiment 60 is a compound according to embodiment 47, wherein [ka] teeth, [ka] Provided herein as embodiment 61 is a compound according to embodiment 47, wherein [ka] teeth, [ka] Provided herein as embodiment 62 is a compound according to embodiment 47, wherein [ka] teeth, [ka] Provided herein as embodiment 63 is a compound as described in embodiment 47, wherein [ka] teeth, [ka] Provided herein as embodiment 64 is a compound according to embodiment 47, wherein [ka] teeth, [ka] Provided herein as embodiment 65 is a compound according to embodiment 47, wherein [ka] teeth, [ka] is a compound.

[0027] Provided herein as embodiment 66 is a compound according to embodiment 26, wherein X is CH. Provided herein as embodiment 67 is a compound according to embodiment 66, wherein n is 0 and m is 1, or m is 0 and n is 1.

[0028] Provided herein as embodiment 68 is a compound according to embodiment 67, wherein p is 1. Provided herein as embodiment 69 is a compound according to embodiment 68, wherein R x is C 1~4 Alkyl, cyano, or -TR y Provided herein as embodiment 70 is a compound according to embodiment 69, wherein R x is a compound in which is methyl, cyano, -CHOH, -CHCN, or -CHOMe.

[0029] Provided herein as embodiment 71 is a compound according to embodiment 67, wherein p is 2.

[0030] Provided herein as embodiment 72 is a compound according to embodiment 71, wherein each R x is C 1~4 Alkyl, hydroxyl, or -TR y or two R x With the same carbon atom, R yProvided herein as embodiment 73 are compounds according to embodiment 72, wherein one R x is methyl, and the other R x Provided herein as embodiment 74 is a compound according to embodiment 72, wherein one R x is methyl, and the other R x Provided herein as embodiment 75 is a compound according to embodiment 72, wherein R x Both have the same carbon atom and R y Provided herein as embodiment 76 is a compound according to embodiment 75, wherein R y are both oxo compounds.

[0031] Provided herein as embodiment 77 is a compound according to any one of embodiments 66-76, [ka] teeth, [ka] is a compound.

[0032] Provided herein as embodiment 78 is a compound according to embodiment 77, [ka] teeth, [ka] Provided herein as embodiment 79 is a compound according to embodiment 77, wherein [ka] teeth, [ka] Provided herein as embodiment 80 is a compound according to embodiment 77, wherein [ka] teeth, [ka] Provided herein as embodiment 81 is a compound according to embodiment 77, wherein [ka] teeth, [ka] Provided herein as embodiment 82 is a compound according to embodiment 77, wherein [ka] teeth, [ka] Provided herein as embodiment 83 is a compound according to embodiment 77, wherein [ka] teeth, [ka] Provided herein as embodiment 84 is a compound according to embodiment 77, wherein [ka] teeth, [ka] Provided herein as embodiment 85 is a compound according to embodiment 77, wherein [ka] teeth, [ka] Provided herein as embodiment 86 is a compound according to embodiment 77, wherein [ka] teeth, [ka] is a compound.

[0033] Provided herein as embodiment 87 is a compound according to embodiment 66, wherein n is 1 and m is 1. Provided herein as embodiment 88 is a compound according to embodiment 87, wherein p is 0. Provided herein as embodiment 89 is a compound according to embodiment 87, wherein p is 1. Provided herein as embodiment 90 is a compound according to embodiment 89, wherein R x is hydroxyl, cyano, or -TR y Provided herein as embodiment 91 is a compound according to embodiment 90, wherein R x is a compound that is hydroxyl, cyano, or -S(O)2-NH2.

[0034] Provided herein as embodiment 92 is a compound according to embodiment 87, wherein p is 2. Provided herein as embodiment 93 is a compound according to embodiment 92, wherein each R x is hydroxyl, C 1~4Alkyl, -TR y or two R x With the same carbon atom, R y C replaced with 0-3 occurrences of 3~7 Provided herein as embodiment 94 are compounds according to embodiment 93, wherein one R x is hydroxyl, and the other R x Provided herein as embodiment 95 is a compound according to embodiment 93, wherein one R x is hydroxyl, and the other R x Provided herein as embodiment 96 is a compound according to embodiment 93, wherein one R x is methyl, and the other R x Provided herein as embodiment 97 is a compound according to embodiment 93, wherein one R x is methyl, and the other R x is a compound that is -C(O)NH2.

[0035] Provided herein as embodiment 98 is a compound according to embodiment 93, comprising two R x With the same carbon atom, R y Provided herein as embodiment 99 is a compound according to embodiment 98, wherein R y Provided herein as embodiment 100 are compounds according to embodiment 93, wherein two R x With the same carbon atom, R y Provided herein as embodiment 101 is a compound according to embodiment 100, wherein R y is a compound which is oxo.

[0036] Provided herein as embodiment 102 is a compound according to embodiment 93, comprising two R x With the same carbon atom, -TR y Provided herein as embodiment 103 is a compound according to embodiment 102, wherein one occurrence of -TR y is the compound -SO2-Me.

[0037] Provided herein as embodiment 104 is a compound according to embodiment 93, comprising two R x With the same carbon atom, R y Provided herein as embodiment 105 is a compound according to embodiment 104, wherein R y is a compound which is oxo.

[0038] Provided herein as embodiment 106 is a compound according to embodiment 93, comprising two R x With the same carbon atom, R y Provided herein as embodiment 107 are compounds according to embodiment 93, comprising two R x With the same carbon atom, R y is a compound having 0 occurrences of substituted 2-oxetanyl.

[0039] Provided herein as embodiment 108 is a compound according to embodiment 93, comprising two R x With the same carbon atom, R y Provided herein as embodiment 109 is a compound according to embodiment 108, wherein R y are both oxo compounds.

[0040] Provided herein as embodiment 110 is a compound according to embodiment 93, comprising two R x With the same carbon atom, R y Provided herein as embodiment 111 is a compound according to embodiment 110, wherein R y are both oxo compounds.

[0041] Provided herein as embodiment 112 is a compound according to embodiment 93, comprising two R x With the same carbon atom, R y Provided herein as embodiment 113 is a compound according to embodiment 93, comprising two R x With the same carbon atom, R y is a compound in which 0 occurrences of form a substituted 3-tetrahydrofuranyl.

[0042] Provided herein as embodiment 114 is a compound according to any one of embodiments 87 to 113, [ka] teeth, [ka] is a compound.

[0043] Provided herein as embodiment 115 is a compound according to embodiment 114, [ka] teeth, [ka] Provided herein as embodiment 116 is a compound according to embodiment 114, wherein [ka] teeth, [ka] Provided herein as embodiment 117 is a compound according to embodiment 114, wherein [ka] teeth, [ka] Provided herein as embodiment 118 is a compound according to embodiment 114, wherein [ka] teeth, [ka] Provided herein as embodiment 119 is a compound according to embodiment 114, wherein [ka] teeth, [ka] Provided herein as embodiment 120 is a compound according to embodiment 114, wherein [ka] teeth, [ka] Provided herein as embodiment 121 is a compound according to embodiment 114, wherein [ka] teeth, [ka] Provided herein as embodiment 122 is a compound according to embodiment 114, wherein [ka] teeth, [ka] Provided herein as embodiment 123 is a compound according to embodiment 114, wherein [ka] teeth, [ka] Provided herein as embodiment 124 is a compound according to embodiment 114, wherein [ka] teeth, [ka] Provided herein as embodiment 125 is a compound according to embodiment 114, wherein [ka] teeth, [ka] Provided herein as embodiment 126 is a compound according to embodiment 114, wherein [ka] teeth, [ka] Provided herein as embodiment 127 is a compound according to embodiment 114, wherein [ka] teeth, [ka] Provided herein as embodiment 128 is a compound according to embodiment 114, wherein [ka] teeth, [ka] Provided herein as embodiment 129 is a compound according to embodiment 114, wherein [ka] teeth, [ka] Provided herein as embodiment 130 is a compound according to embodiment 114, wherein [ka] teeth, [ka] Provided herein as embodiment 131 is a compound according to embodiment 114, wherein [ka] teeth, [ka] Provided herein as embodiment 132 is a compound according to embodiment 114, wherein [ka] teeth, [ka] Provided herein as embodiment 133 is a compound according to embodiment 114, wherein [ka] teeth, [ka] Provided herein as embodiment 134 is a compound according to embodiment 114, wherein [ka] teeth, [ka] Provided herein as embodiment 135 is a compound according to embodiment 114, wherein [ka] teeth, [ka] Provided herein as embodiment 136 is a compound according to embodiment 114, wherein [ka] teeth, [ka] is a compound.

[0044] Provided herein as embodiment 137 is a compound according to embodiment 66, wherein n is 1 and m is 2, or m is 1 and n is 2. Provided herein as embodiment 138 is a compound according to embodiment 137, wherein p is 0. Provided herein as embodiment 139 is a compound according to embodiment 137, wherein p is 1. Provided herein as embodiment 140 is a compound according to embodiment 139, wherein R x is halogen, cyano, oxo, hydroxyl, C 1~4 Alkyl, or -TR y Provided herein as embodiment 141 is a compound according to embodiment 140, wherein R x is a compound which is fluorine, cyano, oxo, hydroxyl, or -SO2-NH2.

[0045] Provided herein as embodiment 142 are compounds according to embodiment 137, wherein p is 2. Provided herein as embodiment 143 are compounds according to embodiment 142, wherein one R x is hydroxyl, and the other R x is C 1~4 A compound that is an alkyl (e.g., methyl).

[0046] Provided herein as embodiment 144 are compounds according to embodiment 137, wherein p is 3. Provided herein as embodiment 145 are compounds according to embodiment 144, wherein two R x form a bridged ring together with the carbon atoms to which they are attached, where the bridging atom is -C 1~4 alkylene, and the remaining R x Provided herein as embodiment 146 is a compound according to embodiment 145, wherein two R x form a methylene bridged ring together with the carbon atom to which they are attached, and the remaining R x is a compound that is hydroxyl.

[0047] Provided herein as embodiment 147 is a compound described in embodiment 66, wherein n is 2 and m is 2. Provided herein as embodiment 148 is a compound described in embodiment 147, wherein p is 0.

[0048] Provided herein as embodiment 149 is a compound according to any one of embodiments 137-148, [ka] teeth, [ka] is a compound.

[0049] Provided herein as embodiment 150 is a compound according to embodiment 149, [ka] teeth, [ka] Provided herein as embodiment 151 is a compound according to embodiment 149, wherein [ka] teeth, [ka] Provided herein as embodiment 152 is a compound according to embodiment 149, wherein [ka] teeth, [ka] Provided herein as embodiment 153 is a compound according to embodiment 149, wherein [ka] teeth, [ka] Provided herein as embodiment 154 is a compound according to embodiment 149, wherein [ka] teeth, [ka] Provided herein as embodiment 155 is a compound according to embodiment 149, wherein [ka] teeth, [ka] Provided herein as embodiment 156 is a compound according to embodiment 149, wherein [ka] teeth, [ka] Provided herein as embodiment 157 is a compound according to embodiment 149, wherein [ka] teeth, [ka] Provided herein as embodiment 158 ​​is a compound according to embodiment 149, wherein [ka] teeth, [ka] Provided herein as embodiment 159 is a compound according to embodiment 149, wherein [ka] teeth, [ka] Provided herein as embodiment 160 is a compound according to embodiment 149, wherein [ka] teeth, [ka] Provided herein as embodiment 161 is a compound according to embodiment 149, wherein [ka] teeth, [ka] Provided herein as embodiment 162 is a compound according to embodiment 149, wherein [ka] teeth, [ka] Provided herein as embodiment 163 is a compound according to embodiment 149, wherein [ka] teeth, [ka] is a compound.

[0050] Provided herein as embodiment 164 is a compound according to embodiment 26, wherein X is -CH=CH-. Provided herein as embodiment 165 is a compound according to embodiment 164, wherein n is 1 and m is 1. Provided herein as embodiment 166 is a compound according to embodiment 165, wherein p is 1. Provided herein as embodiment 167 is a compound according to embodiment 166, wherein R x is a compound that is hydroxyl.

[0051] Provided herein as embodiment 168 is a compound according to any one of embodiments 164 to 167, [ka] teeth, [ka] is a compound.

[0052] Provided herein as embodiment 169 is a compound according to any one of embodiments 1 or 2, wherein W is -C=. Provided herein as embodiment 170 is a compound according to embodiment 169, wherein X is O. Provided herein as embodiment 171 is a compound according to embodiment 170, wherein [ka] is a double bond. Provided herein as embodiment 172 are compounds according to embodiment 171, wherein n is 0 and m is 2. Provided herein as embodiment 173 are compounds according to embodiment 172, wherein p is 0.

[0053] Provided herein as embodiment 174 is a compound according to any one of embodiments 169 to 173, [ka] teeth, [ka] is a compound.

[0054] Provided herein as embodiment 175 is a compound according to any one of embodiments 1 or 2, wherein W is -CH-. Provided herein as embodiment 176 is a compound according to embodiment 175, wherein X is a bond. Provided herein as embodiment 177 is a compound according to embodiment 176, wherein [ka] is a single bond. Provided herein as embodiment 178 are compounds according to embodiment 177, wherein n is 0 and m is 0. Provided herein as embodiment 179 are compounds according to embodiment 178, wherein p is 0.

[0055] Provided herein as embodiment 180 is a compound according to any one of embodiments 175-179, [ka] teeth, [ka] is a compound.

[0056] Provided herein as embodiment 181 is a compound according to any one of embodiments 1 to 180, wherein R 8 is amino, R 9 is a compound that is cyano.

[0057] Provided herein as embodiment 182 is a compound according to any one of embodiments 1 to 181, wherein R 2 is a halogen, C 1~4 Alkyl, C 2~4 Provided herein as embodiment 183 are compounds according to embodiment 182, wherein R is aryl, aryl, or cyano. 2 R is chlorine, methyl, ethyl, vinyl, or cyano. Provided herein as embodiment 184 are compounds according to embodiment 182, wherein R 2 Provided herein as embodiment 185 is a compound according to embodiment 182, wherein R is chlorine. 2Provided herein as embodiment 186 are compounds according to embodiment 182, wherein R 2 Provided herein as embodiment 187 is a compound according to embodiment 182, wherein R 2 Provided herein as embodiment 188 is a compound according to embodiment 182, wherein R 2 Provided herein as embodiment 189 are compounds according to embodiment 182, wherein R 2 is a compound that is cyano.

[0058] Provided herein as embodiment 190 is a compound according to any one of embodiments 1 to 189, wherein R 4 is a compound in which is a halogen (e.g., fluorine).

[0059] Provided herein as embodiment 191 is a compound according to any one of embodiments 1 to 190, wherein R 4 is a compound in which is fluorine.

[0060] Provided herein as embodiment 192 is a compound according to any one of embodiments 1 to 191, wherein R 3 is hydrogen or halogen (e.g., fluorine). Provided herein as embodiment 193 are compounds according to embodiment 192, wherein R 3 Provided herein as embodiment 194 is a compound according to embodiment 192, wherein R 3 is a compound in which is fluorine.

[0061] Provided herein as embodiment 195 is a compound according to any one of embodiments 1 to 194, wherein R qProvided herein as embodiment 196 is a compound according to any one of embodiments 1 to 194, wherein R q is a halogen (e.g., chlorine or fluorine). Provided herein as embodiment 197 are compounds according to any one of embodiments 1 to 194, wherein R q is C 1~4 A compound that is an alkyl (e.g., methyl).

[0062] Provided herein as embodiment 198 is a compound according to any one of embodiments 1 to 197, wherein R q is represented by formula (IIa): [ka] The compound is bonded as shown in FIG.

[0063] Provided herein as embodiment 199 is a compound according to any one of embodiments 1 to 198, wherein R q is represented by formula (IIb): [ka] The compound is bonded as shown in FIG.

[0064] Provided herein as embodiment 200 is a compound according to any one of embodiments 1 to 199, wherein R q is represented by formula (IIc): [ka] The compound is bonded as shown in FIG.

[0065] Provided herein as embodiment 201 is a compound according to any one of embodiments 1 to 200, wherein R q is represented by formula (IId): [ka] The compound is bonded as shown in FIG.

[0066] Provided herein as embodiment 201 is a compound according to embodiment 1, comprising the compound: 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,5-oxazocane-5-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-oxoazepan-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-4-(6-ethyl-6-hydroxy-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-3-hydroxyazepan-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-4-(3-fluoroazepan-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-Amino-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-vinylquinazolin-7-yl)benzo[b]thiophene-3-carbonitrile; 2-amino-4-(4-(azepan-1-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 1-(7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)azepane-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-4-(6-fluoro-1,4-oxazepan-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-Amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(4-oxoazepan-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-4-(6-fluoro-1,4-oxazepan-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-6-hydroxy-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-hydroxy-2,3,6,7-tetrahydro-1H-azepin-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazocane-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-4-(6,6-difluoro-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-Amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-3-hydroxyazepan-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-hydroxy-3-methylazepan-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-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)-7-fluorobenzo[b]thiophene-3-carbonitrile; 1-(7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)azepane-4-carbonitrile; (2S)-1-(7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)pyrrolidine-2-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-oxo-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-4-(6-(difluoromethyl)-6-hydroxy-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; or 2-Amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile The compound is selected from one of the following:

[0067] Provided herein as embodiment 202 is a compound according to embodiment 1, comprising: 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,5-oxazocane-5-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-oxoazepan-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-4-(6-ethyl-6-hydroxy-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-3-hydroxyazepan-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-4-(3-fluoroazepan-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-Amino-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-vinylquinazolin-7-yl)benzo[b]thiophene-3-carbonitrile; 2-amino-4-(4-(azepan-1-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; or 1-(7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)azepane-3-carbonitrile The compound is selected from one of the following:

[0068] Provided herein as embodiment 203 is a compound according to embodiment 1, comprising: 2-Amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,5-oxazocane-5-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (isomer 1); 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (isomer 1); 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-oxoazepan-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-4-(6-ethyl-6-hydroxy-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (isomer 1); 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-3-hydroxyazepan-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-4-(3-fluoroazepan-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-Amino-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-vinylquinazolin-7-yl)benzo[b]thiophene-3-carbonitrile; 2-amino-4-(4-(azepan-1-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 1-(7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)azepane-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-4-(6-fluoro-1,4-oxazepan-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (isomer 2); 2-Amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(4-oxoazepan-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-4-(6-fluoro-1,4-oxazepan-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (isomer 1); 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-6-hydroxy-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-hydroxy-2,3,6,7-tetrahydro-1H-azepin-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazocane-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-4-(6,6-difluoro-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-Amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-3-hydroxyazepan-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-Amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-hydroxy-3-methylazepan-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3carbonitrile (isomer 1); 2-amino-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)-7-fluorobenzo[b]thiophene-3-carbonitrile; 1-(7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)azepane-4-carbonitrile; (2S)-1-(7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)pyrrolidine-2-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-oxo-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-4-(6-(difluoromethyl)-6-hydroxy-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (isomer 1); or 2-Amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile The compound is selected from one of the following:

[0069] Provided herein as embodiment 204 is a compound according to embodiment 1, comprising: 2-Amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,5-oxazocane-5-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (isomer 1); 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (isomer 1); 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-oxoazepan-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-4-(6-ethyl-6-hydroxy-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (isomer 1); 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-3-hydroxyazepan-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-4-(3-fluoroazepan-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-Amino-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-vinylquinazolin-7-yl)benzo[b]thiophene-3-carbonitrile; 2-amino-4-(4-(azepan-1-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; or 1-(7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)azepane-3-carbonitrile The compound is selected from one of the following:

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

[0071] Formulation and Route of Administration In the described 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 diluents, carriers, adjuvants, 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.

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

[0073] The pharmaceutical composition may be in the form of, for example, a tablet, chewable tablet, mini-tablet, caplet, pill, bead, hard capsule, soft capsule, gelatin capsule, granule, powder, lozenge, patch, cream, gel, sachet, microneedle array, syrup, flavored syrup, juice, drop, injection, emulsion, microemulsion, ointment, aerosol, aqueous suspension, or oily suspension. The pharmaceutical composition may be made in the form of a dosage unit typically containing a particular amount of the active ingredient.

[0074] Provided herein as embodiment 205 is a pharmaceutical composition comprising a compound according to any one of embodiments 1-204, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, and a pharma- ceutically acceptable excipient.

[0075] Provided herein as embodiment 206 is a compound according to any one of embodiments 1 to 204, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 205, for use as a medicament.

[0076] How to use As described 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 above, or solvates of any of the above. Thus, the scope of methods and uses provided in this disclosure should be understood to encompass methods and uses using all such forms.

[0077] In addition to being useful for human treatment, the compounds provided herein may be useful for veterinary treatment of companion animals, exotic animals, and farm animals, including mammals, rodents, etc. For example, animals including horses, dogs, and cats may be treated with the compounds provided herein.

[0078] In one embodiment, the disclosure provides a method of treating a disease state using a compound or pharmaceutical composition of the disclosure, including but not limited to a condition involving KRAS G12D, G12V, G12A, G12S, or G12C mutations (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.

[0079] KRAS G12D mutations occur with the alteration frequencies shown in the table below (TCGA dataset; 1~3 For example, this table shows that 32.4% of subjects with pancreatic cancer have cancer in which one or more cells express the KRAS G12D mutant protein. G12D The 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.

[0080] [Table 1]

[0081] Provided herein as embodiment 207 is a compound according to any one of embodiments 1 to 204, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 205, for use in treating cancer.

[0082] Provided herein as embodiment 208 is a compound according to any one of embodiments 1 to 204, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 205, for use in the treatment of cancer, wherein one or more cells express a KRAS G12D, G12V, G12A, G12S, or G12C mutant protein.

[0083] Provided herein as embodiment 209 is a compound or pharmaceutical composition for use according to embodiment 207 or 208, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small intestine cancer, appendix cancer, cancer of unknown primary site, endometrial cancer, mixed cancer type, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

[0084] Provided herein as embodiment 210 is the use of a compound according to any one of embodiments 1 to 204, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 205, in the preparation of a medicament for treating cancer.

[0085] Provided herein as embodiment 211 is the use of a compound according to any one of embodiments 1 to 204, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 205, in the preparation of a medicament for treating a cancer, wherein one or more cells express a KRAS G12D, G12V, G12A, G12S, or G12C mutant protein.

[0086] Provided herein as embodiment 212 is the use according to embodiment 210 or 211, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer type, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

[0087] Provided herein as embodiment 213 is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described in any one of embodiments 1 to 204, or a pharma- ceutically acceptable salt thereof.

[0088] Provided herein as embodiment 214 is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described in any one of embodiments 1-204, or a pharma- ceutically acceptable salt thereof, wherein one or more cells express a KRAS G12D, G12V, G12A, G12S, or G12C mutant protein.

[0089] Provided herein as embodiment 215 is the method of embodiment 213 or 214, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer type, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine carcinoma, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

[0090] Provided herein as embodiment 216 is the method of embodiment 213 or 214, 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.

[0091] Provided herein as embodiment 217 is the method of embodiment 216, wherein the cancer is non-small cell lung cancer.

[0092] Provided herein as embodiment 218 is the method of embodiment 216, wherein the cancer is colorectal cancer.

[0093] Provided herein as embodiment 219 is the method of embodiment 216, wherein the cancer is pancreatic cancer.

[0094] Provided herein as embodiment 220 is the method of any one of embodiments 213-219, wherein the subject has a 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.

[0095] Combination therapy The present disclosure also provides 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 treatments 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.

[0096] Provided herein as embodiment 221 is the method of any one of embodiments 190-197, 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.

[0097] 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.

[0098] Aurora kinase A inhibitors Provided herein is a method according to any one of embodiments 213 to 220, 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.

[0099] Exemplary Aurora kinase A inhibitors for use in the methods provided herein include, but are not limited to, alisertib, cenisertib, danusertib, tozasertib, LY3295668 ((2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyridin-2-yl]methyl]-2-methylpiperidine-4-carboxylic acid), ENMD-2076 (6-(4- Methylpiperazin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[(E)-2-phenylethenyl]pyrimidin-4-amine), TAK-901 (5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide), TT-00420 (4-[9-(2-chlorophenyl)-6-methyl-2,4,5,8,12-pentazatricyclo[8.4.0.03,7]tetradeca-1(14),3,6,8,10,12-hexaen-13-yl]morpholine), AMG 900 (N-[4-[3-(2-aminopyrimidin-4-yl)pyridin-2-yl]oxyphenyl]-4-(4-methylthiophen-2-yl)phthalazin-1-amine), MLN 8054 (4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid), PF-03814735 (N-[2-[(1R,8S)-4-[[4-(cyclobutylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-11-azatricyclo[6.2.1.02,7]undec-2(7),3,5-trifluorophenyl)pyrimidin-2-yl)amino) [1-(3-chlorophenyl)-3-[5-[2-(thieno[3,2-d]pyrimidin-4-ylamino)ethyl]-1,3-thiazol-2-yl]urea), CYC116 (4-methyl-5-[2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]-1,3-thiazol-2-amine), TAS-119, BI 811283, and TTP607.

[0100] AKT inhibitors Provided herein is a method according to any one of embodiments 213 to 220, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an AKT inhibitor.

[0101] Exemplary AKT inhibitors for use in the methods provided herein include, but are not limited to, afarestib, capivasertib, ipatasertib, uprosertib, BAY1125976 (2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide), ARQ 092 (3-[3-[4-(1-aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2-amine), MK2206 (8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one), SR13668 (indolo[2,3-b]carbazole-2,10-dicarboxylic acid, 5,7-dihydro-6-methoxy-, 2,10 -diethyl ester), ONC201 (11-benzyl-7-[2-methylphenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one), ARQ751 (N-(3-aminopropyl)-N-[(1R)-1-(3-anilino-7-chloro-4-oxoquinazolin-2-yl)but-3-ynyl]-3-chloro-2-fluorobenzamide), RX-0201, and LY2780301.

[0102] Arginase inhibitors Provided herein are methods according to any one of embodiments 213 to 220, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an arginase inhibitor.

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

[0104] CDK4 / 6 inhibitors Provided herein is a method according to any one of embodiments 213 to 220, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a CDK4 / 6 inhibitor.

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

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

[0107] Exemplary CDK4 / 6 inhibitors for use in the methods provided herein include, but are not limited to, abemaciclib, palbociclib, ribociclib, trilaciclib, and PF-06873600 ((pyrido[2,3-d]pyrimidin-7(8H)-one, 6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[[1-(methylsulfonyl)-4-piperidinyl]amino]).

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

[0109] ErbB family inhibitors Provided herein is a method according to any one of embodiments 213 to 220, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an ErbB family inhibitor.

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

[0111] The term "ErbB family inhibitor" as used herein refers to an agent (e.g., a compound or an antibody) capable of negatively modulating or inhibiting all or part of the activity of at least one member of the ErbB family. Modulation or inhibition of one or more ErbB tyrosine kinases can occur by modulating or inhibiting the kinase enzymatic activity of one or more ErbB family members, or by blocking homodimerization or heterodimerization of ErbB family members.

[0112] In one embodiment, the ErbB family inhibitor is an EGFR inhibitor, for example, an anti-EGFR antibody.Exemplary anti-EGFR antibodies 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.

[0113] In another embodiment, the ErbB family inhibitor is a HER2 inhibitor, e.g., 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.

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

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

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

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

[0118] In one embodiment, the ErbB family inhibitor is a reversible inhibitor. Exemplary reversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to, erlotinib, gefitinib, sapitinib, varlitinib, tarloxotinib, TAK-285 (N-(2-(4-((3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl)-3-hydroxy-3-methylbutanamide), AEE788 ((S)-6-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-N-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine), BMS 599626 ((3S)-3-morpholinylmethyl-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamate), and GW 583340 (N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[2-[(2-methylsulfonylethylamino)methyl]-1,3-thiazol-4-yl]quinazolin-4-amine).

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

[0120] ERK inhibitors Provided herein is a method according to any one of embodiments 213-220, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an ERK inhibitor.

[0121] Exemplary ERK inhibitors for use in the methods provided herein include, but are not limited to, 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-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5-(2-morpholin-4-ylethyl)thieno[2,3-c]pyrrol-4-one), KO-947 (1,5,6,8-tetrahydro-6-(phenylmethyl)-3-(4-pyridinyl)-7H-pyrazolo[4,3-g]quinazolin-7-one), ASTX029, LTT462, and JSI-1187.

[0122] FAK inhibitors Provided herein is a method according to any one of embodiments 213 to 220, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a FAK inhibitor.

[0123] Exemplary FAK inhibitors for use in the methods provided herein include, but are not limited to, GSK2256098 (2-[[5-chloro-2-[(5-methyl-2-propan-2-ylpyrazol-3-yl)amino]pyridin-4-yl]amino]-N-methoxybenzamide), PF-00562271 (N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]methyl]pyridin-2-yl]methanesulfonamide), VS-4718 (2-[[2-(2-methoxy-4-morpholin-4-ylanilino)-5-(trifluoromethyl)pyridin-4-yl]amino]-N-methylbenzamide), and APG-2449.

[0124] FGFR inhibitors Provided herein is a method according to any one of embodiments 213 to 220, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an FGFR inhibitor.

[0125] Exemplary FGFR inhibitors for use in the methods provided herein include, but are not limited to, futibatinib, pemigatinib, ASP5878 (2-[4-[[5-[(2,6-difluoro-3,5-dimethoxyphenyl)methoxy]pyrimidin-2-yl]amino]pyrazol-1-yl]ethanol), AZD4547 (N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]benzamide). ), Debio 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.

[0126] Glutaminase Inhibitors Provided herein is a method according to any one of embodiments 213 to 220, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a glutaminase inhibitor.

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

[0128] IGF-1R inhibitors Provided herein is a method according to any one of embodiments 213 to 220, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an IGF-1R inhibitor.

[0129] Exemplary IGF-1R inhibitors for use in the methods provided herein include, but are not limited to, cixutumumab, dalotuzumab, linsitinib, ganitumab, lobatumumab, BMS-754807 ((2S)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]- N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide), KW-2450 (N-[5-[[4-(2-hydroxyacetyl)piperazin-1-yl]methyl]-2-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-3-methylthiophene-2-carboxamide), PL225B, AVE1642, and BIIB022.

[0130] KIF18A inhibitors Provided herein is a method according to any one of embodiments 213 to 220, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a KIF18A inhibitor.

[0131] Exemplary KIF18A inhibitors for use in the methods provided herein include, but are not limited to, those disclosed in U.S. Patent Application Publication No. 2020 / 0239441, WO 2020 / 132649, WO 2020 / 132651, and WO 2020 / 132653 (each of which is incorporated by reference in its entirety).

[0132] MCL-1 inhibitors Provided herein is the method of any one of embodiments 213-220, further comprising simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an MCL-1 inhibitor.

[0133] Exemplary MEK inhibitors for use in the methods provided herein include, but are not limited to, murizatoclax, topotoclax, AZD 5991 ((3aR)-5-chloro-2,11,12,24,27,29-hexahydro-2,3,24,33-tetramethyl-22H-9,4,8-(metheniminomethino)-14,20:26,23-dimetheno-10H,20H-pyrazolo[4,3-l][2,15,22,18,19]benzoxadithiadiazacyclohexacosine-32-carboxylic acid), 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.

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

[0135] MEK inhibitors Provided herein is a method according to any one of embodiments 213 to 220, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a MEK inhibitor.

[0136] Exemplary MEK inhibitors for use in the methods provided herein include, but are not limited to, trametinib, cobimetinib, selumetinib, pimasertib, refametinib, PD-325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), AZD8330 (2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1,5-dimethyl- 6-oxopyridine-3-carboxamide), GDC-0623 (5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide), RO4987655 (3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-5-[(3-oxooxazinan-2-yl)methyl]benzamide), TAK-733 (3-[(2R)-2,3-dihydroxypropyl]- 6-Fluoro-5-(2-fluoro-4-iodoanilino)-8-methylpyrido[2,3-d]pyrimidine-4,7-dione), PD0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), CI-1040 (2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide), PD318088 (5-bromo-N-(2, 3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide), PD98059 (2-(2-amino-3-methoxyphenyl)-4H-chromen-4-one), PD334581 (N-[5-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl]-1,3,4-oxadiazol-2-yl]-4-morpholineethanamine), FCN-159, CS3006, HL-085, SHR 7390, and WX-554.

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

[0138] mTOR inhibitors Provided herein are methods according to any one of embodiments 213 to 220, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an mTOR inhibitor.

[0139] Exemplary mTOR inhibitors for use in the methods provided herein include, but are not limited to, everolimus, rapamycin, zotarolimus (ABT-578), ridaforolimus (deforolimus, MK-8669), sapanisertib, buparlisib, pictilisib, bistosertib, dactolisib, torin-1 (1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)cyclohexyl)-9-(quinolinol), cyclohexyl stearate, ... (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-7-(oxetan-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea), and VS-5584 (SB2343, (5-(8-methyl-2-morpholin-4-yl-9-propan-2-ylpurin-6-yl)pyrimidin-2-amine).

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

[0141] PD-1 inhibitors Provided herein is the method of any one of embodiments 213-220, further comprising simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a PD-1 inhibitor.

[0142] Exemplary PD-1 inhibitors for use in the methods provided herein include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (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, line 24, and col. 67, lines 54-57), which are incorporated by reference herein.

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

[0144] PD-L1 inhibitors Provided herein is the method of any one of embodiments 213-220, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a PD-L1 inhibitor.

[0145] Exemplary PD-L1 inhibitors for use in the methods provided herein include, but are not limited to, atezolizumab, avelumab, durvalumab, ZKAB001, TG-1501, SHR-1316, MSB2311, MDX-1105, KN035, IMC-001, HLX20, FAZ053, CS1001, CK-301, CBT-502, BGB-A333, BCD-135, and A167.

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

[0147] PI3K inhibitors Provided herein is a method according to any one of embodiments 213 to 220, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a PI3K inhibitor.

[0148] Exemplary PI3K inhibitors for use in the methods provided herein include, but are not limited to, 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-methylpyridine, ... 4-methyl-1,3,5-triazin-2-amine), ME-401 (N-[2-methyl-1-[2-(1-methylpiperidin-4-yl)phenyl]propan-2-yl]-4-(2-methylsulfonylbenzimidazol-1-yl)-6-morpholin-4-yl-1,3,5-triazin-2-amine), IPI-549 (2-amino-N-[(1S)-1-[8-[ 2-(1-methylpyrazol-4-yl)ethynyl]-1-oxo-2-phenylisoquinolin-3-yl]ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide), SF1126 (((2S)-2-[[(2S)-3-carboxy-2-[[2-[[(2S)-5-(diaminomethylideneamino)-2-[[4-oxo-4-[[4-(4-oxo-8-phenylchromen-2-yl)morpholin-4-ium-4-yl]meth [Ci]butanoyl]amino]pentanoyl]amino]acetyl]amino]propanoyl]amino]-3-hydroxypropanoate), XL147 (N-[3-(2,1,3-benzothiadiazol-5-ylamino)quinoxalin-2-yl]-4-methylbenzenesulfonamide), GSK1059615 ((5Z)-5-[(4-pyridin-4-ylquinolin-6-yl)methylidene]-1,3-thiazolidine-2,4-dione), and AMG 319 (N-[(1S)-1-(7-fluoro-2-pyridin-2-ylquinolin-3-yl)ethyl]-7H-purin-6-amine).

[0149] Raf kinase inhibitors Provided herein is a method according to any one of embodiments 213 to 220, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a Raf kinase inhibitor.

[0150] The term "RAF kinase," as used herein, refers to a member of the mammalian serine / threonine kinases that are composed of three isoforms (C-Raf, B-Raf, and A-Raf), including homodimers of each isoform and heterodimers between the isoforms (e.g., C-Raf / B-Raf heterodimers).

[0151] The term "Raf kinase inhibitor," as used herein, 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 to a compound capable of disrupting Raf homo- or heterodimer formation, thereby inhibiting activity.

[0152] In one embodiment, Raf kinase inhibitors include, but are not limited to, encorafenib, sorafenib, lifirafenib, vemurafenib, dabrafenib, PLX-8394 (N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-3a,7a-dihydro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide), Raf-709 (N-(2-methyl-5- Morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide), LXH254 (N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide), LY3009120 (1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino) pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea), Tak-632 (N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide), CEP-32496 (1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazole- 3-yl)urea), CCT196969 (1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-((3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yl)oxy)phenyl)urea), and RO5126766 (N-[3-fluoro-4-[[4-methyl-2-oxo-7-(2-pyrimidinyloxy)-2H-1-benzopyran-3-yl]methyl]-2-pyridinyl]-N'-methyl-sulfamide).

[0153] In one embodiment, the Raf kinase inhibitor is encorafenib. In one embodiment, the Raf kinase inhibitor is sorafenib. In one embodiment, the Raf kinase inhibitor is lifirafenib.

[0154] SHP2 Inhibitors Provided herein are methods according to any one of embodiments 213-220, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an SHP2 inhibitor.

[0155] Exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, SHP-099 (6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine dihydrochloride), RMC-4550 ([3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl]methanol), TNO155 ((3S,4S)-8-[6-amino-5-(2-amino-3-chloropyridin-4-yl)sulfanylpyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine), and RMC-4630 (Revolution Medicine). In one embodiment, the SHP inhibitor used in the methods provided herein is RMC-4630 (Revolution Medicine).

[0156] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 3-[(1R,3R)-1-amino-3-methoxy-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyrazinemethanol (CAS 2172651-08-8), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2-pyrazinemethanol (CAS 2172652-13-8), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-[[3-chloro-2-(3-hydroxy-1-azetidinyl)-4-pyridinyl]thio]-5-methyl-2-pyrazinemethanol (CAS 2172652-38-7), and 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-methyl-2-pyrazinemethanol (CAS 2172652-48-9).

[0157] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 1-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-4-methyl-4-piperidinamine (CAS 2240981-75-1), (1R)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine (CAS 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]decane-4-amine (CAS 2240982-77-6).

[0158] 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).

[0159] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-54-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56-5), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-(2,3-dichlorophenyl)-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.

[0160] 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).

[0161] 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.

[0162] SOS1 inhibitors Provided herein is a method according to any one of embodiments 213 to 220, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an SOS1 inhibitor.

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

[0164] Src kinase inhibitors Provided herein is a method according to any one of embodiments 213-220, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a Src kinase inhibitor.

[0165] The term "Src kinase," as used herein, refers to members of the mammalian non-receptor tyrosine kinase family including Src, Yes, Fyn, and Fgr (SrcA subfamily); Lck, Hck, Blk, and Lyn (SrcB subfamily), and the Frk subfamily.

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

[0167] Exemplary Src kinase inhibitors for use in the methods provided herein include, but are not limited to, dasatinib, ponatinib, vandetanib, bosutinib, saracatinib, KX2-391 (N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide), SU6656 ((Z)-N,N-dimethyl-2-oxo-3-((4,5,6,7-tetrahydro-1H-indol-2-yl)methylene)indoline-5-sulfonamide), PP 1 (1-(tert-butyl)-3-(p-tolyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), WH-4-023 (2,6-dimethylphenyl(2,4-dimethoxyphenyl)(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)carbamate), and KX-01 (N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide).

[0168] In one embodiment, the Src kinase inhibitor is dasatinib. In one embodiment, the Src kinase inhibitor is saracatinib. In one embodiment, the Src kinase inhibitor is ponatinib. In one embodiment, the Src kinase inhibitor is vandetanib. In one embodiment, the Src kinase inhibitor is KX-01.

[0169] Chemotherapeutic agents Provided herein are methods according to any one of embodiments 213-220, 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.

[0170] Exemplary chemotherapeutic agents for use in the methods provided herein include, but are not limited to, leucovorin calcium (calcium folate), 5-fluorouracil, irinotecan, oxaliplatin, cisplatin, carboplatin, pemetrexed, docetaxel, paclitaxel, gemcitabine, vinorelbine, chlorambucil, cyclophosphamide, and methotrexate.

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

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

[0173] As used herein, when any variable occurs more than once in a chemical formula, its definition on 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.

[0174] 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.

[0175] If the stereochemistry of a structure, or 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.

[0176] for example, [ka] teeth, [ka] 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.

[0177] 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.

[0178] In certain cases, a bond drawn with a wavy line indicates that both stereoisomers are encompassed. This should not be confused with a wavy line drawn perpendicular to a bond that indicates the point of attachment of the group to the remainder of the molecule.

[0179] The term "stereoisomer" or "stereoisomerically pure" compound, as used herein, refers to one stereoisomer (e.g., geometric isomer, enantiomer, diastereomer, and atropisomer) of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center is substantially free of the mirror image enantiomer of that compound, and a stereoisomerically pure compound having two chiral centers is substantially free of other enantiomers or diastereomers of that compound. Typical stereoisomerically pure compounds contain greater than about 80% by weight of one stereoisomer of the compound and not more than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and not more than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and not more than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and not more than about 3% by weight of other stereoisomers of the compound.

[0180] The present disclosure also encompasses pharmaceutical compositions comprising stereoisomerically pure forms and the use of stereoisomerically pure forms of any of the compounds disclosed herein. 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 may be synthesized according to methods known in the art and disclosed herein. Mixtures of stereoisomers may 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).

[0181] Tautomers As known to those skilled in the art, certain compounds disclosed herein may exist in one or more tautomeric forms. Because a chemical structure may be used to represent only one tautomeric form, for convenience, reference to a compound of a given structural formula should be understood to include other tautomeric forms of that structural formula.

[0182] 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 typically 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 (e.g., those incorporating a radioactive isotope) are useful in drug and / or substrate tissue distribution studies. 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 (e.g., 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 may generally be prepared by conventional techniques known to those skilled in the art, or may be prepared by processes analogous to those illustrated in the accompanying general synthetic schemes and examples, using suitable isotopically labeled reagents in place of conventionally used non-labeled reagents.

[0183] 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.

[0184] The term "solvate" as used herein 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."

[0185] 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.

[0186] Various definitions This section defines additional terms used to describe the scope of the compounds, compositions, and uses disclosed herein.

[0187] 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.

[0188] "C 1~4 Alkyl" and "C 1~6 The term "alkyl" as used herein 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.

[0189] "C 1~4 Alkylene" and "C 1~6 The term "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.

[0190] "C 2~4The term "alkenyl" as used herein 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.

[0191] "C 2~4 The term "alkynyl" as used herein 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.

[0192] "C 1~4 Alkoxy" or "C 1~6 The term "alkoxy" as used herein means -OR # R # are C, as defined herein, 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. ~6 Representative examples of alkoxy include, but are not limited to, ethoxy, propoxy, iso-propoxy, and butoxy.

[0193] "C 3~8 The term "cycloalkyl" as used herein refers to a saturated carbocyclic molecule having a cyclic backbone of 3 to 8 carbons. 3~8 Representative examples of cycloalkyl include, but are not limited to, cyclopropyl and cyclobutyl.

[0194] The term "deuterium," when used herein as a prefix for another term in reference to a chemical group, refers to an atom or atoms in which one or more hydrogen atoms have been replaced with deuterium ("D" or " 2 This refers to the modification of a chemical group in which a fluorine atom has been substituted with a fluorine atom (H). For example, "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).

[0195] The term "halogen" as used herein refers to -F, -Cl, -Br, or -I.

[0196] The term "halo," when used herein as a prefix of another term relating to a chemical group, refers to a modification of a chemical group in which one or more hydrogen atoms have been replaced with a halogen, as defined herein. Each occurrence of a halogen is independently selected. For example, "C 1~4 The term "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).

[0197] 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.

[0198] The term "heteroaryl" also refers to groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings.

[0199] 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 ring system, a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring system, or a 10-, 11-, 12-, 13-, 14-, or 15-membered tricyclic ring system, and containing at least one heteroatom selected from O, S, and N, which may also be optionally oxidized to various oxidation states. The heterocyclic group may be attached at 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.

[0200] The term "pharmacologically acceptable," as used herein, refers to generally accepted for use in subjects, particularly humans.

[0201] The term "pharmaceutical acceptable salt" as used herein 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 an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion); or salts formed when coordinated with an organic base 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).

[0202] The term "pharmaceutical acceptable excipient" as used herein refers to a wide variety of ingredients that can be combined with the compounds or salts disclosed herein to prepare pharmaceutical compositions or formulations. Typically, excipients include, but are not limited to, diluents, colorants, vehicles, anti-adherents, glidants, disintegrants, flavorings, coatings, binders, sweeteners, lubricants, adsorbents, preservatives, and the like.

[0203] The term "subject" as used herein 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.

[0204] The term "therapeutically effective amount," as used herein, refers to an amount of a compound disclosed herein that will elicit the biological or medical response of a tissue, system, or subject desired by a researcher, veterinarian, physician, or other clinician.

[0205] General synthesis procedure The compounds provided herein may be synthesized according to the procedures described in this section and the following sections. The synthetic methods described herein are merely exemplary, and the compounds disclosed herein may also be synthesized by alternative routes using alternative synthetic strategies, as would be understood by those skilled in the art. It should 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.

[0206] Generally, the compound of formula I can be synthesized according to the following scheme. Any variables used in the following scheme are as defined for formula I unless otherwise stated. All starting materials are either commercially available, for example from Merck Sigma-Aldrich Inc, Fluorochem Ltd, and Enamine Ltd., or known in the art, and can be synthesized by using known procedures using conventional techniques. Starting materials can also be synthesized by the procedures disclosed herein. Suitable reaction conditions (e.g., solvents, reaction temperatures, and reagents) for the schemes discussed in this section can be found in the examples provided herein. [ka]

[0207] Compounds of formula (I) may be prepared according to Scheme I. In step A, compound (1) is treated with sodium thiomethoxide in a solvent such as tetrahydrofuran to give compound (2). In step B, compound (2) is pretreated with a fluoride source such as potassium fluoride or in the presence of a base such as sodium hydride or cesium carbonate with or without a nucleophilic catalyst such as 1,4-diazabicyclo[2.2.2]octane in a solvent such as dimethylsulfoxide or in a mixture of solvents such as tetrahydrofuran and N,N-dimethylformamide to give compound (3). 1 -LH-bearing nucleophiles and S N In step C, compound (3) is coupled with an organometallic reagent derived from a benzthiophene, such as a boronic acid (ester), to give compound (4). This coupling reaction proceeds in a solvent such as 1,4-dioxane, with or without a base, such as potassium phosphate, and in a catalyst such as Pd2(dba)3 and (R)-MOP. In step D, compound (4) is treated with sulfuryl chloride in a solvent such as dichloromethane to give compound (5). In step E, compound (5) is reacted with an optionally substituted amine and S in a solvent such as acetonitrile and in the presence of a base, such as N,N-diisopropylethylamine, to give compound (6). N Reacting with Ar gives compound (6). 8 The species includes a protecting group, which can be removed after step E in the synthetic sequence. [ka]

[0208] Compounds of formula (I) may be prepared according to Scheme II. In step A, compound (1) is reacted with an optionally substituted amine and S in a solvent such as acetonitrile and in the presence of a base such as N,N-diisopropylethylamine. NIn step B, compound (6) is pretreated with a fluoride source such as potassium fluoride or in the presence of a base such as sodium hydride or cesium carbonate, with or without a nucleophilic catalyst such as 1,4-diazabicyclo[2.2.2]octane, in a solvent such as dimethylsulfoxide or in a mixture of solvents such as tetrahydrofuran and N,N-dimethylformamide, to give compound (6). 1 -LH-bearing nucleophiles and S N In step C, compound (7) is coupled with an organometallic reagent derived from a benzthiophene, such as a boronic acid (ester), to give compound (I). This coupling reaction proceeds in the presence or absence of a base, such as potassium phosphate, in a solvent, such as 1,4-dioxane, and in a catalyst, such as Pd2(dba)3 and (R)-MOP. In some cases, R 8 The species includes a protecting group, which can be removed after step C in the synthetic sequence. EXAMPLES

[0209] In this section, specific examples of compounds of formula I and methods for their preparation are provided.

[0210] List of abbreviations

[0211] [Table 2]

[0212] [Table 3]

[0213] [Table 4]

[0214] [Table 5]

[0215] General analytical and purification methods Provided in this section is a general description of the analytical and purification methods used to prepare the specific examples provided herein.

[0216] Chromatography: Unless otherwise indicated, residues containing the crude product were purified by passing the crude material or crude concentrate through a Biotage or ISCO brand silica gel column pre-packed with flash silica (SiO2) and eluting the product from the column with a solvent gradient as indicated.

[0217] Preparative HPLC Method: Where so indicated, the compounds described herein were purified by reverse-phase HPLC using a Waters FractionLynx semi-preparative HPLC-MS system utilizing one of two HPLC columns: (a) a Phenomenex Gemini column (5 micron, C18, 150 x 30 mm) or (b) a Waters X-select CSH column (5 micron, C18, 100 x 30 mm). A typical run 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) over 10 minutes at 45 mL / min; conditions may be varied to achieve optimal separation.

[0218] Proton NMR spectra: Unless otherwise indicated, all 1 H NMR spectra were collected on a Bruker NMR instrument at 300, 400, or 500 MHz. All observed protons are reported as parts per million (ppm) downfield from tetramethylsilane (TMS) using the internal solvent peak as the reference. Some protons may be due to exchange with D from MeOD or due to signal suppression. 1 The H signal may be absent.

[0219] Mass Spectrum (MS): Unless otherwise indicated, all mass spectrum data of starting materials, intermediates, and / or exemplary 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.

[0220] 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. A 20 mL vial was charged with 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 overnight at rt. The crude material was purified by column chromatography on a silica gel column eluted 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). + .

[0221] Step 2: 4-(4-Methoxybenzyl)-6-methyl-1,4-oxazepan-6-ol. A 100 mL round bottom flask was charged with 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., and then methylmagnesium bromide solution (3 M in Et2O, 3.7 mL, 11.1 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). + .

[0222] 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 produce 246 mg of peak 1 with an ee of >99% and 292 mg of peak 2 with an ee of >99%.

[0223] 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 rt 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). Isomer 2, intermediate A2, was obtained by the same method.

[0224] 6-(Difluoromethyl)-1,4-oxazepan-6-ol hydrochloride Isomer 1 (Intermediate B1) and Isomer 2 (Intermediate B2) [ka] Intermediate A1 and A2 were synthesized in a similar manner with the following modification of step 2: To a solution of 4-(4-methoxybenzyl)-1,4-oxazepan-6-one (0.97 g, 4.14 mmol) in 2-MeTHF (20 mL) at rt, HMPA (3.70 g, 3.70 mL, 20.68 mmol, Sigma-Aldrich Corporation) and cesium fluoride (0.31 g, 2.07 mmol, Sigma-Aldrich Corporation) were added, followed by (difluoromethyl)trimethylsilane (1.50 g, 1.7 mL, 12.41 mmol, Oakwood Products, Inc.). The resulting mixture was stirred overnight at rt. To this reaction mixture, tetrabutylammonium fluoride solution (1.0 M in THF, 8.3 mL, 8.27 mmol, Sigma-Aldrich Corporation) was added, and the resulting mixture was stirred at rt for 1 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was concentrated and purified by column chromatography eluting with a gradient of 0-60% 3:1 EtOAc / EtOH (with 0.2% Et3N) in heptane to give 6-(difluoromethyl)-4-(4-methoxybenzyl)-1,4-oxazepan-6-ol (0.45 g, 1.57 mmol, 38% yield) as a light brownish oil, which was used directly without further purification. m / z (ESI): 288.0 (M+H). + .

[0225] Chiral SFC separation conditions:

[0226] [Table 6]

[0227] 6-Ethyl-1,4-oxazepan-6-ol hydrochloride isomer 1 (intermediate C1) and isomer 2 (intermediate C2) [ka] Synthesized in a similar manner to intermediates A1 and A2.

[0228] Chiral SFC separation conditions:

[0229] [Table 7]

[0230] 2,3,6,7-Tetrahydro-1H-azepin-3-ol hydrochloride (Intermediate D) [ka] Step 1: tert-Butyl 3-hydroxy-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate. A 25 mL round bottom flask was charged with tert-butyl 3-oxo-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (75 mg, 0.36 mmol, AstaTech, Inc) and sodium borohydride (40 mg, 1.07 mmol, Sigma-Aldrich Corporation) in THF (1.8 mL). A small amount of MeOH was added. The reaction was stirred at rt for 1 h. The reaction mixture was diluted with saturated NH4Cl (10 mL) and extracted with EtOAc (2 x 10 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material, which was used directly in the next step. m / z(ESI):236.2(M+Na) + .

[0231] Step 2: 2,3,6,7-tetrahydro-1H-azepin-3-ol hydrochloride. The above material was dissolved in DCM (2 mL). To this mixture was added TFA (2 mL) at 0° C. The reaction was stirred for 1 h. The mixture was completely concentrated under reduced pressure. 1N HCl (1.0 mL) was added and the material was lyophilized to give 2,3,6,7-tetrahydro-1H-azepin-3-ol hydrochloride.

[0232] 3-Methylazepan-3-ol hydrochloride isomer 1 (intermediate E1) and isomer 2 (intermediate E2) [ka] Step 1: Benzyl 3-hydroxy-3-methylazepane-1-carboxylate. A 100 mL round bottom flask was charged with 3-methylazepan-3-ol hydrochloride (0.25 g, 1.51 mmol, Asta-tech), benzyl chloroformate (0.28 g, 0.24 mL, 1.66 mmol, Oakwood Products, Inc.), DIPEA (0.59 g, 0.8 mL, 4.53 mmol, Sigma-Aldrich Corporation), and THF (5.0 mL). The reaction was stirred overnight at rt. The solution was concentrated in vacuo. The crude material was purified by column chromatography on a silica gel column eluting with a gradient of 0-100% EtOAc in hexanes to give benzyl 3-hydroxy-3-methylazepane-1-carboxylate (0.33 g, 1.25 mmol, 83% yield) as a colorless oil. m / z(ESI):264.2(M+H) + .

[0233] Step 2: Chiral separation. Benzyl 3-hydroxy-3-methylazepane-1-carboxylate (0.24 g) was purified by SFC using a Chiralpak IG, 21×250 mm, 5 μm column with a mobile phase of 20% methanol with 0.2% triethylamine using a flow rate of 80 mL / min to produce 89 mg of peak 1 with an ee of >99% and 91 mg of peak 2 with an ee of >99%.

[0234] Step 3: 3-Methylazepan-3-ol hydrochloride. Benzyl 3-hydroxy-3-methylazepan-1-carboxylate (89 mg, 0.34 mmol, peak 1) was dissolved in ethanol (1.7 mL). Palladium on activated carbon (74 mg, 0.07 mmol, Sigma-Aldrich Corporation) and aqueous HCl (1N, 0.2 mL, 0.42 mmol, Sigma-Aldrich Corporation) were added and the mixture was stirred at rt under H2 atmosphere for 10 h. The catalyst was removed and the solution was concentrated to give 3-methylazepan-3-ol hydrochloride (isomer 1, intermediate E1, 60 mg, 0.36 mmol). Isomer 2, intermediate E2, was obtained by the same method. m / z (ESI): 130.2 (M+H). + .

[0235] tert-Butyl (4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(methylthio)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (Intermediate F, F1, F2) [ka] Step 1: 7-Bromo-2,6-dichloro-8-fluoro-4-(methylthio)quinazoline. To a stirred solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (2.30 g, 6.96 mmol, Advanced ChemBlocks Inc.) in THF (25 mL) was added sodium methanethiolate (0.54 g, 7.66 mmol, Sigma-Aldrich Corporation) in water (6.0 mL) at 0° C. The reaction was then stirred at rt for 1 h. The precipitate was collected by filtration and washed with heptane to give 7-bromo-2,6-dichloro-8-fluoro-4-(methylthio)quinazoline (1.60 g, 4.68 mmol, 67% yield) as an off-white solid. m / z (ESI): 342.8 (M+H). + .

[0236] Step 2: 7-Bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(methylthio)quinazoline. A mixture of 7-bromo-2,6-dichloro-8-fluoro-4-(methylthio)quinazoline (1.60 g, 4.68 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (1.12 g, 7.02 mmol, LabNetwork), and DIPEA (2.42 g, 3.27 mL, 18.71 mmol, Sigma-Aldrich Corporation) was stirred overnight at 80° C. in acetonitrile (20 mL). The precipitate was collected by filtration and washed with heptane to give 7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(methylthio)quinazoline (1.18 g, 2.55 mmol, 54% yield) as an orange solid. m / z (ESI): 464.8 (M+H). + .

[0237] Step 3: tert-Butyl (4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(methylthio)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate. Potassium phosphate (0.91 g, 4.30 mmol, Combi-Blocks Inc.), (R)-(+)-2-(diphenylphosphino)-2'-methoxy-1,1'-binaphthyl (81 mg, 0.17 mmol, Strem Chemicals, Inc.), bis[tris(dibenzylideneacetone)palladium(0)] (79 mg, 0.09 mmol, Sigma-Aldrich Corporation), 7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(methylthio)quinazoline (0.40 g, 0.86 mmol), and tert-butyl (3-Cyano-4-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (0.70 g, 1.72 mmol, PharmaBlock) was mixed in 1,4-dioxane (6.8 mL). The reaction mixture was stirred at 80° C. for 1 hour. The crude mixture was purified by column chromatography on silica gel eluting with a gradient of 0-50% 3:1 EtOAc / EtOH in heptane containing 2% triethylamine as additive to give tert-butyl (4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(methylthio)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (Intermediate F, 0.24 g, 0.35 mmol, 41% yield). m / z (ESI): 675.7 (M+H). + .

[0238] Step 4: Chiral separation. Conditions for chiral SFC separation:

[0239] [Table 8]

[0240] Experimental procedure 2-Amino-4-(4-(azepan-1-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Example 1) [ka] Step 1: tert-Butyl (3-cyano-4-(4,6-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate. To a solution of tert-butyl (4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(methylthio)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (57 mg, 0.08 mmol, intermediate F) in DCM (2 mL) at 0° C. was slowly added sulfuryl chloride (1.0 M in DCM, 0.25 mL, 0.25 mmol, Sigma-Aldrich Corporation). The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was concentrated under reduced pressure without heating. The crude product was used directly in the next step. m / z (ESI): 664.0 (M+H) + .

[0241] Step 2: tert-Butyl (4-(4-(azepan-1-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate. To a solution of tert-butyl (3-cyano-4-(4,6-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (19 mg, 0.03 mmol) in acetonitrile (1.0 mL) was added DIPEA (11 mg, 0.08 mmol, Sigma-Aldrich Corporation) and hexamethyleneimine (5.6 mg, 5.6 μL, 0.06 mmol, Combi-Blocks Inc.). The resulting mixture was stirred at rt for 1 h. The reaction mixture was purified by reverse phase HPLC to give tert-butyl (4-(4-(azepan-1-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (14 mg, 0.02 mmol, 69%) as a pale yellow solid. m / z (ESI): 727.2 (M+H). + .

[0242] Step 3: 2-amino-4-(4-(azepan-1-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile. tert-Butyl (4-(4-(azepan-1-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophene-2-yl)carbamate (14 mg, 0.02 mmol) was dissolved in DCM (0.5 mL) and trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give 2-amino-4-(4-(azepan-1-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile as the bis(2,2,2-trifluoroacetate) and as a pale yellow solid (8.1 mg, 9.47 μmol, 34%). m / z(ESI): 627.0 (M+H). + . 1 H NMR(400MHz, methanol-d4)δ ppm 8.13(d,J=1.9Hz,1H),7.22-7.27(m,1H),7.07(dd,J=9.3,8.5Hz,1H),5.42-5.68(m,1H),4.54-4.75(m,2H),4.04-4 .12(m,4H),3.83-4.01(m,3H),3.43-3.52(m,1H),2.54-2.72(m,2H),2.31-2.48(m,3H),2.10-2.22(m,1H),2.06(br s,4H),1.69-1.78(m,4H).

[0243] [Table 9]

[0244]

Table 10

[0245]

Table 11

[0246]

Table 12

[0247]

Table 13

[0248]

Table 14

[0249]

Table 15

[0250]

Table 16

[0251]

Table 17

[0252]

Table 18

[0253]

Table 19

[0254]

Table 20

[0255]

Table 21

[0256]

Table 22

[0257]

Table 23

[0258]

Table 24

[0259]

Table 25

[0260]

Table 26

[0261]

Table 27

[0262]

Table 28

[0263]

Table 29

[0264]

Table 30

[0265]

Table 31

[0266]

Table 32

[0267]

Table 33

[0268]

Table 34

[0269]

Table 35

[0270]

Table 36

[0271]

Table 37

[0272]

Table 38

[0273]

Table 39

[0274]

Table 40

[0275]

Table 41

[0276] [Table 42]

[0277] [Table 43]

[0278] 2-Amino-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)-7-fluorobenzo[b]thiophene-3-carbonitrile (Example 55) [ka] Step 1: 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-1,4-oxazepane. To a mixture of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (2.03 g, 6.13 mmol, WuXi App Tec Co. Ltd.) in acetonitrile (15 mL) was added DIPEA (0.83 g, 1.1 mL, 6.44 mmol, Sigma-Aldrich Corporation) and [1,4]oxazepane (0.63 g, 6.25 mmol, Oakwood Products, Inc.). The reaction was stirred overnight at rt. The solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a gradient of 0-50% EtOAc in heptane to give 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-1,4-oxazepane (0.53 g, 1.34 mmol, 22% yield). m / z (ESI): 394.0 (M+H). + .

[0279] Step 2: 4-(7-Bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-oxazepane. A 20 mL vial was charged with 1,4-diazabicyclo[2.2.2]octane (15 mg, 0.13 mmol, Sigma-Aldrich Corporation), cesium carbonate (2.61 g, 8.02 mmol, Sigma-Aldrich Corporation), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol hydrochloride (0.79 g, 4.01 mmol, AChemBlock), 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-1,4-oxazepane (0.53 g, 1.34 mmol), N,N-dimethylformamide (2.2 mL), and tetrahydrofuran (4.5 mL). The reaction was stirred overnight at 40° C. 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 4-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-oxazepane (0.27 g, 0.52 mmol, 39% yield). m / z (ESI): 517.0 (M+H). + .

[0280] Step 3: tert-butyl (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)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate. In an 8 mL vial was added potassium phosphate (0.54 g, 2.55 mmol, Combi-Blocks Inc.), (R)-(+)-2-(diphenylphosphino)-2′-methoxy-1,1′-binaphthyl (48 mg, 0.10 mmol, Strem Chemicals, Inc.), bis[tris(dibenzylideneacetone)palladium(0)] (47 mg, 0.05 mmol, Sigma-Aldrich Corporation), and tert-butyl phosphate (0.54 g, 2.55 mmol, Combi-Blocks Inc.). (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (0.62 g, 1.53 mmol, PharmaBlock), 4-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-oxazepane (0.26 g, 0.51 mmol), and 1,4-dioxane (5.0 mL) were charged. The reaction mixture was stirred at 80° 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 tert-butyl (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)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (0.21 g, 0.29 mmol, 56% yield). m / z (ESI): 729.7 (M+H). + .

[0281] Step 4: 2-amino-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)-7-fluorobenzo[b]thiophene-3-carbonitrile. tert-Butyl (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)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (0.21 g, 0.29 mmol) was stirred in trifluoroacetic acid (0.7 mL) and dichloromethane (0.7 mL) at rt for 1 h. The volatiles were removed under reduced pressure. The crude product was purified by reverse phase HPLC to give 2-amino-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)-7-fluorobenzo[b]thiophene-3-carbonitrile as the bis(2,2,2-trifluoroacetate) and as a pale yellow solid (89 mg, 0.10 mmol, 36% yield). m / z(ESI): 629.8(M+H). + . 1 H NMR(400MHz, methanol-d4)δ ppm 8.10-8.14(m,1H),7.21-7.28(m,1H),7.03-7.11(m,1H),5.46-5.66(m,1H),4.5 7-4.76(m,2H),4.17-4.30(m,4H),3.83-4.10(m,7H),3.42-3.54(m,1H),2.59(br s,2H),2.37(br d,J=7.9Hz,3H),2.06-2.27(m,3H).

[0282] [Table 44]

[0283] [Table 45]

[0284] [Table 46]

[0285] [Table 47]

[0286] [Table 48]

[0287] [Table 49]

[0288] [Table 50]

[0289] 2-Amino-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-vinylquinazolin-7-yl)benzo[b]thiophene-3-carbonitrile (Example 61) [ka] A 2.0 mL microwave vial was charged with tert-butyl (4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (39 mg, 0.05 mmol, prepared according to Example 22), vinyl boronic acid pinacol ester (40 mg, 0.26 mmol, TCI America), SPhos Pd G3 (18 mg, 0.02 mmol, Sigma-Aldrich Corporation), and potassium phosphate (57 mg, 0.27 mmol, Acros Organics). The vial was purged with nitrogen and suspended in 1,4-dioxane (2.0 mL) and water (0.4 mL). The reaction was then heated in a microwave reactor at 150° C. for 45 min. The reaction mixture was purified by reverse phase HPLC to give tert-butyl (3-cyano-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-vinylquinazolin-7-yl)benzo[b]thiophen-2-yl)carbamate (8.0 mg, 10.65 μmol, 21% yield) as an orange solid (m / z (ESI): 751.0 (M+H). + ), and 2-amino-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-vinylquinazolin-7-yl)benzo[b]thiophene-3-carbonitrile as bis(2,2,2-trifluoroacetate and as a yellow solid (8 mg, 9.1 μmol, 18% yield) (m / z(ESI): 651.0 (M+H) + ). 1H NMR (400MHz, methanol-d4) δ ppm 8.66 (d, J = 3.3Hz, 1H), 7.18 (ddd, J = 8.4, 5.1, 3.4Hz, 1H), 7.04-7.11 (m, 1H), 6.34-6.43 (m, 1H), 5.85 (dd, J = 17.0, 3.4Hz, 1H), 5.45-5.65 (m, 1H), 5.26 (d, J = 11.1 Hz,1H),4.58-4.72(m,2H),3.82-4.18(m,8H),3.61-3.81(m,2H),3.45-3.54(m, 1H),2.55-2.75(m,2H),2.29-2.54(m,4H),2.08-2.24(m,1H),1.26-1.36(m,3H).

[0290] 2-Amino-4-(6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Example 62) [ka] Step 1: tert-butyl (3-cyano-4-(6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate. tert-Butyl (3-cyano-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-vinylquinazolin-7-yl)benzo[b]thiophen-2-yl)carbamate (8 mg, 10.7 μmol, prepared according to Example 61) was dissolved in ethanol (1.0 mL). Palladium on activated carbon (2.3 mg, 2.13 μmol, Sigma-Aldrich Corporation) was added and the mixture was stirred at rt under an atmosphere of H2 (40 psi) for 4 h. The reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated and purified by reverse phase HPLC to give tert-butyl (3-cyano-4-(6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate as a white solid, which was used directly in the next step. m / z(ESI): 752.8(M+H). + .

[0291] Step 2: 2-amino-4-(6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile. The above-mentioned tert-butyl (3-cyano-4-(6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-2-yl)carbamate was dissolved in DCM (0.5 mL) and trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give 2-amino-4-(6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile as bis(2,2,2-trifluoroacetate) and as a white solid (2.1 mg, 2.38 μmol, 22% yield). m / z(ESI): 652.9(M+H). + . 1 H NMR (400MHz, methanol-d4) δ ppm 8.24 (d, J = 12.5Hz, 1H), 7.21 (ddd, J = 8.3, 5.1, 3.3Hz, 1H), 7.07 (ddd, J = 9.5, 8.3, 1.5Hz, 1H), 5.43-5.66 (m, 1H), 4.62-4.77 (m, 3H), 4.47-4.60 (m, 2H), 4.09-4.15 (m, 1H ),4.02-4.07(m,1H),3.84-4.01(m,5H),3.65-3.76(m,2H),3.43-3.54(m,1H),2.45 -2.66(m,4H),2.31-2.43(m,2H),2.08-2.23(m,1H),1.29(s,3H),1.08-1.15(m,3H).

[0292] 2-Amino-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-hydroxy-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)benzo[b]thiophene-3-carbonitrile (Example 63) [ka] Step 1: tert-butyl (3-cyano-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-hydroxy-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)benzo[b]thiophen-2-yl)carbamate. A mixture of tert-butyl (4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (61 mg, 0.08 mmol, prepared according to Example 22), potassium hydroxide (23 mg, 0.40 mmol, VWR International, LLC), and tBuXPhos Pd G3 (6.4 mg, 8.03 μmol, Sigma-Aldrich Corporation) in 1,4-dioxane (2.0 mL) and water (0.5 mL) was stirred at 100° C. for 1.5 hours. The reaction mixture was purified by reverse phase HPLC to give tert-butyl (3-cyano-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-hydroxy-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)benzo[b]thiophen-2-yl)carbamate (30 mg, 0.04 mmol, 50% yield) as an orange solid. m / z (ESI): 741.0 (M+H). + .

[0293] Step 2: 2-amino-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-hydroxy-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)benzo[b]thiophene-3-carbonitrile. tert-Butyl (3-cyano-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-hydroxy-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)benzo[b]thiophen-2-yl)carbamate (30 mg, 0.04 mmol) was dissolved in DCM (1.0 mL) and trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give 2-amino-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-hydroxy-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)benzo[b]thiophene-3-carbonitrile as the bis(2,2,2-trifluoroacetate) and as a yellow solid (20 mg, 0.02 mmol, 57% yield). m / z (ESI): 641.0 (M+H). + . 1 H NMR(400MHz, methanol-d4)δ ppm 7.57(s,1H),7.25(ddd,J=8.4,5.0,4.2Hz,1H),7.04(ddd,J=9.5,8.5,2.1Hz,1H),5.45-5.69(m,1H),4.56-4.73(m,2H),4.38-4.49(m ,2H),3.84-4.16(m,7H),3.63-3.75(m,2H),3.43-3.53(m,1H),2.54-2.71(m,2H),2.30-2.52(m,3H),2.08-2.22(m,1H),1.28(s,3H).

[0294] 2-Amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-hydroxy-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Example 64) [ka] Step 1: tert-butyl (4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-hydroxy-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate. To a stirred solution of tert-butyl (4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-oxo-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (44 mg, 0.06 mmol, synthesized according to Example 40) in methanol (1.0 mL) was added sodium borohydride (3.2 mg, 0.09 mmol, Sigma-Aldrich Corporation) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes. The reaction was quenched with water. The crude mixture was purified by reverse phase HPLC to give tert-butyl (4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-hydroxy-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (20 mg, 0.03 mmol, 46% yield) as a yellow solid. m / z (ESI): 769.2 (M+H). + .

[0295] Step 2: 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-hydroxy-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile. tert-Butyl (4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-hydroxy-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (20 mg, 0.03 mmol) was dissolved in DCM (0.5 mL) and trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-hydroxy-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile as the bis(2,2,2-trifluoroacetate) and as a yellow solid (13 mg, 0.01 mmol, 26% yield). m / z(ESI): 669.2 (M+H). + . 1 H NMR(400MHz, methanol-d4)δ ppm 7.95-7.99(m,1H),7.23-7.27(m,1H),7.07(t,J=8.9Hz,1H),5.45-5.68(m,1H),4.55-4.73(m,2H),4.25-4.33(m,1H) ),3.82-4.06(m,7H),3.44-3.53(m,1H),2.54-2.83(m,2H),2.25-2.48(m,4H),2.11-2.24(m,2H),1.67-1.87(m,6H).

[0296] 2-Amino-4-(6-chloro-4-(5,6-dihydro-2H-pyran-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile bis(2,2,2-trifluoroacetate) (Example 70). [ka] Step 1: tert-Butyl (4-(6-chloro-4-(5,6-dihydro-2H-pyran-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate. In a red capped vial, tert-butyl (3-cyano-4-(4,6-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (21 mg, 0.032 mmol), 2-(5,6-dihydro-2h-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13 mg, 0.063 mmol), [1,1'-bis(diphenylphosphino)ferrocene] in 1,4-dioxane (0.8 mL) and water (0.2 mL). A mixture of dichloropalladium(ii) (4.6 mg, 6.32 μmol) and potassium phosphate tribasic (20 mg, 0.095 mmol) was charged. The reaction mixture was heated at 90° C. for 1 h. After cooling to rt, the mixture was purified by preparative HPLC to give tert-butyl (4-(6-chloro-4-(5,6-dihydro-2H-pyran-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate as a yellow solid. m / z (ESI, +ve ion): 711.7 (M+H). + .

[0297] Step 2: 2-amino-4-(6-chloro-4-(5,6-dihydro-2H-pyran-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile bis(2,2,2-trifluoroacetate). The tert-butyl from the previous step (4-(6-chloro-4-(5,6-dihydro-2H-pyran-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at rt for 1 h, then concentrated and purified by reverse phase HPLC to give 2-amino-4-(6-chloro-4-(5,6-dihydro-2H-pyran-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile bis(2,2,2-trifluoroacetate) (3.8 mg, 4.52 μmol, 14% yield for two steps) as a yellow solid. 1 H NMR(400MHz, methanol-d4)δ ppm 8.25(d,J=1.7Hz,1H),7.26(dd,J=8.4,5.0Hz,1H),7.09(dd,J=9.3,8.5Hz,1H),6.64-6.68(m,1H),5.49-5.76(m,1H),4.65-4.8 0(m,4H),3.88-4.09(m,5H),3.47-3.56(m,1H),2.61-2.88(m,2H),2.34-2.59(m,5H),2.13-2.31(m,1H).m / z(ESI):611.8(M+H) + .

[0298] 2-Amino-4-(6-chloro-4-cyclopropyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile bis(2,2,2-trifluoroacetate) (Example 71). [ka] Step 1: tert-Butyl (4-(6-chloro-4-cyclopropyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate. To a stirred solution of tert-butyl (3-cyano-4-(4,6-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (20 mg, 0.030 mmol) in tetrahydrofuran (1.0 mL) was added iron(III) acetylacetonate (5.3 mg, 0.015 mmol) followed by cyclopropylmagnesium bromide (1 M solution in THF, 0.06 mL, 0.060 mmol) at 0° C. The resulting mixture was stirred for 1 h at 0° C., quenched with water, and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by reverse phase HPLC to give tert-butyl (4-(6-chloro-4-cyclopropyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (10 mg, 0.015 mmol, 50% yield) as a white solid. m / z (ESI): 670.0 (M+H). + .

[0299] Step 2: 2-amino-4-(6-chloro-4-cyclopropyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile bis(2,2,2-trifluoroacetate). tert-Butyl (4-(6-chloro-4-cyclopropyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophene-2-yl)carbamate (10 mg, 0.015 mmol) was dissolved in dichloromethane (0.5 mL), trifluoroacetic acid (0.5 mL) was added, and the reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated and purified by reverse phase HPLC to give 2-amino-4-(6-chloro-4-cyclopropyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile bis(2,2,2-trifluoroacetate) (7.8 mg, 9.8 μmol, 65% yield) as a yellow solid. 1 H NMR(400MHz, methanol-d4)δ ppm 8.50(s,1H),7.25(t,J=6.5Hz,1H),7.05-7.12(m,1H),5.48-5.72(m,1H),4.64-4.83(m,2H),3.87-4.09(m,3H),3.45-3.56( m,1H),2.98-3.05(m,1H),2.56-2.82(m,2H),2.32-2.51(m,3H),2.12-2.26(m,1H),1.29-1.57(m,4H).m / z(ESI):570.2(M+H) + .

[0300] Biological evaluation Provided in this section is a biological evaluation of the specific examples provided herein.

[0301] 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 uL was added to the appropriate wells of the 384-well plate. The plate was incubated at rt for 30 min. 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 h. 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 at rt for 1 h. Plates were read using a PerkinElmer En Vision (ex: 320 nm, em1: 665 nm, em2: 615 nm) and the em1 / em2 data was used to generate a curve fit using a 4-parameter logistic model to calculate IC 50 The value was calculated.

[0302] KRAS G12D-binding nucleotide exchange assay Purified GDP-bound KRAS protein (aa1-169) containing both G12D and C118A amino acid substitutions and an N-terminal His tag was preincubated in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCl2, and 0.01% TritonX-100) and a dose-response titration of compounds was performed for 2 hours. After compound preincubation, purified SOS protein (aa564-1049) and GTP (Roche10106399001) were added to the assay wells and incubated for an additional 30 minutes. To determine the extent of inhibition of SOS-mediated nucleotide exchange, purified GST-tagged cRAF (aa1-149), nickel-chelating AlphaLISA acceptor beads (PerkinElmer AL108R), and AlphaScreen glutathione donor beads (PerkinElmer 6765302) were added to the assay wells and incubated for 10 minutes. The assay plates were then read on a PerkinElmer EnVision Multilabel Reader using AlphaScreen® technology and the data were analyzed using a four-parameter logistic model to determine IC 50 The value was calculated.

[0303] Phospho-ERK1 / 2 MSD assay AsPC-1 (ATCC® CRL-1682™) cells were cultured in RPMI 1640 medium (ThermoFisher Scientific 11875093) containing 10% fetal bovine serum (ThermoFisher Scientific 16000044) and 1× penicillin-streptomycin-glutamine (ThermoFisher Scientific 10378016). 16 hours prior to compound treatment, AsPC-1 cells were seeded into 96-well cell culture plates at a density of 25,000 cells / well and incubated at 37° C., 5% CO2. Dose-response titrations of compounds were diluted in growth medium and added to the appropriate wells of the cell culture plate, then incubated for 2 hours at 37° C., 5% CO2. After compound treatment, cells were incubated for 2 hours at 37° C., 5% CO2, and 10% CO2 for 2 hours at 37° C. for 2 hours at 37° C., 5% CO2 ... 2+ or Mg2+ Cells were washed with ice-cold Dulbecco's Phosphate Buffered Saline (ThermoFisher Scientific 14190144) without ATP and then lysed in RIPA buffer (50 mM Tris-HCl pH 7.5, 1% Igepal, 0.5% sodium deoxycholate, 150 mM NaCl, and 0.5% sodium dodecyl sulfate) containing protease inhibitors (Roche 4693132001) and phosphatase inhibitors (Roche 4906837001). Phosphorylation of ERK1 / 2 in compound-treated lysates was assayed using the Phospho-ERK1 / 2 Whole Cell Lysate kit (Meso Scale Discovery K151DWD) according to the manufacturer's protocol. Assay plates were read on a Meso Scale Discovery Sector Imager 6000 and data were analyzed using a 4-parameter logistic model to determine IC 50 The value was calculated.

[0304] [Table 51]

[0305] [Table 52]

[0306] [Table 53]

[0307] [Table 54]

[0308] References All references (e.g., scientific publications or published patent applications) cited in this specification are 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 tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, During the ceremony, 【Chemistry 2】 is a single or double bond; W is C, CH, or N, and when W is N, 【Transformation 3】 is a single bond; X is a bond, 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, 3, or 4; Each R ｘ is hydroxyl, halogen, oxo, cyano, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, -TR ｙ or two R ｘ C together with the same carbon or adjacent carbon atoms ３～７ cycloalkyl or 5- to 7-membered heterocycloalkyl, wherein each C ３～７ Cycloalkyl or 5- to 7-membered heterocycloalkyl is R ｙ or two R ｘ with the same carbon atom, R ｙ C substituted with 0 to 3 occurrences of ３～８ cycloalkyl or 4- to 7-membered heterocycloalkyl, or two R ｘ may, together with the carbon atoms to which they are attached, form a bridged ring, where the bridging atom is: １～４ Alkylene, -C １～４ Alkylene -O-, -C １～４ Alkylene -O-C １～４ Alkylene-, -C １～４ Alkylene -S-C １～４ Alkylene- or -C １～４ alkylene-S-; Z is CH, CR′, or N; R' is halogen, cyano, or C １～４ is alkyl; L is a bond, -C １～４ Alkylene, —O—C １～４ Alkylene, —S—C １～４ Alkylene, —NR ｚ -, -O-, or -S-; R １ is hydroxyl, aryl, heteroaryl, C ３～８ cycloalkyl, or R ５ is heterocycloalkyl optionally substituted with 0-3 occurrences of R ２ is hydrogen, halogen, C １～４ Alkyl, C ２～４ alkenyl, or cyano; R ３ is hydrogen, halogen, cyano, C １～４ Alkyl, C １～４ haloalkyl, or C ２～４ alkynyl; R ４ is hydrogen or halogen; Each R ５ is halogen, oxo, hydroxyl, amino, or C １～４ is alkyl, p is 0, 1, 2, or 3; R ８ is amino; R ９ is cyano; T is C １～４ Alkylene, —C(O)—, —O—, —S(O) ２ - or -S-; R ｑ is hydrogen, halogen, or C １～４ is alkyl; R ｙ is halogen, hydroxyl, oxo, cyano, or amino; R ｚ is hydrogen or C １～４ is alkyl, A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

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

3. L is -C １～４ Alkylene or —O—C １～４ The compound of claim 1 which is an alkylene.

4. R １ is R ５ 4. The compound of claim 3, wherein the compound is 7-(hexahydro-1H-pyrrolidine), 2-pyrrolidine, or N-morpholinyl substituted with 0 to 3 occurrences of:

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

6. The compound of claim 1 , wherein W is N.

7. X is O, CH ２、 S or S(O) ２ 7. The compound of claim 6, wherein:

8. 8. The compound of claim 7, wherein X is O.

9. 8. The compound of claim 7, wherein n is 1 and m is 2, or m is 1 and n is 2, or n is 2 and m is 2. 【Request Item 10】 【Chemistry 5】 teeth, 【Transformation 6】 2. The compound of claim 1, wherein:

11. X is CH ２ 8. The compound of claim 7, wherein:

12. 11. The compound of claim 10, wherein n is 0 and m is 1, or m is 0 and n is 1. 【Request Item 13】 【Chemistry 7】 teeth, 【Transformation 8】 2. The compound of claim 1, wherein:

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

16. 11. The compound of claim 10, wherein n is 1 and m is 2, or m is 1 and n is 2, or n is 2 and m is 2. 【Request Item 17】 【Chemistry 11】 teeth, 【Chemistry 12】 2. The compound of claim 1, wherein:

18. W is C; 【Chemistry 13】 is a double bond or W is C; 【Chemistry 14】 The compound of claim 1 , wherein is a single bond.

19. 18. The compound of claim 17, wherein X is O or a bond. 【Request Item 20】 【Chemistry 15】 teeth, 【Chemistry 16】 2. The compound of claim 1, wherein:

21. R ２ is a halogen, C １～４ Alkyl, C ２～４ The compound of claim 1 , which is alkenyl or cyano.

22. R ４ The compound of claim 1 , wherein is a halogen.

23. R ３ The compound of claim 1 , wherein is hydrogen or halogen.

24. The compound is the following compound: 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,5-oxazocane-5-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-oxoazepan-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-4-(6-ethyl-6-hydroxy-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-3-hydroxyazepan-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-4-(3-fluoroazepan-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-vinylquinazolin-7-yl)benzo[b]thiophene-3-carbonitrile; 2-amino-4-(4-(azepan-1-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 1-(7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)azepane-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-4-(6-fluoro-1,4-oxazepan-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(4-oxoazepan-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-4-(6-fluoro-1,4-oxazepan-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-6-hydroxy-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-hydroxy-2,3,6,7-tetrahydro-1H-azepin-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazocane-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-4-(6,6-difluoro-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-3-hydroxyazepan-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-hydroxy-3-methylazepan-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-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)-7-fluorobenzo[b]thiophene-3-carbonitrile; 1-(7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)azepane-4-carbonitrile; (2S)-1-(7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)pyrrolidine-2-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-oxo-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-4-(6-(difluoromethyl)-6-hydroxy-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; or 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 2. The compound of claim 1, wherein the compound is selected from one of:

25. The compound is the following compound: 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,5-oxazocane-5-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-oxoazepan-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-4-(6-ethyl-6-hydroxy-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-3-hydroxyazepan-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(6-chloro-8-fluoro-4-(3-fluoroazepan-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-amino-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-6-vinylquinazolin-7-yl)benzo[b]thiophene-3-carbonitrile; 2-amino-4-(4-(azepan-1-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; or 1-(7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)azepane-3-carbonitrile 2. The compound of claim 1, wherein the compound is selected from one of:

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

27. 25. 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 24, for use as a medicament.

28. 27. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26, for use in the treatment of cancer.

29. 27. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 26, for use in treating cancer, wherein one or more cells express a KRAS G12D mutant protein.

30. 29. The compound or pharmaceutical composition for use of claim 28, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small intestine cancer, appendix cancer, cancer of unknown primary site, endometrial cancer, mixed cancer types, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

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

32. 27. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 26, in the preparation of a medicament for treating cancer, wherein one or more cells express a KRAS G12D mutant protein.

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

34. 27. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 26.

35. 27. 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 26, wherein one or more cells express a KRAS G12D mutant protein.

36. 35. The method of claim 34, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

37. 35. The method of claim 34, 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.

38. 38. The method of claim 37, wherein the cancer is non-small cell lung cancer.

39. 38. The method of claim 37, wherein the cancer is colorectal cancer.

40. 38. The method of claim 37, wherein the cancer is pancreatic cancer.

41. 35. The method of claim 34, wherein the subject has a cancer determined to have one or more cells that express the KRAS G12D mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof.

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