2-Aminobenzothiazole compounds and methods of use thereof

Abstract

The present disclosure provides compounds useful for inhibiting KRAS G12D. The compounds have the general formula (I): TIFF2024517693000326.tif39170, where the variables of formula I are defined herein. The disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions, for example, for treating cancer.

Description

[Technical field]

[0001] The present disclosure provides compounds having activity as inhibitors of G12D mutant KRAS protein. The present disclosure also provides pharmaceutical compositions comprising the compounds, as well as uses and methods for treating certain disorders, such as cancer, including, but not limited to, non-small cell lung cancer (NSCLC), colorectal cancer, and / or pancreatic cancer. [Background technology]

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

[0003] KRAS is a G protein that couples extracellular mitogenic signaling to intracellular growth-promoting responses. KRAS acts as an intracellular "on / off" switch. Mitogen stimulation induces the binding of GTP to KRAS, resulting in a conformational change that allows KRAS to interact with downstream effector proteins, 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- 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 (Ostrem 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] Ostrem 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 other KRAS such as KRAS G12D, and therefore there is a need to develop new inhibitors of KRAS G12D for the treatment of diseases such as cancer. [Means for solving the problem]

[0007] In one embodiment, the present application provides a compound of formula (I): [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer. (In the formula, [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; n is 0, 1, 2, or 3; m is 0, 1, 2, 3, or 4; Each R x is hydroxyl, oxo, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, -TR y or two R x together with the carbon atom to which they are attached, C 3~8 A cycloalkyl or bridged ring may be formed, the bridging atom being: -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 -, -NR z -C 1~4 alkylene, -O-, or -S-, 1~4 Alkylene, -OC 1~4 Alkylene, or -SC 1~4 Alkylene is a group consisting of 0 to 2 R b may be substituted with; R 1 is -N(R a )2, aryl, heteroaryl, C 3~8 cycloalkyl, or heterocycloalkyl, each aryl, heteroaryl, cycloalkyl, or heterocycloalkyl having 0 to 3 R 5 is further substituted with; R 2is 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 a halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, -N(R w )2, -(CH2) p -OH, -C(O)-R z , heteroaryl, or heterocycloalkyl, or two R 5 can be joined together with the same carbon atom to form a spirocyclic heteroaryl or heterocycloalkyl, each heteroaryl or heterocycloalkyl being selected from 0 to 3 R 7 is further substituted with; p is 1, 2, or 3; Each R 7 is hydroxyl, oxo, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, -C(O)R z , or -C(O)OR z and; T is for C 1~4 alkylene, -O-, or -S-; Each R a is hydrogen, C 1~4 Alkyl or C 1~4 is alkoxy; Each R b is hydroxyl or C 1~4 is alkyl; Each R v is halogen or C 1~4 is alkyl; Each R w is hydrogen, C 1~4 Alkyl, C 1~4 alkoxy, or heterocycloalkyl; R q is hydrogen, halogen, or C 1~4 is alkyl; R y is halogen, hydroxyl, cyano, or amino; R z is hydrogen or C 1~4 (It is alkyl).

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

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

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

[0011] In embodiment 1, the present specification provides a compound of formula (I) [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer is provided. (In the formula, [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; n is 0, 1, 2, or 3; m is 0, 1, 2, 3, or 4; Each R x is hydroxyl, oxo, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, -TR y or two R x together with the carbon atom to which they are attached, C 3~8 A cycloalkyl or bridged ring may be formed, the bridging atom being: -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 -, -NR z -C 1~4 alkylene, -O-, or -S-, 1~4 Alkylene, -OC 1~4 Alkylene, or -SC 1~4 Alkylene is a group consisting of 0 to 2 R b may be substituted with; R 1 is -N(R a )2, aryl, heteroaryl, C 3~8 cycloalkyl, or heterocycloalkyl, each aryl, heteroaryl, cycloalkyl, or heterocycloalkyl having 0 to 3 R 5 is further substituted with; 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 a halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, -N(R w )2, -(CH2) p -OH, -C(O)-R z , heteroaryl, or heterocycloalkyl, or two R 5 can be joined together with the same carbon atom to form a spirocyclic heteroaryl or heterocycloalkyl, each heteroaryl or heterocycloalkyl being selected from 0 to 3 R 7 is further substituted with; p is 1, 2, or 3; Each R 7 is hydroxyl, oxo, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, -C(O)R z , or -C(O)OR z and; T is for C 1~4 alkylene, -O, or -S-; Each R a is hydrogen, C 1~4 Alkyl or C 1~4 is alkoxy; Each R b is hydroxyl or C 1~4 is alkyl; Each R v is halogen or C 1~4 is alkyl; Each R w is hydrogen, C 1~4 Alkyl, C 1~4alkoxy, or heterocycloalkyl; R q is hydrogen, halogen, or C 1~4 is alkyl; R y is halogen, hydroxyl, cyano, or amino; R z is hydrogen or C 1~4 (It is alkyl).

[0012] As embodiment 2, provided herein is a compound of embodiment 1, wherein Z is H.

[0013] As embodiment 3, provided herein is a compound of embodiment 1, wherein Z is N.

[0014] As a fourth embodiment, the present invention relates to a compound wherein W is C; [ka] As embodiment 5, provided herein is a compound of any one of embodiments 1-3, wherein W is N.

[0015] As embodiment 6, provided herein is a compound of any one of embodiments 1-5, wherein n is 0. As embodiment 7, provided herein is a compound of embodiment 6, wherein m is 0. As embodiment 8, provided herein is a compound of any one of embodiments 1-5, wherein n is 0 and m is 0.

[0016] As embodiment 9, the present specification provides [ka] but [ka] The compound of embodiment 8 is provided, wherein

[0017] As embodiment 10, provided herein is a compound of any one of embodiments 1-5, wherein n is 1. As embodiment 11, provided herein is a compound of embodiment 10, wherein m is 0. As embodiment 12, provided herein is a compound of embodiment 10, wherein m is 1. As embodiment 13, provided herein is a compound of any one of embodiments 1-5, wherein n is 1 and m is 0. As embodiment 14, provided herein is a compound of any one of embodiments 1-5, wherein n is 1 and m is 1.

[0018] As embodiment 15, the present specification provides x C 1~4 Provided herein as embodiment 14 is a compound in which R is alkyl (e.g., methyl). x As an embodiment 17, the compound of embodiment 14 is provided herein, wherein R x C 1~4 Provided herein as embodiment 18 is a compound of embodiment 14, wherein R is alkyl (e.g., methyl). x C 1~4 Provided herein as embodiment 19 is a compound of embodiment 14, wherein R is haloalkyl (e.g., trifluoromethyl). x Ga-TR y As an embodiment 20, the compound of embodiment 14 is provided herein, wherein T is -C 1~4 Provided herein as embodiment 19 is a compound in which R is an alkylene (e.g., methylene or ethylene). y Compounds of embodiment 20 are provided herein where R is hydroxyl. y Provided herein as embodiment 23 is a compound of embodiment 20, wherein -TR y Provided herein as embodiment 19 is a compound in which -TR is -CHOH, where X is H. Provided herein as embodiment 24 is a compound in which -TR is -CHOH, where X is H. y As embodiment 25, the compound of embodiment 19 is provided herein, wherein -TR yThe compound of embodiment 19 is provided where is -CH2CH2OH.

[0019] As embodiment 26, the present specification provides [ka] but [ka] The compound of embodiment 14 is provided, wherein

[0020] As embodiment 27, provided herein is a compound of any one of embodiments 1-5, wherein n is 1 and m is 2.

[0021] As embodiment 28, the present invention relates to a compound having two R x together with the carbon atom to which they are attached, C 3~8 Compounds of embodiment 27 are provided in which two R x and R are taken together with the carbon atom to which they are attached to form a cyclopropyl ring. x taken together with the carbon to which they are attached form a cyclopentyl ring.

[0022] As embodiment 31, the present invention relates to a compound having two R x can form a bridged ring together, and the bridging atoms are -C 1~4 Alkylene, -C 1~4 Alkylene-O- or -C 1~4 Alkylene-OC 1~4 As provided herein as embodiment 27, a compound is provided in which two R are selected from one of alkylene-. x together form a bridged ring, and the bridging atom is -C 1~4Compounds of embodiment 27 are provided in which R is an alkylene (e.g., methylene or ethylene). x together form a bridged ring, with the bridging atom being -OC 1~4 Compounds of embodiment 27 are provided in which the two R are alkylene (e.g., -O-methylene- or -methylene-O-). x together form a bridged ring, and the bridging atom is -C 1~4 Alkylene-OC 1~4 Compounds of embodiment 27 are provided which are alkylene (eg, -methylene-O-methylene).

[0023] As embodiment 35, the present specification provides [ka] but [ka] The compound of embodiment 27 is provided, wherein

[0024] As embodiment 36, provided herein is a compound of any one of embodiments 1-5, wherein n is 1 and m is 3.

[0025] As embodiment 37, the present disclosure relates to a compound comprising one R x C 1~4 Alkyl (e.g., methyl) and the other two R x together form a bridged ring, and the bridging atom is -C 1~4 Compounds of embodiment 36 are provided, wherein the alkylene is alkylene (eg, methylene or ethylene).

[0026] As embodiment 38, the present disclosure relates to a compound comprising one R x C 1~4 Alkyl (e.g., methyl) and the other two R x together form a bridged ring, and the bridging atom is -C 1~4 Compounds of embodiment 36 are provided, wherein the alkylene is alkylene (eg, ethylene).

[0027] As embodiment 39, the present disclosure relates to a compound comprising one R x C 1~4 Alkyl (e.g., methyl) and the other two R x together form a bridged ring, and the bridging atom is -C 1~4 Compounds of embodiment 36 are provided, wherein the alkylene is alkylene (eg, methylene).

[0028] As embodiment 40, the present disclosure provides a method for treating a pulmonary circulation comprising administering to a patient a x C 1~4 Alkyl (e.g., methyl) and the other two R x together form a bridged ring, and the bridging atom is -C 1~4 Alkylene-OC 1~4 Compounds of embodiment 36 are provided which are alkylene- (eg, methylene-O-methylene).

[0029] As embodiment 41, the present invention relates to a compound comprising one R x is cyano and the other two R x together form a bridged ring, and the bridging atom is -C 1~4 Compounds of embodiment 36 are provided, wherein the alkylene is alkylene (eg, methylene or ethylene).

[0030] As embodiment 42, the present invention relates to a compound comprising one R x is cyano and the other two R x together form a bridged ring, and the bridging atom is methylene.

[0031] As embodiment 43, the present invention relates to a compound comprising one R x is cyano and the other two R x together form a bridged ring, and the bridging atom is ethylene.

[0032] As embodiment 44, the present invention relates to a compound comprising one R x is oxo and the other two R xtogether form a bridged ring, and the bridging atom is -C 1~4 Compounds of embodiment 36 are provided, wherein the alkylene is alkylene (eg, methylene or ethylene).

[0033] As embodiment 45, the present invention relates to a compound comprising one R x is oxo and the other two R x together form a bridged ring, and the bridging atom is ethylene.

[0034] As embodiment 46, the present disclosure relates to a compound comprising one R x is cyano and the other two R x together form a bridged ring, and the bridging atom is -C 1~4 Alkylene-OC 1~4 Compounds of embodiment 36 are provided which are alkylene- (eg, methylene-O-methylene).

[0035] As embodiment 47, the present invention relates to a compound comprising one R x Ga-TR y and the other two R x together form a bridged ring, and the bridging atom is -C 1~4 Compounds of embodiment 36 are provided in which R is alkylene (e.g., methylene or ethylene). x Ga-TR y and the other two R x Compounds according to embodiment 47 are provided in which R is substituted or unsubstituted with R together to form a bridged ring, and the bridge atom is methylene. x Ga-TR y and the other two R x together form a bridged ring, and the bridging atom is ethylene.

[0036] As embodiment 50, the present disclosure relates to a compound in which T is -C 1~4 Provided herein as embodiment 51 are compounds of any one of embodiments 47-49, in which R is alkylene (e.g., methylene). yCompounds of embodiment 50 are provided herein where R is hydroxyl. y Provided herein as embodiment 53 is a compound of embodiment 50, wherein -TR y Provided herein as embodiment 54 is a compound of embodiment 50, wherein -TR y The compound of embodiment 50 is provided where is -CH2CN.

[0037] As embodiment 55, the present specification provides -TR y is -CH2OH and the other two R x together form a bridged ring, and the bridge is -C 1~4 Compounds of embodiment 36 are provided, wherein the alkylene is alkylene (eg, methylene).

[0038] As embodiment 56, the present specification provides -TR y is -CH2CN and the other two R x together form a bridged ring, and the bridge is -C 1~4 Compounds of embodiment 36 are provided, wherein the alkylene is alkylene (eg, methylene).

[0039] As embodiment 57, the present specification provides -TR y is -CH2OH and the other two R x together form a bridged ring, and the bridging atom is -C 1~4 Compounds of embodiment 36 are provided, wherein the alkylene is alkylene (eg, ethylene).

[0040] As embodiment 58, the present specification provides -TR y is -CH2CN and the other two R x together form a bridged ring, and the bridging atom is -C 1~4 Compounds of embodiment 36 are provided, wherein the alkylene is alkylene (eg, ethylene).

[0041] As embodiment 59, the present disclosure relates to a compound comprising one R x Ga-TR y and the other two R xtogether form a bridged ring, and the bridging atom is -C 1~4 Alkylene-OC 1~4 Provided herein as embodiment 60 are compounds of embodiment 36, wherein one R is alkylene (e.g., methylene-O-methylene). x Ga-TR y and the other two R x and -C are together formed a bridged ring, the bridge atom being -methylene-O-methylene-. 1~4 Provided herein as embodiment 62 are compounds of any one of embodiments 59-60, in which R is alkylene (e.g., methylene). y Compounds of embodiment 61 are provided herein where R is hydroxyl. y Provided herein as embodiment 64 is a compound of embodiment 61, wherein -TR y Provided herein as embodiment 65 is a compound of embodiment 61, in which -TR y The compound of embodiment 61 is provided where is -CH2CN.

[0042] As embodiment 66, the present specification provides -TR y is -CH2OH and the other two R x together form a bridged ring, and the bridge is -C 1~4 Alkylene-OC 1~4 Compounds of embodiment 36 are provided which are methylene (eg, -methylene-O-methylene-).

[0043] As embodiment 67, the present specification provides -TR y is -CH2CN and the other two R x together form a bridged ring, and the bridge is -C 1~4 Alkylene-OC 1~4 Compounds of embodiment 36 are provided which are alkylene (eg, -methylene-O-methylene-).

[0044] As embodiment 68, the present specification provides [ka] but [ka] The compound of embodiment 36 is provided, wherein

[0045] As embodiment 69, provided herein is a compound of any one of embodiments 1-5, wherein n is 1 and m is 4. As embodiment 70, provided herein is a compound of any one of embodiments 1-5, wherein n is 1 and m is 4. x However, each independently, C 1~4 Alkyl (e.g., methyl) and the other two R x together form a bridged ring, and the bridging atom is C 1~4 Compounds of embodiment 69 are provided in which R is alkylene (e.g., methylene or ethylene). x However, each independently, C 1~4 Alkyl (e.g., methyl) and the other two R x Compounds according to embodiment 69 are provided in which R are joined together to form a bridged ring, and the bridge atom is methylene. x However, each independently, C 1~4 Alkyl (e.g., methyl) and the other two R x Compounds according to embodiment 69 are provided, in which R are joined together to form a bridged ring, and the bridge atom is ethylene. x However, each independently, C 1~4 Alkyl (e.g., methyl) and the other two R x together form a bridged ring, and the bridging atom is -C 1~4 Alkylene-OC 1~4 Compounds of embodiment 69 are provided which are alkylene (eg, -methylene-O-methylene).

[0046] As embodiment 74, the present specification provides [ka] but [ka] 69. The compound of embodiment 69, wherein

[0047] As embodiment 75, provided herein is a compound of any one of embodiments 1-5, wherein n is 2. As embodiment 76, provided herein is a compound of embodiment 75, wherein m is 0. As embodiment 77, provided herein is a compound of embodiment 75, wherein m is 1. As embodiment 78, provided herein is a compound of any one of embodiments 1-5, wherein n is 2 and m is 0. As embodiment 79, provided herein is a compound of any one of embodiments 1-5, wherein n is 2 and m is 1. As embodiment 80, provided herein is a compound of any one of embodiments 1-5, wherein R x

[0046] Provided herein is a compound of embodiment 79, wherein is oxo.

[0048] As embodiment 81, the present specification provides [ka] but [ka] There is provided a compound of any one of embodiments 78-79, wherein

[0049] As embodiment 82, provided herein is a compound of any one of embodiments 1-5, wherein n is 2 and m is 2. As embodiment 83, provided herein is a compound of any one of embodiments 1-5, wherein n is 2 and m is 2. x can form a bridged ring together, and the bridging atom is -C 1~4 Alkylene, -C 1~4 Alkylene-O- or -C 1~4 Alkylene-OC 1~4 As embodiment 84, provided herein is a compound of embodiment 82, wherein two R x can form a bridged ring together, and the bridging atom is -C 1~4Compounds of embodiment 82 are provided in which R is an alkylene (e.g., methylene or ethylene). x Compounds of embodiment 82 are provided in which two R can be joined together to form a bridged ring, and the bridge atom is methylene. x can together form a bridged ring, and the bridging atom is ethylene.

[0050] As embodiment 87, the present specification provides [ka] but [ka] The compound of embodiment 82 is provided, wherein

[0051] As embodiment 88, provided herein is a compound of any one of embodiments 1-5, wherein n is 2 and m is 3. As embodiment 89, provided herein is a compound of any one of embodiments 1-5, wherein n is 2 and m is 3. x is a halogen (e.g., fluorine) and the other two R x can form a bridged ring together, and the bridging atom is -C 1~4 Alkylene, -C 1~4 Alkylene-O- or -C 1~4 Alkylene-OC 1~4 As embodiment 90, provided herein is a compound according to embodiment 88, wherein one R is selected from one of alkylene-. x is a halogen (e.g., fluorine) and the other two R x can form a bridged ring together, and the bridging atom is -C 1~4 Compounds of embodiment 88 are provided in which R is alkylene (e.g., methylene or ethylene). x is a halogen (e.g., fluorine) and the other two R x can together form a bridged ring, and the bridging atom is -ethylene.

[0052] As embodiment 92, the present specification provides [ka] but [ka] The compound of embodiment 88 is provided, wherein

[0053] As embodiment 93, provided herein is a compound of any one of embodiments 1-5, wherein n is 2 and m is 4. As embodiment 94, provided herein is a compound of any one of embodiments 1-5, wherein n is 2 and m is 4. x is a halogen (e.g., fluorine) and the other two R x can form a bridged ring together, and the bridging atom is -C 1~4 Alkylene, -C 1~4 Alkylene-O- or -C 1~4 Alkylene-OC 1~4 As embodiment 95, provided herein is a compound of embodiment 93, wherein two R x is a halogen (e.g., fluorine) and the other two R x can form a bridged ring together, and the bridging atom is -C 1~4 Compounds of embodiment 93 are provided herein in which two R are alkylene (e.g., methylene or ethylene). x is a halogen (e.g., fluorine) and the other two R x can together form a bridged ring, and the bridging atom is ethylene.

[0054] As embodiment 97, the present specification provides [ka] but [ka] The compound of embodiment 93 is provided, wherein

[0055] As embodiment 98, the present specification provides [ka] but [ka] There is provided a compound of any one of embodiments 1-97, wherein

[0056] As embodiment 99, the present specification provides [ka] but [ka] The compound of embodiment 98 is provided, wherein

[0057] As an embodiment 100, the present specification provides [ka] but [ka] 99. The compound of embodiment 99, wherein

[0058] As embodiment 101, the present specification provides a method for the preparation of a compound in which L is a bond, 0 to 2 R b -C replaced with 1~4 Alkylene, -NR z -C 1~4 Alkylene, -NR z -, -O-, or -OC 1~4 Provided is a compound of any one of embodiments 1-100, which is alkylene.

[0059] As embodiment 102, the present specification provides a method for the preparation of a compound in which L is 0 to 2 R b -C replaced with 1~4Provided herein as embodiment 101 are compounds in which L is an alkylene (e.g., methylene or ethylene). b -C replaced with 1~4 Provided herein as embodiment 101 are compounds in which L is alkylene (e.g., methylene or ethylene). b Provided herein as embodiment 105 is a compound of embodiment 103, wherein L is methylene substituted with 0 R b The compound of embodiment 103 is provided, wherein the compound is ethylene substituted with:

[0060] As embodiment 106, the present specification relates to a compound in which L is 0 to 2 R b -OC replaced with 1~4 Provided herein as embodiment 101 are compounds in which L is an alkylene (e.g., -O-methylene- or -O-ethylene-). b -OC replaced with 1~4 Compounds of embodiment 106 are provided herein in which L is an alkylene (e.g., -O-methylene- or -O-ethylene-). b

[0046] As embodiment 109, compounds are provided herein in which L is -O-methylene substituted with 0 R b As embodiment 110, provided herein is a compound of embodiment 107, wherein L is -O-ethylene substituted with one R b -OC replaced with 1~4 Compounds of embodiment 106 are provided in which L is alkylene (e.g., -O-methylene- or -O-ethylene-). b As embodiment 112, provided herein is a compound of embodiment 110, wherein L is -O-methylene substituted with one R b As embodiment 113, provided herein is a compound of embodiment 110, wherein R is -O-ethylene substituted with b C 1~4Provided herein as embodiment 114 is a compound of embodiment 111 or 112, wherein L is alkyl (e.g., methyl). [ka] The compound of embodiment 113 is provided, wherein

[0061] As embodiment 115, provided herein is a compound of embodiment 101, wherein L is -O-.

[0062] As embodiment 116, the present specification relates to a compound in which L is 0 to 2 R b -NR z -C 1~4 Provided herein as embodiment 101 is a compound of embodiment 101, wherein L is alkylene-. As embodiment 117, provided herein is a compound of embodiment 101, wherein L is one R b -NR z -C 1~4 Provided herein as embodiment 118 is a compound of embodiment 116, wherein R is alkylene-. z Provided herein as embodiment 119 is a compound of embodiment 117, wherein R b Compounds of embodiment 117, wherein L is hydroxyl. [ka] The compound of embodiment 117 is provided, wherein

[0063] As embodiment 121, provided herein is the method of embodiment 101, wherein L is a bond.

[0064] As provided herein in embodiment 122, L is -NR z As embodiment 123, the method herein is provided, wherein L is R z is hydrogen. As embodiment 124, provided herein is the method of embodiment 122, wherein L is -NH-.

[0065] As embodiment 125, the present specification provides 1 However, 0 to 3 R 5 Compounds according to any one of embodiments 1-124 are provided, wherein R is heterocycloalkyl optionally substituted with R.

[0066] As embodiment 126, the present specification provides 1 However, 0 to 3 R 5 As embodiment 127, provided herein is a compound of embodiment 125, wherein R is 7-(hexahydro-1H-pyrrolidine) substituted with 1 But 0 R 5 As embodiment 128, there is provided herein a compound of embodiment 126, which is 7-(hexahydro-1H-pyrrolidine) substituted with LR 1 but [ka] The compound of embodiment 127 is provided, wherein

[0067] As embodiment 129, the present specification provides 1 But one R 5 As embodiment 130, provided herein is a compound of embodiment 126, wherein R is 7-(hexahydro-1H-pyrrolidine) substituted with 5 Compounds of embodiment 129 are provided in which R is halogen (e.g., fluorine). 5 Compounds of embodiment 129 are provided herein where R is oxo. 5 Ga-(CH2) p As embodiment 133, provided herein is a compound of embodiment 132, wherein p is 1. As embodiment 134, provided herein is a compound of embodiment 132, wherein R 5 Ga-(CH2) p Compounds of embodiment 129 are provided in which -OH and p is 1. As embodiment 135, compounds of LR 1 but [ka] The compound of embodiment 129 is provided, wherein

[0068] As embodiment 136, the present specification provides a method for producing a compound comprising the steps of: 1 But two R 5 As embodiment 137, provided herein is a compound of embodiment 126, wherein both R 5 Compounds of embodiment 136, in which LR is halogen (e.g., fluorine) are provided herein as embodiment 138. 1 but [ka] The compound of embodiment 136 is provided, wherein

[0069] As embodiment 139, the present specification provides 1 However, 0 to 3 R 5 As embodiment 140, the compound of embodiment 126 is provided herein which is 8a-(octahydroindolizine) substituted with R 1 But 0 R 5 As embodiment 141, there is provided herein a compound of embodiment 139, which is an 8a-(octahydroindolizine) substituted with LR 1 but [ka] The compound of embodiment 140 is provided, wherein

[0070] As embodiment 142, the present specification provides 1 However, 0 to 3 R 5 As embodiment 143, provided herein is a compound of embodiment 125, which is 2-pyrrolidine substituted with 1 But 0 R 5 The compound of embodiment 142 is provided which is a 2-pyrrolidine substituted with:

[0071] As embodiment 144, the present specification provides 1 But one R 5 As embodiment 145, provided herein is a compound of embodiment 142, which is a 2-pyrrolidine substituted with 5 Compounds of embodiment 144 are provided in which R is halogen (e.g., fluorine). 5 C 1~4 Provided herein as embodiment 144 is a compound in which R is alkyl (e.g., methyl). 5 Provided herein as embodiment 148 is a compound of embodiment 144, wherein R is oxo. 5 -C(O)R z As embodiment 149, provided herein is a compound of embodiment 144, wherein R z C 1~4 Provided herein as embodiment 148 is a compound in which R is alkyl (e.g., methyl). 5 Provided herein as embodiment 148 is a compound in which R is -C(O)-methyl. 5 C 1~4 Provided herein as embodiment 144 is a compound of haloalkyl (e.g., 2-fluoroethyl or 2,2-difluoroethyl). 1 but [ka] The compound of embodiment 144 is provided, wherein

[0072] As embodiment 153, the present specification provides 1 But two R 5 Provided herein as embodiment 154 is a compound of embodiment 142 which is a 2-pyrrolidine substituted with 5 Compounds of embodiment 153 are provided in which R is halogen (e.g., fluorine). 5 C 1~4Alkyl (e.g. methyl) and other R 5 Compounds of embodiment 153, in which LR is halogen (e.g., fluorine) are provided herein as embodiment 156. 1 but [ka] The compound of embodiment 153 is provided, wherein

[0073] As embodiment 157, the present specification provides a method for the preparation of a compound comprising the steps of: 1 But, three R 5 As embodiment 158, provided herein is a compound of embodiment 142, which is a 2-pyrrolidine substituted with 5 is a halogen (e.g., fluorine) and the third R 5 C 1~4 Compounds of embodiment 157 are provided herein, in which LR is alkyl (e.g., methyl). 1 but [ka] The compound of embodiment 157 is provided, wherein

[0074] As embodiment 160, the present specification provides 1 However, 0 to 3 R 5 As embodiment 161, provided herein is a compound of embodiment 125, which is a 3-pyrrolidine substituted with 1 But one R 5 As embodiment 162, provided herein is a compound of embodiment 160, which is a 3-pyrrolidine substituted with 5 C 1~4 Compounds of embodiment 160 are provided herein in which LR is alkyl (e.g., methyl). 1 but [ka] The compound of embodiment 160 is provided, wherein

[0075] As embodiment 164, the present specification provides 1 However, 0 to 3 R 5 Provided herein as embodiment 165 is a compound of embodiment 125, wherein R is 2-azetidinyl substituted with 1 But one R 5 Provided herein as embodiment 166 is a compound of embodiment 164, wherein R is 2-azetidinyl substituted with 5 C 1~4 Provided herein as embodiment 167 are compounds of embodiment 165, in which LR is alkyl (e.g., methyl). 1 but [ka] The compound of embodiment 164 is provided, wherein

[0076] As embodiment 168, the present specification provides a method for producing a compound comprising the steps of: 1 However, 0 to 3 R 5 As embodiment 169, there is provided herein a compound of embodiment 125, wherein R is 2-piperidinyl substituted with 1 But one R 5 Provided herein as embodiment 170 is a compound of embodiment 168, wherein R is 2-piperidinyl substituted with 5 C 1~4 Provided herein as embodiment 171 are compounds of embodiment 169, in which LR is alkyl (e.g., methyl). 1 but [ka] The compound of embodiment 168 is provided, wherein

[0077] As embodiment 172, the present invention relates to a compound comprising R 1 However, 0 to 3 R 5 Provided herein as embodiment 173 is a compound of embodiment 125, wherein R is 4-piperidinyl substituted with 1 But one R 5Provided herein as embodiment 174 is a compound of embodiment 172, wherein R is 4-piperidinyl substituted with 5 But, C 1~4 Compounds of embodiment 173 are provided herein in which LR is alkyl (e.g., ethyl). 1 but [ka] The compound of embodiment 172 is provided, wherein

[0078] As embodiment 176, the present disclosure relates to a compound comprising R 1 However, 0 to 3 R 5 Provided herein as embodiment 125 is a compound of embodiment 177, wherein R is 1-(7-azabicyclo[2.2.1]heptanyl) substituted with 1 But 0 R 5 As embodiment 178, there is provided herein a compound of embodiment 176, which is 1-(7-azabicyclo[2.2.1]heptanyl) substituted with LR. 1 but [ka] The compound of embodiment 176 is provided, wherein

[0079] As embodiment 179, the present specification provides 1 However, 0 to 3 R 5 Provided herein as embodiment 125 is a compound of embodiment 125, wherein R is 6-(2,6-diazabicyclo[3.2.0]heptanyl) substituted with 1 But 0 R 5 As embodiment 181, provided herein is a compound of embodiment 179, wherein R is 6-(2,6-diazabicyclo[3.2.0]heptanyl) substituted with 1 However, 0 to 3 R 5 Provided herein as embodiment 179 is a compound of embodiment 182, wherein R is 6-((1S,5R)-2,6-diazabicyclo[3.2.0]heptanyl) substituted with1 But 0 R 5 Provided herein as embodiment 183 is a compound of embodiment 181, which is 6-((1S,5R)-2,6-diazabicyclo[3.2.0]heptanyl) substituted with LR. 1 but [ka] The compound of embodiment 181 is provided, wherein

[0080] As embodiment 184, the present specification provides 1 However, 0 to 3 R 5 Provided herein as embodiment 125 is a compound of embodiment 185, wherein R is 3-(3,6-diazabicyclo[3.2.0]heptanyl) substituted with 1 But 0 R 5 As embodiment 186, there is provided herein a compound of embodiment 184, which is 3-(3,6-diazabicyclo[3.2.0]heptanyl) substituted with LR. 1 but [ka] The compound of embodiment 184 is provided, wherein

[0081] As embodiment 187, the present disclosure provides 1 However, 0 to 3 R 5 As embodiment 188, provided herein is a compound of embodiment 125, wherein R is 5-(octahydropyrrolo[3,4-b]pyrrolyl) substituted with 1 But 0 R 5 As embodiment 189, provided herein is a compound of embodiment 187, wherein R is 5-(octahydropyrrolo[3,4-b]pyrrolyl) substituted with 1 However, 0 to 3 R 5 As embodiment 190, provided herein is a compound of embodiment 187, wherein R is 5-((3aS,6aS)-(octahydropyrrolo[3,4-b]pyrrolyl)) substituted with 1 But 0 R5 As embodiment 191, provided herein is a compound of embodiment 189, wherein R is 5-((3aS,6aS)-(octahydropyrrolo[3,4-b]pyrrolyl)) substituted with 1 But one R 5 As embodiment 192, provided herein is a compound of embodiment 189, wherein R is 5-((3aS,6aS)-(octahydropyrrolo[3,4-b]pyrrolyl)) substituted with 5 C 1~4 Compounds of embodiment 191 are provided herein in which LR is alkyl (e.g., methyl). 1 but [ka] The compound of embodiment 187 is provided, wherein

[0082] As embodiment 194, the present specification provides 1 However, 0 to 3 R 5 As embodiment 195, provided herein is a compound of embodiment 125, wherein R is 4-(1,4-diazabicyclo[3.2.1]octanyl) substituted with 1 But 0 R 5 As embodiment 196, provided herein is a compound of embodiment 194, wherein R is 4-(1,4-diazabicyclo[3.2.1]octanyl) substituted with 1 However, 0 to 3 R 5 As embodiment 197, provided herein is a compound of embodiment 194, wherein R is 4-((5S)-(1,4-diazabicyclo[3.2.1]octanyl)) substituted with 1 But 0 R 5 As embodiment 198, there is provided herein a compound of embodiment 196, wherein the compound is 4-((5S)-(1,4-diazabicyclo[3.2.1]octanyl)) substituted with LR. 1 but [ka] The compound of embodiment 194 is provided, wherein

[0083] As embodiment 199, the present specification provides 1 However, 0 to 3 R 5 As embodiment 200, provided herein is a compound of embodiment 125, wherein R is 3-(3,6-diazabicyclo[3.2.1]octanyl) substituted with 1 But 0 R 5 As embodiment 201, the present specification provides a compound of embodiment 199, wherein R is 3-(3,6-diazabicyclo[3.2.1]octanyl) substituted with 1 However, 0 to 3 R 5 As embodiment 202, provided herein is a compound of embodiment 199, wherein R is 3-((1S,5S)-(3,6-diazabicyclo[3.2.1]octanyl)) substituted with 1 But 0 R 5 As embodiment 203, there is provided herein a compound of embodiment 201, wherein the compound is 3-((1S,5S)-(3,6-diazabicyclo[3.2.1]octanyl)) substituted with LR. 1 but [ka] 200. The compound of embodiment 199, wherein

[0084] As embodiment 204, the present specification provides 1 However, 0 to 3 R 5 As embodiment 205, there is provided herein a compound of embodiment 125, wherein R is 1-(octahydro-1H-pyrrolo[3,2-b]piperidinyl) substituted with 1 But one R 5 As embodiment 206, provided herein is a compound of embodiment 204, wherein R is 1-(octahydro-1H-pyrrolo[3,2-b]piperidinyl) substituted with 5 C 1~4 Provided herein as embodiment 205 is a compound in which R is alkyl (e.g., methyl). 1 However, 0 to 3 R 5Provided herein as embodiment 208 is a compound of embodiment 204, wherein R is 1-((3aR,7aR)-(octahydro-1H-pyrrolo[3,2-b]piperidinyl)) substituted with 1 But one R 5 As embodiment 209, there is provided herein a compound of embodiment 207, wherein R is 1-((3aR,7aR)-(octahydro-1H-pyrrolo[3,2-b]piperidinyl)) substituted with 5 but 1~4 Compounds of embodiment 208 are provided herein, in which LR is alkyl (e.g., methyl). 1 but [ka] The compound of embodiment 204 is provided, wherein

[0085] As an embodiment 211, the present invention relates to a compound represented by the formula: 1 However, 0 to 3 R 5 As embodiment 212, provided herein is a compound of embodiment 125, wherein R is 6-(octahydropyrrolo[3,4-b][1,4]oxazinyl) substituted with 1 But one R 5 As embodiment 213, compounds according to embodiment 212 are provided herein, wherein R is 6-(octahydropyrrolo[3,4-b][1,4]oxazinyl) substituted with 5 but 1~4 Compounds of embodiment 212 are provided, wherein is alkyl (eg, methyl).

[0086] As embodiment 214, the present specification provides 1 But one R 5 As embodiment 215, there is provided herein a compound of embodiment 211, wherein R is 6-(4aS,7aS)-(octahydropyrrolo[3,4-b][1,4]oxazinyl) substituted with 5 C 1~4 Compounds of embodiment 214 are provided herein, in which R is alkyl (e.g., methyl).1 But one R 5 As embodiment 217, there is provided herein a compound of embodiment 211, wherein R is 6-(4aS,7aR)-(octahydropyrrolo[3,4-b][1,4]oxazinyl) substituted with 5 C 1~4 Compounds of embodiment 216 are provided in which LR is alkyl (e.g., methyl). 1 but [ka] The compound of embodiment 211 is provided, wherein

[0087] As embodiment 219, the present specification provides a method for producing a compound comprising the steps of: 1 However, 0 to 3 R 5 The compound of embodiment 125 is provided wherein the N-azetidinyl is substituted with

[0088] As an embodiment 220, the present specification provides 1 But 0 R 5

[0071] In accordance with embodiment 219, there is provided a compound, wherein N-azetidinyl is substituted with

[0089] As an embodiment 221, the present invention relates to a compound comprising R 1 But one R 5 As embodiment 222, compounds are provided herein in which R is an N-azetidinyl substituted with 5 But -N(R W 2, heteroaryl, or heterocycloalkyl, each heteroaryl or heterocycloalkyl being selected from 0 to 3 R 7 As embodiment 223, provided herein is a compound of embodiment 221, substituted with R 5 However, 0 to 3 R 7 Provided herein as embodiment 224 is a compound of embodiment 222, wherein R is a heterocycloalkyl substituted with 5is N-piperidinyl, N-pyrrolidinyl, N-piperazinyl, N-morpholinyl, N-azetidinyl, 7-(3-oxa-7,9-diazabicyclo[3.3.1]nonanyl), N-thiomorpholinyl, or N-(thiomorpholinyl-1,1-dioxide), each of which is 0 to 3 R 7 As embodiment 225, provided herein is a compound of embodiment 223, wherein R is substituted with 5 But 0 R 7 As embodiment 226, compounds of embodiment 223 are provided herein, wherein R is a heterocycloalkyl substituted with 5 is N-piperidinyl, N-pyrrolidinyl, N-piperazinyl, N-morpholinyl, N-azetidinyl, 7-(3-oxa-7,9-diazabicyclo[3.3.1]nonanyl), N-thiomorpholinyl, or N-(thiomorpholinyl-1,1-dioxide), each of which is zero R 7 As embodiment 227, provided herein is a compound of embodiment 225, substituted with 5 is N-piperidinyl, N-morpholinyl, 7-(3-oxa-7,9-diazabicyclo[3.3.1]nonanyl), or N-(thiomorpholinyl-1,1-dioxide), each of which is zero R 7 As embodiment 228, provided herein is a compound of embodiment 226, wherein R is substituted with 5 But 0 R 7 Provided herein as embodiment 229 is a compound of embodiment 227, wherein R is N-piperidinyl substituted with 5 But 0 R 7 Provided herein as embodiment 227 is a compound of embodiment 227, which is N-morpholinyl substituted with 5 But 0 R 7 As embodiment 231, provided herein is a compound of embodiment 227, wherein R is 7-(3-oxa-7,9-diazabicyclo[3.3.1]nonanyl) substituted with 5 But 0 R 7Provided herein as embodiment 227 is a compound of embodiment 227, which is N-(thiomorpholinyl-1,1-dioxide) substituted with LR. 1 but [ka] The compound of embodiment 221 is provided, wherein

[0090] As embodiment 233, the present invention relates to a compound comprising R 5 But one R 7 As embodiment 234, compounds of embodiment 223 are provided herein, wherein R is a heterocycloalkyl substituted with 5 is N-piperidinyl, N-pyrrolidinyl, N-piperazinyl, N-morpholinyl, N-azetidinyl, 7-(3-oxa-7,9-diazabicyclo[3.3.1]nonanyl), N-thiomorpholinyl, or N-(thiomorpholinyl-1,1-dioxide), each of which is represented by one R 7 As embodiment 235, provided herein is a compound of embodiment 233, wherein R is substituted with 5 But one R 7 Provided herein as embodiment 236 is a compound of embodiment 234, wherein R is N-azetidinyl, N-piperidinyl, or N-piperazinyl substituted with 5 But one R 7 As embodiment 237, compounds are provided herein in which R is an N-azetidinyl substituted with 5 But one R 7 Provided herein as embodiment 238 is a compound of embodiment 234, wherein R is N-piperidinyl substituted with 5 But one R 7 Provided herein as embodiment 239 is a compound of embodiment 234, wherein R is an N-piperazinyl substituted with 7 But hydroxyl, halogen, C 1~4 Alkoxy (e.g., methoxy), or C 1~4Provided herein as embodiment 234 is a compound in which R is alkyl (e.g., methyl or ethyl). 7 Provided herein as embodiment 241 are compounds of embodiment 239, in which R 7 Compounds of embodiment 239 are provided in which R is halogen (e.g., fluorine). 7 C 1~4 Provided herein as embodiment 239 is a compound in which R is alkoxy (e.g., methoxy). 7 C 1~4 Provided herein as embodiment 244 are compounds of embodiment 239, in which LR is alkyl (e.g., ethyl). 1 but [ka] The compound of embodiment 233 is provided, wherein

[0091] As embodiment 245, the present invention relates to a compound comprising R 5 But two R 7 Provided herein as embodiment 223 is a heterocycloalkyl substituted with R 5 is N-piperidinyl, N-pyrrolidinyl, N-piperazinyl, N-morpholinyl, N-azetidinyl, 7-(3-oxa-7,9-diazabicyclo[3.3.1]nonanyl), N-thiomorpholinyl, or N-(thiomorpholinyl-1,1-dioxide), each of which is selected from two R 7 As embodiment 247, provided herein is a compound of embodiment 245, substituted with R 5 But two R 7 Provided herein as embodiment 248 is a compound of embodiment 246, wherein R is N-azetidinyl or N-morpholinyl substituted with 5 But two R 7 Provided herein as embodiment 249 is a compound of embodiment 247, wherein R is N-morpholinyl substituted with 5But two R 7 Provided herein as embodiment 247 is a compound of embodiment 247, wherein each R is an N-azetidinyl substituted with 7 But independently, C 1~4 Provided herein as embodiment 247 is a compound in which one R is alkyl (e.g., methyl). 7 is hydroxyl and the other R 7 C 1~4 Provided herein as embodiment 247 is a compound in which LR is alkyl (e.g., methyl). 1 but [ka] The compound of embodiment 245 is provided, wherein

[0092] As embodiment 253, the present invention relates to a compound comprising R 5 -N(R w )2. As embodiment 254, provided herein is a compound of embodiment 222, wherein both R w Compounds of embodiment 253, wherein is hydrogen. w is hydrogen and other R w C 1~4 Compounds of embodiment 253 are provided herein in which both R are alkyl (e.g., methyl). w C 1~4 Compounds of embodiment 253 are provided herein in which one R is alkyl (e.g., methyl). w C 1~4 alkyl (e.g., methyl) and other R w C 1~4 Provided herein as embodiment 253 is a compound in which one R is alkoxy (e.g., methoxy). w C 1~4 alkyl (e.g., methyl) and other R wCompounds of embodiment 253 are provided in which R is heterocycloalkyl (e.g., 3-tetrahydrofuranyl or 2-oxetanyl). w C 1~4 alkyl (e.g., methyl) and other R w Provided herein as embodiment 253 is a compound in which R is 3-tetrahydrofuranyl. w C 1~4 alkyl (e.g., methyl) and other R w Compounds according to embodiment 253, in which LR is 2-oxetanyl, are provided herein as embodiment 261. 1 but [ka] The compound of embodiment 253 is provided, wherein

[0093] As embodiment 262, the present specification provides 5 However, 0 to 3 R 7 As embodiment 263, compounds of embodiment 222 are provided herein, wherein R is a heteroaryl substituted with 5 However, 0 to 3 R 7 As embodiment 264, compounds are provided herein in which R is 1-imidazolyl or 1-pyrazolyl substituted with 5 But 0 R 7 Compounds according to embodiment 263 are provided which are 1-imidazolyl substituted with:

[0094] As embodiment 265, the present specification provides 5 But one R 7 As embodiment 266, compounds are provided herein in which R is 1-pyrazolyl substituted with 7 -C(O)OR z and R z C 1~4 Compounds of embodiment 265 are provided herein, in which R is alkyl (e.g., ethyl). 7Compounds according to embodiment 265, wherein LR is -C(O)OEt are provided herein as embodiment 268. 1 but [ka] The compound of embodiment 262 is provided, wherein

[0095] As embodiment 269, the present specification provides 1 But two R 5 As embodiment 270, provided herein is a compound of embodiment 219, wherein the compound is N-azetidinyl substituted with 5 -N(R w )2 and other R 5 C 1~4 Provided herein as embodiment 269 are compounds in which both R are alkyl (e.g., methyl or ethyl). w Provided herein as embodiment 270 are compounds in which both R w C 1~4 Provided herein as embodiment 270 are compounds in which one R is alkyl (e.g., methyl). w is hydrogen and other R w C 1~4 Provided herein as embodiment 270 are compounds in which one R is alkyl (e.g., methyl). 5 is -NH2 and the other R 5

[0081] As embodiment 275, compounds are provided herein in which one R 5 is -NH2 and the other R 5 Provided herein as embodiment 276 is a compound of embodiment 269, wherein R is ethyl. 5 is -N(Me)2 and other R 5

[0081] As embodiment 277, compounds are provided herein in which one R 5 is -NH(Me) and other R 5Provided herein as embodiment 278 is a compound of embodiment 269, wherein LR is methyl. 1 but [ka] The compound of embodiment 269 is provided, wherein

[0096] As embodiment 279, the present disclosure provides a method for the preparation of a compound having two R 5 With the same carbon atom, 0 to 3 R 7

[0082] Compounds according to embodiment 269 are provided, in which the compound forms a spirocyclic heteroaryl or heterocycloalkyl substituted with:

[0097] As an embodiment 280, the present specification provides a method for producing a compound having two R 5 With the same carbon atom, 0 to 3 R 7

[0082] Compounds according to embodiment 279 are provided, which form a spirocyclic heterocycloalkyl substituted with (eg, 2-azetidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, or 5-(1,4-oxazepanyl)).

[0098] As an embodiment 281, the present invention relates to a compound having two R 5 But with the same carbon atom, 0 R 7 Compounds according to embodiment 280 are provided, which form a spirocyclic heterocycloalkyl substituted with (eg, 2-azetidinyl, 2-pyrrolidinyl, or 3-pyrrolidinyl).

[0099] As embodiment 282, the present invention relates to a compound having two R 5 But with the same carbon atom, 0 R 7 As embodiment 283, provided herein is a compound of embodiment 281, forming a spirocyclic 2-azetidinyl substituted with two R 5 But with the same carbon atom, 0 R 7 As embodiment 284, provided herein is a compound of embodiment 281, forming a spirocyclic 2-pyrrolidinyl substituted with two R 5But with the same carbon atom, 0 R 7 Compounds according to embodiment 281 are provided, which form a spirocyclic 3-pyrrolidinyl substituted with:

[0100] As embodiment 285, the present invention relates to a compound having two R 5 However, with the same carbon atom, one R 7 Compounds of embodiment 280 are provided herein that form a spirocyclic heterocycloalkyl substituted with R (e.g., 5-(1,4-oxazepanyl)). 7 Compounds of embodiment 285 are provided where is oxo.

[0101] As embodiment 287, the present invention relates to a compound having two R 5 and R are joined together with the same carbon atom to form a spirocyclic 5-(1,4-oxazepan-3-onyl). 5 But with the same carbon atom, there are two R 7 Compounds according to embodiment 280 are provided herein in which both R 7 Compounds according to embodiment 288 are provided, wherein is halogen (eg, fluorine).

[0102] As embodiment 290, the present specification provides a method for producing a compound having two R 5 With the same carbon atom, 0 to 3 R 7 Compounds according to embodiment 279 are provided herein, in which the compound forms a spirocyclic heteroaryl substituted with (e.g., 5-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl) or 5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidinyl)). 5 But with the same carbon atom, 0 R 7Compounds according to embodiment 290 are provided herein, in which the compound forms a spirocyclic heteroaryl substituted with (e.g., 5-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl) or 5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidinyl)). 5 However, with the same carbon atom, one R 7 Compounds according to embodiment 290 are provided herein, in which the compound forms a spirocyclic heteroaryl substituted with (e.g., 5-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl) or 5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidinyl)). 5 However, with the same carbon atom, one R 7 As embodiment 294, compounds according to embodiment 292 are provided herein that form a spirocyclic 5-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl) substituted with R 7 Provided herein as embodiment 295 are compounds of embodiment 293, in which R is hydroxyl. 5 together with the same carbon atom form a spirocyclic 5-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl).

[0103] As embodiment 296, the present disclosure provides a method for the preparation of a compound having two R 5 But with the same carbon atom, there are two R 7 Compounds according to embodiment 290 are provided herein, in which the compound forms a spirocyclic heteroaryl substituted with (e.g., 5-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl) or 5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidinyl)). 5 But with the same carbon atom, there are two R 7 As embodiment 298, the present specification provides a compound according to embodiment 296, which forms a spirocyclic 5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidinyl) substituted with one R7 is oxo and other R 7 C 1~4 Provided herein as embodiment 297 is a compound in which two R are alkyl (e.g., methyl). 5 together with the same carbon atom form a spirocyclic 5-(8-methyl-5,6-dihydroimidazo[1,2-a]pyrimidin-7(8H)-onyl).

[0104] As an embodiment 300, the present specification provides 1 but [ka] The compound of embodiment 279 is provided, wherein

[0105] As an embodiment 301, the present specification provides 1 However, 0 to 3 R 5 As embodiment 302, provided herein is a compound of embodiment 125, wherein R is an N-pyrrolidinyl substituted with 1 But 0 R 5 Provided herein as embodiment 303 is a compound of embodiment 301, wherein R is an N-pyrrolidinyl substituted with 1 But one R 5 Provided herein as embodiment 301 is a compound of embodiment 301, which is N-pyrrolidinyl substituted with 5 -N(R w )2. As embodiment 305, provided herein is a compound of embodiment 303, wherein both R w Compounds of embodiment 304, wherein is hydrogen. w is hydrogen and other R w C 1~4 Provided herein as embodiment 304 are compounds in which both R are alkyl (e.g., methyl). w C 1~4 Compounds of embodiment 304 are provided, wherein is alkyl (eg, methyl).

[0106] As embodiment 308, the present specification provides 1 But two R 5 Provided herein as embodiment 309 is a compound of embodiment 301, wherein the compound is N-pyrrolidinyl substituted with one R 5 -N(R w )2 and other R 5 C 1~4 Provided herein as embodiment 308 are compounds in which both R are alkyl (e.g., methyl). w Compounds of embodiment 309 are provided in which R is hydrogen. 5 is -NH2 and the other R 5 Compounds according to embodiment 309, wherein R is methyl. 5 With the same carbon atom, 0 to 3 R 7 Compounds according to embodiment 308 are provided herein that form a spirocyclic heteroaryl or heterocycloalkyl substituted with two R 5 With the same carbon atom, 0 to 3 R 7 Compounds according to embodiment 312 are provided herein that form a spirocyclic heterocycloalkyl (e.g., 2-azetidinyl) substituted with two R 5 But with the same carbon atom, 0 R 7 Compounds according to embodiment 313 are provided herein, in which two R 5 But with the same carbon atom, 0 R 7 As embodiment 316, there is provided herein a compound of embodiment 313, forming a spirocyclic 2-azetidinyl substituted with LR 1 but [ka] The compound of embodiment 301 is provided, wherein

[0107] As embodiment 317, the present specification provides 1 However, 0 to 3 R 5 Provided herein as embodiment 318 is a compound of embodiment 125, wherein R is N-piperidinyl substituted with 1 But one R 5 Provided herein as embodiment 317 is a compound of embodiment 317, wherein R is N-piperidinyl substituted with 5 However, 0 to 3 R 7 As embodiment 320, compounds of embodiment 318 are provided herein, wherein R is a heteroaryl substituted with 5 However, 0 to 3 R 7 As embodiment 321, provided herein is a compound of embodiment 319, wherein R is 2-thiazolyl substituted with 5 But 0 R 7 As embodiment 322, there is provided herein a compound of embodiment 320, which is 2-thiazolyl substituted with LR. 1 but [ka] The compound of embodiment 317 is provided, wherein

[0108] As an embodiment 323, the present invention relates to a compound comprising R 1 -N(R a As embodiment 324, provided herein is a compound of any one of embodiments 1 to 124, wherein each R a C 1~4 Provided herein as embodiment 323 is a compound in which R is alkyl (e.g., methyl). 1 -N(R a )2 and each R a Provided herein as embodiment 326 is a compound of embodiment 323, wherein LR is methyl. 1 but [ka] The compound of embodiment 323 is provided, wherein

[0109] As embodiment 327, the present specification provides 1 However, 0 to 3 R 5 Provided herein as embodiment 328 is a compound of any one of embodiments 1 to 124, wherein R is a heteroaryl substituted with R (e.g., 5-thiazolyl). 1 But 0 R 5 Compounds according to embodiment 327 are provided herein, where R is a heteroaryl substituted with (e.g., 5-thiazolyl). 1 But 0 R 5 Provided herein as embodiment 327 is a compound of embodiment 327, which is 5-thiazolyl substituted with R 1 However, 0 to 3 R 5 Provided herein as embodiment 327 is a compound of embodiment 327, which is 6-(4,5,6,7-tetrahydrobenzo[d]thiazolyl) substituted with 1 But 0 R 5 Provided herein as embodiment 332 is a compound of embodiment 330, which is 6-(4,5,6,7-tetrahydrobenzo[d]thiazolyl) substituted with LR. 1 but [ka] The compound of embodiment 327 is provided, wherein

[0110] As an embodiment 333, the present invention relates to -LR 1 but [ka] [ka] [ka] The compound of any one of embodiments 1-124 is provided, wherein

[0111] As embodiment 334, the present specification provides -LR 1 but [ka] The compound of embodiment 333 is provided, wherein

[0112] As embodiment 335, the present specification provides -LR 1 but [ka] The compound of embodiment 334 is provided, wherein

[0113] As embodiment 336, the present invention relates to 2 But halogen, C 1~4 Alkyl, C 2~4 Provided herein as embodiment 337 is a compound of any one of embodiments 1 to 335, wherein R is aryl, alkenyl, or cyano. 2 Provided herein as embodiment 338 are compounds of embodiment 336, wherein R is chlorine, methyl, ethyl, vinyl, or cyano. 2 Provided herein as embodiment 339 are compounds of embodiment 336, in which R 2 Provided herein as embodiment 336 is a compound where R is methyl or ethyl. 2 Provided herein as embodiment 341 are compounds of embodiment 339, in which R 2 Provided herein as embodiment 342 are compounds of embodiment 339, in which R 2 Provided herein as embodiment 336 is a compound where R is vinyl (i.e., 2-ethenyl). 2 Compounds of embodiment 336 are provided where is cyano.

[0114] As embodiment 344, the present specification provides 4 Compounds of any one of embodiments 1-343 are provided wherein is halogen (eg, fluorine).

[0115] As embodiment 345, the present invention relates to a compound comprising R 4 Compounds of any one of embodiments 1-343 are provided wherein is fluorine.

[0116] As embodiment 346, the present invention relates to a compound comprising R 3 Provided herein as embodiment 347 are compounds of any one of embodiments 1 to 345, wherein R 3 Provided herein as embodiment 348 is a compound of any one of embodiments 1 to 345, wherein R 3 Compounds of any one of embodiments 1-345 are provided wherein is fluorine.

[0117] As embodiment 349, the present specification provides q Compounds of any one of embodiments 1-348 are provided, wherein is linked as shown in formula (IIa): [ka]

[0118] As an embodiment 350, the present specification provides q Compounds of any one of embodiments 1-348 are provided, wherein is linked as shown in formula (IIb): [ka]

[0119] As an embodiment 351, the present invention relates to a compound comprising R q Provided herein as embodiment 352 is a compound of any one of embodiments 1 to 350, wherein R qCompounds of any one of embodiments 1 to 350 are provided herein, where R is halogen (e.g., chlorine or fluorine). q But, C 1~4 Provided is a compound of any one of embodiments 1-350, wherein is alkyl (eg, methyl).

[0120] As embodiment 354, provided herein is a compound of embodiment 1 selected from one of the following compounds: 4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(3-(trifluoromethyl)piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-diazepan-2-one; 4-(4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-4-(piperazin-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-chloro-2-((2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-6-chloro-8-fluoro-2-(2-((S)-1-methylpyrrolidin-2-yl)ethoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-diazepan-2-one; 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-diazepan-5-one; 4-(4-((1R,5S)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-6-chloro-2-((2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-4-(1,4-diazepan-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(4-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1,4-diazepan-2-one; 4-(4-(2,5-diazabicyclo[4.1.0]heptan-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1,4-diazepan-5-one; 4-(7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1,4-diazepan-2-one; 4-(7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-one; 1-(7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1,4-diazepan-5-one; ((2R)-4-(7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)methanol; 2-((2S)-4-(7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile; 4-(4-((1R,4R)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-4-(1,4-diazepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-(3,6-diazabicyclo[3.2.1]octan-6-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-(3,6-diazabicyclo[3.2.1]octan-6-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-(3,6-diazabicyclo[3.2.2]nonan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-(3,9-diazabicyclo[4.2.1]nonan-9-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-(3,9-diazabicyclo[4.2.1]nonan-9-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-(2,6-diazabicyclo[3.2.1]octan-6-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 2-((2S)-1-(7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)ethan-1-ol; ((2R)-1-(7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)methanol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-(2,5-diazabicyclo[4.1.0]heptan-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(octahydro-1H-cyclopenta[b]pyrazin-1-yl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 7a-(((7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)oxy)methyl)hexahydro-3H-pyrrolidin-3-one; 4-(6-chloro-8-fluoro-4-(piperazin-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((2S,4R)-4-fluoropyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-2-(((S)-1-(dimethylamino)propan-2-yl)oxy)-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; ((3R,7aR)-7a-(((7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)oxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methanol; ((3R,7aS)-7a-(((7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)oxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methanol; 4-(6-chloro-8-fluoro-2-(((S)-1-methylazetidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((R)-1-methylpyrrolidin-3-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-2-((2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((2S,4S)-4-fluoropyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((S)-1-(2-fluoroethyl)pyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-((hexahydroindolizin-8a(1H)-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((R)-1-methylazetidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-2-(((S)-4,4-difluoropyrrolidin-2-yl)methoxy)-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(2-(1-methylpiperidin-2-yl)ethoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(2-((S)-1-methylpyrrolidin-2-yl)ethoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-2-((1-ethylpiperidin-4-yl)methoxy)-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((S)-1-methylpiperidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-2-(((S)-1-(2,2-difluoroethyl)pyrrolidin-2-yl)methoxy)-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; (5S)-5-(((7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)oxy)methyl)pyrrolidin-2-one; 4-(6-chloro-2-(((R)-1-(dimethylamino)propan-2-yl)oxy)-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methyl)amino)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 1-((2S)-2-(((7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)oxy)methyl)pyrrolidin-1-yl)ethan-1-one; 4-(6-chloro-8-fluoro-4-(piperazin-1-yl)-2-(((S)-pyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((S)-2-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((R)-2-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(2-(((1s,4s)-7-azabicyclo[2.2.1]heptan-1-yl)methoxy)-6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-[6-chloro-8-fluoro-2-[3-methyl-3-(methylamino)azetidin-1-yl]-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-8-fluoro-4-piperazin-1-yl-2-[3-(1-piperidyl)azetidin-1-yl]quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[2-(3-amino-3-methyl-azetidin-1-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[2-[(2R,3S)-3-amino-2-methyl-azetidin-1-yl]-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[2-(3-amino-3-ethyl-azetidin-1-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 8-(7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-2-one; 1-[1-[7-(2-amino-1,3-benzothiazol-4-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-2-yl]azetidin-3-yl]piperidin-4-ol; 4-[6-chloro-2-(2,5-diazaspiro[3.4]octan-2-yl)-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 1-[1-[7-(2-amino-1,3-benzothiazol-4-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-2-yl]azetidin-3-yl]azetidin-3-ol; 1-[1-[7-(2-amino-1,3-benzothiazol-4-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-2-yl]azetidin-3-yl]-3-methyl-azetidin-3-ol; 4-(2-(3-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)azetidin-1-yl)-6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-[6-chloro-8-fluoro-2-[3-(4-methoxy-1-piperidyl)azetidin-1-yl]-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-8-fluoro-2-[3-[methyl-[(3R)-tetrahydrofuran-3-yl]amino]azetidin-1-yl]-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-8-fluoro-2-[3-(3-fluoroazetidin-1-yl)azetidin-1-yl]-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazole-2-amine; 4-[6-chloro-8-fluoro-2-[3-(methylamino)azetidin-1-yl]-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 1-[1-[7-(2-amino-1,3-benzothiazol-4-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-2-yl]azetidin-3-yl]piperidin-3-ol; 4-[6-chloro-2-[(1S,5R)-2,6-diazabicyclo[3.2.0]heptan-6-yl]-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-8-fluoro-4-piperazin-1-yl-2-[3-(dimethylamino)pyrrolidin-1-yl]quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[2-(3-aminoazetidin-1-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-8-fluoro-4-piperazin-1-yl-2-[3-(methylamino)pyrrolidin-1-yl]quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-(6-chloro-8-fluoro-2-(1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(4-methyloctahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-[6-chloro-8-fluoro-2-[3-[methyl(oxetan-3-yl)amino]azetidin-1-yl]-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-(6-chloro-8-fluoro-2-(trans-4-methylhexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-[6-chloro-2-(1,6-diazaspiro[3.3]heptan-6-yl)-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-(6-chloro-8-fluoro-2-(cis-4-methylhexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-[6-chloro-8-fluoro-2-[3-[methoxy(methyl)amino]azetidin-1-yl]-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 2-[7-(2-amino-1,3-benzothiazol-4-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-2-yl]-8-oxa-2,5-diazaspiro[3.6]decan-6-one; 2-[[7-(2-amino-1,3-benzothiazol-4-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-2-yl]amino]-1-thiazol-5-yl-ethanol; 4-[6-chloro-8-fluoro-4-piperazin-1-yl-2-[1,4-diazabicyclo[3.2.1]octan-4-yl]quinazolin-7-yl]-1,3-benzothiazol-2-amine; 1'-[7-(2-amino-1,3-benzothiazol-4-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-2-yl]spiro[6,7-dihydropyrrolo[1,2-a]imidazol-5,3'-azetidin]-7-ol; 4-[6-chloro-8-fluoro-4-piperazin-1-yl-2-[1,7-diazaspiro[3.4]octan-7-yl]quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-8-fluoro-4-piperazin-1-yl-2-[[(6S)-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl]amino]quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-2-[3-(1,1-dioxo-1,4-thiazin-4-yl)azetidin-1-yl]-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-2-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 1'-[7-(2-amino-1,3-benzothiazol-4-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-2-yl]-8-methyl-spiro[6H-imidazo[1,2-a]pyrimidin-5,3'-azetidin]-7-one; 4-[6-chloro-8-fluoro-4-piperazin-1-yl-2-[3,6-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-2-[(1S,5S)-2,6-diazabicyclo[3.2.0]heptan-6-yl]-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazole-2-amine; 4-[6-chloro-8-fluoro-2-(3-imidazo-1-ylazetidin-1-yl)-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-2-[3-(2,2-dimethylmorpholin-4-yl)azetidin-1-yl]-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazole-2-amine; 4-[6-chloro-2-(3,3-difluoro-1,6-diazaspiro[3.3]heptan-6-yl)-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; Ethyl 1-[1-[7-(2-amino-1,3-benzothiazol-4-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-2-yl]azetidin-3-yl]pyrazole-3-carboxylate; 4-[6-chloro-2-(2,7-diazaspiro[3.4]octan-2-yl)-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-8-fluoro-4-piperazin-1-yl-2-[3-thiazol-2-yl-1-piperidyl]quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-(4-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-6-chloro-2-((2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-2-((1-ethylpiperidin-4-yl)oxy)-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)-6-methylbenzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)-7-(trifluoromethyl)benzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(6,8-difluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-methylquinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-4-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-4-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-4-(5-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-4-(2,5-dihydro-1H-pyrrol-3-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-6-vinylquinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-vinylquinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-vinylquinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(6-ethyl-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(8-fluoro-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 7-(2-aminobenzo[d]thiazol-4-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazoline-6-carbonitrile; 7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinoline-3-carbonitrile; 7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinoline-3-carbonitrile; 7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-chloro-8-fluoro-2-(((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinoline-3-carbonitrile; 7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinoline-3-carbonitrile; or 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine.

[0121] As an embodiment 355, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0122] As embodiment 356, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0123] As embodiment 357, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0124] As embodiment 358, the present specification provides a compound comprising [ka] A compound according to embodiment 1, or a pharma- ceutically acceptable salt thereof, is provided.

[0125] As an embodiment 359, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0126] As an embodiment 360, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0127] As an embodiment 361, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0128] As an embodiment 362, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0129] As an embodiment 363, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0130] As embodiment 364, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0131] As an embodiment 365, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0132] As embodiment 366, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0133] As embodiment 367, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0134] As embodiment 368, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0135] As an embodiment 369, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0136] As an embodiment 370, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0137] As an embodiment 371, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0138] As embodiment 372, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0139] As an embodiment 373, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0140] As embodiment 374, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0141] As an embodiment 375, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0142] As embodiment 376, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0143] As embodiment 377, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0144] As embodiment 378, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0145] As an embodiment 379, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0146] As an embodiment 380, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0147] As an embodiment 381, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0148] As an embodiment 382, ​​the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0149] As an embodiment 383, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0150] As embodiment 384, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0151] As an embodiment 385, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0152] As embodiment 386, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0153] As embodiment 387, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0154] As embodiment 388, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0155] As an embodiment 389, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0156] As an embodiment 390, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0157] As an embodiment 391, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0158] As an embodiment 392, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0159] As an embodiment 393, the present disclosure relates to a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0160] As an embodiment 394, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0161] As an embodiment 395, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0162] As embodiment 396, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0163] As an embodiment 397, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0164] As embodiment 398, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0165] As an embodiment 399, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0166] As embodiment 400, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0167] As embodiment 401, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0168] As embodiment 402, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0169] As embodiment 403, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0170] As embodiment 404, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0171] As embodiment 405, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0172] As embodiment 406, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0173] As embodiment 407, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0174] As embodiment 408, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0175] As embodiment 409, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0176] As an embodiment 410, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0177] As an embodiment 411, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0178] As embodiment 412, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0179] As an embodiment 413, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0180] As embodiment 414, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0181] As embodiment 415, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0182] As embodiment 416, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0183] As embodiment 417, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0184] As embodiment 418, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0185] As an embodiment 419, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0186] As an embodiment 420, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0187] As an embodiment 421, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0188] As an embodiment 422, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0189] As an embodiment 423, the present disclosure relates to a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0190] As embodiment 424, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0191] As embodiment 425, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0192] As embodiment 426, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0193] As embodiment 427, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0194] As embodiment 428, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0195] As an embodiment 429, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0196] As an embodiment 430, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0197] As an embodiment 431, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0198] As embodiment 432, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0199] As an embodiment 433, the present disclosure relates to a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0200] As embodiment 434, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0201] As an embodiment 435, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0202] As embodiment 436, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0203] As embodiment 437, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0204] As embodiment 438, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0205] As an embodiment 439, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0206] As an embodiment 440, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0207] As an embodiment 441, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0208] As embodiment 442, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0209] As an embodiment 443, the present disclosure relates to a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0210] As embodiment 444, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0211] As embodiment 445, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0212] As embodiment 446, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0213] As embodiment 447, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0214] As embodiment 448, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0215] As embodiment 449, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0216] As an embodiment 450, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0217] As an embodiment 451, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0218] As embodiment 452, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0219] As embodiment 453, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0220] As embodiment 454, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0221] As embodiment 455, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0222] As embodiment 456, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0223] As embodiment 457, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0224] As embodiment 458, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0225] As embodiment 459, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0226] As an embodiment 460, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0227] As embodiment 461, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0228] As embodiment 462, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0229] As embodiment 463, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0230] As embodiment 464, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0231] As embodiment 465, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0232] As embodiment 466, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0233] As embodiment 467, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0234] As embodiment 468, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0235] As embodiment 469, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0236] As embodiment 470, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0237] As embodiment 471, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0238] As embodiment 472, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0239] As embodiment 473, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0240] As embodiment 474, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0241] As embodiment 475, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0242] As embodiment 476, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0243] As embodiment 477, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0244] As embodiment 478, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0245] As embodiment 479, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0246] As an embodiment 480, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0247] As embodiment 481, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0248] As embodiment 482, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0249] As embodiment 483, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0250] As embodiment 484, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0251] As embodiment 485, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0252] As embodiment 486, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0253] As embodiment 487, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0254] As embodiment 488, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0255] As embodiment 489, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0256] As an embodiment 490, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0257] As embodiment 491, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0258] As embodiment 492, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0259] As an embodiment 493, the present disclosure relates to a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0260] As embodiment 494, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0261] As embodiment 495, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0262] As embodiment 496, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0263] As embodiment 497, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0264] As embodiment 498, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0265] As embodiment 499, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0266] As embodiment 500, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0267] As embodiment 501, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0268] As embodiment 502, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0269] As embodiment 503, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0270] As embodiment 504, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0271] As embodiment 505, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0272] As embodiment 506, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0273] As embodiment 507, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0274] As embodiment 508, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0275] As embodiment 509, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0276] As an embodiment 510, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0277] As an embodiment 511, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0278] As embodiment 512, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0279] As an embodiment 513, the present disclosure relates to a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0280] As an embodiment 514, the present specification provides a compound comprising [ka] or a pharma- ceutically acceptable salt thereof.

[0281] The foregoing description merely summarizes certain aspects of the disclosure and is not intended, nor should it be construed, as limiting the disclosure in any way.

[0282] Formulation and Route of Administration In the disclosed use, the compound disclosed herein may be administered alone, but the compound administered will usually be 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, for example, Remington: The Science and Practice of Pharmacy, Volume I and Volume II, 22nd Edition, Philadelphia, PA, Pharmaceutical Press, 2012; Pharmaceutical Dosage Forms (Vol. 1-3), Liberman et al., Eds., Marcel Dekker, New York, NY, 1992; Handbook of Pharmaceutical Excipients (3rd Ed.), edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, 2000; Pharmaceutical Formulation: The Science and Technology of Dosage Forms (Drug Discovery), 1st Edition, Royal Society of Chemistry, edited by GD Tovey, 2018. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein.

[0283] The compounds disclosed herein may be administered by any suitable route of administration in the form of a pharmaceutical composition adapted for such route and in a dose effective for the intended treatment. The compounds and compositions provided herein may be administered, for example, orally, mucosally, topically, transdermally, rectally, pulmonary, parenterally, intranasally, intravascularly, intravenously, intraarterially, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, intravaginally, or by injection techniques in dosage unit formulations containing conventional pharma- ceutically acceptable excipients.

[0284] The pharmaceutical composition may be in the form of, for example, a tablet, chewable tablet, mini-tablet, caplet, pill, bead, hard capsule, soft capsule, gelatin capsule, granule, powder, lozenge, patch, cream, gel, sachet, microneedle array, syrup, flavored syrup, juice, drop, injectable solution, emulsion, microemulsion, ointment, aerosol, aqueous suspension, or oily suspension. Pharmaceutical compositions are usually made in the form of a dosage unit containing a particular amount of the active ingredient.

[0285] As embodiment 515, there is provided herein a pharmaceutical composition comprising a compound of any one of embodiments 1-514, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, and a pharma- ceutically acceptable excipient.

[0286] As embodiment 516, there is provided herein a compound of any one of embodiments 1 to 514, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition of embodiment 515, for use as a medicament.

[0287] How to use As described herein (see the section entitled "Definitions"), the compounds described herein are 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 the methods and uses provided in this disclosure should be understood to encompass methods and uses using all such forms.

[0288] 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.

[0289] In one embodiment, the present disclosure provides a method of using a compound or pharmaceutical composition of the present disclosure to treat a disease state, including but not limited to a condition caused by a mutation in KRAS G12D, such as 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, bile duct cancer, or melanoma.

[0290] KRAS G12D mutations occur with the alteration frequencies shown in the table below (TCGA dataset; 1~3 For example, the table shows that 32.4% of subjects with pancreatic cancer have cancer in which one or more cells express the KRAS G12D mutant protein. G12D Compounds provided herein that bind to (see the section entitled "Biological Evaluation" below) are useful for treating subjects with cancers, including but not limited to those listed in the table below.

[0291] [Table 1]

[0292] As embodiment 517, there is provided herein a compound of any one of embodiments 1 to 514, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 515, for use in treating cancer.

[0293] As embodiment 518, there is provided herein a compound of any one of embodiments 1 to 514, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 515, for use in treating a cancer in which one or more cells express a KRAS G12D mutant protein.

[0294] As embodiment 519, there is provided herein a compound or pharmaceutical composition for use in embodiment 517 or 518, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small intestine cancer, appendix cancer, cancer of unknown primary site, endometrial cancer, mixed type cancer of unknown primary site, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

[0295] As embodiment 520, provided herein is the use of a compound of any one of embodiments 1 to 514, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 515, in the preparation of a medicament for treating cancer.

[0296] As embodiment 521, there is provided herein the use of a compound of any one of embodiments 1 to 514, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 515, in the preparation of a medicament for treating a cancer in which one or more cells express a KRAS G12D mutant protein.

[0297] As embodiment 522, the present specification provides the use of embodiment 520 or 521, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed type cancer of unknown primary, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

[0298] As embodiment 523, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1 to 514, or a pharma- ceutically acceptable salt thereof.

[0299] As embodiment 524, provided herein is a method of treating cancer in a subject in need thereof, wherein one or more cells express a KRAS G12D mutant protein, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1 to 514, or a pharma- ceutically acceptable salt thereof.

[0300] As embodiment 525, the present specification provides the method of embodiment 523 or 524, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed type cancer of unknown primary, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophageal and gastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

[0301] As embodiment 526, the present specification provides the method of embodiment 523 or 524, 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.

[0302] As embodiment 527, provided herein is the method of embodiment 526, wherein the lung cancer is non-small cell lung cancer.

[0303] As embodiment 528, provided herein is the method of embodiment 526, wherein the lung cancer is colorectal cancer.

[0304] As embodiment 529, provided herein is the method of embodiment 526, wherein the lung cancer is pancreatic cancer.

[0305] As embodiment 530, provided herein is the method of any one of embodiments 523-529, wherein the subject has a cancer determined to have one or more cells that express a KRAS G12D mutant protein prior to administration of the compound or a pharma- ceutically acceptable salt thereof.

[0306] Combination therapy The present disclosure further provides a method of combination therapy in which an overlapping set of agents known to regulate other pathways, or other components of the same pathway, or even target enzymes, is used in combination with the compounds of the present disclosure, or pharma- ceutically acceptable salts thereof. In one embodiment, such therapy includes, but is not limited to, the combination of one or more compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation therapy to produce synergistic or additive therapeutic effects. See, for example, U.S. Patent No. 10,519,146 B2, issued December 31, 2019, specifically sections 201 (line 37) to 212 (line 46) and 219 (line 64) to 220 (line 39), which are incorporated herein by reference.

[0307] As embodiment 531, provided herein is the method of any one of embodiments 523-530, 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.

[0308] 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.

[0309] Aurora kinase A inhibitors Provided herein is the method of any one of embodiments 523-530, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an Aurora kinase A inhibitor.

[0310] Exemplary Aurora kinase A inhibitors for use in the methods provided herein include alisertib, cenisertib, danusertib, tozasertib, LY3295668 (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyridin-2-yl]methyl]-2-methylpiperidine-4-carboxylic acid), ENMD-20 76 (6-(4-methylpiperazin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[(E)-2-phenylethenyl]pyrimidin-4-amine), TAK-901 (5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide), TT-00420 (4-[9-(2-chlorophenyl)-6-methyl-2,4,5,8,12-pentazatricyclo[8.4.0.03,7]tetradeca-1(14),3 ,6,8,10,12-Hexaen-13-yl]morpholine), AMG900 (N-[4-[3-(2-aminopyrimidin-4-yl)pyridin-2-yl]oxyphenyl]-4-(4-methylthiophen-2-yl)phthalazin-1-amine), MLN8054 (4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid), PF-03814735 (N-[2-[(1R,8S)-4-[[4-(cyclobutylamino)-5-(trifluorophenyl)

[0036] SNS-314 (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.

[0311] AKT inhibitors Provided herein is the method of any one of embodiments 523-530, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an AKT inhibitor.

[0312] Exemplary AKT inhibitors for use in the methods provided herein include afarestib, capivasertib, ipatasertib, uprosertib, BAY1125976 (2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide), ARQ 092 (3-[3-[4-(1-aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2-amine), MK2206 (8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one), SR13668 (indolo[2,3-b]carbazole-2,10-dicarboxylic acid, 5,7-dihydro-6-methoxy-, 2,10-diethyl ester ter), ONC201 (11 benzyl-7-[2-methylphenyl)methyl]-2,5,7,11 tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one), ARQ751 (N-(3-aminopropyl)-N-[(1R)-1-(3-anilino-7-chloro-4-oxoquinazolin-2-yl)but-3-ynyl]-3-chloro-2-fluorobenzamide), RX-0201, and LY2780301.

[0313] Arginase inhibitors Provided herein is a method as in any one of embodiments 523-530, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an arginase inhibitor.

[0314] Exemplary arginase inhibitors for use in the methods provided herein include, but are not limited to, numidargistat and CB280.

[0315] CDK4 / 6 inhibitors Provided herein is a method according to any one of embodiments 523-530, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a CDK4 / 6 inhibitor.

[0316] As used herein, the term "CDK4 / 6" refers to cyclin-dependent kinases ("CDKs") 4 and 6, which are members of the mammalian serine / threonine protein kinases.

[0317] As used herein, the term "CDK4 / 6 inhibitor" refers to a compound capable of negatively regulating or inhibiting all or part of the enzymatic activity of CDK4 and / or 6.

[0318] Exemplary CDK4 / 6 inhibitors for use in the methods provided herein include, but are not limited to, abemaciclib, palbociclib, ribociclib, trilaciclib, and PF-06873600 ((pyrido[2,3-d]pyrimidin-7(8H)-one, 6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[[1-(methylsulfonyl-1)-4-piperidinyl]amino]).

[0319] In one embodiment, the CDK4 / 6 inhibitor is palbociclib.

[0320] ErbB family inhibitors Provided herein is a method according to any one of embodiments 523-530, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an ErbB family inhibitor.

[0321] As used herein, the term "ErbB family" refers to members of the mammalian transmembrane protein tyrosine kinase family that includes: ErbB1 (EGFR HER1), ErbB2 (HER2), ErbB3 (HER3) and ErbB4 (HER4).

[0322] The term "ErbB family inhibitor" as used herein refers to an agent, e.g., a compound or an antibody, capable of negatively regulating or inhibiting all or part of the activity of at least one member of the ErbB family. The regulation or inhibition of one or more ErbB tyrosine kinases can occur by regulating or inhibiting the kinase enzymatic activity of one or more ErbB family members, or by blocking homodimerization or heterodimerization of ErbB family members.

[0323] In one embodiment, the ErbB family inhibitor is an EGFR inhibitor, such as an anti-EGFR antibody. Exemplary anti-EGFR antibodies for use in the methods provided herein include, but are not limited to, zalutumumab, nimotuzumab, matuzumab, necitumumab, panitumumab and cetuximab. In one embodiment, the anti-EGFR antibody is cetuximab. In one embodiment, the anti-EGFR antibody is panitumumab.

[0324] In another embodiment, the ErbB family inhibitor is a HER2 inhibitor, such as an anti-HER2 antibody. Exemplary anti-HER-2 antibodies for use in the methods provided herein include, but are not limited to, pertuzumab, trastuzumab, and trastuzumab emtansine.

[0325] In yet another embodiment, the ErbB family inhibitor is a HER3 inhibitor, such as an anti-HER3 antibody, such as HMBD-001 (Hummingbird Bioscience).

[0326] In one embodiment, the ErbB family inhibitor is a combination of an anti-EGFR antibody and an anti-HER2 antibody.

[0327] In one embodiment, the ErbB family inhibitor is an irreversible inhibitor. Exemplary irreversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to, afatinib, dacomitinib, canertinib, poziotinib, AV412 ((N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butyn-1-yl]-6-quinazolinyl]-2-propenamide), PF6274484 (N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-2-propenamide), and HKI357 ((E)-N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide).

[0328] In one embodiment, the irreversible ErbB family inhibitor is afatinib.In one embodiment, the irreversible ErbB family inhibitor is dacomitinib.

[0329] In one embodiment, the ErbB family inhibitor is a reversible inhibitor. Exemplary reversible ErbB family inhibitors for use in the methods provided herein include erlotinib, gefitinib, sapitinib, valitinib, taloxotinib, TAK-285 (N-(2-(4-((3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl)-3-hydroxy-3-methylbutanamide), AEE788 ((S)-6-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-N-(1-phenylethyl)-7H-pyrrolo[2, 3-d]pyrimidin-4-amine), BMS599626 ((3S)-3-morpholinylmethyl-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamate) and GW583340 (N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[2-[(2-methylsulfonylethylamino)methyl]-1,3-thiazol-4-yl]quinazolin-4-amine).

[0330] In one embodiment, the reversible ErbB family inhibitor is sapitinib.In one embodiment, the reversible ErbB family inhibitor is tarloxotinib.

[0331] ERK inhibitors Provided herein is a method according to any one of embodiments 523-530, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an ERK inhibitor.

[0332] Exemplary ERK inhibitors for use in the methods provided herein include ulixertinib, ravosertinibe, 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- ... These include, but are not limited to, 1,5,6,8-tetrahydro-6-(phenylmethyl)-3-(4-pyridinyl)-7H-pyrazolo[4,3-g]quinazolin-7-one), ASTX029, LTT462, and JSI-1187.

[0333] FAK inhibitors Provided herein is a method according to any one of embodiments 523-530, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a FAK inhibitor.

[0334] 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.

[0335] FGFR inhibitors Provided herein is a method according to any one of embodiments 523-530, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an FGFR inhibitor.

[0336] Exemplary FGFR inhibitors for use in the methods provided herein include futibatinib, pemigatinib, ASP5878 (2-[4-[[5-[(2,6-difluoro-3,5-dimethoxyphenyl)methoxy]pyrimidin-2-yl]amino]pyrazol-1-yl]ethanol), AZD4547 (N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]benzamide), Devio 1347 ([5-amino- These include, but are not limited to, 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.

[0337] Glutaminase Inhibitors Provided herein is a method according to any one of embodiments 523-530, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a glutaminase inhibitor.

[0338] Exemplary glutaminase inhibitors for use in the methods provided herein include, but are not limited to, telaglenastat, IPN60090, and OP330.

[0339] IGF-1R inhibitors Provided herein is a method according to any one of embodiments 523-530, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an IGF-1R inhibitor.

[0340] Exemplary IGF-1R inhibitors for use in the methods provided herein include, but are not limited to, cixutumumab, dalotuzumab, linsitinib, ganitumab, lovatumumab, BMS-754807 ((2S)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide), KW-2450 (N-[5-[[4-(2-hydroxyacetyl)piperazin-1-yl]methyl]-2-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-3-methylthiophene-2-carboxamide), PL225B, AVE1642, and BIIB022.

[0341] KIF18A inhibitors Provided herein is a method according to any one of embodiments 523 to 530, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a KIF18A inhibitor.

[0342] 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.

[0343] MCL-1 inhibitors Provided herein is a method according to any one of embodiments 523-530, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an MCL-1 inhibitor.

[0344] Exemplary MEK inhibitors for use in the methods provided herein include murizatoclax, tapotoclax, AZD5991 ((3aR)-5-chloro-2,11,12,24,27,29 hexahydro-2,3,24,33 tetramethyl-22H-9,4,8-(metheniminomethyl)-14,20:26,23 dimetheno-10H,20H-pyrazolo[4,3-l][2,15,22,18,19]benzoxadithiadiazacit These include, but are not limited to, rohexacosine-32-carboxylic acid), MIK665 ((αR)-α-[[(5S)-5-[3-chloro-2-methyl-4-[2-(4-methyl-1-piperazinyl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy]-2-[[2-(2-methoxyphenyl)-4-pyrimidinyl]methoxy]benzenepropanoic acid), and ABBV-467.

[0345] In one embodiment, the MCL-1 inhibitor is murizatoclax. In another embodiment, the MCL-1 inhibitor is tapotoclax.

[0346] MEK inhibitors Provided herein is a method according to any one of embodiments 523-530, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a MEK inhibitor.

[0347] Exemplary MEK inhibitors for use in the methods provided herein include trametinib, cobimetinib, selumetinib, pimasertib, refametinib, PD-325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), AZD8330 (2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxopyridine-3-carboxylate), cyclosporine, ... ruboxamide), GDC-0623 (5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide), RO4987655 (3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-5-[(3-oxooxazinan-2-yl)methyl]benzamide), TAK-733 (3-[(2R)-2,3-dihydroxypropyl]-6-fluoro-5- (2-Fluoro-4-iodoanilino)-8-methylpyrido[2,3-d]pyrimidine-4,7-dione), PD0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), CI-1040 (2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide), PD318088 (5-bromo-N-(2,3-dihydro

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

[0348] In one embodiment, the MEK inhibitor is trametinib.

[0349] mTOR inhibitors Provided herein is a method according to any one of embodiments 523-530, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an mTOR inhibitor.

[0350] Exemplary mTOR inhibitors for use in the methods provided herein include everolimus, rapamycin, zotarolimus (ABT-578), ridaforolimus (deforolimus, MK-8669), sapanisertib, buparlisib, pitilisib, bistosertib, dactolisib, trilin-1(1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)cyclohexyl)-9-(quinolin-3-yl)benzo[h][1,6] naphthyridin-2(1H)-one), GDC-0349 ((S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-7-(oxetan-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea) and VS-5584 (SB2343, (5-(8-methyl-2-norpholin-4-yl-9-propan-2-ylpurin-6-yl)pyrimidin-2-amine).

[0351] In one embodiment, the mTOR inhibitor is everolimus.

[0352] PD-1 inhibitors Provided herein is a method according to any one of embodiments 523-530, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a PD-1 inhibitor.

[0353] Exemplary PD-1 inhibitors for use in the methods provided herein include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS001), dostallimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, and the anti-PD-1 antibodies described in U.S. Pat. No. 10,640,504 B2 ("Anti-PD-1 Antibody A," column 66, line 56 to column 67, line 24, and column 67, lines 54-57), which are incorporated by reference herein.

[0354] In one embodiment, the PD-1 inhibitor is pembrolizumab. In another embodiment, the PD-1 inhibitor is anti-PD-1 antibody A.

[0355] PD-L1 inhibitors Provided herein is a method according to any one of embodiments 523-530, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a PD-L1 inhibitor.

[0356] 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.

[0357] In one embodiment, the PD-L1 inhibitor is atezolizumab.

[0358] PI3K inhibitors Provided herein is a method according to any one of embodiments 523-530, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a PI3K inhibitor.

[0359] Exemplary PI3K inhibitors for use in the methods provided herein include idelalisib, copanlisib, duvelisib, alpelisib, taselisib, perifosine, buparlisib, ambralisib, pitilisib, dactolisib, boctalisib, sonolisib, tenalisib, selavelisib, acalisib, CUDC-907 (N-hydroxy-2-[[2-(6-methoxypyridin-3-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl]pyrimidin-4-yl, cytosine ... -methylamino]pyrimidine-5-carboxamide), ME-401 (N-[2-methyl-1-[2-(1-methylpiperidin-4-yl)phenyl]propan-2-yl]-4-(2-methylsulfonylbenzimidazol-1-yl)-6-morpholin-4-yl-1,3,5-triazin-2-amine), IPI-549 (2-amino-N-[(1S)-1-[8-[2-(1-methylpyrazol-4-yl)ethynyl]-1-oxo-2-phenylisoquinolinyl-3-isopropyl)-1,3,5-triazin-2-amine), pyrazolo[1,5-a]pyrazolopyrimidine-3-carboxamide), SF1126 (((2S)-2-[[(2S)-3-carboxy-2-[[2-[[(2S)-5-(diaminomethylideneamino)-2-[[4-oxo-4-[[4-(4-oxo-8-phenylchromen-2-yl)morpholin-4-ium-4-yl]methoxy]butanoyl]amino]pentanoyl]amino]acetyl]amino]propanoyl]amino]-3-hydroxypropanoate), XL These include, but are not limited to, 147 (N-[3-(2,1,3 benzothiadiazol-5-ylamino)quinoxalin-2-yl]-4-methylbenzenesulfonamide), GSK1059615 ((5Z)-5-[(4-pyridin-4-ylquinolin-6-yl)methylidene]-1,3-thiazolidine-2,4-dione) and AMG319 (N-[(1S)-1-(7-fluoro-2-pyridin-2-ylquinolin-3-yl)ethyl]-7H-purin-6-amine).

[0360] Raf kinase inhibitors Provided herein is a method according to any one of embodiments 523-530, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a Raf kinase inhibitor.

[0361] As used herein, the term "RAF kinase" refers to a member of the mammalian serine / threonine kinase family consisting of three isoforms (C-Raf, B-Raf and A-Raf), including homodimers of each isoform as well as heterodimers between isoforms, e.g., C-Raf / B-Raf heterodimers.

[0362] 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 disrupting Raf homodimer or heterodimer formation to inhibit activity.

[0363] In one embodiment, the Raf kinase inhibitors include encorafenib, sorafenib, lifirafenib, vemurafenib, dabrafenib, PLX-8394 (N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-3a,7a-dihydro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide), Raf-709 (N-(2-methyl-5,-morpholino-6'-((tetrahydro-2H -pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide), LXH254 (N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide), LY3009120 (1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl) (1-(3-(tert-phenyl)urea), Tak-632 (N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide), CEP-32496 (1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1 trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea), CCT196969 (1-(3-(tert-phenyl)urea), 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).

[0364] 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.

[0365] SHP2 inhibitors Provided herein is a method according to any one of embodiments 523-530, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a SHP2 inhibitor.

[0366] 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 for use in the methods provided herein is RMC-4630 (Revolution Medicine).

[0367] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include 3-[(1R,3R)-1-amino-3-methoxy-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyrazinemethanol (CAS 2172651-08-8), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2-pyrazinemethanol (CAS 2172652-13-8), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-[[3-chloro-2-(3-hydroxy [(2-amino-3-chloro-4-pyridinyl)thio]-5-methyl-2-pyrazinemethanol (CAS 2172652-38-7), and 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-methyl-2-pyrazinemethanol (CAS 2172652-48-9).

[0368] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include 1-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-4-methyl-4-piperidinamine (CAS 2240981-75-1), (1R)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine ( CAS2240981-78-4), (3S,4S)-8-[7-(2,3-dichlorophenyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS2240982-45-8), (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]pyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[ 4.5]decane-4-amine (CAS 2240982-57-2), 4-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-7-(2,3-dichlorophenyl)-6-methyl-pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-69-6), 7-[(2-amino-3-chloro-4-pyridinyl)thio]-4-[(3S,4S)-4-amino-3-methyl-2-oxa-8 -azaspiro[4.5]dec-8-yl]-6-methyl-pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-73-2) and (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-77-6).

[0369] In one embodiment, the SHP inhibitor for use in the methods provided herein is (1R)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine (CAS2240981-78-4).

[0370] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-54-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-54-3), 238840-56-5), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-(2,3-dichlorophenyl)-3-pyridinol (CAS 2238840-58-7), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-60-1), (1R)-8-[6-(2,3-dichlorophenyl)-5-methyl-3-pyridinyl] -8-Azaspiro[4.5]decane-1-amine (CAS 2238840-62-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2-pyridinemethanol (CAS 2238840-63-4), (1R)-8-[6-[(2,3-dichlorophenyl)thio]-5-methyl-3-pyridinyl]-8-azaspiro[4.5]decane-1-amine (CAS 2238840-64-5), 5-( 4-Amino-4-methyl-1-piperidinyl)-2-[(2,3-dichlorophenyl)thio]-3-pyridinol (CAS 2238840-65-6), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-[[(2,3-dichlorophenyl)thio]-3-pyridinol (CAS 2238840-66-7), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-3S, 4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-hydroxy-2-pyridinemethanol (CAS 2238840-67-8), 3-(4-amino-4-methyl-1-piperidinyl)-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-68-9), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-69-0), 6-[(2-a 3-(4-amino-4-methyl-1-piperidinyl)-6-[(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-71-4), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-(4-amino-4-methyl-1-piperidinyl)- 2-Pyridinemethanol (CAS 2238840-72-5), 5-[(2-amino-3-chloro-4-pyridinyl)thio]-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-methyl-3-pyridinemethanol (CAS 2238840-73-6), 2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-(2,3-dichlorophenyl)-6-methyl-3-pyridinemethanol (CAS 22388 40-74-7), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-75-8) and 2-[(2-amino-3-chloro-4-pyridyl)sulfanyl]-5-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(hydroxymethyl)pyridin-3-ol.

[0371] In one embodiment, the SHP inhibitor for use in the methods provided herein is 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56-5).

[0372] In one embodiment, the SHP2 inhibitor for use in the methods provided herein is an inhibitor disclosed in U.S. Pat. No. 10,590,090 B2, U.S. Patent Application Publication No. 2020 / 017517 A1, U.S. Patent Application Publication No. 2020 / 017511 A1, or WO 2019 / 075265 A1, each of which is incorporated by reference in its entirety.

[0373] SOS1 inhibitors Provided herein is a method according to any one of embodiments 523-530, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an SOS1 inhibitor.

[0374] Exemplary SOS1 inhibitors for use in the methods provided herein include, but are not limited to, BI3406 (N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-7-methoxy-2-methyl-6-[(3S)-oxolan-3-yl]oxyquinazolin-4-amine) and BI1701963.

[0375] Src kinase inhibitors Provided herein is a method according to any one of embodiments 523-530, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a Src kinase inhibitor.

[0376] As used herein, the term "Src kinase" refers to members of the mammalian non-receptor tyrosine kinase family that includes: Src, Yes, Fyn and Fgr (SrcA subfamily); Lck, Hck, Blk and Lyn (SrcB subfamily) and the Frk subfamily.

[0377] 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.

[0378] Exemplary Src kinase inhibitors for use in the methods provided herein include dasatinib, ponatinib, vandetanib, bosutinib, saracatinib, KX2-391 (N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide), SU6656 ((Z)-N,N-dimethyl-2-oxo-3-((4,5,6,7-tetrahydro-1H-indol-2-yl)methylene)indoline-5-sulfonamide), PP1( These include, but are not limited to, 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).

[0379] 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 aspect, the Src kinase inhibitor is KX-01.

[0380] Chemotherapeutic agents Provided herein is a method according to any one of embodiments 523-530, 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.

[0381] 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.

[0382] definition The following definitions are provided to aid in understanding the scope of the present disclosure.

[0383] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless otherwise indicated, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending on the standard deviation found in their respective testing measurements.

[0384] As used herein, when any variable occurs more than one time in a chemical formula, its definition at each occurrence is independent of its definition at every other occurrence. In the case of conflict between the chemical structure and the chemical name, the chemical structure is determinative of the compound's identity.

[0385] 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.

[0386] If the stereochemistry of a structure or portion of a structure is not shown, e.g., with bold or dashed lines, then the structure or portion of a structure is to be interpreted as encompassing all stereoisomers thereof. If the stereochemistry of a structure or portion of a structure is not shown, e.g., with bold or dashed lines, then the structure or portion of a structure is to be interpreted as encompassing only the specified stereoisomer. A bond drawn with a wavy line indicates that both stereoisomers are encompassed. This wavy line should not be confused with a wavy line drawn perpendicular to a bond, which indicates where a group is attached to the remainder of the molecule.

[0387] As used herein, the term "stereoisomer" or "stereoisomerically pure" compound refers to one stereoisomer of a compound (e.g., geometric isomer, enantiomer, diastereomer, and atropisomer) that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of that compound, and a stereoisomerically pure compound having two chiral centers will be substantially free of other enantiomers or diastereomers of that compound. Typical stereoisomerically pure compounds contain greater than about 80% by weight of one stereoisomer of the compound and about 20% or less by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and about 10% or less by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and about 5% or less by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and about 3% or less by weight of other stereoisomers of the compound.

[0388] 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 can be synthesized according to methods well known in the art and disclosed herein. Mixtures of stereoisomers can be resolved using standard techniques, such as chiral columns or chiral resolving agents. Additionally, the present disclosure encompasses pharmaceutical compositions comprising mixtures of any of the compounds disclosed herein with one or more other active agents disclosed herein. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725; Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0389] 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 said structural formula.

[0390] isotope labeled compounds Additionally, the scope of the present disclosure includes all pharma- ceutically acceptable isotopically labeled compounds of the compounds disclosed herein, such as compounds of Formula I, in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds disclosed herein include: 2 H and 3 Hydrogen such as H 11 C. 13 C and 14 Carbon, such as C 36 Chlorine such as Cl, 18 Fluorine such as F 123 I and 125 Iodine, such as I 13 N and 15 Nitrogen such as N 15 O. 17 O and 18 Oxygen, such as O 32 Phosphorus such as P, 35 Certain isotopically labeled compounds of formula I, for example those incorporating a radioactive isotope, are useful in 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 afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be advantageous. 11 C. 18 F, 15 O and 13 Substitution with positron-emitting isotopes such as N can be useful, for example, in positron emission tomography (PET) studies to examine target occupancy. Isotopically labeled compounds of the compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the accompanying general synthetic schemes and examples, using suitable isotopically labeled reagents in place of conventionally used non-labeled reagents.

[0391] 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.

[0392] As used herein, the term "solvate" refers to a molecular complex comprising a compound described herein or a pharma- ceutically acceptable salt thereof and a stoichiometric or non-stoichiometric amount of one or more pharma- ceutical acceptable solvent molecules. When the solvent is water, the solvate is referred to as a "hydrate."

[0393] Accordingly, the scope of the present disclosure should be understood to encompass all solvates of 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.

[0394] Various definitions This section will define additional terms used to describe the scope of the compounds, compositions and uses disclosed herein.

[0395] 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.

[0396] As used herein, the term "C 1~4 Alkyl" and "C 1~6 "Alkyl" refers to a straight or branched chain hydrocarbon containing 1 to 4 and 1 to 6 carbon atoms, respectively. 1~4 Alkyl or C 1~6 Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, and hexyl.

[0397] The term “C 1~4 Alkylene" and "C 1~6 "Alkylene" refers to a straight or branched chain divalent alkyl group, as defined herein, containing 1 to 4 and 1 to 6 carbon atoms, respectively. Representative examples of alkylene include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, and the like.

[0398] As used herein, the term "C 2~4 "Alkenyl" refers to a saturated hydrocarbon containing 2 to 4 carbon atoms having at least one carbon-carbon double bond. Alkenyl groups include both straight-chain and branched-chain moieties. 2~4 Representative examples of alkenyl include, but are not limited to, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, and butenyl.

[0399] As used herein, "C 2~4 The term "alkynyl" refers to a saturated hydrocarbon containing 2 to 4 carbon atoms with at least one carbon-carbon triple bond. This term includes both straight and branched chain moieties. 3~6 Representative examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, and 3-butynyl.

[0400] As used herein, the term "C 1~4 Alkoxy" or "C 1~6 "Alkoxy" refers to -OR, where R is as defined herein. # are C 1~4 Alkyl group or C 1~6 Represents an alkyl group. 1~4 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy. 1~6 Representative examples of alkoxy include, but are not limited to, ethoxy, propoxy, isopropoxy, and butoxy.

[0401] As used herein, the term "C 3~8 "Cycloalkyl" refers to a saturated carbocyclic molecule whose cyclic backbone has 3 to 8 carbons. 3~8 Representative examples of cycloalkyl include, but are not limited to, cyclopropyl and cyclobutyl.

[0402] When used herein as a prefix for another term of a chemical group, the term "deuterium" means that one or more hydrogen atoms have been replaced with a heavy atom ("D" or " 2 It refers to the modification of a chemical group in which the group is replaced with a fluorine-containing fluorine atom (H). For example, "C 1~4 The term "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).

[0403] As used herein, the term "halogen" refers to -F, -CI, -Br, or -I.

[0404] The term "halo," as used herein as a prefix of another term for a chemical group, refers to a modification of that 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).

[0405] 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 or 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.

[0406] The term "heteroaryl" also refers to groups in which a heteroaromatic ring is fused to one or more aryl, aliphatic, or heterocyclyl rings.

[0407] As used herein, the term "heterocycle", "heterocycloalkyl" or "heterocyclo" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6- or 7-membered monocyclic, a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic or a 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system, and containing at least one heteroatom selected from O, S and N, which may 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.

[0408] As used herein, the term "pharmaceutical acceptable" generally refers to something that is recognized for use in subjects, particularly humans.

[0409] As used herein, the term "pharmaceutical acceptable salt" refers to a salt of a compound that is pharmaceutical acceptable and has the desired pharmacological activity of the parent compound. Such salts include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, etc.; or (2) salts formed when the acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth ions, or aluminum ions; or when coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine, etc. Further examples of such salts can be found in Berge et al., J. Pharm. Sci. 66(1):1-19 (1977). Stahl et al., Pharmaceutical Salts: Properties, Selection, and Use, 2 nd See also the Revised Edition (2011).

[0410] As used herein, the term "pharmaceutical acceptable excipient" refers to a wide range of ingredients that can be combined with the compounds or salts disclosed herein to prepare pharmaceutical compositions or formulations.Typically, excipients include, but are not limited to, diluents, colorants, vehicles, anti-adhesive agents, glidants, disintegrants, flavoring agents, coating agents, binders, sweeteners, lubricants, adsorbents, preservatives, etc.

[0411] As used herein, the term "subject" refers to humans and mammals, including, but not limited to, primates, cows, sheep, goats, horses, dogs, cats, rabbits, rats, and mice. In one embodiment, the subject is a human.

[0412] As used herein, the term "therapeutically effective amount" refers to an amount of a compound disclosed herein that elicits the biological or medical response in a tissue, system, or subject desired by a researcher, veterinarian, medical doctor, or other clinician.

[0413] General synthetic procedure The compounds provided herein can be synthesized according to the procedures described in this section and in the following sections. The synthetic methods described herein are merely exemplary, and the compounds disclosed herein can also be synthesized by alternative routes using alternative synthetic strategies as would be understood by 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.

[0414] In general, the compound of formula I can be synthesized according to the following scheme. Any variables used in the following scheme are defined as for formula I unless otherwise noted. All starting materials are either commercially available, for example, from Merck Sigma-Aldrich Inc., Fluorochem Ltd, and Enamine Ltd., or known in the art, and may be synthesized by using known procedures using conventional techniques. Starting materials can also be synthesized via the procedures disclosed herein. Suitable reaction conditions, such as solvents, reaction temperatures, and reagents for the schemes described in this section can be found in the examples provided herein. [ka] Scheme I

[0415] Compounds of formula (I) can 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 is reacted with a fluoride source such as potassium fluoride in the presence of a base such as sodium hydride or cesium carbonate in the presence of a nucleophilic catalyst such as 1,4-diazabicyclo[2.2.2]octane or without a nucleophilic catalyst in a solvent such as dimethylsulfoxide or in a mixture of solvents such as tetrahydrofuran and N,N-dimethylformamide to give compound (2). 1 -LH-bearing nucleophiles and S N In step C, compound (3) is coupled with an organometallic reagent derived from 2-aminobenzothiazole, such as a boronic acid (ester), to give compound (4). This coupling reaction proceeds in a solvent such as 1,4-dioxane and a catalyst such as Pd(dppf)Cl2, with or without a base such as potassium phosphate. 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 mono-Boc protected amine and S in a solvent such as acetonitrile in the presence of a base such as N,N-diisopropylethylamine. N Reacting with Ar affords compound (6). In step F, the protecting group is removed using conditions known in the art. For example, Boc can be removed using TFA or HCl. [ka] Scheme II

[0416] Compounds of formula (I) can be prepared according to Scheme II. In step A, compound (1) is reacted with an optionally substituted mono-Boc protected amine and S in the presence of a base such as N,N-diisopropylethylamine in a solvent such as acetonitrile. NIn step B, compound (7) is treated with sodium thiomethoxide in a solvent such as tetrahydrofuran to give compound (8). In step C, compound (8) is coupled with an organometallic reagent derived from 2-aminobenzothiazole, such as a boronic acid (ester), to give compound (9). This coupling reaction proceeds in a solvent such as 1,4-dioxane and a catalyst such as Pd(dppf)Cl2 with or without a base such as potassium phosphate. In step D, compound (9) is treated with an oxidizing agent such as 3-chloroperbenzoic acid to give compound (10). In step E, compound (10) is reacted with an organometallic reagent of formula R in a solvent such as tetrahydrofuran in the presence of a base such as potassium tert-butoxide. 1 -LH-bearing nucleophiles and S N Reacting with Ar affords compound (6). In step F, the protecting group is removed using conditions known in the art. For example, Boc can be removed using TFA or HCl. [ka] Scheme III

[0417] Compounds of formula (I) can be prepared according to Scheme III. In step A, compound (1) is reacted with an optionally substituted mono-Boc protected amine and S in the presence of a base such as N,N-diisopropylethylamine in a solvent such as acetonitrile. N In step B, compound (7) is pretreated with a fluoride source such as potassium fluoride or is reacted with a fluoride source such as potassium fluoride in the presence of a base such as sodium hydride or cesium carbonate in the presence or absence of a nucleophilic catalyst such as 1,4-diazabicyclo[2.2.2]octane in a solvent such as dimethylsulfoxide or a mixture of solvents such as tetrahydrofuran and N,N-dimethylformamide to give a compound of formula R 1 -LH-bearing nucleophiles and S NReaction with 1,2-dichlorophenyl ether affords compound (11). In step C, compound (11) is coupled with an organometallic reagent derived from 2-aminobenzothiazole, such as a boronic acid (ester), to give compound (6). The coupling reaction proceeds in a solvent such as 1,4-dioxane and a catalyst such as Pd(dppf)Cl2, with or without a base such as potassium phosphate. In step D, the protecting group is removed using conditions known in the art. For example, Boc can be removed using TFA or HCl. [ka] Scheme IV

[0418] Compounds of formula (II) can be prepared according to Scheme IV. In step A, compound (5) is coupled with an organometallic reagent such as a boronic acid (ester) to give compound (12). The coupling reaction proceeds in a solvent such as 1,4-dioxane and a catalyst such as Pd(dppf)Cl2 with or without a base such as potassium phosphate. In step B, the protecting group is removed using conditions known in the art. For example, Boc can be removed using TFA or HCl. [ka] Scheme V

[0419] Compounds of formula (III) can be prepared according to Scheme V. In step A, compound (13) is hydrolyzed in the presence of an acid such as sulfuric acid in a solvent such as 1,4-dioxane. In step B, compound (14) is converted to compound (15) by treatment with trifluoromethanesulfonic anhydride in the presence of a base such as N,N-diisopropylethylamine in a solvent such as dichloromethane. In step C, compound (15) is converted to compound (16) of formula R in the presence of a base such as sodium hydride in a solvent such as tetrahydrofuran. 1 -LH-bearing nucleophiles and S NIn step D, compound (16) is coupled with an organometallic reagent derived from 2-aminobenzothiazole, such as a boronic acid (ester), to give compound (17). The coupling reaction proceeds in a solvent such as 1,4-dioxane and a catalyst such as Pd(dppf)Cl2, with or without a base such as potassium phosphate. In step E, compound (17) is coupled with an optionally substituted mono-Boc protected amine to give compound (18). The coupling reaction proceeds in a solvent such as 1,4-dioxane in the presence of a base such as cesium carbonate, with a catalyst such as Ruphos Pd G4. In step F, the protecting group is removed using conditions known in the art. For example, Boc can be removed using TFA or HCl. [ka] Scheme VI

[0420] Compounds of formula (IV) can be prepared according to Scheme VI. In step A, compound (6) is coupled with a nucleophile such as a boronic acid (ester) or an organometallic reagent to give compound (19). The coupling reaction proceeds in a solvent such as 1,4-dioxane and a catalyst such as SPhos Pd G3 with or without a base such as potassium phosphate. In step B, the protecting group is removed using conditions known in the art. For example, Boc can be removed using TFA or HCl. [ka] Scheme VII

[0421] Compounds of formula (V) can be prepared according to Scheme VII. In step A, compound (19) is reduced using a reducing agent such as hydrogen gas with a catalyst such as Pd / C in a solvent such as ethanol to give compound (20). In step B, the protecting group is removed using conditions known in the art. For example, Boc can be removed using TFA or HCl. EXAMPLES

[0422] This section provides specific examples of compounds of Formula I and methods for making them.

[0423] List of abbreviations

[0424] [Table 2]

[0425] [Table 3]

[0426] General analytical and purification methods This section provides a description of the general analytical and purification methods used to prepare the specific examples provided herein.

[0427] Chromatography: Unless otherwise indicated, residues containing crude product were purified by passing the crude material or concentrate through a Biotage or ISCO brand silica gel column pre-packed with flash silica (SiO2) and eluting the product from the column with a solvent gradient as indicated.

[0428] Preparative HPLC Method: Where so indicated, compounds described herein were purified by reverse-phase HPLC on a Waters FractionLynx semi-preparative HPLC-MS system using one of two HPLC columns: (a) a Phenomenex Gemini column (5 micron, C18, 150 x 30 mm) or (b) a Waters X-select CSH column (5 micron, C18, 100 x 30 mm). A typical run through the instrument involves elution with a linear gradient of 10% (v / v) to 100% MeCN (0.1% v / v formic acid) in water (0.1% formic acid) at 45 mL / min over 10 minutes, conditions may be varied to achieve optimal separation.

[0429] Proton NMR Spectra: Unless otherwise indicated, all 1H NMR spectra were collected on a Bruker NMR instrument at 300, 400, or 500 MHz. When so characterized, all observed protons are reported as parts per million (ppm) downfield from tetramethylsilane (TMS) using the internal solvent peak as reference.

[0430] 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 typically reported according to the detected isotopic pattern.

[0431] Preparation of intermediates ((2R,7aR)-2-Fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (Intermediate A) [ka]

[0432] Step 1: 1-(tert-butyl) 2-methyl (4R)-2-(3-chloropropyl)-4-fluoropyrrolidine-1,2-dicarboxylate. To a mixture of 1-tert-butyl 2-methyl (2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate (45.0 g, 182 mmol) and HMPA (42.4 g, 237 mmol, 41.6 mL) in THF (250 mmol) was added LiHMDS (1.0 M, 237 mL) in portions at −70° C. under N2. The mixture was stirred at −70° C. for 1 h. Then, to the mixture was added 1-bromo-3-chloro-propane (143.3 g, 910 mmol, 90 mL) in portions at −70° C. under N2. The resulting mixture was warmed to 15° C. and stirred for 5 h. TLC showed that the starting material was completely consumed. The mixture was poured into aqueous NH4Cl (1-L) and stirred for 20 min. The aqueous phase was extracted with EtOAc (500 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with petroleum ether / EtOAc (10 / 1 to 1 / 1) to give 1-(tert-butyl) 2-methyl(4R)-2-(3-chloropropyl)-4-fluoropyrrolidine-1,2-dicarboxylate (68.0 g, 210 mmol, 57% yield) as a yellow oil.

[0433] Step 2: Methyl (4R)-2-(3-chloropropyl)-4-fluoropyrrolidine-2-carboxylate. To a mixture of 1-(tert-butyl) 2-methyl (4R)-2-(3-chloropropyl)-4-fluoropyrrolidine-1,2-dicarboxylate (34.0 g, 105 mmol) in CH3CN (200 mL) was added HCl / dioxane (4 M, 150 mL) in one portion at 15° C. under N2. The mixture was stirred at 15° C. for 2 h. TLC showed that the material was completely consumed. The mixture was concentrated under reduced pressure at 45° C. The crude methyl (4R)-2-(3-chloropropyl)-4-fluoro-pyrrolidine-2-carboxylate (55.0 g, crude) was obtained, which was used directly in the next step.

[0434] Step 3: Methyl (2R)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate. To a mixture of methyl (4R)-2-(3-chloropropyl)-4-fluoro-pyrrolidine-2-carboxylate (55.0 g, 211 mmol) in CH3CN (550 mL) was added NaHCO3 (88.8 g, 1.06 mol, 41 mL) and KI (3.51 g, 21.1 mmol) in one portion at 15 °C under N2. The mixture was stirred at 50 °C for 12 h. TLC showed that the material was completely consumed and one new spot was formed. The mixture was filtered and the filter cake was washed with EtOH (100 mL x 3). The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with petroleum ether / EtOAc (3 / 1 to 0 / 1) to give methyl (2R)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (27.0 g, 144 mmol, 49% yield) as a yellow oil.

[0435] Step 4: ((2R)-2-Fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol. To a mixture of methyl (2R)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (10.0 g, 53.4 mmol) in THF (100 mL) was added LiAlH4 (4.05 g, 107 mmol) portionwise at -40 °C. The mixture was then stirred at -40 °C for 1 h. TLC showed the reaction was complete. To the reaction mixture was added Na2SO4·10H2O (20 g) portionwise slowly at 0 °C. The mixture was diluted with THF (50 mL) and filtered. The filter cake was washed with THF (300 mL). The organic layer was concentrated under vacuum. Crude ((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (10.0 g, crude) was obtained as a colorless oil, which was used directly in the next step.

[0436] Step 5: (2R)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2-fluorohexahydro-1H-pyrrolidine. To a mixture of ((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (20.0 g, 126 mmol) and imidazole (34.2 g, 503 mmol) in DMF (25 mL) was added TBDPSCl (69.1 g, 251 mmol, 64.54 mL). The mixture was then stirred at 20° C. for 3 h. TLC (EtOAc:MeOH=6:1) showed the reaction was complete. The mixture was diluted with H2O (100 mL) and extracted with EtOAc (400 mL×2). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel eluting with petroleum ether / EtOAc (20 / 1 to 10 / 1) to give (2R)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2-fluorohexahydro-1H-pyrrolidine (11.0 g, 17.7 mmol, 26% yield for two steps) as a colorless oil. m / z (ESI, +ve ion): 398.3 (M+H). + .

[0437] Step 6: (2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2-fluorohexahydro-1H-pyrrolidine. (2R)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2-fluorohexahydro-1H-pyrrolidine (6.50 g, 16.4 mmol) was separated by column chromatography on silica gel eluted with petroleum ether / EtOAc (7 / 1 to 0 / 1) to give (2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2-fluorohexahydro-1H-pyrrolidine (2.35 g, 5.66 mmol, 36% yield, 96% purity) as a yellow oil.

[0438] Step 7: ((2R,7aR)-2-Fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol. To a mixture of (2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2-fluorohexahydro-1H-pyrrolidine (500 mg, 1.26 mmol) in DMF (5 mL) was added CsF (1.91 g, 12.6 mmol) in one portion at 15° C. under N2. The mixture was stirred at 70° C. for 72 h. Another batch containing 9 g of (2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2-fluorohexahydro-1H-pyrrolidine was set up following the same procedure. The two batches were combined for purification. The crude product was purified by elution with EtOAc / methanol (6 / 1 to 1 / 1, NH3 . Purification by column chromatography on silica gel eluting with HO additive) gave ((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (2.60 g, 16.3 mmol, 68% yield) as a yellow oil. 1 H NMR (400MHz, chloroform-d) δ ppm 5.22 (dt, J=54Hz, 4.6Hz, 1H), 3.47 - 3.31 (m, 3H), 3.00 - 2.98 (m, 1H), 2.88 - 2.75 (m, 1H), 2.67-2.65 (m, 1H), 2.25- 2.15 (m, 1H), 1.92 - 1.80 (m, 4H), 1.60 - 1.55 (m, 1H).

[0439] (2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)boronic acid (Intermediate B) [ka] Step 1: tert-Butyl (4-bromobenzo[d]thiazol-2-yl)carbamate. To a mixture of 4-bromo-1,3-benzothiazol-2-amine (50 g, 218 mmol) and Boc2O (42.9 g, 196 mmol, 45.1 mL) in DCM (2 L) was added DMAP (1.87 g, 15.3 mmol) in one portion at 20 °C under N2. The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with water (1 L). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with petroleum ether / EtOAc (1:0 to 30:1) to give tert-butyl (4-bromobenzo[d]thiazol-2-yl)carbamate (40 g, 122 mmol, 56% yield) as a white solid.

[0440] Step 2: (2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)boronic acid. tert-Butyl (4-bromobenzo[d]thiazol-2-yl)carbamate (50.0 g, 152 mmol) was dissolved in THF (675 mL). NaH (60%, 9.11 g, 228 mmol) was added portionwise at 20° C. under N2. The mixture was stirred at 20° C. for 10 min and then cooled to −78° C. To the mixture was added n-butyllithium (2.5 M, 91.1 mL) dropwise. The reaction mixture was stirred at −78° C. for 25 min. Triisopropyl borate (85.7 g, 456 mmol, 105 mL) was added dropwise and the reaction was stirred for 25 min. The reaction mixture was allowed to warm to 20° C. and stirred for 1 h. The reaction mixture was quenched by adding 500 mL of H2O at 0°C and extracted with EtOAc (800 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was stirred in petroleum ether (500 mL) for 10 min. The mixture was filtered and the filter cake was dried under reduced pressure. The compound (2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)boronic acid (20.6 g, 70.0 mmol, 46% yield) was obtained as a yellow solid. m / z (ESI, +ve ion): 295.1 (M+H) + .

[0441] (2-Amino-6-methylbenzo[d]thiazol-4-yl)boronic acid (Intermediate C) [ka] An 8 mL vial was charged with bis(pinacolato)diboron (247 mg, 0.971 mmol, Sigma-Aldrich Corporation), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (118 mg, 0.162 mmol, Sigma-Aldrich Corporation), potassium acetate (119 mg, 1.214 mmol, Sigma-Aldrich Corporation), 4-bromo-6-methylbenzo[d]thiazol-2-amine, and 1,4-dioxane (4047 μL). The reaction was stirred at 80° C. overnight. The mixture was filtered through a plug of Celite and rinsed with EtOAc. The combined organic layers were dried under vacuum. The crude product was used in the next step without further purification. m / z (ESI, +ve ion): 209.0 (M+H) + .

[0442] (2-Amino-7-(trifluoromethyl)benzo[d]thiazol-4-yl)boronic acid (Intermediate D) [ka] Intermediate D was synthesized in a similar manner to intermediate C using 4-bromo-7-(trifluoromethyl)benzo[d]thiazol-2-amine. m / z (ESI, +ve ion): 262.9 (M+H). + .

[0443] tert-Butyl (4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(methylthio)quinazolin-7-yl)benzo[d]thiazol-2-yl)carbamate (Intermediate E) [ka] Step 1: 7-Bromo-2,6-dichloro-8-fluoro-4-(methylthio)quinazoline. NaSMe (6.40 g, 18.3 mmol, 5.82 mL, 20% purity) was added to a solution of 7-Bromo-2,4,6-trichloro-8-fluoro-quinazoline (6.00 g, 18.2 mmol) in THF (120 mL) at 0° C. under N2. The mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with 150 mL water and extracted with 300 mL EtOAc. The organic layer was concentrated under reduced pressure to give a residue. After drying the residue in vacuum, the desired compound 7-Bromo-2,6-dichloro-8-fluoro-4-(methylthio)quinazoline (4.35 g, 12.7 mmol, 70% yield) was obtained as a yellow solid. m / z (ESI, +ve ion): 342.8 (M+H) + .

[0444] Step 2: (S)-7-Bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(methylthio)quinazoline. To a mixture of 7-bromo-2,6-dichloro-8-fluoro-4-(methylthio)quinazoline (9.90 g, 29.0 mmol) and [(2S)-1-methylpyrrolidin-2-yl]methanol (5.00 g, 43.4 mmol, 5.16 mL) in THF (120 mL) and DMF (60.5 mL) at 20° C. under N2 was added DIPEA (7.48 g, 57.9 mmol, 10.1 mL) in one portion. The mixture was stirred at 80° C. for 10 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with petroleum ether / EtOAc (1 / 0 to 0 / 1). The compound (S)-7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(methylthio)quinazoline (5.48 g, 13.0 mmol, 45% yield) was obtained as a yellow solid. m / z (ESI, +ve ion): 422.0 (M+H). + .

[0445] Step 3: tert-Butyl (4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(methylthio)quinazolin-7-yl)benzo[d]thiazol-2-yl)carbamate. To a mixture of (S)-7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(methylthio)quinazoline (4.50 g, 10.7 mmol) and [2-(tert-butoxycarbonylamino)-1,3-benzothiazol-4-yl]boronic acid (3.78 g, 12.8 mmol) in dioxane (90 mL) and HO (9 mL) was added KCO (4.43 g, 32.1 mmol) in one portion at 20 °C under N. Then, Pd(dppf)Cl2 (0.78 g, 1.07 mmol) was added to the mixture. The reaction mixture was stirred at 100 °C for 10 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with petroleum ether / EtOAc (1 / 0 to 0 / 1). tert-Butyl (4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(methylthio)quinazolin-7-yl)benzo[d]thiazol-2-yl)carbamate (4.60 g, 7.80 mmol, 73% yield) was obtained as a yellow solid. m / z (ESI, +ve ion): 590.2 (M+H) + .

[0446] [Table 4]

[0447] tert-Butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(methylsulfinyl)quinazolin-4-yl)piperazine-1-carboxylate (Intermediate K) [ka]

[0448] Step 1: tert-Butyl 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate. To a mixture of 7-bromo-2,4,6-trichloro-8-fluoro-quinazoline (20.0 g, 60.5 mmol) in MeCN (240 mL) was added DIPEA (23.5 g, 183 mmol, 31.6 mL) and tert-butyl-piperazine-1-carboxylate (11.3 g, 60.5 mmol). The mixture was then stirred at 25° C. for 1 h to give an orange suspension. This suspension was combined with another batch (5 g scale). The reaction mixture was filtered, and the filter cake was washed with 15 mL of MeCN and dried in vacuum to give tert-butyl 4-(7-bromo-2,6-dichloro-8-fluoro-quinazolin-4-yl)piperazine-1-carboxylate (32.0 g, crude) as a yellow solid.

[0449] Step 2: tert-Butyl 4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate. To a mixture of tert-butyl 4-(7-bromo-2,6-dichloro-8-fluoro-quinazolin-4-yl)piperazine-1-carboxylate (16.0 g, 33.3 mmol) in DMSO (150 mL) was added KF (19.4 g, 333 mmol, 7.81 mL). The mixture was then heated at 120° C. for 12 h. LCMS showed the reaction was complete. Another batch of the same scale was combined for purification. The reaction mixture was diluted with H2O (500 mL) and EtOAc (800 mL) and extracted with EtOAc (500 mL×3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with petroleum ether / EtOAc (100 / 1 to 1 / 1) to give tert-butyl 4-(7-bromo-6-chloro-2,8-difluoro-quinazolin-4-yl)piperazine-1-carboxylate (19.0 g, 4.09 mmol, 54% yield for two steps) as a yellow solid. m / z (ESI, +ve ion): 463.0 (M+H). + .

[0450] Step 3: tert-Butyl 4-(7-bromo-6-chloro-8-fluoro-2-(methylthio)quinazolin-4-yl)piperazine-1-carboxylate. To a solution of tert-butyl 4-(7-bromo-6-chloro-2,8-difluoro-quinazolin-4-yl)piperazine-1-carboxylate (7.0 g, 15.1 mmol) in THF (180 mL) was added NaSMe (5.29 g, 15.1 mmol, 4.81 mL, 20% purity) at 0° C. The mixture was stirred at 25° C. for 12 h. The reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with petroleum ether / EtOAc (1 / 0 to 5 / 1). Obtained tert-butyl 4-(7-bromo-6-chloro-8-fluoro-2-methylsulfanyl-quinazolin-4-yl)piperazine-1-carboxylate (5.0 g, 10.2 mmol, 67% yield) as a yellow solid.

[0451] Step 4: tert-Butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(methylthio)quinazolin-4-yl)piperazine-1-carboxylate. To a solution of tert-butyl 4-(7-bromo-6-chloro-8-fluoro-2-methylsulfanyl-quinazolin-4-yl)piperazine-1-carboxylate (5.00 g, 10.2 mmol), [2-(tert-butoxycarbonylamino)-1,3-benzothiazol-4-yl]boronic acid (3.29 g, 11.2 mmol), and K3PO4 (4.32 g, 20.3 mmol) in dioxane (116 mL) and H2O (23 mL) was added Pd(dppf)Cl2 (0.74 g, 1.02 mmol) under N2. The mixture was stirred at 95 °C under N2 for 7 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with petroleum ether / EtOAc (1 / 0 to 3 / 1). The compound tert-butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(methylthio)quinazolin-4-yl)piperazine-1-carboxylate (3.35 g, 5.07 mmol, 50% yield) was obtained as a white solid. m / z (ESI, +ve ion): 661.1 (M+H) + .

[0452] Step 5: tert-Butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(methylsulfinyl)quinazolin-4-yl)piperazine-1-carboxylate. To a solution of tert-butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(methylthio)quinazolin-4-yl)piperazine-1-carboxylate (6.7 g, 10.1 mmol) in DCM (48 mL) was added m-CPBA (2.46 g, 12.2 mmol, 85% purity). The mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched by adding saturated aqueous Na2SO3 solution (500 mL) and extracted with DCM (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with petroleum ether / EtOAc (1 / 1 to 1 / 0). tert-Butyl 4-(7-(2-(tert-butoxycarbonylamino)-1,3-benzothiazol-4-yl)-6-chloro-8-fluoro-2-methylsulfinyl-quinazolin-4-yl)piperazine-1-carboxylate (5.46 g, 7.82 mmol, 80% yield) was obtained as a white solid. m / z (ESI, +ve ion): 677.1 (M+H). + .

[0453] 7-Bromo-2,4,6-trichloro-8-fluoroquinoline (Intermediate L) [ka]

[0454] Step 1: 3-Bromo-4-chloro-2-fluoroaniline. To a mixture of 3-bromo-2-fluoro-aniline (100 g, 526 mmol) in DMF (1000 mL) was added NCS (73.79 g, 553 mmol) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 3 h. The reaction mixture was diluted with H2O (3000 mL) and extracted with EtOAc (700 mL×3). The combined organic layers were washed with brine (500 mL×3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluted with petroleum ether / ethyl acetate=1 / 0 to 5 / 1. The desired product (60 g, 267 mmol, 51% yield) was obtained as a yellow solid.

[0455] Step 2: 5-(((3-Bromo-4-chloro-2-fluorophenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione. 2,2-Dimethyl-1,3-dioxane-4,6-dione (14.13 g, 98 mmol) was added to trimethoxymethane (47.28 g, 446 mmol, 48.84 mL) and the mixture was warmed to 110° C. under N2 for 0.5 h. The resulting solution was stirred at 85° C. for 1.5 h. 3-Bromo-4-chloro-2-fluoroaniline (20 g, 89 mmol) was added. The solution was stirred at 85° C. for an additional 1 h. The reaction was cooled to 25° C. and then filtered. The filter cake was dried. Crude 5-(((3-bromo-4-chloro-2-fluorophenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (25 g, 66 mmol, 74% yield) was obtained as an off-yellow solid, which was used in the next step without further manipulation.

[0456] Step 3: 7-Bromo-6-chloro-8-fluoroquinolin-4(1H)-one. 5-(((3-Bromo-4-chloro-2-fluorophenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10 g, 26 mmol) in diphenyl ether (44.96 g, 264 mmol, 42.02 mL) was stirred at 180° C. for 40 minutes. The reaction was cooled to 25° C. Petroleum ether (200 ml) was added and the reaction was stirred for 10 minutes. The suspension was filtered and the filter cake was dried. The residue was purified by column chromatography on silica gel eluting with petroleum ether / ethyl acetate=30 / 1 to 1 / 1. The desired product (1.83 g, 6.63 mmol, 25% yield) was obtained as a brown solid.

[0457] Step 4: To a mixture of 7-bromo-6-chloro-8-fluoroquinolin-4(1H)-one (2.5 g, 9.04 mmol) in toluene (5 mL) was added POCl3 (5.55 g, 36.17 mmol, 3.36 mL), DMF (6.61 mg, 90.42 umol, 6.96 μL) under N2 at 25 °C. The mixture was stirred at 110 °C for 3 h. The reaction mixture was concentrated under reduced pressure to remove POCl3 and toluene. The residue was diluted with aqueous NaHCO3 (20 mL), extracted with EtOAc (20 mL x 3), filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography on silica gel eluted with petroleum ether / ethyl acetate = 100 / 1 to 200 / 1. The desired product (2.3 g, 7.64 mmol, 85% yield) was obtained as a white solid. m / z (ESI): 295.9 (M+H) + .

[0458] Step 5: 7-Bromo-4,6-dichloro-8-fluoroquinoline 1-oxide. To a mixture of 7-bromo-4,6-dichloro-8-fluoroquinoline (12 g, 40.69 mmol) in DCM (240 mL) was added hydrogen peroxide (22.96 g, 244.12 mmol) and TFA (55.67 g, 488.24 mmol, 36 mL) in one portion at 0° C. under N2. The mixture was stirred at 0° C. for 30 min and then at 40° C. for 23.5 h. The reaction mixture was poured into H2O (250 mL) at 15° C. and then extracted with DCM (150 mL×3). The combined organic layers were washed with saturated Na2SO3 (200 mL×3), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluted with petroleum ether / ethyl acetate=100 / 1 to 0 / 1 to give the product (6 g, 19.30 mmol, 47% yield) as a white solid. m / z (ESI): 309.9 (M+H). + .

[0459] Step 6: 7-Bromo-2,4,6-trichloro-8-fluoroquinoline. A mixture of 7-bromo-4,6-dichloro-8-fluoroquinoline 1-oxide (6.3 g, 20 mmol) in POCl3 (46.60 g, 304 mmol, 28 mL) was stirred at 110 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL) and poured into H2O (100 mL) at 15 °C, then extracted with EtOAc (70 mL x 3). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluted with petroleum ether / ethyl acetate = 1 / 0 to 0 / 1 to give 7-bromo-2,4,6-trichloro-8-fluoroquinoline (5 g, 15.12 mmol, 73% yield) as a white solid. m / z(ESI):329.7(M+H) + .

[0460] Experimental procedure 4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(3-(trifluoromethyl)piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine (Example 1) [ka]

[0461] Step 1: tert-Butyl (4-(4,6-dichloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-yl)carbamate. To a 0° C. solution of tert-butyl (4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(methylthio)quinazolin-7-yl)benzo[d]thiazol-2-yl)carbamate (60 mg, 0.10 mmol) in DCM (2 mL) was added sulfuryl chloride (1.0 M in DCM, 0.31 mL, 0.31 mmol, Sigma-Aldrich Corporation) slowly. The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was concentrated without heating and used directly in the next step. m / z (ESI, +ve ion): 578.0 (M+H + ).

[0462] Step 2: tert-Butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(trifluoromethyl)piperazine-1-carboxylate. To a solution of tert-butyl (4-(4,6-dichloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-yl)carbamate (20 mg, 0.034 mmol) in acetonitrile (1 mL) was added Hunig's base (13 mg, 0.018 mL, 0.10 mmol, Sigma-Aldrich Corporation) and 2-trifluoromethyl-piperazine-1-carboxylic acid tert-butyl ester HCl (17 mg, 0.068 mmol, Anichem Inc.). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was purified by reverse phase HPLC to give tert-butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(trifluoromethyl)piperazine-1-carboxylate as a white solid. m / z (ESI, +ve ion): 796.2 (M+H). + .

[0463] Step 3: 4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(3-(trifluoromethyl)piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine. tert-Butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(trifluoromethyl)piperazine-1-carboxylate was dissolved in 0.5 mL of DCM. Trifluoroacetic acid (0.77 g, 0.5 mL, 6.71 mmol, Sigma-Aldrich Corporation) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC to give 4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(3-(trifluoromethyl)piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine (8.4 mg, 0.014 mmol, 41% yield) as a white solid. m / z (ESI, +ve ion): 596.2 (M+H). + . 1 H NMR(400MHz, methanol-d4)δ ppm 8.04(d,J=1.5Hz,1H),7.87(dt,J=7.5,1.5Hz,1H),7.35-7.42(m,2H),4.89-4.97(m,1H),4.58-4.82(m,2H),4.38-4.45(m,1H) ,4.18(td,J=6.8,3.6Hz,1H),3.87-3.98(m,1H),3.56-3.81(m,3H),3.35-3.50(m,1H),3.20-3.31(m,2H),3.11(s,3H),2.43(br d,J=7.3Hz,1H),2.23(br s,1H),2.05-2.19(m,2H).

[0464] [Table 5]

[0465] [Table 6]

[0466]

Table 7

[0467]

Table 8

[0468]

Table 9

[0469]

Table 10

[0470]

Table 11

[0471]

Table 12

[0472]

Table 13

[0473]

Table 14

[0474]

Table 15

[0475]

Table 16

[0476] [Table 17]

[0477] [Table 18]

[0478] 7a-(((7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)oxy)methyl)hexahydro-3H-pyrrolidin-3-one (Example 43) [ka]

[0479] Step 1: tert-Butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-((3-oxotetrahydro-1H)-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate. To a solution of 7a-(hydroxymethyl)hexahydro-3H-pyrrolidin-3-one (8.3 mg, 0.053 mmol, PharmaBlock) in tetrahydrofuran (0.5 mL) was added potassium tert-butoxide (1.0 M in THF, 0.071 mL, 0.071 mmol, Sigma-Aldrich Corporation) at 0° C. This mixture was then added to a solution of tert-butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(methylsulfinyl)quinazolin-4-yl)piperazine-1-carboxylate (24 mg, 0.035 mmol) in tetrahydrofuran (0.5 mL) at 0° C. The resulting mixture was stirred at 0° C. for 10 min. The reaction mixture was purified by reverse phase HPLC to give tert-butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-((3-oxotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate as a white solid. m / z (ESI, +ve ion): 768.2 (M+H) + .

[0480] Step 2: 7a-(((7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)oxy)methyl)hexahydro-3H-pyrrolidin-3-one. tert-Butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-((3-oxotetrahydro-1H-pyrrolidine-)7a(5H)-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate was dissolved in 0.5 mL of dichloromethane. Trifluoroacetic acid (0.77 g, 0.5 mL, 6.71 mmol, Sigma-Aldrich Corporation) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC to give 7a-(((7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)oxy)methyl)hexahydro-3H-pyrrolidin-3-one (13 mg, 0.023 mmol, 65% yield) as a white solid. m / z (ESI, +ve ion): 568.2 (M+Na). + . 1 H NMR(400MHz, methanol-d4)δ ppm 8.02(s,1H),7.90(d,J=7.5Hz,1H),7.39-7.47(m,2H),4.70(dd,J=11.1,8.6Hz,1H),4.48(d,J=11.4Hz,1H),4.13(br s,4H),3.57-3.70(m,1H),3.46-3.56(m,4H),2.99-3.16(m,2H),2.40-2.50(m,2H),2.05-2.32(m,4H),1.74-1.83(m,1H).

[0481] [Table 19]

[0482] [Table 20]

[0483] [Table 21]

[0484] [Table 22]

[0485] [Table 23]

[0486] [Table 24]

[0487] [Table 25]

[0488] [Table 26]

[0489] [Table 27]

[0490] [Table 28]

[0491] [Table 29]

[0492] 4-(6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine (Example 76) [ka]

[0493] Step 1: tert-butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate. To a solution of tert-butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(methylsulfinyl)quinazolin-4-yl)piperazine-1-carboxylate (1 eq., 100 mM in DMSO), a solution of N,N,3-trimethylazetidin-3-amine (1 eq., 100 mM in DMSO) was added, followed by DIPEA (4.75 eq.). The mixture was shaken at 80° C. overnight and then at 100° C. for 4 h. The volatiles were then removed under reduced pressure to give tert-butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate, which was used directly in the next step.

[0494] Step 2: 4-(6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine. tert-Butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate was dissolved in 30% TFA (24 mM) in DCM. The reaction was shaken at room temperature for 2 hours. The volatiles were removed in a stream of air to give the crude product. This was then purified by HPLC to give the final product 4-(6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine. 95% purity by UV. m / z(ESI): 527.2(M+H). + . RT: 1.64 minutes.

[0495] [Table 30]

[0496] [Table 31]

[0497] [Table 32]

[0498] [Table 33]

[0499] [Table 34]

[0500] [Table 35]

[0501] [Table 36]

[0502] [Table 37]

[0503] [Table 38]

[0504] [Table 39]

[0505] [Table 40]

[0506] [Table 41]

[0507] 4-(4-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine (Example 122) [ka]

[0508] Step 1: tert-Butyl (1R,5S)-9-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate. To a stirred solution of tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (0.28 g, 1.21 mmol, Aurum Pharmatech LLC) in acetonitrile (6 mL) was added 1,1'-dimethyltriethylamine (0.47 g, 0.63 mL, 3.63 mmol, Sigma-Aldrich Corporation) and 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (0.40 g, 1.21 mmol, Advanced Chem Blocks Inc.). The reaction was stirred at room temperature for 30 min. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate and evaporated in vacuo to give tert-butyl (1R,5S)-9-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (0.64 g, 1.23 mmol, 100% yield) as a yellow solid, which was used directly in the next step without further purification. m / z (ESI, +ve ion): 522.4 (M+H). + .

[0509] Step 2: tert-Butyl (1R,5S)-9-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate. A mixture of tert-butyl (1R,5S)-9-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (71 mg, 0.14 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol hydrochloride (53 mg, 0.27 mmol, PharmaBlock), 1,4-diazabicyclo[2.2.2]octane (3.1 mg, 0.027 mmol, Sigma-Aldrich Corporation), and cesium carbonate (0.13 g, 0.41 mmol, Sigma-Aldrich Corporation) was stirred in N,N-dimethylformamide (0.4 mL) and tetrahydrofuran (2 mL) at room temperature for 3 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a gradient of 0-50% (20% MeOH in DCM) / DCM followed by reverse phase HPLC to give tert-butyl (1R,5S)-9-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (38 mg, 0.059 mmol, 43% yield) as a white solid. m / z (ESI, +ve ion): 644.0 (M+H). + .

[0510] Step 3: tert-Butyl (1R,5S)-9-(7-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate. In an 8 mL vial, tert-butyl (1R,5S)-9-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (38 mg, 0.059 mmol), [2-(tert-butoxycarbonylamino)-7-fluoro-1,3-benzothiazol-4-yl]boronic acid (37 mg, 0.12 mmol, Synnovator, Inc.), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (19 mg, 0.029 mmol, Sigma-Aldrich) in 1,4-dioxane (1 mL) and water (0.1 mL) were added. A mixture of tert-butyl (1R,5S)-9-(7-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate was stirred at 90° C. for 2 h. The reaction mixture was purified by reverse phase HPLC to give tert-butyl (1R,5S)-9-(7-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate as a white solid. m / z (ESI, +ve ion): 832.2 (M+H). + .

[0511] Step 4: 4-(4-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine. tert-Butyl (1R,5S)-9-(7-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate was dissolved in 0.5 mL of DCM. Trifluoroacetic acid (0.77 g, 0.5 mL, 6.71 mmol, Sigma-Aldrich Corporation) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC to give 4-(4-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine (28 mg, 0.044 mmol, 75% yield) as a white solid. m / z (ESI, +ve ion): 632.2 (M+H). + . 1 H NMR(400MHz, methanol-d4)δ ppm 7.87(d,J=1.5Hz,1H),7.24(ddd,J=8.4,5.4,1.5Hz,1H),7.05(dd,J=9.1,8.5Hz,1H),5.45-5.73(m,1H),4.79-4.83(m,2H),4.67-4.76(m, 2H),4.22-4.33(m,4H),3.85-4.07(m,3H),3.72-3.82(m,4H),3.46-3 .54(m,1H),2.57-2.81(m,2H),2.31-2.49(m,3H),2.13-2.26(m,1H).

[0512] [Table 42]

[0513] [Table 43]

[0514] [Table 44]

[0515] [Table 45]

[0516] [Table 46]

[0517] [Table 47]

[0518] [Table 48]

[0519] 4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine (Example 144) [ka]

[0520] Step 1: tert-Butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate. An 8 mL vial was charged with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (25 mg, 0.035 mmol, Sigma-Aldrich Corporation), (1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)boronic acid pinacol ester (80 mg, 0.26 mmol, Combi-Blocks Inc.), potassium phosphate tribasic (0.11 g, 0.52 mmol, Acros Organics), tert-butyl (4-(4,6-dichloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-yl)carbamate (0.10 g, 0.17 mmol), 1,4-dioxane (1.4 mL), and water (0.35 mL). The reaction was stirred at 90° C. for 1 h. The crude mixture was purified by column chromatography on silica gel eluting with 0-50% EtOAc / ethanol in heptane with 2% triethylamine additive to give tert-butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.10 g, 0.14 mmol, 80% yield). m / z (ESI, +ve ion): 725.3 (M+H). + .

[0521] Step 2: 4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine. tert-Butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (27 mg, 0.037 mmol) was stirred in trifluoroacetic acid (93 μL) and DCM (93 μL) for 1 h at room temperature. The solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC to give 4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine (14 mg, 0.026 mmol, 70% yield). m / z (ESI, +ve ion): 525.2 (M+H). + . 1 H NMR(400MHz, methanol-d4)δ ppm 8.25-8.31(m,1H),7.83-7.90(m,1H),7.32-7.43(m,2H),6.40-6.49(m, 1H),4.96-5.05(m,1H),4.74-4.82(m,1H),4.05-4.14(m,2H),3.91-4.0 3(m,1H),3.71-3.84(m,1H),3.57-3.68(m,2H),3.24-3.30(m,1H),3.11 -3.18(m,3H),2.97-3.08(m,2H),2.41-2.53(m,1H),2.06-2.32(m,3H).

[0522] [Table 49]

[0523] [Table 50]

[0524] 4-(8-Fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-6-vinylquinazolin-7-yl)benzo[d]thiazol-2-amine (Example 149) [ka]

[0525] Step 1: tert-Butyl 4-(7-(2-aminobenzo[d]thiazol-4-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-vinylquinazolin-4-yl)piperazine-1-carboxylate. A microwave vial was charged with tert-butyl 4-(7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (35 mg, 0.056 mmol), potassium phosphate (62 mg, 0.29 mmol), and (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (17 mg, 0.022 mmol). The vial was then purged with nitrogen gas for 5 minutes and vinylboronic acid pinacol ester (44 mg, 48 μL, 0.28 mmol) was added. The resulting mixture was suspended in 1,4-dioxane (0.45 mL) and water (0.11 mL). The reaction was then heated to 150° C. by microwave irradiation. After 1.5 h, the reaction was cooled to room temperature and diluted with water (3 mL). The aqueous layer was extracted with EtOAc (3×3 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude oil was then purified by column chromatography on silica gel eluting with a 0-50% gradient of a 3:1 EtOAc:EtOH mixture in heptane containing 2% triethylamine to give tert-butyl 4-(7-(2-aminobenzo[d]thiazol-4-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-vinylquinazolin-4-yl)piperazine-1-carboxylate. m / z (ESI, +ve ion): 620.2 (M+H) + .

[0526] Step 2: 4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-6-vinylquinazolin-7-yl)benzo[d]thiazol-2-amine. tert-Butyl 4-(7-(2-aminobenzo[d]thiazol-4-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-vinylquinazolin-4-yl)piperazine-1-carboxylate was dissolved in DCM (2.4 mL). Trifluoroacetic acid (0.47 g, 0.32 mL, 4.2 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC to give 4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-6-vinylquinazolin-7-yl)benzo[d]thiazol-2-amine (5.3 mg, 10.2 μmol, 18% yield over two steps) as a white solid. m / z (ESI, +ve ion): 520.2 (M+H). + . 1 H NMR (400MHz, methanol-d4) δ ppm 7.92-8.01(m,1H),7.66-7.75(m,1H),7.15 -7.23(m,1H),7.08-7.14(m,1H),6.23-6.52(m,1H),5.59-5.74(m,1H),5.00-5.19(m, 1H),4.45-4.56(m,1H),4.32-4.43(m,1H),3.83-4.00(m,4H),3.01-3.12(m,5H),2.75 -2.83(m,1H),2.52(s,3H),2.30-2.40(m,1H),2.06-2.17(m,1H),1.70-1.89(m,3H).

[0527] [Table 51]

[0528] 4-(6-Ethyl-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine (Example 152) [ka]

[0529] Step 1: tert-Butyl 4-(7-(2-aminobenzo[d]thiazol-4-yl)-6-ethyl-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate. A reaction tube was charged with tert-butyl 4-(7-(2-aminobenzo[d]thiazol-4-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-vinylquinazolin-4-yl)piperazine-1-carboxylate (45 mg, 0.072 mmol, 60% purity). The solid was dissolved in ethanol (2.5 mL). To this solution was added 5% Pd / carbon (15 mg, 7.18 μmol) and the reaction was placed under a hydrogen gas atmosphere (1 atm) at room temperature. The reaction was stirred vigorously for 1.5 h and then the pressure was increased to 3 atm. After 2 days, the reaction was filtered through a plug of Celite and the plug was washed with MeOH. The resulting solution was then concentrated under reduced pressure and purified by reverse phase HPLC to give tert-butyl 4-(7-(2-aminobenzo[d]thiazol-4-yl)-6-ethyl-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate as a white solid. m / z (ESI, +ve ion): 622.2 (M+H). + .

[0530] Step 2: 4-(6-ethyl-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine. tert-Butyl 4-(7-(2-aminobenzo[d]thiazol-4-yl)-6-ethyl-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (13 mg, 0.021 mmol) was dissolved in DCM (1.8 mL). Trifluoroacetic acid (0.35 g, 0.24 mL, 3.10 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC to give 4-(6-ethyl-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine (12 mg, 0.024 mmol, 56% yield over two steps) as a white solid. m / z (ESI, +ve ion): 522.2 (M+H). + . 1 H NMR (400MHz, methanol-d4) δ ppm 7.83-7.92(m,1H),7.74-7.79(m,1H),7.39 -7.47(m,1H),7.33-7.38(m,1H),4.90-5.01(m,1H),4.66-4.76(m,1H),4.18(br s,4H),3.84-3.98(m,1H),3.69-3.83(m,1H),3.53(br s,4H),3.19-3.30(m,1H),3.12(br s,3H),2.49-2.73(m,2H),2.36-2.49(m,1H),2.18-2.28(m,1H),2.05-2.18(m,2H),1.09(d,J=1.3Hz,3H).

[0531] [Table 52]

[0532] 4-(8-Fluoro-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine (Example 155) [ka]

[0533] Step 1: tert-Butyl 4-(7-(2-aminobenzo[d]thiazol-4-yl)-8-fluoro-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate. Into an 8 mL vial was placed tert-butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (40 mg, 0.055 mmol), 1,4-diazabicyclo[2.2.2]octane bis(trimethylalmane) (14 mg, 0.055 mmol), and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II))methanesulfonate (7.0 mg, 8.24 μmol). The vial was purged with nitrogen gas. The solid was suspended in tetrahydrofuran (1.1 mL) and the reaction mixture was then heated to 70° C. After 1 h, the reaction was cooled to room temperature and diluted with water (1.5 mL), saturated aqueous ammonium chloride (1.5 mL), and EtOAc (3 mL). The layers were separated and the aqueous layer was then extracted with EtOAc (3×3 mL). The combined organic layers were then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified sequentially using column chromatography on silica gel eluting with a gradient of 0-50% 3:1 EtOAc:EtOH mixture in heptane containing 2% triethylamine followed by reverse phase HPLC to give tert-butyl 4-(7-(2-aminobenzo[d]thiazol-4-yl)-8-fluoro-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate. m / z (ESI, +ve ion): 607.9 (M+H) + .

[0534] Step 2: 4-(8-fluoro-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine. tert-Butyl 4-(7-(2-aminobenzo[d]thiazol-4-yl)-8-fluoro-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate was dissolved in DCM (2.4 mL). Trifluoroacetic acid (0.47 g, 0.32 mL, 4.16 mmol) was added and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC to give 4-(8-fluoro-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine (2.54 mg, 5.00 μmol, 9% yield over two steps) as a yellow solid. m / z (ESI, +ve ion): 507.850 (M+H). + . 1 H NMR(400MHz,chloroform-d)δ ppm 7.62-7.69(m,1H),7.48-7.53(m,1H),7.18 -7.25(m,2H),5.43-5.66(m,1H),4.52-4.68(m,1H),4.25-4.40(m,1H),3.72-3.91(m,4H),3.03-3.16(m,5H),2 .68-2.83(m,1H),2.52(d,J=2.1Hz,3H),2.19(s,4H),1.99-2.13(m,1H),1.79-1.91(m,2H),0.84-1.18(m,3H).

[0535] 7-(2-aminobenzo[d]thiazol-4-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazoline-6-carbonitrile (Example 156) [ka]

[0536] Step 1: tert-Butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-cyano-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate. A 4 mL vial was charged with tert-butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (48 mg, 0.066 mmol), potassium acetate (19 mg, 0.20 mmol), potassium ferrocyanide trihydrate (0.11 g, 0.26 mmol), and (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (21 mg, 0.026 mmol). The vial was purged with nitrogen gas, then the solid was suspended in tetrahydrofuran (0.33 mL) and water (0.33 mL) was added. The reaction was then sealed and stirred at 100° C. After 2.5 h, the reaction was cooled to room temperature and diluted with water (3 mL) and EtOAc (3 mL). The mixture was filtered through Celite. The layers were separated and the aqueous layer was then extracted with EtOAc (3×3 mL). The combined organic layers were then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude oil was then purified by column chromatography on silica gel eluting with a gradient of 0-50% 3:1 EtOAc:EtOH mixture in heptane containing 2% triethylamine to give tert-butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-cyano-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate as a yellow solid. m / z (ESI, +ve ion): 719.2 (M+H). + .

[0537] Step 2: 7-(2-aminobenzo[d]thiazol-4-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl))quinazoline-6-carbonitrile. tert-Butyl 4-(7-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-6-cyano-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate was dissolved in DCM (3.0 mL). Trifluoroacetic acid (0.56 g, 0.38 mL, 4.90 mmol) was added and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC to give 7-(2-aminobenzo[d]thiazol-4-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazoline-6-carbonitrile (2.7 mg, 5.11 μmol, 8% yield over two steps) as a white solid. m / z (ESI, +ve ion): 518.850 (M+H). + . 1 H NMR (400MHz, methanol-d4) δ ppm 8.39-8.43(m,1H),7.81-7.86(m,1H),7.34 -7.40(m,1H),7.27-7.33(m,1H),4.93-5.00(m,1H),4.68-4.77(m,1H),4.17-4.22(m, 4H),3.89-4.01(m,1H),3.74-3.85(m,1H),3.51-3.56(m,4H),3.21-3.29(m,1H),3.10 -3.16(m,3H),2.32-2.51(m,1H),2.21-2.32(m,1H),2.08-2.18(m,2H).

[0538] 7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinoline-3-carbonitrile (Example 157) [ka]

[0539] Step 1: tert-Butyl 4-(7-bromo-2,6-dichloro-3-cyano-8-fluoroquinolin-4-yl)piperazine-1-carboxylate. To a suspension of 7-bromo-2,4,6-trichloro-8-fluoroquinoline-3-carbonitrile (0.35 g, 1.0 mmol, Enamine) in DCM (6.7 mL) was added triethylamine (0.56 mL, 4.0 mmol, Sigma-Aldrich Corporation) followed by tert-butyl piperazine-1-carboxylate (0.37 g, 2 mmol, Combi-Blocks Inc.). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NaHCO3 solution and partitioned between EtOAc and water. The precipitate that formed was collected by filtration and dried in a vacuum oven at 60° C. to give tert-butyl 4-(7-bromo-2,6-dichloro-3-cyano-8-fluoroquinolin-4-yl)piperazine-1-carboxylate (0.31 g, 0.61 mmol, 61% yield) as an off-white solid, which was used directly in the next step. m / z (ESI, +ve ion): 505.0 (M+H + ).

[0540] Step 2: tert-Butyl (S)-4-(7-bromo-6-chloro-3-cyano-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinolin-4-yl)piperazine-1-carboxylate. To a mixture of tert-butyl 4-(7-bromo-2,6-dichloro-3-cyano-8-fluoroquinolin-4-yl)piperazine-1-carboxylate (81 mg, 0.16 mmol) and (2S)-1-methyl-2-pyrrolidinemethanol (23 μL, 0.19 mmol, Sigma-Aldrich Corporation) in tetrahydrofuran (0.8 mL) was added sodium hydride (9.6 mg, 0.24 mmol, Sigma-Aldrich Corporation). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was back-extracted with EtOAc (3×) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated. The crude material was purified by column chromatography on silica gel eluting with a gradient of 10-40% 3:1 EtOAc:EtOH in heptane to give tert-butyl (S)-4-(7-bromo-6-chloro-3-cyano-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinolin-4-yl)piperazine-1-carboxylate (55 mg, 0.09 mmol, 58% yield) as a white solid. m / z (ESI, +ve ion): 582.1 (M+H + ).

[0541] Step 3: tert-Butyl 4-(7-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-3-cyano-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinolin-4-yl)piperazine-1-carboxylate. In a vial, a mixture of tert-butyl (S)-4-(7-bromo-6-chloro-3-cyano-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinolin-4-yl)piperazine-1-carboxylate (35 mg, 0.06 mmol), (2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)boronic acid (37 mg, 0.12 mmol, e-Novation), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (20 mg, 0.03 mmol, Strem Chemicals, Inc.), and tribasic potassium phosphate (38 mg, 0.18 mmol, Acros Organics) was deoxygenated in vacuum and then flushed with nitrogen. 1,4-Dioxane (0.4 mL) and water (57 μL) were added and the reaction mixture was stirred at 90° C. for 1.5 h. Sodium sulfate was added to the reaction mixture. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0-40% 3:1 EtOAc:EtOH in heptane to give tert-butyl 4-(7-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-3-cyano-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinolin-4-yl)piperazine-1-carboxylate (10 mg, 13 μmol, 21% yield) as an off-white solid. m / z (ESI, +ve ion):770.5(M+H + ).

[0542] Step 4: 7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinoline-3-carbonitrile. To a solution of tert-butyl 4-(7-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-3-cyano-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinolin-4-yl)piperazine-1-carboxylate (10 mg, 13 μmol) in DCM (50 μL) was added trifluoroacetic acid (20 μL, 0.2 mmol, Sigma-Aldrich Corporation). The reaction mixture was stirred at room temperature for 2 h and the solvent was removed under vacuum. The crude material was dissolved in DMSO and purified by reverse phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150×30 mm, CH3CN / H2O with 0.1% TFA, gradient 0% to 70% in 15 min, to give 7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinoline-3-carbonitrile (9 mg, 0.011 mmol, 86% yield) as a white solid. m / z (ESI, +ve ion): 570.1 (M+H + ). 1 H NMR(400MHz, methanol-d4)δ 8.00(d,J=1.25Hz,1H),7.24(dd,J=5.64,8.36Hz,1H),7.04(t,J=8.88Hz,1H),5.05(td,J=2.90,1 3.01Hz,1H),4.68(ddd,J=5.12,7.52,12.85Hz,1H),3.95-4.10(m,5H),3.73-3.84(m,1H),3.61(br t,J=5.02Hz,5H),3.20(s,3H),2.40-2.56(m,1H),2.06-2.32(m,3H).

[0543] [Table 53]

[0544] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine (Example 161) [ka]

[0545] Step 1: 7-Bromo-4,6-dichloro-8-fluoroquinolin-2(1H)-one. A mixture of 7-bromo-2,4,6-trichloro-8-fluoroquinoline (1.00 g, 3.04 mmol) in sulfuric acid (4.94 g, 4.99 mL, 50.4 mmol) diluted to 20% with water and 1,4-dioxane (25.3 mL) was stirred at 100° C. for 30 h. After cooling to room temperature, the reaction mixture was diluted with water. The solid was collected by filtration, washed with water, and dried in a vacuum oven at 50° C. for 2 days to give 7-bromo-4,6-dichloro-8-fluoroquinolin-2(1H)-one (0.855 g, 2.75 mmol, 91% yield) as an off-white solid, which was used directly in the next step. m / z (ESI, +ve ion): 310.0 (M+H + ).

[0546] Step 2: 7-Bromo-4,6-dichloro-8-fluoroquinolin-2-yl trifluoromethanesulfonate. To a suspension of 7-bromo-4,6-dichloro-8-fluoroquinolin-2(1H)-one (0.84 g, 2.71 mmol) in dichloromethane (9 mL) was added 1,1'-dimethyltriethylamine (0.53 g, 0.71 mL, 4.07 mmol, Sigma-Aldrich Corporation), followed by the dropwise addition of a 1 M solution of trifluoromethanesulfonic anhydride in methylene chloride (3 mL, 2.99 mmol, Sigma-Aldrich Corporation). The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated and the residual solid was used directly in the next step. m / z (ESI, +ve ion): 441.8 (M+H + ).

[0547] Step 3: 7-Bromo-4,6-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinoline. To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (0.86 g, 5.42 mmol, PharmaBlock) in THF (6.5 mL) was added sodium hydride (0.23 g, 5.69 mmol, TCI America). The reaction mixture was stirred at room temperature for 25 min and added dropwise to a solution of 7-bromo-4,6-dichloro-8-fluoroquinolin-2-yl trifluoromethanesulfonate (1.20 g, 2.71 mmol) in THF (6 mL). The alkoxide vial was rinsed with THF (1 mL) and immediately added to the reaction. The reaction mixture was stirred at room temperature for 10 min. The reaction mixture was heated at 60° C. for 40 min and at 55° C. overnight. After cooling to room temperature, water was added to quench the reaction, the aqueous layer was back-extracted with EtOAc (2×), and the combined organic layers were dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (80 g) eluting with a gradient of 0% to 30% 3:1 EtOAc / EtOH in heptane to give 7-bromo-4,6-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinoline (0.37 g, 0.83 mmol, 31% yield) as a light brown solid, which was used directly in the next step. m / z (ESI, +ve ion): 450.7 (M+H + ).

[0548] Step 4: tert-Butyl (4-(4,6-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinolin-7-yl)-7-fluorobenzo[d]thiazol-2-yl)carbamate. In a round-bottom flask, a mixture of 7-bromo-4,6-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinoline (0.18 g, 0.40 mmol), (2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)boronic acid (0.13 g, 0.40 mmol, Synnovator), [1,1′-bis(di-tert)-butylphosphino)ferrocene]dichloropalladium(II) (0.10 g, 0.16 mmol, Strem Chemicals, Inc.), and tribasic potassium phosphate (0.17 g, 0.80 mmol, Acros Organics) was deoxygenated in vacuo and then flushed with nitrogen. 1,4-Dioxane (2.3 mL) and water (0.38 mL) were added and the reaction mixture was stirred at 80° C. for 1 h. Na2SO4 was added to the reaction. The crude material was purified by chromatography through a silica gel column (40 g) eluting with a gradient of 0-20% 3:1 EtOAc / EtOH in heptane to give tert-butyl (4-(4,6-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinolin-7-yl)-7-fluorobenzo[d]thiazol-2-yl)carbamate (44 mg, 0.069 mmol, 17% yield) as a light brown solid. m / z (ESI, +ve ion): 640.7 (M+H + ).

[0549] Step 5: tert-Butyl (1R,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. In a round-bottom flask, a mixture of tert-butyl (4-(4,6-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinolin-7-yl)-7-fluorobenzo[d]thiazol-2-yl)carbamate (44 mg, 0.069 mmol), 8-boc-3,8-diaza-bicyclo[3.2.1]octane (29 mg, 0.14 mmol, Chem-Impex International, Inc.), RuPhos Pd G4 (12 mg, 0.014 mmol, Sigma-Aldrich Corporation), and cesium carbonate (67 mg, 0.21 mmol, Strem Chemicals, Inc.) was deoxygenated and then flushed with nitrogen. 1,4-Dioxane (0.34 mL) was added and the reaction mixture was stirred at 85° C. for 1 h. Additional amine (15 mg) and RuPhosG4 (6 mg) were added and the reaction mixture was stirred for an additional hour at 85° C. After cooling to room temperature, the crude material was purified by chromatography through a silica gel column (12 g) eluting with a gradient of 0-40% 3:1 EtOAc / EtOH in heptane to give tert-butyl (1R,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4 mg, 4.91 μmol, 7.1% yield) as a white solid. m / z (ESI, +ve ion):815.5(M+H + ).

[0550] Step 6: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine bis(2,2,2-trifluoroacetate). To a solution of tert-butyl (1R,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4 mg, 4.91 μmol) in dichloromethane (16 μL) was added dropwise 1,1,1-trifluoroacetic acid (15 mg, 10 μL, 0.13 mmol, Sigma-Aldrich Corporation). The reaction mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the residue was dissolved in DMSO and purified by reverse phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150×30 mm, CH3CN / H2O with 0.1% TFA, gradient 5% to 80% in 15 min to give 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine bis(2,2,2-trifluoroacetate) (2.5 mg, 2.97 μmol, 60% yield) as a white solid. 1H NMR(400MHz, methanol-d4)δ 7.99(s,1H),7.21-7.30(m,1H),6.99-7.08(m,1H),6.87(s,1H),4.26-4.33(m,2H),3.91-3.94(m,1H),3.82-3.91(m,3H),3.65-3.74(m ,4H),3.49-3.52(m,4H),2.61-2.65(m,1H),2.49(d,J=7.52Hz,2H),2.28-2.38(m,4H),1.29-1.42(m,8H).m / z(ESI,+ve ion):614.8(M+H + ).

[0551] Biological evaluation In this section, a biological evaluation of the embodiments provided herein is provided.

[0552] KRAS G12D TR-FRET assay Compounds of interest were prepared in dose-response titrations in DMSO and 80 nL was added to each well of a 384-well plate (Perkin Elmer 6008280) from a Labcyte Echo. His-tagged KRAS G12D protein (Amgen) was diluted to 20 nM in assay buffer (20 mM HEPES, pH 7.4, 10 mM MgCl2, 50 mM NaCl, 0.1% BSA, 0.01% Tween-20, 10 μM MGDP) and 2 μL was added to the appropriate wells of the 384-well plate. The plate was incubated at room temperature for 30 minutes. Biotinylated KRPep-2d substrate (Amgen) was diluted to 20 nM in assay buffer and 2 μL was added to all wells and incubated at room temperature for 1 hour. Detection reagents (0.4 nM LANCE Eu-W1024 Anti-6xHis (Perkin Elmer AD0401), 5 nM streptavidin-d2 (Cisbio 610SADLA)) were prepared in assay buffer, then 4 μL was added to the plate and incubated for 1 h at room temperature. Plates were read using a PerkinElmer 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 four-parameter logistic model to calculate IC 50 values ​​were calculated.

[0553] 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 h. After compound preincubation, purified SOS protein (aa564-1049) and GTP (Roche10106399001) were added to the assay wells and incubated for an additional 30 min. 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 min. 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 values ​​were calculated.

[0554] Phospho-ERK1 / 2 MSD assay A-427 (ATCC® HTB-53™) 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). A-427 cells were seeded at a density of 25,000 cells / well in 96-well cell culture plates 16 hours prior to compound treatment 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, followed by incubation for 2 hours at 37° C., 5% CO2. After compound treatment, cells were incubated for 2 hours at 37° C. for 24 hours at 4° C. for 24 hours at 4° C. for 24 hours at 4° C., and 5% CO2 for 24 hours at 4° C. After compound treatment, cells were incubated for 2 hours at 4° C. for 24 ... 2+ or Mg 2+Cells were washed with ice-cold Dulbecco's Phosphate Buffered Saline (Thermo Fisher 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 four-parameter logistic model to determine IC 50 The value was calculated.

[0555] [Table 54]

[0556] [Table 55]

[0557] [Table 56]

[0558] [Table 57]

[0559] [Table 58]

[0560] [Table 59]

[0561] [Table 60]

[0562] [Table 61]

[0563] References All references cited in this specification, e.g., scientific articles or published patent applications, are hereby incorporated by reference in their entirety for all purposes to the same extent as if each reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer. (In the formula, 【Chemistry 2】 is a single bond or a double bond; W is C, CH, or N, and when W is N, 【Chemistry 3】 is a single bond; n is 0, 1, 2, or 3; m is 0, 1, 2, 3, or 4; Each R ｘ is hydroxyl, oxo, cyano, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, -T-R ｙ or two R ｘ together with the carbon atom to which they are attached, ３～８ A cycloalkyl or bridged ring may be formed, the bridge atom being: 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-; each bridge or C ３～８ Cycloalkyl is 0 to 3 R ｖ is substituted with; 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 --, --NR ｚ -C １～４ alkylene, —O—, or —S—, and each —C １～４ Alkylene, —O—C １～４ Alkylene, or -S-C １～４ Alkylene is 0 to 2 R ｂ may be substituted with; R １ is -N(R ａ ) ２ , aryl, heteroaryl, C ３～８ , cycloalkyl, or heterocycloalkyl, each aryl, heteroaryl, cycloalkyl, or heterocycloalkyl being selected from 0 to 3 R ５ is further substituted with; 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, C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, -N(R ｗ ) ２ , -(CH ２ ) ｐ -OH, -C(O)-R ｚ , heteroaryl, or heterocycloalkyl, or two R ５ can be joined together with the same carbon atom to form a spirocyclic heteroaryl or heterocycloalkyl, each heteroaryl or heterocycloalkyl being selected from 0 to 3 R ７ is further substituted with; p is 1, 2, or 3; Each R ７ is hydroxyl, oxo, halogen, C １～４ Alkyl, C １～４ Alkoxy, -C(O)R ｚ or -C(O)OR ｚ and T is for C １～４ alkylene, -O-, or -S-; Each R ａ is hydrogen, C １～４ Alkyl, or C １～４ is alkoxy; Each R ｂ is hydroxyl or C １～４ is alkyl; Each R ｖ is halogen or C １～４ is alkyl; Each R ｗ is hydrogen, C １～４ Alkyl, C １～４ alkoxy, or heterocycloalkyl; R ｑ is hydrogen, halogen, or C １～４ is alkyl; R ｙ is halogen, hydroxyl, cyano, or amino; R ｚ is hydrogen or C １～４ (alkyl).

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

3. The compound of claim 1 , wherein W is N or C.

4. The compound of claim 1 , wherein n is 0, 1, or 2.

5. 2. The compound of claim 1, wherein m is 0, 1, 2, 3, or 4.

6. The compound of claim 1 , wherein n is 1 and m is 1.

7. The compound of claim 1 , wherein n is 1 and m is 2.

8. 2. The compound of claim 1, wherein n is 1 and m is 3.

9. 2. The compound of claim 1, wherein n is 1 and m is 4.

10. The compound of claim 1 , wherein n is 2 and m is 1.

11. The compound of claim 1 , wherein n is 1 and m is 0.

12. The compound of claim 1 , wherein n is 2 and m is 0.

13. R ｘ But, C １～４ Alkyl, oxo, haloalkyl, or -T-R ｙ 2. The compound of claim 1 ,

14. R ｘ is methyl, trifluoromethyl, -CH ２ OH or -CH ２ CN. The compound of claim 13 .

15. Two R's ｘ together with the carbon atom to which they are attached, C ３～８ The compound of claim 1 which forms a cycloalkyl ring or a bridged ring.

16. Two R's ｘ together with the carbon atom to which they are attached, C ３～８ 16. The compound of claim 15, which forms a cycloalkyl ring (e.g., cyclopropyl).

17. Two R's ｘ can be joined together to form a bridged ring, said bridge being -C 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 16. The compound of claim 15, wherein the alkylene-S- is selected from one of the following:

18. Two R's ｘ together form a bridged ring, said bridge being methylene, ethylene, -O-methylene-, -methylene-O-, or -methylene-O-methylene.

19. One R ｘ But, C １～４ Alkyl, cyano, oxo, or -T-R ｙ and the other two R ｘ together form a bridged ring, said bridge being -C １～４ Alkylene or -C １～４ Alkylene -O-C １～４ The compound of claim 1 which is alkylene-.

20. One R ｘ is methyl, ethyl, cyano, oxo, -CH ２ OH or -CH ２ CN and the other two R ｘ together form a bridged ring, said bridge being methylene, ethylene, or methylene-O-methylene.

21. Two R's ｘ However, each independently C １～４ alkyl, and the other two R ｘ together form a bridged ring, said bridge being C １～４ The compound of claim 1 which is an alkylene.

22. Two R's ｘ are both methyl, and the other two R ｘ together form a bridged ring, said bridge being methylene or ethylene.

23. 【Chemical 4】 but, 【Chemistry 5】 2. The compound of claim 1 ,

24. L is a bond, 0 to 2 R ｂ -C substituted with １～４ Alkylene, -NR ｚ -C １～４ Alkylene, -NR ｚ -, -O-, or -O-C １～４ The compound of claim 1 which is an alkylene.

25. L is methylene, ethylene, -O-methylene, -O-ethylene, -NR ｚ -Ethylene, -NR ｚ -, -O-, or a bond, each of methylene, ethylene, -O-methylene, -O-ethylene, or -NR ｚ -ethylene is 0 to 2 R ｂ 25. The compound of claim 24 substituted with:

26. R ｂ is methyl or hydroxyl.

27. R ｚ 26. The compound of claim 25, wherein is hydrogen.

28. R １ is heterocycloalkyl, heteroaryl, or -N(R ａ ) ２ and each heterocycloalkyl or heteroaryl is 0 to 3 R ５ 2. The compound of claim 1 , substituted with:

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

30. R １ But 0 to 3 R ５ 7-(hexahydro-1H-pyrrolidine), 8a-(octahydroindolizine), 2-pyrrolidine, 3-pyrrolidine, 2-azetidinyl, 2-piperidinyl, 4-piperidinyl, 1-(7-azabicyclo[2.2.1]heptanyl), 6-(2,6-diazabicyclo[3.2.0]heptanyl), 6-((1S,5R)-2,6-diazabicyclo[3.2.0]heptanyl), substituted with 3-(3,6-diazabicyclo[3.2.0]heptanyl), 5-(octahydropyrrolo[3,4-b]pyrrolyl), 5-((3aS,6aS)-(octahydropyrrolo[3,4-b]pyrrolyl)), 4-(1,4-diazabicyclo[3.2.1]octanyl), 4-((5S)-(1,4-diazabicyclo[ 3.2.1]octanyl), 3-(3,6-diazabicyclo[3.2.1]octanyl), 3-((1S,5S)-(3,6-diazabicyclo[3.2.1]octanyl)), 1-(octahydro-1H-pyrrolo[3,2-b]piperidinyl), 1-((3aR,7aR)-(octahydro-1H-pyrrolo[3,2-b]piperidinyl)), 6-( 30. The compound of claim 29, which is 6-(4aS,7aS)-(octahydropyrrolo[3,4-b][1,4]oxazinyl), 6-(4aS,7aR)-(octahydropyrrolo[3,4-b][1,4]oxazinyl), N-azetidinyl, N-pyrrolidinyl, or N-piperidinyl.

31. R １ But there are 0 R ５ 7-(hexahydro-1H-pyrrolidine), 8a-(octahydroindolizine), 2-pyrrolidine, 1-(7-azabicyclo[2.2.1]heptanyl), 6-(2,6-diazabicyclo[3.2.0]heptanyl), 6-((1S,5R)-2,6-diazabicyclo[3.2.0]heptanyl), 3-(3,6-diazabicyclo[3.2.0]heptanyl), 5-(octahydropyrrolo[3,4-b]pyrrolyl), 5-((3aS, 31. The compound of claim 30, which is 4-((6aS)-(octahydropyrrolo[3,4-b]pyrrolyl)), 4-(1,4-diazabicyclo[3.2.1]octanyl), 4-((5S)-(1,4-diazabicyclo[3.2.1]octanyl)), 3-(3,6-diazabicyclo[3.2.1]octanyl), 3-((1S,5S)-(3,6-diazabicyclo[3.2.1]octanyl)), N-azetidinyl, N-pyrrolidinyl, or N-piperidinyl.

32. R １ But one R ５ 7-(hexahydro-1H-pyrrolidine), 2-pyrrolidine, 3-pyrrolidine, 2-azetidinyl, 2-piperidinyl, 4-piperidinyl, 5-((3aS,6aS)-(octahydropyrrolo[3,4-b]pyrrolyl)), 1-(octahydro-1H-pyrrolo[3,2-b]piperidinyl), 1-((3aR,7aR)-(octahydro-1H-pyrrolo[3,2-b ]piperidinyl), 6-(octahydropyrrolo[3,4-b][1,4]oxazinyl), 6-(4aS,7aS)-(octahydropyrrolo[3,4-b][1,4]oxazinyl), 6-(4aS,7aR)-(octahydropyrrolo[3,4-b][1,4]oxazinyl), N-azetidinyl, N-pyrrolidinyl, or N-piperidinyl.

33. R ５ is oxo, halogen, -(CH ２ ) ｐ -OH, C １～４ Alkyl, —C(O)—R ｚ , C １～４ Haloalkyl, -N(R ｗ ) ２ , heteroaryl, or heterocycloalkyl, each heteroaryl or heterocycloalkyl having 0 to 3 R ７ 33. The compound of claim 32 substituted with:

34. Each R ｗ The compound of claim 33, wherein is hydrogen, methyl, methoxy, 3-tetrahydrofuranyl, or 2-oxetanyl.

35. R ５ is oxo, fluorine, -CH ２ OH, methyl, ethyl, -C(O)-methyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, N-piperidinyl, N-pyrrolidinyl, N-piperazinyl, N-morpholinyl, N-azetidinyl, 7-(3-oxa-7,9-diazabicyclo[3.3.1]nonanyl), N-thiomorpholinyl, or N-(thiomorpholinyl-1,1-dioxide), 1-imidazolyl, or 1-pyrazolyl, and each heteroaryl or heterocycloalkyl is selected from 0 to 3 R ７ 34. The compound of claim 33 which is substituted.

36. Each R ７ Hydroxyl, halogen, C １～４ Alkoxy, -C(O)OR ｚ , or C １～４ 34. The compound of claim 33, which is alkyl.

37. Each R ７ is hydroxyl, fluorine, methoxy, -C(O)-O-ethyl, methyl, or ethyl.

38. R １ But two R ５ 31. The compound of claim 30, which is 7-(hexahydro-1H-pyrrolidine), 8a-(octahydroindolizine), 2-pyrrolidine, N-azetidinyl, N-pyrrolidinyl, or N-piperidinyl substituted with.

39. Each R ５ are independently halogen, C １～４ Alkyl, -N(R ｗ ) ２ or two R ５ with the same carbon atom, 0 to 3 R ７ 39. The compound of claim 38, forming a spirocyclic heteroaryl or heterocycloalkyl substituted with:

40. Each R ｗ 39. The compound of claim 38, wherein is methyl, ethyl, or hydrogen.

41. Each R ５ are independently fluorine, methyl, ethyl, -NH ２ , -NHMe, or -N(Me) ２ or two R ５ together with the same carbon atom form a spirocyclic 2-azetidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 5-(1,4-oxazepanyl), 5-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl), or 5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidinyl), each spirocyclic heterocycloalkyl or heteroaryl having 0 to 3 R ７ 40. The compound of claim 39 , substituted with:

42. Each R ７ are independently oxo, hydroxyl, halogen, or C １～４ 40. The compound of claim 38, which is alkyl.

43. Each R ７ The compound of claim 42, wherein is independently oxo, hydroxyl, fluorine, or methyl.

44. R １ But, three R ５ 31. The compound of claim 30, which is 2-pyrrolidine or N-azetidinyl substituted with.

45. Each R ５ are independently halogen or C １～４ 45. The compound of claim 44, which is alkyl.

46. Each R ５ 46. ​​The compound of claim 45, wherein is fluorine or methyl.

47. R １ -N(R ａ ) ２ 2. The compound of claim 1 ,

48. Each R ａ But independently, C １～４ 48. The compound of claim 47, which is alkyl (e.g., methyl).

49. R １ But 0 to 3 R ５ 2. The compound of claim 1, wherein the heteroaryl is substituted with

50. R １ But 0 to 3 R ５ 50. The compound of claim 49, which is 5-thiazolyl or 6-(4,5,6,7-tetrahydrobenzo[d]thiazolyl) substituted with

51. R １ But 0 to 3 R ５ 51. The compound of claim 50, which is 5-thiazolyl or 6-(4,5,6,7-tetrahydrobenzo[d]thiazolyl) substituted with

52. -L-R １ but, 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 2. The compound of claim 1 ,

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

54. R ２ 54. The compound of claim 53, wherein is chlorine, methyl, ethyl, vinyl, or cyano.

55. R ４ The compound according to claim 1 , wherein is a halogen (e.g., fluorine).

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

57. R ｑ The compound of claim 1 , wherein is hydrogen or halogen.

58. The compound is the following compound: 4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(3-(trifluoromethyl)piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-diazepan-2-one; 4-(4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-4-(piperazin-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-chloro-2-((2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-6-chloro-8-fluoro-2-(2-((S)-1-methylpyrrolidin-2-yl)ethoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-diazepan-2-one; 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-diazepan-5-one; 4-(4-((1R,5S)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-6-chloro-2-((2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-4-(1,4-diazepan-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(4-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1,4-diazepan-2-one; 4-(4-(2,5-diazabicyclo[4.1.0]heptan-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1,4-diazepan-5-one; 4-(7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1,4-diazepan-2-one; 4-(7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-one; 1-(7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1,4-diazepan-5-one; ((2R)-4-(7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)methanol; 2-((2S)-4-(7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile; 4-(4-((1R,4R)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-4-(1,4-diazepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-(3,6-diazabicyclo[3.2.1]octan-6-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-(3,6-diazabicyclo[3.2.1]octan-6-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-(3,6-diazabicyclo[3.2.2]nonan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-(3,9-diazabicyclo[4.2.1]nonan-9-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-(3,9-diazabicyclo[4.2.1]nonan-9-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-(2,6-diazabicyclo[3.2.1]octan-6-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 2-((2S)-1-(7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)ethan-1-ol; ((2R)-1-(7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)methanol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-(2,5-diazabicyclo[4.1.0]heptan-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(octahydro-1H-cyclopenta[b]pyrazin-1-yl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 7a-(((7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)oxy)methyl)hexahydro-3H-pyrrolidin-3-one; 4-(6-chloro-8-fluoro-4-(piperazin-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((2S,4R)-4-fluoropyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-2-(((S)-1-(dimethylamino)propan-2-yl)oxy)-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; ((3R,7aR)-7a-(((7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)oxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methanol; ((3R,7aS)-7a-(((7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)oxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methanol; 4-(6-chloro-8-fluoro-2-(((S)-1-methylazetidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((R)-1-methylpyrrolidin-3-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-2-((2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((2S,4S)-4-fluoropyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((S)-1-(2-fluoroethyl)pyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-((hexahydroindolizine-8a(1H)-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((R)-1-methylazetidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-2-(((S)-4,4-difluoropyrrolidin-2-yl)methoxy)-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(2-(1-methylpiperidin-2-yl)ethoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(2-((S)-1-methylpyrrolidin-2-yl)ethoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-2-((1-ethylpiperidin-4-yl)methoxy)-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((S)-1-methylpiperidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-2-(((S)-1-(2,2-difluoroethyl)pyrrolidin-2-yl)methoxy)-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; (5S)-5-(((7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)oxy)methyl)pyrrolidin-2-one; 4-(6-chloro-2-(((R)-1-(dimethylamino)propan-2-yl)oxy)-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methyl)amino)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 1-((2S)-2-(((7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)oxy)methyl)pyrrolidin-1-yl)ethan-1-one; 4-(6-chloro-8-fluoro-4-(piperazin-1-yl)-2-(((S)-pyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((S)-2-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((R)-2-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(2-(((1s,4s)-7-azabicyclo[2.2.1]heptan-1-yl)methoxy)-6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-[6-chloro-8-fluoro-2-[3-methyl-3-(methylamino)azetidin-1-yl]-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-8-fluoro-4-piperazin-1-yl-2-[3-(1-piperidyl)azetidin-1-yl]quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[2-(3-amino-3-methyl-azetidin-1-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[2-[(2R,3S)-3-amino-2-methyl-azetidin-1-yl]-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[2-(3-amino-3-ethyl-azetidin-1-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 8-(7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octan-2-one; 1-[1-[7-(2-amino-1,3-benzothiazol-4-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-2-yl]azetidin-3-yl]piperidin-4-ol; 4-[6-chloro-2-(2,5-diazaspiro[3.4]octan-2-yl)-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 1-[1-[7-(2-amino-1,3-benzothiazol-4-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-2-yl]azetidin-3-yl]azetidin-3-ol; 1-[1-[7-(2-amino-1,3-benzothiazol-4-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-2-yl]azetidin-3-yl]-3-methyl-azetidin-3-ol; 4-(2-(3-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)azetidin-1-yl)-6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-[6-chloro-8-fluoro-2-[3-(4-methoxy-1-piperidyl)azetidin-1-yl]-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-8-fluoro-2-[3-[methyl-[(3R)-tetrahydrofuran-3-yl]amino]azetidin-1-yl]-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-8-fluoro-2-[3-(3-fluoroazetidin-1-yl)azetidin-1-yl]-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-8-fluoro-2-[3-(methylamino)azetidin-1-yl]-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 1-[1-[7-(2-amino-1,3-benzothiazol-4-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-2-yl]azetidin-3-yl]piperidin-3-ol; 4-[6-chloro-2-[(1S,5R)-2,6-diazabicyclo[3.2.0]heptan-6-yl]-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-8-fluoro-4-piperazin-1-yl-2-[3-(dimethylamino)pyrrolidin-1-yl]quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[2-(3-aminoazetidin-1-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-8-fluoro-4-piperazin-1-yl-2-[3-(methylamino)pyrrolidin-1-yl]quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-(6-chloro-8-fluoro-2-(1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(4-methyloctahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-[6-chloro-8-fluoro-2-[3-[methyl(oxetan-3-yl)amino]azetidin-1-yl]-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-(6-chloro-8-fluoro-2-(trans-4-methylhexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-[6-chloro-2-(1,6-diazaspiro[3.3]heptan-6-yl)-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-(6-chloro-8-fluoro-2-(cis-4-methylhexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-[6-chloro-8-fluoro-2-[3-[methoxy(methyl)amino]azetidin-1-yl]-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 2-[7-(2-amino-1,3-benzothiazol-4-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-2-yl]-8-oxa-2,5-diazaspiro[3.6]decan-6-one; 2-[[7-(2-amino-1,3-benzothiazol-4-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-2-yl]amino]-1-thiazol-5-yl-ethanol; 4-[6-chloro-8-fluoro-4-piperazin-1-yl-2-[1,4-diazabicyclo[3.2.1]octan-4-yl]quinazolin-7-yl]-1,3-benzothiazol-2-amine; 1'-[7-(2-amino-1,3-benzothiazol-4-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-2-yl]spiro[6,7-dihydropyrrolo[1,2-a]imidazol-5,3'-azetidin]-7-ol; 4-[6-chloro-8-fluoro-4-piperazin-1-yl-2-[1,7-diazaspiro[3.4]octan-7-yl]quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-8-fluoro-4-piperazin-1-yl-2-[[(6S)-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl]amino]quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-2-[3-(1,1-dioxo-1,4-thiazin-4-yl)azetidin-1-yl]-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-2-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 1'-[7-(2-amino-1,3-benzothiazol-4-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-2-yl]-8-methyl-spiro[6H-imidazo[1,2-a]pyrimidin-5,3'-azetidin]-7-one; 4-[6-chloro-8-fluoro-4-piperazin-1-yl-2-[3,6-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-2-[(1S,5S)-2,6-diazabicyclo[3.2.0]heptan-6-yl]-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-8-fluoro-2-(3-imidazo-1-ylazetidin-1-yl)-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-2-[3-(2,2-dimethylmorpholin-4-yl)azetidin-1-yl]-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-2-(3,3-difluoro-1,6-diazaspiro[3.3]heptan-6-yl)-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; Ethyl 1-[1-[7-(2-amino-1,3-benzothiazol-4-yl)-6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-2-yl]azetidin-3-yl]pyrazole-3-carboxylate; 4-[6-chloro-2-(2,7-diazaspiro[3.4]octan-2-yl)-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-[6-chloro-8-fluoro-4-piperazin-1-yl-2-[3-thiazol-2-yl-1-piperidyl]quinazolin-7-yl]-1,3-benzothiazol-2-amine; 4-(4-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-6-chloro-2-((2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-2-((1-ethylpiperidin-4-yl)oxy)-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)-6-methylbenzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)-7-(trifluoromethyl)benzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(6,8-difluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-methylquinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-4-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-4-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-8-fluoro-4-(5-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(6-chloro-4-(2,5-dihydro-1H-pyrrol-3-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-6-vinylquinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-vinylquinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-vinylquinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(6-ethyl-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine; 4-(8-fluoro-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)benzo[d]thiazol-2-amine; 7-(2-aminobenzo[d]thiazol-4-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazoline-6-carbonitrile; 7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinoline-3-carbonitrile; 7-(2-aminobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinoline-3-carbonitrile; 7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-chloro-8-fluoro-2-(((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinoline-3-carbonitrile; 7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinoline-3-carbonitrile; or 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine;

59. 13. A pharmaceutical composition comprising a compound of claim 1, or a pharma- ceutically acceptable salt of said compound, and a pharma- ceutically acceptable excipient.

60. 60. A compound according to claim 1, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound, or a pharmaceutical composition according to claim 59, for use as a medicament.

61. 60. A compound according to claim 1 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 59, for use in the treatment of cancer.

62. 60. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition of claim 59, for use in the treatment of cancer, wherein one or more cells express a KRAS G12D mutant protein.

63. 62. The compound or pharmaceutical composition for use according to claim 61, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small intestine cancer, appendix cancer, cancer of unknown primary origin, endometrial cancer, mixed type cancer of unknown primary origin, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

64. 60. Use of a compound of claim 1, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of claim 59, in the preparation of a medicament for treating cancer.

65. 60. Use of a compound of claim 1, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of claim 59, in the preparation of a medicament for treating cancer, wherein one or more cells express a KRAS G12D mutant protein.

66. 65. The use of claim 64, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed type cancer of unknown primary, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine carcinoma, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

67. 1. A pharmaceutical composition for use in a method of treating cancer in a subject in need thereof, comprising: The pharmaceutical composition comprises a therapeutically effective amount of a compound of claim 1, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of claim 59; and The method comprises administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of claim 59.

68. 1. A pharmaceutical composition for use in a method of treating cancer in a subject in need thereof, comprising: The pharmaceutical composition comprises a therapeutically effective amount of a compound of claim 1, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of claim 59; and The method comprises administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of claim 59, wherein one or more cells express a KRAS G12D mutant protein.

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

70. 68. The pharmaceutical composition of claim 67, 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.

71. 71. The pharmaceutical composition of claim 70, wherein the cancer is non-small cell lung cancer.

72. 71. The pharmaceutical composition of claim 70, wherein the cancer is colorectal cancer.

73. 71. The pharmaceutical composition of claim 70, wherein the cancer is pancreatic cancer.

74. 68. The pharmaceutical composition of claim 67, 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 pharma- ceutically acceptable salt thereof.

Images