KRAS inhibitors

Abstract

To provide a novel KRAS inhibitor for treating cancer patients. [Solution] The present invention provides compounds of the following formulas, pharmaceutically acceptable salts thereof, and methods for using these compounds and pharmaceutically acceptable salts thereof to treat cancer patients. TIFF2026052679000192.tif26128 (In the formula, R3 is the following group) TIFF2026052679000193.tif31128

Description

[Technical Field]

[0001] This disclosure pertains to KRAS inhibitors useful in treating diseases or disorders related to KRAS modulation. [Background technology]

[0002] The MAPK / ERK signaling pathway transmits extracellular stimuli to the nucleus, thereby regulating a variety of cellular responses, including cell proliferation, differentiation, and apoptosis. The KRAS protein initiates the MAPK / ERK signaling pathway and functions as a switch involved in inducing cell division. In its inactive state, KRAS binds to guanosine diphosphate (GDP), effectively sending a negative signal and suppressing cell division. In response to extracellular signals, KRAS is allosterically activated, enabling nucleotide exchange between GDP and guanosine triphosphate (GTP). In its GTP-bound active state, KRAS recruits and activates proteins necessary for the propagation of growth factor-induced signaling, as well as other cellular signaling receptors. Examples of proteins recruited by KRAS-GTP include c-Raf and PI3 kinase. As a GTPase, KRAS converts bound GTP back to GDP, thereby deactivating itself and again transmitting signals to suppress cell division. Gain-of-function mutations in KRAS exhibit increased GTP binding and decreased ability to convert GTP to GDP. As a result, MAPK / ERK signaling, which promotes the proliferation of cancer cells, increases. Missense mutations in KRAS at codon 12 are the most common and significantly reduce GTPase activity.

[0003] Oncogenic KRAS mutations have been identified in approximately 30% of human cancers and have been demonstrated to activate multiple downstream signaling pathways. Despite the prevalence of KRAS mutations, it remains a challenging therapeutic target. (Cox, ADDrugging the Undruggable RAS: Mission Possible? Nat. Rev. Drug Disc. 2014, 13, 828-851; Pylayeva-Gupta, y et al. RAS Oncogenes: Weaving a Tumorigenic Web. Nat. Rev. Cancer 2011, 11, 761-774).

[0004] To date, research has focused on KRAS G12C variant inhibitors (for example, International Publication Nos. 2019 / 099524, 2020 / 081282, 2020 / 101736, 2020 / 146613, and 2021 / 118877 disclose KRAS G12C inhibitors), while International Publication No. 2021 / 041671 discloses KRAS G12D small molecule inhibitors, and International Publication No. 2017 / 011920 discloses KRAS G12C, G12D, and G12V small molecule inhibitors.

[0005] There remains a need to provide alternative small molecule KRAS inhibitors. Specifically, there is a need to provide orally deliverable KRAS inhibitors useful for the treatment of cancer. More specifically, there is a need to provide small molecule inhibitors that specifically inhibit KRAS GTP activity. There is also a need to provide small molecule KRAS inhibitors that exhibit higher efficacy with the same or reduced KRAS inhibitory activity. Furthermore, there is a demand for KRAS inhibitors that exhibit better pharmacokinetic / pharmacodynamic properties. In addition, it is desirable to provide KRAS inhibitors that exhibit good oral bioavailability and target range (KRAS G12V inhibition). Moreover, there is a need to provide KRAS inhibitors that exhibit selective inhibitory preference for KRAS G12V variants over KRAS wild-type, and preferably selective inhibitory preference for KRAS G12V variants over HRAS or NRAS. Furthermore, there is a need to provide more potent KRAS inhibitors that exhibit increased efficacy with reduced or minimized adverse or undesirable effects. The present invention addresses one or more of these needs by providing a novel KRAS inhibitor. [Overview of the project]

[0006] Compound of formula I,

[0007] [ka] During the ceremony, R1 is given by the formula

[0008] [ka] It is a base selected from, R 1a is H or C 1~3 It is alkyl, R 1b H, C 1~3 Alkyl or cyclopropyl, n is either 0 or 1. R 1c C 1~3 It is alkyl, R2 is H, halogen, or methyl, R3 is a group of the formula

[0009]

Chem.

[0010]

Chem.

[0011] Methods of using compounds of formula I, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable compositions thereof for the treatment of cancer, specifically lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, colorectal cancer, gastric adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumor, bladder cancer, small intestinal adenocarcinoma, appendiceal cancer, and peritoneal cancer. The methods include administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a patient in need.

[0012] Compounds of formula I and pharmaceutically acceptable salts thereof for use in therapy are further provided herein. Furthermore, compounds of formula I and pharmaceutically acceptable salts thereof for use in the treatment of cancer, specifically lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, colorectal cancer, gastric adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumor, bladder cancer, small intestinal adenocarcinoma, appendiceal cancer, and peritoneal cancer are also provided herein. In addition, the use of compounds of formula I or pharmaceutically acceptable salts thereof in the manufacture of agents for the treatment of cancer, specifically lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, colorectal cancer, gastric adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumor, bladder cancer, small intestinal adenocarcinoma, appendiceal cancer, and peritoneal cancer is also provided herein. [Modes for carrying out the invention]

[0013] Novel inhibitors of the KRAS gain-of-function mutant G12V are described herein. These novel compounds can address the above-mentioned need for inhibitors of KRAS GTP activity in gain-of-function variants in the treatment of cancer, such as lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, gastric adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumor, bladder cancer, small intestinal adenocarcinoma, or appendiceal cancer, or peritoneal cancer. Some of these novel KRAS G12V variant inhibitor compounds are more selective to KRAS G12V variants than wild-type KRAS, and preferably they are also more selective to hRAS and nRAS. In addition, some of these novel selective KRAS G12V variant inhibitor compounds are also inhibitors of other variant types such as KRAS G12C or G12D. Some of these novel KRAS G12V mutant inhibitor compounds have good oral bioavailability and a good target range (inhibition of KRAS G12V mutants).

[0014] The present invention relates to a compound of formula I,

[0015] [ka] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4 are as defined above.

[0016] As used herein, the term halogen means fluoro(F), chloro(Cl), bromo(Br), or iod(I). As used herein, the term alkyl means a saturated linear or branched monovalent hydrocarbon radical having one to a specific number of carbon atoms, e.g., "C 1-4 "Alkyl" or "C 1-3 It means "alkyl". Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, 1-propyl, isopropyl, butyl, and isobutyl.

[0017] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R3 is of formula

[0018] [ka] It is the basis of.

[0019] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R3 is of formula

[0020] [ka] It is the basis of.

[0021] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R3 is of formula

[0022] [ka] It is the base of, and in the formula, preferably R 3b is F or Cl, most preferably R 3b It is F.

[0023] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R3 is of formula

[0024] [ka] It is the base of, and in the formula, preferably R 3b H is H.

[0025] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R3 is of formula

[0026] [ka] It is the base of, and in the formula, preferably R 3b It is methyl.

[0027] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R3 is of formula

[0028] [ka] It is the base of, and in the formula, preferably R 3b It is either H or F.

[0029] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R3 is of formula

[0030] [ka] It is the base of, and in the formula, preferably R 3b H is H.

[0031] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R3 is of formula

[0032] [ka] It is the base of, and in the formula, preferably R 3b F is F.

[0033] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R3 is of formula

[0034] [ka] It is a base selected from among them.

[0035] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R3 is of formula

[0036] [ka] It is a base selected from among them.

[0037] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R3 is of formula

[0038] [ka] It is the basis of.

[0039] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R3 is of formula

[0040] [ka] It is the basis of.

[0041] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R3 is of formula

[0042] [ka] It is the basis of.

[0043] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R2 is F or Cl.

[0044] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R2 is F.

[0045] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R2 is Cl.

[0046] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is the following formula

[0047] [ka] It is the basis of.

[0048] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is the following formula

[0049] [ka] It is the basis of, and in the formula, R 1a H is H.

[0050] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is the following formula

[0051] [ka] It is the basis of, and in the formula, R 1a It is preferably H.

[0052] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is the following formula

[0053] [ka] It is the basis of, and in the formula, R 1a It is preferably H.

[0054] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1a H is H.

[0055] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1b The compound is H, methyl, ethyl, isopropyl, or cyclopropyl.

[0056] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1b is H or methyl, preferably R 1b It is methyl.

[0057] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1b C 1~3 It is alkyl.

[0058] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, n is 0.

[0059] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, n is 1, and R 1c is C 1~3 It is alkyl, preferably R 1c It is methyl.

[0060] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1a H is R 1b is C 1~3 It is an alkyl group, and n is 0.

[0061] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is of formula

[0062] [ka] It is the basis of.

[0063] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R 1a H is R 1b is C 1~3 It is alkyl, n is 1, R 1c is C 1~3 It is alkyl, preferably R 1b and R 1c It is methyl.

[0064] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is of formula

[0065] [ka] It is a base selected from among them.

[0066] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is of formula

[0067] [ka] It is a base selected from among them.

[0068] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is of formula

[0069] [ka] It is the basis of.

[0070] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is of formula

[0071] [ka] It is a base selected from among them.

[0072] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is of formula

[0073] [ka] It is a base selected from among them.

[0074] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is of formula

[0075] [ka] It is the basis of.

[0076] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is of formula

[0077] [ka] It is the basis of.

[0078] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R7 is H or C 1~3 It is alkyl, and preferably R7 is H.

[0079] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R7 is selected from H, methyl, ethyl, and isopropyl.

[0080] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R7 is methyl or ethyl.

[0081] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R7 is methyl.

[0082] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R7 is ethyl.

[0083] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R 7a The compound is selected from methyl, ethyl, isopropyl, and methoxyethyl.

[0084] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R 7a It is methyl.

[0085] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R 7a It is ethyl.

[0086] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R 7a It is isopropyl.

[0087] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R 7a It is methoxyethyl.

[0088] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, p is 0.

[0089] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, p is 1.

[0090] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R5 is methyl, R7 is H, and R 7a It is isopropyl, and p is 1.

[0091] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R5, R7, and R 7a Each of these is methyl, and p is 1.

[0092] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R5 is methyl, R7 is methyl, and R 7a is ethyl, and p is 1.

[0093] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R5 and R7 are each methyl, and R 7a is ethyl, and p is 1.

[0094] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R5 is methyl, and R7 and R 7a Each of these is ethyl, and p is 1.

[0095] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R5 and R7 are each methyl, and R 7a It is isopropyl, and p is 1.

[0096] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R7 and R 7a Each of these is ethyl, and p is 0.

[0097] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R5 and R 7a Each of the following is methyl, R7 is methoxyethyl, and p is 1.

[0098] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is of formula

[0099] [ka] It is a base selected from among them.

[0100] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is of formula

[0101] [ka] It is a base selected from among them.

[0102] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is of formula

[0103] [ka] It is the basis of.

[0104] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R 6a is selected from methyl, ethyl, and isopropyl, preferably R 6a It is methyl.

[0105] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R6 is a halogen or C 1~3 It is an alkoxy.

[0106] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R6 is F.

[0107] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R6 is methoxy.

[0108] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is of formula

[0109] [ka] It is a base selected from among them.

[0110] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is of formula

[0111] [ka] It is a base selected from among them.

[0112] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is of formula

[0113] [ka] It is the basis of.

[0114] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is of formula

[0115] [ka] It is the basis of.

[0116] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is of formula

[0117] [ka] It is the basis of.

[0118] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R8 and R 8a Each of them is independent of C 1~3 It is alkyl.

[0119] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R8 is methyl, and R 8a It is ethyl.

[0120] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R8 and R 8aTogether with the nitrogen atoms to which they are bonded, they form an optionally substituted 4, 5, or 6-membered heterocycle that optionally contains a further heteroatom selected from N, O, and S, and the heterocycle is C 1~3 It is optionally replaced with an alkyl group.

[0121] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R8 and R 8a These, together with the nitrogen atom to which they are bonded, form a 4- or 5-membered heterocycle that optionally contains further heteroatoms selected from N, O, and S.

[0122] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R 5a This is methyl or ethyl, and preferably methyl.

[0123] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, p is 1.

[0124] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, p is 0.

[0125] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R8 and R 8a Each of these is ethyl, and p is 0.

[0126] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R5 is methyl, and R8 and R 8a These atoms, together with the nitrogen atoms to which they are bonded, form a four-membered heterocycle, and the p-value is 1.

[0127] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R5 is methyl, and R8 and R 8a These atoms, together with the nitrogen atoms to which they are bonded, form a five-membered heterocycle, and the p-value is 1.

[0128] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is of formula

[0129] [ka] It is a base selected from among them.

[0130] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is of formula

[0131] [ka] It is a base selected from among them.

[0132] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is of formula

[0133] [ka] It is a base selected from among them.

[0134] In the above embodiments of the compounds of formula I, the chemical diagrams are shown monotonically without chiral information. These compounds often have multiple chiral centers and are intended to exist in various forms with various combinations of chiral centers. In addition, these compounds may have various enantiomers, diastereomers, and atropisomers, which are included herein.

[0135] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, the compound is an isotopic derivative of any one of the compounds described herein or a pharmaceutically acceptable salt thereof.

[0136] It is understood that isotopic derivatives can be prepared using any of the various techniques recognized in the art. For example, isotopic derivatives can generally be prepared by performing the procedures disclosed in the schemes and / or examples described herein, by using an isotopic labeling reagent or a pharmaceutically acceptable salt thereof instead of a non-isotopic labeling reagent.

[0137] In further embodiments of the compounds of formula I or their pharmaceutically acceptable salts, the compounds are obtained by deuteration at one or more positions. Unless otherwise specified, when an atom is specifically designated as "H" or "hydrogen," it is understood that the atom has hydrogen in its isotopic composition of natural abundance. Also, unless otherwise specified, when an atom is specifically designated as "D" or "deuterium," it is understood that the atom has deuterium in an abundance substantially greater than the natural abundance of deuterium, which is 0.015%.

[0138] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, the compound is a deuterium-labeled compound of any one of the compounds and pharmaceutically acceptable salts thereof described herein.

[0139] The following are further numbered embodiments of the present invention: 1. Formula:

[0140] [ka] During the ceremony, R1 is,

[0141] [ka] It is the basis of; R 1a is H or C 1~3 It is alkyl, R 1b H, C 1~3 Alkyl or cyclopropyl, n is either 0 or 1. R 1c C 1~3 It is alkyl, R2 is H, halogen, or methyl. R3 is given by the formula

[0142] [ka] It is the basis of, Z is -C(R 3c )- or -N-, R 3a , R 3b , and R 3c are each independently H, halogen, or methyl, R4 is a group of the formula

[0143] [Chemical formula] and R5 is -NR7R 7a , p is​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ It is a base selected from, R 1a is H or C 1~3 It is alkyl, R 1b H, C 1~3 Alkyl or cyclopropyl, n is either 0 or 1. R 1c C 1~3 It is alkyl, R2 is H, halogen, or methyl. R3 is given by the formula

[0146] [ka] It is the basis of, Z is -C(R 3c )- or -N-, R 3a , R 3b , and R 3c Each of these is independently H, halogen, or methyl. R4 is the formula

[0147] [ka] It is a base selected from, R5 is -NR7R 7a And, p is either 0 or 1. R 5a and R 6a Each of them is independent of C 1~3 It is alkyl, R6 is halogen, R7 is H or C 1~3 It is alkyl, R 7a C 1~3 A compound that is alkyl, or a pharmaceutically acceptable salt thereof. 3. R3 is given by the formula

[0148] [ka] The composition according to Embodiment 1 having the group, or a pharmaceutically acceptable salt thereof. 4. R3 is a group of the formula

[0149]

Chemical formula

[0150]

Chemical formula

[0151]

Chemical formula

[0152]

Chemical formula

[0153]

Chemical formula

[0154]

Chem.

[0155]

Chem.

[0156]

Chem.

[0157]

Chem.

[0158]

Chem.

[0159]

Chem.

[0160] [ka] A compound described in any one of Embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, which is the base of the compound. 19. R1 is,

[0161] [ka] The compound described in Embodiment 18, or a pharmaceutically acceptable salt thereof, which is the base of the compound. 20. R1 is,

[0162] [ka] The compound described in Embodiment 18, or a pharmaceutically acceptable salt thereof, which is the base of the compound. 21. R 1a The compound described in any one of Embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, wherein is H. 22. R 1b The compound described in any one of Embodiments 1 to 21, or a pharmaceutically acceptable salt thereof, wherein is H, methyl, ethyl, isopropyl, or cyclopropyl. 23. R 1b is H or methyl, preferably R 1b The compound described in any one of Embodiments 1 to 22, or a pharmaceutically acceptable salt thereof, is methyl. 24. A compound according to any one of embodiments 18 to 23, or a pharmaceutically acceptable salt thereof, wherein n is 0. 25. n is 1, and R 1c C 1~3 It is alkyl, preferably R 1c The compound described in any one of embodiments 18 to 23, or a pharmaceutically acceptable salt thereof, wherein the compound is methyl. 26. R 1a H is R 1b C 1~3 A compound according to any one of Embodiments 1 to 20, wherein the compound is alkyl and n is 0, or a pharmaceutically acceptable salt thereof. 27. R1 is,

[0163] [ka] The compound described in Embodiment 26, or a pharmaceutically acceptable salt thereof, which is the base of the compound. 28. R 1a H is R 1b C 1~3 It is alkyl, n is 1, and R 1c C 1~3 It is alkyl, preferably R 1b and R 1c The compound described in any one of Embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, is methyl. 29. R1 is,

[0164] [ka] A compound according to Embodiment 28, or a pharmaceutically acceptable salt thereof, which is a group selected from the above. 30. R1 is,

[0165] [ka] The compound described in Embodiment 28, or a pharmaceutically acceptable salt thereof, which is the base of the compound. 31. R1 is,

[0166] [ka] A compound according to Embodiment 18, or a pharmaceutically acceptable salt thereof, which is a group selected from the above. 32. R1 is,

[0167] [ka] A compound according to Embodiment 18, or a pharmaceutically acceptable salt thereof, which is a group selected from the above. 33. R1 is,

[0168] [ka] A compound according to Embodiment 18, or a pharmaceutically acceptable salt thereof, which is a group selected from the above. 34. R4 is,

[0169] [ka] A compound described in any one of Embodiments 1 to 33, or a pharmaceutically acceptable salt thereof, which is the base of the compound. 35. R4 is,

[0170] [ka] A compound described in any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, which is the base of the compound. 36. R4 is,

[0171] [ka] A compound according to Embodiment 34 or 35, or a pharmaceutically acceptable salt thereof, which is a group selected from the above. 37. R4 is,

[0172] [ka] A compound according to Embodiment 36, or a pharmaceutically acceptable salt thereof, which is a group selected from the above. 38. R4 is,

[0173] [ka] A compound described in any one of Embodiments 1 to 33, or a pharmaceutically acceptable salt thereof, which is the base of the compound. 39. R4 is,

[0174] [ka] A compound according to Embodiment 38, or a pharmaceutically acceptable salt thereof, which is a group selected from the above. 40. R4 is,

[0175] [ka] A compound according to Embodiment 39, or a pharmaceutically acceptable salt thereof, which is a group selected from the above. 41. R4 is,

[0176] [ka] A compound described in any one of Embodiments 1 or 3 to 33, or a pharmaceutically acceptable salt thereof, which is the base of the compound. 42. R4 is,

[0177] [ka] The compound described in Embodiment 41, or a pharmaceutically acceptable salt thereof, which is the base of the compound. 43. R4 is,

[0178] [ka] A compound according to Embodiment 41 or 42, or a pharmaceutically acceptable salt thereof, which is a group selected from the above. 44. R4 is,

[0179] [ka] A compound according to any one of Embodiments 1 or 3 to 33, or a pharmaceutically acceptable salt thereof, which is a group selected from the above. 45. R4 is,

[0180] [ka] A compound according to any one of Embodiments 1 to 33, or a pharmaceutically acceptable salt thereof, which is a group selected from the above. 46.

[0181] [ka]

[0182] [ka] A compound selected from, according to Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof. 47. The compound is

[0183] [ka]

[0184] [ka] A compound selected from the compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof. 48. A pharmaceutical composition comprising a compound described in any one of Embodiments 1 to 47, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. 49. A method for treating a patient having cancer, comprising administering to a patient in need of such treatment an effective amount of the pharmaceutical composition described in Embodiment 48, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, colorectal cancer, gastric adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumor, bladder cancer, small intestinal adenocarcinoma, appendiceal cancer, and peritoneal cancer. 50. A method for treating a patient having cancer, comprising administering to a patient in need an effective amount of any one of Embodiments 1 to 47, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, colorectal cancer, gastric adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumor, bladder cancer, small intestinal adenocarcinoma, appendiceal cancer, and peritoneal cancer. 51. The method according to Embodiment 49 or 50, wherein the patient has cancer determined to have one or more cells expressing the KRAS G12V mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof. 52. The method according to Embodiment 49 or 50, wherein one or more cells express the KRAS G12V mutant protein. 53. A method for treating a patient having cancer with a KRASG12V mutation, comprising administering to a patient in need of treatment an effective amount of any one of Embodiments 1 to 47, or a pharmaceutically acceptable salt thereof. 54. The method according to Embodiment 53, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, colorectal cancer, gastric adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumor, bladder cancer, small intestine adenocarcinoma, appendiceal cancer, and peritoneal cancer. 55. The method according to any one of embodiments 49 to 54, wherein the patient is also administered one or more of the following: a PD-1 inhibitor, a PD-L1 inhibitor, a CDK4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, an SHP2 inhibitor, a platinum agent, and pemetrexed, or a pharmaceutically acceptable salt thereof. 56. A compound described in any one of Embodiments 1 to 47 for use in therapy, or a pharmaceutically acceptable salt thereof. 57. A compound described in any one of Embodiments 1 to 47 for use in the treatment of cancer, or a pharmaceutically acceptable salt thereof. 58. The cancer is a compound for use described in Embodiment 57, or a pharmaceutically acceptable salt thereof, having the KRAS G12V mutation. 59. The cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, colorectal cancer, gastric adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumor, bladder cancer, small intestinal adenocarcinoma, appendiceal cancer, and peritoneal cancer, and is one of the compounds for use described in Embodiment 57 or 58, or a pharmaceutically acceptable salt thereof. 60. A compound according to any one of Embodiments 1 to 47, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in combination with, separately, or sequentially with one or more of the following: a PD-1 or PD-L1 inhibitor, a CDK4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, an SHP2 inhibitor, a platinum agent, and pemetrexed, or a pharmaceutically acceptable salt thereof. 61. The method according to Embodiment 55, or the compound for use described in Embodiment 60, or a pharmaceutically acceptable salt thereof, wherein the patient is also administered an effective amount of a PD-1 inhibitor. 62. The method according to Embodiment 55, or the compound for use described in Embodiment 60, or a pharmaceutically acceptable salt thereof, wherein the patient is also administered an effective amount of a PD-L1 inhibitor. 63. The method according to Embodiment 55, or the compound for use described in Embodiment 60, or a pharmaceutically acceptable salt thereof, wherein the patient is also administered an effective dose of a CDK4 / CDK6 inhibitor. 64. The method according to Embodiment 55, or the compound for use described in Embodiment 60, or a pharmaceutically acceptable salt thereof, wherein the patient is also administered an effective amount of an EGFR inhibitor. 65. The method according to Embodiment 55, or the compound for use described in Embodiment 60, or a pharmaceutically acceptable salt thereof, wherein the patient is also administered an effective amount of an ERK inhibitor. 66. The method according to Embodiment 55, or the compound for use described in Embodiment 60, or a pharmaceutically acceptable salt thereof, wherein the patient is also administered an effective amount of an Aurora A inhibitor. 67. The method according to Embodiment 55, or the compound for use described in Embodiment 60, or a pharmaceutically acceptable salt thereof, wherein the patient is also administered an effective amount of an SHP2 inhibitor. 68. The method according to Embodiment 55, or the compound for use described in Embodiment 60, or a pharmaceutically acceptable salt thereof, wherein the patient is also administered an effective amount of platinum. 69. The method according to Embodiment 55, or the compound for use described in Embodiment 60 or a pharmaceutically acceptable salt thereof, wherein the patient is also administered an effective amount of pemetrexed or a pharmaceutically acceptable salt thereof. 70. The cancer is non-small cell lung cancer, and the method is described in any one of Embodiments 49-55 or 61-69, or the compound for use described in Embodiments 57-69, or a pharmaceutically acceptable salt thereof. 71. The cancer is colorectal cancer, according to the method of any one of Embodiments 49-55 or 61-69, or the compound for use described in Embodiments 57-69, or a pharmaceutically acceptable salt thereof. 72. Cancer is pancreatic cancer, according to any one of Embodiments 49-55 or 61-69, or the compounds for use described in Embodiments 57-69, or pharmaceutically acceptable salts thereof. 73. Cancer is cervical cancer, the compound for use described in any one of Embodiments 49-55 or 61-69, or any pharmaceutically acceptable salt thereof, as described in any one of Embodiments 57-69. 74. The cancer is esophageal cancer, and the compound for use described in any one of Embodiments 49-55 or 61-69, or any pharmaceutically acceptable salt thereof, is described in any one of Embodiments 57-69. 75. The cancer is endometrial cancer, the method according to any one of Embodiments 49-55 or 61-69, or the compound for use described in any one of Embodiments 57-69, or a pharmaceutically acceptable salt thereof. 76. The cancer is ovarian cancer, the compound for use described in any one of Embodiments 49-55 or 61-69, or any pharmaceutically acceptable salt thereof, as described in any one of Embodiments 57-69. 77. The cancer is cholangiocarcinoma, the compound for use described in any one of Embodiments 49-55 or 61-69, or any pharmaceutically acceptable salt thereof. 78. The cancer is gastric adenocarcinoma, the compound for use described in any one of Embodiments 49-55 or 61-69, or any pharmaceutically acceptable salt thereof, as described in any one of Embodiments 57-69. 79. The cancer is invasive ductal carcinoma, the method according to any one of Embodiments 49-55 or 61-69, or the compound for use described in any one of Embodiments 57-69, or a pharmaceutically acceptable salt thereof. 80. The cancer is uterine carcinosarcoma, the method according to any one of Embodiments 49-55 or 61-69, or the compound for use described in any one of Embodiments 57-69, or a pharmaceutically acceptable salt thereof. 81. Cancer is a germ cell tumor, and the compound for use described in any one of Embodiments 49-55 or 61-69, or any pharmaceutically acceptable salt thereof, is a germ cell tumor. 82. The cancer is bladder cancer, the compound for use described in any one of Embodiments 49-55 or 61-69, or any pharmaceutically acceptable salt thereof as described in any one of Embodiments 57-69. 83. The cancer is small intestinal adenocarcinoma, the compound for use described in any one of Embodiments 49-55 or 61-69, or any pharmaceutically acceptable salt thereof. 84. The cancer is appendiceal cancer, the compound for use described in any one of Embodiments 49-55 or 61-69, or any pharmaceutically acceptable salt thereof, as described in any one of Embodiments 57-69. 85. The cancer is peritoneal cancer, the compound for use described in any one of Embodiments 49-55 or 61-69, or any pharmaceutically acceptable salt thereof, as described in any one of Embodiments 57-69.

[0185] The chemical diagrams of the compounds described above include representations of the chiral aspects of the specific compounds shown. However, the chemical diagrams of the compounds described above do not include all possible chiral features of those compounds, and the chiral representations shown are not intended to exclude changes to the indicated chiral aspects. Therefore, alternative chiral versions of the compounds, as well as different combinations of chiral attributes, are contemplated and included herein.

[0186] A method for treating cancer is further provided herein, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof. In this method, cancer may be lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, colorectal cancer, gastric adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumor, bladder cancer, small intestinal adenocarcinoma, appendiceal cancer, or peritoneal cancer. In this method, cancer may be more specifically non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In one embodiment, cancer may be non-small cell lung cancer. In one embodiment, cancer may be pancreatic cancer. In one embodiment, cancer may be colorectal cancer. In one embodiment, cancer may be gastric adenocarcinoma. In one embodiment, cancer may be invasive ductal carcinoma. In one embodiment, cancer may be uterine carcinosarcoma. In one embodiment, cancer may be germ cell tumor. In one embodiment, the cancer may be bladder cancer. In one embodiment, the cancer may be small intestine adenocarcinoma. In one embodiment, the cancer may be appendiceal cancer. In one embodiment, the cancer may be peritoneal cancer.

[0187] A method for treating cancer is also provided herein, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a mutant KRAS G12V protein. In this method, the cancer may be non-small cell lung cancer, pancreatic cancer, or colorectal cancer having one or more cells expressing a mutant KRAS G12V protein. In one embodiment, the cancer is non-small cell lung cancer having one or more cells expressing a mutant KRAS G12V protein. In one embodiment, the cancer is mutant pancreatic cancer having one or more cells expressing a mutant KRAS G12V protein. In one embodiment, the cancer is colorectal cancer having one or more cells expressing a mutant KRAS G12V protein. The method also includes treating cancers of other origins having a KRAS G12V mutant.

[0188] A method for treating a patient having cancer with a KRAS G12V mutation is further provided herein, comprising administering to the patient in need of treatment an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof. In this method, cancers with the KRAS G12V mutation may include KRAS G12V mutant lung cancer, KRAS G12V mutant pancreatic cancer, KRAS G12V mutant cervical cancer, KRAS G12V mutant esophageal cancer, KRAS G12V mutant endometrial cancer, KRAS G12V mutant ovarian cancer, KRAS G12V mutant bile duct cancer, KRAS G12V mutant colorectal cancer, KRAS G12V mutant gastric adenocarcinoma, KRAS G12V mutant invasive ductal carcinoma, KRAS G12V mutant uterine carcinosarcoma, KRAS G12V mutant germ cell tumor, KRAS G12V mutant bladder cancer, KRAS G12V mutant small intestinal adenocarcinoma, KRAS G12V mutant appendiceal cancer, and KRAS G12V mutant peritoneal cancer. In one embodiment, the cancer having the KRAS G12V mutation can be KRAS G12V mutant non-small cell lung cancer. In one embodiment, the cancer having the KRAS G12V mutation can be KRAS G12V mutant pancreatic cancer. In one embodiment, the cancer having the KRAS G12V mutation can be KRAS G12V mutant colorectal cancer.

[0189] This specification further provides a method for modulating the mutant KRAS G12V enzyme in patients requiring modification of the mutant KRAS G12V enzyme by administering a compound according to Formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the method comprises inhibiting the human mutant KRAS G12V enzyme.

[0190] Also provided herein are methods for treating cancer in patients requiring cancer treatment, wherein the patient has cancer determined to express the KRAS G12V mutant protein. The method comprises administering to the patient an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof. The G12V mutation status of one or more cancer cells can be determined by several assays known in the art. Typically, one or more biopsies containing one or more cancer cells are obtained and subjected to sequencing and / or polymerase chain reaction (PCR). Circulating cell-free DNA can also be used, for example, in advanced cancer. Non-limiting examples of sequencing and PCR techniques used to determine mutation status (e.g., G12C, G12D, and / or G12V mutation status in one or more cancer cells or circulating cell-free DNA) include direct sequencing, next-generation sequencing, reverse transcription polymerase chain reaction (RT-PCR), multiplex PCR, and pyrosequencing and multi-sample profiling.

[0191] Compounds according to Formula I or pharmaceutically acceptable salts thereof for use in therapy are further provided herein. Compounds or pharmaceutically acceptable salts thereof may be for use in the treatment of cancer. For this use in the treatment of cancer, cancer may be lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, colorectal cancer, gastric adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumor, bladder cancer, small intestinal adenocarcinoma, appendiceal cancer, or peritoneal cancer. In one embodiment, cancer is non-small cell lung cancer. In one embodiment, cancer is pancreatic cancer. In one embodiment, cancer is cervical cancer. In one embodiment, cancer is esophageal cancer. In one embodiment, cancer is endometrial cancer. In one embodiment, cancer is ovarian cancer. In one embodiment, cancer is bile duct cancer. In one embodiment, cancer is colorectal cancer. In one embodiment, cancer is gastric adenocarcinoma. In one embodiment, cancer is invasive ductal carcinoma. In one embodiment, the cancer is uterine carcinosarcoma. In one embodiment, the cancer is a germ cell tumor. In one embodiment, the cancer is bladder cancer. In one embodiment, the cancer is small intestine adenocarcinoma. In one embodiment, the cancer is appendiceal cancer. In one embodiment, the cancer is peritoneal cancer. Cancer may have one or more cancer cells expressing the mutant KRAS G12V protein, such as KRAS G12V mutant lung cancer, KRAS G12V mutant pancreatic cancer, KRAS G12V mutant cervical cancer, KRAS G12V mutant esophageal cancer, KRAS G12V mutant endometrial cancer, KRAS G12V mutant ovarian cancer, KRAS G12V mutant cholangiocarcinoma, KRAS G12V mutant colorectal cancer, KRAS G12V mutant gastric adenocarcinoma, KRAS G12V mutant invasive ductal carcinoma, KRAS G12V mutant uterine carcinosarcoma, KRAS G12V mutant germ cell tumor, KRAS G12V mutant bladder cancer, KRAS G12V mutant small intestinal adenocarcinoma, KRAS G12V mutant appendiceal cancer, or KRAS G12V mutant peritoneal cancer. Additionally, the cancer may be non-small cell lung cancer in which one or more cells express the KRAS G12V mutant protein. Furthermore, the cancer may be colorectal cancer in which one or more cells express the KRAS G12V mutant protein.Additionally, the cancer may be pancreatic cancer in which one or more cells express the KRAS G12V mutant protein. Furthermore, the cancer may be KRAS G12V mutant cervical cancer in which one or more cells express the KRAS G12V mutant protein. Additionally, the cancer may be KRAS G12V mutant esophageal cancer in which one or more cells express the KRAS G12V mutant protein. Furthermore, the cancer may be KRAS G12V mutant endometrial cancer in which one or more cells express the KRAS G12V mutant protein. Additionally, the cancer may be KRAS G12V mutant ovarian cancer in which one or more cells express the KRAS G12V mutant protein. Furthermore, the cancer may be KRAS G12V mutant cholangiocarcinoma in which one or more cells express the KRAS G12V mutant protein. Additionally, the cancer could be KRAS G12V mutant gastric adenocarcinoma, in which one or more cells express the KRAS G12V mutant protein. Furthermore, the cancer could be KRAS G12V mutant invasive ductal carcinoma, in which one or more cells express the KRAS G12V mutant protein. Additionally, the cancer could be KRAS G12V mutant uterine carcinosarcoma, in which one or more cells express the KRAS G12V mutant protein. Furthermore, the cancer could be KRAS G12V mutant germ cell tumor, in which one or more cells express the KRAS G12V mutant protein. Additionally, the cancer could be KRAS G12V mutant bladder cancer, in which one or more cells express the KRAS G12V mutant protein. Furthermore, the cancer could be KRAS G12V mutant small intestinal adenocarcinoma, in which one or more cells express the KRAS G12V mutant protein. Additionally, the cancer may be a KRAS G12V mutant appendiceal cancer in which one or more cells express the KRAS G12V mutant protein. Furthermore, the cancer may be a KRAS G12V mutant peritoneal cancer in which one or more cells express the KRAS G12V mutant protein. A patient may have a cancer that has been determined to have one or more cells expressing the KRAS G12V mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof. The patient may have been treated in a different therapeutic course prior to being treated as described herein.

[0192] Compounds provided herein according to Formula I, or pharmaceutically acceptable salts thereof, may also be used in the manufacture of agents for the treatment of cancer. When used in the manufacture of pharmaceuticals, cancer may be lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, colorectal cancer, gastric adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumor, bladder cancer, small intestinal adenocarcinoma, appendiceal cancer, and peritoneal cancer. In one embodiment, cancer is non-small cell lung cancer. In one embodiment, cancer is pancreatic cancer. In one embodiment, cancer is cervical cancer. In one embodiment, cancer is esophageal cancer. In one embodiment, cancer is endometrial cancer. In one embodiment, cancer is ovarian cancer. In one embodiment, cancer is bile duct cancer. In one embodiment, cancer is colorectal cancer. In one embodiment, cancer is gastric adenocarcinoma. In one embodiment, cancer is invasive ductal carcinoma. In one embodiment, cancer is uterine carcinosarcoma. In one embodiment, the cancer is a germ cell tumor. In one embodiment, the cancer is bladder cancer. In one embodiment, the cancer is small intestinal adenocarcinoma. In one embodiment, the cancer is appendiceal cancer. In one embodiment, the cancer is peritoneal cancer. The cancer may have one or more cancer cells expressing the mutant KRAS G12V protein. When cancer cells express the KRAS G12V protein, the cancer may be selected from KRAS G12V mutant lung cancer, KRAS G12V mutant pancreatic cancer, KRAS G12V mutant cervical cancer, KRAS G12V mutant esophageal cancer, KRAS G12V mutant endometrial cancer, KRAS G12V mutant ovarian cancer, KRAS G12V mutant cholangiocarcinoma, KRAS G12V mutant colorectal cancer, KRAS G12V mutant gastric adenocarcinoma, KRAS G12V mutant invasive ductal carcinoma, KRAS G12V mutant uterine carcinosarcoma, KRAS G12V mutant germ cell tumor, KRAS G12V mutant bladder cancer, KRAS G12V mutant small intestinal adenocarcinoma, KRAS G12V mutant appendiceal cancer, and KRAS G12V mutant peritoneal cancer.

[0193] A method for treating cancer is also provided herein, comprising administering to a patient in need of treatment an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and one or more of the following: a PD-1 inhibitor, a PD-L1 inhibitor, a CDK4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, an SHP2 inhibitor, a platinum agent, and pemetrexed, or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a variant KRAS G12V protein. Further provided herein are compounds according to Formula I, or pharmaceutically acceptable salts thereof, for use in the treatment of cancer, either simultaneously, separately, or sequentially, in combination with one or more of the following: a PD-1 or PD-L1 inhibitor, a CDK4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, an SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof. Additional combinations are provided, for use simultaneously, separately, or sequentially in the treatment of cancer, comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and one or more of the following: PD-1 or PD-L1 inhibitors, CDK4 / CDK6 inhibitors, EGFR inhibitors, ERK inhibitors, Aurora A inhibitors, SHP2 inhibitors, platinum agents, and pemetrexed, or pharmaceutically acceptable salts thereof.

[0194] A method for treating cancer is also provided, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, and a PD-1 or PD-L1 inhibitor, wherein the cancer has one or more cells expressing a variant KRAS G12V protein. Further provided are compounds according to formula I, or pharmaceutically acceptable salts thereof, for use in combination with a PD-1 or PD-L1 inhibitor, simultaneously, separately, or sequentially, for use in the treatment of cancer. Additionally provided are combinations comprising a compound according to formula I, or a pharmaceutically acceptable salt thereof, and a PD-1 or PD-L1 inhibitor, for use simultaneously, separately, or sequentially in the treatment of cancer. As used herein, the PD-1 or PD-L1 inhibitor may be pembrolizumab, nivolumab, semiprimab, cintilimab, atezolizumab, avelumab, durvalumab, or rodapilimab.

[0195] A method for treating cancer is also provided, comprising administering to a patient in need of treatment an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a mutant KRAS G12V protein. Further provided are compounds according to Formula I, or pharmaceutically acceptable salts thereof, for use in combination with a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, to be used simultaneously, separately, or sequentially, for use in treating cancer having one or more cells expressing a mutant KRAS G12V protein. Additionally provided are combinations comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, for use simultaneously, separately, or sequentially, in the treatment of cancer having one or more cells expressing a mutant KRAS G12V protein. As used herein, the CDK4 / CDK6 inhibitor may be abemaciclib, palbociclib, or ribociclib.

[0196] A method for treating cancer is also provided, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a variant KRAS G12V protein. Further provided are compounds according to formula I, or pharmaceutically acceptable salts thereof, for use in combination with an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, simultaneously, separately, or sequentially, for the treatment of cancer. Additional combinations are provided, comprising a compound according to formula I, or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, for use simultaneously, separately, or sequentially, for the treatment of cancer. As used herein, the EGFR inhibitor may be erlotinib, the EGFR inhibitor may be afatinib, the EGFR inhibitor may be gefitinib, and the EGFR inhibitor may be cetuximab.

[0197] A method for treating cancer is also provided, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, and an ERK inhibitor, or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a mutant KRAS G12V protein. A method for treating cancer is also provided, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, wherein the cancer has one or more cells expressing a mutant KRAS G12V protein. Further provided are compounds according to formula I, or pharmaceutically acceptable salts thereof, for use in combination with, separately, or sequentially with an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer in which the cancer has one or more cells expressing a mutant KRAS G12V protein. Further provided are compounds conforming to Formula I, or pharmaceutically acceptable salts thereof, for use in combination with, separately, or sequentially with, an ERK inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer having one or more cells expressing a variant KRAS G12V protein. Additional combinations are provided, comprising a compound conforming to Formula I, or a pharmaceutically acceptable salt thereof, and an ERK inhibitor, or a pharmaceutically acceptable salt thereof, for use in combination with, separately, or sequentially with, an ERK inhibitor. As used herein, the ERK inhibitor may be LY3214996, the ERK inhibitor may be LTT462, or the ERK inhibitor may be KO-947.

[0198] A method for treating cancer is also provided, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, wherein the cancer has one or more cells expressing a mutant KRAS G12V protein. Further provided are compounds according to formula I, or pharmaceutically acceptable salts thereof, for use in combination with, separately, or sequentially with, an Aurora A inhibitor or a pharmaceutically acceptable salt thereof for the treatment of cancer having one or more cells expressing a mutant KRAS G12V protein. Additionally provided are combinations comprising a compound according to formula I, or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor for use in combination with, separately, or sequentially with, a cancer. As used herein, Aurora A inhibitors are aricertib, tozacertib, (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid, (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole- The salts may be (3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salts, and (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:amine (1:1) salts, or pharmaceutically acceptable salts thereof. In one embodiment, the Aurora A inhibitor is (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid.

[0199] A method for treating cancer is also provided, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, and an SHP2 inhibitor, wherein the cancer has one or more cells expressing a mutant KRAS G12V protein. Further provided are compounds according to formula I, or pharmaceutically acceptable salts thereof, for use in combination with, separately, or sequentially with, an SHP2 inhibitor or a pharmaceutically acceptable salt thereof for the treatment of cancer having one or more cells expressing a mutant KRAS G12V protein. Additional combinations are provided, comprising a compound according to formula I, or a pharmaceutically acceptable salt thereof, and an SHP2 inhibitor for use in combination with, separately, or sequentially with, an SHP2 inhibitor. As used herein, an SHP2 inhibitor or a pharmaceutically acceptable salt thereof may be a type I SHP2 inhibitor or a type II SHP2 inhibitor. Examples of type I SHP2 inhibitors include, but are not limited to, PHPS1, GS-493, NSC-87877, NSC-117199, and cefsulodine, as well as their pharmaceutically acceptable salts. Examples of type II SHP2 inhibitors include, but are not limited to, JAB-3068, JAB-3312, RMC-4550, RMC-4630, SHP099, SHP244, SHP389, SHP394, TNO155, RG-6433, and RLY-1971, as well as their pharmaceutically acceptable salts. Additional examples of SHP2 inhibitors include, but are not limited to, BBP-398, IACS-15509, IACS-13909, X37, ERAS-601, SH3809, HBI-2376, ETS-001, and PCC0208023, as well as their pharmaceutically acceptable salts. This method also includes treating cancers of other origins that have KRAS G12V mutant protein variants.

[0200] A method for treating cancer is also provided, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, and a platinum agent, wherein the cancer has one or more cells expressing a mutant KRAS G12V protein. Further provided are compounds according to formula I, or pharmaceutically acceptable salts thereof, for use in combination with a platinum agent, or a pharmaceutically acceptable salt thereof, simultaneously, separately, or sequentially, for the treatment of cancer having one or more cells expressing a mutant KRAS G12V protein. Additional combinations are provided, comprising a compound according to formula I, or a pharmaceutically acceptable salt thereof, and a platinum agent, for use simultaneously, separately, or sequentially, for the treatment of cancer. As used herein, the platinum agent may be cisplatin, carboplatin, or oxaliplatin.

[0201] A method for treating cancer is also provided, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, and pemetrexed, wherein the cancer has one or more cells expressing a mutant KRAS G12V protein. Further provided are compounds according to formula I, or pharmaceutically acceptable salts thereof, for use in combination with pemetrexed, separately, or sequentially, for the treatment of cancer having one or more cells expressing a mutant KRAS G12V protein. Additionally provided are combinations comprising a compound according to formula I, or a pharmaceutically acceptable salt thereof, and pemetrexed, for use in combination with pemetrexed, separately, or sequentially, for the treatment of cancer having one or more cells expressing a mutant KRAS G12V protein.

[0202] As described in paragraphs

[0101] to

[0115] above in this specification, cancer may be lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, colorectal cancer, gastric adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumor, bladder cancer, small intestinal adenocarcinoma, appendiceal cancer, or peritoneal cancer, in which the cancer has one or more cells expressing the KRAS G12V mutant protein, or cancer may be mutant lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, colorectal cancer, gastric adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumor, bladder cancer, small intestinal adenocarcinoma, appendiceal cancer, or peritoneal cancer, in which the cancer has one or more cells expressing the KRAS G12V mutant protein. These methods also include treating cancers of other origins that have the KRAS G12V mutant.

[0203] As used herein, the term “pharmaceutically acceptable salt” refers to a salt of a compound that is considered acceptable for clinical and / or veterinary use. Examples of pharmaceutically acceptable salts and general methodologies for preparing them can be found in “Handbook of Pharmaceutical Salts: Properties, Selection and Use” P. Stahl, et al., 2nd Revised Edition, Wiley-VCH, 2011 and SMBerge, et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 1977, 66(1), 1–19.

[0204] Pharmaceutical compositions containing the compound of Formula I described herein may be prepared using pharmaceutically acceptable additives. As used herein with respect to pharmaceutical compositions, the term “pharmaceutically acceptable additive” refers to one or more carriers, diluents, and excipients that are compatible with other additives in the composition or preparation and are not harmful to the patient. Examples of processes for pharmaceutical compositions and their preparations can be found in “Remington: The Science and Practice of Pharmacy,” Loyd, V., et al. Eds., 22. nd This can be found in Ed., Mack Publishing Co., 2012. Non-limiting examples of pharmaceutically acceptable carriers, diluents, and excipients include physiological saline, water, starch, sugar, mannitol, and silica derivatives; binders such as carboxymethylcellulose, alginates, gelatin, and polyvinylpyrrolidone; kaolin and bentonite; and polyethyl glycol.

[0205] As used herein, the term “effective dose” refers to the amount of medication that is effective in achieving a desired therapeutic outcome, such as the treatment of a disorder or disease, for example, a cancerous lesion or the progression of abnormal cell proliferation and / or cell division. Factors to be considered in determining the effective dose or dosage of a compound include: whether the compound or a salt thereof is administered; if used, concomitant administration of other drugs; the type of patient being treated; the patient’s size, age, sex, and overall health status; the degree or involvement or severity of the disorder; the individual patient’s response; the mode of administration; the bioavailability characteristics of the preparation being administered; the chosen administration regimen; and the use of other concomitant medications.

[0206] A treating physician, veterinarian, or other healthcare professional may determine an effective dose of the compound for the treatment of a patient requiring treatment. The pharmaceutical composition may be formulated as oral tablets or capsules, as an oral solution, or as an injectable solution. The tablets, capsules, or solution may contain an effective dose of the compound of the present invention for the treatment of a patient requiring treatment for cancer.

[0207] As used herein, the terms “to treat,” “to cure,” or “to treat” include slowing, managing, delaying, reducing, preventing, reversing, preventing, or improving the progression or severity of an existing symptom, disorder, or condition, which may include specifically slowing the growth of a cancerous lesion or the progression of abnormal cell proliferation and / or cell division. Treatment does not necessarily mean the complete disappearance of all symptoms of the disorder or disease.

[0208] As used herein, the term “patient” refers to a mammal in need of treatment. Specifically, a patient may be a human being in need of treatment for cancer, for example, cancer with a KRAS G12V mutant protein variant.

[0209] Certain abbreviations are defined as follows: "ACN" refers to acetonitrile, "AcOH" or "HOAc" refers to acetic acid, "aq." refers to aqueous solution, "conc." refers to concentrated solution, "DCM" refers to dichloromethane, "DIBAL-H" refers to diisobutylaluminum hydride, "DIEA" and "DIPEA" refer to N,N-diisopropylethylamine, "DMAP" refers to 4-dimethylaminopyridine, "DMEA" refers to N,N-dimethylethylamine, "DMF" refers to N,N-dimethylformamide, "DMSO" refers to dimethyl sulfoxide, and "ELISA" refers to enzyme-linked immunosorbent assay."ERK" refers to extracellular signal-regulated kinase, "Et" refers to an ethyl group, "RINKAN" refers to ethyl acetate, "Et2O" refers to diethyl ether, "EtOH" refers to ethanol, "FA" refers to formic acid, "FBS" refers to fetal bovine serum, "GDP" refers to guanosine diphosphate, "GTP" refers to guanosine triphosphate, "h" refers to time, "Hex" or "hex" refers to hexane or hexanes, "HPLC" refers to high-performance liquid chromatography, and "IPA" refers to isopropyl alcohol. "IPAm" refers to isopropylamine, "KOAc" refers to potassium acetate, "LC-ES / MS" refers to liquid chromatography-electrospray mass spectrometry, "LC / MS" refers to liquid chromatography-mass spectrometry, "LiHMDS" refers to lithium bis(trimethylsilyl)amide, "MAPK" refers to mitogen-activated protein kinase, "mCPBA" refers to 3-chloroperoxybenzoic acid, "Me" refers to a methyl group, "MeOH" refers to methanol, "min" refers to minutes, "MTBE" refers to methyl tert-butyl ether, "NMP" refers to 1-methylpyrrolidine-2-one, "Pd(OAc)2" refers to palladium(II) acetate, and "RT" refers to room temperature. "Sat." refers to temperature, "SCX" refers to strong cation exchange, "TBAF" refers to tetrabutylammonium fluoride, "tBu" refers to the tert-butyl group, "t-BuOH" refers to tert-butanol or tert-butyl alcohol, "TEA" refers to triethylamine, "TFA" refers to trifluoroacetic acid, "THF" refers to tetrahydrofuran, "XantPhos" refers to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and "XPhos" refers to 2-(dicyclohexylphosphino)-2',4',6'-tri-isopropyl-1,1'-biphenyl.

[0210] Individual isomers, enantiomers, diastereomers, and atropisomers can be separated or divided at any convenient point in the synthesis of the compounds listed below by selective crystallization techniques or chiral chromatography, etc. (see, for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions," John Wiley and Sons, Inc., 1981, and ELEliel and SHWilen, "Stereochemistry of Organic Compounds," Wiley-Interscience, 1994). The molecules described herein include compounds that are atropisomers and may exist in different conformations or as different rotational isomers. Atropisomers are compounds that exist in different conformations resulting from restricted rotation around a single bond. Atropisomers can be isolated as distinct chemical species if the energy barrier to rotation around the single bond is sufficiently high and the interconversion rate is sufficiently slow to separate the individual rotational isomers from each other. This specification is intended to include all isomers, enantiomers, diastereomers, and atropisomers that are possible with or can be produced using the compounds disclosed herein. In the molecules described herein, only those molecules for which the absolute conformation (or atropisomer conformation) of the chiral center is known use the nomenclature rules or chemical formulas depicted to indicate chirality or atropisomerism. Those skilled in the art will readily understand and identify when other chiral centers are present in the molecules described herein.

[0211] Any compound of formula I that can chemically form a salt can be readily converted to a pharmaceutically acceptable salt and isolated as such. Salt formation can occur upon addition of a pharmaceutically acceptable acid to form an acid addition salt. Salts can also be formed simultaneously upon deprotection of nitrogen or oxygen, i.e., upon removal of a protecting group. Examples of reactions and conditions for salt formation can be found in Gould, PL, "Salt selection for basic drugs," International Journal of Pharmaceutics, 33:201-217 (1986), Bastin, RJ, et al., "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4:427-435 (2000), and Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66:1-19 (1977).

[0212] The compounds of the present invention, or salts thereof, can be prepared by various procedures, some of which are described in the following schemes, preparations, and examples. The specific synthesis steps of each described pathway may be combined in different ways, or combined with steps from different pathways, to prepare the compounds of the present invention or salts thereof. The products of each step in the following preparations can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, grinding, and crystallization. [Examples]

[0213] Preparation 1 (4-bromo-5-fluorobenzo[d]thiazole-2-yl)carbamate tert-butyl

[0214] [ka]

[0215] 4-Brom-5-fluorobenzo[d]thiazole-2-amine (10.6 g, 42.9 mmol) and di-tert-butyl dicarbonate (10.3 g, 47.2 mmol) in DCM (100 mL) were mixed with 4-dimethylaminopyridine (0.262 g, 2.14 mmol). The mixture was stirred overnight at room temperature and then combined with diatomaceous earth. The crude material was purified with silica eluted with 0-100% siRNA in DCM to obtain the title compound (13.4 g, 90%) as an off-white solid. MS(ES)m / z=347(M-1).

[0216] The compounds listed in Table 1 below were prepared in the same manner as described in Preparation 1. A base such as triethylamine or diisopropylethylamine may be used. The compounds were purified using various methods that would be apparent to those skilled in the art.

[0217] Table 1: [Table 1]

[0218] Preparation 4 (2-((tert-butoxycarbonyl)amino)-5-fluorobenzo[d]thiazole-4-yl)boronic acid

[0219] [ka]

[0220] Sodium hydride (60% by weight in mineral oil, 1.73 g, 43.2 mmol) was mixed with THF (100 mL) under argon and cooled to 0°C. (4-bromo-5-fluorobenzo[d]thiazole-2-yl)carbamate tert-butyl (10.0 g, 28.8 mmol) was added to the mixture in THF (35 mL). The mixture was stirred at 0°C for 30 minutes and cooled to -78°C, and n-butyllithium (2.5 M in hexane, 17.3 mL, 43.2 mmol) was slowly added. The mixture was stirred at -78°C for 15 minutes, and then triisopropyl borate (19.9 mL, 86.4 mmol) was slowly added. The mixture was stirred at -78°C for 1 hour, at -40°C for 1 hour, and at -10°C for 45 minutes, and then slowly quenched with saturated ammonium chloride aqueous solution. The mixture was diluted with water (100 mL) and extracted with dimethyl (300 mL, 200 mL). The combined organic matter was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was diluted with hexane, stirred at 50°C for 30 minutes, cooled to room temperature, and filtered. The solid was washed with hexane and dried under vacuum to obtain the title compound (7.2 g, 80%) as a white solid. MS(ES)m / z=313(M+1).

[0221] Preparation 5 5-Fluorisobenzofuran-1(3H)-one

[0222] [ka]

[0223] (2-bromo-5-fluorophenyl)methanol (500 g, 2.44 mol) and TEA (474.6 mL, 3.41 mol, 1.4 equivalents) were stirred in ACN (2500 mL) to a mixture of these. Pd(OAc)2 (10.95 g, 48.77 mmol, 0.02 equivalents) and XantPhos (42.33 g, 73.16 mmol, 0.03 equivalents) were added at room temperature, and the mixture was stirred at 120 °C for 3 days under 10 atm carbon monoxide. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with H2O (1,000 mL) and then extracted with HCl (2 × 2000 mL). The combined organic layers were washed with brine (2 × 1,000 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was ground with 10:1 hexane / HCl (1,100 mL) and then filtered. The filtered cake was dried at 50°C for approximately 18 hours to obtain the title compound (300g, 81%) as a yellow solid. MS(ES)m / z=153(M+1).

[0224] Preparation 6 4-Bromo-5-fluoro-6-nitroisobenzofuran-1(3H)-one

[0225] [ka]

[0226] 5-Fluorisobenzofuran-1(3H)-one (300 g, 1.97 mol) was stirred in H2SO4 (1,500 mL) and HNO3 (273.38 g, 4.348 mol, 2.2 equivalents) was added dropwise at 65°C. The reaction mixture was stirred for 1 hour and then cooled to room temperature. 1,3-Dibromo-5,5-Dimethylimidazolidin-2,4-dione (2,255.43 g, 7.88 mol, 4 equivalents) was added in small amounts over 20 minutes and stirred at room temperature for approximately 18 hours. The mixture was poured into ice / water (pre-treated with 3 kg of Na2SO3) and filtered. The filtered cake was dissolved in ELISA (3,000 mL), washed with saturated Na2CO3 aqueous solution (2 × 1,000 mL) and brine (2 × 1,000 mL), dried over anhydrous Na2SO4, and concentrated. The residue was ground with 10:1 hexane / siRNA (660 mL), filtered, and dried at 50°C for approximately 18 hours to obtain the title compound (270 g, 49%) as a yellow solid, which was used in the next step without further purification. 1 H NMR (400MHz, DMSO-d6) δ8.58 (s, 1H), 5.51 (s, 2H).

[0227] Preparation 7 4-Bromo-5-fluoro-6-nitro-1,3-dihydroisobenzofuran

[0228] [ka]

[0229] To a stirred mixture of 4-bromo-5-fluoro-6-nitroisobenzofuran-1(3H)-one (270 g, 978 mmol) in DCM (2,500 mL), DIBAL-H (1 M THF solution, 1,467 mL, 1.467 mol, 1.5 equivalents) was added dropwise under N2 at -78°C. The reaction mixture was stirred at -78°C for 5 hours, and then quenched with 5N NaOH (300 mL) at -78°C. The resulting mixture was warmed to room temperature and then concentrated. The residue was diluted with HCl (2,500 mL), washed with brine (2 × 1,000 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was ground with 10:1 hexane / HCl (550 mL) and filtered. The solid was dried (190 g, 683.4 mmol), then dissolved in DCM (1,500 mL), and treated with droplets of Et3SiH (662 mL, 4.10 mol, 6 equivalents) at 0°C. The reaction mixture was stirred at 0°C for 20 minutes. TFA (152 mL, 2.05 mol, 3 equivalents) was added dropwise at 0°C. The ice bath was removed, and the reaction mixture was stirred at room temperature for approximately 18 hours. The reaction mixture was concentrated to an oily substance, diluted with ELISA (2,000 mL), washed with saturated Na2CO3 aqueous solution (2 × 500 mL) and brine (2 × 500 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the title compound (110 g, 42%), which was used in the next step without further purification. 1 H NMR (400MHz, DMSO-d6) δ8.16 (d, J = 6.2 Hz, 1H), 5.18-5.15 (m, 2H), 5.11-5.06 (m, 2H).

[0230] Preparation 8 7-Bromo-6-fluoro-1,3-dihydroisobenzofuran-5-amine

[0231] [ka]

[0232] 4-Bromo-5-fluoro-6-nitro-1,3-dihydroisobenzofuran (110 g, 420 mmol) and NH4Cl (112.3 g, 2.10 mol, 5 equivalents) were stirred in EtOH (1,000 mL) and H2O (200 mL). Fe (117.22 g, 2.09 mol, 5 equivalents) was added in small amounts at room temperature, and the mixture was stirred at 80°C for approximately 18 hours. The mixture was filtered and concentrated. The mixture was diluted with H2O (500 mL) and extracted with siRNA (2 × 1,000 mL). The combined organic layers were washed with brine (2 × 500 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified with silica (25%~50% siRNA / hexane) to obtain the title compound (70 g, 72%) as a yellow solid. MS(ES)m / z=231(M+1).

[0233] Preparation 9 (4-Chloro-1,2-phenylene)dimethanol

[0234] [ka]

[0235] To a stirred mixture of LiAlH4 (1.9 L, 2.74 mol, 2 equivalents, 2.5 M THF solution) in THF (1 L), a solution of 4-chlorophthalic anhydride (250 g, 1.34 mol, 1.00 equivalent) in THF (500 mL) was added dropwise under N2 at -20°C. The resulting mixture was stirred under N2 at 45°C for 30 minutes. The reaction was quenched by adding H2O (1.5 L) and 15% NaOH (500 mL) at room temperature. The mixture was filtered, and the filtered cake was washed with MTBE (3 × 250 mL). The filtrate was extracted with MTBE (3 × 1.5 L). The combined organic layers were washed with brine (2 × 2 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (219.5 g, 93%) as an off-white solid. 1 H NMR (300MHz, DMSO-d6) δ7.45-7.36(m,2H),7.28(dd,J=8.2Hz,1H),5.40-5.13(m,2H),4.54(s,2H),4.49(s,2H).

[0236] Preparation 10 5-Chloro-1,3-dihydroisobenzofuran

[0237] [ka]

[0238] (4-chloro-1,2-phenylene)dimethanol (219.5 g, 1.271 mol) and dimethyl carbonate (458.2 g, 5.082 mol, 4 equivalents) were stirred in ACN (3 L) to a mixture of these, to which NaOMe (137.4 g, 2.544 mol, 2 equivalents) was added in small amounts at room temperature. The resulting mixture was stirred at 80°C under N2 for approximately 18 hours. The mixture was concentrated under reduced pressure, diluted with H2O (2 L), and extracted with SiO2 (3 × 2 L). The combined organic layers were washed with brine (2 × 2 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified with silica (hexane / SiO2 in a 10:1-8:1 ratio) to obtain the title compound (165 g, 82%) as a light brown solid. 1 H NMR (300MHz, DMSO-d6) δ7.42-7.37 (m, 1H), 7.33 (d, J = 1.4Hz, 2H), 4.99 (s, 4H).

[0239] Preparation 11 5-Chloro-6-nitro-1,3-dihydroisobenzofuran

[0240] [ka]

[0241] A solution of 5-chloro-1,3-dihydroisobenzofuran (110 g, 712 mmol) in H2SO4 (700 mL) was dropwise packed at -5°C to 0°C with a solution of KNO3 (64.74 g, 640 mmol, 0.9 equivalents) in H2SO4 (200 mL) at -5°C to 0°C. The resulting mixture was stirred at 0°C for a further 30 minutes, and then slowly added to stirred ice-cold H2O. The precipitated solid was collected by filtration and washed with H2O (3 × 1 L). The filtration cake was dried in vacuum to obtain the title compound (110 g, 77%) as a light brown solid, which was used in the next step without further purification. 1 H NMR (400MHz, DMSO-d6) δ 8.05 (s, 1H), 7.75 (s, 1H), 5.07-5.02 (m, 4H).

[0242] Preparation 12 4-Bromo-5-chloro-6-nitro-1,3-dihydroisobenzofuran

[0243] [ka]

[0244] 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (179.1 g, 626.3 mmol, 1 equivalent) was added in small amounts at -10°C to a stirred solution of 5-chloro-6-nitro-1,3-dihydroisobenzofuran (125 g, 626 mmol) in H2SO4 (700 mL). The mixture was stirred at -10°C for 1 hour, and then slowly added to stirred ice-cold H2O. The precipitated solid was collected by filtration and washed with H2O (3 × 0.5 L). The filtration cake was dried in vacuum and purified with silica (hexane / siRNA in a 10:1-5:1 ratio) to obtain the title compound (83.5 g, 47.9%) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ8.07 (d, J = 1.1 Hz, 1H), 5.19 (dt, J = 2.3, 1.1 Hz, 2H), 5.08 (t, 2H).

[0245] Preparation 13 7-Bromo-6-chloro-1,3-dihydroisobenzofuran-5-amine

[0246] [ka]

[0247] 4-Bromo-5-chloro-6-nitro-1,3-dihydroisobenzofuran (37.0 g, 133 mmol) and NH4Cl (42.64 g, 797.2 mmol, 6 equivalents) were stirred in EtOH (200 mL) and H2O (40 mL). Fe (44.52 g, 797.2 mmol, 6 equivalents) was added in small amounts at room temperature. The resulting mixture was stirred at 80°C for approximately 18 hours. The resulting mixture was filtered while still hot, and the filter cake was washed with siRNA (3 × 500 mL). The filtrate was concentrated under reduced pressure and purified with silica (hexane / siRNA in a 15:1-10:1 ratio) to obtain the title compound (25 g, 76%) as a pale yellow solid. MS(ES)m / z = 248 (M+1).

[0248] Preparation 14 N-[(7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)carbamate ethyl]carbamate

[0249] [ka]

[0250] To a solution of 7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-amine (20.4 g, 87.9 mmol) in DCM (550 mL), ethoxycarbonyl isothiocyanate (9.7 mL, 82 mmol, 0.93 equivalents) was slowly packed using an additive funnel, and the mixture was stirred at room temperature for approximately 4 hours. The solid was filtered. The filtrate was concentrated and suspended in DCM (100 mL) and hexane (350 mL), and stirred at room temperature. The resulting filtered solid and the previously filtered solid were dried under vacuum at 50°C for 2 hours. The batches were combined to obtain the title compound (32.6 g, quantitatively) as a white solid. MS(ES)m / z=363(M+1).

[0251] Preparation 15 N-[(7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)carbamate ethyl]carbamate

[0252] [ka]

[0253] 7-Bromo-6-chloro-1,3-dihydroisobenzofuran-5-amine was used in a manner similar to that of Preparation 14 to obtain the title compound (14 g, 92%) as a white solid. MS(ES)m / z=379(M+1).

[0254] Preparation 16 (((7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate ethyl

[0255] [ka]

[0256] A 2 L three-necked RBF equipped with an overhead stirrer, dropping funnel, and thermocouple was filled with a suspension of N-[(7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)carbamate ethyl (32.6 g, 89.8 mmol) in acetone (450 mL). Solid K2CO3 (37.2 g, 269 mmol, 3.00 equivalent) was added in several portions, followed by the dropwise addition of EtI (7.2 mL, 90 mmol, 1.0 equivalent) over 20 minutes. The mixture was stirred at room temperature for approximately 18 hours. The solid was filtered, the filtrate was concentrated, and partitioned between DCM (500 mL) and H2O (500 mL). The organic layer was further washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified with silica (0-30% toluene / hexane) to obtain the title compound (30.9 g, 85.6%) as a white solid. MS(ES)m / z=391(M+1).

[0257] Preparation 17 (((7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate ethyl

[0258] [ka]

[0259] Ethyl N-[(7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)carbamate]carbamate was used in a manner similar to that of Preparation 16 to obtain the title compound (15.4 g, crude) as a brown solid. MS(ES)m / z=407(M+1).

[0260] Preparation 18 6-Bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofl[3,4-f]quinazolin-1-ol

[0261] [ka]

[0262] A 2 L four-necked RBF was equipped with an overhead stirrer, dropping funnel, N2 inlet, and thermocouple, and purged with N2. 300 mL of anhydrous NMP was added. The mixture was heated to 175°C. In a second flask, 22.63 g, 57.83 mmol of (((7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate ethyl (NMP) and 100 mL of anhydrous NMP were combined and stirred under N2 until a homogeneous solution was obtained. When the first flask reached 175°C, the contents of the second flask were poured into the dropping funnel and rapidly added dropwise to the hot NMP. After 30 minutes, the heat was turned off and the reaction mixture was cooled to 45°C. 500 mL of H2O was slowly added, and the mixture was stirred at room temperature for 1 hour. The solid was filtered, rinsed with H2O (300 mL), and dried under vacuum at 50°C for approximately 18 hours to obtain the title compound (15.2 g, 73%) as an off-white solid. MS(ES)m / z=363(M+1).

[0263] Preparation 19 6-Bromo-5-chloro-3-(ethylthio)-7,9-dihydrofl[3,4-f]quinazolin-1-ol

[0264] [ka]

[0265] Ethyl (((7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate was used in a manner similar to that of Preparation 18 to obtain the title compound (11.4 g, 86%) as a white solid. MS(ES)m / z=361(M+1).

[0266] Preparation 20 6-Bromo-3-(ethylthio)-5-fluoro-1-((2-(trimethylsilyl)ethoxy)methoxy)-7,9-dihydrofl[3,4-f]quinazoline

[0267] [ka]

[0268] A mixture of 6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofluoro[3,4-f]quinazolin-1-ol (30.1 g, 87.3 mmol) in DMF was heated to approximately 70°C to dissolve the solid, and then cooled to 40°C. Diisopropylethylamine (30.4 mL, 175 mmol) and 2-(chloromethoxyethyl)trimethylsilane (23.2 mL, 131 mmol) were added to this mixture. The reaction mixture was stirred at 40°C for 1 hour, then cooled to room temperature and diluted with water (1 L) and ethylethanol (500 mL). The layers were separated, the organic layer was washed with brine (2 × 500 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude title compound (49.2 g, 85% purity) as a yellow oil. MS(ES)m / z=475(M+1).

[0269] Preparation 1A 6-Bromo-3-(ethylthio)-5-fluoro-2-((2-(trimethylsilyl)ethoxy)methyl)-7,9-dihydroflou[3,4-f]quinazoline-1(2H)-one

[0270] [ka]

[0271] The title compound was obtained by using 6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofluoro[3,4-f]quinazolin-1-ol and 2-(chloromethoxyethyl)trimethylsilane in a manner similar to that of Preparation 20. MS(ES)m / z=475(M+1).

[0272] Preparation 21 6-Bromo-5-chloro-3-(ethylthio)-1-((2-(trimethylsilyl)ethoxy)methoxy)-7,9-dihydrofl[3,4-f]quinazoline

[0273] [ka]

[0274] Using 6-bromo-5-chloro-3-(ethylthio)-7,9-dihydrofl[3,4-f]quinazolin-1-ol in a manner similar to that of Preparation 20, the title compound (10.5 g, 96%) was obtained as a pink solid. MS(ES)m / z=491(M+1).

[0275] Preparation 2A 6-Bromo-5-chloro-3-(ethylthio)-2-((2-(trimethylsilyl)ethoxy)methyl)-7,9-dihydroflou[3,4-f]quinazoline-1(2H)-one

[0276] [ka]

[0277] The title compound was obtained by using 6-bromo-5-chloro-3-(ethylthio)-7,9-dihydrofl[3,4-f]quinazolin-1-ol in a manner similar to that of Preparation 20. MS(ES)m / z=491(M+1).

[0278] Preparation 22 6-Bromo-1-chloro-3-(ethylthio)-5-fluoro-7,9-dihydrofl[3,4-f]quinazoline

[0279] [ka]

[0280] A 5 L three-necked RBF equipped with a dropping funnel, thermocouple, and overhead stirrer was filled with a 1,000 mL solution of DCM (50 mL, 646 mmol, 4 equivalents) of DMF (100 mL) and placed in an ice / water bath to cool to approximately 4°C. Oxalyl chloride (50.0 mL, 576 mmol, 4 equivalents) was added dropwise using an addition funnel over approximately 40 minutes. After the addition was complete, the reaction mixture was stirred at approximately 4°C for 15 minutes. Solid 6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofluoro[3,4-f]quinazolin-1-ol (50.4 g, 140 mmol) was added to the reaction mixture in several portions, and the resulting suspension was stirred at approximately 4°C for 30 minutes. The ice bath was removed, and the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. Then, H2O (1 L) was added, and the mixture was stirred for 15 minutes. The mixture was partitioned, the organic layer was washed with brine (1 L), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified with silica eluted with DCM / hexane (60%-90%) to obtain the title compound (45.1 g, 89%) as a white solid. MS(ES)m / z=363(M+1).

[0281] Preparation 23 6-Bromo-1,5-dichloro-3-(ethylthio)-7,9-dihydrofl[3,4-f]quinazoline

[0282] [ka]

[0283] 6-Bromo-5-chloro-3-(ethylthio)-7,9-dihydrofl[3,4-f]quinazolin-1-ol was used in a manner similar to that of Preparation 22 to obtain the title compound (0.81 g, 77%) as a yellow solid. MS(ES)m / z=382(M+1).

[0284] Preparation 24 (4-(5-chloro-3-(ethylthio)-1-((2-(trimethylsilyl)ethoxy)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[d]thiazole-2-yl) tert-butyl carbamate

[0285] [ka]

[0286] 6-bromo-5-chloro-3-(ethylthio)-1-((2-(trimethylsilyl)ethoxy)methoxy)-7,9-dihydrofluoro[3,4-f]quinazoline (2.00 g, 4.07 mmol), (2-tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazole-4-yl)boronic acid (1.52 g, 4.88 mmol), triphosphate in 1,4-dioxane (10 mL) and water (0.4 mL). A mixture of phosphate (2.59 g, 12.2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.298 g, 0.41 mmol) was stirred at 90°C for 16 hours and then concentrated under reduced pressure. The residue was purified with silica eluted with 0-100% ethyl acetate in heptane to obtain the title compound (1.90 g, 69%) as a yellow solid. MS(ES)m / z=679(M+1).

[0287] Preparation 3A (4-(5-chloro-3-(ethylthio)-1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2,7,9-tetrahydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[d]thiazole-2-yl) tert-butyl carbamate

[0288] [ka]

[0289] The title compound was obtained by using 6-bromo-5-chloro-3-(ethylthio)-2-((2-(trimethylsilyl)ethoxy)methyl)-7,9-dihydroflou[3,4-f]quinazolin-1(2H)-one in a manner similar to that of Preparation 24. MS(ES)m / z=679(M+1).

[0290] Preparation 25 (4-(5-chloro-3-(ethylthio)-1-hydroxy-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[d]thiazole-2-yl) tert-butyl carbamate

[0291] [ka]

[0292] (4-(5-chloro-3-(ethylthio)-1-((2-(trimethylsilyl)ethoxy)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[d]thiazole-2-yl)carbamate tert-butyl (1.90 g, 2.80 mmol) and DMF (10 mL) were mixed with cesium fluoride (2.97 g, 19.6 mmol). The mixture was stirred at 120 °C for 24 hours, then cooled to room temperature and diluted with water (50 mL). The resulting solid was filtered and dried to obtain the title compound as a yellow solid (1.28 g, 83%). MS(ES)m / z=549(M+1).

[0293] Alternative preparation 25 (4-(5-chloro-3-(ethylthio)-1-hydroxy-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[d]thiazole-2-yl) tert-butyl carbamate

[0294] [ka]

[0295] The title compound was obtained from (4-(5-chloro-3-(ethylthio)-1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2,7,9-tetrahydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[d]thiazole-2-yl)carbamate tert-butyl using a method similar to that of Preparation 25. MS(ES)m / z=549(M+1).

[0296] Preparation 26 (4-(1,5-dichloro-3-(ethylthio)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[d]thiazole-2-yl) tert-butyl carbamate

[0297] [ka]

[0298] To a solution of (4-(5-chloro-3-(ethylthio)-1-hydroxy-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[d]thiazole-2-yl)carbamate tert-butyl (0.219 g, 0.40 mmol) in DCM (3 mL), chloromethylene(dimethyl)ammonium chloride (0.061 g, 0.48 mmol) was gradually added. The mixture was stirred at room temperature for 2 hours, diluted with water (100 mL), and extracted with DCM (200 mL). The organic matter was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (0.23 g, crude) as a yellow solid. MS(ES)m / z=567(M+1).

[0299] Preparation 27 (2S,3S)-3-(isopropylamino)-2-methylpyrrolidine-1-carboxylate tert-butyl

[0300] [ka]

[0301] (2S,3S)-3-amino-2-methylpyrrolidine-1-carboxylate tert-butyl (0.500 g, 2.50 mmol), acetone (0.275 mL, 3.74 mmol), and sodium triacetoxyborohydride (1.59 g, 7.49 mmol) were dissolved in methanol (6 mL). The mixture was heated to 50°C. After 18 hours, the mixture was cooled, concentrated under reduced pressure, and diluted with saturated sodium bicarbonate aqueous solution (20 mL). The mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure to obtain the crude title compound (0.600 g) as a colorless oil. MS(ES)m / z=243(M+1).

[0302] The compounds listed in Table 2 below were prepared in the same manner as described in Preparation 27. Different reductive amination conditions, such as sodium borohydride and sodium dihydrogen phosphate, may be substituted. The compounds were purified using various methods that would be apparent to those skilled in the art.

[0303] Table 2: [Table 2] 1 The product generated during the stepwise preparation of preparation 7A, used in situ.

[0304] Preparation 8A (2S,3S)-3-(ethyl(methyl)amino)-2-methylpyrrolidine-1-carboxylate tert-butyl

[0305] [ka]

[0306] (S)-2-methyl-3-oxopyrrolidine-1-carboxylate tert-butyl (1.00 g, 5.02 mmol), acetic acid (0.287 mL, 5.02 mmol), and N-methylethaneamine (0.445 g, 7.53 mmol) were dissolved in 5 mL of DCM, to which sodium triacetoxyborohydride (1.70 g, 8.03 mmol) was gradually added. The mixture was stirred at room temperature. After 22 hours, the mixture was cooled to 0°C and quenched with aqueous sodium bicarbonate solution. The two layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase purification (C18 column) eluting with 0-100% acetonitrile in (0.1% formic acid in water) to obtain the title compound (1.32 g) as a colorless oil. MS(ES)m / z = 243(M+1).

[0307] Preparation 9A (2S)-3-(azetidine-1-yl)-2-methylpyrrolidine-1-carboxylate tert-butyl

[0308] [ka]

[0309] Azetidine was used in a manner similar to that of preparation 8A to obtain the title compound (0.59 g, 85%) as a yellow oily substance. MS(ES)m / z=241(M+1).

[0310] Preparation 10A (2'S,3'S)-2'-methyl-[1,3'-bipyrrolidine]-1'-carboxylate tert-butyl

[0311] [ka]

[0312] Pyrrolidine was used in a manner similar to that of preparation 8A to obtain the title compound (0.53 g, 78%) as a yellow oily substance. MS(ES)m / z=255(M+1).

[0313] Preparation 33 (2S,3S)-N-isopropyl-2-methylpyrrolidine-3-amine dihydrochloride

[0314] [ka]

[0315] A mixture of (2S,3S)-3-(isopropylamino)-2-methylpyrrolidine-1-carboxylate tert-butyl (0.600 g, 2.48 mmol) in DCM (3 mL) was mixed with HCl (4 M in 1,4-dioxane, 3 mL). The mixture was stirred at room temperature. After 6 hours, the mixture was concentrated under reduced pressure to obtain the crude title compound (0.533 g) as a yellow solid. MS(ES)m / z=143(M+1).

[0316] The compounds listed in Table 3 below were prepared in the same manner as described in Preparation 33. Different acidic conditions, such as trifluoroacetic acid, may be substituted. The compounds were purified using various methods that would be apparent to those skilled in the art.

[0317] Table 3: [Table 3]

[0318] Preparation 39 (6S)-3-amino-1,6-dimethylpiperidine-2-one

[0319] [ka]

[0320] (S)-1,6-dimethylpiperidine-2-one. Sodium hydride (60% by weight in mineral oil, 0.212 g, 5.30 mmol) was added to a solution of (S)-6-methylpiperidine-2-one (0.500 g, 4.42 mmol) in THF (5 mL). The mixture was stirred at room temperature for 30 minutes, then cooled to 0°C. A solution of iodomethane (0.41 mL, 6.63 mmol) in THF (0.3 mL) was added dropwise, and the mixture was stirred at 0°C for 5 minutes, then warmed to room temperature and stirred overnight. The mixture was diluted with water (5 mL) and extracted with siRNA and DCM. The combined organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude (S)-1,6-dimethylpiperidine-2-one as a white solid. MS(ES)m / z=128(M+1).

[0321] (6S)-3-chloro-1,6-dimethylpiperidine-2-one. A solution of (S)-1,6-dimethylpiperidine-2-one (0.600 g, 4.72 mmol) in THF (2 mL) was cooled to -78°C. Lithium diisopropylamide (2.0 M, 3.07 mL, 6.13 mmol) in THF / heptane / ethylbenzene was added. The mixture was stirred at -78°C for 20 minutes, and then a solution of tosyl chloride (2.70 g, 14.2 mmol) in THF (0.5 mL) was slowly added. The mixture was stirred at -78°C for 90 minutes. The mixture was diluted with water and extracted with DCM. The organic matter was dried over anhydrous Na2SO4 and purified with silica eluted with 0-40% MeOH in DCM to obtain crude (6S)-3-chloro-1,6-dimethylpiperidine-2-one as a brown oil. MS(ES)m / z = 162(M+1).

[0322] (6S)-3-amino-1,6-dimethylpiperidine-2-one. A solution of (6S)-3-chloro-1,6-dimethylpiperidine-2-one (0.250 g, 1.55 mmol) in acetonitrile (5 mL) and ammonium hydroxide (5 mL) was heated at 80°C for 22 hours under microwave irradiation. The mixture was concentrated under reduced pressure to obtain the title compound (0.220 g, crude) as a brown oily substance. MS(ES)m / z=143(M+1).

[0323] Preparation 40 (6R)-3-amino-1,6-dimethylpiperidine-2-one

[0324] [ka]

[0325] (R)-6-methylpiperidine-2-one was used in a manner similar to that of Preparation 39 to obtain the title compound (0.220 g, crude) as a brown oily substance. MS(ES)m / z=143(M+1).

[0326] Preparation 41 (R)-3-((6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofl[3,4-f]quinazolin-1-yl)amino)-1-methylpiperidine-2-one

[0327] [ka]

[0328] Triethylamine (28.3 mL, 202 mmol) was added to a mixture of 6-bromo-1-chloro-3-(ethylthio)-5-fluoro-7,9-dihydrofl[3,4-f]quinazoline (10.5 g, 28.9 mmol) and (R)-3-amino-1-methylpiperidine-2-one hydrochloride (4.75 g, 28.9 mmol) in acetonitrile (100 mL). The mixture was stirred at room temperature. After 2 hours, the mixture was diluted with water (600 mL) and filtered. The solid was washed with acetonitrile (2 × 80 mL) and dried under vacuum to obtain the title compound (9.04 g, 69%) as a white solid. MS(ES)m / z=457(M+1).

[0329] The compounds listed in Table 4 below were prepared in the same manner as described in Preparation 41. The compounds were purified using various methods that would be obvious to those skilled in the art.

[0330] Table 4: [Table 4-1]

[0331] (Continued from Table 4) [Table 4-2]

[0332] Preparation 46 (4-(5-chloro-3-(ethylthio)-1-(((R)-1-methyl-2-oxopiperidine-3-yl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-5,7-difluorobenzo[d]thiazole-2-yl) tert-butyl carbamate

[0333] [ka]

[0334] A solution of (R)-3-((6-bromo-5-chloro-3-(ethylthio)-7,9-dihydrofluoro[3,4-f]quinazolin-1-yl)amino)-1-methylpiperidine-2-one (4.80 g, 10.2 mmol) and (2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazole-4-yl)boronic acid (2.69 g, 8.14 mmol) in 1,4-dioxane (400 mL) and water (80 mL) is prepared by adding dipotassium phosphate (5.32 g, 30.5 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.97 g, 2.04 mmol), and XPhos Pd(clotyl)Cl(CAS (1798782-02-1, 1.37 g, 2.04 mmol) was added gradually under nitrogen. The mixture was stirred at 80°C for 1 hour, and then concentrated under reduced pressure. The residue was diluted with water (250 mL) and extracted with pharmaceutically acceptable ammonium compounds (400 mL). The organic matter was washed with brine (2 × 250 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The crude substance was purified with silica eluted with 50-67% pharmaceutically acceptable ammonium compounds in petroleum ether to obtain the title compound (2.3 g, 33%) as a yellow solid. MS(ES)m / z=677(M+1).

[0335] The compounds listed in Table 5 below were prepared in a manner similar to that described in Preparation 24 or 46. Different coupling conditions, such as bases, ligands, or palladium sources, may be substituted. The compounds were purified using various methods that would be apparent to those skilled in the art.

[0336] Table 5: [Table 5]

[0337] Preparation 51 (4-(5-chloro-3-(ethylthio)-1-(((R)-1-methyl-2-oxopiperidine-3-yl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorothiazolo[4,5-c]pyridine-2-yl) tert-butyl carbamate

[0338] [ka]

[0339] (R)-3-((5-chloro-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(ethylthio)-7,9-dihydrofl[3,4-f]quinazolin-1-yl)amino)-1-methylpiperidine-2-one. A mixture of (R)-3-((6-bromo-5-chloro-3-(ethylthio)-7,9-dihydrofl[3,4-f]quinazolin-1-yl)amino)-1-methylpiperidine-2-one (92% purity, 14.95 g, 29.15 mmol), 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (13.17 g, 58.30 mmol), potassium acetate (8.58 g, 87.46 mmol), and Pd-117 (CAS 205319-06-8, 1.25 g, 1.75 mmol) in 1,4-dioxane (150 mL) was degassed for 10 minutes (direct nitrogen sparging). The mixture was stirred at 90°C for 4 hours, then cooled and diluted with water (250 mL) and 2-methyltetrahydrofuran (150 mL). The layers were separated. The organic matter was washed with brine (150 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude substance was purified with silica eluted with 0-8% MeOH in DCM to obtain (R)-3-((5-chloro-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(ethylthio)-7,9-dihydrofl[3,4-f]quinazolin-1-yl)amino)-1-methylpiperidine-2-one (86% purity, 14.2 g, 83%) as a yellow solid. MS (ES) m / z = 437 (M+1, boronic acid).

[0340] (4-(5-chloro-3-(ethylthio)-1-(((R)-1-methyl-2-oxopiperidine-3-yl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorothiazolo[4,5-c]pyridine-2-yl)carbamate tert-butyl. A mixture of tert-butyl (4-chloro-7-fluorothiazolo[4,5-c]pyridine-2-yl)carbamate (4.00 g, 12.9 mmol), dipotassium phosphate (6.74 g, 38.7 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.62 g, 1.29 mmol), and XPhos Pd(clotyl)Cl (CAS 1798782-02-1, 1.04 g, 1.55 mmol) in water (38.7 mL) was degassed for 5 minutes (direct nitrogen sparging). The mixture was stirred at 85°C, and (R)-3-((5-chloro-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(ethylthio)-7,9-dihydrofl[3,4-f]quinazolin-1-yl)amino)-1-methylpiperidine-2-one (81% by weight, 11.3 g, 18.1 mmol) was added in four portions every 8 minutes. The mixture was stirred at 85°C for 2.5 hours, and then XPhos Pd(clotyl)Cl (CAS 1798782-02-1, 0.35 g, 0.52 mmol) was added. After 3 hours, the mixture was cooled and poured into water (600 mL). The mixture was filtered, the solid was washed with water (2 × 50 mL) and dried under vacuum. The solid was purified with silica, eluted with 30-100% siRNA in cyclohexane. The clean fractions were combined and partially concentrated under reduced pressure. The resulting solid was filtered to obtain the title compound (3.59 g, 42%). MS(ES)m / z=660(M+1).

[0341] Preparation 52 (4-(5-chloro-3-(ethylsulfonyl)-1-(((R)-1-methyl-2-oxopiperidine-3-yl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-5,7-difluorobenzo[d]thiazole-2-yl) tert-butyl carbamate

[0342] [ka]

[0343] (4-(5-chloro-3-(ethylthio)-1-(((R)-1-methyl-2-oxopiperidine-3-yl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-5,7-difluorobenzo[d]thiazole-2-yl)carbamate tert-butyl (2.3 g, 3.4 mmol) was dissolved in THF (100 mL) and mCPBA (2.07 g, 10.2 mmol) was gradually added at 0°C. The mixture was stirred under nitrogen at room temperature for 2 hours and then cooled to 0°C. The mixture was diluted with ice water (30 mL) and saturated sodium sulfite aqueous solution (200 mL), and then extracted with ELISA (300 mL). The organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (2.3 g) as a yellow solid. MS(ES)m / z = 709(M+1).

[0344] The compounds listed in Table 6 below were prepared in the same manner as described in Preparation 52. The compounds were purified using various methods that would be obvious to those skilled in the art.

[0345] Table 6: [Table 6-1]

[0346] (Continued from Table 6) [Table 6-2]

[0347] (Continued from Table 6) [Table 6-3]

[0348] Preparation 61 (4-(5-chloro-3-((2S,3S)-3-(isopropyl(methyl)amino)-2-methylpyrrolidine-1-yl)-1-(((R)-1-methyl-2-oxopiperidine-3-yl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-5,7-difluorobenzo[d]thiazole-2-yl) tert-butyl carbamate

[0349] [ka]

[0350] To a solution of (4-(5-chloro-3-(ethylsulfonyl)-1-(((R)-1-methyl-2-oxopiperidine-3-yl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-5,7-difluorobenzo[d]thiazole-2-yl)carbamate tert-butyl (0.400 g, 0.564 mmol) and (2S,3S)-N-isopropyl-N,2-dimethylpyrrolidine-3-amine (1.32 g, 8.46 mmol), triethylamine (2.85 g, 28.2 mmol) was added dropwise under nitrogen at room temperature. The mixture was stirred at 80°C for 30 hours, then diluted with water (150 mL) and extracted with ELISA (200 mL). The organic matter was washed with brine (150 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude substance was purified with silica eluted at 15-25% DCM (30% MeOH in GaN) to obtain the title compound (0.32 g, 74%) as a yellow solid. MS(ES)m / z=771(M+1).

[0351] The compounds listed in Table 7 below were prepared in the same manner as described in Preparation 61. Different bases, such as sodium hydride, may be used. The compounds were purified using various methods that would be apparent to those skilled in the art.

[0352] Table 7: [Table 7-1]

[0353] (Continued from Table 7) [Table 7-2]

[0354] (Continued from Table 7) [Table 7-3]

[0355] (Continued from Table 7) [Table 7-4]

[0356] (Continued from Table 7) [Table 7-5]

[0357] (Continued from Table 7) [Table 7-6]

[0358] (Continued from Table 7) [Table 7-7]

[0359] (Continued from Table 7) [Table 7-8] 1 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-100% ethanol in heptane, 42.5 mL / min

[0360] The compounds listed in Table 8 below were prepared in a manner similar to that described in Preparation 24 or 46. Different coupling conditions, such as bases, ligands, or palladium sources, may be substituted. The compounds were purified using various methods that would be apparent to those skilled in the art.

[0361] Table 8: [Table 8-1]

[0362] (Continued from Table 8) [Table 8-2]

[0363] The compounds listed in Table 9 below were prepared in a manner similar to that described in Preparation 51. Different coupling conditions, such as bases, ligands, or palladium sources, may be substituted. The compounds were purified using various methods that would be apparent to those skilled in the art.

[0364] Table 9: [Table 9-1]

[0365] (Continued from Table 9) [Table 9-2] 1 Pure isomers at the 3-position of piperidinone from preparation 31A, and chiral purification.

[0366] Example 1 (3R)-3-((6-(2-amino-7-fluorobenzo[d]thiazole-4-yl)-3-((2S,3S)-3-(dimethylamino)-2-methylpyrrolidine-1-yl)-5-fluoro-7,9-dihydrofluoro[3,4-f]quinazolin-1-yl)amino)-1-methylpiperidine-2-one

[0367] [ka]

[0368] (4-(3-((2S,3S)-3-(dimethylamino)-2-methylpyrrolidine-1-yl)-5-fluoro-1-(((R)-1-methyl-2-oxopiperidine-3-yl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[d]thiazole-2-yl)carbamate tert-butyl (0.040 g, 0.056 mmol) was added to a mixture of chloroform (0.5 mL) and trifluoroacetic acid (0.5 mL). The mixture was stirred at room temperature. After 1 hour, the mixture was purified by reverse-phase purification by elution with 10-100% acetonitrile in (10 mM aqueous solution of ammonium bicarbonate in a 95:5 ratio:methanol) to obtain the title compound (0.036 g, 100%). MS(ES)m / z=609(M+1).

[0369] The compounds listed in Table 10 below were prepared in the same manner as described in Example 1. Different neutral or acidic conditions, such as HCl in hexafluoroisopropanol or 1,4-dioxane, may be substituted. The compounds were purified using various methods that would be apparent to those skilled in the art. Methods for isomer separation can be found in footnotes.

[0370] Table 10: [Table 10-1]

[0371] (Continued from Table 10) [Table 10-2]

[0372] (Continued from Table 10) [Table 10-3]

[0373] (Continued from Table 10) [Table 10-4]

[0374] (Continued from Table 10) [Table 10-5]

[0375] (Continued from Table 10) [Table 10-6]

[0376] (Continued from Table 10) [Table 10-7]

[0377] (Continued from Table 10) [Table 10-8]

[0378] (Continued from Table 10) [Table 10-9]

[0379] (Continued from Table 10) [Table 10-10]

[0380] (Continued from Table 10) [Table 10-11]

[0381] (Continued from Table 10) [Table 10-12]

[0382] (Continued from Table 10) [Table 10-13]

[0383] (Continued from Table 10) [Table 10-14]

[0384] (Continued from Table 10) [Table 10-15] 1 Preparative chiral HPLC; Phenomenex Lux i-Cellulose-5, 30 x 150 mm, 30-100% heptane (ethanol containing 0.1% isopropylamine), 42.5 mL / min 2 Reverse phase, C18, 49-100% acetonitrile in (10 mM ammonium bicarbonate aqueous solution in a 95:5 ratio: methanol) 3 Preparative chiral HPLC, (S,S)-Whelk-O1, 30 x 150 mm, 20-95% ethanol in heptane, 45 mL / min 4 Preparative chiral HPLC; Chiralpak-IK, 30 x 250 mm, 50% ethanol in methanol treated with 10 mM ammonia in hexane, 40 mL / min 5 Reverse phase, C18, 45-51% acetonitrile in 10 mM ammonium bicarbonate aqueous solution 6 Reverse phase, C18, 44-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol). Enantiomer refers to the pure isomer at the 3-position of piperidinone. 7Preparative chiral HPLC, (S,S)-Whelk-O1, 30 × 150 mm, 10-100% ethanol in heptane, 42.5 mL / min. The enantiomer refers to the pure isomer at the 3-position of piperidinone. 8 Preparative chiral HPLC, Phenomenex Lux Cellulose-1, 30 x 150 mm, 10-85% ethanol in heptane, 37.5 mL / min. 9 Reverse phase, C18, 41-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol) 10 Reverse phase, C18, 41-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol). Diastereomers refer to both the pure atropisomer and the pure isomer at the 3-position of piperidinone. 11 Reverse phase, C18, 40-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol) 12 Reverse phase, C18, 10 mM ammonium bicarbonate aqueous solution containing 37-43% acetonitrile. Subsequently, reverse phase, C18, 10 mM ammonium bicarbonate aqueous solution containing 58-68% methanol. 13 Preparative chiral HPLC; Chiralpak-IK, 30 x 250 mm, 50% ethanol in methanol treated with 10 mM ammonia in hexane, 40 mL / min 14 Preparative chiral SFC, (R,R)-Whelk-O1, 30 x 250 mm, 45% methanol in CO2 (containing 10 mM ammonium acetate), 85 mL / min 15 Reverse phase, C18, 37-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol) 16 Pure isomers at the 3-position of piperidinone from preparation 31A, and chiral purification. 17 Reverse phase, C18, 35-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol) 18Preparative chiral SFC, Chiralpak ID, 20 x 250 mm, 45% in CO2 (isopropanol containing 0.5% dimethylethylamine), 80 mL / min 19 Preparative chiral SFC, Chiralpak IH, 20 x 250 mm, 35% methanol in CO2 (containing 0.5% dimethylethylamine), 80 mL / min 20 Preparative chiral SFC, Chiralpak IH, 20 x 250 mm, 35% methanol in CO2 (containing 0.5% dimethylethylamine), 80 mL / min 21 Reverse phase, C18, 35-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol)

[0385] Biological assays The following assays demonstrate that the exemplified compounds are potent inhibitors of KRAS G12V and inhibit the growth of certain tumors in vitro and / or in vivo.

[0386] Cellular Phospho-ERK AlphaLISA® assay for KRAS inhibition The objective of these assays was to quantify the ability of test compounds to selectively inhibit KRAS signaling in cells exhibiting KRAS amplification and expressing activated KRAS G12 mutations (Table 1A). Cancer cell lines used in this study were selected based on the presence of homozygous activated KRAS G12 mutations or KRAS gene amplification.

[0387] Table 1A: Cell line information [Table 11]

[0388] The activity of the compound is determined by measuring the change in phosphorylation levels of the downstream effectors, extracellular signal-regulated kinases 1 and 2 (ERK1 / 2), in cells treated with the compound. The phosphorylation level of ERK-1 / 2 is measured using the AlphaLISA® SureFire® Ultra® p-ERK1 / 2(Thr202 / Tyr204) assay kit (number ALSU-PERK-A50K, PerkinElmer® Waltham, MA). The AlphaLISA® assay is a quantitative sandwich immunoassay that can be used to detect phosphorylation of target proteins from cell lysates using bead-based alpha technology. This assay kit contains two antibodies, one of which binds to the phosphorus-Thr202 / Tyr204 epitope on ERK-1 / 2, and the other which recognizes distinct sites on the protein. One of these antibodies is biotinylated and conjugated to streptavidin-coated Alpha donor beads, while the other antibody is conjugated to AlphaLISA® acceptor beads. The donor and acceptor beads are brought close together during phosphorylation of ERK-1 / 2 in cell lysates. When the donor beads are excited with 600 nm wavelength light, the photosensitizer within the beads converts ambient oxygen to an excited singlet state. If the acceptor beads are within 200 nm of this reaction, the singlet oxygen reacts with the acceptor, resulting in chemiluminescence emission. The amount of light measured is proportional to the amount of phosphorylated ERK-1 / 2 in the lysate. The AlphaLISA®, SureFire®, and Ultra® p-ERK 1 / 2 (Thr202 / Tyr204) assay kit includes AlphaLISA® antibody conjugate donor beads and acceptor beads, lysis buffer concentrate, and a set of proprietary buffers (activation buffer, reaction buffer 1, reaction buffer 2, and dilution buffer).

[0389] To perform these assays, the test compounds and controls were acoustically dispensed into a white 384-well assay plate (Proxiplate-384, PerkinElmer No. 6008280) in a 10-point 3-fold dilution series in 30 nL of DMSO (Labcyte ECHO®, San Jose, CA). Cells were then added to the assay plate (HBSS, Sigma No. 55021C, 10% FBS, GIBCO No. 10082-147) in 8 μL / well of assay medium at cell line-specific densities (Table 1A). In each well, the final compound concentration ranged from 0.5 to 10,000 nM, and the final DMSO concentration was 0.375%. The maximum signal control well contained only 0.375% DMSO (negative control), and the minimum signal control well contained 10,000 nM of the control compound (positive control). Cells in suspension are incubated with the test compound and reference compound at 37°C / 5% CO2 for 2 hours. After 2 hours of incubation, cells are lysed by adding 2 μL of AlphaLISA® lysis buffer concentrate (5-fold) supplemented with a protease / phosphatase inhibitor cocktail (Thermo Scientific No. 78442). The assay plate is covered with an opaque lid and shaken at 750 rpm for 30 minutes at room temperature on a multi-plate shaker (Heidolph, Schwabach, Germany) to induce cell lysis. During lysis, AlphaLISA® acceptor beads are diluted 1:50 in the prepared buffer mixture (1:1 AlphaLISA® reaction buffers 1 and 2 and 1:25 dilution of AlphaLISA® activation buffer). After cell lysis, the plate is briefly centrifuged and 5 μL / well of the prepared acceptor beads is added. The plate is then covered and incubated in the dark at room temperature for 2 hours. During the incubation of the acceptor beads, the donor beads are prepared by diluting Alpha streptavidin donor beads in AlphaLISA® dilution buffer at a ratio of 1:50. After incubation of the acceptor beads, 5 μL / well of the donor bead mixture is added to the plate. The plate is then covered and incubated in the dark at room temperature for 2 hours.After this incubation period, the AlphaLISA signal is read using a PHERAstar® FSX multimode plate reader (BMG Labtech, Ortenberg, Germany) equipped with an AlphaLISA®-compatible optical cube.

[0390] The raw signals obtained from the AlphaLISA® assay are analyzed using Geneda Screener® 17.0.3. Within this program, the data are normalized to 32 wells treated with an inhibitory control (maximum inhibition / positive control) and 32 wells treated with 0.375% DMSO alone (minimum inhibition / negative control) to calculate the compound's activity %.

[0391]

number

[0392]

number

[0393] Compounds 1, 2, 4, 7, 8, 11, 12, 15-20, 22, 24, 28-31, 33, 34, 36, 38-40, 42-45, 47-49, 51, 54, 56-59, 61, and 62 were tested using the SW620 Cellular Phospho-ERK AlphaLISA® assay. They demonstrated the ability to reduce the level of phosphorylated ERK-1 / 2 in KRAS-expressing cells and inhibited constitutive RAS activity in KRAS G12V-expressing cells, with a relative IC50 of <50 nM. Compounds from Examples 1-5, 7-9, 11-13, 15-31, 33, 34, 36, 38-49, 51, 54, and 56-62 were tested using both of the above assays (SW620 and MKN 45 Cellular Phospho-ERK AlphaLISA® assays) and showed a significant (i.e., more than 5-fold) selective inhibitory preference against the KRAS G12V mutant compared to the KRAS wild type. Furthermore, compounds from Examples 1, 2, 4, 7, 12, 15-28, 31, 33, 38-40, 42, 43, 45-47, 49, 51, 54, and 57-61 showed a more than 10-fold selective inhibitory preference against the KRAS G12V mutant compared to the KRAS wild type.

[0394] These data demonstrate that the compound of formula I described herein is a potent inhibitor of KRAS-expressing human cancer cells, and that it has the ability to inhibit the KRAS G12V mutant with significantly selective inhibitory preference over the KRAS WT.

[0395] CellTiter-Glo® bioluminescent cell viability assay for antiproliferative activity The purpose of these assays was to quantify the ability of test compounds to selectively inhibit proliferation activity in cells (Table 1B) that possess KRAS wild-type (WT) and activate the KRAS G12 mutation, grown as tumor spheroids. The cancer cell lines used in this study were selected based on the presence of homozygous activating KRAS G12 mutations or the KRAS WT gene.

[0396] Table 1B: Cell line information [Table 12]

[0397] The antiproliferative activity of the compound is determined by the CellTiter-Glo 2.0 assay, which quantifies changes in cellular levels of ATP in compound-treated cells. Mg 2+ In the presence of ATP and molecular oxygen, Ultra-Glo® recombinant luciferase catalyzes the monooxygenation of beetle luciferin, generating light. The readout of luminescence is directly proportional to the metabolic activity of the cultured cells.

[0398] To perform the assay, 75 nL of the test compound, control, and DMSO were acoustically dispensed in a 10-point 3-fold dilution series into clear, round-bottom, ultra-low-adhesion spheroid 384-well assay plates (Spheroid Microplates, Corning® #CLS 3830) using an ECHO 655 Acoustic Liquid Handler (Beckman Life Sciences). Spheroid microplates facilitate spheroid formation at the center of the wells by inhibiting cell adhesion. 40 μL / well of cell suspension was dispensed into the compound-containing microplates using a Multidrop Combi Reagent Dispenser (Thermo Fisher Scientific). Cells (Table 1B) were seeded in growth medium (RPMI Gibco #11875-093, 10% FBS Gibco #10082-147) at a density of 25,000 live cells / mL or 1,000 cells / well. In each well, the final compound concentration ranged from 0.5 to 10,000 nM, and the final DMSO concentration was 0.2%. The maximum signal control well contained only 0.2% DMSO (negative control), and the minimum signal control well contained 10,000 nM of the control compound (positive control). The plates were sealed with Breathe-Easy® sealed membranes (Diversified Biotech) and transferred to a 37°C incubator containing 5% CO2, where they were incubated for 4 days.

[0399] After a 4-day incubation, the CTG 2.0 reagent and assay plates were equilibrated at 25°C for at least 30 minutes. 40 μL / well of CTG reagent was dispensed into microplates using a Multidrop Combi Reagent Dispenser (Thermo Fisher Scientific). The assay plates were placed on a multiplate shaker (Heidolph, Schwabach, Germany) at 750 RPM for 10 minutes at room temperature to induce cell lysis, followed by centrifugation at 1200 RPM for 1 minute. Luminescence was read using a PHERAstar FSX Multimode plate reader (BMG LABTECH).

[0400] Raw luminescence data obtained by CTG assay were analyzed using Geneda Screener® 20.0.5. Within the program, the data were normalized to the mean signal from 14 wells treated with a positive control (10 mM LY3841814) and the mean signal from 14 wells treated with a negative control (0.2% DMSO) to calculate the compound activity %.

[0401]

number

[0402]

number

[0403] Compounds 1, 2, 4, 7, 8, 11, 12, 15-22, 24, 27-31, 33, 34, 36, 38-40, 43-45, 47-49, 51, 54, 56-59, and 62 were tested in a 4-day 3D growth assay using SW620 and showed the ability to reduce ATP levels, indicating inhibition of growth activity, with a relative IC50 < 250 nM. Compounds 1, 2, 4, 8, 12, 16, 18, 19, 24-31, 33, 36, 38, 39, 42, 44-46, 48, 49, 51, 52, 54, 56-58, and 60-62 were tested in both of the above assays (SW620 and MKN45 4-day 3D growth assays) and showed a more than 5-fold selective inhibitory preference against the KRAS G12V mutant compared to KRAS wild-type.

[0404] These data demonstrate that the compound of formula I described herein is an inhibitor of proliferative activity in KRAS tumor spheroids and inhibits the KRAS G12V mutant with selective inhibitory preference over KRAS WT.

[0405] Table 1C: Abbreviations [Table 13]

Claims

1. formula: 【Chemistry 1】 During the ceremony, R １ is, formula 【Chemistry 2】 It is the basis of, R １ａ is H or C １～３ It is alkyl, R １ｂ H, C １～３ Alkyl or cyclopropyl, n is either 0 or 1, R １ｃ C １～３ It is alkyl, R ２ However, it is H, halogen, or methyl, R ３ is the formula 【Transformation 3】 It is the basis of; Z is -C(R ３ｃ ) - or -N-, R ３ａ , R ３ｂ , and R ３ｃ Each of these is independently H, halogen, or methyl. R ４ is, formula 【Chemistry 4】 It is a base selected from, R ５ -NR ７ R ７ａ And, p is either 0 or 1. R ５ａ and R ６ａ Each of them is independent of C １～３ It is alkyl, R ６ is halogen, or C １～３ It is an alkoxy, R ７ is H or C １～３ It is alkyl, R ７ａ C １～３ Alkyl or C １～３ Alkoxy-C １～３ It is alkyl, R ８ and R ８ａ Each of them is independent of C １～３ Alkyl, or R ８ and R ８ａ Together with the nitrogen atoms to which they are bonded, they form an optionally substituted 4, 5, or 6-membered heterocycle that optionally contains further heteroatoms selected from N, O, and S, wherein the heterocycle is C １～３ Compounds optionally substituted with alkyl groups, or a pharmaceutically acceptable salt thereof.

2. R １ is, formula 【Transformation 5】 It is the basis of, R １ａ is H or C １～３ It is alkyl, R １ｂ H, C １～３ Alkyl or cyclopropyl, n is either 0 or 1, R １ｃ C １～３ It is alkyl, R ２ However, it is H, halogen, or methyl, R ３ is, formula 【Transformation 6】 It is the basis of, Z is -C(R ３ｃ ) - or -N-, R ３ａ , R ３ｂ , and R ３ｃ Each of these is independently H, halogen, or methyl. R ４ is, formula 【Transformation 7】 It is the basis of, R ５ -NR ７ R ７ａ And, p is 0 or 1, R ５ａ and R ６ａ Each of them is independent of C １～３ It is alkyl, R ６ It is a halogen, R ７ is H or C １～３ It is alkyl, R ７ａ C １～３ The compound according to claim 1, which is alkyl, or a pharmaceutically acceptable salt thereof.

3. R ３ is, formula 【Transformation 8】 A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

4. R ３ is, formula 【Chemistry 9】 A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

5. R ３ is, formula 【Chemistry 10】 A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

6. R ３ is, formula 【Chemistry 11】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

7. R ３ is, formula 【Chemistry 12】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the group is selected from the group.

8. R ３ is, formula 【Chemistry 13】 The compound according to claim 1 or 7, which is the base of or a pharmaceutically acceptable salt thereof.

9. R ２ The compound according to any one of claims 1 to 8, wherein is F or Cl, or a pharmaceutically acceptable salt thereof.

10. R １ teeth, 【Chemistry 14】 The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

11. R １ａ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein is H.

12. R １ｂ C １～３ A compound according to any one of Embodiments 1 to 11, which is alkyl, or a pharmaceutically acceptable salt thereof.

13. n is 0, and the compound is one of the compounds described in any one of Embodiments 1 to 12, or a pharmaceutically acceptable salt thereof.

14. n is 1, and R １ｃ C １～３ A compound according to any one of Embodiments 1 to 12, which is alkyl, or a pharmaceutically acceptable salt thereof.

15. R １ is, formula 【Chemistry 15】 The compound according to claim 10, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

16. R ４ is, formula 【Chemistry 16】 A compound according to any one of claims 1 or 3 to 15, or a pharmaceutically acceptable salt thereof, wherein the group is selected from the above.

17. R ４ is, formula 【Chemistry 17】 A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, which is the base of the compound. 【Request Item 18】 【Chemistry 18】 【Chemistry 19】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

19. The aforementioned compound, 【Chemistry 20】 【Chemistry 21】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

21. A method for treating a patient having cancer, comprising administering to a patient in need an effective amount of the pharmaceutical composition according to claim 20, or an effective amount of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, colorectal cancer, gastric adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumor, bladder cancer, small intestinal adenocarcinoma, appendiceal cancer, and peritoneal cancer.

22. The method according to claim 21, wherein the patient has cancer that has been determined to have one or more cells expressing the KRAS G12V mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof.

23. The method according to claim 21, wherein one or more cells express the KRAS G12V mutant protein.

24. A method for treating a patient having cancer having the KRASG12V mutation, comprising administering to a patient in need an effective amount of a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, colorectal cancer, gastric adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumor, bladder cancer, small intestinal adenocarcinoma, appendiceal cancer, and peritoneal cancer.

25. The method according to any one of claims 21 to 24, wherein the patient is also administered one or more of the following: a PD-1 inhibitor, a PD-L1 inhibitor, a CDK4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a SHP2 inhibitor, a platinum agent, and pemetrexed, or a pharmaceutically acceptable salt thereof.

26. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, for use in therapeutic purposes.

27. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

28. The cancer is a compound for use according to claim 27, or a pharmaceutically acceptable salt thereof, having the KRAS G12V mutation.

29. The aforementioned cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, colorectal cancer, gastric adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumor, bladder cancer, small intestinal adenocarcinoma, appendiceal cancer, and peritoneal cancer, and is the compound for use according to claim 27 or 28, or a pharmaceutically acceptable salt thereof.

30. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in combination with, separately, or sequentially with one or more of the following: a PD-1 or PD-L1 inhibitor, a CDK4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, an SHP2 inhibitor, a platinum agent, and pemetrexed, or a pharmaceutically acceptable salt thereof.

31. The cancer is non-small cell lung cancer, according to the method according to any one of claims 21 to 25, or the compound for use according to any one of claims 27 to 30, or a pharmaceutically acceptable salt thereof.

32. The cancer is colorectal cancer, according to the method according to any one of claims 21 to 25, or the compound for use according to any one of claims 27 to 30, or a pharmaceutically acceptable salt thereof.

33. The cancer is pancreatic cancer, according to the method according to any one of claims 21 to 25, or the compound for use according to any one of claims 27 to 30, or a pharmaceutically acceptable salt thereof.

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