KRAS inhibitors

Abstract

This invention provides a KRAS inhibitor useful for treating diseases or disorders related to KRAS regulation. [Solution] The compound provided is the compound of the following formula. TIFF2026064227000396.tif46128 This includes their pharmaceutically acceptable salts, as well as methods of using these compounds and their pharmaceutically acceptable salts to treat patients with cancer.

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 result in increased GTP binding and decreased ability to convert GTP to GDP. Consequently, 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 harmful or undesirable effects. The present invention addresses one or more of these needs by providing a novel KRAS inhibitor. [Overview of the Initiative]

[0006] Compound of formula I, [ka] During the ceremony, A is -C(H)- or -N-, B is -C(R4)- or -N-, R1 is given by the following equation [ka] It is the basis of, R 1b However, H or C 1~3 It is alkyl, R 1d However, C 1~3 Alkyl, C 1~3 Haloalkyl, or C 3~4 It is a cycloalkyl, R 1e However, C1~3 is an alkylene, rings A1 and A2 are C 3~4 cycloalkyl, or a 3- or 4-membered heterocyclic ring containing a heteroatom selected from N, O, and S, X1 and X2 are -CH- or -N-, X3 is -CH2- or -O-, X4 and X5 are each independently C 1~3 alkyl, halogen, or H, m, m’, s, t, u, v, and w are each 0 or 1, R2 is halogen or C 1~3 alkyl, Z1 is -C(CN)- or -N-, Z2 is -C(R 3c )- or -N-, Z3 is -O- or -S-, R 3a , R 3b , and R 3c are each independently H, halogen, or C 1~3 alkyl, R4 is H, C 1~3 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from hydroxyl and methyl, or 1~3 R4 is C alkoxy, or (i) [Chemical formula] (wherein, R 4b is H or methyl, R 4c and R 4d are each independently C 1~3 alkyl, hydroxyl, or C 1~3 haloalkyl, or R 4c and R 4d together with the nitrogen or carbon atom to which they are attached form a 4-, 5-, or 6-membered heterocyclic ring), or (ii) [ka] (In the formula, R 5a However, halogens, hydroxy, C 1~3 Alkyl, C 1~3 Alkoxy, or C 1~3 Alkoxy-C 1~3 It is alkyl, R 5d However, C 1~3 It is alkyl, R 5e and R 5f However, together with the carbon atoms to which they are bonded, Forming a 4-member, 5-member, or 6-member complex ring, R 5b and R 5c However, each is independently replaced by H and C, which are optionally substituted with one or more deuterium atoms. 1~6 Alkyl, halogen, hydroxyl, or C 1~3 C optionally substituted with a haloalkyl group 3~5 It is a cycloalkyl, or a 3-membered, 4-membered, or 5-membered heterocycle containing a heteroatom selected from N, O, and S, or R 5b and R 5c However, together with the nitrogen atoms to which they are bonded, they form optionally substituted 4-membered, 5-membered, or 6-membered heterocycles or 6-membered, 7-membered, or 8-membered spiroheterocycles that optionally contain further heteroatoms selected from N, O, and S, and each heterocycle and spiroheterocycle contains one or more halogens, deuterium, and C 1~3 Alkyl, or C 1~3 It is optionally substituted with a haloalkyl, or R 5a and R 5b However, together with the atoms to which they are bonded, they form a 4-membered, 5-membered, or 6-membered heterocyclic fused ring that optionally contains further heteroatoms selected from N, O, and S, R 5c However, C 1~3It is alkyl, and the 4-membered, 5-membered, or 6-membered fused ring is C 1~3 It is further optionally substituted with alkyl groups. (where p and r are 0, 1, or 2, respectively) (iii) [ka] (In the formula, R6 is halogen, hydroxyl, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, and C 1~3 Selected from dialkylaminos, n is 0 or 1), and (iv) [ka] (In the formula, R7 is C 1~3 It is alkyl, R 7a However, it is a 4-membered, 5-membered, or 6-membered heterocycle that optionally contains further heteroatoms selected from N, O, and S, or R7 and R 7a However, together with the atoms to which they are bonded, they form a compound that is a group of 4-membered, 5-membered, or 6-membered heterocyclic ring (which optionally contains further heteroatoms selected from N, O, and S), Or a pharmaceutically acceptable salt thereof is provided herein.

[0007] 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.

[0008] Compounds of formula I and pharmaceutically acceptable salts thereof are further provided herein for use in therapy. Compounds of formula I and pharmaceutically acceptable salts thereof are additionally provided herein for use in the treatment of cancer, specifically for the treatment of 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 use of compounds of formula I or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for the treatment of cancer, specifically for the treatment of 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 additionally provided herein. [Modes for carrying out the invention]

[0009] 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).

[0010] The present invention relates to a compound of formula I, [ka] In the formula, A, B, R1, R2, R 3a , R 3b The present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein Z1, Z2, and Z3 are as defined above. In some embodiments, the compound of formula I is represented by the following formula I'. [ka]

[0011] The present invention relates to the following compound of formula I', [ka] In the formula, R1, R2, R 3a , R 3b The present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R4, Z1, Z2, and Z3 are as defined above.

[0012] 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.

[0013] As used herein, the terms “heterocyclyl” or “heterocyclic” mean a monocyclic or polycyclic ring containing carbon and one or more heteroatoms selected from N, O, S, P, and B, preferably 1, 2, 3, or 4 heteroatoms selected from N, O, and S, comprising 3 to 24 atoms, preferably 3 to 10 atoms, wherein the ring is not aromatic. Examples of heterocyclyl rings include, but are not limited to, oxetanil, azetidinil, tetrahydrofuranil, tetrahydropyranil, pyrrolidinil, oxazolinil, oxazolidinil, thiazolinil, thiazolidinil, pyranil, thiopyranil, tetrahydropyranil, dioxalinil, piperidinil, morpholinil, thiomorpholinil, thiomorpholinil S-oxide, thiomorpholinil S-dioxide, piperazinil, azepinil, oxepinil, diazepinil, tropanil, oxazolidinonil, and homotropanil.

[0014] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R1 is the following formula [ka] It is the basis of. In one embodiment, R 1b However, it is methyl or a pharmaceutically acceptable salt thereof. In one embodiment, R 1d However, it is methyl or ethyl, or a pharmaceutically acceptable salt thereof. In one embodiment, R 1d However, it is methyl or a pharmaceutically acceptable salt thereof. In one embodiment, R 1d However, it is ethyl or a pharmaceutically acceptable salt thereof. In one embodiment, R 1b However, it is methyl, and R 1d However, it is methyl or ethyl, or a pharmaceutically acceptable salt thereof. In one embodiment, R 1b However, it is methyl, and R 1d However, it is methyl or a pharmaceutically acceptable salt thereof. In one embodiment, R 1b However, it is methyl, and R 1dHowever, it is ethyl or a pharmaceutically acceptable salt thereof. In one embodiment, R 1b However, it is methyl, and R 1d However, C 3~4 It is a cycloalkyl or a pharmaceutically acceptable salt thereof. In one embodiment, R 1b However, it is methyl, and R 1d However, it is either cyclopropyl or a pharmaceutically acceptable salt thereof.

[0015] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R1 is the following formula [ka] It is the basis of. In one embodiment, R 1b However, it is methyl or a pharmaceutically acceptable salt thereof. In one embodiment, R 1d However, it is methyl, ethyl, or difluoromethyl, or a pharmaceutically acceptable salt thereof. In one embodiment, R 1d However, it is methyl or a pharmaceutically acceptable salt thereof. In one embodiment, R 1d However, it is ethyl or a pharmaceutically acceptable salt thereof. In one embodiment, R 1b However, it is methyl, and R 1d However, it is methyl or ethyl, or a pharmaceutically acceptable salt thereof. In one embodiment, R 1b However, it is methyl, and R 1d However, it is methyl or a pharmaceutically acceptable salt thereof. In one embodiment, R 1b However, it is methyl, and R 1d However, it is ethyl or a pharmaceutically acceptable salt thereof. In one embodiment, R 1b is methyl, and R 1d This is difluoromethyl or a pharmaceutically acceptable salt thereof.

[0016] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, A is -N-.

[0017] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, A is -C(H)-.

[0018] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, B is -N-.

[0019] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, B is -C(H)-.

[0020] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, B is -C(R4)-.

[0021] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R1 is of the following formula

Chemical formula

[0022] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R1 is of the following formula

Chemical formula

[0023] In one embodiment of the compound of formula I or its pharmaceutically acceptable salt, R1 is of the following formula

Chemical formula

[0024] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R1 is the following formula [ka] It is the basis of. In one embodiment, R 1b However, it is methyl or a pharmaceutically acceptable salt thereof. In one embodiment, ring A2 is C 3~4It is a cycloalkyl group or a pharmaceutically acceptable salt thereof. In one embodiment, ring A2 is a cyclopropyl group or a pharmaceutically acceptable salt thereof. In one embodiment, ring A2 is a cyclobutyl group or a pharmaceutically acceptable salt thereof. In one embodiment, ring A2 is a three-membered or four-membered heterocycle containing a heteroatom selected from N, O, and S, or a pharmaceutically acceptable salt thereof. In one embodiment, ring A2 is an oxetanyl group or a pharmaceutically acceptable salt thereof. In one embodiment, R 1b However, it is methyl, and ring A2 is C 3~4 It is a cycloalkyl or a pharmaceutically acceptable salt thereof. In one embodiment, R 1b However, the ring A2 is methyl, and the ring A2 is cyclopropyl or a pharmaceutically acceptable salt thereof. In one embodiment, R 1b However, is methyl, and ring A2 is cyclobutyl or a pharmaceutically acceptable salt thereof. In one embodiment, R 1b However, the compound is methyl, and ring A2 is a three- or four-membered heterocycle containing a heteroatom selected from N, O, and S, or a pharmaceutically acceptable salt thereof. In one embodiment, R 1b is methyl, and ring A2 is oxetanyl or a pharmaceutically acceptable salt thereof.

[0025] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R1 is the following formula [ka] It is the basis of. In one embodiment, X1 is -CH- or a pharmaceutically acceptable salt thereof. In another embodiment, X1 is -N- or a pharmaceutically acceptable salt thereof.

[0026] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R1 is the following formula [ka] It is the basis of. In one embodiment, X1 is -CH- or a pharmaceutically acceptable salt thereof. In one embodiment, X1 is -N- or a pharmaceutically acceptable salt thereof. In one embodiment, X3 is -O- or a pharmaceutically acceptable salt thereof. In one embodiment, X3 is -CH2- or a pharmaceutically acceptable salt thereof. In one embodiment, X4 and X5 are each halogen or a pharmaceutically acceptable salt thereof. In one embodiment, X4 and X5 are each fluoro or a pharmaceutically acceptable salt thereof. In one embodiment, X4 is hydrogen and X5 is a halogen (preferably fluoro) or a pharmaceutically acceptable salt thereof. In one embodiment, X4 and X5 are each hydrogen or a pharmaceutically acceptable salt thereof. In one embodiment, X4 is C 1~3 It is alkyl, and X5 is hydrogen or a pharmaceutically acceptable salt thereof. In one embodiment, X4 is C 1~3 It is an alkyl group, and X5 is a halogen (preferably fluoro) or a pharmaceutically acceptable salt thereof. In one embodiment, m and m' are each 1. In another embodiment, m is 1 and m' is 0.

[0027] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R1 is the following formula [ka] It is the basis of. In one embodiment, X1 is -CH- or a pharmaceutically acceptable salt thereof. In one embodiment, X1 is -N- or a pharmaceutically acceptable salt thereof. In one embodiment, X4 is a halogen and X5 is a halogen or a pharmaceutically acceptable salt thereof. In one embodiment, X4 is a fluoro and X5 is a fluoro or a pharmaceutically acceptable salt thereof. In one embodiment, X4 is hydrogen and X5 is a halogen (preferably fluoro) or a pharmaceutically acceptable salt thereof. In one embodiment, X4 is hydrogen and X5 is hydrogen or a pharmaceutically acceptable salt thereof. In one embodiment, X4 is C1~3 It is alkyl, and X5 is hydrogen or a pharmaceutically acceptable salt thereof. In one embodiment, X4 is C 1~3 It is an alkyl group, and X5 is a halogen (preferably fluoro) or a pharmaceutically acceptable salt thereof. In one embodiment, m and m' are each 1. In another embodiment, m is 1 and m' is 0.

[0028] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R1 is the following formula [ka] It is the basis of. In one embodiment, X3 is -CH- or a pharmaceutically acceptable salt thereof. In one embodiment, X3 is -O- or a pharmaceutically acceptable salt thereof. In one embodiment, X4 and X5 are hydrogen or pharmaceutically acceptable salts thereof. In one embodiment, X4 is C 1~2 It is alkyl, and X5 is hydrogen or a pharmaceutically acceptable salt thereof. In one embodiment, X4 is methyl, and X5 is hydrogen or a pharmaceutically acceptable salt thereof. In one embodiment, m is 1.

[0029] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R1 is the following formula [ka] It is the basis of. In one embodiment, X2 is -CH- or a pharmaceutically acceptable salt thereof. In one embodiment, X2 is -N- or a pharmaceutically acceptable salt thereof. In one embodiment, X3 is -CH2- or a pharmaceutically acceptable salt thereof. In one embodiment, X3 is -O- or a pharmaceutically acceptable salt thereof. In one embodiment, X2 is -CH- and X3 is -CH2- or a pharmaceutically acceptable salt thereof. In one embodiment, X2 is -N- and X3 is -CH2- or a pharmaceutically acceptable salt thereof. In one embodiment, X2 is -CH- and X3 is -O- or a pharmaceutically acceptable salt thereof.

[0030] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R1 is the following formula [ka] It is the basis of.

[0031] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R1 is the following formula [ka] It is the basis of.

[0032] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R1 is the following formula [ka] It is the basis of.

[0033] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R1 is the following formula [ka] It is the basis of.

[0034] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R1 is the following formula [ka] It is the basis of.

[0035] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R1 is the following formula [ka] It is the basis of.

[0036] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R2 is F, Cl, or methyl.

[0037] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R2 is F or Cl.

[0038] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R2 is F.

[0039] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R2 is Cl.

[0040] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R2 is methyl.

[0041] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, Z1 is -C(CN)- and Z2 is -C(R 3c )- and Z3 is -S-. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )- and Z3 is -S- and R 3a However, H. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )- and Z3 is -S- and R 3a However, H is R 3b However, it is a halogen (preferably fluoro), and R 3c However, H. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c)- and Z3 is -S- and R 3a However, H is R 3b However, H is R 3c However, it is a halogen (preferably fluoro). In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )- and Z3 is -S- and R 3a However, H is R 3b However, it is a halogen (preferably fluoro), and R 3c However, it is a halogen (preferably fluoro).

[0042] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, Z1 is -C(CN)-, Z2 is -N-, and Z3 is -S-. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R 3a However, H. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R 3a However, H is R 3b However, it is a halogen (preferably fluoro).

[0043] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, Z1 is -N- and Z2 is -C(R 3c )- and Z3 is -S-. In one embodiment, Z1 is -N- and Z2 is -C(R 3c )- and Z3 is -S- and R 3a However, it is H. In one embodiment, Z1 is -N- and Z2 is -C(R 3c )- and Z3 is -S- and R 3a However, H is R 3b However, it is a halogen (preferably fluoro), and R 3c However, it is H. In one embodiment, Z1 is -N- and Z2 is -C(R 3c )- and Z3 is -S- and R 3a However, H is R 3b However, H is R 3cHowever, it is a halogen (preferably fluoro). In one embodiment, Z1 is -N- and Z2 is -C(R 3c )- and Z3 is -S- and R 3a However, H is R 3b However, it is a halogen (preferably fluoro), and R 3c However, it is a halogen (preferably fluoro). In one embodiment, Z1 is -N- and Z2 is -C(R 3c )- and Z3 is -S- and R 3a However, H is R 3b However, H is R 3c However, it is H.

[0044] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, Z1 is -N-, Z2 is -N-, and Z3 is -S-. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R 3a However, H. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R 3a However, H is R 3b However, it is a halogen (preferably fluoro).

[0045] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, Z1 is -C(CN)- and Z2 is -C(R 3c )- and Z3 is -O-. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )- and Z3 is -O- and R 3a However, H. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )- and Z3 is -O- and R 3a However, H is R 3b However, it is a halogen (preferably fluoro), and R 3c However, H. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )- and Z3 is -O- and R 3a However, H is R 3b However, H is R3c However, it is a halogen (preferably fluoro). In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )- and Z3 is -O- and R 3a However, H is R 3b However, it is a halogen (preferably fluoro), and R 3c However, it is a halogen (preferably fluoro).

[0046] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, Z1 is -C(CN)-, Z2 is -N-, and Z3 is -O-. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R 3a However, H. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R 3a However, H is R 3b However, it is a halogen (preferably fluoro).

[0047] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, Z1 is -N- and Z2 is -C(R 3c )- and Z3 is -O-. In one embodiment, Z1 is -N- and Z2 is -C(R 3c )- and Z3 is -O- and R 3a However, it is H. In one embodiment, Z1 is -N- and Z2 is -C(R 3c )- and Z3 is -O- and R 3a However, H is R 3b However, it is a halogen (preferably fluoro), and R 3c However, it is H. In one embodiment, Z1 is -N- and Z2 is -C(R 3c )- and Z3 is -O- and R 3a However, H is R 3b However, H is R 3c However, it is a halogen (preferably fluoro). In one embodiment, Z1 is -N- and Z2 is -C(R 3c )- and Z3 is -O- and R 3a However, H is R3b However, it is a halogen (preferably fluoro), and R 3c However, it is a halogen (preferably fluoro). In one embodiment, Z1 is -N- and Z2 is -C(R 3c )- and Z3 is -O- and R 3a However, H is R 3b However, H is R 3c However, it is H.

[0048] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, Z1 is -N-, Z2 is -N-, and Z3 is -O-. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R 3a However, H. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R 3a However, H is R 3b However, it is a halogen (preferably fluoro).

[0049] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is H, C 1~3 C is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, hydroxyl, and methyl. 1~3 It is an alkoxy. In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is H, C 1~3 C is optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxyl, and methyl. 1~3 It is an alkoxy. In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is H, C 1~3 C is optionally substituted with three substituents independently selected from alkyl, hydroxyl, and methyl. 1~3 It is an alkoxy. In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is H, C 1~3 C is optionally substituted with alkyl or two substituents independently selected from hydroxyl and methyl. 1~3It is an alkoxy. In one embodiment, R4 is H. In one embodiment, R4 is methyl. In one embodiment, R4 is methoxy. In one embodiment, R4 is [ka] That is the case.

[0050] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the following formula: [ka] In the formula, R 4b However, it is H or methyl, and R 4c and R 4d However, each is independent of C 1~3 It is alkyl. In one embodiment, R 4b However, H. In some embodiments, R 4b However, it is methyl.

[0051] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the following formula: [ka] In the formula, R 4b However, it is H or methyl, and R 4c and R 4d However, each is independent of C 1~3 It is alkyl. In one embodiment, R 4b However, H. In some embodiments, R 4b However, it is methyl. In one embodiment, R 4b However, H is R 4c and R 4d However, together with the nitrogen atoms to which they are bonded, they form a 4-membered, 5-membered, or 6-membered heterocycle. In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R 4b However, H is R 4c and R 4d However, together with the nitrogen atom to which they are bonded, they form a four-membered heterocycle (for example, azetidinyl).

[0052] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the following formula: [ka] In the formula, R 4c and R 4d However, together with the carbon atoms to which they are bonded, they form a 4-membered, 5-membered, or 6-membered heterocycle. In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R 4c and R 4d However, together with the carbon atoms to which they are bonded, they form a four-membered heterocycle (e.g., oxetanyl). In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R 4c and R 4d However, together with the carbon atoms to which they are bonded, they form a five-membered heterocycle. In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R 4c and R 4d However, together with the carbon atoms to which they are bonded, they form a six-membered heterocycle (for example, tetrahydro-2H-pyran-4-yl, 1,4-dioxanyl).

[0053] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0054] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0055] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0056] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0057] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the following formula: [ka] In the formula, R 5a However, halogens, hydroxy, C 1~3 Alkyl, C 1~3 Alkoxy, or C 1~3 Alkoxy-C 1~3 It is alkyl, R 5d However, C 1~3 It is alkyl, R 5b and R 5c However, each is independently replaced by H and C, which are optionally substituted with one or more deuterium atoms. 1~5 Alkyl (preferably triduteromethyl), halogen (preferably F), or C 1~3 C optionally substituted with a haloalkyl (preferably fluoromethyl) 4~5 A cycloalkyl group, or a 3-membered, 4-membered, or 5-membered heterocycle containing a heteroatom selected from N, O, and S, or R 5b and R 5c However, together with the nitrogen atoms to which they are bonded, they form optionally substituted 4-membered, 5-membered, or 6-membered heterocycles or 6-membered or 7-membered spiroheterocycles, each heterocycle or spiroheterocycle optionally containing a further heteroatom selected from N, O, and S, and each heterocycle and spiroheterocycle contains one or more halogens (preferably F), deuterium, and C 1~3 Alkyl, or C 1~3 It is optionally substituted with a haloalkyl, or R 5a and R 5bHowever, together with the atoms to which they are bonded, they form a 4-membered, 5-membered, or 6-membered heterocyclic fused ring that optionally contains further heteroatoms selected from N, O, and S, R 5d and R 5c However, each is independently methyl, and p and r are each 0 or 1. In one embodiment, R 5b and R 5c However, each C is independently substituted with H, 1, 2, or 3 deuterium atoms of any choice. 1~5 Alkyl (e.g., triduteromethyl), halogen (preferably F), or C 1~3 C optionally substituted with a haloalkyl (preferably fluoromethyl) 4~5 It is a cycloalkyl or a three-membered, four-membered, or five-membered heterocycle containing a heteroatom selected from N, O, and S. In one embodiment, R 5b and R 5c These, together with the nitrogen atoms to which they are bonded, form optionally substituted 4-membered, 5-membered, or 6-membered heterocycles or 6-membered or 7-membered spiroheterocycles, each heterocycle or spiroheterocycle optionally containing a further heteroatom selected from N, O, and S, and the heterocycles and spiroheterocycles may contain halogens (preferably F), deuterium, and C 1~3 Alkyl, or C 1~3 Each substituent is optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents selected from haloalkyl groups.

[0058] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0059] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0060] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the following formula: [ka] In the formula, R 5e and R 5f However, together with the carbon atoms to which they are bonded, they form a four-membered or five-membered heterocycle.

[0061] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0062] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the following formula: [ka] In the formula, R 5a However, halogens, hydroxy, C 1~3 Alkyl, C 1~3 Alkoxy, or C 1~3 Alkoxy-C 1~3 It is alkyl, R 5b and R 5c However, H and C are independent of each other. 1~6 Alkyl, C 3~5 A cycloalkyl group, or a 3-membered, 4-membered, or 5-membered heterocycle containing a heteroatom selected from N, O, and S, or R 5b and R 5c However, together with the nitrogen atom to which they are bonded, they form an optionally substituted 4-membered, 5-membered, 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 substituted with alkyl, or R 5a and R 5b However, together with the atoms to which they are bonded, they form a 4, 5, or 6-membered heterocyclic fused ring that optionally contains further heteroatoms selected from N, O, and S, R5c However, C 1~3 Alkyl, and 4-membered, 5-membered, or 6-membered fused rings are C 1~3 It is further optionally substituted with an alkyl group, and p is either 0 or 1.

[0063] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the following formula: [ka] In the formula, R 5a However, halogens, hydroxy, C 1~3 Alkyl, C 1~3 Alkoxy, or C 1~3 Alkoxy-C 1~3 It is alkyl, R 5b and R 5c However, H and C are independent of each other. 1~6 Alkyl, C 3~5 A cycloalkyl, or a 3-membered, 4-membered, or 5-membered heterocycle containing a heteroatom selected from N, O, and S, wherein p is 0 or 1. In one embodiment, R 5b However, H, C 1~6 Alkyl, C 3~5 It is a cycloalkyl, or a 3-membered, 4-membered, or 5-membered heterocycle, R 5c However, H or C 1~6 It is alkyl.

[0064] In one embodiment, R4 is given by the following formula [ka] It is the basis of.

[0065] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the following formula: [ka] In the formula, R 5a However, halogens, hydroxy, C 1~3 Alkyl, C 1~3 Alkoxy, or C 1~3 Alkoxy-C1~3 It is alkyl, R 5b and R 5c However, together with the nitrogen atom to which they are bonded, they form an optionally substituted 4-membered, 5-membered, 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 substituted with an alkyl group, and p is 0 or 1. In one embodiment, R4 is given by the following formula [ka] It is the basis of.

[0066] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the following formula: [ka] In the formula, R 5a However, halogens, hydroxy, C 1~3 Alkyl, C 1~3 Alkoxy, or C 1~3 Alkoxy-C 1~3 It is alkyl, R 5b and R 5c However, together with the nitrogen atom to which they are bonded, they form an optionally substituted 4-membered, 5-membered, 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 substituted with an alkyl group, and p is 0 or 1. In one embodiment, R4 is given by the following formula [ka] It is the basis of.

[0067] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the following formula: [ka] In the formula, R 5a and R 5bHowever, together with the atoms to which they are bonded, they form a 4-membered, 5-membered, or 6-membered heterocyclic fused ring that optionally contains further heteroatoms selected from N, O, and S, R 5c However, C 1~3 It is alkyl, and a 4-membered, 5-membered, or 6-membered fused ring is optionally C 1~3 It is further substituted with alkyl. In one embodiment, R 5a and R 5b However, together with the atoms to which they are bonded, they form a four-membered heterocyclic fused ring, R 5c However, C 1~3 It is alkyl. In one embodiment, R 5a and R 5b However, together with the atoms to which they are bonded, they form a 5-membered heterocyclic fused ring, R 5c However, C 1~3 It is alkyl. In one embodiment, R 5a and R 5b However, together with the atoms to which they are bonded, they form a 6-membered heterocyclic fused ring, R 5c However, C 1~3 It is alkyl. In one embodiment, R4 is of the following formula [ka] It is the basis of.

[0068] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0069] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0070] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0071] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0072] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0073] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

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

[0075] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

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

[0077] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0078] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0079] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0080] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the following formula: [ka] In the formula, R 5a However, halogens, hydroxy, C 1~3 Alkyl, C 1~3 Alkoxy, or C 1~3 Alkoxy-C 1~3 It is alkyl, R 5b and R 5c However, H and C are independent of each other. 1~6 Alkyl, C 3~5 A cycloalkyl, or a 3-membered, 4-membered, or 5-membered heterocycle containing a heteroatom selected from N, O, and S, wherein p is 0, 1, or 2. In one embodiment, R 5a However, hydroxy or C 1~3 It is alkyl. In one embodiment, p is 1. In one embodiment, p is 2. In one embodiment, R 5b However, H, C 1~6 Alkyl, C 3~5 It is a cycloalkyl, or a 3-membered, 4-membered, or 5-membered heterocycle, R 5cHowever, H or C 1~6 It is alkyl. In one embodiment, R 5b and R 5c However, each is independent of C 1~3 It is alkyl. In one embodiment, R4 is of the following formula [ka] It is the basis of.

[0081] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0082] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0083] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0084] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0085] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0086] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the following formula: [ka] In the formula, R 5a However, halogens, hydroxy, C 1~3 Alkyl, C 1~3 Alkoxy, or C 1~3 Alkoxy-C 1~3 It is alkyl, R 5b and R 5c However, together with the nitrogen atom to which they are bonded, they form an optionally substituted 4-membered, 5-membered, 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 substituted with alkyl, and p is 0, 1, or 2. In one embodiment, R 5b and R 5c However, together with the nitrogen atom to which they are bonded, they form an optionally substituted four- or five-membered heterocycle that optionally contains further heteroatoms selected from N, O, and S, and p is 1. In one embodiment, R 5b and R 5c However, together with the nitrogen atom to which they are bonded, they form a substituted four- or five-membered heterocycle, and p is 1. In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0087] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0088] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0089] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0090] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the following formula: [ka] In the formula, R6 is a halogen, hydroxyl, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 1~3 Selected from dialkylaminos (preferably dimethylaminos), where n is 0 or 1. In one embodiment, R6 is dimethylamino. In one embodiment, n is 1. In one embodiment, n is 0. In one embodiment, R4 is the following formula [ka] It is the basis of.

[0091] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the following formula: [ka] In the formula, R7 is C 1~3 It is alkyl, R 7a However, it is a 4-membered, 5-membered, or 6-membered heterocycle that optionally contains further heteroatoms selected from N, O, and S, or R7 and R 7a These, together with the atoms to which they are bonded, form a four-membered, five-membered, or six-membered heterocyclic ring optionally containing further heteroatoms selected from N, O, and S.

[0092] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0093] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0094] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0095] In one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is the following formula [ka] It is the basis of.

[0096] The present invention also relates to compounds of the following formulas: Ia, Ib, Ic, Id, Ie, or If, [ka] In the formula, R 1b , R 1d , R 1e , R2, R 3a , R 3b The present invention provides a compound or a pharmaceutically acceptable salt thereof in which R4, Z1, Z2, Z3, X1, X2, X3, ring A1, ring A2, s, t, u, v, and w are as defined above. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c)-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, and Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -N-, and Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c)-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c)-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is hydrogen, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1bHowever, Z1 is methyl, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is F. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b However, is methyl, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1bis methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z2 is -C(CN)-, Z3 is -N-, and Z3 is -S-. R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is hydrogen, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1bis methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1.

[0097] The present invention also relates to compounds of the following formulas: Ia, Ib, Ic, Id, Ie, If, Ih, Ii, Ij, Ik, or Im. [ka] [ka] In the formula, R 1b , R 1d , R 1e , R2, R 3a , R 3b The present invention also provides compounds, or pharmaceutically acceptable salts thereof, in which R4, Z1, Z2, Z3, X1, X2, X3, X4, X5, ring A1, ring A2, m, m', s, t, u, v, and w are as defined above. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, and Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -N-, and Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c)-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c)-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is hydrogen, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1bHowever, Z1 is methyl, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is F. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b However, is methyl, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1bis methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is - N is -, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is hydrogen, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1bis methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, and Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, R 3c However, H. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, R 3cHowever, it is F. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is F. In some embodiments, the compound is a compound of formula Ia, formula Ib, formula Ic, formula Id, formula Ie, or formula If. In some embodiments, the compound is a compound of formula Ih, formula Ii, formula Ij, formula Ik, or formula Im.

[0098] The present invention also relates to the following formula Ia * , formula Ib * , formula Ic * , formula Id * Formula Ie * , or the expression If * A compound of, [ka] In the formula, R 1b , R 1d , R 1e , R2, R 3a , R 3b The present invention provides a compound or a pharmaceutically acceptable salt thereof in which R4, Z1, Z2, Z3, X1, X2, X3, ring A1, ring 2, s, t, u, v, and w are as defined above. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, and Z2 is -C(R 3cIn one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -N-, and Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c)-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, R1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is hydrogen, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is F. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1bis methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b However, is methyl, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z2 is -C(CN)-, Z3 is -N-, and R 2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c)-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is hydrogen, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1bis methyl, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1.

[0099] The present invention also relates to the following formula Ia * , formula Ib * , formula Ic * , formula Id * Formula Ie * If expression * Formula Ih * , formula II * , formula Ij * , formula Ik * , or formula Im * A compound of, [ka] [ka] In the formula, R 1b , R 1d , R 1e , R2, R 3a , R 3b The present invention also provides compounds, or pharmaceutically acceptable salts thereof, in which R4, Z1, Z2, Z3, X1, X2, X3, X4, X5, ring A1, ring A2, m, m', s, t, u, v, and w are as defined above. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -N-, Z2 is -C(R 3c)-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, and Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -N-, and Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3cIn one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3cIn one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is hydrogen, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is F. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b However, is methyl, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is - N is -, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is hydrogen, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1bHowever, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1.

[0100] The present invention also relates to compounds of the following formulas: Ia-1, Ib-1, Ic-1, Id-1, Ie-1, or If-1. [ka] In the formula, R 1b , R 1d , R 1e , R2, R 3a , R 3b , R 4b , R 4c , R 4d The present invention also provides compounds, or pharmaceutically acceptable salts thereof, in which Z1, Z2, Z3, X1, X2, X3, ring A1, ring A2, s, t, u, v, and w are as defined above. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3cIn one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, and Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -N-, and Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3cIn one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3cIn one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is hydrogen, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is F. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b However, is methyl, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b Z1 is methyl, Z1 is -C(CN)-, and Z2 is -N- In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is hydrogen, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1bHowever, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1.

[0101] The present invention also relates to the following formula Ia * -1, formula Ib * -1, formula Ic * -1, formula Id * -1, formula Ie * -1, or expression If * A compound of -1, [ka] In the formula, R 1b , R 1d , R 1e , R2, R 3a , R 3b , R 4b , R 4c , R 4d The present invention also provides compounds, or pharmaceutically acceptable salts thereof, in which Z1, Z2, Z3, X1, X2, X3, ring A1, ring A2, s, t, u, v, and w are as defined above. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3cIn one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, and Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -N-, and Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3cIn one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3cIn one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is hydrogen, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is F. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b However, is methyl, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b Z1 is methyl, Z1 is -C(CN)-, and Z2 is -N- In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is hydrogen, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1bHowever, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1.

[0102] The present invention also relates to a compound of the following formula Ih-1, [ka] In the formula, R2, R 3a , R 3b , R 4c , R 4d The present invention also provides compounds, or pharmaceutically acceptable salts thereof, in which Z1, Z2, Z3, X1, and v are as defined above. In one embodiment, R 4c and R 4d However, together with the carbon atoms to which they are bonded, they form a 4-membered, 5-membered, or 6-membered heterocycle. In one embodiment, R 4c and R 4d However, together with the carbon atoms to which they are bonded, they form a four-membered heterocycle. In one embodiment, R 4c and R 4d However, together with the carbon atoms to which they are bonded, they form a five-membered heterocycle. In one embodiment, R 4c and R 4d However, together with the carbon atoms to which they are bonded, they form a six-membered heterocycle. In one embodiment, R 4c However, it is hydroxyl, and R 4d However, C 1~3It is a haloalkyl. In one embodiment, R 4c is hydroxyl, R 4d is fluoromethyl, and v is 1.

[0103] The present invention also relates to the following formula Ih * A compound of -1, [ka] In the formula, R2, R 3a , R 3b , R 4c , R 4d The present invention also provides compounds, or pharmaceutically acceptable salts thereof, in which Z1, Z2, Z3, X1, and v are as defined above. In one embodiment, R 4c and R 4d However, together with the carbon atoms to which they are bonded, they form a 4-membered, 5-membered, or 6-membered heterocycle. In one embodiment, R 4c and R 4d However, together with the carbon atoms to which they are bonded, they form a four-membered heterocycle. In one embodiment, R 4c and R 4d However, together with the carbon atoms to which they are bonded, they form a five-membered heterocycle. In one embodiment, R 4c and R 4d However, together with the carbon atoms to which they are bonded, they form a six-membered heterocycle. In one embodiment, R 4c However, it is hydroxyl, and R 4d However, C 1~3 It is a haloalkyl. In one embodiment, R 4c is hydroxyl, R 4d is fluoromethyl, and v is 1.

[0104] The present invention also relates to compounds of the following formulas: Ia-2, Ib-2, Ic-2, Id-2, Ie-2, or If-2. [ka] In the formula, R 1b , R 1d , R 1e , R2, R3a , R 3b , R 5a , R 5b , R 5c The present invention also provides compounds, or pharmaceutically acceptable salts thereof, in which Z1, Z2, Z3, X1, X2, X3, ring A1, ring A2, p, s, t, u, v, and w are as defined above. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, and Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -N-, and Z2 is -C(R 3c)- and Z3 is -O-, and R2 is F. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )- and Z3 is -S-, and R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )- and Z3 is -S-, and R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )- and Z3 is -S-, and R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )- and Z3 is -S-, and R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )- and Z3 is -O-, and R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c)- wherein Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )- wherein Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )- wherein Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -C(R 3c )- wherein Z3 is -S-, and R2 is Cl. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -C(R 3c )- wherein Z3 is -S-, and R2 is F. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, R 1b is methyl, Z1 is -N-, ZT is -C(R 3c )- wherein Z3 is -S-, and R2 is Cl. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -C(R 3c)-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is hydrogen, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is F. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -O-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, R 1b However, Z1 is methyl, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c)-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is - N is -, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is hydrogen, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -S-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b However, Z1 is methyl, Z1 is -C(CN)-, and Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1bis methyl, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is Cl, and s, t, u, v, and w are 1. In one embodiment, R 1b is methyl, Z1 is -N-, Z2 is -N-, Z3 is -O-, R2 is F, and s, t, u, v, and w are 1.

[0105] The present invention also relates to a compound of the following formula Ia * -2, formula Ib * -2, formula Ic * -2, formula Id * -2, formula Ie * -2, or formula If * -2, wherein

Chemical formula

[0106] The present invention also relates to the following compound of formula Ig-2, [ka] In the formula, R2, R 3a , R 3b , R 5a , R 5b , R 5c , R 5d The present invention also provides compounds, or pharmaceutically acceptable salts thereof, in which Z1, Z2, Z3, X1, p, r, and v are as defined above. In one embodiment, Z1 is -N- and Z2 is -C(R3c )-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -N-, and Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, Z2 is N-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -N-, Z2 is N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, r is 0, and p and v are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is N-, Z3 is -S-, R2 is Cl, r is 0, and p and v are 1. In one embodiment, Z1 is -N-, Z2 is N-, Z3 is -S-, R2 is F, r is 0, and p and v are 1. In one embodiment, Z1 is -N-, Z2 is N-, Z3 is -S-, R2 is Cl, r is 0, and p and v are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, p' is 0, and p and v are 1. In one embodiment, R 5b and R 5c However, each is independent, C 1~3 Alkyl, C substituted with one or more deuterium atoms 1~3 Alkyl, or halogen, or C 1~3 C optionally substituted with a haloalkyl group 3~5 It is a cycloalkyl. In one embodiment, R 5b and R 5c However, together with the nitrogen atoms to which they are bonded, they form optionally substituted 4-membered, 5-membered, or 6-membered heterocycles, and the heterocycles are halogens, C 1~3 Alkyl, or C 1~3 It is optionally substituted with a haloalkyl. In one embodiment, R5b and R 5c However, together with the nitrogen atom to which they are bonded, they form optionally substituted 6-membered, 7-membered, or 8-membered spiroheterocycles, the spiroheterocycles optionally containing further heteroatoms selected from N, O, and S, and the spiroheterocycles contain halogens, C 1~3 Alkyl, or C 1~3 It is optionally substituted with a haloalkyl. In one embodiment, R 5b and R 5c However, together with the nitrogen atom to which they are bonded, they form an optionally substituted 6-membered spiroheterocycle, the 6-membered spiroheterocycle optionally contains further heteroatoms selected from N, O, and S, and the spiroheterocycle is optionally substituted with a halogen. In one embodiment, R 5b and R 5c However, together with the nitrogen atoms to which they are bonded, they form an optionally substituted 7-membered spiroheterocycle, the 7-membered spiroheterocycle optionally contains further heteroatoms selected from N, O, and S, and the spiroheterocycle is optionally substituted with halogens. In one embodiment, R 5a and R 5b However, together with the atoms to which they are bonded, they form a 4-membered, 5-membered, or 6-membered heterocyclic fused ring that optionally contains further heteroatoms selected from N, O, and S, R 5c However, C 1~2 It is alkyl, and the 4-membered, 5-membered, or 6-membered fused ring is C 1~2 It is further optionally substituted with alkyl groups.

[0107] The present invention also relates to the following formula Ig * A compound of -2, [ka] In the formula, R2, R 3a , R 3b , R 5a , R 5b , R 5c , R 5dThe present invention also provides compounds, or pharmaceutically acceptable salts thereof, in which Z1, Z2, Z3, X1, p, r, and v are as defined above. In one embodiment, Z1 is -N- and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -N-, and Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, Z2 is N-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -N-, Z2 is N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -N-, and Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, r is 0, and p and v are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is N-, Z3 is -S-, R2 is Cl, r is 0, and p and v are 1. In one embodiment, Z1 is -N-, Z2 is N-, Z3 is -S-, R2 is F, r is 0, and p and v are 1. In one embodiment, Z1 is -N-, Z2 is N-, Z3 is -S-, R2 is Cl, r is 0, and p and v are 1. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, r is 0, and p and v are 1. In one embodiment, R 5b and R 5c However, each is independent, C 1~3 C substituted with alkyl, 1, 2, or 3 deuterium atoms 1~3 Alkyl, or halogen, or C 1~3 C optionally substituted with a haloalkyl group 3~5 It is a cycloalkyl. In one embodiment, R 5b and R 5cHowever, together with the nitrogen atoms to which they are bonded, they form optionally substituted 4-membered, 5-membered, or 6-membered heterocycles, and the heterocycle contains one or more halogens, deuterium, and C 1~3 Alkyl, or C 1~3 It is optionally substituted with a haloalkyl. In one embodiment, R 5b and R 5c However, together with the nitrogen atom to which they are bonded, they form optionally substituted 6-membered, 7-membered, or 8-membered spiroheterocycles, the spiroheterocycles optionally containing further heteroatoms selected from N, O, and S, and the spiroheterocycles contain halogens, C 1~3 Alkyl, or C 1~3 It is optionally substituted with a haloalkyl. In one embodiment, R 5b and R 5c However, together with the nitrogen atom to which they are bonded, they form an optionally substituted 6-membered spiroheterocycle, the 6-membered spiroheterocycle optionally contains further heteroatoms selected from N, O, and S, and the spiroheterocycle is optionally substituted with a halogen. In one embodiment, R 5b and R 5c However, together with the nitrogen atoms to which they are bonded, they form an optionally substituted 7-membered spiroheterocycle, the 7-membered spiroheterocycle optionally contains further heteroatoms selected from N, O, and S, and the spiroheterocycle is optionally substituted with halogens. In one embodiment, R 5a and R 5b However, together with the atoms to which they are bonded, they form a 4-membered, 5-membered, or 6-membered heterocyclic fused ring that optionally contains further heteroatoms selected from N, O, and S, R 5c However, C 1~2 It is alkyl, and the 4-membered, 5-membered, or 6-membered fused ring is C 1~2 It is further optionally substituted with alkyl groups.

[0108] The present invention also relates to the following compound of formula Ih-2, [ka] In the formula, R2, R 3a , R3b , R 5e , R 5f The present invention also provides compounds, or pharmaceutically acceptable salts thereof, in which Z1, Z2, Z3, X1, and v are as defined above. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and v is 1. In one embodiment, R 5e and R 5f However, together with the carbon atoms to which they are bonded, they form a 4-membered, 5-membered, or 6-membered heterocycle. In one embodiment, R 5e and R 5f However, together with the carbon atoms to which they are bonded, they form a four-membered heterocycle (for example, oxetanyl). In one embodiment, R 5e and R 5f However, together with the carbon atoms to which they are bonded, they form a five-membered heterocycle. In one embodiment, R 5e and R 5f However, together with the carbon atoms to which they are bonded, they form a six-membered heterocycle.

[0109] The present invention also relates to the following formula Ih * A compound of -2, [ka] In the formula, R2, R 3a , R 3b , R 5e , R 5f The present invention also provides compounds, or pharmaceutically acceptable salts thereof, in which Z1, Z2, Z3, X1, and v are as defined above. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R3c )-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, and v is 1. In one embodiment, R 5e and R 5f However, together with the carbon atoms to which they are bonded, they form a 4-membered, 5-membered, or 6-membered heterocycle. In one embodiment, R 5e and R 5f However, together with the carbon atoms to which they are bonded, they form a four-membered heterocycle (for example, oxetanyl). In one embodiment, R 5e and R 5f However, together with the carbon atoms to which they are bonded, they form a five-membered heterocycle. In one embodiment, R 5e and R 5f However, together with the carbon atoms to which they are bonded, they form a six-membered heterocycle.

[0110] The present invention further relates to the following compound of formula Ia-3, [ka] In the formula, R2, R 3a , R 3b , R7, R 7a The present invention also provides compounds, or pharmaceutically acceptable salts thereof, in which Z1, Z2, Z3, X1, and v are as defined above. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, R7 is C 1~2 It is alkyl, R 7aHowever, it is a 4-membered, 5-membered, or 6-membered heterocycle optionally containing further heteroatoms selected from N, O, and S. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, R7 is C 1~2 It is alkyl, R 7a However, it is a four-membered heterocycle that optionally contains further heteroatoms selected from N, O, and S. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, R is 7 is C 1~2 It is alkyl, R 7a However, it is a five-membered heterocycle that optionally contains further heteroatoms selected from N, O, and S. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, R7 is C 1~2 It is alkyl, R 7a However, it is a six-membered heterocycle that optionally contains further heteroatoms selected from N, O, and S. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, R7 is C 1~2 It is alkyl, and R7 and R 7a However, together with the atoms to which they are bonded, they form a 4-membered, 5-membered, or 6-membered heterocyclic ring optionally containing further heteroatoms selected from N, O, and S. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, R7 is C 1~2 It is alkyl, and R7 and R 7a However, together with the atoms to which they are bonded, they form a six-membered heterocyclic ring that optionally contains further heteroatoms selected from N, O, and S.

[0111] The present invention further includes the following formula Ia * A compound of -3, [ka] In the formula, R2, R 3a , R 3b , R7, R 7a The present invention also provides compounds, or pharmaceutically acceptable salts thereof, in which Z1, Z2, Z3, X1, and v are as defined above. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, R7 is C 1~2 It is alkyl, R 7a However, it is a 4-membered, 5-membered, or 6-membered heterocycle optionally containing further heteroatoms selected from N, O, and S. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, R7 is C 1~2 It is alkyl, R 7a However, it is a four-membered heterocycle that optionally contains further heteroatoms selected from N, O, and S. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, R7 is C 1~2 It is alkyl, R 7a However, it is a five-membered heterocycle that optionally contains further heteroatoms selected from N, O, and S. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, R7 is C 1~2 It is alkyl, R 7a However, it is a six-membered heterocycle (e.g., 1,4-dioxanyl) optionally containing further heteroatoms selected from N, O, and S. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c)-, Z3 is -S-, R2 is Cl, R7 is C 1~2 It is alkyl, and R7 and R 7a However, together with the atoms to which they are bonded, they form a 4-membered, 5-membered, or 6-membered heterocyclic ring optionally containing further heteroatoms selected from N, O, and S. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, R7 is C 1~2 It is alkyl, and R7 and R 7a However, together with the atoms to which they are bonded, they form a six-membered heterocyclic ring (e.g., morpholinyl) which optionally contains further heteroatoms selected from N, O, and S.

[0112] The present invention also relates to the following compound of formula Ig-1, [ka] In the formula, R2, R 3a , R 3b , R 3c The present invention also provides a compound, or a pharmaceutically acceptable salt thereof, in which R6, Z1, Z2, Z3, X1, v, and n are as defined above. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, and Z2 is -C(R 3cIn one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -N-, and Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, v is 1, and n is 0. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3cIn one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is Cl, v is 1, and n is 0. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is Cl, v is 1, and n is 0. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is F, v is 1, and n is 0. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is F, v is 1, and n is 0. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, v is 1, and n is 0.

[0113] The present invention also relates to the following formula Ig * A compound of -1, [ka] In the formula, R2, R 3a , R 3b , R 3c The present invention also provides a compound, or a pharmaceutically acceptable salt thereof, in which R6, Z1, Z2, Z3, X1, v, and n are as defined above. In one embodiment, Z1 is -C(CN)- and Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, and Z2 is -C(R 3cIn one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R2 is Cl. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -S-, and R2 is F. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -N-, and Z2 is -C(R 3c In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is Cl. In one embodiment, Z1 is -N-, Z2 is -N-, Z3 is -O-, and R2 is F. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3c )-, Z3 is -S-, R2 is Cl, v is 1, and n is 0. In one embodiment, Z1 is -C(CN)-, Z2 is -C(R 3cIn one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is Cl, v is 1, and n is 0. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is Cl, v is 1, and n is 0. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is F, v is 1, and n is 0. In one embodiment, Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R2 is F, v is 1, and n is 0. In one embodiment, Z1 is -N-, Z2 is -C(R 3c )-, Z3 is -S-, R2 is F, v is 1, and n is 0.

[0114] References to Equation I include Equations I', Ia, Ib, Ic, Id, Ie, If, Ih, Ii, Ij, Ik, Im, Ia * Ib * ,I C * Id * , Ie * If * Ih * , II * Ij * Ik * Im * , Ia-1, Ib-1, Ic-1, Id-1, Ie-1, If-1, Ig-1, Ih-1, Ia * -1, Ib * -1, Ic * -1, Id * -1, Ie * -1, If * -1, Ig * -1, Ih * -1, Ia-2, Ib-2, Ic-2, Id-2, Ie-2, If-2, Ig-2, Ih-2, Ia * -2, Ib * -2, Ic * -2, Id * -2, Ie * -2, If * -2, Ig * -2, Ih * -2, Ia-3, or Ia *It should be understood that this refers to compounds of formula I, including -3, along with any and all subformulas disclosed herein.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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 described herein. In further embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, the compound is obtained by deuteration at one or more positions. Unless otherwise specified, when an atom is specifically designated as "H" or "hydrogen", the atom is understood to have hydrogen in its isotopic composition of natural abundance. Also, unless otherwise specified, when an atom is specifically designated as "D" or "deuterium", the atom is understood to have deuterium in an abundance substantially greater than the natural abundance of deuterium, which is 0.015%.

[0119] The following are further numbered embodiments of the present invention:

[0120] Embodiment 1. A compound of the following formula, [ka] During the ceremony, A is -C(H)- or -N-, B is -C(R4)- or -N-, R1 is given by the following equation [ka] It is the basis of, R 1b However, H or C 1~3 It is alkyl, R 1d However, C 1~3 Alkyl, C 1~3 Haloalkyl, or C 3~4 It is a cycloalkyl, R 1e However, C 1~3 It is alkylene, Rings A1 and A2 are C 3~4 A cycloalkyl or a three- or four-membered heterocycle containing a heteroatom selected from N, O, and S, X1 and X2 are -CH- or -N-, X3 is -CH2- or -O-, X4 and X5 each operate independently, C 1~3 Alkyl, halogen, or H, m, m', s, t, u, v, and w are each 0 or 1. R2 is halogen or C 1~3 It is alkyl, Z1 is -C(CN)- or -N-, Z2, -C(R 3c )- or -N-, Z3 is -O- or -S-, R 3a , R 3b , and R 3c However, each is independent of H, halogen, or C. 1~3 It is alkyl, R4 is H, C1~3 C is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, hydroxyl, and methyl. 1~3 It is an alkoxy, or R4 is given by the following formula (i) [ka] (In the formula, R 4b However, it is either H or methyl, R 4c and R 4d However, each is independent, C 1~3 Alkyl, hydroxyl, or C 1~3 It is a haloalkyl, or R 4c and R 4d However, together with the nitrogen or carbon atom to which they are bonded, they form a 4-membered, 5-membered, or 6-membered heterocycle), or (ii) [ka] (In the formula, R 5a However, halogens, hydroxy, C 1~3 Alkyl, C 1~3 Alkoxy, or C 1~3 Alkoxy-C 1~3 It is alkyl, R 5d However, C 1~3 It is alkyl, R 5e and R 5f However, together with the carbon atoms to which they are bonded, Forming a 4-member, 5-member, or 6-member complex ring, R 5b and R 5c However, each is independently replaced by H and C, which are optionally substituted with one or more deuterium atoms. 1~6 Alkyl, halogen, or C 1~3 C optionally substituted with a haloalkyl group 3~5It is a cycloalkyl, or a 3-membered, 4-membered, or 5-membered heterocycle containing a heteroatom selected from N, O, and S, or R 5b and R 5c However, together with the nitrogen atoms to which they are bonded, they form optionally substituted 4-membered, 5-membered, or 6-membered heterocycles or 6-membered, 7-membered, or 8-membered spiroheterocycles, each heterocycle or spiroheterocycle optionally containing a further heteroatom selected from N, O, and S, and each heterocycle and spiroheterocycle contains one or more halogens, deuterium, and C 1~3 Alkyl, or C 1~3 It is optionally substituted with a haloalkyl, or R 5a and R 5b However, together with the atoms to which they are bonded, they form a 4-membered, 5-membered, or 6-membered heterocyclic fused ring that optionally contains further heteroatoms selected from N, O, and S, R 5c However, C 1~3 It is alkyl, and the 4-membered, 5-membered, or 6-membered fused ring is C 1~3 It is further optionally substituted with alkyl groups. (where p and r are 0, 1, or 2, respectively) (iii) [ka] (In the formula, R6 is halogen, hydroxyl, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, and C 1~3 Selected from dialkylaminos, n is 0 or 1), and (iv) [ka] (In the formula, R7 is C 1~3 It is alkyl, R 7aHowever, it is a 4-membered, 5-membered, or 6-membered heterocycle that optionally contains further heteroatoms selected from N, O, and S, or R7 and R 7a Compounds that are groups of (but together with the atoms to which they are bonded, form a 4-membered, 5-membered, or 6-membered heterocyclic ring which optionally contains further heteroatoms selected from N, O, and S), or a pharmaceutically acceptable salt thereof.

[0121] Embodiment 2. A compound of the following formula, [ka] During the ceremony, R1 is given by the following equation [ka] It is the basis of, R 1b However, H or C 1~3 It is alkyl, R 1d However, C 1~3 It is alkyl, R 1e However, C 1~3 It is alkylene, Rings A1 and A2 are C 3~4 A cycloalkyl or a three- or four-membered heterocycle containing a heteroatom selected from N, O, and S, X1 and X2 are -CH- or -N-, X3 is -CH2- or -O-, X4 and X5 each operate independently, C 1~3 Alkyl, halogen, or H, m, m', s, t, u, v, and w are each 0 or 1. R2 is a halogen, Z1 is -C(CN)- or -N-, Z2, -C(R 3c )- or -N-, Z3 is -O- or -S-, R 3a , R3b , and R 3c However, each is independently either H or halogen, R4 is given by the following formula (i) [ka] (In the ceremony R 4b However, it is H or methyl, R 4c and R 4d However, each is independent, C 1~3 (It is alkyl), or (ii) [ka] (In the formula, R 5a However, halogens, hydroxy, C 1~3 Alkyl, C 1~3 Alkoxy, or C 1~3 Alkoxy-C 1~3 It is alkyl, R 5b and R 5c However, H and C are independent of each other. 1~6 Alkyl, C 3~5 It is a cycloalkyl, or a 3-membered, 4-membered, or 5-membered heterocycle containing a heteroatom selected from N, O, and S, or R 5b and R 5c However, together with the nitrogen atom to which they are bonded, they form an optionally substituted 4-membered, 5-membered, 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 substituted with alkyl, or R 5a and R 5b However, together with the atoms to which they are bonded, they form a 4-membered, 5-membered, or 6-membered heterocyclic fused ring that optionally contains further heteroatoms selected from N, O, and S, R 5c However, C 1~3 It is alkyl, and the 4-membered, 5-membered, or 6-membered fused ring is C 1~3It is further optionally substituted with alkyl groups. p is 0, 1, or 2), (iii) [ka] (In the formula, R6 is halogen, hydroxyl, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, and C 1~3 Selected from dialkylaminos, A compound in which n is the group (where n is 0 or 1), or a pharmaceutically acceptable salt thereof.

[0122] Embodiment 3. A compound of the following formula, [ka] During the ceremony, R1 is given by the following equation [ka] It is the basis of, R 1b However, C 1~3 It is alkyl, R 1d However, C 1~3 It is alkyl, R 1e However, C 1~3 It is alkylene, Rings A1 and A2 are C 3~4 A cycloalkyl or a three- or four-membered heterocycle containing a heteroatom selected from N, O, and S, X1 and X2 are -CH- or -N-, X3 is -CH2- or -O-, s, t, u, v, and w are each 0 or 1. R2 is a halogen, Z1 is -C(CN)- or -N-, Z2, -C(R 3c)- or -N-, Z3 is -O- or -S-, R 3a , R 3b , and R 3c However, each is independently either H or halogen, R4 is given by the following formula (i) [ka] (In the ceremony R 4b However, it is H or methyl, R 4c and R 4d However, each is independent, C 1~3 (It is alkyl), or (ii) [ka] (In the ceremony R 5a However, halogens, hydroxy, C 1~3 Alkyl, C 1~3 Alkoxy, or C 1~3 Alkoxy-C 1~3 It is alkyl, R 5b and R 5c However, H and C are independent of each other. 1~6 Alkyl, C 3~5 It is a cycloalkyl, or a 3-membered, 4-membered, or 5-membered heterocycle containing a heteroatom selected from N, O, and S, or R 5b and R 5c However, together with the nitrogen atom to which they are bonded, they form an optionally substituted 4-membered, 5-membered, 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 substituted with alkyl, or R 5a and R 5b However, together with the atoms to which they are bonded, they form a 4-membered, 5-membered, or 6-membered heterocyclic fused ring that optionally contains further heteroatoms selected from N, O, and S, R 5cHowever, C 1~3 It is alkyl, and the 4-membered, 5-membered, or 6-membered fused ring is C 1~3 It is further optionally substituted with alkyl groups. Compounds in which p is a group (where p is 0 or 1), or a pharmaceutically acceptable salt thereof.

[0123] Embodiment 4.R1 is the following formula [ka] The compound described in any one of Embodiments 1 to 3, which is the base of or a pharmaceutically acceptable salt thereof.

[0124] Embodiment 5.R 1d The compound described in Embodiment 4, or a pharmaceutically acceptable salt thereof, wherein the compound is methyl or ethyl.

[0125] Embodiment 6.R1 is the following formula [ka] The compound described in Embodiment 1, which is the base of or a pharmaceutically acceptable salt thereof.

[0126] Embodiment 7.R 1d The compound described in Embodiment 1 or 6, or a pharmaceutically acceptable salt thereof, wherein the compound is methyl, ethyl, or difluoromethyl.

[0127] Embodiment 8.R1 is the following formula [ka] The compound described in any one of Embodiments 1 to 3, which is the base of or a pharmaceutically acceptable salt thereof.

[0128] Embodiment 9.R 1e However, the compound described in Embodiment 8, or a pharmaceutically acceptable salt thereof, is methylene.

[0129] Embodiment 10.R1 is the following formula [ka] The compound described in any one of Embodiments 1 to 3, which is the base of or a pharmaceutically acceptable salt thereof.

[0130] Embodiment 11. Ring A1 is C 3~4 A cycloalkyl compound as described in Embodiment 10, or a pharmaceutically acceptable salt thereof.

[0131] Embodiment 12. The compound according to Embodiment 10, or a pharmaceutically acceptable salt thereof, wherein ring A1 is cyclopropyl.

[0132] Embodiment 13. The compound according to Embodiment 10, or a pharmaceutically acceptable salt thereof, wherein ring A1 is cyclobutyl.

[0133] Embodiment 14. The compound according to Embodiment 10, or a pharmaceutically acceptable salt thereof, wherein ring A1 is a three-membered or four-membered heterocycle containing a heteroatom selected from N, O, and S.

[0134] Embodiment 15. The compound according to Embodiment 10, or a pharmaceutically acceptable salt thereof, wherein ring A1 is oxetanyl.

[0135] Embodiment 16.R1 is the following formula [ka] The compound described in any one of Embodiments 1 to 3, which is the base of or a pharmaceutically acceptable salt thereof.

[0136] Embodiment 17. Ring A2 is C 3~4 A cycloalkyl compound as described in Embodiment 16, or a pharmaceutically acceptable salt thereof.

[0137] Embodiment 18. The compound according to Embodiment 16, or a pharmaceutically acceptable salt thereof, wherein ring A2 is cyclopropyl.

[0138] Embodiment 19. The compound according to Embodiment 16, or a pharmaceutically acceptable salt thereof, wherein ring A2 is cyclobutyl.

[0139] Embodiment 20. The compound according to Embodiment 16, or a pharmaceutically acceptable salt thereof, wherein ring A2 is a three-membered or four-membered heterocycle containing a heteroatom selected from N, O, and S.

[0140] Embodiment 21. The compound according to Embodiment 16, or a pharmaceutically acceptable salt thereof, wherein ring A2 is oxetanyl.

[0141] Embodiment 22.A is a compound according to any one of Embodiments 1 or 4 to 21, or a pharmaceutically acceptable salt thereof, wherein the compound is -C(H)-.

[0142] Embodiment 23.A is a compound according to any one of Embodiments 1 or 4 to 21, or a pharmaceutically acceptable salt thereof, wherein Embodiment 23.A is -N-.

[0143] Embodiment 24.B is a compound according to any one of Embodiments 1 or 4 to 23, or a pharmaceutically acceptable salt thereof, wherein Embodiment 24.B is -C(R4)-.

[0144] Embodiment 25.B is a compound according to any one of Embodiments 1 or 4 to 23, or a pharmaceutically acceptable salt thereof.

[0145] Embodiment 26.R 1b However, C 1~3 A compound according to any one of Embodiments 1 to 25, or a pharmaceutically acceptable salt thereof, which is alkyl.

[0146] Embodiment 27.R 1b The compound described in any one of Embodiments 1 to 25, or a pharmaceutically acceptable salt thereof, wherein the compound is methyl.

[0147] Embodiment 28.R 1b However, the compound described in any one of Embodiments 1 to 25, or a pharmaceutically acceptable salt thereof, is hydrogen.

[0148] Embodiment 29.R1 is the following formula [ka] The compound described in Embodiment 1, which is the base of or a pharmaceutically acceptable salt thereof.

[0149] Embodiment 30. The compound according to Embodiment 29, or a pharmaceutically acceptable salt thereof, wherein X4 and X5 are fluoro.

[0150] Embodiment 31.X3 is, A compound according to Embodiment 29 or 30, or a pharmaceutically acceptable salt thereof, which is -O-.

[0151] Embodiment 32.X3 is, A compound according to Embodiment 29 or 30, which is -CH2-, or a pharmaceutically acceptable salt thereof.

[0152] Embodiment 33.R1 is given by the following formula [ka] The compound described in Embodiment 1, which is the base of or a pharmaceutically acceptable salt thereof.

[0153] Embodiment 34. The compound according to Embodiment 33, or a pharmaceutically acceptable salt thereof, wherein X4 is methyl and X5 is hydrogen.

[0154] Embodiment 35.X3 is, A compound according to Embodiment 33 or 34, or a pharmaceutically acceptable salt thereof, which is -O-.

[0155] Embodiment 36.R1 is the following formula [ka] The compound described in any one of Embodiments 1 to 3, which is the base of or a pharmaceutically acceptable salt thereof.

[0156] Embodiment 37. The compound according to Embodiment 36, or a pharmaceutically acceptable salt thereof, wherein X1 is -CH-.

[0157] Embodiment 38. The compound according to Embodiment 36, or a pharmaceutically acceptable salt thereof, wherein X1 is -N-.

[0158] Embodiment 39.R1 is the following formula [ka] The compound described in any one of Embodiments 1 to 3, which is the base of or a pharmaceutically acceptable salt thereof.

[0159] Embodiment 40.X2 is -CH-, the compound according to Embodiment 39, or a pharmaceutically acceptable salt thereof.

[0160] Embodiment 41. The compound according to Embodiment 39, or a pharmaceutically acceptable salt thereof, wherein X2 is -N-.

[0161] Embodiment 42.X3 is a compound according to any one of Embodiments 39 to 41, or a pharmaceutically acceptable salt thereof.

[0162] Embodiment 43.X3 is -O-, a compound according to any one of Embodiments 39 to 41, or a pharmaceutically acceptable salt thereof.

[0163] Embodiment 44.R1 is given by the following formula [ka] A compound described in any one of Embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

[0164] Embodiment 45.R1 is the following formula [ka] The compound described in Embodiment 44, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

[0165] Embodiment 46.R1 is the following formula [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

[0166] Embodiment 47.R1 is the following formula [ka] A compound described in Embodiments 1 to 2 or 46, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

[0167] Embodiment 48.R1 is the following formula [ka] The compound described in Embodiment 46, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

[0168] Embodiment 49.R1 is the following formula [ka] The compound described in Embodiment 46 or 47, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

[0169] Embodiment 50. A compound according to any one of Embodiments 1 to 49, or a pharmaceutically acceptable salt thereof, wherein R2 is F or Cl.

[0170] Embodiment 51. A compound according to any one of Embodiments 1 to 50, or a pharmaceutically acceptable salt thereof, wherein R2 is F.

[0171] Embodiment 52. A compound according to any one of Embodiments 1 to 50, or a pharmaceutically acceptable salt thereof, wherein R2 is Cl.

[0172] Embodiment 53. The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R2 is methyl.

[0173] Embodiment 54. Z1 is -C(CN)- and Z2 is -C(R 3c )- and Z3 is -S- and R 3a The compound described in any one of Embodiments 1 to 53, or a pharmaceutically acceptable salt thereof, wherein H is present.

[0174] Embodiment 55.R 3b However, it is a halogen (preferably fluoro), and R 3c The compound described in Embodiment 54, or a pharmaceutically acceptable salt thereof, wherein H is present.

[0175] Embodiment 56.R 3b However, H is R 3c The compound described in Embodiment 54, or a pharmaceutically acceptable salt thereof, wherein the compound is halogen (preferably fluoro).

[0176] Embodiment 57.R 3b However, it is a halogen (preferably fluoro), and R 3c The compound described in Embodiment 54, or a pharmaceutically acceptable salt thereof, wherein the compound is halogen (preferably fluoro).

[0177] Embodiment 58. Z1 is -C(CN)-, Z2 is -N-, Z3 is -S-, R 3a The compound described in any one of Embodiments 1 to 53, or a pharmaceutically acceptable salt thereof, wherein H is present.

[0178] Embodiment 59.R 3b The compound described in Embodiment 58, or a pharmaceutically acceptable salt thereof, wherein the compound is halogen (preferably fluoro).

[0179] Embodiment 60. Z1 is -N- and Z2 is -C(R 3c )- and Z3 is -S- and R 3a The compound described in any one of Embodiments 1 to 53, or a pharmaceutically acceptable salt thereof, wherein H is present.

[0180] Embodiment 61.R 3b However, it is a halogen (preferably fluoro), and R 3c The compound described in Embodiment 60, or a pharmaceutically acceptable salt thereof, wherein H is present.

[0181] Embodiment 62.R 3b However, H is R 3c The compound described in Embodiment 60, or a pharmaceutically acceptable salt thereof, is a halogen (preferably fluoro).

[0182] Embodiment 63.R 3b However, it is a halogen (preferably fluoro), and R 3c The compound described in Embodiment 60, or a pharmaceutically acceptable salt thereof, is a halogen (preferably fluoro).

[0183] Embodiment 64.R 3b However, H is R 3c The compound described in Embodiment 60, or a pharmaceutically acceptable salt thereof, wherein H is present.

[0184] Embodiment 65. Z1 is -N-, Z2 is -N-, Z3 is -S-, R 3a The compound described in any one of Embodiments 1 to 53, or a pharmaceutically acceptable salt thereof, wherein H is present.

[0185] Embodiment 66.R 3b The compound described in Embodiment 65, or a pharmaceutically acceptable salt thereof, wherein the compound is halogen (preferably fluoro).

[0186] Embodiment 67. Z1 is -N- and Z2 is -C(R 3c )- and Z3 is -O- and R3a The compound described in any one of Embodiments 1 to 53, or a pharmaceutically acceptable salt thereof, wherein H is present.

[0187] Embodiment 68.R 3b However, the compound described in Embodiment 67, or a pharmaceutically acceptable salt thereof, is hydrogen.

[0188] Embodiment 69.R 3b The compound according to any one of Embodiments 1 to 53, or a pharmaceutically acceptable salt thereof, wherein the compound is fluoro or hydrogen.

[0189] Embodiment 70.R 3b However, the compound described in any one of Embodiments 1 to 53, or a pharmaceutically acceptable salt thereof, is fluoro.

[0190] Embodiment 71.R 3a The compound described in any one of Embodiments 1 or 4 to 53, or a pharmaceutically acceptable salt thereof, wherein the compound is methyl.

[0191] Embodiment 72.R 3b However, the compound described in any one of Embodiments 1 to 53, or a pharmaceutically acceptable salt thereof, is hydrogen.

[0192] Embodiment 73.R4 is H, C 1~3 C is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, hydroxyl, and methyl. 1~3 A compound that is an alkoxy, as described in any one of Embodiments 1 or 4 to 72, or a pharmaceutically acceptable salt thereof.

[0193] Embodiment 74. The compound described in Embodiment 73, or a pharmaceutically acceptable salt thereof, wherein R4 is H.

[0194] Embodiment 75.R4 is given by the following formula [ka] A compound described in any one of Embodiments 1 to 72, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

[0195] Embodiment 76.R4 is given by the following formula [ka] The compound described in Embodiment 75, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

[0196] Embodiment 77.R4 is given by the following formula [ka] The compound described in Embodiment 76, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

[0197] Embodiment 78.R4 is given by the following formula [ka] A compound described in any one of Embodiments 1 or 4 to 72, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

[0198] Embodiment 79.R4 is given by the following formula [ka] A compound described in Embodiment 1 or 78, which is the base of, or a pharmaceutically acceptable salt thereof.

[0199] Embodiment 80.R4 is given by the following formula [ka] A compound described in any one of Embodiments 1 or 4 to 72, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

[0200] Embodiment 81.R4 is given by the following formula [ka] A compound described in any one of Embodiments 1 or 4 to 72, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

[0201] Embodiment 82.R4 is the following formula [ka] The compound described in Embodiment 81, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

[0202] Embodiment 83.R4 is given by the following formula [ka] The compound described in any one of embodiments 1 to 72 or 81, which is the base of or a pharmaceutically acceptable salt thereof.

[0203] Embodiment 84.R4 is given by the following formula [ka] The compound described in Embodiment 83, which is the base of or a pharmaceutically acceptable salt thereof.

[0204] Embodiment 85.R4 is given by the following formula [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

[0205] Embodiment 86.R4 is given by the following formula [ka] The compound described in Embodiment 84 or 85, which is the base of, or a pharmaceutically acceptable salt thereof.

[0206] Embodiment 87.R4 is given by the following formula [ka] The compound described in Embodiment 84 or 85, which is the base of, or a pharmaceutically acceptable salt thereof.

[0207] Embodiment 88.R4 is given by the following formula [ka] The compound described in Embodiment 84 or 85, which is the base of, or a pharmaceutically acceptable salt thereof.

[0208] Embodiment 89.R4 is given by the following formula [ka] The compound described in Embodiment 84 or 85, which is the base of, or a pharmaceutically acceptable salt thereof.

[0209] Embodiment 90.R4 is given by the following formula [ka] The compound described in Embodiment 84 or 85, which is the base of, or a pharmaceutically acceptable salt thereof.

[0210] Embodiment 91.R4 is the following formula [ka] The compound described in Embodiment 84 or 85, which is the base of, or a pharmaceutically acceptable salt thereof.

[0211] Embodiment 92.R4 is the following formula [ka] The compound described in Embodiment 84 or 85, which is the base of, or a pharmaceutically acceptable salt thereof.

[0212] Embodiment 93.R4 is given by the following formula [ka] The compound described in Embodiment 84 or 85, which is the base of, or a pharmaceutically acceptable salt thereof.

[0213] Embodiment 94.R4 is the following formula [ka] The compound described in Embodiment 84 or 85, which is the base of, or a pharmaceutically acceptable salt thereof.

[0214] Embodiment 95.R4 is given by the following formula [ka] The compound described in Embodiment 84 or 85, which is the base of, or a pharmaceutically acceptable salt thereof.

[0215] Embodiment 96.R4 is given by the following formula [ka] The compound described in Embodiment 84 or 85, which is the base of, or a pharmaceutically acceptable salt thereof.

[0216] Embodiment 97.R4 is the following formula [ka] The compound described in Embodiment 84 or 85, which is the base of, or a pharmaceutically acceptable salt thereof.

[0217] Embodiment 98.R4 is the following formula [ka] The compound described in Embodiment 84 or 85, which is the base of, or a pharmaceutically acceptable salt thereof.

[0218] Embodiment 99.R4 is given by the following formula [ka] The compound described in Embodiment 84 or 85, which is the base of, or a pharmaceutically acceptable salt thereof.

[0219] Embodiment 100.R4 is given by the following formula [ka] The compound described in any one of Embodiments 1-2 or 4-72, which is the base of or a pharmaceutically acceptable salt thereof.

[0220] Embodiment 101. The compound described in Embodiment 100, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0221] Embodiment 102.R6 is C 1~3 Alkyl, C 1~3 Haloalkyl and C 1~3 A compound selected from dialkylaminos, as described in Embodiment 100, or a pharmaceutically acceptable salt thereof.

[0222] Embodiment 103. A compound according to any one of Embodiments 100 to 102, or a pharmaceutically acceptable salt thereof, wherein R6 is dimethylamino.

[0223] Embodiment 104.R4 is given by the following formula [ka] A compound described in any one of embodiments 102 to 103, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

[0224] Embodiment 105.R4 is given by the following formula [ka] A compound described in any one of Embodiments 1 or 4 to 72, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

[0225] Embodiment 106. R7 is C 1~3 It is alkyl, R 7a However, it is a 4-membered, 5-membered, or 6-membered heterocycle that optionally contains further heteroatoms selected from N, O, and S, or R7 and R 7a The compound according to Embodiment 105, wherein these atoms, together with the atoms to which they are bonded, form a four-membered, five-membered, or six-membered heterocyclic ring optionally containing further heteroatoms selected from N, O, and S.

[0226] Embodiment 107.R4 is given by the following formula [ka] A compound described in Embodiment 105 or 106, which is the base of, or a pharmaceutically acceptable salt thereof.

[0227] Embodiment 108. The compound is [ka] [ka] A compound selected from any one of Embodiments 1 to 3, or a pharmaceutically acceptable salt thereof.

[0228] Embodiment 109. The compound is [ka] [ka] A compound selected from any one of Embodiments 1 to 3 or 108, or a pharmaceutically acceptable salt thereof.

[0229] Embodiment 110. The compound is [ka] [ka] [ka] [ka] A compound selected from Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof.

[0230] Embodiment 111. The compound is [ka] [ka] [ka] A compound according to any one of Embodiments 1, 2, or 110, or a pharmaceutically acceptable salt thereof, selected from the above.

[0231] Embodiment 112. The compound is [ka] [ka] [ka] [ka] A compound selected from Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0232] Embodiment 113. The compound is [ka] [ka] [ka] [ka] A compound selected from Embodiment 1 or 112, or a pharmaceutically acceptable salt thereof.

[0233] Embodiment 114. A pharmaceutical composition comprising a compound described in any one of Embodiments 1 to 113, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0234] Embodiment 115. A method for treating a patient having cancer, comprising administering an effective amount of the pharmaceutical composition described in Embodiment 114 to a patient in need of treatment, 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.

[0235] Embodiment 116. A method for treating a patient having cancer, comprising administering to a patient in need of treatment an effective amount of a compound described in any one of Embodiments 1 to 113, 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.

[0236] Embodiment 117. The method according to Embodiment 115 or 116, 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.

[0237] Embodiment 118. The method according to Embodiment 115 or 116, wherein one or more cells express the KRAS G12V mutant protein.

[0238] Embodiment 119. A method for treating a patient having cancer with a KRAS G12V mutation, comprising administering to a patient in need of treatment an effective amount of a compound described in any one of Embodiments 1 to 113, or a pharmaceutically acceptable salt thereof.

[0239] Embodiment 120. The method according to Embodiment 119, 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.

[0240] Embodiment 121. The method according to any one of Embodiments 115 to 120, wherein the patient is also administered an effective dose of 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.

[0241] Embodiment 122. A compound according to any one of Embodiments 1 to 113, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0242] Embodiment 123. A compound according to any one of Embodiments 1 to 113, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0243] Embodiment 124. A compound for use described in Embodiment 123, or a pharmaceutically acceptable salt thereof, wherein the cancer has a KRAS G12V mutation.

[0244] Embodiment 125. A compound for use according to Embodiment 123 or 124, 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.

[0245] Embodiment 126. A compound according to any one of Embodiments 1 to 113, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in combination with, separately combined with, or sequentially combined with 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.

[0246] Embodiment 127. The method according to Embodiment 121, or the compound for use described in Embodiment 126, or a pharmaceutically acceptable salt thereof, wherein the patient is also administered an effective amount of a PD-1 inhibitor.

[0247] Embodiment 128. The method according to Embodiment 121, or the compound for use described in Embodiment 126, or a pharmaceutically acceptable salt thereof, wherein the patient is also administered an effective amount of a PD-L1 inhibitor.

[0248] Embodiment 129. The method according to Embodiment 121, or the compound for use described in Embodiment 126, or a pharmaceutically acceptable salt thereof, wherein the patient is also administered an effective amount of a CDK4 / CDK6 inhibitor.

[0249] Embodiment 130. The method according to Embodiment 121, or the compound for use described in Embodiment 126, or a pharmaceutically acceptable salt thereof, wherein the patient is also administered an effective amount of an EGFR inhibitor.

[0250] Embodiment 131. The method according to Embodiment 121, or the compound for use described in Embodiment 126, or a pharmaceutically acceptable salt thereof, wherein the patient is also administered an effective amount of an ERK inhibitor.

[0251] Embodiment 132. The method according to Embodiment 121, or the compound for use described in Embodiment 126, or a pharmaceutically acceptable salt thereof, wherein the patient is also administered an effective amount of an Aurora A inhibitor.

[0252] Embodiment 133. The method according to Embodiment 121, or the compound for use described in Embodiment 126, or a pharmaceutically acceptable salt thereof, wherein the patient is also administered an effective amount of an SHP2 inhibitor.

[0253] Embodiment 134. The method according to Embodiment 121, or the compound for use described in Embodiment 126, or a pharmaceutically acceptable salt thereof, wherein the patient is also administered an effective amount of platinum.

[0254] Embodiment 135. The method according to Embodiment 121, or the compound for use described in Embodiment 126, or a pharmaceutically acceptable salt thereof, wherein the patient is also administered an effective amount of pemetrexed, or a pharmaceutically acceptable salt thereof.

[0255] Embodiment 136. The method according to any one of Embodiments 115-121 or 127-135, or the compound for use described in any one of Embodiments 123-135, or a pharmaceutically acceptable salt thereof, wherein the cancer is non-small cell lung cancer.

[0256] Embodiment 137. The method according to any one of Embodiments 115-121 or 127-135, or a compound for use according to any one of Embodiments 123-135, or a pharmaceutically acceptable salt thereof, wherein the cancer is colorectal cancer.

[0257] Embodiment 138. The method according to any one of Embodiments 115-121 or 127-135, or the compound for use described in any one of Embodiments 123-135, or a pharmaceutically acceptable salt thereof, wherein the cancer is pancreatic cancer.

[0258] Embodiment 139. The method according to any one of Embodiments 115-121 or 127-135, or a compound for use according to any one of Embodiments 123-135, or a pharmaceutically acceptable salt thereof, wherein the cancer is cervical cancer.

[0259] Embodiment 140. The method according to any one of Embodiments 115-121 or 127-135, or the compound for use described in any one of Embodiments 123-135, or a pharmaceutically acceptable salt thereof, wherein the cancer is esophageal cancer.

[0260] Embodiment 141. The method according to any one of Embodiments 115-121 or 127-135, or a compound for use according to any one of Embodiments 123-135, or a pharmaceutically acceptable salt thereof, wherein the cancer is endometrial cancer.

[0261] Embodiment 142. The method according to any one of Embodiments 115-121 or 127-135, or the compound for use described in any one of Embodiments 123-135, or a pharmaceutically acceptable salt thereof, wherein the cancer is ovarian cancer.

[0262] Embodiment 143. The method according to any one of Embodiments 115-121 or 127-135, or the compound for use described in any one of Embodiments 123-135, or a pharmaceutically acceptable salt thereof, wherein the cancer is cholangiocarcinoma.

[0263] Embodiment 144. The method according to any one of Embodiments 115-121 or 127-135, or the compound for use described in any one of Embodiments 123-135, or a pharmaceutically acceptable salt thereof, wherein the cancer is gastric adenocarcinoma.

[0264] Embodiment 145. The method according to any one of Embodiments 115-121 or 127-135, or the compound for use described in any one of Embodiments 123-135, or a pharmaceutically acceptable salt thereof, wherein the cancer is invasive ductal carcinoma.

[0265] Embodiment 146. The method according to any one of Embodiments 115-121 or 127-135, or a compound for use according to any one of Embodiments 123-135, or a pharmaceutically acceptable salt thereof, wherein the cancer is uterine carcinosarcoma.

[0266] Embodiment 147. The method according to any one of Embodiments 115-121 or 127-135, or the compound for use described in any one of Embodiments 123-135, or a pharmaceutically acceptable salt thereof, wherein the cancer is a germ cell tumor.

[0267] Embodiment 148. The method according to any one of Embodiments 115-121 or 127-135, or a compound for use according to any one of Embodiments 123-135, or a pharmaceutically acceptable salt thereof, wherein the cancer is bladder cancer.

[0268] Embodiment 149. The method according to any one of Embodiments 115-121 or 127-135, or the compound for use described in any one of Embodiments 123-135, or a pharmaceutically acceptable salt thereof, wherein the cancer is small intestinal adenocarcinoma.

[0269] Embodiment 150. The method according to any one of Embodiments 115-121 or 127-135, or the compound for use described in any one of Embodiments 123-135, or a pharmaceutically acceptable salt thereof, wherein the cancer is appendiceal cancer.

[0270] Embodiment 151. The method according to any one of Embodiments 115-121 or 127-135, or a compound for use according to any one of Embodiments 123-135, or a pharmaceutically acceptable salt thereof, wherein the cancer is peritoneal cancer.

[0271] 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 these 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.

[0272] 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 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.

[0273] 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 KRAS G12V mutant protein. In one embodiment, the cancer is non-small cell lung cancer having one or more cells expressing a KRAS G12V mutant protein. In one embodiment, the cancer is mutant pancreatic cancer having one or more cells expressing a KRAS G12V mutant protein. In one embodiment, the cancer is colorectal cancer having one or more cells expressing a KRAS G12V mutant protein. The method also includes treating cancers of other origins having a KRAS G12V mutant.

[0274] 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 possessing the KRAS G12V mutation can be defined 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 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.

[0275] 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.

[0276] 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.

[0277] Compounds according to Formula I or pharmaceutically acceptable salts thereof for therapeutic use 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 can be pancreatic cancer, in which one or more cells express the KRAS G12V mutant protein. Furthermore, the cancer can be KRAS G12V mutant cervical cancer, in which one or more cells express the KRAS G12V mutant protein. Additionally, the cancer can be KRAS G12V mutant esophageal cancer, in which one or more cells express the KRAS G12V mutant protein. Furthermore, the cancer can be KRAS G12V mutant endometrial cancer, in which one or more cells express the KRAS G12V mutant protein. Additionally, the cancer can be KRAS G12V mutant ovarian cancer, in which one or more cells express the KRAS G12V mutant protein. Furthermore, the cancer can be KRAS G12V mutant cholangiocarcinoma, in which one or more cells express the KRAS G12V mutant protein. Additionally, the cancer can be KRAS G12V mutant gastric adenocarcinoma, in which one or more cells express the KRAS G12V mutant protein. Furthermore, the cancer can be KRAS G12V mutant invasive ductal carcinoma, in which one or more cells express the KRAS G12V mutant protein. Additionally, the cancer can be KRAS G12V mutant uterine carcinosarcoma, in which one or more cells express the KRAS G12V mutant protein. Furthermore, the cancer can be KRAS G12V mutant germ cell tumor, in which one or more cells express the KRAS G12V mutant protein. Additionally, the cancer can be KRAS G12V mutant bladder cancer, in which one or more cells express the KRAS G12V mutant protein. Furthermore, the cancer can 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 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.Patients may have been treated in a different course of treatment prior to being treated as described herein.

[0278] Compounds provided herein according to Formula I, or pharmaceutically acceptable salts thereof, may also be used in the manufacture of pharmaceuticals 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 can 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.

[0279] 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 combination with, separately combined with, or sequentially combined 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 simultaneous, separate, or sequential use 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.

[0280] 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, either concurrently, 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 concurrent, separately, or sequential use 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.

[0281] 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, separately, or sequentially with a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, for use in 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 a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, for simultaneous, separately, or sequential use 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.

[0282] 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 simultaneous, separately, or sequential use in the treatment of cancer. As used herein, the EGFR inhibitor may be erlotinib, afatinib, gefitinib, or cetuximab.

[0283] 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. Further provided are compounds according to formula I, or pharmaceutically acceptable salts thereof, for simultaneous, separate, or sequential use in combination with an ERK 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 ERK inhibitor, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the ERK inhibitor may be LY3214996, the ERK inhibitor may be LTT462, or the ERK inhibitor may be KO-947.

[0284] 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 simultaneous, separate, or sequential use in combination 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. Additional combinations are provided, comprising a compound according to formula I, or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, for simultaneous, separate, or sequential use in the treatment of 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.

[0285] 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 simultaneous, separate, or sequential use in combination 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 simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the 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.

[0286] 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 simultaneous, separate, or sequential use in combination with a platinum agent, 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 a platinum agent, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the platinum agent may be cisplatin, carboplatin, or oxaliplatin.

[0287] 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 simultaneous, separate, or sequential use with pemetrexed 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 simultaneous, separate, or sequential use in the treatment of cancer having one or more cells expressing a mutant KRAS G12V protein.

[0288] As described in paragraphs

[0279] to

[0287] 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 the 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.

[0289] 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.

[0290] 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 formulation and are not harmful to the patient. Examples of pharmaceutical compositions and processes for their preparation 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.

[0291] 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, cancerous lesions 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 and / or severity of the disorder or stage; 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.

[0292] 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.

[0293] 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.

[0294] 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.

[0295] 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, "ELISA" refers to enzyme-linked immunosorbent assay, and "ERK" refers to extracellular signal-regulated kinase. "Kinesa" refers to ethyl group, "Et" refers to ethyl acetate, "siRNA" 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, "IPA" refers to isopropyl alcohol, "IPAm" refers to isopropylamine, "KOAc" refers to potassium acetate, "LC-ES / MS" refers to liquid chromatography-electrospray mass spectrometry, and "LC / MS" refers to liquid chromatography-mass spectrometry. mass"Spectrometry" refers to 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, "RT" refers to room temperature, "sat." refers to saturated, "SCX" refers to strong cation exchange, and "TBAF" refers to tetrabutylammonium fluoride. "Fluoride" refers to tert-butyl group, "t-BuOH" refers to tert-butanol or tert-butyl alcohol, "TEA" refers to triethylamine, "TFA" refers to trifluoracetic 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.

[0296] 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.

[0297] 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).

[0298] 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.

[0299] Preparation 1 (4-bromo-5-fluorobenzo[d]thiazole-2-yl)carbamate tert-butyl [ka] 4-dimethylaminopyridine (0.262 g, 2.14 mmol) was added to a mixture of 4-bromo-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). 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).

[0300] The compounds listed in Table 1 below were prepared in the same manner as described in Preparation 1. Bases 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. [Table 1]

[0301] Preparation 3 (2-((tert-butoxycarbonyl)amino)-5-fluorobenzo[d]thiazole-4-yl)boronic acid [ka] 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. A mixture of (4-bromo-5-fluorobenzo[d]thiazole-2-yl)carbamate tert-butyl (10.0 g, 28.8 mmol) in THF (35 mL) was added. 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).

[0302] Preparation 1A (2-((tert-butoxycarbonyl)amino)benzo[d]oxazole-4-yl)boronic acid [ka] (4-bromobenzo[d]oxazol-2-yl)carbamate tert-butyl was used in a manner similar to that of Preparation 3 to obtain the title compound (0.23 g, 69%) as a white solid. MS(ES)m / z=279(M+1).

[0303] Preparation 4 4-Bromo-5-fluorobenzo[b]thiophene-2-carboxylate methyl [ka] N2 was passed through a 5 mL THF solution of methyl thioglycolate (0.18 mL, 2.0 mmol, 1 equivalent), and a 60% NaH mineral oil solution (0.101 g, 2.53 mmol, 1.24 equivalents) was added at room temperature. Gas generation was observed, and a precipitate formed in the flask. The reaction mixture was stirred at room temperature for 20 minutes. A 5 mL THF solution of 2-bromo-3,6-difluorobenzaldehyde (0.475 g, 2.04 mmol) was slowly added via syringe over approximately 2 minutes. The reaction mixture was stirred at room temperature for 9 hours. Additional methyl thioglycolate (0.1 mL, 1 mmol, 0.5 equivalents) and 60% sodium hydride mineral oil (0.050 g, 1.3 mmol, 0.6 equivalents) were added, and stirring was continued at room temperature for approximately 18 hours. The mixture was diluted with siRNA and washed with saturated NH4Cl aqueous solution and brine. The organic matter was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified with silica eluted with 2% MTBE / hexane to obtain the title compound (0.346 g, 59%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.23-8.19(dd,J=4.49,8.9Hz,1H),8.05(s,1H),7.62(t,J=9.0Hz,1H),3.93(s,3H).

[0304] Preparation 5 4-Bromo-5-fluorobenzo[b]thiophene-2-carboxylic acid [ka] A solution of methyl 4-bromo-5-fluorobenzo[b]thiophene-2-carboxylate (19.2 g, 66.4 mmol, 1 equivalent) in MeOH (130 mL) and THF (130 mL) was filled with 5N NaOH (66 mL, 330 mmol, 5 equivalents) and stirred at room temperature for 40 minutes. The mixture was concentrated and H2O (500 mL) was added. The pH was adjusted to approximately 2 with 5N HCl. The mixture was extracted with ELISA (2 × 500 mL), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The solid was dried under vacuum at 50°C to obtain the title compound (17.6 g, 96%) as a white solid. MS(ES)m / z=229(M-1-CO2).

[0305] Preparation 6 (4-bromo-5-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl [ka] A solution of 4-bromo-5-fluorobenzo[b]thiophene-2-carboxylic acid (1.5 g, 5.5 mmol) in t-butanol (30 mL) was filled with TEA (1.5 mL, 11 mmol, 2.0 equivalents) and diphenyl phosphoryl azide (1.5 mL, 6.9 mmol, 1.3 equivalents), and the mixture was heated at 95 °C for 1 hour. The mixture was cooled and concentrated. The residue was purified with silica eluted with MTBE / hexane (4%~20%) to obtain the title compound (0.987 g, 52%) as a white solid. MS(ES)m / z=290(M+1).

[0306] Preparation 7 (4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluorobenzo[b]thiophene-2-yl)carbamate tert-butyl [ka] A mixture of tert-butyl (4-bromo-5-fluorobenzo[b]thiophen-2-yl)carbamate (3.08 g, 8.90 mmol), bis(neopentyl glycolate)diboron (4.02 g, 17.8 mmol, 2 equivalents), and KOAc (2.62 g, 26.7 mmol, 3 equivalents) in 1,4-dioxane (70 mL, 819.9 mmol) was sparged with N2 for 20 minutes. Pd(ddpf)Cl2 (0.69 g, 0.90 mmol, 0.1 equivalent) was added to the mixture. The reaction mixture was sonicated for 3 minutes, then subjected to a vacuum / N2 refill cycle (3 times) and heated at 100°C for 3 hours. The mixture was cooled to room temperature, filtered through diatomaceous earth, and rinsed with 1:4 siRNA / hexane. The filtrate was concentrated, and the residue was purified with silica (0-40% MTBE / hexane) to obtain the title compound (2.95 g, 87%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 10.81-10.79(bs,1H),7.84-7.74(dd,J=5.07,8.59,1H),7.14(s,1H),6.94-6.88(m,1H),3.89(bs,4H),1.49(s,10H),1.03(s,6H).

[0307] Preparation 8 (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate tert-butyl [ka] Ethyl (3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate. A solution of 2-(4-chloro-5-fluoropyridine-3-yl)acetonitrile (11.8 g, 56.1 mmol) in DMF (112 mL) was cooled to 0°C. Potassium tert-butoxide (7.00 g, 61.1 mmol) was added. After 15 minutes, ethoxycarbonyl isothiocyanate (7.45 mL, 61.8 mmol) was added dropwise. The reaction mixture was slowly warmed to room temperature overnight. The reaction mixture was poured into an ice / water mixture (1.5 L), stirred until all the ice had melted, and filtered through diatomaceous earth. The solid was dried overnight in a vacuum oven (60°C) and separated from the diatomaceous earth to obtain ethyl N-(3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate (11.9 g, 79%) as a solid. MS(ES)m / z=266(M+1).

[0308] 2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile. A suspension of ethyl (3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate (11.9 g, 44.4 mmol) in DMSO (90 mL) was cooled to 0°C. NaOH (5 M aqueous solution, 90 mL) was added dropwise over 15 minutes. The reaction mixture was heated to 105°C over 1 hour and then cooled to room temperature. The reaction mixture was poured into an ice / water mixture (1.8 L), stirred until all the ice had melted, and filtered through diatomaceous earth. The solid was dried overnight in a vacuum oven (50°C) and separated from the diatomaceous earth to obtain crude 2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile.

[0309] (3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate tert-butyl. A mixture of crude 2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile (8.6 g, 44.4 mmol), DCM (90 mL), DMF (90 mL), and N,N-diisopropylethylamine (15.5 mL, 88.9 mmol) was cooled to 0°C. 4-dimethylaminopyridine (0.54 g, 4.42 mmol) and di-tert-butyl dicarbonate (14.6 g, 66.7 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the remaining substance was diluted with DCM (400 mL) and 5% citric acid aqueous solution (250 mL). The aqueous phase was washed twice with DCM. The combined organic phases were washed with saturated NaHCO3 aqueous solution, dried over MgSO4, filtered, and concentrated to obtain tert-butyl N-(3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate (7.5 g, 58%) as a brown solid. MS(ES)m / z=294(M+1).

[0310] 2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine 5-oxide. 3-chloroperoxybenzoic acid (9.00 g, 40.2 mmol) was added to a solution of (3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate tert-butyl (7.85 g, 26.8 mmol) in DCM (180 mL). The reaction mixture was stirred overnight at room temperature and then cooled to 0°C over approximately 15 minutes. The solid was collected by filtration and dried in a vacuum oven (60°C). The filtrate was diluted with MeOH and silica gel, concentrated, and the residue was purified with silica eluted with 0-6% MeOH / DCM. The fraction containing the desired substance was combined with the solid obtained by filtration and concentrated to obtain tert-butyl N-(3-cyano-7-fluoro-5-oxide-thieno[3,2-c]pyridine-5-ium-2-yl)carbamate (7.26 g, 88%) as an off-white solid. MS(ES)m / z=310(M+1).

[0311] (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate tert-butyl. A suspension of 2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine 5-oxide (5.27 g, 17.0 mmol) in 1,2-dichloroethane (34 mL) was cooled to 0°C. A solution of phosphoryl chloride (32 mL, 344 mmol) in 1,2-dichloroethane (34 mL) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes, then stirred at 45°C for 90 minutes, and cooled to room temperature. The reaction mixture was diluted with 1,2-dichloroethane (100 mL) and added to a mixture of saturated NaHCO3 aqueous solution (500 mL), NaOH (5M aqueous solution, 40 mL), and ice. Solid NaHCO3 was added to the stirred mixture to maintain a pH of approximately 6-7. The phases were separated once foaming ceased. The aqueous phase was extracted three times with DCM. The combined organic phases were dried over MgSO4 and filtered. The filtrate was diluted with MeOH and silica gel, concentrated, and the residue was purified with silica eluted with 50-100% DCM / hexane. The fraction containing the desired substance was concentrated to obtain the title compound (3.87 g, 69%) as a white solid. MS(ES)m / z=328(M+1).

[0312] Preparation 9 5-Fluorisobenzofuran-1(3H)-one [ka] A stirred mixture of (2-bromo-5-fluorophenyl)methanol (500 g, 2.44 mol) and TEA (474.6 mL, 3.41 mol, 1.4 equivalents) in ACN (2500 mL) was mixed with Pd(OAc)2 (10.95 g, 48.77 mmol, 0.02 equivalents) and XantPhos (42.33 g, 73.16 mmol, 0.03 equivalents) at room temperature, and the mixture was stirred at 120 °C under 10 atm carbon monoxide for 3 days. 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).

[0313] Preparation 10 4-Bromo-5-fluoro-6-nitroisobenzofuran-1(3H)-one [ka] To a stirred mixture of 5-fluoroisobenzofuran-1(3H)-one (300 g, 1.97 mol) in H2SO4 (1,500 mL), 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 the mixture was 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).

[0314] Preparation 11 4-Bromo-5-fluoro-6-nitro-1,3-dihydroisobenzofuran [ka] 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=6.2Hz, 1H), 5.18-5.15 (m, 2H), 5.11-5.06 (m, 2H).

[0315] Preparation 12 7-Bromo-6-fluoro-1,3-dihydroisobenzofuran-5-amine [ka] 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).

[0316] Preparation 13 (4-Chloro-1,2-phenylene)dimethanol [ka] To a stirred mixture of LiAlH4 (1.9 L, 2.74 mol, 2 equivalents, 2.5 M in THF) in THF (1 L), 250 g, 1.34 mol, 1.00 equivalent of 4-chlorophthalic anhydride (500 mL) in THF 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).

[0317] Preparation 14 5-Chloro-1,3-dihydroisobenzofuran [ka] To a stirred mixture of (4-chloro-1,2-phenylene)dimethanol (219.5 g, 1.271 mol) and dimethyl carbonate (458.2 g, 5.082 mol, 4 equivalents) in ACN (3 L), 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).

[0318] Preparation 15 5-Chloro-6-nitro-1,3-dihydroisobenzofuran [ka] 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).

[0319] Preparation 16 4-Bromo-5-chloro-6-nitro-1,3-dihydroisobenzofuran [ka] To a stirred solution of 5-chloro-6-nitro-1,3-dihydroisobenzofuran (125 g, 626 mmol) in H2SO4 (700 mL), 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. 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) δ 8.07 (d, J = 1.1 Hz, 1H), 5.19 (dt, J = 2.3, 1.1 Hz, 2H), 5.08 (t, 2H).

[0320] Preparation 17 7-Bromo-6-chloro-1,3-dihydroisobenzofuran-5-amine [ka] To a stirred mixture of 4-bromo-5-chloro-6-nitro-1,3-dihydroisobenzofuran (37.0 g, 133 mmol) and NH4Cl (42.64 g, 797.2 mmol, 6 equivalents) 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).

[0321] Preparation 1B 4-Bromo-7,9-dichloro-5-fluoro-1,3-dihydrofl[3,4-f]quinoline [ka] A mixture of 7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-amine (5.00 g, 21.5 mmol), malonic acid (3.36 g, 32.3 mmol), and phosphoryl trichloride (19.9 mL, 215 mmol) was stirred at 110°C for 15 hours and then cooled to room temperature. The mixture was diluted with cold water and extracted with DCM (3 × 200 mL). The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica eluted in 0-100% ethyl acetate in heptane to obtain the title compound (3.4 g, 47%) as a solid. MS(ES)m / z=336(M+1).

[0322] Preparation 2B 4-Bromo-5,7,9-trichloro-1,3-dihydrofl[3,4-f]quinoline [ka] The title compound (2.0 g, 28%) was obtained as a yellow solid using 7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-amine in a manner similar to that of Preparation 1B. MS(ES)m / z=352(M+1).

[0323] Preparation 3B 4-Bromo-5-chloro-1,3-dihydrofl[3,4-f]quinoline-9-ol [ka] A mixture of 5-(((7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)amino)methylene)-2,2-dimethyl-1,3-dioxan-4,6-dione (13 g, 89 mmol) and trimethoxymethane (180 mL, 1.64 mol) was stirred at 100°C for 2 hours and then cooled to room temperature. 7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-amine (20 g, 80 mmol) was added, and the mixture was stirred at 100°C for 18 hours and then cooled to room temperature. The mixture was filtered. The solid was washed with methanol and dried to obtain 5-(((7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)amino)methylene)-2,2-dimethyl-1,3-dioxan-4,6-dione (31.4 g, 97%) as an orange solid. MS(ES)m / z=402(M+1).

[0324] A mixture of 4-bromo-5-chloro-1,3-dihydrofl[3,4-f]quinoline-9-ol:5-(((7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)amino)methylene)-2,2-dimethyl-1,3-dioxan-4,6-dione (10 g, 25 mmol) and oxydibenzene (100 mL, 629 mmol) was stirred at 203 °C for 30 minutes and then cooled to room temperature. Heptane (300 mL) was added, and the mixture was filtered. The solid was washed with heptane and dried to obtain the title compound (6.9 g, 92%) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δppm 5.03(t,J=2.69Hz,2H)5.55(t,J=2.69Hz,2H)6.12(d,J=7.50Hz,1H)7.81-7.86(m,1H)11.37-11.50(m,1H).

[0325] Preparation 4B 4-Bromo-5,9-dichloro-1,3-dihydrofl[3,4-f]sinnoline [ka] 7-Bromo-6-chloro-4-((trimethylsilyl)ethynyl)-1,3-dihydroisobenzofuran-5-amine: A solution of cuprous iodide (0.560 g, 2.94 mmol) and ethinyl-trimethyl-silane (1.88 g, 19.1 mmol) in triethylamine (45 mL) was sparged with argon. Bis-(triphenylphosphin)-palladium chloride (1.03 g, 1.47 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. 7-Bromo-6-chloro-4-iodo-1,3-dihydroisobenzofuran-5-amine (prepared as described in International Publication No. 2023183585; 5.50 g, 14.7 mmol) was added. The reaction vessel was sealed, and the mixture was heated at 90°C for 2 hours. The mixture was filtered over anhydrous sodium sulfate, and the solid was washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure. The residue was purified with silica eluted with 0-60% ethyl acetate in DCM to obtain 7-bromo-6-chloro-4-((trimethylsilyl)ethynyl)-1,3-dihydroisobenzofuran-5-amine (4.58 g, 90%) as a yellow solid. MS(ES)m / z=344(M+1).

[0326] A suspension of 7-bromo-6-chloro-4-((trimethylsilyl)ethynyl)-1,3-dihydroisobenzofuran-5-amine (1.31 g, 3.80 mmol) in HCl (concentrated aqueous solution, 15 mL) was slowly treated with sodium nitrite (3.0 M in water; 1.58 mL, 4.75 mmol). The reaction vessel was sealed and the mixture was heated at 80°C for 30 minutes. The mixture was poured into a stirring mixture of ice and water. The resulting mixture was stirred for 20 minutes until the ice melted. The resulting suspension was filtered to obtain 4-bromo-5-chloro-1,3-dihydroflu[3,4-f]sinnolin-9-ol (0.94 g, 73%) as a yellowish-brown solid. MS(ES)m / z=301(M+1).

[0327] A solution of 4-bromo-5,9-dichloro-1,3-dihydrofl[3,4-f]sinnoline-9-ol (0.94 g, 3.10 mmol) in 4-bromo-5,9-dichloro-1,3-dihydrofl[3,4-f]sinnoline:DCM (10 mL) was treated with chloromethylene(dimethyl)ammonium chloride (0.834 g, 6.51 mmol). The mixture was stirred at room temperature for 15 minutes. The mixture was concentrated under reduced pressure. The resulting solid was suspended in water (40 mL), sonicated (10 min), and filtered. The solid was washed with water (20 mL) and heptane:methyl tert-butyl ether (4:1, 30 mL), then dried to obtain the title compound (0.92 g, 93%) as a brown solid. MS(ES)m / z=319(M+1).

[0328] Preparation 18 N-[(7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)carbamate ethyl]carbamate [ka] 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).

[0329] Preparation 19 N-[(7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)carbamate ethyl]carbamate [ka] Using 7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-amine in a manner similar to that of Preparation 18, the title compound (14 g, 92%) was obtained as a white solid. MS(ES)m / z=379(M+1).

[0330] Preparation 20 (((7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate ethyl [ka] 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) and 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 matter 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).

[0331] Preparation 21 (((7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate ethyl [ka] Ethyl N-[(7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)carbamate]carbamate was used in a manner similar to that of Preparation 20 to obtain the title compound (15.4 g, crude) as a brown solid. MS(ES)m / z=407(M+1).

[0332] Preparation 22 6-Bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofl[3,4-f]quinazolin-1-ol [ka] 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).

[0333] Preparation 23 6-Bromo-5-chloro-3-(ethylthio)-7,9-dihydrofl[3,4-f]quinazolin-1-ol [ka] Ethyl (((7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate was used in a manner similar to that of Preparation 22 to obtain the title compound (11.4 g, 86%) as a white solid. MS(ES)m / z=361(M+1).

[0334] Preparation 24 6-Bromo-3-(ethylthio)-5-fluoro-2-((2-(trimethylsilyl)ethoxy)methyl)-7,9-dihydroflou[3,4-f]quinazoline-1(2H)-one [ka] 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 toluene (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).

[0335] Preparation 25 6-Bromo-5-chloro-3-(ethylthio)-2-((2-(trimethylsilyl)ethoxy)methyl)-7,9-dihydroflou[3,4-f]quinazoline-1(2H)-one [ka] Using 6-bromo-5-chloro-3-(ethylthio)-7,9-dihydrofl[3,4-f]quinazolin-1-ol in a manner similar to that of Preparation 24, the title compound (10.5 g, 96%) was obtained as a pink solid. MS(ES)m / z=491(M+1).

[0336] Preparation 26 6-Bromo-1-chloro-3-(ethylthio)-5-fluoro-7,9-dihydrofl[3,4-f]quinazoline [ka] 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).

[0337] Preparation 27 6-Bromo-1,5-dichloro-3-(ethylthio)-7,9-dihydrofl[3,4-f]quinazoline [ka] Using 6-bromo-5-chloro-3-(ethylthio)-7,9-dihydrofl[3,4-f]quinazolin-1-ol in a manner similar to that of Preparation 26, the title compound (0.81 g, 77%) was obtained as a yellow solid. MS(ES)m / z=382(M+1).

[0338] Preparation 28 (3-Cyano-4-(3-(ethylthio)-5-fluoro-1-hydroxy-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-2-yl) tert-butyl carbamate [ka] 6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofluoro[3,4-f]quinazolin-1-ol (0.80 g, 2.32 mmol), (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophene-2-yl)carbamate tert-butyl (1.12 g, 2.78 mmol), and cesium carbonate (2.27 g, 6.95 mmol) were combined in DMF (12 mL), and the mixture was degassed by sparging with argon for 10 minutes. Dichloro[bis(2-(diphenylphosphino)phenyl) ether]palladium(II) (Pd-117, 0.166 g, 0.232 mmol) was added, and the mixture was heated to 100°C. After 24 hours, the mixture was concentrated under reduced pressure. The residue was purified with silica eluted with 0-10% MeOH in DCM to obtain the title compound (0.96 g, 74%) as a yellow solid. MS(ES)m / z=557(M+1).

[0339] The compounds listed in Table 2 below were prepared in the same manner as described in Preparation 28. 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. [Table 2-1] [Table 2-2] 1 Preparative chiral HPLC, Phenomenex Lux Cellulose-5, 30 x 150 mm, 18-30% heptane (1:1 methanol:ethanol), 42.5 mL / min 2 Chiral SFC, Chiralpak-IC, 50 x 250 mm, 25% in CO2 (methanol containing 0.2% dimethylethylamine), 300 g / min 3 Chiral SFC, Chiralpak-IC, 20 x 250 mm, 25% in CO2 (isopropanol containing 0.5% dimethylethylamine), 80 mL / min 4Chiral SFC, ColumnTek Enantiocel C4-5, 30 x 250 mm, 40% methanol in CO2, 75 mL / min 5 Prepared in the same format as described in Preparation 73

[0340] Preparation 9B (4-(9-bromo-5-chloro-1,3-dihydrofluoro[3,4-f]quinazolin-4-yl)-3-cyano-7-fluorobenzo[b]thiophene-2-yl) tert-butyl carbamate [ka] 4-(2-(tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-5-chloro-1,3-dihydrofluoro[3,4-f]quinoline-9-yltrifluoromethanesulfonate:1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (8.4 g, 23 mmol) was added to a suspension of (4-(5-chloro-9-hydroxy-1,3-dihydrofluoro[3,4-f]quinoline-4-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl (10 g, 20 mmol) and triethylamine (8.2 mL, 59 mmol) in acetonitrile (60 mL). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified with silica eluted in 0-100% ethyl acetate in heptane to obtain 4-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-5-chloro-1,3-dihydrofluoro[3,4-f]quinoline-9-yltrifluoromethanesulfonate (10.1 g, 80%). MS(ES)m / z=644(M+1).

[0341] A mixture of 4-(2-(tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-2-yl)-5-chloro-1,3-dihydrofluoro[3,4-f]quinoline-9-yltrifluoromethanesulfonate (3.74 g, 5.81 mmol) and lithium bromide (10.1 g, 116 mmol) in 4-(9-bromo-5-chloro-1,3-dihydrofluoro[3,4-f]thiophene-2-yl)carbamate tert-butyl:acetonitrile (20 mL) was stirred at 40°C for 75 minutes. The mixture was concentrated under reduced pressure. The residue was diluted with DCM and saturated sodium chloride aqueous solution. The organic layer was concentrated under reduced pressure. The residue was purified with silica eluted in 0-100% ethyl acetate in heptane to obtain the title compound (2.82 g, 85%) as a white solid. MS(ES)m / z=574(M+1).

[0342] Preparation 10B (4-(5-chloro-1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2,7,9-tetrahydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophene-2-yl) tert-butyl carbamate [ka] A mixture of (4-(5-chloro-3-(ethylthio)-1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2,7,9-tetrahydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl, atrop isomer 1 (0.500 g, 0.711 mmol) and palladium(II) chloride (6.30 mg, 0.036 mmol) in THF (5 mL) was sparged with argon. Triethylsilane (0.165 g, 0.227 mmol) was added, the reaction vessel was sealed, and the mixture was stirred at room temperature for 5 hours. The mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (0.46 g). MS(ES) m / z = 643 (M+1). Chiral purification of the pure (clean) atropisomer from preparation 6B.

[0343] Preparation 36 (3-Cyano-4-(3-(ethylthio)-5-fluoro-1-hydroxy-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophene-2-yl) tert-butyl carbamate [ka] A mixture of (4-(3-(ethylthio)-5-fluoro-1-hydroxy-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophene-2-yl)carbamate tert-butyl (0.750 g, 1.41 mmol) and acetonitrile (10 mL) was stirred at -40°C. Sulfur isocyanatidic acid chloride (0.184 mL, 2.12 mmol) was slowly added, and the mixture was heated to 0°C. After the starting material was consumed (monitored by LC-MS), the mixture was cooled to 0°C. DMF (4 mL) was slowly added. Once the reaction was complete (monitored by LC-MS), the mixture was diluted with DCM (20 mL) and saturated ammonium chloride aqueous solution (20 mL). The layers were separated, and the aqueous layer was extracted with DCM (3 × 30 mL). The combined extracts were passed through a hydrophobic frit and concentrated under reduced pressure to obtain the crude title compound. MS(ES)m / z=557(M+1).

[0344] The compounds listed in Table 3 below were prepared in the same manner as described in Preparation 36. The compounds were purified using various methods that would be obvious to those skilled in the art. [Table 3] 1 Pure atropisomer, chiral purification from preparation 32 2 Pure atropisomer, chiral purification from preparation 34

[0345] Preparation 40 (3-Cyano-4-(3-(ethylthio)-5-fluoro-1-hydroxy-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophene-2-yl) tert-butyl carbamate [ka] To a mixture of (3-cyano-4-(3-(ethylthio)-5-fluoro-1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2,7,9-tetrahydrofluoro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl (19.2 g, 26.3 mmol) in THF (192 mL), activated molecular sieve (4 angstroms, 38 g), followed by tetrabutylammonium fluoride (1 M in THF, 105 mL, 105 mmol). The reaction mixture was heated in a bath at 80°C for 9 hours and then cooled to room temperature. Additional activated molecular sieve (4 angstroms, 17 g) was added, and the reaction mixture was heated overnight in a bath at 80°C and then cooled to room temperature. The mixture was filtered, and the filtered cake was washed with ELISA. The combined filtrate was concentrated under reduced pressure, diluted with 2-methyltetrahydrofuran (300 mL), and washed with water (3 × 300 mL). The combined aqueous layer was extracted with 2-methyltetrahydrofuran (300 mL). The combined organic layer was washed with 5% citric acid aqueous solution (300 mL), dried on magnesium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified with silica eluted with 0-60% ethyl acetate in cyclohexane to obtain the title compound (9.42 g) as a yellow foam. MS(ES) m / z = 557 (M+1). Pure atrop isomer, chiral purification from preparation 32.

[0346] The compounds listed in Table 4 below were prepared in a manner similar to that described in Preparation 40. Different deprotection conditions, such as cesium fluoride in DMF, may be substituted. The compounds were purified using various methods that would be apparent to those skilled in the art. [Table 4] 1Pure atropisomer, chiral purification from preparation 34 2 Pure atropisomer, chiral purification from preparation 6B

[0347] The compounds listed in Table 5 below were prepared in the same manner as described in Preparation 26. The compounds were purified using various methods that would be obvious to those skilled in the art. [Table 5] 1 Chiral purification from pure atropisomer, preparation 30. 2 Pure atropisomer, chiral purification from preparation 34

[0348] Preparation 49 6-amino-4-methyl-4-azaspiro[2.5]octan-5-one [ka] 4-Methyl-4-azaspiro[2.5]octan-5-one. Sodium hydride (60% by weight, 1.92 g, 47.9 mmol) was added to a solution of 4-azaspiro[2.5]octan-5-one (5.00 g, 40.0 mmol) in THF (30 mL). The mixture was stirred at room temperature for 30 minutes and then cooled to 0°C. A solution of iodomethane (3.73 mL, 59.9 mmol) in THF (5 mL) was added dropwise, and the mixture was stirred at 0°C for 5 minutes, then warmed to room temperature and stirred for 16 hours. The mixture was diluted with water (5 mL) and extracted with siRNA and DCM. The combined organic matter was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude 4-methyl-4-azaspiro[2.5]octan-5-one (3.03 g, 55%) as a pale yellow oil. MS(ES)m / z = 140(M+1).

[0349] 6-Chloro-4-methyl-4-azaspiro[2.5]octan-5-one. A solution of 4-methyl-4-azaspiro[2.5]octan-5-one (3.03 g, 21.8 mmol) in THF (50 mL) was cooled to -78°C. Lithium diisopropylamide (2.0 M, 14.2 mL, 28.4 mmol) in THF / heptane / ethylbenzene was added. The mixture was stirred at -78°C for 20 minutes, and then a solution of tosyl chloride (12.45 g, 65.3 mmol) in THF (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 with anhydrous Na2SO4, followed by reverse-phase purification (C18 column) with elution in 0-100% acetonitrile in (0.1% formic acid in water) to obtain 6-chloro-4-methyl-4-azaspiro[2.5]octan-5-one (2.33 g, 62%) as a yellow oily substance. MS(ES)m / z=174(M+1).

[0350] 6-amino-4-methyl-4-azaspiro[2.5]octan-5-one. A solution of 6-chloro-4-azaspiro[2.5]octan-5-one (7.02 g, 40.4 mmol) in acetonitrile (5 mL) and ammonium hydroxide (10 mL) was heated at 80°C for 22 hours under microwave irradiation. The mixture was concentrated under reduced pressure to obtain the title compound (5.8 g, crude) as a brown solid. MS(ES)m / z=155(M+1).

[0351] The compounds listed in Table 6 below were prepared in the same manner as described in Preparation 49. The compounds were purified using various methods that would be obvious to those skilled in the art. [Table 6]

[0352] Preparation 3A 7-amino-5-azaspiro[3.5]nonane-6-one [ka] 6-Oxo-5-Azaspiro[3.5]nonane-5-carboxylate tert-butyl. Di-tert-butyl dicarbonate (1.02 g, 4.67 mmol) and 4-dimethylaminopyridine (0.088 g, 0.718 mmol) were added to a solution of 5-Azaspiro[3.5]nonanone (0.500 g, 3.59 mmol) in THF (10 mL). The mixture was stirred at 65 °C for 12 hours and then 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 6-Oxo-5-Azaspiro[3.5]nonane-5-carboxylate tert-butyl (0.610 g, 71%) as a brown oil. MS(ES) m / z = 184 (M + 1-tBu).

[0353] 7-chloro-6-oxo-5-azaspiro[3.5]nonane-5-carboxylate tert-butyl. 6-oxo-5-azaspiro[3.5]nonane-5-carboxylate tert-butyl was used in a manner similar to the method of Preparation 49 (step 6-chloro-4-methyl-4-azaspiro[2.5]octan-5-one) to obtain 7-chloro-6-oxo-5-azaspiro[3.5]nonane-5-carboxylate tert-butyl (0.28 g, 78%) as a yellow oil. MS(ES)m / z=218(M+1-tBu).

[0354] 7-Chloro-5-azaspiro[3.5]nonane-6-one. A mixture of tert-butyl 7-chloro-6-oxo-5-azaspiro[3.5]nonane-5-carboxylate in DCM (3 mL) was treated with HCl solution (3 mL) and stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to obtain crude 7-chloro-5-azaspiro[3.5]nonane-6-one as a white solid. MS(ES)m / z=174(M+1).

[0355] 7-amino-5-azaspiro[3.5]nonan-6-one. 7-chloro-5-azaspiro[3.5]nonan-6-one was used in a manner similar to that of Preparation 49 (step 6-amino-4-methyl-4-azaspiro[2.5]octan-5-one) to obtain the title compound (0.24 g) as a yellow solid. MS(ES)m / z=155(M+1).

[0356] Preparation 52 4-amino-2-methyl-2-azabicyclo[3.1.1]heptan-3-one dihydrochloride [ka] 2-Methyl-2-azabicyclo[3.1.1]heptan-3-one. Sodium hydride (60% by weight in mineral oil, 0.346 g, 8.64 mmol) was added to a solution of 2-azabicyclo[3.1.1]heptan-3-one (0.800 g, 7.20 mmol) in THF (15 mL). The mixture was stirred at 25°C for 30 minutes and then cooled to 0°C. A solution of iodomethane (0.67 mL, 10.8 mmol) in THF (0.3 mL) was added dropwise. The mixture was stirred at 0°C for 5 minutes and then at 25°C for 16 hours. Diluted with water (5 mL), extracted with ethyl acetate and then with DCM. The combined organic matter was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude 2-methyl-2-azabicyclo[3.1.1]heptan-3-one as a pale yellow oil. MS(ES)m / z = 126(M+1).

[0357] Methyl 2-methyl-3-oxo-2-azabicyclo[3.1.1]heptane-4-carboxylate. To a solution of 2-methyl-2-azabicyclo[3.1.1]heptane-3-one (1.09 g, 8.71 mmol) in THF (60 mL) at -78°C, lithium diisopropylamide (2.0 M in THF / heptane / ethylbenzene; 8.71 mL, 17.4 mmol) was added. The mixture was stirred at -78°C for 30 minutes. Methyl chloroformate (0.81 mL, 10.5 mmol) was added, and the mixture was stirred at -78°C for 2 hours. The mixture was quenched with water, warmed to room temperature, and extracted with siRNA, then DCM. The combined organic matter was concentrated under reduced pressure to obtain crude 2-methyl-3-oxo-2-azabicyclo[3.1.1]heptane-4-carboxylate methyl (1.37 g, 86%) as a pale yellow oil. MS(ES)m / z=184(M+1).

[0358] 2-methyl-3-oxo-2-azabicyclo[3.1.1]heptane-4-carboxamide. Sodium methoxide (0.404 g, 7.47 mmol) was added to a mixture of methyl 2-methyl-3-oxo-2-azabicyclo[3.1.1]heptane-4-carboxylate (1.37 g, 7.47 mmol) in ammonia-treated methanol (7 M; 53.4 mL, 374 mmol). The mixture was stirred at 45 °C for 5 hours and then cooled. The mixture was concentrated under reduced pressure. The residue was diluted with water and subsequently subjected to reverse-phase purification (C18 column) by elution with 0-100% acetonitrile in (0.1% formic acid in water) to obtain 2-methyl-3-oxo-2-azabicyclo[3.1.1]heptane-4-carboxamide (0.904 g, 72%) as a yellow solid. MS(ES)m / z = 169(M+1).

[0359] Methyl (2-methyl-3-oxo-2-azabicyclo[3.1.1]heptan-4-yl)carbamate. A mixture of 2-methyl-3-oxo-2-azabicyclo[3.1.1]heptan-4-carboxamide (1.04 g, 6.20 mmol) and THF (15 mL) was mixed with (diacetoxyiodo)benzene (2.20 g, 6.82 mmol). The mixture was stirred at 25°C for 20 minutes and then concentrated under reduced pressure. MeOH (15 mL) was added, and the mixture was stirred at 70°C for 1 hour. The mixture was concentrated under reduced pressure to obtain crude methyl (2-methyl-3-oxo-2-azabicyclo[3.1.1]heptan-4-yl)carbamate as a pale yellow oil. MS(ES)m / z=199(M+1).

[0360] (Methoxycarbonyl)(2-methyl-3-oxo-2-azabicyclo[3.1.1]heptan-4-yl)carbamate tert-butyl. To a solution of methyl (2-methyl-3-oxo-2-azabicyclo[3.1.1]heptan-4-yl)carbamate (1.23 g, 6.21 mmol) in THF (12 mL), di-tert-butyl dicarbonate (2.71 g, 12.4 mmol) and dimethylaminopyridine (0.227 g, 1.86 mmol) were added. The mixture was stirred at 65°C for 4 hours and then concentrated under reduced pressure. The residue was purified with silica eluted with 60-100% ethyl acetate in heptane to obtain (methoxycarbonyl)(2-methyl-3-oxo-2-azabicyclo[3.1.1]heptan-4-yl)carbamate tert-butyl (0.571 g, 31%) as a brown oily substance. MS(ES)m / z=199(M+1, -Boc).

[0361] (2-methyl-3-oxo-2-azabicyclo[3.1.1]heptan-4-yl)carbamate tert-butyl. Sodium methoxide (0.031 g, 0.57 mmol) was added to a solution of (methoxycarbonyl)(2-methyl-3-oxo-2-azabicyclo[3.1.1]heptan-4-yl)carbamate tert-butyl (0.571 g, 1.91 mmol) in MeOH (5 mL) at 0°C. The mixture was stirred at 0°C for 20 minutes, then at 25°C for 12 hours. The mixture was quenched with ice and diluted with brine. The mixture was extracted with ethyl acetate, then with dimethylcellulose. The combined organic matter was dried over anhydrous sodium 2SO4 and concentrated under reduced pressure to obtain crude (2-methyl-3-oxo-2-azabicyclo[3.1.1]heptan-4-yl)carbamate tert-butyl. MS(ES)m / z=185(M+1, -tert-butyl).

[0362] 4-amino-2-methyl-2-azabicyclo[3.1.1]heptan-3-one dihydrochloride. HCl (4M in 1,4-dioxane, 3 mL) was added to a solution of (2-methyl-3-oxo-2-azabicyclo[3.1.1]heptan-4-yl)carbamate tert-butyl (0.460 g, 1.91 mmol) in DCM (3 mL). The mixture was stirred at room temperature for 6 hours, then concentrated under reduced pressure to obtain the title compound (0.400 g, 98%). MS(ES)m / z=141 (M+1, free base).

[0363] Preparation 4A 4-amino-2-methyl-2-azabicyclo[3.1.1]heptan-3-one hydrochloride [ka] The title compound was prepared in a manner similar to that of preparation 52. MS(ES)m / z=141 (M+1, free base).

[0364] Preparation 53 (8aR)-6-aminohexahydroindoridine-5(1H)-one dihydrochloride [ka] (R)-2-(2-bromoethyl)pyrrolidine-1-carboxylate tert-butyl. To a mixture of (R)-2-(2-hydroxyethyl)pyrrolidine-1-carboxylate tert-butyl (10 g, 46 mmol) in THF (200 mL), carbon tetrabromide (23 g, 70 mmol) was added. The mixture was stirred at 0°C for 10 minutes, and then triphenylphosphine (18 g, 70 mmol) was added. The mixture was stirred at room temperature for 10 minutes, and then quenched with saturated sodium bicarbonate aqueous solution (100 mL). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified with silica eluted with 5-75% ethyl in heptane to obtain (R)-2-(2-bromoethyl)pyrrolidine-1-carboxylate tert-butyl (7.4 g, 57%) as a colorless oil.

[0365] Dimethyl(S)-2-(2-(1-tert-butoxycarbonyl)pyrrolidine-2-yl)ethyl)malonate. Sodium hydride (60% by weight in mineral oil; 2.1 g, 53 mmol) was added to a mixture of dimethyl malonate (7.0 g, 53 mmol) in THF (100 mL). The mixture was stirred at room temperature for 15 minutes. A solution of (R)-2-(2-bromoethyl)pyrrolidine-1-carboxylate tert-butyl (7.4 g, 27 mmol) in THF (100 mL) was added dropwise. The mixture was stirred at 75°C for 20 hours, then cooled and quenched with acetic acid (1.5 mL, 27 mmol). The mixture was diluted with chloroform (150 mL) and water (100 mL). The organic layer was passed through hydrophobic frit and concentrated under reduced pressure. The residue was purified with silica eluted with 5-100% ethyl in heptane to obtain dimethyl(S)-2-(2-(1-tert-butoxycarbonyl)pyrrolidine-2-yl)ethyl)malonate (7.0 g, 80%).

[0366] Dimethyl(S)-2-(2-(pyrrolidine-2-yl)ethyl)malonate hydrochloride. Acetyl chloride (30 mL, 430 mmol) was added dropwise to MeOH (20 mL) at 0°C. The mixture was stirred at 0°C for 5 minutes, and then a solution of dimethyl(S)-2-(2-(1-tert-butoxycarbonyl)pyrrolidine-2-yl)ethyl)malonate (7.0 g, 21 mmol) in MeOH (5 mL) was added. The mixture was stirred at room temperature for 24 hours. The mixture was concentrated under reduced pressure to obtain crude dimethyl(S)-2-(2-(pyrrolidine-2-yl)ethyl)malonate hydrochloride.

[0367] (8aS)-5-oxooctahydroindridine-6-carboxylate methyl. A mixture of dimethyl(S)-2-(2-(pyrrolidine-2-yl)ethyl) malonate hydrochloride (4.9 g, 18 mmol) and triethylamine (7.7 mL, 55 mmol) in DCM (100 mL) was stirred at room temperature for 24 hours. The mixture was diluted with DCM (50 mL) and saturated sodium bicarbonate aqueous solution (75 mL). The organic layer was passed through hydrophobic frit and concentrated under reduced pressure to obtain (8aS)-5-oxooctahydroindridine-6-carboxylate methyl (1.8:1 mixture of diastereomers; 2.6 g, 71%). MS(ES)m / z=198(M+1).

[0368] (8aS)-5-oxooctahydroindridine-6-carboxamide. Sodium methoxide (0.74 g, 14 mmol) was added to a mixture of (8aS)-5-oxooctahydroindridine-6-carboxylate methyl (2.7 g, 14 mmol) in ammonia-treated methanol (7 M; 60 mL, 420 mmol). The mixture was stirred at 45°C for 5 hours and then cooled. The mixture was concentrated under reduced pressure. The residue was purified with silica eluted with 1-20% MeOH in DCM to obtain (8aS)-5-oxooctahydroindridine-6-carboxamide (1.2 g, 48%) as a colorless oil.

[0369] ((8aR)-5-oxooctahydroindridine-6-yl)carbamate tert-butyl. (8aS)-5-oxooctahydroindridine-6-carboxamide (5.7 g, 31 mmol), THF (75 mL), and tert-butanol (100 mL) were mixed with (diacetoxyiodo)benzene (11 g, 34 mmol). The mixture was stirred at room temperature for 20 minutes, then at 70°C overnight. The mixture was concentrated under reduced pressure. The residue was purified with silica eluted with 0-10% MeOH in DCM to obtain ((8aR)-5-oxooctahydroindridine-6-yl)carbamate tert-butyl (7.0 g, 88%) as a colorless oil. MS(ES)m / z=255(M+1).

[0370] (8aR)-6-aminohexahydroindridine-5(1H)-one dihydrochloride. HCl (4M, 3 mL in 1,4-dioxane) was added to a solution of ((8aR)-5-oxooctahydroindridine-6-yl)carbamate tert-butyl (0.270 g, 1.06 mmol) in DCM (3 mL). The mixture was stirred at room temperature for 6 hours and then concentrated under reduced pressure to obtain the title compound (0.241 g, 100%). MS(ES)m / z=155 (M+1, free base).

[0371] Preparation 5A (8aR)-6-aminohexahydroindolidine-5(1H)-one hydrochloride [ka] The title compound was prepared in a manner similar to that of preparation 53 ((6R,8aR) diastereomer was dominant). MS(ES)m / z=155 (M+1, free base).

[0372] Preparation 6A (9aS)-7-aminohexahydropyrido[2,1-c][1,4]oxazine-6(1H)-one hydrochloride [ka] (S)-3-(2-hydroxyethyl)morpholine-4-carboxylate tert-butyl was used in a manner similar to the method of Preparation 53 to obtain the title compound ((7R,9aS) diastereomer dominant, 0.44 g). MS(ES)m / z=171 (M+1, free base).

[0373] Preparation 54 6-aminotetrahydro-1H-pyrazolo[1,2-a]pyridazine-5(6H)-one trihydrochloride [ka] (4-hydroxy-1-oxo-1-(pyrazolidine-1-yl)butan-2-yl)carbamate tert-butyl. A solution of (R)-(2-oxotetrahydrofuran-3-yl)carbamate tert-butyl (5.00 g, 24.8 mmol) and pyrazolidine dihydrochloride (3.60 g, 24.8 mmol) in chloroform (34 mL) was treated with triethylamine (13.9 mL, 99.4 mmol). The mixture was stirred at 70°C for 16 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was purified with silica eluted with 0-10% MeOH in DCM to obtain (4-hydroxy-1-oxo-1-(pyrazolidine-1-yl)butan-2-yl)carbamate tert-butyl ((R) enantiomer rich; 3.51 g, 52%) as a colorless oil. MS(ES)m / z = 274(M+1).

[0374] (5-oxohexahydro-1H-pyrazolo[1,2-a]pyridazin-6-yl)carbamate tert-butyl. A mixture of (4-hydroxy-1-oxo-1-(pyrazolidin-1-yl)butan-2-yl)carbamate tert-butyl ((R) enantiomer-rich; 2.51 g, 9.18 mmol) and 2-(tributylphosphoranylidene)acetonitrile (2.44 g, 10.1 mmol) in toluene (23 mL) was stirred at 100 °C for 15 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was purified with silica eluted with 0-10% MeOH in DCM to obtain (5-oxohexahydro-1H-pyrazolo[1,2-a]pyridazin-6-yl)carbamate tert-butyl ((R) enantiomer-rich; 1.96 g, 84%) as a pale yellow solid. MS(ES)m / z=256(M+1).

[0375] 6-aminotetrahydro-1H-pyrazolo[1,2-a]pyridazine-5(6H)-one trihydrochloride. HCl (4M in 1,4-dioxane, 18.9 mL) was added to a solution of (5-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-6-yl)carbamate tert-butyl ((R) enantiomer-rich; 1.93 g, 7.56 mmol) in DCM (19 mL). The mixture was stirred at room temperature for 31 hours and then concentrated under reduced pressure. The solid was dried under vacuum to obtain the title compound ((R) enantiomer-rich; 2.00 g, 100%). MS(ES) m / z = 156 (M+1, free base).

[0376] Preparation 7A 6-aminotetrahydro-1H-pyrazolo[1,2-a]pyridazine-5(6H)-one dihydrochloride [ka] The title compound was prepared in a manner similar to that of Preparation 54 (the (R) enantiomer was dominant). MS(ES)m / z=156 (M+1, free base).

[0377] Preparation 55 2-aminohexahydropyridazino[1,2-a]pyridazine-1(2H)-one trihydrochloride [ka] Hexahydropyridazine dihydrochloride was used in a manner similar to that of Preparation 54 to obtain the title compound ((R) enantiomer-rich; 4.08 g). MS(ES)m / z=170 (M+1, free base).

[0378] Preparation 8A 2-aminohexahydropyridazino[1,2-a]pyridazine-1(2H)-one dihydrochloride [ka] The title compound was prepared in a manner similar to that of Preparation 54 (the (R) enantiomer was dominant). MS(ES)m / z=170 (M+1, free base).

[0379] Preparation 16B (6R,8aR)-6-aminohexahydroindoridine-5(1H)-one hydrochloride [ka] (6R,8aR)-5-oxooctahydroindridine-6-yl)carbamate tert-butyl (6.85 kg, 26.9 mol) was mixed with dichloromethane:hexane (1:50; 35 L). The mixture was filtered to obtain ((6R,8aR)-5-oxooctahydroindridine-6-yl)carbamate tert-butyl (998 g, 14%) as an off-white solid. MS(ES)m / z=255(M+1).

[0380] (6R,8aR)-6-aminohexahydroindridine-5(1H)-one hydrochloride:((6R,8aR)-5-oxooctahydroindridine-6-yl)carbamate tert-butyl (27 g, 0.11 mol) was stirred overnight in HCl (4 M ethyl acetate; 270 mL, 1.1 mol). The mixture was concentrated under reduced pressure, and the solid was dried to obtain the title compound (20 g, 99%) as a white solid. 1 H NMR(400MHz,MeOD)δ3.91(dd,J=12.1,6.3Hz,1H),3.69-3.43(m,3H),2.39(dddd,J=12.8,6.5,4.1,2.7Hz,1H ),2.29(dq,J=13.6,3.6Hz,1H),2.19-2.12(m,1H),2.11-1.98(m,1H),1.98-1.83(m,2H),1.71-1.46(m,2H).

[0381] Preparation 17B (6S)-3-amino-1-azabicyclo[4.2.0]octan-2-one 2,2,2-trifluoroacetate [ka] A solution of dipotassium phosphate (28.9 g, 166 mmol), (R)-2-(1-tert-butoxycarbonyl)azetidine-1-carboxylic acid tert-butyl:DMF (1.25 L), (R)-2-(1-tert-butoxycarbonyl)azetidine-2-yl)acetic acid (23.1 g, 108 mmol, 1.3 equivalents), methyl 2-[bis-tert-butoxycarbonyl)amino]propane-2-enoate (25 g, 83.0 mmol), and Ir[dF(CF3)ppy]2(dtbpy)(PF6) (2.33 g, 2.07 mmol) in (2S)-2-(3-(bis(tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutyl)azetidine-1-carboxylic acid tert-butyl:DMF (1.25 L) was circulated for 12 hours through a photoreactor (light source 450 nm, 2400 W). The mixture was diluted with ice water (1 L) and extracted with ethyl acetate (3 × 500 mL). The combined organic phase was washed with saturated sodium chloride aqueous solution (3 × 300 mL). The organic phase was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified with silica eluted with 0-20% ethyl acetate in hexane to obtain (2S)-2-(3-(bis-tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutyl)azetidine-1-carboxylate tert-butyl (19.8 g, 45%) as a yellow viscous substance.

[0382] Methyl 2-amino-4-((S)-azetidine-2-yl)butanoate bis-2,2,2-trifluoroacetate: Trifluoroacetic acid (35.4 mL, 476 mmol) was added at 0°C to a solution of (2S)-2-(3-(bis-tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutyl)azetidine-1-carboxylate tert-butyl (15.0 g, 31.7 mmol) in DCM (150 mL). The mixture was stirred at 25°C for 4 hours and then concentrated under reduced pressure. The residue was diluted in DCM (80 mL) and concentrated under reduced pressure to obtain methyl 2-amino-4-((S)-azetidine-2-yl)butanoate bis-2,2,2-trifluoroacetate (12.71 g, 100%) as a yellow viscous substance.

[0383] (6S)-3-amino-1-azabicyclo[4.2.0]octan-2-one: At 0°C, potassium carbonate (18.6 g, 135 mmol) was added to a solution of methyl 2-amino-4-((S)-azetidine-2-yl)butanoate bis-2,2,2-trifluoroacetate (12.71 g, 31.7 mmol) in water (120 mL) and methanol (120 mL). The mixture was stirred at 0°C for 15 minutes and then at 25°C for 12 hours. Potassium carbonate (4.39 g, 31.7 mmol) was added at 0°C, and the mixture was stirred at 25°C for 24 hours. The mixture was concentrated under reduced pressure to obtain crude (6S)-3-amino-1-azabicyclo[4.2.0]octan-2-one as a yellow oil.

[0384] (6S)-2-oxo-1-azabicyclo[4.2.0]octan-3-yl)carbamate tert-butyl, isomers 1 and 2: Di-tert-butyl dicarbonate (12.3 g, 56.5 mmol) was added to a solution of crude (6S)-3-amino-1-azabicyclo[4.2.0]octan-2-one in THF (20 mL) over 5 minutes at 0°C. The mixture was stirred at 0°C for 5 minutes and then at 25°C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified with silica eluted with 0-60% ethyl acetate in DCM, followed by chiral HPLC separation to obtain ((6S)-2-oxo-1-azabicyclo[4.2.0]octan-3-yl)carbamate tert-butyl, isomer 1 (5.0 g) and isomer 2 (5.3 g). For both, MS(ES)m / z = 241(M+1). Isomer 1 elutes before isomer 2 in chiral SFC (ChiralPak AD-3, 4.6 × 100 mm, 5-40% CO2 (ethanol containing 0.2% methylamine), 2.8 mL / min). The isomer refers to the pure isomer at the 3-position of azabicyclooctanone.

[0385] (6S)-3-amino-1-azabicyclo[4.2.0]octan-2-one 2,2,2-trifluoroacetate:((6S)-2-oxo-1-azabicyclo[4.2.0]octan-3-yl) tert-butyl carbamate, isomer 2 (0.500 g, 2.08 mmol) and trifluoroacetic acid (1.60 mL, 20.8 mmol) were stirred in DCM (10 mL) for 24 hours. The mixture was concentrated under reduced pressure, and the substance was dried to obtain the title compound (single diastereomer; 0.53 g, 100%) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ4.81-4.64(m,1H),4.25(q,J=8.9Hz,1H),4.20-4.09(m,1H),4.00(dd,J= 11.5,6.5Hz,1H),2.50-2.38(m,3H),2.22-2.13(m,1H),2.07-1.92(m,1H),1.88-1.74(m,1H).

[0386] Preparation 18B (8aS)-6-amino-2,2-difluorohexahydroindridine-5(1H)-one hydrochloride [ka] S-2-(1-tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-yl)acetic acid was used in a manner similar to that of Preparation 17B to obtain ((8aS)-2,2-difluoro-5-oxooctahydroindolidine-6-yl)carbamate tert-butyl, isomer 1 (5.5 g) and isomer 2 (5.5 g). Isomer 1 was eluted before isomer 2 in chiral SFC (ChiralPak AD-3, 4.6 × 100 mm, 5-40% CO2 (isopropanol containing 0.2% methylamine), 2.8 mL / min). The isomer refers to the pure isomer at the 6-position of hexahydroindolidine. Isomer 2 was used in a manner similar to that of Preparation 17B to obtain the title compound (single diastereomer; 1.5 g) as a white solid. 1H NMR(400MHz,MeOD)δ4.11-3.92(m,3H),3.73(ddd,J=19.4,14.0,5.7Hz,1H),2.68-2. 52(m,1H),2.49-2.16(m,2H),2.04-1.89(m,1H),1.80(tdd,J=13.7,10.8,2.3Hz,1H).

[0387] Preparation 19B 4-amino-1,2-dimethyltetrahydropyridazine-3(2H)-one [ka] (1-(1,2-dimethylhydrazinyl)-4-hydroxy-1-oxobutan-2-yl)benzyl carbamate (6.00 g, 25.5 mmol) and 1,2-dimethylhydrazine hydrochloride (10.2 g, 76.5 mmol) were stirred in (1-(1,2-dimethylhydrazinyl)-4-hydroxy-1-oxobutan-2-yl)benzyl carbamate (150 mL) of tetrahydrofuran. Triethylamine (33.6 g, 332 mmol) was added dropwise under nitrogen at room temperature. The mixture was stirred at 80 °C for 24 hours and then filtered. The solid was washed with ethyl acetate (200 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase purification (C18 column) using elution with 25-35% acetonitrile in (10 mM ammonium bicarbonate in water) to obtain benzyl (1-(1,2-dimethylhydrazinyl)-4-hydroxy-1-oxobutan-2-yl)carbamate (6.05 g, 80%) as a colorless oil. MS(ES)m / z=296(M+1).

[0388] A solution of benzyl (1,2-dimethylhydrazinyl)-4-hydroxy-1-oxobutan-2-yl)carbamate (5.50 g, 18.6 mmol) and 2-(tributyl-lambda-5-phosphanylidene)acetonitrile (45.0 g, 186 mmol) in toluene (150 mL) was stirred under nitrogen at 100 °C for 1.5 hours. The mixture was concentrated under reduced pressure. The residue was purified using silica gel eluted with 14-25% DCM (7:3 ethyl acetate:methanol), followed by reverse-phase purification (C18 column) eluted with 25-35% acetonitrile in (0.1% formic acid in water) to obtain (1,2-dimethyl-3-oxohexahydropyridazine-4-yl)carbamate benzyl (1.5 g, 29%) as a yellow solid. MS(ES)m / z=278(M+1).

[0389] To a stirred solution of benzyl (1,2-dimethyl-3-oxohexahydropyridazin-4-yl)carbamate (1.5 g, 5.41 mmol) in 4-amino-1,2-dimethyltetrahydropyridazine-3(2H)-one:methanol (50 mL), palladium hydroxide (Pd 20% carbon powder, nominally 50% water; 1.2 g) was added in small amounts under nitrogen at room temperature. The mixture was stirred at room temperature for 2 hours and then filtered. The solid was washed with methanol (200 mL). The combined filtrate was concentrated under reduced pressure to obtain the crude title compound (0.85 g) as a yellow oil. 1 H NMR (300MHz, DMSO-d6) δ3.28(t,1H), 3.06(dd,2H), 2.91(s,3H), 2.59(s,3H), 2.11(ddt,1H), 1.81(ddt,1H).

[0390] Preparation 20B (4-(5-chloro-9-(((6R,8aR)-5-oxooctahydroindoridine-6-yl)amino)-1,3-dihydrofluoro[3,4-f]quinoline-4-yl)-3-cyano-7-fluorobenzo[b]thiophene-2-yl)carbamate tert-butyl [ka] A mixture of (4-(9-bromo-5-chloro-1,3-dihydrofluoro[3,4-f]quinoline-4-yl)-3-cyano-7-fluorobenzo[b]thiophene-2-yl)carbamate tert-butyl (0.152 g, 0.264 mmol), (6R,8aR)-6-aminohexahydroindidine-5(1H)-one hydrochloride (0.151 g, 0.793 mmol), cesium carbonate (0.172 g, 0.529 mmol), 2,2'-bis(diphenylphosphanyl)-1,1'-binaphthalene (0.020 g, 0.032 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.029 g, 0.032 mmol) in toluene (2.40 mL) was stirred at 100°C for 16 hours. The mixture was diluted with water and extracted with DCM (2 × 50 mL). The combined organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with silica eluted with 0-15% methanol in DCM to obtain the title compound (0.16 g, 93%). MS(ES)m / z = 648(M+1).

[0391] Preparation 21B (3-Cyano-4-(3-(ethylthio)-5-fluoro-1-(((6R,8aR)-5-oxooctahydroindoridine-6-yl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophene-2-yl)carbamate tert-butyl [ka] BOP-Cl (CAS No. 68641-49-6; 0.274 g, 1.08 mmol) was added to a solution of (3-cyano-4-(3-(ethylthio)-5-fluoro-1-hydroxy-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl (4.1 g, 7.2 mmol) and diisopropylethylamine (0.469 mL, 2.69 mmol). The mixture was stirred at 60°C for 1 hour. ((6R,8aR)-6-aminohexahydroindridine-5(1H)-one hydrochloride (0.257 g, 1.35 mmol) was added, and the mixture was stirred at 60°C for 2 hours. The mixture was concentrated under reduced pressure, diluted with DCM (150 mL), and washed with saturated sodium bicarbonate aqueous solution (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with silica eluted with 0-100% ethyl acetate in DCM to obtain the title compound (0.515 g, 83%) as a yellow solid. MS(ES) m / z = 693 (M+1). Pure atrop isomer, chiral purification from preparation 32.

[0392] The compounds listed in Table 7 below were prepared in the same manner as described in Preparation 21B. The compounds were purified using various methods that would be obvious to those skilled in the art. [Table 7] 1 Chiral purification from pure atropisomer, preparation 30. 2 Pure atropisomer, chiral purification from preparation 34 3 A dominant chiral center exists based on the starting material from preparations 53, 54, 55, 5A, 6A, 7A, or 8A. 4 Pure atropisomer, chiral purification from preparation 32 5 Pure isomer of hexahydroindolidinone at position 6, chiral purification from preparation 18B. 6 Pure atropisomer, chiral purification from preparation 6B 7 Pure isomer at the 3-position of azabicyclooctanone, chiral purification from preparation 17B.

[0393] Preparation 56 (4-(5-chloro-3-(ethylthio)-1-((4-methyl-5-oxo-4-azaspiro[2.5]octan-6-yl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-5-fluorobenzo[b]thiophene-2-yl) tert-butyl carbamate [ka] Diisopropylethylamine (0.30 mL, 1.74 mmol) was added to a mixture of (3-cyano-4-(1,5-dichloro-3-(ethylthio)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophene-2-yl)carbamate tert-butyl (0.206 g, 0.348 mmol) and 6-amino-4-methyl-4-azaspiro[2.5]octan-5-one (0.161 g, 1.04 mmol) in acetonitrile (4 mL). The mixture was stirred at room temperature. After 16 hours, the mixture was concentrated under reduced pressure. The residue was purified with silica eluted with 0-100% ethyl phosphate in heptane to obtain the title compound (0.107 g, 43%) as a white solid. MS(ES)m / z=709(M+1).

[0394] The compounds listed in Table 8 below were prepared in the same manner as described in Preparation 56. The compounds were purified using various methods that would be obvious to those skilled in the art. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] 1 Chiral purification from pure atropisomer, preparation 30. 2 Pure atropisomer, chiral purification from preparation 34 3 Normal phase, silica, DCM containing 0-100% siRNA; isomers refer to pure isomers at the 6-position of hexahydroindolidinone. 4 A dominant chiral center exists based on the starting material from preparations 53, 54, 55, 5A, 6A, 7A, or 8A.

[0395] The compounds listed in Table 9 below were prepared in the same manner as described in Preparation 28. 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. [Table 9-1] [Table 9-2] 1 A dominant chiral center exists based on the starting material from preparations 53, 54, 55, 5A, 6A, 7A, or 8A.

[0396] Preparation 73 (4-(5-chloro-3-(ethylthio)-1-((5-methyl-6-oxo-5-azapiro[3.5]nonan-7-yl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorothiazolo[4,5-c]pyridine-2-yl) tert-butyl carbamate [ka] 7-((5-chloro-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(ethylthio)-7,9-dihydrofl[3,4-f]quinazolin-1-yl)amino)-5-methyl-5-azaspiro[3.5]nonan-6-one. Pd-117 (CAS 205319-06-8; 0.012 g, 0.017 mmol) was added to a solution of 7-((6-bromo-5-chloro-3-(ethylthio)-7,9-dihydrofl[3,4-f]quinazolin-1-yl)amino)-5-methyl-5-azaspiro[3,5]nonan-6-one (0.292 g, 0.570 mmol), 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (0.258 g, 1.14 mmol), and potassium acetate (0.168 g, 1.71 mmol) in 1,4-dioxane (5 mL). The mixture was stirred at 80°C for 16 hours, cooled, and filtered. The solid was washed with 1,4-dioxane (3 × 60 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified with silica eluted with 0-60% MeOH in DCM to obtain 7-((5-chloro-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(ethylthio)-7,9-dihydrofl[3,4-f]quinazolin-1-yl)amino)-5-methyl-5-azaspiro[3.5]nonan-6-one (0.331 g) as a white solid. MS(ES)m / z=477(M+1, boronic acid).

[0397] (4-(5-chloro-3-(ethylthio)-1-((5-methyl-6-oxo-5-azaspiro[3.5]nonan-7-yl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorothiazolo[4,5-c]pyridine-2-yl) tert-butyl carbamate. 1,4-Dioxane (5 mL) contains (4-chloro-7-fluorothiazolo[4,5-c]pyridine-2-yl)carbamate tert-butyl (0.316 g, 1.04 mmol), 7-((5-chloro-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(ethylthio)-7,9-dihydrofluoro[3,4-f]quinazolin-1-yl)amino)-5-methyl-5-azaspiro[3.5]nonan-6-one (0.331 g, 0.570 mmol), 2-(dicyclohexylphosphanyl)-2',4',6'-tris(isopropyl)biphenyl (0.033 g, 0.069 mmol), and XPhos Pd(clotyl)Cl(CAS A mixture of 1798782-02-1 (0.047 g, 0.069 mmol) was mixed with a solution of dipotassium phosphate (0.362 g, 2.08 mmol) in water (1 mL). The mixture was degassed for 5 minutes (direct nitrogen sparge), stirred at 80°C for 16 hours, and concentrated under reduced pressure. The residue was purified with silica eluted in 0-100% ethyl acetate in heptane to obtain the title compound (0.276 g, 57%). MS(ES)m / z=700(M+1).

[0398] The compounds listed in Table 10 below were prepared in a manner similar to that described in Preparation 73. 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. [Table 10]

[0399] Preparation 23A (6R,8aR)-6-((6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofluoro[3,4-f]quinazolin-1-yl)amino)hexahydroindolidine-5(1H)-one [ka] To a solution of (8aR)-6-((6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofl[3,4-f]quinazolin-1-yl)amino)hexahydroindridine-5(1H)-one (21.8 g, 45.2 mmol) in MeOH (400 mL), potassium carbonate (12.5 g, 90.5 mmol) was added. The mixture was stirred at 40°C for 16 hours and then concentrated under reduced pressure. The residue was diluted with water (200 mL) and filtered to obtain the title compound (18.2 g, 84%) as a yellow solid. MS(ES)m / z=481(M+1).

[0400] Preparation 74 (4-(5-chloro-3-(ethylsulfonyl)-1-((4-methyl-5-oxo-4-azaspiro[2.5]octan-6-yl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-5-fluorobenzo[b]thiophene-2-yl) tert-butyl carbamate [ka] To a solution of tert-butyl (4-(5-chloro-3-(ethylthio)-1-((4-methyl-5-oxo-4-azaspiro[2.5]octan-6-yl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-5-fluorobenzo[b]thiophene-2-yl)carbamate (0.107 g, 0.150 mmol) in DCM (5 mL), mCPBA (70 wt%; 0.081 g, 0.330 mmol) was gradually added at 0°C. The mixture was stirred at 0°C for 30 minutes, then at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The crude substance was purified with silica eluted with 0-100% ethyl in DCM to obtain the title compound (0.115 g, 100%) as a pale yellow solid. MS(ES)m / z = 741(M+1).

[0401] The compounds listed in Table 11 below were prepared in the same manner as described in Preparation 74. Different oxidation conditions, such as hydrogen peroxide in ethanol and DCM and ammonium heptamolybdate tetrahydrate, may be substituted. The compounds were purified using various methods that would be apparent to those skilled in the art. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5] [Table 11-6] [Table 11-7] [Table 11-8] 1 Chiral purification from pure atropisomer, preparation 30. 2 Pure atropisomer, chiral purification from preparation 34 3 Normal phase, silica, DCM with 0-100% toluene 4 Normal phase, silica, DCM containing 0-100% siRNA; isomers refer to pure isomers at the 6-position of hexahydroindolidinone. 5 Pure isomer of hexahydroindolidinone at position 6, chiral purification from preparation 13A. 6 Pure isomer of hexahydroindolidinone at position 6, chiral purification from preparation 14A. 7A dominant chiral center exists based on the starting material from preparations 53, 54, 55, 5A, 6A, 7A, or 8A. 8 Pure atropisomer, chiral purification from preparation 32 9 Pure isomer of hexahydroindolidinone at position 6, chiral purification from preparation 18B.

[0402] Preparation 89 6-methyl-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate tert-butyl [ka] 3,6-Diazabicyclo[3.2.0]heptane-3-carboxylate tert-butyl (a mixture of cis isomers; 0.300 g, 1.51 mmol), formaldehyde (37% by weight; 0.737 g, 9.08 mmol), and sodium triacetoxyborohydride (1.92 g, 9.08 mmol) were dissolved in methanol (6 mL). The mixture was heated at 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 toluene (3 × 50 mL). The combined organic layer was washed with brine (25 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude title compound (a mixture of cis isomers, 0.365 g) as a colorless oil. MS(ES)m / z=213(M+1).

[0403] The compounds listed in Table 12 below were prepared in a manner similar to that described in Preparation 89. 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. [Table 12] 1 Reactions using deuterated formaldehyde, deuterated acetic acid, and sodium cyanodeuterated borochloride in methanol. 2It was not isolated, was produced, and consumed in the synthesis of preparation 42B. 3 It was not isolated, was produced, and consumed in the synthesis of preparation 44B.

[0404] Preparation 48A (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-methyl-3-oxopyrrolidine-1-carboxylate tert-butyl [ka] To a solution of DMSO (2.03 mL, 28.6 mmol) in DCM (60 mL), oxalyl chloride (2 M in DCM; 7.15 mL, 14.3 mmol) was added under nitrogen at -78°C. The mixture was stirred at -78°C for 1 hour, and then (2S,3S,4S)-4-((tert-butyldimethylsilyl)oxy)-3-hydroxy-2-methylpyrrolidine-1-carboxylic acid tert-butyl (2.37 g, 7.15 mmol) in DCM (10 mL) was added. Triethylamine (5.98 mL, 42.9 mmol) was added. The mixture was stirred at -78°C for 10 minutes, and then at 25°C for 45 minutes. The mixture was diluted with water and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude title compound as an orange oil. MS(ES)m / z = 274(M+1-tBu).

[0405] Preparation 49A (2S,3S)-3-(ethyl(methyl)amino)-2-methylpyrrolidine-1-carboxylate tert-butyl [ka] To a solution of (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) in DCM (5 mL), 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).

[0406] Preparation 50A (2S,3R,4S)-4-((tert-butyldimethylsilyl)oxy)-3-(dimethylamino)-2-methylpyrrolidine-1-carboxylate tert-butyl [ka] (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-methyl-3-oxopyrrolidine-1-carboxylic acid tert-butyl and dimethylamine were used in a manner similar to that of Preparation 49A to obtain the title compound (1.12 g) as a yellow oily substance. MS(ES)m / z=359(M+1).

[0407] Preparation 51A (2S)-3-(azetidine-1-yl)-2-methylpyrrolidine-1-carboxylate tert-butyl [ka] (S)-2-methyl-3-oxopyrrolidine-1-carboxylate tert-butyl was used in a manner similar to that of preparation 49A to obtain the title compound (0.60 g, 99%) as a yellow oily substance. MS(ES)m / z=241(M+1).

[0408] The compounds listed in Table 13 below were prepared in the same manner as described in Preparation 49A. The compounds were purified using various methods that would be obvious to those skilled in the art. [Table 13]

[0409] Preparation 52A (2'S,3'S)-2'-methyl-[1,3'-bipyrrolidine]-1'-carboxylate tert-butyl [ka] (2S,3S)-3-amino-2-methylpyrrolidine-1-carboxylate tert-butyl (2.5 g, 12 mmol), potassium iodide (1.0 g, 6.2 mmol), 1,4-dibromobutane (4.0 g, 19 mmol), and potassium carbonate (8.6 g, 62 mmol) were combined in acetonitrile (50 mL). The mixture was stirred overnight at 70°C. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude title compound (3.0 g, 94%). MS(ES)m / z=255(M+1).

[0410] Preparation 92 6-Methyl-3,6-diazabicyclo[3.2.0]heptane dihydrochloride [ka] A mixture of 6-methyl-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate tert-butyl (a mixture of cis isomers; 0.370 g, 1.74 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 (a mixture of cis isomers, 0.300 g) as a yellow solid. MS(ES)m / z=113(M+1).

[0411] The compounds listed in Table 14 below were prepared in a manner similar to that described in Preparation 92. 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. [Table 14-1] [Table 14-2]

[0412] Preparation 59B (6R,8aR)-6-((4-bromo-7-((2S,3S)-3-(dimethylamino)-2-methylpyrrolidine-1-yl)-5-fluoro-1,3-dihydrofluoro[3,4-f]quinoline-9-yl)amino)hexahydroindridine-5(1H)-one [ka] Diisopropylethylamine (0.32 mL, 1.83 mmol) was added to a mixture of (6R,8aR)-6-((4-bromo-7-chloro-5-fluoro-1,3-dihydrofl[3,4-f]quinoline-9-yl)amino)hexahydroindidine-5(1H)-one (0.083 g, 0.183 mmol), (2S,3S)-N,N,2-trimethylpyrrolidine-3-amine dihydrochloride (0.128 g, 0.639 mmol), and CsF (0.028 g, 0.183 mmol) in NMP (0.913 mL). The mixture was heated at 110 °C for 32 hours, then cooled to room temperature and diluted with water. The mixture was purified by reverse-phase purification (C18 column) using elution with 0-100% acetonitrile in (0.1% formic acid in water) to obtain the title compound (0.070 g, 70%). MS(ES)m / z=546(M+1).

[0413] The compounds listed in Table 15 below were prepared in the same manner as described in Preparation 59B. The compounds were purified using various methods that would be obvious to those skilled in the art. [Table 15]

[0414] Preparation 96 (4-(3-((2S,3S)-3-(dimethylamino)-2-methylpyrrolidine-1-yl)-5-fluoro-1-((5-methyl-6-oxo-5-azapiro[2.5]octan-7-yl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[d]thiazole-2-yl) tert-butyl carbamate [ka] (4-(3-(ethylsulfonyl)-5-fluoro-1-((5-methyl-6-oxo-5-azaspiro[2.5]octan-7-yl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[d]thiazole-2-yl)carbamate tert-butyl (0.080 g, 0.11 mmol) was mixed with diisopropylethylamine (0.30 mL, 1.7 mmol), (2S,3S)-N,N,2-trimethylpyrrolidine-3-amine dihydrochloride (0.11 g, 0.57 mmol), CsF (0.017 g, 0.11 mmol), and acetonitrile (3 mL). The mixture was heated at 70°C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified with silica eluted with 0-40% MeOH in DCM to obtain the title compound (0.072 g, 86%) as a yellow solid. MS(ES)m / z=735(M+1).

[0415] The compounds listed in Table 16 below were prepared in the same manner as described in Preparation 96. Different bases may have been substituted. The compounds were purified using various methods that would be obvious to those skilled in the art. [Table 16-1] [Table 16-2] [Table 16-3] [Table 16-4] [Table 16-5] [Table 16-6] [Table 16-7] [Table 16-8] [Table 16-9] [Table 16-10] [Table 16-11] [Table 16-12] 1 Chiral purification from pure atropisomer, preparation 30. 2 Pure atropisomer, chiral purification from preparation 34 3 Pure enantiomer of hexahydroindolidinone at position 6, chiral purification from preparation 86. 4 A mixture of cis isomers 5 Pure isomer of hexahydroindolidinone at position 6, chiral purification from preparation 28A. 6 Pure isomer of hexahydroindolidinone at position 6, chiral purification from preparation 29A. 7 Pure isomer of hexahydroindolidinone at position 6, chiral purification from preparation 13A. 8 Pure isomer of hexahydroindolidinone at position 6, chiral purification from preparation 14A. 9 Normal phase, silica, DCM containing 0-40% MeOH; isomers refer to pure isomers at the 3-position of pyrrolidine. 10 A dominant chiral center exists based on the starting material from preparations 53, 54, 55, 5A, 6A, 7A, or 8A. 11 Lithium bis(trimethylsilyl)amide was used as the base.

[0416] The compounds listed in Table 17 below were prepared in the same manner as described in Preparation 26. The compounds were purified using various methods that would be obvious to those skilled in the art. [Table 17] 1 Chiral purification from pure atropisomer, preparation 30.

[0417] The compounds listed in Table 18 below were prepared in the same manner as described in Preparation 56. Different bases may be substituted. The compounds were purified using various methods that would be apparent to those skilled in the art. [Table 18] 1 Chiral purification from pure atropisomer, preparation 30. 2 Chiral SFC, ChiralPak AD, 30 x 250 mm, 50% CO2 (isopropanol containing 20 mM ammonia), 100 mL / min. The isomer refers to the pure isomer at the 4-position of pyridazinone. 3 Chiral SFC, ChiralPak IK, 30 x 250 mm, 50% CO2 (3:1 isopropanol:dichloromethane (containing 20 mM ammonia)), 100 mL / min, isomer refers to the pure isomer at the 4-position of pyridazinone.

[0418] Preparation 115 2-((6-bromo-3-((2S,3S)-3-(dimethylamino)-2-methylpyrrolidine-1-yl)-5-fluoro-7,9-dihydrofluoro[3,4-f]quinazolin-1-yl)amino)hexahydropyridazino[1,2-a]pyridazin-1(2H)-one [ka] Diisopropylethylamine (0.55 mL, 3.14 mmol) was added to a mixture of 6-bromo-3-((2S,3S)-3-(dimethylamino)-2-methylpyrrolidine-1-yl)-5-fluoro-7,9-dihydrofluoro[3,4-f]quinazolin-1-ol (0.129 g, 0.314 mmol) and (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.326 g, 0.627 mmol) in acetonitrile (2.6 mL). The mixture was stirred at room temperature for 1 hour, and then 2-aminohexahydropyridazino[1,2-a]pyridazine-1(2H)-one trihydrochloride ((R) enantiomer-rich; 0.306 g, 1.10 mmol) was added. The mixture was stirred at room temperature for 2.5 hours, and then concentrated under reduced pressure. The crude substance was purified with silica eluted with 10% MeOH in DCM to obtain the title compound ((R) enantiomer-rich; 0.176 g, 100%) as an off-white solid. MS(ES)m / z=564(M+1).

[0419] The compounds listed in Table 19 below were prepared in the same manner as described in Preparation 115. The compounds were purified using various methods that would be obvious to those skilled in the art. [Table 19-1] [Table 19-2] 1 (R) Enantiomer-rich 2 Pure atropisomer, chiral purification from preparation 34 3A dominant chiral center exists based on the starting material from preparations 53, 54, 55, 5A, 6A, 7A, or 8A.

[0420] The compounds listed in Table 20 below were prepared in the same manner as described in Preparation 28. 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. [Table 20-1] [Table 20-2] [Table 20-3] [Table 20-4] [Table 20-5] 1 (R) Enantiomer-rich 2 A dominant chiral center exists based on the starting material from preparations 53, 54, 55, 5A, 6A, 7A, or 8A. 3 Normal phase, silica, dichloromethane containing 0-10% methanol; isomers refer to pure diastereomers on pyrrolidine.

[0421] The compounds listed in Table 21 below were prepared in the same manner as described in Preparation 73. 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. [Table 21-1] [Table 21-2] [Table 21-3] [Table 21-4] 1 Pure isomer of hexahydroindolidinone at position 6, chiral purification from preparation 13A. 2 Pure isomer of hexahydroindolidinone at position 6, chiral purification from preparation 14A. 3 Chiral SFC, Chiralcel OD, 20 x 250 mm, 20% in CO2 (isopropanol containing 0.5% dimethylethylamine), 80 mL / min. The isomer refers to the pure isomer at position 6 of azaspirooctanone. 4 Pure isomer of pyridazinone at position 4, chiral purification from preparation 78B 5 Pure isomer of pyridazinone at position 4, chiral purification from preparation 79B

[0422] Preparation 100B 2-Amino-4-(5-Chloro-3-(ethylsulfonyl)-1-(((6R,8aR)-5-oxooctahydroindolidine-6-yl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile [ka] (4-(5-chloro-3-(ethylsulfonyl)-1-(((6R,8aR)-5-oxooctahydroindolidine-6-yl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl (0.200 g, 0.270 mmol) was diluted with acetonitrile (1.80 mL) and HCl (3 M in cyclopentyl methyl ether; 0.45 mL, 1.35 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to obtain the title compound (0.17 g, 98%) as a yellow solid. MS(ES) m / z = 641 (M+1). Pure atrop isomer, chiral purification from preparation 34.

[0423] The compounds listed in Table 22 below were prepared in the same manner as described in Preparation 100B. The compounds were purified using various methods that would be obvious to those skilled in the art. [Table 22] 1 Chiral purification from pure atropisomer, preparation 30.

[0424] Preparation 102B (4-(5-chloro-1-(((6R,8aR)-5-oxooctahydroindoridine-6-yl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophene-2-yl)carbamate tert-butyl [ka] A mixture of (4-(5-chloro-3-(ethylsulfonyl)-1-(((6R,8aR)-5-oxooctahydroindolidine-6-yl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl (0.050 g, 0.067 mmol) and sodium borohydride (0.0064 g, 0.17 mmol) in DCM (1 mL) and isopropanol (1 mL) was stirred at room temperature for 40 minutes. The mixture was concentrated under reduced pressure. The residue was diluted with DCM and saturated sodium bicarbonate aqueous solution. The organic layer was concentrated under reduced pressure to obtain the crude title compound (0.044 g) as a white solid. MS(ES) m / z = 651 (M+1). Chiral purification of the pure atrop isomer from preparation 30.

[0425] The compounds listed in Table 23 below were prepared in the same manner as described in Preparation 102B. The compounds were purified using various methods that would be obvious to those skilled in the art. [Table 23-1] [Table 23-2] 1 Chiral purification from pure atropisomer, preparation 30. 2 Pure atropisomer, chiral purification from preparation 32 3 By-product from preparation 104B. Methanol was used in the reaction. 4 Pure isomer of hexahydroindolidinone at position 6, chiral purification from preparation 18B.

[0426] The compounds listed in Table 24 below were prepared in the same manner as described in Preparation 28. 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. [Table 24]

[0427] Examples 1-4 2-Amino-4-(5-Chloro-3-((S)-3-(dimethylamino)pyrrolidine-1-yl)-1-((4-methyl-5-oxo-4-azaspiro[2.5]octan-6-yl)amino)-7,9-dihydrofl[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile, diastereomers 1-4 [ka] (4-(5-chloro-3-((S)-3-(dimethylamino)pyrrolidine-1-yl)-1-((4-methyl-5-oxo-4-azapiro[2.5]octan-6-yl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl (0.082 g, 0.11 mmol) was added to a mixture of DCM (1 mL) and trifluoroacetic acid (1 mL). The mixture was stirred at room temperature. After 1 hour, the mixture was concentrated under reduced pressure and diluted with aqueous ammonium hydroxide solution and DCM. The layers were separated, and the organic layer was concentrated under reduced pressure. The residue was purified by reverse-phase purification (C18 column) with elution in 40-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol) to obtain the four title diastereomer compounds (0.017g, 0.013g, 0.014g, 0.014g; 81%). Diastereomers refer to both the pure atrop isomer and the pure isomer on piperidinone. For all four compounds, MS(ES)m / z = 661(M+1).

[0428] The compounds listed in Table 25 below were prepared in the same manner as described in Examples 1-4. Different acidic conditions, such as HCl in 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. [Table 25-1] Table 25-2 Table 25-3 Table 25-4 Table 25-5 Table 25-6 Table 25-7 Table 25-8 Table 25-9 Table 25-10 Table 25-11 Table 25-12 Table 25-13 Table 25-14 Table 25-15 Table 25-16 Table 25-17 Table 25-18 [Table 25-19] [Table 25-20] [Table 25-21] [Table 25-22] [Table 25-23] [Table 25-24] [Table 25-25] [Table 25-26] [Table 25-27] [Table 25-28] [Table 25-29] [Table 25-30] 1 Chiral purification from pure atropisomer, preparation 30. 2 Pure atropisomer, chiral purification from preparation 34 3 Pure enantiomer of hexahydroindolidinone at position 6, chiral purification from preparation 86. 4Reverse phase, C18, 51-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol). The enantiomer refers to the pure isomer at position 7 of azaspirononanone. 5 Reverse phase, C18, 56-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol). The enantiomer refers to the pure isomer at position 6 of azaspirooctanone. 6 Reverse phase, C18, 51-100% (95:5 acetonitrile:water) in (10 mM ammonium bicarbonate aqueous solution pH 10:methanol). Enantiomers refer to the pure isomer at the 6-position of azaspirooctanone. Mixed cis isomers on pyrrolidine. 7 Reverse phase, C18, 43-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol). The enantiomer refers to the pure isomer at position 7 of azaspirooctanone. 8 Reverse phase, C18, 47-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol). Diastereomers refer to the pure atropisomer and the pure isomer at position 6 of azaspirooctanone. 9 Mixtures of diastereomers 1 and 2 and diastereomers 3 and 4 were obtained by reverse-phase C18 with 39-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol). Diastereomers 1 and 2 were further separated by preparative chiral HPLC; Phenomenex Lux Cellulose-2, 30 × 150 mm, 10-70% ethanol in heptane, 42.5 mL / min. Diastereomers 3 and 4 were further separated by preparative chiral HPLC; Phenomenex Lux i-Cellulose-5, 30 × 150 mm, 10-100% ethanol in heptane, 42.5 mL / min. Diastereomers refer to the pure atrop isomer and the pure isomer at the 6-position of azaspirooctanone. 10Mixtures of diastereomers 1 and 2 and diastereomers 3 and 4 were obtained by reverse-phase C18 chromatography using 46-100% acetonitrile in a 10 mM aqueous solution of ammonium bicarbonate (95:5, pH 10:methanol). Diastereomers 1 and 2 were further separated by preparative chiral HPLC; (S,S)-Whelk-O1, 30 × 150 mm, 25-100% in heptane (1:1 methanol:ethanol (containing 0.1% isopropylamine)), 45 mL / min. Diastereomers 3 and 4 were further separated by preparative chiral HPLC; (S,S)-Whelk-O1, 30 × 150 mm, 20-100% in heptane (1:1 methanol:ethanol (containing 0.1% isopropylamine)), 45 mL / min. Diastereomers refer to the pure atrop isomer and the pure isomer at position 7 of azaspirooctanone. 11 In reverse phase, C18, 10-70% acetonitrile enantiomers in a 10 mM aqueous solution of ammonium bicarbonate (95:5, pH 10:methanol) refer to the pure isomer at the 4-position of azabicycloheptanone. 12 Reverse phase, C18, 35-100% acetonitrile in (10 mM ammonium bicarbonate aqueous solution, pH 10: methanol, 95:5). The enantiomer refers to the pure isomer at the 4-position of azabicycloheptanone. 13 Preparative chiral HPLC, (S,S)-Whelk-O1, 30 × 150 mm, 10-100% in heptane (1:1 methanol:ethanol (containing 0.1% isopropylamine)), 42.5 mL / min. The enantiomer refers to the pure isomer at the 2-position of hexahydropyridadinopyridazinone. 14 Reverse phase, C18, 2-100% acetonitrile in (0.1% formic acid in water), followed by preparative chiral HPLC; (S,S)-Whelk-O1, 30 × 150 mm, 10-80% (1:1 methanol:ethanol (containing 0.1% isopropylamine)) in heptane, 42.5 mL / min. Enantiomer refers to the pure isomer at position 7 of azaspirononanone. 15Reverse phase, C18, 53-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol). Diastereomers refer to the pure atropisomer and the pure isomer at position 7 of azaspirooctanone. 16 Reverse phase, C18, 55-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol). Diastereomers refer to the pure atropisomer and the pure isomer at position 6 of azaspirooctanone. 17 Mixtures of diastereomers 1 and 2 and diastereomers 3 and 4 were obtained by reverse-phase HPLC with 46-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol) on C18. Diastereomers 1 and 2 were further separated by preparative chiral HPLC; (S,S)-Whelk-O1, 30 × 150 mm, 10-100% ethanol (containing 0.1% isopropylamine) in heptane, 42.5 mL / min. Diastereomers 3 and 4 were further separated by preparative chiral HPLC; (S,S)-Whelk-O1, 30 × 150 mm, 10-100% ethanol in heptane, 42.5 mL / min. Diastereomers refer to the pure atrop isomer and the pure isomer at the 6-position of azaspirooctanone. 18 (R) Enantiomer-rich 19 Preparative chiral HPLC, Phenomenex Lux i-Cellulose-5, 30 × 150 mm, 15-100% heptane (ethanol containing 0.1% isopropylamine), 42.5 mL / min. The enantiomer refers to the pure isomer at the 6-position of tetrahydropyrazolopyridazinone. 20 Preparative 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 6-position of azaspirooctanone. 21Preparative chiral HPLC, (S,S)-Whelk-O1, 30 × 150 mm, 25-85% in heptane (1:1 methanol:ethanol (containing 0.1% isopropylamine)), 45 mL / min. The enantiomer refers to the pure isomer at position 7 of azaspirooctanone. 22 Preparative chiral HPLC, Phenomenex Lux i-Cellulose-5, 30 × 150 mm, 10-100% in heptane (1:1 methanol:ethanol (containing 0.1% isopropylamine)), 42.5 mL / min. The isomer refers to the pure isomer at position 7 of azaspirooctanone. 23 Reverse phase, C18, 10-70% acetonitrile in a 10 mM aqueous solution of ammonium bicarbonate (95:5, pH 10:methanol). The isomer refers to the pure isomer at the 4-position of azabicycloheptanone. 24 Reverse phase, C18, 35-100% acetonitrile in (10 mM ammonium bicarbonate aqueous solution, pH 10: methanol, 95:5). The isomer refers to the pure isomer at the 6-position of tetrahydropyrazolopyridazinone. 25 Reverse phase, C18, 44-100% acetonitrile in (10 mM ammonium bicarbonate aqueous solution, pH 10: methanol, 95:5). The isomer refers to the pure isomer at position 6 of azaspirooctanone. 26 Preparative chiral HPLC, (S,S)-Whelk-O1, 30 x 150 mm, 30-100% ethanol in heptane, 45 mL / min. The isomer refers to the pure isomer at the 6-position of azaspiroheptanone. 27 Preparative chiral HPLC, Phenomenex Lux Cellulose-4, 30 × 150 mm, 15-60% in heptane (1:1 methanol:ethanol), 45 mL / min. Isomers refer to the pure isomer at the 2-position of hexahydropyridadinopyridazinone. 28 Pure isomer of piperidinone at position 6, chiral purification from preparation 28A 29Pure isomer of piperidinone at position 6, chiral purification from preparation 29A 30 Reverse phase, C18, 38-100% acetonitrile in (10 mM aqueous solution of ammonium acetate at pH 10: methanol, 95:5). Isomers refer to the pure isomer at position 7 of azaspirononanone. 31 Pure isomer of hexahydroindolidinone at position 6, chiral purification from preparation 13A. 32 Pure isomer of hexahydroindolidinone at position 6, chiral purification from preparation 14A. 33 Pure isomer of azaspirooctanone at position 6, chiral purification from preparation 112A. 34 Pure isomer of azaspirooctanone at position 6, chiral purification from preparation 113A. 35 Chiral SFC, ChiralPak IJ, 30 x 250 mm, 20% in CO2 (10 mM ammonium acetate in methanol), 85 mL / min. The isomer refers to the pure isomer at position 7 of azaspirooctanone. 36 Preparative chiral HPLC, (S,S)-Whelk-O1, 30 × 150 mm, 10-100% in heptane (1:1 methanol:ethanol (containing 0.1% isopropylamine)), 45 mL / min. Isomers refer to the pure isomer at position 7 of azaspirooctanone. 37 Pure isomer at the 3-position of pyrrolidine, chiral purification from preparation 73A 38 Pure isomer at the 3-position of pyrrolidine, chiral purification from preparation 72A 39 Chiral SFC, ChiralPak IH, 20 x 250 mm, 35% CO2 (isopropanol containing 0.5% dimethylethylamine), 80 mL / min. The isomer refers to the pure isomer at position 7 of azaspirooctanone. 40 Pure isomer of hexahydropyridoxazinon at position 7 41 Preparative chiral HPLC, (S,S)-Whelk-O1, 30 × 150 mm, 20-100% in heptane (1:1 methanol:ethanol (containing 0.1% isopropylamine)), 45 mL / min. Isomers refer to the pure isomer at position 7 of azaspirononanone. 42 Preparative chiral HPLC, Phenomenex Lux Cellulose-1, 30 x 150 mm, 20-65% ethanol in heptane, 45 mL / min. The isomer refers to the pure isomer at the 2-position of hexahydropyridadinopyridazinone. 43 Preparative chiral HPLC, Phenomenex Lux Cellulose-4, 30 x 150 mm, 25-100% ethanol in heptane, 45 mL / min. Isomers refer to the pure isomer at position 7 of azaspirononanone. 44 Reverse phase, C18, 31-100% acetonitrile in (10 mM ammonium bicarbonate aqueous solution, pH 10: methanol, 95:5). The isomer refers to the pure isomer at the 6-position of hexahydroindolidinone. 45 Preparative chiral HPLC, Phenomenex Lux i-Cellulose-5, 30 × 150 mm, 35-100% in heptane (1:1 methanol:ethanol (containing 0.1% isopropylamine)), 45 mL / min. Isomers refer to pure atropisomers. 46 Reverse phase, C18, 25-100% acetonitrile in a 10 mM aqueous solution of ammonium acetate (95:5, pH 10:methanol). Isomers refer to pure atropisomers. 47 Preparative chiral HPLC, Phenomenex Lux i-Cellulose-5, 30 x 150 mm, 15-100% ethanol in heptane, 42.5 mL / min. Isomers refer to pure atropisomers. 48Preparative chiral HPLC, Phenomenex Lux i-Cellulose-5, 30 x 150 mm, 35-100% in heptane (1:1 methanol:ethanol), 45 mL / min. Isomers refer to pure atropisomers. 49 Reverse phase, C18, 39-100% acetonitrile in (10 mM ammonium bicarbonate aqueous solution, pH 10: methanol, 95:5). Isomers refer to pure atropisomers. 50 Preparative chiral HPLC, (S,S)-Whelk-O1, 30 × 150 mm, 10-100% heptane (ethanol containing 0.1% isopropylamine), 42.5 mL / min. Diastereomers refer to the pure atrop isomer and the pure isomer at the 6-position of tetrahydropyrazolopyridazinone. 51 Reverse phase, C18, 44-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol). Isomers refer to the pure isomer at position 7 of azaspirononanone. 52 Reverse phase, C18, 26-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol). Isomers refer to pure atropisomers. 53 Reverse phase, C18, 35-100% acetonitrile in (10 mM ammonium bicarbonate aqueous solution, pH 10: methanol, 95:5). Isomers refer to the pure isomer at position 7 of azaspirononanone. 54 Reverse phase, C18, 10-100% acetonitrile in (0.1% formic acid in water). The isomer refers to the pure isomer at position 6 of hexahydroindolidinone. 55 Preparative chiral HPLC, (S,S)-Whelk-O1, 30 × 150 mm, 25-100% in heptane (1:1 methanol:ethanol), 45 mL / min. Isomers refer to pure atropisomers. 56 Pure atropisomer, chiral purification from preparation 6B 57Pure isomer at the 3-position of azabicyclooctanone, chiral purification from preparation 17B. 58 Pure atropisomer, chiral purification from preparation 32 59 Pure isomer of hexahydroindolidinone at position 6, chiral purification from preparation 18B. 60 Preparative chiral HPLC, Phenomenex Lux Cellulose-4, 30 x 150 mm, 20-100% in heptane (1:1 methanol:ethanol), 45 mL / min. Isomers refer to pure atropisomers. 61 Preparative chiral HP...

Claims

1. The following compound is given by the formula: 【Chemistry 1】 During the ceremony, A is -C(H)- or -N-, B is -C(R ４ ) - or -N-, R １ However, the following formula 【Chemistry 2】 It is the basis of, R １ｂ However, H or C １～３ It is alkyl, R １ｄ However, C １～３ Alkyl, C １～３ Haloalkyl, or C ３～４ It is a cycloalkyl, R １ｅ is C １～３ alkylene, and Ring A １ and ring A ２ However, C ３～４ A cycloalkyl or a three- or four-membered heterocycle containing a heteroatom selected from N, O, and S, X １ and X ２ However, it is -CH- or -N-, X ３ However, -CH ２ - or -O-, X ４ and X ５ However, each is independent of C １～３ Alkyl, halogen, or H, m, m', s, t, u, v, and w are each 0 or 1. R ２ However, halogen or C １～３ It is alkyl, Z １ However, it is -C(CN)- or -N-, Z ２ However, -C(R ３ｃ ) - or -N-, Z ３ However, it is -O- or -S-, R ３ａ , R ３ｂ , and R ３ｃ However, each is independent of H, halogen, or C. １～３ It is alkyl, R ４ However, H, C １～３ C is optionally substituted with one, two, three, or four substituents independently selected from alkyl, hydroxyl, and methyl. １～３ It is an alkoxy, or R ４ However, the following formula (i) 【Transformation 3】 (In the formula, R ４ｂ However, it is either H or methyl, R ４ｃ and R ４ｄ However, each is independent of C １～３ Alkyl, hydroxyl, or C １～３ It is a haloalkyl, or R ４ｃ and R ４ｄ However, together with the nitrogen or carbon atom to which they are bonded, they form a four-membered, five-membered, or six-membered heterocycle), or (ii) 【Chemistry 4】 (In the formula, R ５ａ However, halogens, hydroxy, C １～３ Alkyl, C １～３ Alkoxy, or C １～３ Alkoxy-C １～３ It is alkyl, R ５ｄ However, C １～３ It is alkyl, R ５ｅ and R ５ｆ However, together with the carbon atoms to which they are bonded, Forming a 4-member, 5-member, or 6-membered heteroring, R ５ｂ and R ５ｃ However, each is independently replaced by H and C, which are optionally substituted with one or more deuterium atoms. １～６ Alkyl, halogen, or C １～３ C optionally substituted with a haloalkyl group ３～５ It is a cycloalkyl, or a three-membered, four-membered, or five-membered heterocycle containing a heteroatom selected from N, O, and S, or R ５ｂ and R ５ｃ However, together with the nitrogen atoms to which they are bonded, they form optionally substituted 4-membered, 5-membered, or 6-membered heterocycles or 6-membered, 7-membered, or 8-membered spiroheterocycles, each heterocycle or spiroheterocycle optionally containing a further heteroatom selected from N, O, and S, and each heterocycle and spiroheterocycle contains one or more halogens, deuterium, and C １～３ Alkyl, or C １～３ It is optionally substituted with a haloalkyl, or R ５ａ and R ５ｂ However, together with the atoms to which they are bonded, A four-membered, five-membered, or six-membered heterocyclic fused ring is formed, optionally containing further heteroatoms selected from N, O, and S, R ５ｃ However, C １～３ It is alkyl, and the aforementioned 4-membered, 5-membered, or 6-membered condensed ring is C １～３ It is further optionally substituted with alkyl groups. p and r are 0, 1, or 2, respectively. (iii) 【Transformation 5】 (In the formula, R ６ However, halogens, hydroxy, C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Hydroxyalkyl, C １～３ Alkoxy and C １～３ Selected from dialkylaminos, n is 0 or 1), and (iv) 【Transformation 6】 (In the formula, R ７ However, C １～３ It is alkyl, R ７ａ However, it is a four-membered, five-membered, or six-membered heterocycle that optionally contains further heteroatoms selected from N, O, and S, or R ７ and R ７ａ However, together with the atoms to which they are bonded, they form a compound that is a group of four-membered, five-membered, or six-membered heterocyclic ring (which optionally contains further heteroatoms selected from N, O, and S). or a pharmaceutically acceptable salt thereof.

2. The compound is defined by the following formula: 【Transformation 7】 During the ceremony, R １ However, the following formula 【Transformation 8】 It is the basis of, R １ｂ However, H or C １～３ It is alkyl, R １ｄ However, C １～３ It is alkyl, R １ｅ However, C １～３ It is alkylene, Ring A １ and ring A ２ However, C ３～４ A cycloalkyl or a three- or four-membered heterocycle containing a heteroatom selected from N, O, and S, X １ and X ２ However, it is -CH- or -N-, X ３ However, -CH ２ - or -O-, X ４ and X ５ are each independently C １～３ alkyl, halogen, or H, m, m', s, t, u, v, and w are each 0 or 1. R ２ However, it is a halogen, Z １ However, it is -C(CN)- or -N-, Z ２ However, -C(R ３ｃ ) - or -N-, Z ３ is -O- or -S-, R ３ａ , R ３ｂ , and R ３ｃ However, each is independently either H or halogen, R ４ However, the following formula (i) 【Chemistry 9】 (In the formula, R ４ｂ However, it is H or methyl, R ４ｃ and R ４ｄ However, each is independent of C １～３ (It is alkyl), or (ii) 【Chemistry 10】 (In the formula, R ５ａ However, halogens, hydroxy, C １～３ Alkyl, C １～３ Alkoxy, or C １～３ Alkoxy-C １～３ It is alkyl, R ５ｂ and R ５ｃ However, H and C are independent of each other. １～６ Alkyl, C ３～５ It is a cycloalkyl, or a three-membered, four-membered, or five-membered heterocycle containing a heteroatom selected from N, O, and S, or R ５ｂ and R ５ｃ However, together with the nitrogen atoms to which they are bonded, they form optionally substituted four-membered, five-membered, or six-membered heterocycles that optionally contain further heteroatoms selected from N, O, and S, and the heterocycle is C １～３ It is optionally substituted with alkyl, or R ５ａ and R ５ｂ However, together with the atoms to which they are bonded, they form a four-membered, five-membered, or six-membered heterocyclic fused ring that optionally contains further heteroatoms selected from N, O, and S, R ５ｃ However, C １～３ It is alkyl, and the aforementioned 4-membered, 5-membered, or 6-membered condensed ring is C １～３ It is further optionally substituted with alkyl groups. (where p is 0, 1, or 2) (iii) 【Chemistry 11】 (In the formula, R ６ However, halogens, hydroxy, C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Hydroxyalkyl, C １～３ Alkoxy and C １～３ Selected from dialkylaminos, The compound according to claim 1, which is a group of the formula n (where n is 0 or 1), or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is -C(H)-.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is -N-.

5. B is -C(R ４ ) - the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein B is -N-.

7. R １ However, the following formula 【Chemistry 12】 The basis of, A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

8. R １ However, the following formula 【Chemistry 13】 The basis of, A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

9. R １ｅ The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein the compound is methylene.

10. R １ However, the following formula 【Chemistry 14】 The basis of, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. R １ｄ The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein the compound is methyl, ethyl, or difluoromethyl.

12. R １ However, the following formula 【Chemistry 15】 The basis of, A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

13. Ring A １ The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein the compound is cyclopropyl or cyclobutyl.

14. R １ However, the following formula 【Chemistry 16】 The basis of, A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

15. Ring A ２ The compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein the compound is cyclopropyl or cyclobutyl.

16. R １ｂ However, C １～３ A compound according to any one of claims 1 to 15, which is alkyl, or a pharmaceutically acceptable salt thereof.

17. R １ｂ A compound according to any one of claims 1 to 16, wherein the compound is methyl, or a pharmaceutically acceptable salt thereof.

18. R １ However, the following formula 【Chemistry 17】 The basis of, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

19. X ４ and X ５ However, it is fluoro, X ３ However, -CH ２ - The compound according to claim 18, or a pharmaceutically acceptable salt thereof.

20. R １ However, the following formula [Chemistry 18] The basis of, A compound according to claim 1, 2, or 18, or a pharmaceutically acceptable salt thereof.

21. R １ However, the following formula 【Chemistry 19】 The basis of, A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

22. R １ However, the following formula 【Chemistry 20】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

23. R １ However, the following formula 【Chemistry 21】 A compound according to claim 1 or 22, which is the base of, or a pharmaceutically acceptable salt thereof.

24. R １ However, the following formula 【Chemistry 22】 A compound according to claim 1 or 22, which is the base of, or a pharmaceutically acceptable salt thereof.

25. R １ However, the following formula 【Chemistry 23】 The compound according to claim 24, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

26. R １ However, the following formula 【Chemistry 24】 The compound according to claim 1 or 2, which is the base of.

27. R １ However, the following formula 【Chemistry 25】 The compound according to claim 26, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

28. R ２ The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein the compound is F, Cl, or methyl.

29. R ２ A compound according to any one of claims 1 to 28, wherein the compound is F or Cl, or a pharmaceutically acceptable salt thereof.

30. Z １ However, it is -C(CN)- and Z ２ However, -C (CR ３ｃ ) and Z ３ However, it is -S- and R ３ａ A compound according to any one of claims 1 to 29, wherein H is present, or a pharmaceutically acceptable salt thereof.

31. R ３ｂ However, it is halogen, R ３ｃ The compound according to claim 30, or a pharmaceutically acceptable salt thereof, wherein H is present.

32. R ３ｂ However, H is R ３ｃ The compound according to claim 30, or a pharmaceutically acceptable salt thereof, which is a halogen.

33. R ３ｂ However, it is halogen, R ３ｃ The compound according to claim 30, or a pharmaceutically acceptable salt thereof, which is a halogen.

34. Z １ However, it is -C(CN)- and Z ２ However, it is -N- and Z ３ However, it is -S- and R ３ａ A compound according to any one of claims 1 to 29, wherein H is present, or a pharmaceutically acceptable salt thereof.

35. R ３ｂ The compound according to claim 34, or a pharmaceutically acceptable salt thereof, which is a halogen.

36. Z １ However, it is -N- and Z ２ However, -C(R ３ｃ ) - and Z ３ However, it is -S- and R ３ａ A compound according to any one of claims 1 to 29, wherein H is present, or a pharmaceutically acceptable salt thereof.

37. R ３ｂ However, it is halogen, R ３ｃ The compound according to claim 36, or a pharmaceutically acceptable salt thereof, wherein H is present.

38. R ３ｂ However, H is R ３ｃ The compound according to claim 36, or a pharmaceutically acceptable salt thereof, which is a halogen.

39. R ３ｂ However, it is halogen, R ３ｃ The compound according to claim 36, or a pharmaceutically acceptable salt thereof, which is a halogen.

40. R ３ｂ However, H is R ３ｃ The compound according to claim 36, or a pharmaceutically acceptable salt thereof, wherein H is present.

41. Z １ However, it is -N- and Z ２ However, it is -N- and Z ３ However, it is -S- and R ３ａ A compound according to any one of claims 1 to 29, wherein H is present, or a pharmaceutically acceptable salt thereof.

42. R ３ｂ The compound according to claim 41, or a pharmaceutically acceptable salt thereof, which is a halogen.

43. Z １ However, it is -N- and Z ２ However, -C(R ３ｃ ) - and Z ３ However, it is -O-, and R ３ａ A compound according to any one of claims 1 to 29, wherein H is present, or a pharmaceutically acceptable salt thereof.

44. R ３ｂ The compound according to claim 43, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

45. R ４ However, H, C １～３ C is optionally substituted with one, two, three, or four substituents independently selected from alkyl, hydroxyl, and methyl. １～３ A compound according to any one of claims 1 or 4 to 44, which is an alkoxy, or a pharmaceutically acceptable salt thereof.

46. R ４ However, the following formula 【Chemistry 26】 A compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

47. R ４ However, the following formula 【Chemistry 27】 The compound according to claim 46, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

48. R ４ However, the following formula 【Chemistry 28】 A compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

49. R ４ However, the following formula 【Chemistry 29】 The compound according to claim 48, or a pharmaceutically acceptable salt, which is the base of the compound, or a pharmaceutically acceptable salt.

50. R ４ However, the following formula 【Transformation 30】 A compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

51. R ４ However, the following formula 【Chemistry 31】 A compound according to any one of claims 1 to 44 or 50, which is the base of, or a pharmaceutically acceptable salt thereof.

52. R ４ However, the following formula 【Chemistry 32】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

53. R ４ However, the following formula 【Transformation 33】 The compound according to any one of claims 50 to 52, which is the base of or a pharmaceutically acceptable salt thereof.

54. R ４ However, the following formula 【Transformation 34】 The compound according to claim 53, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

55. R ４ However, the following formula 【Chemistry 35】 The compound according to claim 53, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

56. R ４ However, the following formula 【Transformation 36】 The compound according to claim 55, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

57. R ４ However, the following formula 【Chemistry 37】 A compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

58. R ４ However, the following formula 【Transformation 38】 The compound according to claim 57, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

59. The aforementioned compound, 【Chemistry 39】 【Chemistry 40】 A compound selected from the compounds described in claim 1, or a pharmaceutically acceptable salt thereof.

60. The aforementioned compound, 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

61. The aforementioned compound, 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

62. A pharmaceutical composition comprising a compound according to any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

63. A method for treating a patient having cancer, comprising administering to a patient in need of treatment an effective amount of the pharmaceutical composition described in claim 62, or an effective amount of any one of claims 1 to 61, 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.

64. The method according to claim 63, 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.

65. The method according to claim 63 or 64, wherein one or more cells express the KRAS G12V mutant protein.

66. A method for treating a patient having cancer having a KRAS G12V mutation, comprising administering to a patient in need of treatment an effective amount of a compound according to any one of claims 1 to 61, 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.

67. The method according to any one of claims 63 to 66, wherein the patient is also administered an effective amount of 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.

68. A compound according to any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, for use in therapy.

69. A compound according to any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

70. The aforementioned cancer has the KRAS G12V mutation, and the compound for use according to claim 69, or a pharmaceutically acceptable salt thereof.

71. The compound for use according to claim 69 or 70, 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.

72. A compound according to any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in combination with, separately from, 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.

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