4-aminobuta-2-enamide derivatives and salts thereof

Abstract

The present invention provides an antitumor agent comprising, as an active ingredient, a compound that covalently binds to GTP-bound KRAS G12C or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] The present invention relates to 4-aminobuta-2-enamide derivatives having inhibitory activity against the active form of the KRAS G12C mutation, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing the same as active ingredients. [Background technology]

[0002] RasGAP is a small monomeric GTP-binding protein with a molecular weight of approximately 21 kDa, acting as a molecular on / off switch. RAS can bind to GTP by binding to guanine nucleotide exchange factor (GEF) proteins (e.g., SOS1), which force the release of bound nucleotides, thereby releasing GDP. Once RAS binds to GTP, it is activated (turned on), recruiting and activating proteins necessary for the propagation of other receptor signals, such as c-Raf and PI3-kinase. RAS also possesses enzymatic activity that cleaves the terminal phosphate of nucleotides and converts them to GDP. The conversion rate is usually slow, but can be dramatically accelerated by proteins of the GTPase-activating protein (GAP) class, such as RasGAP. Once GTP is converted to GDP, RAS is inactivated (turned off).

[0003] The main known members of the RAS subfamily include HRAS, KRAS, and NRAS. Of these, mutations in KRAS are found in many malignant tumors (95% of pancreatic cancers, 45% of colorectal cancers, and 35% of lung cancers). Mutations often occur at the glycine residue at position 12, and in lung adenocarcinoma in particular, mutations at the glycine residue at position 12 are found in approximately 90% of cases. Among these mutations, the most common (44%) is reported to be a mutation in cysteine ​​(Non-Patent Literature (NPL)1).

[0004] KRAS mutations have historically been thought to exist constitutively active (GTP-bound) in cancer cells. However, recent studies have shown that KRAS G12C mutations have basal GTPase activity. K-Ras has a pocket structure to which a medicinal agent can bind. Part of the pocket contains switch 1 (residues 30 - 40) and switch 2 (residues 60 - 76). Switch 1 has threonine-35 and switch 2 has glycine-60, and these amino acids form hydrogen bonds with the γ-phosphate of GTP respectively, keeping switch 1 and switch 2 in the active form. These two regions relax freely by hydrolysis of GTP and release of phosphate, forming an inactive GDP form. When the GTP bound to K-Ras is replaced by GDP, the three-dimensional structure of the switch region containing these switches changes. The change may be related to the binding between K-Ras and target genes such as c-Raf.

[0005] Actually, ARS-853 has been reported to bind to the cysteine of the G12C mutant of inactive KRAS (GDP), prevent the conversion of inactive KRAS (GDP) to active KRAS (GTP), inhibit downstream signal transduction, and induce apoptosis in cancer cells having KRAS G12C mutations (Patent Literature (PTL) 1 and Non-Patent Literature 2). Also, ARS-1620 having a quinazoline skeleton has been reported to exhibit an antitumor effect in tumor-bearing mice expressing KRAS G12C mutations by improving metabolic stability in mice (Patent Literature 2, Non-Patent Literature 3).

[0006] However, due to its mechanism of action, inhibitors that bind to the inactive KRAS G12C mutation may not be able to exert sufficient effects on KRAS G12C-positive cancer patients who tend to have an increased active form of the KRAS protein (GTP) due to activation of the KRAS upstream pathway or inactivation of GTPase activity in the clinical setting. Actually, it has been reported that in KRAS G12C mutant cell lines, inhibition of KRAS activity and the anti-proliferative effect of ARS-853 are attenuated by EGFR activation (Non-Patent Literature 2, Non-Patent Literature 4).

Prior Art Documents

Patent Document

[0007]

Patent Document 1

Patent Document 2

Non-Patent Document

[0008]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0009] Abnormal specific influx or GAP function to the KRAS protein into KRAS is likely to be cancer type or patient-specific. Therefore, appropriate treatment with GDP-form KRAS G12C mutation inhibitors such as ARS-853 and ARS-1620 may require an accurate understanding of the vulnerability of tumor-specific signal transduction upstream or downstream of the KRAS pathway. Therefore, inhibitors of GDP-form KRAS G12C mutations need to select an effective patient population and are likely to need to select a drug combination strategy based on the vulnerability of upstream / downstream signal transduction of KRAS. On the other hand, inhibitors against the active form of the KRAS G12C mutation are expected to have little influence from the state upstream of KRAS even as a single agent and have a therapeutic opportunity for a wider range of G12C-positive patients.

[0010] Therefore, there is a need for novel compounds or salts thereof that bind to the active variant cysteine ​​of the KRAS G12C mutation, and for pharmaceutical compositions containing the same. [Means for solving the problem]

[0011] This invention relates to the following invention.

[0012] (1) An antitumor agent containing as an active ingredient a compound that covalently binds to GTP-bound KRAS G12C or a pharmaceutically acceptable salt thereof.

[0013] (2) The compound is of formula: A-L1-L2-GJ (In the formula, A is a chemical moiety that can interact with the region between Switch 2 and α3-Helix. L1 is the linker, L2 is the linker, G is an electrophilic chemical moiety that can form a covalent bond with cysteine ​​12 in the GTP-bonded KRAS G12C. The antitumor agent according to (1), having J being a chemical portion that can interact with GTP.

[0014] (3) The antitumor agent is of formula: A-L1-L2-GJ (In the formula, G is expressed by the following formula: [ka] An antitumor agent according to (1) or (2), comprising a compound having ).

[0015] (4) In formula A-L1-L2-GJ, L1 is represented by D having -C(=O)-, L2 is represented by E having -NR1-, J is represented by NR2R3, and the compound is of formula (i): [ka] (In the formula, A is a ring system selected from substituted or unsubstituted monorings, or substituted or unsubstituted fused rings, D is a monocycle having at least one amino group bonded to a carbonyl between D and E to form an amide, wherein the monocycle is either unsubstituted or substituted with a substituent other than the amino group, or D is a substituted or unsubstituted fused ring. E is a ring system selected from substituted or unsubstituted monorings, or substituted or unsubstituted fused rings. R1 is hydrogen, or a substituted or unsubstituted C1-C6 alkyl group. R2 and R3 together are either unsubstituted or R a They form a 4-10 member saturated heterocycle substituted with 1-2 substituents independently represented by, or R2 and R3 are represented independently, where R2 is hydrogen, or a C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C6-C10 aromatic hydrocarbon, 4-10 member saturated heterocyclic group, 4-10 member partially saturated heterocyclic group, or 4-10 member unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra. R3 is hydrogen, or a C1-C6 alkyl group that is unsubstituted or substituted with one or two substituents independently represented by Ra. R aThe antitumor agent according to any one of (1) to (3), wherein (independently represents a halogen, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 haloalkoxy, substituted or unsubstituted C1-C10 alkylsulfonyl, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted 4-10 member saturated heterocyclic group).

[0016] (5) The compound is of formula (ii): [ka] (In the formula, A, D, R1, R2, and R3 are as defined in formula (i), E is an unsubstituted or R4-substituted unsaturated 6-membered ring, and E1, E2, E3, and E4 independently represent C, CH, CH2, N, or NH. R4 is a halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl. An antitumor agent as described in (4), where m is an integer from 0 to 4.

[0017] (6) The compound is of formula (iii): [ka] (In the formula, D, R1, R2, and R3 are as defined in formula (i), and E, R4, and m are as defined in formula (ii), If A is a monoring, then A' and A'' do not exist, and the monoring is represented by ring A, which is an unsubstituted or R5-substituted unsaturated 6-membered ring, and A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N, or NH. If A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring A'', where ring A is an unsubstituted or R5-substituted unsaturated 6-membered ring, A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH, and ring A' or A'' is an unsubstituted or R6-substituted saturated or unsaturated ring that forms a fused ring with ring A containing A3 and A4 or A4 and A5. R5 is a halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl. If the number of R6 atoms is two or more, two R6 atoms may bond to each other to form a 4-10 membered saturated heterocycle that shares two adjacent atoms with a C3-C10 hydrocarbon ring or ring A' or ring A'', or R6 may independently represent a halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl. n is an integer from 0 to 5. The antitumor agent described in (5), wherein p is represented as 0, 1, or 2.

[0018] (7) The compound is of formula (iv): [ka] (In the formula, R1, R2 and R3 are as defined in formula (i), E, ​​R4 and m are as defined in formula (ii), and A, R5, R6, n and p are as defined in formula (iii), If D is a monoring, then D' does not exist, and the monoring is represented by ring D, which is an unsubstituted or R7-substituted unsaturated 6-membered ring, where D1 represents N or NH, and D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH. If D is a fused ring, the fused ring is represented by ring D and ring D', where ring D is an unsubstituted or R7-substituted unsaturated 6-membered ring, and D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is an unsubstituted or R8-substituted saturated or unsaturated ring that forms a fused ring with ring D containing D1, D2 and D7. R7 is a halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl. R8 is a halogen or a substituted or unsubstituted C1-C10 alkyl group. The antitumor agent according to (6), wherein q and r each independently represent 0, 1, or 2.

[0019] (8) The antitumor agent according to (7), wherein ring A' forms a fused ring with ring A containing A3 and A4, and A1 and A5 are C, CH, or CH2.

[0020] (9) The antitumor agent described in (8), wherein R1 is hydrogen.

[0021] (10) The antitumor agent according to (9), wherein R2 and R3 are expressed independently, and R3 is hydrogen or a C1-C3 alkyl group.

[0022] (11) The antitumor agent described in (10), wherein D6 in ring D is C.

[0023] (12) The antitumor agent described in (11), wherein D3, D4 and D5 are C.

[0024] (13) The compound is of formula (v): [ka] (In the formulas, R2 and R3 are defined as in formula (i), E, ​​R4 and m are defined as in formula (ii), A, R5, n and p are defined as in formula (iii), and D, R7, R8, q and r are defined as in formula (iv), Ring A' is a saturated or unsaturated five-membered ring that forms a fused ring containing A3 and A4 with ring A, and A1', A2', and A3' independently represent C, CH, CH2, N, NH, O, or S. If the number of R6 atoms is two or more, the two R6 atoms may bond to each other to form a C3-C10 hydrocarbon ring or a 4-10 member saturated heterocycle, or The antitumor agent according to (7), wherein R6 may be independently represented as a halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy.

[0025] (14) An antitumor agent as described in any of (6) to (13), wherein A2 is C.

[0026] (15) An antitumor agent according to any one of (4) to (14), wherein R2 is an unsubstituted or Ra-substituted C1-C10 alkyl group, an unsubstituted or Ra-substituted C3-C10 cycloalkyl group, or an unsubstituted or Ra-substituted 4-10 member saturated heterocyclic group.

[0027] (16) An antitumor agent according to any of (1) to (15), wherein R3 is hydrogen.

[0028] (17) An antitumor agent according to any one of (5) to (16), wherein R4 is a halogen, cyano, or C1-C6 alkyl.

[0029] (18) An antitumor agent according to any one of (6) to (17), wherein R5 is hydroxy, halogen, C1-C10 alkyl, C1-C6 haloalkyl, or C1-C10 alkoxy.

[0030] (19) If the number of R6 is 2 or more, two R6 may bond to each other to form a C3-C10 hydrocarbon ring or a 4-10 membered saturated heterocycle, or Each R6 may independently represent a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group, as described in any of (6) to (18).

[0031] (20) The compound is of formula (vi): [ka] (wherein R2 is defined as in equation (i), E, ​​R4 and m are defined as in equation (ii), A, R5, n and p are defined as in equation (iii), R8, q and r are defined as in equation (iv), and R6 and A' are defined as in equation (v), D is a fused ring represented by ring D and ring D', where ring D' is a saturated or unsaturated 5-membered ring that forms a fused ring containing D1, D2, and D7 with ring D, and D1' and D2' independently represent C, CH, CH2, N, NH, or S. The antitumor agent according to (13), wherein R7 is represented as a halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy.

[0032] (21) The antitumor agent according to (20), wherein R7 is a halogen or a substituted or unsubstituted C1-C10 alkyl group.

[0033] (22) Equation (i): [ka] (In the formula, A is a ring system selected from substituted or unsubstituted monorings, or substituted or unsubstituted fused rings, D is a monocycle having at least one amino group bonded to a carbonyl between D and E to form an amide, wherein the monocycle is either unsubstituted or substituted with a substituent other than the amino group, or D is a substituted or unsubstituted fused ring. E is a ring system selected from substituted or unsubstituted monorings, or substituted or unsubstituted fused rings. R1 is hydrogen, or a substituted or unsubstituted C1-C6 alkyl group. R2 and R3 together are either unsubstituted or R a They form a 4-10 member saturated heterocycle substituted with 1-2 substituents independently represented by, or R2 and R3 are represented independently, where R2 is hydrogen, or a C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C6-C10 aromatic hydrocarbon, 4-10 member saturated heterocyclic group, 4-10 member partially saturated heterocyclic group, or 4-10 member unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra. R3 is hydrogen, or a C1-C6 alkyl group that is unsubstituted or substituted with one or two substituents independently represented by Ra. R aCompounds represented independently by a halogen, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 haloalkoxy, substituted or unsubstituted C1-C10 alkylsulfonyl, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted 4-10 membered saturated heterocyclic group, or pharmaceutically acceptable salts thereof.

[0034] (23) The compound is of formula (ii): [ka] (In the formula, A, D, R1, R2, and R3 are as defined in formula (i), E is an unsubstituted or R4-substituted unsaturated 6-membered ring, and E1, E2, E3, and E4 independently represent C, CH, CH2, N, or NH. R4 is a halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl. A compound as described in (22), represented by m being an integer from 0 to 4, or a pharmaceutically acceptable salt thereof.

[0035] (24) The compound is of formula (iii): [ka] (In the formula, D, R1, R2, and R3 are as defined in formula (i), and E, R4, and m are as defined in formula (ii), If A is a monoring, then A' and A'' do not exist, and the monoring is represented by ring A, which is an unsubstituted or R5-substituted unsaturated 6-membered ring, and A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N, or NH. If A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring A'', where ring A is an unsubstituted or R5-substituted unsaturated 6-membered ring, A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH, and ring A' or A'' is an unsubstituted or R6-substituted saturated or unsaturated ring that forms a fused ring with ring A containing A3 and A4 or A4 and A5. R5 is a halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl. If the number of R6 atoms is two or more, two R6 atoms may bond to each other to form a 4-10 membered saturated heterocycle that shares two adjacent atoms with a C3-C10 hydrocarbon ring or ring A' or ring A'', or R6 may independently represent a halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl. n is an integer from 0 to 5. A compound described in (24) or a pharmaceutically acceptable salt thereof, represented by p being 0, 1, or 2.

[0036] (25) The compound is of formula (iv): [ka] (In the formula, R1, R2 and R3 are as defined in formula (i), E, ​​R4 and m are as defined in formula (ii), and A, R5, R6, n and p are as defined in formula (iii), If D is a monoring, then D' does not exist, and the monoring is represented by ring D, which is an unsubstituted or R7-substituted unsaturated 6-membered ring, where D1 represents N or NH, and D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH. If D is a fused ring, the fused ring is represented by ring D and ring D', where ring D is an unsubstituted or R7-substituted unsaturated 6-membered ring, and D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is an unsubstituted or R8-substituted saturated or unsaturated ring that forms a fused ring with ring D containing D1, D2 and D7. R7 is a halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl. R8 is a halogen or a substituted or unsubstituted C1-C10 alkyl group. The compound described in (24), or a pharmaceutically acceptable salt thereof, represented by q and r (each independently representing 0, 1, or 2).

[0037] (26) The compound described in (25) or a pharmaceutically acceptable salt thereof, wherein ring A' forms a fused ring with ring A containing A3 and A4, and A1 and A5 are C, CH or CH2.

[0038] (27) The compound described in (26) or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen.

[0039] (28) The compound described in (27) or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are independently represented and R3 is hydrogen or a C1-C3 alkyl group.

[0040] (29) The compound described in (28) or a pharmaceutically acceptable salt thereof, wherein D6 of ring D is C.

[0041] (30) The compound described in (29) or a pharmaceutically acceptable salt thereof, wherein D3, D4 and D5 are C.

[0042] (31) The compound is of formula (v): [ka] (In the formulas, R2 and R3 are defined as in formula (i), E, ​​R4 and m are defined as in formula (ii), A, R5, n and p are defined as in formula (iii), and D, R7, R8, q and r are defined as in formula (iv), Ring A' is a saturated or unsaturated five-membered ring that forms a fused ring containing A3 and A4 with ring A, and A1', A2', and A3' independently represent C, CH, CH2, N, NH, O, or S. If the number of R6 atoms is two or more, the two R6 atoms may bond to each other to form a C3-C10 hydrocarbon ring or a 4-10 member saturated heterocycle, or R6 may independently be represented by a halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy) the compound described in (25), or a pharmaceutically acceptable salt thereof.

[0043] (32) A compound described in any of (24) to (31) or a pharmaceutically acceptable salt thereof, wherein A2 is C.

[0044] (33) A compound according to any of (28) to (32), wherein R2 is an unsubstituted or Ra-substituted C1-C10 alkyl group, an unsubstituted or Ra-substituted C3-C10 cycloalkyl group, or an unsubstituted or Ra-substituted 4-10 member saturated heterocyclic group, or a pharmaceutically acceptable salt thereof.

[0045] (34) A compound described in any of (28) to (33) or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen.

[0046] (35) A compound according to any of (23) to (34) or a pharmaceutically acceptable salt thereof, wherein R4 is a halogen, cyano, or C1-C6 alkyl.

[0047] (36) A compound according to any of (24) to (35) or a pharmaceutically acceptable salt thereof, wherein R5 is hydroxy, halogen, C1-C10 alkyl, C1-C6 haloalkyl, or C1-C10 alkoxy.

[0048] (37) If the number of R6 is 2 or more, two R6 may bond to each other to form a C3-C10 hydrocarbon ring or a 4-10 membered saturated heterocycle, or Each R6 may independently represent a substituted or unsubstituted C1-C10 alkyl, or a substituted or unsubstituted C1-C10 alkoxy, and the compound is one of those described in (24) to (36), or a pharmaceutically acceptable salt thereof.

[0049] (38) The compound is of formula (vi): [ka] (wherein R2 is defined as in equation (i), E, ​​R4 and m are defined as in equation (ii), A, R5, n and p are defined as in equation (iii), R8, q and r are defined as in equation (iv), and R6 and A' are defined as in equation (v), D is a fused ring represented by ring D and ring D', where ring D' is a saturated or unsaturated 5-membered ring that forms a fused ring containing D1, D2, and D7 with ring D, and D1' and D2' independently represent C, CH, CH2, N, NH, or S. The compound or a salt thereof described in (31), or a pharmaceutically acceptable salt thereof, represented by R7 being a halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy.

[0050] (39) The compound described in (38), or a pharmaceutically acceptable salt thereof, wherein R7 is a halogen, or a substituted or unsubstituted C1-C10 alkyl group.

[0051] A pharmaceutical product comprising any of the compounds described in (40), (22), to (39), or a pharmaceutically acceptable salt thereof.

[0052] A pharmaceutical composition comprising any of the compounds described in (41), (22), to (39), or a pharmaceutically acceptable salt thereof.

[0053] An antitumor agent comprising any of the compounds described in (42)(22) to (39) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0054] An orally administered antitumor agent comprising, as an active ingredient, one of the compounds described in (43)(22) to (39) or a pharmaceutically acceptable salt thereof.

[0055] (44) Use of any of the compounds described in (22) to (39) or pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical composition.

[0056] (45) Use of any of the compounds described in (22) to (39) or pharmaceutically acceptable salts thereof for the manufacture of an antitumor agent.

[0057] (46) Use of any of the compounds described in (22) to (39) or pharmaceutically acceptable salts thereof for the manufacture of an antitumor agent for oral administration.

[0058] (47) A compound described in any of (22) to (39) or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

[0059] (48) A compound described in any of (22) to (39) or a pharmaceutically acceptable salt thereof, used for the treatment of tumors.

[0060] (49) A compound described in any of (22) to (39) or a pharmaceutically acceptable salt thereof, used for the treatment of tumors by oral administration.

[0061] (50) A method for treating a tumor, comprising administering a therapeutically effective amount of any of the compounds described in (22) to (39) or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0062] (51) The antitumor agent described in (1), which is administered to a subject in need in combination with one or more other antitumor agents in a pharmaceutically effective amount.

[0063] (52) The antitumor agent according to (1), wherein the tumor is cancer.

[0064] (53) The antitumor agent according to (52), wherein the cancer is one or more selected from the group consisting of carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

[0065] (54) The antitumor agent according to (53), wherein the squamous cell carcinoma is a cancer of the cervix, tarsal, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx, or esophagus.

[0066] (55) The antitumor agent according to (53), wherein the adenocarcinoma is cancer of the prostate, small intestine, endometrium, cervix, large intestine, lung, pancreas, esophagus, rectum, uterus, stomach, breast, or ovary.

[0067] (56) The method according to (51), wherein the tumor is rectal cancer, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, breast cancer, or leukemia.

[0068] An antitumor agent comprising, as an active ingredient, a compound described in any one of paragraphs (57), (22), to (39), or a pharmaceutically acceptable salt thereof, and one or more other antitumor agents.

[0069] (58) An antitumor agent comprising as an active ingredient any of the compounds described in any one of paragraphs (22) to (39) or a pharmaceutically acceptable salt thereof, which is administered in combination with one or more other antitumor agents.

[0070] (59) Use of any compound or salt thereof described in any one of paragraphs (22) to (39) and one or more other antitumor agents for the manufacture of an antitumor agent.

[0071] (60) Use of any one of the compounds or salts thereof described in (22) to (39) for the manufacture of an antitumor agent administered in combination with one or more other antitumor agents.

[0072] (61) A combination of a compound or salt thereof described in any one of items (22) to (39) used for the treatment of tumors, and one or more other antitumor agents.

[0073] (62) A compound described in any of (22) to (39) or a pharmaceutically acceptable salt thereof, used for the treatment of a tumor, administered in combination with one or more other antitumor agents.

[0074] (63) A method for treating a tumor, comprising administering a therapeutically effective amount of any of the compounds described in (22) to (39) or a pharmaceutically acceptable salt thereof, and one or more other antitumor agents to a subject in need thereof.

[0075] (64) A method for treating a tumor, comprising administering a therapeutically effective amount of any of the compounds described in (22) to (39) or a pharmaceutically acceptable salt thereof to a subject in need, in combination with one or more other antitumor agents.

[0076] (65) Use of compounds that covalently bind to GTP-bound KRAS G12C or pharmaceutically acceptable salts thereof for the manufacture of antitumor agents.

[0077] (66) Compounds that covalently bind to GTP-bound KRAS G12C used in the treatment of tumors, or pharmaceutically acceptable salts thereof.

[0078] (67) A method for treating a tumor, comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof that covalently binds to GTP-bound KRAS G12C to a subject in need thereof.

[0079] (68) The antitumor agent is of formula: A-L1-L2-GJ (In the formula, G is expressed by the following formula: [ka] An antitumor agent according to (1) or (2), comprising a compound having ).

[0080] (69) In formula A-L1-L2-GJ, L1 is represented by D having -C(=O)-, L2 is represented by E having -NR1-, and J is represented by -CHR2'-NR2R3, and the compound is of formula (vii): [ka] (In the formula, A is a ring system selected from substituted or unsubstituted monorings, or substituted or unsubstituted fused rings, D is a monocycle having at least one amino group bonded to a carbonyl between D and E to form an amide, wherein the monocycle is either unsubstituted or substituted with a substituent other than the amino group, or D is a substituted or unsubstituted fused ring. E is a ring system selected from substituted or unsubstituted monorings, or substituted or unsubstituted fused rings. R1 is hydrogen, or a substituted or unsubstituted C1-C6 alkyl group. R2 and R3 or R2 and R2' together are either unsubstituted or R a They form a 4-10 member saturated heterocycle substituted with 1-2 substituents independently represented by, or R2, R2', and R3 are represented independently, where R2 is hydrogen, or a C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C6-C10 aromatic hydrocarbon, 4-10 member saturated heterocyclic group, 4-10 member partially saturated heterocyclic group, or 4-10 member unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra. R2' is hydrogen, or a C1-C6 alkyl group that is unsubstituted or substituted with 1-2 substituents independently represented by Ra. R3 is hydrogen, or a C1-C6 alkyl group that is unsubstituted or substituted with one or two substituents independently represented by Ra. R a The antitumor agent according to any one of (1), (2), or (68), wherein (independently represents a halogen, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 haloalkoxy, substituted or unsubstituted C1-C10 alkylsulfonyl, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted 4-10 member saturated heterocyclic group).

[0081] (70) The compound is of formula (viii): [ka] (In the formula, A, D, R1, R2, R2', and R3 are defined in formula (vii) of (69), E is an unsubstituted or R4-substituted unsaturated 6-membered ring, and E1, E2, E3, and E4 independently represent C, CH, CH2, N, or NH. R4 is a halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl. An antitumor agent as described in (69), where m is an integer from 0 to 4.

[0082] (71) The compound is of formula (ix): [ka] (In the formula, D, R1, R2, R2' and R3 are defined in formula (vii) of (69), and E, R4 and m are defined in formula (viii) of (70), If A is a monoring, then A' and A'' do not exist, and the monoring is represented by ring A, which is an unsubstituted or R5-substituted unsaturated 6-membered ring, and A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N, or NH. If A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring A'', where ring A is an unsubstituted or R5-substituted unsaturated 6-membered ring, A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH, and ring A' or A'' is an unsubstituted or R6-substituted saturated or unsaturated ring that forms a fused ring with ring A containing A3 and A4 or A4 and A5. R5 is a halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl. If the number of R6 atoms is two or more, two R6 atoms may bond to each other to form a 4-10 membered saturated heterocycle that shares two adjacent atoms with a C3-C10 hydrocarbon ring or ring A' or ring A'', or R6 may independently represent a halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl; n is an integer from 0 to 5. The antitumor agent according to (70), wherein p is represented as 0, 1, or 2.

[0083] (72) The compound is of formula (x): [ka] (wherein R1, R2, R2' and R3 are defined as in equation (vii) of (69), E, ​​R4 and m are defined as in equation (viii) of (70), and A, R5, R6, n and p are defined as in equation (ix) of (71), If D is a monoring, then D' does not exist, and the monoring is represented by ring D, which is an unsubstituted or R7-substituted unsaturated 6-membered ring, where D1 represents N or NH, and D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH. If D is a fused ring, the fused ring is represented by ring D and ring D', where ring D is an unsubstituted or R7-substituted unsaturated 6-membered ring, and D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is an unsubstituted or R8-substituted saturated or unsaturated ring that forms a fused ring with ring D containing D1, D2 and D7. R7 is a halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl. R8 is a halogen or a substituted or unsubstituted C1-C10 alkyl group. The antitumor agent according to (71), wherein q and r each independently represent 0, 1, or 2.

[0084] (73) The antitumor agent according to (72), wherein ring A' forms a fused ring with ring A containing A3 and A4, and A1 and A5 are C, CH, or CH2.

[0085] (74) The antitumor agent described in (73), wherein R1 is hydrogen.

[0086] (75) The antitumor agent according to (74), wherein R2 and R3 are expressed independently, and R3 is hydrogen or a C1-C3 alkyl group.

[0087] (76) The antitumor agent described in (75), wherein D6 in ring D is C.

[0088] (77) The antitumor agent described in (76), wherein D3, D4 and D5 are C.

[0089] (78) The compound is of formula (xi): [ka] (wherein R2 and R2' are defined as in formula (vii) of (69), R2 and R3 are expressed independently, R3 is hydrogen or C1-C3 alkyl, E, R4 and m are defined as in formula (viii) of (70), A, R5, n and p are defined as in formula (ix) of (71), and D, R7, R8, q and r are defined as in formula (x) of (72), Ring A' is a saturated or unsaturated five-membered ring that forms a fused ring containing A3 and A4 with ring A, and A1', A2', and A3' independently represent C, CH, CH2, N, NH, O, or S. If the number of R6 atoms is two or more, the two R6 atoms may bond to each other to form a C3-C10 hydrocarbon ring or a 4-10 member saturated heterocycle, or The antitumor agent according to any one of (72) to (77), wherein R6 may be independently represented as a halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy.

[0090] (79) An antitumor agent as described in any of (71) to (78), wherein A2 is C.

[0091] (80) R2 and R2' together form a 4-6 member saturated heterocycle that is unsubstituted or substituted with 1-2 substituents independently represented by Ra, or The antitumor agent according to any one of (75) to (79), wherein R2 and R2' are represented independently, and R2 is an unsubstituted or Ra-substituted C1-C10 alkyl group, an unsubstituted or Ra-substituted C3-C10 cycloalkyl group, or an unsubstituted or Ra-substituted 4-10 member saturated heterocyclic group.

[0092] (81) An antitumor agent as described in any of (75) to (80), wherein R3 is hydrogen.

[0093] (82) An antitumor agent according to any one of (70) to (81), wherein R4 is a halogen, cyano, or C1-C6 alkyl.

[0094] (83) An antitumor agent according to any one of (71) to (82), wherein R5 is hydroxy, halogen, C1-C10 alkyl, C1-C6 haloalkyl, or C1-C10 alkoxy.

[0095] (84) If the number of R6 is 2 or more, two R6 may bond to each other to form a C3-C10 hydrocarbon ring or a 4-10 membered saturated heterocycle, or Each R6 may independently represent a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkoxy group, as described in any of (71) to (83).

[0096] (85) The compound is of formula (xii): [ka] (wherein R2 and R2' are defined in (80), E and m are defined in equation (viii) of (70), A, n and p are defined in equation (ix) of (71), R8, q and r are defined in equation (x) of (72), A' is defined in equation (xi) of (78), R4 is defined in (82), R5 is defined in (83), and R6 is defined in (84), D is a fused ring represented by ring D and ring D', where ring D' is a saturated or unsaturated 5-membered ring that forms a fused ring containing D1, D2, and D7 with ring D, and D1' and D2' independently represent C, CH, CH2, N, NH, or S. An antitumor agent according to any one of (78) to (84), wherein R7 is represented as a halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy.

[0097] (86) The antitumor agent according to (85), wherein R7 is a halogen or a substituted or unsubstituted C1-C10 alkyl group.

[0098] (87) Formula (vii): [ka] (In the formula, A is a ring system selected from substituted or unsubstituted monorings, or substituted or unsubstituted fused rings, D is a monocycle having at least one amino group bonded to a carbonyl between D and E to form an amide, wherein the monocycle is either unsubstituted or substituted with a substituent other than the amino group, or D is a substituted or unsubstituted fused ring. E is a ring system selected from substituted or unsubstituted monorings, or substituted or unsubstituted fused rings. R1 is hydrogen, or a substituted or unsubstituted C1-C6 alkyl group. R2 and R3 or R2 and R2' together are either unsubstituted or R a They form a 4-10 member saturated heterocycle substituted with 1-2 substituents independently represented by, or R2, R2', and R3 are represented independently, where R2 is hydrogen, or a C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C6-C10 aromatic hydrocarbon, 4-10 member saturated heterocyclic group, 4-10 member partially saturated heterocyclic group, or 4-10 member unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra. R2' is hydrogen, or a C1-C6 alkyl group that is unsubstituted or substituted with 1-2 substituents independently represented by Ra. R3 is hydrogen, or a C1-C6 alkyl group that is unsubstituted or substituted with one or two substituents independently represented by Ra. R aCompounds represented independently by a halogen, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 haloalkoxy, substituted or unsubstituted C1-C10 alkylsulfonyl, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted 4-10 membered saturated heterocyclic group, or pharmaceutically acceptable salts thereof.

[0099] (88) The compound is of formula (viii): [ka] (In the formula, A, D, R1, R2, R2', and R3 are defined in formula (vii) of (87), E is an unsubstituted or R4-substituted unsaturated 6-membered ring, and E1, E2, E3, and E4 independently represent C, CH, CH2, N, or NH. R4 is a halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl. A compound as described in (87), represented by m being an integer between 0 and 4, or a pharmaceutically acceptable salt thereof.

[0100] (89) The compound is of formula (ix): [ka] (wherein D, R1, R2, R2' and R3 are defined in equation (vii) of (87), and E, R4 and m are defined in equation (viii) of (88), If A is a monoring, then A' and A'' do not exist, and the monoring is represented by ring A, which is an unsubstituted or R5-substituted unsaturated 6-membered ring, and A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N, or NH. If A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring A'', where ring A is an unsubstituted or R5-substituted unsaturated 6-membered ring, A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH, and ring A' or A'' is an unsubstituted or R6-substituted saturated or unsaturated ring that forms a fused ring with ring A containing A3 and A4 or A4 and A5. R5 is a halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl. If the number of R6 atoms is two or more, two R6 atoms may bond to each other to form a 4-10 membered saturated heterocycle that shares two adjacent atoms with a C3-C10 hydrocarbon ring or ring A' or ring A'', or R6 may independently represent a halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl. n is an integer from 0 to 5. A compound described in (88) or a pharmaceutically acceptable salt thereof, represented by p being 0, 1, or 2.

[0101] (90) The compound is of formula (x): [ka] (wherein R1, R2, R2' and R3 are defined in equation (vii) of (87), E, ​​R4 and m are defined in equation (viii) of (88), and A, R5, R6, n and p are defined in equation (ix) of (89), If D is a monoring, then D' does not exist, and the monoring is represented by ring D, which is an unsubstituted or R7-substituted unsaturated 6-membered ring, where D1 represents N or NH, and D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH. If D is a fused ring, the fused ring is represented by ring D and ring D', where ring D is an unsubstituted or R7-substituted unsaturated 6-membered ring, and D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is an unsubstituted or R8-substituted saturated or unsaturated ring that forms a fused ring with ring D containing D1, D2 and D7. R7 is a halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl. R8 is a halogen or a substituted or unsubstituted C1-C10 alkyl group. The compound described in (89), or a pharmaceutically acceptable salt thereof, represented by q and r (each independently representing 0, 1, or 2).

[0102] (91) The compound described in (90) or a pharmaceutically acceptable salt thereof, wherein ring A' forms a fused ring with ring A containing A3 and A4, and A1 and A5 are C, CH or CH2.

[0103] (92) The compound described in (91) or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen.

[0104] (93) The compound described in (92) or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are independently represented and R3 is hydrogen or a C1-C3 alkyl group.

[0105] (94) The compound described in (93) or a pharmaceutically acceptable salt thereof, wherein D6 of ring D is C.

[0106] (95) The compound described in (94) or a pharmaceutically acceptable salt thereof, wherein D3, D4 and D5 are C.

[0107] (96) The compound is of formula (xi): [ka] (wherein R2 and R2' are defined as in formula (vii) of (87), R2 and R3 are expressed independently, R3 is hydrogen or C1-C3 alkyl, E, R4 and m are defined as in formula (viii) of (88), A, R5, n and p are defined as in formula (ix) of (89), and D, R7, R8, q and r are defined as in formula (x) of (90), Ring A' is a saturated or unsaturated five-membered ring that forms a fused ring containing A3 and A4 with ring A, and A1', A2', and A3' independently represent C, CH, CH2, N, NH, O, or S. If the number of R6 atoms is two or more, the two R6 atoms may bond to each other to form a C3-C10 hydrocarbon ring or a 4-10 member saturated heterocycle, or R6 may independently be a halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy, one of the compounds described in (90) to (95), or a pharmaceutically acceptable salt thereof.

[0108] (97) A compound described in any of (89) to (96) or a pharmaceutically acceptable salt thereof, wherein A2 is C.

[0109] (98) R2 and R2' together form a 4-6 member saturated heterocycle that is unsubstituted or substituted with 1-2 substituents independently represented by Ra, or A compound according to any of (93) to (97), or a pharmaceutically acceptable salt thereof, wherein R2 and R2' are represented independently, and R2 is an unsubstituted or Ra-substituted C1-C10 alkyl group, an unsubstituted or Ra-substituted C3-C10 cycloalkyl group, or an unsubstituted or Ra-substituted 4-10 member saturated heterocyclic group.

[0110] (99) A compound described in any of (93) to (98) or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen.

[0111] (100) A compound according to any of (88) to (99) or a pharmaceutically acceptable salt thereof, wherein R4 is a halogen, cyano, or C1-C6 alkyl.

[0112] (101) A compound according to any of (89) to (100) or a pharmaceutically acceptable salt thereof, wherein R5 is hydroxy, halogen, C1-C10 alkyl, C1-C6 haloalkyl, or C1-C10 alkoxy.

[0113] (102) If the number of R6 is 2 or more, two R6 may bond to each other to form a C3-C10 hydrocarbon ring or a 4-10 membered saturated heterocycle, or Each R6 may independently represent a substituted or unsubstituted C1-C10 alkyl, or a substituted or unsubstituted C1-C10 alkoxy, and the compound is one of those described in (89) to (101), or a pharmaceutically acceptable salt thereof.

[0114] (103) The compound is of formula (xii): [ka] (wherein R2 and R2' are defined in (98), E and m are defined in equation (viii) of (88), A, n and p are defined in equation (ix) of (89), R8, q and r are defined in equation (x) of (90), A' is defined in equation (xi) of (96), R4 is defined in (100), R5 is defined in (101), and R6 is defined in (102), D is a fused ring represented by ring D and ring D', where ring D' is a saturated or unsaturated 5-membered ring that forms a fused ring containing D1, D2, and D7 with ring D, and D1' and D2' independently represent C, CH, CH2, N, NH, or S. A compound or salt thereof described in any of (96) to (102), or a pharmaceutically acceptable salt thereof, represented by R7 being a halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy.

[0115] (104) The compounds described in (103), or pharmaceutically acceptable salts thereof, wherein R7 is a halogen, or a substituted or unsubstituted C1-C10 alkyl group.

[0116] A pharmaceutical product comprising any of the compounds described in (105), (87), to (104), or a pharmaceutically acceptable salt thereof.

[0117] A pharmaceutical composition comprising any of the compounds described in (106), (87), to (104), or a pharmaceutically acceptable salt thereof.

[0118] An antitumor agent comprising as an active ingredient any of the compounds described in (107), (87), to (104) or a pharmaceutically acceptable salt thereof.

[0119] An orally administered antitumor agent comprising, as an active ingredient, one of the compounds described in (108), (87), to (104), or a pharmaceutically acceptable salt thereof.

[0120] (109) Use of any of the compounds described in (87) to (104) or pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical composition.

[0121] (110) Use of any of the compounds described in (87) to (104) or pharmaceutically acceptable salts thereof for the manufacture of an antitumor agent.

[0122] (111) Use of any of the compounds described in (87) to (104) or pharmaceutically acceptable salts thereof for the manufacture of an antitumor agent for oral administration.

[0123] (112) A compound described in any of (87) to (104) or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

[0124] (113) A compound described in any of (87) to (104) or a pharmaceutically acceptable salt thereof, used for the treatment of tumors.

[0125] (114) A compound described in any of (87) to (104) or a pharmaceutically acceptable salt thereof, used for the treatment of tumors by oral administration.

[0126] (115) A method for treating a tumor, comprising administering a therapeutically effective amount of any of the compounds described in (87) to (104) or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0127] An antitumor agent comprising a compound described in any one of items (116), (87), to (104) or a pharmaceutically acceptable salt thereof, and one or more other antitumor agents as active ingredients.

[0128] (117) An antitumor agent comprising as an active ingredient any of the compounds described in any one of paragraphs (87) to (104) or a pharmaceutically acceptable salt thereof, administered in combination with one or more other antitumor agents.

[0129] (118) Use of any compound or salt thereof described in any one of items (87) to (104) and one or more other antitumor agents for the manufacture of an antitumor agent.

[0130] (119) Use of any one of the compounds described in (87) to (104) or a salt thereof for the manufacture of an antitumor agent administered in combination with one or more other antitumor agents.

[0131] (120) A combination of a compound or salt thereof described in any one of items (87) to (104) used for the treatment of tumors, and one or more other antitumor agents.

[0132] (121) A compound described in any of (87) to (104) or a pharmaceutically acceptable salt thereof, used for the treatment of a tumor, administered in combination with one or more other antitumor agents.

[0133] (122) A method for treating a tumor, comprising administering a therapeutically effective amount of any of the compounds described in (87) to (104) or a pharmaceutically acceptable salt thereof, and one or more other antitumor agents to a subject in need thereof.

[0134] (123) A method for treating a tumor, comprising administering a therapeutically effective amount of any of the compounds described in (87) to (104) or a pharmaceutically acceptable salt thereof to a subject in need, in combination with one or more other antitumor agents. [Effects of the Invention]

[0135] A compound or salt thereof according to one embodiment of the present invention binds to a mutant cysteine ​​(G12C) of the active form of KRAS. Compounds or salts thereof according to preferred embodiments of the present invention exhibit antitumor activity by impairing KRAS function in KRAS G12C mutation-positive cancer cells and can be used as anticancer agents. [Brief explanation of the drawing]

[0136] [Figure 1] Figure 1 shows a 2D interaction diagram of the binding site of the compound in Example 19. Residues are annotated with their three-letter amino acid codes. Figure 1 was created using the Ligand Interaction Tool in Molecular Operating Environment (MOE, version 2019.0101) (Molecular Operating Environment; CCG, I., 1255 University St., Suite 1600, Montreal, Quebec, Canada, H3B 3X3). [Figure 2] Figure 2 shows the cocrystal structures of Example 19 and Gppcp-bonded K-Ras4B G12C, focusing on the covalent bond between chemical part G of Example 19 and cysteine ​​12 of K-Ras4B G12C, and the hydrogen bond (shown by the black dashed line) between chemical part J of Example 19 and the γ-phosphate group of Gppcp. Figure 2 was created using the molecular visualization system PyMOL (version 2.2.0) (Schrodinger). [Modes for carrying out the invention]

[0137] The compound represented by formula (i) above is a novel compound and is neither taught nor disclosed in any of the above-mentioned literature.

[0138] In this specification, unless otherwise specified, "substituents" include hydrogen, halogens, cyano, nitro, amino, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkenyl, unsaturated hydrocarbons, alkoxy, haloalkoxy, cycloalkoxy, cycloalkyl-alkoxy, aralkyl, aralkyloxy, alkylthio, cycloalkyl-alkylthio, alkoxyalkyl, mono- or dialkylamino, cycloalkyl-alkylamino, aromatic hydrocarbons, acyl, alkylcarbonyl, acyloxy, arylcarbonyl, oxo, carboxy, alkoxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aralkyloxycarbonyl, carbamoyl, sulfonyl, saturated, partially saturated or unsaturated heterocyclic groups, aromatic hydrocarbons, and the like. Unless otherwise specified, when any of the substituents listed above are present, their number is typically 1, 2, or 3, preferably 1 or 2, and most preferably 1.

[0139] As used herein, specific examples of "halogen" include chlorine, bromine, fluorine, and iodine, with chlorine, fluorine, and bromine being preferred, and chlorine and fluorine being more preferred.

[0140] As used herein, "alkyl" refers to a linear or branched saturated hydrocarbon group. Examples include C1-C10 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, and hexyl. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl are preferred as alkyl groups.

[0141] As used herein, “alkenyl” refers to a linear or branched unsaturated hydrocarbon group containing at least one double bond (e.g., one to two double bonds, preferably one double bond). Examples include C2-C6 alkenyls such as vinyl, allyl, 1-propenyl, 2-methyl-2-propenyl, isopropenyl, 1-, 2- or 3-butenyl, 2-, 3- or 4-pentenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, and 5-hexenyl, with vinyl, allyl, 1-propenyl, and 2-methyl-2-propenyl being preferred.

[0142] As used herein, "alkynyl" refers to a linear or branched unsaturated hydrocarbon containing at least one triple bond (e.g., one or two triple bonds, preferably one triple bond). Examples include C2-C6 alkynyl groups, such as ethynyl, 1- or 2-propynyl, 1-, 2- or 3-butynyl, and 1-methyl-2-propynyl, with ethynyl and 2-propynyl being preferred.

[0143] As used herein, "haloalkyl" refers to the alkyl having at least one halogen atom (preferably 1 to 10, more preferably 1 to 3 halogen atoms). Examples include C1 to C10 haloalkyls, such as fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1,1,1-trifluoroethyl, monofluoro-n-propyl, 1,1,1-trifluoro-n-propyl, perfluoro-n-propyl, and perfluoroisopropyl, with trifluoromethyl, difluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, and 1,1,1-trifluoroethyl being preferred.

[0144] As used herein, "hydroxyalkyl" refers to the alkyl having at least one hydroxyl group (preferably 1 to 10, more preferably 1 to 2 hydroxyl groups). Examples include C1 to C6 hydroxyalkyls such as hydroxymethyl, hydroxyethyl, 1-hydroxypropyl, 2-hydroxybutyl, and 1,2-dihydroxyisopropyl, with 2-hydroxybutyl and 2-dihydroxyisopropyl being preferred.

[0145] As used herein, "cycloalkyl" refers to monocyclic or polycyclic saturated hydrocarbons, including bicyclic, tricyclic, crosslinked, and spirocyclic hydrocarbons. Examples include C3-C10 cycloalkyls such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclodecyl, [2.2.0]bicyclohexyl, [2.2.1]bicycloheptanyl, [3.1.1]bicycloheptanyl, and [3.2.1]bicyclooctanyl. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, [2.2.0]bicyclohexyl, [2.2.1]bicycloheptanyl, [3.1.1]bicycloheptanyl, and [3.2.1]bicyclooctanyl are preferred, with cyclobutyl and cyclopentyl being particularly preferred.

[0146] As used herein, "cycloalkenyl" refers to a monocyclic or polycyclic unsaturated hydrocarbon containing at least one carbon-carbon double bond (e.g., one to two carbon-carbon double bonds, preferably one carbon-carbon double bond). Examples include C4-C10 cycloalkenyls such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclodecenyl, with cyclopropenyl, cyclobutenyl, and cyclopentenyl being preferred, and cyclobutenyl and cyclopentenyl being particularly preferred.

[0147] As used herein, “unsaturated hydrocarbon” refers to a straight-chain or branched unsaturated hydrocarbon containing at least one carbon-carbon double or triple bond. Examples include C2-C10 unsaturated hydrocarbons such as vinyl, allyl, methylvinyl, 1-propenyl, butenyl, pentenyl, hexenyl, ethynyl, and 2-propynyl, with C2-C4 straight-chain or branched hydrocarbons containing at least one carbon-carbon double or triple bond being preferred, and vinyl, allyl, and 1-propenyl being more preferred.

[0148] As used herein, "alkoxy" refers to the alkyl-containing oxy compounds described above. Examples include C1-C10 alkoxy compounds such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, and hexyloxy, with methoxy, ethoxy, and n-propoxy being preferred, and methoxy and ethoxy being more preferred.

[0149] As used herein, "haloalkoxy" refers to the above-mentioned alkoxy having at least one halogen atom (preferably 1 to 13, more preferably 1 to 3 halogen atoms). Examples include C1 to C10 haloalkoxys such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, fluoroethoxy, 1,1,1-trifluoroethoxy, monofluoro-n-propoxy, perfluoro-n-propoxy, and perfluoro-isopropoxy.

[0150] As used herein, "cycloalkoxy" refers to the oxy having the cycloalkyl group described above. Examples include C3-C10 cycloalkoxys such as cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and cycloheptyloxy, with cyclobutoxy, cyclopentyloxy, and cyclohexyloxy being preferred.

[0151] As used herein, "cycloalkyl-alkoxy" refers to the alkoxy having at least one of the cycloalkyl groups described above. Examples include C3-C10 cycloalkyl-C1-C10 alkoxys such as cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, and cycloheptylmethoxy, with cyclohexylmethoxy being preferred.

[0152] As used herein, "aralkyl" refers to the alkyl group substituted with the aromatic hydrocarbons described above. Examples include C7-C16 aralkyl groups, such as benzyl, phenylethyl, phenylpropyl, naphthylmethyl, and naphthylethyl, with benzyl being preferred.

[0153] As used herein, "aralkyloxy" refers to an oxy compound having the aralkyl properties described above. Examples include C7-C20 aralkyloxy compounds, such as benzyloxy, phenethyloxy, naphthylmethyloxy, and fluorenylmethyloxy.

[0154] As used herein, "alkylthio" refers to the alkyl-containing thiooxy described above. Examples include C1-C10 alkylthios such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, n-pentylthio, isopentylthio, and hexylthio.

[0155] As used herein, "cycloalkyl-alkylthio" refers to the alkylthio having at least one of the cycloalkyl groups described above. Examples include C3-C10 cycloalkyl-C1-C10 alkylthios such as cyclopropylmethylthio, cyclobutylmethylthio, cyclopentylmethylthio, cyclohexylmethylthio, and cycloheptylmethylthio.

[0156] As used herein, "alkoxyalkyl" refers to the alkyl having at least one of the above-mentioned alkoxy groups. Examples include C1-C10 alkoxy-C1-C10 alkyls such as methoxymethyl, ethoxyethyl, methoxyethyl, and methoxypropyl, with methoxymethyl being preferred.

[0157] As used herein, "alkylamino" refers to an amino acid having one or two alkyl groups as described above. Specific examples include C1-C10 alkylaminos such as methylamino, ethylamino, dimethylamino, diethylamino, and ethylmethylamino, with methylamino, dimethylamino, and diethylamino being preferred.

[0158] As used herein, "monoalkylamino" refers to an amino acid having one alkyl group as described above. Examples include C1-C10 monoalkylaminos such as methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, n-pentylamino, isopentylamino, and hexylamino, with methylamino and ethylamino being preferred.

[0159] As used herein, "dialkylamino" refers to an amino acid having the two alkyl groups described above. Examples include C1-C10 dialkylaminos having two alkyl groups, each having 1 to 10 carbon atoms, such as dimethylamino, diethylamino, di(n-propyl)amino, diisopropylamino, di(n-butyl)amino, diisobutylamino, di(n-pentyl)amino, diisopentylamino, dihexylamino, methylethylamino, and methylisopropylamino, with dimethylamino and diethylamino being preferred.

[0160] As used herein, "cycloalkyl-alkylamino" refers to the alkylamino having the cycloalkyl group, wherein the cycloalkyl group is bonded to the alkyl portion of the alkylamino. Examples include C3-C10 cycloalkyl-C1-C10 alkylaminos such as cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino, cycloheptylmethylamino, and cyclohexyldimethylamino, with cyclohexyldimethylamino being preferred.

[0161] In this specification, "aromatic hydrocarbon" means a monocyclic or polycyclic aromatic hydrocarbon that is an unsaturated bond-containing ring substituent containing carbon and hydrogen, and which contains 4e+2 electrons (where e is an integer of 1 or more) in its cyclic π-electron system. Examples include phenyl, naphthyl, tetrahydronaphthyl, anthracenyl, etc., with phenyl being preferred.

[0162] As used herein, "acyl" refers to an alkylcarbonyl or arylcarbonyl.

[0163] As used herein, "alkylcarbonyl" refers to a carbonyl having the alkyl group described above. Examples include C1-C10 alkylcarbonyls such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, and hexylcarbonyl, with methylcarbonyl being preferred. Furthermore, in the present invention, C1-C10 alkylcarbonyl refers to (C1-C10 alkyl)carbonyl.

[0164] As used herein, "acyloxy" refers to an acyl having the carbonyloxy described above. Examples include C1-C10 acyloxys such as alkylcarbonyloxys or arylcarbonyloxys.

[0165] As used herein, "arylcarbonyl" refers to a carbonyl having the above-mentioned aromatic hydrocarbon. Examples include (C6-C20 aryl)carbonyls such as phenylcarbonyl, naphthylcarbonyl, fluorenylcarbonyl, anthrylcarbonyl, biphenylylcarbonyl, tetrahydronaphthylcarbonyl, chromanylcarbonyl, 2,3-dihydro-1,4-dioxanaphthalenylcarbonyl, indanylcarbonyl, and phenanthrylcarbonyl.

[0166] As used herein, "alkoxycarbonyl" refers to a carbonyl having the above-mentioned alkoxy. Examples include (C1-C10 alkoxy)carbonyls such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, and hexyloxycarbonyl, with tert-butoxycarbonyl being preferred.

[0167] As used herein, "alkylcarbonyloxy" refers to an oxy having the alkylcarbonyl described above. Examples include (C1-C10 alkyl) carbonyloxy such as methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, isobutylcarbonyloxy, tert-butylcarbonyloxy, n-pentylcarbonyloxy, isopentylcarbonyloxy, and hexylcarbonyloxy, with tert-butylcarbonyloxy being preferred.

[0168] As used herein, "arylcarbonyloxy" refers to the oxy having the arylcarbonyl described above. Examples include (C6-C13 aryl)carbonyloxys such as phenylcarbonyloxy, naphthylcarbonyloxy, fluorenylcarbonyloxy, anthrylcarbonyloxy, biphenylylcarbonyloxy, tetrahydronaphthylcarbonyloxy, chromanylcarbonyloxy, 2,3-dihydro-1,4-dioxanaphthalenylcarbonyloxy, indanylcarbonyloxy, and phenanthrylcarbonyloxy.

[0169] As used herein, "aralkyloxycarbonyl" refers to a carbonyl having the above-mentioned aralkyloxy. Examples include (C6-C20 aralkyl)oxycarbonyls, such as benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethyloxycarbonyl, and fluorenylmethyloxycarbonyl.

[0170] As used herein, "saturated heterocyclic group" refers to a monocyclic or polycyclic saturated heterocyclic group containing at least one heteroatom (preferably 1 to 5, more preferably 1 to 3 heteroatoms) selected from nitrogen, oxygen, and sulfur. Examples of monocyclic or polycyclic saturated heterocyclic groups include monocyclic, bicyclic, tricyclic, bridging, and spirocyclic saturated heterocyclic groups. Examples include azilidinyl, azetidinyl, imidazolidinyl, morpholino, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranil, tetrahydropyranil, tetrahydrothiophenyl, thiazolidinyl, oxazolidinyl, etc., with azetidinyl, pyrrolidinyl, and piperidinyl being preferred, and azetidinyl and pyrrolidinyl being more preferred.

[0171] As used herein, “partially saturated heterocyclic group” refers to a monocyclic or polycyclic partially saturated heterocyclic group having at least one heteroatom (preferably 1 to 5, more preferably 1 to 3 heteroatoms) selected from nitrogen, oxygen, and sulfur. Examples of monocyclic or polycyclic partially saturated heterocyclic groups include monocyclic, bicyclic, tricyclic, bridging, and spirocyclic partially saturated heterocyclic groups. Examples include indoline, 1,3-dihydroisobenzofuran, 2,3-dihydro-1H-benzo[d]imidazole, and 1,3-benzodioxole, with indoline, 2,3-dihydro-1H-benzo[d]imidazole, and 1,3-benzodioxole being preferred, and indoline and 1,3-benzodioxole being more preferred.

[0172] As used herein, “unsaturated heterocyclic group” refers to a monocyclic or polycyclic fully unsaturated heterocyclic group containing at least one heteroatom (preferably 1 to 5, more preferably 1 to 3) selected from nitrogen, oxygen, and sulfur. Examples of monocyclic or polycyclic unsaturated heterocyclic groups include monocyclic, bicyclic, tricyclic, bridging, and spirocyclic unsaturated heterocyclic groups. Examples include imidazolyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, triazolopyridyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, furanyl, benzofuranyl, purinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalyl, methylenedioxyphenyl, ethylenedioxyphenyl, dihydrobe Examples include furanzofuranil, imidazopyridinil, and indazolyl, with imidazolyl, pyrazolyl, thiazolyl, isoxazolyl, pyridyl, benzoxazolyl, benzothiazolyl, imidazopyridinil, indazolyl, indolyl, indolidinil, and furanil being preferred, imidazolyl, pyrazolyl, pyridyl, benzoxazolyl, benzothiazolyl, imidazopyridinil, indazolyl, indolyl, and indolidinil being more preferred, and benzoxazolyl, benzothiazolyl, imidazopyridinil, indolyl, indazolyl, and indolidinil being most preferred.

[0173] As used herein, the term "CA-CB" in the description of a group indicates that the group has A to B carbon atoms. For example, "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms, and "C6-C14 aromatic hydrocarbon oxy" refers to an oxy group to which C6-C14 aromatic hydrocarbons are bonded. Also, "A-B member" indicates that the number of atoms constituting the ring (number of ring members) is A to B. More specifically, "4-10 member saturated heterocyclic group" refers to a saturated heterocyclic group containing 4 to 10 ring members.

[0174] As used herein, the term C means carbon, N means nitrogen, S means sulfur, and O means oxygen.

[0175] As used herein, the term “linker” in formula A-L1-L2-GJ refers to a divalent linker. Examples of linkers include -O-, -S-, -NH-, -NR1-, -C(=O)-, -NHC(=O)-, -NR1C(=O)-, -C(=O)NH-, -C(=O)NR1-, substituted or unsubstituted C1-C6 alkylenes (preferably -CH2-, -CH(CH3)-, -C(CH3)2-), substituted or unsubstituted C2-C6 alkenylenes, substituted or unsubstituted C2-C6 alkynylenes, substituted or unsubstituted monorings or substituted or unsubstituted condensed rings, and combinations thereof. Preferably, the linker is selected from combinations of -C(=O)- with substituted or unsubstituted monorings or substituted or unsubstituted condensed rings, and combinations of -NR1- with substituted or unsubstituted monorings or substituted or unsubstituted condensed rings.

[0176] As used herein, the term "monocyclic" refers to a substituted or unsubstituted ring having a single ring structure, and may refer to a substituted or unsubstituted monocyclic ring. In one embodiment, examples of monocyclic rings include substituted or unsubstituted C3-C10 cycloalkyl groups, substituted or unsubstituted C6-C10 aromatic hydrocarbons, substituted or unsubstituted 4-10 member saturated heterocyclic groups, substituted or unsubstituted 4-10 member partially saturated heterocyclic groups, or substituted or unsubstituted 4-10 member unsaturated heterocyclic groups.

[0177] As used herein, the term “condensed ring” refers to a substituted or unsubstituted ring formed by two or more rings, where the two or more rings share two or more atoms. In one embodiment, examples of condensed rings include those formed by two or more rings selected from substituted or unsubstituted C4-C10 hydrocarbon rings, substituted or unsubstituted C7-C10 aromatic hydrocarbon rings, substituted or unsubstituted 7-10 member saturated heterocycles, substituted or unsubstituted 7-10 member partially saturated heterocycles, and substituted or unsubstituted 7-10 member unsaturated heterocycles.

[0178] In one embodiment, the anti-tumor agent of the present invention contains, as an active ingredient, a compound that covalently binds to GTP-bound KRAS G12C or a pharmaceutically acceptable salt thereof, and the compound has the following formula: A-L1-L2-G-J (wherein, A is a chemical moiety capable of interacting with the region between Switch 2 and α3-Helix, L1 is a linker, L2 is a linker, J is a chemical moiety capable of interacting with GTP, and G is an electrophilic chemical moiety capable of forming a covalent bond with cysteine 12 of GTP-bound KRAS G12C).

[0179] In a preferred embodiment, G is represented by the following formula:

Chemical formula

[0180] In another preferred embodiment, G is represented by the following formula:

Chemical formula

[0181] In one embodiment, the anti-tumor agent of the present invention contains, as an active ingredient, a compound that covalently binds to GTP-bound KRAS G12C or a pharmaceutically acceptable salt thereof, and the compound has the following formula: A-L1-L2-G-J (wherein, A is a chemical moiety capable of interacting with the region between Switch 2 and α-3-Helix, L1 is a linker, L2 is a linker, G-J is represented by the following formula.

Chemical formula

[0182] In another preferred embodiment, GJ is represented by the following formula: [ka]

[0183] When used in this specification, the symbol " [ka] " This refers to the bonding point of a chemical part to the rest of a molecule or chemical formula.

[0184] As used herein, the term “chemical portion capable of interacting with the region between Switch 2 and α3-Helix” in portion A refers to a chemical portion capable of interacting with the region between Switch 2 (residues 60-76) and α3-Helix (residues 86-103) of K-Ras. In one embodiment, portion A interacts with the region via hydrogen bonds, van der Waals forces, covalent bonds, ionic bonds, or hydrophobic interactions. As used herein, “the region between Switch2 and α3-Helix” means a region formed by one or more amino acids selected from methionine-67, arginine-68, aspartic acid-69, aspartic acid-70, glutamine-71, methionine-72, arginine-73, threonine-75, histidine-95, tyrosine-96, glutamine-99, isoleucine-100, lysine-101, arginine-102, and valine-103, preferably a region formed by one or more amino acids selected from arginine-68, aspartic acid-69, methionine-72, glutamine-99, isoleucine-100, and valine-103. In one embodiment, the K-Ras protein may have an amino acid sequence that is at least 50%, at least 85%, at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100% identical to, for example, one of SEQ ID NOs: 1 and 2.

[0185] In one embodiment, the term "chemical moiety capable of interacting with the region between Switch2 and α3-Helix" in portion A of the compound of the present invention can be determined by performing X-ray crystallography of the compound of the present invention and GTP-bound KRAS G12C and identifying the moiety that interacts with at least one amino acid moiety present in the region between Switch2 and α3-Helix of GTP-bound KRAS G12C. Such X-ray crystallography can be performed using the ligand interaction tool in the Molecular Operating Environment. In one embodiment, at least one amino acid moiety that interacts with the compound is selected from methionine-67, arginine-68, aspartic acid-69, aspartic acid-70, glutamine-71, methionine-72, arginine-73, threonine-75, histidine-95, tyrosine-96, glutamine-99, isoleucine-100, lysine-101, arginine-102, and valine-103, preferably selected from arginine-68, aspartic acid-69, methionine-72, glutamine-99, isoleucine-100, and valine-103. In one embodiment, the chemical moiety that can interact with the region between Switch 2 and α3-Helix may be a ring system selected from substituted or unsubstituted monocycles or substituted or unsubstituted fused rings.

[0186] As used herein, the term “electrophilic chemical moiety capable of forming a covalent bond with GTP-bound K-Ras G12C” in part G refers to a chemical moiety capable of electrophilically reacting with a mutation at the 12th amino acid (cysteine-12 residue) of GTP-bound K-Ras to form a covalent bond.

[0187] As used herein, the term "chemical moiety capable of interacting with GTP" in Subpart J represents a chemical moiety capable of interacting with GTP bound to K-ras. In one embodiment, the chemical moiety interacts with the γ-phosphate located at the terminus of GTP, preferably interacting with the γ-phosphate via hydrogen bonding, covalent bonding or ionic bonding. In a preferred embodiment, Subpart J is -NR2R3, which may be directly bonded to Subpart G via -CH2- or -CHR2'- or may be bonded to Subpart G. In a more preferred embodiment, Subpart J is -CHR2'-NR2R3.

[0188] In one embodiment, in the compound represented by any one of Formulas (i) to (xii), R1 represents hydrogen or C1-C6 alkyl.

[0189] In one embodiment, the "C1-C6 alkyl" represented by R1 can be C2-C6 alkyl, C3-C6 alkyl, C4-C6 alkyl, C5-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl or C1-C2 alkyl, preferably methyl, ethyl or tert-butyl, more preferably methyl or ethyl, and particularly preferably methyl.

[0190] In one embodiment, R1 is hydrogen or substituted or unsubstituted C1-C3 alkyl.

[0191] R1 is preferably hydrogen, methyl, ethyl or tert-butyl.

[0192] [[ID=K19]] More preferably, R1 is hydrogen or methyl.

[0193] Most preferably, R1 is hydrogen.

[0194] In one embodiment, in a compound represented by any one of formulas (i) to (xi) of the present invention, R2 and R3 may be bonded to each other to form a 4-10 member saturated heterocycle which is unsubstituted or substituted with 1-2 substituents independently represented by Ra, and R2' is hydrogen or an unsubstituted or substituted with 1-2 substituents independently represented by Ra, C1-C6 alkyl.

[0195] In the "unsubstituted or substituted 4-10 member saturated heterocycles represented independently by Ra" formed by R2 and R3, the "4-10 member saturated heterocycle group" is preferably an unsubstituted or substituted 4-8 member, 5-8 member, 5-7 member, or 5-6 member saturated heterocycle, and more preferably pyrrolidinyl, piperidinyl, or piperazinyl.

[0196] In the "unsubstituted or substituted 4-10 member saturated heterocycle formed by R2 and R3 with 1-2 substituents independently represented by Ra," "substituted with Ra" preferably means substitution with halogen, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 alkylsulfonyl, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted 4-10 member saturated heterocycle group, more preferably with halogen, hydroxyl, or C1-C6 alkyl, most preferably with hydroxyl.

[0197] The "unsubstituted or substituted 4-10 member saturated heterocycle" formed by R2 and R3 is preferably pyrrolidinyl, piperidinyl, or piperazinyl.

[0198] In the "unsubstituted or substituted 4-10 member saturated heterocycle" formed by R2 and R2', the "4-10 member saturated heterocycle group" is preferably an unsubstituted or substituted 4-8 member, 5-8 member, 5-7 member, or 5-6 member saturated heterocycle, and more preferably pyrrolidinyl, piperidinyl, or piperazinyl.

[0199] In the "unsubstituted or substituted 4-10 member saturated heterocycle formed by R2 and R2' with 1-2 substituents independently represented by Ra", "substituted with Ra" preferably means substitution with halogen, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 alkylsulfonyl, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted 4-10 member saturated heterocycle group, more preferably with halogen, hydroxyl, or C1-C6 alkyl, most preferably with hydroxyl.

[0200] The "unsubstituted or substituted 4-10 member saturated heterocycle" formed by R2 and R2' is preferably pyrrolidinyl, piperidinyl, or piperazinyl.

[0201] In one embodiment, R2, R2', and R3 may be represented independently, and in a compound represented by any one of formulas (i) to (xii) of the present invention, R2 is hydrogen, or a C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C6-C10 aromatic hydrocarbon, 4-10 member saturated heterocyclic group, 4-10 member partially saturated heterocyclic group, or 4-10 member unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra, and R2' is hydrogen, or a C1-C6 alkyl that is unsubstituted or substituted with 1-2 substituents independently represented by Ra. R3 is hydrogen, or a C1-C6 alkyl group that is unsubstituted or substituted with one or two substituents independently represented by Ra.

[0202] The "C1-C10 alkyl" represented by R2 may be C2-C6 alkyl, C3-C6 alkyl, C4-C6 alkyl, C5-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1-C2 alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, or n-pentyl, and more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, or n-pentyl (C3-C6 alkyl).

[0203] The "Ra" which may be substituted with the "C1-C10 alkyl" represented by R2 may be, for example, one of the above substituents, preferably a halogen, cyano, hydroxy, C3-C7 cycloalkyl or a 4-10 membered saturated heterocyclic group, and more preferably hydroxy.

[0204] The "unsubstituted or substituted C1-C10 alkyl group represented by R2 with 1-2 substituents independently represented by Ra" is preferably C1-C6 alkyl, 1,2-dihydroxyisopropyl, 2-hydroxypropyl, more preferably C1-C6 alkyl, even more preferably methyl, ethyl, isopropyl, or tert-butyl, and most preferably tert-butyl.

[0205] The "C2-C10 alkenyl" represented by R2 may be a C2-C6 alkenyl, C3-C6 alkenyl, C4-C6 alkenyl, C5-C6 alkenyl, C2-C5 alkenyl, C2-C4 alkenyl, or C2-C3 alkenyl, preferably vinyl, 1-propenyl, allyl, or isopropenyl, and more preferably vinyl or isopropenyl.

[0206] The "Ra" that can substitute for the "C2-C10 alkenyl" represented by R2 may be, for example, one of the above substituents, preferably a halogen, cyano, C1-C6 alkyl, or hydroxyl, more preferably chlorine, fluorine, or methyl, and more preferably fluorine.

[0207] The "unsubstituted or substituted C2-C10 alkenyl represented by R2 with 1-2 substituents independently represented by Ra" is preferably a C2-C6 alkenyl which may contain a halogen, more preferably vinyl, 1-propenyl, 2-methyl-2-propenyl, or 1-(trifluoromethyl)vinyl, and more preferably vinyl or 1-(trifluoromethyl)vinyl.

[0208] The "C2-C10 alkynyl" represented by R2 may be a C2-C6 alkynyl, C3-C6 alkynyl, C4-C6 alkynyl, C5-C6 alkynyl, C2-C5 alkynyl, C2-C4 alkynyl, or C2-C3 alkynyl, and is preferably ethynyl or 1-propynyl.

[0209] The "Ra" that can substitute for the "C2-C10 alkynyl" represented by R2 may be, for example, one of the above substituents, preferably a halogen or hydroxyl, and more preferably fluorine or chlorine.

[0210] The "unsubstituted or substituted C2-C10 alkynyl" represented by R2 is preferably ethynyl, 1-chloroethynyl, or 1-propynyl.

[0211] The "C3-C10 cycloalkyl" represented by R2 may be a C3-C8 cycloalkyl, a C4-C8 cycloalkyl, a C5-C8 cycloalkyl, a C5-C6 cycloalkyl, a C3-C6 cycloalkyl, or a C4-C6 alkynyl, preferably a monocyclic or bicyclic C3-C10 cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or bicyclo[3.1.0]hexanyl, and more preferably cyclohexyl.

[0212] The "Ra" that can substitute for the "C3-C10 cycloalkyl" represented by R2 may be any of the above substituents, preferably hydroxyl, halogen, C2-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 monoalkylamino, C1-C6 dialkylamino, or saturated heterocyclic group; more preferably fluorine, chlorine, hydroxyl, methyl, ethyl, n-propyl, methoxy, ethoxy, difluoromethoxy, dimethylamino, diethylamino, isopropylamino, trifluoromethyl, or dioxolane.

[0213] The "unsubstituted or substituted with 1-2 substituents independently represented by Ra" represented by R2 is preferably a hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 monoalkylamino, C1-C6 dialkylamino, or a C3-C6 cycloalkyl that may be substituted with a saturated heterocyclic group. Preferably a hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 monoalkylamino, C1-C3 dialkylamino, or a C3-C10 cycloalkyl that may be substituted with a saturated heterocyclic group. The more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-hydroxycyclohexyl, 4-methoxycyclohexyl, 4-ethoxycyclohexyl, 4-diethylaminocyclohexyl, 4-dimethylaminocyclohexyl, 4-difluoromethoxycyclohexyl, 4,4-difluorocyclohexyl, difluoro-bicyclo[3.1.0]hexane, 8-methyl-1,4-dioxaspiro{4,5}decane or 4-dioxaspiro{4,5}decanedecane, more preferably 4-hydroxycyclohexyl, 4-methoxycyclohexyl, 4-ethoxycyclohexyl, or 4-diethylaminocyclohexyl.

[0214] The "unsubstituted or substituted C1-C10 alkoxy represented by R2, which is either unsubstituted or substituted with one or two substituents independently represented by Ra," is preferably methoxy or ethoxy.

[0215] The "unsubstituted or substituted C6-C10 aromatic hydrocarbon represented by Ra" in R2 is preferably phenyl.

[0216] The "4-10 member saturated heterocyclic group" represented by R2 may be a 4-8 member, 5-8 member, 5-7 member, or 5-6 member saturated heterocyclic group, preferably a monocyclic or bicyclic 4-10 member saturated heterocyclic group containing 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur, more preferably a monocyclic 4-8 member saturated heterocyclic group containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, more preferably pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranil, tetrahydropyranil, 1,4-dioxanil, 8-oxabicyclo[3,2,1]octanil, 8-methyl-1,4-dioxaspiro{4,5}decantianil, and more preferably piperidinyl, piperazinyl, 2-ethyltetrahydropyranil, or tetrahydropyranil.

[0217] The "Ra" that can substitute for the "4-10 member saturated heterocyclic group" represented by R2 may be any of the above substituents, or preferably a halogen, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 monoalkylamino, C1-C6 dialkylamino, C1-C6 alkylsulfonyl, or C1-C6 alkylcarbonyl. More preferably, it is fluorine, chlorine, hydroxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, difluoromethoxy, dimethylamino, diethylamino, isopropylamino, trifluoromethyl, dioxolane, methoxycarbonyl, or ethylcarboxyl. Most preferably, it is methyl, dimethylamino, diethylamino, or isopropylamino.

[0218] The "unsubstituted or substituted 4-10 member saturated heterocyclic group" represented by R2 is preferably a monocyclic 4-8 member saturated heterocyclic group containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, substituted with at least one substituent selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 monoalkylamino, C1-C6 dialkylamino, C1-C6 alkylsulfonyl, and C1-C6 alkylcarbonyl, more preferably N-isopropyl-4-piperidinyl. The compounds are N-methylsulfonyl-4-piperidinyl, 2-methyl-4-tetrahydropyranyl, 1-methyl-4-tetrahydropyranyl, 2,2-dimethyl-4-tetrahydropyranyl, 2,4-dimethyl-4-tetrahydropyranyl, 3,3-dimethyl-4-tetrahydropyranyl, 4-isopropyl-4-piperidinyl, 2-ethyltetrahydropyranyl, or tert-butylcarbamatetrahydropyranyl, more preferably N-isopropyl-4-piperidinyl, 1-methyl-4-tetrahydropyranyl, 2-ethyltetrahydropyranyl, or 3,5-dimethyltetrahydropyranyl.

[0219] The "unsubstituted or substituted 4-10 membered partially saturated heterocyclic group" represented by R2 is preferably a monocyclic or bicyclic 4-10 membered, 4-8 membered, 5-8 membered, 5-7 membered, or 5-6 membered partially saturated heterocyclic group containing 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur, and more preferably a monocyclic 4-7 membered partially saturated heterocyclic group containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, and is 4H-pyranyl, indoline, 1,3-dihydroisobenzofuran, 2,3-dihydro-1H-benzo[d]imidazole, or 1,3-benzodioxole.

[0220] The "unsubstituted or substituted 4-10 membered unsaturated heterocyclic group" represented by R2 is preferably a monocyclic or bicyclic 4-10 membered, 4-8 membered, 5-8 membered, 5-7 membered, or 5-6 membered unsaturated heterocyclic group containing 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur, more preferably a monocyclic 5-7 membered unsaturated heterocyclic group containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, and more preferably pyridyl, imidazolyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isoth Asiazolyl, oxadiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrazyl, pyrimidinyl, pyridadinyl, indolyl, isoindolyl, indazolyl, triazolopyridyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, furanyl, benzofuranyl, purinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalyl, methylenedioxyphenyl, ethylenedioxyphenyl, dihydrobenzofuranyl, imidazopyridinyl, and indazolyl, more preferably pyridyl.

[0221] R2 is preferably a C1-C6 alkyl, C3-C10 cycloalkyl, or 4-10 membered saturated heterocyclic group, each of which is either unsubstituted or substituted with 1-2 substituents independently represented by Ra.

[0222] R2 is more preferably a C3-C6 alkyl, cycloalkyl, or 6-10 member saturated heterocyclic group, each of which is either unsubstituted or substituted with one or two substituents independently represented by Ra.

[0223] Ra, which can substitute for R2, is preferably a halogen, cyano, hydroxy, C1-C10 alkylamino, C1-C10 alkoxy, C1-C10 alkylsulfonyl, C3-C7 cycloalkyl, or a 4-10 membered saturated heterocyclic group.

[0224] Ra, which can substitute for R2, is more preferably hydroxy, dimethylamino, methoxy, or methylsulfonyl.

[0225] R2, which is either unsubstituted or substituted with Ra, is preferably methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-hydroxycyclohexyl, 4-methoxycyclohexyl, 4-ethoxycyclohexyl, 4-diethylaminocyclohexyl, 4-dimethylaminocyclohexyl, 4-difluoromethoxycyclohexyl, 4,4-difluorocyclohexyl, difluoro-bicyclo[3.1.0]hexane, 4-Dioxaspiro[4.5]decane, N-isopropyl-4-piperidinyl, N-methylsulfonyl-4-piperidinyl, 2-methyl-4-tetrahydropyranyl, 1-methyl-4-tetrahydropyranyl, 2,2-dimethyl-4-tetrahydropyranyl, 2,4-dimethyl-4-tetrahydropyranyl, 3,3-dimethyl-4-tetrahydropyranyl, 4-isopropyl-4-piperidinyl, 2-ethyltetrahydropyranyl, or tert-butylcarbametatetrahydropyranyl.

[0226] R2 is more preferably methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, 4-hydroxycyclohexyl, 4-methoxycyclohexyl, 4-ethoxycyclohexyl, 4-diethylaminocyclohexyl, N-isopropyl-4-piperidinyl, 1-methyl-4-tetrahydropyranyl, 2-ethyltetrahydropyranyl, or 3,5-dimethyltetrahydropyranyl.

[0227] R2 is most preferably tert-butyl, cyclohexyl, 4-hydroxycyclohexyl, 4-methoxycyclohexyl, or 4-diethylaminocyclohexyl.

[0228] In R2', the "C1-C6 alkyl group" in "unsubstituted or substituted with 1-2 substituents independently represented by Ra" is preferably methyl, ethyl, isopropyl, or tert-butyl, more preferably methyl or ethyl, and most preferably methyl.

[0229] The "unsubstituted or substituted C1-C6 alkyl group in R2' with 1-2 substituents independently represented by Ra" is preferably methyl, ethyl, isopropyl, or tert-butyl, more preferably methyl or ethyl, and most preferably methyl.

[0230] The "Ra" which may be substituted with the "C1-C10 alkyl" represented by R2', may be, for example, one of the above substituents, preferably a halogen, cyano, hydroxy, C3-C7 cycloalkyl or a 4-10 member saturated heterocyclic group, and more preferably hydroxy.

[0231] R2' is preferably hydrogen or a C1-C6 alkyl group.

[0232] R2' is more preferably hydrogen, methyl, ethyl, isopropyl, or tert-butyl.

[0233] R2' is most preferably hydrogen.

[0234] The "C1-C6 alkyl" represented by R3 is preferably methyl, ethyl, isopropyl, or tert-butyl, more preferably methyl or ethyl, and most preferably methyl.

[0235] The "Ra" which may be substituted with the "C1-C10 alkyl" represented by R3 is, for example, one of the above substituents, preferably a halogen, cyano, hydroxy, C3-C7 cycloalkyl, or 4-10 membered saturated heterocyclic group, and more preferably hydroxy.

[0236] R3 is more preferably hydrogen, or methyl, ethyl, isopropyl, or tert-butyl.

[0237] R3 is more preferably hydrogen or methyl.

[0238] R3 is most preferably hydrogen.

[0239] In one embodiment, R2 and R3 may be represented independently, and in a compound represented by any one of formulas (i) to (xii) of the present invention, R2 and R2' are bonded to each other to form a 4-10 member saturated heterocycle that is unsubstituted or substituted with 1-2 substituents independently represented by Ra. R3 is either hydrogen, unsubstituted, or a C1-C6 alkyl group substituted with one or two substituents independently represented by Ra.

[0240] In the "unsubstituted or substituted 4-10 member saturated heterocycle" formed by R2 and R2', the "4-10 member saturated heterocycle group" is preferably an unsubstituted or substituted 4-8 member, 5-8 member, 5-7 member, or 5-6 member saturated heterocycle, and more preferably pyrrolidinyl, piperidinyl, or piperazinyl.

[0241] In the "unsubstituted or substituted 4-10 member saturated heterocycle formed by R2 and R2' with 1-2 substituents independently represented by Ra", "substituted with Ra" preferably means substitution with halogen, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 alkylsulfonyl, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted 4-10 member saturated heterocycle group, more preferably with halogen, hydroxyl, or C1-C6 alkyl, most preferably with hydroxyl.

[0242] The "unsubstituted or substituted 4-10 member saturated heterocycle" formed by R2 and R2' is preferably pyrrolidinyl, piperidinyl, or piperazinyl.

[0243] The "C1-C6 alkyl" represented by R3 is preferably methyl, ethyl, isopropyl, or tert-butyl, more preferably methyl or ethyl, and most preferably methyl.

[0244] The "Ra" which may be substituted with the "C1-C10 alkyl" represented by R3 is, for example, one of the above substituents, preferably a halogen, cyano, hydroxy, C3-C7 cycloalkyl, or 4-10 membered saturated heterocyclic group, and more preferably hydroxy.

[0245] R3 is more preferably hydrogen, or methyl, ethyl, isopropyl, or tert-butyl.

[0246] R3 is more preferably hydrogen or methyl.

[0247] R3 is most preferably hydrogen.

[0248] In one embodiment, in a compound represented by any one of formulas (ii) to (xii) of the present invention, R4 represents cyano, hydroxy, halogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 sulfonyl.

[0249] The "halogen" represented by R4 is preferably chlorine, bromine, fluorine, and iodine, with chlorine, fluorine, and bromine being preferred, chlorine and fluorine being more preferred, and fluorine being the most preferred.

[0250] In the "substituted or unsubstituted C1-C10 alkyl" represented by R4, the "C1-C10 alkyl" is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, or n-pentyl; more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, or n-pentyl (C3-C6 alkyl); and even more preferably methyl.

[0251] The "substituent" in "substituted or unsubstituted C1-C10 alkyl" represented by R4 may be, for example, one of the substituents mentioned above, preferably a halogen, cyano, hydroxy, or C3-C7 cycloalkyl, and more preferably a hydroxyl group.

[0252] The "substituted or unsubstituted C1-C10 alkyl" represented by R4 is preferably C1-C6 alkyl, hydroxymethyl, 2-hydroxyethyl, 1,2-dihydroxyisopropyl, 2-hydroxypropyl, more preferably C1-C3 alkyl, even more preferably methyl, isopropyl, tert-butyl, hydroxymethyl, or 2-hydroxyethyl, and most preferably methyl.

[0253] In the "substituted or unsubstituted C2-C10 alkenyl" represented by R4, the "C2-C10 alkenyl" is preferably vinyl, 1-propenyl, allyl, or isopropenyl, and more preferably vinyl or isopropenyl.

[0254] The "substituent" in the "substituted or unsubstituted C2-C10 alkenyl" represented by R4 may be, for example, one of the above substituents, preferably a halogen, cyano, or hydroxyl, more preferably chlorine or fluorine, and more preferably fluorine.

[0255] The "substituted or unsubstituted C2-C10 alkenyl" represented by R4 is preferably a C2-C6 alkenyl which may contain a halogen, more preferably vinyl, 1-propenyl, 2-methyl-2-propenyl, or 1-(trifluoromethyl)vinyl, and more preferably vinyl or 1-(trifluoromethyl)vinyl.

[0256] In the "substituted or unsubstituted C2-C10 alkynyl" represented by R4, the "C2-C10 alkynyl" is preferably ethynyl or 1-propynyl.

[0257] The substituents in the "substituted or unsubstituted C2-C10 alkynyl" represented by R4 may be, for example, the substituents mentioned above, preferably halogens or hydroxyls, and more preferably fluorine or chlorine.

[0258] The "substituted or unsubstituted C2-C10 alkynyl" represented by R4 is preferably ethynyl or 1-propynyl.

[0259] In the "substituted or unsubstituted C3-C10 cycloalkyl" represented by R4, the "C3-C10 cycloalkyl" is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and more preferably cyclopropyl.

[0260] The "substituted or unsubstituted C1-C10 haloalkyl" represented by R4 is preferably fluoromethyl, difluoromethyl, or trifluoromethyl.

[0261] The "substituted or unsubstituted C1-C10 alkoxyl" represented by R4 is preferably methoxy, ethoxy, or 1-fluoromethoxy.

[0262] The "substituted or unsubstituted C1-C10 acyl" represented by R4 is preferably formyl, acetyl, or propionyl.

[0263] The "substituted or unsubstituted C1-C10 alkoxycarbonyl" represented by R4 is preferably a methoxycarbonyl or ethoxycarbonyl.

[0264] The "substituted or unsubstituted C1-C10 alkylsulfonyl" represented by R4 is preferably methoxysulfonyl or ethoxysulfonyl.

[0265] R4 is preferably a halogen, cyano, or a substituted or unsubstituted C1-C6 alkyl group.

[0266] R4 is more preferably a halogen, cyano, or C1-C3 alkyl.

[0267] R4 is more preferably a halogen or cyanoacrylate.

[0268] R4 is most preferably fluorine or cyanoacrylate.

[0269] In one embodiment, in a compound represented by any one of formulas (iii) to (xii) of the present invention, R5 represents cyano, hydroxy, halogen, amino, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 or C2-C6 alkenyl, substituted or unsubstituted C2-C10 or C2-C6 alkynyl, substituted or unsubstituted C1-C10 or C2-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl.

[0270] The "halogen" represented by R5 is preferably chlorine, bromine, fluorine, and iodine, with chlorine, fluorine, and bromine being preferred, chlorine and fluorine being more preferred, and chlorine being the most preferred.

[0271] In the "substituted or unsubstituted C1-C10 alkyl" represented by R5, the "C1-C10 alkyl" is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, or n-pentyl; more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, or n-pentyl (C3-C6 alkyl); and even more preferably methyl.

[0272] The "substituent" in "substituted or unsubstituted C1-C10 alkyl" represented by R5 may be, for example, one of the substituents mentioned above, preferably a halogen, cyano, hydroxy, or C3-C7 cycloalkyl, and more preferably fluorine.

[0273] The "substituted or unsubstituted C1-C10 alkyl" represented by R5 is preferably a C1-C6 alkyl, and more preferably a methyl alkyl.

[0274] In the "substituted or unsubstituted C2-C10 alkenyl" represented by R5, the "C2-C10 alkenyl" is preferably vinyl, 1-propenyl, allyl, or isopropenyl, and more preferably vinyl or isopropenyl.

[0275] The "substituents" in the "substituted or unsubstituted C2-C10 alkenyl" represented by R5 may be, for example, the substituents listed above, preferably halogens, cyanos, or hydroxyls, more preferably chlorine or fluorine, and more preferably fluorine.

[0276] The "substituted or unsubstituted C2-C10 alkenyl" represented by R5 is preferably a C2-C6 alkenyl which may contain a halogen, more preferably vinyl, 1-propenyl, 2-methyl-2-propenyl, or 1-(trifluoromethyl)vinyl, and more preferably vinyl or 1-(trifluoromethyl)vinyl.

[0277] In the "substituted or unsubstituted C2-C10 alkynyl" represented by R5, the "C2-C10 alkynyl" is preferably ethynyl or 1-propynyl.

[0278] The substituents in the "substituted or unsubstituted C2-C10 alkynyl" represented by R5 may be, for example, the substituents mentioned above, preferably halogens or hydroxyls, and more preferably fluorine or chlorine.

[0279] The "substituted or unsubstituted C2-C10 alkynyl" represented by R5 is preferably ethynyl or 1-propynyl.

[0280] The "substituted or unsubstituted C1-C10 haloalkyl" represented by R5 is preferably fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, or 1,1-difluoroethyl, and more preferably fluoromethyl, difluoromethyl, or trifluoromethyl.

[0281] The "substituted or unsubstituted C1-C10 alkoxyl" represented by R5 is preferably methoxy, ethoxy, or 1-fluoromethoxy.

[0282] The "substituted or unsubstituted C1-C10 acyl" represented by R5 is preferably formyl, acetyl, or propionyl.

[0283] The "substituted or unsubstituted C1-C10 alkoxycarbonyl" represented by R5 is preferably a methoxycarbonyl or ethoxycarbonyl.

[0284] The "substituted or unsubstituted C1-C10 alkylsulfonyl" represented by R5 is preferably methoxysulfonyl or ethoxysulfonyl.

[0285] R5 is more preferably a halogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 alkoxy, or a substituted or unsubstituted C1-C6 haloalkyl.

[0286] R5 is more preferably a halogen, an unsubstituted or fluorine-substituted C1-C6 alkyl, an unsubstituted or fluorine-substituted C1-C6 alkoxy, or an unsubstituted or fluorine-substituted C1-C6 haloalkyl.

[0287] R5 is more preferably chlorine, fluorine, methyl, tert-butyl, fluoromethyl, fluoroethyl, difluoromethyl, or trifluoromethyl.

[0288] R5 is most preferably chlorine or trifluoromethyl.

[0289] In the compound represented by any one of formulas (iii) to (vi) of the present invention, If the number of R6 atoms is two or more, two R6 atoms may bond to each other to form a 4-10 membered saturated heterocycle that shares two adjacent atoms with a C3-C10 hydrocarbon ring or ring A' or ring A''. R6 represents, in essence, cyano, hydroxy, halogen, amino, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 or C2-C6 alkenyl, substituted or unsubstituted C2-C10 or C2-C6 alkynyl, substituted or unsubstituted C1-C10 or C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl.

[0290] The "C3-C10 hydrocarbon ring," which may be formed by two R6s, is preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and more preferably cyclopentyl.

[0291] The "4- to 10-membered saturated heterocycle" which may be formed by two R6 rings is preferably a nitrogen-containing 4- to 10-membered ring, more preferably pyrrolidinyl, tetrahydrofuranil, or tetrahydrothiophenyl, and more preferably pyrrolidinyl or tetrahydrofuranil.

[0292] The halogen represented by R6 is preferably chlorine, bromine, fluorine, or iodine, with chlorine, fluorine, and bromine being preferred, and chlorine and fluorine being more preferred.

[0293] In the "substituted or unsubstituted C1-C10 alkyl" represented by R6, the "C1-C10 alkyl" is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, or n-pentyl; more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, or n-pentyl (C3-C6 alkyl); and even more preferably methyl or ethyl.

[0294] The "substituent" in the "substituted or unsubstituted C1-C10 alkyl" represented by R6 may be, for example, one of the substituents mentioned above, preferably a halogen, cyano, hydroxy, or C1-C6 alkoxy, and more preferably a methoxy.

[0295] The "substituted or unsubstituted C1-C10 alkyl" represented by R6 is preferably C1-C6 alkyl, 1,2-dihydroxyisopropyl, 2-hydroxypropyl, methoxymethyl, or ethoxymethyl; more preferably C1-C3 alkyl; even more preferably methyl, ethyl, methoxymethyl, or ethoxymethyl; and most preferably methyl or methoxymethyl.

[0296] In the "substituted or unsubstituted C2-C10 alkenyl" represented by R6, the "C2-C10 alkenyl" is preferably vinyl, 1-propenyl, allyl, or isopropenyl, and more preferably vinyl or isopropenyl.

[0297] The "substituents" in the "substituted or unsubstituted C2-C10 alkenyl" represented by R6 may be, for example, the substituents mentioned above, preferably halogens, cyanos, or hydroxyls, more preferably chlorine or fluorine, and more preferably fluorine.

[0298] The "substituted or unsubstituted C2-C10 alkenyl" represented by R6 is preferably a C2-C6 alkenyl which may contain a halogen, more preferably vinyl, 1-propenyl, 2-methyl-2-propenyl, or 1-(trifluoromethyl)vinyl, and more preferably vinyl or 1-(trifluoromethyl)vinyl.

[0299] In the "substituted or unsubstituted C2-C10 alkynyl" represented by R6, the "C2-C10 alkynyl" is preferably ethynyl or 1-propynyl.

[0300] The substituents in the "substituted or unsubstituted C2-C10 alkynyl" represented by R6 may be, for example, the substituents mentioned above, preferably halogens or hydroxyls, and more preferably fluorine or chlorine.

[0301] The "substituted or unsubstituted C2-C10 alkynyl" represented by R6 is preferably ethynyl or 1-propynyl.

[0302] The "substituted or unsubstituted C1-C10 haloalkyl" represented by R6 is preferably a C1-C6 haloalkyl, and more preferably a fluoromethyl, difluoromethyl, or trifluoromethyl group.

[0303] The "substituted or unsubstituted C1-C10 alkoxyl" represented by R6 is preferably methoxy, ethoxy, or 1-fluoromethoxy.

[0304] The "substituted or unsubstituted C1-C10 acyl" represented by R6 is preferably formyl, acetyl, or propionyl.

[0305] The "substituted or unsubstituted C1-C10 alkoxycarbonyl" represented by R6 is preferably a methoxycarbonyl or ethoxycarbonyl.

[0306] The "substituted or unsubstituted C1-C10 alkylsulfonyl" represented by R6 is preferably methoxysulfonyl or ethoxysulfonyl.

[0307] R6 is more preferably a halogen or a substituted or unsubstituted C1-C6 alkyl group, or two R6s may be bonded to each other to form a C3-C10 hydrocarbon ring or a 4-10 membered saturated heterocycle.

[0308] R6 is more preferably a halogen, methyl, ethyl, or methoxymethyl, and may bond with each other to form cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydrothiophenyl.

[0309] R6 is most preferably methyl or ethyl, and may combine with each other to form cyclopentyl or pyrrolidinyl.

[0310] In the compounds represented by any one of formulas (iv) to (vi) and (x) to (xii) of the present invention, R7 represents cyano, hydroxy, halogen, amino, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 or C2-C6 alkenyl, substituted or unsubstituted C2-C10 or C2-C6 alkynyl, substituted or unsubstituted C1-C10 or C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl.

[0311] The halogen represented by R7 is preferably chlorine, bromine, fluorine, or iodine, with chlorine, fluorine, and bromine being preferred, and chlorine and fluorine being more preferred.

[0312] In the "substituted or unsubstituted C1-C10 alkyl" represented by R7, the "C1-C10 alkyl" is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, or n-pentyl; more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, or n-pentyl (C3-C6 alkyl); and even more preferably methyl, ethyl, or tert-butyl.

[0313] The "substituent" in "substituted or unsubstituted C1-C10 alkyl" represented by R7 may be, for example, one of the substituents mentioned above, preferably a halogen, cyano, hydroxy, or C3-C7 cycloalkyl, and more preferably a hydroxyl group.

[0314] The "substituted or unsubstituted C1-C10 alkyl" represented by R7 is preferably C1-C6 alkyl, 1,2-dihydroxyisopropyl, 2-hydroxypropyl, more preferably C3-C6 alkyl, even more preferably methyl, ethyl, isopropyl, or tert-butyl, and most preferably methyl.

[0315] In the "substituted or unsubstituted C2-C10 alkenyl" represented by R7, the "C2-C10 alkenyl" is preferably vinyl, 1-propenyl, allyl, or isopropenyl, and more preferably vinyl or isopropenyl.

[0316] The "substituents" in the "substituted or unsubstituted C2-C10 alkenyl" represented by R7 may be, for example, the substituents listed above, preferably halogens, cyanos, or hydroxyls, more preferably chlorine or fluorine, and more preferably fluorine.

[0317] The "substituted or unsubstituted C2-C10 alkenyl" represented by R7 is preferably a C2-C6 alkenyl which may contain a halogen, more preferably vinyl, 1-propenyl, 2-methyl-2-propenyl, or 1-(trifluoromethyl)vinyl, and more preferably vinyl or 1-(trifluoromethyl)vinyl.

[0318] In the "substituted or unsubstituted C2-C10 alkynyl" represented by R7, the "C2-C10 alkynyl" is preferably ethynyl or 1-propynyl.

[0319] The substituents in the "substituted or unsubstituted C2-C10 alkynyl" represented by R7 may be, for example, the substituents mentioned above, preferably halogens or hydroxyls, and more preferably fluorine or chlorine.

[0320] The "substituted or unsubstituted C2-C10 alkynyl" represented by R7 is preferably ethynyl or 1-propynyl.

[0321] In the "substituted or unsubstituted C3-C10 cycloalkyl" represented by R7, the "C3-C10 cycloalkyl" is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and more preferably cyclohexyl.

[0322] The "substituted or unsubstituted C1-C10 haloalkyl" represented by R7 is preferably fluoromethyl, difluoromethyl, or trifluoromethyl.

[0323] The "substituted or unsubstituted C1-C10 alkoxyl" represented by R7 is preferably methoxy, ethoxy, or 1-fluoromethoxy.

[0324] The "substituted or unsubstituted C1-C10 acyl" represented by R7 is preferably formyl, acetyl, or propionyl.

[0325] The "substituted or unsubstituted C1-C10 alkoxycarbonyl" represented by R7 is preferably a methoxycarbonyl or ethoxycarbonyl.

[0326] The "substituted or unsubstituted C1-C10 sulfonyl" represented by R7 is preferably methoxysulfonyl or ethoxysulfonyl.

[0327] R7 is preferably a halogen, or a substituted or unsubstituted C1-C6 alkyl group.

[0328] R7 is more preferably a halogen or a C1-C3 alkyl group.

[0329] R7 is most preferably fluorine or methyl.

[0330] In one embodiment, in a compound represented by any one of the formulas (iv) to (vi) and (x) to (xii) of the present invention, R8 represents a halogen or a substituted or unsubstituted C1 to C6 alkyl group.

[0331] The halogens represented by R8 are preferably chlorine, bromine, fluorine, and iodine, with chlorine, fluorine, and bromine being preferred, and chlorine and fluorine being more preferred.

[0332] In the "substituted or unsubstituted C1-C6 alkyl" represented by R8, the "C1-C6 alkyl" is preferably methyl, ethyl, n-propyl, or isopropyl, more preferably methyl or ethyl, and particularly preferably methyl.

[0333] The substituents in the "substituted or unsubstituted C1-C6 alkyl" represented by R8 may be, for example, the substituents mentioned above, preferably halogens, cyanos, or hydroxyls, and more preferably fluorine, chlorine, cyanos, or hydroxyls.

[0334] The "substituted or unsubstituted C1-C6 alkyl" represented by R8 is preferably a C1-C6 alkyl, more preferably methyl, ethyl, or tert-butyl, more preferably methyl or ethyl, and particularly preferably methyl.

[0335] R8 is preferably a halogen, or a substituted or unsubstituted C1-C6 alkyl group.

[0336] R8 is more preferably a halogen or a C1-C6 alkyl group.

[0337] R8 is most preferably fluorine or methyl.

[0338] In one embodiment of the present invention, in the compound represented by formula A-L1-L2-GJ, (i), (ii), (vii), or (viii) of the present invention, A represents a chemical part that can interact with the region between Switch 2 and α3-Helix, more preferably A is a ring A which is a cyclic system, a substituted or unsubstituted monocycle, or a substituted or unsubstituted fused ring, more preferably A is a substituted or unsubstituted C3-C10 cycloalkyl, a substituted or unsubstituted C6-C10 aromatic hydrocarbon, a substituted or unsubstituted 4-10 member saturated heterocyclic group, or a substituted or unsubstituted 4-10 member partially saturated heterocyclic group, or a substituted or unsubstituted 4-10 member unsaturated heterocyclic group.

[0339] In one embodiment of the present invention, in a compound represented by formula (iii), (iv), (ix), or (x) of the present invention, if A is a monoring, then A' and A'' are absent, and the monoring is represented by ring A, which is an unsubstituted or R5-substituted unsaturated 6-membered ring, and A1, A2, A3, A4, and A5 independently represent C, CH, CH2, N, or NH; If A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring A'', where ring A is an unsubstituted or R5-substituted unsaturated 6-membered ring, A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH, and ring A' or A'' is an unsubstituted or R6-substituted saturated or unsaturated ring that forms a fused ring with ring A containing A3 and A4 or A4 and A5.

[0340] In preferred embodiments, in the compounds represented by formula (iii), (iv), (ix), or (x) of the present invention, ring A' forms a fused ring with ring A containing A3 and A4, and A1 and A5 are C, CH, or CH2.

[0341] More preferably, in the compounds represented by formula (iii), (iv), (ix), or (x) of the present invention, A2 of ring A represents C.

[0342] More preferably, in the compounds represented by formula (iii), (iv), (ix), or (x) of the present invention, ring A and ring A' are both benzimidazolyl, benzothiazolyl, indazolyl, benzodioxanyl, or imidazopyridinyl, and more preferably benzimidazolyl.

[0343] In one embodiment, in the compound represented by the formula A-L1-L2-GJ of the present invention, L1 represents a linker. More preferably, L1 is a combination of a substituted or unsubstituted monoring, or a fused ring with a substituted or unsubstituted -C(=O)-. More preferably, L1 is [ka] In the formula, D is a monocycle having at least one amino group bonded to a carbonyl between D and E to form an amide, the monocycle being unsubstituted or substituted with substituents other than the amino group, or D being a substituted or unsubstituted fused ring, more preferably a substituted or unsubstituted C6-C10 aromatic hydrocarbon, or a substituted or unsubstituted 4-10 member partially saturated heterocyclic group, or a substituted or unsubstituted 4-10 member unsaturated heterocyclic group.

[0344] In one embodiment, in the compounds represented by formula (i), (ii), (iii), (vii), (viii), or (ix) of the present invention, D is a monocycle having at least one amino group bonded to a carbonyl between D and E to form an amide, the monocycle is either unsubstituted or substituted with substituents other than the amino group, or D is a substituted or unsubstituted fused ring, more preferably a substituted or unsubstituted C6-C10 aromatic hydrocarbon, or a substituted or unsubstituted 4-10 member partially saturated heterocyclic group, or a substituted or unsubstituted 4-10 member unsaturated heterocyclic group.

[0345] More preferably, in the compounds represented by formula (iv) or (x) of the present invention, if D is a monoring, D' is absent, and the monoring is represented by ring D which is an unsubstituted or R7-substituted unsaturated 6-membered ring, where D1 represents N or NH, and D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH; If D is a fused ring, the fused ring is represented by ring D and ring D', where ring D is an unsubstituted or R7-substituted unsaturated 6-membered ring, and D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is an unsubstituted or R8-substituted saturated or unsaturated ring that forms a fused ring with ring D containing D1, D2 and D7.

[0346] More preferably, in the compound represented by formula (iv) or (x) of the present invention, D6 of ring D is C.

[0347] More preferably, in the compound represented by formula (iv) or (x) of the present invention, D3, D4 and D5 are C.

[0348] More preferably, in the compounds represented by formulas (iv), (v), (vi), (x), (xi), or (xii) of the present invention, D is a fused ring represented by ring D and ring D', ring D' is a saturated or unsaturated 5-membered ring that forms a fused ring containing D1, D2, and D7 and ring D, and D1' and D2' each independently represent C, CH, CH2, N, NH, or S. More preferably, D1' and D2' each independently represent C, CH, CH2, N, or NH.

[0349] More preferably, in the compounds represented by formula (iv), (v), (vi), (x), (xi), or (xii) of the present invention, ring D and ring D' both represent indole, indoridine, imidazopyridine, indoline, or benzothiophene, and even more preferably indole, indoridine, imidazopyridine, or indoline.

[0350] In the compound represented by formula A-L1-L2-GJ of the present invention, L2 represents a linker, more preferably a combination of a substituted or unsubstituted monoring or a substituted or unsubstituted fused ring and -NR1-, more preferably [ka] That is the case.

[0351] In the compounds represented by formula (i) or (vii) of the present invention, E represents a ring system, more preferably a ring system selected from substituted or unsubstituted monocyclic rings, or substituted or unsubstituted fused rings.

[0352] More preferably, in the compounds represented by any of formulas (i) to (xii) of the present invention, E represents a 6-membered ring, and represents a substituted or unsubstituted C6-C10 aromatic hydrocarbon, a substituted or unsubstituted 4-10 membered partially saturated heterocyclic group, or a substituted or unsubstituted 4-10 membered unsaturated heterocyclic group.

[0353] More preferably, in the compounds represented by any of formulas (ii) to (vi) and (viii) to (xii) of the present invention, E1, E2, E3, and E4 in E are each independently C, CH, CH2, N, or NH, and E is a saturated or unsaturated 6-membered ring.

[0354] More preferably, in the compound represented by any of formulas (i) to (xii) of the present invention, E is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl, and is preferably phenyl or pyridinyl.

[0355] In one embodiment, in the compounds represented by formulas (ii), (iv), (v), (vi), (viii), (x), (xi), or (xii) of the present invention, m represents an integer from 0 to 4, more preferably 0, 1, or 2, and more preferably 1.

[0356] In one embodiment, in the compounds represented by formula (iii), (iv), (v), (ix), (x), (xi), or (xii) of the present invention, n represents an integer from 0 to 5, more preferably 1, 2, or 3, and more preferably 1.

[0357] In one embodiment, in the compounds represented by formula (iii), (iv), (v), (ix), (x), (xi), or (xii) of the present invention, p represents 0, 1, or 2.

[0358] In one embodiment, in the compounds represented by formula (iv), (v), (vi), (x), (xi), or (xii) of the present invention, q represents 0, 1, or 2, and more preferably 0.

[0359] In one embodiment, in the compounds represented by formula (iv), (v), (vi), (x), (xi), or (xii) of the present invention, r represents 0, 1, or 2, and more preferably 0.

[0360] In one embodiment, in the compound represented by the formula A-L1-L2-GJ of the present invention, G represents an electrophilic chemical moiety capable of forming a covalent bond with cysteine ​​12 of GTP-bonded KRAS G12C, more preferably [ka] or [ka] That is the case.

[0361] In one embodiment, in the compound represented by the formula A-L1-L2-GJ of the present invention, J represents a chemical part that can interact with GTP, more preferably [ka] or [ka] That is the case.

[0362] In one embodiment, in the compound represented by formula (i) of the present invention, A is selected from the following: [ka]

[0363] In one embodiment, in the compound represented by formula (i) of the present invention, D is selected from the following: [ka]

[0364] In one embodiment, in the compound represented by formula (i) of the present invention, E is selected from the following: [ka]

[0365] In one embodiment, in the compound represented by formula (i) of the present invention, -NR2R3 is selected from the following: [ka]

[0366] Embodiment A In one embodiment, a compound represented by formula (iv) or a pharmaceutically acceptable salt thereof is provided, wherein, If A is a monoring, then A' and A'' do not exist, and the monoring is represented by ring A, which is an unsubstituted or R5-substituted unsaturated 6-membered ring, and A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N, or NH. If A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring A'', where ring A is an unsubstituted or R5-substituted unsaturated 6-membered ring, A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH, and ring A' or A'' is an unsubstituted or R6-substituted saturated or unsaturated ring that forms a fused ring with ring A containing A3 and A4 or A4 and A5. If D is a monoring, then D' does not exist, and the monoring is represented by ring D, which is an unsubstituted or R7-substituted unsaturated 6-membered ring, where D1 represents N or NH, and D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH. If D is a fused ring, the fused ring is represented by ring D and ring D', where ring D is an unsubstituted or R7-substituted unsaturated 6-membered ring, and D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is an unsubstituted or R8-substituted saturated or unsaturated ring that forms a fused ring with ring D containing D1, D2 and D7. E is an unsubstituted or R4-substituted unsaturated 6-membered ring, and E1, E2, E3, and E4 independently represent C, CH, CH2, N, or NH. R1 is hydrogen, or a substituted or unsubstituted C1-C6 alkyl group. R2 and R3 may bond to each other to form a 4-10 member saturated heterocycle that is unsubstituted or substituted with 1-2 substituents independently represented by Ra, or R2 and R3 may be represented independently, where R2 is hydrogen, or a C1-C10 alkyl, C2-C10 or C2-C6 alkenyl, C2-C10 or C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C6-C10 aromatic hydrocarbon, a 4-10 member saturated heterocyclic group, a 4-10 member partially saturated heterocyclic group, or a 4-10 member unsaturated heterocyclic group, each of which is either unsubstituted or substituted with 1-2 substituents independently represented by Ra. R3 is a C1-C6 alkyl group that is hydrogen, unsubstituted, or substituted with one or two substituents independently represented by Ra. R4 is a halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 or C1-C6 alkyl, substituted or unsubstituted C2-C10 or C2-C6 alkenyl, substituted or unsubstituted C2-C10 or C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl. R5 is a halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl. If the number of R6 atoms is two or more, two R6 atoms may bond to each other to form a 4-10 membered saturated heterocycle that shares two adjacent atoms with a C3-C10 hydrocarbon ring or ring A' or ring A''. R6 can independently represent a halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl, R7 is a halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C10 or C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl; R8 is a halogen or a substituted or unsubstituted C1-C10 alkyl group. Ra independently represents a halogen, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 haloalkoxy, substituted or unsubstituted C1-C10 alkylsulfonyl, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted 4-10 member saturated heterocyclic group. m is an integer between 0 and 4. n is an integer from 0 to 5. p, q, and r independently represent 0, 1, or 2.

[0367] In preferred embodiments, a compound represented by formula (iv) or a pharmaceutically acceptable salt thereof is provided, wherein, If A is a monoring, then A' and A'' do not exist, and the monoring is represented by ring A, which is an unsubstituted or R5-substituted unsaturated 6-membered ring, where A1 and A5 represent C, CH, or CH2, and A2, A3, and A4 independently represent C, CH, CH2, N, or NH. If A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring A'', where ring A is an unsubstituted or R5-substituted unsaturated 6-membered ring, A1 and A5 represent C, CH, or CH2, A2, A3 and A4 independently represent C, CH, CH2, N, or NH, and ring A' or A'' is an unsubstituted or R6-substituted saturated or unsaturated ring that forms a fused ring with ring A containing A3 and A4 or A4 and A5. If D is a monoring, then D' does not exist, and the monoring is represented by ring D, which is an unsubstituted or R7-substituted unsaturated 6-membered ring, where D1 represents N or NH, D6 represents C, CH or CH2, and D2, D3, D4, D5 and D7 independently represent C, CH, CH2, N or NH. If D is a fused ring, the fused ring is represented by ring D and ring D', where ring D is an unsubstituted or R7-substituted unsaturated 6-membered ring, and D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is an unsubstituted or R8-substituted saturated or unsaturated ring that forms a fused ring with ring D containing D1, D2 and D7. E is an unsubstituted or R4-substituted unsaturated 6-membered ring, and E1, E2, E3, and E4 independently represent C, CH, CH2, N, or NH. R1 is hydrogen, R2 and R3 are represented independently, where R2 is hydrogen, or a C1-C10 alkyl, C2-C10 or C2-C6 alkenyl, C2-C10 or C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C6-C10 aromatic hydrocarbon, 4-10 member saturated heterocyclic group, 4-10 member partially saturated heterocyclic group, or 4-10 member unsaturated heterocyclic group, each of which is either unsubstituted or substituted with 1-2 substituents independently represented by Ra. R3 is a C1-C6 alkyl group that is hydrogen, unsubstituted, or substituted with one or two substituents independently represented by Ra. R4 is a halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 or C1-C6 alkyl, substituted or unsubstituted C2-C10 or C2-C6 alkenyl, substituted or unsubstituted C2-C10 or C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl. R5 is a halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl. If the number of R6 atoms is two or more, two R6 atoms may bond to each other to form a 4-10 membered saturated heterocycle that shares two adjacent atoms with a C3-C10 hydrocarbon ring or ring A' or ring A''. R6 can independently represent a halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl, R7 is a halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C10 or C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl; R8 is a halogen or a substituted or unsubstituted C1-C10 alkyl group. Ra independently represents a halogen, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 haloalkoxy, substituted or unsubstituted C1-C10 alkylsulfonyl, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted 4-10 member saturated heterocyclic group. m is an integer between 0 and 3. n is an integer from 0 to 4. p, q, and r independently represent 0, 1, or 2.

[0368] In a more preferred embodiment, a compound represented by formula (iv) or a pharmaceutically acceptable salt thereof is provided, where, A is a fused ring, represented by ring A and ring A' or ring A and ring A'', where ring A is an unsubstituted or R5-substituted unsaturated 6-membered ring, where A1 and A5 represent C, CH, or CH2, A2, A3, and A4 independently represent C, CH, CH2, N, or NH, where ring A' or A'' is an unsubstituted or R6-substituted unsaturated 5-membered ring forming a fused ring with ring A containing A3 and A4 or A4 and A5, where A1', A2', and A3' independently represent C, CH, CH2, N, NH, O, or S. If D is a monoring, then D' does not exist, and the monoring is represented by ring D, which is an unsubstituted or R7-substituted unsaturated 6-membered ring, where D1 represents N or NH, D6 represents C, CH or CH2, and D2, D3, D4, D5 and D7 independently represent C, CH, CH2, N or NH. If D is a fused ring, the fused ring is represented by ring D and ring D', where ring D is an unsubstituted or R7-substituted unsaturated 6-membered ring, and D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is an unsubstituted or R8-substituted saturated or unsaturated ring that forms a fused ring with ring D containing D1, D2 and D7. E is an unsubstituted or R4-substituted unsaturated 6-membered ring, and E1, E2, E3, and E4 independently represent C, CH, CH2, N, or NH. R1 is hydrogen, R2 and R3 are represented independently, where R2 is a C1-C10 alkyl, C3-C10 cycloalkyl, or 4-10 membered saturated heterocyclic group, each of which is either unsubstituted or substituted with 1-2 substituents independently represented by Ra. R3 is hydrogen, or a C1-C6 alkyl group that is unsubstituted or substituted with one or two substituents independently represented by Ra. R4 is a halogen, cyano, or substituted or unsubstituted C1-C10 alkyl. R5 is a halogen, a substituted or unsubstituted C1-C10 alkyl, a substituted or unsubstituted C1-C6 haloalkyl, or a substituted or unsubstituted C1-C10 alkoxy. If the number of R6 atoms is two or more, two R6 atoms may bond to each other to form a C3-C10 hydrocarbon ring, or a 4-10 membered saturated heterocycle that shares two adjacent atoms with ring A' or ring A''. R6 may independently represent a halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy. R7 is halogen R8 is a halogen or a substituted or unsubstituted C1-C10 alkyl group. Each Ra independently represents a halogen, hydroxyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, or substituted or unsubstituted C1-C10 alkylsulfonyl. m is an integer between 0 and 2. n is an integer between 0 and 3. p, q, and r independently represent 0, 1, or 2.

[0369] In a more preferred embodiment, a compound represented by formula (iv) or a pharmaceutically acceptable salt thereof is provided, where, A is a fused ring, represented by ring A and ring A' or ring A and ring A'', where ring A is an unsaturated 6-membered ring that is either unsubstituted or substituted with R5, where A1, A2, and A5 represent C, CH, or CH2, and A3 and A4 independently represent C, CH, CH2, N, or NH, where ring A' or A'' is an unsaturated 5-membered ring that is either unsubstituted or substituted with R6 and forms a fused ring with ring A containing A3 and A4 or A4 and A5, where A1' and A3' independently represent C, CH, CH2, N, NH, O, or S, and A2' represents C. If D is a monoring, then D' does not exist, and the monoring is represented by ring D, which is an unsubstituted or R7-substituted unsaturated 6-membered ring, where D1 represents N or NH, D6 represents C, CH or CH2, and D2, D3, D4, D5 and D7 independently represent C, CH, CH2, N or NH. If D is a fused ring, the fused ring is represented by ring D and ring D', where ring D is an unsubstituted or R7-substituted unsaturated 6-membered ring, and D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is an unsubstituted or R8-substituted saturated or unsaturated ring that forms a fused ring with ring D containing D1, D2 and D7. E is an unsubstituted or R4-substituted unsaturated 6-membered ring, and E1, E2, E3, and E4 independently represent C, CH, CH2, N, or NH. R1 is hydrogen, R2 and R3 are represented independently, where R2 is a C3-C10 cycloalkyl or 4-10 membered saturated heterocyclic group, each of which is either unsubstituted or substituted with 1-2 substituents independently represented by Ra. R3 is hydrogen, R4 is a halogen, cyano, or substituted or unsubstituted C1-C10 alkyl. R5 is a halogen, a substituted or unsubstituted C1-C10 alkyl, a substituted or unsubstituted C1-C6 haloalkyl, or a substituted or unsubstituted C1-C10 alkoxy. If the number of R6 atoms is two or more, two R6 atoms may bond to each other to form a C3-C10 hydrocarbon ring, or a 4-10 membered saturated heterocycle that shares two adjacent atoms with ring A' or ring A''. R6 may independently represent a substituted or unsubstituted C1-C10 alkyl, a substituted or unsubstituted C1-C6 haloalkyl, or a substituted or unsubstituted C1-C10 alkoxy. R7 is halogen R8 is a halogen or a substituted or unsubstituted C1-C6 alkyl group. Each Ra independently represents a halogen, hydroxyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, or substituted or unsubstituted C1-C10 alkylsulfonyl. m is an integer between 0 and 1. n is an integer between 0 and 2. p, q, and r independently represent 0, 1, or 2.

[0370] In the most preferred embodiment, a compound represented by formula (iv) or a pharmaceutically acceptable salt thereof is provided, where, A is a fused ring, represented by ring A and ring A' or ring A and ring A'', where ring A is an unsaturated 6-membered ring that is either unsubstituted or substituted with R5, where A1, A2, and A5 represent C, CH, or CH2, and A3 and A4 independently represent C, CH, CH2, N, or NH, where ring A' or A'' is an unsaturated 5-membered ring that is either unsubstituted or substituted with R6 and forms a fused ring with ring A containing A3 and A4 or A4 and A5, where A1' and A3' independently represent C, CH, CH2, N, NH, O, or S, and A2' represents C. D is a fused ring, represented by rings D and D', where ring D is an unsubstituted or R7-substituted unsaturated 6-membered ring, and D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH; ring D' is an unsubstituted or R8-substituted saturated or unsaturated 5-membered ring forming a fused ring with ring D containing D1, D2 and D7, where D1' and D2' independently represent C, CH, CH2, N, NH or S. E is an unsubstituted or R4-substituted unsaturated 6-membered ring, and E1, E2, E3, and E4 independently represent C, CH, CH2, N, or NH. R1 is hydrogen, R2 and R3 are represented independently, where R2 is a C3-C10 cycloalkyl or 4-10 membered saturated heterocyclic group, each of which is either unsubstituted or substituted with 1-2 substituents independently represented by Ra, and R3 is hydrogen. R4 is a halogen, cyano, or substituted or unsubstituted C1-C10 alkyl. R5 is a halogen, a substituted or unsubstituted C1-C10 alkyl, a substituted or unsubstituted C1-C6 haloalkyl, or a substituted or unsubstituted C1-C10 alkoxy. If the number of R6 atoms is two or more, two R6 atoms may bond to each other to form a C3-C10 hydrocarbon ring, or a 4-10 membered saturated heterocycle that shares two adjacent atoms with ring A' or ring A''. R6 may independently represent a substituted or unsubstituted C1-C10 alkyl, a substituted or unsubstituted C1-C6 haloalkyl, or a substituted or unsubstituted C1-C10 alkoxy. R7 is halogen R8 is a halogen or a substituted or unsubstituted C1-C6 alkyl group. The number of Ra is 1 or 2, and each Ra independently represents a halogen, hydroxyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, or substituted or unsubstituted C1-C10 alkylsulfonyl. m is an integer between 0 and 1. n is an integer between 0 and 2. p, q, and r independently represent 0, 1, or 2.

[0371] In one embodiment, a compound represented by formula (x) or a pharmaceutically acceptable salt thereof is provided, where, If A is a monoring, then A' and A'' do not exist, and the monoring is represented by ring A, which is an unsubstituted or R5-substituted unsaturated 6-membered ring, and A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N, or NH. If A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring A'', where ring A is an unsubstituted or R5-substituted unsaturated 6-membered ring, A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH, and ring A' or A'' is an unsubstituted or R6-substituted saturated or unsaturated ring that forms a fused ring with ring A containing A3 and A4 or A4 and A5. If D is a monoring, then D' does not exist, and the monoring is represented by ring D, which is an unsubstituted or R7-substituted unsaturated 6-membered ring, where D1 represents N or NH, and D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH. If D is a fused ring, the fused ring is represented by ring D and ring D', where ring D is an unsubstituted or R7-substituted unsaturated 6-membered ring, and D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is an unsubstituted or R8-substituted saturated or unsaturated ring that forms a fused ring with ring D containing D1, D2 and D7. E is an unsubstituted or R4-substituted unsaturated 6-membered ring, and E1, E2, E3, and E4 independently represent C, CH, CH2, N, or NH. R1 is hydrogen, or a substituted or unsubstituted C1-C6 alkyl group. R2 and R3 or R2 and R2' may bond to each other to form a 4-10 member saturated heterocycle that is unsubstituted or substituted with 1-2 substituents independently represented by Ra, or R2, R2', and R3 may be represented independently, where R2 is hydrogen, or a C1-C10 alkyl, C2-C10 or C2-C6 alkenyl, C2-C10 or C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C6-C10 aromatic hydrocarbon, a 4-10 member saturated heterocyclic group, a 4-10 member partially saturated heterocyclic group, or a 4-10 member unsaturated heterocyclic group, each of which is either unsubstituted or substituted with 1-2 substituents independently represented by Ra. R2' is hydrogen, or a C1-C6 alkyl group that is unsubstituted or substituted with 1-2 substituents independently represented by Ra. R3 is a C1-C6 alkyl group that is hydrogen, unsubstituted, or substituted with one or two substituents independently represented by Ra. R4 is a halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 or C1-C6 alkyl, substituted or unsubstituted C2-C10 or C2-C6 alkenyl, substituted or unsubstituted C2-C10 or C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl. R5 is a halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl. If the number of R6 atoms is two or more, two R6 atoms may bond to each other to form a 4-10 membered saturated heterocycle that shares two adjacent atoms with a C3-C10 hydrocarbon ring or ring A' or ring A''. R6 can independently represent a halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl, R7 is a halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C10 or C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl; R8 is a halogen or a substituted or unsubstituted C1-C10 alkyl group. Ra independently represents a halogen, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 haloalkoxy, substituted or unsubstituted C1-C10 alkylsulfonyl, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted 4-10 member saturated heterocyclic group. m is an integer between 0 and 4. n is an integer from 0 to 5. p, q, and r independently represent 0, 1, or 2.

[0372] In preferred embodiments, a compound represented by formula (x) or a pharmaceutically acceptable salt thereof is provided, where, If A is a monoring, then A' and A'' do not exist, and the monoring is represented by ring A, which is an unsubstituted or R5-substituted unsaturated 6-membered ring, where A1 and A5 represent C, CH, or CH2, and A2, A3, and A4 independently represent C, CH, CH2, N, or NH. If A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring A'', where ring A is an unsubstituted or R5-substituted unsaturated 6-membered ring, A1 and A5 represent C, CH, or CH2, A2, A3 and A4 independently represent C, CH, CH2, N, or NH, and ring A' or A'' is an unsubstituted or R6-substituted saturated or unsaturated ring that forms a fused ring with ring A containing A3 and A4 or A4 and A5. If D is a monoring, then D' does not exist, and the monoring is represented by ring D, which is an unsubstituted or R7-substituted unsaturated 6-membered ring, where D1 represents N or NH, D6 represents C, CH, or CH2, and D2, D3, D4, D5, and D7 independently represent C, CH, CH2, N, or NH. If D is a fused ring, the fused ring is represented by ring D and ring D', where ring D is an unsubstituted or R7-substituted unsaturated 6-membered ring, and D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is an unsubstituted or R8-substituted saturated or unsaturated ring that forms a fused ring with ring D containing D1, D2 and D7. E is an unsubstituted or R4-substituted unsaturated 6-membered ring, and E1, E2, E3, and E4 independently represent C, CH, CH2, N, or NH. R1 is hydrogen, R2 and R2' may bond to each other to form a 4-10 member saturated heterocycle that is unsubstituted or substituted with 1-2 substituents independently represented by Ra, or R2, R2', and R3 are represented independently, where R2 is hydrogen, or a C1-C10 alkyl, C2-C10 or C2-C6 alkenyl, C2-C10 or C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C6-C10 aromatic hydrocarbon, 4-10 member saturated heterocyclic group, 4-10 member partially saturated heterocyclic group, or 4-10 member unsaturated heterocyclic group, each of which is either unsubstituted or substituted with 1-2 substituents independently represented by Ra. R2' is hydrogen, or a C1-C6 alkyl group that is unsubstituted or substituted with 1-2 substituents independently represented by Ra. R3 is a C1-C6 alkyl group that is hydrogen, unsubstituted, or substituted with one or two substituents independently represented by Ra. R4 is a halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 or C1-C6 alkyl, substituted or unsubstituted C2-C10 or C2-C6 alkenyl, substituted or unsubstituted C2-C10 or C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl. R5 is a halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl. If the number of R6 atoms is two or more, two R6 atoms may bond to each other to form a 4-10 membered saturated heterocycle that shares two adjacent atoms with a C3-C10 hydrocarbon ring or ring A' or ring A''. R6 can independently represent a halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl, R7 is a halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C10 or C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl; R8 is a halogen or a substituted or unsubstituted C1-C10 alkyl group. Ra independently represents a halogen, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 haloalkoxy, substituted or unsubstituted C1-C10 alkylsulfonyl, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted 4-10 member saturated heterocyclic group. m is an integer between 0 and 3. n is an integer from 0 to 4. p, q, and r independently represent 0, 1, or 2.

[0373] In a more preferred embodiment, a compound represented by formula (x) or a pharmaceutically acceptable salt thereof is provided, where, A is a fused ring, represented by ring A and ring A' or ring A and ring A'', where ring A is an unsubstituted or R5-substituted unsaturated 6-membered ring, where A1 and A5 represent C, CH, or CH2, A2, A3, and A4 independently represent C, CH, CH2, N, or NH, where ring A' or A'' is an unsubstituted or R6-substituted unsaturated 5-membered ring forming a fused ring with ring A containing A3 and A4 or A4 and A5, where A1', A2', and A3' independently represent C, CH, CH2, N, NH, O, or S. If D is a monoring, then D' does not exist, and the monoring is represented by ring D, which is an unsubstituted or R7-substituted unsaturated 6-membered ring, where D1 represents N or NH, D6 represents C, CH or CH2, and D2, D3, D4, D5 and D7 independently represent C, CH, CH2, N or NH. If D is a fused ring, the fused ring is represented by ring D and ring D', where ring D is an unsubstituted or R7-substituted unsaturated 6-membered ring, and D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is an unsubstituted or R8-substituted saturated or unsaturated ring that forms a fused ring with ring D containing D1, D2 and D7. E is an unsubstituted or R4-substituted unsaturated 6-membered ring, and E1, E2, E3, and E4 independently represent C, CH, CH2, N, or NH. R1 is hydrogen, R2 and R2' bond to each other to form a 4-6 member saturated heterocycle that is either unsubstituted or substituted with 1-2 substituents independently represented by Ra. R2, R2', and R3 are represented independently, where R2 is an unsubstituted or Ra-substituted C1-C10 alkyl group, an unsubstituted or Ra-substituted C3-C10 cycloalkyl group, or an unsubstituted or Ra-substituted 4-10 member saturated heterocyclic group. R2' is hydrogen or a C1-C3 alkyl group. R3 is hydrogen or a C1-C3 alkyl group. R4 is a halogen, cyano, or substituted or unsubstituted C1-C10 alkyl. R5 is a halogen, a substituted or unsubstituted C1-C10 alkyl, a substituted or unsubstituted C1-C6 haloalkyl, or a substituted or unsubstituted C1-C10 alkoxy. If the number of R6 atoms is two or more, two R6 atoms may bond to each other to form a C3-C10 hydrocarbon ring, or a 4-10 membered saturated heterocycle that shares two adjacent atoms with ring A' or ring A''. R6 may independently represent a halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy. R7 is halogen R8 is a halogen or a substituted or unsubstituted C1-C10 alkyl group. Each Ra independently represents a halogen, hydroxyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, or substituted or unsubstituted C1-C10 alkylsulfonyl. m is an integer between 0 and 2. n is an integer between 0 and 3. p, q, and r independently represent 0, 1, or 2.

[0374] In a more preferred embodiment, a compound represented by formula (x) or a pharmaceutically acceptable salt thereof is provided, where, A is a fused ring, represented by ring A and ring A' or ring A and ring A'', where ring A is an unsaturated 6-membered ring that is either unsubstituted or substituted with R5, A1, A2, and A5 represent C, CH, or CH2, A3, and A4 independently represent C, CH, CH2, N, or NH, ring A' or A'' is an unsaturated 5-membered ring that is either unsubstituted or substituted with R6 and forms a fused ring with ring A containing A3 and A4 or A4 and A5, where A1' and A3' independently represent C, CH, CH2, N, NH, O, or S, and A2' represents C. If D is a monoring, then D' does not exist, and the monoring is represented by ring D, which is an unsubstituted or R7-substituted unsaturated 6-membered ring, where D1 represents N or NH, D6 represents C, CH or CH2, and D2, D3, D4, D5 and D7 independently represent C, CH, CH2, N or NH. If D is a fused ring, the fused ring is represented by ring D and ring D', where ring D is an unsubstituted or R7-substituted unsaturated 6-membered ring, and D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is an unsubstituted or R8-substituted saturated or unsaturated ring that forms a fused ring with ring D containing D1, D2 and D7. E is an unsubstituted or R4-substituted unsaturated 6-membered ring, and E1, E2, E3, and E4 independently represent C, CH, CH2, N, or NH. R1 is hydrogen, R2 and R2' bond to each other to form a 4-6 member saturated heterocycle that is unsubstituted or substituted with 1-2 substituents independently represented by Ra, or R2, R2', and R3 are represented independently, where R2 is a C3-C10 cycloalkyl or 4-10 membered saturated heterocyclic group, each of which is either unsubstituted or substituted with 1-2 substituents independently represented by Ra. R2' is hydrogen or a C1-C3 alkyl group. R3 is hydrogen, R4 is a halogen, cyano, or substituted or unsubstituted C1-C10 alkyl. R5 is a halogen, a substituted or unsubstituted C1-C10 alkyl, a substituted or unsubstituted C1-C6 haloalkyl, or a substituted or unsubstituted C1-C10 alkoxy. If the number of R6 atoms is two or more, two R6 atoms may bond to each other to form a C3-C10 hydrocarbon ring, or a 4-10 membered saturated heterocycle that shares two adjacent atoms with ring A' or ring A''. R6 may independently represent a substituted or unsubstituted C1-C10 alkyl, a substituted or unsubstituted C1-C6 haloalkyl, or a substituted or unsubstituted C1-C10 alkoxy. R7 is halogen R8 is a halogen or a substituted or unsubstituted C1-C6 alkyl group. Each Ra independently represents a halogen, hydroxyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, or substituted or unsubstituted C1-C10 alkylsulfonyl. m is an integer between 0 and 1. n is an integer between 0 and 2. p, q, and r independently represent 0, 1, or 2.

[0375] In the most preferred embodiment, a compound represented by formula (x) or a pharmaceutically acceptable salt thereof is provided, where, A is a fused ring, represented by ring A and ring A' or ring A and ring A'', where ring A is an unsaturated 6-membered ring that is either unsubstituted or substituted with R5, where A1, A2, and A5 represent C, CH, or CH2, and A3 and A4 independently represent C, CH, CH2, N, or NH, where ring A' or A'' is an unsaturated 5-membered ring that is either unsubstituted or substituted with R6 and forms a fused ring with ring A containing A3 and A4 or A4 and A5, where A1' and A3' independently represent C, CH, CH2, N, NH, O, or S, and A2' represents C. D is a fused ring, represented by rings D and D', where ring D is an unsubstituted or R7-substituted unsaturated 6-membered ring, and D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH; ring D' is an unsubstituted or R8-substituted saturated or unsaturated 5-membered ring forming a fused ring with ring D containing D1, D2 and D7, where D1' and D2' independently represent C, CH, CH2, N, NH or S. E is an unsubstituted or R4-substituted unsaturated 6-membered ring, and E1, E2, E3, and E4 independently represent C, CH, CH2, N, or NH. R1 is hydrogen, R2 and R2' together form a 4-6 member saturated heterocycle, or R3 is hydrogen, R4 is a halogen, cyano, or substituted or unsubstituted C1-C10 alkyl. R5 is a halogen, a substituted or unsubstituted C1-C10 alkyl, a substituted or unsubstituted C1-C6 haloalkyl, or a substituted or unsubstituted C1-C10 alkoxy. If the number of R6 atoms is two or more, two R6 atoms may bond to each other to form a C3-C10 hydrocarbon ring, or a 4-10 membered saturated heterocycle that shares two adjacent atoms with ring A' or ring A''. R6 may independently represent a substituted or unsubstituted C1-C10 alkyl, a substituted or unsubstituted C1-C6 haloalkyl, or a substituted or unsubstituted C1-C10 alkoxy. R7 is halogen R8 is a halogen or a substituted or unsubstituted C1-C6 alkyl group. The number of Ra is 1 or 2, and each Ra independently represents a halogen, hydroxyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, or substituted or unsubstituted C1-C10 alkylsulfonyl. m is an integer between 0 and 1. n is an integer between 0 and 2. p, q, and r independently represent 0, 1, or 2.

[0376] In the most preferred embodiment, the compound of the present invention is selected from the following: (1)3-Cyano-N-(3-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)phenyl)-4-((E)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide)benzamide (2)(E)-4-(4-(tert-butyl(methyl)amino)buta-2-enamide)-3-cyano-N-(3-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)phenyl)benzamide (3)3-Cyano-4-((E)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide)-N-(6-(7-methyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-6-yl)pyridine-2-yl)benzamide (4)(E)-N-(2-cyano-4-(8-(1,6-dimethyl-1H-benzo[d]imidazole-5-yl)indridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (5)(E)-4-(tert-butylamino)-N-(2-cyano-4-(8-(1,6-dimethyl-1H-benzo[d]imidazole-5-yl)indolidine-3-carbonyl)phenyl)buta-2-enamide (6)(E)-N-(2-cyano-4-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)indridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (7)(E)-N-(2-cyano-4-(8-(1,2-dimethyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)indridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (8)(E)-N-(2-cyano-4-(7-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)-1H-indole-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (9)(E)-N-(2-cyano-4-(8-(1,6-dimethyl-1H-benzo[d]imidazole-5-yl)imidazo[1,2a]pyridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (10)(E)-N-(2-cyano-4-(4-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)indoline-1-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (11)(E)-N-(6'-chloro-2',3'-dimethoxy-[1,1'-biphenyl]-3-yl)-3-cyano-4-(4-((1-(methylsulfonyl)piperidine-4-yl)amino)buta-2-enamide)benzamide (12)N-(3-(5-chloro-1-methyl-1H-indazole-4-yl)phenyl)-3-cyano-4-((E)-4-(((1r,4r)-4-(diethylamino)silohexyl)amino)buta-2-enamide)benzamide (13)N-(3-(6-chloro-1,2-dimethyl-1H-benzo[d]diimidazole-5-yl)phenyl)-4-((E)-4-(((1r,4r)-4-(diethylamino)cyclohexyl)amino)buta-2-enamide)-3-fluorobenzamide (14)N-(3-(6-chloro-1H-benzo[d]diimidazole-5-yl)phenyl)-6-((E)-4-(((1r,4r)-4-hydroxycyclohexyl)amino)buta-2-enamide)nicotinamide (15)N-(3-(4-chloro-2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)phenyl)-3-cyano-4-((E)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide)benzamide (16)3-Cyano-4-((E)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide)-N-(3-(6-methylbenzo[d]thiazole-5-yl)phenyl)benzamide (17)(E)-N-(3-(6-chloroimidazo[1,2-a]pyridine-7-yl)phenyl)-3-cyano-4-(4-((1-(methylsulfonyl)piperidine-4-yl)amino)buta-2-enamide)benzamide (18)3-Cyano-N-(3-(1,6-dimethyl-1H-benzo[d]imidazole-5-yl)-4,5-difluorophenyl)-4-((E)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide)benzamide (19)N-(3-(6-chloro-1-methyl-1H-benzo[d]imidazole-5-yl)phenyl)-3-cyano-4-((E)-4-(((1r,4r)-4-(diethylamino)silohexyl)amino)buta-2-enamide)benzamide (20)(E)-3-Cyano-N-(3-(4,6-Dichloro-1,2-dimethyl-1H-benzo[d]imidazole-5-yl)phenyl)-4-(4-((4,4-difluorosilohexyl)amino)buta-2-enamide)benzamide (21)3-Cyano-4-((E)-4-(((1r,4r)-4-Methoxycyclohexyl)amino)buta-2-enamide)-N-(3-(2-(Methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)phenyl)benzamide (22)4-((E)-4-(((1R,5S)-8-oxabicyclo[3.2.1]octan-3-yl)amino)buta-2-enamide)-3-cyano-N-(3-(2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)phenyl)benzamide (23)3-Cyano-4-((E)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide)-N-(3-(2((R)-1-methoxyethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)phenyl)benzamide (24)(E)-3-Cyano-N-(3-(2-(Methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)phenyl)-4-(4-((8-methyl-1,4-dioxaspiro[4.5]decane-8-yl)amino)buta-2-enamide)benzamide (25)(E)-3-cyano-4-(4-((6,6-difluorobicyclo[3.1.0]hexane-3-yl)amino)buta-2-enamide)-N-(3-(2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)phenyl)benzamide (26)(E)-3-cyano-4-(4-(cyclobutylamino)buta-2-enamide)-N-(3-(2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)phenyl)benzamide (27)(E)-3-cyano-4-(4-(cyclohexylamino)buta-2-enamide)-N-(3-(2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)phenyl)benzamide (28)3-Cyano-4-((E)-4-(((1r,3r)-3-Methoxycyclobutyl)amino)buta-2-enamide)-N-(3(7-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-6-yl)phenyl)benzamide (29)(E)-N-(2-cyano-4-(4-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)indoline-1-carbonyl)phenyl)-4-(((1r,4r)-4-(pyrroridine-1-yl)silohexyl)amino)buta-2-enamide (30)(E)-N-(2-cyano-4-(4-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)indoline-1-carbonyl)phenyl)-4-((1-isopropylpiperidine-4-yl)amino)buta-2-enamide (31)(E)-N-(2-cyano-4-(8-(7-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-6-yl)indolidine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (32)3-Cyano-N-(3-(7-ethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-6-yl)phenyl)-4-((E)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide)benzamide (33)(E)-N-(2-cyano-4-(8-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)indridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (34)3-Cyano-4-((E)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide)-N-(6-(7-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-6-yl)pyridine-2-yl)benzamide (35)(E)-N-(2-cyano-4-(7-(7-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-6-yl)-1H-indole-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (36)(E)-N-(2-cyano-4-(8-(6-(difluoromethyl)-1-methyl-1H-benzo[d]imidazole-5-yl)indridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (37)3-Cyano-4-((E)-4-(((1r,4r)-4-(diethylamino)silohexyl)amino)buta-2-enamide)-N-(6-(7-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-6-yl)pyridine-2-yl)benzamide (38)(E)-N-(2-cyano-4-(1-methyl-7-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)-1H-indole-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (39)(E)-4-(((1r,4r)-4-methoxycyclohexyl)amino)-N-(4-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]diimidazole-5-yl)indolidine-3-carbonyl)phenyl)buta-2-enamide (40)(E)-N-(2-cyano-4-(8-(2-methoxyphenyl)indridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (41)(E)-N-(4-(8-(2-chloro-6-methoxyphenyl)indridine-3-carbonyl)-2-cyanophenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (42)(R,E)-N-(2-cyano-4-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)indridine-3-carbonyl)phenyl)-3-(pyrrolidine-2-yl)acrylamide (43)(E)-N-(2-cyano-4-(8-(2-fluoro-6-methoxyphenyl)indridin-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (44)(S,E)-N-(2-cyano-4-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)indridine-3-carbonyl)phenyl)-3-(pyrrolidine-2-yl)acrylamide (45)(E)-N-(4-(8-(2-chlorophenyl)indridine-3-carbonyl)-2-cyanophenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (46)(E)-N-(2-cyano-4-(8-(2-fluoro-6-hydroxyphenyl)indridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (47)(E)-N-(4-(5-chloro-7-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)-1H-indole-3-carbonyl)-2-cyanophenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (48)(2E)-N-{1-[8-(1,6-dimethyl-1H-1,3-benzodiazole-5-yl)indolidine-3-carbonyl]piperidine-4-yl}-4-{[trans-4-methoxycyclohexyl]amino}buta-2-enamide (49)(2E)-4-(tert-butylamino)-N-(2,6-difluoro-4-{8-[1-methyl-6-(trifluoromethyl)-1H-1,3-benzodiazole-5-yl]indridine-3-carbonyl}phenyl)buta-2-enamide (50)(2E)-4-(tert-butylamino)-N-(2-cyano-6-methyl-4-{8-[1-methyl-6-(trifluoromethyl)-1H-1,3-benzodiazole-5-yl]indridine-3-carbonyl}phenyl)buta-2-enamide (51)(2E)-4-(tert-butylamino)-N-(2-fluoro-4-{8-[1-methyl-6-(trifluoromethyl)-1H-1,3-benzodiazole-5-yl]indridine-3-carbonyl}phenyl)buta-2-enamide (52)(2E)-4-(tert-butylamino)-N-{4-[8-(4-chloro-2-methyl-2H-indazole-5-yl)indridine-3-carbonyl]-2-cyanophenyl}buta-2-enamide (53)(2E)-4-(tert-butylamino)-N-{2-cyano-4-[8-(1,5-dimethyl-1H-indazole-4-yl)indridine-3-carbonyl]phenyl}buta-2-enamide (54)(2E)-4-(tert-butylamino)-N-{2-cyano-4-[8-(1,6-dimethyl-1H-indazole-5-yl)indridine-3-carbonyl]phenyl}buta-2-enamide (55)(E)-4-(tert-butylamino)-N-(2-cyano-4-(8-(4,6-dichloro-1-methyl-1H-benzo[d]imidazole-5-yl)indolidine-3-carbonyl)phenyl)buta-2-enamide (56)(E)-N-(2-cyano-4-(7-(1,6-dimethyl-1H-benzo[d]imidazole-5-yl)benzo[b]thiophene-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (57)(E)-N-(2-cyano-4-(8-(1,6-dimethyl-1H-benzo[d]imidazole-5-yl)imidazo[1,5a]pyridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (58)(E)-N-(2-cyano-4-(7-(1,6-dimethyl-1H-benzo[d]imidazole-5-yl)-1-methyl-1H-indazole-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (59)(E)-4-(tert-butylamino)-N-(4-(8-(4-chloro-1,6-dimethyl-1H-benzo[d]imidazole-5-yl)indridine-3-carbonyl)-2-cyanophenyl)buta-2-enamide (60)(E)-N-(4-(8-(4-chloro-1,6-dimethyl-1H-benzo[d]imidazole-5-yl)indridine-3-carbonyl)-2-cyanophenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (61)(E)-4-(tert-butylamino)-N-(2-cyano-4-(8-(1,6-dimethyl-4-(propo-1-en-2-yl)-1H-benzo[d]imidazole-5-yl)indolidine-3-carbonyl)phenyl)buta-2-enamide (62)(E)-N-(2-cyano-4-(8-(4,6-dichloro-1-methyl-1H-benzo[d]imidazole-5-yl)indridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (63)(E)-N-(2-cyano-4-(8-(4,6-dichloro-1-methyl-1H-benzo[d]imidazole-5-yl)indridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (64)(E)-N-(2-cyano-4-(8-(4-isopropyl-1,6-dimethyl-1H-benzo[d]imidazole-5-yl)indolidine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (65)(E)-N-(4-(1-chloro-8-(1,6-dimethyl-1H-benzo[d]imidazole-5-yl)indridine-3-carbonyl)-2-cyanophenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (66)(E)-N-(2-cyano-4-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)indridine-3-carbonyl)phenyl)-4-(dimethylamino)buta-2-enamide (67)(E)-4-(tert-butylamino)-N-(2,6-difluoro-4-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]diimidazole-5-yl)imidazo[1,2-a]pyridine-3-carbonyl)phenyl)buta-2-enamide (68)(E)-N-(2,6-difluoro-4-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]diimidazole-5-yl)imidazo[1,2a]pyridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (69)(E)-N-(2-cyano-4-(8-(1,6-dimethyl-4-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-yl)indolidine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (70)(E)-N-(2,6-difluoro-4-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]diimidazole-5-yl)indridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (71)(E)-N-(4-(8-(4-chloro-2-methyl-2H-indazole-5-yl)indridine-3-carbonyl)-2-cyanophenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (72)(E)-4-(tert-butylamino)-N-(4-(8-(1,6-dimethyl-1H-benzo[d]diimidazole-5-yl)indridine-3-carbonyl)-2,6-difluorophenyl)buta-2-enamide (73)(E)-N-(4-(8-(1,6-dimethyl-1H-benzo[d]diimidazole-5-yl)indolidine-3-carbonyl)-2,6-difluorophenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (74)(E)-N-(4-(8-(4-chloro-1-isopropyl-1H-imidazole-5-yl)indridine-3-carbonyl)-2-cyanophenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (75)(E)-N-(2-cyano-4-(8-(2,5-dimethyl-2H-indazole-6-yl)indridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (76)(E)-N-(2-cyano-4-(8-(2,6-dimethyl-2H-indazole-5-yl)indridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (77)(E)-4-(tert-butylamino)-N-(2-chloro-4-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]diimidazole-5-yl)indridine-3-carbonyl)phenyl)buta-2-enamide (78)(E)-N-(2-cyano-4-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)indridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)(methyl)amino)buta-2-enamide (79)(E)-N-(2-cyano-4-(8-(3,4-dichloro-2-methyl-2H-indazole-5-yl)indridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (80)(E)-N-(2-cyano-4-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)imidazol[1,2-a]pyridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (81)(E)-N-(2-cyano-4-(8-(6-methoxy-1-methyl-1H-benzo[d]imidazole-5-yl)indridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (82)(E)-N-(2-cyano-4-(8-(1,6-dimethyl-4-(pyridine-3-yl)-1H-benzo[d]imidazole-5-yl)indridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide (83)(E)-N-(3-Fluoro-4-(7-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazo[2,1-b][1,3]thiazol-5-yl)-1H-indole-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide Details of the method for producing the compound of the present invention are as follows. The compound represented by formula (I) or (vii) of the present invention can be produced, for example, by the following production method or the method described in the Examples. However, the method for producing the compound represented by formula (I), (I'), (i) or (vii) of the present invention is not limited to these reaction examples. The reaction products obtained in each step can be subjected to subsequent steps with or without isolation and purification by known separation and purification methods such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, chromatography, etc.

[0377] To the reaction products and starting materials obtained in each step, a protecting group that can be easily converted into a functional group can be introduced if effective in each step or so as to change the order of the steps. The protecting group used here can be a protecting group used by the method disclosed in the literature "Protective Groups in Organic Synthesis," 5th edition, Greene and Wuts, John Wiley & Sons Inc., 2014, etc. The protecting group can be appropriately selected according to the reaction conditions of each step. After introducing the protecting group and carrying out the reaction, the protecting group is removed to obtain the desired compound.

[0378] As used herein, "mole" refers to the unit indicating a compound of 6.02×10 23 molecules.

[0379] Production Method 1 Scheme 1 [Chemical formula] In Scheme 1, L aR' represents a halogen, each R' independently represents hydrogen or a substituted or unsubstituted alkyl, and two R's may together form a 5-10 membered ring, and the other symbols are as defined in Embodiment A.

[0380] (Process 1) This step involves L in the compound represented by general formula (II). a If the compound has a leaving group such as a halogen, the process involves a cross-coupling reaction between the compound represented by general formula (II) and an arylboronic acid or arylboronic acid ester, or an unsaturated heterocyclic boronic acid or unsaturated heterocyclic boronic acid ester (III) to obtain the compound represented by general formula (IV). Commercial products may be used, or they can be produced by known methods. The compound represented by general formula (II) may be a commercial product, or it can be produced in accordance with known methods.

[0381] This process can usually be carried out in accordance with known methods (e.g., Chemical Reviews, Vol. 95, p. 2457, 1995), for example, in a solvent that does not adversely affect the reaction, in the presence of a transition metal catalyst and a base.

[0382] Arylboronic acid or arylboronic acid ester, or unsaturated heterocyclic boronic acid or unsaturated heterocyclic boronic acid ester can be used in an amount of 1 to 10 moles, preferably 1 to 3 moles, per mole of the compound of general formula (II).

[0383] As transition metal catalysts, for example, palladium catalysts (e.g., palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium, and dichlorobis(triphenylphosphine)palladium), nickel catalysts (e.g., nickel chloride), etc. Ligands (e.g., triphenylphosphine and tri-tert-butylphosphine) may be added to the catalyst as needed, and metal oxides (e.g., copper oxide and silver oxide), etc., may be used as co-catalysts. The amount of transition metal catalyst used depends on the type of catalyst, but is usually about 0.0001 to 1 mole, preferably about 0.01 to 0.5 moles, per mole of compound of general formula (II). The amount of ligand used is usually about 0.0001 to 4 moles, preferably about 0.01 to 2 moles, per mole of compound of general formula (II). The amount of co-catalyst used is usually about 0.0001 to 4 moles, preferably about 0.01 to 2 moles, per mole of compound of general formula (II).

[0384] Examples of bases include organic amines (e.g., trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undeca-7-ene, pyridine, and N,N-dimethylaniline), alkali metal salts (e.g., sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, and potassium hydroxide), metal hydrides (e.g., potassium hydride and sodium hydride), alkali metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide), and alkali metal disilazides (e.g., lithium disilazide, sodium disilazide, and potassium disilazide). The amount of base used is usually 0.1 to 10 moles, preferably about 1 to 5 moles, per mole of the compound represented by general formula (II).

[0385] The solvent can be any solvent that does not adversely affect the reaction. Examples of solvents include hydrocarbons (e.g., benzene, toluene, and xylene), halogenated hydrocarbons (e.g., chloroform and 1,2-dichloroethane), nitriles (e.g., acetonitrile), ethers (e.g., 1,2-dimethoxyethane and THF), alcohols (e.g., methanol and ethanol), aprotic polar solvents (e.g., DMF, dimethyl sulfoxide, and hexamethylphosphoramide), water, and mixtures thereof.

[0386] The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 0°C to the boiling point of the solvent, preferably 0°C to 150°C.

[0387] The resulting compound of general formula (IV) may be isolated and purified by known separation and purification methods, or it may be subjected to subsequent steps without isolation and purification.

[0388] (Process 2) This step involves the amidation reaction of an amine represented by general formula (IV) with a carboxylic acid (V) to obtain a compound represented by general formula (VI). This compound may be a commercially available product or can be manufactured by known methods.

[0389] This step is carried out using 0.5 to 10 moles, preferably 1 to 3 moles, of carboxylic acid (V) per mole of compound represented by general formula (IV). A suitable condensing agent is added as an amidation reagent in a solvent inert to the reaction, and the mixture is stirred under cooling or heating, preferably at -20°C to 80°C, usually for 1 minute to 1 week.

[0390] The condensing agent is not particularly limited, but examples include N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, benzotriazole-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate, benzotriazole-1-yloxytris-pyrrolidinophosphonium hexafluorophosphate, bromotris-(dimethylamino)phosphonium hexafluorophosphate, diphenylphosphoryl azide, 1,1'-carbonyldiimidazole, and propylphosphonic anhydride (cyclic trimer).

[0391] The solvent is not particularly limited, but examples include toluene, methylene chloride, chloroform, THF, 1,4-dioxane, DMF, N,N-dimethylacetamide, NMP, 2-propanol, ethanol, methanol, water, and mixtures thereof.

[0392] In addition, additives such as 1-hydroxybenzotriazole and bases may be added as needed. The bases are not particularly limited, but examples include inorganic bases such as sodium carbonate, potassium carbonate, and sodium bicarbonate, or organic bases such as triethylamine, N,N-diisopropylethylamine, and 4-dimethylaminopyridine, or mixtures thereof.

[0393] The compound represented by general formula (VI) obtained in this manner may be isolated and purified by known separation and purification methods such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography, or it may be used to produce the compound represented by general formula (I) without isolation and purification.

[0394] Manufacturing method 2 Scheme 2 [ka] In Scheme 2, R1 represents hydrogen, and the other symbols are as defined in Embodiment A.

[0395] (Step 3) This step involves subjecting a compound represented by general formula (IV), which may be a commercially available product or can be produced by known methods, to a carboxylic acid represented by general formula (VIII) in an amidation reaction to obtain a compound represented by general formula (VII).

[0396] This process can be carried out in the same manner as in process 2.

[0397] (Step 4) This process involves reducing a compound represented by general formula (VIII) to produce a compound represented by general formula (VI).

[0398] This step can be carried out in a solvent that does not adversely affect the reaction, such as acetonitrile, ethyl acetate, THF, methanol, ethanol, DMF, DMA, or NMP, using a hydrogen source such as hydrogen, formic acid, ammonium formate, or cyclohexadiene, and using palladium / carbon or palladium hydroxide / carbon as a catalyst. This step is carried out using typically 0.01 to 5 moles, preferably 0.05 to 1 mole, of catalyst per mole of compound represented by general formula (VIII). The reaction temperature is typically room temperature to the reflux temperature of the solvent. The reaction time is typically 1 to 24 hours.

[0399] The compound represented by general formula (VI) obtained in this manner may be isolated and purified by known separation and purification methods such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography, or it may be used to produce the compound represented by general formula (I) without isolation and purification.

[0400] Manufacturing method 3 Scheme 3 [ka] In scheme 3, Lb represents halogen, L c represents a hydroxyl group, or a chlorine atom or a bromine atom, and the other symbols are as defined in Embodiment A.

[0401] (Step 5) This process involves a compound represented by general formula (IX) and a carboxylic acid (L) represented by general formula (X). c =OH) or acid halide (L c This is a step in obtaining a compound represented by general formula (XI) through an amidation reaction with Cl and Br.

[0402] Carboxylic acid represented by general formula (X) (L c If using =OH), this step can be carried out in the same way as step 2.

[0403] Acid halides represented by general formula (X) (L c When using (=Cl, Br), typically 0.5 to 10 moles, preferably 1 to 5 moles, of the acid halide is used per mole of the compound represented by general formula (IX). The acid halide may be a commercially available product or can be manufactured according to known methods.

[0404] A base may be added as needed. Examples of bases include organic amines (e.g., trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undeca-7-ene, pyridine, and N,N-dimethylaniline), alkali metal salts (e.g., sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, and potassium hydroxide), metal hydrides (e.g., potassium hydride and sodium hydride), and alkali metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide). The amount of base used is usually 1 to 100 moles, preferably about 1 to 10 moles, per mole of the compound represented by general formula (IX).

[0405] The solvent used in the reaction can be any solvent that does not adversely affect the reaction. Examples of solvents include alcohols (e.g., methanol), hydrocarbons (e.g., benzene, toluene, and xylene), halogenated hydrocarbons (e.g., methylene chloride, chloroform, and 1,2-dichloroethane), nitriles (e.g., acetonitrile), ethers (e.g., 1,2-dimethoxyethane and THF), aprotic polar solvents (e.g., DMF, dimethyl sulfoxide, and hexamethylphosphoramide), and mixtures thereof. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 0°C to the boiling point of the solvent, preferably 0°C to 100°C.

[0406] The compound of general formula (XI) obtained in this manner may be isolated and purified by known separation and purification methods, or it may be subjected to subsequent steps without isolation and purification.

[0407] (Step 6) This process involves L in the compound represented by general formula (XI). b If the compound has a leaving group such as a halogen, the process involves a coupling reaction between the compound represented by general formula (XI) and an arylboronic acid or arylboronic acid ester, or an unsaturated heterocyclic boronic acid or unsaturated heterocyclic boronic acid ester (XII) to obtain the compound represented by general formula (VI). Commercial products may be used, or they can be produced by known methods.

[0408] This process can be carried out in the same manner as in process 1.

[0409] Manufacturing method 4 Scheme 4 [ka] In Scheme 4, the symbols are as defined in Embodiment A.

[0410] (Step 7) This step involves the amidation reaction of a compound represented by general formula (VI) with a carboxylic acid (XIII) to obtain a compound represented by general formula (XIV).

[0411] This process can be carried out in the same manner as in process 2.

[0412] (Step 8) This process involves reacting a compound represented by general formula (XIV) with an amine represented by general formula (XV) to produce the compound of the present invention represented by general formula (I).

[0413] The amine represented by general formula (XV) may be used in amounts of 1 to 20 moles, preferably 1 to 10 moles, per mole of the compound represented by general formula (XIV).

[0414] A base may be added to the above reaction as needed. Examples of bases include organic bases such as triethylamine, N,N-diisopropylethylamine, pyridine, lutidine, colidine, 4-dimethylaminopyridine, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and butyllithium, or inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, and potassium phosphate. The amount of base added may be 1 to 100 moles, preferably 1 to 20 moles, per mole of the compound represented by general formula (XIV).

[0415] In addition, inorganic salts may be added as needed. Examples of inorganic salts include sodium iodide and potassium iodide. The amount of inorganic salt used is usually 1 to 100 moles, preferably about 1 to 10 moles, per mole of the compound represented by general formula (XIV).

[0416] The reaction solvent is not particularly limited as long as it does not adversely affect the reaction. For example, DMF, N,N-dimethylacetamide, dimethyl sulfoxide, THF, 1,4-dioxane, N-methylpyrrolidine-2-one, and acetonitrile can be used individually or in combination. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 0°C to the boiling point of the solvent, preferably 0 to 100°C.

[0417] The compound of the present invention, represented by general formula (I), obtained in this manner, can be isolated and purified by known separation and purification methods such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.

[0418] Manufacturing method 5 Scheme 5 [ka] In scheme 5, L d represents a fluorine atom, or an amino group or NHR1, L e represents a halogen, and the other symbols are as defined in Embodiment A.

[0419] (Step 9) This process is a method for obtaining a compound represented by general formula (XVII) by a bromination reaction of a compound represented by general formula (XVI), which may be commercially available or manufactured by known methods.

[0420] This step can be carried out using a bromine source such as bromine or copper(II) bromide in a solvent that does not adversely affect the reaction, such as acetonitrile, ethyl acetate, dichloromethane, chloroform, 1,4-dioxane, or ethanol. Iodine may also be used as an additive if necessary. In this step, typically 1 to 100 moles, preferably 1 to 10 moles, of the bromine source should be used per mole of the compound represented by general formula (XVI). The reaction temperature is typically room temperature to the reflux temperature of the solvent. The reaction time is typically 1 to 24 hours.

[0421] The compound represented by general formula (XVII) obtained in this manner may be isolated and purified by known separation and purification methods, or it may be subjected to subsequent steps without isolation and purification.

[0422] (Step 10) This process involves a nucleophilic substitution reaction between a compound represented by general formula (XVII) and a substituted pyridine, which may be commercially available or can be produced by known methods, followed by an intramolecular cyclization reaction to obtain a compound represented by general formula (XVIII).

[0423] D2 is N, D1' and D2' are C, CH or CH2, L d When the substituent L is a fluorine atom, in a solvent that does not adversely affect the reaction, such as THF or ethanol, the substituent L is added per mole of the compound represented by general formula (XVII). e 2-methylpyridine having R7 may be used in amounts of typically 0.5 to 10 moles, preferably 1 to 5 moles. 2-methylpyridine may be commercially available or can be produced according to known methods. The reaction temperature is typically room temperature to the reflux temperature of the solvent. The reaction time is typically 1 hour to 4 days.

[0424] The pyridinium salt obtained in this manner may be isolated and purified by known separation and purification methods, or it may be subjected to subsequent reactions without purification.

[0425] For every mole of the pyridinium salt obtained above, 1 to 100 moles, preferably 1 to 20 moles, of (methoxymethylene)dimethylammonium methyl sulfate, which can be commercially available or produced by known methods, may be used, and a base may be added as needed. Examples of bases include organic amines (e.g., trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undeca-7-ene, pyridine, and N,N-dimethylaniline), alkali metal salts (e.g., sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, and potassium hydroxide), metal hydrides (e.g., potassium hydride and sodium hydride), and alkali metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide). The amount of base used is typically 1 to 100 moles per mole of pyridinium salt, preferably about 1 to 10 moles.

[0426] The solvent used in the reaction can be any solvent that does not adversely affect the reaction. Examples of solvents include aprotic polar solvents (e.g., DMF, dimethyl sulfoxide, and hexamethylphosphoramide). The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 0°C to the boiling point of the solvent, preferably 0°C to 100°C.

[0427] The compound represented by general formula (XVIII) obtained in this manner may be isolated and purified by known separation and purification methods such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography, or it may be used to produce compound (I') of the present invention without isolation and purification.

[0428] When D2 and D2' are N or NH and D1' is C, CH or CH2, in a solvent that does not adversely affect the reaction, such as DMF or ethanol, the substituent L is added to 1 mole of the compound represented by general formula (XVII).e (E)-N,N-dimethyl-N'-(pyridine-2-yl)formimamide having R7 can usually be used in amounts of 0.5 to 10 moles, preferably 1 to 5 moles. (E)-N,N-dimethyl-N'-(pyridine-2-yl)formimamide may be a commercially available product or can be produced according to known methods. A base may be added as needed. Examples of bases include organic amines (e.g., trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undeca-7-ene, pyridine, and N,N-dimethylaniline) and alkali metal salts (e.g., sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, and potassium hydroxide). The reaction temperature is usually room temperature to the reflux temperature of the solvent. The reaction time is usually 1 to 24 hours.

[0429] The compound represented by general formula (XVIII) obtained in this manner may be isolated and purified by known separation and purification methods such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography, or it may be used to produce compound (I') of the present invention without isolation and purification.

[0430] Manufacturing method 6 Scheme 6 [ka] In scheme 6, L f represents a hydroxyl group, a chlorine atom, or a bromine atom, and the other symbols are as defined in Embodiment A.

[0431] (Step 11) This process involves a Friedel-Crafts reaction between a compound represented by general formula (XXI), which may be a commercially available product or can be produced by known methods, and a compound represented by general formula (XX), to obtain a compound represented by general formula (XXI).

[0432] Carboxylic acids represented by general formula (XX) (L f When using (=OH), the reaction can be carried out in a solvent that does not adversely affect the reaction, such as dichloromethane, THF, or 1,4-dioxane, using trifluoroacetic anhydride, phosphoric acid, etc. A base may be added as needed. Examples of bases include organic amines (e.g., trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undeca-7-ene, pyridine, and N,N-dimethylaniline). In this step, typically 1 to 100 moles, preferably 1 to 10 moles, of acid can be used per mole of compound represented by general formula (XIX). The reaction temperature is usually room temperature to the reflux temperature of the solvent. The reaction time is usually 1 hour to 3 days.

[0433] Acid halides represented by general formula (XX) (L f When using (=Cl, Br), the reaction can be carried out in a solvent that does not adversely affect the reaction, such as dichloromethane, THF, or 1,4-dioxane, in the presence of a Lewis acid such as aluminum chloride or an organic amine (e.g., trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undeca-7-ene, pyridine, and N,N-dimethylaniline). In this step, typically 1 to 100 moles, preferably 1 to 10 moles, of Lewis acid or Lewis base can be used per mole of compound represented by general formula (XIX). The reaction temperature is typically 0°C to the reflux temperature of the solvent. The reaction time is typically 1 to 24 hours.

[0434] The compound represented by general formula (XXI) obtained in this manner may be subjected to subsequent reactions after isolation and purification by known separation and purification methods, or without isolation and purification.

[0435] (Step 12) This process is L dWhen the atom is a fluorine atom, this method yields a compound represented by the general formula (XXII) through an aromatic electrophilic substitution reaction of an amine.

[0436] This step can be carried out using an aqueous ammonia solution (R1=H), alkylamine (R1-NH2), etc., in a solvent that does not adversely affect the reaction, such as THF, 1,4-dioxane, and 1,2-dimethoxyethane. In this step, typically 1 to 100 moles, preferably 1 to 50 moles, of amine can be used per mole of the compound represented by general formula (XXI). The reaction temperature is typically room temperature to the reflux temperature of the solvent. The reaction time is typically 1 to 24 hours.

[0437] Manufacturing method 7 Scheme 7 [ka] In Scheme 7, the symbols are as defined in Embodiment A.

[0438] (Step 13) This step involves L in the compound represented by the general formula (XXII). e If the compound has a leaving group such as a halogen, the process involves a cross-coupling reaction between the compound represented by general formula (XXII) and an arylboronic acid or arylboronic acid ester, or an unsaturated heterocyclic boronic acid or unsaturated heterocyclic boronic acid ester (XII) to obtain the compound represented by general formula (XXIII). Commercial products may be used, or they can be produced by known methods.

[0439] This process can be carried out in the same manner as in process 1.

[0440] (Step 14) This step involves the amidation reaction of a compound represented by general formula (XXIII) with a carboxylic acid (XIII) to obtain a compound represented by general formula (XXIV).

[0441] This process can be carried out in the same manner as in process 2.

[0442] (Step 15) This process involves reacting a compound represented by general formula (XXIV) with an amine represented by general formula (XV) to produce the compound of the present invention represented by general formula (I').

[0443] This process can be carried out in the same manner as in process 8.

[0444] Manufacturing method 8 Scheme 8 [ka] In scheme 8, L g represents halogen, L h represents chlorine or bromine, L i represents a halogen, and the other symbols are as defined in Embodiment A.

[0445] (Step 16) This process involves adding a strong base to an aryl halide (XXVI) to a compound represented by general formula (XXVII) to generate an anion, and then producing an acid halide (L) represented by general formula (XXV). h This process involves obtaining the material through an electrophilic addition reaction with (Cl, Br), and these materials may be commercially available or manufactured by known methods.

[0446] This reaction involves, for example, adding a strong base to a suitable solvent and stirring at a temperature of -78°C to room temperature, usually for 10 minutes to 12 hours, to generate an anion, to which an acid halide (L) represented by the general formula (XXV) is added. hThis can be carried out by adding (Cl, Br). The usable reaction solvent is not particularly limited as long as it is a solvent that does not participate in the reaction. Examples of solvents include ethers such as THF and 1,4-dioxane, hydrocarbons such as benzene and toluene, and mixtures thereof. Examples of strong bases that can be used include, but are not particularly limited, butyllithium, lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidide, 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex, and isopropyl magnesium chloride lithium chloride complex.

[0447] The compound represented by general formula (XXVII) obtained in this manner may be isolated and purified by known separation and purification methods such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography, or it may be used to produce the compound of the present invention without isolation and purification.

[0448] If a compound according to one embodiment of the present invention has isomers such as optical isomers, stereoisomers, rotational isomers, and tautomers, then unless otherwise specified, any of these isomers and mixtures thereof are included within the scope of the compound of the present invention. For example, if the compound of the present invention has optical isomers, then unless otherwise specified, racemic mixtures and optical isomers separated from racemic mixtures are also included within the scope of the compound of the present invention.

[0449] A compound or salt thereof according to one embodiment of the present invention may be in amorphous or crystalline form. Single crystals and polymorphic mixtures are included within the scope of the compound or salt thereof of the present invention. Such crystals can be produced by crystallization according to crystallization methods known in the art. The compound or salt thereof of the present invention may be a solvate (e.g., hydrate) or a non-solvate. Both are included within the scope of the compound or salt thereof of the present invention. Isotopes (e.g., 2 H, 3 H, 13 C, 14 C, 35 S, 125Compounds labeled in I) are also included in the range of compounds or salts thereof of the present invention.

[0450] A salt of a compound according to one embodiment of the present invention refers to any pharmaceutically acceptable salt, examples of which include base addition salts and acid addition salts.

[0451] A compound or salt thereof according to one embodiment of the present invention also includes its prodrug. A prodrug is a compound that can be converted to the compound or salt thereof of the present invention by reaction with enzymes or gastric acid, etc., under physiological conditions in vivo; that is, a compound that can be converted to the compound or salt thereof of the present invention by enzymatic oxidation, reduction, hydrolysis, etc., or a compound that can become the compound or salt thereof of the present invention by hydrolysis by gastric acid, etc. Furthermore, a prodrug may also be a compound that can be converted to the compound or salt thereof of the present invention under physiological conditions, as described in "Iyakuhin no Kaihatsu," "Development of Pharmaceuticals," Vol. 7, Molecular Design, published in 1990 by Hirokawa Shoten Co., pp. 163-198.

[0452] As used herein, “effective amount” of a compound according to one embodiment of the present invention means an amount of the compound sufficient to cause a decrease or prevention of enzyme or protein activity; or to achieve a target biological or therapeutic response, such as improvement of symptoms, alleviation of a medical condition, delay or cessation of the progression of a disorder, or prevention of a disease (therapeutic effective amount).

[0453] As used herein, “Subject” includes mammals and non-mammals. Examples of mammals include, but are not limited to, humans, chimpanzees, apes, monkeys, cattle, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, rhesus macaques (Cavia porcellus), hedgehogs, kangaroos, moles, wild boars, bears, tigers, and lions. Examples of non-mammals include, but are not limited to, birds, fish, and reptiles. In one embodiment, the subject may be a human being diagnosed with a condition, medical state, or disease disclosed herein that requires treatment.

[0454] In one embodiment, a pharmaceutical, pharmaceutical composition, or pharmaceutical preparation comprising the compound of the present invention or a pharmaceutically acceptable salt thereof may be provided. In another embodiment, an antitumor agent comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient may be provided.

[0455] When a compound or salt thereof according to one embodiment of the present invention is used as a pharmaceutical preparation, a pharmaceutical, or a pharmaceutical composition, a pharmaceutically acceptable carrier can be added as needed to form an appropriate dosage form for preventive and therapeutic purposes. Examples of dosage forms include oral preparations, injections, suppositories, ointments, inhalants, patches, etc. Such dosage forms can be formed by methods conventionally known to those skilled in the art.

[0456] Various conventional organic or inorganic carrier materials used as pharmaceutically acceptable carriers or preparation materials may be incorporated into solid formulations as excipients, binders, disintegrants, lubricants, or colorants, or into liquid formulations as solvents, solubilizers, suspending agents, isotonic agents, buffers, or analgesics. Furthermore, pharmaceutical additives such as preservatives, antioxidants, colorants, sweeteners, and stabilizers may be used as needed.

[0457] In one embodiment, an orally administered pharmaceutical, pharmaceutical composition, pharmaceutical preparation, or oral solid dosage form may be provided, comprising the compound of the present invention or a pharmaceutically acceptable salt thereof. In another embodiment, an orally administered antitumor agent may be provided, comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient. The oral solid dosage form, or the orally administered pharmaceutical, pharmaceutical composition, antitumor agent, or pharmaceutical preparation, is prepared as follows: The compound of the present invention or a salt thereof is optionally combined with an excipient and a binder, disintegrant, lubricant, coloring agent, flavoring agent, or flavoring agent, and the resulting mixture is then formulated into tablets, coated tablets, granules, powders, capsules, etc., by conventional methods.

[0458] When preparing an injectable preparation, pH adjusters, buffers, stabilizers, isotonic agents, local anesthetics, etc., may be added to the compound of the present invention, and the mixture can be formulated for subcutaneous, intramuscular, or intravenous injection according to conventional methods.

[0459] The amount of compound according to one embodiment of the present invention incorporated into each of these dosage forms depends on the patient's condition, the dosage form, etc. Generally, for oral preparations, the amount of compound is preferably about 0.05 to 1000 mg per unit dosage form. For injectable preparations, the amount of compound is preferably about 0.01 to 500 mg per unit dosage form, and for suppositories, the amount of compound is preferably about 1 to 1000 mg per unit dosage form.

[0460] Furthermore, the daily dose of the drug in this dosage form varies depending on the patient's condition, weight, age, sex, etc., and cannot be determined in general terms. For example, the daily dose of the compound of the present invention for an adult (weight: 50 kg) may be around 0.05 to 5000 mg, preferably 0.1 to 1000 mg.

[0461] A compound or salt thereof according to one embodiment of the present invention has excellent KRAS inhibitory activity against KRAS G12C mutation-positive cancer cells. Therefore, a compound or salt thereof according to one embodiment of the present invention is useful as an antitumor agent against KRAS G12C mutation-positive cancer cells and has the advantage of having few side effects.

[0462] A compound or salt thereof according to one embodiment of the present invention inhibits KRAS function due to its excellent KRAS G12C inhibitory activity and is useful as a pharmaceutical formulation for the prevention and treatment of KRAS-related signaling disorders.

[0463] In one embodiment, the use of the compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition may be provided. In one embodiment, the use of the compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of an antitumor agent may be provided. In one embodiment, the use of the compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of an antitumor agent for oral administration may be provided. In one embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof for use as a pharmaceutical may be provided. In one embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof for use in the prevention and / or treatment of tumors may be provided. In one embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof for use in the prevention and / or treatment of tumors by oral administration may be provided.

[0464] In one embodiment, a method for preventing and / or treating a tumor is provided, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need. In one embodiment, an antitumor agent may be provided, which is administered to a subject in need in combination with one or more other antitumor agents in a pharmaceutically effective amount.

[0465] Regarding RAS-related signaling in KRAS-related signaling disorders, KRAS is involved in various signaling pathways as a RAS-related signaling pathway, primarily activating RAF, PI3K, RAL-GEF, etc., but not limited to these. Examples of diseases include those whose incidence can be reduced, and whose symptoms can be remitted, alleviated, and / or completely cured by eliminating, suppressing, and / or inhibiting the function of the relevant receptors. Examples of such diseases include, but are not limited to, tumors, cancer, autoimmune diseases, and macroglobulinemia. Cancers or tumors as defined herein include, but are not limited to, adenomas, carcinoid tumors, undifferentiated carcinomas, angiosarcomas, adenocarcinomas, sarcomas, neuromas, gastrointestinal cancers (e.g., colorectal cancers including colon and rectal cancers ("CRC"), biliary tract cancers including gallbladder and bile duct cancers, anal cancers, esophageal cancers, gastric (stomach) cancers, gastrointestinal carcinoid tumors (may be multiple), gastrointestinal stromal tumors (may be multiple) ("GIST"), liver cancers, duodenal cancers and small intestine cancers), gastrointestinal cancers, lung cancers (e.g., , non-small cell lung cancer ("NSCLC"), squamous cell lung cancer, large cell lung carcinoma, small cell lung carcinoma, mesothelioma, and other lung cancers such as bronchial tumors and pleuroblastoma), urological cancers (e.g., kidney cancer, transitional cell carcinoma of the kidney ("TCC"), TCC of the renal pelvis and ureter ("PDQ"), bladder cancer, urethral cancer, and prostate cancer), head and neck cancers (e.g., eye cancer, retinoblastoma, intraocular melanoma, hypopharyngeal cancer, pharyngeal cancer, laryngeal cancer, laryngeal papillomatosis, occult primary oculi Metastatic squamous cell carcinoma of the neck with oral cancer, lip cancer, throat cancer, oropharyngeal cancer, sensory neuroblastoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, and salivary gland cancer), endocrine cancers (e.g., thyroid cancer, parathyroid cancer, multiple endocrine neoplasm syndrome, thymoma and thymic carcinoma, pancreatic cancer including ductal adenocarcinoma ("PDAC"), pancreatic neuroendocrine tumors and islet cell tumors), breast cancer (extrahepatic ductal carcinoma in situ "DCIS"), carcinoma in situ of the lobular ("LCIS"), triple neoplasm Cancers of the male and female reproductive organs and / or genital cancers (e.g., cervical cancer, ovarian cancer, endometrial cancer, uterine sarcoma, uterine cancer, vaginal cancer, vulvar cancer, trophoblastic tumor of pregnancy ("GTD"), extragonadal germ cell tumors, extracranial germ cell tumors, germ cell tumors, testicular cancer and penile cancer), cancers of the brain and nervous system (e.g., astrocytoma, brainstem glioma, brain tumor, craniopharyngioma, central nervous system ("CNS") cancer, chordoma, ependymoma, embryonic tumor,These include neuroblastoma, paraganglioma, and atypical teratomas; skin cancers (e.g., basal cell carcinoma ("BCC"), squamous cell carcinoma ("SCC"), Merkel cell carcinoma, and melanoma); tissue and bone cancers (e.g., soft tissue sarcoma, rhabdomyosarcoma, fibrous histiocytoma of bone, Ewing's sarcoma, malignant fibrous histiocytoma of bone ("MFH"), osteosarcoma, and chondrosarcoma); cardiovascular cancers (e.g., cardiac cancer and cardiac tumors); appendiceal cancer; childhood and adolescent cancers (e.g., adrenocortical carcinoma childhood, midline tract carcinoma, hepatocellular carcinoma ("HCC"), hepatoblastoma, and Wilms' tumor); and virus-induced cancers (e.g., HHV-8-related cancer (Kaposi's sarcoma) and HIV / AIDS-related cancers). In some embodiments, cancer is lung cancer, pancreatic cancer, rectal cancer, colon cancer, or colorectal cancer. In one embodiment, squamous cell carcinoma is cancer of the cervix, tarsal, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx, or esophagus. In one embodiment, adenocarcinoma is cancer of the prostate, small intestine, endometrium, cervix, large intestine, lung, pancreas, esophagus, rectum, uterus, stomach, breast, or ovary. In one embodiment, tumor is rectal cancer, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, breast cancer, or leukemia. In one embodiment, a subject suffering from any of the diseases selected above may not have the K-Ras G12C mutant protein. In a preferred embodiment, a subject suffering from any of the diseases selected above has the K-Ras G12C mutant protein.

[0466] Cancers as described herein include, but are not limited to, hematological and plasma cell malignancies, as well as hematopoietic malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes), such as multiple myeloma, leukemia and lymphoma, myelodysplastic syndromes, and myeloproliferative disorders. Leukemias include, but are not limited to, acute lymphoblastic leukemia ("ALL"), acute myeloid (bone marrow) leukemia ("AML"), chronic lymphocytic leukemia ("CLL"), chronic myeloid leukemia ("CML"), acute monocytic leukemia ("AMoL"), hairy cell leukemia, and / or other leukemias. Lymphomas include, but are not limited to, Hodgkin lymphoma and non-Hodgkin lymphoma ("NHL"). In some embodiments, NHL is B-cell lymphoma and / or T-cell lymphoma. In some embodiments, NHLs include, but are not limited to, diffuse large B-cell lymphoma ("DLBCL"), small lymphocytic lymphoma ("SLL"), chronic lymphocytic leukemia ("CLL"), mantle cell lymphoma ("MCL"), Burkitt lymphoma, cutaneous T-cell lymphomas including mycosis fungoides and Sézary syndrome, AIDS-associated lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma (Waldenstrem hypergammaglobulinemia ("WM")), primary central nervous system (CNS) lymphoma and / or other lymphomas.

[0467] In one embodiment, an antitumor agent may be provided comprising the compound of the present invention or a pharmaceutically acceptable salt thereof and one or more other antitumor agents as active ingredients. In one embodiment, an antitumor agent may be provided comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, administered in combination with one or more other antitumor agents. In one embodiment, the use of the compound of the present invention or a salt thereof and one or more other antitumor agents for producing an antitumor agent may be provided. In one embodiment, the use of the compound of the present invention or a salt thereof for producing an antitumor agent administered in combination with one or more other antitumor agents may be provided. In one embodiment, a combination of the compound of the present invention or a salt thereof and one or more other antitumor agents used for the treatment of a tumor may be provided. In one embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof used for the treatment of a tumor may be provided, administered in combination with one or more other antitumor agents. In one embodiment, a method for treating a tumor may be provided, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof and one or more other antitumor agents to a subject in need thereof. In one embodiment, a method for treating a tumor may be provided, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, in combination with one or more other antitumor agents, to a subject in need thereof.

[0468] The compounds of the present invention or pharmaceutically acceptable salts thereof can be used in combination with one or more other antitumor agents to treat cancer. In other words, a single compound of the present invention or a pharmaceutically acceptable salt thereof, or a pair or more compounds of the present invention or pharmaceutically acceptable salts thereof, can be used in combination with a single other antitumor agent or with one or more other antitumor agents.

[0469] As used herein, “other antitumor agents” may be any pharmaceutically active substance (or a pharmaceutically acceptable salt thereof) that is active in the body and is different from the compound of the present invention or a pharmaceutically acceptable salt thereof. Examples of other antitumor agents include prodrugs, free acids, free bases, and pharmaceutically acceptable salts of additional activators. Generally, any suitable other antitumor agent, including chemotherapeutic agents or therapeutic antibodies, may be used in any combination with the compound of the present invention or a pharmaceutically acceptable salt thereof in a single-dose formulation (e.g., a combination of fixed-dose drugs) or in one or more separate-dose formulations that allow for simultaneous or sequential administration of the pharmaceutically acceptable agents to a target (simultaneous administration of separate activators). In certain embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof and the other antitumor agent may be administered several minutes apart, several hours apart, or several days apart. Furthermore, the compound of the present invention or a pharmaceutically acceptable salt thereof may be administered in combination with radiotherapy, hormone therapy, targeted therapy, surgery, or immunotherapy. In one embodiment, one or more other antitumor agents may be included in the pharmaceutical composition described above.

[0470] In one embodiment, other antitumor agents are additional anticancer agents (also known as antineoplastic agents). As used herein, “anticancer agent” is any pharmaceutically active substance (or a pharmaceutically active salt thereof) that is active against cancer in the body. Examples of anticancer agents include chemotherapeutic agents (e.g., cytotoxic agents), immunotherapeutic agents, hormonal and antihormone agents, targeted therapies, and anti-angiogenic agents. Many anticancer agents can be classified into one or more of these groups. Certain anticancer agents are classified herein into specific groups or subgroups, but many of these agents can also be enumerated in one or more other groups or subgroups, as is currently understood in the art. It should be understood that the classification of certain agents into specific groups herein is not intended to be limiting. Many anticancer agents are now known in the art and can be used in combination with the compounds of the present invention or pharmaceutically acceptable salts thereof.

[0471] Furthermore, the drugs may be agonists, antagonists, allosteric modulators, toxins, or more generally, they may act to inhibit or stimulate their targets (e.g., the activation or inhibition of receptors or enzymes). Suitable for use are, for example, one or more drugs (e.g., antibodies, antigen-binding domains, or soluble receptors) that specifically bind to and inhibit the activity of growth factors, such as hepatocyte growth factor (HGF) antagonists, and antibodies or antigen-binding domains that specifically bind to the receptor "c-met".

[0472] In one embodiment, additional anticancer agents are chemotherapeutic agents, immunotherapeutic agents, hormones, antihormone agents, targeted therapy agents, or anti-angiogenic agents (or angiogenesis inhibitors). In one embodiment, additional anticancer agents are chemotherapeutic agents, mitotic inhibitors, plant alkaloids, alkylating agents, antimetabolites, platinum analogs, enzymes, topoisomerase inhibitors, retinoids, aziridines, antibiotics, hormones, antihormone agents, anti-estrogens, anti-androgens, anti-adrenal agents, androgens, targeted therapy agents, immunotherapy agents, biological response modifiers, cytokine inhibitors, tumor vaccines, monoclonal antibodies, immune checkpoint inhibitors, anti-PD-1 agents, anti-PD-L1 agents, colony-stimulating factors, immunomodulators, immunomodulatory imides (IMiDs), anti-CTLA4 agents, anti-LAGl agents, anti-OX40 agents, GITR agonists, CAR-T cells, BiTE, signal transduction inhibitors, proliferation The following group of inhibitors is selected: factor inhibitors, tyrosine kinase inhibitors, EGFR inhibitors, histone deacetylase (HDAC) inhibitors, proteasome inhibitors, cell cycle inhibitors, anti-angiogenic agents, matrix metalloproteinase (MMP) inhibitors, hepatocyte growth factor inhibitors, TOR inhibitors, KDR inhibitors, VEGF inhibitors, HIF-1α inhibitors, HIF-2α inhibitors, fibroblast growth factor (FGF) inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, HER-2 inhibitors, BRAF inhibitors, gene expression regulators, autophagy inhibitors, apoptosis inducers, antiproliferative agents, and glycolysis inhibitors.

[0473] In one embodiment, the additional anticancer agent(s) is a chemotherapeutic agent. Non-limiting examples of therapeutic agents include mitotic inhibitors, as well as plant alkaloids, alkylating agents, antimetabolites, platinum analogs, enzymes, topoisomerase inhibitors, retinoids, aziridines, and antibiotics.

[0474] Non-exclusive examples of mitotic inhibitors and plant alkaloids include taxanes such as cabazitaxel, docetaxel, larotaxel, ortataxel, paclitaxel, and tesetaxel; demecolsin; epothilone; eribulin; etoposide (VP-16); etoposide phosphate; navelbine; noscapine; teniposide; taliblastine; vinblastine; vincristine; vindesine; buflunin; and vinorelbine.

[0475] Non-limiting examples of alkylating agents include nitrogen mustards, e.g., chlorambucil, chlornafadin, chlorophosphamide, cytophosphan, estramustine, ifosfamide, mannomustine, mechloretamine, mechloretamine oxide hydrochloride, melphalan, nobenbitin, phenesterine, prednimustine, tris(2-chloroethyl)amine, trophosphamide, and uracil mustard; alkyl sulfonates, e.g., busulfan, improsulfan, biposulfan; and nitrosoureas, e.g., carmustine, chloro Zotosine, fotemustine, lomustine, nimustine, ranimustine, streptozotosine, TA-07; ethyleneimines and methylamelamines, such as altoretamine, thiotepa, triethylenemelamine, triethylenethiophosphamide, triethylenephosphoramide and trimethylomelamine; ambamustine; bendamustine; dacarbazine; etogluside; ilofluben; maphosphamide; mitobronitol; mitractol; pipobromane; procarbazine; temozolomide; treosulfan; and triadicone.

[0476] Non-limiting examples of antimetabolites include folate analogs, e.g., aminopterin, denopterin, edatrexate, methotrexate, pteropterin, larcitrexed and trimethrexate; purine analogs, e.g., 6-mercaptopurine, 6-thioguanine, fludarabine, folodesine, thiamipurine and thioguanine; pyrimidine analogs, 5-fluorouracil (5-FU), 6-azauridine, ancitabine, azacitidine, capecitabine, carmoflu, syl Examples include tarabine, decitabine, dideoxyuridine, doxyphyuridine, doxyfluridine, enocitabine, phloxuridine, gallocitabine, gemcitabine and sapacitabine; 3-aminopyridine-2-carboxyaldehyde thiosemicarbazone; broxuridine; cladribine; cyclophosphamide; cytarabine; emiteflu; hydroxyurea; mercaptopurine; nerarabine; pemetrexed; pentostatin; tegafur; and troxacitabine.

[0477] Non-exclusive examples of platinum analogs include carboplatin, cisplatin, dicycloplatin, heptaplatin, lobaplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate.

[0478] Non-specific examples of enzymes include asparaginase and pegaspargase.

[0479] Non-exclusive examples of topoisomerase inhibitors include acridine carboxamide, amonafide, amsacrin, berotecan, eriptinium acetate, exatecan, indolocarbazole, irinotecan, rutotecan, mitoxantrone, razoxane, rubitecan, SN-38, sobuzoxane, and topotecan.

[0480] Non-specific examples of retinoids include alitretinoin, bexarotene, fenretinide, isotretinoin, rialozol, RII retinamide, and tretinoin.

[0481] Non-exclusive examples of aziridines include benzodopa, carbocone, metredopa, and uredopa.

[0482] Non-exclusive examples of antibiotics include intercalating antibiotics; anthracendions; anthracyclines; anthracycline antibiotics, e.g., acralubicin, amrubicin, daunomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogalil, nogaramycin, pirarubicin, barurubicin; 6-diazo-5-oxo-L-norleucine; acrasinomycin; actinomycin; ausramycin; azaserin; bleomycin; kakutinomycin; calicheamicin; carabicin; carminomycin; cardinophilin; chromomycin; Examples include dactinomycin; detobicin; doxorubicin; esorubicin; esperamycin; geldanamycin; marcelomycin; mitomycin; mitomycin C; mycophenolic acid; olibomycin; novanthron; peplomycin; porphyromycin; pophylromycin; puromycin; queramycin; rebeccamycin; rhodorubicin; streptonigrin; streptozocin; tanespimycin; tubercidine; ubenimex; dinostatin; dinostatin stimaramer; and zolubicin.

[0483] In one embodiment, additional anticancer agents (may include more than one) are hormones and / or antihormone agents (i.e., hormone therapy). Non-limiting examples of hormones and antihormone agents include antiandrogens, e.g., abiraterone, apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, goserelin, leuprolide, and nilutamide; and antiestrogenic drugs, e.g., 4-hydroxytamoxifen, aromatase inhibitor 4(5)-imidazole, EM-800, phosfestrol, fulvestrant, keoxyfen, and LY Examples include 117018, onapristone, raloxifene, tamoxifen, toremifene and trioxyfen; anti-adrenergics, e.g., aminoglutethimide, dexamethasone, mitotane and trilostane; androgens, e.g., carsterone, dromostanolone propionate, epithiostanol, mepitiostane and testolactone; abalelix; anastrozole; cetrorelix; deslorerin; exemestane; fadrozol; finasteride; formestan; histrelin (RL 0903); human chorionic gonadotropin; lanreotide; LDI 200 (Milkhaus); letrozole; leuprorelin; mifepristone; nafarelin; napoxidine; osaterone; prednisone; thyrotropin alpha; and triptorelin.

[0484] In one embodiment, the additional anticancer agent(s) is an immunotherapy agent (i.e., immunotherapy). Non-limiting examples of immunotherapy agents include biological response modifiers, cytokine inhibitors, tumor vaccines, monoclonal antibodies, immune checkpoint inhibitors, colony-stimulating factors, and immunomodulators.

[0485] Non-exclusive examples of biological response modifiers, including cytokine inhibitors (cytokines) such as interferons and interleukins, include interferon alpha / interferon alpha, e.g., interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-nl, interferon alpha-n3, interferon alpha-1, pegylated interferon alpha-2a, pegylated interferon alpha-2b, and leukocyte alpha interferon; interferon beta, e.g., interferon beta-1a and interferon beta-1b; interferon gamma, e.g., natural interferon gamma-1a and interferon gamma-1b; aldesleukin; interleukin-1 beta; interleukin-2; oprelbequin; sonelmin; tasonelmin; and billysine.

[0486] Non-exclusive examples of tumor vaccines include APC 8015, AVICINE, bladder cancer vaccine, cancer vaccine (Biomira), gastrin-17 immunogen, Maruyama vaccine, melanoma lysate vaccine, melanoma tumor lysis product vaccine (New York Medical College), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), TICE® BCG (Bacillus Calmette-Guerin), and viral melanoma cell lysate vaccine (Royal Newcastle Hospital).

[0487] Non-exclusive examples of monoclonal antibodies include avagovomab, adecatumumab, aflibercept, alemtuzumab, blinatumomab, brentuximab vedotin, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), daclizumab, daratumumab, denosumab, edrecolomab, gemtuzumab zogamicin, HER-2 and Fc MAb (Medarex), ibritumomab tiuxetan, idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), ipilimumab, lintuzumab, LYM-1-iodine-131 MAb (Techni clone), mitumomab, moxetumomab, ofatumumab, and pleomorphic epithelial mucin-yttrium 90 Examples include MAb (Antisoma), ranibizumab, rituximab, and trastuzumab.

[0488] Non-exclusive examples of immune checkpoint inhibitors include anti-PD-1 agents or antibodies, e.g., cemiprimab, nivolumab, and pembrolizumab; anti-PD-L1 agents or antibodies, e.g., atezolizumab, avelumab, and durvalumab; anti-CTLA-4 agents or antibodies, e.g., ipilimumab; anti-LAG1 agents; and anti-OX40 agents.

[0489] Non-exclusive examples of colony-stimulating factors include darbepoetin alfa, epoetin alfa, epoetin beta, filgrastim, granulocyte-macrophage colony-stimulating factor, lenograstim, religistim, myrimostim, morglamostim, naltograstim, pegfilgrastim, and salglamostim.

[0490] Further non-exclusive examples of immunotherapies include BiTE, CAR-T cells, GITR agonists, imiquimod, immunomodulatory imides (IMiD), mismatched double-stranded RNA (Ampligen), reximod, SRL 172, and thymalfacin.

[0491] In one embodiment, the additional anticancer agent(s) is a targeted therapy agent (i.e., targeted therapy). Examples of targeted therapy agents include monoclonal antibodies and small molecule drugs. Non-limiting examples of targeted therapy agents include signaling inhibitors, growth factor inhibitors, tyrosine kinase inhibitors, EGFR inhibitors, histone deacetylase (HDAC) inhibitors, proteasome inhibitors, cell cycle inhibitors, angiogenesis inhibitors, matrix-metalloproteinase (MMP) inhibitors, hepatocyte growth factor inhibitors, TOR inhibitors, KDR inhibitors, VEGF inhibitors, fibroblast growth factor (FGF) inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, HER-2 inhibitors, BRAF inhibitors, gene expression regulators, autophagy inhibitors, apoptosis inducers, antiproliferative agents, and glycolysis inhibitors.

[0492] Non-exclusive examples of signal transduction inhibitors include tyrosine kinase inhibitors, multi-kinase inhibitors, anlotinib, avapritinib, axitinib, dasatinib, dovitinib, imatinib, lenvatinib, ronidamine, nilotinib, nintedanib, pazopanib, pegvisomant, ponatinib, vandetanib, and EGFR inhibitors.

[0493] Non-limiting examples of EGFR inhibitors include small molecule antagonists of EGFR, such as afatinib, brigatinib, erlotinib, gefitinib, lapatinib, and osimertinib; and antibody-based EGFR inhibitors, including any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its natural ligand. Antibody-based EGFR inhibitors include, for example, those described in Modjtahedi, H., et al., 1993, Br.J. Cancer 67:247-253; Teramoto, T., et al., 1996, Cancer 77:639-645; Goldstein et al, 1995, Clin. Cancer Res. 1:1311-1318; Huang, SM, et al., 1999, Cancer Res. 15:59(8):1935-40; and Yang, X., et al., 1999, Cancer Res. 59:1236-1243; monoclonal antibody Mab E7.6.3 (Yang, 1999, previously mentioned); Mab Examples include antibodies or antibody fragments having binding specificity for C225 (ATCC accession number HB-8508), or specific antisense nucleotides or siRNAs; afatinib, cetuximab, matuzumab, nesitumumab, nimotuzumab, panitumumab, and saltumumab.

[0494] Non-exclusive examples of histone deacetylase (HDAC) inhibitors include bellinostat, panobinostat, romidepsin, and vorinostat.

[0495] Non-exclusive examples of proteasome inhibitors include bortezomib, carfilzomib, ixazomib, marizomib (salinosporamide a), and oprozomib.

[0496] Non-exclusive examples of cell cycle inhibitors, including CDK inhibitors, include abemaciclib, arbocidicib, palbociclib, and ribociclib.

[0497] In one embodiment, additional anticancer agents (may include, but are not limited to, matrix metalloproteinase (MMP) inhibitors; VEGF inhibitors; EGFR inhibitors; TOR inhibitors, e.g., everolimus and temsirolimus; PDGFR kinase inhibitors, e.g., clenolanib; HIF-1α inhibitors, e.g., PX478; HIF-2α inhibitors such as berzutifan and HIF-2α inhibitors described in International Publication No. 2015 / 035223; fibroblast growth factor (FGF) or FGFR inhibitors, e.g., B-FGF and RG13577; hepatocyte growth factor inhibitors; KDR inhibitors; anti-Ang1 and anti-Ang2 agents; anti-Tie2 kinase inhibitors; Tek antagonists (US Patent Application Publication No. 2003 / 01 U.S. Patent No. 62712; U.S. Patent No. 6,413,932); anti-Tweak agents (U.S. Patent No. 6,727,225); ADAM distointegrin domains that antagonistize the binding of integrins to their ligands (U.S. Patent Application Publication No. 2002 / 0042368); anti-eph receptors and / or anti-ephrin antibodies or antigen-binding regions (U.S. Patent Nos. 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; and 6,057,124); and anti-PDGF-BB antagonists, as well as anti-angiogenic agents (or angiogenesis inhibitors) comprising antibodies or antigen-binding regions that specifically bind to PDGF-BB ligands.

[0498] Non-limiting examples of matrix metalloproteinase (MMP) inhibitors include MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, prinomast, RO32-3555, and RS13-0830. Examples of useful matrix metalloproteinase inhibitors include, for example, International Publication No. 96 / 33172, International Publication No. 96 / 27583, European Patent No. 1004578, International Publication No. 98 / 07697, International Publication No. 98 / 03516, International Publication No. 98 / 34918, International Publication No. 98 / 34915, International Publication No. 98 / 33768, International Publication No. 98 / 30566, European Patent No. 0606046, and European Patent No. 0931788. These are described in International Publication Nos. 90 / 05719, 99 / 52910, 99 / 52889, 99 / 29667, 1999 / 007675, European Patent No. 1786785, European Patent No. 1181017, U.S. Patent Application Publication No. 2009 / 0012085, U.S. Patent Application Publication No. 5,863,949, U.S. Patent No. 5,861,510, and European Patent No. 0780386. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity to inhibit MMP-1. More preferably, it selectively inhibits MMP-2 and / or MMP-9 compared to other matrix metalloproteinases (i.e., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

[0499] Non-exclusive examples of VEGF and VEGFR inhibitors include bevacizumab, cedilanib, CEP7055, CP547632, KRN633, olanchinib, pazopanib, pegaptanib, pegaptanib octasodium, semaxanib, sorafenib, sunitinib, VEGF antagonists (Borean, Denmark), and VEGF-TRAP®.

[0500] Other antitumor agents (multiple may be listed) also include, but are not limited to, 2-methoxyestradiol, AE 941, alemtuzumab, alpha-D148 Mab (Amgen, USA), alpha-statin, akancortarb acetate, angiocidin, angioplasty inhibitor (SUGEN, USA), angiostatin, anti-Vn Mab (Crucell, Netherlands), atiprimod, axitinib, AZD 9935, BAY RES2690 (Bayer, Germany), BC1 (Genoa Institute of Cancer Research, Italy), beroranib, benefin (Lane Labs, USA), cabozantinib, CDP791 (Celltech Group, UK), chondroitinase AC, sirengitide, combretastatin A4 prodrug, CP 564959 (OSI, USA), CV247, CYC381 (Harvard University, USA), E7820, EHT0101, Endostatin, Enzastaurin Hydrochloride, ER-68203-00 (IVAX, USA), Fibrinogen-E Fragment, Flk-1 (ImClone Systems, USA), FLT1 Form (VEGFR1), FR-111142, GCS-100, GW2286 (GlaxoSmithKline, UK), IL-8, Ilomast, IM-862, Ilsogladine, KM-2550 (Kyowa Hakko, Japan), Lenalidomide, Lenvatinib, MAb Alpha 5 Beta 3 Integrin, Second Generation (Applied Molecular Evolution, USA and Medlmmune, USA), MAb VEGF (Xenova, UK), Marimastate, Masupin (Sosei, Japan), Metastatin, Motupolamine C, M-PGA, Ombrabrin, OXI4503, PI 88, Platelet Factor 4, PPI 2458, Ramucirumab, rBPI21 and BPI-derived anti-angiogenic agents (XOMA, USA), regorafenib, SC-236, SD-7784 (Pfizer, USA), SDX103 (University of California, San Diego, USA), SG292 (Telios, USA), SU-0879 (Pfizer, USA), TAN-1120, TBC-1635, tesevatinib, tetrathiomolybdate, thalidomide, thrombospongin 1 inhibitors, Tie-2 ligand (Rege Other anti-angiogenic agents may include neron (USA), tissue factor pathway inhibitors (EntreMed, USA), tumor necrosis factor alpha inhibitors, tanstatin, TZ93, urokinase plasminogen activator inhibitors, badimesan, vandetanib, vasostatin, batalanib, VE-cadherin-2 antagonists, xantrizole, XL784 (Exelixis, USA), ziv-aflibercept, and ZD6126.

[0501] In some embodiments, other antitumor agents are additional activators that disrupt or inhibit the RAS-RAF-ERK or PI3K-AKT-TOR signaling pathway, or PD-1 and / or PD-L1 antagonists. In some embodiments, other antitumor agents are RAF inhibitors, EGFR inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, or immunotherapies including monoclonal antibodies, immunomodulatory imides (IMiDs), anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAGl, and anti-OX40 agents, GITR agonists, CAR-T cells, and BiTE.

[0502] Non-exclusive examples of RAF inhibitors include dabrafenib, encorafenib, regorafenib, sorafenib, and vemurafenib.

[0503] Non-exclusive examples of MEK inhibitors include binimetinib, CI-1040, cobimetinib, PD318088, PD325901, PD334581, PD98059, refametinib, selumetinib, and trametinib.

[0504] Non-exclusive examples of ERK inhibitors include LY3214996, LTT462, MK-8353, SCH772984, labocertinib, urixertinib, and ERKi described in International Publication No. 2017 / 068412.

[0505] Non-exclusive examples of PI3K inhibitors include 17-hydroxywoltmannin analogs (e.g., International Publication No. 06 / 044453); AEZS-136; alpelisib; AS-252424; buparlisib; CAL263; copanlisib; CUDC-907; dactricib (International Publication No. 06 / 122806); demethoxypyridine; duvelisib; GNE-477; GSK1059615; IC87114; idelalisib; INK1117; LY294002; paromide 529; paxalisib; perifosine; PI-103; PI-103 hydrochloride; pictilisib (e.g., International Publication No. 09 / 036,082; International Publication No. 09 / 055,730); PIK Examples include 90; PWT33597; SF1126; Sonolicib; TGI 00-115; TGX-221; XL147; XL-765; Waltmannin; and ZSTK474.

[0506] Non-exclusive examples of AKT inhibitors include Akt-1-1 (inhibits Aktl) (Barnett et al. (2005) Biochem. J., 385 (Pt. 2), 399-408); Akt-1-1,2 (Barnett et al. (2005) Biochem. J. 385 (Pt. 2), 399-408); API-59 CJ-Ome (e.g., Jin et al. (2004) Br. J. Cancer 91, 1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., International Publication No. 05011700); indole-3-carbinol and its derivatives (e.g., U.S. Patent No. 6,656,963; Sarkar and Li (2004) J Nutr. 134 (12) Suppl), 3493S-3498S); Perifosin, Dasmahapatra et al. (2004) Clin. Cancer Res. 10(15), 5242-52, 2004); Phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis (2004) Expert. Opin. Investig. Drugs 13, 787-97); Tricyridine (Yang et al. (2004) Cancer Examples include imidazooxazone compounds containing trans-3-amino-1-methyl-3-[4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl]-cyclobutanol hydrochloride (International Publication No. 2012 / 137870); afalestib; capivacertib; MK2206; and patasertib.

[0507] Non-limiting examples of TOR inhibitors include defololimus; ATP-competitive TORC1 / TORC2 inhibitors including PI-103, PP242, PP30, and Torin1; TOR inhibitors in temsirolimus, everolimus, FKBP12 enhancers, rapamycin, and their derivatives, including International Publication No. 9409010; rapalogs such as those disclosed in International Publication No. 98 / 02441 and International Publication No. 01 / 14387, e.g., AP23573, AP23464, or AP23841; 40-(2-hydroxyethyl)rapamycin, 40-[3-hydroxy(hydroxymethyl)methylpropanoate]rapamycin; 40-epi-(tetrazolyl)-rapamycin (also known as ABT578); 32-deoxorapamycin; 16-pentinyloxy-32(S)-dihydro Panicin and other derivatives disclosed in International Publication No. 05 / 005434; U.S. Patent No. 5,258,389, International Publication No. 94 / 090101, International Publication No. 92 / 05179, U.S. Patent No. 5,118,677, U.S. Patent No. 5,118,678, U.S. Patent No. 5,100,883, U.S. Patent No. 5,151,413, U.S. Patent No. 5,120,842, International Publication No. 93 / 111130 Examples include derivatives disclosed in International Publication Nos. 94 / 02136, 94 / 02485, 95 / 14023, 94 / 02136, 95 / 16691, 96 / 41807, 96 / 41807 and U.S. Patent No. 5,256,790; as well as phosphorus-containing rapamycin derivatives (e.g., International Publication No. 05 / 016252).

[0508] Non-exclusive examples of MCL-1 inhibitors include AMG-176, MIK665, and S63845.

[0509] Non-exclusive examples of SHP2 inhibitors include those described in International Publication No. 2019 / 167000 and International Publication No. 2020 / 022323.

[0510] Further non-limiting examples of additional anticancer agents suitable for combination therapy include 2-ethylhydrazide, 2,2',2''-trichlorotriethylamine, ABVD, acegraton, acemannan, aldofosamide glycoside, alfarazine, amifostin, aminolevulinic acid, anagrelide, ANCER, ancestim, anti-CD22 immunotoxin, antitumor herbs, apadicon, algravin, arsenic trioxide, azathioprine, BAM002 (Novelos), bcl-2 (Genta), and Best Labsin. Lu, Bilicodal, Bisanthren, Bromocriptine, Brostalysin, Briostatin, Butionine sulfoximine, Kalikrin, Cell cycle nonspecific antitumor agents, Ceromoleukin, Clodronate, Clotrimazole, Cytarabine ocphosphate, DA3030 (Dong-A), Dehofamine, Denileukin difutitox, Dexrazoxane, Diadicone, Dichloroacetic acid, Dilazep, Discodermolide, Docosanol, Docercalcerol, Edelfosine, Eflornithine, EL 532 (Elan), erhomitin, erusamitrusine, enyluracil, etanidazole, exislind, ferginol, folic acid supplements such as folic acid, gacytosine, gallium nitrate, gimeracil / oteracil / tegafur combination (S-1), glycopine, histamine dihydrochloride, HIT diclofenac, HLA-B7 gene therapy (Vical), human fetal alpha-fetoprotein, ibandronate, ICE chemotherapy regimen, i Mexon, Iobenguan, IT-101 (CRLX101), Lanikidal, LC9018 (Yakult), Leflunomide, Lentinan, Lebamisol + Fluorouracil, Lovastatin, Lucanton, Masopropyl, Melalsoprole, Metoclopramide, Miltefosine, Miproxyfen, Mitoguazone, Mitozolomide, Mopidamol, Motexafingadolinium, MX6 (Galderma), Naloxone + Pentazocine, Nitracrine, Noratexed, NSC631570 Octreotide (Ukrain), Olaparib, P-30 protein, PAC-1, Palifermin, Pamidronate, Pamidronic acid, Pentosan sodium polysulfate, Fenamet, Picibanil, Pixantrone, Platinum, Podophyllic acid, Porfimer sodium, PSK (Polysaccharide-K), Rabbit anti-thymocyte polyclonal antibody, Rasbrifidimen, Retinoic acid, Rhenium Re186 ethyl Examples include doronate, romultide, samarium (153Sm) lexidronam, schizophyllan, sodium phenylacetate, sparfosic acid, spirogermanium, strontium-89 chloride, suramin, swinesonin, talaporfin, talikidal, tazarotene, tegafur-uracil, temoporfin, tenuazonic acid, tetrachlorodecaoxide, thrombopoietin, tin ethylethiopurine, tirapazamin, TLC ELL-12, tositumomab-iodine-131, trifluridine and tipiracil combination, troponin I (Harvard University, USA), urethane, valspodal, verteporfin, zoledronic acid, and zoskidar.

[0511] The present invention further provides methods for using the compounds of the present invention or pharmaceutically acceptable salts thereof, or pharmaceutical compositions provided herein, in combination with radiotherapy for the treatment of cancer. Techniques for administering radiotherapy are known in the art, and these techniques can be used in the combination therapy described herein. The dosage of the compounds of the present invention or pharmaceutically acceptable salts thereof in this combination therapy can be determined as described herein.

[0512] Radiotherapy can be administered by one or a combination of several methods, including, but not limited to, external beam therapy, internal radiotherapy, implantable radiotherapy, stereotactic radiosurgery, total body radiotherapy, radiotherapy, and permanent or transient intra-tissue near-brightness radiotherapy. As used herein, the term “near-brightness radiotherapy” refers to radiotherapy delivered by a spatially confined radioactive material inserted into the body at or near a tumor or other proliferative tissue disease site. This term is intended to include, but not limited to, exposure to radioisotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioisotopes of Lu). Suitable radioactive sources for use as cell conditioners in this disclosure include both solid and liquid sources. As a non-limiting example, the radiation source may be a radionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma rays, or other therapeutic radiation. The radioactive material may also be a fluid made from any solution of radionuclide(s), such as a solution of I-125 or I-131, or a radioactive fluid can be produced using a suitable fluid slurry containing small particles of solid radionuclides such as Au-198, Y-90. Furthermore, the radionuclide(s) may be embodied in a gel or radioactive microspheres.

[0513] The present invention also provides methods for combination therapies in which other antitumor agents are known to modulate other pathways in which the compounds of the present invention or pharmaceutically acceptable salts thereof are used in combination with other components of the same pathway, or even overlapping sets of target enzymes. In one embodiment, such therapies include, but are not limited to, combinations of one or more compounds of the present invention or pharmaceutically acceptable salts thereof with chemotherapeutic agents, immunotherapeutic agents, hormonal therapy agents, therapeutic antibodies, targeted therapy agents, and radiotherapy to provide synergistic or additive therapeutic effects.

[0514] In one embodiment, the use of a compound covalently bound to GTP-conjugated KRAS G12C or a pharmaceutically acceptable salt thereof for the manufacture of an antitumor agent may be provided. In one embodiment, a compound covalently bound to GTP-conjugated KRAS G12C or a pharmaceutically acceptable salt thereof for use in the treatment of a tumor may be provided. In one embodiment, a method for treating a tumor may be provided, comprising administering a therapeutically effective amount of a compound covalently bound to GTP-conjugated KRAS G12C or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0515] In one embodiment, a method is provided for regulating the activity of a Ras protein, including a human K-Ras G12C mutant protein, comprising contacting the Ras protein with an effective amount of the compound of the present invention. Examples of regulated activity include GTPase activity, nucleotide exchange, effector protein binding, effector protein activation, guanine exchange factor (GEF) binding, GEF-mediated nucleotide exchange, phosphate release, nucleotide release, nucleotide binding, intracellular localization of Ras, e.g., K-Ras, post-translational processing of Ras, e.g., K-Ras, and post-translational modification of Ras, e.g., K-Ras, preferably intracellular K-Ras localization, post-translational processing of K-Ras, and post-translational modification of K-Ras. "Regulating" or "modulating" may mean increasing or decreasing the activity of a Ras protein, e.g., a K-Ras protein.

[0516] In some embodiments, Ras, such as the K-Ras protein, is present in living cells, such as living cells that form part of an organism.

[0517] The present invention also provides the use of the compound of the present invention or a pharmaceutically acceptable salt thereof for use in therapeutic treatment, or the use of the compound of the present invention or a pharmaceutically acceptable salt thereof in therapeutic treatment. The present invention also provides a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof for use in the treatment of tumors, or the use of a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof for the treatment of tumors. The present invention also provides a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof and other antitumor agents for use in the treatment of cancer, or the use of a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof and other antitumor agents for the treatment of tumors.

[0518] [Examples] The present invention will be described in more detail below with reference to examples and test examples. However, the present invention is not limited to these examples.

[0519] Unless otherwise specified, the reagents used in the examples are commercially available. For silica gel column chromatography and basic silica gel column chromatography, pre-packed columns from Shoko Scientific Co., Ltd. or Biotage were used. For NMR spectroscopy, an AL400 spectrometer (400 MHz; JEOL Ltd. (JEOL)) or a Mercury 400 (400 MHz; Varian) spectrometer was used. For deuterated solvents containing tetramethylsilane, tetramethylsilane was used as an internal standard. In other cases, the NMR solvent was used as an internal standard for measurement. All δ values ​​are shown in ppm. Microwave reactions were performed using a Biotage Initiator®.

[0520] The following explains the meaning of the abbreviations.

[0521] s: singlet d: doublet t: triplet q: Quartet Septet dd: Double Doublet dt: double triplet td: Triple Doublet tt: Triple Triplet ddd: Double Double Double ddt: double double triplet dtd: Double Triple Doublet tdd: Triple Double Doublet m: Multilet Broad brs: Broad Singlet tert: tertiary DMSO-d6: Deuterated Dimethyl Sulfoxide CDCl3: Deuterated chloroform CD3OD: Deuterated methanol THF: Tetrahydrofuran DMF: N,N-dimethylformamide NMP: 1-methyl-2-pyrrolidinone DMSO: Dimethyl sulfoxide WSC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HATU: (Dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridine-3-yloxy)methaniminium hexafluorophosphate Boc:tert-butoxycarbonyl group Preparation of compounds [Example 1] 3-Cyano-N-(3-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]diimidazole-5-yl)phenyl)-4-((E)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide)benzamide Step 1: Methylamine (2M THF solution, 36 mL) was added to a solution of 2-fluoro-1-nitro-4-(trifluoromethyl)benzene (5.00 g) in THF (60 mL). After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure to obtain crude N-methyl-2-nitro-5-(trifluoromethyl)aniline.

[0522] Step 2: Crude N-methyl-2-nitro-5-(trifluoromethyl)aniline and N-bromosuccinimide (5.11 g) obtained in Step 1 were added to acetic acid (80 ml). The mixture was refluxed for 1 hour, then cooled to room temperature and poured into water. The resulting solid was filtered to obtain crude 4-bromo-N-methyl-2-nitro-5-(trifluoromethyl)aniline (6.63 g).

[0523] Step 3: The suspension of crude 4-bromo-N-methyl-2-nitro-5-(trifluoromethyl)aniline (6.63 g) and iron powder (6.19 g) obtained in Step 2 in 2M aqueous ammonium chloride (55 mL), THF (110 mL), and methanol (110 mL) was stirred at 70°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting mixture was diluted with water and ethyl acetate, after which the insoluble matter was filtered off. The organic layer was separated and washed with saturated sodium chloride solution, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (hexane:ethyl acetate) to obtain 4-bromo-N1-methyl-5-(trifluoromethyl)benzene-1,2-diamine (5.25 g).

[0524] Step 4: Concentrated hydrochloric acid (300 μL) was added to a suspension of 4-bromo-N1-methyl-5-(trifluoromethyl)benzene-1,2-diamine (5.25 g) obtained in Step 3 in 1,1,1-triethoxypropane (30 mL), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (hexane:ethyl acetate) to obtain 5-bromo-2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole (5.22 g).

[0525] Step 5: The suspension of 5-bromo-2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole (1.70 g), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.80 g), dichlorobis(triphenylphosphine)palladium (190 mg), and 1M aqueous sodium carbonate (14 mL) in 1,2-dimethoxyethane (28 mL) was refluxed for 6 hours. Ethyl acetate and water were added to the reaction mixture to separate the organic layer, and the organic layer was washed with saturated sodium chloride solution. The washed organic layer was dried over sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform:methanol) to obtain 3-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)aniline (1.77 g).

[0526] Step 6: To a solution of 3-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)aniline (1.77 g) obtained in Step 5 in DMF (55 mL), 1-hydroxybenzotriazole monohydrate (1.12 g), 4-amino-3-cyanobenzoic acid (1.35 g), triethylamine (1.2 mL), and WSC hydrochloride (1.60 g) were added. The reaction was carried out overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, after which the organic layer was washed with saturated sodium chloride solution. The washed layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (chloroform:methanol) to obtain 4-amino-3-cyano-N-(3-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)phenyl)benzamide (1.91 g).

[0527] Step 7: To a solution of 4-amino-3-cyano-N-(3-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)phenyl)benzamide (1.91 g) obtained in Step 6 in DMF (21 mL), (E)-4-chlorobuta-2-enoic acid (745 mg), cyclic trimer of 1-propanephosphonic anhydride (1.7 M THF solution, 4.8 mL), and triethylamine (860 μL) were added. The mixture was reacted at room temperature for 2 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate, followed by washing of the organic layer with saturated sodium chloride solution. The washed layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (chloroform:methanol) to obtain (E)-4-(4-chlorobuta-2-enamide)-3-cyano-N-(3-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)phenyl)benzamide (932 mg).

[0528] Step 8: (1r,4r)-4-methoxycyclohexane-1-amine hydrochloride (28.5 mg), potassium carbonate (47.6 mg), and potassium iodide (34.3 mg) were added to the solution of (E)-4-(4-chlorobuta-2-enamide)-3-cyano-N-(3-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)phenyl)benzamide (39.0 mg) obtained in Step 7 in DMF (690 μL). The mixture was reacted at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, after which the organic layer was washed with saturated sodium chloride solution. The washed layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative reverse-phase HPLC (water:acetonitrile (0.1% formic acid)). Saturated sodium bicarbonate solution was added to the purified fraction containing the title compound, and then extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (8.50 mg).

[0529] [Example 2] (E)-4-(4-(tert-butyl(methyl)amino)buta-2-enamide)-3-cyano-N-(3-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)phenyl)benzamide To a solution of (E)-4-(4-chlorobuta-2-enamide)-3-cyano-N-(3-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)phenyl)benzamide (150 mg) obtained in Example 1 (Step 7) in DMF (1.0 mL), N,2-dimethylpropan-2-amine (660 μL), potassium carbonate (220 mg), and potassium iodide (132 mg) were added. The mixture was reacted at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, after which the organic layer was washed with saturated sodium chloride solution. The washed layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (chloroform:methanol) and diluted with diethyl ether. The title compound (70.9 mg) was obtained by filtration of the resulting solid.

[0530] [Example 3] 3-Cyano-4-((E)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide)-N-(6-(7-methyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-6-yl)pyridine-2-yl)benzamide Step 1: Bis(pinacolato)diborone (1.52 g) was added to a suspension in DMSO (10 mL) of 6-bromo-7-methyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (1.00 g), potassium acetate (1.17 g), and a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (325 mg), followed by stirring at 100°C for 3 hours. Then, XphosPdG2 (313 mg) and bis(pinacolato)diborone (1.52 g) were added, and the mixture was stirred at 100°C for 2 hours. Ethyl acetate and water were added, followed by filtering off the insoluble matter. The organic layer was separated, washed with saturated sodium chloride solution, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate:ethanol) to obtain 7-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (639 mg).

[0531] Step 2: A suspension of 4-amino-3-cyanobenzoic acid (500 mg) and thionyl chloride (2.5 mL) was heated at 100°C for 15 minutes. The excess thionyl chloride was then evaporated under reduced pressure. Toluene was added again to the resulting residue to dissolve it, and the solvent was then evaporated under reduced pressure. The residue was dissolved in dichloromethane (5.0 mL), and 6-bromopyridine-2-amine (800 mg) and triethylamine (1.3 mL) were added, followed by stirring at 50°C for 1 hour. The mixture was cooled to room temperature and then purified by column chromatography (hexane:ethyl acetate) to obtain 4-amino-N-(6-bromopyridine-2-yl)-3-cyanobenzamide (212 mg).

[0532] Step 3: To a suspension of 7-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (151 mg) obtained in Step 1, 4-amino-N-(6-bromopyridine-2-yl)-3-cyanobenzamide (107 mg) obtained in Step 2, and XphosPdG2 (26.6 mg) in 1,4-dioxane (1.5 mL), 340 μL of 2 M sodium carbonate aqueous solution was added, followed by stirring at 100°C for 2 hours. Then, XphosPdG2 (26.6 mg) was added, and the mixture was stirred at 105°C for 3 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (chloroform:ethanol) to obtain 4-amino-3-cyano-N-(6-(7-methyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-6-yl)pyridine-2-yl)benzamide (127 mg).

[0533] Step 4: To a solution of 4-amino-3-cyano-N-(6-(7-methyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-6-yl)pyridine-2-yl)benzamide (127 mg), (E)-4-chlorobuta-2-enoic acid (56.4 mg), and 1-propanephosphonic anhydride cyclic trimer (48% in DMF, 390 μL) obtained in Step 3, triethylamine (170 μL) was added in DMF (1.5 mL), and the mixture was then stirred at room temperature for 1.5 hours. Ethyl acetate and aqueous sodium bicarbonate solution were added to the reaction mixture. The organic layer was separated, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate:ethanol) to obtain (E)-4-(4-chlorobuta-2-enamide)-3-cyano-N-(6-(7-methyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-6-yl)pyridine-2-yl)benzamide (106 mg).

[0534] Step 5: Potassium carbonate (56.8 mg) was added to the suspension in DMF (400 μL) of (E)-4-(4-chlorobuta-2-enamide)-3-cyano-N-(6-(7-methyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-6-yl)pyridine-2-yl)benzamide (30.0 mg), (1r,4r)-4-methoxycyclohexane-1-amine hydrochloride (24.3 mg), and potassium iodide (29.2 mg) obtained in Step 4, and the mixture was stirred at room temperature for 2 hours. Insoluble matter from the reaction mixture was filtered off, and the filtrate was purified by preparative reverse-phase HPLC (water:acetonitrile (0.1% formic acid)). Saturated sodium bicarbonate solution was added to the purified fraction containing the title compound, and the mixture was subsequently extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (9.2 mg).

[0535] [Example 4] (E)-N-(2-cyano-4-(8-(1,6-dimethyl-1H-benzo[d]imidazole-5-yl)indridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide Step 1: 37.6 g of dibromocopper was added to a solution of 25.0 g of 5-acetyl-2-fluorobenzonitrile in 380 mL of ethyl acetate, and the mixture was stirred at 70°C for 6 hours. Another 37.6 g of dibromocopper was added to the reaction mixture, and the mixture was stirred at 70°C for 2 hours. The reaction mixture was filtered through Celite and then washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and concentrated, and the resulting residue was added to diisopropyl ether and stirred at ambient temperature for 30 minutes. 5-(2-bromoacetyl)-2-fluorobenzonitrile (32.0 g) was obtained by filtering off the precipitated solid.

[0536] Step 2: To the solution of 5-(2-bromoacetyl)-2-fluorobenzonitrile (32.0 g) obtained in Step 1 in THF (130 mL), 3-bromo-2-methylpyridine (30 mL) was added and the mixture was stirred at 85°C for 4 days. Heptane was added to the reaction mixture at ambient temperature and the mixture was stirred for 30 minutes. The precipitated solid was filtered to obtain 3-bromo-1-(2-(3-cyano-4-fluorophenyl)-2-oxoethyl)-2-methylpyridine-1-ium bromide (55.0 g).

[0537] Step 3: The mixture of DMF (41 mL) and dimethyl sulfate (50 mL) was stirred at 80°C for 3 hours. After the mixture cooled to room temperature, it was added at room temperature to the solution of 3-bromo-1-(2-(3-cyano-4-fluorophenyl)-2-oxoethyl)-2-methylpyridine-1-ium bromide (14.6 g) obtained in Step 2 in DMF (44 mL). After stirring at room temperature for 30 minutes, N,N-diisopropylethylamine (61 mL) was added to the reaction mixture, followed by stirring at room temperature for 1 hour. Water (230 mL) was added to the reaction mixture, followed by collection of the precipitated solid. The obtained solid was vacuum-dried overnight, ethyl acetate was added to the solid, followed by stirring at room temperature for 30 minutes. After adding heptane to the solution, the precipitated solid was filtered to obtain 5-(8-bromoindridin-3-carbonyl)-2-fluorobenzonitrile (9.69 g).

[0538] Step 4: Add 70 mL of 28% aqueous ammonia to the solution of 5-(8-bromoindridin-3-carbonyl)-2-fluorobenzonitrile (9.69 g) obtained in Step 3 in 1,4-dioxane (60 mL) and 1,2-dimethoxyethane (10 mL), and stir overnight at 115°C. After cooling to room temperature, water (200 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 hours, and the precipitated solid was collected. The solid was vacuum-dried overnight at 60°C, and ethyl acetate was added to the solid. After stirring for 30 minutes, heptane was added to the suspension. The mixture was stirred at room temperature for 30 minutes, and the precipitated solid was collected to obtain 2-amino-5-(8-bromoindridin-3-carbonyl)benzonitrile (8.06 g).

[0539] Step 5: Methylamine (approximately 7% in THF, 53 mL) was added to 1-bromo-4-fluoro-2-methyl-5-nitrobenzene (5.00 g), and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and ethyl acetate and water were added to the residue. The organic layer was separated, washed with saturated sodium chloride solution, and then dried over sodium sulfate. Crude 4-bromo-N,5-dimethyl-2-nitroaniline (5.45 g) was obtained by evaporating the solvent under reduced pressure.

[0540] Step 6: The suspension of crude 4-bromo-N,5-dimethyl-2-nitroaniline (5.45 g), iron powder (5.97 g), and ammonium chloride (5.71 g) obtained in Step 5 in methanol (100 mL), THF (100 mL), and water (50 mL) was stirred at 85°C for 2 hours. Insoluble matter was filtered off, and the solvent was subsequently evaporated under reduced pressure. The residue was diluted with ethyl acetate, washed with water and saturated sodium chloride solution, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the crude 4-bromo-N 1 ,5-dimethylbenzene-1,2-diamine (4.80 g) was obtained.

[0541] Step 7: Crude 4-bromo-N obtained in Step 6 14.80 g of 5-dimethylbenzene-1,2-diamine was suspended in 50 mL of triethyl orthoformate, to which concentrated hydrochloric acid (250 μL) was added and the mixture was stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, and the precipitate was collected and washed with a hexane-ethyl acetate (3:1) mixed solvent to obtain 5-bromo-1,6-dimethyl-1H-benzo[d]imidazole (2.56 g).

[0542] Step 8: A suspension of 5-bromo-1,6-dimethyl-1H-benzo[d]imidazole (2.00 g) obtained in Step 7, a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (726 mg), bis(pinacolato)diborone (3.38 g), and potassium acetate (2.62 g) in DMSO (30 mL) was heated at 100 °C for 3 hours. After the reaction mixture was cooled to room temperature, ethyl acetate, water, and Celite were added, and the mixture was stirred for 10 minutes. Insoluble material was filtered through a Celite pad, the organic layer was separated, washed with saturated sodium chloride solution, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate:ethanol) to obtain 1,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (1.16 g).

[0543] Step 9: The suspension of 2-amino-5-(8-bromoindridin-3-carbonyl)benzonitrile (80.0 mg) obtained in Step 4, 1,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (75.0 mg) obtained in Step 8, dichlorobis(triphenylphosphine)palladium (18.0 mg), and 2M aqueous sodium carbonate solution (240 μL) in 1,4-dioxane (2.0 mL) and DMF (2.0 mL) was stirred at 110°C for 2 hours. Ethyl acetate and water were added to the reaction mixture to separate the organic layer, and the organic layer was washed with saturated sodium chloride solution. The washed organic layer was dried over sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate:methanol) to obtain 2-amino-5-(8-(1,6-dimethyl-1H-benzo[d]imidazole-5-yl)indridine-3-carbonyl]benzonitrile (83.0 mg).

[0544] Step 10: The procedure of Example 1 (Steps 7 and 8) was carried out, except that 2-amino-5-(8-(1,6-dimethyl-1H-benzo[d]imidazole-5-yl)indolidine-3-carbonyl)benzonitrile (80.0 mg) obtained in Step 9 was used instead of 4-amino-3-cyano-N-(3-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)phenyl)benzamide obtained in Step 9, to obtain the title compound (11.0 mg).

[0545] [Example 5] (E)-4-(tert-butylamino)-N-(2-cyano-4-(8-(1,6-dimethyl-1H-benzo[d]imidazole-5-yl)indridine-3-carbonyl)phenyl)buta-2-enamide Step 1: To a solution of 2-amino-5-(8-(1,6-dimethyl-1H-benzo[d]imidazole-5-yl)indolidine-3-carbonyl]benzonitrile (104 mg) obtained in Example 4 (Step 9) in DMF (2.0 mL), (E)-4-chlorobuta-2-enoic acid (54.2 mg) and 1-propanephosphonic anhydride cyclic trimer (1.7 M) were added. THF solution (350 μL) and triethylamine (140 μL) were added. The mixture was reacted at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, after which the organic layer was washed with saturated sodium chloride solution. The washed layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate:methanol) to obtain (E)-4-chloro-N-(2-cyano-4-(8-(1,6-dimethyl-1H-benzo[d]imidazole-5-yl)indolidine-3-carbonyl)phenyl)buta-2-enamide (110 mg).

[0546] Step 2: 2-methylpropan-2-amine (36 μL) and potassium iodide (35.0 mg) were added to the solution of (E)-4-chloro-N-(2-cyano-4-(8-(1,6-dimethyl-1H-benzo[d]imidazole-5-yl)indolidine-3-carbonyl)phenyl)buta-2-enamide (38.0 mg) obtained in Step 1 in DMF (1.0 mL). The reaction was carried out overnight at room temperature. Water was added to the reaction mixture, and extraction was performed with ethyl acetate, followed by washing of the organic layer with saturated sodium chloride solution. The washed layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative reverse-phase HPLC (water:acetonitrile (0.1% formic acid)). Saturated sodium bicarbonate solution was added to the purified fraction containing the title compound, followed by extraction with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (20.1 mg).

[0547] [Example 6] (E)-N-(2-cyano-4-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)indridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide Step 1: A suspension of 4-bromo-N1-methyl-5-(trifluoromethyl)benzene-1,2-diamine (1.00 g) obtained in Example 1 (Step 3) in triethyl orthoformate (5.0 mL) was added to concentrated hydrochloric acid (40 μL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 5 M aqueous sodium hydroxide solution. Water was added to the mixture, and extraction was performed with ethyl acetate, after which the organic layer was washed with saturated sodium chloride solution. The washed layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was diluted with ethyl acetate and heptane. The resulting solid was filtered to obtain 5-bromo-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole (850 mg).

[0548] Step 2: The suspension of 5-bromo-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole (597 mg), potassium acetate (557 mg), bis(pinacolato)diborone (888 mg), and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride dichloromethane adduct (189 mg) obtained in Step 1 was stirred in DMSO (7.0 mL) for 17 hours at 105°C. Ethyl acetate and water were added to the reaction mixture to separate the organic layer, and the organic layer was washed with saturated sodium chloride solution. After drying the washed organic layer over sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (hexane:ethyl acetate) to obtain 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (565 mg).

[0549] Step 3: The suspension of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (80.0 mg) obtained in Step 2, 2-amino-5-(8-bromoindridinyl-3-carbonyl)benzonitrile (49.0 mg) obtained in Example 4 (Step 4), XPhos Pd G3 (8.0 mg), and 200 μL of 2M aqueous sodium carbonate in 1,4-dioxane (2.0 mL) was refluxed for 18 hours. Ethyl acetate and water were added to the reaction mixture to separate the organic layer, and the organic layer was washed with saturated sodium chloride solution. The washed organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate:methanol) to obtain 2-amino-5-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)indridine-3-carbonyl)benzonitrile (50.7 mg).

[0550] Step 4: The procedure of Example 1 (Steps 7 and 8) was carried out, except that 2-amino-5-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)indolidine-3-carbonyl)benzonitrile (50.7 mg) obtained in Step 3 was used instead of 4-amino-3-cyano-N-(3-(2-ethyl-, to obtain the title compound (13.7 mg).

[0551] [Example 7] (E)-N-(2-cyano-4-(8-(1,2-dimethyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)indridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide Step 1: Concentrated hydrochloric acid (610 μL) was added to a suspension of 4-bromo-N1-methyl-5-(trifluoromethyl)benzene-1,2-diamine (19.8 g) obtained in Example 1 (Step 3) in 1,1,1-trimethoxyethane (130 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 5 M aqueous sodium hydroxide solution. Water was added to the mixture, and the mixture was extracted with ethyl acetate, after which the organic layer was washed with saturated sodium chloride solution. The washed layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (hexane:ethyl acetate) to obtain 5-bromo-1,2-dimethyl-6-(trifluoromethyl)-1H-benzo[d]imidazole (19.3 g).

[0552] Step 2: The suspension of 5-bromo-1,2-dimethyl-6-(trifluoromethyl)-1H-benzo[d]imidazole (12.6 g), potassium acetate (11.0 g), bis(pinacolato)diborone (17.5 g), and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride dichloromethane adduct (3.51 g) obtained in Step 1 was stirred in DMSO (190 mL) for 12 hours at 105 °C. Ethyl acetate and water were added to the reaction mixture, and the resulting mixture was filtered through Celite. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated sodium chloride solution. The washed organic layer was dried over sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was then purified by column chromatography (hexane:ethyl acetate) to obtain 1,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (6.61 g).

[0553] Step 3: The procedure of Example 6 (Steps 3 and 4) was carried out, except that 1,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (167 mg) obtained in Step 2 was used instead of 1-methyl, to obtain the title compound (22.0 mg).

[0554] [Example 8] (E)-N-(2-cyano-4-(7-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)-1H-indole-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide Step 1: Thionyl chloride (20 mL) was added to 4-amino-3-cyanobenzoic acid (2.00 g), and the mixture was stirred at 110°C for 90 minutes. The solvent was evaporated under reduced pressure, and toluene (20 mL) was added to the resulting residue. Crude 4-amino-3-cyanobenzoyl chloride was obtained by evaporating the solvent under reduced pressure.

[0555] Step 2: To the solution of 4-amino-3-cyanobenzoyl chloride obtained in Step 1 in dichloromethane (40 mL), aluminum chloride (3.29 g) was added at 0°C and the mixture was stirred at 0°C for 30 minutes. 7-bromoindole (1.93 g) was added to the reaction mixture and the mixture was subsequently stirred at 0°C for 2 hours. Ice water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform:ethanol) to obtain 2-amino-5-(7-bromo-1H-indole-3-carbonyl)benzonitrile (570 mg).

[0556] Step 3: To a solution of 2-amino-5-(7-bromo-1H-indole-3-carbonyl)benzonitrile (80.0 mg) obtained in Step 2 in 1,4-dioxane (2.0 mL), 470 μL of 2 M aqueous sodium carbonate, 13.9 mg of XPhosPdG3, and 130 mg of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (130 mg) obtained in Example 6 (Step 2) were added, and the mixture was stirred overnight at 100°C. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (chloroform:ethanol) to obtain 2-amino-5-(7-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)-1H-indole-3-carbonyl)benzonitrile (85.0 mg).

[0557] Step 4: The procedure of Example 1 (Steps 7 and 8) was carried out, except that 2-amino-5-(7-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)-1H-indole-3-carbonyl)benzonitrile (85.0 mg) obtained in Step 3 was used instead of 4-amino-3-cyano-N-(3-(2-ethyl-phenyl)benzamide obtained in Example 1 (Step 7), to obtain the title compound (42.0 mg).

[0558] [Example 9] (E)-N-(2-cyano-4-(8-(1,6-dimethyl-1H-benzo[d]imidazole-5-yl)imidazo[1,2a]pyridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide Step 1: 3-bromopyridine-2-amine (220 mg) was dissolved in 1,1-di-tert-butoxy-N,N-dimethylmethaneamine (800 μL). After stirring at 50°C for 30 minutes, the reaction mixture was concentrated under reduced pressure to obtain (E)-N'-(3-bromopyridine-2-yl)-N,N-dimethylformimamide (290 mg).

[0559] Step 2: 5-acetyl-2-aminobenzonitrile (523 mg) and copper(II) bromide (1.00 g) were added to ethyl acetate (20 ml). The mixture was refluxed for 2 hours, then an additional copper(II) bromide (500 mg) was added, and the mixture was refluxed for another 2 hours. The mixture was cooled to room temperature and filtered through a Celite pad. The resulting filtrate was washed with aqueous sodium bicarbonate and saturated sodium chloride solution, and dried over sodium sulfate. Crude 2-amino-5-(2-bromoacetyl)benzonitrile (360 mg) was obtained by evaporating the solution under reduced pressure.

[0560] Step 3: The (E)-N'-(3-bromopyridine-2-yl)-N,N-dimethylformimidoamide (176 mg) obtained in Step 1 and the crude 2-amino-5-(2-bromoacetyl)benzonitrile (176 mg) obtained in Step 2 were added to ethanol (5.0 ml), and the resulting mixture was refluxed for 5 hours. After cooling to room temperature, the resulting solid was filtered to obtain 2-amino-5-(8-bromoimidazo[1,2-a]pyridine-3-carbonyl)benzonitrile (107 mg).

[0561] Step 4: A mixture of 1,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (76.0 mg) obtained in Example 4 (Step 8), 2-amino-5-(8-bromoimidazo[1,2-a]pyridine-3-carbonyl)benzonitrile (126 mg) obtained in Step 3, dichlorobis(triphenylphosphine)palladium (17.0 mg), sodium carbonate (2.0 M in water, 280 μL), and 1,4-dioxane (3.0 ml) was heated at 110°C for 2 hours. The mixture was diluted with water, the resulting solid was filtered, rinsed with water, and dried under reduced pressure to obtain 2-amino-5-(8-(1,6-dimethyl-1H-benzo[d]imidazole-5-yl)imidazo[1,2-a]pyridine-3-carbonyl)benzonitrile (136 mg).

[0562] Step 5: The procedure of Example 1 (Steps 7 and 8) was carried out, except that 2-amino-5-(8-(1,6-dimethyl-1H-benzo[d]imidazole-5-yl)imidazole[1,2-a]pyridine-3-carbonyl)benzonitrile (80.0 mg) obtained in Step 4 was used instead of 4-amino-3-cyano-N-(3-(2-ethyl-1-methyl-6-(trifluoromethyl)benzonitrile (1,2-a)pyridine-3-carbonyl)benzonitrile (80.0 mg) obtained in Step 4 was used instead of 4-amino-3-cyano-N-(3-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)phenyl)benzamide (80.0 mg) obtained in Example 1 (Step 7), to obtain the title compound (18.0 mg).

[0563] [Example 10] (E)-N-(2-cyano-4-(4-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)indoline-1-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)buta-2-enamide Step 1: The suspension of 5-bromo-2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole (1.00 g), potassium acetate (959 mg), bis(pinacolato)diborone (1.24 g), and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride dichloromethane adduct (266 mg) obtained in Example 1 (Step 4) was stirred in DMSO (15 mL) for 6 hours at 100 °C. Ethyl acetate and water were added to the reaction mixture to separate the organic layer, and the organic layer was washed with saturated sodium chloride solution. The washed organic layer was dried over sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was then purified by column chromatography (hexane:ethyl acetate) to obtain 2-ethyl-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (942 mg).

[0564] Step 2: A solution of 1-hydroxybenzotriazole monohydrate (804 mg), 4-amino-3-cyanobenzoic acid (851 mg), N,N-diisopropylethylamine (1.4 mL), and WSC hydrochloride (1.00 g) in DMF (4.0 mL) was stirred at room temperature for 30 minutes. A solution of 4-bromoindoline (829 mg) in DMF (4.0 mL) was added, and the resulting mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the resulting solid was filtered to obtain 2-amino-5-(4-bromoindoline-1-carbonyl)benzonitrile (1.43 g).

[0565] Step 3: The suspension of 2-ethyl-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (942 mg) obtained in Step 1, 2-amino-5-(4-bromoindoline-1-carbonyl)benzonitrile (445 mg) obtained in Step 2, dichlorobis(triphenylphosphine)palladium (91.2 mg), and 2M aqueous sodium carbonate solution (2.0 mL) in 1,4-dioxane (10 mL) was refluxed for 3 hours. Ethyl acetate and water were added to the reaction mixture to separate the organic layer, and the organic layer was washed with saturated sodium chloride solution. The washed organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was diluted with ethyl acetate and diethyl ether. By filtering the obtained solid, 2-amino-5-(4-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)indoline-1-carbonyl)benzonitrile (587 mg) was obtained.

[0566] Step 4: The procedure of Example 1 (Step 7) was carried out, except that 2-amino-5-(4-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)indoline-1-carbonyl)benzonitrile (350 mg) obtained in Step 3 was used instead of 4-amino-3-cyano-N-(3-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)indoline-1-carbonyl)benzonitrile (350 mg) obtained in Step 3 was used instead of 4-amino-3-cyano-N-(3-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)indoline-1-carbonyl)phenyl)buta-2-enamide (332 mg).

[0567] Step 5: The procedure of Example 1 (Step 8) was carried out, except that (E)-4-(4-chlorobuta-2-enamide)-3-cyano-N-(3-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)phenyl)benzamide obtained in Step 4 was used instead of (E)-4-chloro-N-(2-cyano-4-(4-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)indoline-1-carbonyl)phenyl)buta-2-enamide (20.0 mg) obtained in Step 4, to obtain the title compound (9.95 mg).

[0568] [Example 11] (E)-N-(6'-chloro-2',3'-dimethoxy-[1,1'-biphenyl]-3-yl)-3-cyano-4-(4-((1-(methylsulfonyl)piperidine-4-yl)amino)buta-2-enamide)benzamide Step 1: 1.89 g of 1-hydroxybenzotriazole monohydrate, 1.00 g of 4-amino-3-cyanobenzoic acid, 1.7 mL of triethylamine, and 2.36 g of WSC hydrochloride were added to a solution of 2.03 g of 3-iodoaniline in 30 mL of DMF. The reaction was carried out overnight at room temperature. Water was added to the reaction mixture, and the resulting solid was filtered to obtain 2.19 g of 4-amino-3-cyano-N-(3-iodophenyl)benzamide.

[0569] Step 2: The suspension of 4-amino-3-cyano-N-(3-iodophenyl)benzamide (300 mg), (6-chloro-2,3-dimethoxyphenyl)boronic acid (268 mg), tetrakis(triphenylphosphine)palladium (47.7 mg), and 1M aqueous sodium carbonate (4.1 mL) obtained in Step 1 in 1,2-dimethoxyethane (4.1 mL) was refluxed for 2 hours. Ethyl acetate and water were added to the reaction mixture to separate the organic layer, and the organic layer was washed with saturated sodium chloride solution. The washed organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain crude 4-amino-N-(6'-chloro-2',3'-dimethoxy-[1,1'-biphenyl]-3-yl)-3-cyanobenzamide (340 mg).

[0570] Step 3: To a solution of crude 4-amino-N-(6'-chloro-2',3'-dimethoxy-[1,1'-biphenyl]-3-yl)-3-cyanobenzamide (340 mg) obtained in Step 2 in DMF (4.2 mL), (E)-4-chlorobuta-2-enoic acid (151 mg), cyclic trimer of 1-propanephosphonic anhydride (1.7 M THF solution, 980 μL), and N,N-diisopropylethylamine (580 μL) were added. The mixture was reacted at room temperature for 2 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate, after which the organic layer was washed with saturated sodium chloride solution. The washed layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (hexane:ethyl acetate) to obtain (E)-N-(6'-chloro-2',3'-dimethoxy-[1,1'-biphenyl]-3-yl)-4-(4-chlorobuta-2-enamide)-3-cyanobenzamide (180 mg).

[0571] Step 4: To a solution of (E)-N-(6'-chloro-2',3'-dimethoxy-[1,1'-biphenyl]-3-yl)-4-(4-chlorobuta-2-enamide)-3-cyanobenzamide (15.0 mg) obtained in Step 3 in DMF (300 μL), 1-(methylsulfonyl)piperidine-4-amine (13.0 mg), potassium carbonate (10.0 mg), and potassium iodide (2.0 mg) were added. The mixture was reacted at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, followed by washing of the organic layer with saturated sodium chloride solution. The washed layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative reverse-phase HPLC (water:acetonitrile (0.1% formic acid)). Saturated sodium bicarbonate solution was added to the purified fraction containing the title compound, followed by extraction with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (16.2 mg).

[0572] [Example 12] N-(3-(5-chloro-1-methyl-1H-indazole-4-yl)phenyl)-3-cyano-4-((E)-4-(((1r,4r)-4-(diethylamino)silohexyl)amino)buta-2-enamide)benzamide Step 1: The procedure of Example 1 (Steps 5-7) was carried out, except that 4-bromo-5-chloro-1-methyl-1H-indazole (320 mg) was used instead of 5-bromo-2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole used in Example 1 (Step 5), to obtain (E)-N-(3-(5-chloro-1-methyl-1H-indazole-4-yl)phenyl)-4-(4-chlorobuta-2-enamide)-3-cyanobenzamide (160 mg).

[0573] Step 2: To a solution of (E)-N-(3-(5-chloro-1-methyl-1H-indazole-4-yl)phenyl)-4-(4-chlorobuta-2-enamide)-3-cyanobenzamide (15.0 mg) obtained in Step 1 in DMF (300 μL), trans-N,N-diethyl-cyclohexane-1,4-diamine dihydrochloride (18.0 mg), potassium carbonate (10.0 mg), and potassium iodide (2.0 mg) were added. The mixture was reacted at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform, followed by washing of the organic layer with saturated sodium chloride solution. The washed layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative reverse-phase HPLC (water:acetonitrile (0.1% formic acid)). Saturated sodium bicarbonate solution was added to the purified fraction containing the title compound, followed by extraction with chloroform. The extract was washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (2.68 mg).

[0574] [Example 13] N-(3-(6-chloro-1,2-dimethyl-1H-benzo[d]diimidazole-5-yl)phenyl)-4-((E)-4-(((1r,4r)-4-(diethylamino)cyclohexyl)amino)buta-2-enamide)-3-fluorobenzamide Step 1: 5-bromo-6-chloro-1,2-dimethyl-1H-benzo[d]imidazole (67.0 mg) was obtained by following the procedure of Example 1 (Steps 2-4), except that 5-chloro-N-methyl-2-nitroaniline (100 mg) was used instead of N-methyl-2-nitro-5-(trifluoromethyl)aniline used in Example 1 (Step 2), and 1,1,1-trimethoxyethane (670 μL) was used instead of 1,1,1-triethoxypropane in Example 1 (Step 4).

[0575] Step 2: The suspension of 5-bromo-6-chloro-1,2-dimethyl-1H-benzo[d]imidazole (218 mg), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (276 mg), tetrakis(triphenylphosphine)palladium (48.5 mg), and 2M aqueous sodium carbonate (1.4 mL) in 1,4-dioxane (2.8 mL) obtained in Step 1 was refluxed overnight. Ethyl acetate and water were added to the reaction mixture to separate the organic layer, and the organic layer was washed with saturated sodium chloride solution. The washed organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (chloroform:methanol) to obtain 3-(6-chloro-1,2-dimethyl-1H-benzo[d]imidazole-5-yl)aniline (234 mg).

[0576] Step 3: To a solution of 3-(6-chloro-1,2-dimethyl-1H-benzo[d]imidazole-5-yl)aniline (100 mg) obtained in Step 2 in DMF (1.6 mL), 1-hydroxybenzotriazole monohydrate (99.4 mg), 4-amino-3-fluorobenzoic acid (75.5 mg), triethylamine (140 μL), and WSC hydrochloride (124 mg) were added. The reaction was carried out overnight at room temperature. Water was added to the reaction mixture, and extraction was performed with ethyl acetate, followed by washing of the organic layer with saturated sodium chloride solution. The washed layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (chloroform:methanol) to obtain 4-amino-N-(3-(6-chloro-1,2-dimethyl-1H-benzo[d]imidazole-5-yl)phenyl)-3-fluorobenzamide (90.0 mg).

[0577] Step 4: The procedure of Example 1 (Step 7) was carried out, except that 4-amino-N-(3-(6-chloro-1,2-dimethyl-1H-benzo[d]imidazole-5-yl)phenyl)-3-fluorobenzamide (90.0 mg) obtained in Step 3 was used instead of 4-amino-3-cyano-N-(3-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)phenyl)-3-fluorobenzamide (90.0 mg) obtained in Step 3 was used instead of 4-amino-3-cyano-N-(3-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-5-yl)phenyl)-4-(4-chlorobuta-2-enamide)-3-fluorobenzamide (90.0 mg).

[0578] Step 5: The procedure of Example 12 (Step 2) was carried out, except that (E)-N-(3-(6-chloro-1-,2-dimethyl-1H-benzo[d]imidazole-5-yl)phenyl)-4-(4-chlorobuta-2-enamide)-3-fluorobenzamide (15.0 mg) obtained in Step 4 was used instead of (E)-N-(3-(6-chloro-1-,2-dimethyl-1H-benzo[d]imidazole-5-yl)phenyl)-4-(4-chlorobuta-2-enamide)-3-fluorobenzamide (15.0 mg) used in Example 12 (Step 2), to obtain the title compound (6.30 mg).

[0579] ...

Claims

1. Compounds selected from the following or pharmaceutically acceptable salts thereof: 【Chemistry 1】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 And, 【change】

2. A pharmaceutical product comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof, A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. An antitumor agent comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, wherein, a) The antitumor agent may be for oral administration, and / or b) The antitumor agent may further contain one or more other antitumor agents as active ingredients, and / or c) The antitumor agent may be administered in combination with one or more other antitumor agents. The aforementioned antitumor agent.

4. Use of the compound described in claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition.

5. The use of the compound described in claim 1 or a pharmaceutically acceptable salt thereof for the production of an antitumor agent, wherein a) The antitumor agent may be for oral administration, and / or b) The antitumor agent may be administered in combination with one or more other antitumor agents. The aforementioned use.

6. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof and one or more other antitumor agents for the production of an antitumor agent.

7. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, used for the treatment of a tumor, administered in combination with one or more other antitumor agents.

8. The antitumor agent according to any one of claims 3, 5, or 6, or the compound according to claim 7, wherein the tumor is cancer.

9. The antitumor agent according to claim 8, wherein the cancer is one or more selected from the group consisting of carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.

10. The antitumor agent according to claim 9, wherein the squamous cell carcinoma is a cancer of the cervix, tarsal area, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx, or esophagus.

11. The antitumor agent according to claim 9, wherein the adenocarcinoma is cancer of the prostate, small intestine, endometrium, cervix, large intestine, lung, pancreas, esophagus, rectum, uterus, stomach, breast, or ovary.

12. The antitumor agent according to claim 8, wherein the cancer is rectal cancer, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, breast cancer, or leukemia.

13. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof, used for the treatment of tumors.

14. A pharmaceutical composition for use in the treatment of tumors, comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and other antitumor agents.

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