4-aminobutyl-2-alkenyl amide derivative and salt thereof

Abstract

The present invention provides an antitumor agent comprising, as an active ingredient, a compound covalently bound to GTP-bound KRASG12C, or a pharmaceutically acceptable salt thereof.

Description

[0001] This application is a divisional application of the Chinese invention patent application with an application date of October 29, 2020, application number 202080087842.9, and invention name “4-aminobut-2-enamide derivatives and their salts”. Technical Field

[0002] The present invention relates to 4-aminobut-2-enamide derivatives and pharmaceutically acceptable salts thereof having inhibitory activity against the active form of KRAS G12C mutation, and to pharmaceutical compositions containing the same as active ingredients. Background Art

[0003] Ras is a small monomeric GTP-binding protein with a molecular weight of approximately 21 kDa that acts as a molecular two-position switch (on / off switch). Ras can bind to GTP by binding to proteins of guanine nucleotide exchange factors (GEFs) (e.g., SOS1), forcing the release of bound nucleotides and releasing GDP. When RAS binds to GTP, it is activated (turned on) and recruits and activates proteins necessary for the propagation of other receptor signals, such as c-Raf and PI 3-kinase. Ras also has enzymatic activity by which it cuts the terminal phosphate of nucleotides and converts them into GDP. The conversion rate is usually slow, but can be significantly accelerated by proteins of the GTPase activating protein (GAP) class (e.g., RasGAP). When GTP is converted into GDP, RAS is inactivated (turned off).

[0004] The main known members of the RAS subfamily include HRAS, KRAS, and NRAS. KRAS mutations are observed in many malignancies: 95% of pancreatic cancers, 45% of colorectal cancers, and 35% of lung cancers. Mutations often occur at the glycine residue at position 12; in particular, mutations at position 12 account for approximately 90% of all mutations in lung adenocarcinomas. Among these mutations, the most common mutation (44%) reportedly is to cysteine ​​(Non-Patent Literature (NPL) 1).

[0005] Historically, KRAS mutations were thought to exist in a constitutively active state (GTP-bound) in cancer cells. However, recent studies have shown that the KRAS G12C mutation has basal GTPase activity. K-ras has a pocket structure to which drug agents can bind. In part of the pocket, switch 1 (residues 30 to 40) and switch 2 (residues 60 to 76) are contained. 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, which then keep switch 1 and switch 2 in their active forms. These two regions will be free to release through the hydrolysis of GTP and the release of phosphate to form an inactive GDP form. When the GTP bound to K-Ras is replaced by GDP, the three-dimensional conformation of the switch region containing these switches changes. The changes may involve the bond between K-Ras and the target gene (e.g., c-Raf).

[0006] In fact, ARS-853 has been reported to bind to the cysteine ​​of the G12C mutant of inactive KRAS(GDP), thereby preventing the conversion of inactive KRAS(GDP) to active KRAS(GTP), inhibiting downstream signaling, and inducing apoptosis in cancer cells with the KRAS G12C mutation (Patent Documents (PTL) 1 and NPL 2). ARS-1620, which has a quinazoline skeleton, has also been reported to exert anti-tumor effects in tumor-bearing mice expressing the KRAS G12C mutation by improving metabolic stability in mice (PTL 2 and NPL 3).

[0007] However, due to its mode of action, inhibitors that bind to the inactive form of the KRAS G12C mutation may not be able to exert sufficient effects in patients with KRAS G12C-positive cancers, in whom the active form of the KRAS protein (GTP) tends to increase through activation of KRAS upstream pathways or inactivation of GTPase activity in clinical settings. In fact, it has been reported that in KRASG12C mutant cell lines (NPL 2 and NPL 4), the inhibition of KRAS activity and the antiproliferative effect of ARS-853 were attenuated by EGFR activation.

[0008] List of citations

[0009] Patent Literature

[0010] PTL 1: WO 2014 / 152588

[0011] PTL 2: WO 2015 / 054572

[0012] Non-patent literature

[0013] NPL 1: Nature Reviews Drug Discovery 13(11),828-51,2014

[0014] NPL 2: Cancer Discov.6(3),316-29,2016

[0015] NPL 3: Cell.172(3),578-89,2018

[0016] NPL 4: Science.351(6273),604-8,2016 SUMMARY OF THE INVENTION

[0017] Technical issues

[0018] Abnormalities in specific KRAS upstream input or GAP function to the KRAS protein are 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 a precise understanding of tumor-specific signaling weaknesses upstream or downstream of the KRAS pathway. Therefore, inhibitors of GDP-form KRASG12C mutations will need to select effective patient populations, and drug combination strategies may have to be selected based on the weaknesses of KRAS upstream and downstream signaling. On the other hand, inhibitors of the active form of the KRAS G12C mutation are expected to have therapeutic opportunities for a wider range of G12C-positive patients, even as a single agent, and are hardly affected by the upstream status of KRAS.

[0019] Therefore, there is a need for a novel compound or a salt thereof that binds to the active form of the mutant cysteine ​​of the KRAS G12C mutation and a pharmaceutical composition comprising the same.

[0020] Solutions to the Problem

[0021] The present invention relates to the following inventions.

[0022] (1) An antitumor agent comprising a compound covalently binding to GTP-bound KRAS G12C or a pharmaceutically acceptable salt thereof as an active ingredient.

[0023] (2) The antitumor agent according to (1), wherein the compound has the following formula:

[0024] A-L1-L2-GJ

[0025] in,

[0026] A is a chemical moiety capable of interacting with the region between switch 2 and the α3-helix;

[0027] L1 is a linker;

[0028] L2 is a linker;

[0029] G is an electrophilic chemical moiety capable of forming a covalent bond with cysteine ​​12 of GTP-bound KRAS G12C;

[0030] J is a chemical moiety capable of interacting with GTP.

[0031] (3) The antitumor agent according to (1) or (2), wherein the agent is a compound having the following formula:

[0032] A-L1-L2-GJ

[0033] Where G is represented by the following formula:

[0034]

[0035] (4) The antitumor agent according to any one of (1) to (3), wherein in the 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 NR2R3, and the compound is represented by the formula (i):

[0036]

[0037] wherein A is a ring system selected from a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted fused ring;

[0038] D is a monocyclic ring having at least one amino group, the amino group combining with the carbonyl group between D and E to form an amide, wherein the monocyclic ring is unsubstituted or substituted with a substituent other than the amino group, or D is a substituted or unsubstituted fused ring;

[0039] E is a ring system selected from a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted fused ring;

[0040] R1 is hydrogen or substituted or unsubstituted C1-C6 alkyl;

[0041] R2 and R3 are joined together to form a 4- to 10-membered saturated heterocyclic ring, which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; or

[0042] R2 and R3 independently represent, and R2 is hydrogen; or a C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C6-C10 aromatic hydrocarbon, a 4- to 10-membered saturated heterocyclic group, a 4- to 10-membered partially saturated heterocyclic group or a 4- to 10-membered unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;

[0043] R3 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted by 1-2 substituents independently represented by Ra;

[0044] Ra independently represents halogen, hydroxy, 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.

[0045] (5) The antitumor agent according to (4), wherein the compound is represented by formula (ii):

[0046]

[0047] wherein A, D, R1, R2 and R3 are as defined in formula (i),

[0048] E is an unsaturated 6-membered ring which is unsubstituted or substituted by R4, wherein E1, E2, E3 and E4 independently represent C, CH, CH2, N or NH;

[0049] R4 is 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;

[0050] m is an integer from 0 to 4.

[0051] (6) The antitumor agent according to (5), wherein the compound is represented by formula (iii):

[0052]

[0053] wherein D, R1, R2 and R3 are as defined in formula (i), and E, R4 and m are as defined in formula (ii),

[0054] When A is a monocyclic ring, A' and A" are absent, and the monocyclic ring is represented by Ring A, which is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH;

[0055] When A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring A", wherein ring A is an unsubstituted or unsaturated 6-membered ring substituted by R5, wherein A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH, and ring A' or A" is a saturated or unsaturated ring unsubstituted or substituted by R6 and forms a fused ring with ring A containing A3 and A4 or A4 and A5;

[0056] R5 is 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;

[0057] When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring that shares two adjacent atoms with ring A' or ring A"; or

[0058] R6 may independently represent halogen, cyano, amino, hydroxyl, 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;

[0059] n is an integer from 0 to 5; and

[0060] p is 0, 1 or 2.

[0061] (7) The antitumor agent according to (6), wherein the compound is represented by formula (iv):

[0062]

[0063] wherein 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);

[0064] When D is a monocyclic ring, D' is absent, and the monocyclic ring is represented by ring D, which is an unsaturated 6-membered ring that is unsubstituted or substituted with R7, wherein D1 represents N or NH, and D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH;

[0065] When D is a fused ring, the fused ring is represented by ring D and ring D', wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted by R7, wherein D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is a saturated or unsaturated ring which is unsubstituted or substituted by R8 and forms a fused ring with ring D containing D1, D2 and D7;

[0066] R7 is 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;

[0067] R8 is halogen or substituted or unsubstituted C1-C10 alkyl;

[0068] q and r independently represent 0, 1 or 2.

[0069] (8) The antitumor agent according to (7), wherein

[0070] Ring A' forms a condensed ring with Ring A containing A3 and A4, and A1 and A5 are C, CH or CH2.

[0071] (9) The antitumor agent according to (8), wherein R1 is hydrogen.

[0072] (10) The antitumor agent according to (9), wherein R2 and R3 are independently represented, and R3 is hydrogen or a C1-C3 alkyl group.

[0073] (11) The antitumor agent according to (10), wherein D6 in ring D is C.

[0074] (12) The antitumor agent according to (11), wherein D3, D4 and D5 are C.

[0075] (13) The antitumor agent according to (7), wherein the compound is represented by formula (V):

[0076]

[0077] wherein R2 and R3 are as defined in formula (i), E, ​​R4 and m are as defined in formula (ii), A, R5, n and p are as defined in formula (iii), and D, R7, R8, q and r are as defined in formula (iv);

[0078] Ring A' is a saturated or unsaturated 5-membered ring, which forms a condensed ring with Ring A containing A3 and A4, wherein A1', A2', A3' independently represent C, CH, CH2, N, NH, O or S,

[0079] When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring; or

[0080] R6 may independently be halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy.

[0081] (14) The antitumor agent according to any one of (6) to (13), wherein A2 is C.

[0082] (15) The antitumor agent according to any one of (4) to (14), wherein R2 is a C1-C10 alkyl group which is unsubstituted or substituted by Ra, a C3-C10 cycloalkyl group which is unsubstituted or substituted by Ra, or a 4- to 10-membered saturated heterocyclic group which is unsubstituted or substituted by Ra.

[0083] (16) The antitumor agent according to any one of (1) to (15), wherein R3 is hydrogen.

[0084] (17) The antitumor agent according to any one of (5) to (16), wherein R4 is halogen, cyano or C1-C6 alkyl.

[0085] (18) The 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.

[0086] (19) The antitumor agent according to any one of (6) to (18), wherein, when the number of R6 is two or more, two R6 can be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring; or

[0087] Each R6 may independently represent a substituted or unsubstituted C1-C10 alkyl group or a substituted or unsubstituted C1-C10 alkoxy group.

[0088] (20) The antitumor agent according to (13), wherein the compound is represented by formula (vi):

[0089]

[0090] wherein R2 is as defined in formula (i), E, ​​R4 and m are as defined in formula (ii), A, R5, n and p are as defined in formula (iii), R8, q and r are as defined in formula (iv), and R6 and A' are as defined in formula (v);

[0091] D is a condensed ring represented by ring D and ring D', ring D' is a saturated or unsaturated 5-membered ring, which forms a condensed ring containing D1, D2 and D7 with ring D, and D1' and D2' independently represent C, CH, CH2, N, NH or S,

[0092] R7 is halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy.

[0093] (21) The antitumor agent according to (20), wherein R7 is halogen or a substituted or unsubstituted C1-C10 alkyl group.

[0094] (22) Compounds represented by formula (i):

[0095]

[0096] or a pharmaceutically acceptable salt thereof, wherein

[0097] A is a ring system selected from a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted fused ring;

[0098] D is a monocyclic ring having at least one amino group, the amino group combining with the carbonyl group between D and E to form an amide, wherein the monocyclic ring is unsubstituted or substituted with a substituent other than the amino group, or D is a substituted or unsubstituted fused ring;

[0099] E is a ring system selected from a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted fused ring;

[0100] R1 is hydrogen or substituted or unsubstituted C1-C6 alkyl;

[0101] R2 and R3 are joined together to form a 4- to 10-membered saturated heterocyclic ring, which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; or

[0102] R2 and R3 independently represent, and R2 is hydrogen; or a C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C6-C10 aromatic hydrocarbon, a 4- to 10-membered saturated heterocyclic group, a 4- to 10-membered partially saturated heterocyclic group or a 4- to 10-membered unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;

[0103] R3 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted by 1-2 substituents independently represented by Ra;

[0104] Ra independently represents halogen, hydroxy, 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- to 10-membered saturated heterocyclic group.

[0105] (23) The compound according to (22), wherein the compound is represented by formula (ii):

[0106]

[0107] wherein A, D, R1, R2 and R3 are as defined in formula (i),

[0108] E is an unsaturated 6-membered ring which is unsubstituted or substituted by R4, wherein E1, E2, E3 and E4 independently represent C, CH, CH2, N or NH;

[0109] R4 is 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;

[0110] m is an integer from 0 to 4; or a pharmaceutically acceptable salt thereof.

[0111] (24) The compound according to (24), wherein the compound is represented by formula (iii):

[0112]

[0113] wherein D, R1, R2 and R3 are as defined in formula (i), and E, R4 and m are as defined in formula (ii),

[0114] When A is a monocyclic ring, A' and A" are absent, and the monocyclic ring is represented by Ring A, which is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH;

[0115] When A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring A", wherein ring A is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH; and ring A' or A" is a saturated or unsaturated ring which is unsubstituted or substituted by R6 and forms a fused ring with ring A containing A3 and A4 or A4 and A5;

[0116] R5 is 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;

[0117] When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring that shares two adjacent atoms with ring A' or ring A"; or

[0118] R6 may independently represent halogen, cyano, amino, hydroxyl, 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;

[0119] n is an integer from 0 to 5; and

[0120] p is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0121] (25) The compound according to (24), wherein the compound is represented by formula (iv):

[0122]

[0123] wherein 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);

[0124] When D is a monocyclic ring, D' is absent and the monocyclic ring is represented by ring D, which is an unsaturated 6-membered ring that is unsubstituted or substituted with R7, wherein D1 represents N or NH, and D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH;

[0125] When D is a fused ring, the fused ring is represented by ring D and ring D', wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted by R7, wherein D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is a saturated or unsaturated ring which is unsubstituted or substituted by R8 and forms a fused ring with ring D containing D1, D2 and D7;

[0126] R7 is 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;

[0127] R8 is halogen or substituted or unsubstituted C1-C10 alkyl;

[0128] q and r independently represent 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0129] (26) The compound according to (25), wherein

[0130] Ring A' forms a condensed ring with Ring A containing A3 and A4, and A1 and A5 are C, CH or CH2; or a pharmaceutically acceptable salt thereof.

[0131] (27) The compound according to (26), wherein R1 is hydrogen; or a pharmaceutically acceptable salt thereof.

[0132] (28) The compound according to (27), wherein R2 and R3 are independently represented, and R3 is hydrogen or C1-C3 alkyl; or a pharmaceutically acceptable salt thereof.

[0133] (29) The compound according to (28), wherein D6 in ring D is C; or a pharmaceutically acceptable salt thereof.

[0134] (30) The compound according to (29), wherein D3, D4 and D5 are C; or a pharmaceutically acceptable salt thereof.

[0135] (31) The compound according to (25), wherein the compound is represented by formula (v):

[0136]

[0137] wherein R2 and R3 are as defined in formula (i), E, ​​R4 and m are as defined in formula (ii), A, R5, n and p are as defined in formula (iii), and D, R7, R8, q and R are as defined in formula (iv);

[0138] Ring A' is a saturated or unsaturated 5-membered ring, which forms a condensed ring with Ring A containing A3 and A4, wherein A1', A2', A3' independently represent C, CH, CH2, N, NH, O or S,

[0139] When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring; or

[0140] R6 may independently be halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy; or a pharmaceutically acceptable salt thereof.

[0141] (32) The compound according to any one of (24) to (31), wherein A2 is C; or a pharmaceutically acceptable salt thereof.

[0142] (33) The compound according to any one of (28) to (32), wherein R2 is C1-C10 alkyl which is unsubstituted or substituted by Ra, C3-C10 cycloalkyl which is unsubstituted or substituted by Ra, or a 4- to 10-membered saturated heterocyclic group which is unsubstituted or substituted by Ra; or a pharmaceutically acceptable salt thereof.

[0143] (34) The compound according to any one of (28) to (33), wherein R3 is hydrogen; or a pharmaceutically acceptable salt thereof.

[0144] (35) The compound according to any one of (23) to (34), wherein R4 is halogen, cyano or C1-C6 alkyl; or a pharmaceutically acceptable salt thereof.

[0145] (36) The compound according to any one of (24) to (35), wherein R5 is hydroxy, halogen, C1-C10 alkyl, C1-C6 haloalkyl or C1-C10 alkoxy; or a pharmaceutically acceptable salt thereof.

[0146] (37) The compound according to any one of (24) to (36), wherein, when the number of R6 is two or more, two R6 can be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring; or

[0147] Each R6 may independently represent a substituted or unsubstituted C1-C10 alkyl group or a substituted or unsubstituted C1-C10 alkoxy group; or a pharmaceutically acceptable salt thereof.

[0148] (38) The compound according to (31), wherein the compound is represented by formula (vi) or a salt thereof:

[0149]

[0150] wherein R2 is as defined in formula (i), E, ​​R4 and m are as defined in formula (ii), A, R5, n and p are as defined in formula (iii), and R8, q and r are as defined in formula (iv), R6 and A' are as defined in formula (v);

[0151] D is a condensed ring represented by ring D and ring D', ring D' is a saturated or unsaturated 5-membered ring, which forms a condensed ring containing D1, D2 and D7 with ring D, and D1' and D2' independently represent C, CH, CH2, N, NH or S,

[0152] R7 is halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy; or a pharmaceutically acceptable salt thereof.

[0153] (39) The compound according to (38), wherein R7 is halogen or substituted or unsubstituted C1-C10 alkyl; or a pharmaceutically acceptable salt thereof.

[0154] (40) A drug comprising the compound according to any one of (22) to (39) or a pharmaceutically acceptable salt thereof.

[0155] (41) A pharmaceutical composition comprising the compound of any one of (22) to (39) or a pharmaceutically acceptable salt thereof.

[0156] (42) An antitumor agent comprising the compound according to any one of (22) to (39) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0157] (43) An antitumor agent for oral administration, comprising the compound of any one of (22) to (39) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0158] (44) Use of the compound according to any one of (22) to (39) or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition.

[0159] (45) Use of the compound according to any one of (22) to (39) or a pharmaceutically acceptable salt thereof for preparing an antitumor agent.

[0160] (46) Use of the compound according to any one of (22) to (39) or a pharmaceutically acceptable salt thereof for the preparation of an antitumor agent for oral administration.

[0161] (47) The compound of any one of (22) to (39) or a pharmaceutically acceptable salt thereof for use as a medicament.

[0162] (48) A compound according to any one of (22) to (39) or a pharmaceutically acceptable salt thereof for use in treating tumors.

[0163] (49) A compound according to any one of (22) to (39) or a pharmaceutically acceptable salt thereof for use in treating tumors by oral administration.

[0164] (50) A method for treating tumors, comprising administering a therapeutically effective amount of a compound according to any one of (22) to (39) or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0165] (51) The antitumor agent of (1), wherein the agent is administered to a subject in need thereof in combination with a pharmaceutically effective amount of one or more other antitumor drugs.

[0166] (52) The antitumor agent of (1), wherein the tumor is cancer.

[0167] (53) The antitumor agent of (52), wherein the cancer is one or more selected from carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma and lymphoma.

[0168] (54) The antitumor agent of (53), wherein the squamous cell carcinoma is cancer of the cervix, tarsus, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx or esophagus.

[0169] (55) The antitumor agent of (53), wherein the adenocarcinoma is a cancer of the prostate, small intestine, endometrium, cervix, large intestine, lung, pancreas, esophagus, rectum, uterus, stomach, breast or ovary.

[0170] (56) The method of (51), wherein the tumor is rectal cancer, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, breast cancer or leukemia.

[0171] (57) An antitumor agent comprising the compound of any one of (22) to (39) or a pharmaceutically acceptable salt thereof, and one or more other antitumor agents as active ingredients.

[0172] (58) An antitumor agent comprising the compound of any one of (22) to (39) or a pharmaceutically acceptable salt thereof as an active ingredient, which is administered in combination with one or more other antitumor agents.

[0173] (59) Use of the compound according to any one of (22) to (39) or a salt thereof and one or more other antitumor agents for preparing an antitumor agent.

[0174] (60) Use of the compound according to any one of (22) to (39) or a salt thereof for preparing an antitumor agent to be administered in combination with one or more other antitumor agents.

[0175] (61) A combination of the compound according to any one of (22) to (39) or a salt thereof and one or more other antitumor agents for use in treating tumors.

[0176] (62) The compound of any one of (22) to (39) or a pharmaceutically acceptable salt thereof for use in treating tumors, wherein the compound is administered in combination with one or more other anti-tumor agents.

[0177] (63) A method for treating tumors, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of (22) to (39) or a pharmaceutically acceptable salt thereof, and one or more other anti-tumor agents.

[0178] (64) A method for treating a tumor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of (22) to (39) or a pharmaceutically acceptable salt thereof in combination with one or more other anti-tumor agents.

[0179] (65) Use of a compound covalently binding to GTP-bound KRAS G12C or a pharmaceutically acceptable salt thereof for preparing an antitumor agent.

[0180] (66) A compound that covalently binds to GTP-bound KRAS G12C or a pharmaceutically acceptable salt thereof for use in treating tumors.

[0181] (67) A method for treating a tumor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound that covalently binds to GTP-bound KRAS G12C or a pharmaceutically acceptable salt thereof.

[0182] (68) The antitumor agent according to (1) or (2), wherein the antitumor agent has a compound of the following formula:

[0183] A-L1-L2-GJ

[0184] Where G is represented by the following formula:

[0185]

[0186] (69) The antitumor agent according to any one of (1), (2) or (68), wherein in the 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 represented by the formula (vii):

[0187]

[0188] wherein A is a ring system selected from a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted fused ring;

[0189] D is a monocyclic ring having at least one amino group, the amino group combining with the carbonyl group between D and E to form an amide, wherein the monocyclic ring is unsubstituted or substituted with a substituent other than the amino group, or D is a substituted or unsubstituted fused ring;

[0190] E is a ring system selected from a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted fused ring;

[0191] R1 is hydrogen or substituted or unsubstituted C1-C6 alkyl;

[0192] R2 and R3 or R2 and R2' are joined together to form a 4- to 10-membered saturated heterocyclic ring, which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; or

[0193] R2, R2' and R3 independently represent, and R2 is hydrogen; or a C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C6-C10 aromatic hydrocarbon, a 4- to 10-membered saturated heterocyclic group, a 4- to 10-membered partially saturated heterocyclic group or a 4- to 10-membered unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;

[0194] R2' is hydrogen or C1-C6 alkyl which is unsubstituted or substituted by 1-2 substituents independently represented by Ra; and

[0195] R3 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted by 1-2 substituents independently represented by Ra;

[0196] Ra independently represents halogen, hydroxy, 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- to 10-membered saturated heterocyclic group.

[0197] (70) The antitumor agent according to (69), wherein the compound is represented by formula (viii):

[0198]

[0199] wherein A, D, R1, R2, R2′ and R3 are as defined in formula (vii) in (69),

[0200] E is an unsaturated 6-membered ring which is unsubstituted or substituted by R4, wherein E1, E2, E3 and E4 independently represent C, CH, CH2, N or NH;

[0201] R4 is 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;

[0202] m is an integer from 0 to 4.

[0203] (71) The antitumor agent according to (70), wherein the compound is represented by formula (ix):

[0204]

[0205] wherein D, R1, R2, R2′ and R3 are as defined in formula (vii) in (69), and E, R4 and m are as defined in formula (viii) in (70),

[0206] When A is a monocyclic ring, A' and A" are absent, and the monocyclic ring is represented by Ring A, which is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH;

[0207] When A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring A", wherein ring A is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH; and ring A' or A" is a saturated or unsaturated ring which is unsubstituted or substituted by R6 and forms a fused ring with ring A containing A3 and A4 or A4 and A5;

[0208] R5 is 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;

[0209] When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring that shares two adjacent atoms with ring A' or ring A"; or

[0210] R6 may independently represent halogen, cyano, amino, hydroxyl, 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;

[0211] n is an integer from 0 to 5; and

[0212] p is 0, 1 or 2.

[0213] (72) The antitumor agent according to (71), wherein the compound is represented by formula (x):

[0214]

[0215] wherein R1, R2, R2′ and R3 are as defined in formula (vii) in (69), E, ​​R4 and m are as defined in formula (viii) in (70), and A, R5, R6, n and p are as defined in formula (ix) in (71);

[0216] When D is a monocyclic ring, D' is absent, and the monocyclic ring is represented by ring D, which is an unsaturated 6-membered ring that is unsubstituted or substituted with R7, wherein D1 represents N or NH, and D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH;

[0217] When D is a fused ring, the fused ring is represented by ring D and ring D', wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted by R7, wherein D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is a saturated or unsaturated ring which is unsubstituted or substituted by R8 and forms a fused ring with ring D containing D1, D2 and D7;

[0218] R7 is 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;

[0219] R8 is halogen or substituted or unsubstituted C1-C10 alkyl;

[0220] q and r independently represent 0, 1 or 2.

[0221] (73) The antitumor agent according to (72), wherein

[0222] Ring A' forms a condensed ring with Ring A containing A3 and A4, and A1 and A5 are C, CH or CH2.

[0223] (74) The antitumor agent according to (73), wherein R1 is hydrogen.

[0224] (75) The antitumor agent according to (74), wherein R2 and R3 are independently represented, and R3 is hydrogen or a C1-C3 alkyl group.

[0225] (76) The antitumor agent according to (75), wherein D6 in ring D is C.

[0226] (77) The antitumor agent according to (76), wherein D3, D4 and D5 are C.

[0227] (78) The antitumor agent according to any one of (72) to (77), wherein the compound is represented by formula (xi):

[0228]

[0229] wherein R2 and R2′ are as defined in formula (vii) in (69); R2 and R3 are independently represented, and R3 is hydrogen or C1-C3 alkyl; E, R4 and m are as defined in formula (viii) in (70); A, R5, n and p are as defined in formula (ix) in (71), and D, R7, R8, q and r are as defined in formula (x) in (72);

[0230] Ring A' is a saturated or unsaturated 5-membered ring, which forms a condensed ring with Ring A containing A3 and A4, wherein A1', A2', A3' independently represent C, CH, CH2, N, NH, O or S,

[0231] When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring; or

[0232] R6 may independently be halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy.

[0233] (79) The antitumor agent according to any one of (71) to (78), wherein A2 is C.

[0234] (80) The antitumor agent according to any one of (75) to (79), wherein R2 and R2' are linked together to form a 4- to 6-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 2 substituents independently represented by Ra; or

[0235] R2 and R2' independently represent, and R2 is unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, or unsubstituted or substituted 4- to 10-membered saturated heterocyclic group.

[0236] (81) The antitumor agent according to any one of (75) to (80), wherein R3 is hydrogen.

[0237] (82) The antitumor agent according to any one of (70) to (81), wherein R4 is halogen, cyano or C1-C6 alkyl.

[0238] (83) The 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.

[0239] (84) The antitumor agent according to any one of (71) to (83), wherein, when the number of R6 is two or more, two R6 can be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring; or

[0240] Each R6 may independently represent a substituted or unsubstituted C1-C10 alkyl group or a substituted or unsubstituted C1-C10 alkoxy group.

[0241] (85) The antitumor agent according to any one of (78) to (84), wherein the compound is represented by formula (xii):

[0242]

[0243] wherein R2 and R2′ are as defined in (80), E and m are as defined in formula (viii) in (70), A, n, and p are as defined in formula (ix) in (71), R8, q, and r are as defined in formula (x) in (72), A′ is as defined in formula (xi) in (78), R4 is as defined in (82), R5 is as defined in (83), and R6 is as defined in (84);

[0244] D is a condensed ring represented by ring D and ring D', ring D' is a saturated or unsaturated 5-membered ring, which forms a condensed ring containing D1, D2 and D7 with ring D, and D1' and D2' independently represent C, CH, CH2, N, NH or S,

[0245] R7 is halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy.

[0246] (86) The antitumor agent according to (85), wherein R7 is halogen or a substituted or unsubstituted C1-C10 alkyl group.

[0247] (87) Compounds represented by formula (ii):

[0248]

[0249] or a pharmaceutically acceptable salt thereof, wherein

[0250] A is a ring system selected from a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted fused ring;

[0251] D is a monocyclic ring having at least one amino group, the amino group combining with the carbonyl group between D and E to form an amide, wherein the monocyclic ring is unsubstituted or substituted with a substituent other than the amino group, or D is a substituted or unsubstituted fused ring;

[0252] E is a ring system selected from a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted fused ring;

[0253] R1 is hydrogen or substituted or unsubstituted C1-C6 alkyl;

[0254] R2 and R3 or R2 and R2' are joined together to form a 4- to 10-membered saturated heterocyclic ring, which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; or

[0255] R2, R2' and R3 independently represent, and R2 is hydrogen; or a C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C6-C10 aromatic hydrocarbon, a 4- to 10-membered saturated heterocyclic group, a 4- to 10-membered partially saturated heterocyclic group or a 4- to 10-membered unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;

[0256] R2' is hydrogen or C1-C6 alkyl which is unsubstituted or substituted by 1-2 substituents independently represented by Ra; and

[0257] R3 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted by 1-2 substituents independently represented by Ra;

[0258] Ra independently represents halogen, hydroxy, 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- to 10-membered saturated heterocyclic group.

[0259] (88) The compound according to (87), wherein the compound is represented by formula (viii):

[0260]

[0261] wherein A, D, R1, R2, R2′ and R3 are as defined in formula (vii) in formula (87),

[0262] E is an unsaturated 6-membered ring which is unsubstituted or substituted by R4, wherein E1, E2, E3 and E4 independently represent C, CH, CH2, N or NH;

[0263] R4 is 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;

[0264] m is an integer from 0 to 4; or a pharmaceutically acceptable salt thereof.

[0265] (89) The compound according to (88), wherein the compound is represented by formula (ix):

[0266]

[0267] wherein D, R1, R2, R2′ and R3 are as defined in formula (vii) in (87), and E, R4 and m are as defined in formula (viii) in (88),

[0268] When A is a monocyclic ring, A' and A" are absent, and the monocyclic ring is represented by Ring A, which is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH;

[0269] When A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring A", wherein ring A is an unsubstituted or unsaturated 6-membered ring substituted by R5, wherein A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH, and ring A' or A" is a saturated or unsaturated ring unsubstituted or substituted by R6 and forms a fused ring with ring A containing A3 and A4 or A4 and A5;

[0270] R5 is 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;

[0271] When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring that shares two adjacent atoms with ring A' or ring A"; or

[0272] R6 may independently represent halogen, cyano, amino, hydroxyl, 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;

[0273] n is an integer from 0 to 5; and

[0274] p is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0275] (90) The compound according to (89), wherein the compound is represented by formula (x):

[0276]

[0277] wherein R1, R2, R2′ and R3 are as defined in formula (vii) in (87), E, ​​R4 and m are as defined in formula (viii) in (88), and A, R5, R6, n and p are as defined in formula (ix) in (89);

[0278] When D is a monocyclic ring, D' is absent and the monocyclic ring is represented by ring D, which is an unsaturated 6-membered ring that is unsubstituted or substituted with R7, wherein D1 represents N or NH, and D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH;

[0279] When D is a fused ring, the fused ring is represented by ring D and ring D', wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted by R7, wherein D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is a saturated or unsaturated ring which is unsubstituted or substituted by R8 and forms a fused ring with ring D containing D1, D2 and D7;

[0280] R7 is 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;

[0281] R8 is halogen or substituted or unsubstituted C1-C10 alkyl;

[0282] q and r independently represent 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0283] (91) The compound according to (90), wherein

[0284] Ring A' forms a condensed ring with Ring A containing A3 and A4, and A1 and A5 are C, CH or CH2; or a pharmaceutically acceptable salt thereof.

[0285] (92) The compound according to (91), wherein R1 is hydrogen; or a pharmaceutically acceptable salt thereof.

[0286] (93) The compound according to (92), wherein R2 and R3 are independently represented, and R3 is hydrogen or C1-C3 alkyl; or a pharmaceutically acceptable salt thereof.

[0287] (94) The compound according to (93), wherein D6 in ring D is C; or a pharmaceutically acceptable salt thereof.

[0288] (95) The compound according to (94), wherein D3, D4 and D5 are C; or a pharmaceutically acceptable salt thereof.

[0289] (96) The compound according to any one of (90) to (95), wherein the compound is represented by formula (xi):

[0290]

[0291] wherein R2 and R2′ are as defined in formula (vii) in (87); R2 and R3 are independently represented, and R3 is hydrogen or C1-C3 alkyl; E, R4 and m are as defined in formula (viii) in (88); A, R5, n and p are as defined in formula (ix) in (89), and D, R7, R8, q and r are as defined in formula (x) in (90);

[0292] Ring A' is a saturated or unsaturated 5-membered ring, which forms a condensed ring with Ring A containing A3 and A4, wherein A1', A2', A3' independently represent C, CH, CH2, N, NH, O or S,

[0293] When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring; or

[0294] R6 may independently be halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy; or a pharmaceutically acceptable salt thereof.

[0295] (97) The compound according to any one of (89) to (96), wherein A2 is C; or a pharmaceutically acceptable salt thereof.

[0296] (98) The compound according to any one of (93) to (79), wherein R2 and R2' are linked together to form a 4- to 6-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 2 substituents independently represented by Ra; or

[0297] R2 and R2' are independently represented, and R2 is unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C3-C10 cycloalkyl,

[0298] a substituted 4- to 10-membered saturated heterocyclic group; or a pharmaceutically acceptable salt thereof.

[0299] (99) The compound according to any one of (93) to (98), wherein R3 is hydrogen; or a pharmaceutically acceptable salt thereof.

[0300] (100) The compound according to any one of (88) to (99), wherein R4 is halogen, cyano or C1-C6 alkyl; or a pharmaceutically acceptable salt thereof.

[0301] (101) The compound according to any one of (89) to (100), wherein R5 is hydroxy, halogen, C1-C10 alkyl, C1-C6 haloalkyl or C1-C10 alkoxy; or a pharmaceutically acceptable salt thereof.

[0302] (102) A compound according to any one of (89) to (101), wherein, when the number of R6 is two or more, two R6 can be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring; or each R6 can independently represent a substituted or unsubstituted C1-C10 alkyl group or a substituted or unsubstituted C1-C10 alkoxy group; or a pharmaceutically acceptable salt thereof.

[0303] (103) The compound according to any one of (96) to (102), wherein the compound is represented by formula (xii) or a salt thereof:

[0304]

[0305] wherein R2 and R2′ are as defined in (98), E and m are as defined in formula (viii) in (88), A, n, and p are as defined in formula (ix) in (89), R8, q, and r are as defined in formula (x) in (90), A′ is as defined in formula (xi) in (96), R4 is as defined in (100), R5 is as defined in (101), and R6 is as defined in (102);

[0306] D is a condensed ring represented by ring D and ring D', ring D' is a saturated or unsaturated 5-membered ring, which forms a condensed ring containing D1, D2 and D7 with ring D, and D1' and D2' independently represent C, CH, CH2, N, NH or S,

[0307] R7 is halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy; or a pharmaceutically acceptable salt thereof.

[0308] (104) The compound according to (103), wherein R7 is halogen or substituted or unsubstituted C1-C10 alkyl; or a pharmaceutically acceptable salt thereof.

[0309] (105) A drug comprising the compound according to any one of (87) to (104) or a pharmaceutically acceptable salt thereof.

[0310] (106) A pharmaceutical composition comprising the compound of any one of (87) to (104) or a pharmaceutically acceptable salt thereof.

[0311] (107) An antitumor agent comprising the compound of any one of (87) to (104) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0312] (108) An antitumor agent for oral administration, comprising the compound of any one of (87) to (104) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0313] (109) Use of the compound according to any one of (87) to (104) or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition.

[0314] (110) Use of the compound according to any one of (87) to (104) or a pharmaceutically acceptable salt thereof for preparing an antitumor agent.

[0315] (111) Use of the compound according to any one of (87) to (104) or a pharmaceutically acceptable salt thereof for preparing an antitumor agent for oral administration.

[0316] (112) A compound according to any one of (87) to (104) or a pharmaceutically acceptable salt thereof for use as a medicament.

[0317] (113) A compound according to any one of (87) to (104) or a pharmaceutically acceptable salt thereof for use in treating tumors.

[0318] (114) A compound according to any one of (87) to (104) or a pharmaceutically acceptable salt thereof for use in treating a tumor by oral administration.

[0319] (115) A method for treating a tumor, comprising administering a therapeutically effective amount of a compound of any one of (87) to (104) or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0320] (116) An antitumor agent comprising the compound of any one of (87) to (104) or a pharmaceutically acceptable salt thereof, and one or more other antitumor agents as active ingredients.

[0321] (117) An antitumor agent comprising the compound of any one of (87) to (104) or a pharmaceutically acceptable salt thereof as an active ingredient, which is administered in combination with one or more other antitumor agents.

[0322] (118) Use of the compound according to any one of (87) to (104) or a salt thereof and one or more other antitumor agents for preparing an antitumor agent.

[0323] (119) Use of the compound according to any one of (87) to (104) or a salt thereof for preparing an antitumor agent to be administered in combination with one or more other antitumor agents.

[0324] (120) A combination of a compound according to any one of (87) to (104) or a salt thereof and one or more other anti-tumor agents for use in treating tumors.

[0325] (121) The compound of any one of (87) to (104) or a pharmaceutically acceptable salt thereof for use in treating tumors, wherein the compound is administered in combination with one or more other anti-tumor agents.

[0326] (122) A method for treating a tumor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of (87) to (104) or a pharmaceutically acceptable salt thereof, and one or more other anti-tumor agents.

[0327] (123) A method for treating a tumor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of (87) to (104) or a pharmaceutically acceptable salt thereof in combination with one or more other anti-tumor agents.

[0328] The present invention also relates to the following items:

[0329] An antitumor agent comprising as an active ingredient a compound that covalently binds to GTP-bound KRAS G12C or a pharmaceutically acceptable salt thereof.

[0330] 2. The antitumor agent according to item 1, wherein the compound has the following formula:

[0331] A-L1-L2-GJ

[0332] in,

[0333] A is a chemical moiety capable of interacting with the region between switch 2 and the α3-helix;

[0334] L1 is a linker;

[0335] L2 is a linker;

[0336] G is an electrophilic chemical moiety capable of forming a covalent bond with cysteine ​​12 of GTP-bound KRAS G12C;

[0337] J is a chemical moiety capable of interacting with GTP.

[0338] 3. The antitumor agent according to item 1 or 2, wherein the antitumor agent is a compound having the following formula:

[0339] A-L1-L2-GJ

[0340] Where G is represented by the following formula:

[0341]

[0342] 4. The antitumor agent according to any one of items 1 to 3, wherein in the 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 represented by formula (vii):

[0343]

[0344] wherein A is a ring system selected from a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted fused ring;

[0345] D is a monocyclic ring having at least one amino group, the amino group combining with the carbonyl group between D and E to form an amide, wherein the monocyclic ring is unsubstituted or substituted with a substituent other than the amino group, or D is a substituted or unsubstituted fused ring;

[0346] E is a ring system selected from a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted fused ring;

[0347] R1 is hydrogen or substituted or unsubstituted C1-C6 alkyl;

[0348] R2 and R3 or R2 and R2' are joined together to form a 4- to 10-membered saturated heterocyclic ring, which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; or

[0349] R2, R2' and R3 independently represent, and R2 is hydrogen; or a C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C6-C10 aromatic hydrocarbon, a 4- to 10-membered saturated heterocyclic group, a 4- to 10-membered partially saturated heterocyclic group or a 4- to 10-membered unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;

[0350] R2' is hydrogen or C1-C6 alkyl which is unsubstituted or substituted by 1-2 substituents independently represented by Ra; and

[0351] R3 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted by 1-2 substituents independently represented by Ra;

[0352] Ra independently represents halogen, hydroxy, 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 a substituted or unsubstituted 4- to 10-membered saturated heterocyclic group.

[0353] 5. The antitumor agent according to item 4, wherein the compound is represented by formula (viii):

[0354]

[0355] wherein A, D, R1, R2, R2' and R3 are as defined in formula (vii) in item 4,

[0356] E is an unsaturated 6-membered ring which is unsubstituted or substituted by R4, wherein E1, E2, E3 and E4 independently represent C, CH, CH2, N or NH;

[0357] R4 is 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;

[0358] m is an integer from 0 to 4.

[0359] 6. The antitumor agent according to item 5, wherein the compound is represented by formula (ix):

[0360]

[0361] wherein D, R1, R2, R2' and R3 are as defined in formula (vii) in item 4, and E, R4 and m are as defined in formula (viii) in item 5,

[0362] When A is a monocyclic ring, A' and A" are absent, and the monocyclic ring is represented by Ring A, which is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH;

[0363] When A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring A", wherein ring A is an unsubstituted or unsaturated 6-membered ring substituted by R5, wherein A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH, and ring A' or A" is a saturated or unsaturated ring unsubstituted or substituted by R6 and forms a fused ring with ring A containing A3 and A4 or A4 and A5;

[0364] R5 is 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;

[0365] When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring that shares two adjacent atoms with ring A' or ring A"; or

[0366] R6 may independently represent halogen, cyano, amino, hydroxyl, 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;

[0367] n is an integer from 0 to 5; and

[0368] p is 0, 1 or 2.

[0369] 7. The antitumor agent according to item 6, wherein the compound is represented by formula (x):

[0370]

[0371] wherein R1, R2, R2' and R3 are as defined in formula (vii) in item 4, E, R4 and m are as defined in formula (viii) in item 5, and A, R5, R6, n and p are as defined in formula (ix) in item 6;

[0372] When D is a monocyclic ring, D' is absent and the monocyclic ring is represented by ring D, which is an unsaturated 6-membered ring that is unsubstituted or substituted with R7, wherein D1 represents N or NH, and D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH;

[0373] When D is a fused ring, the fused ring is represented by ring D and ring D', wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted by R7, wherein D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is a saturated or unsaturated ring which is unsubstituted or substituted by R8 and forms a fused ring with ring D containing D1, D2 and D7;

[0374] R7 is 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;

[0375] R8 is halogen or substituted or unsubstituted C1-C10 alkyl;

[0376] q and r independently represent 0, 1 or 2.

[0377] 8. The antitumor agent according to item 7, wherein Ring A' forms a condensed ring with Ring A containing A3 and A4, and A1 and A5 are C, CH or CH2.

[0378] 9. The antitumor agent according to item 8, wherein R1 is hydrogen.

[0379] 10. The antitumor agent according to item 9, wherein R2 and R3 are independently represented, and R3 is hydrogen or a C1-C3 alkyl group.

[0380] 11. The antitumor agent according to item 10, wherein D6 in ring D is C.

[0381] 12. The antitumor agent according to item 11, wherein D3, D4 and D5 are C.

[0382] 13. The antitumor agent according to any one of items 7 to 12, wherein the compound is represented by formula (xi):

[0383]

[0384] wherein R2 and R2′ are as defined in formula (vii) in item 4; R2 and R3 are independently represented, and R3 is hydrogen or C1-C3 alkyl; E, R4 and m are as defined in formula (viii) in item 5; A, R5, n and p are as defined in formula (ix) in item 6, and D, R7, R8, q and r are as defined in formula (x) in item 7;

[0385] Ring A' is a saturated or unsaturated 5-membered ring, which forms a condensed ring with Ring A containing A3 and A4, wherein A1', A2', A3' independently represent C, CH, CH2, N, NH, O or S,

[0386] When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring; or

[0387] R6 may independently be halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy.

[0388] 14. The antitumor agent according to any one of items 6 to 13, wherein A2 is C.

[0389] 15. The antitumor agent according to any one of items 10 to 14, wherein R2 and R2' are linked together to form a 4- to 6-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 2 substituents independently represented by Ra; or

[0390] R2 and R2' independently represent, and R2 is unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, or unsubstituted or substituted 4- to 10-membered saturated heterocyclic group.

[0391] 16. The antitumor agent according to any one of items 10 to 15, wherein R3 is hydrogen.

[0392] 17. The antitumor agent according to any one of items 5 to 16, wherein R4 is halogen, cyano or C1-C6 alkyl.

[0393] 18. The antitumor agent according to any one of items 6 to 17, wherein R5 is hydroxy, halogen, C1-C10 alkyl, C1-C6 haloalkyl or C1-C10 alkoxy.

[0394] 19. The antitumor agent according to any one of items 6 to 18, wherein when the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring; or

[0395] Each R6 may independently represent a substituted or unsubstituted C1-C10 alkyl group or a substituted or unsubstituted C1-C10 alkoxy group.

[0396] 20. The antitumor agent according to any one of items 13 to 19, wherein the compound is represented by formula (xii):

[0397]

[0398] wherein R2 and R2' are as defined in item 15; E and m are as defined in formula (viii) in item 5, A, n and p are as defined in formula (ix) in item 6, R8, q and r are as defined in formula (x) in item 7, A' is as defined in formula (xi) in item 13, R4 is as defined in item 17, R5 is as defined in item 18, and R6 is as defined in item 19;

[0399] D is a condensed ring represented by ring D and ring D', ring D' is a saturated or unsaturated 5-membered ring, which forms a condensed ring containing D1, D2 and D7 with ring D, and D1' and D2' independently represent C, CH, CH2, N, NH or S,

[0400] R7 is halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy.

[0401] 21. The antitumor agent according to item 20, wherein R7 is halogen or a substituted or unsubstituted C1-C10 alkyl group.

[0402] 22. The compound represented by formula (vii):

[0403]

[0404] or a pharmaceutically acceptable salt thereof, wherein

[0405] A is a ring system selected from a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted fused ring;

[0406] D is a monocyclic ring having at least one amino group, the amino group combining with the carbonyl group between D and E to form an amide, wherein the monocyclic ring is unsubstituted or substituted with a substituent other than the amino group, or D is a substituted or unsubstituted fused ring;

[0407] E is a ring system selected from a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted fused ring;

[0408] R1 is hydrogen or substituted or unsubstituted C1-C6 alkyl;

[0409] R2 and R3 or R2 and R2' are joined together to form a 4- to 10-membered saturated heterocyclic ring, which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; or

[0410] R2, R2' and R3 independently represent, and R2 is hydrogen; or a C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C6-C10 aromatic hydrocarbon, a 4- to 10-membered saturated heterocyclic group, a 4- to 10-membered partially saturated heterocyclic group or a 4- to 10-membered unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;

[0411] R2' is hydrogen or C1-C6 alkyl which is unsubstituted or substituted by 1-2 substituents independently represented by Ra; and

[0412] R3 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted by 1-2 substituents independently represented by Ra;

[0413] R independently represents halogen, hydroxy, 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 a substituted or unsubstituted 4- to 10-membered saturated heterocyclic group;

[0414] 23. The compound according to item 22, wherein the compound is represented by formula (viii):

[0415]

[0416] wherein A, D, R1, R2' and R3 are as defined in formula (vii) in item 22,

[0417] E is an unsaturated 6-membered ring which is unsubstituted or substituted by R4, wherein E1, E2, E3 and E4 independently represent C, CH, CH2, N or NH;

[0418] R4 is 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;

[0419] m is an integer from 0 to 4; or a pharmaceutically acceptable salt thereof.

[0420] 24. The compound according to item 23, wherein the compound is represented by formula (ix):

[0421]

[0422] wherein D, R1, R2′ and R3 are as defined in formula (vii) in item 22, and E, R4 and m are as defined in formula (viii) in item 23,

[0423] When A is a monocyclic ring, A' and A" are absent, and the monocyclic ring is represented by Ring A, which is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH;

[0424] When A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring A", wherein ring A is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH, and ring A' or A" is a saturated or unsaturated ring which is unsubstituted or substituted by R6 and forms a fused ring with ring A comprising A3 and A4 or A4 and A5;

[0425] R5 is 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;

[0426] When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring that shares two adjacent atoms with ring A' or ring A"; or

[0427] R6 may independently represent halogen, cyano, amino, hydroxyl, 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;

[0428] n is an integer from 0 to 5; and

[0429] p is 0, 1, or 2;

[0430] or a pharmaceutically acceptable salt thereof.

[0431] 25. The compound according to item 24, wherein the compound is represented by formula (x):

[0432]

[0433] wherein R1, R2, R2' and R3 are as defined in formula (vii) in item 22, E, R4 and m are as defined in formula (viii) in item 23, and A, R5, R6, n and p are as defined in formula (ix) in item 24;

[0434] When D is a monocyclic ring, D' is absent and the monocyclic ring is represented by ring D, which is an unsaturated 6-membered ring that is unsubstituted or substituted with R7, wherein D1 represents N or NH, and D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH;

[0435] When D is a fused ring, the fused ring is represented by ring D and ring D', wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted by R7, wherein D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is a saturated or unsaturated ring which is unsubstituted or substituted by R8 and forms a fused ring with ring D containing D1, D2 and D7;

[0436] R7 is 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;

[0437] R8 is halogen or substituted or unsubstituted C1-C10 alkyl;

[0438] q and r independently represent 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0439] 26. The compound according to item 25, wherein Ring A' forms a condensed ring with Ring A containing A3 and A4, and A1 and A5 are C, CH or CH2; or a pharmaceutically acceptable salt thereof.

[0440] 27. The compound according to item 26, wherein R1 is hydrogen; or a pharmaceutically acceptable salt thereof.

[0441] 28. The compound according to item 27, wherein R2 and R3 are independently represented, and R3 is hydrogen or C1-C3 alkyl; or a pharmaceutically acceptable salt thereof.

[0442] 29. The compound according to item 28, wherein D6 in ring D is C; or a pharmaceutically acceptable salt thereof.

[0443] 30. The compound according to item 29, wherein D3, D4 and D5 are C; or a pharmaceutically acceptable salt thereof.

[0444] 31. The compound according to any one of items 25 to 30, wherein the compound is represented by formula (xi):

[0445]

[0446] wherein R2 and R2′ are as defined in formula (vii) in item 22; R2 and R3 are independently represented, and R3 is hydrogen or C1-C3 alkyl; E, R4 and m are as defined in formula (viii) in item 23; A, R5, n and p are as defined in formula (ix) in item 24, and D, R7, R8, q and r are as defined in formula (x) in item 25;

[0447] Ring A' is a saturated or unsaturated 5-membered ring, which forms a condensed ring with Ring A containing A3 and A4, wherein A1', A2', A3' independently represent C, CH, CH2, N, NH, O or S,

[0448] When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring; or

[0449] R6 may independently be halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy; or a pharmaceutically acceptable salt thereof.

[0450] 32. The compound according to any one of items 24 to 31, wherein A2 is C; or a pharmaceutically acceptable salt thereof.

[0451] 33. The compound according to any one of items 28 to 32, wherein R2 and R2' are linked together to form a 4- to 6-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; or

[0452] R2 and R2' independently represent, and R2 is unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, or unsubstituted or substituted 4-10 membered saturated heterocyclic group; or a pharmaceutically acceptable salt thereof.

[0453] 34. The compound according to any one of items 28 to 33, wherein R3 is hydrogen; or a pharmaceutically acceptable salt thereof.

[0454] 35. The compound according to any one of items 23 to 34, wherein R4 is halogen, cyano or C1-C6 alkyl; or a pharmaceutically acceptable salt thereof.

[0455] 36. The compound according to any one of items 24 to 35, wherein R5 is hydroxy, halogen, C1-C10 alkyl, C1-C6 haloalkyl or C1-C10 alkoxy; or a pharmaceutically acceptable salt thereof.

[0456] 37. The compound according to any one of items 24 to 36, wherein, when the number of R6 is two or more, two R6 can be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring; or

[0457] Each R6 may independently represent a substituted or unsubstituted C1-C10 alkyl group or a substituted or unsubstituted C1-C10 alkoxy group; or a pharmaceutically acceptable salt thereof.

[0458] 38. The compound according to any one of items 31 to 37, wherein the compound is represented by formula (xii) or a salt thereof:

[0459]

[0460] wherein R2 and R2' are as defined in item 33; E and m are as defined in formula (viii) in item 23, A, n and p are as defined in formula (ix) in item 24, R8, q and r are as defined in formula (x) in item 25, A' is as defined in formula (xi) in item 31, R4 is as defined in item 35, R5 is as defined in item 36, and R6 is as defined in item 37;

[0461] D is a condensed ring represented by ring D and ring D', ring D' is a saturated or unsaturated 5-membered ring, which forms a condensed ring containing D1, D2 and D7 with ring D, and D1' and D2' independently represent C, CH, CH2, N, NH or S,

[0462] R7 is halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy; or a pharmaceutically acceptable salt thereof.

[0463] 39. The compound according to item 38, wherein R7 is halogen or substituted or unsubstituted C1-C10 alkyl; or a pharmaceutically acceptable salt thereof.

[0464] 40. A medicament comprising the compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof.

[0465] 41. A pharmaceutical composition comprising the compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0466] 42. An antitumor agent comprising the compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0467] 43. An antitumor agent for oral administration, comprising the compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0468] 44. Use of a compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition.

[0469] 45. Use of the compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof for preparing an antitumor agent.

[0470] 46. ​​Use of the compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof for the preparation of an antitumor agent for oral administration.

[0471] 47. A compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof for use as a medicament.

[0472] 48. The compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof for use in treating tumors.

[0473] 49. A compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof for use in treating tumors by oral administration.

[0474] 50. A method for treating a tumor, comprising administering a therapeutically effective amount of a compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0475] 51. An antitumor agent comprising the compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof, and one or more other antitumor agents as active ingredients.

[0476] 52. An antitumor agent comprising the compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof as an active ingredient, which is administered in combination with one or more other antitumor agents

[0477] 53. Use of the compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof and one or more other antitumor agents for the preparation of an antitumor agent.

[0478] 54. Use of the compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof for the preparation of an antitumor agent, which is administered in combination with one or more other antitumor agents.

[0479] 55. A combination of a compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof and one or more other anti-tumor agents for use in treating tumors.

[0480] 56. A compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof for use in treating tumors, in combination with one or more other anti-tumor agents.

[0481] 57. A method for treating tumors, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof, and one or more other anti-tumor agents.

[0482] 58. A method for treating tumors, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof, in combination with one or more other anti-tumor agents.

[0483] 59. The antitumor agent according to item 1, wherein the tumor is cancer.

[0484] 60. The antitumor agent according to item 59, wherein the cancer is one or more selected from carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma and lymphoma.

[0485] 61. The antitumor agent according to item 60, wherein the squamous cell carcinoma is cancer of the cervix, tarsus, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx or esophagus.

[0486] 62. The antitumor agent according to item 60, wherein the adenocarcinoma is cancer of the prostate, small intestine, endometrium, cervix, large intestine, lung, pancreas, esophagus, rectum, uterus, stomach, breast or ovary.

[0487] 63. The antitumor agent according to item 59, wherein the tumor is rectal cancer, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, breast cancer or leukemia.

[0488] 64. A compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof for use in therapy, or a compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof for use in therapy.

[0489] 65. A pharmaceutical composition comprising the compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof for treating a tumor, or use of a pharmaceutical composition comprising the compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof for treating a tumor.

[0490] 66. A pharmaceutical composition comprising a compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof and other anti-tumor agents for use in treating tumors, or use of a pharmaceutical composition comprising a compound according to any one of items 22 to 39 or a pharmaceutically acceptable salt thereof and other anti-tumor agents for treating tumors.

[0491] Beneficial effects of the present invention

[0492] The compound or salt thereof according to one embodiment of the present invention binds to the mutant cysteine ​​(G12C) in the active form of KRAS. The compound or salt thereof according to a preferred embodiment of the present invention impairs KRAS function in KRAS G12C mutation-positive cancer cells, thereby exhibiting antitumor effects and being useful as an anticancer agent. BRIEF DESCRIPTION OF THE DRAWINGS

[0493] Figure 1 Illustration of a 2D interaction map of the binding site for the compound of Example 19. Residues are annotated with their 3-letter amino acid code. Figure 1 It was generated by the ligand interaction tool within the Molecular Operating Environment (MOE, version 2019.0101) (Molecular Operating Environment; CCG, I., 1255 University St., Suite 1600, Montreal, Quebec, Canada, H3B 3X3.).

[0494] Figure 2 Illustration of the co-crystal structure of Example 19 and Gppcp-bound K-Ras4B G12C, focusing on the covalent bond between chemical moiety G of Example 19 and cysteine ​​12 of K-Ras4B G12C, and the hydrogen bond between chemical moiety J of Example 19 and the γ-phosphate group of Gppcp (shown as a black dashed line). Figure 2 The molecular visualization system PyMOL (version 2.2.0) was used create.

[0495] Description of the implementation plan

[0496] The compound represented by the above formula (i) is a novel compound and is not taught or disclosed in any of the above documents.

[0497] Unless otherwise specified, examples of "substituents" as used herein include hydrogen, halogen, cyano, nitro, amino, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkenyl, unsaturated hydrocarbon, alkoxy, haloalkoxy, cycloalkyloxy, cycloalkyl-alkoxy, aralkyl, aralkyloxy, alkylthio, cycloalkyl-alkylthio, alkoxyalkyl, mono- or dialkylamino, cycloalkyl-alkylamino, aromatic hydrocarbon, acyl, alkylcarbonyl, acyloxy, arylcarbonyl, oxo, carboxyl, alkoxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aralkyloxycarbonyl, carbamoyl, sulfonyl, saturated, partially saturated or unsaturated heterocyclic group, aromatic hydrocarbon, etc. Unless otherwise specified, when the above-mentioned substituents are present, their number is generally one, two or three, preferably one or two, and most preferably one.

[0498] Specific examples of "halogen" as used herein include chlorine, bromine, fluorine and iodine, among which chlorine, fluorine and bromine are preferred, and chlorine and fluorine are more preferred.

[0499] As used herein, "alkyl" refers to a straight-chain 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. "Alkyl" is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

[0500] As used herein, "alkenyl" refers to a straight or branched unsaturated hydrocarbon group containing at least one double bond (e.g., one to two double bonds, and preferably one double bond). Examples include C2-C6 alkenyl, such as vinyl, allyl, 1-propenyl, 2-methyl-2-propenyl, isopropenyl, 1-butenyl, 2-butenyl or 3-butenyl, 2-pentenyl, 3-pentenyl or 4-pentenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl and 5-hexenyl, of which vinyl, allyl, 1-propenyl and 2-methyl-2-propenyl are preferred.

[0501] As used herein, "alkynyl" refers to a straight 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, such as ethynyl, 1-propynyl or 2-propynyl, 1-butynyl, 2-butynyl or 3-butynyl, and 1-methyl-2-propynyl, of which ethynyl and 2-propynyl are preferred.

[0502] As used herein, "haloalkyl" refers to an alkyl group as described above having at least one halogen atom (preferably 1 to 10, more preferably 1 to 3 halogen atoms). Examples include C1-C10 haloalkyl groups 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, of which trifluoromethyl, difluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, and 1,1,1-trifluoroethyl are preferred.

[0503] As used herein, "hydroxyalkyl" refers to an alkyl group as described above having at least one hydroxyl group (preferably 1 to 10, more preferably 1 to 2 hydroxyl groups). Examples include C1-C6 hydroxyalkyl groups such as hydroxymethyl, hydroxyethyl, 1-hydroxypropyl, 2-hydroxybutyl, and 1,2-dihydroxyisopropyl, of which 2-hydroxybutyl and 2-dihydroxyisopropyl are preferred.

[0504] As used herein, "cycloalkyl" refers to a monocyclic or polycyclic saturated hydrocarbon, including bicyclic, tricyclic, bridged, and spirocyclic hydrocarbons. Examples include C3-C10 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclodecyl, [2.2.0]bicyclohexyl, [2.2.1]bicycloheptyl, [3.1.1]bicycloheptyl, and [3.2.1]bicyclooctyl, of which cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, [2.2.0]bicyclohexyl, [2.2.1]bicycloheptyl, [3.1.1]bicycloheptyl, and [3.2.1]bicyclooctyl are preferred, and cyclobutyl and cyclopentyl are particularly preferred.

[0505] 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 cycloalkenyl groups, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclodecenyl, of which cyclopropenyl, cyclobutenyl, and cyclopentenyl are preferred, and cyclobutenyl and cyclopentenyl are particularly preferred.

[0506] As used herein, "unsaturated hydrocarbon" refers to a linear 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. Among them, C2-C4 linear or branched hydrocarbons containing at least one carbon-carbon double or triple bond are preferred, and vinyl, allyl, and 1-propenyl are more preferred.

[0507] As used herein, "alkoxy" refers to an oxy group having the above-mentioned alkyl group. Examples include C1-C10 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, and hexyloxy groups, of which methoxy, ethoxy, and n-propoxy groups are preferred, and methoxy and ethoxy groups are more preferred.

[0508] As used herein, "haloalkoxy" refers to an alkoxy group as described above having at least one halogen atom (preferably 1 to 13, more preferably 1 to 3 halogen atoms). Examples include C1-C10 haloalkoxy groups such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, fluoroethoxy, 1,1,1-trifluoroethoxy, monofluoro-n-propoxy, perfluoro-n-propoxy, and perfluoro-isopropoxy.

[0509] As used herein, "cycloalkoxy" refers to an oxy group having the above-mentioned cycloalkyl group. Examples include C3-C10 cycloalkoxy groups such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, among which cyclobutyloxy, cyclopentyloxy and cyclohexyloxy are preferred.

[0510] As used herein, "cycloalkyl-alkoxy" refers to an alkoxy group as described above having at least one cycloalkyl group as described above. Examples include C3-C10 cycloalkyl-C1-C10 alkoxy groups such as cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, and cycloheptylmethoxy, among which cyclohexylmethoxy is preferred.

[0511] As used herein, "aralkyl" refers to the above-mentioned alkyl group substituted by the above-mentioned aromatic hydrocarbon. Examples include C7-C16 aralkyl groups such as benzyl, phenethyl, phenylpropyl, naphthylmethyl and naphthylethyl, among which benzyl is preferred.

[0512] As used herein, "aralkyloxy" refers to an oxy group having the above-mentioned aralkyl group. Examples include C7-C20 aralkyloxy groups such as benzyloxy, phenethyloxy, naphthylmethoxy, and fluorenylmethoxy.

[0513] As used herein, "alkylthio" refers to a sulfhydryl group having the above-mentioned alkyl group. Examples include C1-C10 alkylthio groups such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, n-pentylthio, isopentylthio, and hexylthio.

[0514] As used herein, "cycloalkyl-alkylthio" refers to an alkylthio group as described above having at least one cycloalkyl group as described above. Examples include C3-C10 cycloalkyl-C1-C10 alkylthio groups, such as cyclopropylmethylthio, cyclobutylmethylthio, cyclopentylmethylthio, cyclohexylmethylthio, and cycloheptylmethylthio.

[0515] As used herein, "alkoxyalkyl" refers to an alkyl group as described above having at least one alkoxy group as described above. Examples include C1-C10 alkoxy-C1-C10 alkyl groups such as methoxymethyl, ethoxyethyl, methoxyethyl and methoxypropyl, among which methoxymethyl is preferred.

[0516] As used herein, "alkylamino" refers to an amino group having one or two alkyl groups as described above. Specific examples include C1-C10 alkylamino groups such as methylamino, ethylamino, dimethylamino, diethylamino, and ethylmethylamino, among which methylamino, dimethylamino, and diethylamino groups are preferred.

[0517] As used herein, "monoalkylamino" refers to an amino group having one alkyl group as described above. Examples include C1-C10 monoalkylamino groups such as methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, n-pentylamino, isopentylamino, and hexylamino, among which methylamino and ethylamino are preferred.

[0518] As used herein, "dialkylamino" refers to an amino group having two alkyl groups as described above. Examples include C1-C10 dialkylamino groups 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(tert-butyl)amino, di(n-pentyl)amino, diisopentylamino, dihexylamino, methylethylamino, and methylisopropylamino, among which dimethylamino and diethylamino are preferred.

[0519] As used herein, "cycloalkyl-alkylamino" refers to the above-mentioned alkylamino group having the above-mentioned cycloalkyl group, wherein the cycloalkyl group is attached to the alkyl portion of the alkylamino group. Examples include C3-C10 cycloalkyl-C1-C10 alkylamino groups such as cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino, cycloheptylmethylamino, and cyclohexyldimethylamino, among which cyclohexyldimethylamino is preferred.

[0520] As used herein, "arene" refers to a monocyclic or polycyclic aromatic hydrocarbon as a ring substituent containing carbon and hydrogen and containing an unsaturated bond, wherein the monocyclic or polycyclic aromatic hydrocarbon contains 4e+2 electrons (e is an integer of 1 or greater) in the cyclic n-electron system. Examples include phenyl, naphthyl, tetrahydronaphthyl, anthracenyl, etc., and phenyl is preferred.

[0521] As used herein, "acyl" refers to an alkylcarbonyl group or an arylcarbonyl group.

[0522] As used herein, "alkylcarbonyl" refers to a carbonyl group having the above-mentioned alkyl group. Examples include C1-C10 alkylcarbonyl groups such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, and hexylcarbonyl, of which methylcarbonyl is preferred. In addition, in the present invention, C1-C10 alkylcarbonyl refers to a (C1-C10 alkyl)carbonyl group.

[0523] As used herein, "acyloxy" refers to an acyl group having the above-mentioned carbonyloxy group. Examples include C1-C10 acyloxy groups such as alkylcarbonyloxy or arylcarbonyloxy.

[0524] As used herein, "arylcarbonyl" refers to a carbonyl group having the above-mentioned aromatic hydrocarbon. Examples include (C6-C20 aryl)carbonyl groups such as phenylcarbonyl, naphthylcarbonyl, fluorenylcarbonyl, anthracenylcarbonyl, diphenylcarbonyl, tetrahydronaphthylcarbonyl, chromanylcarbonyl, 2,3-dihydro-1,4-dioxanaphthylcarbonyl, indanylcarbonyl, and phenanthrenylcarbonyl.

[0525] As used herein, "alkoxycarbonyl" refers to a carbonyl group having the above-mentioned alkoxy group. Examples include (C1-C10 alkoxy)carbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, and hexyloxycarbonyl, among which tert-butoxycarbonyl is preferred.

[0526] As used herein, "alkylcarbonyloxy" refers to an oxy group having the above-mentioned alkylcarbonyl group. Examples include (C1-C10 alkyl)carbonyloxy groups, such as methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, isobutylcarbonyloxy, tert-butylcarbonyloxy, n-pentylcarbonyloxy, isopentylcarbonyloxy, and hexylcarbonyloxy, among which tert-butylcarbonyloxy is preferred.

[0527] As used herein, "arylcarbonyloxy" refers to an oxy group having the above-mentioned arylcarbonyl group. Examples include (C6-C13 aryl)carbonyloxy groups such as phenylcarbonyloxy, naphthylcarbonyloxy, fluorenylcarbonyloxy, anthracenylcarbonyloxy, diphenylcarbonyloxy, tetrahydronaphthylcarbonyloxy, chromanylcarbonyloxy, 2,3-dihydro-1,4-dioxanaphthylcarbonyloxy, indanylcarbonyloxy, and phenanthrenylcarbonyloxy.

[0528] As used herein, the "aralkyloxycarbonyl group" refers to a carbonyl group having the above-mentioned aralkyloxy group. Examples include (C6-C20 aralkyl)oxycarbonyl groups such as benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethoxycarbonyl, and fluorenylmethoxycarbonyl.

[0529] As used herein, " saturated heterocyclic group " refers to a monocyclic or polycyclic saturated heterocyclic group containing at least one heteroatom (preferably with 1 to 5, more preferably 1 to 3 heteroatoms) selected from nitrogen, oxygen and sulfur. Monocyclic or polycyclic saturated heterocyclic groups include monocyclic, bicyclic, tricyclic, bridged and spirocyclic saturated heterocyclic groups. Examples include aziridine, azetidinyl, imidazolidinyl, morpholino, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, thiazolidinyl, oxazolidinyl etc., wherein azetidinyl, pyrrolidinyl and piperidinyl are preferred, and azetidinyl and pyrrolidinyl are more preferred.

[0530] As used herein, "partially saturated heterocyclic group" refers to a monocyclic or polycyclic partially saturated heterocyclic group containing at least one heteroatom selected from nitrogen, oxygen and sulfur (preferably having 1 to 5, more preferably 1 to 3 heteroatoms). Monocyclic or polycyclic partially saturated heterocyclic groups include monocyclic, bicyclic, tricyclic, bridged and spirocyclic partially saturated heterocyclic groups. Examples include indoline, 1,3-dihydroisobenzofuran, 2,3-dihydro-1H-benzo[d]imidazole, 1,3-benzodioxole, etc., of which indoline, 2,3-dihydro-1H-benzo[d]imidazole and 1,3-benzodioxole are preferred, and indoline, 1,3-benzodioxole are more preferred.

[0531] As used herein, "unsaturated heterocyclic group" refers to a monocyclic or polycyclic fully unsaturated heterocyclic group containing at least one heteroatom selected from nitrogen, oxygen and sulfur (preferably containing 1 to 5, more preferably 1 to 3 heteroatoms). Monocyclic or polycyclic unsaturated heterocyclic groups include monocyclic, bicyclic, tricyclic, bridged and spirocyclic unsaturated heterocyclic groups. Examples include imidazolyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, triazolopyridinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, furanyl, benzofuranyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, methylenedioxyphenyl, ethylenedioxyphenyl, dihydrobenzofuranyl, imidazopyridinyl, indazolyl, etc., among which imidazolyl, pyrazolyl, thiazolyl, isoxazolyl, pyridinyl, benzoxazolyl, benzothiazolyl, imidazopyridinyl, indazolyl, indolyl, indolizinyl and furyl are preferred, imidazolyl, pyrazolyl, pyridinyl, benzoxazolyl, benzothiazolyl, imidazopyridinyl, indazolyl, indolyl and indolizinyl are more preferred, and benzoxazolyl, benzothiazolyl, imidazopyridinyl, indolyl, indolyl and indolizinyl are most preferred.

[0532] As used herein, the term "CA-CB" used in the description of a group means 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 a C6-C14 aromatic hydrocarbon is bonded. In addition, the term "A- to B-membered" means that the number of atoms constituting the ring (the number of ring members) is A to B. More specifically, "4- to 10-membered saturated heterocyclic group" refers to a saturated heterocyclic group containing 4 to 10 ring members.

[0533] As used herein, the term C refers to carbon, N refers to nitrogen, S refers to sulfur, and O refers to oxygen.

[0534] 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 alkenyl (preferably -CH2-, -CH(CH3)-, -C(CH3)2-), substituted or unsubstituted C2-C6 alkenylene, substituted or unsubstituted C2-C6 alkynylene, substituted or unsubstituted monocyclic or substituted or unsubstituted fused rings, and combinations thereof. Preferably, the linker is selected from a combination of a substituted or unsubstituted monocyclic or substituted or unsubstituted fused ring and -C(=O)-; and a combination of a substituted or unsubstituted monocyclic or substituted or unsubstituted fused ring and -NR1-.

[0535] As used herein, the term "monocycle" refers to a substituted or unsubstituted ring having a monocyclic structure, and may refer to a substituted or unsubstituted monocycle. In one embodiment, examples of the monocycle include a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted C6-C10 aromatic hydrocarbon, a substituted or unsubstituted 4- to 10-membered saturated heterocyclic group, a substituted or unsubstituted 4- to 10-membered partially saturated heterocyclic group, or a substituted or unsubstituted 4- to 10-membered unsaturated heterocyclic group.

[0536] As used herein, the term "fused ring" refers to a substituted or unsubstituted group formed by two or more rings, wherein the two or more rings share two or more atoms. In one embodiment, examples of fused rings include fused rings 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- to 10-membered saturated heterocycles, substituted or unsubstituted 7- to 10-membered partially saturated heterocycles, and substituted or unsubstituted 7- to 10-membered unsaturated heterocycles.

[0537] In one embodiment, the antitumor agent of the present invention comprises a compound covalently bound to GTP-bound KRAS G12C or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the compound has the following formula:

[0538] A-L1-L2-GJ

[0539] in,

[0540] A is a chemical moiety capable of interacting with the region between switch 2 and the α3-helix;

[0541] L1 is a linker;

[0542] L2 is a linker;

[0543] 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.

[0544] In a preferred embodiment, G is represented by the formula:

[0545]

[0546] In another preferred embodiment, G is represented by the formula:

[0547]

[0548] In one embodiment, the antitumor agent of the present invention comprises a compound covalently bound to GTP-bound KRAS G12C or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the compound has the following formula:

[0549] A-L1-L2-GJ

[0550] in,

[0551] A is a chemical moiety capable of interacting with the region between switch 2 and the α3-helix;

[0552] L1 is a linker;

[0553] L2 is a linker;

[0554] And GJ is represented by the following formula:

[0555]

[0556] In another preferred embodiment, GJ is represented by the formula:

[0557]

[0558] Notation used in this article Refers to the point where a chemical moiety is attached to the rest of a molecule or chemical formula.

[0559] As used herein, the term "a chemical moiety capable of interacting with the region between switch 2 and α3-helix" in moiety A refers to a chemical moiety that can interact with the region between switch 2 (residues 60 to 76) and α3-helix (residues 86 to 103) of K-Ras. In one embodiment, moiety 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 switch 2 and the α3-helix" refers to a region formed by one or more amino acids selected from the group consisting of 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 the group consisting of arginine-68, aspartic acid-69, methionine-72, glutamine-99, isoleucine-100, and valine-103. In one embodiment, the K-Ras protein can comprise an amino acid sequence that is, for example, 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 one of SEQ ID NOs 1 and 2.

[0560] In one embodiment, the term "chemical moiety capable of interacting with the region between switch 2 and α3-helix" in part A of a compound of the invention can be determined by performing X-ray structural analysis on a co-crystal of a compound of the invention and GTP-bound KRAS G12C and identifying a moiety that interacts with at least one amino acid moiety present in the region between switch 2 and α3-helix of GTP-bound KRAS G12C. Such X-ray structural analysis can be performed using a ligand interaction tool in a molecular manipulation environment. In one embodiment, the 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 capable of interacting with the region between switch 2 and the α3-helix can be a ring system selected from a substituted or unsubstituted single ring or a substituted or unsubstituted fused ring.

[0561] As used herein, the term "an electrophilic chemical moiety capable of forming a covalent bond with GTP-bound K-Ras G12C" in Section G refers to a chemical moiety that can electrophilically react with a mutation at the 12th amino acid (cysteine-12 residue) of GTP-bound K-Ras to form a covalent bond.

[0562] As used herein, the term "chemical moiety capable of interacting with GTP" in moiety J refers to a chemical moiety that can interact with GTP bound to K-Ras. In one embodiment, the chemical moiety interacts with the γ-phosphate at the end of GTP, preferably via a hydrogen bond, a covalent bond, or an ionic bond. In a preferred embodiment, moiety J is -NR2R3 and can bind directly to moiety G or bind to moiety G via -CH2- or -CHR2'-. In a more preferred embodiment, moiety J is -CHR2'-NR2R3.

[0563] In one embodiment, in the compound represented by any one of formulae (i) to (xii), R1 represents hydrogen or C1-C6 alkyl.

[0564] In one embodiment, the "C1-C6 alkyl" represented by R1 can be a 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, and is preferably a methyl group, an ethyl group or a tert-butyl group, more preferably a methyl group or an ethyl group, and particularly preferably a methyl group.

[0565] In one embodiment, R1 is hydrogen or substituted or unsubstituted C1-C3 alkyl.

[0566] R1 is preferably hydrogen, methyl, ethyl or tert-butyl.

[0567] R1 is more preferably hydrogen or methyl.

[0568] Most preferably, R1 is hydrogen.

[0569] In one embodiment, in the compound represented by any one of formulas (i) to (xi) of the present invention, R2 and R3 can be linked together to form a 4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra, and R2' is hydrogen or a C1-C6 alkyl group which is unsubstituted or substituted with 1-2 substituents independently represented by Ra.

[0570] The “4- to 10-membered saturated heterocyclic group” in the “4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted by 1 to 3 substituents independently represented by Ra” formed by R2 and R3 is preferably a 4- to 8-membered, 5- to 7-membered or 5- to 6-membered saturated heterocyclic ring which is unsubstituted or substituted by 1 to 2 substituents, more preferably a pyrrolidinyl, piperidinyl or piperazinyl group.

[0571] In the "4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted by 1 to 2 substituents independently represented by Ra" formed by R2 and R3, "substituted by Ra" preferably means substituted by halogen, hydroxy, 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 The alkyl group may be a substituted or unsubstituted C1-C10 monoalkylamino group, a substituted or unsubstituted C1-C10 dialkylamino group, a substituted or unsubstituted C1-C10 alkoxy group, a substituted or unsubstituted C1-C10 alkylsulfonyl group, a substituted or unsubstituted C1-C10 acyl group, a substituted or unsubstituted C1-C10 alkoxycarbonyl group, or a substituted or unsubstituted 4- to 10-membered saturated heterocyclic group, more preferably substituted by halogen, hydroxyl or C1-C6 alkyl, and most preferably hydroxyl.

[0572] The "4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted by 1 to 2 substituents independently represented by Ra" formed by R2 and R3 preferably refers to a pyrrolidinyl group, a piperidinyl group or a piperazinyl group.

[0573] The “4- to 10-membered saturated heterocyclic group” in the “4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted by 1 to 3 substituents independently represented by Ra” formed by R2 and R2′ is preferably a 4- to 8-membered, 5- to 7-membered or 5- to 6-membered saturated heterocyclic ring which is unsubstituted or substituted by 1 to 2 substituents, more preferably a pyrrolidinyl, piperidinyl or piperazinyl group.

[0574] In the "4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted by 1 to 2 substituents independently represented by Ra" formed by R2 and R2', "substituted by Ra" preferably means substituted by 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 ...3-C10 cycloalkyl, substituted or unsubstituted C3-C10 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C The alkyl group may be a substituted or unsubstituted C1-C10 monoalkylamino group, a substituted or unsubstituted C1-C10 dialkylamino group, a substituted or unsubstituted C1-C10 alkoxy group, a substituted or unsubstituted C1-C10 alkylsulfonyl group, a substituted or unsubstituted C1-C10 acyl group, a substituted or unsubstituted C1-C10 alkoxycarbonyl group, or a substituted or unsubstituted 4- to 10-membered saturated heterocyclic group, more preferably substituted by halogen, hydroxyl or C1-C6 alkyl, and most preferably hydroxyl.

[0575] The "4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted by 1 to 2 substituents independently represented by Ra" formed by R2 and R2' is preferably pyrrolidinyl, piperidinyl or piperazinyl.

[0576] In one embodiment, R2, R2' and R3 may independently represent, and in the compound represented by any one of formulae (i) to (xii) of the present invention,

[0577] R2 is hydrogen; or a C1-C10 alkyl group, a C2-C10 alkenyl group, a C2-C10 alkynyl group, a C3-C10 cycloalkyl group, a C1-C10 alkoxy group, a C6-C10 aromatic group, a 4- to 10-membered saturated heterocyclic group, a 4- to 10-membered partially saturated heterocyclic group, or a 4- to 10-membered 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 which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; and

[0578] R3 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted with 1 to 2 substituents independently represented by Ra.

[0579] The "C1-C10 alkyl group" represented by R2 may be a C2-C6 alkyl group, a C3-C6 alkyl group, a C4-C6 alkyl group, a C5-C6 alkyl group, a C1-C5 alkyl group, a C1-C4 alkyl group, a C1-C3 alkyl group or a C1-C2 alkyl group, preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, a sec-butyl group, an isobutyl group or an n-pentyl group, and more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, a sec-butyl group, an isobutyl group or an n-pentyl group (C3-C6 alkyl group).

[0580] "Ra" which may substitute the "C1-C10 alkyl" represented by R2 may be, for example, the substituents described above, and is preferably halogen, cyano, hydroxy, C3-C7 cycloalkyl or a 4- to 10-membered saturated heterocyclic group, more preferably hydroxy.

[0581] The “C1-C10 alkyl group which is unsubstituted or substituted by 1 to 2 substituents independently represented by Ra” represented by R2 is preferably a C1-C6 alkyl group, 1,2-dihydroxyisopropyl group, 2-hydroxypropyl group, more preferably a C1-C6 alkyl group, still more preferably a methyl group, an ethyl group, an isopropyl group or a tert-butyl group, and most preferably a tert-butyl group.

[0582] The "C2-C10 alkenyl" represented by R2 may be 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, more preferably vinyl or isopropenyl.

[0583] "Ra" which may substitute the "C2-C10 alkyl" represented by R2 may be, for example, the substituents described above, and is preferably halogen, cyano, C1-C6 alkyl or hydroxy, more preferably chlorine, fluorine or methyl, more preferably fluorine.

[0584] The “unsubstituted or substituted C2-C10 alkenyl group” represented by R2 is preferably a C2-C6 alkenyl group which may contain halogen, more preferably vinyl, 1-propenyl, 2-methyl-2-propenyl or 1-(trifluoromethyl)vinyl, and more preferably vinyl or 1-(trifluoromethyl)vinyl.

[0585] The "C2-C10 alkynyl" represented by R2 may be a C2-C6 alkynyl, a C3-C6 alkynyl, a C4-C6 alkynyl, a C5-C6 alkynyl, a C2-C5 alkynyl, a C2-C4 alkynyl or a C2-C3 alkynyl, and is preferably an ethynyl or 1-propynyl.

[0586] "Ra" which may substitute the "C2-C10 alkynyl group" represented by R2 may be, for example, the substituents described above, and is preferably halogen or hydroxy, more preferably fluorine or chlorine.

[0587] The "C2-C10 alkynyl group which is unsubstituted or substituted by 1 to 2 substituents independently represented by Ra" represented by R2 is preferably ethynyl, 1-chloroethynyl or 1-propynyl.

[0588] 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, and more preferably a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[3.1.0]hexyl, more preferably a cyclohexyl.

[0589] "Ra" which can replace the "C3-C10 cycloalkyl" represented by R2 can be the above-mentioned substituents, preferably hydroxyl, halogen, C2-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 monoalkylamino, C1-C6 dialkylamino, saturated heterocyclic group, more preferably fluorine, chlorine, hydroxyl, methyl, ethyl, n-propyl, methoxy, ethoxy, difluoromethoxy, dimethylamino, diethylamino, isopropylamino, trifluoromethyl, dioxolane.

[0590] The “unsubstituted or substituted C3-C10 cycloalkyl group which is independently substituted by 1-2 substituents represented by Ra” represented by R2 is preferably a C3-C10 cycloalkyl group which may be substituted by a hydroxyl group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C6 monoalkylamino group, a C1-C6 dialkylamino group or a saturated heterocyclic group, and is preferably a C3-C10 cycloalkyl group which may be substituted by a hydroxyl group, a C1-C3 alkyl group, a C1-C3 haloalkyl group, a C1-C3 alkoxy group, a C1-C3 haloalkoxy group, a C1-C3 monoalkylamino group, a C1-C3 dialkylamino group or a saturated heterocyclic group. The present invention further comprises a C3-C6 cycloalkyl group substituted by a cyclopropyl group, a saturated heterocyclic group, more preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a 4-hydroxycyclohexyl group, a 4-methoxycyclohexyl group, a 4-ethoxycyclohexyl group, a 4-diethylaminocyclohexyl group, a 4-dimethylaminocyclohexyl group, a 4-difluoromethoxycyclohexyl group, a 4,4-difluorocyclohexyl group, a difluorobicyclo[3.1.0]hexane group, a 8-methyl-1,4-dioxaspiro{4,5}decane group or a 4-dioxaspiro{4,5}decane group, more preferably a 4-hydroxycyclohexyl group, a 4-methoxycyclohexyl group, a 4-ethoxycyclohexyl group or a 4-diethylaminocyclohexyl group.

[0591] The "unsubstituted or substituted C1-C10 alkoxy group" represented by R2 is preferably a methoxy group or an ethoxy group.

[0592] The "unsubstituted or substituted C6-C10 aromatic hydrocarbon" represented by R2 is preferably a phenyl group.

[0593] The “4- to 10-membered saturated heterocyclic group” represented by R2 may be a 4- to 8-membered, 5- to 8-membered, 5- to 7-membered or 5- to 6-membered saturated heterocyclic group, preferably a monocyclic or bicyclic 4- to 10-membered saturated heterocyclic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a monocyclic 4- to 8-membered saturated heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably a pyrrolidinyl, piperidinyl, piperazinyl (piperadinyl), tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, 8-oxabicyclo[3,2,1]octanyl, 8-methyl-1,4-dioxaspiro{4,5}decanethianyl, more preferably a piperidinyl, piperazinyl, 2-ethyltetrahydropyranyl or tetrahydropyranyl.

[0594] "Ra" which may replace the "4- to 10-membered saturated heterocyclic group" represented by R2 may be the above-mentioned substituents, or preferably halogen, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 monoalkylamino, C1-C6 dialkylamino, C1-C6 alkylsulfonyl, C1-C6 alkylcarbonyl, more preferably fluorine, chlorine, hydroxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, difluoromethoxy, dimethylamino, diethylamino, isopropylamino, trifluoromethyl, dioxolane, methoxycarbonyl or ethylcarboxyl, and most preferably methyl, dimethylamino, diethylamino or isopropylamino.

[0595] The “4- to 10-membered saturated heterocyclic group which is unsubstituted or substituted by 1 to 2 substituents independently represented by Ra” represented by R2 is preferably a monocyclic 4- to 8-membered saturated heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, which is substituted by at least one substituent selected from the group consisting of 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 Preferred are 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-butylcarbamatetetrahydropyranyl, more preferably N-isopropyl-4-piperidinyl, 1-methyl-4-tetrahydropyranyl, 2-ethyltetrahydropyranyl or 3,5-dimethyltetrahydropyranyl.

[0596] The “4- to 10-membered partially saturated heterocyclic group which is unsubstituted or substituted by 1 to 2 substituents independently represented by Ra” represented by R2 is preferably a monocyclic or bicyclic 4- to 10-membered, 4- to 8-membered, 5- to 8-membered, 5- to 7-membered or 5- to 6-membered partially saturated heterocyclic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a monocyclic 4- to 7-membered partially saturated heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, and is preferably 4H-pyranyl, indoline, 1,3-dihydroisobenzofuran, 2,3-dihydro-1H-benzo[d]imidazole, 1,3-benzodioxole.

[0597] The "5- to 10-membered unsaturated heterocyclic group which is unsubstituted or substituted by 1 to 2 substituents independently represented by Ra" represented by R2 is preferably a monocyclic or bicyclic 4- to 10-membered, 4- to 8-membered, 5- to 8-membered, 5- to 7-membered or 5- to 6-membered unsaturated heterocyclic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a monocyclic 5- to 7-membered unsaturated heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably pyridyl, imidazolyl, thienyl, pyrrole phenyl, benzothiazolyl, benzothiophenyl, furanyl, benzofuranyl, purinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, methylenedioxyphenyl, ethylenedioxyphenyl, dihydrobenzofuranyl, imidazopyridinyl, indazolyl, more preferably pyridyl.

[0598] R6 is preferably a C1-C6 alkyl group, a C3-C10 cycloalkyl group, a 4- to 10-membered saturated heterocyclic group, each of which is unsubstituted or substituted with 1 to 2 substituents independently represented by Ra.

[0599] R2 is more preferably a C3-C6 alkyl group, a cycloalkyl group, a 6- to 10-membered saturated heterocyclic group, each of which is unsubstituted or substituted with 1 to 2 substituents independently represented by Ra.

[0600] Ra which may substitute for R2 is preferably halogen, cyano, hydroxy, C1-C10 alkylamino, C1-C10 alkoxy, C1-C10 alkylsulfonyl, C3-C7 cycloalkyl or a 4- to 10-membered saturated heterocyclic group.

[0601] More preferably, Ra which may substitute for R2 is hydroxy, dimethylamino, methoxy or methylsulfonyl.

[0602] R2 which is unsubstituted or substituted by 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-butylcarbamatetetrahydropyranyl.

[0603] 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.

[0604] R2 is most preferably tert-butyl, cyclohexyl, 4-hydroxycyclohexyl, 4-methoxycyclohexyl, or 4-diethylaminocyclohexyl.

[0605] The "C1-C6 alkyl" in the "unsubstituted or substituted C1-C6 alkyl group independently represented by Ra" in R2' is preferably methyl, ethyl, isopropyl or tert-butyl, more preferably methyl or ethyl, most preferably methyl.

[0606] The "unsubstituted or substituted C1-C6 alkyl group" in R2' is preferably a methyl group, an ethyl group, an isopropyl group or a tert-butyl group, more preferably a methyl group or an ethyl group, and most preferably a methyl group.

[0607] "Ra" which may substitute the "C1-C10 alkyl" represented by R2 may be, for example, the substituents described above, and is preferably halogen, cyano, hydroxy, C3-C7 cycloalkyl or a 4- to 10-membered saturated heterocyclic group, more preferably hydroxy.

[0608] R2' is preferably hydrogen or C1-C6 alkyl.

[0609] More preferably, R2' is hydrogen, methyl, ethyl, isopropyl or tert-butyl.

[0610] R2' is most preferably hydrogen.

[0611] The "C1-C6 alkyl group" represented by R3 is preferably a methyl group, an ethyl group, an isopropyl group or a tert-butyl group, more preferably a methyl group or an ethyl group, most preferably a methyl group.

[0612] "Ra" which may substitute the "C1-C10 alkyl" represented by R3 may be, for example, the substituents described above, and is preferably halogen, cyano, hydroxy, C3-C7 cycloalkyl or a 4- to 10-membered saturated heterocyclic group, more preferably hydroxy.

[0613] More preferably, R3 is hydrogen or methyl, ethyl, isopropyl or tert-butyl.

[0614] More preferably, R3 is hydrogen or methyl.

[0615] Most preferably, R3 is hydrogen.

[0616] In one embodiment, R2 and R3 can be independently represented, and in the compound represented by any one of formulas (i) to (Xii) of the present invention, R2 and R2' are linked together to form a 4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra, and R3 is hydrogen or a C1-C6 alkyl which is unsubstituted or substituted with 1-2 substituents independently represented by Ra.

[0617] The “4- to 10-membered saturated heterocyclic group” in the “4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted by 1 to 3 substituents independently represented by Ra” formed by R2 and R2′ is preferably a 4- to 8-membered, 5- to 7-membered or 5- to 6-membered saturated heterocyclic ring which is unsubstituted or substituted by 1 to 2 substituents, more preferably a pyrrolidinyl, piperidinyl or piperazinyl group.

[0618] In the "4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted by 1 to 2 substituents independently represented by Ra" formed by R2 and R2', "substituted by Ra" preferably means substituted by 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 ...3-C10 cycloalkyl, substituted or unsubstituted C3-C10 haloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C The alkyl group may be a substituted or unsubstituted C1-C10 monoalkylamino group, a substituted or unsubstituted C1-C10 dialkylamino group, a substituted or unsubstituted C1-C10 alkoxy group, a substituted or unsubstituted C1-C10 alkylsulfonyl group, a substituted or unsubstituted C1-C10 acyl group, a substituted or unsubstituted C1-C10 alkoxycarbonyl group, or a substituted or unsubstituted 4- to 10-membered saturated heterocyclic group, more preferably substituted by halogen, hydroxyl or C1-C6 alkyl, and most preferably hydroxyl.

[0619] The "4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted by 1 to 2 substituents independently represented by Ra" formed by R2 and R2' is preferably pyrrolidinyl, piperidinyl or piperazinyl.

[0620] The "C1-C6 alkyl group" represented by R3 is preferably a methyl group, an ethyl group, an isopropyl group or a tert-butyl group, more preferably a methyl group or an ethyl group, most preferably a methyl group.

[0621] "Ra" which may substitute the "C1-C10 alkyl" represented by R3 may be, for example, the substituents described above, and is preferably halogen, cyano, hydroxy, C3-C7 cycloalkyl or a 4- to 10-membered saturated heterocyclic group, more preferably hydroxy.

[0622] More preferably, R3 is hydrogen or methyl, ethyl, isopropyl or tert-butyl.

[0623] More preferably, R3 is hydrogen or methyl.

[0624] Most preferably, R3 is hydrogen.

[0625] In one embodiment, in the compounds of the present invention represented by any one of formulae (ii) to (xii), R4 represents cyano, hydroxyl, 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.

[0626] The "halogen" represented by R4 is preferably chlorine, bromine, fluorine and iodine, among which chlorine, fluorine and bromine are preferred, chlorine and fluorine are more preferred, and fluorine is most preferred.

[0627] The "C1-C10 alkyl group" in the "substituted or unsubstituted C1-C10 alkyl group" represented by R4 is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, a sec-butyl group, an isobutyl group or an n-pentyl group, more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, a sec-butyl group, an isobutyl group or an n-pentyl group (C3-C6 alkyl group), and still more preferably a methyl group.

[0628] The "substituent" in the "substituted or unsubstituted C1-C10 alkyl group" represented by R4 may be, for example, the substituents described above, preferably halogen, cyano, hydroxy or C3-C7 cycloalkyl, more preferably hydroxy.

[0629] The “substituted or unsubstituted C1-C10 alkyl group” represented by R4 is preferably a C1-C6 alkyl group, a hydroxymethyl group, a 2-hydroxyethyl group, a 1,2-dihydroxyisopropyl group, a 2-hydroxypropyl group, more preferably a C1-C3 alkyl group, still more preferably a methyl group, an isopropyl group, a tert-butyl group, a hydroxymethyl group or a 2-hydroxyethyl group, and most preferably a methyl group.

[0630] The "C2-C10 alkenyl group" in the "substituted or unsubstituted C2-C10 alkenyl group" represented by R4 is preferably a vinyl group, a 1-propenyl group, an allyl group or an isopropenyl group, more preferably a vinyl group or an isopropenyl group.

[0631] The "substituent" in the "substituted or unsubstituted C2-C10 alkenyl group" represented by R4 may be, for example, the substituents described above, preferably halogen, cyano or hydroxy, more preferably chlorine or fluorine, further preferably fluorine.

[0632] The "substituted or unsubstituted C2-C10 alkenyl group" represented by R4 is preferably a C2-C6 alkenyl group which may contain halogen, more preferably vinyl, 1-propenyl, 2-methyl-2-propenyl or 1-(trifluoromethyl)vinyl, more preferably vinyl or 1-(trifluoromethyl)vinyl.

[0633] The "C2-C10 alkynyl group" in the "substituted or unsubstituted C2-C10 alkynyl group" represented by R4 is preferably an ethynyl group or a 1-propynyl group.

[0634] The substituent in the "substituted or unsubstituted C2-C10 alkynyl group" represented by R4 may be, for example, the substituents described above, preferably halogen or hydroxy, more preferably fluorine or chlorine.

[0635] The "substituted or unsubstituted C2-C10 alkynyl group" represented by R4 is preferably an ethynyl group or a 1-propynyl group.

[0636] The "C3-C10 cycloalkyl group" in the "substituted or unsubstituted C3-C10 cycloalkyl group" represented by R4 is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or a cycloheptyl group, and more preferably a cyclopropyl group.

[0637] The "substituted or unsubstituted C1-C10 haloalkyl group" represented by R4 is preferably a fluoromethyl group, a difluoromethyl group or a trifluoromethyl group.

[0638] The "substituted or unsubstituted C1-C10 alkoxy group" represented by R4 is preferably a methoxy group, an ethoxy group, or a 1-fluoromethoxy group.

[0639] The "substituted or unsubstituted C1-C10 acyl group" represented by R4 is preferably a formyl group, an acetyl group, or a propionyl group.

[0640] The "substituted or unsubstituted C1-C10 alkoxycarbonyl group" represented by R4 is preferably a methoxycarbonyl group or an ethoxycarbonyl group.

[0641] The "substituted or unsubstituted C1-C10 alkylsulfonyl group" represented by R4 is preferably a methoxysulfonyl group or an ethoxysulfonyl group.

[0642] R4 is preferably halogen, cyano or substituted or unsubstituted C1-C6 alkyl.

[0643] R4 is more preferably halogen, cyano or C1-C3 alkyl.

[0644] R4 is more preferably halogen or cyano.

[0645] Most preferably, R4 is fluoro or cyano.

[0646] In one embodiment, in the compounds of the present invention represented by any one of formulae (iii) to (xii), R5 represents cyano, hydroxyl, 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.

[0647] The "halogen" represented by R5 is preferably chlorine, bromine, fluorine and iodine, among which chlorine, chlorine and bromine are preferred, chlorine and chlorine are more preferred, and chlorine is most preferred.

[0648] The "C1-C10 alkyl group" in the "substituted or unsubstituted C1-C10 alkyl group" represented by R5 is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, a sec-butyl group, an isobutyl group or an n-pentyl group, more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, a sec-butyl group, an isobutyl group or an n-pentyl group (C3-C6 alkyl group), and still more preferably a methyl group.

[0649] The "substituent" in the "substituted or unsubstituted C1-C10 alkyl group" represented by R5 may be, for example, the substituents described above, preferably halogen, cyano, hydroxy or C3-C7 cycloalkyl, more preferably fluorine.

[0650] The "substituted or unsubstituted C1-C10 alkyl group" represented by R5 is preferably a C1-C6 alkyl group, more preferably a methyl group.

[0651] The "C2-C10 alkenyl group" in the "substituted or unsubstituted C2-C10 alkenyl group" represented by R5 is preferably a vinyl group, a 1-propenyl group, an allyl group or an isopropenyl group, more preferably a vinyl group or an isopropenyl group.

[0652] The "substituent" in the "substituted or unsubstituted C2-C10 alkenyl group" represented by R5 may be, for example, the substituents described above, preferably halogen or hydroxy, cyano or hydroxy, more preferably chlorine or fluorine, more preferably fluorine.

[0653] The "substituted or unsubstituted C2-C10 alkenyl group" represented by R5 is preferably a C2-C6 alkenyl group which may contain halogen, more preferably vinyl, 1-propenyl, 2-methyl-2-propenyl or 1-(trifluoromethyl)vinyl, more preferably vinyl or 1-(trifluoromethyl)vinyl.

[0654] The "C2-C10 alkynyl group" in the "substituted or unsubstituted C2-C10 alkynyl group" represented by R5 is preferably an ethynyl group or a 1-propynyl group.

[0655] The substituent in the "substituted or unsubstituted C2-C10 alkynyl group" represented by R5 may be, for example, the substituents described above, preferably halogen or hydroxy, more preferably fluorine or chlorine.

[0656] The "substituted or unsubstituted C2-C10 alkynyl group" represented by R5 is preferably an ethynyl group or a 1-propynyl group.

[0657] The "substituted or unsubstituted C1-C10 haloalkyl group" represented by R5 is preferably a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 1-fluoroethyl group or a 1,1-difluoroethyl group, more preferably a fluoromethyl group, a difluoromethyl group or a trifluoromethyl group.

[0658] The "substituted or unsubstituted C1-C10 alkoxy group" represented by R5 is preferably a methoxy group, an ethoxy group, or a 1-fluoromethoxy group.

[0659] The "substituted or unsubstituted C1-C10 acyl group" represented by R5 is preferably a formyl group, an acetyl group, or a propionyl group.

[0660] The "substituted or unsubstituted C1-C10 alkoxycarbonyl group" represented by R5 is preferably a methoxycarbonyl group or an ethoxycarbonyl group.

[0661] The "substituted or unsubstituted C1-C10 alkylsulfonyl group" represented by R5 is preferably a methoxysulfonyl group or an ethoxysulfonyl group.

[0662] R5 is more preferably halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, or substituted or unsubstituted C1-C6 haloalkyl.

[0663] R5 is more preferably halogen, unsubstituted or fluorine-substituted C1-C6 alkyl, unsubstituted or fluorine-substituted C1-C6 alkoxy, or unsubstituted or fluorine-substituted C1-C6 haloalkyl.

[0664] More preferably, R5 is chlorine, fluorine, methyl, tert-butyl, fluoromethyl, fluoroethyl, difluoromethyl or trifluoromethyl.

[0665] Most preferably, R5 is chloro or trifluoromethyl.

[0666] In the compound represented by any one of formulae (iii) to (vi) of the present invention,

[0667] When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring that shares two adjacent atoms with ring A' or ring A″; or R6 may independently represent 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.

[0668] The "C3-C10 hydrocarbon ring" which may be formed with two R6 is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, more preferably a cyclopentyl group.

[0669] The "4- to 10-membered saturated heterocyclic ring" which can be formed with two R6 is preferably a 4- to 10-membered ring containing nitrogen, more preferably pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, more preferably pyrrolidinyl or tetrahydrofuranyl.

[0670] The "halogen" represented by R6 is preferably chlorine, bromine, fluorine and iodine, among which chlorine, fluorine and bromine are preferred, and chlorine and fluorine are more preferred.

[0671] The "C1-C10 alkyl group" in the "substituted or unsubstituted C1-C10 alkyl group" represented by R6 is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, a sec-butyl group, an isobutyl group or an n-pentyl group, more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, a sec-butyl group, an isobutyl group or an n-pentyl group (C3-C6 alkyl group), still more preferably a methyl group or an ethyl group.

[0672] The "substituent" in the "substituted or unsubstituted C1-C10 alkyl group" represented by R6 may be, for example, the substituents described above, preferably halogen, cyano, hydroxy or C1-C6 alkoxy, more preferably methoxy.

[0673] The “substituted or unsubstituted C1-C10 alkyl group” represented by R6 is preferably a C1-C6 alkyl group, 1,2-dihydroxyisopropyl group, 2-hydroxypropyl group, methoxymethyl group, ethoxyethyl group, more preferably a C1-C3 alkyl group, still more preferably a methyl group, an ethyl group, a methoxymethyl group or an ethoxymethyl group, and most preferably a methyl group or a methoxymethyl group.

[0674] The "C2-C10 alkenyl group" in the "substituted or unsubstituted C2-C10 alkenyl group" represented by R6 is preferably a vinyl group, a 1-propenyl group, an allyl group or an isopropenyl group, more preferably a vinyl group or an isopropenyl group.

[0675] The "substituent" in the "substituted or unsubstituted C2-C10 alkenyl group" represented by R6 may be, for example, the substituents described above, preferably halogen, cyano or hydroxy, more preferably chlorine or fluorine, more preferably fluorine.

[0676] The "substituted or unsubstituted C2-C10 alkenyl group" represented by R6 is preferably a C2-C6 alkenyl group which may contain halogen, more preferably vinyl, 1-propenyl, 2-methyl-2-propenyl or 1-(trifluoromethyl)vinyl, more preferably vinyl or 1-(trifluoromethyl)vinyl.

[0677] The "C2-C10 alkynyl group" in the "substituted or unsubstituted C2-C10 alkynyl group" represented by R6 is preferably an ethynyl group or a 1-propynyl group.

[0678] The substituent in the "substituted or unsubstituted C2-C10 alkynyl group" represented by R6 may be, for example, the substituents described above, preferably halogen or hydroxy, more preferably fluorine or chlorine.

[0679] The "substituted or unsubstituted C2-C10 alkynyl group" represented by R6 is preferably an ethynyl group or a 1-propynyl group.

[0680] The "substituted or unsubstituted C1-C10 haloalkyl group" represented by R6 is preferably a C1-C6 haloalkyl group, more preferably a fluoromethyl group, a difluoromethyl group, or a trifluoromethyl group.

[0681] The "substituted or unsubstituted C1-C10 alkoxy group" represented by R6 is preferably a methoxy group, an ethoxy group, or a 1-fluoromethoxy group.

[0682] The "substituted or unsubstituted C1-C10 acyl group" represented by R6 is preferably a formyl group, an acetyl group, or a propionyl group.

[0683] The "substituted or unsubstituted C1-C10 alkoxycarbonyl group" represented by R6 is preferably a methoxycarbonyl group or an ethoxycarbonyl group.

[0684] The "substituted or unsubstituted C1-C10 alkylsulfonyl group" represented by R6 is preferably a methoxysulfonyl group or an ethoxysulfonyl group.

[0685] R6 is more preferably halogen or substituted or unsubstituted C1-C6 alkyl, or two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring.

[0686] R6 is more preferably halogen or methyl, ethyl, methoxymethyl, which can be linked together to form cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl.

[0687] R6 is most preferably methyl or ethyl, which can be linked together to form cyclopentyl or pyrrolidinyl.

[0688] In the compounds represented by any one of formulae (iv) to (vi) and (x) of the present invention, R7 represents cyano, hydroxyl, 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.

[0689] The "halogen" represented by R7 is preferably chlorine, bromine, fluorine and iodine, among which chlorine, fluorine and bromine are preferred, and chlorine and fluorine are more preferred.

[0690] The "C1-C10 alkyl group" in the "substituted or unsubstituted C1-C10 alkyl group" represented by R7 is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, a sec-butyl group, an isobutyl group or an n-pentyl group, more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, a sec-butyl group, an isobutyl group or an n-pentyl group (C3-C6 alkyl group), still more preferably a methyl group, an ethyl group or a tert-butyl group.

[0691] The "substituent" in the "substituted or unsubstituted C1-C10 alkyl group" represented by R7 may be, for example, the substituents described above, preferably halogen, cyano, hydroxy or C3-C7 cycloalkyl, more preferably hydroxy.

[0692] The "substituted or unsubstituted C1-C10 alkyl group" represented by R7 is preferably a C1-C6 alkyl group, 1,2-dihydroxyisopropyl group, 2-hydroxypropyl group, more preferably a C3-C6 alkyl group, still more preferably a methyl group, ethyl group, isopropyl group or tert-butyl group, most preferably a methyl group.

[0693] The "C2-C10 alkenyl group" in the "substituted or unsubstituted C2-C10 alkenyl group" represented by R7 is preferably a vinyl group, a 1-propenyl group, an allyl group or an isopropenyl group, more preferably a vinyl group or an isopropenyl group.

[0694] The "substituent" in the "substituted or unsubstituted C2-C10 alkenyl group" represented by R7 may be, for example, the substituents described above, preferably halogen, cyano or hydroxy, more preferably chlorine or fluorine, more preferably fluorine.

[0695] The "substituted or unsubstituted C2-C10 alkenyl group" represented by R7 is preferably a C2-C6 alkenyl group which may contain halogen, more preferably vinyl, 1-propenyl, 2-methyl-2-propenyl or 1-(trifluoromethyl)vinyl, more preferably vinyl or 1-(trifluoromethyl)vinyl.

[0696] The "C2-C10 alkynyl group" in the "substituted or unsubstituted C2-C10 alkynyl group" represented by R7 is preferably an ethynyl group or a 1-propynyl group.

[0697] The substituent in the "substituted or unsubstituted C2-C10 alkynyl group" represented by R7 may be, for example, the substituents described above, preferably halogen or hydroxy, more preferably fluorine or chlorine.

[0698] The "substituted or unsubstituted C2-C10 alkynyl group" represented by R7 is preferably an ethynyl group or a 1-propynyl group.

[0699] The "C3-C10 cycloalkyl group" in the "substituted or unsubstituted C3-C10 cycloalkyl group" represented by R7 is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or a cycloheptyl group, and more preferably a cyclohexyl group.

[0700] The "substituted or unsubstituted C1-C10 haloalkyl group" represented by R7 is preferably a fluoromethyl group, a difluoromethyl group or a trifluoromethyl group.

[0701] The "substituted or unsubstituted C1-C10 alkoxy group" represented by R7 is preferably a methoxy group, an ethoxy group, or a 1-fluoromethoxy group.

[0702] The "substituted or unsubstituted C1-C10 acyl group" represented by R7 is preferably a formyl group, an acetyl group, or a propionyl group.

[0703] The "substituted or unsubstituted C1-C10 alkoxycarbonyl group" represented by R7 is preferably a methoxycarbonyl group or an ethoxycarbonyl group.

[0704] The "substituted or unsubstituted C1-C10 sulfonyl group" represented by R7 is preferably a methoxysulfonyl group or an ethoxysulfonyl group.

[0705] R7 is preferably halogen or substituted or unsubstituted C1-C6 alkyl.

[0706] R7 is more preferably halogen or C1-C3 alkyl.

[0707] Most preferably, R7 is fluoro or methyl.

[0708] In one embodiment, in the compounds of the present invention represented by any one of formulae (iv) to (vi) and (x), R8 represents halogen or substituted or unsubstituted C1-C6 alkyl.

[0709] The "halogen" represented by R8 is preferably chlorine, bromine, fluorine and iodine, among which chlorine, fluorine and bromine are preferred, and chlorine and fluorine are more preferred.

[0710] The "C1-C6 alkyl group" in the "substituted or unsubstituted C1-C6 alkyl group" represented by R8 is preferably a methyl group, an ethyl group, an n-propyl group or an isopropyl group, more preferably a methyl group or an ethyl group, particularly preferably a methyl group.

[0711] The substituent in the "substituted or unsubstituted C1-C6 alkyl group" represented by R8 may be, for example, the substituents described above, preferably halogen, cyano or hydroxy, more preferably fluorine, chlorine, cyano or hydroxy.

[0712] The "C1-C6 alkyl group" in the "substituted or unsubstituted C1-C6 alkyl group" represented by R8 is preferably a C1-C6 alkyl group, more preferably a methyl group, an ethyl group or a tert-butyl group, more preferably a methyl group or an ethyl group, particularly preferably a methyl group.

[0713] R8 is preferably halogen or substituted or unsubstituted C1-C6 alkyl.

[0714] R8 is more preferably halogen or C1-C6 alkyl.

[0715] Most preferably, R8 is fluoro or methyl.

[0716] In one embodiment of the present invention, in the compounds of the present invention represented by formula A-L1-L2-GJ, (i), (ii), (vii) or (viii), A represents a chemical moiety capable of interacting with the region between switch 2 and the α3-helix, more preferably A represents a ring system, ring A is a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted fused ring, more preferably A represents ring A, which is a substituted or unsubstituted C3-C10 cycloalkyl, a substituted or unsubstituted C6-C10 aromatic hydrocarbon, a substituted or unsubstituted 4- to 10-membered saturated heterocyclic group, a substituted or unsubstituted 4- to 10-membered partially saturated heterocyclic group or a substituted or unsubstituted 4- to 10-membered unsaturated heterocyclic group.

[0717] In one embodiment of the present invention, in the compounds represented by formula (iii), (iv), (ix) or (x) of the present invention, when A is a monocyclic ring, A' and A" are absent, and the monocyclic ring is represented by ring A, which is an unsaturated 6-membered ring which is unsubstituted or substituted by R8, wherein A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH;

[0718] When A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring A", wherein ring A is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH, and ring A' or A" is a saturated or unsaturated ring which is unsubstituted or substituted by R6 and forms a fused ring with ring A containing A3 and A4 or A4 and A5.

[0719] In a preferred embodiment, in the compound represented by formula (iii), (iv), (ix) or (x) of the present invention, ring A' forms a condensed ring with ring A containing A3 and A4, and A1 and A4 are C, CH or CH2.

[0720] More preferably, in the compound represented by formula (iii), (iv), (ix) or (x) of the present invention, A2 in ring A represents C.

[0721] More preferably, in the compound represented by formula (iii), (iv), (ix) or (x) of the present invention, ring A and ring A' together represent benzimidazolyl, benzothiazolyl, indazolyl, benzodioxanyl, imidazopyridinyl, more preferably benzimidazolyl.

[0722] 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 monocyclic ring or a substituted or unsubstituted fused ring and -C(=O)-. More preferably, L1 is wherein D is a monocyclic ring having at least one amino group, the amino group combines with the carbonyl group between D and E to form an amide, wherein the monocyclic ring is unsubstituted or substituted with a substituent other than the amino group, or D is a substituted or unsubstituted condensed ring, more preferably a substituted or unsubstituted C6-C10 aromatic hydrocarbon, or a substituted or unsubstituted 4- to 10-membered partially saturated heterocyclic group, or a substituted or unsubstituted 4- to 10-membered unsaturated heterocyclic group.

[0723] In one embodiment, in the compounds represented by formula (i), (ii), (iii), (vii), (viii) or (ix) of the present invention, D represents a monocyclic ring having at least one amino group which combines with the carbonyl group between D and E to form an amide, wherein the monocyclic ring is unsubstituted or substituted with a substituent other than the amino group, or D is a substituted or unsubstituted condensed ring, more preferably a substituted or unsubstituted C6-C10 aromatic hydrocarbon, or a substituted or unsubstituted 4- to 10-membered partially saturated heterocyclic group, or a substituted or unsubstituted 4- to 10-membered unsaturated heterocyclic group.

[0724] More preferably, in the compound represented by formula (iv) or (x) of the present invention, when D is a monocyclic ring, D' is absent, and the monocyclic ring is represented by ring D, which is an unsaturated 6-membered ring which is unsubstituted or substituted by R7, wherein D1 represents N or NH, and D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH;

[0725] When D is a fused ring, the fused ring is represented by ring D and ring D', wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted by R7, wherein D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is a saturated or unsaturated ring which is unsubstituted or substituted by R8 and forms a fused ring with ring D containing D1, D2 and D7.

[0726] More preferably, in the compound represented by formula (iv) or (x) of the present invention, D6 in ring D is C.

[0727] More preferably, in the compound represented by formula (iv) or (x) of the present invention, D3, D4 and D5 are C.

[0728] More preferably, in the compound represented by formula (iv), (v), (vi), (x), (xi) or (xii) of the present invention, D is a condensed ring represented by ring D and ring D', ring D' is a saturated or unsaturated 5-membered ring which forms a condensed ring containing D1, D2 and D7 with ring D, and D1' and D2' independently represent C, CH, CH2, N, NH or S. More preferably, D1' and D2' independently represent C, CH, CH2, N or NH.

[0729] More preferably, in the compound represented by formula (iv), (v), (vi), (x), (xi) or (xii) of the present invention, ring D and ring D' together represent indole, indolizine, imidazopyridine, dihydroindole or benzothiophene, still more preferably indole, indolizine, imidazopyridine or dihydroindole.

[0730] In the compound represented by the formula A-L1-L2-GJ of the present invention, L2 represents a linking group, more preferably a combination of a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted fused ring and -NR1-, more preferably

[0731] In the compound represented by formula (i) or (vii) of the present invention, E represents a ring system, more preferably a ring system selected from a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted condensed ring.

[0732] More preferably, in the compound represented by any one of formulae (i) to (xii) of the present invention, E represents a 6-membered ring, more preferably a substituted or unsubstituted C6-C10 aromatic hydrocarbon, a substituted or unsubstituted 4- to 10-membered partially saturated heterocyclic group or a substituted or unsubstituted 4- to 10-membered unsaturated heterocyclic group.

[0733] More preferably, in the compounds represented by any one of formulae (ii) to (vi) and (viii) to (xii) of the present invention, E1, E2, E3, E4 in E independently represent C, CH, CH2, N or NH, and E is a saturated or unsaturated 6-membered ring.

[0734] More preferably, in the compound represented by any one of formulae (i) to (xii) of the present invention, E represents a phenyl group, a pyridyl group, a pyrimidyl group, a pyridazinyl group, a pyrazinyl group or a triazinyl group, preferably a phenyl group or a pyridyl group.

[0735] In one embodiment, in the compound represented by formula (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, more preferably 1.

[0736] In one embodiment, in the compound 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, more preferably 1.

[0737] In one embodiment, in the compounds of the present invention represented by formula (iii), (iv), (v), (ix), (x), (xi) or (xii), p represents 0, 1 or 2.

[0738] In one embodiment, in the compounds of the present invention represented by formula (iv), (v), (vi), (x), (xi) or (xii), q represents 0, 1 or 2, more preferably 0.

[0739] In one embodiment, in the compounds of the present invention represented by formula (iv), (v), (vi), (x), (xi) or (xii), r represents 0, 1 or 2, more preferably 0.

[0740] In one embodiment, in the compound of the present invention represented by the formula A-L1-L2-GJ, G represents an electrophilic chemical moiety capable of forming a covalent bond with cysteine ​​12 of GTP-bound KRAS G12C, more preferably

[0741] In one embodiment, in the compound of the present invention represented by the formula A-L1-L2-GJ, J represents a chemical moiety capable of interacting with GTP, more preferably

[0742] In one embodiment, in the compound represented by formula (i) of the present invention, A is selected from:

[0743]

[0744] In one embodiment, in the compound represented by formula (i) of the present invention, D is selected from:

[0745]

[0746] In one embodiment, in the compound represented by formula (i) of the present invention, E is selected from:

[0747]

[0748] In one embodiment, in the compound represented by formula (i) of the present invention, -NR2R3 is selected from:

[0749]

[0750] Implementation Plan A

[0751] In one embodiment, a compound represented by formula (iv) or a pharmaceutically acceptable salt thereof is provided, wherein

[0752] When A is a monocyclic ring, A' and A" are absent, and the monocyclic ring is represented by Ring A, which is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH;

[0753] When A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring A", wherein ring A is an unsubstituted or unsaturated 6-membered ring substituted by R5, wherein A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH, and ring A' or A" is a saturated or unsaturated ring unsubstituted or substituted by R6 and forms a fused ring with ring A containing A3 and A4 or A4 and A5;

[0754] When D is a monocyclic ring, D' is absent and the monocyclic ring is represented by ring D, which is an unsaturated 6-membered ring that is unsubstituted or substituted with R7, wherein D1 represents N or NH, and D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH;

[0755] When D is a fused ring, the fused ring is represented by ring D and ring D', wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted by R7, wherein D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is a saturated or unsaturated ring which is unsubstituted or substituted by R8 and forms a fused ring with ring D containing D1, D2 and D7;

[0756] E is an unsaturated 6-membered ring which is unsubstituted or substituted by R4, wherein E1, E2, E3 and E4 independently represent C, CH, CH2, N or NH;

[0757] R1 is hydrogen or substituted or unsubstituted C1-C6 alkyl;

[0758] R2 and R3 may be linked together to form a 4- to 10-membered saturated heterocyclic ring, which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; or

[0759] R2 and R3 may independently represent, and 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- to 10-membered saturated heterocyclic group, a 4- to 10-membered partially saturated heterocyclic group or a 4- to 10-membered unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;

[0760] R3 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted by 1-2 substituents independently represented by Ra;

[0761] R4 is 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;

[0762] R5 is 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;

[0763] When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring that shares two adjacent atoms with ring A' or ring A";

[0764] R6 may independently represent halogen, cyano, amino, hydroxyl, 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;

[0765] R7 is 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;

[0766] R8 is halogen or substituted or unsubstituted C1-C10 alkyl;

[0767] R independently represents halogen, hydroxy, 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 a substituted or unsubstituted 4- to 10-membered saturated heterocyclic group;

[0768] m is an integer from 0 to 4;

[0769] n is an integer from 0 to 5; and

[0770] p, q and r independently represent 0, 1 or 2.

[0771] In a preferred embodiment, a compound represented by formula (iv) or a pharmaceutically acceptable salt thereof is provided, wherein

[0772] When A is a monocyclic ring, A' and A" are absent, and the monocyclic ring is represented by Ring A, which is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1 and A5 represent C, CH, CH2, and A2, A3 and A4 independently represent C, CH, CH2, N or NH;

[0773] When A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring A", wherein ring A is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1 and A5 independently represent C, CH or CH2, A2, A3 and A4 independently represent C, CH, CH2, N or NH, and ring A' or A" is a saturated or unsaturated ring which is unsubstituted or substituted by R6 and forms a fused ring with ring A containing A3 and A4 or A4 and A5;

[0774] When D is a monocyclic ring, D' is absent and the monocyclic ring is represented by ring D, which is an unsaturated 6-membered ring that is unsubstituted or substituted with R7, wherein 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;

[0775] When D is a fused ring, the fused ring is represented by ring D and ring D', wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted by R7, wherein D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is a saturated or unsaturated ring which is unsubstituted or substituted by R8 and forms a fused ring with ring D containing D1, D2 and D7;

[0776] E is an unsaturated 6-membered ring which is unsubstituted or substituted by R4, wherein E1, E2, E3 and E4 independently represent C, CH, CH2, N or NH;

[0777] R1 is hydrogen;

[0778] R2 and R3 independently represent, and R2 is hydrogen; or 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- to 10-membered saturated heterocyclic group, 4- to 10-membered partially saturated heterocyclic group or 4- to 10-membered unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;

[0779] R3 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted by 1-2 substituents independently represented by Ra;

[0780] R4 is 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;

[0781] R5 is 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;

[0782] When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring that shares two adjacent atoms with ring A' or ring A";

[0783] R6 may independently represent halogen, cyano, amino, hydroxyl, 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;

[0784] R7 is 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;

[0785] R8 is halogen or substituted or unsubstituted C1-C10 alkyl;

[0786] R independently represents halogen, hydroxy, 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 a substituted or unsubstituted 4- to 10-membered saturated heterocyclic group;

[0787] m is an integer from 0 to 3.

[0788] n is an integer from 0 to 4; and

[0789] p, q and r independently represent 0, 1 or 2.

[0790] In a more preferred embodiment, there is provided a compound represented by formula (iv) or a pharmaceutically acceptable salt thereof, wherein

[0791] A is a fused ring, and the fused ring is represented by ring A and ring A' or ring A and ring A", wherein ring A is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein 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 unsaturated 5-membered ring which is unsubstituted or substituted by R6 and forms a fused ring with ring A containing A3 and A4 or A4 and A5, and A1', A2' and A3' independently represent C, CH, CH2, N, NH, O or S

[0792] When D is a monocyclic ring, D' is absent and the monocyclic ring is represented by ring D, which is an unsaturated 6-membered ring that is unsubstituted or substituted with R7, wherein 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;

[0793] When D is a fused ring, the fused ring is represented by ring D and ring D', wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted by R7, wherein D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is a saturated or unsaturated ring which is unsubstituted or substituted by R8 and forms a fused ring with ring D containing D1, D2 and D7;

[0794] E is an unsaturated 6-membered ring which is unsubstituted or substituted by R4, wherein E1, E2, E3 and E4 independently represent C, CH, CH2, N or NH;

[0795] R1 is hydrogen;

[0796] R2 and R3 are independently represented, and R2 is a C1-C10 alkyl group, a C3-C10 cycloalkyl group or a 4- to 10-membered saturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;

[0797] R3 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted by 1-2 substituents independently represented by Ra;

[0798] R4 is halogen, cyano or substituted or unsubstituted C1-C10 alkyl;

[0799] R5 is halogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy;

[0800] When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring that shares two adjacent atoms with ring A' or ring A";

[0801] R6 may independently represent halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl or substituted or unsubstituted C1-C10 alkoxy;

[0802] R7 is halogen;

[0803] R8 is halogen or substituted or unsubstituted C1-C10 alkyl;

[0804] Ra independently represents halogen, hydroxy, 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;

[0805] m is an integer from 0 to 2;

[0806] n is an integer from 0 to 3; and

[0807] p, q and r independently represent 0, 1 or 2.

[0808] In a still more preferred embodiment, there is provided a compound represented by formula (iv) or a pharmaceutically acceptable salt thereof, wherein

[0809] A is a fused ring, and the fused ring is represented by ring A and ring A' or ring A and ring A", wherein ring A is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1, A2 and A5 represent C, CH or CH2, A3 and A4 independently represent C, CH, CH2, N or NH, and ring A' or A" is an unsaturated 5-membered ring which is unsubstituted or substituted by R6 and forms a fused ring with ring A containing A3 and A4 or A4 and A5, A1' and A3' independently represent C, CH, CH2, N, NH, O or S, and A2' represents C;

[0810] When D is a monocyclic ring, D' is absent and the monocyclic ring is represented by ring D, which is an unsaturated 6-membered ring that is unsubstituted or substituted with R7, wherein 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;

[0811] When D is a fused ring, the fused ring is represented by ring D and ring D', wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted by R7, wherein D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is a saturated or unsaturated ring which is unsubstituted or substituted by R8 and forms a fused ring with ring D containing D1, D2 and D7;

[0812] E is an unsaturated 6-membered ring which is unsubstituted or substituted by R4, wherein E1, E2, E3 and E4 independently represent C, CH, CH2, N or NH;

[0813] R1 is hydrogen;

[0814] R2 and R3 are independently represented, and R2 is a C3-C10 cycloalkyl group or a 4- to 10-membered saturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;

[0815] R3 is hydrogen;

[0816] R4 is halogen, cyano or substituted or unsubstituted C1-C10 alkyl;

[0817] R5 is halogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy;

[0818] When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring that shares two adjacent atoms with ring A' or ring A";

[0819] R6 may independently represent a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, or a substituted or unsubstituted C1-C10 alkoxy group;

[0820] R7 is halogen;

[0821] R8 is halogen or substituted or unsubstituted C1-C6 alkyl;

[0822] Ra independently represents halogen, hydroxy, 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;

[0823] m is an integer from 0 to 1;

[0824] n is an integer from 0 to 2; and

[0825] p, q and r independently represent 0, 1 or 2.

[0826] In a most preferred embodiment, there is provided a compound represented by formula (iv) or a pharmaceutically acceptable salt thereof, wherein

[0827] A is a fused ring, and the fused ring is represented by ring A and ring A' or ring A and ring A", wherein ring A is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1, A2 and A5 represent C, CH or CH2, A3 and A4 independently represent C, CH, CH2, N or NH, and ring A' or A" is an unsaturated 5-membered ring which is unsubstituted or substituted by R6 and forms a fused ring with ring A containing A3 and A4 or A4 and A5, A1' and A3' independently represent C, CH, CH2, N, NH, O or S, and A2' represents C;

[0828] D is a fused ring represented by ring D and ring D', wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted by R7, wherein D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is a saturated or unsaturated 5-membered ring which is unsubstituted or substituted by R8 and forms a fused ring with ring D containing D1, D2 and D7, and D1' and D2' independently represent C, CH, CH2, N, NH or S;

[0829] E is an unsaturated 6-membered ring which is unsubstituted or substituted by R4, wherein E1, E2, E3 and E4 independently represent C, CH, CH2, N or NH;

[0830] R1 is hydrogen; R2 and R3 are independently represented, and R2 is a C3-C10 cycloalkyl group or a 4- to 10-membered saturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; R3 is hydrogen;

[0831] R4 is halogen, cyano or substituted or unsubstituted C1-C10 alkyl;

[0832] R5 is halogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy;

[0833] When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring that shares two adjacent atoms with ring A' or ring A";

[0834] R6 may independently represent a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, or a substituted or unsubstituted C1-C10 alkoxy group;

[0835] R7 is halogen;

[0836] R8 is halogen or substituted or unsubstituted C1-C6 alkyl;

[0837] The number of Ra is one or two, and each Ra independently represents halogen, hydroxy, 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;

[0838] m is an integer from 0 to 1;

[0839] n is an integer from 0 to 2; and

[0840] p, q and r independently represent 0, 1 or 2.

[0841] In one embodiment, there is provided a compound represented by formula (x) or a pharmaceutically acceptable salt thereof, wherein

[0842] When A is a monocyclic ring, A' and A" are absent, and the monocyclic ring is represented by Ring A, which is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH;

[0843] When A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring A", wherein ring A is an unsubstituted or unsaturated 6-membered ring substituted by R5, wherein A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH, and ring A' or A" is a saturated or unsaturated ring unsubstituted or substituted by R6 and forms a fused ring with ring A containing A3 and A4 or A4 and A5;

[0844] When D is a monocyclic ring, D' is absent and the monocyclic ring is represented by ring D, which is an unsaturated 6-membered ring that is unsubstituted or substituted with R7, wherein D1 represents N or NH, and D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH;

[0845] When D is a fused ring, the fused ring is represented by ring D and ring D', wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted by R7, wherein D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is a saturated or unsaturated ring which is unsubstituted or substituted by R8 and forms a fused ring with ring D containing D1, D2 and D7;

[0846] E is an unsaturated 6-membered ring which is unsubstituted or substituted by R4, wherein E1, E2, E3 and E4 independently represent C, CH, CH2, N or NH;

[0847] R1 is hydrogen or substituted or unsubstituted C1-C6 alkyl;

[0848] R2 and R3 or R2 and R2' may be linked together to form a 4- to 10-membered saturated heterocyclic ring, which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; or

[0849] R2, R2' and R3 may independently represent, and 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- to 10-membered saturated heterocyclic group, 4- to 10-membered partially saturated heterocyclic group or 4- to 10-membered unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;

[0850] R2' is hydrogen or C1-C6 alkyl which is unsubstituted or substituted by 1-2 substituents independently represented by Ra; and

[0851] R3 is hydrogen or a C1-C6 alkyl group which is unsubstituted or substituted by 1-2 substituents independently represented by Ra, wherein the C1-C6 alkyl group is;

[0852] R4 is 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;

[0853] R5 is 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;

[0854] When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring that shares two adjacent atoms with ring A' or ring A";

[0855] R6 may independently represent halogen, cyano, amino, hydroxyl, 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;

[0856] R7 is 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;

[0857] R8 is halogen or substituted or unsubstituted C1-C10 alkyl;

[0858] R independently represents halogen, hydroxy, 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 a substituted or unsubstituted 4- to 10-membered saturated heterocyclic group;

[0859] m is an integer from 0 to 4;

[0860] n is an integer from 0 to 5; and

[0861] p, q and r independently represent 0, 1 or 2.

[0862] In a preferred embodiment, a compound represented by formula (x) or a pharmaceutically acceptable salt thereof is provided, wherein

[0863] When A is a monocyclic ring, A' and A" are absent, and the monocyclic ring is represented by Ring A, which is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1 and A5 represent C, CH or CH2, and A2, A3 and A4 independently represent C, CH, CH2, N or NH;

[0864] When A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring A", wherein ring A is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1 and A5 independently represent C, CH or CH2, A2, A3 and A4 independently represent C, CH, CH2, N or NH, and ring A' or A" is a saturated or unsaturated ring which is unsubstituted or substituted by R6 and forms a fused ring with ring A containing A3 and A4 or A4 and A5;

[0865] When D is a monocyclic ring, D' is absent and the monocyclic ring is represented by ring D, which is an unsaturated 6-membered ring that is unsubstituted or substituted with R7, wherein 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;

[0866] When D is a fused ring, the fused ring is represented by ring D and ring D', wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted by R7, wherein D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is a saturated or unsaturated ring which is unsubstituted or substituted by R8 and forms a fused ring with ring D containing D1, D2 and D7;

[0867] E is an unsaturated 6-membered ring which is unsubstituted or substituted by R4, wherein E1, E2, E3 and E4 independently represent C, CH, CH2, N or NH;

[0868] R1 is hydrogen;

[0869] R2 and R2' may be linked together to form a 4- to 10-membered saturated heterocyclic ring, which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; or

[0870] R2, R2' and R3 independently represent, and R2 is hydrogen; or 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- to 10-membered saturated heterocyclic group, 4- to 10-membered partially saturated heterocyclic group or 4- to 10-membered unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;

[0871] R2' is hydrogen or C1-C6 alkyl which is unsubstituted or substituted by 1-2 substituents independently represented by Ra; and

[0872] R3 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted by 1-2 substituents independently represented by Ra;

[0873] R4 is 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;

[0874] R5 is 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;

[0875] When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring that shares two adjacent atoms with ring A' or ring A";

[0876] R6 can independently represent 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;

[0877] R7 is 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;

[0878] R8 is halogen or substituted or unsubstituted C1-C10 alkyl;

[0879] R independently represents halogen, hydroxy, 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 a substituted or unsubstituted 4- to 10-membered saturated heterocyclic group;

[0880] m is an integer from 0 to 3.

[0881] n is an integer from 0 to 4; and

[0882] p, q and r independently represent 0, 1 or 2.

[0883] In a more preferred embodiment, there is provided a compound represented by formula (x) or a pharmaceutically acceptable salt thereof, wherein

[0884] A is a fused ring, and the fused ring is represented by ring A and ring A' or ring A and ring A", wherein ring A is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein 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 unsaturated 5-membered ring which is unsubstituted or substituted by R6 and forms a fused ring with ring A containing A3 and A4 or A4 and A5, and A1', A2' and A3' independently represent C, CH, CH2, N, NH, O or S

[0885] When D is a monocyclic ring, D' is absent and the monocyclic ring is represented by ring D, which is an unsaturated 6-membered ring that is unsubstituted or substituted with R7, wherein 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;

[0886] When D is a fused ring, the fused ring is represented by ring D and ring D', wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted by R7, wherein D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is a saturated or unsaturated ring which is unsubstituted or substituted by R8 and forms a fused ring with ring D containing D1, D2 and D7;

[0887] E is an unsaturated 6-membered ring which is unsubstituted or substituted by R4, wherein E1, E2, E3 and E4 independently represent C, CH, CH2, N or NH;

[0888] R1 is hydrogen;

[0889] R2 and R2' are linked together to form a 4- to 6-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra, or

[0890] R2, R2' and R3 independently represent, and R2 is unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, or unsubstituted or substituted 4-10 membered saturated heterocyclic group;

[0891] R2' is hydrogen or C1-C3 alkyl;

[0892] R3 is hydrogen or C1-C3 alkyl;

[0893] R4 is halogen, cyano or substituted or unsubstituted C1-C10 alkyl;

[0894] R5 is halogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy;

[0895] When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring that shares two adjacent atoms with ring A' or ring A";

[0896] R6 may independently represent halogen, cyano, amino, hydroxy substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl or substituted or unsubstituted C1-C10 alkoxy;

[0897] R7 is halogen;

[0898] R8 is halogen or substituted or unsubstituted C1-C10 alkyl;

[0899] Ra independently represents halogen, hydroxy, 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;

[0900] m is an integer from 0 to 2;

[0901] n is an integer from 0 to 3; and

[0902] p, q and r independently represent 0, 1 or 2.

[0903] In a still more preferred embodiment, there is provided a compound represented by formula (x) or a pharmaceutically acceptable salt thereof, wherein

[0904] A is a fused ring, and the fused ring is represented by ring A and ring A' or ring A and ring A", wherein ring A is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1, A2 and A5 represent C, CH or CH2, A3 and A4 independently represent C, CH, CH2, N or NH, and ring A' or A" is an unsaturated 5-membered ring which is unsubstituted or substituted by R6 and forms a fused ring with ring A containing A3 and A4 or A4 and A5, A1' and A3' independently represent C, CH, CH2, N, NH, O or S, and A2' represents C;

[0905] When D is a monocyclic ring, D' is absent and the monocyclic ring is represented by ring D, which is an unsaturated 6-membered ring that is unsubstituted or substituted with R7, wherein 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;

[0906] When D is a fused ring, the fused ring is represented by ring D and ring D', wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted by R7, wherein D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is a saturated or unsaturated ring which is unsubstituted or substituted by R8 and forms a fused ring with ring D containing D1, D2 and D7;

[0907] E is an unsaturated 6-membered ring which is unsubstituted or substituted by R4, wherein E1, E2, E3 and E4 independently represent C, CH, CH2, N or NH;

[0908] R1 is hydrogen;

[0909] R2 and R2' are linked together to form a 4- to 6-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra, or

[0910] R2, R2' and R3 are independently represented, and R2 is a C3-C10 cycloalkyl group or a 4- to 10-membered saturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;

[0911] R2' is hydrogen or C1-C3 alkyl;

[0912] R3 is hydrogen;

[0913] R4 is halogen, cyano or substituted or unsubstituted C1-C10 alkyl;

[0914] R5 is halogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy;

[0915] When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring that shares two adjacent atoms with ring A' or ring A";

[0916] R6 may independently represent a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, or a substituted or unsubstituted C1-C10 alkoxy group;

[0917] R7 is halogen;

[0918] R8 is halogen or substituted or unsubstituted C1-C6 alkyl;

[0919] Ra independently represents halogen, hydroxy, 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;

[0920] m is an integer from 0 to 1;

[0921] n is an integer from 0 to 2; and

[0922] p, q and r independently represent 0, 1 or 2.

[0923] In a most preferred embodiment, there is provided a compound represented by formula (x) or a pharmaceutically acceptable salt thereof, wherein

[0924] A is a fused ring, and the fused ring is represented by ring A and ring A' or ring A and ring A", wherein ring A is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1, A2 and A5 represent C, CH or CH2, A3 and A4 independently represent C, CH, CH2, N or NH, and ring A' or A" is an unsaturated 5-membered ring which is unsubstituted or substituted by R6 and forms a fused ring with ring A containing A3 and A4 or A4 and A5, A1' and A3' independently represent C, CH, CH2, N, NH, O or S, and A2' represents C;

[0925] D is a fused ring represented by ring D and ring D', wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted by R7, wherein D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is a saturated or unsaturated 5-membered ring which is unsubstituted or substituted by R8 and forms a fused ring with ring D containing D1, D2 and D7, and D1' and D2' independently represent C, CH, CH2, N, NH or S;

[0926] E is an unsaturated 6-membered ring which is unsubstituted or substituted by R4, wherein E1, E2, E3 and E4 independently represent C, CH, CH2, N or NH;

[0927] R1 is hydrogen;

[0928] R2 and R2' are linked together to form a 4- to 6-membered saturated heterocyclic ring, or

[0929] R3 is hydrogen;

[0930] R4 is halogen, cyano or substituted or unsubstituted C1-C10 alkyl;

[0931] R5 is halogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl, or substituted or unsubstituted C1-C10 alkoxy;

[0932] When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring that shares two adjacent atoms with ring A' or ring A";

[0933] R6 may independently represent a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, or a substituted or unsubstituted C1-C10 alkoxy group;

[0934] R7 is halogen;

[0935] R8 is halogen or substituted or unsubstituted C1-C6 alkyl;

[0936] The number of Ra is one or two, and each Ra independently represents halogen, hydroxy, 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;

[0937] m is an integer from 0 to 1;

[0938] n is an integer from 0 to 2; and

[0939] p, q and r independently represent 0, 1 or 2.

[0940] In the most preferred embodiment, the compound of the present invention is selected from the following compounds:

[0941] (1) 3-cyano-N-(3-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)phenyl)-4-((E)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enoylamino)benzamide

[0942] (2) (E)-4-(4-(tert-Butyl(methyl)amino)but-2-enoylamino)-3-cyano-N-(3-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)phenyl)benzamide

[0943] (3) 3-Cyano-4-((E)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enoylamino)-N-(6-(7-methyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)pyridin-2-yl)benzamide

[0944] (4)(E)-N-(2-cyano-4-(8-(1,6-dimethyl-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[0945] (5) (E)-4-(tert-Butylamino)-N-(2-cyano-4-(8-(1,6-dimethyl-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)phenyl)but-2-enamide

[0946] (6) (E)-N-(2-cyano-4-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[0947] (7) (E)-N-(2-cyano-4-(8-(1,2-dimethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[0948] (8) (E)-N-(2-cyano-4-(7-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1H-indole-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[0949] (9) (E)-N-(2-cyano-4-(8-(1,6-dimethyl-1H-benzo[d]imidazol-5-yl)imidazo[1,2-a]pyridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[0950] (10) (E)-N-(2-cyano-4-(4-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indoline-1-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[0951] (11) (E)-N-(6'-chloro-2',3'-dimethoxy-[1,1'-biphenyl]-3-yl)-3-cyano-4-(4-((1-(methylsulfonyl)piperidin-4-yl)amino)but-2-enoylamino)benzamide

[0952] (12) N-(3-(5-chloro-1-methyl-1H-indazol-4-yl)phenyl)-3-cyano-4-((E)-4-(((1r,4r)-4-(diethylamino)cyclohexyl)amino)but-2-enoylamino)benzamide

[0953] (13) N-(3-(6-chloro-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)phenyl)-4-((E)-4-(((1r,4r)-4-(diethylamino)cyclohexyl)amino)but-2-enoylamino)-3-fluorobenzamide

[0954] (14) N-(3-(6-chloro-1H-benzo[d]imidazol-5-yl)phenyl)-6-((E)-4-(((1r,4r)-4-hydroxycyclohexyl)amino)but-2-enoylamino)nicotinamide

[0955] (15) N-(3-(4-chloro-2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)phenyl)-3-cyano-4-((E)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enoylamino)benzamide

[0956] (16) 3-Cyano-4-((E)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enoylamino)-N-(3-(6-methylbenzo[d]thiazol-5-yl)phenyl)benzamide

[0957] (17) (E)-N-(3-(6-chloroimidazo[1,2-a]pyridin-7-yl)phenyl)-3-cyano-4-(4-((1-(methylsulfonyl)piperidin-4-yl)amino)but-2-enoylamino)benzamide

[0958] (18) 3-Cyano-N-(3-(1,6-dimethyl-1H-benzo[d]imidazol-5-yl)-4,5-difluorophenyl)-4-((E)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enoylamino)benzamide

[0959] (19) N-(3-(6-chloro-1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)-3-cyano-4-((E)-4-(((1r,4r)-4-(diethylamino)cyclohexyl)amino)but-2-enoylamino)benzamide

[0960] (20) (E)-3-cyano-N-(3-(4,6-dichloro-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)phenyl)-4-(4-((4,4-difluorocyclohexyl)amino)but-2-enoylamino)benzamide

[0961] (21) 3-Cyano-4-((E)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enoylamino)-N-(3-(2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)phenyl)benzamide

[0962] (22) 4-((E)-4-(((1R,5S)-8-oxabicyclo[3.2.1]oct-3-yl)amino)but-2-enoylamino)-3-cyano-N-(3-(2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)phenyl)benzamide

[0963] (23) 3-Cyano-4-((E)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enoylamino)-N-(3-(2-((R)-1-methoxyethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)phenyl)benzamide

[0964] (24) (E)-3-cyano-N-(3-(2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)phenyl)-4-(4-((8-methyl-1,4-dioxaspiro[4.5]dec-8-yl)amino)but-2-enoylamino)benzamide

[0965] (25) (E)-3-Cyano-4-(4-((6,6-difluorobicyclo[3.1.0]hex-3-yl)amino)but-2-enoylamino)-N-(3-(2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)phenyl)benzamide

[0966] (26) (E)-3-Cyano-4-(4-(cyclobutylamino)but-2-enoylamino)-N-(3-(2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)phenyl)benzamide

[0967] (27) (E)-3-Cyano-4-(4-(cyclohexylamino)but-2-enoylamino)-N-(3-(2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)phenyl)benzamide

[0968] (28) 3-Cyano-4-((E)-4-(((1r,3r)-3-methoxycyclobutyl)amino)but-2-enoylamino)-N-(3-(7-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)phenyl)benzamide

[0969] (29) (E)-N-(2-cyano-4-(4-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indoline-1-carbonyl)phenyl)-4-(((1r,4r)-4-(pyrrolidin-1-yl)cyclohexyl)amino)but-2-enamide

[0970] (30) (E)-N-(2-cyano-4-(4-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indoline-1-carbonyl)phenyl)-4-((1-isopropylpiperidin-4-yl)amino)but-2-enamide

[0971] (31) (E)-N-(2-cyano-4-(8-(7-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)indolizine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[0972] (32) 3-Cyano-N-(3-(7-ethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)phenyl)-4-((E)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enoylamino)benzamide

[0973] (33) (E)-N-(2-cyano-4-(8-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[0974] (34) 3-Cyano-4-((E)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enoylamino)-N-(6-(7-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)pyridin-2-yl)benzamide

[0975] (35) (E)-N-(2-cyano-4-(7-(7-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)-1H-indole-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[0976] (36) (E)-N-(2-cyano-4-(8-(6-(difluoromethyl)-1-methyl-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[0977] (37) 3-Cyano-4-((E)-4-(((1r,4r)-4-(diethylamino)cyclohexyl)amino)but-2-enoylamino)-N-(6-(7-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)pyridin-2-yl)benzamide

[0978] (38) (E)-N-(2-cyano-4-(1-methyl-7-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1H-indole-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[0979] (39) (E)-4-(((1r,4r)-4-methoxycyclohexyl)amino)-N-(4-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)phenyl)but-2-enamide

[0980] (40) (E)-N-(2-cyano-4-(8-(2-methoxyphenyl)indolizine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[0981] (41) (E)-N-(4-(8-(2-chloro-6-methoxyphenyl)indolizine-3-carbonyl)-2-cyanophenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[0982] (42) (R,E)-N-(2-cyano-4-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)phenyl)-3-(pyrrolidin-2-yl)acrylamide

[0983] (43) (E)-N-(2-cyano-4-(8-(2-fluoro-6-methoxyphenyl)indolizine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[0984] (44) (S,E)-N-(2-cyano-4-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)phenyl)-3-(pyrrolidin-2-yl)acrylamide

[0985] (45) (E)-N-(4-(8-(2-chlorophenyl)indolizine-3-carbonyl)-2-cyanophenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[0986] (46) (E)-N-(2-cyano-4-(8-(2-fluoro-6-hydroxyphenyl)indolizine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[0987] (47) (E)-N-(4-(5-chloro-7-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1H-indole-3-carbonyl)-2-cyanophenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[0988] (48) (2E)-N-{1-[8-(1,6-dimethyl-1H-1,3-benzodiazol-5-yl)indolizine-3-carbonyl]piperidin-4-yl}-4-{[trans-4-methoxycyclohexyl]amino}but-2-enamide

[0989] (49) (2E)-4-(tert-Butylamino)-N-(2,6-difluoro-4-{8-[1-methyl-6-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl]indolizine-3-carbonyl}phenyl)but-2-enamide f50) (2E)-4-(tert-Butylamino)-N-(2-cyano-6-methyl-4-{8-[1-methyl-6-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl]indolizine-3-carbonyl}phenyl)but-2-enamide

[0990] (51) (2E)-4-(tert-Butylamino)-N-(2-fluoro-4-{8-[1-methyl-6-(trifluoromethyl)-1H-1,3-benzodiazol-5-yl]indolizine-3-carbonyl}phenyl)but-2-enamide

[0991] (52) (2E)-4-(tert-Butylamino)-N-{4-[8-(4-chloro-2-methyl-2H-indazol-5-yl)indolizine-3-carbonyl]-2-cyanophenyl}but-2-enamide

[0992] (53) (2E)-4-(tert-Butylamino)-N-{2-cyano-4-[8-(1,5-dimethyl-1H-indazol-4-yl)indolizine-3-carbonyl]phenyl}but-2-enamide

[0993] (54) (2E)-4-(tert-Butylamino)-N-{2-cyano-4-[8-(1,6-dimethyl-1H-indazol-5-yl)indolizine-3-carbonyl]phenyl}but-2-enamide

[0994] (55) (E)-4-(tert-Butylamino)-N-(2-cyano-4-(8-(4,6-dichloro-1-methyl-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)phenyl)but-2-enamide

[0995] (56) (E)-N-(2-cyano-4-(7-(1,6-dimethyl-1H-benzo[d]imidazol-5-yl)benzo[b]thiophene-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[0996] (57) (E)-N-(2-cyano-4-(8-(1,6-dimethyl-1H-benzo[d]imidazol-5-yl)imidazo[1,5-a]pyridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[0997] (58) (E)-N-(2-cyano-4-(7-(1,6-dimethyl-1H-benzo[d]imidazol-5-yl)-1-methyl-1H-indazole-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[0998] (59) (E)-4-(tert-Butylamino)-N-(4-(8-(4-chloro-1,6-dimethyl-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)-2-cyanophenyl)but-2-enamide

[0999] (60) (E)-N-(4-(8-(4-chloro-1,6-dimethyl-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)-2-cyanophenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[1000] (61) (E)-4-(tert-Butylamino)-N-(2-cyano-4-(8-(1,6-dimethyl-4-(prop-1-en-2-yl)-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)phenyl)but-2-enamide

[1001] (62) (E)-N-(2-cyano-4-(8-(4,6-dichloro-1-methyl-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[1002] (63) (E)-N-(2-cyano-4-(8-(4,6-dichloro-1-methyl-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[1003] (64) (E)-N-(2-cyano-4-(8-(4-isopropyl-1,6-dimethyl-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[1004] (65) (E)-N-(4-(1-chloro-8-(1,6-dimethyl-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)-2-cyanophenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[1005] (66) (E)-N-(2-cyano-4-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide

[1006] (67) (E)-4-(tert-Butylamino)-N-(2,6-difluoro-4-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)imidazo[1,2-a]pyridine-3-carbonyl)phenyl)but-2-enamide

[1007] (68) (E)-N-(2,6-difluoro-4-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)imidazo[1,2-a]pyridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[1008] (69) (E)-N-(2-cyano-4-(8-(1,6-dimethyl-4-(pyrimidin-5-yl)-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[1009] (70) (E)-N-(2,6-difluoro-4-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[1010] (71) (E)-N-(4-(8-(4-chloro-2-methyl-2H-indazol-5-yl)indolizine-3-carbonyl)-2-cyanophenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[1011] (72) (E)-4-(tert-Butylamino)-N-(4-(8-(1,6-dimethyl-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)-2,6-difluorophenyl)but-2-enamide

[1012] (73) (E)-N-(4-(8-(1,6-dimethyl-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)-2,6-difluorophenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[1013] (74) (E)-N-(4-(8-(4-chloro-1-isopropyl-1H-imidazol-5-yl)indolizine-3-carbonyl)-2-cyanophenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[1014] (75) (E)-N-(2-cyano-4-(8-(2,5-dimethyl-2H-indazol-6-yl)indolizine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[1015] (76) (E)-N-(2-cyano-4-(8-(2,6-dimethyl-2H-indazol-5-yl)indolizine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[1016] (77) (E)-4-(tert-Butylamino)-N-(2-chloro-4-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)phenyl)but-2-enamide

[1017] (78) (E)-N-(2-cyano-4-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)(methyl)amino)but-2-enamide

[1018] (79) (E)-N-(2-cyano-4-(8-(3,4-dichloro-2-methyl-2H-indazol-5-yl)indolizine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[1019] (80) (E)-N-(2-cyano-4-(8-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)imidazo[1,2-a]pyridine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[1020] (81)(E)-N-(2-cyano-4-(8-(6-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[1021] (82)(E)-N-(2-cyano-4-(8-(1,6-dimethyl-4-(pyridin-3-yl)-1H-benzo[d]imidazol-5-yl)indolizine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[1022] (83)(E)-N-(3-Fluoro-4-(7-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1H-indole-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide

[1023] The following are details of the method for preparing the compound of the present invention. The compound represented by formula (I) or (vii) of the present invention can be manufactured, for example, by the following preparation method or the method described in the examples. However, the method for manufacturing the compound represented by formula (I), (I'), (i) or (vii) of the present invention is not limited to these reaction examples. The reaction product obtained in each step can be separated and purified by a known separation and purification method such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography, or without separation and purification, and then proceed to the subsequent step.

[1024] If the blocking group is effective in each step, or in order to change the order of the steps, a blocking group that can be easily converted into a functional group can be introduced into the reaction product and starting material obtained in each step. The example of the blocking group used herein can be the blocking group used in the method disclosed in document "Protective Groups in Organic Synthesis", the 5th edition, Greene and Wuts, John Wiley & Sons Inc., 2014, etc. The blocking group can be appropriately selected according to the reaction conditions of each step. After introducing the blocking group and reacting, the blocking group is optionally removed to obtain the desired compound.

[1025] As used herein, "mole" refers to 6.02×10 23 The unit of the number of molecules of a compound, also known as Avogadro's constant.

[1026] Production method 1

[1027] Solution 1

[1028]

[1029] In Scheme 1, La represents a halogen, each R' independently represents hydrogen or a substituted or unsubstituted alkyl group, two R's may together form a 5- to 10-membered ring, and other symbols are as defined in Embodiment A.

[1030] (Step 1)

[1031] When La in the compound represented by general formula (II) has a leaving group such as a halogen, this step is a step of obtaining a compound represented by general formula (IV) by a cross-coupling reaction of the compound represented by general formula (II) with an aryl boronic acid or aryl boronic ester or an unsaturated heterocyclic boronic acid or unsaturated heterocyclic boronic ester (III) (each of which may be a commercial product or may be prepared by a known method). The compound represented by general formula (II) may be a commercial product or may be prepared by a known method.

[1032] This step can be generally performed according to a known method (eg, Chemical Reviews, vol. 95, p. 2457, 1995), and can be performed, for example, in the presence of a transition metal catalyst and a base in a solvent that does not adversely influence the reaction.

[1033] The amount of the aryl boronic acid or aryl boronic ester, or the unsaturated heterocyclic boronic acid or unsaturated heterocyclic boronic ester used may be 1-10 moles, preferably about 1-3 moles, based on 1 mole of the compound of formula (II).

[1034] As transition metal catalyst, for example, palladium catalyst (such as palladium acetate, palladium chloride, tetrakis (triphenylphosphine) palladium and dichlorobis (triphenylphosphine) palladium), nickel catalyst (such as nickel chloride) etc. can be used.As required, ligand (such as triphenylphosphine and tri-tert-butylphosphine) is added to catalyst, and metal oxide (such as copper oxide and silver oxide) etc. can be used as promotor.The usage amount of transition metal catalyst, depending on the type of catalyst, is usually about 0.0001 to 1 mole based on 1 mole of compound of general formula (II), preferably about 0.01 to 0.5 molar magnitude.Based on 1 mole of compound of general formula (II), the usage amount of ligand is usually about 0.000 to 4 moles, preferably about 0.01 to 2 molar magnitude.Based on 1 mole of compound of general formula (II), the usage amount of promotor is usually about 0.0001 to 4 moles, preferably about 0.01 to 2 molar magnitude.

[1035] Examples of the base include organic amines (e.g., trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-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 disilazane, sodium disilazane, and potassium disilazane). The base is typically used in an amount of 0.1 to 10 moles, preferably about 1 to 5 moles, based on 1 mole of the compound represented by general formula (II).

[1036] The solvent is only required not to adversely affect the reaction. Examples of the solvent 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.

[1037] 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, and preferably 0°C to 150°C.

[1038] The compound of formula (IV) thus obtained can be isolated and purified by known isolation and purification means, or can be directly subjected to the subsequent steps without such isolation and purification.

[1039] (Step 2)

[1040] This step is a step of obtaining a compound represented by the general formula (VI) through an amidation reaction between an amine represented by the general formula (IV) and a carboxylic acid (V). The carboxylic acid (V) may be a commercially available product or may be prepared by a known method.

[1041] This step is carried out using 0.5-10 moles, preferably 1-3 moles, of carboxylic acid (V) based on 1 mole of the compound represented by general formula (IV). A suitable condensing agent as an amidating agent is added to a solvent inert to the reaction, and the mixture is stirred under cooling or heating, preferably at -20°C to 80°C, for usually 1 minute to 1 week.

[1042] Examples of the condensing agent include, but are not particularly limited to, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, benzotriazol-1-yloxy-tris-(dimethylamino)phosphonium hexafluorophosphate, benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate, bromotris-(dimethylamino)phosphonium hexafluorophosphate, diphenylphosphoryl azide, 1,1'-carbonyldiimidazole and propylphosphonic anhydride (cyclic trimer).

[1043] Examples of the solvent include, but are not particularly limited to, toluene, dichloromethane, chloroform, THF, 1,4-dioxane, DMF, N,N-dimethylacetamide, NMP, 2-propanol, ethanol, methanol, water, and mixtures thereof.

[1044] If necessary, additives such as 1-hydroxybenzotriazole and a base may also be added. Examples of the base include, but are not particularly limited to, 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.

[1045] The compound represented by the general formula (VI) thus obtained can be isolated and purified by known isolation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, chromatography, or can be used to prepare the compound represented by the general formula (I) without isolation and purification.

[1046] Production Method 2

[1047] Option 2

[1048]

[1049] In Scheme 2, R1 represents hydrogen, and the other symbols are as defined in Embodiment A.

[1050] (Step 3)

[1051] This step is a step of obtaining a compound represented by general formula (VIII) by subjecting a compound represented by general formula (IV) and a carboxylic acid represented by general formula (VII) (which may be a commercially available product or may be prepared by a known method) to an amidation reaction.

[1052] This step can be performed in the same manner as step 2.

[1053] (Step 4)

[1054] This step is a step of reducing the compound represented by the general formula (VIII) to produce the compound represented by the general formula (VI).

[1055] This step can be carried out by using a hydrogen source (such as hydrogen, formic acid, ammonium formate or cyclohexadiene) and using palladium / carbon or palladium hydroxide / carbon as catalyst in the solvent (such as acetonitrile, ethyl acetate, THF, methanol, ethanol, DMF, DMA or NMP) that does not adversely affect the reaction.The compound represented by the general formula (VIII) based on 1 mole is usually used 0.01-5 mole, preferably 0.05-1 mole of catalyst is carried out this step.Reaction temperature is usually room temperature to the reflux temperature of solvent.Reaction times is usually 1 hour to 24 hours.

[1056] The compound represented by the general formula (VI) thus obtained can be isolated and purified by known isolation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, chromatography, or can be used to prepare the compound represented by the general formula (I) without isolation and purification.

[1057] Production Method 3

[1058] Option 3

[1059]

[1060] In Scheme 3, L b Indicates 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.

[1061] (Step 5)

[1062] This step is to react a compound represented by the general formula (IX) with a carboxylic acid represented by the general formula (X) (L c =OH) or acyl halide (L c =Cl, Br) to obtain a compound represented by the general formula (XI).

[1063] When a carboxylic acid (1c=OH) represented by the general formula (X) is used, this step can be performed in the same manner as in Step 2.

[1064] When using an acyl halide (L c =Cl, Br), based on 1 mol of the compound represented by general formula (IX), usually 0.5 to 10 mol, preferably about 1 to 5 mol of the acyl halide is used. The acyl halide may be a commercially available product or can be prepared according to a known method.

[1065] Base can also be added as needed. Examples of bases include organic amines (such as trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] undec-7-ene, pyridine and N, N-dimethylaniline), alkali metal salts (such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide and potassium hydroxide), metal hydrides (such as potassium hydride and sodium hydride) and alkali metal alkoxides (such as sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide). Based on 1 mole of the compound represented by general formula (IX), the usage amount of the base is generally 1 to 100 moles, preferably about 1 to 10 moles.

[1066] The solvent used in the reaction is only required not to adversely affect the reaction. Examples of solvents include alcohols (such as methanol), hydrocarbons (such as benzene, toluene and xylene), halogenated hydrocarbons (such as dichloromethane, chloroform and 1,2-dichloroethane), nitrile (such as acetonitrile), ethers (such as 1,2-dimethoxyethane and THF), aprotic polar solvents (such as 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.

[1067] The compound of the general formula (XI) thus obtained can be subjected to subsequent steps after isolation and purification by a known isolation and purification method or without isolation and purification.

[1068] (Step 6)

[1069] This step is a step of obtaining a compound represented by the general formula (VI) by a coupling reaction of the compound represented by the general formula (XI) with an aryl boronic acid or aryl boronic ester, or with an unsaturated heterocyclic boronic acid or unsaturated heterocyclic boronic ester (XII) (each of which may be a commercially available product or can be prepared by a known method) when LB in the compound represented by the general formula (XI) has a leaving group such as a halogen.

[1070] This step is when L in the compound represented by the general formula (XI) b When the compound has a leaving group such as a halogen, a step of obtaining a compound represented by the general formula (VI) by coupling a compound represented by the general formula (XI) with an aryl boronic acid or aryl boronic ester, or with an unsaturated heterocyclic boronic acid or unsaturated heterocyclic boronic ester (XII) (each of which may be a commercially available product or can be prepared by a known method).

[1071] This step can be performed in the same manner as step 1.

[1072] Production Method 4

[1073] Option 4

[1074]

[1075] In Scheme 4, the symbols are as defined in Embodiment A.

[1076] (Step 7)

[1077] This step is a step of obtaining a compound represented by the general formula (XIV) by an amidation reaction between the compound represented by the general formula (VI) and the carboxylic acid (XIII).

[1078] This step can be performed in the same manner as step 2.

[1079] (Step 8)

[1080] This step is a step of producing the compound of the present invention represented by general formula (I) by reacting a compound represented by general formula (XIV) with an amine represented by general formula (XV).

[1081] The amine represented by the general formula (XV) may be used in an amount of 1 to 20 moles, preferably 1 to 10 moles, based on 1 mole of the compound represented by the general formula (XIV).

[1082] As required, alkali can be added in the above-mentioned reaction.The example of alkali includes organic base, such as triethylamine, N, N-diisopropylethylamine, pyridine, lutidine, coltidine, 4-dimethylaminopyridine, potassium tert-butoxide, sodium tert-butoxide, sodium methylate, sodium ethoxide, lithium hexamethyldisilazane, sodium hexamethyldisilazane, potassium hexamethyldisilazane and butyllithium, or inorganic base, such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride and potassium phosphate.As the addition of alkali, based on 1 mole of the compound represented by general formula (XIV), 1 to 100 moles can be used, preferably 1 to 20 moles.

[1083] Inorganic salts may also be added as needed. Examples of inorganic salts include sodium iodide and potassium iodide. The amount of inorganic salt used is generally 1 to 100 moles, preferably about 1 to 10 moles, based on 1 mole of the compound represented by general formula (XIV).

[1084] The reaction solvent is not particularly limited as long as the solvent does not adversely affect the reaction. For example, DMF, N,N-dimethylacetamide, dimethyl sulfoxide, THF, 1,4-dioxane, N-methylpyrrolidin-2-one, and acetonitrile can be used alone 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.

[1085] The compound of the present invention represented by the general formula (VI) thus obtained can be isolated and purified by known separation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.

[1086] Production Method 5

[1087] Option 5

[1088]

[1089] In Scheme 5, L d represents a fluorine atom or an amino group or NHR1, L e represents halogen, and the other symbols are as defined in Embodiment A.

[1090] (Step 9)

[1091] This step is a method of obtaining a compound represented by the general formula (XVII) by bromination reaction of a compound represented by the general formula (XVI) (which may be a commercially available product or can be prepared by a known method).

[1092] This step can be carried out in a solvent (such as acetonitrile, ethyl acetate, dichloromethane, chloroform, 1,4-dioxane or ethanol) that does not adversely affect the reaction by using a bromine source (such as bromine or copper (II) bromide). If necessary, iodine can also be used as an additive. In this step, based on 1 mole of the compound represented by general formula (XVI), 1 to 100 moles, preferably about 1 to 10 molar magnitude of bromine sources can be used. The reaction temperature is generally room temperature to the reflux temperature of the solvent. The reaction times is generally 1 hour to 24 hours.

[1093] The compound represented by the general formula (XVII) thus obtained can be subjected to the subsequent step after isolation and purification by a known isolation and purification method or without isolation and purification.

[1094] (Step 10)

[1095] This step is a step of obtaining a compound represented by the general formula (XVIII) by subjecting a substituted pyridine (which may be a commercially available product or can be prepared by a known method) to a nucleophilic substitution reaction with a compound represented by the general formula (XVII), followed by an intramolecular cyclization reaction.

[1096] When D2 is N, D1' and D2' are C, CH or CH2, and L d The amount of the substituent L is usually 0.5 to 10 moles, preferably about 1 to 5 moles, based on 1 mole of the compound represented by the general formula (XVII), in a solvent that does not adversely affect the reaction (such as THF and ethanol). e and 2-picoline of R7. 2-picoline can be a commercially available product or can be prepared according to known methods. The reaction temperature is generally room temperature to the reflux temperature of the solvent. The reaction time is generally on the order of 1 hour to about 4 days.

[1097] The pyridinium salt thus obtained can be subjected to subsequent reactions after isolation and purification by a known isolation and purification method or without isolation and purification.

[1098] Based on 1 mole of the above-mentioned pyridinium salt obtained, 1 to 100 moles can be usually used, preferably about 1 to 20 molar magnitude of methylsulfate (methoxymethylene) dimethylammonium, which can be a commercially available product or can be prepared by a known method, and alkali can also be added as needed. The example of alkali includes organic amine (such as trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] 11 carbon -7- ene, pyridine and N, N-dimethylaniline), alkali metal salt (such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide and potassium hydroxide), metal hydride (such as potassium hydride and sodium hydride) and alkali metal alkoxide (such as sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide). Based on 1 mole of pyridinium salt, the usage amount of alkali is generally 1 to 100 moles, preferably about 1 to 10 molar magnitude.

[1099] The solvent used in the reaction is only required not to adversely affect the reaction. Examples of solvents include aprotic polar solvents (such as 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.

[1100] The compound represented by the general formula (XVIII) thus obtained can be isolated and purified by known isolation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography, or used to prepare the compound (I') of the present invention without isolation and purification.

[1101] When D2 and D2' are N or NH, and D1' is C, CH or CH2, a solvent that does not adversely affect the reaction, such as DMF and ethanol, is added, usually in an amount of 0.5 to 10 moles, preferably about 1 to 5 moles, of a substituent L based on 1 mole of the compound represented by the general formula (XVII). eand R7 (E) -N, N- dimethyl -N'- (pyridine -2- bases) formamide (formimidamide). (E) -N, N- dimethyl -N'- (pyridine -2- bases) formamide can be a commercially available product or can be prepared according to a known method. A base can be added as needed. Examples of bases include organic amines (such as trimethylamine, triethylamine, N, N- diisopropylethylamine, N- methylmorpholine, 1,8- diazabicyclo [5,4,0] undec-7-ene, pyridine and N, N- dimethylaniline) and alkali metal salts (such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide and potassium hydroxide). The reaction temperature is generally room temperature to the reflux temperature of the solvent. The reaction time is generally 1 hour to 24 hours.

[1102] The compound represented by the general formula (XVIII) thus obtained can be used to prepare the compound (I') of the present invention after or without isolation and purification by known isolation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation and chromatography.

[1103] Production Method 6

[1104] Option 6

[1105]

[1106] In Scheme 6, L f represents a halogen, a chlorine atom or a bromine atom, and the other symbols are as defined in Embodiment A.

[1107] (Step 11)

[1108] This step is a step of obtaining a compound represented by general formula (XXI) by a Friedel-Crafts reaction between a compound represented by general formula (XIX) (which may be a commercially available product or can be produced by a known procedure) and a compound represented by general formula (XX).

[1109] When a carboxylic acid (L f =OH), this step can be carried out by using trifluoroacetic anhydride, phosphoric acid, etc. in a solvent (such as dichloromethane, THF and 1,4-dioxane) that does not adversely affect the reaction. As needed, a base can also be added. The example of the base includes organic amine (for example, trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] undec-7-ene, pyridine and N,N-dimethylaniline). In this step, based on 1 mole of the compound represented by general formula (XIX), 1 to 100 moles, preferably about 1 to 10 moles of acid can be used. The reaction temperature is generally room temperature to the reflux temperature of the solvent. The reaction time is generally 1 hour to 3 days.

[1110] When an acyl halide (Lf=Cl, Br) represented by the general formula (XX) is used, this step can be carried out in the presence of a Lewis acid such as aluminum chloride or an organic amine (such as trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, pyridine and N,N-dimethylaniline) in a solvent (such as dichloromethane, THF and 1,4-dioxane) that does not adversely affect the reaction. In this step, based on 1 mole of the compound represented by the general formula (XIX), 1 to 100 moles, preferably about 1 to 10 moles of Lewis acid or base can be used. The reaction temperature is generally 0°C to the reflux temperature of the solvent. The reaction time is generally 1 hour to 24 hours.

[1111] The compound represented by the general formula (XXI) thus obtained can be subjected to subsequent reactions after isolation and purification by a known isolation and purification method or without isolation and purification.

[1112] (Step 12)

[1113] This step is when L d When it is a fluorine atom, a compound represented by the general formula (XXII) is obtained by an aromatic electrophilic substitution reaction of an amine.

[1114] This step can be carried out in a solvent (such as THF, 1,4-dioxane and 1,2-dimethoxyethane) that does not adversely affect the reaction by using an aqueous ammonia solution (R1=H), an alkylamine (R1-NH2) and the like. In this step, based on 1 mole of the compound represented by general formula (XXI), 1 to 100 moles, preferably 1 to 50 moles of amine can generally be used. The reaction temperature is generally room temperature to the reflux temperature of the solvent. The reaction time is generally 1 hour to 24 hours.

[1115] Production Method 7

[1116] Option 7

[1117]

[1118] In Scheme 7, the symbols are as defined in Embodiment A.

[1119] (Step 13)

[1120] This step is a step of obtaining a compound represented by the general formula (XXIII) by a cross-coupling reaction of the compound represented by the general formula (XXII) with an aryl boronic acid or aryl boronic ester or an unsaturated heterocyclic boronic acid or unsaturated heterocyclic boronic ester (XII) (each of which may be a commercially available product or can be prepared by a known method) when La in the compound represented by the general formula (XXII) has a leaving group (such as a halogen).

[1121] This step can be performed in the same manner as step 1.

[1122] (Step 14)

[1123] This step is a step of obtaining a compound represented by the general formula (XXIV) by an amidation reaction between the compound represented by the general formula (XXIII) and the carboxylic acid (XIII).

[1124] This step can be performed in the same manner as step 2.

[1125] (Step 15)

[1126] This step is a step of producing the compound of the present invention represented by general formula (I') by reacting the compound represented by general formula (XXIV) with an amine represented by general formula (XV).

[1127] This step can be performed in the same manner as step 8.

[1128] Production Method 8

[1129] Option 8

[1130]

[1131] In Scheme 8, L g Indicates halogen, L h Indicates chlorine or bromine, L i represents halogen, and the other symbols are as defined in Embodiment A.

[1132] (Step 16)

[1133] This step is a step of obtaining a compound represented by the general formula (XXVII) by an electrophilic addition reaction, wherein a strong base is added to the halogenated aryl group (XXVI) to generate an acyl halide (L) represented by the general formula (XXV). h =Cl, Br) reacting anions, the acyl halide may be a commercially available product or may be prepared by a known method.

[1134] The reaction can be carried out, for example, by adding a strong base in an appropriate solvent, stirring the mixture at -78°C to room temperature, usually for 10 minutes to 12 hours to generate anions, and adding thereto an acyl halide (L) represented by the general formula (XXV) h=Cl, Br). The reaction solvent that can be used is not particularly limited as long as the solvent 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 to, butyllithium, lithium diisopropylamide, 2,2,6,6-tetramethylpiperidinium lithium, 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex, and isopropylmagnesium chloride lithium chloride complex.

[1135] The compound represented by the general formula (XXVII) thus obtained can be isolated and purified by known isolation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, chromatography, or can be used to prepare the compound of the present invention without isolation and purification.

[1136] When the compound according to one embodiment of the present invention has isomers, such as optical isomers, stereoisomers, rotational isomers and tautomers, unless otherwise specified, any isomers and mixtures thereof are included within the scope of the compound of the present invention. For example, when the compound of the present invention has optical isomers, unless otherwise specified, the racemic mixture and the optical isomers separated from the racemic mixture are also included within the scope of the compound of the present invention.

[1137] The 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 may be prepared 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., a hydrate) or an ansolvate. Any such form is included within the scope of the compound or salt thereof of the present invention. 2 H. 3 H. 13 C. 14 C. 35 S. 125 I) The compound labeled is also included in the scope of the compound or its salt of the present invention.

[1138] The salt of the compound according to one embodiment of the present invention refers to any pharmaceutically acceptable salt; examples include base addition salts and acid addition salts.

[1139] The compound or its salt according to one embodiment of the present invention also includes a prodrug thereof. A prodrug refers to a compound that can be converted into a compound of the present invention or its salt by reacting with an enzyme, gastric acid, etc. under physiological conditions in vivo, that is, a compound that can be converted into a compound of the present invention or its salt by enzymatic oxidation, reduction, hydrolysis, etc.; or a compound that can be converted into a compound of the present invention or its salt by hydrolysis with gastric acid, etc. In addition, a prodrug can be a compound that can be converted into a compound of the present invention or its salt under physiological conditions, such as those described in Iyakuhin no Kaihatsu, "Development of Pharmaceuticals," Vol.7, Molecular Design, published by Hirokawa AShoten Co., 1990, pp. 163-198.

[1140] As used herein, an "effective amount" of a compound according to one embodiment of the present invention refers to an amount of the compound sufficient to achieve a biological or therapeutic response in a subject (e.g., causing a reduction or prevention of enzyme or protein activity); or to improve symptoms, alleviate a medical condition, delay or slow the progression of a disorder, or prevent a disease (therapeutically effective amount).

[1141] As used herein, "subject" includes mammals and non-mammals. Examples of mammals include, but are not limited to, humans, chimpanzees, apes, monkeys, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, guinea pigs, hedgehogs, kangaroos, moles, boars, bears, tigers, and lions. Examples of non-mammals include, but are not limited to, birds, fish, and reptiles. In one embodiment, the subject is a human, and may be a human who has been diagnosed as needing treatment for a symptom, medical condition, or disease as disclosed herein.

[1142] In one embodiment, a medicament, a pharmaceutical composition or a pharmaceutical preparation comprising a compound of the present invention or a pharmaceutically acceptable salt thereof may be provided. In another embodiment, an antitumor agent comprising a compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient may be provided.

[1143] When the compound according to one embodiment of the present invention or a salt thereof is used as a pharmaceutical preparation, a medicine or a pharmaceutical composition, a pharmaceutically acceptable carrier may be added if necessary to form a suitable dosage form according to the purpose of prevention and treatment. Examples of dosage forms include oral preparations, injections, suppositories, ointments, inhalants, patches, etc. Such dosage forms can be formed by conventional methods known to those skilled in the art.

[1144] As pharmaceutically acceptable carriers, various conventional organic or inorganic carrier materials used as preparation materials can be blended as excipients, binders, disintegrants, lubricants or colorants in solid preparations; or as solvents, solubilizers, suspending agents, isotonic agents, buffers or soothing agents in liquid preparations. In addition, if necessary, pharmaceutical preparation additives such as preservatives, antioxidants, colorants, sweeteners and stabilizers can also be used.

[1145] In one embodiment, a medicine, pharmaceutical composition or pharmaceutical preparation for oral administration or an oral solid preparation comprising a compound of the present invention or a pharmaceutically acceptable salt thereof can be provided. In other embodiments, an antitumor agent for oral administration can be provided, which comprises a compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient. An oral solid preparation or a medicine, pharmaceutical composition, antitumor agent or pharmaceutical preparation for oral administration is prepared as follows. After optionally adding an excipient and a binder, a disintegrant, a lubricant, a colorant, a taste masking agent or a flavoring agent to the compound of the present invention or a salt thereof, the mixture is formulated into tablets, coated tablets, granules, powders, capsules, etc. by conventional methods.

[1146] When preparing injections, pH adjusters, buffers, stabilizers, isotonic agents, local anesthetics, etc. may be added to the compound of the present invention; and according to ordinary methods, the mixture can be formulated for subcutaneous, intramuscular or intravenous injection.

[1147] The amount of the compound according to one embodiment of the present invention incorporated into each such dosage unit form depends on the condition of the patient to whom the compound is administered, the dosage form, etc. Generally, for oral agents, the amount of the compound is preferably about 0.05 to 1000 mg per dosage unit form. For injections, the amount of the compound is preferably about 0.01 to 500 mg per dosage unit form, and for suppositories, the amount of the compound is preferably about 1 to 1000 mg per dosage unit form.

[1148] In addition, the daily dose of the drug in this dosage form varies depending on the patient's condition, body weight, age, sex, etc., and cannot be determined unconditionally. For example, the daily dose of the compound of the present invention for an adult (50 kg body weight) may generally be about 0.05 to 5000 mg, and preferably 0.1 to 1000 mg.

[1149] The compound or salt thereof according to one embodiment of the present invention has excellent KRas inhibitory activity against KRASG12C mutation-positive cancer cells. Therefore, the compound or salt thereof according to one embodiment of the present invention is used as an antitumor agent against KRASG12C mutation-positive cancer cells and has the advantage of having fewer side effects.

[1150] Due to its excellent KRAS G12C inhibitory activity, the compound according to one embodiment of the present invention or a salt thereof inhibits KRas function and is useful as a pharmaceutical preparation for preventing and treating KRas-related signaling-related diseases.

[1151] In one embodiment, a compound of the present invention or a pharmaceutically acceptable salt thereof may be provided for use in preparing a pharmaceutical composition. In one embodiment, a compound of the present invention or a pharmaceutically acceptable salt thereof may be provided for use in preparing an anti-tumor agent. In one embodiment, a compound of the present invention or a pharmaceutically acceptable salt thereof may be provided for use in preparing an orally administered anti-tumor agent. In one embodiment, a compound of the present invention or a pharmaceutically acceptable salt thereof may be provided for use as a medicament. In one embodiment, a compound of the present invention or a pharmaceutically acceptable salt thereof may be provided for use in preventing and or treating tumors. In one embodiment, a compound of the present invention or a pharmaceutically acceptable salt thereof may be provided for use in preventing and or treating tumors by oral administration.

[1152] In one embodiment, a method for preventing and or treating tumors is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. In one embodiment, an antitumor agent can be provided for administration to a subject in need thereof in combination with a pharmaceutically effective amount of one or more other antitumor drugs.

[1153] With respect to RAS-related signaling in KRAS-related signaling diseases, KRAS participates in various signal transduction pathways as a RAS-related signaling pathway; KRAS primarily activates, but is not limited to, RAF, PI3K, and Ral-GEF. Examples of diseases include those whose incidence can be reduced, and whose symptoms can be alleviated, mitigated, or completely cured by eliminating, inhibiting, and / or suppressing their function. Examples of such diseases include, but are not limited to, tumors, cancers, autoimmune diseases, and macroglobulinemia.Cancers or tumors according to the present disclosure include, but are not limited to, glandular tumors, carcinoid tumors, undifferentiated carcinomas, angiosarcomas, adenocarcinomas, sarcomas, neuromas, gastrointestinal cancers (e.g., colorectal cancer ("CRC"), including colon cancer and rectal cancer, bile duct cancer (including gallbladder cancer and bile duct cancer), anal cancer, esophageal cancer, stomach (gastric) cancer, gastrointestinal carcinoids, gastrointestinal stromal tumors ("GIST"), liver cancer, duodenal cancer, and small intestine cancer), digestive organ cancers, lung cancers (e.g., non-small cell lung cancer ("NSCLC"), squamous cell lung cancer, large cell lung cancer, small cell lung cancer, mesothelioma and other lung cancers (e.g., bronchogenic carcinoma and pleuropulmonary blastoma), urinary tract cancers (e.g., renal (kidney) cancer, transitional cell carcinoma of the kidney ("TCC"), renal pelvis and ureteral TCC ("PDQ"), bladder cancer, urethral cancer, and prostate cancer), head and neck cancer (e.g., eye cancer, retinoblastoma, intraocular melanoma, hypopharyngeal cancer, pharyngeal cancer, laryngeal cancer, laryngeal papillomatosis, metastatic squamous neck cancer with occult primary, mouth (oral) cancer, lip cancer, laryngeal cancer, oropharyngeal cancer, olfactory neuroblastoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, and salivary gland cancer), endocrine cancer (e.g., thyroid cancer, parathyroid cancer, multiple endocrine neoplasia syndrome, thymoma and thymic carcinoma, pancreatic cancer including pancreatic ductal adenocarcinoma ("PDAC"), pancreatic neuroendocrine tumors, and islet cell tumors), breast cancer (extrahepatic ductal carcinoma in situ ("DCIS"), lobular carcinoma in situ ("LCIS"), triple-negative breast cancer, and inflammatory bowel disease). breast cancer), male and female reproductive and / or genital cancer (e.g., cervical cancer, ovarian cancer, endometrial cancer, uterine sarcoma, uterine cancer, vaginal cancer, vulvar cancer, gestational trophoblastic tumor (“GTD”), extragonadal germ cell tumors, extracranial germ cell tumors, germ cell tumors, testicular cancer, and penile cancer), brain and nervous system cancer (e.g., astrocytoma, brain stem glioma, brain tumor, craniopharyngioma, central nervous system (“CNS”) cancer, chordoma, ependymoma, embryonal tumor, neuroblastoma, paraganglioma, and atypical teratoma), skin cancer (e.g., basal cell carcinoma (“BCC”), squamous cell skin cancer (“SCC”), Merkel cell carcinoma, and melanoma), tissue and bone cancer (e.g., soft tissue sarcoma), and ovarian cancer (e.g., ovarian cancer, endometrial cancer, uterine sarcoma, uterine cancer, vaginal cancer, vulvar cancer, gestational trophoblastic tumor (“GTD”), extragonadal germ cell tumors, extracranial germ cell tumors, germ cell tumors, testicular cancer, and penile cancer), In some embodiments, the cancer is a type of cancer of the lung, pancreas, rectum, colon, or colorectum. In one embodiment, the squamous cell carcinoma is a type of cancer of the cervix, tarsal plate, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx, or esophagus.In one embodiment, adenocarcinoma is a carcinoma of the prostate, small intestine, endometrium, cervix uteri, large intestine, lung, pancreas, esophagus, rectum, uterus, stomach, breast or ovary. In one embodiment, the tumor is rectal cancer, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, breast cancer or leukemia. In one embodiment, the subject suffering from any of the above diseases does not necessarily have K-ras G12C mutant protein. In a preferred embodiment, the subject suffering from any of the above diseases has K-ras G12C mutant protein.

[1154] According to the present disclosure, cancer also includes, but is not limited to, blood and plasma cell malignancies and hematopoietic tumors (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes) such as multiple myeloma, leukemias and lymphomas, myelodysplastic syndromes, and myeloproliferative disorders. Leukemias include, but are not limited to, acute lymphoblastic leukemia ("ALL"), acute myeloid (myeloid) 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's lymphoma and non-Hodgkin's lymphoma ("NHL"). In some embodiments, NHL is a B-cell lymphoma and / or a T-cell lymphoma. In some embodiments, NHL includes, but is 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 lymphoma (including mycosis fungoides and Sézary syndrome), AIDS-related lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia ("WM")), primary central nervous system (CNS) lymphoma, and / or other lymphomas.

[1155] In one embodiment, an antitumor agent comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more other antitumor agents as active ingredients may be provided. In one embodiment, an antitumor agent comprising a compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient may be provided, which is administered in combination with one or more other antitumor agents. In one embodiment, the use of a compound of the present invention or a salt thereof and one or more other antitumor agents for the preparation of an antitumor agent may be provided. In one embodiment, the use of a compound of the present invention or a salt thereof for the preparation of an antitumor agent may be provided, which is administered in combination with one or more other antitumor agents. In one embodiment, a combination of a compound of the present invention or a salt thereof and one or more other antitumor agents may be provided for treating tumors. In one embodiment, a compound of the present invention or a pharmaceutically acceptable salt thereof for treating tumors may be provided, which is administered in combination with one or more other antitumor agents. In one embodiment, a method for treating tumors may be provided, comprising administering a therapeutically effective amount of a 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 tumors may be provided, comprising administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more other antitumor agents to a subject in need thereof.

[1156] The compounds of the present invention or pharmaceutically acceptable salts thereof can be used in combination with one or more other anti-tumor agents for the treatment of cancer. In other words, a single compound of the present invention or pharmaceutically acceptable salts thereof or more than one compound of the present invention or pharmaceutically acceptable salts thereof can be used in combination with a single other anti-tumor agent or more than one other anti-tumor agent.

[1157] As used herein, "other anti-tumor agents" can be any pharmaceutically active agent (or a pharmaceutically acceptable salt thereof) that is active in vivo, and it is different from the compound of the present invention or its pharmaceutically acceptable salt. Other anti-tumor agents include prodrugs, free acids, free bases and pharmaceutically acceptable salts of other active agents. Generally, any suitable other anti-tumor agent, including chemotherapeutic agents or therapeutic antibodies, can be used with the compound of the present invention or its pharmaceutically acceptable salt in a single dose formulation (e.g., fixed dose drug combination) or in any combination of one or more separate dosage formulations, which allow the pharmaceutically active agent to be administered simultaneously or sequentially (co-administered separate active agents) to the subject. In certain embodiments, the compound of the present invention or its pharmaceutically acceptable salt and other anti-tumor agents are administered a few minutes apart, or a few hours apart, or a few days apart. In addition, the compound of the present invention or its pharmaceutically acceptable salt can be administered in combination with radiotherapy, hormone therapy, targeted therapy, surgery or immunotherapy. In one embodiment, one or more other anti-tumor agents are included in the pharmaceutical composition as described above.

[1158] In one embodiment, other antitumor agents are other anticancer agents (also referred to as antitumor agents). "Anticancers" as used herein are any pharmaceutically active agents (or pharmaceutically active salts thereof) with anticancer activity in vivo. Examples of anticancer agents include chemotherapeutic agents (e.g., cytotoxic agents), immunotherapeutic agents, hormones and antihormonal agents, targeted therapeutic agents, and anti-angiogenic agents. Many anticancer agents can be classified in one or more of these groups. Although some anticancer agents have been classified in a specific group or subgroup herein, as currently understood in the art, many of these agents can also be listed in one or more other groups or subgroups. It should be understood that it is not restrictive to classify a specific agent as a specific group herein. Many anticancer agents are currently known in the art and can be used in combination with a compound of the present invention or a pharmaceutically acceptable salt thereof.

[1159] In addition, the agent can be an agonist, antagonist, allosteric modulator, toxin, or more generally, can act to inhibit or stimulate its target (e.g., receptor or enzyme activation or inhibition). For example, suitable for use are one or more agents (e.g., antibodies, antigen binding regions, or soluble receptors) that specifically bind to a growth factor and inhibit its activity, such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor), and antibodies or antigen binding regions that specifically bind to its receptor "c-met".

[1160] In one embodiment, the additional anticancer agent is a chemotherapeutic agent, an immunotherapeutic agent, a hormone agent, an antihormonal agent, a targeted therapeutic agent or an anti-angiogenic agent (or angiogenesis inhibitor). In one embodiment, the additional anticancer agent is selected from a chemotherapeutic agent, a mitotic inhibitor, a plant alkaloid, an alkylating agent, an antimetabolite, a platinum analog, an enzyme, a topoisomerase inhibitor, a retinoid, an aziridine, an antibiotic, a hormone agent, an antihormonal agent, an anti-estrogen, an anti-androgen, an anti-adrenaline, an androgen, a targeted therapeutic agent, an immunotherapeutic agent, a biological response modifier, a cytokine inhibitor, a tumor vaccine, a monoclonal antibody, an immune checkpoint inhibitor, an anti-PD-1 agent, an anti-PD-L1 agent, a colony stimulating factor, an immunomodulator, an immunomodulatory imide (IMiD), an anti-CTLA4 agent, an anti-LAGL agent, an anti-OX40 agent, a GITR agonist, a CAR-T cell, a BiTE, a signal transduction inhibitor, a growth factor inhibitor, a tyrosine kinase ... The invention also includes but is not limited to amino acid 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 modulators, autophagy inhibitors, apoptosis inducers, anti-proliferative agents and glycolysis inhibitors.

[1161] In one embodiment, the additional anticancer agent is a chemotherapeutic agent. Non-limiting examples of chemotherapeutic agents include mitotic inhibitors and plant alkaloids, alkylating agents, antimetabolites, platinum analogs, enzymes, topoisomerase inhibitors, retinoids, aziridines, and antibiotics.

[1162] Non-limiting examples of mitotic inhibitors and plant alkaloids include taxanes, such as cabazitaxel, docetaxel, larotaxel, ortataxel, paclitaxel, and tesetaxel; colchicine; epothilones; eribulin; etoposide (VP-16); etoposide phosphate; navelbine; narcotine; teniposide; thaliblastine; vinblastine; vincristine; vindesine; vinflunine; and vinorelbine.

[1163] Non-limiting examples of alkylating agents include nitrogen mustards such as chlorambucil, naphthiazolin, clofosamide, cyclophosphamide, estramustine, ifosfamide, mannomustine, mechlorethamine, mechlorethamine hydrochloride, melphalan, mechlorethamine, phenylephrine, prednimustine, tris(2-chloroethyl)amine, trofosfamide, and uracil mustard; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; nitrosoureas such as carmustine, chlorozolin, fotemustine, lomustine, and chlorambucil. and TA-07; ethyleneimines and methylmelamines, such as altretinoin, thiotepa, triethylenemelamine, triethylenethiophosphoramide, triethylenephosphoramide, and trimethylolmelamine; aminostine; bendamustine; dacarbazine; etoglucid; irofulven; mafosfamide; dibromomannitol; dibromodulcitol; pipobroman; procarbazine; temozolomide; treosulfan; and triazinon.

[1164] Non-limiting examples of antimetabolites include folic acid analogs such as aminopterin, dimethylformamide, edatrexate, methotrexate, pteropterin, raltitrexed, and trimetrexate; purine analogs such as 6-mercaptopurine, 6-thioguanine, fludarabine, forodesine, thiabendine, and thioguanine; pyrimidine analogs such as 5-fluorouracil (5-FU), 6-azauridine, ancitabine, azacytidine, capecitabine, carmofuracil, and dapoxetine; , cytarabine, decitabine, dideoxyuridine, doxifiuridine, doxifluridine, enocitabine, floxuridine, galocipabine, gemcitabine, and sapacitabine; 3-aminopyridine-2-carboxaldehyde thiosemicarbazone; bromuridine; cladribine; cyclophosphamide; cytarabine; ethiprole; hydroxyurea; mercaptopurine; nelarabine; pemetrexed; pentostatin; tegafur; and troxacitabine.

[1165] Non-limiting examples of platinum analogs include carboplatin, cisplatin, bicycloplatin, heptaplatin, lobaplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate.

[1166] Non-limiting examples of enzymes include asparaginase and pegaspargase.

[1167] Non-limiting examples of topoisomerase inhibitors include acridinium carboxamide, afatinib, amsacrine, belotecan, ilitinib acetate, exatecan, indolecarbazole, irinotecan, lertotecan, mitoxantrone, razoxane, rubitecan, SN-38, sobuzoxane, and topotecan.

[1168] Non-limiting examples of retinoids include alitretinoin, bexarotene, fenretinide, isotretinoin, liarozole, RII tretinoin, and tretinoin.

[1169] Non-limiting examples of aziridines include benzodopa, carboquinone, metodopa, and uredopa.

[1170] Non-limiting examples of antibiotics include intercalating antibiotics; anthracenediones; anthracyclines such as aclarubicin, amrubicin, daunorubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, menorubicin, nogamycin, pirarubicin, and valrubicin; 6-diazo-5-oxo-L-norleucine; aclarubicin; actinomycin; doxorubicin; azaserine; bleomycin; actinomycin C; calicheamicin; carabicin; carminomycin; carmophorin; chromomycin; dactinomycin; detoximum serotonin; dactinomycin ... rubicin; esorubicin; epothilone; geldanamycin; marcellomycin; mitomycin; mitomycin C; mycophenolic acid; olivomycin; novantrone; peplomycin; porfibrinocin; polybleomycin; puromycin; levofloxacin; rebeccamycin; roxithromycin; streptozocin; streptozocin; tuberculate; ubenimex; zinostatin; zinostatinstimalamer; and daurubicin.

[1171] In one embodiment, the additional anti-cancer agent is a hormonal and or anti-hormonal agent (ie, hormone therapy). Non-limiting examples of hormones and anti-hormonal agents include anti-androgens such as abiraterone, apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, goserelin, leuprolide, and nilutamide; anti-estrogens such as 4-hydroxytamoxifen, aromatase inhibiting 4(5)-imidazole, EM-800, fosestrol, fulvestrant, raloxifene, LY 117018, onapristone, raloxifene, tamoxifen, toremifene, and troloxifene; anti-adreners such as aminoglutethimide, dexaminoglutethimide, mitotane, and trilostane; androgens such as calostosterone, drostanolone propionate, cyclothiocarbamate, melastane, and testolactone; abarelix; anastrozole; cetrorelix; deslorelin; exemestane; fadrozole; finasteride; formestane; histrelin (RL 0903); human chorionic gonadotropin; lanreotide; LDI 200 (Milkhaus); letrozole; leuprorelin; mifepristone; nafarelin; nafoxidine; osatetron; prednisone; thyrotropin alfa; and triptorelin.

[1172] In one embodiment, the additional anticancer agent is an immunotherapeutic agent (i.e., immunotherapy). Non-limiting examples of immunotherapeutic agents include biological response modifiers, cytokine inhibitors, tumor vaccines, monoclonal antibodies, immune checkpoint inhibitors, colony stimulating factors, and immunomodulators.

[1173] Non-limiting examples of biological response modifiers include cytokine inhibitors (cytokines), such as interferons and interleukins, including interferon alphas, such as interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon alpha-n3, interferon alfacon-1, pegylated interferon alpha-2a, pegylated interferon alpha-2b, and leukocyte alpha interferon; interferon betas, such as interferon beta-1a and interferon beta-1b; interferon gammas, such as natural interferon gamma-1a and interferon gamma-1b; aldesleukin; interleukin-1 beta; interleukin-2; oprelleukin; sonamin; tasonamine; and virulizin.

[1174] Non-limiting examples of tumor vaccines include APC 8015, AVICINE, bladder cancer vaccine, cancer vaccine (Biomira), gastrin 17 immunogen, Maruyama vaccine, melanoma lysate vaccine, melanoma oncolysate vaccine (NewYork Medical College), melanoma vaccine (New York University), melanoma vaccine (SloanKettering Institute), BCG (bacillus Calmette-Guérin) and viral melanoma cell lysate vaccines (Royal New Castle Hospital).

[1175] Non-limiting examples of monoclonal antibodies include abagovomab, adecatumumab, aflibercept, alemtuzumab, blinatumomab, brentuximab vedotin, CA125 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 CEAmAb (Trilex), ipilimumab, lintuzumab, Lym-1-iodo-131 mAb (Techni Clone), mitumomab, moxetumomab, ofatumumab, polymorphic epithelial mucin-yttrium 90 mAb (Antisoma), ranibizumab, tocilizumab, and trastuzumab.

[1176] Non-limiting examples of immune checkpoint inhibitors include anti-PD-1 agents or antibodies, such as cemiplimab, nivolumab, and pembrolizumab; anti-PD-L1 agents or antibodies, such as atezolizumab, avelumab, and durvalumab; anti-CTLA-4 agents or antibodies, such as ipilimumab; anti-LAGL agents; and anti-OX40 agents.

[1177] Non-limiting examples of colony stimulating factors include darbepoetin alfa, epoetin alfa, epoetin beta, filgrastim, granulocyte macrophage colony stimulating factor, lenograstim, lerdigrastim, milipasin, molaspasin, nartograstim, pegfilgrastim, and sargramostim.

[1178] Non-limiting examples of additional immunotherapeutic agents include BiTEs, CAR-T cells, GITR agonists, imiquimod, immunomodulatory imide (IMID), mismatched double-stranded RNA (Ampligen), resiquimod, SRL 172, and thymalfasin.

[1179] In one embodiment, other anticancer agent is a targeted therapy agent (i.e., targeted therapy). Targeted therapy agent includes, for example, monoclonal antibodies and small molecule drugs. The limiting examples of targeted therapy agent include signal transduction 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.

[1180] Non-limiting examples of signal transduction inhibitors include tyrosine kinase inhibitors, multikinase inhibitors, anlotinib, afatinib, axitinib, dasatinib, dovitinib, imatinib, lenvatinib, lonidamine, nilotinib, nintedanib, pazopanib, pegvisomant, ponatinib, vandetanib, and EGFR inhibitory agents.

[1181] Non-limiting examples of EGFR inhibitory agents 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 inhibitory agents can 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 supra); Mab C225 (ATCC Accession No. 2001005); No. HB-8508) or an antibody or antibody fragment having the binding specificity thereof; specific antisense nucleotides or siRNA; afatinib, cetuximab; matuzumab; necituzumab; nimotuzumab; panitumumab; and zalutumumab.

[1182] Non-limiting examples of histone deacetylase (HDAC) inhibitors include belinostat, panobinostat, romidepsin, and vorinostat.

[1183] Non-limiting examples of proteasome inhibitors include bortezomib, carfilzomib, ixazomib, salinosporamide a, and oprozomib.

[1184] Non-limiting examples of cell cycle inhibitors, including CDK inhibitors, include abemaciclib, avocidib, palbociclib, and ribociclib.

[1185] In one embodiment, the additional anticancer agent is an anti-angiogenic agent (or angiogenesis inhibitor), including but not limited to matrix metalloproteinase (MMP) inhibitors; VEGF inhibitors; EGFR inhibitors; TOR inhibitors, such as everolimus and temsirolimus; PDGFR kinase inhibitory agents, such as crenolanib; HIF-1α inhibitors, such as PX478; HIF-2α inhibitors, such as bezotifen and the HIF-2α inhibitors described in WO 2015035223; fibroblast growth factor (FGF) or FGFR inhibitory agents, such as B-FGF and RG 13577; hepatocyte growth factor inhibitors; KDR inhibitors; anti-Ang1 and anti-Ang2 agents; anti-TiE2 kinase inhibitory agents; TEK antagonists (US20030162712; US 6,413,932); anti-TWEAK agents (US 6,727,225); ADAM disintegrin domains to antagonize the binding of integrins to their ligands (US2002 / 0042368); anti-eph receptor and or anti-ephrin antibodies or antigen binding regions (US 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447 and 6,057,124); and anti-PDGF-BB antagonists and antibodies or antigen binding regions that specifically bind to PDGF-BB ligands.

[1186] Non-limiting examples of matrix metalloproteinase (MMP) inhibitors include MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, prinomastat, RO 32-3555, and RS13-0830. Examples of useful matrix metalloproteinase inhibitors are described, for example, in WO 96 / 33172, WO 96 / 27583, EP 1004578, WO 98 / 07697, WO 98 / 03516, WO 98 / 34918, WO 98 / 34915, WO 98 / 33768, WO 98 / 30566, EP 0606046, EP 0931788, WO 90 / 05719, WO 99 / 52910, WO 99 / 52889, WO 99 / 29667, WO 1999 / 007675, EP 1786785, EP 1181017, US 2009 / 0012085, US 5,863,949, US 5,861,510 and EP 0780386. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no MMP-1 inhibitory activity. More preferred are those that selectively inhibit MMP-2 and / or MMP-9 relative 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).

[1187] Non-limiting examples of VEGF and VEGFR inhibitory agents include bevacizumab, cediranib, CEP 7055, CP547632, KRN 633, ocretinib, pazopanib, pegaptanib, pegaptanib octasodium, semaxanib, sorafenib, sunitinib, VEGF antagonist (Borean, Denmark), and VEGF-TRAP TM .

[1188] The other anti-tumor agent can also be another anti-angiogenic agent, including but not limited to 2-methoxyestradiol, AE941, alemtuzumab, α-D148 Mab (Amgen, US), αstatin, anecortave acetate, angiostatin, angiogenesis inhibitor (Sugen, US), angiostatin, anti-Vn Mab (Crucell, Netherlands), atimod, axitinib, AZD9935, Bay Res 2690 (Bayer, Germany), BC 1 (GenoA Institute of Cancer Research, Italy), beloranib, fluazifop (Lane Labs, US), cabozantinib, CDP 791 (Celltech Group, UK), chondroitinase AC, cilengitide, combretastatin A4 prodrug, CP 564959 (OSI, US), CV247, CYC 381 (Harvard University,US), E 7820, EHT 0101, endostatin, enzastaurin hydrochloride, ER-68203-00 (Ivax, US), fibrinogen-E fragment, FLK-1 (ImClone Systems, US), form of FLT 1 (VEGFR 1), FR-111142, GCS-100, GW 2286 (GlaxoSmithKline, UK), IL-8, ilomastat, IM-862, irsogladine, KM-2550 (Kyowa Hakko, Japan), lenalidomide, lenvatinib, MAb α5β3 integrin, second generation (Applied Molecular Evolution, USA and MedImmune, US), MAb VEGF (Xenova, UK), marimastat, maspin (Sosei, Japan), mestatin, motuporamine C, M-PGA, Ombrabulin, OX14503, PI88, platelet factor 4, PPI2458, ramucirumab, RBPI 21 and BPI-derived antiangiogenic agents (Xoma, US), regorafenib, SC-236, SD-7784 (Pfizer, US), SDX 103 (University of California at San Diego, US), SG 292 (Telios, US), SU-0879 (Pfizer, US), TAN-1120, TBC-1635, tesifatinib, tetrathiomolybdate, thalidomide, thrombospondin 1 inhibitor, Tie-2 ligand (Regeneron, US), tissue factor pathway inhibitor (Entremed, US), tumor necrosis factor-α inhibitor, turnstatin, TZ 93. Urokinase plasminogen activator inhibitor, vadimezan, vandetanib, vasostatin, vatalanib, VE-cadherin-2 antagonist, xanthorrhizol, XL 784 (Exelixis, US), ziv-aflibercept, and ZD 6126.

[1189] In various embodiments, the other anti-tumor agent is an additional active agent that disrupts or inhibits the RAS-RAF-ERK or PI3K-AKT-TOR signaling pathway or is a PD-1 and or PD-L1 antagonist. In various embodiments, the other anti-tumor agent is a RAF inhibitor, EGFR inhibitor, MEK inhibitor, ERK inhibitor, PI3K inhibitor, AKT inhibitor, TOR inhibitor, MCL-1 inhibitor, Bcl-2 inhibitor, SHP2 inhibitor, proteasome inhibitor or immunotherapy, including monoclonal antibodies, immunomodulatory imides (IMIDs), anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1, and anti-OX40 agents, GITR agonists, CAR-T cells and BiTEs.

[1190] Non-limiting examples of RAF inhibitors include dabrafenib, encorfenib, regorafenib, sorafenib, and vemurafenib.

[1191] Non-limiting examples of MEK inhibitors include binitinib, CI-1040, cobimetinib, PD318088, PD325901, PD334581, PD98059, rifatinib, selumetinib, and trametinib.

[1192] Non-limiting examples of ERK inhibitors include LY3214996, LTT462, MK-8353, SCH772984, ravoxertinib, ulixertinib, and ERKi as described in WO 2017068412.

[1193] Non-limiting examples of PI3K inhibitors include 17-hydroxywortmannin analogs (e.g., WO 06 / 044453); AEZS-136; alpelisib; AS-252424; buparisib; CAL263; copanlisib; CUDC-907; Dactolisib (WO 06 / 122806); demethoxyglobin; duvelisib; GNE-477; GSK1059615; IC87114; idelalisib; INK1117; LY294002; Palomid 529; paxalisib; perifosine; PI-103; PI-103 hydrochloride; pictilisib (e.g., WO 09 / 036,082; WO 09 / 055,730); PIK 90; PWT33597; SF1126; sonolisib; TGI 00-115; TGX-221; XL147; XL-765; wortmannin; and ZSTK474.

[1194] Non-limiting examples of AKT inhibitors include Akt-1-1 (inhibits Akt1) (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-59CJ-Ome (e.g., Jin et al. (2004) Br J. Biol. Biol. J Cancer 91, 1808-12); lH-imidazo[4,5-c]pyridinyl compounds (e.g., WO05011700); indole-3-methanol and its derivatives (e.g., U.S. Pat. No. 6,656,963; Sarkar and Li (2004) J Nutr. 134(12 Suppl), 3493S-3498S); perifosine, Dasmahapatrat 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); triciribine (Yang et al. (2004) Cancer Res. 64,4394-9); imidazooxazolone compounds, including 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 (WO2012 / 137870); afusetinib; capivasertinib; MK2206; and patasertib.

[1195] Non-limiting examples of TOR inhibitors include deflulimus; ATP-competitive TORC1 / TORC2 inhibitors, including PI-103, PP242, PP30, and Torin1; TOR inhibitors in the FKBP12 enhancer, rapamycin and its derivatives, including temsirolimus, everolimus, WO9409010; rapamycin analogs, such as those disclosed in WO98 / 02441 and WO01 / 14387, such as AP23573, AP23464, or AP23841; 40-(2-hydroxyethyl)rapamycin, 40-[3-hydroxy(hydroxymethyl)methylpropionic acid]rapamycin; 40-epi-(tetrazolyl)-rapamycin (also known as ABT578); 32-deoxyrapamycin; 1 6-pentynyloxy-32(S)-dihydrostreptomycin and other derivatives disclosed in WO05 / 005434; derivatives disclosed in US5,258,389, WO94 / 090101, WO92 / 05179, US5,118,677, US5,118,678, US5,100,883, US5,151,413, US5,120,842, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807 and US5,256,790; and phosphorus-containing rapamycin derivatives (e.g., WO05 / 016252).

[1196] Non-limiting examples of MCL-1 inhibitors include AMG-176, MIK665, and S63845.

[1197] Non-limiting examples of SHP2 inhibitors include the SHP2 inhibitors described in WO2019 / 167000 and WO2020 / 022323.

[1198] Additional non-limiting examples of additional anticancer agents suitable for use in combination include 2-ethylhydrazide, 2,2',2"-trichlorotriethylamine, ABVD, acetoglatone, acemannan, aldophosphamide glycoside, alpharadin, amifostine, aminolevulinic acid, anagrelide, ANCER, anciplostatin, anti-CD22 immunotoxin, anti-tumorigenic herbs, apachetone, aglabin, arsenic trioxide, azathioprine, BAM 002 (Novelos), bcl-2 (Genta), betribucil, biricodar, bisantrene, bromocriptine, bromostatin, buthionine sulfoximine, calyxol, cell cycle nonspecific antitumor agents, cymoleukin, clodronate, clotrimazole, cytarabine, HLA3030 (Dong-A), defofamine, denileukin 2 ( diftitox), dexrazoxane, diazocone, dichloroacetic acid, dilazepoxide, discodermolide, docosanol, doxercalciferol, edelfosine, eflornithine, EL532 (Elan), ilonisel, elsamitrucin, eniluracil, etanercept, ixazolin, ferricrucin, folic acid supplements,Such as folinic acid, cytosine, gallium nitrate, gimeracil / oteracil / tegafur combination (S-1), glipidemia, histamine dihydrochloride, HIT diclofenac, HLA-B7 gene therapy (Vical), human fetal alpha-fetoprotein, ibandronate, ibandronate, ICE chemotherapy regimen, imesen, iodobenzylguanidine, IT-101 (CRLX101), lanizide, LC 9018 (Yakult), leflunomide, lentinan, levamisole + fluorouracil, lovastatin, thiophenecarboxamide, masoprofen, melatosin, metoclopramide, miltefosine, miproxifen, mitoguanzone, mitozolamide, mopidarol, motixafin gadolinium, MX6 (Galderma), naloxone + pentazocine, nitrile, nolatrexed, NSC631570 octreotide (Ukracin), olaparib, P-30 protein, PAC-1, palifermin, pamidronate, pamidronate, pentosan polysulfate sodium, methionine nitrogen mustard, picibanil, pixibanil, platinum, podophyllic acid, porfimer sodium, PSK (polysa rix-K), rabbit anti-thymocyte polyclonal antibody, rasburiembodiment, tretinoin, rhenium RE186 fosetyl phosphate, romotide, samarium (153) Sm) lexidronam, sizofiran, sodium phenylacetate, fospartate, germanium spiroamine, strontium-89 chloride, suramin, swainsonine, talaporfin, tariquidar, tazarotene, tegafur-uracil, temoporfin, tenuisporin acid, tetrachlorodecoxide, thrombopoietin, ethyltin propurpurin ethyl etiopurpurin), tiraporazamine, TLC ELL-12, tositumomab-iodine 131, trifluridine and tipiracil combination, troponin I (Harvard University, US), urethane, valspodar, verteporfin, zoledronic acid, and zosuquidar.

[1199] The present invention also provides methods for treating cancer using a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, in combination with radiation therapy. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapies described herein. Administration of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in the combination therapy can be determined as described herein.

[1200] Radiation therapy can be administered by one of several methods or a combination of methods, including but not limited to external beam therapy, internal irradiation therapy, implant irradiation, stereotactic radiosurgery, whole body irradiation therapy, radiotherapy and lasting or temporary interstitial brachytherapy. As used herein, the term "brachytherapy" refers to the radiation therapy delivered by spatially confined radioactive materials embedded in the body or at or near a tumor or other proliferative tissue disease site. The term is intended to include (without limitation) exposure to radioisotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and Lu radioisotopes). Suitable radioactive sources for use as cell regulators of the present invention include solids and liquids. As non-limiting examples, the radiation source can 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 radiation, or other therapeutic radiation. The radioactive material can also be a fluid made from any solution of a radionuclide, such as a solution of I-125 or I-131, or a radioactive fluid can be prepared using a slurry of a suitable fluid containing small particles of a solid radionuclide (e.g., Au-198, Y-90). In addition, the radionuclide can be contained in a gel or radioactive microspheres.

[1201] The present invention also provides methods for combination therapy where other anti-tumor agents are known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes for use in combination with the compounds of the present invention or pharmaceutically acceptable salts thereof. 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 chemotherapeutics, immunotherapeutics, hormonal therapeutics, therapeutic antibodies, targeted therapeutics, and radiation therapy to provide a synergistic or additive therapeutic effect.

[1202] In one embodiment, a compound covalently bound to GTP-bound KRASG12C or a pharmaceutically acceptable salt thereof for use in preparing an anti-tumor agent can be provided. In one embodiment, a compound covalently bound to GTP-bound KRASG12C or a pharmaceutically acceptable salt thereof for treating tumors can be provided. In one embodiment, a method for treating tumors can be provided, comprising administering a therapeutically effective amount of a compound covalently bound to GTP-bound KRASG12C or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[1203] In one embodiment, a method for regulating the activity of a Ras protein (including human K-Ras G12C mutant) is provided, comprising contacting the Ras protein with an effective amount of a compound of the present invention. Examples of the activity to be regulated include GTPase activity, nucleotide exchange, effector protein binding, effector protein activation, guanine exchange factor (GEF) binding, GEF-promoted nucleotide exchange, phosphate release, nucleotide release, nucleotide binding, Ras (e.g., K-Ras) localization in cells, post-translational processing of Ras (e.g., K-Ras), and post-translational modification of Ras (e.g., K-Ras), and preferably includes K-Ras localization in cells, post-translational processing of K-Ras, and post-translational modification of K-Ras. "Regulating" can be increasing or decreasing the activity of Ras (e.g., K-Ras protein).

[1204] In some embodiments, the Ras (eg, K-Ras) protein is present in a living cell, eg, a living cell that forms part of a living organism.

[1205] The present invention also provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in treatment, or the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in treatment. The present invention also provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof for treating tumors, or the use of a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof for treating tumors. The present invention also provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and other anti-tumor agents, which is used to treat cancer, or the use of a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and other anti-tumor agents for treating tumors. Example

[1206] The present invention is described in more detail below, showing Examples and Test Examples. However, the present invention is not limited to these Examples.

[1207] Unless otherwise stated, the reagents used in the examples are commercially available products. Pre-packed columns manufactured by Shoko Scientific Co., Ltd. or Biotage were used for silica gel column chromatography and basic silica gel column chromatography. NMR spectra were performed using an AL 400 spectrometer (400 MHz; JEOL Ltd. (JEOL)) or a Mercury 400 (400 MHz; Varian) spectrometer. For deuterated solvents containing tetramethylsilane, tetramethylsilane was used as an internal standard. For other cases, measurements were performed using the NMR solvent as an internal standard. All δ values ​​are expressed in ppm. Microwave reactions were performed using initiators (trademark) manufactured by Biotage.

[1208] The meanings of the abbreviations are described below.

[1209] s: single peak

[1210] d: doublet

[1211] t: triplet

[1212] q: quartet

[1213] sep: Sept.

[1214] dd: doublet

[1215] dt: double triplet

[1216] td: three doublets

[1217] tt: three triple peaks

[1218] ddd: double double peak

[1219] DDT: Double Double Triple

[1220] DTD: Double triplet

[1221] TDD: triple double double peak

[1222] m: multiple peaks

[1223] br: broad peak

[1224] brs: broad single peak

[1225] tert: third

[1226] DMSO-D6: tritiated dimethyl sulfoxide

[1227] CDCl3: tritiated chloroform

[1228] CD3OD: tritiated methanol

[1229] THF: Tetrahydrofuran

[1230] DMF: N,N-dimethylformamide

[1231] NMP: 1-Methyl-2-pyrrolidone

[1232] DMSO: dimethyl sulfoxide

[1233] WSC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

[1234] HATU: (Dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methanimine hexafluorophosphate

[1235] Boc: tert-Butoxycarbonyl

[1236] Preparation of compounds

[1237] Example 1

[1238] 3-cyano-N-(3-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)phenyl)-4- ((E)-4-(((1r,4r)-4-Methoxycyclohexyl)amino)but-2-enoylamino)benzamide

[1239] Step 1: Methylamine (2M in THF, 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 give thick N-methyl-2-nitro-5-(trifluoromethyl)aniline.

[1240] Step 2: The crude N-methyl-2-nitro-5-(trifluoromethyl)aniline obtained in Step 1 and N-bromosuccinimide (5.11 g) were added to acetic acid (80 ml). After the mixture was refluxed for 1 hour, the mixture was cooled to room temperature and poured into water. The resulting solid was collected by filtration to give crude 4-bromo-N-methyl-2-nitro-5-(trifluoromethyl)aniline (6.63 g).

[1241] Step 3: A solution of the crude 4-bromo-N-methyl-2-nitro-5-(trifluoromethyl)aniline (6.63 g) obtained in step 2 and iron powder (6.19 g) in 2M aqueous ammonium chloride solution (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, and then the insoluble material was filtered off. 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 (hexane:ethyl acetate) to give 4-bromo-N1-methyl-5-(trifluoromethyl)benzene-1,2-diamine (5.25 g).

[1242] 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), followed by stirring at room temperature overnight. The solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (hexane:ethyl acetate) to give 5-bromo-2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole (5.22 g).

[1243] Step 5: A 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 g), and 1 M aqueous sodium carbonate solution (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, which was then 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 give 3-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)aniline (1.77 g).

[1244] Step 6: 1-Hydroxybenzotriazole monohydrate (1.12 g), 4-amino-3-cyano-benzoic acid (1.35 g), triethylamine (1.2 ml) and WSC hydrochloride (1.60 g) were added to a solution of 3-(2-ethyl-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)aniline (1.77 g) obtained in Step 5 in DMF (55 ml). The reaction was allowed to proceed overnight at room temperature. Water...

Claims

1. An antitumor agent comprising as an active ingredient a compound covalently bound to GTP-bound KRAS G12C or a pharmaceutically acceptable salt thereof, wherein the compound has the following formula: A-L1-L2-GJ in, A is a chemical moiety capable of interacting with the region between switch 2 and the α3-helix; L1 is a linker; L2 is a linker; G is an electrophilic chemical moiety capable of forming a covalent bond with cysteine ​​12 of GTP-bound KRAS G12C; J is a chemical moiety capable of interacting with GTP, Where G is represented by the following formula: Wherein in the formula A-L1-L2-GJ, L1 is represented by D having -C=(O)-, L2 is represented by E having -NR1-, J is represented by -CHR2'-NR2R3, and the compound is represented by the formula (x): wherein A is a ring system selected from a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted fused ring; wherein when A is a monocyclic ring, A' and A" are absent, and the monocyclic ring is represented by ring A, which is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH; When A is a condensed ring, the condensed ring is represented by ring A and ring A' or ring A and ring A", wherein ring A is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH, and ring A' or A" is a saturated or unsaturated ring which is unsubstituted or substituted by R6 and forms a condensed ring with ring A containing A3 and A4 or A4 and A5; D is a monocyclic ring having at least one amino group, the amino group combining with the carbonyl group between D and E to form an amide, wherein the monocyclic ring may be additionally substituted with a substituent other than the amino group, or D is a substituted or unsubstituted condensed ring; wherein when D is a monocyclic ring, D' is absent, and the monocyclic ring is represented by ring D, which is an unsaturated 6-membered ring that may be substituted by R7, wherein D1 represents N or NH, and D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH; wherein when D is a condensed ring, the condensed ring is represented by ring D and ring D', wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted by R7, wherein D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is a saturated or unsaturated ring which is unsubstituted or substituted by R8 and forms a condensed ring with ring D containing D1, D2 and D7; E is an unsaturated 6-membered ring which is unsubstituted or substituted by R4, wherein E1, E2, E3 and E4 independently represent C, CH or CH2; R1 is hydrogen; R2 and R2' are linked together to form a 4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; or R2, R2' and R3 are independently represented, and R2 is hydrogen or C1-C4 alkyl, C3-C10 cycloalkyl or 4- to 10-membered saturated heterocyclic group, each of which is unsubstituted or substituted by 1-2 substituents independently represented by Ra, R2' is hydrogen; and R3 is hydrogen; Ra independently represents halogen, hydroxyl, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 haloalkyl, C1-C6 monoalkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, C1-C6 alkylsulfonyl, or a 4- to 10-membered saturated heterocyclic group; R4 is halogen or cyano; m is an integer from 0 to 2; R5 is halogen, amino, pyridyl, hydroxy, substituted or unsubstituted C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy; When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring that shares two adjacent atoms with ring A' or ring A"; or Each R6 may independently represent halogen, substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted C1-C6 alkoxy; R7 is halogen or C1-C4 alkyl; R8 is halogen or C1-C4 alkyl; q and r independently represent 0, 1 or 2; n is an integer from 0 to 3; and p is 0, 1 or 2.

2. The antitumor agent according to claim 1, wherein Ring A' forms a condensed ring with Ring A containing A3 and A4, and A1 and A5 are C, CH or CH2.

3. The antitumor agent according to claim 2, wherein D6 in ring D is C.

4. The antitumor agent according to claim 3, wherein D3, D4 and D5 are C.

5. The antitumor agent according to any one of claims 1 to 4, wherein the compound is represented by formula (xi): wherein ring A' is a saturated or unsaturated 5-membered ring, which forms a condensed ring containing A3 and A4 with ring A, wherein A1', A2', A3' independently represent C, CH, CH2, N, NH, O or S, When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring; or Each R6 may independently be halogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 alkoxy. The antitumor agent according to any one of claims 1 to 5, wherein A2 is C.

7. The antitumor agent according to any one of claims 3 to 6, wherein R2 and R2' are linked together to form a 4- to 6-membered saturated heterocyclic ring which is unsubstituted; or R2 and R2' represent independently, and R2 is unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, or unsubstituted or substituted 4- to 10-membered saturated heterocyclic group.

8. The antitumor agent according to any one of claims 1 to 7, wherein R5 is hydroxyl, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy.

9. The antitumor agent according to any one of claims 1 to 8, wherein when the number of R6 is two or more, two R6 can be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring; or Each R6 may independently represent a substituted or unsubstituted C1-C3 alkyl group or a substituted or unsubstituted C1-C6 alkoxy group.

10. The antitumor agent according to any one of claims 5 to 9, wherein the compound is represented by formula (xii): wherein R2 and R2' are as defined in claim 7; R5 is as defined in claim 8, and R6 is as defined in claim 9; wherein D is a condensed ring represented by ring D and ring D', ring D' is a saturated or unsaturated 5-membered ring, which forms a condensed ring containing D1, D2 and D7 with ring D, and D1' and D2' independently represent C, CH, CH2, N, NH or S, and R7 is halogen or C1-C3 alkyl.

11. A compound represented by formula (x): or a pharmaceutically acceptable salt thereof, wherein A is a ring system selected from a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted fused ring; wherein when A is a monocyclic ring, A' and A" are absent, and the monocyclic ring is represented by ring A, which is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH; When A is a condensed ring, the condensed ring is represented by ring A and ring A' or ring A and ring A", wherein ring A is an unsaturated 6-membered ring which is unsubstituted or substituted by R5, wherein A1, A2, A3, A4 and A5 independently represent C, CH, CH2, N or NH, and ring A' or A" is a saturated or unsaturated ring which is unsubstituted or substituted by R6 and forms a condensed ring with ring A containing A3 and A4 or A4 and A5; D is a monocyclic ring having at least one amino group, the amino group combines with the carbonyl group between D and E to form an amide, wherein the monocyclic ring may be substituted with a substituent other than the amino group, or D is a substituted or unsubstituted condensed ring; wherein when D is a monocyclic ring, D' is absent, and the monocyclic ring is represented by ring D, which is an unsaturated 6-membered ring that may be substituted by R7, wherein D1 represents N or NH, and D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH; wherein when D is a condensed ring, the condensed ring is represented by ring D and ring D', wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted by R7, wherein D1, D2, D3, D4, D5, D6 and D7 independently represent C, CH, CH2, N or NH, and ring D' is a saturated or unsaturated ring which is unsubstituted or substituted by R8 and forms a condensed ring with ring D containing D1, D2 and D7; E is an unsaturated 6-membered ring which is unsubstituted or substituted by R4, wherein E1, E2, E3 and E4 independently represent C, CH or CH2; R1 is hydrogen; R2 and R2' are linked together to form a 4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; or R2, R2' and R3 are independently represented, and R2 is hydrogen or C1-C4 alkyl, C3-C10 cycloalkyl, or 4- to 10-membered saturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; R2' is hydrogen; and R3 is hydrogen; Ra independently represents halogen, hydroxyl, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 haloalkyl, C1-C6 monoalkylamino, C1-C6 dialkylamino, C1-C6 alkoxy, C1-C6 alkylsulfonyl, or a 4- to 10-membered saturated heterocyclic group; R4 is halogen or cyano; m is an integer from 0 to 2; R5 is halogen, amino, pyridyl, hydroxy, substituted or unsubstituted C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy; When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring that shares two adjacent atoms with ring A' or ring A"; or Each R6 may independently represent halogen, substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted C1-C6 alkoxy; R7 is halogen or C1-C4 alkyl; R8 is halogen or C1-C4 alkyl; q and r independently represent 0, 1 or 2; n is an integer from 0 to 3; and p is 0, 1 or 2.

12. The compound according to claim 11, wherein Ring A' forms a condensed ring with Ring A containing A3 and A4, and A1 and A5 are C, CH or CH2; or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 12, wherein D6 in ring D is C; or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 13, wherein D3, D4 and D5 are C; or a pharmaceutically acceptable salt thereof.

15. The compound according to any one of claims 11 to 14, wherein the compound is represented by formula (xi): wherein ring A' is a saturated or unsaturated 5-membered ring, which forms a condensed ring containing A3 and A4 with ring A, wherein A1', A2', A3' independently represent C, CH, CH2, N, NH, O or S, When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring; or Each R6 may independently be halogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 alkoxy; or a pharmaceutically acceptable salt thereof.

16. The compound according to any one of claims 11 to 15, wherein A2 is C; or a pharmaceutically acceptable salt thereof.

17. A compound according to any one of claims 12 to 16, wherein R2 and R2' are joined together to form a 4- to 6-membered saturated heterocyclic ring which is unsubstituted; or R2 and R2' independently represent, and R2 is unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted 4-10 membered saturated heterocyclic group; or a pharmaceutically acceptable salt thereof.

18. The compound according to any one of claims 11 to 17, wherein R5 is hydroxy, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy; or a pharmaceutically acceptable salt thereof.

19. A compound according to any one of claims 11 to 18, wherein When the number of R6 is two or more, two R6 may be linked together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring; or Each R6 may independently represent a substituted or unsubstituted C1-C3 alkyl group or a substituted or unsubstituted C1-C6 alkoxy group; or a pharmaceutically acceptable salt thereof.

20. The compound according to any one of claims 15 to 19, wherein the compound is represented by formula (xii) or a salt thereof: wherein R2 and R2' are as defined in claim 17; R5 is as defined in claim 18, and R6 is as defined in claim 19; wherein D is a condensed ring represented by ring D and ring D', ring D' is a saturated or unsaturated 5-membered ring, which forms a condensed ring containing D1, D2 and D7 with ring D, and D1' and D2' independently represent C, CH, CH2, N, NH or S, R7 is halogen or C1-C3 alkyl; or a pharmaceutically acceptable salt thereof.

21. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

22. A medicament comprising the compound according to any one of claims 11 to 21 or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition comprising a compound according to any one of claims 11 to 21 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

24. An antitumor agent comprising the compound according to any one of claims 11 to 21 or a pharmaceutically acceptable salt thereof as an active ingredient.

25. An antitumor agent for oral administration, comprising the compound according to any one of claims 11 to 21 or a pharmaceutically acceptable salt thereof as an active ingredient.

26. Use of a compound according to any one of claims 11 to 21 or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition.

27. Use of a compound according to any one of claims 11 to 21 or a pharmaceutically acceptable salt thereof for preparing an antitumor agent.

28. Use of a compound according to any one of claims 11 to 21 or a pharmaceutically acceptable salt thereof for the preparation of an antitumor agent for oral administration.

29. A compound according to any one of claims 11 to 21, or a pharmaceutically acceptable salt thereof, for use as a medicament.

30. A compound according to any one of claims 11 to 21 or a pharmaceutically acceptable salt thereof for use in treating a tumor.

31. A compound according to any one of claims 11 to 21, or a pharmaceutically acceptable salt thereof, for use in treating a tumour by oral administration.

32. An antitumor agent comprising the compound according to any one of claims 11 to 21 or a pharmaceutically acceptable salt thereof, and one or more other antitumor agents as active ingredients.

33. An antitumor agent comprising the compound according to any one of claims 11 to 21 or a pharmaceutically acceptable salt thereof as an active ingredient, which is administered in combination with one or more other antitumor agents.

34. Use of a compound according to any one of claims 11 to 21 or a pharmaceutically acceptable salt thereof and one or more other antitumor agents for the preparation of an antitumor agent.

35. Use of a compound according to any one of claims 11 to 21 or a pharmaceutically acceptable salt thereof for the preparation of an antitumor agent for administration in combination with one or more other antitumor agents.

36. A combination of a compound according to any one of claims 11 to 21 or a pharmaceutically acceptable salt thereof and one or more other anti-tumor agents for use in treating a tumor.

37. A compound according to any one of claims 11 to 21, or a pharmaceutically acceptable salt thereof, for use in treating a tumor in combination with one or more other anti-tumor agents.

38. The antitumor agent according to claim 1, wherein the tumor is cancer.

39. The antitumor agent according to claim 38, wherein the cancer is one or more selected from carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma and lymphoma.

40. The antitumor agent according to claim 39, wherein the squamous cell carcinoma is cancer of the cervix, tarsus, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx or esophagus.

41. The antitumor agent according to claim 39, wherein the adenocarcinoma is cancer of the prostate, small intestine, endometrium, cervix, large intestine, lung, pancreas, esophagus, rectum, uterus, stomach, breast or ovary.

42. The antitumor agent according to claim 38, wherein the tumor is rectal cancer, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, breast cancer or leukemia.

43. A compound according to any one of claims 11 to 21, or a pharmaceutically acceptable salt thereof, for use in therapy, or a compound according to any one of claims 11 to 21, or a pharmaceutically acceptable salt thereof, for use in therapy.

44. A pharmaceutical composition comprising a compound according to any one of claims 11 to 21 or a pharmaceutically acceptable salt thereof for use in treating a tumor, or use of a pharmaceutical composition comprising a compound according to any one of claims 11 to 21 or a pharmaceutically acceptable salt thereof for treating a tumor.

45. A pharmaceutical composition comprising a compound according to any one of claims 11 to 21 or a pharmaceutically acceptable salt thereof and other anti-tumor agents for use in treating tumors, or use of a pharmaceutical composition comprising a compound according to any one of claims 11 to 21 or a pharmaceutically acceptable salt thereof and other anti-tumor agents for treating tumors.

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