WO2022234867A1 - Sulfonamide ayant une action inhibitrice vis-à-vis de la mmp 7 - Google Patents
Sulfonamide ayant une action inhibitrice vis-à-vis de la mmp 7 Download PDFInfo
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- WO2022234867A1 WO2022234867A1 PCT/JP2022/020131 JP2022020131W WO2022234867A1 WO 2022234867 A1 WO2022234867 A1 WO 2022234867A1 JP 2022020131 W JP2022020131 W JP 2022020131W WO 2022234867 A1 WO2022234867 A1 WO 2022234867A1
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- 230000002401 inhibitory effect Effects 0.000 title abstract description 9
- 101100130647 Rattus norvegicus Mmp7 gene Proteins 0.000 title abstract 2
- 229940124530 sulfonamide Drugs 0.000 title description 2
- 150000003456 sulfonamides Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 988
- -1 Carboxy, tetrazolyl Chemical group 0.000 claims description 587
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 437
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 414
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 409
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 314
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 304
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 291
- 125000000623 heterocyclic group Chemical group 0.000 claims description 263
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 258
- 125000003545 alkoxy group Chemical group 0.000 claims description 182
- 101150098207 NAAA gene Proteins 0.000 claims description 174
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 154
- 125000005843 halogen group Chemical group 0.000 claims description 152
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 148
- 125000003118 aryl group Chemical group 0.000 claims description 147
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 136
- 125000004076 pyridyl group Chemical group 0.000 claims description 134
- 229910052757 nitrogen Inorganic materials 0.000 claims description 128
- 125000001072 heteroaryl group Chemical group 0.000 claims description 120
- 125000003386 piperidinyl group Chemical group 0.000 claims description 120
- 125000005647 linker group Chemical group 0.000 claims description 100
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 96
- 150000001924 cycloalkanes Chemical class 0.000 claims description 82
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 78
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 68
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 60
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 60
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 54
- 125000002757 morpholinyl group Chemical group 0.000 claims description 54
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 52
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 50
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 50
- 125000002393 azetidinyl group Chemical group 0.000 claims description 49
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 46
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 44
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- 125000001425 triazolyl group Chemical group 0.000 claims description 38
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 37
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 36
- QPMLSUSACCOBDK-UHFFFAOYSA-N diazepane Chemical compound C1CCNNCC1 QPMLSUSACCOBDK-UHFFFAOYSA-N 0.000 claims description 36
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 36
- 229920006395 saturated elastomer Polymers 0.000 claims description 35
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 34
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- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 32
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- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 32
- 125000000335 thiazolyl group Chemical group 0.000 claims description 32
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 31
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 31
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 30
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 29
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 28
- 125000002883 imidazolyl group Chemical group 0.000 claims description 28
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 28
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 27
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 26
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 26
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 claims description 24
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 24
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 24
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- 125000002541 furyl group Chemical group 0.000 claims description 24
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- 125000001624 naphthyl group Chemical group 0.000 claims description 24
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 24
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 24
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 24
- 125000005493 quinolyl group Chemical group 0.000 claims description 24
- 125000001544 thienyl group Chemical group 0.000 claims description 24
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 24
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 23
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 23
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 23
- 125000003830 C1- C4 alkylcarbonylamino group Chemical group 0.000 claims description 22
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 22
- 125000004414 alkyl thio group Chemical group 0.000 claims description 22
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- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 21
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 20
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 20
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 claims description 18
- 101100132433 Arabidopsis thaliana VIII-1 gene Proteins 0.000 claims description 18
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 18
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 18
- 125000005959 diazepanyl group Chemical group 0.000 claims description 18
- 229910052731 fluorine Inorganic materials 0.000 claims description 17
- 125000001153 fluoro group Chemical group F* 0.000 claims description 17
- 235000011960 Brassica ruvo Nutrition 0.000 claims description 16
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 14
- 101001053395 Arabidopsis thaliana Acid beta-fructofuranosidase 4, vacuolar Proteins 0.000 claims description 13
- 125000003725 azepanyl group Chemical group 0.000 claims description 13
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 claims description 12
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 12
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 12
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- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 10
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- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 10
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 10
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 claims description 10
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- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 9
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- NFDXQGNDWIPXQL-UHFFFAOYSA-N 1-cyclooctyldiazocane Chemical compound C1CCCCCCC1N1NCCCCCC1 NFDXQGNDWIPXQL-UHFFFAOYSA-N 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
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- 239000012973 diazabicyclooctane Substances 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 claims description 8
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
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- GJPYYNMJTJNYTO-UHFFFAOYSA-J sodium aluminium sulfate Chemical compound [Na+].[Al+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O GJPYYNMJTJNYTO-UHFFFAOYSA-J 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/07—Tetrapeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
Definitions
- the present invention relates to a specific aryl or heteroarylsulfonamide that has an inhibitory effect on matrix metalloproteinase 7 (hereinafter abbreviated as "MMP7" as appropriate).
- MMP7 matrix metalloproteinase 7
- Matrix metalloprotease is an endopeptidase having zinc as its active center, and 24 kinds of genes are known. Since MMPs degrade extracellular matrices such as collagen and gelatin, they are involved not only in physiological phenomena such as bone remodeling and wound healing, but also in pathological processes such as inflammation and cancer progression (Non-Patent Document 1). reference). Focusing on the anticancer effects of MMP inhibition, clinical trials of multiple MMP inhibitors have been conducted so far, but skeletal muscle pain etc., which are thought to be caused by non-selective inhibitory effects on various MMP subtypes. It has been abandoned due to the possibility of side effects and promotion of cancer metastasis (see Non-Patent Documents 2 and 3).
- MMP7 Activation of MMP7 has been reported to play an important role in tumor metastasis and inflammatory processes (see Non-Patent Document 4). While MMP7 expression is low in normal tissues, it is widely expressed in adenoma and cancer tissues, and has been identified in epithelial tumors such as breast cancer, esophageal cancer, colorectal cancer, colorectal adenoma, pancreatic cancer, lung cancer, and skin cancer. . Unlike other MMPs, MMP7 is produced in epithelial-derived tumor cells and is thought to be involved in the invasion and metastasis of the tumor cells themselves (see Non-Patent Document 5).
- MMP7 is also involved in the pathogenesis of non-neoplastic diseases.
- MMP7 induces fibrosis by changing the structure of the renal tubular basement membrane, causing epithelial-mesenchymal transition of renal tubules, etc., and glomerular filtration by changing the structure of glomerular epithelial cells. It has been reported that it disrupts the barrier function and induces urinary excretion of albumin (see Non-Patent Document 6).
- Non-Patent Documents 7 and 8 Furthermore, in patients with diabetic nephropathy and patients with chronic kidney disease, elevated levels of MMP7 in blood and urine have been observed (see Non-Patent Documents 7 and 8). In addition, it has been reported that kidney fibrosis induced by unilateral ureteral ligation and albumin excretion induced by angiotensin II are suppressed in MMP7 gene-deficient animals (see Non-Patent Documents 8 and 9). Therefore, suppression of MMP7 activity can be an effective therapeutic means for controlling the progression of pathological conditions of various renal disorders.
- Non-Patent Documents 10, 11, 12 and 13 idiopathic pulmonary fibrosis, aortic aneurysm, left ventricular hypertrophy, myocardial infarction, HIV-associated neurocognitive disorders, multiple sclerosis, Dupuytren's contracture, inflammatory muscle disease, osteoarthritis, endometriosis, systemic Non-neoplastic diseases such as lupus erythematosus, non-alcoholic steatohepatitis, liver cirrhosis and colitis are suggested to be associated with MMP7 (see Non-Patent Documents 10, 11, 12 and 13). From these facts, finding a means to inhibit MMP7 is a highly feasible approach for establishing an effective therapeutic method for diseases associated with MMP7.
- Non-Patent Document 14 As a low-molecular-weight compound having an MMP7 inhibitory action, there is a report of a compound into which a hydroxamic acid or a carboxylic acid is introduced as a zinc chelator (see Non-Patent Document 14). There are also reports of compounds incorporating nitro as a zinc chelator. (See Non-Patent Document 15). However, there is no disclosure of aryl or heteroaryl sulfonamides, which are compounds of the present invention.
- An object of the present invention is to provide a novel compound that has an inhibitory effect on MMP7.
- Ring A represents an aromatic ring or heteroaromatic ring
- R A1 , R A2 , and R A3 are independently hydrogen atom, carbamoyl, cyano, nitro, halogen atom, C 1-6 alkyl, haloC 1-6 alkyl, aryl, heteroaryl (the aryl and heteroaryl may be substituted with one halogen atom), arylcarbonylamino, heteroarylcarbonylamino (the aryl of arylcarbonylamino and the heteroaryl of heteroarylcarbonylamino may be substituted with one group selected from the group consisting of carbamoyl and halogen atoms), C 1-6 alkoxy, haloC 1-6 alkoxy, represents mono-C 1-6 alkylamino or di-C 1-6 alkylamino, ZBG is Carboxy, tetrazolyl, a group represented by the formula -CO-NH-OH, C 1-6 alkoxy
- Ring B 11 represents a 5- to 6-membered saturated heterocyclic ring containing a nitrogen atom
- R N2 represents a hydrogen atom or C 1-3 alkyl
- AA r1 is as described later.
- Ring B 21 represents a C 3-6 cycloalkane, a 4- to 6-membered saturated heterocycle, benzene, or a 5- to 6-membered heteroaromatic ring;
- L 12c and L 12d independently represent a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl).
- L 12a and L 12b independently represent a chain C 1-3 alkanediyl (the chain C 1-3 alkanediyl may be substituted with one methyl);
- R N4 represents a hydrogen atom or C 1-3 alkyl
- L 13 is a chain C 1-5 alkanediyl (the chain C 1-5 alkanediyl may be substituted with 1 methyl) of the formula -L 13a -OL 13b - the structure represented by the formula -L 13a -NR N4 -L 13b -, or the following formula [II-3]
- Ring B 22 represents a C 3-6 cycloalkane, a 4- to 6-membered saturated heterocycle, benzene, or a 5- to 6-membered heteroaromatic ring;
- L 13c and L 13d independently represent a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl).
- R N3 represents a hydrogen atom or C 1-3 alkyl
- L 13a represents a chain C 1-3 alkanediyl (the chain C 1-3 alkanediyl may be substituted with one methyl)
- L 13b represents a chain C 2-3 alkanediyl (the chain C 2-3 alkanediyl may be substituted with one methyl)
- R N4 represents a hydrogen atom or C 1-3 alkyl
- L 15 represents a chain C 1-3 alkanediyl (the chain C 1-3 alkanediyl may be substituted with one methyl);
- Ring B 23 represents a C 3-6 cycloalkane, a 4- to 6-membered saturated heterocycle, benzene, or a 5- to 6-membered heteroaromatic ring;
- L 16c and L 16d independently represent chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl).
- R N2 represents a hydrogen atom or C 1-3 alkyl
- L 16a represents a chain C 1-3 alkanediyl (the chain C 1-3 alkanediyl may be substituted with one methyl)
- L 16b represents a chain C 2-3 alkanediyl (the chain C 2-3 alkanediyl may be substituted with one methyl)
- R N4 represents a hydrogen atom or C 1-3 alkyl
- Z is (i) a group represented by the formula -R Z ; (ii) a group represented by the formula -Y 5 -R Z , (iii) a group represented by the formula -Y 5 -Y 6 -R Z , or (iv) a group represented by the formula -Y 5 -Y 6 -Y 7 -R Z , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 and Y 7 are independently (i) an aminocarboxylic acid linker
- Ring B 31 is C 3-8 cycloalkane, C 8-10 cycloalkane with condensed ring structure, C 7-11 cycloalkane with spiro ring structure, 4-8 membered saturated hetero ring, containing nitrogen atom a saturated heterocyclic ring having an 8- to 10-membered condensed ring structure or a saturated heterocyclic ring having a 7- to 11-membered spiro ring structure containing a nitrogen atom, L AAa and L AAb independently represent a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl). . ) A structure represented by Formula [III-2] below
- Ring B 32 represents a C 3-8 cycloalkane, a 4- to 8-membered saturated heterocycle, benzene, or a 5- to 6-membered heteroaromatic ring; the C3-8 cycloalkane, 4-8 membered saturated heterocycle, benzene, and 5-6 membered heteroaromatic ring optionally substituted with one oxo; the C 3-8 cycloalkane and the 4-8 membered saturated heterocycle may be bridged by a C 1-3 alkanediyl;
- the benzene, a 5- to 6-membered heteroaromatic ring may be substituted with one halogen atom, and L AAa and L AAb are independently a single bond or a chain C 1-2 alkanediyl (the Chained C 1-2 alkanediyl may be substituted with one methyl.)
- LAAa and LAAb do not simultaneously represent a
- Ring B 33 represents a 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom or dihydropyridine, and the 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom may be substituted with one oxo.
- the 4- to 8-membered saturated heterocycle containing a nitrogen atom may be bridged by C 1-3 alkanediyl; the dihydropyridine is optionally substituted with one oxo
- L AAc represents a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl).
- R NAAa represents a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with aryl;
- the linkers are each:
- Ring B 34 is a 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom (the 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom is selected from the group consisting of hydroxy, amino, aryl, and oxo 1 ), indoline, isoindoline, or tetrahydroisoquinoline (the indoline, isoindoline, and tetrahydroisoquinoline are one group selected from the group consisting of hydroxy, amino, phenyl, and oxo may be replaced with.)
- L AAb represents a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl);
- Ring B 35 is a 5- to 8-membered saturated heterocycle containing 2 nitrogen atoms (the 5- to 8-membered saturated heterocycle containing 2 nitrogen atoms
- L AAg represents a chain C 4-7 alkanediyl (the chain C 4-7 alkanediyl may be substituted with one amino)
- RNAAa represents a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with aryl.
- an aminocarboxylic acid linker represented by Formula [IV-2] below
- an aminocarboxylic acid linker represented by The following formula [IV-3]
- L AAd is a chain C 2-3 alkanediyl (the chain C 2-3 alkanediyl is substituted with one group selected from the group consisting of hydroxy, amino, C 1-4 alkyl, and benzyl may be used.
- RAAa ' is hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, C 3-8 cycloalkyl (wherein said C 3-8 cycloalkyl is optionally substituted with one haloC 1-6 alkyl), 4- to 8-membered saturated heterocyclyl, Aryl, heteroaryl, C 1-4 alkyl substituted with C 3-8 cycloalkyl, C 1-4 alkyl substituted by 4-8 membered saturated heterocyclyl, Aryl (wherein said aryl is hydroxy, amino, cyano, nitro, halogen atom, C 1-4 alkyl, haloC
- Ring B 41 represents benzene or a 5- to 6-membered heteroaromatic ring (the benzene and 5- to 6-membered heteroaromatic ring may be substituted with one halogen atom)
- L AAe is a chain C 2-3 alkanediyl (the chain C 2-3 alkanediyl is substituted with one group selected from the group consisting of hydroxy, amino, C 1-4 alkyl, and benzyl may be used.
- Q 2 represents a structure represented by the formula -O- or the formula -NR N5 -, R N5 represents a hydrogen atom or C 1-3 alkyl, R NAAa represents a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with aryl.
- an aminocarboxylic acid linker represented by Formula [IV-5] below
- Ring B 41 represents benzene or a 5- to 6-membered heteroaromatic ring (the benzene and 5- to 6-membered heteroaromatic ring may be substituted with one halogen atom)
- RNAAa represents a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with aryl.
- an aminocarboxylic acid linker represented by The following formula [IV-6]
- Ring B 41 represents benzene or a 5- to 6-membered heteroaromatic ring (the benzene and 5- to 6-membered heteroaromatic ring may be substituted with one halogen atom)
- Ring B 42 is a 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom (the 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom may be bridged by C 1-3 alkanediyl); a saturated heterocyclic ring having an 8- to 10-membered condensed ring structure containing a nitrogen atom, or a saturated heterocyclic ring having a 7- to 11-membered spiro ring structure containing a nitrogen atom,
- Ring B 41 represents benzene or a 5- to 6-membered heteroaromatic ring (the benzene and 5- to 6-membered heteroaromatic ring may be substituted with one halogen atom)
- Ring B 43 is a 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom (the 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom may be bridged by C 1-3 alkanediyl); a saturated heterocyclic ring having an 8- to 10-membered condensed ring structure containing a nitrogen atom, or a saturated heterocyclic ring having a 7- to 11-membered spiro ring structure containing a nitrogen atom,
- Ring B 41 represents benzene or a 5- to 6-membered heteroaromatic ring (the benzene and 5- to 6-membered heteroaromatic ring may be substituted with one halogen atom)
- Ring B 44 is a 5- to 8-membered saturated heterocyclic ring containing 2 nitrogen atoms (the 5- to 8-membered saturated heterocyclic ring containing 2 nitrogen atoms is bridged by C 1-3 alkanediyl ), a saturated heterocyclic ring having an 8- to 10-membered condensed ring structure containing a nitrogen atom, or a saturated heterocyclic ring having a 7- to 11-membered spiro ring structure containing a nitrogen atom,
- ring B 45 represents a C 3-8 cycloalkane, a 4-8 membered saturated heterocycle, benzene, or a 5-6 membered heteroaromatic ring;
- L AAa and L AAb independently represent a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl);
- RNAAa represents a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with aryl.
- an aminocarboxylic acid linker represented by The following formula [IV-10]
- Ring B 46 represents a 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom
- L AAa represents a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl)
- L AAc represents a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl);
- RNAAa represents a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with aryl.
- an aminocarboxylic acid linker represented by Formula [IV-11] below
- Ring B 47 represents a 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom
- L AAb represents a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl);
- L AAe is a chain C 2-3 alkanediyl (the chain C 2-3 alkanediyl is substituted with one group selected from the group consisting of hydroxy, amino, C 1-4 alkyl, and benzyl may be used.
- RNAAa represents a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with aryl.
- an aminocarboxylic acid linker represented by The following formula [IV-12]
- Ring B 48 represents a 5- to 8-membered saturated heterocycle containing 2 nitrogen atoms
- L AAb represents a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl);
- L AAe is a chain C 2-3 alkanediyl (the chain C 2-3 alkanediyl is substituted with one group selected from the group consisting of hydroxy, amino, C 1-4 alkyl, and benzyl may be used.
- RNAAa represents a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with aryl.
- an aminocarboxylic acid linker represented by the following formula [IV-13]
- RAAa'' is hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, C 3-8 cycloalkyl (wherein said C 3-8 cycloalkyl is optionally substituted with one haloC 1-6 alkyl), 4- to 8-membered saturated heterocyclyl, Aryl, heteroaryl, C 1-4 alkyl substituted with C 3-8 cycloalkyl, C 1-4 alkyl substituted by 4-8 membered saturated heterocyclyl, Aryl (wherein said aryl is hydroxy, amino, cyano, nitro, halogen atom, C 1-4 alkyl, haloC 1-4 alkyl, aryl, heteroaryl (wherein said heteroaryl is substituted with one C 1-4 alkyl) ), C 1-4 alkoxy (wherein said C 1-4 alkoxy may be substituted with one aryl), C 2-4 alken
- RAAa'' is hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, C 3-8 cycloalkyl (wherein said C 3-8 cycloalkyl is optionally substituted with one haloC 1-6 alkyl), 4- to 8-membered saturated heterocyclyl, Aryl, heteroaryl, C 1-4 alkyl substituted with C 3-8 cycloalkyl, C 1-4 alkyl substituted by 4-8 membered saturated heterocyclyl, Aryl (wherein said aryl is hydroxy, amino, cyano, nitro, halogen atom, C 1-4 alkyl, haloC 1-4 alkyl, aryl, heteroaryl (wherein said heteroaryl is substituted with one C 1-4 alkyl) ), C 1-4 alkoxy (wherein said C 1-4 alkoxy may be substituted with one aryl), C 2-4 al
- Z C and AA X may form a group represented by Furthermore, Z C and AA X (where X represents an integer of 1 to 7) may form a cyclic structure together with the structure existing therebetween, W2, W3 , W4 , W5 , W6 , and W7 are independently (i) a diamine linker of the formula -NR NWa -L W -NR NWb -; (ii) a diamine linker represented by formula [V-1] below, (iii) a diamine linker represented by formula [V-2] below, (iv) a diamine linker represented by formula [V-3] below, or a diamine linker represented by (v) formula [V-4] below, here, In the diamine linker represented by the formula (i) -NR NWa -L W -NR NWb -, L W represents a chain C 1-3 alkanediyl, R NWa and R NWb independently represent a hydrogen atom or C 1-2 alkyl, (ii
- Ring B 51 is a C 3-8 cycloalkane (the C 3-8 cycloalkane may be bridged by a C 1-3 alkanediyl), a 4-8 membered saturated heterocyclic ring (the 4-8 The saturated membered heterocycle may be substituted with one group selected from the group consisting of carbamoyl and oxo, and may be bridged by C 1-3 alkanediyl.), benzene, or 5- represents a 6-membered heteroaromatic ring, L Wa and L Wb independently represent a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl); , R NWa and R NWb independently represent a hydrogen atom or C 1-2 alkyl. ) shows the structure represented by (iii) In the diamine linker represented by formula [V-2], The linker is
- Ring B 52 is a 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom (the 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom is substituted with one group selected from the group consisting of carbamoyl and oxo and may be crosslinked by a C 1-3 alkanediyl.)
- L Wa represents a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl);
- RNWa represents a hydrogen atom or C 1-2 alkyl.
- Ring B 53 is a 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom (the 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom is substituted with one group selected from the group consisting of carbamoyl and oxo and may be crosslinked by a C 1-3 alkanediyl.)
- L Wb represents a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl);
- RNWa represents a hydrogen atom or C 1-2 alkyl.
- Ring B 54 is a 5- to 8-membered saturated heterocyclic ring containing 2 nitrogen atoms (the 5- to 8-membered saturated heterocyclic ring containing 2 nitrogen atoms is selected from the group consisting of carbamoyl and oxo optionally substituted with one group and optionally bridged by C 1-3 alkanediyl.).
- Ring B 61 is C 3-8 cycloalkane, C 8-10 cycloalkane with condensed ring structure, C 7-11 cycloalkane with spiro ring structure, 4-8 membered saturated hetero ring, containing nitrogen atom a saturated heterocyclic ring having an 8- to 10-membered condensed ring structure or a saturated heterocyclic ring having a 7- to 11-membered spiro ring structure containing a nitrogen atom, L AAra and L AArb independently represent a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl). .
- a structure represented by Formula [IV-2] below A structure represented by Formula [IV-2] below
- Ring B 62 represents a C 3-8 cycloalkane, a 4- to 8-membered saturated heterocycle, benzene, or a 5- to 6-membered heteroaromatic ring; the C3-8 cycloalkane, 4- to 8-membered saturated heterocycle, benzene, and 5- to 6-membered heteroaromatic ring) optionally substituted with one oxo; the C 3-8 cycloalkane and the 4-8 membered saturated heterocycle may be bridged by a C 1-3 alkanediyl; L AAra and L AArb independently represent a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl). . ) or the following formula [VI-3]
- Ring B 63 represents a 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom, the 4- to 8-membered saturated heterocycle containing a nitrogen atom may be substituted with one oxo, the 4- to 8-membered saturated heterocycle containing a nitrogen atom may be bridged by C 1-3 alkanediyl;
- L AArc represents a chain C 2-3 alkanediyl (the chain C 2-3 alkanediyl may be substituted with one methyl).
- R NAAr represents a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with aryl;
- the linkers are each:
- Ring B 64 is a 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom (the 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom is selected from the group consisting of hydroxy, amino, aryl, and oxo 1 ), indoline, isoindoline, or tetrahydroisoquinoline (the indoline, isoindoline, and tetrahydroisoquinoline are one group selected from the group consisting of hydroxy, amino, phenyl, and oxo may be replaced with.)
- L AAra represents a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl);
- Ring B 65 is a 5- to 8-membered saturated heterocycle containing 2 nitrogen atoms (the 5- to 8-membered saturated heterocycle containing 2 nitrogen atoms (the 5- to 8-membered saturated
- Ring B 71 represents a C 3-8 cycloalkane, a 4- to 8-membered saturated heterocycle, benzene, or a 5- to 6-membered heteroaromatic ring; the C 3-8 cycloalkane and the 4-8 membered saturated heterocycle may be bridged by a C 1-3 alkanediyl; L Va and L Vb independently represent a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl). .
- RZC shows the structure represented by RZC is hydroxy, C 1-6 alkoxy, amino, mono C 1-12 alkylamino (wherein said mono C 1-12 alkylamino is hydroxy, carboxy, amino, a halogen atom, C 3-8 cycloalkyl (wherein said C 3-8 cycloalkyl is substituted with 1 amino) ), 4- to 8-membered saturated heterocyclyl (the 4- to 8-membered saturated heterocyclyl may be substituted with one group selected from the group consisting of amino and C 1-6 alkyl.
- di-C 1- may be substituted with 1 to 3 groups identically or differently selected from the group consisting of 6 alkylamino), mono C 3-8 cycloalkylamino (wherein said mono C 3-8 cycloalkylamino is optionally substituted with hydroxy, amino and C 1-6 alkyl (wherein said C 1-6 alkyl is 1 amino); ), monoadamantylamino, monospiroheptanylamino, mono 4- to 8-membered saturated heterocyclylamino (the mono 4- to 8-membered saturated heterocyclylamino may be substituted with 1 to 2 oxo), monoazaspiroheptanylamino, monoarylamino, monoheteroarylamino, Di-C 1-6 alkylamino (each C 1-6 alkyl of said di
- n 2 represents an integer of 1 to 8
- R N4 represents a hydrogen atom or C 1-3 alkyl.
- RZN is C 1-6 alkyl, wherein said C 1-6 alkyl is substituted with one group selected from the group consisting of hydroxy, amino, and aryl (wherein said aryl is haloC 1-6 alkyl and C 1-6 alkoxy may be substituted with 1 to 2 groups identically or differently selected from the group consisting of haloC 1-6 alkyl, C 3-8 cycloalkyl, C 8-10 cycloalkyl having an 8-10 membered condensed ring structure, or C 7-11 cycloalkyl having a spiro ring structure, 4- to 8-membered saturated heterocyclyl (the 4- to 8-membered saturated heterocyclyl may be bridged by C 1-3 alkanediyl), 8- to 10-membered saturated heterocyclyl having a condensed
- 4- to 8-membered saturated heterocyclylcarbonyl (the 4- to 8-membered saturated heterocyclylcarbonyl optionally substituted with one amino); arylcarbonyl, heteroarylcarbonyl (the arylcarbonyl and heteroarylcarbonyl may be substituted with one halogen atom), C 1-6 alkylsulfonyl, C 1-6 alkoxycarbonyl, or C 1-6 alkylaminocarbonyl (said C 1-6 alkylaminocarbonyl is one C 3-8 cycloalkyl (said C 3-8 cycloalkyl is one amino may be replaced.) may be replaced with indicates ) is to provide a compound represented by or a pharmaceutically acceptable salt thereof, In this aspect, preferably In the above formula [III-3], Ring B 33 represents a 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom, the 4- to 8-membered saturated heterocycle containing a nitrogen atom may be substituted with one halogen atom
- di-C 1- may be substituted with 1 to 3 groups identically or differently selected from the group consisting of 6 alkylamino), mono C 3-8 cycloalkylamino (wherein said mono C 3-8 cycloalkylamino is optionally substituted with hydroxy, amino and C 1-6 alkyl (wherein said C 1-6 alkyl is 1 amino); ), monoadamantylamino, monospiroheptanylamino, mono 4- to 8-membered saturated heterocyclylamino (the mono 4- to 8-membered saturated heterocyclylamino may be substituted with 1 to 2 oxo); monoarylamino, monoheteroarylamino, Di-C 1-6 alkylamino (each C 1-6 alkyl of said di-C 1-6 alkylamino is amino,
- n 2 represents an integer of 1 to 8
- R N4 represents a hydrogen atom or C 1-3 alkyl.
- Ring A is benzene, pyridine, or dihydrobenzofuran
- R A1 , R A2 , and R A3 are independently hydrogen atom, carbamoyl, cyano, nitro, halogen atom, C 1-6 alkyl, haloC 1-6 alkyl, phenyl, pyridyl (the phenyl and pyridyl may be substituted with one halogen atom), phenylcarbonylamino, pyridylcarbonylamino (the phenyl in phenylcarbonylamino and the pyridyl in pyridylcarbonylamino may be substituted with one group selected from the group consisting of carbamoyl and halogen atoms), C 1-6 alkoxy, haloC 1-6 alkoxy, mono-C 1-6 alkylamino or di-C 1-6 alkylamino, ZBG is Car
- Ring B 11 is pyrrolidine or piperidine; R N2 is a hydrogen atom or C 1-3 alkyl, AA r1 is as described later.
- Ring B 21 is cyclopentane, cyclohexane, pyrrolidine, piperidine, benzene, triazole, or pyridine;
- L 12c and L 12d are each independently a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl).
- L 12a and L 12b are each independently a chain C 1-3 alkanediyl (the chain C 1-3 alkanediyl may be substituted with one methyl); R N4 is a hydrogen atom or C 1-3 alkyl,
- L 13 is a chain C 1-5 alkanediyl (the chain C 1-5 alkanediyl may be substituted with 1 methyl) of the formula -L 13a -OL 13b - the structure represented by the formula -L 13a -NR N4 -L 13b -, or the following formula [II-3]
- Ring B 22 is cyclopentane, cyclohexane, pyrrolidine, piperidine, benzene, triazole, or pyridine;
- L 13c and L 13d are each independently a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl).
- R N3 is a hydrogen atom or C 1-3 alkyl
- L 13a is a chain C 1-3 alkanediyl (the chain C 1-3 alkanediyl may be substituted with one methyl)
- L 13b is a chain C 2-3 alkanediyl (the chain C 2-3 alkanediyl may be substituted with one methyl)
- R N4 is a hydrogen atom or C 1-3 alkyl
- L 15 is a chain C 1-3 alkanediyl (the chain C 1-3 alkanediyl may be substituted with one methyl);
- L 15 is a chain C 1-3 alkanediyl (the chain C 1-3 alkanediyl may be substituted with one
- ring B 23 is cyclopentane, cyclohexane, pyrrolidine, piperidine, benzene, triazole, or pyridine;
- L 16c and L 16d are each independently a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl).
- R N2 is a hydrogen atom or C 1-3 alkyl
- L 16a is a chain C 1-3 alkanediyl (the chain C 1-3 alkanediyl may be substituted with one methyl)
- L 16b is a chain C 2-3 alkanediyl (the chain C 2-3 alkanediyl may be substituted with one methyl)
- R N4 is a hydrogen atom or C 1-3 alkyl
- an aminocarboxylic acid linker represented by the formula -NR NAAa -L AAa -C( O)-, or (iii) represented by any of formulas [III-4] to [
- Ring B 31 is C 3-8 cycloalkane, oxetane, or piperidine; L AAa and L AAb are independently a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl). . )
- Ring B 32 is C 3-8 cycloalkane, pyrrolidine, azepane, benzene, thiazole, pyridine, or dihydropyridine; the C3-8 cycloalkanes, pyrrolidines, azepanes , and dihydropyridines are optionally substituted with one oxo;
- the C 3-8 cycloalkanes, pyrrolidines and azepanes may be bridged by C 1-3 alkanediyls, the benzene, thiazole, and pyridine may be substituted with one halogen atom;
- L AAa and L AAb are independently a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl); , However, LAAa and LAAb are not chained C 1-2 alkanediyl at the same time. ), or the following formula [
- Ring B 33 is piperidine, azepane, or dihydropyridine; the piperidine and azepane are optionally substituted with one oxo;
- the piperidine and azepane may be crosslinked by a C 1-3 alkanediyl, the dihydropyridine is optionally substituted with one oxo,
- L AAc is a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl).
- R NAAa represents a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl;
- Ring B 34 is azetidine, pyrrolidine, thiazolidine, piperidine, morpholine, indoline, isoindoline, or tetrahydroisoquinoline (the azetidine, pyrrolidine, thiazolidine, piperidine, morpholine, indoline, isoindoline, and tetrahydroisoquinoline are hydroxy, amino, phenyl , and may be substituted with one group selected from the group consisting of oxo.)
- L AAb is a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl);
- Ring B 35 is piperazine or diazepane (the piperazine and diazepane may be substituted with one group selected from the group consisting of hydroxy, amino, phenyl, and oxo);
- L AAb is a single bond or a chain C
- L AAb is a linear C 4-7 alkanediyl (the linear C 4-7 alkanediyl may be substituted with one amino);
- R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl.
- an aminocarboxylic acid linker represented by Formula [IV-2] below
- L AAd is a chain C 2-3 alkanediyl (the chain C 2-3 alkanediyl is substituted with one group selected from the group consisting of hydroxy, amino, C 1-4 alkyl, and benzyl may be used.) and RAAa ' is hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, C 3-8 cycloalkyl (wherein said C 3-8 cycloalkyl is optionally substituted with one haloC 1-6 alkyl), piperidinyl, phenyl, pyridyl, C 1-4 alkyl substituted with C 3-8 cycloalkyl, C 1-4 alkyl substituted with piperidinyl, Phenyl, naphthyl (the phenyl and naphthyl are hydroxy, amino, cyano, nitro, halogen atom, C 1-4 alkyl
- Ring B 41 is benzene or pyridine (the benzene and pyridine may be substituted with one halogen atom)
- L AAe is a chain C 2-3 alkanediyl (the chain C 2-3 alkanediyl is substituted with one group selected from the group consisting of hydroxy, amino, C 1-4 alkyl, and benzyl may be used.
- Q 2 is a structure represented by the formula -O- or the formula -NR N5 -, R N5 is a hydrogen atom or C 1-3 alkyl, R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl.
- an aminocarboxylic acid linker represented by Formula [IV-5] below
- Ring B 41 is benzene or pyridine (the benzene and pyridine may be substituted with one halogen atom), R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl.
- an aminocarboxylic acid linker represented by The following formula [IV-6]
- Ring B 41 is benzene or pyridine (the benzene and pyridine may be substituted with one halogen atom)
- Ring B 42 is pyrrolidine, piperidine, azepane (the pyrrolidine, piperidine and azepane may be bridged by a C 1-3 alkanediyl), azabicyclooctane, or azaspiroheptane;
- the pyrrolidine, piperidine, azepane, azabicyclooctane, azaspiroheptane, and azaspirononane may be substituted with one group selected from the group consisting of halogen atoms and C 1-4 alkyl
- L AAf is a single bond or a chain C 1-3 alkanediyl (the chain C 1-3 alkanediyl is one selected from the group consisting of hydroxy, amino, C 1-4 alkyl, and benzyl It may
- Ring B 41 is benzene or pyridine (the benzene and pyridine may be substituted with one halogen atom)
- Ring B 43 is pyrrolidine, piperidine, azepane (the pyrrolidine, piperidine and azepane may be bridged by C 1-3 alkanediyl), azabicyclooctane, azaspiroheptane, or azaspirononane;
- the pyrrolidine, piperidine, azepane, azabicyclooctane, azaspiroheptane, and azaspirononane may be substituted with one group selected from the group consisting of halogen atoms and C 1-4 alkyl
- L AAa is a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl);
- R NAAa is a hydrogen atom, C
- Ring B 41 is benzene or pyridine (the benzene and pyridine may be substituted with one halogen atom)
- Ring B 44 is piperazine, diazepane (the piperazine and diazepane may be bridged by a C 1-3 alkanediyl), diazabicyclooctane, diazaspiroheptane, or diazaspirononane;
- the piperazine, diazepane, diazabicyclooctane, diazaspiroheptane and diazaspirononane may be substituted with one group selected from the group consisting of halogen atoms and C 1-4 alkyl.
- an aminocarboxylic acid linker represented by Formula [IV-9] below
- Ring B 45 is C 3-8 cycloalkane, piperidine, benzene, or pyridine;
- L AAa and L AAb are independently a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl);
- R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl.
- an aminocarboxylic acid linker represented by The following formula [IV-10]
- Ring B 46 is piperidine
- L AAa is a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl)
- L AAc is a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl);
- R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl.
- an aminocarboxylic acid linker represented by Formula [IV-11] below
- Ring B 47 is piperidine
- L AAb is a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl)
- L AAe is a chain C 2-3 alkanediyl (the chain C 2-3 alkanediyl is substituted with one group selected from the group consisting of hydroxy, amino, C 1-4 alkyl, and benzyl may be used.
- R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl.
- an aminocarboxylic acid linker represented by The following formula [IV-12]
- Ring B 48 is piperazine, L AAb is a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl); L AAe is a chain C 2-3 alkanediyl (the chain C 2-3 alkanediyl is substituted with one group selected from the group consisting of hydroxy, amino, C 1-4 alkyl, and benzyl may be used.) and R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl. ) and an aminocarboxylic acid linker represented by the following formula [IV-13]
- RAAa'' is hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, C 3-8 cycloalkyl (wherein said C 3-8 cycloalkyl is optionally substituted with one haloC 1-6 alkyl), piperidinyl, phenyl, pyridyl, C 1-4 alkyl substituted with C 3-8 cycloalkyl, C 1-4 alkyl substituted with piperidinyl, Phenyl, naphthyl (the phenyl and naphthyl are hydroxy, amino, cyano, nitro, halogen atom, C 1-4 alkyl, haloC 1-4 alkyl, phenyl, pyrazolyl, pyridyl (the pyrazolyl and pyridyl are one C optionally substituted with 1-4 alkyl), C 1-4 alkoxy (where
- RAAa''' is hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, C 3-8 cycloalkyl (wherein said C 3-8 cycloalkyl is optionally substituted with one haloC 1-6 alkyl), piperidinyl, phenyl, pyridyl, C 1-4 alkyl substituted with C 3-8 cycloalkyl, C 1-4 alkyl substituted with piperidinyl, Phenyl, naphthyl (the phenyl and naphthyl are hydroxy, amino, cyano, nitro, halogen atom, C 1-4 alkyl, haloC 1-4 alkyl, phenyl, pyrazolyl, pyridyl (the pyrazolyl and pyridyl are one C optionally substituted with 1-4 alkyl), C 1-4 alkoxy (
- Z C and AA X may form a group represented by Furthermore, Z C and AA X (where X is an integer of 1 to 7) may form a cyclic structure together with the structure existing therebetween, W2, W3 , W4 , W5 , W6 , and W7 are independently (i) a diamine linker of the formula -NR NWa -L W -NR NWb -; (ii) a diamine linker represented by formula [V-1] below, (iii) a diamine linker represented by formula [V-2] below, (iv) a diamine linker represented by formula [V-3] below, or a diamine linker represented by (v) formula [V-4] below, here, In the diamine linker represented by the formula (i) -NR NWa -L W -NR NWb -, L W is a chain C 1-3 alkanediyl, R NWa and R NWb are independently a hydrogen atom or C 1-2 alkyl, (ii
- ring B 51 is a C 3-8 cycloalkane (the C 3-8 cycloalkane may be bridged by a C 1-3 alkanediyl), benzene, or pyridine;
- L Wa and L Wb are independently a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl);
- R NWa and R NWb are independently a hydrogen atom or C 1-2 alkyl.
- the linker is a structure represented by (iii) In the diamine linker represented by formula [V-2], The linker is
- Ring B 52 is azetidine, pyrrolidine, piperidine, azepane (the azetidine, pyrrolidine, piperidine and azepane may be substituted with one group selected from the group consisting of carbamoyl and oxo, and C 1-3 may be crosslinked by an alkanediyl.)
- L Wa is a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl);
- R NWa is a hydrogen atom or C 1-2 alkyl.
- ) is a structure represented by (iv) In the diamine linker represented by formula [V-3], The linker is
- Ring B 53 is azetidine, pyrrolidine, piperidine, azepane (the azetidine, pyrrolidine, piperidine and azepane may be substituted with one group selected from the group consisting of carbamoyl and oxo, and C 1-3 may be crosslinked by an alkanediyl.)
- L Wb is a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl);
- R NWa is a hydrogen atom or C 1-2 alkyl.
- ) is a structure represented by (v) In the diamine linker represented by formula [V-4], The linker is
- Ring B 54 is piperazine, diazepane (the piperazine and diazepane may be substituted with one group selected from the group consisting of carbamoyl and oxo, and may be bridged by C 1-3 alkanediyl. ) or diazaspirooctane.
- Ring B 61 is C 3-8 cycloalkane, oxetane, or piperidine; L AAra and L AArb are independently a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl). . ) A structure represented by The following formula [VI-2]
- Ring B 62 is a C 3-8 cycloalkane, pyrrolidine, piperidine, azepane, benzene, pyridine, or dihydropyridine (the C 3-8 cycloalkane, pyrrolidine, piperidine, azepane, benzene, pyridine, and dihydropyridine are optionally substituted with oxo and optionally bridged by a C 1-3 alkanediyl); L AAra and L AArb are independently a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl). . ) or the following formula [VI-3]
- Ring B 63 is pyrrolidine, piperidine, or azepane; the pyrrolidine, piperidine, azepane may be substituted with one oxo, and the pyrrolidine, piperidine, azepane may be bridged by C 1-3 alkanediyl; L AArc is a chain C 2-3 alkanediyl (the chain C 2-3 alkanediyl may be substituted with one methyl).
- Ring B 64 is azetidine, pyrrolidine, thiazolidine, piperidine, morpholine, indoline, isoindoline, or tetrahydroisoquinoline; the azetidine, pyrrolidine, thiazolidine, piperidine, morpholine, indoline, isoindoline, and tetrahydroisoquinoline optionally substituted with one group selected from the group consisting of hydroxy, amino, phenyl, and oxo; L AAra is a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl); In the above formula [VI-5], ring B 65 is piperazine or diazepane; L AAra is a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl); In the above formula [
- Ring B 71 is C 3-8 cycloalkane, pyrrolidine, piperidine, piperazine, benzene, or pyridine;
- the C 3-8 cycloalkanes, pyrrolidines, piperidines and piperazines may be bridged by C 1-3 alkanediyls, L Va and L Vb are each independently a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl).
- RZC is hydroxy, C 1-6 alkoxy, amino, mono C 1-12 alkylamino (wherein said mono C 1-12 alkylamino is hydroxy, carboxy, amino, a halogen atom, C 3-8 cycloalkyl (wherein said C 3-8 cycloalkyl is substituted with 1 amino) ), azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl (the azetidinyl, pyrrolidinyl, piperidinyl and piperidinyl may be substituted with one group selected from the group consisting of amino and C 1-6 alkyl.) , phenyl, pyrazolyl, pyridyl, C 1-6 alkoxy (wherein said C 1-6 alkoxy is optionally substituted with C 1-6 alkoxy which is optionally substituted with one amino), and di-C 1- may be substituted with 1 to 3 groups identically or differently selected from the
- n 2 is an integer of 1 to 8
- R N4 is a hydrogen atom or C 1-3 alkyl.
- RZN is C 1-6 alkyl, wherein said C 1-6 alkyl is substituted with one group selected from the group consisting of hydroxy, amino, and phenyl (wherein said phenyl is haloC 1-6 alkyl and C 1-6 alkoxy; may be substituted with 1 to 2 groups identically or differently selected from the group consisting of haloC 1-6 alkyl, C 3-8 cycloalkyl, C 8-10 cycloalkyl having an 8-10 membered condensed ring structure, or C 7-11 cycloalkyl having a spiro ring structure, piperidinyl (which piperidinyl may be bridged by a C 1-3 alkanediyl), phenyl, pyridinyl, isoquinolyl (the phenyl, pyri
- Ring B 33 represents piperidine or azepane, the piperidine and azepane are optionally substituted with one oxo;
- the piperidine and azepane may be crosslinked by a C 1-3 alkanediyl
- L AAf is a chain C 1-3 alkanediyl (the chain C 1-3 alkanediyl is substituted with one group selected from the group consisting of hydroxy, amino, C 1-4 alkyl, and benzyl )
- Ring B 54 is piperazine or diazepane (the piperazine and diazepane may be substituted with one group selected from the group consisting of carbamoyl and oxo, and may be bridged by C 1-3 alkanediyl. ).
- Ring A is benzene, pyridine, or dihydrobenzofuran
- R A1 , R A2 , and R A3 are independently hydrogen atom, carbamoyl, cyano, nitro, halogen atom, C 1-6 alkyl, haloC 1-6 alkyl, phenyl (the phenyl may be substituted with one halogen atom), phenylcarbonylamino (phenyl of said phenylcarbonylamino may be substituted with one group selected from the group consisting of carbamoyl and halogen atoms), C 1-6 alkoxy, haloC 1-6 alkoxy, or di-C 1-6 alkylamino;
- ZBG is Carboxy, a group represented by the formula -CO-NH-OH, C 1-6 alkoxycarbonyl, C 2-6 alkenyloxycarbonyl, C 1-6 alkylaminocarbonyl (C 1-6 alkylaminocarbonyl (C 1-6 al
- Ring B 11 is pyrrolidine, R N2 is a hydrogen atom or C 1-3 alkyl, AA r1 is as described later.
- Ring B 21 is a triazole
- L 12c and L 12d are each independently a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl).
- L 12a and L 12b are each independently a chain C 1-3 alkanediyl (the chain C 1-3 alkanediyl may be substituted with one methyl); R N4 is a hydrogen atom or C 1-3 alkyl,
- L 13 is a chain C 1-5 alkanediyl (the chain C 1-5 alkanediyl may be substituted with 1 methyl) of the formula -L 13a -OL 13b - the structure represented by the formula -L 13a -NR N4 -L 13b -, or the following formula [II-3]
- Ring B 22 is pyrrolidine
- L 13c and L 13d are each independently a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl).
- R N3 is a hydrogen atom or C 1-3 alkyl
- L 13a is a chain C 1-3 alkanediyl (the chain C 1-3 alkanediyl may be substituted with one methyl)
- L 13b is a chain C 2-3 alkanediyl (the chain C 2-3 alkanediyl may be substituted with one methyl)
- R N4 is a hydrogen atom or C 1-3 alkyl
- L 15 is a chain C 1-3 alkanediyl (the chain C 1-3 alkanediyl may be substituted with one methyl);
- L 15 is a chain C 1-3 alkanediyl (the chain C 1-3 alkanediyl may be substituted with one
- Ring B 31 is C 3-8 cycloalkane, oxetane, or piperidine; L AAa and L AAb are independently a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl). . )
- Ring B 32 is C 3-8 cycloalkane, pyrrolidine, azepane, benzene, thiazole, pyridine, or dihydropyridine; the C3-8 cycloalkanes, pyrrolidines and dihydropyridines are optionally substituted with one oxo;
- the C 3-8 cycloalkanes, pyrrolidines and azepanes may be bridged by C 1-3 alkanediyls, the benzene, thiazole, and pyridine may be substituted with one halogen atom;
- L AAa and L AAb are independently a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl); , However, LAAa and LAAb are not chained C 1-2 alkanediyl at the same time. ), or the following formula [III-3]
- Ring B 33 is piperidine, azepane, or dihydropyridine; the piperidine and azepane are optionally substituted with one oxo; the dihydropyridine is optionally substituted with one oxo, L AAc is a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl).
- L AAc is a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl).
- the linkers are each:
- Ring B 34 is azetidine, pyrrolidine, thiazolidine, piperidine, morpholine, indoline, isoindoline, or tetrahydroisoquinoline (the azetidine, pyrrolidine, thiazolidine, piperidine, morpholine, indoline, isoindoline, and tetrahydroisoquinoline are hydroxy, amino, phenyl , and may be substituted with one group selected from the group consisting of oxo.)
- L AAb is a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl);
- Ring B 35 is piperazine or diazepane (the piperazine and diazepane may be substituted with one group selected from the group consisting of hydroxy, amino, phenyl, and oxo);
- L AAb is a single bond or a chain C
- L AAb is a linear C 4-7 alkanediyl (the linear C 4-7 alkanediyl may be substituted with one amino);
- R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl.
- an aminocarboxylic acid linker represented by Formula [IV-2] below
- Q 1 is a structure represented by the formula -O-, n 1 is an integer of 1 to 3, R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl.
- an aminocarboxylic acid linker represented by The following formula [IV-3]
- L AAd is a chain C 2-3 alkanediyl (the chain C 2-3 alkanediyl is substituted with one group selected from the group consisting of hydroxy, amino, C 1-4 alkyl, and benzyl may be used.) and R AAb ' is C 1-4 alkyl substituted with thiazolyl, R AAb ' is a hydrogen atom or methyl, R NAAa and R NAAb are independently a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl.
- an aminocarboxylic acid linker represented by Formula [IV-4] below
- Ring B 41 is benzene, the benzene may be substituted with one halogen atom
- L AAe is a chain C 2-3 alkanediyl (the chain C 2-3 alkanediyl may be substituted with one group selected from the group consisting of hydroxy and C 1-4 alkyl;
- Q 2 is a structure represented by the formula -O- or the formula -NR N5 -;
- R N5 is a hydrogen atom or C 1-3 alkyl,
- R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl.
- an aminocarboxylic acid linker represented by Formula [IV-5] below
- Ring B 41 is benzene or pyridine (the benzene and pyridine may be substituted with one halogen atom);
- Ring B 42 is pyrrolidine, piperidine, or azaspiroheptane;
- the pyrrolidine, piperidine and azaspiroheptane may be substituted with one group selected from the group consisting of halogen atoms and C1-4 alkyl,
- L AAf is a single bond or a chain C 1-3 alkanediyl (the chain C 1-3 alkanediyl is one selected from the group consisting of hydroxy, amino, C 1-4 alkyl, and benzyl
- It may be substituted with a group of Q 2 is a structure represented by the formula -O- or the formula -NR N5 -; R N5 is a hydrogen atom or C 1-3 alkyl.
- an aminocarboxylic acid linker represented by Formula [IV-8] below
- Ring B 41 is benzene or pyridine (the benzene and pyridine may be substituted with one halogen atom)
- Ring B 44 is piperazine (which piperazine may be bridged by a C 1-3 alkanediyl), diazepane, diazabicyclooctane, or diazaspiroheptane;
- the piperazine, diazepane, diazabicyclooctane, diazaspiroheptane and diazaspirononane may be substituted with one group selected from the group consisting of halogen atoms and C 1-4 alkyl.
- an aminocarboxylic acid linker represented by Formula [IV-9] below
- Ring B 45 is C 3-8 cycloalkane, piperidine, benzene, or pyridine;
- L AAa and L AAb are independently a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl);
- R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl.
- an aminocarboxylic acid linker represented by Formula [IV-11] below
- Ring B 47 is piperidine
- L AAb is a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl)
- L AAe is a chain C 2-3 alkanediyl (the chain C 2-3 alkanediyl may be substituted with one group selected from the group consisting of hydroxy and benzyl)
- R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl.
- an aminocarboxylic acid linker represented by The following formula [IV-12]
- Ring B 48 is piperazine, L AAb is a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl); L AAe is a chain C 2-3 alkanediyl (the chain C 2-3 alkanediyl is substituted with one group selected from the group consisting of hydroxy, amino, C 1-4 alkyl, and benzyl may be used.) and R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl. ) and an aminocarboxylic acid linker represented by the following formula [IV-13]
- R AAa′′ is C 1-6 alkyl; RAAb'' is a hydrogen atom, R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl.
- R AAa′′ is C 1-6 alkyl; RAAb'' is a hydrogen atom, R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl.
- adjacent Z C and AA X are combined to form [IV-14] or [IV-15] below.
- R AAa''' is C 1-4 alkyl substituted with 1 amino
- RAAb''' is a hydrogen atom
- R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl
- Ring B 49 is pyrrolidine
- RAAa''' and RAAb''' are the same as those in formula [IV-14] above.
- Z and AA X together with the structure existing between them, are represented by the following formula [IV-16-1]
- W2 may form a cyclic structure represented by W2, W3 , W4 , W5 , W6 , and W7 are independently (i) a diamine linker of the formula -NR NWa -L W -NR NWb -; (ii) a diamine linker represented by formula [V-1] below, (iii) a diamine linker represented by formula [V-2] below, (iv) a diamine linker represented by formula [V-3] below, or a diamine linker represented by (v) formula [V-4] below, here, In the diamine linker represented by the formula (i) -NR NWa -L W -NR NWb -, L W is a chain C 1-3 alkanediyl, R NWa and R NWb are independently a hydrogen atom or C 1-2 alkyl, (ii) In the diamine linker represented by formula [V-1], The linker is
- Ring B 51 is a C 3-8 cycloalkane
- L Wa and L Wb are independently a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl);
- R NWa and R NWb are independently a hydrogen atom or C 1-2 alkyl.
- the linker is
- Ring B 52 is azetidine, pyrrolidine, piperidine (the azetidine, pyrrolidine and piperidine may be substituted with one group selected from the group consisting of carbamoyl and oxo);
- L Wa is a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl);
- R NWa is a hydrogen atom or C 1-2 alkyl.
- Ring B 53 is piperidine (the piperidine may be substituted with one group selected from the group consisting of carbamoyl and oxo);
- L Wb is a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl);
- R NWa is a hydrogen atom or C 1-2 alkyl.
- v In the diamine linker represented by formula [V-4], The linker is
- Ring B 54 is piperazine, diazepane (the piperazine and diazepane may be substituted with one group selected from the group consisting of carbamoyl and oxo), or diazaspirooctane.
- Ring B 62 is benzene
- L AAra and L AArb are independently a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl).
- . is a structure represented by R NAAr is a hydrogen atom or C 1-2 alkyl
- V2, V3 , V4 , V5 , V6 , and V7 are independently (ii) a dicarboxylic acid linker represented by the following formula [VII-1], (ii) In the dicarboxylic acid linker represented by formula [VII-1], The linker is
- Ring B 71 is benzene
- L Va and L Vb are each independently a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl).
- RZC is hydroxy, C 1-6 alkoxy, amino, mono C 1-12 alkylamino (wherein said mono C 1-12 alkylamino is hydroxy, carboxy, amino, a halogen atom, C 3-8 cycloalkyl (wherein said C 3-8 cycloalkyl is substituted with 1 amino) ), azetidinyl, piperidinyl, piperazinyl (the azetidinyl, piperidinyl and piperidinyl may be substituted with one group selected from the group consisting of amino and C 1-6 alkyl), phenyl, pyrazolyl , pyridyl, C 1-6 alkoxy (wherein said C 1-6 alkoxy is optionally substituted with C 1-6 alkoxy which is optionally substituted with one amino), and di-C 1-6 alkylamino may be substituted with 1 to 3 groups selected identically or differently from the group consisting of mono C 3-8 cycloal
- RZN is C 1-6 alkyl, wherein said C 1-6 alkyl is substituted with one group selected from the group consisting of hydroxy, amino, and phenyl (wherein said phenyl is haloC 1-6 alkyl and C 1-6 alkoxy; may be substituted with 1 to 2 groups identically or differently selected from the group consisting of haloC 1-6 alkyl, C 3-8 cycloalkyl, piperidinyl, phenyl, pyridinyl, isoquinolyl (the phenyl, pyridinyl and isoquinolyl are halogen atoms, C 1-6 alkyl, haloC 1-6 alkyl and pyrrolidinyl (the pyrrolidinyl is optionally substituted with one oxo); optionally substituted with one group selected
- Ring B 33 represents piperidine or azepane, The piperidine and azepane may be substituted with one oxo, and in formula [IV-6] above, L AAf is a chain C 1-3 alkanediyl (the chain C 1-3 alkanediyl is substituted with one group selected from the group consisting of hydroxy, amino, C 1-4 alkyl, and benzyl may be used).
- L 1 is a structure represented by (i-1) to (i-4) above,
- the group represented by the formula -Y 2 -Y 3 -Y 4 -Z is (i-1) a group represented by the formula -AA 2 -AA 3 -AA 4 -ZC or (i-2) a group represented by the formula -AA 2 -AA 3 -W 4 -R ZN or
- L 1 is a structure represented by (ii-1) to (ii-2) above,
- the group represented by the formula -Y 2 -Y 3 -Y 4 -Z is (ii-1) a group represented by the formula -AA r2 -AA r3 -AA r4 -ZN , or (ii-2) a group represented by the formula -AA r2 -AA r3 -V 4 -R ZC , (1) to (3), or a pharmaceutically acceptable salt thereof.
- RAAa is hydrogen atom, methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, tert-amyl,
- n-butyl substituted with methyl methylamino (methyl of said methylamino may be substituted with one azetidinyl), methylamino (methyl of said methylamino may be substituted with one pyrrolidinyl) n-butyl substituted with ), methyl substituted with isopropylamino, piperidinylamino (piperidinyl of said piperidinylamino may be substituted with one methyl).
- R AAb is a hydrogen atom or methyl
- RNAAa is a hydrogen atom or methyl, ethyl substituted with amino, ethyl substituted with phenyl, propyl substituted with phenyl, or butyl substituted with phenyl;
- Ring B 31 is cyclopropane, cyclobutane, cyclopentane, oxetane, or piperidine; L AAa is a single bond, L AAb is a single bond or methanediyl.
- Ring B 32 is cyclobutane, cyclopentane, cyclohexane, pyrrolidine, benzene, thiazole, or pyridine;
- the cyclobutane may be bridged by a C 1-3 alkanediyl, the benzene may be optionally substituted with one chlorine atom, L AAa and L AAb are independently a single bond or methanediyl; However, LAAa and LAAb never show methanediyl at the same time.
- RNAAa is a hydrogen atom or methyl, ethyl substituted with amino, ethyl substituted with phenyl, propyl substituted with phenyl, or butyl substituted with phenyl;
- Ring B 34 is azetidine, pyrrolidine, thiazolidine, piperidine, piperazine, morpholine, indoline, isoindoline, or tetrahydroisoquinoline;
- the azetidine, pyrrolidine may be substituted with one group selected from the group consisting of hydroxy, amino and phenyl, the piperidine is optionally substituted with one amino, L AAb is a single bond or methanediyl.
- ) is a structure represented by here, Two adjacent AA X (where X is an integer of 1 to 7) are together
- An aminocarboxylic acid linker represented by the following formula [IV-1] may be formed, where the linker is
- L AAbs are n-butane-1,4-diyl, n-pentane-1,5-diyl (the n-butane-1,4-diyl, n-pentane-1,5-diyl are ), n-hexane-1,6-diyl, RNAAa is a hydrogen atom.
- RNAAa is a hydrogen atom.
- Ring B 41 is benzene or pyridine, the benzene may be optionally substituted with one chlorine atom, Ring B 42 is pyrrolidine or piperidine, The pyrrolidine may be substituted with one group selected from the group consisting of a fluorine atom and methyl, L AAf is a single bond or methanediyl, Q 2 is a structure represented by the formula -NR N5 -, RN5 is a hydrogen atom.
- W 4 , W 5 , W 6 and W 7 are independently (i) a diamine linker of the formula -NR NWa -L W -NR NWb -; (iii) a diamine linker represented by formula [V-2] below, (iv) a diamine linker represented by formula [V-3] below, or a diamine linker represented by (v) formula [V-4] below, here,
- L W is ethane-1,2-diyl
- R NWa and R NWb are hydrogen atoms
- the linker is
- Ring B 52 is azetidine, pyrrolidine, piperidine (the azetidine, pyrrolidine and piperidine may be substituted with one oxo); L Wa is a single bond or methanediyl, RNWa is a hydrogen atom.
- ) is a structure represented by (iv) In the diamine linker represented by formula [V-3], The linker is
- Ring B 53 is piperidine (the piperidine may be substituted with one carbamoyl); L Wb is a single bond, RNWa is a hydrogen atom.
- ) is a structure represented by (v) In the diamine linker represented by formula [V-4], The linker is
- Ring B 54 is piperazine, diazepane, or diazaspirooctane.
- Ring B 71 is benzene, L Va and L Vb are identically a single bond.
- L 1 is a structure represented by (i-1) to (i-4) above,
- the group represented by the formula -Y 2 -Y 3 -Y 4 -Z is (i-1) a group represented by the formula -AA 2 -AA 3 -AA 4 -ZC or (i-2) a group represented by the formula -AA 2 -AA 3 -W 4 -R ZN , (1) to (5), or a pharmaceutically acceptable salt thereof.
- Ring A is benzene or pyridine
- R A1 and R A2 are independently hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, methyl, difluoromethyl, trifluoromethyl
- phenylcarbonylamino the phenyl of the phenylcarbonylamino may be substituted with one group selected from the group consisting of carbamoyl and chlorine atoms), methoxy, difluoromethoxy, or dimethylamino
- R A3 is a hydrogen atom
- ZBG is Carboxy, a group represented by the formula -CO-NH-OH, tert-butoxycarbonyl, allyloxycarbonyl, methylaminocarbonyl, ethylaminocarbonyl (ethyl in said ethylaminocarbonyl may be substituted with one hydroxy), or trifluoroethylaminocarbon
- Ring B 21 is pyrrolidine or triazole;
- L 12c and L 12d are independently methanediyl or ethane-1,2-diyl.
- ) is a structure represented by and, L 12a and L 12b are independently methanediyl, ethane-1,2-diyl, or n-propane-1,3-diyl;
- R N4 is a hydrogen atom or methyl,
- L 13 is n-butane-1,4-diyl or a structure represented by the formula -L 13a -OL 13b -;
- R N3 is a hydrogen atom, and, L 13a is methanediyl, L 13b is ethane-1,2-diyl,
- -L 14 -C( O)-NH-NH-
- Ring B 31 is cyclopropane or cyclopentane, L AAa is a single bond, L AAb is a single bond.
- Ring B 31 is cyclopropane or cyclopentane, L AAa is a single bond, L AAb is a single bond.
- Ring B 32 is benzene, LAAa and LAAb are identically a single bond.
- RNAAa is a hydrogen atom
- aminocarboxylic acid linker represented by formula [III-4] The linker is
- Ring B 34 is pyrrolidine, L AAb is a single bond or methanediyl.
- L AAb is a single bond or methanediyl.
- Adjacent AA 1 and AA 2 together An aminocarboxylic acid linker represented by the following formula [IV-1] may be formed, where the linker is
- L AAb is n-pentane-1,5-diyl or n-hexane-1,6-diyl
- RNAAa is a hydrogen atom.
- Ring B 32 is benzene, LAAa and LAAb are identically a single bond.
- RNAAa is a hydrogen atom
- RAAa is isopropyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, trifluoroethyl,
- Ring B 31 is cyclopropane, cyclobutane, cyclopentane, or piperidine; L AAa is a single bond, L AAb is a single bond.
- ring B 32 is benzene or thiazole; the benzene may be optionally substituted with one chlorine atom, L AAa and L AAb are independently a single bond or methanediyl; However, LAAa and LAAb are not methanediyl at the same time. ) or a structure represented by the following formula [III-3]
- Ring B 33 is azepane (the azepane is optionally substituted with one oxo) and L AAc is methanediyl.
- RNAAa is a hydrogen atom
- aminocarboxylic acid linker represented by formula [III-4] The linker is
- Ring B 34 is pyrrolidine, thiazolidine, piperidine, piperazine, or morpholine; L AAb is a single bond or methanediyl.
- RAAa is hydrogen atom, isopropyl, isobutyl, phenyl, methyl substituted by phenyl,
- Ring B 31 is oxetane, LAAa and LAAb are independently a single bond or methanediyl.
- Ring B 32 is cyclobutane, cyclopentane, cyclohexane, pyrrolidine, benzene, or pyridine;
- the cyclobutane may be bridged by a C 1-3 alkanediyl, the benzene may be optionally substituted with one chlorine atom, L AAa and L AAb are independently a single bond or methanediyl; However, LAAa and LAAb never show methanediyl at the same time.
- ring B 33 is piperidine, azepane (the azepane may be substituted with one oxo), or dihydropyridine (the dihydropyridine may be substituted with one oxo);
- L AAc is methanediyl.
- RNAAa is a hydrogen atom
- aminocarboxylic acid linker represented by formula [III-4] The linker is
- Ring B 34 is azetidine, pyrrolidine, thiazolidine, piperidine, piperazine, morpholine, indoline, isoindoline, or tetrahydroisoquinoline;
- the azetidine, pyrrolidine may be substituted with one group selected from the group consisting of hydroxy, amino and phenyl, L AAb is a single bond or methanediyl.
- Adjacent AA 4 and AA 5 together,
- An aminocarboxylic acid linker represented by the following formula [IV-1] may be formed, where the linker is
- L AAbs are n-butane-1,4-diyl, n-pentane-1,5-diyl (the n-butane-1,4-diyl, n-pentane-1,5-diyl are ), n-hexane-1,6-diyl, RNAAa is a hydrogen atom.
- RNAAa is a hydrogen atom.
- Ring B 41 is benzene or pyridine, the benzene optionally substituted with one chlorine atom
- Ring B 42 is pyrrolidine or piperidine
- the pyrrolidine may be substituted with one group selected from the group consisting of a fluorine atom and methyl
- L AAf is a single bond or methanediyl
- Q 2 is a structure represented by the formula -NR N5 -
- RN5 is a hydrogen atom.
- Z is (i) a group represented by the formula -R Z , (ii) a group represented by the formula -Y 5 -R Z , (iii) a group represented by the formula -Y 5 -Y 6 -R Z , or (iv) a group represented by the formula -Y 5 -Y 6 -Y 7 -R Z , Y 5 , Y 6 and Y 7 are independently (i) an aminocarboxylic acid linker represented by the formula -AA X' -, or (ii) a diamine linker represented by the formula -W X' -, here, X' is an integer of 5 to 7,
- RZ is (i-1) a group represented by the formula -R ZC or (ii-1) a group represented by the formula -R ZN , moreover, L 1 is a structure represented by (i-1) to (i-4) above, The group represented by the formula -
- RNAAa is a hydrogen atom
- aminocarboxylic acid linker represented by formula [III-4] The linker is
- Ring B 34 is pyrrolidine or piperidine, The pyrrolidine and piperidine may be substituted with one amino, L AAb is a single bond or methanediyl.
- W5 is (iii) a diamine linker represented by formula [V-2] below, (iv) a diamine linker represented by formula [V-3] below, or a diamine linker represented by (v) formula [V-4] below, here, (iii) In the diamine linker represented by formula [V-2], The linker is
- Ring B 53 is piperidine (the piperidine may be substituted with one carbamoyl); L Wb is a single bond, RNWa is a hydrogen atom.
- ) is a structure represented by (v) In the diamine linker represented by formula [V-4], The linker is
- Ring B 54 is piperazine, diazepane, or diazaspirooctane.
- RZC is hydroxy, C 1-6 alkoxy, amino, mono C 1-12 alkylamino (the mono C 1-12 alkylamino is optionally substituted with amino, a halogen atom, C 3-8 cycloalkyl (the C 3-8 cycloalkyl is optionally substituted with 1 amino); ), azetidinyl, piperidinyl, piperazinyl (the azetidinyl, piperidinyl and piperidinyl may be substituted with one group selected from the group consisting of amino and C 1-6 alkyl), phenyl, pyrazolyl, pyridyl, and optionally substituted with 1 to 3 groups identically or differently selected from the group consisting of diC 1-6 alkylamino), mono C 3-8 cycloalkylamino (wherein
- RZN is C 1-6 alkyl, wherein said C 1-6 alkyl is substituted with one group selected from the group consisting of hydroxy, amino, and phenyl (wherein said phenyl is haloC 1-6 alkyl and C 1-6 alkoxy; may be substituted with 1 to 2 groups identically or differently selected from the group consisting of piperidinyl, phenyl, pyridyl, isoquinolyl (the phenyl, pyridyl, and isoquinolyl are selected from the group consisting of halogen atoms, haloC 1-6 alkyl, and pyrrolidinyl (the pyrrolidinyl may be substituted with one oxo); optionally substituted with one group), and dihydrobenzodioxinyl, C 1-6 alkylcarbonyl ( said C 1-6 alkylcarbonyl ( said C 1-6 alky
- Ring A is benzene
- R A1 and R A2 are independently hydrogen atom, fluorine atom, chlorine atom, bromine atom, methyl, difluoromethyl, trifluoromethyl, or phenylcarbonylamino (the phenyl of the phenylcarbonylamino is substituted with one group selected from the group consisting of carbamoyl and chlorine atoms).
- R A3 is a hydrogen atom
- ZBG is carboxy or a group represented by the formula -CO-NH-OH
- R ZBG is a hydrogen atom
- R N1 is a hydrogen atom
- L 11 is methanediyl or ethane-1,2-diyl
- AA 1 is as described below;
- L 12 is n-butane-1,4-diyl, n-pentane-1,5-diyl,
- Z is (i) a group represented by the formula -R Z ; (ii) a group represented by the formula -Y 5 -R Z , (iii) a group represented by the formula -Y 5 -Y 6 -R Z , or (iv) a group represented by the formula -Y 5 -Y 6 -Y 7 -R Z , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are independently (i) an aminocarboxylic acid linker represented by the formula -AA X' -, or (ii) a diamine linker represented by the formula
- RNAAa is a hydrogen atom
- aminocarboxylic acid linker represented by formula [III-4] The linker is
- R AAa is n-butyl substituted with amino or n-propyl substituted with guanidinyl
- R AAb is a hydrogen atom or methyl
- RNAAa is a hydrogen atom or methyl
- RNAAa is a hydrogen atom
- RZC is hydroxy, amino, methylamino substituted with 1 cyclobutyl (the cyclobutyl is substituted with 1 amino), ethylamino substituted with 1 amino, substituted with 1 dimethylamino ethylamino, cyclobutylamino substituted with 1 amino, or pyrrolidinyl substituted with 1 amino;
- RZN is The compound according to any one of (1) to (9), which is n-propyl substituted with one amino, or n-pentyl substituted with 1 to 2 aminos, or pharmaceuticals thereof to provide a commercially acceptable salt.
- Ring A is benzene
- R A1 and R A2 are independently hydrogen atom, chlorine atom, methyl, trifluoromethyl, phenylcarbonylamino (the phenylcarbonylamino is substituted with one carbamoyl);
- R A3 is a hydrogen atom
- ZBG is carboxy;
- R ZBG is a hydrogen atom
- R N1 is a hydrogen atom,
- L 11 is ethane-1,2-diyl
- AA 1 is (i) an aminocar
- RNAAa is a hydrogen atom
- R AAa is n-butyl substituted with amino or n-propyl substituted with guanidinyl
- R AAb is a hydrogen atom
- RNAAa is a hydrogen atom or methyl
- RNAAa is a hydrogen atom
- W5 is a diamine linker represented by the following (v) formula [ V -4], here,
- the diamine linker represented by the formula [V-4] has the following
- RZC is hydroxy, amino, methylamino (wherein the methylamino is substituted with cyclobutyl substituted with one amino), ethylamino (the ethylamino is substituted with one group selected from the group consisting of amino and dimethylamino), cyclobutylamino (the cyclobutylamino is substituted with 1 amino), or pyrrolidino (the pyrrolidino is substituted with 1 amino) and RZN is n-propyl (the n-propyl is substituted with 1 amino) or n-pentyl (the n-pentyl is substituted with 2 aminos) It is to provide a compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (10).
- An object of the present invention is to provide a medicament containing, as an active ingredient, the compound according to any one of (1) to (12) or a pharmaceutically acceptable salt thereof.
- An object of the present invention is to provide an MMP7 inhibitor containing the compound according to any one of (1) to (12) or a pharmaceutically acceptable salt thereof as an active ingredient.
- One or more diseases selected from the group consisting of cancer diseases and non-neoplastic diseases containing the compound according to any one of (1) to (12) or a pharmaceutically acceptable salt thereof as an active ingredient. , or to provide prophylactic or therapeutic agents for symptoms associated with these.
- the compound of the present invention (hereinafter sometimes referred to as the "compound of the present invention") has an inhibitory effect on MMP7.
- some of the compounds of the present invention have the activity of selectively inhibiting MMP7.
- the present invention provides a compound represented by the above formula [I] or a pharmaceutically acceptable salt thereof having an MMP7 inhibitory action.
- the compounds of the present invention are described in more detail below, but the present invention is not limited to the exemplified ones.
- amino acid is broadly defined as an organic compound having both amino and carboxy functional groups.
- ⁇ -amino acid which is a structural unit of biological proteins It refers to the amino acids that contain Amino acids herein include, for example, naturally occurring proteinogenic L-amino acids; naturally occurring non-proteinogenic amino acids; non-naturally occurring amino acids.
- unnatural amino acids include D-forms of naturally occurring proteinogenic L-amino acids; chemically modified amino acids, such as amino acid mutants and derivatives; and chemically modified amino acids having properties known in the art that are characteristic of amino acids. Synthesized compounds and the like are included.
- an "amino acid” when the name of an "amino acid” is written without abbreviations such as three-letter code or one-letter code, it indicates an amino acid containing L-configuration, D-configuration, or both.
- an "amino acid” when abbreviated by a three-letter code, a one-letter code, or the like, it indicates an L-form amino acid.
- “L” or “l” is added just before “amino acid” to clarify that it is an L-form amino acid.
- “D” or "d” when “D” or “d” is added immediately before “amino acid”, it indicates a D-form amino acid.
- naturally occurring proteinogenic L-amino acid refers to naturally occurring L-form amino acids that constitute proteins, such as Gly, Ala, Val, Leu, Ile, Pro, Phe, His, Trp, Tyr, Ser, Thr, Met, Cys, Asp, Glu, Asn, Gln, Lys, Arg and the like.
- the D form of a natural proteinogenic L-amino acid refers to the enantiomer of the natural proteinogenic L-amino acid.
- Naturally occurring proteinogenic L-amino acids other than glycine have at least one asymmetric carbon and are optically active.
- the structures of these amino acids are distinguished into L- and D-forms according to the structures of L- and D-forms of glyceraldehyde.
- Amino acids other than natural proteinogenic L-amino acids may also have D-form amino acids.
- natural non-proteinogenic amino acid refers to a naturally occurring amino acid that does not constitute a protein.
- parenthetical combination indicates an abbreviation.
- ⁇ -alanine ⁇ -Ala
- L-ornithine Orn
- a natural non-proteinogenic amino acid has an asymmetric carbon
- the amino acid has an L-form and a D-form.
- amino acids other than natural non-proteinogenic amino acids may also exist in L- and D-forms.
- non-natural amino acid refers to an amino acid that does not constitute a protein and is mainly artificially produced. It refers to amino acids other than "amino acids".
- unnatural amino acids include D-forms of natural proteinogenic L-amino acids (D-Cys, D-Ser, etc.); ⁇ -methyl amino acids (2-aminoisobutyric acid (Aib), etc.); amino acids (L- ⁇ -homoproline ( ⁇ -Hep or ⁇ -homoPro), L-homoserine (Hes or homoSer), L-homocysteine (Hec or homoCys), L-homoproline (homoPro), L-homoglutamic acid (homoGlu ); amino acids in which the carboxylic acid functional amino acid in the side chain is replaced with a sulfonic acid group (such as L-cysteic acid); chemically modified amino acids such as amino acid variants and derivatives (hydroxyproline , L-2,3-
- Nitrogen atoms involved in peptide bonds of amino acids herein may be alkylated.
- the amino acid is also referred to as an "N-alkylamino acid".
- the alkyl includes, for example, C 1-4 alkyl substituted with methyl, ethyl, amino, and C 1-4 alkyl substituted with phenyl.
- n is normal, "i” is iso, “s” and “sec” are secondary, “t” and “tert” are tertiary, “c” is cyclo, “o” indicates ortho, “m” indicates meta, and “p” indicates para.
- Halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
- C 1-2 alkyl refers to linear or branched alkyl having 1 to 2 carbon atoms. Examples include methyl and ethyl.
- C 1-3 alkyl means linear or branched alkyl having 1 to 3 carbon atoms. Methyl, ethyl, n-propyl, isopropyl.
- C 1-4 alkyl refers to linear or branched alkyl having 1 to 4 carbon atoms. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.
- C 2-4 alkyl refers to linear or branched alkyl having 2 to 4 carbon atoms. Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. “C 1-6 alkyl” means linear or branched alkyl having 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-amyl, n-hexyl.
- C 1-7 alkyl refers to linear or branched alkyl having 1 to 7 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-amyl, n-hexyl, n-heptyl. “C 1-12 alkyl” refers to linear or branched alkyl having 1 to 12 carbon atoms.
- C 2-6 alkenyl means straight or branched alkenyl having 2 to 6 carbon atoms.
- C 2-6 alkynyl refers to linear or branched alkynyl having 2 to 6 carbon atoms.
- ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, but-3-yn-1-yl, penta-4-yn-1-yl, hex-5-yn- 1-yl can be mentioned.
- HaloC 1-4 alkyl denotes linear or branched alkyl having 1 to 4 carbon atoms which is substituted with a halogen atom.
- the number of substituted halogen atoms is preferably 1 to 5, and the preferred halogen atom is a fluorine atom.
- HaloC 1-6 alkyl refers to linear or branched alkyl having 1 to 6 carbon atoms which is substituted with a halogen atom.
- the number of substituted halogen atoms is preferably 1 to 5, and the preferred halogen atom is a fluorine atom.
- monofluoromethyl, difluoromethyl, trifluoromethyl 1-fluoroethyl, 1,1-difluoroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2,2- pentafluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, 6,6,6-trifluorohexyl.
- C 3-6 cycloalkane denotes a hydrocarbon ring having 3 to 6 carbon atoms. Examples include cyclopropane ring, cyclobutane ring, cyclopentane ring, and cyclohexane ring. Furthermore, the C 3-6 cycloalkane may be bridged with a C 1-3 alkanediyl, such as bicyclo[1.1.1]pentane ring, bicyclo[2.2.1]heptane ring. . “C 3-8 cycloalkane” denotes a hydrocarbon ring having 3 to 8 carbon atoms.
- C 3-8 cycloalkane may be bridged with a C 1-3 alkanediyl, such as bicyclo[1.1.1]pentane ring, bicyclo[2.2.1]heptane ring. .
- C8-10 cycloalkane having a condensed ring structure refers to a hydrocarbon ring having a condensed ring structure having 8 to 10 carbon atoms.
- a bicyclo[4.2.0]octane ring is included.
- C 7-11 cycloalkane having a spiro ring structure refers to a hydrocarbon ring having a spiro-condensed structure having 3 to 8 carbon atoms. Examples thereof include spiro[3.3]heptane ring, spiro[3.5]nonane ring and spiro[4.4]nonane ring.
- C 3-6 cycloalkyl refers to cyclic alkyl having 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
- said C 3-6 cycloalkyl may be bridged with a C 1-3 alkanediyl, eg bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl.
- C 3-8 cycloalkyl refers to cyclic alkyl having 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
- the C 3-8 cycloalkyl may be bridged with a C 1-3 alkanediyl, for example bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl.
- 4- to 6-membered saturated heterocyclic ring means a 4- to 6-membered monocyclic ring consisting of one atom and 3 to 5 carbon atoms selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom represents a saturated heterocyclic ring, wherein in addition to the aforementioned oxygen, sulfur, or nitrogen atoms, it may further contain one atom selected from the group consisting of oxygen, sulfur, and nitrogen atoms; .
- Examples include oxetane ring, tetrahydrofuran ring, tetrahydropyran ring, tetrahydrothiopyran ring, azetidine ring, pyrrolidine ring, piperidine ring, oxazolidine ring, thiazolidine ring, imidazolidine ring, morpholine ring, thiomorpholine ring and piperazine ring.
- the 4- to 8-membered saturated heterocycle may be bridged with C 1-3 alkanediyl, for example, azabicyclo[1.1.1]pentane ring, azabicyclo[2.1.1]hexane ring , azabicyclo[2.2.1]heptane ring, diazabicyclo[2.2.1]heptane ring, diazabicyclo[3.2.1]octane ring, oxa-azabicyclo[3.2.1]octane ring, diazabicyclo[4 .2.1] nonane ring.
- C 1-3 alkanediyl for example, azabicyclo[1.1.1]pentane ring, azabicyclo[2.1.1]hexane ring , azabicyclo[2.2.1]heptane ring, diazabicyclo[3.2.1]octane ring, oxa-azabicyclo[3.2.1]octane ring, diaza
- 4- to 8-membered saturated heterocyclic ring means a 4- to 8-membered monocyclic ring consisting of one atom selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom and 3 to 7 carbon atoms represents a saturated heterocyclic ring, wherein in addition to the aforementioned oxygen, sulfur, or nitrogen atoms, it may further contain one atom selected from the group consisting of oxygen, sulfur, and nitrogen atoms; .
- oxetane ring tetrahydrofuran ring, tetrahydropyran ring, tetrahydrothiopyran ring, azetidine ring, pyrrolidine ring, piperidine ring, azepane ring, oxazolidine ring, thiazolidine ring, imidazolidine ring, morpholine ring, thiomorpholine ring, piperazine ring, diazepane ring.
- the 4- to 8-membered saturated heterocycle may be bridged with C 1-3 alkanediyl, for example, azabicyclo[1.1.1]pentane ring, azabicyclo[2.1.1]hexane ring , azabicyclo[2.2.1]heptane ring, diazabicyclo[2.2.1]heptane ring, diazabicyclo[3.2.1]octane ring, oxa-azabicyclo[3.2.1]octane ring, diazabicyclo[4 .2.1] nonane ring.
- C 1-3 alkanediyl for example, azabicyclo[1.1.1]pentane ring, azabicyclo[2.1.1]hexane ring , azabicyclo[2.2.1]heptane ring, diazabicyclo[3.2.1]octane ring, oxa-azabicyclo[3.2.1]octane ring, diaza
- a 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom refers to a 4- to 8-membered monocyclic saturated heterocyclic ring consisting of one nitrogen atom and 3 to 7 carbon atoms, In addition to the nitrogen atoms described above, it may further contain one atom selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom. Examples include azetidine ring, pyrrolidine ring, piperidine ring, azepane ring, morpholine ring, thiomorpholine ring, piperazine ring and diazepane ring, and other examples include piperazine ring and thiazolidine ring.
- the 4- to 8-membered saturated heterocycle containing a nitrogen atom may be bridged with C 1-3 alkanediyl, for example, azabicyclo[1.1.1]pentane ring, azabicyclo[2.1. 1] hexane ring, azabicyclo[2.2.1]heptane ring, diazabicyclo[2.2.1]heptane ring, diazabicyclo[3.2.1]octane ring, oxa-azabicyclo[3.2.1]octane ring , diazabicyclo[4.2.1]nonane ring, and other examples include azabicyclooctane and diazabicyclooctane.
- 5- to 6-membered saturated heterocyclic ring containing a nitrogen atom refers to a 5- to 6-membered monocyclic saturated heterocyclic ring consisting of one nitrogen atom and 4 to 5 carbon atoms, In addition to the nitrogen atoms described above, it may further contain one atom selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom. Examples include pyrrolidine ring, piperidine ring, morpholine ring, thiomorpholine ring and piperazine ring.
- said 5-6 membered saturated heterocycle containing a nitrogen atom may be bridged with C 1-3 alkanediyl, for example, azabicyclo[2.1.1]hexane ring, azabicyclo[2.2. 1]heptane ring, diazabicyclo[2.2.1]heptane ring, diazabicyclo[3.2.1]octane ring and oxa-azabicyclo[3.2.1]octane ring.
- a saturated heterocyclic ring having an 8- to 10-membered condensed ring structure containing a nitrogen atom means a saturated heterocyclic ring having an 8- to 10-membered condensed ring structure consisting of one nitrogen atom and 7 to 9 carbon atoms. represents a ring, wherein in addition to the aforementioned nitrogen atoms, it may further contain one atom selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom. Examples include azabicyclo[4.2.0]octane ring and diazabicyclo[4.2.0]octane ring.
- a saturated heterocyclic ring having a 7-11 membered spiro ring structure containing a nitrogen atom means a saturated hetero ring having a 7-11 membered spiro ring structure consisting of one nitrogen atom and 6 to 10 carbon atoms. represents a ring, wherein in addition to the aforementioned nitrogen atoms, it may further contain one atom selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom.
- azaspiro[3.3]heptane ring, azaspiro[3.5]nonane ring, azaspiro[4.4]nonane ring, diazaspiro[3.3]heptane ring, diazaspiro[3.5]nonane ring, diazaspiro[4 .4] nonane ring and other examples include azaspiroheptane ring, azaspirononane ring, diazaspiroheptane ring, and diazaspirononane ring.
- "5- to 8-membered saturated heterocyclic ring containing 2 nitrogen atoms” means a 5- to 8-membered monocyclic saturated heterocyclic ring consisting of 2 nitrogen atoms and 3 to 6 carbon atoms. Examples include piperazine ring and diazepane ring. Furthermore, said 5-8 membered saturated heterocycle containing two nitrogen atoms may be bridged with C 1-3 alkanediyl, for example diazabicyclo[2.2.1]heptane ring, diazabicyclo[3 .2.1]octane ring and diazabicyclo[4.2.1]nonane ring.
- “Saturated heterocyclic ring having an 8-10 membered condensed ring structure containing 2 nitrogen atoms” means an 8-10 membered condensed ring structure consisting of 2 nitrogen atoms and 6-8 carbon atoms shows a saturated heterocycle with For example, a diazabicyclo[4.2.0]octane ring is included.
- “Saturated heterocyclic ring having a 7-11 membered spiro ring structure containing 2 nitrogen atoms” means a 7-11 membered spiro ring structure consisting of 2 nitrogen atoms and 5-9 carbon atoms.
- 4- to 8-membered saturated heterocyclyl means a 4- to 8-membered monocyclic ring consisting of one atom selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom and 3 to 7 carbon atoms represents a saturated heterocyclic group, wherein in addition to the oxygen atom, sulfur atom, or nitrogen atom described above, it may further contain one atom selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom. .
- Examples include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, diazepanyl.
- said 4-8 membered saturated heterocyclyl may be bridged with C 1-3 alkanediyl, for example azabicyclo[1.1.1]pentyl, azabicyclo[2.1.1]hexyl, azabicyclo[ 2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, diazabicyclo[3.2.1]octyl, oxa-azabicyclo[3.2.1]octyl, diazabicyclo[4.2.1]nonyl mentioned.
- C 1-3 alkanediyl for example azabicyclo[1.1.1]pentyl, azabicyclo[2.1.1]hexyl, azabicyclo[ 2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, diazabicyclo[3.2.1]octyl, oxa-azabicyclo[3.2.1]octyl, diazabicyclo[4.2.1]nonyl mentioned.
- Aromatic ring means a monocyclic aromatic hydrocarbon ring or condensed polycyclic aromatic hydrocarbon ring having 6 to 14 carbon atoms. Examples thereof include benzene ring, naphthalene ring, anthracene ring and the like.
- Aryl denotes a monocyclic aromatic hydrocarbon group or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. Examples include phenyl, naphthyl, anthryl and the like. "Aryl” also includes partially saturated aryl. Similar considerations apply to aromatic rings.
- Partially saturated aryl and the corresponding aromatic ring “partially saturated aromatic ring” refer to a monocyclic aromatic hydrocarbon group having 6 to 14 carbon atoms or a condensed poly A partially saturated cyclic aromatic hydrocarbon group is shown, as well as rings having such structures. Examples include dihydroindenyl, dihydroindene ring, tetrahydronaphthalenyl, tetrahydronaphthalene ring and the like.
- Heteroaromatic ring means a 5- to 7-membered monocyclic ring consisting of one or more atoms selected identically or differently from the group consisting of oxygen atoms, sulfur atoms and nitrogen atoms and 1 to 6 carbon atoms Condensation composed of 9 to 14 atoms consisting of 1 to 13 carbon atoms with one or more atoms selected the same or different from the group consisting of aromatic heterocycles or oxygen atoms, sulfur atoms and nitrogen atoms Indicates a polycyclic aromatic heterocycle.
- a 5- to 6-membered monocyclic aromatic hetero ring is also called a "5- to 6-membered hetero aromatic ring”.
- Heteroaryl means a 5- to 7-membered monocyclic aromatic ring consisting of one or more atoms selected the same or different from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom and 1 to 6 carbon atoms. a group heterocyclic group or a condensed group consisting of 9 to 14 atoms consisting of 1 to 13 carbon atoms and one or more atoms selected the same or different from the group consisting of oxygen, sulfur and nitrogen atoms Indicates a polycyclic aromatic heterocyclic group.
- Other examples include furanyl, benzothiazolyl.
- Heteroaryl also includes partially saturated heteroaryl. Similar considerations apply to heteroaromatic rings. "Partially saturated heteroaryl” and the corresponding heteroaromatic ring “partially saturated heteroaromatic ring” are the same or different from the group consisting of oxygen, sulfur and nitrogen atoms. and a 5- to 7-membered partially saturated monocyclic heterocyclic group consisting of one or more atoms selected from 1 to 6 carbon atoms, or the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom.
- a partially saturated condensed polycyclic heterocyclic group composed of 9 to 14 atoms consisting of 1 to 13 carbon atoms and one or more atoms selected differently, and such structures shows a ring with
- C 1-4 alkylcarbonyl means a group in which the above “C 1-4 alkyl” and carbonyl are bonded. Methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl. “C 1-6 alkylcarbonyl” means a group in which the aforementioned “C 1-6 alkyl” and carbonyl are bonded.
- Examples include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl.
- “4- to 8-membered saturated heterocyclylcarbonyl” means a group in which the above “4- to 8-membered saturated heterocyclyl” and carbonyl are bonded.
- oxetanylcarbonyl tetrahydrofuranylcarbonyl, tetrahydropyranylcarbonyl, tetrahydrothiopyranylcarbonyl, azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, azepanylcarbonyl, oxazolidinylcarbonyl, thiazolidinyl Carbonyl, imidazolidinylcarbonyl, morpholinylcarbonyl, thiomorpholinylcarbonyl, piperazinylcarbonyl, diazepanylcarbonyl.
- the 4- to 8-membered saturated heterocyclyl may also be bridged with C 1-3 alkanediyl.
- Arylcarbonyl means a group in which the above “aryl” and carbonyl are bonded. Examples include phenylcarbonyl, naphthylcarbonyl, anthrylcarbonyl and the like. Also included in “arylcarbonyl” are partially saturated arylcarbonyls.
- Heteroarylcarbonyl means a group in which the above “heteroaryl” and carbonyl are bonded.
- C 1-4 alkoxy means linear or branched alkoxy having 1 to 4 carbon atoms. Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy. “C 1-6 alkoxy” means linear or branched alkoxy having 1 to 6 carbon atoms. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy.
- HaloC 1-4 alkoxy refers to linear or branched alkoxy having 1 to 4 carbon atoms and substituted with a halogen atom.
- the number of substituted halogen atoms is preferably 1 to 5, and the preferred halogen atom is a fluorine atom.
- HaloC 1-6 alkoxy means straight or branched alkoxy having 1 to 6 carbon atoms and substituted with a halogen atom.
- the number of substituted halogen atoms is preferably 1 to 5, and the preferred halogen atom is a fluorine atom.
- C 2-4 alkenyloxy refers to linear or branched alkenyloxy having 2 to 4 carbon atoms. Examples include allyloxy.
- C 2-6 alkenyloxy means a linear or branched alkenyloxy having 2 to 6 carbon atoms. Examples include allyloxy.
- “4- to 8-membered saturated heterocyclyloxy” means a group in which the above-mentioned “4- to 8-membered saturated heterocyclyl” is bonded to an oxygen atom.
- the 4- to 8-membered saturated heterocyclyloxy may also be bridged with C 1-3 alkanediyl.
- Aryloxy represents a group in which the above "aryl” and an oxygen atom are bonded. Examples include
- C 1-6 alkylsulfanyl refers to a group in which the aforementioned “C 1-6 alkyl” and sulfanyl are bonded. Examples include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, n-pentylsulfanyl, n-hexylsulfanyl.
- C 1-6 alkylsulfinyl refers to a group in which the aforementioned “C 1-6 alkyl” and sulfinyl are bonded. Examples include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, n-pentylsulfinyl, n-hexylsulfinyl.
- C 1-4 alkylsulfonyl represents a group in which the above “C 1-4 alkyl” and sulfonyl are bonded. Methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl. “C 1-6 alkylsulfonyl” means a group in which the above “C 1-6 alkyl” and sulfonyl are bonded.
- Examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, n-hexylsulfonyl.
- “HaloC 1-6 alkylsulfonyl” means a group in which the aforementioned “haloC 1-6 alkyl ” and sulfonyl are bonded.
- Examples include monofluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 1-fluoroethylsulfonyl, 1,1-difluoroethylsulfonyl, 2-fluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl.
- “Mono-C 1-4 alkylamino” means amino having one of the above-mentioned “C 1-4 alkyl” as a substituent. Examples include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino. “Mono-C 1-6 alkylamino” means amino having one of the above-mentioned “C 1-6 alkyl” as a substituent.
- Examples include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino, n-hexylamino.
- “Mono-C 1-12 alkylamino” means amino having one of the aforementioned “C 1-12 alkyl” as a substituent.
- “Mono-C 3-8 cycloalkylamino” means amino having one of the aforementioned “C 3-8 cycloalkyl” as a substituent. Examples include cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino. Additionally, the C 3-8 cycloalkyl of said mono C 3-8 cycloalkylamino may be bridged with a C 1-3 alkanediyl.
- “Mono 4- to 8-membered saturated heterocyclylamino” refers to amino having one of the above-mentioned “4- to 8-membered saturated heterocyclyl” as a substituent.
- the 4- to 8-membered saturated heterocyclyl of the mono 4- to 8-membered saturated heterocyclylamino may be bridged with C 1-3 alkanediyl
- “Monoarylamino” means amino having one of the above-mentioned “aryl” as a substituent. Examples include phenylamino, naphthylamino and anthrylamino. “Monoheteroarylamino” means amino having one of the above-mentioned “heteroaryl” as a substituent.
- “Di-C 1-6 alkylamino” means amino having two identical or different “C 1-6 alkyl” as substituents. Examples include dimethylamino, diethylamino, di(n-propyl)amino, di(isopropyl)amino, ethylmethylamino, methyl(n-propyl)amino.
- “C 3-8 cycloalkyl(C 1-3 alkyl)amino” means amino having the aforementioned “C 3-8 cycloalkyl” and “C 1-3 alkyl” as substituents, respectively.
- Examples include cyclopropyl(methyl)amino, cyclobutyl(methyl)amino, cyclopentyl(methyl)amino and cyclohexyl(methyl)amino.
- the C3-8 cycloalkyl of said C3-8 cycloalkyl( C1-3 alkyl)amino may be bridged with a C1-3 alkanediyl.
- C 1-4 alkoxycarbonyl refers to a group in which the aforementioned “C 1-4 alkoxy” and carbonyl are bonded. Examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl.
- C 1-6 alkoxycarbonyl means a group in which the aforementioned “C 1-6 alkoxy” and carbonyl are bonded.
- Examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl. .
- “HaloC 1-6 alkoxycarbonyl” refers to a group in which the aforementioned “haloC 1-6 alkoxy ” and carbonyl are bonded.
- C 2-6 alkenyloxycarbonyl means a group in which the aforementioned “C 2-6 alkenyloxy” and carbonyl are bonded. Examples include allyloxycarbonyl.
- C 1-4 alkylcarbonylamino means amino having one of the above-mentioned “C 1-4 alkylcarbonyl” as a substituent. Methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, n-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino, tert-butylcarbonylamino. “C 1-6 alkylcarbonylamino” refers to amino having one of the aforementioned “C 1-6 alkylcarbonyl” as a substituent.
- Arylcarbonylamino means amino having one of the above-mentioned "arylcarbonyl” as a substituent. Examples include phenylcarbonylamino, naphthylcarbonylamino, anthrylcarbonylamino and the like.
- arylcarbonylamino also included in “arylcarbonylamino” are partially saturated arylcarbonylamino.
- Heteroarylcarbonylamino means amino having one of the above-mentioned “heteroarylcarbonyl” as a substituent.
- C 1-6 alkylsulfonylaminocarbonyl means a group in which amino and carbonyl having one “C 1-6 alkylsulfonyl” as a substituent are bonded.
- Halo-C 1-6 alkylsulfonylaminocarbonyl means a group in which amino and carbonyl are bonded having one of the above-mentioned “halo-C 1-6 alkylsulfonyl” as a substituent.
- monofluoromethylsulfonylaminocarbonyl difluoromethylsulfonylaminocarbonyl, trifluoromethylsulfonylaminocarbonyl, 1-fluoroethylsulfonylaminocarbonyl, 1,1-difluoroethylsulfonylaminocarbonyl, 2-fluoroethylsulfonylaminocarbonyl, 2, 2,2-trifluoroethylsulfonylaminocarbonyl may be mentioned.
- C 1-6 alkoxycarbonylamino refers to amino having one of the aforementioned “C 1-6 alkoxycarbonyl” as a substituent.
- C 2-6 alkenyloxycarbonylamino means amino having one of the aforementioned “C 2-6 alkenyloxycarbonyl” as a substituent. Examples include allyloxycarbonylamino.
- Saturated heterocyclyl substituted with oxo includes, for example, 2-oxopyrrolidinyl, 2-oxopiperidinyl, 2-oxopiperazinyl, 1,1-dioxidotetrahydrothiophenyl, 1-oxidetetrahydro- 2H-thiopyranyl, 1,1-dioxidetetrahydro-2H-thiopyranyl, 1,1-dioxideisothiazolidinyl, 2-oxo-1,3-oxazolidinyl, 2-oxo-1,3-oxazinanyl.
- Partially saturated heteroaryl substituted with oxo includes, for example, 6-oxo-1,6-dihydropyridinyl, 6-oxo-1,1-dihydropyridazinyl, 2- oxo-1,2-dihydroquinolyl, 2-oxo-1,2-dihydroquinazolyl, 1-oxo-1,2,3,4-tetrahydroisoquinolyl.
- C 1-7 alkanediyl refers to a divalent hydrocarbon group obtained by removing one hydrogen atom from alkyl having 1 to 7 carbon atoms.
- “Straight-chain C 1-2 alkanediyl” refers to a divalent straight-chain hydrocarbon group obtained by removing one hydrogen atom from alkyl having 1 to 2 carbon atoms.
- “Straight-chain C 1-3 alkanediyl” refers to a divalent straight-chain hydrocarbon group obtained by removing one hydrogen atom from alkyl having 1 to 3 carbon atoms. methanediyl, ethane-1,2-diyl, propane-1,3-diyl.
- “Straight-chain C 2-3 alkanediyl” refers to a divalent straight-chain hydrocarbon group obtained by removing one hydrogen atom from alkyl having 2 to 3 carbon atoms. ethane-1,2-diyl, propane-1,3-diyl. “Straight-chain C 1-5 alkanediyl” refers to a divalent straight-chain hydrocarbon group obtained by removing one hydrogen atom from alkyl having 1 to 5 carbon atoms. methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl.
- “Straight-chain C4-5 alkanediyl” refers to a divalent straight-chain hydrocarbon group obtained by removing one hydrogen atom from alkyl having 4 to 5 carbon atoms. butane-1,4-diyl and pentane-1,5-diyl. “Straight-chain C 4-7 alkanediyl” refers to a divalent straight-chain hydrocarbon group obtained by removing one hydrogen atom from alkyl having 4 to 7 carbon atoms. butane-1,4-diyl, pentane-1,5-diyl, n-hexane-1,6-diyl, heptane-1,7-diyl.
- C 3-6 alkanediyl refers to a divalent hydrocarbon group obtained by removing one hydrogen atom from alkyl having 3 to 6 carbon atoms.
- One preferred embodiment of the compound of the present invention is as follows. A compound represented by the formula [I] or a pharmaceutically acceptable salt thereof,
- Preferred ring A is benzene, pyridine, or dihydrobenzofuran, more preferred ring A is benzene or pyridine, A more preferred ring A is benzene.
- Preferred ring A is benzene, pyridine, or dihydrobenzofuran, more preferred ring A is benzene or pyridine, A more preferred ring A is benzene.
- R A1 , R A2 and R A3 are as follows.
- Preferred R A1 , R A2 and R A3 are independently hydrogen atom, carbamoyl, cyano, nitro, halogen atom, C 1-6 alkyl, haloC 1-6 alkyl, phenyl (the phenyl may be substituted with one halogen atom), phenylcarbonylamino (phenyl of said phenylcarbonylamino may be substituted with one group selected from the group consisting of carbamoyl and halogen atoms), C 1-6 alkoxy, haloC 1-6 alkoxy, or di-C 1-6 alkylamino;
- R A1 and R A2 are independently hydrogen atom, halogen atom, C 1-6 alkyl, haloC 1-6 alkyl, phenylcarbonylamino (phenyl of said phenylcarbonylamino may be substituted with one group selected from the group consist
- R A3 is a hydrogen atom
- one particularly preferred R A1 , R A2 is independently hydrogen atom, fluorine atom, chlorine atom, methyl, difluoromethyl, trifluoromethyl, or phenylcarbonylamino (the phenyl of said phenylcarbonylamino is substituted with one carbamoyl).
- R A3 is a hydrogen atom
- other particularly preferable R A1 and R A2 are represented by the following formula [IA-1] in the above formula [I]
- R A3 is a hydrogen atom.
- R A1 , R A2 and R A3 are as follows.
- Preferred R A1 , R A2 and R A3 are independently hydrogen atom, carbamoyl, cyano, nitro, halogen atom, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, or di-C 1-6 alkylamino;
- more preferable R A1 and R A2 are independently hydrogen atom, halogen atom, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, or di-C 1-6 alkylamino;
- R A3 is a hydrogen atom
- Further preferred R A1 and R A2 are independently hydrogen atom, fluorine atom, chlorine atom, bromine atom, methyl, monofluoromethyl, difluoromethyl, or trifluoromethyl, At this time, R A3 is a hydrogen atom
- R A3 is a hydrogen atom.
- a preferred ZBG is Carboxy, a group represented by the formula -CO-NH-OH, C 1-6 alkoxycarbonyl, C 2-6 alkenyloxycarbonyl, C 1-6 alkylaminocarbonyl (C 1-6 alkyl of said C 1-6 alkylaminocarbonyl may be substituted with one hydroxy), haloC 1-6 alkylaminocarbonyl, or C 1- 6 alkylsulfonylaminocarbonyl,
- a more preferred ZBG is Carboxy, a group represented by the formula -CO-NH-OH, C 1-6 alkoxycarbonyl, C 2-6 alkenyloxycarbonyl, C 1-6 alkylaminocarbonyl (C 1-6 alkyl of said C 1-6 alkylaminocarbonyl may be substituted with one hydroxy), or haloC 1-6 alkylaminocarbonyl;
- a more preferred ZBG is carboxy or a group represented by the formula -CO-NH-OH, A particularly preferred
- a preferred R ZBG is a hydrogen atom or methyl
- a more preferred R ZBG is a hydrogen atom.
- R N1 is a hydrogen atom or C 1-2 alkyl, or together with the adjacent structure represented by the formula -N-C-L 1 -, the following formula [II-1]
- Ring B 11 is pyrrolidine
- R N2 is a hydrogen atom
- AA r1 is as described later.
- R N1 is a hydrogen atom or methyl, or together with the adjacent structure represented by the formula -N-C-L 1 -, the following formula [II-1-1a]
- AA r1 is as described later.
- RN1 is It is a hydrogen atom.
- L 1 are (ii-1) a structure represented by the formula -L 15 -NR N2 -AA r1 - or (ii-2) a structure represented by the formula -L 16 -NR N2 -, and at this time, One more preferred L 1 is (ii-1) a structure represented by the formula -L 15 -NR N2 -AA r1 -, Other more preferred L 1 is (ii-2) A structure represented by the formula -L 16 -NR N2 -.
- Preferred L 11 is a chain C 1-3 alkanediyl, more preferred L 11 is methanediyl or ethane-1,2-diyl, more preferred L 11 is ethane-1,2-diyl,
- Preferred L 12 is a chain C 4-5 alkanediyl, a structure represented by the formula -L 12a -OL 12b -, a structure represented by the formula -L 12a -NR N4 -L 12b -, or the following Formula [II-2]
- Ring B 21 is a triazole
- L 12c and L 12d are independently a chain C 1-2 alkanediyl.
- L 12a and L 12b are independently a chain C 1-3 alkanediyl
- R N4 is C 1-3 alkyl
- More preferred L 12 is a chain C 4-5 alkanediyl, a structure represented by the formula -L 12a -NR N4 -L 12b -, or the following formula [II-2]
- Ring B 21 is a triazole
- L 12c and L 12d are independently a chain C 1-2 alkanediyl.
- L 12a and L 12b are independently a chain C 1-3 alkanediyl
- R N4 is C 1-3 alkyl
- More preferred L 12 is n-butane-1,4-diyl, n-pentane-1,5-diyl, a structure represented by the formula -(CH 2 )-N(CH 3 )-(CH 2 ) 3 - , a structure represented by the formula -(CH 2 ) 2 -N(CH 3 )-(CH 2 )-, a structure represented by the formula -(CH 2 ) 2 -N(CH 3 )-(CH 2 )-, a structure represented by the formula -(CH 2 ) 2 -N(CH 3 )-(CH 2 ) 2 - structure, a structure represented by the formula -(CH 2 ) 3 -N
- L 12 is n-pentane-1,5-diyl or the following formula [II-2-1]
- Preferred L 13 is a chain C 1-5 alkanediyl, a structure represented by the formula -L 13a -OL 13b -, a structure represented by the formula -L 13a -NR N4 -L 13b -, or the following Formula [II-3]
- Ring B 22 is pyrrolidine
- L 13c and L 13d are independently a chain C 1-2 alkanediyl.
- L 13a is a chain C 1-3 alkanediyl
- L 13b is a chain C 2-3 alkanediyl
- R N4 is C 1-3 alkyl
- More preferred L 13 is a chain C 1-5 alkanediyl, a structure represented by the formula -L 13a -OL 13b -, or the following formula [II-3-1]
- Ring B 22 is pyrrolidine
- L 13c and L 13d are independently a chain C 1-2 alkanediyl.
- L 13a is a chain C 1-3 alkanediyl
- L 13b is a chain C 2-3 alkanediyl
- More preferred L 13 is ethane-1,2-diyl, n-propane-1,3-diyl, n-butane-1,4-diyl, of the formula -( CH2 )-O-( CH2 ) 2- represented structure, or the following formula [II-3-1]
- L 13 is n-butane-1,4-diyl
- Preferred L 14 is a chain C 1-3 alkanediyl, more preferred L 14 is ethane-1,2-diyl,
- Preferred L 15 is a chain C 1-3 alkanediyl, More preferred L 15 is methanediyl, ethane-1,2-diyl, or n-propane-1,3-diyl.
- a preferred L 16 is a chain C 4-5 alkanediyl, A more preferred L 16 is n-butane-1,4-diyl.
- a preferred Z is (i) a group represented by the formula -R Z , (ii) a group represented by the formula -Y 5 -R Z , (iii) a group represented by the formula -Y 5 -Y 6 -R Z , or (iv) a group represented by the formula -Y 5 -Y 6 -Y 7 -R Z ,
- a preferred group represented by the formula -Y 2 -Y 3 -Y 4 -Z is (i-1) a group represented by the formula -AA 2 -AA 3 -AA 4 -ZC , (i-2) a group represented by the formula -AA 2 -AA 3 -W 4 -R ZN ; (i-3) a group represented by the formula -AA 2 -AA 3 -R ZC (at this time, Y 4 represents a single bond); (i-4) a group represented by the formula -AA 2 -W 3 -R ZN (at this time, Y 4 represents a single bond), or (i-5) a group represented by the formula -AA 2 -R ZC (At this time, Y 3 and Y 4 represent a single bond.) and A more preferred group represented by the formula -Y 2 -Y 3 -Y 4 -Z is (i-1) a group represented by the formula -AA 2 -AA 3 -AA 4 -ZC , (
- a preferred ZC is (i-1) a group represented by the formula -R ZC , (ii-1) a group represented by the formula -AA 5 -R ZC , (ii-2) a group represented by the formula -W 5 -R ZN , (iii-1) a group represented by the formula -AA 5 -AA 6 -R ZC , or (iv-1) a group represented by the formula -AA 5 -AA 6 -AA 7 -R ZC ,
- One more preferred Z C is (i-1) a group represented by the formula -R ZC
- Other more preferred Z C are (ii-1) a group represented by the formula -AA 5 -R ZC , (ii-2) a group represented by the formula -W 5 -R ZN , (iii-1) a group represented by the formula -AA 5 -AA 6 -R ZC , or (iv-1) a group represented by the formula -AA 5 -
- a preferred ZN is (v-1) a group represented by the formula -R ZN or (vi- 2 ) a group represented by the formula -V -R ZC
- One more preferred ZN is (v-1) a group represented by the formula -R ZN
- Other more preferred ZN are (vi-2) a group represented by the formula -V 5 -R ZC
- Ring B 31 is C 3-8 cycloalkane, oxetane, or piperidine; L AAa and L AAb are independently a single bond or a chain C 1-2 alkanediyl.
- Ring B 32 is C 3-8 cycloalkane, pyrrolidine, benzene, thiazole, or pyridine;
- the C 3-8 cycloalkane may be bridged by a C 1-3 alkanediyl, the benzene may be substituted with one halogen atom, L AAa and L AAb are independently single-bonded or linear C 1-2 alkanediyl, However, L AAa and L AAb do not simultaneously represent chain C 1-2 alkanediylmethane.
- ring B 33 is piperidine, azepane (the azepane may be substituted with one oxo), or dihydropyridine (the dihydropyridine may be substituted with one oxo);
- L AAc is a chain C 1-2 alkanediyl.
- R NAAa represents a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl;
- (iii) In the aminocarboxylic acid linker represented by formula [III-4], The linker is
- Ring B 34 is azetidine, pyrrolidine, thiazolidine, piperidine, piperazine, morpholine, indoline, isoindoline, or tetrahydroisoquinoline;
- the azetidine, pyrrolidine may be substituted with one group selected from the group consisting of hydroxy, amino and phenyl, L AAbs are single-bonded or chained C 1-2 alkanediyls.
- AA X is a structure represented by here, Two adjacent AA X (where X represents an integer of 1 to 7) together selected from the group consisting of aminocarboxylic acid linkers represented by the following formulas [IV-1] to [IV-6], [IV-8] to [IV-9], [IV-11] to [IV-13]; may form a single structure that The aminocarboxylic acid linkers represented by the formulas [IV-1] to [IV-6], [IV-8] to [IV-9], [IV-11] to [IV-13] are each represented by the following Formula [IV-1] below
- L AAb is a linear C 4-7 alkanediyl (the linear C 4-7 alkanediyl may be substituted with one amino);
- R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl.
- an aminocarboxylic acid linker represented by Formula [IV-2] below
- Q 1 is a structure represented by the formula -O-, n 1 is an integer of 1 to 3, R NAAa and R NAAb are independently a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl.
- an aminocarboxylic acid linker represented by The following formula [IV-3]
- L AAd is a chain C 2-3 alkanediyl (the chain C 2-3 alkanediyl is substituted with one group selected from the group consisting of hydroxy, amino, C 1-4 alkyl, and benzyl may be used.) and R AAb ' is C 1-4 alkyl substituted with thiazolyl, R AAb ' is a hydrogen atom or methyl, R NAAa and R NAAb are independently a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl.
- an aminocarboxylic acid linker represented by Formula [IV-4] below
- Ring B 41 is benzene, the benzene may be substituted with one halogen atom
- L AAe is a chain C 2-3 alkanediyl (the chain C 2-3 alkanediyl may be substituted with one group selected from the group consisting of hydroxy and C 1-4 alkyl;
- Q 2 is a structure represented by the formula -O- or the formula -NR N5 -;
- R N5 is a hydrogen atom or C 1-3 alkyl,
- R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl.
- an aminocarboxylic acid linker represented by Formula [IV-5] below
- Ring B 41 is benzene or pyridine (the benzene and pyridine may be substituted with one halogen atom)
- Ring B 42 is pyrrolidine, piperidine, or azaspiroheptane;
- the pyrrolidine, piperidine and azaspiroheptane may be substituted with one group selected from the group consisting of halogen atoms and C1-4 alkyl
- L AAf is a single bond or chain C 1-3 alkanediyl (the chain C 1-3 alkanediyl is one selected from the group consisting of hydroxy, amino, C 1-4 alkyl, and benzyl may be substituted with a group), preferably chain C 1-3 alkanediyl (the chain C 1-3 alkanediyl is from hydroxy, amino, C 1-4 alkyl, and benzyl may be substituted with one group selected from the group consisting of Q 2 is a structure represented by the formula -O-
- Ring B 41 is benzene or pyridine (the benzene and pyridine may be substituted with one halogen atom)
- Ring B 44 is piperazine (which piperazine may be bridged by a C 1-3 alkanediyl), diazepane, diazabicyclooctane, or diazaspiroheptane;
- the piperazine, diazepane, diazabicyclooctane, diazaspiroheptane and diazaspirononane may be substituted with one group selected from the group consisting of halogen atoms and C 1-4 alkyl.
- an aminocarboxylic acid linker represented by Formula [IV-9] below
- Ring B 45 is C 3-8 cycloalkane, piperidine, benzene, or pyridine;
- L AAa and L AAb are independently a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl);
- R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl.
- an aminocarboxylic acid linker represented by Formula [IV-11] below
- Ring B 47 is piperidine
- L AAb is a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl)
- L AAe is a chain C 2-3 alkanediyl (the chain C 2-3 alkanediyl may be substituted with one group selected from the group consisting of hydroxy and benzyl)
- R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl.
- an aminocarboxylic acid linker represented by The following formula [IV-12]
- Ring B 48 is piperazine, L AAb is a single bond or a chain C 1-2 alkanediyl (the chain C 1-2 alkanediyl may be substituted with one methyl); L AAe is a chain C 2-3 alkanediyl (the chain C 2-3 alkanediyl is substituted with one group selected from the group consisting of hydroxy, amino, C 1-4 alkyl, and benzyl may be used.) and R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl. ) and an aminocarboxylic acid linker represented by the following formula [IV-13]
- R AAa′′ is C 1-6 alkyl; RAAb'' is a hydrogen atom, R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl.
- R AAa′′ is C 1-6 alkyl; RAAb'' is a hydrogen atom, R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl.
- adjacent Z C and AA X are combined to form [IV-14] or [IV-15] below.
- R AAa''' is C 1-4 alkyl substituted with 1 amino
- RAAb''' is a hydrogen atom
- R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl
- Ring B 49 is pyrrolidine
- RAAa''' and RAAb''' are the same as those in formula [IV-14] above.
- Z and AA X together with the structure existing between them, are represented by the following formula [IV-16]
- RAAa'''' is C1-4alkyl substituted with pyridyl
- L Z-AAxa is a chain C 1-6 alkanediyl
- L Z-AAxa is a chain C 1-6 alkanediyl.
- n-butyl substituted with methyl methylamino (methyl of said methylamino may be substituted with one azetidinyl), methylamino (methyl of said methylamino may be substituted with one pyrrolidinyl) n-butyl substituted with ), methyl substituted with isopropylamino, piperidinylamino (piperidinyl of said piperidinylamino may be substituted with one methyl).
- R AAb is a hydrogen atom or methyl
- RNAAa is a hydrogen atom or methyl, ethyl substituted with amino, ethyl substituted with phenyl, propyl substituted with phenyl, or butyl substituted with phenyl;
- Ring B 31 is cyclopropane, cyclobutane, cyclopentane, oxetane, or piperidine; LAAa and LAAb are independently a single bond or methanediyl.
- Ring B 32 is cyclobutane, cyclopentane, cyclohexane, pyrrolidine, benzene, thiazole, or pyridine;
- the cyclobutane may be bridged by a C 1-3 alkanediyl, the benzene optionally substituted with one chlorine atom, L AAa and L AAb are independently a single bond or methanediyl; However, LAAa and LAAb never show methanediyl at the same time.
- ring B 33 is piperidine, azepane, dihydropyridine (the azepane may be substituted with one oxo), or dihydropyridine (the dihydropyridine may be substituted with one oxo);
- L AAc is methanediyl.
- RNAAa is a hydrogen atom or methyl, ethyl substituted with amino, ethyl substituted with phenyl, propyl substituted with phenyl, or butyl substituted with phenyl;
- the linker is
- Ring B 34 is azetidine, pyrrolidine, thiazolidine, piperidine, piperazine, morpholine, indoline, isoindoline, or tetrahydroisoquinoline;
- the azetidine, pyrrolidine may be substituted with one group selected from the group consisting of hydroxy, amino and phenyl, the piperidine is optionally substituted with one amino, L AAb is a single bond or methanediyl.
- An aminocarboxylic acid linker formed by two AA X (where X is an integer of 1 to 7) together, adjacent Z C and AA X (where X is an integer of 1 to 7).
- L AAbs are n-butane-1,4-diyl, n-pentane-1,5-diyl (the n-butane-1,4-diyl, n-pentane-1,5-diyl are ), or n-hexane-1,6-diyl, RNAAa is a hydrogen atom.
- RNAAa is a hydrogen atom.
- Ring B 41 is benzene or pyridine, the benzene may be optionally substituted with one chlorine atom, Ring B 42 is pyrrolidine or piperidine, The pyrrolidine may be substituted with one group selected from the group consisting of a fluorine atom and methyl, L AAf is a single bond or methanediyl, Q 2 is a structure represented by the formula -NR N5 -, RN5 is a hydrogen atom.
- AA X (where X represents an integer of 1 to 7) together selected from the group consisting of aminocarboxylic acid linkers represented by the following formulas [IV-1] to [IV-6], [IV-8] to [IV-9], [IV-11] to [IV-13]; may form a single structure that The aminocarboxylic acid linkers represented by the formulas [IV-1] to [IV-6], [IV-8] to [IV-9], [IV-11] to [IV-13] are each represented by the following Formula [IV-1] below
- L AAbs are n-butane-1,4-diyl, n-pentane-1,5-diyl (the n-butane-1,4-diyl, n-pentane-1,5-diyl are ), n-hexane-1,6-diyl, RNAAa is a hydrogen atom.
- an aminocarboxylic acid linker represented by Formulas [IV-2-1] to [IV-2-2] below
- aminocarboxylic acid linker represented by Formulas [IV-4-1] to [IV-4-3] below
- aminocarboxylic acid linker represented by Formulas [IV-6-1] to [IV-6-4] below
- aminocarboxylic acid linker represented by Formulas [IV-11-1] to [IV-11-2] below
- Ring B 31 is piperidine, LAAa and LAAb are identically a single bond.
- Ring B 32 is cyclobutane, cyclopentane, or benzene; LAAa and LAAb are independently a single bond or methanediyl.
- RNAAa is a hydrogen atom or methyl
- aminocarboxylic acid linker represented by formula [III-4] The linker is
- Ring B 34 is pyrrolidine or piperidine, The pyrrolidine and piperidine may be substituted with one amino, L AAb is a single bond or methanediyl.
- L AAb is a single bond or methanediyl.
- RNAAa is a hydrogen atom or methyl
- linker is
- One preferred configuration is
- aminocarboxylic acid linker represented by (iii) formula [III-4] above represented by One preferred configuration is
- Ring B 31 is a C 3-8 cycloalkane, LAAa and LAAb are identically a single bond.
- Ring B 32 is benzene, LAAa and LAAb are identically a single bond.
- R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl;
- R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl;
- the linker is
- Ring B 34 is pyrrolidine, L AAbs are single-bonded or chained C 1-2 alkanediyls.
- L AAbs are single-bonded or chained C 1-2 alkanediyls.
- Adjacent AA 1 and AA 2 together An aminocarboxylic acid linker represented by the following formula [IV-1] may be formed, where the linker is
- L AAbs are linear C4-7 alkanediyls
- RNAAa is a hydrogen atom.
- Ring B 31 is cyclopropane or cyclopentane, LAAa and LAAb are identically a single bond.
- Ring B 32 is benzene, LAAa and LAAb are identically a single bond.
- RNAAa is a hydrogen atom, methyl, ethyl substituted with amino, ethyl substituted with phenyl, propyl substituted with phenyl, or butyl substituted with phenyl;
- iii In the aminocarboxylic acid linker represented by formula [III-4], The linker is
- Ring B 34 is pyrrolidine, L AAb is a single bond or methanediyl.
- L AAb is a single bond or methanediyl.
- Adjacent AA 1 and AA 2 together An aminocarboxylic acid linker represented by the following formula [IV-1] may be formed, where the linker is
- Ring B 31 is cyclopropane, cyclobutane, cyclopentane, oxetane, or piperidine; LAAa and LAAb are independently a single bond or methanediyl.
- Ring B 32 is cyclobutane, cyclopentane, cyclohexane, pyrrolidine, benzene, thiazole, or pyridine;
- the cyclobutane may be bridged by a C 1-3 alkanediyl, the benzene may be optionally substituted with one chlorine atom, L AAa and L AAb are independently a single bond or methanediyl; However, LAAa and LAAb never show methanediyl at the same time.
- ring B 33 is piperidine, azepane, dihydropyridine (the azepane may be substituted with one oxo), or dihydropyridine (the dihydropyridine may be substituted with one oxo);
- L AAc is methanediyl.
- RNAAa is a hydrogen atom or methyl, ethyl substituted with amino, ethyl substituted with phenyl, propyl substituted with phenyl, or butyl substituted with phenyl;
- the linker is
- Ring B 34 is azetidine, pyrrolidine, thiazolidine, piperidine, piperazine, morpholine, indoline, isoindoline, or tetrahydroisoquinoline;
- the azetidine, pyrrolidine may be substituted with one group selected from the group consisting of hydroxy and phenyl, the piperidine is optionally substituted with one amino, L AAb is a single bond or methanediyl.
- Ring B 31 is a C 3-8 cycloalkane, LAAa and LAAb are identically a single bond.
- Ring B 32 is benzene, LAAa and LAAb are identically a single bond.
- R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl;
- R NAAa is a hydrogen atom, C 1-2 alkyl, C 2-4 alkyl substituted with amino, or C 1-4 alkyl substituted with phenyl;
- the linker is
- Ring B 34 is pyrrolidine, L AAbs are single-bonded or chained C 1-2 alkanediyls.
- L AAbs are single-bonded or chained C 1-2 alkanediyls.
- Adjacent AA 1 and AA 2 together An aminocarboxylic acid linker represented by the following formula [IV-1] may be formed, where the linker is
- L AAbs are linear C4-7 alkanediyls
- RNAAa is a hydrogen atom.
- Ring B 31 is cyclopropane or cyclopentane, LAAa and LAAb are identically a single bond.
- Ring B 32 is benzene, LAAa and LAAb are identically a single bond.
- RNAAa is a hydrogen atom, methyl, ethyl substituted with amino, ethyl substituted with phenyl, propyl substituted with phenyl, or butyl substituted with phenyl;
- iii In the aminocarboxylic acid linker represented by formula [III-4], The linker is
- Ring B 34 is pyrrolidine, L AAb is a single bond or methanediyl.
- L AAb is a single bond or methanediyl.
- Adjacent AA 1 and AA 2 together An aminocarboxylic acid linker represented by the following formula [IV-1] may be formed, where the linker is
- One preferred configuration is
- RAAa is hydrogen atom, C 1-6 alkyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 1-4 alkyl substituted with C 3-8 cycloalkyl, C 1-4 alkyl substituted with piperidinyl, phenyl (the phenyl is hydroxy, amino, cyano, nitro, halogen atom, C 1-4 alkyl, haloC 1-4 alkyl, C
- R AAb is a hydrogen atom
- RNAAa is a hydrogen atom or C 1-2 alkyl
- LAAa is Chain C 2-3 alkanediyl (the chain C 2-3 alkane
- Ring B 32 is benzene, LAAa and LAAb are identically a single bond.
- RNAAa is a hydrogen atom or C 1-2 alkyl
- RAAa is hydrogen atom, methyl, isopropyl, isobutyl, tert-butyl, isopentyl, tert-amyl, propargyl, cyclohexy
- Ring B 32 is benzene, LAAa and LAAb are identically a single bond.
- RNAAa is a hydrogen atom or methyl
- One preferred configuration is
- Ring B 31 is C 3-8 cycloalkane or piperidine; LAAa and LAAb are identically a single bond.
- ring B 32 is benzene or thiazole; the benzene may be substituted with one halogen atom, L AAa and L AAb are independently single-bonded or linear C 1-2 alkanediyl, However, LAAa and LAAb are not chained C 1-2 alkanediyl at the same time. ), or the following formula [III-3]
- Ring B 33 is an azepane (the azepane may be substituted with one oxo) and L AAc is a C 1-2 alkanediyl chain.
- R NAAa is a hydrogen atom, C 1-2 alkyl, or C 1-4 alkyl substituted with phenyl;
- the linker is
- Ring B 34 is pyrrolidine, thiazolidine, piperidine, piperazine, or morpholine; L AAbs are single-bonded or chained C 1-2 alkanediyls.
- Ring B 31 is cyclopropane, cyclobutane, cyclopentane, or piperidine; LAAa and LAAb are identically a single bond.
- ring B 32 is benzene or thiazole; the benzene may be optionally substituted with one chlorine atom, L AAa and L AAb are independently a single bond or methanediyl; However, LAAa and LAAb are not methanediyl at the same time. ) or a structure represented by the following formula [III-3]
- Ring B 33 is azepane (the azepane may be substituted with one oxo); L AAc is methanediyl.
- RNAAa is a hydrogen atom, methyl, ethyl substituted with phenyl, propyl substituted with phenyl, or butyl substituted with phenyl;
- iii In the aminocarboxylic acid linker represented by formula [III-4], The linker is
- Ring B 34 is pyrrolidine, thiazolidine, piperidine, piperazine, or morpholine; L AAb is a single bond or methanediyl.
- n-butyl substituted with methyl methylamino (methyl of said methylamino may be substituted with one azetidinyl), methylamino (methyl of said methylamino may be substituted with one pyrrolidinyl) n-butyl substituted with ), methyl substituted with isopropylamino, piperidinylamino (piperidinyl of said piperidinylamino may be substituted with one methyl).
- R AAb is a hydrogen atom or methyl;
- RNAAa is a hydrogen atom or methyl, ethyl substituted with amino, ethyl substituted with phenyl, propyl substituted with phenyl, or butyl substituted with phenyl;
- LAAa is ethane-1,2-diyl (the ethane-1,2-diyl may be substituted with 1 methyl (the methyl may be substituted with
- Ring B 31 is cyclopropane, cyclobutane, cyclopentane, oxetane, or piperidine; LAAa and LAAb are independently a single bond or methanediyl.
- Ring B 32 is cyclobutane, cyclopentane, cyclohexane, pyrrolidine, benzene, thiazole, or pyridine;
- the cyclobutane may be bridged by a C 1-3 alkanediyl, the benzene may be optionally substituted with one chlorine atom, L AAa and L AAb are independently a single bond or methanediyl; However, LAAa and LAAb never show methanediyl at the same time.
- ring B 33 is piperidine, azepane, dihydropyridine (the azepane may be substituted with one oxo), or dihydropyridine (the dihydropyridine may be substituted with one oxo);
- L AAc is methanediyl.
- RNAAa is a hydrogen atom or methyl, ethyl substituted with amino, ethyl substituted with phenyl, propyl substituted with phenyl, or butyl substituted with phenyl;
- the linker is
- Ring B 34 is azetidine, pyrrolidine, thiazolidine, piperidine, piperazine, morpholine, indoline, isoindoline, or tetrahydroisoquinoline;
- the azetidine, pyrrolidine may be substituted with one group selected from the group consisting of hydroxy, amino and phenyl, the piperidine is optionally substituted with one amino, L AAb is a single bond or methanediyl.
- Ring B 31 is C 3-8 cycloalkane or piperidine; LAAa and LAAb are identically a single bond.
- ring B 32 is benzene or thiazole; the benzene may be substituted with one halogen atom, L AAa and L AAb are independently single-bonded or linear C 1-2 alkanediyl, However, LAAa and LAAb are not chained C 1-2 alkanediyl at the same time.
- Ring B 33 is azepane (the azepane may be substituted with one oxo);
- L AAc is a chain C 1-2 alkanediyl.
- R NAAa is a hydrogen atom, C 1-2 alkyl, or C 1-4 alkyl substituted with phenyl;
- Ring B 34 is pyrrolidine, thiazolidine, piperidine, piperazine, or morpholine; L AAbs are single-bonded or chained C 1-2 alkanediyls.
- Ring B 31 is cyclopropane, cyclobutane, cyclopentane, or piperidine; LAAa and LAAb are identically a single bond.
- ring B 32 is benzene or thiazole; the benzene may be optionally substituted with one chlorine atom, L AAa and L AAb are independently a single bond or methanediyl; However, LAAa and LAAb are not methanediyl at the same time. ) or a structure represented by the following formula [III-3]
- Ring B 33 is azepane (the azepane may be substituted with one oxo); L AAc is methanediyl.
- RNAAa is a hydrogen atom, methyl, ethyl substituted with phenyl, propyl substituted with phenyl, or butyl substituted with phenyl;
- iii In the aminocarboxylic acid linker represented by formula [III-4], The linker is
- Ring B 34 is pyrrolidine, thiazolidine, piperidine, piperazine, or morpholine; L AAb is a single bond or methanediyl.
- One preferred configuration is
- Ring B 31 is oxetane, L AAa and L AAb are independently a single bond or a chain C 1-2 alkanediyl.
- Ring B 32 is C 3-8 cycloalkane, pyrrolidine, benzene, or pyridine;
- the C 3-8 cycloalkane may be bridged by a C 1-3 alkanediyl, the benzene may be substituted with one halogen atom,
- L AAa and L AAb are independently single-bonded or linear C 1-2 alkanediyl, However, L AAa and L AAb do not simultaneously represent chain C 1-2 alkanediylmethane.
- ring B 33 is piperidine, azepane, dihydropyridine (the azepane may be substituted with one oxo), or dihydropyridine (the dihydropyridine may be substituted with one oxo);
- L AAc is a chain C 1-2 alkanediyl.
- RNAAa is a hydrogen atom or C 1-2 alkyl,
- aminocarboxylic acid linker represented by formula [III-4] The linker is
- Ring B 34 is azetidine, pyrrolidine, thiazolidine, piperidine, piperazine, morpholine, indoline, isoindoline, or tetrahydroisoquinoline;
- the azetidine, pyrrolidine may be substituted with one group selected from the group consisting of hydroxy, amino and phenyl, L AAbs are single-bonded or chained C 1-2 alkanediyls.
- Adjacent AA 4 and AA 5 together, Formula [IV-1] below
- L AAb is a linear C 4-7 alkanediyl (the linear C 4-7 alkanediyl may be substituted with one amino);
- RNAAa is a hydrogen atom or C 1-2 alkyl.
- Ring B 41 is benzene or pyridine, the benzene or pyridine may be substituted with one halogen atom
- Ring B 42 is pyrrolidine or piperidine
- the pyrrolidine and piperidine may be substituted with one group selected from the group consisting of halogen atoms and C 1-4 alkyl
- L AAf is single-bonded or chained C 1-3 alkanediyl
- Q 2 is a structure represented by the formula -NR N5 -
- RN5 is a hydrogen atom.
- Ring B 31 is oxetane, LAAa and LAAb are independently a single bond or methanediyl.
- Ring B 32 is cyclobutane, cyclopentane, cyclohexane, pyrrolidine, benzene, or pyridine;
- the cyclobutane may be bridged by a C 1-3 alkanediyl, the benzene may be optionally substituted with one chlorine atom, L AAa and L AAb are independently a single bond or methanediyl; However, LAAa and LAAb never show methanediyl at the same time.
- ring B 33 is piperidine, azepane, dihydropyridine (the azepane may be substituted with one oxo), or dihydropyridine (the dihydropyridine may be substituted with one oxo);
- L AAc is methanediyl.
- RNAAa is a hydrogen atom or methyl
- aminocarboxylic acid linker represented by formula [III-4] The linker is
- Ring B 34 is azetidine, pyrrolidine, thiazolidine, piperidine, piperazine, morpholine, indoline, isoindoline, or tetrahydroisoquinoline;
- the azetidine, pyrrolidine may be substituted with one group selected from the group consisting of hydroxy, amino and phenyl, L AAb is a single bond or methanediyl.
- Adjacent AA 4 and AA 5 are together represented by the following formula [IV-1]
- L AAbs are n-butane-1,4-diyl, n-pentane-1,5-diyl (the n-butane-1,4-diyl, n-pentane-1,5-diyl are ), or n-hexane-1,6-diyl, RNAAa is a hydrogen atom or methyl.
- RNAAa is a hydrogen atom or methyl.
- Adjacent AA 3 and AA 4 together are represented by the following formula [IV-6]
- Ring B 41 is benzene or pyridine, the benzene may be optionally substituted with one chlorine atom, Ring B 42 is pyrrolidine or piperidine, The pyrrolidine may be substituted with one group selected from the group consisting of a fluorine atom and methyl, L AAf is a single bond or methanediyl, Q 2 is a structure represented by the formula -NR N5 -, RN5 is a hydrogen atom.
- LAAa is Formula [III-2] below
- Ring B 32 is cyclobutane, cyclopentane, or benzene; L AAa and L AAb are independently a single bond or methanediyl; However, LAAa and LAAb never show methanediyl at the same time.
- Ring B 32 is cyclobutane, cyclopentane, or benzene; L AAa and L AAb are independently a single bond or methanediyl; However, LAAa and LAAb never show methanediyl at the same time.
- the linker is a structure represented by (iii) In the aminocarboxylic acid linker represented by formula [III-4], The linker is
- Ring B 34 is pyrrolidine, L AAb is a single bond or methanediyl.
- L AAb is a single bond or methanediyl.
- Adjacent AA 3 and AA 4 together is a structure represented by here, Adjacent AA 3 and AA 4 together, The following formula [IV-6-1]
- L Aaa is the following formula [III-2-2a] or [III-2-3]
- RNAAa is a hydrogen atom
- One preferred configuration is
- aminocarboxylic acid linker represented by (iii) formula [III-4] above represented by One preferred configuration is
- Ring B 31 is piperidine, LAAa and LAAb are identically a single bond.
- the linker is
- Ring B 34 is pyrrolidine or piperidine, The pyrrolidine and piperidine may be substituted with one amino, L AAbs are single-bonded or chained C 1-2 alkanediyls.
- Ring B 31 is piperidine, LAAa and LAAb are identically a single bond.
- the linker is
- Ring B 34 is pyrrolidine or piperidine, The pyrrolidine and piperidine may be substituted with one amino, L AAb is a single bond or methanediyl.
- Ring B 31 is piperidine, LAAa and LAAb are identically a single bond.
- ) is a structure represented by (iii) In the aminocarboxylic acid linker represented by formula [III-4], The linker is
- Ring B 34 is pyrrolidine or piperidine, The pyrrolidine and piperidine may be substituted with one amino, L AAb is a single bond.
- RNAAa is a hydrogen atom
- linkers are each:
- RNAAa is a hydrogen atom
- One preferred configuration is
- Preferred W2, W3 , W4 , W5 , W6 , and W7 are independently: (i) a diamine linker of the formula -NR NWa -L W -NR NWb -; (iii) a diamine linker represented by formula [V-2] below, (iv) a diamine linker represented by formula [V-3] below, or a diamine linker represented by (v) formula [V-4] below, here, In the diamine linker represented by the formula (i) -NR NWa -L W -NR NWb -, L W is a chain C 1-3 alkanediyl, R NWa and R NWb are independently a hydrogen atom or C 1-2 alkyl, again, (iii) In the diamine linker represented by formula [V-2], The linker is
- Ring B 52 is azetidine, pyrrolidine, or piperidine (the azetidine, pyrrolidine, and piperidine may be substituted with one oxo); LWa is a single bond, R NWa is a hydrogen atom or C 1-2 alkyl.
- LWa is a single bond
- R NWa is a hydrogen atom or C 1-2 alkyl.
- the linker is
- Ring B 53 is piperidine (the piperidine may be substituted with one carbamoyl); L Wb is a single bond, RNWa is a hydrogen atom.
- ) is a structure represented by (v) In the diamine linker represented by formula [V-4], The linker is
- Ring B 54 is piperazine, diazepane, or diazaspirooctane.
- Ring B 54 is piperazine, diazepane, or diazaspirooctane.
- W 2 , W 3 , W 4 , W 5 , W 6 , and W 7 are independently The following (v) formula [V-4]
- Ring B 54 represents a piperazine.
- Ring B 54 is a diamine linker represented by
- W 2 , W 3 , W 4 , W 5 , W 6 and W 7 are independently (v) the following formula [V-4-1]
- RAAra is a hydrogen atom
- RAArb is a hydrogen atom
- R NAAr is a hydrogen atom or C 1-2 alkyl
- RNAAr is a hydrogen atom or methyl
- V2, V3 , V4 , V5 , V6 , and V7 are independently: (ii) a dicarboxylic acid linker represented by the following formula [VII-1], here, The dicarboxylic acid linker represented by the above formula [VII-1] is
- Ring B 71 is benzene, L Va and L Vb are identically a single bond.
- V 2 , V 3 , V 4 , V 5 , V 6 , and V 7 are (ii) a dicarboxylic acid linker represented by the following formula [VII-1], here, The dicarboxylic acid linker represented by the above formula [VII-1] is
- a preferred RZC is hydroxy, C 1-6 alkoxy, amino, mono C 1-12 alkylamino (wherein said mono C 1-12 alkylamino is hydroxy, carboxy, amino, a halogen atom, C 3-8 cycloalkyl (wherein said C 3-8 cycloalkyl is substituted with 1 amino) ), azetidinyl, piperidinyl, piperazinyl (the azetidinyl, piperidinyl and piperidinyl may be substituted with one group selected from the group consisting of amino and C 1-6 alkyl), phenyl, pyrazolyl , pyridyl, C 1-6 alkoxy (wherein said C 1-6 alkoxy is optionally substituted with C 1-6 alkoxy which is optionally substituted with one amino), and di-C 1-6 alkylamino may be substituted with 1 to 3 groups selected identically or differently from the group consisting of mono C 3-8 cycloalkylamino (
- RZC is hydroxy, amino, mono C 1-12 alkylamino (wherein the mono C 1-12 alkylamino is amino, C 3-8 cycloalkyl (wherein the C 3-8 cycloalkyl is substituted with 1 amino), and di substituted with one group selected from the group consisting of C 1-6 alkylamino), mono-C 3-8 cycloalkylamino (the mono-C 3-8 cycloalkylamino is substituted with 1 amino), or pyrrolidinyl (the pyrrolidinyl is substituted with 1 amino) and A more preferred RZC is hydroxy, amino, methylamino (wherein the methylamino is substituted with cyclobutyl substituted with one amino), ethylamino (the ethylamino is substituted with one group selected from the group consisting
- a preferred R ZN is C 1-6 alkyl, wherein said C 1-6 alkyl is substituted with one group selected from the group consisting of hydroxy, amino, and phenyl (wherein said phenyl is haloC 1-6 alkyl and C 1-6 alkoxy; may be substituted with 1 to 2 groups identically or differently selected from the group consisting of haloC 1-6 alkyl, C 3-8 cycloalkyl, piperidinyl, phenyl, pyridinyl, isoquinolyl (the phenyl, pyridinyl and isoquinolyl are halogen atoms, C 1-6 alkyl, haloC 1-6 alkyl and pyrrolidinyl (the pyrrolidinyl is optionally substituted with one oxo); optionally substituted with one group selected from the group consisting of), dihydrobenzodioxinyl, C 1-6 alkylcarbonyl (said C 1-6 alkylcarbonyl
- Ring A is benzene, R A3 is a hydrogen atom, ZBG is carboxy; R ZBG is a hydrogen atom, R N1 is a hydrogen atom,
- a compound or a pharmaceutically acceptable salt thereof represented by Preferred aspects of R A1 , R A2 , L 1 , Y 2 , Y 3 , Y 4 and Z are as described above.
- R AAa is a hydrogen atom or C 1-6 alkyl
- R AAb is a hydrogen atom
- RNAAa is a hydrogen atom
- Ring B 21 is a triazole
- L 12c and L 12d are independently a chain C 1-2 alkanediyl.
- Ring B 32 is C 3-8 cycloalkane or benzene; LAAa and LAAb are identically a single bond.
- RNAAa is a hydrogen atom
- aminocarboxylic acid linker represented by formula [III-4] The linker is
- Ring B 34 is pyrrolidine
- L AAbs are linear C 1-2 alkanediyls.
- Adjacent AA 3 and AA 4 together is a structure represented by here, Adjacent AA 3 and AA 4 together, The following formula [IV-6]
- Ring B 41 is benzene
- Ring B 42 is piperidine
- L AAf is a single bond
- Q 2 is a structure represented by the formula -NR N5 -
- RN5 is a hydrogen atom.
- R ZC is hydroxy or amino.
- the compound represented by the formula [IB] is the compound represented by the above formula [IB-1], R A1 and R A2 are independently a chlorine atom, methyl, or trifluoromethyl;
- RNAAa is a hydrogen atom
- RZC aminocarboxylic acid linker
- a particularly preferred embodiment of the compound represented by the above formula [IB] is any one of the following.
- Ring A is benzene, R A3 is a hydrogen atom, ZBG is carboxy; R ZBG is a hydrogen atom, R N1 is a hydrogen atom,
- Z C ′′ is (ii-1) a group represented by the formula -AA 5 -R ZC , (ii-2) a group represented by the formula -W 5 -R ZN , (iii-1) a group represented by the formula -AA 5 -AA 6 -R ZC , or (iv-1) a group represented by the formula -AA 5 -AA 6 -AA 7 -R ZC , a compound or a pharmaceutically acceptable salt thereof
- Preferred aspects of R A1 , R A2 , L 1 , AA 2 , AA 3 , AA 4 , AA 5 , AA 6 , AA 7 , W 5 , R ZC and R ZN are as described above.
- R A1 and R A2 are independently a halogen atom, C 1-6 alkyl, or haloC 1-6 alkyl
- L 11 is a chain C 1-3 alkanediyl
- RAAa is a hydrogen atom
- Ring B 21 is a triazole, L 12c and L 12d are independently a chain C 1-2 alkanediyl.
- Ring B 32 is benzene, LAAa and LAAb are identically a single bond.
- RNAAa is a hydrogen atom
- Ring B 31 is piperidine, LAAa and LAAb are identically a single bond.
- RNAAa is a hydrogen atom
- aminocarboxylic acid linker represented by formula [III-4] The linker is
- Ring B 34 is pyrrolidine or piperidine, the pyrrolidine is optionally substituted with one amino, L AAb is a single bond.
- W 5 is the following (v) formula [V-4]
- Ring B 54 is piperazine.
- RZC is a diamine linker represented by RZC is amino, mono C 1-6 alkylamino (the mono C 1-6 alkylamino is substituted with C 3-8 cycloalkyl substituted with 1 amino), mono-C 1-6 alkylamino (the mono-C 1-6 alkylamino is substituted with one group selected from the group consisting of amino and di-C 1-6 alkylamino), mono-C 3-8 cycloalkylamino (the mono-C 3-8 cycloalkylamino is substituted with 1 amino), or pyrrolidinyl (the pyrrolidinyl is substituted with 1 amino) and RZN is C 1-6 alkyl (the C 1-6 alkyl is substituted with 1-2 aminos) is.
- R A1 and R A2 are independently a chlorine atom, methyl, or trifluoromethyl;
- RAAa is a hydrogen atom or methyl
- R AAb is a hydrogen atom
- RNAAa is a hydrogen atom
- aminocarboxylic acid linker represented by formula [III-4] is represented by the following formula [III-4-1a]
- RNAAa is a hydrogen atom
- W 5 is (v) the following formula [V-4-1]
- RZC is a diamine linker represented by RZC is amino, methylamino (wherein the methylamino is substituted with cyclobutyl substituted with one amino), ethylamino (the ethylamino is substituted with one group selected from the group consisting of amino and dimethylamino), cyclobutylamino (the cyclobutylamino is substituted with 1 amino), or pyrrolidinyl (the pyrrolidinyl is substituted with 1 amino) and RZN is n-propyl (the n-propyl is substituted with 1 amino) or n-pentyl (the n-pentyl is substituted with 2 aminos) is.
- a particularly preferred embodiment is any of the following.
- Ring A is benzene, R A3 is a hydrogen atom, ZBG is carboxy; R ZBG is a hydrogen atom, Y 2 is AA r2 ,
- the group represented by the formula -AA r2 -Y 3 -Y 4 -Z is (ii-1) a group represented by the formula -AA r2 -AA r3 -AA r4 -ZN , (ii-2) a group represented by the formula -AA r2 -AA r3 -V 4 -R ZC ; (ii-3) a group represented by the formula -AA r2 -AA r3 -R ZN , or (ii-5) a group represented by the formula -AA r2 -R ZN , here, ZN is (v-1) a group represented by the formula -R ZN or (vi- 2 ) a group represented by the formula -V -R ZC , and, Preferred aspects of R A1 , R A2 , R N1 , L 1 , AA r2 , AA r3 , AA
- R A1 and R A2 are independently a halogen atom or haloC 1-6 alkyl
- R N1 is a hydrogen atom
- R N1 is represented by the following formula [II-1] together with the adjacent structure represented by the formula -N-C-L 1 -
- Ring B 11 is pyrrolidine, R N2 is a hydrogen atom, AA r1 is as described later.
- L1 is (ii-1) a structure represented by formula -L 15 -NR N2 -AA r1 -, or (ii-2) a structure represented by formula -L 16 -NR N2 -, here,
- L 15 is a chain C 1-3 alkanediyl
- R N2 is a hydrogen atom or C 1-3 alkyl
- AA r1 is as described below
- L 16 is a chain C 4-5 alkanediyl
- R N2 is a hydrogen atom or C 1-3 alkyl
- Z is (i) a group represented by the formula -R Z
- Ring B 71 is benzene, L Va and L Vb are identically a single bond.
- a structure represented by V5 is (ii) a dicarboxylic acid linker represented by the following formula [VII-1], here, The dicarboxylic acid linker represented by the above formula [VII-1] is
- Ring B 71 is benzene, L Va and L Vb are identically a single bond.
- R ZC is amino
- R ZN is C 1-6 alkylcarbonyl (the C 1-6 alkylcarbonyl may be substituted with one amino), phenylcarbonyl, or pyridazinylcarbonyl.
- R A1 and R A2 are independently a chlorine atom or trifluoromethyl;
- R N1 is a hydrogen atom,
- R N1 is represented by the following formula [II-1-1a] together with the adjacent structure represented by the formula -NC-L 1 -
- L1 is (ii-1) a structure represented by formula -L 15 -NR N2 -AA r1 -, or (ii-2) a structure represented by formula -L 16 -NR N2 -, here, L 15 is methanediyl, ethane-1,2-diyl, or n-propane-1,3-diyl, R N2 is a hydrogen atom or methyl, AA r1 is as described below, and L 16 is butane-1,4-diyl, R N2 is a hydrogen atom or methyl, Z is (i) a group represented by the formula -R Z , or ( ii) a group represented by the formula -Y -R Z , Y5 is (iv) a dicarboxylic acid linker of formula -V X' -; here, X' is
- V5 is (ii) a dicarboxylic acid linker represented by the following formula [VII-1], here, The dicarboxylic acid linker represented by the above formula [VII-1] is
- R ZC is amino
- R ZN is methylcarbonyl, isobutylcarbonyl (wherein the isobutylcarbonyl is substituted with one amino), phenylcarbonyl, or pyridazinylcarbonyl.
- Ring A is benzene
- R A3 is a hydrogen atom
- ZBG is carboxy
- R ZBG is a hydrogen atom
- R N1 is a hydrogen atom
- the group represented by the formula -Y 2 -Y 3 -Y 4 -Z is (i-1) a group represented by the formula -AA 2 -AA 3 -AA 4 -Z C , represented by the following formula [IE ]
- a compound or a pharmaceutically acceptable salt thereof represented by Preferred embodiments of R A1 , R A2 , L 1 , AA 2 , AA 3 , AA 4 and Z C are as described above.
- R A1 and R A2 are independently a hydrogen atom, a halogen atom, C 1-6 alkyl, haloC 1-6 alkyl, or phenylcarbonylamino (the phenylcarbonylamino is substituted with one carbamoyl);
- L 11 is a chain C 1-3 alkanediyl
- L 12 is a chain C 4-5 alkane
- Ring B 21 is a triazole
- L 12c and L 12d are independently a chain C 1-2 alkanediyl.
- Ring B 32 is C 3-8 cycloalkane or benzene; LAAa and LAAb are identically a single bond.
- RNAAa is a hydrogen atom
- aminocarboxylic acid linker represented by formula [III-4] The linker is
- Ring B 34 is pyrrolidine
- L AAbs are linear C 1-2 alkanediyls.
- Adjacent AA 3 and AA 4 together is a structure represented by here, Adjacent AA 3 and AA 4 together, The following formula [IV-6]
- Ring B 41 is benzene
- Ring B 42 is piperidine
- L AAf is a single bond
- Q 2 is a structure represented by the formula -NR N5 -
- RN5 is a hydrogen atom.
- Ring B 31 is piperidine, LAAa and LAAb are identically a single bond.
- RNAAa is a hydrogen atom
- aminocarboxylic acid linker represented by formula [III-4] The linker is
- Ring B 34 is pyrrolidine or piperidine, the pyrrolidine is optionally substituted with one amino, L AAb is a single bond.
- W 5 is the following (v) formula [V-4]
- Ring B 54 is piperazine.
- RZC is a diamine linker represented by RZC is hydroxy, amino, mono C 1-12 alkylamino (wherein the mono C 1-12 alkylamino is amino, C 3-8 cycloalkyl (wherein the C 3-8 cycloalkyl is substituted with 1 amino), and di substituted with one group selected from the group consisting of C 1-6 alkylamino), mono-C 3-8 cycloalkylamino (the mono-C 3-8 cycloalkylamino is substituted with 1 amino), or pyrrolidinyl (the pyrrolidinyl is substituted with 1 amino) and RZN is C 1-6 alkyl (the C 1-6 alkyl is substituted with 1-2 aminos) is.
- RZN is C 1-6 alkyl (the C 1-6 alkyl is substituted with 1-2 aminos) is.
- R A1 and R A2 are independently a hydrogen atom, a chlorine atom, methyl, trifluoromethyl, or phenylcarbonylamino (the phenylcarbonylamino is substituted with one carbamoyl);
- R A1 and R A2 are independently a hydrogen atom, a chlorine atom, methyl, trifluoromethyl, or phenylcarbonyla
- RNAAa is a hydrogen atom
- RNAAa is a hydrogen atom
- W 5 is (v) the following formula [V-4-1]
- RZC is a diamine linker represented by RZC is hydroxy, amino, methylamino (wherein the methylamino is substituted with cyclobutyl substituted with one amino), ethylamino (the ethylamino is substituted with one group selected from the group consisting of amino and dimethylamino), cyclobutylamino (the cyclobutylamino is substituted with 1 amino), or pyrrolidinyl (the pyrrolidinyl is substituted with 1 amino) and RZN is n-propyl (the n-propyl is substituted with 1 amino) or n-pentyl (the n-pentyl is substituted with 2 aminos) is.
- a particularly preferred embodiment is a case where the compound represented by the above formula [IE] is any one of the following.
- R A1 and R A2 are independently a chlorine atom, methyl, or trifluoromethyl;
- RAAa is a hydrogen atom or methyl
- R AAb is a hydrogen atom
- RNAAa is a hydrogen atom
- RNAAa is a hydrogen atom
- RNAAa is a hydrogen atom
- RNAAa is a hydrogen atom
- RNAAa is a hydrogen atom
- RNAAa is a hydrogen atom
- RNAAa is a hydrogen atom
- W 5 is (v) the following formula [V-4-1]
- RZC is a diamine linker represented by RZC is hydroxy, amino, methylamino (wherein the methylamino is substituted with cyclobutyl substituted with one amino), ethylamino (the ethylamino is substituted with one group selected from the group consisting of amino and dimethylamino), cyclobutylamino (the cyclobutylamino is substituted with 1 amino), or pyrrolidinyl (the pyrrolidinyl is substituted with 1 amino) and RZN is n-propyl (the n-propyl is substituted with 1 amino) or n-pentyl (the n-pentyl is substituted with 2 aminos) is.
- a particularly preferred embodiment is a case where the compound represented by the above formula [IE] is any one of the following.
- the compound of the present invention has a structure with a sulfonamide as a basic skeleton (the structure has a carboxy or its equivalent that acts with matrix metalloprotease 7 (MMP7)), and the compound has a pharmaceutical acceptable salt form.
- Pharmaceutically acceptable salts include, for example, mineral salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, nitrate, methanesulfonate, ethanesulfone sulfonates such as benzenesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, oxalates, tartrates, citrates, maleates, succinates, acetates, Acid addition salts such as organic acid salts such as fluoroacetate, benzoate, mandelate, ascorbate, lactate, gluconate, malate, glycine salts, lysine salts,
- the salt includes a hydrous salt.
- the compounds of the present invention may have asymmetric centers and thus exist in various optical isomers. Accordingly, the compounds of the invention can exist as separate (R) and (S) optically active forms and as racemates or (RS) mixtures. Further, in the case of a compound having two or more asymmetric centers, diastereomers due to each optical isomerism also exist. Compounds of the invention also include mixtures containing all these forms in any proportion. For example, diastereomers can be separated by methods well known to those skilled in the art, such as fractional crystallization, and optically active forms can be obtained by organic chemical techniques well known for this purpose. can.
- the compounds of the present invention may have geometric isomers such as cis isomers and trans isomers. Furthermore, the compounds of the present invention have tautomerism and exist in various tautomers. The compounds of the present invention also include those isomers and mixtures containing these isomers in any proportion.
- MMP7 Mestrix metalloprotease 7
- MMP7 degrades extracellular matrices such as collagen and elastin, and thus is involved in tumor metastasis, inflammatory processes, and the like, and is involved in the pathology of cancer and non-neoplastic diseases. Therefore, one or more diseases selected from the group consisting of cancer diseases and non-neoplastic diseases, or symptoms related thereto can be prevented or treated by inhibiting MMP7.
- the compounds of the present invention have the activity of inhibiting MMP7. Therefore, the compound of the present invention can be used as an active ingredient of an MMP7 inhibitor, and an active ingredient of a prophylactic or therapeutic drug for one or more diseases selected from the group consisting of cancer diseases and non-neoplastic diseases.
- the compound of the present invention can also be used as an active ingredient of a prophylactic or therapeutic drug for symptoms associated with one or more diseases selected from the group consisting of cancer diseases and non-neoplastic diseases.
- cancer disease includes epithelial tumors such as breast cancer, esophageal cancer, colon cancer, colon adenoma, pancreatic cancer, lung cancer, and skin cancer.
- symptoms associated with cancer disease include neoplastic cell proliferation and pain associated with tumor growth, weight loss, paraneoplastic syndrome, and the like.
- non-neoplastic disease refers to non-neoplastic diseases other than the above-mentioned “cancer disease” and "symptoms related to cancer disease", such as renal disease, organ fibrosis, aortic aneurysm, left ventricular disease Hypertrophy, myocardial infarction, HIV-associated neurocognitive disorders, multiple sclerosis, Dupuytren's contracture, inflammatory muscle disease, osteoarthritis, endometriosis, systemic lupus erythematosus, non-alcoholic steatohepatitis, cirrhosis, colon Fire is included.
- Kidney disease is nephrotic syndrome, chronic kidney disease, and other kidney diseases.
- Nephrotic syndrome is a syndrome characterized by a large amount of urinary protein based on increased protein permeability due to renal glomerular loop disorder and accompanying hypoproteinemia, and is classified into primary nephrosis and secondary nephrosis. be.
- Primary nephrosis is nephrosis that has no obvious causative disease such as microglomerular tangles, membranous nephropathy, membranous proliferative glomerulonephritis, focal segmental glomerulosclerosis, and the like.
- “Secondary nephrosis” is nephrosis having a causative disease such as diabetic nephropathy, lupus nephritis, amyloid nephropathy, Alport's syndrome, drug-induced nephropathy, or the like.
- “Chronic kidney disease” refers to a state in which the glomerular filtration rate is 45 mL/min/1.73 m 2 or less due to diabetes, hypertension, nephritis, etc., and urinary albumin excretion is 30 mg/mg day or 30 mg/g creatinine or more.
- Urinine a state in which urinary protein excretion is 0.15 g/day or 0.15 g/g creatinine or more
- diseases associated with diabetes and hypertension include diabetic kidney disease, diabetic nephropathy, and the like.
- "Other renal diseases” are renal diseases that do not belong to the above classification, such as nephrosclerosis, polycystic kidney disease, IgA nephropathy, and hydronephrosis.
- Organic fibrosis includes interstitial pneumonia, idiopathic pulmonary fibrosis, and fibrodysplasia ossificans.
- MMP7 inhibitory action of the compound of the present invention can be evaluated according to a known method such as the method described in the test examples of the present specification, for example.
- the compound of the present invention that has an inhibitory effect on MMP7 or a pharmaceutically acceptable salt thereof may be used alone or as a pharmaceutically or pharmaceutically acceptable additive.
- Additives include commonly used excipients or diluents, and if necessary, commonly used binders, disintegrants, lubricants, coating agents, sugar coating agents, pH adjusters, solubilizers, or aqueous or non-aqueous Solvents can be used.
- HPC-L low viscosity hydroxypropyl cellulose
- the medicament according to the present invention may be in any form of solid composition, liquid composition and other compositions, and the most suitable one is selected according to need.
- the medicament according to the present invention can be prepared by adding the aforementioned excipients to the compound of the present invention and preparing tablets, pills, capsules, granules, powders, powders, liquids, emulsions, suspensions, It can be prepared as an injection or the like.
- the medicament according to the present invention can be formulated by forming an inclusion compound with the compound of the present invention and ⁇ -, ⁇ -, or ⁇ -cyclodextrin, methylated cyclodextrin, or the like.
- the medicament according to the present invention can be a single formulation (combination drug) or two or more formulations obtained by separately formulating a compound that can be used in combination with the compound of the present invention (combination drug).
- the individual formulations can be administered simultaneously or at regular intervals. In this case, it does not matter which one is administered first.
- the two or more formulations can also be administered at different times per day.
- the two or more formulations can also be administered by different routes.
- these compounds When these compounds are formulated separately to form two formulations, they may be administered at the same time or at very short intervals. It is preferable to describe that the It is also preferable to formulate these active ingredients separately to form a kit comprising two formulations.
- the mode of administration is not particularly limited, and the compound of the present invention can be directly administered orally or parenterally. Alternatively, a drug containing the compound of the present invention as an active ingredient may be administered orally or parenterally.
- the compound of the present invention when used as a prophylactic or therapeutic agent for one or more diseases selected from the group consisting of cancer diseases and non-neoplastic diseases, or symptoms related thereto, the compound of the present invention can be used as it is. It can be administered orally or parenterally. Alternatively, a drug containing the compound of the present invention as an active ingredient may be administered orally or parenterally.
- parenteral administration is preferably intravenous administration, subcutaneous administration, or transdermal administration. Dosage forms for parenteral administration include injections, infusions, implants, percutaneous absorption agents, transmucosal absorption agents, patches, and the like, and may be microsphere preparations.
- the dosage of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptoms, etc.
- the dosage when administered orally or parenterally to an adult patient, is usually 0.1 mg to 1000 mg per dose. , preferably 1 mg to 200 mg, and this amount is desirably administered once to three times a day, or once every two to three days.
- Formulation example 1 A granule containing the following ingredients is prepared. Ingredients: compound represented by formula [I], lactose, corn starch, HPC-L. A compound represented by the formula [I] and lactose are passed through a sieve. Sift the cornstarch through a sieve. These are mixed in a mixer. An aqueous HPC-L solution is added to the mixed powder, kneaded, granulated (extrusion granulated), and then dried. The resulting dry granules are sieved with a vibrating sieve to obtain granules.
- Formulation example 2 A capsule filling powder is prepared containing the following ingredients: Ingredients: compound represented by formula [I], lactose, corn starch, magnesium stearate. A compound represented by the formula [I] and lactose are passed through a sieve. Sift the cornstarch through a sieve. These are mixed with magnesium stearate in a mixer to obtain a powder. The resulting powder can be filled into capsules.
- Formulation example 3 A granule for capsule filling is prepared containing the following ingredients. Ingredients: compound represented by formula [I], lactose, corn starch, HPC-L. A compound represented by the formula [I] and lactose are passed through a sieve. Sift the cornstarch through a sieve.
- Formulation example 4 A tablet containing the following ingredients is manufactured. Ingredients: compound represented by formula [I], lactose, microcrystalline cellulose, magnesium stearate, CMC-Na. The compound represented by the formula [I], lactose, microcrystalline cellulose, and CMC-Na are passed through a sieve and mixed. Magnesium stearate is added to the mixed powder to obtain a mixed powder for formulation.
- Formulation example 5 An injection containing the following ingredients is manufactured. Ingredients: compound represented by formula [I], refined egg yolk lecithin, oleic acid, refined soybean oil, glycerin, water for injection. The compound represented by formula [I], purified egg yolk lecithin and oleic acid are added to purified soybean oil, dissolved, water for injection mixed with glycerin is added, and emulsified with an emulsifier. Water for injection is added to this, and the mixture is dispensed into ampoules, sealed, and sterilized to obtain an injection.
- a general method for producing the compound [I] according to the present invention will be described below, but the production method is not particularly limited to those exemplified. Also, the solvent used in the production is not particularly limited to those described below as long as it does not interfere with each reaction.
- the order of steps in the production can be changed as appropriate.
- the raw material compound may be used as a salt, and examples of the salt include "a pharmaceutically acceptable salt” and a formate salt in the present specification.
- Compound [I] can be produced by solid-phase synthesis, liquid-phase synthesis, or a combination thereof.
- compound [I] can be produced by the methods described in Production Methods 1 to 14 or a combination of these methods.
- the side chain may have a functional group. A functional group may be protected with a protecting group.
- protecting group examples include Trt for carbamoyl, t-Bu (or tert-Bu) for phenolic hydroxy, t-Bu for thiol (sulfanyl), Trt for imidazolyl, Boc for indolyl and Pbf for guanidino. Any of these protecting groups can be deprotected by treating with an acid.
- hydroxy examples include the following. (i) t-Bu, (ii) Me and Et, and (iii) Bn. Any of these protecting groups can be deprotected by the method described in the literature (Protective Groups in Organic Synthesis, 5th edition, 2014, by Peter GM Wuts) or a method based thereon.
- Examples of amino include: (i) Fmoc, (ii) Boc, (iii) Alloc, and (iv) Cbz, Bn. (i) can be deprotected by the action of a base.
- Bases used in this reaction include, for example, piperidine. A base diluted to 20 to 40% is used in a solution of 20 to 30 v/mol (where v indicates volume), and an organic solvent that does not inhibit the reaction is used as a dilution solvent.
- Solvents used in this reaction include, for example, DMF and NMP, and these solvents may be appropriately mixed and used.
- This reaction can be carried out at ice-cold temperature to room temperature for 1 minute to 1 hour, and in solid-phase synthesis, it can be carried out preferably at room temperature for 1 to 5 minutes and 15 to 30 minutes twice.
- (ii) can be deprotected by the action of an acid.
- Acids used in this reaction include, for example, hydrochloric acid and trifluoroacetic acid. The acid is used after diluting with a solvent if necessary, and an organic solvent or water that does not inhibit the reaction is used as the solvent. Examples of the organic solvent used in this reaction include chloroform, 1,4-dioxane, DMF and the like.
- This reaction can be carried out at ice-cold temperature to room temperature for 30 minutes to 5 hours.
- metal catalysts used in this reaction include a combination of Pd(PPh 3 ) 4 , Pd 2 (dba) 3 and 1,4-bis(diphenylphosphino)butane (dppb).
- the amount of metal catalyst used is 0.001 to 1 equivalent, preferably 0.01 to 0.5 equivalent.
- the nucleophilic agent used in this reaction include phenylsilane, morpholine, 1,3-dimethylbarbituric acid and the like. The amount of nucleophile used is 1 to 50 equivalents.
- Solvents used in this reaction include, for example, chloroform and tetrahydrofuran, and these solvents may be appropriately mixed and used.
- deprotection can be performed in the presence of a metal catalyst and a hydrogen source in a solvent that does not inhibit the reaction.
- the metal catalyst used in this reaction include palladium-carbon, palladium hydroxide-carbon and the like.
- the amount of metal catalyst used is 0.001 to 1 equivalent, preferably 0.01 to 0.5 equivalent.
- the hydrogen pressure used in this reaction is normal pressure to 10 atmospheres, preferably normal pressure to 4 atmospheres.
- Solvents used in this reaction include, for example, methanol, ethanol, water, tetrahydrofuran, and ethyl acetate, and these solvents may be appropriately mixed and used. This reaction can usually be carried out at room temperature to reflux temperature for 1 to 24 hours. In addition, any of these protecting groups can be deprotected by the method described in the literature (Protective Groups in Organic Synthesis, 5th edition, 2014, by Peter GM Wuts) or a method according thereto.
- (i) can be deprotected by the action of an acid.
- Acids used in this reaction include, for example, hydrochloric acid and trifluoroacetic acid. The acid is used after diluting with a solvent if necessary, and an organic solvent or water that does not inhibit the reaction is used as the solvent. Examples of the organic solvent used in this reaction include chloroform, 1,4-dioxane, DMF and the like. This reaction can be carried out at ice-cold temperature to room temperature for 30 minutes to 5 hours.
- (ii) can be deprotected in the presence of a metal catalyst and a nucleophile in a solvent that does not inhibit the reaction.
- metal catalysts used in this reaction include a combination of Pd(PPh 3 ) 4 , Pd 2 (dba) 3 and 1,4-bis(diphenylphosphino)butane (dppb).
- the amount of metal catalyst used is 0.001 to 1 equivalent, preferably 0.01 to 0.5 equivalent.
- the nucleophilic agent used in this reaction include phenylsilane, morpholine, 1,3-dimethylbarbituric acid and the like.
- the amount of nucleophile used is 1 to 50 equivalents. It is preferably 10 to 20 equivalents in solid phase synthesis, and preferably 1.5 to 10 equivalents in liquid phase synthesis.
- Solvents used in this reaction include, for example, chloroform and tetrahydrofuran, and these solvents may be appropriately mixed and used. Any of these protecting groups can be deprotected by the method described in the literature (Protective Groups in Organic Synthesis, 5th edition, 2014, by Peter GM Wuts) or a method based thereon. Also, the amino acid can be used for production even if the side chain functional groups are not protected.
- ring A, R A1 , R A2 , R A3 , L 1a , AA 2 , AA 3 and AA 4 are as described above,
- AA X represents AA 2 , AA 3 or AA 4 as described above
- PG 1 indicates a protecting group for carboxy
- PG 2 represents an amino protecting group
- Examples of compound [1-a] include Fmoc-Rink-Amide AM resin, Fmoc-NH-SAL-PEG resin, Fmoc-NH-SAL-MBHA resin, and the like.
- Step 1-1 Compound [1-a] having an Fmoc-protected amino on the resin is subjected to de-Fmoc conversion using a base.
- the base that can be used in this step include piperidine.
- Step 1-2 The amino of the resin obtained in the above (1) is reacted with the carboxy of the aminocarboxylic acid compound [1-b] whose amino is protected with a protecting group (PG 2 ) to form an amide.
- PG 2 includes, for example, Fmoc, Boc, Cbz, and Alloc.
- Step 1-3 The amino-protecting group (PG 2 ) of the N-terminal aminocarboxylic acid compound of the compound obtained in (2) above is deprotected.
- Compound [1-c] can be produced by repeating the above (2) and (3).
- (5) (Step 1-4) The amino of the N-terminal aminocarboxylic acid compound of compound [1-c] obtained in (4) above is reacted with the carboxyl of aminocarboxylic acid compound [1-d] in which amino is protected with a protecting group (PG 2 ). Form an amide.
- (6) (Step 1-5) Compound [1-e] can be produced by deprotecting the amino-protecting group (PG 2 ) of the N-terminal aminocarboxylic acid compound of the compound obtained in (5) above.
- Step 1-6 Compound [1-g] can be produced by reacting compound [1-f] with compound [1-e] obtained in (6) above to sulfonylate it.
- Step 1--7 The compound of the present invention represented by formula [1-h] can be produced by cleaving the bond with the resin of compound [1-g] obtained in (7) above with an acid. At this time, the carboxy-protecting group (PG 1 ) in the aminocarboxylic acid compound [1-d] used in (5) above can be deprotected at the same time.
- the acid that can be used in this step examples include TFA.
- the protective group for the functional group is removed under acidic conditions. If it can be protected, it can be deprotected at the same time.
- the protective group for the above functional group needs to be deprotected under conditions other than acid, the above-mentioned method or literature (Protective Groups in Organic Synthesis, 5th edition, 2014, Peter G. M. Wuts) or a method analogous thereto.
- compound [1-h] thus obtained can be isolated and purified by known means for separation and purification, such as concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.
- compound [1-a], compound [1-b], compound [1-d], and compound [1-f] used as starting compounds are It can be produced by the method described in Reference Examples, or can be obtained by purchasing a commercially available product.
- the compound [1-b] and compound [1-d] natural proteinogenic L-amino acids, natural non-proteinogenic amino acids, D-amino acids, and non-natural amino acids are used. can also In addition to these amino acids, various aminocarboxylic acid compounds synthesized separately can also be used.
- the compound [1-b] includes, for example, two or more aminocarboxylic acid compounds represented by the formula PG 2 -AA 3 -AA 4 -OH. compounds can be used.
- a group represented by formula -Y 2 -Y 3 -Y 4 -Z is a group represented by formula -AA 2 -AA 3 -NH 2 and a group represented by formula -AA 2 - A compound represented by NH 2 can also be produced according to the method described in Scheme 1.
- Z is a group represented by the formula -AA 5 -AA 6 -AA 7 -NH 2
- a group represented by the formula - A compound represented by AA 5 -NH 2 can also be produced according to the method described in Scheme 1.
- Step 2-1 The amino of compound [1-c] obtained in (4) in Production Method 1 described above is reacted with the carboxy of aminocarboxylic acid compound [2-a] whose amino is protected with a protecting group (PG 2 ) to form an amide. form.
- Step 2-2 Compound [2-b] can be produced by deprotecting the amino-protecting group (PG 2 ) of the N-terminal aminocarboxylic acid compound of the compound obtained in (1) above.
- Step 2-3 The amino of compound [2-b] obtained in the above (2) and the carboxy of aminocarboxylic acid compound [2-c] whose amino is protected with a protecting group (PG 2 ) are reacted to form an amide.
- Step 2-4 Compound [2-d] can be produced by deprotecting the amino-protecting group (PG 2 ) of the N-terminal aminocarboxylic acid compound of the compound obtained in (3) above.
- the protecting group of the functional group can be deprotected at the same time.
- the protective group for the above functional group needs to be deprotected under conditions other than acid, the above-mentioned method or literature (Protective Groups in Organic Synthesis, 5th edition, 2014, Peter GM Wuts) or a method analogous thereto.
- the compound [2-a] and the compound [2-c], which are aminocarboxylic acid compounds include natural proteinogenic L-amino acids, natural non-proteinogenic amino acids, D-amino acids and unnatural amino acids. can also be used. In addition to these amino acids, various aminocarboxylic acid compounds synthesized separately can also be used.
- a group represented by formula -Y 2 -Y 3 -Y 4 -Z is a group represented by formula -AA 2 -AA 3 -NH 2 and a group represented by formula -AA 2 - A compound represented by NH 2 can also be produced according to the method described in Scheme 1.
- ring A , RA1, RA2 , RA3 , L1a, AA2, AA3 , AA4 , PG1 , and PG2 are as described above,
- AA X represents the aforementioned AA 2 or AA 3
- Compound [3-a] having R' on the resin indicates, for example, 2-chlorotrityl chloride resin, Wang resin, HMPA-PEGA resin, and the like.
- Step 3-1 A compound [3-a] having an alkyl halide is reacted with an aminocarboxylic acid compound [3-b] whose amino is protected with a protecting group (PG 2 ) on a resin.
- Step 3-2 Compound [3-c] can be produced by deprotecting the amino-protecting group (PG 2 ) of the N-terminal aminocarboxylic acid compound of the compound obtained in (1) above.
- (3) (Step 3-3) The amino of compound [3-c] obtained in the above (2) and the carboxy of aminocarboxylic acid compound [3-d] whose amino is protected with a protecting group (PG 2 ) are reacted to form an amide.
- Step 3-4 The amino-protecting group (PG 2 ) of the N-terminal aminocarboxylic acid compound of the compound obtained in (3) above is deprotected.
- Compound [3-e] can be produced by repeating the above (3) and (4).
- Step 3-5 The amino of the N-terminal aminocarboxylic acid compound of the compound [3-e] obtained in (5) above is reacted with the aminocarboxylic acid compound [1-d] in which the amino is protected with a protecting group (PG 2 ) to form an amide. form.
- (7) (Step 3-6)
- Compound [3-f] can be produced by deprotecting the amino-protecting group (PG 2 ) of the N-terminal aminocarboxylic acid compound of the compound obtained in (6) above.
- (8) (Step 3-7) Compound [3-g] can be produced by reacting compound [1-f] with compound [3-f] obtained in (7) above to sulfonylate it.
- the present compound represented by the formula [3-h] can be produced by cleaving the bond with the resin of the compound [3-g] obtained in the above (8) using an acid.
- the carboxy-protecting group (PG 1 ) in the aminocarboxylic acid compound [1-d] used in (6) above can be deprotected at the same time.
- a protected functional group is present in the side chain of the aminocarboxylic acid compound [3-b] and compound [3-d] used in (1) and (3) above, The protecting group of the functional group can be deprotected.
- the compound has a protective group that needs to be deprotected under conditions other than acid conditions, the method described above or the literature (Protective Groups in Organic Synthesis, 5th edition, 2014, Peter GM Wuts) or a method analogous thereto.
- deprotection when deprotection is required under conditions other than acid conditions, basically the deprotection reaction is first performed under the conditions, and then deprotection of other protecting groups and bonding with the resin are performed under acid conditions. Make a cut.
- the compound [3-h] thus obtained can be isolated and purified by known means for separation and purification, such as concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.
- compound [3-b], compound [3-d], compound [1-d], and compound [1-f] used as starting compounds are prepared by known methods or It can be produced by the method described in Reference Examples, or can be obtained by purchasing a commercially available product.
- the above aminocarboxylic acid compound [3-b], compound [3-d] and compound [1-d] include natural proteinogenic L-amino acids, natural non-proteinogenic amino acids and D-amino acids. and unnatural amino acids can also be used.
- various aminocarboxylic acid compounds synthesized separately can also be used.
- compound [3-b] and compound [3-d] for example, two or more represented by the formula PG 2 -AA 3 -AA 4 -OH
- a compound in which the aminocarboxylic acid compound of is amidated can be used.
- the group represented by the formula -Y 2 -Y 3 -Y 4 -Z is a group represented by the formula -AA 2 -AA 3 -OH and a group represented by the formula -AA 2 -OH
- the compound represented by the group can also be produced according to the method described in Scheme 3.
- Z is a group represented by the formula -AA 5 -AA 6 -AA 7 -OH, a group represented by the formula -AA 5 -AA 6 -OH, and a group represented by the formula -AA 5
- a compound that is a group represented by —OH can also be produced according to the method described in Scheme 3.
- Step 4-1 The amino of compound [3-e] obtained in (5) in Production Method 3 described above is reacted with the carboxy of aminocarboxylic acid compound [2-a] whose amino is protected with a protecting group (PG 2 ) to form an amide. form.
- Step 4-2 Compound [4-a] can be produced by deprotecting the amino-protecting group (PG 2 ) of the N-terminal aminocarboxylic acid compound of the compound obtained in (1) above.
- Step 4-3 The amino of compound [4-a] obtained in the above (2) and the carboxy of aminocarboxylic acid compound [2-c] whose amino is protected with a protecting group (PG 2 ) are reacted to form an amide.
- Step 4-4 Compound [4-b] can be produced by deprotecting the amino-protecting group (PG 2 ) of the N-terminal aminocarboxylic acid compound of the compound obtained in (3) above.
- the aminocarboxylic acid compound bound to the resin of the compound [3-e] used in (1) above and the functional group protected on the side chain of the aminocarboxylic acid compound [2-a] are If present, the protecting group for that functional group can be deprotected at the same time.
- the protective group for the above functional group needs to be deprotected under conditions other than acid, the above-mentioned method or literature (Protective Groups in Organic Synthesis, 5th edition, 2014, Peter G. M. Wuts) or a method analogous thereto.
- the compound [2-a] and the compound [2-c], which are aminocarboxylic acid compounds include natural proteinogenic L-amino acids, natural non-proteinogenic amino acids, D-amino acids and non-natural amino acids. can also be used. In addition to these amino acids, various aminocarboxylic acid compounds synthesized separately can also be used. In addition, compounds in which the group represented by the formula -Y 2 -Y 3 -Y 4 -Z is a group represented by the formula -AA 2 -AA 3 -OH and a group represented by the formula -AA 2 -OH It can be produced according to the method described in Scheme 3.
- Step 5-1 By reacting the amino of the compound [1-c] obtained in (4) in the above-mentioned production method 1 with the carboxy of the carboxylic acid compound [5-a] that forms a sulfonamide with the ring A to form an amide, Compound [1-g] can be produced.
- Step 5-2 The compound [1-g] obtained in the above (1) is cleaved with an acid to produce the compound of the present invention represented by the formula [1-h].
- the carboxy-protecting group (PG 1 ) in the carboxylic acid compound [5-a] used in (1) above can be deprotected at the same time.
- the aminocarboxylic acid compound and the carboxylic acid compound [5-a] bound to the resin of the compound [1-c] used in (1) above have a protected functional group on the side chain.
- the protecting group of the functional group can be deprotected at the same time.
- the protective group for the above functional group needs to be deprotected under conditions other than acid, the above-mentioned method or literature (Protective Groups in Organic Synthesis, 5th edition, 2014, Peter G. M. Wuts) or a method analogous thereto.
- compound [1-h] thus obtained can be isolated and purified by known means for separation and purification, such as concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.
- compound [1-c] used as a starting compound can be produced by a known method or the method described in Reference Examples, or can be obtained by purchasing a commercially available product.
- Step 6-1 By reacting the amino of the compound [3-e] obtained in (5) in the above production method 3 with the carboxy of the carboxylic acid compound [5-a] that forms a sulfonamide with the ring A to form an amide, Compound [3-g] can be produced.
- Step 6-2 The compound of the present invention represented by the formula [3-h] can be produced by cleaving the bond with the resin of the compound [3-g] obtained in the above (1) using an acid.
- the carboxy-protecting group (PG 1 ) in the carboxylic acid compound [5-a] used in (1) above can be deprotected at the same time.
- a protected functional group is present in the side chain of the aminocarboxylic acid compound and carboxylic acid compound [5-a] bound to the resin of compound [3-e] used in (1) above.
- the protecting group of the functional group can be deprotected at the same time.
- the protective group for the above functional group needs to be deprotected under conditions other than acid, the above-mentioned method or literature (Protective Groups in Organic Synthesis, 5th edition, 2014, Peter G. M. Wuts) or a method analogous thereto.
- compound [3-h] thus obtained can be isolated and purified by known means for separation and purification, such as concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.
- compound [3-e] used as a starting compound can be produced by a known method or the method described in Reference Examples, or can be obtained by purchasing a commercially available product.
- di-C 1- may be substituted with 1 to 3 groups identically or differently selected from the group consisting of 6 alkylamino), mono C 3-8 cycloalkylamino (wherein said mono C 3-8 cycloalkylamino is optionally substituted with hydroxy, amino and C 1-6 alkyl (wherein said C 1-6 alkyl is 1 amino); ), monoadamantylamino, monospiroheptanylamino, mono 4- to 8-membered saturated heterocyclylamino (the mono 4- to 8-membered saturated heterocyclylamino may be substituted with 1 to 2 oxo); monoarylamino, monoheteroarylamino, Di-C 1-6 alkylamino (each C 1-6 alkyl of said di-C 1-6 alkylamino is amino,
- n 2 represents an integer of 1 to 8
- R N4 represents a hydrogen atom or C 1-3 alkyl.
- Scheme 7 shows the preparation of a compound represented by the following formula [7-c], wherein ZBG is carboxy, R ZBG is a hydrogen atom, and RN1 is a hydrogen atom.
- Step 7-1 Using a weak acid to selectively cleave the bond with the resin without deprotecting the carboxy-protecting group (PG 1 ) of the compound [3-g] obtained in (8) in Production Method 3 above. can produce compound [7-a].
- Examples of the weak acid include HFIP or its diluted solution.
- Step 7-2) The carboxy of the C-terminal aminocarboxylic acid compound of compound [7-a] obtained in (1) above and the amino of compound [7-b] are reacted to form an amide.
- Step 7-3) The compound of the present invention represented by formula [7-c] can be produced by deprotecting PG 1 of the compound obtained in (2) above. At this time, when there is a protected functional group on the side chain of the resin-bonded aminocarboxylic acid compound [3-g] used in (1) above and the amino compound [7-b] can deprotect the protective group of the functional group at the same time.
- the protective group for the above functional group needs to be deprotected under conditions other than acid, the above-mentioned method or literature (Protective Groups in Organic Synthesis, 5th edition, 2014, Peter G. M. Wuts) or a method analogous thereto.
- compound [7-c] thus obtained can be isolated and purified by known means for separation and purification, such as concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.
- compound [7-b] used as a starting compound can be produced by a known method or the method described in Reference Examples, or can be obtained by purchasing a commercially available product.
- Z is a group represented by the formula -AA 5 -R 6C , a group represented by the formula -AA 5 -AA 6 -R 7C , or the formula
- the compound represented by -AA 5 -AA 6 -AA 7 -R 8C is produced by combining the method described in this production method with the method described in the above-mentioned production method 3 or a method analogous thereto. be able to.
- Z is a group represented by the formula -W 5 -R 6N .
- Manufacturing method 8 Scheme 8 shows the production of a compound represented by formula [8-c] in the following scheme, which is a raw material used for the manufacture of compounds represented by formulas [9-c] and [10-c] described later. show. ⁇ Scheme 8 ⁇
- Step 8-1 Compound [8-b] can be produced by deprotecting the amino-protecting group (PG 3 ) of compound [8-a].
- PG 3 includes, for example, Fmoc, Boc, Cbz, Alloc, and t-Bu.
- Step 8-2) Compound [8-c] can be produced by reacting compound [8-b] obtained in (1) above with 4-nitrophenyl aminohechloroformate (ClOCO-Ph-NO 2 ).
- compound [8-c] thus obtained can be isolated and purified by known means for separation and purification, such as concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.
- compound [8-a] used as a starting compound can be produced by a known method or the method described in Reference Examples, or can be obtained by purchasing a commercially available product.
- L 1 is the aforementioned L 1a
- a group represented by the formula -Y 2 -Y 3 -Y 4 -Z is a group represented by the formula -AA 2 -AA 3 -AA 4 -NH 2
- Scheme 9 shows the preparation of a compound represented by the following formula [9-c], wherein ZBG is carboxy, RZBG is a hydrogen atom, RN1 is a hydrogen atom, and RN3 is a hydrogen atom.
- Step 9-1 The amino of compound [1-c] obtained in (4) in Production Method 1 described above is reacted with compound [8-c] obtained in Production Method 8 described above to form urea.
- Step 9-2) The N-terminal amino-protecting group (PG 2 ) of the compound obtained in (1) above is deprotected.
- Step 9-3) Compound [9-b] can be produced by reacting compound [1-f] with compound [9-a] obtained in (2) above to sulfonylate it.
- Step 9-4 The compound [9-b] obtained in the above (3) is cleaved with an acid to produce the compound of the present invention represented by the formula [9-c].
- the carboxy-protecting group (PG 1 ) in compound [8-c] used in (1) above can be deprotected at the same time.
- the functional group can be deprotected.
- the protective group for the above functional group needs to be deprotected under conditions other than acid, the above-mentioned method or literature (Protective Groups in Organic Synthesis, 5th edition, 2014, Peter G. M. Wuts) or a method analogous thereto. Then, if deprotection is required under conditions other than acid, in principle, after deprotecting the protective group of the above functional group under the conditions, other protective groups are deprotected under acid conditions and the resin and bond is cut.
- the compound [9-c] thus obtained can be isolated and purified by known means for separation and purification, such as concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.
- compound [1-f] used as a starting compound can be produced by a known method or the method described in Reference Examples, or can be obtained by purchasing a commercially available product.
- a group represented by formula -Y 2 -Y 3 -Y 4 -Z is a group represented by formula -AA 2 -AA 3 -NH 2 and a group represented by formula -AA 2
- a compound represented by —NH 2 can also be prepared according to the method described in Scheme 9.
- Z is a group represented by the formula -AA5 -AA6- AA7 - NH2 , a group represented by the formula -AA5 - AA6- NH2 , and a group represented by the formula -
- a compound represented by AA 5 -NH 2 can also be produced according to the method described in Scheme 9.
- L 1 is the aforementioned L 1a , a group represented by the formula -Y 2 -Y 3 -Y 4 -Z is a group represented by the formula -AA 2 -AA 3 -AA 4 -OH, ZBG is carboxy, R ZBG is a hydrogen atom, R N1 is a hydrogen atom, and R N3 is a hydrogen atom;
- Scheme 10 shows the production of a compound represented by the following formula [10-c]. ⁇ Scheme 10 ⁇
- Step 10-1 The amino of compound [3-e] obtained in (5) in Production Method 3 is reacted with compound [8-c] obtained in Production Method 8 to form urea.
- Step 10-2 The N-terminal amino-protecting group (PG 2 ) of the compound obtained in (1) above is deprotected.
- Step 10-3 Compound [10-b] can be produced by reacting compound [1-f] with compound [10-a] obtained in (2) above for sulfonylation.
- Step 10-4 The compound of the present invention represented by the formula [10-c] can be produced by cleaving the bond with the resin of the compound [10-b] obtained in (3) above with an acid. At this time, the carboxy-protecting group (PG 1 ) in compound [8-c] used in (1) above can be deprotected at the same time. At this time, when a protected functional group is present in the side chain of the aminocarboxylic acid compound bound to the resin of the compound [3-e] used in (1) above, at the same time, the functional group can be deprotected.
- the protective group for the above functional group needs to be deprotected under conditions other than acid, the above-mentioned method or literature (Protective Groups in Organic Synthesis, 5th edition, 2014, Peter G. M. Wuts) or a method analogous thereto. Then, if deprotection is required under conditions other than acid, in principle, after deprotecting the protective group of the above functional group under the conditions, other protective groups are deprotected under acid conditions and the resin and bond is cut.
- the compound [10-c] thus obtained can be isolated and purified by known means for separation and purification, such as concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.
- compound [1-f] used as a starting compound can be produced by a known method or the method described in Reference Examples, or can be obtained by purchasing a commercially available product.
- a group represented by the formula -Y 2 -Y 3 -Y 4 -Z is a group represented by the formula -AA 2 -AA 3 -OH
- a group represented by the formula -AA 2 - A compound represented by OH can also be produced according to the method described in Scheme 10.
- Z is a group represented by the formula -AA 5 -AA 6 -AA 7 -OH, a group represented by the formula -AA 5 -AA 6 -OH, and a group represented by the formula -AA 5
- a compound that is a group represented by —OH can also be produced according to the method described in Scheme 10.
- L 12 is the following formula [II-2-2]
- Step 11-1 The carboxy of compound [11-a] is reacted with the amino of compound [1-c] obtained in (4) in Production Method 1 described above to form an amide.
- Step 11-2 The azide of compound [11-b] obtained in (1) above and the ethynyl of compound [11-c] are reacted to form a triazole ring.
- Step 11-3 The N-terminal amino-protecting group (PG 2 ) of the compound obtained in (2) above is deprotected.
- Step 11-4 Compound [11-e] can be produced by reacting compound [1-f] with compound [11-d] obtained in (3) above for sulfonylation.
- Step 11-5 The compound of the present invention represented by formula [11-f] can be produced by cleaving the bond with the resin of compound [11-e] obtained in (4) above with an acid. At this time, the carboxy-protecting group (PG 1 ) in compound [11-c] used in (2) above can be deprotected at the same time.
- compound [11-f] thus obtained can be isolated and purified by known means for separation and purification, such as concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.
- compound [11-a], compound [11-c], and compound [1-f] used as starting compounds are prepared by a known method or the method described in Reference Examples. It can be obtained by manufacturing or by purchasing a commercial product.
- a group represented by formula -Y 2 -Y 3 -Y 4 -Z is a group represented by formula -AA 2 -AA 3 -NH 2 and a group represented by formula -AA 2
- a compound represented by —NH 2 can also be produced according to the method described in Scheme 11.
- Z is a group represented by the formula -AA 5 -AA 6 -AA 7 -NH 2
- a group represented by the formula - A compound represented by AA 5 -NH 2 can also be produced according to the method described in Scheme 11.
- L 12 is a structure represented by the above formula [II-2-2]
- a group represented by the formula -Y 2 -Y 3 -Y 4 -Z is a group represented by the formula -AA 2 -AA 3 -AA 4 -OH
- ZBG is carboxy
- R ZBG is a hydrogen atom
- R N1 is a hydrogen atom
- Scheme 12 shows the production of a compound represented by the following formula [12-d].
- Step 12-1 The carboxy of compound [11-a] is reacted with the amino of compound [3-e] obtained in (5) in Production Method 3 described above to form an amide.
- Step 12-2 The azide of compound [12-a] obtained in (1) above and the ethynyl of compound [11-c] are reacted to form a triazole ring.
- Step 12-3 The N-terminal amino-protecting group (PG 2 ) of the compound obtained in (2) above is deprotected.
- Step 12-4 Compound [12-c] can be produced by reacting compound [1-f] with compound [12-b] obtained in (3) above for sulfonylation.
- Step 12-5 The compound [12-c] obtained in the above (4) is cleaved with an acid to produce the compound of the present invention represented by the formula [12-d].
- the carboxy-protecting group (PG 1 ) in compound [11-c] used in (2) above can be deprotected at the same time.
- the functional group can be deprotected.
- the protective group for the above functional group needs to be deprotected under conditions other than acid, the above-mentioned method or literature (Protective Groups in Organic Synthesis, 5th edition, 2014, Peter G. M. Wuts) or a method analogous thereto. Then, if deprotection is required under conditions other than acid, in principle, after deprotecting the protective group of the above functional group under the conditions, other protective groups are deprotected under acid conditions and the resin and bond is cut.
- the compound [12-d] thus obtained can be isolated and purified by known separation and purification means such as concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.
- compound [11-a], compound [11-c], and compound [1-f] used as starting compounds are prepared by a known method or the method described in Reference Examples. It can be obtained by manufacturing or by purchasing a commercial product.
- a group represented by the formula -Y 2 -Y 3 -Y 4 -Z is a group represented by the formula -AA 2 -AA 3 -OH
- a group represented by the formula -AA 2 - A compound represented by OH can also be produced according to the method described in Scheme 12.
- Z is a group represented by the formula -AA 5 -AA 6 -AA 7 -OH, a group represented by the formula -AA 5 -AA 6 -OH, and a group represented by the formula -AA 5
- a compound represented by -OH can also be produced according to the method described in Scheme 12.
- Step 13-1 The carboxy of compound [13-a] is reacted with the amino of compound [1-c] obtained in (4) in Production Method 1 described above to form an amide.
- Step 13-2 The ethynyl of compound [13-b] obtained in (1) above and the azide of compound [13-c] are reacted to form a triazole ring.
- Step 13-3) The N-terminal amino-protecting group (PG 2 ) of the compound obtained in (2) above is deprotected.
- Step 13-4) Compound [13-e] can be produced by reacting compound [1-f] with compound [13-d] obtained in (3) above to sulfonylate the compound.
- Step 13-5) The compound of the present invention represented by the formula [13-f] can be produced by cleaving the bond with the resin of the compound [13-e] obtained in (4) above with an acid. At this time, the carboxy-protecting group (PG 1 ) in compound [13-c] used in (2) above can be deprotected at the same time.
- compound [13-f] thus obtained can be isolated and purified by known means for separation and purification, such as concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.
- compound [13-a], compound [13-c], and compound [1-f] used as starting compounds are prepared by a known method or the method described in Reference Examples. It can be obtained by manufacturing or by purchasing a commercial product.
- a group represented by formula -Y 2 -Y 3 -Y 4 -Z is a group represented by formula -AA 2 -AA 3 -NH 2 and a group represented by formula -AA 2
- a compound represented by —NH 2 can also be prepared according to the method described in Scheme 13.
- Z is a group represented by the formula -AA5 -AA6- AA7 - NH2 , a group represented by the formula -AA5 - AA6- NH2 , and a group represented by the formula -
- a compound represented by AA 5 -NH 2 can also be produced according to the method described in Scheme 13.
- L 12 is a structure represented by the above formula [II-2-3]
- a group represented by the formula -Y 2 -Y 3 -Y 4 -Z is a group represented by the formula -AA 2 -AA 3 -AA 4 -OH
- ZBG is carboxy
- R ZBG is a hydrogen atom
- R N1 is a hydrogen atom
- Scheme 14 shows the production of a compound represented by the following formula [14-d].
- Step 14-1 The carboxy of compound [13-a] is reacted with the amino of compound [3-e] obtained in (5) in Production Method 3 above to form an amide.
- Step 14-2 The ethynyl of compound [14-a] obtained in (1) above is reacted with the azide of compound [13-c] to form a triazole ring.
- Step 14-3 The N-terminal amino-protecting group (PG 2 ) of the compound obtained in (2) above is deprotected.
- Step 14-4 Compound [14-c] can be produced by reacting compound [1-f] with compound [14-b] obtained in (3) above for sulfonylation.
- Step 14-5 The compound of the present invention represented by the formula [14-d] can be produced by cleaving the bond with the resin of the compound [14-c] obtained in (4) above with an acid. At this time, the carboxy-protecting group (PG 1 ) in compound [13-c] used in (2) above can be deprotected at the same time.
- compound [14-d] thus obtained can be isolated and purified by known separation and purification means such as concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.
- compound [13-a], compound [13-c], and compound [1-f] used as starting compounds are prepared by a known method or the method described in Reference Examples. It can be obtained by manufacturing or by purchasing a commercial product.
- a group represented by formula -Y 2 -Y 3 -Y 4 -Z is a group represented by formula -AA 2 -AA 3 -OH
- a group represented by formula -AA 2 - A compound having a group represented by OH can also be produced according to the method described in Scheme 14.
- Z is a group represented by the formula -AA 5 -AA 6 -AA 7 -OH, a group represented by the formula -AA 5 -AA 6 -OH, and a group represented by the formula -AA 5
- a compound represented by -OH can also be produced according to the method described in Scheme 14.
- amino acids can be used as the aminocarboxylic acid, including natural proteinogenic L-amino acids and natural non-proteinogenic amino acids. , D-amino acids and unnatural amino acids can also be used.
- various aminocarboxylic acid compounds synthesized separately can also be used.
- the various aminocarboxylic acid compounds for example, a compound in which two or more aminocarboxylic acid compounds are amidated can be used.
- Fat-soluble protecting groups include, for example, 9-fluorenylmethoxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), benzyl (Bn), allyl (Allyl), allyloxycarbonyl (Alloc), acetyl (Ac) Carbonate-based, amide-based, or alkyl-based protecting groups such as A fat-soluble protecting group can be introduced into an amino acid by adding 9-fluorenylmethyl-N-succinidyl carbonate and sodium hydrogencarbonate and reacting, for example, in the case of introducing Fmoc. The reaction is preferably carried out at 0 to 50° C., preferably room temperature, for about 1 to 5 hours.
- any resin usually used in solid-phase synthesis may be used, for example, chlorine atom-functionalized 2-chlorotrityl chloride resin, Wang resin, HMPA-PEGA resin, amino-functionalized Amino-PEGA resin can be used.
- a method for obtaining an amide at the C-terminus of a peptide solid phase synthesis using a resin for synthesizing an amide is preferred.
- Rink-Amide-AM resin, SAL-PEG resin, SAL-MBHA resin, Rink-Amide-PEGA resin can be used. By cleaving these resins and peptides with an acid, an amide at the C-terminus of the peptide can be obtained.
- the binding of an amino acid whose amino is protected with a fat-soluble protective group to a resin is achieved by, for example, ester-bonding the carboxy of the amino acid to the resin when using a resin having a hydroxy group or a resin functionalized with a chlorine atom. , can be combined. Alternatively, if an amino-functionalized resin is used, the carboxy of the amino acid can be attached via an amide bond to the resin.
- 2-chlorotrityl chloride resin it can be esterified using a base such as diisopropylethylamine (DIPEA), triethylamine, pyridine, or the like.
- esterification catalysts such as 1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole (MSNT), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC ) and other known dehydration-condensation agents can be used.
- the proportion of the amino acid and the dehydration-condensation agent to be used is usually 1 to 10 equivalents, preferably 2 to 5 equivalents, of the latter to 1 equivalent of the former.
- the esterification reaction is preferably carried out, for example, by placing the resin in a solid phase column, washing the resin with a solvent, and then adding a solution of amino acids.
- washing solvents include chloroform, dimethylformamide (DMF), 2-propanol, and dichloromethane.
- Solvents that dissolve amino acids include, for example, chloroform, dimethylsulfoxide (DMSO), DMF, and dichloromethane.
- the esterification reaction is preferably carried out at 0 to 50° C., preferably room temperature, for about 10 minutes to 30 hours, preferably about 15 minutes to 24 hours. At this time, it is also preferable to treat unreacted hydroxy on the solid phase with an alcohol/base. Detachment of the fat-soluble protective group can be performed, for example, by treatment with a base. Examples of bases include piperidine and morpholine. At that time, it is preferable to carry out in the presence of a solvent.
- solvents examples include DMF, DMSO, and methanol.
- activating agents include dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (WSC/HCl), diphenylphosphorylazide (DPPA), carbonyldiimidazole (CDI), diethyl Cyanophosphonate (DEPC), benzotriazol-1-yloxy-tris pyrrolidinophosphonium (DIPCI), benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (PyBOP), 1-hydroxybenzotriazole (HOBt), hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP),
- DCC dicyclohexylcarbodiimide
- WSC/HCl 1-ethyl-3-(dimethylaminopropyl)carbodiimi
- the amount of the activator used is 1 to 20 equivalents, preferably 1 to 10 equivalents, more preferably 1 to 5 equivalents, relative to any amino acid whose amino is protected with a fat-soluble protecting group. preferable.
- solvents include DMF, DMSO, and dichloromethane.
- the reaction is carried out at 0 to 50° C., preferably room temperature, for about 10 minutes to 30 hours, preferably about 15 minutes to 2 hours. If the rate of progress of the reaction is low at this time, the rate of progress can be increased by repeating the amidation operation. At this time, it is also preferable to acetylate and cap unreacted amino on the solid phase using acetic anhydride or the like.
- Cleavage of the peptide chain from the resin can be carried out by treatment with an acid.
- Acids can include, for example, trifluoroacetic acid (TFA), hydrogen fluoride (HF), hexafluoro-2-propanol (HFIP).
- TFA trifluoroacetic acid
- HF hydrogen fluoride
- HFIP hexafluoro-2-propanol
- the deresin reaction is preferably carried out at 0 to 50° C., preferably room temperature, for about 10 minutes to 10 hours, preferably about 30 minutes to 4 hours.
- room temperature refers to 20 to 30°C unless otherwise specified.
- Under ice cooling refers to 0 to 5°C unless otherwise specified.
- the "silica gel cartridge" when purified using column chromatography includes Biotage (registered trademark) SNAP Ultra, Biotage (registered trademark) Sfar Silica HCD, Biotage (registered trademark) Sfar Amino D, Buchi REVELERIS (registered trademark) Silica, or BUCHI REVELERIS (registered trademark) C18 was used.
- Reversed-phase column chromatography was used for MS preparative purification, and (hereinafter sometimes referred to as preparative LCMS) was appropriately selected from the following four conditions for purification.
- Preparative apparatus Agilent 1260 Infinity and Agilent 6130 (ionization method: Electron Spray Ionization: ESI) manufactured by Agilent, and Agilent 385-ELSD was used when an ELSD detector was attached.
- Solvent Liquid A: Water containing 0.1% formic acid, Liquid B: acetonitrile containing 0.1% formic acid, Liquid C: water containing 0.1% TFA, Liquid D: acetonitrile containing 0.1% TFA Flow rate: 50 mL/min .
- Reversed-phase preparative HPLC used reversed-phase column chromatography (hereinafter sometimes referred to as preparative HPLC) was appropriately selected from the following two conditions for purification.
- Preparative device GILSON, SoftTA Model 300S ELSD was used when an ELSD detector was attached.
- Solvent A solution: water containing 0.1% formic acid (or TFA), B solution: acetonitrile containing 0.1% formic acid (or TFA) Flow rate: 40 mL/min. Either of the following columns was used.
- Zinc (1.66 mmol) and iodine (0.16 mmol) were weighed into a flask and the system was purged with nitrogen.
- a DMF (1.5 mL) solution of the compound (0.61 mmol) obtained in the above (1) was added thereto and stirred for 3 minutes. After that, the mixture was stirred in an oil bath at 60°C for 10 minutes.
- 1,4-dioxane (0.5 mL) was added to the reaction solution, and then 1-( ⁇ [(9H-fluoren-9-yl)methoxy]carbonyl ⁇ oxy)pyrrolidine-2,5-dione (1.4 mmol) was added. It was added in portions and stirred overnight at room temperature. Since a precipitate was observed in the reaction solution, it was filtered ( ⁇ 40, No. 5B) and the residue was thoroughly washed with water. The filtrate was collected and partitioned twice with chloroform (30 mL). The aqueous phase was collected, adjusted to pH around 2 with 1 mol/L hydrochloric acid, and then extracted three times with chloroform (30 mL).
- a saturated aqueous sodium hydrogencarbonate solution (100 mL) was added and the mixture was stirred and extracted twice with ethyl acetate (150 mL). The organic phase was collected and washed with an aqueous sodium hydroxide solution (1 mol/L, 100 mL) and saturated brine (100 mL). Diatomaceous earth (500 mL) was added to the remaining organic phase, and the solvent was distilled off under reduced pressure. A silica gel pad (Nacarai CHROMATREX NH, 400 mL) was placed in a suction filter, and diatomaceous earth containing the desired product was placed on the silica gel.
- the compound obtained in (1) above was treated with a solution of piperidine in DMF (concentration: 20%, 20 mL) for 15 minutes to deprotect the Fmoc group, and washed with DMF (20 mL) three times. followed by N- ⁇ [(9H-fluoren-9-yl)methoxy]carbonyl ⁇ glycine (6.0 mmol), COMU (6.0 mmol), Oxyma (6.0 mmol), and DIPEA (1.05 mL) in DMF (20 mL) solution was added and shaken at room temperature for 40 minutes. The resulting compound was washed with DMF (20 mL) three times.
- Reference Example 7-7 4-( ⁇ (2S,5S,13S)-2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-13- ⁇ [4-chloro-3-(trifluoromethyl)benzene-1 -sulfonyl]amino ⁇ -16,16-dimethyl-5-[(3-methylpyridin-4-yl)methyl]-4,7,10,14-tetraoxo-15-oxa-3,6,9-triazaheptadecanan-1 -oyl ⁇ amino) benzoic acid
- the title compound was obtained from the corresponding starting materials using a method similar to that described in Reference Example 7-1. The compound was subjected to the next reaction without measuring physical property data.
- Aqueous hydrogen peroxide (30%, 4.0 mL) and an aqueous sodium hydroxide solution (1 mol/L, 2.7 mL) were added to a dimethyl sulfoxide (5.0 mL) solution of the compound obtained in (1) above, and the mixture was stirred at room temperature. for 3 days. Water was added and the mixture was extracted with ethyl acetate. The organic phase was collected and washed with water and saturated brine. After drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
- the title compound was obtained from the corresponding starting material using methods similar to those described in Reference Examples 9-23. The compound was subjected to the next reaction without measuring physical property data.
- a hydrogen chloride-ethyl acetate solution (4 mol/L, 1.1 mL) was added to an ethyl acetate (5 mL) solution of the compound (0.91 mmol) obtained in (1) above, and the mixture was stirred at room temperature for 30 minutes.
- a hydrogen chloride-ethyl acetate solution (4 mol/L, 1.1 mL) was added, and the mixture was stirred at room temperature for 3 hours. Further, a hydrogen chloride-ethyl acetate solution (4 mol/L, 1.1 mL) was added and stirred. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain the desired product in step (2) as a brown oily substance.
- Formaldehyde (4.5 mmol) and sodium triacetoxyborohydride (2.3 mmol) were added to a chloroform (5 mL) solution of the compound (0.91 mmol) obtained in (2) above, and the mixture was stirred at room temperature for 2 hours. Furthermore, formaldehyde (4.5 mmol) and sodium triacetoxyborohydride (2.3 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Furthermore, formaldehyde (4.5 mmol), sodium triacetoxyborohydride (2.3 mmol) and ethanol (2 mL) were added, and the mixture was stirred at room temperature for 17 hours. After completion of the reaction, the solvent was distilled off under reduced pressure.
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Abstract
La présente invention concerne un composé représenté par la formule [I] ayant une action inhibitrice vis-à-vis de la MMP 7 ou un sel pharmaceutiquement acceptable de celui-ci.
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Non-Patent Citations (6)
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| AMELIA SANTOS, M. ; MARQUES, S.M. ; TUCCINARDI, T. ; CARELLI, P. ; PANELLI, L. ; ROSSELLO, A.: "Design, synthesis and molecular modeling study of iminodiacetyl monohydroxamic acid derivatives as MMP inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 14, no. 22, 15 November 2006 (2006-11-15), AMSTERDAM, NL, pages 7539 - 7550, XP027992186, ISSN: 0968-0896 * |
| FUJISAWA T., S KATAKURA, S ODAKE, Y MORITA, J YASUDA, I YASUMATSU, T MORIKAWA: "Design and Synthesis of Carboxylate Inhibitors for Matrix Metalloproteinases", CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN, JP, vol. 49, no. 10, 1 October 2001 (2001-10-01), JP , pages 1272 - 1279, XP093000318, ISSN: 0009-2363, DOI: 10.1248/cpb.49.1272 * |
| KORNGUTH M L, A. NEIDLE, AND H. WAELSCH: "The Stability and Rearrangement of iε-N-Glutamyl-Lysines", BIOCHEMISTRY, 1 July 1963 (1963-07-01), pages 740 - 745, XP093000325, ISSN: 0006-2960, DOI: 10.1021/bi00904a020 * |
| MUHAMMED M. A. HABEEB, SHAW AJAY KUMAR, PAL SAMIR KUMAR, PRADEEP T.: "Quantum Clusters of Gold Exhibiting FRET", THE JOURNAL OF PHYSICAL CHEMISTRY C, AMERICAN CHEMICAL SOCIETY, US, vol. 112, no. 37, 18 September 2008 (2008-09-18), US , pages 14324 - 14330, XP093000330, ISSN: 1932-7447, DOI: 10.1021/jp804597r * |
| SCHELLENBERG, PETER, ULLRICH, JOHANNES: " Synthese weiterer Oligopeptide aus L-Glutaminsäure und Glycin sowie L-Tyrosin = Synthesis of further oligopeptides from L-glutaminic acid and glycine as well as L-tyrosine", CHEMISCHE BERICHTE, VCH, DE, vol. 92, no. 6, 1 June 1959 (1959-06-01), DE , pages 1276 - 1287, XP009540750, ISSN: 0009-2940, DOI: 10.1002/cber.19590920608 * |
| SONG JIAN, TANG JIJUN, GUO FEI: "Identification of Inhibitors of MMPS Enzymes via a Novel Computational Approach", INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES, vol. 14, no. 8, 1 January 2018 (2018-01-01), pages 863 - 871, XP093000346, ISSN: 1449-2288, DOI: 10.7150/ijbs.24588 * |
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