CN117377666A - Pharmaceutical compositions containing GLP-1 receptor agonists with fused rings - Google Patents

Pharmaceutical compositions containing GLP-1 receptor agonists with fused rings Download PDF

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Publication number
CN117377666A
CN117377666A CN202280037434.1A CN202280037434A CN117377666A CN 117377666 A CN117377666 A CN 117377666A CN 202280037434 A CN202280037434 A CN 202280037434A CN 117377666 A CN117377666 A CN 117377666A
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Prior art keywords
substituted
group
compound
unsubstituted
halogen
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CN202280037434.1A
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Chinese (zh)
Inventor
北村藤原美智
前野胜光
西浦祐二
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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Priority claimed from PCT/JP2022/013362 external-priority patent/WO2022202864A1/en
Publication of CN117377666A publication Critical patent/CN117377666A/en
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Abstract

The present invention relates to a compound having GLP-1 receptor agonist activity and useful as a therapeutic or prophylactic agent for diseases in which GLP-1 receptor participates, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same. A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, (wherein A 1 Is C (R) 5 ) Etc., A 2 Is C (R) 6 ) Etc., A 3 Is C (R) 7 ) Etc., R is 5 、R 6 And R is 7 Each independently is a hydrogen atom or the like, R 1 Is carboxyl or the like, R 2 Is substituted or unsubstituted alkyl, etc., -X-is-O-or the like, and the ring represented by (AAA) is (BBB) (in the formula, R 10 Each independently halogen or the like, s is 0 or the like), R 13 Each independently is a hydrogen atom or the like, R 3 An aromatic carbocyclyl group, which may be substituted or unsubstituted, and the like).

Description

Pharmaceutical compositions containing GLP-1 receptor agonists with fused rings
Technical Field
The present invention relates to a compound having GLP-1 receptor agonist activity and useful as a therapeutic or prophylactic agent for diseases in which GLP-1 receptor participates, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same, and more particularly, to a prophylactic and/or therapeutic agent for insulin-independent diabetes (type II diabetes) or obesity.
Background
Glucagon-like peptide-1 (GLP-1: glucon-like peptide-1) is an incretin hormone secreted by L cells in the intestine upon ingestion of food. GLP-1 is known to exhibit effects such as promotion of glucose-dependent insulin secretion, reduction of glucagon secretion, delay of gastric content discharge, and appetite reduction via GLP-1 receptor. Up to now, the use of agonists of GLP-1 receptor for diabetes treatment and obesity treatment has been studied (non-patent documents 1 and 2). As a representative agonist, liraglutide is known as an analog preparation of human GLP-1, and it is known that liraglutide exhibits potent HbA1c lowering action and weight loss. Because of such attractive effects, various GLP-1 analogue preparations are put into practical use as therapeutic agents for diabetes and therapeutic agents for obesity. However, most of these GLP-1 analogue formulations are sold in the form of injections because of lack of oral absorbability. Accordingly, it would be desirable to develop GLP-1 receptor agonists that can be orally administered. Specifically, a method of orally absorbing a cable Ma Lutai (semaglutide) which is a GLP-1 analogue by using an absorption accelerator (patent document 1) has been put to practical use, but has been proposed to improve drug properties such as bioavailability. In addition, as non-peptide GLP-1 receptor agonists, various low molecular weight drugs have been attempted to be developed (patent documents 2 to 33), but the compounds substantially disclosed have structures different from those of the present invention.
Prior art literature
Patent literature
Patent document 1: international publication No. 2012/080471
Patent document 2: international publication No. 2009/111700
Patent document 3: international publication No. 2010/114824
Patent document 4: international publication No. 2018/056453
Patent document 5: international publication No. 2018/109607
Patent document 6: international publication No. 2019/239319
Patent document 7: international publication No. 2019/239371
Patent document 8: international publication No. 2020/103815
Patent document 9: international publication No. 2020/207474
Patent document 10: international publication No. 2020/263695
Patent document 11: international publication No. 2021/018023
Patent document 12: international publication No. 2021/081207
Patent document 13: international publication No. 2021/096284
Patent document 14: international publication No. 2021/096304
Patent document 15: international publication No. 2021/112538
Patent document 16: international publication No. 2021/155841
Patent document 17: international publication No. 2021/160127
Patent document 18: international publication No. 2021/187886
Patent document 19: chinese patent application publication No. 113493447 specification
Patent document 20: international publication No. 2021/197464
Patent document 21: international publication No. 2021/219019
Patent document 22: chinese patent application publication No. 113480534 specification
Patent document 23: international publication No. 2021/244645
Patent document 24: international publication No. 2021/249492
Patent document 25: international publication No. 2021/242817
Patent document 26: chinese patent application publication No. 113773310 specification
Patent document 27: chinese patent application publication No. 113816948 specification
Patent document 28: chinese patent application publication No. 113801136 specification
Patent document 29: international publication No. 2021/254470
Patent document 30: international publication No. 2021/259309
Patent document 31: international publication No. 2022/028572
Patent document 32: international publication No. 2022/031994
Patent document 33: international publication No. 2022/040600
Non-patent literature
Non-patent document 1: lancet 374, 1606-1616 (2009)
Non-patent document 2: clin. Invest.2, 59-72 (2012)
Disclosure of Invention
Problems to be solved by the invention
The present invention aims to provide a compound having GLP-1 receptor agonist activity and useful as a therapeutic or prophylactic agent for diseases associated with the GLP-1 receptor, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same, particularly a prophylactic and/or therapeutic agent for insulin-independent diabetes (type II diabetes) or obesity.
Means for solving the problems
The present invention relates to the following.
(1) A compound of formula (I) or a pharmaceutically acceptable salt thereof,
[ chemical 1]
(in the formula (I),
A 1 is C (R) 5 ) Or N, or a combination of two,
A 2 is C (R) 6 ) Or N, or a combination of two,
A 3 is C (R) 7 ) Or N, or a combination of two,
R 5 、R 6 and R is 7 Each independently is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group,
R 1 is a carboxyl group or an equivalent thereof,
R 2 in order to be substituted or unsubstituted alkyl groups,
-X-is-C (R) 8 )(R 9 ) -, -O-, or-N (R) 11 )-，
R 8 And R is 9 Each independently a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group,
R 11 is a hydrogen atom or a substituted or unsubstituted alkyl group,
[ chemical 2]
The ring being represented by
[ chemical 3]
(in the formula (I),
R 10 each independently is halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclyl, or a derivative thereofSubstituted or unsubstituted alkyloxy groups,
s is an integer of 0 to 9),
R 13 each independently a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group,
R 3 is a substituted or unsubstituted aromatic carbocyclyl group or a substituted or unsubstituted aromatic heterocyclic group).
(2) The compound according to the above (1), wherein s is an integer of 1 to 9, or a pharmaceutically acceptable salt thereof.
(3) The compound according to the above (1), or a pharmaceutically acceptable salt thereof, wherein
[ chemical 4]
The ring being represented by
[ chemical 5]
(wherein s' is an integer of 0 to 8, and the other symbols have the same meaning as the ring represented by (1) above).
(4) The compound according to the above (1) or (3), or a pharmaceutically acceptable salt thereof, wherein
[ chemical 6]
The ring being represented by
[ chemical 7]
(wherein s' is an integer of 0 to 8, and the other symbols have the same meaning as the ring represented by (1) above).
(5) The compound according to any one of the above (1) to (4), or a pharmaceutically acceptable salt thereof, wherein R 10 Each independently is halogen, cyano, substituted or unsubstituted alkyl.
(6) The compound according to any one of the above (1) to (5), or a pharmaceutically acceptable salt thereof, wherein R 3 Is that
[ chemical 8]
(in the formula (I),
T 1 is a carbon atom or a nitrogen atom,
T 2 is a carbon atom or a nitrogen atom,
R 4 each independently is halogen, cyano, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy,
m is an integer of 0 to 5).
(7) The compound according to any one of the above (1) to (6), or a pharmaceutically acceptable salt thereof, wherein R 3 Is that
[ chemical 9]
(in the formula, each symbol has the same meaning as in the above (6)).
(8) The compound according to the above (6) or (7), or a pharmaceutically acceptable salt thereof, wherein R 4 Each independently halogen.
(9) The compound according to any one of the above (1) to (8), or a pharmaceutically acceptable salt thereof, wherein R 13 Each independently is a hydrogen atom, a substituted or unsubstituted alkyl group.
(10) The compound according to any one of the above (1) to (9), or a pharmaceutically acceptable salt thereof, wherein (i) A 1 Is C (R) 5 )，A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 ) Or (b)
(ii)A 1 Is N, A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 ) Or (b)
(iii)A 1 Is C (R) 5 )，A 2 Is C (R) 6 ) And A is 3 Is N, or
(iv)A 1 Is N, A 2 Is C (R) 6 ) And A is 3 Is N.
(11) The compound according to any one of the above (1) to (10), or a pharmaceutically acceptable salt thereof, wherein (i) A 1 Is C (R) 5 )，A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 ) Or (b)
(ii)A 1 Is N, A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 )。
(12) The compound according to any one of the above (1) to (11), or a pharmaceutically acceptable salt thereof, wherein R 5 、R 6 And R is 7 Is a hydrogen atom.
(13) The compound according to any one of the above (1) to (12), or a pharmaceutically acceptable salt thereof, wherein R 1 Is carboxyl.
(14) The compound according to any one of the above (1) to (13), or a pharmaceutically acceptable salt thereof, wherein R 2 Is alkyl, alkyl substituted by a substituted or unsubstituted non-aromatic heterocycle, or alkyl substituted by a substituted or unsubstituted aromatic heterocycle.
(15) The compound according to any one of the above (1) to (14), or a pharmaceutically acceptable salt thereof, wherein R 2 Alkyl substituted by a substituted or unsubstituted non-aromatic heterocycle or alkyl substituted by a substituted or unsubstituted aromatic heterocycle.
(16) The compound according to any one of the above (1) to (15), or a pharmaceutically acceptable salt thereof, wherein-X-is-C (R 8 )(R 9 )-。
(17) The compound according to any one of the above (1) to (16), or a pharmaceutically acceptable salt thereof, wherein R 8 And R is 9 Is a hydrogen atom.
(1') a compound of formula (I) or a pharmaceutically acceptable salt thereof,
[ chemical 10]
(in the formula (I),
A 1 is C (R) 5 ) Or N, or a combination of two,
A 2 is C (R) 6 ) Or N, or a combination of two,
A 3 is C (R) 7 ) Or N, or a combination of two,
R 5 、R 6 R 7 each independently is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group,
R 1 is carboxyl or its equivalent or CH 2 COOH，
R 2 Is a substituted or unsubstituted alkyl group or a substituted or unsubstituted non-aromatic heterocyclic group, -X-is-C (R 8 )(R 9 ) -, -O-, or-N (R) 11 )-，
R 8 And R is 9 Each independently is a hydrogen atom, halogen or substituted or unsubstituted alkyl, R 11 Is a hydrogen atom or a substituted or unsubstituted alkyl group,
[ chemical 11]
The ring being represented by
[ chemical 12]
[ chemical 13]
[ chemical 14]
(in the formula (I),
R 10 each independently is halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclyl, or substituted or unsubstituted alkyloxy,
s is an integer of 0 to 9),
R 13 each independently a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group,
R 3 is a substituted or unsubstituted aromatic carbocyclyl group, a substituted or unsubstituted non-aromatic carbocyclyl group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group).
(1' -2) a compound represented by the formula (II) or a pharmaceutically acceptable salt thereof,
[ 15]
(in the formula (I),
A 1 is C (R) 5 ) Or N, or a combination of two,
A 2 is C (R) 6 ) Or N, or a combination of two,
A 3 is C (R) 7 ) Or N, or a combination of two,
R 5 、R 6 and R is 7 Each independently is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group,
R 1 is carboxyl or its equivalent or CH 2 COOH，
R 2 R is a substituted or unsubstituted alkyl or a substituted or unsubstituted non-aromatic heterocyclic group 13 Each independently a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group,
R 3 is a substituted or unsubstituted aromatic carbocyclyl, a substituted or unsubstituted non-aromatic carbocyclyl, a substituted or unsubstituted aromatic heterocyclyl, or a substitutedOr an unsubstituted non-aromatic heterocyclic group,
E 1 is a carbon atom or a nitrogen atom,
E 2 is a carbon atom or a nitrogen atom,
R 10 each independently is halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclyl, or substituted or unsubstituted alkyloxy,
r is an integer from 0 to 9).
(2 ') the compound according to (1') above, wherein s is an integer of 1 to 9, or a pharmaceutically acceptable salt thereof.
(3 ') the compound according to (1') above or a pharmaceutically acceptable salt thereof, wherein
[ 16]
The ring being represented by
[ chemical 17]
[ chemical 18]
[ chemical 19]
(wherein s 'is an integer of 0 to 8, and the other symbols have the same meaning as the ring represented by (1') above).
(4 ') the compound according to (1') above or a pharmaceutically acceptable salt thereof, wherein
[ chemical 20]
The ring being represented by
[ chemical 21]
(wherein s 'is an integer of 0 to 8, and the other symbols have the same meaning as the ring represented by (1') above).
(5 ') the compound according to any one of (1') to (4 ') and (1' -2) above, or a pharmaceutically acceptable salt thereof, wherein R 10 Each independently is halogen, cyano, substituted or unsubstituted alkyl.
(6 ') the compound according to any one of (1') to (5 ') and (1' -2) above, or a pharmaceutically acceptable salt thereof, wherein R 3 Is that
[ chemical 22]
(in the formula (I),
T 1 is a carbon atom or a nitrogen atom,
T 2 is a carbon atom or a nitrogen atom,
R 4 each independently is halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, or substituted or unsubstituted alkylsulfonyl,
R 14 Is a hydrogen atom or a substituted or unsubstituted alkyl group,
m is an integer of 0 to 5,
n is an integer of 0 to 2).
(7 ') the compound according to the above (6'), or a pharmaceutically acceptable salt thereof, wherein R 3 Is that
[ chemical 23]
(in the formula (I),
T 1 is C (R) 12 ) Or N, or a combination of two,
T 2 is C (R) 12 ) Or N, or a combination of two,
R 12 each independently is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted alkylsulfonyl group,
R 4 the meaning of (3) is the same as that of (6') above.
(8 ') the compound or pharmaceutically acceptable salt of the above-mentioned (6 ') or (7 '), wherein R 4 Each independently is halogen, and R 12 Each independently a hydrogen atom or a halogen.
(9 ') the compound according to any one of (1') to (8 ') and (1' -2) above, or a pharmaceutically acceptable salt thereof, wherein R 13 Each independently is a hydrogen atom, a substituted or unsubstituted alkyl group.
(10 ') the compound according to any one of (1') to (9 ') and (1' -2) above, or a pharmaceutically acceptable salt thereof, wherein (i) A 1 Is C (R) 5 )，A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 ) Or (b)
(ii)A 1 Is N, A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 ) Or (b)
(iii)A 1 Is C (R) 5 )，A 2 Is C (R) 6 ) And A is 3 Is N, or
(iv)A 1 Is N, A 2 Is C (R) 6 ) And A is 3 Is N.
(11 ') the compound according to (10') above or a pharmaceutically acceptable salt thereof, wherein (i) A 1 Is C (R) 5 )，A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 ) Or (b)
(ii)A 1 Is N, A 2 Is C (R) 6 ) And (2) andA 3 is C (R) 7 )。
(12 ') the compound or pharmaceutically acceptable salt of the above-mentioned (10 ') or (11 '), wherein R 6 Is a hydrogen atom, and R 5 And R is 7 Each independently a hydrogen atom or a halogen.
(13 ') the compound according to any one of (1') to (12 ') and (1' -2) above, or a pharmaceutically acceptable salt thereof, wherein R 1 Is carboxyl.
(14 ') the compound according to any one of (1') to (13 ') and (1' -2) above, or a pharmaceutically acceptable salt thereof, wherein R 2 Is alkyl, alkyl substituted by a substituted or unsubstituted non-aromatic heterocycle, or alkyl substituted by a substituted or unsubstituted aromatic heterocycle.
(15 ') the compound according to (14') above or a pharmaceutically acceptable salt thereof, wherein R 2 Alkyl substituted by a substituted or unsubstituted non-aromatic heterocycle or alkyl substituted by a substituted or unsubstituted aromatic heterocycle.
(16 ') the compound according to any one of (1 ') to (15 ') above, wherein-X-is-C (R) 8 )(R 9 )-。
(17 ') the compound according to the above (16'), or a pharmaceutically acceptable salt thereof, wherein R 8 And R is 9 Is a hydrogen atom.
(1') a compound of formula (I) or a pharmaceutically acceptable salt thereof,
[ chemical 24]
(in the formula (I),
A 1 is C (R) 5 ) Or N, or a combination of two,
A 2 is C (R) 6 ) Or N, or a combination of two,
A 3 is C (R) 7 ) Or N, or a combination of two,
R 5 、R 6 and R is 7 Each independently is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkaneA group, a substituted or unsubstituted alkyloxy group, or a substituted or unsubstituted non-aromatic carbocyclic group,
R 1 is carboxyl or its equivalent or CH 2 COOH，
R 2 Is a substituted or unsubstituted alkyl group or a substituted or unsubstituted non-aromatic heterocyclic group,
-X-is-C (R) 8 )(R 9 ) -, -O-, or-N (R) 11 )-，
R 8 And R is 9 Each independently a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group,
R 11 is a hydrogen atom or a substituted or unsubstituted alkyl group,
[ chemical 25]
The ring indicated is->
[ chemical 26]
[ chemical 27]
[ chemical 28]
(in the formula (I),
R 10 each independently is halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclyl, or substituted or unsubstituted alkyloxy,
s is an integer of 0 to 9),
R 13 each independently is a hydrogen atom, halogen, or substituted or unsubstitutedA substituted alkyl group,
R 3 is a substituted or unsubstituted aromatic carbocyclyl group, a substituted or unsubstituted non-aromatic carbocyclyl group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group).
(2') a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
[ chemical 29]
(in the formula (I),
A 1 is C (R) 5 ) Or N, or a combination of two,
A 2 is C (R) 6 ) Or N, or a combination of two,
A 3 is C (R) 7 ) Or N, or a combination of two,
R 5 、R 6 and R is 7 Each independently is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, or a substituted or unsubstituted non-aromatic carbocyclic group,
R 1 is carboxyl or its equivalent or CH 2 COOH，
R 2 R is a substituted or unsubstituted alkyl or a substituted or unsubstituted non-aromatic heterocyclic group 13 Each independently a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group,
R 3 is a substituted or unsubstituted aromatic carbocyclyl group, a substituted or unsubstituted non-aromatic carbocyclyl group, a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group,
E 1 is a carbon atom or a nitrogen atom,
E 2 is a carbon atom or a nitrogen atom,
R 10 each independently is halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclyl, or substituted or unsubstituted alkyloxy,
r is an integer from 0 to 9).
(3 ") the compound according to (1") above, or a pharmaceutically acceptable salt thereof, wherein s is an integer of 1 to 9.
(4 ') the compound as described in (1') above or a pharmaceutically acceptable salt thereof, wherein
[ chemical 30]
The ring being represented by
[ 31]
[ chemical 32]
[ 33]
(wherein s 'is an integer of 0 to 8, and the other symbols have the same meaning as the ring represented by the above (1').
(5 ') the compound as described in (1') above or a pharmaceutically acceptable salt thereof, wherein
[ chemical 34]
The ring being represented by
[ 35]
(wherein p is an integer of 0 to 6, and the other symbols have the same meaning as the ring represented by the above (1')).
(5 "-2) the compound of (1") above or a pharmaceutically acceptable salt thereof, wherein
[ 36]
The ring being represented by
[ 37]
(wherein s 'is an integer of 0 to 8, and the other symbols have the same meaning as the ring represented by the above (1').
(5 "-3) the compound of (1") above or a pharmaceutically acceptable salt thereof, wherein
[ 38]
The ring being represented by
[ 39]
(wherein s is an integer of 1 to 9, and the other symbols have the same meaning as the ring represented by the above (1')).
(6 ") the compound according to any one of (1") -5 "), (5" -2) and (5 "-3), or a pharmaceutically acceptable salt thereof, wherein R 10 Each independently is halogen, cyano, or substituted or unsubstituted alkyl.
(7 ") the compound according to any one of (1") -6 "), (5" -2) and (5 "-3), or a pharmaceutically acceptable salt thereof, wherein R 3 Is that
[ 40]
(in the formula (I),
T 1 is a carbon atom or a nitrogen atom,
T 2 is a carbon atom or a nitrogen atom,
R 4 each independently is halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, or substituted or unsubstituted alkylsulfonyl,
R 14 is a hydrogen atom or a substituted or unsubstituted alkyl group,
m is an integer of 0 to 5,
n is an integer of 0 to 2).
(8 ") the compound of (7") above, or a pharmaceutically acceptable salt thereof, wherein R 3 Is that
[ chemical 41]
(in the formula (I),
T 1 is C (R) 12 ) Or N, or a combination of two,
R 12 each independently is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted alkylsulfonyl group,
R 4 and R is 14 The meaning of (3) is the same as that of (7') above.
(9 ') the compound as described in (8') above or a pharmaceutically acceptable salt thereof, wherein R 3 Is that
[ chemical 42]
(in the formula (I),
T 1 is C (R) 12 ) Or N, or a combination of two,
R 12 each independently is a hydrogen atom or a halogen,
R 4 each independently is halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted non-aromatic carbocyclyl).
(10 ") the compound according to any one of (7") to (9 ") above, or a pharmaceutically acceptable salt thereof, wherein R 4 Each independently is halogen, and R 12 Each independently a hydrogen atom or a halogen.
(11 ") the compound according to any one of (1") -10 "), (5" -2) and (5 "-3), or a pharmaceutically acceptable salt thereof, wherein R 13 Each independently is a hydrogen atom or a substituted or unsubstituted alkyl group.
(12 ") the compound according to any one of (1") -11 "), (5" -2) and (5 "-3), or a pharmaceutically acceptable salt thereof, wherein (i) a 1 Is C (R) 5 )，A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 ) Or (b)
(ii)A 1 Is N, A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 ) Or (b)
(iii)A 1 Is C (R) 5 )，A 2 Is C (R) 6 ) And A is 3 Is N, or
(iv)A 1 Is N, A 2 Is C (R) 6 ) And A is 3 Is N.
(13 ') the compound as described in (12') above or a pharmaceutically acceptable salt thereof, wherein (i) A 1 Is C (R) 5 )，A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 ) Or (b)
(ii)A 1 Is N, A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 )。
(14 ') the compound as described in (12 ') or (13 ') above or a pharmaceutically acceptable salt thereof, wherein R 5 Is a hydrogen atom or halogen, R 6 Is a hydrogen atom, and R 7 Is a hydrogen atom, a halogen or a substituted or unsubstituted alkyloxy group.
(15 ") the compound according to any one of (1") -14 "), (5" -2) and (5 "-3), or a pharmaceutically acceptable salt thereof, wherein R 1 Is carboxyl.
(16 ") the compound of any one of (1") -15 "), (5" -2) and (5 "-3), or a pharmaceutically acceptable salt thereof, as described above, wherein R 2 Is alkyl, alkyl substituted by a substituted or unsubstituted non-aromatic heterocycle, or alkyl substituted by a substituted or unsubstituted aromatic heterocycle.
(17 ") the compound according to the above (16"), or a pharmaceutically acceptable salt thereof, wherein R 2 Alkyl substituted by a substituted or unsubstituted non-aromatic heterocycle or alkyl substituted by a substituted or unsubstituted aromatic heterocycle.
(18 ") the compound of any one of (1"), (3 ") -17"), (5 "-2) and (5" -3), or a pharmaceutically acceptable salt thereof, wherein-X-is-C (R) 8 )(R 9 )-。
(19 ") the compound of (18") above, or a pharmaceutically acceptable salt thereof, wherein R 8 And R is 9 Is a hydrogen atom.
(20 ") the compound of (1") above, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of compounds I-035, I-145, I-160, I-218, I-223, I-239, I-242, I-243, I-244, I-245, I-246, I-247, I-249, I-250, I-254, I-255, I-257, I-258, I-259, I-273, and I-274.
(18) A pharmaceutical composition comprising the compound according to any one of (1) to (17), (1 ') to (17'), (1 '-2), (1') to (20 "), (5 '-2) and (5' -3) or a pharmaceutically acceptable salt thereof.
(19) The pharmaceutical composition according to (18) above, which is a GLP-1 receptor agonist.
(20) A method for the treatment and/or prophylaxis of a disease in which the GLP-1 receptor is involved, characterized in that: the compound according to any one of (1) to (17), (1 ') to (17 '), (1 ' -2), (1 ") to (20"), (5 "-2) and (5" -3), or a pharmaceutically acceptable salt thereof, is administered.
(21) The use of the compound according to any one of (1) to (17), (1 ') to (17 '), (1 ' -2), (1 ") to (20"), (5 "-2) and (5" -3), or a pharmaceutically acceptable salt thereof, for producing a therapeutic and/or prophylactic agent for a disease in which a GLP-1 receptor participates.
(22) The compound according to any one of (1) to (17), (1 ') to (17 '), (1 ' -2), (1 ") to (20"), (5 "-2) and (5" -3), or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of a disease in which a GLP-1 receptor participates.
ADVANTAGEOUS EFFECTS OF INVENTION
The compound of the present invention has a GLP-1 receptor agonist effect and is useful as a prophylactic and/or therapeutic agent for diseases in which the GLP-1 receptor participates, particularly insulin-independent diabetes (type II diabetes) or obesity.
Detailed Description
Hereinafter, the meaning of each term used in the present specification will be described. Unless otherwise indicated, each term is used in the same sense either alone or in combination with other terms.
The term "composed of … …" means having only constituent elements.
The term "comprising" means that the constituent elements are not limited to, and that the elements not described are not excluded.
Hereinafter, the present invention will be described with reference to the embodiments. It should be understood that throughout this specification, singular forms include plural concepts unless specifically stated otherwise. Thus, it should be understood that singular forms (e.g., "a," "an," "the," etc. in the case of English) also include plural forms of the concepts unless specifically mentioned. In addition, it is to be understood that the terms used in the present specification are used in the meanings commonly used in the above fields, unless specifically mentioned. Accordingly, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control.
"halogen" includes fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms. Fluorine atoms and chlorine atoms are particularly preferred.
"alkyl" includes straight-chain or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, n-decyl and the like.
As a preferable mode of the "alkyl group", there may be mentioned: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl. Further preferable embodiments include: methyl, ethyl, n-propyl, isopropyl, tert-butyl.
"alkenyl" includes straight-chain or branched hydrocarbon groups having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and still more preferably 2 to 4 carbon atoms, each having 1 or more double bonds at any position. Examples include: vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl (presyl), butadienyl, pentenyl (pentenyl), isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, and the like.
As a preferable mode of the "alkenyl group", there may be mentioned: vinyl, allyl, propenyl, isopropenyl, butenyl.
"alkynyl" includes straight-chain or branched hydrocarbon groups having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and still more preferably 2 to 4 carbon atoms, each having 1 or more triple bonds at any position. Further, a double bond may be present at any position. Examples thereof include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like.
As a preferable mode of "alkynyl", there may be mentioned: ethynyl, propynyl, butynyl, pentynyl.
"aromatic carbocyclyl" means a monocyclic or more cyclic aromatic hydrocarbon group. Examples include: phenyl, naphthyl, anthryl, phenanthryl, and the like.
As a preferred mode of "aromatic carbocyclyl" there may be mentioned: phenyl.
"aromatic carbocycle" means a ring derived from the above "aromatic carbocyclyl".
As a preferred mode of "aromatic carbocycle", there may be mentioned: a benzene ring.
"non-aromatic carbocyclyl" means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having a single ring or more. The "non-aromatic carbocyclyl group" of a double ring or more also includes a group in which a ring in the "aromatic carbocyclyl group" is condensed with a single ring or a non-aromatic carbocyclyl group of a double ring or more, and the bond may be provided in any ring.
For example, the following rings are shown.
[ chemical 43]
Further, "non-aromatic carbocyclyl" also includes a group that crosslinks in the following manner, or a group that forms a spiro ring.
[ 44]
The monocyclic non-aromatic carbocyclyl group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 4 to 8 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl and the like.
The non-aromatic carbocyclyl group having a double ring or more is preferably a C8-20 group, more preferably a C8-16 group. Examples include: indanyl, indenyl, acenaphthylenyl, tetrahydronaphthyl, fluorenyl, and the like.
"non-aromatic carbocycle" means a ring derived from the above "non-aromatic carbocyclyl".
"aromatic heterocyclic" means a monocyclic or bicyclic or more aromatic ring group having 1 or more heteroatoms selected from O, S and N optionally in the ring.
The aromatic heterocyclic group having a double ring or more also includes a group in which a ring in the above "aromatic carbocyclyl" is condensed with a monocyclic or double ring or more aromatic heterocyclic group, and the bond may be present in any ring.
The monocyclic aromatic heterocyclic group is preferably 5 to 8-membered, more preferably 5-membered or 6-membered. Examples of the 5-membered aromatic heterocyclic group include: pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, and the like. Examples of the 6-membered aromatic heterocyclic group include: pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like. The aromatic heterocyclic group of the bicyclic ring is preferably 8 to 10 membered, more preferably 9 or 10 membered. Examples include: indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzotriazole, imidazopyridinyl, triazolopyridinyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridinyl, thiazolopyridinyl, and the like.
The aromatic heterocyclic group having three or more rings is preferably 13 to 15 membered. Examples include: carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiazinyl, phenoxazinyl, dibenzofuranyl, and the like.
"aromatic heterocycle" means a ring derived from the above "aromatic heterocyclic group".
The monocyclic aromatic heterocycle is preferably 5 to 8 membered, more preferably 5 or 6 membered. Examples of the 5-membered aromatic heterocycle include: pyrroline ring, imidazoline ring, pyrazoline ring, triazole ring, tetrazole ring, furan ring, thiophene ring, isoxazole ring, oxazole ring, oxadiazole ring, isothiazole ring, thiazole ring, thiadiazole ring, and the like. Examples of the 6-membered aromatic heterocycle include: pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, and the like.
The aromatic heterocyclic group of the bicyclic ring is preferably 8 to 10 membered, more preferably 9 or 10 membered. Examples include: indole ring, isoindole ring, indazole ring, indolizine ring, quinoline ring, isoquinoline ring, cinnoline ring, phthalazine ring, quinazoline ring, naphthyridine ring, quinoxaline ring, purine ring, pteridine ring, benzimidazole ring, benzisoxazole ring, benzoxadiazole ring, benzisothiazole ring, benzothiazole ring, benzothiadiazole ring, benzofuran ring, isobenzofuran ring, benzothiophene ring, benzotriazole ring, imidazopyridine ring, triazolopyridine ring, imidazothiazole ring, pyrazinopyridine ring, oxazolopyridine ring, thiazolopyridine ring, and the like.
The aromatic heterocycle having three or more rings is preferably 13 to 15 membered. Examples include: carbazole ring, acridine ring, xanthene ring, phenothiazine ring, phenoxathiin ring, phenoxazine ring, dibenzofuran ring, and the like.
"non-aromatic heterocyclic group" means a monocyclic or bicyclic or more non-aromatic cyclic group having 1 or more heteroatoms selected from O, S and N optionally in the ring. The non-aromatic heterocyclic group having a double ring or more may include a group in which each ring of the "aromatic heterocyclic group", "non-aromatic heterocyclic group", and/or "aromatic heterocyclic group" is condensed with a single ring or a non-aromatic heterocyclic group having a double ring or more, and further include a group in which each ring of the "aromatic heterocyclic group" is condensed with a single ring or a non-aromatic heterocyclic group having a double ring or more, and the bond may be provided in any ring.
Further, "non-aromatic heterocyclic group" also includes a group bridged in the following manner, or a group forming a spiro ring.
[ 45]
The monocyclic non-aromatic heterocyclic group is preferably 3 to 8-membered, more preferably 4 to 6-membered.
Examples of the 3-membered non-aromatic heterocyclic group include: thiiranyl, oxiranyl, aziridinyl. Examples of the 4-membered non-aromatic heterocyclic group include: oxetanyl, azetidinyl. Examples of the 5-membered non-aromatic heterocyclic group include: oxathiolyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuranyl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolenyl, tetrahydrothienyl, and the like. Examples of the 6-membered non-aromatic heterocyclic group include: dioxanyl, thialkyl, piperidinyl, piperazinyl, morpholinyl (morpholinyl), morpholino (morpholino), thiomorpholinyl (thiomorpholinyl), thiomorpholino (thiomorpholino), dihydropyridinyl, tetrahydropyridinyl, tetrahydropyranyl, dihydropyrazinyl, tetrahydropyrazinyl, hexahydropyrimidinyl, dioxazinyl, thiazinyl (thiazinyl), and the like. Examples of the 7-membered non-aromatic heterocyclic group include: hexahydroaza Radical, tetrahydrodiaza->A radical, an oxepinyl radical.
The non-aromatic heterocyclic group having a double ring or more is preferably 8 to 20 membered, more preferably 8 to 10 membered. Examples include: indolinyl, isoindolinyl, chromanyl, isochromanyl, and the like.
"non-aromatic heterocyclic ring" means a ring derived from the above-described "non-aromatic heterocyclic group".
The alkyl moiety of "alkyloxy", "haloalkyloxy", "alkylcarbonyloxy", "alkylcarbonyl", "alkyloxycarbonyl", "alkylsulfanyl", "alkylsulfinyl", "alkylsulfonyl", "alkyloxyalkyloxy", and "alkyloxyalkyl" is the same as that of "alkyl" described above.
The alkenyloxy moiety of "alkenylcarbonyloxy", "alkenylcarbonyl", "alkenyloxycarbonyl", "alkenylsulfanyl", "alkenylsulfinyl" and "alkenylsulfonyl" is as defined above for "alkenyl".
The alkynyl moiety of "alkynyloxy", "alkynylcarbonyloxy", "alkynylcarbonyl", "alkynylsulfanyl", "alkynylsulfinyl" and "alkynylsulfonyl" is the same as the meaning of "alkynyl" described above.
As "equivalent thereof" in the "carboxyl group or equivalent thereof", there can be mentioned:
[ chemical 46]
(wherein R is a substituted or unsubstituted alkyl group, a substituted or unsubstituted amine, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group).
In this specification, "may be substituted with the substituent group a" means "may be substituted with 1 or more groups selected from the substituent group a". The same applies to substituent groups B, C, α, β, γ', and the like.
Examples of the substituent such as "substituted alkyl", "substituted alkenyl", "substituted alkynyl", "substituted alkyloxy", "substituted alkenyloxy", "substituted alkynyloxy", "substituted alkylcarbonyloxy", "substituted alkenylcarbonyloxy", "substituted alkylcarbonyl", "substituted alkenylcarbonyl", "substituted alkynylcarbonyl", "substituted alkyloxycarbonyl", "substituted alkenyloxycarbonyl", "substituted alkenylsulfanyl", "substituted alkynylsulfanyl", "substituted alkylsulfinyl", "substituted alkenylsulfinyl", "substituted alkylsulfonyl", "substituted alkenylsulfonyl" and "substituted alkynylsulfonyl" include the following substituent group a. The carbon atom at any position may be bonded to 1 or more groups selected from the following substituent group a.
Substituent group a: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfinyl, sulfo, thiocarbonyl, thiocarboxyl, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl,
alkyloxy which may be substituted with a substituent group α, alkenyloxy which may be substituted with a substituent group α, alkynyloxy which may be substituted with a substituent group α, alkylcarbonyloxy which may be substituted with a substituent group α, alkenylcarbonyloxy which may be substituted with a substituent group α, alkynylcarbonyloxy which may be substituted with a substituent group α, alkylcarbonyl which may be substituted with a substituent group α, alkenylcarbonyl which may be substituted with a substituent group α, alkynylcarbonyl which may be substituted with a substituent group α, alkyloxycarbonyl which may be substituted with a substituent group α, alkenyloxycarbonyl which may be substituted with a substituent group α, alkynyloxycarbonyl which may be substituted with a substituent group α, alkylsulfanyl which may be substituted with a substituent group α alkenylsulfanyl which may be substituted by a substituent group α, alkynylsulfanyl which may be substituted by a substituent group α, alkylsulfinyl which may be substituted by a substituent group α, alkenylsulfinyl which may be substituted by a substituent group α, alkynylsulfinyl which may be substituted by a substituent group α, alkylsulfonyl which may be substituted by a substituent group α, alkenylsulfonyl which may be substituted by a substituent group α, alkynylsulfonyl which may be substituted by a substituent group α, amino which may be substituted by a substituent group β, imino which may be substituted by a substituent group β, carbamoyl which may be substituted by a substituent group β, sulfamoyl which may be substituted by a substituent group β,
An aromatic carbocyclic group which may be substituted with a substituent group γ ', a non-aromatic carbocyclic group which may be substituted with a substituent group γ', an aromatic heterocyclic group which may be substituted with a substituent group γ ', a non-aromatic heterocyclic group which may be substituted with a substituent group γ', an aromatic carbocyclic oxy group which may be substituted with a substituent group γ ', a non-aromatic carbocyclic oxy group which may be substituted with a substituent group γ', an aromatic heterocyclic oxy group which may be substituted with a substituent group γ, a non-aromatic heterocyclic oxy group which may be substituted with a substituent group γ ', an aromatic carbocyclic oxo group which may be substituted with a substituent group γ', a non-aromatic heterocyclic oxo group which may be substituted with a substituent group γ ', an aromatic carbocyclic oxo group which may be substituted with a substituent group γ', a non-aromatic carbocyclic carbonyl group which may be substituted with a substituent group γ ', a non-aromatic carbocyclic oxo group which may be substituted with a substituent group γ an aromatic heterocyclic carbonyl group which may be substituted with a substituent group gamma, a non-aromatic heterocyclic carbonyl group which may be substituted with a substituent group gamma', an aromatic heterocyclic oxy carbonyl group which may be substituted with a substituent group gamma ', a non-aromatic carbocyclic oxy carbonyl group which may be substituted with a substituent group gamma', an aromatic heterocyclic oxy carbonyl group which may be substituted with a substituent group gamma, a non-aromatic heterocyclic oxy carbonyl group which may be substituted with a substituent group gamma ', an aromatic carbocyclic oxy group which may be substituted with a substituent group gamma', a non-aromatic carbocyclic oxy group which may be substituted with a substituent group gamma ', an aromatic heterocyclic oxy group which may be substituted with a substituent group gamma', a non-aromatic heterocyclic oxy group which may be substituted with a substituent group gamma ', an aromatic carbocyclic oxy carbonyl group which may be substituted with a substituent group gamma', a non-aromatic carbocyclic oxy carbonyl group which may be substituted with a substituent group gamma An aromatic heterocycloalkyloxycarbonyl group which may be substituted with a substituent group γ ', a non-aromatic heterocycloalkyloxycarbonyl group which may be substituted with a substituent group γ ', an aromatic carbocyclic sulfanyl group which may be substituted with a substituent group γ ', a non-aromatic carbocyclic sulfanyl group which may be substituted with a substituent group γ ', an aromatic heterocyclic sulfanyl group which may be substituted with a substituent group γ ', a non-aromatic heterocyclic sulfanyl group which may be substituted with a substituent group γ ', an aromatic carbocyclic sulfinyl group which may be substituted with a substituent group γ ', an aromatic heterocyclic sulfinyl group which may be substituted with a substituent group γ ', a non-aromatic heterocyclic sulfinyl group which may be substituted with a substituent group γ ', an aromatic carbocyclic sulfonyl group which may be substituted with a substituent group γ ', a non-aromatic carbocyclic sulfonyl group which may be substituted with a substituent group γ ', an aromatic heterocyclic sulfonyl group which may be substituted with a substituent group γ ', and a non-aromatic heterocyclic sulfonyl group which may be substituted with a substituent group γ '.
Substituent group α: halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, and cyano.
Substituent group beta: halogen, hydroxy, carboxy, cyano, alkyl which may be substituted with a substituent group alpha, alkenyl which may be substituted with a substituent group alpha, alkynyl which may be substituted with a substituent group alpha, alkylcarbonyl which may be substituted with a substituent group alpha, alkenylcarbonyl which may be substituted with a substituent group alpha, alkynylcarbonyl which may be substituted with a substituent group alpha, alkylsulfanyl which may be substituted with a substituent group alpha, alkenylsulfanyl which may be substituted with a substituent group alpha, alkynylsulfanyl which may be substituted with a substituent group alpha, alkylsulfinyl which may be substituted with a substituent group alpha, alkenylsulfinyl which may be substituted with a substituent group alpha, alkylsulfonyl which may be substituted with a substituent group alpha, alkenylsulfonyl which may be substituted with a substituent group alpha, alkynylsulfonyl which may be substituted with a substituent group alpha,
An aromatic carbocyclyl group which may be substituted with a substituent group γ ', a non-aromatic carbocyclyl group which may be substituted with a substituent group γ', an aromatic heterocyclic group which may be substituted with a substituent group γ ', a non-aromatic heterocyclic group which may be substituted with a substituent group γ', an aromatic carbocyclylalkyl group which may be substituted with a substituent group γ ', a non-aromatic carbocyclylalkyl group which may be substituted with a substituent group γ', an aromatic carbocyclyl group which may be substituted with a substituent group γ ', a non-aromatic carbocyclylcarbonyl group which may be substituted with a substituent group γ', an aromatic carbocyclyloxycarbonyl group which may be substituted with a substituent group γ ', a non-aromatic carbocyclyloxycarbonyl group which may be substituted with a substituent group γ' an aromatic heterocyclyloxycarbonyl group which may be substituted with a substituent group γ ', a non-aromatic heterocyclyloxycarbonyl group which may be substituted with a substituent group γ', an aromatic carbocyclic thioalkyl group which may be substituted with a substituent group γ ', a non-aromatic carbocyclic thioalkyl group which may be substituted with a substituent group γ', an aromatic heterocyclic thioalkyl group which may be substituted with a substituent group γ ', a non-aromatic heterocyclic thioalkyl group which may be substituted with a substituent group γ', an aromatic carbocyclic sulfinyl group which may be substituted with a substituent group γ ', a non-aromatic carbocyclic sulfinyl group which may be substituted with a substituent group γ', an aromatic heterocyclic sulfinyl group which may be substituted with a substituent group γ ', an aromatic carbocyclic sulfonyl group which may be substituted with a substituent group γ', a non-aromatic carbocyclic sulfonyl group which may be substituted with a substituent group γ An aromatic heterocyclic sulfonyl group which may be substituted with a substituent group γ and a non-aromatic heterocyclic sulfonyl group which may be substituted with a substituent group γ'.
Substituent group γ: substituent groups α, alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl.
Substituent group γ': substituent groups γ and oxo.
Examples of the substituents on the rings of the "aromatic carbocycle" and "aromatic heterocycle" such as "substituted aromatic carbocyclyl", "substituted aromatic heterocyclyl", "substituted aromatic carbocyclyloxy", "substituted aromatic carbocyclylcarbonyloxy", "substituted aromatic carbocyclylcarbonyl", "substituted aromatic carbocyclyloxycarbonyl", "substituted aromatic carbocyclylthioalkyl", "substituted aromatic carbocyclylsulfinyl", "substituted aromatic heterocyclylsulfinyl", "substituted aromatic carbocyclylsulfonyl" and "substituted aromatic heterocycle sulfonyl" include the following substituent group B. An atom at any position on the ring may be bonded to 1 or more groups selected from the following substituent group B.
Substituent group B: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfinyl, sulfo, thiocarbonyl, thiocarboxyl, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl,
alkyl which may be substituted with a substituent group α, alkenyl which may be substituted with a substituent group α, alkynyl which may be substituted with a substituent group α, alkyloxy which may be substituted with a substituent group α, alkenyloxy which may be substituted with a substituent group α, alkynyloxy which may be substituted with a substituent group α, alkylcarbonyloxy which may be substituted with a substituent group α, alkenylcarbonyloxy which may be substituted with a substituent group α, alkynylcarbonyloxy which may be substituted with a substituent group α, alkylcarbonyl which may be substituted with a substituent group α, alkenylcarbonyl which may be substituted with a substituent group α, alkynylcarbonyl which may be substituted with a substituent group α, alkyloxycarbonyl which may be substituted with a substituent group α alkenyloxycarbonyl optionally substituted by a substituent group α, alkynyloxycarbonyl optionally substituted by a substituent group α, alkylsulfanyl optionally substituted by a substituent group α, alkenylsulfanyl optionally substituted by a substituent group α, alkynylsulfanyl optionally substituted by a substituent group α, alkylsulfinyl optionally substituted by a substituent group α, alkenylsulfinyl optionally substituted by a substituent group α, alkynylsulfinyl optionally substituted by a substituent group α, alkylsulfonyl optionally substituted by a substituent group α, alkenylsulfonyl optionally substituted by a substituent group α, alkynylsulfonyl optionally substituted by a substituent group α,
Amino group which may be substituted by substituent group beta, imino group which may be substituted by substituent group beta, carbamoyl group which may be substituted by substituent group beta, sulfamoyl group which may be substituted by substituent group beta,
An aromatic carbocyclic group which may be substituted with a substituent group γ ', a non-aromatic carbocyclic group which may be substituted with a substituent group γ', an aromatic heterocyclic group which may be substituted with a substituent group γ ', a non-aromatic heterocyclic group which may be substituted with a substituent group γ', an aromatic carbocyclic oxy group which may be substituted with a substituent group γ ', a non-aromatic carbocyclic oxy group which may be substituted with a substituent group γ', an aromatic heterocyclic oxy group which may be substituted with a substituent group γ ', a non-aromatic heterocyclic oxy group which may be substituted with a substituent group γ', an aromatic carbocyclic oxo group which may be substituted with a substituent group γ "," a non-aromatic carbocyclic oxo oxy group which may be substituted with a substituent group γ ', an aromatic heterocyclic oxo group which may be substituted with a substituent group γ ", and an aromatic heterocyclic oxo group which may be substituted with a substituent group γ', an aromatic carbocyclic carbonyl group which may be substituted with a substituent group γ 'a non-aromatic carbocyclylcarbonyl group which may be substituted with a substituent group gamma', an aromatic carbocyclylcarbonyl group which may be substituted with a substituent group gamma ', a non-aromatic carbocyclylcarbonyl group which may be substituted with a substituent group gamma', an aromatic carbocyclyloxycarbonyl group which may be substituted with a substituent group gamma ', a non-aromatic carbocyclyloxycarbonyl group which may be substituted with a substituent group gamma', an aromatic carbocyclylalkyl group which may be substituted with a substituent group gamma ', a non-aromatic carbocyclylalkyl group which may be substituted with a substituent group gamma', an aromatic carbocyclyloxygroup which may be substituted with a substituent group gamma ', a non-aromatic carbocyclylalkyloxy group which may be substituted with a substituent group gamma', a non-aromatic carbocyclyloxyalkyl group which may be substituted with a substituent group gamma An aromatic heterocycloalkyloxy group which may be substituted with a substituent group γ ', a non-aromatic heterocycloalkyloxy group which may be substituted with a substituent group γ', an aromatic carbocyclyloxycarbonyl group which may be substituted with a substituent group γ ', a non-aromatic carbocyclyloxycarbonyl group which may be substituted with a substituent group γ', an aromatic heterocycloalkyloxycarbonyl group which may be substituted with a substituent group γ ', a non-aromatic heterocycloalkyloxycarbonyl group which may be substituted with a substituent group γ', an aromatic carbocyclyloxyalkyl group which may be substituted with a substituent group γ ', a non-aromatic carbocyclyloxyalkyl group which may be substituted with a substituent group γ', an aromatic heterocycloalkyloxyalkyl group which may be substituted with a substituent group γ ', an aromatic carbocyclylthioalkyl group which may be substituted with a substituent group γ' a non-aromatic carbocyclic sulfanyl group which may be substituted with a substituent group γ ', an aromatic heterocyclic sulfanyl group which may be substituted with a substituent group γ', a non-aromatic heterocyclic sulfanyl group which may be substituted with a substituent group γ ', an aromatic carbocyclic sulfinyl group which may be substituted with a substituent group γ', a non-aromatic carbocyclic sulfinyl group which may be substituted with a substituent group γ ', an aromatic heterocyclic sulfinyl group which may be substituted with a substituent group γ', a non-aromatic heterocyclic sulfinyl group which may be substituted with a substituent group γ ', an aromatic carbocyclic sulfonyl group which may be substituted with a substituent group γ', a non-aromatic carbocyclic sulfonyl group which may be substituted with a substituent group γ ', an aromatic heterocyclic sulfonyl group which may be substituted with a substituent group γ, and a non-aromatic heterocyclic sulfonyl group which may be substituted with a substituent group γ'.
Examples of the substituents on the rings of "substituted non-aromatic carbocyclyl", "substituted non-aromatic heterocyclyl", "substituted non-aromatic carbocyclyloxy", "substituted non-aromatic carbocyclylcarbonyloxy", "substituted non-aromatic carbocyclylcarbonyl", "substituted non-aromatic carbocyclyloxycarbonyl", "substituted non-aromatic carbocyclylthioalkyl", "substituted non-aromatic carbocyclylsulfinyl", "substituted non-aromatic carbocyclylsulfonyl", and "non-aromatic heterocycle" include the following substituent group C. An atom at any position on the ring may be bonded to 1 or more groups selected from the following substituent group C.
Substituent group C: substituent group B and oxo.
In the case where "non-aromatic carbocycle", "non-aromatic heterocycle", "non-aromatic carbocyclyl" and "non-aromatic heterocyclyl" are substituted with "oxo", it means a ring in which 2 hydrogen atoms on carbon atoms are substituted as follows.
[ 47]
As the substituents for "substituted amino", "substituted imino", "substituted carbamoyl" and "substituted sulfamoyl", the following substituent group D is exemplified. May be substituted with 1 or 2 groups selected from substituent group D.
Substituent group D: halogen, hydroxy, carboxy, cyano, alkyl which may be substituted with a substituent group alpha, alkenyl which may be substituted with a substituent group alpha, alkynyl which may be substituted with a substituent group alpha, alkylcarbonyl which may be substituted with a substituent group alpha, alkenylcarbonyl which may be substituted with a substituent group alpha, alkynylcarbonyl which may be substituted with a substituent group alpha, alkylsulfanyl which may be substituted with a substituent group alpha, alkenylsulfanyl which may be substituted with a substituent group alpha, alkynylsulfanyl which may be substituted with a substituent group alpha, alkylsulfinyl which may be substituted with a substituent group alpha, alkenylsulfinyl which may be substituted with a substituent group alpha, alkylsulfonyl which may be substituted with a substituent group alpha, alkenylsulfonyl which may be substituted with a substituent group alpha, alkynylsulfonyl which may be substituted with a substituent group alpha,
Amino group which may be substituted by substituent group beta, imino group which may be substituted by substituent group beta, carbamoyl group which may be substituted by substituent group beta, sulfamoyl group which may be substituted by substituent group beta,
An aromatic carbocyclyl group which may be substituted with a substituent group γ ', a non-aromatic carbocyclyl group which may be substituted with a substituent group γ', an aromatic heterocyclic group which may be substituted with a substituent group γ ', a non-aromatic heterocyclic group which may be substituted with a substituent group γ', an aromatic carbocyclylalkyl group which may be substituted with a substituent group γ ', a non-aromatic carbocyclylalkyl group which may be substituted with a substituent group γ', an aromatic carbocyclyl group which may be substituted with a substituent group γ ', a non-aromatic carbocyclylcarbonyl group which may be substituted with a substituent group γ', an aromatic carbocyclyloxycarbonyl group which may be substituted with a substituent group γ ', a non-aromatic carbocyclyloxycarbonyl group which may be substituted with a substituent group γ' an aromatic heterocyclyloxycarbonyl group which may be substituted with a substituent group γ ', a non-aromatic heterocyclyloxycarbonyl group which may be substituted with a substituent group γ', an aromatic carbocyclic thioalkyl group which may be substituted with a substituent group γ ', a non-aromatic carbocyclic thioalkyl group which may be substituted with a substituent group γ', an aromatic heterocyclic thioalkyl group which may be substituted with a substituent group γ ', a non-aromatic heterocyclic thioalkyl group which may be substituted with a substituent group γ', an aromatic carbocyclic sulfinyl group which may be substituted with a substituent group γ ', a non-aromatic carbocyclic sulfinyl group which may be substituted with a substituent group γ', an aromatic heterocyclic sulfinyl group which may be substituted with a substituent group γ ', an aromatic carbocyclic sulfonyl group which may be substituted with a substituent group γ', a non-aromatic carbocyclic sulfonyl group which may be substituted with a substituent group γ An aromatic heterocyclic sulfonyl group which may be substituted with a substituent group γ and a non-aromatic heterocyclic sulfonyl group which may be substituted with a substituent group γ'.
In formula (I), the atom of ring P denoted by a is bonded to the group represented by-X-, and the atom of ring Q denoted by b is bonded to the group represented by-O-.
In formula (III), the atom of ring P marked with a is bonded to-CH 2 -the represented group is bonded, the atom of ring Q marked b being bonded to the group represented by-O-.
[ 48]
Of the rings represented, ring P and/or ring Q may be substituted by R 10 Substitution includes, for example, the rings shown below.
[ 49]
Etc.
[ 50]
Represented ring to
[ 51]
In the case of the same representation, the representation (R 10 ) p Can be bonded on the ring P
[ 52]
/>
In the case of the same representation, the representation (R 10 ) s' May be bonded to ring P and/or ring Q.
A in the compound represented by the formula (I) or (II) 1 、A 2 、A 3 、R 1 、R 2 、-X-、R 3 、R 13 、E 1 、E 2 、r、R 10 And
[ 53]
The preferred manner of the represented ring is shown below. As the compound represented by the formula (I) or the formula (II), all combinations of the specific examples shown below can be exemplified.
As A 1 Examples thereof include C (R 5 ) Or N (set to A-1).
As A 1 Examples thereof include C (R 5 ) (set to A-2).
As A 1 C (H) (set to A-3) can be cited.
As A 1 C (F) (A-4) is exemplified.
As A 1 N (A-5) is exemplified.
A 2 C (R) 6 ) Or N (set to B-1).
A 2 C (R) 6 ) (set to B-2).
A 2 C (H) (B-3) can be exemplified.
As a means ofA 2 N (B-4) is exemplified.
A 3 C (R) 7 ) Or N (set to C-1).
A 3 C (R) 7 ) (set to C-2).
A 3 C (F) (C-3) is exemplified.
A 3 C (Cl) (C-4) is exemplified.
A 3 C (H) (C-5) can be exemplified.
As A 3 N (C-6) is exemplified.
R 5 、R 6 And R is 7 Independent of each other, there may be mentioned: a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted non-aromatic carbocyclic group (provided as D-1).
R 5 、R 6 And R is 7 Independent of each other, there may be mentioned: a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy (provided as D-2).
R 5 、R 6 And R is 7 Independent of each other, there may be mentioned: a hydrogen atom, halogen or cyano (set as D-3).
R 5 、R 6 And R is 7 Independent of each other, there may be mentioned: a hydrogen atom, a halogen or a substituted or unsubstituted alkyloxy group (set as D-4).
R 5 、R 6 And R is 7 Independent of each other, there may be mentioned: a hydrogen atom or halogen (set as D-5).
R 5 、R 6 And R is 7 The hydrogen atom (D-6) may be mentioned.
R 5 Is a hydrogen atom or halogen, R 6 Is a hydrogen atom, and R 7 There may be mentioned: a hydrogen atom, a halogen or a substituted or unsubstituted alkyloxy group (set as D-7).
R 6 Is a hydrogen atom, and R 5 And R is 7 Independent of each other, there may be mentioned: a hydrogen atom or halogen (set as D-8).
R 1 There may be mentioned: carboxyl or equivalent thereof or CH 2 COOH (set to E-1).
R 1 There may be mentioned: carboxyl or an equivalent thereof (set as E-2).
R 1 Carboxyl groups or any of the groups shown below can be cited:
[ 54]
(wherein R is a substituted or unsubstituted alkyl group, a substituted or unsubstituted amine, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group) (provided as E-3).
R 1 Carboxyl groups (E-4) are exemplified.
R 2 There may be mentioned: a substituted or unsubstituted alkyl group or a substituted or unsubstituted non-aromatic heterocyclic group (provided as F-1).
R 2 There may be mentioned: substituted or unsubstituted alkyl (set as F-2).
R 2 There may be mentioned: substituted or unsubstituted methyl (set as F-3).
R 2 There may be mentioned: an alkyl group substituted with a substituted or unsubstituted non-aromatic heterocyclic ring, an alkyl group substituted with a substituted or unsubstituted aromatic heterocyclic group, or an unsubstituted alkyl group (provided as F-4).
R 2 There may be mentioned: oxetanyl or alkylimidazolylalkyl (set as F-5).
R 2 There may be mentioned: oxetanylmethyl or ethylimidazolylmethyl (set to F-6).
R 2 There may be mentioned: oxetanylmethyl (set F-7).
R 2 There may be mentioned: alkyl imidazolylmethyl (set to F-8).
R 2 There may be mentioned: ethylimidazolylmethyl (set to F-9).
-X-can be enumerated: -C (R) 8 )(R 9 ) -, -O-or-N (R) 11 ) - (set to G-1)。
-X-can be enumerated: -C (R) 8 )(R 9 ) -or-O- (set to G-2).
-X-can be enumerated: o- (set to G-3).
-X-can be enumerated: -C (R) 8 )(R 9 ) - (set to G-4).
-X-can be enumerated: c (H) (H) - (set to G-5).
-X-can be enumerated: -N (R) 11 ) - (set to G-6).
R 8 And R is 9 Independent of each other, there may be mentioned: a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group (set as H-1).
R 8 And R is 9 Independent of each other, there may be mentioned: a hydrogen atom or halogen (H-2).
R 8 And R is 9 There may be mentioned: a hydrogen atom (H-3).
R 11 There may be mentioned: a hydrogen atom or a substituted or unsubstituted alkyl group (set as I-1).
R 11 There may be mentioned: a hydrogen atom (I-2).
R 11 There may be mentioned: substituted or unsubstituted alkyl (set as I-3).
[ 55]
The ring shown below may be exemplified as the ring shown below (J-1).
[ 56]
[ 57]
[ 58]
[ 59]
The ring shown below is exemplified by the ring shown below (set as J-2).
[ chemical 60]
[ chemical 61]
The ring shown below is exemplified by the ring shown below (set as J-3).
[ 62]
[ 63]
The ring shown below is exemplified by the ring shown below (set as J-4).
[ 64]
[ 65]
[ chemical 66]
[ 67]
The ring shown below is exemplified by the ring shown below (set as J-5).
[ chemical 68]
[ 69]
The ring shown below is exemplified by the ring shown below (set as J-6).
[ 70]
[ chemical 71]
The ring shown below is exemplified by the ring shown below (set as J-7).
[ chemical 72]
[ 73]
The ring shown below is exemplified by the ring shown below (set as J-8).
[ chemical 74]
[ 75]
The ring shown below is exemplified by the ring shown below (set as J-9).
[ chemical 76]
[ chemical 77]
The ring shown below is exemplified by the ring shown below (set as J-10).
[ 78]
[ chemical 79]
The ring shown below is exemplified by the ring shown below (set as J-11).
[ 80]
[ 81]
The ring shown below is exemplified as the ring shown below (set as J-12).
[ chemical 82]
[ 83]
The ring shown below is exemplified by the ring shown below (set as J-13).
[ chemical 84]
[ chemical 85]
The ring shown below is exemplified as the ring shown below (set as J-14).
[ 86]
[ 87]
The ring shown below is exemplified by the ring shown below (set as J-15).
[ 88]
[ chemical 89]
The ring shown below is exemplified as the ring shown below (set as J-16).
[ chemical 90]
[ 91]
The ring shown below is exemplified by the ring shown below (set as J-17).
[ chemical 92]
[ 93]
The ring shown below is exemplified by the ring shown below (set as J-18).
[ 94]
R 10 Independent of each other, there may be mentioned: halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic A group carbocyclyl group or a substituted or unsubstituted alkyloxy group (set as K-1).
R 10 Independent of each other, there may be mentioned: halogen, cyano, substituted or unsubstituted alkyl, oxo or substituted or unsubstituted alkyloxy (designated as K-2).
R 10 Independent of each other, there may be mentioned: halogen or cyano (set to K-3).
R 10 Independent of each other, there may be mentioned: halogen (set to K-4).
R 10 Independent of each other, there may be mentioned: cyano (set to K-5).
R 10 Independent of each other, there may be mentioned: substituted or unsubstituted alkyl (set as K-6).
R 10 Independent of each other, there may be mentioned: substituted or unsubstituted alkyloxy (set as K-7).
At R 10 In the case of bonding to the ring P, R 10 Independent of each other, there may be mentioned: halogen or substituted or unsubstituted alkyl (set as K-8).
At R 10 In the case of bonding to the ring P, R 10 Independent of each other, there may be mentioned: halogen or alkyl (set to K-9).
At R 10 In the case of bonding to the ring P, R 10 Independent of each other, there may be mentioned: alkyl (set to K-10).
At R 10 In the case of bonding to the ring P, R 10 Independent of each other, there may be mentioned: halogen (set to K-11).
At R 10 In the case of bonding to the ring Q, R 10 Independent of each other, there may be mentioned: halogen or substituted or unsubstituted alkyl (set as K-12).
At R 10 In the case of bonding to the ring Q, R 10 Independent of each other, there may be mentioned: halogen or halogen-substituted alkyl (set as K-13).
At R 10 In the case of bonding to the ring Q, R 10 Independent of each other, there may be mentioned: halogen or fluoro-substituted alkyl (set as K-14).
At R 10 In the case of bonding to the ring Q, R 10 Independent of each other, there may be mentioned: by halogen extractionSubstituted alkyl (set as K-15).
At R 10 In the case of bonding to the ring Q, R 10 Independent of each other, there may be mentioned: fluoro substituted alkyl (set as K-16).
At R 10 In the case of bonding to the ring Q, R 10 Independent of each other, there may be mentioned: halogen (set to K-17).
s is an integer of 0 to 9 (L-1).
s is an integer of 0 to 3 (L-2).
s is an integer of 0 to 2 (L-3).
s is an integer of 0 or 1 (L-4).
s is an integer of 1 or 2 (L-5).
s is 0 (L-6).
s is 1 (L-7).
s is exemplified by 2 (L-8).
s' may be an integer of 0 to 8 (set as M-1).
s' may be an integer of 0 to 3 (set as M-2).
s' may be an integer of 0 to 2 (set as M-3).
s' is an integer of 0 or 1 (M-4).
s' is exemplified by 0 (M-5).
s' is exemplified by 1 (M-6).
R 3 There may be mentioned: a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group (provided as N-1).
R 3 There may be mentioned: a substituted or unsubstituted aromatic carbocyclyl group or a substituted or unsubstituted aromatic heterocyclic group (provided as N-2).
R 3 There may be mentioned: an aromatic carbocyclic group which may be substituted with the substituent group A1 (halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy and cyano) or an aromatic heterocyclic group which may be substituted with the substituent group A1 (provided as N-3).
R 3 There may be mentioned: can be substituted by group A2 (halogen, alkyl, haloalkyl, haloalkyloxy and cyano), pyridinyl which may be substituted by substituent group A2, pyrimidinyl which may be substituted by substituent group A2, pyrazinyl which may be substituted by substituent group A2, pyrazolyl which may be substituted by substituent group A2, imidazolyl which may be substituted by substituent group A2, isoxazolyl which may be substituted by substituent group A2 or thiazolyl which may be substituted by substituent group A2 (provided as N-4).
R 3 There may be mentioned: phenyl (set as N-5) which may be substituted with substituent group A2 (halogen, alkyl, haloalkyl, haloalkyloxy and cyano).
R 3 Can be enumerated by
[ 95]
The indicated group (set as N-6).
R 3 Can be enumerated by
[ chemical 96]
The indicated group (set as N-7).
R 3 Can be enumerated by
[ 97]
The indicated group (set to N-8).
R 3 Can be enumerated by
[ 98]
The indicated group (set as N-9).
R 3 Can be enumerated by
[ chemical 99]
The indicated group (set to N-10).
R 3 Can be enumerated by
[ 100]
The indicated group (set as N-11).
R 3 Can be enumerated by
[ 101]
The indicated group (set as N-12).
R 3 Can be enumerated by
[ chemical 102]
The indicated group (set as N-13).
R 3 Can be enumerated by
[ 103]
The indicated group (set as N-14).
T 1 There may be mentioned: carbon or nitrogen (O-1).
T 1 There may be mentioned: c (R) 12 ) Or N (set to O-2).
T 1 There may be mentioned: carbon atom (set as O-3).
T 1 There may be mentioned: c (R) 12 ) (set to O-4).
T 1 There may be mentioned: nitrogen atom (set as O-5).
T 2 There may be mentioned: carbon atom or nitrogen atom (P-1).
T 2 There may be mentioned: c (R) 12 ) Or N (set to P-2).
T 2 There may be mentioned: carbon atom (P-3).
T 2 There may be mentioned: c (R) 12 ) (set to P-4).
T 2 There may be mentioned: nitrogen atom (P-5).
R 4 Independent of each other, there may be mentioned: halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, or substituted or unsubstituted alkylsulfonyl (provided as Q-1).
R 4 Independent of each other, there may be mentioned: halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted non-aromatic carbocyclyl (designated as Q-2).
R 4 Independent of each other, there may be mentioned: halogen, cyano, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy (set as Q-3).
R 4 Independent of each other, there may be mentioned: halogen or substituted or unsubstituted alkyl (set as Q-4).
R 4 Independent of each other, there may be mentioned: halogen or halogen-substituted or unsubstituted alkyl (set as Q-5).
R 4 Independent of each other, there may be mentioned: halogen or a substituted or unsubstituted alkyloxy group (set as Q-6).
R 4 Independent of each other, there may be mentioned: halogen or halogen-substituted or unsubstituted alkyloxy (set as Q-7).
R 4 Independent of each other, there may be mentioned: halogen, fluoro-substituted alkyloxy or unsubstituted alkyloxy (set as Q-8).
R 4 Independent of each other, there may be mentioned: halogen, cyano, unsubstituted alkyl, unsubstituted alkyloxy or unsubstituted non-aromatic carbocyclyl (designated as Q-9).
R 4 Independent of each other, there may be mentioned: halogen (set as Q-10).
R 14 There may be mentioned: a hydrogen atom or a substituted or unsubstituted alkyl group (set as R-1).
R 14 There may be mentioned: substituted or unsubstituted alkyl (set as R-2).
R 14 There may be mentioned: alkyl (set as R-3).
R 12 Independent of each other, there may be mentioned: a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, or substituted or unsubstituted alkylsulfonyl (provided as S-1).
R 12 Independent of each other, there may be mentioned: a hydrogen atom or halogen (S-2).
R 12 There may be mentioned: a hydrogen atom (S-3).
R 12 Independent of each other, there may be mentioned: halogen (S-4).
m is an integer of 0 to 5 (T-1).
m is an integer of 0 to 3 (T-2).
m is 1 or 2 (T-3).
m is 1 (T-4).
m is exemplified by 2 (T-5).
n is an integer of 0 to 2 (U-1).
n is exemplified by 0 or 1 (U-2).
n is exemplified by 0 (U-3).
n is 1 (U-4).
n is exemplified by 2 (U-5).
R 13 Independent of each other, there may be mentioned: a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group (set as V-1).
R 13 Independent of each other, there may be mentioned: hydrogen atoms or substitutionsOr unsubstituted alkyl (set as V-2).
R 13 Independent of each other, there may be mentioned: substituted or unsubstituted alkyl (set as V-3).
R 13 There may be mentioned: one is a hydrogen atom, and the other is a substituted or unsubstituted alkyl group (set as V-4).
R 13 There may be mentioned: a hydrogen atom (set to V-5).
E 1 There may be mentioned: carbon atom or nitrogen atom (set as W-1).
E 1 There may be mentioned: carbon atom (W-2).
E 1 There may be mentioned: nitrogen atom (W-3).
E 2 There may be mentioned: a carbon atom or a nitrogen atom (X-1).
E 2 There may be mentioned: carbon atom (X-2).
E 2 There may be mentioned: nitrogen atom (X-3).
r may be an integer of 0 to 9 (set as Y-1).
r is an integer of 1 to 9 (set as Y-2).
r is an integer of 1 to 3 (set as Y-3).
r is an integer of 1 to 2 (set as Y-4).
R is 3 (Y-5).
r is exemplified by 2 (Y-6).
r is 1 (Y-7).
p is an integer of 0 to 6 (Z-1).
p is an integer of 0 to 3 (Z-2).
p is an integer of 0 to 2 (Z-3).
p is an integer of 0 or 1 (Z-4).
p is exemplified by 0 (Z-5).
p is 1 (Z-6).
Formula (III):
[ chemical 104]
A in the represented compound 1 、R 2 、R 3 、R 7 And
[ 105]
The preferred manner of the represented ring is shown below. As the compound represented by the formula (III), all combinations of specific examples shown below can be exemplified.
As A 1 Examples of the method include: c (R) 5 ) Or N (A' -1).
As A 1 Examples of the method include: c (R) 5 ) (set to A' -2).
As A 1 Examples of the method include: c (H) (set as A' -3).
As A 1 Examples of the method include: c (F) (A' -4).
As A 1 Examples of the method include: n (A' -5).
R 5 There may be mentioned: a hydrogen atom or halogen (B' -1).
R 5 There may be mentioned: a hydrogen atom (B' -2).
R 5 There may be mentioned: halogen (B' -3).
R 7 There may be mentioned: a hydrogen atom, a halogen, or a substituted or unsubstituted alkyloxy group (set as C' -1).
R 7 There may be mentioned: a hydrogen atom or halogen (C' -2).
R 7 There may be mentioned: a hydrogen atom (C' -3).
R 7 There may be mentioned: halogen (C' -4).
R 2 There may be mentioned: an alkyl group substituted with a substituted or unsubstituted non-aromatic heterocycle or an alkyl group substituted with a substituted or unsubstituted aromatic heterocycle (referred to as D' -1).
R 2 There may be mentioned: oxetanyl or alkylimidazolylalkyl (set to D' -2).
R 2 There may be mentioned: oxetanyl methyl or ethylimidazolylmethyl (set to D' -3).
R 2 There may be mentioned: oxetanylmethyl (set as D' -4).
R 2 There may be mentioned: alkyl imidazolylmethyl (set to D' -5).
R 2 There may be mentioned: ethylimidazolylmethyl (set to D' -6).
[ 106]
The ring represented by the following may be exemplified by the ring shown below (E' -1).
[ chemical 107]
[ chemical 108]
The ring represented by the following may be exemplified by the ring shown below (E' -2).
[ 109]
[ 110]
The ring represented by the following may be exemplified by the ring shown below (E' -3).
[ chemical 111]
[ chemical 112]
The ring represented by the following may be exemplified by the ring shown below (E' -4).
[ 113]
R 10 Independent of each other, there may be mentioned: halogen, cyano or substituted or unsubstituted alkyl (designated F' -1).
R 10 Independent of each other, there may be mentioned: halogen or a substituted or unsubstituted alkyl group (designated as F' -2).
R 10 Independent of each other, there may be mentioned: halogen (F' -3).
R 10 Independent of each other, there may be mentioned: cyano (set as F' -4).
R 10 Independent of each other, there may be mentioned: substituted or unsubstituted alkyl (set as F' -5).
At R 10 In the case of bonding to the ring P, R 10 Independent of each other, there may be mentioned: halogen or a substituted or unsubstituted alkyl group (designated as F' -6).
At R 10 In the case of bonding to the ring P, R 10 Independent of each other, there may be mentioned: halogen or alkyl (set as F' -7).
At R 10 In the case of bonding to the ring P, R 10 Independent of each other, there may be mentioned: alkyl (set as F' -8).
At R 10 In the case of bonding to the ring P, R 10 Independent of each other, there may be mentioned: halogen (F' -9).
At R 10 In the case of bonding to the ring Q, R 10 There may be mentioned: halogen or a substituted or unsubstituted alkyl group (designated as F' -10).
At R 10 In the case of bonding to the ring Q, R 10 There may be mentioned: halogen or halogen-substituted alkyl (designated F' -11).
At R 10 In the case of bonding to the ring Q, R 10 There may be mentioned: halogen or fluorine substituted alkyl (designated as F' -12).
At R 10 In the case of bonding to the ring Q, R 10 There may be mentioned: halogen-substituted alkyl (designated F' -13).
At R 10 In the case of bonding to the ring Q, R 10 There may be mentioned: fluoro-substituted alkyl (set as F' -14).
At R 10 In the case of bonding to the ring Q, R 10 There may be mentioned: halogen (F' -15).
p is an integer of 0 or 1 (G' -1).
p is exemplified by 0 (G' -2).
p is 1 (G' -3).
R 3 Can be enumerated by
[ 114]
/>
The group represented (H' -1).
R 3 Can be enumerated by
[ 115]
The group represented (H' -2).
R 3 Can be enumerated by
[ 116]
The group represented (H' -3).
R 3 Can be enumerated by
[ chemical 117]
The group represented (H' -4).
R 3 Can be enumerated by
[ chemical 118]
The group represented (H' -5).
T 1 There may be mentioned: c (R) 12 ) Or N (set to I' -1).
T 1 There may be mentioned: c (R) 12 ) (set to I' -2).
T 1 There may be mentioned: n (I' -3).
R 4 Independent of each other, there may be mentioned: halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted non-aromatic carbocyclyl (designated J' -1).
R 4 Independent of each other, there may be mentioned: halogen, cyano, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy (designated as J' -2).
R 4 Independent of each other, there may be mentioned: halogen or a substituted or unsubstituted alkyl group (designated as J' -3).
R 4 Independent of each other, there may be mentioned: halogen, halogen-substituted alkyl or unsubstituted alkyl (designated J' -4).
R 4 Independent of each other, there may be mentioned: halogen or a substituted or unsubstituted alkyloxy group (designated as J' -5).
R 4 Independent of each other, there may be mentioned: halogen, halogen-substituted alkyl oxy or unsubstituted alkyl oxy (set as J' -6).
R 4 Independent of each other, there may be mentioned: halogen, fluoro-substituted alkyl oxy or unsubstituted alkyl oxy (set as J' -7).
R 4 Are independent and canThe following are listed: halogen, cyano, unsubstituted alkyl, unsubstituted alkyloxy or unsubstituted non-aromatic carbocyclyl (designated J' -8).
R 4 Independent of each other, there may be mentioned: halogen (J' -9).
R 14 There may be mentioned: unsubstituted alkyl (set as K' -1).
R 14 There may be mentioned: methyl, ethyl, n-propyl or isopropyl (set to K' -2).
R 14 There may be mentioned: methyl or ethyl (set to K' -3).
R 14 There may be mentioned: methyl (set to K' -4).
R 12 Independent of each other, there may be mentioned: a hydrogen atom or halogen (L' -1).
R 12 There may be mentioned: a hydrogen atom (L' -2).
R 12 Independent of each other, there may be mentioned: halogen (L' -3).
The following modes are particularly preferred.
(i) Formula (I):
[ 119]
(in the formula (I),
A 1 is C (R) 5 ) Or N, or a combination of two,
A 2 is C (R) 6 ) Or N, or a combination of two,
A 3 is C (R) 7 ) Or N, or a combination of two,
R 5 、R 6 and R is 7 Each independently is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group,
R 1 Is a carboxyl group, and is a carboxyl group,
R 2 alkyl substituted by a substituted or unsubstituted non-aromatic heterocycle or alkyl substituted by a substituted or unsubstituted aromatic heterocycle,
-X-is-C (R) 8 )(R 9 )-，
R 8 And R is 9 Each independently a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group,
[ 120]
The ring being represented by
[ chemical 121]
(in the formula (I),
R 10 each independently is halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclyl, or substituted or unsubstituted alkyloxy,
s is an integer of 0 to 9),
R 13 each independently a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group,
R 3 a substituted or unsubstituted aromatic carbocyclyl group or a substituted or unsubstituted aromatic heterocyclic group) or a pharmaceutically acceptable salt thereof.
(ii) Formula (I):
[ chemical 122]
(in the formula (I),
A 1 is C (R) 5 ) Or N, or a combination of two,
A 2 is C (R) 6 ) Or N, or a combination of two,
A 3 is C (R) 7 ) Or N, or a combination of two,
R 5 、R 6 and R is 7 Each independently is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstitutedAn alkyl oxygen group,
R 1 is a carboxyl group, and is a carboxyl group,
R 2 alkyl substituted by a substituted or unsubstituted non-aromatic heterocycle or alkyl substituted by a substituted or unsubstituted aromatic heterocycle,
-X-is-C (R) 8 )(R 9 )-，
R 8 And R is 9 Each independently a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group,
[ 123]
The ring being represented by
[ chemical 124]
(in the formula (I),
R 10 each independently is halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclyl, or substituted or unsubstituted alkyloxy,
s' is an integer of 0 to 8),
R 13 each independently a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group,
R 3 a substituted or unsubstituted aromatic carbocyclyl group or a substituted or unsubstituted aromatic heterocyclic group) or a pharmaceutically acceptable salt thereof.
(iii) Formula (I):
[ 125]
(in the formula (I),
(i)A 1 is C (R) 5 )，A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 ) Or (b)
(ii)A 1 Is N, A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 )，
R 5 、R 6 And R is 7 Each independently is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group,
R 1 is a carboxyl group, and is a carboxyl group,
R 2 alkyl substituted by a substituted or unsubstituted non-aromatic heterocycle or alkyl substituted by a substituted or unsubstituted aromatic heterocycle,
-X-is-C (R) 8 )(R 9 )-，
R 8 And R is 9 Each independently a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group,
[ 126]
The ring being represented by
[ 127]
(in the formula (I),
R 10 each independently is halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclyl, or substituted or unsubstituted alkyloxy,
s is an integer of 1 to 9),
R 13 each independently a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group,
R 3 a substituted or unsubstituted aromatic carbocyclyl group or a substituted or unsubstituted aromatic heterocyclic group) or a pharmaceutically acceptable salt thereof.
(iv) Formula (I):
[ 128]
(in the formula (I),
(i)A 1 is C (R) 5 )，A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 ) Or (b)
(ii)A 1 Is N, A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 )，
R 5 、R 6 And R is 7 Each independently is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group,
R 1 is a carboxyl group, and is a carboxyl group,
R 2 alkyl substituted by a substituted or unsubstituted non-aromatic heterocycle or alkyl substituted by a substituted or unsubstituted aromatic heterocycle,
-X-is-C (R) 8 )(R 9 )-，
R 8 And R is 9 Each independently a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group,
[ 129]
The ring being represented by
[ 130]
(in the formula (I),
R 10 each independently is halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclyl, or substituted or unsubstituted alkyloxy,
s' is an integer of 0 to 8),
R 13 each independently a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group,
R 3 a substituted or unsubstituted aromatic carbocyclyl group or a substituted or unsubstituted aromatic heterocyclic group) or a pharmaceutically acceptable salt thereof.
(v) Formula (I):
[ 131]
(in the formula (I),
(i)A 1 is C (R) 5 )，A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 ) Or (b)
(ii)A 1 Is N, A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 )，
R 5 、R 6 And R is 7 Each independently is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group,
R 1 is a carboxyl group, and is a carboxyl group,
R 2 alkyl substituted by a substituted or unsubstituted non-aromatic heterocycle or alkyl substituted by a substituted or unsubstituted aromatic heterocycle,
-X-is-C (R) 8 )(R 9 )-，
R 8 And R is 9 Each independently a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group,
[ chemical 132]
The ring being represented by
[ chemical 133]
/>
(in the formula (I),
R 10 each independently is halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclyl, or substituted or unsubstituted alkyloxy,
s' is an integer of 0 to 8),
R 13 each independently a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group,
R 3 Is that
[ 134]
(in the formula (I),
T 1 is a carbon atom or a nitrogen atom,
T 2 is a carbon atom or a nitrogen atom,
R 4 each independently is halogen, cyano, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy,
R 14 is a hydrogen atom or a substituted or unsubstituted alkyl group,
m is an integer of 0 to 5,
n is an integer of 0 to 2) or a pharmaceutically acceptable salt thereof.
(vi) Formula (I):
[ chemical 135]
(in the formula (I),
(i)A 1 is C (R) 5 )，A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 ) Or (b)
(ii)A 1 Is N, A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 )，
R 5 、R 6 And R is 7 Each independently is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group,
R 1 is a carboxyl group, and is a carboxyl group,
R 2 alkyl substituted by a substituted or unsubstituted non-aromatic heterocycle or alkyl substituted by a substituted or unsubstituted aromatic heterocycle,
-X-is-C (R) 8 )(R 9 )-，
R 8 And R is 9 Each independently a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group,
[ chemical 136]
The ring being represented by
[ 137]
(in the formula (I),
R 10 each independently is halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclyl, or substituted or unsubstituted alkyloxy,
s' is an integer of 0 to 8),
R 13 each independently a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group,
R 3 is that
[ 138]
(in the formula (I),
T 1 is C (R) 12 ) Or N, or a combination of two,
T 2 is C (R) 12 ) Or N, or a combination of two,
R 12 each independently is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted alkylsulfonyl group,
R 4 each independently halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy) or a pharmaceutically acceptable salt thereof.
(vii) Formula (I):
[ chemical 139]
(in the formula (I),
(i)A 1 is C (R) 5 )，A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 ) Or (b)
(ii)A 1 Is N, A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 )，
R 5 、R 6 And R is 7 Each independently is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group,
R 1 is a carboxyl group, and is a carboxyl group,
R 2 is oxetanyl methyl or alkylimidazolylmethyl,
-X-is-C (R) 8 )(R 9 )-，
R 8 And R is 9 Each independently a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group,
[ 140]
The ring being represented by
[ 141]
(in the formula (I),
R 10 each independently is halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclyl, or substituted or unsubstituted alkyloxy,
s' is an integer of 0 to 8),
R 13 each independently a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group,
R 3 is that
[ 142]
(in the formula (I),
T 1 is C (R) 12 ) Or N, or a combination of two,
T 2 is C (R) 12 ) Or N, or a combination of two,
R 12 each independently is a hydrogen atom or a halogen,
R 4 each independently halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy) or a pharmaceutically acceptable salt thereof.
(viii) Formula (I):
[ 143]
(in the formula (I),
(i)A 1 is C (R) 5 )，A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 ) Or (b)
(ii)A 1 Is N, A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 )，
R 5 、R 6 And R is 7 Each independently is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group,
R 1 is a carboxyl group, and is a carboxyl group,
R 2 is oxetanyl methyl or alkylimidazolylmethyl,
-X-is-C (R) 8 )(R 9 )-，
R 8 And R is 9 Is a hydrogen atom, and is preferably a hydrogen atom,
[ 144]
The ring being represented by
[ chemical 145]
(in the formula (I),
R 10 each independently is halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclyl, or substituted or unsubstituted alkyloxy,
s' is an integer of 0 to 8),
R 13 is a hydrogen atom, and is preferably a hydrogen atom,
R 3 is that
[ 146]
(in the formula (I),
T 1 is C (R) 12 ) Or N, or a combination of two,
T 2 is C (R) 12 )，
R 12 Each independently is a hydrogen atom or a halogen,
R 4 each independently halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy) or a pharmaceutically acceptable salt thereof.
(ix) Formula (I):
[ chemical 147]
(in the formula (I),
(i)A 1 is C (R) 5 )，A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 ) Or (b)
(ii)A 1 Is N, A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 )，
R 5 、R 6 And R is 7 Each independently is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group,
R 1 is a carboxyl group, and is a carboxyl group,
R 2 is oxetanyl methyl or alkylimidazolylmethyl,
-X-is-C (R) 8 )(R 9 )-，
R 8 And R is 9 Is a hydrogen atom, and is preferably a hydrogen atom,
[ 148]
The ring being represented by
[ 149]
(in the formula (I),
R 10 each independently is halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclyl, or substituted or unsubstituted alkyloxy,
p is an integer of 0 to 6),
R 13 is a hydrogen atom, and is preferably a hydrogen atom,
R 3 is that
[ 150]
(in the formula (I),
T 1 is C (R) 12 ) Or N, or a combination of two,
R 12 each independently is a hydrogen atom or a halogen,
R 4 each independently a halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted non-aromatic carbocyclyl), or a pharmaceutically acceptable salt thereof.
(x) Formula (III):
[ 151]
(in the formula (I),
A 1 is C (R) 5 ) Or N, or a combination of two,
R 5 is a hydrogen atom or a halogen atom,
R 7 is a hydrogen atom, a halogen or a substituted or unsubstituted alkyloxy group,
R 2 alkyl substituted by a substituted or unsubstituted non-aromatic heterocycle or alkyl substituted by a substituted or unsubstituted aromatic heterocycle,
[ 152]
The ring being represented by
[ chemical 153]
(in the formula (I),
R 10 each independently is halogen, cyano or substituted or unsubstituted alkyl,
p is 0 or 1),
R 3 is that
[ 154]
(in the formula (I),
T 1 is C (R) 12 ) Or N, or a combination of two,
R 12 each independently is a hydrogen atom or a halogen,
R 4 each independently is halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted non-aromatic carbocyclyl,
R 14 a group represented by an unsubstituted alkyl group) or a pharmaceutically acceptable salt thereof.
(xi) Formula (III):
[ chemical 155]
(in the formula (I),
A 1 is C (R) 5 ) Or N, or a combination of two,
R 5 is a hydrogen atom or a halogen atom,
R 7 is a hydrogen atom, a halogen or a substituted or unsubstituted alkyloxy group,
R 2 alkyl substituted by a substituted or unsubstituted non-aromatic heterocycle or alkyl substituted by a substituted or unsubstituted aromatic heterocycle,
[ chemical 156]
The ring being represented by
[ 157]
/>
(in the formula (I),
R 10 each independently is halogen, cyano or substituted or unsubstituted alkyl,
p is 0 or 1),
R 3 is that
[ chemical 158]
(in the formula (I),
T 1 is C (R) 12 ) Or N, or a combination of two,
R 12 each independently is a hydrogen atom or a halogen,
R 4 each independently a halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted non-aromatic carbocyclyl), or a pharmaceutically acceptable salt thereof.
The compound represented by formula (I), formula (II) or formula (III) is not limited to a specific isomer, and includes all possible isomers (e.g., keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer, rotamer, tautomer as described below, etc.), racemate or a mixture thereof.
[ 159]
More than one hydrogen, carbon and/or other atoms of the compound represented by formula (I), formula (II) or formula (III) may be replaced with isotopes of hydrogen, carbon and/or other atoms, respectively. Examples of such isotopes include, for example 2 H、 3 H、 11 C、 13 C、 14 C、 15 N、 18 O、 17 O、 31 P、 32 P、 35 S、 18 F、 123 I and 36 cl such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine. The compounds represented by formula (I), formula (II) or formula (III) also include compounds substituted with such isotopes. The isotopically substituted compounds are also useful as pharmaceuticals, including all radiolabels of compounds represented by formula (I), formula (II), or formula (III). In addition, "radiolabeling methods" for making the "radiolabels" are also included in the present invention, which "radiolabels" may be used as tools for pharmacokinetic studies, research in binding assays, and/or diagnostics.
Radiolabels of compounds of formula (I), formula (II) or formula (III) may be prepared by methods well known in the art. For example, tritium-labeled compounds represented by formula (I), formula (II) or formula (III) can be prepared by introducing tritium into a specific compound represented by formula (I), formula (II) or formula (III) using a catalytic dehalogenation reaction using tritium. The process comprises reacting a suitably halogen substituted precursor of a compound of formula (I), formula (II) or formula (III) with a tritium gas in the presence of a suitable catalyst, such as Pd/C, in the presence or absence of a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, vol.1, labeled Compounds (Part a), chapter 6 (1987)". 14 The C-labeled compound can be prepared by using a compound having the following properties 14 C carbon raw material.
Examples of pharmaceutically acceptable salts of the compounds represented by the formula (I), the formula (II) or the formula (III) include: salts of the compounds represented by the formula (I), the formula (II) or the formula (III) with alkali metals (e.g., lithium, sodium, potassium, etc.), alkaline earth metals (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc.), and amino acids; or with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.), and organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.). In particular, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid, and the like are exemplified. These salts can be formed by a generally performed method.
The present invention also includes such various solvates, co-crystals and polymorphs in the presence of a compound represented by formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof to form solvates (e.g., hydrates, etc.), co-crystals and/or polymorphs. The "solvate" may coordinate any number of solvent molecules (e.g., water molecules, etc.) to the compound represented by formula (I), formula (II), or formula (III). There are cases where the compound represented by the formula (I), the formula (II) or the formula (III) or a pharmaceutically acceptable salt thereof is allowed to stand in the atmosphere to absorb moisture and cause adsorbed water to adhere or form a hydrate. In addition, there are cases where polymorphs are formed by recrystallizing a compound represented by formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof. By "co-crystal" is meant that the compound or salt represented by formula (I), formula (II), or formula (III) is present within the same crystal lattice as the counter molecule, and may comprise any number of counter molecules.
The present invention also includes various prodrugs of the compounds represented by formula (I), formula (II) or formula (III) or pharmaceutically acceptable salts thereof in the presence of the formation of a prodrug. Prodrugs are derivatives of the compounds of the invention having a group that is capable of decomposing chemically or metabolically, which are compounds of the invention that become pharmaceutically active in vivo by solvolysis or under physiological conditions. The prodrugs include compounds which are converted to compounds represented by formula (I), formula (II) or formula (III) by enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in the living body, compounds which are converted to compounds represented by formula (I), formula (II) or formula (III) by hydrolysis with gastric acid, etc. Methods of selecting suitable prodrug derivatives and methods of making suitable prodrug derivatives are described, for example, in "Design of Prodrugs, elsevier, amsterdam, 1985". Prodrugs are often active themselves.
In the case where the compound represented by the formula (I), the formula (II) or the formula (III) or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, the following prodrugs can be exemplified: an acyloxy derivative or a sulfonyloxy derivative produced by reacting a compound having a hydroxyl group with a suitable acid halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable sulfonic anhydride and a mixed acid anhydride or by reacting using a condensing agent. Examples include: CH (CH) 3 COO-、C 2 H 5 COO-, tert-BuCOO-, C 15 H 31 COO-、PhCOO-、(m-NaOOCPh)COO-、NaOOCCH 2 CH 2 COO-、CH 3 CH(NH 2 )COO-、CH 2 N(CH 3 ) 2 COO-、CH 3 SO 3 -、CH 3 CH 2 SO 3 -、CF 3 SO 3 -、CH 2 FSO 3 -、CF 3 CH 2 SO 3 -, a part of for CH 3 O-PhSO 3 -、PhSO 3 -, a part of for CH 3 PhSO 3 -。
(method for producing Compound of the invention)
The compound represented by the formula (I), the formula (II) or the formula (III) can be produced, for example, by the general synthesis method shown below. The starting materials and reagents used in these syntheses are either commercially available or may be prepared using commercially available compounds according to methods well known in the art. Extraction, purification, and the like may be performed by performing treatments performed in ordinary experiments of organic chemistry.
The compounds of the present invention may be synthesized by reference to methods well known in the art.
In the following steps, when a substituent (for example, a hydroxyl group, a mercapto group, an amino group, a formyl group, a carbonyl group, a carboxyl group, or the like) that is an obstacle to the reaction is present, the reaction may be protected beforehand by the method described in Protective Groups in Organic Synthesis, theodora W Greene (John Wiley & Sons), or the like, and the protecting group may be removed at a desired stage.
In addition, the order of the steps to be performed may be changed as appropriate for all the steps described below, and each intermediate may be separated and used for the next step. The reaction time, reaction temperature, solvent, reagent, protecting group, and the like are all exemplified, and are not particularly limited as long as the reaction is not hindered.
The general synthesis of the compounds of the present invention is shown below. The starting materials and reagents used in these syntheses are either commercially available or may be prepared using commercially available compounds according to methods well known in the art.
The compound represented by the general formula (I), the formula (II) or the formula (III) of the present invention can be produced, for example, by the synthetic route shown below.
General Synthesis method 1
[ A method ]
[ 160]
(wherein R is 10 'each independently is cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted non-aromatic carbocyclyl, s' is an integer from 0 to 7, X 1 Is a leaving group of halogen or the like, X 2 The other symbols have the same meaning as (1) above as leaving groups such as halogen
[ step A-1]
The compound a1 is reacted with 2-nitrobenzenesulfonyl chloride in the presence of a base, whereby the compound a2 can be obtained.
As the base, there may be mentioned: sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, calcium carbonate, cesium carbonate, pyridine, triethylamine, and the like can be used in an amount of 1 to 5 molar equivalents relative to the compound a 1.
The reaction temperature is-10 to 80℃and preferably 10 to 60 ℃.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
The reaction solvent may be: dichloromethane, tetrahydrofuran, dioxane, acetonitrile, etc., may be used alone or in combination.
[ step A-2]
Compound a2 and compound a3 are reacted in an acid solvent, whereby compound a4 can be obtained.
The reaction temperature is 20℃to 80℃and preferably 30℃to 60 ℃.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
The reaction solvent may be: acetic acid, concentrated sulfuric acid, etc., may be used alone or in combination.
[ step A-3]
Compound a4 was reacted with a metal catalyst and potassium acetate, bis (pinacolato) diboron, and thereafter, hydrogen peroxide water and water were added, whereby compound a5 was obtained.
As the metal catalyst, there may be mentioned: [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride dichloromethane adduct, palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-t-butylphosphine) palladium and the like can be used in an amount of 0.001 to 0.5 molar equivalent relative to the compound a4.
The reaction temperature is 0 to the reflux temperature of the solvent, and is carried out at a temperature under microwave irradiation according to circumstances.
The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
The reaction solvent may be: tetrahydrofuran, toluene, DMF and dioxane may be used alone or in combination.
[ step A-4]
Compound a6 is allowed to act on compound a5 in the presence of a base, whereby compound a7 can be obtained.
The reaction temperature is 0 to the reflux temperature of the solvent.
The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
As the base, use can be made of: potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, and the like.
The reaction solvent may be: methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, etc., may be used alone or in combination.
[ step A-5]
Compound a7 is reacted with thiol in the presence of a base, whereby compound a8 can be obtained.
The reaction temperature is from 0℃to 80℃and preferably from 30℃to 60 ℃.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
As the base, use can be made of: potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, and the like.
As the thiol, use may be made of: ethanethiol, dodecane-1-thiol, and the like.
The reaction solvent may be: acetonitrile, tetrahydrofuran, DMF, and the like, may be used alone or in combination.
[ step A-6]
Compound a9 is allowed to act on compound a8 in the presence of a base, whereby compound a10 can be obtained.
The reaction temperature is 0 to the reflux temperature of the solvent.
The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
As the base, use can be made of: potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, and the like.
The reaction solvent may be: methanol, ethanol, acetonitrile, tetrahydrofuran, DMF, and the like, may be used alone or in combination.
General Synthesis method 2
[ B method ]
[ 161]
(wherein X is 1 And X 2 In the same manner as in the above [ A ]]The other symbols have the same meaning as in (1) above
[ step B-1]
Compound b3 can be obtained by allowing compound b2 to act on compound b1 in the presence of a base.
The reaction temperature is 0 to the reflux temperature of the solvent.
The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
As the base, use can be made of: potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, and the like.
The reaction solvent may be: methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, etc., may be used alone or in combination.
[ step B-2]
The compound b3 is reacted with a fluorinating agent, whereby the compound b4 can be obtained.
The reaction temperature is from 0℃to 80℃and preferably from 30℃to 60 ℃.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
As the fluorinating agent, use may be made of: n, N-diethylaminosulfur trifluoride, and the like.
The reaction solvent may be: dichloromethane, tetrahydrofuran, etc., may be used alone or in combination.
[ step B-3]
Compound b4 is reacted with an aqueous alkaline solution, whereby compound b5 can be obtained.
The reaction temperature is from 0℃to 50℃and preferably from 0℃to 30 ℃.
The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
As the base, use can be made of: sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like.
The reaction solvent may be: methanol, ethanol, water, acetone, acetonitrile, tetrahydrofuran, etc., may be used alone or in combination.
[ step B-4]
Compound b7 can be obtained by allowing compound b6 to act on compound b5 in the presence of a base.
The reaction temperature is 0 to the reflux temperature of the solvent.
The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
As the base, use can be made of: potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, and the like.
The reaction solvent may be: methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, etc., may be used alone or in combination.
General Synthesis method 3
[ C method ]
[ 162]
(wherein X is 1 And X 2 In the same manner as in the above [ A ]]The other symbols have the same meaning as in (1) above
[ step C-1]
Compound c3 can be obtained by allowing compound c2 to act on compound c1 in the presence of a base.
The reaction temperature is 0 to the reflux temperature of the solvent.
The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
As the base, use can be made of: potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, and the like.
The reaction solvent may be: methanol, ethanol, acetonitrile, tetrahydrofuran, DMF, and the like, may be used alone or in combination.
[ step C-2]
Compound c4 is allowed to act on compound c3 in the presence of a base, whereby compound c5 can be obtained.
The reaction temperature is 0 to the reflux temperature of the solvent.
The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
As the base, use can be made of: sodium hydride, potassium t-butoxide, sodium t-butoxide, and the like.
The reaction solvent may be: methanol, ethanol, acetonitrile, tetrahydrofuran, DMF, and the like, may be used alone or in combination.
General Synthesis method 4
[ D method ]
[ 163]
(wherein X is 3 Is a leaving group of halogen or the like, X 4 The other symbols are as defined in the above (1) and are as leaving groups such as halogen
[ step D-1]
Compound d3 can be obtained by allowing compound d2 to act on compound d1 in the presence of a base.
The reaction temperature is from 0℃to 50℃and preferably from 0℃to 30 ℃.
The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
As the base, use can be made of: potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, and the like.
The reaction solvent may be: methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, etc., may be used alone or in combination.
[ step D-2]
Compound d3 and compound d4 are reacted in the presence of a metal catalyst and zinc fluoride, whereby compound d5 can be obtained.
As the metal catalyst, there may be mentioned: bis (tri-t-butylphosphine) palladium and the like may be used in an amount of 0.001 to 0.5 molar equivalent relative to the compound d3.
The reaction temperature is 20 to the reflux temperature of the solvent, and is carried out at a temperature under microwave irradiation according to circumstances.
The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
The reaction solvent may be: tetrahydrofuran, toluene, DMF, dioxane, water, etc., may be used alone or in combination.
[ step D-3]
If necessary, a base is reacted with the compound d5 in the presence of a condensing agent to react with the compound d6, and then the reaction is carried out in an acid solution, whereby the compound d7 can be obtained.
Examples of the condensing agent include: dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholinium hydrochloride, HATU and the like may be used in an amount of 1 to 5 molar equivalents relative to the compound d 6.
As the base, there may be mentioned: triethylamine, diisopropylethylamine, p-dimethylaminopyridine, and the like.
As the acid, there may be mentioned: acetic acid, and the like.
For the reaction temperature, the condensation reaction is-20 to 60 ℃, preferably 0 to 30 ℃, followed by the reaction in an acid solution of 10 to 80 ℃.
The reaction time is 0.1 to 24 hours, preferably 1 to 12 hours, and the subsequent reaction in the acid solution is 0.5 to 10 hours.
General Synthesis method 5
[ E method ]
[ chemical 164]
(wherein R is 10 '、s”、X 1 And X 2 In the same manner as in the above [ A ]]The other symbols have the same meaning as in (1) above
[ step E-1]
Compound e3 can be obtained by reacting compound e1 with compound e2 in the presence of a base.
As the base, there may be mentioned: sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, calcium carbonate, cesium carbonate, pyridine, triethylamine, etc., may be used in an amount of 1 to 5 molar equivalents relative to the compound e 1.
The reaction temperature is-10 to 80℃and preferably 10 to 60 ℃.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
The reaction solvent may be: dichloromethane, tetrahydrofuran, dioxane, acetonitrile, toluene, etc., may be used alone or in combination.
[ step E-2]
The compound e3 is reacted with phosphorus pentoxide, phosphorus oxychloride, or the like, whereby the compound e4 can be obtained.
The reaction temperature is-10 to 80℃and preferably 10 to 60 ℃.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
Toluene or the like can be used as the reaction solvent.
[ step E-3]
Compound e4 is reacted with formic acid and an amine in the presence of a ruthenium catalyst, whereby compound e5 can be obtained.
The ruthenium catalyst may be: [ (R, R) -N- (2-amino-1, 2-diphenylethyl) -p-toluenesulfonamide ] chloro (p-methylisopropylethyl) ruthenium, [ (S, S) -N- (2-amino-1, 2-diphenylethyl) -p-toluenesulfonamide ] chloro (p-methylisopropylethyl) ruthenium and the like can be used in an amount of 0.05 to 1 molar equivalent relative to the compound e4.
Examples of the amine include: triethylamine, etc., may be used in an amount of 1 to 3 molar equivalents relative to the compound e 4.
The reaction temperature is-10 to 80℃and preferably 10 to 60 ℃.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
As the reaction solvent, acetonitrile or the like can be used.
As an alternative to step E-3, step E-3' may be employed.
[ step E-3' ]
Compound e4 is reacted with a reducing agent, whereby compound e5 can be obtained.
As the reducing agent, there may be mentioned: sodium borohydride, etc., may be used in an amount of 1 to 5 molar equivalents with respect to the compound e 4.
The reaction temperature is-10 to 80℃and preferably 0 to 30 ℃.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
As the reaction solvent, methanol or the like can be used.
[ step E-4]
Compound e5 is reacted with trifluoroacetic anhydride, whereby compound e6 can be obtained.
The reaction temperature is-10 to 80℃and preferably 10 to 40 ℃.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
The reaction solvent may be: dichloromethane, tetrahydrofuran, dioxane, acetonitrile, etc., may be used alone or in combination.
[ step E-5]
The compound e6 is reacted with boron tribromide, aluminum chloride, or the like, whereby the compound e7 can be obtained.
The reaction temperature is-10 to 80 ℃, preferably 0 to 40 ℃.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
As the reaction solvent, methylene chloride, toluene, or the like can be used.
[ step E-6]
Compound e8 is allowed to act on compound e7 in the presence of a base, whereby compound e9 can be obtained.
The reaction temperature is 0 to the reflux temperature of the solvent.
The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
As the base, use can be made of: potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, and the like.
The reaction solvent may be: methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, etc., may be used alone or in combination.
[ step E-7]
Compound e9 is reacted with a base, whereby compound e10 can be obtained.
The reaction temperature is from 0℃to 80℃and preferably from 10℃to 60 ℃.
The reaction time is 0.5 to 12 hours, preferably 1 to 10 hours.
As the base, use can be made of: sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like.
The reaction solvent may be: methanol, ethanol, water, acetone, acetonitrile, tetrahydrofuran, etc., may be used alone or in combination.
[ step E-8]
Compound e11 is allowed to act on compound e10 in the presence of a base, whereby compound e12 can be obtained.
The reaction temperature is 0 to the reflux temperature of the solvent.
The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
As the base, use can be made of: potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, and the like.
The reaction solvent may be: methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, etc., may be used alone or in combination.
General Synthesis method 6
[ F method ]
[ 165]
(wherein R is 50 Is alkyl, t is an integer of 0 to 3, X 3 Is a leaving group of halogen or the like, X 1 And X 2 In the same manner as in the above [ A ]]The other symbols have the same meaning as in (1) above
[ step F-1]
Compound f3 can be obtained by allowing compound f2 to act on compound f1 in the presence of a base.
The reaction temperature is 0 to the reflux temperature of the solvent.
The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
As the base, use can be made of: potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, silver carbonate, and the like.
The reaction solvent may be: methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, dioxane, etc., may be used alone or in combination.
[ step F-2]
Compound f3 is reacted with a reducing agent, whereby compound f4 can be obtained.
As the reducing agent, there may be mentioned: sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, and the like may be used in an amount of 1 to 10 molar equivalents with respect to the compound f 3.
The reaction temperature is from 0 to reflux temperature, preferably from 20 to reflux temperature.
The reaction time is 0.2 to 48 hours, preferably 1 to 24 hours.
The reaction solvent may be: methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, methylene chloride, water, etc., may be used alone or in combination.
[ step F-3]
In the presence of a metal catalyst and a base, tetrabutylammonium bromide or the like is added as needed, and the compound f4 and f5 are reacted to obtain a compound f6.
As the metal catalyst, there may be mentioned: palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium, and the like can be used in an amount of 0.001 to 0.5 molar equivalent relative to the compound f4.
As the base, there may be mentioned: dicyclohexylamine, potassium tert-butoxide, sodium carbonate, potassium carbonate, and the like may be used in an amount of 1 to 10 molar equivalents relative to the compound f4.
The reaction temperature is 20 to the reflux temperature of the solvent, and is carried out at a temperature under microwave irradiation according to circumstances.
The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
The reaction solvent may be: tetrahydrofuran, toluene, DMF, dioxane, water, etc., may be used alone or in combination.
[ step F-4]
Compound f6 is reacted with hydrogen in the presence of a metal catalyst, whereby compound f7 can be obtained.
As the metal catalyst, there may be mentioned: palladium-carbon, platinum oxide, rhodium-alumina, tris (triphenylphosphine) rhodium (I) chloride, etc., may be used in an amount of 0.01 to 100% by weight relative to the compound f 6.
The hydrogen gas pressure may be 1 to 50 atmospheres. As the hydrogen source, it is also possible to use: cyclohexene, 1, 4-cyclohexadiene, formic acid, ammonium formate and the like.
The reaction temperature is 0℃to the reflux temperature of the solvent, preferably 20℃to 40 ℃.
The reaction time is 0.5 to 72 hours, preferably 1 to 12 hours.
The reaction solvent may be: methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, toluene, ethyl acetate, acetic acid, water, etc., may be used alone or in combination.
[ step F-5]
Compound f7 is reacted with hydrazine monohydrate or the like, whereby compound f8 can be obtained.
The reaction temperature is from 0℃to 100℃and preferably from 20℃to 80 ℃.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
As the reaction solvent, ethanol or the like can be used.
[ step F-6]
Compound f8 is reacted with trifluoroacetic anhydride, whereby compound f9 can be obtained.
The reaction temperature is-10 to 80 ℃, preferably 0 to 40 ℃.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
The reaction solvent may be: dichloromethane, tetrahydrofuran, dioxane, acetonitrile, etc., may be used alone or in combination.
[ step F-7]
The triphenylphosphine, and the casting reagent were allowed to act on the compound f9, whereby the compound f10 was obtained.
As the casting agent, there may be mentioned: DEAD, DIAD, etc., may be used in an amount of 1 to 5 molar equivalents relative to the compound f9.
The reaction temperature is from 0℃to 60℃and preferably from 10℃to 40 ℃.
The reaction time is 0.1 to 12 hours, preferably 0.2 to 6 hours.
The reaction solvent may be: tetrahydrofuran, dioxane, ethyl acetate, toluene, acetonitrile, etc., may be used alone or in combination.
[ step F-8]
Compound f10 is reacted with a base, whereby compound f11 can be obtained.
The reaction temperature is from 0℃to 80℃and preferably from 10℃to 60 ℃.
The reaction time is 0.5 to 12 hours, preferably 1 to 10 hours.
As the base, use can be made of: sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like.
The reaction solvent may be: methanol, ethanol, water, acetone, acetonitrile, tetrahydrofuran, etc., may be used alone or in combination.
[ step F-9]
Compound f13 can be obtained by allowing compound f12 to act on compound f11 in the presence of a base.
The reaction temperature is 0 to the reflux temperature of the solvent.
The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
As the base, use can be made of: potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, and the like.
The reaction solvent may be: methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, etc., may be used alone or in combination.
General Synthesis method 7
[ G method ]
[ 166]
(wherein X is 1 And X 2 In the same manner as in the above [ A ]]The other symbols have the same meaning as in (1) above
[ step G-1]
Compound g3 can be obtained by allowing compound g2 to act on compound g1 in the presence of a base.
The reaction temperature is 0 to the reflux temperature of the solvent.
The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
As the base, use can be made of: potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, and the like.
The reaction solvent may be: methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, dioxane, etc., may be used alone or in combination.
[ step G-2]
Compound g3 is reacted with an acid or a lewis acid, whereby compound g4 can be obtained.
As the acid, there may be mentioned: hydrochloric acid-ethyl acetate, hydrochloric acid-methanol, hydrochloric acid-dioxane, sulfuric acid, formic acid, trifluoroacetic acid, and the like. Examples of the lewis acid include: trimethyliodosilane, BBr 3 、AlCl 3 、BF 3 ·(Et 2 O), etc., 1 to 10 molar equivalents relative to the compound g3 can be used.
The reaction temperature is from 0℃to 60℃and preferably from 0℃to 20 ℃.
The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
The reaction solvent may be: methanol, ethanol, water, acetone, acetonitrile, DMF, dichloromethane, etc., may be used alone or in combination.
[ step G-3]
Compound g5 is allowed to act on compound g4 in the presence of a base, whereby compound g6 can be obtained.
The reaction temperature is 0 to the reflux temperature of the solvent.
The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
As the base, use can be made of: potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, and the like.
The reaction solvent may be: methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, etc., may be used alone or in combination.
General Synthesis method 8
[ H method ]
[ 167]
(wherein X is 4 Is a leaving group of halogen or the like, X 1 In the same manner as in the above [ A ]]The other symbols have the same meaning as in (1) above
[ step H-1]
Compound h3 can be obtained by allowing compound h2 to act on compound h1 in the presence of a base.
The reaction temperature is 0 to the reflux temperature of the solvent.
The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
As the base, use can be made of: potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, silver carbonate, and the like.
The reaction solvent may be: methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, dioxane, etc., may be used alone or in combination.
[ step H-2]
Compound h3 is reacted with compound h4 in the presence of a metal catalyst and zinc fluoride, whereby compound h5 is obtained.
As the metal catalyst, there may be mentioned: bis (tri-t-butylphosphine) palladium and the like may be used in an amount of 0.001 to 0.5 molar equivalent relative to the compound h3.
The reaction temperature is 20 to the reflux temperature of the solvent, and is carried out at a temperature under microwave irradiation according to circumstances.
The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
The reaction solvent may be: tetrahydrofuran, toluene, DMF, dioxane, water, etc., may be used alone or in combination.
[ step H-3]
If necessary, a base is reacted with the compound h5 in the presence of a condensing agent to react with the compound h6, and then the reaction is carried out in an acid solution, whereby the compound h7 can be obtained.
Examples of the condensing agent include: dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholinium hydrochloride, HATU and the like may be used in an amount of 1 to 5 molar equivalents relative to the compound h 5.
As the base, there may be mentioned: triethylamine, diisopropylethylamine, p-dimethylaminopyridine, and the like.
As the acid, there may be mentioned: acetic acid, and the like.
For the reaction temperature, the condensation reaction is-20 to 60 ℃, preferably 0 to 30 ℃, followed by the reaction in an acid solution of 10 to 80 ℃.
The reaction time is 0.1 to 24 hours, preferably 1 to 12 hours, and the subsequent reaction in the acid solution is 0.5 to 10 hours.
General Synthesis method 9
[ I method ]
[ chemical 168]
[ 169]
(wherein R is 50 Is alkyl, t is an integer of 0 to 3, X 3 Is a leaving group such as halogen, M is Li, mgCl or MgBr, X 1 And X 2 In the same manner as in the above [ A ]]The other symbols have the same meaning as in (1) above
[ step I-1]
Compound f3 is reacted with an aqueous alkaline solution, whereby compound i1 can be obtained.
The reaction temperature is from 0℃to 70℃and preferably from 0℃to 50 ℃.
The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
As the base, use can be made of: sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like.
The reaction solvent may be: methanol, ethanol, water, acetone, acetonitrile, tetrahydrofuran, etc., may be used alone or in combination.
[ step I-2]
The compound i3 can be obtained by reacting the compound i1 with the compound i2 in the presence of a condensing agent.
Examples of the condensing agent include: dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, HATU and the like may be used in an amount of 1 to 5 molar equivalents relative to the compound i 2.
As the base, there may be mentioned: triethylamine, diisopropylethylamine, p-dimethylaminopyridine, and the like.
The reaction temperature is-20 to 80 ℃, preferably 10 to 70 ℃.
The reaction time is 0.1 to 24 hours, preferably 1 to 12 hours.
The reaction solvent may be: tetrahydrofuran, dichloromethane, DMF, etc., may be used alone or in combination.
[ step I-3]
The compound i3 is reacted with an organometallic reagent, whereby the compound i4 can be obtained.
Examples of the organometallic reagent include: grignard reagent, organolithium reagent, etc., may be used in an amount of 1 to 10 molar equivalents with respect to the compound i 3.
The reaction temperature is-40 to 60 ℃, preferably-20 to 40 ℃.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
The reaction solvent may be: tetrahydrofuran, diethyl ether, dioxane, etc., may be used alone or in combination.
[ step I-4]
Compound i4 is reacted with formic acid and an amine in the presence of a ruthenium catalyst, whereby compound i5 can be obtained.
The ruthenium catalyst may be: [ (R, R) -N- (2-amino-1, 2-diphenylethyl) -p-toluenesulfonamide ] chloro (p-methylisopropylethyl) ruthenium, [ (S, S) -N- (2-amino-1, 2-diphenylethyl) -p-toluenesulfonamide ] chloro (p-methylisopropylethyl) ruthenium and the like can be used in an amount of 0.05 to 1 molar equivalent relative to the compound i4.
Examples of the amine include: triethylamine, etc., may be used in an amount of 1 to 5 molar equivalents relative to the compound i 4.
The reaction temperature is-10 to 80℃and preferably 10 to 60 ℃.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
As the reaction solvent, acetonitrile or the like can be used.
[ step I-5]
In the presence of a metal catalyst and a base, tetrabutylammonium bromide or the like is added as needed to react the compound i5 with f5, thereby obtaining a compound i6.
As the metal catalyst, there may be mentioned: palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium, and the like can be used in an amount of 0.001 to 0.5 molar equivalent with respect to the compound i 5.
As the base, there may be mentioned: dicyclohexylamine, potassium tert-butoxide, sodium carbonate, potassium carbonate, and the like may be used in an amount of 1 to 10 molar equivalents relative to the compound i 5.
The reaction temperature is 20 to the reflux temperature of the solvent, and is carried out at a temperature under microwave irradiation according to circumstances.
The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
The reaction solvent may be: tetrahydrofuran, toluene, DMF, dioxane, water, etc., may be used alone or in combination.
[ step I-6]
Compound i6 is reacted with hydrogen in the presence of a metal catalyst, whereby compound i7 can be obtained.
As the metal catalyst, there may be mentioned: palladium-carbon, platinum oxide, rhodium-alumina, tris (triphenylphosphine) rhodium (I) chloride, etc., may be used in an amount of 0.01 to 100% by weight relative to the compound I6.
The hydrogen gas pressure may be 1 to 50 atmospheres. As the hydrogen source, it is also possible to use: cyclohexene, 1, 4-cyclohexadiene, formic acid, ammonium formate and the like.
The reaction temperature is 0℃to the reflux temperature of the solvent, preferably 20℃to 40 ℃.
The reaction time is 0.5 to 72 hours, preferably 1 to 12 hours.
The reaction solvent may be: methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, toluene, ethyl acetate, acetic acid, water, etc., may be used alone or in combination.
[ step I-7]
The compound i7 is reacted with hydrazine monohydrate or the like, whereby the compound i8 can be obtained.
The reaction temperature is from 0℃to 100℃and preferably from 20℃to 80 ℃.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
As the reaction solvent, ethanol or the like can be used.
[ step I-8]
Compound i8 is reacted with trifluoroacetic anhydride, whereby compound i9 can be obtained.
The reaction temperature is-10 to 80 ℃, preferably 0 to 40 ℃.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
The reaction solvent may be: dichloromethane, tetrahydrofuran, dioxane, acetonitrile, etc., may be used alone or in combination.
[ step I-9]
By allowing triphenylphosphine and a casting reagent to act on the compound i9, the compound i10 can be obtained.
As the casting agent, there may be mentioned: DEAD, DIAD, etc., may be used in an amount of 1 to 5 molar equivalents relative to the compound i 9.
The reaction temperature is from 0℃to 60℃and preferably from 10℃to 40 ℃.
The reaction time is 0.1 to 12 hours, preferably 0.2 to 6 hours.
The reaction solvent may be: tetrahydrofuran, dioxane, ethyl acetate, toluene, acetonitrile, etc., may be used alone or in combination.
[ step I-10]
The compound i10 is reacted with a base, whereby the compound i11 can be obtained.
The reaction temperature is from 0℃to 80℃and preferably from 10℃to 60 ℃.
The reaction time is 0.5 to 12 hours, preferably 1 to 10 hours.
As the base, use can be made of: sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like.
The reaction solvent may be: methanol, ethanol, water, acetone, acetonitrile, tetrahydrofuran, etc., may be used alone or in combination.
[ step I-11]
Compound f12 is allowed to act on compound i11 in the presence of a base, whereby compound i12 can be obtained.
The reaction temperature is 0 to the reflux temperature of the solvent.
The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
As the base, use can be made of: potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, and the like.
The reaction solvent may be: methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, etc., may be used alone or in combination.
The compounds of the present invention have GLP-1 receptor agonist activity and are therefore useful as therapeutic and/or prophylactic agents for diseases in which the GLP-1 receptor is involved.
In the case where "therapeutic agent and/or prophylactic agent" is mentioned in the present invention, a symptom-improving agent is also included.
Examples of diseases in which the GLP-1 receptor participates include: insulin-independent diabetes (type II diabetes), hyperglycemia, glucose intolerance, insulin-dependent diabetes (type I diabetes), diabetic complications, obesity, hypertension, dyslipidemia, arteriosclerosis, myocardial infarction, coronary heart disease, cerebral infarction, nonalcoholic steatohepatitis, parkinson's disease, dementia, etc.
In the present invention, "diabetes" means a disease or state in which the metabolism in the production and use of glucose is abnormal due to the inability to maintain an appropriate blood glucose level in the body, and includes insulin-dependent diabetes mellitus (type I diabetes) and insulin-independent diabetes mellitus (type II diabetes).
"hyperglycemia" refers to a condition in which the plasma glucose level is higher than normal (e.g., 80-110 mg/dL in humans on an empty stomach) on fasting or after administration of glucose, and is also one of the representative symptoms of diabetes.
"glucose intolerance" includes insulin-resistant glucose intolerance and insulin secretion defects.
"diabetic complication" means a complication caused by diabetes or hyperglycemia, which may be any of acute complications and chronic complications. Examples of the "acute complications" include: ketoacidosis, infectious diseases (e.g., skin infection, soft tissue infection, biliary tract infection, respiratory system infection, urinary tract infection), and examples of "chronic complications" include: microvascular (e.g., nephropathy, retinopathy), neurological disorders (e.g., sensory, motor, autonomic), foot necrosis. As major complications of diabetes mellitus, there are: diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy. "coronary heart disease" includes myocardial infarction, angina pectoris, etc.
Examples of the "dementia" include: alzheimer's disease, vascular dementia and diabetic dementia.
The compound of the present invention has not only GLP-1 receptor agonist activity but also usefulness as a drug, and has any one or all of the following excellent characteristics.
a) The inhibition effect on CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.
b) Shows good pharmacokinetics such as high bioavailability, moderate clearance rate and the like.
c) The metabolic stability is higher.
d) The CYP enzyme (e.g., CYP3 A4) does not exhibit an irreversible inhibitory effect in the concentration range of the measurement conditions described in the present specification.
e) Has no mutagenicity.
f) The risk of cardiovascular system is low.
g) The risk of blood toxicity is low.
h) Exhibit high solubility.
The pharmaceutical composition of the present invention may be administered by any of oral or parenteral methods. As a method of non-oral administration, there may be mentioned: transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drops, ear drops, intravaginal administration, and the like.
In the case of oral administration, the pharmaceutical composition may be formulated into any of commonly used dosage forms such as solid preparations for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.), and solutions for internal use (e.g., suspensions, emulsions, elixirs, syrups, lemonades, alcoholic solutions, aromatic solutions, extracts, decoctions, tinctures, etc.), according to a conventional method. The tablet can be sugar-coated tablet, film-coated tablet, enteric coated tablet, sustained release tablet, buccal tablet, sublingual tablet, buccal tablet, chewable tablet or orally disintegrating tablet, the powder and granule can be dry syrup, and the capsule can be soft capsule, microcapsule or sustained release capsule.
In the case of non-oral administration, the composition may be suitably administered in any of commonly used forms such as injections, drops, external preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coating agents, gargles, enemas, ointments, plasters, gels, creams, patches, cataplasms, external powders, suppositories, etc.). The injection can be O/W, W/O, O/W/O, W/O/W type emulsion.
The pharmaceutical composition can be prepared by mixing, as required, an effective amount of the compound of the present invention with various pharmaceutical additives such as excipients, binders, disintegrants, lubricants, etc. suitable for the dosage form thereof. Further, the pharmaceutical composition can be prepared into a pharmaceutical composition for children, the elderly, patients with severe symptoms or for surgery by appropriately changing the effective amount, dosage form and/or various pharmaceutical additives of the compound of the present invention. The pharmaceutical composition for children is preferably administered to a patient less than 12 years of age or 15 years of age. In addition, the pharmaceutical composition for children may be administered to patients less than 27 days postnatal, 28 days to 23 months postnatal, 2 years to 11 years old, or 12 years to 17 years old, or 18 years old. The pharmaceutical composition for the elderly is preferably administered to patients over 65 years old.
The amount of the pharmaceutical composition of the present invention to be administered is desirably set in consideration of the age, weight, type or extent of disease, route of administration, etc. of the patient, and in the case of oral administration, it is usually in the range of 0.05 to 100 mg/kg/day, preferably 0.1 to 10 mg/kg/day. In the case of non-oral administration, there are large differences depending on the route of administration, but it is usually in the range of 0.005 to 10 mg/kg/day, preferably 0.01 to 1 mg/kg/day. It is administered 1 to several times per day.
The compound of the present invention can be used in combination with a pharmaceutical agent for the purpose of enhancing the action of the compound, reducing the administration amount of the compound, or the like. In this case, the timing of administration of the compound of the present invention and the concomitant drug is not limited, and they may be administered to the subject at the same time or with a time difference.
The amount of the pharmaceutical agent to be administered can be appropriately selected based on the clinically used amount. The compounding ratio of the compound of the present invention and the concomitant agent may be appropriately selected according to the administration subject, the administration route, the target disease, the symptom, the combination, and the like. For example, when the compound of the present invention is administered to a human, the pharmaceutical agent may be used in an amount of 0.01 to 100 parts by weight based on 1 part by weight of the compound of the present invention.
The pharmaceutical composition of the present invention can also be used in combination with other anti-obesity agents (pharmaceutical compositions containing compounds having an anti-obesity effect, agents useful for obesity or weight management in obesity, etc.). For example, by combining a pharmaceutical composition containing a compound having an anti-obesity effect with the compound of the present invention, it can be used for the prevention and/or treatment of obesity or weight management in obesity, etc. In addition, the pharmaceutical composition containing the compound of the present invention can be used for the prevention and/or treatment of obesity, weight management in obesity, and the like by combining the pharmaceutical composition with a pharmaceutical composition containing a compound having an anti-obesity effect. The administration therapy of the pharmaceutical composition of the present invention may be used in combination with dietetic therapy, pharmacotherapy, exercise, and the like.
Examples
The present invention will be described in further detail with reference to examples, reference examples, and test examples, but the present invention is not limited thereto.
The abbreviations used in the present specification mean the following meanings.
CHCl 3 : chloroform (chloroform)
CDCl 3 : deuterated chloroform
MeOH: methanol
DMSO-d 6 : deuterated dimethyl sulfoxide
DMSO: dimethyl sulfoxide
DMA: dimethylacetamide
DMF: dimethylformamide
THF: tetrahydrofuran (THF)
NMP: n-methylpyrrolidone
Ns: 2-Nitrophenyl sulfonyl
HOAt: 1-hydroxy-7-azabenzotriazoles
HOBt: 1-hydroxybenzotriazoles
EDC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
HATU:2- (7-azabenzotriazol-1-yl) -1, 3-tetramethylurea hexafluorophosphate
DIBAL: diisobutyl aluminum hydride
DIAD: diisopropyl azodicarboxylate
DEAD: azodicarboxylic acid diethyl ester
BBr 3 : boron tribromide
AlCl 3 : aluminum chloride
BF 3 (Et 2 O): boron trifluoride diethyl etherate complex
TLC: thin layer chromatography
SFC: supercritical fluid chromatography
ODS: octadecylsilyl group
(method for identifying Compound)
NMR analyses obtained in the examples were carried out at 400MHz using DMSO-d 6 Or CDCl 3 The measurement was performed. In addition, in the case of the NMR data, all peaks measured may not be described.
RT in the specification denotes LC/MS: retention time in liquid chromatography/mass spectrometry was measured under the following conditions.
In the specification, [ M+H ] and [ M-H ] are described as values observed in a mass spectrum.
(measurement condition 1)
Column: ACQUITY UPLC BEH C18 (1.7 μm i.d.2.1X150 mm) (Waters)
Flow rate: 0.8 mL/min
UV detection wavelength: 254nm
Mobile phase: [A] an aqueous solution containing 0.1% formic acid, and [ B ] an acetonitrile solution containing 0.1% formic acid
Gradient: after a linear gradient of 5% to 100% solvent [ B ] was performed for 3.5 minutes, 100% solvent [ B ] was maintained for 0.5 minutes.
(measurement condition 2)
Column: shim-pack XR-ODS (2.2 μm, i.d. 3.0X150 mm) (Shimadzu)
Flow rate: 1.6 mL/min; UV detection wavelength: 254nm;
mobile phase: [A] an aqueous solution containing 0.1% formic acid, and [ B ] an acetonitrile solution containing 0.1% formic acid
Gradient: a linear gradient of 10% to 100% solvent [ B ] was performed over 3 minutes, with 100% solvent [ B ] maintained for 0.5 minutes.
(measurement condition 3)
Column: ACQUITY UPLC BEH C18 (1.7 μm i.d.2.1X150 mm) (Waters)
Flow rate: 0.8 mL/min; UV detection wavelength: 254nm;
mobile phase: [A] an aqueous solution containing 0.1% formic acid, and [ B ] an acetonitrile solution containing 0.1% formic acid
Gradient: a linear gradient of 5% to 100% solvent [ B ] was performed over 3.5 minutes, with 100% solvent [ B ] maintained for 0.5 minutes.
(measurement condition 4)
Column: ACQUITY UPLC BEH C18 (1.7 μm i.d.2.1X150 mm) (Waters)
Flow rate: 0.8 mL/min
UV detection wavelength: 254nm
Mobile phase: [A] is an aqueous solution containing 10mM ammonium carbonate, [ B ] is acetonitrile
Gradient: after a linear gradient of 5% to 100% solvent [ B ] was performed for 3.5 minutes, 100% solvent [ B ] was maintained for 0.5 minutes.
(measurement condition 5)
Column: l-column2 ODS (3 μm i.d.3X150 mm) (chemical evaluation research institution)
Flow rate: 1.5 mL/min
UV detection wavelength: 220nm
Mobile phase: [A] is an aqueous solution containing 0.05% trifluoroacetic acid, [ B ] is an acetonitrile solution containing 0.05% trifluoroacetic acid
Gradient: a linear gradient of 5% to 95% solvent [ B ] was performed over 3.5 minutes, and 95% solvent [ B ] was maintained for 2 minutes.
EXAMPLE 1 Synthesis of Compound I-023
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Step 1 Synthesis of Compound 2
Compound 1 (500 mg, 1.87 mmol) and triethylamine (0.776 mL, 5.60 mmol) were dissolved in methylene chloride (5 mL), and 2-nitrobenzenesulfonyl chloride (434 mg, 1.96 mmol) was added to the reaction solution and stirred at room temperature for 75 minutes. The reaction solution was added to water and methylene chloride, and extraction was performed with methylene chloride. The organic layer was washed with 2mol/L aqueous hydrochloric acid, saturated aqueous sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give compound 2 (623 mg, yield 74%). Further, the residue produced in the separated aqueous layer was collected by filtration and dried to obtain compound 2 (178 mg, yield 21%).
1 H-NMR(CDCl 3 )δ：2.87(2H，t，J＝6.8Hz)，3.44(2H，q，J＝6.6Hz)，5.32-5.37(1H，m)，7.17(1H，d，J＝7.3Hz)，7.38(1H，s)，7.54(1H，d，J＝8.3Hz)，7.69-7.76(2H，m)，7.83(1H，d，J＝7.4Hz)，8.03(1H，dd，J＝7.4Hz，1.5Hz).
[ M-H ] = 450.98, assay condition 1: retention time 2.34 min
Step 2 Synthesis of Compound 3
Compound 2 (427 mg, 0.942 mmol) was dissolved in acetic acid (4 mL) and paraformaldehyde (141 mg, 4.71 mmol) and concentrated sulfuric acid (2 mL) were added at room temperature. The reaction mixture was cooled in an ice bath, concentrated sulfuric acid (2 mL) was added thereto, and the mixture was stirred at 60℃for 5 hours. The reaction solution was slowly added dropwise to an ice-cooled 2mol/L aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was washed with a 2mol/L aqueous sodium hydroxide solution and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane-ethyl acetate) to obtain compound 3 (431 mg, 80% by weight, yield 79%, compound 3:4:2=1:0.05:0.2) as a mixture with compound 4 and compound 2.
[ m+h ] = 465.10, assay condition 1: retention time 2.53 min
Step 3 Synthesis of Compound 5
Compound 3 (430 mg, 0.924 mmol) and 4,4', 5' -octamethyl-2, 2' -bis (1, 3, 2-dioxaborolan) (352 mg, 1.39 mmol) were dissolved in 1, 4-dioxane (8 mL), and potassium acetate (454 mg, 4.62 mmol) and (1, 1-bis (diphenylphosphino) ferrocene) palladium (II) dichloromethane adduct (75 mg, 0.092 mmol) were added to the reaction mixture and stirred under a nitrogen stream at 100℃for 9 hours. The reaction solution was cooled in an ice bath, water (4 mL) and 30% hydrogen peroxide water (0.944 mL, 9.24 mmol) were added, and the mixture was allowed to stand at room temperature for one day and night. The reaction solution was added to water and ethyl acetate, and extraction was performed with ethyl acetate. The organic layer was washed with a 10% aqueous sodium thiosulfate solution and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane-ethyl acetate) to obtain compound 5 (312 mg, 68% by weight, yield 57%, compound 5: compound 6=1:0.5) as a mixture with compound 6.
[ m+h ] = 403.19, assay condition 1: retention time 2.10 min
Step 4 Synthesis of Compound 7
Compound 5 (160 mg, 0.398 mmol), cesium carbonate (259 mg, 0.795 mmol) and 1- (bromomethyl) -4-chloro-2-fluorobenzene (0.065 mL, 0.477 mmol) were dissolved in DMF (1.6 mL) and stirred at room temperature for 90 min. The reaction solution was cooled in an ice bath, water was added thereto, and extraction was performed with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by column chromatography (hexane-ethyl acetate) to obtain compound 7 (138 mg, 74% by weight, yield 47%) as a mixture with compound 6.
1 H-NMR(CDCl 3 )δ：2.89-2.93(2H，m)，3.64(2H，t，J＝5.8Hz)，4.55(2H，s)，5.15(2H，s)，6.78(1H，s)，7.13(1H，dd，J＝9.7Hz，1.5Hz)，7.19(1H，d，J＝8.3Hz)，7.35(1H，s)，7.49(1H，t，J＝8.0Hz)，7.64-7.66(1H，m)，7.70-7.74(2H，m)，8.07-8.09(1H，m).
[ m+h ] = 545.07, assay condition 1: retention time 2.88 min
Step 5 Synthesis of Compound 8
Compound 7 (135 mg, 0.248 mmol) was dissolved in DMF (1 mL), cesium carbonate (242 mg, 0.743 mmol) and dodecane-1-thiol (0.177 mL, 0.743 mmol) were added and stirred at room temperature for 1.5 hours. Dodecane-1-thiol (0.087 mL) was added to the reaction mixture, and the mixture was allowed to stand overnight. The reaction solution was added to water and ethyl acetate, and extraction was performed with ethyl acetate. The organic layer was washed with a 2mol/L aqueous sodium carbonate solution and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by amino silica gel column chromatography (hexane-ethyl acetate, followed by ethyl acetate-methanol) to obtain compound 8 (35 mg, 78% by weight, yield 31%, compound 8: compound 9=1:0.5) as a mixture with compound 9.
1 H-NMR(CDCl 3 )δ：2.75(2H，t，J＝5.8Hz)，3.13(2H，t，J＝5.8Hz)，4.01(2H，s)，5.14(2H，s)，6.69(1H，s)，7.12(1H，d，J＝9.8Hz)，7.18(1H，d，J＝8.3Hz)，7.32(1H，s)，7.51(1H，t，J＝8.3Hz).
[ m+h ] = 360.19, assay condition 1: retention time 1.91 min
Step 6 Synthesis of Compound 11
Compound 8 (35 mg, 0.097 mmol) and compound 10 (29 mg, 0.097 mmol) were dissolved in acetonitrile (1.0 mL), and potassium carbonate (27 mg, 0.195 mmol) was added thereto and stirred at 60℃for 2 hours. The reaction solution was added to water and ethyl acetate, and extraction was performed with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by amino silica gel column chromatography (hexane-ethyl acetate) to obtain compound 11 (50 mg, 73% by weight, yield 61%, compound 11: compound 12=1:0.5) as a mixture with compound 12.
[ m+h ] = 618.27, assay condition 1: retention time 2.43 min
Step 7 Synthesis of Compound I-023
Compound 11 (49 mg, 0.079 mmol) was dissolved in tetrahydrofuran (0.5 mL) and methanol (0.5 mL), and 2mol/L aqueous sodium hydroxide solution (0.159 mL, 0.317 mmol) was added thereto, followed by stirring at 50℃for 90 minutes. 2mol/L aqueous hydrochloric acid (0.159 mL, 0.317 mmol) cooled by an ice bath and water were added to the reaction solution. The reaction solution was filtered and washed with water. The obtained residue was purified by reverse phase chromatography (water-acetonitrile) using ODS column to obtain Compound I-023 (11.6 mg, yield 24%,).
1 H-NMR(CDCl 3 )δ：2.36-2.45(1H，m)，2.65-2.71(1H，m)，2.87(4H，br-s)，3.70(2H，s)，4.14-4.22(2H，m)，4.33-4.38(1H，m)，4.58-4.75(3H，m)，5.09(2H，s)，5.16-5.21(1H，m)，6.66(1H，s)，7.10(1H，d，J＝9.8Hz)，7.17(1H，d，J＝8.3Hz)，7.34(1H，s)，7.48(1H，t，J＝8.3Hz)，7.82(1H，d，J＝8.5Hz)，8.06(1H，d，J＝8.5)，8.21(1H，s).[M+H]=604, assay condition 1: retention time 2.18 min
EXAMPLE 2 Synthesis of Compound I-027
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Step 1 Synthesis of Compound 14
Compound 13 (WO 2012033195A) (275 mg, 1.01 mmol) was dissolved in DMF (2.5 mL), and cesium carbonate (984 mg, 3.02 mmol) and 1- (bromomethyl) -4-chloro-2-fluorobenzene (0.204 mL, 1.51 mmol) were added to the reaction solution and stirred at room temperature for 2 hours. The reaction solution was cooled in an ice bath, water was added, and the solid was filtered off. The obtained residue was washed with water and diisopropyl ether and then dried to obtain compound 14 (176 mg, yield 42%).
1 H-NMR(CDCl 3 )δ：2.95(2H，t，J＝5.4Hz)，3.83-3.92(2H，m)，4.77(0.6H，s)，4.82(1.4H，s)，5.19(2H，s)，6.81-6.84(1H，m)，7.16-7.23(2H，m)，7.41-7.47(1H，m)，7.65-7.69(1H，m)，10.44(1H，s).
[ m+h ] = 416.19, assay condition 2: retention time 2.55 min
Step 2 Synthesis of Compound 16
Compound 14 (66 mg, 0.159 mmol) was dissolved in dichloromethane (1 mL), N-diethylaminosulfur trifluoride (0.117 mL, 0.794 mmol) was added thereto under ice-bath cooling, and the reaction solution was stirred for 1 hour at room temperature. Thereafter, N-diethylaminosulfur trifluoride (0.117 mL, 0.794 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. N, N-diethylaminosulfur trifluoride (0.117 mL, 0.794 mmol) was added again, and the mixture was allowed to stand at room temperature for one day and night. The reaction solution was added to a saturated aqueous sodium hydrogencarbonate solution and ethyl acetate, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue (Compound 15) was dissolved in tetrahydrofuran (0.5 mL) and methanol (0.5 mL), and a 2mol/L aqueous sodium hydroxide solution (0.318 mL, 0.636 mmol) was added thereto, followed by stirring at 50℃for 50 minutes. The reaction solution was added to water and ethyl acetate, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by amino column chromatography (hexane-ethyl acetate, followed by ethyl acetate-methanol) to obtain compound 16 (19.7 mg, yield in two steps 36%).
1 H-NMR(CDCl 3 )δ：2.76(2H，t，J＝5.6Hz)，3.13(2H，t，J＝5.6Hz)，4.00(2H，s)，5.10(2H，s)，6.63(1H，s)，6.92(1H，t，J＝55.7Hz)，7.10-7.20(2H，m)，7.30(1H，s)，7.42(1H，t，J＝8.0Hz).
Step 3 Synthesis of Compound 18
Compound 16 (19 mg, 0.056 mmol) and compound 17 (16 mg, 0.056 mmol) were dissolved in acetonitrile (0.7 mL), and potassium carbonate (15 mg, 0.111 mmol) was added to the reaction solution and stirred at 70℃for 2 hours. The reaction solution was cooled in an ice bath, and the solid was filtered off. The obtained residue was purified by amino silica gel column chromatography (hexane-ethyl acetate) to obtain compound 18 (23.1 mg, yield 69%,).
1 H-NMR(CDCl 3 )δ：2.36-2.45(1H，m)，2.64-2.73(1H，m)，2.86(4H，br-s)，3.67(2H，s)，3.95(3H，s)，4.11-4.19(2H，m)，4.33-4.38(1H，m)，4.57-4.65(1H，m)，4.68-4.71(2H，m)，5.05(2H，s)，5.15-5.23(1H，m)，6.59(1H，s)，6.90(1H，t，J＝55.7Hz)，7.09-7.19(2H，m)，7.32(1H，s)，7.38(1H，t，J＝8.0Hz)，7.78(1H，d，J＝8.4Hz)，7.99(1H，d，J＝8.4Hz)，8.14(1H，s).
[ m+h ] = 600.30, assay condition 1: retention time 2.25 min
Step 4 Synthesis of Compound I-027
Compound 18 (22 mg, 0.037 mmol) was dissolved in tetrahydrofuran (0.3 mL) and methanol (0.3 mL), and a 2mol/L aqueous sodium hydroxide solution (0.073 mL, 0.147 mmol) was added to the reaction mixture, followed by stirring at 50℃for 90 minutes. 2mol/L aqueous hydrochloric acid (0.073 mL, 0.147 mmol) cooled by an ice bath and water were added to the reaction solution. The reaction solution was filtered, and the residue was washed with water. The obtained residue was dried to obtain compound I-027 (15.9 mg, yield 74%).
1 H-NMR(CDCl 3 )δ：2.37-2.46(1H，m)，2.65-2.74(1H，m)，2.88(4H，br-s)，3.69(2H，s)，4.17(2H，s)，4.34-4.40(1H，m)，4.58-4.77(3H，m)，5.05(2H，s)，5.16-5.23(1H，m)，6.60(1H，s)，6.90(1H，t，J＝55.7Hz)，7.10-7.18(2H，m)，7.33(1H，s)，7.38(1H，t，J＝8.0Hz)，7.83(1H，d，J＝8.5Hz)，8.05(1H，d，J＝8.5Hz)，8.21(1H，s).
[ m+h ] =586, assay condition 1: retention time 2.03 min
EXAMPLE 3 Synthesis of Compound I-031
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Step 1 Synthesis of Compound 20
After cesium carbonate (789 mg, 2.42 mmol) and 4-chloro-2-fluorobenzyl bromide (164. Mu.L, 1.21 mmol) were added to a solution of compound 19 (350 mg, 1.21 mmol) in DMF (10 mL), the reaction solution was stirred at room temperature for 2 hours. To the reaction mixture was further added 4-chloro-2-fluorobenzyl bromide (23. Mu.L, 0.138 mmol), and the mixture was stirred again at room temperature for 1 hour. Water was added to the reaction solution, and the resultant solid was collected by filtration to obtain compound 20 (0.53 g, yield 100%).
[ m+h ] =432, measurement condition 1: retention time 2.33 min
Step 2 Synthesis of Compound 21
Copper iodide (48.5 mg, 0.255 mmol) and methyl difluoroacetate (146. Mu.L, 1.16 mmol) were added in this order to a DMF (1 mL) solution of compound 20 (100 mg, 0.232 mmol), followed by degassing under reduced pressure and substitution with nitrogen. The reaction solution was stirred under nitrogen atmosphere at 100 ℃ for 5 hours. Water was added to the reaction solution, and extraction was performed 2 times with ethyl acetate.
After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), whereby compound 21 (27 mg, yield 31%) was obtained.
[ m+h ] =374, assay condition 1: retention time 2.30 min
Step 3 Synthesis of Compounds 1-031
To a solution of compound 21 (27 mg, 0.072 mmol) in tetrahydrofuran (0.5 mL) was added sodium hydride (4.1 mg, 0.101 mmol) under ice-bath cooling, and the mixture was stirred under ice-bath cooling for 10 minutes. Then, compound 22 (30 mg, 0.101 mmol) was added to the reaction solution, and after stirring at room temperature for 2 half hours, sodium hydride (2.0 mg, 0.050 mmol) was added thereto, and stirring was again performed at room temperature for 1 hour. Methanol (0.5 mL) and 1mol/L aqueous sodium hydroxide solution (72. Mu.L) were added to the reaction mixture, followed by stirring at room temperature for 2 hours. After adding water to the reaction solution, 2mol/L hydrochloric acid was added until the pH became about 4. The resulting solid was filtered to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol), whereby compound I-031 (20 mg, yield 45%) was obtained.
1 H-NMR(DMS0-D 6 )δ：2.34-2.43(1H，m)，2.68-2.76(1H，m)，3.05(2H，t，J＝6.5Hz)，3.78(2H，t，J＝7.8Hz)，4.31(1H，dt，J＝11.2，4.4Hz)，4.47(1H，q，J＝7.1Hz)，4.63(1H，dd，J＝15.0，3.1Hz)，4.78(1H，dd，J＝15.0，6.5Hz)，5.13-5.17(2H，m)，5.28(1H，d，J＝16.4Hz)，5.36(2H，s)，7.37(1H，d，J＝8.3Hz)，7.51-7.58(2H，m)，7.67(1H，s)，7.79(1H，s)，7.99(1H，d，J＝8.3Hz)，8.12(1H，d，J＝8.3Hz).
[ m+h ] =619, assay condition 1: retention time 2.35 min
EXAMPLE 4 Synthesis of Compound I-006
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Step 1 Synthesis of Compound 24
Compound 23 (100 mg, 0.390 mmol) and (4-chloro-2-fluorophenyl) methanol (94.0 mg, 0.585 mmol) were dissolved in tetrahydrofuran (1.5 mL), and potassium t-butoxide (87 mg, 0.780 mmol) was added to the reaction mixture under ice-bath cooling, followed by stirring at room temperature for 30 minutes. Water was added to the reaction solution. The reaction mixture was filtered, and the residue was washed with water and dried. The obtained residue was purified by column chromatography (hexane-ethyl acetate) to obtain compound 24 (121 mg, yield 81.5%).
1 H-NMR(CDCl 3 )δ：2.33(3H，s)，5.57(2H，s)，7.13-7.16(2H，m)，7.43-7.46(1H，m)，7.49-7.53(2H，m)，7.75(1H，s)，8.01(1H，d，J＝1.5Hz).
[ m+h ] = 380.15, assay condition 3: retention time 3.10 min
Step 2 Synthesis of Compound 25
Compound 24 (113 mg, 0.297 mmol), 1- (t-butyldimethylsilyloxy) -1-methoxyethylene (168 mg, 0.891 mmol), zinc fluoride (92 mg, 0.891 mmol) and bis (tri-t-butylphosphine) palladium (15.2 mg, 0.030 mmol) were dissolved in DMF (3.4 mL) and stirred at 130℃for 3 hours under microwave irradiation while sealing. After the reaction solution was returned to room temperature, water and ethyl acetate were added thereto, and extraction was performed with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane-ethyl acetate) to obtain a residue (32.3 mg). The obtained residue was dissolved in a mixed solvent of tetrahydrofuran (0.31 mL) and methanol (0.31 mL), and 1mol/L aqueous sodium hydroxide solution (0.250 mL, 0.250 mmol) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction solution was added a 10% aqueous solution of citric acid. The reaction solution was filtered, and the residue was washed with water and then dried, whereby a residue (27.3 mg) was obtained. The obtained residue was purified by column chromatography (hexane-ethyl acetate) to obtain compound 25 (23.8 mg, 2-stage yield 23.0%).
1 H-NMR(CDCl 3 )δ：2.34(3H，s)，3.83(2H，s)，5.58(2H，s)，5.58(2H，s)，7.12-7.15(2H，m)，7.29-7.32(1H，dd，J＝8.0，1.5Hz)，7.52(1H，t，J＝8.0Hz)，7.64(1H，d，J＝8.0Hz)，7.76(1H，d，J＝10.3Hz).
[ m+h ] = 360.20, assay condition 3: retention time 2.48 min
Step 3 Synthesis of Compound 27
Compound 25 (23.5 mg, 0.065 mmol) and compound 26 (15.4 mg, 0.065 mmol) were dissolved in DMF (0.35 mL), triethylamine (0.091 mL, 0.065 mmol) and 1- (bis (dimethylaminomethylene) -1H-1,2, 3-triazolo (4, 5-b) pyridinium 3-oxide hexafluorophosphate (24.8 mg, 0.065 mmol) were added, and stirring was performed at room temperature for 1 hour.
1 H-NMR(CDCl 3 )δ：2.28-2.35(1H，m)，2.34(3H，s)，2.56-2.63(1H，m)，3.94(3H，s)，4.24-4.40(3H，m)，4.57-4.70(3H，m)，5.05-5.08(1H，m)，5.55(2H，s)，7.10-7.15(2H，m)，7.26-7.29(1H，m)，7.49(1H，t，J＝8.0Hz)，7.60(1H，d，J＝8.3Hz)，7.68(1H，s)，7.76(1H，s)，7.80(1H，d，J＝8.6Hz)，7.99(1H，dd，J＝8.6，1.3Hz)，8.08(1H，s).
[ m+h ] = 560.10, assay condition 3: retention time 2.56 min
Step 4 Synthesis of Compound I-006
Compound 27 (20.8 mg, 0.037 mmol) was dissolved in a mixed solvent of tetrahydrofuran (0.16 mL) and methanol (0.16 mL), and 1mol/L aqueous sodium hydroxide solution (0.11 mL, 0.11 mmol) was added thereto, followed by stirring at 60℃for 2 hours. After the reaction solution was returned to room temperature, a 10% aqueous solution of citric acid was added thereto. The reaction solution was filtered, and the residue was washed with water and dried to obtain Compound I-006 (18.0 mg, yield 88.8%).
1 H-NMR(DMSO-d6)δ：2.23(3H，s)，2.23-2.36(1H，m)，2.50-2.63(1H，m)，4.31-4.36(1H，m)，4.41-4.47(1H，m)，4.51-4.60(3H，m)，4.64-4.70(1H，m)，4.87-4.93(1H，m)，5.52(2H，s)，7.32(1H，dd，J＝8.3，1.5Hz)，7.39(1H，dd，J＝8.3，1.5Hz)，7.49(1H，dd，J＝10.0，1.5Hz)，7.64(2H，t，8.3Hz)，7.66(1H，s)，7.75-7.81(2H，m)，8.05(1H，s)，8.23(1H，s)
[ m+h ] =546, assay condition 3: retention time 2.27 min
EXAMPLE 5 Synthesis of Compound I-035
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Step 1 Synthesis of Compound 29
Compound 28 (WO 2019200120A) (1.90 g, 10.72 mmol) was dissolved in methylene chloride (19 mL), and trifluoroacetic anhydride (2.27 mL, 16.08 mmol) was added and stirred at room temperature for 3 hours and 15 minutes. Trifluoroacetic anhydride (0.23 mL, 1.61 mmol) was added thereto, and the mixture was stirred at room temperature for 75 minutes. Water was added to the reaction solution, and extraction was performed with methylene chloride. The solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), whereby compound 29 (2.25 g, yield 74%) was obtained.
[ m+h ] = 274.2, assay condition 1: retention time 2.28 min
1 H-NMR(CDCl 3 )δ：1.53(2.4H，d，J＝6.8Hz)，1.61(0.6H，d，J＝6.7Hz)，2.74-2.82(1H，m)，2.91-3.00(1H，m)，3.26(0.2H，td，J＝12.5，4.4Hz)，3.56(0.8H，td，J＝12.5，4.3Hz)，3.79(2.4H，s)，3.80(0.6H，s)，4.04(0.8H，d，J＝12.8Hz)，4.59(0.2H，dd，J＝12.8，5.6Hz)，5.10(0.2H，q，J＝6.8Hz)，5.53(0.8H，q，J＝6.8Hz)，6.62(0.2H，d，J＝2.5Hz)，6.66(0.8H，d，J＝2.5Hz)，6.75-6.80(1H，m)，7.03-7.07(1H，m).
Step 2 Synthesis of Compound 30
Compound 29 (1.95 g, 7.13 mmol) was dissolved in dichloromethane (19 mL), silver trifluoroacetate (1.74 g, 7.87 mmol) and iodine (1.99 g, 7.84 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Insoluble matter was removed by filtration, and an aqueous solution of sodium thiosulfate was added to the filtrate to conduct extraction with methylene chloride. After washing the organic layer with water, it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), whereby compound 30 (2.00 g, yield 70%) was obtained.
[ m+h ] =400.2, assay condition 1: retention time 2.55 min
1 H-NMR(CDCl 3 )δ：1.53(2.4H，d，J＝6.8Hz)，1.61(0.6H，d，J＝6.8Hz)，2.71-2.79(1H，m)，2.89-2.97(1H，m)，3.23(0.2H，td，J＝12.7，4.5Hz)，3.50-3.57(0.8H，m)，3.86(2.4H，s)，3.88(0.6H，s)，4.01-4.05(0.8H，m)，4.59(0.2H，dd，J＝13.3，5.3Hz)，5.08(0.2H，q，J＝6.5Hz)，5.52(0.8H，q，J＝6.8Hz)，6.51(0.2H，s)，6.55(0.8H，s)，7.55(0.8H，s)，7.57(0.2H，s).
Step 3 Synthesis of Compound 31
Compound 30 (1.99 g, 4.99 mmol) was dissolved in N, N-dimethylformamide (20 mL), followed by addition of methyl difluoro (fluorosulfonyl) acetate (3.15 mL, 24.93 mmol) and copper iodide (1.14 g, 5.98 mmol) in this order, followed by degassing under reduced pressure and substitution with nitrogen. After stirring at 100℃for 3 hours under nitrogen, water was added and extraction was performed with ethyl acetate. After the organic layer was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), whereby compound 31 (1.56 g, yield 94%) was obtained.
[ m+h ] =342.2, assay condition 1: retention time 2.51 min
1 H-NMR(CDCl 3 )δ：1.56(2.4H，d，J＝6.9Hz)，1.64(0.6H，d，J＝6.8Hz)，2.77-2.86(1H，m)，2.92-3.02(1H，m)，3.26(0.2H，td，J＝12.3，5.2Hz)，3.52-3.60(0.8H，m)，3.89(2.4H，s)，3.90(0.6H，s)，4.02-4.13(0.8H，m)，4.65(0.2H，dd，J＝13.0，5.6Hz)，5.14(0.2H，q，J＝6.8Hz)，5.59(0.8H，q，J＝6.9Hz)，6.69(0.2H，s)，6.74(0.8H，s)，7.33(0.8H，s)，7.35(0.2H，s).
Step 4 Synthesis of Compound 32
Compound 31 (1.55 g, 4.41 mmol) was dissolved in methylene chloride (7.8 mL), and after adding a 1mol/L methylene chloride solution of boron tribromide (13.2 mL, 13.2 mmol) under ice-cooling, the mixture was stirred at room temperature for 2 hours and 30 minutes. Methanol (7.8 mL) was added under ice-bath cooling, water was added thereto, and extraction was performed with methylene chloride. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), whereby compound 32 (1.20 g, yield 78%) was obtained.
[ M-H ] =326.2, assay condition 1: retention time 2.18 min
Step 5 Synthesis of Compound 33
To compound 32 (114 mg, 0.33 mmol) and cesium carbonate (212 mg, 0.651 mmol) and 1- (bromomethyl) -4-chloro-2-fluorobenzene (0.051 mL, 0.377 mmol) were added N, N-dimethylformamide (1.1 mL), and the mixture was stirred at room temperature for 90 minutes. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with water. The solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by column chromatography (hexane-ethyl acetate), whereby compound 33 (142 mg, yield 92%) was obtained.
1 H-NMR(CDCl 3 )δ：1.53(2.4H，d，J＝6.9Hz)，1.62(0.6H，d，J＝6.8Hz)，2.78-2.86(1H，m)，2.94-3.02(1H，m)，3.25(0.2H，td，J＝12.6，5.2Hz)，3.51-3.58(0.8H，m)，4.09(0.8H，d，J＝15.8Hz)，4.65(0.2H，dd，J＝13.7，5.6Hz)，5.12-5.21(2.2H，m)，5.57(0.8H，q，J＝6.7Hz)，6.78(0.2H，s)，6.80(0.8H，s)，7.14(1H，dd，J＝9.8，1.9Hz)，7.18-7.21(1H，m)，7.36(0.8H，s)，7.39(0.2H，s)，7.47-7.53(1.0H，m).
Step 6 Synthesis of Compound 34
Compound 33 (140 mg, 0.298 mmol) was dissolved in tetrahydrofuran (1.4 mL) and methanol (1.4 mL), and potassium carbonate (82 mg, 0.596 mmol) was added and stirred at 50℃for 8 hours and 45 minutes. Water was added to the reaction solution, extraction was performed with chloroform, and the organic layer was washed with water. The solvent was distilled off under reduced pressure, whereby compound 34 (104 mg, yield 94%) was obtained as a crude product.
[ m+h ] =374.3, assay condition 1: retention time 2.03 min
1 H-NMR(CDCl 3 )δ：1.45(3H，d，J＝6.8Hz)，2.69(1H，dt，J＝16.1，4.6Hz)，2.77-2.84(1H，m)，2.96-3.02(1H，m)，3.26(1H，dt，J＝12.6，5.1Hz)，4.09(1H，q，J＝6.7Hz)，5.16(2H，dd，J＝17.4，12.7Hz)，6.80(1H，s)，7.12(1H，dd，J＝9.9，1.9Hz)，7.18(1H，dd，J＝8.2，1.7Hz)，7.30(1H，s)，7.52(1H，t，J＝8.0Hz).
Step 7 Synthesis of Compound 36
Compound 34 (51 mg, 0.136 mmol) was dissolved in acetonitrile (0.5 mL), and compound 35 (42 mg, 0.143 mmol) and potassium carbonate (38 mg, 0.273 mmol) were added and stirred at 60℃for 6 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. After the organic layer was washed with water, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), whereby compound 36 (80 mg, yield 90%) was obtained.
[ m+h ] = 632.5, assay condition 1: retention time 2.50 min
1 H-NMR(CDCl 3 )δ：1.40(3H，d，J＝6.8Hz)，2.35-2.44(1H，m)，2.61-2.72(2H，m)，2.76-2.81(1H，m)，2.85-2.93(1H，m)，3.07-3.13(1H，m)，3.90(1H，q，J＝6.7Hz)，3.95(3H，s)，4.11-4.35(3H，m)，4.55-4.77(3H，m)，5.10-5.22(3H，m)，6.72(1H，s)，7.11(1H，dd，J＝9.8，2.0Hz)，7.18(1H，dd，J＝8.2，1.6Hz)，7.32(1H，s)，7.51(1H，t，J＝8.1Hz)，7.76(1H，d，J＝8.5Hz)，7.98(1H，dd，J＝8.5，1.5Hz)，8.13(1H，d，J＝0.9Hz).
Step 8 Synthesis of Compound I-035
Compound 36 (79 mg, 0.121 mmol) was dissolved in tetrahydrofuran (0.8 mL) and methanol (0.8 mL), and 1mol/L aqueous sodium hydroxide solution (0.61 mL, 0.61 mmol) was added thereto and stirred at 40℃for 80 minutes. 2mol/L aqueous hydrochloric acid was added at room temperature to adjust the pH to 4. After the pH was adjusted, water was added to the reaction solution, followed by extraction with ethyl acetate. After the organic layer was washed with water, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol). The fractions containing the target material were concentrated to prepare a solid residue, which was then suspended in methyl t-butyl ether and collected by filtration to obtain compound I-035 (54 mg, yield 72%).
[ m+h ] = 618.0, assay condition 2: retention time 2.01 min
1 H-NMR(CDCl 3 )δ：1.40(3H，d，J＝6.7Hz)，2.36-2.45(1H，m)，2.63-2.74(2H，m)，2.78-2.95(2H，m)，3.09-3.16(1H，m)，3.92(1H，q，J＝6.7Hz)，4.17-4.37(3H，m)，4.59-4.79(3H，m)，5.08-5.24(3H，m)，6.72(1H，s)，7.10(1H，dd，J＝9.7，1.8Hz)，7.18(1H，dd，J＝8.2，1.3Hz)，7.32(1H，s)，7.50(1H，t，J＝8.1Hz)，7.83(1H，d，J＝8.5Hz)，8.05(1H，d，J＝8.4Hz)，8.20(1H，s).
EXAMPLE 6 Synthesis of Compound I-110
[ chemical 176]
Step 1 Synthesis of Compound 38
To a suspension of compound 37 (WO 2020146682) (2.07 g, 6.89 mmol) in 1, 4-dioxane (10 mL) was added silver carbonate (2.85 g, 10.3 mmol) and 4-chloro-2-fluorobenzyl bromide (1.85 g, 8.26 mmol), followed by stirring at 65℃for 3.5 hours. After insoluble matter was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), whereby compound 38 (3.11 g, yield 100%) was obtained.
[ m+h ] =442, assay condition 1: retention time 2.83 min
1 H-NMR(CDCl 3 )δ：4.01(3H，s)，5.51(2H，s)，7.12(1H，dd，J＝9.6，1.8Hz)，7.15(1H，dd，J＝8.2，1.8Hz)，7.46(1H，t，J＝8.0Hz)，8.10(1H，s).
Step 2 Synthesis of Compound 39
To a solution of compound 38 (1.0 g, 2.26 mmol) in tetrahydrofuran (10 mL) was added 1mol/L DIBAL hexane solution (4.97 mL, 4.97 mmol) under ice-bath cooling, and the mixture was stirred under ice-bath cooling for 3 hours. After a small amount of sodium sulfate decahydrate was added each time until no foaming was achieved, stirring was carried out at room temperature for 30 minutes. After insoluble matter was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), whereby compound 39 (780 mg, yield 83%) was obtained.
[ m+h ] =414, assay condition 1: retention time 2.60 min
1 H-NMR(CDCl 3 )δ：3.59(1H，td，J＝5.1，1.4Hz)，4.73(2H，dd，J＝5.0，0.9Hz)，5.55(2H，s)，7.13-7.18(2H，m)，7.43(1H，t，J＝7.9Hz)，8.01(1H，s).
Step 3 Synthesis of Compound 40
To a solution of compound 39 (300 mg, 0.724 mmol) in N, N-dimethylformamide (4.5 mL) were added N-vinylphthalimide (125 mg, 0.724 mmol), tetrabutylammonium bromide (233 mg, 0.724 mmol), palladium acetate (16.3 mg, 0.074 mmol) and dicyclohexylmethylamine (230. Mu.L, 1.09 mmol). After degassing under reduced pressure, the mixture was replaced with nitrogen, and stirred at 110℃for 1.5 hours. After water was added to the reaction solution and the resultant solid was collected by filtration, the solid was washed with isopropyl acetate, whereby compound 40 (234 mg, yield 64%) was obtained.
[ m+h ] =507, measurement condition 1: retention time 2.78 min
1 H-NMR(CDCl 3 )δ：3.87(1H，t，J＝4.6Hz)，4.83(2H，d，J＝4.6Hz)，5.59(2H，s)，7.13-7.23(3H，m)，7.47(1H，t，J＝8.0Hz)，7.58(1H，d，J＝14.8Hz)，7.80(2H，dd，J＝5.5，3.0Hz)，7.93(2H，dd，J＝5.3，3.0Hz)，8.04(1H，s).
Step 4 Synthesis of Compound 41
After 10% palladium on carbon (50% aqueous) (94 mg, 0.044 mmol) was added to a solution of compound 40 (224 mg, 0.442 mmol) in methanol (2.2 mL) and tetrahydrofuran (6.7 mL), the mixture was stirred at room temperature under a hydrogen (1 atm) atmosphere for 5 hours. After insoluble matter was removed by filtration, the solvent was distilled off under reduced pressure, whereby compound 41 (163 mg, yield 73%) was obtained. The obtained compound 41 was used in the next step without purification.
[ m+h ] =509, assay condition 1: retention time 2.76 min
1 H-NMR(CDCl 3 )δ：2.90(2H，t，J＝7.7Hz)，3.80(1H，t，J＝4.8Hz)，3.86(2H，t，J＝7.7Hz)，4.83(2H，d，J＝4.8Hz)，5.54(2H，s)，7.11-7.17(2H，m)，7.44(1H，t，J＝8.0Hz)，7.73-7.76(3H，m)，7.82-7.86(2H，m).
Step 5 Synthesis of Compound 42
To a solution of compound 41 (163 mg, 0.32 mmol) in ethanol (3.2 mL) was added hydrazine monohydrate (77.8. Mu.L, 1.6 mmol), and the mixture was stirred at 80℃for 2.5 hours. After insoluble matter was removed by filtration, the solvent was distilled off under reduced pressure, and methylene chloride was added to the obtained residue. After insoluble matter precipitated was removed again by filtration, the solvent was distilled off under reduced pressure, whereby a crude product (122 mg) containing compound 42 was obtained. The obtained compound 42 was used directly in the next step without purification.
[ m+h ] =379, assay condition 1: retention time 1.84 min
Step 6 Synthesis of Compound 43
To a solution of the crude product of compound 42 obtained in step 5 (0.32 mmol) in total (1.2 mL) in methylene chloride was added trifluoroacetic anhydride (136 μl, 0.96 mmol) under ice-bath cooling, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in ethyl acetate, followed by slow injection into an aqueous sodium hydrogencarbonate solution. After stirring at room temperature for 1 hour, extraction was performed 2 times with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), whereby compound 43 (47 mg, yield 31%) was obtained.
[ m+h ] =475, assay condition 1: retention time 2.42 min
1 H-NMR(CDCl 3 )δ：2.87(2H，t，J＝7.2Hz)，3.52(1H，t，J＝5.0Hz)，3.57(2H，q，J＝6.7Hz)，4.77(2H，d，J＝5.0Hz)，5.55(2H，s)，6.77(1H，s)，7.13(1H，dd，J＝9.8，1.9Hz)，7.16(1H，dd，J＝8.2，1.9Hz)，7.45(1H，t，J＝8.0Hz)，7.71(1H，s).
Step 7 Synthesis of Compound 44
Triphenylphosphine (39 mg, 0.15 mmol) and DIAD (29. Mu.L, 0.15 mmol) were added to a tetrahydrofuran (2.5 mL) solution of compound 43 (47 mg, 0.099 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), whereby compound 44 (40 mg, yield 89%) was obtained.
[ m+h ] =457, assay condition 1: retention time 2.88 min
1 H-NMR(CDCl 3 )δ：2.88-2.93(2H，m)，3.87(1.2H，t，J＝5.6Hz)，3.95(0.8H，t，J＝5.9Hz)，4.74(0.8H，s)，4.78(1.2H，s)，5.49(2H，s)，7.11-7.16(2H，m)，7.45(1H，t，J＝7.9Hz)，7.67(0.6H，s)，7.70(0.4H，s).
Step 8 Synthesis of Compound 45
After potassium carbonate (24.2 mg, 0.175 mmol) was added to a solution of compound 44 (40 mg, 0.088 mmol) in methanol (0.5 mL) and tetrahydrofuran (0.5 mL), the mixture was stirred under nitrogen at 50℃for 4 hours. After adding saline to the reaction solution, extraction was performed 2 times with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, whereby a crude product (36 mg) containing compound 45 was obtained. The obtained compound 45 was used directly in the next step without purification.
[ m+h ] =361, measurement condition 1: retention time 1.72 min
1 H-NMR(CDCl 3 )δ：2.75(2H，t，J＝5.8Hz)，3.13(2H，t，J＝5.8Hz)，3.99(2H，s)，5.47(2H，s)，7.10(1H，dd，J＝9.7，1.9Hz)，7.13(1H，d，J＝8.3Hz)，7.46(1H，t，J＝8.0Hz)，7.58(1H，s).
Step 9 Synthesis of Compound 47
After adding compound 46 (27 mg, 0.092 mmol) and potassium carbonate (24.2 mg, 0.175 mmol) to a solution of the crude product of compound 45 obtained in step 8 in total (36 mg) in acetonitrile (0.6 mL), the mixture was stirred under nitrogen atmosphere at 60℃for 2 hours. After adding saline to the reaction solution, extraction was performed 2 times with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-ethyl acetate), whereby compound 47 (51 mg, yield 94%) was obtained.
[ m+h ] =619, assay condition 1: retention time 2.49 min
1 H-NMR(CDCl 3 )δ：2.36-2.45(1H，m)，2.66-2.74(1H，m)，2.82-2.87(4H，m)，3.73(2H，s)，3.95(3H，s)，4.19(2H，dd，J＝14.7，13.8Hz)，4.36(1H，dt，J＝11.0，4.6Hz)，4.59-4.67(2H，m)，4.72(1H，dd，J＝15.4，6.0Hz)，5.19(1H，ddd，J＝13.4，7.2，3.0Hz)，5.43(2H，s)，7.08(1H，dd，J＝9.7，2.0Hz)，7.12(1H，dd，J＝8.3，1.7Hz)，7.43(1H，t，J＝8.0Hz)，7.61(1H，s)，7.79(1H，d，J＝8.5Hz)，8.00(1H，dd，J＝8.4，1.5Hz)，8.14(1H，d，J＝1.0Hz).
Step 10 Synthesis of Compound I-110
To a solution of compound 47 (51 mg, 0.082 mmol) in methanol (0.5 mL) and tetrahydrofuran (0.5 mL) was added 2mol/L aqueous sodium hydroxide solution (206. Mu.L, 0.412 mmol), and the mixture was stirred under nitrogen at 45℃for 4.5 hours. After adding water to the reaction solution, dilute sulfuric acid was added until the ph=about 4, and extraction was performed 2 times with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol), whereby compound I-110 (38 mg, yield 76%) was obtained.
[ m+h ] = 605.5, assay condition 1: retention time 2.18 min
1 H-NMR(DMSO-D 6 )δ：2.32-2.41(1H，m)，2.59-2.67(1H，m)，2.81-2.85(4H，m)，3.69(2H，dd，J＝23.5，17.0Hz)，4.03(1H，d，J＝13.6Hz)，4.16(1H，d，J＝13.7Hz)，4.34(1H，dt，J＝10.9，4.5Hz)，4.45(1H，dd，J＝13.7，7.7Hz)，4.64(1H，dd，J＝15.2，2.5Hz)，4.78(1H，dd，J＝15.2，7.2Hz)，5.04(1H，ddd，J＝14.1，7.2，2.5Hz)，5.42(2H，s)，7.30(1H，dd，J＝8.3，1.9Hz)，7.46(1H，dd，J＝10.0，1.9Hz)，7.51(1H，t，J＝8.3Hz)，7.69(1H，d，J＝8.5Hz)，7.82(1H，dd，J＝8.5，1.4Hz)，7.92(1H，s)，8.27(1H，s).
EXAMPLE 7 Synthesis of Compound I-062
[ chemical 177]
Step 1 Synthesis of Compound 49
Compound 48 (107 mg, 0.43 mmol) and sodium carbonate (91 mg, 0.86 mmol) were dissolved in tetrahydrofuran (2 mL)/water (2 mL), and iodine (114 mg, 0.45 mmol) was added thereto and stirred at room temperature for 4.5 hours. The reaction solution was added to an aqueous sodium thiosulfate solution, and extraction was performed with ethyl acetate. The organic layer was washed with a 10wt% aqueous citric acid solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by column chromatography (hexane-ethyl acetate) to give compound 49 (58 mg, yield 36%).
[ m+h ] = 377.00, assay condition 1: time 1.63 minutes
1 H-NMR(CDCl 3 )δ：1.49(9H，s)，2.92(2H，t，J＝5.8Hz)，3.70(2H，t，J＝5.9Hz)，4.52(2H，s)，6.96(1H，s)
Step 2 Synthesis of Compound 50
Compound 49 (58 mg, 0.154 mmol) was dissolved in cesium carbonate (100 mg, 0.308 mmol) and 1- (bromomethyl) -4-chloro-2-fluorobenzene (0.021 mL, 0.154 mmol) in N, N-dimethylformamide (1.0 mL) and stirred at room temperature for 2.5 hours. The reaction solution was added to water, and extraction was performed with ethyl acetate. After washing the organic layer with water, it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by column chromatography (hexane-ethyl acetate) to give compound 50 (53 mg, yield 66%).
[ m+h ] = 519.00, measurement condition 1: time 1.78 min
1 H-NMR(CDCl 3 )δ：1.50(9H，s)，2.94(2H，t，J＝5.3Hz)，3.70(2H，t，J＝5.8Hz)，4.53(2H，s)，5.14(2H，s)，6.79(1H，s)，7.15(1H，dd，J＝9.8Hz，1.9Hz)，7.22(1H，d，J＝8.3Hz)，7.61(1H，t，J＝7.9Hz).
Step 3 Synthesis of Compound 51
Compound 50 (20 mg, 0.039 mmol) was dissolved in N, N-dimethylformamide (0.1 mL), N-methylpyrrolidone (0.1 mL), copper iodide (59 mg, 0.308 mmol) and methyl fluorosulfonyl difluoroacetate (0.039 mL, 0.308 mmol) were added at room temperature, and stirred at 100℃for 1 hour. The reaction solution was added to ice water, followed by extraction with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogencarbonate and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give compound 51 (21 mg, yield 100%).
[ m+h ] = 461.10, assay condition 1: time 2.84 minutes
1 H-NMR(CDCl 3 )δ：1.50(9H，s)，2.98(2H，t，J＝5.8Hz)，3.75(2H，t，J＝5.8Hz)，4.63(2H，s)，5.18(2H，s)，6.79(1H，s)，7.15(2H，m)，7.21(1H，m)，7.48(1H，t，J＝8.2Hz).
Step 4 Synthesis of Compound 54
Compound 51 (21 mg, 0.046 mmol) was dissolved in methylene chloride (0.2 mL), trifluoroacetic acid (0.029 mL, 2.730 mmol) was added at room temperature, and the mixture was stirred at room temperature for 40 minutes. After the reaction solution was allowed to stand for one day and night, the solvent was distilled off under reduced pressure to obtain compound 52. The obtained residue was dissolved in acetonitrile (1 mL), and potassium carbonate (80 mg, 0.579 mmol) and compound 53 (13 mg, 0.046 mmol) were added thereto, followed by stirring at 50℃for 2 hours. Further, the mixture was stirred at 60℃for 3 hours, and then allowed to stand overnight. The reaction solution was added to ice water, followed by extraction with ethyl acetate. After washing the organic layer with water, it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate, followed by chloroform-methanol) to give compound 54 (12 mg, yield 43%).
[ m+h ] = 619.15, assay condition 1: time 2.22 minutes
1 H-NMR(CDCl 3 )δ：2.41(1H，m)，2.69(1H，m)，2.90-3.10(4H，m)，3.73(2H，s)，3.95(3H，s)，4.20(2H，q，J＝8.8Hz)，4.34(1H，m)，4.55-4.75(3H，m)，5.11(2H，s)，5.19(1H，m)，7.03(1H，s)，7.12(1H，dd，J＝10.4Hz，2.0Hz)，7.18(1H，m)，7.45(1H，t，J＝2.0Hz)，7.79(1H，d，J＝8.4Hz)，8.00(1H，dd，J＝8.4Hz，1.2Hz)，8.14(1H，d，J＝0.8Hz).
Step 5 Synthesis of Compound I-062
Compound 54 (12 mg, 0.019 mmol) was dissolved in tetrahydrofuran (0.2 mL), and 1mol/L aqueous sodium hydroxide solution (0.1 mL, 0.100 mmol) was added thereto, followed by stirring at room temperature for 1 hour and then stirring at 60℃for 1.5 hours. Further, 1mol/L aqueous sodium hydroxide solution (0.1 mL, 0.100 mmol) was added thereto, and the mixture was stirred at 60℃for 1 hour. The reaction solution was added to water, and the mixture was made acidic with a 10% aqueous solution of citric acid, followed by extraction with ethyl acetate. After washing the organic layer with water, it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was solidified with n-hexane to obtain compound I-062 (6.7 mg, yield 57%).
[ m+h ] =605.2, assay condition 1: time 2.02 min
1 H-NMR(CDCl 3 )δ：2.42(1H，m)，2.70(1H，m)，2.95-3.10(4H，m)，3.74(2H，s)，4.22(2H，dd，J＝19.6Hz，13.2Hz)，4.36(1H，m)，4.55-4.75(3H，m)，5.11(2H，s)，5.15(1H，m)，7.04(1H，s)，7.11(1H，dd，J＝9.6Hz，2.0Hz)，7.18(1H，m)，7.45(1H，t，J＝8.0Hz)，7.83(1H，d，J＝8.8Hz)，8.06(1H，m)，8.21(1H，m).
EXAMPLE 8 Synthesis of Compound I-076
[ chemical 178]
Step 1 Synthesis of Compound 56
Compound 55 (WO 2021013735A) (1.02 g, 3.48 mmol) and 4-chloro-2-fluorobenzyl bromide (0.856 g, 3.83 mmol) were dissolved in acetonitrile (20.4 mL), and silver carbonate (1.92 g, 6.96 mmol) was added and stirred at 60℃for 6 hours. After cooling to room temperature, the reaction solution was filtered through celite, and the celite was washed with ethyl acetate to obtain a filtrate. The filtrate was concentrated, and the obtained residue was purified by column chromatography (hexane-ethyl acetate) to obtain compound 56 (0.897 g, yield 59%).
[ m+h ] = 434.90, assay condition 1: retention time 3.05 min
1 H-NMR(CDCl 3 )δ：5.66(2H，s)，7.14-7.19(2H，m)，7.50(1H，t，J＝8.0Hz)，7.76(2H，dd，J＝8.8，2.0Hz)，7.98(1H，d，J＝8.8Hz)，8.11(1H，d，J＝2.0Hz).
Step 2 Synthesis of Compound 57
Compound 56 (100 mg, 0.230 mmol), 1- (tert-butyldimethylsilyloxy) -1-methoxyethylene (130 mg, 0.689 mmol), zinc fluoride (71.2 mg, 0.689 mmol) and bis (tri-tert-butylphosphine) palladium (11.3 mg, 0.023 mmol) were dissolved in N, N-dimethylformamide (2.0 mL) and stirred at 130℃for 3 hours under microwave irradiation. After the reaction solution was returned to room temperature, water and ethyl acetate were added thereto, and extraction was performed with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane-ethyl acetate) to obtain a residue (40.0 mg). The obtained residue was dissolved in a mixed solvent of tetrahydrofuran (0.39 mL) and methanol (0.39 mL), and 1mol/L aqueous sodium hydroxide solution (0.270 mL, 0.270 mmol) was added thereto, followed by stirring at room temperature for 1 hour. After 10% aqueous citric acid was added to the reaction solution, the reaction solution was separated by filtration, and the residue was washed with water and dried, whereby compound 57 (32.8 mg, 2-stage yield 36%) was obtained.
[ m+h ] = 414.85, assay condition 1: retention time 2.43 min
1 H-NMR(CDCl 3 )δ：3.92(2H，s)，5.69(2H，s)，7.54(1H，dd，J＝10.0，2.0 Hz)，7.66(1H，t，J＝10.0Hz)，7.71(1H，dd，J＝8.5，1.6Hz)，7.89(1H，s)，8.11(1H，d，J＝8.5Hz).
Step 3 Synthesis of Compound 59
Compound 57 (32.0 mg, 0.077 mmol) and compound 58 (20.1 mg, 0.085 mmol) were dissolved in N, N-dimethylformamide (0.64 mL), triethylamine (0.021 mL, 0.154 mmol) and 1- (bis (dimethylaminomethylene) -1H-1,2, 3-triazolo (4, 5-b) pyridinium 3-oxide hexafluorophosphate (44.0 mg, 0.116 mmol) were added, and stirring was carried out at room temperature for 30 minutes.
[ m+h ] = 615.15, assay condition 1: retention time 2.63 min
1 H-NMR(CDCl 3 )δ：2.32-2.41(1H，m)，2.65-2.73(1H，m)，3.95(3H，s)，4.27-4.40(3H，m)，4.65(1H，dd，J＝14.0，7.6Hz)，4.68-4.77(2H，m)，5.12-5.18(1H，m)，5.63(2H，s)，7.12-7.18(2H，m)，7.49(1H，t，J＝8.0Hz)，7.62(1H，dd，J＝8.5，2.0Hz)，7.77-7.82(2H，m)，8.01(1H，dd，J＝8.4，1.5Hz)，8.08(1H，s)，8.08(1H，d，J＝8.4Hz).
Step 4 Synthesis of Compound I-076
Compound 59 (24.5 mg, 0.040 mmol) was dissolved in a mixed solvent of tetrahydrofuran (0.25 mL) and methanol (0.25 mL), and a 1mol/L aqueous sodium hydroxide solution (0.12 mL, 0.12 mmol) was added thereto, followed by stirring at 60℃for 1 hour. After the reaction solution was returned to room temperature, a 10% aqueous solution of citric acid was added thereto. The reaction solution was separated by filtration, and the residue was washed with water and dried to obtain a residue. By preparative TLC (0.5 mm, CHCl) 3 -MeOH-H 2 O) the residue obtained was purified, followed by resolution by SFC to give Compound I-076 (14.4 mg, yield 18%).
[ m+h ] =601.1, measurement condition 1: retention time 2.39 min
1 H-NMR(DMSO-d6)δ：2.32-2.40(1H，m)，2.49-2.69(1H，m)，4.32-4.37(1H，m)，4.43-4.48(1H，m)，4.55-4.74(4H，m)，4.95-5.02(1H，m)，5.66(2H，s)，7.36(1H，dd，J＝8.2，1.6Hz)，7.52-7.57(2H，m)，7.62-7.73(1H，m)，7.78(2H，dd，J＝8.5，1.2Hz)，7.90(1H，s)，8.13(1H，d，J＝8.6Hz)，8.19(1H，s).
EXAMPLE 9 Synthesis of Compound I-145
[ chemical 179]
[ 180]
Step 1 Synthesis of Compound 61
To a dichloromethane (400 mL) suspension of compound 60 (51.3 g, 171 mmol) synthesized by the synthesis method described in patent (WO 2020146682) were added N, O-dimethylhydroxylamine hydrochloride (20 g, 205 mmol), HOBt (4.6 g, 34 mmol), EDC hydrochloride (49 g, 257 mmol) and triethylamine (28 mL, 205 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and after separation, the organic layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. To the obtained residue was added isopropyl ether, and the resultant solid was collected by filtration to obtain compound 61 (45.2 g, yield 77%).
1 H-NMR(CDCl 3 )δ：3.41(3H，s)，3.63(3H，s)，4.04(3H，s)，8.02(1H，s).
[ m+h ] =343, assay condition 1: retention time 2.48 min
Step 2 Synthesis of Compound 62
To a solution of compound 61 (54.7 g, 159 mmol) in tetrahydrofuran (550 mL) was added dropwise 3mol/L methyl magnesium bromide in diethyl ether (159 mL, 478 mmol) over 30 min with ice-bath cooling. After stirring for 3 hours under ice bath cooling, the reaction solution was added to an aqueous ammonium chloride solution cooled by ice bath. After adding 2mol/L hydrochloric acid until ph=about 6, extraction was performed 2 times with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), whereby compound 62 (29.1 g, yield 61%) was obtained.
1 H-NMR(CDCl 3 )δ：2.67(3H，s)，4.07(3H，s)，8.10(1H，s).
[ m+h ] =298, assay condition 1: retention time 2.93 min
Step 3 Synthesis of Compound 63
To a solution of compound 62 (29.1 g, 98 mmol) in acetonitrile (400 mL) were added formic acid (16.1 mL, 420 mmol), triethylamine (33.8 mL, 244 mmol), and [ (R, R) -N- (2-amino-1, 2-diphenylethyl) -p-toluenesulfonamide ] chloro (p-isopropylbenzene) ruthenium (II) (1.24 g, 1.95 mmol), followed by stirring at room temperature for 2 hours and 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate, and then, the reaction solution was washed with an aqueous sodium hydrogencarbonate solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), whereby compound 63 (28.5 g, yield 97%) was obtained.
1 H-NMR(CDCl 3 )δ：1.47(3H，d，J＝6.5Hz)，3.69(1H，d，J＝8.7Hz)，4.08(3H，s)，5.10(1H，dt，J＝15.1，6.5Hz)，7.98(1H，s).
[ m+h ] =300, assay condition 1: retention time 2.10 min
Step 4 Synthesis of Compound 64
To a solution of compound 63 (32 g, 107 mmol) in N, N-dimethylformamide (250 mL) were added N-vinylphthalimide (18.9 g, 107 mmol), tetrabutylammonium bromide (34.4 g, 107 mmol), palladium acetate (2.4 g, 10.7 mmol), N-dicyclohexyl-N-methylamine (34 mL, 160 mmol). After degassing under reduced pressure, the mixture was replaced with nitrogen and stirred at 110℃for 4 hours. After water was added to the reaction solution and the resultant solid was collected by filtration, the solid was washed with diisopropyl ether, whereby compound 64 (37 g, yield 88%) was obtained.
1 H-NMR(CDCl 3 )δ：1.47(3H，d，J＝6.5Hz)，4.10-4.15(4H，m)，5.12-5.18(1H，m)，7.21(1H，d，J＝14.9Hz)，7.74(1H，d，J＝14.9Hz)，7.79-7.82(2H，m)，7.91-7.95(2H，m)，8.02(1H，s).
[ m+h ] =393, assay condition 1: retention time 2.35 min
Step 5 Synthesis of Compound 65
After 10% palladium on carbon (50% aqueous) (20 g, 9.4 mmol) was added to a solution of compound 64 (37 g, 94 mmol) in methanol (250 mL) and tetrahydrofuran (500 mL), the mixture was stirred at room temperature under an atmosphere of hydrogen (1 atm) for 8 hours and 30 minutes. After insoluble matter was removed by filtration, the solvent was distilled off under reduced pressure, whereby a crude product (53 g) containing compound 65 was obtained. The obtained compound 65 was used directly in the next step without purification.
1 H-NMR(CDCl 3 )δ：1.50(3H，d，J＝6.4Hz)，2.90-3.04(2H，m)，3.87-3.91(2H，m)，4.06(3H，s)，5.13(1H，d，J＝5.9Hz)，7.72-7.76(3H，m)，7.84-7.88(2H，m).
[ m+h ] =395, assay condition 1: retention time 2.16 min
Step 6 Synthesis of Compound 66
After hydrazine monohydrate (22.8 mL, 470 mmol) was added to a solution of the crude product of compound 65 obtained in step 5 in total (94 mmol) in ethanol (500 mL), the mixture was stirred at 80℃for 1 hour. After insoluble matter was removed by filtration, the solvent was distilled off under reduced pressure, and methylene chloride was added to the obtained residue. After insoluble matter precipitated was removed again by filtration, the solvent was distilled off under reduced pressure, whereby a crude product (24.6 g) containing compound 66 was obtained. The obtained compound 66 was used directly in the next step without purification.
1 H-NMR(CDCl 3 )δ：1.49(3H，d，J＝6.4Hz)，2.69-2.92(3H，m)，3.03-3.09(1H，m)，4.06(3H，s)，5.06(1H，q，J＝6.4Hz)，7.68(1H，s).
[ m+h ] =265, assay condition 1: retention time 1.15 min
Step 7 Synthesis of Compound 67
To a solution of the crude product of compound 66 obtained in step 6 (94 mmol) in methylene chloride (200 mL) was added dropwise trifluoroacetic anhydride (40 mL, 282 mmol) under ice-bath cooling, and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, the obtained residue was dissolved in toluene, and the solvent was distilled off again under reduced pressure. The obtained residue was dissolved in ethyl acetate, and then slowly poured into an aqueous sodium hydrogencarbonate solution. After stirring at 30℃for 6 hours, extraction was performed 2 times with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), whereby compound 67 (22.9 g, yield 68%) was obtained.
1 H-NMR(CDCl 3 )δ：1.51(3H，d，J＝6.4Hz)，2.87-2.99(2H，m)，3.43(1H，d，J＝8.4Hz)，3.51-3.66(2H，m)，4.06(3H，s)，5.05(1H，dt，J＝14.6，6.5Hz)，6.81(1H，s)，7.68(1H，s).
[ m+h ] =361, measurement condition 1: retention time 1.93 min
Step 8 Synthesis of Compound 68
Triphenylphosphine (23.5 g, 89 mmol) was added to a solution of compound 67 (21.5 g, 60 mmol) in tetrahydrofuran (500 mL), and DIAD (17.4 mL, 89 mmol) was added dropwise over 20 minutes with water cooling. After stirring at room temperature for 1 hour and 30 minutes, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), whereby compound 68 (16.4 g, yield 81%) was obtained.
1 H-NMR(CDCl 3 )δ：1.60(2.1H，d，J＝6.9Hz)，1.67(0.9H，d，J＝6.8Hz)，2.71-2.80(1H，m)，2.91-3.02(1H，m)，3.18(0.3H，dt，J＝18.6，6.4Hz)，3.44-3.52(0.7H，m)，4.00-4.01(3H，m)，4.13-4.19(0.7H，m)，4.74(0.3H，dd，J＝13.3，5.6Hz)，5.05(0.3H，q，J＝6.7Hz)，5.48(0.7H，q，J＝6.9Hz)，7.62-7.64(1H，m).
[ m+h ] =343, assay condition 1: retention time 2.56 min
Step 9 Synthesis of Compound 69
To a solution of compound 68 (16.4 g, 48 mmol) in acetonitrile (200 mL) were added sodium iodide (21.6 g, 144 mmol) and trimethylchlorosilane (18.4 mL, 144 mmol), and the mixture was stirred at 45℃for 1 hour. To the reaction solution were added an aqueous sodium hydrogencarbonate solution and an aqueous sodium thiosulfate solution, and extraction was performed 2 times with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, whereby a crude product (15.8 g) of compound 69 was obtained. The obtained compound 69 was used in the next step without purification.
1 H-NMR(CDCl 3 )δ：1.66(2.25H，d，J＝6.9Hz)，1.75(0.75H，d，J＝6.7Hz)，2.57-2.65(1H，m)，2.77-2.89(1H，m)，3.15-3.22(0.25H，m)，3.45-3.52(0.75H，m)，4.16(0.75H，dd，J＝14.3，4.6Hz)，4.73(0.25H，dd，J＝13.7，5.8Hz)，5.01(0.25H，dd，J＝13.7，6.8Hz)，5.50(0.75H，q，J＝6.7Hz)，7.63-7.65(1H，m).
[ m+h ] =329, measurement condition 1: retention time 1.57 min
Step 10 Synthesis of Compound 70
Silver carbonate (8.95 g, 32 mmol) and 4-chloro-2-fluorobenzyl bromide (5.8 g, 26 mmol) were added to a solution of compound 69 (7.1 g, 21.6 mmol) in 1, 4-dioxane (70 mL), and the mixture was stirred at 65℃for 1 hour. After insoluble matter was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), whereby compound 70 (9.89 g, yield 97%) was obtained.
1 H-NMR(CDCl 3 )δ：1.56(2.1H，d，J＝4.8Hz)，1.63(0.9H，d，J＝6.9Hz)，2.72-2.80(1H，m)，2.91-3.02(1H，m)，3.17(0.3H，td，J＝12.9，3.8Hz)，3.43-3.51(0.7H，m)，4.16(0.7H，dd，J＝14.2，3.8Hz)，4.73(0.3H，dd，J＝13.2，5.6Hz)，5.04(0.3H，dd，J＝13.2，6.8Hz)，5.45-5.55(2.7H，m)，7.11-7.16(2H，m)，7.41-7.46(1H，m)，7.65-7.67(1H，m).
[ m+h ] =471, measurement condition 1: retention time 3.11 min
Step 11 Synthesis of Compound 71
To a solution of compound 70 (9.89 g, 21 mmol) in methanol (80 mL) and tetrahydrofuran (80 mL) was added potassium carbonate (5.8 g, 42 mmol), and the mixture was stirred at 50℃for 8 hours. After the solvent was distilled off under reduced pressure, water was added to the residue, and extraction was performed 2 times with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, whereby a crude product (9.31 g) of compound 71 was obtained. The obtained compound 71 was used directly in the next step without purification.
1 H-NMR(CDCl 3 )δ：1.47(3H，d，J＝6.8Hz)，2.68(1H，dt，J＝16.0，4.0Hz)，2.80-2.88(1H，m)，2.97-3.04(1H，m)，3.27(1H，dt，J＝12.2，4.7Hz)，4.00(1H，q，J＝6.5Hz)，5.47(1H，d，J＝13.4Hz)，5.52(1H，d，J＝13.4Hz)，7.08-7.14(2H，m)，7.44(1H，t，J＝8.0Hz)，7.57(1H，s).
[ m+h ] =375, assay condition 1: retention time 2.13 min
Step 12 Synthesis of Compound 73
To a solution of two-thirds (14 mmol) of the entire amount of the crude product of compound 71 obtained in step 11 in acetonitrile (64 mL) was added compound 72 (4.0 g, 13.6 mmol) and potassium carbonate (4.0 g, 29 mmol), followed by stirring at 65℃for 6 hours. After adding saline solution to the reaction solution, extraction was performed 2 times with ethyl acetate, and the solvent was distilled off under reduced pressure. After the residue was dissolved in chloroform, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, whereby a crude product (9.67 g) of compound 73 was obtained. The obtained compound 73 was used directly in the next step without purification.
1 H-NMR(CDCl 3 )δ：1.47(3H，d，J＝6.7Hz)，2.35-2.44(1H，m)，2.61-2.83(4H，m)，3.00-3.06(1H，m)，3.84(1H，q，J＝6.6Hz)，3.95(3H，s)，4.10(1H，d，J＝13.6Hz)，4.32(1H，dt，J＝11.0，4.6Hz)，4.39(1H，d，J＝13.6Hz)，4.60(1H，dd，J＝13.8，8.0Hz)，4.67(1H，dd，J＝15.4，5.7Hz)，4.73(1H，dd，J＝15.4，3.1Hz)，5.17-5.23(1H，m)，5.44(1H，d，J＝13.3Hz)，5.52(1H，d，J＝13.3Hz)，7.07-7.14(2H，m)，7.44(1H，t，J＝8.0Hz)，7.59(1H，s)，7.77(1H，d，J＝8.5Hz)，7.99(1H，dd，J＝8.5，1.5Hz)，8.14(1H，d，J＝1.0Hz).
[ m+h ] =633, measurement condition 1: retention time 2.49 min
Step 13 Synthesis of Compound I-145
After adding 2mol/L aqueous sodium hydroxide solution (21.5 mL, 43 mmol) to a solution of the crude product of compound 73 obtained in step 12 in total (14 mmol) in methanol (55 mL) and tetrahydrofuran (55 mL), the mixture was stirred at 45℃for 2 hours. An aqueous citric acid solution was added to the reaction mixture, which was extracted 2 times with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ethanol was added to the obtained residue, and the solvent was distilled off again under reduced pressure. Ethanol (20 mL) and water (10 mL) were added to the residue, and the resulting suspension was stirred at 40℃for 15 minutes and then at room temperature for 30 minutes. From the obtained suspension, a solid was filtered, whereby compound I-145 (6.55 g, yield 74%) was obtained.
1 H-NMR(DMSO-D 6 )δ：1.37(3H，d，J＝6.8Hz)，2.30-2.38(1H，m)，2.57-2.85(4H，m)，2.96-3.01(1H，m)，3.86(1H，dd，J＝13.3，6.4Hz)，4.09(1H，d，J＝13.9Hz)，4.20(1H，d，J＝13.9Hz)，4.29(1H，dt，J＝10.8，4.5Hz)，4.45(1H，dd，J＝13.7，7.8Hz)，4.68(1H，dd，J＝15.4，2.8Hz)，4.77(1H，dd，J＝15.4，6.7Hz)，5.06-5.12(1H，m)，5.43(1H，d，J＝12.9Hz)，5.52(1H，d，J＝12.9Hz)，7.31(1H，dd，J＝8.3，1.8Hz)，7.46-7.53(2H，m)，7.68(1H，d，J＝8.5Hz)，7.82(1H，dd，J＝8.5，1.3Hz)，7.89(1H，s)，8.27(1H，s).
The compounds shown below were also synthesized in the same manner as the above general synthesis methods or the synthesis methods described in examples. I-032, I-044, I-066 and I-133 in the tables are diastereoisomeric mixtures and I-144 in the tables are racemates.
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TABLE 88
Hereinafter, biological test examples of the compounds of the present invention are described. The compounds of the present invention can be tested essentially as in the following test examples.
The compound represented by the formula (I), the formula (II) or the formula (III) has GLP-1 receptor agonist activity.
Specifically, EC was evaluated by the evaluation method described below 50 The value is preferably 5000nM or less, more preferably 1000nM or less, and still more preferably 100nM or less.
Test example 1 (determination of GLP-1 receptor agonist Activity)
Cell culture
At 37℃with 5% CO 2 Human GLP-1 receptor stably expressing cells (hGLP-1R/CHO-K1 cells) were cultured in alpha-MEM medium (Sigma) containing 10% FBS (Hyclone), 2% Glutamax (Gibco), 1% G418 (Nacalai Tesque), 1% penicillin-streptomycin mixed solution (Sigma) for 10-fold dilutions of 5.0g/l Trypsin/5.3 mmol/l EDTA solution (Nacalai Tesque), thus recovered and cryopreserved.
cAMP analysis
DMSO solutions containing the compound of the present invention or human GLP-1 (7-36) (Phoenix Pharmaceuticals) were dispensed at 62.5 nL/well into 384 well microwell plates (Greiner) and 400 μm Forskolin (Forskolin) (Nacalai Tesque) at 7.5 nL/well. Subsequently, the frozen GLP-1R/CHO-K1 cells were thawed in a constant temperature bath at 37℃to become 2X 10 4 Individual cells/mL were suspended in HBSS buffer (GIBCO) containing 0.1% BSA (Sigma), 20mM HEPES (GIBCO), 0.1mM IBMX (Sigma), 0.2mM RO20-1724 (Calbiochem), and the cell suspension was added at 6. Mu.L/well. The intracellular cAMP concentration was measured at 37℃for 1 hour using cAMP Gs dynamic kit (Cisbio) according to the instructions attached to the preparation. Specifically, cAMP-d2 and Anti-cAMP-Cryptate were added at 3. Mu.L/well, respectively, incubated at room temperature for 1 hour, and time-resolved fluorescence was measured using PHERAstar (BMG Labtech).
The 50% Effect Concentration (EC) of the compound of the present invention was calculated using TIBCO Spotfire (TIBCO Software) with the final concentration of 2nM being 100% for the cAMP concentration when human GLP-1 (7-36) was dispensed, 0% for the cAMP concentration when DMSO alone was dispensed, and the cAMP concentration increase as an index 50 ) And a maximum effect (Emax). The dilution concentration and the dilution solvent are changed as needed.
The compounds of the present invention were tested essentially as described above. EC of each of the inventive compounds 50 Emax is shown in the following table.
TABLE 89
Example No EC50(nM) Emax(％) Example No EC50(nM) Emax(％)
I-001 47.5 75 I-020 75.8 89
I-002 43.3 92.2 I-022 15 92.3
I-004 43.9 75.3 I-023 4.56 86
I-006 54.5 86 I-024 26.4 92.7
I-007 19.8 75.7 I-026 6.35 85
I-008 48.7 84.3 I-027 9.48 80
I-009 27.3 81.3 I-028 78.6 84
I-011 70.8 92.7 I-029 94.6 81.3
I-015 74.3 81.3 I-030 3.56 92.3
I-016 50.3 79 I-031 8.92 91
TABLE 90
Example No EC50(nM) Emax(％) Example No EC50(nM) Emax(％)
I-032 92.7 146 I-067 3.33 130
I-033 1.49 109 I-068 3.54 114
I-034 8.71 103 I-069 7.28 116
I-035 0.298 129 I-070 23.4 119
I-036 99.5 66 I-071 63.9 114
I-037 0.663 126 I-072 12.6 127
I-039 43.8 83.3 I-074 40 100
I-040 37.7 147 I-076 1.59 108
I-041 45.2 102 I-078 28.6 112
I-042 73.8 95 I-079 6.8 103
I-043 13.2 109 I-080 3.89 103
I-044 9.98 103 I-081 7.66 101
I-045 81.5 93.7 I-082 2.32 103
I-046 4.33 118 I-083 21.4 93
I-047 4.3 105 I-084 91.9 106
I-048 75.4 130 I-085 4.47 111
I-049 5.03 95 I-086 17.9 106
I-050 238 67.7 I-088 7.81 147
I-051 24.2 87.3 I-090 6.6 106
I-052 24.5 92 I-093 16.6 111
I-053 14.6 115 I-094 28.5 102
I-054 0.948 104 I-095 10.5 112
I-055 78.8 87.3 I-097 2.42 105
I-056 6.04 110 I-098 10.9 120
I-059 29.9 112 I-099 1.43 114
I-061 1.56 113 I-100 95.2 90.7
I-062 11.6 98.3 I-101 2.23 113
I-063 98.1 128 I-102 5.09 106
I-064 5.74 102 I-103 5.6 113
I-065 9.82 116 I-104 4.78 102
I-066 8.72 124 I-106 6.88 101
TABLE 91
Example No EC50(nM) Emax(％) Example No EC50(nM) Emax(％)
I-107 3.5 101 I-119 0.569 119
I-108 8.33 108 I-120 2.43 103
I-109 0.472 114 I-121 1.21 119
I-110 0.685 114 I-122 1.22 97
I-111 2.51 126 I-123 3.76 97.7
I-112 1.1 114 I-124 1.71 102
I-113 1.46 124 I-125 0.427 99.7
I-114 0.604 132 I-126 1.52 98.7
I-115 0.538 124 I-127 1.15 111
I-116 0.158 119 I-128 40.3 81.3
I-117 0.327 117 I-129 0.329 122
I-118 0.658 113 I-130 0.307 139
TABLE 92
Example No EC50(nM) Emax(％) Example No EC50(nM) Emax(％)
I-131 89 119 I-149 101 93.7
I-132 0.881 105 I-150 18.3 92
I-133 4.5 112 I-151 124 93.7
I-134 1.18 119 I-152 5.88 111
I-135 27.6 91 I-153 5.34 104
I-136 5.73 107 I-154 38.4 97.7
I-137 5.56 114 I-155 25.9 93.7
I-138 58.8 94.3 I-156 36.8 89
I-139 1.23 117 I-157 4.29 109
I-140 18 96 I-158 16.3 94
I-143 25.3 101 I-159 13.3 92.3
I-145 0.0938 108 I-160 0.0524 118
I-146 40.3 102 I-161 1.28 110
I-147 99.3 88 I-162 1.37 106
I-148 32.5 95 I-163 10.6 131
TABLE 93
Example No EC50(nM) Emax(％) Example No EC50(nM) Emax(％)
I-164 0.302 104 I-194 0.741 111
I-165 2.74 103 I-195 3.29 96.3
I-166 1.23 111 I-196 0.136 106
I-167 0.707 102 I-197 1.33 119
I-168 2.24 104 I-198 1.17 128
I-169 1.21 101 I-199 0.86 128
I-170 1.24 120 I-200 0.577 102
I-171 2.37 98.7 I-201 0.274 123
I-172 0.946 113 I-202 1.66 105
I-173 2.3 102 I-203 0.31 104
I-174 1.58 109 I-204 0.509 117
I-175 3.58 101 I-205 0.447 109
I-176 2.12 98.3 I-206 0.511 110
I-177 3.09 107 I-207 1.72 90.3
I-178 1.97 111 I-208 0.0824 109
I-179 1.88 99 I-209 0.984 112
I-180 8.94 97.3 I-210 0.434 113
I-181 0.374 116 I-211 0.181 103
I-182 3.31 126 I-212 1 104
I-183 2.54 98 I-213 0.366 122
I-184 4.75 98 I-214 0.392 104
I-185 2.2 106 I-215 1.82 106
I-186 3.28 111 I-216 8.62 103
I-187 4.2 105 I-217 2.34 103
I-188 1.79 90.3 I-218 0.179 109
I-189 0.0651 122 I-219 1.2 114
I-190 1.08 109 I-220 0.251 110
I-191 0.644 130 I-221 6.07 125
I-192 1.2 123 I-222 0.734 108
I-193 0.73 115 I-223 0.12 103
TABLE 94
Example No EC50(nM) Emax(％) Example No EC50(nM) Emax(％)
I-224 1.41 110 I-251 0.807 120
I-225 0.348 104 I-252 0.0798 125
I-226 0.628 112 I-253 0.366 119
I-227 0.3 103 I-254 0.177 126
I-228 2.41 106 I-255 0.102 122
I-229 0.0656 105 I-256 0.389 119
I-230 0.693 109 I-257 0.0747 115
I-231 0.282 106 I-258 0.0911 107
I-232 0.223 117 I-259 0.104 134
I-233 1.29 97.7 I-260 0.128 115
I-234 0.354 109 I-261 1.27 105
I-235 0.378 102 I-262 4.47 109
I-236 0.429 106 I-263 8.8 105
I-237 0.103 102 I-264 2.36 121
I-238 0.36 106 I-265 3.18 100
I-239 0.0882 95.3 I-266 4.04 111
I-240 0.0648 122 I-267 0.861 112
I-241 0.0302 125 I-268 1.97 108
I-242 0.0124 116 I-269 1.16 109
I-243 0.0556 111 I-270 0.69 116
I-244 0.0394 123 I-271 1.66 118
I-245 0.0605 109 I-272 3.94 107
I-246 0.0264 120 I-273 0.0301 121
I-247 0.351 121 I-274 0.0134 120
I-248 0.902 124 I-275 0.246 107
I-249 0.13 145 I-276 0.0521 114
I-250 0.164 121 I-277 3.2 96.3
TABLE 95
Example No EC50(nM) Emax(％) Example No EC50(nM) Emax(％)
I-278 0.806 109 I-302 1.76 110
I-279 0.362 110 I-303 0.681 119
I-280 0.79 105 I-304 0.869 115
I-281 0.00739 120 I-305 0.949 107
I-282 0.00918 114 I-306 0.876 98.7
I-283 0.0283 118 I-307 0.0609 115
I-284 0.016 119 I-308 0.0871 115
I-285 0.00862 130 I-380 0.382 108
I-286 0.444 115 I-381 0.702 116
I-287 0.103 116 I-382 0.159 125
I-288 0.171 115 I-383 0.516 109
I-289 0.311 117 I-384 0.126 114
I-290 0.266 118 I-385 0.198 112
I-291 0.0864 120 I-386 0.0877 112
I-292 0.146 121 I-387 0.178 122
I-293 2.99 114 I-388 0.0523 115
I-294 0.676 97.7 I-389 0.05 115
I-295 1.29 108 I-390 0.046 107
I-296 0.167 117 I-391 0.396 107
I-297 0.818 102 I-392 0.0156 135
I-298 0.317 109 I-393 0.099 121
I-299 0.42 115 I-394 0.0497 108
I-300 0.296 112 I-395 0.618 89.7
I-301 0.281 117 I-025 109 78.7
TABLE 96
Example No EC50(nM) Emax(％) Example No EC50(nM) Emax(％)
I-309 2.28 84.3 I-334 0.223 114
I-310 0.415 91 I-335 1.23 98
I-311 0.972 124 I-336 0.696 100
I-312 2.03 102 I-337 0.325 104
I-313 7.87 94 I-338 1.27 100
I-314 0.537 98.3 I-339 0.377 105
I-315 2.1 94.3 I-340 0.31 105
I-316 1.66 117 I-341 0.236 125
I-317 2.56 97.7 I-342 1.95 97.3
I-318 4.55 91.3 I-343 0.063 111
I-319 2.43 95.3 I-344 0.0824 110
I-320 1.63 90.3 I-345 0.096 129
I-321 9.85 84 I-346 0.354 117
I-322 3.51 89 I-347 0.241 110
I-323 1.7 101 I-348 0.206 129
I-324 0.466 100 I-349 1.27 117
I-325 0.655 105 I-350 0.0964 113
I-326 1.31 109 I-351 0.156 121
I-327 1.06 100 I-352 0.122 113
I-328 1.73 87.3 I-353 0.0558 115
I-329 1.16 96.7 I-354 0.139 122
I-330 1.22 93 I-355 0.102 119
I-331 2.7 102 I-356 0.25 118
I-332 1.38 105 I-357 0.0425 123
I-333 8.05 116 I-358 0.136 120
TABLE 97
From the above results, the compounds of the present invention exhibit GLP-1 receptor agonist activity, and thus, their effect as therapeutic or prophylactic agents for diseases in which GLP-1 receptor participates can be expected.
Test example 2 (Metabolic stability test)
The degree of metabolism of the compound of the present invention in the liver was evaluated by reacting commercially available mixed human liver microsomes with the compound of the present invention for a predetermined period of time and comparing the reaction sample with the unreacted sample to calculate the residual rate.
In 0.2mL of buffer (50 mmol/L Tris-HCl pH 7.4, 150mmol/L potassium chloride, 10mmol/L magnesium chloride) containing 0.5mg protein/mL of human liver microsomes, in the presence of 1mmol/L NADPH, at 37℃for 0 min or 30 min (oxidative reaction). After the reaction, 50. Mu.L of the reaction solution was added to 100. Mu.L of a methanol/acetonitrile=1/1 (v/v) solution and mixed, and centrifuged at 3000rpm for 15 minutes. The compound of the present invention was quantified in the supernatant of the centrifugation by LC/MS, and the residual amount of the compound of the present invention after the reaction was calculated by setting the amount of the compound at 0 minutes of the reaction to 100%.
The compounds of the present invention may be tested essentially as described above.
Test example 2-2: metabolic stability test
The degree of metabolism of the compound of the present invention in the liver was evaluated by reacting commercially available mixed human liver microsomes with the compound of the present invention for a predetermined period of time and comparing the reaction sample with the unreacted sample to calculate the residual rate.
In 0.2mL of buffer (50 mmol/L Tris-HCl pH 7.4, 150mmol/L potassium chloride, 10mmol/L magnesium chloride) containing 0.5mg protein/mL of human liver microsomes, in the presence of 1mmol/L NADPH, the reaction was carried out at 37℃for 0 min or 30 min (oxidation reaction). After the reaction, 70. Mu.L of the reaction solution was added to 140. Mu.L of a methanol/acetonitrile=1/1 (v/v) solution and mixed, and centrifuged at 3000rpm for 15 minutes. The compound of the present invention was quantified in the supernatant of the centrifugation by LC/MS or Solid Phase Extraction (SPE)/MS, and the ratio of the amount of the compound of the present invention to the amount of the compound after the reaction was expressed as the residual ratio, assuming that the amount of the compound of the present invention at 0 minutes of the reaction was 100%. The hydrolysis reaction was performed in the absence of NADPH, and the glucuronic acid binding reaction was performed in the presence of 5mmol/L UDP-glucuronic acid instead of NADPH, and then the same operation was performed. The dilution concentration and the dilution solvent are changed as needed.
The compounds of the present invention were tested essentially as described above. The results are shown below.
The result shows the residual ratio at a compound concentration of 0.5. Mu. Mol/L.
Compound I-033:87.1%
Compound I-035:87.1%
Compound I-109:99.6%
Compound I-117:96.9%
Compound I-123: > 99.9%
Compound I-145:94.0%
Compound I-160:92.4%
Test example 3 (solubility test)
The solubility of the compounds of the invention was determined with the addition of 1% dmso. 10mmol/L of the compound solution was prepared by using DMSO, and 6. Mu.L of the compound solution of the present invention was added to 594. Mu.L of an artificial intestinal juice having a pH of 6.8 (118 mL of a 0.2mol/L NaOH solution, water, and 1000mL were added to 250mL of a 0.2mol/L potassium dihydrogen phosphate solution). After standing at 25 ℃ for 16 hours, the mixture was filtered with suction. The filtrate was diluted 2-fold with methanol/water=1/1 (V/V), and the concentration in the filtrate was determined by an absolute standard curve method using HPLC or LC/MS.
The compounds of the present invention may be tested essentially as described above.
Test example 3-2 (solubility test)
The solubility of the compounds of the invention was determined with the addition of 1% dmso. 10mmol/L of the compound solution was prepared by using DMSO, and 2. Mu.L of the compound solution of the present invention was added to 594. Mu.L of an artificial intestinal juice having a pH of 6.8 (118 mL of a 0.2mol/L NaOH solution, water, and 1000mL were added to 250mL of a 0.2mol/L potassium dihydrogen phosphate solution). After shaking at room temperature for 1 hour or more (3 hours according to the operability), the mixture was filtered by suction. The filtrate was diluted 100-fold (filtrate 2 μl+mecn/MeOH/purified water=1/1/2 (V/V) 198 μl) and the concentration in the filtrate was determined by absolute standard curve method using HPLC or LC/MS.
The compounds of the present invention may be tested essentially as described above.
Test examples 3 to 3 (solubility test)
The solubility of the compounds of the invention was determined with the addition of 1% dmso. 10mmol/L of the compound solution was prepared using DMSO, and 2. Mu.L of the compound solution of the present invention was added to 198. Mu.L of Japanese pharmacopoeia seventeenth revised edition dissolution test No. 2 solution. Standing at 25deg.C, oscillating for 3 hr, and filtering under suction. The filtrate was diluted 100-fold with methanol/acetonitrile/water=1/1 (V/V), and the concentration in the filtrate was determined by an absolute standard curve method using LC/MS.
The compounds of the present invention may be tested essentially as described above.
Test examples 3 to 4 (solubility test)
The solubility of the compounds of the invention was determined with the addition of 1% dmso. 10mmol/L of the compound solution was prepared using DMSO, and 2. Mu.L of the compound solution of the present invention was added to 198. Mu.L of Japanese pharmacopoeia seventeenth revised edition dissolution test No. 2 solution. After shaking for 3 hours at room temperature, the mixture was filtered with suction. The filtrate was diluted 100-fold with methanol/acetonitrile/water=1/1 (V/V), and the concentration in the filtrate was determined by an absolute standard curve method using LC/MS.
The compounds of the present invention may be tested essentially as described above.
Test example 4 (CYP inhibition test)
The degree to which the production of each metabolite was inhibited by the compounds of the present invention was evaluated using commercially available mixed human liver microsomes as a typical substrate metabolic reaction of the major human CYP5 molecular species (CYP 1A2, 2C9, 2C19, 2D6, 3 A4) using O-deethylation of 7-ethoxyresorufin (CYP 1 A2), methyl-hydroxide of tolbutamide (CYP 2C 9), 4' -hydroxide of mephenytoin (CYP 2C 19), O-demethylation of dextromethorphan (CYP 2D 6), and hydroxide of terfenadine (CYP 3 A4) as indicators.
The reaction conditions are as follows: substrate, 0.5. Mu. Mol/L ethoxyline resorufin (CYP 1A 2), 100. Mu. Mol/L tolbutamide (CYP 2C 9), 30. Mu. Mol/L or 50. Mu. Mol/L S-Mephenytoin (CYP 2C 19), 5. Mu. Mol/L dextromethorphan (CYP 2D 6), 1. Mu. Mol/L terfenadine (CYP 3A 4); reaction time, 15 minutes; the reaction temperature is 37 ℃; enzyme, mixed human liver microsomes 0.2mg protein/mL; the concentration of the compound of the invention was 1, 5, 10, 20. Mu. Mol/L (4 spots).
In a 96-well plate, 5 substrates, human liver microsomes, and the compound of the present invention were added to 50mmol/L Hepes buffer as a reaction solution, and NADPH as a coenzyme was added thereto to initiate a metabolic reaction as an index. After 15 minutes of reaction at 37 ℃, a methanol/acetonitrile=1/1 (V/V) solution was added, whereby the reaction was terminated. After centrifugation at 3000rpm for 15 minutes, the supernatant was quantified for resorufin (CYP 1A2 metabolite) using a fluorescent multi-label counter ( light) or LC/MS/MS, and the supernatant was quantified for mefenodine (CYP 2C9 metabolite), mefenodine 4' hydroxide (CYP 2C19 metabolite), dextromethorphan (CYP 2D6 metabolite), and terfenadine alcohol (CYP 3A4 metabolite) using LC/MS/MS.
The residual activity (%) was calculated using the control (100%) obtained by adding DMSO alone as a solvent for dissolving the drug to the reaction system, and IC was calculated by using the inverse estimation of the Logistic model using the concentration and the inhibition ratio 50 。
The compounds of the present invention may be tested essentially as described above.
Test example 5 (BA test)
Experimental materials and methods for oral absorbability studies
(1) Animals were used: mice or SD rats were used.
(2) Feeding conditions: the mice or SD rats were allowed free access to solid feed and sterilized tap water.
(3) Setting of administration amount and grouping: the administration is carried out orally or intravenously according to a prescribed administration amount. The groups are set as follows. (varying the amount of each compound to be administered)
Orally administered 2-60 mu mol/kg or 1-30 mg/kg (n=2-3)
Intravenous administration of 1-20. Mu. Mol/kg or 0.5-10 mg/kg (n=2-3)
(4) Preparation of the administration solution: oral administration is in the form of a solution or suspension. Intravenous administration is performed by solubilizing.
(5) The administration method comprises the following steps: oral administration is forced into the stomach through an oral feeding tube. Intravenous administration is from the tail vein or thigh vein by a syringe with an injection needle.
(6) Evaluation items: the concentration of the compound of the invention in plasma was determined by chronologically taking blood and using LC/MS.
(7) Statistical analysis: regarding the change in the concentration of the compound of the present invention in plasma, the area under the concentration-time curve (AUC) in plasma was calculated by a moment analysis method, and the Bioavailability (BA) of the compound of the present invention was calculated from the ratio of the administered amount and AUC of the oral administration group to the intravenous administration group.
The compounds of the present invention may be tested essentially as described above.
Test example 6: clearance evaluation test
Experimental materials and methods
(1) Animals were used: SD rats were used.
(2) Feeding conditions: SD rats were allowed free access to solid feed and sterilized tap water.
(3) Setting of administration amount and grouping: is administered intravenously according to a prescribed administration amount. The groups are set as follows.
Intravenous administration of 1. Mu. Mol/kg (n=2)
(4) Preparation of the administration solution: the administration was performed by solubilization using dimethyl sulfoxide/propylene glycol=1/1 solvent.
(5) The administration method comprises the following steps: administered from the tail vein through a syringe with an injection needle.
(6) Evaluation items: the concentration of the compound of the present invention in plasma was measured by taking blood over time using LC/MS.
(7) Statistical analysis: regarding the change in the concentration of the compound of the present invention in plasma, the systemic clearance (CLtot) was calculated by a moment analysis method. The dilution concentration and the dilution solvent are changed as needed.
The compounds of the present invention may be tested essentially as described above.
Test example 6-2: clearance evaluation test
Experimental materials and methods
(1) Animals were used: dogs (Marshall Beagles) were used.
(2) Feeding conditions: the dogs were allowed free access to solid feed and sterilized tap water.
(3) Setting of administration amount and grouping: is administered intravenously according to a prescribed administration amount. The groups are set as follows.
Intravenous administration of 0.1-1 mg/kg (n=2)
(4) Preparation of the administration solution: the composition was administered by solubilizing using any one of solvents dimethylacetamide/ethanol/carbonic acid buffer=2/3/5, ethanol/carbonic acid buffer=1/1, dimethylacetamide/polyethylene glycol 400/20% hydroxypropyl- β -cyclodextrin=1/1/2.
(5) The administration method comprises the following steps: is administered intravenously through a syringe with a needle.
(6) Evaluation items: the concentration of the compound of the present invention in plasma was measured by taking blood over time using LC/MS.
(7) Statistical analysis: regarding the change in the concentration of the compound of the present invention in plasma, the systemic clearance (CLtot) was calculated by a moment analysis method. The dilution concentration and the dilution solvent are changed as needed.
The compounds of the present invention may be tested essentially as described above.
Test example 7 (CYP 3A4 (MDZ) MBI test)
The following tests were carried out: regarding CYP3A4 inhibition of the compounds of the present invention, the ability to mechanically inhibit (Mechanism based inhibition, MBI) is assessed by an enhancement based on metabolic reactions. CYP3A4 inhibition was evaluated using mixed human liver microsomes, using the 1-hydroxide reaction of Midazolam (MDZ) as an index.
The reaction conditions are as follows: a substrate, 10. Mu. Mol/L MDZ; pre-reaction time, 0 or 30 minutes; reaction time, 2 minutes; the reaction temperature is 37 ℃; mixing human liver microsomes, 0.5mg/mL at pre-reaction, 0.05mg/mL at reaction (at 10-fold dilution); the concentration of the compounds of the invention at the time of the pre-reaction was 1, 5, 10, 20. Mu. Mol/L (4 spots).
In a 96-well plate, mixed human liver microsomes and a compound solution of the present invention were added to a K-Pi buffer (pH 7.4) as a pre-reaction solution in the above-described pre-reaction composition, and a part of the mixture was transferred to another 96-well plate so as to be diluted 1/10 with a substrate and the K-Pi buffer, NADPH as a coenzyme was added thereto to initiate a reaction (no pre-reaction) as an index, and after a specific time of the reaction, a methanol/acetonitrile=1/1 (V/V) solution was added to terminate the reaction. In addition, NADPH was also added to the remaining pre-reaction solution to initiate a pre-reaction (there was a pre-reaction), and after a predetermined time period, a part was transferred to another plate so as to be diluted 1/10 by the substrate and the K-Pi buffer, and a reaction was initiated as an index. After a certain time of the reaction, a methanol/acetonitrile=1/1 (V/V) solution was added, thereby terminating the reaction. After centrifugation of the plates for each index reaction at 3000rpm for 15 minutes, the 1-midazolam hydroxide in the supernatant of the centrifugation was quantified by LC/MS.
The residual activity (%) when the compound of the present invention was added at each concentration was calculated using the case where DMSO alone was added as a solvent for dissolving the compound of the present invention in the reaction system as a control (100%), and IC was calculated by using the inverse estimation using the Logistic model using the concentration and the inhibition ratio. The value of the Shifted IC was set to be positive when the value of the Shifted IC was 1.5 or more, and negative when the value of the Shifted IC was 1.0 or less, with the value of the IC pre-cultured for 0 min/the value of the IC pre-cultured for 30 min.
The compounds of the present invention may be tested essentially as described above.
Test example 7-2 (CYP 3A4 (MDZ) MBI test)
The following tests were carried out: regarding CYP3A4 inhibition of the compounds of the present invention, the mechanical inhibition (MBI) ability is assessed by enhancement based on metabolic reactions. CYP3A4 inhibition was evaluated using mixed human liver microsomes, using the 1-hydroxide reaction of Midazolam (MDZ) as an index.
The reaction conditions are as follows: a substrate, 10. Mu. Mol/L MDZ; pre-reaction time, 0 or 30 minutes; reaction time, 2 minutes; the reaction temperature is 37 ℃; mixing human liver microsomes, 0.5mg/mL at pre-reaction, 0.05mg/mL at reaction (at 10-fold dilution); the concentration of the compounds according to the invention at the time of the pre-reaction was 0.83, 5, 10, 20. Mu. Mol/L (4 spots).
In a 96-well plate, mixed human liver microsomes and a compound solution of the present invention were added to a K-Pi buffer (pH 7.4) as a pre-reaction solution in the above-described pre-reaction composition, and a part of the mixture was transferred to another 96-well plate so as to be diluted 1/10 with a substrate and the K-Pi buffer, NADPH as a coenzyme was added thereto to initiate a reaction (no pre-reaction) as an index, and after a specific time of the reaction, a methanol/acetonitrile=1/1 (V/V) solution was added to terminate the reaction. In addition, NADPH was added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction was performed), and after a predetermined time, a part of the pre-reaction was transferred to another plate so as to be diluted 1/10 by the substrate and the K-Pi buffer, and a reaction was initiated as an index. After a certain time of the reaction, a methanol/acetonitrile=1/1 (V/V) solution was added, thereby terminating the reaction. After centrifugation of the plates for each index reaction at 3000rpm for 15 minutes, the 1-midazolam hydroxide in the supernatant of the centrifugation was quantified by LC/MS.
The residual activity (%) when the compound of the present invention was added at each concentration was calculated using the case where DMSO alone was added as a solvent for dissolving the compound of the present invention in the reaction system as a control (100%), and IC was calculated by using the inverse estimation using the Logistic model using the concentration and the inhibition ratio. The value of Shifted IC was set to be positive when the value of Shifted IC was 1.5 or more, and negative when the value of Shifted IC was less than 1.1.
The compounds of the present invention may be tested essentially as described above.
Test example 8 (powder solubility test)
An appropriate amount of the compound of the present invention was placed in a suitable container, and 200. Mu.L of JP-1 solution (1000 mL of water was added to 2.0g of sodium chloride and 7.0mL of hydrochloric acid), JP-2 solution (500 mL of water was added to 500mL of phosphate buffer having a pH of 6.8), and 20mmol/L of sodium Taurocholate (TCA)/JP-2 solution (100 mL of JP-2 solution was added to 1.08g of TCA) were added to each container. After the test solution is added, the compound of the present invention is appropriately added when the entire amount has been dissolved. After sealing and shaking at 37℃for 1 hour, filtration was performed, and 100. Mu.L of methanol was added to 100. Mu.L of each filtrate to make a 2-fold dilution. The dilution ratio is changed as needed. Confirm whether there are no bubbles and precipitates, seal and shake. The compounds of the invention were quantified by absolute standard curve method using HPLC.
The compounds of the present invention may be tested essentially as described above.
Test example 8-2 (powder solubility test)
An appropriate amount of the compound of the present invention was placed in a suitable container, and 200. Mu.L of JP-1 solution (1000 mL of sodium chloride, 7.0mL of hydrochloric acid, and water was added to each container), JP-2 solution (buffer solution having pH of 6.8 to 6.9, prepared by dissolving 1.70g of sodium dihydrogen phosphate and 1.775g of anhydrous disodium hydrogen phosphate in 1000mL of water), and 20mmol/L of sodium Taurocholate (TCA)/JP-2 solution (100 mL of JP-2 solution was added to 1.08g of TCA) were added to each container. After the test solution is added, the compound of the present invention is appropriately added when the entire amount has been dissolved. After sealing and shaking at 37℃for 1 hour, filtration was performed, and 100. Mu.L of methanol was added to 100. Mu.L of each filtrate to make a 2-fold dilution. The dilution ratio is changed as needed. Confirm whether there are no bubbles and precipitates, seal and shake. The compounds of the invention were quantified by absolute standard curve method using HPLC.
The compounds of the present invention may be tested essentially as described above.
Test example 9 (Flconstruction Ames test)
Mutagenicity of the compounds of the present invention was evaluated.
A cryopreserved Salmonella typhimurium (Salmonella typhimurium TA strain, TA100 strain) was inoculated in 20. Mu.L in 10mL of liquid nutrient medium (2.5% Oxoid nutrient broth) No.2 and incubated at 37℃for 10 hours before shaking. For TA98 strain, 8.0 to 11.0mL of the bacterial solution was centrifuged (2000 Xg, 10 minutes) to remove the culture solution. The bacteria were suspended in 8.0 to 11.0mL of Micro F buffer (K) 2 HPO 4 ：3.5g/L、KH 2 PO 4 ：1g/L、(NH 4 ) 2 SO 4 :1g/L, trisodium citrate dihydrate: 0.25g/L, mgSO 4 ·7H 2 0:0.1 g/L) was added to 120mL of Exposure medium (containing biotin: 8 μg/mL, histidine: 0.2 μg/mL, glucose: 8mg/mL of MicroF buffer). For TA100 strain, the test bacterial solution was prepared by adding 3.1mL of the bacterial solution to 120mL of the Exposure medium. The compound DMSO solution of the present invention (diluted in several stages at a 2-3-fold public ratio from the maximum amount of 50 mg/mL), DMSO as a negative control, 12. Mu.L each of the following solutions as a positive control, and 588. Mu.L each of test bacterial liquid (a mixed solution in which 498. Mu.L of test bacterial liquid is mixed with S9 under metabolic activation conditions) were mixed, and shaking culture was carried out at 37℃for 90 minutes, and the solution as a positive control was: under non-metabolic activation conditions, 50 μg/mL of 4-nitroquinoline-1-oxide DMSO solution for TA98 strain and 0.25 μg/mL of 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain; under metabolic activation conditions, 40. Mu.g/mL of 2-aminoanthracene DMSO solution was used for TA98 strain, and 20. Mu.g/mL of 2-aminoanthracene DMSO solution was used for TA100 strain. mu.L of the bacterial liquid exposed to the compound of the present invention was mixed with 1150. Mu.L of an Indicator medium (micro F buffer containing biotin, histidine, glucose, bromocresol purple and bromocresol purple in amounts of 8mg/mL and 37.5. Mu.g/mL), 50. Mu.L was dispensed to each microplate at 48 wells/dose, and the mixture was allowed to stand at 37℃for 3 days. Since the wells containing the bacteria having acquired the proliferation ability by mutation of the amino acid (histidine) synthase gene changed from purple to yellow due to the pH change, the number of the bacteria proliferation wells having changed to yellow in 48 wells per 1 dose was counted, and compared with the negative control group and evaluated. List of patients who were negative for mutagenicity Shown as (-), and those positive are indicated as (+).
The compounds of the present invention may be tested essentially as described above.
Test example 9-2 (Fluction Ames test)
Mutagenicity of the compounds of the present invention was evaluated.
A cryopreserved strain of Salmonella typhimurium (Salmonella typhimurium TA strain, TA100 strain) was inoculated in 10mL of liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) and incubated at 37℃for 10 hours before shaking. For TA98 strain, 8.0 to 11.0mL of the bacterial solution was centrifuged (2000 Xg, 10 minutes) to remove the culture solution. The bacteria were suspended in 8.0 to 11.0mL of Micro F buffer (K) 2 HPO 4 ：3.5g/L、KH 2 PO 4 ：1g/L、(NH 4 ) 2 SO 4 :1g/L, trisodium citrate dihydrate: 0.25g/L, mgSO 4 ·7H 2 0:0.1 g/L) was added to 120mL of Exposure medium (containing biotin: 8 μg/mL, histidine: 0.2 μg/mL, glucose: 8mg/mL of MicroF buffer). For TA100 strain, 3.0mL of the bacterial liquid was added to 120mL of the Exposure medium to prepare a test bacterial liquid. The compound DMSO solution of the present invention (diluted in several stages at a 2-3-fold public ratio from the maximum amount of 50 mg/mL), DMSO as a negative control, 12. Mu.L each of the following solutions as a positive control, and 588. Mu.L each of test bacterial liquid (a mixed solution in which 498. Mu.L of test bacterial liquid is mixed with S9 under metabolic activation conditions) were mixed, and shaking culture was carried out at 37℃for 90 minutes, and the solution as a positive control was: under non-metabolic activation conditions, 50 μg/mL of 4-nitroquinoline-1-oxide DMSO solution for TA98 strain and 0.25 μg/mL of 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain; under metabolic activation conditions, 40. Mu.g/mL of 2-aminoanthracene DMSO solution was used for TA98 strain, and 20. Mu.g/mL of 2-aminoanthracene DMSO solution was used for TA100 strain. The bacterial solution exposed to the compound of the present invention was mixed with an Indicator medium (MicroF buffer containing biotin: 8. Mu.g/mL, histidine: 0.2. Mu.g/mL, glucose: 8mg/mL, bromocresol purple: 37.5. Mu.g/mL) at a ratio of 23:115, and 50. Mu.L of a microbial liquid (2760. Mu.L in total) containing an indicator was dispensed into each microplate at 48 wells/dose L, stationary culture at 37℃for 3 days. Since the wells containing the bacteria having acquired the proliferation ability by mutation of the amino acid (histidine) synthase gene changed from purple to yellow due to the pH change, the number of the bacteria proliferation wells having changed to yellow in 48 wells per 1 dose was counted, and compared with the negative control group and evaluated. Those with mutagenicity negative are denoted as (-), those with positive are denoted as (+).
The compounds of the present invention may be tested essentially as described above.
Test example 10 (hERG test)
For the evaluation of risk of prolongation of the electrocardiographic QT interval of the compounds according to the invention, delayed rectification K, which is an important function for the ventricular repolarization process, was investigated using CHO cells expressing the human ether-a-go-related gene (hERG) channel + Current (I) Kr ) Is effective in (1).
Using a full-automatic patch clamp system (QPatch; sophion Bioscience A/S), cells were held at a membrane potential of-80 mV by whole cell patch clamp, and after applying a leakage potential of-50 mV, I induced when depolarizing stimulus of +20mV was applied for 2 seconds, and further repolarizing stimulus of-50 mV was applied for 2 seconds was recorded Kr . After the generated current was stabilized, the extracellular fluid (NaCl: 145mmol/L, KCl:4mmol/L, caCl) of the compound of the present invention was dissolved at the target concentration 2 ：2mmol/L、MgCl 2 :1mmol/L, glucose: 10mmol/L, HEPES (4- (2-hydroxyyethyl) -1-piperazineethanesulfonic acid, 4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid): 10mmol/L, pH value = 7.4) was applied to cells for 10 minutes at room temperature. According to the obtained I Kr The absolute value of the maximum tail current was measured using analytical software (Falster Patch; sophion Bioscience A/S) with reference to the current value at the membrane potential. Furthermore, the inhibition ratio against the maximum tail current before application of the compound of the present invention was calculated, and the compound of the present invention was evaluated for the effect of I Kr Is a function of (a) and (b).
The compounds of the present invention may be tested essentially as described above.
Test example 10-2 (hERG test)
To carry out the inventionElectrocardiogram QT interval prolongation risk assessment of the Compound Using CHO cells expressing human Ether-a-go-go related Gene (hERG) channel, delayed rectification K, which is an important function of the inventive Compound for the ventricular repolarization process, was studied + Current (I) Kr ) Is effective in (1).
Using a full-automatic patch clamp system (QPatch; sophion Bioscience A/S), cells were held at a membrane potential of-80 mV by whole cell patch clamp, and after applying a leakage potential of-50 mV, I induced when depolarizing stimulus of +20mV was applied for 2 seconds, and further repolarizing stimulus of-50 mV was applied for 2 seconds was recorded Kr . To adjust the dimethyl sulfoxide to 0.1% extracellular fluid (NaCl: 145mmol/L, KCl:4mmol/L, caCl) 2 ：2mmol/L、MgCl 2 :1mmol/L, glucose: 10mmol/L, HEPES (4- (2-hydroxyyethyl) -1-piperazineethanesulfonic acid, 4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid): 10mmol/L, pH value=7.4) as a medium, and the medium and the extracellular fluid in which the compound of the present invention is dissolved at a target concentration are applied to the cells at room temperature for 7 minutes or more, respectively. According to the obtained I Kr Using analytical software (QPatch Assay software; sophion Bioscience A/S), the absolute value of the maximum tail current was measured with reference to the current value at the membrane potential. Furthermore, the ratio of the maximum tail current after application of the compound of the present invention to the maximum tail current after application of the medium was calculated as the inhibition ratio, and the compound of the present invention was evaluated for the ratio I Kr Is a function of (a) and (b). The dilution concentration and the dilution solvent are changed as needed.
The compounds of the present invention may be tested essentially as described above.
Preparation example
The compounds of the invention may be administered as pharmaceutical compositions by any of the previous routes, in particular enterally, e.g. orally, e.g. in the form of tablets or capsules, or parenterally, e.g. in the form of injectable solutions or suspensions, topically, e.g. in the form of lotions, gels, ointments or creams, or nasally or in the form of suppositories. Pharmaceutical compositions comprising at least 1 pharmaceutically acceptable carrier or diluent and a compound of the invention in free form or in pharmaceutically acceptable salt form may be manufactured by mixing, granulating or coating methods using conventional methods. For example, as the composition for oral administration, tablets, granules, capsules containing an excipient, a disintegrant, a binder, a lubricant, etc., an active ingredient, etc. can be prepared. The injectable composition may be formulated into a solution or suspension, may be sterilized, and may contain a preservative, a stabilizer, a buffer, and the like.
The compounds of the invention may be administered as pharmaceutical compositions by any of the previous routes, in particular enterally, e.g. orally, e.g. in the form of tablets or capsules, or parenterally, e.g. in the form of injectable solutions or suspensions, topically, e.g. in the form of lotions, gels, ointments or creams, or nasally or in the form of suppositories. Pharmaceutical compositions comprising at least 1 pharmaceutically acceptable carrier or diluent and a compound of the invention in free form or in pharmaceutically acceptable salt form may be manufactured by mixing, granulating or coating methods using conventional methods. For example, as the composition for oral administration, tablets, granules, capsules containing an excipient, a disintegrant, a binder, a lubricant, etc., an active ingredient, etc. can be prepared. The injectable composition may be formulated into a solution or suspension, may be sterilized, and may contain a preservative, a stabilizer, a buffer, etc.
Industrial applicability
The compounds of the present invention are believed to have GLP-1 receptor agonist activity and are useful as therapeutic and/or prophylactic agents for diseases or conditions in which the GLP-1 receptor is involved.

Claims (22)

1. A compound or a pharmaceutically acceptable salt thereof, the compound being represented by formula (I):
[ chemical 1]
(in the formula (I),
A 1 is C (R) 5 ) Or N, or a combination of two,
A 2 is C (R) 6 ) Or N, or a combination of two,
A 3 is C (R) 7 ) Or N, or a combination of two,
R 5 、R 6 and R is 7 Each independently is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, or a substituted or unsubstituted non-aromatic carbocyclic group,
R 1 is carboxyl or its equivalent or CH 2 COOH，
R 2 Is a substituted or unsubstituted alkyl group or a substituted or unsubstituted non-aromatic heterocyclic group,
-X-is-C (R) 8 )(R 9 ) -, -O-, or-N (R) 11 )-，
R 8 And R is 9 Each independently a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group,
R 11 is a hydrogen atom or a substituted or unsubstituted alkyl group,
[ chemical 2]
The ring being represented by
[ chemical 3]
[ chemical 4]
[ chemical 5]
(in the formula (I),
R 10 each independently is halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclyl, or substituted or unsubstituted alkyloxy,
s is an integer of 0 to 9),
R 13 each independently a hydrogen atom, a halogen or a substituted or unsubstituted alkyl group,
R 3 is a substituted or unsubstituted aromatic carbocyclyl group, a substituted or unsubstituted non-aromatic carbocyclyl group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group).
2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein s is an integer from 1 to 9.
3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
[ chemical 6]
The ring being represented by
[ chemical 7]
[ chemical 8]
[ chemical 9]
(wherein s' is an integer of 0 to 8, and the other symbols have the same meaning as defined in claim 1).
4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
[ chemical 10]
The ring being represented by
[ chemical 11]
(wherein s is an integer of 1 to 9, and the other symbols have the same meaning as defined in claim 1).
5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
[ chemical 12]
The ring being represented by
[ chemical 13]
(wherein p is an integer of 0 to 6, and the other symbols have the same meaning as defined in claim 1).
6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 10 Each independently is halogen, cyano, or substituted or unsubstituted alkyl.
7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 3 Is that
[ chemical 14]
(in the formula (I),
T 1 is a carbon atom or a nitrogen atom,
T 2 is a carbon atom or a nitrogen atom,
R 4 Each independently is halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, or substituted or unsubstituted alkylsulfonyl,
R 14 is a hydrogen atom or a substituted or unsubstituted alkyl group,
m is an integer of 0 to 5,
n is an integer of 0 to 2).
8. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein R 3 Is that
[ 15]
(in the formula (I),
T 1 is C (R) 12 ) Or N, or a combination of two,
R 12 each independently is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted alkylsulfonyl group,
R 4 and R is 14 The meaning of (a) is the same as that of claim 7).
9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R 3 Is that
[ 16]
(in the formula (I),
T 1 is C (R) 12 ) Or N, or a combination of two,
R 12 each independently is a hydrogen atom or a halogen,
R 4 each independently is halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted non-aromatic carbocyclyl).
10. A compound according to any one of claims 7 to 9, or a pharmaceutically acceptable salt thereof, wherein R 4 Each independently is halogen, and R 12 Each independently a hydrogen atom or a halogen.
11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 13 Each independently is a hydrogen atom or a substituted or unsubstituted alkyl group.
12. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein
(i)A 1 Is C (R) 5 )，A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 ) Or (b)
(ii)A 1 Is N, A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 ) Or (b)
(iii)A 1 Is C (R) 5 )，A 2 Is C (R) 6 )，And A is 3 Is N, or
(iv)A 1 Is N, A 2 Is C (R) 6 ) And A is 3 Is N.
13. A compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein
(i)A 1 Is C (R) 5 )，A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 ) Or (b)
(ii)A 1 Is N, A 2 Is C (R) 6 ) And A is 3 Is C (R) 7 )。
14. A compound according to claim 12 or 13, or a pharmaceutically acceptable salt thereof, wherein R 5 Is a hydrogen atom or halogen, R 6 Is a hydrogen atom, and R 7 Is a hydrogen atom, a halogen or a substituted or unsubstituted alkyloxy group.
15. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R 1 Is carboxyl.
16. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R 2 Is alkyl, alkyl substituted by a substituted or unsubstituted non-aromatic heterocycle, or alkyl substituted by a substituted or unsubstituted aromatic heterocycle.
17. The compound according to claim 16, or a pharmaceutically acceptable salt thereof, wherein R 2 Alkyl substituted by a substituted or unsubstituted non-aromatic heterocycle or alkyl substituted by a substituted or unsubstituted aromatic heterocycle.
18. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein-X-is-C (R 8 )(R 9 )-。
19. According to claim 18A compound or pharmaceutically acceptable salt thereof, wherein R 8 And R is 9 Is a hydrogen atom.
20. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of compounds I-035, I-145, I-160, I-218, I-223, I-239, I-242, I-243, I-244, I-245, I-246, I-247, I-249, I-250, I-254, I-255, I-257, I-258, I-259, I-273, and I-274.
21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof.
22. The pharmaceutical composition according to claim 21, which is a GLP-1 receptor agonist.
CN202280037434.1A 2021-03-24 2022-03-23 Pharmaceutical compositions containing GLP-1 receptor agonists with fused rings Pending CN117377666A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2021-050798 2021-03-24
JP2021165955 2021-10-08
JP2021-165955 2021-10-08
PCT/JP2022/013362 WO2022202864A1 (en) 2021-03-24 2022-03-23 Pharmaceutical composition containing glp-1 receptor agonist having fused ring

Publications (1)

Publication Number Publication Date
CN117377666A true CN117377666A (en) 2024-01-09

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