JP2006160733A - Medicine containing cyanofluoropyrrolidine derivative as active ingredient - Google Patents

Medicine containing cyanofluoropyrrolidine derivative as active ingredient Download PDF

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JP2006160733A
JP2006160733A JP2005328431A JP2005328431A JP2006160733A JP 2006160733 A JP2006160733 A JP 2006160733A JP 2005328431 A JP2005328431 A JP 2005328431A JP 2005328431 A JP2005328431 A JP 2005328431A JP 2006160733 A JP2006160733 A JP 2006160733A
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substituent
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selected
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Hiroshi Fukushima
Ayako Mikami
Masato Takahashi
綾子 三上
浩 福島
正人 高橋
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Taisho Pharmaceut Co Ltd
大正製薬株式会社
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Abstract

Disclosed is a prophylactic or therapeutic drug for diseases or conditions that can be improved by inhibiting dipeptidyl peptidase IV (DPPIV), diabetes, immune diseases and the like.
[Solution] The following formula (I)
[Chemical 1]

Diseases or conditions that can be ameliorated by inhibiting dipeptidyl peptidase IV (DPPIV) containing the cyanofluoropyrrolidine compound represented by the above or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient, diabetes, immunity Preventive or therapeutic drugs for diseases.
[Selection figure] None

Description

  The present invention relates to a medicament containing a novel cyanofluoropyrrolidine derivative as an active ingredient.

Dipeptidyl peptidase IV (DPPIV) is a kind of serine protease that hydrolyzes a dipeptide from a peptide chain having proline or alanine second from the N-terminus.
DPPIV is widely distributed in tissues such as kidney and liver and in plasma, and is involved in the metabolism of various bioactive peptides.

Recently, it has been clarified that DPPIV works in the metabolism of glucagon-like peptide-1 (GLP-1). That is, DPPIV hydrolyzes the N-terminal His-Ala dipeptide of GLP-1.
While inactivating GLP-1, the inactivated form acts as an antagonist of the GLP-1 receptor.

  As physiological functions of GLP-1, an insulin secretion promoting action from the pancreas, a gastric emptying time extending action, and an eating suppression action are known. Therefore, inhibiting DPPIV is expected to increase the action of GLP-1, enhance insulin action and improve glucose metabolism, and is useful for the treatment of type 2 diabetes.

  DPPIV is also known to be involved in the metabolism of neuropeptide Y, a neuropeptide, activation of T cells, immunocompetent cells, adhesion of cancer cells to the endothelium, and entry of HIV virus into lymphocytes. Yes. Therefore, inhibition of DPPIV is considered useful for the treatment of immune diseases and the like.

  Also, high levels of DPPIV expression have been found in human skin fibroblasts of patients with psoriasis, rheumatoid arthritis and lichen planus, and high DPPIV activity has been found in patients with benign prostatic hypertrophy. ing. Therefore, inhibition of DPPIV is expected to be effective for skin diseases and benign prostatic hypertrophy.

  So far, cyanopyrrolidine derivatives (Patent Document 1), 4-fluoro-2-cyanopyrrolidine derivatives (Patent Document 2) and the like have been reported as DPPIV-inhibiting compounds.

International Publication No. 98/19998 Pamphlet International Publication No. 02/38541 Pamphlet

  An object of the present invention is to provide a medicament exhibiting excellent DPPIV inhibitory activity for preventing or treating a disease or condition that can be improved by inhibiting dipeptidyl peptidase IV.

  As a result of intensive studies, the present inventors have found that the cyanofluoropyrrolidine derivative represented by the formula (I) achieves the above object, and have completed the present invention.

  That is, according to one embodiment of the present invention, the present invention provides the following formula (I):

[Wherein, A represents a hydrogen atom or a fluorine atom, and R 1 and R 2 are the same or different and each may be substituted with one or more substituents selected from a hydrogen atom and substituent Y 1 group. 6 alkyl group, one or more cycloalkyl group carbon atoms which may be 3-6 substituted with a substituent selected from the substituent Y 2 group; one or more substituents selected from the substituent Y 2 group in the carbon atoms which may be 4-9 substituted cycloalkylalkyl group; substituted one or more alkenyl group having 2 to 6 carbon atoms which may be substituted with a substituent group selected from Y 2 groups; substituents Y 2 A C3-C6 cycloalkenyl group that may be substituted with one or more substituents selected from the group; a substituent Y that has 4 or more carbon atoms that may be substituted with one or more substituents selected from Group 2 or R 1 and the carbon atom to which R 2 is adjacent; 9 cycloalkenylalkyl group Together form one or more of good 3 to 10 carbon atoms optionally substituted by a substituted cycloalkyl group selected from the substituent Y 2 group, X represents a single bond or a 1 to 3 carbon atoms Represents an alkylene group, and R 3 has the formula —N (R 4 ) COR 5 , —N (R 4 ) SO 2 R 5 , —NR 4 R 6 , —SO 2 R 5 , —SO 2 NR 4 R 5 , -OCONR 4 R 5, -CH = CH -R 7,

Or a heteroaryl group containing at least one oxygen and / or sulfur and further containing a nitrogen atom and a 6-membered nitrogen-containing aromatic ring or a 9-11 membered condensed ring thereof in the selected is a heteroaryl group (the heteroaryl group may be substituted with one or more substituents selected from the substituent Y 3 group) shows (the above formulas, R 4 and R 6 are the same or different and each is hydrogen An atom; an alkyl group having 1 to 10 carbon atoms that may be substituted with one or more substituents selected from substituent Y 4 group; may be substituted with one or more substituents selected from substituent Y 2 group A good cycloalkyl group having 3 to 6 carbon atoms; a cycloalkylalkyl group having 4 to 9 carbon atoms which may be substituted with one or more substituents selected from substituent Y 2 group; or a substituent Y selected from group 3 May be substituted with one or more substituents An arylalkyl group, R 5 is an alkyl group having 1 to 10 carbon atoms which may be substituted with one or more substituents selected from substituent Y 4 group, or — (C 1-3 alkylene) — Q or Q, and C 1-3 alkylene may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group, and Q is one or more substituents selected from substituent Y 3 group. A cycloalkyl group having 3 to 10 carbon atoms which may be substituted with a substituent; a bridged ring alkyl group having 4 to 10 carbon atoms which may be substituted with one or more substituents selected from substituent Y 3 group; one or more substituted alkenyl group which may 2-10 carbon atoms substituted with a group selected from Y 3 group; substituents Y 3 1 or more carbon atoms 3 be substituted with a substituent selected from the group To 10 cycloalkenyl groups; selected from the substituent group Y 3 Selected from and one or more optionally substituted aryl group which may be substituted by a group selected from substituent group Y 3 group; 1 or more good 4-10 carbon atoms substituted by a substituent bridged ring alkenyl group that a is an aliphatic or aromatic hydrocarbon which either is; or substituted with one or more substituents selected from the substituent Y 5 group showed a heterocycle which may be, an aryl group or a hetero ring in R 5 is ring R 4 , R 5, or R 4 may be bonded together to form a 5- to 8-membered ring and may contain one or more heteroatoms in the ring. 6 , R 4 and R 5 , R 4 and R 6, and R 5 and R 6 may be substituted with one or more substituents selected from the substituent Y 5 group together with adjacent heteroatoms. may form a heterocyclic good 4-10 membered, R 7 is a hydrogen atom; a substituent Y 1 group Ri 1 or more even better 1 to 6 carbon atoms is substituted with a substituent alkyl group selected which can be substituted by one or more substituents selected from the substituent Y 3 group aryl group; or a substituent Y represents a heteroaryl group which may be substituted with one or more substituents selected from Group 3 . ), Substituent Y group 1 is a group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino group, an aminocarbonyl group, a cycloalkyloxy group having 3 to 5 carbon atoms, and an alkoxy group having 1 to 6 carbon atoms. The substituent Y 2 group is a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino group, an aminocarbonyl group, a cycloalkyloxy group having 3 to 5 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and 1 carbon atom. represents the group consisting of 6 alkyl group, the substituent Y 3 group, a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, -OR 9, -COR 9, -CO 2 R 9,
-CONR 9 R 10, -N (R 9) COR 10, -N (R 9) CONR 10 R 11,
-N (R 9) SO 2 R 10, -NR 9 R 10, -SO 2 R 9, -SO 2 NR 9 R 10,
—SO 2 N═CHNR 9 R 10 and —OCONR 9 R 10 (wherein R 9 , R 10 and R 11 are the same or different and are each a hydrogen atom; substituted with one or more substituents selected from substituent Y 1 group) is alkyl group of good 1 to 6 carbon atoms and; one or more are also a good 3 to 6 carbon atoms substituted with a substituted cycloalkyl group selected from the substituent Y 2 group; selected from the substituent Y 2 group shows a or a substituent one or more substituents phenyl group which may be substituted by a group selected from Y 2 groups; one or more substituted with a substituent carbon atoms which may 4-9 cycloalkylalkyl group. ), substituted with one or more substituents selected from one or more alkyl groups or substituents Y 2 group carbon atoms which may be 1-6 substituted with a substituent selected from the substituent Y 1 group represents the group consisting of a phenyl group, the substituent Y 4 group, a halogen atom, a hydroxyl , A cyano group, a nitro group, an amino group, -OR 9, -COR 9,
-CO 2 R 9, -CONR 9 R 10, -N (R 9) COR 10, -N (R 9) CONR 10 R 11,
-N (R 9) SO 2 R 10, -NR 9 R 10, -SO 2 R 9, -SO 2 NR 9 R 10,
—SO 2 N═CHNR 9 R 10 and —OCONR 9 R 10 (wherein R 9 , R 10 and R 11 are the same or different and are each a hydrogen atom; substituted with one or more substituents selected from substituent Y 1 group) is alkyl group of good 1 to 6 carbon atoms and; one or more are also a good 3 to 6 carbon atoms substituted with a substituted cycloalkyl group selected from the substituent Y 2 group; selected from the substituent Y 2 group shows a or a substituent one or more substituents phenyl group which may be substituted by a group selected from Y 2 groups; one or more substituted with a substituent carbon atoms which may 4-9 cycloalkylalkyl group. ) or show a group consisting of one or more substituents phenyl group which may be substituted by a group selected from the substituent Y 2 group. The substituents Y 5 group, oxo group, a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, -OR 9,
-COR 9, -CO 2 R 9, -CONR 9 R 10, -N (R 9) COR 10,
-N (R 9) CONR 10 R 11, -N (R 9) SO 2 R 10, -NR 9 R 10, -SO 2 R 9,
—SO 2 NR 9 R 10 , —SO 2 N═CHNR 9 R 10 and —OCONR 9 R 10 (wherein R 9 , R 10 and R 11 are the same or different and are a hydrogen atom; selected from the group of substituent Y 1 ) An alkyl group having 1 to 6 carbon atoms which may be substituted with one or more substituents; a cycloalkyl group having 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the group of substituent Y 2 ; substituted by or one or more substituents selected from the substituent Y 2 group; 1 or more cycloalkylalkyl group carbon atoms which may be 4-9 substituted with a substituent selected from the substituent Y 2 group A phenyl group which may be substituted.), One or more selected from the group of substituents Y 2 or an alkyl group having 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the substituent Y 1 group A group consisting of phenyl groups that may be substituted with substituents of Fluoropyrrolidine-compound or a medicament comprising as a pharmaceutically acceptable salt thereof or an active ingredient a hydrate thereof (referred to as "compound of the present invention" hereinafter).

  The compound according to the present invention can suppress dipeptidyl peptidase IV, and according to the present invention, it can provide a medicament for preventing or treating a disease or condition that can be improved by inhibiting dipeptidyl peptidase IV. It has become possible.

  According to another aspect of the present invention, the present invention provides a compound of the following formula (I-2)

(Wherein A, R 1 , R 2 , R 3 and X are as defined in formula (I)) or a salt thereof or a hydrate thereof as an active ingredient It is a medicine.

According to another aspect of the present invention, the present invention provides a compound of the formula (I) or the formula (I-2), wherein R 1 and R 2 are the same or different and are selected from the substituent Y 1 group. The compound which is a C1-C6 alkyl group which may be substituted by this, its salt, or those hydrates as an active ingredient.

According to another aspect of the present invention, the present invention provides a compound or a salt thereof, or a salt thereof, wherein R 1 and R 2 are a methyl group, an ethyl group or a hydroxymethyl group in formula (I) or formula (I-2) It is a medicine containing a hydrate as an active ingredient.

According to another aspect of the present invention, in the present invention, in the formula (I) or the formula (I-2), R 1 and R 2 are as defined in the formula (I), preferably a methyl group , An ethyl group or a hydroxymethyl group, more preferably a methyl group or a hydroxymethyl group, X is a methylene group or an ethylene group, R 3 is a formula —N (R 4 ) COR 5 , R 4 is a hydrogen atom; an alkyl group having 1 to 10 carbon atoms that may be substituted with one or more substituents selected from substituent Y 4 group; one or more substituents selected from substituent Y 2 group A cycloalkyl group having 3 to 6 carbon atoms which may be substituted with; or a cycloalkylalkyl group having 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the group 2 of substituent Y; R 4 is preferably a hydrogen atom; one or more selected from the group of substituent Y 4 An alkyl group having 1 to 10 carbon atoms that may be substituted with a substituent of the above; a cycloalkyl group having 3 to 6 carbon atoms that may be substituted with one or more substituents selected from the group 2 of substituent Y; More preferably, it is a hydrogen atom, and R 5 is an alkyl group having 1 to 10 carbon atoms which may be substituted with one or more substituents selected from substituent Y 4 group, or — (C 1-3 alkylene). -Q or Q, and C 1-3 alkylene may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group, and Q is one or more substituents selected from the group of substituent Y 3 A cycloalkyl group having 3 to 10 carbon atoms which may be substituted with a group; a bridged ring alkyl group having 4 to 10 carbon atoms which may be substituted with one or more substituents selected from substituent Y 3 group; optionally substituted with one or more substituents selected from the group Y 3 group Substituents Y 3 1 or more good 3 to 10 carbon atoms optionally substituted with a substituent selected from the group cycloalkenyl group; an alkenyl group which may C2-10 one selected from the substituent Y 3 group A bridged ring alkenyl group having 4 to 10 carbon atoms which may be substituted with the above substituents; and an aryl group which may be substituted with one or more substituents selected from group 3 of substituent Y The aryl group in R 5 may form a 5- to 8-membered ring by combining adjacent substituents bonded to atoms constituting the ring, and 1 in the ring. R 4 and R 5 , which may contain one or more heteroatoms, may be substituted with one or more substituents selected from the substituent Y 5 group together with adjacent heteroatoms. A compound or a salt thereof, which may form a member heterocycle. Is a medicine containing the hydrate thereof as an active ingredient.

According to another aspect of the present invention, in the present invention, in the formula (I) or the formula (I-2), R 1 and R 2 are as defined in the formula (I), preferably a methyl group , An ethyl group or a hydroxymethyl group, more preferably a methyl group or a hydroxymethyl group, X is a methylene group or an ethylene group, R 3 is a formula —N (R 4 ) COR 5 , R 4 is a hydrogen atom; an alkyl group having 1 to 10 carbon atoms that may be substituted with one or more substituents selected from substituent Y 4 group; one or more substituents selected from substituent Y 2 group A cycloalkyl group having 3 to 6 carbon atoms which may be substituted with; or a cycloalkylalkyl group having 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the group 2 of substituent Y; R 4 is preferably a hydrogen atom; one or more selected from the group of substituent Y 4 An alkyl group having 1 to 10 carbon atoms that may be substituted with a substituent of the above; a cycloalkyl group having 3 to 6 carbon atoms that may be substituted with one or more substituents selected from the group 2 of substituent Y; More preferably, it is a hydrogen atom, and R 5 is selected from a C 1-6 alkyl group which may be substituted with one or more substituents selected from substituent Y 1 group, or substituent Y 2 group. A pharmaceutical comprising a compound or a salt thereof or a hydrate thereof, which is a cycloalkyl group having 3 to 6 carbon atoms which may be substituted with one or more substituents, as an active ingredient.

According to another aspect of the present invention, in the present invention, in the formula (I) or the formula (I-2), R 1 and R 2 are as defined in the formula (I), preferably a methyl group , An ethyl group or a hydroxymethyl group, more preferably a methyl group or a hydroxymethyl group, X is a methylene group or an ethylene group, R 3 is a formula —N (R 4 ) COR 5 , R 4 is a hydrogen atom; an alkyl group having 1 to 10 carbon atoms that may be substituted with one or more substituents selected from substituent Y 4 group; one or more substituents selected from substituent Y 2 group A cycloalkyl group having 3 to 6 carbon atoms which may be substituted with; or a cycloalkylalkyl group having 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the group 2 of substituent Y; R 4 is preferably a hydrogen atom; one or more selected from the group of substituent Y 4 An alkyl group having 1 to 10 carbon atoms that may be substituted with a substituent of the above; a cycloalkyl group having 3 to 6 carbon atoms that may be substituted with one or more substituents selected from the group 2 of substituent Y; More preferably, it is a hydrogen atom, and R 5 is an aryl group which may be substituted with one or more substituents selected from the substituent Y 3 group, and the aryl group is adjacent to the atoms constituting the ring. Containing a compound or a salt thereof or a hydrate thereof as an active ingredient, which may form a 5- to 8-membered ring together with one or more heteroatoms in the ring. It is a medicine.

According to another aspect of the present invention, in the present invention, in the formula (I) or the formula (I-2), R 1 and R 2 are as defined in the formula (I), preferably a methyl group , An ethyl group or a hydroxymethyl group, more preferably a methyl group or a hydroxymethyl group, X is a methylene group or an ethylene group, R 3 is a formula —N (R 4 ) COR 5 , R 4 is a hydrogen atom; an alkyl group having 1 to 10 carbon atoms that may be substituted with one or more substituents selected from substituent Y 4 group; one or more substituents selected from substituent Y 2 group A cycloalkyl group having 3 to 6 carbon atoms which may be substituted with; or a cycloalkylalkyl group having 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the group 2 of substituent Y; R 4 is preferably a hydrogen atom; one or more selected from the group of substituent Y 4 An alkyl group having 1 to 10 carbon atoms that may be substituted with a substituent of the above; a cycloalkyl group having 3 to 6 carbon atoms that may be substituted with one or more substituents selected from the group 2 of substituent Y; More preferably, the compound is a hydrogen atom, and R 5 is a heteroaryl group which may be substituted with one or more substituents selected from the group of substituent Y 3 or a salt thereof or a hydrate thereof as an active ingredient As a pharmaceutical.

According to another aspect of the present invention, in the present invention, in the formula (I) or the formula (I-2), R 1 and R 2 are as defined in the formula (I), preferably a methyl group , An ethyl group or a hydroxymethyl group, more preferably a methyl group or a hydroxymethyl group, X is a methylene group or an ethylene group, R 3 is a formula —N (R 4 ) COR 5 , R 4 is a hydrogen atom; an alkyl group having 1 to 10 carbon atoms that may be substituted with one or more substituents selected from substituent Y 4 group; one or more substituents selected from substituent Y 2 group A cycloalkyl group having 3 to 6 carbon atoms which may be substituted with; or a cycloalkylalkyl group having 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the group 2 of substituent Y; R 4 is preferably a hydrogen atom; one or more selected from the group of substituent Y 4 An alkyl group having 1 to 10 carbon atoms that may be substituted with a substituent of the above; a cycloalkyl group having 3 to 6 carbon atoms that may be substituted with one or more substituents selected from the group 2 of substituent Y; More preferably, it is a hydrogen atom, and R 5 is a monocyclic heteroaryl group which may be substituted with one or more substituents selected from substituent Y 3 group, or a salt thereof, or a hydrate thereof. It is a medicine containing as an active ingredient.

According to another aspect of the present invention, in the present invention, in the formula (I) or the formula (I-2), R 1 and R 2 are as defined in the formula (I), preferably a methyl group , An ethyl group or a hydroxymethyl group, more preferably a methyl group or a hydroxymethyl group, X is a methylene group or an ethylene group, R 3 is a formula —N (R 4 ) COR 5 , R 4 is a hydrogen atom; an alkyl group having 1 to 10 carbon atoms that may be substituted with one or more substituents selected from substituent Y 4 group; one or more substituents selected from substituent Y 2 group A cycloalkyl group having 3 to 6 carbon atoms which may be substituted with; or a cycloalkylalkyl group having 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the group 2 of substituent Y; R 4 is preferably a hydrogen atom; one or more selected from the group of substituent Y 4 An alkyl group having 1 to 10 carbon atoms that may be substituted with a substituent of the above; a cycloalkyl group having 3 to 6 carbon atoms that may be substituted with one or more substituents selected from the group 2 of substituent Y; More preferably, it is a hydrogen atom, and R 5 is a thienyl group which may be substituted with one or more substituents selected from the group of substituent Y 3 or a salt thereof or a hydrate thereof as an active ingredient. It contains a medicine.

According to another aspect of the present invention, in the present invention, in the formula (I) or the formula (I-2), R 1 and R 2 are as defined in the formula (I), preferably a methyl group An ethyl group or a hydroxymethyl group, more preferably a methyl group or a hydroxymethyl group, X is a methylene group or an ethylene group, and R 3 is —N (R 4 ) SO 2 R 5 . , R 4 is a hydrogen atom; an alkyl group having 1 to 10 carbon atoms which may be substituted with one or more substituents selected from substituent Y 4 group; one or more substitutions selected from substituent Y 2 group is 1 or more has been carbon atoms which may 4-9 substituted with a substituent cycloalkylalkyl group selected from or a substituent Y 2 group; a cycloalkyl group having 3 to 6 carbon atoms which may be substituted with group , R 4 is preferably a hydrogen atom; one or more selected from the group of substituent Y 4 An alkyl group having 1 to 10 carbon atoms that may be substituted with a substituent of the above; a cycloalkyl group having 3 to 6 carbon atoms that may be substituted with one or more substituents selected from the group 2 of substituent Y; More preferably, it is a hydrogen atom, and R 5 is an alkyl group having 1 to 10 carbon atoms which may be substituted with one or more substituents selected from substituent Y 4 group, or — (C 1-3 alkylene). -Q or Q, and C 1-3 alkylene may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group, and Q is one or more substituents selected from the group of substituent Y 3 A cycloalkyl group having 3 to 10 carbon atoms which may be substituted with a group; a bridged ring alkyl group having 4 to 10 carbon atoms which may be substituted with one or more substituents selected from substituent Y 3 group; optionally substituted with one or more substituents selected from the group Y 3 group Substituents Y 3 1 or more good 3 to 10 carbon atoms optionally substituted with a substituent selected from the group cycloalkenyl group; an alkenyl group which may C2-10 one selected from the substituent Y 3 group A bridged ring alkenyl group having 4 to 10 carbon atoms which may be substituted with the above substituents; and an aryl group which may be substituted with one or more substituents selected from group 3 of substituent Y Or an aromatic hydrocarbon; or a heterocyclic ring which may be substituted with one or more substituents selected from substituent Y 5 group, and the aryl group or heterocyclic ring in R 5 constitutes a ring Adjacent substituents attached to an atom may be taken together to form a 5- to 8-membered ring and may contain one or more heteroatoms in the ring. R 4 and R 5 are Together with atoms, selected from the group of substituents Y 5 It is a medicament containing, as an active ingredient, a compound or a salt thereof or a hydrate thereof, which may form a 4- to 10-membered heterocyclic ring which may be substituted with one or more substituents.

According to another aspect of the present invention, in the present invention, in the formula (I) or the formula (I-2), R 1 and R 2 are as defined in the formula (I), preferably a methyl group An ethyl group or a hydroxymethyl group, more preferably a methyl group or a hydroxymethyl group, X is a methylene group or an ethylene group, and R 3 is —NR 4 R 6 (R 4 and R 6 is the same or different and is a hydrogen atom; an alkyl group having 1 to 10 carbon atoms which may be substituted with one or more substituents selected from substituent Y 4 group; one or more selected from substituent Y 2 group A cycloalkyl group having 3 to 6 carbon atoms which may be substituted with a substituent of the above; a cycloalkylalkyl group having 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the group 2 of substituent Y; or substituted with one or more substituents selected from the substituent Y 3 group Represents a good arylalkyl group, and R 4 and R 6 , together with the adjacent nitrogen atom, contain a 4 to 10-membered group which may be substituted with one or more substituents selected from the group of substituent Y 5 nitrogen may form a ring wherein, R 4 and R 6 are preferably the same or different and each represents a hydrogen atom;. may be substituted with one or more substituents selected from or a substituent Y 4 groups A 4- to 10-membered nitrogen-containing ring which is an alkyl group having 1 to 10 carbon atoms and may be substituted with one or more substituents selected from substituent Y 5 together with an adjacent nitrogen atom More preferably a hydrogen atom; or an alkyl group having 1 to 10 carbon atoms which may be substituted with one or more hydroxyl groups (preferably 1 to 3). A pharmaceutical comprising a salt or a hydrate thereof as an active ingredient.

According to another aspect of the present invention, in the present invention, in the formula (I) or the formula (I-2), R 1 and R 2 are as defined in the formula (I), preferably a methyl group , An ethyl group or a hydroxymethyl group, X represents a single bond or a methylene group, and R 3 represents
Formula —CH═CH—R 7 or

(Wherein R 7 is a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may be substituted with one or more substituents selected from substituent Y 1 group; one or more selected from substituent Y 3 group) aryl group which may be substituted with substituents;. which or one or more substituted with a substituent shown also heteroaryl groups) is a group represented by the compound or salt thereof selected from the substituent Y 3 group Or it is a pharmaceutical containing those hydrates as an active ingredient.

According to another aspect of the present invention, in the present invention, in the formula (I) or the formula (I-2), R 1 and R 2 are as defined in the formula (I), preferably a methyl group , Ethyl group or hydroxymethyl group, X represents a single bond or a methylene group, and R 3 may be substituted with one or more substituents selected from the substituent Y 3 group, A compound or a salt thereof, or a hydrate thereof, which is a 5-membered or 6-membered heteroaryl or an 8- to 11-membered condensed ring containing oxygen and / or sulfur and further containing a nitrogen atom, As a pharmaceutical.

According to another aspect of the present invention, in the present invention, in the formula (I) or the formula (I-2), R 1 and R 2 are as defined in the formula (I), preferably a methyl group A 6-membered nitrogen group, which is an ethyl group or a hydroxymethyl group, X represents a single bond or a methylene group, and R 3 may be substituted with one or more substituents selected from the group of substituent Y 3 A pharmaceutical comprising a compound or a salt thereof or a hydrate thereof, which is an aromatic ring or a 9-11 membered condensed ring thereof, as an active ingredient.

  According to another aspect of the present invention, the present invention provides a medicament comprising any one of the above cyanofluoropyrrolidine compounds or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient.

  According to another aspect of the present invention, the present invention provides the aforementioned medicament for preventing or treating a disease or condition that can be ameliorated by inhibiting dipeptidyl peptidase IV.

  According to another aspect of the present invention, the present invention provides the aforementioned medicament, wherein the disease or condition that can be ameliorated by inhibiting dipeptidyl peptidase IV is diabetes.

According to another aspect of the present invention, the present invention provides the aforementioned medicament, wherein the disease or condition that can be ameliorated by inhibiting dipeptidyl peptidase IV is an immune disease.
According to another aspect of the present invention, there is provided a therapeutic agent for diabetes or a therapeutic agent for immune diseases comprising the compound according to the present invention as an active ingredient.
The present invention will be described in detail, but is not particularly limited to those exemplified.
The following selected functional group definitions and examples thereof are used throughout the specification and claims, but are provided for purposes of illustration and not limitation.

  The optionally substituted alkyl group having 1 to 6 carbon atoms represents a substituted or unsubstituted linear or branched alkyl group having 1 to 6 carbon atoms. The substituent of the alkyl group having 1 to 6 carbon atoms is a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino group, an aminocarbonyl group, a cycloalkyloxy group having 3 to 5 carbon atoms, and an alkoxy having 1 to 6 carbon atoms. 1 or more (for example, 1 to 6, preferably 1 to 4, more preferably 1 to 2) selected from the group consisting of groups is shown. Examples of preferred substituents include a halogen atom and a hydroxyl group. Such alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 1-ethylpropyl, trifluoro Examples thereof include a methyl group, 2-chloroethyl group, hydroxymethyl group, 2-cyanopropyl group, 2-aminoethyl group, 4-carboxybutyl group, aminocarbonylmethyl group and the like.

  A halogen atom shows a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

  Examples of the cycloalkyloxy group having 3 to 5 carbon atoms include a cyclopropyloxy group, a cyclobutyloxy group, and a cyclopentyloxy group.

  A C1-C6 alkoxy group shows a linear or branched C1-C6 alkoxy group. Examples of the alkoxy group include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group and the like.

  The C3-C6 cycloalkyl group which may be substituted represents a substituted or unsubstituted C3-C6 cycloalkyl group. The substituent of a C3-C6 cycloalkyl group is a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino group, an aminocarbonyl group, a C1-C6 alkyl group, and a C3-C5 cycloalkyl. 1 or more (for example, 1-6 pieces, preferably 1-4 pieces, more preferably 1-2 pieces) chosen from the group which consists of an oxy group and a C1-C6 alkoxy group is shown. Examples of such a cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a 3-cyanocyclobutyl group, a 2-aminocyclopropyl group, a 4-fluorocyclohexyl group, a 3,4-dihydroxycyclopentyl group, Examples thereof include 2-carboxycyclopropyl group and 3-aminocarbonylcyclobutyl group.

  The C4-C9 cycloalkylalkyl group which may be substituted is a group in which a C3-C6 cycloalkyl group which may be substituted and a C1-C3 alkylene group which may be substituted are bonded. Indicates. Examples of such a cycloalkylalkyl group include a cyclopropylmethyl group, a cyclobutylmethyl group, a 2-cyclopentylethyl group, a cyclohexylmethyl group, a 3-cyanocyclobutylmethyl group, a 1- (2-aminocyclopropyl) ethyl group, Examples include 3- (4-fluorocyclohexyl) propyl group, 3,4-dihydroxycyclopentylmethyl group, 2- (2-carboxycyclopropyl) propyl group, (3-aminocarbonylcyclobutyl) methyl group, and the like.

  A C1-C3 alkylene group shows a linear or branched C1-C3 alkylene group. The C1-C3 alkylene group which may be substituted shows a substituted or unsubstituted linear or branched C1-C3 alkylene group. The substituent in the alkylene group represents one or more groups selected from the group consisting of a halogen atom and a hydroxyl group. Examples of such an alkylene group include a methylene group, an ethylene group, a propylene group, a hydroxymethylene group, and a 2-bromopropylene group.

  The C2-C6 alkenyl group which may be substituted represents a substituted or unsubstituted linear or branched alkenyl group having 2-6 carbon atoms. The substituent in the alkenyl group is a halogen atom, hydroxyl group, carboxyl group, cyano group, amino group, aminocarbonyl group, cycloalkyloxy group having 3 to 5 carbon atoms, alkoxy group having 1 to 6 carbon atoms, and 1 to 1 carbon atoms. 1 or more (for example, 1 to 6, preferably 1 to 4, more preferably 1 to 2) selected from the group consisting of 6 alkyl groups. Such alkenyl groups include vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, pentenyl, 2-chlorovinyl, A 3-hydroxypropenyl group, a 3-carboxypropenyl group, a 3-amino-2-cyanobutenyl group, a 3-ethoxyisobutenyl group and the like can be mentioned.

  The C3-C6 cycloalkenyl group that may be substituted represents a substituted or unsubstituted C3-C6 cycloalkenyl group. The substituent in the cycloalkenyl group is a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino group, an aminocarbonyl group, an alkyl group having 1 to 6 carbon atoms, a cycloalkyloxy group having 3 to 5 carbon atoms, and 1 carbon atom. 1 or more (for example, 1 to 6, preferably 1 to 4, more preferably 1 to 2) selected from the group consisting of ˜6 alkoxy groups. Such cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, 3-hydroxycyclopropenyl, 3-carboxycyclopropenyl, 3-amino-2-cyanocyclobutenyl, 3-ethoxycyclo And a butenyl group.

  The optionally substituted cycloalkenylalkyl group having 4 to 9 carbon atoms is a group in which an optionally substituted cycloalkenyl group having 3 to 6 carbon atoms and an optionally substituted alkylene group having 1 to 3 carbon atoms are bonded. Indicates. Examples of such cycloalkenylalkyl groups include 2-cyanocyclobutenylmethyl group and 3-methoxycyclopropenylmethyl group.

An optionally substituted cycloalkyl group having 3 to 10 carbon atoms formed by R 1 and R 2 together with adjacent carbon atoms is a substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms. . The substituent in the cycloalkyl group is a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino group, an aminocarbonyl group, an alkyl group having 1 to 6 carbon atoms, a cycloalkyloxy group having 3 to 5 carbon atoms, and 1 carbon atom. 1 or more (for example, 1 to 6, preferably 1 to 4, more preferably 1 to 2) selected from the group consisting of ˜6 alkoxy groups. Such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bromocyclopropyl, 2-ethyl-3-hydroxycyclohexyl, 3-amino-2 -Cyanocyclobutyl group, 4-methoxycyclooctyl group and the like.

The heteroaryl group containing at least one oxygen and / or sulfur and further containing a nitrogen atom is, for example, containing at least one oxygen and / or sulfur and further containing a nitrogen atom. Or a 5- or 6-membered heteroaryl or an 8-11 membered fused ring thereof. Examples include furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, benz Oxazolyl group, benzisoxazolyl group, benzothiazolyl group, benzisothiazolyl group, thianaphthenyl group, isothianaphthenyl group, benzofuranyl group, isobenzofuranyl group, benzothienyl group, chromenyl group, 2,1,3 -Benzoxadiazolyl group, benzoxazinyl group and the like. From the viewpoint of sustained DPPIV inhibitory activity, a monocyclic group is preferable, and examples thereof include a furyl group and a thienyl group. A more preferred example is a furyl group. The substituent of the heteroaryl group containing at least one oxygen and / or sulfur and further containing a nitrogen atom is a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, —OR 9 , — COR 9, -CO 2 R 9, -CONR 9 R 10,
-N (R 9) COR 10, -N (R 9) CONR 10 R 11, -N (R 9) SO 2 R 10,
-NR 9 R 10 , -SO 2 R 9 , -SO 2 NR 9 R 10 , -SO 2 N = CHNR 9 R 10 and -OCONR 9 R 10 (wherein R 9 , R 10 and R 11 are the same or different) A hydrogen atom; an optionally substituted alkyl group having 1 to 6 carbon atoms; an optionally substituted cycloalkyl group having 3 to 6 carbon atoms; an optionally substituted cycloalkylalkyl group having 4 to 9 carbon atoms; 1 or more selected from the group consisting of an optionally substituted alkyl group having 1 to 6 carbon atoms or an optionally substituted phenyl group (for example, 1 to 6, preferably Represents 1 to 4, more preferably 1 to 2). Substituted examples of heteroaryl groups containing at least one oxygen and / or sulfur and optionally containing a nitrogen atom include a 4-methyl-1,2,3-thiadiazol-5-yl group, Examples include 3- (2-chlorophenyl) -5-methyl-isoxazol-4-yl group and 5-methyl-2-trifluoromethylfuran-3-yl group.

  The phenyl group which may be substituted refers to a substituted or unsubstituted phenyl group. The substituent in the phenyl group is a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino group, an aminocarbonyl group, a cycloalkyloxy group having 3 to 5 carbon atoms, an alkoxy group having 1 to 6 carbon atoms and 1 to 1 carbon atoms. 1 or more (for example, 1 to 6, preferably 1 to 4, more preferably 1 to 2) selected from the group consisting of 6 alkyl groups. Examples of such a phenyl group include a phenyl group and a 3-aminocarbonyl-4-bromophenyl group.

A 6-membered nitrogen-containing aromatic ring or a 9-11 membered condensed ring thereof includes pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3 , 5-triazinyl group, isoquinolyl group, quinolyl group, phthalazinyl group, quinoxalinyl group, quinazolinyl group, cinnolinyl group and the like. Monocyclic groups are preferred, and pyridyl groups are more preferred. The substituent of heteroaryl consisting of a 6-membered nitrogen-containing aromatic ring or a 9-11 membered condensed ring thereof is a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, -OR 9 ,
-COR 9, -CO 2 R 9, -CONR 9 R 10, -N (R 9) COR 10,
-N (R 9) CONR 10 R 11, -N (R 9) SO 2 R 10, -NR 9 R 10, -SO 2 R 9,
—SO 2 NR 9 R 10 , —SO 2 N═CHNR 9 R 10 and —OCONR 9 R 10 , wherein R 9 , R 10 and R 11 are the same or different and are hydrogen atoms; A cycloalkyl group having 3 to 6 carbon atoms which may be substituted; a cycloalkylalkyl group having 4 to 9 carbon atoms which may be substituted or a phenyl group which may be substituted; 1 or more selected from the group consisting of an optionally substituted alkyl group having 1 to 6 carbon atoms or an optionally substituted phenyl group (for example, 1 to 6, preferably 1 to 4, more preferably 1 ~ 2). Examples of substituted 6-membered nitrogen-containing aromatic rings or 9- to 11-membered condensed rings thereof include 5-cyanopyridin-2-yl group and 6- (aminocarbonyl) quinoxalin-2-yl group.

The optionally substituted alkyl group having 1 to 10 carbon atoms represents a substituted or unsubstituted linear or branched alkyl group having 1 to 10 carbon atoms. The substituent in the alkyl group is a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, —OR 9 , —COR 9 , —CO 2 R 9 ,
-CONR 9 R 10, -N (R 9) COR 10, -N (R 9) CONR 10 R 11,
-N (R 9) SO 2 R 10, -NR 9 R 10, -SO 2 R 9, -SO 2 NR 9 R 10,
—SO 2 N═CHNR 9 R 10 and —OCONR 9 R 10 (wherein R 9 , R 10 and R 11 are the same or different and represent a hydrogen atom; an optionally substituted alkyl group having 1 to 6 carbon atoms; An optionally substituted cycloalkyl group having 3 to 6 carbon atoms; an optionally substituted cycloalkylalkyl group having 4 to 9 carbon atoms; or an optionally substituted phenyl group.) Or an optionally substituted phenyl group 1 or more (for example, 1 to 6, preferably 1 to 4, more preferably 1 to 2) selected from the group consisting of: Examples of such an alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, a heptyl group, and an octyl group. , Nonyl group, decyl group, 2-hydroxyethyl group, aminocarbonylmethyl group, cyanomethyl group, chloroethyl group, 3- (N, N-dimethylamino) propyl group, 4- (methanesulfonylamino) butyl group, 2-dimethyl And an amido-4-hydroxyheptyl group.

  The arylalkyl group which may be substituted refers to a group in which an aryl group which may be substituted and an alkylene group having 1 to 3 carbon atoms which may be substituted are bonded. Such arylalkyl groups include benzyl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl, 2- (1-naphthyl) ethyl, 2- (2-naphthyl) ethyl, 3- ( 2-naphthyl) propyl group, 4-cyanobenzyl group, 2- (3-dimethylaminophenyl) -1-hydroxyethyl group and the like.

The cycloalkyl group having 3 to 10 carbon atoms that may be substituted represents a substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms. Examples of the substituent in the cycloalkyl group include a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, —OR 9 , —COR 9 , —CO 2 R 9 ,
-CONR 9 R 10, -N (R 9) COR 10, -N (R 9) CONR 10 R 11,
-N (R 9) SO 2 R 10, -NR 9 R 10, -SO 2 R 9, -SO 2 NR 9 R 10,
—SO 2 N═CHNR 9 R 10 and —OCONR 9 R 10 (wherein R 9 , R 10 and R 11 are the same or different and represent a hydrogen atom; an optionally substituted alkyl group having 1 to 6 carbon atoms; An optionally substituted cycloalkyl group having 3 to 6 carbon atoms; an optionally substituted cycloalkylalkyl group having 4 to 9 carbon atoms; or an optionally substituted phenyl group.), An optionally substituted carbon number 1 1-6 or more (for example, 1-6, Preferably, 1-4, More preferably, 1-2) chosen from the group which consists of a -6 alkyl group or the phenyl group which may be substituted is shown. Such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- (acetylamino) cyclopentyl, 4- (N, N-dimethylaminocarbonyloxy). ) Cyclohexyl group, 3-ethylsulfonyl-4-methoxycyclohexyl group and the like.

In-(C 1 -C 3 alkylene) -Q, examples of the case where Q is an optionally substituted cycloalkyl group having 3 to 10 carbon atoms include cyclopropylmethyl group, cyclopropylethyl group, cyclobutylmethyl Group, cyclopentylmethyl group, cyclohexylmethyl group and the like.

The optionally substituted bridged ring alkyl group having 4 to 10 carbon atoms represents a substituted or unsubstituted bridged ring alkyl group having 4 to 10 carbon atoms. The substituent in the bridged ring alkyl group is a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, —OR 9 , —COR 9 , —CO 2 R 9 ,
-CONR 9 R 10, -N (R 9) COR 10, -N (R 9) CONR 10 R 11,
-N (R 9) SO 2 R 10, -NR 9 R 10, -SO 2 R 9, -SO 2 NR 9 R 10,
—SO 2 N═CHNR 9 R 10 and —OCONR 9 R 10 (wherein R 9 , R 10 and R 11 are the same or different and represent a hydrogen atom; an optionally substituted alkyl group having 1 to 6 carbon atoms; An optionally substituted cycloalkyl group having 3 to 6 carbon atoms; an optionally substituted cycloalkylalkyl group having 4 to 9 carbon atoms; or an optionally substituted phenyl group.), An optionally substituted carbon number 1 1-6 or more (for example, 1-6, Preferably, 1-4, More preferably, 1-2) chosen from the group which consists of a -6 alkyl group or the phenyl group which may be substituted is shown. Examples of such a bridging ring alkyl group include a bicyclopentyl group, a bicyclohexyl group, a bicycloheptyl group, a bicyclooctyl group, a bicyclodecyl group, a bicyclodecyl group, an adamantyl group, a bornyl group, a norbornyl group, a pinanyl group, a tuyoyl group, Examples thereof include a carbyl group, a carphanyl group, a 2-hydroxyadamantyl group, and a 3-methylbicyclopentyl group.

The C2-C10 alkenyl group which may be substituted represents a substituted or unsubstituted linear or branched C2-C10 alkenyl group. The substituent in the alkenyl group is a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, —OR 9 , —COR 9 , —CO 2 R 9 , —CONR 9 R 10 , —N (R 9 ) COR 10. , -N (R 9) CONR 10 R 11,
-N (R 9) SO 2 R 10, -NR 9 R 10, -SO 2 R 9, -SO 2 NR 9 R 10,
—SO 2 N═CHNR 9 R 10 and —OCONR 9 R 10 (wherein R 9 , R 10 and R 11 are the same or different and represent a hydrogen atom; an optionally substituted alkyl group having 1 to 6 carbon atoms; An optionally substituted cycloalkyl group having 3 to 6 carbon atoms; an optionally substituted cycloalkylalkyl group having 4 to 9 carbon atoms; or an optionally substituted phenyl group.), An optionally substituted carbon number 1 1-6 or more (for example, 1-6, Preferably, 1-4, More preferably, 1-2) chosen from the group which consists of a -6 alkyl group or the phenyl group which may be substituted is shown. Such alkenyl groups include vinyl, allyl, 1-propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, 4-acetylamino-2-cyanoheptenyl Etc.

The C3-C10 cycloalkenyl group which may be substituted refers to a substituted or unsubstituted C3-C10 cycloalkenyl group. The substituent in the cycloalkenyl group is a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, —OR 9 , —COR 9 , —CO 2 R 9 ,
-CONR 9 R 10, -N (R 9) COR 10, -N (R 9) CONR 10 R 11,
-N (R 9) SO 2 R 10, -NR 9 R 10, -SO 2 R 9, -SO 2 NR 9 R 10,
—SO 2 N═CHNR 9 R 10 and —OCONR 9 R 10 (wherein R 9 , R 10 and R 11 are the same or different and represent a hydrogen atom; an optionally substituted alkyl group having 1 to 6 carbon atoms; An optionally substituted cycloalkyl group having 3 to 6 carbon atoms; an optionally substituted cycloalkylalkyl group having 4 to 9 carbon atoms; or an optionally substituted phenyl group.), An optionally substituted carbon number 1 1-6 or more (for example, 1-6, Preferably, 1-4, More preferably, 1-2) chosen from the group which consists of a -6 alkyl group or the phenyl group which may be substituted is shown. Examples of such cycloalkenyl groups include a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, a cyclooctenyl group, and a 3- (N, N-dimethylureido) cyclohexenyl group.

In-(C 1 -C 3 alkylene) -Q, examples of the case where Q is an optionally substituted cycloalkenyl group having 3 to 10 carbon atoms include a cyclobutenylmethyl group, a cyclopentenylmethyl group, a cyclohexenyl A methyl group etc. are mentioned.

The optionally substituted bridged alkenyl group having 4 to 10 carbon atoms represents a substituted or unsubstituted bridged ring alkenyl group having 4 to 10 carbon atoms. The substituent in the bridged ring alkenyl group includes a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, —OR 9 , —COR 9 ,
-CO 2 R 9, -CONR 9 R 10, -N (R 9) COR 10, -N (R 9) CONR 10 R 11,
-N (R 9) SO 2 R 10, -NR 9 R 10, -SO 2 R 9, -SO 2 NR 9 R 10,
—SO 2 N═CHNR 9 R 10 and —OCONR 9 R 10 (wherein R 9 , R 10 and R 11 are the same or different and represent a hydrogen atom; an optionally substituted alkyl group having 1 to 6 carbon atoms; An optionally substituted cycloalkyl group having 3 to 6 carbon atoms; an optionally substituted cycloalkylalkyl group having 4 to 9 carbon atoms; or an optionally substituted phenyl group.), An optionally substituted carbon number 1 1-6 or more (for example, 1-6, Preferably, 1-4, More preferably, 1-2) chosen from the group which consists of a -6 alkyl group or the phenyl group which may be substituted is shown. Examples of such a bridged ring alkenyl group include a bicyclopentenyl group, a bicyclohexenyl group, a bicycloheptenyl group, a bicyclooctenyl group, a bicyclononel group, a bicyclodecel group, a 2-cyanobicyclooctenyl group, and a 2-chlorobicyclononel group. Etc.

The aryl group which may be substituted refers to a substituted or unsubstituted aryl group. The substituent in the aryl group is a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, —OR 9 , —COR 9 , —CO 2 R 9 , —CONR 9 R 10 , —N (R 9 ) COR 10. ,
-N (R 9) CONR 10 R 11, -N (R 9) SO 2 R 10, -NR 9 R 10, -SO 2 R 9,
—SO 2 NR 9 R 10 , —SO 2 N═CHNR 9 R 10 and —OCONR 9 R 10 , wherein R 9 , R 10 and R 11 are the same or different and are hydrogen atoms; A cycloalkyl group having 3 to 6 carbon atoms which may be substituted; a cycloalkylalkyl group having 4 to 9 carbon atoms which may be substituted or a phenyl group which may be substituted; 1 or more selected from the group consisting of an optionally substituted alkyl group having 1 to 6 carbon atoms or an optionally substituted phenyl group (for example, 1 to 6, preferably 1 to 4, more preferably 1 ~ 2). Such aryl groups include phenyl, naphthyl, 3,4-methylenedioxyphenyl, 3- (methylsulfonyl) phenyl, 2-trifluoromethylphenyl, 3-cyanophenyl, 2-fluoro Phenyl group, 2-ethoxynaphthyl group, 2-dimethylaminophenyl group, 3-butylsulfonylaminonaphthyl group, 2-carboxyphenyl group, 3,4-dimethoxyphenyl group, 4-[(N, N-dimethylaminomethylene) Aminosulfonyl] phenyl group and the like.

In-(C 1 -C 3 alkylene) -Q, examples where Q is an aryl group which may be substituted include benzyl group, phenethyl group, 3-phenylpropyl group, 1-naphthylmethyl group, 2- (1-naphthyl) ethyl group, 2- (2-naphthyl) ethyl group, 3- (2-naphthyl) propyl group, 4-cyanobenzyl group, 2- (3-dimethylaminophenyl) -1-hydroxyethyl group, etc. Is mentioned.

  An optionally substituted 4-10 membered heterocycle, unless otherwise specified, contains one or more heteroatoms selected from O, S and N and has 4-10 atoms in the ring system Heterocycle means aromatic or non-aromatic (saturated or unsaturated) monocyclic and polycyclic groups. The aromatic heterocycle is also referred to herein as heteroaryl, and will be described later as heteroaryl. The heterocycle can be C-attached or N-attached if it can be C-attached or N-attached.

  The heterocyclic ring of the present invention is preferably a monocyclic heterocyclic ring from the viewpoint of sustained DPPIV inhibitory activity.

The substituent in the heterocyclic ring is an oxo group, a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, —OR 9 , —COR 9 , —CO 2 R 9 , —CONR 9 R 10 , —N (R 9 ) COR 10, -N (R 9 ) CONR 10 R 11, -N (R 9) SO 2 R 10, -NR 9 R 10, -SO 2 R 9,
—SO 2 NR 9 R 10 , —SO 2 N═CHNR 9 R 10 and —OCONR 9 R 10 (wherein R 9 , R 10 and R 11 are the same or different and represent a hydrogen atom; -6 alkyl group; an optionally substituted cycloalkyl group having 3 to 6 carbon atoms; or an optionally substituted cycloalkyl alkyl group having 4 to 9 carbon atoms or an optionally substituted phenyl group. One or more selected from the group consisting of an optionally substituted alkyl group having 1 to 6 carbon atoms or an optionally substituted phenyl group (for example, 1 to 6, preferably 1 to 4, more preferably, 1-2). Such non-aromatic heterocycles include aziridinyl group, azetidinyl group, pyrrolidinyl group, imidazolidinyl group, oxazolidinyl group, thiazolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, azabicycloheptyl group, azabicyclooctyl group, 2, 6-dimethylmorpholino group, 4-cyanopiperidinyl group, diketopiperazinyl group, 2-oxopiperidinyl group, 1,1-dioxo-isothiazolidinyl group, 1,1-dioxo-thiadinanyl group, Examples include 1,1-dioxo-thiazepanyl group.

The heteroaryl group which may be substituted refers to a substituted or unsubstituted heteroaryl group. The substituent in the heteroaryl group is a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, —OR 9 , —COR 9 , —CO 2 R 9 , —CONR 9 R 10 , —N (R 9 ) COR. 10 ,
-N (R 9) CONR 10 R 11, -N (R 9) SO 2 R 10, -NR 9 R 10, -SO 2 R 9,
—SO 2 NR 9 R 10 , —SO 2 N═CHNR 9 R 10 and —OCONR 9 R 10 (wherein R 9 , R 10 and R 11 are the same or different and represent a hydrogen atom; -6 alkyl group; an optionally substituted cycloalkyl group having 3 to 6 carbon atoms; or an optionally substituted cycloalkyl alkyl group having 4 to 9 carbon atoms or an optionally substituted phenyl group. One or more selected from the group consisting of an optionally substituted alkyl group having 1 to 6 carbon atoms or an optionally substituted phenyl group (for example, 1 to 6, preferably 1 to 4, more preferably, 1-2). Such heteroaryl groups include pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, 1,3,5-oxadiazolyl 1,2,4-oxadiazolyl group, 1,2,4-thiadiazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, 1,2,4-triazinyl group, 1,2,3-triazinyl group, 1 , 3,5-triazinyl group, benzoxazolyl group, benzisoxazolyl group, benzothiazolyl group, benzoisothiazolyl group, benzimidazolyl group, thianaphthenyl group, isothianaphthenyl group, benzofuranyl group, isobenzofuranyl group, Benzothienyl group, chromenyl group, isoindolyl group, indolyl group, indazolyl group, Lyl group, quinolyl group, phthalazinyl group, quinoxalinyl group, quinazolinyl group, cinnolinyl group, 2,1,3-benzoxadiazolyl group, benzoxazinyl group, 4-methyl-1,2,3-thiadiazol-5-yl group, 3- (2-chlorophenyl) -5-methyl-isoxazol-4-yl group, 5-methyl-2-phenyl-1,2,3-triazol-4-yl group, 2-phenyl-3-propyl-pyrazole- Examples include 4-yl group, 5-methyl-2-trifluoromethylfuran-3-yl group, 5-cyanopyridin-2-yl group, and 6- (aminocarbonyl) quinoxalin-2-yl group.

In-(C 1 -C 3 alkylene) -Q, examples of the case where Q is a heteroaryl group which may be substituted include a 2-furylmethyl group and a 3-isoxazolylmethyl group.

In the aryl group or heterocycle for R 5 , a 5- to 8-membered ring that may contain one or more heteroatoms in the ring, which is formed by combining adjacent substituents bonded to atoms constituting the ring, In addition, a 5- to 8-membered ring formed by the adjacent substituents taken together to form an alkyleneoxy group or an alkylenedioxy group together with adjacent atoms constituting an aryl group or a heterocyclic ring is preferable. Examples include 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 2,3-dihydrobenzo [b] furan-5-yl and the like.

The “optionally substituted 4- to 10-membered nitrogen-containing ring formed together with the adjacent nitrogen atom” in R 4 and R 6 has one or more nitrogen atoms in the ring, and Means a substituted or unsubstituted cyclic amino group in which one or more oxygen atoms or sulfur atoms may exist, for example, aziridinyl group, azetidinyl group, pyrrolidinyl group, imidazolidinyl group, oxazolidinyl group, thiazolidinyl group, piperidinyl group, piperazinyl And cyclic amino groups such as a group, morpholinyl group, azabicycloheptyl group and azabicyclooctyl group. In addition, the substituent in the 4- to 10-membered nitrogen-containing ring is an oxo group, a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, —OR 9 , —COR 9 , —CO 2 R 9 , —CONR. 9 R 10 ,
-N (R 9) COR 10, -N (R 9) CONR 10 R 11, -N (R 9) SO 2 R 10,
—NR 9 R 10 , —SO 2 R 9 , —SO 2 NR 9 R 10 , —SO 2 N═CHNR 9 R 10 and —OCONR 9 R 10 (wherein R 9 , R 10 and R 11 are the same or different) A hydrogen atom; an optionally substituted alkyl group having 1 to 6 carbon atoms; an optionally substituted cycloalkyl group having 3 to 6 carbon atoms; an optionally substituted cycloalkylalkyl group having 4 to 9 carbon atoms; or A phenyl group which may be substituted; and a group consisting of an optionally substituted alkyl group having 1 to 6 carbon atoms or an optionally substituted phenyl group.

  “Pharmaceutically acceptable salt” is a salt with a mineral acid or an organic acid, for example, acetate, propionate, butyrate, formate, trifluoroacetate, maleate, tartrate. Citrate, stearate, succinate, ethyl succinate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate , Benzenesulfonate, paratoluenesulfonate, lauryl sulfate, malate, aspartate, glutamate, adipate, salt with cysteine, salt with N-acetylcysteine, hydrochloride, hydrogen bromide Acid salt, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoate, acrylic acid polymer and Salts, and salts with carboxyvinyl polymers.

  Certain compounds according to the invention have asymmetric centers and therefore exist in various enantiomeric forms. All optical isomers and stereoisomers of the compounds of the present invention and mixtures thereof are within the scope of the present invention. The present invention includes racemates, one or more enantiomers, one or more diastereomers, or mixtures thereof of the compounds according to the invention. Some of the compounds according to the invention also exist, for example, as keto-enol tautomers. The present invention includes all such tautomers and mixtures thereof.

The preferable aspect of the compound based on this invention is shown.
In the compound in which R 3 is —N (R 4 ) COR 5 (R 5 is an optionally substituted aryl group), a preferred embodiment of R 5 is a substituted or unsubstituted phenyl group, and a phenyl group is preferred. The substituent is a nitro group, a cyano group, a hydroxyl group, a C 1-6 alkyl group substituted with a halogen atom (preferably a fluorine atom or a chlorine atom) (for example, —CF 3 , —CCl 3 ),
-COR 9, -CO 2 R 9, -SO 2 R 9, -SO 2 NR 9 R 10,
-SO 2 N = CHNR 9 R 10 (R 9 and R 10 are the same or different and represent a hydrogen atom, an alkyl group or a phenyl group having 1 to 6 carbon atoms), an alkyl group having 1 to 6 carbon atoms, a halogen atom And 1 or more selected from the group consisting of alkoxy groups having 1 to 6 carbon atoms (for example, 1 to 6, preferably 1 to 4, more preferably 1 to 2).

Further, as a preferred substituent of the phenyl group of R 5 , an alkyleneoxy group having 2 to 3 carbon atoms (an ethyleneoxy group, a propyleneoxy group, or the like) together with a substituent bonded to adjacent atoms constituting the phenyl group Or a C1-C3 alkylenedioxy group (methylenedioxy group, ethylenedioxy group, etc.), which includes a 5- to 8-membered ring formed together with the adjacent atoms constituting the phenyl group. Examples include 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 2,3-dihydrobenzo [b] furan-5-yl and the like.

From the viewpoint of sustained DPPIV inhibitory activity, R 5 is preferably a substituted or unsubstituted phenyl group, and preferred substituents of the phenyl group are a nitro group, a cyano group, a hydroxyl group, a halogen atom (preferably a fluorine atom, A C 1-6 alkyl group (for example, a chlorine atom)
-CF 3, -CCl 3), - COR 9, -CO 2 R 9, -SO 2 R 9 (R 9 is a hydrogen atom, an alkyl group or a phenyl group having 1 to 6 carbon atoms), C 1 -C 1 or more (for example, 1 to 6, preferably 1 to 4, more preferably 1 to 2) selected from the group consisting of ˜6 alkyl groups and halogen atoms, or adjacent groups constituting a phenyl group 5 to 8 members formed together with the adjacent atoms constituting the phenyl group, the substituents bonded to the atoms to form together form an alkyleneoxy group having 2 to 3 carbon atoms or an alkylenedioxy group having 1 to 3 carbon atoms. It is a ring.

Preferred specific compounds of the above embodiment include the following.
(2S, 4S) -2-cyano-4-fluoro-1-[[2- (3,4-methylenedioxybenzoyl) amino-1,1-dimethyl] ethylamino] acetylpyrrolidine
(2S, 4S) -2-Cyano-4-fluoro-1-[[2- [3- (methylsulfonyl) benzoyl] amino-1,1-dimethyl] ethylamino] acetylpyrrolidine
(2S, 4S) -2-cyano-1-[[2- (3-cyanobenzoyl) amino-1,1-dimethyl] ethylamino] acetyl-4-fluoropyrrolidine
(2S, 4S) -2-cyano-4-fluoro-1-[[2- (2-fluorobenzoyl) amino-1,1-dimethyl] ethylamino] acetylpyrrolidine
(2S, 4S) -1-[(2-Benzoylamino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine
(2S, 4S) -2-cyano-1-[[2- (2,3-dihydrobenzo [b] furan-5-yl) carbonylamino-1,1-dimethyl] ethylamino] acetyl-4-fluoropyrrolidine In the compound in which R 3 is —N (R 4 ) COR 5 (R 5 is an optionally substituted heteroaryl group), from the viewpoint of sustained DPPIV inhibitory activity, a preferred embodiment of R 5 is substituted or An unsubstituted monocyclic heteroaryl group, more preferably a thienyl group.

As preferred substituents for the heteroaryl group of R 5 , a C 1-6 alkyl group substituted with a nitro group, a cyano group, a hydroxyl group, or a halogen atom (preferably a fluorine atom or a chlorine atom) (for example, —CF 3 , — CCl 3), - COR 9, -CO 2 R 9, -SO 2 R 9, -SO 2 NR 9 R 10,
—SO 2 N═CHNR 9 R 10 (R 9 and R 10 are the same or different and are a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a phenyl group), an alkyl group having 1 to 6 carbon atoms, a halogen atom , One or more selected from the group consisting of an alkoxy group having 1 to 6 carbon atoms and an optionally substituted phenyl group (for example, 1 to 6, preferably 1 to 4, more preferably 1 to 2) More preferably, a C 1-6 alkyl group (for example, —CF 3 , —CCl 3 ) substituted with a nitro group, a cyano group, a hydroxyl group, or a halogen atom (preferably a fluorine atom or a chlorine atom),
—COR 9 , —CO 2 R 9 , —SO 2 R 9 (R 9 and R 10 are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a phenyl group), 1 to 6 carbon atoms. 1 or more selected from the group consisting of alkyl groups and halogen atoms (for example, 1 to 6, preferably 1 to 4, more preferably 1 to 2), and more preferably 1 Examples thereof include an alkyl group having 1 to 6 carbon atoms which may be substituted with the above (for example, 1 to 6, preferably 1 to 4, more preferably 1 to 2) hydroxyl groups.

Preferred specific compounds of the above embodiment include the following.
(2S, 4S) -2-cyano-4-fluoro-1-[[2- (4-methyl-1,2,3-thiadiazol-5-yl) carbonylamino-1,1-dimethyl] ethylamino] acetyl Pyrrolidine
(2S, 4S) -2-cyano-4-fluoro-1-[[2- (2-pyridyl) carbonylamino-1,1-dimethyl] ethylamino] acetylpyrrolidine
(2S, 4S) -2-Cyano-4-fluoro-1-[[2- (furan-2-yl) carbonylamino-1,1-dimethyl] ethylamino] acetylpyrrolidine
(2S, 4S) -2-cyano-1-[[2- (3,5-dimethylisoxazol-4-yl) carbonylamino-1,1-dimethyl] ethylamino] acetyl-4-fluoropyrrolidine
(2S, 4S) -2-cyano-4-fluoro-1-[[2- (thiophen-2-yl) carbonylamino-1,1-dimethyl] ethylamino] acetyl-pyrrolidine
(2S, 4S) -1-[[2- (1H-1,2,3-benzotriazol-5-yl) carbonylamino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine
(2S, 4S) -2-cyano-4-fluoro-1-[[2- (thiophen-3-yl) carbonylamino-1,1-dimethyl] ethylamino] acetylpyrrolidine
(2S, 4S) -2-cyano-4-fluoro-1-[[2- (5-methylthiophen-2-yl) carbonylamino-1,1-dimethyl] ethylamino] acetylpyrrolidine
(2S, 4S) -2-cyano-4-fluoro-1-[[2- (3-methylthiophen-2-yl) carbonylamino-1,1-dimethyl] ethylamino] acetylpyrrolidine R 3 is —N ( R 4) COR 5 (R 5 is an alkyl group having 1 to 6 carbon atoms which may be substituted or the compound is a cycloalkyl is a group) substituted carbon atoms which may be 3-6, R 5, In a preferred embodiment, the alkyl group or carbon having 1 to 6 carbon atoms which may be substituted with one or more (for example, 1 to 6, preferably 1 to 4, more preferably 1 to 2) hydroxyl groups. A cycloalkyl group having a number of 3 to 6 is exemplified.

Preferred specific compounds of the above embodiment include the following.
(2S, 4S) -2-cyano-4-fluoro-1-[(2-pivaloylamino-1,1-dimethyl) ethylamino] acetylpyrrolidine
(2S, 4S) -2-cyano-4-fluoro-1-[[2- (3-hydroxy-2-methylpropan-2-yl) carbonylamino-1,1-dimethyl] ethylamino] acetylpyrrolidine
(2S, 4S) -2-cyano-1-[(2-cyclopropanecarbonylamino-1,1-dimethyl) ethylamino] acetyl-4-fluoropyrrolidine
(2S, 4S) -1-[[2- (1-methylcyclopropan-1-yl) carbonylamino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine R 3 is at least 1 In a compound which is a heteroaryl group containing one oxygen and / or sulfur and further containing a nitrogen atom (the heteroaryl group may be substituted), the heteroaryl has a sustained DPPIV inhibitory activity From this point, monocyclic is preferable, and thienyl group or furanyl group is more preferable. Preferred substituents for the heteroaryl group of R 3 are carbons that may be substituted with one or more (eg, 1 to 6, preferably 1 to 4, more preferably 1 to 2) hydroxyl groups. A C1-C6 alkyl group or a C3-C6 cycloalkyl group is mentioned.

Preferred specific compounds of the above embodiment include the following.
(2S, 4S) -2-cyano-4-fluoro-1-[[1- (furan-2-yl) -1-methyl] ethylamino] acetylpyrrolidine R 3 is —N (R 4 ) SO 2 R 5 In a compound in which R 5 is a preferred embodiment of R 5 , when R 3 is —N (R 4 ) COR 5 (wherein R 5 is an aryl group that may be substituted, R 5 may be substituted) The same as the preferred embodiment of R 5 in the case of an aryl group and in the case where R 5 is an optionally substituted alkyl group having 1 to 6 carbon atoms or an optionally substituted cycloalkyl group having 3 to 6 carbon atoms. It is.

  The compound according to the present invention can suppress dipeptidyl peptidase IV, and thus can enhance insulin action and improve sugar metabolism. Moreover, it inhibits neuropeptide Y metabolism, T cell activation, It can contribute to inhibition of cancer cell adhesion to the endothelium and prevention of HIV virus entry into lymphocytes.

  Accordingly, the present invention relates to diseases or conditions that can be ameliorated by inhibiting dipeptidyl peptidase IV, such as diabetes (especially type 2), immune diseases, arthritis, obesity, osteoporosis, glucose-resistant damage conditions, benign Provided is the above medicament for preventing or treating prostate enlargement, skin disease and the like.

  Drugs for immune diseases include immunosuppressants in tissue transplantation; for example, cytokine release inhibitors in various autoimmune diseases such as inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis (RA), T-cells Drugs useful for the prevention and treatment of AIDS by preventing HIV entry into the body, prevention of metastasis, particularly drugs that prevent metastasis of breast and prostate tumors to the lung, and the like.

  The medicament of the present invention can be systemically or locally administered orally or parenterally such as rectal, subcutaneous, intramuscular, intravenous and transdermal.

  In order to use the compound according to the present invention as a pharmaceutical, any form of a solid composition, a liquid composition, and other compositions may be used, and the optimum one is selected as necessary. The medicament of the present invention can be produced by blending the compound according to the present invention with a pharmaceutically acceptable carrier. Specifically, conventional excipients, extenders, binders, disintegrants, coating agents, sugar coatings, pH adjusters, solubilizers, or aqueous or non-aqueous solvents are added, and by conventional formulation techniques, It can be prepared into tablets, pills, capsules, granules, powders, powders, solutions, emulsions, suspensions, injections, and the like. Examples of excipients and extenders include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, and other commonly used ones. it can.

  In addition, the compound according to the present invention can be formulated by forming an inclusion compound with α, β, γ-cyclodextrin, methylated cyclodextrin or the like.

The dose of the compound according to the present invention varies depending on the disease, symptoms, body weight, age, sex, route of administration, etc., but is about 1 to about 1000 mg / person / day for an adult, preferably about 5 to about 500 mg / person / day, more preferably about 10 to about 200 mg / person / day, which can be administered once or divided into several times a day.
Although the manufacturing method of the compound based on this invention is demonstrated in detail, it does not specifically limit to what was illustrated. Also, the solvent used in the reaction is not particularly limited as long as it does not inhibit each reaction.

The compound of the formula (I) can be produced by the following general production method.
[General manufacturing method]
[Scheme 1]

(In the formula, A, R 1 , R 2 , R 3 and X are as defined above. Ra represents a leaving group such as a halogen atom and a sulfonyloxy group, and Rb represents a protective group for an amino group. The production methods for compound (II) and compound (III) as starting materials are described in Patent WO0238541. Production methods of compound (IX) and compound (X) will be described later.)
Step (1-1), (1-2), (1-7) or (1-8): Compound (IX) which is a primary amine derivative in compound (II) or compound (III) having a leaving group Ra ) Or compound (X) to obtain compound (IV), compound (V), compound (VIII) or compound (I) which is a secondary amine derivative. A substitution reaction can be performed using a compound having a leaving group such as a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group as Ra, and a primary amine. At this time, these amines may be used in excess or a base may be added separately. Examples of the base to be added include amines such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate. Moreover, in order to accelerate | stimulate reaction depending on the case, sodium iodide etc. can be added. Examples of the solvent used in this reaction include N, N-dimethylformamide, tetrahydrofuran, dioxane, dichloromethane, chloroform and the like, and the reaction can be carried out at 0 to 100 ° C.

Steps (1-3) and (1-4): Steps for deprotecting the protecting group of the amino group. About this deprotection, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, THEODORA W. GREENE and
The method described by PETER GM WU TS can be used.

  For example, the compound (IV) or the compound (V) in which Rb is a group to be deprotected by an acid such as tert-butoxycarbonyl group, trityl group, o-nitrobenzenesulfenyl group, hydrochloric acid, sulfuric acid, trifluoroacetic acid, p -Compound (VI) or Compound (VII) having a primary amino group can be synthesized by deprotection using an acid such as toluenesulfonic acid or methanesulfonic acid. At this time, deprotection can be performed by diluting or dissolving the acid with an organic solvent or water, and the reaction can be performed at −50 to 50 ° C. Examples of the organic solvent include ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, dichloromethane, chloroform, 1,2-dichloroethane and the like. Further, for example, a compound in which Rb is a group to be deprotected by a hydrogenolysis reaction such as a benzyloxycarbonyl group, a hydrogenolysis reaction using a metal catalyst such as palladium, a reaction using hydrogen gas, formic acid-formic acid It can be deprotected by reaction with a combination of reagents such as ammonium. Examples of the solvent used for this reaction include ethanol, methanol, tetrahydrofuran, ethyl acetate and the like, and the reaction can be carried out at 0 to 100 ° C. Further, for example, a compound in which Rb is a group that is deprotected by a base such as a fluorenyloxycarbonyl group can be deprotected using a base such as diethylamine, piperidine, ammonia, sodium hydroxide, or potassium carbonate. These bases can be used alone or diluted, dissolved or suspended in a solvent. Examples of the solvent used in this reaction include water, ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, dichloromethane, chloroform, 1,2-dichloroethane, and the reaction can be performed at 0 to 100 ° C. Further, for example, a compound in which Rb is a group that is deprotected by a metal catalyst such as an allyloxycarbonyl group can be deprotected using tetrakis (triphenylphosphine) palladium or the like as a catalyst or reagent. Examples of the solvent used in this reaction include dichloromethane, chloroform, tetrahydrofuran and the like, and the reaction can be carried out at 0 to 100 ° C.

Steps (1-5) and (1-6): Compound (VI) or Compound (VII) having a primary amino group, or Compound (VIII) or Compound (I) wherein R 3 is formula —NHR 4 , R 3 is a step of converting to compound (VIII) or compound (I) in which —N (R 4 ) COR 5 , —N (R 4 ) SO 2 R 5 or —NR 4 R 6 . The reaction used varies depending on the compound to be synthesized, and these are exemplified below. Moreover, you may convert in a single process and you may convert combining several processes.
(Method of acylating amino group): Compound (VI) or compound having a primary amino group (
VII), or compound (VIII) or compound (I) where R 3 is formula —NHR 4 and converted to compound (VIII) or compound (I) where R 3 is formula —N (R 4 ) COR 5 It is a process to do.

  Examples of amidation reactions include reactions using acyl halides such as acyl chlorides and acyl bromides. Examples of the solvent used in this reaction include dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, toluene, ethyl acetate, and the like. The reaction can be performed at −50 to 100 ° C. In this case, the reaction can be carried out using a suitable base. Examples of the base include amines such as triethylamine and diisopropylethylamine, organic acid salts such as sodium 2-ethylhexanoate and potassium 2-ethylhexanoate, and hydroxylation. Examples thereof include inorganic bases such as sodium and potassium carbonate.

  Another example of the amidation reaction is a reaction using an active ester such as 1-benzotriazolyl ester or succinimidyl ester. Examples of the solvent used in this reaction include dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, tetrahydrofuran, dioxane, toluene, ethyl acetate, and the like. The reaction can be performed at −50 to 50 ° C. it can.

  The amidation reaction can also be performed using, for example, a carboxylic acid and a dehydrating condensing agent. Examples of the dehydrating condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride, dicyclohexylcarbodiimide, diphenylphosphoryl azide, carbonyldiimidazole, and the like. 1-hydroxybenzotriazole, hydroxy An activator such as succinimide can be used. Examples of the solvent used in this reaction include dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, tetrahydrofuran, dioxane, toluene, ethyl acetate, and the like. The reaction can be performed at −50 to 50 ° C. it can. In this case, the reaction can be carried out using a suitable base. Examples of the base include amines such as triethylamine and diisopropylethylamine, organic acid salts such as sodium 2-ethylhexanoate and potassium 2-ethylhexanoate, or the like. Examples thereof include inorganic bases such as sodium hydroxide and potassium carbonate. Further, for example, an amidation reaction can be performed using a mixed acid anhydride obtained from carboxylic acid and chlorocarbonate. Examples of the solvent used in these reactions include tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, toluene, ethyl acetate, and the like. The reaction can be performed at −50 to 50 ° C. In this case, the reaction can be carried out using a suitable base. Examples of the base include amines such as triethylamine and diisopropylethylamine, organic acid salts such as sodium 2-ethylhexanoate and potassium 2-ethylhexanoate, or the like. Examples thereof include inorganic bases such as sodium hydroxide and potassium carbonate.

Examples of the method for aminocarbonylating an amino group include a method for aminocarbonylating an amino group using an aminocarbonyl halide such as morpholine-4-carbonyl chloride. Examples of the solvent used in these reactions include dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, toluene, ethyl acetate, and the like. The reaction can be performed at −50 to 100 ° C. In this case, the reaction can be carried out using a suitable base. Examples of the base include amines such as triethylamine and diisopropylethylamine, organic acids such as sodium 2-ethylhexanoate and potassium 2-ethylhexanoate. Examples thereof include an inorganic base such as a salt or potassium carbonate.
(Method of sulfonylating amino group) Using compound (VI) or compound (VII) having a primary amino group, or compound (VIII) or compound (I) in which R 3 is formula -NHR 4 , R In this step, 3 is converted to compound (VIII) or compound (I) in which —N (R 4 ) SO 2 R 5 is present. For example, a sulfonamide body can be obtained by using a sulfonyl chloride and an amine body raw material. Examples of the solvent used in this reaction include dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, toluene, ethyl acetate, and the like. The reaction can be performed at −50 to 100 ° C. In this case, the reaction can be carried out using a suitable base. Examples of the base include amines such as triethylamine and diisopropylethylamine, organic acid salts such as sodium 2-ethylhexanoate and potassium 2-ethylhexanoate, or the like. And inorganic bases such as potassium carbonate.

(Method of alkylating amino group): For example, using compound (VI) or compound (VII) having a primary amino group, or compound (VIII) or compound (I) wherein R 3 is formula —NHR 4 , R 3 is a step of converting to compound (VIII) or compound (I), which is formula —NR 4 R 6 .

  For example, although the raw materials to be used are different, the N-alkyl derivative can be reacted using the same method as described in the step (1-1), (1-2), (1-7) or (1-8) Can be synthesized.

Also, for example, it can be N-alkylated by reductive amination. This is a method in which an amino derivative and an aldehyde derivative or a ketone derivative are used and the reaction is performed under conditions using an appropriate reduction method. Examples of the reduction method used include a method using a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and a method using hydrogenation using palladium or the like. Examples of the solvent used for this reaction include ethanol, methanol, tetrahydrofuran, dioxane, water and the like, and the reaction can be carried out at −20 to 100 ° C.
(Method of N-alkylating an amide compound): Compound (VIII) in which R 3 is formula —NHCOR 5 or Compound (I) and compound in which R 3 is formula —N (R 4 ) COR 5 (VIII ) Or compound (I).

For example, the target product can be obtained by acting an alkylating reagent such as an alkyl halide. At this time, an appropriate base is added to carry out the reaction, and examples of the base include sodium hydride, tert-butoxypotassium, n-butyllithium, lithium diisopropylamide and the like. Examples of the solvent used for this reaction include N, N-dimethylformamide, tetrahydrofuran, dioxane and the like, and the reaction can be carried out at −50 to 50 ° C.
(Method of N-alkylation of sulfonamide): Using compound (VIII) or compound (I) in which R 3 is formula —NHSO 2 R 5 , R 3 is formula —N (R 4 ) SO 2 R 5 This is a step of converting the compound (VIII) or the compound (I).

  For example, the desired product can be obtained by acting an alkylating reagent such as an alkyl halide. At this time, an appropriate base is added to carry out the reaction, and examples of the base include sodium hydride, tert-butoxy potassium, n-butyl lithium, lithium diisopropylamide and the like. Examples of the solvent used for this reaction include N, N-dimethylformamide, tetrahydrofuran, dioxane and the like, and the reaction can be carried out at −50 to 50 ° C.

Moreover, the target product can be synthesized using the Mitsunobu reaction. At this time, for example, alcohol, diethyl azodicarboxylate and triphenylphosphine are used. Examples of the solvent used in this reaction include N, N-dimethylformamide, tetrahydrofuran, dioxane and the like, and the reaction can be carried out at −50 to 50 ° C.
Steps (1-9), (1-10) and (1-11): Steps for converting a carbamoyl group located at the 2-position of the pyrrolidine ring into a nitrile group. An example is a method using trifluoroacetic anhydride. Examples of the solvent used in this reaction include dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, N, N-dimethylformamide, and the reaction can be performed at −50 to 50 ° C. In this case, a base such as triethylamine, diisopropylethylamine, sodium hydrogen carbonate, potassium carbonate or the like can be added in some cases. Another example is a method using phosphorus oxychloride. Examples of the solvent used in this reaction include dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, pyridine and the like, and these can be used alone or in combination of two or more. Can be performed at 50 ° C. In this reaction, imidazole or the like may be added.

Another example is a method using cyanuric chloride and N, N-dimethylformamide. Examples of the solvent used in this reaction include dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, pyridine and the like. These may be used alone or in combination of two or more, and the reaction is carried out at −50 to 50 ° C. It can be carried out.
Compound (IX) and Compound (X)
[Scheme 2]

(In the formula, R 1 , R 2 , Rb and X are as defined above. With respect to R 3 , among the above, -N (R 4 ) COR 5 , -N (R 4 ) SO 2 R 5 , -NR 4 R 6 , R 4 , R 5 and R 6 are as defined above.
This step is a step of obtaining an amine body (IX) having a protective group Rb or an amine body (X) having a functional group converted from the diamine body (XI) as a raw material.

For example, for the step of obtaining compound (IX), that is, the method of introducing a protecting group into the amino group
The method described by PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, THEODORA W. GREENE and PETER GM WU TS can be used. For example, when Rb is a protective group such as tert-butoxycarbonyl group, benzyloxycarbonyl group, fluorenylcarbonyl group, trityl group, o-nitrobenzenesulfenyl group, di-tert-butyldicarbonate, benzyloxycarbonyl chloride , Fluorenylcarbonyl chloride, trityl chloride, o-nitrobenzenesulfenyl chloride, etc., in a single or mixed solvent such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, toluene, ethyl acetate, water, The reaction can be performed at −50 to 100 ° C. In this case, the reaction can be carried out using a suitable base. Examples of the base include amines such as triethylamine and diisopropylethylamine, organic acid salts such as sodium 2-ethylhexanoate and potassium 2-ethylhexanoate, and hydroxylation. Examples thereof include inorganic bases such as sodium and potassium carbonate.

For example, in the compound (X), when R 3 is the formula —N (R 4 ) COR 5 , —N (R 4 ) SO 2 R 5 or —NR 4 R 6 , the step (1-5) described in Scheme 1 or It can be produced by combining the methods described in (1-6).
Compound (X)
[Scheme 3]

{Wherein R 1 , R 2 and X are as defined above. With respect to R 3 , among the above, it means the formula —CH═CH—R 7 , —C≡C—R 7 or an optionally substituted heteroaryl group. R 7 has the same meaning as described above. }
This step is a step of obtaining amine body (X) using cyano body (XII) as a raw material.

For example, when R 1 and R 2 are methyl groups, the amine form (X) can be obtained from the cyano form (XII) using methyl magnesium bromide, methyl lithium or the like. At this time, anhydrous cerium chloride or the like can be added. Examples of the solvent used in this reaction include dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, toluene, diethyl ether and the like, and the reaction can be carried out at -78 to 100 ° C.

Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited to these Examples.
Reference example 1
Synthesis of (2S, 4S) -1-chloroacetyl-2-cyano-4-fluoropyrrolidine
(2S, 4S) -2-aminocarbonyl-4-fluoropyrrolidine hydrochloride (43.0 g) synthesized by the method described in WO0238541 was suspended in N, N-dimethylformamide (255 mL), and ice-salt was used. Cooled down. Chloroacetyl chloride (22.3 mL) was added all at once, and after 10 minutes, triethylamine (74.7 mL) was added dropwise over 1 hour while maintaining the internal temperature at -7 to -2 ° C. Furthermore, it stirred for 1 hour, keeping internal temperature at -7- + 2 degreeC. Cyanuric chloride (28.2 g) was added as powder in 5 minutes, and the temperature was gradually raised. After 50 minutes, the solidified reaction mixture was poured into ice water composed of water (1000 mL) and ice (500 g), and the precipitated crystals were collected by filtration, washed with water (400 mL), dried and dried to give the title compound (41.94) as a colorless powder. g) was obtained.
MS (ESI pos.) M / z: 213 ([M + Na] + ).
HRMS (ESI pos.): Calcd for C 7 H 8 ClFN 2 ONa [M + Na] + 213.0207, found 213.0201.
1 H-NMR (300MHz, DMSO-d6) δ5.50 (1H, d, J = 51.8Hz), 5.024.96 (1H, m), 4.51 & 4.39 (2H, ABq., J = 14.2Hz), 3.97 (1H, dd like, J = 23.6,12.4Hz), 3.76 (1H, ddd, J = 39.3,12.4,3.4Hz), 2.62.3 (2H, m).

Example 1
Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[2- (3,4-methylenedioxybenzoyl) amino-1,1-dimethyl] ethylamino] acetylpyrrolidine (1) [2 Synthesis of — (3,4-methylenedioxybenzoyl) amino-1,1-dimethyl] ethylamine 1,2-Diamino-2-methylpropane (298 mg) was dissolved in dichloromethane (3.4 mL), and 3 , 4-Methylenedioxybenzoyl chloride (312 mg) was added little by little, and the mixture was stirred for 10 minutes with ice cooling and then for 10 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, diethyl ether (15 mL) was added to the residue, and 6M aqueous hydrochloric acid (10 mL) was added dropwise under ice cooling. After separating the reaction solution, the aqueous phase was further washed with ether (15 mL). The aqueous phase was ice-cooled, 5M aqueous sodium hydroxide solution (12 mL) was added, and the mixture was extracted with chloroform (20 mL). The extract was dried over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure to give the title compound (349 mg) as a colorless oil.
MS (ESI pos.) M / z: 237 ([M + H] + ), 259 ([M + Na] + ), (ESI neg.) M / z: 235 ([M-1] - ).
1 H-NMR (300 MHz, CDCl 3 ) δ 7.34 (1 H, dd, J = 8.0, 1.7 Hz), 7.31 (1 H, d, J = 1.7 Hz), 6.83 (1 H, brd, J = 7.9 Hz), 6.66 (1H, brs), 6.02 (2H, s), 3.30 (2H, d, J = 5.8Hz), 1.32 (2H, brs), 1.17 (6H, s).
(2) Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[2- (3,4-methylenedioxybenzoyl) amino-1,1-dimethyl] ethylamino] acetylpyrrolidine
[2- (3,4-Methylenedioxybenzoyl) amino-1,1-dimethyl] ethylamine (242 mg) was dissolved in methanol (7.3 mL) and (2S, 4S) -1-chloroacetyl-2- Cyano-4-fluoropyrrolidine (98 mg) and potassium iodide (127 mg) were added and stirred for 3 days. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol: 28% aqueous ammonia solution = 30: 1: 0.1) to give the title compound (174 mg) as a colorless amorphous product. Got.
MS (ESI pos.) M / z: 391 ([M + H] + ), 413 ([M + Na] + ), (ESI neg.) M / z: 389 ([M-1] - ).
HRMS (ESI pos.): Calcd for C 19 H 24 FN 4 O 4 [M + H] + 391.1782, found 391.1764.
1 H-NMR (300 MHz, DMSO-d6) δ 8.08 (1 H, m), 7.44 (1 H, dd, J = 8.1, 1.7 Hz), 7.39 (1 H, d, J = 1.7 Hz),
6.97 (1H, brd, J = 8.1Hz), 6.09 (2H, s), 5.49 (1H, brd, J = 53.2Hz), 5.00-4.93 (1H, m), 3.96 (1H, dd, J = 23.8, 12.6Hz), 3.74 (1H, ddd, J = 39.3, 12.8, 3.6Hz), 3.52-3.26 (2H, m), 3.24-3.16 (2H, m),
2.62-2.26 (2H, m), 1.98 (1H, brs), 1.01 (3H, s), 1.00 (3H, s).

Example 2
Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[2- [3- (methylsulfonyl) benzoyl] amino-1,1-dimethyl] ethylamino] acetylpyrrolidine (1) [2- Synthesis of [3- (methylsulfonyl) benzoyl] amino-1,1-dimethyl] ethylamine 3- (methylsulfonyl) benzoic acid (296 mg) was suspended in acetone (3.0 mL), and triethylamine (206 μL) was cooled with ice. Was added. Cyanuric acid chloride (139 mg) was added, then acetone (3.0 mL) was further added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and chloroform (5.0 mL) was added to the residue. Under ice cooling, 1,2-diamino-2-methylpropane (296 mg) was added and stirred for 10 minutes, and then returned to room temperature and stirred for 20 minutes. The reaction solution was concentrated under reduced pressure, and diethyl ether (20 mL) was added to the resulting residue. Under ice-cooling, 6M aqueous hydrochloric acid solution (8.0 mL) was added and stirred, and then the organic phase was separated. Under ice-cooling, 5M aqueous sodium hydroxide solution (8.0 mL) was added to the aqueous phase, and extraction was performed 3 times with chloroform (20 mL). The extract is dried over anhydrous magnesium sulfate, the desiccant is filtered off and concentrated under reduced pressure, and the resulting residue is subjected to silica gel column chromatography (developing solvent; chloroform: methanol: 28% aqueous ammonia solution = 15: 1: 0.1). To give the title compound (225 mg) as a colorless oil.
MS (ESI pos.) M / z: 271 ([M + H] + ), 293 ([M + Na] + ), 541 ([2M + H] + ), (ESI neg.) M / z: 269 ([M-1] - ).
1 H-NMR (300 MHz, CDCl 3 ) δ 8.35 (1H, brs), 8.13 (1H, d, J = 7.8Hz), 8.08 (1H, d, J = 7.8Hz), 7.68 (1H, t, J = 7.8Hz), 6.95 (1H, brs), 3.35 (2H, d, J = 5.6Hz), 3.10 (3H, s), 1.35 (2H, brs), 1.20 (6H, s).
(2) Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[2- [3- (methylsulfonyl) benzoyl] amino-1,1-dimethyl] ethylamino] acetylpyrrolidine Example 1 In the same manner as in (2), [2- [3- (methylsulfonyl) benzoyl] amino-1,1-dimethyl] ethylamine (210 mg) and (2S, 4S) -1-chloroacetyl-2-cyano-4- The title compound (113 mg) was obtained as a colorless amorphous using fluoropyrrolidine (67 mg).
MS (ESI pos.) M / z: 425 ([M + H] + ), 447 ([M + Na] + ), (ESI neg.) M / z: 423 ([M-1] - ).
HRMS (ESI pos.): Calcd for C 19 H 26 FN 4 O 4 S [M + H] + 425.1659, found 425.1646.
1 H-NMR (300 MHz, DMSO-d6) δ 8.60 (1 H, m), 8.36 (1 H, brs), 8.19 (1 H, d, J = 6.8 Hz), 8.08 (1 H, brd, J = 7.5 Hz) , 7.76 (1H, brt, J = 7.9Hz), 5.49 (1H, brd, J = 53.2Hz), 5.00-4.92 (1H, m), 3.97 (1H, dd, J = 23.9,12.4Hz), 3.87- 3.18 (8H, m), 2.62-2.26 (2H, m), 1.96 (1H, brs), 1.04 (6H, s).

Example 3
Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[2- (2-trifluoromethylbenzoyl) amino-1,1-dimethyl] ethylamino] acetylpyrrolidine (1) (2-amino Synthesis of -2-methyl-propyl) -carbamic acid tert-butyl ester 1,2-Diamino-2-methylpropane (2.42 mg) was dissolved in tetrahydrofuran (50 mL) and cooled on ice. While stirring, a solution of di-tert-butyl dicarbonate (3.00 g) in tetrahydrofuran (10 mL) was added dropwise over 5 minutes. The reaction mixture was stirred for 30 minutes under ice-cooling, and insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and diethyl ether (50 mL) and 0.4 M hydrochloric acid (50 mL) were added to the residue for liquid separation. 5M aqueous sodium hydroxide solution (5 mL) was added to the aqueous phase, and extraction was performed twice with chloroform (30 mL). The extract was dried over anhydrous sodium sulfate, the desiccant was filtered off and concentrated under reduced pressure to give the title compound (2.44 g) as a colorless solid.
MS (ESI pos.) M / z: 189 ([M + H] + ), 211 ([M + Na] + ).
1 H-NMR (300 MHz, DMSO-d6) δ 6.70 (1H, brt, J = 6.1 Hz), 2.80 (2H, d, J = 6.1 Hz), 1.38 (9H, s), 1.30 (2H, brs) , 0.92 (6H, s).
(2) Synthesis of (2S, 4S) -1-[[2- (tert-butoxycarbonyl) amino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine
(2S, 4S) -1-Chloroacetyl-2-cyano-4-fluoropyrrolidine (0.95 g) and (2-amino-2-methyl-propyl) -carbamic acid tert-butyl ester (1.88 g) in methanol (20 mL) ), Potassium iodide (0.83 g) was added, and the mixture was stirred overnight at room temperature. After further stirring at 50 ° C. for 2 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol: 25% aqueous ammonia solution = 100: 2: 0.2). Since (2-amino-2-methyl-propyl) -carbamic acid tert-butyl ester could not be removed, the solvent residue of the eluted fraction was dissolved in tetrahydrofuran (30 mL), and di-tert-butyl di- Carbonate (1.09 g), 4-dimethylaminopyridine (12 mg) and 0.5 M aqueous sodium hydroxide solution (10 mL) were added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate (50 mL) and saturated brine (50 mL) were added to the reaction solution and the phases were separated. The extract was dried over anhydrous sodium sulfate, and then the desiccant was filtered off and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol: 25% aqueous ammonia solution = 100: 2: 0.2) to obtain the title compound (1.08 g) as a pale yellow amorphous.
MS (ESI pos.) M / z: 343 ([M + H] + ), 365 ([M + Na] + ), (ESI neg.) M / z: 341 ([MH] - ).
HRMS (ESI pos.): Calcd for C 16 H 28 FN 4 O 3 [M + H] + 343.2145, found 343.2134.
1 H-NMR (300MHz, DMSO-d6) δ 6.64 (1H, brt, J = 6.1Hz), 5.48 (1H, brd, J = 53.5Hz), 4.97-4.91 (1H, m), 3.91 (1H, dd, J = 24.6, 12.5Hz), 3.71 (1H, ddd, J = 39.6, 12.5, 3.5Hz), 3.38 and 3.23 (2H, ABq, J = 16.5Hz), 2.87 (2H, d, J = 6.1Hz) ), 2.60-2.25 (2H, m), 1.76 (1H, brs), 1.38 (9H, s), 0.94 (6H, s).

(3) Synthesis of (2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride
(2S, 4S) -1-[[2- (tert-butoxycarbonyl) amino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine (100 mg) was added to ethyl acetate (
0.5M), 4M hydrochloric acid-ethyl acetate solution (0.5mL) was added, and the mixture was stirred at room temperature for 4 hours. The precipitated crystals were collected by filtration and dried to give the title compound (88 mg) as a colorless powder.
MS (ESI pos.) M / z: 243 ([M + H] + ), (ESI neg.) M / z: 277 ([M + Cl] - ).
HRMS (ESI pos.): Calcd for C 11 H 20 FN 4 O [M + H] + 243.1621, found 243.1639.
1 H-NMR (300 MHz, DMSO-d6) δ 8.61 (3H, brs), 5.57 (1H, brd, J = 50.7Hz), 5.11-5.04 (1H, m), 4.32-3.72 (4H, m), 3.21 (2H, s), 2.58-2.33 (2H, m), 1.43 (6H, s).
(4) Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[2- (2-trifluoromethylbenzoyl) amino-1,1-dimethyl] ethylamino] acetylpyrrolidine
(2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (84 mg) was dissolved in dimethylformamide (0.5 mL), Triethylamine (111 μL) was added dropwise under ice cooling. Under ice cooling, 2- (trifluoromethyl) benzoyl chloride (50 mg) was added to the suspension, and the mixture was stirred for 10 minutes, then warmed to room temperature and stirred overnight. The mixture was ice-cooled again, a 1: 1 mixture (20 mL) of 10% aqueous sodium hydrogen carbonate and saturated brine was added, and the mixture was stirred and extracted with ethyl acetate (20 mL). The extract was washed twice with saturated brine (20 mL), dried over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure to give the title compound (68 mg) as a colorless amorphous.
MS (ESI pos.) M / z: 415 ([M + H] + ), 437 ([M + Na] + ), (ESI neg.) M / z: 413 ([M-1] - ).
HRMS (ESI pos.): Calcd for C 19 H 23 F 4 N 4 O 2 [M + H] + 415.1757, found 415.1753.
1 H-NMR (300 MHz, DMSO-d6) δ 8.36 (1 H, m), 7.76 (1 H, t, J = 7.6 Hz), 7.73 (1 H, t, J = 7.3 Hz), 7.65 (1 H, d, J = 7.6Hz), 7.65 (1H, d, J = 7.5Hz), 5.49 (1H, brd, J = 53.2Hz), 5.00-4.92 (1H, m), 3.94 (1H, dd, J = 23.7,12.2 Hz), 3.72 (1H, ddd, J = 39.6, 12.6, 3.4Hz), 3.52-3.26 (2H, m), 3.25-3.18 (2H, m),
2.62-2.26 (2H, m), 1.05 (6H, s).

Example 4
Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[2- (3-pyridyl) carbonylamino-1,1-dimethyl] ethylamino] acetylpyrrolidine
(2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (100 mg) was dissolved in dimethylformamide (0.5 mL), Triethylamine (177 μL) was added dropwise under ice cooling. Under ice-cooling, nicotinoyl chloride hydrochloride (51 mg) was added to the suspension, dimethylformamide (0.5 mL) was further added, and the mixture was stirred for 10 min, warmed to room temperature, and stirred overnight. Under ice cooling, a 1: 1 mixture (20 mL) of 10% aqueous sodium hydrogen carbonate and saturated brine was added and stirred, followed by extraction three times with chloroform (25 mL). The extract is dried over anhydrous magnesium sulfate, the desiccant is filtered off and concentrated under reduced pressure, and the resulting residue is subjected to silica gel column chromatography (developing solvent; chloroform: methanol: 28% aqueous ammonia solution = 20: 1: 0.1). To give the title compound (23 mg) as a yellow oil.
MS (ESI pos.) M / z: 348 ([M + H] + ), 370 ([M + Na] + ), (ESI neg.) M / z: 346 ([M-1] - ).
HRMS (ESI pos.): Calcd for C 17 H 23 FN 5 O 2 [M + H] + 348.1836, found 348.1831.
1 H-NMR (300 MHz, DMSO-d6) δ 9.00 (1 H, d, J = 1.6 Hz), 8.70 (1 H, dd, J = 4.7, 1.6 Hz), 8.46 (1 H, m),
8.18 (1H, dt, J = 7.9,2.0Hz), 7.51 (1H, dd, J = 7.9,4.8Hz), 5.50 (1H, brd, J = 52.7Hz), 5.00-4.92 (1H, m), 3.96 (1H, dd, J = 23.8,12.3Hz), 3.74 (1H, ddd, J = 39.6,12.5,3.5Hz), 3.48 and 3.30 (2H, ABq, J = 16.6Hz), 3.28-3.22 (2H, m ), 2.60-2.25 (2H, m), 1.06-1.03 (6H, m).

Example 5
Synthesis of (2S, 4S) -1-[(2-benzenesulfonylamino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine
(2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (95 mg) in N, N-dimethylformamide (1 mL) Dissolved and cooled on ice. Triethylamine (0.13 mL) and then a solution of benzenesulfonyl chloride (48 mg) in N, N-dimethylformamide (0.2 mL) were added, and the mixture was stirred for 30 minutes under ice cooling. Ethyl acetate (30 mL), 10% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (20 mL) were added to the reaction solution, and the phases were separated. The extract was dried over anhydrous sodium sulfate, the desiccant was filtered off and concentrated under reduced pressure to give the title compound (90 mg) as a colorless amorphous.
MS (ESI pos.) M / z: 383 ([M + H] + ), 405 ([M + Na] + ), (ESI neg.) M / z: 381 ([MH] - ).
HRMS (ESI pos.): Calcd for C 17 H 24 FN 4 O 3 S [M + H] + 383.1553, found 383.1551.
1 H-NMR (300 MHz, DMSO-d6) δ 7.82 (2H, dd, J = 8.1, 1.9 Hz), 7.67-7.55 (4H, m), 5.49 (1H, brd, J =
53.0Hz), 4.98-4.92 (1H, m), 3.87 (1H, dd, J = 24.3,12.1Hz), 3.66 (1H, ddd, J = 39.4,12.5,3.4Hz), 3.33 and 3.18 (2H, ABq , J = 16.5Hz), 2.63 (2H, s), 2.53-2.30 (2H, m), 0.96 (6H, s).

Example 6
Synthesis of (2S, 4S) -1-[[2- (N-benzenesulfonyl-N-methyl) amino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine
(2S, 4S) -1-[(2-Benzenesulfonylamino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine (57 mg) and triphenylphosphine (59 mg) in tetrahydrofuran (3 mL) And methanol (0.009 mL) and diethyl azodicarboxylate (98 mg as a 40% toluene solution) were added at room temperature. The mixture was stirred overnight at room temperature, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol: 25% aqueous ammonia solution = 100: 3: 0.3 to 100: 5: 0.5) to give the title compound (25 mg) as a colorless amorphous product. .
MS (ESI pos.) M / z: 397 ([M + H] + ), 419 ([M + Na] + ), (ESI neg.) M / z: 395 ([MH] - ).
HRMS (ESI pos.): Calcd for C 18 H 26 FN 4 O 3 S [M + H] + 397.1710, found 397.1718.
1 H-NMR (300 MHz, DMSO-d6) δ 7.79 (2H, brd, J = 8.4Hz), 7.72-7.60 (3H, m), 5.49 (1H, brd, J = 52.7Hz), 4.98-4.92 ( 1H, m), 3.94 (1H, dd, J = 24.1,12.0Hz), 3.70 (1H, ddd, J = 39.5,12.5,3.2Hz), 3.46 and 3.30 (2H, ABq, J = 17.4Hz), 2.92 (2H, s), 2.78 (3H, s), 2.60-2.26 (2H, m), 1.07 (6H, s).

Example 7
Synthesis of (2S, 4S) -2-cyano-1-[[2- (4-cyanobenzyl) amino-1,1-dimethyl] ethylamino] acetyl-4-fluoropyrrolidine
(2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (315 mg) and 4-cyanobenzaldehyde (131 mg) in chloroform ( 5 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (424 mg) was added, and the mixture was further stirred at room temperature for 30 min. Chloroform (50 mL), 10% aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine (20 mL) were added to the reaction solution to separate the layers. The extract was dried over anhydrous sodium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (developing solvent; chloroform: methanol: 25% aqueous ammonia solution = 100: 3: 0.3 to 100: 5: 0.5) to give the title compound (217 mg) as a colorless gum.
MS (ESI pos.) M / z: 358 ([M + H] + ), 380 ([M + Na] + ), (ESI neg.) M / z: 356 ([MH] - ).
HRMS (ESI pos.): Calcd for C 19 H 25 FN 5 O [M + H] + 358.2043, found 358.2044.
1 H-NMR (300 MHz, DMSO-d6) δ 7.77 (2H, d, J = 8.4 Hz), 7.54 (2 H, d, J = 8.2 Hz), 5.49 (1 H, brd, J = 52.8 Hz), 4.99 -4.93 (1H, m), 3.89 (1H, dd, J = 24.1,11.6Hz), 3.68 (1H, ddd, J = 39.6,12.4,3.3Hz),
3.32 and 3.17 (2H, ABq, J = 16.3Hz), 2.60-2.25 (4H, m), 0.98 (6H, s).

Example 8
Synthesis of (2S, 4S) -1-[[2- [N-benzoyl-N- (4-cyanobenzyl)] amino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine
Dissolve (2S, 4S) -2-cyano-1-[[2- (4-cyanobenzyl) amino-1,1-dimethyl] ethylamino] acetyl-4-fluoropyrrolidine (62 mg) in chloroform (1.0 mL). Under ice cooling, a solution of triethylamine (24 μL) and benzoyl chloride (62 mg) in chloroform (200 μL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. Under ice-cooling, a 1: 1 mixture (20 mL) of 5% aqueous sodium hydrogen carbonate and saturated brine was added, and the mixture was stirred and extracted with ethyl acetate (25 mL). The extract was washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol: 28% aqueous ammonia solution = 30: 1: 0.1) to obtain the title compound (61 mg) as a colorless amorphous substance.
MS (ESI pos.) M / z: 462 ([M + H] + ), 484 ([M + Na] + ), (ESI neg.) M / z: 460 ([M-1] - ).
HRMS (ESI pos.): Calcd for C 26 H 29 FN 5 O 2 [M + H] + 462.2305, found 462.2307.
1 H-NMR (300 MHz, DMSO-d6) δ 7.88-7.72 (2H, m), 7.60-7.20 (7H, m), 5.61-5.30 (1H, brd, J = 51.8Hz), 5.08-4.92 (1H , m), 4.81 (2H, brs), 3.89 (1H, dd, J = 24.0, 12.5Hz), 3.80-3.54 (1H, m), 3.50-
3.20 (4H, m), 2.60-2.25 (2H, m), 1.11 (4.3H, s), 0.85 (1.7H, s).
This compound was observed for rotational isomers by 1 H-NMR. The abundance ratio was about 5: 2 from the peak integrated value of dimethyl. It was confirmed that there was a tendency to converge by heating to 100 ° C. in DMSO-d6.

Example 9
Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[1- (furan-2-yl) -1-methyl] ethylamino] acetylpyrrolidine (1) [1- (furan-2- L) Synthesis of 1-methyl] ethylamine 2-Furonitrile (2 g) was dissolved in toluene (136 mL), and methylmagnesium bromide (3M / diethyl ether solution, 21.4 mL) was added dropwise at room temperature. After heating and refluxing in an oil bath for 7 hours, the reaction mixture was ice-cooled and ethanol (13.6 mL) was slowly added dropwise. The suspension was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing solvent; chloroform: methanol: 25% aqueous ammonia solution =
60: 1: 0.1) to give the title compound (131 mg) as a brown liquid material.
MS (ESI pos.) M / z: 126 ([M + H] + ), 109 ([M-NH 2 ] + ).
1 H-NMR (300 MHz, CDCl 3 ) δ 7.35 (1 H, dd, J = 1.8, 0.9 Hz), 6.30 (1 H, dd, J = 3.3, 1.9 Hz), 6.22 (1 H, dd, J = 3.3, 0.9Hz), 1.62 (6H, s).
(2) Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[1- (furan-2-yl) -1-methyl] ethylamino] acetylpyrrolidine Similar to Example 1 (2) [1- (furan-2-yl) -1-methyl] ethylamine (
110 mg) and (2S, 4S) -1-chloroacetyl-2-cyano-4-fluoropyrrolidine (67 mg) were used to give the title compound (20 mg) as a brown gum.
MS (ESI pos.) M / z: 302 ([M + Na] + ), (ESI neg.) M / z: 278 ([M-1] - ).
HRMS (ESI pos.): Calcd for C 14 H 18 FN 3 O 2 Na [M + Na] + 302.1281, found 302.1277.
1 H-NMR (300 MHz, DMSO-d6) δ 7.55 (1 H, dd, J = 1.8, 0.9 Hz), 6.35 (1 H, m), 6.21 (1 H, dd, J = 3.2, 0.9 Hz), 5.40 ( 1H, brd, J = 50.8Hz), 4.95-4.87 (1H, m), 3.84 (1H, dd, J = 23.9,12.6Hz), 3.61 (1H, ddd, J = 39.6,12.5,3.3Hz), 3.21 and 3.02 (2H, ABq, J = 16.0), 2.60-2.22 (2H, m), 1.44-1.32 (6H, m).

Example 10
Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[1- (thiophen-3-yl) -1-methyl] ethylamino] acetylpyrrolidine (1) [1- (thiophen-3- Synthesis of l) -1-methyl] ethylamine Anhydrous cerium chloride (5.0 g) was suspended in tetrahydrofuran (40 mL) and stirred overnight at room temperature. Under cooling with dry ice and acetone, methyllithium (1.2 M / diethyl ether solution, 16.3 mL) was slowly added dropwise to the suspension and stirred for 30 minutes. At the same temperature, a solution of 3-cyanothiophene (710 mg) in tetrahydrofuran (1.0 mL) was added dropwise to the reaction system. Stirring was continued while gradually raising the temperature, and the temperature was raised to room temperature over 5 hours. Under ice cooling, a 25% aqueous ammonia solution (12.5 mL) was added dropwise while stirring the reaction solution. The suspension was filtered through celite, and the resulting filtrate was extracted with diethyl ether (25 mL). The extract was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, and the desiccant was filtered off and reduced in pressure. Concentration under pressure gave the title compound (203 mg) as a black liquid substance.
MS (ESI pos.) M / z: 142 ([M + H] + ), 164 ([M + Na] + ), 125 ([M-NH 2 ] + ).
1 H-NMR (300 MHz, CDCl 3 ) δ 7.27 (1 H, dd, J = 5.2, 3.2 Hz), 7.13 (1 H, d, J = 1.4 Hz), 7.11 (1 H, dd, J =
3.2, 1.3Hz), 1.49 (6H, s).
(2) Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[1- (thiophen-3-yl) -1-methyl] ethylamino] acetylpyrrolidine Similar to Example 1 (2) Using [1- (thiophen-3-yl) -1-methyl] ethylamine (174 mg) and (2S, 4S) -1-chloroacetyl-2-cyano-4-fluoropyrrolidine (106 mg) The title compound (80 mg) was obtained as an oily substance.
MS (ESI pos.) M / z: 318 ([M + Na] + ), (ESI neg.) M / z: 294 ([M-1] - ).
HRMS (ESI pos.): Calcd for C 14 H 18 FN 3 ONaS [M + Na] + 318.1052, found 318.1060.
1 H-NMR (300 MHz, DMSO-d6) δ 7.45 (1 H, dd, J = 5.0, 3.0 Hz), 7.23 (1 H, dd, J = 3.0, 1.4 Hz), 7.13 (1 H, dd, J = 5.0 , 1.4Hz), 5.40 (1H, brd, J = 52.1Hz), 4.95-4.87 (1H, m), 3.82 (1H, dd, J = 24.1,12.4Hz), 3.60 (1H, ddd, J = 39.7, 12.4, 3.4Hz), 3.18 and 3.00 (2H, ABq, J = 16.1Hz), 2.56-2.22 (2H, m), 1.40-1.35 (6H, m).

Example 11
(2S, 4S) -2-cyano-4-fluoro-1-[[2- (4-methyl-1,2,3-thiadiazol-5-yl) carbonylamino-1,1-dimethyl] ethylamino] acetyl Synthesis of pyrrolidine (1) Synthesis of [2- (4-methyl-1,2,3-thiadiazol-5-yl) -1,1-dimethyl] ethylamine 4-methyl-1 as in Example 1 (1) , 2,3-Thiadiazole-5-carbonyl chloride (304 mg) and 1,2-diamino-2-methylpropane (329 mg) gave the title compound (338 mg) as a colorless oil.
MS (ESI pos.) M / z: 215 ([M + H] + ), (ESI neg.) M / z: 213 ([M-1] - ).
(2) (2S, 4S) -2-cyano-4-fluoro-1-[[2- (4-methyl-1,2,3-thiadiazol-5-yl) carbonylamino-1,1-dimethyl] ethyl Synthesis of amino] acetylpyrrolidine [2- (4-Methyl-1,2,3-thiadiazol-5-yl) carbonylamino-1,1-dimethyl] ethylamine (256 mg) in the same manner as in Example 1 (2) And (2S, 4S) -1-chloroacetyl-2-cyano-4-fluoropyrrolidine (103 mg) were used to give the title compound (107 mg) as a colorless amorphous.
MS (ESI pos.) M / z: 369 ([M + H] + ), 391 ([M + Na] + ), (ESI neg.) M / z: 367 ([M-1] - ).
HRMS (ESI pos.): Calcd for C 15 H 22 FN 6 O 2 S [M + H] + 369.1509, found 369.1516.
1 H-NMR (300 MHz, DMSO-d6) δ 8.75-8.60 (1H, m), 5.61-5.30 (1H, m), 4.99-4.92 (1H, m), 3.94 (1H, dd, J = 23.9, 12.6Hz), 3.83-3.61 (1H, m), 3.45-3.21 (4H, m), 2.78 (3H, s), 2.62-2.25 (2H, m),
1.90-1.80 (1H, brs), 1.04 (6H, s).

Example 12
Synthesis of (2S, 4S) -2-cyano-1-[[2- (3-cyanobenzoyl) amino-1,1-dimethyl] ethylamino] acetyl-4-fluoropyrrolidine 3 In the same manner as in Example 3, -Using cyanobenzoyl chloride (45 mg) and (2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (93 mg) The title compound (28 mg) was obtained as a colorless oil.
MS (ESI pos.) M / z: 371 ([M + H] + ), 394 ([M + Na] + ), (ESI neg.) M / z: 370 ([M-1] - ). HRMS (ESI pos.): Calcd for C 19 H 23 FN 5 O 2 [M + H] + 372.1836, found 372.1848.
1 H-NMR (300 MHz, DMSO-d6) δ 8.52-8.44 (1 H, m), 8.29 (1 H, t, J = 1.4 Hz), 8.50 (1 H, dt, J = 7.9, 1.4 Hz), 8.03- 7.98 (1H, m), 7.69 (1H, t, J = 7.9Hz), 5.46 (1H, brd, J = 52.8Hz), 4.99-4.92 (1H, m), 3.96 (1H, dd, J = 25.0, 12.2Hz), 3.73 (1H, ddd, J = 39.6, 12.7, 3.3Hz), 3.52-3.23 (4H, m), 2.62-2.25 (2H, m), 1.04 (6H, s).

Example 13
Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[2- (2-fluorobenzoyl) amino-1,1-dimethyl] ethylamino] acetylpyrrolidine 2 In the same manner as in Example 3, -Using fluorobenzoyl chloride (43 mg) and (2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (95 mg) The title compound (71 mg) was obtained as a colorless amorphous.
MS (ESI pos.) M / z: 365 ([M + H] + ), 387 ([M + Na] + ), (ESI neg.) M / z: 363 ([M-1] - ).
HRMS (ESI pos.): Calcd for C 18 H 23 F 2 N 4 O 2 [M + H] + 365.1789, found 365.1772.
1 H-NMR (300 MHz, DMSO-d6) δ 8.20-8.05 (1H, m), 7.63 (1H, td, J = 7.6, 1.7 Hz), 7.58-7.48 (1H, m), 7.34-7.24 (2H , m), 5.49 (1H, brd, J = 53.0Hz), 4.98-4.92 (1H, m), 3.94 (1H, dd, J = 23.4,12.7Hz), 3.73 (1H, ddd, J = 41.2,12.0 , 3.4Hz), 3.51-3.27 (2H, m), 3.26-3.20 (2H, m), 2.60-2.26 (2H, m),
1.04 (6H, s).

Example 14
Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[2- (2-quinoxalyl) carbonylamino-1,1-dimethyl] ethylamino] acetylpyrrolidine (1) [2- (2- Synthesis of quinoxaline) carbonylamino-1,1-dimethyl] ethylamine In the same manner as in Example 1 (1), using 1,2-diamino-2-methylpropane (176 mg) and 2-quinoxaline carbonyl chloride (193 mg) The title compound as a colorless solid (
140 mg) was obtained.
MS (ESI pos.) M / z: 267 ([M + Na] + ).
1 H-NMR (300 MHz, DMSO-d6) δ 8.76 (1H, brt, J = 6.1 Hz), 8.26-8.18 (2H, m), 8.04-7.95 (2H, m),
3.28 (2H, d, J = 6.1Hz), 1.07 (6H, s).
(2) Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[2- (2-quinoxaline) carbonylamino-1,1-dimethyl] ethylamino] acetylpyrrolidine Example 1 (2) In the same manner, (2S, 4S) -1-chloroacetyl-2-cyano-4-fluoropyrrolidine (48 mg) and [2- (2-quinoxaline) carbonylamino-1,1-dimethyl] ethylamine (123 mg) Was used to obtain the title compound (86 mg) as a pale yellow amorphous.
MS (ESI pos.) M / z: 399 ([M + H] + ), 421 ([M + Na] + ), (ESI neg.) M / z: 397 ([MH] - ).
HRMS (ESI pos.): Calcd for C 20 H 24 FN 6 O 2 [M + H] + 399.1945, found 399.1944.
1 H-NMR (300 MHz, DMSO-d6) δ 9.50 (1 H, s), 8.78 (1 H, brt, J = 6.1 Hz), 8.26-8.18 (2 H, m), 8.04-
7.94 (2H, m), 5.51 (1H, brd, J = 51.8Hz), 5.04-4.97 (1H, m), 4.00 (1H, dd, J = 25.0,12.7Hz), 3.78 (1H, ddd, J = 39.5,12.5,3.4Hz), 3.55 and 3.38 (2H, ABq, J = 16.6Hz), 3.36 (2H, d, J = 6.1Hz),
2.62-2.30 (2H, m), 2.01 (1H, brs), 1.09 (6H, s).

Example 15
(2S, 4S) -1-[[2- [3- (2-Chlorophenyl) -5-methyl-isoxazol-4-yl] carbonylamino-1,1-dimethyl] ethylamino] acetyl-2-cyano- Synthesis of 4-fluoropyrrolidine In the same manner as in Example 3, 3- (2-chlorophenyl) -5-methylisoxazole-4-carbonyl chloride (82 mg) and (2S, 4S) -1-[(2-amino The title compound (86 mg) was obtained as a colorless amorphous using -1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (111 mg).
MS (ESI pos.) M / z: 462 ([M + H] + ), 484 ([M + Na] + ), (ESI neg.) M / z: 460 ([M-1] - ).
HRMS (ESI pos.): Calcd for C 22 H 26 FN 5 O 3 Cl [M + H] + 462.1708, found 462.1726.
1 H-NMR (300 MHz, DMSO-d6) δ7.61-7.42 (4H, m), 7.41-7.35 (1H, m), 5.46 (1H, brd, J = 53.2Hz),
4.99-4.93 (1H, m), 3.89 (1H, dd, J = 24.0,12.0Hz), 3.79-3.57 (1H, m), 3.36-3.10 (2H, m), 3.10-
3.00 (2H, m), 2.66 (3H, s), 2.60-2.26 (2H, m), 0.88 (6H, s).

Example 16
Synthesis of (2S, 4S) -1-[[2- (1-adamantyl) carbonylamino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine 1 In the same manner as in Example 3, -Using adamantanecarbonyl chloride (67 mg) and (2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (117 mg) The title compound (80 mg) was obtained as a colorless amorphous.
MS (ESI pos.) M / z: 405 ([M + H] + ), 427 ([M + Na] + ), (ESI neg.) M / z: 403 ([M-1] - ).
HRMS (ESI pos.): Calcd for C 22 H 34 FN 4 O 2 [M + H] + 405.2666, found 405.2660.
1 H-NMR (300 MHz, DMSO-d6) δ 7.16-7.05 (1H, m), 5.50 (1H, brd, J = 53.0Hz), 5.05-4.93 (1H, m),
4.10-3.85 (1H, m), 3.84-3.62 (1H, m), 3.53-3.20 (2H, m), 3.05-2.97 (2H, m), 2.60-2.25 (2H, m), 2.02-1.92 (3H , m), 1.86-1.60 (12H, m), 0.94 (6H, s).

Example 17
(2S, 4S) -2-cyano-4-fluoro-1-[[2- (5-methyl-2-phenyl-1,2,3-triazol-4-yl) carbonylamino-1,1-dimethyl] Synthesis of ethylamino] acetylpyrrolidine In the same manner as in Example 3, 4-methyl-2-phenyl-1,2,3-triazole-5-carbonyl chloride (62 mg) and (2S, 4S) -1-[(2 The title compound (64 mg) was obtained as a pale yellow amorphous using -amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (97 mg).
MS (ESI pos.) M / z: 428 ([M + H] + ), 450 ([M + Na] + ), (ESI neg.) M / z: 426 ([M-1] - ).
HRMS (ESI pos.): Calcd for C 21 H 27 FN 7 O 2 [M + H] + 428.2210, found 428.2200.
1 H-NMR (300 MHz, DMSO-d6) δ 8.35-8.25 (1H, m), 8.07 (2H, d, J = 7.8Hz), 7.59 (2H, t, J = 7.8Hz),
7.50-7.42 (1H, m), 5.46 (1H, brd, J = 52.9Hz), 5.02-4.95 (1H, m), 3.97 (1H, dd, J = 24.1,12.3Hz), 3.86-3.65 (1H, m), 3.53-3.17 (4H, m), 2.62-2.25 (2H, m), 2.53 (3H, s), 1.05 (6H, s).

Example 18
Of (2S, 4S) -2-cyano-4-fluoro-1-[[2- (2-phenyl-3-propyl-pyrazol-4-yl) carbonylamino-1,1-dimethyl] ethylamino] acetylpyrrolidine Synthesis 1-Phenyl-5-N-propylpyrazole-4-carbonyl chloride (66 mg) and (2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino were prepared in the same manner as in Example 3. The title compound (79 mg) was obtained as colorless amorphous using acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (92 mg).
MS (ESI pos.) M / z: 455 ([M + H] + ), 477 ([M + Na] + ), (ESI neg.) M / z: 453 ([M-1] - ).
HRMS (ESI pos.): Calcd for C 24 H 32 FN 6 O 2 [M + H] + 455.2571, found 455.2555.
1 H-NMR (300 MHz, DMSO-d6) δ 8.14 (1 H, s), 7.95-7.85 (1 H, m), 7.61-7.43 (5 H, m), 5.48 (1 H, brd, J = 52.5 Hz), 5.02-4.94 (1H, m), 3.96 (1H, dd, J = 23.7,12.3Hz), 3.86-3.64 (1H, m), 3.58-3.30 (2H, m), 3.26-3.16 (2H, m), 2.97-2.85 (2H, m), 2.62-2.26 (2H, m), 1.46-1.32 (2H, m), 1.04 (6H, s),
0.70 (3H, t, J = 7.0Hz).

Example 19
Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[2- (2-pyridyl) carbonylamino-1,1-dimethyl] ethylamino] acetylpyrrolidine In the same manner as in Example 4, picoli Using noyl chloride hydrochloride (51 mg) and (2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (100 mg) The title compound (31 mg) was obtained as a yellow oil.
MS (ESI pos.) M / z: 348 ([M + H] + ), 370 ([M + Na] + ), (ESI neg.) M / z: 346 ([M-1] - ).
HRMS (ESI pos.): Calcd for C 17 H 23 FN 5 O 2 [M + H] + 348.1836, found 348.1831.
1 H-NMR (300 MHz, DMSO-d6) δ 8.69-8.63 (1H, m), 8.61-8.52 (1H, m), 8.05 (1H, m), 8.00 (1H, td, J = 7.3,1.7Hz ), 7.65-7.57 (1H, m), 5.46 (1H, brd, J = 52.8Hz), 5.01-4.94 (1H, m), 3.96 (1H, dd, J =
23.9,11.8Hz), 3.86-3.64 (1H, m), 3.54-3.24 (4H, m), 2.62-2.25 (2H, m), 1.04 (6H, s).

Example 20
(2S, 4S) -2-cyano-1-[[2- [4-[(N, N-dimethylaminomethylene) aminosulfonyl] benzoyl] amino-1,1-dimethyl] ethylamino] acetyl-4-fluoro Synthesis of pyrrolidine In the same manner as in Example 4, sulfamidobenzoyl chloride / N, N-dimethylformamide complex (72 mg) and (2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino were synthesized. The title compound (55 mg) was obtained as colorless amorphous using acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (81 mg).
MS (ESI pos.) M / z: 481 ([M + H] + ), 503 ([M + Na] + ), (ESI neg.) M / z: 479 ([M-1] - ).
HRMS (ESI pos.): Calcd for C 21 H 30 FN 6 O 4 S [M + H] + 481.2033, found 481.2027.
1 H-NMR (300MHz, DMSO-d6) δ 8.44-8.36 (1H, m), 8.24 (1H, s), 7.95 (2H, d, J = 8.4Hz), 7.84 (2H, d, J = 8.4 Hz), 5.60-5.35 (1H, m), 4.99-4.92 (1H, m), 3.95 (1H, dd, J = 24.1,12.4Hz), 3.84-3.63 (1H, m), 3.52-3.19 (4H, m), 3.15 (3H, s), 2.91 (3H, s), 2.62-2.25 (2H, m), 2.00-1.98 (1H, brs), 1.03 (3H, s), 1.02 (3H, s).

Example 21
(2S, 4S) -2-cyano-4-fluoro-1-[[2- (5-methyl-2-trifluoromethylfuran-3-yl) carbonylamino-1,1-dimethyl] ethylamino] acetylpyrrolidine In the same manner as in Example 4, 5-methyl-2- (trifluoromethyl) furan-3-carbonyl chloride (51 mg) and (2S, 4S) -1-[(2-amino-1,1-dimethyl) ) Ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (83 mg) was used to give the title compound (60 mg) as a colorless amorphous.
MS (ESI pos.) M / z: 419 ([M + H] + ), 441 ([M + Na] + ), (ESI neg.) M / z: 417 ([M-1] - ).
HRMS (ESI pos.): Calcd for C 18 H 23 F 4 N 4 O 3 S [M + H] + 419.1706, found 419.1691.
1 H-NMR (300 MHz, DMSO-d6) δ 8.30-8.22 (1H, m), 6.63 (1H, s), 5.49 (1H, brd, J = 53.0 Hz), 4.98-
4.92 (1H, m), 3.94 (1H, dd, J = 24.1,12.3Hz), 3.72 (1H, ddd, J = 39.7,12.4,3.4Hz), 3.48-3.24 (2H, m), 3.24-3.08 ( 2H, m), 2.62-2.25 (2H, m), 2.36 (3H, s), 1.95-1.85 (1H, brs), 1.00 (6H, s).

Example 22
Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[2- (4-morpholino) carbonylamino-1,1-dimethyl] ethylamino] acetylpyrrolidine In the same manner as in Example 4, morpholine Using -4-carbonyl chloride (50 mg) and (2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (117 mg) The title compound (105 mg) was obtained as colorless amorphous.
MS (ESI pos.) M / z: 356 ([M + H] + ), 378 ([M + Na] + ), (ESI neg.) M / z: 354 ([M-1] - ).
HRMS (ESI pos.): Calcd for C 16 H 27 FN 5 O 3 [M + H] + 356.2098, found 356.2105.
1 H-NMR (300 MHz, DMSO-d6) δ6.36-6.26 (1H, m), 5.46 (1H, brd, J = 53.0Hz), 4.99-4.92 (1H, m),
3.94 (1H, dd, J = 24.0,12.5Hz), 3.72 (1H, ddd, J = 39.4,12.8,3.4Hz), 3.61-3.47 (4H, m), 3.46-
3.19 (6H, m), 3.00 (2H, d, J = 5.8Hz), 2.62-2.25 (2H, m), 1.90-1.80 (1H, brs), 0.95 (6H, s).

Example 23
Synthesis of (2S, 4S) -1-[[2- (2-carboxyphenyl) carbonylamino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine
(2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (158 mg) was suspended in dioxane (2 mL) and triethylamine ( 0.14 mL) and N, N-dimethylformamide (2 mL) were added. Furthermore, phthalic anhydride (74 mg) was added, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue was purified by resin column chromatography (resin: Toyopearl, developing solvent; 0.1 M aqueous hydrochloric acid solution) to obtain the title compound (123 mg) as a colorless amorphous substance.
MS (ESI pos.) M / z: 391 ([M + H] + ), 413 ([M + Na] + ), (ESI neg.) M / z: 389 ([MH] - ).
HRMS (ESI pos.): Calcd for C 19 H 24 FN 4 O 4 [M + H] + 389.1625, found 389.1640.
1 H-NMR (300 MHz, DMSO-d6) δ: 8.64 (1H, brt, J = 6.1 Hz), 7.95-7.51 (4H, m), 5.57 (1H, brd, J = 52.8 Hz), 5.13-5.05 ( 1H, m), 4.34-3.42 (6H, m), 2.58-2.40 (2H, m), 1.35 (3H, s), 1.34 (3H, s).

Example 24
Synthesis of (2S, 4S) -2-cyano-1-[[2- (2-cyanobenzene) sulfonylamino-1,1-dimethyl] ethylamino] acetyl-4-fluoropyrrolidine In the same manner as in Example 5. (2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (95 mg), triethylamine (0.13 mL) and 2-cyanobenzene The title compound (41 mg) was obtained as a pale yellow amorphous using sulfonyl chloride (54 mg).
MS (ESI pos.) M / z: 408 ([M + H] + ), 430 ([M + Na] + ), (ESI neg.) M / z: 406 ([MH] - ).
HRMS (ESI pos.): Calcd for C 18 H 23 FN 5 O 3 S [M + H] + 408.1506, found 408.1512.
1 H-NMR (300 MHz, DMSO-d6) δ 8.20-7.78 (5H, m), 5.48 (1H, brd, J = 53.0Hz), 4.97-4.91 (1H, m),
3.88 (1H, dd, J = 23.8,12.0Hz), 3.67 (1H, ddd, J = 39.6,12.3,3.4Hz), 3.33 and 3.18 (2H, ABq, J = 16.5Hz), 2.86 (2H, s) , 2.60-2.26 (2H, m), 0.96 (6H, s).

Example 25
Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[(2-methanesulfonylamino-1,1-dimethyl) ethylamino] acetylpyrrolidine Methanesulfonyl chloride (24 μL) was prepared in the same manner as in Example 5. ) And (2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (108 mg) as a colorless amorphous 51 mg) was obtained.
MS (ESI pos.) M / z: 321 ([M + H] + ), 343 ([M + Na] + ), (ESI neg.) M / z: 319 ([M-1] - ).
HRMS (ESI pos.): Calcd for C 12 H 22 FN 4 O 3 S [M + H] + 321.1397, found 321.1405.
1 H-NMR (300 MHz, DMSO-d6) δ 6.90-6.76 (1H, m), 5.46 (1H, brd, J = 51.0Hz), 4.99-4.91 (1H, m), 3.93 (1H, dd, J = 24.4, 12.6Hz), 3.72 (1H, ddd, J = 39.6, 12.6, 3.4Hz), 3.45-3.20 (2H, m), 2.89 (3H, s), 2.87-2.81 (2H, m), 2.62- 2.26 (2H, m), 1.00 (6H, s).

Example 26
Synthesis of (2S, 4S) -2-cyano-1- (1,1-diethylpropargylamino) acetyl-4-fluoropyrrolidine (2S, 4S) -1-chloroacetyl in the same manner as in Example 1 (2) The title compound (215 mg) was obtained as a colorless solid using 2-cyano-4-fluoropyrrolidine (191 mg) and 1,1-diethylpropargylamine (333 mg).
MS (ESI pos.) M / z: 288 ([M + Na] + ).
HRMS (ESI pos.): Calcd for C 14 H 21 FN 3 O [M + H] + 266.1669, found 266.1654.
1 H-NMR (300 MHz, DMSO-d6) δ 5.48 (1 H, brd, J = 51.5 Hz), 4.99-4.93 (1 H, m), 3.95 (1 H, dd, J = 24.6, 12.6 Hz), 3.72 ( 1H, ddd, J = 39.6,12.6,3.4Hz), 3.50-3.27 (2H, m), 3.18 (1H, s), 2.62-2.28 (2H, m), 2.06 (1H, t, J = 5.9Hz) , 1.53 (4H, q, J = 7.4Hz), 0.87 (6H, t, J = 7.4Hz).

Example 27
Synthesis of (2S, 4S) -2-cyano-1- (1,1-dimethylcinnamylamino) acetyl-4-fluoropyrrolidine (1) Synthesis of 1,1-dimethylcinnamylamine Example 10 (1) and In the same manner, the title compound (210 mg) was obtained as a brown oily substance using cinnamonitrile (500 mg).
MS (ESI pos.) M / z: 162 ([M + H] + ), 184 ([M + Na] + ), 145 ([M−NH 2 ] + ).
(2) Synthesis of (2S, 4S) -2-cyano-1- (1,1-dimethylcinnamylamino) acetyl-4-fluoropyrrolidine 1,1-dimethylcin in the same manner as in Example 1 (2) Using namylamine (200 mg) and (2S, 4S) -1-chloroacetyl-2-cyano-4-fluoropyrrolidine (107 mg), the title compound (74 mg) was obtained as a colorless powdery substance.
MS (ESI pos.) M / z: 338 ([M + Na] + ).
HRMS (ESI pos.): Calcd for C 18 H 22 FN 3 ONa [M + Na] + 338.1645, found 338.1641.
1 H-NMR (300 MHz, DMSO-d6) δ 7.44-7.38 (2 H, m), 7.35-7.27 (2 H, m), 7.25-7.17 (1 H, m), 6.40 (1 H, d, J = 16.3 Hz ), 6.21 (1H, d, J = 16.3Hz), 5.42 (1H, brd, J = 51.8Hz), 4.91 (1H, d, J = 8.9Hz), 3.90 (1H, dd, J = 23.5,12.4Hz) ), 3.78-3.56 (1H, m), 3.44-3.14 (2H, m), 2.60-2.20 (2H, m), 2.06-1.98 (1H, m), 1.22 (6H, s).

Example 28
Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[2- (pyridin-2-yl) -1,1-bis (hydroxymethyl)] ethylamino] acetylpyrrolidine (1) 2- Synthesis of [N- (tert-butoxycarbonyl) amino] -2- (pyridin-2-yl) methylmalonic acid diethyl ester A 60% sodium hydride oil (0.88 g) was added to N, N-dimethylformamide (0.88 g) under nitrogen atmosphere. 10 mL), and a solution of 2- [N- (tert-butoxycarbonyl) amino] malonic acid diethyl ester (2.75 g) in N, N-dimethylformamide (110 mL) was added at room temperature. Then, a solution of 2- (chloromethyl) pyridine hydrochloride (1.64 g) in N, N-dimethylformamide (10 mL) was added and stirred overnight at room temperature. Ethyl acetate (100 mL) and saturated brine (100 mL) were added to the reaction solution, and the phases were separated. The extract was washed 4 times with saturated brine (50 mL), dried over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 7 to 1: 5) to give the title compound (2.61 g) as a colorless oil.
MS (ESI pos.) M / z: 389 ([M + Na] + ).
1 H-NMR (300 MHz, DMSO-d6) δ 8.44 (1 H, ddd, J = 4.8, 1.7, 0.9 Hz), 7.57 (1 H, td, J = 7.6, 1.9 Hz),
7.14-7.08 (2H, m), 5.95 (1H, brs), 4.38-4.20 (4H, m), 3.80 (2H, s), 1.42 (9H, s), 1.28 (6H, t, J =
7.1Hz).
(2) Synthesis of N- (tert-butoxycarbonyl) -2- (pyridin-2-yl) -1,1-bis (hydroxymethyl) ethylamine Under nitrogen atmosphere, lithium borohydride (0.419 g) was added to tetrahydrofuran (30 mL). ) And ice-cooled. To this was added dropwise a solution of 2- [N- (tert-butoxycarbonyl) amino] -2- (pyridin-2-yl) methylmalonic acid diethyl ester (2.35 g) in tetrahydrofuran (15 mL) over 15 minutes. The mixture was warmed to room temperature and stirred overnight. The mixture was ice-cooled again, and 10% aqueous potassium carbonate solution (20 mL) was added. Ethyl acetate (100 mL) and saturated brine (50 mL) were added to the reaction mixture, and the phases were separated. The extract was washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 3: 2-7: 1) to give the title compound (0.22 g) as a colorless oil.
MS (ESI pos.) M / z: 305 ([M + Na] + ), (ESI neg.) M / z: 281 ([MH] - ).
1 H-NMR (300 MHz, CDCl 3 ) δ 8.50 (1 H, d like, J = 5.0 Hz), 7.66 (1 H, t like, J = 7.8 Hz), 7.30 (1 H, d, J = 7.9 Hz), 7.21 (1H, t like, J = 5.0Hz), 5.49 (1H, brs), 5.15 (2H, brs), 3.63 and 3.49 (4H, ABq, J = 11.7Hz), 3.27 (2H, s), 1.39 ( 9H, s).

(3) Synthesis of 2- (pyridin-2-yl) -1,1-bis (hydroxymethyl) ethylamine dihydrochloride N- (tert-butoxycarbonyl) -2- (pyridin-2-yl) -1,1 When bis (hydroxymethyl) ethylamine (210 mg) was added with 4M hydrochloric acid-dioxane solution (3 mL) at room temperature, it turned into a white wax. When methanol (0.6 mL) was added, it gradually changed to a powder suspension. After stirring for 30 minutes at room temperature, the precipitate was collected by filtration, and the title compound (
166 mg) was obtained.
MS (ESI pos.) M / z: 182.9 ([M + H] + ), 204.9 ([M + Na] + ).
1 H-NMR (300 MHz, DMSO-d6) δ 8.72 (1H, d, J = 5.1 Hz), 8.35-8.10 (4H, m), 7.84-7.67 (2H, m), 3.53 and 3.48 (4H, ABq , J = 11.5Hz), 3.28 (2H, s).
(4) Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[2- (pyridin-2-yl) -1,1-bis (hydroxymethyl)] ethylamino] acetylpyrrolidine 2- (Pyridin-2-yl) -1,1-bis (hydroxymethyl) ethylamine dihydrochloride (160 mg), (2S, 4S) -1-chloroacetyl-2-cyano-4-fluoropyrrolidine (
80 mg), potassium iodide (70 mg) and triethylamine (0.23 mL) were used in the same manner as in Example 1 (2) to obtain the title compound (30 mg) as a colorless powder.
MS (ESI pos.) M / z: 337 ([M + H] + ), 359 ([M + Na] + ), (ESI neg.) M / z: 335 ([MH] - ).
HRMS (ESI pos.): Calcd for C 16 H 22 FN 4 O 3 [M + H] + 337.1676, found 337.1680.
1 H-NMR (300 MHz, DMSO-d6) δ 8.45 (1 H, d like, J = 5.2 Hz), 7.69 (1 H, td, J = 6.0, 1.7 Hz), 7.31 (1 H, d, J = 7.9 Hz) ), 7.21 (1H, dd, J = 6.9,5.2Hz), 5.48 (1H, brd, J = 50.2Hz), 4.97-4.91 (1H, m), 4.70-
4.63 (2H, m), 3.99 (1H, dd, J = 24.3,12.5Hz), 3.80-3.64 (1H, m), 3.60 and 3.46 (2H, ABq, J = 16.4Hz), 3.31-3.20 (4H, m), 2.80 (2H, s), 2.60-2.25 (2H, m).

Example 29
Synthesis of (2S, 4S) -1-[[1- (benzofuran-2-yl) -1-methyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine (1) [1- (benzofuran-2- Synthesis of l) -1-methyl] ethylamine In the same manner as in Example 9 (1), 2-benzofurancarbonitrile (1000 mg) was used to give the title compound (284 mg) as a brown oily substance.
MS (ESI pos.) M / z: 159 ([M−NH 2 ] + ).
(2) Synthesis of (2S, 4S) -1-[[1- (benzofuran-2-yl) -1-methyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine Similar to Example 9 (2) [1- (Benzofuran-2-yl) -1-methyl] ethylamine (204 mg) and (2S, 4S) -1-chloroacetyl-2-cyano-4-fluoropyrrolidine (89 mg) The title compound (93 mg) was obtained as a solid.
MS (ESI pos.) M / z: 352 ([M + Na] + ), (ESI neg.) M / z: 328 ([M-1] - ).
HRMS (ESI pos.): Calcd for C 18 H 20 FN 3 O 2 Na [M + Na] + 352.1437 found 352.1454.
1 H-NMR (300 MHz, DMSO-d6) δ 7.59-7.48 (2H, m), 7.28-7.26 (2H, m), 6.70 (1H, s), 5.38 (1H, brd, J = 52.2Hz), 4.90-4.83 (1H, m), 3.85 (1H, dd, J = 23.2,12.3Hz), 3.60 (1H, ddd, J = 39.6,12.5,3.4Hz), 3.38-3.04 (2H, m), 2.60- 2.18 (2H, m), 1.48 (6H, s).

Example 30
Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[1- (pyridin-2-yl) -1-methyl] ethylamino] acetylpyrrolidine (1) [1- (pyridine-2- Synthesis of yl) -1-methyl] ethylamine The title compound (196 mg) was obtained as a brown oily substance using 2-cyanopyridine (685 mg) in the same manner as in Example 10 (1).
MS (ES +) m / z: 137 ([M + H] + ), 159 ([M + Na] + ), 120 ([M−NH 2 ] + ).
(2) Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[1- (pyridin-2-yl) -1-methyl] ethylamino] acetylpyrrolidine Similar to Example 1 (2) Using [1- (pyridin-2-yl) -1-methyl] ethylamine (177 mg) and (2S, 4S) -1-chloroacetyl-2-cyano-4-fluoropyrrolidine (112 mg) The title compound (106 mg) was obtained as a brown amorphous. For purification, preparative TLC (developing solvent; chloroform: methanol = 5: 1) was used.
MS (ESI pos.) M / z: 291 ([M + H] + ), 313 ([M + Na] + ), (ESI neg.) M / z: 289 ([M-1] - ).
HRMS (ESI pos.): Calcd for C 15 H 20 FN 4 O [M + H] + 291.1621, found 291.1612.
1 H-NMR (300 MHz, CDCl 3 ) δ8.61-8.54 (1H, m), 7.67 (1H, td, J = 7.7,1.9Hz), 7.49-7.39 (1H, m),
7.19-7.12 (1H, m), 5.48-5.16 (1H, m), 4.92 (1H, d, J = 9.2Hz), 4.03-3.26 (4H, m), 2.63 (1H, t, J =
15.8Hz), 2.40-2.12 (2H, m), 1.53 (6H, s).

Table 1 shows the structures of the compounds obtained in Examples 1-30.


Examples 31-47
The structures of the compounds obtained by the same method as in Example 3 (4) are shown in Table 2.


Example 48
Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[(2-isobutylamino-1,1-dimethyl) ethylamino] acetylpyrrolidine In the same manner as in Example 7, isobutyraldehyde (34 mg) and Using (2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (150 mg) as a colorless oily substance, the title compound (99 mg )
1 H-NMR (300 MHz, DMSO-d6) δ 5.60-5.28 (1H, m), 4.98-4.90 (1H, m), 3.93 (1H, dd, J = 23.5,12.4Hz), 3.71 (1H, ddd , J = 39.6,12.4,3.4Hz), 3.41-3.16 (2H, m), 2.62-2.28 (6H), 1.64 (1H, m, J = 6.7Hz), 0.97 (6H, s), 0.85 (6H, d, J = 6.7Hz).

Example 49
Synthesis of (2S, 4S) -2-cyano-1-[(2-diethylamino-1,1-dimethyl) ethylamino] acetyl-4-fluoropyrrolidine In the same manner as in Example 7, acetaldehyde (23 mg) and (2S , 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (150 mg) as a colorless oil and the title compound (38 mg) and (2S, 4S) -2-cyano-4-fluoro-1-[(2-ethylamino-1,1-dimethyl) ethylamino] acetylpyrrolidine (23 mg) was obtained as a colorless oil.
1 H-NMR (300 MHz, DMSO-d6) δ 5.60-5.30 (1H, m), 4.99-4.90 (1 H, m), 3.93 (1 H, dd, J = 23.3, 12.5 Hz), 3.71 (1 H, ddd , J = 39.6, 12.5, 3.4Hz), 3.44-3.20 (2H, m), 2.62-2.30 (6H), 2.28-2.18 (2H, m), 1.01-0.85 (12H, m).

Example 50
Synthesis of (2S, 4S) -2-cyano-1-[(2-dihexylamino-1,1-dimethyl) ethylamino] acetyl-4-fluoropyrrolidine In the same manner as in Example 7, hexanal (46 mg) and ( 2S, 4S) -1-[(2-Amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (150 mg) was used to give the title compound (75 mg) as a colorless oil. Got.
1 H-NMR (300 MHz, DMSO-d6) δ 5.60-5.30 (1H, m), 4.99-4.90 (1H, m), 4.08-2.80 (6H), 2.60-2.20 (4H), 1.98-1.82 (2H , m), 1.50-1.10 (16H, m), 1.00-0.70 (10H).

Example 51
Synthesis of (2S, 4S) -1-[[[2-bis (3,5,5-trimethylhexyl) amino] -1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine 7,5,5-trimethylhexanal (69 mg) and (2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoro The title compound (106 mg) was obtained as a colorless oil using pyrrolidine dihydrochloride (150 mg).
1 H-NMR (300 MHz, DMSO-d6) δ 5.46 (1H, brd, J = 50.8 Hz), 4.98-4.90 (1H, m), 3.92 (1H, dd, J =
24.2,12.7Hz), 3.83-3.20 (5H), 2.62-2.25 (1H), 1.49-0.98 (14H, m), 0.97-0.82 (30H, m).

Example 52
Synthesis of (2S, 4S) -1-[[2- (N-benzoyl-N-isobutyl) amino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine Example 3 (4) In the same manner as (2S, 4S) -2-cyano-4-fluoro-1-[(2-isobutylamino-1,1-dimethyl) ethylamino] acetylpyrrolidine (67 mg) obtained in Example 48 And benzoyl chloride (32 mg) were used to give the title compound (68 mg) as a colorless oil.
1 H-NMR (300 MHz, DMSO-d6) δ 7.50-7.28 (5H, m), 5.46 (1H, brd, J = 51.1Hz), 5.01-4.91 (1H, m),
4.06-3.18 (8H), 2.62-2.35 (2H, m), 1.90-1.78 (1H, m), 1.13-0.88 (6H, m), 0.86-0.54 (6H, m).

Example 53
Synthesis of (2S, 4S) -1-[[2- (N-benzoyl-N-ethyl) amino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine Example 3 (4) In the same manner as (2S, 4S) -2-cyano-4-fluoro-1-[(2-ethylamino-1,1-dimethyl) ethylamino] acetylpyrrolidine (23 mg) obtained in Example 49 And benzoyl chloride (12 mg) to give the title compound (18 mg) as a pale yellow oil.
1 H-NMR (300 MHz, DMSO-d6) δ 7.47-7.28 (5H, m), 5.46 (1H, brd, J = 51.1Hz), 4.99-4.91 (1H, m),
4.06-3.22 (8H), 2.62-2.26 (2H, m), 1.20-0.74 (9H, m).

Example 54
Synthesis of (2S, 4S) -1-[[2- (N-aminocarbonylmethyl-N-benzoyl) amino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine (1) Synthesis of 2S, 4S) -1-[[(2-aminocarbonylmethyl) amino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine
(2S, 4S) -1-[(2-Amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (150 mg) was added to N, N-dimethylformamide (3.0 mL). After adding triethylamine (199 μL) and 2-chloroacetamide (45 mg) under ice cooling, the mixture was returned to room temperature and stirred for 3 days. After the reaction solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol: 28% aqueous ammonia solution = 15: 1: 0.1 to 12: 1: 0.1). The title compound (41 mg) was obtained as a colorless oil.
1 H-NMR (300MHz, DMSO-d6) δ7.23 (1H, brs), 7.02 (1H, brs), 5.45 (1H, brd, J = 53.3Hz), 4.99-
4.90 (1H, m), 3.94 (1H, dd, J = 39.6,12.7,3.2Hz), 3.73 (1H, ddd, J = 39.6,12.7,3.2Hz), 3.44-
3.20 (2H), 3.04 (2H, s), 2.62-2.26 (4H) 1.03-0.91 (6H, m).
(2) Synthesis of (2S, 4S) -1-[[2- (N-aminocarbonylmethyl-N-benzoyl) amino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine In the same manner as in Example 3 (4), (2S, 4S) -1-[[(2-aminocarbonylmethyl) amino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine ( 34 mg) and benzoyl chloride (13 mg) were used to obtain the title compound (28 mg) as a pale yellow amorphous.
1 H-NMR (300 MHz, DMSO-d6) δ 7.47-7.25 (6H, m), 7.00 (1H, brs), 5.65-5.25 (1H, m), 5.08-4.91 (1H, m), 4.03-3.90 (2H, m), 3.86-2.90 (6H), 2.62-2.25 (2H, m), 1.28-1.05 (6H, m).

Example 55
Synthesis of (2S, 4S) -2-cyano-1-[[2- (2,6-dimethylpiperidino) -1,1-dimethyl] ethylamino] acetyl-4-fluoropyrrolidine (1) (2, Synthesis of 6-dimethylpiperidino) acetonitrile 2,6-dimethylpiperidine (1.00 g) was dissolved in N, N-dimethylformamide (15 mL), and bromoacetonitrile (1.08 g) and sodium carbonate (983 mg) were added at room temperature. The mixture was heated to 80 ° C. and stirred for 3 hours, then returned to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol: 28% aqueous ammonia solution = 50: 1: 0.1) to give the title compound (791 mg) as a yellow oily substance. )
1 H-NMR (300 MHz, CDCl 3 ) δ 3.79 (2H, s), 2.53-2.39 (2H, m), 1.74-1.62 (3H, m), 1.50-1.24 (3H, m), 1.12 (6H, d, J = 6.2Hz).
(2) Synthesis of 1- (2,6-dimethylpiperidino) -2-methyl-2-aminopropane In the same manner as in Example 10 (1), (2,6-dimethylpiperidino) acetonitrile (
781 mg) and methyllithium (1.2 M / diethyl ether solution, 12.8 mL) were used to give the title compound (671 mg) as a yellow oil.
1 H-NMR (300 MHz, CDCl 3 ) δ2.94-2.80 (2H, m), 2.34 (2H, s), 1.74-1.57 (3H, m), 1.51-1.33 (3H, m), 1.07 (3H, s), 1.05 (3H, s), 1.03 (6H, s).

(3) Synthesis of (2S, 4S) -2-cyano-1-[[2- (2,6-dimethylpiperidino) -1,1-dimethyl] ethylamino] acetyl-4-fluoropyrrolidine Example 1 In the same manner as in (2), 1- (2,6-dimethylpiperidino) -2-methyl-2-aminopropane (180 mg) and (2S, 4S) -1-chloroacetyl-2-cyano-4- The title compound (69 mg) was obtained as a colorless amorphous using fluoropyrrolidine (84 mg).
1 H-NMR (300 MHz, DMSO-d6) δ 5.50 (1 H, brd, J = 52.5 Hz), 5.08-5.00 (1 H, m), 4.04 (1 H, dd, J = 23.9, 12.7 Hz), 3.94 3.56 (3H), 3.16-3.06 (2H, m), 2.90-2.74 (2H, m), 2.56-2.24 (2H, m), 1.73-1.30 (6H, m), 1.20-1.14 (12H, m).

Example 56
Synthesis of (2S, 4S) -2-cyano-1-[[2- (2,5-dimethylpyrrolidin-1-yl) -1,1-dimethyl] ethylamino] acetyl-4-fluoropyrrolidine (1) Synthesis of 2,5-dimethyl-1-pyrrolidinyl) acetonitrile 2,5-dimethylpyrrolidine (491 mg) was dissolved in THF (5 mL), bromoacetonitrile (552 mg) and sodium carbonate (513 mg) were added at room temperature, and 1 at room temperature. After raising the temperature to 65 ° C. for 1 hour and stirring for 1 hour, the mixture was returned to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol: 28% aqueous ammonia solution = 50: 1: 0 to 50: 1: 0.1) to give a colorless oil The title compound (357 mg) was obtained as a substance.
1 H-NMR (300 MHz, CDCl 3 ) δ 3.62 (2H, s), 3.30-3.17 (2H, m), 2.79-2.63 (2H, m), 2.14-1.98 (2H, m), 1.10 (3H, s), 1.08 (3H, s).
(2) Synthesis of 1- (2,5-dimethyl-1-pyrrolidinyl) -2-methyl-2-aminopropane (2,5-dimethyl-1-pyrrolidinyl) acetonitrile in the same manner as in Example 10 (1) (350 mg) and methyllithium (1.2 M / diethyl ether solution, 6.3 mL) were used to give the title compound (100 mg) as a brown oil.
1 H-NMR (300 MHz, CDCl 3 ) δ3.07-3.01 (2H, m), 2.64 (1H, d, J = 14.1Hz), 2.16 (1H, d, J = 14.1Hz),
2.05-1.89 (2H, m), 1.44-1.26 (2H, m), 1.07 (3H, s), 1.06 (3H, s), 0.99 (3H, s), 0.97 (3H, s).

(3) Synthesis of (2S, 4S) -2-cyano-1-[[2- (2,5-dimethylpyrrolidin-1-yl) -1,1-dimethyl] ethylamino] acetyl-4-fluoropyrrolidine In the same manner as in Example 1 (2), 1- (2,5-dimethyl-1-pyrrolidinyl) -2-methyl-2-aminopropane (88 mg) and (2S, 4S) -1-chloroacetyl-2-cyano The title compound (22 mg) was obtained as a brown oily substance using -4-fluoropyrrolidine (45 mg).
1 H-NMR (300 MHz, DMSO-d6) δ 5.60-5.30 (1H, m), 4.99-4.90 (1H, m), 4.83-3.85 (1H, m), 3.83
3.60 (1H, m), 3.45-3.20 (2H), 3.12-2.98 (2H, m), 2.64-2.54 (1H, dd, J = 14.0,5.8Hz), 2.53-2.20 (2H), 2.25-2.16 ( 1H, dd, J = 14.0,5.8Hz), 1.99-1.75 (3H, m), 1.40-1.20 (2H, m), 1.00-0.90 (12H, m).

Example 57
Synthesis of (2S, 4S) -1-[[2- (benzothiazol-6-yl) carbonylamino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine (1) 1- [ Synthesis of 2- (benzothiazol-6-yl) carbonylamino] -2-methyl-2-aminopropane In the same manner as in Example 2 (1), benzothiazole-6-carboxylic acid (300 mg) and 1,2- Diamino-2-dimethylpropane (295 mg) was used to give the title compound (261 mg) as a yellow oil.
1 H-NMR (300MHz, DMSO-d6) δ9.52 (1H, s), 8.68 (1H, d, J = 1.5Hz), 8.46-8.34 (1H, m), 8.15 (1H, d, J = 8.6 Hz), 8.01 (1H, dd, J = 8.6,1.5Hz), 3.23 (2H, brd, J = 5.9Hz), 1.08-0.98 (6H, m).
(2) Synthesis of (2S, 4S) -1-[[2- (benzothiazol-6-yl) carbonylamino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine Example 1 In the same manner as in (2), 1- [2- (benzothiazol-6-yl) carbonylamino] -2-methyl-2-aminopropane (205 mg) and (2S, 4S) -1-chloroacetyl-2- Cyano-4-fluoropyrrolidine (71 mg) was used to give the title compound (96 mg) as a pale yellow amorphous.
1 H-NMR (300MHz, DMSO-d6) δ9.53 (1H, s), 8.67 (1H, s), 8.44-8.34 (1H, m), 8.15 (1H, d, J = 8.6Hz), 8.00 ( 1H, d, J = 8.6Hz), 5.45 (1H, brd, J = 51.6Hz), 5.00-4.92 (1H, m), 3.96 (1H, dd, J = 24.3,12.8Hz), 3.86-3.18 (5H ), 2.62-2.25 (2H), 1.06 (6H, s).

Example 58
Synthesis of (2S, 4S) -1-[[2- (N-benzoyl-N-hexyl) amino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine (1) 1-hexyl Synthesis of amino-2-methyl-2-aminopropane Using hexanal (1.13 g) and 1,2-diamino-2-methylpropane (1.00 g) in the same manner as in Example 7, the title compound ( 1.16 g) was obtained.
1 H-NMR (300 MHz, CDCl 3 ) δ 4.35-4.20 (4H, m), 2.69 (1H, t, J = 7.5Hz), 1.60-1.47 (2H, m), 1.38-
1.24 (6H, m), 1.20 (6H, s), 0.94-0.84 (3H, m).
(2) Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[(2-hexylamino-1,1-dimethyl) ethylamino] acetylpyrrolidine In the same manner as in Example 1 (2) Using 1-hexylamino-2-methyl-2-aminopropane (232 mg) and (2S, 4S) -1-chloroacetyl-2-cyano-4-fluoropyrrolidine (117 mg), the title compound ( 110 mg) was obtained.
(3) Synthesis of (2S, 4S) -1-[[2- (N-benzoyl-N-hexyl) amino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine Example 3 In the same manner as (4), (2S, 4S) -2-cyano-4-fluoro-1-[(2-hexylamino-1,1-dimethyl) ethylamino] acetylpyrrolidine (100 mg) and benzoyl chloride ( 43 mg) to give the title compound (17 mg) as a colorless oil.
1 H-NMR (300 MHz, DMSO-d6) δ 7.47-7.28 (5H, m), 5.46 (1H, brd, J = 51.5Hz), 4.99-4.90 (1H, m),
3.97 (1H, dd, J = 23.6,12.5Hz), 3.85-3.22 (5H), 2.62-2.25 (2H, m), 1.44-0.70 (19H).

Example 59
Synthesis of (2S, 4S) -1-[[2- (benzimidazol-5-yl) carbonylamino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine (1) benzimidazole- Synthesis of 5-carbonyl chloride 5-Benzimidazolecarboxylic acid (80 mg) was suspended in benzene (1.5 mL), thionyl chloride (176 μL) was added under ice cooling, and the mixture was heated to reflux for 6 hours. The reaction solution was concentrated under reduced pressure to obtain benzimidazole-5-carbonyl chloride (90 mg).
(2) Synthesis of (2S, 4S) -1-[[2- (benzimidazol-5-yl) carbonylamino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine Example 3 In the same manner as in (4), (2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (50 mg) and benz The title compound (48 mg) was obtained as yellow amorphous using imidazole-5-carbonyl chloride (27 mg).
1 H-NMR (300 MHz, DMSO-d6) δ 12.80-12.50 (1H, m), 8.38-8.18 (3H, m), 7.82-7.70 (1H, m), 5.47 (1H, brd, J = 51.8Hz ), 5.04-4.90 (1H, m), 4.10-3.18 (6H), 2.62-2.25 (2H), 1.06 (6H, s).

Example 60
(2S, 4S) -1-[[2- (1H-1,2,3-benzotriazol-5-yl) carbonylamino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine Synthesis of 1H-1,2,3-benzotriazole-5-carboxylic acid (57 mg) in N, N-dimethylformamide (1.8 mL), N, N′-carbonyldiimidazole (62 mg) was added at room temperature After stirring for 3 hours, (2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (100 mg) was added. Subsequently, triethylamine (133 μL) was added under ice cooling, and the mixture was stirred for 10 minutes, then returned to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (developing solvent; chloroform: methanol: 28% aqueous ammonia solution = 15: 1: 0.1 to 12: 1: 0.1 to 10: 1: 0.1) to give the title compound (61 mg) as a pale yellow powder.
1 H-NMR (300 MHz, DMSO-d6) δ 8.49-8.38 (2H, m), 7.99-7.82 (2H, m), 5.46 (1H, brd, J = 51.0Hz),
5.03-4.90 (1H, m), 3.97 (1H, dd, J = 24.2,12.7Hz), 3.86-3.00 (5H), 2.64-2.25 (2H, m), 1.07 (6H, s).

Example 61
(2S, 4S) -2-cyano-1-[[2- (2,3-dihydrobenzo [b] furan-5-yl) carbonylamino-1,1-dimethyl] ethylamino] acetyl-4-fluoropyrrolidine Synthesis of (2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (97 mg) in the same manner as in Example 60 The title compound (94 mg) was obtained as a colorless gum using 2,3-dihydrobenzo [b] furan-5-carboxylic acid (56 mg).
1 H-NMR (300 MHz, DMSO-d6) δ8.07-7.95 (1H, m), 7.75-7.73 (1H, m), 7.69-7.61 (1H, m), 6.80 (1H, d, J = 8.4 Hz ), 5.46 (1H, brd, J = 51.4Hz), 4.99-4.92 (1H, m), 4.59 (2H, t, J = 8.8Hz), 3.96 (1H, dd, J = 23.5,12.6Hz), 3.74 (1H, ddd, J = 39.8,12.5,3.3Hz), 3.52-3.14 (6H, m), 2.62-2.26 (2H, m),
2.10-1.80 (1H, m), 1.01 (3H, s), 1.00 (3H, s).

Example 62
Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[2- (thiophen-3-yl) carbonylamino-1,1-dimethyl] ethylamino] acetylpyrrolidine Similar method to Example 60 (2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (134 mg) and 3-thiophenecarboxylic acid (60 mg) Used to give the title compound (72mg) as a colorless foam.
1 H-NMR (300 MHz, DMSO-d6) δ8.15 (1H, dd, J = 3.0,1.3 Hz), 8.11-8.02 (1H, m), 7.58 (1H, dd, J =
5.0,3.0Hz), 7.51 (1H, dd, J = 5.0,1.3Hz), 5.46 (1H, brd, J = 50.2Hz), 5.00-4.93 (1H, m), 3.96 (1H, dd, J = 24.5 , 11.9Hz), 3.73 (1H, ddd, J = 39.6,12.6,3.3Hz), 3.52-3.25 (2H, m), 3.26-3.12 (2H, m), 2.62-2.25 (2H, m), 2.00- 1.85 (1H, brs), 1.02 (3H, s), 1.01 (3H, s).

Example 63
Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[2- (5-methylthiophen-2-yl) carbonylamino-1,1-dimethyl] ethylamino] acetylpyrrolidine Example 60 In a similar manner, (2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (129 mg) and 5-methyl-2- The title compound (92 mg) was obtained as a colorless foam using thiophenecarboxylic acid (64 mg).
1 H-NMR (300 MHz, DMSO-d6) δ8.17-8.06 (1H, m), 7.60 (1H, d, J = 3.7 Hz), 6.84 (1H, dd, J = 3.7,1.0 Hz), 5.44 ( 1H, brd, J = 51.6Hz), 5.00-4.92 (1H, m), 3.94 (1H, dd, J = 23.6,12.6Hz), 3.73 (1H, ddd, J = 39.5,12.6,3.3Hz), 3.50 -3.26 (2H, m), 3.25-3.08 (2H, m), 2.62-2.22 (2H, m), 2.48-2.44 (3H, m), 1.98-1.84 (1H, brs), 1.00 (3H, s) , 0.99 (3H, s)

Example 64
Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[2- (3-methylthiophen-2-yl) carbonylamino-1,1-dimethyl] ethylamino] acetylpyrrolidine Example 60 In a similar manner, (2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (129 mg) and 3-methyl-2- The title compound (74 mg) was obtained as a colorless foam using thiophenecarboxylic acid (64 mg).
1 H-NMR (300 MHz, DMSO-d6) δ 7.75-7.66 (1 H, m), 7.56 (1 H, d, J = 5.0 Hz), 6.96 (1 H, d, J = 5.0 Hz),
5.46 (1H, brd, J = 53.2Hz), 5.00-4.92 (1H, m), 3.94 (1H, dd, J = 24.2,11.9Hz), 3.83-3.61 (1H, m), 3.50-3.25 (2H, m), 3.24-3.10 (2H, m), 2.62-2.25 (2H, m), 2.43 (3H, s), 2.10-1.86 (1H, brs),
1.03 (3H, s), 1.02 (3H, s)

Example 65
Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[2- (3-hydroxy-2-methylpropan-2-yl) carbonylamino-1,1-dimethyl] ethylamino] acetylpyrrolidine Hydroxypivaloyl acid (41 mg) and (2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (110 mg) in N , N-dimethylformamide (1.1 mL) and 1-hydroxybenzotriazole monohydrate (54 mg) was added at room temperature. Diisopropylethylamine (128 μL) was added dropwise under ice-cooling, 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (76 mg) was added, and the mixture was stirred for 10 min. After returning to room temperature and stirring overnight, the reaction mixture was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (developing solvent; chloroform: methanol: 28% aqueous ammonia solution = 20: 1: 0 to 15: 1: 0). Purified in 1). The resulting colorless solid was suspended in isopropyl ether and stirred to give the title compound (60 mg) as a colorless powder.
1 H-NMR (300 MHz, DMSO-d6) δ 7.60-7.40 (1H, m), 5.48 (1H, brd, J = 50.4Hz), 5.05-4.96 (1H, m),
4.00 (1H, dd, J = 24.4,12.7Hz), 3.86-3.47 (3H, m), 3.44-3.24 (2H), 3.22-3.06 (2H, m), 2.56-
2.25 (2H, m), 1.18-0.95 (12H, m).

Example 66
(2S, 4S) -2-cyano-4-fluoro-1-[[2- (1,3-dihydroxy-2-methylpropan-2-yl) carbonylamino-1,1-dimethyl] ethylamino] acetylpyrrolidine Synthesis of (2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (106 mg) in the same manner as in Example 65 The title compound (55 mg) was obtained as a colorless gum using 2,2-bis (hydroxymethyl) propionic acid (45 mg).
1 H-NMR (300 MHz, DMSO-d6) δ7.52-7.40 (1H, m), 5.44 (1H, brd, J = 50.7Hz), 4.98-4.91 (1H, m),
4.86-4.70 (2H, brs), 3.92 (1H, dd, J = 23.8,12.6Hz), 3.73 (1H, ddd, J = 39.8,12.6,3.3Hz), 3.52-3.21 (6H, m), 3.08- 2.97 (2H, m), 2.62-2.26 (2H, m), 0.99 (3H, s), 0.96 (6H, s).

Example 67
Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[2- (cis-4-hydroxycyclohexane-1-yl) carbonylamino-1,1-dimethyl] ethylamino] acetylpyrrolidine (2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (128 mg) and cis-4- The title compound (65 mg) was obtained as a pale yellow solid using hydroxycyclohexanecarboxylic acid (59 mg).
1 H-NMR (300 MHz, DMSO-d6) δ7.51-7.41 (1H, m), 5.46 (1H, brd, J = 53.4Hz), 4.98-4.91 (1H, m),
4.27 (1H, d, J = 3.3Hz), 3.93 (1H, dd, J = 23.4,12.4Hz), 3.82-3.61 (1H, m), 3.44-3.21 (2H, m),
3.08-2.91 (2H, m), 2.62-2.26 (2H, m), 2.24-2.08 (1H, m), 1.86-1.69 (2H, m), 1.68-1.55 (2H, m), 1.48-1.32 (4H , m), 0.95 (3H, s), 0.94 (3H, s).

Example 68
Synthesis of (2S, 4S) -2-cyano-4-fluoro-1-[[2- (1-methylcyclohexane-1-yl) carbonylamino-1,1-dimethyl] ethylamino] acetylpyrrolidine Example 65 and In a similar manner, (2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (129 mg) and 1-methyl-1- Cyclohexanecarboxylic acid (58 mg) was used to give the title compound (74 mg) as a pale yellow oil.
1 H-NMR (300 MHz, DMSO-d6) δ 7.29-7.19 (1H, m), 5.43 (1H, brd, J = 51.5Hz), 4.99-4.90 (1H, m),
3.94 (1H, dd, J = 24.0,11.6Hz), 3.82-3.61 (1H, m), 3.48-3.22 (2H, m), 3.10-2.95 (2H, m), 2.62-2.26 (2H, m) 2.04-1.75 (3H, m), 1.54-1.10 (8H, m), 1.05 (3H, s), 0.96 (3H, s), 0.95 (3H, s).

Example 69
Example 2 Synthesis of (2S, 4S) -1-[[2- (1-methylcyclopropan-1-yl) carbonylamino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine (2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (146 mg) and 1-methylcyclopropyl The title compound (51 mg) was obtained as a colorless oil using carboxylic acid (46 mg).
1 H-NMR (300 MHz, DMSO-d6) δ 7.30-7.16 (1H, m), 5.62-5.29 (1H, m), 5.00-4.92 (1H, m), 3.90 (1H, dd, J = 24.8, 12.4Hz), 3.82-3.61 (1H, m), 3.47-3.22 (2H, m), 3.05-2.96 (2H, m), 2.62-2.25 (2H, m), 2.05-1.80 (1H, brs), 1.29 (3H, s), 1.03-0.88 (8H, m), 0.50 (2H, dd, J = 6.1,3.2Hz).

Example 70
Synthesis of (2S, 4S) -1-[[2- [bis (4-chlorophenyl)] acetylamino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine (1) 1- [ Synthesis of 2- [bis (4-chlorophenyl)] acetylamino] -2-methyl-2-aminopropane Bis (4-chlorophenyl) acetic acid (320 mg) was dissolved in N, N-dimethylformamide (3.0 mL) and iced. Under cooling 1,2-diamino-2-dimethylpropane (100 mg), 1-hydroxybenzotriazole monohydrate (219 mg) and 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (301 mg) And stirred for 30 minutes. After returning to room temperature and stirring overnight, a 1: 1 mixture (20 mL) of 5% aqueous sodium hydrogen carbonate and saturated brine was added under ice-cooling, and the mixture was extracted with chloroform (30 mL). The organic phase was dried over anhydrous magnesium sulfate, suction filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol: 28% aqueous ammonia solution = 20: 1: 0.1) to obtain the title compound (283 mg) as a pale yellow solid.
1 H-NMR (300 MHz, DMSO-d6) δ8.24-8.13 (1H, m), 7.35 (8H, dd, J = 21.5,8.6Hz), 5.10 (1H, s),
2.97 (2H, d, J = 5.8Hz), 0.89 (6H, s).
(2) Synthesis of (2S, 4S) -1-[[2- [bis (4-chlorophenyl)] acetylamino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine Example 1 In the same manner as (2), 1- [2- [bis (4-chlorophenyl)] acetylamino] -2-methyl-2-aminopropane (229 mg) and (2S, 4S) -1-chloroacetyl-2- Cyano-4-fluoropyrrolidine (57 mg) was used to give the title compound (119 mg) as a pale yellow foam.
1 H-NMR (300 MHz, DMSO-d6) δ8.22-8.13 (1H, m), 7.41-7.27 (8H, m), 5.45 (1H, brd, J = 53.2Hz),
5.10 (1H, s), 4.97-4.90 (1H, m), 3.90 (1H, dd, J = 24.2,12.0Hz), 3.78-3.58 (1H, m), 3.48-3.20 (
2H, m), 3.15-2.90 (2H, m), 2.60-2.25 (2H, m), 0.94 (6H, s).

Example 71
Synthesis of (2S, 4S) -1-[[2- (2-hydroxybenzoyl) amino-1,1-dimethyl] ethylamino] acetyl-2-cyano-4-fluoropyrrolidine
(2S, 4S) -1-[(2-amino-1,1-dimethyl) ethylamino] acetyl-2-cyano-4-fluoropyrrolidine dihydrochloride (195 mg) was dissolved in methanol (0.2 mL) and iced. A 3M methanol solution of potassium hydroxide (412 μL) was added dropwise under cooling. The precipitated potassium chloride was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in N, N-dimethylformamide (0.8 mL), and a solution of O-acetylsalicyloyl chloride (123 mg) in chloroform under ice-cooling (
0.8 mL). Subsequently, triethylamine (130 μL) was added dropwise, and the mixture was stirred for 10 minutes under ice cooling. After returning to room temperature and stirring for 3 hours, a mixed solution of saturated aqueous sodium hydrogencarbonate (1.0 mL) and methanol (1.5 mL) was added, and the mixture was allowed to stand overnight in a freezer. Under ice-cooling, saturated brine (20 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (30 mL). The organic phase was dried over anhydrous magnesium sulfate, suction filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol: 28% aqueous ammonia solution = 20: 1: 0.1) to give the title compound (36 mg) as a colorless foam.
1 H-NMR (300 MHz, DMSO-d6) δ8.75-8.60 (1H, m), 7.89 (1H, dd, J = 8.1,1.7Hz), 7.38 (1H, td, J =
7.7, 1.7Hz), 6.94-6.86 (2H, m), 5.46 (1H, brd, J = 51.5Hz), 4.99-4.92 (1H, m), 3.95 (1H, dd, J =
24.3, 12.4Hz), 3.74 (1H, ddd, J = 39.5, 12.4, 3.2Hz), 3.53-3.19 (4H), 2.62-2.25 (2H, m), 1.04 (
6H, s).
The structures of the compounds obtained in Examples 48 to 71 are shown in Table 3.

Test Example 1 [Dipeptidyl peptidase IV activity inhibition experiment]
Dipeptidyl peptidase IV (DPPIV) activity inhibition experiments are described in Diabetes, 47,
764-769, 1998. Plasma containing dipeptidyl peptidase IV was prepared by collecting blood from healthy volunteers and centrifuging. The enzyme reaction was performed using a 96-well flat bottom plate in a buffer solution consisting of 25 mM HEPES, 140 mM NaCl, 1% BSA, pH 7.8. 100 μM Gly-Pro-4-methylcoumaryl-7-amide (manufactured by Peptide Institute) solution 25 μl, 133 mM magnesium chloride solution 7.5 μl, sample compound 5 μl were mixed, and then plasma 12 diluted 1 / 100-fold with the above buffer solution .5 μl was added. After reacting for 2 hours at room temperature, 50 μl of 25% acetic acid aqueous solution was added to stop the reaction. The amount of released 7-amino-4-methylcoumarin was measured using a fluorescent plate reader (1420 ARVO Multilabel Counter;
Fluorescence intensity at 460 nm was measured when excited at 390 nm using Wallac). The fluorescence intensity when the solvent was added and the reaction time was 0 minutes was taken as the blank value, and the value obtained by subtracting the blank value from each measured value was taken as the specific fluorescence intensity. From the obtained specific fluorescence intensity, the dipeptidyl peptidase IV activity inhibition rate (%) was determined by the following equation. As the test compound, a dimethyl sulfoxide solution having a concentration 1000 times higher was prepared and diluted with the above buffer solution. The compound concentration (IC 50 value) showing 50% inhibition was calculated from the inhibition rate of each concentration. Table 4 shows the test results of the example compounds.

Inhibition rate (%) = A ÷ B × 100
(A = fluorescence intensity when solvent is added-fluorescence intensity when sample compound is added)
(B = fluorescence intensity upon addition of solvent)

It was confirmed that the compound according to the present invention has excellent DPPIV inhibitory activity.

Test Example 2 [Test for measuring plasma DPPIV activity during oral administration in rats]
Eight-week-old male SD (IGS) rats (Nippon Charles River Co., Ltd.) were used in the experiment. The test compound was dissolved in Japanese Pharmacopoeia water for injection (Hikari Pharmaceutical Co., Ltd.) at a concentration of 0.2 mg / mL and orally administered at a volume of 5 mL / kg (1 mg / kg dose). All blood samples were collected from orbital veins by heparinized blood collection tubes (Drummond Scientific Company) before and after compound administration under diethyl ether anesthesia. The blood was centrifuged at 3,000 rpm for 15 minutes at 4 ° C., and plasma was collected. Plasma was stored at -80 ° C. Fasting was performed from 16 hours before administration of the test compound to 6 hours after administration, and drinking water was freely ingested with sterilized water.
Plasma DPPIV activity was determined by the following method.
The enzyme reaction was performed using a 96-well plate in a buffer consisting of 25 mM HEPES, 140 mM NaCl, 1% BSA, pH 7.8. As a substrate solution, 10 mM H-Gly-Pro-4-methylcoumaryl-7-amide (BACHEM) was prepared to 1/100 with a buffer solution. In advance, 100 μM substrate solution 25 μL per well, buffer 5 μL,
A reaction solution was prepared by mixing 7.5 μL of 133 mM magnesium chloride.
The plasma reaction was dispensed at 12.5 μL per well, and 37.5 μL of the reaction solution was added to start the enzyme reaction. After reacting at room temperature for 5 minutes, 50 μL of 25% aqueous acetic acid solution was added to stop the reaction. The amount of 7-amino-4-methylcoumarin released was measured using a fluorescence plate reader (1420 ARVO Multilabel Counter; manufactured by Wallac), and the fluorescence intensity at 460 nm was measured when excited at 390 nm. In addition, the fluorescence intensity obtained by inactivating enzyme activity in advance by adding 25% aqueous acetic acid to rat plasma before administration of the compound (all the pools are pooled) and then adding the reaction solution is defined as the blank value. did. The specific fluorescence intensity was obtained by subtracting the blank value from each measurement value, and the amount of 7-amino-4-methylcoumarin (nmol, hereinafter referred to as AMC) generated from a standard calibration curve was calculated. The DPPIV activity was expressed as follows, assuming that the amount of AMC produced before compound administration was 100%.

DPPIV activity (% of Control) = A ÷ B × 100
(A = AMC production after test compound administration)
(B = AMC production before administration of test compound)

The results are shown in Table A. The compound according to the present invention was confirmed to continuously inhibit DPPIV activity when orally administered to rats at a dose of 1 mg / kg.

The compounds according to the present invention are useful as preventive or therapeutic agents for diabetes, immune diseases, etc.
According to the present invention, it has become possible to provide a preventive or therapeutic agent for diseases or conditions, diabetes, immune diseases and the like that can be improved by inhibiting excellent dipeptidyl peptidase IV (DPPIV).

Claims (21)

  1. Formula (I)
    [Wherein, A represents a hydrogen atom or a fluorine atom, and R 1 and R 2 are the same or different and each may be substituted with one or more substituents selected from a hydrogen atom and substituent Y 1 group. 6 alkyl group, one or more cycloalkyl group carbon atoms which may be 3-6 substituted with a substituent selected from the substituent Y 2 group; one or more substituents selected from the substituent Y 2 group in the carbon atoms which may be 4-9 substituted cycloalkylalkyl group; substituted one or more alkenyl group having 2 to 6 carbon atoms which may be substituted with a substituent group selected from Y 2 groups; substituents Y 2 A C3-C6 cycloalkenyl group that may be substituted with one or more substituents selected from the group; a substituent Y that has 4 or more carbon atoms that may be substituted with one or more substituents selected from Group 2 or R 1 and the carbon atom to which R 2 is adjacent; 9 cycloalkenylalkyl group Together form one or more of good 3 to 10 carbon atoms optionally substituted by a substituted cycloalkyl group selected from the substituent Y 2 group, X represents a single bond or a 1 to 3 carbon atoms Represents an alkylene group, and R 3 has the formula —N (R 4 ) COR 5 , —N (R 4 ) SO 2 R 5 , —NR 4 R 6 , —SO 2 R 5 , —SO 2 NR 4 R 5 , -OCONR 4 R 5, -CH = CH -R 7,
    Or a heteroaryl group containing at least one oxygen and / or sulfur and further containing a nitrogen atom and a 6-membered nitrogen-containing aromatic ring or a 9-11 membered condensed ring thereof in the selected is a heteroaryl group (the heteroaryl group may be substituted with one or more substituents selected from the substituent Y 3 group) shows (the above formulas, R 4 and R 6 are the same or different and each is hydrogen An atom; an alkyl group having 1 to 10 carbon atoms that may be substituted with one or more substituents selected from substituent Y 4 group; may be substituted with one or more substituents selected from substituent Y 2 group A good cycloalkyl group having 3 to 6 carbon atoms; a cycloalkylalkyl group having 4 to 9 carbon atoms which may be substituted with one or more substituents selected from substituent Y 2 group; or a substituent Y selected from group 3 May be substituted with one or more substituents An arylalkyl group, R 5 is an alkyl group having 1 to 10 carbon atoms which may be substituted with one or more substituents selected from substituent Y 4 group, or — (C 1-3 alkylene) — Q or Q, and C 1-3 alkylene may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group, and Q is one or more substituents selected from substituent Y 3 group. A cycloalkyl group having 3 to 10 carbon atoms which may be substituted with a substituent; a bridged ring alkyl group having 4 to 10 carbon atoms which may be substituted with one or more substituents selected from substituent Y 3 group; one or more substituted alkenyl group which may 2-10 carbon atoms substituted with a group selected from Y 3 group; substituents Y 3 1 or more carbon atoms 3 be substituted with a substituent selected from the group To 10 cycloalkenyl groups; selected from the substituent group Y 3 Selected from and one or more optionally substituted aryl group which may be substituted by a group selected from substituent group Y 3 group; 1 or more good 4-10 carbon atoms substituted by a substituent bridged ring alkenyl group that a is an aliphatic or aromatic hydrocarbon which either is; or substituted with one or more substituents selected from the substituent Y 5 group showed a heterocycle which may be, an aryl group or a hetero ring in R 5 is ring R 4 , R 5, or R 4 may be bonded together to form a 5- to 8-membered ring and may contain one or more heteroatoms in the ring. 6 , R 4 and R 5 , R 4 and R 6, and R 5 and R 6 may be substituted with one or more substituents selected from the substituent Y 5 group together with adjacent heteroatoms. may form a heterocyclic good 4-10 membered, R 7 is a hydrogen atom; a substituent Y 1 group Ri 1 or more even better 1 to 6 carbon atoms is substituted with a substituent alkyl group selected which can be substituted by one or more substituents selected from the substituent Y 3 group aryl group; or a substituent Y represents a heteroaryl group which may be substituted with one or more substituents selected from Group 3 . ), Substituent Y group 1 is a group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino group, an aminocarbonyl group, a cycloalkyloxy group having 3 to 5 carbon atoms, and an alkoxy group having 1 to 6 carbon atoms. The substituent Y 2 group is a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino group, an aminocarbonyl group, a cycloalkyloxy group having 3 to 5 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and 1 carbon atom. represents the group consisting of 6 alkyl group, the substituent Y 3 group, a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, -OR 9, -COR 9, -CO 2 R 9,
    -CONR 9 R 10, -N (R 9) COR 10, -N (R 9) CONR 10 R 11, -N (R 9) SO 2 R 10, -NR 9 R 10, -SO 2 R 9, - SO 2 NR 9 R 10 , —SO 2 N═CHNR 9 R 10 and —OCONR 9 R 10 (wherein R 9 , R 10 and R 11 are the same or different and represent a hydrogen atom; substituent Y 1 selected from group 1) An alkyl group having 1 to 6 carbon atoms that may be substituted with one or more substituents; a cycloalkyl group having 3 to 6 carbon atoms that may be substituted with one or more substituents selected from the group 2 of substituent Y; substituted by or one or more substituents selected from the substituent Y 2 group; 1 or more cycloalkylalkyl group carbon atoms which may be 4-9 substituted with a substituent selected from the substituent Y 2 group also shows a phenyl group.) carbon atoms, which may be substituted with 1 or more substituents selected from the substituent Y 1 group It represents the group consisting of one or more phenyl group which may be substituted with a substituent selected from alkyl groups or a substituent Y 2 group 6, the substituent Y 4 group, a halogen atom, a hydroxyl group, a cyano group, a nitro Group, amino group, —OR 9 , —COR 9 , —CO 2 R 9 , —CONR 9 R 10 ,
    -N (R 9) COR 10, -N (R 9) CONR 10 R 11, -N (R 9) SO 2 R 10,
    —NR 9 R 10 , —SO 2 R 9 , —SO 2 NR 9 R 10 , —SO 2 N═CHNR 9 R 10 and —OCONR 9 R 10 (wherein R 9 , R 10 and R 11 are the same or different) A hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may be substituted with one or more substituents selected from substituent Y 1 group; substituted with one or more substituents selected from substituent Y 2 group cycloalkyl group which may having 3 to 6 carbon atoms and; substituents Y 2 carbon atoms which may be substituted with one or more substituents selected from the group 4-9 cycloalkylalkyl group; or a substituent Y 2 group Or a group consisting of phenyl groups that may be substituted with one or more substituents selected from the substituent Y 2 group. . Substituent Y 5 group includes an oxo group, a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, —OR 9 , —COR 9 , —CO 2 R 9 ,
    -CONR 9 R 10, -N (R 9) COR 10, -N (R 9) CONR 10 R 11,
    -N (R 9) SO 2 R 10, -NR 9 R 10, -SO 2 R 9, -SO 2 NR 9 R 10,
    —SO 2 N═CHNR 9 R 10 and —OCONR 9 R 10 (wherein R 9 , R 10 and R 11 are the same or different and are each a hydrogen atom; substituted with one or more substituents selected from substituent Y 1 group) is alkyl group of good 1 to 6 carbon atoms and; one or more are also a good 3 to 6 carbon atoms substituted with a substituted cycloalkyl group selected from the substituent Y 2 group; selected from the substituent Y 2 group shows a or a substituent one or more substituents phenyl group which may be substituted by a group selected from Y 2 groups; one or more substituted with a substituent carbon atoms which may 4-9 cycloalkylalkyl group. ), substituted with one or more substituents selected from one or more alkyl groups or substituents Y 2 group carbon atoms which may be 1-6 substituted with a substituent selected from the substituent Y 1 group Represents a group consisting of good phenyl groups] A pharmaceutical comprising a compound or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.
  2. Following formula (I-2)
    (Wherein A, R 1 , R 2 , R 3 and X are as defined in claim 1).
    A pharmaceutical comprising the compound according to claim 1 or a salt thereof or a hydrate thereof as an active ingredient.
  3. The compound according to claim 1 or 2, wherein R 1 and R 2 are the same or different and each is an alkyl group having 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the group of substituent Y 1. A pharmaceutical comprising a salt or a hydrate thereof as an active ingredient.
  4. R < 1 > and R < 2 > is a methyl group, an ethyl group, or a hydroxymethyl group, The pharmaceutical which contains the compound of any one of Claims 1-3, its salt, or those hydrates as an active ingredient.
  5. X is a methylene group or ethylene group, R 3 is a formula —N (R 4 ) COR 5 , and R 4 is a hydrogen atom; substituted with one or more substituents selected from substituent Y 4 group An alkyl group having 1 to 10 carbon atoms which may be substituted; a cycloalkyl group having 3 to 6 carbon atoms which may be substituted with one or more substituents selected from substituent Y 2 group; or from substituent Y 2 group represents one or more substituted cycloalkyl alkyl group carbon atoms which may be 4 to 9 optionally substituted with a group selected, R 5 is substituted with one or more substituents selected from the substituent Y 4 groups A C1-C10 alkyl group, or-( C1-3alkylene ) -Q or Q, wherein C1-3alkylene is substituted with one or more substituents selected from a halogen atom and a hydroxyl group; may, Q is one or more substituents selected from the substituent Y 3 group Cycloalkyl group substituted carbon atoms which may be 3 to 10; one or more of good 4-10 carbon atoms substituted by a substituent bridged cyclic alkyl group selected from the substituent Y 3 group; substituent Y one or more of good 2 to 10 carbon atoms optionally substituted with a substituent alkenyl group selected from the three groups; substituents Y 3 1 or more good carbon atoms 3 to be substituted with a substituent selected from the group 10 cycloalkenyl group; one or more bridged ring alkenyl group carbon atoms which may be 4-10 substituted with a substituent selected from substituent group Y 3 groups; and substituents Y 3 than one or more selected group An aryl or an aromatic hydrocarbon selected from aryl groups that may be substituted with the substituents of R 5, wherein the aryl group in R 5 is a combination of adjacent substituents bonded to the atoms constituting the ring; 5-8 membered ring may be formed, one in the ring May contain a hetero atom of the above, R 4 and R 5 together with the adjacent heteroatom, one or more may be substituted with a substituent 4-10 membered selected from substituent group Y 5 group The pharmaceutical which contains the compound of any one of Claims 1-4 which may form the heterocyclic ring of this, its salt, or those hydrates as an active ingredient.
  6. R 5 is substituted with an alkyl group having 1 to 6 carbon atoms which may be substituted with one or more substituents selected from substituent Y 1 group, or one or more substituents selected from substituent Y 2 group A pharmaceutical comprising the compound according to claim 5 or a salt thereof, or a hydrate thereof as an active ingredient, which may be a C 3-6 cycloalkyl group.
  7. R 5 is an aryl group which may be substituted with one or more substituents selected from the group of substituent Y 3 , and the aryl group is a combination of adjacent substituents bonded to atoms constituting the ring; The pharmaceutical which contains the compound of Claim 5 or its salt, or those hydrates as an active ingredient which may form a 5-8 membered ring and may contain a 1 or more hetero atom in a ring.
  8. X is a methylene group or ethylene group, R 3 is a formula —N (R 4 ) COR 5 , and R 4 is a hydrogen atom; substituted with one or more substituents selected from substituent Y 4 group An alkyl group having 1 to 10 carbon atoms which may be substituted; a cycloalkyl group having 3 to 6 carbon atoms which may be substituted with one or more substituents selected from substituent Y 2 group; or from substituent Y 2 group It represents one or more substituted cycloalkyl alkyl group carbon atoms which may be 4 to 9 optionally substituted with a group selected, R 5 is substituted with one or more substituents selected from the substituent Y 3 group A pharmaceutical comprising the compound or a salt thereof or a hydrate thereof according to any one of claims 1 to 4 as an active ingredient, which is a good heteroaryl group.
  9. 9. R 5 is a monocyclic heteroaryl group which may be substituted with one or more substituents selected from the group of substituent Y 3. 9. The compound according to claim 8 or a salt thereof or a hydrate thereof as an active ingredient. Contains medicines.
  10. A pharmaceutical comprising the compound according to claim 9 or a salt thereof or a hydrate thereof as an active ingredient, wherein R 5 is a thienyl group optionally substituted with one or more substituents selected from the group of substituent Y 3 .
  11. X is a methylene group or ethylene group, R 3 is —N (R 4 ) SO 2 R 5 , R 4 is a hydrogen atom; one or more substituents selected from the group of substituent Y 4 An optionally substituted alkyl group having 1 to 10 carbon atoms; a cycloalkyl group having 3 to 6 carbon atoms that may be substituted with one or more substituents selected from substituent Y 2 group; or substituent Y 2 group A cycloalkylalkyl group having 4 to 9 carbon atoms which may be substituted with one or more substituents selected from R 5 is substituted with one or more substituents selected from substituent Y 4 group; Or an alkyl group having 1 to 10 carbon atoms, or-( C1-3alkylene ) -Q or Q, wherein C1-3alkylene is substituted with one or more substituents selected from a halogen atom and a hydroxyl group. at best, Q is one or more substituents selected from the substituent Y 3 group Cycloalkyl group substituted carbon atoms which may be 3 to 10; one or more of good 4-10 carbon atoms substituted by a substituent bridged cyclic alkyl group selected from the substituent Y 3 group; substituent Y one or more of good 2 to 10 carbon atoms optionally substituted with a substituent alkenyl group selected from the three groups; substituents Y 3 1 or more good carbon atoms 3 to be substituted with a substituent selected from the group 10 cycloalkenyl group; one or more bridged ring alkenyl group carbon atoms which may be 4-10 substituted with a substituent selected from substituent group Y 3 groups; and substituents Y 3 than one or more selected group whether aliphatic or aromatic hydrocarbon is selected from even an aryl group is substituted with a substituent; or a heterocycle which may be substituted with one or more substituents selected from the substituent Y 5 group And the aryl group or heterocycle in R 5 is Adjacent substituents bonded to the atoms constituting the ring may form together to form a 5- to 8-membered ring and may contain one or more heteroatoms in the ring. R 4 and R 5 are , together with the adjacent heteroatom, it may form a heterocyclic ring of one or more 4-10 membered optionally substituted by substituents selected from the substituent Y 5 group,
    The pharmaceutical which contains the compound of any one of Claims 1-4, its salt, or those hydrates as an active ingredient.
  12. X is a methylene group or ethylene group, and R 3 is —NR 4 R 6 (R 4 and R 6 are the same or different and are hydrogen atoms; one or more substituents selected from the group of substituent Y 4 one or more cycloalkyl groups having 3 to 6 carbon atoms which may be substituted with a substituent selected from the substituent Y 2 group; an alkyl group carbon atoms which may be 1 to 10 substituted by a group substituent Y 2 one or more substituted with a substituent carbon atoms which may 4-9 cycloalkylalkyl group selected from the group; or one or more aryl alkyl optionally substituted with a substituent selected from substituent group Y 3 group R 4 and R 6 represent a 4- to 10-membered nitrogen-containing ring which may be substituted with one or more substituents selected from the substituent Y 5 group together with the adjacent nitrogen atom. The compound according to any one of claims 1 to 4 or a compound thereof. Salts or pharmaceutical comprising the hydrate thereof as an active ingredient.
  13. X represents a single bond or a methylene group, and R 3 represents the formula —CH═CH—R 7 or
    (Wherein R 7 is a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may be substituted with one or more substituents selected from substituent Y 1 group; one or more selected from substituent Y 3 group) substituted aryl group which may be substituted group;. showing a or one or more may be substituted with a substituted heteroaryl group selected from the substituent Y 3 group) according to claim 1 is a group represented by 5. A medicament comprising the compound according to any one of 4 or a salt thereof or a hydrate thereof as an active ingredient.
  14. X represents a single bond or a methylene group, R 3 contains at least one oxygen and / or sulfur which may be substituted with one or more substituents selected from the group of substituent Y 3 ; The compound or a salt thereof, or a hydrate thereof according to any one of claims 1 to 4, which is a 5-membered or 6-membered heteroaryl which may contain a nitrogen atom or an 8-11 membered condensed ring thereof. As an active ingredient.
  15. A 6-membered nitrogen-containing aromatic ring or a 9-11 membered condensed ring thereof, wherein X represents a single bond or a methylene group, and R 3 may be substituted with one or more substituents selected from the substituent Y 3 group The pharmaceutical which contains the compound of any one of Claims 1-4 which is these, its salt, or those hydrates as an active ingredient.
  16.   The pharmaceutical which contains the cyanofluoropyrrolidine compound of any one of Claims 1-15, its pharmaceutically acceptable salt, or those hydrates as an active ingredient.
  17.   The medicament according to claim 16, for preventing or treating a disease or condition that can be improved by inhibiting dipeptidyl peptidase IV.
  18.   The medicament according to claim 16, wherein the disease or condition that can be ameliorated by inhibiting dipeptidyl peptidase IV is diabetes.
  19.   The medicine according to claim 16, wherein the disease or condition that can be ameliorated by inhibiting dipeptidyl peptidase IV is an immune disease.
  20.   The therapeutic agent for diabetes which contains the cyanofluoropyrrolidine compound of any one of Claims 1-15, its pharmaceutically acceptable salt, or those hydrates as an active ingredient.
  21. The therapeutic agent for immune diseases which contains the cyanofluoropyrrolidine compound of any one of Claims 1-15, its pharmaceutically acceptable salt, or those hydrates as an active ingredient.
JP2005328431A 2004-11-15 2005-11-14 Medicine containing cyanofluoropyrrolidine derivative as active ingredient Pending JP2006160733A (en)

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