JP2005306839A - Bicyclic piperazine compound and its use - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a compound which has a TGR23 (G protein conjugated type receptor) antagonist activity and is useful for preventing and treating cancer. <P>SOLUTION: The compound represented by the formula (wherein R<SP>1</SP>is an acyl group; R<SP>2</SP>, R<SP>3</SP>, and R<SP>4</SP>are each an optionally substituted hydrocarbon group, or the like; (n) is 0-4; and X is O or S) or its salt is provided. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a novel compound useful for prevention / treatment of cancer. More specifically, the present invention relates to a compound having a preventive / therapeutic effect on cancer by regulating the function of TGR23 receptor, in particular, inhibiting the function.

  TGR23 which is a G protein-coupled receptor has an amino acid sequence represented by SEQ ID NO: 1 or 2 in the sequence listing. The TGR23 and its ligand (TGR23 ligand) are reported in WO 02/31145 (Patent Document 1) and WO 03/025179 (Patent Document 2), and when TGR23 responds to the ligand, feeding Behavior is suppressed and the tumor grows (WO 03/025179). Thus, TGR23 antagonists include, for example, cancer (eg, colon cancer, colon cancer, rectal cancer, breast cancer, lung cancer, non-small cell lung cancer, prostate cancer, esophageal cancer, stomach cancer, liver cancer, biliary tract cancer, spleen cancer, kidney Cancer, bladder cancer, uterine cancer, ovarian cancer, cervical cancer, testicular cancer, thyroid cancer, pancreatic cancer, brain tumor, blood tumor, etc.) prevention / treatment agent, eating (appetite) promoter, anorexia prevention / It is useful as a safe drug with low toxicity, such as a therapeutic agent and an apoptosis inducer.

On the other hand, the following compounds are known as bicyclic piperazine compounds.
(1) Synthesis, page 833, 1996 (Non-patent Document 1) describes the following compounds as 2,6-disubstituted piperazine derivatives synthesized by asymmetric synthesis, but their actions and uses There is no description about.

(2) WO 97/19089 (Patent Document 3) describes the following compounds as intermediates of oxazolidinone derivatives having antibacterial action.

(3) WO 98/58947 (Patent Document 4) describes the following compounds as intermediates of dipeptide derivatives having a growth hormone secretion promoting action.

(4) J. Org. Chem., 67, 3866, 2002 (Non-Patent Document 2) describes the following compounds as related compounds of monocyclic oxopiperazine derivatives having CCK receptor affinity. Has been.

(5) WO 03/30907 (Patent Document 5) describes the following compounds as examples of compounds useful as prophylactic / therapeutic agents for inflammation, diseases involving cell adhesion, and central nervous system diseases. .

WO 02/31145 Publication WO 03/025179 WO 97/19089 Publication WO 98/58947 Publication WO 03/30907 Publication Synthesis, 833 pages, 1996 J. Org. Chem., 67, 3866, 2002

  Since anticancer agents that have been used in the past have not been sufficiently effective, safe and excellent anticancer agents are desired.

  As a result of intensive studies to solve the above problems, the present inventors have found that the bicyclic piperazine compound has an acyl group at the 7-position and a substituent at the 1-position. Formulas with chemical structural characteristics

[Wherein R ¹ represents an acyl group,
R ² represents a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent,
R ³ represents a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent,
R ⁴ represents a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent,
n is an integer of 0 to 4 (when n is an integer of 2 to 4, R ⁴ may be the same or different), and X is an oxygen atom, a sulfur atom, or the formula NR ⁵ (wherein R ⁵ represents a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent. ]
Or a salt thereof [hereinafter sometimes abbreviated as compound (I)], and the compound (I) was unexpectedly superior in TGR23 based on its specific chemical structure. The present inventors have found that it has antagonist activity and is useful as a safer drug for preventing and treating cancer, and based on this, the present invention has been completed.

That is, the present invention is as follows.
[1] Formula

[In the formula (I), R ¹ represents an acyl group,
R ² represents a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent,
R ³ represents a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent,
R ⁴ represents a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent,
n is an integer of 0 to 4 (when n is an integer of 2 to 4, R ⁴ may be the same or different), and X is an oxygen atom, a sulfur atom, or the formula NR ⁵ (wherein R ⁵ represents a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent. ]
Or a salt thereof.
[2] The acyl group represented by R ¹ is represented by the formula — (C═O) —R ⁶ , — (C═O) —OR ⁶ , — (C═O) —NR ⁷ R ⁸ , — (C═S). ^{) -NR 7 R 8, -SO-} R 6, -SO 2 -R 6 or -SO ₂ -NR ⁷ R ⁸
[Wherein R ⁶ represents a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent,
R ⁷ represents a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, a C _6-12 aryl-carbonyl group, a C _1-6 alkoxy-carbonyl group. Or a 5- or 6-membered aromatic heterocyclic carbonyl group, and R ⁸ represents a hydrogen atom, a C _1-6 alkyl group or an optionally substituted amino group, or
R ⁷ and R ⁸ together with the adjacent nitrogen atom may form a ring that may have a substituent.
The compound of [1] which is group represented by these.

[3] The acyl group represented by R ¹ is represented by the formula — (C═O) —R ⁶ , — (C═O) —OR ⁶ or — (C═O) —NR ⁷ R ⁸ [wherein each symbol Is the same as defined in claim 2, and is a group represented by [2].
[4] The compound according to [2], wherein R ⁶ is an aromatic group, a heterocyclic group or a chain hydrocarbon group, each optionally having a substituent.
[5] R ⁶ is a C _6-12 aryl group which may have a substituent, or a C _1-6 alkyl group having a 5- to 7-membered cyclic amino group which may have a substituent. [2] The compound described.
[6] R ⁷ is a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, a C _6-12 aryl-carbonyl group, or C _1-6. The compound according to [2], which is an alkoxy-carbonyl group.

[7] R ⁷ is (a) (i) a 5- to 7-membered cyclic amino group which may have a substituent, and / or (ii) a 5- to 10-membered aromatic which may have a substituent. A heterocyclic group,
A C _1-6 alkyl group _optionally having
The compound according to [2], which is (b) a C _6-12 aryl group which may have a substituent, or (c) a C _7-13 aralkyl group which may have a substituent.
[8] The compound according to [2], wherein R ⁷ is a group having an aromatic group which may have a substituent.
[9] The compound according to [2], wherein R ⁷ and R ⁸ together with an adjacent nitrogen atom form a 5- to 10-membered heterocyclic ring which may have a substituent.
[10] The compound according to [2], wherein R ⁸ is a hydrogen atom or an amino group which may have a substituent.
[11] The compound according to [ ¹ ], wherein R ¹ is a group represented by the formula — (C═O) —NR ⁷ R ⁸ , wherein each symbol is as defined in claim 2.
[12] The compound according to [ ¹ ], wherein R ¹ is a group represented by the formula — (C═O) —R ⁶ , wherein each symbol is as defined in claim 2.
[13] The compound according to [1], wherein R ² is an aryl group which may have a substituent.
[14] The compound according to [1], wherein R ³ is an aryl group which may have a substituent.
[15] The compound according to [1], wherein n is 0.
[16] The compound according to [1], wherein X is an oxygen atom.

[17] R ¹ is represented by the formula-(C = O) -R ^6b or-(C = O) -NR ^7b R ^8b ,
[Wherein R ^6b has (a) a C _1-6 alkyl group optionally having a 5- to 7-membered cyclic amino group, or (b) 1 to 2 C _1-6 alkyl groups. A C _6-12 aryl group _optionally having a C _1-6 alkyl group _{optionally having an} amino group,
R ^7b is (a) a hydrogen atom,
(B) a C _6-12 aryl group _optionally having a halogen atom,
(C) a C _7-13 aralkyl group _optionally having a halogen atom,
(D) a 5- or 6-membered aromatic heterocyclic group,
(E) a C _1-6 alkyl group optionally having a 5- to 7-membered cyclic amino group, or (f) a 5- or 6-membered non-aromatic heterocyclic ring optionally having a C _1-6 alkyl group Group,
R ^8b is a hydrogen atom or a C _6-12 arylamino group, or R ^7b and R ^8b together with the adjacent nitrogen atom form a 5- to 10-membered heterocyclic ring optionally having a 5- to 7-membered cyclic amino group A group represented by
R ² and R ³ are each a C _6-12 aryl group,
The compound according to [1], wherein n is 0, and X is an oxygen atom.

[18] R ¹ is represented by the formula — (C═O) —R ^6a , — (C═O) —OR ^6a , — (C═O) —NR ^7a R ^8a or —SO ₂ —R ^6a.
[Wherein R ^6a is (a) a C _7-13 aralkyl group,
(B) a C _2-6 alkenyl group _optionally having a halogenated C _6-12 aryl group,
(C) a C _6-12 aryl group which may have a substituent selected from a halogen atom, a C _1-6 alkoxy group, a nitro group, and an optionally halogenated C _1-6 alkyl group,
(D) a 5- or 6-membered aromatic heterocyclic group, or (e) a substituent selected from a C _6-12 aryl group, a C _6-12 aryloxy group and an optionally condensed C _3-8 cycloalkyl group A C _1-6 alkyl group _optionally having
R ^7a is (a) a hydrogen atom,
(B) a C _6-12 aryl group optionally having a substituent selected from a C _1-6 alkoxy-carbonyl group, a halogen atom and a C _1-6 alkoxy group,
(C) having a substituent selected from a halogen atom, an optionally halogenated C _1-6 alkyl group, a C _1-6 alkylsulfonyl group, and a mono- or di-C _1-6 alkylamino group; C _7-13 aralkyl group,
(D) a C _1-6 alkyl group which may have a 5- or 6-membered aromatic heterocyclic group, or (e) a C _3-8 cycloalkyl group which may be condensed,
R ^8a may form a 5- to 10-membered non-aromatic heterocyclic ring with a hydrogen atom, a C _1-6 alkyl group, or a C _6-12 arylamino group, or R ^7a and R ^8a together with the adjacent nitrogen atom. A group represented by
R ² and R ³ are each a C _1-6 alkyl group, a C _3-6 cycloalkyl group or a C _6-12 aryl group,
The compound according to [1], wherein n is 0, and X is an oxygen atom.

[19] R ¹ is represented by the formula — (C═O) —R ^6a , — (C═O) —OR ^6a , — (C═O) —NR ^7a R ^8a or —SO ₂ —R ^6a.
[Wherein R ^6a is (a) a C _7-13 aralkyl group,
(B) a C _2-6 alkenyl group _optionally having a halogenated C _6-12 aryl group,
(C) (i) a halogen atom,
(Ii) a C _1-6 alkoxy group,
(Iii) a nitro group, and (iv) (1) a halogen atom, and (2) one or two substituents selected from a C _1-6 alkoxy-carbonyl group and a C _1-6 alkyl group A good amino group, a C _1-6 alkyl group which may have a substituent selected from:
A C _6-12 aryl group _optionally having a substituent selected from:
(D) a 5- or 6-membered aromatic heterocyclic group,
(E) (i) a C _6-12 aryloxy group,
(Ii) a C _3-8 cycloalkyl group which may be condensed with one or two benzene rings,
(Iii) an optionally halogenated C _6-12 arylamino group,
(Iv) a carboxy group,
(V) a 5- to 7-membered cyclic amino group,
(Vi) a C _6-12 aryl group, and (vii) a halogen atom,
A C _1-6 alkyl group _optionally having a substituent selected from:
(F) 6-membered non-aromatic heterocyclic group optionally having C _1-6 alkoxy-carbonyl group, or (g) 5- to 10-membered (preferably 9-membered) optionally having oxo group An aromatic heterocyclic group,
R ^7a is (a) a hydrogen atom,
(B) a C _6-12 aryl group optionally having a substituent selected from a C _1-6 alkoxy-carbonyl group, a halogen atom and a C _1-6 alkoxy group,
(C) (i) a halogen atom,
(Ii) C _1-6 alkoxy - carbonyl group, an optionally substituted amino group, and a C _1-6 alkyl group optionally having a substituent selected from halogen atoms,
(Iii) a C _1-6 alkylsulfonyl group, and (iv) a mono- or di-C _1-6 alkylamino group,
A C _7-13 aralkyl group which may have a substituent selected from:
(D) (i) a 5- or 6-membered aromatic heterocyclic group which may be oxidized and may have a cyano group,
(Ii) a 5- to 7-membered cyclic amino group which may have a C _1-6 alkyl group and may be condensed with a benzene ring;
(Iii) a C _1-6 alkoxy-carbonyl group,
(Iv) a carboxy group,
(V) a 5- to 7-membered saturated cyclic aminocarbonyl group,
(Vi) a C _6-12 aryl group,
(Vii) a C _6-12 aryl-carbonyl group,
(Viii) a hydroxy group, and (ix) a substituent 1 selected from a C _1-6 alkyl group, a C _1-6 alkoxy-C _1-6 alkyl group, an azidocarbonyl group, an aminocarbonyl group, and a C _7-13 aralkyl group Or an amino group optionally having two,
A C _1-6 alkyl group _optionally having a substituent selected from:
(E) a C _3-8 cycloalkyl group which may be condensed with one or two benzene rings,
(F) a 5- to 10-membered aromatic heterocyclic group optionally having a substituent selected from an oxo group and a C _1-6 alkoxy-carbonyl group,
(G) a C _6-12 aryl-carbonyl group,
(H) a C _1-6 alkoxy-carbonyl group, or (i) a substituent selected from a C _1-6 alkyl group, a C _1-6 alkoxy-carbonyl group and an oxo group, An optionally fused 5- to 7-membered non-aromatic heterocyclic group,
R ^8a may have a hydrogen atom, a C _1-6 alkyl group or a C _6-12 arylamino group, or R ^7a and R ^8a may have a 5- to 7-membered saturated cyclic amino group together with the adjacent nitrogen atom. A 5- to 10-membered non-aromatic heterocyclic ring may be formed],
R ² is a hydrogen atom, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, an optionally halogenated C _6-12 aryl group or a C _7-13 aralkyl group,
R ³ is a C _1-6 alkyl group, a C _3-6 cycloalkyl group, an optionally halogenated C _6-12 aryl group or a C _7-13 aralkyl group,
The compound according to [1], wherein n is 0, and X is an oxygen atom.

[20] R ¹ is represented by the formula — (C═O) —R ^6a , — (C═O) —OR ^6a , — (C═O) —NR ^7a R ^8a or —SO ₂ —R ^6a.
[Wherein R ^6a is (a) a C _7-13 aralkyl group,
(B) a C _2-6 alkenyl group _optionally having a halogenated C _6-12 aryl group,
(C) (i) a halogen atom,
(Ii) a C _1-6 alkoxy group,
(Iii) a nitro group,
(Iv) may have one or two substituents selected from a formyl group, and (v) (1) a halogen atom, (2) a C _1-6 alkoxy-carbonyl group and a C _1-6 alkyl group A C _1-6 alkyl group _optionally having a substituent selected from an amino group, and (3) an optionally substituted 5- to 7-membered cyclic amino group,
A C _6-12 aryl group _optionally having a substituent selected from:
(D) a 5- or 6-membered aromatic heterocyclic group,
(E) (i) a C _6-12 aryloxy group,
(Ii) a C _3-8 cycloalkyl group which may be condensed with one or two benzene rings,
(Iii) an optionally halogenated C _6-12 arylamino group,
(Iv) a carboxy group,
(V) a 5- to 7-membered cyclic amino group,
(Vi) a 5- to 7-membered non-aromatic heterocyclic group,
(Vii) a C _6-12 aryl group, and (viii) a halogen atom,
A C _1-6 alkyl group _optionally having a substituent selected from:
(F) (i) a C _1-6 alkoxy-carbonyl group,
(Ii) a carbamoyl group,
(Iii) a hydroxy group,
(Iv) a 5- to 7-membered cyclic amino-carbonyl group,
(V) a C _3-8 cycloalkyl group, and (vi) a C _2-8 alkenyl group,
A 5- to 7-membered non-aromatic heterocyclic group optionally having a C _1-6 alkyl group, a C _1-6 alkoxy-carbonyl group or a formyl group optionally having a substituent selected from:
(G) a 5- to 10-membered (preferably 9-membered) aromatic heterocyclic group optionally having an oxo group, or (h) an oxo group optionally having a benzene ring condensed A good 5- to 10-membered cyclic amino group,
R ^7a is (a) a hydrogen atom,
(B) (i) a C _1-6 alkoxy-carbonyl group,
(Ii) a halogen atom, and (iii) a C _1-6 alkoxy group,
A C _6-12 aryl group _optionally having a substituent selected from:
(C) (i) a halogen atom,
(Ii) C _1-6 alkoxy - carbonyl group, an optionally substituted amino group, and a C _1-6 alkyl group optionally having a substituent selected from halogen atoms,
(Iii) a C _1-6 alkylsulfonyl group, and (iv) a mono- or di-C _1-6 alkylamino group,
A C _7-13 aralkyl group which may have a substituent selected from:
(D) (i) a 5- or 6-membered aromatic heterocyclic group which may be oxidized and may be substituted with a cyano group, a hydroxy group or a C _1-6 alkyl group,
(Ii) a 5- to 7-membered cyclic amino group which may have a C _1-6 alkyl group, a hydroxy group, an oxo group or a C _1-6 alkoxy-carbonyl group and may be condensed with a benzene ring;
(Iii) a C _1-6 alkoxy-carbonyl group,
(Iv) a carboxy group,
(V) a 5- to 7-membered cyclic aminocarbonyl group,
(Vi) an optionally halogenated C _6-12 aryl group,
(Vii) a C _6-12 aryl-carbonyl group,
(Viii) a hydroxy group,
(Ix) (1) a C _1-6 alkyl group optionally substituted with a C _3-8 cycloalkyl group, (2) a C _1-6 alkoxy-C _1-6 alkyl group, (3) an azidocarbonyl group, (4) aminocarbonyl group, (5)
A C _7-13 aralkyl group, (6) a C _3-8 cycloalkyl group, (7) a sulfonyl group optionally substituted with a benzene ring optionally substituted with a nitro group, (8) C _2-8 alkenyl An amino group optionally having one or two substituents selected from a group, (9) a C _1-6 alkylsulfonyl group, and (10) a C _1-6 alkyl-carbonyl group,
(X) a C _3-8 cycloalkyl group, and (xi) a 5- to 7-membered non-aromatic heterocyclic group,
A C _1-6 alkyl group optionally having 1 or 2 substituents selected from:
(E) a C _3-8 cycloalkyl group which may be condensed with one or two benzene rings,
(F) a 5- to 10-membered aromatic heterocyclic group optionally having a substituent selected from an oxo group, a C _1-6 alkoxy-carbonyl group, and a C _1-6 alkyl group,
(G) a C _6-12 aryl-carbonyl group,
(H) a C _1-6 alkoxy-carbonyl group,
(I) a 5- to 7-membered non-aromatic which may have a substituent selected from a C _1-6 alkyl group, a C _1-6 alkoxy-carbonyl group and an oxo group and may be condensed with a benzene ring A heterocyclic group,
(J) a 5- to 7-membered cyclic amino-C _1-6 alkyl-carbonyl group,
(K) a C _3-8 cycloalkyl group optionally substituted with a C _1-6 alkyl group optionally having a 5- to 7-membered cyclic amino group, or (L) a C _6-12 arylamino group,
R ^8a is a hydrogen atom, a C _1-6 alkyl group, or R ^7a and R ^8a have a substituent selected from a 5- to 7-membered saturated cyclic amino group and a C _1-6 alkyl group together with the adjacent nitrogen atom. A 5- to 10-membered non-aromatic heterocyclic ring which may optionally be formed]
R ² is
(i) a hydrogen atom,
(ii) a C _1-6 alkyl group,
(iii) a C _3-6 cycloalkyl group,
(iv) a C _6-12 aryl group optionally having a substituent selected from a halogen atom and a C _1-6 alkyl group, or
(v) C _7-13 aralkyl group,
R ³ is
(i) a C _1-6 alkyl group,
(ii) a C _3-6 cycloalkyl group,
(iii) a C _6-12 aryl group optionally having a substituent selected from a halogen atom and a C _1-6 alkyl group, or
(iv) C _7-13 aralkyl group,
The compound according to [1], wherein n is 0, and X is an oxygen atom.

[21] tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid phenyl ester,
Hexahydro-7- (1-oxo-3-phenyl-2-propenyl) -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one,
(+)-N-[(4-fluorophenyl) methyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide,
(-)-N-[(4-fluorophenyl) methyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide,
(+)-N- [2- (3,6-Dihydropyridin-1 (2H) -yl) ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine- 7 (1H) -carboxamide,
(-)-N- [2- (3,6-Dihydropyridin-1 (2H) -yl) ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine- 7 (1H) -carboxamide,
1,1-bis (3-fluorophenyl) -N- [2- (3,6-dihydropyridin-1 (2H) -yl) ethyl] -tetrahydro-3-oxo-3H-oxazolo [3,4-a] Pyrazine-7 (1H) -carboxamide,
N- [2- (3,6-Dihydropyridin-1 (2H) -yl) ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -Carboxamide,
1,1-bis (3-fluorophenyl) -N- [2- (cyclopropylamino) ethyl] -tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hydrochloride salt,
Tetrahydro-3-oxo-1,1-diphenyl-N-[(3-thienyl) methyl] -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide,
7- [4- (3,6-Dihydropyridin-1 (2H) -yl) -1-oxobutyl] -hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H)- 3-on,
N- [2-[(cyclopropylmethyl) amino] ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hydrochloride,
N-[(4-fluorophenyl) methyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide, or
1,1-bis (3-fluorophenyl) -tetrahydro-3-oxo-N- [2- (1-piperidinyl) ethyl] -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide, Or their salts.
[22] A medicament comprising the compound according to [1] or a salt thereof or a prodrug thereof. [23] Formula

[In the formula (II),
Ring A is a 5- to 10-membered ring,
Ring B is a 5- to 9-membered ring,
R ¹ ′ represents a hydrogen atom, an acyl group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,
R ⁴ ′ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,
R ⁴ ″ represents an oxo group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,
m is an integer of 0 to 8 (when m is an integer of 2 to 8, R ⁴ ′ may be the same or different),
k is an integer of 0 to 8 (when k is an integer of 2 to 8, R ⁴ ″ may be the same or different),
X represents an oxygen atom, a sulfur atom, or a group represented by NR ⁵ (wherein R ⁵ represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group). . ]
Or a salt thereof (hereinafter sometimes abbreviated as compound (II)).
[24] It is a prophylactic / therapeutic agent for cancer, Alzheimer's disease, dementia, eating disorders, hypertension, gonadal dysfunction, thyroid dysfunction, pituitary dysfunction, diabetes, lipid metabolism disorder, hyperlipidemia or anorexia [22] The medicine according to [23].
[25] The medicament according to [22] or [23], which is a prophylactic / therapeutic agent for a disease caused by TGR23.
[26] A cancer, Alzheimer's disease, dementia, eating disorder, hypertension, gonadal dysfunction, thyroid dysfunction, pituitary gland characterized by administering an effective amount of the compound or salt thereof according to [1] to a mammal Methods for preventing / treating dysfunction, diabetes, lipid metabolism disorder, hyperlipidemia or anorexia. [27] A method for preventing / treating a disease caused by TGR23 in a mammal, comprising administering an effective amount of the compound or salt thereof according to [1] to the mammal.
[28] Production of preventive / therapeutic agent for cancer, Alzheimer's disease, dementia, eating disorders, hypertension, gonadal dysfunction, thyroid dysfunction, pituitary dysfunction, diabetes, lipid metabolism disorder, hyperlipidemia or anorexia Use of the compound according to [1] for
[29] Use of the compound according to [1] for the manufacture of a prophylactic / therapeutic agent for diseases caused by TGR23.
[30] A cancer, Alzheimer's disease, dementia, eating disorder, hypertension, gonadal function, wherein an effective amount of the compound represented by formula (II) or a salt thereof according to [23] is administered to a mammal Methods for preventing / treating abnormalities, thyroid dysfunction, pituitary dysfunction, diabetes, lipid metabolism abnormality, hyperlipidemia or anorexia.
[31] A method for preventing / treating a disease caused by TGR23 in a mammal, comprising administering an effective amount of the compound represented by the formula (II) according to [23] or a salt thereof to the mammal.
[32] Manufacture of preventive and therapeutic agents for cancer, Alzheimer's disease, dementia, eating disorders, hypertension, gonadal dysfunction, thyroid dysfunction, pituitary dysfunction, diabetes, lipid metabolism disorder, hyperlipidemia or anorexia Use of the compound represented by formula (II) according to [23] for
[33] Use of the compound represented by formula (II) according to [23] for the manufacture of a prophylactic / therapeutic agent for diseases caused by TGR23.

  Since compound (II) containing compound (I) has excellent TGR23 antagonist activity based on its specific chemical structure, compound (II) containing this compound (I) is used for cancer, Alzheimer's disease, dementia, It is useful as a medicine for prevention / treatment of prevention / treatment of eating disorders, hypertension, gonadal dysfunction, thyroid dysfunction, pituitary dysfunction, diabetes, dyslipidemia, hyperlipidemia, anorexia.

Each symbol in the formula will be described.
1) About R ¹ (R ¹ ′) In formulas (I) and (II), as the “acyl group” represented by R ¹ or R ¹ ′, for example, the formula — (C═O) —R ⁶ , — (C═O) —OR ⁶ , — (C═O) —NR ⁷ R ⁸ , — (C═S) —NR ⁷ R ⁸ , —SO—R ⁶ , —SO ₂ —R ⁶ or —SO ₂ —. NR ⁷ R ⁸
[Wherein R ⁶ represents a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent,
R ⁷ represents a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, a C _6-12 aryl-carbonyl group, a C _1-6 alkoxy-carbonyl group. Or a 5- or 6-membered aromatic heterocyclic carbonyl group, and R ⁸ represents a hydrogen atom, a C _1-6 alkyl group or an amino group which may have a substituent, or
R ⁷ and R ⁸ together with the adjacent nitrogen atom may form a ring which may have a substituent, and the like.
In the above formula, examples of the “hydrocarbon group” of the “hydrocarbon group optionally having substituents” represented by R ⁶ include a chain or cyclic hydrocarbon group (eg, alkyl group, alkenyl group, Alkynyl group, cycloalkyl group, aryl group, aralkyl group, etc.). Of these, a chain or cyclic hydrocarbon group having 1 to 16 carbon atoms is preferred.

Examples of the “alkyl group” include a C _1-6 alkyl group (eg, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group). Etc.) are preferred.
Examples of the “alkenyl group” include a C _2-6 alkenyl group (eg, vinyl group, allyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-2-propenyl group). , 1-methyl-2-propenyl group, 2-methyl-1-propenyl group, and the like.
As the “alkynyl group”, for example, a C _2-6 alkynyl group (eg, ethynyl group, propargyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-hexynyl group, etc.) and the like are preferable.
As the “cycloalkyl group”, for example, a C _3-6 cycloalkyl group (eg, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, etc.) and the like are preferable. The “cycloalkyl group” may be condensed with 1 or 2 C _6-14 aromatic carbocycles (eg, benzene ring, etc.) (eg, 1-indanyl group, 1,2,3,4). -Tetrahydro-1-naphthyl group, etc.).
Examples of the “aryl group” include C _6-14 aryl groups (eg, phenyl group, 1-naphthyl group, 2-naphthyl group, 2-biphenylyl group, 3-biphenylyl group, 4-biphenylyl group, 2-anthryl group, etc.) Etc.) are preferred.
Examples of the “aralkyl group” include a C _7-16 aralkyl group (eg, benzyl group, phenethyl group, diphenylmethyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, 2,2-diphenylethyl group, 3-phenylpropyl group). Group, 4-phenylbutyl group, 5-phenylpentyl group, etc.).

As the “substituent” of the “hydrocarbon group optionally having substituent (s)” represented by R ⁶ , for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine etc.), C _1-3 alkylenedioxy Group (eg, methylenedioxy group, ethylenedioxy group, etc.), nitro group, cyano group, optionally substituted C _1-6 alkyl group, optionally halogenated C _2-6 alkenyl Group, carboxy C _2-6 alkenyl group (eg, 2-carboxyethenyl group, 2-carboxy-2-methylethenyl group, etc.), C _2-6 alkynyl group which may be halogenated, halogenated C _3-8 cycloalkyl group which may be condensed, C _6-14 aryl group which may be halogenated, C _1-8 alkoxy group which may be halogenated, C _1-6 alkoxy- carbonyl -C _1-6 alkoxy groups ( And ethoxycarbonylmethyl group), hydroxy group, C _6-14 aryloxy group (e.g., phenyl group, 1-naphthyloxy group, 2-naphthyloxy group), C _7-16 aralkyloxy group (e.g., Benzyloxy group, phenethyloxy group, etc.), mercapto group, optionally halogenated C _1-6 alkylthio group, C _6-14 arylthio group (eg, phenylthio group, 1-naphthylthio group, 2-naphthylthio group, etc.) , C _7-16 aralkylthio group (eg, benzylthio group, phenethylthio group, etc.), amino group, mono-C _1-6 alkylamino group (eg, methylamino group, ethylamino group, etc.), di-C _{1- 6} alkylamino group (e.g., dimethylamino group, diethylamino group, ethyl methyl amino group), an optionally halogenated mono - or di -C _6-14 a Ruamino group may sulfonyl optionally substituted by also benzene ring substituted with nitro group - amino group (e.g., nitrobenzyl sulfonylamino group), C _3-7 cycloalkylamino group (e.g., cyclopropylamino group ), C _1-6 alkylsulfonyl-amino group (eg, methylsulfonylamino group), C _3-8 cycloalkyl-C _1-6 alkyl-amino group (eg, cycloalkylmethylamino group), C _1-6 alkyl -Carbonyl-amino group (eg, methylcarbonylamino group), C _2-8 alkenyl-amino group (eg, allylamino group), C _1-6 alkoxy-C _1-6 alkylamino group (eg, methoxyethylamino group) , azido carbonyl - amino group, aminocarbonyl - amino _{group, C 7-13} aralkyl - amino group (e.g., benzyl Amino group), a formyl group, a carboxy group, C _1-6 alkyl - carbonyl group (e.g., acetyl, propionyl and the like groups), C _3-6 cycloalkyl - carbonyl group (e.g., cyclopropyl group, cyclopentyl group, Cyclohexylcarbonyl group, etc.), C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, tert-butoxycarbonyl group, etc.), 5- to 7-membered cyclic amino-carbonyl group (eg, morpholino) Carbonyl group), C _6-14 aryl-carbonyl group (eg, benzoyl group, 1-naphthoyl group, 2-naphthoyl group, etc.), C _7-16 aralkyl-carbonyl group (eg, phenylacetyl group, 3-phenylpropionyl group) etc.), C _6-14 aryloxy - carbonyl group (e.g., Fenokishikaru Such cycloalkenyl group), C _7-16 aralkyloxy - carbonyl group (e.g., benzyloxycarbonyl group, etc. phenethyloxycarbonyl group), 5- or 6-membered heterocyclic carbonyl group (e.g., nicotinoyl group, isonicotinoyl group, thenoyl group, furoyl Group, morpholinocarbonyl group, thiomorpholinocarbonyl group, piperazin-1-ylcarbonyl group, pyrrolidin-1-ylcarbonyl group, etc.), carbamoyl group, mono-C _1-6 alkyl-carbamoyl group (eg, methylcarbamoyl group, ethyl) Carbamoyl group, etc.), di-C _1-6 alkyl-carbamoyl group (eg, dimethylcarbamoyl group, diethylcarbamoyl group, ethylmethylcarbamoyl group, etc.), C _6-14 aryl-carbamoyl group (eg, phenylcarbamoyl group, 1- Naphthylcarbamoyl group, 2-naphth Etc. carbamoyl group), 5- or 6-membered heterocyclic carbamoyl group (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl group, 4-pyridylcarbamoyl group, 2-thienylcarbamoyl group, 3-thienylcarbamoyl group), C _{1 -6} alkylsulfonyl group (eg, methylsulfonyl group, ethylsulfonyl group, etc.), C _6-14 arylsulfonyl group (eg, phenylsulfonyl group, 1-naphthylsulfonyl group, 2-naphthylsulfonyl group, etc.), formylamino group, C _1-6 alkyl-carbonylamino group (eg, acetylamino group, etc.), C _6-14 aryl-carbonylamino group (eg, benzoylamino group, naphthoylamino group, etc.), C _1-6 alkoxy-carbonylamino group (Eg, methoxycarbonylamino group, ethoxycarbonylamino group, propo Aryloxycarbonyl amino group, such as butoxycarbonylamino group), C _1-6 alkylsulfonylamino group (e.g., methylsulfonylamino group, etc. ethylsulfonylamino group), C _6-14 arylsulfonylamino group (e.g., phenylsulfonylamino group , 2-naphthylsulfonylamino group, 1-naphthylsulfonylamino group, etc.), C _1-6 alkyl-carbonyloxy group (eg, acetoxy group, propionyloxy group, etc.), C _6-14 aryl-carbonyloxy group (eg, Benzoyloxy group, naphthylcarbonyloxy group, etc.), C _1-6 alkoxy-carbonyloxy group (eg, methoxycarbonyloxy group, ethoxycarbonyloxy group, propoxycarbonyloxy group, butoxycarbonyloxy group, etc.), mono-C _{1- 6} alkyl - carbamoyloxy group (e.g. Methylcarbamoyloxy group, ethylcarbamoyl group), di -C _1-6 alkyl - carbamoyloxy group (e.g., dimethylcarbamoyl group, diethylcarbamoyl group, etc.), C _6-14 aryl - carbamoyloxy group (e.g., Phenylcarbamoyloxy group, naphthylcarbamoyloxy group, etc.) 5 to 6-membered heterocyclic carbonyloxy group (eg, nicotinoyloxy group, isonicotinoyloxy group, etc.), substituent (eg, oxo group, etc.) A 5- to 10-membered (preferably 5- to 7-membered) cyclic amino group that may be condensed with a benzene ring, a 5- or 7-membered non-aromatic heterocyclic group that may have a substituent, A 5- to 10-membered aromatic heterocyclic group which may have a group (eg, 2-thienyl group, 3-thienyl group, 2-furyl group, -Furyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl group, 8-quinolyl group, 1-isoquinolyl group, 3 -Isoquinolyl group, 4-isoquinolyl group, 5-isoquinolyl group, 1-indolyl group, 2-indolyl group, 3-indolyl group, 2-benzothiazolyl group, 2-benzo [b] thienyl group, 3-benzo [b] thienyl Group, 2-benzo [b] furanyl group, 3-benzo [b] furanyl group, preferably 5- to 6-membered aromatic heterocyclic group), sulfo group, oxo group and the like.
The “hydrocarbon group” may have, for example, the above-mentioned substituents at 1 to 5, preferably 1 to 3, substituents. When the number of substituents is 2 or more, each substituent is They may be the same or different.

Examples of the “C _1-6 alkyl group” of the “ _optionally substituted C _1-6 alkyl group” include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, sec And C _1-6 alkyl groups such as -butyl group, tert-butyl group, pentyl group, hexyl group and the like.
Examples of the “substituent” of the “optionally substituted C _1-6 alkyl group” include (i) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), (ii) a halogen atom. A substituent 1 selected from a C _1-6 alkoxy-carbonyl group, a C _1-6 alkyl group, a C _1-6 alkoxy-C _1-6 alkyl group, an azidocarbonyl group, an aminocarbonyl group and a C _7-13 aralkyl group Or an amino group which may have two (eg, amino group, methylamino group, ethylamino group, propylamino group, isopropylamino group, sec-butylamino group, dimethylamino group, diethylamino group, dipropylamino group) Group, diisopropylamino group, methoxycarbonylamino group, ethoxycarbonylamino group, tert-butoxycarbonylamino group, [(methoxycarbonyl) methyl] amino group, (methoxy group) Methyl) amino group, azidocarbonylamino group, aminocarbonylamino group, benzylamino group, dibenzylamino group, etc.), (iii) may be oxidized and may have cyano 5- to 10-membered aromatic Group heterocyclic groups (eg, 2-thienyl group, 3-thienyl group, 2-furyl group, 3-furyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-quinolyl group, 3-quinolyl group) Group, 4-quinolyl group, 5-quinolyl group, 8-quinolyl group, 1-isoquinolyl group, 3-isoquinolyl group, 4-isoquinolyl group, 5-isoquinolyl group, 1-indolyl group, 2-indolyl group, 3-indolyl group Group, 2-benzothiazolyl group, 2-benzo [b] thienyl group, 3-benzo [b] thienyl group, 2-benzo [b] furanyl group, 3-benzo [b] furanyl group, etc. , (Iv) a substituent (eg, 1 to 5 C _1-6 alkyl groups, etc.) may have one or two 5- or may be condensed with the benzene ring to 7-membered cyclic amino Groups (eg, pyrrolidino group, piperidino group, piperazino group, morpholino group, thiomorpholino group, hexahydroazepin-1-yl group, etc.), (v) C _1-6 alkoxy-carbonyl group, (vi) carboxy group, ( vii) 5- to 7-membered saturated cyclic amino-carbonyl group (eg, pyrrolidinocarbonyl group, piperidinocarbonyl group, morpholinocarbonyl group, etc.), (viii) C _6-12 aryl group (eg, phenyl group, 1-naphthyl) Group, 2-naphthyl group, etc.), (ix) C _6-12 aryl-carbonyl group (eg, benzoyl group, 1-naphthoyl group, 2-naphthoyl group, etc.), (x) hydroxy group, (xi) C _{3- 8} cycloalkyl group, (xi i) C _2-8 alkenyl group, (xiii) carbamoyl group and the like. The “C _1-6 alkyl group” may have, for example, 1 to 5, preferably 1 to 3 of the above substituents at substitutable positions. When the number of substituents is 2 or more, The substituents may be the same or different.
Specific examples of the “optionally substituted C _1-6 alkyl group” include a methyl group, a trifluoromethyl group, a (2-thienyl) methyl group, an ethyl group, a 2-piperidinoethyl group, and a propyl group. , 3- (1-oxide-3-pyridyl) propyl group, 2- (4-chlorophenyl) butyl group and the like.

The “optionally halogenated C _2-6 alkenyl group” has, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). C _2-6 alkenyl group (eg, vinyl group, propenyl group, isopropenyl group, 2-buten-1-yl group, 4-penten-1-yl group, 5-hexen-1-yl group, etc.) ) And the like.
The “optionally halogenated C _2-6 alkynyl group” has, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). C _2-6 alkynyl groups (eg, 2-butyn-1-yl group, 4-pentyn-1-yl group, 5-hexyn-1-yl group, etc.) and the like may be mentioned.

Examples of the “optionally halogenated C _3-8 cycloalkyl group” in the “optionally halogenated and optionally condensed C _3-8 cycloalkyl group” include 1 to 5, Preferably a C _3-6 cycloalkyl group (eg, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group) optionally having 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) Etc.). Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a 4,4-dichlorocyclohexyl group, a 2,2,3,3-tetrafluorocyclopentyl group, and a 4-chlorocyclohexyl group.
The “condensed C _3-8 cycloalkyl group” of the “optionally halogenated and condensed C _3-8 cycloalkyl group” is, for example, a 3- to 8-membered bicyclic or tricyclic group. A cyclic cycloalkyl group (eg, 9-fluorenyl group, 1-indanyl group, 1,2,3,4-tetrahydro-1-naphthyl group, etc.), preferably C ₃₋ condensed with 1 or 2 benzene rings. ₈ cycloalkyl group and the like can be mentioned. The “condensed C _3-8 cycloalkyl group” may be halogenated.

The “optionally halogenated C _6-14 aryl group” has, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). C _6-14 aryl group (eg, phenyl group, 1-naphthyl group, 2-naphthyl group, 2-biphenylyl group, 3-biphenylyl group, 4-biphenylyl group, 2-anthryl group, etc.) may be mentioned. . Specific examples include 3,4-dichlorophenyl group, 4-bromophenyl group, 6-fluoro-1-naphthyl group, 2′-chloro-4-biphenylyl group and the like.
The “optionally halogenated C _1-8 alkoxy group” has, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). C _1-8 alkoxy groups (eg, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, pentyloxy group, hexyloxy group, etc.) may be mentioned. Specific examples include, for example, methoxy group, difluoromethoxy group, trifluoromethoxy group, ethoxy group, 2,2,2-trifluoroethoxy group, propoxy group, isopropoxy group, butoxy group, 4,4,4-trifluoro. Examples include butoxy group, isobutoxy group, sec-butoxy group, pentyloxy group, and hexyloxy group.

The “optionally halogenated mono- or di-C _6-14 arylamino group” is, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine). Mono-C _6-14 arylamino group (eg, phenylamino group, 1-naphthylamino group, 2-naphthylamino group, etc.), or 1 to 5, preferably 1 to 3 And a di-C _6-14 arylamino group (eg, diphenylamino group) and the like which may have one halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.). Specific examples include 2,4-difluorophenylamino group, 3-chlorophenylamino group, bis (4-chlorophenyl) amino group, and the like.
The “optionally halogenated C _1-6 alkylthio group” has, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). C _1-6 alkylthio groups (eg, methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, sec-butylthio group, tert-butylthio group, etc.) may be mentioned. Specific examples include methylthio group, difluoromethylthio group, trifluoromethylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, 4,4,4-trifluorobutylthio group, pentylthio group, hexylthio group and the like. It is done.

“5- to 10-membered (preferably 5- to 7-membered) of the“ 5- to 10-membered (preferably 5- to 7-membered) cyclic amino group which may have a substituent and the benzene ring may be condensed ”” The “) cyclic amino group” may contain, for example, 1 or 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to one nitrogen atom and carbon atom. 5- to 10-membered (preferably 5- to 7-membered) cyclic amino group saturated or unsaturated cyclic amino group may be mentioned. Specific examples of the 5- to 10-membered (preferably 5- to 7-membered) saturated cyclic amino group include pyrrolidino group, piperidino group, piperazino group, morpholino group, thiomorpholino group, hexahydroazepin-1-yl group and the like. . Specific examples of the 5- to 10-membered (preferably 5- to 7-membered) unsaturated cyclic amino group include 3,6-dihydropyridin-1 (2H) -yl group, 1,2,5,6-tetrahydro-1H-azepine A -1-yl group etc. are mentioned.
Examples of the “substituent” of the “5- to 10-membered (preferably 5- to 7-membered) cyclic amino group which may have a substituent and may be condensed with a benzene ring” include, for example, C _1-6 Alkyl group (eg, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, etc.), hydroxy group, C _1-6 alkoxy- Carbonyl group (eg, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, t-butoxycarbonyl group), C _6-14 aryl group (eg, phenyl group, 1-naphthyl group, 2-naphthyl group, 2-biphenylyl group, 3-biphenylyl group, 4-biphenylyl group, a 2-anthryl group), C _1-6 alkyl - carbonyl group (e.g., acetyl group, propionyl Groups) 5- to 10-membered aromatic heterocyclic groups (eg, 2-thienyl group, 3-thienyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-quinolyl group, 3-quinolyl group) 4-quinolyl group, 5-quinolyl group, 8-quinolyl group, 1-isoquinolyl group, 3-isoquinolyl group, 4-isoquinolyl group, 5-isoquinolyl group, 1-indolyl group, 2-indolyl group, 3-indolyl group 2-benzothiazolyl group, 2-benzo [b] thienyl group, 3-benzo [b] thienyl group, 2-benzo [b] furanyl group, 3-benzo [b] furanyl group, etc.), oxo group, etc. . The “5- to 7-membered cyclic amino group” may have, for example, 1 to 5 substituents, preferably 1 to 3 substituents as described above, and when the number of substituents is 2 or more, Each substituent may be the same or different.

As the “5- or 7-membered non-aromatic heterocyclic group” of the “optionally substituted 5- or 7-membered non-aromatic heterocyclic group”, for example, a 2-morpholinyl group, a 3-morpholinyl group, Examples include 2-piperidyl group, 4-piperidinyl group, 2-piperazinyl group and the like.
The “optionally substituted 5- or 7-membered non-aromatic heterocyclic group” or “optionally substituted 5- to 10-membered (preferably 5- or 6-membered) aromatic heterocyclic group As the “substituent”, for example, a C _1-6 alkyl group (eg, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, Hexyl group, etc.), hydroxy group, cyano group, C _6-14 aryl group (eg, phenyl group, 1-naphthyl group, 2-naphthyl group, 2-biphenylyl group, 3-biphenylyl group, 4-biphenylyl group, 2- Anthryl group), C _1-6 alkyl-carbonyl group (eg, acetyl group, propionyl group, etc.), 5- to 10-membered aromatic heterocyclic group (eg, 2-thienyl group, 3-thienyl group, 2-pyridyl group) 3-pyridyl group, 4-pi Lysyl group, 2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl group, 8-quinolyl group, 1-isoquinolyl group, 3-isoquinolyl group, 4-isoquinolyl group, 5-isoquinolyl group, 1- Indolyl group, 2-indolyl group, 3-indolyl group, 2-benzothiazolyl group, 2-benzo [b] thienyl group, 3-benzo [b] thienyl group, 2-benzo [b] furanyl group, 3-benzo [b ] Furanyl group and the like, and oxo group. The “5- or 7-membered non-aromatic heterocyclic group” and “5- to 10-membered (preferably 5- or 6-membered) aromatic heterocyclic group” include, for example, 1 to 5 substituents at the substitutable positions. The number of substituents may be 1 or 3, and when the number of substituents is 2 or more, each substituent may be the same or different.

As the “heterocyclic group” of the “heterocyclic group optionally having substituent (s)” represented by R ⁶ , for example, one or two kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom, 5 to 14 membered (monocyclic, bicyclic or tricyclic) heterocycles containing 1 to 4 heteroatoms, preferably (i) 5 to 14 members (preferably 5 to 10 members, more preferably 5 or 6) A member) an aromatic heterocycle, (ii) a 5- to 10-membered (preferably 5- or 6-membered) non-aromatic heterocycle, or (iii) a 7- to 10-membered hetero-bridged ring by removing any one hydrogen atom And monovalent groups that can be produced.
Examples of the “5- to 14-membered (preferably 5- to 10-membered aromatic heterocycle)” include, for example, thiophene, benzo [b] thiophene, benzo [b] furan, benzimidazole, benzoxazole, benzothiazole, benziso Thiazole, naphtho [2,3-b] thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine Quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, isoxazole, furazane, phenoxazine, etc. Family heterocycle or thereof, rings (preferably monocyclic) aromatic ring (e.g., benzene ring, etc.) with one or more (preferably 1 or 2), such as condensation formed ring are exemplified with.
Examples of the “5- to 10-membered (preferably 5- or 6-membered) non-aromatic heterocyclic ring” include, for example, pyrrolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, dioxazole, oxadiazoline, thiadiazoline , Triazoline, thiadiazole, dithiazole and the like.
Examples of the “7 to 10-membered hetero-bridged ring” include quinuclidine, 7-azabicyclo [2.2.1] heptane, and the like.

The “heterocyclic group” is preferably a 5- to 14-membered (preferably 5 to 14) member containing 1 or 2 kinds, preferably 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. Or a 10-membered, more preferably 5- or 6-membered (monocyclic or bicyclic) heterocyclic group. Specifically, for example, 2-thienyl group, 3-thienyl group, 2-furyl group, 3-furyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-quinolyl group, 3-quinolyl group 4-quinolyl group, 5-quinolyl group, 8-quinolyl group, 1-isoquinolyl group, 3-isoquinolyl group, 4-isoquinolyl group, 5-isoquinolyl group, pyrazinyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 3 -Pyrrolyl group, 2-imidazolyl group, 3-pyridazinyl group, 3-isothiazolyl group, 3-isoxazolyl group, 1-indolyl group, 2-indolyl group, 3-indolyl group, 2-benzothiazolyl group, 2-benzo [b] Aromatic heterocyclic groups such as thienyl group, 3-benzo [b] thienyl group, 2-benzo [b] furanyl group, 3-benzo [b] furanyl group, such as 1-pyro Zinyl group, 2-pyrrolidinyl group, 3-pyrrolidinyl group, 2-imidazolinyl group, 4-imidazolinyl group, 2-pyrazolidinyl group, 3-pyrazolidinyl group, 4-pyrazolidinyl group, piperidino group, 2-piperidyl group, 3-piperidyl group , 4-piperidyl group, 1-piperazinyl group, 2-piperazinyl group, morpholino group, thiomorpholino group and other non-aromatic heterocyclic groups.
Among these, for example, a 5- to 6-membered non-aromatic or aromatic heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms is more preferable. Specifically, 2-thienyl group, 3-thienyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-furyl group, 3-furyl group, pyrazinyl group, 2-pyrimidinyl group, 3- Pyrrolyl group, 3-pyridazinyl group, 3-isothiazolyl group, 3-isoxazolyl group, 1-pyrrolidinyl group, 2-pyrrolidinyl group, 3-pyrrolidinyl group, 2-imidazolinyl group, 4-imidazolinyl group, 2-pyrazolidinyl group, 3- Examples include pyrazolidinyl group, 4-pyrazolidinyl group, piperidino group, 2-piperidyl group, 3-piperidyl group, 4-piperidyl group, 1-piperazinyl group, 2-piperazinyl group, morpholino group, thiomorpholino group and the like.
Examples of the “substituent” of the “heterocyclic group optionally having substituent (s)” include the “substituent” of the “hydrocarbon group optionally having substituent (s)” represented by R ⁶ above. The same thing and an oxo group etc. are mentioned.
The “heterocyclic group” may have, for example, 1 to 5 substituents, preferably 1 to 3 substituents as described above, and when the number of substituents is 2 or more, They may be the same or different.

Examples of the “hydrocarbon group optionally having substituent (s)” represented by R ⁷ and the “heterocyclic group optionally having substituent (s)” include, for example, the “having substituent (s) represented by R ^6. Having the same thing as “optionally substituted hydrocarbon group” and “optionally substituted heterocyclic group” and (a) a substituent (hydroxy group, C _1-6 alkoxy-carbonyl group, etc.) Or a 5- to 7-membered cyclic amino group that may be condensed with a benzene ring, and (b) a substituent (such as a hydroxy group, a C _1-6 alkyl group, a cyano group). An optionally oxidized 5- to 6-membered aromatic heterocyclic-C _1-6 alkyl group, (c) a substituent (an oxo group, a C _1-6 alkoxycarbonyl group, a C _1-6 alkyl group, etc.) 5- to 10-membered (preferably 5- or 6-membered) aromatic heterocyclic group which may have, (d) substituted (C _1-6 alkyl groups, C _1-6 alkoxycarbonyl group, an oxo group, etc.) to 5 which may have a 7-membered non-aromatic heterocyclic group, (e) 5 to 7-membered cyclic amino -C _{1 -6} alkyl-carbonyl group, (f) a C _3-8 cycloalkyl group _optionally substituted with a C _1-6 alkyl group _optionally having a cyclic amino group, (g) a substituent (C _{3- 8} cycloalkyl-amino group, C _1-6 alkyl-amino group _optionally substituted with C _3-8 cycloalkyl, sulfonylamino group optionally substituted with a benzene ring optionally substituted with nitro group A C _1-6 alkyl group _optionally having a C _2-8 alkenyl-amino group and the like.
Examples of the “C _6-12 aryl-carbonyl group” represented by R ⁷ include a benzoyl group, a 1-naphthoyl group, and a 2-naphthoyl group.
Examples of the “C _1-6 alkoxy-carbonyl group” represented by R ⁷ include a methoxy group, a carbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a tert-butoxycarbonyl group, and the like.
Examples of the “5- or 6-membered aromatic heterocyclic carbonyl group” represented by R ⁷ include a 3-furoyl group, a 2-thenoyl group, a nicotinoyl group, and an isonicotinoyl group.
Examples of the “C _1-6 alkyl group” represented by R ⁸ 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, and a hexyl group. Groups and the like.
The “substituent” of the “amino group optionally having substituent (s)” represented by R ⁸ is “substitution” of the “hydrocarbon group optionally having substituent (s)” represented by R ^6. One or two groups may be mentioned. When the number of substituents is 2, each substituent may be the same or different.

The “ring” of the “optionally substituted ring” formed by R ⁷ and R ⁸ together with the adjacent nitrogen atom includes, in addition to one nitrogen atom and carbon atom, a nitrogen atom, a sulfur atom, and Monocyclic or polycyclic (preferably monocyclic, bicyclic or tricyclic) 5- to 14-membered ring optionally containing 1 or 2 types selected from oxygen atoms and 1 to 4 heteroatoms (Preferably a 5- to 10-membered ring) and the like (eg, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, etc.) . Examples of the “substituent” of the “optionally substituted ring” include the “substituent” of the “optionally substituted hydrocarbon group” represented by R ⁶ above. Are one or two. For example, a 5- to 7-membered saturated cyclic amino group, a C _1-6 alkyl group and the like are used. When the number of substituents is 2, each substituent may be the same or different.

In the compound represented by the formula (II), R ¹ ′ is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, in addition to the acyl group. In the formula (II), examples of the “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R ¹ ′ include “substituted” represented by R ⁶ above. And a hydrocarbon group optionally having a group and a heterocyclic group optionally having a substituent.

2) R ² and R ³ as "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group" represented by R ^2, for example, in the R ⁶ Examples thereof include “optionally substituted hydrocarbon group” and “optionally substituted heterocyclic group”.
Examples of the “hydrocarbon group optionally having substituent (s)” represented by R ³ and the “heterocyclic group optionally having substituent (s)” include the “having substituent (s)” represented by R ⁶ above. And “optionally substituted hydrocarbon group” and “optionally substituted heterocyclic group”.
3) R ⁴ , R ^{4 ′} , R ^{4 ″} and R ⁵ are represented by R ⁴ , R ^{4 ′} , R ^{4 ″} and R ⁵ , “optionally substituted hydrocarbon groups” and “ Examples of the “optionally substituted heterocyclic group” include the “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic ring” represented by the above R ^6. Group ". R ⁴ ″ may further be an oxo group, and R ⁵ may be a hydrogen atom.
4) For n, m and k, n, m and k are each an integer of 0 to 4, 0 to 8 and 0 to 8, wherein n is 2 to 4, m is 2 to 8, and k is 2 to 8. Sometimes R ⁴ , R ^{4 ′} and R ^{4 ″} may be the same or different.
5) About X X is an oxygen atom, sulfur atom, or formula NR ⁵ (wherein R ⁵ is a hydrogen atom, a hydrocarbon group optionally having substituent (s) or a heterocycle optionally having substituent (s)). Represents a cyclic group). R ⁵ has the same meaning as described above.
6) A ring and B ring A ring is a 5- to 10-membered ring, that is, a 5- to 10-membered ring containing a nitrogen atom to which R ¹ ′ is bonded, preferably a 5- to 7-membered ring containing a nitrogen atom.
The ring B represents a 5- to 9-membered ring, that is, a 5- to 9-membered ring containing X, preferably a 5- to 6-membered ring containing X.

R ¹ and R ¹ ′ may be represented by the formula — (C═O) —R ⁶ , — (C═O) —OR ⁶ or — (C═O) —NR ⁷ R ⁸ wherein each symbol is as defined above. The group having the same significance] is preferred. More preferably, a group represented by the formula — (C═O) —R ⁶ or — (C═O) —NR ⁷ R ⁸ [wherein each symbol is as defined above] is exemplified. More preferably, a group represented by the formula — (C═O) —NR ⁷ R ⁸ [wherein each symbol is as defined above] is exemplified.
R ⁶ includes (i) an aromatic group which may have a substituent, (ii) a heterocyclic group which may have a substituent, and (iii) a chain which may have a substituent. A hydrocarbon group (eg, a) an alkyl group optionally having a 5- to 7-membered cyclic amino group which may have a substituent, and b) an aryl group optionally having a substituent. An alkyl group which may be substituted) and the like. More preferably, it may have a C _7-13 aralkyl group which may have a substituent, a C _6-12 aryl group which may have a substituent, or a 5- to 7-membered cyclic which may have a substituent. Examples thereof include a C _1-6 alkyl group which may have an amino group. More preferred are a C _6-12 aryl group which may have a substituent, a C _1-6 alkyl group having a 5- to 7-membered cyclic amino group which may have a substituent, and the like.
R ⁷ is a hydrogen atom, a hydrocarbon group which may have a substituent [eg, a) (i) a 5- to 7-membered cyclic amino group which may have a substituent and / or (ii) An alkyl group which may have a 5- to 10-membered heterocyclic group which may have a substituent, b) an aryl group which may have a substituent, c) which may have a substituent A good aralkyl group, etc.], an optionally substituted heterocyclic group (eg, a 5- or 6-membered non-aromatic heterocyclic group optionally having an alkyl group), an aryl-carbonyl group (eg, C _6-12 aryl-carbonyl group), alkoxy-carbonyl group (eg, C _1-6 alkoxy-carbonyl group) and the like are preferable. More preferably, (a) (i) a 5- to 7-membered cyclic amino group which may have a substituent and / or (ii) a 5- to 10-membered aromatic heterocyclic group which may have a substituent. A C _1-6 alkyl group which may have a substituent, (b) a C _6-12 aryl group which may have a substituent, and (c) a C _7-13 aralkyl which may have a substituent. Groups and the like. As the R ^7, preferred groups having an aromatic group which may have a substituent.
R ⁸ is preferably a hydrogen atom or an amino group which may have a substituent.
In the case where R ⁸ is an amino group which may have a substituent, R ⁷ is preferably a hydrogen atom.
The “ring” of the “optionally substituted ring” formed by R ⁷ and R ⁸ together with the adjacent nitrogen atom is preferably a 5- to 10-membered (non-aromatic) heterocyclic ring (eg, Pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, etc.).
R ² is preferably an aryl group which may have a substituent. More preferred is a C _6-12 aryl group.
R ³ is preferably an aryl group which may have a substituent. More preferred is a C _6-12 aryl group.

Further, as R ⁶ , (a) a C _7-13 aralkyl group,
(B) a C _2-6 alkenyl group _optionally having a halogenated C _6-12 aryl group,
(C) (i) a halogen atom,
(Ii) a C _1-6 alkoxy group,
(Iii) a nitro group,
(Iv) may have one or two substituents selected from a formyl group, and (v) (1) a halogen atom, (2) a C _1-6 alkoxy-carbonyl group and a C _1-6 alkyl group A C _1-6 alkyl group _optionally having a substituent selected from an amino group, and (3) an optionally substituted 5- to 7-membered cyclic amino group,
A C _6-12 aryl group _optionally having a substituent selected from:
(D) a 5- or 6-membered aromatic heterocyclic group,
(E) (i) a C _6-12 aryloxy group,
(Ii) a C _3-8 cycloalkyl group which may be condensed with one or two benzene rings,
(Iii) an optionally halogenated C _6-12 arylamino group,
(Iv) a carboxy group,
(V) a 5- to 7-membered cyclic amino group,
(Vi) a 5- to 7-membered non-aromatic heterocyclic group,
(Vii) a C _6-12 aryl group, and (viii) a halogen atom,
A C _1-6 alkyl group _optionally having a substituent selected from:
(F) (i) a C _1-6 alkoxy-carbonyl group,
(Ii) a carbamoyl group,
(Iii) a hydroxy group,
(Iv) a 5- to 7-membered cyclic amino-carbonyl group,
(V) a C _3-8 cycloalkyl group, and (vi) a C _2-8 alkenyl group,
A 5- to 7-membered non-aromatic heterocyclic group optionally having a C _1-6 alkyl group, a C _1-6 alkoxy-carbonyl group or a formyl group optionally having a substituent selected from:
(G) a 5- to 10-membered (preferably 9-membered) aromatic heterocyclic group optionally having an oxo group, or (h) an oxo group optionally having a benzene ring condensed A good 5- to 10-membered cyclic amino group,
It is preferable that

Further, R ⁷ includes (a) a hydrogen atom,
(B) (i) a C _1-6 alkoxy-carbonyl group,
(Ii) a halogen atom, and (iii) a C _1-6 alkoxy group,
A C _6-12 aryl group _optionally having a substituent selected from:
(C) (i) a halogen atom,
(Ii) C _1-6 alkoxy - carbonyl group, an optionally substituted amino group, and a C _1-6 alkyl group optionally having a substituent selected from halogen atoms,
(Iii) a C _1-6 alkylsulfonyl group, and (iv) a mono- or di-C _1-6 alkylamino group,
A C _7-13 aralkyl group which may have a substituent selected from:
(D) (i) a 5- or 6-membered aromatic heterocyclic group which may be oxidized and may be substituted with a cyano group, a hydroxy group or a C _1-6 alkyl group,
(Ii) a 5- to 7-membered cyclic amino group which may have a C _1-6 alkyl group, a hydroxy group, an oxo group or a C _1-6 alkoxy-carbonyl group and may be condensed with a benzene ring;
(Iii) a C _1-6 alkoxy-carbonyl group,
(Iv) a carboxy group,
(V) a 5- to 7-membered cyclic aminocarbonyl group,
(Vi) an optionally halogenated C _6-12 aryl group,
(Vii) a C _6-12 aryl-carbonyl group,
(Viii) a hydroxy group,
(Ix) (1) a C _1-6 alkyl group optionally substituted with a C _3-8 cycloalkyl group, (2) a C _1-6 alkoxy-C _1-6 alkyl group, (3) an azidocarbonyl group, (4) aminocarbonyl group, (5) C _7-13 aralkyl group, (6) C _3-8 cycloalkyl group, (7) sulfonyl optionally substituted with a benzene ring optionally substituted with nitro group 1 or 2 substituents selected from a group, (8) C _2-8 alkenyl group, (9) C _1-6 alkylsulfonyl group, and (10) C _1-6 alkyl-carbonyl group An amino group,
(X) a C _3-8 cycloalkyl group, and (xi) a 5- to 7-membered non-aromatic heterocyclic group,
A C _1-6 alkyl group optionally having 1 or 2 substituents selected from:
(E) a C _3-8 cycloalkyl group which may be condensed with one or two benzene rings,
(F) a 5- to 10-membered aromatic heterocyclic group optionally having a substituent selected from an oxo group, a C _1-6 alkoxy-carbonyl group, and a C _1-6 alkyl group,
(G) a C _6-12 aryl-carbonyl group,
(H) a C _1-6 alkoxy-carbonyl group,
(I) a 5- to 7-membered non-aromatic which may have a substituent selected from a C _1-6 alkyl group, a C _1-6 alkoxy-carbonyl group and an oxo group and may be condensed with a benzene ring A heterocyclic group,
(J) a 5- to 7-membered cyclic amino-C _1-6 alkyl-carbonyl group,
(K) a C _3-8 cycloalkyl group optionally substituted with a C _1-6 alkyl group optionally having a 5- to 7-membered cyclic amino group, or (L) a C _6-12 arylamino group,
It is preferable that

R ⁸ is preferably a hydrogen atom or a C _1-6 alkyl group. Or R ⁷ and R ⁸ may have a substituent selected from a 5- to 7-membered saturated cyclic amino group and a C _1-6 alkyl group together with the adjacent nitrogen atom, and a 5- to 10-membered non-aromatic heterocycle May be formed.
As R ²
(i) a hydrogen atom,
(ii) a C _1-6 alkyl group,
(iii) a C _3-6 cycloalkyl group,
(iv) a C _6-12 aryl group optionally having a substituent selected from a halogen atom and a C _1-6 alkyl group, or
(v) C _7-13 aralkyl group,
It is preferable that
As R ³
(i) a C _1-6 alkyl group,
(ii) a C _3-6 cycloalkyl group,
(iii) a C _6-12 aryl group optionally having a substituent selected from a halogen atom and a C _1-6 alkyl group, or
(iv) C _7-13 aralkyl group,
It is preferable that
n is preferably 0.
X is preferably an oxygen atom.

As preferred examples of compound (I),
R ¹ is of the formula — (C═O) —R ^6a , — (C═O) —OR ^6a , — (C═O) —NR ^7a R ^8a or —SO ₂ —R ^6a
[Wherein R ^6a is (a) a C _7-13 aralkyl group,
(B) a C _2-6 alkenyl group _optionally having a halogenated C _6-12 aryl group,
(C) (i) a halogen atom,
(Ii) a C _1-6 alkoxy group,
(Iii) a nitro group,
(Iv) may have one or two substituents selected from a formyl group, and (v) (1) a halogen atom, (2) a C _1-6 alkoxy-carbonyl group and a C _1-6 alkyl group A C _1-6 alkyl group _optionally having a substituent selected from an amino group, and (3) an optionally substituted 5- to 7-membered cyclic amino group,
A C _6-12 aryl group _optionally having a substituent selected from:
(D) a 5- or 6-membered aromatic heterocyclic group,
(E) (i) a C _6-12 aryloxy group,
(Ii) a C _3-8 cycloalkyl group which may be condensed with one or two benzene rings,
(Iii) an optionally halogenated C _6-12 arylamino group,
(Iv) a carboxy group,
(V) a 5- to 7-membered cyclic amino group,
(Vi) a 5- to 7-membered non-aromatic heterocyclic group,
(Vii) a C _6-12 aryl group, and (viii) a halogen atom,
A C _1-6 alkyl group _optionally having a substituent selected from:
(F) (i) a C _1-6 alkoxy-carbonyl group,
(Ii) a carbamoyl group,
(Iii) a hydroxy group,
(Iv) a 5- to 7-membered cyclic amino-carbonyl group,
(V) a C _3-8 cycloalkyl group, and (vi) a C _2-8 alkenyl group,
A 5- to 7-membered non-aromatic heterocyclic group optionally having a C _1-6 alkyl group, a C _1-6 alkoxy-carbonyl group or a formyl group optionally having a substituent selected from:
(G) a 5- to 10-membered (preferably 9-membered) aromatic heterocyclic group optionally having an oxo group, or (h) an oxo group optionally having a benzene ring condensed A good 5- to 10-membered cyclic amino group,
R ^7a is (a) a hydrogen atom,
(B) (i) a C _1-6 alkoxy-carbonyl group,
(Ii) a halogen atom, and (iii) a C _1-6 alkoxy group,
A C _6-12 aryl group _optionally having a substituent selected from:
(C) (i) a halogen atom,
(Ii) C _1-6 alkoxy - carbonyl group, an optionally substituted amino group, and a C _1-6 alkyl group optionally having a substituent selected from halogen atoms,
(Iii) a C _1-6 alkylsulfonyl group, and (iv) a mono- or di-C _1-6 alkylamino group,
A C _7-13 aralkyl group which may have a substituent selected from:
(D) (i) a 5- or 6-membered aromatic heterocyclic group which may be oxidized and may be substituted with a cyano group, a hydroxy group or a C _1-6 alkyl group,
(Ii) a 5- to 7-membered cyclic amino group which may have a C _1-6 alkyl group, a hydroxy group, an oxo group or a C _1-6 alkoxy-carbonyl group and may be condensed with a benzene ring;
(Iii) a C _1-6 alkoxy-carbonyl group,
(Iv) a carboxy group,
(V) a 5- to 7-membered cyclic aminocarbonyl group,
(Vi) an optionally halogenated C _6-12 aryl group,
(Vii) a C _6-12 aryl-carbonyl group,
(Viii) a hydroxy group,
(Ix) (1) a C _1-6 alkyl group optionally substituted with a C _3-8 cycloalkyl group, (2) a C _1-6 alkoxy-C _1-6 alkyl group, (3) an azidocarbonyl group, (4) aminocarbonyl group, (5) C _7-13 aralkyl group, (6) C _3-8 cycloalkyl group, (7) sulfonyl optionally substituted with a benzene ring optionally substituted with nitro group 1 or 2 substituents selected from a group, (8) C _2-8 alkenyl group, (9) C _1-6 alkylsulfonyl group, and (10) C _1-6 alkyl-carbonyl group An amino group,
(X) a C _3-8 cycloalkyl group, and (xi) a 5- to 7-membered non-aromatic heterocyclic group,
A C _1-6 alkyl group optionally having 1 or 2 substituents selected from:
(E) a C _3-8 cycloalkyl group which may be condensed with one or two benzene rings,
(F) a 5- to 10-membered aromatic heterocyclic group optionally having a substituent selected from an oxo group, a C _1-6 alkoxy-carbonyl group, and a C _1-6 alkyl group,
(G) a C _6-12 aryl-carbonyl group,
(H) a C _1-6 alkoxy-carbonyl group,
(I) a 5- to 7-membered non-aromatic which may have a substituent selected from a C _1-6 alkyl group, a C _1-6 alkoxy-carbonyl group and an oxo group and may be condensed with a benzene ring A heterocyclic group,
(J) a 5- to 7-membered cyclic amino-C _1-6 alkyl-carbonyl group,
(K) a C _3-8 cycloalkyl group optionally substituted with a C _1-6 alkyl group optionally having a 5- to 7-membered cyclic amino group, or (L) a C _6-12 arylamino group,
R ^8a is a hydrogen atom, a C _1-6 alkyl group, or R ^7a and R ^8a have a substituent selected from a 5- to 7-membered saturated cyclic amino group and a C _1-6 alkyl group together with the adjacent nitrogen atom. A 5- to 10-membered non-aromatic heterocyclic ring which may optionally be formed]
R ² is
(i) a hydrogen atom,
(ii) a C _1-6 alkyl group,
(iii) a C _3-6 cycloalkyl group,
(iv) a C _6-12 aryl group optionally having a substituent selected from a halogen atom and a C _1-6 alkyl group, or
(v) C _7-13 aralkyl group,
R ³ is
(i) a C _1-6 alkyl group,
(ii) a C _3-6 cycloalkyl group,
(iii) a C _6-12 aryl group optionally having a substituent selected from a halogen atom and a C _1-6 alkyl group, or
(iv) C _7-13 aralkyl group,
a compound in which n is 0, and X is an oxygen atom.

Further, as other preferred examples of compound (I),
R ¹ is of the formula — (C═O) —R ^6a , — (C═O) —OR ^6a , — (C═O) —NR ^7a R ^8a or —SO ₂ —R ^6a
[Wherein R ^6a is (a) a C _7-13 aralkyl group,
(B) a C _2-6 alkenyl group _optionally having a halogenated C _6-12 aryl group,
(C) (i) a halogen atom,
(Ii) a C _1-6 alkoxy group,
(Iii) a nitro group, and (iv) (1) a halogen atom, and (2) one or two substituents selected from a C _1-6 alkoxy-carbonyl group and a C _1-6 alkyl group A good amino group, a C _1-6 alkyl group which may have a substituent selected from:
A C _6-12 aryl group _optionally having a substituent selected from:
(D) a 5- or 6-membered aromatic heterocyclic group,
(E) (i) a C _6-12 aryloxy group,
(Ii) a C _3-8 cycloalkyl group which may be condensed with one or two benzene rings,
(Iii) an optionally halogenated C _6-12 arylamino group,
(Iv) a carboxy group,
(V) a 5- to 7-membered cyclic amino group,
(Vi) a C _6-12 aryl group, and (vii) a halogen atom,
A C _1-6 alkyl group _optionally having a substituent selected from:
(F) 6-membered non-aromatic heterocyclic group optionally having C _1-6 alkoxy-carbonyl group, or (g) 5- to 10-membered (preferably 9-membered) optionally having oxo group An aromatic heterocyclic group,
R ^7a is (a) a hydrogen atom,
(B) a C _6-12 aryl group optionally having a substituent selected from a C _1-6 alkoxy-carbonyl group, a halogen atom and a C _1-6 alkoxy group,
(C) (i) a halogen atom,
(Ii) C _1-6 alkoxy - carbonyl group, an optionally substituted amino group, and a C _1-6 alkyl group optionally having a substituent selected from halogen atoms,
(Iii) a C _1-6 alkylsulfonyl group, and (iv) a mono- or di-C _1-6 alkylamino group,
A C _7-13 aralkyl group which may have a substituent selected from:
(D) (i) a 5- or 6-membered aromatic heterocyclic group which may be oxidized and may have a cyano group,
(Ii) a 5- to 7-membered cyclic amino group which may have a C _1-6 alkyl group and may be condensed with a benzene ring;
(Iii) a C _1-6 alkoxy-carbonyl group,
(Iv) a carboxy group,
(V) a 5- to 7-membered saturated cyclic aminocarbonyl group,
(Vi) a C _6-12 aryl group,
(Vii) a C _6-12 aryl-carbonyl group,
(Viii) a hydroxy group, and (ix) a substituent 1 selected from a C _1-6 alkyl group, a C _1-6 alkoxy-C _1-6 alkyl group, an azidocarbonyl group, an aminocarbonyl group, and a C _7-13 aralkyl group Or an amino group optionally having two,
A C _1-6 alkyl group _optionally having a substituent selected from:
(E) a C _3-8 cycloalkyl group which may be condensed with one or two benzene rings,
(F) a 5- to 10-membered aromatic heterocyclic group optionally having a substituent selected from an oxo group and a C _1-6 alkoxy-carbonyl group,
(G) a C _6-12 aryl-carbonyl group,
(H) a C _1-6 alkoxy-carbonyl group, or (i) a substituent selected from a C _1-6 alkyl group, a C _1-6 alkoxy-carbonyl group and an oxo group, An optionally fused 5- to 7-membered non-aromatic heterocyclic group,
R ^8a may have a hydrogen atom, a C _1-6 alkyl group or a C _6-12 arylamino group, or R ^7a and R ^8a may have a 5- to 7-membered saturated cyclic amino group together with the adjacent nitrogen atom. A 5- to 10-membered non-aromatic heterocyclic ring may be formed],
R ² is a hydrogen atom, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, an optionally halogenated C _6-12 aryl group or a C _7-13 aralkyl group,
R ³ is a C _1-6 alkyl group, a C _3-6 cycloalkyl group, an optionally halogenated C _6-12 aryl group or a C _7-13 aralkyl group,
a compound in which n is 0, and X is an oxygen atom.

Further, as another preferable example of compound (I), R ¹ is represented by the formula-(C = O) -R ^6a ,-(C = O) -OR ^6a ,-(C = O) -NR ^7a R ^8a or- SO ₂ -R ^6a
[Wherein R ^6a is (a) a C _7-13 aralkyl group,
(B) a C _2-6 alkenyl group _optionally having a halogenated C _6-12 aryl group,
(C) a C _6-12 aryl group which may have a substituent selected from a halogen atom, a C _1-6 alkoxy group, a nitro group, and an optionally halogenated C _1-6 alkyl group,
(D) a 5- or 6-membered aromatic heterocyclic group, or (e) a substituent selected from a C _6-12 aryl group, a C _6-12 aryloxy group and an optionally condensed C _3-8 cycloalkyl group A C _1-6 alkyl group _optionally having
R ^7a is (a) a hydrogen atom,
(B) a C _6-12 aryl group optionally having a substituent selected from a C _1-6 alkoxy-carbonyl group, a halogen atom and a C _1-6 alkoxy group,
(C) having a substituent selected from a halogen atom, an optionally halogenated C _1-6 alkyl group, a C _1-6 alkylsulfonyl group, and a mono- or di-C _1-6 alkylamino group; C _7-13 aralkyl group,
(D) a C _1-6 alkyl group which may have a 5- or 6-membered aromatic heterocyclic group, or (e) a C _3-8 cycloalkyl group which may be condensed,
R ^8a may form a 5- to 10-membered non-aromatic heterocyclic ring with a hydrogen atom, a C _1-6 alkyl group, or a C _6-12 arylamino group, or R ^7a and R ^8a together with the adjacent nitrogen atom. A group represented by
R ² and R ³ are each a C _1-6 alkyl group, a C _3-6 cycloalkyl group or a C _6-12 aryl group,
a compound in which n is 0, and X is an oxygen atom.

Further, as other preferred examples of compound (I),
R ¹ is of the formula — (C═O) —R ^6b or — (C═O) —NR ^7b R ^8b ,
[Wherein R ^6b has (a) a C _1-6 alkyl group optionally having a 5- to 7-membered cyclic amino group, or (b) 1 to 2 C _1-6 alkyl groups. A C _6-12 aryl group _optionally having a C _1-6 alkyl group _{optionally having an} amino group,
R ^7b is (a) a hydrogen atom,
(B) a C _6-12 aryl group _optionally having a halogen atom,
(C) a C _7-13 aralkyl group _optionally having a halogen atom,
(D) a 5- or 6-membered aromatic heterocyclic group,
(E) a C _1-6 alkyl group optionally having a 5- to 7-membered cyclic amino group, or (f) a 5- or 6-membered non-aromatic heterocyclic ring optionally having a C _1-6 alkyl group Group,
R ^8b is a hydrogen atom or a C _6-12 arylamino group, or R ^7b and R ^8b together with the adjacent nitrogen atom form a 5- to 10-membered heterocyclic ring optionally having a 5- to 7-membered cyclic amino group A group represented by
R ² and R ³ are each a C _6-12 aryl group,
a compound in which n is 0, and X is an oxygen atom.

More specifically,
Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid phenyl ester,
Hexahydro-7- (1-oxo-3-phenyl-2-propenyl) -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one,
(+)-N-[(4-fluorophenyl) methyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide,
(-)-N-[(4-fluorophenyl) methyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide,
(+)-N- [2- (3,6-Dihydropyridin-1 (2H) -yl) ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine- 7 (1H) -carboxamide,
(-)-N- [2- (3,6-Dihydropyridin-1 (2H) -yl) ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine- 7 (1H) -carboxamide,
1,1-bis (3-fluorophenyl) -N- [2- (3,6-dihydropyridin-1 (2H) -yl) ethyl] -tetrahydro-3-oxo-3H-oxazolo [3,4-a] Pyrazine-7 (1H) -carboxamide,
N- [2- (3,6-Dihydropyridin-1 (2H) -yl) ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -Carboxamide,
1,1-bis (3-fluorophenyl) -N- [2- (cyclopropylamino) ethyl] -tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hydrochloride salt,
Tetrahydro-3-oxo-1,1-diphenyl-N-[(3-thienyl) methyl] -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide,
7- [4- (3,6-Dihydropyridin-1 (2H) -yl) -1-oxobutyl] -hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H)- 3-on,
N- [2-[(cyclopropylmethyl) amino] ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hydrochloride,
N-[(4-fluorophenyl) methyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide, and
1,1-bis (3-fluorophenyl) -tetrahydro-3-oxo-N- [2- (1-piperidinyl) ethyl] -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide, Examples thereof include salts thereof.

  In compound (II), as ring A, for example,

Etc. are used.
As R ¹ ′, in addition to the acyl group represented by R ¹ described above, (i) a hydrogen atom, (ii) a C _6-14 aryl-carbonyl group (eg, benzoyl group), a C _6-14 aryl group (eg, , Phenyl group), C _6-14 aryloxy-carbonyl group (eg, phenyloxycarbonyl group) and the like, a C _1-6 alkyl group (eg, methyl group) optionally substituted with a substituent selected from (iii), (iii) ) A 5- to 10-membered heterocyclic group having 1 to 3 nitrogen atoms, oxygen atoms, or sulfur atoms (eg, benzoxazol-2-yl group) is preferable.
As ring B, for example

Etc. are used.
X is preferably an oxygen atom or NH, and particularly preferably an oxygen atom.
More specifically, as B ring

Etc. are preferable.
As a combination of A ring and B ring,

Etc. are preferable.
Here, R ² ′ and R ² ″ represent a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent, and is the same as R ² In particular, a C _6-14 aryl group (eg, phenyl group) is preferable.
R ³ ′ and R ³ ″ each represent a hydrocarbon group that may have a substituent or a heterocyclic group that may have a substituent, and those similar to R ³ are used. However, a C _6-14 aryl group (eg, phenyl group) is preferred. R ² and R ³ are preferably the same as those described above.

Examples of salts of compounds (I), (II) and intermediates thereof include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids. Etc. Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzylethylenediamine. And the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfone. And salts with acid, p-toluenesulfonic acid and the like. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid, for example. It is done.
Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt), In the case where the compound has a basic functional group, for example, a salt with an inorganic acid such as hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, oxalic acid, Examples thereof include salts with organic acids such as tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.

Compounds (I) and (II) (hereinafter abbreviated as compound (I)) may be either hydrates or non-hydrates. Examples of the hydrate include 0.5 hydrate, monohydrate, 1.5 hydrate and dihydrate.
Compound (I) can be obtained as the desired R-form and S-form by using a method known per se, for example, asymmetric synthesis, optical resolution, etc., if necessary.
A prodrug of compound (I) is a compound that is converted into compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc. A compound that changes to compound (I) upon hydrolysis by gastric acid or the like. Compound (I) prodrugs include compounds in which the amino group of compound (I) is acylated, alkylated and phosphorylated [eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated. , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.] Compounds in which the hydroxy group of compound (I) is acylated, alkylated, phosphorylated or borated [eg, hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated , Alanylated, dimethylaminomethylcarbonylated compounds, etc.), or a compound of compound (I) Compounds in which the xy group is esterified or amidated [eg, the carboxy group of the compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxy Carbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds, etc.) Can be mentioned. These compounds can be produced from compound (I) by a method known per se.
The prodrug of compound (I) changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Drug Development”, Volume 7, Molecular Design, pages 163 to 198. There may be.

The production method of compound (I) is described below.
Compound (I) can be obtained by the method shown in the following reaction formulas 1 to 4 or a method analogous thereto.
Each symbol of the compounds in the following reaction formulas 1 to 4 has the same meaning as described above. The compound in the reaction formula includes a case where a salt is formed, and examples of the salt include those similar to the salt of compound (I).
The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.) Can also be easily purified.
A description of the generically used solvents used in the following reactions is given below.
Examples of “alcohols” include methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, and the like.
Examples of the “ethers” include diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like.
Examples of “hydrocarbons” include benzene, toluene, cyclohexane, hexane, and the like.
As the “amides”, for example, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide and the like are used.
Examples of the “halogenated hydrocarbons” include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and the like.
As the “nitriles”, for example, acetonitrile, propionitrile and the like are used.
As the “ketones”, for example, acetone, ethyl methyl ketone and the like are used.
Examples of the “organic acids” include formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid and the like.
As the “aromatic amines”, for example, pyridine, 2,6-lutidine, quinoline and the like are used.
Examples of the “sulfoxides” include dimethyl sulfoxide.

The explanation of the bases shown in generic terms used in the following reactions is shown below.
Examples of “inorganic bases” include sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide and the like.
Examples of the “basic salts” include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium acetate, ammonium acetate and the like.
As the “aromatic amines”, for example, pyridine, lutidine and the like are used.
Examples of “tertiary amines” include triethylamine, tripropylamine, tributylamine, diisopropylethylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine. N-methylmorpholine and the like are used.
As the “alkali metal hydrides”, for example, sodium hydride, potassium hydride and the like are used.
Examples of the “metal amides” include sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like.
Examples of the “alkyl metals” include butyl lithium, sec-butyl lithium, tert-butyl lithium and the like.
As the “aryl metals”, for example, phenyl lithium and the like are used.
As the “metal alkoxides”, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like are used.

In the above formula, R ^a represents ^a hydrocarbon group which may have ^a substituent.
Examples of the “hydrocarbon group optionally having substituent (s)” represented by R ^a include the “hydrocarbon group optionally having substituent (s)” represented by R ⁶ .
R ^b represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent.
Examples of the “hydrocarbon group optionally having substituent (s)” and the “heterocyclic group optionally having substituent (s)” represented by R ^b include, for example, the “having substituent (s)” represented by R ⁶ above. And “optionally substituted hydrocarbon group” and “optionally substituted heterocyclic group”.
R ^c and R ^d each represent a protecting group.
Examples of the “protecting group” represented by R ^c or R ^d include a C _7-19 aralkyl group (for example, benzyl group, trityl group, etc.).
R ^e represents a hydrocarbon group which may have a substituent.
Examples of the “hydrocarbon group optionally having substituent (s)” represented by R ^e include the “hydrocarbon group optionally having substituent (s)” represented by R ⁶ .
M represents a metal. When M is multivalent, a salt is also included.
Examples of the “metal” represented by M include magnesium halide (eg, magnesium bromide, magnesium chloride, etc.), lithium and the like.
L represents a leaving group.
Examples of the “leaving group” represented by L include a halogen atom (eg, chlorine, bromine, etc.) or a formula —O (C═O) —O—R ^f (wherein R ^f has a substituent). A hydrocarbon group that may be present.) And the like.
Examples of the “hydrocarbon group optionally having substituent (s)” represented by R ^f include the “hydrocarbon group optionally having substituent (s)” represented by R ⁶ .

Compound (III ′) can be produced by reacting compound (I ′) with compound (II ′).
Compound (I ′) is easily commercially available, and can also be produced according to a method known per se or a method analogous thereto.
Compound (II ′) can be easily obtained as a commercially available product, and can also be produced according to a method known per se or a method analogous thereto.
The amount of compound (II ′) to be used is about 2 to about 12 mol, preferably about 2 to about 7 mol, per 1 mol of compound (I ′).
In this reaction, an additive may be used if desired. Examples of the “additive” include cerium (III) chloride and copper (I) iodide. The amount of the additive to be used is about 0.1 to about 12 mol, preferably about 0.1 to about 7 mol, per 1 mol of compound (I ′).
This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, and examples thereof include solvents such as ethers and hydrocarbons, or a mixture of two or more thereof.
The reaction time is usually about 10 minutes to about 48 hours, preferably about 30 minutes to about 24 hours. The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about −80 ° C. to about 100 ° C.

Compound (V ′) can be produced by reacting compound (IV ′) with compound (II ′).
Compound (IV ′) is easily commercially available, and can also be produced according to a method known per se or a method analogous thereto.
The amount of compound (II ′) to be used is about 2 to about 10 mol, preferably about 2 to about 5 mol, per 1 mol of compound (IV ′).
In this reaction, an additive may be used if desired. Examples of the “additive” include cerium (III) chloride and copper (I) iodide. The amount of the additive to be used is about 0.1 to about 1 mol, preferably about 0.1 to about 5 mol, per 1 mol of compound (IV ′).
This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, and examples thereof include solvents such as ethers and hydrocarbons, or a mixture of two or more thereof.
The reaction time is usually about 10 minutes to about 48 hours, preferably about 30 minutes to about 24 hours. The reaction temperature is usually about −100 ° C. to about 150 ° C., preferably about −80 ° C. to about 100 ° C.

Compound (III ′) can also be produced by subjecting compound (V ′) to a deprotection reaction.
This reaction can be carried out according to a method known per se, for example, the method described in the chapter of Protective Groups in Organic Synthesis 3rd edition (1999), “Protection for the Amino Group” and the like.
When the “protecting group” represented by R ^c or R ^d is “benzyl group optionally having substituent (s)”, the deprotection reaction proceeds easily by hydrogenation. In this case, for example, a catalyst (eg, palladium carbon, Raney nickel, Raney cobalt, etc.) may be used. The amount of the catalyst to be used is about 1 to about 1000% by weight, preferably about 5 to about 300% by weight, relative to compound (V ′).
This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, a solvent such as alcohols, ethers, hydrocarbons, halogenated hydrocarbons, amides, organic acids, water, or two or more of these solvents Mixtures and the like are preferred.
While the reaction time varies depending on the activity or amount of the catalyst, it is generally about 1 hour to about 100 hours, preferably about 1 hour to about 50 hours. The reaction temperature is generally about −20 ° C. to about 120 ° C., preferably about 0 ° C. to about 80 ° C. The pressure of hydrogen is usually about 1 to about 100 atmospheres. Various hydrogen sources can be used instead of gaseous hydrogen. Examples of the “hydrogen source” include formic acid, ammonium formate, triethylammonium formate, sodium phosphinate, hydrazine and the like. The amount of the hydrogen source to be used is about 1 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of compound (V ′).

Compound (VI ′) can be produced by reacting compound (III ′) with an acylating agent, if desired, in the presence of a base.
Examples of the “acylating agent” include acids represented by the formula R ¹ —OH or reactive derivatives thereof (eg, acid halides, acid anhydrides, carboxylic acid esters, isocyanate esters, dicarbonate diesters, etc.). Can be mentioned. The amount of the acylating agent to be used is about 1 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol of compound (III ′).
Examples of the “base” used as desired include inorganic bases, basic salts, aromatic amines, tertiary amines and the like. The amount of the base to be used is about 1 to about 5 mol, preferably about 1 to about 3 mol, per 1 mol of compound (III ′).
This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers, hydrocarbons, amides, halogenated hydrocarbons, nitriles, ketones, sulfoxides, aromatic amines, water, etc. Or a mixture of two or more of these.
The reaction temperature is about -20 ° C to about 200 ° C, preferably about 0 ° C to about 150 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 10 minutes to about 24 hours.
In the compound (VI ′), a compound in which R ¹ is represented by the formula — (C═O) —NR ⁷ R ⁸ includes compound (III ′), an amine represented by the formula R ⁷ R ⁸ NH, and an active carbonyl compound [ For example, phosgene, bis (trichloromethyl) carbonate, N, N′-carbonyldiimidazole, isobutyl chlorocarbonate, etc.).
The amount of the amine represented by the formula R ⁷ R ⁸ NH to be used is about 1 to about 3 mol, preferably about 1 to about 2 mol, per 1 mol of compound (III ′).
The amount of the active carbonyl compound to be used is about 1 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of compound (III ′).
This reaction can be carried out in the presence of a base if desired. Examples of the “base” used as desired include inorganic bases, basic salts, aromatic amines, tertiary amines and the like. The amount of the base to be used is about 1 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of compound (III ′).
This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers, hydrocarbons, amides, halogenated hydrocarbons, nitriles, ketones, sulfoxides, aromatic amines and the like Or a mixture of two or more of these is preferred.
The reaction temperature is about -20 ° C to about 200 ° C, preferably about -10 ° C to about 100 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 10 minutes to about 24 hours.

Compound (VIII ′) can be produced by reacting compound (VI ′) and compound (VII ′) in the presence of a base, if desired.
The amount of compound (VII ′) to be used is about 1 to about 10 mol, preferably about 1 to about 4 mol, per 1 mol of compound (VI ′).
Examples of the “base” used as desired include inorganic bases, basic salts, aromatic amines, tertiary amines and the like. The amount of the base to be used is about 1 to about 10 mol, preferably about 1 to about 4 mol, per 1 mol of compound (VI ′).
This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers, hydrocarbons, amides, halogenated hydrocarbons, nitriles, ketones, sulfoxides, aromatic amines, water, etc. Or a mixture of two or more of these.
The reaction temperature is about -20 ° C to about 200 ° C, preferably about 0 ° C to about 150 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 10 minutes to about 24 hours.

In compound (VIII ′), a compound in which R ¹ is represented by the formula — (C═O) —OR ^e is produced by reacting compound (III ′) with an acylating agent in the presence of a base, if desired. You can also
Examples of the “acylating agent” include halogeno carbonates (eg, ethyl chlorocarbonate, benzyl chlorocarbonate, etc.), dicarbonate diesters (eg, di-tert-butyl dicarbonate, etc.) and the like. The amount of the acylating agent to be used is about 2 to about 10 mol, preferably about 2 to about 7 mol, per 1 mol of compound (III ′).
Examples of the “base” used as desired include inorganic bases, basic salts, aromatic amines, tertiary amines and the like. The amount of the base to be used is about 2 to about 10 mol, preferably about 1 to about 7 mol, per 1 mol of compound (III ′).
This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers, hydrocarbons, amides, halogenated hydrocarbons, nitriles, ketones, sulfoxides, aromatic amines, water, etc. Or a mixture of two or more of these.
The reaction temperature is about -20 ° C to about 200 ° C, preferably about 0 ° C to about 150 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 10 minutes to about 24 hours.

Compound (I) can be produced by subjecting compound (VIII ′) to a ring-closing reaction in the presence of a base.
The ring closure reaction is performed according to a known method.
Examples of the “base” include inorganic bases, basic salts, aromatic amines, tertiary amines, alkali metal hydrides, metal amides, metal alkoxides and the like. The amount of the base to be used is about 0.1 to about 10 mol, preferably about 0.1 to about 5 mol, per 1 mol of compound (VIII ′).
This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, a solvent such as alcohols, ethers, hydrocarbons, water, or a mixture of two or more of these is preferable.
The reaction time is usually about 10 minutes to about 48 hours, preferably about 30 minutes to about 24 hours. The reaction temperature is usually about −20 ° C. to about 150 ° C., preferably about −10 ° C. to about 120 ° C.

Compound (I) can also be produced by reacting compound (VI ′) with an acylating agent, if desired, in the presence of a base.
Examples of the “acylating agent” include halogeno carbonates (eg, ethyl chlorocarbonate, benzyl chlorocarbonate, etc.), dicarbonate diesters (eg, di-tert-butyl dicarbonate, etc.) and the like. The amount of the acylating agent to be used is about 1 to about 10 mol, preferably about 1 to about 4 mol, per 1 mol of compound (VI ′).
Examples of the “base” used as desired include inorganic bases, basic salts, aromatic amines, tertiary amines and the like. The amount of the base to be used is about 1 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of compound (VI ′).
This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers, hydrocarbons, amides, halogenated hydrocarbons, nitriles, ketones, sulfoxides, aromatic amines, water, etc. Or a mixture of two or more of these.
The reaction temperature is about -20 ° C to about 200 ° C, preferably about 0 ° C to about 150 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 10 minutes to about 36 hours.

Compound (I) can also be produced from compound (III ′) using a method similar to the method for producing compound (I) from compound (VI ′).
Compound (IX ′) can be produced by removing “R ¹ ” of compound (I).
This reaction is carried out by a method known per se, for example, Protective Groups in Organic Synthesis, 3rd edition (1999), “Protection
This can be done according to the method described in the chapter “for the Amino Group”.
Compound (I) can also be produced from compound (IX ′) using a method similar to the method for producing compound (VI ′) from compound (III ′).

In the above formula, R ^c and R ^e are as defined above.
Compound (XII ′) can be obtained by reacting compound (X ′) with a base and then condensing with compound (XI ′).
Compound (X ′) is easily commercially available, and can also be produced according to a method known per se or a method analogous thereto.
As the base used in this reaction, for example, alkyl metals (eg, sec-butyllithium etc.) and tertiary amines (eg, tetramethylethylenediamine etc.) are used in combination. The amount of the alkyl metal to be used is about 1 to about 10 mol, preferably about 2 to about 5 mol, per 1 mol of compound (X ′). The amount of the tertiary amine to be used is about 1 to about 10 mol, preferably about 2 to about 5 mol, per 1 mol of compound (X ′).
Compound (XI ′) is easily commercially available, and can also be produced according to a method known per se or a method analogous thereto. The amount of compound (XI ′) to be used is about 1 to about 10 mol, preferably about 1.5 to about 5 mol, per 1 mol of compound (X ′).
This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, solvents such as ethers and hydrocarbons or a mixture of two or more of these are preferable.
The reaction temperature is usually about −100 ° C. to about 80 ° C., preferably about −80 ° C. to about 50 ° C. The reaction time is usually about 30 minutes to about 48 hours, preferably about 1 hour to about 24 hours.

Compound (XIII ′) can be produced from compound (XII ′) using a method similar to the method for producing compound (I) from compound (VIII ′).
In compound (IX ′), a compound in which X is an oxygen atom can also be produced from compound (XIII ′) using a method similar to the method for producing compound (IX ′) from compound (I).
Compound (I) is produced from compound (IX ′) obtained in Reaction Scheme 2 using a method similar to the method for producing Compound (I) from Compound (IX ′) obtained in Reaction Scheme 1. You can also.

In the above formula, R ^c , R ^d , R ^e , L and M are as defined above.
Y represents a leaving group.
Examples of the “leaving group” represented by Y include a halogen atom (eg, chlorine, bromine, etc.), a formula —O (C═O) —R ^g (wherein R ^g has a substituent). Or a group represented by the formula —N (R ^h ) —O—R ⁱ (wherein R ^h and R ⁱ each represents a hydrocarbon optionally having a substituent). A group represented by the following formula:
Examples of the “hydrocarbon group optionally having substituents” represented by R ^g , R ^h and R ⁱ include, for example, the “hydrocarbon group optionally having substituents” represented by R ⁶ above. Etc.

Compound (XV ′) in which Y is a halogen atom can be produced by reacting compound (XIV ′) with a halogenating agent.
Compound (XIV ′) is easily commercially available, and can also be produced according to a method known per se or a method analogous thereto.
Examples of the halogenating agent used in this reaction include phosphorus halides such as phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride and phosphorus tribromide, halogen, thionyl chloride and the like. The amount of the halogenating agent to be used is about 1 to about 100 mol, preferably about 1 to about 10 mol, per 1 mol of compound (XIV ′).
This reaction is advantageously carried out using no solvent or a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, and examples thereof include solvents such as ethers, hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, or a mixture of two or more of these. It is done.
The reaction temperature is usually about 0 ° C to about 200 ° C, preferably about 10 ° C to about 100 ° C. The reaction time is usually about 10 minutes to about 24 hours, preferably about 30 minutes to about 12 hours.

Compound (XV ′) in which Y is a group represented by the formula —O (C═O) —R ^g is obtained by reacting compound (XIV ′) with an acylating agent in the presence of a base, if desired. Can be manufactured.
Compound (XIV ′) is easily commercially available, and can also be produced according to a method known per se or a method analogous thereto.
Examples of the “acylating agent” include halogeno carbonates (eg, ethyl chlorocarbonate, benzyl chlorocarbonate, etc.), dicarbonate diesters (eg, di-tert-butyl dicarbonate, etc.) and the like. The amount of the acylating agent to be used is about 1 to about 10 mol, preferably about 1 to about 4 mol, per 1 mol of compound (XIV ′).
Examples of the “base” used as desired include inorganic bases, basic salts, aromatic amines, tertiary amines and the like. The amount of the base to be used is about 1 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of compound (XIV ′).
This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, a solvent such as ethers, hydrocarbons, amides, halogenated hydrocarbons, nitriles, ketones, aromatic amines, or the like. A mixture of two or more species is preferred.
The reaction temperature is usually about −20 ° C. to about 100 ° C., preferably about −10 ° C. to about 60 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 10 minutes to about 36 hours.

The compound (XV ′), in which Y is a group represented by the formula —N (R ^h ) —O—R ⁱ , has the compound (XIV ′) and the formula N (R ^h ) H—O—R ⁱ (wherein Each symbol has the same meaning as described above.) And can be produced by condensation.
Compound (XIV ′) is easily commercially available, and can also be produced according to a method known per se or a method analogous thereto.
Examples of the “hydroxylamine derivative” include N, O-dimethylhydroxylamine hydrochloride. The amount of the hydroxylamine derivative to be used is about 1 to about 10 mol, preferably about 1 to about 3 mol, per 1 mol of compound (XIV ′).
Examples of the condensing agent used in this reaction include N, N′-disubstituted carbodiimides (eg, N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, etc.), Azolides (eg, N, N′-carbonyldiimidazole, etc.), dehydrating agents (eg, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, alkoxyacetylene, etc.), 2-halogenopyridinium Salts (eg, 2-chloromethylpyridinium iodide, 2-fluoro-1-methylpyridinium iodide, etc.) are used. The amount of the condensing agent to be used varies depending on the condensing agent to be used, but it is about 1 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of compound (XIV ′).
In this reaction, an additive (eg, 1-hydroxybenzotriazole, N-hydroxysuccinimide, etc.) may be added. The amount of the additive to be used is about 1 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of compound (XIV ′).
This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds. For example, solvents such as ethers, hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, water, or a mixed solvent thereof are preferable. .
The reaction temperature is usually about 0 ° C to about 100 ° C, preferably about 0 ° C to about 70 ° C. The reaction time is usually about 30 minutes to about 24 hours, preferably about 30 minutes to about 4 hours.

Compound (XVII ′) can be produced by reacting compound (XV ′) with compound (XVI ′).
Compound (XVI ′) is easily commercially available, and can also be produced according to a method known per se or a method analogous thereto. The amount of compound (XVI ′) to be used is about 1 to about 10 mol, preferably about 1 to about 4 mol, per 1 mol of compound (XV ′).
This reaction is advantageously performed using a solvent inert to the reaction. Although it does not specifically limit as long as reaction advances as such a solvent, For example, solvents, such as ethers and hydrocarbons, or those mixed solvents are preferable.
The reaction temperature is usually about 0 ° C to about 100 ° C, preferably about 0 ° C to about 70 ° C. The reaction time is usually about 30 minutes to about 24 hours, preferably about 1 hour to about 15 hours.
Compound (XVIII ′) can be produced from compound (XVII ′) using a method similar to the method for producing compound (III ′) from compound (V ′).
Compound (XIX ′) in which R ¹ is represented by the formula — (C═O) —OR ^e in Compound (XIX ′) produces Compound (VIII ′) from Compound (VI ′) and Compound (VII ′). It can be produced from compound (XVIII ′) and compound (VII ′) using a method similar to the method.
In compound (XX ′), a compound in which R ² is a hydrogen atom can be produced by reducing the carbonyl group of compound (XIX ′).
As the reducing agent used, for example, metal hydrogen complex compounds (eg, sodium borohydride) and the like are used. The amount of the reducing agent to be used is, for example, about 1 to about 10 mol, preferably about 1 to about 3 mol, per 1 mol of compound (XIX ′) in the case of metal hydrogen complex compounds.
This reaction is advantageously performed using a solvent inert to the reaction. Although it does not specifically limit as long as reaction advances as such a solvent, For example, solvents, such as alcohol, ethers, hydrocarbons, amides, or those mixed solvents are preferable.
The reaction temperature is usually about −30 ° C. to about 80 ° C., preferably about −20 ° C. to about 50 ° C. The reaction time is usually about 10 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
Compound (I) can also be produced from compound (XX ′) using a method similar to the method for producing compound (I) from compound (XIII ′).

In the above reaction, when the raw material compound has amino, carboxy, or hydroxy as a substituent, these groups may be introduced with a protecting group generally used in peptide chemistry, etc. Depending on the above, the target compound can be obtained by removing the protecting group.
Examples of the amino-protecting group include a formyl group or a C _1-6 alkyl-carbonyl group (for example, acetyl group, propionyl group, etc.) each optionally having a substituent, a phenylcarbonyl group, C _1-6 alkoxy- A carbonyl group (eg, methoxycarbonyl group, ethoxycarbonyl group, etc.), a phenyloxycarbonyl group, a C _7-10 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl group, etc.), a trityl group, a phthaloyl group, or the like is used. As these substituents, halogen atoms (for example, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl-carbonyl groups (for example, acetyl group, propionyl group, valeryl group, etc.), nitro groups and the like are used. The number of substituents is 1 to 3.
Examples of the protecting group for the carboxy group include C _1-6 alkyl groups each having a substituent (for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, 2- Trimethyl group, etc.), phenyl group, trityl group or silyl group. Examples of these substituents include halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), formyl groups, C _1-6 alkyl-carbonyl groups (eg, acetyl groups, propionyl groups, butylcarbonyl groups, etc.), nitro groups. , C _1-6 alkyl groups (for example, methyl group, ethyl group, tert-butyl group, etc.), C _6-10 aryl groups (for example, phenyl group, naphthyl group, etc.) and the like, and the number of substituents is 1 Or three.
Examples of the protecting group for the hydroxy group include, for example, C _1-6 alkyl groups each having a substituent (for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group), Phenyl group, C _7-11 aralkyl group (eg, benzyl group, etc.), formyl group, C _1-6 alkyl-carbonyl group (eg, acetyl group, propionyl group, etc.), phenyloxycarbonyl group, C _7-11 aralkyloxy group -A carbonyl group (for example, benzyloxycarbonyl group, etc.), a tetrahydropyranyl group, a tetrahydrofuranyl group or a silyl group is used. Examples of these substituents include halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl groups (eg, methyl group, ethyl group, tert-butyl group, etc.), C _7-11 aralkyl groups. (For example, benzyl group), C _6-10 aryl group (for example, phenyl group, naphthyl group, etc.), nitro group and the like are used, and the number of substituents is 1 to 4.
In addition, as a method for removing the protecting group, a method known per se or a method equivalent thereto is used. For example, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate and the like. A processing method or a reduction reaction is used.
In any case, a known deprotection reaction, acylation reaction, alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction, carbon chain extension reaction, or substituent exchange reaction may be performed alone or in combination, as desired. Compound (I) can be synthesized by combining two or more compounds. For these reactions, for example, the method described in New Experimental Chemistry Course 14, Vol. 15, 1977 (Maruzen Publishing) is adopted.

  Specifically, for example, as shown in Reaction Scheme 4, the compound (XXI ′) contained in the compound (I) of the present invention is included in the compound (I) of the present invention using a substituent exchange reaction. Compound (XXII ′) can be produced.

When the desired product is obtained in the free state by the above reaction, it may be converted into a salt according to a conventional method. You can also. The compound (I) thus obtained can be isolated and purified from the reaction solution by known means such as phase transfer, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography and the like.
When compound (I) exists as a configurational isomer (configuration isomer), diastereomer, conformer, or the like, each can be isolated by the above-described separation and purification means, if desired.
When a stereoisomer exists in the compound (I), the case where this isomer is used alone or a mixture thereof is also included in the present invention.

Compound (I), (II) of the present invention, a salt thereof or a prodrug thereof (hereinafter abbreviated as Compound (I) of the present invention) is represented by TGR23 (for example, SEQ ID NO: 1 or SEQ ID NO: 2). Has a function of changing the binding property of TGR23 ligand, particularly TGR23 function (preferably TGR23 antagonist activity), has low toxicity and has few side effects . Thus, the compound (I) of the present invention is useful as a safe pharmaceutical, for example, a TGR23 function regulator (preferably a TGR23 antagonist), a disease caused by TGR23, such as cancer (eg, colon cancer). , Colon cancer, rectal cancer, breast cancer, lung cancer, non-small cell lung cancer, prostate cancer, esophageal cancer, stomach cancer, liver cancer, biliary tract cancer, spleen cancer, kidney cancer, bladder cancer, uterine cancer, ovarian cancer, cervical cancer, Useful as a low-toxic and safe medicine such as testicular cancer, thyroid cancer, pancreatic cancer, brain tumor, blood tumor, etc.), feeding (appetite) promoter, anorexia prevention / treatment agent, apoptosis inducer, etc. It is. Alternatively, central diseases (eg, Alzheimer's disease, dementia, eating disorders, etc.), endocrine diseases (eg, hypertension, gonadal dysfunction, thyroid dysfunction, pituitary dysfunction, etc.), metabolic diseases (eg, diabetes, lipid metabolism) It is useful as a pharmaceutical for safe and low-toxic preventive / therapeutic agents such as abnormalities and hyperlipidemia). Preferably, they are cancer preventive / therapeutic agents, apoptosis inducers, feeding accelerators and the like.
When the compound (I) of the present invention is used as the above-mentioned prophylactic and / or therapeutic agent, apoptosis inducer, feeding accelerator, etc., it can be administered orally or parenterally according to a method known per se. Usually mixed with a pharmaceutically acceptable carrier, and orally administered as a solid preparation such as tablets, capsules, granules, powders, or injections, suppositories, or sublingual tablets intravenously, subcutaneously, intramuscularly, etc. As such, it is administered parenterally. Alternatively, it may be administered sublingually, subcutaneously or intramuscularly as a sustained release preparation such as a sublingual tablet or a microcapsule.
The dose of the compound (I) of the present invention varies depending on the administration subject, administration route, and symptoms, and is not particularly limited. For example, when administered orally to an adult patient for the purpose of cancer treatment, 0.01 to about 20 mg / kg body weight, preferably about 0.1 to about 10 mg / kg body weight, more preferably about 0.1 to about 2 mg / kg body weight. It is desirable to administer about 1 to 3 times.
The content of the compound (I) of the present invention in the above-mentioned “agent (pharmaceutical composition)” varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight of the total pharmaceutical composition, preferably about 0.
1 to 50% by weight, more preferably 0.5 to 20% by weight.
The content of the pharmaceutically acceptable carrier in the “agent (pharmaceutical composition)” varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight of the total pharmaceutical composition, preferably About 10 to 90% by weight.

As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations, dissolution aids It is formulated as an agent, suspending agent, isotonic agent, buffering agent, soothing agent and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
Preferable examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Suitable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; And hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol and the like. Preferable examples of the buffer include buffers such as phosphate, acetate, carbonate and citrate. Preferable examples of the soothing agent include benzyl alcohol. Preferable examples of the preservative include paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include sulfite and ascorbic acid.

To the compound (I) of the present invention, a suspending agent, a solubilizing agent, a stabilizing agent, a tonicity agent, a preservative and the like are added, and a intravenous, subcutaneous and intramuscular injection is obtained by a method known per se. Can do. At that time, if necessary, a freeze-dried product can be obtained by a method known per se.
When the compound (I) of the present invention is administered to, for example, humans, it is mixed with itself or an appropriate pharmacologically acceptable carrier, excipient, diluent, and orally or parenterally as a pharmaceutical composition. Can be administered safely.
Examples of the pharmaceutical composition include oral preparations (eg, powders, granules, capsules, tablets), injections, drops, external preparations (eg, nasal preparations, transdermal preparations, etc.), suppositories (eg, Rectal suppository, vaginal suppository) and the like.
These preparations can be produced by a method known per se generally used in the preparation process.
Compound (I) of the present invention contains a dispersant (eg, Tween 80 (manufactured by Atlas Powder, USA), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, etc.), preservative (eg, Methyl paraben, propyl paraben, benzyl alcohol, etc.), isotonic agents (eg, sodium chloride, mannitol, sorbitol, glucose, etc.), etc. It can be dissolved, suspended or emulsified into an oily injection and made into an injection.

  In order to obtain a preparation for oral administration, according to a method known per se, the compound (I) of the present invention is mixed with, for example, an excipient (eg, lactose, sucrose, starch, etc.), a disintegrant (eg, starch, calcium carbonate, etc.), Add a binder (eg, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.), etc. If necessary, it can be made into an orally-administered preparation by coating by a method known per se for the purpose of masking of taste, enteric property or sustainability. Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (Rohm) Manufactured by Germany, methacrylic acid / acrylic acid copolymer) and dyes (eg, bengara, titanium dioxide, etc.). In the case of an enteric preparation, an intermediate phase can be provided between the enteric phase and the drug-containing phase by a method known per se for the purpose of separating both phases.

In order to obtain an external preparation, the compound (I) or a salt thereof of the present invention can be converted into a solid, semi-solid or liquid external preparation according to a method known per se. For example, as the solid, the compound (I) of the present invention or a salt thereof is used as it is, or an excipient (eg, glycol, mannitol, starch, microcrystalline cellulose, etc.), a thickener (eg, natural gum) Etc., cellulose derivatives, acrylic acid polymers, etc.) are added and mixed to obtain a powdery composition. The liquid form is almost the same as in the case of injections, and is an oily or aqueous suspension. In the case of a semi-solid form, an aqueous or oily gel or an ointment is preferred. In addition, these are all pH adjusters (eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, paraoxybenzoates, chlorobutanol, benzalkonium chloride, etc.), etc. May be added.
For example, to make a suppository, the compound (I) of the present invention can be converted into an oily or aqueous solid, semisolid or liquid suppository according to a method known per se. Examples of the oily base used in the composition include glycerides of higher fatty acids (eg, cacao butter, witepsols (manufactured by Dynamite Nobel, Germany)), intermediate fatty acids (eg, miglyols (manufactured by Dynamite Nobel, Germany)) Etc.], or vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.). Examples of the aqueous base include polyethylene glycols and propylene glycol. Examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers.

Examples of a drug that can be used in combination with the compound (I) of the present invention (hereinafter sometimes abbreviated as a concomitant drug) include, for example, other therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, antihypertensive agents Agent, anti-obesity agent, diuretic, chemotherapeutic agent, immunotherapy agent, immunomodulator, anti-inflammatory agent, antithrombotic agent, osteoporosis therapeutic agent, antibacterial agent, antifungal agent, antiprotozoal agent, antibiotic, antitussive Drugs, sedatives, anesthetics, anti-ulcer drugs, tranquilizers, antipsychotics, antitumor drugs, muscle relaxants, antiepileptic drugs, antidepressants, antiallergic drugs, cardiotonic drugs, antiarrhythmic drugs, vasodilators Vasoconstrictor, narcotic antagonist, vitamin, vitamin derivative, anti-asthma, anti-dementia, frequent urinary incontinence, dysuria, atopic dermatitis, allergic rhinitis, pressurization Drugs, endotoxin antagonists or antibodies, signal transduction inhibitors, inflammatory Dieta action inhibitors, inflammatory mediator action suppressing antibodies, anti-inflammatory mediator action suppressing drugs, anti-inflammatory mediator action suppressing antibodies. Specific examples include the following.

Other therapeutic agents for diabetes include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using Escherichia coli and yeast; insulin zinc; protamine insulin zinc; insulin Fragments or derivatives (eg, INS-1 etc.), oral insulin preparations, etc., insulin sensitivity enhancers (eg, pioglitazone or a salt thereof (preferably hydrochloride), troglitazone, rosiglitazone or a salt thereof (preferably maleate) ), Reglixane (JTT-501), Netoglitazone (MCC-555), YM-440, GI-262570, KRP-297, FK-614, CS-011, (γE) -γ- [ [[4-[(5-Methyl-2-phenyl-4-oxazolyl) methoxy] phenyl] methoxy] imino] Compounds such as nzenbutanoic acid and the like (for example, (E) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid) described in WO99 / 58510, WO01 / 38325 compounds, Tesaglitazar (AZ-242), Ragaglitazar (NN-622), BMS-298585, ONO-5816, BM-13-1258, LM-4156, MBX-102, LY -519818, MX-6054, LY-510929, Balaglitazone (NN-2344), T-131 or its salt, THR-0921), α-glucosidase inhibitor (eg, voglibose, acarbose, miglitol, emiglitate, etc. ), Biguanides (eg, phenformin, metformin, buformin, etc.), insulin secretagogues [sulfonylureas (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide ), Repaglinide, senaglinide, mitiglinide or its calcium salt hydrate, nateglinide, etc.], GLP-1 receptor agonist [eg, GLP-1, GLP-1MR agent, NN-2211, AC-2993 (exendin-4 ), BIM-51077, Aib (8,35) hGLP-1 (7,37) NH ₂ , CJC-1131, etc.], dipeptidyl peptidase IV inhibitors (eg, NVP-DPP-278, PT-100, P32 / 98, P93 / 01, NVP-DPP-728, LAF237, TS-021, etc.), β3 agonist (eg, CL-316243, SR-58611-A, UL-TG-307, AJ-9679, AZ40140, etc.), amylin Agonists (eg, pramlintide, etc.), phosphotyrosine phosphatase inhibitors (eg, vanadic acid, etc.), gluconeogenesis inhibitors (eg, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, etc.), GLT (sodium-glucose cotransporter) inhibitors (eg, T-1095, etc.), 11β-hydroxysteroid dehydrogenase inhibitors (eg, BVT-3498, etc.), adiponectin or agonists thereof, IKK inhibitors (eg, AS-2868, etc.) ), Leptin resistance improver, somatostatin receptor agonist (compound described in WO01 / 25228, WO03 / 42204, compound described in WO98 / 44921, WO98 / 45285, WO99 / 22735, etc.), glucokinase activator (eg, Ro-28-1675).

Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (eg, tolrestat, epalrestat, zenarestat, zopolrestat, fidarestat (SNK-860), minarerestat (ARI-509), CT-112, etc.), nerves Nutritional factor and its increasing drug (eg, NGF, NT-3, BDNF, neurotrophin production / secretion promoter described in WO01 / 14372 (eg 4- (4-chlorophenyl) -2- (2-methyl-1- Imidazolyl) -5- [3- (2-methylphenoxy) propyl] oxazole etc.), protein kinase C (PKC) inhibitors (eg LY-333531 etc.), AGE inhibitors (eg ALT-945, pimagedin) , Pyratoxatin, N-phenacylthiazolium bromide (ALT-766), EXO-226, ALT-711, pyridorin, pyridoxa Active oxygen scavengers (eg, thioctic acid, etc.), cerebral vasodilators (eg, thioprid, etc.), somatostatin receptor agonists (BIM23190), apoptosis signal regulating kinase-1 (ASK-1) inhibitors Etc.
Antihyperlipidemic agents include statins that are cholesterol synthesis inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin or their salts (eg, sodium salt, etc.)), squalene synthase inhibition Agent (
Examples, compounds described in WO 97/10224, for example N-[[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid), fibrate compounds (eg, bezafibrate, clofibrate, shim) Fibrates, clinofibrate, etc.), antioxidants (eg, lipoic acid, probucol) and the like.

Antihypertensive agents include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonists (eg, losartan, candesartan cilexetil, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, 1-[[2 ' -(2,5-Dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethoxy-1H-benzimidazole-7-carboxylic acid Etc.), calcium antagonists (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine, etc.), clonidine and the like.
Anti-obesity agents include, for example, central anti-obesity agents (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonist (Eg, SB-568849; SNAP-7941; compounds included in WO01 / 82925 and WO01 / 87834, etc.); neuropeptide Y antagonists (eg, CP-422935, etc.); cannabinoid receptor antagonists (eg, SR-141716) SR-147778, etc.); Ghrelin antagonist; 11β-hydroxysteroid dehydrogenase inhibitor (eg, BVT-3498 etc.), pancreatic lipase inhibitor (eg, orlistat, ATL-962 etc.), β3 agonist (eg, CL) -316243, SR-58611-A, UL-TG-307, AJ-9677, AZ40140, etc.), peptidic appetite suppressant Examples, leptin, CNTF (ciliary neurotrophic factor) etc.), cholecystokinin agonists (e.g., lintitript, FPL-15849 etc.), feeding inhibitors (examples include P-57, etc.) and the like.
Examples of diuretics include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, pentfurizide, polythiazide, Methiclotiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.), azosemide, isosorbide, Examples include ethacrynic acid, piretanide, bumetanide, furosemide and the like.

Examples of chemotherapeutic agents include alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate, 5-fluorouracil, etc.), anticancer antibiotics (eg, mitomycin, adriamycin, etc.), Plant-derived anticancer agents (eg, vincristine, vindesine, taxol, etc.), cisplatin, carboplatin, etopoxide and the like can be mentioned. Of these, 5-fluorouracil derivatives such as furuluron or neofluturon are preferable.
Examples of immunotherapeutic agents include microorganisms or bacterial components (eg, muramyl dipeptide derivatives, picibanil, etc.), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin, etc.), cytokines obtained by genetic engineering techniques ( Examples include interferon, interleukin (IL), etc., colony stimulating factors (eg, granulocyte colony stimulating factor, erythropoietin, etc.), among them interleukins such as IL-1, IL-2, IL-12, etc. Is preferred.
Examples of the anti-inflammatory drug include non-steroidal anti-inflammatory drugs such as aspirin, acetaminophen, and indomethacin.

Examples of the antithrombotic agent include heparin (eg, heparin sodium, heparin calcium, dalteparin sodium), warfarin (eg, warfarin potassium), antithrombin drug (eg, argatroban), thrombus Soluble drugs (eg, urokinase, tisokinase, alteplase, nateplase, monteplase, pamitepase), platelet aggregation inhibitors (eg, ticlopidine hydrochloride) Cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride, etc.).
Examples of osteoporosis therapeutic agents include alfacalcidol, calcitriol, elcatonin, salmon calcitonin salmon, estriol, ipriflavone, disodium pamidronate disodium. ), Alendronate sodium hydrate, incadronate disodium, and the like.
Examples of vitamin drugs include vitamin B ₁ and vitamin B ₁₂ .
Examples of anti-dementia agents include tacrine, donepezil, rivastigmine, galantamine, and the like.
Examples of the frequent urinary / urinary incontinence therapeutic agent include flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride and the like.
Examples of the dysuria therapeutic agent include acetylcholinesterase inhibitors (eg, distigmine).

Furthermore, drugs that have been shown to improve cachexia in animal models and clinically, ie, cyclooxygenase inhibitors (eg, indomethacin, etc.) [Cancer Research, 49, 5935-5939, 1989] ], Progesterone derivatives (eg, megesterol acetate) [Journal of Clinical Oncology, Vol. 12, pp. 213-225, 1994], carbohydrate steroids (eg, dexamethasone, etc.), metoclopramide Drugs, tetrahydrocannabinol drugs (the literature is the same as above), fat metabolism improvers (eg, eicosapentaenoic acid, etc.) [British Journal of Cancer, Vol. 68, 314 -318, 1993], growth hormone, IG -1, or TNF-alpha is a factor which induce cachexia, LIF, IL-6, or oncostatin M, can also be used in combination with the compounds of the present invention (I).
Furthermore, glycation inhibitors (eg, ALT-711, etc.), nerve regeneration promoters (eg, Y-128, VX853, prosaptide, etc.), antidepressants (eg, desipramine, amitriptyline, imipramine), antiepileptic drugs (eg, Lamotrigine, Trileptal, Keppra, Zonegran, Pregabalin, Hercoside (Harkoseride), Carbamazepine), Antiarrhythmic drugs (eg, Mexiletine), Acetylcholine receptor ligands (eg, ABT-594) , Endothelin receptor antagonists (eg, ABT-627), monoamine uptake inhibitors (eg, tramadol), narcotic analgesics (eg, morphine), GABA receptor agonists (eg, gabapentin, gabapentin MR agent), α2 Receptor agonists (eg clonidine), local analgesics (eg capsaicin), anxiolytics (eg benzothiazepine), phosphodiesterase inhibitors (eg, Sildenafil), a dopamine receptor agonist (eg, apomorphine) and the like can also be used in combination with the compound (I) of the present invention.

By combining the compound (I) of the present invention with a concomitant drug,
(1) The dose can be reduced as compared with the case where the compound (I) of the present invention or the concomitant drug is administered alone.
(2) A drug to be used in combination with the compound (I) of the present invention can be selected according to the patient's symptoms (mild, severe, etc.),
(3) By selecting a concomitant drug having a different mechanism of action from the compound (I) of the present invention, the treatment period can be set longer.
(4) By selecting a concomitant drug having a different mechanism of action from the compound (I) of the present invention, the therapeutic effect can be sustained.
(5) By combining the compound (I) of the present invention and the concomitant drug, excellent effects such as a synergistic effect can be obtained.

Hereinafter, the combined use of the compound (I) of the present invention and a concomitant drug is referred to as “the combination drug of the present invention”.
When using the concomitant drug of the present invention, the timing of administration of the compound (I) of the present invention and the concomitant drug is not limited, and the compound (I) of the present invention and the concomitant drug are administered simultaneously to the administration subject. Alternatively, administration may be performed with a time difference. The dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
The administration form of the concomitant drug of the present invention is not particularly limited as long as the compound (I) of the present invention and the concomitant drug are combined at the time of administration. Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound (I) of the present invention and a concomitant drug, and (2) concomitant use with the compound (I) of the present invention. Simultaneous administration of two preparations obtained by separately formulating a drug by the same route of administration, (3) Two preparations obtained by separately formulating the compound (I) of the present invention and a concomitant drug Administration at different time intervals in the same administration route, (4) simultaneous administration in different administration routes of two types of preparations obtained by separately formulating the compound (I) of the present invention and a concomitant drug, (5) Administration of two types of preparations obtained by separately formulating the compound (I) of the present invention and a concomitant drug at different administration routes (for example, the compound (I) of the present invention; the order of the concomitant drug) Administration, or administration in the reverse order).

The concomitant drug of the present invention has low toxicity. For example, the compound (I) of the present invention or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier according to a method known per se, For example, tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release preparations, etc., orally or parenterally (eg , Topical, rectal, intravenous administration, etc.). An injection can be administered intravenously, intramuscularly, subcutaneously, or into an organ, or directly into a lesion.
The pharmacologically acceptable carrier that may be used for the production of the concomitant drug of the present invention is the same as the pharmacologically acceptable carrier that may be used for the production of the pharmaceutical of the present invention described above. Is given. Furthermore, if necessary, additives such as preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like that may be used in the production of the medicament of the present invention may be appropriately used in appropriate amounts. it can.
The compounding ratio of the compound (I) of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
For example, the content of the compound (I) of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to about 0.1% by weight based on the whole preparation. It is about 50% by weight, more preferably about 0.5 to 20% by weight.
The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 90% by weight, preferably about 0.1 to 50% by weight, more preferably based on the whole preparation. About 0.5 to 20% by weight.
The content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.98% by weight, preferably about 10 to 90% by weight, based on the whole preparation. is there.
When the compound (I) of the present invention and the concomitant drug are formulated separately, the compound (I) of the present invention and the concomitant drug may have the same content, and the content of additives such as carriers is usually The amount is about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation.

These preparations can be produced by a method known per se generally used in the preparation process.
For example, the compound (I) or the concomitant drug of the present invention includes a dispersant (eg, Tween 80 (manufactured by Atlas Powder Co., USA), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethyl cellulose, sodium alginate, Hydroxypropylmethylcellulose, dextrin, etc.), stabilizers (eg, ascorbic acid, sodium pyrosulfite, etc.), surfactants (eg, polysorbate 80, macrogol, etc.), solubilizers (eg, glycerin, ethanol, etc.), buffering agents (Eg, phosphoric acid and its alkali metal salts, citric acid and its alkali metal salts, etc.), isotonic agents (eg, sodium chloride, potassium chloride, mannitol, sorbitol, glucose etc.), pH regulators (eg, hydrochloric acid, Sodium hydroxide, etc.), preservatives (eg, ethyl paraoxybenzoate, benzoate) Acids, methylparaben, propylparaben, benzyl alcohol, etc.), solubilizers (eg, concentrated glycerin, meglumine, etc.), solubilizers (eg, propylene glycol, saccharose, etc.), soothing agents (eg, glucose, benzyl alcohol, etc.), etc. At the same time, it can be formed into an oily injection by dissolving, suspending or emulsifying in an aqueous injection, or in a vegetable oil such as olive oil, sesame oil, cottonseed oil or corn oil, or a solubilizing agent such as propylene glycol.
In addition, according to a method known per se, the compound (I) or the concomitant drug of the present invention is mixed with, for example, an excipient (eg, lactose, sucrose, starch, etc.), a disintegrant (eg, starch, calcium carbonate, etc.), a binder. (Eg, starch, gum arabic, carboxymethyl cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, etc.) or lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) etc. are added and then compression molded, if necessary For the purpose of taste masking, enteric or sustained, it can be made into an orally administered preparation by coating by a method known per se. Examples of the coating agent used for coating include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (manufactured by Rohm, Germany, methacrylic acid / acrylic acid copolymer) and pigments (eg, Bengala, titanium dioxide, etc.) are used. The preparation for oral administration may be either an immediate release preparation or a sustained release preparation.
Further, according to a method known per se, the compound (I) of the present invention or the concomitant drug is mixed with an oily base, an aqueous base or an aqueous gel base to give an oily or aqueous solid, semisolid or liquid. Suppository. Examples of the oily base include glycerides of higher fatty acids (eg, cacao butter, witepsols (manufactured by Dynamite Nobel, Germany)), intermediate fatty acids (eg, miglyols (manufactured by Dynamite Nobel, Germany), etc.), Or vegetable oils (for example, sesame oil, soybean oil, cottonseed oil etc.) etc. are mentioned. Examples of the aqueous base include polyethylene glycols and propylene glycol. Examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, acrylic acid polymers, and the like.
Examples of the sustained-release preparation include sustained-release microcapsules. The sustained-release microcapsule is produced according to a method known per se, for example, the method shown in the following [2].
The compound (I) of the present invention is preferably molded into a preparation for oral administration such as a solid preparation (eg, powder, granule, tablet, capsule) or into a preparation for rectal administration such as a suppository. Particularly preferred are preparations for oral administration.
The concomitant drug can be in the above-mentioned dosage form depending on the type of drug.

[1] An injection of the compound (I) of the present invention or a concomitant drug and its preparation; [2]
Sustained-release preparation or immediate-release preparation of compound (I) or concomitant drug of the present invention and preparation thereof, [3] Sublingual tablet, buccal or intraoral quick disintegrating agent of compound (I) of the present invention or concomitant drug and The preparation will be specifically described.
[1] Injection and preparation thereof An injection prepared by dissolving the compound (I) of the present invention or the concomitant drug in water is preferred. The injection may contain benzoate and / or salicylate.
The injection is obtained by dissolving both the compound (I) of the present invention or the concomitant drug and, optionally, a benzoate and / or salicylate in water.
Examples of the benzoic acid and salicylic acid salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, meglumine salts, and other organic acid salts such as trometamol.
The concentration of the compound (I) of the present invention or the concomitant drug in the injection is 0.5 to 50 w / v%, preferably about 3 to 20 w / v%. The concentration of benzoate or / and salicylate is about 0.5 to 50 w / v%, preferably about 3 to 20 w / v%.
In addition, the present injection includes additives generally used in injections, such as stabilizers (eg, ascorbic acid, sodium pyrosulfite, etc.), surfactants (eg, polysorbate 80, macrogol, etc.), solubilizers (eg, Examples, glycerin, ethanol, etc.), buffering agents (eg, phosphoric acid and its alkali metal salts, citric acid and its alkali metal salts, etc.), isotonic agents (eg, sodium chloride, potassium chloride, etc.), dispersants (eg, , Hydroxypropylmethylcellulose, dextrin), pH adjusters (eg, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, ethyl paraoxybenzoate, benzoic acid, etc.), solubilizers (eg, concentrated glycerin, meglumine, etc.), dissolved Adjuvants (eg, propylene glycol, sucrose, etc.), soothing agents (eg, glucose, benzyl alcohol, etc.) and the like can be appropriately blended. Generally these additives are mix | blended in the ratio normally used for an injection.
The injection is adjusted to pH 2 to 12, preferably pH 2.5 to 8.0, by adding a pH adjusting agent.
An injection is obtained by dissolving both the compound (I) of the present invention or the concomitant drug and, optionally, a benzoate and / or salicylate, and if necessary, the above-mentioned additives in water. These dissolutions may be performed in any order, and can be appropriately performed in the same manner as in the conventional method for producing an injection.
The aqueous solution for injection is preferably warmed, and can be provided as an injection by performing, for example, filtration sterilization, high-pressure heat sterilization, etc. in the same manner as ordinary injections.
The aqueous solution for injection is preferably sterilized by high-pressure heat for 5 to 30 minutes, for example, at 100 to 121 ° C.
Furthermore, it is good also as a formulation which provided the antibacterial property of the solution so that it could be used as a multi-dose administration formulation.

[2] Sustained-release preparation or immediate-release preparation and preparation thereof Slowly-formulated preparation is prepared by optionally coating a core comprising Compound (I) of the present invention or a concomitant drug with a coating agent such as a water-insoluble substance or a swelling polymer A releasable formulation is preferred. For example, a once-daily administration type sustained-release preparation for oral administration is preferred.
Examples of water-insoluble substances used in the coating agent include cellulose ethers such as ethyl cellulose and butyl cellulose, cellulose esters such as cellulose acetate and cellulose propionate, polyvinyl esters such as polyvinyl acetate and polyvinyl butyrate, acrylic acid / Methacrylic acid copolymer, methyl methacrylate copolymer, ethoxyethyl methacrylate / cinnamoethyl methacrylate / aminoalkyl methacrylate copolymer, polyacrylic acid, polymethacrylic acid, methacrylic acid alkylamide copolymer, poly (methyl methacrylate) , Polymethacrylate, polymethacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic anhydride), glycidyl methacrylate copolymer, wrinkle Eudragit RS-100, RL-100, RS-3
0D, RL-30D, RL-PO, RS-PO (ethyl acrylate / methyl methacrylate / methacrylic acid trimethyl / ammonium ethyl copolymer), Eudragit NE-30D (methyl methacrylate / ethyl acrylate) Polymers), Eudragits such as Eudragit (Rohm Pharma), hardened oils such as hardened castor oil (eg, Lovely Wax (Freund Industries)), waxes such as carnauba wax, fatty acid glycerin ester, paraffin And polyglycerol fatty acid esters.
As the swellable polymer, a polymer having an acidic dissociation group and exhibiting pH-dependent swelling is preferable. Swelling is small in an acidic region such as the stomach, and swelling is large in a neutral region such as the small intestine and large intestine. A polymer having an acidic dissociation group is preferred.
Examples of such a polymer having an acidic dissociable group and exhibiting pH-dependent swelling include, for example, Carbomer 934P, 940, 941, 974P, 980, and 1342, polycarbophil, calcium polycarbophile, and the like. Examples thereof include cross-linked polyacrylic acid polymers such as (carcium polycarbophil) (all of which are manufactured by BF Goodrich) and Hibiswako 103, 104, 105, 304 (all of which are manufactured by Wako Pure Chemical Industries, Ltd.).
The film agent used in the sustained release preparation may further contain a hydrophilic substance.
Examples of the hydrophilic substance include hydroxyalkyl groups or carboxyalkyl groups such as polysaccharides, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and the like, which may have a sulfate group such as pullulan, dextrin, and alkali metal alginate. And polysaccharides having the following structure: methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol and the like.
The content of the water-insoluble substance in the film of the sustained release preparation is about 30 to about 90% (w / w), preferably about 35 to about 80% (w / w), more preferably about 40 to 75% ( w / w), the swellable polymer content is about 3 to about 30% (w / w), preferably about 3 to about 15% (w / w). The coating agent may further contain a hydrophilic substance, in which case the content of the hydrophilic substance in the coating agent is about 50% (w / w) or less, preferably about 5 to about 40% (w / w), More preferably, it is about 5 to about 35% (w / w). Here, the above% (w / w) represents the weight% with respect to the coating agent composition obtained by removing the solvent (eg, water, lower alcohol such as methanol, ethanol, etc.) from the coating agent solution.

The sustained-release preparation is prepared by preparing a core containing a drug as exemplified below, and then the obtained core is a film agent solution in which a water-insoluble substance or a swellable polymer is dissolved by heating or dissolved or dispersed in a solvent. Manufactured by coating.
I. Preparation of Nuclei Containing Drug A form of a nucleus containing a drug to be coated with a film agent (hereinafter sometimes simply referred to as a nucleus) is not particularly limited, but is preferably formed into particles such as granules or fine granules.
When the core is a granule or a fine granule, the average particle size is preferably about 150 to 2,000 μm, more preferably about 500 to about 1,400 μm.
The preparation of the nucleus can be carried out by a usual production method. For example, suitable excipients, binders, disintegrants, lubricants, stabilizers and the like are mixed with the drug, and prepared by a wet extrusion granulation method, a fluidized bed granulation method, or the like.
The drug content of the nucleus is about 0.5 to about 95% (w / w), preferably about 5.0 to about 80% (w / w), more preferably about 30 to about 70% (w / w) It is.
Examples of excipients contained in the core include saccharides such as sucrose, lactose, mannitol and glucose, starch, crystalline cellulose, calcium phosphate, corn starch and the like. Among these, crystalline cellulose and corn starch are preferable.
As the binder, for example, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, pluronic F68, gum arabic, gelatin, starch and the like are used. As the disintegrant, for example, carboxymethylcellulose calcium (ECG505), croscarmellose sodium (Ac-Di-Sol), cross-linked polyvinyl pyrrolidone (crospovidone), low-substituted hydroxypropylcellulose (L-HPC) and the like are used. Of these, hydroxypropylcellulose, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose are preferable. For example, talc, magnesium stearate and its inorganic salt are used as a lubricant and an aggregation inhibitor, and polyethylene glycol is used as a lubricant. As the stabilizer, acids such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid are used.
In addition to the production method described above, the nucleus may be prepared by spraying a binder dissolved in an appropriate solvent such as water or a lower alcohol (eg, methanol, ethanol, etc.) It can also be prepared by a rolling granulation method, a pan coating method, a fluidized bed coating method, or a melt granulation method in which a mixture of this and an excipient, a lubricant or the like is added little by little. As the inert carrier particles, for example, those made of sucrose, lactose, starch, crystalline cellulose, waxes can be used, and those having an average particle size of about 100 μm to about 1,500 μm are preferable.
In order to separate the drug contained in the nucleus and the coating agent, the surface of the nucleus may be coated with a protective agent. As the protective agent, for example, the hydrophilic substance, the water-insoluble substance, or the like is used. The protective agent is preferably polyethylene glycol or a polysaccharide having a hydroxyalkyl group or a carboxyalkyl group, more preferably hydroxypropylmethylcellulose or hydroxypropylcellulose. The protective agent may contain as stabilizers acids such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid, and lubricants such as talc. When a protective agent is used, the coating amount is about 1 to about 15% (w / w), preferably about 1 to about 10% (w / w), more preferably about 2 to about 8% (w / w) based on the nucleus. w / w).
The protective agent can be coated by a normal coating method. Specifically, the protective agent can be coated by spray coating the core by, for example, a fluidized bed coating method, a pan coating method, or the like.

II. Coating the core with the coating agent The core obtained in the above I is coated with a coating agent solution in which the water-insoluble substance, the pH-dependent swelling polymer, and the hydrophilic substance are dissolved by heating or dissolved or dispersed in a solvent. As a result, a sustained-release preparation is produced.
Examples of the method of coating the core with the coating agent solution include a spray coating method.
The composition ratio of the water-insoluble substance, the swellable polymer, or the hydrophilic substance in the coating agent solution is appropriately selected so that the content of each component in the film is the above-described content.
The coating amount of the coating agent is about 1 to about 90% (w / w), preferably about 5 to about 50% (w / w) with respect to the core (excluding the coating amount of the protective agent), more preferably About 5 to about 35% (w / w).
As the solvent of the film agent solution, water or an organic solvent can be used alone or a mixture of the two can be used. The mixing ratio of water and organic solvent (water / organic solvent: weight ratio) in the case of using the mixed liquid can be varied in the range of 1 to 100%, preferably 1 to about 30%. The organic solvent is not particularly limited as long as it dissolves water-insoluble substances. For example, lower alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and n-butyl alcohol, lower alkanones such as acetone, acetonitrile, chloroform, Methylene chloride or the like is used. Of these, lower alcohols are preferred, and ethyl alcohol and isopropyl alcohol are particularly preferred. Water and a mixed solution of water and an organic solvent are preferably used as the solvent for the film agent. At this time, if necessary, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, and maleic acid may be added to the coating agent solution for stabilizing the coating agent solution.
The operation in the case of coating by spray coating can be carried out by a usual coating method, specifically, by carrying out spray coating of a film agent solution on the core by, for example, fluidized bed coating method, pan coating method, etc. Can do. If necessary, plasticize glycerin fatty acid ester, hydrogenated castor oil, triethyl citrate, cetyl alcohol, stearyl alcohol, etc. using talc, titanium oxide, magnesium stearate, calcium stearate, light anhydrous silicic acid as lubricant. You may add as an agent.
After coating with a coating agent, an antistatic agent such as talc may be mixed as necessary.

The immediate release preparation may be liquid (solution, suspension, emulsion, etc.) or solid (particle, pill, tablet, etc.). As the immediate-release preparation, a parenterally administered agent such as an orally administered agent and an injectable agent is used, and an orally administered agent is preferable.
The immediate-release preparation usually contains a carrier, an additive or an excipient (hereinafter sometimes abbreviated as an excipient) commonly used in the pharmaceutical field in addition to the drug as the active ingredient. . The excipient used is not particularly limited as long as it is an excipient commonly used as a pharmaceutical excipient. For example, excipients for oral solid preparations include lactose, starch, corn starch, crystalline cellulose (manufactured by Asahi Kasei Corporation, Avicel PH101, etc.), powdered sugar, granulated sugar, mannitol, light anhydrous silicic acid, magnesium carbonate, calcium carbonate , L-cysteine and the like, preferably corn starch and mannitol. These excipients can be used alone or in combination of two or more. The content of the excipient is, for example, about 4.5 to about 99.4 w / w%, preferably about 20 to about 98.5 w / w%, more preferably about 30 to about 9%, based on the total amount of the immediate-release preparation. 97 w / w%.
The content of the drug in the immediate-release preparation can be appropriately selected from the range of about 0.5 to about 95%, preferably about 1 to about 60% with respect to the total amount of the immediate-release preparation.
When the immediate-release preparation is an oral solid preparation, it usually contains a disintegrant in addition to the above components. Examples of such disintegrants include carboxymethylcellulose calcium (manufactured by Gotoku Pharmaceutical Co., ECG-505), croscarmellose sodium (for example, Asahi Kasei Co., Ltd., Acjisol), crospovidone (for example, BASF Corp., Kollidon CL) , Low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd.), carboxymethyl starch (Matsutani Chemical Co., Ltd.), sodium carboxymethyl starch (manufactured by Kimura Sangyo Co., Ltd., Proprotab), partially pregelatinized starch (manufactured by Asahi Kasei Co., Ltd.) , PCS), etc. can be used. For example, a substance that disintegrates granules by contacting with water, absorbing water, swelling, or forming a channel between the active ingredient constituting the core and the excipient can be used. . These disintegrants can be used alone or in combination of two or more. The amount of the disintegrant is appropriately selected depending on the type and amount of the drug to be used, the design of the releasable preparation, and the like, but for example, about 0.05 to about 30 w / w%, Is about 0.5 to about 15 w / w%.
When the immediate-release preparation is an oral solid preparation, in the case of an oral solid preparation, an additive commonly used in the solid preparation may further be included, if desired, in addition to the above composition. Examples of such additives include binders (for example, sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, pullulan, dextrin, etc.), lubricants (for example, , Polyethylene glycol, magnesium stearate, talc, light anhydrous silicic acid (eg, Aerosil (Nippon Aerosil)), surfactants (eg, anionic surfactants such as sodium alkyl sulfate, polyoxyethylene fatty acid esters and polyoxyethylene) Sorbitan fatty acid esters, nonionic surfactants such as polyoxyethylene castor oil derivatives), colorants (eg tar dyes, caramel, bengara, titanium oxide, riboflavins), If necessary, flavoring agents (for example, sweeteners, fragrances, etc.), adsorbents, preservatives, wetting agents, antistatic agents, etc. Also used as stabilizers are tartaric acid, citric acid, succinic acid, fumaric acid, etc. Organic acids may be added.
As the binder, hydroxypropylcellulose, polyethylene glycol, polyvinylpyrrolidone and the like are preferably used.
The immediate-release preparation can be prepared by mixing the above-described components, further kneading, if necessary, and molding based on a normal preparation manufacturing technique. The mixing is performed by a generally used method such as mixing and kneading. Specifically, for example, when an immediate-release preparation is formed in a particulate form, a vertical granulator, a universal kneader (manufactured by Hata Iron Works), fluidized by the same method as the core preparation method of the sustained-release preparation It can be prepared by mixing using a layer granulator FD-5S (manufactured by POWREC) or the like and then granulating by a wet extrusion granulation method, a fluidized bed granulation method or the like.
The immediate-release preparation and the sustained-release preparation thus obtained are administered as they are or as appropriate, together with preparation excipients, etc., separately according to a conventional method, and then simultaneously or in combination with an arbitrary administration interval. Alternatively, both of them may be formulated into one orally administered preparation (eg, granules, fine granules, tablets, capsules, etc.) together with preparation excipients or the like as they are or as appropriate. Both preparations may be made into granules or fine granules and filled in the same capsule or the like for preparation for oral administration.

[3] Sublingual tablet, buccal or intraoral quick disintegrating agent and preparation thereof The sublingual tablet, buccal preparation and intraoral quick disintegrating agent may be a solid preparation such as a tablet, or an oral mucosa patch (film). There may be.
As the sublingual tablet, buccal or intraoral quick disintegrating agent, a preparation containing the compound (I) of the present invention or a concomitant drug and an excipient is preferable. Further, it may contain auxiliary agents such as a lubricant, an isotonic agent, a hydrophilic carrier, a water-dispersible polymer, and a stabilizer. Further, β-cyclodextrin or β-cyclodextrin derivatives (eg, hydroxypropyl-β-cyclodextrin, etc.) may be contained in order to facilitate absorption and increase bioavailability.
Examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, and light anhydrous silicic acid. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like, and magnesium stearate and colloidal silica are particularly preferable. Examples of the isotonic agent include sodium chloride, glucose, fructose, mannitol, sorbitol, lactose, saccharose, glycerin, urea and the like, and mannitol is particularly preferable. Examples of hydrophilic carriers include swellable hydrophilic carriers such as crystalline cellulose, ethyl cellulose, crosslinkable polyvinyl pyrrolidone, light anhydrous silicic acid, silicic acid, dicalcium phosphate, calcium carbonate, and particularly crystalline cellulose (eg, microcrystalline cellulose). Is preferred. Water-dispersible polymers include gums (eg, tragacanth gum, acacia gum, guar gum), alginates (eg, sodium alginate), cellulose derivatives (eg, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose), gelatin Water-soluble starch, polyacrylic acid (eg, carbomer), polymethacrylic acid, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, polycarbophil, ascorbyl palmitate, etc., hydroxypropyl methylcellulose, polyacrylic acid, alginate Gelatin, carboxymethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol and the like are preferable. Hydroxypropyl methylcellulose is particularly preferable. Examples of the stabilizer include cysteine, thiosorbitol, tartaric acid, citric acid, sodium carbonate, ascorbic acid, glycine, sodium sulfite and the like, and citric acid and ascorbic acid are particularly preferable.
A sublingual tablet, buccal or intraoral quick disintegrating agent can be produced by mixing the compound (I) of the present invention or the concomitant drug and an excipient by a method known per se. Further, if desired, auxiliary agents such as the above-mentioned lubricants, tonicity agents, hydrophilic carriers, water-dispersible polymers, stabilizers, colorants, sweeteners, preservatives and the like may be mixed. After mixing the above components simultaneously or with a time difference, a sublingual tablet, a buccal tablet or an intraoral quick disintegrating tablet is obtained by compression tableting. In order to obtain an appropriate hardness, it may be produced by humidifying and wetting with a solvent such as water or alcohol as necessary before and after the tableting molding process, and drying after molding.

In the case of molding into a mucosal patch (film), the compound (I) of the present invention or the concomitant drug and the above-mentioned water-dispersible polymer (preferably hydroxypropylcellulose, hydroxypropylmethylcellulose), an excipient, etc. Dissolve in solvent and cast the resulting solution into a film. In addition, additives such as plasticizers, stabilizers, antioxidants, preservatives, colorants, buffers, sweeteners and the like may be added. Contains glycols such as polyethylene glycol and propylene glycol to give the film proper elasticity, and contains bioadhesive polymers (eg, polycarbophil, carbopol) to enhance film adhesion to the mucosal lining of the oral cavity You may let them. Casting is performed by pouring the solution onto a non-adhesive surface, spreading it to a uniform thickness (preferably about 10 to 1000 microns) with an application tool such as a doctor blade, and then drying the solution to form a film. Achieved. The film thus formed may be dried at room temperature or under heating and cut into a desired surface area.

A preferred intraoral quick disintegrating agent comprises a network of the compound (I) or a concomitant drug of the present invention and a water-soluble or water-diffusible carrier that is inactive with the compound (I) or the concomitant drug of the present invention. Examples include solid rapid diffusion dosage agents. The network is obtained by sublimating a solvent from the solid composition comprising the compound (I) of the present invention or a concomitant drug dissolved in an appropriate solvent.
The composition of the intraoral quick disintegrating agent preferably contains a matrix forming agent and a secondary component in addition to the compound (I) or the concomitant drug of the present invention.
Examples of the matrix forming agent include gelatins, dextrins, and animal or vegetable proteins such as soybean, wheat and psyllium seed protein; gum substances such as gum arabic, guar gum, agar and xanthan; polysaccharides Alginates; carboxymethylcelluloses; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; materials derived from gelatin-gum arabic complex and the like. Further, saccharides such as mannitol, dextrose, lactose, galactose and trehalose; cyclic saccharides such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicate; glycine, L-alanine, L-aspartic acid, L- Examples include amino acids having 2 to 12 carbon atoms such as glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine.
One or more of the matrix forming agents can be introduced into a solution or suspension before solidification. Such a matrix forming agent may be present in addition to the surfactant, or may be present with the surfactant excluded. In addition to forming the matrix, the matrix-forming agent can help maintain the diffusion state of the compound (I) of the present invention or the concomitant drug in the solution or suspension.
Secondary components such as preservatives, antioxidants, surfactants, thickeners, colorants, pH adjusters, flavoring agents, sweeteners or taste masking agents may be included in the composition. Suitable colorants include red, black and yellow iron oxides and FD & C dyes such as FD & C Blue 2 and FD & C Red 40 from Ellis and Everald. Suitable flavors include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavors and combinations thereof. Suitable pH adjusting agents include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid. Suitable sweeteners include aspartame, acesulfame K and thaumatin. Suitable taste masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbate materials, and microencapsulated apomorphine.

The preparation usually contains about 0.1 to about 50% by weight, preferably about 0.1 to about 30% by weight of the compound (I) of the present invention or a concomitant drug, preferably for about 1 minute to about 60 minutes. Is a preparation capable of dissolving 90% or more of the compound (I) of the present invention or the concomitant drug (in water) for about 1 minute to about 15 minutes, more preferably about 2 minutes to about 5 minutes (The above-mentioned sublingual tablets, buccals, etc.) or fast disintegrating agents in the oral cavity that disintegrate in the oral cavity within 1 to 60 seconds, preferably within 1 to 30 seconds, more preferably within 1 to 10 seconds Is preferred.
The content of the excipient in the whole preparation is about 10 to about 99% by weight, preferably about 30 to about 90% by weight. The content of β-cyclodextrin or β-cyclodextrin derivative in the whole preparation is 0 to about 30% by weight. The content of the lubricant in the whole preparation is about 0.01 to about 10% by weight, preferably about 1 to about 5% by weight. The content of the tonicity agent in the whole preparation is about 0.1 to about 90% by weight, preferably about 10 to about 70% by weight. The content of the hydrophilic carrier in the whole preparation is about 0.1 to about 50% by weight, preferably about 10 to about 30% by weight. The content of the water-dispersible polymer in the whole preparation is about 0.1 to about 30% by weight, preferably about 10 to about 25% by weight. The content of the stabilizer in the whole preparation is about 0.1 to about 10% by weight, preferably about 1 to about 5% by weight. The preparation may further contain additives such as colorants, sweeteners, preservatives and the like as necessary.

The amount of the concomitant drug can be set as long as side effects do not become a problem.
The dose of the concomitant drug of the present invention varies depending on the type of compound (I) of the present invention and the concomitant drug, age, weight, symptoms, dosage form, administration method, administration period, etc. About 60 kg) per person, usually about 0.01 to about 20 mg / kg, preferably about 0.01 to about 10 mg / kg, more preferably about 0, as the compound (I) of the present invention and the concomitant drug, respectively. .1 to about 2 mg / kg is administered intravenously in one to several divided doses per day. Of course, as described above, the dosage varies depending on various conditions. Therefore, a dosage smaller than the dosage may be sufficient, or the dosage may need to be administered beyond the range.
When administering the concomitant drug of the present invention, the compound (I) of the present invention and the concomitant drug may be administered at the same time, but after administering the concomitant drug first, the compound (I) of the present invention The compound (I) of the present invention may be administered first, followed by the concomitant drug. When administered at a time difference, the time difference varies depending on the active ingredient to be administered, dosage form, and administration method. For example, when administering the concomitant drug first, within 1 minute to 3 days after administering the concomitant drug, preferably The method of administering the compound (I) of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour is mentioned. When the compound (I) of the present invention is administered first, it is within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after the administration of the compound (I) of the present invention. And a method of administering a concomitant drug.

The sequence numbers in the sequence listing in the present specification indicate the following sequences.
[SEQ ID NO: 1]
The amino acid sequence of human-derived G protein-coupled receptor protein TGR23-1 (human TGR23-1) is shown.
[SEQ ID NO: 2]
The amino acid sequence of human-derived G protein-coupled receptor protein TGR23-2 (human TGR23-2) is shown.

Hereinafter, the present invention will be described more specifically with reference to Reference Examples, Examples, Formulation Examples and Experimental Examples, but the present invention is not limited thereto.
In the following Reference Examples and Examples, “%” means weight percent unless otherwise specified.
¹ H NMR spectrum was measured with a Bruker AVANCE DPX-300 (300 MHz) spectrometer using tetramethylsilane as an internal standard. All δ values are given in ppm.
Other abbreviations used in the text have the following meanings.
s: singlet
d: Doublet
t: triplet
q: quartet
m: multiplet
br: broad
J: coupling constant
Hz: Hertz
CDCl ₃ : Deuterated chloroform
DMSO-d ₆ : Dimethyl sulfoxide-d ₆
Room temperature usually indicates a range of about 10 ° C. to 35 ° C., but is not particularly limited.

Reference Example 1 3- (Hydroxydiphenylmethyl) -1-piperazinecarboxylic acid (1,1-dimethylethyl) ester
2-piperazinecarboxylic acid methyl ester dihydrochloride (20 g, 87 mmol) was suspended in tetrahydrofuran (300 mL), diisopropylethylamine (22 g, 0.17 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Subsequently, 2.0 M phenylmagnesium bromide tetrahydrofuran solution (260 mL, 0.52 mol) was added dropwise over 30 minutes, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was ice-cooled, water (400 mL) was added dropwise, and the mixture was stirred for 30 min under ice-cooling. To this was added ditert-butyl dicarbonate (13 g, 61 mmol) dropwise and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (9.7 g, yield 30%).
Amorphous.
¹ H NMR (CDCl ₃ ) δ1.39 (9H, s), 2.71-2.93 (4H, m), 3.63 (1H, d, J = 9.3 Hz), 3.75 (1H, d, J = 12.6 Hz), 3.98 (1H, m), 4.11 (1H, m), 7.14-7.36 (6H, m), 7.50 (2H, d, J = 7.4 Hz), 7.60 (2H, d, J = 7.4 Hz).
Reference Example 2 Hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine- Trifluoroacetic acid (4 mL) was added to a solution of 7 (1H) -carboxylic acid (1,1-dimethylethyl) ester (2.3 g, 5.5 mmol) in dichloromethane (20 mL), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to give the title compound (1.6 g, yield 99%).
Melting point 188-191 ° C (decomposition).
¹ H NMR (DMSO-d ₆ ) δ2.09 (1H, t, J = 12.0 Hz), 2.96 (1H, dt, J = 12.3 Hz, 4.1 Hz), 3.12 (1H, dd, J = 12.0 Hz, 3.1 Hz), 3.21-3.33 (2H, m), 3.81 (1H, dd, J = 14.1 Hz, 3.7 Hz), 4.81 (1H, m), 7.31-7.55 (10H, m), 8.84 (1H, br s) .

Reference Example 3 1,4-Bis (phenylmethyl) -2-piperazinecarboxylic acid ethyl ester
1,4-Bis (phenylmethyl) -2-piperazinecarboxylic acid ethyl ester dihydrochloride (21 g, 52 mmol) was neutralized with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (18 g, quantitative). This was used in the next reaction without further purification.
Oily.
Reference Example 4 2- (1-hydroxy-1-methylethyl) -1,4-piperazinedicarboxylic acid bis (phenylmethyl) ester
A solution of 1,4-bis (phenylmethyl) -2-piperazinecarboxylic acid ethyl ester (2.0 g, 5.9 mmol) in tetrahydrofuran (30 mL) under ice-cooling, 1 M methylmagnesium bromide tetrahydrofuran solution (24 mL, 24 mmol) Was added dropwise over 5 minutes, and the mixture was stirred for 30 minutes under ice-cooling. After further stirring at room temperature overnight, saturated aqueous ammonium chloride solution (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethanol / water (30 mL / 10 mL), 10% palladium carbon (0.20 g) was added, and the mixture was stirred overnight at room temperature under hydrogen pressure (2.8 atm). The reaction solution was filtered through celite, and the celite was washed with ethanol, and then the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (50 mL), 0.5 M aqueous sodium hydrogen carbonate solution (100 mL) and chlorocarbonic acid benzyl ester (3.4 mL, 24 mmol) were added, and the mixture was stirred at room temperature for 6 hr. The reaction solution was extracted with ethyl acetate (200 mL), and the extract was washed with water. This was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 1: 1) to give the title compound (1.8 g, yield 73%). Got.
Oily.
¹ H NMR (CDCl ₃ ) δ1.10-1.29 (6H, m), 3.00-3.18 (1H, m), 3.40-3.52 (2H, m), 3.86-4.16 (4H, m), 5.08-5.20 (4H m), 7.28-7.39 (10H, m).

Reference Example 5 Hexahydro-1,1-dimethyl-3H-oxazolo [3,4-a] pyrazin-3-one Tetrahydro-3-oxo-1,1-dimethyl-3H-oxazolo [3,4-a] pyrazine- 7 (1H) -carboxylic acid (phenylmethyl) ester (0.97 g, 3.2 mmol) was dissolved in ethanol (50 mL), 10% palladium carbon (0.10 g) was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The reaction solution was filtered through celite, and the celite was washed with ethanol. The filtrate was concentrated under reduced pressure and allowed to stand overnight at room temperature. The resulting crystals were collected by filtration and washed with diethyl ether to give the title compound (0.39 g, yield 73%).
Melting point 92-93 ° C.
¹ H NMR (DMSO-d ₆ ) δ1.22 (3H, s), 1.35 (3H, s), 2.31-2.41 (2H, m), 2.78-2.90 (3H,
m), 3.18-3.60 (2H, m).
Reference Example 6 1,4-bis (phenylmethyl) -α, α-dicyclopropyl-2-piperazinemethanol
To a solution of 1,4-bis (phenylmethyl) -2-piperazinecarboxylic acid ethyl ester (5.0 g, 15 mmol) in tetrahydrofuran (70 mL) under ice-cooling, 0.5 M cyclopropylmagnesium bromide tetrahydrofuran solution (100 mL, 50 mmol) ) Was added dropwise over 20 minutes, and the mixture was stirred for 30 minutes under ice-cooling. After further stirring at room temperature overnight, saturated aqueous ammonium chloride solution (300 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1) to give the title compound (1.3 g, yield 24%).
Oily.
¹ H NMR (CDCl ₃ ) δ-0.11-0.00 (2H, m), 0.13-0.21 (1H, m), 0.29-0.41 (5H, m), 0.63-0.74 (1H, m), 1.12-1.20 (1H , m), 2.34-2.61 (5H, m), 3.34-3.41 (3H, m), 3.60-3.72
(1H, m), 3.99-4.12 (2H, m), 5.79 (1H, br s), 7.23-7.39 (10H, m).

Reference Example 7 2- (Dicyclopropylhydroxymethyl) -1,4-piperazinedicarboxylic acid bis (phenylmethyl) ester
1,4-bis (phenylmethyl) -α, α-dicyclopropyl-2-piperazinemethanol (1.2 g, 3.1 mmol) was dissolved in ethanol / water (40 mL / 4 mL) and 10% palladium on carbon (0.12 g) was added, and the mixture was stirred overnight at room temperature under hydrogen pressure (3.6 atm). The reaction solution was filtered through celite, and the celite was washed with ethanol, and then the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (50 ml), 0.5 M aqueous sodium hydrogen carbonate solution (50 mL) and chlorocarbonic acid benzyl ester (1.8 mL, 12 mmol) were added, and the mixture was stirred at room temperature for 4 hr. The reaction solution was extracted with ethyl acetate (100 mL), and the extract was washed with water. This was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 21: 1 to 4: 1) to give the title compound (1.4 g, quantitative) as an oil. Obtained as a thing.
Reference Example 8 Hexahydro-1,1-diphenyl-7- (phenylmethyl) -3H-oxazolo [3,4-a] pyrazin-3-one
4- (Phenylmethyl) -1-piperazinecarboxylic acid 1,1-dimethylethyl ester (20 g, 72
mmol) with tetramethylethylenediamine (18 g, 0.16 mol) in tetrahydrofuran (100
(mL) and cooled to -78 ° C. 1.0 M sec-butyllithium hexane and cyclohexane solution (150 mL, 0.15 mol) were added, the mixture was stirred for 2 hours, and the temperature was raised to −30 ° C. After cooling again to −78 ° C., a tetrahydrofuran solution (70 mL) of benzophenone (28 g, 0.15 mol) was added dropwise, and the mixture was stirred for 18 hours while warming to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (18 g, yield 64%) as crystals.
¹ H NMR (CDCl ₃ ) δ1.58 (1H, m), 1.94 (1H, dt, J = 11.7 Hz, 3.6 Hz), 2.55 (1H, dd, J = 11.4 Hz, 2.4 Hz), 2.69 (1H, dd, J = 11.7 Hz, 3.6 Hz), 3.10 (1H, dt, J = 13.0 Hz, 3.6 Hz), 3.32, 3.50 (2H, ABq, J = 13.1 Hz), 3.81 (1H, dd, J = 13.2 Hz) , 2.4 Hz), 4.54 (1H, dd, J = 11.0 Hz, 3.6 Hz), 7.18-7.40 (13H, m), 7.50 (2H, d, J = 7.2 Hz).

Reference Example 9 Hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one Hexahydro-1,1-diphenyl-7- (phenylmethyl) -3H-oxazolo [3,4-a ] To a solution of pyrazin-3-one (19 g, 48 mmol) in 1,2-dichloroethane (80 mL) was added 1-chloroethyl chloroformate (8.7 g, 61 mmol), and the mixture was stirred at 60 ° C for 3 hr. 1-Chloroethyl chloroformate (1.7 g, 12 mmol) was further added, and the mixture was stirred at 60 ° C. for 2 hr. The reaction solution was concentrated under reduced pressure, methanol was added, and the mixture was heated to reflux for 2.5 hours. After the reaction liquid was concentrated under reduced pressure, ethyl acetate-hexane was added for crystallization, and the precipitated crystals were collected by filtration. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to dissolve the crystals, and the organic layer was washed with water and concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the precipitated crystals were washed with diisopropyl ether and dried to give the title compound (13 g, yield 92%). ¹ H NMR of this compound was consistent with the compound obtained in Reference Example 2.
Reference Example 10 1,1-Dicyclohexyl-hexahydro-7- (triphenylmethyl) -3H-oxazolo [3,4-a] pyrazin-3-one
4- (Triphenylmethyl) -1-piperazinecarboxylic acid 1,1-dimethylethyl ester (1.0 g, 2.3 mmol) and tetramethylethylenediamine (1.0 g, 8.6 mmol) were dissolved in tetrahydrofuran (10 mL). Cooled to ° C. 1.0 M sec-butyllithium hexane and cyclohexane solution (7.2 mL, 7.2 mmol) were added and the mixture was stirred for 2 hours and warmed to -50 ° C. After cooling to −78 ° C. again, a solution of dicyclohexylketone (1.1 g, 5.9 mmol) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was stirred for 15 hours while warming to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to give the title compound (0.95 g, yield 74%).
¹ H NMR (CDCl ₃ ) δ0.86 (3H, m), 1.00-1.29 (10H, m), 1.40-1.60 (4H, m), 1.65 (1H, m), 1.76 (3H, m), 1.88 ( 3H, m), 2.99 (1H, m), 3.10 (1H, m), 3.23 (1H, dt, J = 12.3
Hz, 3.6 Hz), 3.67 (1H, dd, J = 12.2 Hz, 3.1 Hz), 4.06 (1H, dd, J = 11.1 Hz, 3.5 Hz), 7.16-7.20 (3H, m), 7.24-7.32 (6H , m), 7.49 (6H, m).

Reference Example 11 1,1-dicyclohexyl-hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one hexahydro-1,1-dicyclohexyl-7- (triphenylmethyl) -3H-oxazolo [3,4- To a tetrahydrofuran (5 mL) solution of a] pyrazin-3-one (0.92 g, 1.7 mmol), 4 M hydrogen chloride ethyl acetate solution (5 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was washed with diethyl ether. The aqueous layer was adjusted to pH 7 by adding sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The precipitated crystals were washed with hexane and dried to give the title compound (0.41 g, yield 80%). Melting point 151-152 ° C.
¹ H NMR (CDCl ₃ ) δ0.81-1.40 (10H, m), 1.48 (2H, m), 1.69-1.83 (8H, m), 1.96 (2H, m), 2.66 (1H, dt, J = 12.3 Hz, 2.4 Hz), 2.80-2.92 (3H, m), 3.01 (1H, m), 3.60 (1H,
dd, J = 9.2 Hz, 5.7 Hz), 3.74 (1H, dd, J = 12.6 Hz, 3.0 Hz).
Reference Example 12 1,1-bis (4-fluorophenyl) -hexahydro-7- (triphenylmethyl) -3H-oxazolo [3,4-a] pyrazin-3-one In the same manner as in Reference Example 10, dicyclohexyl was used. The title compound was obtained using 4,4′-difluorobenzophenone instead of ketone. Yield 67%.
¹ H NMR (CDCl ₃ ) δ0.72 (1H, t, J = 11.3 Hz), 1.37 (1H, dt, J = 11.9 Hz, 3.0 Hz), 2.77
(1H, m), 3.07 (1H, m), 3.37 (1H, dt, J = 12.4 Hz, 3.5 Hz), 3.79 (1H, m), 4.65 (1H, dd, J = 10.9 Hz, 3.3 Hz), 6.84 (2H, t, J = 8.6 Hz), 6.94-7.45 (21H, m).

Reference Example 13 1,1-bis (4-fluorophenyl) -hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one In the same manner as in Reference Example 11, 1,1-bis (4-fluoro The title compound was obtained from (phenyl) -hexahydro-7- (triphenylmethyl) -3H-oxazolo [3,4-a] pyrazin-3-one. Yield 72%.
¹ H NMR (CDCl ₃ ) δ2.08 (1H, t, J = 11.3 Hz), 2.61 (1H, dt, J = 12.0 Hz, 3.6 Hz), 2.68
(1H, dd, J = 12.0 Hz, 3.5 Hz), 2.92 (1H, dd, J = 12.0 Hz, 3.6 Hz), 3.10 (1H, dt, J = 12.2 Hz, 3.7 Hz), 3.84 (1H, dd, J = 13.1 Hz, 3.2 Hz), 4.35 (1H, dd, J = 11.0 Hz, 3.5
Hz), 6.99-7.22 (4H, m), 7.24 (2H, m), 7.47 (2H, m).
Reference Example 14 α, α, 1,4-Tetrakis (phenylmethyl) -2-piperazinemethanol
1,4-bis (phenylmethyl) -2-piperazinecarboxylic acid ethyl ester (8.2 g, 24 mmol) was dissolved in tetrahydrofuran (100 mL) under an argon atmosphere, and 1.0 M benzylmagnesium bromide tetrahydrofuran solution ( 100 mL, 0.10 mol) was added dropwise over 30 minutes. After stirring at room temperature for 14 hours, saturated aqueous ammonium chloride solution (300 mL) was added dropwise under ice cooling, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane to hexane: ethyl acetate = 5: 1) to give the title compound (5.1 g, yield 44%).
Oily.
¹ H NMR (CDCl ₃ ) δ2.35-2.48 (3H, m), 2.54-2.78 (6H, m), 3.23-3.37 (3H, m), 3.61-3.74 (2H, m), 3.92 (1H, d , J = 13.4 Hz), 6.48 (1H, br s), 7.03-7.33 (20H, m).

Reference Example 15 α, α-bis (phenylmethyl) -2-piperazinemethanol α, α, 1,4-tetrakis (phenylmethyl) -2-piperazinemethanol (4.9 g, 10 mmol) was added to ethanol / water (100 mL / 5%), 10% palladium carbon (0.49 g) was added, and the mixture was stirred at room temperature for a whole day under hydrogen pressure (3.0 atm). The reaction system was filtered through celite, and the celite was washed with ethanol, and then the filtrate was concentrated under reduced pressure. The resulting crystals were washed with diethyl ether to obtain the title compound (2.8 g, yield 91%).
Melting point 144-145 ° C.
¹ H NMR (CDCl ₃ ) δ2.55-2.89 (9H, m), 3.06 (1H, d, J = 13.6 Hz), 3.20 (1H, d, J = 12.5
Hz), 7.20-7.34 (10H, m).
Reference Example 16 2- [1-Hydroxy-2-phenyl-1- (phenylmethyl) ethyl] -1,4-piperazinedicarboxylic acid bis (1,1-dimethylethyl) ester α, α-bis (phenylmethyl)- 2-piperazinemethanol (2.7 g, 9.1 mmol) is dissolved in tetrahydrofuran (100 mL), 0.5 M aqueous sodium hydrogen carbonate solution (100 mL) is added, and di-t-butyl dicarbonate (5.9 g, 27 mmol) is added at room temperature. Was added dropwise and stirred overnight. The mixture was extracted with ethyl acetate, washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the resulting crystals were collected by filtration and washed with diisopropyl ether to give the title compound (4.1 g, yield 90%).
Melting point 150 ° C.
¹ H NMR (CDCl ₃ ) δ1.28-1.54 (18H, m), 2.75-2.79 (3H, m), 3.00-3.06 (2H, m), 3.25-3.35 (1H, m), 3.60-4.11 (5H , m), 7.21-7.33 (10H, m).

Reference Example 17 1,1-bis (phenylmethyl) -hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one
1,1-bis (phenylmethyl) -tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (
1H) -Carboxylic acid 1,1-dimethylethyl ester (1.3 g, 3.2 mmol) in dichloromethane (15
To the solution was added trifluoroacetic acid (4 mL) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, extracted with ethyl acetate, washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the residue, and the resulting crystals were collected by filtration and washed with diethyl ether to give the title compound (0.86 g, yield 85%).
Melting point 132-133 ° C.
¹ H NMR (CDCl ₃ ) δ2.58-2.97 (8H, m), 3.27 (1H, d, J = 16.7 Hz), 3.35-3.60 (2H, m), 7.14-7.40 (10H, m).
Reference Example 18 1,4-bis (phenylmethyl) -2-piperazinecarboxylic acid
Ethanol (300 mL) and 1 M aqueous sodium hydroxide (300 mL, 0.30 mmol) were added to 1,4-bis (phenylmethyl) -2-piperazinecarboxylic acid ethyl ester dihydrochloride (21 g, 52 mmol), The mixture was stirred at 80 ° C. for 3 hours. The reaction mixture was concentrated, and 1 M hydrochloric acid was added until the pH reached 5. Extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the resulting crystals, which were collected by filtration and washed with diethyl ether to give the title compound (12 g, yield 76%).
Melting point 184-185 ° C.
¹ H NMR (CDCl ₃ ) δ2.50-2.56 (2H, m), 2.62-2.78 (3H, m), 2.82-3.08 (2H, m), 3.40-3.56 (2H, m), 3.65 (2H, s ), 3.86-3.90 (1H, m), 7.26-7.37 (10H, m).

Reference Example 19 1,4-bis (phenylmethyl) -N-methoxy-N-methyl-2-piperazinecarboxamide
1,4-bis (phenylmethyl) -2-piperazinecarboxylic acid (5.0 g, 16 mmol) was dissolved in N, N-dimethylformamide (80 mL) and 1-ethyl-3- (3-dimethylaminopropyl) was dissolved. Carbodiimide hydrochloride (3.1 g, 16 mmol), 1-hydroxybenzotriazole (2.2 g, 16 mmol), N, O-dimethylhydroxylamine hydrochloride (1.9 g, 19 mmol) and triethylamine (2.7 mL, 19 mmol). The mixture was stirred at room temperature for 3 days. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Silica gel column chromatography of the residue (hexane: ethyl acetate = 2: 1 to 1: 1)
To give the title compound (5.0 g, yield 87%).
Oily.
¹ H NMR (CDCl ₃ ) δ2.32-2.79 (5H, m), 3.06-3.09 (1H, m), 3.18 (3H, s), 3.33-3.60 (7H, m), 3.87 (1H, d, J = 12.9 Hz), 7.19-7.34 (10H, m).
Reference Example 20 2-Benzoyl-1,4-bis (phenylmethyl) piperazine dihydrochloride
1,4-Bis (phenylmethyl) -N-methoxy-N-methyl-2-piperazinecarboxamide (2.9 g, 8.1 mmol) was dissolved in tetrahydrofuran (30 mL) under an argon atmosphere, and 1.0 M phenyl was added under ice cooling. Magnesium bromide tetrahydrofuran solution (24 mL, 24 mmol) was added dropwise over 30 minutes. The mixture was stirred at room temperature for 14 hours, saturated aqueous ammonium chloride solution (200 mL) was added dropwise under ice cooling, and the mixture was extracted with ethyl acetate (200 ml). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane to hexane: ethyl acetate = 2: 1). Fractions were collected and the concentrated residue was dissolved in ethyl acetate, 4N hydrogen chloride ethyl acetate solution (4 mL) was added, and the mixture was stirred at room temperature for 5 min. The resulting crystals were collected by filtration and washed with ethyl acetate to give the title compound (1.5
g, yield 51%).
Melting point 153-155 ° C.
¹ H NMR (DMSO-d ₆ ) δ 2.71-3.49 (7H, m), 4.20-4.44 (4H, m), 7.08-8.13 (15H, m).

Reference Example 21 2-Benzoyl-1,4-piperazinedicarboxylic acid bis (1,1-dimethylethyl) ester
2-Benzoyl-1,4-bis (phenylmethyl) piperazine dihydrochloride (7.1 g, 16 mmol) was suspended in ethanol / water (50 mL / 10 mL), 10% palladium carbon (0.50 g) was added, The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction system was filtered through celite, and the celite was washed with ethanol, and then the filtrate was concentrated under reduced pressure. Ethanol-ethyl acetate was added to the residue, and the resulting solid was collected by filtration. Tetrahydrofuran (200 mL) and 0.5 M aqueous sodium hydrogen carbonate solution (250 mL) were added to the obtained solid (4.2 g), and di-t-butyl dicarbonate (10.4 g, 47.7 mmol) was added dropwise at room temperature overnight. Stir. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 40: 1 to 7: 3) to give the title compound (1.2 g, yield 19%).
Amorphous.
¹ H NMR (CDCl ₃ ) δ1.13-1.56 (18H, m), 2.96-3.13 (3H, m), 4.00-4.16 (2H, m), 4.40-4.70 (2H, m), 7.26-7.32 (3H m), 7.47-7.88 (2H, m).
Reference Example 22 4-Nitro-1H-benzimidazole-1-carboxylic acid 1,1-dimethylethyl ester
Dinitroethylamine (1.2 mL, 6.8 mmol), di-t-butyl dicarbonate (1.6 mL, 6.8 mmol) and 4- (dimethylamino) in a solution of 4-nitrobenzimidazole (0.74 g, 4.5 mmol) in tetrahydrofuran (30 mL) Pyridine (5 mg) was added sequentially and the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the residue, and the resulting crystals were collected by filtration and washed with diethyl ether to give the title compound (1.0 g, yield 85%).
Melting point 249 ° C.
¹ H NMR (CDCl ₃ ) δ1.73 (9H, s), 7.53 (1H, t, J = 8.2 Hz), 8.20 (1H, dd, J = 0.81 Hz, 8.2 Hz), 8.39 (1H, dd, J = 0.81 Hz, 8.2 Hz), 8.61 (1H, s).

Reference Example 23 4-Amino-1H-benzimidazole-1-carboxylic acid 1,1-dimethylethyl ester
To a solution of 4-nitro-1H-benzimidazole-1-carboxylic acid 1,1-dimethylethyl ester (0.95 g, 3.6 mmol) in ethanol (20 mL) was added 10% palladium carbon (0.10 g), and the mixture was charged with a hydrogen atmosphere. The mixture was stirred at room temperature for 4 hours. The reaction solution was filtered through celite, and the celite was washed with ethanol. The back solution was concentrated under reduced pressure to obtain the title compound (0.84 g, quantitative).
Melting point 117 ° C.
¹ H NMR (CDCl ₃ ) δ1.69 (9H, s), 4.35 (2H, br s), 6.61 (1H, dd, J = 0.69 Hz, 7.7 Hz), 7.16 (1H, t, J = 7.9 Hz) , 7.32 (1H, dd, J = 0.63 Hz, 8.2 Hz), 8.29 (1H, s).
Reference Example 24 4- (Chloroacetyl) morpholine Morpholine (3.6 mL, 41 mmol) and triethylamine (5.2 g, 51 mmol) in tetrahydrofuran (100 mL) were added chloroacetyl chloride (3.0 mL, 38 mmol) at 0 ° C. And stirred at 0 ° C. for 20 minutes. The reaction mixture was concentrated and ethyl acetate was added. The extract was washed with water and saturated brine, and dried over magnesium sulfate. The solid was removed by filtration, and the filtrate was concentrated to give the title compound (4.0 g, yield 64%) as an oil.
¹ H NMR (CDCl ₃ ) δ 3.52-3.55 (2H, m), 3.62-3.65 (2H, m), 3.69-3.75 (4H, m), 4.07 (2H, s).

Reference Example 25 2,2,2-Trichloro-N- (5-quinolinyl) acetamide
To a solution of 5-aminoquinoline (1.0 g, 6.9 mmol) and triethylamine (1.0 mL, 7.2 mmol) in dichloromethane (40 mL) was added trichloroacetyl chloride (1.4 g, 7.7 mmol) at 0 ° C and stirred at room temperature for 90 minutes. . The reaction mixture was concentrated, ethyl acetate was added to the residue, and the mixture was extracted 3 times with 1N hydrochloric acid. The aqueous layers were combined and neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solid was removed by filtration and the filtrate was concentrated. The residue was washed with diisopropyl ether and collected by filtration to give the title compound (1.9 g, yield 94%) as colorless crystals.
Melting point 145-147 ° C.
¹ H NMR (CDCl ₃ ) δ7.49 (1H, dd, J = 4.2 Hz, 8.6 Hz), 7.75 (1H, t, J = 7.8 Hz), 7.85 (1H, d, J = 7.3 Hz), 8.09 ( 1H, d, J = 8.4 Hz), 8.18 (1H, d, J = 8.5 Hz), 8.76 (1H, br s), 8.97 (1H, dd, J = 1.5 Hz, 4.2 Hz).
Reference Example 26 2,2,2-Trichloro-N- (3-pyridinyl) acetamide
To a solution of 3-aminopyridine (1.0 g, 11 mmol) and triethylamine (1.3 g, 13 mmol) in tetrahydrofuran (30 mL) was added trichloroacetyl chloride (1.4 mL, 13 mmol) at 0 ° C, and the mixture was stirred at 0 ° C for 20 min. did. The reaction mixture was concentrated, ethyl acetate was added to the residue, washed with water and saturated brine, and dried over magnesium sulfate. The solid was removed by filtration and the filtrate was concentrated. The residue was washed with diisopropyl ether and collected by filtration to give the title compound (2.3 g, yield 89%) as a colorless powder.
Melting point 149-151 ° C.
¹ H NMR (CDCl ₃ ) δ 7.38 (1H, dd, J = 4.8 Hz, 8.3 Hz), 8.18 (1H, d, J = 8.3 Hz), 8.48 (1H, d, J = 4.8 Hz), 8.70 ( 1H, d, J = 2.2 Hz), 8.74 (1H, br s).

Reference Example 27 2,2,2-Trichloro-N- (4-pyridinyl) acetamide In the same manner as in Reference Example 26, 4-aminopyridine was used instead of 3-aminopyridine to give the title compound. Yield 94%.
Melting point 151-153 ° C.
¹ H NMR (CDCl ₃ ) δ 7.58-7.60 (2H, m), 8.60-8.62 (2H, m), 8.91 (1H, br s).
Reference Example 28 2,2,2-Trichloro-N- (isoquinolin-6-yl) acetamide In the same manner as in Reference Example 26, 6-aminoisoquinoline was used instead of 3-aminopyridine to give the title compound. Yield 80%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ7.62-7.69 (2H, m), 8.03 (1H, d, J = 8.8 Hz), 8.32 (1H, s), 8.56 (1H, d, J = 5.7 Hz), 8.62 (1H, br s), 9.24 (1H, s).

Reference Example 29 2,2,2-Trichloro-N- (isoquinolin-5-yl) acetamide In the same manner as in Reference Example 26, the title compound was obtained using 5-aminoisoquinoline instead of 3-aminopyridine. Yield 82%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ7.61-7.71 (2H, m), 7.95 (1H, d, J = 8.2 Hz), 8.15 (1H, d, J = 7.6 Hz), 8.62 (1H, d, J = 6.0 Hz), 8.88 (1H, br s), 9.31 (1H, s).
Reference Example 30 1,1-bis (4-methylphenyl) -hexahydro-7-[(4-methylphenyl) methyl] -3H-oxazolo [3,4-a] pyrazin-3-one Similar to Reference Example 37 According to the method, the title compound was obtained using 4,4′-dimethylbenzophenone instead of benzophenone. Yield 86%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ1.58 (1H, t, J = 11.2 Hz), 1.84-1.93 (1H, m), 2.32 (3H, s), 2.326
(3H, s), 2.332 (3H, s), 2.55 (1H, dd, J = 2.6 Hz, 11.3 Hz), 2.64-2.69 (1H, m), 3.01-3.11 (1H, m), 3.24 (1H, d, J = 13.0 Hz), 3.49 (1H, d, J = 13.0 Hz), 3.78 (1H, dd,
J = 2.6 Hz, 14.0 Hz), 4.49 (1H, dd, J = 3.5 Hz, 10.9 Hz), 7.08-7.11 (6H, m), 7.16 (4H, d, J = 8.1 Hz), 7.38 (2H, d , J = 8.2 Hz).

Reference Example 31 1,1-bis (4-methylphenyl) -hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one Hexahydro-7-[(4-methyl Instead of (phenyl) methyl] -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one, 1,1-bis (4-methylphenyl) -hexahydro-7-[(4- The title compound was obtained using methylphenyl) methyl] -3H-oxazolo [3,4-a] pyrazin-3-one. Yield 79%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.09 (1H, t, J = 11.6 Hz), 2.30 (3H, s), 2.33 (3H, s), 2.55-2.65 (1H, m), 2.72 (1H, dd, J = 3.5 Hz, 11.9 Hz), 2.90 (1H, dd, J = 3.6 Hz, 12.0 Hz), 3.01-3.11 (1H, m), 3.82 (1H, d, J = 10.0 Hz), 4.36 (1H, dd , J = 3.6 Hz, 11.0 Hz), 7.09-7.19 (6H, m), 7.37-7.39 (2H, m).
Reference Example 32 N-cyclopropyl-2-nitrobenzenesulfonamide 2-nitrobenzenesulfonyl chloride (3.9 g) in a solution of cyclopropylamine (1.0 g, 18 mmol) and triethylamine (3.7 mL, 27 mmol) in tetrahydrofuran (20 mL) at 0 ° C. g, 18 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and concentrated. The residue was washed with hexane and collected by filtration to give the title compound (3.7 g, 87%).
¹ H NMR (CDCl ₃ ) δ0.65-0.76 (4H, m), 2.32-2.39 (1H, m), 5.59 (1H, br s), 7.75-7.80 (2H, m), 7.85-7.88 (1H, m), 8.20-8.23 (1H, m).

Reference Example 33 N- (2-aminoethyl) -N-cyclopropyl-2-nitrobenzenesulfonamide In the same manner as in Reference Example 52, instead of N- (cyclopropylmethyl) -2-nitrobenzenesulfonamide, N-cyclo The title compound was obtained using propyl-2-nitrobenzenesulfonamide. Yield 73%.
Oily.
¹ H NMR (CDCl ₃ ) δ0.63-0.72 (4H, m), 1.37 (2H, br s), 2.47-2.54 (1H, m), 2.96 (2H, t, J = 6.4 Hz), 3.41 (2H , t, J = 6.4 Hz), 7.61-7.73 (3H, m), 8.13-8.16 (1H, m).
Reference Example 34 N-allyl-2-nitrobenzenesulfonamide In the same manner as in Reference Example 32, the title compound was obtained as pale brown crystals using allylamine instead of cyclopropylamine. Yield 85%.
¹ H NMR (CDCl ₃ ) δ3.75-3.80 (2H, m), 5.11 (1H, dd, J = 1.2 Hz, 10.3 Hz), 5.18-5.24 (1H, m), 5.40 (1H, br s), 5.68-5.79 (1H, m), 7.72-7.78 (2H, m), 7.85-7.89 (1H, m), 8.12-8.15 (1H, m).

Reference Example 35 N-allyl-N- (2-aminoethyl) -2-nitrobenzenesulfonamide In the same manner as in Reference Example 52, instead of N- (cyclopropylmethyl) -2-nitrobenzenesulfonamide, N-allyl- The title compound was obtained using 2-nitrobenzenesulfonamide using 1,1 ′-(azodicarbonyl) dipiperidine instead of diethyl azodicarboxylate. Yield 41%.
Oily.
¹ H NMR (CDCl ₃ ) δ2.85 (2H, t, J = 6.5 Hz), 3.36 (2H, t, J = 6.5 Hz), 3.96 (2H, d, J = 6.4 Hz), 5.17-5.27 (2H , m), 5.66-5.75 (1H, m), 7.62-7.72 (3H, m), 8.05-8.08 (1H,
m).
Reference Example 36 4-[(4-Methylphenyl) methyl] -1-piperazinecarboxylic acid 1,1-dimethylethyl ester Piperazine (170 g, 2.0 mol) was suspended in toluene (800 mL) and heated to 85 ° C. The solution was stirred for 10 minutes to dissolve. 4-Methylbenzyl chloride (53 mL, 0.4 mol) was added to this solution, and the mixture was stirred at 85 ° C. for 2 hours and then allowed to cool to 50 ° C. 1N aqueous sodium hydroxide solution (440 mL) and ethyl acetate (100 mL) were added to carry out a liquid separation operation. The obtained organic layer was washed with 1N aqueous sodium hydroxide solution (400 mL), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in tetrahydrofuran (420 mL) and triethylamine (84 mL, 0.6 mL).
mol) was added and cooled on ice. T-Butyl dicarbonate (97 mL, 0.42 mol) was added, and the mixture was stirred overnight while warming to room temperature. The solvent was distilled off under reduced pressure, and 4N aqueous sodium hydroxide solution (200 mL) and ethyl acetate (300 mL) were added to carry out a liquid separation operation. The obtained organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution (400 mL), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. A small amount of hexane was added to the residue, and the mixture was ice-cooled. The resulting crystals were collected by filtration and washed with ice-cold hexane to obtain the title compound (70 g, yield 60%). After concentrating the mother liquor under reduced pressure, the residue was purified by silica gel column chromatography (hexane to hexane: ethyl acetate = 3: 1), and the resulting oil was allowed to stand at room temperature. The resulting crystals were collected by filtration and washed with ice-cold hexane to obtain the title compound (22 g, yield 19%).
Melting point 61-62 ° C.
¹ H NMR (CDCl ₃ ) δ 1.47 (9H, s), 2.34-2.38 (7H, m), 3.41-3.48 (6H, m), 7.12-7.27 (4H, m).

Reference Example 37 Hexahydro-7-[(4-methylphenyl) methyl] -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one
4-[(4-Methylphenyl) methyl] -1-piperazinecarboxylic acid 1,1-dimethylethyl ester
(58 g, 0.2 mol) and N, N, N ′, N′-tetramethylethylenediamine (35 g, 0.3 mol) were dissolved in tetrahydrofuran (400 mL) and cooled to −78 ° C. under an argon atmosphere. 1.0 M sec-butyllithium hexane and cyclohexane solution (240 mL, 0.24 mol) were added dropwise over 1.5 hours, and the mixture was stirred at -78 ° C for 3 hours and then heated to -30 ° C over 2 hours. After cooling to -78 ° C again, a solution of benzophenone (55 g, 0.3 mol) in tetrahydrofuran (200
mL) was added dropwise over 1 hour and stirred overnight while warming to room temperature. The mixture was ice-cooled, saturated aqueous ammonium chloride solution (300 mL) was added, and the mixture was stirred for 30 min under ice-cooling. Ethyl acetate (300 mL) was added to carry out a liquid separation operation. The obtained organic layer was washed with water (500 mL), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether-hexane (3: 1, v / v, 300 mL) was added to the residue, and the resulting crystals were collected by filtration and washed with diisopropyl ether-hexane (3: 1, v / v) to give the title compound (66 g, yield 82%).
Melting point 154-155 ° C.
¹ H NMR (CDCl ₃ ) δ1.55-1.60 (1H, m), 1.85-1.95 (1H, m), 2.33 (3H, s), 2.52-2.58 (1H, m), 2.66-2.71 (1H, m ), 3.05-3.13 (1H, m), 3.26 (1H, d, J = 13.0 Hz), 3.47 (1H,
d, J = 13.0 Hz), 3.79 (1H, dd, J = 2.5 Hz, 13.2 Hz), 4.53 (1H, dd, J = 3.5 Hz, 11.0 Hz), 7.06-7.10 (4H, m), 7.26-7.37 (8H, m), 7.50-7.53 (2H, m).
Reference Example 38 Hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one hexahydro-7-[(4-methylphenyl) methyl] -1,1-diphenyl-3H-oxazolo [ 3,4-a] pyrazin-3-one (65 g, 0.16 mol) was dissolved in 1,2-dichloroethane (300 mL), and 1-chloroethyl chloroformate (22 mL, 0.2 mol) was added and heated. And refluxed for 3 hours. The solvent was distilled off under reduced pressure, methanol (300 mL) was added and the mixture was heated and refluxed for 3 hours. The solvent was distilled off under reduced pressure, and ethyl acetate (500 mL) was added to the residue to form a powder. The resulting powder was collected by filtration, washed with ethyl acetate and dried under reduced pressure. To the obtained powder (54 g), a saturated aqueous sodium hydrogen carbonate solution (500 mL) and ethyl acetate (500 mL) were added for liquid separation operation. The obtained organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution (400 mL), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from diethyl ether, and the obtained crystals (42 g) were further recrystallized from ethyl acetate to obtain the title compound (38 g, yield 78%). ¹ H NMR of this compound was consistent with the compound obtained in Reference Example 2.

Reference Example 39 N- [2- (3,6-Dihydropyridin-1 (2H) -yl) ethyl] carbamic acid 1,1-dimethylethyl ester
N- (2-oxoethyl) carbamic acid 1,1-dimethylethyl ester (2.0 g, 13 mmol) was added to N, N-dimethylformamide (50 mL), tetrahydrofuran (50 mL), 1,2,3,6-tetrahydro Pyridine (1.2 mL, 13 mmol) and sodium triacetoxyborohydride (5.3 g, 25 mmol) were added, and the mixture was stirred at room temperature for 14 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 8: 2) and then further amino silica gel column chromatography (hexane:
Purification with ethyl acetate = 9: 1 to ethyl acetate) gave the title compound (1.2 g, yield 41%).
Oily.
¹ H NMR (CDCl ₃ ) δ1.45 (9H, s), 2.02-2.05 (2H, m), 2.50-2.58 (4H, m), 2.94-2.97 (2H, m), 3.23-3.27 (2H, m ), 5.04 (1H, br), 5.64-5.74 (2H, m).
Reference Example 40 N- [2- (3,6-dihydropyridin-1 (2H) -yl) ethyl] -N-methylamine
80% lithium aluminum hydride (0.36 g, 7.5 mmol) in tetrahydrofuran (10 mL)
And a solution of N- [2- (3,6-dihydropyridin-1 (2H) -yl) ethyl] carbamic acid 1,1-dimethylethyl ester (0.68 g, 3.0 mmol) in tetrahydrofuran (10 mL) at room temperature. Bottom 10
After dropwise addition over a period of 3 minutes, the mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature, and 1N aqueous sodium hydroxide solution (20 mL) was added in small portions. The insoluble material was removed by filtration through celite and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure, and the residue was purified by amino silica gel column chromatography (hexane: ethyl acetate = 19: 1 to ethyl acetate) to give the title compound (0.18 g, yield 42%).
Oily.
¹ H NMR (CDCl ₃ ) δ2.17 (2H, s), 2.44 (3H, s), 2.56 (4H, s), 2.69-2.73 (2H, m), 2.96-2.98 (2H, m), 5.67- 5.73 (2H, m).

Reference Example 41 N- [2- (3,6-dihydropyridin-1 (2H) -yl) -1,1-dimethylethyl] carbamic acid 1,1-dimethylethyl ester In the same manner as in Reference Example 39, (2 The title compound was obtained by using (1,1-dimethyl-2-oxoethyl) carbamic acid 1,1-dimethylethyl ester instead of -oxoethyl) carbamic acid 1,1-dimethylethyl ester. Yield 14%.
Oily.
¹ H NMR (CDCl ₃ ) δ1.27 (6H, s), 1.43 (9H, s), 2.12-2.16 (2H, m), 2.50 (2H, s), 2.66 (2H, t, J = 5.6 Hz) , 3.07-3.10 (2H, m), 4.94 (1H, br), 5.65-5.77 (2H, m).
Reference Example 42 N- [2- (3,6-dihydropyridin-1 (2H) -yl) -1,1-dimethylethyl] amine dihydrochloride 4-[[(tetrahydro- 3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] amino] -1H-benzimidazole-1-carboxylic acid 1,1-dimethylethyl ester The title compound was obtained using N- [2- (3,6-dihydropyridin-1 (2H) -yl) -1,1-dimethylethyl] carbamic acid 1,1-dimethylethyl ester instead of. Yield 94%.
Melting point 228-229 ° C.
¹ H NMR (DMSO-d ₆ ) δ1.46 (6H, s), 2.27-2.37 (1H, m), 2.50-2.72 (1H, m), 3.28-3.52
(4H, m), 3.70-3.97 (2H, m), 5.68-5.72 (1H, m), 5.89-5.92 (1H, m), 8.76 (3H, br).

Reference Example 43 N- [2- (3,6-dihydropyridin-1 (2H) -yl) -2,2-dimethylethyl] carbamic acid 1,1-dimethylethyl ester
A solution of acetone cyanohydrin (1.1 mL, 12 mmol) and 1,2,3,6-tetrahydropyridine (1.1 mL, 12 mmol) in toluene (60 mL) was refluxed for 24 hours while dehydrating using a Dean-Stark apparatus. . The reaction mixture was concentrated under reduced pressure, and the resulting residue (0.72 g) was diluted with diethyl ether (20 mL).
The solution was added dropwise to a suspension of 80% lithium aluminum hydride (0.27 g, 7.2 mmol) in diethyl ether (20 mL) under ice-cooling and stirred at room temperature for 14 hours. Water (10 mL) was added little by little, and insoluble matters were removed by Celite filtration and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (50 mL), triethylamine (0.84 mL, 6.0 mmol) and ditert-butyl dicarbonate (1.0 g, 4.7 mmol) were added, and the mixture was stirred at room temperature for 14 hr. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 to ethyl acetate) to give the title compound (0.74 g, yield 24%
)
Oily.
¹ H NMR (CDCl ₃ ) δ1.04 (6H, s), 1.45 (9H, s), 2.08-2.12 (2H, m), 2.50-2.56 (2H, m), 3.05-3.10 (4H, m), 5.13 (1H, br), 5.68-5.76 (2H, m).
Reference Example 44 N- [2- (3,6-dihydropyridin-1 (2H) -yl) -2,2-dimethylethyl] amine dihydrochloride 4-[[(tetrahydro- 3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] amino] -1H-benzimidazole-1-carboxylic acid 1,1-dimethylethyl ester The title compound was obtained using N- [2- (3,6-dihydropyridin-1 (2H) -yl) -2,2-dimethylethyl] carbamic acid 1,1-dimethylethyl ester instead of. Yield 95%.
Melting point 246-247 ° C.
¹ H NMR (DMSO-d ₆ ) δ1.43 (6H, s), 2.27-2.31 (1H, m), 2.58-2.73 (1H, m), 2.92-2.98
(1H, m), 3.28-3.31 (2H, m), 3.70-3.74 (3H, m), 5.70-5.74 (1H, m), 5.88-5.91 (1H, m), 8.47 (3H, br).

Reference Example 45 N- [1-[(3,6-Dihydropyridin-1 (2H) -yl) methyl] cyclopropyl] carbamic acid 1,1-dimethylethyl ester In the same manner as in Reference Example 39, (2-oxoethyl ) [(1-Oxomethyl) cyclopropyl] carbamic acid 1,1-dimethylethyl ester was used instead of carbamic acid 1,1-dimethylethyl ester to give the title compound. Yield 92%.
Oily.
¹ H NMR (CDCl ₃ ) δ0.60-0.64 (2H, m), 0.84-0.88 (2H, m), 1.43 (9H, s), 2.14-2.17 (2H, m), 2.51 (2H, s), 2.64 (2H, t, J = 5.7 Hz), 3.01-3.05 (2H, m), 5.01 (1H, br), 5.63-5.68 (1H, m), 5.72-5.77 (1H, m).
Reference Example 46 N- [1-[(3,6-Dihydropyridin-1 (2H) -yl) methyl] cyclopropyl] amine dihydrochloride 4-[[(tetrahydro-3- Oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] amino] -1H-benzimidazole-1-carboxylic acid instead of 1,1-dimethylethyl ester The title compound was obtained using N- [1-[(3,6-dihydropyridin-1 (2H) -yl) methyl] -cyclopropyl] carbamic acid 1,1-dimethylethyl ester. Yield 80%.
Melting point 204-205 ° C.
¹ H NMR (DMSO-d ₆ ) δ1.05 (2H, s), 1.19 (2H, s), 2.27-4.02 (8H, m), 5.69-5.74 (1H,
m), 5.90-5.94 (1H, m), 8.89 (3H, br).

Reference Example 47 1,1-bis (3-fluorophenyl) -hexahydro-7-[(4-methylphenyl) methyl] -3H-oxazolo [3,4-a] pyrazin-3-one Similar to Reference Example 37 Using the method, the title compound was obtained using 3,3′-difluorobenzophenone instead of benzophenone. Yield 59%.
Melting point 144-145 ° C.
¹ H NMR (CDCl ₃ ) δ1.53-1.61 (1H, m), 1.92 (1H, dt, J = 3.7 Hz, 11.8 Hz), 2.34 (3H, s), 2.54 (1H, dd, J = 3.4 Hz , 11.3 Hz), 2.69 (1H, dd, J = 3.6 Hz, 11.6 Hz), 3.08 (1H, dt, J = 3.7 Hz, 12.1 Hz), 3.29 (1H, d, J = 13.0 Hz), 3.48 (1H , d, J = 13.0 Hz), 3.78
(1H, dd, J = 2.6 Hz, 13.0 Hz), 4.46 (1H, dd, J = 3.5 Hz, 11.0 Hz), 7.01-7.10 (8H, m), 7.17-7.36 (4H, m).
Reference Example 48 1,1-bis (3-fluorophenyl) -hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one In the same manner as in Reference Example 38, hexahydro-7-[(4-methyl Instead of (phenyl) methyl] -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one, 1,1-bis (3-fluorophenyl) -hexahydro-7-[(4- The title compound was obtained using methylphenyl) methyl] -3H-oxazolo [3,4-a] pyrazin-3-one. Yield 75%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.12 (1H, t, J = 9.4 Hz), 2.59-2.67 (1H, m), 2.72-2.77 (1H, m), 2.90-2.95 (1H, m), 3.04- 3.14 (1H, m), 3.81-3.86 (1H, m), 4.35 (1H, dd, J = 3.4 Hz, 10.9 Hz), 6.96-7.07 (4H, m), 7.23-7.37 (4H, m).

Reference Example 49 (+)-Hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one Hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine- 3-one racemate (5.0
g) was fractionated under the following HPLC conditions.
HPLC preparative conditions
Column; CHIRALPAK AD 50 mmID × 500 mmL (Daicel Chemical Industries, Ltd.)
Mobile phase; hexane / ethanol = 50/50
Flow rate; 60 mL / min
Temperature; 30 ℃
Detection; UV 220 nm
Load; 4.5 g
Each fraction was concentrated under reduced pressure, and hexane / ethanol was added to give the title compound (2.3 g, yield 46%, 99.9% ee) as a powder as an enantiomer with a long retention time. ¹ H NMR of this compound was consistent with the compound obtained in Reference Example 2.
[α] ²⁰ _D + 272.9 ° (c 0.971, chloroform).
Reference Example 50 (-)-Hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one When Reference Example 49 was performed, the title compound (2.1 g, Yield 43%, 99.9% ee) was obtained as a powder. ¹ H NMR of this compound was consistent with the compound obtained in Reference Example 2.
[α] ²⁰ _D -273.1 ° (c 0.998, chloroform).

Reference Example 51 A solution of N- (cyclopropylmethyl) -2-nitrobenzenesulfonamide cyclopropylmethylamine (0.5 g, 7.0 mmol) and triethylamine (1.5 mL, 11 mmol) in tetrahydrofuran (30 mL) under ice-cooling (2 -Nitrobenzene) sulfonyl chloride (1.7 g, 7.0 mmol) was added, and the mixture was stirred for 16 hours under ice cooling. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water, 1N hydrochloric acid, and 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 49: 1 to hexane: ethyl acetate = 1: 1) to give the title compound (1.7 g, yield 92%).
Amorphous.
¹ H NMR (CDCl ₃ ) δ0.14-0.15 (2H, m), 0.48 (2H, dd, J = 6.0 Hz, 13.8 Hz), 0.88-0.94 (1H, m), 2.98 (2H, t, J = 6.0 Hz), 5.39 (1H, br), 7.72-7.75 (2H, m), 7.86-7.89 (1H, m), 8.13-8.16 (1H, m).
Reference Example 52 N- (2-aminoethyl) -N- (cyclopropylmethyl) -2-nitrobenzenesulfonamide
N- (cyclopropylmethyl) -2-nitrobenzenesulfonamide (1.7 g, 6.4 mmol), t-butyl N- (2-hydroxyethyl) carbamate (1.3 g, 8.3 mmol), triphenylphosphine (2.2 g, 8.3 mmol) mmol) in toluene (20 mL) was added 40% azodicarboxylic acid diethyltoluene solution (3.6 g, 8.3 mmol) under ice cooling and stirred at room temperature for 16 hours. The reaction mixture was concentrated to half volume under reduced pressure, diethyl ether (30 mL) was added, the precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 49: 1 to hexane: ethyl acetate = 1: 1) to obtain a condensed compound as an oil. 4M Hydrogen chloride ethyl acetate solution (20 mL) was added, and the mixture was stirred at room temperature for 30 min. Water (70 mL) was added to the reaction solution and extracted. The aqueous layer was separated and washed with ethyl acetate. The aqueous layer was made basic (pH = 12) using 4N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Amino silica gel column chromatography of the residue
Purification by (hexane: ethyl acetate = 19: 1 to ethyl acetate) gave the title compound (1.2 g, 62% yield).
Oily.
¹ H NMR (CDCl ₃ ) δ0.18-0.23 (2H, m), 0.51-0.57 (2H, m), 0.88-1.02 (1H, m), 2.92 (2H, t, J = 6.3 Hz), 3.18- 3.20 (2H, m), 3.46 (2H, t, J = 6.3 Hz), 7.61-7.70 (3H, m), 8.05-8.08 (1H, m).

Reference Example 53 4- (Chloroacetyl) -3- [hydroxy (diphenyl) methyl] piperazine-1-carboxylic acid 1,1-dimethylethyl ester
To a solution of 3- [hydroxy (diphenyl) methyl] -1-piperazinecarboxylic acid 1,1-dimethylethyl ester (0.50 g, 1.4 mmol) in tetrahydrofuran (5 mL) under ice-cooling, diisopropylethylamine (2 mL), chloroacetyl Chloride (0.46 g, 4.1 mmol) was added in order, and the mixture was stirred while warming to room temperature over 4 hours. Ethyl acetate was added to the reaction mixture, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (0.28 g, yield 46%)
Got.
Oily.
Amide rotamer ratio (α: β = 1: 3.2).
¹ H NMR (CDCl ₃ ) δ1.34-1.38 (9H of α, 9H of β, m), 2.80-4.41 (8H of α, 8H of β, m), 4.52-4.55 (1H of β, m), 4.68-4.71 (1H of α, m), 7.15-7.60 (10H of α, 10H of β, m).
Reference Example 54 Hexahydro-4-oxo-1,1-diphenylpyrazino [2,1-c] [1,4] oxazine-8 (1H) -carboxylic acid 1,1-dimethylethyl ester
4- (Chloroacetyl) -3- [hydroxy (diphenyl) methyl] piperazine-1-carboxylic acid 1,1-dimethylethyl ester (0.28 g, 0.63 mmol) in tetrahydrofuran (5 mL) in 60% sodium hydride ( 40 mg, 1.0 mmol) was added and the mixture was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture, which was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (0.24 g, yield 93%).
Amorphous.
¹ H NMR (CDCl ₃ ) δ1.44 (9H, s), 2.81-2.88 (3H, m), 3.42 (1H, br), 3.73 (1H, d, J = 15.9 Hz), 4.08-4.16 (2H, m), 4.27 (2H, d, J = 16.9 Hz), 4.70-4.73 (1H, m), 7.19-7.41 (10H, m).

Reference Example 55 Piperazine-1,2,4-tricarboxylic acid 2-ethyl ester 1,4-bis (1,1-dimethylethyl) ester
Ethanol (150 mL), water (20 mL), 10% palladium on carbon (0.60 g) were added to 1,4-bis (phenylmethyl) -2-piperazinecarboxylic acid ethyl ester dihydrochloride (10 g, 24 mmol). The mixture was stirred for 7 hours at room temperature under hydrogen atmosphere. The reaction solution was filtered through celite, and the celite was washed with ethanol-water (4: 1), and then the filtrate was concentrated under reduced pressure. Tetrahydrofuran (300 mL), 0.5 M aqueous sodium hydrogen carbonate solution (300 mL) and ditert-butyl dicarbonate (18 g, 81 mmol) were added to the residue, and the mixture was stirred at room temperature for 16 hours. The mixture was extracted with ethyl acetate (500 mL), and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 to hexane: ethyl acetate = 1: 1) to obtain the title compound (8.8 g, quantitative).
Oily.
¹ H NMR (CDCl ₃ ) δ1.25-1.30 (3H, m), 1.44 (18H, s), 2.72-3.26 (3H, m), 3.71-4.22 (4H, m), 4.42-4.72 (2H, m ).
Reference Example 56 2- (Phenylmethyl) piperazine-1,2,4-tricarboxylic acid 2-ethyl ester 1
, 4-Bis (1,1-dimethylethyl) ester Piperazine-1,2,4-tricarboxylic acid 2-ethylester 1,4-bis (1,1-dimethylethyl) ester (4.4 g, 12 mmol) in tetrahydrofuran (120 mL) and N, N-dimethylformamide (12 mL) were added and dissolved, and the mixture was cooled to -78 ° C. 1M sodium bis (trimethylsilyl) amide tetrahydrofuran solution (19 mL, 19 mmol) was added, and the mixture was stirred at −78 ° C. for 1 hour, and then benzyl bromide (3.2 g, 19 mmol) was added. The mixture was stirred at -78 ° C for 30 minutes, then warmed to room temperature and stirred for 70 hours. To the reaction solution was added 0.5 M aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 to hexane: ethyl acetate = 7: 3) to give the title compound (4.9 g, yield 90%).
Oily.
¹ H NMR (CDCl ₃ ) δ1.23-1.29 (3H, m), 1.41-1.43 (9H, s), 1.51 (9H, s), 2.40-2.52 (1H, m), 2.93-3.06 (2H, m ), 3.28-3.52 (2H, m), 3.63-3.89 (2H, m), 4.02-4.18 (3H, m), 7.14-7.26 (5H, m).

Reference Example 57 2- (Hydroxymethyl) -2- (phenylmethyl) piperazine-1,4-dicarboxylic acid bis (1,1-dimethylethyl) ester
2- (Phenylmethyl) piperazine-1,2,4-tricarboxylic acid 2-ethyl ester 1,4-bis (1,1-dimethylethyl) ester (4.8 g, 11 mmol) was dissolved in tetrahydrofuran (50 mL). Under ice-cooling, 1M triethyl lithium borohydride tetrahydrofuran solution (24 mL, 24 mmol) was added, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added 0.5 M aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 to hexane: ethyl acetate = 1: 1) to obtain the title compound (3.7 g, yield 87%).
Oily.
¹ H NMR (CDCl ₃ ) δ1.46-1.53 (18H, m), 2.68-2.85 (2H, m), 3.10- 3.50 (4H, m), 3.52-3.60 (2H, m), 3.72-3.90 (3H , m), 7.17-7.31 (5H, m).
Reference Example 58 Tetrahydro-3-oxo-8a- (phenylmethyl) -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid 1,1-dimethylethyl ester
2- (Hydroxymethyl) -2- (phenylmethyl) piperazine-1,4-dicarboxylic acid bis (1,1-dimethylethyl) ester (3.6 g, 8.9 mmol) to N, N-dimethylformamide (40 mL) Dissolved, 60% sodium hydride (0.43 g, 11 mmol) was added and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added 0.5 M aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Diethyl ether was added to the residue, and the precipitated crystals were collected by filtration to give the title compound (2.6 g, yield 88%).
Melting point 188-190 ° C.
¹ H NMR (CDCl ₃ ) δ1.52 (9H, m), 2.75-3.07 (4H, m), 3.20-3.30 (1H, m), 3.72 (1H, d, J = 9.2 Hz), 3.81 (1H, dd, J = 3.5 Hz, 13.6 Hz), 4.10-4.30 (3H, m), 7.21-7.36 (5H,
m).

Reference Example 59 1,4-bis (phenylmethyl) -1,4-diazepan-2-carboxylic acid ethyl ester
1,3-propanediamine (50 g, 0.67 mol) was dissolved in ethanol (500 mL), benzaldehyde (140 g, 1.4 mol) was added under ice cooling, and the mixture was stirred at 70 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, methanol (1000 mL) and ethanol (500 mL) were added to the residue, and sodium borohydride (61 g, 1.6 mol) was added in portions over 1 hour under ice-cooling. After the mixture was stirred at room temperature overnight, the reaction mixture was concentrated under reduced pressure, water was added to the residue, extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. An oily matter (180 g) was obtained. Of these, toluene (1000 mL), triethylamine (76 g, 0.75 mol) and ethyl 2,3-dibromopropionate (43 mL) were added to 81 g, and the mixture was stirred at 70 ° C. overnight. The reaction mixture was cooled to room temperature, ethyl acetate was added, the mixture was washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 to hexane: ethyl acetate = 9: 1) to give the title compound (52 g, yield 49%).
Oily.
¹ H NMR (CDCl ₃ ) δ1.20 (3H, t, J = 7.1 Hz), 1.63-1.82 (2H, m), 2.60-2.82 (3H, m), 2.93-3.18 (2H, m), 3.22- 3.32 (1H, m), 3.55-3.59 (1H, m), 3.66-3.77 (2H, m), 3.80-3.93 (2H, m), 4.08-4.18 (2H, m), 7.21-7.39 (10H, m ).
Reference Example 60 2- [hydroxy (diphenyl) methyl] -1,4-diazepane-1,4-dicarboxylic acid bis (1,1-dimethylethyl) ester
1,4-bis (phenylmethyl) -1,4-diazepan-2-carboxylic acid ethyl ester (57 g, 0.16 mol) was dissolved in ethanol (300 mL), 10% palladium carbon (7.0 g) was added, The mixture was stirred at room temperature for 1 week under a hydrogen atmosphere of 3 atm. The reaction solution was filtered through celite, and the celite was washed with ethanol, and then the filtrate was concentrated under reduced pressure. Tetrahydrofuran (400 mL) was added to the residue, the precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to give an oil (26.6 g). Among them, 8.6 g was dissolved in tetrahydrofuran (250 mL), 1M phenylmagnesium bromide tetrahydrofuran solution (250 mL) was added dropwise over 1 hour, and the mixture was stirred at room temperature overnight. The reaction mixture was ice-cooled, water (500 mL) was added, and the mixture was stirred under ice-cooling for 1 hr. Di-tert-butyl dicarbonate (44 g, 0.2
mol) was added and the mixture was stirred overnight at room temperature. Ethyl acetate (500 mL) was added to the reaction mixture, and the mixture was washed with a saturated aqueous ammonium chloride solution (500 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 9: 1 to hexane: ethyl acetate = 8: 2) to give the title compound (1.4 g, yield 6%) as a crude product. Amorphous. This compound was used in the next reaction without further purification.

Reference Example 61 Tetrahydro-3-oxo-1,1-diphenyl-1H- [1,3] oxazolo [3,4-a] [1,4] diazepine-8 (5H) -carboxylic acid 1,1-dimethylethyl Esters 2- [Hydroxy (diphenyl) methyl] -1,4-diazepane-1,4-dicarboxylic acid bis (1,1-dimethylethyl) ester obtained in Reference Example 60 (crude product, 1.4 g, 2.8 mmol) ) Was added N, N-dimethylformamide (30 mL) and 60% sodium hydride (0.11 g, 2.8 mmol), and the mixture was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 to hexane: ethyl acetate = 1: 1) to give the title compound (0.44 g, yield 38%).
Oily.
¹ H NMR (CDCl ₃ ) δ1.55 (9H, s), 1.80-1.95 (1H, m), 2.13-2.34 (1H, m), 2.86-3.01 (2H, m), 3.12-3.18 (1H, m ), 3.78-4.03 (3H, m), 4.42-4.54 (1H, m), 7.26-7.61 (10H,
m).
Reference Example 62 Hexahydro-1,1-diphenyl-1H- [1,3] oxazolo [3,4-a] [1,4] diazepin-3-one tetrahydro-3-oxo-1,1-diphenyl-1H- [1,3] Oxazolo [3,4-a] [1,4] diazepine-8 (5H) -carboxylic acid 1,1-dimethylethyl ester (0.30 g, 0.73 mmol) dissolved in ethyl acetate (5 mL) 4M hydrogen chloride ethyl acetate solution (4 mL) was added and the mixture was stirred at room temperature for 1 hour. After concentration of the reaction mixture, ethyl acetate was added to the residue, washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.16 g, yield 70%). It was.
Oily.
¹ H NMR (CDCl ₃ ) δ1.80-1.99 (2H, m), 2.04 (1H, dd, J = 8.1 Hz, 14.1 Hz), 2.62-2.75 (1H, m), 2.81 (1H, dd, J = 3.0 Hz, 14.1 Hz), 2.96-3.00 (1H, m), 3.36-3.39 (1H, m),
3.70-3.73 (1H, m), 4.56 (1H, dd, J = 3.0 Hz, 8.0 Hz), 7.24-7.51 (10H, m).

Reference Example 63 Octahydro-7,9-dioxo-6,6-diphenyl-2H-pyrazino [1,2-a] pyrazine
2-Carboxylic acid (phenylmethyl) ester Chloro (diphenyl) acetic acid (0.56 g, 2.3 mmol) is dissolved in acetonitrile (10 mL) and dicyclohexylcarbodiimide (0.41 g, 2.0 mmol), 1H-1,2,3-benzo Triazole-1-olate ammonium salt (0.30 g, 2.0 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. Dissolve the residue in ethyl acetate (20 mL) and add 0.5 M
The extract was washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in acetonitrile (10 mL), piperazine-1,3-dicarboxylate 3-ethyl 1-benzyl (0.58 g, 2.0 mmol), potassium carbonate (0.55 g, 4.0 mmol) was added, and the mixture was heated at 60 ° C. Stir overnight. After cooling to room temperature, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane to dichloromethane: methanol = 99: 1) and recrystallized from methanol to give the title compound (0.16 g, yield).
16%).
Melting point 151-152 ° C.
¹ H NMR (CDCl ₃ ) δ2.67-2.87 (2H, m), 2.97-3.07 (1H, m), 3.97 (1H, dd, J = 4.8 Hz, 10.8 Hz), 4.06-4.10 (1H, m) 4.18-4.31 (1H, m), 4.57-4.68 (1H, m), 5.16 (2H, s), 6.48 (1H, br), 7.26-7.40 (15H, m).
Reference Example 64 N-[(4-fluorophenyl) methyl] -hexahydro-4-oxo-1,1-diphenylpyrazino [2,1-c] [1,4] oxazine-8 (1H) -carboxamide hexahydro- 4-oxo-1,1-diphenylpyrazino [2,1-c] [1,4] oxazine-8 (1H) -carboxylic acid 1,1-dimethylethyl ester (0.11 g, 0.26 mmol) to trifluoroacetic acid (2.0 mL) was added, and the mixture was stirred for 2 hours under ice cooling. The reaction mixture was concentrated under reduced pressure, neutralized with 0.5 M aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in toluene (2 mL), (4-fluorophenyl) methyl isocyanate (61 mg, 0.4 mmol) was added, and the mixture was stirred at 60 ° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to hexane: ethyl acetate = 1: 9), triturated with diisopropyl ether, and the title compound (90 mg, Yield 75%) was obtained.
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.87-2.98 (3H, m), 3.20-3.25 (1H, m), 3.76 (1H, d, J = 16.9 Hz), 3.90-3.94 (1H, m), 4.21- 4.37 (5H, m), 4.71-4.75 (1H, m), 6.96-7.02 (2H, m), 7.15-7.37 (12H, m).

Reference Example 65 Hexahydro-8a- (phenylmethyl) -3H-oxazolo [3,4-a] pyrazin-3-one tetrahydro-3-oxo-8a- (phenylmethyl) -3H-oxazolo [3,4-a] Dichloromethane (40 mL) and trifluoroacetic acid (9.7 g, 86 mmol) were added to pyrazine-7 (1H) -carboxylic acid 1,1-dimethylethyl ester (2.8 g, 8.6 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.74 g, yield 88%). Got.
Oily.
¹ H NMR (CDCl ₃ ) δ2.65-2.82 (2H, m), 3.01-3.14 (3H, m), 3.23-3.36 (2H, m), 3.70-3.79 (2H, m), 4.28 (1H, d , J = 8.8 Hz), 7.17-7.37 (5H, m).
Reference Example 66 N-[(4-Fluorophenyl) methyl] -tetrahydro-3-oxo-1,1-diphenyl-1H-oxazolo [3,4-a] [1,4] diazepine-8 (5H) -carboxamide Hexahydro-1,1-diphenyl-1H-oxazolo [3,4-a] [1,4] diazepin-3-one (60 mg, 0.2 mmol) in tetrahydrofuran (5 mL) and 4-fluorobenzyl isocyanate (59 mg, 0.39 mmol) was added, and the mixture was stirred at 50 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1 to hexane: ethyl acetate = 1: 4) and triturated with diethyl ether to give the title compound (73 mg, yield) 82%).
Amorphous.
¹ H NMR (CDCl ₃ ) δ1.97-2.05 (2H, m), 2.22-2.30 (1H, m), 2.91-2.99 (1H, m), 3.18-3.23 (1H, m), 3.46-3.50 (1H , m), 4.06-4.18 (2H, m), 4.35-4.52 (2H, m), 4.59-4.66 (2H, m), 6.99-7.04 (2H, m), 7.26-7.44 (10H, m), 7.64 -7.67 (2H, m).

Reference Example 67 Tetrahydro-3-oxo-1,1-diphenyl-1H-oxazolo [3,4-a] [1,4] diazepine-8 (5H) -carboxylic acid phenyl ester hexahydro-1,1-diphenyl-1H -Oxazolo [3,4-a] [1,4] diazepin-3-one (60 mg, 0.2 mmol) to tetrahydrofuran (5 mL), triethylamine (60 mg, 0.59 mmol), phenyl chlorocarbonate (69 mg, 0.44) mmol) was added and stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 to hexane: ethyl acetate = 3: 2) and triturated with diisopropyl ether to give the title compound (69 mg, yield 83%).
Amorphous.
¹ H NMR (CDCl ₃ ) δ1.95-2.13 (2H, m), 2.33-2.50 (1H, m), 3.04-3.23 (2H, m), 4.03-4.14 (3H, m), 4.63-4.72 (1H , m), 7.10-7.61 (15H, m).
Reference Example 68 Hexahydro-7- (2-oxo-2-phenylethyl) -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one hexahydro-1,1-diphenyl-3H-oxazolo Diisopropylethylamine (0.6 mL) and phenacyl bromide (0.10 g, 0.51 mmol) were added sequentially to a solution of [3,4-a] pyrazin-3-one (0.10 g, 0.34 mmol) in tetrahydrofuran (2 mL), and the mixture was Stir at room temperature for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and then pulverized by adding hexane to give the title compound (92 mg, yield 66%).
Amorphous.
¹ H NMR (CDCl ₃ ) δ1.73 (1H, t, J = 11.1 Hz), 2.20-2.27 (1H, m), 2.65 (1H, dd, J = 2.5
Hz, 11.2 Hz), 2.88 (1H, dd, J = 3.4 Hz, 11.4 Hz), 3.30 (1H, dt, J = 3.7 Hz, 12.0 Hz), 3.80 (2H, d, J = 6.5 Hz), 3.85- 3.90 (1H, m), 4.68 (1H, dd, J = 3.6 Hz, 11.0 Hz), 7.23-7.55 (13H, m), 7.88-7.90 (2H, m).

Reference Example 69 Hexahydro-1,1-diphenyl-7- [1- (phenylmethyl) -4-piperidinyl] -3H-oxazolo [3,4-a] pyrazin-3-one hexahydro-1,1-diphenyl-3H -Oxazolo [3,4-a] pyrazin-3-one (0.15 g, 0.51 mmol), acetic acid (0.045 mL, 0.79 mmol), 1-benzyl-4-piperidone (0.12 g, 0.63 mmol) in tetrahydrofuran (5 mL) ) Sodium triacetoxyborohydride (0.16 g, 0.75 mmol) was added to the solution and stirred at room temperature for 16 hours. 1-Benzyl-4-piperidone (0.060 mL) and sodium triacetoxyborohydride (0.16 g) were added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solid was removed by filtration. The filtrate was concentrated, and the residue was purified by column chromatography on amino silica gel (hexane: ethyl acetate = 98: 2 to hexane: ethyl acetate = 1: 1) and recrystallized from ethyl acetate-hexane to give the title compound (70
mg, yield 29%).
Melting point 153-155 ° C.
¹ H NMR (CDCl ₃ ) δ1.37-1.62 (4H, m), 1.73 (1H, t, J = 11.1 Hz), 1.83-1.92 (2H, m), 2.20-2.29 (2H, m), 2.45- 2.49 (1H, m), 2.70-2.74 (1H, m), 2.88 (2H, d, J = 11.3 Hz), 3.04-3.13 (1H, m), 3.44 (2H, s), 3.83 (1H, dd, J = 2.5 Hz, 13.0 Hz), 4.45 (1H, dd, J = 3.5 Hz, 10.8 Hz), 7.23-7.36 (13H, m), 7.49-7.52 (2H, m).
Reference Example 70 7- (Benzoxazol-2-yl) -hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one hexahydro-1,1-diphenyl-3H-oxazolo [3 , 4-a] pyrazin-3-one (60 mg, 0.2 mmol) in tetrahydrofuran (2 mL) and diisopropylethylamine (0.3 mL) and
2-Chlorobenzoxazole (45 mg, 0.29 mmol) was added sequentially and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) and recrystallized from diisopropyl ether to give the title compound.
(51 mg, 62% yield) was obtained.
Melting point 260 ° C.
¹ H NMR (CDCl ₃ ) δ2.56 (1H, t, J = 12.4 Hz), 3.09-3.25 (2H, m), 3.96-4.01 (1H, m), 4.10-4.15 (1H, m), 4.28 ( 1H, dd, J = 3.8 Hz, 13.0 Hz), 4.57 (1H, dd, J = 3.8 Hz, 11.3 Hz), 7.06-7.41 (12H, m), 7.53-7.56 (2H, m).

Reference Example 71 (Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) acetic acid phenyl ester hexahydro-1,1-diphenyl-3H-oxazolo [ 3,4-a] pyrazin-3-one (60 mg, 0.2 mmol) in tetrahydrofuran (2 mL) was added sequentially with diisopropylethylamine (0.3 mL) and phenyl bromoacetate (65 mg, 0.29 mmol), and the mixture was allowed to cool to room temperature. For 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) and recrystallized from diisopropyl ether to give the title compound (51 mg, yield 60%). .
Melting point 172 ° C.
¹ H NMR (CDCl ₃ ) δ1.86 (1H, t, J = 11.1 Hz), 2.34-2.42 (1H, m), 2.64-2.69 (1H, m), 2.87 (1H, dd, J = 3.7 Hz, 11.2 Hz), 3.22-3.29 (1H, m), 3.43 (2H, dd, J = 3.0 Hz), 3.88 (1H, dd, J = 2.6 Hz, 13.3 Hz), 4.62 (1H, dd, J = 3.6 Hz) , 10.9 Hz), 7.00-7.02 (2H,
m), 7.24-7.40 (11H, m), 7.50-7.54 (2H, m).

Example 1 Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid (1,1-dimethylethyl) ester
Potassium carbonate (20 g, 0.14 mol) in a solution of 3- (hydroxydiphenylmethyl) -1-piperazinecarboxylic acid (1,1-dimethylethyl) ester (9.6 g, 26 mmol) in N, N-dimethylformamide (180 mL) ) And ethyl chlorocarbonate (14 g, 0.26 mol) were added and the mixture was stirred at 50 ° C. for 16 h. To the reaction solution were added potassium carbonate (20 g, 0.14 mol) and ethyl chlorocarbonate (14 g, 0.26 mol) again, and the mixture was further stirred at 50 ° C. for 18 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (6.9 g, yield 64%) as a solid.
Melting point 151-152 ° C.
¹ H NMR (CDCl ₃ ) δ1.46 (9H, s), 2.15 (1H, t, J = 12.6 Hz), 2.73 (1H, t, J = 12.6 Hz),
3.03 (1H, dt, J = 12.6 Hz, 3.7 Hz), 3.82 (1H, dd, J = 12.6 Hz, 3.2 Hz), 4.00 (2H, m), 4.35 (1H, dd, J = 11.3 Hz, 3.2 Hz ), 7.27-7.42 (8H, m), 7.51 (2H, m).
Example 2 Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid phenyl ester tetrahydro-3-oxo-1,1-diphenyl-3H- Oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid (1,1-dimethylethyl) ester (99 mg, 0.25 mmol) in dichloromethane (2 mL) in trifluoroacetic acid (0.19 mL, 2.5 mmol) ) Was added and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. This solution was washed with sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to produce hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one Obtained as a thing. This was dissolved in tetrahydrofuran (2 mL), diisopropylethylamine (60 μL, 0.35 mmol) and phenyl chlorocarbonate (44 μL, 0.35 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give the title compound (70 mg, yield 67%).
Melting point 189-191 ° C.
¹ H NMR (CDCl ₃ ) δ2.22-2.54 (1H, m), 2.82-3.08 (1H, m), 3.17 (1H, dt, J = 12.7 Hz, 3.6 Hz), 3.95 (1H, dd, J = 13.2 Hz, 3.2 Hz), 4.08 (1H, br d, J = 14.0 Hz), 4.27 (1H,
br d, J = 12.5 Hz), 4.49 (1H, dd, J = 11.3 Hz, 3.5 Hz), 7.08 (2H, d, J = 7.8 Hz), 7.26-7.43 (11H, m), 7.51-7.54 (2H , m).

Example 3 Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid (4-fluorophenyl) ester hexahydro-1,1-diphenyl-3H -Oxazolo [3,4-a] pyrazin-3-one (50 mg, 0.17 mmol) in tetrahydrofuran (2 mL) in diisopropylethylamine (0.30 mL, 1.7 mmol) and 4-fluorophenyl chlorocarbonate (45 mg, 0.26) mmol) were added sequentially and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) and crystallized from diisopropyl ether to give the title compound (58 mg, yield 79%).
Melting point 188-189 ° C.
¹ H NMR (CDCl ₃ ) δ2.26-2.50 (1H, m), 2.80-3.03 (1H, m), 3.17 (1H, dt, J = 12.5 Hz, 3.7 Hz), 3.95 (1H, dd, J = 13.2 Hz, 3.0 Hz), 4.06 (1H, d, J = 12.9 Hz), 4.26 (1H, d,
J = 12.9 Hz), 4.48 (1H, dd, J = 11.2 Hz, 3.5 Hz), 7.05 (4H, d, J = 6.3 Hz), 7.26-7.43
(8H, m), 7.52 (2H, m).
Example 4 Tetrahydro-3-oxo-N, 1,1-triphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hexahydro-1,1-diphenyl-3H-oxazolo [3, To a solution of 4-a] pyrazin-3-one (85 mg, 0.29 mmol) in toluene (3 mL) was added phenyl isocyanate (70 mg, 0.59 mmol), and the mixture was stirred at 60 ° C. for 4 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) and crystallized from diisopropyl ether to give the title compound (0.12 g, yield 99%).
Melting point 117-118 ° C.
¹ H NMR (CDCl ₃ ) δ2.22 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.97 (1H, dt, J = 10.4 Hz, 3.5
Hz), 3.13 (1H, dt, J = 13.3 Hz, 3.5 Hz), 3.86 (2H, dt, J = 12.6 Hz, 2.7 Hz), 4.05 (1H, m), 4.47 (1H, dd, J = 11.3 Hz , 3.7 Hz), 6.53 (1H, s), 7.08 (1H, m), 7.26-7.41 (12H, m), 7.50 (2H, m).

Example 5 Tetrahydro-N-methyl-3-oxo-N, 1,1-triphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide tetrahydro-3-oxo-N, 1, 1-Triphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide (60 mg, 0.15 mmol) in tetrahydrofuran (2 mL) in 60% sodium hydride (10 mg, 0.25 mmol) Was added and the mixture was stirred at room temperature for 1 hour. Subsequently, methyl iodide (0.15 g, 1.1 mmol) was added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and crystallized from diisopropyl ether to give the title compound (30 mg, yield 48%).
Melting point 146-147 ° C.
¹ H NMR (CDCl ₃ ) δ2.00 (1H, dd, J = 13.2 Hz, 11.2 Hz), 2.57 (1H, dt, J = 13.2 Hz, 3.6
Hz), 2.89 (1H, dt, J = 13.2 Hz, 3.7 Hz), 3.20 (3H, s), 3.54 (1H, m), 3.74 (2H, dt, J = 13.2 Hz, 2.7 Hz), 4.05 (1H , dd, J = 11.2 Hz, 3.7 Hz), 7.06-7.15 (4H, m), 7.23-7.34 (9H, m), 7.41 (2H, m).
Example 6 Hexahydro-7- (1-oxo-3-phenyl-2-propenyl) -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one In the same manner as in Example 3. The title compound was obtained using cinnamoyl chloride instead of 4-fluorophenyl chlorocarbonate. Yield 79%.
Melting point 230-232 ° C (recrystallized from dichloromethane-petroleum ether).
¹ H NMR (CDCl ₃ ) δ2.00-2.27 (1H, m), 3.00-3.23 (2H, m), 3.87-4.25 (1H, m), 3.97 (1H, d, J = 9.6 Hz), 4.43 ( 1H, dd, J = 11.2 Hz, 3.4Hz), 4.48-4.75 (1H, m), 6.80 (1H, d, J = 15.4 Hz), 7.28-7.58 (15H, m), 7.71 (1H, d, J = 15.4 Hz).

Example 7 Hexahydro-1,1-diphenyl-7- (2-pyridinylcarbonyl) -3H-oxazolo [3,4-a] pyrazin-3-one In the same manner as in Example 3, The title compound was obtained using picolinic acid chloride hydrochloride instead of fluorophenyl. Yield 51%.
Melting point 169-170 ° C (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.24 (0.5H, t, J = 12.6 Hz), 2.39 (0.5H, dd, J = 13.1 Hz, 11.0 Hz),
2.77 (0.5H, m), 3.05 (0.5H, m), 3.25 (1H, m), 3.85 (0.5H, dd, J = 13.0 Hz, 2.7 Hz), 4.00 (0.5H, dd, J = 13.2 Hz) , 3.5 Hz), 4.18 (1H, d, J = 12.8 Hz), 4.57 (1H, m), 4.76 (0.5H, m), 4.94 (0.5H, dd, J = 10.8 Hz, 3.2 Hz), 7.24- 7.45 (9H, m), 7.55-7.85 (4H, m), 8.58 (0.5H, d, J = 4.6 Hz), 8.70 (0.5H, d, J = 4.6 Hz).
Example 8 Hexahydro-7- (1-oxo-3-phenylpropyl) -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one In the same manner as in Example 3, The title compound was obtained using 3-phenylpropionyl chloride instead of 4-fluorophenyl. Yield 54%.
Melting point 129-130 ° C (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ1.95 (0.7H, t, J = 12.2 Hz), 2.35-2.75 (3.0H, m), 2.96 (2.7H, m),
3.32 (0.3H, m), 3.63-4.00 (1.9H, m), 4.27 (0.7H, dd, J = 11.2, 3.6 Hz), 4.52 (0.7H, d, J = 13.2 Hz), 4.18 (0.7H , d, J = 12.8 Hz), 4.66 (0.3H, m), 7.18-7.42 (13H, m),
7.50 (2H, m).

Example 9 Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid (4-chlorophenyl) ester In the same manner as in Example 3, The title compound was obtained using 4-chlorophenyl chlorocarbonate instead of 4-fluorophenyl carbonate. Yield 65%.
Melting point 205-206 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.26-2.50 (1H, m), 2.80-3.03 (1H, m), 3.17 (1H, dt, J = 12.5 Hz, 3.7 Hz), 3.95 (1H, dd, J = 13.2 Hz, 3.0 Hz), 4.09 (1H, m), 4.25 (1H, d, J = 13.2 Hz), 4.48 (1H, dd, J = 11.3 Hz, 3.6 Hz), 7.03 (2H, m), 7.24- 7.43 (10H, m), 7.52 (2H, m).
Example 10 Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid 2-phenylhydrazide hexahydro-1,1-diphenyl-3H-oxazolo [ 3,4-a] pyrazin-3-one (0.10 g, 0.34 mmol) in tetrahydrofuran (1 mL) was added diisopropylethylamine (0.15 mL) and bis (trichloromethyl) carbonate (0.10 g, 0.34 mmol) sequentially. Mix the mixture at room temperature 45
Stir for minutes. Subsequently, phenylhydrazine (39 mg, 0.36 mmol) was added and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and crystallized from ethyl acetate-diisopropyl ether to give the title compound (44 mg, yield 30%).
Melting point 227-228 ° C.
¹ H NMR (CDCl ₃ ) δ2.31 (1H, dd, J = 13.2 Hz, 11.3 Hz), 2.93 (1H, dt, J = 13.2 Hz, 3.5
Hz), 3.11 (1H, dt, J = 12.4 Hz, 3.7 Hz), 3.83-3.92 (3H, m), 4.42 (1H, dd, J = 11.3 Hz, 3.7 Hz), 5.97 (1H, s), 6.33 (1H, s), 6.85 (2H, d, J = 7.7 Hz), 6.91 (1H, m), 7.21-7.37 (10H, m), 7.48 (2H, m).

Example 11 Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid (4-methoxyphenyl) ester In the same manner as in Example 3, The title compound was obtained using 4-methoxyphenyl chlorocarbonate instead of 4-fluorophenyl chlorocarbonate. Yield 67%.
Melting point 198-199 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.26-2.50 (1H, m), 2.80-3.03 (1H, m), 3.17 (1H, dt, J = 12.5 Hz, 3.7 Hz), 3.80 (3H, s), 3.94 (1H, dd, J = 13.2 Hz, 3.0 Hz), 4.07 (1H, d, J = 11.9 Hz), 4.26 (1H, d, J = 13.2 Hz), 4.48 (1H, dd, J = 11.2 Hz, 3.6 Hz), 6.88 (2H, d, J = 9.1 Hz), 6.99 (2H, d, J = 9.1 Hz), 7.32-7.43 (8H, m), 7.52 (2H, m).
Example 12 Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid (9H-fluoren-9-ylmethyl) ester Similar to Example 3 According to the method, the title compound was obtained by using chlorocarbonate (9H-fluoren-9-ylmethyl) instead of 4-fluorophenyl chlorocarbonate. Yield 76%.
Melting point 168-169 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.12 (1H, dd, J = 13.2 Hz, 11.5 Hz), 2.66-2.90 (2H, m), 3.44 (0.5H, m), 3.75 (1.5H, m), 3.90 -4.22 (3H, m), 4.52 (1.5H, m), 4.80 (0.5H, m), 7.14-7.40 (14H, m), 7.53 (2H, m), 7.76 (2H, t, J = 7.7 Hz ).

Example 13 Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid (3-trifluoromethylphenyl) ester The same method as in Example 3 Gave the title compound using 3-trifluoromethylphenyl chlorocarbonate instead of 4-fluorophenyl chlorocarbonate. Yield 46%.
Melting point 183-184 ° C (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.28-2.52 (1H, m), 2.84-3.07 (1H, m), 3.19 (1H, dt, J = 12.6 Hz, 3.7 Hz), 3.97 (1H, dd, J = 13.2 Hz, 3.0 Hz), 4.07 (1H, d, J = 12.2 Hz), 4.26 (1H, d,
J = 11.7 Hz), 4.50 (1H, dd, J = 11.7 Hz, 2.9 Hz), 7.27-7.34 (10H, m), 7.51 (4H, m).
Example 14 Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid (4-nitrophenyl) ester In the same manner as in Example 3, The title compound was obtained using 4-nitrophenyl chlorocarbonate instead of 4-fluorophenyl chlorocarbonate. Yield 69%.
Melting point 214-215 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.31-2.53 (1H, m), 2.84-3.08 (1H, m), 3.20 (1H, dt, J = 12.5 Hz, 3.7 Hz), 3.99 (1H, dd, J = 13.2 Hz, 3.0 Hz), 4.06 (1H, m), 4.26 (1H, d, J = 13.2 Hz), 4.50 (1H, m), 7.26-7.44 (10H, m), 7.52 (2H, m), 8.27 (2H, d, J = 9.1 Hz).

Example 15 Hexahydro-7- (phenoxyacetyl) -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one In the same manner as in Example 3, instead of 4-fluorophenyl chlorocarbonate The title compound was obtained using phenoxyacetyl chloride. Yield 68%.
Melting point 119-120 ° C (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.06 (0.7H, m), 2.46-2.66 (1H, m), 2.96-3.08 (1.4H, m), 3.84-4.07 (1.9H, m), 4.29-4.45 ( 1.6H, m), 4.55-4.74 (2.4H, m), 6.92 (1H, d, J = 8.1 Hz), 6.98-7.11 (2H, m), 7.26-7.39 (11H, m), 7.48 (1H, m).
Example 16 N- (4-Fluorophenyl) -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 4 The title compound was obtained using 4-fluorophenyl isocyanate in place of phenyl isocyanate. Yield 71%.
Melting point 110-111 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.24 (1H, dd, J = 13.3 Hz, 11.3 Hz), 3.01 (1H, dt, J = 12.8 Hz, 3.2
Hz), 3.15 (1H, dt, J = 12.6 Hz, 3.6 Hz), 3.82 (1H, d, J = 12.8 Hz), 3.91 (1H, dd, J = 13.3 Hz, 2.6 Hz), 4.04 (1H, dd , J = 13.3 Hz, 2.6 Hz), 4.47 (1H, dd, J = 11.3 Hz, 3.6 Hz), 6.39 (1H, br s), 6.99 (2H, t, J = 8.5 Hz), 7.02-7.39 (10H , m), 7.51 (2H, m).

Example 17 Tetrahydro-3-oxo-1,1-diphenyl-N- (phenylmethyl) -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Isocyanate was prepared in the same manner as in Example 4. The title compound was obtained using benzyl isocyanate instead of acid phenyl. Yield 71%.
Melting point 98-99 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.17 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.90 (1H, dt, J = 13.1 Hz, 3.5
Hz), 3.08 (1H, dt, J = 12.8 Hz, 3.6 Hz), 3.64 (1H, m), 3.84 (1H, dd, J = 12.8 Hz, 2.6 Hz), 4.04 (1H, dd, J = 13.3 Hz , 2.6 Hz), 4.39-4.43 (3H, m), 4.75 (1H, m), 7.24-7.39 (13H, m), 7.51 (2H, m).
Example 18 Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid (2-methoxyphenyl) ester In the same manner as in Example 3, The title compound was obtained using 2-methoxyphenyl chlorocarbonate instead of 4-fluorophenyl chlorocarbonate. Yield 40%.
Melting point 99-100 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.31-2.43 (1H, m), 2.80-3.08 (1H, m), 3.21 (1H, m), 3.82 (3H, s), 3.92 (1H, dd, J = 13.0 Hz, 3.0 Hz), 4.11 (1H, m), 4.27 (1H, m), 4.51 (1H, m), 6.96 (2H, d, J = 7.8 Hz), 7.10-7.44 (10H, m), 7.54 ( 2H, m).

Example 19 (E) -7- [3- (4-Fluorophenyl) -1-oxo-2-propenyl] -hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-3- on
Oxalyl chloride (46 mg, 0.36 mmol) and N, N-dimethylformamide (1 drop) were added sequentially to a solution of 4-fluorocinnamic acid (50 mg, 0.30 mmol) in tetrahydrofuran (1 mL), and the mixture was stirred at room temperature for 1 hour. Stir. After the reaction solution was concentrated under reduced pressure, a solution of hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one (60 mg, 0.20 mmol) in tetrahydrofuran (1.5 mL) and diisopropylethylamine (0.3 mL) was added sequentially and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and crystallized from ethyl acetate-diisopropyl ether to give the title compound (32 mg, yield 36%).
Melting point 250-251 ℃.
¹ H NMR (CDCl ₃ ) δ2.12 (1H, m), 3.10 (2H, m), 3.97 (1H, d, J = 10.8 Hz), 4.11 (1H, m), 4.42 (1H, dd, J = 11.3 Hz, 3.5 Hz), 4.61 (1H, m), 6.73 (1H, d, J = 13.8 Hz), 7.08 (2H, t, J = 8.6 Hz), 7.32-7.52 (12H, m), 7.66 (1H , d, J = 15.6 Hz).
Example 20 Hexahydro-7- (1-oxo-4-phenylbutyl) -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one By a method similar to that in Example 19, The title compound was obtained using 4-phenylbutyric acid instead of fluorocinnamic acid. Yield 34%.
Melting point 128-129 ° C (crystallized from ethanol).
¹ H NMR (CDCl ₃ ) δ1.97 (2H, m), 2.21-2.35 (2H, m), 2.45 (1H, m), 2.67 (2H, m), 2.96 (2H, m), 3.38 (0.3H , d, J = 12.6 Hz), 3.65 (0.7H, m), 3.87 (1H, d, J = 9.8 Hz), 4.29 (1H, m), 4.52 (0.7H, d, J = 13.1 Hz), 4.63 (0.3H, d, J = 12.9 Hz), 7.15-7.39 (13H, m), 7.52 (2H, m).

Example 21 N- (3-Fluorophenyl) -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 4 The title compound was obtained by using 3-fluorophenyl isocyanate instead of phenyl isocyanate. Yield 49%.
Melting point 112-113 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.24 (1H, dd, J = 13.3 Hz, 11.2 Hz), 3.01 (1H, m), 3.15 (1H, m), 3.82 (1H, d, J = 13.1 Hz), 3.91 (1H, d, J = 13.1 Hz), 4.04 (1H, dd, J = 13.3 Hz, 2.4 Hz), 4.47 (1H, dd, J = 11.2 Hz, 3.5 Hz), 6.50 (1H, m), 6.76 (1H, dt, J = 8.3 Hz, 2.4 Hz), 7.00 (1H, m), 7.22-7.39 (10H, m), 7.50 (2H, m).
Example 22 N- (2-Fluorophenyl) -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 4 The title compound was obtained using 2-fluorophenyl isocyanate in place of phenyl isocyanate. Yield 50%.
Melting point 105-106 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.28 (1H, dd, J = 13.3 Hz, 11.3 Hz), 3.05 (1H, dt, J = 12.6 Hz, 3.0
Hz), 3.18 (1H, dt, J = 12.6 Hz, 3.3 Hz), 3.85 (1H, d, J = 13.0 Hz), 3.94 (1H, m), 4.05 (1H, dd, J = 13.4 Hz, 2.5 Hz ), 4.50 (1H, dd, J = 11.2 Hz, 3.6 Hz), 6.54 (1H, m),
7.00-7.11 (3H, m), 7.32-7.51 (8H, m), 7.52 (2H, m), 7.98 (1H, m).

Example 23 4-[[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] amino] benzoic acid methyl ester Example 4 In the same manner as above, the title compound was obtained using 4-isocyanatobenzoic acid methyl ester instead of phenyl isocyanate. Yield 70%.
Melting point 145-146 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.26 (1H, dd, J = 13.3 Hz, 11.3 Hz), 3.04 (1H, dt, J = 12.5 Hz, 3.0
Hz), 3.16 (1H, dt, J = 12.6 Hz, 3.0 Hz), 3.84-3.94 (2H, m), 3.89 (3H, s), 4.06 (1H, dd, J = 13.2 Hz, 2.4 Hz), 4.49 (1H, dd, J = 11.3 Hz, 3.6 Hz), 6.68 (1H, s), 7.31-7.52 (12H, m), 7.98 (2H, d, J = 8.7 Hz).
Example 24 3-[[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] amino] benzoic acid methyl ester Example 4 In the same manner as above, the title compound was obtained using 3-isocyanatobenzoic acid methyl ester instead of phenyl isocyanate. Yield 70%.
Melting point 105-106 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.26 (1H, dd, J = 13.3 Hz, 11.2 Hz), 3.01 (1H, dt, J = 12.7 Hz, 3.3
Hz), 3.15 (1H, dt, J = 12.6 Hz, 3.4 Hz), 3.85-3.94 (2H, m), 3.89 (3H, s), 4.04 (1H, dd, J = 13.3 Hz, 2.4 Hz), 4.48 (1H, dd, J = 11.2 Hz, 3.6 Hz), 6.64 (1H, s), 7.30-7.40 (9H, m), 7.50 (2H, m), 7.65-7.75 (2H, m), 7.88 (1H, m).

Example 25 N-[(4-Fluorophenyl) methyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Same as Example 4 The title compound was obtained using 4-fluorobenzyl isocyanate instead of phenyl isocyanate. Yield 72%.
Melting point 105-106 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ 2.16 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.91 (1H, dt, J = 12.9 Hz, 3.3
Hz), 3.07 (1H, dt, J = 12.8 Hz, 3.4 Hz), 3.62 (1H, m), 3.84 (1H, dd, J = 12.8 Hz, 2.4 Hz), 4.02 (1H, dd, J = 13.3 Hz) , 2.4 Hz), 4.36 (2H, m), 4.42 (1H, dd, J = 11.2 Hz,
3.5 Hz), 4.78 (1H, t, J = 5.2 Hz), 7.00 (2H, m), 7.22-7.39 (10H, m), 7.50 (2H, m).
Example 26 N-[(2-Fluorophenyl) methyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Same as Example 4 The title compound was obtained using 2-fluorobenzyl isocyanate instead of phenyl isocyanate. Yield 64%.
Melting point 109-110 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ 2.15 (1H, dd, J = 13.3 Hz, 11.2 Hz), 2.89 (1H, dt, J = 13.0 Hz, 3.4
Hz), 3.07 (1H, dt, J = 12.9 Hz, 3.4 Hz), 3.61 (1H, m), 3.84 (1H, dd, J = 13.0 Hz, 2.4 Hz), 3.99 (1H, dd, J = 13.3 Hz , 2.4 Hz), 4.40 (1H, dd, J = 11.3 Hz, 3.6 Hz), 4.45
(2H, m), 4.89 (1H, t, J = 5.2 Hz), 7.00-7.15 (2H, m), 7.25-7.38 (10H, m), 7.50 (2H, m).

Example 27 Tetrahydro-1,1-dimethyl-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid (phenylmethyl) ester
2- (1-hydroxy-1-methylethyl) -1,4-piperazinedicarboxylic acid bis (phenylmethyl) ester (1.7 g, 4.2 mmol) was dissolved in N, N-dimethylformamide (20 mL) and 60% Sodium hydride (0.25 g, 6.3 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (200 ml) and washed with aqueous sodium hydrogen carbonate solution. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 1: 1) and recrystallized from ethyl acetate-hexane to give the title compound (0.97 g, yield 76%).
Melting point 86-88 ° C.
¹ H NMR (CDCl ₃ ) δ1.36 (3H, s), 1.47 (3H, s), 2.76-2.98 (3H, m), 3.25-3.35 (1H, m), 3.75-3.83 (1H, m), 4.09-4.18 (2H, m), 5.16 (2H, s), 7.33-7.37 (5H, m).
Example 28 N-[(3-Fluorophenyl) methyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Same as Example 4 The title compound was obtained by using 3-fluorobenzyl isocyanate instead of phenyl isocyanate. Yield 64%.
Melting point 110-111 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ 2.18 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.93 (1H, dt, J = 12.8 Hz, 3.4
Hz), 3.09 (1H, dt, J = 12.8 Hz, 3.4 Hz), 3.66 (1H, m), 3.86 (1H, dd, J = 12.9 Hz, 2.5 Hz), 4.02 (1H, dd, J = 13.3 Hz) , 2.5 Hz), 4.38-4.46 (3H, m), 4.83 (1H, t, J = 5.3 Hz), 6.96-7.06 (2H, m), 7.25-7.39 (10H, m), 7.51 (2H, m) .

Example 29 Tetrahydro-N-[(4-methylphenyl) methyl] -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Same as Example 4 The title compound was obtained by 4-methylbenzyl isocyanate instead of phenyl isocyanate. Yield 31%.
Melting point 112-113 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.16 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.33 (3H, s), 2.89 (1H, dt, J = 12.9 Hz, 3.5 Hz), 3.07 (1H, dt, J = 12.9 Hz, 3.5 Hz), 3.62 (1H, m), 3.83 (1H, dd, J = 13.0 Hz, 2.4 Hz), 4.02 (1H, dd, J = 13.3 Hz, 2.4 Hz), 4.36 ( 2H, t, J = 5.4 Hz), 4.42 (1H, dd, J = 11.2 Hz, 3.7 Hz), 4.69 (1H, m), 7.15 (4H, m), 7.27-7.39 (8H, m),
7.51 (2H, m).
Example 30 Tetrahydro-3-oxo-1,1-diphenyl-N- (2-thienylmethyl) -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 10. The title compound was obtained using thiophen-2-methylamine instead of phenylhydrazine. Yield 58%.
Melting point 94-95 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ 2.18 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.90 (1H, dt, J = 13.1 Hz, 3.5
Hz), 3.08 (1H, dt, J = 12.9 Hz, 3.5 Hz), 3.64 (1H, m), 3.84 (1H, dd, J = 13.1 Hz, 2.6 Hz), 4.00 (1H, m), 4.42 (1H , dd, J = 11.3 Hz, 3.6 Hz), 4.58 (2H, m), 4.81 (1H, m), 6.96 (2H, m), 7.21-7.39 (9H, m), 7.51 (2H, m).

Example 31 Tetrahydro-3-oxo-1,1-diphenyl-N- (2-pyridinylmethyl) -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 10, The title compound was obtained using 2- (aminomethyl) pyridine in place of phenylhydrazine. Yield 58%.
Melting point 65-66 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ 2.20 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.93 (1H, dt, J = 13.3 Hz, 3.6
Hz), 3.10 (1H, dt, J = 12.9 Hz, 3.6 Hz), 3.85 (2H, dt, J = 12.9 Hz, 2.6 Hz), 4.04 (1H, m), 4.44 (1H, dd, J = 11.2 Hz , 2.4 Hz), 4.51 (2H, t, J = 4.5 Hz), 6.02 (1H, t, J = 4.5 Hz), 7.25-7.38 (10H, m), 7.52 (2H, m), 7.75 (1H, m ), 8.52 (1H, d, J = 4.4 Hz).
Example 32 Hexahydro-1,1-diphenyl-7-[(1,2,3,4-tetrahydroisoquinolin-2-yl) carbonyl] -3H-oxazolo [3,4-a] pyrazin-3-one In the same manner as in No. 10, the title compound was obtained using 1,2,3,4-tetrahydroisoquinoline instead of phenylhydrazine. Yield 49%.
Melting point 93-94 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.23 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.86-2.95 (3H, m), 3.14 (1H,
dt, J = 12.9 Hz, 3.5 Hz), 3.43 (1H, m), 3.52-3.65 (3H, m), 3.84 (1H, dd, J = 13.0 Hz, 2.8 Hz), 4.43 (2H, m), 4.59 (1H, dd, J = 11.2 Hz, 3.4 Hz), 7.08-7.19 (4H, m), 7.25-7.39 (8H, m), 7.52 (2H, m).

Example 33 Tetrahydro-3-oxo-1,1-diphenyl-N-[[4- (trifluoromethyl) phenyl] methyl] -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 10, 4- (trifluoromethyl) benzylamine was used instead of phenylhydrazine to give the title compound. Yield 55%.
Melting point 109-110 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.19 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.94 (1H, dt, J = 12.8 Hz, 3.3
Hz), 3.07 (1H, dt, J = 12.8 Hz, 3.5 Hz), 3.65 (1H, m), 3.86 (1H, dd, J = 13.0 Hz, 2.6 Hz), 4.02 (1H, dd, J = 13.3 Hz , 2.4 Hz), 4.40-4.54 (3H, m), 4.88 (1H, m), 7.26-7.41 (10H, m), 7.50 (2H, m), 7.58 (2H, d, J = 8.1 Hz).
Example 34 N-[(4-Chlorophenyl) methyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Similar to Example 10 According to the method, 4-chlorobenzylamine was used instead of phenylhydrazine to obtain the title compound. Yield 45%.
Melting point 110-111 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.17 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.91 (1H, dt, J = 12.8 Hz, 3.3
Hz), 3.08 (1H, dt, J = 12.8 Hz, 3.5 Hz), 3.64 (1H, m), 3.85 (1H, dd, J = 12.8 Hz, 2.6 Hz), 4.02 (1H, m), 4.34-4.43 (3H, m), 4.79 (1H, m), 7.20-7.39 (12H, m), 7.51 (2H, m).

Example 35 N-[[4- (Dimethylamino) phenyl] methyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Example In the same manner as in Example 10, 4- (dimethylamino) benzylamine was used instead of phenylhydrazine to obtain the title compound. Yield 26%.
Melting point 100-101 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.14 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.91 (1H, m), 2.93 (6H, s), 3.06 (1H, dt, J = 12.8 Hz, 3.5 Hz), 3.60 (1H, m), 3.82 (1H, dd, J = 13.0 Hz, 2.6 Hz), 4.03 (1H, dd, J = 13.3 Hz, 2.4 Hz), 4.30 (2H, m), 4.42 (1H , dd, J = 11.2 Hz, 3.6 Hz), 4.58 (1H, m), 6.69 (2H, d, J = 4.4 Hz), 7.16 (2H, d, J = 4.4 Hz), 7.25-7.39 (8H,
m), 7.51 (2H, m).
Example 36 Tetrahydro-N-[[4- (methylsulfonyl) phenyl] methyl] -3-oxo-1,1-
Diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 10, 4- (methylsulfonyl) benzylamine was used instead of phenylhydrazine to give the title compound. . Yield 33%.
Melting point 147-148 ° C (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.19 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.92 (1H, dt, J = 12.9 Hz, 3.3
Hz), 3.01 (3H, s), 3.08 (1H, m), 3.71 (1H, m), 3.84 (1H, dd, J = 12.8 Hz, 2.4 Hz), 4.03 (1H, dd, J = 13.3 Hz, 2.4 Hz), 4.43 (1H, dd, J = 11.2 Hz, 3.7 Hz), 4.49 (2H, m), 5.23 (1H, t, J = 5.8 Hz), 7.26-7.44 (10H, m), 7.51 (2H , m), 7.82 (2H, d, J = 8.4
Hz).

Example 37 N-[(4-Fluorophenyl) methyl] -tetrahydro-1,1-dimethyl-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide tetrahydro-3-oxo -1,1-Dimethyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid (phenylmethyl) ester (0.12 g, 0.39 mmol) dissolved in ethanol (10 mL), 10% Palladium on carbon (12 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered through celite, the celite was washed with ethanol, and the back solution was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), 4-fluorobenzyl isocyanate (0.20 mL, 1.6 mmol) was added, and the mixture was stirred at 50 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 to 1: 9) to give the title compound (0.11 g, yield 86%).
Oily.
¹ H NMR (CDCl ₃ ) δ1.37 (3H, s), 1.48 (3H, s), 2.65-2.73 (1H, m), 2.95-3.03 (2H, m), 3.34-3.39 (1H, m), 3.66-3.83 (2H, m), 4.17-4.23 (1H, m), 4.40 (2H, d, J = 5.5 Hz), 4.77 (1H, br s), 6.99-7.05 (2H, m), 7.25-7.30 (2H, m).
Example 38 Tetrahydro-1,1-dimethyl-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid phenyl ester hexahydro-1,1-dimethyl-3H-oxazolo [3, 4-a] pyrazin-3-one (0.10 g, 0.59 mmol) was dissolved in tetrahydrofuran (10 mL), triethylamine (0.17 mL, 1.2 mmol) and phenyl chlorocarbonate (0.11 mL, 0.88 mmol) were added, and the mixture was dissolved. Stir at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 1: 2). After purification, the crystals precipitated during concentration under reduced pressure were collected by filtration to give the title compound (0.14 g, yield 80%).
Melting point 144-145 ° C.
¹ H NMR (CDCl ₃ ) δ1.41 (3H, s), 1.51 (3H, s), 2.74-3.16 (3H, m), 3.43-3.47 (1H, m), 3.88-3.91 (1H, m), 4.19-4.31 (2H, m), 7.09-7.41 (5H, m).

Example 39 N- (4-Fluorophenyl) -tetrahydro-1,1-dimethyl-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hexahydro-1,1-dimethyl- 3H-oxazolo [3,4-a] pyrazin-3-one (0.10 g, 0.59 mmol) was dissolved in tetrahydrofuran (10 mL) and 4-fluorophenyl isocyanate (0.12
g, 0.88 mmol) was added and the mixture was stirred at 50 ° C. for 4 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to 1: 9). After purification, the crystals precipitated during concentration under reduced pressure were collected by filtration to give the title compound (136 mg, yield 75%).
Melting point 199-201 ℃.
¹ H NMR (CDCl ₃ ) δ1.41 (3H, s), 1.50 (3H, s), 2.73-2.81 (1H, m), 3.07-3.11 (2H, m), 3.42-3.46 (1H, m), 3.79-3.91 (2H, m), 4.24-4.28 (1H, m), 6.32 (1H, br s), 6.99-7.04 (2H, m), 7.26-7.31 (2H, m).
Example 40 N- (2-furylmethyl) -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide By a method similar to that in Example 10. The title compound was obtained using furfurylamine instead of phenylhydrazine. Yield 55%.
Melting point 120-121 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.16 (1H, dd, J = 13.2 Hz, 11.3 Hz), 2.90 (1H, dt, J = 12.8 Hz, 3.3
Hz), 3.08 (1H, dt, J = 12.8 Hz, 3.5 Hz), 3.64 (1H, m), 3.84 (1H, dd, J = 13.0 Hz, 2.8 Hz), 4.00 (1H, dd, J = 13.1 Hz , 2.3 Hz), 4.41 (3H, m), 4.77 (1H, m), 6.22 (1H, d, J = 3.1 Hz), 6.31 (1H, m), 7.27-7.41 (9H, m), 7.51 (2H , m).

Example 41 Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid (phenylmethyl) ester In the same manner as in Example 3, The title compound was obtained using benzyl chlorocarbonate instead of 4-fluorophenyl. Yield 75%.
Melting point 157-158 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.23 (1H, m), 2.80 (1H, m), 3.04 (1H, dt, J = 12.8 Hz, 10.3 Hz), 3.85 (1H, dd, J = 13.2 Hz, 3.1 Hz), 4.01-4.14 (2H, m), 4.36 (1H, d, J = 10.3 Hz), 5.16 (2H, m), 7.28-7.40 (13H, m), 7.47 (2H, m).
Example 42 Tetrahydro-3-oxo-1,1-diphenyl-N- (2-phenylethyl) -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide By a method similar to that in Example 10. The title compound was obtained using 2-phenethylamine in place of phenylhydrazine. Yield 26%.
Melting point 75-76 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.13 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.78-2.87 (3H, m), 3.00 (1H,
dt, J = 12.8 Hz, 3.5 Hz), 3.45-3.55 (3H, m), 3.80 (1H, dd, J = 12.8 Hz, 2.6 Hz), 3.89 (1H, m), 4.36 (2H, m), 7.18 -7.48 (13H, m), 7.49 (2H, m).

Example 43 N- (2,3-dihydro-1H-inden-1-yl) -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H)- Carboxamide In the same manner as in Example 10, 1-aminoindane was used in place of phenylhydrazine to obtain the title compound. Yield 29%.
Melting point 133-134 ° C (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ1.77 (1H, m), 2.16 (1H, m), 2.62 (1H, m), 2.86-3.10 (4H, m), 3.60 (1H, m), 3.85 (1H, d, J = 12.9 Hz), 4.08 (1H, m), 4.48 (1H, m), 4.63 (1H, d, J = 8.0 Hz), 5.37 (1H, m), 7.24-7.40 (12H, m), 7.52 (2H, m).
Example 44 Tetrahydro-3-oxo-1,1-diphenyl-N- (1-phenylethyl) -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide By a method similar to that in Example 10. The title compound was obtained using 1-phenethylamine in place of phenylhydrazine. Yield 60%.
Melting point 120-121 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ1.48 (3H, dd, J = 6.7 Hz, 5.8 Hz), 2.12 (1H, m), 2.91 (1H, m), 3.05 (1H, m), 3.59 (1H, m ), 3.84 (1H, d, J = 12.6 Hz), 4.03 (1H, m), 4.40 (1H, dt, J = 11.3 Hz, 3.7 Hz), 4.64 (1H, t, J = 7.0 Hz), 4.97 ( 1H, quintet, J = 7.0 Hz), 7.22-7.40 (13H, m), 7.50 (2H, m).

Example 45 1,1-Dicyclopropyl-tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid (phenylmethyl) ester
2- (Dicyclopropylhydroxymethyl) -1,4-piperazinedicarboxylic acid bis (phenylmethyl) ester (1.4 g, 3.0 mmol) was dissolved in N, N-dimethylformamide (15 mL) and dissolved in 60% sodium hydride. (0.13 g, 3.3 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with aqueous sodium hydrogen carbonate solution. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1 to 3: 1) to give the title compound (0.62 g, yield 58%).
Oily.
¹ H NMR (CDCl ₃ ) δ0.44-0.60 (8H, m), 0.85-0.92 (1H, m), 1.03-1.11 (1H, m), 2.82-3.13 (3H, m), 3.43-3.48 (1H m), 3.73-3.78 (1H, m), 4.09-4.20 (2H, m), 5.17 (2H, s), 7.26 (2H, s), 7.37 (3H, s).
Example 46 Tetrahydro-3-oxo-1,1-diphenyl-N- (3-pyridinylmethyl) -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 10, The title compound was obtained using 3- (aminomethyl) pyridine in place of phenylhydrazine. Yield 41%.
Melting point 191-192 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ 2.18 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.92 (1H, dt, J = 13.0 Hz, 3.3
Hz), 3.08 (1H, dt, J = 12.9 Hz, 3.5 Hz), 3.66 (1H, m), 3.86 (1H, dd, J = 12.9 Hz, 2.6 Hz), 4.00 (1H, d, J = 13.3 Hz) , 2.4 Hz), 4.42 (3H, m), 4.92 (1H, m), 7.25-7.39 (10H, m), 7.51 (2H, m), 7.64 (1H, m), 8.52 (1H, s).

Example 47 N- (2,4-Difluorophenyl) -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Similar to Example 4 The title compound was obtained by the method using 2,4-difluorophenyl isocyanate instead of phenyl isocyanate. Yield 51%.
Melting point 98-99 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.28 (1H, dd, J = 13.3 Hz, 11.3 Hz), 3.05 (1H, dt, J = 12.8 Hz, 3.0
Hz), 3.18 (1H, dt, J = 12.7 Hz, 3.0 Hz), 3.83 (1H, d, J = 13.0 Hz), 3.94 (1H, dd, J = 13.3 Hz, 2.4 Hz), 4.03 (1H, dd , J = 13.3 Hz, 2.4 Hz), 4.49 (1H, dd, J = 11.3 Hz, 3.6 Hz), 6.38 (1H, br s), 6.86 (2H, m), 7.30-7.42 (8H, m), 7.52 (2H, m), 7.89 (1H,
m).
Example 48 N- (4-Chlorophenyl) -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide By a method similar to that in Example 4, The title compound was obtained using 4-chlorophenyl isocyanate instead of phenyl isocyanate. Yield 70%.
Melting point 121-122 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.23 (1H, dd, J = 13.3 Hz, 11.3 Hz), 3.01 (1H, dt, J = 12.7 Hz, 2.9
Hz), 3.14 (1H, dt, J = 12.7 Hz, 3.0 Hz), 3.82 (1H, d, J = 13.0 Hz), 3.91 (1H, dd, J = 13.0 Hz, 2.6 Hz), 4.03 (1H, dd , J = 13.3 Hz, 2.5 Hz), 4.47 (1H, dd, J = 11.3 Hz, 3.6 Hz), 6.43 (1H, br s), 7.23-7.42 (12H, m), 7.52 (2H, m).

Example 49 Tetrahydro-N- (4-methoxyphenyl) -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 4. The title compound was obtained using 4-methoxyphenyl isocyanate instead of phenyl isocyanate. Yield 80%.
Melting point 241-242 ° C. (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ2.22 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.98 (1H, dt, J = 12.9 Hz, 3.0
Hz), 3.14 (1H, dt, J = 12.8 Hz, 3.0 Hz), 3.78 (3H, s), 3.87-3.92 (2H, m), 4.02 (1H, dd, J = 13.3 Hz, 3.0 Hz), 4.46 (1H, dd, J = 11.3 Hz, 3.6 Hz), 6.25 (1H, br s), 6.85 (2H, d, J = 9.0 Hz), 7.20 (2H, d, J = 9.0 Hz), 7.29-7.39 ( 8H, m), 7.50 (2H, m).

Example 50 Tetrahydro-N- (2-naphthylmethyl) -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 10. The title compound was obtained using 2- (aminomethyl) naphthalene instead of phenylhydrazine. Yield 43%.
Melting point 163-164 ° C (crystallized from diisopropyl ether).
¹ H NMR (CDCl ₃ ) δ 2.16 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.85 (1H, dt, J = 12.9 Hz, 3.3
Hz), 3.03 (1H, dt, J = 12.8 Hz, 3.4 Hz), 3.56 (1H, m), 3.78 (1H, dd, J = 13.0 Hz, 2.8 Hz), 4.03 (1H, dd, J = 13.3 Hz) , 2.4 Hz), 4.41 (1H, dd, J = 11.3 Hz, 3.6 Hz), 4.76
(1H, t, J = 4.6 Hz), 4.87 (2H, m), 7.25-7.54 (14H, m), 7.80 (1H, m), 7,87 (1H, m), 8.01 (1H, m).

Example 51 1,1-Dicyclopropyl-N-[(4-fluorophenyl) methyl] -tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide
1,1-dicyclopropyl-tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid (phenylmethyl) ester (0.18 g, 0.50 mmol) in ethanol (10 mL ), 10% palladium carbon (17 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered through celite, and the celite was washed with ethanol, and then the filtrate was concentrated under reduced pressure. The obtained 1,1-dicyclopropyl-hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one was dissolved in tetrahydrofuran (10 mL), and isocyanic acid (4-fluoro) benzyl ester (0.25
mL, 2.0 mmol) was added and the mixture was stirred at 50 ° C. for 4 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to 1: 4) to give the title compound (0.16 g, 1,1-dicyclopropyl-tetrahydro-3- The yield from oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid (phenylmethyl) ester was 87%.
Oily.
¹ H NMR (CDCl ₃ ) δ0.44-0.61 (8H, m), 0.87-0.91 (1H, m), 1.07-1.12 (1H, m), 2.92-3.10 (3H, m), 3.53 (1H, dd , J = 3.6 Hz, 11.2 Hz), 3.70-3.79 (2H, m), 4.27-4.42 (3H,
m), 4.76 (1H, br s), 7.03 (2H, t, J = 8.6 Hz), 7.26-7.31 (2H, m).
Example 52 1,1-Dicyclopropyl-N- (4-fluorophenyl) -tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Similar to Example 51 1,1-dicyclopropyl-tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid (phenylmethyl) ester obtained by the method From cyclopropyl-hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one and (4-fluoro) phenyl isocyanate, the title compound (0.15 g, 1,1-dicyclopropyl-tetrahydro-3-oxo -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid (phenylmethyl) ester yield 83%).
Oily.
¹ H NMR (CDCl ₃ ) δ0.46-0.62 (8H, m), 0.89-0.93 (1H, m), 1.13-1.28 (1H, m), 3.03-3.13 (3H, m), 3.60 (1H, dd , J = 3.7 Hz, 11.3 Hz), 3.83-3.90 (2H, m), 4.33-4.37 (1H,
m), 6.35 (1H, br s), 6.99 (2H, t, J = 8.7 Hz), 7.26-7.32 (2H, m).

Example 53 1,1-Dicyclopropyl-tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid phenyl ester
1,1-dicyclopropyl-tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid (phenylmethyl) ester (0.18 g, 0.50 mmol) in ethanol (10 mL ), 10% palladium on carbon (17 mg) was added, and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. The reaction solution was filtered through celite, and the celite was washed with ethanol, and then the filtrate was concentrated under reduced pressure. The resulting 1,1-dicyclopropyl-hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one was dissolved in tetrahydrofuran (10 mL), triethylamine (0.14 mL, 0.99 mmol) and phenyl chlorocarbonate (90 μL, 0.74 mmol) was added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1 to 1: 1) and recrystallized from diisopropyl ether-hexane to give the title compound (0.15 g, 1,1-dicyclopropyl-tetrahydro- 3-Oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid (phenylmethyl) ester, 88% yield) was obtained.
Mp 102-104 ° C.
¹ H NMR (CDCl ₃ ) δ0.47-0.60 (8H, m), 0.89-0.92 (1H, m), 1.10-1.18 (1H, m), 2.80-3.10 (3H, m), 3.62 (1H, dd , J = 3.7 Hz, 11.3 Hz), 3.84-3.88 (1H, m), 4.20-4.26 (2H,
m), 7.12 (2H, d, J = 7.9 Hz), 7.21-7.26 (1H, m), 7.39 (2H, t, J = 7.9 Hz).
Example 54 Hexahydro-1,1-diphenyl-7- (phenylsulfonyl) -3H-oxazolo [3,4-a] pyrazin-3-one Hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a Pyrazine-3-one (50 mg, 0.17 mmol) in chloroform (2 mL) was added sequentially with pyridine (0.5 mL) and benzenesulfonyl chloride (43 mg, 0.24 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and crystallized from diisopropyl ether to give the title compound (27 mg, yield 37%).
Melting point 236-237 ° C.
¹ H NMR (CDCl ₃ ) δ1.70 (1H, t, J = 11.4 Hz), 2.22 (1H, dt, J = 12.0 Hz, 3.6 Hz), 3.23
(1H, m), 3.43 (1H, m), 3.69 (1H, dd, J = 11.9 Hz, 3.6 Hz), 3.90 (1H, dd, J = 13.5 Hz, 2.6 Hz), 4.57 (1H, dd, J = 11.1 Hz, 3.7 Hz), 7.27-7.51 (14H, m), 7.60 (1H, m).

Example 55 1,1-Dicyclohexyl-N- (2,4-difluorophenyl) -tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide
1,1-dicyclohexyl-hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one (0.13 g, 0.42 mmol) was dissolved in toluene (1.5 mL) and 2,4-difluorophenyl isocyanate (0.10 g, 0.64 mmol) was added and the mixture was stirred at 60 ° C. for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) and crystallized from hexane to give the title compound (0.12 g, yield 59%).
Amorphous.
¹ H NMR (CDCl ₃ ) δ0.88 (2H, m), 1.00 (2H, m), 1.17-1.41 (9H, m), 1.70-2.04 (9H, m), 2.99 (1H, dt, J = 12.3 Hz, 3.2 Hz), 3.10 (2H, m), 3.66 (1H, dd, J = 11.3 Hz, 3.6 Hz), 3.84 (1H, dd, J = 12.8 Hz, 2.2 Hz), 3.93 (1H, m), 4.18 (1H, m), 6.46 (1H, br s), 6.88 (2H, m), 7.93 (1H, m).
Example 56 1,1-Dicyclohexyl-N-[(4-fluorophenyl) methyl] -tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide As in Example 55 The title compound was obtained by the above method using 4-fluorobenzyl isocyanate instead of 2,4-difluorophenyl isocyanate. Yield 58%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ0.88 (2H, m), 0.99 (2H, m), 1.17-1.45 (8H, m), 1.53 (1H, m), 1.68-2.04 (9H, m), 2.90- 2.99 (3H, m), 3.60 (1H, dd, J = 11.4 Hz, 3.7 Hz), 3.74 (2H, m), 4.13 (1H, m), 4.41 (2H, dq, J = 17.2 Hz, 5.3 Hz) , 4.80 (1H, t, J = 5.3 Hz), 7.03
(2H, t, J = 8.6 Hz), 7.28 (2H, m).

Example 57 1,1-Dicyclohexyl-tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid phenyl ester
To a solution of 1,1-dicyclohexyl-hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one (0.13 g, 0.42 mmol) in tetrahydrofuran (1 mL) was added diisopropylethylamine (0.5 mL) and phenyl chlorocarbonate (0.10 mL). g, 0.64 mmol) was added sequentially and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3), crystallized from diisopropyl ether and dried to give the title compound (88 mg, yield 49%).
Melting point 171.2-172.2 ° C.
¹ H NMR (CDCl ₃ ) δ1.00 (2H, m), 1.15-1.35 (7H, m), 1.40-1.60 (3H, m), 1.72-2.05 (10H, m), 2.95-3.35 (3H, m ), 3.67 (1H, m), 3.84 (1H, m), 4.21 (1H, dd, J = 12.9 Hz,
3.2 Hz), 4.35 (1H, m), 7.12 (2H, d, J = 7.7 Hz), 7.21 (1H, m), 7.39 (2H, t, J = 7.7
Hz).
Example 58 Tetrahydro-3-oxo-1,1-diphenyl-N- (2-pyridinyl) -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hexahydro-1,1-diphenyl-3H -Oxazolo [3,4-a] pyrazin-3-one (0.10 g, 0.34 mmol) in tetrahydrofuran (1 mL) was diluted with diisopropylethylamine (0.4 mL) and bis (trichloromethyl) carbonate (0.10 g, 0.34 mmol). Sequentially added and the mixture was stirred at room temperature for 1 hour. Subsequently, 2-aminopyridine (48 mg, 0.51 mmol) was added, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 4) and then purified by alumina column chromatography (hexane: ethyl acetate = 1: 1), powdered from diisopropyl ether and purified by the title compound (4.0 mg Yield 3%).
Amorphous.
¹ H NMR (CDCl ₃ ) δ 2.27 (1H, dd, J = 13.2 Hz, 11.3 Hz), 2.77 (1H, dt, J = 13.2 Hz, 3.7
Hz), 3.08 (1H, dt, J = 12.6 Hz, 3.7 Hz), 3.77 (1H, dd, J = 13.3 Hz, 3.1 Hz), 4.05 (2H, m), 4.43 (1H, dd, J = 11.3 Hz) , 3.6 Hz), 7.04 (2H, d, J = 8.0 Hz), 7.07 (1H, m), 7.19-7.39 (10H, m), 7.66 (1H, t, J = 8.0 Hz), 8.40 (1H, d , J = 4.7 Hz).

Example 59 N-benzoyl-tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide benzamide (1.0 g, 8.3 mmol) was converted to 1,2- It melt | dissolved in dichloroethane (5 mL), the oxalyl dichloride (1.2 g, 9.1 mmol) was added, and it stirred at 90 degreeC for 30 hours. After the reaction solution was concentrated under reduced pressure, toluene (4 mL) was added and dissolved, and hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one (0.20 g, 0.68 mmol) was added. In addition, the mixture was stirred at 60 ° C. for 6 hours. The reaction solution was concentrated under reduced pressure to half the volume, and the precipitated crystals were filtered off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1), and precipitated by adding toluene (4 mL). The crystals were removed by filtration. The residue obtained by concentrating the filtrate was again subjected to silica gel column chromatography.
After purification with (hexane: ethyl acetate = 1: 1), crystallization from diisopropyl ether gave the title compound (70 mg, yield 23%).
Melting point 170-171 ° C.
¹ H NMR (CDCl ₃ ) δ2.38 (1H, m), 2.96 (1H, m), 3.32 (1H, m), 3.80 (1H, m), 3.93 (1H, dd, J = 13.3 Hz, 3.3 Hz ), 4.05 (1H, m), 4.85 (1H, m), 7.25-7.62 (13H, m), 7.86 (2H, d, J = 7.3 Hz), 8.01 (1H, m).
Example 60 1,1-bis (4-fluorophenyl) -N- (2,4-difluorophenyl) -tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 55, instead of 1,1-dicyclohexyl-hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one, 1,1-bis (4-fluorophenyl) -hexahydro-3H The title compound was obtained using -oxazolo [3,4-a] pyrazin-3-one as a starting material. Yield 34%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.24 (1H, dd, J = 13.3 Hz, 11.3 Hz), 3.08 (1H, dt, J = 12.3 Hz, 3.0
Hz), 3.19 (1H, dt, J = 12.0 Hz, 3.1 Hz), 3.81 (1H, d, J = 12.2 Hz), 3.94 (1H, dd, J = 13.2 Hz, 3.0 Hz), 4.03 (1H, m ), 4.43 (1H, dd, J = 11.3 Hz, 3.6 Hz), 6.39 (1H, s),
6.87 (2H, t, J = 8.2 Hz), 7.03-7.12 (4H, m), 7.26-7.31 (2H, m), 7.47 (2H, m), 7.87 (1H, m).

Example 61 1,1-bis (4-fluorophenyl) -N-[(4-fluorophenyl) methyl] -tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H)- Carboxamide In the same manner as in Example 55, instead of 1,1-dicyclohexyl-hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one, 1,1-bis (4-fluorophenyl) -hexahydro- The title compound was obtained using 3H-oxazolo [3,4-a] pyrazin-3-one and 4-fluorobenzyl isocyanate in place of 2,4-difluorophenyl isocyanate. Yield 52%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.13 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.94 (1H, dt, J = 13.1 Hz, 3.3
Hz), 3.09 (1H, dt, J = 12.9 Hz, 3.3 Hz), 3.59 (1H, m), 3.86 (1H, dd, J = 13.1 Hz, 3.0 Hz), 4.03 (1H, m), 4.30-4.45 (3H, m), 4.76 (1H, m), 7.01-7.11 (6H, m), 7.22-7.28 (4H, m), 7.46 (2H, m).
Example 62 1,1-bis (4-fluorophenyl) -tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid phenyl ester By a method similar to that in Example 57 1,1-bis (4-fluorophenyl) -hexahydro-3H-oxazolo [3,4-a instead of 1,1-dicyclohexyl-hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one The title compound was obtained using pyrazin-3-one. Yield 52%.
Melting point 140-141 ° C.
¹ H NMR (CDCl ₃ ) δ2.20-2.50 (1H, m), 2.80-3.10 (1H, m), 3.19 (1H, dt, J = 12.6 Hz, 3.7 Hz), 3.95 (1H, dd, J = 13.3 Hz, 3.2 Hz), 4.04 (1H, d, J = 11.5 Hz), 4.30 (1H, d,
J = 12.5 Hz), 4.44 (1H, dd, J = 11.3 Hz, 3.3 Hz), 7.03-7.12 (6H, m), 7.20-7.31 (3H,
m), 7.38 (2H, m), 7.47 (2H, m).

Example 63 N-[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] -β-alanine ethyl ester Example 55 In a similar manner, instead of 1,1-dicyclohexyl-hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one, hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] The title compound was obtained using pyrazin-3-one using ethyl 3-isocyanate propionate instead of 2,4-difluorophenyl isocyanate. Yield 45%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ1.26 (3H, t, J = 7.1 Hz), 2.15 (1H, dd, J = 13.4 Hz, 11.3 Hz), 2.53
(2H, m), 2.87 (1H, dt, J = 13.1 Hz, 3.6 Hz), 3.06 (1H, dt, J = 13.0 Hz, 3.6 Hz), 3.48 (2H, m), 3.64 (1H, m), 3.84 (1H, dd, J = 13.0 Hz, 2.7 Hz), 3.97 (1H, m), 4.15 (2H, q, J = 7.1 Hz), 4.40 (1H, dd, J = 11.3 Hz, 3.6 Hz), 5.29 (1H, t, J = 5.7 Hz), 7.27-7.42 (8H, m), 7.51 (2H, m).
Example 64 Tetrahydro-N- [2- (4-morpholinyl) ethyl] -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hexahydro-1, 1-Diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one (0.17 g, 0.58 mmol) is dissolved in toluene (1.5 mL) and 2-bromoethyl isocyanate (0.10 g, 0.67 mmol) is added. And stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (ethyl acetate), and the fractions were collected and concentrated. The residue was dissolved in N, N-dimethylformamide (2 mL), morpholine (0.20 g, 3.9 mmol) was added, and the mixture was stirred at 60 ° C. for 16 hr. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (ethyl acetate) and crystallized from hexane to give the title compound (66 mg, yield 26%).
Melting point 174-175 ° C.
¹ H NMR (CDCl ₃ ) δ 2.18 (1H, dd, J = 13.2 Hz, 11.3 Hz), 2.44 (4H, m), 2.49 (2H, t, J = 5.4 Hz), 2.89 (1H, dt, J = 13.1 Hz, 3.6 Hz), 3.09 (1H, dt, J = 13.0 Hz, 3.6 Hz), 3.31 (2H, m), 3.65-3.70 (5H, m), 3.89 (2H, m), 4.42 (1H, dd, J = 11.3 Hz, 3.6 Hz), 5.12 (1H, m), 7.30-7.41 (8H, m), 7.51 (2H, m).

Example 65 Tetrahydro-3-oxo-1,1-diphenyl-N-[(4-pyridinyl) methyl] -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide
4- (Aminomethyl) pyridine (0.50 g, 4.6 mmol) is dissolved in tetrahydrofuran (5 mL).
g, 5.0 mmol) was added, and the mixture was stirred at 0 ° C for 30 minutes. Subsequently, hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one (0.15 g, 0.51 mmol) was added, and the mixture was stirred for 16 hours while warming from 0 ° C. to room temperature. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and water, and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (ethyl acetate) and then pulverized from hexane to obtain the title compound (0.12 g, yield 56%).
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.20 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.96 (1H, dt, J = 13.0 Hz, 3.3
Hz), 3.11 (1H, dt, J = 12.8 Hz, 3.5 Hz), 3.69 (1H, m), 3.88 (1H, dd, J = 13.0 Hz, 2.7 Hz), 4.02 (1H, m), 4.31-4.47 (3H, m), 5.02 (1H, t, J = 5.7 Hz), 7.18 (2H, d, J = 6.0 Hz), 7.27-7.40 (8H, m), 7.51 (2H, m), 8.54 (2H, d, J = 6.0 Hz).
Example 66 Tetrahydro-N-[(1-oxide-4-pyridinyl) methyl] -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide tetrahydro- 3-Oxo-1,1-diphenyl-N-[(4-pyridinyl) methyl] -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide (60 mg, 0.14 mmol) in dichloromethane (1 m-Chloroperbenzoic acid (40 mg, 0.23 mmol) was added and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and water, and concentrated under reduced pressure. Hexane was added to the residue to make it powder, and dried to obtain the title compound (34 mg, yield 55%).
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.21 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.92 (1H, m), 3.10 (1H, dt, J = 13.0 Hz, 3.5 Hz), 3.88 (2H, m), 4.06 (1H, m), 4.34-4.46 (3H, m), 5.83 (1H, t, J = 5.9 Hz), 7.14 (2H, d, J = 7.0 Hz), 7.27-7.39 (8H, m ), 7.53 (2H, m), 7.96 (2H, d,
J = 7.0 Hz).

Example 67 N-[(2-cyano-4-pyridinyl) methyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide tetrahydro- N-[(1-oxide-4-pyridinyl) methyl] -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide (34 mg, 0.08 mmol) Acetanilide
(1 mL), trimethylsilylcyanide (15 mg, 0.15 mmol) and dimethylcarbamyl chloride (16 mg, 0.15 mmol) were added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate), and pulverized with hexane to give the title compound (6 mg, yield 17%).
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.23 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.98 (1H, dt, J = 13.0 Hz, 3.2
Hz), 3.13 (1H, dt, J = 12.9 Hz, 3.5 Hz), 3.70 (1H, m), 3.91 (1H, dd, J = 13.0 Hz, 2.7 Hz), 3.97 (1H, m), 4.35-4.50 (3H, m), 5.16 (1H, t, J = 5.8 Hz), 7.27-7.41 (9H, m), 7.51 (2H, m), 7.60 (1H, s), 8.63 (1H, d, J = 5.7 Hz).
Example 68 Tetrahydro-N- [2- (4-methyl-1-piperazinyl) ethyl] -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 64, the title compound was obtained using 1-methylpiperazine instead of morpholine. Yield 15%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.17 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.29 (3H, s), 2.35-2.52 (10H, m), 2.88 (1H, dt, J = 13.2 Hz , 3.5 Hz), 3.08 (1H, dt, J = 12.9 Hz, 3.7 Hz), 3.30 (2H, m), 3.68 (1H, m), 3.86 (1H, dd, J = 13.2 Hz, 2.9 Hz), 3.91 (1H, m), 4.42 (1H, dd, J = 11.3 Hz, 3.6 Hz), 5.23 (1H, t, J = 4.1 Hz), 7.30-7.41 (8H, m), 7.52 (2H, m).

Example 69 [[3-[[[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] amino] methyl] phenyl] Methyl] carbamic acid 1,1-dimethylethyl ester In the same manner as in Example 65, instead of 4- (aminomethyl) pyridine, [[3- (aminomethyl) phenyl] methyl] carbamic acid 1,1-dimethylethyl The title compound was obtained using the ester. Yield 63%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ1.44 (9H, s), 2.15 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.87 (1H, dt, J = 13.0 Hz, 3.4 Hz), 3.06 (1H, dt, J = 12.9 Hz, 3.6 Hz), 3.66 (1H, m), 3.81 (1H, dd, J = 13.0 Hz, 2.7 Hz), 4.03 (1H, dd, J = 13.3 Hz, 2.7 Hz), 4.28 ( 2H, d, J = 5.9 Hz), 4.31-4.44 (3H, m), 4.88 (1H, br s), 4.94 (1H, t, J = 5.4 Hz), 7.17 (3H, m), 7.25-7.39 ( 9H, m), 7.51 (2H, m).
Example 70 N-[[3- (Aminomethyl) phenyl] methyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide trifluoro Acetate
[[3-[[[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] amino] methyl] phenyl] methyl] carbamine To the acid 1,1-dimethylethyl ester (0.12 g, 0.22 mmol) was added trifluoroacetic acid (1.5 mL) and the mixture was stirred at room temperature for 2 hours. Diisopropyl ether was added to the reaction solution, and the precipitated powder was collected by filtration and dried to obtain the title compound (0.11 g, yield 84%).
Amorphous.
¹ H NMR (DMSO-d ₆ ) δ2.08 (1H, dd, J = 13.1 Hz, 11.3 Hz), 2.69 (1H, dt, J = 13.0 Hz, 3.0 Hz), 3.05 (1H, dt, J = 12.9 Hz, 2.9 Hz), 3.54-3.65 (2H, m), 3.87-4.02 (4H, m), 4.27 (2H, m), 4.50 (1H, dd, J = 11.1 Hz, 3.5 Hz), 7.25-7.46 ( 12H, m), 7.56 (2H, m), 8.10 (2H, br s).

Example 71 N-[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] glycine ethyl ester Method similar to that in Example 55 Gave the title compound using ethyl isocyanatoacetate instead of 2,4-difluorophenyl isocyanate. Yield 99%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ1.29 (3H, t, J = 7.1 Hz), 2.21 (1H, dd, J = 13.4 Hz, 11.3 Hz), 2.93
(1H, dt, J = 13.1 Hz, 3.4 Hz), 3.11 (1H, dt, J = 12.9 Hz, 3.6 Hz), 3.75 (1H, m), 3.87 (1H, dd, J = 12.9 Hz, 2.8 Hz) , 3.92-3.99 (3H, m), 4.22 (2H, q, J = 7.1 Hz), 4.43 (1H, dd, J = 11.3 Hz, 3.6 Hz), 4.95 (1H, m), 7.27-7.40 (8H, m), 7.51 (2H, m).
Example 72 N-[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] glycine
N-[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] glycine ethyl ester (1.5 g, 3.6 mmol) was added to ethanol ( 10 mL) and tetrahydrofuran (2 mL), 4 M aqueous sodium hydroxide solution (1.0 mL, 4.0 mmol) was added under ice cooling, and the mixture was stirred at 0 ° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, diethyl ether and water were added to the residue, the aqueous layer was neutralized with 4 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and hexane was added to the residue to make it powder, followed by drying to obtain the title compound (1.2 g, yield 84%).
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.22 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.91 (1H, dt, J = 13.0 Hz, 3.3
Hz), 3.10 (1H, dt, J = 12.8 Hz, 3.4 Hz), 3.75 (1H, m), 3.85 (1H, dd, J = 13.2 Hz, 2.8 Hz), 3.92 (1H, dd, J = 13.4 Hz , 2.9 Hz), 3.98 (2H, d, J = 5.3 Hz), 4.44 (1H, dd, J = 11.3 Hz, 3.6 Hz), 5.22 (1H, t, J = 5.3 Hz), 7.27-7.39 (8H, m), 7.51 (2H, m).

Example 73 Tetrahydro-N- [2- (4-morpholinyl) -2-oxoethyl] -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide
N-[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] glycine (0.15 g, 0.38 mmol) was replaced with N, N- Dissolve in dimethylformamide (3 mL), morpholine (0.14 g, 1.2 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.15 g, 0.76 mmol) and 1-hydroxybenzotriazole (0.11
g, 0.77 mmol) was added and stirred at room temperature for 20 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium bicarbonate solution, and water, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 95: 5) and then pulverized from hexane to give the title compound (90 mg, yield 51%).
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.20 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.90 (1H, dt, J = 13.3 Hz, 3.0
Hz), 3.09 (1H, dt, J = 13.0 Hz, 3.2 Hz), 3.44 (2H, m), 3.64-3.71 (6H, m), 3.84 (2H, m), 3.94-4.02 (3H, m), 4.41 (1H, dd, J = 11.3 Hz, 3.5 Hz), 5.59 (1H, m), 7.28-7.41 (8H, m), 7.51 (2H, m).
Example 74 7-[[(4-Fluorophenyl) amino] acetyl] -hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one hexahydro-1,1-diphenyl-3H -Oxazolo [3,4-a] pyrazin-3-one (0.20 g, 0.68 mmol) was dissolved in tetrahydrofuran (3 mL), and diisopropylethylamine (1 mL) and chloroacetyl chloride (70 μL, 0.82 mmol) were cooled with ice. ) Was added and stirred at room temperature for 3 hours. Subsequently, 4-fluoroaniline (0.13 mL, 1.4 mmol) was added, and the mixture was stirred at 50 ° C. for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and crystallized from hexane to give the title compound (45 mg, yield 15%).
Melting point 203-204 ° C.
¹ H NMR (CDCl ₃ ) δ2.11 (1H, m), 3.09 (2H, m), 3.73 (1H, m), 3.83-4.00 (3H, m), 4.38 (1H, dd, J = 11.4 Hz, 3.3 Hz), 4.50 (1H, m), 4.60 (1H, m), 6.55 (2H, m), 6.91 (2H, t, J = 8.3 Hz), 7.33-7.43 (8H, m), 7.50 (2H, m).

Example 75 Tetrahydro-N- [2- (1H-imidazol-1-yl) ethyl] -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 64, the title compound was obtained using imidazole instead of morpholine. Yield 34%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.17 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.84 (1H, m), 3.03 (1H, dt, J = 12.8 Hz, 3.5 Hz), 3.52 (2H, m), 3.69 (1H, m), 3.82 (1H, d, J = 13.1 Hz), 3.93 (1H, m), 4.10 (2H, m), 4.38 (1H, dd, J = 11.2 Hz, 3.6 Hz) , 5.25 (1H, m), 6.86 (1H, s), 7.00 (1H, m), 7.11 (1H, s), 7.28-7.42 (8H, m), 7.51 (2H, m).
Example 76 α-[[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] amino] benzeneacetic acid methyl ester Example 65 In the same manner as described above, the title compound was obtained using phenylglycine methyl ester instead of 4- (aminomethyl) pyridine. Yield 78%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.16 (1H, q, J = 12.4 Hz), 2.90-3.16 (2H, m), 3.70 (1H, m), 3.73 (3H, s), 3.87 (1H, m) , 4.02 (1H, dd, J = 13.4 Hz, 2.5 Hz), 4.41 (1H, dd, J = 11.3 Hz, 3.6 Hz), 5.42-5.50 (2H, m), 7.27-7.40 (13H, m), 7.49 (2H, m).

Example 77 N- (Benzoylmethyl) -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide By a method similar to that in Example 124, 4 -Amino-1H-benzimidazole-1-carboxylic acid 1,
The title compound was obtained by using 2-aminoacetophenone (2-aminoacetophenone hydrochloride neutralized with 1 equivalent of diisopropylethylamine) instead of 1-dimethylethyl ester. Yield 33%.
Melting point 99-102 ° C.
¹ H NMR (CDCl ₃ ) δ2.20-2.28 (1H, m), 2.92-3.01 (1H, m), 3.11-3.18 (1H, m), 3.85-3.93 (2H, m), 3.98-4.04 (1H , m), 4.45 (1H, dd, J = 3.5 Hz, 11.2 Hz), 4.74-4.80 (2H,
m), 5.60 (1H, br s), 7.26-7.40 (8H, m), 7.49-7.55 (4H, m), 7.61-7.65 (1H, m), 7.97-8.01 (2H, m).
Example 78 Tetrahydro-N- (2-hydroxy-1-phenylethyl) -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide α-[[ (Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] amino] benzeneacetic acid methyl ester (0.15 g, 0.31 mmol) in tetrahydrofuran ( 2 mL), lithium borohydride (14 mg, 0.64 mmol) was added, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and then triturated with hexane to give the title compound (0.13 g, yield 90%).
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.14 (1H, m), 2.42 (1H, m), 2.96 (1H, m), 3.08 (1H, m), 3.67 (1H, m), 3.87 (3H, m) , 4.05 (1H, dd, J = 13.4 Hz, 3.5 Hz), 4.41 (1H, m), 4.93 (1H, m), 5.17 (1H, m), 7.27-7.38 (13H, m), 7.49 (2H, m).

Example 79 α-[[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] amino] benzeneacetic acid Same as Example 72 In place of N-[(tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] glycine ethyl ester, α- [ The title compound was obtained using [(tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] amino] benzeneacetic acid methyl ester. Yield 96%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.16 (1H, q, J = 11.3 Hz), 2.85-3.08 (2H, m), 3.65 (1H, m), 3.84 (1H, m), 3.98 (1H, m) , 4.41 (1H, m), 5.43 (2H, m), 7.28-7.39 (13H, m), 7.47 (2H,
m).
Example 80 Tetrahydro-3-oxo-1,1-diphenyl-N- [2- (1-piperidinyl) ethyl] -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Example 64 In a similar manner, the title compound was obtained using piperidine instead of morpholine. Yield 67%.
Melting point 139-140 ° C.
¹ H NMR (CDCl ₃ ) δ1.44-1.54 (5H, m), 1.70 (2H, m), 2.18 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.36 (3H, m), 2.43 (2H , t, J = 6.0 Hz), 2.86 (1H, dt, J = 13.1 Hz, 3.5 Hz), 3.08 (1H, dt, J = 12.9 Hz, 3.7 Hz), 3.27 (2H, m), 3.73 (1H, m), 3.87 (2H, m), 4.42 (1H, dd, J = 11.3 Hz, 3.6 Hz), 5.36 (1H, m), 7.29-7.39 (8H, m), 7.52 (2H, m).

Example 81 Tetrahydro-N- [2-[(2-methoxyethyl) methylamino] ethyl] -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H)- Carboxamide In the same manner as in Example 64, N- (2-methoxyethyl) -N-methylamine was used instead of morpholine to obtain the title compound. Yield 67%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.12 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.28 (3H, s), 2.51 (2H, t, J = 5.8 Hz), 2.57 (2H, t, J = 5.3 Hz), 2.85 (1H, dt, J = 13.1 Hz, 3.5 Hz), 3.07 (1H, dt, J = 12.9 Hz, 3.7 Hz), 3.25 (2H, m), 3.29 (3H, s), 3.43 (2H, t, J = 5.3 Hz), 3.71 (
1H, m), 3.83 (1H, dd, J = 13.1 Hz, 2.7 Hz), 4.08 (1H, m), 4.40 (1H, dd, J = 11.2 Hz,
3.6 Hz), 5.57 (1H, t, J = 4.3 Hz), 7.29-7.39 (8H, m), 7.52 (2H, m).
Example 82 [[[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] amino] methyl] carbamic acid azide
N-[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] glycine (0.30 g, 0.76 mmol) in tetrahydrofuran (5 mL ) Oxalyl dichloride (0.11 g, 0.85 mmol) and N, N-dimethylformamide (1 drop) were added and stirred at room temperature for 1 hour. After concentrating the reaction solution under reduced pressure, the residue was washed with N, N-dimethylformamide.
(3 mL), sodium azide (0.12 g, 1.9 mmol) was added, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 9) and then powdered from hexane to give the title compound (0.11 g, yield 31%). .
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.21 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.86 (1H, dt, J = 13.1 Hz, 3.5
Hz), 3.07 (1H, dt, J = 13.0 Hz, 3.6 Hz), 3.72 (1H, m), 3.85 (2H, m), 4.39 (1H, dd, J = 11.3 Hz, 3.6 Hz), 4.56 (2H , t, J = 6.4 Hz), 5.55 (1H, t, J = 6.2 Hz), 6.20 (1H, t, J = 6.0 Hz), 7.29-7.40 (8H, m), 7.50 (2H, m).

Example 83 N-[[(Aminocarbonyl) amino] methyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide
[[[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] amino] methyl] carbamic acid azide (68 mg, 0.16 mmol ) Was dissolved in methanol (3 mL), nickel (II) chloride hexahydrate (77 mg, 0.32 mmol) and sodium borohydride (12 mg, 0.32 mmol) were added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The precipitated powder was washed with diisopropyl ether and dried to give the title compound (52 mg, yield 81%).
Amorphous.
¹ H NMR (DMSO-d ₆ ) δ2.05 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.58 (1H, m), 3.00 (1H, dt, J = 12.8 Hz, 3.4 Hz), 3.58 ( 1H, m), 3.85 (1H, m), 3.94 (1H, m), 4.28 (2H, t, J = 5.9 Hz), 4.48 (1H, dd, J = 11.0 Hz, 3.4 Hz), 5.60 (2H, m), 6.42 (1H, t, J = 6.2 Hz), 6.52 (1H, s), 7.30-7.45 (8H, m), 7.57 (2H, m).
Example 84 Tetrahydro-N- [2- (4-methyl-1-piperidinyl) ethyl] -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 64, the title compound was obtained using 4-methylpiperidine instead of morpholine. Yield 54%.
Melting point 136-137 ° C.
¹ H NMR (CDCl ₃ ) δ0.93 (3H, d, J = 6.5 Hz), 1.12 (2H, m), 1.37 (1H, m), 1.63 (2H, m), 1.96 (2H, m), 2.17 (1H, dd, J = 13.2 Hz, 11.3 Hz), 2.45 (2H, t, J = 5.9 Hz), 2.78-2.90 (3H, m), 3.08 (1H, dt, J = 12.9 Hz, 3.6 Hz), 3.27 (2H, m), 3.72 (1H, m), 3.88 (2H, m), 4.42 (1H, dd, J = 11.3 Hz, 3.6 Hz), 5.33 (1H, m), 7.27-7.42 (8H, m ), 7.52 (2H, m).

Example 85 N- [2- (3,6-Dihydropyridin-1 (2H) -yl) ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -Carboxamide In the same manner as in Example 64, the title compound was obtained using 1,2,3,6-tetrahydropyridine in place of morpholine. Yield 34%.
Melting point 142-143 ° C.
¹ H NMR (CDCl ₃ ) δ2.15 (3H, m), 2.56 (4H, t, J = 5.6 Hz), 2.85 (1H, dt, J = 13.2 Hz, 3.5 Hz), 2.96 (2H, m), 3.07 (1H, dt, J = 13.0 Hz, 3.7 Hz), 3.32 (2H, m), 3.71 (1H,
m), 3.84 (1H, dd, J = 13.3 Hz, 3.0 Hz), 3.92 (1H, m), 4.40 (1H, dd, J = 11.3 Hz, 3.
6 Hz), 5.27 (1H, m), 5.67 (1H, m), 5.74 (1H, m), 7.27-7.39 (8H, m), 7.51 (2H, m).
Example 86 N- [2- (Diethylamino) ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Similar to Example 64 The method gave the title compound using diethylamine instead of morpholine. Yield 9%.
Melting point 97-98 ° C.
¹ H NMR (CDCl ₃ ) δ0.98 (6H, t, J = 7.1 Hz), 2.17 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.46-2.55 (6H, m), 2.85 (1H, dt , J = 13.2 Hz, 3.5 Hz), 3.08 (1H, dt, J = 13.0 Hz, 3.8 Hz), 3.23 (2H, m), 3.72 (1H, m), 3.87 (2H, m), 4.41 (1H, dd, J = 11.3 Hz, 3.6 Hz), 5.34 (1H, m), 7.27-7.39 (8H, m), 7.51 (2H, m).

Example 87 N- [2- (3,4-Dihydroisoquinolin-2 (1H) -yl) ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine- 7 (1H) -carboxamide In the same manner as in Example 64, 1,2,3,4-tetrahydroisoquinoline was used instead of morpholine to obtain the title compound. Yield 66%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.14 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.67 (2H, t, J = 5.9 Hz), 2.72-2.88 (5H, m), 3.05 (1H, dt , J = 12.9 Hz, 3.7 Hz), 3.40 (2H, m), 3.64 (2H, s), 3.73 (1H, m), 3.83 (2H, m), 4.38 (1H, dd, J = 11.3 Hz, 3.6 Hz), 5.27 (1H, t, J = 4.3 Hz), 7.04 (1H, m), 7.13-7.37 (11H, m), 7.48 (2H, m).
Example 88 Tetrahydro-3-oxo-1,1-diphenyl-N- [2- (1-pyrrolidinyl) ethyl] -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Example 64 In a similar manner, the title compound was obtained using pyrrolidine instead of morpholine. Yield 30%.
Mp 153-154 ° C.
¹ H NMR (CDCl ₃ ) δ1.74-1.78 (4H, m), 2.15 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.45-2.55
(4H, m), 2.59 (2H, t, J = 5.9 Hz), 2.87 (1H, dt, J = 13.1 Hz, 3.6 Hz), 3.08 (1H, dt, J = 12.9 Hz, 3.7 Hz), 3.31 ( 2H, m), 3.70 (1H, m), 3.85 (1H, dd, J = 13.1 Hz, 2.7 Hz), 3.97 (1H, m), 4.41 (1H, dd, J = 11.3 Hz, 3.6 Hz), 5.22 (1H, m), 7.27-7.41 (8H,
m), 7.53 (2H, m).

Example 89 Tetrahydro-3-oxo-1,1-diphenyl-N- [2- (4-thiomorpholinyl) ethyl] -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Example 64 In a similar manner, the title compound was obtained using thiomorpholine instead of morpholine. Yield 64%.
Melting point 177-178 ° C.
¹ H NMR (CDCl ₃ ) δ2.19 (1H, dd, J = 13.2 Hz, 11.3 Hz), 2.50 (2H, t, J = 6.0 Hz), 2.63
(4H, m), 2.69 (4H, m), 2.87 (1H, dt, J = 13.1 Hz, 3.5 Hz), 3.09 (1H, dt, J = 12.9 Hz, 3.7 Hz), 3.29 (2H, m), 3.72 (1H, m), 3.86 (2H, m), 4.42 (1H, dd, J = 11.3 Hz, 3.7 Hz), 5.10 (1H, t, J = 4.3 Hz), 7.30-7.42 (8H, m), 7.52 (2H, m).
Example 90 Tetrahydro-3-oxo-1,1-diphenyl-N- [3- (1-piperidinyl) propyl] -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Example 64 In the same manner, the title compound was obtained using 3-chloropropyl isocyanate instead of 2-bromoethyl isocyanate and piperidine instead of morpholine. Yield 45%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ1.40-1.54 (4H, m), 1.62-1.70 (4H, m), 2.10 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.37-2.45 (6H, m) , 2.89 (1H, dt, J = 13.1 Hz, 3.5 Hz), 3.07 (1H, dt, J = 13.0 Hz, 3.5 Hz), 3.32 (2H, m), 3.70 (1H, m), 3.85 (1H, dd , J = 12.9 Hz, 2.8 Hz), 4
.15 (1H, m), 4.41 (1H, dd, J = 11.2 Hz, 3.7 Hz), 7.06 (1H, m), 7.27-7.41 (8H, m), 7.52 (2H, m).

Example 91 N- [3- (3,6-Dihydropyridin-1 (2H) -yl) propyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -Carboxamide In the same manner as in Example 64, the title compound was prepared using 3-chloropropyl isocyanate instead of 2-bromoethyl isocyanate and 1,2,3,6-tetrahydropyridine instead of morpholine. Obtained. Yield 72%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ1.71 (2H, m), 2.03 (1H, dd, J = 13.2 Hz, 11.3 Hz), 2.14 (2H, m), 2.50-2.65 (4H, m), 2.77 (1H , dt, J = 13.3 Hz, 3.6 Hz), 2.89-3.10 (3H, m), 3.36 (2H, m), 3.50 (1H, m), 3.75 (1H, dd, J = 13.1 Hz, 2.8 Hz), 4.19 (1H, m), 4.36 (1H, dd, J = 11.2 Hz, 3.7 Hz), 5.70 (2H, m), 7.24-7.38 (8H, m), 7.52 (3H, m).
Example 92 [(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] carbamic acid ethyl ester By a method similar to that in Example 55 The title compound was obtained by using ethyl isocyanatoformate instead of 2,4-difluorophenyl isocyanate. Yield 40%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ1.31 (3H, t, J = 7.1 Hz), 2.31 (1H, dd, J = 13.2 Hz, 11.2 Hz), 2.91
(1H, dt, J = 13.1 Hz, 3.6 Hz), 3.20 (1H, dt, J = 13.2 Hz, 3.8 Hz), 3.77 (1H, m), 3.87-3.99 (2H, m), 4.22 (2H, q , J = 7.1 Hz), 4.69 (1H, dd, J = 11.2 Hz, 3.4 Hz), 6.53 (1H, s), 7.27-7.42 (8H, m), 7.56 (2H, m).

Example 93 Tetrahydro-N- (1-naphthyl) -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 55, The title compound was obtained by using 1-naphthyl isocyanate instead of 2,4-difluorophenyl isocyanate. Yield 40%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.26 (1H, dd, J = 13.3 Hz, 11.4 Hz), 3.02 (1H, dt, J = 13.1 Hz, 3.4
Hz), 3.20 (1H, dt, J = 12.9 Hz, 3.4 Hz), 3.94 (3H, m), 4.41 (1H, dd, J = 11.3 Hz, 3.5 Hz), 6.49 (1H, s), 7.17-7.56 (13H, m), 7.72-7.91 (4H, m).
Example 94 7-[[((E) -2- (4-fluorophenyl) ethenyl] sulfonyl] -hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one hexahydro-1 , 1-Diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one (50 mg, 0.17 mmol) in chloroform (2 mL) and pyridine (0.5 mL) and (E) -2- (4- Fluorophenyl) vinylsulfonyl chloride (43 mg, 0.24 mmol) was added sequentially and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and crystallized from diisopropyl ether to give the title compound (27 mg, yield 64%).
Melting point 248-249 ° C.
¹ H NMR (CDCl ₃ ) δ2.11 (1H, dd, J = 11.9 Hz, 11.3 Hz), 2.64 (1H, dt, J = 12.2 Hz, 3.6
Hz), 3.25 (1H, dt, J = 13.4 Hz, 3.9 Hz), 3.51 (1H, m), 3.68 (1H, dd, J = 12.2 Hz, 3.9 Hz), 3.96 (1H, dd, J = 13.3 Hz) , 2.8 Hz), 4.59 (1H, dd, J = 11.0 Hz, 3.7 Hz), 6.40
(1H, d, J = 15.5 Hz), 7.10 (2H, t, J = 8.5 Hz), 7.26-7.43 (11H, m), 7.51 (2H, m).

Example 95 Hexahydro-1,1-diphenyl-7-[(phenylmethyl) sulfonyl] -3H-oxazolo [3,4-a] pyrazin-3-one By a method similar to that in Example 94, (E) -2 The title compound was obtained using benzylsulfonyl chloride instead of-(4-fluorophenyl) vinylsulfonyl chloride. Yield 52%.
Mp 153-154 ° C.
¹ H NMR (CDCl ₃ ) δ1.85 (1H, dd, J = 12.8 Hz, 11.1 Hz), 2.56 (1H, dt, J = 12.5 Hz, 3.5
Hz), 3.07 (1H, dt, J = 13.3 Hz, 3.9 Hz), 3.20 (1H, m), 3.56 (1H, dd, J = 12.8 Hz, 3.9 Hz), 3.81 (1H, dd, J = 13.4 Hz , 2.8 Hz), 4.16 (2H, s), 4.31 (1H, dd, J = 11.1 Hz,
3.8 Hz), 7.17-7.39 (15H, m).
Example 96 Tetrahydro-3-oxo-1,1-diphenyl-N-[(3-thienyl) methyl] -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Similar to Example 65 The title compound was obtained by the method using 3-thienylmethylamine instead of 4- (aminomethyl) pyridine. Yield 73%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.17 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.90 (1H, dt, J = 12.8 Hz, 3.4
Hz), 3.08 (1H, dt, J = 12.8 Hz, 3.5 Hz), 3.63 (1H, m), 3.85 (1H, dd, J = 12.9 Hz, 2.8 Hz), 4.02 (1H, m), 4.30-4.50 (3H, m), 4.69 (1H, m), 7.02 (1H, m), 7.12 (1H, s), 7.27-7.40 (9H, m), 7.51 (2H, m).

Example 97 N-[(3,4-Difluorophenyl) methyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Example 58 In the same manner as in 3, the title compound was obtained using 3,4-difluorobenzylamine instead of 2-aminopyridine. Yield 44%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ 2.18 (1H, dd, J = 13.3 Hz, 11.3 Hz), 2.93 (1H, dt, J = 12.9 Hz, 3.4
Hz), 3.09 (1H, dt, J = 12.8 Hz, 3.4 Hz), 3.64 (1H, m), 3.87 (1H, dd, J = 13.0 Hz, 2.6 Hz), 4.02 (1H, dd, J = 13.4 Hz , 2.4 Hz), 4.35 (2H, m), 4.42 (1H, dd, J = 11.3 Hz,
3.6 Hz), 4.84 (1H, t, J = 5.3 Hz), 7.00 (1H, m), 7.10 (2H, m), 7.27-7.40 (8H, m),
7.51 (2H, m).
Example 98 Tetrahydro-N- [2- [methyl (phenylmethyl) amino] ethyl] -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 64, the title compound was obtained using N-methylbenzylamine instead of morpholine. Yield 62%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.11 (1H, dd, J = 13.2 Hz, 11.3 Hz), 2.24 (3H, s), 2.50 (2H, m), 2.85 (1H, dt, J = 12.9 Hz, 3.4 Hz), 3.02 (1H, dt, J = 12.9 Hz, 3.5 Hz), 3.27 (2H, q,
J = 5.6 Hz), 3.45-3.55 (3H, m), 3.83 (1H, dd, J = 12.9 Hz, 2.7 Hz), 3.98 (1H, m), 4.37 (1H, dd, J = 11.3 Hz, 3.6 Hz ), 5.10 (1H, m), 7.21-7.38 (13H, m), 7.52 (2H, m).

Example 99 1,1-bis (phenylmethyl) -tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid 1,1-dimethylethyl ester
2- [1-Hydroxy-2-phenyl-1- (phenylmethyl) ethyl] -1,4-piperazinedicarboxylic acid bis (1,1-dimethylethyl) ester (2.0 g, 4.0 mmol) in N, N-dimethyl It melt | dissolved in formamide (20 mL), 60% sodium hydride (0.19 g, 4.8 mmol) was added, and it stirred at room temperature for 6 hours. The mixture was extracted with ethyl acetate, washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the resulting crystals were collected by filtration and washed with diisopropyl ether to give the title compound (1.4 g, yield 82%).
Melting point 188-189 ° C.
¹ H NMR (CDCl ₃ ) δ1.47 (9H, s), 2.59-2.98 (6H, m), 3.26 (1H, d, J = 14.3 Hz), 3.48-3.56 (2H, m), 3.95-4.10 ( 2H, m), 7.13-7.38 (10H, m).
Example 100 1,1-bis (phenylmethyl) -N-[(4-fluorophenyl) methyl] -tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide
1,1-bis (phenylmethyl) -hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one (0.1
To 6 g, 0.50 mmol) were added tetrahydrofuran (10 mL) and 4-fluorobenzyl isocyanate (0.30 g, 2.0 mmol), and the mixture was stirred at 50 ° C. for 4 hours. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to ethyl acetate). Fractions were collected and concentrated, and diisopropyl ether was added to the residue. The resulting solid was collected by filtration and washed with diisopropyl ether to give the title compound (0.17 g, yield 70%).
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.65-2.95 (6H, m), 3.26 (1H, d, J = 14.3 Hz), 3.55-3.71 (3H, m), 3.94-3.98 (1H, m), 4.37- 4.39 (2H, m), 4.58 (1H, br s), 7.01-7.37 (14H, m).

Example 101 1,1-bis (phenylmethyl) -N- (4-fluorophenyl) -tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Example 100 In the same manner, the title compound was obtained using 4-fluorophenyl isocyanate in place of 4-fluorobenzyl isocyanate. Yield 49%.
Melting point 165-166 ° C (crystallized from diethyl ether).
¹ H NMR (CDCl ₃ ) δ2.74-2.98 (6H, m), 3.27-3.32 (1H, m), 3.60-3.66 (2H, m), 3.75-3.82 (1H, m), 4.00-4.08 (1H m), 6.10-6.16 (1H, m), 7.00-7.39 (14H, m).
Example 102 1,1-bis (phenylmethyl) -tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid phenyl ester
Triethylamine (0.14 mL) and chlorocarbonic acid in a solution of 1,1-bis (phenylmethyl) -hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one (0.16 g, 0.50 mmol) in tetrahydrofuran (10 mL) Phenyl (0.12 g, 0.75 mmol) was added sequentially and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 to ethyl acetate). Diisopropyl ether was added to crystals formed by concentrating the fraction, and the crystals were collected by filtration and washed with diisopropyl ether to obtain the title compound (0.19 g, yield 85%).
Melting point 140-141 ° C.
¹ H NMR (CDCl ₃ ) δ2.74-3.01 (6H, m), 3.29-3.33 (1H, m), 3.64-3.68 (2H, m), 4.20-4.30 (2H, m), 7.09-7.39 (15H , m).

Example 103 Tetrahydro-3-oxo-1-phenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid 1,1-dimethylethyl ester
2-benzoyl-1,4-piperazinedicarboxylic acid bis (1,1-dimethylethyl) ester (0.10
g, 0.26 mmol) in methanol (2 mL) and sodium borohydride (19 mg, 0.51
mmol) was added and stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (3 mL) and 60% sodium hydride (12 mg, 0.30
mmol) was added and stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate, washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 to 1: 1) to give the title compound (47 mg, yield 57%) as a diastereomer mixture. Diastereomeric ratio (α: β = 1: 5).
Melting point 133-135 ° C.
¹ H NMR (CDCl ₃ ) δ1.42 (9H of α, 9H of β, s), 2.10-2.20 (1H of α, 1H of β, m), 2.62-3.09 (2H of α, 2H of β, m ), 3.50-4.10 (4H of α, 4H of β, m), 5.03-5.06 (1H of α, m), 5.68-5.71 (1H of β, m), 7.27-7.38 (5H of α, 5H of β , m).
Example 104 N- (4-Fluorophenyl) -tetrahydro-3-oxo-1-phenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide tetrahydro-3-oxo-1-phenyl- 3H-Oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid
To a solution of 1,1-dimethylethyl ester (94 mg, 0.30 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.5 mL), and the mixture was stirred at room temperature for 4 hours. After the reaction solution was concentrated, ethyl acetate was added to the residue. This was washed with 0.5 M aqueous sodium hydrogen carbonate solution (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Tetrahydrofuran (5 mL) and 4-fluorophenyl isocyanate (0.10 g, 0.73 mmol) were added to the residue, and the mixture was stirred at 50 ° C. for 1 hour. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to ethyl acetate) to give the title compound (20 mg, yield 19%) as a diastereomer mixture. Diastereomeric ratio (α: β = 3: 1).
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.31 (1H of α, t, J = 13.3 Hz), 2.95-3.18 (2H of α, 3H of β, m), 3.58-3.62 (1H of α), 3.68-3.78 (1H of β, m), 3.83-3.96 (2H of α, 2H of β,
m), 4.04-4.14 (1H of α, m), 4.43-4.48 (1H of β, m), 5.10 (1H of β, d, J = 6.4 Hz), 5.73 (1H of α, d, J = 8.2 Hz), 6.18 (1H of α, br), 6.32 (1H of β, br s), 6.95-7.03 (2H of α, 2H of β, m), 7.20-7.43 (7H of α, 7H of β, m ).

Example 105 N-[(4-Fluorophenyl) methyl] -tetrahydro-3-oxo-1-phenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Similar method to Example 104 Gave the title compound as a diastereomeric mixture using 4-fluorobenzyl isocyanate instead of 4-fluorophenyl isocyanate. Yield 91%. Diastereomeric ratio (α: β = 5: 2).
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.21 (1H of α, t, J = 12.2 Hz), 2.82-2.90 (1H of α, 1H of β, m), 2.99-3.13 (1H of α, 2H of β, m), 3.56-3.72 (2H of α, 1H of β, m), 3.81-3.88 (1H of α, 2H of β, m), 3.96-4.03 (1H of α, m), 4.31-4.42 (2H of α, 3H of β, m), 4.72 (1H of α, br s), 4.82 (1H of β, br s), 5.06 (1H of β, d, J = 7.1 Hz), 5.68 (1H of α, d , J = 8.2 Hz), 6.96-7.01 (2H of α, 1H of β, m), 7.20-7.40 (7H of α, 8H of β, m).
Example 106 Tetrahydro-3-oxo-1-phenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid phenyl ester tetrahydro-3-oxo-1-phenyl-3H-oxazolo [3, 4-a] pyrazine-7 (1H) -carboxylic acid
To a solution of 1,1-dimethylethyl ester (0.12 g, 0.38 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 4 hours. After concentrating the reaction solution, ethyl acetate was added to the residue. This was washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Tetrahydrofuran (5 mL), triethylamine (0.10 ml, 0.75 mmol) and phenyl chlorocarbonate (88 mg, 0.56 mmol) were added to the residue, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction solution, washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 to ethyl acetate) to give the title compound (0.10 g, yield 80%) as a diastereomeric mixture. Diastereomeric ratio (α: β = 3: 1).
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.28-2.56 (1H of α, m), 2.82-3.32 (2H of α, 3H of β, m), 3.71-3.77 (1H of α, 1H of β, m), 3.94-3.98 (1H of α, 1H of β, m), 4.07-4.11 (1H
of α, m), 4.23-4.40 (1H of α, 1H of β, m), 4.53-4.58 (1H of β, m), 5.11 (1H
of β, d, J = 6.3 Hz), 5.74 (1H of α, d, J = 8.3 Hz), 7.02-7.40 (10H of α, 10H of
β, m).

Example 107 Tetrahydro-3-oxo-1,1-diphenyl-N- (8-quinolinyl) -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide
8-Quinolinecarboxylic acid (0.17 g, 1.0 mmol) was suspended in toluene (5 mL), and triethylamine (0.14 mL, 1.0 mmol) and diphenylphosphoryl azide (0.28 g, 1.0 mmol) were sequentially added under ice cooling. . The mixture was stirred at room temperature for 1 hour and then stirred at 80 ° C. for 3 hours. After cooling to 50 ° C, tetrahydrofuran (5 mL), hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one (88 mg, 0.30 mmol) were added, and the mixture was added to 50 ° C. And stirred overnight. After cooling the reaction solution to room temperature, ethyl acetate was added. This was washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 to ethyl acetate) to give the title compound (46 mg, yield 33%).
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.18-2,30 (1H, m), 2.82-3.10 (2H, m), 3.90-4.14 (2H, m), 4.40-4.82 (2H, m), 6.77-8.33 (16H, m), 14.48 (1H, br s).
Example 108 Tetrahydro-3-oxo-1,1-diphenyl-N- (4-quinolinyl) -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 107, The title compound was obtained using 4-quinolinecarboxylic acid instead of 8-quinolinecarboxylic acid. Yield 66%.
238-241 ° C.
¹ H NMR (CDCl ₃ ) δ2.37 (1H, t, J = 12.1 Hz), 3.17-3.25 (2H, m), 3.94-4.11 (3H, m), 4.54 (1H, dd, J = 3.3 Hz, 11.2 Hz), 7.08 (1H, br s), 7.35-7.41 (8H, m), 7.52-7.76 (5H, m), 7.93 (1H, d, J = 5.0 Hz), 8.14 (1H, d, J = 8.5 Hz), 8.82 (1H, d, J = 5.1 Hz).

Example 109 Tetrahydro-N- (1H-indol-3-yl) -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Same as Example 107 By the method described above, the title compound was obtained using 3-indolecarboxylic acid instead of 8-quinolinecarboxylic acid. Yield 60%.
Melting point 239-243 ° C.
¹ H NMR (CDCl ₃ ) δ2.27 (1H, t, J = 12.8 Hz), 3.01-3.24 (2H, m), 3.92 (2H, t, J = 11.3
Hz), 4.05 (1H, d, J = 14.0 Hz), 4.43-4.46 (1H, m), 6.24 (1H, s), 7.12-7.49 (14H, m), 7.95 (1H, br s).
Example 110 Tetrahydro-N- (2-hydroxy-3-pyridinyl) -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Similar to Example 107 By the method described above, the title compound was obtained using 2-hydroxynicotinic acid instead of 8-quinolinecarboxylic acid. Yield 69%.
Melting point 277-278 ° C.
¹ H NMR (CDCl ₃ ) δ2.27 (1H, t, J = 11.8 Hz), 2.99-3.20 (2H, m), 3.90-3.96 (2H, m), 4.09 (1H, t, J = 6.8 Hz) , 4.44-4.49 (1H, m), 6.32 (1H, t, J = 6.8 Hz), 6.95 (1H, d, J = 6.5 Hz), 7.26-7.47 (8H, m), 7.52-7.55 (2H, m ), 7.77 (1H, s), 8.16 (1H, d, J = 7.4 Hz), 10.61 (1H, br s).

Example 111 Tetrahydro-3-oxo-N- [5-oxo-2-pyrrolidinyl] -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Same as Example 107 The title compound was obtained by using DL-pyroglutamic acid instead of 8-quinolinecarboxylic acid. Yield 36%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ1.56-2.48 (6H, m), 2.78-3.08 (2H, m), 3.74-3.95 (3H, m), 4.39-4.42 (1H, m), 5.40-5.53 (1H m), 6.49-6.63 (1H, m), 7.26-7.50 (10H, m).
Example 112 N- (Benzo [b] thien-3-yl) -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Example 107 In the same manner as described above, the title compound was obtained using 3-benzothiophenecarboxylic acid instead of 8-quinolinecarboxylic acid. Yield 41%.
Melting point 228-230 ° C.
¹ H NMR (CDCl ₃ ) δ2.30 (1H, t, J = 12.3 Hz), 3.09-3.22 (2H, m), 3.87-4.08 (3H, m), 4.49 (1H, dd, J = 3.6 Hz, 11.3 Hz), 6.59 (1H, br s), 7.32-7.52 (13H, m), 7.61 (1H,
s), 7.84-7.86 (1H, m).

Example 113 Tetrahydro-N- (1H-indol-2-yl) -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Same as Example 107 By the method described above, the title compound was obtained using 2-indolecarboxylic acid instead of 8-quinolinecarboxylic acid. Yield 32%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.13-2.36 (1H, m), 2.62-2.90 (1H, m), 3.03-3.11 (1H, m), 3.80-3.90 (2H, m), 4.31-4.51 (2H m), 4.69-4.83 (1H, m), 6.89-7.67 (15H, m), 11.20 (1H, br s).
Example 114 Tetrahydro-N- (1H-indol-4-yl) -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Same as Example 107 By the above method, the title compound was obtained using 4-indolecarboxylic acid instead of 8-quinolinecarboxylic acid. Yield 61%.
Melting point 143-145 ° C.
¹ H NMR (CDCl ₃ ) δ2.26 (1H, t, J = 12.6 Hz), 2.95-3.21 (2H, m), 3.88-4.01 (3H, m), 4.41 (1H, dd, J = 3.4 Hz, 11.1 Hz), 6.41-6.44 (2H, m), 7.16-7.46 (14H, m), 8.28 (1H, br s).

Example 115 Tetrahydro-N- (1H-indol-5-yl) -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Similar to Example 107 The title compound was obtained by the above method using 5-indolecarboxylic acid instead of 8-quinolinecarboxylic acid. Yield 76%.
Melting point 263-265 ℃.
¹ H NMR (CDCl ₃ ) δ2.22 (1H, t, J = 11.5 Hz), 2.88-3.17 (2H, m), 3.84-3.92 (2H, m), 4.00-4.05 (1H, m), 4.45 ( 1H, dd, J = 3.4 Hz, 11.2 Hz), 6.30 (1H, s), 6.51 (1H, s),
7.04-7.55 (14H, m), 8.16 (1H, br s).
Example 116 Tetrahydro-N- (1H-indol-6-yl) -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Similar to Example 107 The title compound was obtained by the above method using 6-indolecarboxylic acid instead of 8-quinolinecarboxylic acid. Yield 50%.
Melting point 258-260 ° C.
¹ H NMR (CDCl ₃ ) δ2.15 (1H, t, J = 11.1 Hz), 2.70-2.77 (1H, m), 3.08-3.16 (1H, m), 3.61-3.66 (1H, m), 3.93- 4.11 (2H, m), 4.58-4.63 (1H, m), 6.30 (1H, s), 6.94 (1H,
d, J = 8.5 Hz), 7.18-7.20 (1H, m), 7.33-7.43 (9H, m), 7.57-7.60 (3H, m), 8.57 (1H, br), 10.87 (1H, br s).

Example 117 N- (2,3-Dihydro-3-oxo-1H-isoindol-1-yl) -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine- 7 (1H) -carboxamide In the same manner as in Example 107, the title compound was diastereomerized using 2,3-dihydro-3-oxo-1H-isoindole-1-carboxylic acid instead of 8-quinolinecarboxylic acid. Obtained as a mer mixture. Yield 32%. Diastereomeric ratio (α: β = 1: 1).
Melting point 152-156 ° C.
¹ H NMR (CDCl ₃ ) δ2.18-2.27 (1H of α, 1H of β, m), 2.80-2.89 (1H of α, 1H of β, m), 3.04-3.13 (1H of α, 1H of β , m), 3.80-3.89 (2H of α, 2H of β, m), 4.03-4.15 (1H of α, 1H of β, m), 4.36-4.41 (1H of α or β, m), 4.48-4.54 (1H of
α or β, m), 5.71-5.74 (1H of α or β, m), 5.83 (1H of α or β, br), 6.29-6.38 (1H of α, 1H of β, 1H of α or β, m ), 6.82 (1H of α or β, br), 7.26-7.39
(9H of α, 9H of β, m), 7.49-7.59 (5H of α, 5H of β, m).
Example 118 Tetrahydro-N- (6-hydroxy-2-pyridinyl) -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Similar to Example 107 The title compound was obtained by the above method using 6-hydroxypicolinic acid instead of 8-quinolinecarboxylic acid. Yield 55%.
Melting point 260-263 ° C.
¹ H NMR (DMSO-d ₆ ) δ2.24-2.32 (1H, m), 2.73-2.85 (1H, m), 3.11-3.18 (1H, m), 3.63-3.67 (1H, m), 3.84-3.87 (1H, m), 4.01-4.07 (1H, m), 4.67-4.71 (1H, m), 6.02 (1H, br s), 7.34-7.46 (9H, m), 7.59-7.62 (2H, m), 9.27 (1H, br s), 10.30 (1H, br s), 11.44 (1H, br s).

Example 119 Tetrahydro-N- (6-hydroxy-3-pyridinyl) -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Same as Example 107 By the method described above, the title compound was obtained using 6-hydroxynicotinic acid instead of 8-quinolinecarboxylic acid. Yield 26%.
Melting point 259 ° C.
¹ H NMR (DMSO-d ₆ ) δ2.07-2.18 (1H, m), 2.71-2.79 (1H, m), 3.06-3.13 (1H, m), 3.59-3.64 (1H, m), 3.86-4.00 (2H, m), 4.55-4.60 (1H, m), 6.27 (1H, d, J = 9.7 Hz), 7.09-7.17 (1H, m), 7.30-7.44 (9H, m), 7.55-7.58 (2H m), 8.98 (1H, br s), 11.29 (1H, br s).
Example 120 Tetrahydro-γ, 3-dioxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -butanoic acid hexahydro-1,1-diphenyl-3H-oxazolo [3, To a solution of 4-a] pyrazin-3-one (0.15 g, 0.50 mmol) in tetrahydrofuran (10 mL) was added triethylamine (0.14 mL, 1.0 mmol) and succinic anhydride (55 mg, 0.55 mmol), and the mixture was stirred at room temperature. For 2 hours. Ethyl acetate was added to the reaction mixture, washed with 2 M hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to ethyl acetate). Diethyl ether was added to the residue obtained by concentrating the fractions, and the resulting crystals were collected by filtration and washed with diethyl ether to obtain the title compound (99 mg, yield 50%).
Melting point 158-164 ° C.
Amide rotamer (α: β = 7: 3).
¹ H NMR (CDCl ₃ ) δ1.99-2.07 (1H of α, m), 2.42-2.46 (1H of β, m) 2.52-2.72 (4H of α, 5H of β, m), 3.06-3.10 (2H of α, 1H of β, m), 3.50-3.52 (1H of β, m),
3.78-3.96 (2H of α, 1H of β, m), 4.33-4.38 (1H of α, m), 4.45-4.49 (1H of α, 1H of β, m), 4.59-4.64 (1H of β, m ), 7.17-7.52 (10H of α, 10H of β, m).

Example 121 Hexahydro-7-[(4-morpholinyl) acetyl] -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -3-one hexahydro-1,1-diphenyl- Add triethylamine (0.14 mL, 1.0 mmol) and chloroacetyl chloride (62 mg, 0.55 mmol) to a solution of 3H-oxazolo [3,4-a] pyrazin-3-one (0.15 g, 0.50 mmol) in tetrahydrofuran (10 mL). Sequentially added and the mixture was stirred at room temperature for 30 min. Morpholine (0.87 g, 10 mmol) and sodium iodide (0.15 g, 1.0 mmol)
And stirred for another 5 hours at room temperature. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to ethyl acetate). To the residue obtained by concentrating the fractions, diethyl ether-ethyl acetate was added, and the resulting crystals were collected by filtration and washed with diethyl ether to obtain the title compound (0.16 g, yield 76%).
Melting point 175-177 ° C.
Amide rotamer ratio (α: β = 1: 1).
¹ H NMR (CDCl ₃ ) δ1.95-2.04 (1H of α, m), 2.45-2.77 (5H of α, 5H of β, m), 2.95-3.28 (3H of α, 4H of β, m), 3.70-3.94 (5H of α, 6H of β, m), 4.11-4.15 (1H
of α, m), 4.26-4.31 (1H of α, m), 4.42-4.55 (1H of α, 2H of β, m), 7.26-7.56 (10H of α, 10H of β, m).
Example 122 7-Acetyl-hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -3-one In the same manner as in Example 120, instead of succinic anhydride The title compound was obtained using acetic anhydride. Yield 58%.
Melting point 226-227 ° C.
Amide rotamer ratio (α: β = 7: 3).
¹ H NMR (CDCl ₃ ) δ1.93-2.01 (1H of α, 1H of β, m), 2.06 (3H of β, s), 2.13 (3H
of α, s), 2.53-2.61 (1H of α, m), 2.98-3.13 (1H of α, 2H of β, m), 3.38-3.42 (1H of β, m), 3.73-3.77 (1H of α , m), 3.88-3.93 (1H of α, 1H of β, m), 4.31-4.39 (1H of α, 1H of β, m), 4.49-4.54 (1H of α, m), 4.60-4.65 (1H of β), 7.26-7.61 (10H of α, 10H of β, m).

Example 123 Hexahydro-7- [3- (4-morpholinyl) -1-oxopropyl] -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -3-one In the same manner as in 121, the title compound was obtained using 3-chloropropionyl chloride in place of chloroacetyl chloride. Yield 68%.
Melting point 173-175 ° C.
Amide rotamer ratio (α: β = 7: 3).
¹ H NMR (CDCl ₃ ) δ1.95-2.05 (1H of α, m), 2.47-2.56 (6H of α, 8H of β, m), 2.68-2.70 (2H of α, 2H of β, m), 2.98-3.06 (2H of α, 1H of β), 3.47-3.50 (1H of
β, m), 3.68-3.70 (4H of α, 4H of β, m), 3.75-3.80 (1H of α, m), 3.83-3.95 (1H of α, 1H of β, m), 4.31-4.35 ( 1H of α, 1H of β, m), 4.49-4.54 (1H of α, m), 4.62-4.66 (1H of β), 7.26-7.52 (10H of α, 10H of β, m).
Example 124 4-[[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] amino] -1H-benzimidazole-1 -Carboxylic acid 1,1-dimethylethyl ester
To a solution of 4-amino-1H-benzimidazole-1-carboxylic acid 1,1-dimethylethyl ester (0.12 g, 0.50 mmol) in tetrahydrofuran (10 ml) was added diisopropylethylamine (90 μL, 0.50 mmol) and chloroformate 4-nitro Phenyl (0.11 g, 0.50 mmol) was added and the mixture was stirred at room temperature for 4 hours. To this was sequentially added hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one (88 mg, 0.30 mmol) and diisopropylethylamine (90 μL, 0.50 mmol), and the mixture was stirred at room temperature. Stir overnight. Ethyl acetate (50 mL) and 0.5 M aqueous sodium hydrogen carbonate solution (50 mL) were added to the reaction mixture, and the resulting crystals were collected by filtration. The crude crystals were washed successively with 0.5 M aqueous sodium hydrogen carbonate solution, water and ethyl acetate to give the title compound (0.11 g, yield 65%).
Melting point 183-185 ° C.
¹ H NMR (CDCl ₃ ) δ1.71 (9H, s), 2.25-2.34 (1H, m), 3.10-3.26 (2H, m), 3.94-4.00 (2H, m), 4.17-4.21 (1H, m ), 4.50-4.55 (1H, m), 7.26-7.36 (9H, m), 7.52-7.55 (3H, m), 7.69-7.71 (1H, m), 8.00-8.02 (1H, m), 8.32-8.35 (1H, m).

Example 125 N- (1H-benzimidazol-4-yl) -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hydrochloride
4-[[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H)-
Yl) carbonyl] amino] -1H-benzimidazole-1-carboxylic acid 1,1-dimethylethyl ester (74 mg, 0.13 mmol) was suspended in ethyl acetate (5 mL) and 4 M hydrogen chloride in ethyl acetate (6 mL) was added and the mixture was stirred at room temperature overnight. After concentrating the reaction solution, ethyl acetate was added to the residue. The resulting crystals were collected by filtration and washed with ethyl acetate to give the title compound (51 mg, yield 79%).
Melting point 201-203 ° C.
¹ H NMR (DMSO-d ₆ ) δ 2.30 (1H, t, J = 11.8 Hz), 2.88-2.92 (1H, m), 3.21-3.26 (1H, m), 3.69-3.74 (1H, m), 3.98-4.16 (2H, m), 4.79-4.83 (1H, m), 7.28-7.65 (13H, m), 9.43 (2H, s).
Example 126 Hexahydro-7- [4- (4-morpholinyl) -1-oxobutyl] -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -3-one Example 121 In the same manner as described above, the title compound was obtained using 4-chlorobutyryl chloride instead of chloroacetyl chloride. Yield 32%.
Melting point 138-139 ° C.
Amide rotamer ratio (α: β = 1: 3).
¹ H NMR (CDCl ₃ ) δ1.80-1.85 (2H of α, 2H of β, m), 1.94-2.05 (1H of β, m), 2.34-2.54 (10H of α, 8H of β, m), 3.01-3.08 (1H of α, 2H of β, m), 3.51-3.68 (5H of α, 4H of β, m), 3.84-3.94 (1H of α, 2H of β, m), 4.31-4.34 (1H of α, 1H of β, m), 4.50-4.54 (1H of β, m), 4.58-4.63 (1H of α, m), 7.25-7.39 (8H of α, 8H of β, m), 7.50-7.52 (2H of α, 2H of β, m).

Example 127 Methyl [[3-[(tetrahydro-3-oxo-1,1-diphenyloxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] phenyl] methyl] carbamic acid 1,1 -Dimethyl ethyl ester
[[3-[(Tetrahydro-3-oxo-1,1-diphenyloxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] phenyl] methyl] carbamic acid 1,1-dimethylethyl ester To a solution of (0.20 g, 0.38 mmol) in N, N-dimethylformamide (5 mL) was added 60% sodium hydride (15 mg, 0.38 mmol) under an argon atmosphere and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (54 mg, 0.38 mmol) was added and stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Hexane-ethyl acetate was added to the residue and the resulting crystals were collected by filtration and washed with hexane to give the title compound (0.17 g, yield 82%).
Melting point 194-195 ° C.
¹ H NMR (CDCl ₃ ) δ1.46 (9H, s), 2.15-2.20 (1H, m), 2.80-2.83 (3H, m), 2.91-3.02 (2H, m), 3.81-3.90 (2H, m ), 4.40-4.50 (4H, m), 7.26-7.52 (14H, m).
Example 128 [[4-[(Tetrahydro-3-oxo-1,1-diphenyloxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] phenyl] methyl] carbamic acid 1,1- Dimethyl ethyl ester In the same manner as in Example 144, but using 4-[[((tert-butoxycarbonyl) amino] methyl] benzoic acid instead of 3-[[(tert-butoxycarbonyl) amino] methyl] benzoic acid The title compound was obtained. Yield 74%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ1.47 (9H, s), 2.18-2.24 (1H, m), 2.95-3.03 (2H, m), 3.72-3.85 (2H, m), 4.35-4.54 (4H, m ), 4.90 (1H, br s), 7.30-7.51 (14H, m).

Example 129 N- (2,3-dihydro-2-oxo-1H-indol-4-yl) -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -Carboxamide In the same manner as in Example 124, instead of 4-amino-1H-benzimidazole-1-carboxylic acid 1,1-dimethylethyl ester, 4-amino-1,3-dihydro-2H-indole The title compound was obtained using 2-one. Yield 34%.
Melting point 200-201 ℃.
¹ H NMR (CDCl ₃ ) δ2.24-2.32 (1H, m), 3.03-3.17 (2H, m), 3.43 (2H, s), 3.81-4.00 (3H, m), 4.46-4.51 (1H, m ), 6.16 (1H, s), 6.66 (1H, d, J = 7.7 Hz), 6.96 (1H, d, J = 8.1 Hz), 7.10-7.40 (9H, m), 7.50-7.58 (3H, m) .
Example 130 3-[(Hexahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] -N-methylbenzenemethanamine hydrochloride In a manner similar to Example 125, 4-[[[tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl] carbonyl] amino] -1H -Methyl [[3-[(tetrahydro-3-oxo-1,1-diphenyloxazolo [3,4-a] pyrazine-7 (1H instead of 1,1-dimethylethyl ester) ) -Yl) carbonyl] phenyl] methyl] carbamic acid 1,1-dimethylethyl ester was used to give the title compound. Yield 86%.
Melting point: 241-242 ° C.
¹ H NMR (DMSO-d ₆ ) δ2.28-2.34 (1H, m), 2.54 (3H, s), 2.95-3.05 (1H, m), 3.18-3.26
(1H, m), 3.55-3.63 (1H, m), 4.10-4.23 (4H, m), 4.78-4.84 (1H, m), 7.35-7.67 (14H, m), 8.84 (2H, br s).

Example 131 4-[(Hexahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] benzenemethanamine hydrochloride As in Example 125 4-[[[Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl] carbonyl] amino] -1H-benzimidazole- 1-carboxylic acid instead of 1,1-dimethylethyl ester [[4-[(tetrahydro-3-oxo-1,1-diphenyloxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl The title compound was obtained using [phenyl] methyl] carbamic acid 1,1-dimethylethyl ester. Yield 64%.
Melting point 237-240 ° C.
¹ H NMR (DMSO-d ₆ ) δ2.26-2.32 (1H, m), 2.92-3.45 (3H, m), 3.54-3.62 (1H, m), 4.00-4.29 (3H, m), 4.77-4.85 (1H, m), 7.35-7.59 (14H, m), 8.20 (2H, br s).
Example 132 Hexahydro-7- [5- (4-morpholinyl) -1-oxopentyl] -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -3-one hexahydro- 1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one (0.15 g, 0.50 mmol) was dissolved in tetrahydrofuran (10 mL) and 1-ethyl-3- (3-dimethylaminopropyl) was dissolved. ) Carbodiimide hydrochloride (0.12 g, 0.60 mmol), 1-hydroxybenzotriazole (81 mg, 0.60 mmol) and 5-bromovaleric acid (0.11 g, 0.60 mmol) were added and the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, washed with 1 M hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), diisopropylethylamine (0.17 mL, 1.0 mmol) and morpholine (0.87 g, 10 mmol) were added, and the mixture was stirred at room temperature for 2 days. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane: ethyl acetate = 9: 1 to ethyl acetate). Hexane-ethyl acetate was added to the residue obtained by concentrating the fractions, and the resulting crystals were collected by filtration and washed with hexane to obtain the title compound (0.11 g, yield 46%).
Melting point 92-96 ° C.
Amide rotamer ratio (α: β = 1: 3.2).
¹ H NMR (CDCl ₃ ) δ1.50-1.72 (4H of α, 4H of β, m), 1.97 (1H of β, t, J = 11.9 Hz), 2.28-2.54 (10H of α, 8H of β, m), 2.98-3.06 (1H of α, 2H of β, m), 3.44-3.47 (1H of α, m), 3.68-3.71 (4H of α, 4H of β, m), 3.76-3.80 (1H of β, m), 3.88-3.95 (1H of α, 1H of β, m), 4.30-4.35 (1H of α, 1H of β, m), 4.50-4.54 (1H of β, m), 4.61-4.66 ( 1H of α, m), 7.32-7.61 (10H of α, 10H of β, m).

Example 133 Hexahydro-7- [1-oxo-4- (1-piperidinyl) butyl] -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -3-one In the same manner as in 121, the title compound was obtained using 4-chlorobutyryl chloride in place of chloroacetyl chloride and piperidine in place of morpholine. Yield 50%.
Melting point 129-130 ° C.
Amide rotamer ratio (α: β = 1: 3).
¹ H NMR (CDCl ₃ ) δ1.41-1.56 (6H of α, 6H of β, m), 1.76-1.85 (2H of α, 2H of β, m), 1.97 (1H of β, t, J = 12.5 Hz), 2.27-2.39 (8H of α, 8H of β, m), 2.47-2.53 (2H of α, m), 2.97-3.08 (1H of α, 2H of β, m), 3.49-3.58 (1H of α, m), 3.86-3.93 (1H of α, 2H of β, m), 4.30-4.35 (1H of α, 1H of β, m), 4.49-4.55 (1H of β, m), 4.61-4.67 ( 1H of α, m), 7.31-7.61 (10H of α, 10H of β, m).
Example 134 7- (4-Chloro-1-oxobutyl) -hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -3-one hexahydro-1,1-diphenyl -3H-oxazolo [3,4-a] pyrazin-3-one (1.0 g, 3.4 mmol) was dissolved in tetrahydrofuran (50 mL) and triethylamine (0.96 mL, 6.8 mmol) and 4-chlorobutyryl chloride (0.42 mL, 3.7 mmol) was added and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Hexane-ethyl acetate was added to the residue and the resulting crystals were collected by filtration and washed with hexane to give the title compound (1.2 g, yield 85%).
Melting point 144-145 ° C.
Amide rotamer ratio (α: β = 1: 2.4).
¹ H NMR (CDCl ₃ ) δ1.99 (1H of β, t, J = 12.5 Hz), 2.10-2.16 (2H of α, 2H of β, m), 2.32-2.37 (1H of α, m), 2.48 -2.60 (3H of α, 2H of β, m), 2.99-3.12 (1H of α, 2H of β, m), 3.52-3.65 (3H of α, 2H of β, m), 3.83-3.96 (1H of α, 2H of β, m), 4.31-4.40 (1H of α, 1H of β, m), 4.48-4.53 (1H of β, m), 4.62-4.66 (1H of α, m), 7.28-7.52 ( 10H of α, 10H of β, m).

Example 135 Hexahydro-7- [6- (4-morpholinyl) -1-oxohexyl] -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -3-one In the same manner as in 132, the title compound was obtained using 6-bromohexanoic acid instead of 5-bromovaleric acid. Yield 38%.
Melting point 112 ° C.
Amide rotamer ratio (α: β = 1: 3.4).
¹ H NMR (CDCl ₃ ) δ1.34-1.37 (2H of α, 2H of β, m), 1.45-1.67 (4H of α, 4H of β, m), 1.93-2.01 (1H of β, m), 2.20-2.57 (10H of α, 8H of β, m), 2.95-3.03 (1H of α, 2H of β, m), 3.45-3.48 (1H of α, m), 3.70-3.78 (4H of α, 5H of β, m), 3.91-3.95 (1H of α, 1H of β, m), 4.31-4.35 (1H of α, 1H of β, m), 4.50-4.55 (1H of β, m), 4.62-4.66 (1H of α, m), 7.32-7.50 (10H of α, 10H of β, m).
Example 136 Hexahydro-7- [1-oxo-5- (1-piperidinyl) pentyl] -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -3-one In the same manner as in 132, the title compound was obtained using piperidine instead of morpholine. Yield 18%.
Melting point 93-94 ° C.
Amide rotamer ratio (α: β = 1: 3).
¹ H NMR (CDCl ₃ ) δ1.42-1.67 (10H of α, 10H of β, m), 1.96 (1H of β, t, J = 11.7 Hz), 2.22-2.58 (10H of α, 8H of β, m), 2.97-3.08 (1H of α, 2H of β, m), 3.47-3.51 (1H of α, m), 3.82-3.94 (1H of α, 2H of β, m), 4.30-4.35 (1H of α, 1H of β, m), 4.50-4.54 (1H of β, m), 4.61-4.66 (1H of α, m), 7.32-7.61 (10H of α, 10H of β, m).

Example 137 7- [5- (3,6-Dihydropyridin-1 (2H) -yl) -1-oxopentyl] -hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -3-one In the same manner as in Example 132, the title compound was obtained using 1,2,3,6-tetrahydropyridine in place of morpholine. Yield 46%.
Amorphous.
Amide rotamer ratio (α: β = 1: 3.3).
¹ H NMR (CDCl ₃ ) δ1.55-1.67 (4H of α, 4H of β, m), 1.96 (1H of β, t, J = 11.9 Hz), 2.13-2.17 (2H of α, 2H of β, m), 2.26-2.43 (4H of α, 4H of β, m), 2.50-2.54 (4H of α, 2H of β, m), 2.93-2.95 (2H of α, 2H of β, m), 3.00- 3.04 (1H of α, 2H of β, m), 3.45-3.51 (1H of α, m), 3.83-3.93 (1H of α, 2H of β, m), 4.29-4.34 (1H of α, 1H of β , m), 4.49-4.55 (1H of β, m), 4.61-4.66 (1H of α, m), 5.63-5.75 (2H of α, 2H of β, m), 7.30-7.50 (10H of α, 10H of β, m).
Example 138 7- [4- (3,6-Dihydropyridin-1 (2H) -yl) -1-oxobutyl] -hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 ( 1H) -3-one In the same manner as in Example 121, the title compound was obtained using 4-chlorobutyryl chloride instead of chloroacetyl chloride and 1,2,3,6-tetrahydropyridine instead of morpholine. It was. Yield 27%.
Amorphous.
Amide rotamer ratio (α: β = 1: 4).
¹ H NMR (CDCl ₃ ) δ1.83-2.01 (2H of α, 3H of β, m), 2.12-2.16 (2H of α, 2H of β, m), 2.26-2.52 (8H of α, 6H of β , m), 2.93-3.08 (3H of α, 4H of β, m), 3.54-3.59 (1H of α, m), 3.85-3.92 (1H of α, 2H of β, m), 4.31-4.35 (1H of α, 1H of β, m), 4.51-4.55 (1H of β, m), 4.62-4.66 (1H of α, m), 5.63-5.71 (2H of α, 2H of β, m), 7.31-7.66 (10H of α, 10H of β, m).

Example 139 Hexahydro-7- [1-oxo-4- (1-pyrrolidinyl) butyl] -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -3-one In the same manner as in 121, the title compound was obtained using 4-chlorobutyryl chloride in place of chloroacetyl chloride and pyrrolidine in place of morpholine. Yield 26%.
Melting point 87-89 ° C.
Amide rotamer ratio (α: β = 1: 2.6).
¹ H NMR (CDCl ₃ ) δ1.73-1.88 (6H of α, 6H of β, m), 1.97 (1H of β, t, J = 12.2 Hz), 2.32-2.49 (10H of α, 8H of β, m), 2.97-3.08 (1H of α, 2H of β, m), 3.55-3.59 (1H of α, m), 3.82-3.93 (1H of α, 2H of β, m), 4.30-4.35 (1H of α, 1H of
β, m), 4.50-4.55 (1H of β, m), 4.63-4.67 (1H of α, m), 7.27-7.52 (10H of α,
10H of β, m).
Example 140 4-[[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] amino] -1-piperidinecarboxylic acid 1 , 1-dimethylethyl ester In the same manner as in Example 124, instead of 4-amino-1H-benzimidazole-1-carboxylic acid 1,1-dimethylethyl ester, 4-amino-1-piperidinecarboxylic acid 1,1 -The title compound was obtained using dimethyl ethyl ester. Yield 42%.
Melting point 208-209 ° C.
¹ H NMR (CDCl ₃ ) δ1.22-1.30 (2H, m), 1.45 (9H, s), 1.90-1.95 (2H, m), 2.09-2.17 (1H, m), 2.79-2.95 (3H, m ), 3.04-3.14 (1H, m), 3.55-3.61 (1H, m), 3.71-3.88 (2H, m), 3.97-4.07 (3H, m), 4.22-4.26 (1H, m), 4.41 (1H , dd, J = 3.7 Hz, 11.3 Hz), 7.27-7.41 (8H, m), 7.50-7.61 (2H, m).

Example 141 Tetrahydro-3-oxo-1,1-diphenyl-N- (4-piperidinyl) -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hydrochloride Method similar to Example 125 4-[[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] amino] -1H-benzimidazole-1- 4-[[((Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] instead of 1,1-dimethylethyl ester of carboxylic acid The title compound was obtained using amino] -1-piperidinecarboxylic acid 1,1-dimethylethyl ester. Yield 60%.
Melting point 206-210 ° C.
¹ H NMR (DMSO-d ₆ ) δ1.55-1.64 (2H, m), 1.81-1.91 (2H, m), 1.97-2.08 (1H, m), 2.60-2.71 (1H, m), 2.87-3.06 (3H, m), 3.22-3.38 (2H, m), 3.56-3.65 (2H, m), 3.84-3.92 (2H, m), 4.45-4.50 (1H, m), 6.67 (1H, br s), 7.30-7.45 (8H, m), 7.55-7.57 (2H,
m), 8.51 (1H, br s).
Example 142 7-[(2,3-dihydro-3-oxo-1H-isoindol-1-yl) carbonyl] -hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-3 -On (single diastereomer)
In the same manner as in Reference Example 19, instead of 1,4-bis (phenylmethyl) -2-piperazinecarboxylic acid, 2,3-dihydro-3-oxo-1H-isoindole-1-carboxylic acid was added to N, The reaction was carried out using hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one instead of O-dimethylhydroxylamine hydrochloride and triethylamine. The mixture was extracted with ethyl acetate, washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Hexane-ethyl acetate was added to the residue, and the resulting crystals were collected by filtration and washed with hexane to give the title compound. Yield 14%.
Melting point 227-228 ° C.
Amide rotamer ratio (α: β = 1: 1).
¹ H NMR (DMSO-d ₆ ) δ2.14-2.27 (2H of α or β, m), 2.65-2.72 (1H of α or β, m),
2.82-2.91 (1H of α or β, m), 3.00-3.09 (1H of α or β, m), 3.40-3.49 (1H of α or β, m), 3.69-3.82 (2H of α or β, m ), 3.91-3.95 (1H of α or β, m), 4.06-4.10 (1H of α or β, m), 4.27-4.32 (1H of α or β, m), 4.39-4.43 (1H of α or
β, m), 4.60-4.65 (2H of α or β, m), 5.83 (1H of α or β, s), 5.90 (1H of α
or β, s), 7.13-7.69 (14H of α, 14H of β, m), 8.65 (1H of α or β, br s), 8.88 (1H of α or β, br s).

Example 143 7-[(2,3-dihydro-3-oxo-1H-isoindol-1-yl) carbonyl] -hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-3 -On (diastereomeric mixture)
The mother liquor used for the crystallization of Example 142 was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 to ethyl acetate). Hexane-diisopropyl ether was added, and the resulting crystals were collected by filtration and washed with hexane to give the title compound. Yield 36%.
Melting point 200-202 ° C.
Diastereomer A (identical to the compound of Example 142): Diastereomer B = 1: 2.
Amide Rotamer Ratio of Diastereomer A (α: β = 1: 1).
Amide rotamer ratio of diastereomer B (α ′: β ′ = 1: 2).
¹ H NMR (DMSO-d ₆ ) δ2.17-4.81 (7H of α, 7H of β, 7H of α ', 7H of β', m), 5.70 (1H of α ', s), 5.81 (1H of α or β, s), 5.88 (1H of α or β, s), 5.91 (1H
of β ', s), 7.11-7.64 (14H of α, 14H of β, 14H of α', 14H of β ', m), 8.64-8.67 (1H of α or β, 1H of β', br s) , 8.87 (1H of α or β, br), 9.00 (1H of α ', br s).
Example 144 [[3-[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] phenyl] methyl] carbamic acid 1, 1-dimethylethyl ester hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one (0.20 g, 0.67
mmol), 3-[[((tert-butoxycarbonyl) amino] methyl] benzoic acid (0.17 g, 0.67 mmol), 1-hydroxybenzotriazole (0.10 g, 0.74 mmol) and triethylamine (69 mg, 0.68 mmol) in acetonitrile. To the (10 mL) solution was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.20 g, 1.0 mmol) and the mixture was stirred at room temperature for 15 hours. Ethyl acetate and water were added to the reaction solution, and the separated organic layer was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 3: 7) to give the title compound (0.27 g, yield 75%).
Amorphous.
¹ H-NMR (CDCl ₃ ) δ1.45 (9H, s), 2.22 (1H, br s), 2.87-3.10 (2H, m), 3.60-3.95 (2H, m), 4.33 (2H, d, J = 6.0 Hz), 4.30-4.60 (2H, m), 4.85 (1H, br s), 7.20-7.60 (14H, m).

Example 145 3-[(Hexahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] benzenemethanamine hydrochloride
[[3-[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] phenyl] methyl] carbamic acid 1,1-dimethyl To the ethyl ester (0.25 g, 0.46 mmol) was added 4 M hydrogen chloride ethyl acetate solution (10 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and crystallized from 2-propanol-ethyl acetate to obtain the title compound (0.19 g, yield 90%).
Melting point 270-271 ° C.
¹ H NMR (DMSO-d ₆ ) δ2.20-2.40 (1H, m), 3.05 (1H, br s), 3.26 (1H, m), 3.40-3.70 (2H, m), 4.06 (2H, s) , 4.05-4.30 (1H, m), 4.81 (1H, br s), 7.10-7.70 (14H, m), 8.54 (3H, br s).
Example 146 Tetrahydro-N- [1- (1-methylethyl) -4-piperidinyl] -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Tetrahydro-3-oxo-1,1-diphenyl-N- (4-piperidinyl) -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hydrochloride (0.23 g, 0.50 mmol) to N, N-dimethylformamide (5 mL), triethylamine (0.14 mL, 1.0 mmol), acetone (58 mg, 1.0 mmol) and sodium triacetoxyborohydride (0.32 g, 1.5 mmol) were added, and the mixture was stirred at room temperature for 14 hours. . Ethyl acetate was added to the reaction mixture, and the mixture was washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane: ethyl acetate = 9: 1 to ethyl acetate) and then triturated from diisopropyl ether to give the title compound (64 mg, yield 28%).
Amorphous.
¹ H NMR (CDCl ₃ ) δ1.01-1.04 (6H, m), 1.34-1.37 (2H, m), 1.93-1.97 (2H, m), 2.08-2.27 (2H, m), 2.69-2.94 (4H , m), 3.02-3.12 (1H, m), 3.57-3.62 (2H, m), 3.83-3.87 (1H, m), 3.95-4.00 (1H, m), 4.20-4.24 (1H, m), 4.38 -4.43 (1H, m), 7.26-7.40 (8H,
m), 7.50-7.53 (2H, m).

Example 147 N- [2- (hexahydro-1H-azepin-1-yl) ethyl] tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H)- Carboxamide In the same manner as in Example 64, the title compound was obtained using hexahydro-1H-azepine instead of morpholine. Yield 12%.
Melting point 118-120 ° C.
¹ H NMR (CDCl ₃ ) δ1.55-1.58 (8H, m), 2.18 (1H, t, J = 13.4 Hz), 2.58-2.61 (6H, m), 2.83-2.91 (1H, m), 3.04- 3.13 (1H, m), 3.21-3.25 (2H, m), 3.70-3.75 (1H, m), 3.84-3.94 (2H, m), 4.39-4.44 (1H, m), 5.42 (1H, br), 7.26-7.41 (8H, m), 7,50-7,54 (2H, m).
Example 148 Hexahydro-1,1-diphenyl-7-[[4- (1-piperidinyl) -1-piperidinyl] carbonyl] -3H-oxazolo [3,4-a] pyrazin-7 (1H) -3-one
Bis (trichloromethyl) carbonate (0.10 g, 0.34 mmol) was added to a solution of 4-piperidinopiperidine (0.17 g, 1.0 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 30 minutes. Hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one (0.29 g, 1.0 mmol) and diisopropylethylamine (0.36 mL, 2.0 mmol) were added sequentially to the reaction mixture, and the mixture was allowed to cool to For 14 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to amino silica gel column chromatography (hexane: ethyl acetate = 9: 1 to ethyl acetate) and then purified by silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 1: 9) and crystallized from diethyl ether. To give the title compound (0.16 g, yield 32%).
Melting point 147-149 ° C.
¹ H NMR (CDCl ₃ ) δ1.40-1.57 (9H, m), 1.78-1.82 (2H, m), 2.18 (1H, t, J = 13.3 Hz), 2.32-2.48 (4H, m), 2.67- 2.93 (3H, m), 3.05-3.13 (1H, m), 3.46-3.55 (2H, m), 3.67-3.83 (3H, m), 4.52-4.57 (1H, m), 7.26-7.40 (8H, m ), 7.53-7.60 (2H, m).

Example 149 N- [2- (dimethylamino) -1-phenylethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 124, the title compound was obtained using 2- (dimethylamino) -1-phenylethylamine in place of 1,1-dimethylethyl ester of 4-amino-1H-benzimidazole-1-carboxylic acid. . Yield 33%. Diastereomeric mixture (α: β = 1: 1).
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.10-2.16 (1H, m), 2.25 (6H, s), 2.32-2.38 (1H, m), 2.47-2.55 (1H, m), 2.95-3.02 (1H, m ), 3.04-3.14 (1H, m), 3.72-3.82 (1H, m), 3.84-3.91 (1H, m), 3.95-4.04 (1H, m), 4.35-4.40 (1H, m), 4.60-4.65 (1H, m), 5.79 [0.5H (1H of α), s], 5.83 [0.5H (1H of β), s], 7.27-7.40 (8H, m), 7.48-7.52 (2H, m).
Example 150 Tetrahydro-N- [2- (4-morpholinyl) -1-phenylethyl] -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide The title compound was prepared in a similar manner to that described in Example 124 using 2- (4-morpholinyl) -1-phenylethylamine instead of 4-amino-1H-benzimidazole-1-carboxylic acid 1,1-dimethylethyl ester. Obtained. Yield 62%. Diastereomeric mixture (α: β = 1: 1).
Melting point 112-113 ° C.
¹ H NMR (CDCl ₃ ) δ2.11-2.19 (1H, m), 2.36-2.39 (2H, m), 2.51-2.58 (4H, m), 2.88-3.13 (2H, m), 3.53-3.75 (5H , m), 3.88-4.02 (2H, m), 4.37-4.43 (1H, m), 4.63-4.72 (1H, m), 5.74 [0.5H (1H of α), br], 5.78 [0.5H (1H of β), br], 7.25-7.37 (8H, m), 7.47-7.53 (2H, m).

Example 151 7- [4- (3,6-Dihydropyridin-1 (2H) -ylmethyl) benzoyl] -hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one
4-[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] benzaldehyde (0.15 g, 0.35 mmol) and 1,2, To a tetrahydrofuran solution (4 mL) of 3,6-tetrahydropyridine (44 mg, 0.53 mmol) was added sodium triacetoxyborohydride (0.11 g, 0.52 mmol), and the mixture was stirred at room temperature for 27 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 4: 1) and crystallized from diisopropyl ether to give the title compound (70 mg, yield 41%).
Melting point 189-191 ° C.
¹ H NMR (CDCl ₃ ) δ 2.18 (2H, t, J = 2.6 Hz), 2.26 (1H, br s), 2.57 (2H, t, J = 5.6 Hz), 2.98 (2H, t, J = 2.6 Hz), 2.99 (2H, br s), 3.61 (2H, s), 3.84 (2H, br s), 4.40-4.70 (2H, m), 5.65-5.68 (1H, m), 5.75-5.79 (1H, m), 7.26-7.44 (12H, m), 7.52 (2H,
br s).
Example 152 7- [3- (3,6-Dihydropyridin-1 (2H) -ylmethyl) benzoyl] -hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one 151, instead of 4-[(tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] benzaldehyde The title compound was obtained using [(tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] benzaldehyde. Yield 42%.
Melting point 170-172 ° C.
¹ H NMR (CDCl ₃ ) δ2.15-2.35 (3H, m), 2.55 (2H, t, J = 5.5 Hz), 2.96 (4H, br s), 3.60 (2H, s), 3.83 (2H, br s), 4.49 (2H, br s), 5.65 (1H, d, J = 10.0 Hz), 5.76 (1H, d, J = 10.0 Hz), 7.24-7.61 (14H, m).

Example 153 Tetrahydro-3-oxo-1,1-diphenyl-N- [2- (1H-pyrrol-1-yl) ethyl] -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one (0.20 g, 0.68 mmol) was dissolved in tetrahydrofuran (7 mL) and 2-bromoethyl isocyanate (0.07 mL, 0.77). mmol) was added at 0 ° C. and stirred as such for 1 hour. The reaction mixture was concentrated under reduced pressure, dissolved in N-methyl-2-pyrrolidinone (7 mL), 3-pyrroline (0.21 mL, 2.7 mmol) was added, and the mixture was stirred at 60 ° C. for 25 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over magnesium sulfate. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane: ethyl acetate = 1: 1 to ethyl acetate) and silica gel column chromatography (hexane: ethyl acetate = 8: 2 to ethyl acetate) to give the title compound (0.21 g, yield) 72%) was obtained as amorphous.
¹ H NMR (CDCl ₃ ) δ 2.16 (1H, dd, J = 11.1 Hz, 13.2 Hz), 2.76-2.86 (1H, m), 2.97-3.06
(1H, m), 3.44-3.67 (3H, m), 3.81 (2H, dd, J = 3.0 Hz, 13.2 Hz), 4.02 (2H, t, J = 5.7 Hz), 4.36 (1H, dd, J = 3.6 Hz, 11.1 Hz), 4.46 (1H, t, J = 5.7 Hz), 6.17 (2H, t, J = 2.1 Hz), 6.62 (2H, t, J = 2.1 Hz), 7.28-7.43 (8H, m ), 7.49-7.52 (2H, m).
Example 154 7- [2- (3,6-Dihydropyridin-1 (2H) -ylmethyl) benzoyl] -hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one 2- Formylbenzoic acid (0.15 g, 1.0 mmol) was dissolved in thionyl chloride (1 mL), 1 drop of pyridine was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated, and the residue was dissolved in tetrahydrofuran (5 mL). This solution was added to a solution of triethylamine (0.19 mL, 1.4 mmol) and hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one (0.20 g, 0.68 mmol) in tetrahydrofuran (3 mL). The solution was added dropwise and stirred at room temperature for 24 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1 to ethyl acetate), and the fractions were collected and concentrated. Dissolve the residue in tetrahydrofuran (4 mL), add 1,2,3,6-tetrahydropyridine (0.08 mL, 0.88 mmol) and sodium triacetoxyborohydride (0.13 g, 0.61 mmol) in this order, and stir at room temperature for 25 hours. did. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by amino silica gel column chromatography (ethyl acetate: hexane = 2: 98 to ethyl acetate: hexane = 1: 1) and silica gel column chromatography (ethyl acetate: hexane = 1: 1 to ethyl acetate), and then diisopropyl Recrystallization from ether gave the title compound (68 mg, yield 14%).
Melting point 155-157 ° C.
¹ H NMR (CDCl ₃ ) δ1.84 (1H, br s), 1.96-2.04 (1H, m), 2.17-2.89 (5H, m), 3.00-3.58 (4H, m), 3.74-3.87 (1H, m), 4.22-4.35 (1H, m), 4.41-4.49 (1H, m), 4.57-4.67 (1H, m), 5.45-5.68 (2H, m), 7.04-7.58 (14H, m).

Example 155 2- [4-[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] -1-piperidinyl] acetamide hexahydro -1,1-diphenyl-7-[(4-piperidinyl) carbonyl] -3H-oxazolo [3,4-a] pyrazin-3-one hydrochloride (0.15 g, 0.34 mmol), potassium carbonate (0.12 g, 0.87 mmol), sodium iodide (51 mg, 0.34 mmol), 2-chloroacetamide (38 mg, 0.41 mmol) in N, N-dimethylacetamide (3 mL) was stirred at room temperature for 26 hours. The reaction mixture was diluted with water and extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solid was removed by filtration and the filtrate was concentrated to dryness. The residue was recrystallized from ethanol to obtain the title compound (80 mg, yield 50%).
Melting point 253-255 ° C.
¹ H NMR (CDCl ₃ ) δ1.62-2.03 (5H, m), 2.16-2.26 (2H, m), 2.47 (1H, br s), 2.92-3.12 (6H, m), 3.83 (1H, d, J = 10.3 Hz), 3.96 (1H, d, J = 10.0 Hz), 4.33 (1H, dd, J = 3.5
Hz, 11.3 Hz), 4.52 (1H, d, J = 12.8 Hz), 5.39 (1H, br s), 7.01 (1H, br s), 7.26-7.61 (10H, m).
Example 156 Hexahydro-1,1-diphenyl-7- (quinolin-6-ylcarbonyl) -3H-oxazolo [3,4-a] pyrazin-3-one hexahydro-1,1-diphenyl-3H-oxazolo [3 , 4-a] pyrazin-3-one (0.15 g, 0.51 mmol), quinoline-6-carboxylic acid (0.11 g, 0.63 mmol), 1-hydroxybenzotriazole
(0.10 g, 0.74 mmol) was dissolved in N, N-dimethylformamide (5 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.15 g, 0.78 mmol) was added, and at room temperature. Stir for 2 hours 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution, water and saturated brine, and dried over magnesium sulfate. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by amino silica gel column chromatography (hexane: ethyl acetate = 1: 1 to ethyl acetate) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain the title compound (0.13 g, yield 57%).
Melting point 190-192 ° C.
¹ H NMR (CDCl ₃ ) δ2.04 (1H, br s), 3.08 (2H, br s), 3.86 (2H, br s), 4.51 (2H, br
s), 7.26-7.61 (11H, m), 7.68 (1H, dd, J = 1.8 Hz, 8.7 Hz), 7.90 (1H, d, J = 1.6 Hz), 8.17-8.22 (2H, m), 9.01 ( 1H, d, J = 2.8 Hz).

Example 157 Hexahydro-7-[[1- (2-hydroxyethyl) piperidin-4-yl] carbonyl] -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one
[4-[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] piperidin-1-yl] acetic acid ethyl ester (0.13 g , 0.26 mmol) in tetrahydrofuran (3 mL) at 0 ° C with lithium aluminum hydride (10 mg, 0.26 mmol)
And stirred at 0 ° C. for 30 minutes. An excess amount of ethyl acetate was added, and the mixture was further stirred at 0 ° C. for 5 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution, water and saturated brine, and dried over magnesium sulfate. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by amino silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 9: 1) and recrystallized from diisopropyl ether-ethyl acetate to give the title compound (25 mg, yield 21%).
Melting point 160-162 ° C.
¹ H NMR (CDCl ₃ ) δ1.67-2.29 (7H, m), 2.43-2.55 (3H, m), 2.93-3.12 (4H, m), 3.60 (2H, t, J = 5.3 Hz), 3.83 ( 1H, d, J = 10.3 Hz), 3.95 (1H, d, J = 9.8 Hz), 4.33 (1H, dd,
J = 3.5 Hz, 11.3 Hz), 4.53 (1H, d, J = 12.2 Hz), 7.26-7.42 (8H, m), 7.50-7.52 (2H, m).
Example 158 1-[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] -2,3-dihydroquinoline-4 ( 1H) -ON
To a solution of 2,3-dihydroquinolin-4 (1H) -one (75 mg, 0.51 mmol) and diisopropylethylamine (0.25 mL) in tetrahydrofuran (3 mL) was added triphosgene (0.15 g, 0.51 mmol), and then at room temperature for 20 minutes. Stir. Hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one (0.15 g, 0.51 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by amino silica gel column chromatography (hexane: ethyl acetate = 1: 1 to ethyl acetate) and recrystallized from diisopropyl ether to give the title compound (25 mg, yield 10%).
Melting point 202-205 ° C.
¹ H NMR (CDCl ₃ ) δ2.25 (1H, dd, J = 11.4 Hz, 13.2 Hz), 2.74-2.79 (2H, m), 2.82-2.91
(1H, m), 3.04-3.14 (1H, m), 3.72-3.89 (4H, m), 4.04-4.12 (1H, m), 4.49 (1H, dd,
J = 3.4 Hz, 11.2 Hz), 6.72-7.46 (13H, m), 8.02-8.05 (1H, m).

Example 159 Hexahydro-7-[[1- [2- (4-morpholinyl) -2-oxoethyl] piperidin-4-yl] carbonyl] -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine -3-one In the same manner as in Example 155, 4- (chloroacetyl) morpholine was used instead of 2-chloroacetamide, and the reaction mixture was subjected to amino silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 9: 1). ) To give the title compound. Yield 66%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ1.79-2.13 (7H, m), 2.45 (1H, br s), 2.92-3.12 (4H, m), 3.17 (2H, s), 3.61-3.65 (8H, m) , 3.83 (1H, d, J = 9.3 Hz), 3.95 (1H, d, J = 9.6 Hz), 4.32 (1H, d, J = 10.7 Hz), 4.51 (1H, d, J = 12.2 Hz), 7.27 -7.39 (8H, m), 7.49 (2H, br s).
Example 160 [4-[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] piperidin-1-yl] acetic acid ethyl ester Hexahydro-1,1-diphenyl-7-[(4-piperidinyl) carbonyl] -3H-oxazolo [3,4-a] pyrazin-3-one hydrochloride (0.20 g, 0.45 mmol) and potassium carbonate (0.16 g, 1.2 mmol) in tetrahydrofuran (5 mL) was added ethyl bromoacetate (0.055 mL, 0.50 mmol) at 0 ° C., and the mixture was stirred at 0 ° C. for 2 hours and at room temperature for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solid was removed by filtration and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain the title compound (0.20 g, yield 90%).
Amorphous.
¹ H NMR (CDCl ₃ ) δ1.27 (3H, t, J = 7.1 Hz), 1.62-1.70 (2H, m), 1.80-2.01 (3H, m), 2.27-2.48 (3H, m), 2.94- 3.11 (4H, m), 3.24 (2H, s), 3.81-3.96 (2H, m), 4.18 (2H, q, J = 7.1 Hz), 4.33 (1H, dd, J = 3.6 Hz, 11.3 Hz), 4.52 (1H, d, J = 13.2 Hz), 7.27-7.41 (8H, m), 7.51 (2H, d, J = 7.2 Hz).

Example 161 Tetrahydro-3-oxo-1,1-diphenyl-N- (5-quinolinyl) -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hexahydro-1,1-diphenyl-3H -Oxazolo [3,4-a] pyrazin-3-one (0.15 g, 0.51 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (0.19 g, 1.3 mmol) in acetonitrile (6 mL) To the solution, 2,2,2-trichloro-N- (5-quinolinyl) acetamide (0.16 g, 0.55
mmol) was added and heated to reflux for 6 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed twice with water and once with saturated brine, and dried over magnesium sulfate. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to ethyl acetate) and recrystallized from hexane-ethyl acetate to give the title compound (78 mg, yield 33%).
Melting point 234-236 ° C.
¹ H NMR (CDCl ₃ ) δ2.27 (1H, dd, J = 11.3 Hz, 13.2 Hz), 2.98-3.08 (1H, m), 3.14-3.23
(1H, m), 3.89-4.10 (3H, m), 4.46 (1H, dd, J = 3.6 Hz, 11.3 Hz), 6.73 (1H, br s), 7.22-7.50 (12H, m), 7.67 (1H , t, J = 8.4 Hz), 8.00 (1H, d, J = 8.5 Hz), 8.15 (1H, d,
J = 8.5 Hz), 8.92 (1H, dd, J = 1.5 Hz, 4.2 Hz).
Example 162 Tetrahydro-3-oxo-1,1-diphenyl-N- (3-pyridinyl) -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide By a method similar to that of Example 161, The title compound was obtained using 2,2,2-trichloro-N- (3-pyridinyl) acetamide instead of 2,2,2-trichloro-N- (5-quinolinyl) acetamide. Yield 66%.
Melting point 196-198 ° C. (recrystallization from hexane-ethyl acetate).
¹ H NMR (CDCl ₃ ) δ2.26 (1H, dd, J = 11.3 Hz, 13.3 Hz), 2.96-3.06 (1H, m), 3.10-3.20
(1H, m), 3.88-3.93 (2H, m), 4.03-4.13 (1H, m), 4.48 (1H, dd, J = 3.6 Hz, 11.3 Hz), 6.92 (1H, br s), 7.22-7.41 (9H, m), 7.48-7.52 (2H, m), 7.90-7.94 (1H, m), 8.28
(1H, dd, J = 1.4 Hz, 4.7 Hz), 8.44 (1H, d, J = 2.5 Hz).

Example 163 Tetrahydro-3-oxo-1,1-diphenyl-N- (4-pyridinyl) -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 161, The title compound was obtained using 2,2,2-trichloro-N- (4-pyridinyl) acetamide instead of 2,2,2-trichloro-N- (5-quinolinyl) acetamide. Yield 76%.
Melting point 157-159 ° C. (recrystallization from hexane-ethyl acetate).
¹ H NMR (CDCl ₃ ) δ2.26 (1H, dd, J = 11.4 Hz, 13.2 Hz), 2.97-3.18 (2H, m), 3.88-3.92
(2H, m), 4.04-4.09 (1H, m), 4.49 (1H, dd, J = 3.6 Hz, 11.3 Hz), 7.07 (1H, br s), 7.26-7.43 (10H, m), 7.49-7.52 (2H, m), 8.40-8.42 (2H, m).
Example 164 7-[[1- (Cyclopropylmethyl) piperidin-4-yl] carbonyl] -hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one Example 160 In a similar manner, the title compound was obtained using (bromomethyl) cyclopropane instead of ethyl bromoacetate. Yield 48%.
Melting point 145-147 ° C. (recrystallization from hexane-ethyl acetate).
¹ H NMR (CDCl ₃ ) δ0.06-0.11 (2H, m), 0.48-0.54 (2H, m), 0.82-0.90 (1H, m), 1.64-2.04 (7H, m), 2.25 (2H, d , J = 6.5 Hz), 2.42 (1H, br s), 2.97-3.11 (4H, m), 3.82-3.96 (2H, m), 4.33 (1H, dd, J = 3.6 Hz, 11.3 Hz), 4.52 ( 1H, d, J = 13.2 Hz), 7.32-7.52
(10H, m).

Example 165 Hexahydro-1,1-diphenyl-7-[[1- (2-propenyl) piperidin-4-yl] carbonyl] -3H-oxazolo [3,4-a] pyrazin-3-one hydrochloride Example In the same manner as in 160, the title compound was synthesized using allyl bromide instead of ethyl bromoacetate. The obtained free base of the title compound was converted into a hydrochloride using an excess amount of 4M hydrogen chloride ethyl acetate solution and crystallized from diethyl ether to obtain the title compound. Yield 11%.
Melting point 161-163 ° C.
¹ H NMR (DMSO-d ₆ ) δ1.62-2.07 (5H, m), 2.88-3.39 (7H, m), 3.67 (3H, br s), 3.93-4.14 (2H, m), 4.54-4.67 ( 1H, m), 5.49-5.54 (2H, m), 5.97 (1H, br s), 7.36-7.57 (10H, m), 10.49 (1H, br s).
Example 166 Tetrahydro-N- (isoquinolin-6-yl) -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Similar method to Example 161 Gave the title compound using 2,2,2-trichloro-N- (isoquinolin-6-yl) acetamide instead of 2,2,2-trichloro-N- (5-quinolinyl) acetamide. Yield 55%.
Melting point 176-178 ° C. (recrystallization from hexane-ethyl acetate).
¹ H NMR (CDCl ₃ ) δ2.29 (1H, dd, J = 11.4 Hz, 13.2 Hz), 3.01-3.22 (2H, m), 3.90-3.97
(2H, m), 4.09-4.16 (1H, m), 4.52 (1H, dd, J = 3.6 Hz, 11.3 Hz), 7.10 (1H, br s), 7.28-7.42 (8H, m), 7.47-7.54 (4H, m), 7.87 (1H, d, J = 8.8 Hz), 7.97 (1H, d, J = 1.5
Hz), 8.43 (1H, d, J = 5.8 Hz), 9.11 (1H, s).

Example 167 Tetrahydro-N- (isoquinolin-5-yl) -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Similar method to Example 161 Gave the title compound using 2,2,2-trichloro-N- (isoquinolin-5-yl) acetamide in place of 2,2,2-trichloro-N- (5-quinolinyl) acetamide. Yield 59%.
Melting point 204-206 ° C. (recrystallization from hexane-ethyl acetate).
¹ H NMR (CDCl ₃ ) δ 2.30 (1H, dd, J = 11.3 Hz, 13.3 Hz), 3.03-3.12 (1H, m), 3.17-3.26
(1H, m), 3.92-3.97 (2H, m), 4.02-4.07 (1H, m), 4.50 (1H, dd, J = 3.6 Hz, 11.3 Hz), 6.74 (1H, s), 7.24-7.41 ( 8H, m), 7.48-7.51 (2H, m), 7.54-7.61 (2H, m), 7.78-7.84 (2H, m), 8.54 (1H, d, J = 6.0 Hz), 9.26 (1H, s) .
Example 168 1,1-bis (4-methylphenyl) -N- (2,4-difluorophenyl) -tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide
To a solution of 1,1-bis (4-methylphenyl) -hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one (0.20 g, 0.62 mmol) in tetrahydrofuran (6 mL) isocyanic acid 2,4- Difluorophenyl (0.090 mL, 0.76 mmol) was added at 0 ° C. and the mixture was stirred at 0 ° C. for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 98: 2 to hexane: ethyl acetate = 1: 1) and recrystallized from diisopropyl ether to give the title compound (0.20 g, yield 68%). It was.
Melting point 120-122 ° C.
¹ H NMR (CDCl ₃ ) δ2.28 (1H, dd, J = 11.4 Hz, 13.4 Hz), 2.32 (3H, s), 2.34 (3H, s), 2.98-3.21 (2H, m), 3.81-3.85 (1H, m), 3.90-4.01 (2H, m), 4.44 (1H, dd, J = 3.6 Hz,
11.3 Hz), 6.38-6.39 (1H, m), 6.82-6.89 (2H, m), 7.13-7.21 (6H, m), 7.38 (2H, d,
J = 8.3 Hz), 7.84-7.92 (1H, m).

Example 169 1,1-bis (4-methylphenyl) -N- [2- (3,6-dihydropyridin-1 (2H) -yl) ethyl] -tetrahydro-3-oxo-3H-oxazolo [3,4 -a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 153, instead of hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one, 1,1- Use bis (4-methylphenyl) -hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one and 1,2,3,6-tetrahydropyridine in place of 3-pyrroline to give the title compound. It was. Yield 61%.
Melting point 155-157 ° C. (recrystallization from ethyl acetate-hexane).
¹ H NMR (CDCl ₃ ) δ2.21-2.20 (3H, m), 2.30 (3H, s), 2.33 (3H, s), 2.53-2.57 (4H, m), 2.79-2.88 (1H, m), 2.95-2.97 (2H, m), 3.01-3.11 (1H, m), 3.29-3.38 (2H, m), 3.69-3.74 (1H, m), 3.80-3.89 (2H, m), 4.35 (1H, dd , J = 3.6 Hz, 11.3 Hz), 5.27 (1H,
t, J = 4.3 Hz), 5.64-5.68 (1H, m), 5.73-5.78 (1H, m), 7.10-7.19 (6H, m), 7.38 (2H, d, J = 8.3 Hz).
Example 170 1,1-bis (4-methylphenyl) -tetrahydro-3-oxo-N- [2- (1-piperidinyl) ethyl] -3H-oxazolo [3,4-a] pyrazine-7 (1H) -Carboxamide In the same manner as in Example 153, instead of hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one, 1,1-bis (4-methylphenyl) -hexahydro -3H-oxazolo [3,4-a] pyrazin-3-one was synthesized using piperidine instead of 3-pyrroline to give the title compound. Yield 51%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ1.43-1.55 (6H, m), 2.18 (1H, dd, J = 11.3 Hz, 13.2 Hz), 2.30 (3H,
s), 2.34 (3H, s), 2.37 (4H, br s), 2.44 (2H, t, J = 5.9 Hz), 2.78-2.88 (1H, m), 3.02-3.11 (1H, m), 3.25- 3.30 (2H, m), 3.74-3.87 (3H, m), 4.36 (1H, dd, J = 3.7 Hz, 11.3 Hz), 5.44 (1H, br s), 7.11-7.20 (6H, m), 7.39 ( 2H, d, J = 8.3 Hz).

Example 171 N- [2- [cyclopropyl [(2-nitrophenyl) sulfonyl] amino] ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -Carboxamide
A solution of N- (2-aminoethyl) -N-cyclopropyl-2-nitrobenzenesulfonamide (0.47 g, 1.7 mmol) and diisopropylethylamine (0.71 mL, 4.1 mmol) in tetrahydrofuran (15 mL) at 0 ° C with chloroformate 4 -Nitrophenyl (0.33 g, 1.7 mmol) was added and at room temperature
Stir for 1 hour. Hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one
(0.40 g, 1.4 mmol) was added and stirred at room temperature for 60 hours. Add ethyl acetate to the reaction and add 1N
The extract was washed with hydrochloric acid, 1N aqueous sodium hydroxide solution, water and saturated brine, and dried over magnesium sulfate. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 98: 2 to ethyl acetate), and the fractions were collected and concentrated. The residue was washed with diethyl ether and collected by filtration to give the title compound (0.76 g, yield 92%).
Melting point 136-138 ° C.
¹ H NMR (CDCl ₃ ) δ0.49-0.56 (2H, m), 0.65-0.74 (2H, m), 2.28 (1H, dd, J = 11.3 Hz, 13.4 Hz), 2.64-2.68 (1H, m) , 2.77-2.86 (1H, m), 3.13-3.22 (1H, m), 3.43-3.67 (4H, m), 3.79-3.84 (2H, m), 4.49 (1H, d, J = 10.4 Hz), 4.57 (1H, dd, J = 3.6 Hz, 11.2 Hz), 4.95 (1H, br s), 7.24-7.38 (8H, m), 7.55-7.59 (2H, m), 7.65-7.78 (3H, m), 8.13 -8.17 (1H, m).
Example 172 N- [2- (cyclopropylamino) ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hydrochloride
N- [2- [cyclopropyl [(2-nitrophenyl) sulfonyl] amino] ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -To a solution of carboxamide (0.60 g, 0.99 mmol) and potassium carbonate (0.41 g, 3.0 mmol) in N, N-dimethylformamide (10 mL) was added thiophenol (0.12 mL, 1.2 mmol) and stirred at room temperature for 90 minutes. . Thiophenol (0.010 mL, 0.097 mmol) was added and stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and dried over magnesium sulfate. The solid was removed by filtration and the filtrate was concentrated. Ethyl acetate was added to the residue, and the mixture was extracted 3 times with 1N hydrochloric acid. The aqueous layers were combined and sodium hydroxide (pellet) was added to adjust the pH to 12. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solid was removed by filtration and the filtrate was concentrated. An excess amount of 4M hydrogen chloride ethyl acetate solution was added and concentrated. The residue was crystallized from diethyl ether to give the title compound (0.30 g, yield 66%).
Melting point 140-142 ° C.
¹ H NMR (DMSO-d ₆ ) δ0.70-0.77 (2H, m), 0.85-0.90 (2H, m), 2.10 (1H, t, J = 12.4 Hz), 2.60-2.73 (2H, m), 3.00-3.08 (3H, m), 3.32-3.42 (2H, m), 3.60 (1H, dd, J = 2.4 Hz, 12.8 Hz), 3.87-3.97 (2H, m), 4.55 (1H, dd, J = 3.3 Hz, 11.1 Hz), 7.11 (1H, t, J = 5.2 Hz), 7.30-7.45 (8H, m), 7.60 (2H, d, J = 7.1 Hz), 9.06 (2H, br s).

Example 173 Tetrahydro-N- [2-[[(2-nitrophenyl) sulfonyl] (2-propenyl) amino] ethyl] -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] Pyrazine-7 (1H) -carboxamide In the same manner as in Example 171, instead of N- (2-aminoethyl) -N-cyclopropyl-2-nitrobenzenesulfonamide, N-allyl-N- (2-aminoethyl The title compound was obtained using) -2-nitrobenzenesulfonamide. Yield 89%.
Melting point 145-147 ° C.
¹ H NMR (CDCl ₃ ) δ2.24 (1H, dd, J = 11.3 Hz, 13.4 Hz), 2.74-2.83 (1H, m), 3.08-3.18
(1H, m), 3.29-3.54 (4H, m), 3.76-3.85 (2H, m), 3.92-3.97 (3H, m), 4.50 (1H, dd,
J = 3.6 Hz, 11.2 Hz), 5.07 (1H, br s), 5.16-5.26 (2H, m), 5.56-5.69 (1H, m), 7.24-7.39 (8H, m), 7.54-7.57 (2H, m), 7.64-7.76 (3H, m), 8.01-8.04 (1H, m).
Example 174 N- [2- [cyclopropyl (ethyl) amino] ethyl] -tetrahydro-3-oxo-1
, 1-Diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hydrochloride
N- [2- (Cyclopropylamino) ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hydrochloride (0.15 g, 0.33 mmol), triethylamine (67 mg, 0.66 mmol), 90% acetaldehyde (0.040 mL, 0.64 mmol) in 1,2-dichloroethane (5 mL) and sodium triacetoxyborohydride (0.14 g, 0.66 mmol) Stir at room temperature for 13 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solid was removed by filtration. The filtrate was concentrated and the residue was purified by amino silica gel column chromatography (hexane: ethyl acetate = 1: 1 to ethyl acetate). The mixture was concentrated, 4M hydrogen chloride ethyl acetate solution (5 mL) was added, and the mixture was concentrated. The residue was crystallized from diethyl ether to give the title compound (54 mg, yield 34%).
Melting point 138-140 ° C.
¹ H NMR (DMSO-d ₆ ) δ0.83-0.86 (2H, m), 1.00-1.20 (2H, m), 1.28 (3H, t, J = 7.2 Hz),
2.11 (1H, t, J = 12.8 Hz), 2.62-2.73 (1H, m), 2.82 (1H, br s), 2.98-3.07 (1H, m),
3.24-3.30 (4H, m), 3.42-3.46 (2H, m), 3.58-3.63 (1H, m), 3.86-3.96 (2H, m), 4.53 (1H, dd, J = 3.3 Hz, 11.1 Hz) , 7.14 (1H, br s), 7.30-7.45 (8H, m), 7.60 (2H, d, J = 8.1 Hz), 10.15 (1H, br s).

Example 175 Tetrahydro-3-oxo-1,1-diphenyl-N- [2-[(2-propenyl) amino] ethyl] -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hydrochloride Salt In the same manner as in Example 172, N- [2- [cyclopropyl [(2-nitrophenyl) sulfonyl] amino] ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3, 4-a] pyrazine-7 (1H) -carboxamide instead of tetrahydro-N- [2-[[(2-nitrophenyl) sulfonyl] (2-propenyl) amino] ethyl] -3-oxo-1,1- The title compound was obtained using diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide. Yield 78%.
Melting point 139-141 ° C.
¹ H NMR (DMSO-d ₆ ) δ 2.10 (1H, t, J = 12.6 Hz), 2.60-2.70 (1H, m), 2.93 (2H, br s), 3.00-3.10 (1H, m), 3.26 -3.37 (2H, m), 3.57-3.63 (3H, m), 3.87-3.97 (2H, m), 4.56
(1H, dd, J = 3.7 Hz, 11.1 Hz), 5.40 (1H, d, J = 10.4 Hz), 5.46 (1H, dd, J = 1.1 Hz, 17.3 Hz), 5.83-5.97 (1H, m), 7.16 (1H, t, J = 5.2 Hz), 7.30-7.45 (8H, m), 7.60 (2H,
d, J = 7.1 Hz), 9.00 (2H, br s).
Example 176 Tetrahydro-N- (1-methyl-4-piperidinyl) -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide tetrahydro-3-oxo -1,1-diphenyl-N- (4-piperidinyl) -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hydrochloride (0.14 g, 0.30 mmol) to N, N-dimethylformamide ( 5 mL) and potassium carbonate (0.14 g, 1.0 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Methyl iodide (43 mg, 0.30 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane: ethyl acetate = 9: 1 to ethyl acetate) and then triturated from diisopropyl ether to give the title compound (18 mg, yield 14%).
Amorphous.
¹ H NMR (CDCl ₃ ) δ1.37-1.47 (2H, m), 1.92-2.13 (4H, m), 2.22-2.24 (3H, m), 2.77-3.09 (4H, m), 3.56-3.61 (2H m), 3.85-4.00 (2H, m), 4.18-4.42 (2H, m), 7.27-7.51 (10H, m).

Example 177 4-[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] -1-piperidinecarboxylic acid 1,1- Dimethyl ethyl ester In the same manner as in Example 144, but using 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid instead of 3-[[(tert-butoxycarbonyl) amino] methyl] benzoic acid, the title compound Got. Yield 90%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ1.47 (9H, s), 1.63-2.06 (4H, m), 2.60-2.82 (4H, m), 3.03-3.06 (2H, m), 3.82-3.97 (2H, m ), 4.04-4.12 (2H, m), 4.33-4.52 (2H, m), 7.28-7.51 (10H,
m).
Example 178 Tetrahydro-3-oxo-1,1-diphenyl-N- (1-propyl-4-piperidinyl) -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide As in Example 146 The title compound was obtained by using propionaldehyde in place of acetone. Yield 69%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ0.89 (3H, t, J = 7.3 Hz), 1.45-1.53 (4H, m), 1.91-2.16 (5H, m), 2.25-2.32 (2H, m), 2.82- 2.91 (3H, m), 3.07-3.11 (1H, m), 3.56-3.61 (2H, m), 3.83-3.87 (1H, m), 3.97-4.02 (1H, m), 4.21-4.23 (1H, m ), 4.41 (1H, dd, J = 3.5 Hz, 11.2
Hz), 7.26-7.42 (8H, m), 7.50-7.53 (2H, m).

Example 179 Hexahydro-1,1-diphenyl-7-[(4-piperidinyl) carbonyl] -3H-oxazolo [3,4-a] pyrazin-3-one hydrochloride By a method similar to that in Example 125, 4- [[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] amino] -1H-benzimidazole-1-carboxylic acid 1, 4-[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] -1-piperidinecarboxylic acid instead of 1-dimethylethyl ester The title compound was obtained using acid 1,1-dimethylethyl ester. Yield 94%.
Melting point 186-190 ° C.
Amide rotamer ratio (α: β = 1: 3.7).
¹ H NMR (DMSO-d ₆ ) δ1.58-1.82 (4H of α, 4H of β, m), 2.03 (1H of β, t, J = 12.2 Hz), 2.49-2.51 (1H of α, m) , 2.85-3.30 (7H of α, 7H of β, m), 3.62-3.78 (2H of α, 1H of β, m), 3.94-4,15 (2H of β, m), 4.32-4.38 (1H of α, m), 4.53-4.62 (1H of α, 1H of β, m), 7.33-7.43 (8H of α, 8H of β, m), 7.56-7.60 (2H of α,
2H of β, m), 8.68 (1H of α, 1H of β, m), 8.98 (1H of β, br), 9.18 (1H of α, br).
Example 180 Hexahydro-7-[[1- (1-methylethyl) -4-piperidinyl] carbonyl] -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one Example 146 and In a similar manner, tetrahydro-3-oxo-1,1-diphenyl-N- (4-piperidinyl) -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hydrochloride instead of hexahydro- The title compound was obtained using 1,1-diphenyl-7-[(4-piperidinyl) carbonyl] -3H-oxazolo [3,4-a] pyrazin-3-one hydrochloride. Yield 18%.
Melting point 161-162 ° C.
¹ H NMR (CDCl ₃ ) δ1.03-1.05 (6H, m), 1.59-1.97 (5H, m), 2.09-2.18 (2H, m), 2.35-3.39 (1H, m), 2.67-2.74 (1H , m), 2.82-3.04 (4H, m), 3.82-3.95 (2H, m), 4.30-4.35 (1H, m), 4.50-4.55 (1H, m), 7.25-7.39 (8H, m), 7.49 -7.51 (2H, m).

Example 181 4-[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] -1-piperidinecarboxaldehyde Example 180 To give the title compound as a by-product. Yield 39%.
Melting point 133-136 ° C.
¹ H NMR (CDCl ₃ ) δ1.70-1.75 (4H, m), 1.98-2.02 (1H, m), 2.52-2.78 (2H, m), 2.98-3.14 (3H, m), 3.64-3.82 (2H m), 3.96-3.99 (1H, m), 4.32-4.48 (3H, m), 7.26-7.42 (8H, m), 7.49-7.52 (2H, m), 8.03 (1H, s).
Example 182 N- [2- (3,6-dihydropyridin-1 (2H) -yl) ethyl] -tetrahydro-N-methyl-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a ] Pyrazine-7 (1H) -carboxamide In the same manner as in Example 10, N- [2- (3,6-dihydropyridin-1 (2H) -yl) ethyl] -N-methylamine was used instead of phenylhydrazine. Used to obtain the title compound. Yield 41%.
Amorphous.
Amide rotamer ratio (α: β = 1: 5.3).
¹ H NMR (CDCl ₃ ) δ2.11-2.22 (3H of α, 3H of β, m), 2.54-2.63 (4H of α, 4H of β, m), 2.82-3.15 (7H of α, 7H of β , m), 3.28-3.55 (4H of α, 4H of β, m), 3.62-3.64 (1H of α, m), 3.77-3.82 (1H of β, m), 4.58 (1H of β, dd, J = 3.5 Hz, 11.2 Hz), 4.92-4.96 (1H of α, m), 5.60-5.76 (2H of α, 2H of β, m), 7.26-7.39 (8H of α, 8H of β, m), 7.51 -7.54 (2H of α, 2H of β, m).

Example 183 Hexahydro-1,1-diphenyl-7-[(1-propyl-4-piperidinyl) carbonyl] -3H-oxazolo [3,4-a] pyrazin-3-one In the same manner as in Example 146, Hexahydro-1,1-diphenyl instead of tetrahydro-3-oxo-1,1-diphenyl-N- (4-piperidinyl) -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hydrochloride The title compound was obtained using 7-[(4-piperidinyl) carbonyl] -3H-oxazolo [3,4-a] pyrazin-3-one hydrochloride and propionaldehyde instead of acetone. Yield 40%.
Melting point 151 ° C.
¹ H NMR (CDCl ₃ ) δ0.89 (3H, t, J = 7.3 Hz), 1.49-1.68 (4H, m), 1.72-2.02 (5H, m), 2.25-2.42 (3H, m), 2.94- 3.04 (4H, m), 3.82-3.96 (2H, m), 4.32 (1H, dd, J = 3.6 Hz, 11.3 Hz), 4.50-4.55 (1H, m), 7.26-7.42 (8H, m), 7.49 -7.52 (2H, m).
Example 184 Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid [2- (3,6-dihydropyridin-1 (2H) -yl ) Ethyl] ester hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one (0.15 g, 0.50 mmol) was dissolved in tetrahydrofuran (5 mL) and triethylamine (0.14 mL, 1.0 mmol) and 2-bromoethyl chlorocarbonate (0.10 g, 0.55 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Diisopropylamine (0.36 mL, 2.0 mmol), N, N-dimethylformamide (5 mL) and
1,2,3,6-Tetrahydropyridine (0.23 mL, 2.5 mmol) was added sequentially and the mixture was stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane: ethyl acetate = 9: 1 to ethyl acetate) and crystallized from diisopropyl ether to give the title compound (0.13 g, yield 59%).
Melting point 107-108 ° C.
¹ H NMR (CDCl ₃ ) δ2.10-2.28 (3H, m), 2.59-2.83 (5H, m), 3.02-3.10 (3H, m), 3.82-3.86 (1H, m), 3.95-4.11 (2H , m), 4.25-4.29 (2H, m), 4.37 (1H, dd, J = 3.4 Hz, 11.1 Hz), 5.63-5.76 (2H, m), 7.26-7.42 (8H, m), 7.49-7.51 ( 2H, m).

Example 185 Hexahydro-1,1-diphenyl-7-[(4-propyl-1-piperazinyl) carbonyl] -3H-oxazolo [3,4-a] pyrazin-3-one By a method similar to that in Example 10, Piperazine carboxylic acid instead of phenylhydrazine
1,1-dimethylethyl ester was used to give 4-[(tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] -1 -Piperazinecarboxylic acid 1,1-dimethylethyl ester was obtained as a crude product. In a manner similar to Example 125, 4-[(tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] -1-piperazine Crude hexahydro-1,1-diphenyl-7-[(piperazin-4-yl) carbonyl] -3H-oxazolo [3,4-a] pyrazin-3-one hydrochloride from 1,1-dimethylethyl ester of carboxylic acid Obtained as product. Further, in the same manner as in Example 146, using propionaldehyde instead of acetone, hexahydro-1,1-diphenyl-7-[(piperazin-4-yl) carbonyl] -3H-oxazolo [3,4-a The title compound was obtained from pyrazin-3-one hydrochloride. Yield 18%.
Melting point 125-127 ° C.
¹ H NMR (CDCl ₃ ) δ0.90 (3H, t, J = 7.3 Hz), 1.46-1.55 (2H, m), 2.18 (1H, t, J = 11.8 Hz), 2.22-2.40 (6H, m) , 2.84-2.94 (1H, m), 3.09 (1H, dt, J = 3.9 Hz, 12.8 Hz), 3.20-3.35 (4H, m), 3.47-3.56 (2H, m), 3.79-3.83 (1H, m ), 4.55 (1H, dd, J = 3.1 Hz, 11.0 Hz), 7.26-7.41 (8H, m), 7.51-7.54 (2H, m).
Example 186 Hexahydro-7-[(1-pentyl-4-piperidinyl) carbonyl] -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one By a method similar to that of Example 146, Hexahydro-1,1-diphenyl instead of tetrahydro-3-oxo-1,1-diphenyl-N- (4-piperidinyl) -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hydrochloride The title compound was obtained by substituting -7-[(4-piperidinyl) carbonyl] -3H-oxazolo [3,4-a] pyrazin-3-one hydrochloride for pentanal instead of acetone. Yield 72%.
Melting point 115-117 ° C.
¹ H NMR (CDCl ₃ ) δ0.89 (3H, t, J = 7.1 Hz), 1.24-1.31 (4H, m), 1.43-1.68 (4H, m), 1.75-2.01 (5H, m), 2.27- 2.42 (3H, m), 2.94-3.04 (4H, m), 3.82-3.96 (2H, m), 4.32 (1H, dd, J = 3.6 Hz, 11.3 Hz), 4.50-4.55 (1H, m), 7.31 -7.41 (8H, m), 7.50-7.53 (2H, m).

Example 187 N- [2- (3,6-dihydropyridin-1 (2H) -yl) -1,1-dimethylethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4 -a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 124, instead of 4-amino-1H-benzimidazole-1-carboxylic acid 1,1-dimethylethyl ester, N- [2- (3 , 6-Dihydropyridin-1 (2H) -yl) -1,1-dimethylethyl] amine dihydrochloride was used to give the title compound. Yield 57%.
Melting point 154-155 ° C.
¹ H NMR (CDCl ₃ ) δ1.34 (6H, s), 2.08-2.16 (3H, m), 2.45 (2H, s), 2.69 (2H, t, J = 5.5 Hz), 2.82 (1H, dt, J = 3.3 Hz, 12.9 Hz), 3.01-3.09 (3H, m), 3.61-3.65 (1H, m), 3.81-3.95 (2H, m), 4.39 (1H, dd, J = 3.5 Hz, 11.1 Hz) , 5.62-5.76 (3H, m), 7.26-7.41 (8H, m), 7.50-7.53 (2H, m).
Example 188 N- [2- (3,6-dihydropyridin-1 (2H) -yl) -1-oxoethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] Pyrazine-7 (1H) -carboxamide Hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one (0.22 g, 0.75 mmol) is dissolved in tetrahydrofuran (7.5 mL) and isocyanic acid 2-Chloroacetyl (0.10 g, 0.83 mmol) was added and stirred at −20 ° C. for 1 hour. 1,2,3,6-Tetrahydropyridine (0.27 mL, 3.0 mmol) was added and the mixture was stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to ethyl acetate) and crystallized from ethyl acetate-hexane to give the title compound (0.25 g, yield 72%).
Melting point 156-157 ° C.
¹ H NMR (CDCl ₃ ) δ2.17-2.20 (2H, m), 2.33 (1H, t, J = 11.9 Hz), 2.60-2.70 (2H, m), 2.87-2.95 (1H, m), 3.06- 3.26 (5H, m), 3.62-4.08 (3H, m), 4.72-4.78 (1H, m), 45.62-5.66 (1H, m), 5.76-5.80 (1H, m), 7.29-7.42 (8H, m ), 7.56-7.59 (2H, m), 9.06 (1H, br).

Example 189 N- [2- (3,6-dihydropyridin-1 (2H) -yl) -2,2-dimethylethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4 -a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 124, instead of 4-amino-1H-benzimidazole-1-carboxylic acid 1,1-dimethylethyl ester, N- [2- (3 , 6-Dihydropyridin-1 (2H) -yl) -2,2-dimethylethyl] amine dihydrochloride was used to give the title compound. Yield 48%.
Melting point 196-198 ° C.
¹ H NMR (CDCl ₃ ) δ1.06 (6H, s), 2.05 (2H, s), 2.17 (1H, t, J = 13.2 Hz), 2.53-2.57 (2H, m), 2.79-2.88 (1H, m), 3.02-3.51 (5H, m), 3.70-3.90 (3H, m), 4.37-4.42 (1H,
m), 5.53-5.73 (3H, m), 7.26-7.39 (8H, m), 7.50-7.52 (2H, m).
Example 190 N- [1-[(3,6-dihydropyridin-1 (2H) -yl) methyl] cyclopropyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a ] Pyrazine-7 (1H) -carboxamide In the same manner as in Example 124, instead of 4-amino-1H-benzimidazole-1-carboxylic acid 1,1-dimethylethyl ester, N- [1-[(3, The title compound was obtained using 6-dihydropyridin-1 (2H) -yl) methyl] cyclopropyl] amine dihydrochloride. Yield 20%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ0.63-0.65 (2H, m), 0.86-0.90 (2H, m), 2.04-2.16 (3H, m), 2.44 (1H, d, J = 12.9 Hz), 2.57- 2.64 (3H, m), 2.82-2.92 (1H, m), 3.00-3.12 (3H, m), 3.59-3.66 (1H, m), 3.78-3.83 (1H, m), 3.93-3.97 (1H, m ), 4.40 (1H, dd, J = 3.6 Hz, 11.2 Hz), 5.12 (1H, br), 5.66-5.72 (2H, m), 7.26-7.42 (8H, m), 7.50-7.53 (2H, m) .

Example 191 1,1-bis (4-fluorophenyl) -N- [2- (3,6-dihydropyridin-1 (2H) -yl) ethyl] -tetrahydro-3-oxo-3H-oxazolo [3,4 -a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 64, 1,2,3,6-tetrahydropyridine was replaced with hexahydro-1,1-diphenyl-3H-oxazolo [3, The title compound was obtained using 1,1-bis (4-fluorophenyl) -hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one instead of 4-a] pyrazin-3-one. Yield 65%.
Mp 153-154 ° C.
¹ H NMR (CDCl ₃ ) δ2.09-2.17 (3H, m), 2.55-2.64 (4H, m), 2.82-3.13 (4H, m), 3.32-3.35 (2H, m), 3.66-3.71 (1H , m), 3.82-3.93 (2H, m), 4.35 (1H, dd, J = 3.6 Hz, 11.2 Hz), 5.29 (1H, br), 5.64-5.76 (2H, m), 7.00-7.11 (4H, m), 7.26-7.28 (2H, m), 7.44-7.49 (2H, m).
Example 192 1,1-bis (4-fluorophenyl) -tetrahydro-3-oxo-N- [2- (1-piperidinyl) ethyl] -3H-oxazolo [3,4-a] pyrazine-7 (1H) -Carboxamide In the same manner as in Example 64, piperidine was used in place of morpholine, and 1,1-bis (in place of hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one. 4-Fluorophenyl) -hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one was used to give the title compound. Yield 52%.
Melting point 161 ° C.
¹ H NMR (CDCl ₃ ) δ1.49-1.55 (6H, m), 2.14 (1H, t, J = 12.3 Hz), 2.36-2.44 (6H, m), 2.89 (1H, dt, J = 3.4 Hz, 13.2 Hz), 3.10 (1H, dt, J = 3.5 Hz, 13.0 Hz), 3.26-3.28 (2H, m), 3.66-3.71 (1H, m), 3.83-3.92 (2H, m), 4.36 (1H, dd, J = 3.5 Hz, 11.1 Hz), 5.36 (1H, br), 7.01-7.11 (4H, m), 7.26-7.29 (2H, m), 7.45-7.49 (2H, m).

Example 193 1,1-bis (3-fluorophenyl) -N- [2- (3,6-dihydropyridin-1 (2H) -yl) ethyl] -tetrahydro-3-oxo-3H-oxazolo [3,4 -a] pyrazine-7 (1H) -carboxamide In the same manner as in Example 64, 1,2,3,6-tetrahydropyridine was replaced with hexahydro-1,1-diphenyl-3H-oxazolo [3, The title compound was obtained using 1,1-bis (3-fluorophenyl) -hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one instead of 4-a] pyrazin-3-one. Yield 74%.
Melting point 146 ° C.
¹ H NMR (CDCl ₃ ) δ2.14-2.22 (3H, m), 2.54-2.58 (4H, m), 2.84-3.14 (4H, m), 3.31-3.34 (2H, m), 3.65-3.70 (1H , m), 3.82-3.97 (2H, m), 4.36 (1H, dd, J = 3.4 Hz, 11.0 Hz), 5.27 (1H, br), 5.65-5.78 (2H, m), 6.98-7.08 (4H, m), 7.26-7.40 (4H, m).
Example 194 1,1-bis (3-fluorophenyl) -tetrahydro-3-oxo-N- [2- (1-piperidinyl) ethyl] -3H-oxazolo [3,4-a] pyrazine-7 (1H) -Carboxamide In the same manner as in Example 64, piperidine was used in place of morpholine, and 1,1-bis (in place of hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one. The title compound was obtained using 3-fluorophenyl) -hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one. Yield 43%.
Melting point 138-141 ° C.
¹ H NMR (CDCl ₃ ) δ1.50-1.58 (6H, m), 2.20 (1H, t, J = 12.3 Hz), 2.33-2.46 (6H, m), 2.85-2.94 (1H, m), 3.05- 3.14 (1H, m), 3.24-3.27 (2H, m), 3.67-3.72 (1H, m), 3.84-3.96 (2H, m), 4.35-4.39 (1H, m), 5.36 (1H, br), 7.02-7.10 (4H, m), 7.24-7.40 (4H, m).

Example 195 1,1-bis (3-fluorophenyl) -N-[(4-fluorophenyl) methyl] -tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H)- Carboxamide
1,1-bis (3-fluorophenyl) -hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one (0.18 g, 0.55 mmol) is dissolved in tetrahydrofuran (5 mL) and isocyanic acid (4 -Fluorophenyl) methyl (0.15 g, 1.0 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1 to ethyl acetate) to give the title compound (0.25 g, yield 96%).
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.17 (1H, t, J = 12.3 Hz), 2.92-3.13 (2H, m), 3.61-3.65 (1H, m), 3.81-3.86 (1H, m), 4.03- 4.12 (1H, m), 4.34-4.35 (3H, m), 4.88 (1H, br), 6.97-7.08 (6H, m), 7.19-7.39 (6H, m).
Example 196 1- [2-[[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] amino] ethyl] -4 -Piperidinecarboxylic acid ethyl ester In the same manner as in Example 64, the title compound was obtained using isonipecotic acid ethyl ester instead of morpholine. Yield 91%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ1.26 (3H, t, J = 7.1 Hz), 1.62-1.72 (2H, m), 1.88-1.92 (2H, m), 2.00-2.07 (2H, m), 2.17 ( 1H, t, J = 13.2 Hz), 2.26-2.30 (1H, m), 2.44-2.48 (2H, m),
2.80-2.91 (3H, m), 3.04-3.11 (1H, m), 3.26-3.29 (2H, m), 3.68-3.72 (1H, m), 3.85-3.89 (2H, m), 4.10-4.18 (2H m), 4.39-4.43 (1H, m), 5.20 (1H, br), 7.28-7.41 (8H, m), 7.50-7.53 (2H, m).

Example 197 1,1-bis (3-fluorophenyl) -tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid phenyl ester In the same manner as in Example 3 , Chlorocarbonic acid phenyl instead of 4-fluorophenyl, hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one instead of 1,1-bis (3-fluoro The title compound was obtained using (phenyl) -hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one. Yield 84%.
Melting point 159-160 ° C.
¹ H NMR (CDCl ₃ ) δ2.28-2.52 (1H, m), 2.82-3.06 (1H, m), 3.20 (1H, dt, J = 2.9 Hz, 12.7 Hz), 3.93-3.97 (1H, m) , 4.05-4.10 (1H, m), 4.27-4.32 (1H, m), 4.44 (1H, dd, J = 3.4 Hz, 11.3 Hz), 7.03-7.10 (6H, m), 7.21-7.44 (7H, m ).
Example 198 1,1-bis (3-fluorophenyl) -N- (4-fluorophenyl) -tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Example In the same manner as in 195, 4-fluorophenyl isocyanate was used in place of (4-fluorophenyl) methyl isocyanate to give the title compound. Yield 88%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ2.26 (1H, t, J = 12.3 Hz), 3.06-3.23 (2H, m), 3.76-3.80 (1H, m), 3.90-3.96 (1H, m), 4.04- 4.09 (1H, m), 4.43 (1H, dd, J = 3.5 Hz, 11.2 Hz), 6.28 (1H
, br), 6.98-7.10 (6H, m), 7.19-7.39 (6H, m).

Example 199 (+)-N-[(4-Fluorophenyl) methyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide
Racemate of N-[(4-fluorophenyl) methyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide (320 mg) Fractionation was performed under the following HPLC conditions.
HPLC preparative conditions
Column; CHIRALPAK AD 50 mmID × 500 mmL (Daicel Chemical Industries, Ltd.)
Mobile phase; hexane / 2-propanol = 90/10
Flow rate; 80 mL / min
Temperature; 30 ℃
Detection; UV 220 nm
Load; 160 mg
Each fraction was concentrated under reduced pressure, and hexane was added to give the title compound (158 mg, yield 49%, 99.9% ee) as a powder as an enantiomer with a long retention time. ¹ H NMR of this compound was consistent with the compound obtained in Example 25.
[α] ²⁰ _D + 158.0 ° (c 0.991, chloroform).
Example 200 (-)-N-[(4-Fluorophenyl) methyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide When Example 199 was performed, the title compound (158 mg, yield 49%, 99.9% ee) was obtained as a powder as an enantiomer with a short retention time. ¹ H NMR of this compound was consistent with the compound obtained in Example 25.
[α] ²⁰ _D -159.1 ° (c 0.871, chloroform).

Example 201 (+)-N- [2- (3,6-Dihydropyridin-1 (2H) -yl) ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a Pyrazine-7 (1H) -carboxamide
N- [2- (3,6-Dihydropyridin-1 (2H) -yl) ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -A racemate of carboxamide (2.0 g) was fractionated under the following HPLC conditions.
HPLC preparative conditions
Column; CHIRALCEL OD 50 mmID × 500 mmL (Daicel Chemical Industries, Ltd.)
Mobile phase; hexane / ethanol = 93/7
Flow rate; 70 mL / min
Temperature; 35 ℃
Detection; UV 220nm
Load amount; 100 mg
Each fraction was concentrated under reduced pressure, redissolved in ethanol, and insoluble matters were removed with a membrane filter. After concentration under reduced pressure, hexane was added to give the title compound (957 mg, yield 48%, 99.4% ee) as a powder as an enantiomer with a long retention time. ¹ H NMR of this compound was consistent with the compound obtained in Example 85.
[α] ²⁰ _D + 165.3 ° (c 1.010, chloroform).
In addition, in the same manner as in Example 64, instead of hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one, (+)-hexahydro-1,1-diphenyl-3H The title compound was obtained using -oxazolo [3,4-a] pyrazin-3-one and 1,2,3,6-tetrahydropyridine in place of morpholine. Yield 44%, 99.9% ee. ¹ H NMR of this compound was consistent with the compound obtained in Example 85.
Melting point 177-179 ° C.
[α] ²⁰ _D + 165.9 ° (c 0.930, chloroform).
Example 202 (-)-N- [2- (3,6-dihydropyridin-1 (2H) -yl) ethyl] -tetrahydro-3-
Oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide When carrying out Example 199, the title compound (970 mg, yield 49%) was obtained as an enantiomer with a short retention time. , 99.9% ee) as a powder. ¹ H NMR of this compound was consistent with the compound obtained in Example 85.
[α] ²⁰ _D -159.4 ° (c 0.929, chloroform).
Further, in the same manner as in Example 64, instead of hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one, (-)-hexahydro-1,1-diphenyl-3H The title compound was obtained using -oxazolo [3,4-a] pyrazin-3-one and 1,2,3,6-tetrahydropyridine in place of morpholine. Yield 51%, 99.9% ee. ¹ H NMR of this compound was consistent with the compound obtained in Example 85.
Melting point 177-178 ° C.
[α] ²⁰ _D -165.5 ° (c 0.791, chloroform).

Example 203 (-)-N- (4-Bromophenyl) -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Example 4 In a similar manner, instead of hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one, (-)-hexahydro-1,1-diphenyl-3H-oxazolo [3,4 The title compound was obtained using [-a] pyrazin-3-one and 4-bromophenyl isocyanate instead of phenyl isocyanate. Yield 96%.
Melting point 244-246 ° C.
¹ H NMR (CDCl ₃ ) δ2.25 (1H, t, J = 11.5 Hz), 2.99-3.21 (2H, m), 3.78-3.82 (1H, m), 3.90-3.95 (1H, m), 4.01- 4.06 (1H, m), 4.47 (1H, dd, J = 3.6 Hz, 11.3 Hz), 6.29 (1H, br), 7.20-7.42 (12H, m), 7.50-7.53 (2H, m).
[α] ²⁰ _D -119.3 ° (c 0.850, chloroform).
Example 204 Tetrahydro-N- [2- (4-hydroxy-4-methyl-1-piperidinyl) ethyl] -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 ( 1H) -Carboxamide In the same manner as in Example 64, 4-hydroxy-4-methylpiperidine was used instead of morpholine to obtain the title compound. Yield 52%.
Melting point 154 ° C.
¹ H NMR (CDCl ₃ ) δ1,25 (3H, s), 1.58-1.65 (4H, m), 2.16 (1H, t, J = 12.9 Hz), 2.36-2.52 (6H, m), 2.88-2.92 ( 1H, m), 3.07 (1H, dt, J = 2.5 Hz, 12.9 Hz), 3.27-3.30 (2H, m), 3.66-3.70 (1H, m), 3.84-3.96 (2H, m), 4.41 (1H , dd, J = 2.4 Hz, 11.2 Hz), 5.22 (1H, br), 7.26-7.41 (8H, m), 7.50-7.53 (2H, m).

Example 205 Hexahydro-1,1-diphenyl-7- (4-piperidinylacetyl) -3H-oxazolo [3,4-a] pyrazin-3-one hydrochloride In the same manner as in Example 144, 4- [2-oxo-2- (tetrahydro-3) was obtained by using 4- (carboxymethyl) piperidine-1-carboxylic acid t-butyl ester instead of [[(tert-butoxycarbonyl) amino] methyl] benzoic acid. -Oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) ethyl] -1-piperidinecarboxylic acid 1,1-dimethylethyl ester was obtained as a crude product . In a manner similar to Example 125, 4- [2-oxo-2- (tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) The title compound was obtained from 1,1-dimethylethyl ester of ethyl] -1-piperidinecarboxylic acid. Yield 69%.
Melting point 180-182 ° C.
Amide rotamer ratio (α: β = 1: 2).
¹ H NMR (DMSO-d ₆ ) δ1.32-1.36 (2H of α, 2H of β, m), 1.78-2.02 (4H of α, 4H of
β, m), 2.14-2.35 (2H of α, 2H of β, m), 2.73-3.21 (6H of α, 4H of β, m), 3.60-3.64 (2H of β, m), 3.75-3.89 ( 2H of α, 1H of β, m), 4.13-4.17 (1H of β, m), 4.31-4.39 (1H of α, 1H of β, m), 4.51-4.54 (1H of β, m), 4.69- 4.72 (1H of
α, m), 7.35-7.42 (8H of α, 8H of β, m), 7.54-7.63 (2H of α, 2H of β, m), 8
.74 (2H of α, 2H of β, br).
Example 206 1,1-bis (3-fluorophenyl) -N- [2- [cyclopropyl [(2-nitrophenyl) sulfonyl] amino] ethyl] -tetrahydro-3-oxo-3H-oxazolo [3,4 -a] pyrazine-7 (1H) -carboxamide
Chloroformic acid was added to a solution of N- (2-aminoethyl) -N-cyclopropyl-2-nitrobenzenesulfonamide (0.51 g, 1.8 mmol) and diisopropylethylamine (0.80 mL, 4.5 mmol) in tetrahydrofuran (20 mL) under ice-cooling. 4-Nitrophenyl (0.36 g, 1.8 mmol) was added and the mixture was stirred at room temperature for 1 hour. To this was added 1,1-bis (3-fluorophenyl) -hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one (0.50 g, 1.5 mmol) and the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction solution, which was washed in turn with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 49: 1 to ethyl acetate) and crystallized from ethyl acetate-diethyl ether to give the title compound (0.24 g, yield 25%).
Melting point 203 ° C.
¹ H NMR (CDCl ₃ ) δ0.50 (2H, s), 0.70-0.72 (2H, m), 2.35 (1H, t, J = 11.4 Hz), 2.69-2.87 (2H, m), 3.21 (1H, t, J = 12.3 Hz), 3.40-3.79 (6H, m), 4.03 (1H, d, J = 12.9 Hz), 4.56-4.60 (1H, m), 4.91 (1H, br), 6.98-7.00 (2H m), 7.13-7.16 (2H, m), 7.26-7.35 (4H, m), 7.68-7.76 (3H, m), 8.18-8.20 (1H, m).

Example 207 N- [2-[(cyclopropylmethyl) [(2-nitrophenyl) sulfonyl] amino] ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] Pyrazine-7 (1H) -carboxamide In the same manner as in Example 206, instead of N- (2-aminoethyl) -N-cyclopropyl-2-nitrobenzenesulfonamide, N- (2-aminoethyl) -N- ( Cyclopropylmethyl) -2-nitrobenzenesulfonamide instead of 1,1-bis (3-fluorophenyl) -hexahydro-3H-oxazolo [3,4-a] pyrazin-3-one The title compound was obtained using diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one. Yield 85%.
Melting point 174-175 ° C.
¹ H NMR (CDCl ₃ ) δ0.16-0.21 (2H, m), 0.49-54 (2H, m), 0.85-0.90 (1H, m), 2.24 (1H, t, J = 12.6 Hz), 2.77 ( 1H, dt, J = 3.6 Hz, 13.2 Hz), 3.07-3.22 (3H, m), 3.36-3.48 (1H, m), 3.54-3.62 (3H, m), 3.76-3.85 (2H, m), 3.93 -3.97 (1H, m), 4.49 (1H, dd, J = 3.6 Hz, 11.1 Hz), 5.11 (1H, br), 7.26-7.40 (8H, m), 7.54-7.56 (2H, m), 7.64- 7.73 (3H, m), 8.00-8.04 (1H, m).
Example 208 1,1-bis (3-fluorophenyl) -N- [2- (cyclopropylamino) ethyl] -tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -Carboxamide hydrochloride
1,1-bis (3-fluorophenyl) -N- [2- [cyclopropyl [(2-nitrophenyl) sulfonyl] amino] ethyl] -tetrahydro-3-oxo-3H-oxazolo [3,4-a] Add thiophenol (50 mg, 0.45 mmol) to a solution of pyrazine-7 (1H) -carboxamide (0.19 g, 0.3 mmol) and potassium carbonate (0.12 g, 0.9 mmol) in N, N-dimethylformamide (5 mL). Mix the mixture at room temperature
Stir for 3 hours. Ethyl acetate was added to the reaction mixture, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 1: 1), 4M hydrogen chloride ethyl acetate solution (1.0 mL) was added, and the mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the residue to make a powder, to obtain the title compound (0.10 g, yield 66%).
Amorphous.
¹ H NMR (DMSO-d ₆ ) δ0.69-0.81 (4H, m), 2.15-2.27 (1H, m), 2.66-2.73 (2H, m), 3.01-3.10 (3H, m), 3.30-3.40 (2H, m), 3.58-3.62 (1H, m), 3.86-3.95 (2H, m), 4.59 (1H, dd, J = 3.3 Hz, 11.1 Hz), 7.03 (1H, br), 7.17-7.27 ( 4H, m), 7.44-7.54 (4H, m), 8.84 (2H, br).

Example 209 N- [2-[(Cyclopropylmethyl) amino] ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hydrochloride Salt In the same manner as in Example 208, 1,1-bis (3-fluorophenyl) -N- [2- [cyclopropyl [(2-nitrophenyl) sulfonyl] amino] ethyl] -tetrahydro-3-oxo- Instead of 3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide, N- [2-[(cyclopropylmethyl) [(2-nitrophenyl) sulfonyl] amino] ethyl] -tetrahydro-3- The title compound was obtained using oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide. yield
40%.
Amorphous.
¹ H NMR (DMSO-d ₆ ) δ0.32-0.38 (2H, m), 0.52-0.58 (2H, m), 1.02-1.08 (1H, m), 2.06-2.14 (1H, m), 2.66-2.74 (1H, m), 2.80 (2H, d, J = 7.2 Hz), 2.94-3.08 (3H, m), 3.30-3.40 (2H, m), 3.59-3.63 (1H, m), 3.86-3.92 (2H , m), 4.53 (1H, dd, J = 3.6 Hz, 11.1 Hz), 7.10 (1H, br), 7.30-7.45 (8H, m), 7.58-7.60 (2H, m), 8.57 (2H, br) .
Example 210 N- [2- [acetyl (2-propenyl) amino] ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Tetrahydro-3-oxo-1,1-diphenyl-N- [2-[(2-propenyl) amino] ethyl] -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hydrochloride (0.13 g, 0.29 mmol) was added 0.5 M aqueous sodium hydrogen carbonate solution (20 mL), and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL), triethylamine (58 mg, 0.57 mmol) and acetic anhydride (32 mg, 0.31 mmol) were sequentially added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether to obtain the title compound (90 mg, yield 68%).
Melting point 104-105 ° C.
¹ H NMR (CDCl ₃ ) δ2.05-2.18 (4H, m), 2.77 (1H, dt, J = 3.6 Hz, 13.2 Hz), 3.02 (1H, dt, J = 3.9 Hz, 12.6 Hz), 3.28- 3.67 (4H, m), 3.78-3.98 (5H, m), 4.37 (1H, dd, J = 3.6 Hz, 11.1 Hz), 5.15-5.28 (2H, m), 5.73-5.84 (1H, m), 6.25 (1H, br), 7.26-7.41 (8H, m), 7.55-7.58 (2H, m).

Example 211 Tetrahydro-N- [2- [methylsulfonyl (2-propenyl) amino] ethyl] -3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H)- Carboxamide In the same manner as in Example 210, methanesulfonyl chloride was used in place of acetic anhydride to obtain the title compound. Yield 77%.
Melting point 131 ° C.
¹ H NMR (CDCl ₃ ) δ2.21 (1H, t, J = 11.4 Hz), 2.79 (1H, dt, J = 3.6 Hz, 13.2 Hz), 2.90
(3H, s), 3.09 (1H, dt, J = 2.4 Hz, 12.6 Hz), 3.26-3.45 (4H, m), 3.80-3.91 (5H, m), 4.43 (1H, dd, J = 3.6 Hz, 11.4 Hz), 5.29-5.35 (3H, m), 5.75-5.87 (1H, m), 7.26-7.41 (8H, m), 7.54-7.56 (2H, m).
Example 212 N- [2- [ethyl (2-propenyl) amino] ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide Hydrochloride Tetrahydro-3-oxo-1,1-diphenyl-N- [2-[(2-propenyl) amino] ethyl] -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hydrochloride To (0.13 g, 0.29 mmol) was added 0.5 M aqueous sodium hydrogen carbonate solution (20 mL), and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 1,2-dichloroethane solution (5 mL), acetaldehyde (25 mg, 0.57 mmol) and sodium triacetoxyborohydride (0.12 g, 0.57 mmol) were sequentially added, and the mixture was stirred at room temperature for 8 hours. . Ethyl acetate was added to the reaction mixture, and the mixture was washed with 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue was added 4M hydrogen chloride ethyl acetate solution (1.0 mL), and the mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was triturated with 2-propanol-ethyl acetate to give the title compound (77 mg, yield 56%).
Amorphous.
¹ H NMR (DMSO-d ₆ ) δ1.18-1.22 (3H, m), 2.04-2.12 (1H, m), 2.62-2.70 (2H, m), 3.00-3.18 (4H, m), 3.31-3.42 (2H, m), 3.60-3.63 (1H, m), 3.75-3.92 (4H, m), 4.51-4.54 (1H, m), 5.50-5.60 (2H, m), 5.85-6.01 (1H, m) , 7.12 (1H, br), 7.33-7.45 (8H, m), 7.57-7.60 (2H, m), 9.89 (1H, br).

Example 213 N- [2- [acetyl (cyclopropyl) amino] ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide In a manner similar to Example 210, tetrahydro-3-oxo-1,1-diphenyl-N- [2-[(2-propenyl) amino] ethyl] -3H-oxazolo [3,4-a] pyrazine-7 ( 1H) -Carboxamide hydrochloride instead of N- [2- (cyclopropylamino) ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -The title compound was obtained using carboxamide hydrochloride. Yield 70%.
Amorphous.
¹ H NMR (CDCl ₃ ) δ0.79-0.81 (2H, m), 0.91-0.93 (2H, m), 2.09-2.22 (4H, m), 2.72-2.81 (2H, m), 2.97-3.07 (1H , m), 3.26-3.68 (4H, m), 3.73-3.96 (3H, m), 4.37 (1H, dd, J = 3.3 Hz, 11.1 Hz), 6.11 (1H, br), 7.26-7.41 (8H, m), 7.54-7.57 (2H, m).
Example 214 N- [2- [cyclopropyl (methanesulfonyl) amino] ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide In a manner similar to Example 210, tetrahydro-3-oxo-1,1-diphenyl-N- [2-[(2-propenyl) amino] ethyl] -3H-oxazolo [3,4-a] pyrazine-7 N- [2- (Cyclopropylamino) ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H instead of (1H) -carboxamide hydrochloride ) -Carboxamide hydrochloride was used in place of acetic anhydride to give methanesulfonyl chloride to give the title compound. Yield 86%.
Melting point 168-169 ° C.
¹ H NMR (CDCl ₃ ) δ0.84-0.86 (4H, m), 2.21 (1H, t, J = 13.2 Hz), 2.51-2.57 (1H, m), 2.79 (1H, dt, J = 3.6 Hz, 13.5 Hz), 2.94 (3H, s), 3.10 (1H, dt, J = 2.4 Hz, 13.2 Hz), 3.35-3.53 (4H, m), 3.80-3.92 (3H, m), 4.45 (1H, dd, J = 3.3 Hz, 11.4 Hz), 5.27 (1H, br), 7.26-7.41 (8H, m), 7.54-7.57 (2H, m).

Example 215 3-[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] benzaldehyde
3-Formylbenzoic acid (0.10 g, 0.67 mmol) was dissolved in toluene (7 mL), thionyl chloride (0.80 g, 6.7 mmol) was added, and the mixture was heated to reflux for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in tetrahydrofuran (5 mL). A solution of triethylamine (69 mg, 0.68 mmol) and hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one (0.20 g, 0.68 mmol) in tetrahydrofuran (3 mL) The solution was added dropwise at 0 ° C. and stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over magnesium sulfate. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1 to ethyl acetate) and the fractions were collected and concentrated. The residue was collected by filtration and washed with diisopropyl ether to give the title compound (0.19 g, yield 66%).
Melting point 174-176 ° C.
¹ H NMR (CDCl ₃ ) δ2.30 (1H, br s), 3.06 (2H, br s), 3.60-3.69 (1H, m), 3.89 (1H, br s), 4.49-4.52 (2H, m) , 7.26-7.65 (12H, m), 7.91 (1H, s), 7.97-8.00 (1H, m), 10.06 (1H, s).
Example 216 4-[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-7 (1H) -yl) carbonyl] benzaldehyde By a method similar to that of Example 215, The title compound was obtained using 4-formylbenzoic acid instead of 3-formylbenzoic acid. Yield 63%.
Melting point 210-212 ° C.
¹ H NMR (CDCl ₃ ) δ2.26 (1H, br s), 3.04 (2H, br s), 3.61-3.67 (1H, m), 3.88 (1H, br s), 4.52 (2H, br s), 7.17-7.64 (12H, m), 7.96 (2H, d, J = 8.1 Hz), 10.07 (1H, s).

  The structural formulas of the compounds obtained in Examples 1 to 216 are shown in [Table 1] to [Table 23].

Experimental Example 1 Binding inhibition experiment
Cysteine is added to the carboxyl terminus of TGR23 ligand (using human TGR23-2 ligand (1-20) shown in SEQ ID NO: 23 of WO 03/25179) by an amide bond, and the thiol group of the added cysteine A peptide in which Cy-5 (ANYGEN Co. Ltd., manufactured in Korea) was introduced via a synthetic technique obtained by Enigen (hereinafter also referred to as Cy-5-labeled TGR23 ligand), A binding inhibition experiment was conducted.
TGR23-2 expressing CHO cells (Example 1 of WO 03/25179) were cultured in MEM-α medium (without nucleic acid) containing 10% dialyzed serum. After removing the medium and washing the adhered cells with PBS, PBS containing 5 mM EDTA was added, and the cells were detached from the flask by pipetting. After centrifugation, the measurement buffer (10 mM HEPES pH 7.4, 140 mM NaCl, 2.5 mM CaCl ₂ , 3 mM MgCl ₂ , 0.5% BSA, 0.01% NaN _{3 is} used so that the cells become 2.22 × 10 ⁵ cells / mL. ) To a final concentration of 1
nM Cy-5 labeled TGR23 ligand was added. In each well of a 96-well black clear bottom plate (Applied Biosystems), 10 μL of measurement buffer containing 1% dimethyl sulfoxide was used to examine total binding, and 10 μM diluted with measurement buffer to examine non-specific binding. 10 μL of unlabeled peptide [human TGR23-2 ligand (1-20) shown in SEQ ID NO: 23 of WO 03/25179] solution was diluted with a measurement buffer to examine the binding inhibitory activity of the test compound 10 μL of each test compound was added, and 90 μL of the cell suspension was further dispensed. After 1 hour, the amount of Cy-5-labeled TGR23 ligand bound to the cells was measured with FMAT 8100 HTS system (Applied Biosystems). Specific binding is the value obtained by subtracting non-specific binding from total binding. The binding inhibitory activity of the test compound is expressed as a ratio of the value obtained by subtracting the measured value when the test compound is added from the total binding to the specific binding. The concentration of the compound exhibiting 50% binding inhibitory activity (IC ₅₀ value) was calculated from the dose response curve.
In this experimental system, Examples 2 to 4, 6, 10, 16 to 19, 21, 22, 25, 26, 28 to 31, 34, 40, 43, 44, 46, 47, 59 to 61, 64, 65 70, 76-78, 80, 84-86, 88-93, 96, 97, 109, 112, 114, 115, 117, 126, 129, 132, 133, 137-139, 147, 148, 150, 154 157, 161, 162, 164, 165, 167, 169, 171-176, 178-180, 182-185, 187-195, 197-199, 201, 20
The compounds obtained with 4 and 206-214 showed IC ₅₀ values of 100 nM or less.

Experimental Example 2 Measurement of antagonist activity
Using TGR23-2 expressing CHO cells (Example 1 of WO 03/25179), a TGR23 ligand [human TGR23-2 ligand (1-20) represented by SEQ ID NO: 23 of WO 03/25179 Inhibition of intracellular Ca ion concentration increasing activity by use of the test compound was measured by FLIPR (Molecular Device), and the antagonist activity of the test compound was evaluated.
Suspend human TGR23-2 expressing CHO cells in RPMI medium containing 10% dialyzed fetal bovine serum to 3 × 10 ⁵ cells / mL, and multiplex 8 cells in 96 well plate for FLIPR (Black plate clear bottom, Coaster) Inoculate 100 μL of each well using a channel pipette (3 × 10 ⁴ cells / 100 μL / well), incubate overnight at 37 ° C. in a carbon dioxide incubator (5% CO ₂ ), and use it in the assay (hereinafter referred to as “this”). The plate is called the cell plate). HANKS '/ HBSS [Nissui Hanks 2, (Nissui Pharmaceutical) 9.8 g, sodium bicarbonate 0.35 g, HEPES (Dojindo Laboratories) 4.77 g, dissolved in 1 L of distilled water, pH with 5 M sodium hydroxide solution Filter sterilization according to 7.4) One vial (50 μg) of Fluo 3-AM (Dojindo Laboratories) was mixed with 10 mL of 250 mM Probenecid 100 μL (Sigma) and fetal bovine serum (FBS) 100 μL. Dissolve in 20 μL and 20% Pluronic acid (Molecular Probes) in 20 μL, add, mix, and use 100 μL in each well of the cell plate after removing the culture solution using an 8 pipette.
Dispensed one by one. The cell plate was incubated in a carbon dioxide incubator (5% CO ₂ ) at 37 ° C. for 1 hour to load the cells with the dye. After loading of the dye on the cell plate, the cell plate was washed 4 times with a washing buffer with 2.5 mM Probenecid added to HANKS '/ HBSS. After washing, HANKS containing 100 μL of 2.5 mM Probenecid was added to each well. '/ HBSS was dispensed. Add 50 μL of test compound solution (final concentration, 0, 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000, 10000 nM) to cells, followed by 30 s pretreatment, followed by 50 μL of human TGR23 ligand solution (final concentration, 1 nM) was added. After addition of human TGR23 ligand, the change in fluorescence intensity associated with the change in intracellular calcium concentration in the cells was measured by FLIPR for 3 minutes. For each test compound at each concentration, create a dose-response curve for the maximum fluorescence intensity value for 3 minutes and calculate the compound concentration (IC ₅₀ value) that inhibits the increase in fluorescence intensity when no compound is added by 50%. did.
In this experimental system, Examples 2 to 4, 6, 8 to 10, 16 to 19, 21, 22, 25, 26, 28 to 31, 34, 40, 43, 44, 46 to 48, 50, 59 to 62 64, 65, 70, 73-78, 80, 83-93, 96-98, 108, 109, 112-117, 125, 126, 129, 132, 133, 136-139, 145-150, 154, 164 , 167, 169, 171-176, 178-180, 182-185, 187-195, 197-199 and 201 exhibited IC ₅₀ values of 1 μM or less.

Experimental Example 3 Cancer Cell DNA Synthesis Inhibitory Action Human colon cancer cell line LS 174T (ATCC number: CL-188) was seeded in a 96-well plate at a rate of 20,000 per well, and then 0.05% fatty acid-free bovine serum albumin ( The cells were cultured for 24 hours in an EMEM medium (Niken Biomedical Research Institute) containing Sigma. In the presence of 10 nM TGR23 ligand (using human TGR23-2 ligand (1-20) shown in SEQ ID NO: 23 of WO 03/25179) after 15-minute preculture of these cells and test compound For 18 hours. They were then cultured for 6 h in the presence [methyl- ³ H] -Thymidine (Amersham Biosciences) of 0.25 [mu] Ci per well. Incorporated into a cancer cell DNA [methyl- ³ H] -Thymidine was measured as follows. After discarding the culture supernatant, 100 μL of ice-cooled 10% trichloroacetic acid per well was added to the cells incorporating [methyl- ³ H] -Thymidine and placed on ice for 15 minutes. After discarding the trichloroacetic acid solution, 300 μL / well of 0.2N sodium hydroxide solution was added to the immobilized cells, and then incubated at 37 ° C. overnight. The [methyl- ³ H] -Thymidine amount of cell lysates were measured with a liquid scintillation counter.
DNA synthesis inhibition rate of the test compound, by TGR23 ligand stimulation of 10 nM [methyl- ³ H] from -Thymidine uptake of when the value obtained by subtracting the same according to unstimulated as 100%, the test compound and 10 nM TGR23 and a relative value of the value obtained by subtracting the same according to unstimulated from [methyl- ³ H] -Thymidine uptake under ligand coexist. The IC ₅₀ value of the test compound for DNA synthesis was defined as the concentration of the test compound necessary to bring the DNA synthesis inhibition rate to 50%.
In this experimental system, the compounds obtained in Examples 17, 25, 28, 85, 96 to 97, 138, 147, 201 exhibited IC ₅₀ values of 1 μM or less.

Experimental Example 4 Cell growth inhibitory effect Human colon cancer cell line LS 174T (ATCC number: CL-188) was seeded in a 96-well plate at a rate of 40,000 per well, and then EMEM containing 0.05% fatty acid-free bovine serum albumin Cultured in medium for 24 hours. In the presence of 10 nM TGR23 ligand (using human TGR23-2 ligand (1-20) shown in SEQ ID NO: 23 of WO 03/25179) after 15-minute preculture of these cells and test compound At LS
174T was cultured for 24 hours. Cell proliferation was evaluated by the MTT method. Cells in MTT solution (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium bromide) at a final concentration of 0.5 mg / mL for 4 hours at 37 ° C and then in 5% SDS solution It melt | dissolved by heat-retaining at 37 degreeC for 24 hours. The absorbance of the cell lysate was measured with a 96-well plate reader. The value of the change in absorbance obtained by subtracting the absorbance at 640 nm from the absorbance at 540 nm of the cell lysate was used as an index reflecting the number of cells.
The cell growth inhibition rate of the test compound was not calculated from the change in absorbance in the presence of the test compound and 10 nM TGR23 ligand when the value obtained by subtracting that caused by no stimulation from the change in absorbance caused by 10 nM TGR23 ligand stimulation was taken as 100%. The relative value of the value obtained by subtracting that caused by stimulation was used. The IC ₅₀ value for the cell proliferation of the test compound was defined as the concentration of the test compound necessary to bring the cell growth inhibition rate to 50%. The IC ₅₀ value of the test compound with respect to cell proliferation was defined as the concentration of the test compound necessary to bring the cell growth inhibition rate to 50%.
In this experimental system, the compounds obtained in Examples 17 and 25 exhibited IC ₅₀ values of 1 μM or less.

Formulation Example 1
(1) Compound of Example 1 50 mg
(2) Lactose 34mg
(3) Corn starch 10.6mg
(4) Corn starch (paste) 5mg
(5) Magnesium stearate 0.4mg
(6) Carboxymethylcellulose calcium 20mg
120mg total
According to a conventional method, the above (1) to (6) are mixed and tableted with a tableting machine to obtain tablets.
Formulation Example 2
(1) Compound of Example 2 10.0 mg
(2) Lactose 60.0mg
(3) Corn starch 35.0mg
(4) Gelatin 3.0mg
(5) Magnesium stearate 2.0mg
Compound of Example 2 10.0 mg, lactose 60.0 mg and corn starch 35.0 mg were granulated through a 1 mm mesh sieve using 0.03 ml of 10% gelatin aqueous solution (3.0 mg as gelatin), and then 40 ° C. Dry and sieve again. The granules thus obtained are mixed with 2.0 mg of magnesium stearate and compressed. The resulting core tablet is coated with a sugar coating with a water suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablet is polished with beeswax to obtain a coated tablet.
Formulation Example 3
(1) Compound of Example 3 10.0 mg
(2) Lactose 70.0mg
(3) Corn starch 50.0mg
(4) Soluble starch 7.0mg
(5) Magnesium stearate 3.0mg
Compound of Example 3 10.0 mg and magnesium stearate 3.0 mg were granulated with 0.07 ml of an aqueous solution of soluble starch (7.0 mg as soluble starch), then dried, 70.0 mg of lactose and 50.0 mg of corn starch Mix. The mixture is compressed to obtain tablets.

  The compound (I) of the present invention has an excellent TGR23 antagonist activity based on its specific chemical structure, and is useful as a safe cancer prevention / treatment drug.

Claims (33)

formula

[In the formula (I), R ¹ represents an acyl group,
R ² represents a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent,
R ³ represents a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent,
R ⁴ represents a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent,
n is an integer of 0 to 4 (when n is an integer of 2 to 4, R ⁴ may be the same or different), and X is an oxygen atom, a sulfur atom, or the formula NR ⁵ (wherein R ⁵ represents a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent. ]
Or a salt thereof. The acyl group represented by R ¹ is represented by the formula — (C═O) —R ⁶ , — (C═O) —OR ⁶ , — (C═O) —NR ⁷ R ⁸ , — (C═S) —NR. ⁷ R ⁸ , —SO—R ⁶ , —SO ₂ —R ⁶ or —SO ₂ —NR ⁷ R ⁸
[Wherein R ⁶ represents a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent,
R ⁷ represents a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, a C _6-12 aryl-carbonyl group, a C _1-6 alkoxy-carbonyl group. Or a 5- or 6-membered aromatic heterocyclic carbonyl group, and R ⁸ represents a hydrogen atom, a C _1-6 alkyl group or an optionally substituted amino group, or
R ⁷ and R ⁸ together with the adjacent nitrogen atom may form a ring that may have a substituent.
The compound of Claim 1 which is group represented by these. The acyl group represented by R ¹ is represented by the formula — (C═O) —R ⁶ , — (C═O) —OR ⁶ or — (C═O) —NR ⁷ R ⁸ , wherein each symbol is claimed. The compound of Claim 2 which is group represented by the same meaning as 2 description. The compound according to claim 2, wherein R ⁶ is an aromatic group, a heterocyclic group or a chain hydrocarbon group, each of which may have a substituent. 3. R ⁶ is a C _6-12 aryl group which may have a substituent, or a C _1-6 alkyl group having a 5- to 7-membered cyclic amino group which may have a substituent. The described compound. R ⁷ represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, a C _6-12 aryl-carbonyl group, or a C _1-6 alkoxy-carbonyl. The compound according to claim 2, which is a group. R ⁷ is (a) (i) a 5- to 7-membered cyclic amino group which may have a substituent, and / or (ii) a 5- to 10-membered aromatic heterocyclic group which may have a substituent. ,
A C _1-6 alkyl group _optionally having
The compound according to claim 2, which is (b) a C _6-12 aryl group which may have a substituent, or (c) a C _7-13 aralkyl group which may have a substituent. The compound according to claim 2, wherein R ⁷ is a group having an aromatic group which may have a substituent. The compound according to claim 2, wherein R ⁷ and R ⁸ together with the adjacent nitrogen atom form a 5- to 10-membered heterocyclic ring which may have a substituent. The compound according to claim 2, wherein R ⁸ is a hydrogen atom or an amino group which may have a substituent. The compound according to claim 1, wherein R ¹ is a group represented by the formula-(C = O) -NR ⁷ R ⁸ , wherein each symbol is as defined in claim 2. The compound according to claim 1, wherein R ¹ is a group represented by the formula-(C = O) -R ⁶ , wherein each symbol is as defined in claim 2. The compound according to claim 1, wherein R ² is an aryl group which may have a substituent. The compound according to claim 1, wherein R ³ is an aryl group which may have a substituent.   The compound according to claim 1, wherein n is 0.   The compound according to claim 1, wherein X is an oxygen atom. R ¹ is of the formula — (C═O) —R ^6b or — (C═O) —NR ^7b R ^8b ,
[Wherein R ^6b has (a) a C _1-6 alkyl group optionally having a 5- to 7-membered cyclic amino group, or (b) 1 to 2 C _1-6 alkyl groups. A C _6-12 aryl group _optionally having a C _1-6 alkyl group _{optionally having an} amino group,
R ^7b is (a) a hydrogen atom,
(B) a C _6-12 aryl group _optionally having a halogen atom,
(C) a C _7-13 aralkyl group _optionally having a halogen atom,
(D) a 5- or 6-membered aromatic heterocyclic group,
(E) a C _1-6 alkyl group optionally having a 5- to 7-membered cyclic amino group, or (f) a 5- or 6-membered non-aromatic heterocyclic ring optionally having a C _1-6 alkyl group Group,
R ^8b is a hydrogen atom or a C _6-12 arylamino group, or R ^7b and R ^8b together with the adjacent nitrogen atom form a 5- to 10-membered heterocyclic ring optionally having a 5- to 7-membered cyclic amino group A group represented by
R ² and R ³ are each a C _6-12 aryl group,
The compound according to claim 1, wherein n is 0, and X is an oxygen atom. R ¹ is of the formula — (C═O) —R ^6a , — (C═O) —OR ^6a , — (C═O) —NR ^7a R ^8a or —SO ₂ —R ^6a
[Wherein R ^6a is (a) a C _7-13 aralkyl group,
(B) a C _2-6 alkenyl group _optionally having a halogenated C _6-12 aryl group,
(C) a C _6-12 aryl group which may have a substituent selected from a halogen atom, a C _1-6 alkoxy group, a nitro group, and an optionally halogenated C _1-6 alkyl group,
(D) a 5- or 6-membered aromatic heterocyclic group, or (e) a substituent selected from a C _6-12 aryl group, a C _6-12 aryloxy group and an optionally condensed C _3-8 cycloalkyl group A C _1-6 alkyl group _optionally having
R ^7a is (a) a hydrogen atom,
(B) a C _6-12 aryl group optionally having a substituent selected from a C _1-6 alkoxy-carbonyl group, a halogen atom and a C _1-6 alkoxy group,
(C) having a substituent selected from a halogen atom, an optionally halogenated C _1-6 alkyl group, a C _1-6 alkylsulfonyl group, and a mono- or di-C _1-6 alkylamino group; C _7-13 aralkyl group,
(D) a C _1-6 alkyl group which may have a 5- or 6-membered aromatic heterocyclic group, or (e) a C _3-8 cycloalkyl group which may be condensed,
R ^8a may form a 5- to 10-membered non-aromatic heterocyclic ring with a hydrogen atom, a C _1-6 alkyl group, or a C _6-12 arylamino group, or R ^7a and R ^8a together with the adjacent nitrogen atom. A group represented by
R ² and R ³ are each a C _1-6 alkyl group, a C _3-6 cycloalkyl group or a C _6-12 aryl group,
The compound according to claim 1, wherein n is 0, and X is an oxygen atom. R ¹ is of the formula — (C═O) —R ^6a , — (C═O) —OR ^6a , — (C═O) —NR ^7a R ^8a or —SO ₂ —R ^6a
[Wherein R ^6a is (a) a C _7-13 aralkyl group,
(B) a C _2-6 alkenyl group _optionally having a halogenated C _6-12 aryl group,
(C) (i) a halogen atom,
(Ii) a C _1-6 alkoxy group,
(Iii) a nitro group, and (iv) (1) a halogen atom, and (2) one or two substituents selected from a C _1-6 alkoxy-carbonyl group and a C _1-6 alkyl group A good amino group, a C _1-6 alkyl group which may have a substituent selected from:
A C _6-12 aryl group _optionally having a substituent selected from:
(D) a 5- or 6-membered aromatic heterocyclic group,
(E) (i) a C _6-12 aryloxy group,
(Ii) a C _3-8 cycloalkyl group which may be condensed with one or two benzene rings,
(Iii) an optionally halogenated C _6-12 arylamino group,
(Iv) a carboxy group,
(V) a 5- to 7-membered cyclic amino group,
(Vi) a C _6-12 aryl group, and (vii) a halogen atom,
A C _1-6 alkyl group _optionally having a substituent selected from:
(F) a 6-membered non-aromatic heterocyclic group optionally having a C _1-6 alkoxy-carbonyl group, or (g) a 5- to 10-membered aromatic heterocyclic group optionally having an oxo group,
R ^7a is (a) a hydrogen atom,
(B) a C _6-12 aryl group optionally having a substituent selected from a C _1-6 alkoxy-carbonyl group, a halogen atom and a C _1-6 alkoxy group,
(C) (i) a halogen atom,
(Ii) C _1-6 alkoxy - carbonyl group, an optionally substituted amino group, and a C _1-6 alkyl group optionally having a substituent selected from halogen atoms,
(Iii) a C _1-6 alkylsulfonyl group, and (iv) a mono- or di-C _1-6 alkylamino group,
A C _7-13 aralkyl group which may have a substituent selected from:
(D) (i) a 5- or 6-membered aromatic heterocyclic group which may be oxidized and may have a cyano group,
(Ii) a 5- to 7-membered cyclic amino group which may have a C _1-6 alkyl group and may be condensed with a benzene ring;
(Iii) a C _1-6 alkoxy-carbonyl group,
(Iv) a carboxy group,
(V) a 5- to 7-membered saturated cyclic aminocarbonyl group,
(Vi) a C _6-12 aryl group,
(Vii) a C _6-12 aryl-carbonyl group,
(Viii) a hydroxy group, and (ix) a substituent 1 selected from a C _1-6 alkyl group, a C _1-6 alkoxy-C _1-6 alkyl group, an azidocarbonyl group, an aminocarbonyl group, and a C _7-13 aralkyl group Or an amino group optionally having two,
A C _1-6 alkyl group _optionally having a substituent selected from:
(E) a C _3-8 cycloalkyl group which may be condensed with one or two benzene rings,
(F) a 5- to 10-membered aromatic heterocyclic group optionally having a substituent selected from an oxo group and a C _1-6 alkoxy-carbonyl group,
(G) a C _6-12 aryl-carbonyl group,
(H) a C _1-6 alkoxy-carbonyl group, or (i) a substituent selected from a C _1-6 alkyl group, a C _1-6 alkoxy-carbonyl group and an oxo group, An optionally fused 5- to 7-membered non-aromatic heterocyclic group,
R ^8a may have a hydrogen atom, a C _1-6 alkyl group or a C _6-12 arylamino group, or R ^7a and R ^8a may have a 5- to 7-membered saturated cyclic amino group together with the adjacent nitrogen atom. A 5- to 10-membered non-aromatic heterocyclic ring may be formed],
R ² is a hydrogen atom, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, an optionally halogenated C _6-12 aryl group or a C _7-13 aralkyl group,
R ³ is a C _1-6 alkyl group, a C _3-6 cycloalkyl group, an optionally halogenated C _6-12 aryl group or a C _7-13 aralkyl group,
The compound according to claim 1, wherein n is 0, and X is an oxygen atom. R ¹ is of the formula — (C═O) —R ^6a , — (C═O) —OR ^6a , — (C═O) —NR ^7a R ^8a or —SO ₂ —R ^6a
[Wherein R ^6a is (a) a C _7-13 aralkyl group,
(B) a C _2-6 alkenyl group _optionally having a halogenated C _6-12 aryl group,
(C) (i) a halogen atom,
(Ii) a C _1-6 alkoxy group,
(Iii) a nitro group,
(Iv) may have one or two substituents selected from a formyl group, and (v) (1) a halogen atom, (2) a C _1-6 alkoxy-carbonyl group and a C _1-6 alkyl group A C _1-6 alkyl group _optionally having a substituent selected from an amino group, and (3) an optionally substituted 5- to 7-membered cyclic amino group,
A C _6-12 aryl group _optionally having a substituent selected from:
(D) a 5- or 6-membered aromatic heterocyclic group,
(E) (i) a C _6-12 aryloxy group,
(Ii) a C _3-8 cycloalkyl group which may be condensed with one or two benzene rings,
(Iii) an optionally halogenated C _6-12 arylamino group,
(Iv) a carboxy group,
(V) a 5- to 7-membered cyclic amino group,
(Vi) a 5- to 7-membered non-aromatic heterocyclic group,
(Vii) a C _6-12 aryl group, and (viii) a halogen atom,
A C _1-6 alkyl group _optionally having a substituent selected from:
(F) (i) a C _1-6 alkoxy-carbonyl group,
(Ii) a carbamoyl group,
(Iii) a hydroxy group,
(Iv) a 5- to 7-membered cyclic amino-carbonyl group,
(V) a C _3-8 cycloalkyl group, and (vi) a C _2-8 alkenyl group,
A 5- to 7-membered non-aromatic heterocyclic group optionally having a C _1-6 alkyl group, a C _1-6 alkoxy-carbonyl group or a formyl group optionally having a substituent selected from:
(G) a 5- to 10-membered aromatic heterocyclic group which may have an oxo group, or (h) a 5- to 10-membered ring which may have an oxo group and may be condensed with a benzene ring An amino group,
R ^7a is (a) a hydrogen atom,
(B) (i) a C _1-6 alkoxy-carbonyl group,
(Ii) a halogen atom, and (iii) a C _1-6 alkoxy group,
A C _6-12 aryl group _optionally having a substituent selected from:
(C) (i) a halogen atom,
(Ii) C _1-6 alkoxy - carbonyl group, an optionally substituted amino group, and a C _1-6 alkyl group optionally having a substituent selected from halogen atoms,
(Iii) a C _1-6 alkylsulfonyl group, and (iv) a mono- or di-C _1-6 alkylamino group,
A C _7-13 aralkyl group which may have a substituent selected from:
(D) (i) a 5- or 6-membered aromatic heterocyclic group which may be oxidized and may be substituted with a cyano group, a hydroxy group or a C _1-6 alkyl group,
(Ii) a 5- to 7-membered cyclic amino group which may have a C _1-6 alkyl group, a hydroxy group, an oxo group or a C _1-6 alkoxy-carbonyl group and may be condensed with a benzene ring;
(Iii) a C _1-6 alkoxy-carbonyl group,
(Iv) a carboxy group,
(V) a 5- to 7-membered cyclic aminocarbonyl group,
(Vi) an optionally halogenated C _6-12 aryl group,
(Vii) a C _6-12 aryl-carbonyl group,
(Viii) a hydroxy group,
(Ix) (1) a C _1-6 alkyl group optionally substituted with a C _3-8 cycloalkyl group, (2) a C _1-6 alkoxy-C _1-6 alkyl group, (3) an azidocarbonyl group, (4) aminocarbonyl group, (5) C _7-13 aralkyl group, (6) C _3-8 cycloalkyl group, (7) sulfonyl optionally substituted with a benzene ring optionally substituted with nitro group 1 or 2 substituents selected from a group, (8) C _2-8 alkenyl group, (9) C _1-6 alkylsulfonyl group, and (10) C _1-6 alkyl-carbonyl group An amino group,
(X) a C _3-8 cycloalkyl group, and (xi) a 5- to 7-membered non-aromatic heterocyclic group,
A C _1-6 alkyl group optionally having 1 or 2 substituents selected from:
(E) a C _3-8 cycloalkyl group which may be condensed with one or two benzene rings,
(F) a 5- to 10-membered aromatic heterocyclic group optionally having a substituent selected from an oxo group, a C _1-6 alkoxy-carbonyl group, and a C _1-6 alkyl group,
(G) a C _6-12 aryl-carbonyl group,
(H) a C _1-6 alkoxy-carbonyl group,
(I) a 5- to 7-membered non-aromatic which may have a substituent selected from a C _1-6 alkyl group, a C _1-6 alkoxy-carbonyl group and an oxo group and may be condensed with a benzene ring A heterocyclic group,
(J) a 5- to 7-membered cyclic amino-C _1-6 alkyl-carbonyl group,
(K) a C _3-8 cycloalkyl group optionally substituted with a C _1-6 alkyl group optionally having a 5- to 7-membered cyclic amino group, or (L) a C _6-12 arylamino group,
R ^8a is a hydrogen atom, a C _1-6 alkyl group, or R ^7a and R ^8a have a substituent selected from a 5- to 7-membered saturated cyclic amino group and a C _1-6 alkyl group together with the adjacent nitrogen atom. A 5- to 10-membered non-aromatic heterocyclic ring which may optionally be formed]
R ² is
(i) a hydrogen atom,
(ii) a C _1-6 alkyl group,
(iii) a C _3-6 cycloalkyl group,
(iv) a C _6-12 aryl group optionally having a substituent selected from a halogen atom and a C _1-6 alkyl group, or
(v) C _7-13 aralkyl group,
R ³ is
(i) a C _1-6 alkyl group,
(ii) a C _3-6 cycloalkyl group,
(iii) a C _6-12 aryl group optionally having a substituent selected from a halogen atom and a C _1-6 alkyl group, or
(iv) C _7-13 aralkyl group,
The compound according to claim 1, wherein n is 0, and X is an oxygen atom. Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxylic acid phenyl ester,
Hexahydro-7- (1-oxo-3-phenyl-2-propenyl) -1,1-diphenyl-3H-oxazolo [3,4-a] pyrazin-3-one,
(+)-N-[(4-fluorophenyl) methyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide,
(-)-N-[(4-fluorophenyl) methyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide,
(+)-N- [2- (3,6-Dihydropyridin-1 (2H) -yl) ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine- 7 (1H) -carboxamide,
(-)-N- [2- (3,6-Dihydropyridin-1 (2H) -yl) ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine- 7 (1H) -carboxamide,
1,1-bis (3-fluorophenyl) -N- [2- (3,6-dihydropyridin-1 (2H) -yl) ethyl] -tetrahydro-3-oxo-3H-oxazolo [3,4-a] Pyrazine-7 (1H) -carboxamide,
N- [2- (3,6-Dihydropyridin-1 (2H) -yl) ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -Carboxamide,
1,1-bis (3-fluorophenyl) -N- [2- (cyclopropylamino) ethyl] -tetrahydro-3-oxo-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hydrochloride salt,
Tetrahydro-3-oxo-1,1-diphenyl-N-[(3-thienyl) methyl] -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide,
7- [4- (3,6-Dihydropyridin-1 (2H) -yl) -1-oxobutyl] -hexahydro-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H)- 3-on,
N- [2-[(cyclopropylmethyl) amino] ethyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide hydrochloride,
N-[(4-fluorophenyl) methyl] -tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide, or
1,1-bis (3-fluorophenyl) -tetrahydro-3-oxo-N- [2- (1-piperidinyl) ethyl] -3H-oxazolo [3,4-a] pyrazine-7 (1H) -carboxamide, Or their salts.   A medicament comprising the compound according to claim 1 or a salt thereof or a prodrug thereof. formula

[In the formula (II),
Ring A is a 5- to 10-membered ring,
Ring B is a 5- to 9-membered ring,
R ¹ ′ represents a hydrogen atom, an acyl group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,
R ⁴ ′ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,
R ⁴ ″ represents an oxo group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,
m is an integer of 0 to 8 (when m is an integer of 2 to 8, R ⁴ ′ may be the same or different),
k is an integer of 0 to 8 (when k is an integer of 2 to 8, R ⁴ ″ may be the same or different),
X represents an oxygen atom, a sulfur atom, or a group represented by NR ⁵ (wherein R ⁵ represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group). . ]
A TGR23 function regulator comprising a compound represented by the formula:   23. A preventive or therapeutic agent for cancer, Alzheimer's disease, dementia, eating disorders, hypertension, gonadal dysfunction, thyroid dysfunction, pituitary dysfunction, diabetes, lipid metabolism disorder, hyperlipidemia or anorexia. Or the medicine of 23.   The medicament according to claim 22 or 23, which is a prophylactic / therapeutic agent for a disease caused by TGR23.   A cancer, Alzheimer's disease, dementia, eating disorder, hypertension, gonadal dysfunction, thyroid dysfunction, pituitary dysfunction characterized by administering an effective amount of the compound according to claim 1 or a salt thereof to a mammal, Methods for preventing and treating diabetes, dyslipidemia, hyperlipidemia or anorexia.   A method for preventing or treating a disease caused by TGR23 in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.   For the manufacture of prophylactic / therapeutic agents for cancer, Alzheimer's disease, dementia, eating disorders, hypertension, gonadal dysfunction, thyroid dysfunction, pituitary dysfunction, diabetes, lipid metabolism disorder, hyperlipidemia or anorexia Use of a compound according to claim 1.   Use of the compound according to claim 1 for the manufacture of a prophylactic / therapeutic agent for diseases caused by TGR23.   A cancer, Alzheimer's disease, dementia, eating disorder, hypertension, gonadal dysfunction, thyroid, which comprises administering an effective amount of a compound represented by the formula (II) or a salt thereof according to claim 23 to a mammal. Methods for preventing / treating dysfunction, pituitary dysfunction, diabetes, lipid metabolism disorder, hyperlipidemia or anorexia.   A method for preventing or treating a disease caused by TGR23 in a mammal, comprising administering an effective amount of the compound represented by formula (II) or a salt thereof according to claim 23 to the mammal.   For the manufacture of prophylactic / therapeutic agents for cancer, Alzheimer's disease, dementia, eating disorders, hypertension, gonadal dysfunction, thyroid dysfunction, pituitary dysfunction, diabetes, lipid metabolism disorder, hyperlipidemia or anorexia Use of a compound represented by formula (II) according to claim 23.   Use of the compound represented by formula (II) according to claim 23 for the manufacture of a prophylactic / therapeutic agent for diseases caused by TGR23.