WO2004096806A1

WO2004096806A1 - Fused imidazole derivative

Info

Publication number: WO2004096806A1
Application number: PCT/JP2004/006104
Authority: WO
Inventors: Hiroyuki Nakahira; Hitoshi Hochigai
Original assignee: Sumitomo Pharmaceuticals Co. Ltd.
Priority date: 2003-04-30
Filing date: 2004-04-27
Publication date: 2004-11-11
Also published as: JPWO2004096806A1

Abstract

A compound represented by the following formula (I), a prodrug thereof, or a pharmaceutically acceptable salt of either. The compound has high DPP-IV inhibitory activity and has been improved in safety, toxicity, etc. (I) [In the formula, R1 represents hydrogen, optionally substituted alkyl, etc.; R2 represents hydrogen, optionally substituted alkyl, optionally substituted aryl, etc.; R3 represents hydrogen, optionally substituted aryl, etc.; and -Y-NH2 represents, e.g., a group represented by the formula (A) (wherein m is 0, 1, or 2; and R4 is absent or one or two R4's are present, the R4's each independently representing optionally substituted alkyl, etc.).]

Description

Description Condensed imidazole derivatives

The present invention relates to a novel condensed imidazole useful as a medicament. More specifically, it relates to a novel condensed imidazole effective as a dipeptidyl peptidase-IV (DPP-IV) inhibitor. Furthermore, the present invention relates to a novel antidiabetic agent containing a novel condensed imidazole as an active ingredient, which is effective as a dipeptidylpeptidase-IV (DPP-IV) inhibitor. Landscape technology

DPP-IV is a serine protease that exists widely in the body.It is a type of dipeptidylaminobeptidase that hydrolyzes the N-terminal dipeptide, and the second amino acid from the N-terminal is Because it acts particularly strongly on the proline beptide, it is also called prolylendopeptidase. It is known that DPP-IV uses various biological peptides involved in endocrine system, neuroendocrine system, immune function and the like as substrates. Peptide (VIP) represented by puncturetic polypeptide (PP) and neuropeptide Y (Y), glucagon-like peptide-1 (GLP-1), glucose-dependent insulin-tropic polypeptide Many physiologically active peptides such as glucagon ZV IP family represented by peptide (GIP) and growth hormone secretagogue (GRF), and chemokine family are used as substrates for DPP-IV to activate / inactivate and promote metabolism (J. Langner and S. Ansorge edited "Cellular Peptidases in Immun Functions and Disease2", Advances in Experimental Medicine and Biology Vol. 77) ₀

DPP-IV cleaves two amino acids (His-Ala) from the N-terminus of GLP-1. Although the cleaved peptide binds weakly to the GLP-1 receptor, it is known to have no receptor activating action and to act as an antagonistic gonist (LB Knudsen et al., European Journal of Pharmacology). , Vol. 318, p429-435, 1996). GLP-1 by the DPP-IV It is known that the metabolism of GLP-1 is very rapid, and that the inhibition of DPP-IV increases the concentration of active GLP-1 in the blood (TJ Kieffer et al., Endocrinolgy, Vol. 136, P3585-3596, 1 995). GLP-1 is a peptide secreted from the intestinal tract by ingestion of sugar, and is a major promoter of dalcose-responsive secretory insulin secretion. It is known that GLP-1 has an action of promoting insulin synthesis in 3 cells of the kidney and a function of promoting 6 cell proliferation. It is also known that the GLP-1 receptor is expressed in the digestive tract, liver, muscle, adipose tissue, etc., and GLP-1 is expressed in these tissues in gastrointestinal tract activity, gastric acid secretion, glycogen It is known to act on the synthesis and degradation of insulin and on insulin-dependent glucose uptake. Therefore, an increase in blood GLP-1 concentration has the effects of promoting blood glucose-dependent insulin secretion, improving knee function, improving postprandial hyperglycemia, improving glucose intolerance, and improving insulin resistance. The development of DPP-IV inhibitors that are effective against type 2 diabetes (non-insulin-dependent diabetes) is expected (RA Pederson et al., Diabetes Vol. 47, pl 253-1258, 1998). Various DPP-IV inhibitors have been reported.For example, in WO 02/025060, a xanthine derivative having a piperazine ring is effective as a DPP-IV inhibitor Have been reported. In WO 02Z068420 pamphlet and WO 03/004 496 pamphlet, a xanthine derivative having a piperidine ring or the like is used as a DPP-IV inhibitor. Reported to be valid. In the pamphlet of International Publication No. 03Z024695, it is reported that a xanthine derivative containing a 2-aminocyclohexylamino group is effective as a DPP-IV inhibitor. WO 02/024698 pamphlet reports that xanthine derivatives are effective as phosphodiesterase V inhibitors. Disclosure of the invention

An object of the present invention is to provide a novel compound having excellent DPP-IV inhibitory activity. The present inventors have conducted intensive studies to achieve the above object, and as a result, have found that the following compound or a prodrug thereof, or a pharmaceutically acceptable salt thereof (hereinafter, the present invention Have been found to have excellent DPP-IV inhibitory activity, and have completed the present invention. That is, the present invention:

[1] Formula (I)

[Wherein, R ¹ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group. ;

R ² is a hydrogen atom, a halogen atom, a cyano group, a formyl group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkyloxy group, an optionally substituted alkenyl Group, optionally substituted amino group, optionally substituted sorbamoyl group, carboxy group, optionally substituted alkoxy group, optionally substituted alkoxycarbonyl group, optionally substituted aryl group, substituted Optionally substituted aryloxy group, optionally substituted aryloxycarbonyl group, optionally substituted arylalkyl group, optionally substituted arylalkyloxy group, optionally substituted arylo group, optionally substituted aryloxy group Monophenylthio group, optionally substituted arylsulfinyl group, optionally substituted arylsulfonyl group, substituted An alkylthio group, an optionally substituted alkylsulfiel group, an optionally substituted alkylsulfonyl group, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group, an optionally substituted Represents a heteroarylcarbonyl group, an optionally substituted heteroaryloxy group, an optionally substituted alkylcarbonyl group, or an optionally substituted nitrogen-containing saturated heterocyclic group, or a compound represented by the following formula (T 1) A group represented by to (T 6): Four

(T4) (T5) (T6)

(In the formula, R ^T is absent, or one or more, and each independently represents a halogen atom, a hydroxyl group, an oxo group, an optionally substituted alkoxy group, an optionally substituted alkyl group, A group, an optionally substituted alkoxycarbonyl group, a saturated heterocyclic group, an oxycarbonyl group or an optionally substituted alkamoyl group, or methylene, ethylene, trimethylene, Represents tetramethylene or buterene, and may form a new ring by bonding with one or two carbon atoms constituting the ring.);

R ³ represents a hydrogen atom, an alkyl group which may be substituted, a cycloalkyl group which may be substituted, an aryl group which may be substituted, a vinyl group which may be substituted, T represents a heterocyclic group or a substituted or heteroaryl group;

— Y—NH ₂ represents a group represented by the following formula (A) or a group represented by the following formula (B).

(In the formula, m represents 0, 1, or 2, and R ⁴ is absent, presents 1 or 2 times, and is each independently a halogen atom, a hydroxyl group, an oxo group, or may be substituted. An alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxy group, an optionally substituted Ca or two R ⁴ representing a have alkoxycarbonyl groups or substituted with a good force Rubamoiru group, together represent a methylene or ethylene, combined with two carbon atoms constituting the ring to form a new ring You can also. ),

(In the formula, n represents 0, 1, or 2, and R ⁵ is absent, presents 1 or 2 times, and is each independently a halogen atom, a hydroxyl group, an oxo group, or may be substituted. An alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxy group, an optionally substituted alkoxycarbonyl group, Alternatively, R ⁵ represents an optionally substituted radical group, or two R 5s together represent methylene or ethylene, and may form a new ring by bonding with the two carbon atoms constituting the ring. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof,

[2] One Y—NH ₂ is a group represented by the formula (A), and m is 1 or 2, or _Y—NH ₂ is a group represented by the formula (B), and n Is 1 or 2, or the compound according to [1] or a prodrug thereof, or a pharmaceutically acceptable salt thereof,

[3] The compound according to any one of [1] to [2], wherein R ³ is a group of any of the following formulas (C), (D) and (E), or a prodrug thereof, or a pharmaceutical agent thereof. Above acceptable salts,

(Wherein, z is an oxygen atom, or one NCR ¹¹ ) R ⁶ is absent, or one or two, and each independently represents a halogen atom, a hydroxyl group, a formyl group, a carboxy group, a cyano group, an alkylthio group, an alkylsulfinyl group /, an alkylsulfonyl group, an alkyl group , A haloalkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, an optionally substituted amino group, an optionally substituted rubamoyl group, an alkoxycarbonyl group, an optionally substituted alkyl carbonyl group, cyclo alkylcarbonyl group, an optionally substituted Ariru group, unsubstituted or to be Teroariru group or substituted also to nitrogen-containing represent a heteroaryl group, or taken two R ⁶ gar緖, - 3 represents an alkylenedioxy group,

R ⁷ is absent, presents one or two, and each independently represents a halogen atom, a cyano group, an alkyl group, a haloalkyl group, a cycloalkyl group, an alkoxy group, or a haloalkoxy group;

R ⁸ represents a methyl, ethyl, chlorine, or bromine atom,

R ⁹ represents a hydrogen atom, a methyl, an ethyl, a chlorine atom, or a bromine atom,

R ¹⁰ represents a hydrogen atom, methyl or ethyl,

pW: represents 0, 1 or 2,

R ¹¹ represents a hydrogen atom or an alkyl group. )

[4] The compound according to [3], wherein R ³ is formula (C) or formula (E), or a prodrug thereof, or a pharmaceutically acceptable salt thereof,

[5] R ³ is a group represented by the formula (C), and R ⁶ is absent, or one or two, and is each independently a halogen atom, a cyano group, an alkylthio group, an alkylsulfonyl group

, C _x _ 3 alkylenedioxy group, alkyl group, haloalkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, alkoxycarbonyl group, alkyl group, haloalkyl group and cycloalkylcarbonyl group [ 4] The compound or a prodrug thereof, or a pharmaceutically acceptable salt thereof,

[6] The compound according to [4] or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is a group represented by the formula (C), and one R ⁶ is a halogen atom.

[7] R ³ is 2-chlorophenyl, 2-chloro-5-fluorophenyl, 2-methyl-5-fluorophenyl, 2-methoxy-15-fluorophenyl, or 2-cyano-5-fluorophenyl [4] or a prodrug thereof, or a pharmaceutically acceptable salt thereof, [8] R ¹ is a hydrogen atom, an optionally substituted alkyl group having 1 to 3 carbon atoms, or an optionally substituted aryl group, wherein the substituent of the optionally substituted alkyl group is fluorine An atom, an optionally substituted aryloyl group, a carboxy group, an optionally substituted alkoxycarbonyl group, an optionally substituted arylyl group and an optionally substituted aryloxy group, [1] to [7] Or a prodrug thereof, or a pharmaceutically acceptable salt thereof,

[9] The compound according to any one of [1] to [7] or a prodrug thereof, or a pharmaceutically acceptable compound thereof, wherein R ¹ is a group represented by the formula: R a—Rb—R c Salt. here,

R a represents an alkylene chain,

R b represents a single bond or a haponyl group,

Rc represents an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted aryl group, or an optionally substituted aryloxy group,

[10] The compound according to any one of [1] to [7], wherein R ¹ is a hydrogen atom, methyl, or ethyl, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,

[11] The compound according to any one of [1] to [7], wherein R ¹ is methyl, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,

[12] R ² is a hydrogen atom, a cyano group, an optionally substituted alkyl group, a carboxy group, an optionally substituted alkoxy group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryl group, Optionally substituted aryloxy group, optionally substituted aryloxycarbonyl group, optionally substituted aralkyl group, optionally substituted aralkyloxy group, optionally substituted aroyl group, or optionally substituted The compound according to any one of [1] to [11], which is an alkylcarbonyl group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof;

[13] The compound according to any one of [1] to [11] or a prodrug thereof, wherein R ² is a cyano group, an optionally substituted alkoxycarbonyl group, or an optionally substituted aryloxy group. Or a pharmaceutically acceptable salt thereof,

[14] The compound according to [13], wherein R ² is a substituted aryloxy group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, [15] The compound of any of the above, wherein R ² is a substituted heteroaryloxy group, a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[16] The compound according to any one of [1] to [11], wherein R ² is a group represented by formulas (T 1) to (T6), or a prodrug thereof, or a pharmaceutically acceptable salt thereof. Salt,

[17] R ² is a compound represented by the formula: O—Tx—O—Ty (where O represents an oxygen atom, Tx represents a phenylene group, a pyridinediyl group, a pyrimidinediyl group, or a thiofendyl group; Ty Represents an optionally substituted alkyl group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkylalkyl group, or an optionally substituted saturated heterocyclic group. [1] The compound according to any of [1] to [11] or a prodrug thereof, or a pharmaceutically acceptable salt thereof,

[18] The compound according to [1.7] or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein Tx is a phenyl group.

[19] The compound according to [18], wherein Tx is m-phenylene, a prodrug thereof, or a pharmaceutically acceptable salt thereof,

[20] Ty force The compound according to [19], which is a substituted alkyl group, a substituted cycloalkyl group, or an optionally substituted cycloalkylalkyl group, a prodrug thereof, or a pharmaceutically acceptable salt thereof,

[21] The compound according to [20], wherein the substituent of the group represented by Ty is a halogen atom, a carboxy group, or an alkoxycarbonyl group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof;

[22] The compound represented by the formula (I) is represented by the following formulas (c1) to (c36):

^ 01900 contract Zdf / e :) d 908 960 contract OAV

(εζ.)

1 ^ 01900 contract Zdf / e :) d 908 960 contract OAV Two

(c35) the compound according to [1], or a prodrug thereof, or a pharmaceutically acceptable salt thereof, which is (c36);

[23] A medicament comprising the compound according to any one of [1] to [22] or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient,

[24] A dipeptidyl peptidase-IV inhibitor comprising as an active ingredient the compound according to any one of [1] to [22] or a prodrug thereof, or a pharmaceutically acceptable salt thereof,

[25] A therapeutic agent for diabetes comprising the compound according to any one of [1] to [22] or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient,

[26] Use of the compound according to any one of [1] to [22] or a prodrug thereof, or a pharmaceutically acceptable salt thereof, for the production of a dipeptidyl peptidase-IV inhibitor;

[27] The method according to any one of [1] to [22] for the manufacture of a therapeutic agent for diabetes. A compound or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or

[28] administering to a patient in need of treatment an effective amount of the compound according to any of [1] to [22] or a prodrug thereof, or a pharmaceutically acceptable salt thereof, The present invention relates to a method for treating diabetes. The compound of the present invention has excellent DPP-IV inhibitory activity and is useful as a therapeutic agent for diabetes. In particular, the compounds included in [16] and [17] have excellent oral absorbability. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail.

In the present specification, the number of substituents in the group defined by “may be substituted” or “substituted” is not particularly limited as long as it can be substituted, and is 1 or more.

When R ^T there are multiple, or Table 2 or more integer multiple A when there are a plurality of substituents, preferably represents a 2, 3, 4 or 5. More preferably, it represents 2 or 3.

“Lower” in the alkyl portion of “lower alkyl group”, “lower alkoxy group” and “lower alkyl carboel” means an alkyl group having 1 to 6 carbon atoms and an alkoxy group unless otherwise specified. And

As the alkyl group of the “optionally substituted alkyl group” for R ¹ and R ^2,

For example, a linear or branched lower alkyl group and the like can be mentioned. Specifically, for example, a linear or branched alkyl group having 1 to 6 carbon atoms and the like can be mentioned. Examples thereof include methyl, ethyl, propynole, 2-propynole, butynole, isoptinole, sec-butyl, tert-butyl, pentyl and hexyl.

Examples of the substituent in the “optionally substituted alkyl group” for R ¹ and R ² include (1) a halogen atom, (2) an optionally substituted nitrogen-containing heteroaryl group, and (3) an optionally substituted An aryloyl group, (4) an optionally substituted arylaminocarbonyl group, (5) an optionally substituted nitrogen-containing heteroarylcarbonyl group, (6) an optionally substituted nitrogen-containing heteroarylaminocarbyl group (7) carboxy group, (8) optionally substituted alkoxycarbonyl group, (9) optionally substituted Bamoyl group, (10) optionally substituted cycloalkyl group, (11) optionally substituted aryl group, (12) optionally substituted aryloxy group, (13) substituted Arylsulfonyl group, (14) alkylsulfonyl group, (15) optionally substituted aralkylsulfonyl group, (16) hydroxyl group, or (17) optionally substituted alkoxy And the like.

(1) Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

(2) Examples of the nitrogen-containing heteroaryl in the “nitrogen-containing heteroaryl group which may be substituted” include a 5- to 10-membered ring group having 1 to 2 nitrogen atoms. Specific examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, triazolyl, triazinyl, tetrazolyl, indolyl and imidazo [1,2-a] pyridyl.

Examples of the substituent in the “optionally substituted nitrogen-containing heteroaryl group” include, for example,

(a) a hydroxyl group,

(b) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom);

(c) alkyl group (for example, a linear or branched lower alkyl group and the like, specifically, for example, a linear or branched alkyl group having 1 to 6 carbon atoms, and the like; More specifically, examples include methyl, ethyl, propyl, 2-propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.)

(d) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) or an alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms) And more specifically, methoxy, ethoxy, propoxy, butoxy, etc.). An alkyl group substituted with (for example, a linear or branched lower alkyl group) Specific examples include straight-chain or branched alkyl groups having 1 to 4 carbon atoms, and more specifically, for example, methyl, ethyl, propyl, 2-propyl and the like. Or butyl. Specific examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-diphorethyl, perfluoroethyl, and methoxyethyl. ),

(e) an alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms, more specifically, methoxy, ethoxy, propoxy, or butoxy, etc.) ),

(D halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) or an alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms) And more specifically, methoxy, ethoxy, propoxy, butoxy and the like.) An alkoxy group substituted with (wherein the alkoxy moiety is, for example, a lower alkoxy group, etc.). Examples include alkoxy groups 1 to 4, more specifically, for example, methoxy, ethoxy, propoxy, butoxy, etc. Specific examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, methoxymethoxy, Ethoxy methoxy, methoxy ethoxy, ethoxy ethoxy, methoxy propoxy Or E Bok Kishipu port epoxy, and the like.),

0 carboxy group,

(i) An alkoxyl group substituted with an alkoxyl group (for example, an alkoxy group having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, or butoxy). Methoxycarbonyl or ethoxycarbonyl, etc.)

(j) a carbamoyl group which may be substituted with an alkyl group (for example, methyl, ethyl, propyl, 2-propyl or butyl, etc.) (specifically, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, And ethyl carbamoyl or acetyl carbamoyl.

(1 aryl group (for example, phenyl, 1-naphthyl or 2-naphthyl, etc.),

Or (1) an amino group and the like.

(3) The arylo group of the “optionally substituted aryloyl group” includes, for example, The following arylcarbonyl groups are mentioned, and more specifically, benzoyl or naphthoyl and the like.

Examples of the substituent in the “optionally substituted arylo group” include, for example,

(a) a hydroxyl group,

(d) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) or an alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms) And more specifically, methoxy, ethoxy, propoxy, butoxy, etc.). An alkyl group substituted with (for example, a linear or branched lower alkyl group) Specific examples include a linear or branched alkyl group having 1 to 4 carbon atoms, and more specifically, for example, methyl, ethyl, propyl, 2-propyl, or the like. Butyl, etc. Specifically, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-diphorethyl And perfluoroethyl or methoxyethyl.

(f) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) or an alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms) And more specifically, methoxy, ethoxy, propoxy, butoxy, etc ..) An alkoxy group substituted with (an alkoxy moiety is, for example, a lower alkoxy group, etc.). Examples include alkoxy groups of Formulas 1 to 4, and more specifically, for example, methoxy, ethoxy And propoxy or butoxy. Specific examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyshethoxy, methoxypropoxy or ethoxypropoxy. ),

(g) a cyano group,

(h) a carboxy group,

(i) An alkoxyl group substituted with an alkoxyl group (for example, an alkoxy group having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, or butoxy). Methoxycarbonyl or ethoxycarbonyl.),

(k) an alkylsulfonyl group (for example, methanesulfonyl, etc.), (1) methylenedioxy,

(m) ethylenedioxy,

(n) a nitrogen-containing saturated heterocyclic group (for example, pyrrolidinyl, piperidinyl, morphonyl and the like);

(0) cycloalkyloxy group (for example, lower cycloalkyloxy group and the like, specifically, cycloalkyloxy group having 3 to 10 carbon atoms, more specifically, cyclopropyl An alkoxy group (for example, a lower alkoxy group, etc.) substituted with oxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, adamantyloxy or norpoloxy. Specific examples include alkoxy groups having 1 to 4 carbon atoms, and more specific examples include methoxy, ethoxy, propoxy, butoxy, etc. Specific examples include cyclopropyloxymethoxy, cyclobutyl Methoxymethoxy or cyclopropyloxyethoxy.),

(P) cycloalkyloxy group (for example, lower cycloalkyloxy group and the like, specifically, cycloalkyloxy group having 3 to 10 carbon atoms, more specifically Examples thereof include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, adamantyloxy and norpoloxy. ),

Or (q) an amino group.

(4) Examples of the aryl group in the “optionally substituted arylaminocarbonyl group” include phenyl, 1-naphthyl and 2-naphthyl.

Examples of the substituent in the “optionally substituted arylaminocarbonyl group” include those exemplified as the substituent in the aforementioned “optionally substituted aryloyl group” in (3).

(5) Examples of the nitrogen-containing heteroaryl in the “optionally substituted nitrogen-containing heteroarylcarbonyl group” include the nitrogen-containing heteroaryl in the above-mentioned “(2) optionally substituted nitrogen-containing heteroaryl”. What was done.

Examples of the substituent in the “optionally substituted nitrogen-containing heteroarylcarbonyl group” include those exemplified as the substituent in the aforementioned “optionally substituted nitrogen-containing heteroaryl group” in (2).

(6) The nitrogen-containing heteroaryl in the “optionally substituted nitrogen-containing heteroarylaminocarbonyl group” includes the nitrogen-containing heteroaryl in the above (2) “optionally substituted nitrogen-containing heteroaryl”. Those exemplified as teloaryl are exemplified.

Examples of the substituent in the “optionally substituted nitrogen-containing heteroarylaminocarbonyl group” include those exemplified as the substituent in the “optionally substituted nitrogen-containing heteroarylamino” in the above (2).

(8) The alkoxy group in the "optionally substituted alkoxycarbonyl group" includes, for example, an alkoxy group having 1 to 4 carbon atoms (eg, methoxy, ethoxy, propoxy, 2-propoxy, butoxy or tert-butoxy) And the like. Specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl and tert-butoxycarbonyl.

Examples of the substituent in the “optionally substituted alkoxycarbonyl group” include (a) a hydroxyl group, (b) a carboxy group,

(d) an alkoxy group (for example, a lower alkoxy group and the like, specifically, an alkoxy group having 1 to 4 carbon atoms, and more specifically, methoxy, ethoxy, propoxy, or butoxy, etc. ),

(e) an alkyl group (for example, methyl, ethyl, propyl, 2-propyl, butyl, tert-butyl, etc.); a substituted carbonyl group (specifically, methyl carbonyloxy, Butyl carbonyl, propyl carbonyl, 2-propyl carbonyl, butyl carbonyl, tert-butyl carbonyl, and the like.)

(f) Alkoxy group A carbonyl group substituted with an alkoxy group having 1 to 4 carbon atoms (for example, methoxy, ethoxy, propoxy, 2-propoxy, butoxy or tert-butyloxy). Specific examples include methoxycarbonyl and ethoxycarbonyl.)

(g) an amino group substituted with an alkyl group (for example, methyl, ethyl, propyl, 2-propyl, butyl or tert-butyl, etc.);

(h) an alkyl group (for example, methyl, ethyl, propyl, 2-propyl, butyl or tert-butyl, etc.);

(i) a sulfamoyl group substituted with an alkyl group (for example, methyl, ethyl, propyl, 2-propyl, butyl or tert-butyl, etc.);

A ureido group substituted with an alkyl group (eg, methyl, ethyl, propyl, 2-propyl, butyl or tert-butyl);

(k) a carbonyloxy group substituted by an alkyloxy group such as an alkyloxy group having 1 to 4 carbon atoms (for example, methoxy, ethoxy, propoxy, 2-propoxy, butoxy or tert-butyloxy); Specifically, methoxy carboxy, ethoxy carboxy, 2-pro Poxycarponyloxy or tert-butyloxycarbonyloxy. ),

(1) Cycloalkyloxy group (eg, cycloalkyloxy having 3 to 10 carbon atoms (eg, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, adamantyloxy or And a carbonyloxy group substituted with) .Specifically, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, or cycloheptyloxycarbonyl. Etc.).

(m) phenyl,

(n) 5-methyl-2-oxo-1,3-dioxolen-4-yl,

(0) 5-oxo-1 2-tetrahydrofuranyl,

(p) 1,3-dihydro-3-oxo-1-isobenzofuranyl,

(q) tetrahydrofuranyl,

(r) a nitrogen-containing saturated heterocyclic group (for example, pyrrolidinyl, piperidinyl, morphonyl and the like);

Or (s) an octogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.).

(9) Examples of the substituent in the "optionally substituted rubamoyl group" include an alkyl group (for example, a linear or branched alkyl group having 1 to 4 carbon atoms, and more specifically, for example, , Methyl, ethyl, propyl, 2-propyl or butyl, etc.). Further, two substituents of the carbamoyl group are bonded to form, for example, pyrrolidine (the pyrrolidine may be further substituted with a hydroxyl group), piperidine, morpholine, thiomorpholine, thiomorpholine oxide, thiomorpholine. Forming an aliphatic heterocyclic ring which may contain carbon, nitrogen and oxygen, such as phosphorus oxide or piperazine (the nitrogen atom of the piperazine may be substituted by methyl or ethyl); May be. Specific examples of the “optionally substituted carbamoyl group” include, for example, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, getylcarbamoyl, ethylmethylcarbamoyl, methylpropylcarbamoyl, and cyclopropylcarbamoyl. The cyclopropyl methyl carpamo Yl, pyrrolidino carbonyl, piperidino carbonyl, morpholinocarbonyl and the like.

(10) Examples of the cycloalkyl group in the “optionally substituted cycloalkyl group” include a cycloalkyl group having 3 to 10 carbon atoms.Specifically, for example, cyclopropyl, cyclobutyl, cyclopentyl, Examples include cyclohexyl, cycloheptyl, 7-damantyl or norpolnyl.

Examples of the substituent in the “optionally substituted cycloalkyl group” include an alkyl group (for example, methyl, ethyl, propyl, 2-propyl, butyl, tert-butyl, etc.), an aralkyl group (for example, benzyl, 2-phenylethyl or 1-naphthylmethyl) or a fluorine atom.

(11) Examples of the aryl group in the "aryl group which may be substituted" include an aryl group having 6 to 10 carbon atoms. Specifically, for example, phenyl, 1-naphthyl or 2 _ Naphthyl and the like.

As the substituent in the “optionally substituted aryl group”,

(a) a hydroxyl group,

(c) alkyl group (for example, a linear or branched lower alkyl group and the like, specifically, for example, a linear or branched alkyl group having 1 to 4 carbon atoms; More specifically, examples include methyl, ethyl, propyl, 2-propyl or butyl.

(d) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) or an alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms) And more specifically, methoxy, ethoxy, propoxy, butoxy, etc.). An alkyl group substituted with (for example, a linear or branched lower alkyl group) Specific examples include, for example, linear or branched alkyl groups having 1 to 4 carbon atoms, and more specifically, for example, methyl, ethyl, propyl, 2-propyl or Butyl, etc. Specifically, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-diphoretic Le, Perfolo And methoxyethyl. ),

(f) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) or an alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms) And more specifically, methoxy, ethoxy, propoxy, butoxy, etc ..) An alkoxy group substituted with (an alkoxy moiety is, for example, a lower alkoxy group, etc.). Examples include the alkoxy groups of Formulas 1 to 4, more specifically, for example, methoxy, ethoxy, propoxy, butoxy, etc. Specific examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and methoxymethoxy. , Ethoxy methoxy, methoxy ethoxy, ethoxy ethoxy, methoxy propoxy Shi or Etokishipu port epoxy, and the like.),

(g) a phenyl group optionally substituted with the following (aa), (bb) or (cc):

(aa) an alkoxy group which may be substituted with a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) (Examples of the alkoxy moiety include a lower alkoxy group, etc. Specific examples include an alkoxy group having 1 to 4 carbon atoms, and more specific examples include methoxy, ethoxy, propoxy, and butoxy.

(bb) an alkyl group which may be substituted with a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.) (The alkyl moiety is, for example, a linear or branched lower group; Examples thereof include an alkyl group and the like, specifically, for example, a linear or branched alkyl group having 1 to 4 carbon atoms and the like. More specifically, for example, methyl, ethyl, propyl, 2 —Propyl or butyl, etc.), (cc) halogen atom (for example, fluorine atom, chlorine atom, bromine atom or iodine atom, etc.),

(h) a cyano group,

(i) a carboxy group,

(j) Alkoxy group (for example, an alkoxy group having 1 to 4 carbon atoms (for example, Toxic, ethoxy, propoxy or butoxy and the like. ), And specifically includes, for example, methoxycarbonyl and ethoxycarbonyl. ),

(k) an alkyl group (for example, methyl, ethyl, propyl, 2-propyl or butyl, etc.), and a substituted carbamoyl group (specifically, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, And ethyl carbamoyl or acetyl carbamoyl.

(1) an alkylsulfonyl group (for example, methylsulfonyl, etc.), (m) methylenedioxy,

(n) ethylenedioxy,

Or (0) phenyloxy and the like.

(12) Examples of the aryloxy group of the “optionally substituted aryloxy group” include, for example, an aryloxy group having 6 to 10 carbon atoms. Specifically, for example, phenoxy, 1— Examples include naphthyloxy or 2-naphthyloxy.

Examples of the substituent of the "optionally substituted aryloxy group" include those exemplified as the substituent in the "optionally substituted aryl group" of the above (11).

(13) Examples of the arylsulfonyl group of the “optionally substituted arylsulfonyl group” include an arylsulfonyl group having 6 to 10 carbon atoms. Examples include benzenesulfonyl, toluenesulfonyl, and naphthalenesulfonyl.

(14) Examples of the alkylsulfonyl group of the “alkylsulfonyl group” include an alkylsulfonyl group having 1 to 6 carbon atoms.Specifically, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, 2 —Propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like.

(15) Examples of the aralkylsulfonyl group of the “optionally substituted aralkylsulfonyl group” include, for example, an optionally substituted alkylene chain (for example, methylene, ethylene or propylene. Is, for example, fluorine atom, methoxy, ethoxy, propoxy, methyl, ethyl, propyl or 2-propyl. I can do it. Examples thereof include those in which the “optionally substituted arylsulfonyl group” of the above (13) is bonded.

(17) The alkoxy group of the "optionally substituted alkoxy group" includes, for example, a lower alkoxy group and the like, specifically, an alkoxy group having 1 to 4 carbon atoms, and more specifically. Include methoxy, ethoxy, propoxy or butoxy and the like.

Examples of the substituent of the “optionally substituted alkoxy group” include those exemplified as the substituent in the aforementioned “optionally substituted alkoxycarbonyl group” of (8).

Examples of the cycloalkyl group of the "optionally substituted cycloalkyl group" for R ¹ and R ² include a cycloalkyl group having 3 to 10 carbon atoms.Specifically, for example, cyclopropyl, cyclobutyl, Examples include cyclopentyl, cyclohexyl, cycloheptyl, adamantyl or norpolnyl.

The substituent of the `` optionally substituted cycloalkyl group '' in R ¹ and R ^{2 includes} the `` substituted alkyl group '' as the substituent of the `` optionally substituted alkyl group '' represented by R ¹ and R ² above. And the like.

As the “halogen atom” for R ^2, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like can be mentioned.

Examples of the cycloalkyloxy group of the “optionally substituted cycloalkyloxy group” for R ² include a cycloalkyloxy group having 3 to 10 carbon atoms. Specifically, for example, cyclopropyl Oxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, adamantyloxy or norpolnyoxy.

As the substituent of the “optionally substituted cycloalkyloxy group” for R ^2, the “optionally substituted cycloalkyl” for the aforementioned “optionally substituted alkyl group” for R ¹ and R ² Examples of the substituent in the “group” include those exemplified above.

The alkenyl group of "optionally substituted alkenyl group optionally" in R ^2, include alkenyl group having 2 to 6 carbon atoms For example, specifically, for example, vinyl, pro Benyl, methylprobenyl, butenyl or methylbutenyl and the like can be mentioned.

As the substituent of the “optionally substituted alkenyl group” for R ² ,

(a) a hydroxyl group,

0)) Perogen atom (for example, fluorine atom, chlorine atom, bromine atom, iodine atom, etc.),

(c) alkyl group (for example, a linear or branched lower alkyl group and the like, specifically, for example, a linear or branched alkyl group having 1 to 4 carbon atoms; More specifically, examples include methyl, ethyl, propyl, 2-propyl and butyl.

(d) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) or an alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms) And more specifically, methoxy, ethoxy, propoxy, butoxy, etc.). An alkyl group substituted with (for example, a linear or branched lower alkyl group) Specific examples include, for example, linear or branched alkyl groups having 1 to 4 carbon atoms, and more specifically, for example, methyl, ethyl, propyl, 2-propyl or Butyl etc. Specifically, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-diphoretic , Perfluoroethyl or methoxyethyl, etc.)

(Halogen atom (for example, fluorine atom, chlorine atom, bromine atom or iodine atom, etc.) or alkoxy group (for example, lower alkoxy group, etc., specifically, alkoxy group having 1 to 4 carbon atoms) More specifically, methoxy, ethoxy, propoxy, butoxy, etc. may be mentioned.) An alkoxy group substituted with an alkoxy group (the alkoxy moiety is, for example, a lower alkoxy group, etc.). To 4, more specifically, for example, methoxy, ethoxy, propoxy, butoxy, etc. Specific examples include: ??? fluoromethoxy, difluoromethoxy, trifluoromethoxy, methoxymethoxy, Ethoxy methoki And methoxy ethoxy, ethoxy ethoxy, methoxy propoxy or ethoxy oxy oxy. ),

(bb) an alkyl group which may be substituted with a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) (an alkyl moiety is, for example, a linear or branched lower group) Examples thereof include an alkyl group and the like, specifically, for example, a linear or branched alkyl group having 1 to 4 carbon atoms and the like. More specifically, for example, methyl, ethyl, propyl, 2 —Propyl or butyl, etc.),

(cc) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.),

(i) a carboxy group,

(j) alkoxy group having a carbon number of 1 to 4 (for example, methoxy, ethoxy, propoxy or butoxy, etc.). Methoxycarbonyl or ethoxycarbonyl, etc.)

(1) an alkylsulfonyl group (for example, methylsulfonyl and the like); and (m) phenyloxy and the like.

As the substituent of the “optionally substituted amino group” for R ² ,

ω alkyl group (for example, a straight-chain or branched lower alkyl group and the like, specifically, for example, a straight-chain or branched alkyl group having 1 to 4 carbon atoms, and the like; More specifically, examples include methyl, ethyl, propyl, 2-propyl and butyl. ),

(b) alkyl carbonyl group (for example, lower alkyl carbonyl, etc., specifically, an alkyl carbonyl group having 1 to 4 carbon atoms, more specifically, acetyl or propionyl, etc.) ),

(c) an aryloyl group (for example, an arylcarbonyl group having 11 or less carbon atoms, specifically, for example, benzoyl or naphthoyl);

1) an alkylsulfonyl group (for example, an alkylsulfonyl group having 1 to 4 carbon atoms, specifically, for example, methanesulfonyl, ethanesulfonyl and the like);

(e) arylsulfonyl group (for example, arylsulfonyl group having 10 or less carbon atoms, specifically, benzenesulfonyl, toluenesulfonyl, naphthalenesulfonyl, etc.),

(f) an aryl group which may be substituted (for example, an aryl group having 10 or less carbon atoms, specifically, phenyl, 1-naphthyl or 2-naphthyl, etc .; Examples include a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom), an alkyl group (for example, a linear or branched lower alkyl group), and specifically, for example, Examples thereof include a linear or branched alkyl group having 1 to 4 carbon atoms, and more specifically, for example, methyl, ethyl, propyl, 2-propyl or butyl, etc.), an alkoxy group ( Examples thereof include an alkoxy group having 1 to 4 carbon atoms, and specific examples thereof include methoxy, ethoxy, propoxy, or butoxy.) And the like.

Or (g) an aralkyl group (for example, benzyl, 2-phenylethyl, 1-naphthylmethyl and the like) and the like.

The amino group which may be substituted also includes (h) imide. Specific examples of the "substituted amino group" include amino, methylamino, ethylamino, dimethylamino, acetylamino, methylethylamino, acetylamino, propionylamino, benzoylamino, naphthoylamino, methylsulfonylamino, and ethylamino. Examples include rusulfonylamino, methylcarbonylamino, ethylcarbonylamino, benzenesulfonylamino, phthalimide, succinimide, and maleimide. It is.

The substituent of the “optionally substituted rubamoyl group” for R ² includes:

(a) an alkyl group (for example, a linear or branched lower alkyl group and the like, specifically, for example, a linear or branched alkyl group having 1 to 4 carbon atoms; More specifically, examples include methyl, ethyl, propyl, 2-propyl or butyl.

Or (b) an aryl group which may be substituted with the following (aa), (bb) or (cc) (for example, phenyl, 1-naphthyl or 2-naphthyl).

(aa) Halogen atom (for example, fluorine atom, chlorine atom, bromine atom, iodine atom, etc.)

(bb) an alkoxy group which may be substituted with a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) (Examples of the alkoxy moiety include a lower alkoxy group, etc. Specific examples include an alkoxy group having 1 to 4 carbon atoms, and more specific examples include methoxy, ethoxy, propoxy, and butoxy.

(cc) an alkyl group which may be substituted with a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) (The alkyl moiety is, for example, a linear or branched lower group; Examples thereof include an alkyl group and the like, specifically, for example, a linear or branched alkyl group having 1 to 4 carbon atoms and the like. More specifically, for example, methyl, ethyl, propyl, 2 —Propyl or butyl, etc.)

Specific examples of "optionally substituted carbamoyl group" include carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, getylcarbamoyl, ethylmethylcarbamoyl, phenylcarbamoyl or phenylmethylcarbamoyl. .

Further, two substituents of the carbamoyl group are bonded to form pyrrolidine, piperidine, morpholine, thiomorpholine, thiomorpholine oxide, thiomorpholine dioxide, or piperazine (the nitrogen atom of the piperazine is May be substituted with, for example, methyl, ethyl, or propyl), and may form an aliphatic heterocyclic ring which may contain carbon, nitrogen, oxygen, or sulfur. , Pyrrolidino carbamoyl, piperidino carbamoyl or morpholino carbamoyl. The alkoxy in the “optionally substituted alkoxy group” for R ² includes, for example, a lower alkoxy group and the like, specifically, an alkoxy group having 1 to 4 carbon atoms, and more specifically, methoxy , Ethoxy, propoxy or butoxy.

The substituent of the “optionally substituted alkoxy group” in R ^{2 includes} the “optionally substituted alkoxycarbonyl group” as the substituent of the “optionally substituted alkyl group” in R ¹ and R ² . Those exemplified as the substituents in

Examples of the alkoxycarbonyl in the “optionally substituted alkoxycarbonyl group” for R ² include, for example, methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl.

The substituent of the “optionally substituted alkoxycarbonyl group” in R ^{2 includes} the “optionally substituted alkoxycarbonyl group” as the substituent of the “optionally substituted alkyl group” in R ¹ and R ² . Examples of the substituent in are exemplified.

Examples of the aryl group in the “optionally substituted aryl group” for R ¹ and R ² include an aryl group having 6 to 10 carbon atoms. Specifically, for example, Examples thereof include phenyl, 1-naphthyl and 2-naphthyl.

Examples of the substituent in the “optionally substituted aryl group” for R ¹ and R ² include:

(a) a hydroxyl group,

(b) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.),

(d) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) or an alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms) And more specifically, methoxy , Ethoxy, propoxy or butoxy. ) -Substituted alkyl group (an example of the alkyl moiety is a straight-chain or branched lower alkyl group and the like. Specifically, for example, a straight-chain or branched C 1 to C 4 alkyl group) Examples thereof include an alkyl group and the like, and more specifically, for example, methyl, ethyl, propyl, 2-propyl or butyl, etc. Specifically, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2 , 2-diphoroethyl, perfluoroethyl or methoxyethyl.

(f) an alkoxy group substituted with a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) (The alkoxy moiety is, for example, a lower alkoxy group, etc. Examples include an alkoxy group having 1 to 4 carbon atoms, more specifically, for example, methoxy, ethoxy, propoxy, butoxy, etc. Specific examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, etc. ),

(g) a phenyl group which may be substituted by the following (aa), (bb) or (cc):

0 cyano group, (i) a carboxy group,

(j) an alkoxy group optionally substituted by a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) (for example, an alkoxy group having 1 to 4 carbon atoms (for example, methoxy, Ethoxy, propoxy, butoxy, etc.), and carbonyl groups substituted with, specifically, for example, methoxycarbonyl, ethoxycarbonyl, and the like.),

(k) an alkyl group (for example, methyl, ethyl, propyl, 2-propyl or butyl, etc.), and a substituted carbamoyl group (specifically, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, And ethyl carbamoyl and acetyl carbamoyl.

(1) an alkylsulfonyl group (for example, methylsulfonyl and the like can be mentioned),

On) methylenedioxy,

(n) ethylenedioxy,

(0) a phenyloxy group which may be substituted (as a substituent, a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.); or an alkoxy group (for example, having 1 to 4 carbon atoms) And an alkoxy group, specifically, methoxy, ethoxy, propoxy or butoxy, etc.)).

(P) phenyl,

(q) Nitrogen-containing saturated heterocyclic groups (for example, pyrrolidinyl, piberidinyl, morphonyl, or piperazinyl (the nitrogen atom of the piperazine may be substituted with, for example, methyl, ethyl or propyl)), and the like.

(r) an alkyl group (for example, methyl, ethyl, propyl, 2-propyl or butyl, etc.), a halogen atom (for example, fluorine atom, chlorine atom, bromine atom or iodine atom). Or an alkoxy group (for example, a lower alkoxy group and the like, specifically, an alkoxy group having 1 to 4 carbon atoms, and more specifically, methoxy, ethoxy, propoxy or butoxy, etc.). A cycloalkyloxy group which may be substituted (the cycloalkyloxy moiety includes, for example, a lower cycloalkyloxy group and the like; specifically, a cycloalkyloxy group having 3 to 10 carbon atoms (eg, cyclopropyloxy group) Xy, cyclobutyloxy, cyclo pliers Roxy, cyclohexyloxy, cycloheptyloxy, adamantyloxy or norpolnyroxy and the like. Specifically, for example, 2-methylcyclopropyloxy, 2-fluorocyclopropyloxy, 3-methoxycyclobutyloxy or 3-fluorocyclobutyloxy and the like can be mentioned. ),

(t) an alkenyl group (for example, an alkenyl group having 2 to 6 carbon atoms, specifically, for example, pinyl, probenyl, methylprobenyl, butenyl, methylbutenyl, etc.),

(u) an alkenyl group which may be substituted with a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.) (for example, an alkenyl group having 2 to 6 carbon atoms; Specifically, for example, vinyl, propenyl, methylprobenyl, butenyl, methylbutenyl and the like can be mentioned.)

(V) An amino group which may be substituted by an alkyl group (for example, methyl, ethyl or propyl, etc.) (specific examples include amino, methylamino, ethylamino, propylamino, dimethylamino, etc.). ),

(w) alkyl carbonyl group (for example, lower alkyl carbonyl, etc., specifically, an alkyl carbonyl group having 1 to 4 carbon atoms, and more specifically, acetyl or propionyl, etc.) ),

(X) acetoxy,

(y) an alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms, more specifically, methoxy, ethoxy, propoxy, or butoxy, etc.) ) Is substituted with an alkoxy group (for example, a lower alkoxy group and the like, specifically, an alkoxy group having 1 to 4 carbon atoms, and more specifically, methoxy, ethoxy, propoxy, butoxy, etc. Specific examples include methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy or ethoxypropoxy.) Or (z) a cycloalkyloxy group (for example, lower cycloalkyloxy) And specifically, cycloalkyloxy groups having 3 to 10 carbon atoms. Gerare, more specifically, cyclopropyl O alkoxy, cyclobutyl O alkoxy, cyclopentyloxy Ruo carboxymethyl And cyclohexyloxy, cycloheptyloxy, adamantyloxy or norpolnyoxy. ) -Substituted alkoxy group (e.g., a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms, more specifically, methoxy, ethoxy, propoxy, Butoxy, etc. Specific examples include cyclopropyloxymethoxy, cyclobutyloxymethoxy, cyclopropyloxyethoxy, etc.).

The aryloxy group of the “optionally substituted aryloxy group” for R ² includes, for example, an aryloxy group having 6 to 10 carbon atoms. Specifically, for example, phenoxy, 1-naphthyloxy or 2-naphthoxy and the like.

The substituent of the “optionally substituted aryloxy group” in R ² includes the aforementioned R

Examples of the substituent for the “aryl group which may be substituted” in ¹ and R ² include those exemplified above. The substituent in the “optionally substituted aryloxy group” in R ² also includes, in addition to the above, a group represented by the following formula: 1 O—T y.

Examples of the aryloxycarbonyl group in the "optionally substituted aryloxycarbonyl group" for R ² include an aryloxycarbonyl group having 7 to 11 carbon atoms. Is, for example, a phenyloxycarbonyl, 2-naphthyloxycarbonyl or 1-naphthyloxycarbonyl group.

The substituent of the "optionally substituted § Li one also Ruo carboxymethyl Cal Poni Le group" in R ^2, include those exemplified as the substituents of "optionally substituted Ariru group" in R ¹ and R ² .

Examples of the “optionally substituted aralkyl group” for R ² include, for example, those in which an optionally substituted alkylene chain is bonded to an optionally substituted aralkyl group.

Examples of the "aryl" moiety include an aryl group having 6 to 10 carbon atoms, and specific examples include phenyl and naphthyl. Examples of the substituent in the “optionally substituted aryl group” portion include those exemplified as the substituent in the “optionally substituted aryl group” in R ¹ and R ² .

Examples of the alkylene chain of the “optionally substituted alkylene chain” include an alkylene chain having 1 to 4 carbon atoms, and specific examples include methylene, ethylene, trimethylene and tetramethylene. "Optionally substituted alkylene chain" Examples of the substituent of the moiety include an alkyl group (for example, a linear or branched alkyl group having 1 to 4 carbon atoms and the like, and more specifically, for example, methyl, ethyl, propyl, 2-propyl or butyl And a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom). The number of substituents is one or two or more. In addition, two alkyl groups adjacent to each other or on the same carbon are bonded to form a cycloalkyl having 3 to 10 carbon atoms (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl or norpolnyl, etc.). ) May be formed.

The Ararukiru group "optionally substituted Ararukiruokishi group" for R ^2, the Ararukiru group of the "unsubstituted or optionally Ararukiru group" is levator Gerare in R ^2, specifically, for example, Benjiruokishi or 2- Phenylethyloxy and the like. The substituent of the “optionally substituted aryl group” in the “optionally substituted aralkyloxy group” includes the substitution in the “optionally substituted aryl group” in R ¹ and R ² above. Examples of the group include those exemplified above.

Examples of the arylo group of the “optionally substituted aryloyl group” in R ² include an aryloyl group having 7 to 11 carbon atoms, and specific examples thereof include, for example, benzoyl, 1-naphthoyl and 2-naphthoyl Is mentioned.

The substituent of the "optionally substituted Aroiru group optionally" in R ^2, also the the like are exemplified as the substituents of the "optionally substituted Ariru group optionally" in R ¹ and R ^2.

Examples of the arylthio group of the “optionally substituted arylthio group” for R ² include an arylthio group having 6 to 10 carbon atoms, and specific examples include phenylthio, 11-naphthylthio and 2-naphthylthio and the like.

The substituent of the "optionally substituted Ariruchio group optionally" in R ^2, those exemplified as the substituents of "optionally substituted Ariru group" can be mentioned in R ¹ and R ^2.

Examples of the arylsulfinyl group of the “optionally substituted arylsulfinyl group” for R ² include an arylsulfinyl group having 6 to 10 carbon atoms. Specifically, for example, Examples include enylsulfinyl, 1-naphthylsulfinyl and 2-naphthylsulfinyl. Examples of the substituent of the "optionally substituted § reel sulfinyl group" of R ^2, those exemplified as the substituent of the "optionally substituted Ariru group" in R ¹ and R ² can be mentioned.

Examples of the arylsulfonyl group of the “optionally substituted arylsulfonyl group” for R ² include an arylsulfonyl group having 6 to 10 carbon atoms. Specifically, for example, phenyl Sulfonyl, tosyl, 1-naphthylsulfonyl or 2-naphthylsulfonyl and the like can be mentioned.

The substituent of the "optionally substituted § Li one also Rusuruhoniru group" in R ^2, include those exemplified as the substituents of "optionally substituted Ariru group" before Symbol R ¹ and R ² .

Examples of the alkylthio group of the “optionally substituted alkylthio group” for R ² include an alkylthio group having 1 to 6 carbon atoms. Specifically, for example, methylthio, ethylthio, propylthio, 2-propylthio, Butylthio, sec-butylthio, tert-butylthio, pentylthio or hexylthio.

The substituent of the "optionally substituted alkylthio group" in R ^2, those exemplified as the substituents of "optionally substituted alkyl group" can be mentioned in R ¹ and R ^2.

Examples of the alkylsulfinyl group of the “optionally substituted alkylsulfinyl group” for R ² include an alkylsulfinyl group having 1 to 6 carbon atoms. Specifically, for example, methylsulfinyl, ethylsulfinyl And propylsulfinyl, 2-propylsulfenyl, butylsulfinyl, pentylsulfinyl and hexylsulfinyl.

Examples of the substituent of the "optionally substituted alkyl sulfide El group" in R ^2, those exemplified as the substituent of the "optionally substituted alkyl group" in R ¹ and R ² can be mentioned.

Examples of the alkylsulfonyl group of the “optionally substituted alkylsulfonyl group” for R ² include an alkylsulfonyl group having 1 to 6 carbon atoms, and specifically, for example, methylsulfonyl, ethylsulfonyl, propyl Sulfonyl, 2-propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like can be mentioned. The substituent of the "optionally substituted alkylsulfonyl group" in the ^2, include those shown examples of the substituents of the "substituted alkyl group" in R ¹ and R ^2.

Examples of the heteroaryl group of the “optionally substituted heteroaryl group” for R ¹ and R ² include, for example, one or more (eg, 1 to 4) heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. And a 5- or 6-membered, monocyclic or polycyclic group, preferably a 5- or 6-membered, monocyclic or bicyclic heterocyclic group. Specifically, pyrrolyl, chenyl, benzochenyl, benzofuranyl, benzoxazolyl, benzothiazolyl, furyl, oxazolyl, thiazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazyl, pyrimidyl, pyridyl, quinolyl, quinolyl, quinolyl, quinolyl, quinolyl Examples include tetrazolyl, indolyl, imidazo [1,2-a] pyridyl or dibenzofuranyl.

Examples of the substituent in the “optionally substituted heteroaryl group” in R ¹ and R ² include, for example,

(1) hydroxyl group,

(2) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.),

(3) Alkyl group (for example, a linear or branched lower alkyl group and the like, specifically, for example, a linear or branched alkyl group having 1 to 6 carbon atoms and the like. More specifically, for example, methyl, ethyl, propyl, 2-propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like can be mentioned.

(4) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) or an alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy having 1 to 4 carbon atoms) And more specifically, methoxy, ethoxy, propoxy, or butoxy, etc.). An alkyl group substituted with (an example of the alkyl moiety is a linear or branched lower alkyl group). Specific examples include, for example, a linear or branched alkyl group having 1 to 4 carbon atoms, and more specifically, for example, methyl, ethyl, propyl, 2-propyl Or butyl, etc. Specifically, fluoromethyl, difluoromethyl, Examples include trifluoromethyl, 2-fluoroethyl, 2,2-diphorethyl, perfluoromethyl or methoxyethyl. ),

(5) Alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms, and more specifically, methoxy, ethoxy, propoxy, butoxy, etc. ),

(6) A halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) or an alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms) And more specifically, methoxy, ethoxy, propoxy, butoxy, etc.). An alkoxy group substituted with (an alkoxy moiety is, for example, a lower alkoxy group, etc.). Examples include an alkoxy group having 1 to 4 carbon atoms, more specifically, for example, methoxy, ethoxy, propoxy, butoxy, etc. Specific examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and methoxy. Methoxy, ethoxy methoxy, methoxy ethoxy, ethoxy ethoxy, methoxy Epoxy or ethoxy propoxy and the like.),

(7) a cyano group,

(8) a carboxy group,

(9) Alkoxy group A carbonyl group substituted with an alkoxy group having 1 to 4 carbon atoms (for example, methoxy, ethoxy, propoxy, or butoxy, etc.). And carboxyl or ethoxycarbonyl.),

(10) An alkyl group (for example, methyl, ethyl, propyl, 2-propyl or butyl, etc.) which may be substituted with a rubamoyl group (specifically, rubamoyl, methylcarbamoyl, dimethyl Carbamoyl, ethylcarbamoyl, getylcarbamoyl, etc.)

Or (11) an aryl group which may be substituted (for example, an aryl group having a carbon number of 10 or less, specifically, phenyl, 1-naphthyl or 2-naphthyl, etc .; A halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom); an alkyl group (for example, a linear or branched lower alkyl group; , For example, a linear or branched C 1 And more specifically, for example, methyl, ethyl, propyl, 2-propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl. . Or an alkoxy group (for example, an alkoxy group having 1 to 4 carbon atoms, specifically, methoxy, ethoxy, propoxy, butoxy, etc.). ) And the like.

The Teroariru group to the "substituted heteroarylalkyl group to a good" in R ^2, those exemplified can be mentioned as Heteroari Ichiru group of the "substituted heteroaryl group to be" in R ¹ and R ² Can be

The substituent of the "substituted heteroarylalkyl group to a good" in R ^2, those exemplified as the location substituent in the "heteroaryl group which may be substituted" can be mentioned in R ¹ and R ^2.

The Teroari Le group to the "to optionally substituted heteroarylalkyl Cal Poni Le group" in R ^2, those exemplified as Heteroari Ichiru group of the "substituted heteroaryl group to be" in R ¹ and R ² No.

The substituent of the "Teroari one to optionally substituted Rukaruponiru group" for R ^2, those exemplified as the substituents of the "heteroaryl group which may be substituted" can be mentioned in R ¹ and R ^2.

The Teroariru group to the "substituted heteroarylamino O carboxymethyl group to be" in R ^2, is mentioned those exemplified as Heteroariru group definitive in "substituted heteroaryl group optionally" in the above R ¹ and R ² Can be

The substituent of the "substituted heteroarylamino O carboxymethyl group to be" in R ^2, those exemplified as the substituents of the "heteroaryl group which may be substituted" can be mentioned in R ¹ and R ^2. Further, the substituent in the “optionally substituted heteroaryloxy group” for R ² also includes a group represented by the following formula: 1 O—T y, in addition to the above.

Examples of the alkyl carbonyl group of the `` optionally substituted alkyl carbonyl group '' for R ² include a lower alkyl carbonyl group and the like, specifically, an alkyl carbonyl group having 1 to 4 carbon atoms, and more specifically, , Acetyl or propionyl.

Examples of the substituent of the “optionally substituted alkylcarbonyl group” for R ² include: And a halogen atom (eg, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), and specific examples thereof include trifluoromethylcarbonyl and pentafluoroethylcarbonyl.

Examples of the nitrogen-containing saturated heterocyclic group of the “optionally substituted nitrogen-containing saturated heterocyclic group” for R ² and R ³ include, for example, one or two nitrogen atoms, and further an oxygen atom or a sulfur atom And a 5- to 6-membered saturated heterocyclic ring which may be included, specifically, for example, pyrrolidinyl, imidazolidinyl, piberidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethylene Iminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxoimidazolidinyl, dioxomidazolidinyl, oxoxoazolidinyl, dioxoxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, tetrahydropyridinyl, etc. It is.

Examples of the substituent of the “optionally substituted nitrogen-containing saturated heterocyclic group” in R ² and R ³ include, for example,

(1) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.),

(2) an alkyl group (for example, a linear or branched lower alkyl group and the like; specifically, for example, a linear or branched alkyl group having 1 to 4 carbon atoms; And more specifically, for example, methyl, ethyl, propyl, 2-propyl or butyl, etc.)

(3) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) or an alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms) And more specifically, methoxy, ethoxy, propoxy or butoxy, etc.). The alkyl group substituted with a) group (the alkyl moiety is, for example, a linear or branched lower alkyl group). Specific examples include, for example, a linear or branched alkyl group having 1 to 4 carbon atoms, and more specifically, for example, methyl, ethyl, propyl, 2-propyl Or butyl, etc. Specifically, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-diphoroyl Le, etc. Pafuruo port Echiru or Metokishechiru the like.), · (4) an alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms, more specifically, methoxy, ethoxy, propoxy, or butoxy, etc.) ),

(5) A halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) or an alkoxy group (for example, a lower alkoxy group, etc.)

Specific examples include alkoxy groups having 1 to 4 carbon atoms, and more specific examples include methoxy, ethoxy, propoxy, and butoxy. (Alkoxy portion is, for example, a lower alkoxy group, specifically, an alkoxy group having 1 to 4 carbon atoms. More specifically, for example, methoxy, ethoxy, Specific examples include propoxy or butoxy, etc. Specific examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy, and ethoxypropoxy. ),

(6) a cyano group,

Or (7) an oxo group.

The alkyl group of the "optionally substituted alkyl group" for R ^3, include those shown examples of the alkyl group in the "optionally substituted alkyl group" in the ¹ and R ^2.

Examples of the substituent of the “optionally substituted alkyl group” for R ³ include (1) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like).

(2) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) or an alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms) And more specifically, methoxy, ethoxy, propoxy, or butoxy, etc.). An alkyl group substituted with (an example of the alkyl moiety is a linear or branched lower alkyl group). Specific examples include, for example, a linear or branched alkyl group having 1 to 4 carbon atoms, and more specifically, for example, methyl, ethyl, propyl, 2-propyl Or butyl, etc. Specifically, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-diphoroyl Chill, Perfluo Mouthethyl or methoxyethyl and the like. ),

(3) Alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms, more specifically, methoxy, ethoxy, propoxy, or butoxy, etc. ),

(4) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) or an alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy having 1 to 4 carbon atoms) And more specifically, methoxy, ethoxy, propoxy, butoxy, etc.). An alkoxy group substituted with (an alkoxy moiety is, for example, a lower alkoxy group, etc.). Examples include an alkoxy group having 1 to 4 carbon atoms, more specifically, for example, methoxy, ethoxy, propoxy, butoxy, etc. Specific examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and methoxy. Methoxy, ethoxy methoxy, methoxy ethoxy, ethoxy ethoxy, methoxy Epoxy or ethoxy propoxy and the like.),

(5) a cyano group,

(6) a carboxy group,

(7) Alkoxy group A carbonyl group substituted with an alkoxy group having 1 to 4 carbon atoms (for example, methoxy, ethoxy, propoxy or butoxy, etc.). And carboxy or ethoxycarbonyl.),

(8) An alkyl group (for example, methyl, ethyl, propyl, 2-propyl or butyl, etc.) which may be substituted with a carbamoyl group (specifically, carbamoyl, methylcarbamoyl, dimethylcarbamoyl) , Ethyl carbamoyl or dimethyl carbamoyl, etc.)

(9) an alkylsulfonyl group (for example, methanesulfonyl, etc.) or (10) a nitrogen-containing saturated heterocyclic group (for example, having one or two nitrogen atoms and further having an oxygen atom And a 5- to 6-membered saturated heterocyclic group, specifically, for example, pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl and the like.)

The “optionally substituted cycloalkyl group” for R ³ is the same as R ¹ and R ² above. Has the same meaning as "cycloalkyl group which may be substituted" in the above.

Examples of the aryl group in the “aryl group which may be substituted” for R ³ include, for example, an aryl group having 6 to 10 carbon atoms, and specifically, for example, phenyl, 1-naphthyl or 2-naphthyl and the like. Preferably, fuel is mentioned.

Examples of the substituent in the “optionally substituted aryl group” for R ³ include, for example,

(2) an alkyl group (for example, a linear or branched lower alkyl group and the like; specifically, for example, a linear or branched alkyl group having 1 to 4 carbon atoms;

More specifically, for example, methyl, ethyl, propyl, 2-propyl or petyl and the like can be mentioned. ),

(3) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) or an alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms) And more specifically, methoxy, ethoxy, propoxy, or butoxy, etc.). An alkyl group substituted with (an example of the alkyl moiety is a linear or branched lower alkyl group). Specific examples include, for example, a linear or branched alkyl group having 1 to 4 carbon atoms, and more specifically, for example, methyl, ethyl, propyl, 2-propyl Or butyl, etc. Specifically, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-diphoroyl Le, etc. Pafuruo port Echiru or Metokishechiru the like.),

(4) Alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms, more specifically, methoxy, ethoxy, propoxy, butoxy, etc. ),

(5) A halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) or an alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms) And more specifically, methoxy, ethoxy, propoxy, butoxy, etc.). An alkoxy group substituted with (an alkoxy moiety is, for example, a lower alkoxy group, etc.). Charcoal Examples thereof include alkoxy groups having a prime number of 1 to 4, and more specific examples include methoxy, ethoxy, propoxy, and butoxy. Specific examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyxethoxy, methoxypropoxy, and ethoxypropoxy. ),

(6) a cyano group,

(7) Alkoxy group A carbonyl group substituted with an alkoxy group having 1 to 4 carbon atoms (for example, methoxy, ethoxy, propoxy, or butoxy, etc.). Carbonyl or ethoxycarponyl, etc.),

(8) A carbamoyl group (specifically, carbamoyl, methylcarbamoyl, dimethylcarbamoyl) which may be substituted with an alkyl group (for example, methyl, ethyl, propyl, 2-propyl, or butyl, etc.) , Ethyl carbamoyl or dimethyl carbamoyl.)

(9) An amino group which may be substituted with an alkyl group (for example, methyl, ethyl or propyl, etc.) (specifically, methylamino, ethylamino, propylamino or dimethylamino, etc.),

(10) A phenyl group which may be substituted with a halogen atom (for example, a fluorine atom or a chlorine atom, etc.) (specifically, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl or 4-chlorophenyl, etc.),

(11) a cycloalkyl group which may be substituted with a fluorine atom (specifically, cyclobutyl propyl, 2-fluorocyclopropyl, cyclobutyl, cyclopentyl, adamantyl, norpolnyl, etc.),

(12) Cycloalkyl propylonyl groups which may be substituted by a fluorine atom (specifically, cyclopropyl propylonyl, 2-fluorocyclopropyl carbonyl or cyclobutyl carbonyl, cyclopentyl carbonyl, etc.),

(13) a carboxy group,

(14) a pyrrolidinyl group, (15) piperidyl group,

(16) a morpholinyl group,

(17) a piperazinyl group,

(18) methylenedioxy,

Or (19) ethylenedioxy and the like.

Examples of the substituent of the “optionally substituted vinyl group” for R ³ include (1) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.), and (2) an alkyl group ( For example, straight-chain or branched lower alkyl groups and the like can be mentioned. More specifically, for example, straight-chain or branched alkyl groups having 1 to 4 carbon atoms and the like can be mentioned. Is, for example, methyl, ethyl, propyl, 2-propyl or butyl, etc.). Specific examples of the substituted Bier group include 1-propylene, 2-methyl-1-propylene and 2-chloro-11-propylene.

The Teroariru group "to optionally substituted Teroari Ichiru group" to those in R ^3, those exemplified can be mentioned as Heteroari Ichiru group of the "substituted heteroaryl group to be" in R ¹ and R ² Can be

Examples of the substituent for the “optionally substituted heteroaryl group” for R ³ include those exemplified as the substituent for the “optionally substituted heteroaryl group” for R ¹ and R ² .

The “halogen atom” in R ⁴ and R ⁵ includes, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

Examples of the alkoxy group of the “optionally substituted alkoxy group” in R ⁴ and R ⁵ include, for example, a lower alkoxy group and the like, specifically, an alkoxy group having 1 to 4 carbon atoms, and more specifically. Specifically, methoxy, ethoxy, propoxy, butoxy and the like can be mentioned.

Examples of the substituent for the “optionally substituted alkoxy group” for R ⁴ and R ⁵ include those exemplified as the substituent for the “optionally substituted alkoxy group” for R ² .

Examples of the alkyl group of the “optionally substituted alkyl group” in R ⁴ and R ⁵ include, for example, a linear or branched lower alkyl group and the like. And straight-chain or branched alkyl groups having 1 to 4 carbon atoms, and more specifically, for example, methyl, ethyl, propyl, 2-propyl or butyl, etc.

Examples of the substituent of the “optionally substituted alkyl group” for R ⁴ and R ⁵ include, for example,

(1) hydroxyl group,

(2) an amino group,

(3) a cyano group,

(4) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom);

(5) an alkoxy group (for example, methoxy, ethoxy, propoxy, butoxy, etc.),

(6) An amino group which may be substituted with any of the following (a), (b), (c), (d), or (e):

(a) alkyl group (for example, a linear or branched lower alkyl group and the like, specifically, for example, a linear or branched alkyl group having 1 to 4 carbon atoms and the like; And more specifically, for example, methyl, ethyl, propyl, 2-propyl or butyl, etc.)

(b) alkyl carbonyl group (for example, lower alkyl carbonyl, etc., specifically, an alkylcarbonyl group having 1 to 4 carbon atoms, more specifically, acetyl or propionyl, etc.) ),

(d) an alkylsulfonyl group (for example, an alkylsulfonyl group having 1 to 4 carbon atoms, specifically, for example, methanesulfonyl or ethanesulfonyl, etc.),

(e) arylsulfonyl group (for example, arylsulfonyl group having 10 or less carbon atoms, specifically, benzenesulfonyl, toluenesulfonyl, naphthalenesulfonyl, etc.)

(Specifically, methylamino, ethylamino, dimethylamino, And methylethylamino, acetylamino, propionylamino, benzoylamino, naphthoylamino, methylsulfonylamino, ethylsulfonylamino or methylcarbonylamino, ethylcarbonylamino, benzenesulfonylamino and the like. ),

Or (7) a nitrogen-containing saturated heterocyclic group (for example, a 5- to 6-membered saturated heterocyclic ring having 1 to 2 nitrogen atoms and optionally an oxygen atom; Specific examples include pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, and the like.)

Examples of the aryl group in the “optionally substituted aryl group” for R ⁴ and R ⁵ include phenyl, 1-naphthyl and 2-naphthyl.

Examples of the substituent in the “optionally substituted aryl group” for R ⁴ and R ⁵ include, for example,

(2) an alkoxy group (for example, methoxy, ethoxy, propoxy or butoxy, etc.);

Or (3) an alkyl group (for example, methyl, ethyl, propyl, 2-propyl and the like).

The “optionally substituted aralkyl group” in R ⁴ and R ⁵ has the same meaning as the “optionally substituted aralkyl group” in R ² .

Examples of the substituent of the “optionally substituted amino group” in R ⁴ and R ⁵ include, for example,

(1) Alkyl group (for example, a linear or branched lower alkyl group and the like, specifically, for example, a linear or branched alkyl group having 1 to 4 carbon atoms and the like. And more specifically, for example, methyl, ethyl, propyl, 2-propyl or butyl, etc.)

(2) Alkyl carbonyl group (for example, lower alkyl carbonyl group and the like, specifically, an alkyl carbonyl group having 1 to 4 carbon atoms, and more specifically, acetyl or propionyl, etc.) ),

(3) an aryloyl group (for example, an arylcarbonyl group having 11 or less carbon atoms; Physically, for example, benzoyl or naphthoyl and the like can be mentioned. ),

(4) an alkylsulfonyl group (for example, an alkylsulfonyl group having 1 to 4 carbon atoms, specifically, for example, methanesulfonyl or ethanesulfonyl);

(5) arylsulfonyl group (for example, arylsulfonyl group having 10 or less carbon atoms, specifically, benzenesulfonyl, toluenesulfonyl, naphthalenesulfonyl, etc.),

Or (6) alkoxycarbonylmethyl (the methyl carbon atom may be substituted by one or two alkyl groups (such as methyl, ethyl, propyl or 2-propyl), and the two alkyl groups on the methyl carbon atom May combine with each other to form cyclopropyl, cyclobutyl or cyclopentyl together with the methyl carbon atom.).

Examples of the alkoxycarbonyl group of the “optionally substituted alkoxycarbonyl group” for R ⁴ and R ⁵ include, for example, an alkoxy group having 1 to 4 carbon atoms (for example, methoxy, ethoxy, propoxy or butoxy and the like). And a substituted carbonyl group. Specific examples include methoxycarbonyl and ethoxycarbonyl.

Examples of the substituent of the `` optionally substituted alkoxycarbonyl group '' in R ⁴ and R ⁵ include those exemplified as the substituent in the `` optionally substituted alkoxycarbonyl group '' of R ² . .

Examples of the substituent of the “optionally substituted carbamoyl group” in R ⁴ and R ⁵ include, for example, an alkyl group (for example, a linear or branched alkyl group having 1 to 4 carbon atoms, etc.) And more specifically, for example, methyl, ethyl, propyl, 2-propyl or butyl.) And the like. Specific examples of the “optionally substituted carbamoyl group” include carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, getylcarbamoyl, and ethylmethylcarbamoyl.

Further, two substituents of the carbamoyl group are bonded to form pyrrolidine, piperidine, morpholine, thiomo "rephorin, thiomorpholine oxide, thiomorpholine dioxide, or piperazine (the nitrogen atom of the piperazine). Is, for example, methyl, ethyl or May be substituted with propyl, etc.), and may form an aliphatic heterocyclic ring which may contain carbon, nitrogen, oxygen, or sulfur. Specific examples include pyrrolidino-powerbamoyl and piperidine. Nocarbamoyl or morpholinocanolevamoyl and the like.

When two R ⁴ or R ⁵ are present, they may be on the same or different carbons. Two R ⁴ or R ⁵ represent methylene or ethylene by combining with two carbon atoms constituting a ring to form a new ring means that a spiro ring or a To form a bicyclo ring.

As the “halogen atom” for R ^6, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom can be mentioned.

As the “alkylthio group” for R ⁶ , for example, a thio group substituted with an alkyl group having 1 to 4 carbon atoms (for example, methyl, ethyl, propyl, 2-propyl or butyl) can be mentioned. Specifically, for example, methylthio, ethylthio, propylthio and the like can be mentioned.

As the “alkylsulfiel group” for R ⁶ , for example, a sulfiel group substituted with an alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, 2-propyl or butyl, etc.) can be mentioned. Can be Specific examples include methyls / refinyl, ethylsulfiel, propylsulfinyl and the like.

As the “alkylsulfonyl group” for R ⁶ , for example, a sulfonyl group substituted with an alkyl group having 1 to 4 carbon atoms (for example, methyl, ethyl, propyl, 2-propyl or butyl, etc.) can be mentioned. . Specific examples include methyl sulfol, ethyl / resulfol, and propyl sulfonyl.

The “alkyl group” for R ⁶ includes, for example, a linear or branched lower alkyl group and the like. Specifically, for example, a linear or branched alkyl group having 1 to 6 carbon atoms And more specifically, for example, methyl, ethyl, propyl, 2-propynole, butynole, isopti / le, sec-butynole, tert-butynole, pentynole, hexyl and the like.

As the “haloalkyl group” for R ^6, an alkyl group substituted with a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) And a branched lower alkyl group. Specific examples include straight-chain or branched alkyl groups having 1 to 4 carbon atoms, and more specifically, for example, methyl, ethyl, propyl, 2-propyl or butyl And the like. And specific examples thereof include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl and perfluoroethyl.

The “cycloalkyl group” for R ⁶ includes, for example, a cycloalkyl group having 3 to 10 carbon atoms. Specifically, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl Or, norpol nitrate and the like.

As the “alkoxy group” for R ⁶ , for example, an alkyl group having 1 to 4 carbon atoms

(For example, methyl, ethyl, propyl, 2-propyl or butyl and the like). Specific examples include methoxy, ethoxy, propoxy and butoxy.

The “haloalkoxy group” in 6 includes an alkoxy group substituted with a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.). And the like. Specific examples include an alkoxy group having 1 to 4 carbon atoms, and more specific examples include, for example, methoxy, ethoxy or propoxy, butoxy, etc.). Examples thereof include fluoromethoxy, difluoromethoxy and trifluoromethoxy.

Examples of the substituent of the “optionally substituted amino group” for R ⁶ include an alkyl group (for example, a linear or branched alkyl group having 1 to 4 carbon atoms, and more specifically, For example, methyl, ethyl, propyl, 2-propyl, butyl and the like can be mentioned. Specific examples of the “optionally substituted amino group” include, for example, amino, methylamino, dimethylamino, ethylamino, getylamino or propylamino.

Examples of the substituent of the "optionally substituted rubamoyl group" for R ⁶ include, for example, an alkyl group (for example, a linear or branched alkyl group having 1 to 4 carbon atoms, etc.) And more specifically, for example, methyl, ethyl, propyl, 2-propyl or butyl. · "Carbamo which may be substituted Specific examples of the "yl group" include, for example, carpamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, getylcarbamoyl, and ethylmethylcarbamoyl.

As the “alkoxycarbonyl group” for R ⁶ , for example, a carbonyl group substituted with an alkoxy group having 1 to 4 carbon atoms (for example, methoxy, ethoxy, propoxy, butoxy and the like can be mentioned) can be mentioned. Specific examples include methoxycarbonyl, ethoxycarbonyl and 2-propyloxycarbonyl. ),

Examples of the alkyl carbonyl group of the `` optionally substituted alkyl carbonyl group '' for R ⁶ include lower alkyl carbonyl groups, specifically, an alkyl carbonyl group having 1 to 4 carbon atoms, and more specifically, , Acetyl or propionyl.

Examples of the substituent of the “optionally substituted alkylcarbonyl group” for R ⁶ include a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.). Trifluoromethylcarbonyl, pentafluoromethylcarbonyl and the like.

As the “cycloalkylcarbonyl group” for R ^6, a cycloalkyl group substituted with a cycloalkyl group having 3 to 10 carbon atoms (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) can be mentioned. Can be Specific examples include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, adamantylcarbonyl, and norporylcarbonyl.

Examples of the aryl group in the “aryl group which may be substituted” for R ⁶ include, for example, an aryl group having 6 to 10 carbon atoms, and specifically, for example, phenyl, 1 Mononaphthyl or 2-naphthyl and the like.

Examples of the substituent in the “optionally substituted aryl group” for R ⁶ include:

(2) an alkyl group (for example, a linear or branched lower alkyl group and the like; specifically, for example, a linear or branched alkyl group having 1 to 4 carbon atoms; More specifically, for example, methyl, tyl, propyl, 2-propyl, petyl and the like can be mentioned. ),

(3) an octogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) or an alkoxy group (for example, a lower alkoxy group, etc., specifically having 1 to 4 carbon atoms) An alkoxy group, and more specifically, methoxy, ethoxy, propoxy, or butoxy, etc.). (Alkyl portion includes, for example, a linear or branched lower alkyl.) And specifically include, for example, a linear or branched alkyl group having 1 to 4 carbon atoms, and more specifically, for example, methyl, ethyl, propyl, 2_ Propyl or butyl, etc. Specifically, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-diphoretic , Perfluoromethyl or methoxyethyl, etc.)

(4) an alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms, more specifically, methoxy, ethoxy, propoxy or butoxy, etc. ),

(5) A halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) or an alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms) And more specifically, methoxy, ethoxy, propoxy, butoxy, etc.). An alkoxy group substituted with (an alkoxy moiety is, for example, a lower alkoxy group, etc.). Examples include an alkoxy group having 1 to 4 carbon atoms, more specifically, for example, methoxy, ethoxy, propoxy, butoxy, etc. Specific examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and methoxy. Methoxy, ethoxy methoxy, methoxy ethoxy, ethoxy ethoxy, methoxy Epoxy or ethoxy propoxy and the like.),

(6) a cyano group,

(7) methylenedioxy,

Or (8) ethylenedioxy and the like.

The heteroaryl group in the “optionally substituted heteroaryl group” for R ⁶ includes, for example, one or more hetero atoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. A 5- to 6-membered, monocyclic or polycyclic group including the above (for example, 1 to 4) is preferred, and a 5- to 6-membered, monocyclic or bicyclic heterocyclic group is preferred. Specific examples include pyrrolyl, phenyl, benzoenyl, benzofurael, benzoxazolyl, benzothiazolyl, furyl, oxazolyl, thiazolyl, and isoxazolyl.

Examples of the substituent in the “optionally substituted heteroaryl group” include, for example,

(2) an alkyl group (for example, a linear or branched lower alkyl group and the like; specifically, for example, a linear or branched alkyl group having 1 to 6 carbon atoms;

More specifically, for example, methyl, ethyl, propyl, 2-propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl;

(3) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) or an alkoxy group (for example, a lower alkoxy group, etc.)

Specific examples include alkoxy groups having 1 to 4 carbon atoms, and more specific examples include methoxy, ethoxy, propoxy, and butoxy. ) -Substituted alkyl group (an alkyl moiety includes, for example, a straight-chain or branched lower alkyl group and the like; And more specifically, for example, methyl, ethyl, propyl, 2-propyl or butyl, etc. Specifically, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl , 2,2-diphoroethyl, perfluoromethyl or methoxyethyl.

(5) A halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) or an alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms) And more specifically, methoxy, ethoxy, propoxy or butoxy, etc.). Xyl group (The alkoxy moiety includes, for example, a lower alkoxy group, specifically, an alkoxy group having 1 to 4 carbon atoms, and more specifically, methoxy, ethoxy, propoxy, butoxy, etc. Specific examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy or ethoxypropoxy.

Or (6) a cyano group or the like.

The nitrogen-containing heteroaryl in the `` nitrogen-containing heteroaryl group which may be substituted '' for R ⁶ is, for example, a 5- to 6-membered ring group having 1 to 2 nitrogen atoms, and specifically, Examples thereof include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl.

Examples of the substituent in the “optionally substituted nitrogen-containing heteroaryl group” for R ⁶ include, for example,

(2) an alkyl group (for example, a linear or branched lower alkyl group and the like; specifically, for example, a linear or branched alkyl group having 1 to 6 carbon atoms; More specifically, for example, methyl, ethyl, propyl, 2-propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like can be mentioned.

(3) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) or an alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms) And more specifically, methoxy, ethoxy, propoxy, butoxy, etc.). An alkyl group substituted with (an alkyl moiety is, for example, a linear or branched lower alkyl group). Specific examples include, for example, linear or branched alkyl groups having 1 to 4 carbon atoms, and more specifically, for example, methyl, ethyl, propyl, 2-propyl Or butyl, etc. Specifically, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-diphoro Chill, and the like Pafuruo port Echiru or Metokishechiru.). (4) an alkoxy group (for example, a lower alkoxy group, etc., specifically, an alkoxy group having 1 to 4 carbon atoms, more specifically, methoxy, ethoxy, propoxy, or butoxy, etc.) ),

(5) an octogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, etc.) or an alkoxy group (for example, a lower alkoxy group, etc.)

Specific examples include alkoxy groups having 1 to 4 carbon atoms, and more specific examples include methoxy, ethoxy, propoxy, and butoxy. (Alkoxy portion is, for example, a lower alkoxy group, specifically, an alkoxy group having 1 to 4 carbon atoms. More specifically, for example, methoxy, ethoxy, Specific examples thereof include propoxy or butoxy, etc. Specific examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyxethoxy, methoxypropoxy, and ethoxypropoxy. ),

Or (6) a cyano group or the like.

As the “rc _{x —} 3 alkylenedioxy group for R ⁶ ”, for example, methylenedioxy, ethylenedioxy, propylenedioxy and the like can be mentioned.

As the “halogen atom” for R ⁷ , those exemplified as the “halogen atom” for R ⁶ can be mentioned.

As the “alkyl group” for R ⁷ , those exemplified as the “alkyl group” for R ⁶ can be mentioned.

As the “haloalkyl group” for R ⁷ , those exemplified as the “haloalkyl group” for R ⁶ can be mentioned.

As the “cycloalkyl group” for R ⁷ , those exemplified as the “cycloalkyl group” for R ⁶ can be mentioned.

As the “alkoxy group” for R ⁷ , those exemplified as the “alkoxy group” for R ⁶ can be mentioned.

As the “haloalkoxy group” for R ⁷ , those exemplified as the “haloalkoxy group” for R ⁶ can be mentioned.

As "alkyl group" in R ^{1 1} include those exemplified as the "alkyl group" in the R ^6. As the “alkylene chain” for Ra, for example, methylene, ethylene, propylene and the like can be mentioned.

In R c, the “optionally substituted alkyl group”, the “optionally substituted alkoxy group”, the “optionally substituted aryl group” and the “optionally substituted aryloxy group” are the above-mentioned R ¹ and R ¹ , respectively. "optionally substituted alkyl group" in the ^2, "optionally substituted alkoxy group" is synonymous with "optionally substituted Ariru group" and "replacement which may § Li one also Ruokishi group".

Examples of the “halogen atom” in R ^T include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

Examples of the alkyl group of the “optionally substituted alkyl group” in R ^T include a straight-chain or branched lower alkyl group and the like. Specifically, for example, a straight-chain or branched Examples thereof include an alkyl group having 1 to 6 carbon atoms, and more specifically, for example, methyl, ethyl, propyl, 2-propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. Is mentioned.

Examples of the substituent in the “optionally substituted alkyl group” in R ^T include, for example, an alkoxyl group (for example, methoxycarbonyl or ethoxycarbonyl).

^Examples of the alkoxy group of the “optionally substituted alkoxy group” in R ^T include, for example, a lower alkoxy group and the like, specifically, an alkoxy group having 1 to 4 carbon atoms, and more specifically, , Methoxy, ethoxy, propoxy, isopropoxy, butoxy, or tert-butoxy.

Examples of the substituent in the “optionally substituted alkoxy group” in R ^T include an octogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.).

Examples of the alkoxycarbonyl group in the “optionally substituted alkoxycarbonyl group” in R ^T include, for example, an alkoxy group having 1 to 4 carbon atoms (eg, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, etc.) And specific examples thereof include methoxycarbonyl, ethoxycarbonyl, propoxyl-ponyl, 2-propoxyl-ponyl, and te rt-butoxycarbonyl and the like.

Examples of the substituent in the “optionally substituted alkoxycarbonyl group” for R ^T include a cycloalkyl group (for example, a cycloalkyl group having 3 to 6 carbon atoms, specifically, for example, cyclopropyl, cyclobutyl, and the like) , Cyclopentyl, or cyclohexyl / yl, etc.).

Is a saturated heterocyclic group in the "heterocyclic group Okishikarubo two ^ group to saturation" in the R ^T, for example, an oxygen atom, a chromatic nitrogen atom and Z, or one sulfur atom or 2 Dzu, 6 membered 5 Examples thereof include a saturated heterocyclic group of a ring, and specific examples include tetrahydrofuranyl and tetrahydroviranyl.

As the substituent in the "optionally substituted rubamoyl group" in R, ^{T and T} , an alkyl group (for example, a linear or branched alkyl group having 1 to 4 carbon atoms and the like, and more specifically, And, for example, methyl, ethyl, propyl, 2-propyl, and butyl. Specific examples of the “optionally substituted carbamoyl group” include, for example, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, getylcarbamoyl, ethylmethinolate, and propylcarbamoyl. No.

Methylene become two R ^T gar cord represents ethylene, trimethylene, tetramethylene or butenylene and bind to one or two carbon atoms constituting the ring and form a new shelf ring, identical or different To form a spiro ring or a bicyclic ring through carbon.

When R ² represents the formula: O—T x—O—T y, the bonding position of a phenylene group, a pyridinediyl group, a pyrimidinediyl group, and a thiophendyl group represented by Tx can be bonded Any position on the atom may be used.

Examples of the alkyl group of the “optionally substituted alkyl group” in T y include a straight-chain or branched lower alkyl group and the like. Specifically, for example, a straight-chain or branched Examples thereof include an alkyl group having 1 to 6 carbon atoms, and more specifically, for example, methinole, ethyl, propyl, 2-propyl, petinole, isobutynole, sec-butyl, tert-butyl, pentyl, 3-pentyl, Or hexyl.

Examples of the alkenyl group of the “alkenyl group which may be substituted” in T y include, for example, an alkenyl group having 2 to 6 carbon atoms. Benyl, methylpropenyl, pthenyl, methylbutenyl and the like can be mentioned.

Examples of the cycloalkyl group in the “optionally substituted cycloalkyl group” in T y include a cycloalkyl group having 3 to 6 carbon atoms. Specifically, for example, cyclopropyl, cyclobutyl, cyclopentyl, or And cyclohexyl.

Examples of the cycloalkylalkyl group in the “optionally substituted cycloalkylalkyl group” in T y include an alkyl group having 1 to 4 carbon atoms, which is substituted with a cycloalkyl group having 3 carbon atoms or 6 carbon atoms. Specific examples include cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

Examples of the saturated heterocyclic group in the “optionally substituted saturated heterocyclic group” in T y include, for example, 5 to 6 having one or two oxygen atoms, nitrogen atoms and Z or sulfur atoms. Specific examples include a membered saturated heterocyclic group, specifically, for example, tetrahydrofuranyl, tetrahydropyranyl, dihydrofuranyl, tetrahydrothiopyranyl, tetrahydrodioxothioviranyl, pyrrolidinyl, piperidyl, piperazyl, imidazolidinyl, Oxazolidinyl or thiazolidinyl.

In T y, “optionally substituted alkyl group”, “optionally substituted alkenyl group”, “optionally substituted cycloalkyl group”, “optionally substituted cycloalkylalkyl group”, and “optionally substituted Examples of the substituent in the `` saturated heterocyclic group '' include, for example,

(1) hydroxyl group,

(3) an oxo group,

(4) a cyano group,

(5) a carboxy group,

(6) Alkyl group (for example, a linear or branched lower alkyl group and the like, specifically, for example, a linear or branched alkyl group having 1 to 6 carbon atoms and the like. , More specifically, for example, methyl, ethyl, propyl, 2-propyl, butyl, Isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like can be mentioned. ),

(7) A halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), an alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, etc.) ), A hydroxyl group, a carboxy group, an alkoxyl group (for example, methoxycarponyl, ethoxyl compound, propoxyl compound, isopropoxycarbonyl, butoxycarponyl or tert-butoxycarbonyl), or a cycloalkoxy group. (For example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.). An alkyl group substituted with an alkyl group (an alkyl moiety is, for example, a linear or branched alkyl group). Low Examples thereof include an alkyl group and the like, specifically, for example, a linear or branched alkyl group having 1 to 4 carbon atoms, and more specifically, for example, methyl, ethyl, propyl, 2 Propyl, or butyl, etc. Specific examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-diphorethyl, perfluoroethyl, methoxymethyl, hydroxymethyl, ethoxycarbonyl, ethoxycarbonyl, and cyclopropoxy. And methyl etc.),

(8) alkoxy group (for example, lower alkoxy group and the like, specifically, an alkoxy group having 1 to 4 carbon atoms, more specifically, methoxy, ethoxy, propoxy, isopropoxy, butoxy, Or tert-butoxy, etc.),

(9) A carbonyl group substituted with an alkoxy group (e.g., an alkoxy group having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, or tert-butoxy). Specific examples include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, etc.)

(10) a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.) or a cycloalkyl group (for example, a cycloalkyl group having 3 to 6 carbon atoms; For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like can be mentioned.) A substituted alkoxycarbonyl group (specifically, fluoromethoxycarbonyl, difluoromethoxycaprolyl) Examples thereof include luponyl, trifluoromethoxycarbonyl, fluoroethoxycarbonyl, and cyclopropylmethoxycarbonyl. ),

(11) cycloalkoxyl ponyl group (for example, cyclopropyloxycarbonyl, etc.),

(12) a saturated heterocyclic group oxycarbonyl group (for example, a 5-membered, 6-membered saturated heterocyclic group having one or two oxygen atoms, nitrogen atoms and Z or sulfur atoms; A substituted carbonyl group, specifically, tetrahydrofuranyloxycarbonyl or tetrahydropyranyloxycarbonyl, etc.), (13) a carbamoyl group,

(14) An alkyl group (for example, methyl, ethyl, propyl, 2-propyl, or butyl, etc.) which may be substituted with a rubamoyl group (when two substituents of the carbamoyl group are bonded to each other) For example, it may form an aliphatic heterocyclic ring which may contain carbon, nitrogen or oxygen, such as pyrrolidine, piperidine or morpholine. , Ethyl carbamoyl, getyl carbamoyl, pyrrolidino oleponyl, morpholino carbonyl, etc.)

(15) alkyl group (for example, a linear or branched lower alkyl group and the like, specifically, for example, a linear or branched alkyl group having 1 to 4 carbon atoms and the like; More specifically, for example, methyl, ethyl, propyl, 2-propyl, butyl, isoptyl, sec-butyl, tert-butyl, etc.), a cycloalkyl group (for example, having 3 to 6 carbon atoms) And a cycloalkyl group, specifically, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) or an alkoxy group (for example, lower alkoxy group, etc.). Represents an alkoxy group having 1 to 4 carbon atoms, and more specifically, methoxy, ethoxy, propoxy, or butoxy. Substituted sulfonylcarbamoyl group (specifically, that include methylsulfonyl carbamoylmethyl, Shikuropuropi Rusuru Honi carbamoyl or methoxy sulfonylcarbamoyl, etc., is.),

(16) Alkyl group (for example, methylcarbonyl, etc.), (17) Alkylsulfonyl group (for example, methylsulfonyl, etc.), (18) a cycloalkylidene group (for example, cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, etc.);

(19) tetrahydropyranylidene,

(20) tetrahydropyranyl,

(21) a heteroaryl group (for example, a 5- or 6-membered, monocyclic or polycyclic group containing one or more (for example, 1 to 4) heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom) And preferably a 5- or 6-membered monocyclic heterocyclic group, for example, pyrrolyl, cyenyl, furyl, oxazolyl, thiazolyl, isooxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazyl, Pyrimidyl, pyridazyl, triazolyl, triazinyl, or tetrazolyl, etc.)

(22) an alkylcarbonylamino group (for example, acetylamino, etc.),

(23) an alkylamino carboxy group (for example, dimethylamino carboxy group, etc.), or

(24) An alkoxycarbonylamino group (for example, methoxycarbonylamino and the like can be mentioned).

R ¹ is preferably, for example, a hydrogen atom, methyl, or ethyl, and more preferably, methyl.

Preferably, R ³ is, for example, a phenyl group substituted with an octogen atom, more preferably, 2-phenyl phenyl. In addition, 2-chloro-5-fluorophenyl, 2-methyl-5-fluorophenyl, 2-methoxy-5-fluorophenyl, or 2-cyano-5-fluorophenyl is also mentioned as a preferable R ³ .

R ² preferably includes, for example, an optionally substituted aryloxy group, an optionally substituted heteroaryloxy group, and groups represented by formulas (T1) to (T6). Preferably, a substituted phenyl group or a group represented by any of formulas (T1) to (T6) is exemplified.

The substituent in the substituted phenoxy group is preferably, for example, a compound represented by the formula: A group represented by 1 Ty and the like are preferable, and a group substituted at the m-position is preferable.

Ty preferably includes, for example, a substituted alkyl group, a substituted cycloalkyl group, a cycloalkylalkyl group which may be substituted, and the like.

Further, the substituent in the substituted alkyl group, the substituted cycloalkyl group, and the substituted cycloalkylalkyl group is preferably, for example, an octogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or the like. ) Or an alkoxylponyl group (for example, methoxycarbonyl, ethoxycarbonyl, isopropoxylponyl, sec-butoxycarbonyl, tert-butoxycarbonyl, etc.). As a compound which can be easily hydrolyzed in a living body to regenerate the compound (I) of the present invention, specifically, for example, an amino group of a compound represented by the formula (I): _NH ₂ is And compounds derived from _NHQ. Here, Q has the following significance.

(1)

(2) -COR ^{1 7}

(3) -COO-CR ^{1 8} (R ¹ "One OCOR ^{2 0}

(4) -COOR ^{2 1}

[Wherein, R ¹⁷ represents a hydrogen atom, an alkyl group, or an aryl group such as a substituted or unsubstituted phenyl group or a naphthyl group. R ^{1 8} and R ^{1 9} represents a hydrogen atom or _ ₆ alkyl group independently. R ^2. Represents a hydrogen atom, _ ₆ alkyl, prior Symbol Ariru group or a benzyl group. R ^{2 1} represents _ ₆ alkyl group or benzyl group. ]

Preferred Q includes the group (1) and the group (3). Preferred examples of the group (3) include those in which R ¹⁸ is a hydrogen atom, R ¹⁹ is a hydrogen atom, methyl or ethyl, and R ^{2 G} is a hydrogen atom, methyl or ethyl. these The compound can be produced according to a conventional method (for example, J. Med. Chem. 35, 4727 (1992), WO 01/40180, etc.). In addition, prodrugs are prepared under the physiological conditions as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals, Vol. 7, Molecular Design,” pp. 163 to 198. May be changed.

“Pharmaceutically acceptable salts” include, for example, inorganic salts such as hydrochloride, hydrogen bromide, sulfate, phosphate or nitrate, or acetate, propionate, oxalate, succinate Organic salts such as lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonic acid, P-toluenesulfonate or ascorbate, etc. Is mentioned. The present invention also includes a compound represented by the formula (I) or a prodrug thereof, or a hydrate or a solvate of an ethanol solvate of a pharmaceutically acceptable salt thereof. Further, the present invention includes all tautomers, all existing stereoisomers, and any of the crystalline forms of the compound (I) of the present invention. Next, the compounds of the present invention are exemplified, but the compounds of the present invention are not limited thereto.

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zzi contract Zdf / e :) d 908 960 contract OAV In the compounds of the above compound numbers 1 to 1088, the portion corresponding to Y—NH ₂ described in item [1] is an unsubstituted or substituted 3-aminopyrrolidine-1-yl group, unsubstituted or substituted A 3-aminopiperidine-1-yl group of formula (1) or an unsubstituted or substituted (3-amino) hexahydroazepin-1-yl group, the 3-position amino group is represented by the following formula (Fi) Compounds having the absolute configuration represented by are more preferred.

(In the formula, m and R ⁴ are the same as those described in the item [1].)

In the compounds of the above compound numbers 1 to 1088, when the portion corresponding to Y—NH _{2 according} to item [1] is an unsubstituted or substituted (2-aminocycloalkyl) amino group, And a compound in which the 2-amino group has an absolute configuration represented by the following formula (F ₂ ) or (F ₃ ) is more preferable. (F ₃ )

(In the formula, n and R ⁵ are the same as those described in the item [1].)

Further, a compound in which the 1- and 2-position amino groups have an absolute configuration represented by the following formula (F ₄ ) is more preferable.

—— H NH ₂

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(In the formula, n and; ⁵ are the same as those described in the item [1].)

In the following description, when the bond is represented by a solid line and a broken wedge as in the formula (J i) and the formula (J ₂ ), it represents the absolute configuration of the amino group, and the formula (J ₃ ) When the bond is represented by a bold line, the relative configuration of the amino group (for example, the formula (J ₃ ) represents (Sat) -cis isomer) is represented.

( ^J 3)

(In the formula, n and R ⁵ are the same as those described in the item [1].) Hereinafter, the method for producing the compound represented by the formula (I) in the present invention will be described with reference to examples, but the present invention is not limited to these examples. In this specification, the following abbreviations may be used for simplification of the description.

Bo c: tert-butoxycarponyl group

Cb z: benzyloxycarbonyl group

TBS: tert-butyldimethylsilyl group

P h: phenyl group

Bn: benzyl group

E t: ethyl group

Me: methyl group The compound represented by the formula (I) can be synthesized from a known compound by combining known synthesis methods. For example, it can be synthesized by the following method.

Among the compounds represented by the formula (I), the compounds represented by the formulas (14), (17), (16), and (18), or salts thereof are, for example, shown below. Manufactured by the method.

[Wherein, R ¹ R ² R ³ R ⁴ R ⁵ m and n have the same meanings as described in item [1], and X ¹ and X ² represent a leaving group (for example, bromine atom, chlorine atom, methanesulfonyloxy) Si, trifluoromethanesulfonyloxy, or P-toluenesulfonyloxy X ³ represents a chlorine atom or a bromine atom, R ^l °° represents a methyl group, an ethyl group, a propyl group, a 2-propyl group or a phenyl group, and R ¹¹¹¹ represents a methyl group, a Represents a tyl, propyl, 2-propyl, benzyl or phenyl group. ]

1) Process 1

Compound (3) can be produced by reacting compound (1) with compound (2) in an inert solvent in the presence or absence of an additive or in the presence of a base (J. Org. Chem. 39, 3651 (1974), US3450693, etc.). Examples of the additive include 4- (dimethylamino) pyridine, and the amount of the additive is generally selected from the range of 0.05 to 0.2 equivalents relative to compound (1). Bases include triethylamine, diisopropylethylamine, tributylamine, 1,5-diazabicyclo [4.3.0] nona5_en, 1,4-diazapicyclo [2.2.2] octane, 1,8- Diazapicilo [5.4.0] organic bases such as 7-ene, pyridine, 4- (dimethylamino) pyridine or picoline. The amount of the base to be used is generally selected from the range of 3 to 10 equivalents relative to the compound (1). Examples of the inert solvent include aprotic solvents (acetitolitol, N, N-dimethylformamide, dimethylsulfoxide, etc.) and ether solvents (getyl ether, tetrahydrofuran, 1,4-dioxane, etc.). ), Ketone (acetone or the like), or a mixed solvent thereof, and more preferably, acetonitrile or dimethyl sulfoxide. When the compound (2) is a liquid, the compound (2) can be used as a solvent. The amount of compound (2) to be used is generally selected from the range of 3 to 10 equivalents based on compound (1). The reaction temperature can be selected from the range of about 10 ° C to about 80 ° C.

2) Process 2

Compound (4) can be produced by reacting compound (3) with N-promoacetamide or N-chlorosuccinimide in an inert solvent (J. Org. Chem. 39, 3651 (1974), etc.) . The amount of N-bromoacetamide or N-chlorosuccinimide used is usually selected from the range of 1 to 3 equivalents to the compound of the formula (3). Examples of the inert solvent include aprotic solvents (acetonitrile, N, N-dimethylformamide or dimethyl sulfoxide), ether solvents (tetrahydrofuran, 1,4-dioxane, getyl ether, etc.), and mixed solvents thereof. And preferably, tetrahydrofuran or 1,4-dioxane. The reaction temperature can be selected from the range of about −30 ° C. to about 50 ° C. When X ³ of compound (4) is a bromine atom, it can be produced by reacting compound (3) with an aqueous bromine solution in an aqueous solvent (J. Org. Cem. 33, 1070 (1968) ) etc) . The aqueous bromine solution is prepared in a volume ratio of bromine: water in the range of 0.1: 1 to 5: 100. The amount of the aqueous bromine solution is usually selected from the range of 1 to 2 equivalents (molar ratio) to the compound of the formula (3). The reaction temperature can be selected from the range of about 10 ° C to about 50 ° C.

3) Process 3

Compound (6) can be produced by reacting compound (4) with compound (5) in an inert solvent in the presence of an organic acid. Examples of the inert solvent include aprotic solvents (acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, and the like) and the like, and preferably, N, N-dimethylformamide and the like. Examples of the organic acid include acetic acid, propionic acid and formic acid, and preferably acetic acid. The organic acid can be used as a solvent, and is usually selected from a range of 0.5 to 1.5 as a volume ratio to the inert solvent. The reaction temperature can be selected from the range of about 50 ° C to about 150 ° C. Compound (5) can be a commercially available product or can be produced by a known method. Specifically, it can be produced according to the method described in “New Experimental Chemistry Course 14: Synthesis of Organic Compounds and Reaction Solution (II)” (edited by The Chemical Society of Japan, Maruzen).

4) Process 4

Compound (7) can be produced by reacting compound (6) with a base in an inert solvent. Examples of the base include potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, potassium carbonate, sodium carbonate, sodium phenoxide, potassium phenoxide, sodium hydride and the like, and preferably potassium tert-butoxide and the like. Can be The amount of the base to be used is generally selected from the range of 1 to 5 equivalents based on compound (6). Examples of the inert solvent include tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and a mixed solvent thereof. The reaction temperature can be selected from the range of about 10 ° C to about 50. 5) Process 5

Compound (8) can be produced by reacting compound (7) with an acid in acetic anhydride. Examples of the acid include phosphoric acid, sulfuric acid, and hydrochloric acid, and preferably, phosphoric acid and the like. The amount of the acid to be used is generally selected from the range of 0.05 to 10 equivalents relative to compound (7). The reaction temperature can be selected from the range of about 50 ° C to about 130 ° C.

6) Process 6

Compound (10) can be produced by reacting compound (8) with compound (9) in an inert solvent in the presence or absence of a base (J. Heterocycl. Chem. 37, 1033 ( 2000), J. Chem. Soc, Perkin Trans. 1, 13, 1833 (1999), J. Med. Chem. 38, 3838 (1995), etc.). The amount of compound (9) to be used is generally selected from the range of 1 to 3 equivalents based on the compound of formula (8). Examples of the base include alkali carbonate (eg, potassium carbonate, sodium carbonate, potassium hydrogen carbonate or sodium hydrogen carbonate), alkali hydride (eg, sodium hydride or potassium hydride), or alkaline hydroxide (eg, hydroxylated hydroxide). And the like, and preferably potassium carbonate and the like. The amount of the base to be used is generally selected from the range of 1 to 5 equivalents relative to compound (8). Examples of the inert solvent include aprotic solvents (such as N, N-dimethylformamide or dimethyl sulfoxide), ether solvents (such as getyl ether, tetrahydrofuran or 1,4-dioxane), ketones (such as acetate), And N, N-dimethylformamide, dimethylsulfoxide and the like. The reaction temperature can be selected from the range of about 10 ° (: to about 120 ° C).

In addition, in the production of compound (10), one in which an R ³ CH ₂ group is introduced into a different nitrogen atom can generally be by-produced, but the by-product can be easily removed by a usual purification method.

7) Process 7

Compound (12) can be produced by reacting compound (10) with compound (11) in an inert solvent in the presence of a base. The amount of compound (11) to be used is generally selected from the range of 1 to 3 equivalents based on compound (10). Examples of the base include, for example, carbon dioxide (carbon dioxide, sodium carbonate, hydrogen carbonate, Is sodium hydrogen carbonate, etc.), aluminum hydroxide (such as sodium hydroxide or sodium hydroxide), sodium hydride alkali hydride or potassium hydride), or alkali alkali (such as potassium t-butoxide). And preferably, potassium carbonate or sodium hydride. The amount of the base to be used is generally selected from the range of 1 to 5 equivalents based on compound (10). Examples of the inert solvent include nonprotonic solvents (such as N, N-dimethylformamide or dimethyl sulfoxide), ether solvents (such as getyl ether, tetrahydrofuran or 1,4-dioxane), and ketones (such as acetone). Or a mixed solvent thereof, and preferably, N, N-dimethylformamide and the like. The reaction temperature can be selected from the range of about 10 "€ to about 100 ° C.

8) Process 8

Compound (14) can be produced by reacting compound (12) with compound (13) in an inert solvent in the presence or absence of an additive, in the presence or absence of a base. Examples of the additive include 4- (dimethylamino) pyridine and the like. Examples of the base include diisopropylethylamine, triethylamine, pyridin, N-methylmorpholine, and trimethylpiperidine. Ethylamine or triethylamine. The amount of the base to be used is generally selected from the range of 1 to 10 equivalents relative to compound (12). Examples of the inert solvent include alcohol solvents (such as ethanol, methanol or 2-propanol), ether solvents (such as 1,4-dioxane), and mixed solvents thereof. The reaction temperature can be selected from the range of about 50 ° C to about 200 ° C. The reaction can also be performed in a closed reaction vessel such as an autoclave.

Compound (14) in which R ¹ is a hydrogen atom can be produced by a method similar to the above using compound (10) as a starting material.

9) Process 9

Compound (16) can be produced by reacting compound (12) with compound (15) in an inert solvent, in the presence or absence of an additive, or in the presence or absence of a base. Examples of the additive include 4- (dimethylamino) pyridine and the like. Examples of the base include diisopropylethylamine, triethylamine, pyridin and N-methylmorpholine. And the like. The amount of the base to be used is generally selected from the range of 1 to 10 equivalents based on compound (12). Examples of the inert solvent include N-methyl-2-piperidone, N-methyl-2-pyrrolidinone, alcohol solvents (such as ethanol, methanol, and 2-propanol), N, N-dimethylformamide, toluene, and a mixed solvent thereof. Is mentioned. Preferably, N-methyl-2-piperidone or N-methyl-2-pyrrolidinone is used. The reaction temperature can be selected from the range of about 50 ° C to about 200 ° C. The reaction can also be carried out in a closed reaction vessel such as an autoclave.

The compound (16) in which R ¹ is a hydrogen atom can be produced by using the compound (10) as a starting material by a method similar to the above.

1 0) Process 1 0

Compound (17) can be produced by optically resolving compound (14). As the optical resolution method, for example, compound (14) is dissolved in an inert solvent (for example, an alcohol solvent such as methanol, ethanol or 2-propanol, an ether solvent such as getyl ether, or an ester solvent such as ethyl acetate). Solvents, hydrocarbon solvents such as toluene, etc., or acetonitrile, etc., and mixed solvents thereof), optically active acids (for example, monocarboxylic acid such as mandelic acid, N-benzyloxyalanine, or lactic acid, tartaric acid, etc.) O-isopropylidene tartaric acid or a dicarboxylic acid such as malic acid, or a sulfonic acid such as camphorsulfonic acid or bromocamphorsulfonic acid). The temperature at which the salt is formed includes a range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature once to near the boiling point of the solvent. Before the precipitated salt is collected by filtration, the salt can be cooled if necessary to improve the yield. The amount of the optically active acid used is in the range of about 0.5 to about 2.0 equivalents, preferably about 1 equivalent, relative to the substrate. If necessary, the crystals are placed in an inert solvent (for example, an alcohol solvent such as methanol, ethanol or 2-propanol, an ether solvent such as ethyl ether, an ester solvent such as ethyl acetate, a hydrocarbon solvent such as toluene, High-purity optically active salts can also be obtained by recrystallization with acetonitrile or the like and a mixed solvent thereof. If necessary, the obtained salt can be treated with a base by a usual method to obtain a free form. In addition, compound (14) was fractionated using a commercially available chiral column, Compound (17) can be produced.

11) Process 11

Compound (18) can be produced from compound (16) by the same method as in step 10 of production method 1. Manufacturing method 2

When the compound (19) in which the 3-amino group of the compound (13) is protected is used, the compound (14) can be produced by the method shown below.

[Wherein, R ¹ , R ² , R ³ R ⁴ and m have the same meanings as described in the item [1], and X ³ has the same meaning as that of the production method 1. ]

1) Process 1

Compound (20) can be produced from compound (12) by a method similar to step 8 described in production method 1.

Compound (20) in which R ¹ is a hydrogen atom can be produced by a method similar to the above, using compound (10) described in Production Method 1 as a starting material.

2) Process 2

Compound (14) can be produced by deprotecting the Boc group of compound (20) in an inert solvent in the presence of an acid. Examples of the acid include hydrochloric acid, sulfuric acid, and trifluoroacetic acid, and preferably, hydrochloric acid and trifluoroacetic acid. The amount of the acid to be used is generally selected from the range of 1 to a large excess with respect to compound (20). Examples of the inert solvent include halogenated hydrocarbon solvents (dichloromethane, Chloroethane or chloroform), ether solvents α, 4-dioxane, etc.), or a mixed solvent thereof. The reaction temperature can be selected from the range of about -20 ° C to about 30 ° C. Manufacturing method 3

When the compound (202) in which the 3-amino group of the compound (13) is protected is used, the compound (17) can be produced by the method shown below.

[Wherein, R ¹ , R ² , R ³ , R ⁴ and m have the same meaning as described in the item [1], and X ³ has the same meaning as described in the production method 1. ]

1) Process 1

Compound (203) can be produced from compound (12) in the same manner as in step 8 of production method 1.

The compound (203) in which R ¹ is a hydrogen atom can be produced by a method similar to the above using the compound (10) described in Production Method 1 as a starting material.

2) Process 2

Compound (17) can be produced from compound (203) by a method similar to Step 2 described in Production Method 2. Manufacturing method 4

Compound (17) described in Production Method 1 can also be produced by using the optically active compound (21) according to the following method.

[Wherein, R ¹ , R ² , R ³ , R ⁴ and m have the same meanings as described in the item [1], and X ³ has the same meaning as described in the production method 1. ]

1) Process 1

Compound (17) can be produced from compound (12) by the same method as in step 8 described in production method 1.

Compound (17) in which R ¹ is a hydrogen atom can be produced by a method similar to the above, using compound (10) described in Production Method 1 as a starting material. Manufacturing method 5

Compound (18) described in Production Method 1 can also be produced using compound (22), which is an optically active substance, by the method shown below.

_R 2

[Wherein, R ¹ R ² , R ³ , R ⁵ and n have the same meanings as described in item [1], and X ³ has the same meaning as described in Production Method 1. ]

1) Process 1

Compound (18) can be produced from compound (12) in the same manner as in Step 9 described in Production Method 1. Manufacturing method 6

When the optically active compound (23) is used, the compound (24) can be produced by the method shown below. 34

R ²

[In the formula, R ¹ , R ² , R ³ , R ⁵ and n have the same meanings as described in the item [1], and 'X ³ has the same meaning as that in the production method 1. ]

1) Process 1

Compound (24) can be produced from compound (12) by the same method as in step 9 described in production method 1.

Compound (24) in which R ¹ is a hydrogen atom can be produced by a method similar to the above, using compound (10) described in Production Method 1 as a starting material. Manufacturing method 7

Compound (18) described in Production Method 1 can also be produced using compound (25), which is an optically active substance, by the method shown below.

Process 2

[Wherein, R ¹ , R ² , R ³ , R ⁵ and n have the same meanings as described in the item [1], and X ³ has the same meaning as described in the production method 1. ]

1) Process 1

Compound (26) can be produced from compound (12) by the same method as in step 9 described in production method 1.

Compound (26) in which R ¹ is a hydrogen atom starts from compound (10) described in Production Method 1. 04006104

135 As a raw material, it can be produced by the same method as described above.

2) Process 2

Compound (18) can be produced from compound (26) by a method similar to Step 2 described in Production Method 2. Manufacturing method 8

Compound (19) can be produced, for example, according to the method shown below.

[Wherein, R ⁴ and m have the same meaning as described in the item [1]. ]

1) Process 1

Compound (19) can be produced from compound (27) by a method similar to the production method described in a literature (eg, J. Org. Chem. 58, 879 (1993)). Manufacturing method 9

Compound (202) can be produced, for example, according to the method shown below.

Process 3

[Wherein, R ⁴ and m have the same meanings as described in item [1], and R ^{6 Q} represents a methyl group or an ethyl group. ]

1) Process 1

Compound (201) can be produced by reacting compound (200) with thionyl chloride in an alcoholic solvent. Examples of alcohol solvents include meta And ethanol or ethanol. The amount of thiol chloride to be used is generally selected from the range of 2 to 10 equivalents based on compound (200). The reaction temperature can be selected from the range of about -90 ° C to about 30 ° C.

2) Process 2

Compound (201) can be produced by reacting compound (200-1) with a base in an aqueous solvent. Examples of the base include sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate and potassium carbonate. The reaction temperature can be selected from the range of about 30 ° C to about 100 ° C.

3) Process 3

Compound (201-1) can be produced from compound (201) by a method similar to the method described in a literature (eg, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, In) etc.). .

4) Process 4

Compound (202) can be produced by reacting compound (201-1) with a reducing agent in an inert solvent. Examples of the reducing agent include lithium aluminum hydride and dipolane. Examples of the inert solvent include tetrahydrofuran, 1,4-dioxane, and a mixed solvent thereof. The reaction temperature is selected, for example, from the range of about -20 ° C to about 40 ° C when using lithium aluminum hydride, and from the range of about 50 ° C to about 80 ° C when using diborane. Is performed.

As a specific example of the compound (13), a synthesis example of the compound (13-4C) from the compound (13-1A) is shown below. Compounds (13-1A) to (13-4C) include pharmaceutically acceptable salts. 37 Compound Production Method, Perkin Trans. 1, 2233 (1999)

(13-1 A): X ⁴ = CH ₃

(13-1B): X ⁴ = CH ₂ CH ₃

(13-1C): X ⁴ = CH ₂ CH20H

(13-1D): X ⁴ = CH ₂ CH ₂ F

(13-1E): X = H

J. Org. Chem. 44, 2732 (1979)

J. Chem. Soc, Perkin Trans. 1, 2233 (1999)

(13-2)

(13-4A): X ⁴ = CH ₃

(13-4B): X ⁴ = CH ₂ CH ₃

(13-4C): X ⁴ = CH ₂ CH ₂ CH ₃

Wherein, R ^{1 1 0} represents a hydrogen atom, 80 characters or 〇 2. ]

As the hydrochloride of compound (13-1E), a commercially available product can also be used. Compound (13) can also be synthesized from substituted DL-orditin by a known method. Specifically, literature (eg, Comprehensive Organic transformation, R.C.

VCH publisher Inc., (1989)).

Specific examples of compound (21) include compound (21-1) to compound (21-9)

) Are shown below. Compounds (21-1) to (21-9) include pharmaceutically acceptable salts. Compound production method (1999) 992) 1999) 999) 999)

99)

)

Or J. Chem. Soc. PT1 499 (1972),

J. Chem. Soc., Perkin Trans. 1, 2233 (1999)

Follow the method described in (21-9).

[Wherein, R ¹¹ ° represents a hydrogen atom, Boc or Cbz. ] As a specific example of the compound (21), a synthesis example of the compound (21-18) from the compound (21-10) is shown below. The compound (21-18) to the compound (21-18) include a pharmaceutically acceptable salt.

Compound Production Method Compound (R ^{11 Q} is a hydrogen atom 21-6)

Starting materials, for example

J. Chem. Soc. Chem. Commun. 61 1 (1981),

J. Chem. Soc, Perkin Trans. 1, 2233 (1999)

Follow the method described in

Compound ( ^21-11 with R ^11Q being a hydrogen atom)

Starting materials, for example

J. Chem. Soc. Chem. Commun. 61 1 (1981),

J. Chem. Soc, Perkin Trans. 1, 2233 (1999)

Follow the method described in Starting from compound (21-8), for example

J. Org. Chem. 44, 3872 (1979),

J. Chem. Soc, Perkin Trans. 1, 2233 (1999)

Follow the method described in Starting from compound (21-5), for example

J. Org. Chem. 44, 3872 (1979),

J. Chem. Soc, Perkin Trans. 1, 2233 (1999)

Follow the method described in Starting from compound (21-8), for example

Bull. Chem. Soc. Jpn, 64, 2857 (1991),

J. Chem. Soc, Perkin Trans. 1, 2233 (1999)

Follow the method described in

40 Compound Production Method

Starting from a compound (21-6 in which R ^{11 Q} is a hydrogen atom), for example,

Tetrahedron Lett. 40, 5609 (1999),

J. Chem. Soc, Perkin Trans. 1, 2233 (1999)

Follow the method described in

J. Med. Chem. 35, 833 (1992), "Comprehensive Organic transformation, RC Laroch, VCH publisher Inc., 1989,

J. Chem. Soc., Perkin Trans. 1, 2233 (1999)

(21-16A): Y ² = (R) -C ₆ H ₅

(21-16B): Y ² = (S) -C ₆ H ₅ compound (R ^{11 D} is a hydrogen atom 21 -6) as a starting material, for example,

Comprehensive Organic transformation,

R. C. Lalock, VCH publisher Inc., 1989,

(21-17A): Ύ ^ύ = NHS (0) 2〇H ₃

J. Chem. Soc, Perkin Trans. 1, 2233 (1999) (21-17B): Y ³ = According to the method described in NHC (0) CH ₃ .

(21-17C): Y ³ = NHC (0) C ₆ H ₅

(21-17D): Y ³ = N (CH ₃ ) C (0) CH ₃

Perkin Trans. 1, 2233 (1999)

[Wherein, R ^{11 Q} represents a hydrogen atom, B oc or C bz. ]

As a specific example of the compound (21), a synthesis example of the compound (21-1H) from the compound (21-1A) is shown below. The compound (21-1H) to the compound (21-1H) include pharmaceutically acceptable salts. 41

Compound manufacturing method

(21-1A): Y ⁴ :: Starting from the 2-CH3-C6H5 compound (21-14), for example,

(21-1B): Y ⁴ : Comprehensive Organic transformation,

: Shi H3-R. C. Lalock, VCH publisher Inc., 1989

^{_{(21-1C): Y 4;:}} 4- h3-CgH5 J. Org .. C em.66, 3593 (2001),

(21-1D): Υ ⁴ :-2-CH ₃ 0-C ₆ H ₅ J. Prakt. Chem. 342, 421 (2000),

Tetrahedron Lett. 36, 5611 (1994),

(21-1Ε): Υ ⁴ : 3-shi H3-shi J. Org. Chem. 53, 5143 (1988),

(21-1F): Υ ⁴ = 4-CH ₃ 0-C ₆ H ₅ Bioorg. Med. Chem. Lett. 11, 1281 (2001),

J. Chem. Soc, Perkin Trans. 1, 2233 (1999)

(21-1G): Υ ⁴ = Follow the method described in C / 6H5.

(21-1Η): Υ ⁴ = CH2C6H5

Wherein, R ^{1 1} ⁰ represents a hydrogen atom, Betashita C or Cb Z. ]

Compound (21) can be synthesized from substituted D-orudin by a known method.

. Specific examples include methods described in literatures (eg, Comprehensive Organic transformation, RC Lalock, VCH publisher Inc., (1989)). Manufacturing method 10

Compound (25) can be produced, for example, according to the method shown below.

Process 3

(31) (25)

[Wherein, R ⁵ and n have the same meanings as described in the item [1]. ]

1) Process 1

Compound (29) can be produced from compound (28) by a method similar to the method described in a literature (eg, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.). . Compound (28) can be produced by a method similar to the production method described in J. Org. Chem. 50, 4154 (1985). 42

2) Steps 2-4,

Compounds can be prepared by methods similar to those described in the literature (^^ Common organic transformation, R.C. Lalock, VCH publisher Inc., (1989), etc.).

Compound (25) can be produced from (29).

As a specific example of the compound (22), a synthesis example of the compound (22-27) from the compound (22-1) is shown below. Compounds (22-1) to (22-27) include pharmaceutically acceptable salts. From compound (22-1) to compound (22-27)

(For example, WO01 / 74774 and Co-immediate rehensive Organic transformation, RC Lalock, VCH publisher Inc., (1989)).

As a specific example of the compound (22), a synthesis example of the compound (22-46) from the compound (22-28) is shown below. Compound (22-28) is a compound (22-46) , Including pharmaceutically acceptable salts. From compound (22-28) to compound (22-46) can be obtained from the literature (eg, WO01 / 74774 and Co-immediate rehensive Organic

transformation, R.C. Lalock, VCH publisher Inc., (1989), etc.).

As compound (15) and compound (23), commercially available products can be used ₍ Production method 11).

Compound (12) described in Production Method 1 can also be produced, for example, by the method shown below.

(36)

[Wherein, R ^1, R ² and R ^3, Section [1] have the same meanings as described, X ^1, X ² and X ³ are as defined in Process 1, R ^{5 0} is a methyl group, Echiru Represents a propyl group, a propyl group, a benzyl group or a phenyl group. ]

1) Process 1

Compound (32) can be produced by reacting compound (1) and compound (32-1) in an inert solvent in the presence of a base. Examples of the base include sodium methoxide and sodium ethoxide. The amount of compound (32-1) to be used is generally selected from the range of 5 to 30 equivalents based on compound (1). Examples of the inert solvent include ethanol and methanol. The reaction temperature can be selected from the range of about 30 to about 100 ° C.

2) Process 2

Compound (33) can be produced by reacting compound (32) with tert-butyldimethylsilyl chloride in an inert solvent, in the presence or absence of an additive, in the presence of a base. Examples of the additive include 4- (dimethylamino) pyridine, and the amount of the additive is usually selected from the range of 0.05 to 0.5 equivalent based on Compound (32). Examples of the base include imidazole and the like. The amount of the base to be used is generally selected from the range of 3 to 20 equivalents relative to compound (32). The amount of tert-butyldimethylsilyl chloride to be used is generally selected from the range of 3 to 6 equivalents based on compound (32). As an inert solvent, N, N-dimethylforma Examples thereof include amide, tetrahydrofuran, 1,4-dioxane, dichloromethane, and a mixed solvent thereof, and preferably, N, N-dimethylformamide. The reaction temperature can be selected from the range of about 10 ° C to about 40 ° C.

3) Process 3

Compound (34) can be produced by reacting compound (33) with a base in an inert solvent, and further reacting it with an octalogenating agent. The amount of the base to be used is generally selected from the range of 2 to 5 equivalents relative to compound (33). The amount of the octalogenating agent to be used is generally selected from the range of 3 to 6 equivalents to compound (33). Examples of the base include lithium diisopropylamide, n-butyllithium, sec-butyllithium, tert-butyllithium and the like, and preferably tert-butyllithium and the like. Examples of the halogenating agent include dibromotetrafluoroethane, dibromotetrachloroethane, bromine, N-bromosuccinimide or N-chlorosuccinimide, and preferably, dibromotetrafluoroethane. Examples of the inert solvent include tetrahydrofuran, getyl ether, 1,4-dioxane, and a mixed solvent thereof, and preferably, tetrahydrofuran and the like. The reaction temperature when reacting with a base can be selected from the range of about -100 ° C to about 25 ° C. Further, the reaction temperature can be raised within the range of the reaction temperature. The reaction temperature when reacting with the halogenating agent can be selected from the range of about −100 ° C. to about 25 ° C., and within the range of the reaction temperature, the reaction temperature may be increased. You can also.

4) Process 4

Compound (36) can be produced from compound (34) by the same method as in step 7 described in Production method 1.

5) Process 5

Compound (37) can be produced from compound (36) by the same method as in step 5 described in production method 1.

6) Process 6

Compound (12) can be produced from compound (37) by a method similar to step 6 described in production method 1.

In the production of compound (12), the R ³ .CH ₂ group is generally substituted with a different nitrogen atom. The introduced product can also be a by-product, but the by-product can be easily removed by a usual purification method. Compound (32) can also be produced by a known method. Specifically, the method described in the literature (for example, J. Med. Chem., 32, 218 (1989)) can be mentioned. Manufacturing method 12

Compound (37) described in Production Method 11 can also be produced, for example, by the method shown below.

[Wherein, R ¹ and R ² have the same meanings as described in item [1], and X ² X ³ and R ¹⁰⁰ have the same meanings as described in Production Method 1. ]

1) Process 1

Compound (41) can be produced from compound (32) by a method similar to step 1 described in production method 1.

2) Process 2

Compound (43) can be produced from compound (41) by a method similar to step 7 described in production method 1.

3) Process 3

Compound (44) can be produced from compound (43) in the same manner as in step 2 of production method 1.

4) Process 4 Compound (37) can be produced from compound (44) in the same manner as in step 5 of production method 1. Manufacturing method 13

Among the compounds represented by the formula (I), the compounds represented by the formulas (56-5), (57), and (60) or salts thereof are produced by, for example, the method shown below.

(57)

[Wherein, R ¹ , R ³ and Y have the same meanings as described in Item [1], R ¹ Q °, XX ² and X ³ have the same meanings as described in Production Method 1, and R ^{1 (130} is Item [1] described in R ² And R ⁴⁰⁰ represents an alkyl group exemplified as a substituent of the “optionally substituted amino group” in R ² described in [1]. ]

1) Process 1

Compound (51) can be produced from compound (50) by a method similar to that described in the literature (eg, Synthesis 385 (1986)). As the compound (50), a commercially available product can be used.

2) Process 2

Compound (52) can be produced from compound (51) by the same method as in step 2 described in production method 1.

3) Process 3

Compound (53) can be produced from compound (52) in the same manner as in Step 5 of Production Method 1.

4) Process 4

Compound (55) can be produced from compound (53) by a method similar to the production method described in the literature (eg, Synthesis 775 (1999) and the like). In addition, in the production of compound (55), compounds in which an R ³ CH ₂ group is introduced into a different nitrogen atom can generally be by-produced, but the by-product can be easily removed by a usual purification method.

5) Process 5

Compound (56) can be produced by reacting compound (55) with an organic amine in an inert solvent. Examples of the organic amine include methylamine, dimethylamine, ethylamine, and getylamine. The amount of the organic amine to be used is generally selected from the range of 10 to 200 equivalents relative to compound (55). Examples of the inert solvent include alcohol solvents such as methanol, ethanol, and 2-propanol. Preferably, ethanol or the like is used. The reaction temperature can be selected from the range of about 0 ° C to about 40.

6) Process 6

Literature (for example, Tetrahedron 58, 3361 (2002), J. Med. Chem. 34, 2380 (1991), Tetrahedron Letters 34, 4595 (1993), J. Org. Chem. 40, 185 (1975), Chem. Ber. 80, 401 (1947) and L Org. Chem. 41, 568 (1976)) to produce compound (56-2) from compound (56). Can be.

7) Process 7

Compound (57) can be produced from compound (56-2) by a method similar to Steps 8 to 11 described in Production Method 1.

Compound (57) in which R ¹ is a hydrogen atom can be produced by a method similar to the above using compound (56) as a starting material.

8) Process 8

Compound (59) can be produced by reacting compound (56), compound (58), and nitrite in the presence of an acid. Nitrite includes sodium nitrite and potassium nitrite. Acids include sulfuric acid and nitric acid. Usually, compound (58) can be used as a solvent. The amount of nitrite to be used is generally selected from the range of 2 to 5 equivalents based on compound (56). The amount of sulfuric acid used is selected from the range of 0.05 to 0.1 times (volume ratio) the compound (58). The reaction temperature can be selected from the range of about 50 ° C to about 150 ° C.

9) Process 9

Compound (59-12) can be produced from compound (59) by a method similar to step 7 described in production method 1.

10) Process 10

Compound (60) can be produced from compound (59-2) by a method similar to steps 8 to 11 described in production method 1.

Compound (60) in which R ¹ is a hydrogen atom can be produced by a method similar to the above, using compound (59) as a starting material.

11) Process 11

Compound (56-4) can be produced from compound (56-2) by the same method as in step 7 described in Production method 1.

12) Process 12

Compound (56-5) can be produced from compound (56-4) by a method similar to Steps 8 to 11 described in Production Method 1. Manufacturing method 14

Among the compounds represented by the formula (I), the compound represented by the formula (63) or a salt thereof is produced, for example, by the method shown below.

Wherein, R ³ and Y, Section [1] have the same meanings as described, X ² and X ³ have the same meanings as the mounting process 1 SL, R ^Lfl4 is "in R ² of the item [1], wherein Represents an alkyl group exemplified as the substituent for the “amino group which may be substituted”. ]

1) Process 1

Compound (62) can be produced from compound (56) by a method similar to step 7 described in production method 1.

2) Process 2

Compound (63) can be produced from compound (62) by a method similar to Steps 8 to 11 described in Production Method 1. Manufacturing method 15

Among the compounds represented by the formula (I), the compound represented by the formula (71) or a salt thereof is produced, for example, by the method shown below.

— NH ₂

[Wherein, R ³ and Y have the same meanings as described in [1], X ³ has the same meaning as that of Production Method 1, and Ri. s _Rl . ₆ N is an amino group which may be substituted in R ² described in [1]. And "a nitrogen-containing saturated heterocyclic group which may be substituted". ] 1) Process 1

Compound (65) can be produced by reacting compound (64) with phosphorus oxychloride in an inert solvent, if necessary, in the presence of a base such as dimethylaniline or getylaniline. . When the base is a liquid, it can be used as a solvent. The amount of phosphorus oxychloride to be used is generally selected from the range of 1 to 5 equivalents based on compound (64). Examples of the inert solvent include ether solvents such as tetrahydrofuran or 1,4-dioxane; aprotic solvents such as N, N-dimethylformamide or dimethyl sulfoxide; and hydrocarbons such as toluene, benzene, or xylene. And a halogenated hydrocarbon solvent such as dichloromethane, dichloroethane, or chloroform, and the like, and a mixed solvent thereof may be used. Preferably, toluene and the like are used. The reaction temperature is selected from the range of about 50 ° C to about 150 ° C. As the compound (64), a commercially available product can be used 2) Step 2

Compound (67) can be produced by reacting compound (65) with compound (66) in an inert solvent in the presence of an inorganic base. Examples of the inorganic base include potassium carbonate and sodium carbonate. Examples of the inert solvent include alcohol solvents such as methanol, ethanol, or 2-propanol; hydrocarbon solvents such as toluene or benzene; aprotic solvents such as N, N-dimethylformamide or acetate nitrile; or Examples include ether solvents such as tetrahydrofuran and 1,4-dioxane. The reaction temperature is selected from the range of about 0 ° C to about 150 ° C.

3) Process 3

Compound (68) can be produced from compound (67) by a method similar to Step 2 described in Production Method 1.

4) Step 4-Compound (70) can be produced from compound (68) by the same method as in Step 6 described in Production method 1. In the production of compound (70), compounds in which an R ³ CH ₂ group is introduced into a different nitrogen atom can be generally produced as a by-product. It can be easily removed by a purification method.

5) Process 5

Compound (71) can be produced from compound (70) by a method similar to Steps 8 to 11 described in Production Method 1. Manufacturing method 16

Compound (32) described in Production Method 11 can also be produced, for example, according to the following Production Method 16.

Wherein, 'R ² have the same meanings as in claim [1] wherein, R ^{1 0 6} represents a methyl group, Echiru group, propyl group, 2-propyl or a benzyl group. ]

1) Process :! ~ 2

Compound (75) can be produced from compound (72) by a method similar to that described in the literature (eg, J. Org. Chem. 26, 4504 (1961) and US6423720).

2) Process 3

Compound (76) can be produced from compound (75) by a method similar to that described in the literature (eg, Synthesis 125 (1993)).

3) Process 4

58, 7258 (1993), J. Heterocycl. Chem. 30, 1229 (1993) and Comprehensive Organic transformation, RC Laroque, VCH publisher Inc., (1989), etc. The compound ( Compound (32) can be produced from 76) Production method 17

Among the compounds represented by the formula (I), the compound represented by the formula (84) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ¹ , R ³ and Y have the same meanings as described in item [1], and X ¹ and X ² have the same meanings as described in Production Method 1. ]

1) Process 1

Compound (78) can be produced from compound (77) by a method similar to the production method described in the literature (eg, Tetrahedron Letters 31, 3019 (1990)). Compound (77) can be produced using guanosine as a starting material by a method similar to Steps 1 and 2 of Production Method 13.

2) Process 2

Compound (79) can be produced from compound (78) by the same method as in step 5 described in production method 1.

3) Process 3

Compound (81) can be produced from compound (79) in the same manner as in Step 6 described in Production Method 1. In addition, in the production of compound (81), one in which an R ³ CH ₂ group is introduced into a different nitrogen atom can generally be produced as a by-product, but the by-product can be easily removed by a usual purification method. 4) Process 4

Compound (83) can be produced from compound (81) by the same method as in step 7 of production method 1.

5) Process 5

Compound (84) can be produced from compound (83) by a method similar to Steps 8 to 11 described in Production Method 1. Manufacturing method 18

Among the compounds represented by the formula (I), the compound represented by the formula (97) or a salt thereof is produced, for example, by the method shown below.

About 3

(93)

[Wherein, R ¹ , R ² , R ³ and Y have the same meanings as described in [1], X ¹ , X ² and X ³ have the same meanings as described in Production Method 1, and R ^{1 G 7} Represents a methyl group or an ethyl group; R ¹ . ⁸ represents a benzyl group, a methyl group or Echiru group, R ^1. ⁹ represents a methyl group or an ethyl group. ]

1) Process 1

Compound (87) was obtained from compound (85) by reference (for example, J. Med. Chem. 36, 3230). (1993), etc.). Compound (86) can be produced using a commercially available product or according to a method described in a literature (for example, Tetrahedron 50, 5361 (1994) and the like).

2) Process 2

Production described in literature (eg, J. Chem. Soc., Perkin Trans. 1, 3489 (1999), Chem. Parm. Bull. 4, 288 (1996), and Tetrahedron Letters 34, 103 (1993)). Compound (88) can be produced from compound (87) by a method similar to the method.

3) Process 3

Compound (89) can be produced from compound (88) by the same method as in step 2 described in production method 1.

4) Process 4

Compound (91) can be produced from compound (89) by a method similar to the production method described in the literature (eg, Heterocycles 42, 691 (1996)).

5) Process 5

Compound (92) can be produced from compound (91) by a method similar to Step 5 described in Production Method 1.

6) Process 6

Compound (94) can be produced from compound (92) in the same manner as in Step 6 described in Production Method 1. In addition, in the production of compound (94), one in which an R ³ CH ₂ group is generally introduced into a different nitrogen atom can also be by-produced, but the by-product can be easily removed by a usual purification method.

7) Process 7

Compound (96) can be produced from compound (94) by a method similar to step 7 described in production method 1.

8) Process 8

Compound (97) can be produced from compound (96) by a method similar to Steps 8 to 11 described in Production Method 1. Manufacturing method 19 Among the compounds represented by the formula (I), the compound represented by the formula (115) or a salt thereof is produced, for example, by the method shown below.

Khehe 3

_D 110

R ¹¹⁰ _R 3 / ^r or ^R

^R — ^N -ί ^N

o

RJ ² NX N ~ Λ _Ν — ^NH2

(114) (115)

[Wherein, R ² , R ³ and Y have the same meanings as described in [1], X ³ has the same meaning as in Production method 1, and R ^{1 1} QR ^{1 1 1} NC (〇) has the same meaning as [1] ] represents the illustrated "optionally substituted Cal Bamoiru group optionally" as the substituent of the "optionally substituted alkyl group" in R ¹ and R ² described. ]

1) Process 1

Compound (110) can be produced from compound (10) by a method similar to Steps 8 to 11 described in Production Method 1.

2) Process 2

Compound (110-1) can be produced from compound (11) by the same method as in step 1 of production method 10.

3) Process 3

Compound (111) can be produced from compound (110-1) by a method similar to step 7 described in production method 1.

4) Process 4

Compound (112) can be produced by hydrolyzing compound (111) in an inert solvent in the presence of a base. Examples of the base include alkali hydroxides (such as sodium hydroxide and potassium hydroxide), and an aqueous solution thereof is usually used. . Examples of the inert solvent include alcohol solvents such as methanol and ethanol. The reaction temperature is selected from the range of about 25 ° C to about 80 ° C.

5) Process 5

Compound (114) can be prepared by adding a dehydrating condensing agent such as dicyclohexylcarbodiimide or lyponyldiimidazole in an inert solvent and adding 4- (dimethylamino) pyridine or the like as necessary. It can be produced by condensing compound (112) with compound (113) in the presence of an agent. Examples of the inert solvent include ether solvents such as getyl ether, tetrahydrofuran, and 1,4-dioxane; aprotic solvents such as N, N-dimethylformamide; and halogenated hydrocarbon solvents such as dichloromethane and dichloroethane. And the like, and a mixed solvent thereof may be used. Preferably, N, N-dimethylformamide and the like are mentioned. The reaction temperature is usually selected in the range of about 0 ° C to about 50 ° C.

6) Process 6

Compound (115) can be produced from compound (114) by a method similar to step 2 described in production method 2. Manufacturing method 20

Among the compounds represented by the formula (I), the compound represented by the formula (124) or a salt thereof is produced, for example, by the method shown below.

[Wherein, R ² , R ³ and Y have the same meanings as described in item [1], and R ^{11 Q} R ^{11 1} NC (O) is the same as “substituted in R ¹ and R ² described in item [1]. exemplified as the substituent group which may alkyl group "is represents an" optionally substituted force Rubamoiru group optionally ", R ^{1 1 4} is 58

Represents a hydrogen atom or a fluorine atom. ]

1) Process 1

Similar to the production method described in the literature (for example, Angew. Cem. 108, 1082 (1996), Bioorg. Med. Chem. Lett. 8, 3275 (1998) and Tetrahedron Lett. 32, 1779 (1991)). According to the method, compound (121) can be produced from compound (111).

2) Process 2

Compound (122) can be produced from compound (121) by a method similar to step 4 described in Production method 19.

3) Process 3

Compound (1.23) can be produced from compound (122) by a method similar to step 5 described in Production method 19.

4) Process 4

Compound (124) can be produced from compound (123) by a method similar to Step 2 described in Production Method 2. Manufacturing method 21

Among the compounds represented by the formula (I), the compound represented by the formula (134) or a salt thereof is produced, for example, by the following method.

(133) (134) [Wherein, R ¹ R ² R ³ and Y have the same meanings as described in item [1], and X ² and X ³ have the same meanings as in Production Method 1. ]

1) Process 1 5

Compound (130) can be produced from compound (125) by a method similar to the production method described in a literature (eg, W099 / 03858).

2) Process 6

Compound (131) can be produced from compound (130) by a method similar to Step 3 of Production Method 11. Suitable bases in this step include tert-butyllithium and the like.

3) Process 7

Compound (131) and compound (133) can be produced by the same method as in Step 7 described in Production Method 1.

4) Process 8

Compound (134) can be produced from compound (133) by the same method as in step 8 11 described in Production method 1.

Compound (134) in which R ¹ is a hydrogen atom can be produced by a method similar to the above, using compound (131) as a starting material. Manufacturing method 22

Among the compounds represented by the formula (I), the compound represented by the formula (139) or a salt thereof is produced, for example, by the following method.

[Wherein, R ¹ R ³ and Y have the same meanings as described in the item [1], and R ^{1 15} C (は) represents the item [ 1] represents an “optionally substituted aryloyl group” and an “optionally substituted heteroarylcarbonyl group” in R ² , R 75 ^Q represents vinyl or topropropenyl, and M ¹ represents Represents lithium, magnesium chloride, or magnesium bromide. ]

1) Process 1

Compound (136) can be produced from compound (135) by a method similar to the production method described in a literature (eg, Tetrahedron 45, 3653 (1989)). Compound (135) is specifically Compound (17) or Compound (18) described in Production Method 1, Compound (134) described in Production Method 21, Compound (142-3) described in Production Method 23, The compound (188-5) described in the production method 29 and the compound (228) or the compound (224) described in the production method 32 are represented.

2) Process 2

Compound (138) can be produced by reacting compound (136) with compound (137) in an inert solvent. The amount of the compound (137) to be used is generally selected from the range of 1 to 5 equivalents relative to the compound (136). Examples of the inert solvent include tetrahydrofuran, dimethyl ether, 1,4-dioxane, a mixed solvent thereof and the like, and preferably tetrahydrofuran and the like. The reaction temperature can be selected from the range of about -100 ° C to about 25 ° C. Compound (137) can be commercially available or can be produced by the method described in Experimental Chemistry Lecture (edited by The Chemical Society of Japan, Maruzen), vol.

3) Process 3

Compound (139) can be produced from compound (138) by a method similar to that described in literature (eg, Comprehensive Organic transformation, by RC Laroch, VCH publisher Inc., (1989)). . Manufacturing method 23

Among the compounds represented by the formula (I), the compound represented by the formula (142-3) or a salt thereof is produced, for example, by the following method.

(142-2) (142-3)

[Wherein, R ² , R ³ and Y have the same meanings as described in item [1], M ¹ has the same meaning as described in Production Method 22, and R ^{1 16} C (〇) has the same meaning as described in item [1]. It represents the "optionally substituted aryloyl group" and the "optionally substituted nitrogen-containing heteroarylcarbonyl group" exemplified as the substituent of the "optionally substituted alkyl group" for R ¹ and R ² . ] 1) Process 1

Compound (140) can be produced from compound (111) by the same method as in step 4 described in Production method 19.

2) Process 2-3

Literature (eg Bioorg. Med. Chem. Lett. 11, 2951 (2001), Tetrahedron

Letters- 42, 8955 (2001), Synthesis 1852 (2000), Organic Letters 2, 4091 (2000), Tetrahedron Letters 42, 5609 (2001), Synthesis 2239 (2001),

Synlett 5, 715 (2002), J. Org.Chem. 67, 5032 (2002), Bioorg.Med.Chem. Lett. 11, 287 (2001) and Tetrahedron Letters 42, 3763 (2001)). Compound (142-2) can be produced from compound (140) by a method similar to the production method described above. Compound (142) can be produced using a commercially available product or by the method described in Experimental Chemistry Course (edited by The Chemical Society of Japan, Maruzen), Vol. 3) Process 4

Compound (142-3) can be produced from compound (142-2) by a method similar to Step 2 described in Production Method 2. Manufacturing method 24

Among the compounds represented by the formula (I), the compound represented by the formula (143) or a salt thereof Is manufactured, for example, by the method shown below,

(57) (143)

[Wherein, R ¹ R ³ and Y have the same meanings as described in item [1]. ]

1) Process 1

Literature (eg Bioorganic & Medicinal Chemistry 10, 3555 (2002),

Tetrahedron Lett. 31, 3019 (1990), Tetrahedron 52, 23 (1996) and

Compound (143) can be produced from compound (57) by a method similar to the production method described in Nucleosides, Nucleotides & Nucleic Acids 20, 59 (2001)). Manufacturing method 25

Among the compounds represented by the formula (I), the compounds represented by the formulas (149), (155) and (157-1), or salts thereof, are produced, for example, by the method shown below. .

, R

O O O

H ₂ N N N N Process H ₂ ^A N F ^F N

(56) (144) (145)

(157-1) (155)

[Wherein, R ¹ R ³ and Y have the same meanings as in item [1], wherein X ² and X ³ have the same meanings as in Production Method 1, and M ¹ has the same meaning as in Production Method 22. , R ^{1 16} C (O) has the same meaning as described in Production Method 23, and R ^{11 Q} R ^{11 1} NC (〇) represents “substituted even in R ¹ and R ² described in [1]. A good alkyl group.

It represents "optionally substituted rubamoyl group" and "optionally substituted nitrogen-containing heteroaminocarbonyl group". ]

1) Process 1

Compound (14) can be produced from compound (56) by the same method as in step 8 11 described in Production method 1.

2) Process 2

The compound (144) was converted to the compound ( 145) can be manufactured.

3) Process 3

The compound (145) was converted to the compound (

146) can be produced.

4) Process 4

Compound (146) was converted to compound (1) in the same manner as in Step 7 of Production Method 1.

48) can be manufactured.

5) Process 5

Compound (148) ^ Compound (149) can be produced by the same method as in Step 2 described in Production Method 2.

6) Process 6

50) can be manufactured.

7) Process 7

Compound (150) was converted to Compound (150) in the same manner as in Step 4 of Production Method 19.

151) can be manufactured.

8) Steps 8-9

Compound (154) can be produced from compound (151) by a method similar to Steps 2 and 3 described in Production Method 23.

9) Process 10

Compound (155) can be produced from compound (154) by a method similar to Step 2 described in Production Method 2.

10) Process 11

Compound (157) can be produced from compound (151) by a method similar to step 5 described in Production method 19.

1 1) Process 12

Compound (157-1) can be produced from compound (157) by a method similar to Step 2 described in Production Method 2. Manufacturing method 26 Among the compounds represented by the formula (I), the compounds represented by the formulas (161) and (164) or salts thereof are produced, for example, by the following method.

[Wherein, R ¹ , R ³ and Y have the same meanings as described in item [1]. ]

1) Process 1

Compound (158) can be produced from compound (57) in the same manner as in Step 1 of Production Method 10.

2) Process 2

The compound (159) can be produced from the compound (158) by a method similar to that described in the literature (eg, Tetrahedron 46, 7677 (1990) and Bioorganic & Medicinal Chemistry 10, 3555 (2002)). it can.

3) Process 3

The compound (160) can be produced from the compound (159) by a method similar to that described in the literature (eg, Tetrahedron 46, 7677 (1990) and Bioorganic & Medicinal Chemistry 10, 3555 (2002)). it can.

4) Process 4

Compound (161) can be produced from compound (160) by a method similar to Step 2 described in Production Method 2. 5) Process 5

Production of compound (162) from compound (159) by a method similar to that described in the literature (eg, Tetrahedron 46, 7677 (1990) and Bioorganic & Medicinal Chemistry 10, 3555 (2002)). Can be.

6) Process 6

The compound (162) is converted to the compound (163) by a method similar to the production method described in the literature (eg, Tetrahedron Lett. 39, 6667 (1998) and J. Am. Chem. Soc. 100, 5437 (1978)). Can be manufactured.

7) Process 7

Compound (164) can be produced from compound (163) by a method similar to step 2 described in production method 2. Manufacturing method 27

Among the compounds represented by the formula (I), the compounds represented by the formulas (173) and (175-1) or salts thereof are produced, for example, by the following method.

67

(175-1) (173)

[Wherein, R ³ and Y have the same meanings as described in item [1], Μ ¹ has the same meaning as described in Production Method 22, R ^{1 16} C (〇) has the same meaning as described in Production Method 23, R ^{1 1} . R ¹¹ NC (〇) has the same meaning as in Production Method 25. ]

1) Process 1.

Compound (165) can be produced from compound (144) by a method similar to Step 1 described in Production Method 10.

2) Process 2

The compound (165) was converted to the compound ( 166) can be produced.

3) Process 3

Compound (167) can be produced from compound (166) by a method similar to Step 2 described in Production Method 26.

4) Process 4

Compound (168) can be produced from compound (167) by a method similar to that in step 3 of production method 26.

5) Process 5

The compound (168) was converted to the compound (

169) can be produced.

6) Process 6-7

Compound (172) can be produced from compound (169) by a method similar to Steps 2 and 3 described in Production Method 23. Compound (171) can be used as a commercially available product, or can be produced by the method described in Experimental Chemistry Course (edited by The Chemical Society of Japan, Maruzen), Vol.

7) Process 8

Compound (173) can be produced from compound (172) by a method similar to Step 2 described in Production Method 2.

8) Process 9

The compound (169) was converted to the compound (

175) can be manufactured.

9) Process 10

Compound (175-1) can be produced from compound (175) by a method similar to step 2 described in production method 2. Manufacturing method 28

Among the compounds represented by the formula (I), the compounds represented by the formulas (182) and (185-1) or salts thereof are produced, for example, by the following method. 69

[Wherein, R ³ and Y have the same meanings as described in item [1], Μ ¹ has the same meaning as described in Production Method 22, R ^{1 16} C (0) has the same meaning as described in Production Method 23, R ^{1 1} . R ^{11 1} NC (Ο) has the same meaning as in Production Method 25. ]

1) Process 1

Compound (176) can be produced from compound (167) by a method similar to step 5 of production method 26.

2) Process 2

The compound (176) was converted to the compound ( 177) can be manufactured.

3) Process 3-4

Compound (180) can be produced from compound (177) by a method similar to Steps 2 and 3 described in Production Method 23. Compound (179) can be used as a commercially available product, or can be produced by the method described in Experimental Chemistry Lecture (edited by The Chemical Society of Japan, Maruzen), vol.

4) Process 5

Compound (180) was converted into compound (

181) can be manufactured.

5) Process 6

Compound (182) can be produced from compound (181) by a method similar to Step 2 described in Production Method 2.

6) Process 7

Compound (184) can be produced from compound (177) by a method similar to step 5 described in Production method 19.

7) Process 8

Compound (185) can be produced from compound (184) in the same manner as in Step 6 of Production Method 26.

8) Process 9

Compound (185-1) can be produced from compound (185) by a method similar to Step 2 described in Production Method 2. Manufacturing method 29

Among the compounds represented by the formula (I), the compound represented by the formula (188-5) or a salt thereof is produced, for example, by the method shown below. 17

Process 5

[Wherein, R ^] R ² and R ³ have the same meanings as described in the item [1], X ³ has the same meaning as described in the production method 1, and R ⁷ . Represents a P- nitrobenzenesulfonyl group or 0- nitrobenzene sulfonyl Le group, R ^{7 0 1} represents hydrogen atom, a benzenesulfonyl group, p- Torue Nsuruhoniru group, or a methanesulfo two Le group. ] ·

1) Process 1

Compound (186) can be produced from compound (12) by a method similar to the production method described in the literature (eg, Heterocycles 38, 529 (1994), etc.).

2) Process 2

Compound (187) can be produced from compound (186) by a method similar to the production method described in the literature (eg, Tetrahedron Lett. 42, 871 (2001)).

3) Process 3

When 70 ¹ is a hydrogen atom, compound (188-8) is prepared from compound (187) by a method similar to the method described in the literature (eg, Tetrahedron Lett. 42, 871 (2001)). be able to. R ^{7 0 1} benzene sulfonyl group, when the p- Torue Nsuruhoniru group or methanesulfonyl group, the literature (e.g. Comprehensive Compound (188-2) can be produced from compound (187) by a method similar to the method described in Organic Transformation, RC Lalock, VCH publisher Inc., (1989)). Compound (188-1) also includes optically active forms.

4) Process 4〜5

Compound (188-4) can be produced from compound (188-2) by a method similar to the production method described in the literature (eg, Tetrahedron Lett. 42, 871 (2001)).

5) Process 6

Compound (188-5) can be produced from compound (188-4) by a method similar to Steps 2 to 4 described in Production Method 10. Manufacturing method 30

Y—NH ₂ is represented by the following formula (G): Compound (57) described in Production Method 13, Compound (56-5) described in Production Method 13, Compound (84) described in Production Method 17, Production Method 21 The compound (134) described in the description, the compound (204) described in the production method 31 and the compound (144) described in the production method 25 correspond to each other by the same method as in Steps 1 to 6 described in the production method 29, respectively. Starting compound, compound (56-2) according to production method 13, compound (56-4) according to production method 13, compound (83) according to production method 17, compound (133) according to production method 21, production method It can be produced from the compound (203) described in 31 and the compound (56) described in Production Method 25.

Manufacturing method 31

Compound (111) described in Production Method 19 can also be produced, for example, according to the following production method.

[Wherein, R ² R ³ and Y have the same meanings as described in the item [1], and R ¹ Q represents X ¹ and X ³ have the same meanings as Process 1, wherein, R ^{5 0} is as defined production process 11 described, R ^{1 1 2} represents methyl, Echiru, propyl, 2 _ propyl or phenyl. ] 1) Process 1

Compound (191) can be produced from compound (189) by a method similar to Step 1 described in Production Method 1.

2) Process 2

Compound (193) can be produced from compound (191) by a method similar to Step 6 described in Production Method 1.

3) Process 3

Compound (194) can be produced from compound (193) by a method similar to Step 2 described in Production Method 18.

4) Process 4

Compound (195) can be produced from compound (194) by a method similar to step 1 described in production method 1.

5) Process 5

Compound (196) can be produced from compound (195) by the same method as in step 5 described in production method 1.

6) Steps 6-8

Compound (200) can be produced from compound (196) by a method similar to Steps 1 to 3 described in Production Method 21.

7) Process 9

Compound (202) can be produced from compound (200) by a method similar to Step 1 described in Production Method 11.

8) Process 10

Compound (203) can be produced from compound (202) in the same manner as in step 3 of Production method 11. Suitable bases in this step include tert-butyllithium and the like.

9) Process 11

Compound (204) can be produced from compound (203) by a method similar to Steps 8 to 11 described in Production Method 1.

10) Process 12

Compound (204) was converted to compound (Compound (204)) in the same manner as in Step 1 of Production Method 10. 205) can be manufactured.

11) Process 13

Compound (206) can be produced from compound (205) by a method similar to Step 1 described in Production Method 22.

12) Process 14

The compound (206) was prepared from the compound (206) by a method similar to the production method described in the literature (eg, Tetrahedron Letters 37, 2573 (1996), Tetrahedron 52, 8989 (1996), Synlett 1555 (2001) and Synlett 1599 (2001)). Compound (112) can be produced.

13) Process 15

The compound (111) can be produced from the compound (112) by a method similar to that described in the literature (eg, Comprehensive Organic transformation, RC Laroch, VCH publisher Inc., (1989)). it can. Manufacturing method 32

Among the compounds represented by the formula (I), the compounds represented by the formulas (224) and (228) or salts thereof are produced, for example, by the following method.

(228)

^{Wherein, m, n, R 2,} R 3, R 4, R 5 and Y are as defined according to claim [1], M 1 has the same meaning as process 22 described, R ^{5 1} is methyl , Echiru represents 3-methyl-2-butenyl or 2-propenyl, R ^{5 5} represents Bo c or Cb z, R ¹¹² has the same meaning as process 31 described, R ^{1 1 6} C (〇 ) Has the same meaning as described in Production Method 23, and R ¹¹ ° R ^{11 1} NC (〇) has the same meaning as described in Production Method 25. ]

1) Process 1

Literature (eg, Bioorg. Med. Chem. Lett. 12, 653 (2002), Chem. Pharni. Bull. 45, 2005 (1997), Tetrahedron Letters 39, 7983 (1998), Tetrahedron 46, 7803 (1990), Tetrahedron Letters 32, 691 (1991), Tetrahedron 51, 5369 (1995), J. Med.Chem. 38, 3236 (1995) and J. Heterocycl.Chem. 24, 275 (1987), etc.) Compound (209) can be produced from compound (207) by an appropriate method. 2) Process 2

Compound (211) can be produced from compound (209) by the same method as in step 8 or step 9 described in production method 1.

3) Process 3

Compound (213) can be produced from compound (21 1) by a method similar to step 6 described in production method 1.

4) Process 4

Compound (214) can be produced from compound (213) by a method similar to the production method described in the literature (for example, W02 / 068420).

5) Process 5

Literature (e.g., W099 / 03858, Tetrahedron Letters 38, 7963 (1997), Bioorg.Med.Chem. Lett. 12, 543 (2002), Heterocycles 57, 123 (2002), Tetrahedron Letters 41, 9957 (2000) and Tetrahedron Letters Compound (2 15) can be produced from compound (214) by a method similar to the production method described in P. 42, 2201 (2001).

6) Process 6

R ^{5 1} is, in the case of methyl or Echiru group, by the same method as process recited in preparation 19, wherein step 4 or literature (e.g. WO 99/64426, etc.), the compound (21 5) Compound (216) can be produced. R ^{5 1} is 3 - For methyl-2-butenyl group, the literature (for example, Synlett 137 (2002), etc.) by the same method as the manufacturing method described in, compounds (2 1 5) (2 16) Can be manufactured. R ^{5 1} is, in the case of 2-propenyl group, literature (e.g. Synlett 722 (2000), Tetrahedron 57 , 3435 (2001), Tetrahedron 56, 5353 (2000) J. Org. Chem. 67, 4975 (2002) And J. Org. Chem. 63, 9103 (1998)) can produce compound (216) from compound (215).

7) Process 7

Literature (eg, Bioorg. Med. Chem. Lett. 6, 1483 (1996), Tetrahedron Letters 37, 7031 (1996), Tetrahedron Letters 37, 8081 (1996), Tetrahedron Letters 41, 6171 (2000) and Synth. Commun. 23 , 2265 (1993), etc.) Compound (218) can be produced from compound (216) by the same method as in.

8) Process 8

Compound (219) can be produced from compound (218) by a method similar to the production method described in the literature (for example, W9999858).

9) Process 9

Compound (220) can be produced from compound (219) by a method similar to Step 1 described in Production Method 22.

10) Process 10

Compound (221) can be produced from compound (220) in the same manner as in step 14 of production method 31.

11) Process 1 1

Compound (223) can be produced from compound (221) by a method similar to Step 5 described in Production Method 19.

12) Process. 12

When R ^{5 5} is Bo c, it can be by a similar manner to Step 2 of Preparation 2 described method, of producing compound (224) from the compound (223). Also, ^{5 5} (:...... For 132, the literature (for example] Am Chem Soc 85, 2149 (1963 ), Tetrahedron Lett 41, 3029 (2000) and Tetrahedron Lett 36, 8677 (1995), etc.) Compound (224) can be produced from compound (223) by a method similar to the production method described in (1) When compound (224) is a racemic compound, a method similar to Step 10 in Production Method 1 Can produce an optically active substance.

13) Process 13-14

Compound (227) can be produced from compound (221) by a method similar to Steps 2 and 3 described in Production Method 23. Compound (226) can be used as a commercially available product, or can be produced by the method described in Experimental Chemistry Lecture (edited by The Chemical Society of Japan, Maruzen), vol.

14) Process 15

When R ^{5 5} is Bo c, it can be by a similar manner to Step 2 of Preparation 2 described method, of producing compound (228) from the compound (227). In addition, R ^{5 5} is Cb z In the case, it is the same as the production method described in the literature (for example, J. Am. Chem. Soc. 85, 2149 (1963), Tetrahedron Lett. 41, 3029 (2000) and Tetrahedron Lett. 36, 8677 (1995)). By the method, compound (228) can be produced from compound (227). When compound (228) is in a racemic form, an optically active form can be produced by the same method as in step 10 described in Production method 1. Manufacturing method 33

Compound (210_1) described in Production Method 32 can be produced by the following method.

Wherein, m and R ⁴ are as defined in claim [1] wherein, R ^{5 5} is as defined production process 32 described. ]

1) Process 1

Production of Compound (21) Compound (210-1) by a method similar to the production method described in the literature (eg, J. Chem. Soc, Perkin Trans. 1, 2233 (1999), etc.) Can be. Manufacturing method 34

Compound (210-2) described in Production Method 32 can be produced by the following method.

1) Process 1

Compound (13) was converted to Compound (2) in the same manner as in Step 1 described in Production Method 33. 10-2) can be manufactured. Manufacturing method 35

Compound (210-3) described in Production Method 32 can be produced by the following method.

Process 3

(232) (210-3)

Wherein, n and R ⁵ have the same meanings as in claim [1] wherein, R ^{5 5} is as defined production process 32 described. ]

1) Process 1 4

Compound (210-3) can be produced from compound (28) by a method similar to step 14 described in Production Method 10. Manufacturing method 36

Compound (210-4) described in Production Method 32 can be produced by the following method.

(15) (210-4)

1) Process 1

Compound (2 10-4) can be produced from compound (15) by a method similar to Step 1 described in Production Method 33. Manufacturing method 37

Compound (219) described in Production Method 32 can also be produced by the following method.

R ⁵ ,

Process 2

(214) (233)

(219)

[Wherein, R ^2, R ³ and Y are as defined in claim [1] wherein, R ^{5 1} and R ^{5 5} is as defined manufacturing technique 32, wherein, R ^{1 1 2} is a production process 31 described Synonymous. ]

1) Process 1

Compound (233) can be produced from compound (214) by a method similar to step 4 described in Production method 19.

2) Process 2-3

Compound (219) can be produced from compound (233) by a method similar to that described in the literature (eg, J. Med. Chem. 15, 106, etc.). Manufacturing method 38

Among the compounds represented by the formula (I), the compounds represented by the formulas (238) and (241) or salts thereof are produced, for example, by the following method. 83

Wherein, R ^1, R ³ and Y are as defined in claim [1] wherein, R ^{1 1 5} C (〇) has the same meaning as that described preparation 22, R ^{5 1} and R ^{5 5} the production process 32 have the same meanings as described, M ¹ is the same meaning as process 22 according. ]

1) Process 1

The compound (237) can be produced from the compound (214) and the compound (236) by a method similar to that described in the literature (eg, J. Heterocycl. Chem. 35, 659 (1998)). it can.

2) Process 2

Compound (238) can be produced from compound (237) in the same manner as in Step 12 described in Production Method 32.

3) Process 3

Compound (240) can be produced from compound (237) by a method similar to the production method described in the literature (eg, J. Org. Chem. 59, 4844 (1994)).

4) Process 4

Compound (241) can be produced from compound (240) by a method similar to step 12 of production method 32. Manufacturing method 39

Among the compounds represented by the formula (I), the compound represented by the formula (247) and the formula (25.1) or a salt thereof is produced, for example, by the following method.

Process 2

Step 5 Step 4

Wherein, R ³ and Y are as defined in claim [1] wherein, Micromax ¹ has the same meaning as process 22 described, R ^{5 1} and R ^{5 5} is as defined production process 32 described, R ^{1 2} has the same meaning as process 3 1 ^{wherein, R 1 1 6 C (0} ) has the same meaning as that described preparation ^{^{23, R 1 1 0 R 1}} 1 1 NC (0) is a production method 25 described Synonymous. ]

1) Process 1

Compound (243) can be produced from compound (214) and compound (242) by a method similar to step 1 described in production method 38.

2) Process 2

Compound (244) can be produced from compound (243) by a method similar to step 1 of production method 22 and step 14 of production method 31. 3) Process 3

Compound (246) can be produced from compound (244) by a method similar to step 5 described in Production method 19.

4) Process 4

Compound (247) can be produced from compound (246) by a method similar to step 12 described in production method 32.

5) Process 5-6

Compound (250) can be produced from compound (244) by a method similar to Steps 2 and 3 described in Production Method 23.

6) Process 7

Compound (251) can be produced from compound (250) in the same manner as in step 12 of production method 32. Manufacturing method 40

Among the compounds represented by the formula (I), the compounds represented by the formulas (257) and (261) or a salt thereof are produced, for example, by the following method.

R " ⁶ — M ¹

Process 6

(259)

Wherein, R ³ and Y are as defined in claim [1] wherein, Micromax ¹ has the same meaning as process 22 described, R ^{5 5} is as defined production process 32 described, R ^{1 1 2} is has the same meaning as process 31 ^{described, R 1 1 6 C (Ο} ) has the same meaning as that described preparation ^{23, R 1 1 5 C (} Ο) has the same meaning as manufacturing method 22 wherein, R ^{1 1 Q} R ^{11 1} NC (Ο) has the same meaning as described in Production method 25.

1) Process 1

Compound (253) can be produced from compound (243) in the same manner as in Step 3 described in Production Method 38.

2) Process 2 Compound (254) can be produced from compound (253) by the same method as in step 1 of production method 22 and step 14 of production method 31.

3) Process 3

Compound (256) can be produced from compound (254) by a method similar to step 5 described in Production method 19.

4) Process 4

Compound (257) can be produced from compound (256) by a method similar to step 12 described in Production Method 32.

5) Process 5-6

Compound (260) can be produced from compound (254) by the same method as in Steps 2 and 3 described in Production Method 23.

6) Process 7

Compound (261) can be produced from compound (260) by a method similar to step 12 described in production method 32. Manufacturing method 41

Compound (218) described in Production Method 32 can also be produced, for example, according to the following production method.

(276)

^{Wherein, m, n, R 2,} R 3, R 4, R 5 and and Y Section [1] Ri described synonymous der, R ¹¹² has the same meaning as process 31 described, R ^{5 5} is has the same meaning as process 32 described, R ^{6 0} represents methyl or Echiru, R ^{6 1} represents the Bo c. ]

1) Process 1

Compound (264) can be produced from compound (262) by a method similar to the production method described in a literature (for example, WO00 / 18790 and the like).

2) Process 2

Compound (264) was converted to Compound (2) by the same method as in Step 3 described in Production Method 9. 65) can be manufactured.

3) Process 3

Compound (266) can be produced from compound (265) by a method similar to step 4 described in Production method 19.

4) Process 4

Compound (268) can be produced from compound (266) by a method similar to step 5 described in Production method 19.

5) Process 5

Compound (269) can be produced from compound (268) by a method similar to Step 2 described in Production Method 2.

6) Process 6

Compound (271) can be produced from compound (269) by a method similar to Step 1 described in Production Method 32.

7) Process 7

Compound (276) can be produced from compound (271) by a method similar to Steps 8 to 9 described in Production Method 1.

8) Process 8

Compound (277) can be produced from compound (276) by the same method as in step 4 of production method 32.

9) Process 9

Compound (218) can be produced from compound (277) in the same manner as in step 5 of production method 32. Manufacturing method 42

Compound (218) described in Production Method 32 can also be produced, for example, according to the following production method. 90

Wherein, R ² R ³ and and Y are as defined in claim [1] wherein, R ^{5 1} and R ⁵ ⁵ is as defined production process 32 described, Rl 12 is a manufacturing process 31 according synonymous . ]

1) Process 1

Compound (278) can be produced from compound (214) by a method similar to Step 1 described in Production Method 21.

2) Process 2

Compound (279) can be produced from compound (278) by a method similar to Step 6 described in Production Method 32.

3) Process 3

Compound (281) can be produced from compound (279) by a method similar to Step 7 described in Production Method 32.

4) Process 4

Compound (282) can be produced from compound (281) in the same manner as in Step 3 of Production Method 21. When R ^{5 5} compound (281) is Bo c, the In step, there is a case where the compound R ^{5 5} is a hydrogen atom of the compound (282) is formed, by a similar manner to Step 1 of Preparation 10 described method, the R ^{5 5} compound (282) from a hydrogen atom Bo c can be.

5) Process 5

Compound (218) can be produced from compound (282) by the same method as in step 5 described in Production method 32. Manufacturing method 43

Compound (211) described in Production Method 32 can also be produced, for example, according to the following production method.

Ph

(211)

Wherein, mn R ⁴ R ⁵ and Y are as defined in claim [1] wherein, R ^{5 1} and R ^{5 5} has the same meaning as process 32 according. ]

1) Process 1

Compound (283) can be produced from compound (208) by a method similar to Step 2 of Production Method 32.

2) Process 2 92 Compound (211) can be produced from compound (283) by a method similar to Step 1 described in Production Method 32.

3) Process 3

Compound (211) can also be produced from compound (208) by performing the following reactions (1) and (2).

(1) The compound (208) is reacted with the compound (210-1), the compound (210-2), the compound (210-3) or the compound (210-4) in an inert solvent. Examples of the inert solvent include alcohol solvents such as methanol, ethanol, and 2-propanol.

(2) The base and compound (207) are added to the reaction mixture obtained in step (1) of step 3 of production method 43, and the mixture is reacted. Bases include imidazole, triethylamine, diisopropylethylamine, triptylamine, 1,5_diazavicic mouth [4.3.0] nona-5-ene, 1,4-diazabicyclo [2.2.2] octa Organic bases such as 1,4-diazabicyclo [5.4.0] pentane, 4- (dimethylamino) pyridine and picoline. Preferably, triethylamine and the like are mentioned. The amount of compound (207) to be used is generally selected from the range of 3 to 10 equivalents based on compound (208). The amount of the base used is usually selected from the range of 5 to 15 equivalents relative to the compound (208). The reaction temperature can be selected from the range of about 50 ° C to about 150 ° C. Manufacturing method 44

Compound (286) can also be produced, for example, according to the following production method.

Process 1 (285)

(214)

Process 2

Wherein, R ^1, R ³ and Y are as defined in claim [1], wherein the same meanings as R ^{5 1} and R ^{5 5} granulation method 32 described. ]

1) Process 1

Compound (285) can be produced from compound (214) by performing the following reactions (1) to (3).

Compound (214) in the presence of a base in pyridine,

Expression

R, _N (284)

[Wherein, R ¹ has the same meaning as described in item [1]. ] (284). The reaction temperature can be selected from the range of about 50 ° C to about 150 ° C. The amount of compound (284) to be used is generally selected from the range of 1 to 3 equivalents.

(2) A base is added to and reacted with the reaction mixture in step (1) of step 1 of production method 44. Examples of the base include cesium carbonate, potassium carbonate and sodium carbonate. The amount of the base used is usually selected from the range of 1 to 5 equivalents. The reaction temperature is selected from the range of about 50 ° C to about 150 ° C.

(3) Methyl iodide is added to the reaction mixture obtained in step (2) of production method 44 to cause a reaction. The amount of methyl iodide used is usually selected from the range of 1 to 5 equivalents. The reaction temperature is selected from the range of about -10 ° C to about 40 ° C.

2) Process 2

As step 2, the following production method (A) and production method (B) can be used. Production method (A): Compound (286) can be produced by reacting compound (285) with a mixture of sodium tandastanoate and aqueous hydrogen peroxide in an inert solvent. Examples of the inert solvent include alcohol solvents (ethanol, methanol, 2-propanol, etc.) and organic acids (acetic acid, propionic acid, etc.). Usually, a mixed solvent of an alcohol solvent and an organic acid is used. Can be The amount of sodium tungstate to be used is generally selected from the range of 1 to 5 equivalents based on compound (285). The amount of the aqueous hydrogen peroxide (usually a 30% aqueous solution) is selected from the range of usually 10 to 100 equivalents to compound (285). The reaction temperature can be selected from the range of about -10 ° C to about 40 ° C. Production method (B): Compound (286) can be produced by reacting compound (285) with oxone (registered trademark, Aldrich) in an inert solvent. Examples of the inert solvent include alcohol solvents (such as ethanol, methanol, and 2-propanol). The amount of oxone (registered trademark, Aldrich) to be used is generally selected from the range of 1 to 20 equivalents based on compound (285). The reaction temperature can be selected from the range of about 110 ° C to about 40 ° C. Manufacturing method 45

Among the compounds represented by the formula (I), the compound represented by the formula (288) or a salt thereof is produced, for example, by the following method.

Process 2 (288)

Wherein, R ^1, R ³ and and Y are as defined in claim [1] wherein,: R ^{5 1} is as defined Process 3 wherein, R "° 〇, Section [1] according In R ^2, an “optionally substituted alkoxy group”, an “optionally substituted aryloxy group”, an “optionally substituted aralkyloxy group”, an “optionally substituted heteroaryloxy group”, and a formula ( T1) represents a group represented by (T6). ]

1) Process 1

Compound (287) can be produced by reacting compound (286) and compound (287-1) reacted with a base in an inert solvent. Examples of the base include potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, potassium carbonate, sodium carbonate, sodium phenoxide, potassium phenoxide, sodium hydride, and the like. Sodium and the like. The amount of the base to be used is generally selected from the range of 1 to 5 equivalents to the compound (287-1). Selected. Examples of the inert solvent include tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and a mixed solvent thereof. The reaction temperature can be selected from the range of about 110 ° C to about 50 ° C.

2) Process 2

Compound (288) can be produced from compound (287) by a method similar to step 12 of production method 32. Manufacturing method 46

Among the compounds represented by the formula (I), the compound represented by the formula (290) or a salt thereof is produced, for example, by the method shown below.

Process 2 (290)

Wherein, R ^1, R ³ and and Y are as defined in claim [1] wherein, R ^{5 5} is as defined Process 3 wherein, R ⁹⁴¹ S, Section [1] as claimed R ² Represents an "optionally substituted alkylthio group" and an "optionally substituted arylthio group". ]

1) Process 1

Compound (289) can be produced from compound (286) by a method similar to Step 1 described in Production Method 45.

2) Process 2

Compound (290) can be produced from compound (289) by a method similar to step 12 described in production method 32. Manufacturing method 47

Among the compounds represented by the formula (I), the compound represented by the formula (292) or a compound thereof The salt is produced, for example, by the method shown below ₍

Process 2 (292)

Wherein, R ^1, R ³ and and Y are as defined in claim [1] wherein, R ^{5 5} is as defined Production Method 3 wherein. ]

1) Process 1

Compound (291) can be produced by reacting compound (286) with sodium or potassium cyanide in an inert solvent. The amount of sodium cyanide or potassium cyanide to be used is generally selected from the range of 0.8 to 5 equivalents relative to compound (286). Examples of the inert solvent include tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and a mixed solvent thereof. The reaction temperature can be selected from the range of about 110 ° C to about 50 ° C.

2) Process 2

Compound (290) can be produced from compound (289) by a method similar to step 12 described in production method 32. Manufacturing method 48

Among the compounds represented by the formula (I), the compound represented by the formula (294) or a salt thereof is produced, for example, by the method shown below. 97

Wherein, R ^1, R ³ and and Y are as defined in claim [1] wherein, R ^{5 5} is as defined Process 3 wherein, R ⁹⁴² R ⁹⁴³ N, Section [1] according R ² represents a “optionally substituted nitrogen-containing saturated heterocyclic group” and an “optionally substituted amino group”. ]

1) Process 1

Compound (293) can be produced by reacting compound (286) with compound (293-1) in the presence or absence of an inert solvent. The amount of compound (293-1) to be used is generally selected from the range of 10 to 100 equivalents to compound (286). When compound (293-1) is a liquid, it can be used as a solvent. Examples of the inert solvent include alcohol solvents (eg, ethanol, methanol, and 2-propanol). The reaction temperature can be selected from the range of about 50 ° C to about 150 ° C.

2) Process 2

Compound (294) can be produced from compound (293) in the same manner as in Step 12 of Production Method 32. Manufacturing method 49

Among the compounds represented by the formula (I), the compound represented by the formula (296) or a salt thereof is produced, for example, by the following method.

Process 2 (296)

Wherein, R ^1, R ³ and and Y are as defined in claim [1] wherein, Micromax ¹ has the same meaning as Process 2 wherein, R ^{5 5} is as defined production process 32 described, R ⁹⁴² represents the “optionally substituted alkyl group”, the “optionally substituted cycloalkyl group”, the “optionally substituted alkenyl substituent”, the “optionally substituted alkyl group” for R ² in the above [1]. And "optionally substituted heteroaryl group", "optionally substituted heteroarylalkyl" and "optionally substituted aralkyl group". ]

1) Process 1

Compound (295) can be produced by reacting compound (286) with compound (295-1) in an inert solvent. The amount of compound (295-1) to be used is generally selected from the range of 3 to 10 equivalents based on compound (286). Examples of the inert solvent include tetrahydrofuran, 1,4-dioxane, Ν, Ν-dimethylformamide, and a mixed solvent thereof. The reaction temperature can be selected from the range of about -10 ° C to about 50 ° C.

2) Process 2

Compound (296) can be produced from compound (295) by a method similar to step 12 of production method 32. Manufacturing method 50

Among the compounds represented by the formula (I), the compound represented by the formula (298) or a salt thereof is produced, for example, by the following method.

Wherein, R ^1, R ³ and and Y are as defined in claim [1] wherein, R ^{5 5} is Production Method 3

R ⁹⁴⁴ C (〇) is the same as R ² described in item [1], except that “optionally substituted caroyl group” and “optionally substituted nitrogen-containing heteroarylcarbonyl group” Represent. ]

1) Process 1

Compound (297) can be produced by reacting compound (286) with compound (297-1) in an inert solvent in the presence of a base. Compound (297—

The amount of 1) to be used is generally selected from the range of 3 to 10 equivalents based on compound (286). Examples of the base include sodium hydride and the like. Examples of the inert solvent include tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and a mixed solvent thereof. The reaction temperature can be selected from the range of about 50 ° C to about 150 ° C.

2) Process 2

Compound (298) can be produced from compound (297) in the same manner as in Step 12 of Production Method 32. Manufacturing method 51

Among the compounds represented by the formula (I), the compound represented by the formula (300) or a salt thereof is produced, for example, by the method shown below.

Wherein, R ^1, R ³ and and Y are as defined in claim [1] wherein, R ^{5 5} is as defined Process 3 wherein, R ⁹⁴⁵ R ⁹⁴⁶ N, Section [1] according R ² represents an optionally substituted heteroaryl group (pyrrolyl, imidazole, pyrazole, etc.) and an optionally substituted amino group. ]

1) Process 1

Compound (299) can be produced by reacting compound (286) and compound (299-1) reacted with a base in an inert solvent. Examples of the base include potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, potassium carbonate, sodium carbonate, sodium phenoxide, potassium phenoxide, sodium hydride, and the like. Sodium and the like. The amount of the base to be used is generally selected from the range of 1 to 3 equivalents to compound (299-1). The amount of compound (299-1) to be used is generally selected from the range of 2 to 10 equivalents based on compound (286). Examples of the inert solvent include tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and a mixed solvent thereof. The reaction temperature can be selected from the range of about 110 ° C to about 50 ° C.

2) Process 2

Compound (300) can be produced from compound (299) in the same manner as in step 12 of production method 32. Manufacturing method 52 20 Of the compounds represented by the formula (I), the compounds represented by the formula (309), the formula (312), the formula (315) and the formula (319), or a salt thereof are, for example, obtained by the method shown below. Manufactured by

2 Process 4

Process 8

(308)

(316)

R 952

(317) Process 15

Wherein, R ³ and Y are as defined in claim [1] wherein, Micromax ¹ has the same meaning as process 22 described, R ^{5 1} and R ^{5 5} is as defined production process 32 described, R ^{9 4 7} represents methyl, Echiru, propyl and 2-propyl, R ^{9 4 9} OC (0), section [1] the substituent of the "substituted alkyl group" in R ¹ and R ² described stands for "optionally substituted alkoxycarbonyl Cal Poni Le group" exemplified as, R ^{9 5.} R ^{9 5 1} NC (〇), Section [1] represents the illustrated "an optionally substituted force Rubamoiru group" as the substituent of the "optionally substituted alkyl group" in R ¹ and R ² described, R ^{9 5 2} C (〇), section [1] represents the illustrated "optionally substituted Aroiru group" as the substituent of the "optionally substituted alkyl group" in R ¹ and R ² described, R ^{9 4 8} Is a cyano group, an “optionally substituted alkoxy group”, an “optionally substituted aryloxy group”, an “optionally substituted aralkyloxy group” in R ^{2 according to} item [1],

“Optionally substituted heteroaryloxy group”, “optionally substituted alkylthio group”, “optionally substituted arylthio group”, “optionally substituted alkyl group”, “optionally substituted "Cycloalkyl group", "optionally substituted alkenyl substituent", "optionally substituted aryl group", "optionally substituted heteroaryl group", "optionally substituted heteroarylalkyl" and " Optionally substituted aralkyl group, optionally substituted amino group, optionally substituted nitrogen-containing saturated heterocyclic group, optionally substituted heteroaryl group (pyrrolyl, imidazole , Pyrazole, etc.)], "optionally substituted aryloyl group" and "optionally substituted nitrogen-containing heteroarylcarbonyl group". ]

Process :! ~ 3

Compound (303) can be produced from compound (214) by a method similar to the production method described in a literature (eg, J. Heterocyclic Cem. 36, 1119 (1999)).

Process 4

Compound (304) can be produced from compound (303) by a method similar to Step 6 described in Production Method 32.

Process 5

Compound (305) can be produced from compound (304) by a method similar to the production method described in a literature (eg, Co Immediate Rehensive Organic Transformation, RC Lalock, VCH publisher Inc., (1989)). .

4) Process 6

Compound (306) can be produced from compound (305) by a method similar to Step 2 described in Production Method 44.

Process 7 Step 1 described in production method 45, step 1 described in production method 46, step 1 described in production method 47, step 1 described in production method 48, step 1 described in production method 49, step 1 described in production method 50 and Compound (307) can be produced from compound (306) by a method similar to Step 1 described in Production Method 51.

Process 8

Compound (308) can be produced from compound (307) in the same manner as in Step 6 of Production Method 32.

7) Process 9

Compound (309) can be produced from compound (308) by a method similar to Step 15 described in Production Method 32.

8) Process 10

Compound (311) can be produced from compound (308) by a method similar to that described in the literature (eg, Co Immediate Rehensive Organic Transformation, RC Laroch, VCH publisher Inc., (1989)). .

9) Process 11

Compound (312) can be produced from compound (311) by a method similar to step 15 described in production method 32.

10) Process 12

Compound (314) can be produced from compound (308) by a method similar to step 5 described in Production method 19.

11) Process 13

Compound (315) can be produced from compound (314) by a method similar to step 15 described in production method 32.

12) Process 14 ~ 15

Compound (318) can be produced from compound (308) by a method similar to Steps 2 and 3 described in Production Method 23.

13) Process 16

Compound (319) can be produced from compound (318) by a method similar to step 15 described in production method 32. In each of the above production steps, a salt thereof can also be used as a raw material compound. If the starting compound for each reaction has a group active in the reaction, such as a hydroxyl group, an amino group, or a propyloxyl group, these groups other than the site to be reacted may be appropriately protected as necessary. The desired compound can be obtained by protecting with a group and removing the protecting group after each reaction or after performing some reactions. As a protecting group for protecting a hydroxyl group, an amino group or a propyloxyl group, an ordinary protecting group used in the field of organic synthetic chemistry may be used, and such a protecting group may be introduced and removed according to a usual method. (For example, the method described in Protective Groups in Organizing Synthes is, co-authored by TW Greene and PGM Wuts, 2nd edition, Wiohn Wiley & Sons, Inc. (1991)).

For example, as a protecting group for a hydroxyl group, a tert-butyldimethylsilyl group, a methoxymethyl group or a tetrahydropyranyl group may be mentioned, and as a protecting group for an amino group, a tert-butyloxycarbonyl group or a benzyloxycarbonyl group may be used. And the like. Such a hydroxyl-protecting group can be removed by a reaction in a solvent such as aqueous methanol, aqueous ethanol or aqueous tetrahydrofuran in the presence of a base, an acid such as sulfuric acid or acetic acid. Also, the tert-butyldimethylsilyl group can be bound in a solvent such as tetrahydrofuran, for example, in the presence of tetrabutylammonium fluoride. For the removal of the protecting group for the amino group, in the case of the tert-butyloxycarbonyl group, for example, the reaction is to be carried out in the presence of an acid such as hydrochloric acid or trifluoroacetic acid in a solvent such as aqueous tetrahydrofuran, dichloromethane, chloroform, or aqueous methanol. In the case of a benzyloxycarbonyl group, for example, the reaction can be carried out in the presence of an acid such as hydrobromic acid in a solvent such as acetic acid.

Examples of the form of protection in the case of protecting the carbonyl group include tert-butyl ester, orthoester and acid amide. In the case of tert-butyl ester, such a protective group is removed by reacting in a solvent containing water, for example, in the presence of hydrochloric acid. It is carried out by treating with an acid in a solvent such as hydrofuran or water-containing 1,2-dimethoxyethane, and then treating with an alkali such as sodium hydroxide. In the case of an acid amide, for example, hydrochloric acid or sulfuric acid Water, hydrated methanol, Alternatively, the reaction can be carried out in a solvent such as aqueous tetrahydrofuran. The compounds represented by the formula (I) include those having an optically active center, and therefore, they are obtained as a racemic form or as an optically active form when an optically active starting material is used. be able to. If necessary, the racemate obtained can be physically or chemically resolved into the respective enantiomers by known methods. Preferably, a diastereomer is formed from a racemate by a reaction using an optically active resolving agent. Different diastereomers can be separated by known methods such as fractional crystallization. The compound represented by the formula (I) or a prodrug thereof can be converted to a salt by mixing with a pharmaceutically acceptable acid in a solvent such as water, methanol, ethanol, or acetone. Pharmaceutically acceptable acids include, for example, inorganic acids such as hydrochloric, hydrobromic, sulfate, phosphoric or nitric acid, or acetic, propionic, oxalic, succinic, lactic, malic, tartaric, cunic acid And organic acids such as maleic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid and ascorbic acid. The compound of the present invention is expected to be applied to the treatment of various diseases by its inhibitory effect on DPP-IV. The compound of the present invention suppresses postprandial hyperglycemia in a pre-diabetic state, treats non-insulin-dependent diabetes, treats autoimmune diseases such as arthritis and rheumatoid arthritis, treats intestinal mucosal disease, promotes growth, improves It is useful for suppressing rejection, treating obesity, treating eating disorders, treating HIV infection, suppressing cancer metastasis, treating benign prostatic hyperplasia, treating periodontitis, and treating osteoporosis. The compounds of the present invention, when used in therapy, may be administered orally or parenterally (e.g., intravenously, subcutaneously, or intramuscularly, topically, rectally, transdermally, or transdermally) as a pharmaceutical composition. Nasal) can be administered. Compositions for oral administration include, for example, tablets, capsules, pills, granules, powders, solutions or suspensions, and the like. Compositions for parenteral administration include, for example, aqueous injection solutions or oily agents, ointments, creams, lotions, aerosols, suppositories, patches and the like. These formulations are prepared using conventionally known techniques, and can contain nontoxic and inert carriers or excipients usually used in the field of formulation.

The dose varies depending on the individual compound and on the disease, age, body weight, sex, symptoms, administration route, etc. of the patient, but is usually 0.1 to 1000 mg of the compound of the present invention for an adult (body weight 50 kg). Per day, preferably 1 to 300 mg / day, once or twice or three times a day. It can also be administered once every few days to several weeks.

Further, the compound of the present invention can be used in combination with other therapeutic agents for diabetes. Example

Hereinafter, the present invention will be described more specifically with reference examples, examples, and test examples, but the present invention is not limited to these examples. The compound names shown in the following Reference Examples and Examples do not always follow the IUPAC nomenclature.

Example 1

8-[(3R) _ 3-Aminopiperidin-1-yl] _ 7- (2-Bromobenzyl) -1-methyl-2-trifluoromethyl-1,7-dihydro-6H-purine- 6-ON

8-Bromo-7- (2-bromobenzyl) -1-methyl-2_trifluoromethyl-1,7-dihydro-6H-purine-6-one (36 mg), triethylamine (22 (ih), (R A solution of) -tert_3-butylbiperidine-3-ylcarbamate (158 mg) in ethanol (6 mL) was heated and stirred in a sealed tube at 100 ° C for 12 hours, cooled to 25, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate = 5 / ί to 2/1) to obtain the product (42 mg). To 2 mL) was added a 4N hydrochloric acid / 1,4-dioxane solution (20 mL), and the mixture was stirred at 25 ° C for 2.5 hours. The solvent was removed by concentration under reduced pressure, saturated aqueous sodium hydrogen carbonate (50 mL) was poured, and the mixture was extracted with chloroform (30 mL X2), followed by ethyl acetate (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative thin-layer chromatography (silica gel, chloroform / methanol = 10/1) to give the title compound (25 mg) as a white solid. Obtained as a colored solid.

_{Ή NMR (300 MHz, CDC1 3} ) ά ρηι 7.62 (d, J = 7.9 Hz, 1H), 7.26-7.15 (m, 2H), 6.77 (d, J = 7.5 Hz, 1H), 5.53 (s, 2H) , 3.68 (s, 3H), 3.57-3.54 (m, 1H), 3.39-3.34 On, 1H), 3.05-2.95 (m, 2H), 2.85-2.78 (m, 1H), 1.97-1.94 (m, 1H) ), 1.72-1.58 (m, 2H), 1.37-1.22 (m, 1H).

MS (ESI +) 485 (M ++ 1, 100%).

8 _ [(3R) _3-Aminopiperidin-1-yl] 7- (2-cyanobenzylmethyl-2-trifluoromethyl-1,7-dihydropent-6H-purine-6-one

H ₂

Synthesis was carried out in the same manner as in Example 1 using the compound of Reference Example 3 as a starting material, to obtain the title product (21 mg) as a white solid.

_{Ή NMR (300 MHz, CDC1 3} ) δ ρπι 7.73 (d, J = 6.8 Hz, 1H), 7.57-7.53 (m, 1H), 7.45-7.40 (t, J = 7.7 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 5.72 (s, 2H), 3.66 (s, 3H), 3.50-3.47 (m, 1H), 3.35-3.31 (m, 1H), 3.05-2.96 (m , 2H), 2.80- 2.73 (m, 1H), 1.95-1.91 (m, 1H), 1.75-1.61 (m, 2H), 1.28-1.25 (m, 1H) .MS (ESI +) 432 (MHl, 100% Example 3

8-[(3 R) -3-aminopiperidin-1-yl] -7- (2-bromobenzyl) -1_ (2-oxo-2-phenylethylyl) -2-methyl-1,7-dihydro -6 H-pudding-6-on

Synthesis was carried out in the same manner as in Example 1 using the compound of Reference Example 2 as a starting material, to obtain the title product (55 mg) as a white solid.

_{Ή NMR (300 MHz, CDC1 3} ) 5 pm 8.01 (d, J = 7.5 Hz, 1H), 7.66-7.48 (m, 4H), 7.27-7.21 On, 2H), 7.15-7.10 (m, 1H), 6.82 (d, J = 7.3 Hz, 1H), 5.54 (s, 2H), 5.46 (s, 2H), 3.49-3.44 (m, 1H), 3.38-3.33 (m, 1H), 2.99-2.95 (m, 2H ), 2.75-2.68 (m, 1H), 2.49 (s, 3H), 1.94-1.88 (m, 1H), 1.68-1.63 (m, 2H), 1.35-1.25 (m, 1H).

MS (ESI +) 535 (M ⁺ +1, 100%). Example 4

8-[(3R) _ 3-aminopiperidin-1-ylyl] -7- (2-bromobenzyl)-, 2-dimethyl-1,7-dihydro-6H-purine-6-one

8-bromo-7- (2-bromobenzyl) -1,2-dimethyl-1,7-dihydro-6H-purin-6-one (88 mg), (R) _tert-3-butylpiperidine-3 A solution of -ylcarpamate (215 mg) in ethanol (8 mL) was heated and stirred at 100 ° C in a sealed tube for 25 hours. The reaction solution was cooled to 25 ° C and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform / methanol = 200/1 to 50/1) to obtain the product (120 mg). Next, a 4N solution of 1,4-dioxane hydrochloride (20 mL) was added to a 4-dioxane solution (2 mL) of the product, and the mixture was stirred at 25 ° C for 3 hours. The reaction solvent was removed by concentration under reduced pressure, saturated aqueous sodium hydrogen carbonate (5 O mL) was poured, and the mixture was extracted with chloroform (50 mL × 2) and ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (94 mg) as a white solid. _{Ή NMR (300 MHz, CDC1 3} ) δ ρηι 7.61-7.58 (m, 1H), 7.24-7.12 (m, 2H), 6.77 (d, J = 7.3 Hz, 1H), 5.49 (s, 2H), 3.54 ( s 3H), 3.46-3.43 On, 1H), 3.35-3.30 (m, 1H), 2.97-2.91 (m, 2H), 2.73-2.66 (m, 1H), 2.60 (s 3H), 1.91-1.83 (m, 1H), 1.69-1.57 (m, 2H), 1.30-1.22 (m 1H).

MS (ESI +) 431 (MHl, 88%). Example 5

8 _ [(3R) -3-aminopiperidin-1-yl] -7- (2-bromobenzyl) -1-methyl-1,7-dihydro-6H-purine-6-one

Synthesis was carried out in the same manner as in Example 1 using the compound of Reference Example 8 as a starting material, to obtain the title product (86 mg) as a white solid.

'Η NMR (400 MHz, CDC1 3) <5 pm 8.00 (s 1H), 7.60 (dd J = 1.2, 7.6 Hz, 1H), 7.25-7.13 (m, 2H), 6.76 (dd, J = 1.3, 7.6 Hz, 1H), 5.54 (d J = 17.0 Hz, 1H), 5.50 (d J = 17.0 Hz, 1H), 3.55 (s, 3H), 3.6-3.2 (m, 1H), 3.35-3.3 0 (m, 1H), 2.98-2.90 (ι, 2H), 2.74-2.68 (m 1H), 1.95-1.85 (m, 1H), 1.74-1.53 (m 2H), 1.28-1.19 (m, 1H ).

MS (ESI +) 417 (MHl, 82%). Example 6

8-[(3R) -3-aminobiperidin-1-yl] -7- (2_cyclobenzyl) -1-methyl-1

, 7-Dihydro-6H-purine-6-one

Synthesis was carried out in the same manner as in Example 1 using the compound of Reference Example 7 as a starting material. The title compound (87 mg) was obtained as a white solid.

_{Ή NMR (400 MHz, CDC1 3} ) δ ρπι 8.02 (s, 1H), 7.40 (dd, J = 1.4, 7.8 Hz, 1H), 7.25-7.16 (m, 2H), 6.79 (dd, J = 1.3, 7.5 Hz, 1H), 5.58 (d, J = 17.0 Hz,

1H), 5.52 (d, J = 17.0 Hz, 1H), 3.55 (s, 3H), 3.52-3.48 (m, 1H), 3.33-3.28 (m, 1H), 3.05-2.95 (m, 2H), 2.82-2.77 (m, 1H), 1.98-1.90 (m, 1H), 1.85-1.57 (m, 2H) 1.37-1.26 (m, 1H).

MS (ESI +) 373 (MHl, 100%).

8-[(3R) -3-Aminopiperidin-1-yl] -7- (2 bromobenzyl) 2-oxo _2 2-phenylenyl) -1,7-dihydro-6H-purine -6-on

Using the compound of Reference Example 9 as a starting material, synthesis was carried out in the same manner as in Example 1, to obtain the title product (90 mg) as a white solid.

Ή NMR '(400 MHz, CDC1 3) δρρηι 8.00-7.98 (m, 2Η), 7.93 (s, 1H), 7.63-7.56 (m, 2H), 7.51-7.48 (m, 2H), 7.24-7.22 On, 1H), 7.15-7.12 (m, 1H), 6.82-6.80 (m, 1H), 5.52 (d, J = 18.0 Hz, 1H), 5.48 (d, J = 18.0 Hz, 1H), 5.40 (s, 2 H), 3.48-3.33 (m, 2H), 2.98-2.93 (m, 2H), 2.75-2.69 (m, 1H) 1.92-1.89 (m, 1H), 1.70-1.60 (m, 2H), 1.26-1.23 (m, 1H).

MS (ESI +) 521 (MHl, 88%). Example 8

8-{(cis-2_aminocyclohexyl) amino} -7- (2-bromobenzyl) -1_ (2-oxo-2-phenylethyl) -1,7-dihydro-6H-purin-6-one

8-bromo-7- (2-bromobenzyl) -1- (2-oxo-2-phenylphenyl) -1,7-dihydro-6H-purin-6-one (75 mg), diisopropylethylamine (50 xL) and cis-l, 2-diaminocyclohexane (86 L) in ethanol (2 mL) were heated and stirred at 100 ° C in a sealed tube for 12 hours. After the reaction solution was cooled to 25 ° C., the solvent was concentrated under reduced pressure, and chloroform was added thereto. Next, the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (silica gel, chloroform / methanol = 5/1) to give the title compound. (6 mg) was obtained as a pale yellow solid.

_{Ή NMR (400 MHz, CDC1 3} ) δ ριη 7.98-7.96 (m, 2H), 7.86 (s, 1H), 7.62-7.60 (m, 1H), 7.52-7.43 (m, 3H), 7.26-7.21 (m , 1H), 7.11-7.05 (m, 2H), 5.83 (d, J = 17.0 Hz, 1H), 5.61 (d, J = 17.0 Hz, 1H), 5.40 (s, 2H), 4.60-4.53 (m, 1H), 3.72-3.69 (m, 1H), 3.13-3.08 (m, 1H), 1.98-1.24 (m, 7H).

MS (ESI +) 535 (M ++ 1, 80%).

8-{[cis-2-a = _7_ (2-bromobenzyl) -1-methyl-1,7-dihydro-6H-purine-6-one

8-Bromo-7- (2-bromobenzyl) -1-methyl-1,7, -dihydro-6H-purin-6-one (70 mg), diisopropylethylamine (46 L), and cis-1 160 mL of 2,2-diaminocyclohexane (0.2 mL) in N_methylpyrrolidinone (3 mL) The mixture was heated and stirred in a sealed tube at 6 ° C for 6 hours. After the reaction solution was cooled to 25 ° C., the solvent was concentrated under reduced pressure, and chloroform was added, and the organic layer was washed with water. Next, the organic layer is dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the obtained residue is subjected to silica gel column chromatography (silica gel, chloroform-form / methanol = 10/1 to chloroform-form / methanol / triethylamine = 10/1). 10/1 / 0.1) to give the title compound (71 mg) as a pale yellow solid.

_{Ή NMR (400 MHz, CDC1 3} ) (5 pm 7.92 (s, 1H), 7.59-7.57 (m, 1H), 7.24-7.21 (m, 1H), 7.19-7.16 (i, 1H), 6.97-6.94 ( m, 1H), 5.67 (d, J = 16.0 Hz, 1H), 5.60 (d, J = 16.0 Hz, 1H), 5.23-5.17 (m, 1H), 4.13-4.11 (m, 1H), 3.56 (s, 3H), 3.3-3.1 (m, 1H), 1.76-1.26 (m, 7H).

MS (ESI +) 431 (M ++ 1, 100%). Example 10

8-[(3 R)-3 -Aminopiperidin-1-yl] _ 7-(2 -Methyl-5 -fluorobenzylmethyl-1,7-dihydro-6H -purine-6-one trifluoroacetate

Using the compound of Reference Example 14 as a starting material, synthesis was carried out in the same manner as in Reference Example 2, and using the product obtained here as a starting material, synthesis was carried out in the same manner as in Example 1. The reaction mixture was purified by liquid chromatography (HPLC) to give the title compound (21 mg) as a white solid.

_{Ή NMR (400 MHz, CDC1 3} ) άρρπι 7.99 (s, 1H), 7.16-7.13 On, 1H), 6.88-6.84 (m, 1H), 6.40-6.37 (m, 1H), 5.42 (d, J = 17.0 Hz, 1H), 5.37 (d, J-17.0 Hz, 1H), 3.53 (s, 3H), 3.48-3.44 (m, 1H), 3.34-3.30 (m, 1H), 2.98-2.93 (m, 2H ), 2.78-2.73 (in, 1H), 2.34 (s, 3H), 1.92-1.87 (m, 1H), 1.71-1.59 (m, 2H),

1.26-1.23 (m, 1H).

MS (ESH) 371 (MHl, 100%). Example 11

2-Amino-8- (3-aminobiperidin-1-yl) -1-7-benzyl-1,7-dihydro-6H-purin-6-one and 2-ethoxy-8- (3-aminopiperidine-1-y -) 7-benzyl-1,7-dihydro-6H-purine-6-one

Under reflux with heating, a solution of 2-amino-8-bromo-7-benzyl-17-dihydro-6H-purin-6-one (500 mg) and concentrated sulfuric acid (0.4 mL) in ethanol (10 mL) was added to the solution. Sodium nitrate (323 mg) was added, and the mixture was stirred for 2 hours. Water (50 mL) and saturated aqueous sodium hydrogen carbonate (20 mL) were added, and the precipitated crystals were separated by filtration and dried under reduced pressure. Next, the obtained solid was suspended in N-methylpyrrolidinone (10 mL), and 3-aminobiperidine dihydrochloride (500 mg) and diisopropylethylamine (1.6 mL) were added. The mixture was stirred for 30 hours in a sealed tube. After cooling the reaction solution to 25 ° C, 2N-hydrochloric acid aqueous solution (30 mL) was added, and the mixture was extracted with ethyl acetate (5 O mL). The aqueous layer was made alkaline by adding potassium carbonate, and the precipitated solid was filtered. To the filtrate was added chloroform (30 mL), the precipitated crystals were separated by filtration, and the crystals were washed with methanol (10 mL) and dried. Thereby, 2-amino-8- (3-aminopiperidin-1_yl) -7-benzyl-17-dihydro-6H-purine-6-one (48 mg) was obtained. The above-mentioned form-form layer is dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue is subjected to column chromatography (silica gel, form-form / methanol = 10/1 to form-form / methanol / triethylamine = 10/1 / 0.1) to give 2-ethoxy-8- (3-aminopiperidin-1-yl) -7-benzyl-1,7-dihydro-6H-purine-6-one (10 mg).

2-Amino-8- (3-aminopiperidin-1-yl) -7-benzyl-1,7-dihydro-6H-purine-6-one:

Ή NMR (400 MHz, DMSO- d ₆ ) <5 pm 7.32-7.14 (m, 5H), 6.05 (s, 2H), 5.30 (d, J = 15.9 Hz, 1H) 5.6 (d, J = 15.9 Hz, 1H), 3.43-3.17 (m, 2H), 2.80-2.6 7 (m, 2H), 2.57-2.46 (m, 1H), 1.84-1.76 (m, 1H), 1.72-1.60 (m, 1H) , 1.59-1 .45 (m, 1H), 1.20-1.07 (in, 1H).

MS (ESI +) 340 (MHl, 45%).

2-Ethoxy-8- (3-aminopiperidin-1-yl) -7-benzyl-1,7-dihydropen-6H-purin-6-one:

_{Ή NMR (400 MHz, CD 3} 0D) άρριη 7.34-7.17 (m, 5H), 5.47 (d, J = 15.6Hz, 1H), 5.42 (d, J = 15.6 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 3.58-3.52 (m, 1H), 3.28-3.15 (m, 2H), 2.98-2.88 (ι, 2H), 2.06-1.98 (m, 1H), 1.83-1.73 (m, 1H) , 1.70-1.58 (m, 1H), 1.55-1.43 (m, 1H), 1.40 (t, J = 7.1 Hz, 3H). MS (ESI +) 369 (MHl, 100%).

2-dimethylamino-8-[(3R) -1-3-aminopiperidin-1-yl] -7_benzyl-1-methyl-1, 7-dihydro-6H-purine-6-one

1-methyl-2-dimethylamino-8-bromo-7-benzyl-1,7-dihydro-6H-purin-6-one (55 mg), (R) -3-aminopiperidine dihydrochloride (53 mg) A suspension of diisopropylpyrethylamine (0.26 mL) in ethanol (5 mL) was heated and stirred at 110 ° C in a sealed tube for 100 hours. The reaction solution was cooled to 25 ° C and concentrated under reduced pressure. To the residue was added saturated saline and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (61 mg).

_{Ή NMR (400 MHz, CDC1 3} ) δ ριη 7.40-7.18 (m, 5H), 5.46 (d, J - 15.7 Hz, 1H), 5.39 (d, J = 15.7 Hz, 1H), 3.52 (s, 3H) , 3.56-3.46 (m, 1H), 3.32-3.25 (m, 1H), 2.83 (s, 6H), 3.12-2.78 (m, 3H), 2.01-1.92 (m, 1H), 1.80-1. 70 On, 1H), 1.69-1.57 (m, 1H), 1.43-1.33 (m, 1H).

MS (ESI +) 382 (MHl, picture) Example 13

2-dimethylamino-8-[(3R) _3-aminobiperidin-1-yl] -7- (2-cyclobenzyl) -1-methyl-1,7-dihydro-6H-purine-6-one

Synthesis was carried out in the same manner as in Example 12 using the compound of Reference Example 6 as a starting material, to obtain the title product (34 mg) as a brown oil.

lH thigh _{(400 MHz, CDC1 3) δρριιι} 7.42-7.37 (m, 1H), 7.23-7.13 (m, 2H), 6.8 6-6.81 (m, 1H), 5.52 (d, J = 17.1 Hz, 1H), 5.48 (d, J = 17.1 Hz, 1H), 3.51 (s, 3H), 3.45-3.39 (m, 1H), 3.34-3.26 (m, 1H), 2.97-2.87 (m, 2H), 2.86 (s, 6H), 2.72-2.65 (m, 1H), 1.93-1.84 On, 1H), 1.73-1.53 (m, 2H), 1.28-1.17 (m, 1H).

MS (ESI +) 416 (MHl, 100%). Example 14

2-Amino-8 — [(3R) -3-aminopiperidin-1-yl] -1-7- (2 _cloral benzyl) -1, 7-dihydro-6H-purine-6-one

Reference Example 11 Using the compound of 1 as a starting material, synthesis was carried out in the same manner as in Example 12.

The title compound (83 mg) was obtained as a brown solid.

Ή NMR (400 MHz, DMS0-d ₆ ) <5 pm 7.50-7.45 (m, 1H), 7.36-7.23 (m, 2H), 6.72-6.67 (m, 1H) 6.10 (s, 2H), 5.32 (s, 2H), 3.40-3.25 (m, 1H), 3.18-3.10 (m, 1H), 2.77-2.60 (m, 2H), 2.56-2.47 (m, 1H), 1.79-1.70 (m, 1H) , 1.63-1.53 (m, 1H), 1.48-1.34 (m, 1H), 1.15-1.03 (1, 1H).

MS (ESI +) 37 (MHl, 100%). Example 15

8-[(3 R)-3-aminobiperidin-1-yl]-7-(2-cyclobenzyl) -methyl-2-trifluoromethyl-1,7-dihydro-6H-purine-6- On

Synthesis was carried out in the same manner as in Example 1 using the compound of Reference Example 25 as a starting material, to obtain the title object product (53 mg) as a white solid.

_{Ή NR (300 MHz, CDC1 3} ) δρριιι 7.45-7.42 (m, 1H), 7.26-7.18 (m, 2H), 6.80 (d, J = 7.5 Hz, 1H), 5.57 (s, 2H), 3.68 (d , J-1.3 Hz, 3H), 3.51-3.48 (i, 1H), 3.41-3.37 (m, 1H), 3.05-2.91 (m, 2H), 2.77-2.70 (m, 1H), 1.90-1.88 (m , 1H), 1.71-1.58 (m, 2H), 1.28-1.25 (m, 1H).

MS (ESI +) 441 (MHl, 100%). Reference Example 1

8-bromo-7- (2-bromobenzyl)-, 2-dimethylyl-1,7-dihydro-6-purine-6-year

Under 10 CTC, 2 ', 3', 5'-tri-0- (acetoxy) -2-methyl-8-bromoinosine (393 nig), 85% phosphoric acid aqueous solution (160 L), and acetic anhydride (4 mL) The mixture was stirred for 1.5 hours. Thereafter, the mixture was cooled to 25 ° C, and the precipitated solid was separated by filtration. The solid was washed with a pore-form and dried under reduced pressure to obtain a de-reported product (0.427 g). The spectrum of this compound is as follows. Ή NMR (300 MHz, DMS0-d ₆ ) δ ρι 12.30 (bs, 1H), 2.34 (s 3H).

MS (ESI +) 229 (M + 100).

Subsequently, the dereported form (0.701 g) was dissolved in N, N-dimethylformamide (20 mL) at 25 ° C, and sodium bicarbonate (390 mg) was added to the resulting solution, followed by stirring overnight. . In addition, potassium carbonate (270 mg) and 2-bromobenzyl bromide

(390 mg) was added and the mixture was stirred for 7 hours. Toluene (20 mL) was added to the reaction solution, and the operation of concentration under reduced pressure was repeated four times. To the residue was added saturated aqueous sodium hydrogen carbonate (50 mL), and ethyl acetate was added.

(100 mL) twice. The organic layer was concentrated under reduced pressure, and the precipitated solid was filtered with toluene, washed, and sufficiently dried to obtain a crude product (250 mg). Next, to a solution of the crude product (250 mg) in NN-dimethylformamide (10 mL) was added sodium hydride (30 mg, 60% oil) under 25, and the mixture was stirred for 15 minutes. 195 uD was added, and the mixture was stirred for 4 hours at 25 ° C. A saturated sodium bicarbonate solution (10 mL) was poured into the reaction solution, toluene (20 mL) was added, and the operation of concentration under reduced pressure was repeated twice. Water (40 mL) was added, and the mixture was extracted twice with ethyl acetate (80 mL) .The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel, ethyl acetate / ethyl acetate). Hexane = 1/2 3/1) to give the title compound (88 mg).

_{Ή NMR (300 MHz, CDC1 3} ) δρρπι 7.63-7.60 (m, 1H), 7.20-7.13 (m, 2H), 6.43-6 .40 (m, 1H) 5.74 (s, 2H), 3.57 (s, 3H ), 2.65 (s, 3H).

MS (ESI +) 411 (M ++ 1 57%). Reference Example 2

8-bromo-7 (2-bromobenzyl) -1- (2-oxo-2-phenylethyl) -2-methyl-1,7-dihydro-6H-purine-6-one

At 100 ° C, 2 ', 3', 5'-tri-0- (acetoxy) -2-methyl-8-bromoinosine (1.052 g), 85% phosphoric acid aqueous solution (440 h), and acetic anhydride (10 mL) ) Was stirred for 1.5 hours. Thereafter, the mixture was cooled to 25 ° C, and the precipitated solid was separated by filtration. The solid was washed with chloroform and dried under reduced pressure to obtain a de-liposome (1.157 g).

Subsequently, this dereported product (1.157 g) was dissolved in N, N-dimethylformamide (30 mL) at 25 ° C, and potassium carbonate (896 mg) and 2-bromobenzylbutamide were added to the resulting solution. (670 mg) was added and stirred overnight. Toluene (20 mL) was added to the reaction solution, and the procedure of concentration under reduced pressure was repeated four times. To the residue was added saturated aqueous sodium hydrogen carbonate (50 mL), and the mixture was extracted twice with ethyl acetate (100 mL). The organic layer was concentrated under reduced pressure, and the precipitated solid was filtered with toluene, washed, and sufficiently dried to obtain a crude product (200 mg). Then, at 25 ° C, a solution of the crude product (200 mg) in N, N-dimethylformamide (10 mL) was added with sodium hydride (24 mg, 60% oil), and the mixture was stirred for 30 minutes. Poly-bromoacetophenone (110 mg) was added, and the mixture was stirred at 25 ° C overnight. A saturated aqueous solution of sodium bicarbonate (10 mL) was poured into the reaction solution, and the mixture was concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate (50 mL) was added to the residue, and the mixture was extracted twice with ethyl acetate (80 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate / hexane = 1/5 to 3/1) to give the title compound (61 mg). ).

_{Ή NMR (300 MHz, CDC1 3} ) δ ριιι 8.03-8.00 (m, 2H), 7.68-7.49 (m, 4H), 7.22- 7.12 (m, 2H), 6.48-6.45 (m, 1H), 5.70 (s , 2H), 5.56 (s, 2H), 2.52 (s, 3H). MS (ESI +) 517 (MHl, 100%).

8-Bromo-7- (2-cyanobenzyl) -1-methyl-2-trifluoromethyl-1,7-dihydro-6H-purine-6-one

2 ', 3', 5'-tri_0- [ter-butyl (dimethyl) silyl] -1-methyl-2_trifluoromethyl-8-bromoinosine (244 mg) as starting material By the method, a dellipid form (268 mg) was synthesized. The spectrum data of this compound are as follows.

_{Ή NMR (300 MHz, CDC1 3} ) (5ppm 3.75 (d, J = 1.3 Hz, 3H).

MS (ESI +) 297 (MHl, 81%).

Subsequently, this dereported product (268 mg) was dissolved in N, N-dimethylformamide (10 mL) at 25 ° C, and potassium carbonate (437 mg) and 2-bromobenzyl bromide were dissolved.

(248 mg) was added, the temperature was raised to 80 ° C, and the mixture was stirred for 4 hours. The operation of adding toluene (20 mL) to the reaction solution and concentrating under reduced pressure was repeated three times. To the residue was added saturated aqueous sodium hydrogen carbonate (50 mL), and the mixture was extracted twice with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate / hexane = 1/5 to 1/1) to give the title compound (58%). mg).

[H NMR (300 MHz, CDC1 3) 5ppm 7.77-7.40 (m, 3H), 6.88 (d, J = 7.9 Hz, 1H),

5.94 (s, 2H), 3.75 (s, 3H).

MS (ESI +) 412 (MHl, 99%). Reference Example 4

8-bromo-7- (2-bromobenzyl) -1-methyl-2-trifluoromethyl-1,7-dihydro-6H-purine-6-one

Using the compound of Reference Example 23 as a starting material, synthesis was carried out in the same manner as in Reference Example 2, to obtain the title compound (36 mg) as a white solid.

_{Ή NMR (300 MHz, CDC1 3} ) δ ρηι 7.65-7.62 (m, 1H), 7.24-7.14 (m, 2H), 6.45-6 .41 (m, 1H), 5.78 (s, 2H), 3.72 (d , J = 1.3 Hz, 3H).

MS (ESI +) 465 (MHl, 46%). Reference Example 5

Trimethyl-2-dimethylamino-8-bromo-7-benzyl-1, 7-dihydro-6H-purine

At room temperature, a suspension of 2-amino-3-bromo-7-benzyl-1,7-dihydro-6H-purin-6-one (300 mg) in N, N-dimethylformamide (3 mL) was treated with hydrogen. Sodium bromide (150 mg, 60% oil) was added and stirred for 1 hour. After adding methyl iodide (0.3 mL) and stirring at the same temperature for 5 hours, ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate = 1/1 to ethyl acetate) to obtain the desired product (55 mg).

'Η NMR (400 MHz, CDC1 3) <5ppm 7.38-7.25 (m, 5H), 5.58 (s, 2H), 3.55 (s, 3H

), 2.86 (s, 6H).

MS (ESH) 362 (MHl, 92%). Reference Example 6

Trimethyl-2-dimethylamino-8-bromo-7- (2-cyclobenzyl) -1,7-dihydro 6 H-purine 6-year-old

At room temperature, 2-amino-2-bromo-7- (2-chlorobenzyl) -1,7-dihydro-6H-purin-6-one (300 mg) in N, N-dimethylformamide (2 mL) was suspended. Sodium hydride (118 mg, 60% oily) was added to the suspension, followed by stirring for 1 hour. Methyl iodide

(0.26 mL), and the mixture was stirred at the same temperature for 5 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with water and saturated saline, dried over anhydrous sodium sulfate, and filtered. Then, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate = 1/1) to obtain the desired product (67 mg).

_{Ή NMR (400 MHz, CDC1 3} ) δρρπι 7.43-7.40 (m, 1H), 7.25-7.11 (m, 2H), 6.54-6 .52 (m, 1H), 5.73 (s, 2H), 3.52 (s, 3H), 2.89 (s, 6H).

MS (ESI +) 398 (MHl, respectable). Reference Example 7

8 -Bromo-7- (2-chloro benzyl) '' methylile-1,7-dihydro-6H-purine 6-one

The compound of Reference Example 14 was used as a starting material, and synthesis was carried out in the same manner as in Reference Example 2 using 2-cyclomouth benzylbutemide to obtain the title compound (130 mg) as a white solid.

_{Ή NMR (400 MHz, CDC1 3} ) δ ρι 8.07 (s, 1H), 7.43-7.42 (m, 1H), 7. 6-7.22 (m, 1H), 7.16-7.13 (m, 1H), 6.51-6.49 (m, 1H), 5.79 (s, 2H), 3.59 (s, 3H). MS (ESI +) 352 (M ⁺ , 66%). Reference Example 8

8-bromo-7- (2-bromobenzyl) -1-methyl-1,7-dihydro-6H-purine-6one

Using the compound of Reference Example 14 as a starting material, synthesis was carried out in the same manner as in Reference Example 2, to obtain the title compound (164 mg) as a white solid.

Ή NMR (400 MHz, CDCL) δρριη 8.07 (s, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.21- 7.14 (m, 2H), 6.43 (d, J = 7.3 Hz, 1H), 5.63 (s, 2H), 3.59 (s, 3H)

MS (ESI +) 396 (MH1, 51¾). Reference example 9

8-Bromo-7- (2-bromobenzyl) -1- (2-oxo-2-phenylethyl)-, 7-dihydro-6H-purine-6-one

Using the compound of Reference Example 15 as a starting material, synthesis was carried out in the same manner as in Reference Example 2, to obtain the title compound (215 mg) as a white solid.

_{l NMR (400 MHz, CDC1 3} ) δ ριη 8.02-7.99 (m, 2Η), 7.98 (s, 1H), 7.67-7.64 (m, 1H), 7.61-7.59 (m, 1H), 7.54-7.50 (m , 2H), 7.22-7.20 (m, 1H), 7.20-7.15

(m, 1H), 6.49-6.47 (m, 1H), 5.74 (s, 2H), 5.43 (s, 2H).

MS (ESI +) 501 (MHl, 62%). Reference example 10

2-amino 8-bromo-7-benzyl-1,7-dihydro-6H-purin-6-one

2-Acetylamino-8-bromo-7-benzyl-1,7-dihydro-6H-purin-6-one (2.23 g) is suspended in 30% methylamine-ethanol solution (100 mL) and stirred at room temperature for 15 hours. did. About half of the solvent was distilled off, water (200 mL) was added, and the resulting crystals were separated by filtration and dried under reduced pressure to obtain the title compound (1.88 g).

MS (ESI +) 320 (MHl, 100%). Reference Example 11 2-Amino-8-bromo-7 · (2-cyclobenzyl) -1,7-dihydro-6Η-purine-6-one

Synthesis was carried out in the same manner as in Reference Example 10 using the compound of Reference Example 13 as a starting material, to obtain the title product (1.16 g) as a white solid.

MS (ESI +) 354 (M ++ 1, 75%).

.2

2-acetylamino-8-bromo-7-benzyl-1,7-dihydro-6H-purine-6-one

A mixture of 2 ', 3', 5'-tri-0-acetyl-8-bromoguanosine (36.20 g), 85% aqueous phosphoric acid (1.5 mL), and acetic anhydride (400 mL) was added at 100 ° C. Stir for 1 hour. Thereafter, the temperature was cooled to 25 ° C., and the precipitated crystals were separated by filtration. After the crystals were washed with a black hole form, they were dried under reduced pressure to obtain a product (18.23 g). The spectrum of this product is as follows.

MS (ESI +) 272 (MHl, 100%).

Subsequently, benzyl bromide (22.9 g) was added to a suspension of this product (18.23 g) in N, N-dimethylformamide (500 mL). The reaction solution was stirred at 100 ° C for 10 hours. After the reaction solution was cooled to 25 ° C, water (500 mL) and chloroform (500 mL) were added. The resulting insolubles were filtered off and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, chloroform-form / methanol = 50/1 to 20/1, chroma-form / acetic acid). Ethyl = 1/1) to give the title product (3.31 g).

Ή NMR (400 MHz, DMS0-d ₆ ) δ ριη 12.22 (s, 1H), 11.71 (s, 1H), 7.38-7.25 (m, 5H), 5.54 (s, 2H), 2.16 (s, 3H).

MS (ESI +) 362 (Ml, 100%). Reference Example 13

2-Acetylamino _8-bromo-7- (2-chlorobenzoyl) _1,7-dihydro-6H-purin-6-one

The synthesis was carried out in the same manner as in Reference Example 12, to obtain the title compound (1.80 g) as a white solid.

Ή NMR (400 MHz, DMS0-d ₆ ) dppm 12.20 (s, 1H), 11.74 (s, 1H), 7.57-7.53 (m, 1H), 7.38-7.25 (m, 2H), 6.61-6.57 (i, 1H), 5.62 (s, 2H), 2.17 (s, 3H). MS (ESH) 396 (M ++ 1, 65%). Reference Example 14

2 ', 3', 5'-tri_0- [ter-butyl (dimethyl) silyl] _1-methyl-8-promoinosin

Under ice-cooling, a solution of 2 ', 3', 5'-tri-0- [tert-butyl (dimethyl) silyl] -8-bromoinosine (2.0 g) in tetrahydrofuran (30 mL) was added with sodium hydride (0.13 g, 60% oily) and stirred for 30 minutes. Methyl iodide (0.70 mL) was added to the reaction solution, and the mixture was stirred at 25 ° C for 4 hours, and then water was added. Extract the form from the black mouth and saturate the organic layer After washing with brine, it was dried over anhydrous magnesium sulfate. The residue obtained after filtration and concentration under reduced pressure was purified by silica gel column chromatography (silica gel, hexane / ethyl acetate = 3/1 to 1/1) to obtain the title product (1.8 g).

_{Ή NMR (400 MHz, CDC1 3} ) (5ppm 7.89 (s, 1H), 5.95 (d, J = 6.0 Hz, 1H), 5.2 3-5.20 (m, 1H), 4.51-4.49 (m, 1H), 4.08 -4.05 (m, 1H), 3.98-3.95 (m, 1H), 3.73-3.71 (m, 1H), 3.65 (s, 3H), 0.91 (s, 9H), 0.85 (s, 9H), 0.81 (s, 9H), 0.15 (s, 3H), 0.14 (s, 3H), 0.03 (s, 3H), -0.01 (s, 3H), -0.05 (s, 3H), -0.30 ( s, 3H).

MS (ESI +) 703 (MHl, 85%). Reference Example 15

2 ', 3', 5 'tri-0- [tert-I- (2-oxo-2-phenylethyl) -8-

Sodium hydride (0.13 g, 60% oil) was added to a solution of promoinosine (2.0 g) in tetrahydrofuran (30 mL), and the mixture was stirred for 30 minutes. To the reaction solution was added -bromoacetophenone (0.61 g), and the mixture was stirred at 25 for 6 hours, and then water was added. After extraction with ethyl acetate, the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The residue obtained after filtration and concentration under reduced pressure was purified by silica gel column chromatography (silica gel, hexane / ethyl acetate 2 5/1 to 2/1) to give the title compound (2.3 g).

_{Ή NR (400 MHz, CDC1 3} ) <5 pm 8.05-8.03 (m, 2H), 7.83 (s, 1H), 7.69-7.65 (m, 1H), 7.56-7.52 (m, 2H), 5.99 (d, J = 6.0 Hz, 1H), 5.69 (d, J = 17.0 Hz, 1H), 5.36 (d, J = 17.0 Hz, 1H), 5.27-5.25 (m, 1H), 4.52-4.50 (m, 1H), 4.08-4.05 (m, 1H), 4.00-3.98 (m, 1H), 3.77-3.73 (m, 1H), 0.96 (s, 9H), 0.86 (s, 9H), 0.82 (s, 9H), 0.15 (s, 3H), 0.14 (s, 3H), 0.03 (s, 3H), 0.01 (s, 3H), -0.02 (s, 3H),- 0.25 (s, 3H).

MS (ESI +) 807 (MHl, 83%). Reference Example 16

2 ', 3', 5'-tri-0- (acetoxy) -2-methyl-8-bromoinosine

2-bromo-5-aminoimidazole-4-carboxyamide-2,3,5_tri-0-acetyl-1-i3-D-lipofuranoside (463 mg) of N, N-dimethylformamide (3 To the (mL) solution, a solution of triethyl orthoacetate (1.82 mL) in acetic acid (3 mL) was added, and the mixture was heated with stirring at 80-100 ° C for 4 hours. After cooling the reaction solution to 25 ° C, toluene (20 mL) was added, and the operation of concentrating under reduced pressure was performed four times to obtain a product [MS (ESI +) 533 (MHl, 97%)]. · Next, potassium tetra-butoxide (168 mg) was added to a solution of this product in tetrahydrofuran (10 mL), and the mixture was stirred at 25 ° C for 2 hours. After pouring water (10 mL) into the reaction solution, the solution was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution (30 mL) was added to the residue, and the mixture was extracted three times with ethyl acetate (80 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform / methanol = 200/1 to 40/1) to give the title compound (282 mg). _{Ή NMR (300 MHz, CDC1 3} ) δρρηι 13.22 (s, 1H), 6.19 (dd, J = 4.0, 5.9Hz, 1H), 6.08 (d ,, J = 3.8 Hz, 1H), 5.96 (t, J = 6.0 Hz, 1H), 4.52-4.47 (m, 1H), 4.43-4.38 (m, 1H), 4.34-4.28 (m, 1H), 2.64 (s, 3H), 2.15 (s, 3H), 2.13 (s ,

3H), 2.05 (s, 3H).

MS (ESI +) 487 (MHl, 85%). Reference Example 17 2-Promo-5-aminoimidazole-4-carboxyamide-2,3,5-tri-0-acetyl-i3-D-lipofuranoside

Under nitrogen atmosphere, at _5 ° C, 5-aminoimidazole-4-carboxyamide-2,3,3

To a solution of 5_tri-0-acetyl-1-jS-D-lipofuranoside (19.52 g) in tetrahydrofuran (100 mL), slowly add a solution of N-bromoacetamide (6.05 g) in tetrahydrofuran (100 mL), The mixture was stirred at 25 ° C for 1.5 hours. Water (100 mL) was poured, tetrahydrofuran was removed under reduced pressure, and the mixture was extracted with chloroform (100 mLX3). The organic layer is dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue is purified by column chromatography (silica gel, chloroform / methanol = 200/1 to 40/1) to give the title compound (10.39 g) Got.

_{Ή NMR (300 MHz, CDC1 3} ) δρρΕ 6.44 (bs, 1H), 5.93 (d, J - 7.1 Hz, 1H), 5.6 6-5.61 On, 1H), 5.56 (s, 2H), 5.40-5.37 (m , 1H), 5.22 (bs, 1H), 4.62 (dd,

J = 2.6, 12.1 Hz, 1H), 4.33-4.25 (m, 2H), 2.17 (s, 3H), 2.15 (s, 3H),

2.09 (s, 3H).

MS (ESI +) 463 (MHl, 86%). Reference Example 18

2 ', 3', 5'-tri-0 acetyl-8-bromoguanosine

Suspension of 2 ', 3', 5'-tri-0-acetylacetylguanosine (37.93 g) in water (1000 mL) ί On the other hand, a solution composed of bromine (5 mL) and water (500 mL) was injected at 25 ° C in a total of 10 times and stirred for 20 minutes. The resulting crystals were collected by filtration and dried under reduced pressure to obtain the desired product (36.20 g).

MS (ESI +) 488 (Hl, 100%). Reference Example 19

5-Aminoimidazole-4-carboxamide-2,3,5-tri-0-acetyl; 6-D-ribofuranoside

Under a nitrogen atmosphere, a suspension of 5-aminoimidazole-4_carboxamide / 3-D-ribofuranoside (10.30 g), acetic anhydride (14.70 g), and triethylamine (21,90 g) was heated at 50 ° C. And stirred in a sealed tube for 4 hours. After cooling the reaction solution to 25 ° C, the operation of adding toluene (100 mL) and concentrating under reduced pressure was repeated three times to obtain a crude product (19.52 g).

MS (ESI +) 385 (MH1, 100%). Reference example 20

2 ', 3', 5'_tri-0-acetylguanosine

To a suspension of guanosine (28.32 g) in acetonitrile (1250 mL) was added 4- (dimethylamino) pyridine (0.92 g), triethylamine (55.7 mL), and acetic anhydride (34 mL). ) Was added at room temperature and stirred for 30 minutes. After adding methanol (20 mL) and stirring for 5 minutes, the solvent was distilled off under reduced pressure, 2-propanol (300 mL) was added to the residue, and the residue was taken out and dried under reduced pressure to obtain the desired product (37.93 g).

MS (ESI +) 410 (MH1, 100%). Reference example 21

2 ', 3', 5'_tri-0- [tert-butyl (dimethyl) silyl] -8-bromoinosine

A solution of diisopropylethylamine (3.2 mL) in tetrahydrofuran (8 mL) was ice-cooled, and n-butyllithium (1.58 M hexane solution, 15 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred for 15 minutes, and the reaction solution was cooled to -78 ° C. To this solution, a solution of 2 ', 3', 5'-tri-0- [tert-butyl (dimethylene) silyl] inosine (5.0 g) in tetrahydrofuran (20 mL) was added dropwise over 10 minutes. The mixture was stirred for 1 hour. Further, dibromotetrafluoroethane (2.9 mL) was added dropwise to the reaction solution at _78 ° C, and the mixture was stirred for 2 hours after completion of the addition. To the reaction mixture, a saturated aqueous solution of ammonium chloride was added, and the mixture was subjected to port-hole extraction. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, hexane / ethyl acetate = 3/1 to 1/1) to obtain the desired product (4.8 g) as a pale yellow solid.

_{Ή NMR (400 MHz, CDC1 3} ) άρριη 13.21 (s, 1H), 8.33 (s, 1H), 5.96 (d, J = 5.0 Hz, 1H), 5.30-5.32 (m, 1H), 4.46-4.45 (m , 1H), 4.04-3.98 (m, 1H), 3.98-3.96 (m, 1H), 3.72-3.69 (m, 1H), 0.93 (s, 9H), 0.83 (s, 9H), 0.77 (s , 9H), 0.13 (s, 3H), 0.12 (s, 3H), 0.01 (s, 3H), -0.01 (s, 3H), -0.08 (s, 3H), -0.34 (s, 3H) .

MS (ESI +) 689 (MHl, 76%). Reference Example 22

2 ', 3', 5'-tri-0- [tert-butyl (dimethyl) silyl] inosine

To a solution of (-)-inosine (22.7 g) in N, N-dimethylformamide (600 mL) was added tert-butyldimethylchlorosilane (76.6 g) and imidazole (69.3 g), and the resulting solution was heated at 25 ° C. Stir for 18 hours. Water was added to the reaction solution to perform extraction with black-mouthed form. The organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel, hexane / ethyl acetate = 3/1-chloroform / methanol = 10/1) to give the title compound (50.2 g ).

'H NMR (400 MHz, CDC1 3) δ ριη 8.24 (s, 1Η), 8.11 (s, 1H), 6.01 (d, J = 5.0 Hz, 1H), 4.51-4.49 (m, 1H), 4.31-4.29 (m, 1H), 4.14-4.12 (m, 1H), 4.02-3.98 (in, 1H), 3.81-3.78 (m, 1H), 0.96 (s, 9H), 0.93 (s, 9H), 0.81 (s, 9H), 0.15 (s, 3H), 0.14 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.01 (s, 3H), -0.18 (s, 3H).

MS (ESI +) 611 (MHl, 100%). Reference Example 23

2 ', 3', 5'-Tri 0- [tert-4-methyl-2-trifluoromethyl-8 _ bromoinosine

Under a nitrogen atmosphere, a solution of 2 ', 3', 5'-tri-0- [tert-butyl (dimethyl) silyl] -1-methyl-2-trifluoromethylinosine (883 mg) in tetrahydrofuran (20 mL) was added. At 0 ° C., tert-butyllithium (1.50 M pentane solution, 2.6 mL) was slowly added dropwise, followed by stirring for 1.5 hours. After cooling to -78 ° C, a solution of 1,2-dibromo-1,1,2,2-tetrafluoroethane (617 ^ L) in tetrahydrofuran (2 mL) was slowly added dropwise, and the mixture was stirred for 1 hour. Thereafter, the temperature was raised to 25t over 5 hours. A saturated aqueous solution of ammonium chloride (10 mL) was poured, and the reaction solution was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate (100 mL), and the mixture was extracted twice with ethyl acetate (80 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product (981 mg). Under a nitrogen atmosphere, sodium hydride (62 mg) was added to a solution of the crude product (981 mg) in N, N-dimethylformamide (15 mL), the mixture was stirred at 25 ° C for 30 minutes, and methyl iodide ( 404 L) was added dropwise and the mixture was stirred at 25 ° C overnight. After pouring a saturated aqueous solution of ammonium chloride (2 mL), the reaction solvent was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the residue, and the mixture was extracted twice with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane / ethyl acetate = 200/1 to 10/1) to obtain the desired product (398 mg). Was.

_{Ή NMR (300 MHz, CDC1 3} ) άρριη 6.02 (d, J = 6.9 Hz, 1H), 5.20 (dd, J = 4.4, 7.0Hz, 1H), 4.35-4.34 (m, 1H), 4.08-4.03 (m , 1H), 3.91-3.84 (m, 1H), 3.79 (s, 3H), 3.73-3.65 (m, 1H), 0.96 (s, 9H), 0.89 (s, 9H), 0.78 (s, 9H) , 0.15-0.02 (m, 12H), -0.08 (s, 3H), -0.34 (s, 3H).

MS (ESI +) 771 (M ⁺ + l, 81%). Reference example 24

2 ', 3', 5'-tri-0- [tert-butyl (dimethyl) silyl] -2-trifluoromethylino

Under a nitrogen atmosphere, slowly add a 21% by weight sodium ethoxide Z ethanol solution (15 mL) to a solution of 5-aminoimidazole-4-carboxyamide-l-j6_D-ribofuranoside (1.03 g) in ethanol (15 mL). The mixture was stirred at 25 ° C for 30 minutes. Next, ethyl trifluoroacetate (4.8 mL) was slowly added, and the mixture was heated with stirring at 80 ° C for 8 hours. After cooling to 25 ° C, the reaction solution was neutralized with 2N hydrochloric acid to adjust the pH to 5, and then saturated aqueous sodium hydrogen carbonate was added to adjust the pH to 8. The reaction solvent was distilled off under reduced pressure, water was added, and the precipitated solid was collected by filtration and washed with toluene. The product was sufficiently dried under reduced pressure to obtain a crude product (0.93 g). Next, a solution of this crude product (0.93 g) in N, N-dimethylformamide (20 mL) was added to imidazole (2.26 g), tert-butyldimethylchlorosilane (2.50 g), and 4- (dimethylamino) pyridine ( 100 mg) and stirred at 25 ° C overnight. The reaction solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate (80 mL) was added, and the mixture was extracted twice with ethyl acetate (80 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Subsequently, the residue was again converted into a solution of N, N-dimethylformamide (20 mL), and imidazole (2.26 g), tert-butyldimethylchlorosilane (2.50 g), and 4- (dimethylamino) pyridine (100 mg) were added. Stirring at 25 ° C. overnight was repeated. The reaction solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate (80 mL) was added, and the mixture was extracted twice with ethyl acetate (80 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, chloroform / methanol = 100/1 to 25/1) to give the desired product (1.83 g) Got.

_{Ή NMR (300 MHz, CDC1 3} ) δ ριη 8.37 (s, 1H), 5.99 (d, J = 4. Hz, 1H), 4.54 (t, J = 4.2 Hz, 1H), 4.31 (t, J = 4.2 Hz, 1H), 4.16-4.15 (m, 1H), 4.06-4.01 (in, 1H), 3.83-3.78 (m, 1H), 0.96 (s, 9H), 0.93 (s, 9H), 0.83 ( s, 9H), 0.17-0.07 (m, 12H), 0.00 (s, 3H), -0.15 (s, 3H). MS (ESH) 679 (Ml, 100%), Reference example 25

8-bromo-7- (2-chlorobenzyl) -1-methyl-2-trifluoromethyl-1,7-dihydro-6H-purine-6-one

Using the compound of Reference Example 26 (530 ig) as a starting material, synthesis was carried out by the same method as in Reference Example 14, to obtain the title target product (61 ig) as a white solid.

_{lH NMR (400 MHz, CDC1 3} ) ά ρηι 7.44 (d, J = 7.9 Hz, 1H), 7.26 (t, J = 8.5 H z, 1H), 7.16 (t, J = 7.6 Hz, 1H), 6.50 ( t, J = 7.6 Hz, 1H), 5.81 (s, 2H), 3.72 (s, 3H).

MS (ESI +) 423 (MHl, 46¾). Reference Example 26

8-bromo-7- (2-chlorobenzyl) -2-trifluoromethyl-1,7-dihydro-6H-purin-6-one

Under a nitrogen atmosphere, 7- (2-chlorobenzyl) -1-methyl-2-trifluoromethyl-1,

To a solution of 7-dihydro-6H-purin-6-one (4.80 g) in tetrahydrofuran (300 mL), slowly add tert-butyllithium α · 49Μpentane solution (29.4 mL) under 0 and stir for 2 hours did. Next, 1,2-dibromo-1,1,2,2-tetrafluoroethane (6.37 mL) was added at -10 ° C, and the mixture was stirred at 0 ° C for 3 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution, and tetrahydrofuran was distilled off under reduced pressure. The mixture was acidified with dilute hydrochloric acid, and extracted three times with chloroform (100 mL). Saturate organic layer After washing with brine, the extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform / acetic acid = 100/1 to 25/1) to obtain the desired product (1.11 g).

Ή NMR (400 MHz, DMS0-d ₆ ) <5 pm 7.55 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.29-7.25 (i, 1H), 6.65 (d , J = 7.7 Hz, 1H), 5.69 (s, 2H), 3.34 (s, 1H).

MS (ESH) 409 (MHl, 14%). Reference Example 27

7- (2_methyl benzyl)-1-methyl-2-trifluoromethyl-1,7-dihydro-6H-purine-6-one

Under a nitrogen atmosphere, 4-amino-1- (2-chloro benzyl) -5-imidazolpalkoxamide (5.01 g), trifluoroacetamide (22.6 g), trifluoroacetic acid

(1.54 mL) was stirred at 160 ° C. for 1 hour. After cooling, getyl ether (50 mL) was added, and the mixture was heated under reflux for 10 minutes. After cooling, the solid was collected by filtration. Acetonitrile on solid

(25 mL), heat to reflux for 10 minutes, allow to cool, collect the solid, filter, and dry to give the title compound.

(4.97 g) was obtained as a white solid.

Ή NMR (400 MHz, DMS0-d ₆ ) <5 pm 13.8 (s, 1H), 8.49 (s, 1H), .7.53 (d, J = 7.9 Hz, 1H), 7.36 (t, J-7.9 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 6.90 (d, J

= 7.6 Hz, 1H), 5.72 (s, 2H).

MS (ESI +) 329 (MHl, 50%). Reference Example 28

4-amino-1- (2-chlorobenzyl) -1-5-imidazolecarpoxamide

Using the compound of Reference Example 29 (27.0 g) as a starting material, synthesis was carried out in the same manner as described in the literature (for example, W099 / 03 858, etc.), and the title compound (17.0 g) was obtained as a white solid. Obtained.

Ή NMR (400 MHz, DMS0-d ₆ ) δ ρπι 7.50 (s, 1H), 7.44 (d, J = 7.1 Hz, 1H), 7.30-7.24 (m, 2H), 6.77 (s, 2H), 6.61-6.59 (m, 1H), 5.51 (s, 2H), 5.22 (s, 2H).

MS (ESI +) 251 (M ++ l, 26¾). Reference example 29

4_benzylideneamino (2-chloro benzyl) 1-5-imidazolecarpoxamide

Using the compound of Reference Example 30 (21.4 g) as a starting material, synthesis was carried out in the same manner as described in the literature (for example, W099 / 03858, etc.), and the title compound (27.4 g) was obtained as a white solid. Obtained.

Ή NMR (400 MHz, D S0 -d 6) 5 pm 9.25 (s, 1H), 8.18 (s, 1H), 8.00 (d, J = 7 .4 Hz, 1H), 7.95 (s, 1H), 7.60 -7.49 (m, 6H), 7.37-7.32 (m, 2H), 6.62 (d, J2 7.3 Hz, 1H), 5.74 (s, 2H).

MS (ESI +) 339 (M ++ l, 55¾). Reference example 30

4 Benzene ¹ Ridenamino 1 5 Imidazole carpoxamide

Using 4-aminoimidazole-5-carboxamide hydrochloride (32.6 g) as a starting material, synthesis was carried out in the same manner as that described in the literature (W 99/9958, etc.), and the title compound (39.9 g) was obtained. g) was obtained as a white solid.

Ή NMR (400 MHz, DMS0-d ₆ ) 5ppm 13.0 (s, 1H), 9.17 (s, 1H), 8.00-7.98 (m, 2H), 7.83 (s, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 7.56-7.51 (m, 3H).

8-[(3R) -3-Aminopiperidin-1-yl] -7- (2-benzyl benzyl) -1-methyl-2-phenoxy-1,7-dihydro-6H-purine-6 -ON

tert-butyl {(3R) -l- [7- (2-octabenzyl) -1_methyl-6-oxo-2-phenoxy-6,7-dihydro-1Η-purine-8-y L] Piperidine-3-yl} capillate (4.30 g) in 1,4-dioxane (20 mL) was added to a 4N solution of 1,4-dioxane hydrochloride (30 mL) and the mixture was added at 25 ° C for 4 hours. Stirred. Saturated aqueous sodium hydrogen carbonate (100 mL) was added to the residue to make the solution alkaline, and the mixture was extracted twice with chloroform (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (3.55 g).

_{Ή NMR (300 MHz, CDC1 3} ) δρριη 7.44-7.38 (m, 3H), 7.28-7.16 (m 5H), 6.82 (d, J = 7.1Hz, 1H), 5.52-5.50 (m, 2H), 3.63 ( s, 3H), 3.39-3.36 (ra, 1H), 3.27- 3.23 (m, 1H), 2.92-2.85 (m, 2H), 2.69-2.62 (m, 1H), 1.84-1.82 (m, 1H), 1.6 5-1.55 (m, 2H), 1.23-1.21 (m, 1H)

MS (ESI +) 465 (M ++ 1, 35%). In the same manner as in Example 16, the compounds of Examples 17 to 61 were synthesized from the corresponding compounds of Reference Examples.

Example number Raw material reference example number Implemented 1 7 CH ₃ Reference Example 3 2 Implemented 伢 18 CH ₃ Reference Example 3 3 Implemented 0 | 19 CH ₃ Reference Example 3 4 Implemented 2 0 CH ₃ Reference Example 3 5 Implemented 2 1 CH ₃ reference example 3 6 implementation 伃 2 2 CH ₃ reference example 3 7 implementation I 2 3 CH reference example 3 8 implementation I 2 4 CH reference example 3 9 implementation ί system I 25 CH, reference example 4 0

Implementation 伢 2 6 CH ₃ CH ₂ OC (0) CH ₂ PhO Reference Example 4 1 Implementation ί system I 2 7 HOC (0) CH ₂ PhO Reference Example 4 2 Implementation 0 | 2 8 H COOH Reference Example 4 3 Implementation ί I 2 9 CN Reference example 4 4

Implementation 伢 30 HOC (0) CH ₂ CONH ₂ Reference Example 4 5 Implementation I 3 1 CH ₃ PhC (O) Reference Example 4 6 Example number Reference material example number

Example 3 2 CH, Reference Example 4 7 Example 3 3 CH Reference Example 4 8

Example 3 4 CH ₃ CN Reference Example 4 9 Example 3 5 CH ₃ C (0) CH ₃ Reference Example 50 Example 3 6 CH ₃ SCH ₃ Reference Example 5 1 Example 3 7 CH ₃ S (0) ₂ CH ₃ Reference Example 5 2 Example 3 8 CH ₃ S (0) ₂ Ph Reference Example 5 3 Example 3 9 CH ₃ SPh Reference Example 5 4 Example 4 0 CH ₃ C ^N Reference Example 5 5

0

Example 4 1 CH Reference Example 5 6 Example 4 2 Reference Example 5 7 Example 4 3 CH, Reference Example 5 8

Example 4 4 CHc Reference Example 5 9 Example 4 5 CH, Reference Example 60 Example 4 6 CH, Reference Example 6 1 Example 4 7 CH, Reference Example 6 2 Example 4 8 CH, Reference Example 6 3

2 4 Example No.Reference Material No. Example 4 9 Reference Example 6 4 Example 5 0 CH _? Reference Example 6 5

Example 5 1 ° Reference Example 6 6

Example 5 2 CH, Reference Example 80 Example 5 3 CH, Reference Example 8 1

Example 5 4 CH Reference Example 8 2

MeO

Example 5 5 Reference Example 8 3

MeO

OMe

Example 5 6 Reference Example 8 4

CH 0, 0

Example 5 CH, Reference Example 8 5 Example 5 8 CH, Reference Example 8 6 Example 5 9 CH, Reference Example 8 Example 6 0 Reference Example 8 8

Example 6 1 CHc EtO

0 ° Reference example 8 9 • (Ηΐ 'οι)'('«99 · U'l' (HI S8'I-06'ΐ '(ΗΪ' OS m'Z \ '8" 8 = f' ΡΡ) 99 'Ζ' (Η2 88 · Ζ— S6 '(HI' ω) SZ'S-OS'S '(HI' ω) "S-S '(Η8' s) S '(ΗΖ' ω) OS'WS '(HI' ΖΗ fL = i 'Ρ ) 08 9 '(HZ' ω) 6

0-L-Z \ -L 'im' ui) QZ-L-LZ-L '(HI OfL-ZfL ldQd' ZH image recommended H,

• (% ooi Ή ₊ ι¾) m (+ isa) si¾

'(HI' ω) ΪΠ-9ΓΙ '(HZ IS' to 9 Ί '(HI 99Ί-ΖΓΪ' (Ηΐ 'ΖΗΓΖΪ' 8 · 8 = ί '' ΡΡ) S9 '(HZ' ω) 88 — S6 '( Ηΐ

) '(Ηΐ' «0 ίζ · ζ-Ζ ^ · 2, '(Η8' s) Z9'S '(Μ'« 0 09 'S-99' 9 '(ΗΙ' «0 I

8 9-λ8 9 '(Η') it Ά-ΟΖ '(HS' ω) 98 -2 ^ ( ^ε Ι3αθ 'ZHWOO ^ H Η,

• (% 0Ζ Ή + W) Ζ99 (+ ISH) • (HI 'ιπ) δΓΐ-ΐΖ'ΐ' (Η2 '«8S" 1

-99 Ί '(Ηΐ' ιπ) 8ί-98Ί '(Ηΐ S9 ー 69Ζ Ζ (ΕΖ' ω) 8 ー '(HI ¾) u

· 9-9Γε '(HI' in) AS'S— OS '(HC'Z9'S'(HZIS'S—ZS'S' (HI ^£ ΖΗΓΑ = ί

'Ρ) Z8'9' (Η6 'πι) ΐθ'Ζ-8ΓΖ ^£ (Η8' ω) HL-ZfL lddd 'ζOS) Leakage H _t 9ΐ

6 τ mm

• (% Π 99 (+ IS3) SK "(Ηΐ 'ιπ) 8ΓΪ-9Π' (HZ Ί—09 Ί '(Ηΐ £ 8 -68 "8 '(HI' ω) rS-9Z'S '(HI 9S' ε- OS '(HC' s

) 99 '8' (HZ '«ig-g-gg-g' (HI 'ω) Ι8.9-8.9' OK '« 6ΐ "2, -22"i' (Η2 ¾) 9 Ot ξ- L-ZfL '(HI' πΐ) S9-Z-89'Z '(IK ΐ 8-93' 8 inddp ( ^ε ΐοα3 ', 00S) leak H)

8 τ mm

• (% η Ή + W) 60S (+ IH) SW • (Ηΐ 'ω) 6ΐ l-SZ'I' (ΗΖ 'ω) 29' 1-39 'ΐ' (Ηΐ 28 "1- ^ 8 'ΐ '(Η1' «· Ζ_6

9 ⁴ (HZ 'ιπ) 98'Z-Z6 "Z' (HI Η'2- Ζ '' (Ηΐ 'ω) ε- 6Γ2' (Η8 '09 * 9 3

'(Μ' πΐ) OS'S— IS · 3 '(Η2' 00 · 9 '(Ηΐ' Ζ · 8 'fZ = i' ΡΡ) S9.9 '(Η8' ω) '9-88 "9'(' «91 '(HI'« 讓 ί> ( ⁸ 1θαθ 'ΖΗί¾002) Μ Η,

L Τ P ¾

Ζ ^ 2

1 ^ 01900 contract Zdf / e :) d 908 960 contract OAV MS (ESI +) 483 (MHl, 100%).

Example 22

_{Ή NMR (300MHz, CDC1 3)} άρρπι 7.42-7.39 (m, IH), 7.23-7.13 (m, 6H), 6.86-6.8 3 (m, IH), 5.51-5.50 (m, 2H), 3.65 (s, 3H), 3.38-3.35 (m, IH), 3.27-3.23 (m, IH), 2.91-2.84 (m, 2H), 2.68-2.61 (m, IH), 2.21 (s, 3H), 1.85-1.83 ( m, IH), 1.66-1.52 (m, 2H), 1.22-1.20 (m, IH).

MS (ESI +) 479 (MHl, 29%).

Example 23

_{lE NMR (300MHz, CDC1 3)} <5 pm 7.42-7.39 (m, IH), 7.31-7.16 (m, 3H), 7.07-7.0 0 (m, 3H), 6.82 (d, J = 7.1Hz, IH) , 5.52-5.50 (m, 2H), 3.61 (s, 3H), 3.39-3.34 (m, IH), 3.27-3.23 On, IH), 2.92-2.84 (m, 2H), 2.69-2.62 (m , IH), 2.37

(s, 3H), 1.84-1.82 (m, IH), 1.65-1.57 (m, 2H), 1.22-1.18 (m, IH).

MS (ESI +) 479 (MHl, 30%).

Example 24

_{LH NMR (300MHz, CDC1 3)} <5 pm 7.43-7.40 (m, IH), 7.27-7.16 (m, 6H), 6.82 (d, J = 7.3Hz, IH), 5.55 (d, J = 17.4Hz, 1H), 5.48 (d, J = 17.4Hz, IH), 3.62 (s, 3H), 3.40-3.36 (in, IH), 3.29-3.25 (m, IH), 2.94-2.84 (m, 2H), 2.69 -2.62 (m, IH), 2.36 (s, 3H), 1.85-1.83 (m, IH), 1.68-1.53 (m, 2H), 1.26-1.18 On, IH) MS (ESI +) 549 (MHl, 33% ).

Example 25

_{l NMR (300MHz, CDC1 3)} δ ρπι 7.44-7.35 (m, 2H), 7.25-7.19 (m 2H), 7.11-7.0 9 (m, 2H), 7.04-7.00 (m, IH), 6.90-6.88 ( m, IH), 5.60-5.59 (m, 2H), 3.85 (s, 3H), 3.49-3.47 (m, IH), 3.48 (s, 3H), 3.35-3.33 (m, IH), 3.00-2.91 ( m, 2H), 2.76-2.69 (m, IH), 1.90-1.88 (m, IH), 1.69-1.63 (m, 2H), 1.27-1.25 (m, IH).

MS (BSI +) 479 (MHl, 31¾).

Example 26

Ή NMR (400MHz, DMSO- d ₆ ) (5 pm 7.44-7.39 (m, 3H), 7.26-7.21 (m, 3H), 7.14-7.09 (m, 2H), 6.70-6.65 (m, 1H) , 5.31 (s, 2H), 4.79 (s, 2H), 4.06 (q, J = 7.1 Hz, 2H), 3.23-3.17 (m, IH), 3.70-3.65 (m, 1H), 2.31-2.56 (i, 1H), 2.40-2.22 (i, 2H), 1.68-1.63 (m, IH) , 1.50-1.45 (m, IH), 1.33-1.28 (m, 2H), 1.08 (t, J = 7.1 Hz, 3H).

MS (ESI +) 537 (MHl, 100%).

Example 27

Ή NMR (400MHz, DMS0-d ₆ ) <5ppm 7.57-7.52 (m, 3H), 7.41-7.36 (m, 3H), 7.26-7.21 (m, 2H), 6.88-6.82 (m, IH), 5.46 (s, 2H), 4.82 (s, 2H), 3.59-3.54 (m, IH), 3.18-3.13 (m, IH), 3.14-3.09 (m, 2H), 2.92-2.87 (m, 1H), 1.97-1.92 (m, IH), 1.77-1.72 (m, IH), 1.55-1.50 (m, 2H).

MS (ESII) 509 (MHl, 100%).

Example 28

Ή NMR (300MHz, DMSO- d ₆ ) (5 pm 7.51 (d, J = 7.7Hz, 1H), 7.36-7.25 (m, 2H), 6.87-6.81 (m, IH), 5.53 (s, 2H ), 3.68-3.66 (m, IH), 3.31-3.29 (m, IH), 3.18- 3.11 (m, 2H), 2.85-2.83 (m, 1H), 1.95-1.93 (m, IH), 1.73-1.71 (m, IH), 1.5 6-1.52 (m, 2H).

MS (ESI +) 403 (MHl, 100%).

Example 29

_{Ή NMR (400MHz, CD 3 0D} ) δ ppm 8.29- 8.24 (m, 1H), 7.89-7.84 (m, 2H), 7.60-7.5 5 (m, IH), 7.55-7.50 (m, IH), 7.35 ( d, J = 7.8Hz, IH), 7.22-7.17 (m, 2H), 8.0 (d, J = 8.0Hz, IH), 5.52 (s, 2H), 5.12 (s, 2H), 3.71-3.66 (m, IH), 3.43-3.38 (m, 2H), 3.20-3.15 (m, IH), 2.95-2.90 (m, IH), 2.05-2.00 (m, IH), 1.73-1.68 (m, IH), 1.57-1.52 (m, 2H).

MS (ESI +) 518 (MHl, 100%).

Example 30

_{Ή NMR (400MHz, CD 3 0D} ) δ ριιι 7.42-7.37 (m, IH), 7.25-7.20 (m, 2H), 6.90-6.8 5 (m, IH), 5.54 (s, 2H), 5.10 (s, 2H), 3.70-3.65 (m, IH), 3.42-3.37 (m, IH), 3.20-3.15 (m, 2H), 2.98-2.93 (m, IH), 2.05-2.00 (m, IH), 1.77- 1.72 (m, IH), 1.62-1.57 (m, 2H).

MS (ESII) 460 (MHl, 100%)

Example 31 • (Ηΐ 'πΐ) η-Ζ' (ΗΖ 'ω) 89'I-U'l' (HI 'ω) 88' OS 1-06 Ί '(Ηΐ' ω) fL'Z-9fZ '(HS' s) ll'l '(' ω) S6 — '(Ηΐ' ω) SS 'S-6 S'S' (HI '«9FS-09-8' (HS 's) OA' 8 '(ΆΖ 69' 5- 09 '9' (HI 'ZHf = ί' Ρ) 08'9 '(HZ ¾) LVL-Η-ί' (Ηΐ 'ZHSΑΑ = ί' Ρ) ( ^ε ΐθα3 'ZHR00S) W Η,

• (% 00ΐ 868 (+ ISH) m 9Ζ • (Ηΐ '«ι) ΠΊ-9Ζ-1' (ΗΖ '« 0

09 ・ T U'l '(ΙΠ' ω) 88-Ι-06 '(Ηΐ' ω) ΙίΊ- ^ ί 'ΟΚ' «68 ー SO 'S' (HI 'ω) 8S-g-Zf 8' ( HI ^£ m) 8f S-29 '8' (HS 's) 8Γ2' (H2 's) Ζ9'9' (HI 'ΖΗΐ' 9 = Γ 'Ρ) 9' (ΗΖ 'ιπ)' (Hi Ζ ΉΓ 讓 9 ('ΐθαθ' ZHW00S) M Η,

'(% L' ΐ + ^) 189 (+ IS3) • (HI 'πΐ) SI Ί-Ζΐ Ί' OK ^£ ui) 8Η9'1 '(Ηΐ' υι) ΖΓΐ-6ΖΊ '(ΗΙ' ω) 9S-S9 '(HZ Ζ8Ζ-98Ζ' (Ζ '«0 9ΐ -g-OZ-g' (Ηΐ 'in) 8Γ8-Ϊ9-2'('2' δ) 69 'δ'('' «0 OS'S-IS 'S' (Ηΐ 'Ί = f' Ρ) 9Α9 '(Η2' πΐ) -LHL '(Ηΐ 8' (Η2 ¾) 09 '-β Ζ' (Ηΐ 91 'ω) Α--Α9ΖΖ '(HS' πι) '(Ηΐ' s) 8Γ8 mJdfi) OD 'ZH drawing ε)

ε ε m

• (Mardal 'Ι ++ Ι¾) S99 (+ ISH) SW

'(HI' ιπ) si

-0Π '(Η2') 6 ^ ΐ-Ζ9ΐΐ '(ΗΙ' «88 '1-38 -ΐ' (Ηΐ 'ω) 6S-99' (ΗΖ 'πΐ) θΐ \%-Ζ-ί '(Ηΐ Μ · ε— 9ΐ · ε' (Ηΐ 'ω) ΖΓ8-6Γ9' (HS 'LQ' '(HZ' «S9 • 9-9'S '(HI' Ί = ί 'Ρ) Ζί' (HZ ' «0 8ΙΉΖ · Α '(HI 6S-' (Η2 'αι) -L-ffL' (Η '«!) 961-90' 8 '(Ηΐ' S9 -8 l Qd 'ΖΗS)

• (% οοι 'η, η) (iisa) s'

• (HI '"I) Sri-An' (M 'πι) 09 · 9 9 · I' (Ηΐ 'ω) U'l-ZQ'l ^£ (Ηΐ

9ΓΖ— S8 'αι) S6-66' (HI 'ω) OS'S-ZS' S '(HS ^£ s) gg'g' (HI · S-9S-S '(H2) 69'S-09-9' (Ηΐ 'ω) Α8 · 9— 68 · 9' (HZ 'ω) ΙΖ'ί-WL' (Η8 '«0 8 S'HS'A' (Ηΐ '« ι) 9Ή9 · Α' (ΗΖ ¾) ΐΟ '8-80'8 ^ 9 ( ^ε 13αθ ^£ ZHTO0S) N Η,

1 ^ 01900 contract Zdf / e :) d 908 960 contract OAV S 9 inch

. 3H), 1.26-1.21 (m, 1H).

MS (ESI +) 438 (MHl, 100%).

Example 41

_{Ή NMR (300MHz, CDC1 3)} 5 ppm 7.42 - 7.39 (m, 1H), 7.24-7.19 (m, 2H), 6.87-6.8 5 (m, 1H), 5.54 (s, 2H), 3.68-3.62 (m , 2H), 3.53 (s, 3H), 3.46-3.43 (m, 1H), 3.31-3.30 (m, 1H), 2.94-2.91 (m, 2H), 2.73-2.69 (m, 1H), 2.61-2.56 (m, 2H), 2.27-2.23 (m, 2H), 1.87-1.85 (m, 1H), 1.68-1.58 (m, 2H), 1.26-1.24 (m, 1H).

MS (ESI +) 456 (MHl, 100%).

Example 42

_{Ή NMR (300MHz, CDC1 3)} δ ppm 7.97-7.93 (m, 1H), 7.88-7.87 (m, 1H), 7.53-7.3 9 (m, 3H), 7.24-7.17 (m, 2H), 6.83 (d , J = 7.0Hz, 1H), 5.55 (d, J = 17.1Hz, 1H), 5.48 (d, J = 17.1Hz, 1H), 3.92 (s, 3H), 3.64 (s, 3H), 3.39- 3.34 (m, 1H), 3.24-3.22 (m, 1H), 2.91-2.85 (m, 2H), 2.70-2.62 (m, 1H), 1.84-1.82 (m, 1H), 1.60-1.56 (i, 2H ), 1.23-1.21 (m, 1H).

MS (ESI +) 523 (MHl, 29%).

Example 43

Ή NMR (300 MHz, DMSO- d ₆ ) δ ρηι 7.92-7.85 On, 2H), 7; 66-7.51 (m, 3H), 7.35-7.26 (m, 2H), 6.79 (d, J = 6.1 Hz , 1H), 5.46 (s, 2H), 3.57 (s, 3H), 3.46-3.27 (m, 2H), 3.11-3.04 (m, 2H), 2.89-2.79 (m, 1H), 1.92-1.90 (m , 1H), 1.69-1.4 5 (m, 3H).

MS (BSI +) 509 (MHl, 56%).

Example 44

_{Ή NMR (300MHz, CDC1 3)} 5 pm 7.97-7.95 (m, 1H), 7.86 (d, J = 2.2Hz, 1H), 7.52- 7.40 (m, 3H), 7.24-7.17 (m, 2H), 6.83 (d, J = 7.1Hz, lH), 5.52-5.51 (m, 2H), 4.39 (dd, J = 7.1, 14.3Hz, 2H), 3.64 (s, 3H), 3.39-3.35 (m, 1H), 3.25-3.23

(m, 1H), 2.92-2.84 (m, 2H), 2.68-2.61 (m, 1H), 1.85-1.83 (m, 1H), 1.65-1.5

7 (m, 2H), 1.40 (t, J = 7.1Hz 3H), 1.22-1.20 (m, 1H).

MS (ESI +) 537 (MHl, 23%).

Example 45 • 36 ^ (+ ISH) SW OS '(HI' ω) W \ -U '\ ^l (m '89 ΐ-99'ΐ' (Ηΐ Ζ8Ζ8Ηΐ '(HI' πι) gg 'Ζ- β

9 '(HZ) 1-1 ^ 1' (HI 22 '2-82' 2 '(Ηΐ') 98 -g-6S '8' (HS ^£ s) Ζ9 'ε' (HS 's) is · Ε 'απ · = ί' ρ) SS 'απ' mn = i 'ρ)' (Η '«g

9- 9 '(HC' ui) 9 \ ί-Ζξ-ί '(ΗΙ') ^ -L-ZfL ^ 9 ( ^ε Ι0α3 'Image S) Leak 漏【

6 m ^

• (¾58 S8 (+ ISH) SW

· (

HI 'ω) 8ΐ · ΐ-9Γΐ' (ΗΖ '«0 9'ΐ' (Ηΐ 8T-98" l '(HI' ω) S9

'OK' ω) ^ Ί-Π '(Ηΐ' ιπ) 9Γ2-6Γ2 '(Ηΐ' «0 WS-OS '(HS '29' g '(Η ΐ

'Ρ) SS'S' (Η2 08-9-S8-9 '(HS') g QZ 6'9-90 '' (Ηΐ 'πι)' (9 ('ΙΟΟΟ' ΖΗΚ008) Μ Η,

• (% η ') 06 (+ isa) sw

"(HI 'ιπ) 6ΓΙ-8ΓΪ' (HS Z9'l-8'I '(HI S9 · Ζ- U · Ζ' (H l 'ω)' (HI 9Γε-02-8 '(HI' S- OS '(H8' s) C9 '(Ηΐ' 9ΐ

ZH9 l = f 'Ρ)' (HI 'ΖΗ9 · = ί' Ρ) 3 '(Ηΐ' ΖΗΐ "Α = ί 'Ρ) 9' (Η2 'ω) L

'(ΗΙ' πι) QfL- fL '(H' πΐ) 63 · 9 9 'ZHi¾008) H Η,

• (¾tS Ή ₊ Ρί) 6 9 (+ ISH) SW "(HI '« ι)' (Η2 'to S9'I 01

'(Ηΐ 88-Ϊ-98Ί' (Ηΐ '«ΐ9 — 89' (HZ, 8116 '(Ηΐ' ω)

"8 '(Ηΐ' ιπ) S g-6g-g '(Η8' s) ^ 9 * 2 '(HI' 0 · Ι = ί 'Ρ)' (Ηΐ '= ί

'Ρ)' (Ηΐ 'ω) t8'9- Α8 ・ 9' (ΗΑ '«8r -gf Ζ ^ 9 ldQd' ZHW00S) M Η,

• 6 s diss) sw 9 '

'(HI' ui) Ο ΐ-εΖ '(Η2 89' ΐ-99 "ϊ '(Ηΐ' ω) S8'I-98'I '(HI' ω) Ζ9-69 '(HZ) 98-S6' (HI ') S Γδ-OS-g' (Ηΐ 'ω)' (HS 's) Z9 -8' (HZ IS'S-gg'S '(HI' ZH8 = f

'P) 28' 9 '(HS \ -LHL' (HZ 'ω) 0-9' A mdd ρ ( ^ε ΐοαο 'lia OS) leak H,

1 "0l900 / l700Zdf / X3d 908960 contract OAV Example 50

_{Ή NMR (300MHz, CDC1 3)} δρρπι 7.42-7.39 (m, 1H), 7.23-7.16 (m, 2H), 6.85-6.8 1 (m, 1H), 6.38 (s, 2H), 6.37 (s, IH) , 5.54 (d, J = 17.1 Hz, IH), 5.48 (d, J = 17.1 Hz, IH), 3.78 (s, 6H), 3.60 (s, 3H), 3.40-3.36 (m, IH), 3.29- 3.24 (m, IH), 2.93-2.84 (in, 2H), 2.69-2.62 (m, IH), 1.84-1.82 (m, 1H), 1.67-1.58 (m, H), 1.26-1.18 (m, IH ).

MS (ESII) 525 (MHl, 59¾).

Example 51

_{Ή NMR (300MHz, CDC1 3)} <5ppi 7.42-7.39 (m, IH), 7.31-7.16 (m, 3H), 6.84-6.7 1 (m, 4H), 5.54 (d, J = 17.4Hz, IH), 5.48 (d, J = 17.4Hz, IH), 3.87-3.83 (m, 4

H), 3.61 (s, 3H), 3.39-3.36 On, IH), 3.28-3.24 (m, 1H), 3.19-3.16 (m, 4H), 2.92-2.84 (m, 2H), 2.68-2.61 (m , IH), 1.84-1.82 (m, IH), 1.65-1.52 (m, 2H

), 1.21-1.18 (m, IH).

MS (ESII) 550 (MHl, 26%).

Example 52

_{Ή NMR (300MHz, CDC1 3)} δ ριη 7.42-7.38 (m, 1H), 7.23-7.18 (m, 4H), 6.99-6.94 (m, 2H), 6.84-6.83 (m, IH), 5.54 (d, J = 18.1Hz, IH), 5.47 (d, J = 18.1Hz, IH), 3.78 (s, 3H), 3.65 (s, 3H), 3.38-3.34 (m, IH), 3.26-3.22 (m, IH ),

2.90- 2.83 (in, 2H), 2.67-2.60 (m, IH), 1.85-1.82 (m, IH), 1.65-1.52 (m, 2H), 1.25-1.18 (m, IH).

MS (ESI +) 495 (M ++ 1, 100%)

Example 53

_{Ή NMR (300MHz, CDC1 3)} 5ppm 7.42-7.38 (m, IH), 7.23-7.12 (m, 4H), 6.93-6.89 (m, 2H), 6.83-6.80 (m, IH), 5.54 (d, J = 17.4Hz, IH), 5.47 (d, J = 17.4Hz, IH), 3.82 (s, 3H), 3.61 (s, 3H), 3.38-3.34 (m, IH), 3.25-3.21 (m, IH) ,

2.91- 2.84 (m, 2H), 2.68-2.61 (m, IH), 1.85-1.82 (m, IH), 1.65-1.44 (m, 2H), 1.26-1.21 (m, IH).

MS (ESI +) 495 (M ⁺ + l, 100%).

Example 54

_{'Η NMR (400MHz, CDC1 3} ) ^ m 7.54-7.50 On, 2H), 7.48-7.47 (m, 2H), 7.41 (dd, J = 1.5, 7.8Hz, 1H), 7.28-7.18 (m, 2H), 6.82 (dd, J = 1.3, 7.3Hz, 1H), 5.51 (m, 2H), 3.64 (s, 3H), 3.41-3.37 (i, 1H), 3.27-3.24 (m, 1H), 2.91-2.85 (m, 2H), 2.66 (dd, J = 9.0, 12.1Hz, 1H), 1.68-1.53 (m, 3H), 1.22-1.19 (m, 1H). MS (ESI +) 533 (M ++ 1, picture).

Example 55

_{Ή NMR (400MHz, CDC1 3)} δ ριη 7.42-7.40 (m, 1H), 7.26-7.18 (m, 2H), 6.88-6.74 (m, 4H), 5.51-5.50 (ι, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 3.62 (s, 3H), 3.39-3.36 (m, 1H), 3.27-3.24 (m, 1H), 2.91-2.85 (m, 2H), 2.68-2.63 (m, 1H), 1.88-1.84 (m, 1H), 1.68-1.56 (m, 2H), 1.21-1.19 (m, 1H).

MS (ESI +) 525 (M ++ l, 100%).

Example 56

_{'Η NMR (400MHz, CDC1 3} ) δ ρπι 7.37 (dd, J = 1.6, 7.8Hz, 1H), 7.27-7.16 (m, 3H), 6.81-6.77 (m, 4H), 5.52-5.42 (m, 2H ), 4.11-4.09 (m, 2H), 3.74-3.71. (M, 2H), 3.58 (s, 3H), 3.43 (s, 3H), 3.45-3.38 (m, 1H), 3.25-3.15 (m, 1H), 2.87-2.84 (m, 2H), 2.68-2.63 (m, 1H), 1.86-1.82 (m, 1H), 1.63-1.58 (m, 1H), 1.58-1.51 (m, 1H), 1.22- 1.18 (m, 1H).

MS (ESI +) 539 (M ⁺ +1, 100%).

Example 57

Thigh (400MHz, CDC ") δρριη 8.06 (dd, J = 1.6, 7.8Hz, 1H), 7.61-7.60 (ra, 1H), 7.40 (dd, J = 1.7, 7.7Hz, 1H), 7.36-7.32 (m , 1H), 7.23-7.19 (m, 3H), 6.84 (dd, J = 1.6, 7.2Hz, 1H), 5.55-5.45 On, '2H), 3.76 (s, 3H), 3.64 (s, 3H), 3.38-3.50 (m, 1H), 3.23-3.20 (m, 1H), 2.89-2.82 (m, 2H), 2.68-2.63 (m, 1H), 1.87-1.82 (in, 1H), 1.63-1.56 (m , 2H), 1.25-1.18 (, 1H).

MS (ESI +) 523 (M ++ 1, HI).

Example 58

_{Ή NMR (400MHz, CDC1 3)} <5ppm 8.12-8.09 (m, 2H), 7.41 (dd, J = 1.5, 7.8Hz, 1H), 7.33-7.31 (m, 2H), 7.24-7.19 (m, 2H) , 6.83-6.82 (m, 1H), 5.55-5.46 (m, 2H), 3.94 (s, 3H), 3.63 (s, 3H), 3.40-3.37 (m, 1H), 3.28-3.25 (m, 1H) , 2.91-2.85 (m, 2H), 2.69-2.63 (m, 1H), 2.27-1.85 (m, 1H), 1.67-1.43 (m, 2H), 1.21-1.19 (m, 1H). MS (ESI +) 523 (M + + l, 100%).

Example 59

Ή NMR (300MHz, CDC ") 6 pm 7.42-7.39 (m, 1H), 7.23-7.16 (m, 2H), 6.87-6.81 (m, 2H), 6.76-6.66 (ra, 2H), 5.51-5.49 ( m, 2H), 4.26 (s, 4H), 3.67-3.36 (m, 1H), 3.59 (s, 3H), 3.39-3.35 (m, 1H), 3.28-3.23 (m, 1H), 2.92-2.88 ( m, 2H), 2.68-2.61 (m, 1H), 1.85-1.82 (m, 1H), 1.65-1.45 (m, 2H), 1.26-1.21 (m, 1H).

MS (ESI +) 523 (M + + l, 11%).

Example 60

Ή NMR (300 MHz, CDCI ₃ ) δ ρπι 7.43-7.40 (m, 1H), 7.27-7.16 (m, 6H), 6.82 (d, J = 7.3 Hz, 1H), 5.55 (d, J = 17.0 Hz, 1H ), 5.48 (d, J = 17.0Hz, 1H), 3.26 (s, 3H), 3.40-3.36 (m, 1H), 3.29-3.25 (m, 1H), 2.94-2.84 (m, 2H), 2.69- 2.62 (m, 1H), 1.85-1.83 (m, 1H), 1.68-1.53 (m, 2H), 1.26-1.18 (m, 1H).

MS (ESI +) 549 (M ++ l, 33%).

Example 61

_{Ή NMR (300MHz, CDC1 3)} δ ριιι 7.42-7.39 (m, 1H), 7.31-7.16 (m, 3H), 6.84-6.7 4 (m, 4H), 5.57-5.44 (m, 2H), 4.03 (dd , J = 6.9, 13.9Hz, 2H), 3.61 (s, 3H), 3.39-3.35 (m, 1H), 3.23-3.21 (m, 1H), 2.92-2.89 (m, 2H), 2.71-2.64 (m , 1H), 1.84-1.81 (m, 1H), 1.67-1.57 (m, 2H), 1.41 (t, J = 6.9Hz, 3H), 1.26-1.24 (m, 1H).

MS (ESI I) 509 (MHl, 12%) Example 62

8-[(3R) -3-Aminopiperidin-toyl] -7- (2-methylbenzyl) -1-methyl-2-phenoxy-1,7-dihydro-6H-purin-6-one

In the same manner as in Example 16, the compound of Example 62 was converted from the corresponding compound of Reference Example. Synthesized.

_{¾ NMR (300MHz, CDC1 3)} 6ppm 7.40 (t, J = 7.9Hz, 2H), 7.27-7.08 (m, 6H), 6.70 (d, J = 7.5Hz, 1H), 5.44 (d, J = 16.3Hz , 1H), 5.35 (d, J = 16.3Hz, 1H), 3.61 (s, 3H), 3.39-3.36 (m, 1H), 3.29-3.24 (m, 1H), 2.92-2.82 (ι, 2H), 2.71-2.63 (m, 1H), 2.37 (s, 3H), 1.85-1.81 (m, 1H), 1.65-1.53 (m, 2H), 1.27-1.21 (m, 1H).

MS (ESI I) 445 (M ⁺ +1, 18%). Example 63

8-C (3R) -3-7 minopididine-1-yl] -7- (2-methylbenzyl) -1 methyl-2- (3-methoxyphenoxy) -1,7-dihydro-6H-purine -6-on

In the same manner as in Example 16, the compound of Example 63 was synthesized from the corresponding compound of Reference Example.

_{¾ NMR (300MHz, CDC1 3)} <5 pm 7.32-7.12 (m, 4H), 6.83-6.69 (m, 4H), 5.41-5.32 (m, 2H), 3.81 (s, 3H), 3.59 (s, 3H ), 3.40-3.29 (m, 2H), 2.93-2.86 (m, 2H), 2.71-2.64 (m, 1H), 2.37 (s, 3H), 1.88-1.85 (ra, 1H), 1.65-1.43 (m , 2H), 1.26-1.21 (m, 1H).

MS (ESI +) 475 (M ⁺ +1, 14%). Example 64

8-[(3R) -3-Aminopiperidin-1-yl]-7- (2-butoxybenzyl) -tomethyl-2-phenoxy-1,7-dihydro-6H-purine-6-one Hydrochloride

tert-Butyl {(3R) -l- [7- (2-chlorobenzyl) -1-methyl-6-oxo-2-phenoxy-6,7-dihydro-1H-purin-8-yl] piperidine Hydrochloric acid (2N, 0.80 mL) was added to a 2-propanol solution (9.5 mL) of 3-yl} lbamate (0.75 g) at room temperature, and the mixture was heated with stirring at 85 ° C for 30 minutes. The reaction solution was gradually cooled to room temperature, and the crystals were collected by filtration and dried to give the title compound (625 mg) as white crystals.

Ή NMR (400MHz, DMS0-d ₆ ) δρρηι 8.05-7.95 (br, 3H), 7.53-7.47 (m, 3H), 7.35- 7.26 (m, 5H), 6.76 (d, J = 6.3Hz, 1H), 5.43 (s, 2H), 3.52-3.49 (m, 1H), 3.48 (s, 3H), 3.39-3.32 (m, 1H), 3.05-3.00 (m, 2H), 2.83-2.79 (m, 1H), 1.91—1.88 (m, 1H), 1.67-1.51 (m, 1H), 1.47-1.44 (m, 2H).

MS (ESI +) 465 (M ⁺⁺ l, fraction). In the same manner as in Example 64, the compounds of Examples 65 to 94 were synthesized from the corresponding reference examples.

CI

0

The person N

R ² people, N people N-

NH ₂ HCI

Example number 2 Raw material reference example number Example 6 5 Reference example 6 4 Example 6 6 Reference example 9 0 Example 6 7 Reference example 8 9 Example 6 8 Reference example 9 1 Example 6 9 Reference example 9 2 Example 7 0 Reference Example 9 3 Example 7 1 Reference Example 9 4 Example 7 2 Reference Example 9 5 Example 7 3 Reference Example 9 6

0,, 0

Example 7 4 Reference Example 9 7 Example 7 5 Reference Example 3 2 Example 7 6 Reference Example 9 8

Example 7 7 Reference example 6 0

Example number Reference number of raw material 0

Example 7 8 0 ° Reference Example 9 9 Example 7 9 Reference Example 1 0 0

Example 8 0 Reference example 1 0 1

^F Example 8 1 F ', 0 ο

Reference Example 10 2 Example 8 2 Χ ° 0 ° Reference Example 10 3

Example 8 3 Reference example 1 0 4

0

Example 8 4 MeO ^ ⁰ Reference Example 1 0 5 Example 8 5 Reference Example 1 0 6

Example 8 6 Reference Example 1 0 7 Example 8 7 Reference Example 1 0 8

Example 8 8 Reference Example 1 0 9

Example 8 9, Ο Reference Example 1 1 0

Ο Example number Reference material example number

Example 90 Reference Example 5

Example 9 1 Reference example 1 1 1

Example 92 Reference Example 1 1 2 Example 93 Reference Example 1 32

Example 94 Reference Example 1 27

Example 65

¾ NMR (400MHz, DMS0-d ₆ ) (5 pm 8.34 (br, 3H), 7.53-7.51 (m, 1H), 7.41-7.28 (m, 3H), 6.93-6.87 On, 4H), 5.48 (d, J = 17.4Hz, 1H), 5.43 (d, J = 17.4Hz, 1H), 3.78 (s, 3H), 3.57-3.54 (m, 1H), 3.46 (s, 3H), 3.32-3.24 (m, 1H ), 3.13-3.04 (m, 2H), 2.85-2.76 (m, 1H), 1.97--1.90 (m, 1H), 1.72-1.64 (m, 1H), 1.58-1.52 (m, 1H), 1.48-1.40 (m, 1H).

MS (ESH) 495 (M ⁺ + l, 57%).

Example 66

'Η NMR (300MHz, DMS0-d ₆ ) <5 pm 8.34 (br, 3H), 7.52 (d, J = 7.7Hz, 1H), 7.36- 7.22 (m, 3H), 6.85 (d, J = 7.1Hz) , 1H), 6.76-6.69 (m, 3H), 5.48 (d, J = 18.1Hz, 1H), 5.42 (d, J = 18.1Hz, 1H), 3.59-3.55 (m, 1H), 3.45 (s, 3H), 3.30-3.28 (m, 1H), 3.16-3.05 (m, 2H), 2.85-2.83 (m, 1H), 1.92-1.90 (m, 1H), 1.70- 1.68 (m, 1H), 1.56- 1.47 (m, 3H).

MS (ESI +) 481 (M ++ 1, HI)

Example 67

'Η NMR (300MHz, DMSO- d ₆ ) 5ppm 8.19 (br, 3H), 7,52 (t, J = 7.5Hz, 1H), 7.40- -1 'Z' (HZ '20 -8-60 "2' (HI 9Z'S-6Z '(HS' s) 9f 2 '(HI 99' 8 08 -6 '8' (HZ 'ιπ) L'-^ L '' (M 's) SS' (H '· 9-06 · 9' (HS '«0 H'L -88', '(HI

Ι 8 ( ⁹ P-0SWO 'ZHR002) ¾ H,

11 w

• (% 001 'H ₊ W) Z9S (+ IS3) sw • (HS' ΖΗΓΖ ^ ί '\) ΠΌ' (H 8 G SS'I '(HS SZ

'αι) 99ΐ ΐ-8Π' (HI 'ω) 06ίί- Ζ6Ί' (HI 8A'2-t8'Z '(Η2') O'S-irg '(Ηΐ' ϋΐ) AZ'S— 6Z'S '(HS' s) 9f 8 '(HI' ω) 99 '8-63' 8 '(HZ' ^ζ ΗΓ9 = ί Ί) 86 "S '(HZ' s) S '(Ηΐ' -L = 'Ρ) 6Γ9' ( HS 8 · 9 - Ϊ6 · 9 '(HS' «0 ^ ΙΊ -68 '' (HI 'ΖΗ3 · ί' Ρ) 13 '(Η8') 92 '8 nidd ^ (9 p-0SM' ZH) OS) Marauder

0 Lm 02

• (% 00ΐ (+ IS3)

'(HS' = i 6'0 '(H2 09'l- n' (HS

69Ί-9Π '(Hi' αι) 88 'I-06 · Ι' (HI 'ω) 6 18' (HZ SO '8-11 "S' (HI '« ΐ) 8 e-02-e' (HS 's) 9f g' (HI 'αι) 0' 8-8 g '(HZ' ¾S 9 = ί Ί) 86 '9' (HI 'ΖΗ8'8ΐ = ί' Ρ) Of 3 '(HI' ΖΗΓ8 ί 'Ρ) 9f 9' (m 'ω) 069' (Η8 '«91

'(ΗΙ' «8f '(HS' JQ) 62 '8« ιΰύρ ( ⁹ p-0SM' ZHWOOS) fflN H,

69

• (% 00l 'I W (+ IS3) Sti

• (H9 'ΖΗ0'9 = ί

'Ρ)' {m ^£ ui) ΐ-19'ΐ '(Ηΐ' 99 · ΐ— 89 · ΐ '(Ηΐ 88'ΐ-06'ΐ' (Ηΐ 01

'αΐ) 8Ζ-2-08 ^£ (ΗΖ' ω) 10 "8-60 '8 ^£ (Ηΐ 9Z'S— 8Ζ · ε' (HS 's)' (Ηΐ '« ι) Z9 "S- S * 2' ΟΠ 'ω) · Η9 ·' (HZ 's) SS' (H '«9 · 9— 88 · 9' (Η8

ΠΊ-Ιί-ί 'ΟΠ') 8f '(Η8 q) 6Γ8 «ΐ (Μρ ( ⁹ p-0SW' ΖΗίϊ002) Η Η,

89 m ^

• (% Ζ \ ') 609 (+ IS3) SW 9 "' (Η8 'm" 9 = 1' 1) '(Η2' ω) 9 Ιone · 〖'ΟΠ' «Ζ9 · ΐ-0Γΐ '(Ηΐ ) 06 -Ζ6-1 '(Ηΐ' «0 fZ-^ 'Z' (ΗΖ 'ω) gO'8-OrS' (ΗΙ 08 '8-22" 2' (HS 's) f ?,' (Ηΐ '69' S-09 "8 '(ΙΚ' ZH8'SI '8 * 9 = 1' ΡΡ) 90 '' (Η2 's) 9f9' (m 'ω) U" 9-16 -9' (HS ' ω) ^ Ζ'ί

I 9 Ζ

908960 / OOZ OAV 9f ΐ-89'ΐ '(Ηΐ' in) 69 · Ι— U 'l' (HI 'ω) 06 · ΐ— Ζ6 · ΐ' (Ηΐ 'ω) 08 — 98' (HZ OS

'«0 TS—' S '(Ηΐ' ω) '8-08' S '(HS' s) 9f 2 '(Hi' ω) -ί ^ '(Μ' s) SS '(Η2' s) 0Γ9 'OK S8'9' (HZ> 96 '9-00 Ί' (Η2 'ω) 9ΓΖ

-9S'i, '(HI' -L ^ i 'Ρ) 23' OK ^ q) 88 -8 uidclp ( ⁹ p-0SM 'ZHW00S) ¾i H,

g z P Toshiki

• (% 00l Ί ^ Κ) S85 (+ I H) sz

• (H9 'ω) Lf \ -Z-\' (HI

') 8I-06 · ΐ' (HZ 'ω) WZ-LO'Z' (HZ-· Ζ '(Ht' πι) 9Z -88'Z '(Η2' ιπ) lO'S-OO'S '(Η8 ^£ s) W'S '(HI ¾) S SS ^ S' (HI ¾) OS 'S-ZS'S' (Ηΐ 'πΐ) 9 · St' (HZ 's) 8FS' (H ¾) U "9-06 '9' (HC ¾) Ί 'Οίΐ' -L = i 'P) IS Ά' (H8 'πι) gl' 8-0Γ8 ωΰΰρ ( ⁹ p-0SM 'zffiWOS) NH, 02

L

• (¾ooi 't + _† w) m (+ ISH) spi

• (H2 'πΐ) 39-0-69Ό' (HZ ') 9 · 0—08 · 0' (HZ 'ω) 9 G IS'I' (Ηΐ 'ω) 89Ί-0ΓΪ' (HI 'ιπ) 68 -l-26'l '(HI' «-18 '(HZ) SO' g-ZO '(HI'« S-6Z'S ^£ (H8 ^£ s) '(HI t' S-ZS 'S' (HI ' ) 8'8-88 * 8 '(m' SI

SS '(Ηΐ' in)-8i 9 '(HI' ω) 9 1 06 9 '(HZ 86' 9-80 '(HS') UL-lfL ^£ (Ηΐ 'ω) 6f Z-2S'' (HS 'Jq) 80' 8 Μρ ( ⁹ p-. '哪 02) Leakage

ε L

• (% 00ΐ 989 (I I S3)

'(HZ' «0 01

ΙΓ0- Γ0 '(HZ' ω) gg-O-SS'O '(HI' ω) ΙΓΐ-SZ'l '(IK ^<m ) SS'I-SS'I' (HI 'in) 9 69ΐ ΐ '(Ηΐ' ω) 8 · 06 06 Ί '(HI ¾) ί' -0 1 '(ΗΖ' πι)

'(Ηΐ' "I) '(HS' s) Sfg '(HI IS'S-SS'S' (Η2 '2 ^ 7 = 1' Ρ)

18 * 8 '(HZ' s) ^ '9' (HI '¾Ι' i = i 'Ρ) 8Γ9' (HS ') S8'9-689' (HS U'L

'ΟΠ' ZHS · = ί 'Ρ) 05' (HS '^) ( ⁹ P— OSWd' ZHWOOS) ™ H, 9 'z L im

• (Marauder gg (iisa) m

• (H9 'ZH9' 9 = ί 'Ρ) i, 6 "0 ^e (m ¾) 9f ΐ-Ζ9 * ΐ' (Ηΐ 'πΐ) 99Ί-69Ί' (Η2 'ω) 68 (Ηΐ '«6ΓΖ

8 S 2

1 ^ 01900 contract Zdf / e :) d 908 960 contract OAV (m, 2H).

MS (ESI +) 509 (M ⁺ + l, 34¾)

Example 76

¾ NMR (300MHz, DMSO- d ₆ ) δρριη 8.36 (br, 3H), 7.58-7.50 (m, 2H), 7.36-7.16 d, 6H), 6.82 (d, J = 6.Hz, 1H), 5.46 ( d, J = 18.1Hz, 2H), 3.60-3.55 (m, 1H), 3.47 (s, 3H), 3.29-3.27 (m, 1H), 3.14-3.04 (m, 2H), 2.86-2.79 (m, 1H), 1.92-1.90 (m, 1H), 1.71-1.46 (m, 3H).

MS (ESI +) 531 (M ++ 1, 100%).

Example 77

¾ NMR (300MHz, DMS0-d ₆ ) <5ppm 8.22 (br, 3H), 7.62 (t, J = 8.2Hz, 1H), 7.52- 7.45 (m, 2H), 7.41-7.24 (m, 4H), 6.78 -6.76 (m, 1H), 5.44 (s, 2H), 3.54- 3.50 (m, 1H), 3.46 (s, 3H), 3.28-3.26 (m, 1H), 3.09-3.02 (m, 2H), 2.80 -. 2.78 (m, 1H) , 1.90-1.88 (m, 1H), 1.69-1.67 (m, 1H), 1.52-1.47 (m, 2H) MS (ESI +) 549 (M + + l, 33¾).

Example 78

'Η NMR (300MHz, DMS0-d ₆ ) δρριη 8.35 (br, 3H), 7.50 (d, J = 7.5Hz, 1H), 7.40 (t, J = 8.1Hz, 1H), 7.34-7.24 (m, 2H ), 7.03-6.93 (m, 3H), 6.85-6.80 (m, 1H), 6.59-6.57 (m, 0.25H), 6.40-6.38 (m, 0.5H), 6.22-6.20 (, 0.25H), 5.44 (t, J = 18.4Hz, 2H), 4.38-4.27 (m, 2H), 3.58-3.53 (m, 1H), 3.45 (s, 3H), 3.28-3.26 (m, 1H), 3.13-3.06 (m , 2H), 2.82-2.80 (i, 1H), 1.90-1.88 (m, 1H), 1.69-1.67 (m, 1H), 1.54-1.34 (m,-2H).

MS (ESI +) 545 (M + + l, 100%).

Example 79

¾ negation _{R (300MHz, DMSO- d 6)} άρρπι 8.36 (br, 3H), 7.51-7.40 (m, 2H), 7.34-7.25 (m, 2H), 7.09-6.98 (m, 3H), 6.85-6.80 ( m, 1H), 5.44 (t, J = 18.3Hz, 2H),

4.80 (dd, J-8.9, 17.7Hz, 2H), 3.58-3.53 (m, 1H), 3.45 (s, 3H), 3.29-3.27

(m, 1H), 3.13-3.06 (m, 2H), 2.82-2.80 (m, 1H), 1.90-1.88 (m, 1H), 1.69-

1.67 (m, 1H), 1.54-1.34 On, 2H).

MS (ESI +) 563 (M ++ 1, 100%).

Example 80 ¾ NMR (300MHz, DMS0-d ₆ ) άρρπι 8.34 (br, 3H), 7.59 (t, J = 8.5Hz, 1H), 7.52- 7.48 (i, 1H), 7.36-7.26 (m, 5H), 7.03- 7.01 (m, 0.25H), 6.86-6.84 (m, 0.5H), 6.82-6.79 (m, lH), 6.68-6.66 (m, 0.25H), 5.44 (t, J = 18.5Hz, 2H), 3.57 -3.53 (m, 1H), 3.45 (s, 3H), 3.27-3.25 (, 1H), 3.13-3.02 (m, 2H), 2.81-2.79 (m, 1H), 1.90-1.88 (m, 1H), 1.69-1.67 (m, 1H), 1.53-1.44 (m, 2H).

MS (ESI +) 581 (M ⁺ + l, 100%).

Example 81

Ή NMR (300MHz, DMSO-d ₆ ) 5 pm 8.23 (br, 3H), 7.52-7.49 (m, 1H), 7.39 (t, J = 8.1Hz, 1H), 7.34-7.24 (m, 2H), 7.05 -7.00 (m, 2H), 6.94-6.91 (i, 1H), 6.79-6.77 (m, 1H), 5.43 (s, 2H), 4.96-4.56 (m, 5H), 3.52-3.50 (m, 1H) , 3.45 (s, 3H), 3.29-3.27 (m, 1H), 3.10-3.03 (, 2H), 2.81-2.79 On, 1H), 1.89-1.87 (m, 1H), 1.68-1.66 (m, 1H) , 1.50-1.46 (m, 2H).

MS (ESI I) 559 (M ++ 1, 100%).

Example 82

¾ NMR (300MHz, DMSO- d ₆ ) άρρηι 8.21 (br, 3H), 7.52-7.42 (m, 2H), 7.34-7.24 (m, 2H), 7.03-6.98 (m, 3H), 6.78 (d, J = 7.1Hz, 1H), 5.44 (s, 2H), 4.57-4.55 (m, 1H), 3.58-3.54 Cm, 1H), 3.47 (s, 3H), 3.28-3.26 (m, 1H), 3.09-3.02 (m, 2H), 2.81-2.79 (m, 1H), 2.10-2.04 (in, 1H), 1.90-1.75 (m, 3H), 1.50-1.46 (m, 2H).

MS (ESI +) 557 (M ++ 1, 100%).

Example 83

Ή NMR (400MHz, DMSO-d ₆ ) <5ppi 8.24-8.19 (m, 3H), 7.51 (dd, J = 1.4, 7.8Hz, 1H), 7.38 (t, J = 8.2Hz, 1H), 7.33-7.28 (m, 2H), 6.93-6.88 (m, 3H), 6.79 (d, J = 8.9Hz, 1H), 5.44 (s, 2H), 4.71 (s, 2H), 3.54-3.48 (m, 1H), 3.46 (m, 3H), 3.35-3.30 (m, 1H), 3.10-3.05 (m, 2H), 2.83-2.79 (m, 1H), 1.70-1.67 (m, 1H), 1.59-1.52 (m, 1H ), 1.45-1.44 (m, 2H).

MS (ESH) 539 (M ++ l, 100%).

Example 84

Ή NMR (400MHz, DMSO- d ₆ ) δρριη 8.19 (br, 3H), 7.52 (dd, J = 1.4, 7.8Hz, 1H), ^£ (Ηΐ ^s ' Z = i) 88 * 9 '(Ηΐ 6Γ9-08 "9' (Ηΐ ¾) 989-689 '(Ηδ' ω) OS ll'l-ll'l '(ΗΪ' ω) 6f Ζ-Ϊ91 '(Η2') 8Γ8 ( ⁹ P- OSTO 'ZHWOOS) MN H,

• (% ooi Ή + w) (+ isa) m

• (HZ ') 8Γΐ-99'ί' (Ηΐ '«0 ^ Ί- ί

'(Ηΐ ^£ ui) 88 -36-1 ^£ (ΗΙ 9' 2-88 '(ΗΖ ^£ ω) 80'S-' (HI 6Γδ -OS'S '(HS' s) 18 '8' (HS 's) 09' 8 '(Ηΐ'«ZS'S-SS'-g'(HZ' s) SS '(HI' ZHf 9 = 1 'Ρ) 6Γ9' OK 'πΐ) SS' (Hi 'ω) 13 -991' (HZ ''8 = ί' Ρ)

29 '(Η2' ΖΗ9 · 8 = ί 'Ρ) 90 · 8' (HS ^£ JQ) If 8 ωΰΰρ ( ⁹ ρ-OS I 'ZHW00) N Η,

L 8 ^ tow

• (% 00ΐ 'ΐ + ₊ ίΐ) 96f- (+ IS3) SN • (Η2') Ή · ΐ '(Ηΐ' ιπ) 9Ί— 69 · Ι '(Ηΐ

'«68 · 16 16' I 'ΟΠ' ω) .8ΓΖ-98 '(ΗΖ'« '(Ηΐ-IS'S

'(Η8' δ) 8 '(HI' ID) ZS'S— 'S' (Η2 'S3 · ^£ (H2' s) '(HI' ΖΗ9 '= ί

'Ρ) 8Γ9' (Ηΐ 'ΖΗ6 · = ί' Ρ) SI '(Η Wl-9' L '(Ηΐ' ΖΗ6 · Ί Ί)

Ζ '(ΗΙ' ΖΗΓ = ί 'Ρ) Ζ -Α' (Η8 q) L \ '8 ω (Μρ ( ⁹ p-0SM' 0 Marauder H, 91

98 mm

• (Mardal 'H _† W) £ 99 (+ IS3) SN

'(HZ

9 ΐ 一 SS'l '(HI' ιπ) 9I-1 69 69 I '(HI 98'1-I6'l' (Ηΐ ¾) 2Z ^ -88 -2 '(IK' ω) S8-Z- 0r8 '(HI ¾) Srg-SS' (HS ' ^s ) Lfi' (HI ¾) 9 ^ '8-9S'8' (H £ 01 's) Zf2' (HZ 's) 98' t '(' s) '(HI' I 'ΖΊ = ί' ΡΡ) 6Γ9 '(IK

'ΖΗ8' 9 'ΓΖ = ί' ΡΡ) ZO'L '(ΗΖ' 8 · 9 '' Ζ = ί 'ΡΡ) IVl' (El 'WL-n'L' (Ηΐ 'ΖΗ8 · ί' Γΐ-ί 'ΡΡ) 1 ^ 1' (Η8 '^) 6Γ8 uiddp ( ⁹ Ρ-OSMI' lia 0

98 mm

• (% 00ΐ 899 (+ ISH) SK S "'(HZ' ω) Sf I-S9" l '(Ηΐ' ω) 69 · ΗΓΙ '(HI')

68ϊ-ϊ6Ι '(HI ^£ m) OO'e- O'S ^£ (H2' m) 90-9-0ΐ '8' (Ηΐ 'πΐ) 08'S-S8 "S'(HS's) if S '(HI' m) ε-89'S '(HS' s) ZL'Z '(HZ' s) n '(HZ' s) '(m' ω) Ζ '9-6Γ9' (Ht '«0 06 9-6 9 '(Ηΐ' ω) 96 9-6 9 '(Η 6 Ζ Z-Tf A

Τ 9 2 tOl900 / tOOld / 13d 908960 / Ι ^ ΟΟΖ: OAV 6.53-6.50 (m, 1H), 5.44 (s, 2H), 4.16 (dd, J = 7.0, 14.2Hz, 2H), 3.55-3.50 (m, 1H), 3.44 (s, 3H), 3.28-3.26 ( m, 1H), 3.07-3.04 (m, 2H), 2.80-2.68 (m, 3H), 2.41-2.36 (m, 2H), 1.94-1.90 (m, 3H), 1.70-1.67 On, 1H), 1.55 -1.44 (m, 2H), 1.12 (t, J = 7.1Hz, 3H).

MS (ESI +) 607 (M ++ l, 100%).

Example 89

Ή NMR (400MHz, DMS0-d ₆ ) 5ppm 8.08-8.04 (m, 5H), 7.52 (dd, J = 1.4, 7.8Hz, 1H), 7.45-7.43 (m, 2H), 7.34-7.28 (m, 2H ), 6.77 (d, J = 7.5Hz, 1H), 5.44 (s, 2H), 3.55-3.50 (m, 1H), 3.48 (s, 3H), 3.35-3.29 (m, 1H), 3.08-3.01 ( m, 2H), 2.82-2.80 (m, 1H), 1.91-1.88 (m, 1H), 1.69-1.68 (m, 1H), 1.47-1.44 (m, 2H).

MS (ESI +) 509 (M ++ 1, 100%).

Example 90

'Η NMR (400 MHz, DMSO-d ₆ ) δρρι 7.99 (br, 3H), 7.94-7.89 (m, 2H), 7.66-7.62 (m, 2H), 7.53-7.51 (i, 1H), 7.33-7.28 ( m, 2H), 6.77 (dd, J = 1.4, 7.9Hz,

1H), 5.44 (s, 2H), 3.89 (s, 3H), 3.49 (s, 3H), 3.50-3.40 (m, 1H), 3.35-

3.25 (m, 1H), 3.06-3.01 (m, 2H), 2.81-2.78 (m, 1H), 1.69-1.61 (m, 1H),

1.92-1.89 (m, 1H), 1.52-1.44 (m, 2H).

MS (ESI +) 523 (M + + l, 100%).

Example 91

Ή NMR. (400MHz, DMSO - d 6) (5ppm 8.11 (m, 3H), 7.52 (dd, J = 1.4, 7.8Hz, 1H), 7.40-7.28 (m, 6H), 7.29 (t, J H F = 74.0Hz, 1H), 6.77 (d, J = 6.2Hz, 1H), 5.45 (s, 2H), 3.50-3.47 (m, 1H), 3.47 (s, 3H), 3.40-3.30 (m, 1H) , 3.08-3.02 (m, 2H), 2.85-2.79 (m, 1H), 1.90-1.85 (m, 1H), 1.68-1.60 (m, 1H), 1.51-1.46 (m, 2H).

MS (ESI +) 531 (M ++ 1, 100%).

Example 92

Ή NMR (400 MHz, MeOH-d ₄ ) δ ppm 7.50-7.44 (m, 1H), 7.36-7.08 (m, 4H), 6.84-6.74 (m, 2H), 5.56 (s, 2H), 4.89-4.70 (m, 1H), 3.78 (s, 3H), 3.68-3.60 On, 2H), 3.58 (s, 3H), 3.44-3.34 (m, 1H), 3.26-3.18 (m, 1H), 3.05- 2.92 (m, 1H), 2.90-2.79 (m, 1H), 2.78-2.66 (m, 1H), 2.30-2.12 (ι, 2H), 2.10-2.01 (m, 1H), 1.84-1.72 (m, 1H ), 1.68—1.53 (m, 2H).

MS (ESI +) 579 (M ⁺ + l, 100%)

Example 93

l NMR (400 MHz, MeOH-d ₄ ) <5 pm 7.50-7.13 (m, 9H), 5.56 (s, 2H), 3.80-3.69 (m, 1H), 3.55 (s, 3H), 3.44-3.34 ( , 1H), 3.31-3.22 (m, 1H), 3.15-3.00 (m, 2H), 2.12-2.00 (m, 1H), 1.89-1.75 (m, 1H), 1.70-1.51 (m, 2H).

MS (ESH) 464 (MHl, 100%)

Example 94

'Η NMR (400 MHz, MeOH-d ₄ ) δ ppm 7.48-7.40 (m, 1H), 7.38-7.05 (m, 7H), 6.98-6.88 (m, 1H), 5.58 (s, 2H), 4.31 ( s, 2H), 3.78-3.69 (m, 1H), 3.68- 3.59 (m, 2H), 3.65 (s, 3H), 3.49-3.36 (m, 1H), 3.05-2.95 (m, 1H), 2.13- 2.00 (m, 1H), 1.82-1.70 (m, 1H), 1.69-1.52 (m, 2H)

MS (ESI +) 463 (MHl, 100%) Example 95

8-[(3R) _3-Aminopiperidin-1-yl] -7- (2-methylbenzyl)-1-methyl-2-phenoxy-1,7-dihydro-6H-purine-6-one hydrochloride salt

In the same manner as in Example 64, the compound of Example 95 was synthesized from the corresponding compound of Reference Example.

Ή NMR (400 MHz, DMS0-d ₆ ) δ ριη 8.25 (br, 3H), 7.51-7.45 (m, 2H), 7.34-7.28 (m, 3H), 7.22-7.06 (m, 3H), 6.57 (d, J = 7.1Hz, 1H), 5.41 (d, J = 17.2Hz, 1H), 5.35 (d, J = 17.2Hz, 1H), 3.56-3.53 (m, 1H), 3.46 (s, 3H), 3.30- 3.27 (m, 1H), 3.10-3.03 (m, 2H), 2.83-2.76 (m, 1H), 2.33 (s, 3H), 1.91-1.88 (m, 1H), 1.68-1.65 (i, 1H), 1.54-1.40 (m, 2H).

MS (ESH) 445 (M ⁺ H, 18). In the same manner as in Example 95, the compounds of Examples 96 to 105 were synthesized from the corresponding compounds of Reference Examples.

Example number Reference material example number

, 0

Example 9 6 ^{Η0 Ό} Reference Example 1 1 4 Example 9 7 Reference Example〗 1 5

, 0

Example 9 8 Reference Example〗 1 6

,

o

Example 9 9 0 ° Reference Example 1 17 Example 1 0 0 Reference Example 1 1 8 Example 1 0 1 Reference Example 1 1 9

0

Example 1 0 2 Reference example 1 2 0 Example 1 0 3 Reference example〗 2 1 Example 1 0 4 Reference example 1 2 2

O

Example Ί 0 5 <Reference example 1 2 3

O °

Example 9 6 ¾ NMR (300MHz, DMS0-d ₆ ) 5ppm 8.23 (br, 3H), 7.26-7.06 (m, 4H), 6.74-6.68 (m, 3H), 6.57 (d, J = 7.0Hz, IH), 5.38 ( s, 2H), 3.57-3.54 (m, 1H), 3.43 (s, 3H), 3.31-3.29 (m, IH), 3.11-3.04 (m, 2H), 2.81-2.79 (i, IH), 2.33 ( s, 3H), 1.90-1.88 (m, 1H), 1.68-1.66 (m, IH), 1.51-1.42 (m, 2H).

MS (ESH) 461 (M ⁺ + l, 100%).

Example 97

Ή NMR (300MHz, DMS0-d ₆ ) ά ριη 7.83 (br, 3H), 7.36 (t, J = 7.9Hz, IH), 7.26- 7.05 (m, 3H), 6.92-6.84 (m, 3H), 6.55 (d, J = 7.1Hz, IH), 5.41 (d, J = 17.0Hz, IH), 5.34 (d, J-17.0Hz, IH), 3.77 (s, 3H), 3.54-3.51 (m, IH) , 3.44 (s, 3H), 3.23-3.17 (m, 1H), 3.04-2.97 (m, 2H), 2.80-2.74 (m, IH), 2.33 (s, 3H), 1.90-1.84 (m, IH) , 1.69-1.60 (m, IH), 1.51-1.40 (m, 2H).

MS (ESH) 475 (M ⁺ +1, 14%).

Example 98

Ή NMR (300MHz, DMSO-d ₆ ) δρρ 8.18 (br, 3H), 7.36 (t, J = 8.1Hz, IH), 7.23- 7.07 (m, 3H), 6.91-6.84 (m, 3H), 6.57 ( d, J = 7.3Hz, IH), 5.38 (s, 2H), 4.04 (dd, J = 6.8, 13.8Hz, 2H), 3.54-3.52 (m, IH), 3.46 (s, 3H), 3.32-3.30 (m, 1H), 3.09-3.05 (m, 2H), 2.83-2.80 (m, IH), 2.34 (s, 3H), 1.92-1.90 (m, IH), 1.69-1.67 (m, IH), 1.51 -1.46 (m, 2H), 1.34 (t, J = 6.9Hz, 3H).

MS (ESH) 489 (M ++ 1, 100%).

Example 99

¾ NMR (300MHz, DMS0-d ₆ ) a pm 8.18 (br, 3H), 7.35 (t, J = 7.9Hz, IH), 7.23- 7.07 (, 3H), 6.89-6.82 (m, 3H), 6.57 ( d, J = 7.5Hz, IH), .5.38 (s, 2H), 4.66-4.58 (m, 1H), 3.57-3.55 (m, IH), 3.46 (s, 3H), 3.32-3.30 (m, 1H ), 3.10-3.03 (ffl, 2H), 2.83-2.77 (m, IH), 2.34 (s, 3H), 1.92-1.90 (m, IH), 1.69-1.67 (m, IH), 1.54-1.43 (m , 2H), 1.28 (d, J = 5.8Hz, 6H).

MS (ESH) 503 (M ++ 1, picture).

Example 100

Ή NMR (300MHz, DMSO-d ₆ ) (5ppm 8.34 (br, 3H), 7.35 (t, J = 8.2Hz, 1H), 7.23- 7.07 (m, 3H), 6.88-6.83 (m, 3H), 6.60 (d, J = 7.5Hz, IH), 5.44 (d, J = 16.9Hz, IH), 5.36 (d, J = 16.9Hz, IH), 4.83-4.81 (m, IH), .3.59-3.56 (m , IH), 3.45 (s, 3H), 3.32-3.30 (m, 1H), 3.14-3.07 (m, 2H), 2.85-2.81 (m, 1H), 2.35 (s, 3H), 1.94-1.92 (m, 3H), 1.73-1.43 ( ι, 9H).

MS (ESH) 529 (M ++ 1, 100%).

Example 101

¾ NMR (400MHz, DMS0-d ₆ ) (5 ppm 8.47 (br, 3H), 7.48-7.42 (m, 3H), 7.19-7.10 (m, 7H), 7.09-7.08 (m, 1H), 6.98-6.95 (m, 1H), 6.62 (d, J = 7.6Hz, 1H), 5.46 (d, J = 17.0Hz, 1H), 5.37 (d, J = 17.0Hz, 1H), 3.71-3.60 (m, 1H) , 3.44 (s, 3H), 3.36-3.23 (m, 1H), 3.19-3.06 (m, 2H), 2.88-2.79 (m, 1H), 2.34 (s, 3H), 1.95-1.87 (m, 1H) , 1.79-1.69 (m, 1H), 1.64-1.53 (m, 1H), 1.49-1.38 (m, 1H).

MS (ESH) 537 (M ⁺ + l, 100%)

Example 102

¾ NMR (300MHz, DMSO- d ₆ ) 5 pm 8.10 (br, 3H), 7.57-7.52 (m, 1H), 7.23-7.07 (m, 6H), 6.56 (d, J = 7.5Hz, 1H), 5.38 (s, 2H), 3.61-3.56 (m, 1H), 3.47 (s, 3H), 3.28-3.27 (m, 2H), 3.08-3.01 (m, 2H), 2.81-2.79 (m, 1H), 2.34 (s, 3H), 1.92-1.90 (m, 1H), 1.67-1.65 (m, 1H), 1.53-1.46 (m, 2H).

MS (ESH) 511 (M ⁺ +1, 100%).

Example 103

* H NMR (300MHz, DMSO- d ₆ ) δρρηι 8.32 (br, 3H), 7.62 (t, J = 8.2Hz, 1H), 7.46- 7.34 (in, 3H), 7.24-7.06 (m, 3H), 6.57 (d, J = 7.3Hz, 1H), 5.43 (d, J = 17.0Hz,

1H), 5.36 (d, J = 17.0Hz, 1H), 3.58-3.55 (m, 1H), 3.46 (s, 3H), 3.27-3.25

(m, 1H), 3.11-3.04 (m, 2H), 2.83-2.76 (m, 1H), 2.34 (s, 3H), 1.90-1.88 (m, 1H)

1H), 1.69-1.67 (i, 1H), 1.53-1.41 (m, 2H).

MS (ESI +) 529 (M ++ 1, 100%).

Example 104

Ή NMR (300MHz, DMSO-d ₆ ) ρριη 8.36 (br, 3H), 7.33-7.28 (m, 1H), 7.23-7.06 (m, 4H), 6.88-6.81 (m, 1H), 6.60 (d, J = 7.0Hz, 1H), 5.42 (d, J = 16.9Hz, 1H), 5.34 (d, J = l 6.9Hz, 1H), 3.76 (s, 3H), 3.59-3.53 (m, 1H), 3.45 (s, 3H), 3.28-3.20 (m, 1H), 3.13-2.95 (m, 2H), 2.90-2.75 (m, 1H), 2.33 (s, 3H), 1.90-1.84 (in, 1H), 1.70 -1.63 (m, 1H), 1.56-1.49 (m, 1H), 1.44-1.36 (m, 1H)

MS (ESI +) 493 (M ++ l, 100%)

Example 105

¾ NMR (300MHz, DMSO-d ₆ ) δρριη 8.32 (br, 3H), 7.22-7.06 (m, 3H), 6.98-6.95 (m, 2H), 6.74 (dd, J = 2.3, 8.2Hz, 1H), 6.57 (d, J = 7.1Hz, 1H), 6.08 (s, 2H), 5.42 (d, J = 17.1Hz, 1H), 5.35 (d, J = 17.1Hz, 1H), 3.54-3.49 (m, 1H ), 3.43 (s, 3H), 3.30-3.28 (m, 1H), 3.12-3.05 (m, 2H), 2.82-2.80 (m, 1H), 2.33 (s, 3H), 1.90-1.88 (i, 1H ), 1.69-1.67 (m, 1H), 1.52-1.43 (m, 2H).

MS (ESI +) 489 (M ⁺ +1, 100%). Example 106

8-[(3R) -3-7-Minopiperidin-1-yl] -7- (2-kuguchiguchi-5-fluorobenzyl) -1-methyl-2-phenoxy_1,7-dihydro-6H-purine 6-one hydrochloride

In the same manner as in Example 64, the compound of Example 106 was synthesized from the corresponding compound of Reference Example.

¾ NMR (400MHz, DMS0-d ₆ ) <5ppm 8.00-7.99 (br, 3H), 7.52 (dd, J = 5.1, 8.8Hz, 1H), 7.51-7.47 (m, 2H), 7.35-7.23 (m, 4H), 6.77 (dd, J = 2.9, 9.3Hz, 1H), 5.39 (s, 2H), 3.48 (s, 3H), 3.42-3.32 (, 2H), 3.06-2.84 (m, 2H), 2.70- 2.63 (m, 1H), 1.92-1.89 On, 1H), 1.75-1.70 (m, 1H), 1.52-1.48 (m, 2H) .MS (ESI +) 483 (M ⁺ +1, 100%) In the same manner as in Example 64, the compound of Example 10708 was synthesized from the corresponding compound of Reference Example.

Example number R ² Reference example number of raw material Example 1 07 Reference example 1 25

F 丫 O ^^ O

Example 1 08 Reference Example 1 26

Example 107

_{¾ NMR (400MHz, DMS0- d 6} ) δρριη 8.18 (br, 3H), 7.60-7.57 (m, 1H), 7.41-7.36

(m, 1H), 7.25-7.22 (m, 1H), 6.93-6.86 (m, 3H), 6.71-6.68 (m, 1H), 5.40 (s,

2H), 3.79 (s, 3H), 3.52-3.49 (m, 1H), 3.47 (s, 3H), 3.32-3.30 (m, 1H),

3.11-3.03 (m, 2H), 2.86-2.82 (m, 1H), 1.92-1.90 (m, 1H), 1.75-1.71 (m,

1H), 1.59-1.46 (m, 2H).

MS (ESI +) 513 (MHl, 100%).

Example 108

'Η NMR (400MHz, DMS0- d ₆ ) δρριη 8.15 (br, 3H), 7.59-7.49 (m, 2H), 7.22-7.12

(m, 5H), 6.69-6.65 (m, 1H), 5.42 (d, J = 17.9Hz, 1H), 5.37 (d, J = 17.9Hz,

1H), 3.51-3.48 (m, 1H), 3.46 (s, 3H), 3.30-3.28 (m, 1H), 3.10-3.02 (m,

2H), 2.85-2.80 (m, 1H), 1.90-1.88 (m, 1H), 1.73-1.71 (m, 1H), 1.55-1.47 (m, 2H).

MS (ESI +) 549 (M ++ l, 100%) · Example 109

8-[(3R) -3-Aminopiperidin-1-yl] -7- (2-cyclobenzyl) -trimethyl-2-morpholino-1,7-dihydro-6H-purine-6-one

8-[(3R) -3-Aminopyridine-tolyl] -7- (2-methyl benzyl)-trimethyl _2_ (methylsulfonyl)-1,7-dihydro-6H-purine-6 ( Morpholine (2 mL) was added to 10 mg), and the mixture was heated with stirring at 100 ° C for 20 hours in a sealed tube. After cooling the reaction solution to 25 ° C, toluene (20 mL) was added thereto, and the process of distilling under reduced pressure was repeated three times. The residue was purified by preparative thin-layer chromatography (silica gel, chloroform / methanol = 8/1) to give the title compound (5 mg). '

_{Ή NMR (300MHz, CDC1 3)} (5 pm 7.42-7.38 (i, 1H), 7.22-7.14 (m, 2H), 6.84-6.8 1 (d, J = 7.5Hz, 1H), 5.51-5.50 (m, 2H), 3.87-3.83 (m, 4H), 3.54 (s, 3H), 3.46-3.45 (m, 1H), 3.31-3.30 (m, 1H), 3.23-3.20 (m, 4H), 2.97- 2.93 (m, 2H), 2.76-2.68 (m, 1H), 1.80-1.74 (m, 3H), 1.26-1.24 (m, 1H).

MS (ESI +) 458 (M ++ l, 49¾). Example 110

8-[(3R) -3-T-Minopiperidin-toyl] -7- (2-cyclobenzyl) -tomethyl-2-phenyl-1,7-dihydro-6Η-purin-6-one

(R) was added to an ethanol solution (2.0 mL) of 8-bromo-7- (2-chlorobenzyl) -1-methyl-2-phenyl-1,7-dihydro-6Η-purin-6-one (250 mg). ) -tert-3-Butylpiberidin-3-ylcarbamate (291 mg) and diisopropylethylamine (0.304 mL) were added, and the mixture was stoppered and the reaction solution was stirred at 100 ° C for 3 hours. Ethanol was distilled off under reduced pressure, water and potassium carbonate were added to the residue, the solution was made alkaline, and extracted twice with chloroform. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to column chromatography (silica gel, black form / methanol). = 20/1) to obtain an intermediate. The intermediate was dissolved in methanol (1.0 mL), 4N hydrochloric acid in 1,4-dioxane (4.3 mL) was added, and the reaction solution was stirred at room temperature for 4 hours. Water and potassium carbonate were added to the reaction solution to make the solution alkaline, and the mixture was extracted twice with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (44.1 mg).

_{Ή NMR (400 MHz, CDC1 3} ) 5 pm 7.59-7.54 (m, 2H), 7.52-7.47 (m, 3H), 7.47-7

.42 (m, 1H), 7.27-7.22 On, 2H), 6.92-6.87 (m, 1H), 5.61-5.56 (m, 2H), 3.6

0-3.55 (m, 1H), 3.46 (s, 3H), 3.33-3.28 (m, 1H), 2.97-2.92 (m, 1H), 2.90-2

.85 (m, 2H), 1.95-1.90 On, 1H), 1.70-1.65 (m, 1H), 1.47-1.42 (in, 1H), 1.3

0-1.25 (m, 1H).

MS (ESI +) 449 (MHl, painting) Example 111

Methyl 8-[(3R) -3-7-minopiperidine-toyl] -7- (2-butoxybenzyl) -6-oxo-6,7-dihydro-1H-purine-2-carboxylate

Ethyl 4-amino-2-{(3R) _3-[(tert-butoxycarponyl) amino] piperidine-tolyl} -tol- (2-chlorobenzyl) -1H-imidazole-5-carpoxylate ( To a solution of 478 mg) in 1,4-dioxane (2 mL) was added methyl cyanoformate (0.397 mL) and a solution of 4N hydrochloric acid in 1,4,1-dioxane (10 mL). The mixture was heated and stirred at 70 ° C for 10 hours. The reaction solution was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate (50 mL) was added to the residue to make the solution alkaline, and the mixture was extracted three times with chloroform (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, black-mouthed form Z methanol = 100/1 to 8/1) to obtain the title compound (63 mg).

_{Ή NMR (300MHz, CDC1 3)} δ ρηι 7.42-7.38 (m, 1H), 7.29-7.17 (m, 2H), 6.82 (d, J = 5.9Hz, 1H), 5.56 (s, 2H), 4.03 (s , 3H), 3.80-3.76 (m, 1H), 3.34-3.41 ( m, 1H), 3.31-3.20 (m, 2H), 3.02-2.95 (m, 1H), 2.12-2.10 (m, 1H), 1.74-1.72

(m, 2H), 1.59-1.57 (m, 1H).

MS (ESI +) 417 (MHl, 100%) Example 1 12

Ethyl 8-[(3R) -3-7-minopiveridine-toyl] -7- (2-chlorobenzyl) -6-oxo-6,

7-dihydro-1H-purine-2-carboxylate

In the same manner as in Example 111, the compound of Example 112 was synthesized from the corresponding compound of Reference Example.

_{Ή NMR (300MHz, CDC1 3)} δρριη 7.40-7.37 (m, 1H), 7.25-7.15 (m, 2H), 6.82 (d, J = 7.3Hz, 1H), 5.57 (s, 2H), 4.47 (dd, J = 7.1, 14.3Hz, 2H), 3.79-3.74 (m, 1H), 3.35-3.19 (m, 2H), 3.14-2.90 (m, 2H), 2.08-2.06 (m, 1H), 1.74-1.61 ( m, 3H), 1.44-1.40 (t, J-7.0HZ, 3H).

MS (ESI +) 431 (MHl, 100%). Example 113

8-[(3R) -3-7-Minopiperidin-1-yl] -7- (2-cyclo-5-fluorobenzyl) -2-phenoxy-1, 7-dihydro-6H-purine-6 -On

In the same manner as in Example 111, the compound of Example 113 was synthesized from the corresponding compound of Reference Example.

_{Ή NMR (300MHz, CDC1 3)} δρρι 7.53-7.21 (m, 9H), 6.85-6.83 (m, 1H), 5.49 (s, 2H), 3.41-3.37 (m, 1H), 3.23-3.21 (m, 1H ), 2.89-2.86 (m, 2H), 2.72-2.69 (m, 1H), 1.87-1.85 (m, 1H), 1.64-1.53 (m, 2H), 1.25-1.23 (m, 1H)

MS (ESI +) 451 (M ++ l, 100%) · Reference example 31

tert-Butyl {(3R) _1-[7- (2-octabenzyl) _1 -methyl-6-oxo-2-phenoxy-6,7-dihydro-1H-purin-8-yl] piperidine- 3-yl} force bamate

To a solution of phenol (1.45 g) in tetrahydrofuran (40 mL) was added 60% sodium hydride (0.56 g), and the mixture was stirred at 25 ° C for 1 hour. To this reaction solution was added tert-butyl {(3R) -1- [7- (2-cyclobenzyl) -tomethyl-2- (methylsulfonyl) -6-oxo-6,7-dihydro-1H-purine-8. A solution of (-yl) piperidine-3-yl} capillate (3.85 g) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was stirred at 25 ° C for 3 hours. A saturated aqueous solution of ammonium chloride (50 mL) was added to the reaction solution, and tetrahydrofuran was distilled off under reduced pressure, followed by extraction with chloroform (50 mL) three times. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane / ethyl acetate = 10/1 to 1/1) to obtain the title compound (4.30 g).

_{Ή NMR (300 MHz, CDC1 3} ) δρρπι 7.43-7.38 On, 3H), 7.28-7.15 (m 5H), 6.76 (d, J = 7.3Hz, 1H), 5.59 (d, J = 17.0Hz, 1H), 5.49 (d, J = 17.0Hz, 1H), 4.78-4.76 (m, 1H), 3.72-3.70 (m, 1H), 3.63 (s, 3H), 3.39-3.34 (m, 1H), 3.00-2.93 ( m, 3H), 1.71-1.40 (in, 4H), 1.40 (s, 9H).

MS (ESI +) 565 (MHl, 100%) · Compounds of Reference Examples 32-39, Reference Example 57, Reference Examples 59-66, and Reference Examples 80-112 were synthesized in the same manner as in Reference Example 31.

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Reference Example 37 Reference Example 38 Reference Example 39 Reference Example 57 Reference Example 59

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Reference example 85 Reference example 96 Reference example 86

Reference Example 9 Reference Example 87 0,, 0

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Reference example 88 Reference example 99 Reference example 89

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Reference example 90 HO-, 0 Reference example 1 01

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Reference Example 95

Reference Example 1 05

• (Η6 ^c s) Of \ '(' Hi) Of \ -ZL'l '(Η8 ¾) S6 ー tO'S' (HI ¾) 92-S-Of 2 '(H2' Z9 'S' (Ht 'S -'(HI

'(HI' ΖΗ0 · Ι = ί 'Ρ) OS'S' (Ηΐ 'ΖΗΟΖΗΟ ぃ ί' Ρ) 09 'S' (HI 'ΖΗΙ' ί = ί 'Ρ) 9Γ9' (Η6 WL-ΖΖ-ί '( Η8 '«K'L-ZfL ^ ύρ ( ^ε Ι3α3',)

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'δ) Of ΐ' (Η 'πΐ) Of ΐ-8Γΐ' (Η8 'ω) 86' 2-90 * δ '(Η1 8 S-' (HS 's) 99' 8 '(HI') Ο ' 8-ΖΓε '(HI S U' (HI 'ΖΗ6 · 9 ί' Ρ) OS'S '(HI

'ΖΗ691 = ί' Ρ) 63 * S '(Ηΐ' ZHS 'Ρ) 9' (ΗΖ '(ΗΖ 98 "

L-ZfL '(Hi' πι) 39 -89 Ά '(ΗΖ ZS · 8— SS · 8 πκΜ ρ ( ^ε Ι3αο 00S) Η Η, 01 ε ε

• (% 00ΐ Ί + ₊ ί¾) 609 (+ ISH) SPi '(Η6' s) OI 'πΐ) Of ΐ-99' ΐ '(HS I0'S' (HI 'ω) SS 0 • S (HS' s) 09 '(Ηΐ U'S-SZ-g' (HI 9Γ 8Γ '(Ht' ΖΗΐ -ZI = f 'Ρ) 6 S' (Ηΐ 'ΖΗΓΠ-ί' Ρ) 6S'S '(Μ' δ) 00 * 9 ' (Ηΐ 'ω) 89' 9-99 '9' (Η2 9 • 9-08-9 '(Η2 ιπ) ^ \ · 1-Η1' (ΗΙ 8S _ A Q ( ^ε ϊ3αο "m 009) ¾ Η, ζ ε ρ ^^

9 L Z

1 ^ 01900 contract Zdf / e :) d 908 960 contract OAV _{Ή NMR (400MHz, CDC1 3)} <5 pm 7.41-7.36 (m, 3H), 7.20-7.17 (m, 4H), 6.75 (d, J = 7.3Hz, 1H), 5.57-5.52 (ι, 2H), 4.83-4.78 (m, IH), 3.77-3.72 On, IH), 3.61 (s, 3H), 3.38 (dd, J = 3.4, 12.6Hz, 1H), 3.06-2.95 (m, 3H), 1.75 -1.45 (m, 4H), 1.40 (s, 9H).

MS (ESH) 599 (MHl, 66%).

Reference Example 36

_{Ή NMR (400MHz, CDC1 3)} <5ppm 7.40 (d, J = 7.7Hz, IH), 7.21-7.17 (m, 4H), 7.1 4-7.09 (m, 2H), 6.75 (d, J = 7.4Hz, IH), 5.59-5.54 (m, 2H), 4.83-4.78 (m, IH), 3.77-3.72 (m, IH), 3.62 (s, 3H), 3.37 (dd, J = 3.4, 12.4Hz, IH) , 3.04-2.9 5 (m, 3H), 1.75-1.45 (m, 4H), 1.40 (s, 9H).

MS (ESI +) 583 (MHl, 67%).

Reference Example 57

_{Ή NMR (300 MHz, CDC1 3} ) δ ppm 7.96 - 7.94 (m, 1H), 7.86 (s, IH), 7.52-7.39 (m 3H), 7.22-7.16 (m, 2H), 6.76 (d, J = 7.OHz, IH), 5.59 (d, J = 16.9Hz, IH), 5.50 (d, J = l 6.9Hz, IH), 4.76-4.74 (m, IH), 3.92 (s, 3H), 3.72-3.70 (m, IH), 3.64 (s, 3H), 3.40-3.35 (m, IH), 3.03-2.92 (, 3H), 1.75-1.41 (m, 4H), 1.40 (s, 9H) .

Reference example 59

MS (ESH) 637 (MHl, 96%).

Reference Example 60

MS (ESH) 649 (MHl, 92%).

Reference Example 61

_{Ή NMR (300 MHz, CDC1 3} ) δρριιι 7.44-7.17 (m, 7H), 6.80-6.77 (m, IH), 5.59 (d, J = 17.1Hz, IH), 5.49 (d, J = 17.1Hz, IH ), 4.75-4.73 (m, IH), 3.72-3.70 (m, 1H), 3.64 (s, 3H), 3.40-3.35 (i, IH), 3.00-2.94 (m, 3H), 1.71-1.60 (m , 4 H), 1.40 (s, 9H).

Reference Example 62

_{Ή NMR (300 MHz, CDC1 3} ) (5 pm 7.59-7.51 (m, 4H), 7.42-7.39 (m, IH), 7.23-7 .16 (m, 2H), 6.76 (d, J = 9.0Hz, IH), 5.59 (d, J = 17.1 Hz, IH), 5.49 (d, J = 17.1 Hz, IH), 4.72-4.70 (m, 1H), 3.73-3.71 On, IH), 3.63 (s, 3H ), 3.42-3.38 ( m, 1H), 3.06-2.93 (m, 3H), 1.73-1.48 (m, 4H), 1.40 (s, 9H).

Reference Example 63

_{Ή NMR (300 MHz, CDC1 3} ) <5 pm 7.42-7.33 (m, 2H), 7.22-7.15 (m, 2H), 7.05-6 .96 (m, 3H), 6.75 (d, J = 7.9Hz, IH), 5.59 (d, J = 17.0Hz, 1H), 5.49 (d, J = 17.0Hz, IH), 4.78-4.76 (m, IH), 3.72-3.70 (m, IH), 3.61 (s, 3H), 3.41-3.36 (m, IH), 3.01-2.94 (ra, 3H), 1.74-1.61 (m, 4H), 1.40 (s, 9H).

Reference Example 64

_{Ή NMR (300 MHz, CDC1 3} ) δρρηι 7.42-7.39 On, 1H), 7.32-7.15 (m, 3H), 6.84-6 .75 (m, 4H), 5.59 (d, J = 16.8Hz, IH), 5.49 (d, J = 16.8Hz, 1H), 4.76-4.74 (m, IH), 3.81 (s, 3H), 3.74-3.72 (m, IH), 3.62 (s, 3H), 3.39-3.34 (m, IH), 3.02-2.94 (m, 3H), 1.71-1.58 (m, 4H), 1.40 (s, 9H).

Reference example 65

_{Ή NMR (300 MHz, CDC1 3} ) δρρπι 7.42-7.38 (m, IH), 7.22-7.15 (m, 2H), 6.78-6 .75 (m, IH), 6.37 (s, 3H), 5.59 (d, J = 17.1Hz, IH), 5.49 (d, J = 17.1Hz, IH), 4.75-4.73 (m, IH), 3.78 (s, 6H), 3.73-3.71 (m, IH), 3.61 (s, 3H ), 3.40-3. 35 (m, 1H), 3.02-2.94 (m, 3H), 1.76-1.59 (m, 4H), 1.40 (s, 9H).

Reference Example 66

_{Ή NMR (300 MHz, CDC1 3} ) δρριιι 7.42-7.38 (m, 1H), 7.30-7.15 (m, 3H), 6.80-6 .71 (m, 4H), 5.59 (d, J = 16.9Hz, IH) ; 5.49 (d, J = 16.9Hz, IH), 4.73-4.71 (m, IH), 3.87-3.83 (m, 4H), 3.73-3.71 (m, IH), 3.61 (s, 3H), 3.38-3.35 (m, IH), 3.19-3.16 (m, 4H), 2.99-2.93 (m, 3H), 1.74-1.46 (m, 4H), 1.40 (s, 9H).

MS (ESI +) 595 (MHl, 100%).

Reference Example 81

MS (ESI +) 595 (MHl, 92¾).

Reference Example 82

MS (ESI +) 633 (MHl, 75%).

Reference Example 83

MS (ESI +) 625 (MHl, 85%).

Reference Example 84 MS (ESI +) 639 (MHl, 85%).

Reference Example 85

MS (ESI +) 623 (MHl, 80%).

Reference Example 86

MS (ESII) 623 (MHl, 60%).

Reference Example 87

MS (ESI +) 623 (MHl, 100%).

Reference Example 88

MS (ESII) 649 (MHl, 53%).

Reference Example 89

MS (ESI +) 609 (MHl, 100%).

Reference Example 90

MS (ESII) 581 (MHl, 75%).

Reference Example 91

MS (ESII) 623 (MHl, 90%).

Reference Example 92

MS (ESII) 623 (MHl, 76%).

Reference Example 93

MS (ESII) 637 (MHl, 90%).

Reference Example 94

MS (ESII) 637 (MHl, picture).

Reference Example 95

MS (ESI +) 635 (MHl, 71%).

Reference Example 96

_{'Η NMR (300MHz, CDC1 3} ) δ ι 7.42-7.38 (m, 1H), 7.32-7.15 (m, 3H), 6.96-6.75 (m, 4H), 5.59 (d, J = 17.0Hz, 1H), 5.49 (d, J = 17.0Hz, 1H), 4.75-4.73 (m, 1H), 3.74-3.72 (m, 2H), 3.62 (s, 3H), 3.38-3.35 (m, 1H), 3.02-2.98 ( m, 3H), 1.78-1.41 (m, 4H), 1.40 (s, 9H), 0.79-0.78 (m, 4H).

MS (ESI +) 621 (M ⁺ + l, 82¾).

Reference Example 97 MS (ESH) 635 (MHl, 87%). Reference example 98

MS (ESI +) 631 (MHl, 87%) Reference example 99

MS (ESI +) 645 (MHl, 100%) Reference example 100

MS (ESH) 663 (M ++ 1, 100%) Reference example 101

MS (ESII) 681 (MHl, 100%) Reference example 102

MS (ESI +) 659 (MHl, 100%) Reference example 103

MS (ESI +) 657 (MHl, 87%) Reference example 104

MS (ESII) 639 (MHl, 58%). Reference example 105

MS (ESI +) 653 (MHl, 80%) .Reference example 106

MS (ESII) 653 (M ⁺ +1, 80). Reference example 10

MS (ESII) 595 (MHl, 76%), Reference example 108

MS (ESII) 643 (MHl, 40¾). Reference example 109

MS (ESII) 707 (MHl, 100%) Reference example 1 10

MS (ESI +) 609 (M ++ l, 75%). Reference example 11 1

MS (ESH) 631 (MHl, 90%). Reference Example 1 12 MS (ESI +) 679 (M ⁺ ll, 100%) .Reference Example 113

tert-butyl {(3R) -1-[7- (2-methylbenzyl) -trimethyl-6-oxo-2-phenoxy-6 7-dihydro-1H-purine-8-yl] piperidine-3 -Ill

In the same manner as in Reference Example 31, the compound of Reference Example 113 was synthesized from the corresponding compound of Reference Example.

MS (ESI +) 545 (M ++ 1, 88%). In the same manner as in Reference Example 113, the compound of Reference Example 114 123 was synthesized from the corresponding compound of Reference Example.

28

HBoc

Reference example number Reference example number Reference example 1 1 4 Reference example 1 1 5

EtO = ₃ co ^^ o Reference example 1 1 6 0 ° Reference example 1 2 1 Reference example 1 1 7 Reference example 1 1 8

Reference example 114

MS (ESI +) 561 (M ⁺ ll, 81%),

Reference Example 115

MS (ESH) 575 (M ⁺ + l, picture)

Reference Example 116

MS (ESI +) 589 (M ⁺ + l, 100%)

Reference Example 117

MS (ESH) 603 (MHl, 100%)

Reference Example 118

MS (ESH) 629 (MHl, 100%)

Reference Example 119

MS (ESI +) 637 (MHl, 70%).

Reference Example 120 MS (ESI +) 611 (M + +1 picture)

Reference example 1 2 1

MS (ESI +) 629 (MHl, 100%)

Reference example 1 2 2

MS (ESI +) 593 (MHl, picture)

Reference example 1 2 3

MS (ESI +) 589 (MHl, 100%) Reference example 1 2 4

tert-butyl {(3R) -tri [7_ (2_chloro-5-fluorobenzyl) -trimethyl-6-oxo-2-phenoxy_6,7-dihydro-1H-purine-8-yl] piperidine-3 -Ill force

In the same manner as in Reference Example 31, the compound of Reference Example 124 was synthesized from the corresponding compound of Reference Example.

MS (ESI +) 583 (MHl, 54 °). In the same manner as in Reference Example 31, the compounds of Reference Examples 125 to 126 were synthesized from the corresponding reference examples. '

Reference example number

MeO

Reference example〗 25 0 °

Reference example 1 26 Y 0

0 ° Reference example 125

MS (ESI +) 613 (M ++ l, 100%)

Reference Example 126

MS (ESI +) 649 (MHl, 100%) Reference example 40

tert-Butyl ((3R)-1- [7- (2-chlorobenzyl) -2- (3-methoxyphenyl) -1-methyl-6-oxo-6,7-dihydroxy-1H-purine- 8-yl] pyridine-3-yl} force bamate

tert-butyl {(3R) -l- [7- (2-chlorobenzyl) -1-methyl-2- (methylsulfonyl) -6-oxo-6,7-dihydro-1H-purine-8-y [Pipiperidine-3-yl} capillate (110 mg) in tetrahydrofuran (10 mL) was added with a 1 M solution of 3-methoxyphenylmagnesium amide in tetrahydrofuran (0.79 mL) at 0 ° C. Then, the mixture was further heated to 25 ° C. and stirred for 3 hours. Again, a 1M solution of 3-methoxyphenylmagnesium bromide in 1.5M tetrahydrofuran (1.58 mL) was added at 0, and the mixture was stirred for 30 minutes, then heated to 25 ° C and stirred for 3 hours. Add a saturated aqueous ammonium chloride solution (50 mL), and tetrahydrofuran was distilled off under reduced pressure, followed by extraction with chloroform (30 mL) three times. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (silica gel, chloroform / methanol = 30/1) to obtain the title compound (118 mg).

_{Ή NMR (300 MHz, CDC1 3} ) δ ριη 7.41-7.34 (m, 2H), 7.21-7.18 (m, 2H), 7.11-7 .01 (m 3H), 6.84-6.82 (m 1H), 5.66 (d , J = 17.0Hz, 1H), 5.55 (d J = 17.0Hz, 1H), 4.86-4.84 (m, 1H), 3.82 (s 3H), 3.74-3.72 (m, 1H), 3.47 (s 3H), 3.4 7-3.43 (m, 1H), 3.10-3.03 On, 3H), 2.07-2.05 (m, 1H), 1.75-1.43 (m 3H), 1.42 (s 9H).

MS (ESH) 579 (Ml 19%) Reference example 41

Ethyl [8-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidine-toluyl} -7- (2-chlorobenzyl) -6-oxo-2-phenoxy-6,7- Jihide mouth-1H-purintoru] acetate

[8-{(3R) -3-3-[(tert-butoxycarbonyl) amino] piperidine-tolyl} -7- (2-butoxybenzyl) -6-oxo-2-phenoxy-6,7 -Dihydro-1H-purin-1-yl] acetic acid (179 mg) in N, N-dimethylformamide (3.0 mL) in ethanol (0.083 mL), 1-ethyl-3- (3-dimethylaminopropyl) Carposimide hydrochloride (169 mg), 1-hydroxybenzotriazole (119 mg), and triethylamine (0.122 mL) were added, and the reaction solution was stirred for one day. Water and sodium bicarbonate were added to the reaction solution, the solution was made alkaline, and the mixture was extracted twice with chloroform. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to column chromatography.

(Silica gel, hexane / ethyl acetate = 5/1 1/1)

(92.6 mg) was obtained.

_{Ή NMR (400 MHz, CDC1 3} ) (5ppm 7..44-7.39 (m 3H 7.26-7.16 (m, 5H), 6.83-6 .78 (m, 1H), 5.55-5.50 (m, 2H), 4.96 (s, 2H), 4.84-4.79 (i, 1H), 4.22 (q, J = 7.1Hz, 2H), 3.77-3.72 (m , 1H), 3.42-3.37 (m, 1H), 3.05-3.00 (m, 3H), 1.7 6-1.50 (m, 4H), 1.40 (s, 9H), 1.26 (t, J = 7.1Hz, 3H) .

MS (ESI +) 637 (M ⁺ +1, 73%) .Reference example 42

[8-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidine-toyl} -7- (2-butoxybenzyl) -6-oxo-2-phenoxy-6,7-dihydro -1H-Printyl] acetic acid

Aryl [8-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidine-tolyl}-7- (2-cyclobenzyl) -6-oxo-2--2-phenoxy-6,7-dihydro To a solution of [-1H-purintoyl] acetate (330 mg) in tetrahydrofuran (5.0 mL) was added tetrakistriphenylphosphinopalladium (18 mg) and morpholine (0.0532 mL) at 0 ° C. Was stirred at 0 ° C for 1 hour. Water and citric acid were added to the reaction solution to make the solution weakly acidic, and extracted twice with chloroform. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (silica gel, black form Z methanol = 100/1 to 100/3) to give the title compound (372 mg).

_{Ή NMR (400 MHz, CDC1 3} ) δρρι 7.42-7.37 (m, 3H), 7.26-7.16 On, 5H), 6.79 (d, J = 6.7Hz, 1H), 5.53-5.48 0n, 2H), 4.99 (s , 2H), 4.84-4.79 (m, 1H), 3.77-3.72 (m, 1H), 3.42-3.37 (m, 1H), 3.02-2.97 (m, 3H), 1.74-1.50 (m, 4H) , 1.39

(s, 9H).

MS (ESI +) 609 (M ++ 1, 70¾). Reference example 43

8- {(3R) -3-[(tert-butoxycarbonyl) amino] pyridin-1-yl}-7-(2-cyclobenzyl) -6-oxo _6,7-dihydro- 1H-purine-2-carboxylic acid

Methyl 8-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidine-tolyl} _7- (2-chlorobenzyl) -6_oxo-6,7-dihydro-1H-purine -To a solution of 2-carboxylate (98 mg) in methanol (6 mL) and tetrahydrofuran (4 mL) was slowly added a 1 N aqueous sodium hydroxide solution (0.379 mL) dropwise, and the mixture was stirred at 25 ° C overnight. After evaporating the reaction solvent under reduced pressure, a 10% aqueous solution of citric acid (50 mL) was added, and the mixture was extracted twice with chloroform (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (98 mg).

MS (ESI +) 503 (M ++ 1, 28%). Reference example 44

tert-butyl ((3R) -1- {7- (2-chlorobenzyl) -2-cyano-6-oxo-1- [2-oxo-2- (pyridine-2-ylamino) ethyl] -6, 7-dihydro-1H-purin-8-yl} piperidine-3-yl) ylbamate

[8 _ {(3R) -3-[(tert_butoxycarbonyl) amino] piperidine-1-yl}-7- (2-cyclohexyl) -2-cyano-6-oxo-6,7-dihydro N-N-N-dimethylformamide solution (1.0 mL) of _m-purinyl] acetic acid (47.8 mg) in 2-aminopyridine (16.6 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide Hydrochloride (33.8 mg), hydroxybenzotriazole (23.8 mg), and triethylamine (0.0244 mL) were added, and the reaction solution was stirred overnight. Water and sodium bicarbonate were added to the reaction solution, the solution was made alkaline, and the mixture was extracted twice with chloroform. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (silica gel, chloroform / ethyl acetate = 1/2) to give the title compound ( 4.9 ig).

_{Ή NMR (400 MHz, CDC1 3} ) άρρπι 8.98 (br, 1H), 8.26 (d, J = 0.9Hz, 1H 7.73-7 • 68 (m, 2H), 7.38 (d, J = 7.8Hz, 1H), 7.24-7.19 (m, 2H), 7.10-7.05 (m, 1H), 6. '78 (d, J-7.0 Hz, 1H), 5.62-5.57 (m, 2H), 5.07 (s, 2H), 4.78 -4.73 (i, 1H), 3.80-3.75 (m, 1H 3.57-3.52 (m, 1H), 3.28-3.23 (m, 1H), 3.12-3.07 (m, 2 H), 2.04-1.50 (m, 4H ), 1.41 (s, 9H).

MS (ESI +) 618 (MHl, 37%) Reference example 45

[8-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidine-toyl} -7- (2-butoxybenzyl) -2-cyano-6-oxo-6,7 -Dihydro-1H-purine-1-yl] acetic acid

Aryl [8-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidine-toyl} -7- (2-chlorobenzyl) -2-cyano-6-oxo-6,7-dihydro-1H [Printhyl] acetate (166 mg) in tetrahydrofuran (1.4 mL) was added at 0 ° C with tetrakistriphenylphosphinopalladium (18 mg) and morpholine (0.0532 mL). The mixture was stirred at 0 ° C for 1 hour. Water and citric acid were added to the reaction solution to make the solution weakly acidic, and the mixture was extracted twice with chloroform. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (silica gel, chloroform / methanol = 100/1 to 100/3) to give the title compound (145 mg).

Negation _{R (400 MHz, CDC1 3)} δ ρπι 7: 44-7.39 (m, 1H), 7.25-7.20 (m, 2H), 6.81-6 .76 (m, 1H), 5.59-5.54 (m, 2H) , 5.00 (s, 2H), 4.78-4.73 (m, 1H), 3.78-3.73 (m, 1H), 3.42-3.37 (m, 1H), 3.04-2.97 (m, 3H), 1.81-1.56 On, 4H ), 1.40 (s, 9H).

MS (ESI +) 542 (MHl, 53%). Reference Example 46

tert-Butyl {(3R) -l- [2 -7- (2-octabenzyl) -1-methyl-6-oxo-6,7-dihydro-1H-purine-8--3-yl} Force bamate

Add 6 ml of mandelonitrile (286 mg) in N, N-dimethylformamide (15 mL).

0% sodium hydride (64 mg) was added, and the mixture was stirred at 80 ° C for 1 hour. The reaction solution is cooled to 25 ° C and tert-butyl {(3R) -1_ [7- (2-cyclobenzyl) -trimethyl-2- (methylsulfonyl) -6_oxo-6,7-dihydro [1H-Purin-8-yl] piperidin-3-yl} capillate (220 mg) in N, N-dimethylformamide (5 mL) was added dropwise, and the mixture was heated with stirring at 80 ° C for 2 hours. To the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution (50 mL), and the mixture was extracted three times with chloroform (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane / ethyl acetate = 10/1 to 1/1) to obtain the title compound (33 mg).

_{Ή NMR (300 MHz, CDC1 3} ) δρρηι 8.03-8.00 (m, 2H), 7.71-7.42 (ι, 4H), 7.26-7 .23 (m, 2H), 6.86-6.84 (m, 1H), 5.65- 5.55 (m, 2H), 5.14-5.12 (m, 1H), 3.6 9-3.67 (m, 1H), 3.51 (s, 3H), 3.46-3.39 (m, 1H), 3.17-3.05 On, 3H), 1.83-1 .42 (m, 4H), 1.41 (s, 9H).

MS (ESI +) 577 (MHl, 35%). Reference Example 47

ter t-butyl {(3R) -l- [7- (2-octabenzyl) -1-methyl-2- (2-naphthylsulfonyl) -6-oxo-6,7-dihydro-1H-purine- 8-yl] pyridine-3-yl

tert-butyl {(3R) -1- [7- (2-cyclobenzyl) -trimethyl-2- (2-naphthylthio) -6- Oxo-6,7-dihydro-1H-purin-8-yl] piperidin-3-yl} tubamate (170 mg) in acetic acid (10 mL) and methanol solution (2 mL) under ice-cooling An aqueous solution (1 mL) of sodium (114 mg) was added, and an aqueous solution of hydrogen peroxide (0.399 mL) was slowly added dropwise. After 30 minutes, the temperature was raised to 25, followed by stirring for 6 hours. The reaction solution was distilled off under reduced pressure, toluene (30 mL) was added, and the distillation under reduced pressure was repeated three times. Saturated aqueous sodium bicarbonate (30 mL) was added, and the mixture was extracted twice with chloroform (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane / ethyl acetate = 5/1 to 1/1) to obtain the title compound (37 mg).

MS (ESI +) 663 (M l, 24¾). Reference example 48

tert-Butyl {(3R) -1- [7- (2-octabenzyl) -1-methyl-2- (2-naphthylthio) -6-year-old xo-6,7-dihydro-1H-purine- 8-yl] pyridine-3-yl

To a solution of 20-naphthylthiol (400 mg) in tetrahydrofuran (20 mL) was added 60% sodium hydride (80 mg), and the mixture was stirred at 25 ° C for 1 hour. To this reaction solution was added tert-butyl ((3R) -1- [7- (2-octabenzyl) -tomethyl-2- (methylsulfonyl) -6-oxo-6,7-dihydro-1H-purine- A solution of 8-yl] piperidine-3-yl} capillate (275 mg) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was stirred at 25 ° C for 3 hours. A 10% aqueous potassium carbonate solution (50 mL) was added to the reaction solution, and tetrahydrofuran was distilled off under reduced pressure, followed by extraction with chloroform (30 mL) three times. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, gel form / methanol = 100/1 to 20/1) to give the title compound (265 mg).

MS (ESI +) 631 (MHl, 77¾). Reference 49

tert-Butyl {(3R) -1- [7- (2-chlorobenzyl) -2-cyano-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperidine- 3-yl} force bamate

Ethyl 4-amino-2-{(3R) -3--[(tert-butoxy) was added to a dichloromethane solution (10 mL) of 4,5-diclo mouth-1,2,3-dithiazolium chloride (663 mg). [Carbonyl) amino] pyridin-1-yl} -1- (2-chlorobenzyl) -1H-imidazole-5-hydroxypropylate (304 mg) in dichloromethane (10 mL) was added, and pyridine ( 0.512 mL) of dichloromethane solution (2 mL) was added dropwise, and the mixture was stirred at 25 ° C for 6 hours. To the reaction solution was added tetrahydrofuran (20 mL), the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. A tetrahydrofuran solution (20 mL) of the reaction mixture was cooled to 0 ° C, and a methylamine / tetrahydrofuran solution (15 mL) was slowly added dropwise. The temperature was gradually raised to 25 ° C, and the mixture was stirred overnight. After the tetrahydrofuran was distilled off under reduced pressure, a 10% aqueous solution of carbon dioxide (50 mL) was added to the reaction solution, and the mixture was extracted three times with chloroform (40 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane / ethyl acetate = 10/1 to 1/1) to obtain the title compound (199 mg).

_{Ή NMR (300 MHz, CDC1 3} ) δρρπι 7.42 (d, J-7.5Hz, 1H), 7.25-7.16 (m, 2H), 6. 72 (d, J-7.3Hz, 1H), 5.64 (d, J -17.4Hz, 1H), 5.55 (d, J = 17.4Hz, 1H), 4.70- 4.68 (m, 1H), 3.78 (s, 3H), 3.53-3.49 (m, 1H), 3.38-3.34 (m, 1H), 3.24-3.2 2 (m, 1H), 3.09-2.99 (ι, 2H), 1.80-1.48 (m, 4H), 1.41 (s, 9H).

MS (ESI +) 498 (MHl, awake). Reference example 50

tert-butyl {(3R) -1- [2-acetyl-7- (2-chlorobenzyl) -trimethyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperidine-3 -Ill 29

Methylmagnesium bromide A solution of Z3M tetrahydrofuran solution (0.088 mL) in tetrahydrofuran (5 mL) was cooled to −78 ° C., and bromide copper (6 mg), tert-butyldimethylsilyl chloride (29 mg), and -Butyl {(3R) -tri [7- (2-chlorobenzene)]-2-cyano-trimethyl-6-oxo-6,7-dihydro-1H-purine_8_yl] piperidine- A solution of 3-pyruvate (44 mg) in tetrahydrofuran (10 mL) was added, and the mixture was stirred for 1 hour, gradually heated to 25 ° C over 3 hours, and stirred. The reaction solution was further cooled to 0 ° C, and a methylmagnesium bromide / 3M tetrahydrofuran solution (0.750 mL) was added dropwise, followed by stirring for 30 minutes, and then the temperature was raised to 25 ° C and stirred for 5 hours. To this reaction solution was added a saturated aqueous solution of ammonium chloride (50 mL), and tetrahydrofuran was distilled off under reduced pressure, followed by extraction with ethyl acetate (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative thin-layer chromatography (silica gel, hexane / ethyl acetate = 1/1) to give the title compound (12 mg).

_{Ή NMR (300 MHz, CDC1 3} ) (5 pm 7.43-7.40 (m, 1H), 7.24-7.16 (ι H), 6.75 (d, J = 7.1Hz, 1H), 5.68 (d, J = 16.8Hz, 1H), 5.57 (d, J = 16.8Hz, 1H), 4.71-4.69 (m, 1H), 3.78-3.76 (m, 1H), 3.70 (s, 3H), 3.52-3.47 (m, 1H), 3.15 -3.00 (m, 3H), 2.77 (s, 3H), 1.79-1.48 (m, 4H), 1.42 (s, 9H).

MS (ESI +) 515 (MHl, 17%). Reference Example 51

tert-butyl {(3R) -l- [7- (2-chlorobenzyl) -tomethyl-2- (methylthio) -6-oxo-6,7-hydidro-1H-purine-8-yl] Piperidine-3-yl} Rubamate

In a nitrogen atmosphere, ethyl 4-amino-2-((3R-3-[(tert-butoxycarbonyl) amino ] Pyridine-1-yl} -toluene (2_methyl benzyl) -1H-imidazole-5-carboxylate (3.64 g) in pyridine solution (30 mL) was added to methyl isothiocyanate (1.11 g). g) was added, and the mixture was heated and stirred at 125 ° C for 6 hours. The reaction solution was cooled to 25 ° C, potassium carbonate (2.10 g) was added, the temperature was raised again to 125 ° C, and the mixture was heated with stirring for 6 hours. The reaction solution was cooled to 25 ° C., filtered, and the operation of adding toluene (30 mL) to the filtrate and concentrating under reduced pressure was repeated four times. Potassium carbonate (2.10 g) was added to a tetrahydrofuran solution (30 mL) of the reaction mixture, cooled to 0 ° C, methyl iodide (0.948 mL) was added dropwise, and the mixture was heated to 25 ° C and stirred for 4 hours. . The operation of adding toluene (50 mL) to the reaction solution and concentrating under reduced pressure was repeated four times. Water (100 mL) was added to the reaction mixture, and the mixture was extracted three times with chloroform (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane / ethyl acetate = 5/1 to 1/1) to obtain the title compound (4.20 g).

_{Ή NMR (300 MHz, CDC1 3} ) ά ριη 7.41-7.38 (m, 1H), 7.23-7.14 (m, 2H), 6.75 (d, J = 7.1Hz, 1H), 5.60 (d, J = 17.1Hz, 1H), 5.50 (d, J = 17.1Hz, 1H), 4.78-4.76 (m, 1H), 3.77-3.75 (m, 1H), 3.53 (s, 3H), 3.47-3.41 (m, 1H), 3.06 -3.00 (m, 3H), 2.67 (s, 3H), 1.72-1.44 (m, 4H), 1.42 (s, 9H).

MS (ESI +) 519 (M ++ 1, 100%). Reference Example 1 28

tert-butyl {(3R) -1- [7- (2-methylbenzyl) -trimethyl-2-(methylthio) -6-oxo-6,7-hydido-1H-purine-8-y Le] piperidine-3-yl} force bamate

In the same manner as in Reference Example 51, the compound of Reference Example 128 was synthesized.

MS (ESI +) 499 (M 1, 86%)... Reference Example 1 2 9

ter t-butyl {(3R) -1- [7- (2-co-mouth-5-fluoro-benzyl) -methyl-2-(methylthio O) -6-Oxo-6,7-hydido-1H-purin-8-yl] piperidin-3-yl

The compound of Reference Example 129 was synthesized in the same manner as in Reference Example 51.

_{¾ NMR (400MHz, CDC1 3)} ά ρπι 7.35 (dd, J = 5.0, 8.8Hz, 1H), 6.92 (dt, J = 3.0, 8.4Hz, 1H), 6.50-6.47 (m, 1H), 5.54-5.43 (m, 2H), 4.78-4.76 (m, 1H), 3.79- 3.71 (in, 1H), 3.52 (s, 3H), 3.45 (dd, J = 3.3, 12.2Hz, 1H), 3.15-3.14 (m , 1H), 3.03-2.95 (m, 2H), 2.68 (s, 3H), 1.83-1.57 (m, 3H), 1.55-1.53 (m, 1H), 1.41 (s, 9H).

MS (ESI I) 537 (MHl, 88¾). Reference example 52

tert-butyl {(3R) -l- [7- (2-chlorobenzyl) -1-methyl-2- (methylsulfonyl) -6-oxo-6,7-dihydro-1H-purine-8-yl ] Pyridine-3-yl

The compound of Reference Example 52 was synthesized in the same manner as in Reference Example 47.

_{Ή NR (300 MHz, CDC1 3} ) <5 pm 7.44-7.41 (m, 1H), 7.26-7.18 (m, 2H), 6.75 (d, J = 7.1Hz, 1H), 5.66 (d, J = 17.0Hz , 1H), 5.55 (d, J = 17.0Hz, 1H), 4.69-4.67

(m, 1H), 3.89 (s, 3H), 3.77-3.75 (m, 1H), 3.56 (s, 3H), 3.50-3.48 (m, 1H), 3.18-3.16 (m, 1H), 3.07-2.97 (m, 2H), 1.84-1.66 (m, 3H), 1.52-1.48 (m, 1H), 1.42 (s, 9H).

MS (ESI +) 551 (MHl, Sat)

tert-butyl {(3R) -1- [7- (2-methylbenzyl) -tomethyl-2- (methylsulfonyl) -6- Oxo-6,7-dihydro-1H-purin-8-yl] piperidin-3-yl

In the same manner as in Reference Example 47, the compound of Reference Example 130 was synthesized ₍

MS (ESH) 531 (MH1, 66%)

tert-butyl {(3R) -1- [7- (2-cyclo-5-fluorobenzyl) -trimethyl-2-(methylsulfonyl) _6-oxo-6,7-dihydro-1H-purine-8- Yl] pyridin-3-yl} force

The compound of Reference Example 131 was synthesized in the same manner as in Reference Example 47.

_{'Η NMR (400MHz, CDC1 3} ) (5 pm 7.38 (dd, J = 5.0, 8.8Hz, 1H), 6.96 (dt, J = 3.6, 6 .6Hz, 1H), 6.49-6.47 (m, 1H), 5.60-5.48 (m, 2H), 4.69-4.67 (m, 1H), 3.89 (s, 3H), 3.79-3.74 (m, 1H), 3.56 (s, 3H), 3.54-3.52 (m, 1H), 3.25-3.20 (m, 1H), 3.07-2.93 (m, 2H), 1.88-1.85 (m, 1H), 1.76-1.74 (m, 2H), 1.57-1.54 (m, 1H), 1.40 (s, 9H ).

MS (ESH) 569 (MHl, 37%) .Reference Example 53

tert-butyl {(3R) -1- [7- (2-cyclobenzyl) -trimethyl-6-oxo-2- (phenylsulfonyl) -6,7-dihydro-1H-purine-8-yl] Piperidine-3-yl} Rubamate

The compound of Reference Example 53 was synthesized in the same manner as in Reference Example 47.

_{Ή NMR (300 MHz, CDC1 3} ) (5 pm 8.06-8.03 (m, 2H), 7.77-7.72 (i, 1H), 7.65-7 .59 (m, 2H), 7.41 (d, J = 6.4Hz, 1H), 7.24-7.16 (m, 2H), 6.68 (d, J = 7.5Hz, 1H), 5.64 (d, J = 16.8Hz, 1H), 5.53 (d, J = 16.8Hz, 1H), 4.67 -4.65 (m, 1H), 4.0 4 (s, 3H), 3.71-3.69 (m, 1H), 3.41-3.38 (m, 1H), 3.02-2.94 (m, 3H), 1.76-1.43 (m , 4H), 1.39 (s, 9H).

ter t-butyl {(3R) -1- [7- (2-octal benzyl)-1-methyl-6-oxo-2- ((phenylthio) -6,7-dihydro-1H-purine- 8-yl] piperidine-3-yl

To a solution of thiophenol (275 mg) in tetrahydrofuran (20 mL) was added 60% sodium hydride (80 mg), and the mixture was stirred at 25 ° C for 1 hour. To this reaction solution was added tert-butyl {(3R) -1- [7- (2-chlorobenzyl) -trimethyl-2- (methylsulfonyl) -6-oxo-6,7-dihydrido-1 -purine- A solution of (8-yl) piperidine-3-yl} potassium (3.85 g) in tetrahydrofuran (10 mL) was added dropwise and the mixture was stirred at 25 "C for 3 hours. A 10% aqueous solution of potassium carbonate was added to the reaction solution. (50 mL), and tetrahydrofuran was distilled off under reduced pressure, followed by extraction with chloroform (30 mL) three times.The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Was purified by column chromatography (silica gel, chloroform / methanol = 100/1 to 20/1) to give the title compound (262 mg).

_{Ή NMR (300 MHz, CDC1 3} ) dpp 7.64-7.64 (m, 2H), 7.46-7.38 (m, 4H), 7.23-7 .12 (m, 2H), 6.69 (d, J = 6.0Hz, 1H) , 5.59 (d, J = 17.1Hz, 1H), 5.49 (d, J = 17. 1Hz, 1H), 4.75-4.73 (in, 1H), 3.71-3.69 (m, 1H), 3.66 (s, 3H), 3.36-3.32 (m, 1H), 3.01-2.97 (m, 3H), 1.70- 1.40 (m, 4H), 1.40 (s, 9H).

MS (ESI +) 581 (MHl, 28¾). Reference example 55

ter t-butyl {(3R)-1- [7- (2-cu-mouth benzyl)-trimethyl-6-oxo-2- (1H-pyrrol-tolyl) -6, 7-dihydro -1H-purine-8-yl] piperidine-3-yl}

To a solution of pyrrol (67 mg) in tetrahydrofuran (5 mL) was added 60% sodium hydride (32 mg), and the mixture was stirred at 60 ° C for 1 hour. The reaction solution was cooled to 25 ° C and tert-butyl ((3R) -1- [7- (2-c-mouth benzyl) -tomethyl-2- (methylsulfonyl)-6-oxo-6, A solution of 7-dihydro-1H-purin-8-yl] piperidine-3-yl} capillate (110 mg) in tetrahydrofuran (2 mL) was added dropwise, and the mixture was stirred at 25 ° C. for 4 hours. To the reaction solution was added a saturated aqueous sodium chloride aqueous solution (50 mL), and the tetrahydrofuran was distilled off under reduced pressure, followed by extraction with chloroform (50 mL) three times. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane / ethyl acetate = 5/1 to 1/2) to give the title compound (89 mg).

_{Ή NMR (300 MHz, CDC1 3} ) δ ρι 7.43-7.40 (m, 1H), 7.24-7.18 (m, 2H), 7.09 (t, J = 2.2Hz, 2H), 6.82 (d, J = 6.8Hz, 1H), 6.35 (d, J = 2.2Hz, 2H), 5.64 (d, J = 17.0Hz, 1H), 5.54 (d, J = 17.0Hz, 1H), 4.76-4.74 (m, 1H), 3.77- 3.75 (m, 1H), 3.50 (s, 3H), 3.45-3.42 (m, 1H), 3.15-3.02 (m, 3H), 1.77-1.42 (m, 4H), 1.41 (s, 9H).

MS (ESI +) 538 (MHl, Yield) .Reference Example 56

tert-butyl {(3R)-1- [7- (2-chlorobenzyl)-1-methyl-6-oxo-2--(2-oxopi Mouth lysine-1-yl) -6,7-dihydro-1H-purine-8-yl] piperidine-3-yl}

The compound of Reference Example 56 was synthesized in the same manner as in Reference Example 55.

_{Ή NMR (300 MHz, CDC1 3} ) δ ρπι 7.42-7.39 (m, 1H), 7.23-7.17 (m, 2H), 6.81-6 .78 (m, 1H), 5.63 (d, J = 17.0Hz, IH ), 5.52 (d, J = 17.0Hz, 1H), 4.75-4.73 (m, 1H), 3.78-3.76 (m, IH), 3.53 (s, 3H), 3.46-3.42 (m, 1H), 3.08- 3.00 (m, 3 H), 2.61-2.56 (m, 2H), 2.30-2.17 (m, 2H), 1 (m, 6H), 1.41 (s, 9H) .MS (ESH) 556 (MHl, 19% Reference example 132

tert-Butyl {(3R) -tri [7- (2-chlorobenzyl) -2-phenylamino-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] pi Lysine-3-yl

The compound of Reference Example 132 was synthesized in the same manner as in Reference Example 55.

MS (ESH) 564 (MHl, 73¾). Reference example 58

3-{[8-{(3R) -3-[(tert-butoxycarbonyl) amino] piridin-1-yl} -7- (2-chlorobenzyl) -tomethyl-6-oxo-6,7 -Dihydro-1H-purine-2-yl] oxy , N

NN NN 0 _N people N

NHBoc Q.

The compound of Reference Example 58 was synthesized in the same manner as in NHBoc Reference Example 43.

MS (ESI +) 609 (M ++ 1, 56%) Reference example 133

4-{[8-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -7- (2-chlorobenzyl) -1-methyl-6-oxo-6 , 7-Dihydro-1H-purin-2-yl] oxy}

The compound of Reference Example 133 was synthesized in the same manner as in Reference Example 43.

MS (ESI +) 609 (MH1, 75%) Reference example 67

7-lyl [8- {(3R) -3- [(ter t-butoxycarbonyl) amino] piperidine-toyl} -7- (2_cyclobenzyl) -6-oxo_2-phenoxy-6,7-dihydro- 1H-pudding-1-yl] acetate

The compound of Reference Example 67 was synthesized in the same manner as in Reference Example 31.

删_{R (400 MHz, CDC1 3)} δ ριη 7.41-7.37 (m, 3H), 7.26-7.17 (HI, 5H), 6.78 (d, J-7.0, 1H), 5.88-5.85 (1, 1H), 5.55 -5.46 (m, 2H), 5.33-5.21 (m, 2H), 5.00 (s, 2H), 4.79-4.59 (m, 1H), 4.68-4.11 (m, 2H), 3.76-3.68 (m, 1H), 3.37 (dd, J = 3.2, 12.5 Hz, 1H), 3.05-2.96 (ffl, 3H), 1.75-1.50 (m, 4H), 1.40 (s, 9 H).

MS (ESI +) 649 (MHl, 30¾) Reference example 68

Aryl [8-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidine-toluityl 7- (2-cyclobenzyl) -2- (methylsulfonyl) -6-oxo-6 , 7-Dihydro-1H-purine-1_yl] acetate

The compound of Reference Example 68 was synthesized in the same manner as in Reference Example 47.

2-[(3R) -3-Aminopiperidine-tolyl] -3- (2-chloro-5-fluorobenzyl) -5-methyl-6,7-dihydropyrazo [1,5-a] pyrazine Oxone (4.65 g, Aldrich) was added to a methanol-water mixed suspension (25 mL) of -4 (5H) -one (380 mg), and the mixture was vigorously stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution to make it neutral, water was added to the residue that was concentrated under reduced pressure, and the mixture was extracted three times with chloroform. The combined organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product of the desired product (440 mg) was used for the next reaction as it was.

_{Ή NMR (400 MHz, CDC1 3} ) d ppm 7.40 (dd, J = 7.8, 1.5 Hz, 1H), 7.27-7.22 (m, 2H), 6.81-6.76 (m, 1H), 5.93-5.88 (m, 1H ), 5.65-5.60 (m, 1H)., 5.31 (dd, J = 1.4, 17.2Hz, 2H), 5.28-5.23 (m, 2H), 4.73-4.67 (m, 1H), 4.70-4.65 (m, 2H), 3.81-3.76 (m, 1H), 3.55 (s, 3H), 3.19-3.14 (in, 1H), 3.08-3.03 (m, 2H), 1.74-1.69 (m, 1H), 1.61- 1.51 (m, 3H), 1.40 (s, 9H).

MS (ESI +) 635 (MHl, 36¾) .Reference example 6 9

2-[(3 R) -3-7 minopididine-toyl] -3- (2-co-mouth-5-fluoro-benzyl) -5-methyl-6,7-dihydrovirazolo [1,5 -a] Pyrazine-4 (5H)

[8-{(3R) -3- 3-[(tert-butoxycarpenyl) amino] piperidin-1-yl} -7- (2-butoxybenzyl) -2- (methylthio) -6 -Oxo-6,7-dihydro-1H-purin-tolyl] acetic acid (563 mg) in N, N-dimethylformamide-chloroform-form mixed suspension (5 mL + 5 mL) was added with potassium carbonate (828 mg). ), 3-bromopropene (0.312 mL) was added, and the reaction solution was stirred at room temperature for 4 hours. Water was added to the reaction solution to make the solution alkaline, and the mixture was extracted twice with a black hole form. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (silica gel, chloroform / ethyl acetate = 20/1 to 4/1) to give the title product (490 mg).

_{Ή NMR (400 MHz, CDC1 3} ) (5 pm 7.39 (dd, J = 1.5, 7.8Hz, 1H), 7.23-7.18 (m, 2 H), 6.81-6.76 (m, 1H), 5.93-5.88 On, 1H), 5.56-5.51 (m, 2H), 5.30 (dd, J = l .4, 17.2Hz, 1H), 5.23 (d, J = 10.4Hz, 1H), 4.90 (s 2H), 4.80-4.75 ( m, 1H), 4.69-4.64 (m, 2H), 3.82-3.77 (m, 1H), 3.49-3.44 (m, 1H), 3.10-3.05 (m, 3H) 2.68 (s, 3H), 1.83-1.78 (m, 1H), 1.61-1.51 (m, 3H), 1.42 (s 9H).

MS (ESI +) 603 (MHl, 99). Reference example 70

[8-{(3R) -3-[(terbutoxycarbonyl) amino] piperidine-toyl} -7- (2-chlorobenzyl) -2- (methylthio) -6-oxo-6,7-dihydro- 1H-Purin-1-yl] acetic acid

Ethyl [8-{(3R) -3-[[tert-butoxycarbonyl) amino] piperidine-toyl} -7- (2-cyclobenzyl) -2- (methylthio) -6-oxo-6,7 [Dihydro-1H-purine-1-yl] acetate (650 mg) in tetrahydrofuran-ethanol mixture (11 mL + 5.0 mL), lithium hydroxide aqueous solution (IN, 11 mL) was added, and the reaction mixture was stirred at 60 for 10 minutes. Heating and stirring Was. The reaction solution was allowed to cool to room temperature, and water and citric acid were added to the residue that was concentrated under reduced pressure, the solution was made weakly acidic, and extracted twice with chloroform. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Obtained target

The crude product (740 mg) was used for the next reaction as it was.

_{Ή NMR (400 MHz, CDC1 3} ) (5ppm 7.37 (d, J = 7.5 Hz, 1H), 7.22-7.17 (m, 2H), 6 .77 (d, J = 7.4 Hz, 1H), 5.57-5.52 ( m, 2H), 4.87 (s, 2H), 4.85-4.80 (m, 1H),

3.79-3.74 (ffl, 1H), 3.49-3.42 On, 1H), 3.11-3.06 (m, 3H), 2.66 (s, 3H), 1.81-1.76 (m, 1H), 1.75-1.48 (m, 3H), 1.41 (s, 9H).

MS (ESI +) 563 (M ++ 1, 90%). Reference example Ί 1

Ethyl [8-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidine-toyl} -7- (2-cyclobenzyl) -2- (methylthio) -6-oxo_6, 7-dihydro-1H-purine-1-yl] acet

Ethyl [8-{(3R) -3-[(tert-butoxycarponyl) amino] piperidin-1-yl} -7- (2-cyclobenzyl) -6-oxo-2-thioxo-2, To a solution of 3,6,7-tetrahydro-1H-purin-1_yl] acetate (1.07 g) in acetonitrile (27 mL) was added potassium carbonate (489 mg) and methyl iodide (0.110 mL), and the mixture was stirred at room temperature. Stir for 2 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted twice with black hole form. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (silica gel, silica gel / form: ethyl acetate = 10/1 to 5/1) to give the title product (0.690 g).

_{Ή NMR (400 MHz, CDC1 3} ) δ ριη 7.44-7.39 (m, 1H), 7.21-7.16 (m, 2H), 6.81-6 .76 (m, 1H), 5.58-5.53 (m, 2H), 4.86 (s, 2H), 4.82-4.77 (m, 1H), 4.26-4.21 (m, 2H), 3.82-3.77 (m, 1H), 3.48-3.43 (m, 1H), 3.12-3.07 (m, 3H) , 2.68 (s, 3H), 1.82-1.77 (m, 1H), 1.67-1.51 (m, 3H), 1.42 (s, 9H), 1.30-1.25 (m, 3 H).

MS (ESI +) 591 (M ++ 1, 84%). Reference Example 72

Ethyl [8-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidine-toyl} -7- (2-chlorobenzyl) -6-oxo-2-thioxo-2,3,6,7 -Tetrahydric mouth-1H-purine-1_yl] acetate

To a sodium ethoxide solution prepared by adding sodium (625 mg) to ethanol (120 mL), add 2-[(3R) _3_aminobiperidine-tolyl] -3- (2-chloro-5-fluorotetrabutyl). Andyl) -5-methyl-6,7-dihydropyrazolo [1,5-a] pyrazin-4 (5H) -one (15.4 g) was added at room temperature. The reaction solution was stirred at room temperature for 30 minutes, and a saturated aqueous solution of ammonium chloride (5 mL) was added. Water and citric acid were added to the reaction solution to make the solution weakly acidic, and extracted twice with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title target crude product (15.4 g).

_{Ή NMR (400 MHz, CDC1 3} ) <5 pm 7.45-7.40 (m, 1H), 7.28-7.23 On, 2H), 6.97-6 .92 (m, 1H), 5.52-5.47 (m, 2H), 5.19 (s, 2H), 4.68-4.63 (m, 1H), 4.20 (q, J-7.1 Hz, 2H), 3.81-3.76 (m, 1H), 3.72-3.67 (m, 1H), 3.30-3.25 (m , 3H), 1.88-1.83 (m, 1H), 1.66-1.61 (m, 2H), 1.53-1.48 (m, 1H), 1.41 (s, 9H), 1.26 (t, J = 7.1 Hz, 3H ).

MS (ESI I) 577 (M ⁺ +1, 54¾). Reference example 73

2-[(3R)-3 -aminopiperidine-tolyl] -3--(2- kuguchi _5 -fluorobenzyl) -5 -methyl-6,7-dihydropyrazo [1,5 _ &] pyrazine-4 (51 ^)-on

Ethyl 4-amino-2-{(3R) -3-[(tert-butoxycarponyl) amino] piperidine_1-yl 1- (2-chlorobenzyl) -1H-imidazole-5-carpoxylate (14.8 Ethyl isothiocyanatoacetate (10.0 g) was added to an ethanol solution (62 mL) of g) at room temperature, and the reaction solution was heated to reflux for 3 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (silica gel, hexane / ethyl acetate = 5/1 1/1) to give the title compound (15.4 g).

_{Ή NMR (400 MHz, CDC1 3} ) (5ppm 10.9 (s, 1H), 9.50 (brs 1H), 7.44-7.39 (m, 1H), 7.25-7.20 (m, 2H), 6.72-6.67 (m, 1H) , 5.34 (s, 2H), 4.65-4.55 (m, 3H), 4.25 (q, J = 7.1 Hz, 2H), 4.20-4.15 (m, 2H), 3.90-3.85 (m, 1H), 3.11-2.91 (m, 3H), 1.94-1.89 (m, 1H), 1.61-1.48 (m, 3H), 1.41 (s, 9H), 1.31 (t, 1 = 7.1 Hz, 3H), 1.20-1.15 (ι , 3H).

MS (ESI +) 623 (M ++ 1, 100%) Reference example 74

Methyl 8-[(3R) -3-[(tert-butoxycarbonyl) amino] piperidine-toyl} -7- (2-cyclobenzyl) -6-oxo-6 7-dihydro-1H-purine-2 -Carboxylate

Methyl 8-[(3R) -3-aminopiveridine-toyl] -7- (2-chlorobenzyl) -6-oxo-6,7-dihydro-1H-purine-2-carboxylate (367 mg) (367 mg )) In tetrahydrofuran (10 mL), water (5 mL) and saturated aqueous sodium bicarbonate (5 mL) were added, ditert-butyldicarbonate (192 mg) was added, and the mixture was stirred at 25 for 4 hours. After evaporating the reaction solvent under reduced pressure, ethyl acetate (150 mL) was added, and the mixture was diluted with water and saturated aqueous sodium chloride solution. Washed. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, chloroform / methanol = 100/1 to 30/1) to give the title compound (102 mg).

MS (ESI +) 517 (MHl, 19%) .Reference example 75

Aryl [8-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidine-toluityl 7- (2-chlorobenzyl) -2-cyano-6-oxo-6,7-dihydride Mouth -1H-Purine-1-yl] acete 1 h

Aryl [8-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -7- (2-cyclobenzyl) -2- (methylsulfonyl) -6-oxo To a solution of (-6,7-dihydro-1H-purin-1-yl) acetate (505 mg) in N, N-dimethylformamide (3.6 mL) was added sodium cyanide (36.3 mg) at 0 ° C. The reaction solution was stirred at room temperature for 2 hours, water and sodium hydrogen carbonate were added to make the solution alkaline, and the mixture was extracted twice with chloroform. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (silica gel, silica gel / form acetate / 1/10/1/1) to give the title compound (245 rag).

_{Ή MR (400 MHz, CDC1 3} ) (5 pm 7.44-7.39 On, 1H), 7.25-7.20 (m, 2H), 6.80-6 .75 (m, 1H), 5.94-5.89 (m, 1H), 5.63 -5.58 (ι, 2H), 5.36-5.31 (m, 2H), 5.02

(s, 2H), 4.75-4.70 (m, 3H), 3.80-3.75 (m, 1H), 3.57-3.52 (m, 1H), 3.30-3.25 (m, lH), 3.10-3.05 (, 2H ), 1.89-1.84 (m, 1H), 1.71-1.56 (m, 3H), 1.41 (s, 9H).

MS (ESI +) 582 (MHl, 100%). Reference example Ί 6

Ethyl 4-Τamino-2--{(3R)-3-[(tert-butoxycarbonyl) amino] piveridine-1- -卜 (2-chlorobenzyl) -lH-imidazole-5-carboxylate

Sodium hydride (60%, 2.01 g) was added to the mixture at room temperature and stirred for 30 minutes. Ethyl N-[(Z)-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidine-1-yl} (cyanoimino) methyl] -N- (2-chlorobenzyl ) A solution of glycinate (16.0 g) in tetrahydrofuran (100 mL) was added at 0 ° C, and the mixture was stirred at room temperature for 2 hours. The reaction solution was cooled to 0 ° C, water (1.8 mL) was carefully added, and then a saturated aqueous solution of ammonium chloride (10 mL) was added. The reaction solution was concentrated under reduced pressure, water and potassium carbonate were added to the residue to make the solution alkaline, and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title crude product (16.7 g).

_{Ή NR (400 MHz, CDC1 3} ) δρρηι 7.39 (dd, J = 1.6, 7.7Hz, 1H), 7.23-7.18 (m, 2 H), 6.81-6.76 (, 1H), 5.31 (s, 2H), 5.23 -5.03 (m, 1H), 4.12 (q, J = 7.1Hz, 2H), 3.82-3.77 (m, 1H), 3.38-3.33 (m, 1H), 3.05-3.00 (m, 3H), 1.80-1.75 (m, 2H), 1.62-1.57 (m, 2H), 1.41 (s, 9H), 1.02 (t, J = 7.1Hz, 3H).

MS (ESI +) 478 (MHl, respectable) Reference example 134

Ethyl 4-7 mino-2--{(3R)-3-[(tert-butoxycarbonyl) amino] piperidine-toluyl} -1_ (2-methylbenzyl) -1H-imidazole _5-caprolepoxylate

The compound of Reference Example 134 was synthesized in the same manner as in Reference Example No. 6.

_{Ή NMR (400MHz, CDC1 3)} (5ppm 7.15-7.05 (m, 3H), 6.63 (d, J = 7.3Hz, 1H), 5.17- 5.10 (m, 2H), 4.98-4.96 (m, 3H), 4.08 -4.06 (m, 2H), 3.76-3.73 (i, 1H), 3.2 9-3.25 (m, 1H), 2.97-2.86 (m, 3H), 2.33 (s, 3H), 1.85-1.49 (i, 4H), 1.41 (s, 9H), 1.07-1.01 (i, 3H).

MS (ESI +) 458 (MHl, orchid) Reference example 135

Ethyl 4-amino-2-{(3R) -3-[(tert-butoxycarponyl) amino] piperidine-toluyl} -1- (2-methylbenzyl) -1H-imidazole-5-carboxylate

The compound of Reference Example 135 was synthesized in the same manner as in Reference Example 76.

_{¾ NMR (400MHz, CDC1 3)} δρριη 7.33 (dd, J = 5.0, 8.7Hz, 1H), 6.90 (dt, J = 3.0, 8 .4Hz, 1H), 6.54-6.52 (m, 1H), 5.21 (s , 2H), 5.02-4.96 (m, 3H), 4.14-4.10 (m, 2H), 3.79-3.71 (m, 1H), 3.28 (dd, J-3.2, 12.1Hz, 1H), 2.96-2.82 (m , 3H), 1.79-1.51 (m, 4H), 1.41 (s, 9H), 1.10-1.08 (in, 3H).

MS (ESI +) 496 (MHl, 100%) Reference example Ί 7

Ethyl Ν-[(Ζ)-{(310- 3-[(tert-butoxycarbonyl) amino] piperidine-1-cyanoimino) methyl] -N- (2-trimethyl

Ethyl-[(E)-{(3R) -3-3-[(tert-butoxycarbonyl) amino] piperidine-toyl} (cyanoimino) methyl] glycinate (21.0 g) in acetonitrile solution (113 mL) at room temperature Then, 2-chloro mouth benzyl bromide (18.3 g) and potassium carbonate (24.6 g) were added, and the mixture was stirred at 70 ° C for 2 hours. After cooling, the reaction solution was filtered and concentrated under reduced pressure. The resulting residue was separated by column chromatography (silica gel, hexane / ethyl acetate = 2/1 to 2/3) and purified. Then, the target product (16.3 g) was obtained.

_{Ή NMR (400 MHz, CDC1 3} ) δ ριη 7.45-7.40 (m, 1H), 7.34-7.29 (m 3H), 4.63-4. 58 (m, 2H), 4.22 (q, J = 7.1Hz, 2H) , 4.03-3.98 (m, 2H), 3.76-3.71 (m, 2H), 3.54-3.25 (m, .4H), 1.95-1.90 (m, 2H), 1.71-1.59 (m, 2H), 1.44 (s, 9H), 1.29

(t, J = 7.1Hz, 3H).

MS (ESI +) 478 (MUl, 82¾) Reference example 136

Ethyl N-[(Z)-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidine-toluyl} (cyanoimino) methyl] -N- (2-methylbenzyl) glycineto

The compound of Reference Example 136 was synthesized in the same manner as in Reference Example 77.

_{lH NMR (400MHz, CDC1 3)} δ ρι 7.24-7.18 (m, 3H), 7.13-7.11 (m, 1H), 4.89-4.80

(m, 1H), 4.49 (s, 2H), 4.19 (q, J = 7.1Hz, 2H), 4.02-3.88 (m, 2H), 3.76-3.57 (m, 3H), 3.42-3.40 (m, 1H), 3.25-3.20 (m, 1H), 2.23 (s, 3H), 1.95-1.87 (i, 2H), 1.71-1.61 (m, 2H), 1.43 (s, 9H), 1.27 (t, J = 7.1Ηζ, 3H).

MS (ESI +) 458 (Hl, 37¾) Reference example 137

-Ethyl-[(Z)-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidine-toyl} (cyanoimino) methyl] -N- (2-chloro-5-fluorobenzyl) daricinate

The compound of Reference Example 137 was synthesized in the same manner as in Reference Example 77.

_{Ή NMR (400MHz, CDC1 3)} 6 pm 7.36 (dd, J = 5.0, 8.8Hz, 1H), 7.08-7.06 (m, 1H), 7.03-6.98 (m, 1H), 4.79-4.74 (m, 1H), 4.62-4.52 (m, 2H), 4.23 (q, J = 7.1Hz, 2H), 4.03-3.89 (m, 2H), 3.74- 3.59 (m, 3H), 3.42-3.38 (i, 1H), 3.20-3.16 (m, 1H), 1.95-1.71 (m, 2H), 1.70-1.69 (m, 1H), 1.59-1.56 (i, 1H ), 1.43 (s, 9H), 1.29 (t, 1 = 7.1Hz, 3H).

MS (ESI +) 496 (M + + 1, 48%) Reference example 78

Ethyl-[(E)-{(3R) -3- [(tert-butoxycarbonyl) amino] piperidine-toyl} (cyanoimino) methyl] glycinate

(R) -tert-3-Butylpiperidine-3-ylcarbamate (73.0 g) was added to a suspension of diphenylcyanoimide carbonate (86.8 g) in 2-propanol (1.46 L) at room temperature, and the reaction solution was cooled to room temperature. For 30 minutes. The reaction solution was heated to 50 ° C., glycineethyl ester hydrochloride (254 g) and triethylamine (254 mL) were added, and the temperature was further raised, and the reaction solution was stirred for 8 hours (TC and 6 hours. The mixture was allowed to cool, the precipitate was filtered off, washed with ethyl acetate, the filtrate was concentrated under reduced pressure, water and potassium carbonate were added to the residue to make the solution alkaline, and the mixture was extracted twice with chloroform. Was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.The obtained residue was separated and purified by column chromatography (silica gel, hexane / ethyl acetate = 1/1 to 0/1). The title compound (133 g) was obtained as an amorphous substance.

_{Ή NMR (400 MHz, CDC1 3} ) 5ppm 5.61 (br, 1H), 4.66 (br, 1H), 4.24 (q, J = 7.1 Hz, 2H), 4.25-4.20 On, 1H), 3.78-3.37 (m, 5H), 1.98-1.93 (in, 1H), 1.85-1.80 (m, 1H), 1.71-1.66 (m, 2H), 1.45 (s, 9H), 1.30 (t, J = 7.1Hz, 3H).

MS (ESI +) 354 (M + H, 20%). Reference example 79

8-Bromo-7- (2-chlorobenzyl) -1-methyl-2-phenyl-1,7-dihydro-6H-purine-6-one

To a solution of sodium hydride (106 mg) in dimethylformamide (2.4 mL) was added 8-promo-7- (2-cyclobenzyl) -2-phenyl-1,7-dihydro-6H-purine-6-one ( 1.00 g) in dimethylformamide (20 mL) was added, and the reaction solution was stirred at room temperature for 1 hour. Methyl iodide (0.180 mL) was added to the reaction solution, and the mixture was stirred overnight. Dilute hydrochloric acid was added to the reaction solution to make the solution acidic, and the mixture was extracted twice with black hole form. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (silica gel, chloroform / methanol = 100/1 50/1) to give the title product (1.03 g).

Ή NMR (400 MHz, DMS0-d ₆ ) <5 pm 8.13-8.08 (m, 2H), 7.65-7.51 (i, 4H), 7.4 1-7.36 (m, 1H), 7.34-7.29 (m, 1H) , 6.66-6.61 (m, 1H), 5.73 (s, 2H), 3.31 (s, 3H).

MS (ESI +) 431 (MHl, 100%) Reference example 138

3-difluoromethoxyphenol

To a 15% aqueous solution of sulfuric acid (100 mL) of 3-difluoromethoxyaniline (4.90 g) was added dropwise an aqueous solution (20 mL) of sodium nitrite (2.34 g) at 0 ° C, and the mixture was stirred for 30 minutes. Thereafter, the temperature was raised to room temperature, further heated at 70 ° C., and stirred for 2 hours. The reaction solution was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (silica gel, hexane / ethyl acetate = 50/15/1) to obtain the title product (2.13 g).

_{Ή NMR (400 MHz, CDC1 3} ) <5 pm 7.21 (t, J = 8.2Hz, 1H), 6.70-6.62 (m, 3H), 6.4 9 (t, J H. F = 72.5Hz, 1H), 5.40 (br, 1H). Reference Example 139

3-cyclopropoxyphenol

Under a nitrogen atmosphere, cesium carbonate (2.34 g) and 2-chloroethyl-p-toluenesulfonate (9.39 g) were added to a solution of 3_benzyloxyphenol (4.00 g) in tetrahydrofuran (40 mL) at 65 ° C for 30 hours. The mixture was heated and stirred. The reaction solution was cooled to room temperature, solids were removed by filtration, and the filtrate was concentrated under reduced pressure. Further, potassium tert-butoxide (6.73 g) was added to a toluene solution (50 niL) of the crude product, and the mixture was stirred at 110 ° C for 1 hour. The reaction solution was cooled to room temperature, water (300 mL) was added, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (silica gel, hexane / ethyl acetate = 100/1 to 20/1) to give a vinyl ether intermediate (3.44 g).

_{¾ NMR (300 MHz, CDC1 3} ) (5 pm 7.44-7.18 (m, 6H), 6.72-6.59 (m, 4H), 5.04 (s, 2H), 4.77 (dd, J = 1.6, 13.7Hz, 1H) , 4.43 (dd, J = 1.6, 6.1Hz, 1H).

Under a nitrogen atmosphere, cool a solution of getylzinc (11.58 mL IM hexane solution) in 1,2-dichloroethane (12 mL) to -5 ° C, and add a solution of trifluoroacetic acid (1.89 g) in 1,2-dichloroethane. (5 mL) was slowly added dropwise, followed by stirring for 20 minutes. Further, jodmethane (0.93 mL) was added dropwise, and the mixture was stirred for 10 minutes. Then, a 1,2-dichloroethane solution (5 mL) of the above vinyl ether intermediate (1.31 g) was added dropwise. Thereafter, the temperature was gradually raised to room temperature over 2 hours, followed by stirring overnight. To the reaction solution was added 2N hydrochloric acid (20 mL), and 1,2-dichloroethane was distilled off under reduced pressure, followed by dilution with Jethyl ether (200 mL). The organic layer is washed with 1N hydrochloric acid, 2.5N aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, and sulfuric anhydride:

Dried. After filtration, the residue obtained by concentrating the filtrate under reduced pressure is subjected to column chromatography.

(Silica gel, hexane / ethyl acetate = 100/1 to 20/1), followed by purification to obtain benzyl ether of 3-cyclobutoxyphenol (0.74 g). Next, 10% palladium-carbon catalyst (50% wet) (0.36 g) was added to a solution of the obtained benzyl ether (0.74 g) in tetrahydrofuran (20 mL) and ethanol (20 mL), and the mixture was added under a hydrogen atmosphere. The mixture was stirred at room temperature for 5 hours. The reaction solution was dried over anhydrous sodium sulfate, filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the title 3-cyclopropoxyphenol (0.51 g).

_{¾ NMR (300 MHz, CDC1 3} ) (5 pm 7.12 (t, J = 8.0Hz, 1H), 6.65-6.56 (m, 2H), 6.45-6.41 (, 1H), 5.33 (br, 1H), 3.71- 3.66 (m, 1H), 0.76-0.73 (m, 4H). Test example Test example 1

In vitro DPP-IV inhibitory assay

A plasma containing human DPP-IV enzyme or human serum was diluted with Atsey buffer (25 mM Tris-HC1, 140 mM NaCl, 10 mM KC1, pH 7.9) and used for the experiment. Dilution, human serum: final 10-fold dilution). After adding various concentrations of the test compound solution and incubating at room temperature, the substrate (Glycyl-L-Proline 4-Methyl-Coumaryl-7-Amide, Peptide Laboratories) was added to a final concentration of 100 M. Then, the reaction was carried out at room temperature. Acetic acid was added to a final concentration of 12.5 to stop the reaction, and the fluorescence intensity was measured at an excitation wavelength of 360 antinodes and a measurement wavelength of 460 nm using a fluorescence plate reader. From enzyme inhibitory activity during the test compound added in several concentrations, IC ₅ compound concentration that inhibits 50%. It was calculated as a value. Table 1 shows the average of two to seven experiments.

(table 1)

(-: Not considered)

Test example 2

Blood DPP-IV inhibitory activity assay in rats

A 0.5 MC suspension of the test compound was orally administered to SD rats at a dose of 3 mg / kg. The control group was orally administered only a 0.5% MC solution. Blood was collected from the tail vein before administration, and at 1, 2, 4, 6, and 24 hours after administration, and immediately centrifuged to collect plasma. The obtained plasma was diluted with Atsushi buffer (25 mM Tris-HCl, 140 mM NaCl, ΙΟιηΜ KC1, pH 7.9) (final 20-fold dilution). As in Test Example 1, the substrate (Glycyl-L-Proline) was used. 4-Methyl- Coumaryl-7-Amide, Peptide Research Laboratories) was added to a final concentration of IOOM and reacted at room temperature. Acetic acid was added to a final concentration of 12.5% to stop the reaction, and the fluorescence intensity at an excitation wavelength of 360 nm and a measurement wavelength of 460 nm was measured using a fluorescence plate reader. The ratio of the plasma DPPIV activity after administration of the test compound to the plasma DPPIV activity before administration of the test compound was calculated, and the plasma DPV inhibition rate was calculated. In addition, the area under the graph (AU ( _V24h )) under which the DPPIV inhibition rate was plotted was calculated and used as a comprehensive index of the in vivo DPPIV inhibitory activity of the test compound, and the results are shown in Table 2.

(Table 2)

(n = 3) Test example 3

Blood DPP IV Inhibitory Effect Measurement Test in Mice C57BL mice loaded with a high fat diet were orally administered a 0.5 mg MC suspension of the test compound at a dose of 3 mg / kg. The control group was orally administered only a 0.5% MC solution. Blood was collected from the tail vein before administration and 24,610,24 hours after administration of the compound, and plasma was collected immediately by centrifugation. The obtained plasma was diluted with Atsey buffer (25 mM Tris-HC1 HOfflM NaCl, lOmM KC1, pH 7.9) (final 20-fold dilution). The substrate (Glycyl-L-Pro l ine 4-Methy Co Coumary A 7-Amide, Institute for Peptide Research) was added to a final concentration of 100 and reacted at room temperature. Acetic acid was added to a final concentration of 12.5% to stop the reaction, and the fluorescence intensity at an excitation wavelength of 360 nm and a measurement wavelength of 460 mn was measured using a fluorescent plate reader. Calculate the ratio of plasma DPPIV activity after test compound administration to plasma DPPIV activity before test compound administration.Calculate plasma DPPIV inhibition rate. Was. The area under the graph (AUC (0-24h)) plotting the DPPIV inhibition rate was calculated and used as a comprehensive index of the in vivo DPPIV inhibitory activity of the test compound. The results are shown in Table 3. (Table 3)

(n = 2-4) Test example 4

Serum Concentration of Test Compound in Rats Orally Administered (Compound of Example 49) Serum administered with the compound of Example 49 was treated by a liquid-liquid extraction method. That is, the compound of Example 49 was orally administered to a SD rat (male, 7 weeks old) at 10 mg / kg (5 mL / kg) as a 0.5% MC suspension. The serum concentration of the compound of Example 49 was measured by liquid chromatography tandem mass spectrometry (LC / MS / MS). That is, 0.1 mU of rat serum, an internal standard solution (0.5 ug D100) was added, and the mixture was stirred for about 10 seconds with 1 mL of standard buffer (pH 6.86, Wako Pure Chemical Industries) and 3 mL of ethyl acetate. After centrifugation (3,000 rpm, room temperature, 10 minutes), the organic layer was separated, and methanol was added to the residue evaporated to dryness at 40 ° C under a nitrogen stream. The solution 2 ^ obtained by adding mL and 0.1 mL of water and stirring with a mixer for about 10 seconds was measured by LC / MS / MS.

Under LC conditions, the column used was Cadenza CD-C18 (length 50 band, diameter 4.6 band, particle size 3 H. The eluent used was a 10 mM ammonium acetate aqueous solution / methanol (2: 8) mixed solution, and the flow rate was 0.2. Under MS conditions, TSQ7000 LC / MS / MS System (ThermoFinnigan) was used for the instrument, ESI was used for the ionization method, the measurement mode was positive, and the monitoring method was SRM (Selective The average serum concentration at each blood sampling time after oral administration is shown in Table 4. Serum concentration of test compound when orally administered to rats (Compound L of Example 45 or 76 Serum administered with the compound of Example 45 or 76 was subjected to solid phase extraction. That is, SD rats (male, male, At 7 weeks of age, the compound of Example 45 or 76 was orally administered in a 0.5% MC suspension at 10 mg / kg (5 mL / kg), respectively. After adding 400 ^ of the standard solution (0.05 igMl), the mixture was mixed by inversion, and the solution 100 was subjected to solid-phase extraction and concentration using an automatic solid-phase extraction device, and then introduced into an MS / MS analyzer. It was measured.

The automated solid phase extractor used was Prospekt-2 (Spark), and the solid phase cartridge used a 0DS force cartridge. Under LC conditions, the analytical column used was Mightysil RP-18 GP (length 50 mm, diameter 2.1 mm, particle diameter 3 jm), and elution was performed by a gradient method using a 10 mM ammonium acetate aqueous solution / methanol mixture. did. Under MS conditions, API4000 LC / MS / MS System (Applied Biosystem) was used for the instrument, ESI was used for ionization method, measurement mode was positive ion, and monitoring method was MRM (Multiple Reaction Monitoring). Table 4 shows the average serum concentration at each blood sampling time after oral administration.

(Table 4) Serum concentration of each test compound when orally administered to rats

ND: below the detection limit (10 ng / mL). Test example 5

Serum concentration of test compound when administered intravenously to rats (compound of Example 49)

Using an SD rat (male, 7 weeks old), an aqueous solution (physiological saline / 0.1 hydrochloric acid = 9/1) of the compound of Example 49 was administered into the tail vein at 1 mg / kg (5 mL / kg). . Hereinafter, the concentration of the compound of Example 49 in serum was determined in the same manner as in the compound of Example 49 in Test Example 4. It was measured. Table 5 shows the average serum concentration at each blood sampling time after intravenous administration. Serum concentration of test compound when intravenously administered to rats (compound of Example 45 or 76)

Using an SD rat (male, 7 weeks old), an aqueous solution of the compound of Example 45 (50% polyethylene glycol / 0.1 N hydrochloric acid = 9/1) or an aqueous solution of the compound of Example 76 (12% polyethylene) Glycol) was administered at 1 mg / kg (5 mL / kg) via the tail vein. Hereinafter, the concentrations of the compounds of Examples 45 and 76 in the serum were measured in the same manner as in the compounds of Examples 45 and 76 in Test Example 4. Table 5 shows the average serum concentration at each blood sampling time after intravenous administration.

(Table 5) Serum concentrations of each test compound when administered intravenously to rats

ND: below detection limit (10 ng / mL)-industrial applicability

According to the present invention, a compound having DPP-IV inhibitory activity and improved in safety, toxicity, and the like can be provided.

The compound of the present invention suppresses postprandial hyperglycemia in a prediabetic state, treats non-insulin-dependent diabetes, treats autoimmune diseases such as arthritis and rheumatoid arthritis, treats intestinal mucosal disease, promotes growth, and rejects transplanted organs It is useful for suppressing, treating obesity, treating eating disorders, treating HIV infection, suppressing cancer metastasis, treating benign prostatic hyperplasia, treating periodontitis, and treating osteoporosis.

Claims

The scope of the claims

Formula (I)

N (I)

γ-ΝΗ ₂

, 2 I. Μ Ν

[Wherein, R ¹ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group;

R ² is a hydrogen atom, a halogen atom, a cyano group, a formyl group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkyloxy group, an optionally substituted alkenyl Group, optionally substituted amino group, optionally substituted sorbamoyl group, carboxy group, optionally substituted alkoxy group, optionally substituted alkoxycarbonyl group, optionally substituted aryl group, substituted Optionally substituted aryloxy, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, optionally substituted arylalkyloxy, optionally substituted aryloyl, optionally substituted arylthio Group, optionally substituted arylsulfinyl group, optionally substituted arylsulfonyl group, substituted To an optionally substituted alkylthio group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group, and an optionally substituted Represents a teloarylcarbonyl group, an optionally substituted heteroaryloxy group, an optionally substituted alkylcarbonyl group, or an optionally substituted nitrogen-containing saturated heterocyclic group, or a compound represented by the following formula (T 1) A group represented by to (T 6):

(T4) (T5) (T6)

(In the formula, R ^T is absent, or one or more, and each independently represents a halogen atom, a hydroxyl group, an oxo group, an optionally substituted alkoxy group, an optionally substituted alkyl group, group, optionally substituted alkoxy Cal Poni group, heterocyclic group Okishikarubo two Le group or substituted or represents good force Rubamoiru group optionally or two R ^T is together such connexion methylene to saturation, ethylene, trimethylene, tetramethylene Represents methylene or butenylene, and may combine with one or two carbon atoms of a ring to form a new ring.)

R ³ is a hydrogen atom, an alkyl group which may be substituted, a cycloalkyl group which may be substituted, an aryl group which may be substituted, a butyl group which may be substituted, a nitrogen-containing saturated hetero group which may be substituted; ring group or substituted represents a heteroaryl group to good,; single Y- NH ₂ represents a group represented by the group represented by the following formula (a) or the following formula, (B).

(In the formula, m represents 0, 1, or 2, and R ⁴ is absent, presents 1 or 2 times, and is each independently a halogen atom, a hydroxyl group, an oxo group, or may be substituted. An alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, Represents an aralkyl group, an optionally substituted amino group, a carboxy group, an optionally substituted alkoxycarbol group, or an optionally substituted rubamoyl group, or two R ⁴ 's together It stands for methylene or ethylene, and can combine with the two carbon atoms that make up the ring to form a new ring. ),

(In the formula, n represents 0, 1, or 2, and R ⁵ is absent, presents 1 or 2 times, and is each independently a halogen atom, a hydroxyl group, an oxo group, or may be substituted. An alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxy group, an optionally substituted alkoxycarbonyl group, Or, an optionally substituted force, or a force representing a rubamoyl group, or two R ⁵ 's together represent methylene or ethylene, and may combine with the two carbon atoms constituting the ring to form a new ring. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

2. — Y—NH ₂ is a group represented by the formula (A) and m is 1 or 2, or one Y—NH ₂ is a group represented by the formula (B) And n is 1 or 2. The compound according to claim 1, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

3. R ³ is represented by the following formula (C), (D) or any group of (E), a compound or a prodrug according to any one of claims 1-2 or their pharmaceutically, Acceptable salt.

►6

(In the formula, Z represents an oxygen atom, -S (p) p—, or —N (RU) —, and R ⁶ does not exist, or one or two exist, and each is independently halogen Atom, hydroxyl group, formyl group, carboxy group, cyano group, alkylthio group, alkylsulfinyl group, alkylsulfonyl group, alkyl group, haloalkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, optionally substituted amino group, substitution Represents an optionally substituted rubamoyl group, an alkoxycarbonyl group, an optionally substituted alkylcarbonyl group, a cycloalkylcarbonyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group, or 2 R ⁶ together form an alkylenedioxy group,

R ⁸ represents a methyl, ethyl, chlorine, or bromine atom,

R ^{1 Q} represents a hydrogen atom, methyl or ethyl,

p represents 0, 1 or 2;

R ¹¹ represents a hydrogen atom or an alkyl group. )

4. The compound according to claim 3, wherein R ³ is formula (C) or formula (E), or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

5. R ³ is a group represented by the formula (0, R ⁶ is absent, or one or two are present, and each is independently a halogen atom, a cyano group, an alkylthio group, an alkylsulfonyl group, (: 丄 _ ₃ alkylenedioxy O alkoxy group, an alkyl group, a haloalkyl group, a cycloalkyl group, § alkoxy group, a haloalkoxy group, an alkoxycarbonyl Cal Poni group, alkylcarbonyl group, haloalkyl Cal Poni group or cycloalkyl Cal Poni group,, of claim 4, wherein A compound or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 4, wherein R ³ is of the formula (C), one R ⁶ is present and is a halogen atom, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

7. R ³ is 2_chlorophenyl, 2_chloro-5-fluorophenyl, 2-methyl-5-fluorophenyl, 2-methoxy-5-fluorophenyl, or 2-cyano-5-fluorophenyl, The compound according to claim 4 or a prodrug thereof. Or pharmaceutically acceptable salts thereof.

8. R ¹ is a hydrogen atom, an optionally substituted alkyl group having 1 to 3 carbon atoms, or an optionally substituted aryl group, and a substituent of the optionally substituted alkyl group. Is a fluorine atom, an optionally substituted aryloyl group, a carboxy group, an optionally substituted

5. The compound or prodrug thereof according to any one of claims 1 to 7, wherein the compound or prodrug is selected from a substituted alkoxycarbonyl group, an optionally substituted aryl group and an optionally substituted aryloxy group. Their pharmaceutically acceptable salts.

. 9 R ¹ has the formula: - R is a- R b _ R c group represented by The compound or a prodrug thereof according to any one of claims 1 to 7 or is their pharmaceutically acceptable, 0 salt. here,

R a represents an alkylene chain,

R b represents a single bond or a haponyl group,

R c represents an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted aryl group, or an optionally substituted aryloxy group.

5 10. The compound according to any one of claims 1 to 7, wherein R ¹ is a hydrogen atom, methyl, or ethyl, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

1 1. R ¹ is methyl, compound or a prodrug thereof according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

0 1 2. R ² is a hydrogen atom, a cyano group, an optionally substituted alkyl group, a carboxy group, an optionally substituted alkoxy group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryl group, or a substituted Optionally substituted aryloxycarbonyl group, optionally substituted aralkyl group, optionally substituted aralkyloxy group, optionally substituted aroyl group, or optionally substituted aralkyloxy group The compound according to any one of claims 1 to 11, which is a 5-alkylcarbonyl group, a prodrug thereof, or a pharmaceutically acceptable salt thereof.

13. The compound according to any one of claims 1 to 11, wherein R ² is a cyano group, an optionally substituted alkoxycarbonyl group, or an optionally substituted aryloxy group, or a process thereof. Drugs or their pharmaceutically acceptable salts.

0 1 4. The compound according to claim 1.3 or a compound thereof, wherein R ² is a substituted aryloxy group. Prodrugs or their pharmaceutically acceptable salts.

15. The compound according to any one of claims 1 to 11, wherein R ² is a substituted heteroaryloxy group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

16. The compound according to any one of claims 1 to 11, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is a group represented by formulas (T1) to (T6). Salt.

17. R ² has the formula: — O— Tx—〇-Ty (where (represents an oxygen atom, Tx represents a phenylene group, a pyridinediyl group, a pyrimidinediyl group, or a thiofendyl group, and Ty is substituted Represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkylalkyl group, or an optionally substituted saturated heterocyclic group.) The compound according to any one of claims 1 to 11, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, which is a group represented by:

18. The compound according to claim 17, wherein Tx is a phenylene group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 18, wherein Tx is m-phenylene, a prodrug thereof, or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 19, wherein Ty is a substituted alkyl group, a substituted cycloalkyl group, or an optionally substituted cycloalkylalkyl group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 20, wherein the substituent of the group represented by Ty is a halogen atom, a carboxy group, or an alkoxycarbonyl group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

22. A compound represented by the formula (I) is represented by the following formulas (cl) to (c36):

2 Z 0 contract Zdf / e :) d 908 960 contract OAV

1 ^ 01900 contract Zdf / e :) d 908 960 contract OAV

(Wo) (ε)

9Ζ £

1 ^ 01900 contract Zdf / e :) d 908 960 contract OAV O 2004/096806

3 2 6

(c35) The compound according to claim 1, which is (c36) or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

23. A medicament comprising the compound according to any one of claims 1 to 22 or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

24. A dipeptidyl peptidase-IV inhibitor comprising the compound according to any one of claims 1 to 22 or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

25. An antidiabetic agent comprising the compound according to any one of claims 1 to 22 or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. 26. Use of the compound according to any one of claims 1 to 22 or a prodrug thereof, or a pharmaceutically acceptable salt thereof for the production of a dipeptidyl peptidase-IV inhibitor. .

27.The compound according to any one of claims 1 to 2.2 for the manufacture of a therapeutic agent for diabetes. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

28. The ability to administer to a patient in need of treatment an effective amount of a compound according to any one of claims 1-22, or a prodrug thereof, or a pharmaceutically acceptable salt thereof. How to treat diabetes.