WO2010064705A1

WO2010064705A1 - Novel 7-substituted dihydropyranopyrimidine derivative having h4 receptor antagonistic activity

Info

Publication number: WO2010064705A1
Application number: PCT/JP2009/070389
Authority: WO
Inventors: 克巳久保田; 成宏浅野; 貴士高田
Original assignee: 大日本住友製薬株式会社
Priority date: 2008-12-05
Filing date: 2009-12-04
Publication date: 2010-06-10

Abstract

Provided is a dihydropyranopyrimidine derivative useful as a pharmaceutical such as an antiallergic agent or an antiinflammatory agent. A compound represented by formula (1), or a pharmaceutically acceptable salt thereof. In formula (1), R¹ is a group represented by formula (Ya), a group represented by formula (Yd) (wherein R⁸ is a hydrogen atom, an alkyl group, or the like; R^8a1 and R^8a2 are each a hydrogen atom, an alkyl group, or the like; R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ are each independently a hydrogen atom, or the like; h is an integer of 1 to 2; p is an integer of 0 to 2; s is an integer of 1 to 4; and t is an integer of 1 to 4), R² and R³ are each a substituted or unsubstituted alkyl group or the like, or may be joined together with the carbon atom to which they are bonded to form a 3- to 8-membered carbon ring or the like; R⁴, R⁵, R⁶, and R⁷ are each independently a hydrogen atom or the like; X is a hydrogen atom or an amino group.

Description

Novel 7-substituted dihydropyranopyrimidine derivatives having H4 receptor antagonist activity

The present invention has an excellent H4 receptor antagonistic action, allergic conjunctivitis, allergic rhinitis, chronic urticaria, atopic dermatitis, asthma, chronic bronchitis, ulcerative colitis, Crohn's disease, rheumatism, pain, Novel dihydropyranopyrimidine derivatives useful as therapeutic or preventive agents for neurological diseases, chronic obstructive pulmonary disease, cancer, sepsis and the like, more specifically, novel dihydropyrano [4,3- d] Pyrimidine derivatives and their pharmaceutical use.

Allergic diseases such as allergic conjunctivitis, allergic rhinitis, chronic urticaria, atopic dermatitis, asthma, or chronic bronchitis are mainly caused by allergic effects, but eosinophils over time Inflammatory cells mainly composed of infiltrate the affected area and show an inflammatory image, and in some cases, it becomes more painful and itchy. For general allergic diseases, antiallergic agents such as antihistamines (H1 receptor antagonists) are widely used as symptomatic therapeutic agents. However, conventional antiallergic agents often do not provide a sufficient therapeutic effect on inflammation itself. For this reason, in addition to antiallergic agents, treatments using steroidal agents that are anti-inflammatory agents are often performed. Steroids that are anti-inflammatory agents are also used for inflammatory diseases such as ulcerative colitis, Crohn's disease, rheumatism, and chronic obstructive pulmonary disease. However, conventional steroids have side effects that cause problems such as infectivity, adrenal atrophy, osteoporosis, diabetes, and childhood growth disorders. In addition, since steroids do not have analgesic action or anti-pruritic action, they are not effective against itching in atopic dermatitis. Therefore, development of an antiallergic agent having both anti-inflammatory and anti-pruritic effects and a new anti-inflammatory agent is desired.

In recent years, the fourth receptor H4 receptor having histamine as a ligand has been identified, and this H4 receptor is expressed in blood cells such as eosinophils, mast cells, dendritic cells, and Th2 cells. It has become clear. Further, as an action of an H4 receptor antagonist, it inhibits migration of inflammatory cells such as eosinophils and mast cells (see, for example, Non-Patent Document 1), and acts on the antigen presentation process of T cells, thereby causing IgE of B cells. Has been reported to suppress the production of (see, for example, Non-Patent Document 2). Therefore, H4 receptor antagonists are expected to have antiallergic and / or anti-inflammatory effects. In addition, H4 receptor antagonists have been reported to have analgesic action and anti-pruritic action (see, for example, Non-Patent Document 3) and action to stop the cell cycle (see, for example, Non-Patent Document 4).

Dihydropyranopyrimidine derivatives have been reported in several references.
For example, in a document disclosing a pyrimidine compound that acts as a Th2 immune response suppressor or an allergic disease therapeutic agent, the compound is represented by the formula (A):

Has been reported (see Patent Document 1).
In addition, for example, in a document disclosing a pyrimidine derivative as a histamine H4 receptor modulator, as the derivative, the formulas (B) to (H):

Has been reported (see Patent Document 2). However, these literatures do not report derivatives having substituents on the 5-position, 7-position and 8-position on dihydropyranopyrimidine and the influence of the substituents.
On the other hand, recently, monocyclic and tricyclic pyrimidine derivatives having an action on the H4 receptor have been reported in several documents (Patent Documents 3, 4, 5, 6, 7, 8, 9, 10). , 11, and 12). However, these documents do not disclose bicyclic pyrimidine derivatives.

In any of the above-mentioned patent documents, there is no specific disclosure of compounds having limited chemical structural features of the present invention.

International Publication No. 2000/012487 Pamphlet International Publication No. 2008/100565 Pamphlet International Publication No. 2005/014556 Pamphlet International Publication No. 2005/054239 Pamphlet International Publication No. 2007/031529 Pamphlet International Publication No. 2007/072163 Pamphlet International Publication No. 2008/031556 Pamphlet International Publication No. 2006/050965 Pamphlet International Publication No. 2008/008359 Pamphlet International Publication No. 2008/060767 Pamphlet International Publication No. 2008/074445 Pamphlet European Patent Application Publication No. 1829879

The problem to be solved by the present invention is to provide a novel compound having an H4 receptor antagonistic activity and useful as a therapeutic or prophylactic agent for allergic diseases, inflammatory diseases, pain, cancer, sepsis and the like. .

As a result of intensive studies, the present inventors have found that the following novel dihydropyranopyrimidine derivatives exhibit an H4 receptor antagonistic action, thereby completing the present invention.
The present invention relates to a dihydropyranopyrimidine derivative having an H4 receptor antagonistic activity, or a pharmaceutically acceptable salt thereof, represented by the following items 1 to 40. That is, the present invention is as follows.

Term 1: Formula (1)

[Wherein, R ¹ represents the formula (Ya)

Wherein R ⁸ is a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, or an unsubstituted alkanoyl group having 1 to 11 carbon atoms. And
R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and h are
(i) h is an integer of 1 to 2,
R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ are each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms or an unsubstituted carbon. A cycloalkyl group having 3 to 6 atoms, wherein h is 2, a plurality of R ¹¹ and R ¹² are each independently the same or different;
(ii) h is an integer of 1 to 2,
R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹⁴ and R ¹⁶ are each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms or an unsubstituted C 3 to 6 carbon atom. A cycloalkyl group in which h is 2, a plurality of R ¹¹ and R ¹² are each independently the same or different;
R ¹³ and R ¹⁵ together form — (CH ₂ ) ₂ — or — (CH ₂ ) ₃ —,
(iii) h is an integer of 1 to 2,
R ¹⁰ , R ¹¹ , R ¹² , R ¹⁴ , R ¹⁵ and R ¹⁶ are all hydrogen atoms,
R ⁹ and R ¹³ together form — (CH ₂ ) _g — (where g is an integer from 1 to 2),
(iv) h is 1,
R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁶ are all hydrogen atoms,
R ⁹ and R ¹⁵ together form — (CH ₂ ) ₂ —, or
(v) h is 1,
R ⁹ , R ¹⁰ , R ¹² , R ¹⁴ , R ¹⁵ and R ¹⁶ are all hydrogen atoms,
R ¹¹ and R ¹³ together form — (CH ₂ ) ₂ —. )
A group represented by formula (Yb)

(In the formula, h is an integer of 1 to 2,
k is an integer of 1 to 2,
R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁵ and R ¹⁶ are each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms or an unsubstituted carbon atom of 3 And when h is 2, the plurality of R ¹¹ and R ¹² are each independently the same or different. )
A group represented by formula (Yc)

(In the formula, n is an integer of 1 to 3,
p, q and r are each independently an integer of 0 to 2;
R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, And when p is 2, a plurality of R ¹⁷ and R ¹⁸ are each independently the same or different,
R ⁸ is the same as described above. )
A group represented by formula (Yd)

^Wherein R ^8a1 and R ^8a2 are
(i) each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, or
(ii) together with the nitrogen atom to which each is bonded, may form an aziridine ring, azetidine ring, pyrrolidine ring, piperidine ring, perhydroazepine ring or perhydroazocine ring;
p is an integer from 0 to 2, s is an integer from 1 to 4, and t is an integer from 0 to 4. Here, when p is 0, t is an integer from 1 to 4. And
R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms; Here, when p is 2, and when s is an integer of 2 to 4, a plurality of R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are all independently the same or different. )
A group represented by formula (Ye)

(In the formula, one of R ²¹ and R ²² is a hydrogen atom, and the other is —N (R ^8a1 ) (R ^8a2 );
Here, R ^8a1 and R ^8a2 are
(i) each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, or
(ii) together with the nitrogen atom to which each is bonded, may form an aziridine ring, azetidine ring, pyrrolidine ring, piperidine ring, perhydroazepine ring or perhydroazocine ring;
u is an integer of 0-2. )
Or a group represented by formula (Yf)

(In the formula, u, v, wa and wb are each independently an integer of 1 to 2, and R ⁸ is the same as described above.)
A group represented by

R ² represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms, a substituted or unsubstituted alkynyl group having 2 to 10 carbon atoms, substituted or unsubstituted Unsubstituted cycloalkyl group having 3 to 10 carbon atoms, substituted or unsubstituted cycloalkenyl group having 4 to 8 carbon atoms, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted A substituted aralkyl group having 7 to 14 carbon atoms, a substituted or unsubstituted 4- to 10-membered monocyclic or bicyclic saturated aliphatic heterocyclic group, or a substituted or unsubstituted 4- to 10-membered monocyclic or bicyclic group An unsaturated aliphatic heterocyclic group of the ring,
R ³ represents a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms, a substituted or unsubstituted alkynyl group having 2 to 10 carbon atoms. Group, substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms, substituted or unsubstituted cycloalkenyl group having 4 to 8 carbon atoms, substituted or unsubstituted aryl group, or substituted or unsubstituted heteroaryl group Or R ² and R ³ together with the carbon atom to which they are attached may form a 3-8 membered carbon ring or a 5-8 membered heterocycle containing an oxygen atom,
R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, or a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms. Substituted or unsubstituted alkynyl groups having 2 to 10 carbon atoms, substituted or unsubstituted cycloalkyl groups having 3 to 10 carbon atoms, substituted or unsubstituted cycloalkenyl groups having 4 to 8 carbon atoms, substituted or An unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, or R ⁴ and R ⁵ and R ⁶ and R ⁷ together may form an oxo group;
X is a hydrogen atom or an amino group. ]
Or a pharmaceutically acceptable salt thereof.

Item 2: The compound according to item 1, wherein R ⁸ in formula (Ya) is a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms. Or a pharmaceutically acceptable salt thereof.

Item 3: R ¹ is a group represented by the formula (Ya),
Formula (Yc1)

Wherein R ⁸ is a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, and p ′ is an integer of 1 to 2 And q ′ is an integer of 1 to 2.)
A group represented by formula (Yc2)

(Wherein, r ′ is each independently an integer of 1 to 2, and p ′ and R ⁸ are the same as described above.)
Or a group represented by formula (Yd1)

( ^Wherein R ^8a1 and R ^8a2 are each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, p ′ Is the same as described above, s ′ is an integer of 1 to 3, and R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ each independently represents a hydrogen atom or an unsubstituted carbon atom having 1 to 10 carbon atoms. An alkyl group or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, and when s ′ is 2 or 3, a plurality of R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are all independently The same or different)
The compound of claim | item 1 which is group represented by these, or its pharmaceutically acceptable salt.

Term 4: R ¹ is the formula (Ya1)

(Wherein R ⁸ is a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms;
h is an integer of 1 to 2. )
A group represented by formula (Ya2)

(In the formula, g is an integer of 1 to 2, and R ⁸ and h are the same as described above.)
A group represented by formula (Ya3)

(Wherein R ⁸ is the same as described above.)
A group represented by formula (Ya4)

(Wherein R ⁸ is the same as described above.)
A group represented by formula (Yc1) or a group represented by formula (Yc2), or formula (Yd2)

( ^Wherein R ^8a1 and R ^8a2 are each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, p ′ Is an integer from 1 to 2, and s ′ is an integer from 1 to 3.)
A group represented by
R ² is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms, a substituted or unsubstituted alkynyl group having 2 to 10 carbon atoms, substituted or Unsubstituted cycloalkyl group having 3 to 10 carbon atoms, substituted or unsubstituted cycloalkenyl group having 4 to 8 carbon atoms, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted A substituted aralkyl group having 7 to 14 carbon atoms, a substituted or unsubstituted 4- to 10-membered monocyclic or bicyclic saturated aliphatic heterocyclic group, or a substituted or unsubstituted 4- to 10-membered monocyclic or bicyclic group An unsaturated aliphatic heterocyclic group of the ring,
R ³ is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms, a substituted or unsubstituted alkynyl group having 2 to 10 carbon atoms Group, substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms, substituted or unsubstituted cycloalkenyl group having 4 to 8 carbon atoms, substituted or unsubstituted aryl group, or substituted or unsubstituted heteroaryl group Or the compound according to item 1 or 3, wherein R ² and R ³ may form a 3- to 8-membered carbocycle together with the carbon atom to which each is bonded, or A pharmaceutically acceptable salt.

Item 5: The compound according to Item 4, wherein R ⁸ is a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, or a pharmaceutical thereof Acceptable salt.

Item 6: R ¹ represents the formula (Ya1)

(Wherein R ⁸ is a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms,
h is an integer of 1 to 2. )
Item 5. The compound according to Item 4, which is a group represented by: or a pharmaceutically acceptable salt thereof.

Item 7: The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is an unsubstituted alkyl group having 1 to 10 carbon atoms.

Term 8: R ¹ is the formula (Yd2)

^Wherein R ^8a1 and R ^8a2 are each independently a hydrogen atom or an unsubstituted alkyl group having 1 to 10 carbon atoms, p ′ is an integer of 1 to 2, s ′ is 1 to The compound of claim | item 4, or its pharmaceutically acceptable salt which is group represented by this.

Item 9: R ² represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms, a substituted or unsubstituted cyclohexane having 3 to 10 carbon atoms An alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aralkyl group having 7 to 14 carbon atoms, a substituted or unsubstituted 4- to 10-membered monocyclic or bicyclic ring Item 9. The compound according to any one of Items 1 to 8, which is a saturated aliphatic heterocyclic group or a substituted or unsubstituted 4- to 10-membered monocyclic or bicyclic unsaturated aliphatic heterocyclic group. Or a pharmaceutically acceptable salt thereof.

Item 10: R ² represents an unsubstituted alkyl group having 1 to 10 carbon atoms, an unsubstituted cycloalkyl group having 3 to 10 carbon atoms, a substituted or unsubstituted aryl group, or an unsubstituted carbon atom having 7 to Item 14. The compound according to Item 9, which is 14 aralkyl groups, or a pharmaceutically acceptable salt thereof.

Item 11: The compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom or an unsubstituted alkyl group having 1 to 10 carbon atoms. .

Item 12: The compound according to any one of Items 1 to 8, wherein R ² and R ³ together with the carbon atom to which each is bonded form a 3- to 8-membered ring, or a pharmaceutical product thereof Acceptable salt.

Item 13: R ⁴ and R ⁵ are each independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms, substituted or unsubstituted, Item 13. The compound according to any one of Items 1 to 12, which is an unsubstituted cycloalkyl group having 3 to 10 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a compound thereof A pharmaceutically acceptable salt.

Item 14: The compound according to Item 13, or a pharmaceutically acceptable salt thereof, wherein R ⁴ and R ⁵ are each independently a hydrogen atom or an unsubstituted alkyl group having 1 to 10 carbon atoms.

Item 15: The compound according to Item 14, or a pharmaceutically acceptable salt thereof, wherein R ⁴ and R ⁵ are a hydrogen atom.

Item 16: The compound according to any one of Items 1 to 15, or a pharmaceutically acceptable salt thereof, wherein X is a hydrogen atom.

Item 17: The compound according to any one of Items 1 to 15, or a pharmaceutically acceptable salt thereof, wherein X is an amino group.

Item 18: R ¹ is a group represented by the formula (Ya) (wherein R ⁸ is a hydrogen atom or an unsubstituted alkyl group having 1 to 10 carbon atoms, R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ are all hydrogen atoms, and h is an integer of 1.)
Or a group represented by the formula (Yd) (wherein R ^8a1 and R ^8a2 are each independently a hydrogen atom or an unsubstituted alkyl group having 1 to 10 carbon atoms, and p is 1 to 2). S is an integer from 1 to 2, and t is an integer from 0);
R ² is an unsubstituted alkyl group having 1 to 10 carbon atoms, an unsubstituted cycloalkyl group having 3 to 10 carbon atoms, an unsubstituted aryl group, or an unsubstituted aralkyl group having 7 to 14 carbon atoms. Yes;
R ³ is a hydrogen atom or an unsubstituted alkyl group having 1 to 10 carbon atoms, or R ² and R ³ together with the carbon atom to which each is bonded form a 3- to 8-membered carbocyclic ring. May be built;
R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently a hydrogen atom or an unsubstituted alkyl group having 1 to 10 carbon atoms;
Item 2. The compound according to Item 1, or a pharmaceutically acceptable salt thereof, wherein X is an amino group.

Item 19: The compound according to Item 18, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a group represented by the formula (Ya).

Item 20: The compound of Item 18, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a group represented by the formula (Yd).

Item 21: Item 18 to Item 20, wherein R ² is an unsubstituted alkyl group having 1 to 10 carbon atoms, and R ³ is a hydrogen atom or an unsubstituted alkyl group having 1 to 10 carbon atoms. The compound according to any one of the above, or a pharmaceutically acceptable salt thereof.

Item 22: The compound according to any one of Items 18 to 20, wherein R ² and R ³ together with the carbon atom to which each is bonded form a 3- to 8-membered carbocyclic ring, or a pharmaceutical thereof Acceptable salt.

Item 23: The compound or a pharmaceutically acceptable salt thereof according to any one of Items 18 to 22, wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ are all hydrogen atoms.

Item 24: Formula (1a)

[Wherein R ^1a represents the formula (Ya5)

(Wherein R ^8a is a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms.)
Or a group represented by formula (Yd3)

( ^Wherein R ^8a1 and R ^8a2 are each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms; Is an integer from 1 to 3.)
A group represented by
R ^2a is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aralkyl group having 7 to 14 carbon atoms,
R ^3a is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, or a substituted or unsubstituted aryl group, or R ^2a and R ^3a together with the carbon atom to which each is bonded. You may have built a 3-8 membered ring,
X is a hydrogen atom or an amino group. ]
Or a pharmaceutically acceptable salt thereof.

Item 25: The compound according to Item 24 or a pharmaceutically acceptable salt thereof, wherein R ^8a is a hydrogen atom or an unsubstituted alkyl group having 1 to 10 carbon atoms.

Item 26: R ^1a is represented by formula (Ya5) (wherein R ^8a is a hydrogen atom or an unsubstituted alkyl group having 1 to 6 carbon atoms) or formula (Yd3) (wherein R ^8a1 and R ^8a2 each independently represents a hydrogen atom or an unsubstituted alkyl group having 1 to 6 carbon atoms, and s ′ is 1 or 2, and R ^2a represents an unsubstituted carbon atom number. An alkyl group having 1 to 6 carbon atoms or an unsubstituted aralkyl group having 7 to 10 carbon atoms, and R ^3a is a hydrogen atom or an unsubstituted alkyl group having 1 to 6 carbon atoms, or R ^2a and R ^3a may form a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring or a cyclohexyl ring together with the carbon atom to which each is bonded, and X is a hydrogen atom or an amino group. Item 25, or a pharmaceutically acceptable salt thereof.

Item 27: R ^1a is a formula (Ya5) (wherein R ^8a is a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, or an isobutyl group) or a formula (Yd3) (formula R ^8a1 and R ^8a2 are each independently a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or an isobutyl group, and s ′ is 1 or 2. R ^2a is a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, benzyl group or 2-phenylethyl group, and R ^3a is a hydrogen atom, methyl group, ethyl group, propyl group group, isopropyl group, butyl group, or an isobutyl group or pentyl group, or R ^2a and R ^3a is cyclopentyl or cycloalkyl together with the carbon atoms bonded thereto May have built a cyclohexyl ring, X is hydrogen atom or an amino group. ]
Item 26. The compound according to Item 24 or Item 25, or a pharmaceutically acceptable salt thereof.

Item 28: A pharmaceutical composition comprising the compound according to any one of Items 1 to 27 or a pharmaceutically acceptable salt thereof as an active ingredient.

Item 29: A medicament comprising the compound according to any one of Items 1 to 27 or a pharmaceutically acceptable salt thereof as an active ingredient.

Item 30: An H4 receptor antagonist comprising the compound according to any one of Items 1 to 27 or a pharmaceutically acceptable salt thereof as an active ingredient.

Item 31: An antiallergic agent comprising the compound according to any one of items 1 to 27 or a pharmaceutically acceptable salt thereof as an active ingredient.

Item 32: An anti-inflammatory agent comprising the compound according to any one of Items 1 to 27 or a pharmaceutically acceptable salt thereof as an active ingredient.

Item 33: A therapeutic agent for pain comprising the compound according to any one of Items 1 to 27 or a pharmaceutically acceptable salt thereof as an active ingredient.

Item 34: An allergic conjunctivitis, allergic rhinitis, chronic urticaria, atopic dermatitis, comprising the compound according to any one of items 1 to 27 or a pharmaceutically acceptable salt thereof as an active ingredient, A therapeutic or prophylactic agent for asthma, chronic bronchitis, ulcerative colitis, Crohn's disease, rheumatism, pain, cancer, sepsis or chronic obstructive pulmonary disease.

Item 35: Use of the compound according to any one of Items 1 to 27 or a pharmaceutically acceptable salt thereof for the manufacture of an antiallergic agent.

Item 36: Use of the compound according to any one of Items 1 to 27 or a pharmaceutically acceptable salt thereof for the manufacture of an anti-inflammatory agent.

Item 37: Allergic conjunctivitis, allergic rhinitis, chronic urticaria, atopic dermatitis, asthma, chronic bronchitis, ulcerative colitis, Crohn's disease, rheumatism, pain, cancer, sepsis or chronic obstructive pulmonary disease Alternatively, use of the compound according to any one of Items 1 to 27 or a pharmaceutically acceptable salt thereof for the manufacture of a prophylactic agent.

Item 38: An antiallergic disease and / or an antiinflammatory disease characterized by administering an effective amount of the compound according to any one of Items 1 to 27, or a pharmaceutically acceptable salt thereof. Prevention or treatment method.

Item 39: The method for prevention or treatment according to Item 38, wherein the antiallergic disease is allergic conjunctivitis, allergic rhinitis, chronic urticaria, atopic dermatitis, asthma, or chronic bronchitis.

Item 40: The method for prevention or treatment according to Item 38, wherein the anti-inflammatory disease is ulcerative colitis, Crohn's disease, rheumatism, chronic obstructive pulmonary disease, or pain.

According to the present invention, a novel therapeutic or preventive agent for allergic diseases, inflammatory diseases, pain, cancer, sepsis, which exhibits an antiallergic action and / or an antiinflammatory action as an H4 receptor antagonist Offering became possible.

Hereinafter, the present invention will be described more specifically.
The description of each group in the present invention also applies to the case where the group is a part of another group, unless otherwise specified.
The number of substituents in this specification is not particularly limited as long as substitution is possible, and is one or more.

“Alkyl group” means a linear or branched alkyl group having 1 to 10 carbon atoms, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec- Examples thereof include a butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a 1-methylbutyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group. Among them, preferred is an alkyl group having 1 to 8 carbon atoms.

“Alkenyl group” means a straight or branched alkenyl group having 2 to 10 carbon atoms, and specifically includes a vinyl group, 1-propenyl group, allyl group (2-propenyl group), isopropenyl group. (1-methylvinyl group), 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-1-propenyl group, 1-methyl-2-propenyl group, 2-methylallyl group, 1-ethylvinyl group A 1-pentenyl group or a 1-hexenyl group can be exemplified. Among them, preferred is an alkenyl group having 2 to 6 carbon atoms.

The “alkynyl group” represents a linear or branched alkynyl group having 2 to 10 carbon atoms, and specifically includes an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 1-butynyl group, Examples thereof include a methyl-2-propynyl group, a 2-butynyl group, a 3-butynyl group, a 1-pentynyl group, and a 1-hexynyl group. Among them, preferred is an alkynyl group having 2 to 6 carbon atoms.

The “cycloalkyl group” represents a 3 to 10-membered saturated cycloalkyl group, and specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. be able to. Of these, a 3- to 6-membered saturated cycloalkyl group is preferable.

The “cycloalkenyl group” refers to a 4- to 8-membered cycloalkenyl group containing 1 to 2 double bonds in the ring, and specifically includes a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cyclohexyl group, and the like. A ptenyl group or a cyclooctenyl group can be exemplified, and the bonding position is not particularly limited as long as it is chemically stable. Among them, preferred is a 5- to 6-membered cycloalkenyl group.

The “aryl group” represents an aryl group having 6 to 10 carbon atoms, and specific examples include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.

“Aralkyl group” refers to an aralkyl group having 7 to 14 carbon atoms. Specific examples include a benzyl group, a phenethyl group, a 1-phenylethyl group, and a 2-phenylethyl group. Among them, preferred is an aralkyl group having 7 to 9 carbon atoms.

A “heteroaryl group”, also called an aromatic heterocyclic group, is 1 to 4 heteroatoms selected from 0 to 4 nitrogen atoms, 0 to 2 oxygen atoms, and 0 to 2 sulfur atoms. It represents a monocyclic 5- or 6-membered heteroaryl group or a bicyclic 9- or 10-membered heteroaryl group containing an atom. Specifically, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyrazolyl, furazanyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, quinolyl, isoquinolyl Group, quinazolinyl group or imidazopyrimidyl group. The bonding position is not particularly limited as long as it is chemically stable.

“Halogen atom” represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

The “alkoxy group” represents a straight or branched alkoxy group having 1 to 10 carbon atoms, and specifically includes a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, sec -Butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, 1-methylbutoxy group, hexyloxy group, heptyloxy group, octyloxy group, nonyloxy group or A decyloxy group etc. can be mentioned. Among them, preferred is an alkoxy group having 1 to 6 carbon atoms.

The “alkanoyl group” is also called an acyl group or an alkylcarbonyl group, and represents a linear or branched alkanoyl group having 1 to 11 carbon atoms, and specifically includes a formyl group, an acetyl group, a propionyl group, a butyryl group. Group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, heptanoyl group, octanoyl group, nonanoyl group or decanoyl group. Among them, preferred is an alkanoyl group having 1 to 6 carbon atoms.

The “alkanoyloxy group” represents a straight or branched alkanoyloxy group having 1 to 11 carbon atoms, and specifically includes formyloxy group, acetyloxy group, propionyloxy group, butyryloxy group, isobutyryl group. Examples thereof include an oxy group, valeryloxy group, isovaleryloxy group, pivaloyloxy group, hexanoyloxy group, heptanoyloxy group, octanoyloxy group, nonanoyloxy group and decanoyloxy group. Among them, preferred is an alkanoyloxy group having 1 to 6 carbon atoms.

The “alkoxycarbonyl group” represents a straight or branched alkoxycarbonyl group having 2 to 11 carbon atoms, and specifically includes a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxy group. Carbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, tert-pentyloxycarbonyl group, 1-methylbutoxycarbonyl group Hexyloxycarbonyl group, heptyloxycarbonyl group, octyloxycarbonyl group, nonyloxycarbonyl group, decyloxycarbonyl group and the like. Among them, preferred is an alkoxycarbonyl group having 2 to 7 carbon atoms.

The “alkylthio group” represents a linear or branched alkylthio group having 1 to 10 carbon atoms, specifically, a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, sec-butylthio group, tert-butylthio group, pentylthio group, isopentylthio group, neopentylthio group, tert-pentylthio group, 1-methylbutylthio group, hexylthio group, heptylthio group, octylthio group, nonylthio group, decylthio group, etc. Can be mentioned. Among them, preferred is an alkylthio group having 1 to 6 carbon atoms.

“Alkylsulfinyl group” means a linear or branched alkylsulfinyl group having 1 to 10 carbon atoms, and specifically includes a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, an isopropylsulfinyl group, a butylsulfinyl group. Group, isobutylsulfinyl group, sec-butylsulfinyl group, tert-butylsulfinyl group, pentylsulfinyl group, isopentylsulfinyl group, neopentylsulfinyl group, tert-pentylsulfinyl group, 1-methylbutylsulfinyl group, hexylsulfinyl group, heptyl Examples thereof include a sulfinyl group, an octylsulfinyl group, a nonylsulfinyl group, and a decylsulfinyl group. Among them, preferred is an alkylsulfinyl group having 1 to 7 carbon atoms.

“Alkylsulfonyl group” means a linear or branched alkylsulfonyl group having 1 to 10 carbon atoms, specifically, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl Group, isobutylsulfonyl group, sec-butylsulfonyl group, tert-butylsulfonyl group, pentylsulfonyl group, isopentylsulfonyl group, neopentylsulfonyl group, tert-pentylsulfonyl group, 1-methylbutylsulfonyl group, hexylsulfonyl group, heptyl A sulfonyl group, an octyl sulfonyl group, a nonyl sulfonyl group, a decyl sulfonyl group, etc. can be mentioned. Among them, preferred is an alkylsulfonyl group having 1 to 6 carbon atoms.

A “saturated aliphatic heterocyclic group”, also referred to as a saturated aliphatic heterocyclic group, is selected from 0 to 4 nitrogen atoms, 0 to 2 oxygen atoms, and 0 to 2 sulfur atoms. Represents a 4- to 10-membered monocyclic or bicyclic saturated aliphatic heterocyclic group containing 1 to 4 heteroatoms. Specifically, azetidinyl group, pyrrolidinyl group, piperidyl group, piperidino group, piperazinyl group, azepanyl group, azocanyl group, tetrahydrofuryl group, tetrahydrothienyl group, tetrahydropyranyl group, morpholinyl group, morpholino group, thiomorpholinyl group, thiomorpholino Group, 1,4-dioxanyl group or thiazolidinyl group. The bonding position is not particularly limited as long as it is chemically stable.

An “unsaturated aliphatic heterocyclic group”, also called an unsaturated aliphatic heterocyclic group, consists of 0-4 nitrogen atoms, 0-2 oxygen atoms, and 0-2 sulfur atoms. It represents a 4- to 10-membered monocyclic or bicyclic unsaturated aliphatic heterocyclic group containing 1 to 4 heteroatoms and containing 1 to 2 double bonds. Specific examples include 2-pyrrolinyl group, 3-pyrrolinyl group, 2-imidazolinyl group, 3-imidazolinyl group, 2-pyrazolinyl group and 3-pyrazolinyl group. The bonding position is not particularly limited as long as it is chemically stable.

The “aryloxy group” represents an aryloxy group having 6 to 10 carbon atoms, and specific examples include a phenoxy group, a 1-naphthyloxy group, and a 2-naphthyloxy group.

The heteroaryl part of the “heteroaryloxy group” is the same as the “heteroaryl group”. Specific examples include a furyloxy group, a thienyloxy group, and a pyrrolyloxy group.

When the “alkyl group”, “alkenyl group” or “alkynyl group” is substituted, the substituent is selected from the following groups (Ii) to (Iv), and 1 to 5 identical or different substituents: Has replaced:
(Ii) halogen atom, hydroxyl group, carboxyl group, cyano group, oxo group, thioxo group;
(I-ii) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group;
(I-iii) an alkoxy group, an alkanoyl group, an alkanoyloxy group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group [each group in the group (I-iii) is a halogen atom, a hydroxyl group, a carboxyl group, 1 to 5 substituents which are the same or different and may be substituted with a substituent selected from an unsubstituted alkoxy group, a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group and a substituted or unsubstituted sulfamoyl group . ];
(I-iv) a cycloalkyl group, a cycloalkenyl group, a saturated aliphatic heterocyclic group, an unsaturated aliphatic heterocyclic group [the groups (I-iv) are represented by the following groups (1) to ( 5) may be substituted with the same or different 1 to 5 substituents selected from:
(1) halogen atom, hydroxyl group, carboxyl group, cyano group, oxo group, thioxo group;
(2) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group;
(3) an alkyl group, an alkoxy group, an alkanoyl group, an alkanoyloxy group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group (the groups in group (3) are a halogen atom, a hydroxyl group, a carboxyl group, They may be substituted with the same or different 1 to 5 substituents selected from substituted alkoxy groups);
(4) a saturated aliphatic heterocyclic group (the group (4) has 1 to 5 identical or different groups selected from a halogen atom, a hydroxyl group, a carboxyl group, an unsubstituted alkyl group and an unsubstituted alkoxy group; Which may be substituted with a substituent of
(5) aryl group, heteroaryl group, aryloxy group, heteroaryloxy group (each group in group (5) is a halogen atom, a hydroxyl group, a carboxyl group, an unsubstituted alkyl group, an unsubstituted alkoxy group, an It may be substituted with the same or different 1 to 5 substituents selected from a substituted alkanoyloxy group and an unsubstituted alkoxycarbonyl group. ];
(Iv) aryl group, heteroaryl group, aryloxy group, heteroaryloxy group [each group (Iv) is the same or different from 1 to 5 selected from the following groups (1) to (5) May be substituted with:
(1) halogen atom, hydroxyl group, carboxyl group, cyano group, nitro group;
(2) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group;
(3) an alkyl group, an alkoxy group, an alkanoyl group, an alkanoyloxy group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group (each group in group (3) is a halogen atom, a hydroxyl group, a carboxyl group, They may be substituted with 1 to 5 identical or different substituents selected from a substituted alkoxy group, an unsubstituted alkanoyloxy group, and an unsubstituted alkoxycarbonyl group);
(4) a cycloalkyl group, a cycloalkenyl group, a saturated aliphatic heterocyclic group, an unsaturated aliphatic heterocyclic group (each group in group (4) is a halogen atom, a hydroxyl group, a carboxyl group, an unsubstituted alkyl group) And may be substituted with the same or different 1 to 5 substituents selected from a group and an unsubstituted alkoxy group);
(5) Aryl group, heteroaryl group, aryloxy group, heteroaryloxy group (each group in group (5) is selected from a halogen atom, a hydroxyl group, a carboxyl group, an unsubstituted alkyl group and an unsubstituted alkoxy group) And may be substituted with the same or different 1 to 5 substituents. ].

When the “cycloalkyl group” or “cycloalkenyl group” is substituted, the substituent is selected from the following groups (II-i) to (II-v), and the same or different substituents are 1 to 5 Is replaced:
(II-i) halogen atom, hydroxyl group, carboxyl group, cyano group, oxo group, thioxo group;
(II-ii) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group;
(II-iii) alkyl group, alkenyl group, alkynyl group, alkoxy group, alkanoyl group, alkanoyloxy group, alkoxycarbonyl group, alkylthio group, alkylsulfinyl group, alkylsulfonyl group [each group in the group (II-iii) is , Halogen atom, hydroxyl group, carboxyl group, unsubstituted alkoxy group, substituted or unsubstituted amino group, substituted or unsubstituted carbamoyl group, substituted or unsubstituted sulfamoyl group, unsubstituted alkanoyloxy group, and unsubstituted 1 to 5 substituents which are the same or different and may be substituted with a substituent selected from alkoxycarbonyl groups. ];
(II-iv) a cycloalkyl group, a cycloalkenyl group, a saturated aliphatic heterocyclic group, an unsaturated aliphatic heterocyclic group [the groups in the group (II-iv) are represented by the following groups (1) to ( 3) may be substituted with the same or different 1 to 5 substituents selected from:
(1) halogen atom, hydroxyl group, carboxyl group, cyano group, oxo group, thioxo group;
(2) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group;
(3) an alkyl group, an alkoxy group, an alkanoyl group, an alkanoyloxy group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group (the groups in group (3) are a halogen atom, a hydroxyl group, a carboxyl group, It may be substituted with the same or different 1 to 5 substituents selected from substituted alkoxy groups). ];
(II-v) aryl group, heteroaryl group, aryloxy group, heteroaryloxy group [each group in group (II-v) is the same or different selected from the following groups (1) to (3) Optionally substituted with 1 to 5 substituents:
(1) halogen atom, hydroxyl group, carboxyl group, cyano group, nitro group;
(2) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group;
(3) an alkyl group, an alkoxy group, an alkanoyl group, an alkanoyloxy group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group (the groups in group (3) are a halogen atom, a hydroxyl group, a carboxyl group, It may be substituted with the same or different 1 to 5 substituents selected from substituted alkoxy groups). ].

When the aryl part of the “aryl group”, “heteroaryl group” or “aralkyl group” is substituted, the substituent is selected from the following groups (III-i) to (III-v), 1 to 5 different substituents are substituted:
(III-i) halogen atom, hydroxyl group, carboxyl group, cyano group, nitro group;
(III-ii) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group;
(III-iii) alkyl group, alkenyl group, alkynyl group, alkoxy group, alkanoyl group, alkanoyloxy group, alkoxycarbonyl group, alkylthio group, alkylsulfinyl group, alkylsulfonyl group [each group in the group (III-iii) is , Halogen atom, hydroxyl group, carboxyl group, unsubstituted alkoxy group, substituted or unsubstituted amino group, substituted or unsubstituted carbamoyl group, substituted or unsubstituted sulfamoyl group, unsubstituted alkanoyloxy group, and unsubstituted 1 to 5 substituents selected from alkoxycarbonyl groups may be the same or different and may be substituted. ];
(III-iv) a saturated aliphatic heterocyclic group, an unsaturated aliphatic heterocyclic group [each group (III-iv) is the same or selected from the following groups (1) to (3)] Optionally substituted with 1 to 5 different substituents:
(1) halogen atom, hydroxyl group, carboxyl group, cyano group, oxo group, thioxo group;
(2) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group;
(3) an alkyl group, an alkoxy group, an alkanoyl group, an alkanoyloxy group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group (the groups in group (3) are a halogen atom, a hydroxyl group, a carboxyl group, It may be substituted with the same or different 1 to 5 substituents selected from substituted alkoxy groups). ];
(III-v) aryl group, heteroaryl group, aryloxy group, heteroaryloxy group [each group in group (III-v) is the same or different selected from the following groups (1) to (4) Optionally substituted with 1 to 5 substituents:
(1) halogen atom, hydroxyl group, carboxyl group, cyano group, nitro group;
(2) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group;
(3) an alkyl group, an alkoxy group, an alkanoyl group, an alkanoyloxy group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group (the groups in group (3) are a halogen atom, a hydroxyl group, a carboxyl group, They may be substituted with the same or different 1 to 5 substituents selected from substituted alkoxy groups);
(4) a saturated aliphatic heterocyclic group and an unsaturated aliphatic heterocyclic group (each group in group (4) includes a halogen atom, a hydroxyl group, a carboxyl group, an unsubstituted alkyl group, and an unsubstituted alkoxy group; Optionally substituted with 1 to 5 substituents of the same or different selected. ].

When the “amino group”, “carbamoyl group” or “sulfamoyl group” is substituted, the substituent is selected from the following groups (IV-i) to (IV-iii), and the same or different substituents are 1-2 replacements:
(IV-i) an alkyl group, an alkanoyl group, an alkoxycarbonyl group, an alkylsulfonyl group [each group in group (IV-i) is a substituent selected from a halogen atom, a hydroxyl group, a carboxyl group, and an unsubstituted alkoxy group May be the same or different and 1 to 5 may be substituted. ];
(IV-ii) a cycloalkyl group, a cycloalkenyl group, a saturated aliphatic heterocyclic group, an unsaturated aliphatic heterocyclic group [the groups (IV-ii) are represented by the following groups (1) to ( 5) optionally substituted with 1 to 5 substituents selected from the same or different:
(1) halogen atom, hydroxyl group, carboxyl group, cyano group, oxo group, thioxo group;
(2) Amino group optionally substituted with the same or different 1 to 2 alkyl groups, carbamoyl group optionally substituted with the same or different 1 to 2 alkyl groups, 1 to 2 identical or different A sulfamoyl group optionally substituted with an alkyl group of
(3) an alkyl group, an alkoxy group, an alkanoyl group, an alkanoyloxy group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group (the groups in group (3) are a halogen atom, a hydroxyl group, a carboxyl group, They may be substituted with the same or different 1 to 5 substituents selected from substituted alkoxy groups);
(4) a cycloalkyl group, a cycloalkenyl group, a saturated aliphatic heterocyclic group, an unsaturated aliphatic heterocyclic group (each group in group (4) is a halogen atom, a hydroxyl group, a carboxyl group, an unsubstituted alkyl group) And may be substituted with the same or different 1 to 5 substituents selected from a group and an unsubstituted alkoxy group);
(5) Aryl group, heteroaryl group, aryloxy group, heteroaryloxy group (each group in group (5) is selected from a halogen atom, a hydroxyl group, a carboxyl group, an unsubstituted alkyl group and an unsubstituted alkoxy group) And may be substituted with the same or different 1 to 5 substituents. ];
(IV-iii) aryl group, heteroaryl group, aryloxy group, heteroaryloxy group [each group (IV-iii) is the same or different selected from the following (1) to (4)] Optionally substituted with up to 5 substituents:
(1) halogen atom, hydroxyl group, carboxyl group, cyano group, nitro group;
(2) Amino group optionally substituted with the same or different 1 to 2 alkyl groups, carbamoyl group optionally substituted with the same or different 1 to 2 alkyl groups, 1 to 2 identical or different A sulfamoyl group optionally substituted with an alkyl group of
(3) Alkyl group, alkoxy group, alkanoyl group, alkanoyloxy group, alkoxycarbonyl group, alkylthio group, alkylsulfinyl group, alkylsulfonyl group, alkanoyl group (each group in group (3) is a halogen atom, a hydroxyl group, a carboxyl group) And may be substituted with the same or different 1 to 5 substituents selected from a group and an unsubstituted alkoxy group);
(4) a saturated aliphatic heterocyclic group and an unsaturated aliphatic heterocyclic group (each group in group (4) includes a halogen atom, a hydroxyl group, a carboxyl group, an unsubstituted alkyl group, and an unsubstituted alkoxy group; Optionally substituted with 1 to 5 substituents of the same or different selected. ].

The “sulfonic acid ester group” is selected from the group consisting of, for example, an alkylsulfonyloxy group (such as methanesulfonyloxy group), a halogenoalkylsulfonyloxy group (such as trifluoromethanesulfonyloxy group), a methyl group, a methoxy group, and a halogen atom. An arylsulfonyloxy group (such as p-toluenesulfonyloxy group) which may be substituted with a group or an atom.

The definition of the compound represented by the formula (1) will be further described.

In the compound represented by the formula (1), “R ² and R ³ together with the carbon atom to which each is bonded is a 3- to 8-membered carbon ring or a 5- to 8-membered heterocycle containing an oxygen atom. “Constructed” means that the carbon atom to which R ² and R ³ are bonded is the carbon atom at the 7-position of the 7,8-dihydro-5H-pyrano [4,3-d] pyrimidine ring (R ² and R ³ are (Bonded carbon atom) is a spiro atom and means a spiro bond with a 3-8 membered carbon ring or a 5-8 membered heterocycle containing an oxygen atom. Specific examples of the 3- to 8-membered carbocycle include a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, a cyclohexyl ring, a cycloheptyl ring, and a cyclooctyl ring, and a 5- to 8-membered heterocycle containing an oxygen atom. Specific examples of the ring include a tetrahydrofuran ring and a tetrahydropyran ring. Examples of the compound represented by the definition include the following:

(The definition in the formula is the same as in item 1.).

In the compound represented by the formula (1), “R ⁴ and R ⁵ , and R ⁶ and R ⁷ together form an oxo group” means the following

(The definition in the formula is the same as in item 1). That is, R ⁴ and R ⁵ together may be either an oxo group, or R ⁶ and R ⁷ together may be an oxo group, and R ⁴ and R ⁵ and R ⁶ and R ⁷ together may be an oxo group. It may be a group.

The groups represented by formulas (Ya) to (Yf) in R ¹ will be further described.

(1) In the group represented by the formula (Ya), h is an integer of 1 to 2, and R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹⁴ , R ¹⁵ and R ¹⁶ are each independently , A hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, and R ¹³ and R ¹⁵ together represent — (CH ₂ ) ₂ — Or to form — (CH ₂ ) ₃ —

(R ⁸ has the same meaning as in item 1).

(2) In the group represented by the formula (Ya), h is an integer of 1 to 2, R ¹⁰ , R ¹¹ , R ¹² , R ¹⁴ , R ¹⁵ and R ¹⁶ are all hydrogen atoms; ⁹ and R ¹³ together form — (CH ₂ ) _g — (wherein g is an integer of 1 to 2).

(R ⁸ has the same meaning as in item 1).

(3) In the group represented by the formula (Ya), h is 1, R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁶ are all hydrogen atoms, and R ⁹ and R ¹⁵ Together form-(CH ₂ ) _2-

(R ⁸ has the same meaning as in item 1).

(4) In the group represented by the formula (Ya), h is 1, R ⁹ , R ¹⁰ , R ¹² , R ¹⁴ , R ¹⁵ and R ¹⁶ are all hydrogen atoms, and R ¹¹ and R ¹³ Together form-(CH ₂ ) _2-

(R ⁸ has the same meaning as in item 1).

(5) In the group represented by the formula (Yd), R ^8a1 and R ^8a2 are combined with the nitrogen atom to which each is bonded to form an aziridine ring, azetidine ring, pyrrolidine ring, piperidine ring, perhydroazepine ring or A group forming a perhydroazocine ring will be described. For example, R ^8a1 and R ^8a2 together with the nitrogen atom to which each is bonded to form an aziridine ring include the following:

(R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , p, s, and t are as defined in the above item 1).

(6) In the group represented by the formula (Ye), one of R ²¹ and R ²² is a hydrogen atom, and the other is —N (R ^8a1 ) (R ^8a2 ), wherein R ^8a1 and R ^8a2 , together with the nitrogen atom to which each is bonded, describes a group that forms an aziridine ring, azetidine ring, pyrrolidine ring, piperidine ring, perhydroazepine ring or perhydroazocine ring. For example, R ^8a1 and R ^8a2 together with the nitrogen atom to which they are bonded form the aziridine ring,

The group represented by these is mentioned.

Preferable specific examples of R ¹ include the following groups (R ⁸ has the same meaning as in item 1).

In the formula (1), R ¹ is preferably a group represented by the above formula (Ya) and a group represented by the formula (Yd), more preferably a group represented by the formula (Ya1) and It is a group represented by the formula (Yd2). Even more preferred are a group represented by the formula (Ya5) and a group represented by the formula (Yd3). Here, R ⁸ , R ^8a1 and R ^8a2 are preferably each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms. More preferably a hydrogen atom or a methyl group.

R ² is preferably a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms, or a substituted or unsubstituted group. An aralkyl group having 7 to 14 carbon atoms, more preferably an unsubstituted alkyl group having 1 to 6 carbon atoms, an unsubstituted cycloalkyl group having 1 to 6 carbon atoms, and an unsubstituted carbon atom having 7 to 6 carbon atoms. 9 is an aralkyl group, more preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a benzyl group, or a 2-phenylethyl group. R ³ is preferably a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, more preferably an unsubstituted alkyl group having 1 to 6 carbon atoms, more preferably a hydrogen atom, A methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group; It is also preferred when R ² and R ³ together with the carbon atom to which each is bonded form a 3- to 8-membered carbocycle (preferably a cyclopentane ring or cyclohexane ring).

R ⁴ , R ⁵ , R ⁶ and R ⁷ are preferably each independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, and more preferably a hydrogen atom.

R ⁸ is preferably a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, and more preferably a hydrogen atom or a methyl group.

R ^8b1 and R ^8b2 are preferably a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, and more preferably a hydrogen atom or a methyl group. is there.

X is preferably a hydrogen atom or an amino group, particularly preferably an amino group.

R ⁹ , R ¹⁰ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are preferably hydrogen atoms.

R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are preferably each independently a hydrogen atom or a methyl group. When a substituent such as R ⁸ is present on the adjacent nitrogen atom, R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are preferably hydrogen atoms.

This invention compound represented by Formula (1) is manufactured by the manufacturing method shown below using the compound which can be manufactured by combining a commercially available compound, a well-known compound, or a compound which can be manufactured from a commercially available compound or a well-known synthesis method from a well-known compound. can do.

(Manufacturing method 1)
Compound (1) can be synthesized by the method of the following formula (A-1).

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and X are as defined above] Lv represents a leaving group (for example, a halogen atom, a sulfonate group, an alkylsulfinyl group, an alkylsulfonyl group, etc.). ]

Compound (1) can be obtained by reacting compound (1-1) with compound (1-2) in the presence or absence of a base. Examples of the base include alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate, alkaline earth metal carbonates such as calcium carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydride and the like. Metal hydrides, metal alkoxides such as sodium methoxide, organic bases such as triethylamine, diisopropylethylamine, and 4-dimethylaminopyridine can be used. This reaction can be carried out in a solvent or without a solvent. When a solvent is used, examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and diglyme, halogen solvents such as dichloromethane and chlorobenzene, methanol, ethanol, and 2-propanol. And an aprotic solvent such as hexane, heptane, toluene, dimethylformamide, dimethyl sulfoxide, acetonitrile, N-methylpiperidone, and the like. Alternatively, a mixed solvent thereof may be used. The reaction temperature is selected, for example, from the range of about -40 ° C to 200 ° C.

When Lv in the compound (1-1) is a halogen atom or a sulfonate group, the compound [compound represented by the following formula (2)] is synthesized by the method of the following formula (A-1-1). Can do.

[Wherein, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and X are as defined above]. R ²³ and R ²⁴ are each independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkenyl group having 3 to 10 carbon atoms, a substituted or unsubstituted group. An alkynyl group having 3 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms, a substituted or unsubstituted cycloalkenyl group having 4 to 8 carbon atoms, a substituted or unsubstituted aryl group, or It represents a substituted or unsubstituted heteroaryl group, and Lva represents ^a halogen atom or a sulfonate group. ]

The ketoester (1-1-2) can be obtained by treating the ketone (1-1-1) with a base and subsequently reacting it with a carbonate ester or a cyanoformate ester. Examples of the base include metal hydrides such as sodium hydride, metal alkoxides such as sodium methoxide and potassium tert-butoxide, metal amides such as lithium diisopropylamide, lithium hexamethyldisilazide, and potassium hexamethyldisilazide. Can be used. This reaction can be carried out in a solvent or without a solvent. When a solvent is used, examples of the solvent include ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diglyme, hexane, heptane, toluene, dimethylformamide, dimethyl sulfoxide, acetonitrile, And aprotic solvents such as N-methylpiperazine. Alternatively, a mixed solvent thereof may be used. The reaction temperature is selected, for example, from the range of about -40 ° C to 200 ° C.

Ketone (1-1-1) is, for example, J. Chem.Soc. Perkin Trans.2, 1992, 799-803., J. Med. Chem. 1993, 36, 295-296., Chem. Ber., 1955, 1053-1059., J. Am. Chem.Soc. 1982, 104, 4666-4671, J. Fluorine Chem. 1983, .1-18., U.S. published patent US2007 / 173508 A1, U.S. published patent US5208259 A1, etc. Can be synthesized by the methods described in 1) and methods analogous thereto, or can be purchased.

Ketoester (1-1-2) can also be synthesized by treating diester (1-1-4) with a base. Examples of the base include metal hydrides such as sodium hydride, metal alkoxides such as sodium methoxide and potassium tert-butoxide, metal amides such as lithium diisopropylamide and lithium hexamethyldisilazide, and potassium hexamethyldisilazide. Can be used. This reaction can be carried out in a solvent or without a solvent. When a solvent is used, examples of the solvent include ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diglyme, hexane, heptane, toluene, dimethylformamide, dimethyl sulfoxide, acetonitrile, And aprotic solvents such as N-methylpiperazine. Alternatively, a mixed solvent thereof may be used. The reaction temperature is selected, for example, from the range of about -90 ° C to 100 ° C.

Diesters (1-1-4) are, for example, J. Am. Chem. Soc. 1960, 82. 2050-2052. Zhurnal Obshchei Khimii, 1954, 24, 319-327., J. Am. Chem. Soc. 1997 , 119, 4285-4291. And the like and methods based thereon, or can be purchased.

Compound (1-1-3) can be obtained by reacting ketoester (1-1-2) with a guanidine derivative or a salt thereof in the presence or absence of a base. Examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate cesium carbonate, alkaline earth metal carbonates such as calcium carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, metals such as sodium hydride Metal alkoxides such as hydride, sodium methoxide and potassium tert-butoxide, organic bases such as triethylamine, diisopropylethylamine, pyridine and 4-dimethylaminopyridine can be used. This reaction can be carried out in a solvent or without a solvent. When a solvent is used, examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and diglyme, alcohol solvents such as methanol, ethanol, 2-propanol and butanol, hexane, Examples include aprotic solvents such as heptane, toluene, dimethylformamide, dimethyl sulfoxide, acetonitrile and N-methylpiperazine, halogen solvents such as chloroform and chlorobenzene, and water. Alternatively, a mixed solvent thereof may be used. The reaction temperature is selected, for example, from the range of about -40 ° C to 200 ° C.

Compound (2) is compound (1-1-3) obtained by reacting sulfonic acid chloride such as p-toluenesulfonic acid chloride or mesylate acid chloride, sulfonic acid anhydride such as trifluoromethanesulfonic anhydride, phosphorus oxychloride , Thionyl chloride and the like in the presence or absence of a base. This reaction can be carried out in a solvent or without a solvent. When a solvent is used, examples of the solvent include ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diglyme, halogen solvents such as chloroform, dichloromethane, chlorobenzene, acetonitrile, hexane , Aprotic solvents such as heptane and toluene. Alternatively, a mixed solvent thereof may be used. Examples of the base include organic bases such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine, N, N-dimethylaniline, and the like. The reaction temperature is selected, for example, from the range of about -78 ° C to 250 ° C.

When R ³ , R ⁶ and R ⁷ in the ketone (1-1-1) are a hydrogen atom, the compound [compound represented by the following formula (3)] is a method of the following formula (A-1-2): But it can be synthesized.

[Wherein, R ² , R ⁴ and R ⁵ have the same meanings as described above. ]

Compound (1-2-2) can be synthesized by reducing compound (1-2-1) according to a conventional method. Reducing agents include hydrogen, formic acid salts such as ammonium formate, metals such as sodium, magnesium, zinc or Raney nickel, organophosphorus compound reagents such as triphenylphosphine, boron reagents such as diborane, metal hydrides such as silane and tin hydride. Examples of the catalyst that can be used include transition metals such as palladium, nickel, rhodium, cobalt, and platinum, salts thereof, complexes thereof, and catalysts placed on a carrier such as a polymer. The reaction can be carried out in a solvent or without a solvent. When a solvent is used, examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and diglyme, alcohol solvents such as methanol, ethanol, 2-propanol and butanol, trifluoro Examples thereof include carboxylic acids such as acetic acid and acetic acid, aprotic solvents such as hexane, heptane, dimethylformamide and acetonitrile, and water. Alternatively, a mixed solvent thereof may be used. In some cases, an acid such as hydrochloric acid may be added, and the reaction may be performed under pressurized conditions. The reaction temperature is selected, for example, from the range of about -90 ° C to 200 ° C.

Ketone (3) can be synthesized by oxidizing compound (1-2-2) according to a conventional method. Examples of oxidizing agents include metal oxides such as chromic acid and salts thereof, sulfur trioxide / pyridine complexes, chloric acid, hypochlorous acid and salts thereof, and the like, and combinations of oxalyl chloride and dimethyl sulfide used in Swern oxidation. Can be used. This reaction can be carried out in a solvent. Examples of the solvent include ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diglyme, hexane, heptane, toluene, dimethylformamide, dimethyl sulfoxide, acetonitrile, N-methylpiperazine, and the like. Aprotic solvents, halogen solvents such as chloroform, dichloromethane and chlorobenzene, water and the like. Alternatively, a mixed solvent thereof may be used. The reaction temperature is selected, for example, from the range of about −90 to 200 ° C.

Ketone (3) can also be synthesized by selectively reducing the olefin in compound (1-2-1) according to a conventional method. Reducing agents include hydrogen, formic acid salts such as ammonium formate, metals such as sodium, magnesium, zinc, and Raney nickel, organophosphorus compound reagents such as triphenylphosphine, boron reagents such as diborane, and metal hydrides such as silane and tin hydride. Examples of the catalyst that can be used include transition metals such as palladium, nickel, rhodium, cobalt, and platinum, salts thereof, complexes thereof, and catalysts placed on a carrier such as a polymer. The reaction can be carried out in a solvent or without a solvent. When a solvent is used, examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and diglyme, alcohol solvents such as methanol, ethanol, 2-propanol and butanol, trifluoro Examples thereof include carboxylic acids such as acetic acid and acetic acid, aprotic solvents such as hexane, heptane, dimethylformamide and acetonitrile, and water. Alternatively, a mixed solvent thereof may be used. In some cases, an acid such as hydrochloric acid may be added, and the reaction may be performed under pressurized conditions. The reaction temperature is selected, for example, from the range of about −90 to 200 ° C.

Compound (1-2-1) can be synthesized by, for example, the method described in Chemistry Letters, 2003, 608-609., Synlett, 1997, 79-80. Is possible.

In the compound (1-1) in the formula (A-1), when Lv is an alkylsulfinyl group or an alkylsulfonyl group, the compound [compound represented by the following formula (4)] is represented by the following formula (A-1-3): ) Can also be synthesized.

[Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹⁰ , R ²⁵ , and X are as defined above]. R ²⁵ represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms. m is an integer of 1 to 2. ]

Compound (1-3-2) can be obtained by treating ketone (1-1-1) with a base, reacting with carbon disulfide, and subsequently alkylating with an alkyl halide reagent. Examples of the base include metal hydrides such as sodium hydride, metal alkoxides such as sodium methoxide and potassium tert-butoxide, metal amides such as lithium diisopropylamide and lithium hexamethyldisilazide, and potassium hexamethyldisilazide. Can be used. This reaction can be carried out in a solvent or without a solvent. Examples of the alkyl halide reagent include alkyl iodide reagents such as methyl iodide, ethyl iodide, allyl bromide, and benzyl bromide, and alkyl bromide. When a solvent is used, examples of the solvent include ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diglyme, hexane, heptane, toluene, dimethylformamide, dimethyl sulfoxide, acetonitrile, And aprotic solvents such as N-methylpiperazine. Alternatively, a mixed solvent thereof may be used. The reaction temperature is selected, for example, from the range of about −90 to 100 ° C.

Compound (1-3-3) can be obtained by reacting compound (1-3-2) with a guanidine derivative or a salt thereof in the presence or absence of a base. As the reaction conditions, the same conditions as in the synthesis of compound (1-1-3) in formula (A-1-1) can be used.

Compound (4) can be synthesized by oxidizing compound (1-3-3) with a peroxide such as m-chloroperbenzoic acid, peracetic acid or hydrogen peroxide, or a metal oxide such as chromic acid. . This reaction can be carried out in a solvent or without a solvent. When a solvent is used, examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and diglyme, halogen solvents such as dichloromethane and chlorobenzene, methanol, ethanol, and 2-propanol. And alcoholic solvents such as butanol, aprotic solvents such as hexane, heptane, toluene, dimethylformamide, dimethyl sulfoxide, acetonitrile and N-methylpiperidone, and water. Alternatively, a mixed solvent thereof may be used. The reaction temperature is selected, for example, from the range of about -40 ° C to 200 ° C.

(Manufacturing method 2)
Further, when X in the compound (1) is an unsubstituted amino group, the compound [compound represented by the following formula (5)] can also be synthesized by the method of the following formula (B-1).

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above]. Lv ′ represents a leaving group (for example, a halogen atom, a sulfonate group, an alkylsulfinyl group, an alkylsulfonyl group, etc.). ]

Compound (5) can be synthesized by reacting compound (2-1) with ammonia or a salt thereof in the presence or absence of a base. As the reaction conditions, the same conditions as in the synthesis of compound (1) in formula (A-1) can be used.

Compound (5) can also be synthesized by reacting compound (2-1) with sodium azide, a hydrazine derivative or a salt thereof, a hydroxylamine derivative or a salt thereof in the presence or absence of a base, and then reducing the compound. it can. As conditions for the coupling reaction of the compound (2-1) with sodium azide, hydrazine derivative, etc., the following can be used. Examples of the base include alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate, alkaline earth metal carbonates such as calcium carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydride and the like. Metal hydrides, metal alkoxides such as sodium methoxide, organic bases such as triethylamine, diisopropylethylamine, and 4-dimethylaminopyridine can be used. This reaction can be carried out in a solvent or without a solvent. When a solvent is used, examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and diglyme, halogen solvents such as dichloromethane and chlorobenzene, methanol, ethanol, and 2-propanol. And an aprotic solvent such as hexane, heptane, toluene, dimethylformamide, dimethyl sulfoxide, acetonitrile, N-methylpiperidone, and the like. Alternatively, a mixed solvent thereof may be used. The reaction temperature is selected, for example, from the range of about -40 ° C to 200 ° C. The following conditions can be used for the reduction reaction. Reducing agents include hydrogen, formic acid salts such as ammonium formate, metals such as sodium, magnesium, zinc, and Raney nickel, organophosphorus compound reagents such as triphenylphosphine, boron reagents such as diborane, and metal hydrides such as silane and tin hydride. Examples of the catalyst that can be used include transition metals such as palladium, nickel, rhodium, cobalt, and platinum, salts thereof, complexes thereof, polymers and the like. The reaction can be carried out in a solvent or without a solvent. When a solvent is used, examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and diglyme, alcohol solvents such as methanol, ethanol, 2-propanol and butanol, trifluoro Examples thereof include carboxylic acids such as acetic acid and acetic acid, aprotic solvents such as hexane, heptane, dimethylformamide and acetonitrile, and water. Alternatively, a mixed solvent thereof may be used. In some cases, an acid such as hydrochloric acid may be added, and the reaction may be performed under pressurized conditions. The reaction temperature is selected, for example, from the range of about -40 ° C to 200 ° C.

When Lv ′ in the compound (2-1) is an alkylsulfinyl group or an alkylsulfonyl group, the compound [compound represented by the following formula (6)] is synthesized by the method of the following formula (B-1-1). be able to.

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ²⁵ and Lv are as defined above]. m ′ is an integer of 1 to 2. ]

Compound (2-1-3) can be synthesized by reacting compound (2-1-1) and compound (2-1-2) in the presence or absence of a base. As the reaction conditions, the same conditions as in the synthesis of compound (1) in formula (A-1) can be used.

Compound (2-1-4) can be synthesized by oxidizing compound (2-1-1). As the reaction conditions, conditions similar to those for the synthesis of compound (4) in formula (A-2-1) can be used.

Compound (6) can be synthesized by oxidizing compound (2-1-3). As the reaction conditions, conditions similar to those for the synthesis of compound (4) in formula (A-2-1) can be used.

Compound (6) can also be synthesized by reacting compound (2-1-4) and compound (2-1-2) in the presence or absence of a base. As the reaction conditions, the same conditions as in the synthesis of compound (1) in formula (A-1) can be used.

When Lv in the compound (2-1-1) is a halogen atom or a sulfonate group, the compound [compound represented by the following formula (7)] is synthesized by the method of the following formula (B-2-1). can do.

^{^{Wherein, R 2, R 3, R}} 4, R 5, R 6, R 7, R 23, R 25 and Lv ^a are as defined above. ]

Compound (2-2-2) can be obtained by reacting compound (1-1-2) with thiourea or a salt thereof in the presence or absence of a base. As the reaction conditions, conditions similar to those for the synthesis of compound (1-1-3) in formula (A-1-1) can be used.

Compound (2-2-3) is obtained by reacting Compound (2-2-2) with a halogenated alkyl compound such as methyl iodide, ethyl iodide, allyl bromide, benzyl bromide or the like in the presence or absence of a base. Can be obtained by reacting under. Examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate cesium carbonate, alkaline earth metal carbonates such as calcium carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, metals such as sodium hydride Metal alkoxides such as hydride, sodium methoxide and potassium tert-butoxide, organic bases such as triethylamine, diisopropylethylamine, pyridine and 4-dimethylaminopyridine can be used. This reaction can be carried out in a solvent or without a solvent. When a solvent is used, examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and diglyme, alcohol solvents such as methanol, ethanol, 2-propanol and butanol, hexane, Examples include aprotic solvents such as heptane, toluene, dimethylformamide, dimethyl sulfoxide, acetonitrile and N-methylpiperazine, halogen solvents such as chloroform and chlorobenzene, and water. Alternatively, a mixed solvent thereof may be used.

Compound (2-2-3) can be obtained by reacting compound (1-1-2) with alkylisothiourea or a salt thereof in the presence or absence of a base. As the reaction conditions, conditions similar to those for the synthesis of compound (1-1-3) in formula (A-1-1) can be used.

Compound (7) is obtained by converting compound (2-2-3) from sulfonic acid chlorides such as p-toluenesulfonic acid chloride and mesylic acid chloride, sulfonic acid anhydrides such as trifluoromethanesulfonic anhydride, phosphorus oxychloride , Thionyl chloride and the like in the presence or absence of a base. As the reaction conditions, the same conditions as in the synthesis of compound (2) in formula (A-1-1) can be used.

In the compound (2-1), when Lv ′ is a halogen atom or a sulfonate group, the compound [compound represented by the following formula (8)] is synthesized by the method of the following formula (B-3-1). be able to.

^{^{Wherein, R 1, R 2, R}} 3, R 4, R 5, R 6, R 7, R 23 and Lv ^a are as defined above. Lv ^b represents a halogen or sulfonate group. ]

Compound (2-3-2) can be obtained by reacting compound (1-1-2) with urea or a salt thereof in the presence or absence of a base. As the reaction conditions, conditions similar to those for the synthesis of compound (1-1-3) in formula (A-1-1) can be used.

The compound (2-3-3) is obtained by converting the compound (2-3-2) into a sulfonic acid chloride such as p-toluenesulfonic acid chloride or mesyl acid chloride, or a sulfonic acid anhydride such as trifluoromethanesulfonic anhydride. , Phosphorus oxychloride, thionyl chloride and the like in the presence or absence of a base. As the reaction conditions, the same conditions as in the synthesis of compound (2) in formula (A-1-1) can be used.

Compound (8) can be obtained by reacting compound (2-3-3) and compound (2-3-4) in the presence or absence of a base. As the reaction conditions, the same conditions as in the synthesis of compound (1) in formula (A-1) can be used.

When Lv in the compound (2-1-4) is an alkylsulfinyl group or an alkylsulfonyl group, the compound [compound represented by the following formula (9)] is synthesized by the method of the following formula (B-4-1). can do.

[Wherein, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ²⁵ , m and m ′ are as defined above]. R ²⁶ represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms. ]

Compound (2-4-2) can be obtained by reacting compound (1-3-2) with thiourea or a salt thereof in the presence or absence of a base. As the reaction conditions, conditions similar to those for the synthesis of compound (1-1-3) in formula (A-1-1) can be used.

Compound (2-4-3) is obtained by reacting Compound (2-4-2) with a halogenated alkyl compound such as methyl iodide, ethyl iodide, allyl bromide, benzyl bromide or the like in the presence or absence of a base. Can be obtained by reacting under. As the reaction conditions, conditions similar to those for the synthesis of compound (2-2-3) in formula (B-2-1) can be used.

Compound (2-4-3) can also be synthesized by reacting compound (1-3-2) with alkylisothiourea or a salt thereof in the presence or absence of a base. As the reaction conditions, conditions similar to those for the synthesis of compound (1-1-3) in formula (A-1-1) can be used.

Compound (9) can be synthesized by oxidizing compound (2-4-3). As the reaction conditions, conditions similar to those for the synthesis of compound (4) in formula (A-2-1) can be used.

When Lv ′ in the compound (2-1) is a halogen atom or a sulfonate group, the compound [compound represented by the following formula (10)] is synthesized by the method of the following formula (B-4-2). be able to.

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ²⁵ , m and Lv ^b are as defined above]. ]

Compound (2-5-2) can be obtained by reacting compound (1-3-2) with urea or a salt thereof in the presence or absence of a base. As the reaction conditions, conditions similar to those for the synthesis of compound (1-1-3) in formula (A-1-1) can be used.

The compound (2-5-3) is obtained by converting the compound (2-5-2) into a sulfonic acid chloride such as p-toluenesulfonic acid chloride or mesyl acid chloride, or a sulfonic acid anhydride such as trifluoromethanesulfonic anhydride. , Phosphorus oxychloride, thionyl chloride and the like in the presence or absence of a base. As the reaction conditions, the same conditions as in the synthesis of compound (2) in formula (A-1-1) can be used.

Compound (2-5-4) can be synthesized by oxidizing compound (2-5-3). As the reaction conditions, conditions similar to those for the synthesis of compound (4) in formula (A-2-1) can be used.

Compound (10) can be synthesized by reacting compound (2-5-4) with compound (2-5-5). As the reaction conditions, the same conditions as in the synthesis of compound (1) in formula (A-1) can be used.

When Lv in the compound (1-1) is an alkylsulfinyl group or an alkylsulfonyl group and X is an unsubstituted amino group, the compound [compound represented by the following formula (11)] is represented by the following formula (B It can be synthesized by the method of -5-1).

[Wherein, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ²⁵ , m and Lv ^b are as defined above]. ]

Compound (2-6-2) can be obtained by reacting compound (2-5-3) with ammonia or a salt thereof in the presence or absence of a base. As the reaction conditions, the same conditions as in the synthesis of compound (1) in formula (A-1) can be used.

Compound (2-6-2) is obtained by reacting compound (2-5-3) with sodium azide, a hydrazine derivative or a salt thereof, a hydroxylamine derivative or a salt thereof in the presence or absence of a base, It can also be synthesized by reduction. As the reaction conditions, the same conditions as in the synthesis of compound (5) in formula (B-1) can be used.

Compound (11) can be synthesized by oxidizing compound (2-6-2). As the reaction conditions, conditions similar to those for the synthesis of compound (4) in formula (A-2-1) can be used.

When Lv in the compound (1-1) is an alkylsulfinyl group or an alkylsulfonyl group and X is a hydrogen atom, the compound [compound represented by the following formula (12)] is represented by the following formula (B-5-2): ).

Compound (2-7-2) can be synthesized by reducing compound (2-5-3). Reducing agents include hydrogen, formic acid salts such as ammonium formate, metals such as sodium, magnesium, zinc or Raney nickel, boron reagents such as borane tetrahydrofuran complex, and hydrides such as sodium borohydride or sodium cyanoborohydride. Reagents can be used, and examples of the catalyst include transition metals such as palladium, nickel, rhodium, cobalt, and platinum, salts thereof, complexes thereof, polymers and the like. This reaction can be carried out in a solvent or without a solvent. When a solvent is used, examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and diglyme, alcohol solvents such as methanol, ethanol, 2-propanol and butanol, trifluoro Examples thereof include carboxylic acids such as acetic acid and acetic acid, aprotic solvents such as hexane, heptane, dimethylformamide and acetonitrile, and water. Alternatively, a mixed solvent thereof may be used. In some cases, an acid such as hydrochloric acid may be added, and the reaction may be performed under pressurized conditions. The reaction temperature is selected, for example, from the range of about -40 ° C to 200 ° C.

Compound (12) can be synthesized by oxidizing compound (2-7-2). As the reaction conditions, conditions similar to those for the synthesis of compound (4) in formula (A-2-1) can be used.

(Manufacturing method 3)
When X in the compound (1) is a hydrogen atom, the compound [compound represented by the following formula (13)] can be synthesized by the method of the following formula (C-1).

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and Lv ^b are as defined above]. ]

That is, the compound (13) can be obtained by reducing the compound (2-1). As the reaction conditions, conditions similar to those for the synthesis of compound (2-7-2) in formula (B-5-2) can be used.

In the above production method, compound (1-2), compound (2-1-2), compound (2-3-4) and compound (2-5-5) are all the same or different and have the formula: A compound represented by R ¹ —H (wherein R ¹ is as defined above).

When the compound of the present invention represented by the formula (1), an intermediate thereof, or a raw material compound thereof has a functional group, a person skilled in the art can use the production method 1, the production method 2 or the production method 3 as necessary. According to the conventional method, a substituent introduction reaction or a functional group conversion reaction can be performed. These were described in “Experimental Chemistry Course (Edited by Chemical Society of Japan, Maruzen)” or “Comprehensive Organic Transformation, RC Rallock, (VCH Publishers, Inc, 1989)”. A method or the like can be used. For example, functional group conversion reactions include acylation or sulfonylation using acid halides or sulfonyl halides, reactions involving alkylating agents such as alkyl halides, hydrolysis reactions, Friedel-Crafts (Friedel -Crafts reaction and Wittig reaction, carbon-carbon bond formation reaction, reductive amination reaction, carbon-nitrogen bond formation reaction such as amine alkylation reaction, oxidation or reduction reaction and the like.
In addition, when the compound of the present invention represented by the formula (1) and the intermediate thereof have a functional group such as an amino group, a carboxyl group, a hydroxyl group, or an oxo group, protection or deprotection is performed as necessary. Can be done. Suitable protecting groups, protecting methods and deprotecting methods are described in detail in “Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc .; 1990)”.

The compound of the present invention represented by the formula (1) and its intermediate can be separated and purified by methods known to those skilled in the art. Examples thereof include extraction, distribution, reprecipitation, column chromatography (for example, silica gel column chromatography, ion exchange column chromatography, preparative liquid chromatography, etc.), recrystallization and the like. Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as benzene and toluene, acetone and the like. Ketone solvents, halogen solvents such as dichloromethane and chloroform, hydrocarbon solvents such as hexane, aprotic solvents such as dimethylformamide and acetonitrile, water, or a mixed solvent thereof. As other purification methods, the methods described in Experimental Chemistry Course (edited by the Chemical Society of Japan, Maruzen) Vol. 1 can be used. In addition, the molecular structure of the compound of the present invention is determined by referring to the structure derived from each raw material compound, spectroscopic techniques such as nuclear magnetic resonance, infrared absorption, and circular two-spectrum spectroscopy, and mass. It can be easily done by analytical methods.

The compound of the present invention represented by the formula (1) and the pharmaceutically acceptable salt thereof may have asymmetry or may have a substituent having an asymmetric carbon. In such compounds, Optical isomers exist. The compounds of the present invention include mixtures of these isomers and isolated ones, which can be produced according to ordinary methods. Examples of the production method include a method using a raw material having an asymmetric point, or a method of introducing asymmetry at an intermediate stage. For example, in the case of optical isomers, optical isomers can be obtained by using optically active raw materials or by performing optical resolution at an appropriate stage of the production process. As the optical resolution method, for example, when the compound represented by the formula (1) and its intermediate have a basic functional group, the solvent is an inert solvent (for example, an alcohol solvent such as methanol, ethanol, 2-propanol). , Ether solvents such as diethyl ether, ester solvents such as ethyl acetate, hydrocarbon solvents such as toluene, aprotic solvents such as acetonitrile, and mixed solvents thereof), optically active acids (for example, mandelic acid, N-benzyloxyalanine, monocarboxylic acid such as lactic acid, tartaric acid, o-diisopropylidenetartaric acid, dicarboxylic acid such as malic acid, sulfonic acid such as camphorsulfonic acid, bromocamphorsulfonic acid, etc.) to form a salt A diastereomer method is mentioned. When the intermediate of the compound of the present invention represented by the formula (1) has an acidic functional group such as a carboxyl group, an optically active amine (for example, 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine, etc.) The optical resolution can also be carried out by forming a salt using an organic amine or the like.
The temperature for forming the salt is selected from the 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. When the precipitated salt is collected by filtration, it can be cooled as necessary to improve the yield. The amount of the optically active acid or amine used is suitably in the range of about 0.5 to about 2.0 equivalents, preferably in the range of about 1 equivalent, relative to the substrate. Crystals in an inert solvent as necessary (for example, alcohol solvents such as methanol, ethanol, 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, hydrocarbon solvents such as toluene, acetonitrile, etc. And a high purity optically active salt can be obtained. Further, if necessary, the optically resolved salt can be treated with an acid or base by a conventional method to obtain a free form.
Alternatively, when the intermediate of the compound of the present invention represented by the formula (1) has a functional group such as a primary amino group, a secondary amino group or a hydroxyl group, an optically active acid (for example, mandelic acid, N— A monocarboxylic acid such as benzyloxyalanine or lactic acid, tartaric acid, o-diisopropylidenetartaric acid, dicarboxylic acid such as malic acid, sulfonic acid such as camphorsulfonic acid, bromocamphorsulfonic acid, etc.) to form an amide or ester Optical resolution can be performed by a diastereomer method.
Alternatively, when the intermediate of the compound of the present invention represented by the formula (1) has a carboxyl group, an optically active alcohol (such as l-menthol) or an optically active amine (such as 1-phenylethylamine) ) Can be used to form an ester or amide for optical resolution.
Alternatively, the compound or intermediate of the present invention can be optically resolved by HPLC using a chiral column.

The compound of the present invention represented by the formula (1) can form a pharmaceutically acceptable salt thereof as a medicine if necessary. Since the compound of the present invention represented by formula (1) has a basic secondary or tertiary amino group, it can form salts with various acids. Examples of the pharmaceutically acceptable salt in this case include salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate, formate, acetate, fumarate, maleate , Succinate, oxalate, citrate, malate, tartrate, aspartate, salt with organic carboxylic acid such as glutamate, methanesulfonic acid, benzenesulfonate, p-toluenesulfonate And salts with sulfonic acids such as hydroxybenzene sulfonate and dihydroxybenzene sulfonate. These salts can be obtained by a conventional method such as recrystallization after mixing the compound of the present invention represented by the formula (1) with an acid.
When this invention compound represented by Formula (1) has acidic functional groups, such as a carboxyl group, various bases and salts can be formed. Examples of the pharmaceutically acceptable salt in this case include alkali metals such as sodium salt and potassium salt, alkaline earth metals such as calcium salt, ammonium salt and the like. These salts can be obtained by a conventional method such as recrystallization after mixing the compound of the present invention represented by the formula (1) with a base.
The present invention also includes solvates such as a hydrate or ethanol solvate of the compound of the present invention represented by formula (1) or a pharmaceutically acceptable salt thereof. Further, the present invention includes all existing stereoisomers such as tautomers, optical isomers and geometric isomers of the compound of the present invention represented by the formula (1), and crystal forms of all embodiments. Yes.

The compound of the present invention represented by the formula (1) and a pharmaceutically acceptable salt thereof can act as an antagonist of the H4 receptor. Therefore, the compounds and the salts are useful as therapeutic or preventive agents for allergic diseases or inflammatory diseases or pain or cancer or sepsis, that is, antiallergic agents or antiinflammatory agents or analgesics or anticancer agents. Examples of allergic diseases and / or inflammatory diseases include allergic conjunctivitis, allergic rhinitis, chronic urticaria, atopic dermatitis, asthma, chronic bronchitis and the like. Examples of inflammatory diseases include ulcerative colitis, Crohn's disease, rheumatism, chronic obstructive pulmonary disease, and sepsis.

The antiallergic agent, anti-inflammatory agent, analgesic agent or anticancer agent of the present invention can be administered orally or parenterally. When administered orally, it can be administered in a commonly used dosage form, such as a tablet, capsule, pill, granule, fine granule, powder, liquid, syrup, suspension, etc. Examples of administration forms for parenteral administration include aqueous injections, oily injections, suppositories, nasal preparations, transdermal absorption agents [lotions, emulsions, ointments, creams] , Jelly preparations, gel preparations, patches (tape preparations, transdermal patch preparations, poultice preparations, etc.), powders for external use, etc.]. These preparations can be prepared using a conventionally known technique, and can contain a nontoxic and inert carrier or excipient usually used in the pharmaceutical field. Parenterally, it can be administered in the form of topical administration, injection, transdermal, nasal, eye drops and the like.
As the pharmaceutical carrier, a substance which is commonly used in the pharmaceutical field and does not react with the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is used. That is, the pharmaceutical composition containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof includes an excipient, a binder, a lubricant, a stabilizer, a disintegrant, a buffer, and a solubilizing agent. , Tonicity agent, solubilizer, pH adjuster, surfactant, emulsifier, suspending agent, dispersant, suspending agent, thickener, viscosity modifier, gelling agent, soothing agent, preservative , Plasticizers, percutaneous absorption accelerators, anti-aging agents, moisturizers, preservatives, fragrances and the like, and can contain two or more types of pharmaceutical carrier additives as appropriate. it can.

Specific examples of carrier additives for pharmaceutical preparations include lactose, inositol, glucose, sucrose, fructose, mannitol (mannit), dextran, sorbitol (sorbit), cyclodextrin, starch (potato starch, corn starch, amylopectin, etc.) , Partially pregelatinized starch, sucrose, magnesium metasilicate aluminate, synthetic aluminum silicate, sodium alginate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin, gum arabic, pullulan, Hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose , Hydroxyethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, gelatin, alginic acid, sodium alginate, light anhydrous silicic acid, magnesium stearate, calcium stearate, aluminum stearate, cetostearyl alcohol, wax, paraffin, talc, tragacanth, bentonite, bee gum, carboxy Vinyl polymer, titanium oxide, fatty acid ester, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glycerin ester, refined lanolin, glycerogelatin, polysorbate, macrogol, squalane, silicone oil, vegetable oil (sesame oil, olive oil, soybean oil, cottonseed oil, Castor oil), liquid paraffin (liquid paraffin), soft paraffin, white petrolatum, yellow wax Phosphorus, paraffin, wool fat, wax (eg, beeswax, carnauba wax, honey beeswax), water, propylene glycol, polyethylene glycol, glycerol, lauryl alcohol, myristyl alcohol, oleyl alcohol, cetyl alcohol, ethanol, sodium chloride, sodium hydroxide, hydrochloric acid , Citric acid, lauric acid, myristic acid, stearic acid, oleic acid, benzyl alcohol, glutamic acid, glycine, methyl paraoxybenzoate, propyl paraoxybenzoate, p-hydroxybenzoic acid esters, cholesterol ester, ethylene glycol monoalkyl ester, Propylene glycol monoalkyl ester, glyceryl monostearate, sorbitan fatty acid ester, isopropyl myristate, palmitic acid Sopropyl, carboxypolymethylene, saccharin, strawberry flavor, peppermint flavor, cocoa butter, polyisobutylene, vinyl acetate copolymer, acrylic copolymer, triethyl citrate, acetyl triethyl citrate, diethyl phthalate, diethyl sebacate, sebacin Dibutyl acid, acetylated monoglyceride, diethylene glycol, dodecyl pyrrolidone, urea, ethyl laurate, azone, kaolin, bentonite, zinc oxide, agarose, carrageenan, gum acacia, xanthan gum, potassium laurate, potassium palmitate, potassium myristate, cetyl sulfate Sodium, castor oil sulfate (funnel oil), Span (sorbitan stearate, sorbitan monooleate, sorbitan sesquioleate, Sorbitan oleate), Tween (polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, polyoxyethylene sorbitan fatty acid ester, etc.), polyoxyethylene hydrogenated castor oil (so-called HCO), polyoxyethylene lauryl Ether, polyoxyethylene cetyl ether, polyoxyethylene oleyl ether, polyethylene glycol monolaurate, polyethylene glycol monostearate, poloxamer (so-called pluronic), lecithin (including purified phospholipids isolated from lecithin such as phosphatidylcholine and phosphatidylserine) ) And hydrogenated lecithin.

It can also be used in combination with other antiallergic agents or anti-inflammatory agents, analgesics or anticancer agents. Examples of other antiallergic agents include ketotifen, epinastine, fexofenadine, cetirizine antihistamines, leukotriene antagonists such as montelukast, zafirlukast, pranlukast, and the like. Examples of the anti-inflammatory agent include NSAIDs such as diclofenac, aspirin and loxoprofen, and COX-2 inhibitors such as celecoxib. Examples of analgesics include paracetamol and the like in addition to the NSAIDs listed above. Examples of anticancer agents include taxol, cyclophosphamide, methotrexate, doxorubicin and the like.

The dose and frequency of administration vary depending on symptoms, age, body weight, dosage form, and the like. The range of about 300 mg can be administered in one or several divided doses. In addition, for example, when administered as an injection, the range of about 0.1 to about 500 mg, preferably about 1 to about 100 mg can be administered once or divided into several times.

Hereinafter, the present invention will be described in detail with reference to Examples, Reference Examples, and Test Examples, but the technical scope of the present invention is not limited thereto. The compound names shown in the following examples and reference examples do not necessarily follow the IUPAC nomenclature.

The following abbreviations may be used for the simplification described in this specification.
Me: methyl Et: ethyl
ⁿ Pr: Normal propyl
ⁿ Bu: normal butyl Ph: phenyl

(Reference Example 1)
2-Amino-7,7-dimethyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-4-ol

a) To a solution of 2,2-dimethyltetrahydropyran-4H-pyran-4-one 825 mg (6.44 mmol) in tetrahydrofuran (16.5 ml) at −78 ° C., 1.05 M lithium bis (trimethylsilyl) amide in hexane (6.76 mmol) was added dropwise. After 1 hour, methyl cyanoformate 0.575 g (6.76 mmol) was added and stirred for 2 hours. After completion of the reaction, the mixture was extracted with an ethyl acetate-ammonium chloride aqueous solution. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give methyl 6,6-dimethyl-4-oxotetrahydro-2H-pyran-3-carboxylate (Compound 1A) as a colorless oil Obtained as a product (428 mg, 36% yield).
¹ H-NMR (300 MHz, CDCl ₃ , δ ppm): 11.75 (1H, s), 4.28 (2H, t, J = 1.7 Hz), 3.77 (3H, s), 2.24 (2H, t, J = 1.7 Hz), 1.27 (6H, s).
b) To a solution of Compound 1A 478 mg (2.57 mmol) in ethanol (8.5 ml) was added 497 mg (3.08 mmol) of guanidine carbonate, and the mixture was stirred for 3 hours with heating under reflux. After completion of the reaction, the solvent was distilled off under reduced pressure. Methanol was added to the resulting residue and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent; chloroform: methanol) to give the title compound as a white solid (241 mg, yield 48%).
¹ H-NMR (300 MHz, DMSO-d ₆ , δ ppm): 10.75 (1H, br), 6.31 (2H, br), 4.23 (2H, s), 2.23 (2H, s), 1.16 (6H, s ).

(Reference example 2)
2-Amino-7-phenyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-4-ol

a) 1.47 g (13.9 mmol) of benzaldehyde was added to 2.0 g (27.7 mmol) of 3-buten-1-ol, and 80% aqueous sulfuric acid (2.43 g) was slowly added dropwise over 30 minutes at 0 ° C, and the temperature was raised to room temperature After that, it was stirred overnight. After completion of the reaction, ice was added, the pH was adjusted to 5 with 10 N aqueous sodium hydroxide solution, liquid separation and extraction were performed with diethyl ether, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give 2-phenyltetrahydro-2H-pyran-4-ol (Compound 2A) as a pale yellow oil (1.51 g Yield 61%).
¹ H-NMR (300 MHz, CDCl ₃ , δ ppm): 7.25-7.35 (5H, m), 4.30 (1H, dd, J = 11.5, 2.1 Hz), 4.16 (1H, ddd, J = 12.2, 4.9, 2.1 Hz), 3.91 (1H, m), 3.57 (1H, ddd, J = 12.2, 12.2, 2.1 Hz), 2.18 (1H, m), 1.97 (1H, m), 1.65 (1H, m), 1.52 ( 1H, m).
b) To a solution of Compound 2A 178 mg (1.00 mmol) in dichloromethane (4.0 ml), Molecular Sieves 4A 100 mg and pyridinium dichlorochromate 395 mg (1.05 mmol) were added and stirred overnight at room temperature. After completion of the reaction, diethyl ether (20 ml) was added and stirred for 1 hour, followed by filtration through celite. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give 2-phenyltetrahydro-4H-pyran-4-one (Compound 2B) as a colorless oil (157 mg, 89% yield).
¹ H-NMR (300 MHz, CDCl ₃ , δ ppm): 7.29-7.42 (5H, m), 4.74 (1H, m), 4.44 (1H, ddd, J = 11.6, 7.4, 1.6 Hz), 3.85 (1H , ddd, J = 11.6, 11.6, 2.9 Hz), 2.79 (1H, m), 2.67 (2H, m), 2.47 (1H, m).
c) Compound 2B was reacted and treated in the same manner as in Reference Example 1a) to give methyl 4-oxo-6-phenyltetrahydro-2H-pyran-3-carboxylate (Compound 2C) as a colorless oil (yield). 11%).
d) To a solution of Compound 2C 120 mg (0.512 mmol) in ethanol (2.0 ml) was added guanidine carbonate 111 mg (0.768 mmol), and the mixture was stirred for 2 hours while heating under reflux. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent; chloroform: methanol) to obtain the title compound as a white solid (83.1 mg, yield 67%) .
¹ H-NMR (300 MHz, DMSO-d ₆ , δ ppm): 10.83 (1H, s), 7.30 (5H, m), 6.41 (2H, s), 4.65 (1H, dd, J = 8.5, 5.4 Hz ), 4.55 (1H, d, J = 14.9 Hz), 4.38 (1H, d, J = 14.9 Hz), 2.54 (2H, m).

(Reference Example 3)
2-Amino-7-propyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-4-ol (Reference Example 4)
2-Amino-5-propyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-4-ol

a) 2.0 g (27.7 mmol) of n-butyraldehyde was added to 4.0 g (55.5 mmol) of 3-buten-1-ol, and 80% sulfuric acid aqueous solution (4.86 g) was slowly added dropwise at 0 ° C. Stir overnight. After completion of the reaction, ice was added, the mixture was neutralized with 10 N aqueous sodium hydroxide, separated and extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by distillation under reduced pressure (70-73 ° C., 1.4 mmHg) to give 2-propyltetrahydro-2H-pyran-4-ol (compound 3A) as a colorless oil (1.69 g, yield) 42%).
¹ H-NMR (300 MHz, CDCl ₃ , δ ppm): 4.00 (1H, m), 3.77 (1H, m), 3.39 (1H, m), 3.25 (1H, m), 1.93 (2H, m), 1.33-1.62 (6H, m), 0.92 (3H, m).
b) Compound 3A was reacted and treated in the same manner as in Reference Example 2b) to give 2-propyltetrahydro-4H-pyran-4-one (Compound 3B) as a colorless oil (yield 77%).
¹ H-NMR (300 MHz, CDCl ₃ , δ ppm): 4.32 (1H, m), 3.66 (1H, m), 3.59 (1H, m), 2.53 (1H, m), 2.24-2.43 (3H, m ), 1.67 (1H, m), 1.49 (3H, m), 0.94 (3H, t, J = 7.1 Hz).
c) A hexane solution (5.00 mmol) of 1.05 M lithium bis (trimethylsilyl) amide was added dropwise at −78 ° C. to a solution of compound 3B 711 mg (5.00 mmol) in tetrahydrofuran (14 ml). After 1 hour, methyl cyanoformate (5.00 mmol) was added and stirred for 2 hours. After completion of the reaction, the mixture was extracted with an ethyl acetate-ammonium chloride aqueous solution. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Guanidine carbonate (5.00 mmol) was added to a solution of the resulting residue in ethanol (14 ml), and the mixture was stirred for 2 hours with heating under reflux. After completion of the reaction, the solvent was distilled off under reduced pressure, and methanol was added to the resulting residue and filtered. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent; chloroform: methanol). The resulting mixture was repulped with methanol to give 2-amino-7-propyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-4-ol (compound of Reference Example 3) in white Obtained as a solid (198 mg, 19% yield). The filtrate was concentrated under reduced pressure, and the resulting residue was subjected to amino silica gel column chromatography (elution solvent; chloroform: methanol) to give 2-amino-5-propyl-7,8-dihydro-5H-pyrano [4, 3-d] pyrimidin-4-ol (the compound of Reference Example 4) was obtained as a white solid (124 mg, yield 12%).
Reference Example 3); ¹ H-NMR (300 MHz, DMSO-d ₆ , δ ppm): 10.78 (1H, s), 6.34 (2H, s), 4.39 (1H, d, J = 14.7 Hz), 4.15 ( 1H, d, J = 14.7 Hz), 3.51 (1H, m), 2.24 (2H, m), 1.31-1.54 (4H, m), 0.88 (3H, t, J = 7.1 Hz).
Reference Example 4); ¹ H-NMR (300 MHz, DMSO-d ₆ , δ ppm): 10.72 (1H, br), 6.32 (2H, br), 4.34 (1H, d, J = 6.8 Hz), 3.84 ( 1H, ddd, J = 5.8, 5.5, 5.5 Hz), 3.58 (1H, ddd, J = 5.8, 5.5, 5.5 Hz), 2.32 (2H, dd, J = 5.5, 5.5 Hz), 1.80 (1H, m) , 1.55 (1H, m), 1.32 (2H, m), 0.86 (3H, 7.3 Hz).

(Reference Example 5)
4- (4-Methylpiperazin-1-yl) -7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine

Synthesis was performed according to the method described in the literature (WO2008 / 100565A1).

(Reference Example 6)
4- (4-Methylpiperazin-1-yl) -5-propyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine

Using 2-amino-7-propyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-4-ol (compound of Reference Example 4), the reaction was conducted in the same manner as in Example 3. Treatment gave the title compound as a pale yellow solid (42% yield).
¹ H NMR (300 MHz, CDCl ₃ , δ ppm): 4.73 (1H, m), 4.71 (2H, br), 4.10 (1H, ddd, J = 11.3, 6.2, 2.3 Hz), 3.71 (1H, ddd, J = 11.3, 11.3, 3.8 Hz), 3.43 (2H, m), 3.26 (2H, m), 2.88 (1H, m), 2.58 (1H, m), 2.53 (2H, m), 2.46 (2H, m ), 2.34 (3H, s), 2.00 (1H, m), 1.55 (1H, m), 1.35 (2H, m), 0.92 (3H, t, J = 7.3 Hz).

(Reference Example 7)
2'-amino-5 ', 8'-dihydrospiro (cyclopentane-1,7'-pyrano [4,3-d] pyrimidine) -4'-ol

¹ H-NMR (300 MHz, CDCl ₃ , δ ppm): 3.86 (1H, m), 3.79 (1H, m), 3.51 (1H, m), 1.21-1.90 (12H, m).
b) Compound 7A was reacted and treated in the same manner as in Reference Example 2b) to give 6-oxaspiro [4,5] decan-9-one (Compound 7B) as a colorless oil (yield 84%).
¹ H-NMR (300 MHz, CDCl ₃ , δ ppm): 3.96 (2H, t, J = 6.0 Hz), 2.47 (2H, s), 2.44 (2H, t, J = 6.0 Hz), 1.90 (2H, m), 1.78 (2H, m), 1.62 (2H, m), 1.55 (2H, m).
c) Compound 7B was reacted and treated in the same manner as in Reference Example 3c) to give the title compound as a white solid (yield 18%).
¹ H-NMR (300 MHz, DMSO-d ₆ , δ ppm): 10.77 (1H, s), 6.31 (2H, s), 4.23 (2H, s), 2.35 (2H, s), 1.74 (2H, m ), 1.66 (4H, m), 1.42 (2H, m).

(Reference Example 8)
2-Amino-7-ethyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-4-ol

a) Propionaldehyde was reacted and treated in the same manner as in Reference Example 3a) to give 2-ethyltetrahydro-2H-pyran-4-ol (Compound 8A) as a colorless oil (yield 32%).
¹ H-NMR (300 MHz, CDCl ₃ , δ ppm): 4.04 (1H, m), 3.99 (1H, m), 3.39 (1H, m), 3.18 (1H, m), 1.95 (1H, m), 1.86 (1H, m), 1.43-1.61 (3H, m), 1.18 (1H, m), 0.94 (3H, t, J = 7.5Hz).
b) Compound 8A was reacted and treated in the same manner as in Reference Example 3b) to give 2-ethyltetrahydro-4H-pyran-4-one (Compound 8B) as a colorless oil (yield 65%).
¹ H-NMR (300 MHz, CDCl ₃ , δ ppm): 4.33 (1H, ddd, J = 11.4, 7.3, 1.5 Hz), 3.66 (1H, m), 3.50 (1H, m), 2.60 (1H, m ), 2.27-2.44 (3H, m), 1.69 (2H, m), 0.98 (3H, t, J = 7.5 Hz).
c) Lithium diisopropylamide prepared from a solution of compound 8B 897 mg (7.00 mmol) in tetrahydrofuran (12 ml) at -78 ° C from 1.66 M n-butyllithium in hexane (7.70 mmol) and diisopropylamine (7.70 mmol) Of tetrahydrofuran (6 ml) was added dropwise. After 1 hour, ethyl cyanoformate (7.70 mmol) was added and stirred for 2 hours. After completion of the reaction, the mixture was extracted with an ethyl acetate-ammonium chloride aqueous solution, and the organic layer was dried over magnesium sulfate and evaporated under reduced pressure. Guanidine carbonate (7.00 mmol) was added to a solution of the resulting residue in ethanol (16 ml), and the mixture was stirred for 3 hours with heating under reflux. After completion of the reaction, the reaction mixture was cooled to room temperature and the resulting solid was filtered to obtain the title compound as a pale yellow solid (639 mg, yield 47%).
¹ H-NMR (300 MHz, DMSO-d ₆ , δ ppm): 6.16 (2H, br), 4.35 (1H, d, J = 14.3 Hz), 4.16 (1H, d, J = 14.3 Hz), 3.39 ( 1H, m), 2.16 (2H, m), 1.49 (2H, m), 0.90 (3H, t, J = 7.4 Hz).

(Reference Example 9)
2-Amino-7-cyclohexyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-4-ol (Reference Example 10)
2-Amino-7,7-diethyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-4-ol (Reference Example 11)
2'-amino-5 ', 8'-dihydrospiro [cyclohexane-1,7'-pyrano [4,3-d] pyrimidine] -4'-ol (Reference Example 12)
2-Amino-7-phenethyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-4-ol (Reference Example 13)
2-Amino-7-methyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-4-ol

The title compound was obtained by reacting and treating in the same manner as in Reference Example 8 using cyclohexanecarbaldehyde, diethyl ketone, cyclohexanone, dihydrocinnamaldehyde or acetaldehyde.
Reference Example 9 (14% yield, 3 steps); ¹ H-NMR (300 MHz, DMSO-d ₆ , δ ppm): 6.03 (2H, br), 4.36 (1H, d, J = 15.7 Hz), 4.12 (1H, d, J = 15.7 Hz), 3.20 (1H, m), 2.16 (2H, m), 1.92 (1H, m), 1.67 (4H, m), 1.37 (1H, m), 0.91-1.23 ( 5H, m).
Reference Example 10 (Yield 15%, 3 steps); ¹ H-NMR (300 MHz, DMSO-d ₆ , δ ppm): 10.74 (1H, br), 6.30 (2H, br), 4.19 (2H, s) , 2.19 (2H, s), 1.45 (4H, m), 0.80 (6H, t, J = 7.5 Hz).

Reference Example 11 (Yield 1.8%, 3 steps); ¹ H-NMR (400 MHz, DMSO-d ₆ , δ ppm): 4.20 (2H, s), 2.17 (2H, s), 1.65-1.23 (10H, m).
Reference Example 12 (Yield 1.5%, 3 steps); ¹ H-NMR (400 MHz, DMSO-d ₆ , δ ppm): 10.8 (1H, s), 7.29-7.12 (5H, m), 6.33 (2H, br-s), 4.44 (1H, d, J = 14.5 Hz), 4.16 (1H, d, J = 14.5 Hz), 3.51-3.48 (1H, m), 2.78-2.62 (2H, m), 2.77 (2H , d, J = 6.4 Hz), 1.82-1.76 (2H, m).
Reference Example 13 (6% yield, 3 steps); ¹ H-NMR (300 MHz, DMSO-d ₆ , δ ppm): 7.89 (2H, br), 5.53 (1H, br), 4.33 (1H, d, J = 14.3 Hz), 4.14 (1H, d, J = 14.3 Hz), 3.58 (1H, m), 2.15 (2H, m), 1.16 (3H, d, J = 6.1 Hz).

(Reference Example 14)
4'-Chloro-5 ', 8'-dihydrospiro [cyclopentane-1,7'-pyrano [4,3-d] pyrimidine-2'-amine

2'-amino-5 ', 8'-dihydrospiro (cyclopentane-1,7'-pyrano [4,3-d] pyrimidine) -4'-ol (compound of Reference Example 7) 1.1 g (4.97 mmol) To the mixture, phosphorus oxychloride (20 ml) was added and stirred at 110 ° C. for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. Ice and an aqueous sodium hydrogen carbonate solution were added to the resulting residue to adjust the pH to 8, followed by separation and extraction with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent; chloroform: methanol) to obtain the title compound as a brown solid (513 mg, yield 43%).
¹ H NMR (300 MHz, CDCl ₃ , δ ppm): 5.13 (2H, s), 4.60 (2H, s), 2.74 (2H, s), 1.66-1.93 (6H, m), 1.50 (2H, m) .

(Reference Example 15)
4- (4-Methylpiperazin-1-yl) -8-propyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine

a) 3-Allyldihydro-2H-pyran-4 (3H) -one (Compound 15A)
To a tetrahydrofuran (50 ml) solution of 7.35 ml (52 mmol) of diisopropylamine, 34 ml (1.54 M, 52 mmol) of a hexane solution of n-butyllithium was added at 0 ° C. After 30 minutes, the mixture was cooled to −78 ° C., and 4.6 ml (50 mmol) of dihydro-2H-pyran-4 (3H) -one was added and stirred for 1 hour. Allyl bromide (5.11 ml, 60 mmol) and hexamethyltriphosphoramide (26 ml, 150 mmoL) were added, and the mixture was slowly warmed to room temperature and stirred for 3 days. Thereafter, separation and extraction were performed with an ethyl acetate-ammonium chloride aqueous solution, and the organic layer was dried over sodium sulfate and then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate) to give the title compound as a colorless oil (1.04 g, yield 15%).
¹ H-NMR (400 MHz, CDCl ₃ , δ ppm): 5.57-5.67 (1H, m), 4.90-4.96 (2H, m), 4.02-4.08 (2H, m), 3.60-3.65 (1H, m) , 3.30 (1H, dd, J = 9.4, 11.3 Hz), 2.40-2.52 (3H, m), 2.28-2.33 (1H, m), 1.86-1.94 (1H, m).

b) 8-Allyl-2-amino-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-4-ol (Compound 15B)
To a solution of 0.96 ml (6.8 mmol) of diisopropylamine in tetrahydrofuran (10 ml) was added 2.59 ml (2.64 M, 6.8 mmol) of a hexane solution of n-butyllithium at 0 ° C. After 30 minutes, the mixture was cooled to −78 ° C., and a solution of 0.91 g (6.5 mmol) of 3-allyldihydro-2H-pyran-4 (3H) -one in tetrahydrofuran (3 ml) was added and stirred for 2 hours. Ethyl cyanoformate 0.71 ml (7.2 mmol) was added, and the mixture was further stirred for 2.5 hours. After completion of the reaction, the mixture was extracted with an ethyl acetate-ammonium chloride aqueous solution, and the organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was dissolved in ethanol (50 ml), guanidine carbonate 1.4 g (7.8 mmol) was added, and the mixture was heated to reflux for 3 hours. After evaporating the solvent under reduced pressure, the title compound was obtained as a solid by purification by silica gel column chromatography (elution solvent; chloroform: methanol) (426 mg, yield 32%).
¹ H-NMR (400 MHz, MeOH-d ₄ , δ ppm): 5.80-5.89 (1H, m), 5.05-5.12 (2H, m), 4.43 (1H, d, J = 14.8 Hz), 4.33 (1H , dd, J = 1.2, 14.8 Hz), 3.85 (1H, dd, J = 3.3, 11.6 Hz), 3.75 (1H, dd, J = 3.8, 11.6 Hz), 2.51-2.58 (1H, m), 2.27- 2.43 (2H, m).

c) 2-Amino-8-propyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-4-ol (Compound 15C)
3-allyl-2-amino-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-4-ol in a solution of 426 mg (2.06 mmol) in methanol (20 ml) with 3% Pt / S 590 mg was added and stirred under a hydrogen stream for 4 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated to give the title compound as a white solid (449 mg, yield 104%).
¹ H-NMR (400 MHz, MeOH-d ₄ , δ ppm): 4.43 (1H, d, J = 14.7 Hz), 4.33 (1H, dd, J = 1.3, 14.7 Hz), 3.85 (1H, dd, J = 3.4, 11.6 Hz), 3.77 (1H, dd, J = 3.9, 11.6 Hz), 2.30-2.35 (1H, m), 1.36-1.75 (4H, m), 0.95 (3H, t, J = 7,3 Hz).

d) 4- (4-Methylpiperazin-1-yl) -8-propyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine (Reference Example 15)
2-amino-8-propyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-4-ol 284 mg (1.36 mmol), phosphorus oxychloride 3 ml (54 mmol), N, N-dimethyl Aniline (1 ml) was added and heated at 105 ° C. for 7 hours. After concentration with an evaporator, the solution was further diluted with toluene and concentrated again. The residue was dissolved in tetrahydrofuran (3 ml), 1 ml of N-methylpiperazine was added, and the mixture was heated at 160 ° C. for 40 minutes under microwave irradiation. The title compound was obtained by concentrating with an evaporator and then purifying with silica gel column chromatography (326 mg, 82%).
¹ H-NMR (400 MHz, CDCl ₃ , δ ppm): 4.71 (2H, brs), 4.51 (1H, d, J = 13.4 Hz), 4.47 (1H, d, J = 13.4 Hz), 4.04 (1H, dd, J = 5.4, 11.6 Hz), 3.78 (1H, dd, J = 5.9, 11.6 Hz), 3.24-3.34 (4H, m), 2.61-2.68 (1H, m), 2.50 (4H, t, J = 4.9 Hz), 2.34 (3H, s), 1.83-1.94 (1H, m), 1.36-1.58 (3H, m), 0.95 (3H, t, J = 7,3 Hz).

Example 1 (Production method A)
7,7-Dimethyl-4- (4-methylpiperazin-1-yl) -7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine

2-amino-7,7-dimethyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-4-ol (compound of Reference Example 1) 100 mg (0.512 mmol) was added to phosphorus oxychloride ( 2.0 ml) was added and the mixture was stirred at 100 ° C. for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. Ice and an aqueous sodium hydrogen carbonate solution were added to the resulting residue to adjust the pH to 8, followed by separation and extraction with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent; chloroform: methanol) to give 2-amino-4-chloro-7,7-dimethyl-7,8-dihydro-5H-pyrano [4,3- d] pyrimidine (4-chloro compound) was obtained as a white solid (41.4 mg). 1-Methylpiperazine (2.0 ml) was added to the obtained chloro compound and heated at 160 ° C. for 40 minutes under microwave irradiation (160 W). After completion of the reaction, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent; chloroform: methanol) to obtain the title compound as a pale yellow solid (46.2 mg, yield 33%).
¹ H NMR (300 MHz, CDCl ₃ , δ ppm): 4.64 (2H, br), 4.54 (2H, s), 3.33 (4H, m), 2.57 (2H, s), 2.48 (4H, m), 2.33 ( 3H, s), 1.32 (6H, s).

Example 2 (Production method B)
7,7-Dimethyl-4- [3- (methylamino) azetidin-1-yl] -7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine

Phosphorous oxychloride (1.3 ml) was added to 65 mg (0.333 mmol) of the compound of Reference Example 1, and the mixture was stirred at 100 ° C. for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. Toluene was added to the residue and azeotropic distillation was performed, and then azeotropic distillation was performed again using methanol. To a solution of the resulting residue in acetonitrile (2.0 ml), 93 mg (0.499 mmol) of tert-butylazetidin-3-yl (methyl) carbamate synthesized according to the literature (WO2008 / 060767A2) and 232 μl (1.66 mmol) of triethylamine were added, The mixture was stirred at 100 ° C. for 4 hours. After completion of the reaction, the mixture was extracted with ethyl acetate-water, and the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent; chloroform: methanol) to give tert-butyl [1- (2-amino-7,7-dimethyl-7,8-dihydro-5H-pyrano [4 , 3-d] pyrimidin-4-yl) azetidin-3-yl] methylcarbamate (t-butylcarbamate) was obtained as a pale yellow solid (38.2 mg). To a solution of the obtained t-butyl carbamate in methanol (0.5 ml) was added 4 N hydrochloric acid / dioxane (0.5 ml) at room temperature, and the mixture was stirred for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent; chloroform: methanol) to obtain the title compound as a white solid (19.1 mg, 69%).
¹ H NMR (300 MHz, CDCl ₃ , δ ppm): 4.74 (2H, s), 4.61 (2H, s), 4.29 (2H, m), 3.83 (2H, m), 3.62 (1H, m), 2.49 (2H, s), 2.42 (3H, s), 1.28 (6H, s).

Example 3 (Production Method C)
4- (4-Methylpiperazin-1-yl) -7-phenyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine

2-Amino-7-phenyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-4-ol (compound of Reference Example 2) 50 mg (0.206 mmol) and phosphorus oxychloride (1.0 ml) ) Was added and stirred at 100 ° C. for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. Toluene was added to the residue and azeotropic distillation was performed, and then azeotropic distillation was performed again using methanol. 4-Methylpiperazine (1.0 ml) was added to the resulting residue and heated at 160 ° C. for 40 minutes under microwave irradiation (160 W). After completion of the reaction, the reaction mixture was concentrated under reduced pressure, separated and extracted with chloroform-saturated brine, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent; chloroform: methanol). The resulting mixture was repulped with diethyl ether to give the title compound as a pale yellow solid (37.5 mg, yield 56%).
¹ H NMR (300 MHz, CDCl ₃ , δ ppm): 7.29-7.61 (5H, m), 4.81 (1H, dd, J = 10.2, 4.9 Hz), 4.75 (1H, d, J = 13.4 Hz), 4.67 (2H, s), 4.65 (1H, d, J = 13.4 Hz), 3.36 (4H, m), 2.98 (1H, dd, J = 17.9, 4.9 Hz), 2.89 (1H, dd, J = 17.9, 10.2 Hz), 2.54 (4H, m), 2.33 (3H, s).

Example 4-10
Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 2 (Production Method B) or Example 3 (Production Method C) to obtain the compound of Example 4-10 below.

Example 4
4- (4-Methylpiperazin-1-yl) -7-propyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine; process C (yield 19%); ¹ H NMR (300 MHz, CDCl ₃ , δ ppm): 4.62 (2H, s), 4.54 (2H, s), 3.70 (1H, m), 3.31 (4H, m), 2.66 (1H, dd, J = 17.6, 4.0 Hz), 2.50 (3H, m), 2.42 (2H, m), 2.32 (3H, s), 1.39-1.66 (4H, m), 0.96 (3H, t, J = 7.1 Hz).
(+)-4- (4-Methylpiperazin-1-yl) -7-propyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine (-)-4- (4 -Methylpiperazin-1-yl) -7-propyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine Main, 4- (4-Methylpiperazin-1-yl) -7 By optically resolving 81 mg (0.278 mmol) of 2-propyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine with chiral HPLC, (+)-form (26.1 mg, Yield 32%, 98.2% ee) and (−)-isomer (21.7 mg, yield 27%, 94.3% ee) were obtained as white solids, respectively.
Column: AD-H
Solvent: 20% -ethanol / hexane (0.5% -diethylamine)
Flow rate: 1 ml / min (+)-isomer: [α] _D ¹⁹ = 18.9 ° (c = 1.00, chloroform), (-)-isomer: [α] _D ¹⁹ = -16.7 ° (c = 1.00, chloroform)

(Example 5)
4- [3- (Methylamino) azetidin-1-yl] -7-propyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine; Process B (yield 24%) ¹ H NMR (300 MHz, CDCl ₃ , δ ppm): 4.68 (1H, d, J = 13.6 Hz), 4.63 (2H, s), 4.56 (1H, d, J = 13.6 Hz), 4.31 (1H, dd, J = 7.9, 7.9 Hz), 4.22 (1H, dd, J = 7.9, 7.9 Hz), 3.87 (1H, m), 3.77 (1H, m), 3.62 (2H, m), 2.51 (2H, m ), 2.41 (3H, s), 1.37-1.65 (4H, m), 0.95 (3H, t, J = 7.1 Hz).

(Example 6)
4 ′-(4-Methylpiperazin-1-yl) -5 ′, 8′-dihydrospiro (cyclopentane-1,7′-pyrano [4,3-d] pyrimidine) -2′-amine; Process C ( ¹ H NMR (300 MHz, CDCl ₃ , δ ppm): 4.63 (2H, s), 4.52 (2H, s), 3.35 (4H, m), 2.69 (2H, s), 2.48 ( 4H, m), 2.33 (3H, s), 1.93 (2H, m), 1.80 (2H, m), 1.70 (2H, m), 1.55 (2H, m).

(Example 7)
4 '-[3- (methylamino) azetidin-1-yl] -5', 8'-dihydrospiro (cyclopentane-1,7'-pyrano [4,3-d] pyrimidine) -2'-amine; Production method B (yield 81%); ¹ H NMR (300 MHz, CDCl ₃ , δ ppm): 4.63 (2H, s), 4.59 (2H, s), 4.29 (2H, m), 3.83 (2H, m) , 3.61 (1H, m), 2.61 (2H, s), 2.42 (3H, s), 1.88 (2H, m), 1.78 (2H, m), 1.68 (2H, m), 1.50 (2H, m).

(Example 8)
4- (4-Methylpiperazin-1-yl) -7-ethyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine; process C (yield 36%); ¹ H NMR (300 MHz, CDCl ₃ , δ ppm): 4.63 (2H, s), 4.54 (2H, s), 3.62 (1H, m), 3.31 (4H, m), 2.67 (1H, dd, J = 17.7, 4.1 Hz), 2.46 (3H, m), 2.32 (3H, s), 1.67 (2H, m), 1.01 (3H, t, J = 7.5 Hz).

Example 9
4- (4-Methylpiperazin-1-yl) -7-cyclohexyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine; Process C (45% yield); ¹ H NMR (300 MHz, CDCl ₃ , δ ppm): 4.62 (2H, s), 4.53 (2H, s), 3.41 (1H, m), 3.31 (4H, m), 2.66 (2H, m), 2.51 (2H , m), 2.43 (2H, m), 2.32 (3H, s), 2.01 (1H, m), 1.74 (4H, m), 1.48 (1H, m), 0.97-1.30 (5H, m).

(Example 10)
4- (4-Methylpiperazin-1-yl) -7,7-diethyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine; Process C (55% yield); ¹ H NMR (300 MHz, CDCl ₃ , δ ppm): 4.65 (2H, s), 4.47 (2H, s), 3.33 (4H, m), 2.54 (2H, s), 2.48 (4H, m), 2.33 (3H, s), 1.70 (2H, m), 1.54 (2H, m), 0.91 (6H, t, J = 7.4 Hz).

Examples 11-13
The corresponding starting materials were used and reacted and treated in the same manner as in Example 2 (Production Method B) or Example 3 (Production Method C) to give the following Examples 11-13.

(Example 11)
4 ′-(4-Methylpiperazin-1-yl) -5 ′, 8′-dihydrospiro [cyclohexane-1,7′-pyrano [4,3-d] pyrimidine] -2′-amine; ¹ H-NMR (400 MHz, DMSO-d ₆ , δ ppm): 5.98 (2H, brs), 4.41 (2H, s), 3.17-3.15 (4H, m), 2.36-2.32 (6H , m), 2.18 (3H, s), 1.70-1.26 (10H, m).

(Example 12)
4- (4-Methylpiperazin-1-yl) -7-phenethyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine; Process C (22% yield); ¹ H -NMR (400 MHz, DMSO-d ₆ , δ ppm): 7.30-7.15 (5H, m), 6.00 (2H, br-s), 4.51 (1H, d, J = 13.5 Hz), 4.37 (1H, d , J = 13.5 Hz), 3.67-3.60 (1H, m), 3.28-3.12 (4H, m), 2.80-2.23 (8H, m), 2.19 (3H, s), 1.83-1.77 (2H, m).

(Example 13)
4- (4-Methylpiperazin-1-yl) -5-methyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine; process C (yield 31%); ¹ H NMR (300 MHz, CDCl ₃ , δ ppm): 4.69 (2H, s), 4.53 (2H, m), 3.85 (1H, m), 3.32 (4H, m), 2.65 (1H, m), 2.39-2.54 (5H, m), 2.33 (3H, s), 1.34 (3H, d, J = 6.2 Hz).

(Example 14) (Production method D)
4 '-(Piperazin-1-yl) -5', 8'-dihydrospiro [cyclopentane-1,7'-pyrano4,3-d] pyrimidine] -2'-amine

Piperazine 180 mg (2.09 mmol) was added to a solution of the compound of Reference Example 14 50 mg (0.209 mmol) in N-methylpyrrolidinone (1.0 ml), and the mixture was heated at 160 ° C. for 1 hour under microwave irradiation (160 W). After completion of the reaction, the reaction mixture was diluted with 1N aqueous hydrochloric acid and washed with ethyl acetate. The aqueous layer was basified with aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent; chloroform: methanol) to obtain the title compound as a white solid (14.4 mg, yield 24%).
¹ H NMR (300 MHz, CDCl ₃ , δ ppm): 4.68 (2H, s), 4.52 (2H, m), 3.27 (4H, m), 2.94 (4H, m), 2.69 (2H, s), 1.66 -1.96 (6H, m), 1.55 (2H, m).

Examples 15 and 16
The corresponding starting materials were used and reacted and treated in the same manner as in Example 14 (Production D) to give the compounds of Examples 15 and 16 below.

(Example 15)
(R) -4 '-[3- (Dimethylamino) pyrrolidin-1-yl] -5', 8'-dihydrospiro (cyclopentane-1,7'-pyrano [4,3-d] pyrimidine) -2 '-Amine; (51% yield); ¹ H NMR (300 MHz, CDCl ₃ , δ ppm): 4.86 (1H, d, J = 13.9 Hz), 4.73 (1H, d, J = 13.9 Hz), 4.57 (2H, s), 3.72 (2H, m), 3.56 (1H, m), 3.38 (1H, m), 2.70 (1H, m), 2.69 (1H, d, J = 17.1 Hz), 2.59 (1H, d, J = 17.1 Hz), 2.32 (6H, s), 2.15 (1H, m), 1.48-1.97 (9H, m).

(Example 16)
1- (4- (2'-amino-5 ', 8'-dihydrospiro [cyclopentane-1,7'-pyrano [4,3-d] pyrimidin] -4'-yl) piperazin-1-yl) Ethanone; (Yield 47%); ¹ H-NMR (300 MHz, CDCl ₃ , δ ppm); 4.73 (2H, s), 4.53 (2H, s), 4.13 (2H, m), 4.09 (2H, m ), 3.69 (2H, m), 3.24 (2H, m), 2.70 (2H, s), 2.13 (3H, s), 1.94 (2H, m), 1.81 (2H, m), 1.70 (2H, m) , 1.56 (2H, m).

Example 17a (Production Method E)
(R) -4 '-(3-Aminopyrrolidin-1-yl) -5', 8'-dihydrospiro [cyclopentane-1,7'-pyrano [4,3-d] pyrimidine] -2'-amine

To a solution of the compound of Reference Example 14 in 50 mg (0.209 mmol) in dioxane (1.0 ml), (R) -tert-butylpyrrolidin-3-ylcarbamate 77 mg (0.418 mmol), N, N-diisopropylethylamine 54.0 μl (0.418 mmol) and heated at 160 ° C. for 1 hour under microwave irradiation (160 W). After completion of the reaction, the reaction mixture was subjected to liquid separation extraction with ethyl acetate-water. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: chloroform: ethyl acetate) to give (R) -tert-butyl 1- {2'-amino-5 ', 8'-dihydrospiro (cyclopentane -1,7'-pyrano [4,3-d] pyrimidine) -4'-yl} pyrrolidin-3-yl (methyl) carbamate was obtained (88.1 mg). To the obtained carbamate, 2N-hydrochloric acid / methanol (2.0 ml) was added and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. Methanol / triethylamine was added to the residue and azeotropic distillation was performed. The resulting residue was purified by amino silica gel column chromatography (elution solvent; chloroform: methanol) to obtain the title compound as a white solid. (41.2 mg, 68% yield)
¹ H NMR (300 MHz, CDCl ₃ , δ ppm): 4.79 (2H, s), 4.65 (2H, s), 3.74 (2H, m), 3.61 (2H, m), 3.29 (1H, dd, J = 10.5, 4.8 Hz), 2.64 (2H, s), 2.09 (1H, m), 1.90 (2H, m), 1.81 (2H, m), 1.71 (3H, m), 1.57 (2H, m).

Examples 17b, 18
The corresponding starting materials were used and reacted and treated in the same manner as in Example 17a (Production E) to give the compounds of Examples 17a and 18 below.

(Example 17b)
(S) -4 '-(3-Aminopyrrolidin-1-yl) -5', 8'-dihydrospiro [cyclopentane-1,7'-pyrano [4,3-d] pyrimidine] -2'-amine ;
¹ H NMR (300 MHz, CDCl ₃ , δ ppm): 4.79 (2H, s), 4.65 (2H, s), 3.74 (2H, m), 3.61 (2H, m), 3.29 (1H, dd, J = 10.5, 4.8 Hz), 2.64 (2H, s), 2.09 (1H, m), 1.90 (2H, m), 1.81 (2H, m), 1.71 (3H, m), 1.57 (2H, m).

(Example 18)
(R) -4 '-[3-Methylaminopyrrolidin-1-yl] -5', 8'-dihydrospiro (cyclopentane-1,7'-pyrano [4,3-d] pyrimidine) -2'- Amines;
¹ H NMR (300 MHz, CDCl ₃ , δ ppm): 4.79 (2H, s), 4.71 (2H, s), 3.74 (2H, m), 3.61 (2H, m), 3.38 (1H, m), 3.25 (1H, m), 2.63 (2H, s), 2.46 (3H, s), 2.09 (1H, m), 1.90 (2H, m), 1.80 (3H, m), 1.71 (2H, m), 1.52 ( 2H, m).

(Test Example 1)
H4 Receptor Binding Inhibition Test The H4 receptor binding inhibitory activity of histamine of the compound of the present invention was determined by (2,5- [ ³ H]) in a buffer solution (50 mM TrisHCl pH 7.5) for 1 hour at 25 ° C. Assayed by competitive displacement of histamine (Amersham TRK.631) to 100 μg membrane prepared from recombinant CHO-K1 (in-house constructed stable expression cell line) expressing human H4 receptor.
For some example compounds, IC ₅₀ values (nM), the concentration of compound required to inhibit 50% of the specific binding of (2,5- [ ³ H])-histamine, are shown in Table 1. It was.

As shown in Table 1, it was revealed that the compound of the present invention has a binding inhibitory activity against histamine H4 receptor.

(Test Example 2)
Ca ²⁺ Influx Inhibition Test The Ca ²⁺ influx inhibitory activity of the compounds of the present invention was measured with human H4 receptor and Gqi5 at 1 μM histamine dihydrochloride (Nacalai tex) in buffer (HBSS / 20 mM HEPES pH 7.5) As an inhibitory activity of the signal when a recombinant CHO cell (in-house constructed stable expression cell line) expressing stimuli was stimulated, it was evaluated using BD ^™ Calcium Assay Bulk Kit (BD Bioscience).
The IC ₅₀ values (nM), the concentration of compound required to inhibit 50% of 1 μM histamine Ca ²⁺ influx for some example compounds, are shown in Table 2.

As shown in Table 2, the compounds of the present invention were shown to inhibit Ca ²⁺ influx induced by histamine stimulation on the H4 receptor. That is, it was revealed that the compound of the present invention is an antagonist of H4 receptor.

Formulation Example 1: Manufacture of tablets
4- (4-Methylpiperazin-1-yl) -7-propyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine (5 g), lactose (80 g), corn starch (30 g ), Crystalline cellulose (25 g), hydroxypropyl cellulose (3 g), light anhydrous silicic acid (0.7 g) and magnesium stearate (1.3 g) were mixed and granulated by a conventional method, and 145 mg per tablet. Lock and make 1000 tablets.

Formulation Example 2: Production of powder
4- (4-Methylpiperazin-1-yl) -7-propyl-7,8-dihydro-5H-pyrano [4,3-d] pyrimidin-2-amine (10 g), lactose (960 g), hydroxypropylcellulose (25 g) and light anhydrous silicic acid (5 g) are mixed by a conventional method and then made into a powder.

The 7-substituted dihydropyranopyrimidine derivative of the present invention represented by formula (1) and a pharmaceutically acceptable salt thereof act as an antagonist of H4 receptor, and are allergic diseases, inflammatory diseases, neurogenic It can be used as a therapeutic agent or preventive agent for diseases, cancer, and sepsis.

Claims

Formula (1)

[Wherein, R 1 represents the formula (Ya)

Wherein R 8 is a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, or an unsubstituted alkanoyl group having 1 to 11 carbon atoms. And
R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and h are
(i) h is an integer of 1 to 2,
R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms or an unsubstituted carbon. A cycloalkyl group having 3 to 6 atoms, wherein h is 2, a plurality of R 11 and R 12 are each independently the same or different;
(ii) h is an integer of 1 to 2,
R 9 , R 10 , R 11 , R 12 , R 14 and R 16 are each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms or an unsubstituted C 3 to 6 carbon atom. A cycloalkyl group in which h is 2, a plurality of R 11 and R 12 are each independently the same or different;
R 13 and R 15 together form — (CH 2 ) 2 — or — (CH 2 ) 3 —,
(iii) h is an integer of 1 to 2,
R 10 , R 11 , R 12 , R 14 , R 15 and R 16 are all hydrogen atoms,
R 9 and R 13 together form — (CH 2 ) g — (where g is an integer from 1 to 2),
(iv) h is 1,
R 10 , R 11 , R 12 , R 13 , R 14 and R 16 are all hydrogen atoms,
R 9 and R 15 together form — (CH 2 ) 2 —, or
(v) h is 1,
R 9 , R 10 , R 12 , R 14 , R 15 and R 16 are all hydrogen atoms,
R 11 and R 13 together form — (CH 2 ) 2 —. )
A group represented by formula (Yb)

(In the formula, h is an integer of 1 to 2,
k is an integer of 1 to 2,
R 9 , R 10 , R 11 , R 12 , R 13 , R 15 and R 16 are each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms or an unsubstituted carbon atom of 3 And when h is 2, the plurality of R 11 and R 12 are each independently the same or different. )
A group represented by formula (Yc)

(In the formula, n is an integer of 1 to 3,
p, q and r are each independently an integer of 0 to 2;
R 17 , R 18 , R 19 and R 20 are each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, And when p is 2, a plurality of R 17 and R 18 are each independently the same or different,
R 8 is the same as described above. )
A group represented by formula (Yd)

Wherein R 8a1 and R 8a2 are
(i) each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, or
(ii) together with the nitrogen atom to which each is bonded, may form an aziridine ring, azetidine ring, pyrrolidine ring, piperidine ring, perhydroazepine ring or perhydroazocine ring;
p is an integer from 0 to 2, s is an integer from 1 to 4, and t is an integer from 0 to 4. Here, when p is 0, t is an integer from 1 to 4. And
R 17 , R 18 , R 19 and R 20 are each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms; Here, when p is 2, and when s is an integer of 2 to 4, a plurality of R 17 , R 18 , R 19 and R 20 are all independently the same or different. )
A group represented by formula (Ye)

(In the formula, one of R 21 and R 22 is a hydrogen atom, and the other is —N (R 8a1 ) (R 8a2 );
Here, R 8a1 and R 8a2 are
(i) each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, or
(ii) together with the nitrogen atom to which each is bonded, may form an aziridine ring, azetidine ring, pyrrolidine ring, piperidine ring, perhydroazepine ring or perhydroazocine ring;
u is an integer of 0-2. )
Or a group represented by formula (Yf)

(In the formula, u, v, wa and wb are each independently an integer of 1 to 2, and R 8 is the same as described above.)
A group represented by
R 2 represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms, a substituted or unsubstituted alkynyl group having 2 to 10 carbon atoms, substituted or unsubstituted Unsubstituted cycloalkyl group having 3 to 10 carbon atoms, substituted or unsubstituted cycloalkenyl group having 4 to 8 carbon atoms, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted A substituted aralkyl group having 7 to 14 carbon atoms, a substituted or unsubstituted 4- to 10-membered monocyclic or bicyclic saturated aliphatic heterocyclic group, or a substituted or unsubstituted 4- to 10-membered monocyclic or bicyclic group An unsaturated aliphatic heterocyclic group of the ring,
R 3 represents a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms, a substituted or unsubstituted alkynyl group having 2 to 10 carbon atoms. Group, substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms, substituted or unsubstituted cycloalkenyl group having 4 to 8 carbon atoms, substituted or unsubstituted aryl group, or substituted or unsubstituted heteroaryl group Or R 2 and R 3 together with the carbon atom to which they are attached may form a 3-8 membered carbon ring or a 5-8 membered heterocycle containing an oxygen atom,
R 4 , R 5 , R 6 and R 7 are each independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, or a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms. Substituted or unsubstituted alkynyl groups having 2 to 10 carbon atoms, substituted or unsubstituted cycloalkyl groups having 3 to 10 carbon atoms, substituted or unsubstituted cycloalkenyl groups having 4 to 8 carbon atoms, substituted or An unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, or R 4 and R 5 and R 6 and R 7 together may form an oxo group;
X is a hydrogen atom or an amino group. ]
Or a pharmaceutically acceptable salt thereof.
The compound according to claim 1, wherein R 8 in formula (Ya) is a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, or Its pharmaceutically acceptable salt.
R 1 is a group represented by the formula (Ya),
Formula (Yc1)

Wherein R 8 is a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, and p ′ is an integer of 1 to 2 And q ′ is an integer of 1 to 2.)
A group represented by formula (Yc2)

(Wherein, r ′ is each independently an integer of 1 to 2, and p ′ and R 8 are the same as described above.)
Or a group represented by formula (Yd1)

( Wherein R 8a1 and R 8a2 are each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, p ′ Is the same as described above, s ′ is an integer of 1 to 3, and R 17 , R 18 , R 19 and R 20 each independently represents a hydrogen atom or an unsubstituted carbon atom having 1 to 10 carbon atoms. An alkyl group or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, and when s ′ is 2 or 3, a plurality of R 17 , R 18 , R 19 and R 20 are all independently The same or different)
The compound of Claim 1 which is group represented by these, or its pharmaceutically acceptable salt.
R 1 represents the formula (Ya1)

(Wherein R 8 is a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms;
h is an integer of 1 to 2. )
A group represented by formula (Ya2)

(In the formula, g is an integer of 1 to 2, and R 8 and h are the same as described above.)
A group represented by formula (Ya3)

(Wherein R 8 is the same as described above.)
A group represented by formula (Ya4)

(Wherein R 8 is the same as described above.)
A group represented by formula (Yc1) or a group represented by formula (Yc2), or formula (Yd2)

( Wherein R 8a1 and R 8a2 are each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, p ′ Is an integer from 1 to 2, and s ′ is an integer from 1 to 3.)
A group represented by
R 2 is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms, a substituted or unsubstituted alkynyl group having 2 to 10 carbon atoms, substituted or Unsubstituted cycloalkyl group having 3 to 10 carbon atoms, substituted or unsubstituted cycloalkenyl group having 4 to 8 carbon atoms, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted A substituted aralkyl group having 7 to 14 carbon atoms, a substituted or unsubstituted 4- to 10-membered monocyclic or bicyclic saturated aliphatic heterocyclic group, or a substituted or unsubstituted 4- to 10-membered monocyclic or bicyclic group An unsaturated aliphatic heterocyclic group of the ring,
R 3 is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms, a substituted or unsubstituted alkynyl group having 2 to 10 carbon atoms Group, substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms, substituted or unsubstituted cycloalkenyl group having 4 to 8 carbon atoms, substituted or unsubstituted aryl group, or substituted or unsubstituted heteroaryl group Or a compound according to claim 1 or claim 3 wherein R 2 and R 3 together with the carbon atom to which each is attached may form a 3-8 membered carbocyclic ring, Or a pharmaceutically acceptable salt thereof.
The compound according to claim 4, wherein R 8 is a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms, or a pharmaceutically acceptable salt thereof. Salt.
R 1 represents the formula (Ya1)

(Wherein R 8 is a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms,
h is an integer of 1 to 2. )
The compound of Claim 4 which is group represented by these, or its pharmaceutically acceptable salt.
Item 7. The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 8 is an unsubstituted alkyl group having 1 to 10 carbon atoms.
R 1 represents the formula (Yd2)

Wherein R 8a1 and R 8a2 are each independently a hydrogen atom or an unsubstituted alkyl group having 1 to 10 carbon atoms, p ′ is an integer of 1 to 2, s ′ is 1 to 5 is an integer of 2.), or a pharmaceutically acceptable salt thereof.
R 2 is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms, A substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aralkyl group having 7 to 14 carbon atoms, a substituted or unsubstituted 4- to 10-membered monocyclic or bicyclic saturated group The compound according to any one of claims 1 to 8, which is an aliphatic heterocyclic group or a substituted or unsubstituted 4- to 10-membered monocyclic or bicyclic unsaturated aliphatic heterocyclic group, Or a pharmaceutically acceptable salt thereof.
R 2 is aryl-substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, unsubstituted cycloalkyl group having 3 to 10 carbon atoms, substituted or unsubstituted aryl group, or unsubstituted carbon The compound according to claim 9, which is an aralkyl group having 7 to 14 atoms, or a pharmaceutically acceptable salt thereof.
The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom or an unsubstituted alkyl group having 1 to 10 carbon atoms.
The compound according to any one of claims 1 to 8, wherein R 2 and R 3 together with the carbon atom to which each is bonded form a 3- to 8-membered ring, or a pharmaceutical thereof Acceptable salt.
R 4 and R 5 are each independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms, a substituted or unsubstituted group; The compound according to any one of claims 1 to 12, which is a cycloalkyl group having 3 to 10 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a pharmaceutical thereof Acceptable salt.
14. The compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are each independently a hydrogen atom or an unsubstituted alkyl group having 1 to 10 carbon atoms.
The compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are hydrogen atoms.
The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein X is a hydrogen atom.
The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein X is an amino group.
Formula (1a)

[Wherein R 1a represents the formula (Ya5)

(Wherein R 8a is a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms.)
Or a group represented by formula (Yd3)

( Wherein R 8a1 and R 8a2 are each independently a hydrogen atom, an unsubstituted alkyl group having 1 to 10 carbon atoms, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms; Is an integer from 1 to 3.)
A group represented by
R 2a is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aralkyl group having 7 to 14 carbon atoms,
R 3a is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, or a substituted or unsubstituted aryl group, or R 2a and R 3a together with the carbon atom to which each is bonded. You may have built a 3-8 membered ring,
X is a hydrogen atom or an amino group. ]
Or a pharmaceutically acceptable salt thereof.
The compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein R 8a is a hydrogen atom or an unsubstituted alkyl group having 1 to 10 carbon atoms.
R 1a is represented by formula (Ya5) (wherein R 8a is a hydrogen atom or an unsubstituted alkyl group having 1 to 6 carbon atoms) or formula (Yd3) (wherein R 8a1 and R 8a2 are Each independently a hydrogen atom or an unsubstituted alkyl group having 1 to 6 carbon atoms, and s ′ is 1 or 2, and R 2a is an unsubstituted carbon atom having 1 to 6 carbon atoms. Or an unsubstituted aralkyl group having 7 to 10 carbon atoms and R 3a is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or R 2a and R 3a are each bonded Together with a carbon atom to form a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring or a cyclohexyl ring, X is a hydrogen atom or an amino group. The compound of Claim 18 represented by these, or its pharmaceutically acceptable salt.
R 1a is a formula (Ya5) (wherein R 8a is a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or an isobutyl group) or a formula (Yd3) (wherein R 8a1 and R8a2 are each independently a hydrogen atom, methyl group, ethyl group, propyl group, isopropyl group, butyl group or isobutyl group, and s ′ is 1 or 2, and R 2a is , Methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, benzyl group or 2-phenylethyl group, and R 3a is a hydrogen atom, methyl group, ethyl group, propyl group, isopropyl group group, butyl group, or an isobutyl group or pentyl group, or R 2a and R 3a are, cyclopentyl or cyclohexyl together with the carbon atoms bonded thereto May have built, X is hydrogen atom or an amino group. ]
The compound of Claim 18 or Claim 19 represented by these, or its pharmaceutically acceptable salt.
A pharmaceutical composition comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof as an active ingredient.
A medicament comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof as an active ingredient.
An H4 receptor antagonist comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof as an active ingredient.
An antiallergic agent comprising as an active ingredient the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.
An anti-inflammatory agent comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof as an active ingredient.
A therapeutic agent for pain comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof as an active ingredient.
An allergic conjunctivitis, allergic rhinitis, chronic urticaria, atopic dermatitis, asthma containing the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof as an active ingredient , Therapeutic agent or preventive agent for chronic bronchitis, ulcerative colitis, Crohn's disease, rheumatism, pain, cancer, sepsis or chronic obstructive pulmonary disease.
Use of the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof for the manufacture of an antiallergic agent.
Use of the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof for the manufacture of an anti-inflammatory agent.
Allergic conjunctivitis, allergic rhinitis, chronic urticaria, atopic dermatitis, asthma, chronic bronchitis, ulcerative colitis, Crohn's disease, rheumatism, pain, cancer, sepsis or chronic obstructive pulmonary disease Use of the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof for the production of
The prevention of an antiallergic disease and / or an antiinflammatory disease, characterized by administering an effective amount of the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof. Or treatment method.
The method for prevention or treatment according to claim 32, wherein the antiallergic disease is allergic conjunctivitis, allergic rhinitis, chronic urticaria, atopic dermatitis, asthma, or chronic bronchitis.
The prevention or treatment method according to claim 32, wherein the anti-inflammatory disease is ulcerative colitis, Crohn's disease, rheumatism, chronic obstructive pulmonary disease, or pain.