Carboxylic acid compound and medical compositions containing thereof as active ingredient


FIELD: medicine.

SUBSTANCE: carboxylic acid compounds are presented by formula (I) where R1 represents (1) hydrogen atom, (2) C1-4alkyl; E represents -CO-; R2 represents (1) halogen atom, (2) C1-6 alkyl, (3) trihalogen methyl; R3 represents (1) halogen atom, (2) C1-6alkyl; R4 represents (1) hydrogen atom; R5 represents (1) C1-6alkyl; represents phenyl; G represents (1) C1-6alkylene; represents 9-12-merous bicyclic heterocycle containing heteroatoms, chosen of 1-4 nitrogen atoms, one or two oxygen atoms; m represents 0 or an integer 1 to 4, n represents 0 or an integer 1 to 4, and i represents 0 or an integer 1 to 11 where R2 can be identical or different provided m is equal to 2 or more, R3 can be identical or different provided n is equal to 2 or more, and R5 can be identical or different provided i is equal to 2 or more; both R12 and R13, independently represent (1) C1-4alkyl, (2) halogen atom, (3) hydroxyl or (4) hydrogen atom, or R12 and R13 together represent (1) oxo or (2) C2-5alkylene and where provided R12 and R13 simultaneously represent hydrogen atom, carboxylic acid compound presented by formula (I), represents a compound chosen from the group including the compounds (1) - (32), listed in cl.1 of the patent claim. Besides the invention concerns a pharmaceutical composition based in the compound of formula I and to application of the compound of formula I for making the pharmaceutical composition.

EFFECT: there are produced new carboxylic acid derivatives with antagonistic activity with respect to DP receptor.

14 cl, 74 ex

 

The invention relates to (1) coupling the carboxylic acid represented by the formula (I)

where all the symbols have the meanings as set forth herein, its salts, solvate and his proletarienne forms,

(2) method of its production,

(3) to pharmaceutical compositions containing them as active ingredient, and

(4) its use.

Prostaglandin D2(abbreviated PGD2known as one of the metabolites formed via the arachidonic acid cascade, and is considered one of the chemical mediators involved in allergic diseases such as allergic rhinitis, bronchial asthma and allergic conjunctivitis. It is known that PGD2mainly formed in mastocyte and released from them and that released PGD2shows narrowing of the bronchi, stimulation of vascular permeability, expansion or narrowing of blood vessels, stimulation in mucus secretion and inhibition of platelet aggregation. It was also reported that PGD2causes bronchostenosis and plugging nosein vivoand the production of excessive quantities of PGD2on the site of pathological lesions in patients suffering from systemic mastocytosis, allergic rhinitis, bronchial asthma, atopic dermatitis, urticaria, etc. (N. Engl. J. Med. 1989; 303: 1400-4 Am. Rev. Respir. Dis. 1983; 128: 597-602, J. Allergy Clin. Immunol. 1991; 88: 33-42, Arch. Otolaryngol. Head Neck Surg. 1987; 113: 179 - 83, J. Allergy Clin. Immunol. 1988; 82: 869-77, J. Immunol. 1991; 146: 671-6, J. Allergy Clin. Immunol. 1989; 83: 905 - 12, N. Eng. J. Med. 1986; 315: 800-4, Am. Rev. Respir. Dis. 1990; 142, 126-32, J. Allergy Clin. Immunol. 1991; 87: 540-8, J. Allergy Clin. Immunol 1986; 78: 458-61). PGD2that also was reported that participates in neural activity, in particular, in the process of sleep, hormone secretion, and pain. In addition, there were reports that he is involved in platelet aggregation, glycogen metabolism and the regulation of intraocular pressure.

PGD2exerts its biological activity through binding to DP receptor, which is one of the receptors PGD2. Since the DP receptor antagonists bind to their receptor and exhibit antagonistic activity, it is assumed that the DP receptor antagonists applicable for the prevention and/or treatment of diseases such as allergic diseases (e.g. allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma and food Allergy), systemic mastocytosis, disorders accompanied by systemic activation of mastocytes, anaphylactic shock, bronchostenosis, urticaria, eczema, acne, allergic bronchial pulmonary aspergillosis, sinusitis, migraine, nasal polypus, anaphylactic vasculitis, eosinophilic syndrome, contact dermatitis,diseases, accompanied by itch (such as atopic dermatitis, urticaria, allergic conjunctivitis, allergic rhinitis and contact dermatitis), diseases (such as cataract, retinal detachment, inflammation, infection and sleeping disorders)which arise secondarily as a result of behavior accompanied by itch (such as scratching and beat up), inflammation, chronic obstructive pulmonary diseases, ischemic reperfusion lesion, stroke, autoimmune disease, traumatic brain injury, hepatopathy, graft rejection, chronic rheumatoid arthritis, pleurisy, osteoarthritis, Crohn's disease, ulcerative colitis, symptoms of increased irritability of the intestines, interstitial cystitis, muscular dystrophy, polymyositis, multiple sclerosis, etc. He is also involved in the sleep process and in platelet aggregation and probably also applicable in these diseases.

For example, in the description WO86/05779 compounds represented by formula (T)

(in the formula ATrepresents a hydrogen atom, phenyl or phenoxy; nTrepresents an integer from 3 to 10; R1Trepresents a hydrogen atom or lower alkoxy; X1Trepresents-CH2-Y1T- (in the group Y1Tmeans-O-, -S - or-NH-), -CO-Y2T- (in the group

Y2Tmeans-O-, -S - or-NH -), etc.; represents a group represented by the formulaand the like; R2Trepresents a hydrogen atom, halogen atom, nitro, hydroxyl, lower alkoxy, cyano, lower alkyl, lower alkoxy-lower alkyl, halogen-lower alkyl or a group represented by-NR4TR5T-, and the like; X2Trepresents the formula-Y3T-Y4T- (in the group Y3Tmeans a single bond, -O-, -S - or-NH - and Y4Trepresents C1-6 alkylene, which can be interrupted by a sulfur atom) and the like; and DT means carboxyl or lower alkoxycarbonyl and the like), applicable as antagonists for SRS-A (slow reacting substance of anaphylaxis).

Among the receptors of prostaglandin many receptor subtypes, and each of them has specific pharmacological action. So, if new compounds that specifically bind to receptors DP and little contact with other prostaglandin receptors can be detected, they can be pharmaceutical agents having a minor side effect, since no other functions are not introduced. Therefore, such pharmaceutical agents you want to find.

Were conducted intensive studies to identify compounds that specifically bind to receptors DP and show antagonistic activity, and the result was the OBN is hidden, the compounds of carboxylic acids represented by the formula (I), solve the problem with the completion of this invention.

Thus, this invention relates to the next.

1. Connection carboxylic acid represented by the formula (I)

where R1represents (1) hydrogen atom, (2) C1-4 alkyl, (3) C2-4 alkenyl or (4) benzyl;

E represents-CO-, -SO2- or-CH2-;

R2is (1) halogen atom, (2) C1-6 alkyl, (3) C1-6 alkoxy, (4) hydroxyl, (5) trihalomethyl, (6) cyano, (7) phenyl, (8) pyridyl, (9) nitro, (10) -NR6R7or (11) C1-4 alkyl, substituted OR8, (12) oxidized C1-6 alkyl, (13) -SO2R11, (14) -SOR11or (15) -SR11or two substituent R2on adjacent carbon atoms together represent (1) C2-5 alkylene, which can be substituted by the Deputy, one carbon atom of which may be replaced by oxygen atom, nitrogen atom or sulfur atom which may be oxidized, or (2) C2-5 albaniles, which can be substituted by the Deputy, one carbon atom of which may be replaced by oxygen atom, nitrogen atom or sulfur atom;

R3is (1) halogen atom, (2) C1-6 alkyl, (3) C1-6 alkoxy, (4) hydroxyl, (5) trihalomethyl, (6) cyano, (7) phenyl, (8) pyridyl, (9) nitro, (10) -NR6R7or (11) C1-4 alkyl, substituted OR8, (12) oxidized C1 - alkyl, (13) -SO2R11, (14) -SOR11or (15) -SR11;

R6and R7each independently represent a hydrogen atom or C1-4 alkyl;

R8represents C1-4 alkyl, phenyl or pyridyl;

R4represents (1) hydrogen atom, (2) C1-6 alkyl, (3) benzyl or (4) oxidized C1-6 alkyl;

R5represents (1) C1-6 alkyl, (2) C1-10 alkoxy, (3) C1-6 alkyl, substituted C1-6 alkoxy, (4) halogen atom, (5) hydroxyl, (6) trihalomethyl, (7) nitro, (8) -NR9R10, (9) phenyl, (10) phenoxy, (11) oxo, (12) C2-6 acyl, (13) cyano or (14) -SO2R11, (15) -SOR11, (16) -SR11, (12) oxidized C1-6 alkyl;

R9and R10each independently represent a hydrogen atom or C1-4 alkyl, and

R11represents C1-6 alkyl or phenyl which may be substituted;

where the radicals R6- R11in the radicals R2- R5may be the same or each independently different;

represents a C5-12 monocyclic or bicyclic carbocyclic ring, or 5-12 membered monocyclic or bicyclic a heterocycle;

G represents (1) C1-6 alkylene having from 0 to 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, (2) C2-6 albaniles having from 0 to 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, or (3) C2-6 akinyan having from 0 to 2 heteroatoms, wybranych nitrogen atom, oxygen atom and sulfur atom;

represents a C5-12 monocyclic or bicyclic carbocyclic ring, or 5-12 membered monocyclic or bicyclic a heterocycle;

m represents 0 or an integer from 1 to 4

n represents 0 or an integer from 1 to 4, and

i represents 0 or an integer from 1 to 11,

where R2may be the same or different when m is 2 or more, R3may be the same or different when n is 2 or more, and R5may be the same or different, when i is 2 or more; and

R12and R13each independently represent (1) C1-4 alkyl, which can be oxidized, (2) halogen atom, (3) trihalomethyl, (4) hydroxyl which may be protected, (5) an amino group which may be protected, (6) phenyl which may be substituted, (7) pyridyl which may be substituted, or (8) a hydrogen atom, or R12and R13taken together, represent (1) oxo, (2) C2-5 alkylene, which can be substituted by the Deputy, one carbon atom of which may be replaced by oxygen atom, nitrogen atom or sulfur atom, or (3) C1-6 alkylidene, which may be substituted, and

where, when R12and R13both simultaneously represent a hydrogen atom, the compound of carboxylic acid represented by the formula (I), represents the Association, selected from the group consisting of the following compounds(1)-(32);

(1) (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)acetic acid,

(2) (4-chloro-3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(3) (4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(4) (4-chloro-3-((5-chloro-2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(5) (4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(6) (4-chloro-3-((2-fluoro-5-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(7) (4-chloro-3-((2,5-debtor-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(8) (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)acetic acid,

(9) (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-were)acetic acid,

(10) (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(11) (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic Ki the lot,

(12) (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-were)acetic acid,

(13) (5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-forfinal)acetic acid,

(14) (5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-were)acetic acid,

(15) (5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-forfinal)acetic acid,

(16) (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(17) (5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-forfinal)acetic acid,

(18) (5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-were)acetic acid,

(19) (5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-were)acetic acid,

(20) (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)acetic acid,

(21) (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)acetic acid,

(22) (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)acetic acid,

(23) (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)acetic acid,

(24) (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-were)acetic acid,

(25) (4-chloro-3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid,

(26) (2-chloro-5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(27) (2-chloro-5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(28) (2-chloro-5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(29) (4-chloro-3-((4-((3R)-2,3-dihydro-1-benzofuran-3-ylethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid,

(30) (4-chloro-3-((2,6-dimethyl-4-(((3R)-5-methyl-2,3-dihydro-1-benzofuran-3-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(31) (4-chloro-3-((4-((2S)-2,3-dihydro-1-benzofuran-2-ylethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid and

(32) (3-((4-(1,3-benzodioxol-2-ylethoxy)-2,6-dimethylbenzoyl)amino)-4-chlorophenyl)acetic acid, and their salts, solvate or proletarienne form.

2. The compound according to claim 1, where the symbolrepresents a group of the formula

where the symbolis C5-6 saturated carbocyclic ring, or a 5-6-membered saturated, the heterocycle containing one Elida nitrogen atom, one or two oxygen atom and/or sulfur atom;

designationis C5-6 saturated carbocyclic ring, or a 5-6-membered saturated, a heterocycle containing one or two nitrogen atom, one or two oxygen atom and/or sulfur atom;

represents a single or double bond; and

other symbols have the same meanings defined in claim 1, its salt, its MES or proletarienne form.

3. The compound according to claim 2, where a group of the formularepresents a group selected from dihydroisoxazole-2-yl, benzodioxan-2-yl, benzoxazin-2-yl, dihydrobenzofuran-2-yl, dihydrobenzofuran-3-yl, benzodioxan-2-yl, indolin-2-yl and indolin-3-yl.

4. The compound according to claim 2, where n means an integer from 2 to 4.

5. The compound according to claim 4, where a group of the formularepresents a group of the formulawhere all the symbols are indicated in claim 1 values.

6. The compound according to claim 5, where a group of the formularepresents the grouporwhere all the symbols are indicated in claim 1 values.

7. The connection according to claim 6, where the radicals R3each independently represent (1) halogen atom, (2) C1-6 alkyl, (3) C1-6 alkoxy or (4) trihalomethyl.

8. Joint who according to claim 2, where R12and R13each independently represent (1) C1-4 alkyl, (2) halogen atom, (3) hydroxyl which may be protected, or (4) a hydrogen atom, or R12and R13taken together, represent (1) oxo, or (2) C2-5 alkylene, which can be substituted by the Deputy, where one carbon atom may be replaced by oxygen atom, nitrogen atom or sulfur atom.

9. The connection according to claim 7, which is selected from the following:

(1) 2-(4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

(2) (4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(debtor)acetic acid,

(3) (4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(oxo)acetic acid,

(4) 2-(4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

(5) 2-(4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

(6) 2-(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)-2-methylpropanoate acid,

(7) 1-(4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)cyclopropanecarbonyl acid,

(8) 1-(4-chloro-3-((2,5-dimethyl-4-(((2S)-4-ethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)cyclopropanecarbonyl acid,

(9) 1-(4-chloro-3-((2-ethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)cyclopropanecarbonyl acid,

(10) (4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid and

(11) (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-were)acetic acid.

10. Pharmaceutical compositions containing the compound represented by formula (I)

where all symbols have the same meanings as specified in claim 1, its salt, its MES or Palekastro form.

11. The pharmaceutical composition of claim 10, which is a DP receptor antagonist.

12. The pharmaceutical composition of claim 10, which is an agent for prevention and/or treatment of diseases mediated by receptor DP.

13. The pharmaceutical composition according to item 12, where a disease mediated by receptor DP, an allergic disease, systemic mastocytosis, disorders accompanied by systemic activation of mastocytes, anaphylactic shock, bronchostenosis, urticaria, eczema, acne, allergic bronchial pulmonary aspergillosis, sinusitis, migraine, nasal polypus, anaphylactic vasculitis, eosinophilic syndrome, contact dermatitis, diseases accompanied by itch, diseases that occur in again is the result of behavior, accompanied by itching, inflammation, chronic obstructive pulmonary diseases, ischemic reperfusion lesion, stroke, autoimmune disease, traumatic brain injury, hepatopathy, graft rejection, chronic rheumatoid arthritis, pleurisy, osteoarthritis, Crohn's disease, ulcerative colitis, symptoms of increased irritability of the intestines, interstitial cystitis, muscular dystrophy, polymyositis, multiple sclerosis, sleep disorders or disease related to platelet aggregation.

14. The pharmaceutical composition according to item 13, where the allergic disease is allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma or food Allergy.

15. Pharmaceutical compositions containing a combination of compounds represented by formula (I) according to claim 1, its salt, its MES or proletarienne form and one or more other agents selected from such as antihistaminic agent, suppressor of release of mediators, an inhibitor of thromboxane synthetase, receptor antagonist of the thromboxane A2 receptor antagonist leukotriene, a steroid agent, stimulant alpha-adrenergic receptor, a derivative of xanthine, anticholinergic agent and inhibitor synthase nitric oxide.

16. The use of compounds represented by formula (I)according to claim 1, its salt, it is of Lata or proletarienne molds for the production of pharmaceutical compositions for the prevention and/or treatment of diseases, mediated by receptor DP.

17. The use of compounds represented by formula (I)according to claim 1, its salt, its MES or proletarienne form to get the DP receptor antagonist.

18. The method of prevention and/or treatment of diseases mediated by receptor DP, which includes an introduction to the mammal an effective amount of the compound represented by formula (I)according to claim 1, its salt, its MES or proletarienne form.

In this specification, C1-4 alkyl includes linear or branched alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

In this specification, C1-6 alkyl includes linear or branched alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and isohexyl.

In this specification, C2-4 alkenyl includes linear or branched alkenyl, such as ethynyl, propenyl and butenyl.

In this specification, C1-6 alkoxy includes linear or branched alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentylamine, neopentylene, hexyloxy, etexilate.

In this specification, the C1-10 alkoxy includes linear or branched alkoxy selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobolic and, Deut-butoxy, tert-butoxy, pentyloxy, isopentylamine, neopentylene, hexyloxy, etexilate, heptyloxy, octyloxy, nonyloxy, decyloxy.

In this specification, C2-6 acyl includes linear or branched acyl, such as ethanol, propanol, butanol, 2-methylpropanol, pentanoyl, 2-methylbutanoyl, 3-methylbutanoyl, hexanoyl, 2-methylpentanol, 3-methylpentanol, 4-methylpentanol, 2-ethylbutanol and 2,3-dimethylbutanol.

In this specification, the halogen atom includes fluorine atom, chlorine atom, bromine atom and iodine atom.

In this description, trihalomethyl represents methyl substituted by three halogen atoms.

In this specification, C1-4 alkylene includes linear or branched alkylene, such as methylene, ethylene, propylene, isopropylene, butylene and isobutylene.

In this specification, C2-4 albaniles includes linear or branched albaniles, such as vinile, propylen, 1 - or 2-butylen and butadiene.

In this specification, C2-4 akinyan includes linear or branched akinyan, such as ethynylene, 1 - or 2-propylen and 1 - or 2-Butyrin.

In this specification, C1-6 alkylene containing from 0 to 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, include linear or branched alkylene, such as methylene, ethylene, propylene, isopropylene, butylene, isobutylene, pentile, hexylen, or LINEST is th or branched C1-6 alkylene, in which one or two carbon atoms in the methylene, ethylene, propylene, isopropylene, butylene, isobutylene, pentylene and hexylene substituted by one or two heteroatoms selected from a nitrogen atom (the residual connection of the indicated nitrogen atom linked to a hydrogen atom, C1-6 alkyl, C2-6 acyl or C1-6 alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl etc.)), oxygen atom and sulfur atom, for example, linear or branched C1-6 alkylene containing one or two heteroatoms selected from a nitrogen atom, oxygen atom and sulfur atom,- (CH2)2-NH-, -(CH2)2-N(CH3)-, -(CH2)2-O-, -(CH2)2-S-, -(CH2)3-NH-, -(CH2)3-N(CH3)-, -CH2-CH(CH3)-CH2-NH-, -CH2-CH(CH3)-CH2-N(CH3)-, -(CH2)3-O - and -(CH2)3-S-, where a single carbon atom in alkylene associated with the adjacent-O-.

In this specification, C2-6 albaniles having from 0 to 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, include linear or branched albaniles, such as vinile, propylen, 1 - or 2-butylen, butadienyl, penttinen and hexarelin, or C2-6 albaniles, in which one or two carbon atoms in vinylene, propylene, 1 - or 2-butylene, butadiene, pentylene and hexanite substituted by one or two of the heteroatoms, selected from a nitrogen atom (the residual connection of the indicated nitrogen atom bound to a hydrogen atom, C1-6 alkyl, C2-6 acyl or C1-6 alkoxycarbonyl (for example, methoxycarbonyl and etoxycarbonyl, tert-butoxycarbonyl etc.)), oxygen atom and sulfur atom, for example, linear or branched C2-6 albaniles containing one or two heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom,- CH=CH-NH-, -CH=CH-N(CH3)-, -CH=CH-O-, -CH=CH-S-, -CH=CH-CH2-NH-, -CH=CH-CH2-N(CH3)-, -CH=CH-CH2-O - and-CH=CH-CH2-S-, where only the carbon atom in alkeneamine associated with the adjacent-O-.

In this specification, C2-6 akinyan having from 0 to 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, include linear or branched akinyan, such as ethynylene, 1 - or 2-propylen, 1 - or 2-Butylin, pentikinen and geksanalem, or C2-6 akinyan, in which one or two carbon atoms in the ethynylene, 1 - or 2-propylene, 1 - or 2 - butenolide, pentylidene, hexylamine and hexanite substituted by one or two heteroatoms selected from a nitrogen atom (the residual connection of the indicated nitrogen atom bound to a hydrogen atom, C1-6 alkyl, C2-6 acyl or C1-6 alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl etc.)), oxygen atom and sulfur atom, for example, linear or branched C2-6 alkyne is len, containing one or two heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom,- C≡C-NH-, -C≡C-N(CH3)-, -C≡C-O-, -C≡C-S-, -C≡C-CH2-NH-, -C≡C-CH2-N(CH3)-, -C≡C-CH2-O - and-C≡C-CH2-S-, where only the carbon atom in alkeneamine associated with the adjacent-O-.

In this description oxidized C1-6 alkyl includes C1-6 alkyl, substituted by 1-3 hydroxyl groups and/or 1-3 exography, where the carbon atom is attached to two or more hydroxyl groups and/or oxoprop limited to the carbon atom at the terminal position, such as hydroxymethyl, formyl, carboxy, 2-hydroxyethyl, 2-oxoethyl, carboxymethyl, 1-hydroxyethyl, acetyl, 3-hydroxypropyl, 3-oxopropyl, 2-carboxyethyl, 2-hydroxypropyl, 2-oxopropyl, 1-hydroxy-1-methylethyl, 4-hydroxybutyl, 4-oxobutyl, 3-carboxypropyl, 3-hydroxybutyl, 3-oxobutyl, 3-hydroxy-2-methylpropyl, 2-methyl-3-oxopropyl, 2-carboxypropyl, 2-hydroxy-2-methylpropyl, 3-hydroxy-1-methylpropyl, 1-methyl-3-oxopropyl, 2-carboxy-1-methylethyl, 2-hydroxy-1-methylpropyl, 1-methyl-2-oxopropyl, 1-hydroxy-1-methylpropyl, 1-hydroxymethylpropane, 1-formylpropyl, 1-carboxypropyl, 2-hydroxy-1,1-dimethylethyl, 1,1-dimethyl-2-oxoethyl and 1-carboxy-1-methylethyl etc.

In this specification, C1-4 alkyl, which can be oxidized, includes C1-4 alkyl which may be substituted by 1-3 hydroxy groups and/who do 1-3 exography, where the carbon atom is attached to two or more hydroxyl groups and/or oxoprop limited to the carbon atom at the terminal position, such as linear or branched C1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, hydroxymethyl, formyl, carboxy, 2-hydroxyethyl, 2-oxoethyl, carboxymethyl, 1-hydroxyethyl, acetyl, 3-hydroxypropyl, 3-oxopropyl, 2-carboxyethyl, 2-hydroxypropyl, 2-oxopropyl, 1-hydroxy-1-methylethyl, 4-hydroxybutyl, 4-oxobutyl, 3-carboxypropyl, 3-hydroxybutyl, 3-oxobutyl, 3-hydroxy-2-methylpropyl, 2-methyl-3-oxopropyl, 2-carboxypropyl, 2-hydroxy-2-methylpropyl, 3-hydroxy-1-methylpropyl, 1-methyl-3-oxopropyl, 2-carboxy-1-methylethyl, 2-hydroxy-1-methylpropyl, 1-methyl-2-oxopropyl, 1-hydroxy-1-methylpropyl, 1-hydroxymethylpropane, 1-formylpropyl, 1-carboxypropyl, 2-hydroxy-1,1-dimethylethyl, 1,1-dimethyl-2-oxoethyl, 1-carboxy-1-methylethyl etc.

In this description of the protective group in the hydroxyl which may be protected", and "amino group which may be protected", includes, for example, alkyl which may have substituents, carbocyclic ring which may have a Deputy (deputies), a heterocycle which may have a Deputy (deputies), alkylsulfonyl (for example, C1-4 alkylsulfonyl and the like, such as methylsulphonyl, ethylsulfonyl and p), aromatic ring-sulfonyl (for example, C6-10 aromatic cyclic ring sulfonyl etc. such as phenylsulfonyl etc.), accelgroup etc. Alkyl in the "alkyl which may have a Deputy (deputies)"includes, for example, linear or branched C1-20 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, Needell, icosyl etc. Deputy in the "alkyl which may have a Deputy (deputies)includes hydroxyl, amino, carboxy, nitro, azide, mono - or di-C1-6 alkylamino (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino and the like), N-aromatic ring amino (for example, N-phenylamino and the like), N-aromatic ring-N-alkylamino (for example, N-phenyl-N-methylamino, N-phenyl-N-ethylamino, N-phenyl-N-propylamino, N-phenyl-N-butylamino, N-phenyl-N-pentylamine, N-phenyl-N-hexylamino and the like), C1-6 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, hexyloxy and the like), C3-7 cycloalkyl-C1-6 alkoxy (for example, cyclohexylmethoxy, cyclopentyloxy and the like), C3-7 cycloalkane (for example, cyclohexyloxy and the like), C7-15 Arakelots (for example, benzyloxy, penetrate, phenylpropoxy, naphthalenyloxy, negotiations etc.), phenoxy, C1-6 alkoxyaryl the sludge (for example, tert-methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl and the like), C1-4 alkylthio (for example, methylthio, ethylthio, propylthio, butylthio and the like), halogen atom (fluorine atom, chlorine atom, bromine atom and iodine atom), alkylsulfonyl (for example, C1-4 alkylsulfonyl and the like, such as methylsulphonyl, ethylsulfonyl and the like), aromatic ring-sulfonylurea (for example, C6-10 aromatic ring-sulfonyl etc. such as phenylsulfonyl and the like), acyl (e.g., C1-6 alkanoyl and so, such as formyl, acetyl, propanol and pivaloyl, and C6-10 aromatic ring-carbonyl and the like, such as benzoyl and the like) and the like, the Alkyl may be substituted by 1-4 arbitrary substituents in the substituted position. Carbocyclic ring in "carbocyclic ring which may have a Deputy (deputies)" includes C3-15 monocyclic, disilicate or tricyclic aromatic carbocyclic ring which may be saturated or fully or partially.

C3-15 monocyclic, disilicate or tricyclic aromatic carbocyclic ring which may be saturated or fully or partially, includes cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, Cycloheptane, cyclooctane, cyclonona, cyclodecane, cyclodecane, cyclododecane, cycletrader, collaterality, cyclopentadecane, cyclopropene, cyclobutene, cyclopentene, College the Saint, cyclohepten, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, naphthalene, azulene, pergerson, perhydroanthracene, inden, palikonda, indan, naphthalene, tetrahydronaphthalene, peridontal, geptalen, biphenylene, as-indocin, s-indocin, acenaphthylene, acenaphthene, fluorene, finale, phenanthrene, anthracene, etc.

C3-15 monocyclic, disilicate or tricyclic aromatic carbocyclic ring which may be saturated or fully or partially, includes bicyclic carbocyclic ring containing Spiro-linkage and designed bicyclic carbocyclic ring, such as Spiro[4,4]nonan, Spiro[4,5]decane, Spiro[5,5]undecane, bicyclo[2,2,1]heptane, bicyclo[2,2,1]hept-2-ene, bicyclo[3,1,1]heptane, bicyclo[3,3,1]hept-2-ene, bicyclo[2,2,2]octane, bicyclo[2,2,2]Oct-2-ene, the ring of Adamantine, nordmanniana etc.

The substituent in the "carbocyclic ring which may have a Deputy (deputies)" includes C1-8 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like), hydroxyl, amino, carboxyl, nitro, mono - or di-C1-6 alkylamino (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino and the like), C1-6 alkoxy (e.g. methoxy, ethoxy, propoxy, hexyloxy and the like), C1-6 alkoxycarbonyl (for example, tre is methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl and the like), C1-6 alkylcarboxylic (for example, acetoxy, ethylcarbonate and the like), C1-4 alkylthio (for example, methylthio, ethylthio, propylthio, butylthio and the like), halogen atom (fluorine atom, chlorine atom, bromine atom and iodine atom), trihalomethyl (for example, trifluoromethyl and the like) and the like, Carbocyclic ring may be substituted by 1-4 arbitrary substituents in the substituted position. The heterocycle in the "heterocycle which may have a Deputy (deputies)includes 3-15 membered monocyclic, disilicate or tricyclic aromatic heterocycle which may be saturated or fully or partially containing from 1 to 5 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom. Among 3-15 membered monocyclic, dicklicker or tricyclic heterocycle which may be saturated or fully or partially containing from 1 to 5 heteroatoms selected from oxygen atom, nitrogen atom or sulfur atom, 3-15 membered monocyclic, disilicate or tricyclic aromatic heterocycle containing from 1 to 5 heteroatoms selected from oxygen atom, nitrogen atom or sulfur atom, includes, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, azepine, diazepine, furan, Piran, oxepin, thiophene, tiin, tiepin, oxazol, isoxa the ol, the thiazole, isothiazol, furazan, oxadiazole, oxazin, oxadiazon, oxazepine, oxadiazon, thiadiazole, teasin, thiadiazin, diazepin, thiadiazin, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzofuran, ditionally, indazole, quinoline, isoquinoline, hemolysin, purine, phthalazine, pteridine, naphthiridine, cinoxacin, hinzelin, cinnolin, benzoxazole, benzothiazole, benzimidazole, chrome, benzocain, benzoxazepin, benzodiazepin, benzothiophen, benzodiazepin, benzodiazepin, benzazepin, benzodiazepine, benzofurazan, benzothiadiazole, benzotriazole, carbazole, beta carboline, acridine, fenesin, dibenzofuran, Xanten, dibenzothiophen, phenothiazines, phenoxazin, phenoxathiin, tianren, penetratin, phenanthrolin, pyrimidin etc. Among 3-15 membered monocyclic, dicklicker or tricyclic heterocycle which may be saturated or fully or partially containing from 1 to 5 heteroatoms selected from oxygen atom, nitrogen atom or sulfur atom, 3-15 membered monocyclic, disilicate or the tricyclic heterocycle which is saturated or fully or partially containing from 1 to 5 heteroatoms selected from oxygen atom, nitrogen atom or sulfur atom includes aziridine, azetidine, pyrrolin, pyrrolidin, imidazolin, imidazolidine, triazoline, thiazolidin, tetrazolyl, tetraza the one, pyrazolin, pyrazolidine, dihydropyridines, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, dihydropyrimidine, tetrahydropyrimidine, targetability, dihydropyridin, tetrahydropyridine, targetability, dehydroacetic, tetrahydroazepine, peligrosa, dihydrovitamin, tetrahydroazepine, targetrotation, oxiran, oxetan, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dehydroacetic, tetrahydroazepine, perhydroxyl, thiran, tieton, dihydrothiophene, tetrahydrothiophene, dehydration (dihydrothiophene), tetrahydrate (tetrahydrothiopyran), dihydrothiophene, tetrahydrothiophene, pengertian, dihydrooxazolo, tetrahydrooxazolo (oxazolidine), dihydroisoxazole, tetrahydrooxazolo (isoxazolidine), dihydrothiazolo, tetrahydrothieno (thiazolidin), dihydroisoxazole, tetrahydrocortisol (isothiazolin), dihydrofuran, tetrahydrofuran, dihydroimidazole, tetrahydrocortisol (oxadiazolidine), dihydrooxazolo, tetrahydrooxazolo, Dihydrocodeine, tetrahydroimidazo, dihydrooxazoles, tetrahydroazepine, perhydroxyl, dihydroxyvitamin, tetrahydroazepine, perhydroanthracene, dihydroeugenol, tetrahydrocortisol (thiadiazolidin), dihydrotriazine, tetrahydrothiophene, dihydrokavain, tetrahydrolipstatin, dihydrothiazine, tet is hydrotussin, targetrotation, dihydrokavain, tetrahydroazepine, targetrotation, morpholine, thiomorpholine, Ossetian, indolin, isoindoline, dihydrobenzofuran, perhydroanthracene, dihydroisobenzofuran, peligrosamente, dihydrobenzofuran, perhydrophenanthrene, dihydroindol, peritoneal, dihydroquinoline, tetrahydroquinoline, perhydroxyl, dihydroisoquinoline, tetrahydroisoquinoline, perhydrosqualene, dihydrophenazine, tetrahydrophthalate, PermitRootLogin, dihydronaphthalene, tetrahydronaphthalene, perhydroanthracene, dihydroquinoxaline, tetrahydroquinoxalin, perhydrophenanthrene, dihydroquinazolin, tetrahydroquinazolin, perhydrophenanthrene, dihydroindole, tetrahydroindole, permitiendoles, benzocain, dihydroisoxazole, dihydrobenzofuran, pyrazinamidase, dihydroisoxazole, perhydroanthracene, dihydrobenzofuran, perhydroanthracene, dehydrobenzperidol, perhydroanthracene, digitalisation, tetrahydrobenzene, dihydrobenzofuran, tetrahydrolipstatin, benzodioxepin, dihydroisoxazole, tetrahydrobenzoic, dihydrocarvone, tetrahydrocarbazol, perhydrogenized, dihydrouridine, tetrahydrouridine, perhydrosqualene, dihydrobenzofuran, dihydroisobenzofuran, tetrahydroxybenzophenone, tetrahydrolipstatin, perperties the Russian Academy of Sciences, perhydrophenanthrene, dioxolane, dioxane, ditiolan, Titian, dioksiinien, benzodioxan, chroman, benzodithiol and benzodithiol etc. Deputy in the "heterocycle which may have a Deputy (deputies)," includes C1-8 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like), hydroxyl, amino, carboxyl, nitro, mono - or di-C1-6 alkylamino (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino and the like), C1-6 alkoxy (e.g. methoxy, ethoxy, propoxy, hexyloxy and the like), C1-6 alkoxycarbonyl (for example, tert-methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl and the like), C1-6 alkylcarboxylic (for example, acetoxy, ethylcarbonate and the like), C1-4 alkylthio (for example, methylthio, ethylthio, propylthio, butylthio and the like), halogen atom (fluorine atom, chlorine atom, bromine atom and iodine atom), trihalomethyl (for example, trifluoromethyl and the like), etc. the Heterocycle may be substituted by 1-4 arbitrary substituents in the substituted position. Acyl includes (1) alkylsulphonyl, which may have a Deputy (deputies), (2) alkenylboronic, which may have a Deputy (deputies), (3) alkynylaryl, which may have a Deputy (deputies), (4) carbocyclic carbonyl group which may have a Deputy (deputies), (5) heterocyclic carb is niloy group, which may have a Deputy (deputies). Acyl may be substituted by 1-4 arbitrary substituents in the substituted position. Alkyl which may have a Deputy (deputies) in the "alkalicarbonate, which may have a Deputy (deputies)", means the same as "alkyl which may have a Deputy (deputies)". Alkenyl, which may have a Deputy (deputies) in the "alkenylboronic, which may have a Deputy (deputies)"includes, for example, linear or branched C2-20 alkenyl etc., such as ethynyl, propenyl, butenyl, pentenyl, hexenyl etc. Deputy in alkenyl means the same as the substituent in the aforementioned "alkyl which may have a Deputy (deputies)". Quinil, which may have a Deputy (deputies) in the "alkynylaryl, which may have a Deputy (deputies)"includes, for example, linear or branched C2-20 quinil etc. such as ethinyl, PROPYNYL, butynyl, pentenyl, hexenyl etc. Here, the substituent in the quinil means the same as the substituent in the aforementioned "quinil, which may have a Deputy (deputies)". Carbocyclic ring which may have a Deputy (deputies) in "carbocyclic carbonyl group which may have a Deputy (deputies)"means the same thing as the above-mentioned carbocyclic shall ring, which may have a Deputy (deputies)". Carbocyclic ring which may have a Deputy (deputies), in "heterocyclic carbonyl which may have a Deputy (deputies)"means the same thing as the above-mentioned carbocyclic ring which may have a Deputy (deputies)".

In this specification, the substituent in the phenyl which may have a Deputy (deputies)," includes C1-8 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like), hydroxyl, amino, carboxyl, nitro, mono - or di-C1-6 alkylamino (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino and the like), C1-6 alkoxy (for example, methoxy, ethoxy, propoxy, hexyloxy and the like), C1-6 alkoxycarbonyl (for example, tert-methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl and the like), C1-6 alkylcarboxylic (for example, acetoxy, ethylcarbonate and the like), C1-4 alkylthio (for example, methylthio, ethylthio, propylthio, butylthio and the like), halogen atom (fluorine atom, chlorine atom, bromine atom and iodine atom), trihalomethyl (for example, trifluoromethyl and the like) and the like, Phenyl may be substituted by 1-4 arbitrary substituents in the substituted position.

In this specification, the substituent in the "pyridine, which may have a Deputy (deputies)," includes C1-8 alkyl (e.g. methyl, the Teal, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like), hydroxyl, amino, carboxyl, nitro, mono - or di-C1-6 alkylamino (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino and the like), C1-6 alkoxy (e.g. methoxy, ethoxy, propoxy, hexyloxy and the like), C1-6 alkoxycarbonyl (for example, tert-methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl etc.), C1-6 alkylcarboxylic (for example, acetoxy, ethylcarbonate and the like), C1-4 alkylthio (for example, methylthio, ethylthio, propylthio, butylthio and the like), halogen atom (fluorine atom, chlorine atom, bromine atom and iodine atom), trihalomethyl (for example, trifluoromethyl and the like) and the like, Pyridyl may be substituted by 1-4 arbitrary substituents in the substituted position.

In this specification, C2-5 alkylene, in which the carbon atom may be replaced by oxygen atom, nitrogen atom or sulfur atom, include linear or branched C2-5 alkylene, such as ethylene, propylene, isopropylene, butylene, isobutylene, pentile etc., C2-5 alkylene, etc. in which the carbon atom in the ethylene, propylene, isopropylene, butylene, isobutylene or pentylene replaces the oxygen atom, nitrogen atom or sulfur atom.

Residual connection to the nitrogen atom bound to a hydrogen atom, C1-6 alkyl, C2-6 acyl or C1-6 alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl, t is em-butoxycarbonyl etc). C2-5 alkylene can be substituted by the Deputy (deputies). Deputy includes C1-8 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like), hydroxyl, amino, carboxyl, nitro, mono - or di-C1-6 alkylamino (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino and the like), C1-6 alkoxy (e.g. methoxy, ethoxy, propoxy, hexyloxy and the like), C1-6 alkoxycarbonyl (for example, tert-methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl and the like), C1-6 alkylcarboxylic (for example, acetoxy, ethylcarbonate and the like), C1-4 alkylthio (for example, methylthio, ethylthio, propylthio, butylthio and the like), halogen atom (fluorine atom, chlorine atom, bromine atom and iodine atom), trihalomethyl (for example, trifluoromethyl and the like) and the like, C2-5 alkylene may be substituted by 1-4 arbitrary substituents in the substituted position.

C2-5 alkylene includes, for example, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -O-CH2-, -O-(CH2)2-, -O-(CH2)3-, -O-(CH2)4-, -CH2-O-CH2-, -CH2-O-(CH2)2-, -CH2-O-(CH2)3-, -(CH2)2-O-(CH2)2-, -NH-CH2-, -NH-(CH2)2-, -NH-(CH2)3-, -NH-(CH2)4-, -CH2-NH-CH2-, -CH2-NH-(CH2)2-, -CH2-NH-(CH2) 3-, -(CH2)2-NH-(CH2)2-, -N(CH3)-CH2-, -N(CH3)-(CH2)2-, -N(CH3)-(CH2)3-, -N(CH3)-(CH2)4-, -CH2-N(CH3)-CH2-, -CH2-N(CH3)-(CH2)2-, -CH2-N(CH3)-(CH2)3-, -(CH2)2-N(CH3)-(CH2)2-, -S-CH2-, -S-(CH2)2-, -S-(CH2)3-, -S-(CH2)4-, -CH2-S-CH2-, -CH2-S-(CH2)2-, -CH2-S-(CH2)3-, -(CH2)2-S-(CH2)2-, etc.

In this specification, C2-5 albaniles, in which the carbon atom may be substituted for the oxygen atom, nitrogen atom or sulfur atom, include linear or branched C2-5 albaniles, such as vinile, propylen, Isopropenyl, butylen, isobutylene, penttinen etc., or C2-5 albaniles, etc. in which the carbon atom in vinylene, propylene, isopropylene, butylene, isobutylene or pentylene replaces the oxygen atom, nitrogen atom or sulfur atom. Residual connection to the nitrogen atom bound to a hydrogen atom, C1-6 alkyl, C2-6 acyl or C1-6 alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl etc). C2-5 albaniles can be substituted by the Deputy (deputies). Deputy includes C1-8 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl tert-butyl, pentyl, hexyl, heptyl, octyl and the like), hydroxyl, amino, carboxyl, nitro, mono - or di-C1-6 alkylamino (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino and the like), C1-6 alkoxy (e.g. methoxy, ethoxy, propoxy, hexyloxy and the like), C1-6 alkoxycarbonyl (for example, tert-methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl and the like), C1-6 alkylcarboxylic (for example, acetoxy, ethylcarbonate and the like), C1-4 alkylthio (for example, methylthio, ethylthio, propylthio, butylthio and the like), halogen atom (fluorine atom, chlorine atom, bromine atom and iodine atom), trihalomethyl (for example, trifluoromethyl and the like) and the like, C2-5 Albaniles may be substituted by 1-4 arbitrary substituents in the substituted position. C2-5 albaniles includes, for example, -CH=CH-CH=CH-, -CH=CH-CH=N-, -CH=CH-NH-, -CH=CH-S-, -CH=CH-O-, -N=CH-NH -, etc.

In this specification, C1-6 alkylidene in the "C1-6 alkylidene, which may be substituted"includes, for example, methylidene, ethylidene, propylidene, butylidene, pentylidene, hexylidene etc. Deputy in the "C1-6 alkylidene, which may be substituted"includes hydroxyl, amino, carboxyl, nitro, azido, mono - or di-C1-6 alkylamino (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino and the like), N-aromatic ring amino (for example, N-phenylamino and the like), N-aromatic ring-N-alkylamino (for example, N-phenyl-N-methylamino, N-phenyl-N-ethylamino, N-phenyl-N-propyl what Ino, N-phenyl-N-butylamino, N-phenyl-N-pentylamine, N-phenyl-N-hexylamino and the like), C1-6 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, hexyloxy and the like), C3-7 cycloalkyl-C1-6 alkoxy (for example, cyclohexylmethoxy, cyclopentyloxy and the like), C3-7 cycloalkane (for example, cyclohexyloxy and the like), C7-15 Arakelots (for example, benzyloxy, penetrate, phenylpropoxy, naphthalenyloxy, negotiations etc.), phenoxy, C1-6 alkoxycarbonyl (for example, tert-methoxycarbonyl, etoxycarbonyl, butoxycarbonyl and the like), C1-6 alkylcarboxylic (for example, acetoxy, ethylcarbonate and the like), C1-4 alkylthio (for example, methylthio, ethylthio, propylthio, butylthio and the like), halogen atom (fluorine atom, chlorine atom, bromine atom and iodine atom), alkylsulfonyl (for example, C1-4 alkylsulfonyl and the like, such as methylsulphonyl, ethylsulfonyl and the like), aromatic ring-sulfonyl (for example, C6-10 aromatic ring-sulfonyl etc. such as phenylsulfonyl and the like), acyl (e.g., C1-6 alkanoyl etc., such as formyl, acetyl, propanol, pivaloyl and the like, and C6-10 aromatic ring-carbonyl and the like, such as benzoyl and the like) and the like, C1-6 alkylidene may be substituted by 1-4 arbitrary substituents in the substituted position.

In this description C5-12 monocyclic or bicyclic carbocyclic ring includes a monocyclic or bicyclic C5-12 carbocyclic Kohl is on the aryl or carbocyclic ring, which is saturated or fully or partially, such as cyclopentane, cyclohexane, Cycloheptane, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, cyclohexadiene, cycloheptadiene, benzene, pentalene, perhydroanthracene, azulene, pergerson, inden, palikonda, indan, naphthalene, dihydronaphthalene, tetrahydronaphthalene and peritonealis.

In this description, 5-12 membered monocyclic or bicyclic a heterocycle includes a 5-12 membered monocyclic or bicyclic heterocyclic aryl containing heteroatom(s)selected from 1 to 4 nitrogen atoms, one or two oxygen atoms and/or one or two sulfur atoms, and heterocycle is saturated or fully or partially. Such a heterocycle includes, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, azepine, diazepine, furan, Piran, oxepin, thiophene, thiopyran, tiepin, oxazol, isoxazol, thiazole, isothiazol, oxazin, teasin, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzofuran, ditionally, indazole, quinoline, isoquinoline, hinaidi, phthalazine, naphthiridine, cinoxacin, hinzelin, cinnolin, benzoxazole, benzothiazole, benzimidazole, chrome, benzocain, benzoxazepin, benzothiophen, benzodiazepin, benzazepin, benzodiazepine, pyrrolin, pyrrolidin, imidazolin, imidazolidine, triazoline thiazolidin, pyrazolin, pyrazolidine, dihydropyridines, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, dihydropyrimidine, tetrahydropyrimidine, targetability, dihydropyridin, tetrahydropyridine, targetability, dehydroacetic, tetrahydroazepine, peligrosa, dihydrovitamin, tetrahydroazepine, targetrotation, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dehydroacetic, tetrahydroazepine, perhydroxyl, dihydrothiophene, tetrahydrothiophene, dihydrothiophene, tetrahydrothiopyran, dihydrothiophene, tetrahydrothiophene, pengertian, dihydrooxazolo, tetrahydrooxazolo (oxazolidine), dihydroisoxazole, tetrahydrooxazolo (isoxazolidine), dihydrothiazolo, tetrahydrothieno (thiazolidin), dihydroisoxazole, tetrahydrocortisol (isothiazolin), dihydrooxazolo, tetrahydrooxazolo, dihydrooxazoles, tetrahydroazepine, perhydroxyl, dihydrothiazine, tetrahydrothiophene, dihydrothiazine, tetrahydroazepine, targetrotation, morpholine, thiomorpholine, Ossetian, dioxolane, dioxane, indolin, isoindoline, dihydrobenzofuran, perhydroanthracene, dihydroisobenzofuran, peligrosamente, dihydrobenzofuran, targetobjecttype, dihydroisobenzofuran, peligrosamente, dihydroindol, peritoneal, dihydroquinoline, tetrahydroquinoline, perhydro inulin, the dihydroisoquinoline, tetrahydroisoquinoline, perhydrosqualene, dihydrophenazine, tetrahydrophthalate, PermitRootLogin, dihydronaphthalene, tetrahydronaphthalene, perhydroanthracene, dihydroquinoxaline, tetrahydroquinoxalin, perhydrophenanthrene, dihydroquinazolin, tetrahydroquinazolin, perhydrophenanthrene, dihydroindole, tetrahydroindole, permitiendoles, benzocain, dihydroisoxazole, dihydrobenzofuran, dihydroisoxazole, perhydroanthracene, dihydrobenzofuran, perhydroanthracene, dehydrobenzperidol, perhydroanthracene, digitalisation, tetrahydrobenzene, dihydrobenzofuran, tetrahydrolipstatin, benzodioxepin, dihydroisoxazole and tetrahydrobenzoic.

In this description C5-6 saturated carbocyclic ring include a cyclopentane and cyclohexane.

In this description, 5-6-membered saturated, a heterocycle containing one or two nitrogen atom, one or two oxygen atom and/or sulfur atom includes, for example, pyrrolidin, imidazolidin, pyrazolidine, piperidine, piperazine, targetability, targetability, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, tetrahydrooxazolo (oxazolidine), tetrahydrocortisol (isoxazolidine), tetrahydrothieno (thiazolidin), tetrahydrocortisol (isothiazolin), tetrahydrooxazolo, tetrahydrate the zine, morpholine, thiomorpholine, Ossetian, dioxolane, dioxane, etc.

In this description C5-6 carbocyclic ring includes, for example, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, benzene, etc.

In this description, 5-6-membered heterocycle containing one or two nitrogen atom, one or two oxygen atom and/or sulfur atom includes, for example, pyrrole, imidazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, furan, Piran, thiophene, thiopyran, oxazol, isoxazol, thiazole, isothiazol, oxazin, teasin, pyrrolin, pyrrolidin, imidazolin, imidazolidin, pyrazoline, pyrazolidine, dihydropyridines, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, dihydropyrimidine, tetrahydropyrimidine, targetability, dihydropyridin, tetrahydropyridine, targetability, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiophene, tetrahydrothiopyran, dihydrooxazolo, tetrahydrooxazolo (oxazolidine), dihydroisoxazole, tetrahydrooxazolo (isoxazolidine), dihydrothiazolo, tetrahydrothieno (thiazolidin), dihydroisoxazole, tetrahydrocortisol (isothiazolin), digitoxin, tetrahydroxide, dihydrothiazine, tetrahydrothiophene, morpholine, thiomorpholine, Ossetian, dioxolane, dioxane, etc.

In this description the Deputy uvenile, which may be substituted, means the same as the substituent in the alkyl which may be substituted.

In this description, the sulfur atom which may be oxidized, includes sulfon, sulfoxide and sulfide.

Unless otherwise stated, all isomers are included in this description. For example, a linear or branched alkyl, alkenyl, quinil, alkoxy, alkylthio, alkylene, albaniles and akinyan included. Additionally, all isomers are possible because of the presence of a double bond, ring and condensed ring (E-, Z-, CIS - and TRANS-compounds), isomers due to the presence of an asymmetric carbon atom, etc. (R-, S-, α - and β-matter, enantiomers and diastereoisomers), optically active substances having optical rotation (D-, L-, d - and l-substances), polar substances by chromatographic separation (high-polar substance and iskopaemoe substance), equilibrium compounds, rotational isomers, a mixture thereof in any proportion and a racemic mixture are included in this invention.

Unless otherwise specifically stated, in this specification, as should be obvious to experts in this field, the symbolmeans communication with the opposite side of the paper (i.e. α-configuration),means the connection from the front side of the paper (i.e. β-configuration),mean α-configuration, β or their mixture, and mean α-configuration or the β-configuration.

Compounds represented by formula (I), converted into salts by known methods. Salt include a salt of an alkaline metal salt, alkaline earth metal, ammonium salt, amine salt, additive salt with acid and other Salts are preferably pharmaceutically acceptable.

Salts are preferably water-soluble. Suitable salts are salts of alkali metal (potassium, sodium and the like), a salt of alkaline earth metal (calcium, magnesium and the like), ammonium salt, salt with organic amine, which is a pharmaceutically acceptable (Tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, Tris(hydroxymethyl)methylamine, lysine, arginine, N-methyl-D-glucamine etc).

Additive salts with acids are preferably soluble in water. Suitable additive salts with acids include inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and nitrate, and salt of organic acid such as acetate, lactate, tartrate, oxalate, benzoate, citrate, methanesulfonate, aconsultant, bansilalpet, toluensulfonate, isothionate, glucuronate and gluconate.

Compounds represented by formula (I)and their salts into a solvate.

The solvate preferably are non-toxic and soluble in water. Suitable solvate include a solvate, which is formed of water and an alcoholic solvent (e.g. ethanol and the like).

Proletarienne form compounds represented by formula (I)means a compound which is transformed into a compound represented by the formula (I), by interacting with enzymes, gastric acid, etc.in vivo. Proletarienne form compounds represented by formula (I)includes compounds in which the amino group was, for example, allyawan, alkylated or phosphorylated (for example, compounds in which the amino group of compounds represented by formula (I), was eikozanoidov, alanalanalana, intramyocardially, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxycarbonylamino, tetrahydrofurfurylamine, pyrrolidinedione, pivaloyloxymethyl, acetoxylation, tert-Butlerova and the like), when the compound represented by formula (I)has an amino group; compounds in which a hydroxyl group was, for example, allyawan, alkylated, phosphorylated or berteroana (for example, compounds in which a hydroxyl group of the compound represented by formula (I), was azetilirovanna, palmitoylation, propanolamine, pihlajasaari, succinylcholine, fu is allerban, alanalanalana or dimethylaminoethylacrylate), when the compound represented by formula (I)has a hydroxyl group; a carboxyl group of the compound represented by formula (I), was, for example, etherification or liderovna (for example, compounds in which the carboxyl group of the compound represented by formula (I)was converted into ethyl ester, phenyl ester, phenethyl ester, carboxymethoxy ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, ethoxycarbonylmethyl ester, Caligraphy ester, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl ester, cyclohexyloxycarbonyloxy ester or methylamide), when the compound represented by formula (I), has carboxypropyl; compounds in which carboxypropyl replaced hydroxymethylene group. Such compounds can be obtained essentially in a known manner. Proletarienne form compounds represented by formula (I)may be either a hydrate or dehydrator.

R1in the formula (I) means preferably a hydrogen atom, C1-4 alkyl or benzyl and, more preferably, a hydrogen atom or C1-4 alkyl.

R2in the formula (I) means preferably halogen atom, C1-6 alkyl, C1-6 alkoxy, hydroxyl, trihalomethyl, cyano, phenyl, PI is ideal, nitro or NR6R7and, more preferably, halogen atom, C1-6 alkyl, C1-6 alkoxy or hydroxyl.

R3in the formula (I) means preferably halogen atom, C1-6 alkyl, C1-6 alkoxy, hydroxyl, trihalomethyl or cyano and, more preferably, halogen atom, C1-6 alkyl, C1-6 alkoxy or trihalomethyl.

R8in the formula (I) means preferably C1-4 alkyl or phenyl.

R4in the formula (I) means preferably a hydrogen atom, C1-4 alkyl or benzyl and, more preferably, a hydrogen atom or C1-4 alkyl.

R5in the formula (I) means preferably C1-6 alkyl, C1-10 alkoxy, halogen atom, hydroxyl, trihalomethyl, phenyl or cyano, and, more preferably, C1-6 alkyl, C1-10 alkoxy or halogen atom.

R12in the formula (I) means preferably C1-4 alkyl, halogen atom, hydroxyl which may be protected, or a hydrogen atom and, more preferably, C1-4 alkyl or a halogen atom.

R13in the formula (I) means preferably C1-4 alkyl, halogen atom, hydroxyl which may be protected, or a hydrogen atom and, more preferably, C1-4 alkyl or a halogen atom.

The group represented by the combination of R12and R13in the formula (I)is preferably a group in which eliminated one of the hydrogen atoms, and more preferably a group in which eliminated obatala hydrogen.

The group represented by the combination of R12and R13in the formula (I), means preferably oxo or C2-5 alkylene, in which one carbon atom may be replaced by oxygen atom, nitrogen atom or sulfur atom, and more preferably, oxo, ethylene or -(CH2)2-O-(CH2)2-.

in the formula (I) means preferably C5-6 monocyclic carbocyclic ring, or a 5-6-membered monocyclic heterocycle containing one or two nitrogen atom, one or two oxygen atom and/or sulfur atom, such as cyclopentane, cyclohexane, benzene, pyrrole, imidazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, furan, Piran, thiophene, thiopyran, oxazol, isoxazol, thiazole, isothiazol, pyrrolidin, imidazolidine, piperidine or piperazine, and more preferably a benzene ring or pyridine.

Moreover, preferably C5-6 monocyclic carbocyclic ring, such as benzene represented by the formulaor.

A group of the formulain the formula (I) means preferably a group of the formula(in the formula, all symbols have the above values) and more preferablyor(in the formula, all symbols have the above value is tion, where two R3may be the same or different).

G in formula (I) means preferably (1) C1-6 alkylene containing from 0 to 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, (2) C2-6 albaniles or (3) C2-6 akinyan, and, more preferably, (1) C1-6 alkylene containing from 0 to 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, (2) C2-4 albaniles or (3) C2-4 akinyan, and more more preferably (1) C1-4 alkylene, (2) C2-4 albaniles or (3) C2-4 akinyan.

in the formula (I) means preferably a group of the formula(in the formula a group of the formulameans C5-6 saturated carbocyclic ring, or a 5-6-membered saturated, a heterocycle containing one or two nitrogen atom, one or two oxygen atom and/or sulfur atom; and a group of the formulameans C5-6 carbocyclic ring, or a 5-6-membered heterocycle containing one or two nitrogen atom, one or two oxygen atom and/or sulfur atom).

A group of the formulameans preferably 5-6-membered saturated, a heterocycle containing one or two nitrogen atom, one or two oxygen atom and/or sulfur atom, and more preferably 5-6-membered saturated, a heterocycle containing one or two nitrogen atom and/or one or two atom color is Yes. For example, it is preferably morpholine, dioxane, Ossetian, tetrahydrofuran, pyrrolidine, tetrahydrooxazolo (oxazolidin) or imidazolidin and, more preferably, morpholine, tetrahydrofuran or pyrrolidine.

A group of the formulameans preferably C5-6 carbocyclic ring, or a 5-6-membered heterocycle containing one or two nitrogen atom and/or one or two oxygen atom, and more preferably C5-6 carbocyclic ring, or a 5-6-membered heterocycle containing one or two nitrogen atom. For example, is preferably a cyclopentane, cyclohexane, cyclopentadiene, benzene, pyridine, pyrazin, pyrimidine, pyridazine, oxazin, piperidine or piperazine and, more preferably, cyclohexane, benzene, pyridine, pyrazin or pyrimidine, and even more preferably benzene.

means preferably dihydroisoxazole, benzodioxan, benzocain, dihydrobenzofuran or indolin and, more preferably, dihydroisoxazole, dihydrobenzofuran or indolin and, more preferably, dihydroisoxazole.

A group of the formulameans preferably dihydroisoxazole-2-yl, benzodioxan-2-yl, benzoxazin-2-yl, dihydrobenzofuran-2-yl, dihydrobenzofuran-3-yl, benzodioxan-2-yl, indolin-2-yl or indolin-3-yl and, more preferably, the DIAC is robesondesign-2-yl, dihydrobenzofuran-2-yl, dihydrobenzofuran-3-yl, indolin-2-yl or indolin-3-yl, and even more preferably, dihydroisoxazole-2-yl.

The symbol “m” means preferably 0, 1 or 2.

The symbol “n” means preferably 2, 3 or 4 and, more preferably, 2.

The symbol “i” means preferably 0 or an integer from 1 to 5.

As for the compounds represented by formula (I), a preferable compound is a compound represented by formula (I-a)

in which all symbols have the above values, the compound represented by formula (I-b)

in which all symbols have the above values, or the compound represented by formula (I-c)

in which all symbols have the above values.

As specific compounds of this invention include such as:

(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)UKS is SNA acid,

(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)acetic acid,

(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)acetic acid,

(4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(4-chloro-3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)acetic acid,

(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)acetic acid,

(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)acetic acid,

(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-were)acetic acid,

(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-were)acetic acid,

(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-were)acetic acid,

(5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)enzoyl)amino)-2-forfinal)acetic acid,

(5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-forfinal)acetic acid,

(5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-forfinal)acetic acid,

(2-chloro-5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(2-chloro-5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(2-chloro-5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-were)acetic acid,

(5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-were)acetic acid,

(5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-were)acetic acid,

2-(4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

(4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(debtor)acetic acid,

(4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(oxo)acetic acid,

(4-chloro-3-((5-chloro-2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxa the h-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(4-chloro-3-((2-fluoro-5-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(4-chloro-3-((2,5-debtor-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(4-chloro-3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid,

(4-chloro-3-((4-((3R)-2,3-dihydro-1-benzofuran-3-ylethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid,

(4-chloro-3-((2,6-dimethyl-4-(((3R)-5-methyl-2,3-dihydro-1-benzofuran-3-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(4-chloro-3-((4-((2S)-2,3-dihydro-1-benzofuran-2-ylethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid,

(3-((4-(1,3-benzodioxol-2-ylethoxy)-2,6-dimethylbenzoyl)amino)-4-chlorophenyl)acetic acid,

(3-((4-(((2S)-4,6-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,6-differentail)amino)-4-forfinal)acetic acid,

(3-((2,5-debtor-4-(((2S)-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-forfinal)acetic acid,

(5-((4-(((2S)-6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,3-differentail)amino)-2-forfinal)acetic acid,

(4-chloro-3-((2,6-dichloro-4-(((2S)-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl) acetic acid,

(3-chloro-5-((2,5-dichloro-4-(((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic sour is a,

(2-chloro-5-((2,3-dichloro-4-(((2S)-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(3-((4-(((2S)-7-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-fluoro-6-methylbenzoyl)amino)-4-were)acetic acid,

(3-((2-fluoro-4-(((2S)-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-5-methylbenzoyl)amino)-5-were)acetic acid,

(5-((2-fluoro-3-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-were)acetic acid,

(3-((4-(((2S)-4,6-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-5-fluoro-2-methylbenzoyl)amino)-4-forfinal)acetic acid,

(3-fluoro-5-((3-fluoro-4-(((2S)-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-methylbenzoyl)amino)phenyl) acetic acid,

(5-((2-chloro-4-(((2S)-6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-6-methylbenzoyl)amino)-2-forfinal)acetic acid,

(4-chloro-3-((2-chloro-4-(((2S)-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-5-methylbenzoyl)amino)phenyl) acetic acid,

(3-chloro-5-((2-chloro-4-(((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-3-methylbenzoyl)amino)phenyl)acetic acid,

(2-chloro-5-((5-chloro-4-(((2S)-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-methylbenzoyl)amino)phenyl) acetic acid,

(3-((3-chloro-4-(((2S)-7-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-methylbenzoyl)amino)-4-methylphenoxy acid,

(3-((2-chloro-6-fluoro-4-(((2S)-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-were)acetic acid,

(5-((2-chloro-4-((2S)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-5-perbenzoic)amino)-2-were)acetic acid,

(3-((2-chloro-3-fluoro-4-(((2S)-6-methyl-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)benzoyl)amino)-4-forfinal)acetic acid,

(3-((5-chloro-2-fluoro-4-(((2S)-6-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)benzoyl)amino)-5-forfinal)acetic acid,

(5-((3-chloro-4-(((2S)-6-chloro-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)-2-perbenzoic)amino)-2-forfinal)acetic acid,

(4-chloro-3-((4-(((2R)-6-methoxy-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid,

(3-chloro-5-((2,5-dimethyl-4-(((2R)-7-methyl-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(2-chloro-5-((4-(((2R)-7-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)-2,3-dimethylbenzoyl)amino)phenyl)acetic acid,

(3-((4-(((2R)-7-chloro-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)-2,6-dimethylbenzoyl)amino)-4-were)acetic acid,

(3-((4-(((2R)-7-methoxy-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)-2,5-dimethylbenzoyl)amino)-5-were)acetic acid,

(5-((4-(((2R)-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2,6-dimethylbenzoyl)amino)-2-were)acetic acid,

(3-((4-(((2R)-1-ethyl-5-fluoro-2,3-dihydro-1H-indol-2-yl)methoxy)-2,6-dimethylbenzoyl)amino)-4-fluoro who enyl)acetic acid,

(3-((4-(((2R)-5-chloro-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2,5-dimethylbenzoyl)amino)-5-forfinal)acetic acid,

(5-((4-(((2R)-1-ethyl-5-methyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2,3-dimethylbenzoyl)amino)-2-forfinal)acetic acid,

(4-chloro-3-((4-(((2S)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid,

(3-chloro-5-((4-(((2S)-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methoxy)-2,5-dimethylbenzoyl)amino)phenyl)acetic acid,

(2-chloro-5-((2,3-dimethyl-4-(((2S)-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(3-((4-((3S)-2,3-dihydro-1-benzofuran-3-ylethoxy)-2,6-dimethylbenzoyl)amino)-4-were)acetic acid,

(3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-2,6-dimethylbenzoyl)amino)-4-forfinal)acetic acid,

(3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-2,6-dimethylbenzoyl)amino)-5-forfinal)acetic acid,

(5-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-2,6-dimethylbenzoyl)amino)-2-forfinal)acetic acid,

(3-chloro-5-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid,

(2-chloro-5-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid,

(3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-2,6-dimethylbenzoyl)amino)-4-were)acetic acid,

(3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-2,6-imeevent)amino)-5-were)acetic acid,

(5-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-2,6-dimethylbenzoyl)amino)-2-were)acetic acid,

(3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid,

2-(4-fluoro-3-((2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(4-fluoro-3-((2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)-2-methylpropanoate acid,

2-(4-fluoro-3-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)-2-methylpropanoate acid,

2-(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)-2-methylpropanoate acid,

2-(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)-2-methylpropanoate acid,

2-(4-chloro-3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(4-chloro-3-((2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(4-chloro-3-((2-fluoro-4-(((2S)-4-methyl,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(4-chloro-3-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-methyl-2-(4-methyl-3-((2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)propanoic acid

2-(3-((2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)-2-methylpropanoate acid,

2-(3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)-2-methylpropanoate acid,

2-methyl-2-(4-methyl-3-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)propanoic acid

2-(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)-2-methylpropanoate acid,

2-(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)-2-methylpropanoate acid,

2-(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)-2-methylpropanoate acid,

2-(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-were)-2-methylprop the new acid,

2-methyl-2-(3-methyl-5-((2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)propanoic acid

2-(3-((2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-were)-2-methylpropanoate acid,

2-(3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-were)-2-methylpropanoate acid,

2-methyl-2-(3-methyl-5-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)propanoic acid

2-(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-were)-2-methylpropanoate acid,

2-(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-were)-2-methylpropanoate acid,

2-(3-fluoro-5-((2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(3-fluoro-5-((2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-forfinal)-2-methylpropanoate acid,

2-(3-fluoro-5-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-forfinal)-2-methylpropanoate acid

2-(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-forfinal)-2-methylpropanoate acid,

2-(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-forfinal)-2-methylpropanoate acid,

2-(3-chloro-5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(3-chloro-5-((2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(3-chloro-5-((2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(3-chloro-5-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(3-chloro-5-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(3-chloro-5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(3-chloro-5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-methyl-2-(2-methyl-5-((2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)propanoic acid

2-(5-((2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-were)-2-methylpropanol the I acid,

2-(5-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-were)-2-methylpropanoate acid,

2-methyl-2-(2-methyl-5-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)propanoic acid

2-(5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-were)-2-methylpropanoate acid,

2-(5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-were)-2-methylpropanoate acid,

2-(5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-were)-2-methylpropanoate acid,

2-(5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-forfinal)-2-methylpropanoate acid,

2-(2-fluoro-5-((2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(2-fluoro-5-((2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(5-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-forfinal)-2-methylpropanoate acid,

2-(2-fluoro-5-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-forfinal)-2-methylpropanoate to the slot,

2-(5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-forfinal)-2-methylpropanoate acid,

2-(2-chloro-5-((2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(2-chloro-5-((2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(2-chloro-5-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(2-chloro-5-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(2-chloro-5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(2-chloro-5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(2-chloro-5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-methyl-2-(3-((2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)propanoic acid

2-(3-((2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(3-((chlor-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-methyl-2-(3-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)propanoic acid

2-(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(3-((3-chloro-2-fluoro-4-(((2S)-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)-2-methylpropanoate acid,

2-(3-((5-chloro-4-(((2S)-7-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-perbenzoic)amino)-5-forfinal)-2-methylpropanoate acid,

2-(5-((2-chloro-3-fluoro-4-(((2S)-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-forfinal)-2-methylpropanoate acid,

2-(4-chloro-3-((2-chloro-4-(((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-5-perbenzoic)amino)phenyl)-2-methylpropanoate acid,

2-(3-chloro-5-((2-chloro-6-fluoro-4-(((2S)-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(2-chloro-5-((3-chloro-4-(((2S)-6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-methylbenzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(3-((5-chloro-4-(((2S)-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-methylbenzoyl)amino)-4-were)-2-methylpropanoate acid,

2-(3-((2-chloro-4-(((2S)-4,6-dimethyl-3,4-dihydro-2H-1,4-benzox the Zin-2-yl)methoxy)-3-methylbenzoyl)amino)-5-were)-2-methylpropanoate acid,

2-(5-((2-chloro-5-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-were)-2-methylpropanoate acid,

2-(3-((2-chloro-4-(((2R)-7-methoxy-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)-6-methylbenzoyl)amino)-4-forfinal)-2-methylpropanoate acid,

2-(3-((4-(((2S)-7-chloro-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)-3-fluoro-2-methylbenzoyl)amino)-5-forfinal)-2-methylpropanoate acid,

2-(2-fluoro-5-((5-fluoro-4-(((2S)-7-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)-2-methylbenzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(3-fluoro-5-((2-fluoro-3-methyl-4-(((2R)-7-methyl-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(4-fluoro-3-((2-fluoro-4-(((2R)-6-methoxy-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)-5-methylbenzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(3-((4-(((2R)-6-chloro-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)-2-fluoro-6-methylbenzoyl)amino)-5-forfinal)-2-methylpropanoate acid,

2-(5-((2,3-dichloro-4-(((2S)-6-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)benzoyl)amino)-2-forfinal)-2-methylpropanoate acid,

2-(3-((2,5-dichloro-4-(((2S)-6-methyl-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)benzoyl)amino)-5-forfinal)-2-methylpropanoate acid,

2-(5-((2,6-dichloro-4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)benzoyl)amino)-2-forfinal)-2-methylpropanoate acid,

2-(4-chloro-3-((4-(((2R)-1-ethyl-5-methyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2,3-differentail)amino)the dryer is l)-2-methylpropanoate acid,

2-(3-chloro-5-((4-(((2R)-5-chloro-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2,5-differentail)amino)phenyl)-2-methylpropanoate acid,

2-(2-chloro-5-((4-(((2R)-1-ethyl-5-fluoro-2,3-dihydro-1H-indol-2-yl)methoxy)-2,6-differentail)amino)phenyl)-2-methylpropanoate acid,

2-(3-((4-(((2R)-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2,3-dimethylbenzoyl)amino)-4-were)-2-methylpropanoate acid,

2-(3-((2,5-dimethyl-4-(((2S)-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methoxy)benzoyl)amino)-5-were)-2-methylpropanoate acid,

2-(5-((4-(((2S)-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methoxy)-2,6-dimethylbenzoyl)amino)-2-were)-2-methylpropanoate acid,

2-(4-fluoro-3-((2-fluoro-4-(((2S)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(4-chloro-3-((4-((2S)-2,3-dihydro-1-benzofuran-2-ylethoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(3-((2-chloro-4-((3S)-2,3-dihydro-1-benzofuran-3-ylethoxy)benzoyl)amino)-4-were)-2-methylpropanoate acid,

2-(5-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-2,6-dimethylbenzoyl)amino)-2-forfinal)-2-methylpropanoate acid,

2-(2-chloro-5-((4-(((2R)-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2,5-dimethylbenzoyl)amino)phenyl)-2-methylpropanoate acid,

2-(5-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-2,3-dimethylbenzoyl)amino)-2-were)-2-methylpropanoate acid,

(3-(((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)is ethoxy)phenyl)sulfonyl)amino)phenyl)acetic acid,

(3-(((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)phenyl)sulfonyl)(methyl)amino)phenyl) acetic acid,

(3-(((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)phenyl)sulfonyl)(ethyl)amino)phenyl) acetic acid,

(3-(((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)phenyl)sulfonyl)(isobutyl)amino)phenyl) acetic acid,

(3-chloro-5-(((4-(((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,3-dimetilfenil)sulfonyl)amino) phenyl)acetic acid,

(2-chloro-5-(((4-(((2S)-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,3-dimetilfenil)sulfonyl)(methyl) amino)phenyl)acetic acid,

(3-(((4-(((2S)-7-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,3-dimetilfenil)sulfonyl) (ethyl)amino)-4-were)acetic acid,

(4-fluoro-3-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(oxo)acetic acid,

(3-((4-(((2S)-4,6-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-perbenzoic)amino)-5-forfinal)(oxo)acetic acid,

(5-((2-chloro-4-(((2S)-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-forfinal) (oxo)acetic acid,

(4-chloro-3-((4-(((2S)-6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-methylbenzoyl)amino)phenyl) (oxo)acetic acid,

(3-chloro-5-((4-(((2S)-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,6-dimethyl shall entail)amino)phenyl) (oxo)acetic acid,

(2-chloro-5-((4-(((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,5-dimethylbenzoyl)amino)phenyl) (oxo)acetic acid,

(3-((4-(((2S)-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,3-dimethylbenzoyl)amino)-4-were) (oxo)acetic acid,

(3-((4-(((2S)-7-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,6-differentail)amino)-5-were) (oxo)acetic acid,

(5-((2,5-dichloro-4-(((2S)-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-were) (oxo)acetic acid,

(3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-2-fluoro-3-methylbenzoyl)amino)-4-forfinal)(oxo)acetic acid,

(3-((5-chloro-4-(((2R)-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2-methylbenzoyl)amino)-5-forfinal)(oxo)acetic acid,

(5-((3-chloro-4-((2S)-2,3-dihydro-1-benzofuran-2-ylethoxy)-2-perbenzoic)amino)-2-forfinal)(oxo)acetic acid,

(3-((2-fluoro-6-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(oxo)acetic acid,

(3-((2-chloro-4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-5-methylbenzoyl)amino)phenyl)(oxo)acetic acid,

(3-((2-chloro-4-(((2R)-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-3-perbenzoic)amino)phenyl)(oxo)acetic acid,

(4-chloro-3-((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(debtor)acetic acid,

(3-chloro-5-((4-(((2S)-4,6-dimethyl-3,4-dihydro-2H-1,4-benzox the Zin-2-yl)methoxy)-2-perbenzoic)amino)phenyl) (debtor)acetic acid,

(2-chloro-5-((2-chloro-4-(((2S)-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl) (debtor)acetic acid,

(3-((4-(((2S)-6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-methylbenzoyl)amino)-4-were) (debtor)acetic acid,

debtor(3-((4-(((2S)-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,6-dimethylbenzoyl)amino)-5-were)acetic acid,

(5-((4-(((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,5-dimethylbenzoyl)amino)-2-were) (debtor)acetic acid,

debtor(4-fluoro-3-((4-(((2S)-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,3-dimethylbenzoyl)amino)phenyl) acetic acid,

(3-((4-(((2S)-7-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,6-differentail)amino)-5-forfinal) (debtor)acetic acid,

(5-((2,5-dichloro-4-(((2S)-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-forfinal) (debtor)acetic acid,

(4-chloro-3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-2-fluoro-3-methylbenzoyl)amino)phenyl)(debtor)acetic acid,

(3-chloro-5-((5-chloro-4-(((2R)-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2-methylbenzoyl)amino)phenyl)(debtor)acetic acid,

(2-chloro-5-((3-chloro-4-((2S)-2,3-dihydro-1-benzofuran-2-ylethoxy)-2-perbenzoic)amino)phenyl)(debtor)acetic acid,

debtor(3-((2-fluoro-6-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)the dryer is l)acetic acid,

(3-((2-chloro-4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-5-methylbenzoyl)amino)phenyl)(debtor)acetic acid,

(3-((2-chloro-4-(((2R)-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-3-perbenzoic)amino)phenyl)(debtor)acetic acid,

1-(3-((4-(((2S)-4,6-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,3-dimethylbenzoyl)amino)-4-forfinal) cyclopropanecarbonyl acid,

1-(3-fluoro-5-((4-(((2S)-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,5-dimethylbenzoyl)amino)phenyl) cyclopropanecarbonyl acid,

1-(5-((4-(((2S)-6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,6-dimethylbenzoyl)amino)-2-forfinal) cyclopropanecarbonyl acid,

1-(4-chloro-3-((4-(((2S)-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-methylbenzoyl)amino)phenyl) cyclopropanecarbonyl acid,

1-(3-chloro-5-((2-chloro-4-(((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl) cyclopropanecarbonyl acid,

1-(2-chloro-5-((4-(((2S)-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl) cyclopropanecarbonyl acid,

1-(3-((4-(((2S)-7-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-perbenzoic)amino)-4-were) cyclopropanecarbonyl acid,

1-(3-((2,6-dichloro-4-(((2S)-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-were) cyclopropanecarbonyl acid,

1-(5-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-elmet the XI)-2-fluoro-5-methylbenzoyl)amino)-2-were)cyclopropanecarbonyl acid,

1-(3-((2-chloro-3-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal) cyclopropanecarbonyl acid,

1-(4-chloro-3-((5-chloro-4-(((2R)-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2-perbenzoic)amino)phenyl)cyclopropanecarbonyl acid,

1-(3-((2-chloro-4-((2S)-2,3-dihydro-1-benzofuran-2-ylethoxy) -6-methylbenzoyl)amino)-4-were)cyclopropanecarbonyl acid,

1-(5-((2-chloro-4-((3R)-2,3-dihydro-1-benzofuran-3-ylethoxy) -5-perbenzoic)amino)-2-forfinal)cyclopropanecarbonyl acid,

1-(2-chloro-5-((5-fluoro-2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl) cyclopropanecarbonyl acid,

1-(5-((3-chloro-4-((2S)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-2-methylbenzoyl)amino)-2-were) cyclopropanecarbonyl acid,

4-(3-((4-(((2S)-4,6-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2,3-dimethylbenzoyl)amino)-4-forfinal)tetrahydro-2H-Piran-4-carboxylic acid,

4-(4-chloro-3-((4-(((2S)-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-methylbenzoyl)amino)phenyl)tetrahydro-2H-Piran-4-carboxylic acid,

4-(5-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-2-fluoro-5-methylbenzoyl)amino)-2-were)tetrahydro-2H-Piran-4-carboxylic acid,

4-(4-chloro-3-((5-chloro-4-(((2R)-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2-perbenzoic)amino)phenyl)tetrahydro-2H-Piran-4-carboxylic acid,

4-(3-((2-chloro-3-methyl-4-(((2S)-4-meth is l-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)tetrahydro-2H-Piran-4-carboxylic acid,

2-methyl-2-(3-(((4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)phenyl)sulfonyl)amino)phenyl)propanoic acid

2-methyl-2-(3-(methyl((2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)phenyl)sulfonyl)amino)phenyl) propanoic acid

(3-(((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)phenyl)sulfonyl)(isobutyl)amino)phenyl) (debtor)acetic acid,

1-(2-chloro-5-(((4-(((2S)-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)-2-were)sulfonyl) (methyl)amino)phenyl)cyclopropanecarbonyl acid,

(3-(((2-chloro-4-(((2S)-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)phenyl)sulfonyl)(isobutyl)amino)-5-were)(oxo)acetic acid,

(3-chloro-5-(((4-(((2S)-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)phenyl)sulfonyl)amino)phenyl) (debtor)acetic acid,

2-(2-chloro-5-(((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)phenyl)sulfonyl)(isobutyl)amino)phenyl)-2-methylpropanoate acid,

(3-((4-((2S)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid,

(4-chloro-3-((2,6-dimethyl-4-(((2R)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(3-((4-(((2S)-5-chloro-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2,5-dimethylbenzoyl)amino)-5-forfinal)acetic acid,

(4-chloro-3-((4-(((2R)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methoxy)-2,6-dimethylbenzoyl)amino)phenyl)who kasna acid,

(3-((4-((3R)-2,3-dihydro-1-benzofuran-3-ylethoxy)-2,6-dimethylbenzoyl)amino)-4-were)acetic acid,

(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-ethylphenyl)acetic acid,

(5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-isopropylphenyl) acetic acid,

(3-((2-ethyl-5-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(5-((5-ethyl-2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-methoxyphenyl)acetic acid and

(2-chloro-5-((2,5-dimethoxy-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid, compounds represented by, for example, their salts, solvate and their proletarienne forms.

As a more preferred compounds of this invention include such as:

(1) (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)acetic acid,

(2) (4-chloro-3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(3) (4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(4) (4-chloro-3-((5-chloro-2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl) acetic acid is acid,

(5) (4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(6) (4-chloro-3-((2-fluoro-5-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl) acetic acid,

(7) (4-chloro-3-((2,5-debtor-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(8) (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)acetic acid,

(9) (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-were)acetic acid,

(10) (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(11) (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(12) (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-were)acetic acid,

(13) (5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-forfinal)acetic acid,

(14) (5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-were)acetic acid,

(15) (5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-forfinal)acetic acid,

(16) (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzac Azin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(17) (5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-forfinal)acetic acid,

(18) (5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-were)acetic acid,

(19) (5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-were)acetic acid,

(20) (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)acetic acid,

(21) (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)acetic acid,

(22) (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)acetic acid,

(23) (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)acetic acid,

(24) (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-were)acetic acid,

(25) (4-chloro-3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid,

(26) (2-chloro-5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(27) (2-chloro-5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(28) (2-chloro-5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(29) (4-chloro-3-((4-((3R)-2,3-dihydro-1-benzofuran-3-ylethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid,

(30) (4-chloro-3-((2,6-dimethyl-4-(((3R)-5-methyl-2,3-dihydro-1-benzofuran-3-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(31) (4-chloro-3-((4-((2S)-2,3-dihydro-1-benzofuran-2-ylethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid,

(32) (3-((4-(1,3-benzodioxol-2-ylethoxy)-2,6-dimethylbenzoyl)amino)-4-chlorophenyl)acetic acid, etc.

As more preferred compounds of this invention include the following:

(1) 2-(4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

(2) (4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(debtor)acetic acid,

(3) (4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(oxo)acetic acid,

(4) 2-(4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

(5) 2-(4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,

(6) 2-(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)-2-methylpropanoate acid,

(7) 1-(4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)m is toxi)benzoyl)amino)phenyl) cyclopropanecarbonyl acid,

(8) 1-(4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl) cyclopropanecarbonyl acid,

(9) 1-(4-chloro-3-((2-ethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl) cyclopropanecarbonyl acid,

(10) (4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(11) (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-were)acetic acid, etc.

The invention includes compounds in which R12and R13in the formula (I) are both hydrogen atoms and which meet at least one of the following conditions(1)-(6);

(1) R2is oxidized C1-6 alkyl, (2) two R2which are substituents on adjacent carbon atoms, together represent C2-5 alkylene (the C2-5 alkylene can be replaced by Deputy), in which the carbon atom may be replaced by oxygen atom, nitrogen atom or sulfur atom which may be oxidized, (3) two R2which are substituents on adjacent carbon atoms, together represent C2-5 ulkenin (the C2-5 ulkenin can be replaced by Deputy), in which the carbon atom may be replaced by oxygen atom, nitrogen atom or sulfur atom which may be oxidized, (4) R3 is oxidized C1-6 alkyl, (5) R4is oxidized C1-6 alkyl, and (6) R5is oxidized C1-6 alkyl, and their salts, solvate and their proletarienne form.

Specifically, for example, these include:

(3-((5-(hydroxymethyl)-2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-(hydroxymethyl)phenyl) acetic acid,

(4-chloro-3-((4-(((3R)-5-(hydroxymethyl)-2,3-dihydro-1-benzofuran-3-yl)methoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid,

(3-((5-formyl-2-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,

(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-formylphenyl)acetic acid,

(3-((2-chloro-3-fluoro-4-(((2S)-6-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-2-yl)methoxy)benzoyl)amino)-4-forfinal)acetic acid,

(5-((4-(((2R)-1-ethyl-2,3-dihydro-1H-indol-2-yl)methoxy)-2-(hydroxymethyl)-6-methylbenzoyl)amino)-2-were)acetic acid,

5-(((3-(carboxymethyl)phenyl)amino)carbonyl)-4-methyl-2-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy) benzoic acid,

4-(carboxymethyl)-2-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)benzoic acid, or

(6-((2,5-dimethyl-4-(((2)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2,3-dihydro-1H-inden-4-yl)acetic acid, etc.

Since the compounds according to this invention specifically bind to receptors DP and little contact with other receptors of prostaglandin, they have excellent selectivity. Additionally, compounds of this invention have excellent solubility. Physical, chemical and pharmacological properties that are most needed in the development of pharmaceuticals, the compounds of this invention meet the necessary conditions under which they can become excellent medicinal agents (The Merck Manual of Diagnosis and Therapy (17th Ed.), published by Merck & Co.

The method of obtaining the compounds according to this invention

The compounds of this invention represented by formula (I)can be obtained by known methods, for example, by methods shown below, by methods similar to those methods, and the methods shown in the examples. In addition, salt starting material can be used in each of the following processes. As such salts can be used pharmaceutically acceptable salts mentioned formula (I).

I. From among compounds represented by formula (I), the compound in which R1represents C1-4 alkyl, C2-4 alkenyl or benzyl, i.e. compounds represented by formula (IA)

where Q denotes-C(R12)(R13 )-, R1Ameans C1-4 alkyl, C2-4 alkenyl or benzyl, and the other symbols have the above meanings, can be obtained according to the process below.

(a) a Compound in which E is-C(=O)- or-S(O)2in the formula (IA), i.e. the compound represented by formula (IA-1)

where EArepresents-C(=O)- or-S(O)2and other symbols have the above meanings, can be obtained by amidation of the compound represented by formula (II-1)

where Q1is Q, R2-1has the same meanings as R2if necessary, carboxyl, hydroxyl, amino or thiol group represented by R2-1is protected , R4-1represents a hydrogen atom and the other symbols have the above values, or compounds represented by formula (II-2)

where R4-2represents C1-6 alkyl or benzyl, and the other symbols have the above meanings, with a compound represented by the formula (III)

where E1represents-COOH or-SO3H; G1, R3-1and R5-1have the same values as G, R3and R5accordingly, if necessary, carboxyl, hydroxyl, amino, a nitrogen atom or a thiol group represented by G1, R3-1 and R5-1are protected, and other symbols have the above values, with subsequent removal of the protective group.

The amidation reaction is known and its examples are

(1) process with the use of gelegenheid acid,

(2) a process using a mixed acid anhydride and

(3) a process using a condensing agent.

Such processes are more accurately explained next.

(1) process with the use of gelegenheid acid is carried out, for example, so that the carboxylic acid is subjected to reaction with galogenangidridy acid (oxalylamino and thionyl chloride and the like) in an organic solvent (chloroform, dichloromethane, diethyl simple ether, tetrahydrofuran, dimethoxyethane, toluene and the like) or without solvent at a temperature from -20°C to the boiling temperature with the return of phlegmy, and received gelegenheid acid is subjected to interaction with the amine in the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, 5-ethyl-2-methylpyridine (MEP) and the like) in an inert organic solvent (chloroform, dichloromethane, diethyl simple ether, tetrahydrofuran and the like) at a temperature of from 0 to 40°C. This reaction is preferably carried out in anhydrous conditions in an atmosphere of inert gas (argon and nitrogen and the like). This re is Ktsia can be conducted by reacting the obtained gelegenheid acid with amine in an organic solvent (dioxane, tetrahydrofuran, dichloromethane and the like) in the presence of a catalyst phase transfer or without (Quaternary ammonium salt such as tetrabutylammonium chloride, chloride of triethylenediamine, chloride, tri-n-octylacrylamide, chloride of triethyltetramine, bromide of Tetramethylammonium and the like) using an alkaline solution (aqueous sodium bicarbonate and aqueous sodium hydroxide solution and the like) at a temperature of from 0 to 40°C.

(2) a Process using a mixed acid anhydride is carried out, for example, so that the carboxylic acid are prepared to interact with galogenangidridy acid (pivaloyloxy, Teilhard and methylchloride, etc) or acid derivative (ethylchloride and isobutylparaben, and the like) at a temperature of from 0 to 40°C in the presence of an organic solvent or without (chloroform, dichloromethane, diethyl simple ether and tetrahydrofuran, and the like) in the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine and diisopropylethylamine, and the like), and the resulting mixed acid anhydride is subjected to reaction with amine in an organic solvent (chloroform, dichloromethane, diethyl simple ether, tetrahydrofuran and the like) at a temperature of from 0 to 40°C. This reaction is preferably carried out in anhydrous conditions in an atmosphere of inert gas (argon and nitrogen and the like).

(3) Process by using a condensing agent is carried out, for example, in such a way that carboxylic acid is subjected to reaction with an amine using a condensing agent (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1'-carbonyldiimidazole (CDI), iodide 2-chloro-1-methylpyridine, cyclic anhydride 1-propylphosphonic acid; PPA, etc. with 1-hydroxybenzotriazole (HOBt) or without, in the presence of a base or without (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine and the like) in an organic the solvent (chloroform, dichloromethane, dimethylformamide, diethyl simple ether, tetrahydrofuran and the like) or without solvent, at a temperature of 0 to 40°C. This reaction is preferably carried out in anhydrous conditions in an atmosphere of inert gas (argon and nitrogen and the like).

The reaction of removing the protective group for carboxyl, hydroxyl, amino or thiol known and its examples are as follows:

(1) hydrolysis with alkali;

(2) the reaction of removing the protective group in acidic conditions;

(3) the reaction of removing the protective group by hydrogenolysis;

(4) the reaction of removing the protective group silila;

(5) the reaction of removing the protective group using metal and

(6) the reaction of removing the protective group using ORGANOMETALLIC compounds.

These methods will be explained more later.

(1) the Reaction of removing the protective group used is the Finance alkali conduct, for example, at a temperature from 0 to 40°C, using a hydroxide of alkaline metal (sodium hydroxide, potassium hydroxide, lithium hydroxide and the like), hydroxide of alkaline earth metal (barium hydroxide and calcium hydroxide and the like), a carbonate (sodium carbonate and potassium carbonate and the like), an aqueous solution or their mixture in an organic solvent (methanol, tetrahydrofuran and dioxane, and the like).

(2) the Reaction of removing the protective group in acidic conditions is carried out, for example, at temperatures from 0 to 100°C in an organic acid (acetic acid, triperoxonane acid, methanesulfonate acid, p-tasilova acid and the like), inorganic acid (chloromethane acid and sulfuric acid and the like) or a mixture thereof (hydrogen bromide/acetic acid and the like) in an organic solvent (dichloromethane, chloroform, dioxane, ethyl acetate and anisole and the like) in the presence of 2,2,2-triptoreline or without it.

(3) the Reaction of removing the protective group by hydrogenolysis is carried out, for example, at a temperature of from 0 to 200°C in hydrogen atmosphere under normal pressure or high pressure or in the presence of ammonium formate, in the presence of a catalyst (palladium-carbon, palladium black, palladium hydroxide, platinum hydroxide, platinum oxide and Raney Nickel and the like)in a solvent (ethers (tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether and the like), alcohols (the ethanol, ethanol and the like), benzenes (benzene, toluene and the like), ketones (acetone, methyl ethyl ketone and the like), NITRILES (acetonitrile and the like), amides (dimethylformamide, and the like), water, ethyl acetate, acetic acid or a mixed solvent containing two or more of them, and so on).

(4) the Reaction of removing the protective group silila carried out, for example, at a temperature from 0 to 40°C, using tetrabutylammonium fluoride in an organic solvent, miscible with water, tetrahydrofuran, acetonitrile and the like).

(5) the Reaction of removing the protective group using metal carried out, for example, at a temperature from 0 to 40°C with ultrasonic treatment, if necessary, in the presence of powdered zinc in an acidic solvent (acetic acid, a buffer of pH 4.2 to 7.2 and a mixed solution of their solution and an organic solvent, such as tetrahydrofuran).

(6) the Reaction of removing the protective group using complex metal carried out, for example, at a temperature from 0 to 40°C, using a complex metal (tetranitroaniline palladium(0), dichloride, bis(triphenylphosphine)palladium(II)acetate, palladium(II)chloride, Tris(triphenylphosphine)rhodium(I) and the like), in the presence of a phosphine agent (triphenylphosphine and the like) or without it, in the presence of creating centers of capture reagent (anti-hydride, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine and the like), organic the Oh of the acid (acetic acid, formic acid, 2-ethylhexanoate acid and the like) and/or salts of organic acid (2-ethylhexanoate sodium 2-ethylhexanoate, potassium and the like) in an organic solvent (dichloromethane, dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol and the like), water or a mixed solvent.

In addition to this, removing the protective groups are described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999.

The protective group for carboxyl includes such as, for example, methyl, ethyl, allyl, tert-butyl, trichlorethylene, benzyl (Bn), phenacyl, p-methoxybenzyl, trityl, 2-chlorotrityl, solid-phase carrier, etc.

Protective hydroxyl group includes such as, for example, methyl, trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM), 2-tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl, benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl (Alloc), 2,2,2-trichlorocyanuric (Troc), etc.

The protective group for the amino group includes such as, for example, benzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl (Alloc), 1-methyl-1-(4-biphenyl)etoxycarbonyl (Bpoc), TRIFLUOROACETYL, 9-fluorenylmethoxycarbonyl, benzyl (Bn), p-methoxybenzyl, benzoyloxymethyl (BOM), 2-(trimethylsilyl)ethoxymethyl (SEM), etc.

The protective group is t the La includes such as for example, benzyl, methoxybenzyl, methoxymethyl (MOM), 2-tetrahydropyranyl (THP), diphenylmethyl, acetyl (Ac), etc.

As for the protective group for carboxyl, hydroxyl, amino and thiol, specific limitations for it does not exist until it is a group, which can be easily and selectively derived. For example, can be used are described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999”.

The person skilled in the art it is clear that the compound of this invention can be easily obtained by using the most appropriate of these reactions the removal of the protective group.

(b) a Compound of formula (IA)in which E represents-CH2-, i.e. the compound represented by formula (IA-2)

where all the symbols have the above meanings, can be obtained by reductive amination of compounds represented by formula (II-1) or formula (II-2), the compound represented by formula (IV)

where all the symbols have the above values, with subsequent removal of the protective group, if necessary.

The reaction of reductive amination is known, for example, it is conducted at a temperature from 0 to 40°C in the presence of a reducing agent (triacetoxyborohydride sodium, cyanoborohydride sodium, sodium borohydride and the like) in an organic dissolved the Le (tetrahydrofuran, diethyl simple ether, dichloroethane, dichloromethane, dimethylformamide, acetic acid, their mixtures and the like) or at a temperature of from 0 to 200°C in the presence of a catalyst (palladium-carbon, palladium black, palladium hydroxide, oxidized platinum, Raney Nickel and the like) in a solvent (ethers (tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether and the like), alcohols (methanol, ethanol and the like), benzenes (benzene, toluene and the like), ketones (acetone, methyl ethyl ketone and the like), NITRILES (acetonitrile and the like), amides (dimethylformamide, and the like), water, ethyl acetate, acetate or two or more such mixed solvents and the like) in an atmosphere of hydrogen under normal or elevated pressure.

(c) Compound represented by formula (IA)can also be obtained by esterification of the compound represented by formula (V)

where all the symbols have the above values, and compounds represented by the formula (VI)

where Z denotes a leaving group or a hydroxyl, and all other symbols have the above values, with subsequent removal of the protective group, if necessary.

The esterification reaction is known, and is performed, for example, at a temperature from 0°C to the boiling temperature with the return of phlegmy in the presence of a hydroxide of alkaline metal (sodium hydroxide, potassium hydroxide, g is droxia lithium and the like), hydroxide of alkaline earth metal (barium hydroxide, calcium hydroxide and the like), carbonate (cesium carbonate, sodium carbonate, potassium carbonate, calcium carbonate and the like), alkali metal hydride (sodium hydride, potassium hydride and the like), potassium phosphate (K3PO4or its solution, or a mixture thereof in an organic solvent (dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, diethyl simple ether, tetrahydrofuran, methyl-tert-butyl simple ether and the like), when used as a compound represented by formula (VI)in which Z denotes a leaving group. It is conducted, for example, at temperatures from 0 to 60°C in the presence of azo compounds (diethyl-azodicarboxylate, aminobutiramida-azodicarboxylate, 1,1'-(azodicarbon)piperidine, 1,1'-azobis(N,N-dimethylformamide and the like) and phosphine compounds (triphenylphosphine, tributylphosphine, trimethylphosphine, triphenylphosphine on the polymer carrier and the like) in an organic solvent (dichloromethane, diethyl simple ether, tetrahydrofuran, acetonitrile, benzene, toluene and the like), when used as a compound represented by formula (VI)in which Z denotes a hydroxyl.

(d) a Compound in which R4means R4-2or, for example, the compound represented by formula (IA-3)

where all the symbols have the above values, can also be obtained p the means of the reaction of N-alkylation of compounds represented by formula (IA-4)

where all the symbols have the above values, with subsequent removal of the protective group, if necessary.

The reaction of N-alkylation known and carried out, for example, at a temperature from 0 to 40°C, using alkyl(C1-6)halide or benzylamine in the presence of carbonate (cesium carbonate, sodium carbonate, potassium carbonate and the like) in an organic solvent (dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, diethyl simple ether, tetrahydrofuran and the like).

In the case of compounds in which E in the formula (IA-4) means-SO2-, it is also carried out, for example, at temperatures from 0 to 60°C, using C1-6 alkilany alcohol or benzyl alcohol in the presence of azo compounds (diethyl-azodicarboxylate, aminobutiramida-azodicarboxylate, 1,1'-(azodicarbon)piperidine, 1,1'-azobis(N,N-dimethylformamide and the like) and phosphine compounds (triphenylphosphine, tributylphosphine, trimethylphosphine, triphenylphosphine on the polymer carrier and the like) in an organic solvent (dichloromethane, diethyl simple ether, tetrahydrofuran, acetonitrile, benzene, toluene and the like).

II. The compound in which R1in the formula (I) represents a hydrogen atom, i.e. a compound represented by formula (IB)

where all the symbols have the above values, can b the th obtained by removal of the protective group for carboxyl connection represented by formula (IA), followed by reaction of removing the protective group for hydroxyl, amino, a nitrogen atom or thiol, if necessary.

The reaction of removing the protective group carboxyl can be done the same way as described above.

Specialists in this field it is clear that a particular connection according to this invention can easily be obtained by using the properly of these reactions the removal of the protective groups.

The reaction of removing the protective groups of hydroxyl, amino, a nitrogen atom or thiol can be conducted in much the same way as described above.

Compounds represented by formulas (II-1), (II-2), (III), (IV), (V) and (VI), by themselves, are known or can easily be obtained by known methods.

For example, compounds in which Q1means methylene, represented by formulas (II-1) and (II-2)can be obtained by the method shown in the following formula 1 reaction stage.

In the formula 1 stage reaction, X represents a halogen atom, R4-3represents C1-5 alkyl or phenyl and the other symbols have the above values.

For example, compounds in which Q1represents-C(R12A)(R13A)- (R12Aand R13Aeach independently represent C1-4 alkyl) among the compounds represented by formula (II-1)can be obtained by way PR is done in the following formula 2 stages of the reaction.

In the formula 2 reaction stages, all characters have the above values.

For example, compounds in which Q1represents-C(R12A)(R13A)- (R12Aand R13Atogether represent C2-5 alkylene (the C2-5 alkylene can be substituted by the Deputy (deputies)), where the carbon atom may be replaced by oxygen atom, nitrogen atom or sulfur atom which may be oxidized), among the compounds represented by formula (II-1)can be obtained by the method shown in the following formula 2-1 stages of the reaction.

In the formula 2-1 stages of the reaction Y represents C2-5 alkylene (the C2-5 alkylene can be substituted by the Deputy (deputies)), in which the carbon atom may be replaced by oxygen atom, nitrogen atom or sulfur atom which may be oxidized, and other symbols have the above values.

For example, compounds in which Q1is deformation or keto, among the compounds represented by formula (II-1)can be obtained by the method shown in the following formula 3 stages of the reaction.

In the formula 3 reaction stages, all characters have the above values.

In the formula 1-3 stages of the reaction of the compounds represented by formulas (VII), (XII) and (XV)used in the operation of the source materials, known or can easily be obtained by known methods, for example, by the method described in "Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)".

Among the compounds of this invention represented by formula (I), compounds, as expected for the above, can be easily obtained by a combination of the methods described in the examples herein, and known methods, for example, methods described in "Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)".

As is well known to specialists in this field, the reaction temperature in each reaction of this specification can be carried out using a bath, oil bath, sand bath or microwave.

In each reaction the following reagents in solid-phase carrier, printed on high-molecular polymer (for example, polystyrene, polyacrylamide, polypropylene, polyethylene, etc. can be properly used.

In each reaction described herein, the reaction product can be purified by conventional methods of purification, for example, by distillation at atmospheric or reduced pressure, liquid chromatography high-resolution, thin-layer chromatography or column chromatography using silica gel or magnesium silicate, washing or peracre what tellipalai etc., cleaning may be performed after each reaction or after several reactions.

The use of pharmaceutical drugs

Since the compounds according to this invention, represented by formula (I)bind to receptors DP and show antagonism towards them, it is assumed that the compounds applicable for the prevention and/or treatment of diseases mediated by receptors DP, such as allergic disease (such as allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food Allergy, and the like), systemic mastocytosis, disorders accompanied by systemic activation of mastocytes, anaphylactic shock, bronchostenosis, urticaria, eczema, pimples, allergic bronchial pulmonary aspergillosis, sinusitis, migraine, nasal polyp, anaphylactic vasculitis, eosinophilic syndrome, contact dermatitis, diseases accompanied by itch (such as atopic dermatitis, urticaria, allergic conjunctivitis, allergic rhinitis and contact dermatitis), diseases (such as cataract, retinal detachment, inflammation, infection, sleep disorders and so on)that occur secondarily as a result of behavior accompanied by itch (scratching, beat up, etc.), inflammation, chronic obstructive pulmonary diseases, ischemic reperfusion lesion,stroke, autoimmune disease, traumatic brain injury, hepatopathy, graft rejection, chronic rheumatoid arthritis, pleurisy, osteoarthritis, Crohn's disease, ulcerative colitis, symptoms of increased irritability of the intestines, interstitial cystitis, muscular dystrophy, polymyositis, and multiple sclerosis. In addition, it is assumed that connections are relevant to the process of sleep and platelet aggregation and applicable in their pathologies.

Among the compounds of this invention represented by formula (I), compounds having a weak activity of binding to other receptors than the DP receptors, could be used as pharmaceutical agents with reduced side effects, because they do not show other activity.

Toxicity

The toxicity of the compounds represented by formula (I), very low, so that the connection is secure enough for use as pharmaceutical agents.

The compounds of this invention represented by formula (I), their pharmaceutically acceptable salts and solvents can be introduced as a combined preparation by combining with other pharmaceutical agents for the purpose of: (1) to obtain additional and/or enhance the preventive and/or therapeutic effect of the compounds, (2) improve the pharmacokinetics and absorption, and SN is the position of the dose of the compound and/or (3) reducing the side effects of the compounds.

Combined preparation with the connection according to this invention, represented by formula (I), and other pharmaceutical agents can be introduced in the form of compounded remedies, in which both components are combined in the product, or can be in the form in which they are administered through the individual drugs. Case introduction by specific drugs involves the simultaneous introduction and introduction with the time difference. In the case of injections with the time difference, the connection according to this invention, represented by formula (I)may be introduced first, followed by the introduction of another pharmaceutical agent or other pharmaceutical agent may be introduced first, followed by the introduction of compounds according to this invention, represented by formula (I). Methods each of the introduction of the same or different.

The above-mentioned other pharmaceutical agents can be low molecular weight compounds, proteins, polypeptides, polynucleotide (DNA, RNA, and gene), desensibilization, bait, antibodies or vaccines, etc. doses of other pharmaceutical agents may be properly selected on the basis of the clinical dose. Moreover, the ratio of the compounding of another pharmaceutical agent and a pharmaceutical agent according to this invention can be properly selected depending on who is ASTA and weight of the subject, method of treatment, period of administration, disease, symptom, combination, etc. for Example, may be used, the mass ratio of from 0.01 to 100 other pharmaceutical agent per unit weight of the pharmaceutical agent according to this invention. Two or more arbitrary other pharmaceutical agents can be co-introduced appropriate. Pharmaceutical agents, allowing to obtain additional and/or reinforcing the preventive and/or therapeutic effect of the pharmaceutical agent according to this invention include not only those available at the time of this invention, but also those that will be opened in the future.

No specific restrictions diseases, preventable and/or treatable specified combination drug does not exist, since in this disease preventive and/or therapeutic effect when used as a pharmaceutical agent according to this invention is supplemented and/or enhanced.

Other pharmaceutical agents for additional and/or improved preventive and/or therapeutic effect of the compounds of this invention represented by formula (I), in allergic rhinitis include, for example, an antihistamine agent, an inhibitor of the release of mediators, an inhibitor of thromboxane synthetase, receptor antagonist trombon the Ana A2, antagonist of leukotriene receptor, steroid, stimulant receptor α-adrenaline, a derivative of xanthine, cholinergic-blocking agent, an inhibitor synthase nitric monoxide, etc.

Other pharmaceutical agents for additional and/or improved preventive and/or therapeutic effect of the compounds of this invention represented by formula (I), allergic conjunctivitis include, for example, the antagonist of the leukotriene receptor, an antihistamine agent, an inhibitor of the release of mediators, non-steroidal anti-inflammatory agents, prostaglandins, steroid, synthase inhibitor of nitric monoxide, etc.

Antihistamine agents include, for example, ketotifen fumarate, mequitazine, hydrochloride azelastina, oxatomide, terfenadine, the fumarate of emedastine, hydrochloride of epinastine, astemizole, Bastin, cetirizine hydrochloride, bepotastine, Fexofenadine, loratadine, desloratadine, hydrochloride olopatadine, TAK-427, ZCR-2060, NIP-530, mometasone furoate, mizolastine, BP-294, andrast, auranofin, acrivastine etc.

Inhibitors of the release of mediators include, for example, tranilast, sodium cromoglycate, amlexanox, reprint, ibudilast, casinolist and pemirolast potassium, etc.

Inhibitors of the thromboxane synthetase include, for example, the hydrochloride of ozagrel, microdust sodium, etc.

Inhibitors of the thromboxane-Sint the basins include, for example, the hydrochloride of ozagrel, microdust sodium.

Antagonists of thromboxane A2 receptor include, for example, seratrodast, ramatroban, hydrate Dimitrova calcium, KT-2-962 etc.

Antagonists of leukotriene receptor include, for example, the hydrate pranlukast, montelukast, zafirlukast, MCC-847, KCA-757, CS-615, YM-158, L-740515, CP-195494, LM-1484, RS-635, A-93178, S-36496, BIIL-284, ONO-4057, etc.

Steroid agents for external use include, for example, clobetasol propionate, acetate diflorasone, fluocinonide, furancarboxylic mometasone, betamethasone dipropionate, butyrate-propionate betamethasone valerate betamethasone difluprednate, budesonide, valerate of diflucortolone, amcinonide, halcinonide, dexamethasone, dexamethasone propionate, valerate, dexamethasone, dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate, butyrate-propionate hydrocortisone, propionate of depradine, valerate-propionate, prednisolone, acetonide fluoqinolona, propionate, beclomethasone, triamcinolone acetonide, pialat flumetazon, propionate alklometazon, valerate of clobetasone, prednisolone, beclomethasone propionate, fludroxycortide etc.

Medicines for internal use and injection include, for example, cortisone acetate, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, acetate fludrocortisone, prednisolone, prednisolone acetate,prednisolone sodium succinate, butyl acetate prednisolone, prednisolone sodium phosphate, acetate of halopedia, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, triamcinolone, triamcinolone acetate, triamcinolone acetonide, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, dexamethasone palmitate, acetate of paramethasone, betamethasone, etc.

Agents for inhalation include, for example, propionate, beclomethasone, fluticasone propionate, budesonide, flunisolide, triamcinolone, ST-126P, ciclesonide, palmitic dexamethasone, frankenbot mometasone, prasterone sulfonate, deflazacort, sulatan methylprednisolone, methylprednisolone sodium succinate, etc.

Xantina derivatives include, for example, aminophylline, theophylline, doxofylline, cipamfylline, diprophylline etc.

Anticholinergic agents include, for example, ipratropium bromide, bromide oxytrope, bromide plutopia, bromide, tiotropia, temiverine, Tiotropium bromide, reatreat (UK-112166), etc.

Nonsteroidal anti-inflammatory agents include, for example, aspirin, sodium salicylate, aspirin, dialuminum aspirin, diflunisal, indomethacin, suprofen, openmath, dimethylethanolamine, bufexamac, felbinac, diclofenac, tolmetin sodium, clinoril, fenbufen, nabumeton, proglumetacin, indomethacin farnesyl, acemetacin, proglumetacin maleate, amfenac n is tri, movetalk, etodolac, ibuprofen, ibuprofen of Picanol, naproxen, flurbiprofen, flurbiprofen aksetil, Ketoprofen, fenoprofen calcium, cuprofen, oxaprozin, pranoprofen, loxoprofen sodium, alminoprofen, zaltoprofen, marennikova acid, mefenamic aluminum, taftalenovaya acid, floctafenine, ketovinylation, oxyphenbutazone, piroxicam, tenoxicam, ampiroxicam, ointment Napageln, epirizole, hydrochloride tiaramide, hydrochloride tinoridine, emorfazone, colpurin, Amigrenin, Caledon, Sedes G, Amarelo-N, Solmon, cure colds pirazolonovogo type, acetaminophen, phenacetin, mesilate dimethocaine, simetric-compounded agent the cure for the common cold separationof type, etc.

There are no specific limitations to the relationship by mass of the compound represented by formula (I), to another pharmaceutical agent.

Two or more arbitrary other pharmaceutical agents may be introduced in combination.

Other pharmaceutical agents, which allow to obtain additional and/or improved preventive and/or therapeutic effect of the compound represented by formula (I)include not only those, which have already been found but also those which will be opened in the future on the basis of this mechanism.

When compounds represented by formula (I), or their non-toxic salts, use is e in this invention, or combination of drugs of the compounds represented by formula (I), and another pharmaceutical agent used for the specified purpose, they are usually systemically or topically administered in the form for oral or parenteral administration.

The dose varies depending on age, body weight, symptom, therapeutic effect, the route of administration, the treatment time and the like. Typically, an adult orally administered 1 mg to 1000 mg from one to several times a day, or adult parenterally administered from 1 mg to 100 mg, preferably in the form of tools for nose, eye drops or ointments) from one to several times a day, or continuously injected through a vein over 1 to 24 hours a day.

Because changes in the doses depend on various conditions listed above, there are cases when they can be used in doses above or below the specified limits.

Compounds represented by formula (I), or their non-toxic salts or the combined preparation of the compounds represented by formula (I), and another pharmaceutical agent used in the form of solid compositions, liquid compositions and other compositions for oral administration or in the form of a preparation for injection of the preparation for external use, suppositories etc. for parenteral administration.

Solid composition for oral administration VK is uchet pills, pills, capsules, diluted powder, granules, etc.

Capsules include hard capsules and soft capsules.

In such solid compositions one or more active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone and mixed metasilicate-magnesium aluminate. The composition may contain an additive which is different than the usual inert diluent, such as a lubricant, such as magnesium stearate, disintegrity agent, such as calcium glucose glycolate, a stabilizer such as lactose, and solubilizers agent such as glutamic acid and aspartic acid. Tablet or pill, if necessary, may be covered with a film soluble in the gastric or enteric substance such as sugar, gelatin, hydroxypropylcellulose and hypromellose phthalate, or can be covered by two or more layers. Capsule of substances that can be absorbed, such as gelatin, are also included.

Liquid composition for oral administration includes pharmaceutically acceptable emulsion/suspension, syrup, elixir and the like, In such liquid compositions, one or more active substances included in the commonly used inert diluent (what aka as clean water and ethanol). The composition may contain an adjuvant such as a humidifier or suspendisse agent, sweetener, flavoring agent, flavouring agent and antiseptic, in addition to the inert diluent.

Another composition for oral administration include spray agent that contains one or more active substances and prepared essentially known manner. In addition to the inert diluent, the composition may contain a stabilizer, such as hydrosulfite sodium, and a buffer, giving isotonicity, for example, giving isotonicity agent, such as sodium chloride, sodium citrate, citric acid and the like, a production Method of spraying agents are described, for example, in U.S. patent No. 2868691 and No. 3095355 in more detail.

Parenteral preparation for injection according to this invention include aseptic aqueous and/or nonaqueous solution, suspension and emulsion. Aqueous solution and the emulsion containing distilled water for injection and physiological saline. Non-aqueous solution and the emulsion contains propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohol such as ethanol, and Polysorbate 80 (registered trademark). It is also possible that aseptic agent and an aqueous or nonaqueous solution, suspension and emulsion can be mixed and used. Such a composition may further contain the AMB adjuvants, such as an antiseptic, moisturizer, emulsifier, dispersing agent, stabilizer (such as lactose) and solubilizers agent (such as glutamic acid and aspartic acid). They are sterilized, for example, by filtration, passing through catching bacteria filter, mixed with disinfectant substance or radiation. They can also be used in such a way that first of them get liofilizovannye solid active composition, which is then dissolved in sterilized or aseptic distilled water for injection or other solvent.

Form of administration in the form of eye drops for parenteral administration include eye drops, eye drops, suspension-type eye drops emulsion type, eye drops, which is dissolved before use, and eye ointment.

These eye drops can be prepared according to a known method. For example, in the case of eye drops, giving isotonicity agent (sodium chloride, concentrated glycerin and the like), buffering agent (sodium phosphate, sodium acetate and the like), a surfactant (Polysorbate 80 (trade name), polyoxyl stearate 40, polyoxyethylene hydrogenated castor oil and the like), a stabilizer (sodium citrate, edentate sodium and the like), an antiseptic agent (benzalkonium chloride, steam is Ben and the like) and the like are appropriately selected and prepared as necessary. They are sterilized in the final stage or prepared in aseptic conditions.

Agent for inhalation for parenteral administration includes aerosol drug powder for inhalation and liquid for inhalation. Liquid for inhalation may be in such a form that the ingredient is dissolved or suspended in water or another suitable medium immediately before use.

These agents inhalation receive according to a known method. For example, in the case of liquid for inhalation, an antiseptic agent (benzalkonium chloride, paraben and the like), a coloring agent, a buffer (sodium phosphate, sodium acetate and the like), giving isotonicity agent (sodium chloride, concentrated glycerin and the like), thickening agent (carboxyvinyl polymer and the like), an absorption promoter, etc. are suitably selected and prepared as necessary.

In the case of powder for inhalation lubricant (stearic acid, its salt and the like), a binder (starch, dextrin and the like), a diluent (lactose, cellulose and the like), krasivyi agent, antiseptic (benzalkonium chloride, paraben and the like), an absorption promoter, etc. are suitably selected and prepared as necessary.

With the introduction of liquid for inhalation usually use the spray device (spray, spray and the like) and with the introduction of powder for inhalation typically use the device for Inga is acii powder pharmaceutical agent.

Other compositions for parenteral administration include topical solution, ointment, liquid, ointment and suppositories for intrarectal administration and pessaries for intravaginal administration and the like, containing one or more active compounds which can be obtained by known methods.

Advantages of the invention

Since the compounds according to this invention, represented by formula (I)bind to receptors DP and show antagonism towards them, it is assumed that the compounds applicable for the prevention and/or treatment of diseases mediated by DP receptor, such as allergic disease (such as allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food Allergy, and the like), systemic mastocytosis, disorders accompanied by systemic activation of mastocytes, anaphylactic shock, bronchostenosis, urticaria, eczema, pimples, allergic bronchial pulmonary aspergillosis, sinusitis, migraine, nasal polyp, anaphylactic vasculitis, eosinophilic syndrome, contact dermatitis, diseases accompanied by itch (such as atopic dermatitis, urticaria, allergic conjunctivitis, allergic rhinitis and contact dermatitis), diseases (such as cataract, retinal detachment, inflammation, infection, disorders of SN and the like), which arise secondarily as a result of behavior accompanied by itch (scratching, beat up, etc.), inflammation, chronic obstructive pulmonary diseases, ischemic reperfusion lesion, stroke, autoimmune disease, traumatic brain injury, hepatopathy, graft rejection, chronic rheumatoid arthritis, pleurisy, osteoarthritis, Crohn's disease, ulcerative colitis, symptoms of increased irritability of the intestines, interstitial cystitis, muscular dystrophy, polymyositis, and multiple sclerosis. Additionally, connections are assumed to be relevant to the process of sleep and platelet aggregation and should be applicable against these pathologies.

The best course of action for carrying out the invention

The following comparative examples and examples explain the invention, but not limit the invention.

The solvents in parentheses are manifesting or eluting solvents, and used the relationship solvents are relations on the volume of the chromatographic separations or TLC. The solvents in parentheses in NMR are solvents for the dimension.

The names of the compounds presented in the examples given by ACD/Name (Version 6,00, Advanced Chemistry Development Inc.).

Example 1

4-methoxy-2,3-dimethylbenzoic acid

4-methoxy-2,3-dime ivansanchez (14.8 g) was dissolved in a mixed solvent of 2,2-DIMETHYLPROPANE (160 ml) and water (40 ml) and successively added to the mixture of the dihydrate of sodium dihydrophosphate (15.5 g), 2-methyl-2-butene (43 ml) and sodium chlorite (28.5 g) and the mixture is stirred for 2 hours at room temperature. Water and 1 N. chloroethanol acid is added to the reaction mixture, which is extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried with anhydrous magnesium sulfate. Specified in the title compound (14.3 g)having the following physical data, receive, allowing the precipitate obtained by removing the solvent, to precrystallization from a mixed solvent of n-hexane and ethyl acetate.

TLC:Rf value of 0.52 (chloroform:methanol:acetate= 9:1:0,1).

Example 2

4-hydroxy-2,3-dimethylbenzoic acid

In an argon atmosphere to a solution in dichloromethane (50 ml), which is dissolved obtained in example 1 compound (14.3 g), add a solution in dichloromethane of tribromide boron (1 M, 160 ml), the mixture is stirred over night at room temperature. To the reaction mixture, water is added and the aqueous layer was separated from the mixture, extracted with ethyl acetate. Extract mix the organic layer and the mixture is washed with saturated salt solution and dried with anhydrous magnesium sulfate. Specified in the header connection (13,2 g)having the following physical data, receive, allowing the precipitate obtained by removing the solvent, to precrystallization from a mixed solvent of n-Gex is on and ethyl acetate.

TLC:Rf of 0.32 (chloroform:methanol:acetate= 9:1:0,1).

Example 3

Methyl 4-hydroxy-2,3-dimethylbenzoic

In an argon atmosphere to anhydrous methanol (20 ml), to which is added thionyl chloride (4.4 ml) at 0°C, add a solution of compound (5 g)obtained in example 2 in anhydrous methanol (20 ml). The reaction mixture is stirred for 2 hours at 65°C and cooled to room temperature, then concentrated. Specified in the header connection (2,36 g)having the following physical data obtained by purification of the obtained residue column chromatography on silica gel (n-hexane:ethyl acetate = 5:1).

TLC:Rf of 0.29 (n-hexane:acetate = 4:1).

Example 4

(2-forfinal)methylamine

In an argon atmosphere formate (6,1 ml) is added dropwise to acetic anhydride (15,5 ml) at 0°C, stirred for 2 hours at 50°C. After cooling to room temperature the reaction mixture was diluted with tetrahydrofuran (THF; 10 ml). To dilute, add a solution of 2-foronline (5,56 g) in THF (20 ml) at room temperature and the mixture is stirred for 1 hour at room temperature. The residue obtained by concentrating the reaction mixture, dissolved in anhydrous THF (25 ml). In an argon atmosphere to a dry THF solution (25 ml) is added a complex of borane and tetrahydrofuran (1 M THF solution; 125 ml) at 0°C and the mixture is stirred during 2 hours at 50°C. Then the reaction mixture is cooled to room temperature, methanol (30 ml) and 4 n solution of hydrogen chloride in dioxane (10 ml) is added to the bath with ice and the mixture is stirred for 1 hour at 60°C. the Concentrated reaction mixture was added to 2 N. the sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried with anhydrous sodium sulfate. The solution is filtered by alicom (trade name) and the filtrate concentrated. To the residue is added a mixed solvent (hexane:ethyl acetate = 10:1) and filtered on silica gel. Specified in the header connection (6,45 g) obtained by concentration of eluent.

Example 5

(2S)-3-((2-forfinal)(methyl)amino)-1,2-propandiol

In an argon atmosphere a mixture of the compound (1.24 g)obtained in example 4 (R)-(+)-glycidol (1,11 g, aldrich, 98%ee) and ethanol (1 ml) is stirred for 12 hours at 50°C. Specified in the title compound having the following physical data obtained by concentration of the reaction mixture. Received specified in the header of the connection used for the next reaction without purification.

TLC:Rf of 0.40 (n-hexane:ethyl acetate = 1:1).

Example 6

((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methanol

To a solution of the compound obtained in example 5 in anhydrous dimethylformamide (DMF; 10 ml) is added tert-piperonyl ka the Oia (1.68 g) and the mixture is stirred for 3 hours at 80°C. The reaction mixture is added to water, then extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried with anhydrous sodium sulfate. The solution is filtered by alicom (trade name) and concentrate. Specified in the title compound (1.55 g, which is 97.6%ee)having the following physical data obtained by purification of the residue column chromatography on silica gel (hexane:ethyl acetate = 3:1).

TLC:Rf of 0.35 (n-hexane:ethyl acetate = 2:1).

Optical purity specified in the connection header accurately determined using liquid chromatography high resolution (IHVR).

Column: CHIRALCEL OD (Daicel Chemical Industries, Ltd.), and 0.46 cm × 25 cm

Flow rate: 1 ml/min

Solvent: hexane:2-propanol = 93:7

The wavelength of detection: 254 nm

Retention time: 30-70 minutes

Temperature: 24°C.

Example 7

((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl 4-methylbenzenesulfonate

In an argon atmosphere to a solution of the compound (a 3.06 g)obtained in example 6 in tetrahydrofuran (9 ml), add triethylamine (5 ml). To the reaction solution was added a solution of chloride of p-toluensulfonate acid (3.42 g) in tetrahydrofuran (9 ml) and N,N-dimethylaminopyridine (209 mg) and the mixture is stirred for 4 hours at room temperature. After adding water, the reaction solution is extracted with tert-butylmethylamine PR is stim ether. Extract utverjdayut by adding isopropyl alcohol to the residue obtained by concentrating the organic layer. Specified in the header connection (5,12 g)having the following physical data obtained by washing the filtered solids isopropyl alcohol and drying.

TLC:Rf 0,81 (n-hexane:ethyl acetate = 1:1).

Example 8

Methyl 2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoate

In an argon atmosphere to a solution in anhydrous N,N-dimethylformamide (40 ml) of the compound (2,05 g)obtained in example 3, then add cesium carbonate (of 7.82 g) and the compound (4.0 g)obtained in example 7. The reaction mixture is stirred for 4 hours at 75°C. After cooling to room temperature, water added to the reaction mixture, which is extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and dried with anhydrous magnesium sulfate. Specified in the header connection (to 3.89 g)having the following physical data obtained by purification of the residue obtained by removing the solvent, column chromatography on silica gel (n-hexane:ethyl acetate = 4:1).

TLC:Rf 0,73 (n-hexane:ethyl acetate = 2:1).

Example 9

2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoic acid

To the compound (3,85 g)obtained in example 8, add the 1,2-dimethoxyethane (40 ml), methanol (40 ml) and 1 n sodium hydroxide solution (30 ml). The reaction mixture carbonizing overnight at 67°C. After cooling to room temperature, to the reaction mixture is added methyl tert-butyl simple ether. After extraction 1 N. a solution of sodium hydroxide aqueous layer is neutralized 5 N. chloroethanol acid. The aqueous layer was extracted with ethyl acetate and the organic layer washed with water and saturated salt solution and dried with anhydrous magnesium sulfate. Specified in the header connection (3,70 g)having the following physical data, receive, allowing the precipitate obtained by removing the solvent, to precrystallization from a mixed solvent of n-hexane and ethyl acetate.

TLC:Rf 0.24 to (n-hexane:ethyl acetate = 2:1).

Example 10

2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl chloride

In argon atmosphere, the compound (400 mg)obtained in example 9, was dissolved in 1,2-dimethoxyethane (6,0 ml). Anhydrous N,N-dimethylformamide (one drop) and oxacillin (0,22 ml) are added to the reaction mixture, which is stirred for 30 minutes at 40°C. Specified in the title compound is obtained by concentration of the reaction mixture.

Example 11

Methyl (3-amino-4-forfinal)acetate

A mixture of 4-fluoro-2-nitrobenzoic acid (23.1 g), oxalicacid (16 ml), N,N-dimethylformamide is (0.10 ml) and 1,2-dimethoxyethane (250 ml) is stirred for 1 hour at room temperature. The acid chloride is obtained by concentration of the reaction mixture.

To a solution (2.0 M, 75 ml) trimethylsilyldiazomethane in n-hexane and a solution of triethylamine (35 ml) in tetrahydrofuran (100 ml) is added dropwise a solution of the previously obtained acid chloride in tetrahydrofuran (250 ml) and stirred for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate and extracted solid material is separated. Water added to the filtrate, which was extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and dried with anhydrous magnesium sulfate. Diazoketone obtained by removal of solvent.

To a solution (250 ml) diazoketone and triethylamine (15.7 ml) in ethanol added silver acetate (2,09 g) at room temperature, the mixture is stirred for 30 minutes at room temperature and for 30 minutes at 66°C. In addition, the acetate of silver (2,09 g) added and stirred for 30 minutes at 66°C. After cooling to room temperature, ethyl acetate and water added to the reaction mixture, which is filtered by alicom (trade name). The organic layer which separated from the filtrate, washed with water and saturated salt solution and dried with anhydrous magnesium sulfate.

Ethyl ester (3,89 g) is obtained by purification of the residue obtained by removing the solvent, the column is cromatografia on silica gel (n-hexane:ethyl acetate = 8:1). Solution (135 ml), ethyl ether complex and iron (18,8 g) in acetic acid is stirred for 0.5 hour at 60°C. the Reaction mixture is diluted with toluene and filtered by alicom (trade name). The filtrate is washed with water and saturated salt solution and dried with anhydrous magnesium sulfate. Specified in the title compound (10.4 g)having the following physical data obtained by removal of solvent.

TLC:Rf 0.69 (n-hexane:ethyl acetate = 2:1).

Example 12

Methyl (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)acetate

To a solution (1.0 ml) of the compound (135 mg)obtained in example 11, in dichloromethane successively added pyridine (0.10 ml) and the solution (1.5 ml) of the compound (210 mg)obtained in example 10, in dichloromethane. The reaction mixture is stirred for 30 minutes at room temperature. 1 N. chloroethanol acid (3.0 ml) and water added to the reaction mixture, which is extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and dried with anhydrous magnesium sulfate. Specified in the title compound (250 mg)having the following physical data obtained by purification of the residue obtained by removing the solvent, column chromatography on silica gel (n-hexane:ethyl acetate = 3:1).

TLC:Rf of 0.44 (n-hexane:ethyl acetate = 2:1).

Example 13

(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)acetic acid

To a mixture of compound (240 mg)obtained in example 12, 1,2-dimethoxyethane (5.0 ml) and methanol (5.0 ml) was added 1 n sodium hydroxide solution (3.0 ml) and the mixture is stirred for 1 hour at room temperature. Methyl tert-butylmethylamine simple ether is added to the reaction mixture, which is extracted with 1 N. a solution of sodium hydroxide. The aqueous layer was neutralized by adding 5 N. chloroethanol acid and extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and dried with anhydrous magnesium sulfate. Specified in the title compound (208 mg)having the following physical data, receive, allowing the precipitate obtained by removing the solvent, to precrystallization from a mixed solvent of n-hexane, ethyl acetate and tetrahydrofuran.

Property: crystalline;

TLC:Rf of 0.53 (chloroform:methanol:acetate= 9:1:0,1);

1H-NMR (DMSO-d6) δ: 2,16, 2,29, 2,85, 3,22, 3,40, 3,57, 4,22, 4,60, 6,59, 6,76, 6,94, 7,10, 7,19, 7,29, 7,57, 9,88, 12,35.

Example 13(1) example 13(31)

Compounds according to this invention having the following physical data, receive the same procedures as example 12 → example 13 using the appropriate acid chloride instead of the is to be placed, obtained in example 10, or using the corresponding amine instead of the compound obtained in example 11.

Example 13(1)

(4-chloro-3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid

Property: crystal;

TLC:Rf of 0.40 (n-hexane:ethyl acetate:acetic acid= 50:50:1);

1H-NMR (CDCl3) δ: 2,23, 2,43, 2,92, 3,29, 3,42, 3,70, 4,16, 4,27, 4,67, 6,69, 6,85, 7,02, 7,36, 7,94, 8,52.

Example 13(2)

(4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid

Property: crystal;

TLC:Rf of 0.54 (chloroform:methanol = 9:1);

1H-NMR (CDCl3) δ: 2,38, 2,91, 3,24, 3,39, 3,72, 4,12, 4,24, 4,63, 6,69, 6,86, 7,05, 7,37, 7,74, 8,50.

Example 13(3)

(4-chloro-3-((5-chloro-2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid

TLC:Rf of 0.54 (chloroform:methanol:acetic acid= 9:1:0,1);

1H-NMR (DMSO-d6) δ: 2,84, 3,22, 3,39, 3,61, 4,41, 4,63, 6,59, 6,77, 7,16, 7,37, 7,48, 7,71, 7,84, 9,82, 12,42.

Example 13(4)

(4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid

Property: crystal;

TLC:Rf of 0.29 (chloroform:methanol = 9:1);

1H-NMR (DMSO-d6) δ: 2,18, 2,42, 2,85, 3,22, 3,38, 3,58, 4,22, 4,59, 6,58, 6,70, 6,78, 6,87, 7,12, 7,38, 7,41, 7,54, 9,61, 12,36.

Example 13(5)

(4-chloro-3-((2-fluoro-5-methyl-4-(((2S)-4-methyl-3,4-dihyd the on-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid

Property: crystal;

TLC:Rf is 0.49 (chloroform:methanol:acetic acid= 9:1:0,1);

1H-NMR (DMSO-d6) δ: 2,18, 2,85, 3,21, 3,41, 3,60, 4,30, 4,61, 6,60, 6,76, 7,11, 7,47, 7,64, 7,81, 9,57.

Example 13(6)

(4-chloro-3-((2,5-debtor-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid

Property: crystal;

TLC:Rf of 0.44 (chloroform:methanol:acetic acid= 9:1:0,1);

1H-NMR (DMSO-d6) δ: 2,84, 3,17, 3,38, 3,61, 4,38, 4,62, 6,60, 6,76, 7,15, 7,39, 7,48, 7,65, 7,74, 9,75, 12,42.

Example 13(7)

(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)acetic acid

Property: crystal;

TLC:Rf of 0.43 (chloroform:methanol:acetic acid= 9:1:0,1);

1H-NMR (DMSO-d6) δ: 2,16, 2,22, 2,32, 2,85, 3,22, 3,40, 3,52, 4,21, 4,60, 6,59, 6,77, 6,99, 7,17, 7,30, 9,59, 12,28.

Example 13(8)

(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-were)acetic acid

Property: crystal;

TLC:Rf of 0.55 (chloroform:methanol:acetic acid= 9:1:0,1);

1H-NMR (DMSO-d6) δ: 2,15, 2,26, 2,84, 3,22, 3,40, 3,47, 4,21, 4,59, 6,59, 6,76, 6,93, 7,23, 7,44, 10,08, 12,29.

Example 13(9)

(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid

Property: crystal;

TLC:Rf is 0.42 (chloroform:methanol:acetic acid= 9:1:0,1);

1H-NMR (DMSO-d6) δ: 2,16 of 2.26, 2,84, 3,22, 3,40, 3,52, 4,22, 4,59, 6,59, 6,76, 6,95, 7,25, 7,56, 7,68, 10,15, 12,30.

Example 13(10)

(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid

Property: crystal;

TLC:Rf of 0.53 (chloroform:methanol:acetic acid= 9:1:0,1);

1H-NMR (DMSO-d6) δ: 2,24, 2,83, 3,16, 3,35, 3,53, 4,18, 4,56, 6,59, 6,76, 6,96, 7,25, 7,55, 7,67, 10,25, 12,31.

Example 13(11)

(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-were)acetic acid

Property: crystal;

TLC:Rf of 0.33 (chloroform:methanol:acetic acid= 9:1:0,1);

1H-NMR (DMSO-d6) δ: 2,24, 2,83, 3,16, 3,36, 3,47, 4,17, 4,55, 6,59, 6,75, 7,43, 10,17, 12,28.

Example 13(12)

(5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-forfinal)acetic acid

Property: crystal;

TLC:Rf of 0.55 (chloroform:methanol:acetic acid= 9:1:0,1);

1H-NMR (DMSO-d6) δ: 2,23, 2,83, 3,16, 3,36, 3,58, 4,18, 4,55, 6,59, 6,75, 7,13, 7,56, 7,72, 10,29.

Example 13(13)

(5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-were)acetic acid

Property: crystal;

TLC:Rf 0.36 and (n-hexane:ethyl acetate:acetic acid= 50:50:1);

1H-NMR (DMSO-d6) δ: 2,17, 2,19, 2,35, 2,84, 3,21, 3,39, 3,52, 4,23, 4,59, 6,59, 6,72, 6,79, 6,90, 7,09, 7,28, 7,47, 7,56, 9,99.

Example 13(14)

(5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-Benz is casin-2-yl)methoxy)benzoyl)amino)-2-forfinal)acetic acid

Property: crystal;

TLC:Rf of 0.37 (n-hexane:ethyl acetate:acetic acid= 50:50:1);

1H-NMR (DMSO-d6) δ: 2,18, 2,36, 2,84, 3,21, 3,39, 3,57, 4,23, 4,59, 6,59, 6,72, 6,79, 6,91, 7,12, 7,30, 7,58, 7,71, 10,12.

Example 13(15)

(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid

Property: crystal;

TLC:Rf of 0.60 (chloroform:methanol = 9:1);

1H-NMR (DMSO-d6) δ: 2,18, 2,36, 2,84, 3,21, 3,39, 3,51, 4,23, 4,59, 6,59, 6,72, 6,79, 6,94, 7,24, 7,29, 7,57, 7,66, 10,08.

Example 13(16)

(5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-forfinal)acetic acid

Property: crystal;

TLC:Rf of 0.41 (chloroform:methanol:acetic acid= 9:1:0,1);

1H-NMR (DMSO-d6) δ: 2,16, 2,26, 2,84, 3,22, 3,40, 3,59, 4,21, 4,59, 6,59, 6,76, 6,94, 7,13, 7,25, 7,57, 7,73, 10,20, 12,46.

Example 13(17)

(5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-were)acetic acid

Property: crystal;

TLC:Rf of 0.50 (chloroform:methanol:acetic acid= 9:1:0,1);

1H-NMR (DMSO-d6) δ: 2,15, 2,18, 2,26, 2,84, 3,21, 3,40, 3,52, 4,21, 4,59, 6,59, 6,77, 6,93, 7,09, 7,23, 7,47, 7,57, 10,06.

Example 13(18)

(5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-were)acetic acid

Property: crystal;

TLC:Rf of 0.50 (chloroform:methanol:acetic acid= 9:1:0,1);

1H-NMR (DMSO-d 6) δ: 2,18, 2,23, 2,83, 3,16, 3,36, 3,52, 4,17, 4,55, 6,59, 6,76, 7,09, 7,46, 7,56, 10,14.

Example 13(19)

(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)acetic acid

Property: crystal;

TLC:Rf and 0.46 (chloroform:methanol:acetic acid= 9:1:0,1);

1H-NMR (DMSO-d6) δ: 2,24, 2,32, 2,84, 3,16, 3,36, 3,52, 4,18, 4,56, 6,59, 6,76, 7,02, 7,17, 7,28, 9,71.

Example 13(20)

(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)acetic acid

Property: crystal;

TLC:Rf of 0.43 (chloroform:methanol:acetic acid= 9:1:0,1);

1H-NMR (DMSO-d6) δ: 2,28, 2,83, 3,16, 3,36, 3,56, 4,18, 4,56, 6,59, 6,76, 7,14, 7,54, 10,02.

Example 13(21)

(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)acetic acid

Property: crystal;

TLC:Rf of 0.47 (chloroform:methanol = 9:1);

1H-NMR (DMSO-d6) δ: 2,17, 2,38, 2,84, 3,21, 3,39, 3,56, 4,23, 4,59, 6,59, 6,72, 6,79, 6,91, 7,09, 7,18, 7,35, 7,54, 9,81.

Example 13(22)

(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)acetic acid

Property: crystal;

TLC:Rf and 0.62 (chloroform:methanol = 9:1);

1H-NMR (DMSO-d6) δ: 2,18, 2,21, 2,40, 2,84, 3,21, 3,39, 3,51, 4,23, 4,59, 6,60, 6,72, 6,79, 6,91, 7,01, 7,16, 7,25, 7,35, 9,55.

Example 13(23)

(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)enzoyl)amino)-5-were)acetic acid

Property: crystal;

TLC:Rf of 0.47 (chloroform:methanol = 9:1);

1H-NMR (DMSO-d6) δ: 2,17, 2,26, 2,35, 2,84, 3,21, 3,39, 3,46, 4,23, 4,59, 6,61, 6,76, 6,91, 7,28, 7,43, 10,00.

Example 13(24)

(4-chloro-3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid

Property: crystal;

TLC:Rf and 0.46 (chloroform:methanol = 9:1);

1H-NMR (CDCl3) δ: 2,39, 3,73, 4,21, 4,40, 4,57, 6,66, 6,88, 7,06, 7,37, 7,73, 8,51.

Example 13(25)

(2-chloro-5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid

Property: crystal;

TLC:Rf and 0.46 (chloroform:methanol:acetic acid= 9:1:0,1);

1H-NMR (DMSO-d6) δ: 2,16, 2,26, 2,84, 3,22, 3,40, 3,67, 4,22, 4,59, 6,59, 6,76, 6,95, 7,26, 7,37, 7,61, 7,80, 10,29, 12,46.

Example 13(26)

(2-chloro-5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid

Property: crystal;

TLC:Rf 0.39 to (n-hexane:ethyl acetate:acetic acid= 66:33:1);

1H-NMR (DMSO-d6) δ: 2,23, 2,83, 3,16, 3,36, 3,67, 4,18, 4,55, 6,59, 6,75, 7,38, 7,60, 7,79, 10,39.

Example 13(27)

(2-chloro-5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid

Property: crystal;

TLC:Rf 0,42 (n-hexane:ethyl acetate:acetic acid= 66:33:1);

1H-NMR (DMSO-d6) δ: 2,18, 2,36, 2,84, 3,21, 3,39, 3,66, 4,24, 4,59, 6,59, 6,72, 6,79, 6,92, 7,31, 7,37, 7,61, 7,79, 10,21.

Example 13(28)

(4-chloro-3-((4-((3R)-2,3-dihydro-1-benzofuran-3-ylethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid

Property: crystal;

TLC:Rf to 0.39 (chloroform:methanol = 9:1);

1H-NMR (CDCl3) δ: 2,38, 3,72, 3,92, 4,02, 4,16, 4,51, 4,71, 6,63, 6,84, 6,89, 7,05, 7,18, 7,30, 7,37, 7,73, 8,51.

Example 13(29)

(4-chloro-3-((2,6-dimethyl-4-(((3R)-5-methyl-2,3-dihydro-1-benzofuran-3-yl)methoxy)benzoyl)amino)phenyl)acetic acid

Property: crystal;

TLC:Rf to 0.39 (chloroform:methanol = 9:1);

1H-NMR (CDCl3) δ: 2,30, 2,38, 3,73, 3,88, 3,99, 4,16, 4,50, 4,69, 6,63, 6,73, 6,98, 7,05, 7,09, 7,37, 7,73, 8,52.

Example 13(30)

(4-chloro-3-((4-((2S)-2,3-dihydro-1-benzofuran-2-ylethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid

Property: crystal;

TLC:Rf of 0.40 (chloroform:methanol = 9:1);

1H-NMR (CDCl3) δ: 2,38, 3,13, 3,40, 3,73, 4,10, 4,22, 5,15, 6,65, 6,85, 7,05, 7,17, 7,37, 7,73, 8,51.

Example 13(31)

(3-((4-(1,3-benzodioxol-2-ylethoxy)-2,6-dimethylbenzoyl)amino)-4-chlorophenyl)acetic acid

Property: crystal;

TLC:Rf to 0.39 (chloroform:methanol = 9:1);

1H-NMR (CDCl3) δ: 2,38, 3,72, 4,27, 6,44, 6,66, 6,85, 7,05, 7,37, 7,73, 8,50.

Example 14

Methyl 2-(4-chloro-3-nitrophenyl)propanoate

In an argon atmosphere to a solution (14 ml) of methyl (4-chloro-3-nitrophenyl)acetate (300 mg) in tetrahydrofuran is added dropwise methyliodide (0,26 ml), a solution of N,N-aminobutiramida aminocyclohexane lithium (1.5 M, 2,32 ml) at -78°C. the PE clonney the mixture is stirred for 2 hours with increasing temperature up to room temperature. Water added to the reaction mixture, which is extracted with ethyl acetate. The organic layer is successively washed with diluted chloroethanol acid, water and saturated salt solution, dried with anhydrous magnesium sulfate. The compound (245 mg) according to this invention having the following physical data obtained by purification of the residue obtained by removing the solvent, column chromatography on silica gel (n-hexane:ethyl acetate = 5:1).

TLC:Rf of 0.37 (n-hexane:ethyl acetate = 4:1).

Example 15

Methyl 2-(4-chloro-3-nitrophenyl)-2-methylpropanoate

In an argon atmosphere to a solution (5 ml) of the compound obtained in example 14 in tetrahydrofuran is added dropwise methyliodide (0.01 ml) and a solution of N,N-diisopropylethylamine lithium (1.5 M, or 0.83 ml) at -78°C. the Reaction mixture is stirred for 2 hours with increasing temperature up to room temperature. Water added to the reaction mixture, which is extracted with ethyl acetate. The organic layer is successively washed with diluted chloroethanol acid, water and saturated salt solution and dried with anhydrous magnesium sulfate. Compound (118 mg) according to this invention having the following physical data obtained by purification of the residue obtained by removing the solvent, column chromatography on silica gel (n-hexane:ethyl acetate = 8:1).

TLC:Rf 0,42 (h-g is Xan:ethyl acetate = 4:1).

Example 16

Methyl 2-(3-amino-4-chlorophenyl)-2-methylpropanoate

The compound (116 mg)obtained in example 15, was dissolved in a mixed solvent of acetate (2.5 ml) and water (0.5 ml). Iron filings (133 mg) are added to the reaction mixture, which is heated up to 80°C, which is stirred for 30 minutes. Water added to the reaction mixture, which is extracted with ethyl acetate. The organic layer is successively washed with a saturated solution of sodium bicarbonate, water and saturated salt solution and dried with anhydrous magnesium sulfate. The compound (102 mg) according to this invention having the following physical data obtained by removal of solvent.

TLC:Rf 0.26 (n-hexane:ethyl acetate = 4:1).

Example 17

2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl chloride

In the atmosphere of argon oxalicacid (0.3 ml) and N,N-dimethylformamide (1 drop) is added to a solution of (4,5 ml) of 2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoic acid (488 mg, the compound obtained by the same procedures as a series of example 8 → example 9 → example 10 using methyl 4-hydroxy-2-chlorobenzoate instead of the compound obtained in example 3) in 1,2-dimethoxyethane, which is stirred for 1 hour at 40°C. Specified in the title compound is obtained by concentration of the reaction mixture.

Example 8

Methyl 2-(4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate

A solution of the compound obtained in example 17, in dichloromethane (1.8 ml) is added dropwise to a solution of the compound (100 mg)obtained in example 16, in dichloromethane (1.8 ml). Pyridine (0,057 ml) are added to the reaction mixture, which is stirred for 1 hour at room temperature. The reaction mixture is dissolved in water, extracted with ethyl acetate. The organic layer is successively washed with diluted chloroethanol acid, saturated sodium hydrogen carbonate solution and saturated salt solution and dried with anhydrous magnesium sulfate. Specified in the title compound (164 mg)having the following physical data obtained by purification of the residue obtained by removing the solvent, column chromatography on silica gel (n-hexane:ethyl acetate = 4:1).

TLC:Rf 0,41 (n-hexane:ethyl acetate = 2:1).

Example 19

2-(4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid

To a mixture of compound (162 mg)obtained in example 18, tetrahydrofuran (1.5 ml) and methanol (1.5 ml) was added 1 n sodium hydroxide solution (0.6 ml) and the mixture is stirred for 4 hours at 50°C. In addition, 2 N. hydroxide solution three is (0.6 ml) is added to the mixture, which is stirred for 3 hours at 50°C. the Reaction mixture is neutralized by adding 2 N. chloroethanol acid (0.6 ml) and extracted with ethyl acetate after addition of water. The organic layer was washed with saturated salt solution and dried with anhydrous magnesium sulfate. Specified in the title compound (124 mg)having the following physical data obtained by purification of the residue obtained by removing the solvent, column chromatography on silica gel (methylene chloride:ethyl acetate = 4:1).

Property: amorphous;

TLC:Rf 0.26 (n-hexane:ethyl acetate = 1:1);

1H-NMR (CDCl3) δ: 1,64, 2,91, 3,25, 3,38, 4,18, 4,27, 4,66, 6,71, 6,87, 6,96, 7,04, 7,11, 7,36, 7,88, 8,71.

Example 20

(4-chloro-3-nitrophenyl)((trimethylsilyl)oxy)acetonitrile

To a mixture of 4-chloro-3-nitrobenzaldehyde (3,71 g), zinc iodide (128 mg) and dichloromethane (50 ml) add trimethylsilylacetamide (2,9 ml) at a temperature of cooling with ice and the mixture is stirred for 1 hour at the same temperature. 1 N. chloroethanol acid is added to the reaction mixture, which is extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and dried with anhydrous magnesium sulfate. Specified in the header connection (5,95 g)having the following physical data obtained by removal of solvent.

TLC:Rf of 0.55 (n-hexane:ethyl acetate = 4:1).

Example 21

(4-chloro-3-nitrophenyl)hydroxy)acetic acid

Concentrated chloroethanol acid (30 ml) are added to a solution of compound (5,95 g)obtained in example 20 in acetate (30 ml), the mixture is stirred overnight at 90°C. the Reaction mixture was immersed in ice, and after cooling, extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and dried with anhydrous magnesium sulfate. Specified in the header connection (4,48 g)having the following physical data obtained by removal of solvent.

TLC:Rf 0.14 (n-hexane:ethyl acetate = 1:1).

Example 22

Ethyl (4-chloro-3-nitrophenyl)(hydroxy)acetate

R-toluensulfonate acid (367 mg) are added to a solution (50 ml) of the compound (4,48 g)obtained in example 21, in ethanol, and then stirred for 4 hours at 70°C. the Reaction mixture is cooled and extracted with ethyl acetate after addition of water. The organic layer is washed with water and saturated salt solution and dried with anhydrous magnesium sulfate. Specified in the title compound (4.83 g)having the following physical data obtained by removal of solvent.

TLC:Rf of 0.37 (n-hexane:ethyl acetate = 2:1).

Example 23

Ethyl (4-chloro-3-nitrophenyl)(oxo)acetate

To a solution (10 ml) of the compound (1,59 g)obtained in example 22, in acetic acid is added 10% solution of sodium hypochlorite (of 6.78 g) at a temperature of cooling with ice and stirred those which begins 1 hour at the same temperature. Acetate (10 ml) and 10% sodium hypochlorite solution (of 6.78 g) are added to the reaction mixture and optionally add acetate (10 ml) and 10% sodium hypochlorite solution (of 6.78 g) and the mixture is stirred for 2 hours. Water added to the reaction mixture, which is extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and dried with anhydrous magnesium sulfate. Specified in the title compound (414 mg)having the following physical data obtained by purification of the residue obtained by removing the solvent, column chromatography on silica gel (n-hexane:ethyl acetate = 4:1).

TLC:Rf 0.59 is (n-hexane:ethyl acetate = 2:1).

Example 24

Ethyl (4-chloro-3-nitrophenyl)(debtor)acetate

In the atmosphere of argon diethylaminoacetate (DAST) (311 mg) are added to a solution (5 ml) of the compound (414 mg)obtained in example 23, in dichloromethane at a temperature of cooling with ice, and then stirred for 2 hours at room temperature and for 2 hours at 45°C. Water is added to the reaction mixture, which is extracted with ethyl acetate. The organic layer is successively washed with a saturated solution of sodium bicarbonate, water and saturated salt solution and dried with anhydrous magnesium sulfate. Specified in the title compound (278 mg)having the following physical data obtained by purification (n-hexane:ethyl acetate = 9:7).

TLC:Rf of 0.57 (n-hexane:ethyl acetate = 4:1).

Example 25

Ethyl (3-amino-4-chloro)(debtor)acetate

The compound (253 mg)obtained in example 24 was dissolved in a mixed solvent of acetate (3 ml) and water (0.3 ml). Iron filings (253 mg) are added to the reaction mixture at 80°C, the mixture is stirred for 30 minutes at the same temperature. The reaction mixture was immersed into ice and extracted with a mixed solvent (1:1) of n-hexane and ethyl acetate. The organic layer is washed with water and saturated salt solution and dried with anhydrous magnesium sulfate. Specified in the title compound (194 mg)having the following physical data obtained by removal of solvent.

TLC:Rf of 0.48 (n-hexane:ethyl acetate = 4:1).

Example 26

Ethyl (4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(debtor)acetate

In an argon atmosphere to a mixture of compound (180 mg)obtained in example 25, pyridine (0.5 ml) and dichloromethane (1 ml) is added dropwise a solution (4 ml) of the compound (303 mg)obtained in example 17, in dichloromethane at a temperature of cooling with ice and the mixture is stirred over night at room temperature. 1 N. chloroethanol acid is added to the reaction mixture, which is extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and dried with anhydrous magnesium sulfate. Indicated the data in the title compound (207 mg), having the following physical data obtained by purification of the residue obtained by removing the solvent, column chromatography on silica gel (n-hexane:ethyl acetate= 4:1 → 3:1).

TLC:Rf of 0.55 (n-hexane:ethyl acetate = 2:1).

Example 27

(4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(debtor)acetate

To a mixture of compound (207 mg)obtained in example 26, ethanol (4 ml) and tetrahydrofuran (2 ml) was added 1 n sodium hydroxide solution (1 ml) and the mixture is stirred for 2 hours at room temperature. After neutralization by addition of 1 N. chloroethanol acid, the reaction mixture was extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and dried with anhydrous magnesium sulfate. The residue obtained by removal of the solvent, purified column chromatography on silica gel (n-hexane:ethyl acetate = 2:1 → methylene chloride:methanol = 9:1). The compound (135 mg) according to this invention having the following physical data obtained by washing the obtained solid substance methyl tert-butyl simple ether.

Property: amorphous;

TLC:Rf of 0.50 (dichloromethane:methanol:water= 80:20:1);

1H-NMR (DMSO-d6) δ: 2,84, 3,17, 3,37, 4,28, 4,57, 6,59, 6,76, 7,09, 7,21, 7,40, 7 ,58, 7,80, 10,12.

Example 28

Ethyl (atomic charges)(4-chloro-3-nitrophenyl)ACET the t

To a solution (6 ml) of the compound (1,46 g)obtained in example 22, in pyridine added acetic anhydride (2 ml) and the mixture is stirred for 1 hour at room temperature. Specified in the title compound (135 mg)having the following physical data obtained by concentrating the reaction mixture and the azeotropic processing in toluene.

TLC:Rf 0.56 to (n-hexane:ethyl acetate = 2:1).

Example 29

Ethyl (atomic charges)(3-amino-4-chlorophenyl)acetate

Connection (1,94 mg)obtained in example 28, was dissolved in a mixed solvent of acetate (10 ml) and water (1 ml). Iron filings (1,57 mg) are added to the reaction mixture at 80°C, then stirred for 30 minutes at the same temperature. The reaction mixture was immersed into ice and extracted with a mixed solvent (1:1) of n-hexane and ethyl acetate. The organic layer is washed with water and saturated salt solution and dried with anhydrous magnesium sulfate. Specified in the header connection (1,53 g)having the following physical data obtained by removal of solvent.

TLC:Rf of 0.47 (n-hexane:ethyl acetate = 4:1).

Example 30

Ethyl (atomic charges)(4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl) acetate

In an argon atmosphere to a mixture of compound (196 mg)obtained in example 29, pyridine (0.5 ml) and dichloromethane (1 ml) is added dropwise a solution (4 ml) is unity (303 mg), obtained in example 17, in dichloromethane at a temperature of cooling with ice and the mixture is stirred over night at room temperature. 1 N. chloroethanol acid is added to the reaction mixture, which is extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and dried with anhydrous magnesium sulfate. Specified in the title compound (207 mg)having the following physical data obtained by purification of the residue obtained by removing the solvent, column chromatography on silica gel (n-hexane:ethyl acetate= 4:1 → 2:1).

TLC:Rf 0.39 to (n-hexane:ethyl acetate = 2:1).

Example 31

Ethyl (4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(hydroxy)acetate

To a solution of compound (207 mg)obtained in example 30, in a mixed solvent of ethanol and tetrahydrofuran (6 ml) and 2:1) is added potassium carbonate (138 mg) and the mixture is stirred for 2 hours at 50°C. Water is added to the cooled reaction mixture, which is extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and dried with anhydrous magnesium sulfate. Specified in the title compound (169 mg)having the following physical data obtained by removal of solvent.

TLC:Rf of 0.38 (n-hexane:ethyl acetate = 1:1).

Example 32

Ethyl (4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(oxo)acetate

In an argon atmosphere to a mixture of compound (159 mg)obtained in example 31, diisopropylethylamine (0,30 ml), dimethyl sulfoxide (2 ml) and ethyl acetate (4 ml) is added a complex of sulfur trioxide and pyridine (139 mg) at a temperature of cooling with ice and the mixture is stirred for 1 hour at the same temperature. Water added to the reaction mixture, which is extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and dried with anhydrous magnesium sulfate. Specified in the title compound (104 mg)having the following physical data obtained by purification of the residue obtained by removing the solvent, column chromatography on silica gel (n-hexane:ethyl acetate= 3:1 → 2:1).

Example 33

Ethyl (4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(oxo)acetic acid

To a mixture of compound (104 mg)obtained in example 32, ethanol (2 ml) and tetrahydrofuran (2 ml) was added 1 n sodium hydroxide solution (0.5 ml) and the mixture is stirred for 2 hours at room temperature. After neutralization by addition of 1 N. chloroethanol acid, the reaction mixture was extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and dried with anhydrous magnesium sulfate. The compound (37 mg) according to this invention, having the e following physical data get cleaning residue obtained by removing the solvent, column chromatography on silica gel (n-hexane:ethyl acetate = 2:1 → methylene chloride:methanol = 9:1).

Property: amorphous;

TLC:Rf 0.45 in (dichloromethane:methanol:water= 80:20:1);

1H-NMR (DMSO-d6) δ: 2,84, 3,17, 3,37, 4,30, 4,58, 6,60, 6,76, 7,09, 7,21, 7,67, 8 ,10, 10,19.

Example 34

2-(4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid

By the same procedures as a series of example 18 and example 19, using the compound (121 mg)obtained in example 16, and 2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl chloride (211 mg) (compound obtained by the same procedures as a series of example 8 → example 9 → example 10 using methyl 4-hydroxy-2,6-dimethylbenzoic)will be specified in the header connection (132 mg)having the following physical data.

Property: crystalline;

TLC:Rf to 0.17 (hexane:ethyl acetate = 2:1);

1H-NMR (DMSO-d6) δ: 1,47, 2,32, 2,84, 3,16, 3,36, 4,18, 4,55, 6,59, 6,75, 7,24, 7,48, 7,55, 9,94.

Example 34(1)

2-(4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid

By the same procedures as a series of example 18 and example 19, using the compound (139 mg)obtained in example 16, the 2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl chloride (211 mg) (compound obtained by the same procedures as a series of example 8 → example 9 → example 10 using methyl 4-hydroxy-2,5-dimethylbenzoyl), get mentioned in the title compound (211 mg)having the following physical data.

Property: amorphous;

TLC:Rf of 0.18 (hexane:ethyl acetate = 2:1);

1H-NMR (DMSO-d6) δ: 1,47, 2,18, 2,42, 2,84, 3,21, 3,39, 4,24, 4,60, 6,59, 6,72, 6,79, 6,91, 7,22, 7,41, 7,47, 7,57, 9,69.

Example 35

2-(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)-2-methylpropanoate acid

By the same procedures as a series of example 18 and example 19 using methyl 2-(3-amino-4-were)-2-methylpropanoate (132 mg) (compound obtained by the same procedures as example 16) and 2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl chloride (210 mg) (compound obtained by the same procedures as a series of example 8 → example 9 → example 10 using methyl 4-hydroxy-2,5-dimethylbenzoyl), get mentioned in the title compound (202 mg)having the following physical data.

Property: crystalline;

TLC:Rf of 0.43 (chloroform:methanol:acetic acid ethyl ester= 9:1:0,1);

1H-NMR (DMSO-d6) δ: 1,45, 2,18, 2,20, 2,40, 2,84, 3,21, 3,39, 4,23, 4,59, 6,60, 6,75, 6,91, 7,10, 7,19, 7,32, 7,37, 9,56, 12,29.

Example 36

Methyl 2-(4-chloro-3-nitrophenyl)cyclopropane

To a solution of methyl 2-(4-chloro-3-nitrophenyl)aceta is a (2.0 g) and dibromoethane (3.8 ml) in N-methyl-2-pyrrolidone (58 ml) is added sodium hydride (766 mg) at room temperature. The mixture is then stirred for 1 hour at room temperature, for 1 hour at 40°C and then for 1 hour at 60°C. Optionally, add sodium hydride (766 mg) and stirred for 20 minutes. 1 N. chloroethanol acid is added to the reaction solution at a temperature of cooling with ice, the solution is extracted with a mixture of hexane-ethyl acetate (1:1). The extract is dried with anhydrous magnesium sulfate after washing with a saturated solution of salt. Specified in the header connection (762 mg)having the following physical data obtained by filtration, concentration and purification of column chromatography on silica gel (n-hexane:ethyl acetate = 6:1).

TLC:Rf 0,62 (n-hexane:ethyl acetate = 2:1).

Example 37

Methyl 2-(4-chloro-3-AMINOPHENYL)cyclopropenoid

Specified in the title compound (769 mg)having the following physical data obtained by the same procedures as example 16, using the connection (899 mg)obtained in example 36.

TLC:Rf 0,58 (n-hexane:ethyl acetate = 2:1).

Example 38

1-(4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl) cyclopropanecarbonyl acid

By the same procedures as a series of example 18 and example 19, using the compound (138 mg)obtained in example 37, and 2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-the l)methoxy)benzoyl chloride (211 mg) (compound obtained by the same procedures as a series of example 8 → example 9 → example 10 using methyl 4-hydroxy-2,6-dimethylbenzoic), get mentioned in the title compound (79 mg)having the following physical data.

Property: crystal;

TLC:Rf is 0.59 (chloroform:methanol = 9:1);

1H-NMR (DMSO-d6) δ: 1,13, 1,47, 2,32, 2,84, 3,16, 3,36, 4,18, 4,56, 6,59, 6,76, 7,21, 7,43, 7,54, 9,93.

Example 38(1)

1-(4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl) cyclopropanecarbonyl acid

By the same procedures as a series of reactions of example 18 and example 19, using the compound (138 mg)obtained in example 37, and 2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl chloride (211 mg) (compound obtained by the same procedures as a series of example 8 → example 9 → example 10 using methyl 4-hydroxy-2,5-dimethylbenzoyl)will be specified in the header compound (79 mg)having the following physical data.

Property: amorphous;

TLC:Rf is 0.59 (chloroform:methanol = 9:1);

1H-NMR (DMSO-d6) δ: 1,13, 1,46, 2,18, 2,42, 2,84, 3,21, 3,39, 4,24, 4,60, 6,59, 6,72, 6,79, 6,91, 7,20, 7,42, 7,56, 9,67.

Example 38(2)

1-(4-chloro-3-((2-ethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl) cyclopropanecarbonyl acid

By the same procedures as a series of reactions of example 18 and example 19, use the Zuya compound (207 mg), obtained in example 37 and 2-ethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl chloride (211 mg) (compound obtained by the same procedures as a series of example 8 → example 9 → example 10 using methyl 4-hydroxy-2-ethylbenzoic), get mentioned in the title compound (330 mg)having the following physical data.

Property: amorphous;

TLC:Rf of 0.60 (chloroform:methanol = 9:1);

1H-NMR (CDCl3) δ: 1,27, 1,34, 1,71, 2,93, 2,93, 3,28, 3,42, 4,17, 4,29, 4,67, 6,73, 6,86, 7,10, 7,34, 7,49, 7,94, 8,56.

Example 39

The binding of the ligand using cells expressing prostanoid receptor DP

The cells of the Chinese hamster ovary (CHO)expressing the receptor DP man, cultivate and, according to the conventional method, to prepare a membrane fraction. Membrane fraction (50 μl) (protein content: 42,65 μg), 100 μl of buffer for analysis (25 mmol/l HEPES-NaOH containing 1 mmol/l EDTA, 5 mmol/l of Mg2+and 10 mmol/l Mn2+; pH 7,4), 1 μl of vehicle (dimethyl sulfoxide; DMSO) or compound according to this invention (the final concentration of DMSO: 0.5%) and 50 μl of 10 nmol/l [3H]-PGD2(final concentration: 2.5 nmol/l) is added to a polyethylene tube and the incubation mixture is incubated at room temperature. In the group of non-specific binding of 2 mmol/l PGD2add instead of the medium (final concentration PGD2: 10 the KMOL/l). Twenty minutes later, 1 ml ice buffer for washing (10 mmol/l buffer Tris-HCl containing 0.01% of bovine serum albumin (BSA) and 100 mmol/l NaCl; pH 7,4) is added to the test tube to stop the reaction. Immediately collect the membrane fraction on the glass fiber filter (GF/B) by filtration under reduced pressure. Membrane fraction on the glass fiber filter was washed once with approximately 2 ml of buffer for washing and the glass fiber filter is dried. Dry the glass fiber filter is placed in a glass vessel, add scintillation cocktail for account and measure radioactivity with a scintillation counter.

Specific binding of [3H]-PGD2with the DP receptor is calculated by subtracting a value of radioactivity in the group of nonspecific binding of the quantities of radioactivity in the other groups than the group of non-specific binding. Inhibition compound in this invention is calculated on the basis of specific binding of [3H]-PGD2in groups, the media, and the present invention. The value of Ki (dissociation constant of the compound in this invention) is calculated according to the following formula using the estimated value IC50(the concentration of the compounds of this invention required for inhibition of specific binding in the group wear the I 50%).

Ki = IC50/(1+([L]*/Kd))

[L]*: concentration of [3H]-PGD2(2.5 mmol/l)

Kd: dissociation constant of [3H]-PGD2

The Kd value of [3H]-PGD2set based on nonlinear regression analysis after calculating the specific binding of [3H]-PGD2adding different concentrations of [3H]-PGD2in accordance with the above method.

The results of the measurements found that the compounds according to this invention exhibit strong binding to DP receptor with Ki values not more than 10 µmol/L.

Example 40

Measuring antagonistic activity against receptor DP using cells expressing prostanoid receptor DP

The CHO cells, stably expressing the receptor DP man, design, plated on 24-well plate for culturing at a density of cells 1×105cells/well and incubated at 37°C for 2 days in 5% CO2. Each well was washed with 500 μl of MEM (minimum support environment) and the cells incubated at 37°C for 10 minutes after adding 500 μl of MEM containing 2 mmol/l of diclofenac. After removal of the supernatant by aspiration add 450 ál of MEM, soderjasimi 1 mmol/l 3-isobutyl-1-of methylxanthines, 2 µmol/l diclofenac and 1% BSA (environment analysis), followed by incubation at 37°C use the f for 10 minutes. The reaction is initiated by adding 50 μl of medium for analysis containing PGD2the medium or environment for analysis containing PGD2and the connection according to this invention (the final concentration of PGD2: 10 nmol/l), followed by incubation at 37°C. Ten minutes later, add 500 ál of ice trichloroacetic acid (TCA, 10% wt./vol.), to stop the reaction. After freezing (-80°C) and thawing of the reaction mixture of cells extracted from it with a scraper for the cells, followed by centrifugation at 13000 rpm for 3 minutes. The obtained supernatant is collected and the concentration of cAMP in the supernatant determined by radioimmunoassay analysis using a test kit cAMP (manufactured by Amersham). Thus, the buffer set for the analysis of [125I]cAMP added to aliquot the sample 125 µl of the supernatant obtained above to a volume of 500 μl and the resulting solution is mixed with 1 ml of 0.5 mol/l tri-n-octylamine in chloroform. After extraction with TCA in the chloroform layer, the amount of cAMP in the water layer quantitatively determined according to the procedure specified in the test kit [125I]cAMP.

Antagonistic activity of the compounds according to this invention for the DP receptor is expressed, counting as the value of the IC50(the concentration of the compounds according to this invention, which is necessary to suppress the production of cAMP in otsutstvie compounds according to this invention by 50%) the percentage inhibition of the production to the production of cAMP at 10 nmol/l, where PGD2identifies submaximum production cAMP.

From the above measurement results found that the compounds according to this invention show a strong antagonism against the DP receptor at values IC50not more than 10 µmol/L.

An example of the preparation of compositions 1

The following components are mixed in the usual way and tabletirujut to obtain 10,000 tablets each containing 10 mg of active ingredient.

(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)acetic acid100 g
Carboxymethylcellulose calcium (disintegrator)20 g
Magnesium stearate (lubricant)10 g
Microcrystalline cellulose870 g

An example of the preparation of compositions 2

The following components are mixed in the usual way, where the mixture is filtered through removing the dust filter and placed in 5 ml ampoules. Ampoules are sterilized by heating in an autoclave, to thereby obtain 10,000 ampoules each containing 20 mg of active ingredient.

(3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)acetic acid200 g
Mannitol20 g
Distilled water50 l

Industrial application

Since the compounds according to this invention, represented by formula (I), are associated with the DP receptor and exhibit antagonistic activity towards him, it is expected that the compounds applicable for the prevention and/or treatment of diseases mediated by receptors DP, such as allergic disease (such as allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food Allergy, and the like), systemic mastocytosis, disorders accompanied by systemic activation of mastocytes, anaphylactic shock, bronchostenosis, urticaria, eczema, pimples, allergic bronchial pulmonary aspergillosis, sinusitis, migraine, nasal polyp, anaphylactic vasculitis, eosinophilic syndrome, contact dermatitis, diseases accompanied by itch (such as atopic dermatitis, urticaria, allergic conjunctivitis, allergic rhinitis and contact dermatitis), diseases (such as cataract, retinal detachment, in which spalanie, infection, sleep disorders and so on)that occur secondarily as a result of behavior accompanied by itch (scratching, beat up, etc.), inflammation, chronic obstructive pulmonary diseases, ischemic reperfusion lesion, stroke, autoimmune disease, traumatic brain injury, hepatopathy, graft rejection, chronic rheumatoid arthritis, pleurisy, osteoarthritis, Crohn's disease, ulcerative colitis and the syndrome of increased irritability of the intestines. In addition, connections are assumed to be relevant to the process of sleep and platelet aggregation and applies such disorders.

1. Connection carboxylic acid represented by the formula (I)

where R1represents (1) hydrogen atom, (2) C1-4 alkyl;
E represents-CO-;
R2is (1) halogen atom, (2) C1-6 alkyl, (3) trihalomethyl;
R3is (1) halogen atom, (2) C1-6 alkyl;
R4represents (1) hydrogen atom;
R5represents (1) C1-6 alkyl;
represents phenyl;
G represents (1) C1-6 alkylene;
is 9-12-membered ring of the bicyclic heterocycle containing heteroatoms selected from 1 to 4 nitrogen atoms, one or two oxygen atoms;
m represents 0 or an integer from 1 to 4
n represents 0 or an integer Chi is lo from 1 to 4, and
i represents 0 or an integer from 1 to 11,
where R2may be the same or different when m is 2 or more, R3may be the same or different when n is 2 or more, and R5may be the same or different, when i is 2 or more; and
R12and R13each independently represent (1) C1-4 alkyl, (2) halogen atom, (3) hydroxyl, or (4) a hydrogen atom, or R12and R13taken together, represent (1) oxo, or (2) C2-5 alkylene, and where, when R12and R13each simultaneously represent a hydrogen atom, the compound of carboxylic acid represented by the formula (I)is a compound selected from the group consisting of compounds (1)to(32):
(1) (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)acetic acid,
(2) (4-chloro-3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,
(3) (4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,
(4) (4-chloro-3-((5-chloro-2-fluoro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,
(5) (4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,
(6) (4-chloro-3-((2-fluoro-5-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxa the h-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,
(7) (4-chloro-3-((2,5-debtor-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,
(8) (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)acetic acid,
(9) (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-were)acetic acid,
(10) (3-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,
(11) (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,
(12) (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-were)acetic acid,
(13) (5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-forfinal)acetic acid,
(14) (5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-were)acetic acid,
(15) (5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-forfinal)acetic acid,
(16) (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,
(17) (5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-forfinal)acetic acid,
(18) (5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)Ben is oil)amino)-2-were)acetic acid,
(19) (5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-2-were)acetic acid,
(20) (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)acetic acid,
(21) (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)acetic acid,
(22) (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-forfinal)acetic acid,
(23) (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)acetic acid,
(24) (3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-were)acetic acid,
(25) (4-chloro-3-((4-((2R)-2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid,
(26) (2-chloro-5-((2,3-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,
(27) (2-chloro-5-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,
(28) (2-chloro-5-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid,
(29) (4-chloro-3-((4-((3R)-2,3-dihydro-1-benzofuran-3-ylethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid,
(30) (4-chloro-3-((2,6-dimethyl-4-(((3R)-5-methyl-2,3-dihydro-1-benzofuran-3-yl)methoxy)Ben is oil)amino)phenyl)acetic acid,
(31) (4-chloro-3-((4-((2S)-2,3-dihydro-1-benzofuran-2-ylethoxy)-2,6-dimethylbenzoyl)amino)phenyl)acetic acid and
(32) (3-((4-(1,3-benzodioxol-2-ylethoxy)-2,6-dimethylbenzoyl)-amino)-4-chlorophenyl)acetic acid, its salt or its MES.

2. The compound according to claim 1, where the group of the formularepresents a group of the formulaselected from dihydroisoxazole-2-yl, benzodioxan-2-yl, dihydrobenzofuran-2-yl, dihydrobenzofuran-3-yl and benzodioxol-2-yl.

3. The compound according to claim 1, where n means an integer from 2 to 4.

4. The compound according to claim 3, where a group of the formularepresents a group of the formula,
where all the symbols have the meanings indicated in claim 1.

5. The compound according to claim 4, where a group of the formularepresents a group of the formula,or
where all the symbols have the meanings indicated in claim 1.

6. The compound according to claim 5, where R3each independently represent (1) a halogen atom, or (2) 1-6 alkyl.

7. The compound according to claim 1, where R12and R13each independently represent (1) C1-4 alkyl, (2) halogen atom, (3) hydroxy or (4) a hydrogen atom, or R12and R13taken together, represent (1) oxo, or (2) C2-5 alkylene.

8. The connection according to claim 6, which is selected from the trail is affected:
(1) 2-(4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,
(2) (4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(debtor)acetic acid,
(3) (4-chloro-3-((2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)(oxo)acetic acid,
(4) 2-(4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,
(5) 2-(4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)-2-methylpropanoate acid,
(6) 2-(3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-were)-2-methylpropanoate acid,
(7) 1-(4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl) cyclopropanecarbonyl acid,
(8) 1-(4-chloro-3-((2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl) cyclopropanecarbonyl acid,
(9) 1-(4-chloro-3-((2-ethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl) cyclopropanecarbonyl acid,
(10) (4-chloro-3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)phenyl)acetic acid and
(11) (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-5-meth is fenil)acetic acid.

9. Pharmaceutical composition having antagonistic activity against receptor DP containing the compound represented by formula (I)

where all the symbols have the meanings indicated in claim 1, its salt or its MES.

10. The pharmaceutical composition according to claim 9, which is an agent for prevention and/or treatment of diseases mediated by receptor DP.

11. The pharmaceutical composition of claim 10, where the disease mediated by receptor DP, an allergic disease, systemic mastocytosis, disorders accompanied by systemic activation of mastocytes, anaphylactic shock, bronchostenosis, urticaria, eczema, acne, allergic bronchial pulmonary aspergillosis, sinusitis, migraine, nasal polypus, anaphylactic vasculitis, eosinophilic syndrome, contact dermatitis, diseases accompanied by itch, diseases that occur secondarily as a result of conduct, accompanied by itching, inflammation, chronic obstructive pulmonary diseases, ischemic reperfusion lesion, stroke, autoimmune disease, traumatic brain injury, hepatopathy, graft rejection, chronic rheumatoid arthritis, pleurisy, osteoarthritis, Crohn's disease, ulcerative colitis, symptoms of increased irritability of the intestines, interstitial cystitis, mysen what I dystrophy, polymyositis, multiple sclerosis, sleep disorders or disease related to platelet aggregation.

12. The pharmaceutical composition according to claim 11, where the allergic disease is allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma or food Allergy.

13. The use of compounds represented by formula (I)according to claim 1, its salt or its MES to obtain a pharmaceutical composition for prevention and/or treatment of diseases mediated by receptor DP.

14. The use of compounds represented by formula (I)according to claim 1, its salt or its MES to obtain a DP receptor antagonist.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to new compounds of formula I: , where m ranges from 0 to 3, n ranges from 1 to 3, p is 0, Ar is phenyl, possibly substituted with C1-C6-alkyl, cycloalkyl, hydroxyalkyl, halogen, hydroxyl or cyano group, X is -O-,R1 and R2 each is independently hydrogen, C1-6alkyl or C1-6alkoxy-C1-6alkyl or hydroxy-C1-6alkyl, or one of R1 and R2 is hydrogen or C1-6 alkyl, and the other is C1-6alkylcarbonyl, C3-C8 cycloalkyl, aryl-C1-6alkyl or hydroxyl, or R1 and R2 together with the nitrogen atom to which they are bonded can form a three- to seven-member ring, which can possibly contain an additional N heteroatom, or R1 and R2 together with the nitrogen atom to which they are bonded can form a guanidyl group, amidinyl group, carbamyl group or urea group, each R3 is independently C1-6alkyl, R4 and R5 each is independently hydrogen or C1-6alkyl; or their pharmaceutically acceptable salts, as well as pharmaceutical compositions containing these compounds.

EFFECT: invention can selectively modulate 5-HT receptors, including 5-HT6 and 5-HT2A receptors.

17 cl, 1 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I) as separate stereoisomers and their mixtures, or their physiologically acceptable salts possessing with inhibitory effect on VIIa factor. In the general formula of compounds of the formula (I) m = 0, 1, 2, 3 or 4; n = 0, 1, 2 or 3; A represents halogen atom; X represents oxygen atom; R1 is chosen from hydrogen atom, (C1-C6)-alkoxycarbonyl and (C6-C14)-aryloxycarbonyl wherein all aryl groups are free or substituted with (C1-C6)-alkoxy-group; R2is chosen from hydrogen atom, (C1-C6)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl, R20 -(C1-C6)-alkyl, R20-(C6-C14)-aryl and R20-(C6-C14)-(C1-C4)-alkyl wherein R20 is chosen from hydroxycarbonyl, aminocarbonyl; R3 is chosen from hydrogen atom, cyano-, hydroxy-group and (C1-C6)-alkyl; R4 is chosen from (C1-C6)-alkyl, (C-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl, Het and Het-(C1-C4)-alkyl wherin alkyl, atryl and Het groups are free or substituted with one or some similar or different substitutes R10; R5 is chosen from hydrogen atom, (C1-C6)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl wherein alkyl and aryl groups are free or substituted with one or some similar or different substituted R10; or R4 and R5 in common with carbon atom with that they are bound form saturated or unsaturated 5-6-membered ring that represents carbocyclic ring or heterocyclic ring comprising 1 or 2 similar ring heteroatoms chosen from nitrogen and oxygen atoms and possibly condensed with one or two saturated or unsaturated carbocyclic ring system comprising from 5 to 10 ring atoms wherein the final R4(R5)C-group is free or substituted with one or some similar or different substitutes R10; R6 is chosen from hydrogen atom and hydroxy-group. Also, invention relates to a method for synthesis of compound of the formula (I) and pharmaceutical composition based on thereof. Compounds of the formula (I) can be used in preparing medicinal agents useful for inhibition or decreasing blood coagulation or inflammatory response or for using in treatment of cardiovascular disorders, thrombo-embolic diseases or restenosis.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

14 cl, 1 sch, 71 ex

The invention relates to a method of stereoselective obtain enantiomer heterobicyclic alcohol

The invention relates to compounds of dehalogenation, insecticide/acaricidal agents containing these compounds as active ingredients and intermediates for their production

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel soluble pharmaceutical salts formed from salt-forming active compound of the general formula (I) or (II) and sugar substitute that can be used in preparing medicinal agents useful in pain and enuresis treatment. Salt-forming active substance represents a salt-forming compound among 1-phenyl-3-dimethylaminopropane compounds of the general formula (I) wherein X means -OH, F, Cl, H or group -OCOR6; R1 represents (C1-C4)-alkyl group; R2 represents H or (C1-C4)-alkyl group; R3 represents H or (C1-C4)-alkyl group with a direct chain, or R2 and R3 form in common (C4-C7)-cycloalkyl group and if R5 means H then R4 represents group O-Z in meta-position wherein Z means H,(C1-C3)-alkyl, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl), -CONH-C6H4-(C1-C3-alkyl), -CO-C6H4-R7 wherein R7 represents -OCO-C1-C3-alkyl in ortho-position or group -CH2N(R8)2 in meta- or para-position and wherein R8 means (C1-C4)-alkyl or 4-morpholino-group, either R4 represents S-(C1-C3)-alkyl in meta-position, meta-Cl, meta-F, group -CR9R10R11 in meta-position wherein R9, R10 and R11 mean H or F, group -OH in ortho-position, O-(C2-C3)-alkyl in ortho-position, para-F or group -CR9R10R11 in para-position wherein R9, R10 and R11 mean H or F, or if R5 means Cl, F, group -OH or O-C1-C3-alkyl in para-position then R4 means Cl, F, group -OH or O-(C1-C3)-alkyl in meta-position, or R4 and R5 form in common group 3,4-OCH=CH- or OCH=CHO-; R6 means (C1-C3)-alkyl, or salt-forming active substance represents a salt-forming compound among 6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general formula (II) wherein R1' represents H, -OH, Cl or F; R2' and R3' have similar or different values and represent H, (C1-C4)-alkyl, benzyl, -CF3, -OH, -OCH2-C6H5, O-(C1-C4)-alkyl, Cl or F under condition that at least one among radicals R2' either R3' means H; R4' represents H, -CH3, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl, -CO-NH-C6H4-(C1-C3)-alkyl, -CO-C6H4-R5', CO-(C1-C5)-alkyl), -CO-CHR6'-NHR7' or unsubstituted either substituted pyridyl, thienyl, thiazolyl or phenyl group; R5' represents -OC(O)-(C1-C3)-alkyl in ortho-position or -CH2N(R8')2 in meta- or para-position and wherein R8' means (C1-C4)-alkyl, or both radicals R8' in common with nitrogen atom (N) form 4-morpholino-group, and R6' and R7' have similar or different values and represent H or (C1-C6)-alkyl under condition that if both radicals R2' and R3' represent H then R4' doesn't mean -CH3 when R1' represents additionally H, -OH or Cl, either R4' doesn't mean H when R1' represents additionally -OH. Also, invention relates to a medicinal agent based on indicated salts.

EFFECT: valuable medicinal properties of salts and drug.

14 cl, 1 tbl, 8 ex

Novel benzodioxols // 2304580

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzodioxol of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and X are given in the description and the invention claim, and to their pharmaceutically acceptable salts. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I) and their using for preparing medicinal agents used in treatment and/or prophylaxis of diseases associated with modulation of CB1 receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 279 ex

The invention relates to compounds of General formula I

including their optical isomers and mixtures of such isomers, where r1denotes hydrogen, C1-C6alkyl, C3-C6cycloalkyl or aryl, optionally substituted by 1-3 halogen atoms, R2and R3each independently of one another denote hydrogen or C1-C6alkyl, R4stands WITH1-C6alkyl or C3-C6quinil, R5, R6, R7and r8each denotes hydrogen and

,

r10denotes aryl, optionally substituted by 1-3 substituents selected from the group comprising halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl,1-WITH4haloalkoxy,1-C4alkoxy, C1-C4alkyl, C1-C6alkylthio,3-C6alkyloxy, nitro and C1-C6alkoxycarbonyl or optionally substituted heteroaryl representing aromatic kolicevo the t hydrogen, WITH1-C6alkyl or C3-C6quinil, R12denotes hydrogen or C1-C6alkyl, Z represents hydrogen,- CO-R16or-CO-COOR16and R16stands WITH1-C6alkyl, -CH2-CO - C1-C6alkyl or phenyl

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of new complexing analytical reagents which are suitable for doping nanoparticles and for use in luminescence-spectral analysis, biochip technology, as well as extractants of ions of heavy and rare-earth metals. Description is given of complexing benzo-containing heterocyclic compounds, which contain a β-dicarbonyl substitute with fluorinated radicals of formula: HetAr-C(O)CH2C(O)CF3, where HetAr= ,

which form luminescent complexes with Eu3+ ions. Proposed compounds are on the same level as compounds with closely resembling structure with regards to duration of luminescence and bonding efficiency, although they are easily accessible with respect technology of production and have high water solubility >10-4 mol/l, which enables their use in making conceptually new biochips with time, spatial and spectral signal selection.

EFFECT: high output of desired product.

1 cl, 5 dwg, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula II or their pharmaceutically acceptable salts, where R1 is H or C1-C10 alkyl; R2 is H or C1-C10 alkyl; n ranges from 0 to 4; p ranges from 0 to 1; R3 and R4 represent H, as well as to pharmaceutical compositions based on said derivatives and methods of treating cardiac arrhythmia using these compositions.

EFFECT: increased effectiveness of composition and method of treatment.

15 cl, 12 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new substituted phenoxy-aceitic acids (I), in which: X is halogen, cyano, nitro or C1-4alkyl, which is substituted with one or more halogen atoms; Y is chosen from hydrogen, halogen or C1-C6alkyl, Z is phenyl, naphthyl or ring A, where A is a six-member heterocyclic aromatic ring containing one or two nitrogen atoms, or can be 6,6- or 6,5-condensed bicycle which contains one O, N or S atoms, or can be 6,5-condensed bicycle which contains two O atoms, where phenyl, naphthyl or ring A can all be substituted with one or more substitutes, independently chosen from halogen, CN, OH, nitro, COR9, CO2R6, SO2R9, OR9, SR9, SO2NR10R11, CONR10R11, NR10R11, NHSO2R9, NR9SO2R9, NR6CO2R6, NR9COR9, NR6CONR4R5, NR6SO2NR4R5, phenyl or C1-6alkyl, where the last group can possibly be substituted with one or more substitutes, independently chosen from halogen; R1 and R2 independently represent a hydrogen atom or C1-6alkyl group, R4 and R5 independently represent hydrogen, C3-C7cycloalkyl or C1-6alkyl, R6 is a hydrogen atom of C1-6alkyl; R8 is C1-4alkyl; R9 is C1-6alkyl, possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; R10 and R11 independently represent phenyl, 5-member aromatic ring which contains two heteroatoms, chosen from N or S, hydrogen, C3-C7cycloalkyl or C1-6alkyl, where the last two groups are possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; or R10 and R11 together with the nitrogen atom to which they are bonded, can form a 3- to 8-member saturated heterocyclic ring, which possibly contains one or more atoms chosen from O, S(O)n (where n= 0, 1 or 2), NR8.

EFFECT: invention relates to a method of modulating activity of CRTh2 receptors, involving administration of therapeutically effective amount of formula compound or its pharmaceutically acceptable salt to a patient.

9 cl, 170 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): that are useful as antagonists of prostaglandin IP (I2 or PGI2). Invention proposes compound of the formula (I) wherein each R1, R2 and R3 means independently in each case aryl or heteroaryl; R4 means -COOH or tetrazolyl; A, B, m, p, q, n and r are determined in the invention description. Also, invention relates to separated isomers, racemic or nonracemic mixtures of isomers and to their pharmaceutically acceptable salts or solvates also. Also, invention relates to pharmaceutical compositions comprising indicated compounds, to a method for their preparing and using as therapeutic agents. Invention provides the development of pharmaceutical composition possessing property of antagonists of IP wherein antagonists of these receptors can prevent states associated with excessive bleeding, for example, (but not only) hemophilia and hemorrhage and relieve septic shock-associated hypotension and diminish formation of edemas.

EFFECT: valuable medicinal properties of compounds.

28 cl, 15 sch, 29 ex

The invention relates to chemical-pharmaceutical industry, specifically to a method for producing 2-butyl-3-(3,5-dead-4-oxybenzoyl)benzofuran - intermediate production drugs antianginal and antiarrhythmic actions of amiodarone
The invention relates to an improved process for the preparation of 2-butylbenzofuran, which is used as intermediate for the production of 2-butyl-3-[4-(2-diethylaminoethoxy)-3,5-diadvisor]benzofuran

The invention relates to a method for producing derivatives of 3-(5-methylfur-2-yl)-benzofuran having an antihypertensive, antianginal and antiarrhythmic activities

The invention relates to the field of organic chemistry and pharmaceuticals, namely heterobicyclic compounds and pharmaceutical compositions based on them, as well as methods of producing these compounds

The invention relates to new derivatives benzofuranyl-carboxylic acid, which has anti-inflammatory activity of General formula I

< / BR>
in which R1group of the formula OR3where R3- cycloalkyl, 6-membered saturated a heterocycle;

R2is unsubstituted or substituted phenyl;

V - Allenova chain;

W - tetrazolyl, the group COR6or CONR7R8where R6, R7and R8- alkyl, cycloalkyl, phenyl, hydrogen
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