Casr antagonist


FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel compound represented by the following formula (1) , its pharmaceutically acceptable salts or optically active isomers wherein each symbol is given in the invention description. Proposed compound possesses antagonistic effect with respect to calcium-sensitive receptor (CASR). Also, invention relates to a therapeutically medicinal agent used in treatment of osteoporosis based on this compound, to a method for treatment of osteoporosis, calcium receptor antagonist and to agent promoting secretion of parathyroid hormone (PTH).

EFFECT: valuable medicinal properties of antagonist.

33 cl, 66 tbl, 5 ex

 

The technical field

The present invention relates to compounds having antagonistic activity against calcium-sensing receptor (CaSR), hereinafter referred to for simplicity as calcium receptor), pharmaceutical compositions containing the compound, in particular the calcium antagonist receptor, and a therapeutic agent for the treatment of osteoporosis.

The level of technology

Calcium receptors recognize the extracellular concentration of Ca2+and increase the intracellular content of Ca2+, suppressing thus the production of parathyroid hormone (PTH), involved in the control of metabolism of Ca2+and bone metabolism.

Calcium concentration in the serum of healthy mammal is rigidly supported at the level of 9-10 mg/100 ml (approximately 2.5 mm), which is referred to as the calcium homeostasis of living organisms. When this value drops to a level of not more than 50%, it tetany, and on the contrary, when it exceeds 50% of this level, the mind is beclouded, both cases are life threatening. To maintain calcium homeostasis duodenum acts as the body's absorption of Ca2+bones act as a storage organ Ca2+and kidneys act as the body's excretion of Ca2+. T is Kai kinetics of Ca 2+is controlled by various hormones, commonly referred to as the "calcium-regulatory hormone". Illustrative hormones include active vitamin D [1α, 25(OH)2D3], PTH, calcitonin, parathyroid hormone-related protein (PTH-related protein (PTHrP)and the like.

Bones play an important role not only as a support frame and motor organ of the body, but also as a storage organ Ca2+, which is a constituent component. To perform these functions bone repeat its formation (osteogenesis) and absorption (bone resorption) throughout life. In osteogenesis main role of osteoblasts derived from mesenchymal cells and bone resorption main role of osteoclasts formed from hematopoietic cells. The mechanism of osteogenesis involves the formation of osteoid through organic bone matrix (bone matrix proteins such as collagen type I, and the like)produced by osteoblasts present in osteogenesis surface, with subsequent calcination. On the other hand, the mechanism of bone resorbtive includes adhesion osteoclast to the bone surface, intracellular absorption of Ca2+through secretion by acid of ion transport and the selection of absorbion is th Ca 2+to the side of the bone marrow, releasing, thus Ca2+in the blood. The missing part of the bone, absorbed by osteoclasts, restored at the expense of osteogenesis through osteoblast. This series of events is called bone remodeling, and through remodeling, old bone is replaced by new, supporting, thus, the strength of all the bones, while supported on calcium homeostasis.

PTH is a hormone that plays a key role in maintaining calcium homeostasis. When the concentration of Ca2+in the blood is reduced, immediately promoterwise secretion of PTH from the parathyroid gland, which in effect on bone osteoblast (activation osteoclast with the help of osteoblasts, the production of bone organic matrix, the decomposition of the enzyme, and the like) for promotion osteoclastic resorbtive bones, while Ca2+transferred from the bones into the blood. In the kidney, PTH promotiom the resorption of Ca2+in the peripheral twisted tubules and activates 25(OH) vitamin D3in the proximal tubules, promotora thus the production of active vitamin D3[1α, 25(OH)2D3], the function of which is the promotion of resorbtive Ca2+from the intestines. It also inhibits the resorption of phosphorus. As noted above, PTH direct the military and indirectly increases the concentration of Ca 2+blood.

When the concentration of Ca2+in the blood increases, the calcium receptor can feel it, immediately suppressing the secretion of PTH from the parathyroid gland to reduce the number of Ca2+supplied in blood [Brown, E.M., Homeostatic mechanisms regulating and increasing interest among intracellular calcium metabolism in the parathyroids, p.19, (1994), Raven press, New York]. Secretion of PTH is also suppressed active vitamin D [1α, 25(OH)2D3].

Because PTH is a hormone that takes an important role in controlling the metabolism of Ca2+and bone metabolism, attempts were made to use PTH in the treatment of osteoporosis. In 1982, Tam et al. found that long introduction bovine PTH (1-84) rats with remote thyroid/parathyroid gland leads to promotion as osteogenesis and bone resorbtive femoral trabecular bone, resulting in a net bone mass, whereas its periodic subcutaneous introduction does not lead to the promotion of bone resorption, and to the promotion only osteogenesis, causing an increase in bone mass [Endocrinology,110, 506-512 (1982)]. Further, Uzawa and others, compared the effect of prolonged administration and periodic introduction of PTH in respect of long bone epiphyseal and metatithemi spongy bone in young rats. In the result, it was found that the continuous introduction of PTH leads to the considerable increase bone mass metatithemi spongy bone, highly exposed to endochondral ossification, however, associated with anomalous discoveries, such as hyperplasia epiphyseal flat cartilage, fibrous octet and the like, and to a marked promotion of bone resorbtive and reduced bone mass, accompanied by liquefaction of tubular bones, epiphyseal trabecular bone, where the effect was small [Bone,16, 477-484 (1995)]. In addition, it was reported that the periodic introduction of PTH leads to a noticeable increase in bone mass and bone crossbar in the epiphyseal and metatithemi the cancellous bone without increasing osteoclast or decrease bone.

Moreover, Scutt and others, reported that osteoblasts derived from cranial vault chicken, short processing time (10-20 min) using PTH promotiom cell growth compared with continuous treatment (18 hours) [Calcif. Tissue Int.,55, 208-215 (1994)]. This suggests that some of the effects of PTH on osteoblasts are temporary and that the manifestation of the action when processing within an extremely short period of time may be due to the fact that long introduction and periodic introduction of PTH in vivo have different effects on bone tissue.

Ishizuya and other advanced clarified in the study of the actions of PTH on the differentiation is of osteoblasts using the experimental systems in vitro, that the action of PTH varies depending on the processing time. They reported that long-term effect of PTH on osteoblasts derived from the cranial roof rats, leads to a strong inhibition of the differentiation of osteoblasts and almost complete inhibition of osteogenesis in vitro, whereas repeated exposure PTH within the first 6 hours of the 48-hour cycle leads to a significant promotion of the differentiation of osteoblasts and promotion of osteogenesis in vitro.

It is assumed that PTH not only prevents bone mass reduction on the model of osteoporosis, but also has a regenerating effect on bone mass even in animals already suffering from a noticeable decrease in bone mass. Wronski, etc. periodically injected PTH (1-34) human rat SD at the age of 90 days, of which 4 weeks ago was held oophorectomy and which has resulted in a marked decrease in cancellous bone, for 15 weeks, starting from 4 weeks after oophorectomy. As a result, promotion of osteogenesis and inhibiting resorbtive bones was observed in the period from 5 weeks to 10 weeks after the beginning of the introduction that was manifested in the increase of bone mass is approximately two times compared with bone mass in rats of the sham operated group [Endocrinology,132, 823-831 (1993)]. The authors also reported that in this experiment, estrogen and bisphos eat prevented the decrease in bone mass, caused by oophorectomy, but unlike PTH, they did not lead to increased bone mass. The authors examined the tubular bone in this experimental system and identified samples showing promoted osteogenesis and increased bone mass at the periosteal and endosteal side of the periodic introduction of PTH (1-34) of a person based on what they have found out that the increase in spongy bone because PTH is not accompanied by a decrease in bone [Bone,15, 51-58 (1994)].

In addition, Mosekilde et al. reported that the periodic introduction of PTH (1-34) person or PTH (1-84) human causes not only increase bone mass, but also a dose-dependent increase of the compressive strength and bending strength, which are indicators for bone, spongy bone [Endocrinology,129, 421-428 (1991)] and bone [J. Bone Miner. Res.,8, 1097-1101 (1993)] bones of the spine rats. As discussed above, since PTH has obvious increase bone mass effect on experimental animals, various studies relating to restrictive conditions, the expected real-world clinical applications.

Mizoguchi examined, observed or not observed in reality pharmacological action in the periodic introduction of PTH, even when PTH is contained in the blood, which is considered the Xia as one of the factors, responsible for osteoporosis, and concluded that bone mass was increased in the usual way [Journal of Japanese Society of Bone Morphometry, vol. 5, pp. 33 - 39 (1995)]. Takao and others investigated the frequency of introduction of PTH and reported that the introduction of once a week for 12 weeks in healthy rat almost promotiom the resorption of bone, but increases bone mass in a dose-dependent manner [Japanese Journal of Bone Metabolism, vol. 12 (Suppl.), p. S343 (1994)], putting forward the suggestion of a possible clinical efficacy of low-frequency injection. The above achievements have allowed us to suggest the possibility of using PTH to create a strong and promising therapeutic drugs for the treatment of postmenopausal osteoporosis or postovariectomy osteoporosis, which increases bone mass and reduces the percentage of broken bones.

These results clearly show that the periodic introduction of PTH could enable treatment of osteoporosis. On the other hand, PTH is the need of injection as a route of administration that painful for many patients. However, one can expect a considerable extent that oral input pharmaceutical agent that could periodically increase the concentration of PTH in the blood and which is based on a new mechanism of action in contrast to the above PTH and common calcite is Nina, will be a therapeutic drug for the treatment of osteoporosis.

Calcium receptor is associated with a G-protein receptor, cloned as a molecule required for the control of PTH secretion, and which penetrates through the cell membrane 7 times. Calcium receptor of a person consists of 1078 amino acids and has a 93%amino acid homology with bovine calcium receptor. Calcium receptor of a person consists of a large N-terminal extracellular region consisting of 612 amino acids, the field penetration through the cell membrane, consisting of 250 amino acids, and a C-terminal intracellular region, consisting of 216 amino acids.

It is established that the expression of calcium receptor occurs in the parathyroid gland, kidney, thyroid C-cells, brain and the like, as well as in the bones (bone marrow cells).

When the calcium receptor is associated with a ligand, such as Ca2+and the like, it activates the phospholipase C in combination with G-protein, causing the production of inositoltrifosfata and increase the intracellular concentration of Ca2+and as a result suppresses the secretion of PTH [Nature,366, 575-580 (1993)].

As noted above, a pharmaceutical agent that inhibits the activation of the calcium receptor, or pharmaceutical agent that is an antagonist of alliage receptor, stops the suppression of PTH secretion in the cells of the parathyroid gland and promotiom the secretion of PTH. It is assumed that if the antagonistic action can increase the concentration of PTH in the blood periodically and discrete, its antagonist is expected to demonstrate the same effect, which is provided by the periodic introduction of PTH, and thus may be provided with a pharmaceutical agent, is extremely effective for the treatment of osteoporosis.

In contrast, cytochrome (cytochrome P450, then P450) is a protein having a molecular weight of about 50000, which contains protogen. And its physical features may vary in a wide range. For example, it has the function of an enzyme catalyzing different reactions of drug metabolism. CYP2D6, belonging to the family of P450 (CYP)is an important enzyme for drug metabolism and is involved in the metabolism of many compounds. When you enter a drug inhibiting the metabolic function of CYP2D6, the drug accumulates in the body and can have a strong impact. Accordingly, as a drug, preferably a compound which has a weak inhibitory effect on CYP2D6 metabolic functions.

Earlier it was reported about the different compounds, useful to the operation of the CaSR antagonists.

Specifically, for example, noted the connection represented by the following formula:

where A represents an aryl, etc., D represents C or N; each of X1and X5represents hydrogen, cyano, etc. and each of X2X3and X4represents hydrogen, halogen, C1-4alkyl, etc. (WO 02/38106).

Additionally noted the connection represented by the following formula:

where A represents an aryl, etc., D represents C or N; each of X1and X5represents hydrogen, cyano, etc., X2represents hydrogen, etc. and each of X3and X4represents hydrogen, C1-4alkyl, etc. (WO 02/34204).

In addition, the marked compound represented by the following formula:

where A represents C or N, D represents C or N, X is a cyano, nitro, etc., Y represents chlorine, fluorine, etc. and Ar represents a phenyl, naphthyl, etc. (WO 02/07673).

In addition, the described compound represented by the following formula:

where X represents a cyano, nitro, etc., Y represents chlorine, fluorine, etc. and Ar represents a phenyl, naphthyl, etc. (JP 2002-536330-T, WO 00/45816, EP 1148876-A, US 6417215),

and with the Association, represented by the following formula:

where each of X1X2X3X4and X5represents H, halogen and the like, Y1is a covalent bond or unsubstituted or substituted alkylene etc., Y2represents an unsubstituted or substituted methylene, Y3is a covalent bond, and so on, each of R3and R4independently represents a methyl, ethyl, etc., R5represents aryl, polycyclic aryl, etc., R7represents H, OH, etc., R8represents H, C1-4alkyl, etc., A and B independently represent a bond, CH2and so, G is a covalent bond, CHR6(R6represents H, and so on), etc. (JP 2002-510671-T, WO 99/51569, EP 1070048-A, US 6395919).

As a CaSR antagonist described compound represented by the following formula:

where X has the following formula:

where each of X1X2X3and X4independently represents CN, NO2and so on, then W is an R1, SO2R1etc., R2represents H, C1-4alkyl, etc. and the like, Y1is a covalent bond, or unsubstituted or someseni alkylen etc., Y2represents an unsubstituted or substituted methylene, Y3is a covalent bond, O, etc., R3and R4independently represent methyl, ethyl, etc., R5is heteroaryl, condensed heteroaryl etc., R7represents H, OH, etc., R8represents H, C1-4alkyl, etc., A and B, each independently, is a bond, CH2etc., and G represents a covalent bond, CHR6(R6represents H, and so on), etc. (JP 2002-510636-T, WO 99/51241, EP 1069901-A, US 2002052509-A).

As a CaSR antagonist describes the following compounds: compound represented by the following formula:

where Y1is a covalent bond, alkylene etc., Y2represents an unsubstituted or substituted methylene, C1-4alkyl, etc., Z is a covalent bond, O, etc., R3and R4each independently represents methyl, ethyl, etc., R5represents phenyl, naphthyl, etc., G represents a covalent bond or C-R6where R6represents H, OH, etc., R7represents H, OH, etc., R8represents H, C1-4alkyl, etc., fragment A-B represents CH2CH2, covalent bond, etc. and X has the following formula:

img src="https://img.russianpatents.com/855/8553803-s.jpg" height="34" width="89" >

where W is an R1, SO2R1where R1represents hydrogen, C1-4alkyl, etc. and the like, each of X1X2X3and X4independently represents CN, NO2etc., R2represents hydrogen, C1-4alkyl, etc. and the like (JP 2001-523223-T, WO 98/45255, EP 973730-A, US 6294531),

the compound represented by the following formula:

where R1represents aryl, etc., R2represents a hydroxyl group, etc., each of R3and R4represents lower alkyl, etc., R5represents a substituted naphthyl, substituted phenyl, etc., Y1is alkylen etc., Y2is alkylene, Y3is alkylene and Z represents oxygen, etc. (JP 2001-501584-T, WO 97/37967, EP 901459-A, US 6022894),

the compound represented by the following formula:

where X represents nitro, etc., Y represents hydrogen, etc., Q represents C1-4alkyl, etc., Ar represents a phenyl, naphthyl, etc., m is 0-2 and n is 1-3 (JP 2002-522499-T, WO 00/09132, EP 1112073-A)

and the compound represented by the following formula:

where X represents cyano, etc., Y is chlorine and z, Q represents hydrogen, etc., W represents oxygen, etc., D represents hydrogen, etc. and n is 2-4 (JP 2002-522532-T, WO 00/09491, EP 1104411-A).

Maxine Gowen et al. introduced connection with CaSR antagonistic action, called NPS-2143,

oral OVX rats and measured its concentration in the blood and bone density, exploring thus the impact of NPS-2143 on osteogenesis, and reported results (The Journal of Clinical Investigation, vol. 105, pp. 1595-1604 (2000)).

In accordance with this message NPS-2143 significantly promotiom the release of PTH, but he has not demonstrated any direct action on osteoblasts and osteoclasts in vitro and reduction of bone mass or increase bone mass did not depend on him. One of the reasons that were pointed out in this connection, is too long a half-life of NPS-2143 in the blood. That is, when the rat PTH (1-34) was administered to the rat OVX at a dose of 5 µg/kg, the concentration of PTH in the blood reached a maximum of 175 PG/ml for 30 minutes and returned to the original level within 2 hours, but when NPS-2143 was administered at a dose of 100 μmol/kg, the concentration of PTH in the blood reached approximately 115 PG/ml within 30 minutes and continued to increase, demonstrating a level of 140 PG/ml even after 4 hours (The Journal of Clinical Investigation, vol. 105, p.1595-1604 (2000), especially pp. 1598, Fig. 3).

At the same time, the concentration of the blood of the NPS-2143 was maintained at the level not less than 100 ng/ml even after 8 hours after injection. 24 hours until the concentration reached a level of 10 ng/ml or below detectable level.

The above link to Maxine Gowen et al. shows that the calcium antagonist receptor, has long half-life in the blood, leads to the same results as the continuous introduction of PTH, which can be expected to increase bone mass. Thus, most of the usual antagonists calcium receptor permanently increases the concentration of PTH in the blood and is unable to provide sufficient osteogenesis-promoting action. Among the traditional antagonists of calcium receptor described compound represented by the following formula [I]:

where R1represents an optionally substituted aryl group, etc., R2represents a C1-6alkyl group, a C3-7cycloalkyl group, etc., R3represents a hydroxyl group, etc., R4represents a hydrogen atom, etc., R5and R6represents a C1-6alkyl group, etc., R7represents an optionally substituted aryl group, etc., X1represents a simple bond, C1-6alkylen etc., X2represents an optionally substituted C1-6alkylene, X3represents a simple bond and is not necessarily substituted C 1-6alkylene and X4and X5are bound, form a simple bond, methylene, etc. that has an excellent antagonistic action on the calcium receptor, which can be administered orally and from time to time and which may increase the concentration of PTH in the blood periodically and discrete (WO 02/14259). When comparing the activity of the compounds disclosed in this publication, and compounds of the present invention it has been unexpectedly found that the compound of the present invention has a higher activity and lower inhibitory effect against metabolic enzyme CYP2D6.

However, there are not many of these effective compounds and desirable to carry out further research in this area.

The invention

The present invention is to develop compounds with excellent antagonistic action on the calcium receptor, which could be administered orally and from time to time and which could increase the concentration of PTH in the blood periodically and discrete. Also, the present invention is to develop a pharmaceutical composition for oral administration that contains this compound is effective as a therapeutic drug is ri diseases, accompanied by abnormal calcium homeostasis, such as osteoporosis, hypoparathyroidism, osteosarcoma, periodontal disease, bone fractures, osteoarthritis, chronic rheumatoid arthritis, Paget's disease, the syndrome of humoral hypercalcemia, autosomal dominant hypercalcemia and the like, in particular as a drug for the treatment of osteoporosis.

Recently it was reported that increasing the concentration of calcium in the blood causes an increase in dopamine in the brain and then improves with Parkinson's disease and dementia. It is also expected that the compound of the present invention can be a drug for Parkinson's disease and dementia, as it increases the concentration of PTH in the blood and, therefore, increases the concentration of calcium in the blood.

To solve the above problems, the authors of the present invention conducted intensive studies, which found that the compound represented by the following formula (1), has an excellent effect as a calcium antagonist of the receptor, and can be administered orally and periodically, which led to the creation of the present invention. It was unexpectedly found that the compound represented by the following formula (1)increases in the concentration of PTH in the blood periodically and discretely, and in bullseyeing you can expect it will find practical application as excellent therapeutic medicines for the treatment of osteoporosis.

The compound represented by the following formula (1), according to the present invention differs in that the carbon atom adjacent to the oxygen atom has the structure

wherein each symbol is as defined below. As it is explained in the following experimental examples, with such a connection structure of the present invention is excellent in its antagonistic activity against calcium antagonist, and also has a discrete and time producing PTH action. Accordingly, when introducing the compound of the present invention can provide effects similar to the effects in the periodic introduction of PTH, which is considered extremely effective for the treatment of osteoporosis. In addition, as shown in the experimental examples, the compound of the present invention has a weak inhibitory effect on the metabolic function P450, particularly CYP2D6, which is desirable for a pharmaceutical product. It is shown that the action of the compounds of the present invention, causing the secretion of PTH, is even at a lower dose than for the known wound the connection. The compound of the present invention is improved in respect of properties such as absorption and solubility. It is also clear that the compound of the present invention has low side effects.

The present invention relates to a compound represented by the following formula (1), the calcium antagonist receptor and a drug for the treatment of osteoporosis, comprising this compound as an active ingredient. More specifically, the present invention relates to the following items[1] - [44].

[1] a Compound represented by the following formula (1), its pharmaceutically acceptable salt or optically active form (hereinafter sometimes collectively called abbreviated as compound (1)):

where n is 0 or 1,

p is an integer from 1 to 3,

R1represents a hydroxyl group, a C1-6CNS group, or RA,

where RAis an RC-OC(=O)O-C1-4alkylen-O - or OH-NH-,

where RCrepresents a C1-6alkyl group or a C3-6cycloalkyl group,

R2and R3are the same or different, and each represents a hydrogen atom, hydroxyl group, halogen atom, amino group, C1-7allmenalp, halogen-C1-6alkyl GRU is PU, carboxyl group, a C1-6alkoxycarbonyl group, C1-6CNS group, halogen-C1-6CNS group, C1-6alkyl group, hydroxy-C1-6alkyl group, a C1-7acylamino-C1-6alkyl group, a C2-6alkenylphenol group, aracelio group, phenyl group, C1-6alkylamino, di(C1-6alkyl)amino group, a C1-6alkoxy-C1-6alkyl group, mercaptopropyl, a cyano, a nitro-group, morpholinopropan, piperidinium or pyrrolidinone, or R2and R3combined with the formation of ethylenoxide,

X1represents-C=C-, -C=N-, an oxygen atom or a sulfur atom,

Z represents-S-, -SO-, -SO2-, -(CH2)m1-O-, -O-(CH2)m1-, -(CH2)m2-NH-, -NH-(CH2)m2-, -(CH2)m3-N(CH3)-, -N(CH3)-(CH2)m3-C1-4alkylenes group, -SO2-N(CH3)-, -N(CH3)-SO2-, -NHCO-, -CONH -, or C2-4alkynylamino group,

where each of m1, m2 and m3 represents an integer from 0 to 2,

X2represents-C=C-, an oxygen atom or a sulfur atom,

R4represents a C1-6alkyl group or a C3-6cycloalkyl group,

R5represents a hydrogen atom, or RB,

where RBrepresents a C1-7acyl is the group, optionally substituted carboxyl group,

Y represents a carbon atom or a nitrogen atom, and

R6, R7and R8are the same or different and each represents a hydrogen atom, a halogen atom, a C1-6alkyl group, a C1-6CNS group, halogen-C1-6alkyl group, halogen-C1-6CNS group, carboxyl group, hydroxyl group, cyano, a nitro-group, a phenyl group, a C3-6cycloalkyl group, di(C1-6alkyl)aminocarbonyl group or hydroxy-C1-6alkyl group, or adjacent R6and R7merged to form-CH=CH-CH=CH-, -C(OH)=CH-CH=CH-, -CH=C(OH)-CH=CH-, -O-(CH2)k1-O-, -O-(CH2)k2- or -(CH2)k3-,

where k1 is an integer from 1 to 4, k2 is an integer from 2 to 5, k3 represents an integer from 3 to 6,

provided that when both R2and R3represent hydrogen atoms, and n is 1, then Z must be a group that is different from-SO2-N(CH3)-where the sulfur atom linked to ring V and the nitrogen atom linked to ring W.

[2] the Compound according to above item [1]having the structure represented by the following formula (1'):

wherein each symbol is as defined above in paragraph [1], the sludge is its pharmaceutically acceptable salt.

[3] the Compound according to the above-mentioned items [1] or [2], where n is 1, or its pharmaceutically acceptable salt or optically active form.

[4] the Compound according to above item [3], where

n is 1,

p is 1,

R1represents a hydroxyl group or a C1-6CNS group,

R2and R3are the same or different, and each represents a hydrogen atom, hydroxyl group, halogen atom, amino group, C1-7allmenalp, triptorelin group, C1-6alkoxycarbonyl group, C1-6CNS group, C1-6alkyl group, hydroxy-C1-6alkyl group, a C2-6alkenylphenol group, phenyl group, benzyl group, di(C1-6alkyl)amino group or a nitro-group

or R2and R3combined with the formation of ethylenoxide,

X1represents-C=C - or-C=N-,

X2represents-C=C-,

Z represents-S-, -SO-, -SO2-, -(CH2)m1-O-, -O-(CH2)m1-, -(CH2)m2-NH-, -NH-(CH2)m2-, -(CH2)m3-N(CH3)-, -N(CH3)-(CH2)m3-C1-4alkylenes group or a C2-4alkynylamino group,

where each of m1, m2 and m3 represents an integer from 0 to 2,

R4represents a C1-6alkyl group or a C3-6cycloalkyl is inuu group,

R5represents a hydrogen atom,

Y represents a carbon atom or a nitrogen atom, and

R6, R7and R8are the same or different and each represents a hydrogen atom, a halogen atom, a C1-6alkyl group or a C1-6CNS group, or adjacent R6and R7merged to form-CH=CH-CH=CH-,

its pharmaceutically acceptable salt or optically active form.

[5] the Compound according to above item [4], where

n is 1,

p is 1,

R1represents a hydroxyl group or a C1-6CNS group,

R2and R3are the same or different and each represents a hydrogen atom, a halogen atom, a C1-6CNS group or a C1-6alkyl group,

X1represents-C=C-,

Z represents-S-, -SO-, -SO2-, -(CH2)m1-O-, -O-(CH2)m1-, -CH2-NH-, -NH-CH2-, -N(CH3)-, methylene or vinile,

where m1 is 0 or 1,

X2represents-C=C-,

R4represents a methyl group or cyclopropyl group,

R5represents a hydrogen atom,

Y represents a carbon atom or a nitrogen atom, and

R6, R7and R8are the same or different and each represents an atom is odorata, halogen atom or C1-6alkyl group, or adjacent R6and R7merged to form-CH=CH-CH=CH-,

its pharmaceutically acceptable salt or optically active form.

[6] the Compound according to above item [3], which is chosen from the group consisting of

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoic acid,

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-3-methoxybenzoic acid,

methyl-4-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoate,

4-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoic acid,

4-[2-[1-[(2R)-3-[[1-(quinoline-3-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoic acid,

4-[2-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoic acid,

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoic acid,

3-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoic acid,

4-[2-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenyl]vinyl]benzoic acid,

3-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydro is dipropoxy]ethyl]phenylthio]benzoic acid,

4-[2-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenyl]vinyl]benzoic acid,

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]for 3,5-dimethylbenzoic acid,

4-[2-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]for 3,5-dimethylbenzoic acid,

4-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]benzyl]benzoic acid,

3-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]benzyl]benzoic acid,

4-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenylthio]benzoic acid,

4-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenylsulfinyl]benzoic acid,

4-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenylsulfonyl]benzoic acid,

4-[[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenylamino]methyl]benzoic acid,

2-[[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]methyl]benzoic acid,

3-[[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]methyl]benzoic acid,

4-[[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]Fe is oxy]methyl]benzoic acid,

3-[[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]methyl]benzoic acid,

4-[[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]methyl]benzoic acid,

3-fluoro-4-[[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]methyl]benzoic acid,

4-[[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]methyl]-3-methylbenzoic acid,

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]for 3,5-dimethoxybenzoic acid,

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-3-nitrobenzoic acid,

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-2-nitrobenzoic acid,

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-3-chlorbenzoyl acid,

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-2-chlorbenzoyl acid,

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-2-triftorperasin acid,

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-3-triftorperasin is islote,

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-3-fermenting acid,

4-[2-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoic acid and

4-[2-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-5-methylbenzoic acid,

its pharmaceutically acceptable salt or optically active form.

[7] the Compound according to the above-mentioned items [1] or [2], where n is 0, its pharmaceutically acceptable salt or optical acceptable form.

[8] the Compound according to above item [7], where

n is 0,

p is 1,

R1represents a hydroxyl group or a C1-6CNS group,

R2and R3are the same or different and each represents a hydrogen atom, hydroxyl group, halogen atom, amino group, C1-7allmenalp, triptorelin group, C1-6alkoxycarbonyl group, C1-6CNS group, C1-6alkyl group, hydroxy-C1-6alkyl group, a C2-6alkenylphenol group, phenyl group, benzyl group, di(C1-6alkyl)amino group or a nitro-group, or

R2and R3combined with the formation of ethylenoxide,

X1represents-C=C - or-C=N-,

X2present is employed, a-C=C-,

R4represents a C1-6alkyl group or a C3-6cycloalkyl group,

R5represents a hydrogen atom,

Y represents a carbon atom or a nitrogen atom, and

R6, R7and R8are the same or different and each represents a hydrogen atom, a halogen atom, a C1-6alkyl group or a C1-6CNS group, or adjacent R6and R7merged to form-CH=CH-CH=CH-,

its pharmaceutically acceptable salt or optically active form.

[9] the Compound according to above item [8], where

n is 0,

p is 1,

R1represents a hydroxyl group or a C1-6CNS group,

R2and R3are the same or different, and each represents a hydrogen atom, hydroxyl group, halogen atom, amino group, C1-7allmenalp, triptorelin group, C1-6alkoxycarbonyl group, C1-6CNS group, C1-6alkyl group, hydroxy-C1-6alkyl group, a C2-6alkenylphenol group, phenyl group, benzyl group, di(C1-6alkyl)amino group or a nitro-group, or R2and R3combined with the formation of ethylenoxide,

X1represents-C=C - or-C=N-,

X2represents-C=C-,

R4predstavljaet a methyl group or cyclopropyl group,

R5represents a hydrogen atom,

Y represents a carbon atom, and

R6, R7and R8are the same or different and each represents a hydrogen atom, a halogen atom, a C1-6alkyl group or a C1-6CNS group, or adjacent R6and R7merged to form-CH=CH-CH=CH-,

its pharmaceutically acceptable salt or optically active form.

[10] the Compound according to above item [7], selected from the group consisting of

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-chloro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(2,3-debtor-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(2-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-to benovoy acid,

2'-[1-[(2R)-3-[[1-(4-ethyl-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

3-methyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-5-carboxylic acid,

methyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-3,5-in primary forms,

2'-[(cyclopropyl)[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[(cyclopropyl)[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-5-carboxylic acid,

2'-[(cyclopropyl)[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[(cyclopropyl)[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-methoxyphenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-CT is about acid,

3-methyl-2'-[1-[(2R)-3-[[1-(3,4-dimetilfenil)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-methoxyphenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-ethylphenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-2,5-differenl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methoxybiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-2-methoxybiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-(trifluoromethyl)biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(2-fluoro-4-methoxyphenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-(trifluoromethyl)biphenyl-4-carboxylic acid,

3-ethyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3,4-dichlorophenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-(trifluoromethyl)biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-isopropylidene-4-carboxylic acid,

3-ethyl-2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-isopropylidene-4-carboxylic acid,

2-chloro-6-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenyl]pyridine-3-carboxylic acid,

2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-propylbiphenyl-4-carboxylic acid,

2,3-dimethyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-propylbiphenyl-4-carboxylic acid,

2-chloro-6-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenyl]pyridine-3-carboxylic acid,

3,5-dimethyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-m-terphenyl-4'-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-2,3-dimethylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl] - for 3,5-dimethylbiphenyl-4-carboxylic acid,

4-(guide oxymethyl)-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-3-carboxylic acid,

3-isobutyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-isobutylphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-4-(hydroxymethyl)biphenyl-3-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-(2-methyl-1-propenyl)biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-hydroxybiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-hydroxybiphenyl-4-carboxylic acid,

3-ethyl-2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-isopropylidene-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-(1-methylpropyl " biphenyl-4-carboxylic acid,

2-methyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

3-methyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-Carbo the OIC acid,

4-fluoro-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-3-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3,4-dichlorophenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-2-methylbiphenyl-4-carboxylic acid,

6-fluoro-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-3-carboxylic acid,

3-fluoro-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-chlorophenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3,4-dichlorophenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2-fluoro-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[(cyclopropyl)[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[(cyclopropyl)[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-3-forbiden-4-carboxylic acid,

2'-[(cyclopropyl)[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-2-forbiden-4-carboxylic acid,

2'-[(cyclopropyl)[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-2-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3,4-dichl henyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-2-forbiden-4-carboxylic acid,

3-chloro-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-nitrobiphenyl-4-carboxylic acid,

3-amino-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

3-(acetylamino)-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

3-chloro-2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-methoxy-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2,3-dihydro-5-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenyl]benzofuran-7-carboxylic acid,

2,6-dimethyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-2,6-dimethylbiphenyl-4-carboxylic acid,

3-(dimethylamino)-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2,3-dihydro-5-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenyl]benzofuran-7-carboxylic acid is you,

3-benzyl-2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methoxybiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methoxybiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methoxybiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-2-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-2-methylbiphenyl-4-carboxylic acid,

4-methyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-3-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-4-methylbiphenyl-3-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3,5-dichlorophenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(2,5-differenl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(5-chloro-2-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[1-(3-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-triptoreline)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(5-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3,5-dateformatter)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-methyl-3,5-acid)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3,5-acid)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-triptoreline)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-tert-butylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-tert-butylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-tert-butylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methoxybiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-Mor is aminobiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-(triptoreline)biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-trifluoromethyl-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-(hydroxymethyl)biphenyl-4-carboxylic acid and

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-carboxymethyl-4-carboxylic acid,

its pharmaceutically acceptable salt or optically active form.

[11] the Compound represented by the following formula (1"), its pharmaceutically acceptable salt or optically active form:

where R1' represents a hydroxyl group or a C1-6CNS group,

R2' represents a hydroxyl group, a halogen atom, an amino group, a C1-7allmenalp, halogen, C1-6alkyl group, a C1-6alkoxycarbonyl group, C1-6CNS group, halogen, C1-6CNS group, C1-6alkyl group, hydroxy-C1-6alkyl group, di(C1-6alkyl)amino group or a nitro-group,

R4' represents a C1-6alkyl group or a C3-6cycloalkyl group,

R6' pre which represents a halogen atom, C1-6alkyl group, a C1-6CNS group or halogen C1-6alkyl group, or if R7' is a connecting group, R6' and R7' associated with the formation of-CH=CH-CH=CH - and

R7' represents a hydrogen atom, a halogen atom, a C1-6alkyl group, a C1-6CNS group, or a halogen-C1-6alkyl group.

[12] the Compound represented by the following formula (1'"), its pharmaceutically acceptable salt or optically active form:

where R2represents a C1-6alkyl group,

R4" represents a methyl group or cyclopropyl group,

R6represents a halogen atom or C1-6alkyl group, and

R7" represents a hydrogen atom, a halogen atom, a C1-6alkyl group, a C1-6CNS group, or a halogen-C1-6alkyl group.

[13] the Compound according to the above paragraphs [11] or [12], selected from the group consisting of

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-chloro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methyl shall iphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(2-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-ethyl-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-5-carboxylic acid,

2'-[(cyclopropyl)[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[(cyclopropyl)[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-3-methylbiphenyl-4-carboxylic acid,

3-methyl-2'-[1-[(2R)-3-[[1-(3,4-dimetilfenil)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-methoxyphenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic key is lots

2'-[1-[(2R)-3-[[1-(4-ethylphenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

3-ethyl-2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-isopropylidene-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-propylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-isobutylphenyl-4-carboxylic acid,

3-ethyl-2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-isopropylidene-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-(1-methylpropyl " biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-chlorophenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3,4-dichlorophenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-methoxy-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-1-[(2R)-3-[[1-(3,5-dichlorophenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-triptoreline)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-tert-butylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-tert-butylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-tert-butylbiphenyl-4-carboxylic acid and

2'-[1-[(2R)-3-[[1-(3-trifluoromethyl-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

its pharmaceutically acceptable salt or optically active form.

[14] the Compound according to above item [13], selected from the group consisting of

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-chloro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid and

2'-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

its pharmaceutically acceptable salt or optically active the form.

[15] 2'-[1-[(2R)-3-[[1-(3-Fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid, its pharmaceutically acceptable salt or optically active form.

[16] 2'-[1-[(2R)-3-[[1-(4-Chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid, its pharmaceutically acceptable salt or optically active form.

[17] 2'-[1-[(2R)-3-[[1-(3-Chloro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid, its pharmaceutically acceptable salt or optically active form.

[18] 2'-[1-[(2R)-3-[[1-(4-Chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid, its pharmaceutically acceptable salt or optically active form.

[19] a Pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of the above paragraphs [1]-[18], its pharmaceutically acceptable salt or optically active form, as the active ingredient.

[20] the Pharmaceutical composition according to above item [19], where the active ingredient is a compound according to any one of above items [3]-[6], its pharmaceutically acceptable salt or optically active form.

[21] the Pharmaceutical composition according to above item [19], where the active phrases which t represents a connection on any of the above items [7]-[10], its pharmaceutically acceptable salt or optically active form.

[22] the Pharmaceutical composition according to above item [19], where the active ingredient is a compound according to any one of above items [11]-[18], its pharmaceutically acceptable salt or optically active form.

[23] Therapeutic drug for the treatment of osteoporosis, comprising a pharmaceutically acceptable carrier and a compound according to any one of the above paragraphs [1]-[18], its pharmaceutically acceptable salt or optically active form, as the active ingredient.

[24] Therapeutic drug for the treatment of osteoporosis according to the above item [23], where the active ingredient is a compound according to any one of above items [3]-[6], its pharmaceutically acceptable salt or optically active form.

[25] Therapeutic drug for the treatment of osteoporosis according to the above item [23], where the active ingredient is a compound according to any one of above items [7]-[10], its pharmaceutically acceptable salt or optically active form.

[26] Therapeutic drug for the treatment of osteoporosis according to the above item [23], where the active ingredient is a compound according to any one of above items [11]-[18], the th pharmaceutically acceptable salt or optically active form.

[27] Therapeutic drug for the treatment of osteoporosis according to any one of above paragraphs [23]-[26], which is designed for concomitant use with other therapeutic drug for the treatment of osteoporosis.

[28] Therapeutic drug for the treatment of osteoporosis according to the above item [25], where a different therapeutic drug for the treatment of osteoporosis selected from the group consisting of a calcium agent, vitamin D, vitamin K, drug female hormone, drug, antagonist of estrogen, anabolic steroid, parathyroid hormone drug, drug calcitonin drug bisphosphonates and drug ipriflavone.

[29] a Method of treating osteoporosis, comprising introducing an effective amount of a compound according to any one of above paragraphs [1]-[18], its pharmaceutically acceptable salts or optically active form to a patient suffering from osteoporosis.

[30] the calcium Antagonist receptor, comprising a pharmaceutically acceptable carrier and a compound according to any one of above paragraphs [1]-[18], its pharmaceutically acceptable salt or optically active form, as the active ingredient.

[31] the calcium Antagonist receptor on the above item [30], where the active is ingredient is a compound according to any one of above items [3]-[6], its pharmaceutically acceptable salt or optically active form.

[32] the calcium Antagonist receptor on the above item [30], where the active ingredient is a compound according to any one of above items [7]-[10], its pharmaceutically acceptable salt or optically active form.

[33] the calcium Antagonist receptor on the above item [30], where the active ingredient is a compound according to any one of above items [11]-[18], its pharmaceutically acceptable salt or optically active form.

[34] the calcium Antagonist receptor of importance IC50antagonistic action against calcium receptor, which is not less than 10 times the value of the IC50inhibitory effect against metabolic enzyme P450.

[35] the calcium Antagonist receptor on the above item [34], with the value of the IC50antagonistic action against calcium receptor, which is not less than 100 times the values of the IC50inhibitory effect against metabolic enzyme P450.

[36] the calcium Antagonist receptor on the above item [34], where the metabolic enzyme P450 is a CYP2D6.

[37] the calcium Antagonist receptor on the above paragraph [35], where the metabolic enzyme P450 is a CYP2D6./p>

[38] the calcium Antagonist receptor of importance IC50antagonistic action against calcium receptor is not more than 0.1 μm and the value of the IC50inhibitory effect against metabolic enzyme CYP2D6 not less than 1 μm.

[39] the calcium Antagonist receptor on the above item [38], with the value of the IC50antagonistic action against calcium receptor is not more than 0.1 μm and the value of the IC50inhibitory effect against metabolic enzyme CYP2D6 not less than 10 μm.

[40] the calcium Antagonist receptor of any of the above paragraphs [34]-[37], where the calcium antagonist receptor described in any of the above items[30]-[33].

[41] Promoting allocation of PTH agent, comprising a pharmaceutically acceptable carrier and a compound according to any of the above item [1]-[18], its pharmaceutically acceptable salt or optically active form, as the active ingredient.

[42] Promoting allocation of PTH agent according to the above item [41], where the active ingredient is a compound according to any one of above items [3]-[6], its pharmaceutically acceptable salt or optically active form.

[43] Promoting allocation of PTH agent according to the above item [41], where the active ingredient is a connection of the giving by any of the above items [7]-[10], its pharmaceutically acceptable salt or optically active form.

[44] Promoting allocation of PTH agent according to the above item [41], where the active ingredient is a compound according to any one of above items [11]-[18], its pharmaceutically acceptable salt or optically active form.

Detailed description of the invention

The terms used in this application, is defined as follows.

The term "halogen atom" refers to fluorine atom, chlorine atom, bromine atom or iodine atom, preferably to fluorine atom or chlorine atom, particularly preferably for a chlorine atom.

The term "C1-6alkyl group" refers to linear or branched alkyl group containing from 1 to 6, preferably from 1 to 4, carbon atoms, such as methyl group, ethyl group, through the group, isopropyl group, bucilina group, isobutylene group, tert-bucilina group, pencilina group, isopentyl group, tert-pencilina group or exilda group and the like, where the preference for C1-4alkyl group selected from methyl group, ethyl group, through the group, isopropyl group, butilkoi group, isobutylene group and tert-butilkoi group.

The term "halogen C1-6alkyl group" refers to the above "C1-6and Kilroy group", substituted by one or more halogen atoms with the formation of halogenating groups, while the position of substitution is not any particular limitation as long as it is chemically acceptable. Examples of "halogen, C1-6alkyl groups" include pharmacylow group, deformational group, triptorelin group, chloromethylene group, dichloromethylene group, trichlorethylene group, bromatology group, dibromomethyl group, tribromaniline group, otmetilo group, diiodomethyl group, tramadolnow group, 2-foretelling group, 2,2-deperately group, 2,2,2-triptorelin group, 2-chloraniline group, 2,2-dichloroethylene group, 2,2,2-trichlorethylene group, 2-bromatology group, 2,2-dibromomethyl group, 2,2,2-tribromoethyl group, 3-chloropropylene group or 4-chlorobutanol group and the like, preferably a halogen C1-2alkyl group, such as triptorelin group and 2,2,2-trichlorethylene group, particularly preferred is triptorelin group.

The term "hydroxy-C1-6alkyl group" refers to a hydroxyalkyl group, where the above-mentioned "C1-6alkyl group substituted with hydroxyl group, and the position of substitution is not any particular limitation as long as it is chemically acceptable is O. Examples of the "hydroxy-C1-6alkyl groups" include hydroxymethylene group, 1-hydroxyethylene group, 2-hydroxyethyloxy group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 2-hydroxy-1-methylamino group, 1-hydroxybutyl group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxybutyl group, 3-hydroxy-2-methylpropyloxy group, 2-hydroxy-1,1-dimethylethylene group, 5-hydroxypentanal group or 6-hydroxyhexyloxy group and the like, preferably hydroxy-C1-4alkyl group selected from hydroxymethylene group, 2-hydroxyethylene group, 3-hydroxypropyl group and 4-hydroxybutyl group.

The term "C1-6CNS group" refers to linear or branched CNS group containing from 1 to 6, preferably from 1 to 4, carbon atoms, such as, for example, metaxylene group, amoxilina group, premaxilla group, isopropoxyphenyl group, butoxylate group, tert-butoxylate group, PetroChina group, tert-pentylaniline group or hexyloxyphenyl group and the like, preferably C1-4CNS group selected from metaxylene group, ethoxyline group, propoxyphenol group, isopropoxyphenoxy group, betaxolol group and tert-butoxyphenol GRU the dust.

The term "halogen C1-6CNS group" refers to halogenosilanes group, where the above-mentioned "C1-6CNS group substituted by one or more halogen atoms. The position of substitution is not any particular limitation as long as it is chemically acceptable. "Halogen C1-6CNS group" represents, for example, formicoxenini group, diplomatically group, triptoreline group, chlorotoxin group, dichloroethylene group, trichloroethylene group, bromelicola group, dibromototally group, tribromoaniline group, immedately group, diiodoacetylene group, triiodothyronine group, 2-foretokening group, 2,2-diplomatically group, 2,2,2-cryptgetuserkey group, 2-chlorotoxin group, 2,2-diplomatically group, 2,2,2-trichlorethylene group, 2-pomatocalpa group, 2,2-diplomatically group, 2,2,2-tribromoethanol group, 3-chloropropoxy group or 4-chlorotoxin group and so similar, preferably halogen, C1-2CNS group, such as triptoreline group and 2,2,2-trichlorethylene group, particularly preferably triptoreline group.

The term "C1-6alkoxy-C1-6alkyl group" refers to alkoxyalkyl group, where videocase the Naya "C 1-6alkyl group" substituted by the above "C1-6CNS group. The position of substitution is not any particular limitation as long as it is chemically acceptable. Examples of "C1-6alkoxy-C1-6alkyl groups" include methoxymethyl group, ethoxymethyl group, propoxymethyl group, butoxymethyl group, petrochemicals group, hexyloxymethyl group, 1-methoxyamino group, 1-ethoxyethylene group, 2-methoxyaniline group, 2-ethoxyethylene group, 1-methoxypropyl group, 1-ethoxypropanol group, 2-methoxypropyl group, 2-ethoxypropanol group, 3-methoxypropyl group, 3-ethoxypropanol group, 2-methoxy-1-methylamino group, 1-methoxybutyl group, 1-ethoxymethylene group, 2-methoxybutyl group, 2-ethoxymethylene group, 3-methoxybutyl group, 3-ethoxymethylene group, 4-methoxybutyl group, 4-ethoxymethylene group, 3-methoxy-2-methylpropyloxy group, 2-methoxy-1,1-dimethylethylene group, 2-ethoxy-1,1-dimethylethylene group, 5-methoxyphenyl group or 6-methoxyaniline group and the like, preferably C1-4alkoxy-C1-4alkyl group selected from methoxymethyl group, ethoxymethyl group, propoxymethyl group, butoxymethyl group, 2-ethoxyethylene group, 3-methoxy who ropeley group and 4-methoxybutyl group.

The term "C1-6alkoxycarbonyl group" refers to alkoxycarbonyl group, where C1-6CNS fragment is above a "C1-6CNS group", for example methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxyethanol group, tert-butoxycarbonyl group, ventilatsioonile group or hexyloxymethyl group and the like, preferably C1-4alkoxycarbonyl group selected from methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group and tert-butoxycarbonyl group.

The term "C1-6alkylamino" refers to alkylamine, where the above-mentioned "C1-6alkyl group substituted with amino group, such as methylaminopropyl, atramentaria, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, intellimorph, isopentylamine, tert-pentylamine or hexylamino and the like, preferably C1-4alkylamino choose from methylaminopropyl, etilenovomu, profilemanager.py, isopropylamino, butylamino is s, isobutylamino and tert-butylamino.

The term "di(C1-6alkyl)amino group" refers to dialkylamino, where the amino group is disubstituted by the above-mentioned "C1-6alkyl group and the alkyl group can be of different types. For example, you can mark dimethylaminopropyl, ethylmethylamino, diethylaminopropyl, methylpropylamine, ethylpropylamine, dipropylamine, Diisopropylamine, dibutylamine, diisobutylamine, di-tert-butylamino, dimetilaminovogo, diisobutylamine, di-tert-pentylamine or Vexillology and the like, preferably CI-C1-4alkylamino choose from dimethylaminopropyl, diethylaminopropyl, dipropylamino, diisopropylamino, dibutylamino, diisobutylamine and di-tert-butylamino.

The term "di(C1-6alkyl)aminocarbonyl" refers to dialkylaminomethyl group, where aminocarbonyl group is disubstituted by the above-mentioned "C1-6alkyl group and the alkyl group can be of different types. For example, it can be noted dimethylaminocarbonylmethyl group, ethylethylenediamine group, diethylaminocarbonylmethyl group, methylpropionitrile group, ethylpropylamine group, dipropyl decarbonising group, diisopropylaminoethyl group, dibutylaminoethanol group, diisobutylaluminium group, di-tert-butylaminoethyl group, dimetilaminoflavonola group, dietphentermineonline group, di-tert-intramyocardially group or digoxinamiodarone group and the like, preferably di(C1-4alkyl)aminocarbonyl group selected from dimethylaminocarbonylmethyl group, diethylaminocarbonylmethyl group, dipropylthiocarbamate group, diisopropylaminoethyl group, dibutylaminoethanol group, diisobutyldimethoxysilane group and di-tert-butylaminoethyl group.

The term "C1-7acyl group" refers to alkanoyloxy group, alkanoyloxy group or arolina group containing from 1 to 7 carbon atoms, for example, you can mark groups such as formyl group, acetyl group, propylaniline group, Butyrina group, pivellina group, ethanola group, propanola group, bottomline group or benzoline group and the like, preferably formyl group, acetyl group, pivellina group or benzoline group. The acyl group may be substituted by a carboxyl group, for example, carboxyaniline group, 3-carboxypropyl group, 4-carboxybutyl group and t the th similar.

The term "C1-7alluminare" refers to alluminare, where the number of carbon atoms in the acyl fragment is preferably from 1 to 7, more preferably from 2 to 5, where acyl fragment is a chain (linear chain or branched chain or cyclic. As the acyl part, for example, can be marked group, are illustrated for the above-mentioned "C1-7acyl group". Examples of alluminare include alkanolamines, such as formylamino, acetylamino, Propionaldehyde, bucillamine or pivaloylpyruvic and the like, and karamanoglu, such as benzoylamino and the like, preferably formylamino, acetylamino, evaluieringsrapport or benzoylamino.

The term "C3-6cycloalkyl group" refers to a cyclic alkyl group containing 3 to 6 carbon atoms, such as cyclopropyl group, cyclobutyl group, cyclopentenone group, tsiklogeksilnogo group or cycloheptyl group and the like, preferably to the C3-5cycloalkyl group, such as cyclopropyl group, cyclobutyl group or cyclopentenone group and the like, more preferably cyclopropyl group or cyclobutyl group, particularly preferably Cyclops is opalina group.

The term "C2-6Alchemilla group" refers to alkenylphenol group containing from 2 to 6 carbon atoms, such as vinyl group, 1-protanilla group, 2-methyl-1-protanilla group, allyl group, 1-bucinellina group, 2-bucinellina group, 3-bucinellina group, 1-penttila group, 2-penttila group, 3-penttila group, 4-penttila group or 5-examilia group and the like, preferably to the C2-4alkenylphenol group, such as vinyl group, 2-methyl-1-protanilla group or allyl group and the like.

The term "C1-4Allenova group" refers to linear or branched alkalinous group containing from 1 to 4, preferably from 1 to 3, carbon atoms, for example, can be mentioned a methylene group, ethylene group, propylene group, butylene group,

and things like that. Preferred are methylene group, ethylene group or propylene group.

As "C1-4alkalinous groups contained in RApreferred are

in particular

is preferred.

The term "C2-4alkenylamine group" refers to alkenylamine group containing from 2 to 4, preferably 2 or 3, the volume of carbon such as venelinova group, 1-propylea group, 2-propylea group, 1-battilana group, 2-battilana group, 3-battilana group and the like, preferably to vanilinovoi group, 1-propenylidene or 2-propenylidene group.

The term "C1-7acylamino-C1-6alkyl group" refers to a group where the above-mentioned "C1-6alkyl group substituted C1-7allmineral". Examples of such groups include alkanolamine-C1-6alkyl group, such as formylmorpholine group, acetamidomethyl group, propionylthiocholine group, butyrylthiocholine group, pivaloyloxymethyl group, formelementname group, acetylaminoacetylenes group, propionylthiocholine group, butyrylthiocholine group, pivaloyloxymethyl group, parilamentary group, acetylaminofluorene group, propionylthiocholine group, butyrylthiocholine group, pelloidoterapiya group, formylmorpholine group, acetylaminofluorene group, propionylthiocholine group, butyrylthiocholine group, pivaloyloxymethyl group, formylmorpholine group, acetylaminophenol group, propionylcarnitine group, butyrylthiocholine group, pivaloyloxymethyl group, formulatingaction the group, acetylaminofluorene group, propionylthiocholine group, butyrylthiocholine group, pivaloyloxy group and the like, and aroylamino-C1-6alkyl group, such as benzylaminopurine group, benzylaminopurine group, benzylaminopurine group, benzylaminopurine group, benzylaminopurine group, benzylaminopurine group and the like, where predpochtitelnye given acetamidomethyl group or acetylaminophenol group.

The term "kalkilya group" refers to a group in which "C1-6alkyl group" substituted by the above-mentioned "aryl group". As explained in the description of the "aryl group" is preferably one which contains from 6 to 14 carbon atoms, such as phenyl group, naftalina group, antanella group or biphenylene group and the like. Examples of "Uralkaliy group" include benzyl group, fenetylline group, phenylbutyl group, phenylpropyl group, phenylmethylene group, phenylhexanoic group, naphthylmethyl group, internalmedicine group or biphenylmethanol group and the like, where preference is given to benzyl group.

As "salts" of the compounds of the present invention may be noted, but not limited to, acid additive salts of neo the organic acids, such as hydrochloride, hydrobromide, sulfate, phosphate or nitrate, and the like; acid additive salts of organic acids such as acetate, propionate, succinate, glycolate, lactate, malate, oxalate, tartrate, citrate, maleate, fumarate, methanesulfonate, bansilalpet, p-toluensulfonate or ascorbate, and the like; amino acid additive salts such as aspartate or glutamate and the like; salts of inorganic bases, such as salts of sodium, potassium, calcium, magnesium or zinc, and the like; salts of organic bases such as methylamine, dimethylamine, ethylamine, diethylamine, triethylamine, triethanolamine, trihydroxypyrimidine, dicyclohexylamine, Ethylenediamine, guanidine, meglumin or 2-aminoethanol and the like, basic salts of amino acids such as asparagine, glutamine, arginine, histidine or lysine, and the like. Preferred salts are the hydrochloride, sodium salt, potassium salt, calcium salt, and particularly preferred is the hydrochloride or sodium salt.

The compound of the present invention includes the MES. As used in this description, the term "MES connection" means the connection of the present invention, associated with a molecule of solvent, such as water, alcohol and the like, a relatively weak connection, such as van der Waals forces, static is mechanical interaction, the hydrogen bond, the bond charge-transfer, coordination and the like. In some cases, the MES may indicate a connection, United in the solid state of water, alcohol and the like. Preferred MES is a hydrate.

"Prodrug" of a compound is a derivative of the compound of the present invention, which contains a chemically or metabolically degradable group, which is destroyed by hydrolysis or solvolysis or under physiological conditions, demonstrating physiological activity. Deputy represented by RAndand Deputy represented by RBin the formula (1) according to the present invention are alternates relating to the prodrug, and-CORAand/orBis(are) a Deputy (?), turning in-CO2H and/or-OH in a living organism.

"Ring " V" in the present invention is a ring represented as

in the formula (1), where X1is the same as defined above, and the ring W ' is a ring represented as

in the formula (1), where X2is the same as defined above.

The term "value IC50the antagonistic action of the calcium receptor" means the value, the measurement is ing way described in experimental example 1 of the present description.

The term "metabolic enzyme P450" means the cytochrome P450 available to the animal, in particular, one can note CYP2C9, CYP2D6, or CYP3A4.

The term "value IC50inhibitory effect against metabolic enzyme CYP2D6" means the value measured by the method described in experimental example 4 of the present description.

The expression "the value of the IC50antagonistic action against calcium receptor is not less than 10 times the value of the IC50inhibitory effect against metabolic enzyme CYP2D6", "value IC50antagonistic action against calcium receptor is not less than 100 times the value of the IC50inhibitory effect against metabolic enzyme CYP2D6" refer to the values calculated when comparing the above values IC50antagonistic action against calcium receptor and the magnitude of the IC50inhibitory effect against metabolic enzyme CYP2D6".

The expression "the value of the IC50antagonistic activity of a compound in relation to the calcium receptor is not more than 0.1 μm" means that the "value of the IC50the antagonistic action of the compounds against the attachment calcium receptor" is 0.1 μm or less.

The expression "the value of the IC50inhibitory effect against metabolic enzyme CYP2D6 is not less than 10 μm and the value of the IC50inhibitory effect against metabolic enzyme CYP2D6 is not less than 1 μm" means that the above "value IC50inhibitory effect against metabolic enzyme CYP2D6 is not less than 10 μm and not less than 1 μm, respectively.

The compound represented by formula (1) according to the present invention has various isomers such as optical isomers, stereoisomers, geometric isomers, tautomers and the like. The present invention includes all such isomers and mixtures thereof.

In the compound represented by formula (1) according to the present invention,

R1preferably represents a hydroxyl group or a C1-4CNS group, more preferably a hydroxyl group, metaxylene group or ethoxyline group, particularly preferably a hydroxyl group,

each of R2and R3preferably represents a hydrogen atom, hydroxyl group, halogen atom (particularly preferably a chlorine atom, a fluorine atom), an amino group, a C1-7alluminare (particularly preferably C1-4alkylcarboxylic), halogen-C1-6alkyl is the group (particularly preferably triptorelin group), carboxyl group, a C1-6CNS group (particularly preferably C1-4CNS group), halogen-C1-6CNS group, hydroxy-C1-6alkyl group (particularly preferably hydroxy-C1-4alkyl group), C1-7acylamino-C1-6alkyl group (particularly preferably C1-4alkylcarboxylic-C1-4alkyl group), C1-6alkyl group (particularly preferably C1-4alkyl group), C2-4alkenylphenol group, C1-6alkoxycarbonyl group, di(C1-6alkyl)amino group (particularly preferably di(C1-4alkyl)amino group) or a phenyl group, or R2and R3combined with the formation of ethylenoxide,

R2preferably represents a hydroxyl group, a halogen atom, an amino group, a C1-7allmenalp, halogen-C1-6alkyl group, a C1-6alkoxycarbonyl group, C1-6CNS group, halogen-C1-6CNS group, C1-6alkyl group, hydroxy-C1-6alkyl group, di(C1-6alkyl)amino group or a nitro-group, more preferably a C1-6alkyl group, particularly preferably C1-4alkyl group,

R3preferably represents a hydrogen atom,

X1preferably isone-C=C - or-C=N-, particularly preferably-C=C-,

X2preferably represents-C=C-,

Z preferably represents-S-, -SO-, -SO2-, -(CH2)m1-O-, -O-(CH2)m1-, -(CH2)m2-NH-, -NH-(CH2)m2-, -(CH2)m3-N(CH3)-, -N(CH3)-(CH2)m3-C1-4alkylene or C2-4albaniles,

each of m1, m2 and m3 are preferably represents 0 or 1,

alkylen for Z preferably represents methylene or ethylene,

R4preferably represents C1-6alkyl group or cyclopropyl group, particularly preferably C1-4alkyl group such as methyl group and the like,

R5preferably represents a hydrogen atom,

p preferably represents 1,

Y preferably represents a carbon atom, and

each of R6, R7and R8preferably represents a hydrogen atom, a halogen atom (particularly preferably a chlorine atom or a fluorine atom), C1-4alkyl group or a C1-4CNS group, or adjacent R6and R7merged to form-CH=CH-CH=CH-.

The case when R6and R7selected from the group consisting of a halogen atom, and C1-4alkyl group, and the case when R8represents a hydrogen atom, the C is particularly preferred.

R6and R7is preferred to the following:

or.

In the compound represented by formula (1) according to the present invention, when n is 1, for example, an implementation option, where

R1represents a hydroxyl group or a C1-6CNS group,

R2and R3are the same or different and each represents a hydrogen atom, hydroxyl group, halogen atom, amino group, C1-7allmenalp, triptorelin group, C1-6alkoxycarbonyl group, C1-6CNS group, C1-6alkyl group, hydroxy-C1-6alkyl group, a C2-6alkenylphenol group, phenyl group, benzyl group, di(C1-6alkyl)amino group or a nitro-group, or R2and R3combined with the formation of ethylenoxide,

X1represents-C=C - or-C=N-,

X2represents-C=C-,

Z represents-S-, -SO-, -SO2-, -(CH2)m1-O-, -O-(CH2)m1-, -(CH2)m2-NH-, -NH-(CH2)m2-, -(CH2)m3-N(CH3)-, -N(CH3)-(CH2)m3-C1-4alkylenes group or a C2-4alkynylamino group,

where each of m1, m2 and m3 represents an integer from 0 to 2,

R4present is employed, a C 1-6alkyl group or a C3-6cycloalkyl group,

R5represents a hydrogen atom,

p is 1,

Y represents a carbon atom or a nitrogen atom, and

R6, R7and R8are the same or different and each represents a hydrogen atom, a halogen atom, a C1-6alkyl group or a C1-6CNS group, or adjacent R6and R7merged to form-CH=CH-CH=CH-,

is preferred. Among these compounds, compound, where

R1represents a hydroxyl group or a C1-4CNS group, especially a hydroxyl group, metaxylene group or ethoxyline group,

R2and R3are the same or different, and each represents a hydrogen atom, hydroxyl group, halogen atom (particularly chlorine atom or fluorine atom), an amino group, a C1-7alluminare (especially C1-4alkylcarboxylic), triptorelin group, C1-4CNS group (especially metaxylene group), hydroxy-C1-4alkyl group, a C1-4alkyl group, a C2-4alkenylphenol group, C1-4alkoxycarbonyl group or phenyl group, or R2and R3combined with the formation of ethylenoxide,

X1and X2represent-C=C-,

Z presented yet a-S-, -SO-, -SO2-, -(CH2)m1-O-, -O-(CH2)m1-, -(CH2)m2-NH-, -NH-(CH2)m2-, -(CH2)m3-N(CH3)-, -N(CH3)-(CH2)m3-C1-4alkylenes group (especially methylene or ethylene) or C2-4alkynylamino group,

where each of m1, m2 and m3 is 0 or 1,

R4represents a C1-6alkyl group or cyclopropyl group, especially a C1-4alkyl group (methyl group, etc.),

R5represents a hydrogen atom,

p is 1,

Y represents a carbon atom, and

R6, R7and R8are the same or different and each represents a hydrogen atom, a halogen atom (preferably a chlorine atom or a fluorine atom), C1-4alkyl group or a C1-4CNS group, or adjacent R6and R7merged to form-CH=CH-CH=CH-,

is preferred.

In the compound represented by formula (1) according to the present invention, when n is 1, for example, an implementation option, where

R1represents a hydroxyl group or a C1-6CNS group (preferably metaxylene group)

R2and R3are the same or different and each represents a hydrogen atom, a halogen atom (preferably fluorine atom or chlorine atom), C1- CNS group (preferably metaxylene group) or C1-6alkyl group (preferably methyl group, ethyl group, n-sawn group or isopropyl group),

X1represents-C=C-,

X2represents-C=C-,

Z represents-S-, -SO-, -SO2-, -(CH2)m1-O-, -O-(CH2)m1-, -CH2-NH-, -NH-CH2-, -N(CH3)-, methylene or vinile,

where m1 is 0 or 1,

R4represents a methyl group or cyclopropyl group,

R5represents a hydrogen atom,

p is 1,

Y represents a carbon atom or a nitrogen atom, and

R6, R7and R8are the same or different and each represents a hydrogen atom, a halogen atom (preferably fluorine atom or chlorine atom) or C1-6alkyl group (preferably methyl group), or adjacent R6and R7merged to form-CH=CH-CH=CH-,

is more preferable. Among the above-mentioned variant implementation, in which

R1represents a hydroxyl group or a C1-4CNS group, particularly a hydrogen atom, metaxylene group or ethoxyline group,

R2and R3are the same or different and each represents a hydrogen atom or a C1-4Alki is inuu group (particularly methyl group),

X1represents-C=C-,

X2represents-C=C-,

Z represents-S-, -SO-, -SO2-, -(CH2)m1-O-, -O-(CH2)m1-, -CH2-NH-, -NH-CH2-, -N(CH3)-, methylene or vinile,

where m1 is 0 or 1,

R4represents a methyl group or cyclopropyl group,

R5represents a hydrogen atom,

p is 1,

Y represents a carbon atom, and

R6, R7and R8are the same or different and each represents a hydrogen atom, a halogen atom (particularly chlorine atom or fluorine atom), or C1-4alkyl group (particularly methyl group), or adjacent R6and R7merged to form-CH=CH-CH=CH-,

is preferred.

For compounds represented by formula (1) according to the present invention, when n is 0, for example, an implementation option, where

R1represents a hydroxyl group or a C1-6CNS group,

R2and R3are the same or different and each represents a hydrogen atom, hydroxyl group, halogen atom, amino group, C1-7allmenalp, triptorelin group, C1-6alkoxycarbonyl group, C1-6CNS group, C1-6alkyl group, hydroxy-C1-6alkyl group, Csub> 2-6alkenylphenol group, phenyl group, benzyl group, di(C1-6alkyl)amino group or a nitro-group, or R2and R3combined with the formation of ethylenoxide,

X1represents-C=C - or-C=N-,

X2represents-C=C-,

R4represents a C1-6alkyl group or a C3-6cycloalkyl group,

R5represents a hydrogen atom,

p is 1,

Y represents a carbon atom or a nitrogen atom, and

R6, R7and R8are the same or different and each represents a hydrogen atom, a halogen atom, a C1-6alkyl group or a C1-6CNS group, or adjacent R6and R7merged to form-CH=CH-CH=CH-,

is preferred, especially preferred is an implementation option, where

R1represents a hydroxyl group or a C1-4CNS group, especially a hydroxyl group, metaxylene group or ethoxyline group,

R2and R3are the same or different and each represents a hydrogen atom, hydroxyl group, halogen atom (particularly chlorine atom or fluorine atom), an amino group, a C1-7alluminare (especially C1-4alkylcarboxylic), triptorelin group, C1-4CNS g is the SCP (especially metaxylene group), hydroxy-C1-4alkyl group, a C1-4alkyl group, phenyl group, di(C1-6alkyl)amino group, a C2-4alkenylphenol group or a C1-4alkoxycarbonyl group, or R2and R3combined with the formation of ethylenoxide,

X1represents-C=C - or-C=N-,

X2represents-C=C-,

R4represents a C1-6alkyl group or cyclopropyl group, especially a C1-4alkyl group (methyl group, etc.),

R5represents a hydrogen atom,

p is 1,

Y represents a carbon atom, and

R6, R7and R8are the same or different and each represents a hydrogen atom, a halogen atom (particularly chlorine atom or fluorine atom), C1-4alkyl group or a C1-4CNS group, or adjacent R6and R7merged to form-CH=CH-CH=CH-.

In the compound represented by formula (1) according to the present invention, when n is 0, for example, an implementation option, where

R1represents a hydroxyl group or a C1-6CNS group (preferably metaxylene group)

R2and R3are the same or different and each represents a hydrogen atom, a hydroxyl group, a halogen atom (preferably a fluorine atom is or chlorine atom), an amino group, a C1-7alluminare (preferably acetylamino), triptorelin group, C1-6alkoxycarbonyl group (preferably methoxycarbonyl group), C1-6CNS group (preferably metaxylene group), C1-6alkyl group (preferably methyl group, ethyl group, through the group, isopropyl group, isobutylene group), hydroxy-C1-6alkyl group (preferably hydroxymethylene group), C2-6alkenylphenol group (preferably 2-methyl-1-propenyloxy group), phenyl group, benzyl group, di(C1-6alkyl)amino group (preferably dimethylaminopropyl) or nitro-group, or R2and R3combined with the formation of ethylenoxide,

X1represents-C=C - or-C=N-,

X2represents-C=C-,

R4represents a methyl group or cyclopropyl group,

R5represents a hydrogen atom,

p is 1,

Y represents a carbon atom, and

R6, R7and R8are the same or different and each represents a hydrogen atom, a halogen atom (preferably fluorine atom or chlorine atom), C1-6alkyl group (preferably methyl group or ethyl group) or C1-6CNS group (suppose the equipment metaxylene group), or adjacent R6and R7merged to form-CH=CH-CH=CH-,

is more preferred, especially an implementation option, where

R1represents a hydroxyl group or a C1-4CNS group (especially metaxylene group or ethoxyline group)

R2and R3are the same or different and each represents a hydrogen atom, hydroxyl group, halogen atom (particularly chlorine atom or fluorine atom), an amino group, a C1-7alluminare (especially C1-4alkylcarboxylic (for example, acetylamino)), triptorelin group, C1-4CNS group (especially metaxylene group), hydroxy-C1-4alkyl group (particularly hydroxymethylene group), C1-4alkyl group (particularly methyl group, ethyl group, isopropyl group, through group or isobutylene group), C2-4alkenylphenol group (especially 2-methyl-1-propenyloxy group), C1-4alkoxycarbonyl group (especially acetylcarnitine group, benzyl group or phenyl group, or R2and R3combined with the formation of ethylenoxide,

X1represents-C=C - or-C=N-,

X2represents-C=C-,

R4represents a methyl group or cyclopropyl group,

R5 represents a hydrogen atom,

p is 1,

Y represents a carbon atom,

R6, R7and R8are the same or different and each represents a hydrogen atom, a halogen atom (particularly chlorine atom or fluorine atom), C1-4alkyl group (particularly methyl group), or C1-4CNS group (especially metaxylene group), or adjacent R6and R7merged to form-CH=CH-CH=CH-,

is preferred.

The compound represented by formula (1) according to the present invention preferably has a configuration represented by the following formula (1'):

wherein each symbol is as defined above for formula (1).

Preferred examples of compounds where n=0, the following, with the number placed before the name of each connection corresponds to a number.

1-1

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-2

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-3

2'-[1-[(2R)-3-[[1-(3-chloro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-4

2'-[1-[(2R)-3-[[1-(4-chloro-3-were)-2-methyl shall ropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-5

2'-[1-[(2R)-3-[[1-(2,3-debtor-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-6

2'-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-7

2'-[1-[(2R)-3-[[1-(2-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-8

2'-[1-[(2R)-3-[[1-(4-ethyl-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-9

3-methyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-5-carboxylic acid

1-10

methyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-3,5-in primary forms

1-11

2'-[(cyclopropyl)[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-3-methylbiphenyl-4-carboxylic acid

1-12, 1-13

2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-14

2'-[(cyclopropyl)[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-3-methylbiphenyl-4-carboxylic acid

1-15, 1-16

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-17

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-and the]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-5-carboxylic acid

1-18

2'-[(cyclopropyl)[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-3-methylbiphenyl-4-carboxylic acid

1-19

2'-[(cyclopropyl)[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-3-methylbiphenyl-4-carboxylic acid

1-20

2'-[1-[(2R)-3-[[1-(3-fluoro-4-methoxyphenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-21

3-methyl-2'-[1-[(2R)-3-[[1-(3,4-dimetilfenil)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid

1-22

2'-[1-[(2R)-3-[[1-(4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-23

2'-[1-[(2R)-3-[[1-(4-chloro-3-methoxyphenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-24

2'-[1-[(2R)-3-[[1-(4-ethylphenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-25

2'-[1-[(2R)-3-[[1-(4-chloro-2,5-differenl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-26

2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methoxybiphenyl-4-carboxylic acid

1-27

2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-2-methoxybiphenyl-4-carboxylic acid

1-28

2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]the Mino]-2-hydroxypropoxy]ethyl]-3-(trifluoromethyl)biphenyl-4-carboxylic acid

1-29

2'-[1-[(2R)-3-[[1-(2-fluoro-4-methoxyphenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-(trifluoromethyl)biphenyl-4-carboxylic acid

1-30

3-ethyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid

1-31

2'-[1-[(2R)-3-[[1-(3,4-dichlorophenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-(trifluoromethyl)biphenyl-4-carboxylic acid

1-32

2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-isopropylidene-4-carboxylic acid

1-33

3-ethyl-2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid

1-34

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-isopropylidene-4-carboxylic acid

1-35

2-chloro-6-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenyl]pyridine-3-carboxylic acid

1-36

2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-propylbiphenyl-4-carboxylic acid

1-37

2,3-dimethyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid

1-38

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-propylbiphenyl-4-carboxylic acid

1-39

2-chloro-6-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methyl shall ropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenyl]pyridine-3-carboxylic acid

1-40

3,5-dimethyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid

1-41

2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-m-terphenyl-4'-carboxylic acid

1-42

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-2,3-dimethylbiphenyl-4-carboxylic acid

1-43

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl] - for 3,5-dimethylbiphenyl-4-carboxylic acid

1-44

4-(hydroxymethyl)-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-3-carboxylic acid

1-45

3-isobutyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid

1-46

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-isobutylphenyl-4-carboxylic acid

1-47

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-4-(hydroxymethyl)biphenyl-3-carboxylic acid

1-48

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-(2-methyl-1-propenyl)biphenyl-4-carboxylic acid

1-49

2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-hydroxybiphenyl-4-carboxylic acid

1-50

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)--methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-hydroxybiphenyl-4-carboxylic acid

1-51

3-ethyl-2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid

1-52

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-isopropylidene-4-carboxylic acid

1-53

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-(1-methylpropyl " biphenyl-4-carboxylic acid

1-54

2-methyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid

1-55

3-methyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid

1-56

4-fluoro-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-3-carboxylic acid

1-57

2'-[1-[(2R)-3-[[1-(3,4-dichlorophenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-2-methylbiphenyl-4-carboxylic acid

1-58

6-fluoro-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-3-carboxylic acid

1-59

3-fluoro-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid

1-60

2'-[1-[(2R)-3-[[1-(3-chlorophenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-61

2'-[1-[(2R)-3-[[1-(3,4-dichlorophenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylb the phenyl-4-carboxylic acid

1-62

2-fluoro-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid

1-63

2'-[(cyclopropyl)[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-3-methylbiphenyl-4-carboxylic acid

1-64

2'-[(cyclopropyl)[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-3-forbiden-4-carboxylic acid

1-65

2'-[(cyclopropyl)[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-2-forbiden-4-carboxylic acid

1-66

2'-[(cyclopropyl)[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-2-methylbiphenyl-4-carboxylic acid

1-67

2'-[1-[(2R)-3-[[1-(3,4-dichlorophenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-2-forbiden-4-carboxylic acid

1-68

3-chloro-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid

1-69

2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-nitrobiphenyl-4-carboxylic acid

1-70

3-amino-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid

1-71

3-(acetylamino)-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid

1-72

3-chloro-2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid

1-73

2'-[1-[(2R)-3-[[1-(3-methoxy-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-74

2,3-dihydro-5-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenyl]benzofuran-7-carboxylic acid

1-75

2,6-dimethyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid

1-76

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-2,6-dimethylbiphenyl-4-carboxylic acid

1-77

3-(dimethylamino)-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid

1-78

2,3-dihydro-5-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenyl]benzofuran-7-carboxylic acid

1-79

3-benzyl-2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid

1-80

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methoxybiphenyl-4-carboxylic acid

1-81

2'-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methoxybiphenyl-4-carboxylic acid

1-82

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methoxybiphenyl-4-carboxylic acid

1-83

2'-[1-[(2R)-3-[[1-(4-chlorine is-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-2-methylbiphenyl-4-carboxylic acid

1-84

2'-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-2-methylbiphenyl-4-carboxylic acid

1-85

4-methyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-3-carboxylic acid

1-86

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-4-methylbiphenyl-3-carboxylic acid

1-87

2'-[1-[(2R)-3-[[1-(3,5-dichlorophenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-89

2'-[1-[(2R)-3-[[1-(2,5-differenl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-90

2'-[1-[(2R)-3-[[1-(5-chloro-2-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-91

2'-[1-[(2R)-3-[[1-(3-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-92

2'-[1-[(2R)-3-[[1-(3-fluoro-4-triptoreline)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-93

2'-[1-[(2R)-3-[[1-(5-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-94

2'-[1-[(2R)-3-[[1-(3,5-dateformatter)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-95

2'-[1-[(2R)-3-[[1-(4-methyl-3,5-acid)-2-methylprop the-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-96

2'-[1-[(2R)-3-[[1-(3,5-acid)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-97

2'-[1-[(2R)-3-[[1-(4-chloro-3-triptoreline)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-98

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-tert-butylbiphenyl-4-carboxylic acid

1-99

2'-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-tert-butylbiphenyl-4-carboxylic acid

1-100

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-tert-butylbiphenyl-4-carboxylic acid

1-101

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methoxybiphenyl-4-carboxylic acid

1-102

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-morpholinomethyl-4-carboxylic acid

1-103

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-(triptoreline)biphenyl-4-carboxylic acid

1-104

2'-[1-[(2R)-3-[[1-(3-trifluoromethyl-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

1-106

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-(hydroxymethyl)biphenyl-4-carboxylic acid

1-107

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-carboxymethyl-4-carboxylic acid

Preferred examples of compounds where n=1, below.

2-1

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoic acid

2-2

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-3-methoxybenzoic acid

2-3

methyl-4-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoate

2-4

4-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoic acid

2-5

4-[2-[1-[(2R)-3-[[1-(quinoline-3-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoic acid

2-6

4-[2-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoic acid

2-7

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoic acid

2-8

3-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoic acid

2-9

4-[2-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenyl]vinyl]benzoic acid

2-10

3-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]FeNi is thio]benzoic acid

2-11

4-[2-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenyl]vinyl]benzoic acid

2-12

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]for 3,5-dimethylbenzoic acid

2-13

4-[2-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]for 3,5-dimethylbenzoic acid

2-14

4-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]benzyl]benzoic acid

2-15

3-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]benzyl]benzoic acid

2-16

4-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenylthio]benzoic acid

2-17

4-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenylsulfinyl]benzoic acid

2-18

4-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenylsulfonyl]benzoic acid

2-19

4-[[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenylamino]methyl]benzoic acid

2-20

2-[[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]methyl]benzoic acid

2-21

3-[[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]methyl]benzoic acid

2-22

4-[[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]methyl]benzoic acid

2-23

3-[[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]methyl]benzoic acid

2-24

4-[[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]methyl]benzoic acid

2-25

3-fluoro-4-[[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]methyl]benzoic acid

2-26

4-[[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]methyl]-3-methylbenzoic acid

2-27

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]for 3,5-dimethoxybenzoic acid

2-28

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-3-nitrobenzoic acid

2-29

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-2-nitrobenzoic acid

2-30

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-3-chlorbenzene acid

2-31

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-2-chlorbenzene acid

2-32

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroc is propoxy]ethyl]phenoxy]-2-triftorperasin acid

2-33

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-3-triftorperasin acid

2-34

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-3-Formentera acid

2-35

4-[2-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoic acid

2-36

4-[2-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-5-methylbenzoic acid

The form in which the compound of the present invention will be used as a pharmaceutical product, is the connection itself (in free form), salt compounds, MES compound or the prodrug compounds. The preferred form is a compound in a free form, a salt of the compound or MES compounds, particularly preferred is a salt of the compound.

The compound of the present invention can be used in the form of prodrugs. In this case, for example, the compound represented by formula (1), where R1represents a hydroxyl group, is converted into the compound, where R1is an RAi.e. C1-6alkyl-OC(=O)O-C1-4alkylen-O-, C3-6cycloalkyl-OC(=O)O-C1-4alkylen-O - or OH-NH-, and is used as prodrugs, and/or connection, where the R 5represents a hydrogen atom is converted into the compound, where R5is an RBi.e. C1-7acyl group, optionally substituted carboxyl group, used as prodrugs.

Therapeutic drug for the treatment of osteoporosis, containing the compound of the present invention as an active ingredient, can be used in conjunction with other therapeutic drug for the treatment of osteoporosis. Another therapeutic drug for the treatment of osteoporosis is a calcium agent (calcium lactate, calcium gluconate, L-aspartate calcium, calcium chloride, calcium phosphate, etc.), vitamin D (Alphacalcidol (Alfacalcidol), Calcitriol (Calcitriol), Maximality (Maxacalcitol), Falecalcitriol (Falecalcitriol) etc.), vitamin K (Menatetrenone (Menatetrenone), etc.), drug female hormones (Estradiol, Estriol, and so on), the drug is an antagonist of estrogen (Raloxifene (Raloxifen), etc.), anabolic steroid drug the preparation of parathyroid hormone (Teriparatide (Teriparatide), PTH(1-84), and so on), the preparation of calcitonin (Elcatonin (Elcatonin), salmon Calcitonin (Calcitonin salmon), and so on), the drug bisphosphonates (Alendronate sodium hydrate, Risedronate sodium hydrate, Etidronate disodium, Pamidronate disodium, encadrant disodium etc), report of ipriflavone (Ipriflavon (Ipriflavone)and another therapeutic drug for the treatment of osteoporosis, such as strontium Ranelate, a WNT inhibitor, agonist of PPAR-gamma, osteopontin, drug statin, an inhibitor of RANK/RANKL, an inhibitor of Src, Pyk2 inhibitor, Osteoprotegerin (Osteoprotegerin) and the like. Therapeutic drug for the treatment of osteoporosis, containing the compound of the present invention and another therapeutic drug for the treatment of osteoporosis, you can enter in the effective number of patients suffering from osteoporosis.

The calcium antagonist receptor preferably demonstrates the value of the IC50antagonistic action against calcium receptor, which is not less than 10 times, more preferably not less than 100 times than inhibitory effect against metabolic enzyme CYP2D6.

In addition, the calcium antagonist receptor preferably demonstrates the value of the IC50antagonistic action against calcium receptor, which does not exceed 0.1 μm, and the value of the IC50inhibitory effect against metabolic enzyme P450, in particular CYP2D6, not less than 1 μm, more preferably the value of the IC50antagonistic action against calcium receptor does not exceed 0.1 μm, and the size of the IC50inhibitory effect against metabolic enzyme P450, in particular CYP2D6, not less than 10 μm.

SPO is usually used for obtaining the compounds of formula (1) according to the present invention is specifically explained hereinafter. Needless to say, the present invention is not limited to these methods of getting. For the synthesis of compounds of the present invention, the synthesis can be started easily from the synthesized fragment. When at the stage of synthesis is a reactive functional group, it is possible to carry out the introduction and removal of suitable protective groups, and to facilitate interaction appropriately, you can use any reagent that differ from those illustrated.

Connection received at each of the stages can be isolated and purified by conventional means. In some cases, the connection can be used in the next stage without isolation and purification.

Methods for obtaining compounds (1) further explained separately for n=0 and n=1.

<Method get n=0>

where R1'represents a C1-6CNS group, Y1and Y2are the same or different, and each represents a halogen atom (as defined above) or triftormetilfullerenov, L1represents a leaving group such as halogen atom (as defined above) or sulfonyloxy, such as 3-nitrobenzenesulfonamide, p-toluensulfonate, benzolsulfonate, p-bromobenzosulfonyl, methysulfonylmethane is whether triftormetilfullerenov and the like, and other symbols are as defined above.

Stage 1A

The compound (IA) interacts with the compound (IIA) in N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, water and the like or in a solvent, which is their mixture, in the presence of a base such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine and the like, at temperatures from 0°C to room, you get a compound (IIIA). In this case, it may be added hydrosulphate of alkylamine, such as tetrabutylammonium hydrosulfate, and the like.

Stereoselective reaction can be carried out with the use of the reagent and the leaving group.

For example, compound (IA) interacts with (R)-glycidylmethacrylate in N,N-dimethylformamide in the presence of sodium hydride, giving the compound (IIIA).

Stage 2A

At this stage, with a combination of Suzuki compound (VA) is produced from compound (IIIA) or (IVA).

The compound (IVA) interacts with babinkostova in dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane and the like or in a solvent, which is their mixture, when using chloride bis(diphenylmethanediisocyanate(II) and the base, such as potassium acetate and the like, with the receipt of ester Bronevoy acid and compounds (IVA), which then interacts with the compound (IIIA) in toluene, ethanol, benzene, acetone, 1,4-dioxane, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, 1,2-dimethoxyethane, dimethyl sulfoxide, water and the like, or in a solvent, which is their mixture, when using a palladium catalyst, such as chloride bis(diphenylphosphino)ferienparadies(II), tetrakis(triphenylphosphine)palladium(0) and the like, and bases, such as sodium carbonate, tribalistas (K3PO4), potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like, and thus obtain the compound (VA).

Alternatively, the compound (IIIA)obtained in stage 1A, is subjected to the interaction in the presence of a palladium catalyst, such as chloride bis(diphenylphosphino)ferienparadies(II), tetrakis(triphenylphosphine)palladium(0) and the like, potassium acetate and babinkostova in dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane and the like, or in a solvent, representing a mixture of the two, receiving ester Bronevoy acid and compound (IIIA), which then interacts with the compound (IVA) in toluene, ethanol, benzene, acetone, 1,4-dioxane, tetrahydrofuran, acetonitrile, 1,2-dimethoxyethane dimethyl sulfoxide, water and the like, or in a solvent, which is their mixture, in the presence of a palladium catalyst, such as chloride bis(diphenylphosphino)ferienparadies(II), tetrakis(triphenylphosphine)palladium(0) and the like, and a base such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, tribalistic and the like, giving the compound (VA).

Stage 3A

The compound (VA)obtained in stage 2A, subjected to interaction with compound (VIA) in methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene and the like, or in a solvent, which is their mixture, at a temperature from room temperature up to the boiling temperature under reflux, obtaining the compound (1-1). In this case it is preferable to add a perchlorate of an alkali metal such as lithium perchlorate and the like.

Hydrolysis of the compound (1-1), carried out by conventional means, converts the R1'(C1-6CNS group) in the hydroxyl group.

The compound (VIA)used in stage 3A, can be obtained in various ways. Then explains how to obtain the compound (VIA).

The method of obtaining 1 of compound (VIA)

where X3represents a hydrogen atom or a halogen atom (as defined is prohibited above), R represents an alkyl group (preferably methyl group or ethyl group), and other symbols are as defined above.

Stage 4A

The compound (XA) is subjected to interaction with the compound (XIA) in tetrahydrofuran or diethyl ether, obtaining the compound (VIIIA).

Stage 5A

At this stage, the compound (VIIA) is produced from compound (VIIIA) with the use of Ritter reaction. Compound (VIIIA), obtained in stage 4A, is subjected to the interaction with the compound (IXA) in acetic acid with sulfuric acid, obtaining the compound (VIIA).

Stage 6A

When X3in the compound (VIIA), obtained in stage 5A represents a halogen atom, this stage is usually carried out under the conditions normally used to remove halogenoacetyl group. For example, the interaction in water, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, acetic acid and the like or in a solvent, which is their mixture, with the use of thiourea by heating leads to the compound (VIA).

When X3in the compound (VIIA) is a hydrogen atom, this stage is carried out in the conditions normally used for the removal of acetyl groups. For example, the interaction in water, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, diethyl which the glycol and the like using a base, such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, under heating leads to the compound (VIA).

The method of obtaining 2 connections (VIA)

where X4represents a halogen atom (as defined above), and other symbols are as defined earlier.

Stage 7A

The compound (XVA) interacts with magnesium in tetrahydrofuran or diethyl ether, giving the compound (XIVA).

Stage 8A

The compound (XIVA), obtained in stage 7A, is subjected to the interaction with the compound (XIIIA) in tetrahydrofuran or diethyl ether, using, if necessary, as a catalyst of copper iodide, obtaining the compound (XIIA).

The compound (XIIA), obtained in stage 8A, is subjected to reactions similar to those described for stage 5A, obtaining the compound (VIIA), which is then subjected to interaction similar to that described for stage 6A, obtaining the compound (VIA).

The method of obtaining 3 connections (VIA)

where X5represents a halogen atom (as defined above), RhO2C - represents a protective group of amino group, such as benzyloxycarbonyl group, tert-butoxycarbonyl group and the like, and other symbols are as defined above.

Stage 9A

The compound (ia) is subjected to mutually is deystviy with compound (iia) in a solvent, such as tetrahydrofuran, n-hexane and the like, in the presence of a base, such as n-utility and the like, and hexamethylphosphorotriamide, obtaining the compound (iiia).

Stage 10A

At this stage, the compound (iiia)obtained in stage 9A, is subjected to rearrangement of Curtius, obtaining the compound (iva). The compound (iiia) is subjected to interaction with halogenated alkalicarbonate, such as chlorethylene and the like, in water, acetone, methylethylketone and the like, or in mixtures of these solvents, in the presence of a base, such as triethylamine, N,N-diisopropylethylamine and the like. This is followed by interaction with sodium azide, getting the connection. The compound obtained regroup when heated, and then spend interaction with alcohol of the formula Rh-OH, where Rh represents a benzyl group, tert-boutelou group and the like, obtaining the compound (iva).

Stage 11A

At this stage remove the group-CO2Rh, CO2Rh is as defined above for compound (iva)obtained in stage 10A, which is carried out by using a method commonly used for removing the protective group in the compound, where the amino group is protected-CO2Rh. For example, when CO2Rh represents benzyloxycarbonyloxy group, the compound (iva) is subjected to gidrirovanie is with the use of a catalyst, such as palladium-on-charcoal, palladium black, palladium hydroxide-on-charcoal, Raney Nickel and the like, in a solvent such as methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane and the like, obtaining the compound (VIA). When, for example, -CO2Rh represents a tert-butoxycarbonyl group, interaction with acid, such as hydrochloric acid, sulfuric acid, Hydrobromic acid and the like, in water, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, acetic acid, and the like, or in mixtures of these solvents leads to the compound (VIA).

The method of obtaining 4 connections (VIA), (p=1)

where X6represents a halogen atom (as defined above), and other symbols are as defined above.

Stage 12A

In the interaction of the compound (iib) with a compound (ib) in a solvent such as tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide and the like, in the presence of tetraalkylammonium halide such as tetrabutylammonium fluoride and the like, and trialkylaluminium, such as tert-butyldimethylchlorosilane and the like, can be obtained compound (iiib).

Stage 13A

By halogenation of the compound (iiib)obtained in stage 12A, the BL is reattaching the halogenation agent, such as chloride thionyl, oxalicacid and the like, can be obtained compound (ivb). In this reaction itself halogenation reagent can be used as solvent or you can use a solvent, such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like.

Stage 14A

When the hydrogenation of the compound (ivb)obtained at the stage 13A, in a solvent such as methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, ethyl acetate, and the like, in the presence of a catalyst such as palladium-on-charcoal, palladium black, palladium hydroxide-on-coal and the like, can be obtained compound (vb). In this reaction, the pressure increases to a certain degree is preferred.

Stage 15A

When the hydrogenation of the compound (vb)obtained at the stage 14A, using a catalyst such as Raney Nickel, platinum oxide, palladium-on-coal and the like, in a solvent such as methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane and the like, can be obtained compound (VIA). In this reaction, the pressure increases to a certain degree is preferred. In addition, compound (VIA) can also be obtained by reduction using iron, tin chloride and the like to enter the specified solvent.

The method of obtaining 5 connection (VIA)

where Ph represents a phenyl group, and other symbols are as defined above.

Stage 16A

The compound (ic) is subjected to interaction with the compound (iic) in ethanol, isopropanol, tert-butanol, acetone, water, methylene chloride, diethyl ether, N,N-dimethylformamide and the like, or in mixtures of these solvents, at temperatures from room temperature up to the boiling temperature under reflux, obtaining the compound (iiic).

Stage 17A

The compound (ivc) is subjected to interaction with the compound (iiic), obtained at the stage 16A, dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, diethyl ether, and the like, or in mixtures of these solvents, in the presence of sodium methoxide, sodium hydride and the like, receiving a connection (vc).

Stage 18A

Connection (vc)obtained at the stage 17A, is subjected to interaction similar reaction at the stage 15A, obtaining the compound (VIA).

<a Method of obtaining, when n is 1>

When Z represents-O-

where X7represents a halogen atom (as defined above), and other symbols are as defined above.

Stage 1B

Interaction of the compound (IB) with a compound (IIB) in N,N-demethylase amide, N,N-dimethylformamide, dimethyl sulfoxide and the like, or in mixtures of these solvents, in the presence of a base such as potassium carbonate, sodium carbonate, and the like, at temperatures from room temperature up to the boiling temperature under reflux obtain the compound (IIIB).

Stage 2B

The recovery of the compound (IIIB)obtained in stage 1B, using a reducing agent such as sociallyengaged, borohydride sodium, borohydride lithium and the like, isopropanol, tetrahydrofuran, toluene, methanol and the like, or in mixtures of these solvents, at temperatures from -10°C to room temperature can be obtained compound (IVB). In addition, when the recovery of the compound (IIIB) using asymmetric reducing agent, such as B-chlorodiisopinocampheylborane, (S)-5,5-diphenyl-2-methyl-3,4-propane-1,3,2-oxazaborolidine and the like, or by the reaction of asymmetric hydrogenation using ruthenium complex such as dichloro[(S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl][(S)-1,1'-bis(p-methoxyphenyl)-2-isopropylidene-1,2-diamine]ruthenium (II) and the like and tert-butoxide potassium proceeds in a stereoselective reaction, leading to the R-form of compound (IVB).

Stage 3B

Compound (IVB)obtained in stage 2B, the compound (IIA) is subjected to interactions similar to the op is between stage 1A, receiving the compound (VB).

Stage 4B

The compound (VB)obtained in stage 3B, the compound (VIA) is subjected to interactions, similar to that described in stage 3A, obtaining the compound (1-2).

Hydrolysis of the compound (1-2)is carried out by conventional means, converts the R1'(C1-6CNS group) in the hydroxyl group. For example, the compound (1-2) hydrolyzing in a mixed solvent consisting of methanol-tetrahydrofuran-water, using sodium hydroxide.

When Z represents a C2-4alkenylamine group

where Z1represents a C2-4alkenylamine group (as defined for C2-4alkenylamine group in the case of Z), X7represents a halogen atom (as defined above), and the other substituents are as defined above.

Stage 5B

Interaction of the compound (VIB) with compound (VIIB) in acetonitrile, N,N-dimethylformamide, toluene and the like, or a solvent which is their mixture, in the presence of a base, such as triethylamine, potassium carbonate, sodium carbonate, and the like, and three(o-tolyl)phosphine or triphenylphosphine with a palladium catalyst, such as diacetoxybiphenyl, dichloropalladium and the like, at temperatures from room temperature up to the temperature the s boiling under reflux may be obtained compound (VIIIB).

Subjecting the compound (VIIIB), obtained in stage 5B, interaction, similar to that described in stage 4B, can be obtained compound (1-9), where Z represents a C2-4alkenylamine group.

In the case where Z represents -(CH2)m2-NH-

where Pro1represents a protective group of an amino group (for example, trifluoracetyl group, tert-butoxycarbonyl group and the like), Pro2represents a protective group of hydroxyl (for example, acetyl group, benzoyloxy group, chloroacetyl group, trichloroethylene group and the like), X8represents a halogen atom (as defined above), and other symbols are as defined above.

Stage 6B

In the interaction of the compound (IXB) in methanol, ethanol, tetrahydrofuran, diethyl ether, and the like, or in mixtures of these solvents, using sodium borohydride, lithium borohydride and the like can be obtained compound (XB).

Stage 7B

Subjecting the compound (XB)obtained in stage 6B, the compound (IIA) reaction similar to that described for stage 1A, can be obtained compound (XIB).

Stage 8B

Subjecting the compound (XIB), obtained at the stage 7B, the compound (VIA) reaction similar to that described for stage 3A, can the t to be obtained compound (XIIB).

Stage 9B

In the interaction of the compound (XIIB) in tetrahydrofuran, ethanol, water, methanol and the like, or in mixtures of these solvents, using iron and ammonium chloride can be obtained compound (XIIIB).

Stage 10B

When protection using conventional methods, the amino group in compound (XIIIB), obtained at the stage 9B, can be obtained compound (XIVB). For example, when the amino protecting trifluoracetyl group, the compound is subjected to interaction with the anhydride triperoxonane acid in chloroform, methylene chloride, tetrahydrofuran, toluene, ethyl acetate, and the like, or in mixtures of these solvents in the presence of a base, such as pyridine, triethylamine and the like.

Stage 11B

When protection using conventional methods hydroxyl group in the compound (XIVB), obtained in stage 10B, can be obtained compound (XVB). For example, when the hydroxyl group protecting acetyl group, the compound is subjected to interaction with acetic anhydride in chloroform, methylene chloride, tetrahydrofuran, toluene, ethyl acetate, and the like, or in mixtures of these solvents, in the presence of a base, such as pyridine, triethylamine and the like.

Stage 12B

In the interaction of the compound (XVB), obtained at the stage 11B, with the compound (XVI) in N,N-dimethylformamide, tetrahydrofuran, diethyl ether, dimethyl sulfoxide, acetone, acetonitrile, or in mixtures of these solvents, in the presence of a base such as sodium hydride, potassium carbonate, sodium carbonate, and the like, can be obtained compound (XVIIB).

Stage 13B

When removing the usual protective groups in the compound (XVIIB), obtained at the stage 12B, can be obtained compound (1-3). For example, when the amino protecting trifluoracetyl group and hydroxyl group protecting acetyl group, the compound is subjected to interaction in a mixture of tetrahydrofuran-methanol in the presence of sodium hydroxide.

When Z represents-CONH-

where X9represents a halogen atom (as defined above), and other symbols are as defined above.

Stage 14B

In the interaction of the compound (XIIIB), obtained at the stage 9B, with the compound (XVIIIB) in chloroform, methylene chloride, tetrahydrofuran, toluene, ethyl acetate, or mixtures of these solvents, in the presence of a base, such as pyridine, triethylamine, N,N-diisopropylethylamine and the like, can be obtained compound (1-4).

The hydrolysis of compounds (1-4), carried out by conventional means, converts the R1'(C1-6CNS group) in hydroximino the group. For example, the compound (1-4) hydrolyzing a mixed solvent of methanol-tetrahydrofuran-water using sodium hydroxide.

When Z represents-S-

wherein each symbol is as defined above.

Stage 15B

Upon exposure of the compound (IXXB) and compound (IIB) interaction, similar to that described for stage 1B, can be obtained compound (XXB). When the compound of the formula

wherein each symbol is as defined above, are used as starting substances, the group-CO2H in advance is converted into a group-COR1'to obtain a connection (IXXB). For example, the group may be converted by using concentrated sulfuric acid in the C1-6alcohol, such as methanol, ethanol and the like.

Stage 16B

When the exposure of compound (XXB), obtained at the stage 15B, and compounds (XIA) interaction, similar to that described for stage 4A can be obtained compound (XXIB).

Stage 17B

When the exposure of compound (XXIB), obtained at the stage 16B, and the compounds (IIA) interaction, similar to that described for stage 1A, can be obtained compound (XXIIB).

Stage 18B

Upon exposure of the compound (XXIIB), obtained at the stage 17B, and the compound (VIA) interaction, nelogichnogo described for stage 3A, can be obtained compound (1-5).

The hydrolysis of compounds (1-5), carried out by conventional means, converts the R1'(C1-6CNS group) in the hydroxyl group. For example, the hydrolysis is carried out in tetrahydrofuran, methanol and the like, or in mixtures of these solvents, in the presence of sodium hydroxide.

When Z represents a C1-4alkylenes group

where Z2represents a C1-4alkylenes group (as defined in the case of C1-4alkalinous group for Z), and other symbols are as defined above.

Stage 19B

When the exposure of the compounds (IIIA) and a compound (XXIIIB) interaction, similar to that described for stage 2A, can be obtained compound (XXIVB).

Stage 20B

Upon exposure of the compound (XXIVB)obtained at the stage 19B, and the compound (VIA) interaction, similar to that described for stage 3A, can be obtained compound (1-6).

Hydrolysis of the compound (1-6), carried out by conventional means, converts the R1'(C1-6CNS group) in the hydroxyl group. For example, the compound (1-6) hydrolyzing in tetrahydrofuran, methanol and the like, or in mixtures of these solvents, in the presence of sodium hydroxide.

When Z represents -(CH 2)m1-O- (1)

where Z3represents -(CH2)m1- (m1 here is the same as defined for m1 for the group Z), X10represents a halogen atom (as defined above), and other symbols are as defined above.

Stage 21B

When interacting compounds (XXVB) with compound (XXVIB) in N,N-dimethylformamide, tetrahydrofuran, diethyl ether, dimethyl sulfoxide, acetone, acetonitrile and the like, or in mixtures of these solvents, in the presence of a base such as sodium hydride, potassium carbonate, sodium carbonate, and the like, can be obtained compound (XXVIIB).

Stage 22B

Upon exposure of the compound (XXVIIB), obtained at the stage 21B, and the compounds (IIA) interaction, similar to that described for stage 1A, can be obtained compound (XXVIIIB).

Stage 23B

Upon exposure of the compound (XXVIIIB)obtained at the stage 22B, and the compound (VIA) interaction, similar to that described for stage 3A, can be obtained compound (1-7).

Hydrolysis of the compound (1-7), conducted using conventional methods, leads to the conversion of R1'(C1-6CNS group) in the hydroxyl group. For example, the compound (1-7) hydrolyzing in tetrahydrofuran, methanol and the like, or in mixtures of these solvents, in outstay sodium hydroxide.

You can also use the optically active compound (XXVB), and the optically active compound (XXVB) can be obtained below way.

where Pro3is as defined for a Pro2and other symbols are as defined above.

Stage 24B

When the protection of the hydroxyl group in compound (id) in a usual way can be obtained compound (iid). For example, when the hydroxyl group protecting benzyl group, the compound is subjected to interaction with benzylchloride (for example, benzylbromide) in N,N-dimethylformamide in the presence of a base such as potassium carbonate, sodium hydride and the like.

Stage 25B

When interacting compounds (iid), obtained at the stage 24B, with the compound (iiid) in tetrahydrofuran, toluene, methylene chloride, hexane and the like, or in mixtures of these solvents, in the presence of borane-dimethylsulfide complex salt can be obtained compound (ivd).

Stage 26B

When removing the protective group in the compound (ivd), obtained at the stage 25B, using conventional methods can be obtained optically active compound (XXVB). For example, when the hydroxyl group protecting benzyl group, carry out the hydrogenation in tetrahydrofuran, methanol, ethanol, ethyl acetate, and the like, or the mixtures of these solvents, in the presence of palladium-on-charcoal grill.

When Z represents -(CH2)m1-O- (2)

where Pro4is as defined for a Pro2and other symbols are as defined above.

Stage 27B

Upon exposure of the compound (XXIXB) and compound (IIA) interaction, similar to that described for stage 1A, can be obtained compound (XXXB).

Stage 28B

Upon exposure of the compound (XXXB), obtained at the stage 27B, and the compound (VIA) interaction, similar to that described for stage 3A, can be obtained compound (XXXIB).

Stage 29B

When removing the protective groups in the compound (XXXIB), obtained at the stage 28B, using conventional methods can be obtained compound (XXXIIB). For example, when the hydroxyl group in the compound (XXXIB) protect 2-(trimethylsilyl)ethoxymethyl group, removing the protectors in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone in the presence of tetrabutylammonium halide (for example, tetrabutylammonium fluoride and the like) and MS4A.

Stage 30B

Upon exposure of the compound (XXXIIB), obtained at the stage 29B, and the compound (XXVIB) interaction, similar to that described for stage 21B, can be obtained compound (1-7).

Hydrolysis of the compound (1-7)by conventional methods, leads to the conversion of R1' (C1-6CNS group) in the hydroxyl group. For example, the compound (1-7) hydrolyzing in a mixture of tetrahydrofuran-methanol in the presence of sodium hydroxide.

Stage 27B can also be carried out using optically active compounds (XXIXB). For example, if the compound (id) is subjected to the reactions described for stage 24B and stage 25B may be obtained optically active compound (XXIXB). For example, when you want optically active compound (XXIXB), where a hydroxyl group protected by 2-(trimethylsilyl)ethoxymethyl group on stage 24B compound (id) is subjected to interaction with 2-(trimethylsilyl)ethoxymethylene (for example, 2-(trimethylsilyl)ethoxymethylene) in chloroform in the presence of diisopropylethylamine.

When in the present invention, it is desirable to obtain the compound (1), where R1is an RAespecially RC-OC(=O)O-C1-4alkylen-O-, the compound (1), where R1represents a hydroxyl group, is subjected to the interaction with RC-OC(=O)O-C1-4alkylen-L2(L2represents a leaving group such as halogen atom and the like) in N,N-dimethylformamide, tetrahydrofuran, diethyl ether, dimethyl sulfoxide, acetone, acetonitrile and the like, or in mixtures of these solvents, in the presence of a base such as sodium hydride,potassium carbonate, sodium carbonate and the like, can thus be obtained compound (1), where R1is an RC-OC(=O)O-C1-4alkylen-O-.

When connection is required, where R1is an RAespecially OH-NH-, the compound (1), where R1represents a hydroxyl group, is subjected to interaction with trimethylsilylacetamide in N,N-dimethylformamide, tetrahydrofuran, diethyl ether, dimethyl sulfoxide, acetone, acetonitrile and the like, or in mixtures of these solvents, in the presence of a condensing agent, such as dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, diisopropylcarbodiimide, diphenylphosphoryl, 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline(EEDQ), and the like, and an auxiliary agent such as 1-hydroxybenzotriazole, 4-dimethylaminopyridine and the like. Then spend interaction with tetrabutylammonium fluoride in the above solvent, obtaining the compound (1), where R1represents OH-NH-.

To obtain the compounds (1), where R5is an RBfor example, as shown in the following formulas, compound (1-1)obtained in stage 3A, is subjected to the interaction with the acid anhydride such as acetic anhydride, succinic anhydride, maleic anhydride, and the like, or allelochemical in x is orapharma, chloride methylene, tetrahydrofuran, toluene, ethyl acetate, and the like, or in mixtures of these solvents, in the presence of a base, such as pyridine, triethylamine, dimethylaminopyridine and the like, can be obtained compound (1-8).

wherein each symbol is as defined above.

When the desired salt of the compound represented by formula (1), it is possible to use known methods. For example, when the desired acid additive salt, the compound represented by formula (1), dissolved in water, methanol, ethanol, n-propanol, isopropanol, diethyl ether, tetrahydrofuran, 1,4-dioxane, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform and the like, or in mixtures of these solvents, add the above solvent in which is dissolved the desired acid, and precipitated precipitated crystals are collected by filtration or mixture concentrated under reduced pressure.

When it is desirable to get the salt crystals with the use of several solvents, the preferred method is as follows: the compound is dissolved in a solvent with high solubility, add the solvent in which is dissolved the desired acid, and add a solvent which has a low dissolving capacity and then collect fallen to precipitate crystals.

When it is desirable to obtain a basic salt, the compound represented by formula (1), dissolved in water, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane and the like, or in mixtures of these solvents, add the above solvent in which is dissolved an equivalent amount of the desired base, and loose precipitated crystals are collected by filtration or the mixture is concentrated under reduced pressure.

When it is desirable to get the salt crystals with the use of several solvents, the preferred method is as follows: the compound is dissolved in a solvent with high solubility, add the solvent in which is dissolved the desired base, and add a solvent which has a low solubility, and then collect the precipitated precipitate crystals.

When an acid additive salt of the compound represented by formula (1)should be converted into a free form, the acid additive salt of the compound represented by formula (1), is added to aqueous solution of base, such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, bringing the pH of the water solution until neutral-weak acid, and the solution section shall have two layers, applying a solvent, such as ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, methyl ethyl ketone or toluene and the like, can be obtained in the free form of the compound represented by formula (1).

When the basic salt of the compound represented by formula (1)should be converted into a free form, an aqueous solution of acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, acetic acid, citric acid and the like, is added to aqueous solution of a basic salt of the compound represented by formula (1), and precipitated precipitated solid is collected by filtration or the solution separated into two layers, applying a solvent, such as ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, methyl ethyl ketone or toluene and the like, can be obtained in free form the compound represented by formula (1).

When the desired salt of optically active compounds, the compound represented by formula (1), re-suspended in methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, water and the like, the suspension is heated to dissolve, and then the solution is cooled to precipitate a crystal. Crystalline salt get in the way described above using the thus obtained crystal.

Received thisway compound of formula (1) according to the present invention has an excellent antagonistic action on the calcium receptor. When the compound of the present invention propose to use as a therapeutic agent for the treatment of osteoporosis, hypoparathyroidism, osteosarcoma, periodontal disease, bone fracture, osteoarthritis, chronic rheumatoid arthritis, Paget's disease, humoral hypercalcemia, autosomal dominant hypocalcemia, Parkinson's disease, dementia and the like, it is usually injected systemic or local route, oral or parenteral.

Although the dose varies depending on age, body weight, condition, effect of treatment, method of administration, duration of administration and the like, the compound is usually administered in amounts of from 0.01 mg to 10 g per adult person per day, which is administered at once or in several portions during the day by oral or parenteral administration.

When the compound of the present invention introduced into the solid compositions for oral administration, can be used preparative dosage form as tablets, pills, powder, granules and the like. In such solid compositions one or more active ingredients are mixed with at least one inert diluent, dispersing agent, adsorbent, and the like, such as lactose, mannitol, glucose, hydroxypropylcellulose, crystal is ical pulp, starch, polyvinyliden, alumosilicate magnesium, powder anhydrous silicic acid and the like. The composition may contain auxiliary additives, different from the diluent in accordance with generally accepted methods.

To obtain tablets or pills can cause soluble in the stomach or intestines film sucrose, gelatin, hydroxypropylcellulose, phthalate of hydroxymethylcellulose and the like, or can be obtained in two or more layers. In addition, they can be obtained in the form of capsules made of gelatin or ethyl cellulose.

To obtain liquid compositions for oral administration can be used preparative dosage form, such as pharmaceutically acceptable emulsion, solution, suspension, syrup, elixir and the like. Solvent used may represent, for example, purified water, ethanol, vegetable oil, emulsifier and the like. Such a composition may contain a diluent and an adjuvant that is different from the diluent, such as wetting agent, suspendisse agent, sweetener, flavoring, flavouring agent, preservative and the like.

To obtain a drug for parenteral injection using a sterile aqueous or nonaqueous solvent, a solubilizer, suspendisse agent or emulsifier. Examples in the aqueous solvent, a solubilizer and a suspending agent include distilled water for injection, saline solution, cyclodextrin and its derivatives, organic amines such as triethanolamine, diethanolamine, monoethanolamine, triethylamine and the like, solutions of inorganic alkalis, and the like.

When you need to obtain a water-soluble drug solution can be used, for example, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohol such as ethanol, and the like. As a solubilizer can be used, for example, surfactant (forming mixed micelles), such as polyoxyethylene-gidrirovannoe castor oil, esters of sucrose and fatty acids, and the like, lecithin or hydrogenated lecithin (forming liposomes) and the like. In addition, can be obtained emulsion preparation consisting of water-insoluble solvent, such as vegetable oil and the like, lecithin, polyoxyethylene-gidrirovannoe castor oil, polyoxyethylene-polyoxypropyleneglycol and the like.

In addition to other compositions for parenteral administration can be derived liquids for external use, liquid, ointment, such as ointment, suppository, pessary, and the like, containing one or more Akti the different ingredients and ShowLine known in themselves ways.

The form in which the compound of the present invention is used as a pharmaceutical product, is the connection itself (in free form), salt compounds, MES compound or prodrug of the compound where the preferred form is a compound in a free form, a salt of the compound or MES compounds, particularly preferred is a salt of the compound.

Examples

The compound of formula (1) according to the present invention and the means of obtaining it are explained in detail with reference to the following examples, which should not be construed as limiting.

Example 1-1

2'-[(1R)-[(2R)-3-[[1-(3-Fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

Stage 1

(2R)-2-[((1R)-(2-Bromophenyl)ethoxy)methyl]oxirane

(1R)-(2-Bromophenyl)ethanol (30.0 g) and (R)-glycidyl-3-nitrobenzenesulfonate (50,3 g) was dissolved in dimethylformamide (300 ml) was added sodium hydride (7,76 g, 60% in oil). The mixture was stirred at room temperature for 2 hours. To the reaction mixture were added 10%aqueous citric acid solution (600 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Polojenieto was purified column chromatography on silica gel (hexane:ethyl acetate=6:1), getting listed in the title compound (32,9 g).

1H-NMR (300 MHz, δ ppm,CDCl3) 7,53-7,49 (2H, m), 7,37-to 7.32 (1H, m), 7,16-7,10 (1H, m), 4,89 (1H, q, J=6.4 Hz), 3,62 is 3.57 (1H, m), 3,34 of 3.28 (1H, m), 3,18-of 3.12 (1H, m), 2,79 was 2.76 (1H, m), 2,58 is 2.55 (1H, m)of 1.44 (3H, d, J=6,4 Hz).

Stage 2

Methyl-4-bromo-2-methylbenzoate

4-Bromo-2-methylbenzoic acid (75,0 g) was dissolved in methanol (500 ml) was added concentrated sulfuric acid (10 ml). The mixture was heated at the boil under reflux for 20 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the obtained residue was added water (150 ml) and the mixture was extracted with ethyl acetate (150 ml). The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated salt solution, dried over sodium sulfate and concentrated under reduced pressure, obtaining specified in the header connection (78.0 g).

1H-NMR (400 MHz, δ ppm, CDCl3) to 8.20 (1H, s), 8,86 (1H, d, J=8.0 Hz), 7,30 (1H, d, J=8.0 Hz), 3,91 (3H, s), a 2.45 (3H, s).

Stage 3

Methyl-3-methyl-2'-[(1R)-((R)-oxiranylmethyl)ethyl]biphenyl-4-carboxylate

Methyl-4-bromo-2-methylbenzoate (9,16 g)obtained in stage 2, was dissolved in dimethyl sulfoxide (120 ml) was added at 80°C bis(diphenylphosphino)periodiacally) (1,46 g), potassium acetate (11.8 g) and Bisengaliev (11.2 g). The mixture was stirred for 3 hours. The reaction mixture was cooled to room temperature, added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate=9:1) and the compound obtained was dissolved in a mixture of toluene (80 ml) and ethanol (80 ml). To this solution was added a solution of bis(diphenylphosphino)periodically(II) (1,17 g) and (2R)-2-[((1R)-(2-bromophenyl)ethoxy)methyl]oxirane (10,5 g)obtained in stage 1, in ethanol (80 ml) was added 2M aqueous sodium carbonate solution (80 ml). The mixture was heated at the boil under reflux for 3 hours. The reaction mixture was left to cool to room temperature and was extracted with diethyl ether. The organic layer was washed successively with water and saturated salt solution, dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate=5:1), obtaining specified in the header connection (8,93 g).

1H-NMR (300 MHz, δ ppm, CDCl3) of 7.96 (1H, d, J=8.6 Hz), 7,60 (1H, d, J=6,7 Hz), 7,43-7,28 (4H, m), 7.18 in-7,13 (1H, is), 4,55 (1H, q, J=6.4 Hz), to 3.92(3H, s), 3,44 is 3.40 (1H, m), 3,18-of 3.12 (1H, m), 3,07-to 3.02 (1H, m), 2,73-2,70 (1H, m), 2,65 (3H, s), 2,47 at 2.45 (1H, m)to 1.37 (3H, d, J=6,4 Hz).

Stage 4

Methyl(3-fluoro-4-were)acetate

(3-Fluoro-4-were)acetic acid (or 105.3 g) was dissolved in methanol (740 ml) was added concentrated sulfuric acid (9,9 ml). The mixture was stirred at 85°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Added water to the obtained residue, and the mixture was extracted with ethyl acetate (1 liter). The organic layer was washed successively with water, aqueous sodium hydrogen carbonate solution, water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure, obtaining specified in the header connection (114,2 g).

1H-NMR (300 MHz, δ ppm, CDCl3) 7,14-7,10 (1H, m), of 6.96-6,93 (2H, m), 3,70 (3H, s)to 3.58 (2H, s), 2,25-of 2.24 (3H, s).

Stage 5

1-(3-Fluoro-4-were)-2-methylpropan-2-ol

Methyl(3-fluoro-4-were)acetate (114,2 g)obtained in stage 4, was dissolved in tetrahydrofuran (800 ml) and was added dropwise 1M methylmagnesium (1,56 l) at 0°C in a stream of argon. The mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled with ice, was added dropwise a saturated aqueous solution of chlorine is IDA ammonium (155 ml) was added magnesium sulfate (280 g). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, obtaining specified in the header connection (to 130.1 g).

1H-NMR (300 MHz, δ ppm, CDCl3) 7,11-was 7.08 (1H, m), 6,88-6,86 (2H, m), 2,71 (2H, in), 2.25 (3H, s)to 1.22 (6H, s).

Stage 6

2-Chloro-N-[1-(3-fluoro-4-were)-2-methylpropan-2-yl]ndimethylacetamide

1-(3-Fluoro-4-were)-2-methylpropan-2-ol (to 130.1 g)obtained in stage 5, was dissolved in chloroacetonitrile (139 ml) and acetic acid (115 ml) was added dropwise under ice cooling concentrated sulfuric acid (33,4 ml). The mixture was stirred at room temperature for 2 hours and added dropwise under ice cooling 4 N. aqueous sodium hydroxide solution (16 ml). The mixture was extracted twice with toluene and twice with ethyl acetate. The organic layer was twice washed 10%saturated salt solution and concentrated under reduced pressure, obtaining mentioned in the title compound (131, 6mm g).

1H-NMR (300 MHz, δ ppm, CDCl3) 7,10-7,06 (1H, m), 6,80-6,76 (2H, m), to 6.19 (1H, users), of 3.95 (2H, s)of 3.00 (2H, s), 2,24 (3H, s)to 1.37 (6H, s).

Stage 7

(1-(3-Fluoro-4-were)-2-methylpropan-2-yl)Amin

2-Chloro-N-[1-(3-fluoro-4-were)-2-methylpropan-2-yl]ndimethylacetamide (humidity 131.6 g)obtained in stage 6, was dissolved in a mixture of acetic acid (200 ml) and ethanol (1 l) was added thiourea (46.6 g). With the ect was stirred over night at 100° C. the Reaction mixture was cooled to room temperature and precipitated precipitated crystals were filtered off. The filtrate was concentrated under reduced pressure and the obtained residue was added a 4 n solution of sodium hydroxide (300 ml). The mixture was extracted 3 times with toluene. The organic layer was washed with saturated salt solution and concentrated under reduced pressure. The obtained residue was dissolved in diethyl ether (1 l) was added dropwise under ice cooling a solution of 4 N. hydrochloric acid in ethyl acetate (255 ml). The mixture was stirred for 1 hour and precipitated precipitated crystals were collected by filtration. The obtained crystals were added to a mixture of toluene and 4 N. aqueous sodium hydroxide solution. Toluene layer was separated, washed twice with water and concentrated under reduced pressure, obtaining specified in the header connection (57,9 g).

1H-NMR (300 MHz, δ ppm, CDCl3) 7,11-7,07 (1H, m), 6,85-PC 6.82 (2H, m), 2,61 (2H, in), 2.25 (3H, s), is 1.11 (6H, s).

Mass spectrum (APCI, m/z 182(M+H)+.

Stage 8

Methyl-2'-[(1R)-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylate

Methyl-3-methyl-2'-[(1R)-((R)-oxiranylmethyl)ethyl]biphenyl-4-carboxylate (of 2.26 g), obtained in stage 3, was dissolved in toluene (50 ml). Successively added 1-(3-fluoro-4-were-2-methylpropan-2-yl)amine (1,38 g), obtained in stage 7, and lithium perchlorate (815 mg) and the mixture was stirred over night at room temperature. The reaction mixture was washed successively with water and saturated salt solution, dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (chloroform:methanol=9:1), obtaining specified in the header connection (3,37 g).

1H-NMR (400 MHz, δ ppm, DMSO-d6) to 7.95 (1H, d, J=8.6 Hz), 7,56-7,53 (1H, m), 7,41-7,37 (1H, m), 7,32-7,28 (1H, m), 7,17 for 7.12 (3H, m), 7,06-7,02 (1H, m), 6,80-6,77 (2H, m), 4,48 (1H, q, J=6.3 Hz), to 3.92 (3H, s), 3,66-3,63 (1H, m), 3,21-3,13 (2N, m), 2,72 of 2.68 (1H, m)of 2.64 (3H, s), 2,59-of 2.54 (3H, m), of 2.23 (3H, m)of 1.35 (3H, d, J=6.3 Hz), of 1.02 (3H, s), and 1.00 (3H, s).

Mass spectrum (ESI, m/z 508 (M+H)+.

Stage 9

2'-[(1R)-[(2R)-3-[[1-(3-Fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

Methyl-2'-[(1R)-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylate (3,37 g)obtained in stage 8, was dissolved in a mixture of methanol (25 ml) and tetrahydrofuran (25 ml) was added 2 n sodium hydroxide solution (13.5 ml). The mixture was stirred at 60°C for 3 hours and concentrated under reduced pressure. The obtained residue was diluted with water and the mixture was neutralized by adding 10%aqueous solution limnoecology. The obtained white precipitate was collected by filtration and dried, obtaining specified in the header of the connection (of 3.06 g).

1H-NMR (300 MHz, δ ppm, DMSO-d6) a 7.85 (1H, d, J=8,3 Hz), 7,56-7,53 (1H, m), 7,47-7,42 (1H, m), 7,37-to 7.32 (1H, m), 7,19-7,13 (4H, m), 6,97-6,89 (2H, m), 4,47 (1H, q, J=6.4 Hz), 3,70 (1H, s), 3,14 (2H, d, J=5.3 Hz), 2,85 is 2.80 (1H, m), 2,73 (2H, s), 2.63 in at 2.59 (1H, m), of 2.56 (3H, s), are 2.19 (3H, s)of 1.28 (3H, d, J=6.4 Hz), of 1.05 (3H, s), was 1.04 (3H, s).

Mass spectrum (ESI, m/z 494(M+H)+.

Example 1-2

2'-[(1R)-[(2R)-3-[[1-(4-Chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

Stage 1

1-Chloro-2-fluoro-4-(2-methylallyl)benzene

Magnesium (2,43 g) and iodine (10 mg) was added to tetrahydrofuran (40 ml) was added dropwise a solution of 4-bromo-1-chloro-2-fervently (21,0 g) in tetrahydrofuran (40 ml), the mixture was stirred at room temperature for 1 hour, obtaining a Grignard reagent. The reaction mixture was cooled with ice was added copper iodide (1.90 g). Was added 3-chloro-2-methyl-1-propene (14,8 ml) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled on ice, was added a saturated aqueous solution of ammonium chloride (10 ml). The mixture was stirred at room temperature for 20 minutes and was added magnesium sulfate (40 g). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. To the obtained residue, we use the and hexane (100 ml) and the insoluble substance was filtered. The resulting solution was concentrated under reduced pressure, obtaining specified in the header connection (16,9 g).

1H-NMR (300 MHz, δ ppm, CDCl3) 7,40-7,20 (1H, m), of 6.99 (1H, DD, J=9,9, 1.8 Hz), 6,91 (1H, d, J=8.1 Hz), 4,84 (1H, s), to 4.73 (1H, s), or 3.28 (2H, s)of 1.66 (3H, s).

Stage 2

2-Chloro-N-[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]ndimethylacetamide

In a manner analogous to that described for stage 6 of example 1-1, specified in the title compound (10.1 g) was obtained from 1-chloro-2-fluoro-4-(2-methylallyl)benzene (16,9 g)obtained in stage 1.

1H-NMR (400 MHz, δ ppm, CDCl3) 7,30 (1H, DD, J=7,9, 7.9 Hz), 6,92 (1H, DD, J=9,9, 1.8 Hz), 6,85 (1H, DD, J=8,1, 1.8 Hz), 6,14 (1H, users), of 3.96 (2H, s), 3,06 (2H, s)of 1.36 (6H, s).

Mass spectrum (ESI, m/z 278 (M+H)+.

Stage 3

1-(4-Chloro-3-forfinal)-2-methylpropan-2-ylamine

In a manner analogous to that described for stage 6 of example 1-1, specified in the header of the connection (of 6.90 g) was obtained from 2-chloro-N-[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]ndimethylacetamide (10.1 g), obtained in stage 2.

1H-NMR (400 MHz, δ ppm, CDCl3) 7,30 (1H, DD, J=7,9, 7.9 Hz), of 6.99 (1H, DD, J=10,2, 2.0 Hz), 6,91 (1H, DD, J=8,1, 1.9 Hz), 2,62 (2H, s)and 1.15 (6H, s).

Mass spectrum (ESI, m/z 202 (M+H)+.

Stage 4

Methyl-2'-[(1R)-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylate

FPIC is BOM, similar to that described for stage 8 of example 1-1, specified in the title compound (413 mg) was obtained from methyl 3-methyl-2'-[(1R)-((R)-oxiranylmethyl)ethyl]biphenyl-4-carboxylate (248 mg), obtained in stage 3 of example 1-1 and 1-(4-chloro-3-forfinal)-2-methylpropan-2-ylamine (170 mg)obtained in stage 3.

1H-NMR (300 MHz, δ ppm, DMSO-d6) of 7.96 (1H, d, J=8,4 Hz), 7,56-7,53 (1H, m), 7,45-7,39 (2H, m), 7,19-7,11 (3H, m), 6,98-to 6.88 (2H, m), 4,48 (1H, q, J=6.6 Hz), 3,98 (1H, m)to 3.92 (3H, s), 3,29-3,19 (2H, m), 3,05-of 3.00 (1H, m), with 2.93 (1H, m), and 2.83 (2H, s)of 2.64 (3H, s)of 1.34 (3H, d, J=6.6 Hz), to 1.21 (3H, s)to 1.19 (3H, s).

Mass spectrum (ESI, m/z 528 (M+H)+.

Stage 5

2'-[(1R)-[(2R)-3-[[1-(4-Chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid

In a manner analogous to that described for stage 9 of example 1-1, specified in the title compound (345 mg) was obtained from methyl 2'-[(1R)-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylate (413 mg)obtained in stage 4.

1H-NMR (400 MHz, δ ppm, DMSO-d6) to 7.84 (1H, d, J=8.6 Hz), 7,55-7,52 (1H, m), 7,47-7,41 (2H, m), of 7.36-to 7.32 (1H, m), 7,25-7,22 (1H, m), 7.18 in-to 7.15 (3H, m), 7,05-7,03 (1H, m), 4,47 (1H, q, J=6.5 Hz), 3,68 (1H, m), 3,13 (2H, d, J=5.5 Hz), 2,81-2,78 (1H, m), was 2.76 (2H, s), 2,60-to 2.57 (1H, m), of 2.56 (3H, s)of 1.28 (3H, d, J=6.2 Hz), of 1.05 (3H, s)of 1.03 (3H, s).

Mass spectrum (ESI, m/z 514 (M+H)+.

Examples 1-3 - 1-110

The compounds of examples 1-3 - 1-110 were obtained on the OS which implement examples 1-1 and 1-2. The results are presented in tables 1-44.

Table 1
ExampleThe structural formulaPropertiesAnalysis of reporter gene (µm)
1-11H-NMR (300 MHz, δ ppm, DMSO-d6) a 7.85 (1H, d, J=8,3 Hz), 7,56-7,53 (1H, m), 7,47-7,42 (1H, m), 7,37-to 7.32 (1H, m), 7,19-7,13 (4H, m), 6,97-6,89 (2H, m), 4,47 (1H, q, J=6.4 Hz), 3,70 (1H, s), 3,14 (2H, d, J=5.3 Hz), 2,85 is 2.80 (1H, m), 2,73 (2H, s), 2.63 in at 2.59 (1H, m), of 2.56 (3H, s), are 2.19 (3H, s)of 1.28 (3H, d, J=6.4 Hz), of 1.05 (3H, s), was 1.04 (3H, s).

MS (ESI, m/z 494 (M+H)+.
0,024
1-21H-NMR (400 MHz, δ ppm, DMSO-d6) to 7.84 (1H, d, J=8.6 Hz), 7,55-7,52 (1H, m), 7,47-7,41 (2H, m), of 7.36-to 7.32 (1H, m), 7,25-7,22 (1H, m), 7.18 in-to 7.15 (3H, m), 7,05-7,03 (1H, m), 4,47 (1H, q, J=6.5 Hz), 3,68 (1H, m), 3,13 (2H, d, J=5.5 Hz), 2,81-2,78 (1H, m), was 2.76 (2H, s), 2,60-to 2.57 (1H, m), of 2.56 (3H, s)of 1.28 (3H, d, J=6.2 Hz), of 1.05 (3H, s)of 1.03 (3H, s).

MS (ESI, m/z 514 (M+H)+.
0,013

Table 2
1-31H-NMR (400 MHz, δ ppm, DMSO-d6) of 7.82 (1H, d, J=8,4 Hz), 7,54 (1H, d, J=7.9 Hz), the 7.43 (1H, DD, J=7,4, 7,4 Hz), 7,33 (1H, DD, J=7,2, 7,2 Hz), 7,25-7,10 (5H, m),? 7.04 baby mortality (1H, d, J=7,7 Hz), 4,48 (1H, q, J=6.5 Hz), of 3.77-3,66 (1H, m), 3,14 (2H, the, J=5.8 Hz), 2,90-to 2.40 (7H, m), and 2.27 (3H, s)of 1.27 (3H, d, J=6.2 Hz), of 1.05 (3H, s), was 1.04 (3H, s).

MS (ESI, m/z 510 (M+H)+.
0,010
1-41H-NMR (400 MHz, δ ppm, DMSO-d6) 7,83 (1H, d, J=8,4 Hz), 7,54 (1H, d, J=7.9 Hz), 7,44 (1H, DD, J=7,5, 7.5 Hz), 7,34 (1H, DD, J=7,5, 7.5 Hz), 7,28 (1H, d, J=8,2 Hz), 7,20-7,10 (4H, m), 7,01 (1H, d, J=8.1 Hz), 4,48 (1H, q, J=6.3 Hz), 3,80-the 3.65 (1H, m), 3,14 (2H, d, J=5.6 Hz), 2,90-to 2.40 (7H, m), of 2.28 (3H, s)of 1.27 (3H, d, J=6.2 Hz), was 1.04 (3H, s)of 1.03 (3H, s).

MS (ESI, m/z 510 (M+H)+.
0,014
1-51H-NMR (400 MHz, δ ppm, DMSO-d6) a 7.85 (1H, d, J=8,4 Hz), 7,54 (1H, d, J=7.9 Hz), 7,44 (1H, DD, J=7,4, 7,4 Hz), 7,34 (1H, DD, of 7.4, 7.4 Hz), 7,20 for 7.12 (3H, m), 7,01-of 6.90 (2H, m), 4,47 (1H, q, J=6.5 Hz), 3.75 to of 3.60 (1H, m), 3,13 (2H, d, J=5.8 Hz), 2,90-2,70 (3H, m), 2,65-to 2.40 (4H, m), 2,24 (3H, s)of 1.27 (3H, d, J=6.3 Hz), of 1.03 (3H, s)of 1.02 (3H, s).

MS (ESI, m/z 512 (M+H)+.
0,003

Table 3
1-61H-NMR (400 MHz, δ ppm, DMSO-d6) to 7.84 (1H, d, J=8,4 Hz), 7,54 (1H, DD, J=7,9, 1.2 Hz), 7,44 (1H, DDD, J=7,4, to 7.4, 1.2 Hz), 7,38-of 7.25 (3H, m), 7,20-7,13 (4H, m), 4,47 (1H, q, J=6.2 Hz), 3.75 to of 3.60 (1H, m), of 3.12 (2H, d, J=5.8 Hz), 2,85-to 2.65 (3H, m)2,60-to 2.40 (4H, m)of 1.27 (3H, d, J=6.2 Hz), of 1.02 (3H, s), 1.00 and{3H, 3).

MS (ESI, m/z 514 (M+H)+.
0,020
1-7 1H-NMR (400 MHz, δ ppm, DMSO-d6) to 7.84 (1H, d, J=8,3 Hz), 7,54 (1H, DD, J=7,9, 1.2 Hz), 7,44 (1H, DDD, J=7,5, to 7.5, 1.2 Hz), 7,34 (1H, DDD, J=7,4, to 7.4, 1.2 Hz), 7,20-7,07 (4H, m), of 6.96 (1H, d, J=10,9 Hz)6,91 (1H, d, 7.9 Hz), 4,48 (1H, q, J=6.3 Hz), 3,80-of 3.60 (1H, m), 3,14 (2H, d, J=5.5 Hz), 2.95 and-2,70 (3H, m), 2,65-to 2.40 (4H, m), and 2.27 (3H, s)of 1.27 (3H, d, J=6.3 Hz), was 1.04 (6H, c)

MS (ESI, m/z 494 (M+H)+.
0,15

Table 4
1-81H-NMR (400 MHz, δ ppm, DMSO-d6) 7,83 (1H, d, J=8,3 Hz), 7,53 (1H, DD, J=7,8, 1.2 Hz), the 7.43 (1H, DDD, J=7,7, and 7.7, 1.2 Hz), 7,33 (1H, DDD, J=7,6, to 7.6, 1.2 Hz), 7,20 for 7.12 (4H, m), 6,98-6,87 (2H, m), 4,48 {1H, q, J=6.3 Hz), 3.75 to of 3.60 (1H, m), 3,14 (2H, d, J=5.5 Hz), 2,85-to 2.65 (3H, m), 2,60 at 2.45 (6H, m)of 1.27 (3H, d, J=6.3 Hz), 1,14 {2H, t, J=7.5 Hz), of 1.03 (3H, s)of 1.02 (3H, s).

MS (ESI, m/z 508 (M+H)+.
0,015
1-91H-NMR (400 MHz, δ ppm, DMSO-d6) 7,87-7,18 (14H, m), of 4.45 (1H, q, J=6.3 Hz), 3,80-the 3.65 (1H, m), 3,18 (2H, d, J=5,1 Hz), 2.95 and is 2.80 (3H, m), 2,70-2,60 (1H, m), is 2.40 (3H, s)of 1.26 (3H, d, J=6.3 Hz), a 1.08 (3H, s)of 1.07 (3H, s).

MS (ESI, m/z 512 (M+H)+.
0,016
1-101H-NMR (300 MHz, δ ppm, CDCl3) 8,69 (1H, s), 8,16 (1H, d, J=1.6 Hz), 7,78-7,17 (11H, m), 4,43 (1H, q, J=6.4 Hz), of 3.95 (6H, s), 3,80-3,70 (1H, m), 3,30-3,15 (2H, m), 2,90 is 2.75 (3H, m), 2,75-to 2.65 (1H, m)of 1.33 (3H, d, J=6.4 Hz), 1,12 3H, C)of 1.10 (3H, s).

MS (ESI, m/z 570 (M+H)+.
0,029

Table 5
1-111H-NMR (300 MHz, δ ppm, DMSO-d6) 7,88-7,16 (14H, m)to 3.89 (1H, d, J=7,4 Hz), a 3.87 of 3.75 (1H, m), 3,40 is 3.15 (2H, m), 3.00 and-2,85 {3H, m), 2,80-to 2.65 (1H, m), 2,43 (3H, s), 1,20-0,95 (7H, m), 0.50 to 0,35 (1H, m), between 0.30 to 0.20 (2H, m), be-0.05 to 0.15 (1H, m).

MS (ESI, m/z 538 (M+H)+.
0,018
1-121H-NMR (300 MHz, δ ppm, DMSO-d6) a 12.7 (1H, users), to 9.15 (1H, users), to 8.70 (1H, users), 8,00-7,15 (14H, m), 5,59 (1H, users), of 4.49 (1H, q,J=6.4 Hz), 4,00-are 3.90 (1H, m), 3,40 was 3.05 (5H, m), 2,90 is 2.75 (1H, m)2,60 (3H, s)of 1.30 (3H, d, J=6.3 Hz), 1,25 (6H, C).

MS (ESI, m/z 538 (M+H-HCl)+.
0,013
1-131H-NMR (300 MHz, δ ppm, DMSO-d6) of 7.90-of 7.70 (3H, m), the 7.65 (1H, s), 7,60-of 7.25 (7H, m), 7,15 for 7.12 (1H, m), of 6.96-6,93 (2H, m), to 4.62 (1H, users), 4,51 (1H, q,J=6.4 Hz), 3,55 (1H, users), 3,35-3,30 (1H, m), of 3.12 (2H, d, J=5.7 Hz), 2,80-2,60 (3H, m), 2,48 (3H, s)of 1.24 (3H, d, J=6,4 Hz)to 0.97 (3H, s)of 0.95 (3H, s).

MS (ESI, m/z 512 (M+2H-Na)+.
0,015

Table 6
1-141H-NMR (300 MHz, δ ppm, DMSO-d6the 7.85 (1H, d, J=7.8 Hz), 7,60 (1H, d, J=6.6 Hz), 7,50-7,30 (2H, m), 7,20-7,10 (4H, m), 7,00-of 6.90 (2H, m), 3,86 (1H, d, J=7.5 Hz), 3,80-3,70 (1H, m), 3,35 is 3.15 (2H, m), 2.95 and-2,90 (1H, m), 2,77 (2H, s), was 2.76-2,60 (1H, m,), of 2.56 (3H, s), are 2.19 (3H, s), 1,15-1,00 (7H, m), from 0.50 to 0.40 (1H, m), 0,35-,020 (2H, m) , -0,15 - -0,20 (1H, m).

MS (ESI, m/z 520 (M+H)+.
0,006
1-151H-NMR (400 MHz, δ ppm, DMSO-d6) 7,55 was 7.45 (2H, m), 7,40-of 7.25 (2H, m), 7,15-7,05 (2H, m), 6,95-to 6.80 (4H, m), of 4.49 (1H, q,J=6.4 Hz), 3,55-3,50 (1H, m)to 3.09 (2H, s), 2,60 to 2.35 (6H, m)to 2.18 (3H, s)of 1.24 (3H, d, J=6,4 Hz)to 0.89 (3H, s), 0,86 (3H, s).

MS (ESI, m/z 494 (M+2H-Na)+.
0,012
1-161H-NMR (400 MHz, δ ppm, DMSO-d6) a 12.7 (1H, users), to 8.94 (1H, users), 8,49 (1H, users), of 7.90 (1H, d, J=8.0 Hz), 7,60-to 7.15 (7H, m), 7,00-6,90 {2H, m), of 5.55 (1H, d, J=4.0 Hz), 4,46 (1H, q,J=6.3 Hz), 3.95 to of 3.85 (1H, m), 3,20-to 2.65 (6H, m), 2,59 (3H, s), of 2.21 (3H, s)is 1.31 (3H, d, J=6.3 Hz), of 1.18 (6H, s).

MS (ESI, m/z 494 (M+H-HCl)+.
0,011

Table 7
1-171H-NMR (400 MHz, δ ppm, DMSO-d6) 7,76 (1H, s), to 7.64 (1H, s), 7,60-7,10 (6H, m), 7,00-6,85 (2H, m), 4,43 (1H, q, J=6.4 Hz), 3,80-the 3.65 (1H, m)and 3.15 (2H, d, J=5,1 Hz), 3,80-3,55 (4H, m), is 2.40 (3H, s)to 2.18 (3H, s)of 1.26 (3H, d, J=6,4 Hz), of 1.05 (6H, s).

MS (ESI, m/z 494 (M+H)+.
0,015
1-18 1H-NMR (300 MHz, δ ppm, DMSO-d6) 7,86 (1H, d, J=8,4 Hz), 7,65-7,10 (9H, m), 3,85 (1H, d, J=7.8 Hz), 3.75 to the 3.65 (1H, m), 3,35-3,10 (2H, m), 2,90-of 2.50 (7H, m), 1,15-0,95 (7H, m), from 0.50 to 0.40 (1H, m), between 0.30 to 0.20 (2H, m), -0,05--0,20 (1H, m).

MS (ESI, m/z 540 (M+H)+.
0,016
1-191H-NMR (400 MHz, δ ppm, DMSO-d6) to 7.84 (1H, d, J=8,4 Hz), to 7.59 (1H, d, J=7.9 Hz), 7,50-to 7.15 (7H, m), 7,10-7,00 (1H, m), 3,85 (1H, d, J=7,4 Hz), 3.75 to the 3.65 (1H, m), 3,30-3,15 (2H, m), 2,90 is 2.75 (3H, m), 2,70-2,60 (1H, m), of 2.56 (3H, s), 1,15-1,10 (7H, m), 0.50 to 0,40{1H, m), between 0.30 to 0.20 (2H, m), -0,15--0,15 (1H, m).

MS (ESI, m/z 540 (M+H)+.
0,005

Table 8
1-201H-NMR (300 MHz, δ ppm, DMSO-d6) 7,86 (1H, d, J=8,4 Hz), EUR 7.57-rate of 7.54 (1H, m), 7,47-7,42 (1H, m), 7,37-to 7.32 (1H, m), 7,19-7,13 (4H, m), 6,79 of 6.68 (2H, m), 4,48 (1H, q, J=6.2 Hz), 3,74 (3H, s), 3,70 (1H, m), 3,14 (2H, d, J=5.5 Hz), 2,84-2,81 (1H, m), 2,71 (2H, s), 2,62 at 2.59 (1H, m), of 2.56 (3H, s)of 1.28 (3H, d, J=6.2 Hz), of 1.03 (6H, m).

MS (ESI, m/z 510 (M+H)+.
0,040
1-211H-NMR (400 MHz, δ ppm, DMSO-d6) 7,82-7,79 (1H, m), 7,54-7,52 (1H, m), 7,45-7,41 (1H, m), 7,35-7,31 (1H, m), 7,17 for 7.12 (3H, m), 7,02-7,00 (1H, m), 6,93 (1H, s), 6,88-6,86 (1H, m), of 4.49 (1H, q, J=6.5 Hz), of 3.77 (1H, m)and 3.15 (2H, d, J=5.8 Hz), 2,92-2,89 (1H, m), 2,73 (2H, s), 2,66-2,64 {1H, m), of 2.54 (3H, s)of 2.16 (6H, s)of 1.26 (3H, d, J=6.2 Hz), of 1.06 (6H, s)

MS (ESI, m/z 490 (M+H)+.
0,013
1-221H-NMR (400 MHz, δ ppm, DMSO-d6) 7,83 (1H, d, J=8,3 Hz), 7,55-7,53 (1H, m), 7,46-7,42 (1H, m), of 7.36-to 7.32 (1H, m)

7,19-to 7.15 (3H, m), 7,09? 7.04 baby mortality (4H, m), 4,49{1H, q, J=6.5 Hz), 3,76 (1H, m), 3,16-3,14 (2H, m), 2.91 in-2,88 (1H, m), was 2.76 (2H, s), 2,66-of 2.64 (1H, m), of 2.56 (3H, s), and 2.26 (3H, s)of 1.27 (3H, d, J=6.5 Hz), of 1.06 (6H with).

MS (ESI, m/z 476 (M+H)+.
0,012

Table 9
1-231H-NMR (400 MHz, δ ppm, DMSO-d6) 7,83 (1H, d, J=8.6 Hz), 7,54-7,52 (1H, m), 7,46-7,42 (1H, m), of 7.36-7.29 trend (2H, m), 7,19-7,14 (3H, m), to 6.95 (1H, m), 6,78 to 6.75 (1H, m), 4,48 (1H, q, J=6.2 Hz), 3,81 (3H, s), of 3.77 of 3.75 (1H, m), 3,14 (2H, d, J=5.8 Hz), 2,89-2,87 (1H, m), 2,80 (2H, s), 2,66-2,61 (1H, m), of 2.56 (3H, s)of 1.28 (3H, d, J=6.2 Hz), 1,11 (3H, m)of 1.09 (3H, m).

MS (ESI, m/z 526 (M+H)+.
0,016
1-241H-NMR (300 MHz, δ ppm, DMSO-d6) a 7.85 (1H, d, J=8.1 Hz), 7,56-rate of 7.54 (1H, m), of 7.48-the 7.43 (1H, m), 7,38-7,33 (1H, m), 7,20-7,16 (3H, m), 7,13-7,07 (4H, m), of 4.49 (1H, q, J=6.2 Hz), 3.75 to 3,74 (1H, m)and 3.15 (2H, d, J=5.5 Hz), 2,90-of 2.86 (1H, m), of 2.75 (2H, s), 2,67 is 2.55 (6H, m)of 1.27 (3H, d, J=6.2 Hz), of 1.16 (3H, t, J=7,6 Hz)of 1.05 (6H, s).

MS (ESI, m/z 490 (M+H)+.
0,020
1-251H-NMR (400 MHz, δ ppm, d 6) to 7.84 (1H, d, J=8,3 Hz), 7,56-7,52 (2H, m), 7,45-7,41 (1H, m), 7,38-7,31 (2H, m), 7.18 in-to 7.15 (3H, m), 4,46 (1H, q,J=6.5 Hz), 3,66 (1H, m), of 3.12 (2H, d, J=5.5 Hz), 2,78-a 2.71 (3H, m), 2,78-a 2.71 (3H, m), 2,56 (4H, m)of 1.28 (3H, d, J=6.5 Hz), was 1.04 (3H, s)of 1.03 (3H, s).

MS (ESI, m/z 532 (M+H)+.
0,019

Table 10
1-261H-NMR (300 MHz, δ ppm, DMSO-d6) 7,89-7,81 (3H, m), 7,71 (1H, s), 7,66 (1H, d, J=7.5 Hz), EUR 7.57-to 7.35 (6H, m), 7.23 percent (1H, d, J=7.5 Hz), to 6.95 (1H, s), make 6.90 (1H, d, J=7.9 Hz), to 4.52 (1H, q, J=6.4 Hz), 3,81 of 3.75 (4H, m), 3,18 (2H, d, J=4,9 Hz), 2,96-only 2.91 (3H, m), 2,72-to 2.65 (1H, m)of 1.30 (3H, d, J=6.4 Hz), 1,11 (3H, s).

MS (ESI, m/z 528 (M+H)+.
0,014
1-271H-NMR (300 MHz, δ ppm, DMSO-d6) 7,93-7,88 (3H, m), 7,76 (1H, d, J=7,0 Hz), to 7.67-7,20 (9H, m), 7,13-was 7.08 (1H, m), 4,23-4,16 and 3,93-3,91 (1H, m), 3,81 is 3.76 (4H, m), 3.25 to of 2.58 (6H, m), 1.31 and a 1.11 (3H, d, J=6.2 Hz), of 1.26 (3H, s)to 1.22 (3H, s).

MS (ESI, m/z 528 (M+H)+.
0,014
1-281H-NMR (300 MHz, δ ppm, DMSO-d6) of 7.90-to 7.84 (3H, m), 7,74-to 7.68 (2H, m), 7,63-EUR 7.57 (2H, m), 7,53-7,47 (4H, m), 7,41 and 7.36 (2H, m), 7,25-7,22 (1H, m), 4,556-4,47 (1H, m), 3,93-to 3.92 (1H, m), 3,26-of 3.07 (4H, m), 2,94 is 2.80 (2H, m), 1,31-1,22 (9H, m).< / br>
MS (ESI, m/z 566 (M+H)+.
0,007

Tables is 11
1-291H-NMR (300 MHz, δ ppm, DMSO-d6) 7,71 (1H, d, J=8.0 Hz), 7,60-EUR 7.57 (2H, m), 7,52-7,47 (2H, m), 7,25-to 7.18 (2H, m), 6,82-6,74 (2H, m), 4,51 (1H, q,J=6.6 Hz), 3,88-3,86 (1H, m in), 3.75 (3H, s), 3,22-by 2.73 (6H, m)of 1.29 (3H, d, J=6.6 Hz), 1,14{6H, s).

MS (ESI, m/z 564 (M+H)+.
0,082
1-301H-NMR (300 MHz, δ ppm, DMSO-d6) 7,87-7,80 (4H, m), 7,71 (1H, s), EUR 7.57-7,42 (4H, m), 7,38-7,33 (2H, m), 7,21-7,17 (3H, m), 4,48 (1H, q, J=6.3 Hz), of 3.77 is 3.76 (1H, m), 3,17-2.91 in (8H, m), 2,72 of 2.68 (1H, m)of 1.28 (3H, d, J=6.3 Hz), of 1.18 (3H, t, J=7,4 Hz)of 1.12 (3H, s), is 1.11 (3H, s).

MS (ESI, m/z 526 (M+H)+.
0,007
1-311H-NMR (300 MHz, δ ppm, DMSO-d6) of 7.70 (1H, d, J=7,7 Hz), to 7.59-7,46 (6H, m), 7,39 (1H, DDD, J=7,3, to 7.3, 1.4 Hz), 7.24 to 7,19 (2H, m), 4,51 (1H, q, J=6.3 Hz), 3,85-a-3.84 (1H, m), 3,21 of 2.92 (5H, m), 2,74-2,70 (1H, m)of 1.28 (3H, d, J=6.3 Hz), 1,15 (6H, s).

MS (ESI, m/z 584 (M+H)+.
0,005

Table 12
1-321H-NMR (300 MHz, δ ppm, DMSO-d6) 7,87-to 7.77 (3H, m), 7,68 (1H, s), a 7.62 (1H, d, J=8.1 Hz), 7,54 (1H, m), 7,50-7,31 (5H, m), 7,20-to 7.18 (2H, m), 7,10 (1H, DD, J=7,7, 1.5 Hz), 4,47 (1H, q, J=6.2 Hz), a-3.84 (1H, Sept., J=7,0 Hz), 3.72 points-3,71 (1H, m), 3,20-3,10 (2H, m), 2,90 (2H, s), 2,85 is 2.80 (1H, m), 2,63-to 2.57 (1H, m)of 1.26 (3H, d, J=6.2 Hz), 1,1 (6H, d, J=7,0 Hz)of 1.07 (3H, s)of 1.05 (3H, s).

MS (ESI, m/z 540 (M+H)+.
0,002
1-331H-NMR (300 MHz, δ ppm, DMSO-d6) 7,76 (1H, d, J=8.5 Hz), 7,54 (1H, DD, J=7,7, 1.1 Hz), 7,44 (1H, DDD, J=7,7, and 7.7, 1.1 Hz), 7,34 (1H, m), 7,20-7,13 (4H, m), of 6.96-to 6.88 (2H, m), 4,48 (1H, q, J=6.6 Hz), 3,70 at 3.69 (1H, m), 3,15-3,13 (2H, m), 2,97 (2H, q, J=7,3 Hz), 2,81-a 2.71 (3H, m), 2,59-2,47 (1H, m)to 2.18 (3H, s)of 1.27 (3H, d, J=6.6 Hz), of 1.17 (3H, t, J=7,3 Hz)of 1.02 (3H, s)a 1.01 (3H, s).

MS (ESI, m/z 508 (M+H)+.
0,0050

Table 13
1-341H-NMR (300 MHz, δ ppm, DMSO-d6) to 7.64 (3H, d, J=8.1 Hz), 7,54 (1H, DD, J=8,1, 1.1 Hz), 7,44 (1H, DDD, J=7,3, to 7.3, 1.1 Hz), 7,34 (1H, DDD, J=7,3, to 7.3, 1.1 Hz), 7,20-7,10 (4H, m), of 6.96-to 6.88 (2H, m), of 4.45 (1H, q,J=6.3 Hz), 3,82 (1H, Sept, J=6.6 Hz), 3,69-3,68 (1H, m), 3,17-of 3.07 (2H, m), 2,80-2,70 (3H, m), 2,58 is 2.51 (1H, m)to 2.18 (3H, s)of 1.27 (3H, d, J=6.3 Hz), of 1.20 (6H, d, J=6.6 Hz), of 1.02 (3H, s), and 1.00 (3H, s).

MS (ESI, m/z 522 (M+H)+.
0,005
1-351H-NMR (300 MHz, δ ppm, DMSO-d6) of 7.90-7,83 (4H, m), 7,74 (1H, s), 7,60 and 7.36 (8H, m), 4,79 (1H, q, J=6,1 Hz), 3,78 is 3.76 (1H, m), 3,28-to 3.02 (6H, m), 2,82 is 2.75 (1H, m)of 1.39 (3H, d, J=6,1 Hz)of 1.20 (6H, s).

MS (ESI, m/z 533 (M+H)+.
0,010
1-361H-YAM who (300 MHz, δ ppm, DMSO-d6) a 7.85-7,71 (4H, m),7,66 (1H, s), 7,53-7,38 (4H, m), 7,34-7,30 (2H, m), 7,17-7,05 (3H, m), of 4.49 (1H, q, J=6.3 Hz), 3,71-3,70 (1H, m), 3,17-3,10 (2H, m), 2,94-and 2.79 (5H, m), 2,61-of 2.56 (1H, m), 1,58 (2H, t kV, J=7,2, 7,2 Hz), 1,24 (3H, d, J=6.3 Hz), of 1.06 (3H, s), was 1.04 (3H, s)of 0.85 (3H, t, J=7.2 Hz).

MS (ESI, m/z 540 (M+H)+.
0,002

Table 14
1-371H-NMR (300 MHz, δ ppm, DMSO-d6) 7,88-7,79 (3H, m), 7,71 (1H, s), 7,55-7,31 (7H, m), 7,06-to 6.88 (2H, m), or 4.31-4.25 in and 4.13-4,07 (1H, m), of 3.77 is 3.76 (1H, m), 3,25-3,14 (2H, m), 2,96-is 2.88 (3H, m), 2.71 to of 2.64 (1H, m), 2,43 (3H, s), 2.00 and at 1.91 (3H, s), 1,17-of 1.09 (9H, m).

MS (ESI, m/z 526 (M+H)+.
0,003
1-381H-NMR (300 MHz, δ ppm, DMSO-d6) for 7.78 (1H, d, J=7.9 Hz), 7,53 (1H, DD, J=7,9, 1.2 Hz), the 7.43 (1H, DDD, J=7,6, to 7.6 and 1.4 Hz), 7,33 (1H, DDD, J=7,6, to 7.6 and 1.4 Hz), 7.18 in-7,11 (4H, m), 6,95-6,92 (1H, m), 6.89 in (1H, DD, J=7,8, 1.2 Hz), of 4.45 (1H, q, J=6,3 Hz), 3,71-3,70 (1H, m), 3,11-3,10 (2H, m), 2,99-2,82 (3H, m), is 2.74 (2H, s), 2,62-to 2.57 (1H, m), 2,17 (3H, s)of 1.57 (2H, t kV, J=7,4, 7,4 Hz)of 1.26 (3H, d, J=6.3 Hz), was 1.04 (3H, s)of 1.03 (3H, s)0,86 (3H, t, J=7,4 Hz).

MS (ESI, m/z 522 (M+H)+.
0,002
1-391H-NMR (300 MHz, δ ppm, DMSO-d6) to 7.95 (1H, d, J=7,6 Hz), 7,58-7,47 (3H, m), 7,38 and 7.36 (2H, m), 7,20 (1H, DD, J=7,6, 7,6 Hz), 6,99-6,91 (2H, m), was 4.76 (1H, q, J=6.3 Hz), 3,78 is 3.76 (1H, m), 3,23-of 3.12 (2H, m), 2,96-2,87 (H, m), 2,79-by 2.73 (1H, m)to 2.18 (3H, s)of 1.39 (3H, d, J=6.3 Hz)and 1.15 (6H, s).

MS (ESI, m/z 515 (M+H)+.
0,012

Table 15
1-401H-NMR (300 MHz, δ ppm, DMSO-d6) of 7.90-of 7.82 (3H, m), 7,72 (1H, s), 7,54-7,30 (6H, m), to 7.15 (1H, DD, J=7,7, 1.5 Hz), 6,93 (2H, s), a 4.53 (1H, q, J=6.3 Hz), 3,81-of 3.80 (1H, m), 3,21-and 3.16 (2H, m), 3,02 are 2.98 (3H, m), 2.77-to 2,70 (1H, m), is 2.30 (6H, ), of 1.29 (3H, d, J=6.3 Hz), of 1.16 (6H, s).

MS (ESI, m/z 526 (M+H)+.
0,003
1-411H-NMR (300 MHz, δ ppm, DMSO-d6) a 7.85-7,76 (3H, m), to 7.61-to 7.59 (2H, m), 7,53 (1H, DD, J=7,6, 1.0 Hz), 7,47-7,39 (5H, m), 7,34-7,19 (7H, m), 7,13 (1H, d, J=1.6 Hz), 4,60 (1H, q, J=6.3 Hz), 3,74-to 3.73 (1H, m), 3,17-3,15 (2H, m), 2,83 is 2.80 (3H, m), 2,60-of 2.56 (1H, m)of 1.27 (3H, d, J=6.3 Hz), of 0.97 (6H, s).

MS (ESI, m/z 574 (M+H)+.
0,003
1-421H-NMR (300 MHz, δ ppm, DMSO-d6) 7,53-7,39 (3H, m), 7,33-7,29 (1H, m), 7,15-7,11 (1H, m), 7.03 is-6,99 (1H, m), 6,95-6,86 (3H, m), 4.26 deaths-4,22 and 4,08-a 4.03 (1H, m), 3,71-3,70 (1H, m), 3,20-3,10 (2H, m), 2,83 is 2.80 (1H, m), 2,73-a 2.71 (2H, m), 2,61-of 2.56 (1H, m), 2.41 and is 2.40 (3H, s)of 2.16 (3H, s) and 1,89 1,97 (3H, s), 1,15-of 1.12 (3H, m), 1.04 million-a 1.01 (6H, m).

MS (ESI, m/z 508 (M+H)+.
0,024

Table 16
1-43 1H-NMR (300 MHz, δ ppm, DMSO-d6) 7,51 (1H, DD, J=7,6, 1.2 Hz), 7,40 (1H, DDD, J=7,6, to 7.6, 1.2 Hz), 7,31 (1H, DDD, J=7,6, to 7.6 and 1.4 Hz), 7,20-7,16 (1H, m), 7,13 (1H, DD, J=7,6, and 1.4 Hz), 6,98-6,89 (4H, m), 4,50 (1H, q, J=6.3 Hz), 3,78-of 3.77 (1H, m), 3,18-3,10 (1H, m), 2,97-to 2.94 (1H, m), 2,82 (2H, s), 2.71 to to 2.66 (1H, m), and 2.27 (6H, s)to 2.18 (3H, s)of 1.28 (3H, d, J=6.3 Hz), 1,10 (3H, s)of 1.09 (3H, s).

MS (ESI, m/z 508 (M+H)+.
0,016
1-441H-NMR (300 MHz, δ ppm, DMSO-d6) 7,86-to 7.77 (3H, m), of 7.70 (1H, s), 7,53-7,29 (8H, m), 7,26 (1H, DD, J=7,9, 1.8 Hz), 7,18 (1H, DD, J=7,6, and 1.4 Hz), and 4.68 (1H, d, J=13,8 Hz), with 4.64 (1H, d, J=13,8 Hz), 4,47 (1H, q, J=6.2 Hz), 3,88-a 3.87 (1H, m), 3,22-is 3.21 (2H, m), 3,05 (2H, s), 3.00 and-2,96 (1H, m), 2,80-of 2.75 (1H, m)of 1.26 (3H, d, J=6.2 Hz), of 1.16 (6H, s).

MS (ESI, m/z 528 (M+H)+.
0,009
1-451H-NMR (300 MHz, δ ppm, DMSO-d6) 7,88-7,76 (3H, m), 7,68 (1H, s), 7,56-7,31 (7H, m), 7,19-7,13 (2H, m),? 7.04 baby mortality-7,03 (1H, m), 4,50 (1H, q, J=6.6 Hz), 3,71-3,70 (1H, m), 3,18-to 3.09 (2H, m), 2,93-2,78 (5H, m), 2,62-of 2.58 (1H, m), 1,91-of 1.84 (1H, m), of 1.26 (3H, d, J=6.6 Hz), with 1.07 (3H, s)of 1.05 (3H, 3), of 0.85 (3H, d, J=2.6 Hz), or 0.83 (3H, d, J=2,6 Hz).

MS (ESI, m/z 554 (M+H)+.
0,002

Table 17
1-461H-NMR (300 MHz, δ ppm, DMSO-d6) 7,76 (1H, d, J=7,7 Hz), 7,54 (1H, DD, J=7,7, 1.1 Hz), the 7.43 (1H, DDD, J=7,7, and 7.7, 1.1 Hz), 7,34 (H, DDD, J=7,7, and 7.7, 1.1 Hz), 7.18 in? 7.04 baby mortality (4H, m), 6,95-6,87 (2H, m), 4,48 (1H, q, J=6.2 Hz), 3,65-of 3.64 (1H, m), 3,12-to 3.09 (2H, m), 2,93-2,78 (2H, m), 2,70-of 2.66 (3H, m), 2,54-2,47 (1H, m)to 2.18 (3H, s), a 1.88 (1H, Sept., J=6,6 Hz)of 1.26 (3H, d, J=6.2 Hz), 0,99 (3H, s), and 0.98 (3H, s)of 0.85 (3H, d, J=6.6 Hz), is 0.84 (3H, d, J=6.6 Hz),

MS (ESI, m/z 536 (M+H)+.
0,003
1-471H-NMR (300 MHz, δ ppm, DMSO-d6)

for 7.78 (1H, d, J=1,8 Hz), 7,55 (1H, DD, J=7,7, 1.2 Hz), to 7.50 (1H, d, J=8.0 Hz), the 7.43 (1H, DDD, J=7,3, to 7.3, 1.5 Hz), 7,35 (1H, DDD, J=7,3, to 7.3, 1.5 Hz), 7,30 (1H, DD, J=7,7, 1.2 Hz), 7,22-7,17 (2H, m), 7,01-6,92 (2H, m,), 4,72 (1H, q, J=13.5 Hz), of 4.66 (1H, d, J=13.5 Hz), 4,48 (1H, q, J=6.3 Hz), 3,85-a-3.84 (1H, m), 3,23-is 3.21 (2H, m), 2,96-only 2.91 (1H, m), of 2.86 (2H, s), was 2.76-2,70 (1H, m), of 2.20 (3H, s)of 1.29 (3H, d, J=6.3 Hz), of 1.12 (6H, s),

MS (ESI, m/z 536 (M+H)+.
0,065

Table 18
1-481H-NMR (300 MHz, δ ppm, DMSO-d6) to 7.77 (1H, d, J=7.9 Hz), 7,51 (1H, DD, J=7,7, 1.1 Hz), 7,41 (1H, DDD, J=7,4, of 7.4 and 1.4 Hz), 7,31 (1H, DDD, J=7,4, to 7.4, 1.1 Hz), 7,15-7,10 (3H, m), 7,00 (1H, d, J=1.6 Hz), 6,93-of 6.90 (1H, m)6,86 (1H, DD, J=7,7, 1,4 Hz), 6,72 (1H, 3), 4,51 (1H, q, J=6.5 Hz), 3,69-3,68 (1H, m), 3,10-is 3.08 (2H, m), 2,80 was 2.76 (1H, m), 2,70 (2H, s), 2,56 is 2.51 (1H, m)of 2.16 (3H, s)of 1.78 (3H, s)to 1.67 (3H, s), 1,25 (3H, d, J=6.5 Hz), 1,02 (3H, s), and 1.00 (3H, s).

MS (ESI, m/z 534 (M+H)+.
0,002
1-491H-NMR (300 MHz, ; ppm, DMSO-d6) 7,87-7,81 (3H, m), 7,70-to 7.68 (2H, m), 7,49-the 7.43 (3H, m), 7,37 (1H, DDD, J=7,4, of 7.4 and 1.4 Hz), 7,33 (1H, DD, J=8,5, 1.8 Hz), 7,28 (1H, DDD, J=7,4, of 7.4 and 1.4 Hz), 7,14 (1H, DD, J=7,6, and 1.4 Hz), 6,50-6,47 (2H, m), of 4.54 (1H, kV, J=6.3 Hz), 3,81-of 3.80 (1H, m), 3,17-3,03 (5H, m), 2,80-of 2.75 (1H, m)of 1.27 (3H, d, J=6.3 Hz), 1,17 (6H, s).

MS (ESI, m/z 514 (M+H)+.
0,002

Table 19
1-501H-NMR (300 MHz, δ ppm, DMSO-d6) to 7.67 (3H, d, J=7,7 Hz), to 7.84 (1H, DD, J=7,9, 1.2 Hz), 7,37 (1H, DDD, J=7,4 7,4, 1.2 Hz), 7,28 (1H, DDD, J=7,4, to 7.4, 1.2 Hz), 7,17 (1H, DD, J=7,9, 7.9 Hz), 7,13 (1H, DD, J=7,4, 1.2 Hz), 6,97-6,89 (2H, m), 6.48 in-6,45 (2H,, m), a 4.53 (1H, q, J=6.3 Hz), of 3.77 is 3.76 (1H, m), 3,14-of 3.07 (2H, m), 2,98-2,70 (4H, m), 2,17 (3H, s)of 1.27 (3H, d, J=6.3 Hz), 1,10 (6H, s).

MS (ESI, m/z 496 (M+H)+.
0,002
1-511H-NMR (300 MHz, δ ppm, DMSO-d6) 7,76 (1H, d, J=8,4 Hz), 7,55-7,52 (1H, m), 7,45-7,40 (2H, m), 7,34 (1H, DDD, J=7,3, to 7.3, 1.5 Hz), 7.24 to for 7.12 (4H, m), 7,03 (1H, DD, J=8,1, 1.5 Hz), 4,46 (1H, q, J=6.3 Hz), 3,66-3,59 (1H, m), 3,12-3,11 (2H, m), 2,96 (2H, q, J=7,3 Hz), 2,72-to 2.67 (3H, m), 2,53-2,47 (1H, m)of 1.26 (3H, d, J=6.3 Hz), of 1.17 (3H, t, J=7,3 Hz), 0,99 (3H, s)to 0.97 (3H, s).

MS (ESI, m/z 528 (M+H)+.
0,004

Table 20
1-521H-NMR (300 MHz δ ppm, DMSO-d6) 7,56 (1H, d, J=7.9 Hz), 7,49 (1H, DD, J=7,9, and 1.4 Hz), 7,41 and 7.36 (2H, m), 7,30 (1H, DDD, J=7,4 7,4, and 1.4 Hz), 7,18 (1H, DD, J=10,7, 1.8 Hz), 7,15-7,13 (2H, m), 7,06 (1H, DD, J=7,9, and 1.6 Hz), of 6.99 (1H, DD, J=8,3, 1,6 Hz), and 4.40 (1H, q, J=6.3 Hz), of 3.77 (1H, Sept, J=7.0 Hz), 3,63 is 3.57 (1H, m), 3,11-3,03 (2H, m), 2,71 is 2.43 (4H, m)of 1.24 (3H, d, J=6.3 Hz), of 1.16 (3H, d, J=7,0 Hz)and 1.15 (3H, d, J=7,0 Hz)to 0.96 (3H, s)to 0.94 (3H, C).

MS (ESI, m/z 542 (M+H)+.
0,003
1-531H-NMR (300 MHz, δ ppm, DMSO-d6) a 7.62 (1H, d, J=7,7 Hz), 7,55-7,31 (3H, m), 7,19-was 7.08 (4H, m), 6,95-6,87 (2H, m), of 4.45 (1H, q, J=6.2 Hz), 3,64 is 3.57 (2H, m), 3,13-to 3.09 (2H, m), 2,78-2,69 (3H, m), 2,56 of $ 2.53 (1H, m)to 2.18 (3H, s), 1,67 to 1.47 (2H,, m)of 1.27 (3H, d, J=6.2 Hz), 1,19 (3H, d, J=1.5 Hz), 1,01 (3H, s), 0,99 (3H, s), 0.79, which is to 0.74 (3H, s).

MS (ESI, m/z 536 (M+H)+.
0,015

Table 21
1-541H-NMR (300 MHz, δ ppm, DMSO-d6) 7,92-7,80 (5H, m), 7,71 (1H, s), to 7.59-was 7.08 (8H, m), 4,23 and of 4.05 (1H, q, J=6.2 Hz in), 3.75 (1H, users), 3,63-to 3.58 (1H, m), 3,23-3,13 (1H, m), 2,96-only 2.91 (2H, m), 2,73-a 2.71 (1H, m), 2,11 and 2,04 (3H, s)of 1.44 (1H, m), 1,21 (3H, d, J=6.2 Hz), 1,11 (6H, users). MS (ESI, m/z 512 (M+H)+.0,023
1-551H-NMR (300 MHz, δ ppm, DMSO-d6) of 7.90-7,81 (4H, m), 7,71 (1H, s), EUR 7.57-to 7.32 (6H, m), 7,21-to 7.18 (3H, m), 4,48 (1H, q, J=6.3 Hz), and 3.72 (1H, users), 3,17-3,15 (2H, m), 2,96-2,87 (3H, m), 2,73-2,65 1H, m), 2,58 (3H, s)of 1.28 (3H, d, J=6.3 Hz), of 1.12 (3H, s), is 1.11 (3H, s).

MS (ESI, m/z 512 (M+H)+.
0,010
1-561H-NMR (300 MHz, δ ppm, DMSO-d6) 7,89-7,81 (3H, m), 7,72 (1H, s), 7,63-7,13 (10H, m), of 4.45 (1H, q, J=6.5 Hz), 3,81 (1H, users), 3,24-is 3.21 (2H, m), 3,01 (2H, s), 2,93-and 2.83 (1H, m), 2.77-to to 2.67 (1H, m)of 1.27 (3H, d, J=6.5 Hz), to 1.14 (6H, users).

MS (ESI, m/z 516 (M+H)+.
0,019

Table 22
1-571H-NMR (300 MHz, δ ppm, DMSO-d6) 7,92 (1H, s), to 7.84 (1H, t, J=6.5 Hz), to 7.59-7,34 (5H, m), 7,27-was 7.08 (3H, m), 4,21 and a 4.03 (1H, q, J=6.4 Hz), 3,70 (1H, users), 3,62-to 3.58 (2H, m), 3,21-3,14 (2H, m), 2,80 (2H, m), 2,10 and was 2.05 (3H, s), 1,22 and of 1.16 (3H, d, J=6.4 Hz), a 1.08 (6H, users).

MS (ESI, m/z 530 (M+H)+.
0,027
1-581H-NMR (400 MHz, δ ppm, DMSO-d6) 7,98-7,94 {1H, m), a 7.85-to 7.77 (4H, m), to 7.67 (1H, s), 7,56 is 7.50 (1H, m), 7,46-7,42 (3H, m), of 7.36-7,26 (3H, m), 7,21-to 7.15 (1H, m), 4,25 (1H, q, J=6.5 Hz), of 3.78 (1H, users), of 3.13 (2H,users), of 2.97 (2H, users), 2,93-2,85 (1H, m), 2,68-2,62 (1H, m)of 1.23 (3H, users), 1,10 (6H, users).

MS (ESI, m/z 516 (M+H)+.
0,021
1-591H-NMR (300 MHz, δ ppm, DMSO-d6) of 7.90-of 7.82 (4H, m), 7,74 (1H, s), 7,58-7,34 (6H, m), 7.23 percent for 7.12 (3H, m), 453 (1H, kV, J=6.3 Hz), 3,86 (1H, users), 3,21-3,19 (2H, m), 3,07-of 3.00 (3H, m), 2,83-a 2.71 (1H, m)of 1.29 (3H, d, J=6.3 Hz), 1,19 (6H, users).

MS (ESI, m/z 516 (M+H)+.
0,016

Table 23
1-601H-NMR (300 MHz, δ ppm, DMSO-d6) a 7.85-of 7.82 (1H, d, J=8.5 Hz), 7,55 (1H, d, J=7,7 Hz), 7,44 (1H, t, J=7.5 Hz), 7,34 (1H, t, J=7.5 Hz), 7,28-7,13 (7H, m), 4,48 (1H, q, J=6.2 Hz), 3,66 (1H, users), 3,19-of 3.12 (3H, m), 2.77-to a 2.71 (3H, m), of 2.56 (3H,users), of 1.27 (3H, d, J=6.2 Hz), 1,01 (3H, s), and 1.00 (3H, s).

MS (ESI, m/z 496 (M+H)+.
0,096
1-611H-NMR (300 MHz, δ ppm, DMSO-d6) 7,83 (1H, d, J=8,2 Hz), 7,55-7,31 (5H, m), 7.18 in-7,14 (4H, m), 4,47 (1H, q, J=6.4 Hz), 3,61 (1H, users), 3,13-3,11 (3H, m), 2,70-of 2.64 (3H, m)to 2.55 (3H, users), of 1.26 (3H, d, J=6.4 Hz), and 0.98 (3H, s)to 0.97 (3H, s).

MS (ESI, m/z 530 (M+H)+.
0,004
1-621H-NMR (300 MHz, δ ppm, DMSO-d6) 7,89-of 7.82 (4H, m), 7,74 (2H, s), to 7.59-to 7.35 (7H, m), 7,22-7,19 (1H, d, J=7,7 Hz), 4,34 (1H, users), a-3.84 (1H, users), 3,18 (1H, users), 3,05-2,95 (2H, m), 2,80 of 2.68 (1H, m), 2,53-2,49 (2H, users), 1,28-a 1.08 (9H,users).

MS (ESI, m/z 516 (M+H)+.
0,008

Table 24
1-63 1H-NMR (300 MHz, δ ppm, DMSO-d6) to $ 7.91-to 7.77 (4H, m), 7,69 (1H, s), to 7.61-EUR 7.57 (1H, m), 7,49-7,28 (5H, m), 7,19-to 7.15 (3H, m), 3,90-a-3.84 (2H, m), 3,68 (1H, users), 3,34-is 3.21 (2H, m), 2,89 is 2.75 (3H, m)to 2.55 (3H, s), 1,07-0,97 (7H, m), 0,42 (1H, users), between 0.30 to 0.18 (2H, m)-0,12 (1H, users).

MS (ESI, m/z 538 (M+H)+.
0,016
1-641H-NMR (300 MHz, δ ppm, DMSO-d6) 7,88-7,73 (5H, m), 7,63-of 7.60 (1H, m), 7,50-7,33 (5H, m), 7,22? 7.04 baby mortality (3H, m), 3,94-of 3.80 (2H, m), 3,42-3,24 (3H, m), 3,06 is 3.00 (2H, m), 2,88 is 2.75 (1H, m), 1,25-1,00 (7H, m), 0,44 (1H, users), 0,35-0,20 (2H, m)-0,14 (1H,users).

MS (ESI, m/z 542 (M+H)+.
0,017
1-651H-NMR (400 MHz, δ ppm, DMSO-d6) a 7.85-7,56 (7H, m),7,47-of 7.23 (6H, m), 7,17 (1H, d, J=7.5 Hz), a-3.84 (1H, users), 3,74-and 3.72 (1H, m), 3,43-3,18 (3H, m), 3,07-2,90 (2H, m),2,78 of 2.68 (1H, m), 1,16-of 1.13 (6H, m)of 0.95 (1H,users), 0,45 (1H,users)and 0.22 (2H, users), -0,18 (1H,users).

MS (ESI, m/z 542 (M+H)+.
0,016

Table 25
1-661H-NMR (300 MHz, δ ppm, DMSO-d6) of 7.90-EUR 7.57 (7H, m), 7,50-7,33 (5H, m), 7.24 to 7,07 (2H, m), a 3.87-of 3.85 (1H, m), 3,70 (1H, users), 3,57-of 3.53 (1H, m), 3,31-3,17 (2H, m), 2.95 and is 2.80 (2H, m), 2.77-to to 2.65 (1H, m), is 2.09 (3H, s), 1,12-of 1.05 (6H, users), of 0.95 (1H, users), 0,38 (1H, users), between 0.30 to 0.20 (2H, m), -0,34 (1H, users).

MS (ESI, m/z 538 (M+H) +.
0,017
1-671H-NMR (300 MHz, δ ppm, DMSO-d6) of 7.82 (1H, users), of 7.70 (1H, d, J=6.8 Hz), 7,58-7,47 (4H, m), 7,39-7,27 (2H, m), 7,19 (2H, d, J=6.8 Hz), 4,30 (1H, users), 3,70 (1H, users), of 3.13 (2H, users), 2,88 is 2.75 (3H, m), 2,63 of $ 2.53 (1H, m), 1,22 (3H, users), of 1.06 (6H, users).

MS (ESI, m/z 534 (M+H)+.
0,019
1-681H-NMR (300 MHz, δ ppm, DMSO-d6) 7,89-of 7.82 (3H, m), 7,73 (1H, s), 7,62-7,33 (7H, m), 7,25-to 7.18 (3H, m), 4,56 (1H, q, J=6.2 Hz), 3,88 (1H, users), 3,24-3,17 (2H, m), is 3.08-3,03 (3H, m), 2,82-of 2.72 (1H, m)of 1.26 (3H, d, J=6.2 Hz), 1,19 (6H, users).< / br>
MS (ESI, m/z 532 (M+H)+.
0,003

Table 26
1-691H-NMR (300 MHz, δ ppm, DMSO-d6) of 7.90 to 7.75 (5H, m), to 7.59-to 7.35 (8H, m), 7,24 (1H, d, J=7,7 Hz), 4,55 (1H, q, J=6.5 Hz), a 3.87 (1H, users), 3,24 is 3.23 (2H, m), 3,05 (3H, users), 2,83-by 2.73 (1H, m)of 1.27 (3H, d, J=6.5 Hz), 1,17 (6H, users).

MS (ESI, m/z 543 (M+H)+.
0,002
1-701H-NMR (300 MHz, δ ppm, DMSO-d6) 7,88-to 7.77 (4H, m), 7,69 (1H, s), 7,55-7,28 (6H, m), to 7.15 (1H, d, J=7,7 Hz), is 6.61 (1H, s)6,40 (1H, d, J=8.0 Hz), 4,55 (1H, q, J=6.6 Hz), 3,70 (1H, users), 3,16-3,14 (2H, m), 2,89 (2H, users), 2,84-and 2.83 (1H, m), 2,63-to 2.57 (1H, m)of 1.26 (3H, d, J=6,GC), of 1.07 (3H, s)of 1.05 (3H, s).

MS (ESI, m/z 513 (M+H)+.
0,005
1-711H-NMR (300 MHz, δ ppm, DMSO-d6) 8,42 (1H, s), with 8.05 (1H, d, J=7.9 Hz), 7,87-7,81 (3H, m), 7,72 (1H, s), 7,53-7,29 (6H, m), 7,16 (1H, d, J=7,4 Hz), to 6.88 (1H, d, J=7.9 Hz), of 4.57 (1H, q, J=6.3 Hz), a-3.84 (1H, users), 3,17-and 3.16 (2H, m), 3,06 (3H, users), 2,81-and 2.79 (1H, m), 2,02 (3H, s)of 1.29 (3H, d, J=6.3 Hz), 1,19 (6H, users).

MS (ESI, m/z 555 (M+H)+.
0,005

Table 27
1-721H-NMR (400 MHz, δ ppm, CDCl3) 8,01 (1H, d, J=6,7 Hz), 7,60-rate of 7.54 (2H, m), 7,45 (1H, t, J=7,3 Hz), 7,35 (1H, t, J=7.5 Hz) , 7.24 to 7,17 (3H, m), 6,99-6,92 (2H, m), 4,55 (1H, q, J=6.0 Hz), 3,85 (1H, users), 3,60 (1H, users), 3,21-3,17 (1H, m), 3,03-2,95 (1H, m), 2,87 (2H, s), 2.77-to of 2.68 (1H, m), are 2.19 (3H, s)of 1.28 (3H, d, J=6.0 Hz), of 1.13 (6H, users).

MS (ESI, m/z 514 (M+H)+.
0,015
1-731H-NMR (300 MHz, δ ppm, CDCl3) of 7.82 (1H, d, J=8.5 Hz), 7,51 (1H, d, J=8.1 Hz), 7,37 (1H, t, J=7,7 Hz), 7,30-of 7.25 (1H, m), 7,16 (1H, d, J=7,7 Hz), 7,06? 7.04 baby mortality (3H, m), 4,56 (1H, q, J=6.6 Hz), 4,20 (1H, users), with 3.79 (3H, s), 3,38-2,78 (6H, m), at 2.59 (3H, s)of 2.16 (3H, s)to 1.37 (3H, users), 1,28-of 1.26 (6H, users).

MS (ESI, m/z 506 (M+H)+.
0,007
1-741H-NMR (300 MHz, δ ppm, DMSO-d6) 7,88 for 7.78 (3H, m), 7.68 per-7,29 (9H, m), 7,19-7,16 (1H, d, J=7,7 Hz), to 4.62 (2H, t, J=8,8 Hz), 4,51 (1H, q, J=6.2 Hz), 3,71 (1H, users), 3,23 (2H, t, J=8.6 Hz), 3,17-3,15 (2H, m), 2,90 (2H, s), 2,83 is 2.75 (1H, m), 2,64-2,60 (1H, m)of 1.27 (3H, d, J=6.2 Hz), with 1.07 (3H, s)of 1.05 (3H, s).

MS (ESI, m/z 540 (M+H)+.
0,011

Table 28
1-751H-NMR (400 MHz, δ ppm, DMSO-d6) a 7.85-7,66 (6H, m), EUR 7.57 (1H, d, J=7,7 Hz), 7,47-7,33 (5H, m), 6,97 (1H, d, J=7,4 Hz), of 3.97 (1H, q, J=6.2 Hz), 3,68 (1H, users), 3,21 is 3.15 (2H, m), of 2.86 (2H, s), 2,81-2,77 (1H, m), 2,64-2,62 (1H, m), a 2.01 (3H, C)at 1.91 (3H, s)of 1.09 (3H, d, J=6.2 Hz), was 1.04 (3H, s)of 1.03 (3H, s).

MS (ESI, m/z 526 (M+H)+.
0,012
1-761H-NMR (400 MHz, δ ppm, DMSO-d6) 7,71 (2H, d, J=7,3 Hz), 7,56 (1H, d, J=7,7 Hz), 7,44-7,30 (2H, m), 7,10 (1H, t, J=8.0 Hz), 6,98-6,86 (3H, m), of 3.94 (1H, q, J=6.3 Hz), 3,63 (1H, users), 3,17-and 3.16 (2H, m), of 2,75 2,71 (1H, m), 2,65 (2H, users}, to 2.57-of 2.53 (1H, m), 2,17 (3H, s)2,02 (3H, s)of 1.93 (3H, s), is 1.11 (3H, d, J=6.3 Hz), 0,99 (3H, s), and 0.98 (3H, s).

MS (ESI, m/z 508 (M+H)+.
0,022
1-771H-NMR (400 MHz, δ ppm, DMSO-d6) 7,98 (1H, d, J=8.1 Hz), 7,87-7,76 (2H, m), 7,66 (1H, s), EUR 7.57-7,33 (8H, m), 7.24 to 7,20 (2H, m), 4,42 {1H, q, J=6.2 Hz), 4,06-was 4.02 (1H, m), 3,68 (2H, users), 3,16-3,11 (1H, m), 2,83 is 2.80 (8H, m), 2,73-to 2.67 (1H, m,), of 1.28 (3H, d, J=6.2 Hz), 1,01 (3H, s), 0,99 (3H,s).

MS (ESI, m/z 541 (M+H)+.
0,021

Table 29
1-781H-NMR (400 MHz, δ ppm, DMSO-d6) of 7.48-7,46 (1H, d, J=7,7 Hz), 7,40-of 7.25 (4H, m), 7,14-to 7.09 (2H, m), 6,93-6,85 (2H, m), 4,58 (2H, q, J=8,8 Hz), 4,46 (1H, q, J=6.3 Hz), the 3.65 (1H, users), 3,20 (2H, t, J=8,8 Hz), 3,14-to 3.09 (2H, m), 2,72-to 2.67 (3H, m), 2,53 is 2.51 (1H, m), of 2.15 (3H, s), 1,25 (3H, d, J=6.3 Hz), and 0.98 (3H, s)to 0.97 (3H, s).

MS (ESI, m/z 522 (M+H)+.
0,020
1-791H-NMR (300 MHz, δ ppm, DMSO-d6) 7,10(1H, d, J=1.9 Hz), 1,46-of 7.23 (3H, m), 7,22? 7.04 baby mortality (8H, m), 6,92-6,87 (2H, m)

6,83 (1H, DD, J=7,7, 1.2 Hz), of 4.44 (1H, d, J=14.4 Hz), 4,35 (1H, q, J=6.5 Hz), 4,33 (1H, d, J=14.4 Hz), 3,63-3,61 (1H, m), 3.04 from-of 2.97 (2H, m), 2.71 to to 2.65 (3H, m), of 2.51 at 2.45 (1H, m), of 2.15 (3H, s)of 1.12 (3H, d, J=6,5 Hz)to 0.97 (3H, s)to 0.96 (3H, s).

MS (ESI, m/z 570 (M+H)+.
0,004
1-801H-NMR (300 MHz, δ ppm, DMSO-d6) 7,63 (1H, d, J=1.9 Hz), 1,53-7,41 (2H, m), 7,33 (1H, DDD, J=7,5, to 7.5, 1.2 Hz), 7,21-7,13 (2H, m), 6,95-6,85 (4H, m), 4,48 (1H, q, J=6.3 Hz), with 3.79 (3H, s), 3,71-3,70 (1H, m), 3,13-3,11 (2H, m), 2,88-of 2.86 (1H, m,), a 2.75 (2H, s), 2,64 at 2.59 (1H, m), 2,17 (3H, s)of 1.29 (3H, d, J=6.3 Hz), of 1.05 (3H, s), was 1.04 (3H, s).

MS (ESI, m/z 494 (M+H)+.
0,027

Table 30
1-811H-NMR (300 MHz, δ ppm, DMSO-d6) to 7.64 (1H, d, J=7.9 Hz), 7,52 (1H, d, J=7.9 Hz), 7,43-7,16 (6H, m), 6,93 (1H, s), 6,88-6,86 (1H, m), 4,47 (1H, q, J=6.4 Hz), with 3.79 (3H, s), 3,66-of 3.64 (1H, m), 3,11-3,10 (2H, m), 2,80-to 2.74 (2H, m), 2,58-2,53 (1H, m)of 1.28 (3H, d, J=6.4 Hz), 1,01 (3H, s), and 1.00 (3H, s).

MS (ESI, m/z 530 (M+H)+.
0,026
1-821H-NMR (300 MHz, δ ppm, DMSO-d6) of 7.70 (1H, d, J=8.0 Hz), EUR 7.57-7,22 (6H, m), 7,07-6,89 (3H, m), of 4.49 (1H, q,J=6.2 Hz), 3,83 (3H, s), 3,68-to 3.67 (1H, m), 3,15-3,13 (2H, m), 2,82-2,77 (3H, m), 2,63-to 2.57 (1H, m)is 1.31 (3H, d, J=6.2 Hz), 1,05 (3H, s), was 1.04 (3H, s).

MS (ESI, m/z 530 (M+H)+.
0,027
1-831H-NMR (300 MHz, δ ppm, DMSO-d6) 7,89 (1H, users), 7,80 (1H, t, J=8.1 Hz), 7,55 (1H, t, J=6,1 Hz), 7,44 (1H, t, J=7.5 Hz), 7,37-7,24 (3H, m), 7,20-7,06 (3H, m), 4,20 and £ 4.02 (1H, q, J=6.2 Hz), to 3.58 (1H, users),3,20-3,03 (3H, m)to 2.66 (3H, users), of 2.08 and 2.03 (3H, s), 1,19 and 1,13{3H, d, J=6.2 Hz), is 0.96 (6H, users).

MS (ESI, m/z 514 (M+H)+.
0,016

Table 31
1-841H-NMR (300 MHz, δ ppm, DMSO-d6) of 7.90 (1H, users), 7,80 (1H, t, J=8.5 Hz), 7,55 (1H, t, J=6.3 Hz), 7,47-to 7.32 (3H, m), 7,25-7,02 (4H, m), 4,21 and £ 4.02 (1H, q, J=6.6 Hz)and 3.59 (1H, users), 3,18 totaling 3.04 (3H, m), 2,70-2,6 (3H, m), 2,09 and 2.03 (3H, s), 1,19 and of 1.13 (3H, d, J=6.6 Hz), of 0.97 (6H, users).

MS (ESI, m/z 514 (M+H)+.
0,022
1-851H-NMR (300 MHz, δ ppm, DMSO-d6) 7,88-7,80 (3H, m), 7,69-to 7.68 (2H, m), 7,53 (1H, DD, J=7,8, 1.3 Hz), 7,50-7,26 (7H, m), 7,18 (1H, DD, J=7,5, 1.3 Hz), 4,48 (1H, q, J=6.3 Hz), of 3.78 (1H, m), 3,17 (2H, d, J=5.6 Hz), 2,98 (2H, s), only 2.91 (1H, DD, J=12, 3.5 Hz), 2,69 (1H, DD, J=12, 8,2 Hz), of 2.56 (3H, s)of 1.28 (3H, d, J=6.3 Hz), of 1.13 (3H, s)of 1.12 (3H, s).

MS (ESI, m/z 512 (M+H)+.
0,004

Table 32
1-861H-NMR (400 MHz, δ ppm, DMSO-d6) 7,66 (1H, d, J=1.9 Hz), 7,53 (1H, DD, J=7,7, 1.3 Hz), 7,42 (1H, DDD, J=7,6, to 7.6 and 1.4 Hz), 7,35-of 7.25 (3H, m), 7.18 in-7,14 (2H, m), to 6.95 (1H, DD, J=11, 1.2 Hz), make 6.90 (1H, DD, J=7,7, 1,4 Hz), 4,46 (1H, q, J=6.3 Hz), 3,74 (1H, m), 3,14 (2H, d, J=5.6 Hz), 2,84 (1H, DD, J=12, 3.5 Hz), 2,77 (2H, s), 2,62 (1H, DD, J=12 and 8.1 Hz), to 2.55 (3H, s)to 2.18 (3H, s)of 1.28 (3H, d, J=6.3 Hz),of 1.06 (3H, s)of 1.05 (3H, s).

MS (ESI, m/z 494 (M+H)+.
0,014
1-871H-NMR (400 MHz, δ ppm, DMSO-d6) a 7.85 (1H, d, J=8,4 Hz), 7,54 (1H, d, J=7.9 Hz), 7,47-7,40 (2H, m), 7,33 (1H, DDD, 7,2, to 7.2, 1.2 Hz),of 7.25 (2H, q, j 1.9 Hz), 7,20-7,13 (3H, m), 4,47 (1H, q, J=6.5 Hz), 3.75 to of 3.60 (1H, m), 3,13 (2H, d, J=5.6 Hz), 2,85-to 2.65 (3H, m), 2,60 is 2.55 (4H, m)of 1.28 (3H, d, J=6.2 Hz), of 1.03 (3H, s)of 1.02 (3H, s).

MS (ESI, m/z 530 (M+H)+.
0,014

Table 33
1-881H-NMR (400 MHz, δ ppm, DMSO-d6)

EUR 7.57 (1H, d, J=8,Hz),

7,49 (1H, d, J=8,1Hz),

7,38 (2H, q, J=7,GC),

7,29 (1H, DD, J=7,4, 7,4 Hz),

then 7.20 (1H, d, J=10,GC),

7,13 (1H, d, J=7,Hz), 7,03-6,92 (3H, m), 4,48 (1H, q, J=6,3 Hz), 3,57-to 3.49 (1H, m), is 3.08 (2H, d, J=5,GC), 2,64-of 2.54 (3H, m), 2,52-is 2.37 (4H, m), 1,25 (3H, d, J=6,3 Hz), of 0.93 (3H,s)of 0.91 (3H, )

MS (ESI,m/z) 514(M+2H-Na)+.
0,014
1-891H-NMR (400 MHz,δ ppm,DMSO-d6)

7,74 (1H,d,J=7,GC),

7,51 (1H,DD,J=7,9,1,2 Hz),

7,40 (1H,DDD,J=7,9, 7,9, 1,4 Hz),

7,31 (1H,DDD,7,6, 7,6, 1,2 Hz),

7,17? 7.04 baby mortality (6N, m), of 4.45(1H,q,J=6,5 Hz),

to 3.58-to 3.52 (1H, m)to 3.09(2H,d,J=5,GC),

2,64-2,60 (3H, m), 2,52(3H,s),

2,46-to 2.40 (1H, m)of 1.26(3H,d,J=6,5 Hz),

of 0.96 (3H,s)to 0.94 (3H,s)

MS (ESI,m/z) 498(M+H)+.
0,271

Table 34
1-901H-NMR (400 MHz,δ ppm,DMSO-d6)

to 7.84 (1H,d,J=8,Hz),

rate of 7.54 (1H,d,J=7,0Hz),

the 7.43 (1H,DD,J=7,7, 1,4 Hz),

7,35-7,29 (2H, m), 7,19-7,16 (4H, m)

4,47 (1H,q,J=6,5 Hz), the 3.65 (1H, m)

of 3.13 (2H,d,J=5,8gts), was 2.76-to 2.67 (3H, m)

to 2.57-of 2.56 (4H, m), of 2.28 (3H,s),

of 1.27 (3H,d,J=6,5 Hz), of 1.02 (3H,s)

of 1.02 (3H,s)

MS (ESI,m/z) 528(M+H)+.
0,005
1-911H-NMR (400 MHz,δ ppm,DMSO-d6)

7,87 (1H,d,J=8,4 Hz), EUR 7.57-rate of 7.54 (1H, m)

7,47-7,42 (1H, m), 7,38-to 7.32 (1H, m)

7,27-to 7.09 (5H, m), 4,46 (1H,q,J=6,2 Hz),

3,68-of 3.64 (1H, m), 3,13 (2H,d,J=5,5Hz),

2,80-of 2.75 (3H, m), 2,59-to 2.57 (4H, m)

of 1.28 (3H,d,J=6,2 Hz), was 1.04 (3H,s),

of 1.03 (3H,s)

MS(ESI,m/z) 514(M+H)+.
0,028

Table 35
1-921H-NMR (400 MHz,δ ppm, DMSO-d6)

7,89-a 7.85 (1H, m), to 7.67-7,17 (N, m)

4,48 (1H,q,J=6,2 Hz), to 3.64 (1H, m)

of 3.13 (2H,d,J=4,8gts), 2,83 of 2.68 (3H, m)

2,59-to 2.57 (4H, m)of 1.28 (3H,d,J=6,2 Hz), 1.04 million-0,99 (6N, m)

MS(ESI,m/z 548(M+H)+.
0,022
1-931H-NMR (400 MHz,δ ppm,DMSO-d6)

7,89-a 7.85 (1H, m), 7,56-7,03 (N, m)

4,48 (1H,q,J=6,2 Hz), to 3.64 (1H, m)

of 3.13 (2H,d,J=4,8gts), 2,75-of 2.72 (3H, m)

to 2.57 (3H,s)of 1.28 (3H,d,J=6,GC),

a 1.01 (3H,s), and 1.00 (3H,s)

MS(ESI,m/z) 514(M+H)+.
0,027

Table 36
1-941H-NMR (400 MHz,( ppm,DM is About-d6)

7,92-a 7.85 (4H, m), 7,55-7,31 (3H, m)

7,20-7,16 (3H, m), 4,46 (1H,q,J=6,GC),

3,61 (1H, m), of 3.12 (2H,d,J=5,1 Hz),

2,92 of 2.68 (3H, m), of 2.56 (3H,s),

of 1.26 (3H,d,J=6,2 Hz), 1,02-0,99 (6N, m)

MS(ESI,m/z 598(M+H)+.
0,028
1-951H-NMR (400 MHz,( ppm,DMSO-d6)

7,87-of 7.82 (1H, m), 7,54-7,33 (3H, m)

7,20-to 7.15 (3H, m), to 6.43 (2H,s),

4,48 (1H,q,J=6,GC), to 3.73 (6H,s),

3,71-3,70 (1H, m), 3,14 (2H,d,J=4,4 Hz),

2,91-of 2.72 (3H, m), to 2.57 (3H,s),

of 1.95 (3H,s)of 1.27 (3H,d,J=6,2 Hz),

of 1.12 (3H,s), 1,10 (3H,s)

MS(ESI,m/z) 536(M+H)+.

Table 37
1-961H-NMR (400 MHz,δ ppm,DMSO-d6)

the 7.85-of 7.82 (1H, m), 7,55-to 7.32 (3H, m)

7,19-7,14 (3H, m), 6,38-6,33 (3H, m)

4,48 (1H, m), 3,70 (6H,s),

3,15-of 3.12 (2H, m), 2,56-2,654 (3H, m)

of 1.27 (3H,t,J=6,GC) 1,10-1,03 (6N, m)

MS(ESI,m/z) 522(M+H)+.
1-971H-NMR (400 MHz,δ ppm,DMSO-d6)

7,89-to 7.84 (1H, m), 7,65-7,32 (6N, m)

7,20-7,17 (3H, m), 4,46 (1H, m)

of 3.64 (1H, m), 3,13 (2H,d,J=5,1 Hz),

2,89-of 2.72 (3H, m), 2,58-of 2.54 (4H, m)

of 1.27 (3H,d,J=6,GC), was 1.04 (3H,s),

of 1.02 (3H,s)

MS(ESI,m/z) 564(M+H)+.
0,106

Table 38
1-981H-NMR (400 MHz,δ ppm,DMSO-d6)

rate of 7.54 (1H,DD,J=7,7,1,1 Hz),

7,47 (1H,d,J=8,1 Hz), 7,44-7,31 (2H, m)

7,22-7,13 (4H, m), 6,99-6,91 (2H, m)

of 4.49 (1H,q,J=6,3 Hz), 3,82-of 3.80 (1H, m)

3,21-3,19 (2H, m), 2.95 and-to 2.85 (3H, m)

2,74-to 2.67 (1H, m), of 2.20 (3H,s),

of 1.43 (9H,s)of 1.29 (3H,d,J=6,3 Hz),

of 1.12 (6H,s)

MS(ESI,m/z) 536(M+H)+.
0,013
1-991H-NMR (400MHz,δ ppm,DMSO-d6)

at 7.55-7.29 trend (6N, m), 7,22-7,10 (4H, m)

4,48 (1H,q,J=6,4 Hz), of 3.77 of 3.75 (1H, m)

3,19-2,65 (6N, m), USD 1.43 (9H,s),

of 1.29 (3H,d,J=6,4 Hz), a 1.08 (6H,s)

MS(ESI,m/z) 556(M+H)+.
0,023

Table 39
1-1001H-NMR (400 MHz,δ ppm,DMSO-d6)

7,55-7,44 (N, m), 7,08-7,06 (1H, m)

4,48 (1H,q,J=6,4 Hz), 3,76-3,71 (1H, m)

3,19-3,17 (2H, m), 2,87-of 2.64 (4H, m)

of 1.43 (9H,s)of 1.30 (3H,d,J=6,4 Hz),

a 1.11 (6H,s)

MS(ESI,m/z) 556(M+H)+.
0,017
1-1011H-NMR (400 MHz,δ ppm,DMSO-d6)

the 7.65 of 7.60 (2H, m), 7,53-7,29 (3H, m)

7,24-6,91 (5H, m), 4,19 (1H,q,J=6,GC), 3,82-2.57 m (10H, m), are 2.19 (3H,s),

of 1.29 (3H,d,J=6,GC), of 1.13 (3H,s),

of 1.07 (3H,s)

MS(ESI,m/ ) 510(M+H)+.
0,016

Table 40
1-1021H-NMR (400 MHz,δ ppm,DMSO-d6)

of 7.90 (1H,d,J=7,8gts),

at 7.55 (1H,DD,J=7,9, 1,1 Hz),

of 7.48-7,31 (3H, m), 7.23 percent for 7.12 (3H, m)

6,95-6,87 (2H, m), 4,43 (1H,q,J=6,2 Hz),

of 3.77-3,63 (5H, m), 3,12-3,07 (6N, m)

2,75-2,47 (4H, m)to 2.18 (3H,s),

of 1.30 (3H,d,J=6,2 Hz), 1,01 (3H,s),

to 1.00 (3H,s)

MS(ESI,m/z) 565(M+H)+.
0,014
1-1031H-NMR (400 MHz,δ ppm,DMSO-d6)

to 7.84 (1H,d,J=7,Hz), 7,55-to 7.32 (4H, m)

7,21-to 7.15 (3H, m), of 6.96-6.89 in (2H, m)

4,47 (1H,q,J=5,GC), 3,84-a 3.83 (1H, m)

3,31-2,72 (6N, m), 2,17 (3H,s),

of 1.26 (3H,d,J=5,GC), of 1.12 (6H,s)

MS(ESI,m/z) 564(M+H)+.
0,003

Table 41
1-1041H-NMR (400 MHz,δ ppm,DMSO-d6)

to 7.84 (1H,d,J=8,4 Hz),

rate of 7.54 (1H,d,J=6,GC), of 7.48-7,40 (2H, m)

7,37-7,28 (3H, m), 7,20 for 7.12 (3H, m)

to 4.46 (1H,q,J=6,5 Hz), 3.75 to of 3.60 (1H, m)

of 3.13 (2H,d,J=5,GC), 2,85 is 2.75 (3H, m)

2,65 is 2.55 (4H, m), of 2.34 (3H,s),

of 1.27 (3H,d,J=6,5 Hz), of 1.03 (3H,s),

of 1.02 (3H,s)

MS(ESI,m/z) 544(M+H)+.
0,028
1-105 1H-NMR (400 MHz,δ ppm,DMSO-d6)

7,87 (1H,d,J=7,GC),

rate of 7.54 (1H,d,J=7,Hz), 7,50-7,40 (2H, m)

to 7.35 (1H,DD,7,5,7,5Hz),

of 7.25 (1H,d,10,5 Hz), 7,21-7,14 (3H, m)

7,05 (1H,d,J=8,1Hz),

to 4.46 (1H,q,J=6,3 Hz), 3,80-the 3.65 (1H, m)

of 3.13 (2H,d,J=5,4 Hz), 2.95 and is 2.75 (3H, m)

2,70 is 2.55 (4H, m)of 1.29 (3H,d,J=6,3 Hz),

a 1.08 (3H,s)of 1.07 (3H,s)

MS (ESI,m/z) 514(M+H-1/2H2SO4-1/2H2O)+.
0,009

Table 42
1-1061H-NMR (400 MHz,δ ppm,DMSO-d6)

7,87 (1H,d,J=7,GC),

rate of 7.54 (1H,d,J=7,Hz), 7,49-7,37 (3H, m)

7,34 (1H,DD,7,4,7,4 Hz),

of 7.25 (1H,d,10,5 Hz), 7,22-7,13 (2H, m)

7,05 (1H,d,J=8,2Hz), to 4.73 (2H,s),

of 4.49 (1H,q,J=6,3 Hz), 3.75 to of 3.60 (1H, m)

3,14 (2H,d,J=5,GC), 2,90 is 2.75 (3H, m)

2,66-of 2.56 (1H, m)of 1.28 (3H,d,J=6,3 Hz),

of 1.07 (3H,s)of 1.05 (3H,s)

MS(ESI,m/z) 530(M+H)+.
0,020
1-1071H-NMR (400 MHz,δ ppm,DMSO-d6)

compared to 8.26 (1H,d,J=7,GC),

to 8.12 (1H,d,J=1,8gts), 7,60-7,42 (4H, m)

7,38 (1H,DD,J=7,5,7,5Hz),

7,29 (1H,d,10,GC), of 7.23 (1H,d,7,GC),

7,07 (1H,d,J=8,3 Hz),

of 4.45 (1H,q,J=6,3 Hz), 3,83-to 3.73 (1H, m)

3,20-2,71 (6N, m)of 1.33 (3H,d,J=6,3 Hz),

to 1.14 (6H,s)

MS (ESI,m/z) 544(M+H)+
0,200

Table 43
1-1081H-NMR (400 MHz,δ ppm,DMSO-d6)

the 7.85 (1H,d,J=8,Hz),

at 7.55 (1H,DD,J=1,1, 7,8gts),

was 7.45 (1H,DDD,J=7,4,7,4,0,GC),

to 7.35 (1H,DDD,J=7,4,7,41,4 Hz),

7,19-7,16 (4H, m), 6,98-of 6.90 (2H, m)

4,48 (1H,q,J=6,5 Hz), 3,76 (1H, m)

3,14 (2H,d,J=5,8gts), 2,91-is 2.88 (1H, m)

and 2.79 (2H, m), 2,66-2,61 (1H, m)

of 2.56 (3H,s), are 2.19 (s,3H),

of 1.28 (3H,d,J=6,3 Hz), a 1.08 (3H,s),

of 1.07 (3H,s)

MS (ESI,m/z 494(M+H-1/2H2SO4)+.
0,014
1-1091H-NMR (400 MHz,δ ppm, DMSO-d6)

7,88 (1H,d,J=8,1Hz),

7,56 (1H,DD,J=7,8, 1,2 Hz),

7,46 (1H,.J=7,4, 7,4, 1,2 Hz),

7,41-7,29 (4H, m), 7.24 to to 7.18 (3H, m)

4,47 (1H,q,J=6,3 Hz), 3,74 (1H, m)

of 3.13 (2H,d,J=5,3 Hz), 2.91 in-2,84 (3H, m)

2,68-2,61 (1H, m), to 2.57 (3H,s),

of 1.28 (3H,d,J=6,5 Hz), a 1.08 (6H,s)

MS(ESI,m/z 514(M+H-1/2H2SO4)+.
0,015

Example 2-1

4-[2-[(1R)-[(2R)-3-[[1-(3-Fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoic acid

Stage 1

Methyl-4-(2-acetylphenol)benzoate

2'-Peracetate (10.6 g), methyl-4-hydroxybenzoate (11,7 g) and potassium carbonate (11.2 g) suspended in dimethylacetamide (70 ml) and the mixture was stirred at 140°C for one day. The reaction mixture was cooled to room temperature and was extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (n-hexane:ethyl acetate=7:1), obtaining specified in the header connection (8,62 g).

1H-NMR (300 MHz, δ ppm, CDCl3) 8,03 (2H, d, J=6,GC), 7,88 (1H, m)to 7.50 (1H, m), 7,27 (1H, m), 7,01-6,98 (3H, m), 3,90 (3H, s), to 2.57 (3H, s).

Stage 2

Methyl-4-[2-((1R)-hydroxyethyl)phenoxy]benzoate

Methyl-4-(2-acetylphenol)benzoate (3.0 g)obtained in stage 1, dichloro[(S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl][(S)-1,1'-bis(p-methoxyphenyl)-2-isopropylidene-1,2-diamine]ruthenium(II) (68 mg) and tert-piperonyl potassium (301 mg) suspended in isopropanol (30 ml) and the suspension was first made (3.0 kg.ft/cm2) at room temperature for 4.5 hours under medium pressure. To implement the operating mixture was added water (150 ml), the mixture was extracted with ethyl acetate (150 ml) and washed with saturated solution of salt. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in a mixture of tetrahydrofuran (60 ml) and methanol (60 ml) was added a 4 n solution of lithium hydroxide (15 ml). The mixture was stirred over night at room temperature. The reaction mixture was concentrated under reduced pressure and added 1 N. hydrochloric acid (120 ml). The mixture was extracted with ethyl acetate (150 ml). The organic layer was washed successively with water (50 ml) and saturated salt solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in methanol (100 ml) was added 4-dimethylaminopyridine (142 mg), and hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2,49 g). The mixture was stirred for 25 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified column chromatography on silica gel (hexane:ethyl acetate=5:1-4:1), obtaining specified in the header connection (2,63 g).

1H-NMR (300 MHz, δ ppm, CDCl3) 8,00 (2H, d, J=7,Hz), to 7.59 (1H, m), 7,30-7,21 (2H, m), 6,97-6,91 (3H, m)to 5.13 (1H, d, J=6,5 Hz), 3,90 (3H, s)to 1.48 (3H, d, J=6,5 Hz).

Stage 3

Methyl-4-[2-[(1R)-((R)-oxiranylmethyl)ethyl]phenoxy]benzoate

Methyl-4-[2-((1R)-hydroxyethyl)Fe is oxy]benzoate (3.62 in.) obtained in stage 2, was dissolved in tetrahydrofuran (15 ml). The mixture was cooled with ice was added sodium hydride (471 mg, 60% in oil). The mixture was stirred for 3 minutes. Then was added (R)-glycidyl-3-nitrobenzenesulfonate (3,62 g) and dimethyl sulfoxide (3 ml) and the mixture was stirred over night at room temperature. To the reaction mixture were added 10%aqueous citric acid solution (80 ml) and the mixture was extracted with ethyl acetate (150 ml). The organic layer was washed successively with water (50 ml) and saturated salt solution (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate=4:1-3:1), obtaining mentioned in the title compound (315 mg).

1H-NMR (300 MHz, δ ppm, CDCl3) to 7.99 (2H, d, J=6.6 Hz), EUR 7.57 (1H, m), 7,31-of 7.23 (2H, m), of 6.96-6.90 to (3H, m), 4,80 (1H, d, J=6.6 Hz), with 3.89 (3H, s), 3,55 (1H, m), 3,26 (1H, m)of 3.25 (1H, m), is 2.74 (1H, m), of 2.51 (1H, m)of 1.41 (3H, d, J=6,6 Hz).

Stage 4

Methyl-(3-fluoro-4-were)acetate

(3-Fluoro-4-were)acetic acid (or 105.3 g) was dissolved in methanol (740 ml). Added concentrated sulfuric acid (9,9 ml) and the mixture was stirred at 85°C for 1 hour. The reaction mixture was left to cool to room temperature and concentrated under reduced pressure. Added water to receive nomu residue and the mixture was extracted with ethyl acetate (1 liter). The organic layer was washed successively with water, saturated aqueous sodium bicarbonate, water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure, obtaining specified in the header connection (114,2 g).

1H-NMR (300 MHz, δ ppm, CDCl3) 7,14-7,10 (1H, m), of 6.96-6,93 (2H, m), 3,70 (3H, s)to 3.58 (2H, s), 2,25-of 2.24 (3H, s).

Stage 5

1-(3-Fluoro-4-were)-2-methylpropan-2-ol

Methyl-(3-fluoro-4-were)acetate (114,2 g)obtained in stage 4, was dissolved in tetrahydrofuran (800 ml) and added dropwise in a stream of argon at 0°C 1M methylmagnesium (1,56 l). The mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled with ice, was added dropwise a saturated aqueous solution of ammonium chloride (155 ml)and then was added magnesium sulfate (280 g). The reaction mixture was filtered, the filtrate was dried over magnesium sulfate and concentrated under reduced pressure, obtaining specified in the header connection (to 130.1 g).

1H-NMR (300 MHz, δ ppm, CDCl3) 7,11-was 7.08 (1H, m), 6,88-6,86 (2H, m), 2,71 (2H,in), 2.25 (3H,s)to 1.22 (6H, s).

Stage 6

2-Chloro-N-[1-(3-Fluoro-4-were)-2-methylpropan-2-yl]ndimethylacetamide

1-(3-Fluoro-4-were)-2-methylpropan-2-ol (to 130.1 g)obtained in stage 5, was dissolved in chloroacetonitrile (139 ml) dobavlyali dropwise under ice cooling, acetic acid (115 ml) and concentrated sulfuric acid (33,4 ml). The mixture was stirred at room temperature for 2 hours and added dropwise under ice cooling 4 N. aqueous sodium hydroxide solution (160 ml). The mixture was extracted twice with toluene and twice with ethyl acetate. The organic layer was twice washed 10%saturated salt solution and concentrated under reduced pressure, obtaining mentioned in the title compound (131, 6mm g).

1H-NMR (300 MHz, δ ppm, CDCl3) 7,10-7,06 (1H, m), 6,80-6,76 (2H, m), to 6.19 (1H, users), of 3.95 (2H, s)of 3.00 (2H, s), 2,24 (3H, s)to 1.37 (6H, s).

Stage 7

[1-(3-Fluoro-4-were)-2-methylpropan-2-yl]amine

2-Chloro-N-[1-(3-fluoro-4-were)-2-methylpropan-2-yl]ndimethylacetamide (humidity 131.6 g)obtained in stage 6, was dissolved in a mixture of acetic acid (200 ml) and ethanol (1 l) was added thiourea (46.6 g). The mixture was stirred for overnight at 100°C. the Reaction mixture was cooled to room temperature and precipitated precipitated crystals were filtered off. The filtrate was concentrated under reduced pressure and the obtained residue was added a 4 n solution of sodium hydroxide (300 ml). A mixture of 3 times were extracted with toluene. The organic layer was washed with saturated salt solution and concentrated under reduced pressure. The obtained residue was dissolved in diethyl ether (1 l) was added dropwise under ice cooling 4 n solution of hydrochloric acid in atilas the Tata (255 ml). The mixture was stirred for 1 hour and precipitated precipitated crystals were filtered off. The obtained crystals were added to a mixture of toluene and 4 N. aqueous sodium hydroxide solution. Toluene layer was separated, washed twice with water and concentrated under reduced pressure, obtaining specified in the header connection (57,9 g).

1H-NMR (300 MHz, δ ppm, CDCl3) 7,11-7,07 (1H, m), 6,85-PC 6.82 (2H, m), 2,61 (2H, in), 2.25 (3H, s), is 1.11 (6H, s).

Mass spectrum (APCI, m/z 182(M+H)+.

Stage 8

Methyl-4-[2-[(1R)-[(2R)-3-[[1-(3-Fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoate

Methyl-4-[2-[(1R)-((R)-oxiranylmethyl)ethyl]phenoxy]benzoate (109 mg), obtained in stage 3, was dissolved in toluene (3 ml) was added sequentially [1-(3-fluoro-4-were)-2-methylpropan-2-yl]amine (87 mg)obtained in stage 7, and lithium perchlorate (51 mg). The mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate=1:1-chloroform:methanol=10:1), obtaining mentioned in the title compound (193 mg).

1H-NMR (400 MHz, δ ppm, CDCl3) to 7.99 (2H, d, J=6.9 Hz), 7,49 (1H, DD, J=5,4, and 2.1 Hz), 7,35-7,20 (2H, m), 7,15-7,10 (1H, m), 7,00-to 6.80 (5H, m), 4.72 in (1H, q, J=6.5 Hz), 4,20-4,10 (1H, m)to 3.89 (3H, s), 3,50-to 3.35 (2H, m), 3,30-3,20 (1H, m), 3,10 is 2.80 (3H, m), 2,22 3H, C), 1,40-1,20 (N, m).

Mass spectrum (ESI, m/z 510(M+H)+.

Stage 9

4-[2-[(1R)-[(2R)-3-[[1-(3-Fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoic acid

Methyl-4-[2-[(1R)-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoate (185 mg)obtained in stage 8, was dissolved in a mixture of methanol (3 ml) and tetrahydrofuran (3 ml) was added 2 n sodium hydroxide solution (1.5 ml). The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was diluted with water. Was added 10%aqueous citric acid solution and the precipitate was collected by filtration, getting mentioned in the title compound (152 mg).

1H-NMR (300 MHz, δ ppm, DMSO-d6) to 7.93 (2H, d, J=8.7 Hz), 7,55 (1H, d, J=7.5 Hz), 7,40-of 7.25 (2H, m), 7,20-7,10 (1H, m), 7,05-6,85 (5H, m), and 4.68 (1H, q, J=6.3 Hz), 3,80-the 3.65 (1H, m), 3,24 (2H, d, J=5.4 Hz), 2,85 is 2.55 (4H, m), are 2.19 (3H, s), of 1.32 (3H, d, J=6.3 Hz), of 1.03 (3H, s)of 1.02 (3H, s).

Mass spectrum (ESI, m/z 496 (M+H)+.

Example 2-2

4-[2-[1-[(2R)-3-[[1-(3-Fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-3-methoxybenzoic acid

Stage 1

Methyl-4-(2-acetylphenol)-3-methoxybenzoate

2'-Peracetate (1,38 g) and methyl-4-hydroxy-3-methoxybenzoate (1,82 g) was dissolved in dim is telharmonic (10 ml) was added potassium carbonate (1.45 g). The mixture was stirred at 100°C for 15 hours. The reaction mixture was cooled to room temperature and added water. The mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated salt solution and dried over sodium sulfate. The obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate=5:1), obtaining mentioned in the title compound (1.25 g).

Stage 2

Methyl-4-[2-(1-hydroxyethyl)phenoxy]-3-methoxybenzoate

Methyl-4-(2-acetylphenol)-3-methoxybenzoate (1.24 g)obtained in stage 1, was dissolved in methanol (20 ml) and after cooling, ice was added borohydride sodium (312 mg). The mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and added water. The mixture was extracted with ethyl acetate. The organic layer was washed successively with 5%aqueous citric acid solution and saturated salt solution, dried over sodium sulfate. The obtained residue was purified column chromatography on silica gel (hexane:ethyl acetate=3:1), obtaining specified in the header connection (834 mg).

1H-NMR (300 MHz, δ ppm, CDCl3) 7,70 is 7.50 (3H, m), 7,25-7,10 (2H, m), 6.90 to (1H, d, J=8,4 Hz), 6,77 (1H, DD, J=6,6, 1.5 Hz), 5.25 to further 5.15 (1H, m), of 3.94 (3H, s), 3,93 (3H, s), 2,53 (1H, d, J=4,2 Hz)of 1.53 (3H, d, J=6,6 Hz).

Stage 3

Methyl-3-methoxy-4-[2-[1-((R)-ACS is animetake)ethyl]phenoxy]benzoate

Specified in the title compound (150 mg) was obtained from methyl 4-[2-(1-hydroxyethyl)phenoxy]-3-methoxybenzoate (660 mg)obtained in stage 2, in the same manner as described for stage 3 of example 2-1.

1H-NMR (400 MHz, δ ppm, CDCl3) 7,70 is 7.50 (3H, m), 7,25-to 7.15 (2H, m), 6,80-6,70 (2H, m), to 4.87 (1H, q, J=6.4 Hz), 3,91 (6H, s), 3,60-3,50 (1H, m), 3,40-of 3.25 (1H, m), 3,15-3,10 (1H, m), 2,80-2,70 (1H, m), 2,60-of 2.50 (1H, m), 1,45-of 1.40 (3H, m).

Stage 4

Methyl-4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-3-methoxybenzoate

Specified in the title compound (189 mg) was obtained from methyl 3-methoxy-4-[2-[1-((R)-oxiranylmethyl)ethyl]phenoxy]benzoate (146 mg), obtained in stage 3, and 1-(3-fluoro-4-were)-2-methylpropan-2-ylamine (89 mg)obtained in stage 7 of example 2-1, in the same manner as described for stage 8 of example 2-1.

1H-NMR (400 MHz, δ ppm, CDCl3) 7,65 was 7.45 (3H, m), 7,25-to 7.00 (3H, m), 6,85-6,70 (4H, m), a 4.83 (1H, d, J=6.3 Hz), 3,90 (6H, s), 3,80-3,70 (1H, m), 3,40-3,30 (2H, m), 2,85 is 2.55 (4H, m), of 2.23 (3H, s)of 1.45 and 1.35 (3H, m)of 1.05 (6H, s).

MS (ESI, m/z 540 (M+H)+.

Stage 5

4-[2-[1-[(2R)-3-[[1-(3-Fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-3-methoxybenzoic acid

Specified in the title compound (160 mg) was obtained from methyl 4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-3-methoxybenzoate (180 mg), obtained in stage 4, in a manner analogous to that described for stage 9 of example 2-1.

1H-NMR (300 MHz, δ ppm, DMSO-d6) 7,70 was 7.45 (3H, m), 7,30-7,10 (3H, m), 7,05-6,85 (3H, m), 6.75 in-6,70 (1H, m), to 4.81 (1H, q, J=6.0 Hz), 3,90-3,70 (4H, m), 3,30 (2H, d, J=5,1 Hz), 2.95 and-2,60 (4H, m), are 2.19 (3H, s)of 1.36 (3H, d, J=6.0 Hz), 1,05 (6H, s).

MS (ESI, m/z 496 (M+H)+.

Examples 2-3 - 2-36

Compounds of examples 2-3 - 2-36 obtained on the basis of examples 2-1 and 2-2. The results are shown in tables 45-60.

Table 44
1-1101H-NMR (400 MHz,δ ppm, DMSO-d6)

12,89 (1H,s), 8,97(1H,s), at 8.60 (1H,s),

to $ 7.91 (1H,d,J=7,GC),

7,58 (1H,d,J=7,Hz), 7,49-7,44 (3H, m)

7,39-7,19 (5H, m), 4,48 (1H,q,J=6,2 Hz),

to 3.92 (1H, m), 3,20-of 2.97 (5H, m)

and 2.79 (1H, m), 2,59 (NS), of 2.50 (3H,s),

of 1.32 (3H,d,J=6,5 Hz), 1,18 (6N, m)

MS(ESI,m/z 514(M+H-HCl)+.
0,026
1H-NMR (300 MHz, δ ppm, DMSO-d6) 8,00 to 7.75 (5H, m), 7,69 (1H, s), 7,65-of 7.25 (6H, m), 7,15-to 6.95 (3H, m), of 4.66 (1H, q, J=6.6 Hz), 3,81 (3H, s), 3.75 to the 3.65 (1H, users), 3,30-3,15 (2H, m), 3.00, it is 2.55 (4H, m), 1,40-of 1.30 (3H, m)of 1.07 (6H, s).

MS (ESI, m/z 528 (M+H)+.
Table 45
ExampleThe structural formulaPropertiesAnalysis of reporter gene (µm)
2-11H-NMR (300 MHz, δ ppm, DMSO-d6) to 7.93 (2H, d, J=8.7 Hz), 7,55 (1H, d, J=7.5 Hz), 7,40-of 7.25 (2H, m), 7,20-7,10 (1H, m), 7,05-6,85 (5H, m), and 4.68(1H, q, J=6.3 Hz), 3,80-the 3.65 (1H, m), 3,24 (2H, d, J=5.4 Hz), 2,85 is 2.55 (4H, m), are 2.19 (3H, s), of 1.32 (3H, d, J=6.3 Hz), of 1.03 (3H, s)of 1.02 (3H, s).

MS (ESI, m/z 496 (M+H)+.
0,015
2-21H-NMR (300 MHz, δ ppm, DMSO-d6) 7,70 was 7.45 (3H, m), 7,30-7,10 (3H, m), 7,05-6,85 (3H, m), 6.75 in-6,70 (1H, m), to 4.81 (1H, q, J=6.0 Hz), 3,90-3,70 (4H, m), 3,30 (2H, d, J=5,1 Hz), 2.95 and-2,60 (4H, m), are 2.19 (3H, s)of 1.36 (3H, d, J=6.0 Hz), 1,05 (6H, s).

MS (ESI, m/z 496 (M+H)+.
0,021
2-30,071

Table 46
2-41H-NMR (300 MHz, δ ppm, DMSO-d6) 8,00 to 7.75 (5H, m), of 7.70 (1H, s), 7,65-7,20 (6H, m), 7,10-6,85 (3H, m), 4,70 (1H, q, J=6.4 Hz), 3,90-3,70 (1H, m), 3,35-3,20 (2H, m), 3.00 and-is 2.40 (4H, m)is 1.31 (3H, d, J=6.4 Hz), 1,10 (6H, s).

MS (ESI, m/z 514 (M+H)+.
0,010
2-51H-NMR (300 MHz, δ ppm, DMSO-d6), a total of 8.74 (1H, s)to 8.12 (1H, s), 8,05-7,80 (4H, m), 7,71 (1H, DD, J=7,6, 7,6 Hz), of 7.64-of 7.25 (4H, m), 7,10-6,60 (3H, m), of 4.67 (1H, q, J=6.2 Hz), 3,80-of 3.60 (1H, m), 3,55-of 3.00 (2H, m), 2.95 and is 2.55 (4H, m), 1,40-of 1.20 (3H, m), 1,20-of 0.95 (6H, m).

MS (ESI, m/z 515 (M+H)+.
0,057
2-61H-NMR (300 MHz, δ ppm, DMSO-d6) to 7.93 (2H, d, J=8.7 Hz), 7,60 is 7.50 (1H, m), 7,40-7,20 (5H, m), 7,05-of 6.90 (3H, m), of 4.66 (1H, q, J=6.3 Hz), 3.75 to the 3.65 (1H, m), 3,30-3,20 (2H, m), 2,80-of 2.50 (4H, m)is 1.31 (3H, d, J=6.3 Hz), 1,01 (3H, s), 1.00 m (3H, s).

MS (ESI, m/z 516 (M+H)+.
0,022
2-71H-NMR (300 MHz, δ ppm, DMSO-d6) ,95 (2H, d, J=8.7 Hz), 7,58 (1H, s), 7,55-7,29 (2H, m), 7,21 (1H, m),? 7.04 baby mortality-6,93 (5H, m), 4,70 (1H, q, J=6.2 Hz), 3,90 (1H, m), 3,30-3,26 (2H, m), 3.00 and-of 2.72 (4H, m), of 2.20 (3H, s)of 1.34 (3H, d, J=6.2 Hz)and 1.15 (6H, C).

MS (ESI, m/z 496 (M+H)+.
0,017

Table 47
2-81H-NMR (300 MHz, δ ppm, DMSO-d6) 7,63 (1H, d, J=7,2 Hz), 7,53 (1H, m), 7,42 (1H, m), 7,34-7,14 (5H, m), 6,97-6,89 (3H, m), 4,71 (1H, q, J=6.3 Hz), 3,76 (1H, m), 3,32-is 3.21 (2H, m), 2,86-2,62 (2H, m)of 2.75 (2H, s)to 2.18 (3H, s)of 1.32 (3H, d, J=6.3 Hz), of 1.05 (6H, s).

MS (ESI, m/z 496 (M+H)+.
0,054
2-91H-NMR (300 MHz, δ ppm, DMSO-d6) to 7.95 (2H, d, J=7,7 Hz), the 7.85-7,66 (8H, m), 7,46-7,42 (3H, m), 7,35-7,30 (3H, m), 7,17 (1H, d, J=16.2 Hz), at 4.99 (1H, q, J=6.5 Hz), 3,91 (1H, m), of 3.45 (1H, m), 3,40 (1H, m), 2,95 (1H, m), with 2.93 (2H, s), 2,73 (1H, m)of 1.39 (3H, d, J=6.5 Hz), a 1.08 (6H, s).

MS (ESI, m/z 524 (M+H)+.
0,016
2-101H-NMR (500 MHz, δ ppm, CD3OD) 7,92-7,16 (15H, m), 5,07-5,02 (1H, m), 3.96 points-are 3.90 (1H, m), 3,40-of 3.32 (1H, m), 3,28-3,11 (4H, m), 3.04 from are 2.98 (1H, m), 1,42-of 1.30 (9H, m).

MS (ESI, m/z 530 (M+H)+.
0,027

Table 48
2-111 H-NMR (300 MHz, δ ppm, DMSO-d6) to 7.95 (2H, d, J=8.0 Hz), 1,78-of 7.69 (4H, m), 7,44-7,31 (3H, m), 7,20-7,11 (2H, m), 6,95-6,86 (2H, m), equal to 4.97 (1H, q, J=6.6 Hz), 3,81 (1H, users), 3,39-of 3.25 (3H, m), 2,83-2,77 (1H, m)to 2.66 (2H, s), 2,61 is 2.55 (1H, m,), 2,17 (3H, s)to 1.38 (3H, d, J=6.6 Hz), and 0.98 (6H, users).

MS (ESI, m/z 506 (M+H)+.
0,021
2-121H-NMR (400 MHz, δ ppm, DMSO-d6) 7,74-of 7.69 (2H, m), 7,47-7,42 (1H, m), 7,13-6,87 (5H, m), x 6.15 (1H, d, J=8.1 Hz), to 5.03 (1H, q, J=6.3 Hz in), 3.75 (1H, users), 3,35-to 3.33 (3H, m), 2,78 was 2.76 (1H, m), 2,65 is 2.51 (2H, m), of 2.15 (3H, s)2,07 (3H, s), 2,02 (3H, s)of 1.42 (3H, d, J=6.3 Hz), 0,99 (6H, users).

MS (ESI, m/z 524 (M+H)+.
0,005
2-131H-NMR (400 MHz, δ ppm, DMSO-d6) 7,74-of 7.69 (2H, m), of 7.48-7,42 (1H, m), 7,32-7,26 (2H, m), 7,16-7,13 (1H, m), 7,09-6,98 (2H, m), x 6.15 (1H, d, J=8.1 Hz), to 5.03 (1H, q, J=6,1 Hz), to 3.73 (1H, users), 3,38-3,30 (3H, m), 2,80-to 2.55 (3H, m)2,07 (3H, ), 2,03 (3H, s)of 1.43 (3H, d, J=6,1 Hz), and 0.98 (6H, users).

MS (ESI, m/z 544 (M+H)+.
0,022

Table 49
2-141H-NMR (400 MHz, δ ppm, DMSO-d6) a 7.85-7,76 (5H, m), 7,66 (1H, s)of 7.48-7,41 (2H, m), 7,39 (1H, DD, J=7,5) and 1.7 Hz), 7,33 (1H, DD, J=8,4, and 1.6 Hz), 7,28-to 7.15 (5H, m), and 4.68 (1H, q, J=6.3 Hz), 4,12 (1H, d, J=16 Hz), 4,07 (1H, d, J=16 Hz), 3,68 (1H, m)to 3.09 (2H, d, J=5.6 Hz), 2,87 (2H, s), 2,77 (1H, DD, J=11 and 3.5 Hz), to 2.57 (1H, DD, J=11,7,7 Hz), to 1.15 (3H, d, J=6.3 Hz), of 1.05 (3H, s), was 1.04 (3H, s).

MS (ESI, m/z 512 (M+H)+.
0,053
2-14'1H-NMR (300 MHz, δ ppm, DMSO-d6) of 7.90-of 7.70 (5H, m), 7,68 (1H, s), 7,55-7,10 (9H, m), and 4.68 (1H, q, J=6.2 Hz), 4,10 (2H, s), 3,80-3,50 (1H, m), 3,20-2,90 (2H, m), 2,86 (2H, d, J=2,9 Hz), 2,80-of 2.50 (2H, m)and 1.15 (3H, d, J=6.3 Hz), was 1.04 (3H, C)of 1.03 (3H, s).

MS (ESI, m/z 512 (M+H)+.
0,030
2-151H-NMR (300 MHz, δ ppm, DMSO-d6) 7,89-of 7.70 (6H, m), 7,52-7,34 (6H, m), 7,31-7,17 (3H, m), 4,71 (1H, q, J=6.2 Hz), 4,10 (2H, in), 3.75 (1H, m), 3,16-of 3.07 (2H, m), 2,95 (2H, s)2,84 (1H, DD, J=12, 2,9 Hz), 2,64 (1H, DD, J=12, 7,7 Hz), 1,18 (3H, d, J=6.2 Hz), 1,10 (3H, s)of 1.09 (3H, s).

MS (ESI, m/z 512 (M+H)+.
0,016

Table 50
2-161H-NMR (300 MHz, δ ppm, DMSO-d6) 7,88-7,80 (5H, m), 7,71 (1H, s), 7,63-7,58 (1H, m), 7,53-the 7.43 (4H, m), 7,39-7,33 (2H, m), 7,14 (2H, d, J=8,4 Hz), is 4.93 (1H, q, J=6.6 Hz), 3,81 (1H, m), 3,26-3,14 (2H, m), 2,96-2,87 (3H, m), 2.77-to of 2.68 (1H, m,), of 1.27 (3H, d, J=6.6 Hz), 1,11 (6H, s).

MS (ESI, m/z 530 (M+H)+.
0,014
2-171H-NMR (400 MHz, δ ppm, DMSO-d6) 8,12-8,03 (2H, m), 7,89-the 7.65 (7H, m), 7,58-7,44 (5H, m), 7,39-7,34 (1H, m), a total of 5.21 (0,25H, kV, J=6.5 Hz), 5,10 (0,25H, kV, J=6,5 Hz), 98-4,93 (0,5H, m)a 3.87 (1H, m), 3.25 to of 2.68 (6H, m), 1,37 (1,5H, d, J=6.5 Hz), 1,35 (1,5H, d, J=6.5 Hz), 1,20-of 1.15 (6H, m).

MS (ESI, m/z 546 (M+H)+.
0,148
2-181H-NMR (400 MHz, δ ppm, DMSO-d6) 8,16-8,07 (3H, m), of 7.90-7,76 (6H, m), 7,73-to 7.67 (2H, m), 7,65-of 7.60 (1H, m), 7,50-7,44 (2H, m), 7,38 is 1.34 (1H, m), 5,16 (0,5H, kV, J=6.2 Hz), 5,07 (0,5H, kV, J=6.2 Hz), 3,70 (1H, m) to 3.09 (2H, d, J=7,4 Hz), 2,97-2,82 (2H, m), 2,74-to 2.57 (2H, m), 1,26-of 1.18 (9H, m).

MS (ESI, m/z 562 (M+H)+.
0,236

Table 51
2-191H-NMR (300 MHz, δ ppm, DMSO-d6) 7,94-7,80 (5H, m), of 7.70 (1H, m), 7,51-7,44 (4H, m), 7,38-7,34 (1H, m), 7,07 (1H, d, J=7,4 Hz), 6,98 (1H, DDD, J=8,1, 7,0, 1.3 Hz), 6,56 (1H, DD, J=7,4, 7,0 Hz), to 6.43 (1H, d, J=8.1 Hz), 6,12-6,03 (1H, m), 4,67 (0,5H, kV, J=6,6 Hz)and 4.65 (0,5H, kV, J=6,6 Hz)to 4.41 (2H, m), 3,91 (1H, m), 3,42-3,30 (2H, m), 3.00 and-2,90 (3H, m), 2,82-by 2.73 (1H, m), 1,46 (1,5H, d, J=6.6 Hz), 1,45 (1,5H, d, J=6.6 Hz), 1,12-1,10 (6H, m).

MS (ESI, m/z 527 (M+H)+.
0,029
2-201H-NMR (400 MHz, δ ppm, DMSO-d6) 7,89-7,83 (3H, m), to 7.77-7,73 (2H, m), 7,49 was 7.45 (3H, m), 7,38-to 7.32 (4H, m), 7,22 (1H, DDD, J=8,4, to 7.4, 1.8 Hz), to 7.09 (1H, d, J=8,4 Hz), of 6.96 (1H, DD, J=7,4, 7,4 Hz), to 5.58 (1H, d, J=11 Hz), 5,19 (1H, d, J=11 Hz), at 4.99 (1H, q, J=6.3 Hz), 4,01 (1H, m), of 3.43 (1H, DD, J=11, 6,8 Hz)to 3.33 (1H, DD, J=11 and 6.1 Hz), 3,12-of 3.07 (3H, m), and 2.83 (1H, DD, J=12, 6,5 Hz)of 1.26 (3H, d, J=6.3 Hz), of 1.20 (6H,s).
MS (ESI, m/z 528 (M+H)+.
0,020

Table 52
2-20'1H-NMR (300 MHz, δ ppm, DMSO-d6) 8,00-the 7.65 (5H, m), 7,6-7,30 (7H, m), 7.23 percent (1H, DD, J=7,4, 7,4 Hz), 7,10 (1H, d, J=8,4 Hz), 6,97 (1H, DD, J=7,4, 7,41 Hz), 5,68 (0,5H, d, J=10 Hz), 5,59 (0,5H, d, J=10 Hz), 5.25-in the 4.90 (2H, m), 4,25-3,95 (1H, m), 3,50-3,20 (2H, m), 3,15-2,95 (2H, m), 2,90-to 2.65 (1H, m), of 1.35 to 1.00 (9H, m).

MS (ESI, m/z 528 (M+H)+.
0,021
2-211H-NMR (400 MHz, δ ppm, DMSO-d6) of 8.06 (1H, s), 7,88-7,81 (4H, m), 7,72 (1H, s), 7,54-7,34 (6H, m), 7,20 (1H, DDD, J=8,4, to 7.4, 1.8 Hz), 7,05 (1H, d, J=8,4 Hz), to 6.95 (1H, DD, J=7,4, 7,4 Hz), 5,27 (1H, d, J=13 Hz), with 5.22 (1H, d, J=13 Hz), equal to 4.97 (1H, q, J=6.2 Hz), 3,98 (1H, m), 3,40 (1H, DD, J=10, 6,1 Hz)to 3.33 (1H, DD, J=10, a 5.3 Hz), is 3.08 (2H, s)of 3.00 (1H, DD, J=12, 3.5 Hz), 2,78 (1H, DD, J=12 and 7.6 Hz), of 1.34 (3H, d, J=6.2 Hz), of 1.18 (3H, s), of 1.17 (3H, s).

MS (ESI, m/z 528 (M+H)+.
0,017

Table 53
2-21'1H-NMR (300 MHz, δ ppm, DMSO-d6) of 8.06 (1H, s), 7,89-7,81 (4H, m), 7,72 (1H, s), 7,54-7,34 (6H, m)7,24-7,16 (1H, m), 7,06 (1H, d, J=8,4 Hz), of 6.96 (1H, m), 5,33-to 5.21 (2H, m)5,00 (1H, m)to 3.99 (1H, m), 3,42 of 3.28 (2H, m), is 3.08 (2H, s), 3,05 (1H, s), 2,98-a 2.71 (2H, m), 1,34 (1,5H, d, J=6.2 Hz), 1,33 (1,5H, d, J=6.2 Hz)and 1.15 (6H, s).

MS (ESI, m/z 528 (M+H) +.
0,026
2-221H-NMR (400 MHz, δ ppm, DMSO-d6) of 7.97 (2H, d, J=8,3 Hz), 7,86 for 7.78 (3H, m), 7,69 (1H, s), 7,52 (2H, d, J=8,3 Hz), of 7.48-the 7.43 (2H, m), 7,37-7,34 (2H, m), 7,22 (1H, DDD, J=8,3, of 7.4 and 1.7 Hz), 7,06 (1H, d, J=8,3 Hz), 6,97 (1H, DD, J=7,4, 7,4 Hz), 5,20 (2H, s), 4,91(1H, q, J=6.3 Hz), a-3.84 (1H, m), 3,30 (2H, m), 2,94-2,90 (3H, m), 2,70 (1H, DD, J=12, 7.9 Hz), of 1.33 (3H, d, J=6.3 Hz), 1,10 (3H, s)of 1.09 (3H, s).

MS (ESI, m/z 528 (M+H)+.
0,017

Table 54
2-22'1H-NMR (300 MHz, δ ppm, DMSO-d6) 7,98 (2H, d, J=8,3 Hz), 7,87 for 7.78 (3H, m), of 7.70 (1H, s), 7,53 (2H, d, J=8,3 Hz), 7,49-to 7.35( 4H, m), 7.23 percent (1H, m), 7,06 (1H, d, J=8,3 Hz), 6,98 (1H, DD, J=7,4, 7,4 Hz), to 5.21 (2H, s), 4,91 (1H, q, J=6.3 Hz), 3,82 (1H, m), and 3.31 (2H, m), 2.91 in-2,86 (3H, m), 2.77-to of 2.64 (1H, m)of 1.32 (3H, d, J=6.3 Hz), a 1.08 (6H, s).

MS (ESI, m/z 528 (M+H)+.
0,023
2-231H-NMR (400 MHz, δ ppm, DMSO-d6) 8,03 (1H, s), 7,81 (1H, d, J=7,7 Hz), 7,51 (1H, d, J=7,7 Hz), 7,39 (1H, DD, J=7,7, 7,7 Hz), 7,34 (1H, DD, J=7,7, 1,6 Hz), 7,21-to 7.15 (2H, m),? 7.04 baby mortality (1H, d, J=7,7 Hz), 7,00-6,92 (3H, m), 5,27 (1H, d, J=13 Hz), with 5.22 (1H, d, J=13 Hz), 4,96 (1H, q, J=6.4 Hz), 3,93 (1H, m)to 3.38 (1H, DD, J=10, 6.3 Hz), 3,30 (1H, DD, J=10, a 5.4 Hz), 2,93-and 2.83 (3H, m), 2,69 (1H, DD, J=12, 7,3 Hz)to 2.18 (3H,s)of 1.33 (3H, d, J=6,4 Hz), 1,10 (6H, s).

MS (ESI, m/z 510 (M+H)+.
0,027

Table 55
2-241H-NMR (400 MHz, δ ppm, DMSO-d6) of 7.96 (2H, d, J=8,4 Hz), 7,51 (2H, d, J=8,4 Hz), was 7.36 (1H, DD, J=7,6, and 1.6 Hz), 7,22 (1H, DDD, J=7,6, to 7.6, 1.6 Hz), to 7.15 (1H, DD, J=8,1, 8.1 Hz), 7,05 (1H, d, J=8.1 Hz), 6,99-6,94 (2H, m), 6.90 to (1H, DD, J=7,6, the 1.4 Hz), 5,20 (2H, s), the 4.90 (1H, q, J=6.4 Hz), 3,80 (1H, m), 3,31-3,24 (2H, m), of 2.86 (1H, DD, J=12, and 3.2 Hz), 2,73 (2H, s), 2.63 in (1H, DD, J=12 and 8.1 Hz), 2,17 (3H, s)of 1.33 (3H, d, J=6.4 Hz), was 1.04 (3H, s), of 1.03 (3H, s).

MS (ESI, m/z 510 (M+H)+.
0,057
2-251H-NMR (300 MHz, δ ppm, DMSO-d6) 7,89 (1H, DD, J=8,1, 1.5 Hz), the 7.65 (1H, DD, J=11, 1.5 Hz), to 7.59 (1H, DD, J=7,7, 7,7 Hz), 7,37 (1H, DD, J=7,7, 1.8 Hz), 7.29 trend for 7.12 (3H, m), 7.03 is-6,91 (3H, m), 5,20 (2H, s), a 4.86 (1H, q, J=6.2 Hz), 3,90 (1H, m), 3,30-up 3.22 (2H, m), 2,98 (1H, DD, J=12, 2.7 Hz), and 2.83 (2H, s), of 2.72 (1H, DD, J=12, 8,8 Hz)to 2.18 (3H, s)of 1.30 (3H, d, J=6.2 Hz), 1,11 (6H, s).

MS (ESI, m/z 528 (M+H)+.
0,065

Table 56
2-261H-NMR (400 MHz, δ ppm, DMSO-d6) 7,78-7,76 (2H, m), 7,51 (1H, d, J=7,4 Hz), was 7.36 (1H, m), 7,26-7,22 (1H, m), 7,16-7,11 (2H, m), 7,00-to 6.88 (3H, m), 5,16 (1H, d, J=13 Hz), 5,14 (1H, d, J=13 Hz), a 4.83 (1H, m), 3,76 (1H, m), 3,26 (2H, m), and 2.83 (1H, m), 2,70 (2H, s), 2,60 (1H, m), is 2.37 (3H, s), 2,17 (3H, s)of 1.30 (3H, d, J=6.2 Hz), of 1.02 (6H, s).

MS (ESI, m/z 524 (M+) +.
0,024
2-271H-NMR (300 MHz, δ ppm, DMSO-d6) 7,40-7,30 (1H, m), 7,29 (2H, s), 7,12 (1H, DD, J=7,9, 7.9 Hz), 7,03 (1H, DD, J=7,9, 7.9 Hz), 6,97-to 6.88 (3H, m), of 6.31 (1H, d, J=7.9 Hz), of 5.05-of 4.95 (1H, m), 3,81-3,71 (7H, m), 3,37-and 3.31 (2H, m), 2,85-2,77 (1H, m,), 2,70-to 2.55 (3H, m) to 2.15 (3H, s)of 1.40 (3H, d, J=6.3 Hz), 1,01 (3H, s), and 1.00 (3H, s).

MS (ESI, m/z 496 (M+H)+.
0,027

Table 57
2-281H-NMR (300 MHz, δ ppm, DMSO-d6) 8,42 (1H, d, J=1.9 Hz), 8,08 (1H, DD, J=8,5, 1.8 Hz), 7,56 (1H, DD, J =7,2, 2.0 Hz), of 7.36-7,27 (2H, m), 7,17 (1H, t, J=8.1 Hz), 7,01-of 6.90 (4H, m), to 4.73 (1H, q, J=6.3 Hz), 3,85 of 3.75 (1H, m), 3,26 (2H, d, J=5,5 Hz), 2,90-2,63 (7H, m), 2,17 (3H, s)of 1.35 (3H, d, J=6,2 Hz), a 1.08 (3H, s)a 1.08 (3H, s)

MS (ESI,m/z) 541 (M+H)+.
0,003
2-291H-NMR (300 MHz, δ ppm, DMSO-d6) of 7.70 (1H, d, J=1.9 Hz), 7,56 (1H, DD, J=7,6, and 2.1 Hz), 7,41-7,29 (2H, m), 7.23 percent-to 7.18 (2H, m), 7,08-6,94 (4H, m), 4.72 in (1H, q, J=6.6 Hz), 3,90-3,74 (1H, m), 3.27 to of 3.23 (2H, m), 3,05-2,71 (7H, m), of 2.20 (3H, s), of 1.35 (3H, d, J=6.2 Hz), of 1.12 (3H, s)of 1.12 (3H, s) MS (ESI,m/z) 541(M+H)+.0,011

Table 58
2-30 1H-NMR (300 MHz, δ ppm, DMSO-d6) 8,00 (1H, d, J=1.9 Hz), 7,81 (1H, DD, J=8,5, 1.8 Hz), 7,54 (1H, DD, J=7,3, 1.8 Hz), 7,35-of 7.23 (2H, m), 7,16 (1H, t, J=7.9 Hz), 6,98-6,85 (4H, m), 4,74 (1H, q, J=6.2 Hz), 3,83-to 3.73 (1H, m), with 3.27 (2H, d, J=5,5 Hz), 2,89-2,62 (7H, m)to 2.18 (3H, s)of 1.36 (3H, d, J=6.6 Hz), of 1.06 (3H, s)of 1.05 (3H, s)

MS (ESI,m/z) 530 (M+H)+.
0,003
2-311H-NMR (300 MHz, δ ppm, DMSO-d6) to 7.59 (1H, d, J=8,8 Hz), 7,54 (1H, DD, J=5,5, 1.8 Hz), 7,39-7,26 (2H, m), 7,18 (1H, t, J=8,3 Hz), 7,03 (1H, DD, and 6.6, 1.5 Hz), 6,98-to 6.88 (3H, m), for 6.81 (1H, DD, J=8,5, and 2.6 Hz), and 4.68 (1H, q, J=6.6 Hz), 3,74-3,62 (1H, m), 3,28-and 3.16 (2H, m), 2,87-2,64 (7H, m), are 2.19 (3H,s)of 1.34 (3H,d,J=6.2 Hz), a 1.08 (3H,s)a 1.08 (3H,s)

MS(ESI,m/z) 530(M+H)+.
0,016

Table 59
2-321H-NMR (300 MHz, δ ppm, DMSO-d6) EUR 7.57 (2H, t, J=8,8 Hz), 7,40-7,28 (2H, m), 7,22-7,13 (2H, m), 7,09-7,02 (2H, m), 6,98-6,91 (2H, m), 4,71 (1H, q, J=6.4 Hz), 3,81-3,71 (1H, m), 3,29-3,17 (2H, m), 2,96-2,67 (7H, m), are 2.19 (3H,s)of 1.35 (3H, d, J=6,6 Hz)of 1.12 (3H, s)of 1.12 (3H, s)

MS (ESI,m/z) 564 (M+H)+.
0,014
2-331H-NMR (300 MHz, δ ppm, DMSO-d6) by 8.22 (1H, d, J=2.2 Hz), of 8.09 (1H, DD, J=8,5, 1.8 Hz), 7,58 (1H, DD, J=7,4, 2.2 Hz), 7,41-7,30 (2H, m), 7,16 (1H, t, J=8.0 Hz), 7.03 is-of 6.90 (3H, m), 6,83 (1H, d, J=8,4 Hz)and 4.65 (1H, q, J=6.2 Hz), 3,84-3,71 (1H, m), 3,9-3,20 (2H, m), 2.91 in 2.63 in (7H, m), 2,17 (3H,s)of 1.33 (3H, d, J=6.6 Hz), with 1.07 (3H, s)of 1.06 (3H, s)

MS (ESI,m/z) 564 (M+H)+.
0,002

Table 60
2-341H-NMR (300 MHz, δ ppm, DMSO-d6) 7,79 (1H, d, J=1,8 Hz), 7,71 (1H, d, J=8.5 Hz), 7,53 (1H, DD, J=7,4, 2.2 Hz), 7,34-7,22 (2H, m), 7,16 (1H, t, J=7.9 Hz), 6,98-6,87 (4H, m), 4,80 (1H, q, J=6.6 Hz), 3,81-3,71 (1H, m), or 3.28 (2H, d, J=5,5 Hz), 2,85-2,58 (7H, m)to 2.18 (3H, s)of 1.36 (3H, d, J=6.6 Hz), was 1.04 (3H, s)of 1.03 (3H,s)

MS (ESI,m/z) 514 (M+H)+.
0,006
2-351H-NMR (400 MHz, δ ppm, DMSO-d6) of 7.90 (2H, m), 7,60-7,20 (5H, m), 7,05-of 6.90 (4H, m), of 4.66 (1H, q, J=6.4 Hz), 3,70-of 3.60 (1H, m), 3.25 to a 3.15 (2H, m), 2,80-2,70 (2H, m), 2,60-of 2.50 (2H, m), 1,35-of 1.30 (3H, m), of 1.05 to 0.95 (6N, m)

MS (ESI,m/z) 516 (M+H)+.
0,011
2-361H-NMR (300 MHz, δ ppm, DMSO-d6) 7,88 (1H, s), 7,80-7,20 (6N, m), 7,03 (1H, d, J=7.8 Hz), 6.87 in (1H, d, J=6.6 Hz), to 6.67 (1H, d, J=9.0 Hz), and 4.68 (1H, q, J=6.6 Hz), 3,70-of 3.60 (1H, m), 3,30-3,15 (2H, m), 2,70-of 2.50 (4H, m), 2,31 (3H, s), 1,40 is 1.20 (3H, m), 1.00 and-0,90 (6N, m)

MS (ESI,m/z) 530 (M+H)+.
0,013

Experimental examples

The bioactivity of the compounds of the present invention was investigated using the following tests.

The experimental the initial example 1

Evaluation of antagonistic action on the calcium receptor using reporter gene.

In strain cells derived from the adrenal gland of the rat, to transform cells were injected luciferase cDNA and cDNA calcium receptor of human rights and the transformed cells were cultured in medium (80 ml F12 medium containing 0.5% cialisbuynow horse serum and 0.25% cialisbuynow fetal bovine serum). The solution in dimethyl sulfoxide containing the studied compound at a concentration of 0.1 to 10000 μm, diluted environment 100 times and added to the group of test compounds at the rate of 10 μl per well (final concentration of DMSO is 0.1%). In a similar manner as for a group of test compounds, dimethyl sulfoxide and diluted to 100 times the environment was added in the control group and blank group. Then to each well, except for the holes "empty groups", was added 50 μm environment containing calcium chloride at the rate of 10 μl per well (final concentration 5 mm). By itself the medium was added to the "empty" group. After culturing for 4 hours was added to the substrate of luciferase and luciferase activity was measured using photoluminescence. The degree of inhibition (%) was calculated from the obtained value measurements in accordance with the following formula:

N is the basis of the results was determined concentration, in which was observed a 50% degree of inhibition. The results are presented in the above tables 1-60.

Experimental example 2

Effect on the secretion of PTH

The compounds were administered orally to male SD rats (Charles River Japan, Inc.) at the age of 5-9 weeks, which were not fed for 20 hours, using a solvent (0.5% solution of methylcellulose) at a dose of 1 mg/5 ml/kg by Itself, the solvent was administered to rats at a dose of 5 ml/kg of Blood was collected from the tail vein after 15 minutes, 30 minutes, 60 minutes and 120 minutes after administration of the compounds and received the serum. The concentration of PTH in the serum was measured using a set of PTH ELISA kit for rats (Amersham Biosciences). The results are presented in table 61.

As a comparative example, in addition, the following compound was used at a dose of 30 mg/5 ml/kg in a similar test, but the effect of increasing the secretion of PTH were observed.

Table 61
The analyzed connectionThe concentration of PTH in serum (PG/ml)
After 15 minAfter 30 minAfter 60 minAfter 120 min
The control group
Group introduction of a test connection
1-113,2±2,618,0±1,514,6±3,615,9±2,7
43,9±2,025,0±3,217,9±2,014,8±1,6
1-28,8±1,312,5±0,613,4±2,713,0±1,8
28,5±5,327,1±2,310,5±1,312,4±1,6
1-38,8±1,312,5±0,613,4±2,713,0±1,8
23,8±1,625,1±3,9a 9.5±0,5the 11.6±0,9
1-611,9±2,415,9±1,08,7±1,29,4±2,1
28,9±6,919,2±3,110,0±1,78,3±0,6
1-3014,9±1,314,5±2,712,9±2,111,1±2,2
26,1±2,324,2±3,318,2±1,313,8±0,6

Experimental example 3

Effect on the secretion of PTH

The compounds were administered orally to male SD rats (Charles River Japan, Inc.) at the age of 5-9 weeks, Katarine fed for 20 hours, solvent (0.5% solution of methylcellulose) at a dose of 1 mg/5 ml/kg by Itself, the solvent was administered to rats at a dose of 5 ml/kg of Blood was collected from the tail vein after 15 minutes and 30 minutes after administration of the compounds and received the serum. The concentration of PTH in the serum was measured using a set of PTH ELISA kit for rats (Amersham Biosciences). The results are presented in table 62.

Table 62
The analyzed connectionThe concentration of PTH in serum (PG/ml)
After 15 minAfter 30 min
The control group
Group introduction of a test connection
2-113,7±2,317,6±3,1
25,1±2,319,1±0,9

Experimental example 4

Inhibitory activity against metabolic enzyme CYP2D6

With the use of the kit for the measurement of inhibition of metabolic enzyme CYP2D6 (BD Bioscience) and following the manufacturer's instructions, measured the inhibitory activity of the compounds. Because in the absence of the compounds exhibited fermentatively was 100%, determined the concentration leading to 50% inhibition (IC50). The results are presented in table 63 and table 64, where ">10" means more than 10 μm.

Table 63
The analyzed connectionIC50(µm)
1-57>10
1-59>10
1-26>10
1-27>10
1-3210.0
1-33>10
1-34>10
1-35>10
1-73>10
1-39>10
1-48>10
1-80>10

Table 64
The analyzed connectionIC50(µm)
2-5>10
2-20'>10

Experimental example 5

The effect of concurrent introduction of a test compound and estrogen on bone resorption and secretion of PTH.

Ovariectomised rats at the age of 13 weeks were divided into 4 groups including a control group (Group A), group introduction ESTRO is s (Group B), the introduction of a test group of compounds (Group C) and the group accompanying the introduction of the compounds and estrogen (Group D). Also created one sham control group (group E), where rats were subjected to sham surgery. Estradiol was dissolved in a mixture of 5% benzyl alcohol in corn oil and administered subcutaneously to rats in groups injection of estrogen (Group B and Group D) in the dose of 10 mg/kg of a Mixture of 5% benzyl alcohol in corn oil was administered subcutaneously to rats in groups which did not enter estrogen (Group A and Group C). The compound of example 1-1 suspended in a 0.5%solution of methylcellulose and administered orally in groups (Group C and Group D) for introduction of a test compound in a dose of 3 mg/kg in the case of groups (Group A and Group B), which did not enter the study connection, there is administered orally in 0.5%solution of methylcellulose.

On the 13th day after the start of injection, the blood was collected in each group from the tail vein and received the serum. ICTP, which is a marker of resorbtive bones in the blood was measured using a commercially available ELISA kit ("RatLaps ELISA kit, Nordic Bioscience Diagnostics).

In addition, over time the blood was collected for measurements of the concentration of PTH in the blood on day 16 introduction. The blood was collected in each group from the tail vein immediately before oral introduction of the at 0.25, of 0.5, 1, 2 and 4 hours after that and got the serum. For the measurement of PTH used a commercially available ELISA kit (rat intact PTH ELISA kit, Immutopics).

The measurement results ICTP in blood are shown in table 65, and the results of the measurement of PTH in the blood are shown in table 66.

Table 65
The ICTP concentration in blood (ng/ml)
Group A29,21±5,14
Group B20,93±3,18
Group C26,10±3,45
Group Dto 21.77±3,34
Group E18,84±2,356

The average value of the ± standard deviation, n=5

Table 66
The concentration of PTH(1-84) (PG/ml)
0 h0.25 hour0.5 hour1 hour2 hours4 hours
Group A29,45±8,6726,74±of 6.4948,15±10,1333,93±7,0937,29±14,8455,83±18,16
Group B36,83±accounted for 14.4553,65±56,3156,55±21,7135.70 barm�B1; 21,3041,94±20,8546,84±14,62
Group C31,19±16.28 per371,21±77,74370,78±98,28177,39±96,06117,51±123,1256,50±12,29
Group D27,12±4,58407,35±134,53418,87±154,78279,76±117,98115,50±74,9858,84±x 16.75

The average value of the ± standard deviation, n=5

When osteoporosis is supposed to be treated by increasing the concentration of PTH in the blood based on the inhibition of the action of the calcium receptor, the connection that is used for this purpose must have at least the following properties.

(i) the Connection has sufficient antagonistic action on the calcium receptor. In other words, the connection has a relatively low value of the IC50. In the description of WO 99/51241 stated: "In General, a compound that demonstrates a low value IC50in the analysis of the inhibition of the calcium receptor, represents the best connection. The connection that shows the value of the IC50not less than 50 μm, is considered as inactive. The preferred connection is set IC50not more than 10 μm, more preferably 1 μm, and most preferably not more is it than 0.1 μm" .

(ii) Introducing the compound causes a sufficient increase in the concentration of PTH in the blood.

(iii) concentrations in the blood after administration of the compounds over time are not permanent. It is desirable that the concentration of PTH returned to the level before the introduction 3-4 hours after administration of the compound.

Moreover, it is preferred to have the following two aspects.

(1) Introducing the compound did not inhibit the actions of agents that suppress bone resorption, such as estrogen and the like.

(2) the Effect of the connection, causing the secretion of PTH, is not inhibited by agents that inhibit the resorption of bone, such as estrogen and the like.

When considering the results of the above tests it is evident that the compound of the present invention has the above properties.

With regard to paragraph (i), as shown in tables 1-60, the value of the IC50for compounds of the present invention is not more than 1 μm, and the connection has sufficient antagonistic action on the calcium receptor. The compound of the present invention is considered preferable from the viewpoint of the magnitude of the IC50.

With respect to item (ii), as shown in tables 61 and 62, the concentration of PTH in the serum after 15 minutes was 1.8-3.3 times higher (connection, where n=0) and 1.8 R is for the above (connection, where n=1) than for the control, and it was confirmed that the compound of the present invention has an excellent effect of promoting the secretion of PTH.

With respect to item (iii), as shown in table 62, the secretion of PTH under the action of the compounds according to the present invention reaches a maximum at 15 minutes after administration sharply reduced after this and returned to the concentration of PTH before the introduction of about 1-2 hours. From this aspect it is clear that the compound of the present invention is excellent. In contrast, in the reproduced studies of NPS-2143 according to the link, it was confirmed a long action NPS-2143, promoting secretion.

With regard to paragraph (1), as shown in table 65, the comparison of the sham control group subjected to sham surgery and the control group revealed an increase in ICTP due to the removal of the ovaries, confirming thus the promotion resorbtive bones. This increase is suppressed by the introduction of only estrogen and concomitant introduction of the compounds of example 1-1 shows not change the ability of estrogen to suppress.

With regard to paragraph (2), as shown in table 66, did not reveal differences in the amount of PTH in the blood before the introduction between groups. In the study of changes over time is avicenia PTH in the blood was observed with the introduction of exclusively estrogen, however, a transient increase was observed in the group, where he entered the compound of example 1-1, and in the group with concomitant introduction of the compound of example 1-1 and estrogen.

Industrial applicability

As is evident from the above experimental example 1, the compound of formula (1) according to the present invention has an excellent antagonistic activity against calcium receptor. Accordingly, it is expected that the compound is useful as a therapeutic drug for diseases involving abnormal calcium homeostasis, such as osteoporosis, hypoparathyroidism, osteosarcoma, periodontal disease, bone fractures, osteoarthritis, chronic rheumatoid arthritis, disease Paget, humoral hypercalcemia, autosomal dominant hypercalceimia, Parkinson's disease, dementia and the like. As is clear from the experimental examples 2 and 3, the connection of the present invention has a temporary promoting the secretion of PTH action, and as follows from the experimental example 4, it has weak inhibitory activity against metabolic enzyme CYP2D6. Accordingly, the compound is particularly useful as a therapeutic agent for the treatment of osteoporosis.

Moreover, as is clear from the experimental p is the iMER 5, the compound of the present invention did not inhibit the actions of agents that suppress bone resorption, such as estrogen and the like, and PTH-secreting action of the compounds according to the present invention is not inhibited by agents that inhibit the resorption of bone, such as estrogen and the like. Consequently, the use of combinations of compounds of the present invention and agents that suppress bone resorption, such as estrogen and the like, is regarded as extremely effective in osteoporosis.

This application is based on patent application No. 119131/2003 filed in Japan, the contents of which are incorporated in this description by reference.

1. The compound represented by the following formula (I):

where n is 0 or 1,

p is an integer from 1 to 3,

R1represents a hydroxyl group or a C1-6CNS group,

R2and R3are the same or different and each represents a hydrogen atom, hydroxyl group, halogen atom, amino group, C1-7acylamino group, halogen-C1-6alkyl group, a carboxyl group, a C1-6alkoxycarbonyl group, C1-6CNS group, halogen, C1-6CNS group, C1-6alkylen the th group, hydroxy-C1-6alkyl group, a C2-6alkenylphenol group, phenylalkyl group, phenyl group, di(C1-6alkyl)amino group, a nitrogroup, morpholinopropan, or R2and R3combined with the formation of ethylenoxide,

X1represents-C=C - or-C=N-,

Z represents-S-, -SO-, -SO2-, -(CH2)m1-O-, -O-(CH2)m1-, -(CH2)m2-NH-, -NH-(CH2)m2-C1-4alkylenes group or a C2-4alkynylamino group,

where each of m1 and m2 is an integer from 0 to 2,

X2represents-C=C-,

R4represents a C1-6alkyl group or a C3-6cycloalkyl group,

R5represents a hydrogen atom,

Y represents a carbon atom or a nitrogen atom, and

R6, R7and R8are the same or different and each represents a hydrogen atom, a halogen atom, a C1-6alkyl group, a C1-6CNS group or halogen C1-6alkyl group, or adjacent R6and R7merged to form-CH=CH-CH=CH-,

provided that when both R2and R3represent hydrogen atoms, n is 1,

its pharmaceutically acceptable salt or optically active form./p>

2. The compound according to claim 1, which has a structure represented by the following formula (1'):

wherein each symbol is as defined in claim 1, or its pharmaceutically acceptable salt.

3. The compound according to claim 1 or 2, where n is 1, or its pharmaceutically acceptable salt or optically active form.

4. The compound according to claim 3, where

n is 1,

p is 1,

R1represents a hydroxyl group or a C1-6CNS group,

R2and R3are the same or different and each represents a hydrogen atom, hydroxyl group, halogen atom, amino group, C1-7allmenalp, triptorelin group, C1-6alkoxycarbonyl group, C1-6CNS group, C1-6alkyl group, hydroxy-C1-6alkyl group, a C2-6alkenylphenol group, phenyl group, benzyl group, di(C1-6alkyl) amino group or a nitro-group,

or R2and R3combined with the formation of ethylenoxide,

X1represents-C=C - or-C=N-,

X2represents-C=C-,

Z represents-S-, -SO-, -SO2-, -(CH2)m1-O-, -O-(CH2)m1-, -(CH2)m2-NH-, -NH-(CH2)m2-C1-4alkylenes groups is or 2-4alkynylamino group,

where each of m1 and m2 is an integer from 0 to 2,

R4represents a C1-6alkyl group or a C3-6cycloalkyl group,

R5represents a hydrogen atom,

Y represents a carbon atom or a nitrogen atom, and

R6, R7and R8are the same or different and each represents a hydrogen atom, a halogen atom, a C1-6alkyl group or a C1-6CNS group, or adjacent R6and R7merged to form-CH=CH-CH=CH-,

its pharmaceutically acceptable salt or optically active form.

5. The compound according to claim 4, where

n is 1,

p is 1,

R1represents a hydroxyl group or a C1-6CNS group,

R2and R3are the same or different and each represents a hydrogen atom, a halogen atom, a C1-6CNS group or a C1-6alkyl group,

X1represents-C=C-,

Z represents-S-, -SO-, -SO2-, -(CH2)m1-O-, -O-(CH2)m1-, -CH2-NH-, -NH-CH2-, methylene or vinile,

where m1 represents 0 or 1,

X2represents-C=C-,

R4presented yet a methyl group or cyclopropyl group,

R5represents a hydrogen atom,

Y represents a carbon atom or a nitrogen atom, and

R6, R7and R8are the same or different and each represents a hydrogen atom, halogen atom or C1-6alkyl group, or adjacent R6and R7merged to form-CH=CH-CH=CH-,

its pharmaceutically acceptable salt or optically active form.

6. The compound according to claim 3, selected from the group consisting of

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoic acid,

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-3-methoxybenzoic acid,

methyl-4-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoate,

4-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoic acid,

4-[2-[1-[(2R)-3-[[1-(quinoline-3-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoic acid,

4-[2-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoic acid,

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoic acid,

3-[2-[1-[(2R)-3-[[1(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoic acid,

4-[2-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenyl]vinyl]benzoic acid,

3-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenylthio]benzoic acid,

4-[2-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenyl]vinyl]benzoic acid,

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]for 3,5-dimethylbenzoic acid,

4-[2-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]for 3,5-dimethylbenzoic acid,

4-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]benzyl]benzoic acid,

3-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]benzyl]benzoic acid,

4-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenylthio]benzoic acid,

4-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenylsulfinyl]benzoic acid,

4-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenylsulfonyl]benzoic acid,

4-[[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenylamino]methyl]benzoic acid,

2-[[2-[1-[(2R)-3-[[(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]methyl]benzoic acid,

3-[[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]methyl]benzoic acid,

4-[[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]methyl]benzoic acid,

3-[[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]methyl]benzoic acid,

4-[[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]methyl]benzoic acid,

3-fluoro-4-[[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]methyl]benzoic acid,

4-[[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]methyl]-3-methylbenzoic acid,

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]for 3,5-dimethoxybenzoic acid,

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-3-nitrobenzoic acid,

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-2-nitrobenzoic acid,

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-3-chlorbenzoyl acid,

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxy is robaxi]ethyl]phenoxy]-2-chlorbenzoyl acid,

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-2-triftorperasin acid,

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-3-triftorperasin acid,

4-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-3-fermenting acid,

4-[2-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]benzoic acid, and

4-[2-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenoxy]-5-methylbenzoic acid,

its pharmaceutically acceptable salt or optically active form.

7. The compound according to claim 1 or 2, where n is 0, its pharmaceutically acceptable salt or optically active form.

8. The connection according to claim 7, where

n is 0,

p is 1,

R1represents a hydroxyl group or a C1-6CNS group,

R2and R3are the same or different, each represents a hydrogen atom, hydroxyl group, halogen atom, amino group, C1-7allmenalp, triptorelin group, C1-6alkoxycarbonyl group, C1-6CNS group, C1-6alkyl group, hydroxy-C1-6alkiline the group, With2-6alkenylphenol group, phenyl group, benzyl group, di(C1-6alkyl) amino group or a nitro-group, or

R2and R3combined with the formation of ethylenoxide,

X1represents-C=C - or-C=N-,

X2represents-C=C-,

R4represents a C1-6alkyl group or a C3-6cycloalkyl group,

R5represents a hydrogen atom,

Y represents a carbon atom or a nitrogen atom, and

R6, R7and R8are the same or different and each represents a hydrogen atom, a halogen atom, a C1-6alkyl group or a C1-6CNS group, or adjacent R6and R7merged to form-CH=CH-CH=CH-,

its pharmaceutically acceptable salt or optically active form.

9. The connection of claim 8, where

n is 0,

p is 1,

R1represents a hydroxyl group or a C1-6CNS group,

R2and R3are the same or different and each represents a hydrogen atom, hydroxyl group, halogen atom, amino group, C1-7acylamino group, triptorelin group, C1-6alkoxycarbonyl group, C1-6CNS group, C1- alkyl group, hydroxy-C1-6alkyl group, a C2-6alkenylphenol group, phenyl group, benzyl group, di(C1-6alkyl)amino group or a nitro-group, or R2and R3combined with the formation of ethylenoxide,

X1represents-C=C - or-C=N-,

X2represents-C=C-,

R4represents a methyl group or cyclopropyl group,

R5represents a hydrogen atom,

Y represents a carbon atom, and

R6, R7and R8are the same or different and each represents a hydrogen atom, a halogen atom, a C1-6alkyl group or a C1-6CNS group, or adjacent R6and R7merged to form-CH=CH-CH=CH-,

its pharmaceutically acceptable salt or optically active form.

10. The connection according to claim 7, selected from the group consisting of 2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-chloro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-the ENT-3-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(2,3-debtor-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(2-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-ethyl-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

3-methyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-5-carboxylic acid,

methyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-3,5-in primary forms,

2'-[(cyclopropyl)[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[(cyclopropyl)[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-is hydroxypropoxy]ethyl]-3-methylbiphenyl-5-carboxylic acid,

2'-[(cyclopropyl)[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[(cyclopropyl)[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-methoxyphenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

3-methyl-2'-[1-[(2R)-3-[[1-(3,4-dimetilfenil)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-methoxyphenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-ethylphenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-2,5-differenl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methoxybiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-2-methoxybiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-hydroxypropoxy]ethyl]-3-(trifluoromethyl)biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(2-fluoro-4-methoxyphenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-(trifluoromethyl)biphenyl-4-carboxylic acid,

3-ethyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3,4-dichlorophenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-(trifluoromethyl)biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-isopropylidene-4-carboxylic acid,

3-ethyl-2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-isopropylidene-4-carboxylic acid,

2-chloro-6-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenyl]pyridine-3-carboxylic acid,

2'-(1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-propylbiphenyl-4-carboxylic acid,

2,3-dimethyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-propylbiphenyl-4-carboxylic acid,

2-chloro-6-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan--yl]amino]-2-hydroxypropoxy]ethyl]phenyl]pyridine-3-carboxylic acid,

3,5-dimethyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-m-terphenyl-4'-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-2,3-dimethylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl] - for 3,5-dimethylbiphenyl-4-carboxylic acid,

4-(hydroxymethyl)-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-3-carboxylic acid,

3-isobutyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-isobutylphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-4-(hydroxymethyl)biphenyl-3-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-(2-methyl-1-propenyl)biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-hydroxybiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methyl shall ropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-hydroxybiphenyl-4-carboxylic acid,

3-ethyl-2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-isopropylidene-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-(1-methylpropyl " biphenyl-4-carboxylic acid,

2-methyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

3-methyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

4-fluoro-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-3-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3,4-dichlorophenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-2-methylbiphenyl-4-carboxylic acid,

6-fluoro-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-3-carboxylic acid,

3-fluoro-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-chlorophenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3,4-dichlorophenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-carboxylic acid,

2-fluoro-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[(cyclopropyl)[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[(cyclopropyl)[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-3-forbiden-4-carboxylic acid,

2'-[(cyclopropyl)[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-2-forbiden-4-carboxylic acid,

2'-[(cyclopropyl)[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-2-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3,4-dichlorophenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-2-forbiden-4-carboxylic acid,

3-chloro-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-nitrobiphenyl-4-carboxylic acid,

3-amino-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

3-(acetylamino)-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

3-chloro-2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]am is but]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-methoxy-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2,3-dihydro-5-[2-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenyl]benzofuran-7-carboxylic acid,

2,6-dimethyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-2,6-dimethylbiphenyl-4-carboxylic acid,

3-(dimethylamino)-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2,3-dihydro-5-[2-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]phenyl]benzofuran-7-carboxylic acid,

3-benzyl-2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methoxybiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methoxybiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methoxybiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-fluoro who enyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-2-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-2-methylbiphenyl-4-carboxylic acid,

4-methyl-2'-[1-[(2R)-3-[[1-(naphthalene-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-3-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-4-methylbiphenyl-3-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3,5-dichlorophenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(2,5-differenl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(5-chloro-2-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-triptoreline)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(5-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3,5-dateformatter)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-methyl-3,5-acid)-2-methylpropan-2-yl]and the Ino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3,5-acid)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-triptoreline)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-tert-butylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-tert-butylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-tert-butylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methoxybiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-morpholinomethyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-(triptoreline)biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-trifluoromethyl-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-(hydroxymethyl)biphenyl-4-carboxylic acid, and

2-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-carboxymethyl-4-carboxylic acid,

its pharmaceutically acceptable salt or optically active form.

11. The compound according to claim 1, represented by the following formula (I), its pharmaceutically acceptable salt or optically active form

where R1represents a hydroxyl group or a C1-6CNS group,

R2represents a hydroxyl group, a halogen atom, an amino group, a C1-7allmenalp, halogen, C1-6alkyl group, a C1-6alkoxycarbonyl group, C1-6CNS group, halogen, C1-6CNS group, C1-6alkyl group, hydroxy-C1-6alkyl group, di(C1-6alkyl)amino group or a nitro-group,

R4represents a C1-6alkyl group or a C3-6cycloalkyl group,

R6represents a halogen atom, a C1-6alkyl group, a C1-6CNS group or halogen C1-6alkyl group, or when R7represents a connecting group, R6and R7associated with the formation of-CH=CH-CH=CH-, and

R7represents a hydrogen atom, a halogen atom, a C1-6alkyl group, a C1-6CNS group or halogen C1-6alkyl group.

12. The compound according to claim 1, represented by the following form of the Oh (1'"), its pharmaceutically acceptable salt or optically active form

where R2represents a C1-6alkyl group,

R4represents a methyl group or cyclopropyl group,

R6represents a halogen atom or C1-6alkyl group, and

R7represents a hydrogen atom, a halogen atom, a C1-6alkyl group, a C1-6CNS group or halogen C1-6alkyl group.

13. The connection according to item 11 or 12, selected from the group consisting of

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-chloro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(2-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-Carbo the OIC acid,

2'-[1-[(2R)-3-[[1-(4-ethyl-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-5-carboxylic acid,

2'-[(cyclopropyl)[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[(cyclopropyl)[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]methyl]-3-methylbiphenyl-4-carboxylic acid,

3-methyl-2'-[1-[(2R)-3-[[1-(3,4-dimetilfenil)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-methoxyphenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-ethylphenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

3-ethyl-2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]and the Ino]-2-hydroxypropoxy]ethyl]-3-isopropylidene-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-propylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-isobutylphenyl-4-carboxylic acid,

3-ethyl-2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-isopropylidene-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-(1-methylpropyl " biphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-chlorophenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[(1-(3,4-dichlorophenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-methoxy-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3,5-dichlorophenyl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-triptoreline)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-ylamino]-2-hydroxypropoxy]ethyl]-3-tert-butylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-tert-butylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-tert-butylbiphenyl-4-carboxylic acid, and

2'-[1-[(2R)-3-[[1-(3-trifluoromethyl-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

its pharmaceutically acceptable salt or optically active form.

14. The connection 13, selected from the group consisting of

2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

2'-[1-[(2R)-3-[[1-(3-chloro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid and

2'-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid,

its pharmaceutically acceptable salt or optically active form.

15. The connection 14, which represents a 2'-[1-[(2R)-3-[[1-(3-fluoro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid, its pharmaceutically acceptable salt or opticallyactive form.

16. The connection 14, which represents a 2'-[1-[(2R)-3-[[1-(4-chloro-3-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid, its pharmaceutically acceptable salt or optically active form.

17. The connection 14, which represents a 2'-[1-[(2R)-3-[[1-(3-chloro-4-were)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid, its pharmaceutically acceptable salt or optically active form.

18. The connection 14, which represents a 2'-[1-[(2R)-3-[[1-(4-chloro-2-forfinal)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]ethyl]-3-methylbiphenyl-4-carboxylic acid, its pharmaceutically acceptable salt or optically active form.

19. Therapeutic drug for the treatment of osteoporosis, comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to any one of claims 1 to 18, its pharmaceutically acceptable salts or optically active forms as the active ingredient.

20. Therapeutic drug for the treatment of osteoporosis according to claim 19, where the active ingredient is a compound according to any one of p-6, its pharmaceutically acceptable salt or optically active form.

21. Therapeutic drug for the treatment of osteoporosis according to claim 19, where the active ingredient is a compound will love of claims 7-10, its pharmaceutically acceptable salt or optically active form.

22. Therapeutic drug for the treatment of osteoporosis according to claim 19, where the active ingredient is a compound according to any one of § § 11-18, its pharmaceutically acceptable salt or optically active form.

23. Therapeutic drug for the treatment of osteoporosis according to any one of p-22, which is designed for concomitant use with other therapeutic drug for the treatment of osteoporosis.

24. Therapeutic drug for the treatment of osteoporosis in item 23, where another therapeutic drug for the treatment of osteoporosis selected from the group consisting of a calcium agent, vitamin D, vitamin K, drug female hormone, drug, antagonist of estrogen, anabolic steroid, parathyroid hormone drug, drug calcitonin drug bisphosphonates and drug ipriflavone.

25. A method of treating osteoporosis, comprising introducing an effective amount of a compound according to any one of claims 1 to 18, its pharmaceutically acceptable salts or optically active form to a patient suffering from osteoporosis.

26. The calcium antagonist receptor, comprising a pharmaceutically acceptable carrier, and effective the th number of compounds according to any one of claims 1 to 18, its pharmaceutically acceptable salts or optically active forms as the active ingredient.

27. The calcium antagonist receptor on p, where the active ingredient is a compound according to any one of p-6, its pharmaceutically acceptable salt or optically active form.

28. The calcium antagonist receptor on p, where the active ingredient is a compound according to any one of claims 7-10, its pharmaceutically acceptable salt or optically active form.

29. The calcium antagonist receptor on p, where the active ingredient is a compound according to any one of § § 11-18, its pharmaceutically acceptable salt or optically active form.

30. Promoting allocation of PTH agent, comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to any one of claims 1 to 18, its pharmaceutically acceptable salts or optically active forms as the active ingredient.

31. Promoting allocation of PTH agent according to item 30, where the active ingredient is a compound according to any one of p-6, its pharmaceutically acceptable salt or optically active form.

32. Promoting allocation of PTH agent according to item 30, where the active ingredient is a compound according to any one of claims 7-10, its pharmaceutically acceptable salt or optically active form.

33. The way the adequate allocation of PTH agent according to item 30, where the active ingredient is a compound according to any one of § § 11-18, its pharmaceutically acceptable salt or optically active form.



 

Same patents:

FIELD: organic chemistry, medicine.

SUBSTANCE: invention reports about preparing new substituted derivatives of 2-dialkylaminoalkylbiphenyl of the general formula (I):

wherein n = 1 or 2; R1 means cyano-group (CN), nitro-group (NO2), SO2CH3, SO2CF3, NR6aR7a, acetyl or acetamidyl; R2 means hydrogen atom (H), fluorine atom (F), chlorine atom (Cl), bromine atom (Br), cyano-group (CN), nitro-group (NO2), CHO, SO2CH3, SO2CF3, OR6, NR6R7, (C1-C6)-alkyl, acetyl or acetamidyl being alkyl can comprise one or more similar or different substitutes taken among halogen atom or hydroxy-group; or R1 and R mean in common group -OCH2O, -OCH2CH2O, CH=CHO, CH=C(CH3)O or CH=CHNH; R3 means H, F, Cl, Br, CN, NO2, CHO, SO2CH3, SO2CF3, OR6, NR6R7, (C1-C6)-alkyl, acetyl or acetamidyl being alkyl can comprise one or more similar or different substitutes taken among halogen atom or hydroxy-group; R4 and R5 have similar or different values and mean hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R6 and R7 have similar or different values and mean hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R6a means hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R7a means unsubstituted (C1-C6)-alkyl as their bases and/or salts of physiologically acceptable acids, with exception of compound representing 4-chloro-2'-dimethylaminomethylbiphenyl-2-carbonitrile and to a method for their preparing. Derivatives of 2-dialkylaminoalkylbiphenyl can be used in medicine for treatment or prophylaxis of pains, inflammatory and allergic responses, depressions, narcomania, alcoholism, gastritis, diarrhea, enuresis, cardiovascular diseases, respiratory ways diseases, cough, psychiatry disorders and/or epilepsy.

EFFECT: valuable medicinal properties of compounds.

13 cl, 2 tbl, 43 ex

The invention relates to new nitromethylene formula (I)

< / BR>
in which A represents C6-C10aryl, thienyl, benzothiazyl; X denotes halogen, cyano, C1-C7alkyl, trifluoromethyl, C2-C7alkoxy, or cryptometer; p is chosen from 0, 1, 2, 3, 4, or 5; Z represents a bond, -CO-NH-, SO2-NH-, a sulfur atom, sulfinyl group or a C2-C7alkenylamine radical; R1, R2, R3and E indicated in paragraph 1

The invention relates to new N-substituted piperidinylmethyl f-ly I, their N-oxide forms, isomers, and salts, where R1- halogen, C1-6alkylsulfonamides And divalent radical-CH2-CH2; -CH2-CH2-CH2- or-CH=CH-; R2is hydrogen or C1-6alkyloxy; L is a radical of formula-Alk-R4, -Alk-OR5, -Alk-NR6R7; Alk-C1-12alcander; R4is hydrogen, cyano, C1-6alkylsulphonyl,1-6allyloxycarbonyl, etc

The invention relates to new compounds used in the pharmaceutical industry for the manufacture of medicines

The invention relates to new benzofuranol derivatives, process for their preparation and to contain these compounds in pharmaceutical compositions

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to R-2-aminoarylpropionic acid amides and pharmaceutical composition comprising thereof that can be used for prophylaxis and inhibition of recruiting and activation of leukocytes, and in treatment of pathologies directly dependent on indicated activation. Invention proposes compound of the general formula (1): wherein A, q, Ph and R have corresponding values, or its pharmaceutically acceptable salt. Also, invention describes a method for preparing amide of the formula (1) and pharmaceutical composition used in prophylaxis of leukocytes activation. Invention provides the development of pharmaceutical composition that can be used for prophylaxis and treatment of damaged tissues caused by enhancing activation of neutrophile granulocytes (polymorphonuclear leukocytes) in inflammation foci. Also, the invention relates to R-enantiomers 2-(aminoaryl)-propionylamides of the formula (1) that can be used for suppression of neutrophyles hemotaxis caused by IL-8. Also, compounds of this invention can be sued in treatment of psoriasis, ulcerous colitis, glomerulonephritis, acute respiratory insufficiency and rheumatic arthritis.

EFFECT: valuable medicinal properties of compounds.

8 cl, 16 ex

The invention relates to pharmaceutically acceptable salts of the compounds of formula (I) or solvate specified salts in which the compound of formula (I) is in the form of (R)-enantiomer, (S)-enantiomer or the racemate

The invention relates to derivatives of N-(4-carbamimidoyl) glycinamide formula (I), where E denotes hydrogen or HE, Q denotes hydrogen or alkyl, R is aryl, cycloalkyl or alkyl substituted radicals R1, R2, R3, R1denotes hydrogen, COOH, COO-alkyl or aryl, R2denotes hydrogen, aryl, cycloalkyl or heteroaryl, R3denotes hydrogen, aryl or HE (in any position other thanposition relative to the nitrogen atom is attached to an alkyl group R) or optional substituted by an amino group, three of the radicals X1-X4denote the group of C(Ra), C(Rb) or C(Rc), and the fourth represents C(Rd), Ra-Rddenote H, HE, NO2dialkylamino, halogen, alkyl, alkoxy, aryloxy, aralkylated, heteroarylboronic, geterotsiklicheskikh, COOH, COO-alkyl, NH-SO2-alkyl, NH-SO2-aryl, two adjacent groups Ra-Rbdenote alkylenedioxy, G1and G2denote hydrogen, HE, the invention relates to intermediate compounds of the formula (IV), (V), (VI) used in the methods of making compounds of formula (I), and are in взаимодействCN, the nitrile of formula (IV) is transformed into amidinopropane C(N-G1)NH-G2

The invention relates to new compounds of the formula (I), where R1is hydrogen or a fragment of ester, E is hydrogen or hydroxy, three of X1-X4denote the group of C(Ra), C(Rb) or C(Rc), and the fourth represents C(Rdor N, where Ra-Rdis hydrogen, alkenyl, quinil, alkenylacyl, alkoxy, alkylamino, alkoxyalkyl, alkoxyalkanols, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkyl, alkoxycarbonylmethyl, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl, allylurea, allylthiourea, alkylsulfonamides, alkylsulfonyl, aminoethoxy, arylalkyl, Allakaket, arylalkyl, arylalkylamine, arylcarboxylic, arylcarboxamide, aryloxy, aryloxyalkyl, arylsulfonyl, arylsulfonamides, carboxy, carboxylic, substituted alkyl, substituted amino, halogen, substituted halogen, cycloalkyl, substituted cycloalkyl, hydroxy, substituted hydroxy, heterocycle, substituted heterocycle, or two adjacent groups of Ra-Rdtogether form the fragment condensed di - or monooxygenase ring or aryl ring

The invention relates to new derivatives of 1,2,3,4-tetrahydronaphthalene formula (I) as (R)-enantiomers, (S)-enantiomers or racemates, in the form of free base or pharmaceutically acceptable salt or solvate, where X is N or CH; Y is NR2-CH2, NR2-CO or CO-NR2; R2represents N or C1-C6-alkyl; R1represents N or C1-C6-alkyl; R3represents phenyl which may be mono - or Disaese4; R4represents H, halogen, CN, CF3WITH1-C6-alkoxy, optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, or COR8; R8represents a heterocyclic ring containing one or two heteroatoms selected from N, O; R9is1-C6-alkyl, ОСНF2HE, halogen, C1-C6-alkoxy, C1-C6-alkoxy - C1-C6-alkyl

The invention relates to new derivatives of 4-(1-piperazinil)benzoic acid of formula I in which Ar represents a mono-, di - or tricyclic aryl having from 6 to 14 carbon atoms, while Ar may have from 1 to 3 substituents selected from the group comprising (C1-C8)alkyl, (C1-C8)alkoxy, halogen, trifluoromethyl; R1selected from the group comprising a hydrogen atom, cycloalkyl containing from 3 to 8 carbon atoms, (C6-C14)aryl, heteroaryl(C1-C6)alkyl, and heteroaryl selected from the group comprising furyl; R2and R3is hydrogen, a solvate and a pharmaceutically acceptable salt

FIELD: medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes dipeptide-nitrile inhibitors of cathepsin K, their pharmaceutically acceptable salts or their esters that are used in therapeutic or prophylaxis treatment of disease of morbid state mediated by cathepsin K.

EFFECT: valuable medicinal properties of inhibitors.

3 cl, 11 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel ester compounds represented by the formula (1): wherein values for R1, R2, A, X, R3, R4, Alk1, Alk2, l, m, D, R8 and R9 are determined in the invention claim. Also, invention relates to inhibitor of matrix metalloproteinase (MTP), a pharmaceutical composition able to inhibit activity of MTP selectively, agents used in treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes mellitus or hypertension wherein the pharmaceutical composition is prepared in capsulated formulation, and to a biphenyl compound of the formula (100) given in the invention description.

EFFECT: valuable medicinal properties of compounds.

53 cl, 78 tbl, 17 ex

FIELD: catalyst preparation methods.

SUBSTANCE: invention relates to alumina-supported catalyst preparation method and employment thereof in reactions of nucleophilic substitution of aromatic halides containing electron-accepting group. In particular, alumina support impregnated with alkali selected from alkali metal hydroxides is prepared by treating alkali metal hydroxide aqueous solution with aluminum oxide in organic solvent followed by drying thus obtained catalyst mixture at temperature not lower than 150°C. Catalyst is, in particular, used to introduce electron-accepting protective groups into organic compounds comprising at least one of -OH, -SH, and -NH, as well as in reaction of substituting amino, thio, or ether group for halogen in a haloarene and in preparation of 2-puperidinobenzonitrile.

EFFECT: simplified preparation of catalyst and regeneration of spent catalyst, and avoided involvement of dangerous reactants.

11 cl, 20 ex

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to biologically active compounds. Invention represents dipeptide nitrile inhibitors of cathepsin K, their pharmaceutically acceptable salts or their esters of the general formula:

wherein X means -CH or nitrogen atom (N); R means (C1-C7)-(lower)-alkyl, (C1-C7)-(lower)-alkoxy-(C1-C7)-(lower)-alkyl, (C5-C10)-aryl-(C1-C7)-(lower)-alkyl or (C3-C8)-cycloalkyl.

EFFECT: valuable biochemical properties of compounds.

6 cl, 12 ex

The invention relates to benzamide derivative of the formula I

< / BR>
where R3represents (1-6C)alkyl or halogen; Q is aryl or heteroaryl, which optionally carries 1, 2, 3, or 4 substituent selected from hydroxy, halogen, cyano, nitro, amino, carboxy, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-3C)alkylenedioxy, (1-6C)alkylamino and so on; R2- (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino or di-[(1-6C)alkyl]amino; p is 0, 1 or 2; q = 0, 1, 2, 3 or 4; R4- aryl, aryl-(1-6C)alkoxy, aryloxy, arylamino, cycloalkyl or heteroaryl and R4optionally carries 1, 2, 3, or 4 substituent selected from halogen, cyano, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino and so on, or its pharmaceutically acceptable salt, or cleaved in vivo ester
Up!