MXPA00003478A

MXPA00003478A - Prostaglandin agonists and their use to treat bone disorders

Info

Publication number: MXPA00003478A
Application number: MXPA/A/2000/003478A
Authority: MX
Inventors: Kimberly O Keefe Cameron; Bruce Allen Lefker; Robert Louis Rosati
Original assignee: Cameron Kimberly O'keefe; Bruce Allen Lefker; Pfizer Inc; Robert Louis Rosati
Priority date: 1997-10-10
Filing date: 2000-04-07
Publication date: 2001-11-21

Abstract

This invention relates to prostaglandin agonists, methods of using such prostaglandin agonists, pharmaceutical compositions containing such prostaglandin agonists and kits containing such prostaglandin agonists. The prostaglandin agonists are useful for the treatment of bone disorders including osteoporosis.

Description

PROSTAGLANDIN AGONISTS BACKGROUND OF THE INVENTION This invention relates to prostaglandin agonists, to pharmaceutical compositions containing said agonists and to the use of said agonists to prevent bone loss or to restore or increase bone mass and to stimulate bone welding, including the treatment of bone disorders. which causes bone loss and / or bone defects in vertebrates and particularly in mammals, including humans. Osteoporosis is a systemic skeletal disease, characterized by a decrease in bone mass and deterioration of bone tissue, with the consequent increase in bone fragility and susceptibility to fracture. In the United States, this disorder affects more than 25 million people, each year causing more than 1.3 million fractures, corresponding to 500,000 spine, 250,000 hip and 240,000 of wrist per year. Hip fractures are the most serious consequence of osteoporosis, with 5-20% of patients dying after one year and incapacitating more than 50% of survivors. Older people are those who are at higher risk of osteoporosis and, therefore, this problem is expected to increase significantly as the population ages. It has been predicted that the incidence of fractures worldwide will increase by more than three times in the next 60 years, estimating a study that will produce more than 4.5 million hip fractures worldwide by the year 2050. Women are more at risk of osteoporosis than men. Women experience a sharp acceleration of bone loss during the five years following menopause. Other factors that increase the risk are tobacco, alcohol abuse, sedentary life and a low calcium intake. Currently there are two main types of pharmaceutical therapy for the treatment of osteoporosis. The first of these is the use of anti-resorption compounds to reduce bone resorption. Estrogens are an example of anti-resorption agent. It is known that estrogen reduces fractures. Likewise, Black et al., In EP 0605193A1, report that estrogens, especially when taken orally, decrease plasma LDL levels and increase those of high density lipoproteins (HDLs) that are beneficial. However, estrogen does not restore bone to the levels of a young adult in the established osteoporotic skeleton. Likewise, however, long-term estrogen therapy has been shown to be related to several disorders such as increased risk of uterine cancer, endometrial cancer and probably breast cancer, which means that many women avoid following this treatment. The remarkable unwanted side effects associated with estrogen therapy are the cause of the need to develop alternative therapies for osteoporosis that have the desired effect on serum LDL, but without causing unwanted effects. A second type of pharmaceutical therapy for the treatment of osteoporosis is the use of anabolic agents to promote bone formation and increase bone mass. It is believed that this class of agents restore bone in the established osteoporotic skeleton. US Pat. No. 4,112,236 discloses certain interphenylene 8-aza-9-dioxothia-11, 12-secoprostaglandins for the treatment of patients with renal insufficiency. In GB 1478281 and GB 1479156 and in U.S. Patent Nos. 4,175,203, 4,055,596, 4,175,203, 3,987,091 and 3,991,106 certain prostaglandin agonists are described which are useful, for example, as vasodilators. kidney US Patent No. 4,033,996 discloses certain 8-aza-9-oxo (and dioxo) -thia-11,12-secoprostaglandins which are useful as renal vasodilators, for the prevention of thrombus formation, to induce release of growth hormone and as regulators of the immune response. In French Patent No. 897,556 certain amino acid derivatives are described for the treatment of neurological, mental or cardiovascular disease. In J. Org. Chem. 26; 1961; 1437, N-acetyl-N-benzyl-p-aminophenylmercaptoacetic acid is described.

U.S. Patent No. 4,761,430 discloses certain arylbenzenesulfonamide compounds as agents that lower the level of lipids. U.S. Patent No. 4,443,447 discloses certain sulfonamidophenylcarboxylic acids as agents that lower the level of lipids. In U.S. Patent No. 3,528,961 certain e-caprolactam derivatives are described as dyes. In US Patent No. 3,780,095, certain acylated anilinocarboxylic acids are disclosed as choleretics. U.S. Patent No. 4,243,678 discloses certain acylhydrocarbyalkylalkanoic acids which have utility in the treatment of gastric ulcers, as inhibitors of the secretion of sebaceous glands and to combat skin inflammation. U.S. Patent No. 4,386,031 discloses certain N-benzoyl-α-anilinoalkanecarboxylic acids as antiallergic agents, thrombotic aggregation inhibitors, anti-inflammatory agents and agents that decrease lipid levels. In addition to osteoporosis, approximately 20-25 million women and an increasing number of men have detectable vertebral fractures as a result of a reduction in bone mass, reporting an additional 250,000 hip fractures each year in the United States alone. The latter case is associated with a mortality rate of 12% in the first two years, with 30% of patients requiring the attention of a nurse at home after the fracture. Although this is already important enough, it is expected that the economic and medical consequences of convalescence due to slow or imperfect welding of these bone fractures will increase due to the aging of the general population. It has been shown that estrogens (Bolander et al., 38th Annual Meeting of the Orthopedic Research Society, 1992) improve the welding quality of appendiceal fractures. Accordingly, estrogen replacement therapy could be a procedure for the treatment of fracture welding. However, the compliance of estrogen therapy by the patient is relatively poor due to its side effects, such as the resumption of menstruation, mastodynia and increased risk of uterine cancer, a perceived increase in the risk of breast cancer and the concomitant use of progestins. Also, men will probably object to using estrogen treatment. It is clear that there is clearly a need for a therapy that is beneficial for patients who have suffered debilitating bone fractures and that increases compliance with the therapy by the patient. Although there are several therapies for osteoporosis the need still exists, researching continuously in this field of technique, to find alternative therapies for osteoporosis. Likewise, therapies are needed that stimulate bone regeneration in the areas aa skeletal faith where said defects are caused or produced, for example, by bone tumors. Likewise, therapies are needed that stimulate bone regeneration in skeletal areas where grafting is necessary Bones BRIEF DESCRIPTION OF THE INVENTION This invention relates to the compounds of Formula / A ^ / Q ^ G ^ B ^ Z I ^ M Formula I prodrugs thereof and pharmaceutically acceptable salts of said compounds and prodrugs wherein A is SO 2 or CO; G is Ar, Ar1-V-Ar2, -A-alkylene (C6), Ar-CONH-alkylene (C6-6), R1R2-amino, oxyalkylene (Cr6), amino substituted with Ar or amino substituted with Ar- alkylene (C C4) and R11, wherein R11 is H or alkyl (CrC8) R1 and R2 can be taken separately and are independently selected from H and alkyl (CrC8), or R1 and R2 are attached to the nitrogen atom of the group amino to form a six-membered azacycloalkyl, said azacycloalkyl optionally containing an oxygen atom and optionally being mono-, di- or tri-substituted independently with up to two oxo, hydroxy, (C1-C4) alkyl, fluoro or chloro.

B is N or CH; Q is -alkylene (C2-C6) -W-alkylene (d-C3) -, each said alkyl being optionally substituted with up to four substituents independently selected from fluoro or alkyl (C, -C4), -alkylene (C4) -C8) - said alkylene being optionally substituted with up to four substituents independently selected from fluoro or (C-1-C4) alkyl, -X-C 1 -C 5 -alkylene -, said alkylene being optionally substituted with up to four independently selected substituents between fluoro or (C1-C4) alkyl, (C1-C5) -X- alkylene, said alkylene being optionally substituted with up to four substituents independently selected from fluoro or alkyl (CrC4), -alkylene (C -? - C3) - X-alkylene (C -? - C3) - each said alkyl being optionally substituted with up to four substituents independently selected from fluoro or (C1-C4) alkyl, (C2-C4) alkylene-WX-alkylene (C0-) C3) -, said alkalis ca one of them optionally substituted with up to four substituents independently selected from fluoro or (C4) alkyl, (C0-C4) -XW-alkylene (C-? -C3) -, each said alkyl being optionally substituted with up to four substituents independently selected from fluoro or alkyl (CrC), -alkylene (C2-C5) -WXW-alkylene (CrC3) -, wherein the two W's are independent of each other, said alkylene being each optionally substituted with up to four substituents independently selected from fluoro or (C1-C4) alkyl, -alkylene (CrC4) -ethylene-alkylene (C? -C) -, said alkyl ethers and said ethylene being each optionally substituted with up to four substituents independently selected from fluoro or (C1-C4) alkyl, -alkylene (CrC4) -ethylene-alkylene (Co-C2) -X-alkylene (C0-C5), said alkyl ethers and said ethylene being each optionally substituted with up to four substituents independently selected from fluoro or (C1-C4) alkyl, -alkylene (CrC) -ethylene-alkylene (C0-C2) -XW-alkylene (CrC3), said alkylene and said ethenylene each being optionally substituted with up to four substituents independently selected from fluoro or alkyl (CrC4), -alkylene (C? -C4) -ethenylene-alkylene (C1-C4), said alkyl ethers and said ethenylene each being optionally substituted with up to four substituents independently selected from fluoro or alkyl (CrC4), -alkylene (C? -C4) -ethylene-X-alkylene (Co-C3), said alkyl ethers and said ethylene being each optionally substituted with up to four substituents independently selected from fluoro or (C 1 -C 4) alkyl, Z is carboxyl, alkoxy (Ci-Cβ) carbonyl, tetrazolyl, 1,4-oxadiazolyl, 5-oxo-1, 2,4-oxadiazolyl, 5-oxo-1,2, 4-thiadiazolyl, alkyl (C -? - C4) sulfonylcarbamoyl or phenylsulfo nilcarbamoyl; K is a bond, (C1-C9) alkylene, (C1-C4) thioalkylene, alkylene (CrC4) thioalkylene (C1-C4), alkylene (C4) oxyalkylene (C1-C4) or oxyalkylene (C1-C4), said (C 1 -C 9) alkylene optionally monounsaturated and wherein, when K is not a bond, K is optionally mono-, di- or tri- substituted independently with chloro, fluoro, hydroxy or methyl; M is -Ar3, -Ar4-V1-Ar5, -Ar4-S-Ar5, Ar4-SO-Ar5, -Ar4-SO2-Ar5 or -Ar4-O-Ar5; Ar is a five to eight link partially saturated or fully unsaturated ring and optionally has one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two rings of five or six condensed, partially saturated, fully saturated or totally unsaturated, considered independently, and which optionally have one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three rings of five or six condensed, partially saturated, fully saturated or fully unsaturated rings , independently considered, and optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said bicyclic ring or tricyclic ring partially or fully saturated, optionally one or two oxo substituted groups in the ca rbonon, or one or two oxo-substituted groups in the sulfur; or Ar is a fully saturated five to seven link ring having one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; Ar1 and Ar2 are each independently a partially saturated, fully saturated or fully unsaturated five-membered ring and optionally has from one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two rings of five or six condensed links, partially saturated, totally saturated or totally Unsaturated, independently considered, and optionally have one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three rings of five or six condensed, partially saturated, fully saturated or fully unsaturated, independently considered, and optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said ring, bicyclic ring or partially or fully saturated tricyclic ring, optionally one of two oxo-substituted groups on carbon, or one or two oxo-substituted groups on the sulfur; said radicals Ar, Ar1 and Ar2 are optionally substituted on carbon or on nitrogen, on a ring if the radical is monocyclic, on one or both rings if the radical is bicyclic, or on one, two or three rings if the radical is tricyclic, with up to three substituents per radical independently selected from R3, R4 and R5, wherein R3, R4 and R5 are independently hydroxy, nitro, halogen, carboxy, (C -? - C) alkoxy, alkoxy (CrC4,) alkyl (CrC4), alkoxy (C1-C4) carbonyl, alkyl (C? -C7), alkenyl (C2-C7), alkynyl (C2-C), cycloalkyl (C3-C7), cycloalkyl (C3-C7) alkyl ( C1-C4), (C3-C) cycloalkyl, (C1-C4) alkanoyl, formyl, alkanoyl (Cr C8), alkanoyl (C-pCß) alkyl (CrC6), alkanoyl (C -? - C4) amino, alkoxy ( CrC4) carbonylamino, hydroxysulfonyl, aminocarbonylamino or aminocarbonylamino substituted with mono-N-, di-N, N-, di-N, N'- or tri-N, N, N'-alkyl (C4), sulfonamido, alkyl ( C1-C4) sulfonamido, amino, mono-N- or di-N, N-alkyl (Cr C4) amino, ca rbamoyl, mono-N- or di-N, N-alkyl (C C4) carbamoyl, cyano, thiol, Mi ^^ i ^^ ji ^ alkylthio (Ci-Cß), alkyl (Ci-Cß) sulfinyl, alkyl (C -? - C) sulfonyl or mono-N- or di-N, N-alkyl (CrC4) aminosulfinyl; Ar3, Ar4 and Ar5 are each independently a ring of five to eight links partially saturated, fully saturated or totally unsaturated and optionally having from one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two rings of five or six condensed, partially saturated, fully saturated or totally unsaturated, independently considered, and which optionally have one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three rings of five or six condensed, partially saturated, fully saturated or totally unsaturated, independently considered, and optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, having said ring, bicyclic ring or partial tricyclic ring fully or fully saturated, optionally one or two oxo-substituted groups on the carbon, or one or two oxo-substituted groups on the sulfur; said radicals Ar3, Ar4 and Ar5 are optionally substituted on carbon or on nitrogen, on a ring if the radical is monocyclic, on one or both rings if the radical is bicyclic, or on one, two or three rings if the radical is tricyclic, with up to three substituents per radical independently selected from R31, R41 and R51, wherein R31, R41 and R51 are independently hydroxy, nitro, halogen, carboxy, (C -? - C) alkoxy, (C-1) alkoxy C4,) (C1-C4) alkyl, (C1-C4) alkoxycarbonyl, (C? -C) alkyl, (C2-C7) alkenyl, (C2-C7) alkynyl, (C3-C7) cycloalkyl, (C3) cycloalkyl -C7) alkyl (C -? - C4), (C3-C) cycloalkyl (C1-C4) alkanoyl, formyl, (C? -C8) alkanoyl, (C1-C6) alkanoyl (Ci-C?) Alkyl, alkanoyl ( C1-C4) amino, (C1-C4) alkoxycarbonylamino, hydroxysulfonyl, aminocarbonylamino or aminocarbonylamino substituted with mono-N-, di-N, N-, di-N, N'- or tri-N, N, N'- alkyl (CrC4), sulfonamido, alkyl (Cr C4) sulfonamido, amino, mono-N- or di-N, N-alkyl (CrC4) ami no, carbamoyl, mono-N- or di-N, N-alkyl (C -? - C4) carbamoyl, cyano, thiol, alkylthio (d-Cß), alkyl (Ci-Cß) sulfinyl, alkyl (C? -C ) sulfonyl or mono-N- or di-N, N-alkyl (CC) aminosulfinyl; W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-, -mono-N-alkylene (C4) aminosulfonyl-, sulfonylamino, N-(C1-C4) alkylene sulfonylamino, carboxamido, N-alkylene (C1-C4) carboxamido, carboxyamidoxy, N-C 1 -C 4 alkylene carboxamidoxy, carbamoyl, mono-N-alkylene (C 1 -C 4) carbamoyl, carbamoyloxy or -mono-N-alkylene (C 1 -C 4) carbamoyloxy, wherein said alkyl groups W are optionally substituted on carbon with one to three fluorine atoms; X is a five or six link aromatic ring optionally having one or two heteroatoms independently selected from oxygen, nitrogen and sulfur; said ring being optionally mono-, di- or trisubstituted independently with halogen, alkyl (CrC3), trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C1-C4) alkoxy or carbamoyl; R1, R2, R3, R4, R5, R11 R31, R41 and R51, when they contain an alkyl, alkylene or alkynylene radical are optionally mono-, di- or trisubstituted on the carbon independently with halogen or hydroxy; and V and _fo¡ ^; Hg ^ V1 are each independently a bond, (C1-C4) thioalkylene, alkylenethio (C1-C4), (C1-C4) alkyleneoxy, (C1-C4) oxyalkylene, or alkylene (CrC3) optionally mono- or di- substituted independently with hydroxy or fluoro; with the condition that: a. when K is alkylene (C2-C4) and M is Ar3 and Ar3 is cyclopent-1-yl; cyclohex-1-yl, cyclohept-1-yl or cycloot-1-yl, then said cycloalkyl substituents (C5-C8) are not substituted at one position with hydroxy; and b. when K is a link; G is phenyl, phenylmethyl, substituted phenyl or substituted phenylmethyl; Q is alkylene (C3-C8) and M is Ar3 or Ar4-Ar5, then A is sulfonyl. A preferred group of compounds, designated as group A, comprises those compounds having the formula I, as shown above, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein B is N; Z is carboxyl, alkoxy (CrC6) carbonyl or tetrazolyl; Ar is phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, 2H-imidazolyl, 2.imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, 1,2-oxadiazolyl, 1,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1,3, 4-Oxadiazolyl, 1,2,3-triazolyl, 1,4-triazolyl, 2H-pyranyl, 4H-pyranyl, pyridyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thomorpholinyl, piperazinyl, 1, 3,5-triazinyl, 1,4-triazinyl, azepinyl, oxepinyl, thiepinyl, cyclopentenyl, cyclohexenyl, benzo (b) thienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, & ** > > '-. ** "isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl and 1,4-benzodioxane; Ar1, Ar2, Ar3, Ar4 and Ar 5 are each independently cyclopentyl, ciciohexilo, cicioheptilo, cyclooctyl, phenyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, soxazolilo, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 2H pyrrolyl, 3H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1, 3-dioxolanyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, 1, 2,3-oxadiazolyl, 1 , 2,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1,4-oxadiazolyl, 1,2,3-triazolyl, 1,4-triazolyl, 2H-pyranyl, 4H-pyranyl, pyridyl, piperidinyl , 1, 4-dioxanyl, morpholinyl, 1, 4-dithianyl, thiomorpholinyl, piperazinyl, 1, 3,5-triazinyl, 1, 2,4-triazinyl, azepinyl, oxepinyl, thiepinyl, 1, 2,4-diazepinyl, cyclopentenyl I , cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclooctadienyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, 1H-¡so¡ndol¡lo, indolinyl, cyclopenta (b) pyridinyl, pyran (3,4-b) pyrrolyl, benzofuryl, isobenzofuryl, benzo (b) thienyl, benzo (c) thienyl, 1H-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl, benzatriazolilo, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1, 8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1, 3-benzopyranyl, 1,4-benzodioxane, pyrido (3,4-b) -pyridinyl, pyrido (3,2-b) - pyridinyl, pyrido (4,3-b) -pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1 H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1, 2-benzoxazinyl and 4H-1,4-benzoxazinyl; and X is tetrahydrofuranyl, phenyl, thiazolyl, thienyl, pyridyl, pyrrazolyl, furanyl or pyrimidinyl, wherein X is optionally mono-, di- or trisubstituted - ^^ - «Oh- .. ^^^^^^^^^^^^^^ j ^^ gg ^ g > g | g ^^^^^^^^^^^^^^ independently with chlorine, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl; wherein each of said groups Ar, Ar1 and Ar2 are optionally substituted on carbon or on nitrogen with up to three substituents independently selected from R3, R4 and R5; each of said groups Ar, Ar1 and Ar2 are optionally and independently substituted on the carbon or on the sulfur with one or two oxo groups; each of said groups Ar3, Ar4 and Ar5 are optionally substituted on the carbon or on the nitrogen independently with up to three R31, R41 and R51 and each of said groups Ar3, Ar4 and Ar5 are optionally and independently substituted on carbon or on Sulfur with one or two oxo groups. A group of compounds within group A, designated as group B, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein A is CO; G is oxyalkylene (CrC6); Q is -alkylene (C2-C6) -O-alkylene (C? -C3) -, -alkylene (C4-C8) -, said (C4-C8) alkylene being-optionally substituted with up to four substituents independently selected from fluoro or (C 1 -C 4) alkyl, -X-alkylene (C 2 -Cd) -, -alkylene (CrC 5) -X-, -alkylene (C C 3) -X-alkylene (C C 3) -, -alkylene (C 2 -C 4) -OX-alkylene (C0-C3) -, or -alkylene (C0-C4) -XO-alkylene (C -? - C3) -; and X is phenyl, thienyl, furanyl or thiazolyl, wherein X is optionally mono-, di- or trisubstituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl. Another group of compounds that is preferred within group A, HAiMMMMMaafcEhiaaiiiMitflii ^ ^ designated as group C, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein A is CO; G is Ar, Q is -alkylene (C2-C6) -O-alkylene (CrC3) -, (C4-C8) -alkylene, said (C4-C8) -alkylene being optionally substituted with up to four substituents independently selected from fluoro or (C 1 -C 4) alkyl, -X-alkylene (C 2 -C 5) -, -alkylene (CrC 5) -X-, -alkylene (C C 3) -X-alkylene (C C 3) -, (C 2 -C 4) alkylene - OX-alkylene (Co-C3), or alkylene (C0-C4) -XO-alkylene (C C3) -; and X is phenyl, thienyl, furanyl or thiazolyl, wherein X is optionally mono-, di- or trisubstituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl. Another group of compounds that is preferred within group A, designated as group D, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein A is CO; G is R1R2-amino or amino substituted with Ar, or amino substituted with Ar-alkylene (C? -C4) and R11, wherein R11 is H; Q is -alkylene (C2-C6) -O-alkylene (C1-C3) -, (C-C8) -alkylene, said (C4-C8) -alkylene being optionally substituted with up to four substituents independently selected from fluoro or alkyl ( C-1-C4), -X-alkylene (C2-C5) -, -alkylene (C5) -X-, -alkylene (C3) -X-alkylene (C3) -, alkyl (C2-C4) -OX-alkylene (C0-C3) -, or alkylene (Co-C4) -XO-alkylene (C1-C3) -; and X is phenyl, thienyl, furanyl or thiazolyl, wherein X is optionally mono-, di- or t-substituted with chlorine, fluoro, methoxy, dMMlAaMiHailHeiIeI & M ^^ m * mth? difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl; and wherein R1 and R2 can be considered separately and are independently selected from H and (C? -C8) alkyl, or R1 and R2 are taken together to form a five or six link azacycloalkyl, said azacycloalkyl optionally containing a oxygen atom. Another group of compounds that is preferred within group A, designated as group E, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein A is SO2; G is R1R2-amino or substituted amino with Ar and R11; Q is (C 2 -C 6) alkylene-O-alkylene (C Cs) -, (C 4 -C 8) alkylene, said (C -C 8) alkylene being optionally substituted with up to four substituents independently selected from fluoro or alkyl (C 1 -) C4), -X-alkylene (C2-C5) -, -alkylene (C5) -X-, -alkylene (C -? - C3) -X-alkylene (Cr3) -, (C2-C4) alkylene - OX-alkylene (C0-C3) -, or (C0-C4) alkylene-XO-alkylene (CrC3) -; and X is phenyl, thienyl, furanyl or thiazolyl, wherein X is optionally mono-, di- or trisubstituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl; and wherein R1 and R2 can be considered separately and are independently selected from H and (C -? - C8) alkyl, or R1 and R2 are taken together to form a azacycloalkyl of five or six links, said azacycloalkyl optionally containing an oxygen atom. Another group of compounds that is preferred within group A, designated as group F, comprises those compounds, prodrugs of ,. > . ** ..,. f- ^. ~,. -.- L. • ***** £ & £ ». - .... ^. ^. . MMMMIW -..- I ^ -, - jfgftfflfjfc the same and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein A is SO2; G is Ar, Ar-alkylene (CrC2) or Ar1-V-Ar2; Q is (C2-C6) -O-alkylene (C3) alkylene, (C4-C8) alkylene, said (C-C8) alkylene being optionally substituted with up to four substituents independently selected from fluoro or C1-6alkyl C4), -X-alkylene (C2-C5) -, -alkylene (C? -C5) -X-, -alkylene (C? -C3) -X-alkylene (Cr C3) -, (C2-C4) alkylene -OX-alkylene (C0-C3) -, or alkylene (C0-C4) -XO-alkylene (C C3) -; and X is phenyl, pyrimidyl, pyridyl, thienyl, ahydrofuranyl, furanyl or thiazolyl, wherein X is optionally mono-, di- or trisubstituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl. A particularly preferred group of compounds, within the group F, designated as the group FA, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein G is Ar or Ar-alkylene (CrC2) , Ar is phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, siathiazolyl, 1,2,3-triazolyl, 1,4-triazolyl or 1, 3,4-thiadiazolyl, in which each of said Ar groups is optionally substituted on the carbon or on the nitrogen with R1, R2 or R3; Ar 4 is cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, 1,2,3-triazolyl, 1, 2,4-triazoloyl, pyranyl, thiomorpholinyl, piperazinyl, 1, 3,5-triazinyl, 1,4-triazinyl, 1,2,3-triazinyl, azepinyl, oxepinyl or thiepinyl, a ^^^^ j ^^^ gjg in which each of said Ar4 groups is optionally mono-, di- or trisubstituted on the carbon or on the nitrogen with R31, R41 or R51; Ar5 is cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, midazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, 1,2,3-triazolyl. , 1,4-triazolyl, pyranyl, 1,4-dioxanyl, thiomorpholinyl, piperazinyl, 1, 3,5-triazinyl, 1,4-triazinyl, 1,2,3-triazinyl, azepinyl, oxepinyl or thiepinyl , wherein each of said Ar5 is optionally mono-, di- or tri-substituted on the carbon or on the nitrogen with R31, R41 or R51; Q is -alkylene (C5-C7) -, -alkylene (C C2) -X-alkylene (C? -C2) -, -alkylene (C? -C2) -XO- (C C2) -, -alkylene (C2) -C4) -thienyl, -alkylene (C2-C4) -furanyl- or -alkylene (C2-C4) -thiazolyl; X is phenyl, pyridyl, pyrimidyl or thienyl; and said X groups are optionally mono-, di- or trisubstituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl; said -alkylene (C2-C4) -furanyl and -alkylene (C2-C4) -thienyl having a 2.5 substitution pattern, for example, A preferred group of compounds within the group FA, designated as the group FB, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein K is methylene, M is Ar ^ -Ar5, Ar4 -O-Ar5 or Ar4-S-Ar5 and Ar is phenyl, pyridyl, pyrazolyl, imidazolyl, pyrimidyl, thienyl or thiazolyl, wherein A is optionally mono-, di-, or trisubstituted on carbon or on nitrogen with R3 , R4 or R5. A preferred group of compounds within the FB group, designated as the FC group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein M is Ar4-Ar5; Ar is phenyl, pyridyl or imidazolyl; Ar 4 is phenyl, furanyl or pyridyl; Ar5 is cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, imidazolyl, pyrimidyl, thienyl, pyridazinyl, pyrazinyl, midazolyl, pyrazolyl or thiazolyl, wherein Ar, Ar4 and Ar5 are optionally mono-, di-, or trisubstituted with chlorine, fluoro , methyl, methoxy, difluoromethoxy, trifluoromethyl or trifluoromethoxy. An especially preferred group of compounds within the group FC, designated as the FD group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -alkylene (Cs-C7) -. Another especially preferred group of compounds within the group FC, designated as the group FE, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is CH2-X-CH2- and X is metaphenylene optionally mono- or disubstituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl. A preferred group of compounds within the FE group are those compounds and pharmaceutically acceptable salts and prodrugs of á? astfikMte. The same, selected from the acid (3 - (((pyridin-3-sulfonyl) - (4-pyrimidin-5-yl-benzyl) -amino) -methyl) -phenol) -acetic, 3 - (((5-phenyl-furan-2-ylmethyl) - (pyridin-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid, acid (3 - ((( pyridin-3-sulfonyl) - (4-pyrimidin-2-yl-benzyl) -amino) -methyl) -phenyl) -acetic acid (3 - (((pyridin-3-sulfonyl) - (4-thiazole -2- 5-yl-benzyl) -amino) -methyl) -phenyl) -acetic acid and (3 - (((4-prazraz-2-yl-benzyl) - (pyridine-3-sulfonyl) ) -amino) -methyl) -phenyl) -acetic. An especially preferred compound within the group FE is the compound wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar4-Ar5, wherein Ar4 is a furanyl ring and Ar5 is phenyl, wherein said phenyl radical is substituted in the composition 5 of said furanyl ring, and Q is -CH2-X-CH2- wherein X is metaphenylene. Another especially preferred compound within the group FE is the compound wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar4-Ar5, in which Ar4 is phenyl and Ar5 is pyrimid-2-yl and said pyrimid-2-yl radical is substituted in the composition 4 of said phenyl ring, and Q is -CH2-X-CH2- wherein X is metaphenylene. Another especially preferred compound within the group FE is the compound wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar4-Ar5, in which Ar4 is phenyl and Ar5 is thiazol-2-yl and said thiazol-2-yl radical is substituted at the position 4 of said phenyl ring, and Q is -CH2-X-CH2- wherein X is metaphenylene. Another especially preferred compound within the group FE is the compound wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar ^ -Ar5, in which ^ - ^^ ¿¿.Ü .. ^ ^ Afc ^. MÍtM ^ itiüíM ---.

Ar 4 is phenyl and Ar 5 is pyrimid-5-yl and said pyrimid-5-yl radical is substituted at the 4-position of said phenyl ring, and Q is -CH 2 -X-CH 2 - wherein X is metaphenylene. Another especially preferred compound within the group FE is the compound wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar4-Ar5, wherein Ar4 is phenyl and Ar5 is pyrazin-2-yl and said pyrazin-2-yl radical is substituted at the 4-position of said phenyl ring, and Q is -CH2-X-CH2- wherein X is metaphenylene. A preferred group of compound within the group FC, designated as the group G, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -alkylene (C2-C4) -thienyl, -alkylene (C2-C4) -furanyl- or -alkylene (C2-C4) -thiazolyl. An especially preferred compound within the group G is 5- (3 - ((pyridin-3-sulfonyl) - (4-thiazol-2-yl-benzyl) -amino) -propyl) -thiophene-2-carboxylic acid. An especially preferred compound within the group G is the compound, prodrugs thereof and pharmaceutically acceptable salts of said compound and said prodrugs, wherein Q is n-propylene; X is thienyl; Z is carboxy; Ar is 3-pyridyl; Ar 4 is phenyl and Ar 5 is 2-thiazolyl, said 2-thiazolyl being substituted at the 4-position of said phenyl. Another especially preferred compound of compounds within the group FC, designated as the group H, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -CH2-X-O-CH2; Ar 4 is phenyl or pyridyl; said phenyl and pyridyl being optionally substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl and methyl, and X is metaphenylene. A preferred group of compounds within the group H are (3 - (((4-cyclohexyl-benzyl) -pyridin-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid, (3- ( ((pyridin-3-sulfonyl) - (4-pyridin-2-yl-benzyl) -amino) -methyl) -phenoxy) -acetic acid (3 - (((pyridin-3-sulfonyl) - (4-pyridine -3-yl-benzyl) -amino) -methyl) -phenoxy) -acetic acid, (3 - (((pyridin-3-sulfonyl) - (4-pyridin-4-yl-benzyl) -amino) - methyl) -phenoxy) -acetic acid, and (3 - (((pyridin-3-sulfonyl) - (4-thiazol-2-yl-benzyl) -amino) -methyl) -phenoxy) - acetic. An especially preferred compound within the group H is the compound, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Ar is pyrid-3-yl; Z is carboxy, Ar4 is phenyl; Ar5 is cyclohexyl, and said cyclohexyl radical is substituted at the 4-position of said phenyl ring. Another especially preferred compound within the group H is the compound wherein Ar is pyrid-3-yl; Z is carboxy, Ar4 is phenyl; Ar5 is thiazol-2-yl and said thiazol-2-yl radical is substituted at the 4-position of said phenyl ring. Another especially preferred compound within the group H is the compound wherein Ar is pyrid-3-yl; Z is carboxy, Ar4 is phenyl; Ar5 is 2- utfyiA w &"-. pyridyl and said 2-pyridyl radical is substituted at the 4-position of said phenyl ring. Another especially preferred compound within the group H is the compound wherein Ar is pyrid-3-yl; Z is carboxy, Ar4 is phenyl; Ar5 is 3-5 pyridyl and said 3-pyridyl radical is substituted at the 4-position of said phenyl ring. Another compound especially preferred within the group H, is the compound in which Ar is pyrid-3-yl; Z is carboxy, Ar4 is phenyl; Ar5 is 4-pyridyl and said 4-pyridyl radical is substituted at the 4-position of said phenyl ring. A preferred group of compounds within the group FA designated as group I, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein K is methylene, G is Ar; Ar is phenyl, pyridazinyl 15, pyrazolyl, pyrazinyl, pyridyl, imidazolyl, pyrimidyl, thienyl or thiazolyl, Ar is optionally mono-, di- or trisubstituted by R3, R4 or R5, and M is Ar3 wherein Ar3 is cyclopentyl said, ciciohexilo, phenyl, thienyl, pyridazinyl, pyrimidinyl, pirazililo, indolyl, benzofuryl, benzo (b) thienyl, benzoxazolyl, benzatiazolilo, quinolinyl, isoquinolinyl, naphthyl, tetralinyl, 2H-1-benzopyranyl 20 or 1, 4-benzodioxan and is optionally mono- -, di- or trisubstituted with R31, chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethyl or trifluoromethoxy. An especially preferred group of compounds within group I are (3 - (((2,3-dihydro-benzo [1,4] dioxin-6-ylmethyl) - (pyridin-3) * & j ^ ¿g¡l ^^^^ ¡^ ^^^^^^^ Sulfonyl) -amino) -methyl) -phenyl) -acetic acid and (3 - ((benzofuran-2-ylmethyl) - (pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid. An especially preferred compound within group I is the compound, prodrugs thereof and pharmaceutically acceptable salts of Said compound and said prodrugs, wherein Ar is pyrid-3-yl; Z is carboxy, M is 6- (1,4-benzodioxane) and Q is -CH 2 -X-CH 2 -, wherein X is metaphenylene. Another especially preferred compound within group I is the compound wherein Ar is pyrid-3-yl; Z is carboxy, M is 2-benzofuryl and Q is -CH2-X-CH2-, wherein X is metaphenylene. Another especially preferred compound of compounds within group I, designated as group J, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Ar is phenyl, pyridyl or imidazolyl, said phenyl, pyridyl or imidazolyl optionally independently substituted with chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethyl or trifluoromethoxy; Ar3 is phenyl substituted with R31, wherein R31 is (C1-C7) alkyl, mono-N- or di-N, N-(C1-C4) alkyl amine or (C1-C5) alkoxy, said alkyl being (C1 -C7) or (C5) alkoxy optionally mono-, di- or trisubstituted independently with hydroxy or fluoro, wherein Ar3 is optionally mono-, di- or trisubstituted with chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl. A preferred group of compounds within group J, designated niim i IIGTI inri - «- - - .r¡rrr ^ fT |. ftBy ari ^^ a as the group K, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -alkylene (C5-C7) -. Another preferred group of compounds within group J, designated as group L, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -CH2-X-CH2- and X is phenyl optionally mono-, di- or trisubstituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl. An especially preferred group of compounds within the L group are (3 - (((4-butyl-benzyl) - (pyridin-3-sulfonyl) -amino) -methyl) -phenyl] -acetic acid , (3 - ((benzenesulfonyl- (4-butyl-benzyl) -amino) -methyl) -phenyl) -acetic acid, (3 - (((4-butyl-benzyl) - (1-methyl-1) acid H-imidazole-4-sulfonyl) -amino) -methyl) -phenyl) -acetic acid and (3 - (((4-dimethylamino-benzyl) - (pyridin-3-sulfonyl) -amino] ) -metl) -15 phenyl) -acetic. An especially preferred compound within the group L, is the compound, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Ar is phenyl; Z is carboxy, M is phenyl substituted in the 4-position with n-butyl; and Q is -CH2-X-CH2-, in the that X is metaphenylene. Another compound especially preferred within the group L, is the compound, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Ar is pyrid-3-yl; Z is The carboxylic acid, M is phenyl substituted at the 4-position with n-butyl; and Q is -CH2-X- CH2-, wherein X is metaphenylene. Another compound especially preferred within the group L is the compound, prodrugs thereof and pharmaceutically acceptable salts. of said compounds and said prodrugs, wherein Ar is 4- (1-methylimidazolyl); Z is carboxy, M is phenyl substituted in the 4-position with n-butyl; Q is -CH2-X-CH2-, wherein X is metaphenylene. Another compound especially preferred within the group L is the compound, prodrugs thereof and pharmaceutically acceptable salts. of said compound and said prodrugs, wherein Ar is pyrid-3-yl; Z is carboxy, M is phenyl substituted in the 4-position with dimethylamino and Q is -CH2- X-CH2-, wherein X is metaphenylene. Another preferred group of compounds within group J, comprises those compounds, prodrugs thereof and salts Pharmaceutically acceptable compounds of said compounds and said prodrugs, wherein Q is -alkylene (C2-C4) -thienyl, -alkylene (C2-C4) -furanyl- or alkylene (C2-C) -thiazolyl. A preferred group of compounds within group J, designated as group M, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -alkylene (C? -C2) - XO- (CrC2) and X is metaphenylene, said X being optionally mono-, di- or tri- substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl.

A preferred group of compounds within the M group are (3 - (((4-dimethylamino-benzyl) - (pyridine-3-sulfonyl) -amino) -metl) -phenoxy) -acetic acid and the (3 - (((4-tert-butyl-benzyl) - (pyridine-3-sulfonyl) amino) -methyl) -phenoxy) -acetic acid. An especially preferred compound within the group M is the compound, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Ar is pyrid-3-yl; Z is carboxy, M is phenyl substituted in the 4-position with dimethylamino, and Q is -CH 2 -X-O-CH 2 -, wherein X is metaphenylene. An especially preferred compound within the group M is the compound, prodrugs thereof and pharmaceutically acceptable salts of said compound and said prodrugs, wherein Ar is pyrid-3-yl; Z is carboxy, M is phenyl substituted in the 4-position with dimethylamino, and Q is -CH 2 -X-O-CH 2 -, wherein X is metaphenylene. An especially preferred compound within the group M is the compound, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Ar is pyrid-3-yl; Z is carboxy, M is phenyl substituted in the 4-position with fer-butyl and Q is -CH2-X-O-CH2-, wherein X is metaphenylene. Another preferred group of compounds within the group FA, designated as the group N, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein G is Ar; K is alkylene (CH2-CH) or n- propenylene; Ar is phenyl, pyrazolyl, pyridazinyl, pyrazinyl, pyridyl, imidazolyl, pyrimidyl, thienyl or thiazolyl, wherein Ar is optionally mono-, di- or trisubstituted with R3, R4, or R5, and M is Ar3 optionally mono-, di - or trisubstituted with chlorine, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethoxy and trifluoromethyl. An especially preferred compound within the group N is trans- (3 - (((3- (3,5-dichloro-phenyl) -allyl) - (pyridin-3-sulfonyl) -amino) -metl) - phenyl) -acetic. An especially preferred compound within the group N, is the compound, prodrugs thereof and pharmaceutically acceptable salts of said compound and said prodrugs, wherein K is frans-n-propenylene, said group M being attached to position 1 of the n- propenylene and said N atom being attached to the 3-position of the n-propenylene; Ar is pyrid-3-yl; M is 3,5-disubstituted phenyl with chlorine; Z is carboxy and Q is -CH2-X-CH2-, wherein X is metaphenylene. A preferred group of compound within the group N, designated as the group O, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Ar3 is phenyl optionally substituted with chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl. A preferred group of compounds within the group O, designated as the group P, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and * - - ~ »-» '^, ^.,. ^, ^ .. said prodrugs, wherein Q is -alkylene (C5-C7) -. Another preferred group of compounds within group O, designated as group Q, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -CH2-X-CH2-, and X It is metaphenylene. Another preferred group of compounds within the O group, designated as the R group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -alkylene (C2-C4) -X- and X is furanyl, thienyl or thiazolyl. Another preferred group of compounds within the group O, designated as the group S, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -alkylene (CrC2) -XO- (C C2) - and X is metaphenylene. Another preferred group within the group FA, designated as the group T, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein G is Ar; K is thioethylene or oxyethylene, Ar is phenyl, pyrazolyl, pyridazinyl, pyrazinyl, pyridyl, midazolyl, pyrimidyl, thienyl or thiazolyl, wherein Ar is optionally substituted with up to three R3, R4 or R5, and M is Ar3, optionally mono-, di- or trisubstituted with chlorine, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.

A preferred group of compounds within the group T, designated as the group U, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Ar3 is phenyl. A preferred group of compounds within the group U, designated as the group V, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -alkylene (C5-C7) -. Another preferred group of compounds within group U, designated as group W, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -CH2-X-CH2- and X It is metaphenylene. Another preferred group of compounds within the group U, designated as the group X, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -alkylene (C2-C4) -X - and X is furanyl, thienyl or thiazolyl. Another preferred group of compounds within the group U, designated as the group Y, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is - (C? -C2) -XO -alkylene- (C C2) - and X is metaphenylene. An especially preferred compound within the group Y is the »" - - »» -.. ^ - t ^ aA ^. .. "- ... ... *. * ^ Ü - JMiili iiMifn lim * - aStító- - --- - * - - - ^ - (3 - (((2- (3,5-Dichloro-phenoxy) -ethyl) - (pyridin-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid An especially preferred compound within the group Y, is the compound, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein K is ethylenyloxy, said M group being attached to the oxygen atom of the ethylenyloxy group, and N atom bonded to the 2-position of the ethyleneoxy group: Ar is pyrid-3-yl, M is phenyl 3,5-disubstituted with chlorine, Z is carboxy and Q is -CH 2 -XO-CH 2 -, wherein X is a second phenyl ring and said substituents CH 2 and OCH 2 are located in a meta substitution pattern of said second phenyl ring Another preferred group of compounds, designated as the group Z, comprises those compounds of Formula I, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs wherein B is CH. A preferred group of compounds within the group Z comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein A is CO; G is Ar; K is methylenyl, propylenyl, propenynyl or oxyethylenyl; M is Ar3 or Ar4-Ar5; Ar3 is phenyl or pyridyl; Ar4 is phenyl, thienyl, pyridyl or furanyl; Ar5 is (C5-C) cycloalkyl, phenyl, pyridyl, imidazolyl, pyrimidyl, thienyl, pyridyzanyl, pyrazinyl, imidazolyl, pyrazolyl or thiazolyl; Ar is phenyl, pyrazolyl, pyridyzanyl, pyrazinyl, pyridyl, imidazolyl, pyrimidyl, thienyl or thiazolyl; wherein Ar, Ar3, Ar4 and Ar5 are optionally substituted independently with up to three chlorine, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl. Another especially preferred group of compounds within the group Z comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein A is CO; G is Ar; K is methylenyl, propylenyl, propenynyl or oxyethylenyl; M is Ar3 or Ar ^ -Ar5; Ar3 is phenyl or pyrimidyl; Ar4 is phenyl, thienyl, pyridyl or furanyl; Ar5 is (C5-C7) cycloalkyl, phenyl, pyridyl, imidazolyl, pyrimidyl, thienyl, pyridyzanyl, pyrazinyl, imidazolyl, pyrazolyl or thiazolyl; in which Ar, Ar3, Ar4 and Ar5 are optionally independently substituted with up to three chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl. This invention also relates to methods for treating vertebrates, for example a mammal, suffering from a disorder that produces reduction of bone mass, comprising administration to said vertebrate, for example a mammal, suffering from a disorder that produces reduction of bone mass, of a therapeutically effective amount of the compound above of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. 20 Treatment of postmenopausal women and men over 60 years of age is preferably considered. Also included are those people regardless of age, who have a significantly reduced bone mass, that is, greater than or equal to 1, 5 deviations J5a »^» »¿¿« > ^ & »« ^ / a ¡^^ fcft < ^ a ^.! ^. > - ^. ~ ^ * MH¿jgtój ^ standard below the normal levels of a young person. Another aspect of this invention relates to methods for treating osteoporosis, bone fractures, osteotomy, bone loss associated with periodontitis or prosthetic invagination in a vertebrate, for example in a mammal (including a human), comprising administration to said vertebrate, for example a mammal, suffering from osteoporosis, bone fracture, osteotomy, bone loss associated with periodontitis or prosthetic invagination, of a quantity for the treatment of osteoporosis, bone fracture, osteotomy, associated bone loss to periodontitis or prosthetic invagination of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to methods for the treatment of osteoporosis in a vertebrate, for example in a mammal (including a human), comprising administration to said vertebrate, for example a mammal, suffering from osteoporosis, from an amount for the treatment of osteoporosis of a compound of Formula I, a prodrug thereof or a pharmaceutically salt acceptable of said compound or said prodrug. Another aspect of this invention relates to methods for the treatment of bone loss by osteotomy in a vertebrate, for example in a mammal (including a human), comprising administration to said vertebrate, for example a mammal, which It has been ^^^^^^ j ^^^^^ ggS feß g¡ j ^ g ^^^^ í ^ jg ^ subjected to an osteotomy, of a quantity for the treatment of bone restoration of a compound of Formula I , a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug wherein an amount for the treatment of the bone restoration is an amount of said compound of Formula I, prodrug thereof or pharmaceutically acceptable salt of said compound or said prodrug, sufficient to restore bone in areas that contain bone defects due to said osteotomy. In one aspect, the compound of Formula I, prodrugs thereof or pharmaceutically acceptable salt of said compounds or said prodrug, is applied locally at the site of the osteotomy. Another aspect of this invention relates to methods for the treatment of alveolar or mandibular bone loss in a vertebrate, for example in a mammal (including a human), comprising administration to said vertebrate, for example a mammal, which suffers alveolar or mandibular bone loss, of an amount for the treatment of alveolar or mandibular bone loss of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to methods for the treatment of bone loss associated with periodontitis in a vertebrate, for example in a mammal (including a human), comprising administration to said vertebrate, for example a mammal, - •• - * 'A = > ^^ - ^^ suffering from bone loss associated with periodontitis, of an amount for the treatment of bone loss associated with the periodontitis of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug . Another aspect of this invention relates to methods for the treatment of childhood idiopathic bone loss in a child, comprising the administration to a child suffering from childhood idiopathic bone loss, of an amount for the treatment of childhood idiopathic bone loss. a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to methods for the treatment of "secondary osteoporosis", which includes glucocorticoid-induced osteoporosis, osteoporosis induced by hyperthyroidism, immobilization-induced osteoporosis, heparin-induced osteoporosis or osteoporosis induced by immunosuppression in a vertebrate, for example in a mammal (including a human), comprising administration to said vertebrate, for example a mammal, suffering from "secondary osteoporosis", of an amount for the treatment of "secondary osteoporosis" of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to methods for the treatment of glucocorticoid-induced osteoporosis in a ilñrtiMMiMi 'i r i i n i-iWir iüfflir! < Ullllllllllllllllllllllllllllllllllll: vertebrate, for example in a mammal (including a human), comprising administration to said vertebrate, for example a mammal, suffering from glucocorticoid-induced osteoporosis, of an amount for the treatment of the osteoporosis induced by glucocorticoids of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to methods for the treatment of osteoporosis induced by hyperthyroidism in a vertebrate, for example in a mammal (including a human), which comprise the administration to said vertebrate, for example a mammal, suffering from osteoporosis induced by hyperthyroidism, of an amount for the treatment of osteoporosis induced by hyperthyroidism of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt thereof. compound or said prodrug. Another aspect of this invention relates to methods for the treatment of osteoporosis induced by immobilization in a vertebrate, for example in a mammal (including a human), comprising administration to said vertebrate, for example a mammal, which suffer osteoporosis induced by immobilization, of an amount for the treatment of osteoporosis induced by immobilization of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to the methods for the treatment of osteoporosis induced by heparin in a vertebrate, for example in a mammal (including a human), comprising administration to said vertebrate, for example a mammal, suffering from heparin-induced osteoporosis, of an amount for the treatment of heparin-induced osteoporosis of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to methods for the treatment of osteoporosis induced by immunosuppression in a vertebrate, for example in a mammal (including a human), comprising administration to said vertebrate, for example a mammal, suffering from osteoporosis induced by immunosuppression, of an amount for the treatment of osteoporosis induced by immunosuppression of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to methods for the treatment of a bone fracture in a vertebrate, for example in a mammal (including a human), comprising administration to said vertebrate, for example a mammal, having a fracture. Bone, of a quantity for the treatment of a bone fracture of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. In one aspect of this invention for the treatment of a bone fracture, the compound of Formula I, prodrug thereof or pharmaceutically acceptable salt of said compound or said prodrug, is applied locally at the site of the bone fracture. In another aspect of this invention, the compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug is administered systemically. Another aspect of this invention relates to methods for stimulating bone welding after a facial reconstruction, or a maxillary reconstruction or a mandibular reconstruction in a vertebrate, for example in a mammal (including a human), comprising the Administration to said vertebrate, for example a mammal, which has undergone a facial reconstruction, a maxillary reconstruction or a mandibular reconstruction, a quantity for the stimulation of the bony welding, a compound of Formula I, a prodrug of the same or a pharmaceutically acceptable salt of said compound or said prodrug. In one aspect of this method, a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug is applied locally at the site of bone reconstruction. Another aspect of this invention relates to the methods for the treatment of the prosthetic invagination in a vertebrate, as in the case of the stimulation of the bone invagination in a bone prosthesis, for example in a mammal (including a human), comprising the administration to said vertebrate, for example a mammal that suffers ^^ gj ^^ g ^^^^^^^^^^^ g ^^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ an amount for the treatment of the prosthetic invagination, of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention relates to methods for inducing vertebral synostosis in a vertebrate, for example in a mammal (including a human), comprising administering to said vertebrate, for example a mammal, which has been subjected to an operation for vertebral synostosis, of a therapeutically effective amount of a compound of Formula I, a prodrug thereof or a salt Pharmaceutically acceptable of said compound or said prodrug. Another aspect of this invention relates to methods for stimulating the extension of long bones in a vertebrate, for example in a mammal (including a human), comprising administration to said vertebrate, for example a mammal, having long bones of insufficient size, of an amount for the stimulation of the extension of the long bones of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compounds or said prodrug. Another aspect of this invention relates to the methods for reinforcing a bone graft in a vertebrate, for example in a mammal (including a human), comprising administering to said vertebrate, for example a mammal, which has been a recipient of a bone graft, of a reinforcing amount of the graft bone of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. In addition, a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug can be used as an alternative to surgery to implant a graft. In one aspect of this method a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, is applied locally at the site of the bone graft. In another aspect of this process a compound of Formula I, a prodrug thereof or a salt Pharmaceutically acceptable of said compound or said prodrug is applied directly to the bone by injection or by direct application to the bone surface. A preferred dosage is from about 0.001 to 100 mg / kg / day of a compound of Formula I, a prodrug thereof or a The pharmaceutically acceptable salt of said compound or said prodrug. An especially preferred dosage is from about 0.01 to 10 mg / kg / day of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. This invention also relates to the compositions Pharmaceuticals containing a therapeutically effective amount of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.

^. ^ .. M ^^ ^ ..-. ^ ¿^ .¿ ^^ «^ .-- MMMb. ^ r fflÉBJ.

This invention also relates to pharmaceutical compositions for increasing bone mass containing an amount to increase bone mass of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier or diluent. This invention also relates to pharmaceutical compositions for the treatment of a disorder that causes reduction of bone mass in a vertebrate, for example a mammal (including human), which contains an amount for the treatment of a disorder in which there is a reduction in bone mass, a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier or diluent. This invention also relates to pharmaceutical compositions for the local or systemic treatment of osteoporosis, bone fractures, bone loss by osteotomy, bone loss associated with periodontitis or prosthetic invagination in a vertebrate, for example in a mammal (including of a human), which contain a therapeutically effective amount of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier or diluent. This invention also relates to pharmaceutical compositions for the treatment of "secondary osteoporosis", which includes osteoporosis induced by glucocorticoids, osteoporosis induced by hyperthyroidism, osteoporosis induced immobilization, osteoporosis induced by heparin or osteoporosis induced by immunosuppression in a vertebrate, for example in a mammal (including a human), which contain an amount for the treatment of "secondary osteoporosis" of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier or diluent. This invention also relates to pharmaceutical compositions for the treatment of osteoporosis in a vertebrate, for example in a mammal (including a human), which contain an amount for the treatment of osteoporosis of a compound of Formula I, a prodrug of the same or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier or diluent. This invention also relates to pharmaceutical compositions for stimulating the welding of a bone fracture in a vertebrate, for example in a mammal (including a human), which contain an amount for the treatment of a bone fracture of a compound of Formula I , a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier or diluent. This invention also relates to the compositions -i ***** t'-ji ^ * Ma? J * ltA ^ Mlll ^ fc,? A ^ • "lriflir- - * ^ - tt3 -'- a = - ^. - pharmaceutical for the treatment of an osteotomy in a vertebrate, for example in a mammal (including a human), comprising administering to said vertebrate, for example, a mammal, which has undergone an osteotomy, an amount for the treatment of bone restoration of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein the amount for the treatment of the bone restoration is an amount of said compound of Formula I, prodrug thereof or salt pharmaceutically acceptable of said compound or said prodrug, sufficient to restore bone in the areas having bone defects due to said osteotomy In one aspect, the compound of Formula I, prodrug thereof or pharmaceutically acceptable salt thereof is applied locally to the osteotomy site This invention also relates to pharmaceutical compositions for facilitating bone welding after an osteotomy in a vertebrate, for example in a mammal (including a human), comprising administration to said vertebrate, eg, a mammal, which has been subjected to an osteotomy, of a bone-welding amount of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. In one aspect, the compound of Formula I, prodrug thereof or pharmaceutically acceptable salt thereof is applied locally to the site of the osteotomy.

T? .. .., .- ^ ÉJt ^ t. Hgl This invention also relates to pharmaceutical compositions for the treatment of alveolar or mandibular bone loss in a vertebrate, for example in a mammal (including a human), which contain an amount for the treatment of bone loss. alveolar or mandibular of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier or diluent. This invention also relates to pharmaceutical compositions for the treatment of childhood idiopathic bone loss in a child which contain an amount for the treatment of childhood idiopathic bone loss of a compound of Formula I, a prodrug thereof or a pharmaceutically salt acceptable of said compound or said prodrug, and a pharmaceutically acceptable carrier or diluent. This invention also relates to pharmaceutical compositions for stimulating bone welding after facial reconstruction., of a maxillary reconstruction or of a mandibular reconstruction in a vertebrate, for example in a mammal (including a human), containing an amount that stimulates bone welding, of a compound of Formula I, a prodrug thereof or a salt Pharmaceutically acceptable of said compound or said prodrug, and a pharmaceutically acceptable carrier or diluent. This invention also relates to pharmaceutical compositions for the treatment of bone loss associated with ^^^ J ****. ^ Jh wÉiSfc ^ | ^ j? "Periodontitis in a vertebrate, for example in a mammal (including a human), containing an amount for the treatment of bone loss associated with periodontitis, of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier or diluent. This invention also relates to pharmaceutical compositions for the treatment of prosthetic invagination in a vertebrate, for example in a mammal (including a human), containing an amount for the treatment of prosthetic invagination, of a compound of Formula I above, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier or diluent. This invention also relates to pharmaceutical compositions for inducing vertebral synostosis or spinal fusion in a vertebrate, for example in a mammal (including a human), which contain a therapeutically effective amount of a compound of Formula I, a prodrug of the same or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier or diluent. This invention also relates to pharmaceutical compositions for stimulating bone attachment in a method of extending long bones in a vertebrate, for example in a mammal (including a human), which contain an amount for the treatment of the increase. of bone mass of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier or diluent. This invention also relates to pharmaceutical compositions for the treatment of osteoporosis induced by glucocorticoids in a vertebrate, for example in a mammal (including a human), containing an amount for the treatment of glucocorticoid-induced osteoporosis of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier or diluent. This invention also relates to pharmaceutical compositions for the treatment of osteoporosis induced by hyperthyroidism in a vertebrate, for example in a mammal (including a human), containing an amount for the treatment of osteoporosis induced by hyperthyroidism of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier or diluent. This invention also relates to pharmaceutical compositions for the treatment of osteoporosis induced by immobilization in a vertebrate, for example in a mammal (including a human), which contain an amount for the treatment of the S! & amp; & osteoporosis induced by immobilization of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier or diluent. This invention also relates to pharmaceutical compositions for the treatment of heparin-induced osteoporosis in a vertebrate, for example in a mammal (including a human), which contain an amount for the treatment of heparin-induced osteoporosis of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier or diluent. This invention also relates to pharmaceutical compositions for the treatment of osteoporosis induced by immunosuppression in a vertebrate, for example in a mammal (including a human), containing an amount for the treatment of osteoporosis induced by immunosuppression of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier or diluent. Another aspect of this invention are combinations of the compounds of Formula I, prodrugs thereof or pharmaceutically acceptable salts of said compounds or said prodrugs, and other compounds as described above.

** * ,. ~ *? ^. . »... M? MÍL .. a * Another aspect of this invention relates to pharmaceutical compositions containing a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, and an anti-resorption agent, a prodrug of the same or a pharmaceutically acceptable salt of said agent or said prodrug, and to the use of said compositions for the treatment or prevention of disorders that produce a loss of bone mass, including osteoporosis in a vertebrate, for example mammals (eg example, in humans, especially women), or the use of such compositions for other uses that have as an end to increase the bone mass. The combinations of this invention include a therapeutically effective amount of a first compound, said first compound being a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, and a The therapeutically effective amount of a second compound, said second compound being an anti-resorptive agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug, such as an estrogen agonist / antagonist or a bisphosphonate. Another aspect of this invention relates to the methods for the treatment of vertebrates, for example mammals, having reduced bone mass, comprising administering to said vertebrate, for example a mammal, having a disorder that produces reduction of bone mass, of: to. an amount of a first compound, said first compound being a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; and b. an amount of a second compound, said second compound being an anti-resorption agent, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, such as an estrogen agonist / antagonist or a bisphosphonate. Said compositions and methods can also be used for other uses in order to increase bone mass. A preferred aspect of this method is that the disorder that causes bone mass reduction is osteoporosis. Another preferred aspect of this method is wherein the first compound and the second compound are administered substantially simultaneously. Another preferred aspect of this method is wherein the first compound is administered for a period from about one week to about five years. An especially preferred aspect of this method is wherein the first compound is administered for a period from about one week to about three years. Optionally, administration of the first compound is followed by administration of the second compound, wherein the second compound is an estrogen agonist / antagonist, for a period of time. from about three months to about three years, without administering the first compound during the period in which the second is administered and which is from about three months to about three years. On the other hand, administration of the first compound is followed by the administration of the second compound, in which the second compound is an estrogen agonist / antagonist, for a period of more than three years, without administering the first compound during the period in which it is administered. that the second one is administered, which is a period greater than three years. Another aspect of this invention is a test kit containing: a. an amount of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier or diluent in a first unit dosage form; b. an amount of an anti-resorption agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug, such as an estrogen agonist / antagonist or a bisphosphonate, and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and c. a container for containing said first and second dosage form. Another aspect of this invention relates to the compositions ** ^^. ^. ^^^ .. ^^ a ^ - ..MMafet .. ... .... ^^ aate ^. Pharmaceuticals which include a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, and another bone anabolic agent (although the other bone anabolic agent may be a compound of Formula I different), a prodrug of the same or a pharmaceutically acceptable salt of said compound or said prodrug, and the use of said compositions for the treatment of disorders that produce reduction of bone mass, including osteoporosis in a vertebrate, for example mammals (for example, humans, especially in women), or the use of said compositions for other uses whose purpose is to increase bone mass. Said compositions include a therapeutically effective amount of a first compound, said first compound being a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, and a therapeutically effective amount of a second Compound, said second compound being another bone anabolic agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug. Another aspect of this invention relates to methods for the treatment of vertebrates, for example mammals, which have a mass reduced bone, comprising the administration to said vertebrate, for example a mammal, having a disorder that produces reduction of bone mass, of: a. an amount of a first compound, said first compound a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt or prodrug thereof; and b. an amount of a second compound, said second compound being another bone anabolic agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug. Said compositions and methods can also be used for other uses in order to increase bone mass. A preferred aspect of this method is that the disorder that causes reduction of bone mass is osteoporosis. Another preferred aspect of this method is wherein the first compound and the second compound are administered substantially simultaneously. Another aspect of this invention is a test kit containing: a. an amount of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier or diluent in a first unit dosage form; b. an amount of a second compound, said second compound being another bone anabolic agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug in a second unit dosage form; and c. a container for containing said first and second forms of dosage. When in any of the methods, test kits and prior compositions are used bone anabolic agents, estrogen agonists / antagonists and bisphosphonates, there are some that are preferred or especially preferred. Preferred bone anabolic agents include IGF-1, prostaglandins, prostaglandin agonists / antagonists, sodium fluoride, parathyroid hormone (PTH), active parathyroid hormone fragments, peptides and active fragments related to parathyroid hormone, and peptide analogs related to parathyroid hormone, growth hormone or growth hormone secretagogues and pharmaceutically acceptable salts thereof. The preferred estrogen agonists / antagonists are droloxifene, raloxifene, tamoxifen, 4-hydroxy tamoxifen, toremifene, centroman, levormeloxifen, idoxifen, 6- (4-hydroxy-phenyl) -5- (4- (2-piperidin-1-yl- ethoxy) -benzyl) -naphthalen-2-ol; (4- (2- (2-aza-bicyclo [2.2.1] hept-2-yl) -ethoxy) -phenyl) - (6-hydroxy-2- (4-hydroxy-phenyl) -benzo [b ] thiophen-3-yl) -methanone; 3- (4- (1, 2-diphenyl-but-1-enyl) -phenyl) -acrylic acid; 2- (4-methoxy-phenyl) -3- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -benzo [b] thiophen-6-ol; c / -s-6- (4-fluoro-phenyl) -5- (4- (2-piperidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol; »A ^^^ ~~ - • 1 ^^ lji8 > ? "(-) - c / s-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol; c / s-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol; 5 c / s-1 - (6'-pyrrolidinethoxy-3'-pyridyl) -2-phenyl-6-hydroxy-1, 2,3,4-tetrahydronaphthalene; 1- (4'-pyrrolidinetoxyphenyl) -2- (4"-fluorophenyl) ) -6-hydroxy-1, 2,3,4-tetrahydroisoquinoline; c / s- (6- (4-Hydroxyphenyl) -5- (4- (2-piperidin-1-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol; 1- (4'-pyrrolidinolethoxyphenol) -2-phenyl-6-hydroxy-1, 2,3,4-tetrahydroisoquinoline and pharmaceutically acceptable salts thereof Preferred estrogen agonists / antagonists especially are droloxifene, 3- (4- (1, 2-diphenyl-but-1-enyl) -phenyl) -acyclic acid 2- (4-methoxy-phenyl) -3- [4- (2 -piperidin-1-yl-ethoxy) -phenoxy] -benzo [b] thiophen-6-ol; c / s-6- (4-fluoro-phenyl) -5- (4- (2-piperidin-1- il-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol; 20 (-) - c / s-6-phenyl-5- (4- (2-pyrrolidin-1- il-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol; c / s-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalene-2-ol; c / s-1- (6'-pyrrolidinetoxy-3'-pyridyl) -2-phenyl-6-hydroxy-1, 2,3,4-tetrahydronaphthalene; 1- (4'-pyrrolidinethoxyphenyl) -2- (4'-fluorophenyl) -6-hydroxy-1, 2,3,4-tetrahydroisoquinolone; 5 c / s- (6- (4-Hydroxyphenyl) -5- (4- (2-piperidin-1-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol and 1- (4'-pyrrolidinoletoxyphenyl) -2-phenyl) -6-hydroxy-1, 2,3,4-tetrahydroisoquinoline and the pharmaceutically acceptable salts thereof. Preferred bisphosphonates include tiludronic acid, alendronic acid, zolendronic acid, bandronic acid, risedronic acid, etidronic acid, clodronic acid and pamidronic acid and their pharmaceutically acceptable salts. It is understood that prodrugs and pharmaceutically acceptable salts can be formed from the compounds used as the second compounds in the combinations of this invention. All of these prodrugs and pharmaceutically acceptable salts thus formed are within the scope of this invention. Especially preferred salts are droloxifene citrate, raloxifene hydrochloride, tamoxifen citrate and toremifene citrate. The phrase "disorder (s) that cause (s) a reduction in bone mass" refers to a disorder in which the level of bone mass is below normal for a specific age, as defined in the standards of the World Health Organization "Assessment of the Risk of Fracture and its Application for the Determination of Post-Menopausal Osteoporosis (1994), Report of a Study Group of the World Health Organization, Technical Series of the World Health Organization 843" . In "disorder (s) that cause (s) a reduction in bone mass" include primary and secondary osteoporosis. Secondary osteoporosis includes glucocorticoid-induced osteoporosis, osteoporosis induced by hyperthyroidism, immobilization-induced osteoporosis, heparin-induced osteoporosis or osteoporosis induced by immunosuppression. Periodontal disease, alveolar bone loss, bone loss due to postosteotomy, and childhood idiopathic bone loss are also included. The phrase "disorder (s) that produces (n) a reduction in bone mass" also includes the long-term complications of osteoporosis, such as curvature of the spine, loss of height, and prosthetic surgery. The phrase "disorder (s) that cause (s) a reduction in bone mass" also refers to vertebrates, eg, a mammal, which is known to have a significantly higher than average risk of developing such disorders, such as those described. previously, including osteoporosis (for example, postmenopausal women and men over 60). Other uses intended to increase or stimulate bone mass include increasing the welding speed of a bone fracture, the complete replacement of surgery to perform a bone implant; the itt ** «* * ..« t ~ * .ttA.Mria = f-, |,, i BH.BmHl.f? ilii ¡TTin - - "-" ^ * - - ^ tñá ^ stimulation of the speed of acceptance of successful bone grafts, bone welding after facial reconstruction or maxillary reconstruction or mandibular reconstruction, prosthetic invagination, vertebral synostosis or extension of long bones. The compounds and compositions of this invention may also be used in conjunction with orthopedic appliances, such as corsets for spinal fusion, rigid materials for spinal fusion, internal and external bone fixation devices, screws and clamps. Those skilled in the art will realize that the term bone mass actually refers to bone mass per unit area, which is sometimes designated (although strictly not correct) as bone mineral density. The term "to treat", "treat", "treatment", as used herein, includes a preventive (eg, prophylactic), palliative and curative treatment. By "pharmaceutically acceptable" it is meant that the carrier, diluent, excipients and / or salt must be compatible with other ingredients of the formulation and not be deleterious to the recipient. The term "prodrug" refers to compounds that are drug precursors and that once administered release the drug in vivo by some chemical or physiological process (for example, a prodrug that is brought up to the physiological pH becomes the desired drug by the enzymatic action). Examples of prodrugs are those that when cleaved release The corresponding free acid, including, but not limited to, said hydrolysable ester-forming radicals of the compounds of Formula I, the substituents in which the radical Z is independently carboxyl and the free hydrogen is substituted by (C 1 -C 4) alkyl, (C 2 -C 7) alkanoyloxymethyl, 1- (alkanoyloxy) ethyl with 4 to 9 carbon atoms, 1-methyl- (1-alkanoyloxy) -etyl with 5 to 10 carbon atoms carbon, alkoxycarbonyloxymethyl with 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl with 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl with 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl with 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl with 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N, N-alkyl ( C -? - C2) (C2-C3) aminoalkyl (such as b-dimethylaminoethyl), carbamoyl-alkyl (C -? - C2), N, N-dialkyl (C? -C2) carbamoyl-alkyl (C -? - C2) and piperidin-, pyrrolidin- or morpholyalkyl (C2-C3). Examples of aromatic rings of five to six links with optionally one or two heteroatoms independently selected from oxygen, nitrogen and sulfur (ie, X rings), are phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazole, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazanyl, pyrimidinyl and pyrazinyl. Examples of five to eight partially saturated, fully saturated or fully unsaturated linkages with optionally one to four heteroatoms independently selected from oxygen, sulfur and nitrogen (ie, Ar, Ar1 and Ar2), are cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl. Other examples of five-membered rings are furyl, thienyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2- imidazolinyl, imidazolinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, -siathiazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl, 1, 2,3, oxadiazolyl, 1,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1, 3,4-oxadiazolyl, 1,2,3-triazolyl, 1, 2,4-triazolyl, 1,4-thiadiazolyl, 1, 2,3,4-oxatriazolyl, 1, 2,3,5-oxatriazolyl , 3H-1, 2,3-dioxazolyl, 1,4-dioxazolyl, 1,2-dioxazolyl, 1,4-dioxazolyl, 5H-1, 2,5-oxathiazolyl and 1,3-oxathiolyl . 10 Other examples of six-membered rings are 2H-pyranyl4H-pyranyl, pyridyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxinyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1, 3.5 -triazinyl, 1, 2,4-triazinyl, 1, 2,3-triazinyl, 1, 3,5-trityanil, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 6H-1, 3-oxazinyl , 6H-1, 2-oxazinyl, 1, 4-oxazinyl, 2H-1, 2-oxazinyl, 4H-1,4-oxazinyl, 1, 2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1, 2,5-oxathiazinyl, 1, 2,6-oxathiazinyl, 1,4,2-oxadiazinyl and 1, 3,5,2-oxadiazinyl. Other examples of seven-membered rings are azepinyl, oxepinyl, thiepinyl and 1,4-diazepinyl. Other examples of eight-membered rings are cyclooctyl, cyclooctenyl and cyclooctadienyl. Examples of bicyclic rings consisting of two fused rings of five and / or six partially saturated links, totally saturated or totally unsaturated, independently considered and optionally having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen are ethylisoyl, indolyl, isoindolyl, 3H-indolyl, 1 H -sondolyl, indolinyl, cyclopenta (b) pyridinyl, pyran (3,4-b) pyrrolyl, benzofuryl, isobenzofyl, benzo (b) thienyl, benzo (c) thienyl, 1 H-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl, benzathiazolyl, purinyl, 4H -quinolizinyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, pyrido (3,4-b) -pyridinyl, pyrid (3,2-b) -pyridinyl, pyrido (4,3-b) -pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1 H-2,3-benzoxazinyl, 4H 3, 1-benzoxazinyl, 2H-1, 2-benzoxazinyl and 4H-1,4-benzoxazinyl. Examples of tricyclic rings consisting of three fused rings of five and / or six partially saturated, fully saturated or fully unsaturated, independently considered and optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen are indacenyl, biphenylenyl , acenaphthylenyl, fluorenyl, phenalenyl, phenanthrenyl, anthracenyl, naphthothienyl, thiantrenyl, xanthenyl, phenoxythinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl and phenoxazinyl. It is understood that fully saturated forms and all partially unsaturated forms of these rings are within the scope of this invention. In addition, it is understood that the nitrogen may be substituted as the heteroatom in any position, including a bridgehead position in the heterocyclic rings. Also, it is understood that sulfur and oxygen may be substituted as the heteroatom in any position other than bridgehead within the heterocyclic rings. By "alkylene" is meant a saturated hydrocarbon (straight or branched chain), in which a hydrogen atom has been removed from each of the terminal carbons. Examples of such groups (assuming that the desired length includes a particular example) are methylene, ethylene, propylene, butylene, pentylene, hexylene and heptylene. By alkenylene is meant a hydrocarbon containing a monounsaturation in the form of a double bond, said hydrocarbon being straight or branched chain and in which a hydrogen atom has been removed from each of the terminal carbons. Examples of such groups (assuming the desired length includes a particular example) are ethylene (or vinylene), propenylene, butenylene, pentenylene, hexenylene and heptenylene. By "alkynylene" is meant a hydrocarbon containing a diunsaturation in the form of a triple bond, said hydrocarbon being straight or branched chain and in which a hydrogen atom has been removed from each of the terminal carbons. Examples of such groups (assuming that the desired length includes a particular example) are ethynylene, propynylene, butynylene, pentynylene, hexynylene and heptynylene.

By halogen is meant chlorine, bromine, iodine or fluoro. By "alkyl" is meant a saturated straight-chain hydrocarbon or a branched saturated hydrocarbon. Examples of such alkyl groups (assuming that the desired length includes a particular example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertbutyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl. By "alkoxy" is meant a saturated straight-chain alkyl or a branched saturated alkyl attached by an oxy. Examples of such alkoxy groups (assuming that the desired length includes a particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, tert-pentoxy, hexoxy, isohexoxy, heptoxy and octoxy. As used herein, the term mono-N or di-N, N-alkyl (CrCx) ... refers to the alkyl radical (CXx) considered independently when it is di-N, N'-alkyl ( C? -Cx) ... (x refers to integers) and independently considering, when two alkyl groups (CrCx) are present ..., for example, methylethylamino is within the range of di-N, N-alkyl ( C -? - Cx). Unless otherwise indicated, the "M" radicals defined above are optionally substituted (for example, simply citing a substituent as R 1 in a subgenus or in the corresponding claim does not mean that M is always substituted with the radical R 1 a unless it is said that radical M is substituted with R1). Nevertheless, In the compounds of Formula I, when K is a bond and M is phenyl, said phenyl group is substituted with one to three substituents. In addition, in the compounds of Formula I, when Ar or Ar1 is a fully saturated five to eight link ring, said ring is unsubstituted. It is understood that if a carbocyclic or heterocyclic radical can be bound or otherwise bound to the indicated substrate by different ring atoms without denoting a specific binding point, then all possible points are considered, either by a carbon atom or, for example, a trivalent nitrogen atom. For example, him The term "pyridyl" means 2-, 3- or 4-pyridyl, the term "thienyl" denotes 2- or 3-thienyl and so on. The term "pharmaceutically acceptable salt" refers to non-toxic anionic salts containing anions such as (but not limited to) chloride, bromide, iodide, sulfate, phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, methanesulfonate and 4-toluene sulfonate. The term also refers to non-toxic cationic salts such as (but not limited to) protonated, sodium, potassium, calcium, magnesium or ammonium benzathine, (N.N'-dibenzylathylenediamine), choline, ethanolamine, diethanolamine, ethylamine, meglamine (N-methyl-20 glucamine), benetamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol). As used herein, the terms "solvent inert to the reaction" and "inert solvent" refer to a solvent that does not L.m ^ iÚ? At tA kA ?? . interacts with the starting materials, reagents, intermediates or products in a way that adversely affects the performance of the desired product. The chemist skilled in the art will realize that certain compounds of this invention will contain one or more atoms that may be in a particular stereochemical or geometric configuration, giving rise to stereoisomers, such as enantiomers and diastereoisomers and configurational isomers such as cis and olefins. trans and cis and trans substitution patterns on the alicyclic rings. All of these isomers and mixtures thereof are included in this invention. The hydrates and solvates of the compounds of this invention are also included. DTT means dithiothreitol. DMSO means dimethylsulfoxide. EDTA means ethylenediaminetetraacetic acid. The methods and compounds of this invention stimulate bone formation, which results in a decrease in the percentage of fractures. This invention contributes significantly to the art by providing compounds and methods that increase bone formation, which results in the prevention, retardation and / or regression of osteoporosis and related bone disorders. Other features and advantages will become apparent from the specification and the claims describing the invention. This invention also relates to the procedures for the Glaucoma treatment in a mammal suffering from glaucoma, comprising administering to said mammal a therapeutically effective amount of a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. This invention also relates to methods for the treatment of ocular hypertension in a mammal suffering from ocular hypertension, comprising the administration to said mammal of a therapeutically effective amount of a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.

DETAILED DESCRIPTION OF THE INVENTION In general, the compounds of this invention can be prepared by methods including methods known in the chemical art, especially in light of the description contained herein. Certain methods for the preparation of the compounds of this invention are provided as other characteristics of the invention and are illustrated by the following reaction schemes. Other procedures are described in the experimental section. Some substituents (e.g., carboxyl) can be best prepared by converting another functional group (e.g.

H! ^ GÉ &carboxyl substituents can be prepared by the conversion of, for example, hydroxyl or carboxyaldehyde) at a later time in the synthetic sequence. Compounds of Formula I, wherein B is nitrogen can be prepared using the procedures described in SCHEMATICS 1 to 5. These methods include (a) the sequential alkylation of a sulfonamide or an amide with two appropriate alkylating agents, generally halides alkyl or alkyl sulfonates; (b) alkylation of a sulfonamide or amide with an alkyl halide or alkyl sulfonate: or (c) reductive amination of an aldehyde followed by reaction with an acylating agent, such as an acyl chloride, a chloroformate, an isocyanate or a chlorocarbonyl amide; or a sulfonylating agent, such as sulfonyl chloride. When performing sequential alkylation, one of the alkylating agents will contain a Q-Z portion, where the Z-part is protected appropriately if necessary and the other alkylating agent will contain a K-M part, where all the functional groups that require protection are appropriately protected. The order of alkylation, that is, whether the alkylating agent containing the Q-Z portion is added first or second, will depend on the reactivity of the electrophilic side chain. When it's made In a reductive amination, the Q-Z portion can be attached either to the amine reagent or to the aldehyde reagent depending on the ease of the preparation of the reagent and the reactivity of the reagents in the reductive amination reaction. The reductive amination is followed by acylation or sulfonylation with a The appropriate acylating agent or sutonic chloride and, if desired, the product is hydrolyzed. Starting materials, including amines, aldehydes and alkylating agents, are prepared using procedures well known to those skilled in the art. Certain preferred methods for their preparation are described herein. For example, compounds of Formula I wherein B is N, are prepared according to the procedures presented in SCHEMES 1 and 2 below. In general, the sequences involve the sequential alkylation of an appropriate sulfonamide of Formula 1 or amide of formula 1 with two Suitable alkyl halides or alkyl sulfonates. SCHEMES 1 and 2 differ only in the order of addition of the two alkylating agents. The alkylation order is typically chosen depending on the reactivity of the electrophilic side chain. Generally, it is preferable to react first the less reactive electrophilic side chain. This reduces the amount of dialkylation that occurs in this first alkylation step, thus producing a higher yield of monoalkylated material to continue with the next alkylation. In SCHEMAnS 1 and 2, one of the alkylating agents containing a carboxylic acid or an isosteric carboxylic acid, protected, if necessary, with an appropriate protecting group.

In addition, in SCHEMES 1 and 2, the precursor of the carboxylic acid of Formula 3 is a carboxylic acid ester in which R is an appropriate carboxylic acid protecting group. Generally, the protecting group is either a straight-chain lower alkyl, preferably methyl or ethyl, or a tertiary group. butyl or phenyl. Other isosteric acids can be employed by appropriately modifying SCHEMES 1 and 2 of the procedures well known to those skilled in the art (for example, see SCHEME 6, which shows the preparation of a tetrazole). Typically alkylating agents are primary, secondary, benzylic or allylic halides and sulfonates and are preferably alkyl bromides or alkyl iodides. The sulfonamide or amide of Formula 1 is converted to its anion with a strong base, such as sodium hydride, lithium diisoprpilamide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide., potassium tert-butoxide, etc. In an aprotic solvent, such as dimethylformamide, tetrahydrofuran or N, N-dimethylformamide / benzene at a temperature from about -78 ° C to about 100 ° C. The resulting anion is alkylated with an appropriate alkyl halide of Formula 2 or 3 or an appropriate alkyl sulfonate of Formula 2 or 3, wherein X 'is the halide or sulfonate portion of the alkylating agent, at a temperature of about 0 °. C up to about 100 ° C giving the corresponding mono-alkylated compound of Formula 4 or 5. In some cases, the variable amounts of a byproduct resulting from the dialkylation of the amide or sulfonamide are obtained and can be removed using chromatographic techniques, preferably chromatography ultrafast (WC Still, M. Kahn, A. Mitra, J. Org. Chem. 43, 2923, 1978). After the first alkylation is complete, the compound of Formula 4 or 5 is converted to an anion using an appropriate base such as a sodium hydride, lithium bis (trimethylsilyl) amide, .afc ^^^ riti ^ c - ^^ aa ^ ÉJI »- *.!» »*. lithium diisopropylamide, potassium bis (trimethylsilyl) amide, potassium tert-butoxide or potassium carbonate in an aprotic solvent, such as N, N-dimethylformamide, tetrahydrofuran or N, N-dimethylformamide / benzene or acetone at a temperature of about -78 ° C up to approximately 100 ° C. Alkylation of the anion with a second appropriate alkyl halide of Formula 3 or 2 or alkyl sulfonate of Formula 3 or 2, provides the corresponding dialkylated compound of Formula 6. When R is methyl or ethyl, the ester of Formula 6 is hydrolyzed to the corresponding carboxylic acid of Formula I with a dilute aqueous basic solution. This hydrolysis is performed preferably using sodium or potassium hydroxide in aqueous methanol or ethanol or aqueous tetrahydrofuran at a temperature from about 0 ° C to about 80 ° C. On the other hand, the hydrolysis can be carried out using procedures well known to those skilled in the art, for example, the procedures described in "Protecting Groups in.

Organic Synthesis ", Second Edition, T.W. Greene and P.G.M. Wuts, John Wiley and Sons, Inc., 1991.

SCHEME 1 1. Base 1. Base G- A- NH, G- A- N- K- M X'- KK-M H X'-Q- CO2R 2 G- A- N- Q- CO2R l. NaOH G- A- N- Q- CO2H K-M 2. H3O4? -M 6 SCHEME 2 1. Base 1. Base G- A- NH9 * - G - A - - - N - - QQ-- CCOO ,, RR * - 2 2. X '-Q-CO2R H 22 .. XX' '- KK - M 5 2 O9H 6 I Compounds of Formula I wherein B is N are also prepared from the amines presented in SCHEMES 3 and 4. In general, the appropriate amine starting compounds of Formulas 9 and 10 are commercially available or can be obtained prepare using procedures well known to those skilled in the art (see "The Chemistry of Amino, Nitroso and Nitro Compounds and their Derivatives ", Ed. S. Patai, J. Wiley, New York, 1982. For example, the amine starting materials are prepared from the corresponding nitriles of Formulas 7 or 8. Said nitriles are commercially available or can be prepared using methods well known to those skilled in the art (see Rappaport, "The Chemistry of the Cyano Group", Interscience, New York, 1970, or Patai and Rappaport, "The Chemistry of Functional Groups ", p.2, Wiley, New York, 1983) The nitrile of Formula 7 or 8 is reduced with a reducing agent, such as a complex of borane-tetrahydrofuran, a complex methyl borane sulfide or lithium aluminum hydride in an aprotic solvent, such as tetrahydrofuran or diethyl ester at a temperature from about -78 ° C to about 60 ° C. On the other hand, the nitrile is hydrogenated under a hydrogen atmosphere, typically at 0 to 344,737 kPa in the presence of Raney nickel or a palladium or platinum catalyst in a protic solvent, such as methanol or ethanol, at a temperature from about 0 ° C to about 50 ° C. It may be desired to add an equivalent of an acid such as hydrogen chloride to carry out the reduction. The amine of Formula 9 or 10 thus obtained is converted to the sulfonamide of Formula 11 or 12 by sulfonylation with a sulfonyl chloride or Said amine is converted to an amide of Formula 11 or 12 by acylation with an appropriate acid chloride. Both sulfonylation and acylation reactions are generally carried out in the presence of a weak base, such as triethylamine, pyridine or 4-methylmorpholine in an aprotic solvent, such such as methylene chloride or cfelyl ester at a temperature from about -20 ° C to about 50 ° C. On the other hand, the coupling of amines of Formulas 9 or 10 with carboxylic acids is conveniently carried out in an inert solvent, such as dichloromethane or N, N-5-dimethylformamide by a coupling agent, such as 1- (3-dimethylaminopropyl) hydrochloride. 3-ethylcarbodiimide (EDC) or 1,3-dicyclohexylcarbodiimide (DCC) in the presence of 1-hydroxybenzotriazole hydrate (HOBT) to give the compounds of Formulas 11 or 12. When the amine is in the hydrochloride form of another salt, it is preferable to add an equivalent of an appropriate base, such as triethylamine, to the reaction mixture. On the other hand, the coupling can be carried out with a coupling reagent, such as benzotriazol-1-yloxy-tris (dimethylamino) -phosphonium hexafluorophosphate (BOP) in an inert solvent, such as methanol. Said coupling reactions are generally performed at temperatures from about -30 ° C to about 80 ° C, preferably 0 ° C to about 25 ° C. For further details of other conditions used for the coupling peptides, see Houben-Weyl, Vol.XV, part II, E. Wunsch, Ed. George Theime Verlag, 1974, Stuttgart. If desired, the alkylation and deprotection of the compound of Formula 11 or , as described in SCHEMA 1 and 2, gives the corresponding acid compound of Formula 13 and 14. The compounds of Formulas 11 and 12 are alkylated analogously to the alkylation of the compounds of Formula 1, 4 and 5 of SCHEMES 1 and 2 above. The products alkylates are deprotected, if necessary, to give the compounds of Formulas 13 and 14. The amines of Formulas 9 and 10 are also prepared by reducing an appropriate amide of Formulas 15 and 16. This reduction is done using reagents, such as as a borane-tetrahydrofuran complex, a borane-methyl sulfide complex or diisobutylaluminum hydride in an aprotic solvent, such as tetrahydrofuran or diethyl ether at a temperature from about -78 ° C to about 60 ° C. The amines of Formulas 9 and 10 are also obtained from the corresponding nitro precursors by reduction of the nitro group using the reducing reagents, such as zinc / HCl, hydrogenation in the presence of Raney nickel, platinum and palladium catalysts, and others. reagents described by PN Rylander in "Hydrogenation Methods", Academic Press, New York, 15 1985. • .. ^^^ a, ^^ ^^ mt ^^ »^^^^. ^^^ -, t ^ ... ^ U. ^ SCHEME 3 X., M H2N 15 [H] GACI Base SCHEME 4 16 [H] • .z, H2N ^ -a-Z 8 10 20 GACI Base 2 12 3. Hydrolysis ** k ^? * ?*YE*? - ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ "The amines and alkylating agents useful for the above syntheses are described and prepared as presented in the later section entitled PREPARATIONS. Compounds of Formula I wherein B is N are prepared by reductive amination of an aldehyde containing the acid functionality appropriately protected with an amine This sequence is presented in SCHEME 5. On the other hand, the amine may contain the appropriate acid functionality The reductive amination is typically carried out at a pH between 6 and 8, using a reducing agent, such as sodium cyanoborohydride or sodium triacetoxyborohydride.The reaction is usually carried out in a protic solvent such as methanol or ethanol at temperatures from about -78 ° C to about 40 ° C (for example, see A. Abdel-Magid, C. Maryanoff, K. Carson, Tetrahedron, Lett 39, 31, 5595-5598, 1990). The reductive amination reaction can also be carried out using titanium isopropoxide and sodium cyanoborohydride (RJ Mattson et al., J. Org. Chem. 1990, 55, 2552-4) or by pre-formation of the imine under dehydrating conditions followed by reduction. The resulting amine of Formula 42 and 42A is transformed into the desired amide or sulfonamide by coupling with an acid chloride, sulfonyl chloride or carboxylic acid as presented in SCHEMATICS 3 and 4. If desired, the amine intermediate of Formulas 42 or 42A can be converted to a urethane by treatment with a chloroformate or in a tetrasubstituted urea by treatment with a chlorocarbonyl amide. These reactions are carried out in the presence of a weak base, such as triethylamine, pyridine, or 4-methylmorpholine in an aprotic solvent such as methylene chloride or diethyl ether at a temperature from about -20 ° C to about 50 ° C. The conversion of the amine of Formulas 42 or 42A into a trisubstituted urea is carried out by treatment with an isocyanate in an aprotic solvent such as methylene chloride or diethyl ether at temperatures ranging from -20 ° C to 50 ° C (e.g., See SCHEME 5A). In cases where the amine appears as the hydrochloride salt, it is preferable to add one equivalent of one base appropriate as triethylamine to the reaction. If desired, hydrolysis of the resulting sulfonamide or amide gives the corresponding acid.

ESQUIEMA5 13 SCHEME 5 A 1. NaOH 2. HsO + 13 The aldehydes useful in the above SCHEME 5 are described and are prepared as presented in the later section entitled PREPARATIONS. The compounds of Formula I wherein B is N and Z is tetrazolyl are prepared as presented in SCHEME 6. A sulfonamide or amide of Formula 4 is alkylated with the appropriate alkyl halide or sulfonate (wherein X X 'is halide or sulfonate), preferably a primary, secondary, benzyl or allyl alkyl bromide, iodide or sulfonate, which contains a nitrile to give a nitrile of Formula 59. This alkylation is carried out by treatment of the sulfonamide or amide of Formula 59 with a base, such as sodium hydride, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, potassium tert-butoxide or potassium carbonate in an aprotic solvent, such as dimethylformamide, dimethylformamide / benzene or acetone followed by reaction of the resulting anion with an appropriate alkylating agent. The alkylation occurs at a temperature from about -78 ° C to about 100 ° C. A preferred process for converting the resulting nitrile of Formula 59 into the triazole of Formula 60 is the treatment of the alkylated nitrile with dibutyltin oxide and trimethylsilylaZide, in refluxing toluene (SJ Wittenberger and BG Donner, J. Org. Chem 1993, 58, 4139-4141, 1993). For a review of alternative preparations of tetrazoles, see R.N. Butler, "Tetrazoles Comprehensive Heterocyclic Chemistry"; Potts, K.T. Ed. Pergamon Press: Oxford, 1984, Vol. 5, pp. 791 to 838.

SCHEME 6 1. Base G- A- N-K-M - 2 ** G- A- N- Q-CN H Q-CN | 4 X K-M 59 (Bu3Sn) 20 TMSNg toluene On the other hand, certain compounds of Formula I wherein B is N, are prepared as presented in SCHEME 7. Thus, the esters of Formula 46 are prepared using the procedures described above in SCHEMATICS 1 and 2. The subsequent coupling of Heck of this intermediate in an aryl halide (preferably an aryl bromide or aryl iodide), an aryl triflate or a ring system containing a vinyl bromide, iodide or triflate, is carried out with a palladium catalyst , such as a palladium acetate or tetrakis (triphenylfine) palladium (0) in the presence of a trialkylamine such as triethylamine. In some cases, it can be added to the The reaction is an additive, such as a triarylphosphine or triarylasene. The reaction is typically carried out in an aprotic solvent such as dimethylformamide or acetonitrile at a temperature from about 0 ° C to about 150 ° C (see RF Heck in Comp.Org Syn., Vol.4, Chap.4,3, p. 833 or Daves and Hallberg, Chem. Rev. 1989, 89, 1433). If desired, the compound of formula 47, it can be hydrolyzed to the corresponding acid. On the other hand, the compound of formula 47 can be hydrogenated and, if desired, 4fe subsequently hydrolyze the corresponding acid of formula 49. The hydrogenation is preferably carried out in a hydrogen atmosphere typically at 0 to 344,737 kPa in the presence of a palladium or sodium catalyst. platinum in an alcohol solvent such as ethanol or methanol at a temperature from about 0 ° C to about 50 ° C. In cases where M represents a partially saturated ring system, hydrogenation will generate a fully saturated ring system.

SCHEME 7 1. H2, catalyst 2. Hydrolysis 49 On the other hand, certain compounds of formula I, in which 15 B is N, are prepared as described in scheme 8. The compounds of formula 51 are prepared as described in schemes 1 and 2 by alkylation of the compounds of formula 5 with an electrophile of formula 2, which contains the appropriate functionality on the M ring. At least one of the substituents of the M ring must be suitable for the subsequent conversion of an aldehyde. For example, electrophiles of formula 2 containing an alcohol protected on the M ring can be alkylated and then deprotected and oxidized in the aldehyde, using reagents well known to those skilled in the art, to generate the compounds of formula 51.

An alternative procedure is to rent with an electrophile of formula 2, wherein M contains a vinyl group. After alkylation, the oxidative cleavage of the double bond provides the desired aldehyde of formula 51. The oxidative cleavage is carried out by transforming the double bond with the 1,2-diol in the catalytic osmium tetroxide and N-methylmorpholine followed by oxidative cleavage to the aldehyde using sodium periodate. On the other hand, oxidizing excision via ozonolysis followed by reduction using reagents, such as methyl sulfide, triphenylphosphine, zinc / acetic acid or thiourea, generates the desired aldehyde of formula 51. The addition of a metal, where Lmetal is any organometallic reagent, such as an organolithium reagent or a Grignard reagent in an aprotic solvent, such as diethyl ether or tetrahydrofuran at a temperature from about -78 ° C to about 80 ° C, followed by hydrolysis of the ester, as described above , provides the desired compound of formula 50.

SCHEME 8 G- A- 51 50 On the other hand, certain compounds of formula I, in which = ^ iiai "'^ ..., ^^ i - || ÉKÍLJl teL_ l !!: B is N, are prepared as described in scheme 9. The appropriate sulfonamide or amide of formula 5 is alkylated using the conditions described in schemes 1 and 2. The alkylating agent is an electrophile which contains a bromide or an aromatic iodide or a ring system containing a bromide or vinyl iodide (Ar1) to give compounds of formula 53. The Suzuki-type coupling of the compound of formula 53, thus obtained with an arylboronic acid (Ar2), provides compounds of formula 53. For a reaction of Suzuki, see AR Martin and Y. Yang in Acta Chem. Scand. 1993, 47, 221. The coupling reaction is performed using approximately two equivalents of a base, such as sodium carbonate, potassium carbonate, in the presence of a palladium catalyst, such as tetrakis (triphenylphosphine) palladium (0), palladium acetate, palladium chloride, tris (dibencideneacetone) dipalladium (0) or [1,4-bis (diphenyl-phosphin) butan] palladium (0). The reaction can be carried out in an aqueous alcohol solvent such as methanol or ethanol; or in other aqueous solvents such as aqueous tetrahydrofuran, aqueous acetone, aqueous dimethyl glycol ether or aqueous benzene at temperatures ranging from about 0 ° C to about 120 ° C. When Ar1 is a partially saturated ring, the reduction of the ring to give a saturated ring system may, if desired, be carried out at this point. This transformation is carried out by hydrogenating the partially saturated ring in the presence of a catalyst such as palladium or platinum in an alcohol solvent (ethanol or methanol) and / or ethyl acetate. The hydrolysis of the ester of the compounds of formula 53 or 53a, if desired, provides the corresponding ggj ^ É acid. The resulting acids can contain functional groups on any of the ring systems (Ar1 or Ar2), which can be modified using methods well known to those skilled in the art. Examples of such modifiers are shown in scheme 10.

SCHEME 9 G- A- Ar2B (OH) 2 Base Pd Catalyst The compounds of formula 54 which contain a functional aldehyde group are prepared using procedures described in schemes 8 and 9. In scheme 10, the treatment of a compound of formula 54 with an appropriate organometallic reagent (Lmetal), such as a reagent of organolithium or a Grignard reagent, in an aprotic solvent, such as diethyl ether or tetrahydrofuran at a temperature of about -78 ° C & &, < R > to about 80 ° C, followed by hydrolysis of the ester, gives compounds of formula 56. On the other hand, reduction of the aldehyde followed by hydrolysis yields compounds of formula 55.

SCHEME 10 1. LMetal 2. Hydrolysis On the other hand, certain compounds of formula I, wherein B is N, are prepared as described in scheme 11. The starting alcohols of formula 58 are prepared by methods well known to those skilled in the art, for example , using the procedures described in schemes 1 and 2. A person skilled in the art will know that protective groups may be needed in the synthesis of some of these alcohols. Intermediate 58 is coupled with several aryl alcohols (M is ^ ^^^^ ¿fc < ^^^ f «- defined above) using the coupling conditions of Mitsonobu (for a review, see O. Mitsonobu, Synthesis, 1, 1981). Typically the coupling is performed by the addition of a coupling agent such as triphenylphosphine and diethyl azodicarboxylate or diisopropyl azodicarboxylate in an inert solvent, such as methylene chloride or tetrahydrofuran, at a temperature of from about 0 ° C to about 80 ° C. . If desired, the subsequent hydrolysis yields the corresponding acid.

SCHEME 11 On the other hand, certain compounds of formula I, wherein B is N, are prepared as described in scheme 12. A compound of formula 102 is added to a compound of formula 105 (wherein X is defined as above it has been made for the compound of formula I) in the presence of a Lewis acid, such as titanium tetrachloride or a mineral acid such as hydrochloric acid. If desired, the ester of formula 106 can be converted into the corresponding acid by hydrolysis or by deprotection.

SCHEME 12 On the other hand, certain compounds of formula I, wherein B is N, are prepared as described in scheme 13. The chloromethyl compounds of formula 104 are treated with the appropriately substituted aromatic ring system, M, such as a 4-ethoxybenzene or thiophene in the presence of a Lewis acid, such as titanium tetrachloride or a mineral acid, such as hydrochloric acid, in an aprotic solvent, such as chloroform, at a temperature from about 0 ° C to about 80 ° C, giving compounds of formula 107 which can be hydrolyzed or deprotected subsequently as described above giving the corresponding carboxylic acids. On the other hand, the chloromethyl compounds of formula 104 can be treated with a Lewis acid such as titanium tetrachloride and an appropriately substituted vinyl silane, in an aprotic solvent such as methylene chloride, at a temperature of about -50 °. C to about 50 ° C giving compounds of formula 108. If desired, the compounds of formula 108 can be further hydrolyzed or deprotected as described above to give the corresponding acid. If desired, the reduction of the double bond can be made using the conditions described in scheme 7.

SCHEME 13 108 On the other hand, certain compounds of formula I, wherein B is N, are prepared as described in scheme 14. The chloromethyl compounds of formula 104 are treated with a Lewis acid, such as titanium tetrachloride and an appropriately substituted allyl silane in an aprotic solvent such as chloroform at a temperature from about 0 ° C to about 80 ° C to give the compounds of formula 109, which can be subsequently hydrolyzed or deprotected as described above, giving the corresponding carboxylic acids.

^ ^ ^^^^ "¡^ ^ ^ ^^^^^ ^^^^^^^^^^^ B £ if SCHEME 14 On the other hand, certain compounds of formula I, wherein B is N, are prepared as described in scheme 15. The chloromethyl compounds of formula 104 are treated with a sulfinic acid of formula 111 in the presence of a base, such as triethylamine, in an aprotic solvent such as chloroform at a temperature from about -30 ° C to about 50 ° C, giving compounds of formula 112, which can be subsequently hydrolyzed or deprotected as described above, giving the corresponding acid . m? * ¿- ¡¡M4, * Í2_í ?? «aS3, i *: StfUfcfi .. g ÜÜÜ ^^! b ^ ^^? tÜt, SCHEME 15 112 H02S- M 111 The compounds of formula I, wherein B is C (H) and Q, G, M and K are as described above in the summary of the invention, can be prepared according to scheme 16. The beta-ketoesters of formula 113 are alkylated sequentially with the compounds of formula 114 to form the compounds of formula 115, followed by alkylation with compounds of formula 116 to give compounds of formula 117 (J. Med. Chem. 26, 1993, p 335-341). The alkylations can be carried out in an appropriate solvent, such as DMF, THF, ether or benzene, using an appropriate base such as sodium hydride, LDA or potassium carbonate at a temperature from about -78 ° C to about 80 ° C. The resulting disubstituted ketoesters of formula 117 are hydrolyzed and decarboxylated to give the corresponding compound of formula 118 using an aqueous base, such as sodium hydroxide, to hydrolyze the ester, followed by a reaction for acidic quenching, such as with aqueous hydrochloric acid, to effect decarboxylation.

SCHEME 16 118 117 15 On the other hand, the compounds of formula I, wherein B is C (H) and G, Q, M and K are as described above in the summary of the invention, can be prepared according to scheme 17. Sequential alkylation of a malonate derived from formula 119 provides the dialkylated compound of formula 121. Deprotection of the ester group by treatment with a strong acid, such as TFA or HCl in ethanol at a temperature from about -20 ° C to about 50 ° C gives the product *? ~ lai? * * ~ & m? ai ?. j? ^. d) Decarboxylate of formula 122. The conversion of the acid to an acid chloride using thionyl chloride or oxalyl chloride in an aprotic solvent at a temperature from about -78 ° C to about 50 ° C or in an amide of Weinreb using methoxymethylamine in the presence of an appropriate coupling agent, such as DCC or DEC, in an aprotic solvent at a temperature from about -30 ° C to about 50 ° C, gives the compounds 123. The compounds of formula 123 are suitable substrates for the addition of various organometallic species, for example, Grignard reagents and organocadmium reagents, which after hydrolysis of the terminal ester, yield the keto acid compounds of formula 118. Moreover, compounds of formula 118 can be prepared using procedures previously described in schemes 7-11, where one or both side chains are further functionalized after to union of the alkanoyl fragment. - * ¡- * aa m? * M S¡is al¡ &, SCHEME 17 , OMs 120 X = Br, Cl, I, OMs Base that is, NaH 114 10 122 121 123 118 ^^ g PREPARATIONS Amines, amides and sulfonamides Certain amides or sulfonamides described by formulas 5 21, 22 and 23, wherein W and Z are as described above in the summary of the invention, and X and M are aromatic or saturated ring systems, prepare as presented in scheme 18. The alkynylamides or sulfonamides of formulas 25, 26 and 27 are prepared by coupling an alkynylsulfonamide or alkylamide of formula 24 with aromatic or vinyl halide, Preferably an aromatic or vinyl bromide or iodide in which W and Z are as defined above, and wherein X and M represent an aromatic ring or a partially saturated ring system. The coupling is typically performed in the presence of copper iodide, a palladium catalyst, such as palladium chloride, bis (triphenylphosphine) palladium dichloride or Tetrakis (triphenylphosphine) palladium (0) and an amine such as triethylamine, diisopropylamine or butylamine in an aprotic solvent such as acetonitrile at a temperature from about 0 ° C to about 100 ° C. The alkynes of formulas 25, 26 and 27 are converted into the corresponding alkanes of formulas 21, 22 or 23 by hydrogenation in the presence of a platinum catalyst or platinum catalyst in a solvent, such as methanol, ethanol and / or ethyl acetate at a temperature from about 0 ° C to about 50 ° C. In the case where M represents a partially saturated ring system, hydrogenation will convert M into a fully saturated ring system. On the other hand, the alkynes are converted to the cis-alkenes using a Lindlar catalyst (Pd-CaCO3-PbO) or another appropriate catalyst. Alkylation and deprotection, as described in schemes 1 and 2, gives the corresponding compounds of formula I.

SCHEME 18 m GANH ^ ?. 24 ?? / XXz xw X'- M Cu catalyst X '= Br, from Pd 26 27 H2 catalyst GANH "- ?? GANH 'X V GANH' 21 22 23 .. ^. «« A ^ A-, SCHEME 19 H-N ^ ^ X ^ ^^ * - GAN ^ X. 2"H? DCH3 Base U ^ DCH3 32 31 Demethylation GANH Compounds of formula 33 are prepared from an appropriate amine of formula 32 (for example, metaxyarylalkylamine). The amines of formula 32 are commercially available or prepared by methods well known in the art (for example, see scheme 4). The amines of formula 32 are converted to the sulfonamides or amides of Formula 31 using procedures, for example, described in scheme 3 and 4. The resulting aromatic methyl ester of formula 31 is deprotected with reagents, such as boron tribromide, pyridinium hydrochloride, hydrogen bromide / acetic acid or other reagents as are described in Protecting Groups in Organic Synthesis, Second Edition, TW Greene and P.G.M Wuts, John Wiley and Sons Inc., 1991. Alkylation with a bromoalkyl ester using a mild base, such as potassium carbonate in an aprotic solvent such as dimethylformamide or acetone at a temperature from about 0 ° C to about 100 ° C generates a amide or a sulfonamide of formula 33.

SCHEME 20 H3C - M BrCH2 - M or 0 0 initiator 0 H3C-X-f ^ n BrCH2 - X - (- ^ n There are numerous methods for the synthesis of the desired alkylating agents used in the above processes, being known to those skilled in the art (see "The Chemistry of the Carbon-Halogen Bond", Ed. S. Patai, J. Wiley, New York, 1973 and "The Chemistry of Halides, Pseudo-Halides and Azies", Eds. S. Patai and Z.

Rappaport, J. Wiley, New York, 1983). Some are shown in the 20-24 schemes. As seen in scheme 20, the tolyl or allylic substrates can be converted by halogenation into benzylic or allylic bromides in which M, X, W and Z are as described above in the summary of the invention. The reaction is typically carried out with N-bromosuccinimide (NBS) in the presence of an initiator radical, such as 2,2-azobisisobutyronitrile (AIBN) or a peroxide, preferably benzoyl peroxide. On the other hand, the reaction can be initiated with light. The reaction is carried out in an inert solvent, such as carbon tetrachloride or chloroform at a temperature from about 50 ° C to about 100 ° C.

SCHEME 21 Br H3C - Ar1 Pd catalyst M r? Rl NBS ^ - Ar1 10 \ + halóg. - Ar2 * - H3 ° Arv »\ B (OH) 2 base 2 rad? Cal Ar2 34 initiator ^ 5 In scheme 21 presents the synthesis of alkylating agents useful for the preparation of the compounds of formula I wherein M represents a biaryl group or cyclic aryl. The Suzuki type coupling of an iodide or Aryl bromide or a ring system containing a vinyl bromide or iodide (Ar2) with a methyleryl boronic acid (Ar1) using the conditions described in scheme 9 provides compounds of formula 34. When a bromide or iodide of vinyl, the compounds of formula 34 can be reduced to generate a fully saturated ring. The reduction is done by hydrogenation in the presence of palladium or platinum catalysts typically in protic solvents, such as methanol or ethanol, in a tetrahydrofuran or ethyl acetate. Halogenation of the methyl group using reagents and conditions as described in scheme 20, provides agents gjggj ^ g --MÉÜ & alkylating agents of formula 35.

SCHEME 22 O il M hydruro ^. M ^ \ JA halóg. R = H, alkyl Another common procedure for obtaining alkyl halides is by halogenation of an alcohol or an alcohol derivative. The alcohols are obtained from commercial sources or can be prepared using procedures well known to those skilled in the art. For example, scheme 22 shows the reduction of a carboxylic acid or ester in the corresponding alcohol using reagents such as (but not limited to) sodium borohydride, lithium aluminum hydride, borane-tetrahydrofuran complex, borane-methyl sulfide complex, etc. The corresponding alkyl chlorides are typically prepared from alcohols with reagents, such as hydrogen chloride, thionyl chloride, phosphorus pentachloride, phosphorus oxychloride or triphenylphosphine / carbon tetrachloride. For the preparation of alkyl bromides, alcohol is treated generally with reagents such as hydrogen bromide, phosphorus tribromide, triphenylphosphine / bromine or carbonylimidazole / allyl bromide (Kamijo, T. Harada, H., lizuka, K. Chem. Pharm. Bull. 1983, 38, 4189). To obtain the alkyl iodides, an appropriate alcohol is typically reacted with reagents, such as triphenylphosphine / iodine / imidazole or hydrogen iodide. On the other hand, the alkyl chlorides can be converted to the more reactive alkyl alkyl bromides or alkyl iodides by reaction with an inorganic salt such as sodium bromide, lithium bromide, sodium iodide or potassium iodide in solvents such as acetone or methyl ethyl ketone. The alkyl sulfonates can also be used as electrophiles or can be converted to alkyl halides. The alkyl sulfonates are prepared from the corresponding alcohol using a mild base such as triethylamine or pyridine and a sulfonyl chloride in an inert solvent such as methylene chloride or diethyl ether. If desired, the conversion to the halide is carried out by treating the alkyl sulfonate with an inorganic halide (sodium iodide, sodium bromide, potassium iodide, potassium bromide, lithium chloride, lithium bromide, etc.) or a tetrabutylammonium halide.

SCHEME 23 halogen '37 R = H, alkyl hydride H. catalyst halo '38 Cinnamic acids or esters are commercially available and can be converted to alkylating agents of formulas 37 or 38 in the following manner (see scheme 23). The cinnamic acid or ester derivatives are reduced by hydrogenation in the presence of palladium or platinum catalysts typically in protic solvents (for example, methanol or ethanol), tetrahydrofuran or ethyl acetate. The reduction and conversion in alkyl halide or sulfonate as described in scheme 22 provides the compounds of formula 38. Where appropriate, the cinnamic acids or esters are converted directly to the alcohols of formula 39 by the treatment of these cinnamic acids or esters with reactants such as lithium aluminum hydride in an inert solvent such as tetrahydrofuran and diethyl ether. On the other hand, the cinnamic acid or ester can be reduced to an allyl alcohol of formula 40 using reagents, such as lithium aluminum hydride / aluminum chloride, diisobutylaluminium hydride or borohydride. Conversion to the allyl halide or sulfonate, as described in scheme 22, provides the compounds of formula 37.

SCHEME 24 1. Base HW M W- M x) n Br, I 42 41 X = Cl, Br The preparation of the alkylating agents of formula 41, wherein W and M are as described above in the summary of the invention, is presented in scheme 24. The compounds of formula 42 can be alkylated with different bases. The choice of a base depends on the nature of W and M. Some of the preferred bases include (but are not limited to) sodium hydroxide, sodium hydride, lithium diisopropylamide, lithium (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide and potassium tert-butoxide. Treatment of the resulting anion with one of a range of dialkyl halides generates the desired alkylating agents of formula 41. For the preparation of compounds in which W is an oxygen and M is an aromatic ring, it is preferred to form an alkoxide anion with hydroxide sodium followed by the addition of a dihaloalkane, for example, dibromoalkane. The reaction is usually carried out in water from about 75 ° C to about 125 ° C.

SCHEME 25 44 45 H30 ^ OH OHC ^^ M '43 Aldehydes useful for the process described in scheme 5 are commercially available or can be prepared from available intermediates using procedures well known to those skilled in the art (for a general reference, see "The Chemistry of the Carbonyl Group ", Ed. S. Patai, Interscience, New York (1966-70)). Scheme 25 shows an example of a method used to prepare the hydroxyaldehydes of formula 43, wherein M in scheme 5 contains an alkyl group substituted with a hydroxy. The treatment of a dialdehyde, in which one of the aldehydes is protected as an acetal of formula 44, in which the OR groups are conventional substituents used in an acetal protecting group, with an organometallic reagent (Lmetal), preferably an organolithium reagent or Grignard, in an inert solvent, such as tetrahydrofuran or diethyl ether, provides compounds of formula 45. Hydrolysis of the subsequent acetal under mild acidic conditions, eg, diluted hydrogen chloride, resin Amberlyst-15®, silica gel or other reagents described in Protecting Groups in Organic Synthesis, Second Edition, T.W. Greene and P.G.M Wuts, John Wiley and Sons Inc., 1991 provide the desired hydroxyaldehydes of formula 43. The aldehydes useful for the process described in scheme 5 can be prepared using the procedures described in schemes 26-28. For example, as seen in scheme 26, an acid The arylboronic acid containing an aldehyde can be coupled to an aryl bromide, aryl iodide or a ring system, which contains a bromide or vinyl iodide using the Suzuki protocol described for scheme 9, giving aldehydes of formula 60.

, ^^^ S ^ (i, .. ..,.: "> ...",,.: ... .. * ¿^ ^ ..TZ * j * tH ~. ^? 27 describes the preparation of aldehydes of formula 62 which contain an appropriately protected acid radical and which can be used for the preparation of the compounds of formula 42A described in scheme 5. The selective reduction of nitriles (see schemes 3-4 for the preparations) of formula 61 provides aldehydes of formula 62. A preferred process for this reduction involves heating the nitrile with an aluminum-nickel alloy (Raney) in the presence of an acid such as formic acid. Preparation of the compounds of formula 42 (scheme 5) can be prepared from the starting nitriles of formula 63 by treatment with a variety of reducing agents, such as diisobutylaluminum hydride, tin (II) chloride / hydrogen chloride or lithium triethoxyalate, a procedure for the preparation of propionaldehydes of formula 65 are described in scheme 28 and follow the procedures described by Kang (J. Org. Chem. 1996, 61, 2604) and by Jeffrey (J. Chem. Soc. Commun. 1984, 19, 1287). An iodide or aryl bromide is coupled to the allyl alcohol in the presence of an appropriate palladium catalyst, preferably palladium acetate. The reaction is carried out in an appropriate polar aprotic solvent, preferably dimethylformamide, with addition of a base, such as sodium dicarbonate and an ammonium salt, such as tetrabutylammonium chloride and provides propionaldehydes of formula 65.

SCHEME 26 OHC- Ar catalyst of Pd OHC-Ar1 halóg. - Ar2 \ base \ B (OH) 2 Ar2 60 SCHEME 27 63 64 SCHEME 28 15 Pd Ar-Ar halgon catalyst. + NaHC03, Bu4NCI -CHO 65 Chloromethyl Intermediates Chloromethyl intermediates can be prepared as described in schemes 29 and 30. In general, the appropriate sulfonamide or carboxamide of formula 66 or 68 is treated with an equivalent formaldehyde, such as paraformaldehyde in an organic solvent , such as methylene chloride or chloroform, with an appropriate catalyst such as HCl, zinc chloride or trimethylsilyl chloride at temperatures ranging from about 0 ° C to about 60 ° C giving the derivatives of chloromethyl of formula 67 and 69, respectively.

SCHEME 29 (CHO) n G - A- -NH G- A- N XI HCI or TMSCI K. K ^ ^ M M 66 67 SCHEME 30 Scheme 31 presents the synthesis of biaryl aldehydes of formula 60. The fluorobenzonitriles of formula 70 are heated with a nucleophilic group, such as a pyrrazole or imidazole, in an appropriate solvent, preferably DMF to perform the displacement of the fluoro group, giving the intermediates of formula 71. The desired biaryl aldehydes of formula 60 are obtained by reduction of the nitrile by hydrogenation with a Raney alloy in formic acid or by reduction with a hydride, such as hydride of diisobutylaluminum.

Ar2 = pyrazole, J = CH or N pyrrole or inidazole It will be recognized that the compounds of formula I of this invention can exist as radioactively labeled forms, ie, said compounds can contain one or more atoms containing an atomic mass or mass number different from the atomic mass or the mass number that normally exists in nature. The radioisotopes of hydrogen, carbon, phosphorus, fluorine and chlorine include 3H, 14C, 32P, 35S, 18F and 36CI, respectively. The compounds of formula I of this invention which contain these radioactive isotopes and / or other radioactive isotopes of other atoms are within the scope of this invention. Preferred MIM especially the tritiated radioactive isotopes, that is, 3H, and carbon 14, ie 4C, for their ease of preparation and detection. The radiolabelled compounds of formula I of this invention can be prepared generally according to procedures that are well known to those skilled in the art. Conveniently, said radiolabeled compounds can be prepared following the procedures described in the above schemes and / or in the following examples and preparations by substituting a radioactively labeled reagent readily available for a radioactively unlabeled reagent. Those skilled in the art will recognize that anti-resorption agents can be used (eg, progestins, polyphosphonates, bisphosphonate (s), estrogen agonists / antagonists, estrogens, estrogen / progestin combinations, Premarin®, estrone, estriol or 17a- or 17β-ethynyl estradiol) together with the compounds of this invention. Examples of progestins that are commercially available are algestone acetophenide, altrenogest, amadinone acetate, anagestone acetate, chlormadinone acetate, cingestol, clogestone acetate, clomegestone acetate, delmadinone acetate, desogestrel, dimetiestirone, dydrogesterone, etinerone, diacetate of ethinodiol, etonogestrel, flurogestone acetate, gestaclone, gestodene, gestonorone caproate, gestrinone, haloprogesterone, hydroxyprogesterone caproate, levonorgestrel, linestrenol, medrogestone, medroxyprogesterone acetate, melengestrol acetate, methynediol diacetate, norethindrone, norethindrone acetate, norethynodrel , norgestimate, norgestomet, norgestrel, oxogestone fenpropionate, progesterone, quingestanol acetate, quingestrone and tigestol. The preferred progestins are medroxyprogesterone, norethindrone and norethinodrel. Examples of polyphosphonates that inhibit bone resorption are polyphosphonates of the type described in US Patent 3,683,080, the disclosure of which is incorporated herein by reference. The preferred polyphosphonates are geminated diphosphonates (also called bisphosphonates). An especially preferred polyphosphonate is disodium tiludronate. An especially preferred polyphosphonate is ibandronic acid. An especially preferred polyphosphonate is alendronate. An especially preferred polyphosphonate is zoledronic acid. Other preferred polyphosphonates are 6-amino-1-hydroxy-hexylidene-bisphosphonic acid and 1-hydroxy-3 (methylpentylamino) -propylidene-bisphosphonic acid. The polyphosphonates can be administered in the form of an acid, an alkali metal salt or a soluble alkaline earth metal salt. Also, the hydrolysable esters of the polyphosphonates are included. Specific examples include ethane-1-hydroxy-1,1-diphosphonic acid, methane diphosphonic acid, pentane-1-hydroxy-1,1-diphosphonic acid, methane dichloro diphosphonic acid, methane hydroxy diphosphonic acid, ethane-1-amino acid -1, 1 -diphosphonic acid, ethane-2-amino-1,1-diphosphonic acid, propane-3-amino-1-hydroxy-1,1-diphosphonic acid, propane-N, N-dimethyl-3-amino acid- 1-hydroxy-1,1-diphosphonic acid, propane-3-3-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid, phenyl amino methane diphosphonic acid, N, N-dimethylamino methane diphosphonic acid, N (2-hydroxyethyl) amino methane diphosphonic acid, butane-4-amino-1-hydroxy-1,1-diphosphonic acid, pentane-5-amino-1-hydroxyl acid -1, 1-diphosphonic acid, hexane-6-amino-1-hydroxy-1, 1-diphosphonic acid and the esters and pharmaceutically acceptable salts thereof. In particular, the compounds of this invention can be combined with a mammalian estrogen agonist / antagonist. Any estrogen agonist / antagonist can be used as the second compound of this invention. The term "estrogen agonist / antagonist" refers to compounds that can bind to the estrogen receptor, inhibiting bone turnover and preventing bone loss. In particular, estrogen agonists are defined herein as chemical compounds capable of binding to the estrogen receptor sites in the mammalian tissue and mimic the actions of estrogens in one or more tissues. Estrogen antagonists are defined herein as chemical compounds capable of binding to the estrogen receptor sites in the mammalian tissue and blocking the actions of estrogens in one or more tissues. Such activities will be readily determined by those skilled in the art in accordance with conventional assays including estrogen receptor binding assays, bone histomorphometric procedures and conventional densitometric methods and with Eriksen E. F et al., Bone Histomorphometry. , Raven Press, New York, 1994, pages 1-74; Grier S. J. et al., The Use of Dual Energy X-Ray Absorptiometry In Animáis, Inv. Radiol., 1996, 31 (1): 50-62; Wahner H. W. and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice., Martin Dunitz Ltd., London 1994, pages 1-296). Next, several of these compounds are described and described. A preferred estrogen agonist / antagonist is droloxifene: ((E) -3- (1- (4 (2- (dimethylamino) ethoxy) phenyl) -2-phenyl-1-butenyl) -phenol) and related compounds, which are described in U.S. Patent 5,047,431, the disclosure of which is incorporated herein by reference. Another preferred estrogen agonist / antagonist is 3- (4- (1,2-diphenyl-but-1-enyl) -phenyl) -acrylic acid, which is described in Willson et al., Endocrinology, 1977, 138, 3901-3911). Another preferred estrogen agonist / antagonist is the tamoxifen: 2-hydroxy-1, 2,3- ((Z) -2-2- (4- (1, 2-diphenyl-1-butenyl) phenoxy) -N, N-dimethyl-ethanamine propane-tricarboxylate (1: 1)) and related compounds, which are described in U.S. Patent 4,536,516, the disclosure of which is incorporated herein by reference. Another related compound is 4-hydroxy tamoxifen, which is described in U.S. Patent 4,623,660, the disclosure of which is incorporated herein by reference. A preferred estrogen agonist / antagonist is raloxifene: (6-hydroxy-2- (4-hydroxyphenyl) benzo [b] thien-3-yl) hydrochloride (4- (2- (1- piperidinyl) ethoxy) phenyl) -methanone, which is described in U.S. Patent 4,418,068, the disclosure of which is incorporated herein by reference. Another preferred estrogen agonist / antagonist is the Toremifene: (2-hydroxy-1, 2,3- ((Z) -2- (4- (4-chloro-1, 2-diphenyl-1-butenyl) phenoxy) -N, N-dimethyl- propane-tricarboxylate ethanamine (1: 1)), which is described in U.S. Patent 4,996,225, the disclosure of which is incorporated herein by reference.Another preferred estrogen agonist / antagonist is the centchroman: 1 - (2 - ((4- (methoxy-2,2-dimethyl-3-phenyl-chroman-4-yl) -phenoxy) -ethyl) -pyrrolidine), which is described in US Pat. No. 3,822 .287, the disclosure of which is incorporated herein by reference. Levormeloxifen is also preferred. Another preferred estrogen agonist / antagonist is idoxifen: (E) -1 - (2- (4- (1 - (4-iodophenyl) -2-phenyl-but-1-enyl) phenoxy) ethyl) -pyrrolidinone, which is described in U.S. Patent 4,839,155, the disclosure of which is incorporated herein by reference. Another preferred estrogen agonist / antagonist is 2- (4-methoxy-phenyl) -3- [4- (2-pyridin-1-yl-ethoxy) -phenoxy] -benzo [b] thiophen-6-ol , which is described in U.S. Patent 5,488,058, the disclosure of which is incorporated herein by reference. Another preferred estrogen agonist / antagonist is 6- (4-hydroxy-phenyl) -5- (4- (2-piperidin-1-yl-ethoxy) -benzyl) -naphthalene-2-ol, which is described in U.S. Patent 5,484,795, the disclosure of which is incorporated herein by reference. Another preferred estrogen agonist / antagonist is (4- (2- (2-aza-bicyclo [2.2.1] hept-2-yl) -ethoxy) -phenyl) - (6-hydroxy-2- (4-hydroxy) phenyl) -benzo [b] thiophen-3-yl) -methanone, which is described together with the preparation methods, in PCT publication no. WO 95/10513 assigned to Pfizer Inc. Other preferred estrogen agonists / antagonists include the compounds described in co-assigned U.S. Patent No. 5,552,412, the disclosure of which is incorporated herein by reference. Especially preferred compounds thereof are: c / s-6- (4-fluoro-phenyl) -5- (4- (2-pyridin-1-yl-ethoxy) -phenyl) -5,6,7 , 8- tetrahydro-naphthalen-2-ol; (-) - c / -s-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol; c s-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol; c / s-1- [6'-pyrrolidinetoxy-3'-pyridyl] -2-phenyl-6-hydroxy-1, 2,3,4-tetrahydronaphthalene; 1- (4'-pyrrolidinetoxyphenyl) -2- (4"-fluorophenyl) -6-hydroxy-1, 2,3,4-tetrahydroisoquinoline; cs- (6- (4-hydroxyphenyl) -5- (4- ( 2-piperidn-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol and 1- (4'-pyrrolidinolethoxyphenyl) -2-phenyl) -6-hydroxy-1, 2 , 3,4- tetrahydroisoquinoline. Other estrogen agonists / antagonists are described in U.S. Patent 4,133,814, (the disclosure of which is incorporated herein by reference). U.S. Patent 4,133,814 describes the derivatives of 2-phenyl-3-aroyl-benzothiophene and of 2-phenyl-3-aroylbenzothiophene-1-oxide. Those skilled in the art will recognize that other bone anabolic agents (agents that increase bone mass) can be used in conjunction with the compounds of this invention. An agent that increases bone mass is a compound that increases bone mass to a threshold that is above the level of bone fracture, as detailed in the study of the World Health Organization "Assessment of Risk of Fracture and its Application for the Determination of Postmenopausal Osteoporosis (1994) Report of a WHO study group.

World Health Organization technique 843".) Any prostaglandin or prostaglandin agonist / antagonist can be used as a second compound in certain aspects of this invention, including the use of two different compounds of formula I of this invention. experts in the art will recognize that can also be used IGF-1, sodium fluoride, parathyroid hormone (PTH), active fragments of parathyroid hormone, growth hormone or growth hormone secretagogues. The following paragraphs describe in more detail examples of second compounds of this invention. Any prostaglandin can be used as a second compound in certain aspects of this invention. The term "prostaglandin" refers to compounds that are analogous to the natural prostaglandins PGDL PGD2, PGE2, PGE-i and PGF2, which are useful in the treatment of osteoporosis. These compounds bind to the prostaglandin receptors. Such binding will be readily determined by those skilled in the art in accordance with conventional assays (eg, An S. et al., Cloning and Expression of the EP2 Subtype of Human Receptors for Prostaglandin E2, Biochemical and Biophysical Research Communications, 1993, 197 (1): 263-270). Prostaglandins are alicyclic compounds related to the basic compound, prostanoic acid. The carbon atoms of the basic prostaglandins are numbered sequentially from the atom of The carboxylic carbon is passed through the cyclopentyl ring to the terminal carbon atom of the adjacent side chain. Typically, the adjacent side chains are in trans orientation. The presence of an oxo group in the C-9 of the cyclopentyl radical is indicative of a prostaglandin of class E, while the PGE2 contain a trans-unsaturated double bond in C13-C14 and a cis double bond at the C5-C6 position. Several prostaglandins are described and cited subsequently. However, other prostaglandins will be known to those skilled in the art. Some examples of prostaglandins are described in the patents US 4,171,331 and 3,927,197, the disclosures of which are incorporated herein by reference. Norrdin et al., The Role of Prostaglandins in Bone In Vivo, Prostaglandins Leukotriene Essential Fatty Acids 41, 139-150, 1990, is a 5 report about bone anabolic prostaglandins. Any prostaglandin agonist / antagonist can be used as the second compound in certain aspects of this invention. The term "prostaglandin agonist / antagonist" refers to the compounds that bind to the prostaglandin receptors (by example, An S. et al., Cloning and Expression of the EP2 Subtype of Human Receptors for Prostaglandin E2, Biochemical and Biophysical Research Communications, 1993, 197 (1): 263-270) and mimic the action of prostaglandins in vivo. (for example, they stimulate bone formation and increase bone mass). These actions will be easily determined by the experts in the art according to conventional tests. Eriksen E. F et al., Bone Histomorphometry, Raven Press, New York, 1994, pages 1-74; Grier S. J. et al., The Use of Dual Energy X-Ray Absorptiometry In Animáis, Inv. Radiol., 1996, 31 (1): 50-62; Wahner H. W. and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry Clinical Practice., Martin Dunitz Ltd., London 1994, pages 1-296). Several of these compounds are described and cited below. However, other prostaglandin agonists / antagonists will be known to those skilled in the art. Below are examples of £ & ^ ¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ U.S. Pat. No. 3,932,389, the disclosure of which is incorporated herein by reference, discloses useful 2-decarboxy-2- (tetrazol-5-yl) -11-deoxy-15-substituted-omega-pentanoprostaglandins for the activity of bone formation. The commonly assigned US Patent 4,018,892, the disclosure of which is incorporated herein by reference, discloses 16-aryl-13,14-dihydro-PGE 2 p-biphenyl esters useful for bone formation activity. The commonly assigned U.S. Patent 4,219,483, the disclosure of which is incorporated herein by reference, discloses 2,3,6-substituted 4-pyrones useful for bone formation activity. The commonly assigned U.S. Patent 4,132,487, the disclosure of which is incorporated herein by reference, discloses 2,3,6-substituted 4-pyrones useful for bone formation activity. U.S. Patent 4,000,309, the disclosure of which is incorporated herein by reference, discloses 16-aryl-13,14-dihydro-PGE 2 p-biphenyl esters useful for bone formation activity. US Patent 3,982,016, the disclosure of which is incorporated herein by reference, discloses 16-aryl-13,14-dihydro-PGE 2 p-biphenyl esters useful for bone formation activity. U.S. Patent 4,621,100, the disclosure of which is incorporated herein by reference, discloses substituted cyclopentanones useful for bone formation activity.

U.S. Patent 5,216,183, the disclosure of which is incorporated herein by reference, discloses substituted cyclopentanones useful for bone formation activity. Sodium fluoride can be used as a second compound in certain aspects of this invention. The term "sodium fluoride" refers to sodium fluoride in all its forms (e.g., slow release sodium fluoride, sustained release sodium fluoride). Sustained-release sodium fluoride is described in U.S. Patent 4,904,478, the disclosure of which is incorporated herein by reference. The activity of sodium fluoride will be readily determined by those skilled in the art in accordance with biological protocols (see for example, Eriksen E. F et al., Bone Histomorphometrv, Raven Press, New York, 1994, pages 1-74; Grier S. J. et al., The Use of Dual Energy X-Ray Absorptiometry In You encourage, Inv. Radiol., 1996, 31 (1): 50-62; Wahner H. W. and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice., Martin Dunitz Ltd., London 1994, pages 1-296). The bone morphogenetic protein can be used as the second compound of this invention (for example, see Ono, et al., Promotion of the Osteogenectic Activity of Recombinant Human Bone Morphogenetic Protein by Prostaglandin E1, Bone, 1996, 19 (6), 581- 588). Any parathyroid hormone (PTH) can be used as a second compound in certain aspects of this invention. The term "parathyroid hormone" refers to parathyroid hormone, fragments or ^^^ ü t | ???? aaíMMffiM? i iir ?? miii metabolites thereof and structural analogues thereof, which can stimulate bone formation and increase bone mass. Also included are peptides and active fragments related to parathyroid hormone and analogs of parathyroid hormone-related peptides (see PCT publication WO 94/01460). Said anabolic bone functional activity will be readily determined by those skilled in the art in accordance with conventional tests (for example, see Eriksen E. F et al., Bone Histomorphometry, Raven Press, New York, 1994, pages 1-74.; Grier S. J. et al., The Use of Dual Energy X-Ray Absorptiometry In Animáis, Inv. Radiol., 1996, 31 (1): 50-62; Wahner H. W. and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice., Martin Dunitz Ltd., London 1994, pages 1-296). Several of these compounds are described and cited below. However, other parathyroid hormones will be known to those skilled in the art. Examples of parathyroid hormones are described in the following references. "Human Parathyroid Peptide Treatment of Vertebral Osteoporosis", Osteoporosis Int., 3, (Supp 1): 199-203. "PTH 1-34 Treatment of Osteoporosis with Added Hormone Replacement Therapy: Biochemical, Kinetic and Histological Responses" Osteoporosis Int. 1: 162-170. Any growth hormone or growth hormone secretagogue can be used as a second compound in certain aspects of this invention. The term hormone secretagogue growth refers to a compound that stimulates the release of growth hormone or mimics the action of growth hormone (for example, increases bone formation which results in an increase in bone mass). Such actions will be readily determined by those skilled in the art in accordance with conventional assays well known to those skilled in the art. Several of these compounds are described in the following published PCT patent applications: WO 95/14666; WO 95/13069; WO 94/19367; WO 94/13696 and WO 95/34311. However, those skilled in the art will know other growth hormones or growth hormone secretagogues. In particular, a secretagogue of the preferred growth hormone is N- [1 (R) - [1,2-Dihydro-1-methanesulfonyl-spiro [3H-indol-3,4'-piperidin] -1'-yl ) carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide: MK-677. Other preferred growth hormone secretagogues are: 2-amino-N- (2- (3a- ( R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo- [4,3-c] pyridin-5-yl) -1 - (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide or its salt of L-tartaric acid: 2-amino-N- (1- (R) -benzyloxymethyl-2- (3a- (R) - ( 4-fluoro-benzyl) -2-methyl-S-oxo ^ .S.Sa. ..? J.-hexahydro-pyrazolo-^. S ^ pyridin-d-yl ^ -oxo-ethyl) - butynylamide; amino-N- (2- (3a- (R) -benzyl-3-oxo-2,3,3a, 4,6,7, -hexahydro- pyrazolo- [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl) -isobutyramide; and 2-amino-N- (1- (2,4-difluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3a-pyridin-2-ylmethyl-2- (2,2,2-trifluoro- ethyl) -2,3,3a, 4,6,7-hexahydro-pyrazolo- [4,3-c] pyridin-5-yl) -ethyl) -2-methyl-propionamide. Some of the preparation methods useful for the preparation of the compounds described herein may require the protection of remote functionalities (eg, primary amine, secondary amine, carboxyl in the precursors of formula I). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation procedures. The need for such protection will be readily determined by those skilled in the art. The use of such protection / deprotection procedures are also within the technical scope. For a general description of the protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991. The starting materials and reagents for the compounds described above are readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis. For example, many of the compounds used herein are related to or are derived from compounds found in nature, for which there is great scientific interest and a commercial need and accordingly, many of these compounds are commercially available. or they are cited in the literature or they tt-fc-ttfc. they easily prepare from other commonly available substances by procedures described in the literature. Such compounds are, for example, prostaglandins. Those skilled in the art will know that some of the compounds of this invention have at least one asymmetric carbon atom and, accordingly, are enantiomers or diastereomers. The diastereomeric mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods known per se, for example, by chromatography and / or fractional crystallization. The enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (eg, an alcohol), separating the diastereomers and converting (eg, hydrolyzing, chemical hydrolysis procedures and hydrolysis procedures with microbial lipase, for example, enzyme-catalyzed hydrolysis) the individual diastereomers in the corresponding pure enantiomers. All these isomers, including diastereomers, enantiomers and mixtures thereof are considered as part of this invention. Thus, some of the compounds of this invention are atropoisomers (e.g., substituted biaryls) and are considered as part of this invention. Many of the compounds of this invention, including the compounds of formula I, the anti-resorption agents, the anabolic agents Bones, prostaglandin agonists / antagonists, parathyroid hormones, growth hormones and growth hormone secretagogues, are acidic and form a salt with a pharmaceutically acceptable cation. Some of the compounds of this invention, including the compounds of formula I, anti-resorption agents, bone anabolic agents, prostaglandin agonists / antagonists, parathyroid hormones, growth hormones and growth hormone secretagogues, are and form a salt with a pharmaceutically acceptable anion. All these salts are within the scope of this invention and can be prepared by conventional methods. For example, they can be prepared by simply contacting the acidic and basic entities, generally in a stoichiometric ratio, in aqueous, non-aqueous or partially aqueous media, as appropriate. The salts are collected either by filtration, or by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, or in the case of aqueous solutions, by lyophilization, as appropriate. Also, when the compounds of this invention, including the compounds of formula I, anti-resorption agents, bone anabolic agents, prostaglandin agonists / antagonists, parathyroid hormones, growth hormones and growth hormone secretagogues, they form hydrates or solvates, they are also within the scope of the invention. Also, all prodrugs of the compounds of this «^^^^« ^. ^ .. ^^^. ^ A ^ - ^ || | to? g & L ». ^ -Cfe *. ^ »Id * f * faMtv. , invention, including the compounds of formula I, anti-resorption agents, bone anabolic agents, prostaglandin agonists / antagonists, parathyroid hormones, growth hormones and growth hormone secretagogues are within the scope of this invention. The compounds of this invention, prodrugs thereof and pharmaceutically acceptable salts of said compounds and prodrugs are all adapted for therapeutic use as agents that stimulate bone formation and increase bone mass in vertebrates, for example, in mammals and especially in humans. . Since bone formation is closely related to the development of osteoporosis and related bone disorders, these compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, by virtue of their action on bone, prevent, stop and / or produce the regression of osteoporosis. The utility of the compounds of the present invention as medical agents for the treatment of disorders that result in a reduction of bone mass (e.g., osteoporosis) in vertebrates, e.g., in mammals (e.g., in humans, especially in women) is demonstrated by the activity of the compounds of this invention in conventional tests, including the in vivo assay, a receptor binding assay, the cyclic AMP assay and in the fracture welding test (all of which They described below). The in vivo test (with the appropriate technical modifications) can be used ** S & *** -? ^ -, * kCJMa £ l? kZM ±. ,. * »* **. TO??? . .. to determine the activity of other anabolic agents, such as the prostaglandin agonists of this invention. The estrogen agonist / antagonist protocol can be used to determine in particular the activity of estrogen agonists / antagonists and that of other anti-resorption agents 5 (with the appropriate technical modifications). The combination and sequential treatment protocol described below is useful to demonstrate the utility of combinations of anabolic agents (e.g., the compounds of this invention) and anti-resorption agents (e.g., estrogen agonists / antagonists) described at the moment. Sayings tests also provide a means by which the activities of the compounds of this invention (or of other anabolic agents and anti-resorption agents described herein) can be compared with the activities of other known compounds. The results of these comparisons are useful to determine the dosage levels in vertebrates, for example, in mammals, including humans, for the treatment of said diseases.

In vivo test of the anabolic agent The activity of the anabolic bone agents in the stimulation of bone formation and in the increase of the bone mass can be tested in intact male or female rats, in rats deficient in sex hormones, in males (orchiectomy) ) or in females (ovariectomy). Male or female rats can be used in this study TO ?. & ^ .. * afa »« a¿. ^^ ü ^ 1 ^^. ^ flri? Jte? Afti ^ different ages (such as 3 months old). The rats are intact or castrated (ovariectomized or orchidectomized), they are injected subcutaneously or by gavage, different doses of prostaglandin agonists (such as 1, 3 or 10 mg / kg / day) for 30 days. In castrated rats 5, treatment begins the next day after surgery (in order to prevent bone loss) or at the time when bone loss has already occurred (in order to restore bone mass) . During the study, all rats have free access to water and the commercial ball diet (Tekland Rodent Diet # 8064, Harland Teklad, Madíson, Wl) which contains 1.46% calcium, 0.99% phosphorus and 4.96 lU / g of vitamin D3. All rats are injected 10 mg / kg of calcein subcutaneously on days 12 and 2 before slaughter. The rats are sacrificed and the following end variables are determined: Femoral bone mineral measurements: The right femur of each rat is separated at autopsy and is screened using dual-energy X-ray absorptiometry (DXA, QDR 1000 / W, Hologic Inc., Waltham, MA), equipped with the "High Resolution Regional Exploration" program (Hologic Inc., Waltham, 20 MA). The size of the scan field is 5.08 x 1.902 cm, the resolution is 0.0254 x 0.0127 cm and the scanning speed is 7.25 mm / second. The images of the femoral examination are analyzed and the bone area, bone mineral content (BMC) and density are determined ¿^ ^ ¿G ^ i g | gggjg! ggg ^ bone mineral (BMD) of the complete femur (WF), of the distal femoral metaphysis (DFM), of the femoral diaphysis (FS) and of the proximal femurs (FP).

Histomorphometric analysis of the tibial bone: 5 At autopsy, the right tibia is separated, cleaned of the muscle remnants and cut into three parts. The proximal tibia and tibial diaphysis are fixed in 70% ethanol, dehydrated in gradual concentrations of ethanol, fat is removed with acetone and then embedded in methyl methacrylate (Eastman Organic Chemicals, Rochester, NY). 0 Frontal sections of 4 and 10 μm thick proximal tibial metaphyses are cut using a Reichert-Jung Polycut S microtome. The 4 μm sections are stained with a modified Masson 's Trichrome stain, while the 10 μm sections are stained. they leave without dyeing. A 4 μm section and a 10 μm section of each rat are used for the histomorphometry of cancellous bone. Cross sections of the tibial shaft 10 μm thick are cut using a Reichert-Jung Polycut S microtome. These sections are used for cortical bone histomorphometric analysis. 0 Spongy bone histomorphometry: Bioquant OS / 2 histomorphometry system (R &M Biometrics, Inc., Nashville, TN) is used for static and dynamic histomorphometric measurements of secondary cancellous bone of tibial metaphyses j ^ gf¡ ^^^^ j ^? ^ ¡¡¡^ ^ ^ ^ ^ ^ ^ ¡¡¡¡¡Proximal between 1.2 and 3.6 mm from the distal part of the union of the growth plate-epiphysis. The first 1.2 mm of the tibial metaphyseal region should be omitted in order to restrict the measurements to the secondary cancellous bone. The 4 μm sections are used to determine the indexes related to bone volume, bone structure and bone resorption, while the 10 μm sections are used to determine the indexes related to bone formation and turnover.

I) Measurements and calculations related to volume and trabecular bone structure: 1) Total metaphyseal area (TV, mm2): metaphyseal area between 1.2 and 3.6 mm distally from the junction of the growth plate-epiphysis. 2) Trabecular bone area (BV, mm2): total area of the trabeculae within the TV. 3) Trabecular bone perimeter (BS, mm): the length of the total perimeter of the trabeculae 4) Trabecular bone volume (BV / TV,%): BV / TV x 100. 5) Trabecular bone number (TBN, n ° / mm): 1.199 / 2 x BS TV. 6) Trabecular bone thickness (TBT, μm): (2000 / 1.199) x (BV / BS). 7) Trabecular bone separation (TBS, μm): (2000 x 1199) x (TV - BV).

II) Measurements and calculations related to bone resorption: 1) Number of osteoclasts (OCN, n °): total number of osteoclasts within the total metaphyseal area. 2) Osteoclastic perimeter (OCP, mm): length of the trabecular perimeter covered by the osteoclast. 3) Osteoclast number / mm (OCN / mm, n ° / mm): OCN / BS. 4) Percentage of the osteoclastic perimeter (% OCP,%): OCP / BS x 100. lll) Measurements and calculations related to bone formation and turnover: 1) Perimeter marked with simple calcein (SLS, mm): total length of the trabecular perimeter with calcein marking. 2) Perimeter marked with double calcein (DLS, mm): total length of the trabecular perimeter marked with two calcein marreajes. 3) Width between labels (ILW, μm): average distance between two calcein labels. 4) Percentage of the mineralizing perimeter (PMS,%): (SLS / 2 + DLS) / BS x 100. 5) Mineral apposition rate (MAR, μm / day): ILW / marking interval. 6) Bone formation rate / ref surface (BFR / BS, μm2 / d / μm): (SLS / 2 + DLS) x MAR / BS. 7) Bone turnover rate (BTR,% / y): (SLS / 2 + DLS) x MAR / BV x 100.

Bone histomorphometry cortical: histomorphometry system Bioquant OS / 2 (R &M Biometrics, Inc., Nashville, TN) for the static and dynamic histomorphometric measurements of cortical bone of the tibial shaft. Measured Total tissue area, the area of the medullary cavity, periosteal perimeter, endocortical perimeter, the perimeter simple marking the perimeter of double labeling and width between mareajes on periosteal and endocortical surface and bone area are calculated cortical (total tissue area - area of the medullary cavity), percentage of the cortical bone area (cortical area / total tissue area x 100), percentage of the medullary area (area of the medullary cavity / total tissue area x 100), percent perimeter marked periosteal and endocortical [(simple marked perimeter / 2 + perimeter double marking) / total perimeter x 100], 5 mineral apposition velocity (width between markers / intervals) and bone formation velocity [mineral apposition velocity x [(simple marked perimeter / 2 + double marked perimeter) / total perimeter].

Statistical calculations 10 Statistical calculations can be made using packages Stat View 4.0 (Abacus Concepts, Inc., Berkeley, CA). The analysis of variance test (ANOVA) followed by Fisher's PLSD (Stat View, Abacus Concepts, Inc., 1918 Bonita Ave, Berkeley, CA 94704-1014) are used to compare the differences between the groups. 15 Determination of the increase of cAMP in 293-S cell lines stabilized for overexpression of recombinant human receptors of PD? and of the EP4 The cDNAs that represent open reading frames complete human receptor EP2 and EP4 are obtained by polymerase chain reaction reverse transcriptase using oligonucleotide primers based on published sequences (1, 2) and RNA from primary human kidney cells (EP2 ) or cell - **. * m ** aim ***. ^^ 1MMÍÍ ITRI • il - ** "- ^^ - ^^ g &. H primary human lung (EP4) as templates cDNAs are cloned into the multiple cloning site of pcDNA3 (Invitrogen Corporation, 3985B Sorrento Valley BIvd. , San Diego, CA 92121) and used to transfect 293-S human embryonic kidney cells by coprecipitation 5 calcium phosphate. the G418 resistant colonies extend and are assayed for the specific binding [3 H] PGE2. transfectants that show high levels of specific binding [3H] PGE2 are further characterized by Scatchard analysis to determine Bmax and Kds for PGE2.The lines selected for the evaluation of the compound have approximately 338,400 receptors per cell and one Kd = 12 nM for PGE2 (EP2) and approximately 256,400 receptors per cell and one Kd = 2.9 nM for PGE2 (EP4). The constitutive expression of both receptors in parental 293-S cells is negligible. Cells are maintained in RPM I supplemented with fetal bovine serum (final 10%) and G418 (final 700 ug / ml). 15 The cAMP responses on lines 293-S / EP2 and 293-S / EP4 are determined by collecting cells from the culture flasks in 1 ml PBS without Ca ++ or Mg ++ by shaking vigorously, adding RPMI without serum to a final concentration of 1 x 106 cells / ml and adding 3-isobutyl-1-methylxanthine (IBMX) to a final concentration of 1 mM. One milliliter of suspension The cell is immediately distributed in aliquots in microcentrifuge tubes with individual screw cap of 2 ml and incubated for 10 minutes, uncovered at 37 ° C, C02 5%, relative humidity 95%. The test compound is then added to the cells in dilutions of 1: 100, so that The final concentrations of DMSO or ethanol are 1%. Immediately after adding the compound, the tubes are covered, mixed by turning them twice and incubated at 37 ° C for 12 minutes. The samples are then lysed by incubation at 100 ° C for 10 minutes and 5 are immediately cooled on ice for 5 minutes. Cell debris is pelleted by centrifugation at 1000 x g for 5 minutes and the lysed lysates are transferred to clean tubes. Concentrations of cAMP are determined using a radioimmunoassay assay kit for commercially available cAMP, RIA (NEK-033, DuPont / NEN Research Products, 549 Albany St., Boston, MA 02118) after diluting the clarified lysates in RIA assay buffer for cAMP 1: 10 (included in the assay kit). Typically, cells are treated with 6-8 concentrations of the compound to be tested in increments of 1 log. The EC50 calculations are performed with a calculator using a linear regression analysis on the linear portion of the dose-response curves.

Bibliography 1. Regan, J. W. Bailey, T. J. Pepperl, D. J. Pierce, K. L. Bogardus, A. M. Donello, J. E. Fairbairn, C. E. Kedzie, K. M. Woodward, D. F. and Gil, D. W. 1994. Cloning of a Novel Human Prostaglandin Receptor with Characteristics of the Pharmacologically Defined EP2 Subtype. Mol. Pharmacology 46: 213-220. 2. Bastien, L., Sawyer, N., Grygorczyk, R., Metters, K., and Adam, M. 1994. Cloning, Functional Expression, and Characterization of the Human Prostaglandin E2 EP2 Subtype Receiver. J. Biol. Chem. Vol 269, 16: 11873-11877.

Assay of binding to prostaqlandin E receptors? Preparation of the membrane: All operations are carried out at 4 ° C. Transfected cells expressing type 1 receptors of prostaglandin E2 (EP-i), type 2 (EP2), type 3 (EP3) or type 4 (EP4) are collected and suspended at ratio of 2 million cells per ml in buffer A [50 mM Tris-HCl (pH 7.4), 10 mM MgCl2, 1 mM EDTA, 1 mM Pefabloc peptide (Boehringer Mannheim Corp., Indianapolis, IN), 10 uM Phosporamidon peptide (Sigma, St. Louis, MO), 1 uM pepstatin peptide A (Sigma, St. Louis, MO), 10 uM elastatin peptide (Sigma, St. Louis, MO), 100 uM antipain peptide, (Sigma, St. 15 Louis, MO)]. These are lysed by sonication with a Branson Sonicator (Model No. 250, Branson Ultrasonics Corporation, Danbury, CT) in 2 cycles of fifteen seconds. Unused cells and cell debris are removed by centrifugation at 100 x g for 10 minutes. The membranes are then collected by centrifugation at 45,000 x g for 30 minutes. The sedimented membranes are resuspended in 3-10 mg of protein per ml, the concentration of proteins being determined according to the Bradford method [Bradford, M., Anal. Biochem., 72, 248 (1976)]. The resuspended membranes are then stored frozen at -80 ° C until be used.

Binding Assay: The frozen membranes prepared as described above are thawed and diluted to 1 mg of protein per ml in buffer A above. A volume of membrane preparation is combined with 0.05 volumes of the test compound or buffer and a volume of 3 nM of 3H-prostaglandin E2 (n ° TRK 431, Amersham, Arlington Heights, IL) in buffer A. The mixture (205 μl total volume) is incubated for 1 hour at 25 ° C. The membranes are then collected by filtration through glass fiber filters GF / C (n ° 1205-401, Wallac, Gaithersburg, MD) using a Tomtec collector (Model Mach 11/96, Tomtec, Orange, CT). The membranes with bound 3H-prostaglandin E2 are retained by the filter, while the buffer and unbound 3H-prostaglandin E2 pass through the filter and are discarded. Each sample is washed 3 times with 3 ml of [50 mM Tris-HCl (pH 7.4), 10 mM MgCl2, 1 mM EDTA]. The filters are then dried by heating in a microwave oven. To determine the amount of 3H-prostaglandin bound to the membranes, the dried filters are placed in plastic bags with a scintillation fluid and counted on a Betaplate LKB 1205 reader (Wallac, Gaithersburg, MD). Cl50 are determined from the concentration of the test compound required to displace 50% of the specifically bound 3H-prostaglandin E2. The total extension of the EP-i receiver is carried out according to the A ^^ * r - - ** B *? * »*. . ? A? Jb ?? ^ H »*******», **. described in Funk et al., Journal of Biological Chemistry, 1993, 268, 26767-26772. The total extension of the EP2 receptor is performed as described in Regan et al., Molecular Pharmacology, 1994, 46, 213-220. The total extension of the EP3 receptor is performed as described in Regan et al., British 5 Journal of Pharmacology, 1994, 112, 377-385. The total extension of the EP4 receptor is performed as described in Bastien, Journal of Biological Chemistry, 1994, 269, 11873-11877. These receptors for which total extension is available are used to prepare the 293S cells expressing the EP-i, EP2, EP3 and EP receptors. The 239S cells expressing the human prostaglandin receptors EP1, Ep2, EP3 and EP4 are obtained according to procedures known to those skilled in the art. Typically, the PCR primers (polymerase chain reaction) that correspond to the 5 'and 3' ends of the receptor with total extension published are prepared according to the well-known procedures described above and used in the RT-PCR reaction using total RNA from human kidney (for EP-i), human lung (EP2), human lung (EP3), or human lymphocytes (for EP4). The PCR products are cloned by the TA method in pCR2.1 (Invitrogen, Carlsbad, CA); confirming the identity of the cloned receptor by DNA sequencing. 293S cells (Mayo, Dept. of Biochemistry, Univ. Northwestern) are transfected with the cloned receptor in pcDNA3 by electroporation. Stable cell lines that express the receptor are stabilize after selection of cells transfected with G418. Clonal cell lines expressing the maximum number of receptors are chosen after a binding assay of 3 H-PGE 2 to the whole cell using unlabelled PGE 2 as a competitor.

Fracture welding tests Test to measure the effects on fracture welding after systemic administration Fracture technique: 3-month-old Sprague-Dawley rats are anesthetized with ketamine. An incision of 1 cm is made in the anteromedial aspect of the proximal part of the tibia or right femur. The surgical technique for the tibia is described below. The incision is made through the bone, drilling a hole 1mm to 4mm from the distal aspect of the tibial tuberosity, to 2mm in the middle part of the anterior crest. It is stuck intramedullary with a 0.8 mm stainless steel tube (maximum load 36.3 N, maximum hardness 61.8 N / mm, tested under the same conditions as bones). The medullary canal is not pierced. A normalized closed fracture 2mm above the tibiofibular junction is produced by bending three points using specially designed adjustable forceps with blunt jaws. To minimize possible damage to the soft tissue, care is taken not to displace the fracture. The skin is stitched with monifilament nylon sutures. The operation is performed in sterile conditions. They are made "^^^^ ¡^ ^^^^ J ^^^ JJgg ^ BIgWgfe ^^ ^ X-rays of all fractures immediately after nailing and exclude vertebrate rats with fractures outside the area of the specified diaphysis or with nails displaced. The remaining animals are randomly divided into the following groups, with 10-12 animals for each 5 subgroup for each time, to test the fracture welding. The first group receives daily by vehicle probe (water: 100% ethanol = 95: 5) at a rate of 1 ml / rat, while the others receive daily by probe from 0.01 to 100 mg / kg / day of the test compound ( 1 ml / rat) for 10, 20, 40 and 80 days. 10 At 10, 20, 40 and 80 days, 10-12 rats from each group are anesthetized with ketamine and autopsied by exsanguination. Both tibiofibular bones are separated by dissection and all soft tissues are removed. The bones of 5-6 rats of each group are stored in 70% ethanol for histological analysis and the bones of another 5-6 rats each group are stored in buffered Ringer solution (+ 4 ° C, pH 7.4), to perform radiographs and biomechanical assay.

Histological analysis: The procedures for the histological analysis of bone fractured have been previously published by Mosekilde and Bak (The Effects of Growth Hormone on Fracture Healing in Rats: A Histological Description. Bone, 14: 19-27, 1993). In short, the lateral part of the fracture is cut 8 mm on each side of the fracture line, imbibed ÍBAIMI »- &Z ^ - ^ íÍSTI ^ M. , ... decalcified in methyl methacrylate and 8 μm thick frontal sections are cut with a Reichert-Jung Polycut microtome. The middle frontal sections stained with Masson-Trichrome (including the tibia and the fibula) are used for the visualization of the cellular and tissue response to the welding of the fracture with or without treatment. The sections stained with Sirius red are used to determine the characteristics of the callus structure and to differentiate between curved bone and lamellar bone at the fracture site. The following measurements are made: (1) fracture gap, measured as the shortest distance between the ends of the cortical bone in the fracture, (2) callus length and callus diameter, (3) area of total bone volume of the fracture, callus, (4) bone tissue by tissue area within the callus area, (5) fibrous tissue in the callus, and (6) cartilage area in the callus.

Biomechanical analysis: The procedures for biomechanical analysis have been previously published by Bak and Andreassen (The Effects of Aging on Fracture Healing in Rats, Calcif Tissue Int 45: 292-297, 1989). In summary, radiographs of all fractures are made before biomechanical testing. The mechanical properties of the fractures that are welded are analyzed by a three or four point destructive bending procedure. The maximum load, the rigidity, the energy with the maximum load, the deflection with the maximum load and the maximum effort are determined.

Test to determine the effects of fracture welding after local administration. Fracture technique: In this study, female or male hound dogs approximately 2 years old are used. Transverse radial fractures are produced by a three-point continuous load curve as described by Lenehan et al. (Lenahan, T.M.; Balligand, M; Nunamaker, D.M.; Wood, F.E. : Effects of EHDP on Fracture Healing in Dogs. J. Orthop Res 3: 499-507; 1985). A wire is passed through the fracture site to ensure complete anatomical bone disruption. Thereafter, local administration of the prostaglandin agonists at the fracture site is accomplished by slow release of the compound administered by slow release beads or by administration of the compounds in an appropriate formulation, such as a solution. or gel suspension of a paste for 10, 15 or 20 weeks.

Histological Analysis: The procedures for the histological analysis of the fractured bone have been previously described by Peter et al. (Peter, CP, Cook, WO, Nunamaker, DM, Provost, MT, Seedor, JG, Rodan, GA, Effects of Alendronate on Fracture Healing and Bone Remodeling in Dogs, J. Orthop, Res. 14: 74-70, 1996) and Mosekilde and Bak (The Effects of Growth Hormone on Fracture Healing, Rats: A Histological Description, Bone, 14: 19- ^ ^ i ^ M .. ¡£ A. ^ ». »^ ^ M ^ 27, 1993). In short, after the sacrifice, the lateral part of the fracture is cut 3 cm on each side of the fracture line, de-calcified in methyl methacrylate and cut 8 μm thick frontal sections with a Reichert-Junt microtome. The middle frontal sections stained with Masson-Trichrome (including the tibia and the fibula) are used for the visualization of the cellular and tissue response to the welding of the fracture with or without treatment. The sections stained with Sirius red are used to determine the characteristics of the callus structure and to differentiate between curved bone and lamellar bone at the fracture site. fracture gap measured as the shortest distance between the cortical bone ends in the fracture, (2) length calloused callus diameter (1), (3) area total bone volume: The following measurements are performed callus, (4) bone tissue by tissue area within the callus area, (5) fibrous tissue in the callus, and (6) cartilage area in the callus.

Biomechanical Analysis: The methods for biomechanical analysis have been previously published by Bak and Andreassen (The Effects of Aging on Fracture Healing in Rats Calcif Tissue Int. 45: 292-297, 1989) and Peter et al. (Peter, CP, Cook, WO, Nunamaker, DM, Provost, MT, Seedor, JG, Rodan, GA, Effects of Alendronate on Fracture Healing and Bone Remodeling in Dogs, J. Orthop, Res. 14: 74-70, 1996. ). In summary, radiographs of all fractures are made before biomechanical testing. The ^ ^ J ^^ ^^^ H ^^^^^^ g ^ Ui * • -.. "Mechanical properties of welded fractures are analyzed by a destructive process curvature of three or four points are determined the maximum load, stiffness, energy with maximum load, deflection with maximum load and maximum stress 5 Protocol for estrogen agonist / antagonist Estrogen agonists / antagonists are a class of compounds that inhibit bone turnover and avoid bone loss induced by estrogen deficiency The model of bone loss in the ovariectomized rat has been widely used as a model of postmenopausal bone loss.Using this model, the efficacy of the agonist / antagonist compounds of the ovaries can be tested. estrogens to prevent bone loss and inhibiting bone resorption. They are used in these studies rats 15 Sprague-Dawley female (Charles River, Wilmigton, MA) at different ages (such as 5 months old). the rats were they lodge individually in cages of 20 cm x 32 cm x 20 cm during the experimental period. All rats have free access to water and pelleted commercial diet (Agway ProLab 3000, Agway County Food, Inc., Syracuse, NY) containing 0.97% calcium, 0.85% phosphorus and 1.05 lU 20 / g of Vitamin D3 In a group of rats (8 to 10) an operation is simulated and treated with vehicle (10% ethanol and 90% saline solution, 1 ml / day), while the rest of the rats are bilaterally ovariectomized (OVX) and treated with vehicle (po), 17? -estradiol (Sigma, E-8876, E2, 30 μg / kg, daily subcutaneous injection) or with estrogen agonists / antagonists (such as droloxifene, 5, 10 or 20 mg / kg, daily) po) during a certain period (like 4 weeks). All rats are administered subcutaneously 5 injections of 10 mg / kg calcein (fluorochrome bone marker) 12 and 2 days before being sacrificed in order to examine the dynamic changes in the bone tissue. After 4 weeks of treatment, the rats are sacrificed and autopsied. The following endpoints are determined: 10 Increase in body weight: Body weight at the time of autopsy minus body weight at the time of surgery Uterine weight and histology: The uteri of each rat are removed during the autopsy and weighed immediately. From this moment the uterus is processed to take histological measurements, such as the uterine transverse tissue area, stromal thickness and luminal epithelial thickness. 20 Total serum cholesterol: Blood is drawn by cardiac puncture and allowed to clot at 4 ° C, then centrifuged at 2,000 g for 10 minutes. The , »J8fesM < «A« > lifeagg ^ serum samples are analyzed to determine total serum cholesterol using a high performance cholesterol calorimetric assay (Boehringer Mannheim Biochemicals, Indianapolis, IN).

Mineral measurements of the femoral bone: The right femur of each rat is separated at the time of autopsy and is subjected to a scan using dual-energy X-ray absorptiometry (DEXA, QDR 1000 / W, Hologic Inc., Waltham, MA ) equipped with the "High Resolution Regional Exploration" program (Hologic Inc., Waltham, MA). The size of the scan field is 5.08 x 1.902 cm, the resolution is 0.0254 x 0.0127 cm and the scanning speed is 7.25 mm / second. The images of the femoral examination are analyzed and the bone area, bone mineral content (BMC) and bone mineral density (BMD) of the complete femur (WF), of the distal femoral metaphysis (DFM), of the femoral diaphysis are determined. (FS) and the proximal femurs (PF).

Histomorphometric analysis of the cancellous bone of the proximal tibial metaphysis In the autopsy, the right tibia is separated, cleaned of the muscle remnants and cut into three parts. The proximal tibia is fixed in 70% ethanol, dehydrated in gradual concentrations of ethanol, fat is removed with acetone and then impregnated in methyl methacrylate (Eastman Organic Chemicals, Rochester, NY). Front sections of the "* - &- - proximal tibial metaphysis of 4 and 10 μm thickness using a Reichert Jung Polycut S microtome. A 4 μm and a 10 μm section of each rat is used for spongy bone histomorphometry. 4 μm are stained with a modified Masson's Trichrome dye, while 5 sections of 10 μm are left unstained, Bioquant OS / 2 histomorphometry system (R &M Biometrics, Inc., Nashville, TN) is used for measurements static and dynamic histomorphometry of the secondary cancellous bone of the proximal tibial metaphysis between 1.2 and 3.6 mm from the distal part of the growth plate-epiphysis junction The first 1.2 mm of the region tibial metaphyseal are omitted in order to restrict measurements to secondary cancellous bone. The 4 μm sections are used to determine the indexes related to bone volume, bone structure and bone resorption, while the 10 μm sections are used to determine the indexes related to bone formation and turnover. 15 I. Measurements and calculations related to volume and trabecular bone structure: 1. Total metaphyseal area (TV, mm2): metaphyseal area between 1.2 and 3.6 mm distally from the junction of the growth plate-epiphysis. 20 2. Trabecular bone area (BV, mm2): total area of the trabeculae within the TV. 3. Trabecular bone perimeter (BS, mm): the length of the total perimeter of the trabeculae.

MJi.¿. * Z * áj im? Met £ ^^ £ ost G7¡ ^^ g¡ & g ^ "* - * -" «, * -" * • ^ £ ¡¡¡¡¡¡¡¡¡¡¡¡¡4 ¡¡ Trabecular bone volume (BV / TV,%): BV / TV x 100. 5. Trabecular bone number (TBN, n ° / mm): 1.199 / 2 x BS / TV 6. Trabecular bone thickness (TBT, μm): (2000/1199) x (BV / BS) 7. Trabecular bone separation (TBS, μm): (2000 x 1199) x (TV BV).

II. Measurements and calculations related to bone resorption: 1. Number of osteoclasts (OCN, n °): total number of osteoclasts within the total metaphyseal area. 2. Osteoclastic perimeter (OCP, mm): length of the trabecular perimeter covered by the osteoclast. 3. Osteoclast number / mm (OCN / mm, n ° / mm): OCN / BS. 4. Percentage of the osteoclast perimeter (% OCP,%): OCP / BS x 100.

III. Measurements and calculations related to bone formation and turnover: 1. Perimeter marked with simple calcein (SLS, mm): total length of the trabecular perimeter with calcein labeling. 2. Perimeter marked with double calcein (DLS, mm): total length of the trabecular perimeter marked with two calcein labels. 3. Width between labels (ILW, μm): average distance between two calcein labels. tei? ^^^ aaüS 4. Percentage of mineralizing perimeter (PMS,%): (SLS / 2 + DLS) / BS x 100. 5. Mineral apposition rate (MAR, μm / day): ILW / marking interval. 6. Bone formation rate / ref surface (BFR / BS, μm2 / d / μm): (SLS / 2 + DLS) x MAR / BS. 7. Bone turnover rate (BTR,% / y): (SLS / 2 + DLS) x MAR / BV x 100.

Statistical calculations Statistical calculations are performed using Stat View 4.0 packages (Abacus Concepts, Inc., Berkeley, CA). The analysis of variance test (ANOVA) followed by Fisher's PLSD (Stat View, Abacus Concepts, Inc. 1918 Bonita Ave, Berkeley, CA 94704-1014) are used to compare the differences between the groups.

Combination and sequential treatment protocol The following protocols may undergo variations in the judgment of those skilled in the art. For example, intact male or female rats, rats deficient in sex hormones, male (orchiectomy) or female (ovariectomy) can be used. Likewise, male rats or females of different ages (such as 12 months of age) can be used in these studies. The rats may be intact or castrated (ovariectomized or orchidectomized) and they were administered different doses (such as 1, 3 or 6 mg / kg / day) for a certain period (such as two weeks to two months) of anabolic agents such as the compounds of this invention, followed by administration of different doses (such as 1, 5, 10 mg / kg / day) for a 5 given period (such as two weeks to two months), of an anti-resorptive agent such as droloxifene, or a combination treatment with different doses for a certain period (like two weeks to two months), an anabolic agent and an anti-resorption agent. In castrated rats, treatment may begin the next day after surgery (with the to prevent bone loss) or at the time when bone loss has already occurred (in order to restore bone mass). The rats are sacrificed by anesthetizing them with ketamine. The following finalization variables are determined: Mineral measurements of the femoral bone are performed as has previously described in the protocol for the estrogen agonist / antagonist.

Bone mineral measurements of the lumbar vertebrae: Dual-energy X-ray absorptiometry (QDR) is used 1000 / W, Hologic Inc., Waltham, MA) equipped with the "Exploration" program Regional High Resolution "(Hologic ln., Waltham, MA) to determine bone area, bone mineral content (BMC) and bone mineral density (BMD) of the entire lumbar area and of each of the six lumbar vertebrae ( LVI-6) ^^^^^^^^^ "^^^^^^^^^^ g ^^^^^ ¿^? ^^^^^^^ ¿J gj ^^^^^^ in anesthetized rats. The rats are anesthetized with an injection (i.p.) of 1 ml / kg of a ketamine / rompun mixture (ratio of 4 to 3) and then placed on a rat platform. The size of the scanning field is 6 x 1.9 cm, the resolution is 0.0254 x 0.0127 5 cm and the scanning speed is 7.25 mm / sec. A scan image of the entire lower back is obtained and analyzed. Bone area (BA) and bone mineral content (BMC) are determined and bone mineral density (MBC divided by BA) is calculated for the entire lumbar area and for each of the six lumbar vertebrae (LVI-6) 10 Se perform histomorphometric analysis of the metaphyseal cancellous bone of the proximal tibia, as described above for the estrogen agonist / antagonist protocol. The measurements and calculations related to the volume and trabecular bone structure are done as described above for the estrogen agonist / antagonist protocol. Also, measurements and calculations related to bone resorption are also made as described above for the estrogen agonist / antagonist protocol. The measurements and calculations related to bone formation and turnover are also done as described above for the protocol of the estrogen agonist / antagonist. In addition, the data obtained is analyzed using the statistical manipulations described above for the estrogen agonist / antagonist protocol.

Renal regeneration assay The role of an agonist of a prostaglandin in renal regeneration is investigated by the ability of prostaglandins E2 (PGE2) or of a porstaglandin agonist to induce the expression of bone morphogenetic protein 7 (BMP-7) in wild type 293S cells and in 293S cells transfected with EP2.

Methods: 293S cells and 293S EP2 cells are grown in Dulbecco's modified Eagle's medium (DMEM, Gibco, BRL, Gaithersburg, MD). One day before treatment with PGE2 or with a prostaglandin agonist, the cells are transferred to plates, with a density of 1.5 x 106 cells / 10 cm plate. Generally, approximately 16 to 24 hours later, the cell monolayer is washed once with Optimel (Gibco, BRL, Gaithersburg, MD), followed by the addition of 10 ml of OptiMEM / plate in the presence and absence of vehicle (DMSO), PGE2 (106M) or a prostaglandin agonist (106M). The cells are harvested and the RNA is extracted at 8, 16 and 24 hours. A northern blot analysis of the total (20 mg / lanes) is performed testing the blots with the BMP-7 probe labeled with 32P. The blots are normalized for RNA loading by hybridization with the 18P ribosomal RNA probe labeled with 32P. PGE2 and prostaglandin agonists induce the expression of BMP- in 293S EP2 cells in a time-dependent manner. This induction of ,. ^ -A ^^^ i ^ S. ^ B ^.

Expression is not usually observed in the parental cell line. Given the known role of BMP-7 in renal regeneration and the ability of a prostaglandin agonist to induce the expression of BMP-7 in 293S renal cells in a time-specific manner and the receptor, it follows that Prostaglandin agonist plays a role in renal regeneration. The administration of the compounds of the invention can be by any method that releases a compound of this invention systemically and / or locally (for example, at the site of bone fracture, osteotomy or orthopedic surgery). These procedures include oral, parenteral, intraduodenal, etc. Generally, the compounds of this invention are administered orally, although parenteral administration (eg, intravenous, intramuscular, transdermal, subcutaneous, rectal or intramedullary) can be used, for example, when oral administration is inappropriate for the target or when the patient is unable to ingest the drug. The compounds are used for the treatment and stimulation of the welding of bone fractures and osteotomies by local application (for example, at the sites of bone fractures and osteotomies) of the compounds of this invention or of the compositions thereof. The compounds of this invention are applied at the sites of bone fractures or osteotomies, for example, (by injection of the compound in an appropriate solvent (for example, an oily solvent, peanut) in the cartilage growth plate or in cases where it is open surgery, by local application of said compounds in an appropriate vehicle such as bone wax, demineralized bone powder, polymeric bone cements, bone sealants, etc. . On the other hand, local application can be done by applying a solution or dispersion of the compound in an appropriate vehicle on the surface of solid or semi-solid implants conventionally used in orthopedic surgery, as dacron mesh, gelatin sponge and plaster or prosthesis, or incorporating it in them. The compounds of this invention can also be applied locally at the site of fracture or osteotomy in an appropriate vehicle or diluent in combination with one or more of the anabolic agents or anti-resorption agents described above. Such combinations, which are within the scope of this invention, may be administered simultaneously or sequentially in any order, or a single pharmaceutical composition containing a compound of formula I, a prodrug thereof or a pharmaceutical salt of said compound or of said prodrug, as described above and a second compound, which has been described above, in a pharmaceutically acceptable diluent carrier. For example, in this invention a bone anabolic agent can be used alone or in combination with an anti-resorption agent, for three months up to three years, followed by an anti-resorption agent alone, during three months to three years, optionally repeating the complete treatment cycle. On the other hand, for example, the bone anabolic agent can be used alone or in combination with an anti-resorption agent for three months up to three years, followed by an anti-resorption agent alone, for the remainder of the patient's life. For example, in a preferred mode of administration, a compound of Formula I, or a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, as described above, may be administered once a day and a second drug, as described above, (e.g., an agonist / antagonist of estrogens) daily in single or multiple doses. On the other hand, for example, in another preferred mode of administration, the two compounds can be administered sequentially, such that the compound of Formula I, the prodrug thereof or the pharmaceutically acceptable salt of said compound or said prodrug, such and as described above, it can be administered once a day for a period of time sufficient to increase bone mass to a level that is above the threshold for bone fracture (World Health Organization Study "Fracture risk assessment and its application for Determination of postmenopausal osteoporosis (1994) Report of a study group of the Organization World Health. World Health Organization Technical Series 843"), followed by the administration of a second compound, as described above (eg, an estrogen agonist / antagonist), daily in single or multiple doses. first compound, As described above, it is administered once a day in a rapid release form, such as oral administration. In any case, the amount and time during which the compounds will be administered will, of course, depend on the subject to be treated, the severity of the condition, the manner of administration and the opinion of the prescribing physician. Thus, due to the variability that exists in terms of the patient, the dosages presented below are a guide, being the doctor who will determine the dose of the drug for the treatment (for example, increase in bone mass) that considers appropriate for the patient. Taking into account the desired degree of treatment, the doctor must weigh several factors, such as the level of bone mass, age of the patient, previous existence of a disease, as well as the existence of other diseases (for example, cardiovascular disease). In general, an amount of a compound of this invention sufficient to increase bone mass to a level that is above the bone fracture threshold is used (as detailed in the above-cited study of the World Health Organization). Health). In general, an effective dosage for anabolic agents used in this invention described above is in the range of 0.001 to 100 mg / kg / day, preferably 0.01 to 50 mg / kg / day. Preferred dosage ranges for various anti-resorption agents are given in the following paragraphs.

The amount of the anti-resorption agent to be used is determined by its activity as an inhibitor of bone loss. This activity is determined by the pharmacokinetics of an individual compound and its minimum effective dose against maximal to inhibit bone loss using a protocol, as described above (eg, the protocol for the estrogen agonist / antagonist). In general, an effective dosage for an anti-resorption agent is from about 0.001 mg / kg / day to about 20 mg / kg / day. In general, an effective dosage for an anti-resorption agent is from about 0.001 mg / kg / day to about 20 mg / kg / day. In general, an effective dosage for progestins is approximately 0.1 to 10 mg per day; The preferred dose is about 0.25 to 5 mg per day. In general, an effective dosage for polyphosphonates is determined by their potency as an inhibitor of bone resorption according to conventional tests. The intervals for the daily administration of some polyphosphonates are approximately between 0.001 mg / kg / day and approximately 20 mg / kg / day. In general, an effective dosage for the treatment of this invention, for example for the treatment of bone resorption of this invention, for the estrogen agonists / antagonists of this invention is in the range of 0.01 to 200 mg / kg / day , preferably 0.5 to 100 mg / kg / day. In particular, an effective dosage for droloxifene is in the range of 0.1 to 40 mg / kg / day, preferably 0.1 to 5 mg / kg / day. In particular, an effective dosage for raloxifene is in the range of 0.1 to 100 mg / kd / day, preferably 0.1 to 10 mg / kd / day. In particular, an effective dosage for tamoxifen is in the range of 0.1 to 100 mg / kd / day, preferably 0.1 to 5 mg / kd / day. In particular, an effective dosage for 2- (4-methoxy-phenyl) -3- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -benzo [b] thiophen-6-ol is 0.001 at 1 mg / kd / day). In particular, an effective dosage for cis-6- (4-fluoro-phenyl) -5- (4- (2-piperidin-1-yl-ethoxy) -phenyl) -5,6,7, 8-tetrahydro-naphthalene-2-ol; (-) - cys-6-phenyl-5- (4- (2-pyrrolidn-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2- ol; cis-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol; cis-1 - (e'-pyrrolidinetoxy-S'-pyridi ^ -phenyl-β-hydroxy-l, 2,3,4-tetrahydronaphthalene; 20 1 - (4, -pyrrolidinetoxyphenyl) -2- (4"-fluorophenyl) -6-hydroxy-1, 2,3,4-tetrahydroisoquinoline; cis-6- (4-hydroxyphenyl) -5- (4- (2-pyridin-1-ethoxy) -phenyl) ) -5,6,7,8, - tetrahydro-naphthalene-2-ol; , ^ ^ ^ ^ ^ ^ ^ ^ 1 ^^, ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ pyrrolidinolethoxyphenyl) -2-pheny1) -6-hydroxy-1, 2,3,4-tetrahydroisoquinoline is in the range of 0.0001 to 100 mg / kg / day, preferably 0.0001 to 10 mg / kg / day. In particular, an effective dosage for 4-hydroxy tamoxifen is in the range of 0.0001 to 100 mg / kg / day, preferably 0.001 to 10 mg / kg / day.The compounds of the present invention are generally administered in the form of a pharmaceutical composition containing the At least one of the compounds of this invention together with a pharmaceutically acceptable carrier or diluent. Thus, the compounds of this invention can be administered individually or in combination in any conventional oral, parenteral, rectal or transdermal dosage form. For oral administration, a pharmaceutical composition can be in the form of solutions, suspensions, tablets, pills, capsules, powders and the like. Tablets containing various excipients, such as sodium citrate, calcium carbonate and calcium phosphate are used together with various disintegrants, such as starch, preferably potato starch or tapioca and certain complex silicates, together with binding agents, such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. In addition, lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc, are often very useful for the manufacture of tablets.

Solid compositions of a similar type are also used as filling agents in soft and hard gelatin capsules; in this regard, the preferred materials also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When what is desired are aqueous suspensions and / or elixirs for oral administration, the compounds of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and / or suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof. For parenteral administration, solutions in sesame oil or arachis oil or aqueous propylene glycol can be used, as well as sterile aqueous solutions of the corresponding water-soluble salts. Said aqueous solutions may be appropriately buffered if necessary, and the liquid diluent must first be made saline with sufficient saline or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intreaperitoneal injection. In this regard, the sterile aqueous media employed can all be obtained easily by standard techniques well known to those skilled in the art. For transdermal (e.g., topical) administration, dilute, aqueous or partially aqueous solutions are prepared (usually at a concentration of about 0.1% to 5%), and on the other hand, similar to the solutions for previous parenteral use . ^^^^^^^^^^^^^^^ | g ^^^^^^^^^^^^^^^^^^^^^ gg ^ Jgg ^^^^^^? Mß ^^^^^ * ^^^^^^^^^^ The methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in light of this description for those skilled in the art. See Remiqton's Pharmaceutical Sciences, Mack 5 Publishing Company, Eastern, Pa., 15th Edition (1975) for examples of methods of preparing pharmaceutical compositions. The pharmaceutical compositions according to the invention may contain from 0.1% to 95% of the compound (s) of this invention, preferably 1% -70%. In any case, the composition of the The formulation to be administered will contain an amount of a compound (s) of this invention in an amount effective to treat the disease / disorder of the subject to be treated, for example a bone disorder Since the present invention has an aspect related to the augmentation and maintenance of bone mass by treatment with a As a combination of active ingredients that can be administered separately, the invention also relates to the combination of the individual pharmaceutical compositions in the form of a test kit. The test kit contains two individual pharmaceutical compositions: a compound of Formula I, a prodrug thereof or a salt Pharmaceutically acceptable of said compound or of said prodrug and a second compound, as described above. The test kit contains a container for containing the individual compositions, such as a divided bottle or a divided aluminum foil pack, without However, the compositions separately may be contained within a single undivided container. Typically, the test kit contains instructions for the administration of the individual components. The test kit form is particularly advantageous when it is preferred to administer the individual compounds in different dosage forms (eg, oral and parenteral), with different dosing intervals or when the prescribing physician wishes to titrate the individual components. of the combination. An example of a test case of this type is the so-called opening by pressure. Pressure-opening packages are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules and the like). Pressure-opening packages generally consist of a sheet of relatively rigid material covered preferably with a cover of a transparent plastic material. During the packaging process, cavities are drilled in the plastic cover. The cavities have the size and shape of the tablets or capsules to be packaged. Next, the tablets or capsules are placed in the cavities and the sheet of relatively rigid material is sealed with the plastic cover by the side of the cover opposite the direction in which the cavities were formed. In this way, the tablets or capsules are sealed in the cavities between the plastic cover and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removing from the blister pack by manually applying a pressure on the cavities, so that an opening in the sheet occurs at the cavity location. The tablet or capsule can then be removed through said opening. It might be desirable to include a reminder in the test kit, for example, in the form of numbers near the tablets or capsules, so that the numbers correspond to the days of regimen in which the tablets or capsules so specified should be ingested Another example of a reminder of this type is a calendar printed on the cardboard, for example as follows, "First week, Monday, Tuesday ... etc ... Second week, Monday, Tuesday ..." etc. Other variations of reminders will be readily apparent. A "daily dose" can be a single tablet or capsule or several pills or capsules to take on a given day. Also a daily dose of a compound of Formula I, a The prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug may consist of a tablet or capsule, while a daily dose of the second compound may consist of several tablets or capsules and vice versa. The reminder should reflect this aspect. In another specific aspect of the invention, there is provided a dispenser designed to dispense the daily doses, one at a time, for the intended purpose. Preferably, the dispenser is equipped with a reminder to facilitate compliance with the regimen. An example of a Reminder of this type is a mechanical counter that indicates the number of daily doses that have been dispensed. Another example of a reminder of this type is a battery-operated memory microchip, coupled to a liquid crystal reader, or an audible reminder signal, which, for example, reads the date of the last daily dose taken and / or remembers when the next dose should be taken. The compounds of this invention, alone or in combination with each of the other compounds will generally be administered in a convenient formulation. The following formulation examples are only illustrative and are not intended to limit the scope of the present invention. In the following formulations, "active ingredient" denotes a compound or compounds of this invention.

Formulation 1: Gelatin capsules 15 Hard gelatine capsules are prepared using the following: Ingredient Quantity (mg / capsule) Active Ingredient 0.025-100 Starch, NF 0-650 Fluid Powder Starch 0-50 Fluid Silicone 350 centistokes 0-15 A formulation for tablets are prepared using the following: ^^ | ¿^ g ^ rt? ^ N J +? ÍiUÍ? T-? OA - .¿fc g ^^ m ^^ Formulation 2: tablets Ingredient Quantity (mg / tablet) Active ingredient 0.25-100 Microcrystalline cellulose 200-650 Silicone dioxide, pyrolysis 10-650 Stearate acid 5-15 The components are mixed and compressed to form the tablets. On the other hand, the tablets each containing 10 0.25-100 mg of the active ingredients are prepared as follows: Formulation 3: tablets Ingredient Quantity (mg / tablet) Active ingredient 0.25-100 Starch 45 Cellulose, microcrystalline 35 15 Polyvinylpyrrolidone (as 10% dilution in water) 4 Sodium carboxymethylcellulose 4.5 Magnesium stearate 0.5 Talcum 1 The active ingredients, starch and cellulose are passed through a U.S. No. 45 mesh and mix vigorously. The polyvinylpyrrolidone solution is mixed with the resulting powders, then passing it through a U.S. No. 14 mesh. The granules thus produced are dried at 50-60 ° C and passed through a U.S. No. 18 mesh. The sodium carboxymethylcellulose, the stearate magnesium and talc, previously weighed through a U.S. sieve. No. 60, are added to the granules, which, once mixed, are compressed in a compressing machine, obtaining the tablets. The suspensions, each containing 0.25-100 mg of 5 active ingredient per 5 ml of dose, are prepared as follows: Formulation 4: Suspensions Ingredient Quantity (mg / 5 ml) Active ingredient 0.25-100 mg Sodium carboxymethylcellulose 50 mg Syrup 1.25 mg 10 Benzoic acid solution 0.10 ml Aroma q. v. Color q. v. Purified water up to 5 ml The active ingredient is passed through a U.S. of mesh No. 45 and mixed with sodium carboxymethylceulose and syrup until form a soft paste. The benzoic acid solution, the aroma and the color are diluted with some water and added while stirring. Then enough water is added to obtain the required volume. An aerosol solution is prepared including the following ingredients.

Formulation 5: Aerosol Ingredient Quantity (% by weight) Active ingredient 0.25 Ethanol 25.75 Propellant 22 70.00 (chlorodifluoromethane) The active ingredient is mixed with ethanol and the mixture is added to the propellant, cooled to 30 ° C and transferred to the filling device. The required quantity is then introduced into a stainless steel container and diluted with the remaining propellant. Next, the units of the valve to the container. Suppositories are prepared in the following way: Formulation 6: Suppositories Ingredient Quantity (mg / suppository) Active ingredient 250 5 Saturated fatty acid glycerides 2,000 The active ingredient is passed through a U.S. No. 60 mesh and suspended in the glycerides of saturated fatty acids, previously melted using the minimum necessary heat. The mixture is poured then in a suppository mold of 2 g nominal capacity and allowed to cool. An intravenous formulation is prepared in the following way: Formulation 7: Tungsten solution Ingredient Quantity Active ingredient 20 mg Isotonic saline 1000 ml The dissolution of the above ingredients is administered intravenously to a patient at a rate of about 1 ml per minute. The above active ingredient can also be a combination of agents. The abbreviations "Me", "? T", "Pr", "Tf," Bu "," Ph "," EDC "and" Ac ", when used herein, define the terms" methyl "," ethyl, "" sopropyl "," triflyl "," butyl "," phenyl "," 1- (3-dimethylaminopropyl) -3-carbodiimide hydrochloride "and" acetyl "respectively.

General experimental procedures Unless otherwise specified, all reactions were carried out in an inert atmosphere, such as nitrogen (Na2). NMR spectra were recorded on a Varian XL-300 (Varian Co., Palo Alto, California), on a Bruker AM-300 spectrometer (Bruker Co., Billerica, Massachusetts) or on a Varian 400 Unit at approximately 23 ° C. at 300 or 400 MHz for the proton and 75.4 MHz for the carbon nuclei. Chemical shifts are expressed in parts per million downstream of trimethylsilane. The shapes of the peaks are designated the following way: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; sa = wide singlet. The resonances designated as interchangeable did not appear in a separate NMR experiment, where the sample was shaken with several drops of D20 in the same solvent. The chemical ionization mass spectra at atmospheric pressure (APCI) were obtained in a Fisons Platform II spectrometer. The chemical ionization mass spectra were obtained on a Hewlett-Packard 5889 instrument (Hewlett-Packard Co., Palo Alto, California (ammonia ionization, PBMS). When the intensity of the ions containing chlorine or bromine was described, it was observed The ratio of intensity expected (approximately 3: 1 for ions containing 35CI / 37CI and 1: 1 for ions containing 79Br / 81Br), giving only the lowest ionic mass strength. Baker silica gel (40 μm) (JT Baker, Phillipsburg, NJ) or with silica gel 60 (EM Sciences, Gibbstown, NJ) on glass columns at low nitrogen pressure.Rad chromatography was performed using a Chromatatron * ( Model 7924T, Harrison Research Medium pressure chromatography was performed on a Flash 40 Biotage system (Biotage Inc., Dyax Corp., Charlottesville, Va.) Unless otherwise specified, the reagents were used as described e obtained commercially. The dimethylformamide, 2-propanol, acetonitrile, methanol, tetrahydrofuran and dichloromethane used as reaction solvents were anhydrous grade, supplied by Aldrich Chemical Company (Milwaukee, WI). The terms "concentrate" and "coevaporate" refer to the removal of the solvent at the pressure of a water aspirator in a rotary evaporator, the temperature of the bath being less than 45 ° C. Reactions performed at "0-20 ° C" or "0-25 ° C" were performed by initially cooling the vessel in an isolated ice bath, which was allowed to warm to room temperature for several hours. The abbreviation "min" and "h" indicates "minutes" and "hours" respectively.

EXAMPLE 1 7 - ((4-Butyl-benzyl) - (pyridine-3-sulfonyl) -amino) -heptanoic acid Step A: Reductive amination 7- (4-butyl-benzylamino) - methyl ester heptanoic A solution of 7-amino-heptanoic acid methyl ester hydrochloride, prepared in Preparation 1, (1.12 g, 5.9 mmol), 4-butyl-15-benzaldehyde (0.915 g, 5.65 mmol) and triethylamine (0.83 ml, 5.98 mmol) in 20 ml of MeOH was stirred at room temperature for 3 hours. After cooling to 0 ° C, NaBH 4 (0.342 g, 9.04 mmol) was added and the reaction was stirred for 15 minutes at room temperature. The mixture was quenched with NaHCO3: H20 1: 1 and the MeOH was removed in vacuo. The resulting residue was diluted with CH2Cl2 and the organic solution was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to give the title compound of step A (1.4 g). 1 H NMR (400 MHz, CDCl 3) d 7.08-7.38 (m, 4H), 3.62 (s, 2H), 3.29 (s, 3H), 2.52-2.66 (m, 4H), 2.25 (t, 2H), 1.53- 1.63 (m, 6H), 1.25- »* - *, J & , Ím? Kíál¡ah jg ^^ j - ^ - ^? ^^ m 1.40 (m, 6H), 0.85 (t, 3H); MS 306 (M + 1).

Step B; Formation of amide 7 - ((4-Butyl-benzyl) - (pyridine-3-sulfonyl) -amino-heptanoic acid methyl ester A solution of 7- (4-butyl-benzylamino) -heptanoic acid methyl ester prepared in example 1, step A (0.10 g, 0.33 mmol), N, N-diisopropylethylamine (0.85 g, 0.66 mmol) and pyridine-3-sulfonyl chloride hydrochloride, prepared according to Preparation 2 (0.070 g, 0.33 mmol) in 3 ml of CH2CI2 was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and the organic solution was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (10% AcOEt / hexanes to 30% AcOEt / hexanes) to give the title compound from step B. 1 H NMR (400 MHz, CDCl 3) d 9.01 (s, 1 H ), 8.75 (d, 1 H), 8.04 (d, 1 H), 7.41 (dd, 1 H), 7.23 (m, 4H), 4.30 (s, 2H), 3.62 (s, 3H), 3.08 (t , 2H), 2.55 (t, 2H), 2.19 (t, 2H), 1.10-1.58 (m, 12H), 0.87 (t, 3H); MS 447 (M + 1).

Step C: Hydrolysis of the ester 7 - ((4-Butyl-benzyl-pyridin-3-sulfonyl) -amino) -heptanoic acid A solution of 7 - ((4-butyl-benzyl) - (pyridine-3-sulfonyl) methyl ester ) -amino) -heptanoic prepared in example 1, step B (0.040 g, 0.158 mmol) in 2 ml of MeOH and 0.5 ml of 2N NaOH was stirred at Room temperature during the night. The mixture was quenched with 2N HCl and diluted with CH2Cl2. The organic layer was washed with 1 N HCl and water, dried over MgSO 4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (2% MeOH / CH 2 Cl 2 to 5% MeOH / CH 2 Cl 2) to give the title compound (42 mg). 1 H NMR (400 MHz, CDCl 3) d 9.09 (s, 1 H), 8.77 (d, 1 H), 8.08 (d, 1 H), 7.48 (dd, 1 H), 7.09 (m, 4 H), 4.32 ( s, 2H), 3.12 (s, 2H), 2-55 (t, 2H), 2.25 (t, 2H), 1.12-1.58 (m, 12H), 0.88 (t, 3H); MS 431 (M-1).

EXAMPLES 1a-1n Examples 1a-1n were prepared from the appropriate starting materials analogously to the procedure of Example 1, with variations in reaction time and reagents as indicated.

EXAMPLE 1a 7- (Benzenesulfonyl- (4-butyl-benzylamino) -heptanoic acid 1 H NMR (400 MHz, CDCl 3) d 7.83 (d, 2 H), 7.51-7.59 (m, 3 H), 7.11 (m, 4 H), 4.28 (s, 2 H), 3.07 (t, 2 H), 2.57 (t, 2H), 2.24 (t, 2H), 1.51-1.59 (m, 2H), 1.44-1.49 (m, 2H), 1.27-1.35 (m, 4H), 1.08-1.15 (m, 4H), 0.91 (t, 3H); MS 430 (M-1). a ^ yg * EXAMPLE 1b Acid (3 - (((1-methyl-1 H -indol-3-ylmethyl) - (pyridin-3-sulfonyl) -amino) -methyl) -phenyD-acetic 1 H NMR (400 MHz, CDCl 3) d 8.93 (s, 1 H), 8.66 (s, 1 H), 7.96 (d, 1 H), 7.39 (d, 1 H), 7.01-7.37 (m, 9H) , 6.77 (s, 1 H), 4.56 (s, 2H), 4.41 (s, 2H), 3.66 (s, 3H), 3.52 (s, 2H); MS 448 (M-1).

EXAMPLE 1c 10 Acid (3 - (((5-phenyl-furan-2-ylmethyl) - (pyridin-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid 1 H NMR (400 MHz, CDCl 3) d 8.02 (d, 1 H), 7.22-7.34 (m, 12H), 6.42 (s, 2 H), 4.42 (d, 1 H), 6.17 (d, 1 H), 4.40 (s, 2H), 3.60 (s, 2H); EM 461 (M-15 1).

EXAMPLE 1d Acid (3 - (((5-benzyl-pyridin-2-ylmethyl) - (pyridin-3-sulfonyl) -amino) -methyl) -phenypi-acetic acid Step A: Reaction time of 3.5 h at room temperature 1 H NMR environment (400 MHz, CDCl 3) d 8.97 (s, 1 H), 8.71 (d, 1 H), 8.15 (s, 1 H), 7.98 (d, 1 H), 7.44 (d, 1 H), 7.04-7.34 (m, 10H), 4.54 (s, 2H), 4.43 (s, 2H), .87 (s, 2H), 3.50 (s, 2H); MS 486 (M-1).

EXAMPLE 1e Acid (3 - (((4-phenethylsulfanyl-bencip- (pyridin-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid Step A: Reaction time of 4 h at room temperature RMN H (400 MHz, CDCl 3) d 8.00 (d, 1 H), 7.50 (s, 1 H), 6.90- 7.38 (m, 15H), 4.31 (s, 4H ), 3.49 (s, 2H), 3.11 (t, 2H), 2.87 (t, 2H); EM 531 (M-1).

EXAMPLE 1f Acid (3- (3-hydroxy-4-propoxy-benzyl) - (pyridin-3-sulfonyl) -amino) -methyl) -pheniDacetic acid Step A: Reaction time 3.5 h at room temperature 1 H NMR (400 MHz, CDCl 3) d 8.95 (s, 1 H), 8.72 (s, 1 H), 7.98 (d, 1 H), 7.37 (m, 1 H ), 7.13-7.23 (m, 2H), 6.94-7.00 (m, 2H), 6.55-6.68 (m, 3H), .55 (s, 2H), 4.31 (s, 2H), 3.95 (t, 2H) , 3.52 (s, 2H), 1.78 (m, 2H), 0.99 (t, 3H). ^^^^^^^^^ • ^ z ^ EXAMPLE 1g Acid (3- (f (4-pentyl-benzyl- (pyridin-3-sulfonyl) -amino) -methyl) -phenypi-acetic Step A: Reaction time from 3.5 h at room temperature 5 1 H NMR (400 MHz, CDCl 3) d 8.98 (s, 1 H), 8.74 (s, 1 H), 8.00 (d, 1 H), 7.39 (m, 1 H), 7.14-7.26 (m, 2H), 6.95-7.05 (m, 6H), 4.35 (s, 4H), 3.54 (s, 2H), 2.54 (t, 2H), 1.56 (m, 2H), 1.29 (m, 4H), 0.88 (t, 3H); EM 465 (M-1).

EXAMPLE 1h 10 Acid (3 - (((4-methylsulfamoyl-benzyl) - (pyridin-3-sulfonyl) -amino) -met-p-phenyl) -acetic acid Step A: Reaction time of 3.5 h at room temperature 1 H NMR (400 MHz, CDCl 3) d 9.06 (s, 1 H), 8.85 (s, 1 H), 8.16 (d, 15 1 H), 7.53-7.64 (m , 3H), 6.91-7.26 (m, 6H), 4.39 (s, 2H), 4.35 (s, 2H), 3.50 (s, 2H), 2.63 (s, 3H); MS 488 (M-1).

EXAMPLE 1 i Acid (3 - (((4-isopropoxy-benzyl) - (pyridin-3-sulfoniP-amino) -methyl) -phenyl) -20-acetic acid Step A: Reaction time 3.5 h at room temperature 1 H NMR (400 MHz, CDCl 3) d 8.97 (s, 1 H), 8.74 (s, 1 H), 8.03 (m, > 1 & amp! Amp? Amp? M ¿* < * & 1 H), 7.42 (m, 1 H), 6.94-7.25 (m, 6H), 6.72 (m, 2H), 4.48 (m, 1 H), 4.32 (m, 4H), 3.52 (s, 2H), 1.29 (t, 6H); 453 (M-1).

EXAMPLE 1 i 5 Acid (3 - (((4-Chloro-thiophen-2-ylmethyl) - (pyridine-3-sulfonyl) -amino) -methyl-phenyl-P-acetic acid Step A: Reaction time of 3.5 h at room temperature 1 H NMR (400 MHz, CDCl 3) d 9.01 (s, 1 H), 8.79 (s, 1 H), 8.07 (d, 10 1 H), 7.45 (m, 1 H), 7.20-7.29 (m, 2H), 7.12 (d, 1 H), 7.10 (s, 1 H), 7.07 (s, 1 H), 4.46 (s, 2H), 4.42 (s, 2H), 3.60 (s, 2H); MS 435 (M-1).

EXAMPLE 1k Acid (3 - (((4-butyl-benzyl) - (4-nitro-benzenesulfoniP-amino) -methyl) -pheniP-15 acetic acid 1 H NMR (400 MHz, CDCl 3) d 8.23 (m, 2H), 7.85 (m, 2H), 7.15-2.25 (m, 2H), 695-7.02 (m, 6H), 4.32 (m, 4H), 3.53 (m, 2H), s, 2H), 2.52 (m, 2H), 1.51 (m, 2H), 1.30 (m, 2H), 0.89 (t, 3H); MS 495 (M-1). - «**« «tt" tt ». * Fta« «** a» f ^. .., ^^^. ^. ..... ^ HWfgMlll 11 MU IL EXAMPLE 11 Acid (3 - (( (4-butyl-benzyl) - (4-cyano-benzenesulfonyl-P-amino) -methyl) -phenyl-acetic acid 1 H NMR (400 MHz, CDCl 3) d 8.21 (d, 1 H), 7.67-7.84 (m, 3 H), 6.89-7.24 (m, 8 H), 4.46 (s, 1 H), 4.38 (s, 1 H) , 4.32 (m, 2H), 3.54 (s, 1 H), 3.38 (s, 1 H), 2.55 (m, 2H), 1.58 (m, 2H), 1.33 (m, 2H), 1.29 (s, 1 H), 0.89 (t, 3H); MS 475 (M-1).

EXAMPLE 1m Acid (3 - (((4-butyl-benzyl) - (3-fluoro-becenosulfoniP-amino) -methyl) -phenypi-acetic acid 1 H NMR (400 MHz, CDCl 3) d 7.58 (m, 1 H), 7.45 (m, 1 H), 6.92-7.24 (m, 10 H), 4.29 (m, 4 H), 3.52 (d, 2 H), 2.52 ( d, 2H), 1.52 (m, 2H), 1.29 (m, 2H), 0.90 (m, 3H); EM 468 (M-1).

- * ™ ^^ EXAMPLE 1n Acid (3 - (((4-butyl-benzyl- (5-pyridin-2-yl-thiophen-3-sulfoniP-amino) -methyl-phenyl-acetic acid Step B: The NN-diisopropylethylamine was replaced by triethylamine 1 H NMR (400 MHz, CDCl 3) d 7.81 (m, 2H), 7.17-7.27 (m, 6H), 6.94-7.16 (m, 6H), 4.29 (d, 4H), 3.55 (s, 2H), 2.54 (m, 2H), 1.54 (m, 2H), 1.31 (m, 2H), 0.91 (t, 3H); MS 533 (M-1).

EXAMPLE 1o Acid (3 - (((4-butyl-benzyl- (toluene-4-sulfonyl) -amino) -methyl) -phenyl) -acetic acid Step B: L N, N-diisopropylethylamine was replaced by triethylamine 1 H NMR (400 MHz, CDCl 3) d 7.71 (d, 2 H), 7.24-7.29 (m, 2 H), 7. 11-7.19 (m, 2H), 6.87-7.01 (m, 2H), 4.26 (d, 4H), 3.52 (s, 2H), 2.55 (m, 2H), 2.43 (s, 3H), 1.54 (m, 2H), 1.32 (m, 2H), 0.91 (t, 3H); EM 464 (M-1).

EXAMPLE 1p Acid f3-f ((2-2.3-dihydrobenzop.41-dioxin-6-ylmethyl- (pyridin-3-sulfonyl) -amino) -methyl) -phenyD-acetic acid 1 H NMR (400 MHz, CDCl 3) d 8.98 (s, 1 H), 8.76 (s, 1 H), 8.02 (d, 1 H), 7.40 (m, 1 H), 7.14-7.26 (m, 2 H), 7.02 (d, 1H), 6.96 (s, 1H), 6.72 (d, 1H), 6.59 (m, 2H), 4.35 (s, 2H), 4.25 (s, 2H), 4.20 (s, 4H), 3.55 (s, 2H) ); EM 453 (M-1) - EXAMPLE 1q Acid (3 - ((benzofuran-2-ylmethyl- (pyridin-3-sulfonyl) -amino) -methyl) -phenypi-acetic acid 1 H NMR (400 MHz, CDCl 3) d 9.05 (s, 1 H), 8.66 (s, 1 H), 8.04 (d, 15 1 H), 7.11-7.42 (m, 9 H), 6.44 (s, 1 H), 4.45 (s) , 1H), 4.39 (s, 1H), 3.59 (s, 1H); EM435IM-1).

EXAMPLE 1r (3 - (((4-Butyl-benzyl) - (1-methyl-1 H-imidazole-4-sulfonyl) -amino) -methyl-phenyl-acetic acid 1 H NMR (400 MHz, CDCl 3) d 7.58 (s, 1 H), 7.28 (s, 1 H), 6.99-7.26 (m, 8 H), 4.33 (d, 4 H), 3.65 (s, 3 H), 3.52 (s, 2H), 2.54 (t, 2H), 1.54 (m, 2H), 1.32 ^^ j ^^^ j ^^ Hj ^ jg * íegj ifeMtfeMfeiSi | ta ^? SgMtój ^ gg! Jfe '(m, 2H), 0.91 (t, 3H); MS 454 (M-1).

EXAMPLE 1s Acid (3 - (((4-imidazol-1-yl-benzyl) - (pyridin-3-sulfonyl) -amino) -methyl-phenyl) -5-acetic acid 1 H NMR (400 MHz, CD 3 OD) d 9.45 (m, 1 H), 9.44 (s, 1 H), 9.03 (m, 1 H), 8.91 (d, 1 H), 8.19 (t, 1 H), 8.04 (m , 1H), 7.77 (s, 1 H), 7.61 (d, 2H), 7.53 (d, 2H), 7.11 (m, 4H), 4.70 (s, 2H), 4.51 (s, 2H), 3.33 (s) 2H); EM 461 (M-10 1).

EXAMPLE 1t Acid (3 - (((pyridin-3-sulfoniP- (4-pyrimidin-2-yl-benzyl) -amino) -methyl) -phenypi-acetic acid 1 H NMR (400 MHz, CDCl 3) d 9.10 (s, 1 H), 8.80 (m, 3H), 8.14 (d, 1 H), 8.02 (d, 2H), 7.47 (m, 1 H), 7.06-7.25 (m, 6H), 6.83 (s, 1 H) , 4.40 (s, 2H), 4.33 (s, 2H), 3.41 (s, 2H), EM 473 (M-1).

EXAMPLE 1u Acid (3 - (((pyridine-3-sulfoniP- (4-thiazol-2-yl-benzop-amino) -methyl) -phen-P-acetic acid 1 H NMR (400 MHz, CDCl 3) d 9.11 (s, 1 H), 8.85 (s, 1 H), 8.15 (d, 1 H), 7.87 (s, 2 H), 7.63 (d, 2 H), 7.51 ( m, 1 H), 7.37 (s, 1 H), 7.07-7.27 (m, 6H), 6.83 (s, 1 H), 4.37 (s, 2H), 4.33 (s, 2H), 3.41 (s, 2H) ).

EXAMPLE 1v 10 Acid (3 - (((1-methyl-1 H-imidazol-4-sulfonyl) - (4-thiazol-2-yl-benzyl) -amino) -methiP-phenypi-acetic Step B: The N, N-diisopropylethylamine was replaced by triethylamine 15 H NMR (400 MHz, CDCl 3) d 7.85 (s, 1 H), 7.59 (m, 2 H), 7.47 (s, 1 H), 7.34 (s) , 1 H), 7.07-7.25 (m, 6H), 6.88 (s, 1 H), 4.46 (s, 2H), 4.38 (s, 2H), 3.77 (s, 3H), 3.40 (s, 2H); MS 483 (M-1).

EBMyutMalilkE ^^ JttHk £ & | ^^^ EXAMPLE 1w Acid (3 - (((4-d-methylamino-benzyl- (pyridin-3-sulfoniP-amino-methyl-phenyl-p-acetic Step A: Reaction time of 4 h at room temperature Step B: The NN-diisopropylamine was replaced by triethylamine 1 H NMR (400 MHz, CD3OD) d 8.09 (d, 1 H), 7.09-7.16 (m, 2 H),. 93-6.99 (m, 7H), 6.65 (d, 2H), 5.36 (s, 2H), 4.32 (s, 2H), 4.27 (s, 2H), 2.89 (s, H); MS 438 (m-1).

EXAMPLE 1x Acid (3 - (((4-cyclohexyl-benzyl- (pyridine-3-sulfoniP-amino) -methyl) -phenox-acetic acid Step B: L NN-diisopropyethylamine was replaced by triethylamine 1 H NMR (400 MHz, CDCl 3) d 8.95 (s, 1 H), 8.73 (d, 1 H), 8.00 (d, H), 7.39 (m, 1 H ), 7.17 (t, 1 H), 7.13 (d, 2H), 7.08 (d, 2H), 6.81 (d, 1 H), 6.73 (d, H), 6.61 (s, 1 H), 4.54 (s) , 2H), 4.34 (s, 4H), 2.43 (m, 1 H), 1.81 (d, 4H), 1.37 (t, H), 1.23 (m, 1 H); MS 495 (M + 1).

EXAMPLE 1v Acid (3 - (((2- (3,5-dichloro-phenoxy) -etiP- (pyridin-3-sulfonyl) -amino) -methyl) -phenoxp-acetic acid Step B: The NN-diisopropylethylamine was replaced by triethylamine 1 H NMR (400 MHz, CDCl 3) d 9.07 (s, 1 H), 8.78 (d, 1 H), 8.12 (d, 1 H), 7.47 (m, 1 H), 7.25 (m, 1 H), 6.82-6.91 (m, 4H), 6.53 (s, 2H), 4.61 (s, 2H), 4.47 (s, 2H), 3.91 (t, 2H), 3.54 ( t, 2H); MS 511 (M + 1), 509 (M-1).

EXAMPLE 1z Acid (3 - (((4-dimethylamino-benzyl- (pyridin-3-sulfoniP-amino) -met-P-phenoxyp-acetic acid Step B: The NN-diisopropylethylamine was replaced by triethylamine 1 H NMR (400 MHz, CDCl 3) d 8.91 (s, 1 H), 8.79 (m, 1 H), 8.04 (d, 1 H), 7.43 (m, 1 H), 7.16 (t, 1 H), 6.94 (d, 2H), 6.81 (d, 2H), 6.64 (d, 2H), 6.49 (s, 1 H), 4.51 (s, 2H), 4.28 (s) , 4H), 2.91 (s, 6H); MS 456 (M + 1), 454 (M-1).

EXAMPLE 1aa Acid (3 - (((4-tert-butyl-benzyl) - (pyridine-3-sulfonyl) -amino) -methyl-phenoxy) -acetic acid Step B: The N, N-diisopropylethylamine was replaced by triethylamine 1 H NMR (400 MHz, CDCl 3) d 8.95 (s, 1 H), 8.74 (s, 1 H), 7.99 (d, 1 H), 7.39 (m, 1 H) , 7.25 (m, 2H), 7.15 (t, 1H), 7.04 (d, 2H), 6.81 (d, 1H), 6.72 (d, 1H), 6.62 (s, 1H), 4.55 (s, 2H), 4.35 (s, 4H), 1.27 (s, 9H); MS 469 (M + 1), 467 (M-1).

EXAMPLE 1ab Acid (3 - (((3- (3-chloro-phenyp-propiP- (pyridin-3-sulfonyl) -amino) -methyl) -phenoxp-acetic acid Step B: The N, N-diisopropylethylamine was replaced by triethylamine 1 H NMR (400 MHz, CDCl 3) d 8.98 (s, 1 H), 8.77 (d, 1 H), 8.07 (d, 1 H), 7.48 (m, 1 H) , 7.21 (m, 2H), 6.91 (s, 1H), 6.86 (m, 3H), 6.78 (s, 1H), 4.61 (s, 2H), 4.31 (s, 2H), 3.15 (t, 2H), 2.43 (t, 2H), 1.68 (m, 2H); MS 475 (M + 1), 473 (M-1). .: - i »^: ^^ EXAMPLE 1ac Acid (3 - (((4-tert-butyl-benzyl- (1-methyl-1 H-imidazole-4-sulfoniP-amino) -methyl-phenoxy) -acetic Step B: The NN-diisopropylethylamine was replaced by triethylamine 1 H NMR (400 MHz, CDCl 3) d 7.66 (s, 1 H), 7.08-7.31 (m, 6H), 6.70-6.78 (m, 3H), 4.54 (s) , 2H), 4.35 (s, 4H), 3.68 (s, 3H), 1.27 (s, 9H); EM 469.9 (M-1).

EXAMPLE 1ad Acid (3 - (((4-cyclohexyl-benzyl- (pyridin-3-sulfonyl-P-amino) -met-P-phenyl-P-acetic acid Step B: The N, N-diisopropylethylamine was replaced by triethylamine 1 H-NMR (400 MHz, CDCl 3) d 8.98 (br s, 1 H), 8.75 (br s, 1 H), 7.98 (d, 1 H), 7.39 (br , 1 H), 6.97-7.25 (m, 8H), 4.36 (d, 4H), 3.54 (s, 2H), 2.44 (s, 1 H), 1.72-1.82 (m, 4H), 1.24-1.36 (m , 5H); MS 476.9 (M-1). ^? fe ^ jggÉj & EXAMPLE 1a Acid (3 - (((1-methyl-1 H-imidazole-4-sulfoniP- (4-phenoxy-benzyl-P-amino) -rnenyl) -pheniP-acetic Step B: The N, N-diisopropylethylamine was replaced by triethylamine 1 H NMR (400 MHz, CDCl 3) d 7.52 (s, 1 H), 7.06-7.37 (m, 1 OH), 6.94 (d, 2 H), 6.83 (d , 2H), 4.38 (s, 4H), 3.71 (s, 3H), 1.72-1.82 (m, 4H), 3.56 (s, 2H); MS 490 (M-1).

EXAMPLE 1af Acid (3 - (((4-phenoxy-benzyl- (pyridin-3-sulfonop-amino) -methyl-phenylamphatic) 1 H NMR (400 MHz, CDCl 3) d 9.00 (br s, 1 H), 8.76 (br s, 1 H), 8.04 (d, 1 H), 7.41 (t, 1 H), 7.35 (m, 1 H), 6.86 -7.32 (m, 10H), 6.84 (d, 2H), 4.37 (d, 4H), 3.54 (s, 3H); MS 487 (M-1).

EXAMPLE 1ag Acid (3 - (((4- (2-oxo-pyrrolidin-1-yl) -benzyl) - (pyridin-3-sulfoniP-amino) -methiP-phenypi-acetic Step B: The N, N-diisopropylethylamine was replaced by triethylamine. 1 H NMR (400 MHz, CDCl 3) d 9.06 (br s, 1 H), 8.80 (br s, 1 H), 8.14 (m, 1 H), 7.47 (m, 1 H), 6.96-7.26 (m, 7H), 4.28 (m, 4H), 3.78 (m, 2H), 3.35 (m, 2H), 2.59 (m, 2H), 2.11 (m, 2H); MS 478 (M-1).

EXAMPLE 1ah Acid (3 - (((1-methyl-1 H-imidazole-4-sulfoniP- (4-phenoxy-benzop-amino) -methyl-phenyp-acetic acid 1 H NMR (400 MHz, CDCl 3) d 8.98 (s, 1 H), 8.76 (s, 1 H), 8.04 (d, 1 H), 7.41 (m, 1 H), 7.14-7.20 (m, 2 H), 7.00 (m) d, 1H), 6.94 (s, 1 H), 6.64 (t, 2H), 6.55 (d, 1H), 4.34 (s, 2H), 4.26 (s, 2H), 3.54 (s, 2H); MS 439 (M-1).

EXAMPLE 1ai Acid (3 - (((1-methyl-1 H-imidazole-4-sulfoniP- (4-pyrimidin-5-yl-benzop-amino) -methyl-phenyl-acetic acid Step B: The N, N-diisopropylethylamine was replaced by triethylamine 1 H-NMR (400 MHz, CDCl 3) d 9.18 (s, 1 H), 8.91 (s, 2 H), 7.05-7.54 (m, 11 H), 4.49 ( s, 2H), 4.40 (s, 2H), 3.75 (s, 3H), 3.55 (s, 2H); MS 476 (M-1).

EXAMPLE 1ai Acid (3 - (((pyridine-3-sulfoniP- (4-pyrimidin-5-yl-benzy-p-amino) -met-P-phen-P-acetic acid 1 H NMR (400 MHz, CD 3 OD) d 9.17 (s, 1 H), 9.01 (s, 1 H), 8.77 (s, 15 1 H), 7.57 (m, 4 H), 7.45 (d, 2 H), 7.05-7.16 (m, 5H), 4.48 (s, 2H), 4.43 (s, 2H), 3.45 (s, 2H).

EXAMPLE 1ak Acid (3 - (((4-pyrazin-2-yl-benzyl- (pyridin-3-sulfonyl-phenyl) -methyl-phenyl-P-acetic acid) 1 H NMR (400 MHz, DMSO-d 6) δ 9.18 (s, 1 H), 9.02 (s, 1 H), 8.83 (d, 1 H), 8.68 (s, 1 H), 8.57 (s, 1 H), 8.25 (d, 1H), 7.96 (d, 2H), 7.60 (m, 1H), 7.26 - ^^^^ - ^ - * »^^^ (d, 2H), 7.15 (m, 2H), 7.05 (m, 2H), 4.42 (s, 2H), 4.41 (s, 2H).

EXAMPLE 1 to the Acid (3 - (((1-methyl-1 H-imidazole-4-sulfonyl) - (4-pyrimidin-2-yl-benzop-amino) -methyl-phenyl-acetic acid 1 H NMR (400 MHz, CDCl 3) d 8.78 (d, 2 H), 7.94 (d, 2 H), 7.54 (s, 1 H), 7.44 (s, 1 H), 7.22-7.03 (m, 6 H), 6.87 ( s, 1 H), 4.45 (s, 2H), 4.39 (s, 2H), 3.73 (s, 3H), 3.38 (s, 2H); MS 476 (M-1).

EXAMPLE 1am Acid (3 - (((4-butyl-benzyl-P-phenylmethanesulfonyl-amino) -methyl-phenyl-acetic acid 1 H NMR (400 MHz, CDCl 3) d 7.31-6.96 (m, 13H), 4.13 (s, 2H), 4.05 (s, 2H), 4.03 (s, 2H), 3.62 (s, 2H), 2.60 (t, 2H), 1.58 (m, 2H), 1.33 (m, 2H), 0.91 (t, 3H); EM 464 (M-1).

EXAMPLE 1an 5- (3 - ((Pyridine-3-sulfonyl) -P- (4-thiazol-2-yl-benzop-amino) -propiP-thiophene-2-carboxylic acid Step A: Triethylamine was replaced by NN-diisopropylethylamine 1 H NMR (400 MHz, CDCl 3) d 9.18 (d, 1 H), 8.82 (d, 1 H), 8.05 (d, 1 H), 7.73-7.20 (m , 8H), 6.60 (d, 1 H), 4.35 (s, 2H), 3.22 (t, 2H), 2.70 (t, 2H), 1.85-1.70 (m, 2H).

EXAMPLE 2 Acid (3 - (((2- (3-Chloro-phenoxy) -etiP- (pyridine-3-sulfoniP-amino) -methyl-phenyl-acetic acid Step A: Alkylation This (3 - (((2- (3-Chloro-phenoxy) -etyl) - (pyridyl-3-sulfonyl) -amino) -methyl-phenyl) -acetic To a solution of sodium hydride (60% in mineral oil, 0.016 g, 0.3996 mmol) in 2 ml of DMF was added methyl ester of (3 - ((pyridin-3-sulfonylamino) -methyl) -phenol. l) -acetic (from preparation 14, 0.096 g, 0.333 mmol) at 0 ° C and the reaction was stirred at room temperature for 30 minutes, after cooling to 0 ° C, 1- (2-bromo-ethoxy) was added. ) -3-chloro-benzene (from preparation 29, 0.094 g, 0.399 mmol) and the reaction was stirred at * 3¡kA áÍ? B * v- room temperature at night. The DMF was removed in vacuo. The residue was diluted with AcOEt and the organic solution was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (0.5% MeOH / CH2Cl2 to 5% MeOH / 2% CH2Cl2) to give the title compound of step A (0.025 g). MS 475 (M + 1).

Step B: Hydrolysis of the ester. Acid (3 - (((2- (3-chloro-phenoxy) -eti) - (pyridin-3-sulfonyl) -amino) -10-methyP-phenyp-acetic acid A solution of the example 2, step A (0.025 g, 0.053 mmol) in 2 ml of MeOH and 0.5 ml of 2N NaOH was stirred at room temperature overnight. The mixture was quenched with 2N HCl and diluted with CH2Cl2. The organic layer was washed with 1 N HCl and water, dried over MgSO, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel. (2% MeOH / CH 2 Cl 2 to 5% MeOH / CH 2 Cl 2) to give the title compound of step A (20 g). 1 H NMR (400 MHz, CDCl 3) d 9.05 (s, 1 H), 8.77 (d, 1 H), 8.11 (d, 1 H), 7.43 (m, 1 H), 7.08-7.27 (m, 5H), 6.89 (d, 1 H), 6.62 (s, 1 H), 6.55 (d, 1 H), 4.51 (s, 2H), 3.95 (t, 2H), 3.59 20 (s, 4H); MS 495 (M-2). ^ ggg = & g &lj ^ jij ^ &jj ^ EXAMPLES 2a-2c Examples 2a-2c were prepared from the corresponding starting materials analogously to the procedure of example 2.

EXAMPLE 2a rrans- (3 - (((3- (3,5-dichloro-phenyp-aliP- (pyridine-3-sulfoniP-amino) -methiP-phenypi-acetic acid 1 H NMR (400 MHz, CDCl 3) d 9.08 (br s, 1 H), 8.81 (br s, 1 H), 8.11 (d, 1 H), 7.48 (br s, 1 H), 7.12-7.28 (br, 4H), 6.98 (s, 2H), 6.19 (d, 1 H), 5.86 (m, 1 H), 4.38 (s, 2H), 3.93 (d, 2H), 3.58 (s, 2H).

EXAMPLE 2b Acid (3 - (((2- (3,5-dichloro-phenoxy-etiP- (pyridine-3-sulfoniP-amino) -methyl-phenyp-acetic) 1 H NMR (400 MHz, CDCl 3) d 8.96 (br s, 1 H), 8.70 (br s, 1 H), 8.04 (d, 1 H), 7.41 (m, 1 H), 7.24-7.09 (m, 4H), 6.86 (s, 1 H), 6.47 (s, 2H), 4.44 (s, 2H), 3.86 (m, 2H), 3.49 (s, 2H), 3.31 (m, 2H).

EXAMPLE 2c Acid (3 - (((4- (1-hydroxy-hexyP-benzyl- (pyridine-3-sulfoniP-amino) -methylphenyphenic acid) 1 H NMR (400 MHz, CDCl 3) d 8.91 (br s, 1 H), 8.72 (br s, 1 H), 8.03 (d, 1 H), 7.40 (br s, 1 H), 7.16-6.99 (m, 7H), 6.81 (s, 1 H), 4.57 (t, 1 H). 4.29 (s, 4H), 3.43 (m, 2H), 1.70 (m, 1 H), 1.61 (m, 1 H), 1.32-1.16 (m, 8H), 0.82 (t, 3H).

EXAMPLE 3 Acid 5-f3-f (2-benzylsulfanyl-etiP- (pyridine-3-sulfoniP-amino) -propyl) -thiophen-2-carboxylic acid Step A: Reductive amination 5- (3- (2-Bensulfanyl-ethylamino) -propyl) -thiophene-2-carboxylic acid tert-butyl ester Step A was carried out analogously to the procedure of step A of example 1.

Step B: Formation of Amide 5- (3 - ((2-Benzylsulfanyl-ethyl-pyridin-3-sulfonyl) -amino) -propyl-phenyl-2-carboxylic acid tert-butyl ester Step B was performed analogously to the procedure in step B of Example 1, with the exception that triethylamine was used instead of N, N- diisopropylethylamine.

Step C: Hydrolysis of the ester 5- (3 - ((2-Benzylsulfanyl-ethyl) - (pyridin-3-sulfonyl) -amino) -propyl) -thiophene-2-carboxylic acid «TFA A solution of the ester 5- (3 - ((2-Benzylsulfanyl-ethyl) - (pyridin-3-sulfonyl) -amino) -propyl) -thiophene-2-carboxylic acid tert-butyl ester prepared in Example 3, Step B (0.038) g) in 1 ml of CH2Cl2, cooled to 0 ° C and 1 ml of TFA was added. The mixture was warmed to room temperature and stirred for 1 h. CH 2 Cl 2 and TFA were removed by evaporation, azeotroped by adding CH 2 Cl 2 to give the title compound (46.3 mg). MS 475 (M-1). Examples 3a-3i were prepared from the appropriate starting materials analogously to the procedure of Example 3, the variations made therein being mentioned.

EXAMPLE 3a 5- (3 - ((2- (3-Chloro-phenylsulfanyl-etiP- (pyridine-3-sulfoniP-amino) -propiP-thiophene-2-carboxylic acid 1 H NMR (400 MHz, CD3OD) d 8.93 (s, 1 H), 8.78 (d, 1 H), 8.21 (d, 1 H), 7.64 (m, 1 H), 7.57 (s, 1 H), 7.35 (s, 1 H), 7.19-7.28 (m, 3H), 6.87 (s, 1 H), 3.16-3.35 (m, 6H), 2.87 (t, 2H), 1.89 (t, 2H); MS 497, 499 (M +).

M Say *. aaal ^ - EXAMPLE 3b Acid 3 - (((pyridin-3-sulfoniP- (4-thiazol-2-yl-benzyl-amino) -methyl-phenoxyacetic acid * 2TFA 1 H NMR (400 MHz, CDCl 3) d 9.40 (br s, 1 H), 8.98 (s, 1 H), 8.84 (s, 1 H), 8.28 (m, 1 H), 8.10 (s, 1 H), 7.78 (m, 2 H) , 7.68 (m, 1H), 7.51 (s, 1H), 7.24 (m, 3H), 7.12 (t, 1H), 6.77 (m, 1H), 6.48 (s, 1H), 4.53 (s, 2H), 4.45 (s, 2H), 4.34 (s, 2H); EM494 (M-1).

EXAMPLE 3c Acid (3 - (((pyridin-3-sulfoniP- (4-pyrimidin-2-yl-benzyl-amine) -met-P-phenoxy-acetic »2HCl The TFA salt was converted to the HCl salt by stirring in 2 equivalents 1N HCl followed by removal of water and drying in vacuo. 1 H NMR (400 MHz, CD 3 OD) d 9.00 (d, 2 H), 8.78 (d, 1 H), 8.25 (d, 2 H), 8.08 (t, 1 H), 7.60 (t, 1 H), 7.42 (m, 3 H) , 7.11 (m, 1H), 6.81 (d, 1H), 6.72 (m, 3H), 4.65 (s, 2H), 4.60 (s, 2H), 4.49 (s, 2H).

EXAMPLE 3d Acid (3 - (((1-methyl-1 H-imidazol-4-sulfonyl) - (4-thiazol-2-yl-benzyl) -amino) -methyl-Phenoxy) -acetic «2TFA 1 H NMR (400 MHz, CD 3 OD) d 7.93 (s, 1 H), 7.85 (d, 1 H), 7.76 (d, 2 H), 7.70 (s, 1 H), 7.60 (d, 1 H), 7.26 ( d, 2H), 7.09 (t, 1 H), 6.75 (d, 2H), 6.68 (s, 1 H), 4.51 (s, 2H), 4.41 (s, 2H), 4.35 (s, 2H), 3.76 (s, 3H); MS 498 (M +).

EXAMPLE 3e Acid (3 - (((pyridin-3-sulfoniP- (4-pyridin-2-yl-benzy-p-amino) -met-P-phenoxyacetic * HCl Triethylamine was not used in step A. The TFA salt was converted to the HCl salt by stirring in 2 equivalents of 1 N HCl followed by removal of water and drying under vacuum. MS 490 (M + 1), 488 (M-1).

EXAMPLE 3f Acid (3 - (((1-methyl-1 H-imidazole-4-sulfoniP- (4-pyridin-2-yl-benzy-P-amino) -methyl-P-phenox-acetic acid * HCl Triethylamine was not used in step A. The TFA salt was converted to the HCl salt by stirring in 2 equivalents of 1 N HCl followed by removal of water and drying in vacuo. MS 493 (M + 1), 4941 (M-1). .. ** »*» **. »^^. . ñ ^^^^ ^ ^, ^^^^ rf -,. ^ ^^, J ^ .i H? nM EXAMPLE 3g Acid (3 - (((pyridin-3-sulfoniP- (4-pyridine -3-l-benzyl-amino) -methylp-phenoxy-acetic acid * HCI Triethylamine was not used in step A. The TFA salt was converted to the HCl salt by stirring in 2 equivalents of 1 N HCl followed by removal of water and drying under vacuum. MS 490 (M + 1), 488 (M-1).

EXAMPLE 3h 10 Acid (3 - ((f 1 -methyl-1 H-imidazole-4-sulfonyl-4-pyridin-3-yl-benzyl) -amino) -methiD-phenox-acetic acid «HCl Triethylamine was not used in step A. The TFA salt was converted to the HCl salt by stirring in 2 equivalents of 1 N HCl followed by removal of water and drying under vacuum. MS 493 (M + 1), 491 (M-1).

EXAMPLE 3i Acid (3 - (((pyridin-3-sulfon-P- (4-pyridin-4-yl-benzop-amino) -methyl-pheno-p-acetic acid * HCl 20 Triethylamine was not used in step A. The TFA salt was converted to the HCl salt by stirring in 2 equivalents of 1 N HCl followed by removal of water and drying in vacuo, MS 490 (M + 1), 488 (M-1).

Sju &^^^. g ^ ^ ll ^ l ^ ^^^^ j ^ EXAMPLE 4 5- (3 - ((3- (3-Chloro-phenyp-propiP- (pyridin-3-sulfoniP-amino) -propiP-thiophen-2-acid carboxylic Step A: Formation of the sulfonamide 5- (3 - ((3- (3-Chloro-phenyl-propyl) - (pyridine-3-sulfonyl-phenyl) -propyl-thiophenic acid methyl ester 2-carboxylic acid A solution of 5- (3- (3- (3-chloro-phenyl) -propylamino) -propyl) -thiophene-2-carboxylic acid methyl ester of preparation 8, 0.0855 g, 0.243 mmol), triethylamine (0.0541 g, 0.534 mmol) and pyridine-3-sulfonyl chloride hydrochloride (from preparation 2, 0.0572 g, 0.267 mmol) in 10 ml of CH2Cl2 combined at 0 ° C was stirred at room temperature overnight. The organic solution was washed with water, saturated NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo to give the title compound from step A as an oil, MS 494 (M + 1).

Step B: Ester hydrolysis 5- (3 - ((3- (3-Chloro-phenyl-propyl) - (pyridin-3-sulfonyl) -amino) -propyl) -thiophene-2-carboxylic acid dissolution of 5- (3 - ((3- (3-chloro-phenyl) -propl) - (pyridin-3-sulfonyl) -amino) -propyl) -thiophenic acid methyl ester 2-carboxylic acid prepared in Example 4, step B (0.119 g, 0.241 mmol) in 5 mL of EtOH and 0.72 mL of 1 N NaOH was stirred at room temperature overnight. ^^^ itfa ^ A ^ e adjusted to pH 6.2 and the layers separated. The organic solution was washed with water, dried over MgSO4, filtered and concentrated in vacuo to give the title compound (16 mg). 1 H NMR (400 MHz, CDCl 3) d 8.00 (d, 1H, J = 8), 7.70 (d, 1 H, J = 4), 7.30-7.60 (m, 6H), 6.75 (d, 1 H, J = 4), 3.20 (m, 4H), 2.95 (t, 5 2H, J = 7), 2.60 (t, 2H, J = 7), 1.70-2.00 (m, 4H); MS 478 (M + 1), 476 (M-1).

EXAMPLES 4a-4h Examples 4a-4h were prepared from the appropriate starting materials analogously to the procedure of Example 4.

EXAMPLE 4a 5- (3 - ((3- (3-Chloro-Phen-P-propiP- (4-methoxy-benzene-sulfonyl-P-amino) -propiP-thiophene-2-carboxylic acid 1 H-NMR (400 MHz, CDCl 3 ) d 7.70 (d, 1 H, J = 7), 7.00-7.40 (m, 8H), 6.80 (d, 1 H, J = 4), 3.89 (s, 3H), 3.10 (m, 4H), 2.95 (t, 2H, J = 7), 2.50 (t, 2H, J = 7), 1.70-2.00 (m, 2H), EM 508 (M + 1), 506 (M-1).

EXAMPLE 4b 5- (3 - ((Benzoyl, 2,4-thiadiazole-4-sulfoniP- (3- (3-chloro-phenyp-propyP-amino) -propiD-thiophene-2-carboxylic acid H NMR (400 MHz, CDCl 3) d 7.00-7.70 (m, 8H), 6.70 (d, 1H, J = 4), 3.05 (m, 4H), 2.90 (t, 2H, J = 7), 2.54 ( t, 2H, J = 7), 1.72-1.92 (m, 2H); MS 536 (M + 1), 535 (M-1).

EXAMPLE 4c 10 5- (3- (Benzenesulfonyl- (3- (3-chloro-phenyl) -propyl) -amino) -propiP-thiophene-2-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 6.70-7.92 (m, 11 H), 3.26 (m, 4 H), 3.05 (m, 4 H), 2.73 (m, 2 H), 2.50 (m, 2 H), 1.70 (m 2H); MS 578 (M + 1), 576 (M-15 1).

EXAMPLE 4d 5- (3 - ((3- (3-Chloro-phenyl-propyP-phenylmethanesulfonyl-amino) -propyl) -thiophene-2-carboxylic acid 20 H-NMR (400 MHz, CDCl 3) d 7.50 (d, 1 H , J = 4), 7.00-7.40 (m, 9H), 6.85 (d, 1 H, J = 4), 3.00 (m, 4H), 2.60 (m, 2H), 2.40 (m, 2H), 1.60- 1.80 (m, 2H); MS 490 (M-1).

EXAMPLE 4e 5- (3 - ((3- (3-Chloro-phenyp-propiP- (pyridine-3-sulfoniP-amino) -propiP-furan-2-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 9.00 (M, 1 H), 8.70 (m, 1 H), 8.00 (d, 1 H, J = 6), 7.50 (m, 1 H), 6.80-7.04 (m, 6H), 3.20 (m, 4H), 2.78 (m, 2H), 2.50 (m, 2H), 1.62-2.00 ( m, 4H); MS 463 (m + 1), 461 (M-1).

EXAMPLE 4f 5- (3 - ((3- (3-Chloro-Pheni-propiP- (naphthalene-2-sulfoniP-amino) -propiP-thiophene-2-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 8.40 (d, 1 H, J = 2), 7.00-8.00 (m, 11 H), 6.80 (d, 1 H, J = 4), 3.20 (m, 4H), 2.82 (t, 2H), 2.82 (t, 2H, J = 7), 2.60 (t, 2H, J = 7), 1.80-2.00 (m, 2H); MS 528.9 (M + 1).

EXAMPLE 4q 5- (3 - ((3- (3-Chloro-Pheni-propiP- (naphthalen-1-sulfonop-amino) -propiP-thiophene-2-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 8.60 (d, 1 H, J = 5), 6.95-8.22 (m, 11 H), 6.70 (d, 1 H, J = 4), 3.20 (m, 4H), 2.40 (t, 2H, J = 7), 1.72-1.95 (m, 4H); MS 528.9 (M + 1).

EXAMPLE 4h Acid 5- (3 - ((2-Acetyl-lane-4-methyl-thiazole-5-sulfon-P- (3- (3-chloro-phenyl-propiP-amino) -prop-P-thiophene -2-carboxylic 1 H NMR (400 MHz, CDCl 3) d 7.61 (d, 1 H, J = 4), 7.00-7.30 (m, 4H), 3.60 (d, 1 H, J = 3.8), 2.80 (t, 2H, J = 7.0), 2.60 (t, 2H, J = 6.8), 2.40 (s, 3H), 2.30 (s, 3H) , 1.70-2.00 (m, 4H); MS 556 (M + 1), 554 (M-1).

EXAMPLE 5 5- (3 - ((3- (3-Chloro-phen-P-propiP- (pyridine-3-carboniP-amino) -propiP-thiophene-2-carboxylic acid Step A: Formation of amide 5- (3 - ((3- (3-Chloro-phenyl) -propyl- (pyridine-3-carbonyl) -amino) -propyl) -thiophene-2-carboxylic acid methyl ester dissolution of 5- (3- (3- (3-chloro-phenyl) -propylamino) -propyl) -thiophene-2-carboxylic acid methyl ester (of preparation 8, 0.075 g, 0.213 mmol), DCC (0.0483 g) 0.234 mmol) and nicotinic acid (0.0289 g, 0.234 mmol) in 10 ml of CH2Cl2 was stirred at room temperature overnight The mixture was filtered and the filtrate was concentrated in vacuo The residue was dissolved in 15 ml of AcOEt and the insoluble materials were removed by filtration The organic solution was washed with water followed by brine, dried over MgSO 4, filtered, concentrated in vacuo to give the title compound of step A as an oil (113 mg). 457 (M +).

• Step B: Ester hydrolysis Step B was carried out analogously to the procedure of step B of example 4. 1 H NMR (400 MHz, CDCl 3) d 8.60 (d, 1 H, J = 8), 6.80-7.70 (m , 8H), 6.60 (d, 1 H, J = 4), 3.25 (m, 4H), 2.80 (m, 2H), 2.45 (m, 2H), 1.60-2.05 (m, 4H), EM 443 (M +1), 441 (M-1). • 10 EXAMPLES 5a-5b Examples 5a-5b were prepared from the appropriate starting materials analogously to the procedure of Example 5.

EXAMPLE 5a 5- (3 - ((3- (3-Chloro-Pheni-propiP- (pyridin-2-yl-acetyl-amino) -propiP-thiophene-2-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 8.60 (m, 1 H), 7.00-7.80 (m, 8 H), 20 6.60 (m, 1 H), 4.00 (s, 2 H), 3.32 (m, 4 H), 2.72 (m, 2H), 2.50 (m, 2H), 1.70-2.00 (m, 4H); MS 457 (M + 1), 455 (M-1). * wáM ^ - ^ - üñiff- - «* - fc ^ EXAMPLE 5b Acid 5- (3 - ((3- (3-Chloro-phenyp-propiP- (pyridin-3-yl-acetyl) -amino) -propiP - thiophene-2-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 7.60-7.80 (m, 2H), 7.00-7.50 (m, 7H), 6.70 (d, 1H, J = 4), 3.60 (s, 2H), 3.10-3.40 (m, 4H), 2.80 (m, 2H), 2.60 (m, 2H), 1.70-2.00 (m, 4H), MS 457 (M + 1), 455 (M-1).

EXAMPLE 6 5- (3 - ((2-Chloro-benzenesulfonyl) - (3- (3-chloro-phenyl-propiP-amine) -propiP-thiophene-2-carboxylic acid Step A: formation of the amide 5- (3 - ((2-Chloro-benzenesulfonyl) -3- (3-chloro-phenyl) -propyl) -amino) -propyl) -thiophenic acid tert-butyl ester 2-carboxylic acid A stock solution of 5- (3- (3- (3-chloro-phenyl) -propyl) -amino) -propyl) -thiophene-2-carboxylic acid tert-butyl ester (from preparation 9) was prepared., 0.1 Og, 0.254 mmol) in 10 ml of CH2Cl2 and 1 ml of solution (0.010 g, 0.0254 mmol) was added to a vial of 1 dram. To this was added triethylamine (0.78 ml, 0.056 mmol) and 2-chloro-benzenesulfonyl chloride (0.0059 g, 0.028 mmol). The reaction was stirred overnight at room temperature and diluted with 2 ml of CH2Cl2. The organic solution was washed with 3 ml of a 5.5% aqueous HCl solution (2X) and 3 ml of a saturated bicarbonate solution (2X). The organic layer was dried with MgSO 4 and concentrated to give the title compound of step A (10 mg).

Step B: Hydrolysis of the 5-ester 5- (3 - ((2-Chloro-benzenesulfonyl) -3H (3-chloro-phenyl-propyl) -amino) -prop-P-thiophene-2-carboxylic acid prepared a solution of 5- (3- ((2-chloro-benzenesulfonyl) - (3- (3-chloro-phenyl-propyl) -amino) -propyl) -thiophene-2-carboxylic acid tert-butyl ester. from Example 6, step A (0.010 g, 0.010 mmol) in 4N HCl in 1, 4-10 dioxane (3 mL) and the reaction was stirred overnight at room temperature HCl (g) was bubbled until determined The reaction was complete by thin layer chromatography The reaction mixture was concentrated in vacuo The resulting organic residue was azeotroped with CCI to give a powder (5 mg) 1 H NMR (400 MHz CDCI 3) d 8.00 (d, 1 H, J = 4), 7.00-15.72 (m, 8H), 6.75 (d, 1H, J = 4), 3.20-3.40 (m, 4H), 2.81 (m, 2H), 2.52 (m, 2H ), 1.90 (m, 2H), 1.80 (m, 2H), 1.20 (m, 2H), MS 509.9 (M-1).

EXAMPLES 6a-6i Examples 6a-6j were prepared from the appropriate starting materials analogously to the procedure of Example 6.

EXAMPLE 6a 5- (3 - ((3- (3-Chloro-PheniP-propiP- (2,5-dimethyl-benzenesulfoniP-amino) -propiP-thiophene-2-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 7.70 (d, 1 H, J = 7), 7.00-7.40 (m, 7H), 6.80 (d, 1 H, J = 4), 3.32 (m, 4H), 2.50 (s, 3H), 2.36 (s, 3H), 1.84 (m, 2H), 1.75 (m, 2H), 1.22 (m, 2H); MS 506.1 (M + 1), 504.1 (M-1).

EXAMPLE 6b 5- (3-f (3- (3-Chloro-phenyp-propiP- (2,4-dioxo-1, 2,3,4-tetrahydro-quinazolin-6-sulfoniP-amino) -prop-P-thiophene -2-carboxylic 1 H NMR (400 MHz, CDCl 3) d 6.80-7.92 (m, 9H), 3.20 (m, 4H), 2.80 (m, 2H), 1.75-2.00 (m, 4H), 1.20 (m, 2H); MS 594.0 (M-1 + CI).

EXAMPLE 6c 5- (3 - ((4- (2-carboxy-benzoylamino) -butan-1-sulfon-P- (3- (3-chloro-phenyl-prop-P-amino) -prop-P-thiophene) 2 -carboxylic 1 H NMR (400 MHz, CDCl 3) d 7.70 (d, 1 H, J = 6), 7.62 (d, 1 H, J = 4), 7.55 (d, 1 H, J = 8), 7.45-7.20 (m , 6H), 6.80-6.90 (m, 10H), 3.22 (m, 4H), 2.70 (m, 2H), 2.60 (m, 2H), 1.80-2.00 (m, 4H), 1.22 (m, 2H); EM 620.1 (M-1).

EXAMPLE 6d 5- (3 - ((3- (3-Chloro-phenyl) -P-prop! P- (4- (3,5-dioxo-4,5-dihydro-3H-ri, 2,41-triazn-2-y-; P-benzenesulfoniP-amino) -propiP-thiophene-2-carboxylic acid H NMR (400 MHz, CDCl 3) d 7.60-7.92 (m, 4H), 6.80 (m, 7H), 3.22 (m, 4H), 2.80 (m, 2H), 2.60 (m, 2H), 1.82 (m , 2H), 1.22 (m, 2H); EM 587.1 (M-1).

EXAMPLE 6e 10 5- (3 - ((3- (3-Chloro-PheniP-propiP- (2-methoxycarbonyl-benzenesulfoniP-amino) -propiP-thiophene-2-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 7.75 (d, 1 H, J = 4), 7.00-7.70 (m, 8H), 6.85 (d, 1H, J = 4), 3.90 (s, 3H), 3.31 ( m, 4H), 2.70 (m, 2H), 2.50 (m, 2H), 15 1.82-2.00 (m, 4H), 1.20 (m, 2H); EM 534.1 (M-1).

EXAMPLE 6f 5- (3 - ((4-Bromo-benzenesulfoniP- (3- (3-chloro-phenyl) -propi-P-amino) -propyl) -thiophen-2-carboxylic acid 1H NMR (400 MHz, CDCl 3 ) d 7.75 (d, 1 H, J = 4), 7.00-7.70 (m, 8H), 6.80 (d, 1 H, J = 4), 3.10 (m, 4H), 2.86 (m, 2H), 2.55 (m, 2H), 1.90 (m, 2H), 1.80 (m, 2H); MS 557.9 (M + 1), 555.9 (M-1).

EXAMPLE 6q 5- (3 - ((3- (3-chloro-phenyD-propiD- (4-M, 1-dimethyl-propiP-benzenesulfoniP-amino) -propiP-thiophene-2-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 7.95 (d, 1 H, J = 4), 7.00-7.80 (m, 8H), 6.80 (d, 1 H, J = 4), 3.20 (m, 4H), 2.80 (m, 2H), 2.50 (m, 2H), 1.30 (s, 3H), 1.70-1.90 (m, 4H ), 1.55 (m, 2H), 0.60 (t, 3H, J = 7); EM 548 (M + 1).

EXAMPLE 6h Acid 5- (3 - ((3- (3-Chloro-PheniP-propyP- (3,5-dimethyl-isoxazole-4-sulfonylPamino) -propyl) -thiophene-2-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 6.95-7.40 (m, 4H), 6.80 (d, 1 H, J = 8), 6.75 (d, 1 H, J = 8), 2.91 (m, 2H), 2.60 (s, 3H), 2.40 (m, 2H), 2.20 (s, 3H), 1.72-1.92 (m, 4H), 1.20 (m, 2H); MS 495 (M-1).

EXAMPLE 6i 5- (3 - ((3- (3-Chloro-phen-P-propyP- (2,5-dimethoxy-benzenesulfoni-P-amino) -prop-P-thiophene-2-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 7.70 (d, 1 H, J = 4), 7.00-7.50 (m, 7H), 6.80 (d, 1 H, J = 4), 4.00 (s, 3H), 3.80 (s, 3H), 3.25 (m, 4H), 2.85 (m, 2H), .52 (m, 2H), 1.70-2.00 (m, 2H); MS 538.1 (M + 1), 536.1 (M-1).

EXAMPLE 6! 5- (3 - ((3- (Chloro-pheny1-propyP- (2-fluoro-benzene-sulfon-P-amino) -propiP-thiophene-2-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 7.00-8.00 (m, 9H), 6.80 (d, 1 H, J = 7.2), 3.30 (m, 4H), 2.85 (m, 2H), 2.55 (m, 2H) ), 1.70-2.00 (m, 4H), 1.20 (m, 2H); MS 494.1 (M-1).

EXAMPLE 7 10 5- (3- (1- (3- (3-Chloro-phenyp-propyl) -3-ethyl-ureido) -propyl) -thiophene-2-carboxylic acid Step A: Addition of Isocyanate 5- (3- (1- (3- (3-Chloro-Phen-P-prop-P-3-ethyl-15-ureido) -propyl-thiophenic acid tert-butyl ester 2-carboxylic A stock solution of 5- (3- (3- (3-chloro-phenyl) -propylamino) -propyl) -thiophene-2-carboxylic acid tert-butyl ester (from Preparation 9, 0.10 g) was prepared. 0.254 mmol) in 10 ml of CH2Cl2 and 1 ml of solution (0.010 g, 0.0254 mmol) was added to a vial of 1 dram, to which was added triethylamine (0.7 ml, 0.051 mmol) and ethyl isocyanate (0.004 g). , 0.051 mmol) and the mixture was stirred overnight at room temperature The solution was diluted with 2 ml of CH 2 Cl 2 The organic solution was washed with an aqueous HCl solution, 5.5% (2X) followed by 3 ml of a solution of bicarbonate saturated (2X). The organic layer was dried with MgSO 4 and concentrated to give the title compound of step A (10 mg).

Step B: Ester Hydrolysis Step B was performed in a manner analogous to the procedure of step B of Example 6. 1 H NMR (400 MHz, CDCl 3) d 7.70 (d, 1 H, J = 4), 7.00-7.40 (m , 4H), 6.80 (d, 1 H, J = 4), 3.20 (m, 6H), 2.80 (m, 2H), 2.60 (m, 2H), 1.80-2.00 (m, 4H), 1.05 (t, 3H, J = 7); MS 409.1 (M + 1), 407.1 (M-1).

EXAMPLES 7a-7i Examples 7a-7j were prepared from the appropriate starting materials analogously to the procedure of Example 7.

EXAMPLE 7a 5- (3- (1- (3- (3-Chloro-PheπP-propiP-3-isopropyl-ureido) -propiP-thiophene-2-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 7.70 (d, 1 H, J = 4), 7.00-7.40 (m, 20 4H), 6.80 (d, 1 H, J = 4), 3.20 (m, 4H), 2.85 (m, 2H), 2.60 (m, 2H), 1.75-2.00 (m, 4H), 1.05 (d, 6H, J = 7); EM 423.1 (M + 1), 421.1 (M-1).

EXAMPLE 7b 5- (3- (1- (3- (3-Chloro-phenyp-propyl) -3-phenyl-ureido) -propyl) -thiophene-2-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 7.75 (d, 1 H, J = 7), 7.00-7.50 (m, 9H), 6.80 (d, 1 H, J = 4), 3.20 (m, 4H), 2.90 (m, 2H), 2.60 (m, 2H), 1.80-2.00 (m, 4H); MS 457.1 (M + 1), 455.2 (M-1).

EXAMPLE 7c 10 5- (3- (1- (3- (3-Chloro-phenyl-propyl) -3- (3,4-dichloro-phenyl-p-ureido) -propiP-thiophene-2-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 6.80-7.60 (m, 9H), 3.20 (m, 4H), 2.90 (m, 2H), 2.60 (m, 2H), 1.86-2.00 (m, 4H); MS 527.0 (M + 1), 525.0 (M-1). 15 EXAMPLE 7d 5- (3- (1- (3- (3-Chloro-PheπP-propiP-3-propyl-uredo) -propiP-thiophene-2-carboxylic acid NMR 1H (400 MHz, CDCl 3) d 7.70 (d, 1 H, J = 4), 7.00-7.30 (m, 4H), 6.80 (d, 1 H, J = 4), 3.20-3.30 (m, 5H), 2.95 (t, 2H, J = 7), 2.60 (t, 2H, J = 7), 1.70-2.00 ( m, 4H), 0.95 (t, 3H, J = 7); MS 423 (M + 1), 421 (M-1).

EXAMPLE 7e 5- (3- (3- (4-Chloro-phen-P-1- (3- (3-chloro-phenyl-propyl-uredo) -propiP-thiophene-2-carboxylic acid H NMR (400 MHz, CDCl 3) d 7.70 (d, 1 H, J = 4), 7.00-7.30 (m, 8H), 6.80 (d, 1 H, J = 4), 3.22 (m, 4H), 2.90 (m, 2H), 2.65 (m, 2H), 1.69-2.02 (m, 4H); MS 491 (M + 1), 489 (M-1).

EXAMPLE 7f 10 5- (3- (1- (3- (3-Chloro-phenyp-propyP-3- (2,3-dichloro-phenyl-ureido) -propiP-thiophene-2-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 7.70 (br s, 1 H), 7.00-7.30 (br m, 7 H), 6.80 (br s, 1 H), 3.20 (br, 4H), 2.80 (br, 2H), 2.60 ( m, 2H), 1.75-2.00 (m, 4H); MS 15 527 (M + 1), 525.1 (M-1).

EXAMPLE 7q 5- (3- (1- (3- (3-Chloro-phenyl) -propyl) -3- (3,5-dichloro-phe-p-ureido) -propiP-thiophene-2-carboxylic acid 1H-NMR ( 400 MHz, CDCl 3) d 7.70 (d, 1 H, J = 4), 7.00-7.30 (m, 7H), 6.80 (d, 1 H, J = 4), 3.20 (m, 4H), 2.80 (m, 2H), 2.60 (m, 2H), 1.70-2.00 (m, 4H), EM 527.1 (M + 1), 525.1 (M-1).

EXAMPLE 7h 5- (3- (1- (3- (3-Chloro-phenyp-propyP-3- (2,6-difluoro-phenyl) -ureido) -propyl) -thiophene-2-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 7.70 (d, 1 H, J = 4), 7.00-7.30 (m, 7H), 6.80 (d, 1H, J = 4), 3.20 (m, 4H), 2.86 (m, 2H), 2.65 (m, 2H), 1.73-1.95 (m, 4H); MS 493.1 (M + 1), 491.1 (M-1).

EXAMPLE 7i 5- (3- (1- (3- (3-Chloro-phenyp-propyP-3- (4-fluoro-phenyl) -ureido) -propyl) -thiophene-2-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 7.70 (br s, 1 H), 7.00-7.60 (br, 8H), 6.80 (br, 1 H), 3.30 (br, 4H), 2.90 (br, 2H), 2.60 ( m, 2H), 1.80-2.00 (m, 4H); MS 475.1 (M + 1), 473.1 (M-1).

EXAMPLE 7i 5- (3- (3- (Butyl-1- (3- (3-chloro-phen-P-propiP-uredo) -propiP-thiophene-2-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 7.70 (br s, 1 H), 7.70-7.20 (m, 4H), 6.80 (br, 1 H), 3.20 (m, 6H), 2.90 (m, 2H), 2.60 ( m, 2H), 1.70-2.00 (m, 4H), 0.95 (t, 3H, J = 6.8), MS 437.2 (M + 1), 435.2 (M-1). m > *you? ^^ V »- 'EXAMPLE 8 5- (3 - ((3-Chloro-phenyp-propiP- (pyrrolidin-1-carboniP-amino) -propiP-thiophene-2-carboxylic acid Step A: formation of the amide 5- (3- (1- (3- (3-chloro-phen-P-propyl) -3-etyl-ureido) -prop-P-tert-butyl ester thiophene-2-carboxylic acid. A stock solution of 5- (3- (3- (3-chloro-phenyl) -propylamino) -propyl) -thiophene-2-carboxylic acid tert-butyl ester (from the Preparation 9, 0.10 g, 0.254 mmol) in 10 ml of CH2Cl2 and 1 ml (0.010 g, 0.0254 mmol) was added to a vial of 1 dram. To this was added triethylamine (0.7 ml, 0.051 mmol) and ethyl isocyanate (0.004 g, 0.051 mmol) and the reaction was stirred overnight at room temperature. The reaction was diluted with 2 mL of CH2Cl2 and the organic solution was washed with 3 mL of a 5.5% aqueous HCl solution (2X) followed by 3 mL of a saturated bicarbonate solution (2X). The organic layer was dried with MgSO 4 and concentrated to give the title compound of step A (10 mg).

Step B: ester hydrolysis Step B was performed in a manner analogous to the procedure of step B of Example 6. 1 H NMR (400 MHz, CDCl 3) d 7.70 (d, 1 H, J = 4), 7.00-7.40 ( m, 4H), 6.80 (d, 1 H, J = 4), 3.20 (m, 8H), 2.80 (m, 2H), 2.60 (m, 2H), 1.70- 2.00 (m, 8H), 1.20 (m , 4H); MS 435.1 (M + 1), 433.2 (M-1).

EXAMPLES 8a-8c Examples 8a-8c were prepared from the appropriate starting materials analogously to the procedure of Example 8.

EXAMPLE 8a 5- (3 - ((3- (3-Chloro-Pheni-propiP- (morpholin-4-carboniP-amino) -prop-P-thiophene-2-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 7.65 (d, 1 H, J = 4), 7.00-7.40 (m, 4H), 6.80 (d, 1 H, J = 4), 3.60 (m, 4H), 3.00 -3.20 (m, 8H), 2.80 (m, 2H), 2.60 (m, 2H), 1.70-2.00 (m, 4H); MS 451.1 (M + 1), 449.2 (M-1).

EXAMPLE 8b 5- (3 - ((3- (3-Chloro-phenyD-propiP-isopropoxycarbonyl-amino) -propiD-thiophene-2-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 6.70 (d, 1 H, J = 4), 7.00-7.30 (m, H), 6.80 (d, 1 H, J = 4), 3.20 (m, 4H), 2.80 (t, 2H, J = 6.7), 2.60 (t, 2H, J = 6.7), 1.80-2.00 (m, 4H), 1.01 (d, 6H); MS 424 (M + 1), 422 (M-1).

EXAMPLE 8c 5- (3 - ((3- (3-Chloro-Phe-P-propiP-propoxycarbonyl-amino) -propiP-thiophene-2-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 7.70 (br s, 1 H), 7.00-7.30 (m, 4H), 6.80 (br s, 1 H), 4.00 (t, 2H, J = 6.8), 3.30 (m, 4H ), 2.80 (m, 2H), 2.60 (m, 2H), 1.40-2.00 (m, 6H), 0.90 (t, 3H, J = 7); MS 424 (M + 1), 422.2 (M-1).

EXAMPLE 9 Acid (3 - (((4-butyl-benzyl- (pyridin-3-s? Lphon-P-amino) -met-P-phenyp-acetic acid Step A: reductive amination (3 - ((4-butyl-benzyllamine) -methyl) -phenyl) -acetic acid methyl ester A solution of 4-butyl-benzylamine (from preparation 15, 0.918 g, 6 mmol) in MeOH to 4N HCl in dioxane (0.75 ml, 3 mmol) followed by the addition of the methyl ester of (3-formyl-phenyl) -acetic acid (from preparation 13, 0.534 g, 3.0 mmol) . NaCNBH3 (0.194 mL, 3 mmol) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with AcOEt and 2N NaOH was added. The organic solution was dried over MgSO 4, filtered and concentrated in vacuo. The product was purified by flash chromatography (50% hexanes, 50% AcOEt, 0.1% Et 3 N) to give the title compound from step A. 1 H NMR (400 MHz, CDCl 3) d 7. 08-7.38 (m, 8H), 3.75 (s, 2H), 3.73 (s, 2H), 3.70 (s, 3H), 3.62 (s, 2H), 2.61 (t, 2H), 1.58 (m, 2H) , 1.37 (m, 2H), 0.92 (t, 3H); MS 326 (M + 1).

Step B: formation of amide 5 (3 - (((4-Butyl-benzyl) - (pyridine-3-sulfoniP-amino) -methyl) -phenyl) -acetic acid methyl ester Step B was carried out from analogous to the procedure of step B of Example 1, giving the title compound.

Step C: Hydrolysis of the acid ester (3 - (((4-butyl-benzyl-pyridin-3-sulfoniP-amino) -methyl) -phenyl-acetic acid Step C was carried out analogously to the procedure of step C of Example 1 to give the title compound: 1 H NMR (400 MHz, CDCl 3) d 8.99 (sa, 1 H), 8.74 (sa, 1 H), 7.99 (d, 1 H), 7.36 (sa, 1 H), 7.20-7.25 (m, 2H), 6.95-7.19 (m, 6H) , 4.33 (s, 4H), 3.54 (s, 2H), 2.54 (m, 2H), 1.54 (m, 2H), 1.32 (m, 2H), 0.91 (t, 3H).

EXAMPLES 9a-9d 20 Examples 9a-9d were prepared from the appropriate starting materials analogously to the procedure of Example 9.

EXAMPLE 9a (3 - ((Benzenesulfonyl- (4-butyl-benzop-amino) -methyl) -phenypi-acetic acid 1 H NMR (400 MHz, CDCl 3) d 7.83 (d, 2H), 7.46-7.58 (m, 3H), 7.24 (s, 1 H), 7.14 (m, 2H), 6.86-6.98 (m, 5H), 4.29 (d, 4H), 3.51 (s, 2H), 2.52 (t, 2H), 1.53 (m, 2H), 1.30 (m, 2H), 0.90 (t, 2H); MS 450 (M-1).

EXAMPLE 9b Acid (3 - (((4-butyl-benzyl- (thiophen-2-sulfoniP-amino) -methyl-phenyl-p-acetic) 1 H-NMR (400 MHz, CDCl 3) d 7.53 (m, 2H), 7.16 (m, 2H), 6.89- 7.14 (m, 7H), 4.27 (d, 4H), 3.52 (s, 2H), 2.49 (t, 2H), 1.51 (m, 2H), 1.29 (m, 2H), 0.88 (t, 2H); MS 456.

EXAMPLE 9c Acid (3 - (((4-acetylamino-benzenesulfonyl- (4-butyl-benzop-amino) -methyl-phenyp-acetic acid 1 H NMR (400 MHz, CDCl 3) d 7.69 (m, 2 H), 7.49 (d, 2 H), 7.06- 20 7.23 (m, 6 H), 6.91 (d, 1 H), 6.68 (s, 1 H), 4.30 (d, 4H), 3.44 (s, 2H), 2.54 (t, 2H), 2.17 (s, 3H), 1.54 (m, 2H), 1.29 (m, 2H), 0.89 (t, 2H); EM 507 (M-1). $ 18 EXAMPLE 9d Acid (3 - (((benzoH, 2,51-oxadiazol-4-salfonyl- (4-butyl-benz-P-amino) -methyl) -pheniP-acetic 1 H NMR (400 MHz, CDCl 3) d 7.94 (d, 1 H), 7.88 (d, 2 H), 7.36 (t, 1 H), 7.07 (s, 2H), 6.90-6.96 (m, 6H), 5.3 (d, 4H), 3.46 (s, 2H), 2.46 (t, 2H), 1.47 (m, 2H), 1.26 ( m, 2H), 0.88 (t, 2H); MS 4.92 (M-1).

EXAMPLE 10 Acid (3 - (((1-methyl-1 H-imidazole-4-sulfoniP-4-pyrimidin-2-yl-benzop-amino) -methyl-phenoxypylacetic acid HCl Step A. Reductive amination (3 - ((4-pyrimidin-2-yl-benzylamino) -methyl) -phenox-acetic acid t-butyl ester Step A was carried out analogously to the procedure of step A of example 1.

Step B: formation of amide (3 - (((1-methyl-1 H-imidazole-4-sulfonyl) - (4-pyrimidin-2-yl-benzyl) -amino-tert-butyl ester ) -methyl) -phenoxy) -acetic Step B was carried out in a manner analogous to the procedure of step B of Example 1 using triethylamine instead of N, N-diisopropylethylamine as the base.

Step C: Hydrolysis of the acid ester (3 - (((1-methyl-1 H-imidazole-4-sulfonyl- P- (4-pyrimidin-2-yl-benzyl) -amino) ) -methyl) -phenoxy) -acetic acid HCl A solution of (3 - (((1-methyl-1 H-imidazole-4-sulfonyl) - (4-pyrimidin-2-tert -butyl) -s-tert-butyl ester il-benzyl) -amino) -methyl) -phenoxy) -acetic acid prepared in Example 10, step B (0.094 g, 0.17 mmol) in 1 N HCl in diethyl ether was stirred for 20 minutes until a precipitate formed To the mixture was added 1 ml of water and 1 ml of dioxane and the reaction was stirred for 3 hours.The solvent was removed in vacuo, azeotroped with ethanol to give the title compound as a solid (54 mg). 1H (400 MHz, CD30D) d 9.09 (m, 2H), 8.95 (sa, 1 H), 8.24 (d, 2H), 8.04 (s, 1 H), 7.71 (s, 1 H), 7.44 (d, 2H), 7.13 (m, 1 H), 6.82 (d, 1 H), 6.76 (d, 1 H), 6.69 (s, 1 H), 4.61 (s, 2H), 4.54 (s, 2H), 4.46 (s, 2H), 3.92 (s, 3H), MS 494 (M + 1).

EXAMPLES 11a-11z, 12a-12z Examples 11a-11z, 12a-12z were prepared from the appropriate starting materials analogously to the procedure of Example 1, with variations in reaction time, temperature and reagents, as cited.

Irtll iii fF6 '* ^ ** ^ atus ^ U EXAMPLE 11a Acid 3- (3- (r-benzenesulfonyl- (4-pyrazin-2-yl-benzyl-amine-methyl-phenyl-p-propionic) Step A: reductive amination 3- Methyl ester. { 3 - [(4-pyrazin-2-yl-benzylamino) -methyl-phenyl-propionic acid The title compound of step A was prepared from the hydrochloride salt of 3- (3-aminomethyl-phenyl) methyl ester ) -propionic of preparation 44 and 4-pyrazin-2-yl-benzaldehyde of preparation 27, using the procedure described in example 1, step A except that the imine was formed in MeOH at reflux for 2 h. 1 H NMR (400 MHz, CDCl 3) d 9.01 (s, 1 H), 8.62 (dd, 1 H), 8.49 (d, 1 H), 7.98 (d, 2 H), 7.66 (m, 1 H), 7.54- 7.43 (m, 3H), 7.24 (m, 1 H), 7.09 (m, 1H), 3.88 (s, 2H), 3.80 (s, 2H), 3.66 (s, 3H), 2.94 (t, 2H), 15 2.63 (t, 2H); EM 362 (M + 1).

Step B: formation of amide 3- (3. {[[(BenzenesulfoniP- (4-pyrrazin-2-yl-benzyl) -amino] -metl] -phenyl) -prop acid methyl ester The title compound of step B was prepared from the methyl ester of 3-acid. { 3 - [(4-pyrazin-2-yl-benzylamino) -methyl] -phenyl} -propionic acid of step A and benzenesulfonyl chloride according to the procedure described in example 1, step B, using triethylamine instead of N, N-düsopropylethylamine.

J¿ ** ^ »- ^ *? * £ li ?? *. , .Aa £ - 1 H NMR (400 MHz, CDCl 3) d 8.98 (s, 1 H), 8.60 (m, 1 H), 8.50 (d, 1 H), 7.87 (m, 4 H), 7.63 (m, 1 H), 7.56 (m, 2H), 7.17 (d, 2H), 7.12 (m, 1 H), 7.02 (d, 1 H), 6.87 (d, 1 H), 6.78 (s, 1 H), 4.37 (s, 2H), 4.32 (s, 2H), 3.64 (s, 3H), 2.78 (t, 2H), 2.47 (t, 2H); EM 502 (M + 1). Step C: Hydrolysis of the ester 3- (3- (R-benzenesulfonyl- (4-pyrazin-2-yl-benzyl) -amino] -methyl) -pheniP-propionic acid The title compound was prepared according to the procedure described in Example 1, step C from 3- (3. {[[benzenesulfonyl) - (4-pyrazin-2-yl-benzyl) -amino] -methyl] -phenol. ) -propionic from step B. EM 486 (M-1).

EXAMPLE 11 b 15 3- (3- (R-benzenesulfonyl- (4-pyridin-3-yl-benzy-P-amino-1-methyl-phenyl-propionic acid Step A: reductive amination 3- (3. {[[(4-pyridin-3-yl-benzyllamine) -meti-1-phenyl-propionic acid methyl ester The title compound of step A was prepared from the hydrochloride salt of the 3- (3-aminomethyl-phenyl) -propionic acid methyl ester of preparation 44 and 4-pyridin-3-yl-benzaldehyde of preparation 23, using the procedure described in example 1, step A. 1 H NMR (400 MHz, CDCl 3) d 8.81 (d, 1 H), 8.55 (dd, 1 H), 7.84 (m, 1 H), 7.53 (d, 2 H), 7.44 (d, 2H), 7.33 (m, 1 H), 7.26-7.18 (m, 3H), 7.07 (d, 1 H), 3.84 (s, 2H), 3.79 (s, 2H), 3.64 (s, 3H), 2.92 (t, 2H), 2.61 (t, 2H); EM 361 (M + 1). Step B: Amide formation 3- (3. {[[(BenzenesulfoniP- (4-pyridin-3-yl-benzy-p-aminol-methylMeniP-propionic acid methyl ester) The title compound of step B was prepared from the methyl ester of 3- ({3 - [(4-pyridin-3-yl-benzylamino) -methyl] -phenyl} -propionic acid ester of step A and benzenesulfonyl chloride according to the procedure described in Example 1, step B, using triethylamine in place of N, N-diisopropylethylamine, 1 H NMR (400 MHz, CDCl 3) d 8.79 (s, 1 H), 8.58 (d, 1 H), 7.87 (m, 3 H), 7.61 (m, 1 H), 7.54 (m, 2H), 7.40 (m, 3H), 7.18 (m, 3H), 7.03 (d, 1 H), 6.88 (d, 1 H), 6.79 15 (s, 1 H), 4.36 (s, 2H), 4.33 (s, 2H), 3.65 (s, 3H), 2.79 (t, 2H), 2.48 (t, 2H), EM 501 (M + 1).

Step C: Hydrolysis of the ester 3- (3. {[[Benzenesulfonyl- (4-pyridin-3-yl-benzyl) -amino] -methyl) -20-phenyl-propionic acid The compound of The title was prepared according to the procedure described in Example 1, step C from 3- (3. {[[benzenesulfonyl) - (4-pyridin-3-yl-benzyl) -amino] -methyl methyl ester} phenyl) -propionic step B. 1 H NMR (400 MHz, CDCl 3) d 9.14 (s, 1 H), 8.63 (d, 1 H), 8.46 (d, 1 H), 7.90 (m, 3 H), 7.63 (m, 3 H), 7.40 (d, 2H), 7.22 (m, 2H), 6.91 (m, 3H), 6.75 (d, 1H), 4.36 (s, 2H), 4.27 (s, 2H), 2.81 (t, 2H), 2.56 ( t, 2H); MS 485 (M-1).

EXAMPLE 11c 7-R (pyridin-2-sulfonyl) - (4-thiazol-2-yl-benzyl) -amino-1-heptanoic acid Step A: reductive amination 7- (4-thiazol-2-yl-benzylamino) -heptanoic acid methyl ester The title compound was prepared following the procedure described in step A of example 1 from methyl ester hydrochloride of 7-amino-heptanoic acid of preparation 1 and 4-thiazol-2-yl-benzaldeido of preparation 25. 1 H NMR (400 MHz, CDCl 3) d 7.91 (d, 2 H), 7.84 (d, 1 H), 7.38 (d, 2H), 7.30 (d, 1 H), 3.82 (s, 2H), 3.65 (s, 3H), 2.62 (t, 2H), 2.29 (t, 2H), 1.61 (m, 2H), 1.51 (m, 2H), 1.33 (m, 4H); MS 333 (M + 1).

Step B: Sulfonamide formation 7 - [(pyridn-2-sulfonyl) - (4-thiazol-2-yl-benzyl-p-aminol-heptanoic acid methyl ester The title compound is prepared following the procedure described in step B of example 1 from the 7- (4-thiazol-2-yl-benzylamino] -heptanoic acid methyl ester of step A and pyridin-2-sulfonyl chloride hydrochloride of Preparation 47. 1 H NMR (400 MHz, CDCl 3) d 9.06 (d, 1 H), 8.81 (m, 1 H), 8.10 (m, 1 H), 7.91 (d, 2 H), 7.86 (m, 1 H ), 7.46 (m, 1 H), 7.34 (m, 3H), 4.39 (s, 2H), 3.62 (s, 3H), 3.15 (t, 2H), 2.21 (t, 2H), 1.48 (m, 2H) ), 1.37 (m, 2H), 1.15 (m, 4H), MS 474 (M + 1).

Step C: Hydrolysis of the ester 7 - [(pyridin-2-sulfoniP- (4-thiazol-2-yl-benzyl-P-amino-1-heptanoic acid) The title compound was prepared following the procedure described in Step C of Example 1 from 7 - [(pyridin-2-sulfonyl) - (4-thiazol-2-yl-benzyl) -amino] -heptanoic acid methyl ester from step B. 1 H NMR (400 MHz, CDCl 3 ) d 9.07 (s, 1 H), 8.81 (m, 1 H), 8.11 (m, 1 H), 7.87 (m, 3H), 7.48 (m, 1 H), 7.37 (m, 3H), 4.37 ( s, 2H), 3.14 (t, 2H), 2.23 (t, 2H), 1.51 (m, 2H), 1.48 (m, 2H), 1.13 (m, 4H).

EXAMPLE 11d Acid (3- (r (4-butyl-benzyl) -P- (1-methyl-1 H-imidazole-4-sulfonyl-P-aminol-methyl.} - phenypi-acetic Step A: formation of the amide (3- (l- (4-Butyl-benzyl) - (1-methyl-1 H-imidazole-4-sulfonyl) -amino-1-methyl) -phen-P-acetic acid methyl ester compound of the title of step B was prepared following the procedure described in step B of example 1 from the methyl ester fc ^ * - ** ,. ? ** ßmamm. of the acid. { 3 - [(4-Butyl-benzylamino) -methyl] -phenyl} -acetic, prepared in step A of example 9 and 1-methyl-1 H-imidazole-4-sulfonyl chloride. 1 H NMR (400 MHz, CDCl 3) d 7.47 (s, 1 H), 7.34 (s, 1 H), 7.18-7.02 (m, 8 H), 4.38 (s, 4 H), 3.71 (s, 3 H), 3.68 ( s, 3H), 3.52 (s, 2H), 2.55 (t, 2H), 1.55 (m, 2H), 1.32 (m, 2H), 0.91 (t, 3H); MS 470 (M + 1).

Step B: ester hydrolysis Acid (3-. {F (4- (Butyl-benzyl) -1-methyl-1 H-imidazole-4-sulfonyl-D-aminol-methylMeniD-acetylene The title compound was prepared following the procedure described in Step C of Example 1 from (3- {[[(4-butyl-benzyl) - (1-methyl-1 H-imidazole-4-sulfonyl) -amino] -methyl] -methyl ester. phenyl) -acetic from step A. 1 H NMR (400 MHz, CDCl 3) d 7.58 (s, 1 H), 7.28 (s, 1 H), 7.15-6.99 (m, 8H), 4.36 (s, 2H) , 4.33 (s, 2H), 3.65 (s, 3H), 3.52 (s, 2H), 2.54 (t, 2H), 1.54 (m, 2H), 1.32 (m, 2H), 0.91 (t, 3H); MS 454 (M-1).

EXAMPLE 11e 3- (3-fT (1-methyl-1 H -amidazole-4-sulfoniP- (4-thiazol-2-yl-benzyl-aminol-methyl-phenyl-propionic acid Step A: reductive amination 3- (3 - [(4-thiazol-2-yl-benzyl-amino) -methyl-1-phenyl-propionic acid methyl ester The title compound of step A was prepared from the hydrochloride salt of the 3- (3-aminomethyl-phenyl) -propionic acid methyl ester of preparation 44 and 4-thiazol-2-yl-benzaldehyde of preparation 25 using the procedure described in example 1, step A, except that the imine was formed in MeOH at reflux for 2 h. 1 H NMR (400 MHz, CDCl 3) d 7.93 (d, 2 H), 7.85 (d, 1 H), 7.43 (d, 2 H), 7.31 (d, 1 H) , 7.28-7.09 (m, 4H), 3.84 (s, 2H), 3.79 (s, 2H), 3.66 (s, 3H), 2.94 (t, 2H), 2.63 (t, 2H), EM 367 (M + 1 ).

Step B: Formation of amide 3- (3 { [(1-methyl-1 H-imidazole-4-sulfonyl) -2,4-thiazol-2-yl-benzyl-methyl-methyl-phenyl-propionic acid methyl ester The compound of the title of step B was prepared from the methyl ester of 3- ({3 - [(4-thiazol-2-yl-benzylamine) -methyl-phenyl) -propionic acid ester of step A and the 1-methyl-1 H-imidazole-4-sulfonyl following the procedure described in example 1, step B. MS 511 (M + 1).

Step C: ester hydrolysis 3- (3- (r (1-methyl-1 H-imidazole-4-sulfonyl) -P- (4-thiazol-2-yl-benzyl-amino] -methyl) -phenyl ester ) -propionic The title compound was prepared following the procedure described in Example 1, step C from 3- (3. {[[(1-methyl-1H-imidazole-4) methyl ester -sulfonyl) - (4-thiazol-2-yl-benzyl) -amino] -methyl] -phenyl) -propionic from step B. 1 H NMR (400 MHz, CDCl 3) d 7.86 (d, 2 H), 7.69 ( d, 2H), 7.59 (s, 1 H), 7.46 (s, 1 H), 7.36 (m, 1 H), 7.19 (d, 2H), 7.15-6.99 (m, 3H), 6.88 (s, 1 H), 4.46 (s, 2H), 4.37 (s, 2H), 3.76 (s, 3H), 2.80 (t, 2H), 2.50 (t, 2H), MS 495 (M-1), 10 EXAMPLE 11f Acid 7-r (4-pyrazol-1-yl-benzyl- (pyridine-2-sulfonyl-p-aminol-heptanoic) Step A: reductive amination 7- (4-pyrazol-1-yl-benzyl-amino) -heptanoic acid methyl ester The title compound of step A was prepared from the 7-amino-heptanoic acid methyl ester hydrochloride of Preparation 1 and 4-pyrazol-1-yl-benzaldehyde of Preparation 42, using the procedure described in Example 1, Step A. 1 H NMR (400 MHz, CDCl 3) d 7.90 (m, 1 H), 7.70 (d, 1 H), 7.63 (d, 2H), 7.39 (d, 2H), 6.45 (m, 1 H), 3.80 (s, 2H), 3.65 (s, 3H), 2.61 (t, 2H) , 2.29 (t, 2H), 1.63-1.32 (m, 4H), 1.25 (m, 4H). MS 316 (M + 1).

Step B: Formation of amide 7-l (4-pyrrazol-1-yl-benzyl) - (pyridyl-2-sulfonopropylamine-heptanoic acid methyl ester The title compound of step B was prepared from the 7- (4-pyrazol-1-yl-benzylamino) -heptanoic acid methyl ester of step A and the pyridin-2-sulfonyl chloride hydrochloride of preparation 47, following the procedure described in Example 1, step B using triethylamine in place of NN-diisopropylethylamine, 1 H NMR (400 MHz, CDCl 3) d 9.06 (m, 1 H), 8.80 (dd, 1 H), 8.10 (m, 1 H), 7.92 (d , 1 H), 7.71 (d, 1 H), 7.65 (d, 2H), 7.48 (m, 1 H), 7.36 (d, 2H), 6.46 (d, 1 H), 4.38 (s, 2H), 3.62 (s, 3H), 3.14 (t, 2H), 2.21 (t, 2H), 1.48 (m, 2H), 1.36 (m, 2H), 1.25 (m, 4H), MS 457 (M + 1).

Step C: Hydrolysis of the ester 7 - [(4-pyrrazol-1-yl-benzyl- (pyridin-2-sulfonopylamino) heptanoic acid The title compound was prepared following the procedure described in Example 1, step C from the 7 - [(4-pyrrazol-1-yl-benzyl) - (pyridine-2-sulfonyl) -amino] -heptanoic acid methyl ester from step B. 1 H NMR (400 MHz, CDCl 3) d 9.07 (d, 1 H), 8.82 (dd, 1 H), 8.12 (m, 1 H), 7.88 (d, 1 H), 7.74 (d, 1 H), 7.62 (d, 2H ), 7.48 (m, 1 H), 7.41 (d, 2H), 6.48 (m, 1 H), 4.35 (s, 2H), 3.13 (t, 2H), 2.22 (t, 2H), 1.47 (m, 2H), 1.32 (m, 2H), 1.17 (m, 4H), EM 441 (M-1).

EXAMPLE 11q 7-R (4-pyrazol-1-yl-benzyl- (pyridin-3-sulfonyl) -aminol-heptanoic acid Step A: formation of the amide 7 - [(4-pyrrazol-1-yl-benzyl) - (pyridine-3-sulfoniP-aminol-heptanoic acid methyl ester The title compound of step A was prepared from of the 7- (4-pyrazol-1-yl-benzylamino) -heptanoic acid methyl ester of example 11f, step A and the pyridin-3-sulfonyl chloride hydrochloride of preparation 2, following the procedure described in example 1 , step B using triethylamine in place of N, N-diisopropylethylamine, 1 H NMR (400 MHz, CDCl 3) d 8.70 (m, 1 H), 7.99-7.87 (m, 3 H), 7.71 (d, 1 H), 7.63 ( d, 2H), 7.46 (m, 1 H), 7.42 (d, 2H), 6.46 (dd, 1H), 4.56 (s, 2H), 3.62 (s, 3H), 3.25 (t, 2H), 2.20 ( t, 2H), 1.46 (m, 2H), 1.34 (m, 2H), 1.25 (m, 4H), MS 457 (M + 1).

Step B: ester hydrolysis 7 - [(4-pyrrazol-1-yl-benzyl- (pyridin-3-sulfonop-amino) -heptanoic acid ester The title compound was prepared following the procedure described in Example 1, step C from 7 - [(4-pyrazol-1-yl-benzyl) - (pyridine-3-sulfonyl) -amino] -heptanoic acid methyl ester from step B. 1 H NMR (400 MHz, CDCI3) d 8.71 (m, 1H), 7.99 (d, 1H), 7.90 (m, 2H), 7.74 (d, 1H), 7.60 (d, 2H), 7.48 (m, 3H), 6.47 (m, 1 H), 4.56 (s, 2H), 3.24 (t, 2H), 2.20 (t, 2H), 1.46 (m, 2H), 1.29 (m, 2H), 1.12 (m, 2H), 1.05 (m, 2H); MS 441 (M-1).

EXAMPLE 11h 3-Trifen-3-benzenesulfonyl- (4-pyrazol-1-yl-benzyl) -amino-1-methyl > -PheniP- 5 Propionic Step A: reductive amination 3- methyl acid ester. { 3 - [(4-p.orazol-1-yl-benzylamino) -methylphenD-propionic acid The title compound of step A was prepared from the hydrochloride salt of 3- (3-aminomethyl) -phenyl) -propionic acid of Preparation 44 and 4-pyrazol-1-yl-benzaldehyde of Preparation 42, using the procedure described in Example 1, Step A, with the exception that the mine was formed in MeOH at reflux for 2 h. 1 H NMR (400 MHz, CDCl 3) d 7.81 (s, 1 H), 7.44 (d, 2H), 7.32 (d, 2H), 7.24 (m, 2H), 7.17 (m, 3H), 7.07 (d, 1 H), 3.82 (s, 2H), 3.77 (s, 2H), 3.64 (s) , 3H), 2.92 (t, 2H), 2.61 (t, 2H); MS 350 (M + 1).

Step B: Formation of Amide 3- (3. {[[Benzenesulfonyl- (4-pyrrazol-1-yl-20-benzyP-aminol-methylMeniP-propionic acid methyl ester The compound of Step B was prepared Starting from the methyl ester of 3- ({3 - [(4-pyrazol-1-yl-benzylamino) -methyl] -phenyl} -propionic acid ester of step A and benzenesulfonyl chloride following the procedure described in the example 1, step B, using triethylamine in place N, N-diidopropylethylamine (400 MHz, CDCI3) d 7.87 (d, 2H), 7.84 (s, 1 H), 7.64-7.53 (m, 3H), 7.20 (m, 5H) ), 7.11 (m, 1 H), 7.02 (d, 1 H), 6.84 (d, 1 H), 6.78 (d, 1 H), 4.33 (s, 2H), 4.31 (s, 2H), 3.65 ( s, 3H), 2.78 (t, 2H), 2.47 (t, 2H); MS 490 (M + 1). Step C: Hydrolysis of the ester 3- (3. {Fbenzenesulfonyl- (4-pyrazol-1-yl-benzyl-P-amino] -methyl) -pheniP-propionic acid The title compound was prepared following the procedure 0 described in Example 1, step C from 3- (3. {[[benzenesulfonyl- (4-pyrazol-1-yl-benzyl) -amino] -methyl] -phenyl) methyl ester -proper step B. 1 H NMR (400 MHz, CDCl 3) d (selected peaks) 4.44 (s, 2 H), 4.36 (s, 2H), 2.88 (t, 2H), 2.65 (t, 2H); MS 474 (M-1).

EXAMPLE 11i 7-Fpyridin-3-sulfonyl) - (4-pyrimidin-2-yl-benzyl) -amino-1-heptanoic acid Step A: reductive amination 7- (4-pyrimidin-2-yl-benzyllamine) -0 heptanoic acid methyl ester The title compound of step A was prepared from the methyl ester hydrochloride of 7-amino-heptanoic acid of preparation 1 and 4-pyrimidin-2-yl-benzaldehyde of preparation 21 using the The procedure described in Example 1, step A. 1 H NMR (400 MHz, CDCl 3) d 8.78 (d, 2 H), 8.37 (d, 2 H), 7.42 (d, 2 H), 7.16 (t , 1 H), 3.85 (s, 2H), 3.64 (s, 3H), 2.62 (t, 2H), 2.28 (t, 2H), 1.55 (m, 4H), 1.32 (m, 4H); MS 328 (M + 1).

Step B: Formation of amide 7-f-methyl ester (pyridin-3-sulfonyl-P- (4-pyrimidin-2-yl-benzaminophenole-heptanoic acid The title compound of step B was prepared from the 7- (4-pyrimidin-2-yl-benzylamino) -heptanoic acid methyl ester of step A and the pyridin-3-sulfonyl chloride hydrochloride of preparation 2, following the procedure described in the example 1, step B using triethylamine in place of N, N-diisopropyllethanol amine 1 H NMR (400 MHz, CDCl 3) d 9.07 (d, 1 H), 8.80 (m, 3 H), 8.37 (d, 2 H), 8.10 (m, 1 H), 7.46 (m, 1 H), 7.37 (d, 2H), 7.19 (m, 1 H), 4.43 (s, 2H), 3.62 (s, 3H), 3.15 (t, 2H) ), 2.20 (t, 2H), 1.48 (m, 2H), 1.38 (m, 2H), 1.14 (m, 4H), EM 469 (M + 1).

Step C: Hydrolysis of the ester 7 - [(Pyridin-3-sulfonyl-4-pyrimidin-2-yl-benzyl) -amino] -heptanoic acid The title compound was prepared following the procedure described in the example 1, step C, from 7 - [(pyridin-3-sulfonyl) - (4-pyrimidin-2-yl-benzyl) -amino] -heptanoic acid methyl ester from step B. 1 H NMR (400 MHz, CDCl 3 ) d 9.08 (s, 1 H), 8.82 (m, 3H), 8.29 (d, 2H), 8.13 (m, 1H), 7.48 (m, Xia at 1 H), 7.42 (d, 2H), 7.24 (m, 1 H), 4.40 (s, 2H), 3.14 (t, 2H), 2.22 (t, 2H), 1.48 (m, 2H), 1.32 (m, 2H), 1.14 (m, 2H), 1.06 (m, 2H); EM 453 (M-1).

EXAMPLE 11i 7-I (1-methyl-1 H-imidazole-4-sulfonyl) -P- (4-thiazol-2-yl-benzyl-1-heptanoic acid Step A: reductive amination 7- (4-thiazol-2-yl-benzylamino) -heptanoic acid methyl ester The title compound of step A was prepared from the 7-amino-heptanoic acid methyl ester hydrochloride Preparation 1 and 4-thiazol-2-yl-benzaldehyde of Preparation 25 using the procedure described in Example 1, Step A. 1 H NMR (400 MHz, CDCl 3) d 7.91 (d, 2 H), 7.84 (d, 1 H), 7.38 (d, 2H), 7.30 (d, 1 H), 3.82 (s, 2H), 3.65 (s, 3H), 2.62 (t, 2H), 2.29 (t, 2H), 1.61 (m , 2H), 1.51 (m, 2H), 1.33 (m, 4H); MS 333 (M + 1).

Step B: formation of the amide 7 - [(1-methyl-1 H-imidazole-4-sulfonyl! -) - (4-thiazol-2-yl-benzyl-heptanoic acid) methyl ester The title compound of the title Step B was prepared from the 7- (4-thiazol-2-yl-benzylamine) -heptanoic acid methyl ester of step A and the 1-methyl-1 H-imidazole-sulfonyl chloride following the procedure described in «*» »» 8aaiÉÉiti¡¿ gg ^^^^ j ^ ifeaÉfc.

Example 1, step B using triethylamine instead of N, N-diisopropylethylamine. 1 H NMR (400 MHz, CDCl 3) d 7.90 (d, 2 H), 7.85 (d, 1 H), 7.49 (s, 1 H), 7.43 (m, 3 H), 7.32 (d, 1 H), 4.47 (s) , 2H), 3.74 (s, 3H), 3.62 (s, 3H), 3.20 (t, 2H), 2.20 (t, 2H), 1.48 (m, 2H), 1.40 (m, 2H), 1.15 (m, 4H); MS 477 5 (M + 1).

Step C: Hydrolysis of the ester 7-I (1-methyl-1H-methyldazole-4-sulfonyl- (4-thiazol-2-yl-benzyl) -heptanoic acid ester The compound of The title was prepared following the procedure described in example 1, step C, from 7 - [(1-methyl-1 H-imidazole-4-sulfonyl) - (4-thiazol-2-yl-benzyl) methyl ester ) -amino] -heptanoic from step B. 1 H NMR (400 MHz, CDCl 3) d 7.87 (m, 3 H), 7.48-7.34 (m, 4 H), 7.32 (d, 1 H), 4.46 (s, 2 H), 3.75 (s, 3H), 3.19 (t, 2H), 2.21 (t, 2H), 1.48 (m, 2H), 1.31 (m, 2H), 15 1.24 (m, 2H), 1.16 (m, 2H).

EXAMPLE 11k 5-f3-r (pyridin-3-sulfoniP- (4-thiazol-2-yl-benzy-p-amino-propyl) -thiophene-2-carboxylic acid Step A: Reductive amination 5- (3 - [(Pyridin-3-sulfonyl) - (4-thiazole-2-yl-benzopylamino] -propyl-2-phenoxy-2-carboxylic acid methyl ester compound of the title of step B was prepared from the 5- [3- (4-thiazol-2-yl-benzylamino) -propyl] -thiophene-2-carboxylic acid methyl ester of step A and the pyridine chloride hydrochloride -3-sulfonyl of preparation 2 following the procedure described in example 1, step B using triethylamine instead of N, N-diisopropylethylamine EM 514 (M + 1).

Step C: hydrolysis of the ester 5- (3 - [(Pyridin-3-sulfonyl) -P- (4-tiazol-2-yl-benzyl-P-amino) -propyl) -thi-e-n-2 ester -carboxyl The title compound was prepared following the procedure described in Example 1, step C, from the methyl ester of 5-. {3 - [(pyridine-3-sulfonyl) - (4-t! azole-2-yl-benzyl) -amino] -propyl.} -thiophene-2-carboxylic acid from step B using EtOH instead of MeOH as solvent 1 H NMR (400 MHz, CDCl 3) d 9.12 (d, 1 H, J = 4 Hz), 8.81 (d, 1 H, J = 5 Hz), 8.17-7.21 (m, 9H), 6.61 (d, 1 H, J = 4 Hz), 4.41 (s, 2H), 3.25 ( t, 2H, J = 6.5 Hz), 2.72 (t, 2H, J = 6.5 Hz), 1.73 (m, 2H), MS 498 (m-1).

EXAMPLE 111 5- (3- l3- (3-Chloro-pheny P-propyl-cyclopropanesulfonyl-amino.}. -prop.P-thiophene-2-carboxylic acid Step A: formation of the amide 5- (3- (f3- (3-Chloro-phenylP-propylcyclopropanesulfonyl-amino) -propyl) -thiophene-2-carboxylic acid methyl ester To a solution of the methyl ester of 5-. {3- [3- (3-Chloro-phenyl) -propylamino] -propyl] -thiophene-2-carboxylic acid (51.5 mg, 0.1463 mmol) of Preparation 8, in CH2Cl2 (10 mL) At 0 ° C, cyclopropanesulfonyl chloride (22.6 mg, 0.161 mmol) and triethylamine (0.45 mL, 0.32 mmol) were added.The reaction was warmed to room temperature and stirred for 48 h.The reaction was heated to reflux for 48 h and added more triethylamine (0.45 ml) and cyclopropanesulfonyl chloride (22.6 mg) .The reaction was refluxed for 7.5 h, cooled to room temperature and stirred for 72 h.The reaction was heated to reflux for 24 h. The organic solution was washed sequentially with 5.5% aqueous HCl, water, a saturated sodium bicarbonate solution and brine The organic solution was dried (M g S04), filtered and concentrated to give the title compound of step A (78.1 mg). MS 456 (M +). ^ ,. »-, ^ - *» «- to- A». ^ g¡¡¡ ^ ^ j ^^ Step B: ester hydrolysis 5- (3 { [3- (3-Chloro-phenyl-P-propyl-1-cyclopropanesulfonyl-aminol-propyl) - thiophene-2-carboxylic acid The title compound was prepared following the procedure described in example 1, step C from 5- (3. {[3- (3-chloro-phenyl) -propyl] methyl ester] -cyclopropanesulfonyl-amino.}. propyl) -thiophene-2-carboxylic acid from step A, except that the reaction was carried out in EtOH.H NMR (400 MHz, CDCl 3) d 7.62 (d, 1H, J = 3, 4 Hz), 7.42-7.00 (m, 4H), 6.62 (d, 1 H, J = 3, 4 Hz), 3.25 (m, 2H), 2.92 (m, 2H), 2.31 (m, 1 H ), 2.20 (m, 2H), 1332-0.90 (m, 4H, MS 440 (M-1).

EXAMPLE 11m Acid 3- (3-fr (pyridin-3-sulfonyl) - (4-pyridin-3-yl-benzyl) -aminol-methyl > -phenyl) -propionic acid Step A: reductive amination 3- (3-f (4-pyridin-3-yl-benzylamino) -methyl-1-phenyl-propionic acid methyl ester The title compound of Step A was prepared from the salt 3 (-3-aminomethyl-phenyl) -propionic acid methyl ester hydrochloride of preparation 44 and 4-pyridin-3-yl-benzaldehyde of preparation 23, using the procedure described in example 1, step A. 1 H NMR (400 MHz, CDCl 3) d 8.79 (s, 1 H), 8.55 (m, 1 H), 7.81 (d, 1 H), 7.53 (d, 2 H), 7.46 (d, 2 H), 7.32 (m, 1 H), 7.22 (m, 3H), 7.09 (d, 1H), 3.84 (s, 2H), 3.80 (s, 2H), 3.63 (s, 3H), 2.92 (t, 2H), 2.61 (t, 2H).

Step B: Formation of Amide 5 3- (3. {(Pyridin-3-sulfonyl) - (4-pyridin-3-yl-benzopropylamine-methylMeniP-propionic acid) methyl ester of the title of step B was prepared from the 3- ({3 - {(3-pyridin-3-yl-benzylamino) -methyl] -phenyl} -phenyl} -propionic acid methyl ester of step A and the hydrochloride of the pyridine-3-sulfonyl chloride of preparation 2, 10 following the procedure described in example 1, step B, using triethylamine instead of N, N-diisopropylethylamine 1 H NMR (400 MHz, CDCl 3) d 9.05 (d, 1 H), 8.80 (m, 2H), 8.60 (d, 1 H), 8.06 (m, 1 H), 7.91 (m, 1 H), 7.44 (m, 4H), 7.21 (d, 2H), 7.15 (m, 1H), 7.06 (d, 1H), 6.92 (d, 1H), 6.87 (s, 1H), 4.41 (s, 2H), 4.38 (s, 2H), 3.65 (s, 3H), 2.82 (t, 2H), 2.51 (t, 2H); EM 502 (M + 1). 15 Step C: Hydrolysis of the ester Acid 3- (3- (3-pyridin-3-sulfonyl-4-pyridin-3-yl-benzyl-P-amino] -methyl) - phenyD-propionic The compound of the title was prepared following the procedure described in Example 1, step C, from 3- (3. {[[(Pyridin-3-sulfonyl) - (4-pyridyl-3-yl-benzyl) methyl ester] -amino] -methyl.} - phenyl) -propionic from step B. 1 H NMR (400 MHz, CDCl 3) d 9.02 (s, 1 H), 8.89 (m, 1 H), 8.78 (s, 1 H ), 8. 58 (m, 1 H), 8.08 (m, 1 H), 7.99 (d, 1 H), 7.44 (m, 4 H), 7.21 (m, 2 H), 7.07 (m, ^ G ^ g ^ m ^ ^ 2H), 6.87 (m, 2H), 4.37 (s, 2H), 4.34 (s, 2H), 2.83 (t, 2H), 2.54 (t, 2H); MS 486 (M-1).

EXAMPLE 11n 5 3- (3- { Rpyridin-2-sulfoniP- (4-pyridin-3-yl-benzyl-P-amino-1-methyl) -phenidine-phenyl-propionic acid Step A: Formation of amide methyl ester of 3- (3- (Í-pyridine-2-sulfoniP- (4-pyridin-3-yl-10-benzy-p-aminol-methyl-M-phenyl-propionic acid The title compound of step A was prepared from the methyl ester of 3- ({3 - [(4-pyridin-3-yl-benzylamino) -methyl] -phenyl} -propionic acid methyl ester, prepared in step A of example 11m and of the pyridine-2-sulfonyl chloride hydrochloride of preparation 47, following the procedure described in Example 1, step B using triethylamine in place of N, N-diisopropylethylamine.1H-NMR (400 MHz, CDCl3) d 8.79 (s) , 1 H), 8.69 (d, 1 H), 8.59 (d, 1 H), 7.98 (m, 1 H), 7.88 (m, 2 H), 7.49-7.38 (m, 4 H), 7.24 (m, 2 H) ), 7.11 (m, 1 H), 7.02 (d, 1 H), 6.95 (d, 1 H), 6.90 (s, 1 H), 4.54 (s, 2 H), 4.49 (s, 2 H), 3.65 (s, 3H), 2.80 (t, 2H), 2.49 (t, 2H), EM 502 (M + 1).

Step B: Hydrolysis of the ester 3- (3- (rp) rdin-2-sulfoniP- (4-pyridin-3-yl-benzyl) -amino] -methyl) -pheniP-propionic acid The title compound is prepared following the procedure described in example 1, step C, step C, from the methyl ester of 3- (3. {[[(pyridin-2-sulfonyl) - (4-pyridin-3-yl- benzyl) -amino] -methyl] -phenyl) -propionic from step A. 1 H NMR (400 MHz, CDCl 3) d 8.84 (s, 1 H), 8.69 (m, 1 H), 8.55 (d, 1 H ), 7.97 (m, 2H), 7.87 (m, 1 H), 7.47 (m, 2H), 7.37 (m, 2H), 7.22 (m, 2H), 7.02 (m, 2H), 6.89 (m, 2H) ) 4.52 (s, 2H), 4.45 (s, 2H), 2.80 (t, 2H), 2.52 (t, 2H), EM 486 10 (M-1).

EXAMPLE 11o Acid 3- (3- (r (4-pyrazol-1-yl-benzyl- (pyridine-3-sulfonyl-P-amino-1-methyl) -phenyl-pyrionic acid Step A: Reductive amination Acid methyl ester 3 - { 3-f (4-p¡razol-1-yl-benzyl-amino) -methyl-1-phenyl-propionic The title compound of step A was prepared from the salt - 3- (3-aminomethyl-phenyl) -propionic acid methyl ester hydrochloride, preparation 44 and 4-pyrazol-1-yl-benzaldehyde of preparation 42, using the procedure described in example 1, step A except that the imine was formed in refluxing MeOH for 2 h. 1 H NMR (400 MHz, CDCl 3) d J *? I a ^ '^ r. ^ * ± AII * t * < . ^ tMft ^^ g ^ gu-a 7.89 (dd, 1 H), 7.70 (d, 1 H), 7.65 (d, 2H), 7.45 (d, 2H), 7.28-7.19 (m, 3H), 7.10 (d, 1H), 6.45 (dd, 1 H), 3.83 (s, 2H), 3.79 (s, 2H), 3.66 (s, 3H), 2.94 (t, 2H), 2.63 (t, 2H); MS 350 (M + 1).

Step B: Amide formation Acid methyl ester 3- (3. {[[(4-pyrrazol-1-yl-benzyl) - (pyridin-3-sulfonyl) -amino-1-methyl) - phenyl) -propionic The title compound of step B was prepared from the methyl ester of 3-acid. { 3 - [(4-pyrazol-1-yl-benzylamino) -methyl] -phenyl} -propionic of step A and the pyridine-3-sulfonyl chloride hydrochloride of preparation 2, following the procedure described in example 1, step B, using triethylamine instead of N, N-diisopropylethylamine. 1 H NMR (400 MHz, CDCl 3) d 9.03 (s, 1 H), 8.77 (d, 1 H), 8.04 (m, 1 H), 7.87 (d, 1 H), 7.68 (d, 1 H), 7.54 (m, 2H), 7.42 (m, 1 H), 7.14 (m, 3H), 7.07 (m, 1 H), 6.88 (d, 1 H), 6.83 (s, 1 H), 6.44 (dd, 1 H), 4.36 (s, 2H), 4.32 (s, 2H), 3.62 (s, 3H), 2.79 (t, 2H), 2.49 (t, 2H); MS 491 (M + 1).

Step C: Hydrolysis of the ester 3- (3. {[[(4-pyrazol-1-yl-benzyl) - (pyridin-3-sulfonyl) -amino] -methyl) - PheniP-propionic The title compound was prepared following the procedure described in Example 1, step C, from 3- (3. {[[(4-pyrazol-1-yl-benzyl) methyl ester] - (Pyridin-3-sulfonyl) amino] -methyl] -phenyl) -propionic from step B. 1 H NMR (400 MHz, CDCl 3) d 9.08 (yes, 1 H), 8.85 (m, 1 H), 8.18 (d, 1 H), 7.82 (s, 2 H), 7.72 (d, 1 H), 7.52 ( m, 1 H), 7.47 (d, 2H), 7.14 (m, 3H), 7.07 (d, 1 H), 6.96 (d, 1 H), 6.83 (s, 1 H), 6.46 (s, 1 H) ), 4.38 (s, 2H), 4.34 (s, 2H), 2.82 (t, 2H), 2.52 (t, 2H). MS 475 (M-1).

EXAMPLE 11p Acid 3- (3-. {F (4-pyrazol-1-yl-benzyl- (pyridine-2-sulfonyl-amino-1-methyl) -pheniP-propionic acid Step A: Formation of the amide 3- (3- (r4-pyrrazol-1-yl-benzyl- (pyridine-2-sulfonyl-p-aminol-methyl-phenyl-propionic acid) methyl ester. Step A was prepared from the methyl ester of 3- {3 - [(4-pyrazol-1-yl-benzylamino) -methyl] -phenyl} -propionic acid methyl ester prepared in step A of example 11 and of the pyridine-2-sulfonyl chloride hydrochloride of preparation 47, following the procedure described in example 1, step B using triethylamine instead of N, N-diisopropylethylamine. 1 H NMR (400 MHz, CDCl 3) d 8.66 (m, 1 H), 7.96 (m, 1 H), 7.85 (m, 2 H), 7.68 (d, 1 H), 7.50 (d, 2H), 7.46 (m, 1 H), 7.16 (d, 2H), 7.09 (m, 1 H), 6.99 (d, 1 H), 6.92 20 (d, 1 H) , 6.88 (s, 1 H), 6.43 (m, 1 H), 4.48 (s, 2H), 4.44 (s, 2H), 3.63 (s, 3H), 2.78 (t, 2H), 2.48 (t, 2H); MS 491 (M + 1). Ü ^ Í? ^^^ ^ j gU ^ Ujj | Step B: Ether hydrolysis Acid 3- (3 - ([(4-pyrrazol-1-yl-benzyl- (pyridin-3-sulfonyl-P-amino] -methyl-phenyl-propionic) of the title was prepared following the procedure described in example 1, step C, from 3- (3. {[[(4-pyrazol-1-yl-benzyl) - (pyridine-2-sulfonyl) methyl ester amino) -methyl] -phenyl) -propionic from step A, 1 H NMR (400 MHz, CDCl 3) d 8.75 (m, 1 H), 8.04 (m, 1 H), 7.93 (m, 1 H), 7.79 (d, 1 H), 7.74 (s, 1 H), 7.52 (m, 1 H), 7.39 (d, 2H), 7.16-6.99 (m, 5H), 6.80 (s, 1 H), 6.46 ( d, 1 H), 4.55 (s, 2H), 4.44 (s, 2H), 2.78 (t, 2H), 2.47 (t, 2H), MS 475 (M-1).

EXAMPLE 11q 3- (3-ff (1-methyl-1 H-imidazole-4-sulfoniP- (4-pyrazole-1-M-benzD-aminol-methyl) -pheniD-propionic acid Step A: Formation of the amide Methyl ester of the acid 3- (3 - ([(1-methyl-1 H-imidazole-4-sulfonyl) -P- (4-pyrazol-1-yl-benzylp-aminol-methyP- PheniP-propionic The title compound of step A was prepared from 3- ({3 - {(3-pyrazol-1-yl-benzylamino) -methyl] -phenyl} -methyl ester. ion, step A of example 11o and chloride 1-methyl-1 H-imidazole-4-sulfonyl following the procedure described in example 1, step B using triethylamine instead of NN-diisopropylethylamine. 1 H NMR (400 MHz, CDCI3) d 7.89 (d, 1 H), 7.70 (s, 1 H), 7.54 (m, 3H), 7.39 (d, 1 H), 7.24 (m, 2H), 7.14 (m, 1 H), 7.04 -6.97 (m, 3H), 6.45 (m, 1 H), 4.43 (s, 2H), 4.40 (s, 2H), 3.74 (s, 3H), 3.65 (s, 3H), 2.83 (t, 2H), 2.53 (t, 2H); MS 494 (M + 1).

Step B: Hydrolysis of the ester. 3- (3- (f (1-methyl-1 H-imidazole-4-sulfonyl) - (4-pyrrazol-1-yl-benzyl) -aminol-methyl-phenyl-propionic acid ester. The title compound was prepared following the procedure described in Example 1, step C, from 3- (3. {[[(1-methyl-1 H-imidazole-4-sulfonyl) - ( 4-pyrazol-1-yl-benzyl) -amino] -methyl] -phenyl) -propionic from step A. 1 H NMR (400 MHz, CDCl 3) d 7.79 (d, 1 H), 7.70 (d, 1 H ), 7.57 (s, 1 H), 7.46 (s, 1 H), 7.40 (d, 2H), 7.18 (d, 2H), 7.11 (m, 1 H), 7.02 (m, 2H), 6.86 (s) , 1H), 6.44 (m, 1 H), 4.45 (s, 2H), 4.36 (s, 2H), 3.75 (s, 3H), 2.79 (t, 2H), 2.47 (t, 2H), EM 478 ( M-1).

EXAMPLE 11 r Acid 3- (3-. {R (pyridin-3-s? LphonP- (4-thiazol-2-yl-benzyl-P-amino-1-methyl-phenyl-p-propionic) Step A: Formation of the amide 3- (3. {F (pyridin-3-sulfonyl-4-thiazol-2-yl-benzy-p-aminol-methyl-phenyl-propionic acid) methyl ester. from step A was prepared from 3- ({3 - {(4-thiazol-2-yl-benzylamino) -methyl] -phenyl} -propionic acid methyl ester ^^^ ^^^, r ^ .r ^ g? .fr¡ -ffflflflffl-. Z ^^^ JL¡¡¡ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ and pyridine-3-sulfonyl chloride hydrochloride of preparation 2, following the procedure described in Example 1, step B using triethylamine instead of N, N-diisopropylethylamine. 1 H NMR (400 MHz, CDCl 3) d 8.68 (d, 1 H), 7.97 (d, 1 H), 7.87 (m, 2 H), 7.79 (d, 2 H), 7.47 (m, 1 H), 7.33 (d, 1 H), 7.18 (d, 2H), 7.12 (m, 1 H), 7.02 (d, 1 H), 6.94 (d, 1 H), 6.90 (s, 1 H), 4.52 (s, 2H), 4.47 (s, 2H), 3.65 (s, 3H), 2.80 (t, 2H), 2.50 (t, 2H); MS 508 (M + 1).

Step B: Hydrolysis of the ester 3- (3. {[[(Pyridin-3-sulfonyl) - (4-thiazole-2-yl-benzyl) -amino] -methyl) -pheniP-propionic. The title compound was prepared following the procedure described in Example 1, Step C, from 3- (3. {[[(pyridin-3-sulfonyl) - (4-thiazol-2-yl-benzyl) -amino] -methyl] -methyl ester. phenyl) -propionic from step A. 1 H NMR (400 MHz, CDCl 3) d 8.72 (d, 1 H), 8.00 (d, 1 H), 7.89 (m, 1 H), 7.83 (d, 1 H), 7.64 (d, 2H), 7.49 (m, 1 H), 7.33 (d, 1 H), 7.13 (d, 2H), 7.07 (m, 1 H), 6.98 (m, 2H), 6.80 (s, 1 H) ), 4.53 (s, 2H), 4.42 (s, 2H), 2.76 (t, 2H), 2.46 (t, 2H); MS 492 (M-1). s ^^ ^^^ = | & ¡i ^ & EXAMPLE 11s Acid 3- (3-. {R (pyridine-2-sulfoniP- (4-thiazol-2-yl-benzy-P-amino-1-methyl > -pheniP-propionic Step A: Formation of the amide 3- (3 - ([(pyridin-2-sulfoniP- (4-thiazol-2-yl-benzopyaminol-methyD-phenyl-propionic acid) methyl ester. Step A was prepared from the 3- ({3 - {(3-thiazol-2-yl-benzylamino) -methyl] -phenyl} -propionic acid methyl ester prepared in step A of the example 11e and the pyridine-2-sulfonyl chloride hydrochloride of preparation 47, following the procedure described in example 1, step B using triethylamine instead of N, N-diisopropylethylamine, 1 H-NMR (400 MHz, CDCl 3) d 9.05 ( s, 1 H), 8.80 (d, 1 H), 8.05 (m, 1 H), 7.84 (m, 3 H), 7.43 (m, 1 H), 7.34 (d, 1 H), 7.15 (m, 3 H) ), 7.06 (d, 1 H), 6.91 (d, 1 H), 6.86 (s, 1 H), 4.39 (s, 2 H), 4.36 (s, 2 H), 3.65 (s, 3 H), 2 82 (t, 2H), 2.51 (t, 2H), EM 508 (M + 1).

Step B: Hydrolysis of the ester 3- (3 - ([(Pyridin-2-sulfoniP- (4-tiazol-2-yl-benzyl) -amino] -methyl) -pheniP-propionic acid ester. The title compound was prepared following the procedure described in Example 1, step C, starting with 3- (3. {[[(Pyridin-2-sulfonyl) - (4-thiazole-2-yl) methyl ester. benzyl) -amino] -phenyl) -propionic of step A. 1 H NMR ^ ¡^ ¡^^ «gü (400 MHz, CDCI3) d 9.03 (s, 1 H), 8_ß0 (m, 1 H), 8.13 (m, 1 H), 7.84 (m, 1 H), 7.71 (d) , 2H), 7.47 (m, 1 H), 7.34 (d, 1 H), 7.12 (m, 3H), 7.06 (m, 1 H), 6.92 (d, 1 H), 6.82 (s, 1 H) , 4.36 (s, 2H), 4.32 (s, 2H), 2.80 (t, 2H), 2.51 (t, 2H); MS 492 (M-1).

EXAMPLE 11t 3- (3-Benzenesulfonyl- (4-pyrimidin-5-yl-benzyl) -aminol-methyl.} - phenyl-propionic acid Step A: Reductive amination Acid methyl ester 3-. { 3 - [(4-pyrimidin-5-yl-benzyllamine) -methyl-1-phenyD-propionic acid. The title compound of step A was prepared from the hydrochloride salt of 3- (3-aminomethyl-phenyl) -propononic acid methyl ester of preparation 44 and 4-pyrimidin-5-yl-benzaldehyde , from Preparation 26, using the procedure described in Example 1, step A except that the measurement was formed in MeOH at reflux for 2 h. 1 H NMR (400 MHz, CDCl 3) d 9.19 (s, 1 H), 8.92 (s, 2 H), 7.55 (m, 4 H), 7.25 (m, 3 H), 7.11 (d, 1 H), 3.87 (s, 2H), 3.81 (s, 2H), 3.66 (s, 3H), 2.95 (t, 2H), 2.63 (t, 2H); EM 362 (M + 1).

Step B: Formation of Ijjpl Measure 3- (3. {[[Benzenesulfonyl] P- (4-pyrimidin-5-yl-benzyl-methy1-phenyl-propyonic acid methyl ester. The title of step B was prepared from the 3- ({3 - {(4-pyrimidin-5-yl-benzylamino) -methyl] -phenyl} -phenyl} -propionic acid methyl ester of step A and benzenesulfonyl chloride following the procedure described in Example 1, step B using triethylamine in place of N, N-diisopropylethylamine, 1 H NMR (400 MHz, CDCl 3) d 9.20 (s, 1 H), 8.90 (s, 2 H), 7.88 (m, 2 H). ), 7.62 (m, 1 H), 7.55 (m, 2H), 7.42 (d, 2H), 7.21 (d, 2H), 7.12 (m, 1 H), 7.03 (d, 1 H), 6.87 (d) , 1 H), 6.78 (s, 1 H), 4.36 (s, 2H), 4.33 (s, 2H), 3.65 (s, 3H), 2.78 (t, 2H), 2.47 (t.2H).

Step C: Hydrolysis of the ester 3- (3 - ([Benzenesulfonyl- (4-pyrimidin-5-yl-benzyl-P-amino-1-methyl-phenyl-propionic acid) The title compound was prepared following the procedure described in Example 1, step C, starting with 3- (3. {[[benzenesulfonyl- (4-pyrimidin-5-yl-benzyl) -amino] -phenyl) -propionic acid methyl ester from step B 1 H NMR (400 MHz, CDCl 3) d 9.19 (s, 1 H), 8.93 (s, 2 H), 7.89 (m, 2 H), 7.63 (m, 1 H), 7.55 (m, 2 H), 7.43 (d, 2H), 7.21 (d, 2H), 7.11 (m, 1H), 7.03 (d, 1 H), 6.87 (d, 1 H), 6.81 (s, 1 H), 4.36 (s, 2H), 4.33 ( s, 2H), 2.80 (t, 2H), 2.52 (t, 2H), MS 486 (M-1).

EXAMPLE 11u Acid 3- (3-. {R (pyridin-3-sulfonyl) -P- (4-pyrimidin-5-yl-benzyl-amino-1-methyl) -pheniP-propionic acid Step A: Formation of the amide Acid 3- (3-. {F (pyridin-3-sulfoniP- (4-pyridin-5-yl-benzyl-P-amino-1-methylP-pheny1- The title compound of step A was prepared from 3- ({3 - {(3-pyrimidin-5-yl-benzylamino) -methyl] -phenyl} -propionic acid methyl ester, 10% of the step A of example 11t and the pyridine-3-sulfonyl chloride hydrochloride of preparation 2, following the procedure described in example 1, step B using triethylamine instead of N, N-diisopropylethylamine. 1 H NMR (400 MHz, CDCl 3 ) d 9.20 (s, 1H), 9.06 (s, 1 H), 8.92 (s, 2H), 8.81 (s, 1H), 8.08 (m, 1H), 7.46 (m, 3H), 7.26 (m, 2H) ), 7.15 (m, 1 H), 7.06 (d, 1 H), 6.91 (d, 1 H), 6.86 (s, 15 1 H), 4.42 (s, 2 H), 4.37 (s, 2 H), 3.65 (s, 3H), 2.82 (t, 2H), 2.50 (t, 2H).

Step B: Hydrolysis of the ester 3- (3 - ([(pyridin-3-sulfonyl) - (4-pyrimidin-5-yl-benzyl-P-amino-1-methyl-phenyl-propionic acid. The title compound was prepared following the procedure described in Example 1, step C, from 3- (3. {[[(Pyridin-3-sulfonyl) - (4-pyrimidin-5-yl) methyl ester -benzyl) -amino] -phenyl) -propionic from step A. 1 H NMR (400 MHz, CDCl 3) d 9.20 (s, 1 H), 8.98 (d, 1 H), 8.93 (s, 2 H), 8.79 (d , 1 H), 8.15 (m, 1 H), 7.48 (m, 3 H), 7.31 (d, 2 H), 7.20-7.09 (m, 2 H), 6.95 (s, 1 H), 6.91 (d, 1 H) , 4.42 (s, 2H), 4.40 (s, 2H), 2.87 (t, 2H), 2.58 (t, 2H); MS 487 (M-1).

EXAMPLE 11v 5 3- (3-Fr) (pyridine-2-sulfoniP- (4-pyrimidin-5-yl-benzyl-P-amino-1-methyl) -pheniP-propionic acid Step A: Formation of amide 3- methyl acid ester. { [(pyridin-2-sulfonylP- (4-pyrimidin-5-yl-10-benzyP-aminol-methyP-phenyl-propionic acid) The title compound of step A was prepared from the methyl ester of 3- {3 - [(4-pyrimidin-5-yl-benzylamino) -methyl] -phenyl} -propionic acid, prepared in step A of example 11t and pyridin-2-chloride hydrochloride sulfonyl of preparation 47, following the procedure described in Example 1, step B using triethylamine in place of N, N-diisopropylethylamine 1 H NMR (400 MHz, CDCl 3) d 9.20 (s, 1 H), 8.90 (s) , 2H), 8.70 (d, 1 H), 7.99 (m, 1H), 7.89 (m, 1 H), 7.49 (m, 1H), 7.42 (d, 2H), 7.29 (d, 2H), 7.10 ( m, 1H), 7.01 (d, 1 H), 6.93 (d, 1 H), 6.89 (s, 1 H), 4.56 (s, 2H), 4.48 (s, 2H), 3.66 (s, 3H), 2.79 (t, 2H), 2.48 (t, 2H), MS 503 (M + 1). '^^? & ^^. ^ ^ UtlStt l ^ - * -U > jetóte Step B: Hydrolysis of the ester Acid 3- (3. {f (pyridin-2-sulfonyl-4-pyridin-5-yl-benzyl) -amino] - metiP-PheniP-propionic The title compound was prepared following the procedure described in Example 1, step C, starting with 3- (3. {[[(pyridine-2-sulfonyl) - (4- pyrimidin-5-yl-benzyl) -amino] -phenyl) -propionic from step A. 1 H NMR (400 MHz, CDCl 3) d 9.19 (s, 1 H), 8.94 (s, 2 H), 8.71 (m, 1 H ), 8.01 (d, 1 H), 7.90 (m, 1H), 7.50 (m, 1 H), 7.42 (d, 2H), 7.29 (d, 2H), 7.09 (m, 1H), 7.02 (d, 1H), 6.92 (m, 2H), 4.56 (s, 2H), 4.48 (s, 2H), 2.81 (t, 2H), 2.54 (t, 2H), MS 487 (M-1).

EXAMPLE 11w 3- (3- r (4-Chloro-benzenesulfonyl- (4-pyrimidin-5-yl-benzyl-amino-1-methyl-d-phenyl-propionic acid Step A: Formation of the amide 3- (3. {F (4-Chloro-benzenesulfoniP- (4-pyrimidin-5-yl-benzy-p-aminol-methyP-phenyl-propionic acid) methyl ester The title compound from step A was prepared from 3- ({3 - [(4-pyrimidin-5-yl-benzylamino) -methyl] -phenyl} -propionic acid methyl ester. co from step A of example 11t and 4-chlorobenzenesulfonyl chloride, following the procedure described in example 1, step B using triethylamine in place of NN-diisopropylethylamine.1H-NMR (400 MHz, CDCl3) d 9.20 (s, 1 H) , 8.91 (s, 2H), 7.78 (d, 2H), 7.49 (d, 2H), 7.44 (d, 2H), 7.23 (m, 2H), 7.14 (m, 1 H), 7.05 (d, 1 H) ), 6.89 (d, 1 H), 6.81 (s, 1 H), 4.36 (s, 2H), 4.32 (s, 2H), 3.65 (s, 3H), 2.80 (t, 2H), 2.49 (t, 2H); MS 536 (M +).

Step B: Hydrolysis of the ester 3- (3 - ([(4-Chloro-benzenesulfonyl- (4-pyrimidin-5-yl-benzy-p-aminol-methyP-phenyl-propionic acid) The title compound was prepared following the procedure described in example 1, step C, starting with 3- (3. {[[(4-chloro-benzenesulfonyl) - (4-pyrimidin-5-yl-benzyl) -amino] methyl ester] methyl.}. phenyl) -propionic from step A. 1 H NMR (400 MHz, CDCl 3) d 9.20 (s, 1 H), 8.92 (s, 2 H), 7.79 (d, 2 H), 7.50 (d, 2 H) , 7.44 (d, 2H), 7.23 (m, 2H), 7.14 (m, 1 H), 7.06 (m, 1H), 6.89 (d, 1 H), 6.85 (s, 1 H), 4.36 (s, 2H), 4.32 (s, 2H), 2.82 (t, 2H), 2.55 (t, 2H), MS 522 (M + 1).

EXAMPLE 11x Acid 3-f3-frf4-pyrazin-2-yl-benzyl- (pyridin-3-sulfonyl) -amino-1-methyl-phenyl-propionic acid Step A: Reductive amination 3- (3-f (4-pyrrazin-2-yl-benzamino) -methyl] -pheniP-propionic acid methyl ester Step title compound A was prepared from the hydrochloride salt of 3- (3-aminomethyl-phenyl) -proponic acid methyl ester of preparation 44 and 4-pyrazin-2-yl-benzaldehyde of preparation 27, using the procedure described in Example 1, step A, except that the measurement was formed in MeOH at reflux for 2 h. 1 H NMR (400 MHz, CDCl 3) d 9.02 (d, 1 H), 8.61 (m, 1 H), 8.48 ( d, 1 H), 7.98 (d, 2H), 7.49 (d, 2H), 7.25 (m, 1 H), 7.19 (m, 2H), 7.09 (d, 1 H), 3.87 (s, 2H), 3.79 (s, 2H), 3.66 (s, 3H), 2.94 (t, 2H), 2.63 15 (t, 2H), EM 362 (M + 1).

Step B: Formation of the amide 3- (3- (3- (f (4-pyrrazin-2-yl-benzyl- (pyridin-3-sulfonyl-p-aminol-metiP-phenyl) propionate 20 The title compound of step B was prepared from 3- ({3 - [(4-pyrazin-2-yl-benzylamino) -methyl] -phenyl} -propionic acid methyl ester from step A and the pyridin-3-sulfonyl chloride hydrochloride of preparation 2, following the procedure described in example 1, step B, using triethylamine instead of N, N-diisopropylethylamine. 1 H NMR (400 MHz, CDCl 3) d 9.06 (s, 1 H), 8.99 (s, 1 H), 8.80 (d, 1 H), 8.62 (s, 1 H), 8.51 (d, 1 H), 8.06 (m, 1 H) , 7.89 (d, 2H), 7.43 (m, 1H), 7.23 (m, 2H), 7.15 (m, 1H), 7.06 (d, 1H), 6.92 (d, 1H), 6.86 (s, 1H), 4.42 (s, 2H), 4.37 (s, 2H), 3.65 (s, 3H), 2.82 (t, 2H), 2.50 (t, 5 2H), EM502 (M + 1).

Step C: Hydrolysis of the ester Acid 3- (3 - ([(4-pyrrazin-2-yl-benzyl- (pyridin-3-sulfonyl-p-amino-1-methyl-phenyl-propionic) of the title was prepared following the procedure described in example 1, step C, starting with 3- (3. {[[(4-pyrazin-2-yl-benzyl) - (pyridinyl) methyl ester] 3-sulfonyl) -amino] -methyl]. Phenyl) -propionic from step B. 1 H NMR (400 MHz, CDCl 3) d 9.02 (s, 1 H), 8.96 (s, 1 H), 8.78 (m, 1H), 8.58 (s, 1H), 8.53 (d, 1H), 8.13 (m, 1H), 7.78 (d, 2H), 7.46 (m, 1H), 7.22 (m, 2H), 7.13 (m, 1 H), 7.06 (d, 1 H), 6.93 (d, 1 H), 6.85 (s, 1 H), 4.40 (s, 2 H), 4.34 (s, 2 H), 2.82 (t, 2H), 2.53 (t, 2H); MS 487 (M-1). - * áiUíi? at ~ JBJ & i "?? ajr EXAMPLE 11 v Acid 3- (3-fr (4-pyrazin-2-yl-benzyl- (pyridine-2-sulfonyl-amino-1-methyl-phenyl) - propionic Step A: Formation of the amide 3- (3. {[[(4-pyridin-2-yl-benzyl) - (pyridine-2-sulfonyl-P-aminol-metiP-phenyl-3-methyl) The title compound of step A was prepared from the methyl ester of 3- {3 - [(4-pyridin-2-yl-benzylamine) -methyl] -phenyl} -propionic acid. co, prepared in step A of example 11x and pyridine-2-sulfonyl chloride hydrochloride of preparation 47, following the procedure described in example 1, step B using triethylamine instead of N, N-diisopropylethylamine. (400 MHz, CDCl 3) d 8.98 (d, 1 H), 8.69 (m, 1 H), 8.62 (m, 1 H), 8.50 (d, 1 H), 7.99 (m, 1 H), 7.86 (m , 3H), 7.48 (m, 1 H), 7.26 (m, 2H), 7.11 (m, 1 H), 7.01 (d, 1 H), 6.94 (d, 1 H), 6.89 (s, 1 H) , 4.56 (s, 2H), 4.48 (s, 2H), 3.65 (s, 3H), 2.80 (t, 2H), 2.49 (t, 2H), EM 503 (M + 1).

Step B: Hydrolysis of the ester Acid 3- (3. {[[(4-pyrraz-2-yl-benzyl- (pyrimidine-2-sulfonyl-P-amino-1-methyl-phenyl-propionic The title compound was prepared following the procedure described in Example 1, step C, starting with 3- (3. {[[(4-pyridin-2-yl-benzyl) - (pyridin) methyl ester. -2-sulfonyl) -amino] -phenyl) -propionic from step A. 1 H NMR (400 MHz, CDCl 3) d 8.96 (s, 1 H), 8.73 (d, 1 H), 8.60 (s, 1 H), 8.54 (s, 1 H), 8.02 (d, 1 H), 7.91 (m, 1 H), 7.74 (d, 2H), 7.51 (m, 1 H), 7.23 (m, 2H), 7.12 (m, 1 H), 7.04 (m, 2H), 6.85 (s, 1 H), 4.57 (s, 2H), 4.46 (s, 2H), 2.80 (t, 2H), 2.52 (t, 2H), EM 487 ( M-1).

EXAMPLE 11z Acid 3- (3-fí (1-methyl-1 H-imidazole-4-sulfoniP- (4-pyrimidin-2-yl-benzyl-aminol-methyP-phenyD-propionic acid Step A: Reductive amination 3- methyl acid ester. { 3 - [(4-pyrimidin-2-yl-benzyl-amino) -methyl-1-phenyl-propionic acid. The title compound of step A was prepared from the hydrochloride salt of 3- (3-aminomethyl-phenyl) -propionic acid methyl ester of preparation 44 and 4-pyrimidin-2-yl-benzaldehyde of preparation 21 , using the procedure described in Example 1, step A, except that the mine was formed in refluxing MeOH with a reaction time of 2 h. 1 H NMR (400 MHz, CDCl 3) d 8.79 (d, 2 H), 8.40 (d, 2 H), 7.49 (d, 2 H), 3.88 (s, 2 H), 3.80 (s, 2 H), 3.65 (s, 3 H) , 2.94 (t, 2H), 2.63 (t, 2H).

Step B: Formation of the amide 3- (3. {[[(1-methyl-1 H-imidazole-4-sulfonP- (4-pyridine-1-methyl) -3- methyl ester benzyl-P-amino] -methyl-phenyl-propionic acid The title compound of step B was prepared following the procedure described in step B of example 1 from methyl 3- (3. 4-pyrimidin-2-yl-benzylamino) -methyl] -phenyl} -propionic acid, preparing in step A and 1-methyl-1 H-indazole-4-sulfonyl chloride. , CDCl 3) d 8.81 (m, 2H), 8.30 (d, 2H), 7.52 (s, 1 H), 7.39 (s, 1 H), 7.28-7.20 (m, 3H), 7.14 (m, 1 H) , 7.04-6.63 (m, 3H), 4.46 (s, 2H), 4.43 (s, 2H), 3.72 (s, 3H), 3.65 (s, 3H), 2.83 (t, 2H), 2.52 (t, 2H) ); MS 506 (M + 1).

Step C: Hydrolysis of the ester Acid 3- (3. {[[(1-methyl-1 H-imidazole-4-sulfoniP- (4-pyrimidin-2-yl-benzopylamine-methyl) -pheniP-propionic The title compound was prepared following the procedure described in example 1, step C, starting with 3- (3. {[[(1-methyl-1 H-imidazole-4) methyl ester sulfonyl) - (4-pyrimidin-2-yl-benzyl) -amino] -methyl} phenyl) -propionic from step B. 1 H NMR (400 MHz, CDCl 3) d 8.80 (d, 2 H), 8.04 (d, 2H), 7.57 (s, 1 H), 7.47 (s, 1 H), 7.25-6.99 (m, 6H), 6.88 (s, 1H), 4.49 (s, 2H), 4.39 (s, 2H), 3.76 (s, 1 H), 2.81 (t, 2H), 2.52 (t, 2H), MS 490 (M-1).

EXAMPLE 12a 3- (3-ff4-Chloro-benzenesulfoniP- (4-pyrazin-2-yl-benzyl-P-amino-1-methyl-phenyl-propionic acid Step A: Formation of the amide 3- (3 { [4-Chloro-benzenesulfonyl) - (4-pyrazyl-2-yl-benzyl-P-amino-1-methylp-phen-P-) methyl ester The title compound of step A was prepared from the methyl ester of 3- ({3 - [(4-pyrazin-2-yl-benzylamino) -methyl] -phenyl} -propionic acid methyl ester, prepared in step A of example 11x and 4-chlorobenzanesulfonyl chloride, following the procedure described in example 1, step B using triethylamine in place of N, N-diisopropylethylamine.1H-NMR (400 MHz, CDCl3) d 8.99 (s) , 1H), 8.62 (m, 1H), 8.51 (d, 1 H), 7.89 (d, 2H), 7.79 (d, 2H), 7.49 (d, 2H), 7.22 (m, 2H), 7.14 (m , 1 H), 7.05 (d, 1 H), 6.89 (d, 1 H), 6.81 (s, 1 H), 4.37, 4.32 (s, 2 H), 3.64 (s, 3 H), 2.80 (t, 2 H) ), 2.49 (t, 2H); MS 536 (M + 1).

Step B: Hydrolysis of the ester 3- (3. {[[(4-Chloro-benzenesulfonyl) - (4-pyrazin-2-yl-benzopylamine-methyl-phenyl-propionic acid) The title compound is prepared following the procedure described in example 1, step C, starting with 3- (3. {[[(4-chloro-benzenesulfonyl) - (4-pyrazin-2-yl-benzyl) -am] methyl ester. no] -methyl] -phenyl) -propionic from step A. 1 H NMR (400 MHz, CDCl 3) d 9.05 (s, 1 H), 8.64 (s, 1 H), 8.50 (d, 1 H), 7.91 ( d, 2H), 7.86 (d, 2H), 7.59 (d, 2H), 7.27 (d, 2H), 7.09 (m, 1 H), 7.02 (d, 1 H), 6.94 (d, 1 H), 6.83 (s, 1 H), 4.41 (s, 2H), 4.35 (s, 2H), 2.72 (t, 2H), 2.42 (s, 2H), EM 520 (M-1).

EXAMPLE 12b 3- (3-BenzenesulfonM- (4-thiazol-2-yl-benzyl) -amino-1-methyl-phenyl) -propionic acid Step A: Formation of the amide 3- (3- (1-Benzenesulfonyl- (4-tiazol-2-yl-benzyl) -amino] -met-P-phenyl-propionic acid methyl ester. The title compound of step A was prepared from the 3- ({3 - {(3-thiazol-2-yl-benzylamino) -methyl] -phenyl) -propionic acid methyl ester prepared in step A of example 11e and benzenesulfonyl chloride, following the procedure described in step A, example 11e and benzenesulfonyl chloride, following the procedure described in example 1, step B, using triethylamine instead of N, N-diisopropylethylamine. 1 H (400 MHz, CDCl 3) d 7.87 (m, 3 H), 7.80 (d, 2 H), 7.62 (m, 1 H), 7.56 (m, 2 H), 7.33 (d, 1 H), 7.11 (m, 3 H) ), 7.03 (d, 1 H), 6.87 (d, 1 H), 6.78 (s, 1 H), 4.34 (s, 2 H), 4.32 (s, 2 H), 3.65 (s, 3 H), 2.79 (t, 2H), 2.48 (t, 2H), MS 507 (M + 1).

Step B: Hydrolysis of the ester 3- (3. {[[Benzenesulfonyl] -2H-tiazol-2-yl-benzyl-amino] -methyl-phenyl-propionic acid ester The title compound was prepared following the procedure described in Example 1, step C, from 3- (3. {[[benzenesulfonyl- (4-thiazol-2-yl-benzyl) -amino] -methyl] -phenyl) -propionic acid methyl ester from step A. 1 H NMR (400 MHz, CDCl 3) d 7.86 (m, 3 H), 7.67-7.53 (m, 5 H), 7.34 (s, 1 H), 7.06 (m, 3 H), 6.98 (d, 1 H), 6.90 (d, 1 H), 6.71 (s, 1 H), 4.32 (s, 2H), 4.26 (s, 2H), 2.75 (t, 2H), 2.46 (t, 2H), MS 491 (M-1) 10 EXAMPLE 12c 7-r Acid (pyridine-3-sulfoniP- (4-thiazol-2-yl-benzop-amino-1-heptanoic acid) Step A: Formation of the amide 15 7-α (pyridin-3-sulfonyl) - (4-thiazol-2-yl-benzyl-p-aminol-heptanoic acid methyl ester) The title compound of step A prepared from the 7- (4-thiazol-2-yl-benzylamino) -heptanoic acid methyl ester prepared in step A of example 11c and the pyridine-3-sulfonyl chloride hydrochloride of the Preparation 2, following the procedure of example 1, step B. 1 H NMR (400 MHz, CDCl 3) d 9.06 (d, 1 H), 8.80 (m, 1 H), 8.09 (m, 1 H), 7.91 (d , 2H), 7.86 (m, 1 H), 7.46 (m, 1 H), 7.34 (m, 3H), 4.39 (s, 2H), 3.62 (s, 3H), 3.15 (t, 2H), 2.21 ( t, 2H), 1.48 (m, 2H), 1.37 (m, 2H), 1.14 (m, 4H); MS 474 (M + 1).

Step B: Hydrolysis of the ester: 7- [(pyridine-3-sulfoniP- (4-thiazol-2-yl-benzyl-p-aminol-heptanoic acid) The title compound was prepared following the procedure described in example 1, step C, from 7 - [(pyridin-3-sulfonyl) - (4-thiazol-2-yl-benzyl) -amino] -heptanoic acid methyl ester 1 H NMR (400 MHz, CDCl 3) d 9.07 (s, 1 H), 8.81 (m, 1 H), 8.11 (m, 1 H), 7.87 (m, 3 H), 7.48 (m, 1 H), 7.39 (d, 2 H), 7.36 (d, 1 H), 4.37 ( s, 2H), 3.14 (t, 2H), 2.23 (t, 2H), 1.48 (m, 2H), 1.30 (m, 2H), 1.14 (m, 2H), 1.07 (m, 2H), EM 458 ( M-1).

EXAMPLE 12d 7-R (4-pyrazin-2-yl-benzyl- (pyridine-3-sulfonopylamino-heptanoic acid Step A: Reducing aminating 7- (4-pyrazin-2-yl-benzylamino) -heptanoic acid methyl ester. The title compound of step A was prepared from the hydrochloride of the 7-amino-heptanoic acid methyl ester of preparation 1 and 4-pyrazin-2-yl-benzaldehyde of preparation 27 using the procedure described in example 1 , step A. 1 H NMR (400 MHz, CDCl 3) d 9.01 (d, 1 H), 8.61 (m, 1 H), 8.48 (d, 1 H), 7.97 (d, 2 H), 7.46 (d, 2 H) , 3.85 (s, 2H), 3.65 (s, 3H), 2.63 (t, 2H), 2.29 (t, 2H), 1.62 (m, 2H), 1.54 (m, 2H), 1.33 (m, 4H); MS 328 (M + 1).

Step B: Formation of the amide 7 - [(4-Pyrazin-2-yl-benzyl- (pyridin-3-sulfoniP-aminol-methyP-heptanoic acid) methyl ester. step A, was prepared from the 7- (4-pyrazin-2-yl-benzylamino-heptanoic acid methyl ester of step A and the pyridin-3-sulfonyl chloride hydrochloride of preparation 2, following the procedure of Example 1, step B. 1 H NMR (400 MHz, CDCl 3) d 9.04 (d, 1 H), 8.99 (d, 1 H), 8.78 (m, 1 H), 8.60 (d, 1 H), 8.49 (d, 1 H), 8.08 (m, 1 H), 7.95 (m, 2H), 7.46-7.39 (m, 3H), 4.40 (s, 2H), 3.60 (s, 3H), 3.14 (t, 2H), 2.18 (t, 2H), 1.45 (m, 2H), 1.36 (m, 2H), 1.12 (m, 4H).

Step C: Hydrolysis of the ester 7-f (4-pyrazin-2-yl-benzyl- (pyridine-3-sulfoniP-amino] -heptanoic ester.) The title compound was prepared following the procedure described in example 1, step C, from 7 - [(4-pyrazin-2-yl-benzyl) - (pyridin-3-sulfonyl) -amino] -heptanoic acid methyl ester from step B. 1 H NMR (400 MHz, CDCl 3) d 9.07 (m, 1 H), 9.01 (d, 1 H), 8.82 (dd, 1 H), 8.63 (m, 1 H), 8. 55 (m, 1 H), 8.13 (m, 1 H), 7.92 (d, 2H), 7.47 (m, 3H), 4.41 (s, 2H), 3.15 (t, 2H), 2.23 (t, 2H) , 1.48 (m, 2H), 1.33 (m, 2H), 1.13 (m, 4H); EM 453 EXAMPLE 12e 7-R (4-imidazol-1-yl-benzyl) - (pyridin-2-sulfonyl) -amino-1-heptanoic acid Step A: Reductive amination 7- (4-Midazol-1-yl-benzylamino) -heptanoic acid methyl ester. The title compound of step A was prepared from the hydrochloride of the 7-amino-heptanoic acid methyl ester of preparation 1 and 4-imidazol-1-yl-benzaldehyde of preparation 43, using the procedure described in the example 1, step A, except that the imine was formed in MeOH with a reaction time of 1 h. 1 H NMR (400 MHz, CDCl 3) d 7.82 (m, 1 H), 7.43 (d, 2 H), 7.33 (d, 2 H), 7.25 (m, 1 H), 7.18 (m, 1 H), 3.82 (s) , 2H), 3.65 (s, 3H), 2.62 (t, 2H), 2.29 (t, 2H), 1.61 (m, 2H), 1.52 (m, 2H), 1.33 (m, 4H).

Step B: Formation of the amide 7 - [(4-Midazol-1-yl-benzyl) -pyridin-2-sulfonyl-p-aminol-heptanoic acid methyl ester The title compound of step A, prepared from the 7- (4-imidazol-1-yl-benzylamine) -heptanoic acid methyl ester of step A and the pyridine-2-sulfonyl chloride hydrochloride of preparation 47, following the procedure of example 1, step B, with a reaction time of 20 h and using triethylamine instead of N, N-diisopropylethylamine, 1 H NMR (400 MHz, CDCl 3) d 8.70 (m, 1 H), 7.98 (m, 1 H), 7.89 (m, 1 H), 7.84 (s, 1 H), 7.48 (m, 3 H), 7.34 (d, 2 H), 7.27 (s, 1 H), 7.20 (s, 1 H), 4.59 (s, 2 H), 3.62 (s, 3H), 3.25 (t, 2H), 2.19 (t, 2H), 1.45 (m, 2H), 1.34 (m, 2H), 1.13 (m, 4H).

Step C: Hydrolysis of the ester 7 - [(4-imidazol-1-yl-benzyl) - (pyridine-2-sulfoniP-aminol-heptanoic acid) A mixture of 7 - [(4-imidazol-1-yl) methyl ester -benzyl) - (pyridin-2-sulfonyl) -amino] -heptanoic acid (52 mg), porcine pancreatic lipase (81 mg), acetone (1 ml) and phosphate buffer (pH = 7.5 ml), was stirred at room temperature for 20 h. The product was extracted into CH2Cl2 (3x). The organic solution was dried (MgSO4), filtered and concentrated to give the title compound (44 mg). 1 H NMR (400 MHz, CD 3 OD) d 8.71 (m, 1 H), 8.24 (s, 1 H), 8.07-7.98 (m, 2 H), 7.64-7.54 (m, 6 H), 7.19 (s, 1 H) , 4.57 (s, 2H), 3.29 (t, 2H), 2.15 (t, 2H), 1.41 (m, 2H), 1.33 (s, 2H), 1.13 (m, 4H).

EXAMPLE 12f 3- (3-Fibenzenesulfonyl) - (4-pyrimidin-2-yl-benzy-P-amino-1-methyl) -phenimethyl-propionic acid Step A: Formation of the amide 3- (3 - ([Benzenesulfonyl- (4-pyrimidin-2-yl-benz-p-aminol-methyP-phenyl-propionic acid methyl ester) The title compound of step A is prepared following the procedure described in step B of Example 1 from 3- ({3 - [(4-pyrimidin-2-yl-benzylamino) -methyl] -phenyl} methyl ester. -propionic, prepared in step A of example 11z and benzenesulfonyl chloride using triethylamine instead of N, N-diisopropylethylamine.1 H NMR (400 MHz, CDCl 3) d 8.79 (m, 2H), 8.27 (dd, 2H), 7.88 (m, 2H), 7.61 (m, 1 H), 7.55 (m, 2H), 7.18 (m, 1 H), 7.12 (m, 3H), 7.03 (d, 1 H), 6.88 (d, 1 H), 6.79 (s, 1 H), 4.38 (s, 2H), 4.32 (s, 2H), 3.65 (s, 3H), 2.79 (t, 2H), 2.48 (t, 2H), EM 502 (M +1) Step B: Hydrolysis of the ester 3- (3 - ([Benzenesulfonyl- (4-pyrimidin-2-yl-benzyl) -amino-1-methyl-phenyl-propionic acid The title compound was prepared following the procedure described in Example 1, step C, from 3- (3. {[[benzenesulfonyl- (4-pyrimidin-2-yl-benzyl) -amino] -methyl] -phenyl) - methyl ester - propionic from step B. 1 H NMR (400 MHz, CDCl 3) d 8.80 (d, 2 H), 8.07 (m, 2 H), 7.92 (m, 2 H), 7.63 •-* > && amp; (m, 1 H), 7.55 (m, 2H), 7.24 (m, 1 H), 7.10 (m, 3H), 7.01 (d, 1 H), 6.94 (d, 1 H), 6.74 (s, 1 H), 4.38 (s, 2H), 4.29 (s, 2H.), 2.79 (t, 2H), 2.51 (t, 2H), EM 486 (M-1).

EXAMPLE 12q 3- (3-Fipyridin-2-sulfonyl) - (4-pyrimidin-2-yl-benzyl-amino-1-methyl-phenyl-propionic acid) Step A: Formation of the amide 3- (3 - ([Pyridin-2-sulfonyl) - (4-pyrimidin-2-yl-benzopylamine-methyl-phenyl-propionic acid methyl ester The title compound of step A was prepared following the procedure described in step B of example 1 from 3- ({3 - [(4-pyrimidin-2-yl-benzylamino) -methyl) methyl ester] -phenyl.}. -propionic, prepared in step A of example 11z and the hydrochloride salt of pyridine-2-sulfonyl chloride of preparation 47, using triethylamine instead of N, N-diisopropyletilamin. RMN 1H (400 MHz , CDCl 3) d 8.80 (d, 2H), 8.68 (m, 1 H), 8.27 (d, 2H), 7.98 (m, 1 H), 7.86 (m, 1 H), 7.46 (m, 1 H), 7.20 (m, 3H), 7.12 (m, 1 H), 7.02 (d, 1 H), 6.96 (d, 1 H), 6.91 (s, 1 H), 4.55 (s, 2H), 4.48 (s, 2H), 3.65 (s, 3H), 2.80 (t, 2H), 2.50 (t, 2H), EM 503 (M + 1).

Step B: Hydrolysis of the ester 3- (3. {[[Pyridin-2-sulfonyl] - (4-pyridin-2-yl-benzyl) -amino-1-methyl-1-methyl) PheniP-propionic. The title compound was prepared following the procedure described in Example 1, step C, from 3- (3. {[[Pyridine-2-sulfonyl) - (4-pyrimidin-2-yl) methyl ester. benzyl) -amino] -methyl} phenyl) -propionic from step A. 1 H NMR (400 MHz, CDCl 3) d 8.82 (d, 2 H), 8.75 (m, 1 H), 8.06 (m, 3 H), 7.92 (m, 1 H), 7.52 ( m, 1 H), 7.26 (m, 1 H), 7.17 (m, 2H), 7.10 (m, 1 H), 7.01 (m, 2H), 6.84 (s, 1 H), 4.57 (s, 2H) , 4.46 (s, 2H), 2.80 (t, 2H), 2.53 (t, 2H); MS 487 (M-1).

EXAMPLE 12h Acid 3- (3- rpyridin-3-sulfon-P- (4-pyrimidin-2-yl-benzyl-P-amino-1-methyl-P-phenyl-propionic acid Step A: Formation of the amide 3- (3. {[[Pyridine-3-sulfonyl-4-pyrimidin-2-yl-benz-p-aminol-methyP-phenyl-propionic acid methyl ester. The title of step A was prepared following the procedure described in step B of example 1 from the methyl ester of 3-. {3 - [(4-pyrimidin-2-yl-benzylamino) -methyl] -fen. 1-Propionic, prepared in step A of example 11z and the hydrochloride salt of pyridine-3-sulfonyl chloride in preparation 2, using triethylamine instead of N, N-diisopropylethylamine. , CDCl 3) d 9.03 (d, 1 H), 8.77 (m, 3 H), 8.29 (d, 2 H), 8.03 (m, 1 H), 7.40 (m, 1 H), 7.15 (m, 4 H), 7.04 (d, 1 H), 6.90 (d, 1 H), 6.84 (s, 1 H), 4.41 (s, 2H), 4.34 (s, 2H), 3.62 (s, 3H), 2.80 (t, 2H) 2.49 (t, 2H); MS 487 (M-1).

Step B: Hydrolysis of the ester 3- (3. {[[Pyridin-3-sulfonyl] - (4-pyrimidin-2-yl-benzyl-P-amino-methyl-phenyl-propionic acid. The title compound was prepared following the procedure described in Example 1, step C, from 3- (3. {[[Pyridine-3-sulfonyl] - (4-pyrimic acid) methyl ester. Di-n-2-yl-benzyl) -amino] -methyl] -phenyl) -propionic from step A. 1 H NMR (400 MHz, CDCl 3) d 9.05 (s, 1 H), 8.81 (m , 3H), 8.16 (m, 3H), 7.49 (m, 1 H), 7.24 (m, 1 H), 7.16 (m, 3H), 7.06 (d, 1 H), 6.95 (d, 1 H), 6.86 (s, 1 H), 4.42 (s, 2H), 4.35 (s, 2H), 2.84 (t, 2H), 2.56 (t, 2H), MS 487 (M-1).

EXAMPLE 121 3- (3- r4-Chloro-benzenesulfonyl- (4-pyrimidin-2-yl-benzyl-amino-1-methyl-phenyl-propionic acid Step A: Formation of the amide 3- (3- (4-Chloro-benzenesulfonyl- (4-pyrimid-2-yl-benzyl-P-amino] -methyl) -3- methyl ester phen.P-propionic The title compound of step A was prepared following the procedure described in step B of example 1 from methyl 3- (3. il-benzylamino) -methyl] -phenyl] -propionic acid, prepared in step A of example 11z and 4-chlorobenzenesulfonyl chloride using triethylamine instead of N, N-diisopropylethylamine. 400 MHz, CDCl 3) d 8.78 (m, 2H), 8.28 (d, 2H), 7.76 (d, 2H), 7.46 (d, 2H), 7.15 (m, 4H), 7.03 (d, 1 H), 6.88 (d, 1 H), 6.80 (s, 1 H), 4.36 (s, 2H), 4.29 (s, 2H), 3.63 (s, 3H), 2.79 (t, 2H), 2.48 (t, 2H); MS 536 (M + 1).

Step B: Hydrolysis of the ester 3- (3- (f4-Chloro-benzenesulfonyl-P- (4-pyridin-2-yl-benzyl) -aminol-methyl-phenyl-propionic acid ester. prepared following the procedure described in example 1, step C, from 3- (3. {[4-chloro-benzenesulfonyl) - (4-pyrimidin-2-yl-benzyl) methyl ester - amino] -methyl.}. phenyl) -propionic acid from step A. 1 H NMR (400 MHz, CDCl 3) d 8.80 (d, 2 H), 8.09 (d, 2 H), 7.83 (d, 2 H), 7.53 ( d, 2H), 7.11 (m, 4H), 7.02 (d, 1 H), 6.95 (d, 1 H), 6.76 (s, 1 H), 4.37 (s, 2H), 4.28 (s, 2H), 2.80 (t, 2H), 2.53 (t, 2H), MS 520 (M-1).

EXAMPLE 12 Acid 3- (3-benzenesulfonyl- (4-pyrazol-1-yl-benzyl-amino-1-methyl-phenyl-2-methyl-propionic acid Step A: Reduction 3- (3-cyano-phenyD-propionic acid methyl ester A mixture of 3- ({3-cyano-phenyl) -acrylic acid methyl ester (3.24 g, 17.31 mmol), prepared in step B of preparation 44 and palladium on carbon (10%, 0.600 g) in AcOEt (30 ml) was hydrogenated at 172.36 kPa on a Parr shaker for 1 h. The catalyst was removed via filtration through Celite and the solution was concentrated in vacuo. Medium pressure chromatography (hexanes: AcOEt 6: 1) gave the title compound of step A as a clear oil (2.98 g). 1 H NMR (400 MHz, CDCl 3) d 7.50-7.36 (m, 4H), 3.65 (s, 3H), 2.97 (t, 2H), 2.63 (t, 2H); MS 190 (M + 1).

Step B: Alkylation 3- (3-cyano-phenyl-D-2-methyl-propionic acid methyl ester) To a solution of 3- (3-cyano-phenyl) -propionic acid methyl ester from step A ( 220 mg, 1.16 mmol) in THF (5 ml) at -78 ° C was added sodium bis (trimethylsilyl) amide (1M in THF, 1.2 ml, 1.2 mmol) The reaction was stirred for 0.5 h and Mel (0.08 ml) was added. 1.28 mmol) After 1 h, a saturated solution of NaHCO 3: water (1: 1) was added and the reaction was warmed to room temperature The aqueous solution was washed with CH 2 Cl 2 (3x) and the combined organic solutions were dried (MgSO 4), filtered and concentrated, medium pressure chromatography (hexanes: AcOEt 6: 1) gave the title compound from step B as a colorless oil (62 mg). 1 H NMR (400 MHz, CDCl 3) d 7.50 -7.34 (m, 4H), 3.62 (s, 3H), 3.01 (m, 1 H), 2.71 (m, 2H), 1.16 (d, 3H).

Step C: Reduction 3- (3-aminomethyl-phenyl) -2-methyl-propionic acid methyl ester. A mixture of 3- (3-cyano-phenyl) -2-methyl-propionic acid methyl ester from step B (62 mg, 0.30 mmol) and palladium on carbon (10%, 50 mg) in MeOH (10 ml), AcOET (10 ml) and ammonium hydroxide (5 ml) was hydrogenated at 275-78 kPa for 24 h. The catalyst was removed by filtration through Celite by MeOH. The solvent was removed in vacuo. Chromatrog raphy (hexanes: AcOEt 1: 1 to CH2Cl2: MeOH: NH4OH, 95: 5: 0.1) gave the title compound from step C (45 mg). 1 H NMR (400 MHz, CD 3 OD) d 7.31-7.14 (m, 4 H), 3.94 (s, 2 H), 3.59 (s, 3 H), 2.96 (m, 1 H), 2.72 (m, 2 H), 1.12 (d , 3H); MS 208 (M + 1).

Step D: Reductive amination 2-methyl-3-methyl acid ester. { 3-α (4-pyrazol-1-yl-benzyllamine) -methip-phenyl-propionic acid. The title compound of step d was prepared from 3- (3-aminomethyl-phenyl) -2-methyl-propionic acid methyl ester from step C and 4- ^^^ pyrazol-1-yl-benzaldehyde of preparation 42, using the procedure described in Example 1, step A, with the exception that no base was used. 1 H NMR (400 MHz, CDCl 3) d 7.90 (m, 1 H), 7.66 (m, 3 H), 7.41 (m, 2 H), 7.24-7.02 (m, 4 H), 6.45 (m, 1 H), 3.81 ( s, 2H), 3.77 (s, 2H), 3.61 (s, 3H), 3.01 (dd, 1H), 2.76-2.60 (m, 2H), 1.14 (d, 3H); EM 364 (M + 1).

Step E: Formation of the amide 3- (3. {-benzenesulfonyl- (4-pyrazol-1-yl-benzopyaminol-methyD-phenyD-2-methyl-propionic acid methyl ester) Step title compound E was prepared from the methyl ester of 2-methyl-3-. {3 - [(4-pyrazol-1-yl-benzylamine) -methyl] -phenyl} -propionic acid ester of step d and benzenesulfonyl chloride, following the procedure described in Example 1, step B, using triethylamine instead of N, N-diisopropylethylamine and with a reaction time of 4 h. 1 H NMR (400 MHz, CDCl 3) d 7.87 (m, 3 H), 7.69 (m , 1 H), 7.61 (m, 1 H), 7.54 (m, 4 H), 7.10 (m, 3 H), 6.98 (d, 1 H), 6.85 (d, 1 H), 6.75 (s, 1 H) , 6.44 (m, 1 H), 4.31 (s, 2H), 4.29 (s, 2H), 3.61 (s, 3H), 2.87 (dd, 1 H), 2.61-2.47 (m, 2H), 1.06 (d 3 H); MS 504 (M + 1).

Step F: Hydrolysis of the ester 3- (3- (F-benzenesulfonyl- (4-pyrazol-1-benzyl-phenyl) -methyl-phenyl-2-methyl-propionic acid The title compound was prepared following the procedure described in Example 1, step C, from 3- (3. {[[benzenesulfonyl- (4-pyrazol-yl-benzyl) -ar) in] -methyl] -methyl ester. phenyl) -2-methyl-propionic from step E, except that the hydrolysis was performed in refluxing MeOH for 24 hrs. 1 H NMR (400 MHz, CD3OD) d 8.14 (m, 1 H), 7.90 (m , 2H), 7.69-7.53 (m, 6H), 7.17 (m, 2H), 7.07 (m, 1 H), 6.99 (m, 1 H), 6.90 (m, 1 H), 6.79 (s, 1 H) ), 6.49 (m, 1 H), 4.34 (s, 2H), 4.31 (s, 2H), 2.79 (m, 1 H), 2.50 (m, 2H), 1.02 (d, 3H), EM 488 (M -1 ).

EXAMPLE 12k 3- (3- (f (1-methyl-1 H-imidazole-4-sulfoniP- (4-pyrazin-2-yl-benzyl-P-amino-1-methyl-phenyl-propionic acid Step A: Formation of amide 3- (3 - ([(1-methyl-1 H, 4-pyrrazin-2-yl-benzyl) -amidazole-4-sulfonyl- l) -amino] -methiP-phen-P-propionic acid The title compound of step A was prepared following the procedure described in step B of example 1 from the methyl ester of 3- acid. 3 - [(4-Pyrrazin-2-yl-benzylamino) -methyl] -phenyl] -propionic from step A of example 11a and 1-methyl-1H-ylidazole-4-sulfonyl chloride using triethylamine in place of N, N-diisopropylethylamine, 1 H NMR (400 MHz, CDCl 3) d 8.99 (d, 1 H), 8.63 (m, 1 H), 8.50 (d, 1 H), 7.88 (d, 2 H), 7.55 (d). s, 1 H), 7.42 (s, 1 H), 7.32 (d, 2H), 7.13 (m, 1 H), 7.04-6.97 (m, 3H), 4.47 (s, 2H), 4.41 (s, 2H) ), 3.75 (s, 3H), 3.65 (s, 3H), 2.82 (t, 2H), 2.51 (t, 2H), EM 506 (M + 1).

Step B: Hydrolysis of the ester Acid 3- (3. {[[(1-methyl-1 H -amidazole-4-sulfon-D- (4-pyrazin-2-yl-benzyl-D-aminol-methyP -pheniP-propionic The title compound was prepared following the procedure described in example 1, step C from the 3- (3. {[[(1-methyl-1 H-imidazole-4) methyl ester sulfonyl) - (4-pyrazin-2-yl-benzyl) -amino] -methyl] -phenyl) -propionic from step A. 1 H NMR (400 MHz, CDCl 3) d 8.96 (s, 1 H), 8.59 (s, 1 H), 8.52 (s, 1 H), 7.78 (d, 2H), 7.59 (s, 1 H), 7.44 (s, 1 H), 7.28 (d, 2H), 7.11 (m, 1 H), 7.01 (m, 2H), 6.93 (s, 1 H), 4.47 (s, 2H), 4.38 (s, 2H), 3.74 (s, 3H), 2.81 (t, 2H) , 2.52 (t, 2H).

EXAMPLE 12m Acid 3-3-f (benzenesulfonyl-biphenyl-4-ylmethyl-amino) -metn-phenyl-propionic acid Step A: Reductive amination 3- methyl acid ester. { 3-. { [(biphenyl-4-ylmethyl-D-amino-1-methyl-D-phenyl-propionic acid The title compound of step A was prepared from the hydrochloride salt of 3- (3-aminomethyl-phenyl) -methyl ester propionic of preparation 44 and biphenyl-4-carbaldehyde using the procedure described in Example 1, step A, except that the mine was formed in refluxing MeOH for 3 h. 1 H NMR (400 MHz, CDCl 3) d 7.55 (m , 4H), 7.40 (m, 4H), 7.32 (m, I i - - r-tj &sggá 1 H), 7.29-7.22 (m, 2H), 7.17 (m, 1 H), 7.07 (d, 1 H), 3.82 (s, 2H), 3.79 (s, 2H) ), 3.64 (s, 3H), 2.93 (t, 2H), 2.61 (t, 2H); EM 360 (M + 1).

Step B: Formation of the amide 3- (3-f (Benzenesulfonyl-biphenyl-4-methylmethyl) -phenyl) -propionic acid methyl ester. The title compound of Step B was prepared following the procedure described in step B of Example 1 from 3- (3. {[[(Biphenyl-4-ylmethyl) -amino] -methyl] methyl ester. phenyl) -propionic of step A and benzenesulfonyl chloride using triethylamine instead of N, N-diisopropylethylamine. 1 H NMR (400 MHz, CDCl 3) d 7.85 (d, 2 H), 7.60-7.29 (m, 10 H), 7.08 (m, 3 H), 7.01 (d, 1 H), 6.88 (d, 1 H), 6.78 (d. s, 1 H), 4.33 (s, 2H), 4.32 (s, 2H), 3.63 (s, 3H), 2.78 (t, 2H), 2.47 (t, 2H); EM 500 (M + 1).

Step C: Hydrolysis of the ester Acid 3-. { 3-f (benzenesulfonyl-1-phenyl-4-ylmethyl-amino) -methyl] -pheni-propionic acid. The title compound was prepared following the procedure described in Example 1, step C from the methyl ester of 3-acid. { 3 - [(Benzenesulfonyl-biphenyl-4-ylmethyl-amino) -methyl] -phenyl) -propionic from step B. 1 H NMR (400 MHz, CDCl 3) d 7.85 (m, 2 H), 7.60-7.29 (m, 10 H) , 7.13-7.01 (m, 4H), 6.88 (d, 1H), 6.79 (s, 1 H), 4.33 (s, 2H), 4.32 (s, 2H), 2.78 (t, 2H), 2.52 (t, 2H); MS 484 (M-1).

EXAMPLE 12n '«? Acid 3- (3-. {R (benzenesulfonyl- (2,3 (gihidro-benzori, 41dioxin-6-ilmetiP-aminol-metiP-feniP-propiónico Step A: Reductive amination 3- (3 - ([(2,3-dihydro-benzo [1,41-oxo-6-ylmethyl-methy-P-phenyl-propionic acid methyl ester. Step A was prepared from the hydrochloride salt of 3- (3-aminomethyl-phenyl) -propionic acid methyl ester of preparation 44 and 2,3-dihydro-benzo [1,4] dioxin-6 carbaldehyde using the procedure described in Example 1, step A, except that the imine was formed in MeOH at reflux for 3 h. 1 H NMR (400 MHz, CDCl 3) d 7.26-7.16 (m, 3 H), 7.07 (d, 1 H ), 6.85-6.78 (m, 3H), 4.24 (s, 4H), 3.75 (s, 2H), 3.68 (s, 2H), 3.66 (s, 3H), 2.94 (t, 2H), 2.62 (t, 2H); EM 342 (M + 1).

Step B: Formation of the amide 3- (3- (3- benzenesulfonyl- (2,3-dihydro-benzo [1,41-dioxan-6-methyl-1-amino] -met-P-phenyl) The title compound of Step B was prepared following the procedure described in step B of Example 1 from 3- (3. {[[(2,3-dihydro-benzo [methyl]] methyl ester. 1, 4-] dioxin-6-ylmethyl) -amino] -methyl] -phenyl) -propionic of step A and benzenesulfonyl chloride using triethylamine instead of NN-diisopropylethylamine 1 H NMR (400 MHz, CDCl 3) d 7.84 (m, 2H), 7.60-7.49 (m, 3H), 7.14 (m, 1H), 7.04 (d, 1 H), 6.89 (d, 1 H), 6.78 (s, 1 H), 6.69 (d, 1 H), 6.51 (m, 2H), 4.29 (s, 2H), 4.20 (m, 6H), 3.67 (s, 3H), 2.81 (t, 2H), 2.51 (t, 2H).

Step C: Hydrolysis of the ester 3- (3 - ([Benzenesulfonyl- (2,3-dydro-benzo [1,41-dioxin-6-ylmethyl-pyridine] -methyl-phenyl-propionic acid The title compound was prepared following the procedure described in Example 1, step C from 3- (3-O. {[[benzenesulfonyl- (2,3-dihydro-benzo [1,4] dioxin-6-ylmethyl) -amino methyl ester ] -methyl] -phenyl) -propionic from step B. 1 H NMR (400 MHz, CDCl 3) d 7.82 (dd, 2 H), 7.59-7.47 (m, 3 H), 7.12 (m, 1 H), 7.03 (d , 1 H), 6.88 (d, 1 H), 6.78 (s, 1H), 6.67 (d, 1 H), 6.49 (m, 2H), 4.26 (s, 2H), 4.18 (s, 4H), 4.16 (s, 2H), 2.81 (t, 2H), 2.55 (t, 2H), EM 466, IM-1) 5 EXAMPLE 12o Acid 3- (3-fr2.3-dihydro-benzof1, 41-dioxin-6-ylmethyl) (pyridine-2-sulfoniP-aminol-metiP-feniD-propionic 0 Step A: Formation of amide 3- (3 - ([(2,3-dihydro-benzof1, 4] dioxan-6-ylmethyl) - (pyridin-2-methyl) acid methyl ester Sulfon-P-amino-1-met-P-phen-P-propionic acid The title compound of step A was prepared following the procedure described in step B of example 1 from 3- (3. {[[(2,3-dihydro-benzo [1,4] dioxin-6-ylmethyl) -amino] -methyl methyl ester. phenyl) -propionic, prepared in step A of example 12n and pyridine-2-sulfonyl chloride hydrochloride of preparation 47, using triethylamine instead of NN-diisopropylethylamine. 1 H NMR (400 MHz, CDCl 3) d 8.66 (m, 1 H), 7.95 (d, 1 H), 7.85 (m, 1 H), 7.45 (m, 1 H), 7.15-6.91 (m, 4 H), 6.68 -6.54 (m, 3H), 4.45 (s, 2H), 4.36 (s, 2H), 4.19 (s, 4H), 3.68 (s, 3H), 2.82 (t, 2H), 2.53 (t, 2H); MS 483 (M + 1).

Step B: Hydrolysis of the ester Acid 3- (3- (I (2,3-dihydro-benzo [1,4-dioxin-6-ylmethyl-P- (pyridine-2-sulfonyl-P-aminol-methyP-phenyl-propionic) Compound The title was prepared following the procedure described in example 1, step C from 3- (3. {[[(2,3-dihydro-benzo [1,4] dioxan-6-ylmethyl) methyl ether ) - ((pyridin-2-yl-sulfonyl) -amino] -methyl] -phenyl) -propionic from step A. 1 H NMR (400 MHz, CDCl 3) d 8.65 (m, 1 H), 7.93 (d, 1 H ), 7.84 (m, 1H), 7.43 (m, 1H), 7.12 (m, 1H), 7.02 (d, 1H), 6.95 (d, 1 H), 6.88 (s, 1 H), 6.65 (d, 1H), 6.55 (m, 2H), 4.43 (s, 2H), 4.33 (s, 2H), 4.17 (s, 4H), 2.81 (t, 2H), 2.56 (t, 2H), EM 467 (M- 1 ).

EXAMPLE 12p 3- (3-Fr) (4-Chloro-benzenesulfoniP- (4-thiazol-2-yl-benzy-P-amino-1-methyl-phenyl-propionic acid Step A: Formation of the amide 3- (3. {R (4-Chloro-benzenesulfonyl) - (4-thiazol-2-yl-benzyl) -amino-1-meth-P-phen-P acid methyl ester -proponic The title compound of step A was prepared following the procedure described in step B of example 1 from the methyl ester of 3. {3 - [(4-thiazol-2-yl-benzylamino)] -methyl] -phenyl) -propionic, prepared in step A of example 11e and 4-chlorobenzenesulfonyl chloride using triethylamine instead of N, N-diisopropylamine. 1 H NMR (400 MHz, CDCl 3) d 7.85 (d, 1 H), 7.81 (d, 2 H), 7.77 (d, 2 H), 7.48 (d, 2 H), 7.32 (d, 1 H), 7.12 (m, 3H), 7.04 (d, 1 H), 6.88 (d, 1 H), 6.80 (s, 1 H), 4.33 (s, 2H), 4.30 (s, 2H), 3.64 (s, 3H), 2.80 ( t, 2H), 2.49 (t, 2H).

Step B: Hydrolysis of the ester. 3- (3 - ([(4-Chloro-benzenesulfoniP- (4-thiazol-2-yl-benzyl-amino-1-methyl-phenyl-propionic acid) The title compound was prepared following the procedure described in Example 1, step C, from 3- (3. {[[(4-chloro-benzenesulfonyl) - (4-thiazol-2-yl-benzyl) -amino] -methyl methyl ester 1.) - phenyl) -propionic from step A. 1 H NMR (400 MHz, CDCl 3) d 7.84 (d, 1 H), 7.82 (dd, 2 H), 7.68 (d, 2 H), s - ets ¿> iM! 7.51 (d, 2H), 7.34 (m, 1 H), 7.13-7.01 (m, 4H), 6.92 (d, 1 H), 6.74 (s, 1 H), 4.33 (s, 2H), 4.27 (s) , 2H), 2.78 (t, 2H), 2.49 (t, 2H).

EXAMPLE 12q 3- (3- (4-phenyl-4-methylmethyl- (pyridin-2-yl-sulfoniP-amino-1-methyl-phenyl-propionic acid Step A: Formation of the amide 3- (3 { [Biphenyl-4-ylmethyl- (pyridin-2-ylsulfonyl) -aminol-methyl-phenyl-propionic acid methyl ester The title compound of step B was prepared following the procedure described in step B of example 1 from 3- (3. {[Biphenyl-4-ylmethyl) -amino] -methyl methyl ester. phenyl) -propionic, prepared in step A of example 12m and pyridine-2-sulfonyl chloride hydrochloride of preparation 47, using triethylamine instead of N, N-diisopropylethylamine. -RN 1H (400 MHz, CDCl 3) d 8.65 (d, 1 H), 7.95 (d, 1 H), 7.83 (m, 1 H), 7.51 (dd, 2H), 7.45-7.29 (m, 6H), 7.16-7.10 (m, 3H), 7.08-6.90 (m, 3H), 4.50 (s, 2H), 4.48 (s, 2H), 3.64 (s, 3H), 2.79 (t, 2H), 2.49 (t, 2H); MS 501 (M + 1).

Step B: Hydrolysis of the ester Acid 3- (3 - ([b-phenyl-4-methyl-1- (pyridine-2-sulfoniP-amino-1-methylP-phenyl-propionic) The title compound was prepared following the procedure described in Example 1, step C from 3- (3. {[[biphenyl-4-ylmethyl- (pyridin-2-sulfonyl) -amino] -methyl] -phenyl] -propionic acid methyl ester from step B. 1 H NMR (400 MHz, CDCl 3) d 8.68 (m, 1 H), 7.97 (m, 1 H), 7.85 (m, 1 H), 7.53 (dd, 2 H), 7.47-7.31 (m, 6 H) , 7.18-7.11 (m, 3H), 7.04-6.93 (m, 3H), 4.52 (s, 2H), 4.51 (s, 2H), 2.82 (t, 2H), 2.56 (t, 2H), EM 485 ( M-1).

EXAMPLE 12r Acid 3-f3-r (biphenyl-4-ylmethyl-methanesulfonyl) -amino) -methyl-phenyl-propionic acid Step A: Formation of amide 3- methyl acid ester. { 3-f (biphenyl-4-ylmethyl-methanesulfonyl-D-amino) -met-p-phenyl) -proponic acid The title compound of step A was prepared following the procedure described in step B of example 1 to from 3- (3. {[[(biphenyl-4-ylmethyl-) amino) -methyl methyl ester} phenyl) -propionic, prepared in step A of example 12m and methanesulfonyl chloride using triethylamine instead of N.N-diisopropylethylamine. 1 H NMR (400 MHz, CDCl 3) d 7.56 (m, 4 H), 7.44-7.23 (m, 6 H), 7.14 (m, 3 H), 4.35 (s, 2 H), 4.33 (s, 2 H), 3.64 (s, 3H), 2.92 (t, 2H), 2.78 (s, 3H), 2.59 (t, 2H).

Step B: Acid ester hydrolysis 3-. { 3-f (biphenyl-4-ylmethyl-methanesulfonyl) -amino) -methyl] -pheni-propionic acid The title compound was prepared following the procedure described in Example 1, step C, from the methyl ester of the acid 3-. { 3- [(biphenyl-4-ylmethyl-methanesulfonyl) -amino) -methyl] -phenyl) -propionic acid. 1 H NMR (400 MHz, CDCl 3) d 7.57 (m, 4H), 7.45-7.24 (m, 6H), 7.15 (m, 3H), 4.36 (s, 2H), 4. 34 (s, 2H), 2.94 (t, 2H), 2.79 (s, 3H), 2.66 (t, 2H); EM 422 (M-1).

EXAMPLE 12s 3- (3-Fr) (4-tert-butyl-benzyl- (pyridine-2-sulfonyl-amino-1-methyl-phenyl-propionic acid Step A: Reductive amination 3- methyl acid ester. { 3 - [(4-tert-butyl-benzylamino) -methyl] -pheni-propionic acid The title compound of step A was prepared from the hydrochloride salt of 3- (3-aminomethyl-phenyl) methyl ester -propionic of preparation 44 and 4-tert-butylaldehyde using the procedure described in example 1, step A, except that the imine was formed in MeOH at reflux for 3 h. 1 H NMR (400 MHz, CDCl 3) d 7.35 (m, 2 H), 7.25 (m, 2 H), 7.18 (m, 2 H), 7.08 (d, 1 H), 3.79 (s, 2 H), 3.77 (s, 2 H) ), 3.66 (s, 3H), 2.94 (t, 2H), 2.63 (t, 2H), 1.31 (s, 9H); MS 340 (M + 1).

Step B: Formation of amide 3- (3. {[[(4-tert-butyl-benzyl) - (pyridine-2-sulfonyl-p-aminol-methyP-phenyl-propionic acid methyl ester of the title of step B was prepared following the procedure described in step B of example 1 from 3- ({3 - [(4-tert-butyl-benzylamino) -methyl] -phenyl} methyl ester. -propionic of step A and pyridine-2-sulfonyl chloride hydrochloride of preparation 47 using triethylamine instead of N, N-diisopropylethylamine, 1 H NMR (400 MHz, CDCl 3) d 8.62 (m, 1 H), 7.90 (m , 1 H), 7.81 (m, 1 H), 7.41 (m, 1 H), 7.17 (d, 2 H), 7.09 (m, 1 H), 6.99 (m, 3 H), 6.92 (m, 2 H), 4.48 (s, 2H), 4.43 (s, 2H), 3.65 (s, 3H), 2.80 (t, 2H), 2.51 (t, 2H), 1.24 (t, 9H), EM 481 (M + 1).

Step C: Hydrolysis of the ester 3- (3- (f (4-tert-Butyl-benzyl) - (pyridine-2-sulfonyl-P-amino] -met-P-phenypropionic acid The title compound is prepared following the procedure described in Example 1, step C, from 3- (3. {[[(4-tert-butyl-benzyl) - (pyridine-2-sulfonyl) -amino] methyl ester ) -methyl] -phenyl] -propionic from step B. 1 H NMR (400 MHz, CDCl 3) d 8.64 (m, 1 H), 7.92 (m, 1 H), 7.83 (m, 1 H) ), 7.43 (m, 1 H), 7.19 (d, 2H), 7.12 (m, 1 H), 7.02 (m, 3H), 6.94 (m, 2H), 4.48 (s, 2H), 4.43 (s, 2H), 2.82 (t, 2H), 2.57 (t, 2H), 1.26 (t, 9H), EM 465 (M-1).

EXAMPLE 12t 3- (3- (R-benzenesulfonyl- (4-tert-butyl-benzyl-P-amino-1-methyl-P-phenyl-propionic acid Step A: Formation of the amide 3- (3. {Fbenzenesulfonyl- (4-tert-butyl-benzy-p-aminol-methyP-phenyl-propionic acid methyl ester The title compound of step A was prepared following the method described in step B of Example 1 from the methyl 3- ({3 - [(4-tert-butyl-benzylamino) -methyl] -phenyl} -propionic acid methyl ester prepared in step A of example 12s and benzenesulfonyl chloride using triethylamine in place of NN-diisopropylethylamine.1H-NMR (400 MHz, CDCl3) d 7.81 (dd, 2H), 7.56 (m, 1 H), 7.48 (m, 2H), 7.19 (d, 2H) , 7.10 (m, 1 H), 7.01 (d, 1 H), 6.94 (d, 2H), 6.86 (d, 1 H), 6.79 (s, 1 H), 4.28 (s, 2H), 4.26 (s) , 2H), 3.65 (s, 3H), 2.79 (t, 2H), 2.49 (t, 2H), 1.25 (s, 9H), EM 480 (M + 1).

Step B: Hydrolysis of the ester 3- (3. {[[Benzenesulfonyl- (4-tert-butyl-benzyl) -amino] -met-P-phenyl-propionic acid The title compound was prepared following the procedure described in Example 1, step C, from 3- (3. {[[benzenesulfonyl- (4-tert-butyl-benzyl) -amino] -methyl] -methyl ester. phenyl) -propionic from step A. 1 H NMR (400 MHz, CDCl 3) d 7.82 (dd, 2H), 7.59-7.47 (m, 3H), 7.21 (d, 2H), '* Í-Í 7.12 (m, 1 H), 7.03 (d, 1 H), 6.95 (d, 2H), 6.88 (d, 1 H), 6.81 (s, 1 H), 4.30 (s, 2H) , 4.27 (s, 2H), 2.81 (t, 2H), 2.55 (t, 2H), 1.26 (s, 9H); EM 464 (M-1).

EXAMPLE 12u Acid 3-. { 3-r (benzenesulfonyl-benzofuran-2-ylmethyl-p-amino) -methyl-1-phenyl-propionic acid Step A: Reductive amination 3- (3-. {Fbenzofuran-2-methyl-P-amino-1-methyl] -pheniP-propionic acid methyl ester The title compound of step A was prepared from the hydrochloride salt of the 3- (3-aminomethyl) -phenyl) -propionic acid methyl ester of preparation 44 and benzofuran-2-carbaldehyde using the procedure described in example 1, step A, with the exception that the imine was formed in MeOH a reflux for 3 h. 1 H NMR (400 MHz, CDCl 3) d 7.50 (dd, 1 H), 7.42 (d, 1 H), 7.25-7.14 (m, 5H), 7.07 (d, 1 H), 6.55 (d, 1 H), 3.91 (s, 2H), 3.79 (s, 2H), 3.64 (s, 3H), 2.92 (t, 2H), 2.60 (t, 2H).

Step B: Amide Formation 3- (3 - [(Benzenesulfonyl-benzofuran-2-methylmethyl-amino-phenyl-phenyl-propionic acid) methyl ester The title compound of step B was prepared following the procedure described in step B of the example 1 from the methyl ester & amp; - & amp; -3- (3- ({[[(benzofuran-2-ylmethyl) -amino] -methyl] -phenyl} -propionic acid from step A and benzene-sulfonyl chloride using triethylamine in place of N, N-diisopropylethylamine, 1 H NMR (400 MHz, CDCl 3) d 7.83 (m, 2H), 7.52-7.42 (m, 3H), 7.26-7.09 (m, 8H), 6.39 (d, 1 H), 4.46 (s, 2H), 4.39 (s, 2H), 3.68 (s, 3H), 2.88 (t, 2H), 2.57 (t, 2H).

Step C: Hydrolysis of the ester Acid 3-. { 3 - [(Benzenesulfonyl-benzofuran-2-ylmethyl-amino) -metn-phenyl-propionic acid The title compound was prepared following the procedure described in example 1, step C from the methyl ester of the 3-methyl ester. . { 3 - [(benzenesulfonyl-benzofuran-2-ylmethyl) -amino) -methyl] -phenyl} -propion of step B. 1 H NMR (400 MHz, CDCl 3) d 7.81 (m, 2 H), 7.51-7.37 (m, 3 H), 7.25-7.06 (m, 8 H), 6.36 (d, 1 H ), 4.43 (s, 2H), 4.37 (s, 2H), 2.86 (t, 2H), 2.58 (t, 2H); MS 448 (M-1).

EXAMPLE 12v 3- (3- (Rbenzofuran-2-ylmethyl) - (4-fluoro-benzenesulfonyl-amino-1-methyl-phenyl-propionic acid Step A: Amide formation 3- (3. {[[Benzofuran-2-ylmethyl- (4-fluoro-benzenesulfoniP-aminol-metiP-phenyl-propionic acid methyl ester The title compound of step A was prepared following the procedure described in step B of Example 1 from 3- (3. {[[(benzofuran-2-ylmethyl) -amino] -methyl] -phenyl) -proponic acid methyl ester prepared in step A of example 12u and 4-fluorobenzenesulfonyl chloride using triethylamine in place of N, N-d sosopropylethamine, 1 H NMR (400 MHz, CDCl 3) d 7.82 (m, 2H), 7.46 (m, 1 H), 7.28 -7.03 (m, 9H), 6.42 (s, 1 H), 4.45 (s, 2H), 4.38 (s, 2H), 3.67 (s, 3H), 2.90 (t, 2H), 2.58 (t, 2H) .

Step B: Hydrolysis of the ester 3- (3. {[[Benzofuran-2-ylmethyl- (4-fluoro-benzenesulfoniP-amino) -met-P-phenyl) -propionic acid The title compound was prepared following the procedure described in Example 1, step C, from 3- (3. {[[benzofuran-2-ylmethyl) - (4-fluoro-benzenesulfonyl) -amino] -methyl methyl ester} phenyl) -propionic from step B. 1 H NMR (400 MHz, CDCl 3) d 7.81 (m, 2H), 7.45 (m, 1 H), 7.24-7.03 (m, 9H), 6.41 (s, 1 H), 4.44 (s, 2H), 4.38 (s, 2H), 2.90 (t, 2H), 2.62 (t, 12H); EM 466 (M-1).

EXAMPLE 12w 3- (3-Fr (2,3-Dihydro-benzofuran-5-ylmethyl) -methanesulfonyl-amino-1-methyl-phenyl-propionic acid Step A: Reductive amination 3- (3 - ([(2,3-Dihydro-benzofuran-5-ylmethyl-methylamino-phenyl-propionic acid) methyl ester The title compound of step A was prepared from the salt 3- (3-aminomethyl-phenyl) -propionic acid methyl ester hydrochloride of preparation 44 and 2,3-dihydro-benzofuran-5-carbaldehyde using the procedure described in example 1, step A, except that the imine was formed in refluxing MeOH for 3 h. 1 H NMR (400 MHz, CDCl 3) d 7.23 (m, 4 H), 7.07 (m, 2 H), 6.73 (d, 1 H), 4.54 (t, 2 H), 3.77 (s, 2H), 3.71 (s, 2H), 3.66 (s, 3H), 3.18 (t, 2H), 2.94 (t, 2H), 2.63 (t, 2H), EM 326 (M + 1).

Step B: Formation of the amide 3- (3- (K2,3-dithy-benzofuran-5-ylmethyl) -methanesulfonyl-aminol-methyP-phenyl-propionic acid methyl ester The title compound of step B was prepared following the procedure described in step B of Example 1 from 3- (3. {[[(2,3-dihydro-benzofuran-5-ylmethyl) -amino] -methyl] methyl ester. phenyl) - propionic from step A and methanesulfonyl chloride using triethylamine in place of NN-d soopropylethylamine 1 H NMR (400 MHz, CDCl 3) d 7.27 (m, 2 H), 7.14 (m, 3 H), 6.98 (d, 1 H ), 6.73 (d, 1 H), 4.57 (t, 2H), 4.29 (s, 2H), 4.24 (s, 2H), 3.66 (s, 3H), 3.19 (t, 2H), 2.94 (t, 2H) ), 2.75 (s, 3H), 2.61 (t, 2H).

Step C: Hydrolysis of the ester Acid 3- (3- (f (2,3-dihydro-benzofuran-5-ylmethyl-P-methanesulfonyl-amino) -met-P-phen-P-propionic acid The title compound is prepared following the procedure described in Example 1, step C from 3- (3. {[[(2,3-dihydro-benzofuran-5-ylmethyl) -methanesulfonyl-amino] -methyl) methyl ester. phenyl) -propionic from step B. 1 H NMR (400 MHz, CDCl 3) d 7.27 (m, 2 H), 7.15 (m, 3 H), 6.98 (d, 1 H), 6.72 (d, 1 H), 4.57 (t, 2H), 4.29 (s, 2H), 4.24 (s, 2H), 3.18 (t, 2H), 2.94 (t, 2H), 2.75 (s, 3H), 2.66 (t, 2H), EM 388 (M-1).

EXAMPLE 12x Acid 3-f3-frbenzenesulfonyl- (2,3-dihydro-benzofuran-5-ylmethyl-amino-1-methyl-phenyl-propionic acid Step A: Formation of the amide 3- (3. {[[Benzenesulfonyl- (2,3-dihydro-benzofuran-5-ylmethyl-methylamino-phenyl-propionic acid) methyl ester The title compound of step B was prepared by following the procedure described in step A of example 1 from 3- (3. {[[(2,3-dihydro-benzofuran-5-ylmethyl) -amino] -methyl) methyl ester. phenyl) -propionic prepared in step A of example 12w and benzenesulfonyl chloride using triethylamine in place of N, N-diisopropylethylamine, 1 H NMR (400 MHz, CDCl 3) d 7.82 (m, 2H), 7.58-7.47 ( m, 3H), 7.10 (m, 1 H), 7.00 (d, 1 H), 6.89 (s, 1 H), 6.85 (d, 1 H), 6.74 (s, 1 H), 6.68 (d, 1 H), 6.56 (s, 1 H), 4.50 (t, 2H), 4.26 (s, 2H), 4.21 (s, 2H), 3.65 (s, 3H), 3.06 (t, 2H), 2.78 (t, 2H), 2.47 (t, 2H).

Step B: Hydrolysis of the ester. 3- (3. {[[Benzenesulfonyl- (2,3-dihydro-benzofuran-5-methyl-P-aminol-methyl-phenyl-propionic]] The title compound was prepared following the procedure described in Example 1, step C from 3- (3. {[[benzenesulfonyl- (2,3-dihydro-benzofuran-5-ylmethyl] -amino] -methyl] -methyl ester. phenyl) -propionic from step A. 1 H NMR (400 MHz, CDCl 3) d 7.82 (dd, 2 H), 7.59-7.47 (m, 3 H), 7.11 (m, 1 H), 7.02 (d, 1 H), 6.88 (m, 2H), 6.73 (s, 1 H), 6.68 (m, 1 H), 6.56 (d, 1 H), 4.50 (t, 2H), 4.26 (s, 2H), 4.21 (s, 2H) , 3.06 (t, 2H), 2.78 (t, 2H), 2.52 (t, 2H), EM 450 (M-1).

EXAMPLE 12v Acid 3- (3-. {R (2,3-D-Hydro-benzofuran-5-ylmethyl-P- (4-fluoro-benzenesulfonopyridine) -methyl-methyl-phenyl-propionic Step A: Formation of the amide 3- (3- (f (2,3-dihydro-benzofuran-5-ylmethyl) -P- (4-fluoro-benzenesulfoniP-aminol-metiP-pheniP-propionic acid methyl ester compound of the title of step A was prepared following the procedure described in step A of example 1 from 3- (3. {[[(2,3-dihydro-benzofuran-5-ylmethyl) -am) methyl ester No] -methyl] -phenyl) -propionic prepared in step A of example 12w and 4-fluorobenzenesulfonyl chloride, prepared in step A of example 12w and 4-fluorobenzenesulfonyl chloride using triethylamine instead of N, N-diisopropylethylamine 1 H NMR (400 MHz, CDCl 3) d 7.79 (m, 2 H), 7.14 (m, 3 H), 7.03 (d, 1 H), 6.88 (m, 2 H), 6.79 (s, 1 H), 6.71 (d, 1 H), 6.58 (d, 1 H), 4.51 (t, 2H), 4.25 (s, 2H), 4.21 (s, 2H), 3.64 (s, 3H), 3.08 (t, 2H) 2.80 (t, 2H), 2.50 (t, 2H).

Step B: Hydrolysis of the ester Acid 3- (3. {[[(2,3-dihydro-benzofuran-5-ylmethyl) -P- (4-fluoro-benzene-sulfonyl-P-aminol-methyP-phenyl-propionic The title compound was prepared following the procedure described in Example 1, step C from 3- (3. {[[(2,3-dihydro-benzofuran-5-ylmethyl) - (4-fluoro) methyl ester -benzenesulfonyl) -amino] -methyl]. phenyl) -propionic from step A. H NMR (400 MHz, CDCl 3) d 7.79 (m, 2 H), 7.14 (m, 3 H), 7.03 (d, 1 H) , 6.89 (m, 2H), 6.79 (s, 1 H), 6.70 (d, 1 H), 6.58 (d, 1 H), 4.51 (t, 2H), 4.25 (s, 2H), 4.20 (s, 2H), 3.07 (t, 2H), 2.81 (t, 2H), 2.55 (t, 2H), EM 468 (M-1).

EXAMPLE 12z 3- (3-Ff-benzenesulfonyl- (4-isobutyl-benzy-P-amino-1-methyl-phenyl-propionic acid Step A: Reductive amination (3- (3 - [(4-Isobutyl-benzylamino) -methyl-phenyl-propionic acid methyl ester A solution of the hydrochloride salt of 3- (3- (3-methyl) methyl ester aminomethyl-phenyl) -propionic acid (400 mg, 1.74 mmol), 4-isobutylbenzaldehyde (311 mg, 1.91 mmol) and triethylamine (0.26 mL, 1.91 mmol) in CH 2 Cl 2 (4 mL) was stirred at room temperature for 4 h Sodium triacetoxyborohydride (590 mg, 2.78 mmol) was added and the reaction was stirred for 20 h, aqueous NaHCO 3 was added and the aqueous solution was washed with CH 2 Cl 2, the organic solution was dried (MgSO 4), filtered and concentrated. Flash chromatography (65% AcOEt in hexanes) gave the title compound from step A (178 mg). 1 H NMR (400 MHz, CDCl 3) d 7.26-7.04 (m, 8H), 3.77 (s, 2H), 3.75 ( s, 2H), 3.63 (s, 3H), 2.91 (t, 2H), 2.60 (t, 2H), 2.41 (d, 2H), 1.80 (m, 1 H), 0.85 (m, 6H), EM 340 (M + 1) Step B: Formation of amide 3- (3- (f-benzenesulfonyl- (4-isobutyl-benzyl-P-aminol-methyP-phenyl-propionic acid methyl ester) The title compound of step B was prepared following the procedure described in step A of example 1 from 3- ({3 - [(4-isobutyl-benzylamino) -methyl] -phenyl} -phenyl] -propionic acid methyl ester from step A and benzenesulfonyl chloride using triethylamine Instead of N, N-diisopropylethylamine, 1 H NMR (400 MHz, CDCl 3) d 7.83 (dd, 2H), 7.57 (m, 1 H), 7.52 (m, 2H), 7.11 (m, 1 H), 7.03- 6.86 (m, 6H), 6.79 (s, 1 H), 4.29 (s, 2H), 4.28 (s, 2H), 3.67 (s, 3H), 2.80 (t, 2H), 2.50 (t, 2H), 2.40 (d, 2H), 1.80 (m, 1 H), 0.86 (m, 6H), MS 480 (M + 1).

Step C: Hydrolysis of the ester 3- (3. {[[Benzenesulfonyl- (4-isobutyl-benzyl) -amino] -methyl-phenyl-propionic acid The title compound was prepared following the procedure described in example 1, step C from the 3- (3. {[[Benzenesulfonyl- (4-isobutyl-benzyl) -amino] -methyl] -phenyl) -propionic acid methyl ester from step B. 1 H NMR (400 MHz , CDCI3) d 7.82 (d, 2H), 7.58-7.46 (m, 3H), 7.10 (m, 1 H), 7.02-6.84 (m, 6H), 6.78 (s, 1 H), 4.27 (s, 2H ), 4.26 (s, 2H), 2.79 (t, 2H), 2.53 (t, 2H), 2.38 (d, 2H), 1.77 (m, 1 H), 0.84 (m, 6H), EM464 (M-1) ).

EXAMPLES 13a-z. 14a-14e Examples 13a-z, 14a-14e were prepared from the corresponding starting materials analogously to the procedure of Example 3, with the variations in reaction time, reagents and temperature cited.

EXAMPLE 13a (3- (1-Benzenesulfonyl- (4-pyrazol-1-yl-benzyl-aminol-methy-D-phenox-acetic acid) hydrochloride salt Step A: Reductive amination (3 - [(4-pyrazol-1-yl-benzylamino) -methyl-1-phenoxyacetic acid tert-butyl ester The title compound of step A was prepared from the tert-butyl ester of the (3-aminomethyl-phenoxy) -acetic acid of preparation 20 and 4-pyrazol-1-yl-benzaldehyde of preparation 42, using the procedure described in example 3, step A, except that it was not used triethylamine 1 H NMR (400 MHz, CDCl 3) d 7.90 (m, 1 H), 7.70 (m, 1 H), 7.63 (d, 2 H), 7.41 (d, 2 H), 7.23 (m, 1 H), 6.94 (m, 2H), 6.78 (dd, 1 H), 6.44 (dd, 1 H), 4.51 (s, 2H), 3.81 (s, 2H), 3.77 (s, 2H), 1.47 (s, 9H); MS 394 (M + 1).

Step B: Formation of amide (3- {[[Benzenesulfonyl- (4-pyrazol-1-yl-benzyl) -amino-1-methyl-phenoxy) -acetic acid tert-butyl ester The title compound of Step B prepared from the tert-butyl ester of the acid. { 3 - [(4-pyrazol-1-yl-benzylamino) -methyl] -phenoxy} -acetic of step A and benzenesulfonyl chloride following the procedure described in example 3, step B, with a reaction time of 2h. 1 H NMR (400 MHz, CDCl 3) d 8.01 (d, 1 H), 7.86-7.49 (m, 8 H), 7.07 (m, 3 H), 6.73 (m, 1 H), 6.60 (d, 1 H), 6.56 (s, 1 H), 6.42 (m, 1 H), 4.33 (s, 2H), 4.32 (s, 2H), 4.27 (s, 2H), 1.46 (s, 9H); MS 534 (M + 1).

Step C: Hydrolysis of the ester (3- (F-benzenesulfonyl- (4-pyrazol-1-yl-benzopyaminol-methyP-phenoxyp-acetic acid) hydrochloride salt The TFA salt was prepared following the procedure described in Example 3, step C from the (3- {[[benzenesulfonyl- (4-pyrazol-1-yl-benzyl) -amino] -methyl} -phenoxy) -acetic acid tert-butyl ester of step B. The salt HCl was prepared by dissolving the TFA salt in THF (2 ml) followed by the addition of 0.18 ml of 1 N HCl. The solution was concentrated in vacuo, azeotroped with CH2Cl2 (3x) to give the title compound.1H-NMR (400 MHz , CDCI3) d 8.16 (d, 1 H), 7.89-7.51 (m, 8H), 7.17 (d, 2H), 7.06 (t, 1 H), 6.73 (dd, 1 H), 6.67 (d, 1 H ), 6.59 (s, 1 H), 6.52 (m, 1 H), 4.46 (s, 2H), 4.34 (s, 2H), 4.29 (s, 2H), 1.46 (s, 9H), EM 476 (M -1).

EXAMPLE 13b (3- ({r (4-pyrazyl-2-yl-benzyl- (pyridine-3-sulfonyl-D-aminol-methyl-pheno-p-acetic acid) hydrochloride salt Step A: Reductive amination (3 - [(4-pyrazin-2-yl-benzyl-amine) -methyl-phenoxyacetic acid tert-butyl ester The title compound of step A was prepared from the tertiary ester. -butylic acid (3-aminomethyl-phenoxy) -acetic acid of preparation 20 and 4-pyrazin-2-yl-benzaldehyde of preparation 27 using the procedure described in example 3, step A, except that no triethylamine was used, 1 H NMR (400 MHz, CDCl 3) d 9.00 (s, 1 H), 8.60 (m, 1 H), 8.47 (d, 1 H), 7.96 (d, 2 H), 7.62 (m, 1 H ), 7.47 (d, 2H), 7.22 (m, 1 H), 6.94 (m, 1 H), 6.76 (dd, 1 H), 4.50 (s, 2H), 3.85 (s, 2H), 3.78 (s) 2H), 1.46 (s, 9H), MS 406 (M + 1).

Step B: Formation of the amide (3 - ([(4-pyrazin-2-yl-benzyl) - (pyridin-3-sulfonyl) -amino] -met-P-phenoxy) tert-butyl ester The title compound of Step B was prepared from the tert-butyl ester of the acid. {3 - [(4-pyrazin-2-yl-benzyl-amino) -methyl] -phenoxy) - of step A and the pyridine-3-sulfonyl chloride hydrochloride of preparation 2, following the procedure described in example 3, step B. 1 H NMR (400 MHz, CDCl 3) d 9.05 (s, 1 H), 8.97 (m, 1 H), 8.78 (m, 1 H), 8.60 (m, 1 H), 8.50 (d, 1 H), 8.03 (m, 1 H), 7.88 (m, 2H), 7.42 (m, 1 H), 7.23 (m, 2H), 7.13 (m, 1 H), 6.66 (m, 1 H), 6.65 (m, 2H), 4.43 ( s, 2H), 4.39 (s, 2H), 4.35 (s, 2H), 1.47 (s, 9H); EM 547 (M + 1).

Step C: Hydrolysis of the ester (3 - ([(4-pyrazin-2-yl-benzyl- (pyridin-3-sulfonyl) -amino] -methyl-phenoxy) -acid acid hydrochloride salt The title compound was prepared following the procedure described in Example 3, step C, from (3- {[[(4-p¡razin-2-yl-benzyl) - tert -butyl ester) (pyridin-3-sulfonyl) -amino] -methyl] -phenoxy) -acetic acid from step B. The HCl salt was prepared following the procedure described in step C of example 13a to give the title compound. MHz, CD3OD) d 9.25 (s, 1 H), 9.16 (d, 1 H), 9.00 (m, 2H), 8.87 (d, 1 H), 8.66 (d, 1 H), 8.17 (m, 1 H ), 8.04 (m, 2H), 7.45 (m, 2H), 7.10 (m, 1 H), 6.81 (d, 1 H), 6.73 (m, 2H), 4.60 (s, 2H), 4.55 (s, 2H), 4.50 (s, 2H), MS 489 (M-1). < «& & EXAMPLE 13c TFA acid from (3- {R (4-pyrrazol-1-yl-benzyl- (pyridine-3-2-sulfonopropic) amino-1-methyl-phenoxy-acetic acid Step A: Formation of amide (3. {F (4-pyrrazol-1-yl-benzyl) - (pyridyl-2-sulfonopropylamine-methyl-phenoxyphenyl) tert-butyl ester -acetic The title compound of step A was prepared from the tert-butyl ester of. {3 - [(pyrazol-1-yl-benzylamino) -methyl] -phenoxy) -acetic acid from step A of example 13a and pyridine-2-sulfonyl chloride hydrochloride of preparation 47, following the procedure described in example 3, step B, with a reaction time of 2 h. 1 H NMR (400 MHz, CDCl 3) d 8.66 (m, 1 H ), 7.95 (d, 1 H), 7.85 (m, 2H), 7.68 (d, 1 H), 7.49 (d, 2H), 7.45 (m, 1 H), 7.16 (d, 2H), 7.08 (t , 1 H), 6.70 (m, 3H), 6.43 (m, 1 H), 4.49 (s, 2H), 4.44 (s, 2H), 4.38 (s, 2H), 1.46 (s, 9H), EM 535 (M + 1) Step B: Hydrolysis of the ester (3. {F (4-Pyrazol-1-yl-benzyl-pyridin-2-sulfonyl-D-aminol-methyn-phenox-acetic acid) TFA The title compound was prepared following the procedure described in example 3, step C from (3- {[[(4-pyrazol-1-yl-benzyl) - (pyridin-2-sulfonyl) -amino] -methyl tert-butyl ester] -phenoxy.) -acetic from step A. 1 H NMR (400 MHz, CD 3 OD) d 8.68 (m, 1 H), 8.15 (m, 1 H), 7.96 (m, 2 H), 7.68 (d, 1 H), 7.60 (m, 1 H), 7.55 (d, 2H), 7.24 (d, 2H), 7.09 (t, 1 H), 6.73 (m, 3H), 6.49 (m, 1 H), 4.52 ( s, 2H), 4.49 (s, 2H), 4.46 (s, 2H), EM 477 (M-1).

EXAMPLE 13d Sodium salt of the acid (3-benzenesulfonyl- (4-pyridin-2-yl-benzy-P-amino-1-methyl-phenop-acetic acid) Step A: Reductive amination (3- {[[(4-pyridin-2-yl-benzyllamine) -methanol-phenoxy-acetic acid tert-butyl ester The title compound from step A was prepared from the (3-aminomethyl-phenoxy) -acetic acid tert-butyl ester of preparation 20 and 4-pyridin-2-ylbenzaldehyde of preparation 22 using the procedure described in Example 3, step A , with the exception that triethylamine was not used, 1 H NMR (400 MHz, CDCl 3) d 8.67 (d, 1 H), 7.94 (d, 2 H), 7.72 (m, 2 H), 7.44 (d, 2 H), 7.22 (m, 2H), 6.95 (m, 2H), 6.78 (dd, 1 H), 4.51 (s, 2H), 3.84 (s, 2H), 3.78 (s, 2H), 1.47 (s, 9H); 405 (M + 1).

Step B: Formation of the amide (3- (f-benzenesulfonyl- (4-pyridin-2-yl-benzyl-methylamino-p-phenox-acetic acid) tert-butyl ester The title compound of step B was prepared from the ester (. 3 - [(4-pyridin-2-yl-benzylamino) -methyl] -phenoxy] -acetic acid tert-butyl ester of step A and benzenesulfonyl chloride following the procedure described in example 3, step B 1 H NMR (400 MHz, CDCl 3) d 8.67 (d, 1 H), 7.86 (m, 4 H), 7.77-7.51 (m, 5 H), 7.24 (m, 1 H), 7.11 (m, 3 H), 6.76 (dd, 1 H), 6.64 (d, 1 H), 6.59 (d, 1 H), 4.38 (s, 2H), 4.35 (s, 2H), 4.30 (s, 2H), 1.48 (s, 9H); EM 545 (M + 1).

Step C: Hydrolysis of the ester Sodium salt of (3. {F-benzenesulfonyl- (4-pyridin-2-yl-benzD-aminol-methy-D-phenox-acetic acid The title compound was prepared following the procedure described in Example 3, step C from the (3- {[[benzenesulfonyl- (4-pyridin-2-yl-benzyl) -amino] -methyl} -phenoxy) -acetic acid tert-butyl ester of He passed B. The TFA salt was diluted with AcOEt and water and the aqueous solution was made alkaline to about pH 11 with NaOH (1 N). The aqueous solution was acidified with glacial acetic acid to approximately pH 5 and washed with AcOEt (3x). The organic solution was dried (MgSO), filtered and concentrated, azeotroping with toluene, giving the free acid (128 mg), The acid was dissolved in a mixture of acetone (4 ml), MeOH (4 ml) and added water (0.5 ml) and NaHCO 3 (22 mg, 0.258 mmol). The reaction was stirred for 24 h and concentrated in vacuo, azeotroping with EtOH (3x) and CHCl3 (1x) to give the title sodium salt (137 mg). 1 H NMR (400 MHz, CD3OD) d 8.56 (dd, 1 H), 7.89-7.76 (m, 6H), 7.65-7.56 (m, 3H), 7.33 (m, 1 H), 7.21 (d, 2H), 7.05 (t, 1 H), 6.74 (d, 1 H), 6.63 (m, 2H), 4.40 (s, 2H), 4.31 (s, 2H), 4.21 (s, 2H); MS 487 (M-1). gg EXAMPLE 13e Sodium salt of the acid (3-benzenesulfonyl- (4-pyridin-3-yl-benzyl-amino-1-methyl-pheno-p-acetic) Step A: Reductive amination (3 - [(4-pyridin-3-yl-benzylamine) -metn-phenoxyacetic acid tert-butyl ester The title compound of step A was prepared from the tertiary ester. -butylic acid (3-aminomethyl-phenoxy) -acetic acid of preparation 20 and 4-pyrridin-3-yl-benzaldehyde of preparation 23 using the procedure described in example 3, step A, except that no used triethylamine, 1 H NMR (400 MHz, CDCl 3) d 8.82 (d, 1 H), 8.56 (m, 1 H), 7.85 (m, 1 H), 7.53 (d, 2 H), 7.45 (d, 2 H), 7.34 (d, 2 H). m, 1H), 7.24 (m, 1 H), 6.96 (m, 2H), 6.78 (dd, 1 H), 4.51 (s, 2H), 3.84 (s, 2H), 3.80 (s, 2H), 1.47 (s, 9H); MS 405 (M + 1).

Step B: Formation of amide (3- {[[Benzenesulfonyl- (4-pyridin-3-yl-benzyl-D-amino] -methyl-phenoxy) -acetic acid tert-butyl ester The title compound of step B was prepared from the tert-butyl ester of. {3 .3. {[[(4-pyridin-3-yl-benzylamino) -methyl] -phenoxy] -acetic acid from step A and benzenesulfonyl chloride following the procedure described in Example 3, step B. 1 H NMR (400 MHz, CDCl 3) d 8.80 (s, 1 H), 8.59 (d, 1 H), 7. 89 (m, 3H), 7.60 (m, 1 H), 7.50 (m, 2H), 7.41 (m, 3H), 7.17 (d, 2H), 7.10 (t, 1 H), 6.74 (m, 1 H) ), 6.64 (d, 1 H), 6.58 (d, 1 H), 4.37 (s, 2H), 4.34 (s, 2H), 4.32 (s, 2H), 1.48 (s, 9H); EM 545 (M + 1).

Step C: Hydrolysis of the ester Sodium salt of (3 - ([Benzenesulfonyl- (4-pyridin-3-yl-benzyl-P-aminol-methyP-phenox-acetic acid) The title compound was prepared following the procedure described in Example 3, step C from (3- {[[benzenesulfonyl] -1- (4-pyridin-3-yl-benzyl) -amino] -methyl} -phenoxy) -acetic acid tert-butyl ester from step B. The sodium salt was prepared following the procedure described in step C of example 13d. 1H-NMR (400 MHz, CD3OD) d 8.74 (s, 1 H), 8.48 (d, 1H), 8.05 (dd, 1H). ), 7.88 (dd, 2H), 7.67-7.47 (m, 6H), 7.23 (d, 2H), 7.05 (t, 1H), 6.74 (d, 1H), 6.63 (d, 1H), 6.59 (s, 1H), 4.39 (s, 2H), 4.30 (s, 2H), 4.20 (s, 2H), MS 487 (M-1).

EXAMPLE 13f Sodium salt of the acid (3-Ubenzenesulfonyl- (4-pyridin-4-yl-benzyl-D-amino-1-methyl-phenop-acetic acid Step A: Reductive amination 3- (3. (4-pyridin-4-yl-benzyl-amino) -methyl-phenoxy-acetic acid tert-butyl ester The title compound of step A was prepared from the (3-aminomethyl-phenoxy) -acetic acid tert-butyl ester of preparation 20 and 4-pyridin-4-yl-benzaldehyde of preparation 24, using the procedure described in example 3, step A, with the exception that triethylamine was not used, 1 H NMR (400 MHz, CDCl 3) d 8.63 (dd, 2H), 7.60 (dd, 2H), 7.47 (m, 4H), 7.24 (m, 1 H), 6.96 ( m, 2H), 6.78 (dd, 1 H), 4.52 (s, 2H), 3.85 (s, 2H), 3.80 (s, 2H), 1.47 (s, 9H), MS 405 (M + 1).

Step B: Formation of the amide (3- ({fbenzenesulfonyl- (4-pyridin-4-yl-benzy-p-aminol-methyP-phenop-acetic acid) tert-butyl ester The title compound of step B was prepared from the. {3 - [(4-pyridin-4-yl-benzylamino) -methyl] -phenoxy) -acetic acid tert-butyl ester of step A and benzenesulfonyl chloride using the procedure described in example 3, step B with a reaction time of 3 h. 1 H NMR (400 MHz, CDCl 3) d 8.63 (d, 2 H), 7.86 (dd, 2 H), 7.62-7.46 (m, 7 H), 7.17 (d, 2 H), 7.07 (t, 1 H), 6.71 (dd) , 1 H), 6.60 (d, 1 H), 6.54 (s, 1 H), 4.35 (s, 2H), 4.32 (s, 2H), 4.29 (s, 2H), 1.46 (s, 9H); EM 545 (M + 1).

Step C: Hydrolysis of the ester Sodium salt of (3. {[[Benzenesulfonyl] - (4-pyridin-4-yl-benzyl-P-aminol-methyP-phenoxy-acetic acid The title compound was prepared following the procedure described in Example 3, step C, from (3- {[[benzenesulfonyl- (4-pyridin-4-yl-benzyl) -amino] -methyl} -phenoxy-tert-butyl ester. ) -acetic from step B. The sodium salt was prepared following the procedure described in step C of example 13d. 1H-NMR (400 MHz, CD3OD) d 8.56 (br s, 2H), 7.89 (d, 2H), 7.68-7.59 (m, 7H), 7.25 (d, 2H), 7.04 (t, 1H), 6.74 (d, 1 H), 6.63 (d, 1 H), 6.59 (s, 1 H), 4.39 (s, 2H) 4.30 (s, 2H), 4.20 (s, 2H), MS 487 (M-1).

EXAMPLE 13q (3- ({f (pyridin-3-sulfonyl) - (4-pyrimidin-5-yl-benzopropylamine-methyl-phenoxy-acetic acid) hydrochloride salt Step A: Reductive amination (3 - [(4-pyrimidin-5-yl-benzylamino) -methyl-1-phenoxyacetic acid butyl ester The title compound of step A was prepared from the tert-butyl ester of the (3-aminomethyl-phenoxy) -acetic acid of preparation 20 and 4-pyrimidin-5-yl-benzaldehyde of preparation 26, using the procedure described in example 3, step A, with the exception that the time of reaction for imine formation was 1.5 h and triethylamine was not used 1 H NMR (400 MHz, CDCl 3) d 9.18 (s, 1 H), 8.93 (s, 2 H), 7.65 (m, 1 H), 7.48 ( m, 3H), 7.24 (m, 1 H), 6.94 (m, 2H), 6.77 (d, 1 H), 4.51 (s, 2H), 3.85 (s, 2H), 3.79 (s, 2H), 1.46 (s, 9H), MS 406 (M + 1).

Step B: formulation of amide (3- (l- (pyridin-3-sulfoniD- (4-pyrimidin-5-yl-benzyl) -amino] -methyl-phenoxy) -acetic acid tert-butyl ester of the title of step B was prepared from the. {3 - [(4-pyrimidin-5-yl-benzylamino) -methyl] -phenoxy] -acetic acid tert-butyl ester of step A and pyridine-3-sulfonyl chloride hydrochloride of preparation 2, following the procedure described in example 3, step B. 1 H NMR (400 MHz, CDCl 3) d 9.19 (s, 1 H), 9.05 (s, 1 H) , 8.89 (s, 2H), 8.79 (dd, 1 H), 8.06 (m, 1 H), 7.65 (m, 1 H), 7.44 (m, 2H), 7.24 (m, 2H), 7.12 (t, 1 H), 6.74 (dd, 1 H), 6.66 (m, 2H), 4.42 (s, 2H), 4.39 (s, 2H), 4.34 (s, 2H), 1.47 (s, 9H), EM 547 ( M + 1).

Step C: Ester hydrolysis 3-hydrochloride salt. { [pyridine-3-sulfonyl] -4-pyrimidin-5-yl-benzyl-amino-methyl-phenoxy-acetic acid The title compound was prepared following the procedure described in example 3, step C, starting from (3- {[[pyridin-3-sulfonyl) - (4-pyrimidin-5-yl-benzyl) -amino] -methyl tert-butyl ester} -phenoxy) -acetic from step B. The HCl salt was prepared following the procedure described in step C of example 13a. 1 H NMR (400 MHz, CDCl 3) d 9.40 (s, 2 H), 9.17 (m, 1 H), 9.00 (m, 1 H), 8.80 (m, 1 H), 8.11 (m, 1 H), 7.72- 7.29 (m, 5H), 7.1 1 1 h (m, 1 H), 6.80-6.65 (m, 3H), 4.65 (s, 2H), 4.55 (s, 2H), 4.47 (s, 2H); MS 489 (M-1).

EXAMPLE 13h (3-fy (4-pyrrazol-1-yl-benzyl- (pyridine-3-sulfonopropyl) p-aminolmethyl-phenoxyacetic acid hydrochloride salt Step A: Reductive amination Tert-butyl acid ester. { 3 - [(4-Pι-potol-1-yl-ben-cylamino) -methyl-phenox-acetic acid The title compound of step A was prepared from the tert-butyl ester of (3-aminomethyl-phenoxy) - of preparation 20 and 4-pyrazol-1-yl-benzaldehyde of preparation 42, using the procedure described in example 3, step A, with the exception that triethylamine was not used. 1 H NMR (400 MHz, CDCl 3) d 7.89 (m, 1 H), 7.68 (m, 1 H), 7.63 (d, 2 H), 7.41 (d, 2 H), 7.23 (m, 1 H), 6.93 (m , 2H), 6.77 (dd, 1 H), 6.44 (m, 1 H), 4.50 (s, 2H), 3.81 (s, 2), 3.77 (s, 2H), 1.47 (s, 9H); MS 394 (M + 1).

Step B: Formation of the amide (3- {f (4-pyrazol-1-yl-benzyl) - (pyridin-3-sulfonyl) -amino) - tert-butyl ester met.P-phenoxy) -acetic The title compound of step B was prepared from the tert-butyl ester of the acid. { 3 - [(4-pyrazol-1-yl-benzylamino) -methyl] -phenoxy) -acetic acid from step A and the pyridine-3-sulfonyl chloride hydrochloride of preparation 2, following the procedure described in the example 3, step B with a reaction time of 2h. 1 H NMR (400 MHz, CDCl 3) d 9.05 (S, 1 H), 8.78 (d, 1 H), 8.03 (dd, 1 H), 7.88 (m, 1 H), 7.69 (m, 1 H), 7.55 ( d, 2H), 7.42 (m, 1 H), 7.13 (m, 3H), 6.76 (d, 1 H) 6.66 (m, 2H), 6.45 (m, 1 H), 4.39 (s, 2H), 4.38 (s, 2H), 4.33 (s, 2H), 1.47 (s, 9H); MS 535 (M + 1).

Step C: Hydrolysis of the ester (3- (l- (4-pyrazol-1-yl-benzyl- (pyridine-3-sulfoniP-aminolmethyl-phenox-) acetic acid hydrochloride The title compound was prepared following the procedure described in Example 3, step C, from (3- {[[(4-pyrazol-1-yl-benzyl) - (pyridin-3-sulfonyl) -amono] -methyl tert-butyl ester]. -phenoxy) -acetic from step B. The HCl salt was prepared following the procedure described in step C of example 13a.1 H NMR (400 MHz, CDCl 3) d 9.15 (m, 1 H), 9.02 (m, 1 H ), 8.88 (m, 1H), 8.26 (m, 1H), 8.18 (m, 1H), 7.82 (m, 1H), 7.63 (m, 2H), 7.39 (m, 2H), 7.12 (t, 1H) 6.82-6.72 (m, 3H), 6.58 (m, 1H), 4.63 (s, 2H), 4.62 (s, 2H), 4.49 (s, 2H), EM 477 (M-1).

EXAMPLE 13i Acid (3- { R (4-Chloro-benzenesulfoniP- (4-thiazol-2-yl-benzop-amino-1-methyl-phenop-acetic) Step A: Reductive amination Tert-butyl acid ester. { 3-α (4-thiazol-2-yl-benzyl-amino) -methyl-1-phenox-acetic acid The title compound of step A was prepared from the tert-butyl ester of (3-aminomethyl-phenoxy) -acetic acid of Preparation 20 and 4-thiazol-2-yl-benzaldehyde of Preparation 25, following the procedure described in Example 3, Step A, with the exception that triethylamine was not used. 1 H NMR (400 MHz, CDCl 3) d 7.90 (d, 2 H), 7.82 (d, 1 H), 7.39 (d, 2 H), 7.28 (d, 1 H), 7.22 (m, 1 H), 6.92 (m , 2H), 6.77 (m, 1 H), 4.50 (s, 2H), 3.80 (s, 2H), 3.76 (s, 2H), 1.46 (s, 9H); MS 411 (M + 1).

Step B: formation of the amide (3- (f (4-Chloro-benzenesulfonyl) - (4-thiazol-2-yl-benzyl) -amino-meth-P-phenoxy) tert-butyl ester The title compound of step B was prepared from the tert-butyl ester of 3 - [(4-thiazol-2-yl-benzylamino) -methyl] phenoxy] -acetic acid. A and 4-benzenesulfonyl chloride following the procedure described in example 3, step B, with a reaction time of 96 hrs, EM 584 (M + 1).

Step C: Ester hydrolysis Acid (3- { [(4-Chloro-benzenesulfoniP- (4-thiazol-2-yl-benzyl-P-amino-1-methyl-pheno-P-acetic acid) To the tert-butyl ester of the acid-3 - { [(4-Chloro-benzenesulfonyl) - (4-thiazol-2-yl-benzyl) -amino] -methyl] -phenoxy) -acetic acid (48 mg) from step B was added HCl in dioxane (4M, 3 ml) at room temperature for 24 h The reaction was concentrated in vacuo, azeotroped with CH 2 Cl 2 to give the title compound (32 mg). 1 H NMR (400 MHz, CDCl 3) d 8.20-6.80 (m, 11) H), 6.75 (s, 1 H), 6.65 (s, 1 H) 6.38 (s, 1 H), 4.50 (s, 2H), 4.23 (s, 2H), 4.16 (s, 2H), EM 526 (s) m-1).

EXAMPLE 13i (3-Ff-benzenesulfonyl- (4-pyrazin-2-yl-benzyl) -amino-methyl-phenoxyp-acetic acid hydrochloride salt Step A: Formation of the amide (3 - ([(Benzenesulfonyl- (4-pyrazin-2-yl-benz-p-aminol-methyP-phenop-acetic) tert-butyl ester The title compound of step A was prepared at from the. {3 - [(4-pyrazin-2-yl-benzylamino) -methyl] -phenoxy] -acetic acid tert-butyl ester prepared in step A of example 13b and benzenesulfonyl chloride following the procedure described in example 3, step B. 1 H NMR (400 MHz, CDCl 3) d 8.97 (s, 1 H), 8.60 j (m, 1 H), 8.49 (m, 1 H), 7.87 (m, 4 H) , 7.61-7.51 (m, 3H), 7.26-7.08 (m, 3H), 6.75 (m, 1 H), 6.63 (m, 1 H), 6.58 (m, 1H), 4.38 (s, 2H), 4.34 (s, 2H), 4.31 (s, 2H), 1.47 (s, 9H), EM 546 (M + 1).

Step B: Hydrolysis of the ester (3- {[[Benzenesulfonyl-4-pyrazin-2-yl-benz-P-aminol-methyl-pheno-p-acetic acid] hydrochloride] The title compound was prepared following the procedure described in example 3, Step C, from the step (3. {[[benzenesulfonyl) - (4-pyrrazin-2-yl-benzyl) -amino] -methyl] -phenoxy) -acetic acid tert-butyl ester of step A. The HCl salt was prepared following the procedure described in step C of example 13a, 1 H NMR (400 MHz, CDCl 3) d 9.18 (s, 1 H), 8.91 (s, 1 H), 8.62 (s, 1 H ), 7.91 (m, 4H), 7.69-7.58 (m, 3H), 7.26 (m, 2H), 7.05 (m, 1 H), 6.69 (m, 2H), 6.57 (m, 1 H), 4.48 ( s, 2H), 4.38 (s, 2H), 4.30 (s, 2H), MS 488 (M-1).

EXAMPLE 13k (3-f f (1-methyl-1 H-imidazole-4-sulfonyl) - (4-pyrazol-1-yl-benzopylamine-methyl-phenoxy-acetic acid) hydrochloride salt Step A: formation of the amide (3- {f (1-methyl-1 H-imidazole-4-sulfonyl) - (4-pyrazol-1-yl-benzyl) -amino} - tert-butyl ester met.P-phenoxy) -acetic The title compound of step A was prepared from the tert-butyl ester of the acid. { 3 [(4-pyrazol-1-yl-benzylamino) -methyl] -phenoxy} -acetic, prepared in step A of example 13h and the chloride of 1-methyl-1H-imidazole-4- ¿UU¿toak sulfonyl following the procedure described in example 3, step B with a reaction time of 2 h. 1 H NMR (400 MHz, CDCl 3) d 7.87 (d, 1 H), 7.67 (d, 1 H), 7.52 (d, 2 H), 7.48 (d, 1 H), 7.37 (d, 1 H), 7.23 (d. d, 2H), 7.10 (t, 1 H), 6.73 (m, 3H), 6.42 (m, 1 H), 4.41 (s, 4H), 4.36 (s, 2H), 3.70 (s, 3H), 1.46 (s, 9H); MS 538 (M + 1).

Step B: Hydrolysis of the ester (3 - ([(1-methyl-1 H-imidazol-4-pyrazol-1-yl-benz-p-aminol-metiP-phenox-acetic acid) hydrochloride The title compound was prepared following the procedure described in Example 3, step C, from (3- {[[(1-methyl-1 H-imidazole-4-sulfonyl) - (4-pyrrazol-1-tert -butyl) -silyl ester yl-benzyl) -amino] -methyl!} - phenoxy) -acetic from step B. The HCl was prepared following the procedure described in step C of example 13a, EM 480 (M-1).

EXAMPLE 131 (3-Fibenzenesulfonium D- (4-imidazol-1-yl-benzyl-P-aminol-methyl-phenox-acetic acid) hydrochloride salt Step A: Reductive amination Tert-butyl acid ester. { 3-f (4-imidazol-1-yl-benzylamino) -methyl-phenoxy-acetic acid The title compound of step A was prepared from the (3-aminomethyl-phenoxy) -acetic acid tert-butyl ester of the preparation 20 and 4-imidazol-1-yl-benzaldehyde of preparation 43, using the procedure described in example 3, step A, with the exception that triethylamine was not used. 1 H NMR (400 MHz, CDCl 3) d 7.78 (s, 1 H), 7.40 (d, 2 H), 7.28 (d, 2 H), 7.22 (m, 2 H), 7.13 (m, 1 H), 6.89 (m, 2H), 6.73 (m, 1 H), 4.47 (s, 2H), 3.78 (s, 2H), 3.74 (s, 2H), 1.43 (s, 9H); MS 394 (M + 1).

Step B: Formation of the amide (3- (F-benzenesulfonyl-4-imidazol-1-yl-benz-P-aminol-methyl-p-phenox-acetic acid tert-butyl ester) The title compound of step B was prepared from the tert-butyl ester of the { 3 - [(4-imidazol-1-yl-benzylamino) -methyl] -phenoxy) -acetic acid from step A and benzenesulfonyl chloride following the procedure described in example 3, step B. 1 H-NMR (400 MHz, CDCl 3) d 7.86 (m, 3H), 7.62-7.52 (m, 3H), 7.22 (m, 6H), 7.15 (t, 1 H), 6.71 (d, 1 H), 6.61 (d, 1 H ), 6.56 (s, I); EM 534 (M + 1).

Step C: Hydrolysis of the ester (3- {[[benzenesulfonyl- (4-methyl-1-yl-benz-p-aminol-methyl-phenoxyp-acetic acid) hydrochloride The title compound was prepared following the procedure described in Example 3, step C, from (3- {[[benzenesulfonyl- (4-imidazol-1-yl-benzyl) -amino] -methyl} -phenoxy) -acetic acid tert-butyl ester from step B. The HCl salt was prepared following the procedure described in step C of example 13a. 1 H NMR (400 MHz, CDCl 3) d 9.67 (s, 1 H), 7.91 (d, 2 H), 7.67-7.59 (m , 3H), 7.46 (s, 1 H), 7.33 (s, 1 H), 7.27-7.18 (m, 4H), 6.85 (t, 1 H), 6.74 (s, 1 H), 6.67 (d, 1 H), 6.34 (dd, 1H), 4.58 (s, 2H), 4.36 (s, 2H), 4.26 (s, 2H), EM 476 (M-1).

EXAMPLE 13m (3-fí (4-imidazol-1-yl-benzyl) - (pyridin-3-sulfonyl) -aminol-methyP-phenox-acetic acid hydrochloride salt Step A: Formation of amide (3- (f (4-imidazol-1-yl-benzyl-pyridin-3-sulfonyl) -amino] -methyl-phenoxy-acetic acid tert-butyl ester The title compound of step A was prepared from the tert-butyl ester of. {3- [4-imidazol-1-yl-benzylamino) -methyl] -phenoxy] -acetic acid, prepared in step A of example 131 and the hydrochloride of the pyridine-3-sulfonyl chloride of preparation 2, following the procedure described in example 3, step B. 1 H NMR (400 MHz, CDCl 3) d 9.04 (d, 1H), 8.80 (dd, 1H), 8.06 ( d, 1 H), 7.83 (s, 1 H), 7.44 (dd, 1 H), 7.22 (m, 6H), 7.11 (t, 1 H), 6.73 (dd, 1 H), 6.64 (m, 2H ), 4.39 (s, 2H), 4.38 (s, 2H), 4.32 (s, 2H), 1.47 (s, 9H).

Step B: Hydrolysis of the ester (3- (r (4-Midazol-1-yl-benzyl) -pyridin-3-sulfonyl-d-aminol-methyP-phenoxyacetic acid hydrochloride The title compound is prepared following the procedure described in example 3, Step C, from (3- {[[(4-imidazol-1-yl-benzyl) - (pyridin-3-sulfonyl) -amino] -methyl} -phenoxy) tert-butyl ester) -acetic of step B. The HCl salt was prepared following the procedure described in step C of example 13a. 1 H-NMR (400 MHz, CDCI 3 OD, selected peaks) d 4.67 (s, 2 H), 4.58 (s, 2 H), 4.48 (s, 2 H); MS 477 (M-1).

EXAMPLE 13n (3- (R (4-pyrazol-1-yl-benzyl- (thiophene-2-sulfonopylamino-methyl-phenoxy-acetic acid) hydrochloride salt Step A: Formation of the amide (3 - ([(4-pyrazol-1-yl-benzyl- (thiophene-2-sulfoniD-aminoHenoxp-acetic) tert-butyl ester To a solution of the tert-butyl acid ester [ {.3 - [(4-pyrazol-1-yl-benzylamino) -methyl] -phenoxy} -acetic acid (78.9 mg, 0.200 mmol) prepared in step A of example 13a, triethylamine (44.6 mg, 0.221 mmol) ) and dichloroethane (10 ml) was added thiophene-2-sulfonyl chloride (40.3 mg, 0.221 mmol) After stirring for 24 h at room temperature the reaction was heated to reflux for 24 h and cooled to room temperature. washed sequentially with 5.5% HCl, water, a saturated solution of sodium bicarbonate and brine The organic solution was dried (MgSO 4), filtered and concentrated.Short flash chromatography (CHCl 3: MeOH 99: 1) gave the compound of the title of step A (58 mg), MS 539 (M + 1).

Step B: Hydrolysis of the ester (3- {[[(4-pyrazol-1-yl-benzyl) - (thiophene-2-sulfonyl) -amino] -methyl} -phenoxy) -acetic acid hydrochloride The title compound was prepared following the procedure described in example 13i, step C, from the (3- {[[(4-pyrazol-1-yl-benzyl) - (thiophen-2-tert -butyl) ester. sulphonyl) -amino] -methyl.}. - phenoxy) -acetic acid A. 1 H NMR (400 MHz, CDCl 3) d 8.22-6.80 (m, 10H), 6.72 (m, 2H), 6.64 (s, 1H), 6. 52 (s, 1 H), 4.47 (s, 2H), 4.39 (S, 2H), 4.36 (s, 2H); MS 81 (M-1).

EXAMPLE 13 Sodium salt of (3- (f-benzenesulfonyl- (4-pyrimidin-2-yl-benzyl) -amino-1-methyl-d-phenox-acetic acid Step A: Reductive amination Tert-butyl acid ester. { 3-f (4-pyrimidin-2-yl-benzyl) -metillfenoxp-acetic acid The title compound of step A was prepared from (3-aminomethyl-phenoxy) -acetic acid tert-butyl ester of the preparation 20 and 4-pyrimidin-2-yl-benzaldehyde of preparation 3, step A, with the exception that triethylamine was not used. 1 H NMR (400 MHz, CDCl 3) d 8.89 (d, 2 H), 8.38 (d, 2 H), 7.46 (d, 2 H), 7.23 (m, 1 H 9, 7.17 (m, 1 H), 6.95 (m, 2 H) ), 6.78 (dd, 1 H), 4.51 (s, 2H), 3.86 (s, 2H), 3.79 (s, 2H), 1.47 (s, 9H), MS 406 (M + 1).

Step B: Formation of the amide (3- {[[Benzenesulfonyl] - (4-pririmidin-2-yl-benzopylamino] -met-P-phenoxy) -acetic acid tert-butyl ester The compound of the title of step B was prepared from the tert.-butyl ester of 3 - [(4-pyrimidin-2-yl-benzylamino) -methyl] -phenoxy] -acetic acid ester of step A and benzenesulfonyl following the procedure described in example 3, step B. 1 H NMR (400 MHz, CDCl 3) d 8.78 (dd, 2H), 8.27 (d, 2H), 7.87 (m, 2H), 7.59-7.50 (m, 3H) ), 7.18 (m, 1 H), 7.11 (m, 3H), 6.75 (d, 1 H), 6.64 (d, 1H), 6.59 (s, 1 H9, 4.39 (s, 2H), 4.35 (s, 2H), 4.31 (s, 2H), 1.48 (s, 9H), EM 546 (M + 1).

Step C: Hydrolysis of the ester Sodium salt of (3- {[[benzenesulfonyl- (4-pyrimidin-2-yl-benzy-p-aminol-methyl-phenoxyp-acetic acid) The TFA salt was prepared following the procedure described in Example 3, step C, from (3- {[[benzenesulfonyl- (4-pyrimidin-2-yl-benzyl) -amino] -methyl} -phenoxy-tert-butyl ester. ) -acetic from step B. The sodium salt was prepared following the procedure described in step C of example 13d using MeOH (5 ml) and water (1 ml) as solvent 1 H NMR (400 MHz, CDCl 3) d 8.80 (d. , 2H), 8.23 (d, 2H), 7.89 (m, 2H) 7.67-7.56 (m, 3H), 7.32 (m, 1H), 7.21 (d, 2H), 7.06 (m, 1H), 6.75 (dd) , 1H), 6.63 (m, 2H), 4.41 (s, 2H), 4.32 (s, 2H), 4.21 (s, 2H), MS 488 (M-1).

EXAMPLE 13p (3- ({f (5-pyridin-2-yl-thiophene-2-sulfoniP- (4-thiazol-2-yl-benzopylamine-methyl-phenoxy-acetic acid) hydrochloride.

Step A: Formation of the amide Tert-butyl ester of (3- {[[(5-pyridin-2-yl-thiophene-2-sulfonyl) - (4-thiazol-2-yl-benzyl) amino] -methyl-phenoxy) -acetic acid To a solution of. {3 - [(4-thiazol-2-yl-benzylamino) -methyl] -phenoxy) -acetic acid tert-butyl ester (111 mg, 0.270 mmol ) prepared in step A of example 13i, triethylamine (120 mg, 1.19 mmol) and dichloroethane (10 ml) was added 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (77.2 mg, 0.297 mmol). The reaction was stirred for 72 h and 5-pyridin-2-yl-thiophen-2-sulfonyl chloride (38.5 mg) was added. The reaction was stirred for another 48 h. The organic solution was washed sequentially with 5.5% HCl, water, a saturated solution of sodium bicarbonate and brine. The organic solution was dried (MgSO4), filtered and concentrated. Flash chromatography (CHCl3: MeOH 99: 1) gave the title compound from step A (58 mg). EM 633 (m + 1).

- -, -. ? M ^ maaBmss ^ t.

Step B: Hydrolysis of the ester (3- ({-I- (5-pyridin-2-yl-thiophen-2-sulfoniP- (4-thiazol-2-yl-benzyl) -amino] -methihydrochloride -phenoxy) -acetic The title compound was prepared following the procedure described in example 13i, step C, from the tert-butyl ester of (3- {[[5-pyridin-2-yl] -thiophene-2-sulfonyl) - (4-thiazol-2-yl-benzyl) -amino] -methyl] -phenoxy) -acetic acid from step a.H NMR (400 MHz, CDCl 3) d 8.75 (d, J = 5.2 Hz, 1 H), 8.39 (t, J = 7.5 Hz, 1 H), 8.20 (d, J = 8.1 Hz, 1 H), 8.15 (d, J = 3.7 Hz, 1 H), 8.00-7.40 (m, 8H), 7.10 (t, J = 8.1 Hz, 1 H), 6.80 (d, J = 7.5 Hz, 1 H), 6.75 (d, J = 5.3 Hz, 1 H), 6.70 (s, 1 H), 4.50 (s, 2H), 4.49 (s, 2H), 4.42 (s, 2H), EM 575 (M-1).

EXAMPLE 13q (3- (f- (3,5-Dimethyl-isoxazole-4-sulfonyl) - (4-pyrimidin-2-yl-benzyl-diene-methyl-d-phenoxy-acetic) tert-butyl ester Step A. Formation of the amide (3 - ([(3,5-dimethyl-5-oxazole-4-sulfonyl- (4-pyrimidin-2-yl-benzyl) tert-butyl ester P-amino-1-methyl-P-phenoxy-acetic acid To a solution of tert-butyl ester of. {3 - [(4-pyrimidin-2-yl-benzyl) -amino] -methyl} -phenoxy) - acetic acid (83.3 mg, 0.2054 mmol) prepared in step A of example 13 in CH2Cl2 was added triethylamine (0.94 ml, 0.68 mg, 0. 226 mmol) and 3,5-dimethyl-isoxazole-4-sulfonyl chloride (44.2 mg, 0.226 mmol) and the reaction was heated to reflux overnight. After cooling to room temperature, more triethylamine (0.94 ml) and 3,5-dimethyl-isoxazole-4-sulfonyl chloride (44 mg) were added. The reaction was refluxed for 72 h and cooled to room temperature. The organic solution was washed sequentially with 5.5% aqueous HCl, water, a saturated sodium bicarbonate solution, and brine. The organic solution was dried (MgSO4), filtered and concentrated. Flash chromatography (CHC ^ MeOH 99: 1) gave the title compound from step A (61 mg). EM 565 (M + 1).

Step B: Hydrolysis of the ester (3- (f (3,5-dimethyl-lsoxazole-4-sulfonyl) - (4-pyrimidin-2-yl-benzyl-methyl-methyl-hexoxp-acetic acid) hydrochloride of the title was prepared following the procedure described in example 3, step C, from the (3- {[[(3,5-dimethyl-isoxazole-4-sulfonyl) - (4-pyrimid) tert-butyl ester N-2-yl-benzyl) -amino] -methyl] -phenoxy) -acetic acid from step A. The HCl salt was prepared by treating the TFA salt with HCl in dioxane (4M) as described in step C from Example 13i, 1 H-NMR (400 MHz, CDCl 3) d 8.92 (d, 1 H, J = 4.1 Hz), 8.25 (d, 1 H, J = 2.9 Hz), 7.55-671 (m, 8H), 6.62 ( m, 1 H), 4.55 (s, 2H), 4.52 (s, 2H), 4.45 (s, 2H), 2.62 (s, 3H), 2.43 (s, 3H), EM 507 (M-1).

EXAMPLE 13r Sodium salt of the acid (3-fr (Pyridin-2-sulfonylP- (4-pyrimidin-2-yl-benzopropylamine-methyP-phenoxyp-acetic acid Step A: Formation of the amide (3- (I (Pyridin-2-sulfonyl-4-pyrimidin-2-yl-benzyl) -amino-1-met-P-phenoxy) - tert-butyl ester The title compound of step A was prepared from the tert-butyl ester of { - [(4-pyrimidin-2-yl-benzylamino) -methyl] -phenoxy} -acetic acid, prepared in step A of example 13o and pyridine-2-sulfonyl chloride hydrochloride of preparation 47, following the procedure described in example 3, step A. 1 H-NMR (400 MHz, CDCl 3) d 8.78 (d, 2H ), 8.67 (d, 1 H), 8.26 (d, 2H), 7.96 (d, 1 H), 7.85 (m, 1 H), 7.44 (m, 1 H), 7.19-7.09 (m, 4H), 6.73 (m, 3H), 4.54 (s, 2H), 4.48 (s, 2H), 4.40 (s, 2H), 1.48 (s, 9H), EM 547 (M + 1).

Step B: Hydrolysis of the ester (3 - ([(pyridin-2-sulfoniP- (4-pyrimidin-2-yl-benzy-p-aminol-methyP-phenop-acetic acid) hydrochloride The TFA salt was prepared following the procedure described in Example 3, step C, from the (3- {[[(pyridin-2-sulfonyl) - (4-pyrimidin-2-yl-benzyl) -amino] tert-butyl ester] - methyl.}. phenoxy) -acetic from step B. The sodium salt was prepared following the procedure described in step C of example 13d using MeOH (5 ml) and water (1 ml) as solvent. CDCU) d 8.79 (d, 2H), 8.65 (d, 1 H), 8.23 (d, 2H), 7.96 (m, 2H), 7.56 (m, 1 H), 7.31 (m, 1 H), 7.27 (d, d, 2H), 7.04 (m, 1 H), 6.72 (d, 1 H), 6.66 (m, 2H), 4.56 (s, 2H), 4.44 (s, 2H), MS 489 (M-1).

EXAMPLE 13s Acid (3-ff (4-thiazol-2-yl-benzyl) - (thiophene-2-sulfonyl) -amino-1-methyl-phenoxy) -acetic acid Step A: Formation of the amide (3 - ([(4-Tazozol-2-yl-benzyl) - (tofen-2-sulfonyl-P-aminol-methyP-phenoxyacetic acid tert -butyl ester To a 3 - [(4-thiazol-2-yl-benzylamino) -methyl] -phenoxy] -acetic acid tert-butyl ester (87.3 mg, 0.213 mmol) prepared in step A of example 13i , triethylamine (47.3 mg, 0.234 mmol) and dichloroethane (10 ml) was added thiophene-2-sulfonyl chloride (42.7 mg, 0.234 mmol) .The reaction was stirred for 24 hours and more triethylamine (0.234 mmol) and chloride were added. of thiophene-2-sulfonyl (42.7 mg, 0.234 mmol) The reaction was stirred for another 24 h, the organic solution was washed sequentially with 5.5% HCl, water, a saturated solution of sodium bicarbonate and brine. (MgSO 4), filtered and concentrated.Short flash chromatography (CHCl 3: MeOH 99: 1) gave the title compound from step A (63 mg), MS 556 (M + 1).

Step B: Hydrolysis of the ester. Acid (3 - ([(4-thiazol-2-yl-benzyl) - (thiophene-2-sulfonyl-P-amino-1-methylp-phenox-acetic acid The title compound was prepared following the procedure described in Example 13i, step C, from the (3- {[[(4-thiazol-2-yl-benzyl) - (thiophene-2-sulfonyl) -amino) tert-butyl ester ] -methyl.} -phenoxy) -acetic acid A. 1 H NMR (400 MHz, CDCl 3) d 8.20-7.00 (m, 9H), 6.73 (m, 3H), 6.62 (s, 1 H), 4. 46 (s, 2H), 4.41 (s, 2H), 4.32 (s, 2H); MS 499 (M-1).

EXAMPLE 13t (3-ff (4-Pyrazol-1-yl-benzyl) -pyrrolidin-1-carbon-P-aminol-methyl-phenoxy-acetic acid hydrochloride salt Step A: Formation of the amide (3 - ([(4-pyrazol-1-yl-benzyl) -pyrrolidin-1-carboniP-aminol-methyP-phenoxy-acetic acid tert-butyl ester A solution of the 3 - {(3-pyrazol-1-yl-benzylamine) -methyl] -phenoxy] -acetic acid tert-butyl ester (15 mg, 0.038 mmol) prepared in step A of example 13a, pyrrolidin-1-carbonyl chloride (5 eq) and triethylamine (5 eq) in CH2Cl2 (1-2 ml) was stirred at room temperature for 72 h, more pyrrolidin-1-carbonyl chloride (5 eq) and triethylamine were added. (5 eq) and the reaction was stirred for 24 h followed by the addition of tris (2-aminoethyl) amine on a polymer support The reaction was stirred for 24 h and the resin was removed by filtration through CH 2 Cl 2. washed sequentially with 5.5% aqueous HCl and a saturated solution of NaHC 3 3. The organic solution was concentrated and used in step B without further purification.

Step B: Hydrolysis of the ester (3- (f (4-pyrazol-1-yl-benzyl) - (pyrrolidin-1-carboniP-aminol-methyP-phenop-acetic acid) hydrochloride The title compound was prepared following the procedure described in example 13, step C from the tert-butyl ester of (3- {[[(4-pyrazol-1-yl-benzyl) - (pyrrolidin-1-carbonyl) hydrochloride] ) -amino] -methyl] -phenoxy) -acetic from step A. 1 H NMR (400 MHz, CDCl 3) d 8.35 (s, 1 H), 7.95-7.20 (m, 9H), 6.55 (s, 1 H ), 4.65 (s, 2H), 4.39 (s, 2H), 4.33 (s, 2H), 3.42 (m, 4H), 1.82 (m, 4H), MS 433 (M-1).

EXAMPLE 13u (3- f (4-Chloro-benzenesulfonyl) - (4-pyrazol-1-yl-benzopylamino-methyd-phenop-acetic acid) hydrochloride salt Step A: Formation of the amide (3- {[[(4-Chloro-benzenesulfonyl) - (4-pyrazol-1-yl-benzopylamino] -methyl-phenoxy) -acetic acid tert-butyl ester Dissolution of. {3 - [(4-pyrazol-1-yl-benzylamino) -methyl] -phenoxy} -acetic acid tert-butyl ester (15 mg, 0.038 mmol) prepared in step A of example 13a , 4-chlorobenzenesulfonyl chloride (5 eq) and triethylamine (5 eq) in CH2Cl2 (1-2 ml) was stirred at room temperature for 72 h, more 4-chlorobenzenesulfonyl chloride (5 eq) and triethylamine (5 eq) were added. ) and the reaction was stirred for 24 h followed by the addition of tris (2-aminoethyl) amine on a polymer support The reaction was stirred for 24 h and the resin was removed by filtration by CH 2 Cl 2 .The organic solution was washed sequentially with 5.5% aqueous HCl and saturated NaHCO3 solution The above organic solution was concentrated and used in step B without further purification.

Step B: Hydrolysis of the ester (3 - ([(4-Chloro-benzenesulfoniP- (4-pyrazol-1-yl-benzyl) -amino] -met-P-phenoxy) -acetic acid hydrochloride The title compound is prepared following the procedure described in Example 13i, step C, from the (3- {[[(4-chloro-benzenesulfonyl) - (4-pyrazol-1-yl-benzyl) -amino) tert-butyl ester ] -methyl] -phenoxy) -acetic from step A. 1 H NMR (400 MHz, CDCl 3) d 8.37 (s, 1 H), 8.00-6.72 (m, 13 H), 6.55 (s, 1 H), 4.61 (s, 2H), 4.43 (s, 2H), 4.39 (s, 2H), MS 510 (M-1).

EXAMPLE 13v (3-fí (4-Pyrazol-1-yl-benzyl) - (5-pyridin-2-yl-thiophen-2-sulfonyl-D-aminol-methyP-phenox-acetic acid hydrochloride salt Step A: Formation of the amide (3. {R (4-pyrrazol-1-yl-benzyl-2-pyridin-2-yl-thiophen-2-sulfonyl) tert-butyl ester) -amino] -methyl-phenoxy) -acetic acid A solution of (3- {[[(4-pyrazol-1-yl-benzyl) - (5-pyridin-2-yl-thiofen) tert-butyl ester) -2-sulfonyl) -amino] -methyl] -.-phenoxy) -acetic acid (15 mg, 0.038 mmol) prepared in step A of example 13a, 5-pyridin-2-yl-thiophene-2-sulfonyl chloride ( 5 eq) and triethylamine (5 eq) in CH2Cl2 (1-2 ml) was stirred at room temperature for 72 h. Additional 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (5 eq) and triethylamine (5 eq) were added and the reaction was stirred for 24 h followed by the addition of tris (2-aminoethyl) amine on a polymer support. The reaction was stirred for 24 h and the resin was removed by filtration through CH2Cl2. The organic solution was washed sequentially with 5.5% HCl and a saturated solution of NaHCO 3. The organic solution was concentrated and used in step B without further purification.

Step B: hydrolysis of the ester (3 - ([(4-pyrrazol-1-yl-benzyl- (5-pyridin-2-yl-thiophen-2-sulfonopylamino) phenoxy) -hydrochloride ) -acetic The title compound was prepared by following the procedure described in example 13i, step C, from the tert-butyl ester of (3- {[[4-P¡razol-1-yl-benzyl]) - (5-pyridin-2-yl-thiophen-2-sulfonyl) -amino] -methyl] -phenoxy) -acetic from step A. 1 H NMR (400 MHz, CDCl 3) d 8.61 (s, 1 H), 8.00-6.72 (m, 15H), 6.46 (s, 1 H), 4.49 (s, 2H), 4.39 (s, 2H), 4.32 (s, 2H), EM 559 (M-1).

EXAMPLE 13w Acid (3- { R (4-methoxy-benzenesulfoniP- (4-thiazol-2-yl-benzyl-P-amino-1-methyl-phenoxy-acetic) Step A: Formation of the amide (3- {[[(4-methoxy-benzenesulfonyl) P- (4-tiazol-2-yl-benzop-amino] -methyl-p-phenoxy) tert-butyl ester ) -acetic A stock solution of Et3N (0.515 ml) n in CH2Cl2 (80 ml) was prepared and 2 ml was added to the {3-. {(4-thiazol-2-yl-benzylamino) -methyl-phenoxy} ) -acetic (29.80 mg, 0.0726 mmol), prepared in step A of example 13i A solution of 4-methoxybenzenesulfonyl chloride (17 mg, 0.084 mmol) in CH2Cl2 (1 ml) and DMF (1 ml) was prepared and 0.56 ml was added to the reaction mixture, the reaction was stirred at room temperature for 24 h and diluted with aqueous HCl (0.5 N, 1 ml) The aqueous solution was washed with CH 2 Cl 2 (2x) and the combined organic solutions were dried (NaS 4) and concentrated The HPLC purification of the reverse phase using a solvent gradient water: acetonitrile: 0.1% TFA gave the compound from step A (20.4 mg), EM 581 (m + 1).

Step B: Hydrolysis of the ester Acid (3 - ([(4-methoxy-benzenesulfonyl) - (4-thiazole-2-yl-benzyl-amino-1-methyd-phenoxy) -acetic ester To a solution of the tertiary ester - (3- {[[(4-Methoxy-benzenesulfonyl) - (4-thiazol-2-yl-benzyl) -amino] -methyl} -phenoxy) -acetic acid butyl of step A in CH2Cl2 (2) ml) at 0 ° C was added cold TFA (1 ml) and the reaction was stirred at room temperature for 1 h.The reaction was concentrated using a stream of nitrogen, more CH2CI2 (1 ml) was added and the solution was concentrated using A stream of nitrogen This procedure was repeated and the residue was dried in vacuo to give the title compound (24.6 mg), MS 524 (M-1).

EXAMPLE 13x Acid (3-ff (5-chloro-thiophene-2-sulfoniP- (4-thiazol-2-yl-benzyl) -amino-1-methyl-phenoxy-acetic acid Step A: Formation of the amide (3 { [(5-Ctoro-ttofen-2-sulfon¡P- (4-thiazol-2-yl-benzyl-P-amino] -met) tert-butyl ester P-phenoxy) -acetic acid The title compound of step A was prepared following the procedure described in step A of example 13w from the tert-butyl ester of the acid. {3 - [(4-thiazole-2) -yl-benzylamino) -methyl] -phenoxy.} -acetic, prepared in step A of example 13, and 5-chlorothiophen-2-sulfonyl chloride with the following exception. The sulfonyl chloride was dissolved in CH2Cl2 (1 ml) and 0.28 ml was added to the reaction mixture. 1 H NMR (400 MHz, CDCl 3) d 8.03 (d, 1 H), 7.79 (d, 2 H), 7.43 (d, 1 H), 7.34 (d, 1 H), 7.24 (m, 3 H), 7.13 (m , 1 H), 6.94 (d, 1 H), 6.76 (m, 1 H), 6.68 (m, 2H), 4.41 (s, 2H), 4.35 (s, 2H), 4.30 (s, 2H), 1.48 (s, 9H); MS 591 (M +).

Step B: Hydrolysis of the ester. Acid (3- { (5-chloro-thiophene-2-sulfonyl) - (4-thiazol-2-yl-benzyl) -amino] -methyl-phenoxy-acetic acid The title compound was prepared following the procedure described in step B of example 13w from (3- {[[(5-Chloro-thiophene-2-sulfonyl) - (4-thiazole-2-yl) -butyl-tert-butyl ester. benzyl) -amino] -methyl] -phenoxy) -acetic from step A. EM 524, M.-1).

EXAMPLE 13v Acid (3-ir (3-fluoro-benzenesulfoniP- (4-thiazol-2-yl-benzyl) -amino-1-methyl-phenoxy-acetic acid Step A: Formation of the amide (3-f [(3-Fluoro-benzenesulfoni) - (4-thiazol-2-yl-benzyl) -amino-1-meth-P-phenoxy) -acetic acid tert-butyl ester The title compound of step A was prepared following the procedure described in step A of example 13w from the ester ter- butyl of acid. { 3 - [(4-thiazol-2-yl-benzylamino) -methyl] phenoxy} -acetic, prepared in step A of example 13i and 3-fluorobenzenesulfonyl chloride with the following exception. The sulfonyl chloride was dissolved in CH2Cl2 (1 ml) and 0.28 ml was added to the reaction mixture. EM 569 (m + 1).

Step B: Hydrolysis of the ester. Acid (3- (f (3-fluoro-benzenesulfoniP- (4-thiazol-2-yl-benzyl) -amino-1-methyP-phenoxp-acetic acid The title compound was prepared following the procedure described in step B of Example 13W from (3- {[[(3-Fluoro-benzenesulfonyl) - (4-thiazol-2-yl-benzyl) -amino] -meti-tert-butyl ester} -phenoxy) -acetic from step A. EM 534 (M-1).

EXAMPLE 13z Acid (3-fr (4-Methoxy-benzenesulfoniP- (4-pyrazol-1-yl-benzyl-amino-1-methyl-P-phenox-acetic acid Step A: Formation of amide (3- {[[(4-methoxy-benzenesulfonyl-P- (4-pyrazol-1-yl-benzopylamine-methyl-phenoxyp-acetic acid) tert-butyl ester The title of step A was prepared following the procedure described in step A of example 13w from the (3- {[[(4-Methoxy-benzenesulfonyl) - (4-pyrazole-1-yl-) -butyl-tert-butyl ester. benzyl) -amino] - methyl } -phenoxy) -acetic, prepared in step A of example 13a and 4-methoxybenzenesulfonyl chloride. EM 564 (M + 1).

Step B: Hydrolysis of the ester. Acid (3- {[[4-Methoxy] -benzenesulfon-P- (4-pyrazol-1-yl-benzyl-P-aminol-methy-D-phenox-acetic acid The title compound was prepared following the procedure described in step B of example 13w, from the tert-butyl ester of (3- {[[4-methoxy-benzenesulfonyl) - (4-pyrazol-1-yl-benzyl) -amino]] -methyl] -phenoxy) -acetic from step A. 1 H NMR (400 MHz, CDCl 3) d 8.14 (m, 1 H), 7.81 (d, 2 H), 7.68 (s, 1 H), 7.54 (d, 2H), 7.19 (m, 2H), 7.09 (m, 3H), 6.72 (m, 2H), 6.60 (s, 1 H), 6.49 (s, 1 H), 4.47 (s, 2H), 4.32 (s) , 2H), 4.28 (s, 2H), 3.87 (s, 3H), EM 507 (M-1).

EXAMPLE 14a Acid (3-fr (5-chloro-thiophene-2-sulfonyl) - (4-pyrazol-1-yl-benzyl) -amino-1-methyl-phenoxy-acetic acid Step A: Formation of amide (3 - ([(5-Chloro-thiophene-2-sulfonyl) - (4-pyrazol-1-yl-benzyl-methy1-pheno-p-acetic acid) tert-butyl ester of the title of step A was prepared following the procedure described in step A of example 13w from the tert-butyl ester of the acid. {3 - [(4-pyrazol-1-yl-benzylamino) -methyl] -phenoxy] .) - acetic, prepared in step A of example 13a and 5-chlorothiophene-2-sulfonyl chloride with the following exception: The sulfonyl chloride was dissolved in • CH2Cl2 (1 ml) and 0.28 ml was added to the reaction mixture. MS 574 (M +). Step B: Hydrolysis of the ester Acid (3- {[[5-Chloro-thiophene-2-sulfoniP- (4-pyrrazol-1-yl-benzyl) -amino-methyl-d-eneoxp-acetic acid The title compound was prepared by following the procedure described in step B of example 13w from the starting material of (3- {[[5-chloro-thiophene-2-sulfonyl) - tert -butyl ester) -pyrazol-1-yl-benzyl) -amino] -methyl.}. - phenoxy) -acetic from step A. EM 517 (M-1): EXAMPLE 14b 15 Acid (3- { F (3-Fluoro-benzenesulfoniP- (4-pyrazol-1-yl-benzop-amino-1-methyl-phenop-acetic acid Step A: Formation of the amide (3- (f (3-Fluoro-benzenesulfonyl) - (4-pyrazol-1-yl-benzopylamine-methyl-phenoxyp-acetic acid) tert-butyl ester The title compound of the title Step A was prepared following the procedure described in step A of example 13w from the tert-butyl ester of the acid. {3 - [(4-pyrazol-1-yl-benzylamino) -methyl] -phenoxy}. acetic, "^ Fti & k ^ ^ ** M prepared in step a of example 13a and 3-flurobenzenesulfonyl chloride with the following exception. The sulfonyl chloride was dissolved in CH2Cl2 (1 ml) and 0.28 ml was added to the reaction mixture. MS 552 (M +).

Step B: Hydrolysis of the ester. Acid (3- {[[3-fluoro-benzenesulfoniP- (4-pyrazol-1-yl-benzop-aminol-methy-D-phenox-acetic acid The title compound was prepared following the procedure described in step B of Example 13w from (3- {[[(3-fluoro-benzenesulfonyl) - (4-pyrazol-1-yl-benzyl) -amino] -methyl} -butyl tert-butyl ester. -phenoxy) -acetic from step A. EM 495 (M-1).

EXAMPLE 14c Acid (3- { R (3-Chloro-benzenesulfonyl) - (4-thiazol-2-yl-benzopyaminol-methyl-phenoxy-acetic) Step A: Formation of the amide (3. {[[(3-Chloro-benzenesulfonyl) P- (4-thiazol-2-yl-benzyl-P-amino-1-meth) phenoxy) -acetic acid The title compound of step A was prepared following the procedure described in step A of example 13w from the tert-butyl ester of the acid. {- - [(4-thiazol-2-yl-benzylamine ) -methyl] -phenoxy] -acetic acid, prepared in step A of example 13i and 3-chlorobenzenesulfonyl chloride with the following exception: The sulfonyl chloride was dissolved in CH 2 Cl 2 (1 ml) and 0.28 was added. ml to the reaction mixture, EM 585 (M +).

Step B: Hydrolysis of the ester. Acid (3- (1 (3-loro-benzenesulfonyl) - (4-thiazol-2-yl-benzyl-P-amino-1-methyl-D-phenox-acetic acid. The title compound was prepared following the procedure described in step B of example 13w from (3- {[[(3-Chloro-benzenesulfonyl) - (4-thiazol-2-yl-benzyl) -amino] -methyl) -butyl ester. . -phenoxy) -acetic from step A. EM 529 (M +).

EXAMPLE 14d (3- (l- (4-pyrazol-1-yl-benzyl- (thiazole-2-sulfonyl-p-aminol-methyl-pheno-p-acetic acid) hydrochloride Step A: Formation of the amide (3- {[[(4-pyrazol-1-yl-benzyl) - (thiazole-2-sulfonyl-D-aminol-methyD-phenoxy-acetic acid) tert-butyl ester The title compound from step A was prepared following the procedure described in step B of Example 3 from the tert-butyl ester of the acid. {3 - [(4-pyrazol-1-yl-benzylamino) -methyl] -phenoxy}. -acetic, prepared in step A of example 13a and thiazole-2-sulfonyl chloride of preparation 45, with a reaction time of 3 h. 1 H NMR (400 MHz, CD3OD) d 7.95 (d, 1 H ), 7.87 (d, 1 H), 7.69 (m, 1 H), 7.59 (dd, 1 H), 7.54 (d, 2H), 7.15 (m, 3H), 6.74 (m, 3H), 6.44 (m , 1 H), 4.49 (s, 2H), 4.46 (s, 2H), 4.42 (s, 2H), 1.49 (s, 9H), EM 541 (M + 1).

Step B: Hydrolysis of the ester (3-iT4-pyrazol-1-l-benzyl-thiazole-2-sulfoniP-aminol-methyP-phenoxy-acetic acid hydrochloride) The title compound was prepared following the procedure described in step C of Example 3 from (3- {[[(4-pyrazol-1-yl-benzyl) - (thiazole-2-sulfonyl) -amino] -methyl} -phenoxy) -acetic acid tert-butyl ester from step A, with a reaction time of 2 h The TFA salt was converted to the hydrochloride salt as described in step C of example 13a.H NMR (400 MHz, CD3OD) d 8.02 (d, 1 H), 7.83 (s, 1 H), 7.79 (d, 1 H), 7.66 (d, 1 H), 7.39 (d, 2 H), 7.18 (d, 2 H), 7.13 (m, 1 H), 6.81 (d, 1 H), 6.75 (d, 1 H), 6.50 (s, 2 H), 4.53 (s, 4 H), 4.43 (s, 2 H), MS 483 (M-1). l ^^^^^^^^^^^^^^^^^^^^^^^^^ EXEMPTION 14e Sodium salt of 3-r (4-tert-butyl-benzyl- (pyridine-3-sulfoniP-amino-1-methyl-phenoxy) -acetic acid Step A: Reductive amination (3 - [(4-tert-Butyl-benzyl) - (pyridine-3-sulfonyl) -amino] -methyl-phenoxy) -acetic acid tert-butyl ester To a solution of the (3-aminomethyl-phenoxy) -acetic acid tert-butyl ester prepared in step C of preparation 20 (0.497 g, 2.09 mmol) in MeOH (8 ml) was added 4-tert-butylbenzaldehyde (0.33 ml, 1.97 mmol) and the mixture was stirred at room temperature for 2 h. The solution was cooled to 0 ° C and sodium borohydride (0.119 g, 3.15 mmol) was added all at once. The mixture was stirred for 10 min and a solution of water: saturated aqueous sodium bicarbonate 1: 1 was added to the solution. The product was extracted into CH2Cl2 (3X) and the combined organic solutions were dried (MgSO) and concentrated in vacuo. The product was purified by chromatography on silica gel (AcOEt followed by 5% MeOH in CH2Cl2) to give the title compound of step A 80.691 g) as a clear oil. 1 H NMR (400 MHz, CDCl 3) d 7.30-7.38 (m, 2H), 7.19-7.28 (m, 3H), 6.87-6.96 (m, 2H), 6.77 (d, 1 H), 4.50 8s, 2H), 3.77 (s, 2H), 3.75 (s, 2H), 1.46 (s, 9H), 1.30 (s, 9H); MS 384 (M + 1).

Step B: Formation of amide Tert-butyl ester of acid. { [(4-tert-butyl-benzyl- (pyridin-3-sulfonyl-D-aminol-methyd-phenoxy-acetic acid) To a solution of the tert-butyl ester of acid { 3. [(4-tert-butyl-vencylamino) ) -methyl] -phenoxy.} -acetic (10.00 g, 26.1 mmol) prepared in step A in CH 2 Cl 2 (75 mL) at 0 ° C was added triethylamine (8.0 mL, 57.4 mmol) and pyridine-3-sulfonyl chloride hydrochloride (6.10 g, 28.7 mmol) of preparation 2. The mixture was stirred for 0.5 h, the ice bath was removed and the mixture was stirred for an additional 1.5 h. To the water solution was added: saturated aqueous sodium bicarbonate 1: 1 and the product was CH2Cl2 (3X). The combined organic solutions were dried over MgSO 4 and concentrated in vacuo and the product was purified by chromatography on silica gel (Hex: AcOEt 2: 1) to give the title compound of step B (11.0 g) as a clear oil. 1 H NMR (400 MHz, CDCl 3) d 9.01 (s, 1 H), 8.75 (d, 1 H), 7.97 (d, 1 H), 7.38 (m, 1 H), 7.11-7.23 (m, 3H), 6.97 (d, 2H), 6.71 (d, 1 H), 6.65 (d, 1 H), 6.60 (s, 1 H), 4.40 (s, 2H), 4.32 (s, 4H), 1.48 (s, 9H), 1.26 (s, 9H); EM 525 (m + 1).

Step C: Hydrolysis of the ester Acid (3 - [(4-tert-butyl-benzyl) - (pyridin-3-sulfonyl-P-amino] -met-P-phenoxyp-acetic acid To a solution of the {.3 - [(4-tert-Butyl-benzyl) - (pyridin-3-sulfonyl) -amino] -methyl] -phenoxy} -acetic acid tert-butyl ester (11.0 g, 21.0 mmol) SaßZ Sarijfe SuííbSmP fSi was prepared in step B in CH2CI2 (50 ml) at 0 ° C trifluoroacetic acid (25 ml) was added. After 10 minutes, the ice bath was removed and the mixture was stirred for an additional 1.5 h. Another 5 ml of trifluoroacetic acid was added to the solution, the mixture was stirred for 30 min and the reaction was concentrated in vacuo. The residue was azeotroped with CH2Cl2 (3X) and the resulting oil was partitioned between water and AcOEt. The aqueous phase was adjusted to pH 5.0 with 1 N NaOH and the resulting precipitated solid (4.86 g) was collected by filtration. The filtrate layers were separated and the aqueous layer was extracted with AcOEt (2X). The combined organic solutions were dried over MgSO and concentrated in vacuo to give a white foam (2.64 g). The solid precipitate and white foam were combined and recrystallized from ethanol to give the title compound (5.68 g) as a white solid. 1 H NMR (400 MHz, CD 3 OD) d 8.91 (s, 1 H), 8.71 (d, 1 H), 8.15 (d, 1 H), 7.54 (m, 1 H), 7.22 (d, 2 H), 7.11 (t, 1 H), 7.04 (d, 2H), 6.71-6.92 (m, 2H), 6.65 (s, 1 H), 4.50 (s, 2H), 4.36 (s, 4H), 1.25 (s, 9H); EM 469 (M + 1).

Step D: formation of the salt Sodium salt of the acid. { 3 - [(4-tert-Butyl-benzyl) - (pyridin-3-sulfonyl) -amino] -methyl} -phenoxy) -acetic To a solution of the acid. { 3 - [(4-tert-Butyl-benzyl) - (pyridin-3-sulfonyl) -amino] -methyl} -phenoxy) -acetic (5.68 g, 12.13 mmol), prepared in step C in MeOH: water 10: 1 (66 ml), sodium bicarbonate (1.02 g, 12.13 mmol) was added, and the mixture was stirred for 18 h room temperature. The 388 < The mixture was azeotroped with ethanol and concentrated in vacuo to give the title compound (5.95 g) as a white solid. 1 H NMR (400 MHz, CD 3 OD) d 8.88 (s, 1 H), 8.71 (d, 1 H), 8.13 (d, 1 H), 7.52 (m, 1 H), 7.24 (d, 2 H), 7.04- 7.11 (m, 3H), 6.78 (d, 1H), 6.68 (m, 2H), 4.37 (s, 2H), 4.35 (s, 2H), 4.25 (s, 2H), 1.25 (s, 9H); EM 469 (M + 1).

EXAMPLES 15a-15q Examples 15a-15q were prepared from the appropriate starting materials analogously to the procedure of Example 1, with the variations in reaction time, temperature and reagents cited.

EXAMPLE 15a 3- (3-R (Benzenesulfonyl-benzori.31-dioxol-5-ylmethyl-amino) -methane-phenyl-propionic acid Step A: Reductive amination 3- (3-. {[[(Benzo [1,3] dioxol-5-ylmethyl) -amino-1-methyl-phenyl-propionic acid methyl ester The title compound of step A was prepared from the hydrochloride salt of 3- (3-aminomethyl-phenyl) -propionic acid methyl ester, preparation 44 and benzo [1,3] -dixol-5-carbaldehyde, using the procedure described in example 1 , step A, with the exception that the imine was formed in refluxing MeOH for 4 h. 1 H NMR (400 MHz, CDCl 3) d 7.27-6.74 (m, 7H), 5.90 (s, 2H), 3.77 (s, 2H), 3.71 (s, 2H), 3.64 (s, 3H), 2.92 (t, 2H), 2.62 (t, 2H), MS 328 (M + 1).

Step B: Formation of amide 3- (3-f (Benzenesulfonyl-benzof1, 3] dioxol-5-methyl-amino) -metn-phenyl-propionic acid methyl ester Step B was prepared following the procedure described in step A of the example from the methyl ester of 3- (3. {[[(benzo [1,3] dioxol-5-methylmethyl] -amino] -methyl ester} -phenyl.} -propionic of step A and benzenesulfonyl chloride using triethylamine in place of N, N-diisopropylethylamine 1 H NMR (400 MHz, CDCl 3) d 7.85 (d, 2H), 7.62-7.50 (m, 3H ), 7.13 (m, 1 H), 7.03 (m, 1 H), 6.88 (m, 1 H), 6.78 (s, 1 H), 6.62 (d, 1 H), 6.54 (s, 1 H), 6.46 (d, 1 H), 5.90 (s, 2H), 4.28 (s, 2H), 4.21 (s, 2H), 3.67 (s, 3H), 2.81 (t, 2H), 2.50 (t, 2H).

Step C: Acid ester hydrolysis 3-. { 3-f (benzenesulfonyl-benzori, 31-dioxol-5-ylmethyl-amino) -metip-phenyl-propionic acid The title compound was prepared following the procedure described in Example 3, step C, from the methyl ester of 3-acid. { 3 - [(Benzenesulfonyl-benzo [1,3] dioxol-5-ylmethyl-amino) -methyl] -phenyl} -propionic of step B. 1 H NMR (400 MHz, CDCl 3) d 7.84 (d, 2 H), 7.61-7.50 (m, 3 H), 7.13 (m, * .. 1 H), 7.04 (m, 1 H), 6.88 (m, 1 H), 6.79 (s, 1 H), 6.61 (d, 1 H), 6.51 (s, 1 H), 6.46 (m, 1 H) ), 5.90 (s, 2H), 4.28 (s, 2H), 4.19 (s, 2H), 2.82 (t, 2H), 2.55 (t, 2H); MS 452 (M + 1).

EXAMPLE 15b 3- (3-Frbenzof1,31-dioxol-5-ylmethyl- (4-fluoro-benzene-sulfonyl-P-amino-1-methyl-phenyl-propionic acid Step A: Amide formation 10 The title compound of step A was prepared following the procedure described in Example 1, step A, from the methyl ester of 3- (3- {. [Benzo [1, 3] ] dioxol-5-ylmethyl) -amino] -methyl} phenyl) -propionic, prepared in step A of example 15a and 4-benzenesulfonyl chloride using triethylamine instead of N, N-diisopropylethylamine. 1 H NMR (400 MHz, CDCl3) d 7.82 (m, 2H), 7.17 (m, 3H), 7.05 (d, 1 H), 6.89 (d, 1 H), 6.83 (s, 1 H), 6.64 (d, 1 H), 6.56 (s, 1 H), 6.48 (m, 1 H), 5.91 (s, 2H), 4.27 (s, 2H), 4.19 (s, 2H), 3.67 (s, 3H), 2.83 (t, 2H) , 2.52 (t, 2H).

Step B: Hydrolysis of the ester Acid 3- (3- (f-benzo [1,1,3-oxo-5-ylmethyl- (4-fluoro-benzenesulfonyl) -aminol-methyl-phenyl-propionic acid The title compound is prepared following the procedure described in example 1, step C, from the methyl ester of 3-. {3- t. { [benzo [1,3] dioxol-5-ylmethyl- (4-fluoro-benzenesulfonyl) -amino] -methyl} phenyl) -propionic from step B. 1 H NMR (400 MHz, CDCl 3) d 7.81 (m, 2 H), 7.19-7.04 (m, 4 H), 6.90 (d, 1 H), 6.84 (s, 1 H), 6.63 (d, 1 H), 6.53 (s, 1 H), 6.48 (d, 1 H), 5.90 (s, 2H), 4.27 (s, 2H), 4.19 (s, 2H), 2.84 (t, 2H) ), 2.58 (t, 2H); EM 470 (M-1).

EXAMPLE 15c 3- (3. {-Fethanesulfonyl- (4-phenoxy-benzop-amino) -met-P-phen-P-propionic acid Step A: Reductive amination 3- (3 - [(4-phenoxy-benzyllamine) -methyl] -phen? -propionic acid methyl ester The title compound of step A was prepared from the hydrochloride salt of the 3- (3-aminomethyl-phenyl) -propionic acid methyl ester of preparation 44 and 4-phenoxybenzaldehyde, using the procedure described in example 12z, step A. 1 H NMR (400 MHz, CDCl 3) d 7.37-6.95 (m, 13H), 3.82 (s, 2H), 3.79 (s, 2H), 3.64 (s, 3H), 2.93 (t, 2H), 2.63 (t, 2H), EM 376 (M + 1 ).

Step B: Formation of the amide 3- (3. {[Methanesulfonyl- (4-phenoxy-benzyP-aminol-methyP-phenyp-propionic acid methyl ester) The title compound of step B was prepared following the procedure described in step A of Example 1 from the 3- ({3 - [(4-phenoxy-benzylamino) -methyl] -phenyl) -propionic acid methyl ester of step A and methanesulfonyl chloride, using triethylamine instead of N, N-diisopropylethylamine, 1 H NMR (400 MHz, CDCl 3) d 7.36-7.24 (m, 5H), 7.14 (m, 4H), 6.97 (m, 4H), 4.31 (s, 2H), 4.30 (s, 2H), 3.66 (s, 3H) 2.94 (t, 2H), 2.78 (s, 3H), 2.61 (t, 2H).

Step C: Hydrolysis of the ester 3- (3. {[Methanesulfonyl- (4-phenoxy-benzyl-P-amino) -methyl-phenyl) -propionic acid The title compound was prepared following the procedure described in the example 1, step C, from the 3- (3. {[[Methanesulfonyl- (4-phenoxy-benzyl) -amino] -methyl} -phenyl) -propionic acid methyl ester from step B. 1 H NMR (400 MHz, CDCl 3) d 7.35-7.22 (m, 5H), 7.11 (m, 4H), 6.96 (m, 4H), 4.31 (s, 2H), 4.29 (s, 2H), 2.93 (t, 2H) 2.77 (s, 3H), 2.65 (t, 2H).

EXAMPLE 15d 3- (3 (R (4-pyrazol-1-yl-benzyl- (thiazole-2-sulfoniP-amino-1-methyl-phenyl-propionic Step A: Formation of amide 3- (3 - ([(4-pyrazol-1-yl-benzyl) - (t-azole-2-sulfonyl-P-aminol-methyP-phenyl-propionic acid methyl ester title of step A was prepared following the procedure described in step A of example 1 from 3- ({3 - [(4-pyrazol-1-yl-benzylamino) -methyl] -phenyl) methyl ester. -propionic, prepared in step A of example 11 h and thiazole-2-sulfonyl chloride using triethylamine in place of N, N-diisopropylethylamine, 1 H NMR (400 MHz, CDCl 3) d 7.95 (d, 1 H), 7.88 ( d, 1 H), 7.69 (d, 1 H), 7.60 (d, 1 H), 7.54 (d, 2 H), 7.19-7.12 (m, 3 H), 7.04 (m, 1 H), 6.93 (m, 2H), 6.44 (m, 1 H), 4.49 (s, 2H), 4.46 (s, 2H), 3.64 (s, 3H), 2.82 (t, 2H), 2.51 (t, 2H), MS 497 (M +1) Step B: Hydrolysis of the ester. 3- (3- (f (4-piarazol-1-yl-benzyl) - (thiazole-2-sulfoniP-amino] -methyl-phenyl-propionic acid The title compound is prepared following the procedure described in Example 3, step C, from 3- (3. {[[(4-pyrazol-1-yl-benzyl) - (thiazole-2-sulfonyl) -amino] methyl ester ] -methyl] -phenyl) -propionic from step A. 1 H NMR (400 MHz, CDCl 3) d 7.99 (m, 1 H), 7.81 (d, 1 H), 7.71 (d, 1 H), 7.63 (m, 1 H), 7.45 (m, 2H), 7.13 (m, 3H), 7.02 (m, 2H), 6.83 8s, 1 H), 6.44 (m, 1H), 4.52 (s, 2H), 4.45 (s, 2H), 2.80 (t, 2H), 2.50 (t, 2H), MS 481 (M-1).

EXAMPLE 15e 5 3- (3- (R (4-tert-butyl-benzyl) - (thiazole-2-sulfonyl-P-amino-1-methyl-P-phenyl-propionic acid Step A: Formation of amide 3- (3 - ([(4-tert-Butyl-benzyl) - (thiazole-2-sulphonyl-p-aminol-methyl-phenyl-propionic acid methyl ester The title compound of step A was prepared following the procedure described in step A of Example 1 from 3- ({3 - {(3-tert-butyl-benzylamino) -methyl] -phenyl} -propionic acid methyl ester. , prepared in step A of example 12s and thiazole-2-sulfonyl chloride using triethylamine 15 instead of N, N-diisopropylethylamine, 1 H NMR (400 MHz, CDCl 3) d 7.93 (d, 1 H), 7.56 (d, 1 H), 7.23 (d, 2H), 7.14 (m, 1 H), 7.04 (m, 3H), 6.98 (m, 2H), 4.47 (s, 2H), 4.41 (s, 2H), 3.67 (s) , 3H), 2.84 (t, 2H), 2.54 (t, 2H), 1.27 (s, 9H), MS 487 (M + 1).

Step B: Hydrolysis of the ester 3- (3 - ([(4-tert-Butyl-benzyl) - (thiazole-2-sulfonyl-P-amino) -methyl-phenyl-propionic acid The title compound was prepared following the procedure described in Example 1, step C, from 3- (3. {[[(4-tert-butyl-benzyl) - (thiazole-2-sulfonyl) -amino] -methyl] -methyl ester. phenyl propionic with the following exception: The reaction was heated to reflux for 1.5 h and cooled to room temperature The reaction was acidified to pH = 5 and the aqueous solution was washed with CH2Cl2 (3x) .The combined organic layers were dried (MgSO4), filtered and concentrated.Short flash chromatography (CH2Cl2: MeOH 98: 2) gave the title compound.1H-NMR (400MHz, CDCl3) d 7.92 (d, 1H), 7.56 (d, 1H ), 7.24-6.93 (m, 8H), 4.47 (s, 2H), 4.44 (s, 2H), 2.84 (t, 2H), 2.58 (t, 2H), 1.26 (s, 9H), EM 471 (M -1 ).

EXAMPLE 15f 3- (3-ff (4-pyrimidin-2-yl-benzyl) - (thiazole-2-sulfoniP-amino-1-methyl-phenyl-propionic acid Step A: Formation of amide 3- (3. {F (4-pyrimidin-2-yl-benzyl- (thiazole-2-sulfonopropylamine-methyl-phenyl-propionic acid) methyl ester from step A was prepared following the procedure described in step A of example 1 from methyl 3- ({3 - [(4-pyrimidin-2-yl-benzylamino) -methyl] -phenyl} methyl ester. -propionic, prepared in step A of example 11z and thiazole-2-sulfonyl chloride using triethylamine in place of N, N-diisopropylethylamine, 1 H NMR (400 MHz, CDCl 3) d 8.80 (d, 2H), 8.30 (d, 2H), 7.96 (d, 1H), 7.59 (m, 1 H), 7.24-7.13 (m, 4H), 7.05 (d, 1 H), 6.96 (d, 1 H), 6.92 (s, 1 H) , 4.54 (s, 2H), 4.49 (s, 2H), 3.64 (s, 3H), 2.82 (t, 2H), 2.51 (t, 2H), EM 509 (M + 1).

Step B: Hydrolysis of the ester Acid 3- (3. {F (4-pyridin-2-yl-benzyl-thiazole-2-sulfoniP-amino-1-methyl-phenyl-propionic acid The title compound was prepared following the procedure described in example 15e, step B, from 3- (3. {[[(4-pyrimidin-2-yl-benzyl) - (thiazole-2-sulfonyl) -amino] methyl ester] -methyl.} -phenyl-propionic from step A. 1 H NMR (400 MHz, CDCl 3) d 8.79 (d, 2 H), 8.18 (d, 2 H), 7.98 (m, 1 H), 7.61 (m, 1 H ), 7.25-7.11 (m, 4H), 7.05-6.98 (m, 2H), 6.87 (s, 1 H), 4.55 (s, 2H), 4.48 (s, 2H), 2.81 (t, 2H), 2.54 (t, 2H); MS 493 (M-1).

EXAMPLE 15q 3- (3-Ir (4-pyrazin-2-yl-benzyl- (thiazole-2-sulfoniP-amino-1-methyl-phenyl-propionic acid Step A: Formation of amide 3- (3. {[[(4-pyrazin-2-yl-benzyl- (thiazole-2-sulfoniP-aminol-methyP-phenyl-propionic acid) methyl ester The compound of the title of step A was prepared following the procedure described in step A of example 1 from 3- ({3 - [(4-pyrrazin-2-yl-benzylamino) -methyl-phenyl-propionic acid methyl ester , prepared in step A of example 11a and thiazole-2-sulfonyl chloride, using triethylamine instead of N, N-diisopropylethylamine, 1 H NMR (400 MHz, CDCl 3) d 8.98 (s, 1 H), 8.61 (s, 1H), 8.50 (s, 1H), 7.96 (d, 1H), 7.88 (d, 2H), 7.60 (d, 1H), 7.26 (d, 2H), 7.13 (m, 1H), 7.04 (m, 1H) ), 6.95 (m, 1H), 6.91 (s, 1H), 4.54 (s, 2H), 4.48 (s, 2H), 3.64 (s, 3H), 2.81 (t, 2H), 2.52 (t, 2H); EM 509 (M + 1).

Step B: Hydrolysis of the ester Acid 3- (3- (f (4-pyrrazin-2-yl-benzyl-2-azole-2-sulfonyl-P-amino-1-methyl-P-phenyl-propionic acid The title compound was prepared following the procedure described in example 15e, step B, starting from 3- (3 { [(4-pyrazin-2-yl-benzyl) - (thiazole-2-sulfonyl) -methyl ester - amino] -methyl] -phenyl) -propionic acid from step A. 1 H NMR (400 MHz, CDCl 3) d 8.79 (s, 1 H), 8.46 (s, 1 H), 8.31 (s, 1 H) ), 7.81 (d, 1H), 7.69 (d, 2H), 7.56 (d, 1H), 7.09 (d, 2H), 6.95 (m, 1H), 6.88 (m, 1H), 6.76 (m, 1H) , 6.72 (s, 1H), 4.36 (s, 2H), 4.40 (s, 2H), 2.62 (t, 2H), 2.30 (t, 2H), EM493 (M-1).

EXAMPLE 16a 3- (3- (. {- Benzenesulfonyl-r3- (3,5-dichloro-phenyl-propion-amino-methyl-phenyl-propionic acid Step A: Alkylation 3-f3 - ((Benzenesulfonyl- [3- (3,5-dichloro-phe- lo-p-allyl-amino} -methyl) -phenn-propionic acid methyl ester Following the procedure described in step A of Example 2, 3- ({3- (benzenesulfonylamino-methyl) -phenyl) -proponic acid methyl ester was alkylated with 1- (3-bromo-propenyl) -3,5-dichloro -benzene to give the title compound of step A. 1 H NMR (400 MHz, CDCl 3) d 7.87 (dd, 2 H), 7.63 (m, 1 H), 7.55 (m, 2 H), 7.22 (m, 2 H), 7.07. (m, 3H), 6.93 (s, 2H), 6.11 (d, 1 H), 5.77 (m, 1 H), 4.34 (s, 2H), 3.87 (d, 2H), 3.66 (s, 3H), 2.87 (t, 2H), 2.54 (t, 2H).

Step B: Hydrogenation 3- [3- (. {Benzenesulfonyl- [3- (3,5-dichloro-phenyl-propyl-aminol-methyl-phenyl-propionic acid methyl ester A mixture of 3- [3-methyl ester] 3- (. {Benzenesulfonyl- [3- (3,5-dichloro-phenyl) -allyl] -amino} - methyl) -phenyl] -propionic acid from step A (237 mg), Pt? 2 (30 mg) and MeOH, was hydrogenated on a Parr shaker at 344,737 kPa for 2 h.

The catalyst was removed by filtration through Celite and the volatile phase was removed in vacuo to give the title compound (240 mg). 1 H NMR (400 MHz, ¡¡¡¡¡¡¡¡¡¡¡¡Á áAA, á¡? & m > .

CDCl 3) d 7.82 (d, 2H), 7.76-7.50 (m, 3H), 7.23 (m, 1 H), 7.07 (m, 4H), 6.74 (s, 2H), 4.26 (s, 2H), 3.64 (d, s, 3H), 3.09 (t, 2H), 2.90 (t, 2H), 2.56 (t, 2H), 2.37 (t, 2H), 1.56 (m, 2H).

Step C: Hydrolysis of the ester 3-3 3 - ((Benzenesulfonyl- [3- (3,5-dichloro-phenyl-P-propyl) -amino> -methyl-phenylpropionic acid Following the general procedure described in step C of Example 1, 3- [3- (. {Benzenesulfonyl- [3- (3,5-dichloro-phenyl) -propyl] -amino} -methyl) -phenyl] -propionic acid methyl ester from step B was hydrolyzed to give the title compound: 1 H NMR (400 MHz, CDCl 3) d 7.82 (dd, 2H), 7.62-748 (m, 3H), 7.26-709 (m, 5H), 6.74 (s, 2H), 4.27 (s, 2H), 3.10 (t, 2H), 2.91 (t, 2H), 2.62 (t, 2H), 2.38 (t, 2H), 1.56 (m, 2H), EM 506 (M +).

EXAMPLE 16b Acid 3-. { 3- (f-benzenesulfonyl-2 - (3-chloro-phenoxyp-etl-1-amino) -met-P-phenylpropionic acid Step A: Alkylation 3-l3 - ((Benzenesulfonyl- [2- (3-chloro-phenoxyp-ethylamino-methyl-diene-phenyl-propionic acid) methyl ester Following the procedure in step A of example 2, the ester 3- [3- (Benzenesulfonylamino-methyl) -phenyl] -propionic acid methyl was re alkylated with 1- (2-bromo-ethoxy) -3-chloro-benzene to give the title compound from step A. 1 H NMR (400 MHz , CDCl 3) d 7.86 (dd, 2H), 7.60-7.49 (m, 3H), 7.22 (d, 1 H), 7.13-7.06 (m, 4H), 6.88 (m, 1 H), 6.60 (d, 1 H), 6.52 (m, 1 H), 4.42 (s, 2H), 3.88 (s, 2H), 3.65 (s, 3H), 3.47 (t, 2H), 2.87 (t, 2H), 2.54 (t, 2H).

Step B: Hydrolysis of the ester 3-3 3 - ((Benzenesulfonyl-f2- (3-chloro-phenoxy) -ethyl] -amino) -methi-phenyl-propionic acid The title compound was prepared following the procedure described in step C of Example 1 from the 3- [3- (benzenesulfonyl- [2- (3-chloro-phenoxy) -ethyl] -amino] -methyl) -phenyl] -propionic acid methyl ester of step B. 1 H NMR (400 MHz, CDCl 3) d 7.84 (dd, 2 H), 7.60-7.49 (m, 3 H), 7.23 (m, 1 H), 7.10 (m, 4 H), 6.88 (m, 1 H), 6.60 (m, 1H), 6.52 (m, 1 H), 4.43 (s, 2H), 3.88 (t, 2H), 3.47 (t, 2H), 2.87 (t, 2H), 2.59 (t, 2H).

PREPARATION 1 7-amino-heptanoic acid methyl ester hydrochloride A solution of 7-amino-heptanoic acid (3.0 g, 21.0 mmol) in 25 mL of MeOH and 2.4 mL of concentrated HCl was heated to reflux for 4 hours and stirred at room temperature for 60 h. The mixture was concentrated in vacuo to give the title compound (3.3 g). 1 H NMR (400 MHz, CD3OD) d 3.62 (s, 3H), 2.89 (m, 2H), 2.31 (t, 2H), 1.62 (m, 4H), 1.37 (m, 4H).

PREPARATION 2 Pyridin-3-sulfonyl chloride hydrochloride The title compound was prepared using the procedure described by Karaman, R. et al. J. Am. Chem. Soc. 114, 12, 1992, 4889-1898.

PREPARATION 3 3- (3-Chloro-PheniP-propionaldehyde A solution of 1-chloro-3-iodobenzene (9.63 g, 40.38 mmol), allyl alcohol (5.86 g, 100.96 mmol), so bicarbonate (8.48 g, 100.96 mmol), tetrabutylammonium chloride (11.22 g, 40.38 mmol) and Pd (OAc) 2 (317 mg, 1413 mmol) in 25 ml of DMF was stirred at 50 ° C for 16 h. The mixture was cooled to room temperature, diluted with water and the aqueous solution was washed with AcOEt. The organic solution was washed with water followed by brine, dried over MgSO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (hexanes: AcOEt 9: 1) to give the title compound as an oil (5.04 9) - PREPARATION 4 5- (3-Oxo-propiP-thiophene-2-carboxylic acid tert-butyl ester Step A: Formation of the ester 5-bromo-thiophene-2-carboxylic acid tert-butyl ester To a solution of anhydrous MgSO 4 (11.60 g, 96.4 mmol) in 100 ml of CH 2 Cl 2, concentrated H 2 SO 4 (1.45 ml, 24.1 mmol) was added. and the mixture was stirred for 15 minutes followed by the addition of 5-bromo-thiophene-2-carboxylic acid (5.0 g, 24.1 mmol). After stirring for 1 minute, tert-butanol (11.6 g, 20 mmol) was added and the reaction was stirred at room temperature for 16 h. The reaction was quenched with saturated NaHCO 3. The layers were separated, the aqueous layer was extracted with CH2Cl2 and the combined organic layers were dried over MgSO4. The organic solution was concentrated to give a clear oil, which was purified by me pressure chromatography (3% AcOEt in hexanes) to give the title compound of step A (4.97 g). 1 H NMR (400 MHz, CDCl 3) d 7.45 (d, 1 H), 7.02 (d, 1 H), 1.54 (s, 9H).

Step B: Formation of the aldehyde 5- (3-Oxo-propyl) -thiophene-2-carboxylic acid tert-butyl ester To a solution of 5-bromo-thiophene-2-carboxylic acid tert-butyl ester prepared according to procedure of preparation 4, step A (0.50 g, 1.89 mmol) in 5 ml of DMF, allyl alcohol (0.51 ml, 7.57 mmol) was added followed by NaHCO 3 (0.397 g, 4.72 mmol), tetrabutylammonium chloride (0.525 g, 1.89 mmole) and palla acetate (0.021 g, 0.094 mmole) The reaction was placed in an oil bath heated to 65 ° C and heated to 90 ° C for 2 h.The mixture was diluted with AcOEt and 25 ml of Water and the solids were removed by filtration through Celite®, the layers were separated and the organic solution was washed with water (4x)., dried over MgSO4 and concentrated to give a dark yellow oil which was purified by medium pressure chromatography (hexanes: AcOEt 7: 1) to give the title compound (0.190 g). 1 H NMR (400 MHz, CDCl 3) d 9.80 (s, 1 H), 7.51 (d, 1 H), 6.78 (d, 1 H), 3.14 (t, 2 H), 2.86 (t, 2 H), 1.54 (s) , 9H).

PREPARATION 5 5- (3-Amino-propyP-thiophene-2-carboxylic acid methyl ester Step A 5- (3-tert-Butoxycarbonylamino-prop-1-yl) -thiophen-2-carboxylic acid methyl ester A mixture of the tert-butyl ester of prop-2-inylcarbamic acid (from preparation 41, 1.67 g, 0.011 mmol), 5-bromo-thiophene-2-carboxylic acid methyl ester (2.50 g, 0.011 mmol), tetrakistriphenylphosphine (0) palladium (0.622 g, 0.0538 mmol), Cul (0.102) g, 0.538 mmole) and triethylamine (1.57 ml, 0.011 mmole) in 50 ml of acetonitrile was heated to reflux for 16 h. The reaction was cooled to room temperature, diluted with 75 ml < 7 g of AcOEt, washed with 5.5% HCl, water and brine and dried over MgSO 4, filtered and concentrated in vacuo to give an oil. The product was purified by flash chromatography (hexanes: AcOEt 9: 1 to 4: 1) to give the title compound of step A as an oil (2.06 g). MS 313 (M + 18).

Step B 5- (3-tert-Butoxycarbonylamino-propyP-thiophene-2-carboxylic acid methyl ester A solution of 5- (3-tert-butoxycarbonylamino-prop-1-ynyl) -thiophene-2-methyl ester carboxylic acid prepared in preparation 5, step A (2.06 g) and 10% Pd / C / 1.03 g) in 50 ml of MeOH was hydrogenated on a Parr shaker at 344.737 kPa of H2 for 16 h. The reaction was filtered through Celite® by MeOH and the filtrate was concentrated in vacuo to give the title compound from Step B as a solid (1.93 g). MS 317 (M + 18).

Step C 5- (3-Aminopropyl) -thiophene-2-carboxylic acid methyl ester A solution of the 5- (3-tert-butoxycarbonylamino-propyl) -thiophene-2-carboxylic acid methyl ester of the preparation 5, step B (0.118 g, 0.5 mmol) in 50 ml of MeOH was cooled to 0 ° C and saturated with HCl (g). The reaction was stirred at room temperature for 90 minutes. The solution was concentrated to give a solid, which was partitioned between AcOEt and NaHCO3. The layers were separated and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as an oil (399 mg). MS 200 (M + 1).

PREPARATION 6 Hydrochloride salt of 5- (3-amino-propyP-furan-2-carboxylic acid methyl ester The compound of preparation 6 was prepared from the appropriate starting materials analogously to the process of preparation 5, with the following exceptions: (1) the hydrogenation performed in step B was carried out for 5.5 hr. ) in step C, the reaction was stirred for 16 h at room temperature and concentrated in vacuo to give the title compound as the hydrochloride salt.

PREPARATION 7 5- (3-Amino-propiD-thiophene-2-carboxylic acid tert-butyl ester Step A: Benzyl ester of prop-2-inylcarbamic acid To a solution of propargylamine (6.4 g, 71.2 mmol) in pyridine (100 ml) was added benzyl chloroformate (13.37 g, 78.2 mmol) in 100 ml of CH2Cl2 for 0.5 h. The reaction was stirred for 16 h and the volatile phase was removed in vacuo. The residue was dissolved in AcOEt and the organic solution was washed with water (2x). The organic solution was washed with dilute aqueous HCl followed by saturated NaHCO 3. The organic solution was dried over MgSO 4, filtered and concentrated in vacuo to give the title compound of step A (4.43 g).

Step B: 5- (3-Benzyloxycarbonylamino-prop-1-ynyl-thiophene-2-carboxylic acid) tert-butyl ester The title compound of step B was prepared from the appropriate starting material in a manner analogous to the procedure used in step A of preparation 5.

Step C 5- (3-Amino-propyl) -thiophene-2-carboxylic acid tert-butyl ester) To a solution of 5- (3-benzyloxycarbonylamino-prop-1-ynyl) -thiophenic acid tert-butyl ester 2-carboxylic acid from preparation 7, step B (1.0 g, 2.69 mmol) in 15 ml of MeOH and 2.69 ml of 1 N HCl (aq) was added Pd (OH) 2. The mixture was hydrogenated on a Parr shaker at 310.26 kPA of H2 for 16 h. The mixture was filtered through Celite®, the catalyst was replaced and the reaction was stirred for another 6 h. The mixture was filtered through Celite® and concentrated in vacuo. Ef pfsiduo was picked up with CCU and crushed with Et20. The product was isolated as a solid (360 mg).

PREPARATION 8 5- (3- (3-Chloro-phenyl) -propylamino) -propyl) -thiophene-2-carboxylic acid methyl ester A solution of 5- (3-amino-propyl) -thiophene-2-carboxylic acid methyl ester (from preparation 5, step C, 0.118 g, 0.5 mmol) and N, N-diisopropylethylamine (0.071 g, 0.55 mmol) in 10 ml of MeOH was stirred at room temperature for 30 minutes and 3- (3-chloro-phenyl) -propionaldehyde (from preparation 3, 0.093 g, 0.55 mmol) was added. The mixture was stirred for 90 minutes. The reaction was cooled to 0 ° C, NaBH 4 (30.3 mg, 0.801 mmol) was added and the mixture was stirred for 30 minutes. The reaction was quenched with NaHC? 3: H2O 1: 1 and washed with CH2Cl2. The CH2Cl2 extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as an oil (171 mg). MS 352 (M + 1).

PREPARATIONS 9-10 The compounds of preparations 9 and 10 were prepared from the corresponding appropriate starting materials in a manner analogous to the procedure of preparation 8.

PREPARATION 9 5- (3- (3- (3-Chloro-phenyl) -propylamino) -propyl) -thiophene-2-carboxylic acid tert-butyl ester PREPARATION 10 5- (3- (3- (3-Chloro-phenyl) -propylamino) -propiP-furan-2-carboxylic acid methyl ester MS 336 (M + 1).

PREPARATION 11 Methyl ester of (3-formyl-phenoxyp-acetic acid A mixture of (3-formyl-phenoxy) -acetic acid (3.6 g, 20.0 mmol), potassium carbonate (3.30 g, 23.9 mmol) and methyl iodide (1.86 g, 30.0 mmol) in 25 mL of DMF was heated to 110 C for 2 hours and stirred at room temperature for 16 h. The mixture was diluted with water and the aqueous solution was extracted with AcOEt. The organic solution was washed with water, dried over MgSO 4, filtered and concentrated in vacuo. The product was purified by chromatography on silica gel (hexanes: AcOEt 4: 1) to give the title compound as a pale yellow oil (3.4 g). 1 H NMR (400 MHz, CDCl 3) d 9.94 (s, 1 H), 7.33 (S, 1 H), 7.23 (m, 1 H), 4.68 (s, 2 H), 3.79 (s, 3 H).

PREPARATION 12 3- (3-chloro-phenyl) -propylamine Step A 3- (3-chloro-phenylacrylamide) A solution of 3- (3-chloro-phenyl) -acrylic acid (Aldrich, 15.0 g, 82.15 mmol) in 50 ml of thionyl chloride was heated to reflux for 30 minutes The excess thionyl chloride was removed by distillation at atmospheric pressure, the residue was azeotroped with benzene under vacuum to give 17,288 g of an orange oil, the oil was dissolved in 25 ml of CH 2 Cl 2 and the solution was slowly added to the liquid NH 3 ( 20 ml, 80.07 mmoles) in CHCl3 (50 ml) at -78 ° C. The resulting suspension was warmed to room temperature and concentrated in vacuo to give the title compound from step A as a gray solid (19.38 g). (400 MHz, CD3OD) d 7.57 (s, 1H), 7.45 (m, 2H), 7.36 (m, 1 H), 6.64 (d, 1 H), EM 182 (M + 1), 180 (M-1) ).

Step B 3- (3-chloro-phenD-propylamine A 1.0 M solution of LYAH4 in THF (6.0 mL) was added dropwise to a suspension of 3- (3-chloro-phenyl) -acrylamide prepared in the preparation 12, step A (1.0 g, 5.51 mmol) in 30 ml of THF at 0 ° C. The reaction was warmed to room temperature and stirred for 5 h, 4 ml of 1 M LIAH 4 was further added and the reaction was stirred for After 18 h, 2 ml of 1 M LYMIH4 were further added and the reaction was stirred for 24 h.The reaction mixture was quenched by the dropwise addition of water.The mixture was concentrated in vacuo to remove THF and diluted with water. The aqueous solution was extracted with AcOEt The organic solution was washed with water, dried over MgSO 4, filtered and concentrated in vacuo.The residue was dissolved in CHCl 3 and the organic solution was washed with 1 M HCl. The aqueous solution was basified to pH 11 with 1 M NaOH and the product was extracted into CHCl 3. The organic phase was dried over MgSO, filtered and concentrated in vacuo to give the title compound as a yellow oil (0.134 g). 1 H NMR (400 MHz, CDCl 3) d 7.20-7.22 (m, 3 H), 7.16 (m, 1 H), 2.74 (t, 2 H), 2.61 (t, 2 H), 1.74 (m, 2 H); MS 170 (M + 1).

PREPARATION 13 Methyl ester of (3-formyl-phenyl-acetic acid) Step A (3-Cyano-phenyp-acetic acid methyl ester) Nitrogen was bubbled through a mixture of (3-bromo-phenyl) -acetic acid methyl ester (22.85 g, 99.78 mmol), Zn (CN) 2 (7.25 g, 61.75 mmol) and DMF (100 ml) for about 5 minutes followed by the addition of tetrakistriphenylphosphine (0) palladium (4.60 g, 3.98 mmol) The mixture was heated for 3 h at 80 ° C and cooled to room temperature 2N NH4OH was added and the product was extracted with AcOEt (3x) .The organic solution was washed with 2N NH4OH (2x) followed by brine (2x) .The organic solution was dried (MgSO4), filtered and concentrated to dryness. The purification by flash chromatography (hexanes: AcOEt 6: 1) gave the title compound from step A as an oil (15.19 g). 1 H NMR (400 MHz, CDCl 3) d 7.57-7.41 (m, 4H), 3.706 (s, 3H), 3,703 (s, 2H).

Step B (3-formyl-phenyl-acetic acid methyl ester A mixture of (3-cyano-phenyl) -acetic acid methyl ester prepared in preparation 13, step A (1.56 g, 8.91 mmol), aluminum alloy - Nickel (1.63 g) and 75% formic acid (25 ml) was heated to reflux for 17.5 h The mixture was cooled to room temperature and the solids were removed by filtration through Celite® by boiling EtOH. the aqueous solution was washed with CH2Cl2 (3x), saturated NaHC03 was carefully added to the organic solution until the pH was about 8- 9. The organic solution was washed with brine, dried over MgSO4 and concentrated. Flash chromatography (hexanes: AcOEt 5: 1) gave the title compound as a clear, colorless oil (870 mg). 1 H NMR (400 MHz, CDCl 3) d 9.98 (s, 1 H), 7.77 (m, 2H), 7.55-7.46 (m, 2H), 3.68 (s, 5H).

PREPARATION 14 (3 - ((Pyridin-3-sulfonylamino) -methyl) -phenyl-acetic acid methyl ester To a solution of the methyl ester of (3-aminomethyl-phenyl) -acetic acid methyl ester (from preparation 18, 0.56 g) and diisopropylamine (2.2 ml) in 10 ml of dichloromethane was added pyridine-3-sulfonyl chloride (from Preparation 2, 0.601 g, 2.83 mmol) and the reaction was stirred at room temperature for 16 h. 1 N HCl was added and the solution was washed with CH 2 Cl 2. The organic solution was washed with saturated NaHCO3, dried over MgSO4, filtered and concentrated in vacuo to give the title compound. Purification by flash chromatography on silica gel (hexanes: AcOEt 2: 1) gave the title compound as a white solid. 1 H NMR (400 MHz, CDCl 3) d 8.91 (s, 1 H), 8.71 (d, 1 H), 8.04 (d, 1 H), 7.37 (m, 1 H), 7.05-7.24 (m, 4H), 5.87 (sa, 1 H), 4.14 (s, 2H), 3.62 (s, 3H), 3.52 (s, 2H).

PREPARATION 15 Procedure A 4-Butylbenzylamine A solution of 4-butyl-benzonitrile (3.63 g, 22.8 mmol) in THF (10 ml) was placed in a three-necked round bottom flask equipped with a Vigreux column and a short path distillation head. . The solution was heated to reflux and a complex of BH3-methyl sulfide (2.0 M in THF, 15 ml, 30 mmol) was added dropwise during • 15 minutes. Methyl sulfide was distilled from the reaction mixture for 1 h and the solution was cooled to room temperature. Aqueous HCl (6N, 25 ml) was slowly added via an addition funnel and the mixture was heated to reflux for 30 minutes. The reaction was cooled to 0 ° C and NaOH (7.0 g) was added in portions. The aqueous solution was washed with AcOEt (3x) and the organic solution was dried (MgSO 4), filtered and concentrated to give the title compound of procedure A (4.01 g). 1 H NMR (400 MHz, CDCl 3) d 7.34 (m, 2 H), 7.24 (m, 2 H), 4.04 (s, 2 H), 2.62 (t, 2 H), 1.58 (m, 2 H), 1.34 (m, 2 H) , 0.92 (t, 3H).

Method B 15 4-Butylbenzylamine Hydrochloride A solution of 4-butylbenzonitrile (30.09 g) in EtOH (380 ml) and HCl (4N, in dioxane, 50 ml, 200 mmol) was hydrogenated at 344,737 kPa on a Parr shaker in the presence of 10% palladium on carbon (6.09 g). The catalyst was removed by filtration through Celite® and the solution was concentrated in vacuo. The residue was suspended in Et 0 and filtered to give the 4-butylbenzylamine hydrochloride as a grayish solid (32.47 g). 1 H MHz NMR, CD 3 OD) d 7.33 (d, 2 H), 7.22 (d, 2 H), 4.04 (s, 2 H), 2.60 (t, 2 H), 1.56 (m, 2 H), 1.31 (m, 2 H), 0.89 (t, 3H), «Aj * -. at-i Using the appropriate starting materials, the compounds of preparations 16-18 were prepared analogously to the procedure of preparation 15.

PREPARATION 16 2- (3,5-dichloro-phenoxypylamine The title compound was prepared following procedure A of preparation 15.

PREPARATION 17 2-3-chloro-phenoxypylamine The title compound was prepared following the procedure of preparation 15.

PREPARATION 18 (3-aminomethyl-phenyD-acetic acid methyl ester hydrochloride The title compound was prepared from the methyl ester of (3-cyano-phenyl) -acetic acid (from preparation 13, step A), using the procedure described for preparation 15, method B, with the exception that the Hydrogenation was performed in MeOH. The catalyst tt ^ tü was removed by filtration and the organic solution was concentrated in vacuo. The resulting solid was stirred in AcOEt and filtered to give the title compound as a white solid. 1 H NMR (400 MHz, CDCl 3) d 7.42-7.32 (m, 4H). 4.09 (s, 2H), 3.69 (s, 2H), 3.67 (s, 3H): MS 180 (M + 1).

PREPARATION 19 Trans-? - (3-bromo-propenyl) -3,5-dichloro-benzene Step A 1 - (3,5-dichloro-phenyl) -prop-2-en-1 -ol A solution of 3,5-dichlorobenzaldehyde (7.5 g, 43 mmol) in THF (75 ml) was cooled to 0 ° C and vinylmagnesium bromide (1 M in THF, 48 ml, 48 mmol) was added dropwise. The reaction was warmed to room temperature and stirred for 16 h. Aqueous HCl (1 N) and AcEOt were added. The aqueous solution was washed with AcEOt and the organic solution was dried (MgSO4), filtered and concentrated. The residue was used in the next step without further purification.

Step B The residue prepared in step A was dissolved in Et2O and gaseous HBr was bubbled slowly into the solution for about minutes. The reaction was stirred at room temperature for 24 hours and water and AcOEt were added. The aqueous solution was extracted with AcOEt and the organic solution was dried (MgSO 4), filtered and concentrated. Purification by flash chromatography (hexanes) gave the title compound of preparation 19 (6.91 g). 1 H NMR (400 MHz, CDCl 3) d 7.24 (s, 3 H), 6.53 (d, 1 H), 6.40 (m, 1 H), 4.10 (m, 2 H).

PREPARATION 20 (3-aminomethyl-phenoxyp-acetic acid) tert-butyl ester Step A (3-formyl-phenoxy) -acetic acid tert-butyl ester To a solution of 3-hydroxybenzaldehyde (5.00 g, 40.9 mmol) in DMF (40 ml) was added 1 M potassium tert-butoxide in tert-butanol ( 40.9 ml, 40.9 mmol). The reaction was stirred for 2 minutes and tert-butyl bromoacetate (6.61 mmoles, 40.9 mmoles) was added. The reaction was stirred for 1 hour and quenched with 200 ml of water. The product was extracted into AcOEt and the organic solution was washed with water, dried over MgSO 4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel (hexanes: AcOEt 9: 1) gave the title compound of step A as a clear oil (3.53 g). 1 H NMR (400 MHz, CDCl 3) d 9.94 (s, 1 H), 7.48 (m, 2 H), 7.32 (s, 1 H), 7.21 (m, 1 H), 4.56 (s, 2 H), 1.45 (s, 9 H) ).

Step B (3-Hydroxyimino-methyP-phenop-acetic acid) tert-butyl ester To a solution of (3-formyl-phenoxy) -f9-acetic acid tert-butyl ester of preparation 20, step A (2.05 g, 8.68 mmoles) in MeOH (30 ml) was added NH2OH HCl (0.66 g, 9.54 mmol) and pyridine (3.5 ml, 43.4 mmol) and the reaction was stirred for 2 hours.The MeOH was removed under vacuum and the residue was diluted with AcOEt and 1 N HCl The layers were separated and the aqueous solution was washed with AcOEt The combined organic layers were dried over MgSO, filtered and concentrated in vacuo to give the title compound • 10 from step B (1.99 g). 1 H NMR (400 MHz, CDCl 3) d 8.07 (s, 1 H), 7.23-7.28 (m, 2 H), 7.12 (m, 1 H), 6.93 (d, 1 H), 4.51 (s, 2 H), 1.46 (s, 9H).

Step C (3-aminomethyl-phenoxyacetic acid) tert-butyl ester To a solution of (3-hydroxyimino-methyl) -phenoxy) -acetic acid tert-butyl ester prepared in preparation 20, step B (2.25 g) , 5.96 mmole) in EtOH (10 ml) was added Raney nickel (approximately 1 g, washed with water followed by EtOH) in 100 ml EtOH. Additional EtOH (90 ml) was required for the transfer. Ammonium hydroxide (10 ml) was added and the mixture was stirred at 310.26 kPa of H2 for 4 hours. The catalyst was removed by filtration through Celite® and the solution was concentrated to give a clear oil. Purification by flash chromatography on silica gel (CH2Cl2 / MeOH / NH4OH 96.5 / 3.5 / 0.1 to t & Miß ^. 9/1 / 0.1) gave the title compound as a yellow oil. 1 H NMR (400 MHz, CDCl 3) d 7.23 (m, 1 H), 6.92 (m, 2 H), 6.72 (d, 1 H), 4.50 (s, 2 H), 3.82 (s, 2 H), 1.96 (m, 2H), 1.46 (s, 9H); EM 238 (M + 1).

PREPARATION 21 4-pyrimidin-2-yl-benzaldehyde A solution of 2-bromopyridine (1.00 g, 6.3 mmol) and tetrakisphenylphosphine (O) palladium (0.218 g, 0.189 mmol) in ethylene glycol dimethyl ether (30 mL) was stirred at room temperature for 10 minutes. A solution of 4-formylbenzeneboronic acid (1.14 g, 7.61 mmol) and sodium bicarbonate (1.58 g, 18.9 mmol) in 15 mL of water was added and the reaction was heated to reflux for 16 h. The mixture was diluted with water and CH2Cl2. The layers were separated and the aqueous solution was washed with CH2Cl2. The combined organic layers were dried over MgSO 4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexanes in AcOEt 10 to 30%) to give the title compound (0.979 g). 1 H NMR (400 MHz, CDCl 3) d 10.11 (s, 1 H), 8.83 (s, 2 H), 8.82 (s, 1 H), 7.98 (s, 2 H), 7.23 (s, 2 H). fc ^ - ^ - ^ f ^ ^^ u PREPARATIONS 22-27 Preparations 22-27 were prepared from the appropriate starting materials in a manner analogous to the procedure of preparation 21.

PREPARATION 22 4-pyridin-2-yl-benzaldehyde 1 H NMR (400 MHz, CDCl 3) d 10.09 (s, 1 H), 8.72 (s, 1 H), 8.16 (s, 2H), 7.95 (s, 2H), 7.79 (s, 2H), 7.29 (m, 1 H); MS 184 (M + 1).

PREPARATION 23 4-pyridin-3-yl-benzaldehyde 1 H-NMR (400 MHz, CDCl 3) d 10.04 (s, 1 H), 8.88 (s, 1 H), 8.64 (s, 1 H), 7.97 (s, 2 H), 7.91 (m, 1 H), 7.75 ( m, 2H) 7.39 (m, 1 H); MS 184 (M + 1).

PREPARATION 24 4-pyridin-4-yl-benzaldehyde 1 H NMR (400 MHz, CDCl 3) d 10.03 (s, 1 H), 8.70 (s, 2 H), 7.99 (s, H), 7.79 (s, 2 H), 7.52 (s, 2 H); MS 184 (M + 1).

PREPARATION 25 4-thiazol-2-yl-benzaldehyde MS 189 (M +).

PREPARATION 26 4-pyrimidin-5-yl-benzaldehyde 1 H NMR (400 MHz, CDCl 3) d 10.03 (s, 1 H), 9.26 (s, 1 H), 9.00 (s, 2 H), 8.03 (m, 2 H), 7.76 (m, 2 H).

PREPARATION 27 4-pyrazin-2-yl-benzaldehyde 1 H NMR (400 MHz, CDCl 3) d 10.03 (s, 1 H), 9.10 (s, 1 H), 8.69 (s, 1 H), 8.59 (s, 1 H), 8.21 (d, 2H) 8.03 (d, 2H).

PREPARATION 28 1- (2-bromo-ethoxy-3,5-dichloro-benzene) To a solution of NaOH (2.45 g, 61.3 mmol) in water (20 ml) was added 3,5-dichlorophenol (5 g, 30.7 mmol). The solution was refluxed for 1 h and cooled to room temperature. 1,2-Dibromoethane (11.52 g, 61.3 mmol) was added and the reaction was heated to reflux for 24 h. The cooled solution was diluted with AcOEt and the organic solution was washed sequentially with HCl (1 N, 1x), water (1x) and brine (1x). The organic solution was dried (MgSO), filtered and concentrated. Purification by flash chromatography (hexanes, to 5% AcOEt in hexanes) gave the title compound (3.79 g). 1 H NMR (400 MHz, CDCl 3) d 6.98 (m, 1 H), 6.82 (m, 2 H), 4.25 (t, 2 H), 3.61 (t, 2 H).

PREPARATION 29 1 - (2-bromo-ethoxy) -3-chlorobenzene The compound of preparation 29 was prepared from the appropriate starting materials analogously to the procedure of preparation 28.

PREPARATION 30 Bromide of 4-rd-acetiloxp-hexipbencilo Step A: Griqnard reaction and protection of 4 - ((1-acetoxyloxy) -hexyl) -toluene Pentylmagnesium bromide (2.0 M in Et2O) was added slowly, 25 mL, 50 mmol) was added to p-tolylbenzaldehyde (5.0 mL, 42.4 mmol) in THF (50 mL) at 0 ° C. The reaction was warmed to room temperature and stirred for 3 h. Aqueous 1N HCl was added and the aqueous solution was extracted with AcOEt. The organic solution was washed with brine, dried over MgSO 4, filtered and concentrated. The residue was dissolved in pyridine (35 ml) and Ac20 (10 ml) was added. The reaction was stirred for 24 h and diluted with water. The product was extracted into AcOET (3x) and the organic solution was washed with 1 N HCl followed by brine, dried MgSO4, filtered and concentrated. The product was purified by flash chromatography (10% AcOET / hexanes) to give 4 - ((1-acetyloxy) -hexyl) -toluene (2.082 g). 1 H NMR (400 MHz, CDCl 3) d 7.12-7.28 (m, 4 H), 5.69 (t, 1 H), 2.33 (s, 3 H), 2.04 (s, 3 H), 1.88 (m, 1 H), 1.74 ( m, 1 H), 1.27 (m, 6H), 0.86 (m, 3H); EM 252 (M + 18).

Step B Benzyl bromination A mixture of 4 - [(1-acetyloxy) -hexyl] -toluene prepared in preparation 30, step A (2.082 g, 8.89 mmol), N-bromo-succinimide (1.58 g, 8.89 mmol) and 2 , 2, catalytic azobisisobutyronitrile in carbon tetrachloride (30 mL) was heated to reflux for 2 h. The reaction was cooled and washed with aqueous NaHCO3 (saturated), dried over MgSO4, filtered and concentrated. The product was purified by flash chromatography (5% AcOET / hexanes) to give the title compound (2.67 g). 1 H NMR (400 MHz, CDCl 3) d 7.34-7.40 (m, 4 H), 5.70 (t, 1 H), 4.47 (s, 2 H), 2.06 (s, 3 H), 1.86 (m, 1 H), 1.73 ( m, 1 H), 1.27 (m, 6H), 0.85 (m, 3H).

PREPARATION 31 1 -methyl-1 H-indol-2 -carbaldehyde The title compound was prepared using the procedure described by Comins et al. In J. Org. Chem., 52, 1, 104-109, 1987.

PREPARATION 31 5-phenyl-furan-2 -carbaldehyde The title compound can be prepared using the procedure described by D'Auria et al in Heterocycles 24, 6, 1575-1578, 1986.

PREPARATION 33 4-phenethylsulfanyl-benzaldehyde The title compound can be prepared using the procedure described by Clark et al. In EP 332331.

PREPARATION 34 3-hydroxy-4-propoxy-benzaldehyde The title compound can be prepared using the procedure described by Beke in Acta Chim. Acad. Sci. Hung., 14, 325-328, 1958.

PREPARATION 35 4-formyl-N-methyl-benzenesulfonamide The title compound can be prepared using the procedure described by Koetschet in Helv. Chim. Acta., 12, 682, 1929.

PREPARATION 36 4-chloro-thiophene-2-carbaldehyde The title compound can be prepared using the procedure described by Raggon et al. In Org. Prep. Procedure Int; IN 27, 2, 233-236, 1995. teafe - ^^ - u,; - PREPARATION 37 4-cyclohexyl-benzylamine The title compound can be prepared using the procedure described by Meglio et al. In Drug Ed. Sci .; ITEM; 35, 3, 191-202, 1980.

PREPARATION 38 4-imidazol-1-yl-benzaldehyde The title compound can be prepared using the procedure described by Sircar et al. In J. Med. Chem. 30, 6, 1023-1029, 1987.

PREPARATION 39 4- (2-oxo-pyrrolidin-1-iP-benzaldehyde The title compound can be prepared using the procedure described by Kukalenko in Chem. Heterocycl. Compd. (English translation)., 8, 43, 1972.

M PREPARATION 40 2- (3-chloro-phenylsuthaniD-ethylamine The title compound can be prepared using the procedure described by Elz et al. In Fed. Rep. Ger. Sci. Pharm., 56, 4, 229-234, 1988.

PREPARATION 41 Tert-Butyl Ester of Prop-2-Inyl-Carbamic Acid 10 The title compound can be prepared using the procedure described in J. Chem. Soc. Perkin Trans. I, 1985, 2201-2208.

PREPARATION 42 15 4-pyrazol-1-yl-benzaldehyde Step A 4-pyrazol-1 -i-benzonitrile To a solution of 4-fluoro-benzonitrile (1.5 g, 12.35 mmol) and Pyrazole (0.843 g, 12.38 mmol) in DMF (10 mL) was added with NaH (60% in oil, 0.644 g, 16.09 mmol). The reaction was heated to 145 ° C during h. The reaction was cooled to room temperature and diluted with water and AcOEt. The aqueous layer was washed with AcOEt (3x) and the organic layers combined were washed with water (4x). The organic solution was dried (MgSO4), filtered and concentrated. Medium pressure chromatography (hexanes: AcOEt 4: 1) gave 4-pyrazol-1-yl-benzonitrile (1.6 g) as a white solid. f 1 H NMR (400 MHz, CDCl 3) d 7.97 (d, 1 H), 7.82 (d, 2 H), 7.73 (m, 3 H), 6.87 (d, 1 H); MS 170 (M + 1).

Step B 4-pyrazole-1-yl-benzaldehyde To a solution of 4-pyrazole-1-yl-benzonitrile (1.6 g, 9.47 • 10 mmol), prepared in step A of preparation 42, in 75% aqueous formic acid (36 ml) was added a Raney nickel alloy (1.6 g). The reaction was refluxed for 1.25 h and cooled to room temperature. The solids were removed by filtration through Celite by hot EtOH. The solution was diluted with water and CHCl3. The aqueous layer is washed with CHCl3 (3x). Aqueous NaHCO3 was carefully added to the organic solution until a pH of about 8 was reached. • organic dried (MgSO 4), filtered and concentrated. Purification by medium pressure chromatography (hexanes: AcOEt 2: 1) gave the title compound (1.44 g) as a white solid. 1 H NMR (400 MHz, CDCl 3) d 9.99 (s, 1 H), 8.01 (d, 1 H), 7.96 (d, 2 H), 7.87 (d, 2 H), 7.76 (d, 1 H), 6.51 (m, 1 H); MS 173 (M + 1).

PREPARATION 43 4-imidazol-1-yl-benzaldehyde The title compound was prepared following the procedure described for preparation 42. 1 H NMR (400 MHz, CDCl 3) d 10.04 (s, 1 H), 8.10 (s, 1 H), 8.02 (d, 2H), 7.58 (d , 2H), 7.38 (s, 1 H), 7.28 (s, 1 H); MS 173 (M + 1).

PREPARATION 44 3- (3-aminomethyl-phenyl-D-propionic acid methyl ester hydrochloride salt Step A 3- (3-Bromo-phenyl) -acrylic acid methyl ester A solution of 3-bromophenylacrylic acid (5.03 g), MeOH (75 ml) and concentrated HCl (1 ml) was heated at reflux for 3 h followed by stirring at room temperature for 20 h. Saturated NaHC 3 3 was added and the aqueous solution was washed with CH 2 Cl 2 (2x). The organic solution was dried (MgSO 4), filtered and concentrated to give the title ester from step A (4.75 g). 1 H NMR (400 MHz, CDCl 3) d 7.63-7.20 (m, 5H), 6.40 (d, 1 H), 3.78 (s, 3H).

Step B 3- (3-Cyano-phenyl) -acrylic acid methyl ester The title compound was prepared from the 3- (3-bromo-phenyl) -acrylic acid methyl ester of step A (4.75 g, 19.72 mmoles) following the procedure described for preparation 13, step A with a reaction time of 5 h. Purification by medium pressure chromatography (hexanes: AcOEt 9: 1) gave the title compound of step B (3.05 g). 1 H NMR (400 MHz, CDCl 3) d 7.75 (d, 1 H), 7.70 (m, 1 H), 7.64-7.60 (m, 2 H), 7.49 (m, 1 H), 6.46 (d, 1 H), 3.80 (s, 3H).

Step C 3- (3-aminomethyl-phenyl-D-propionic acid methyl ester hydrochloride salt A mixture of 3- (3-cyano-phenyl) -acrylic acid methyl ester from step B (1.37 g, 7.32 mmol), 10% palladium on carbon (1.0 g) and HCl (4N in dixoane, 3 ml) in MeOH (50 ml) was hydrogenated on a Parr shaker at 344.737 kPa for 65 h.The catalyst was removed by filtration through Celite and the solution was concentrated to give the title compound (1.97 g). 1 H NMR (400 MHz, CD3OD) d 7.35-7.24 (m, 4H), 4.06 (s, 2H), 3.60 (s, 3H), 2.92 (t, 2H), 2.64 (t, 2H).

PREPARATION 45 Thiazole-2-sulfonyl chloride To a thiazole solution (2.5 g, 85 mmol) in THF (40 ml) at -78 ° C was added dropwise n-BuLi (2.5 M in hexanes, 11.7 ml, 29.4 mmol). The solution was stirred for 0.5 h and SO2 (g) was bubbled into the reaction for about 10 minutes. The cold bath was removed and the reaction was stirred for 1.5 hours at room temperature. The THF (about 30 ml) was removed in vacuo at room temperature and N-chlorosuccinimide (4.3 g, 32.3 mmol) in THF (50 ml) was added dropwise. The reaction was stirred for 45 minutes and water (80 ml) was added. The aqueous solution was washed with CH2Cl2 (3x) and the organic solution was washed with brine. The organic solution was dried (MgSO), filtered and concentrated in vacuo at room temperature until almost dry. The residue was purified by medium pressure chromatography (hexanes: AcOEt 4: 1) to give the title compound as an amber oil (1.6 g). 1 H NMR (400 MHz, CDCl 3) d 8.11 (d, 1 H), 7.87 (d, 1 H).

PREPARATION 46 Methyl ester of 3-f3- (benzenesulfonylamino-metiP-phenyl-1-propionate acid) The title compound was prepared following the procedure described in step B of Example 3 from the benzenesulfonyl chloride and the hydrochloride salt of the 3- (3-aminomethyl-phenyl) -propionic acid methyl ester prepared in the preparation. 1 H NMR (400 MHz, CDCl 3) d 7.84 (d, 2 H), 7.58-7.47 (m, 3 H), 7.17 (m, 1 H), 7.06 (m, 1 H), 6.99 (m, 2 H), 4.62 (m, 1 H), 4.10 (d, 2H), 3.84 (s, 3H), 2.84 (t, 2H), 2.53 (t, 2H).

PREPARATION 47 1- (3-bromo-propenyl) -3,5-dichloro-benzene Step A: Griqnard reaction 1 - (3,5-dichloro-phenyl) -prop-2-en-1 -ol A solution of 3,5-dichlorobenzaldehyde (7.5 g, 43 mmol) in THF (75 ml) it was cooled to 0 ° C and vinylmagnesium bromide (1 M in THF, 49 mL, 48 mmol) was added dropwise. The reaction was warmed to room temperature and stirred overnight. Aqueous HCl (1 N) and AcOEt were added. The aqueous solution was extracted with AcOEt and the organic solution was dried (MgSO 4), filtered and concentrated. The residue was used in the next step without further purification.

Step B: Bromination 1- (3-bromo-propenyl) -3,5-dichloro-benzene The residue prepared in step A was dissolved in Et20 and slowly bubbled into the HBr gas solution for approximately 15 minutes. The reaction was stirred at room temperature for 24 h and water and AcOEt were added. The aqueous solution was extracted with AcOEt and the organic solution was dried (MgSO 4), filtered and concentrated. Purification by flash chromatography (hexanes) gave the title compound (6.91 g). 1 H NMR (400 MHz, CDCl 3) d 7.24 (s, 3 H), 6.53 (d, 1 H), 6.40 (m, 1 H), 4.10 (m, 2 H). PREPARATION 47 Pyridin-2-sulfonyl chloride hydrochloride The title compound can be prepared using the procedure described by Hanessian et al. In Heterocycles, 28, 1115-1120, 1989,

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula I

^ A. ^ C G ^ B ^ ^ Z

^ M Formula 1

prodrugs thereof and pharmaceutically acceptable salts of said compounds and prodrugs, wherein A is S02 or CO; G is Ar, Ar1-V-Ar2, -Ar-alkylene (C6), Ar-CONH-alkylene (C6-6), R1R2-amino, oxyalkylene (Cr6), amino substituted with Ar or amino substituted with Ar- (C1-C4) alkylene and R11, wherein R11 is H or alkyl (Ci-Cs), R1 and R2 can be taken separately and are independently selected from H and alkyl (CrC8), or R1 and R2 are attached to nitrogen atom of the amino group to form a six-membered azacycloalkyl, said azacycloalkyl optionally containing an oxygen atom and optionally mono-, di- or tri-substituted independently with up to two oxo, hydroxy, (C1-C4) alkyl, fluoro or chlorine; B is N or CH; Q is -alkylene (C2-C6) -W-alkylene (C1-C3) -, each said alkyl being optionally substituted with up to four substituents independently selected from fluoro or (C1-C4) alkyl, -alkylene (C4-) C8) -, said alkylene being optionally substituted with up to four substituents independently selected from fluoro or (C1-C4) alkyl, -X-(C1-C5) alkylene-, said alkylene being optionally substituted with up to four substituents independently selected from fluoro or (C1-C4) alkyl, -alkylene (d-CsJ-X-, said alkylene being optionally substituted with up to four substituents independently selected from fluoro or (C1-C4) alkyl, -alkylene (CrC3) -X-alkylene (C1-) C3) - each said alkyl being optionally substituted with up to four substituents independently selected from fluoro or (C1-C4) alkyl, -alkylene (C2-C4) -WX-alkylene (C0-C3) -, said alkyl cells being each of them optionally substituted with up to four substituents independently selected from fluoro or (C1-C4) alkyl, (C0-C) alkylene-WX-alkylene (C1-C3) -, each said alkylene being optionally substituted with up to four substituents independently selected from fluoro or (C1-C4) alkyl, -alkylene (C2-C5) -WXW-alkylene (C1-C3), wherein the two W's are independent from each other, said alkyl cells being each optionally substituted with up to four substituents independently selected from fluoro or (C1-C4) alkyl, -alkylene (CrC4) -ethylene-(C1-C4) alkylene-, said alkyl ethers and said ethylene being each optionally substituted with up to four independently selected substituents between fluoro or (C1-C4) alkyl, -alkylene (CrC4) -ethylene-alkylene (Co-C2) -X-alkylene (C0-C5), said alkyl ethers and said ethylene being each optionally substituted with up to four substituents independently selected from fluoro or (C-1-C4) alkyl, -alkylene (CrC4) -ethylene-alkylene (C0-C2) -XW-alkylene (C1-C3), said alkyl ethers and said ethylene being each of they optionally substituted with up to four substituents independently selected from fluoro or (C1-C4) alkyl, -alkylene (CrC4) -ethylene-alkylene (C1-C4), said alkyl ethers and said ethylene being each optionally substituted with up to four substituents independently selected from fluoro or (C 1 -C 4) alkyl, -alkylene (C 1 -C 4) -ethynylene-X-alkylene (C 0 -C 3), said alkyl ethers and said ethylene being each optionally substituted with up to four independently selected substituents between fluoro or (C 1 -C 4) alkyl, Z is carboxyl, alkoxy (Ci-C 1 ,carbonyl, tetrazolyl, 1,4-oxadiazolyl, 5-oxo-1, 2,4, -oxadiazolyl, 5-oxo-1, 2 , 4-oxadiazolyl, alkyl (C? -C4) sulfonylcarbamoyl or phenylsulfonylcarbamoyl; K is a bond, (C1-C9) alkylene, (C1-C4) -thioalkylene, alkylene (CrC4) thioalkylene (C1-C4), alkylene (C? -C4) oxyalkylene (C1-C4) or oxyalkylene (C-? - C4), said (C1-C9) alkylene being optionally monounsaturated and wherein, when K is not a bond, K is optionally mono-, di- or tri-substituted independently with chloro, fluoro, hydroxy or methyl; M is -Ar3, -Ar4-V1-Ar5, -Ar4-S-Ar5, -Ar ^ SO-Ar5, -Ar4-S02-Ar5 or -Ar4-0-Ar5; Ar is a five to eight link partially saturated or fully unsaturated ring and optionally has one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two rings of five or six condensed, partially saturated, fully saturated or totally unsaturated, considered independently, and which optionally have one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, or a tricyclic ring consists of three rings of five or six condensed, partially saturated, fully saturated or fully unsaturated , independently considered, and optionally having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said ring, bicyclic ring or tricyclic ring partially or fully saturated, optionally one or two oxo-substituted groups and n the carbon, or one or two oxo-substituted groups on the sulfur; or Ar is a fully saturated five to seven link ring having one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; Ar1 and Ar2 are each independently a ring of five to eight links partially saturated, fully saturated or completely unsaturated and optionally having from one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two rings of five or six condensed, partially saturated, fully saturated or totally unsaturated, independently considered, and optionally have one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three rings of five or six condensed, partially saturated, fully saturated or totally unsaturated, independently considered, and optionally having one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said ring, bicyclic ring or partial tricyclic ring having highly saturated, optionally one or two oxo-substituted groups on the carbon, or one or two oxo-substituted groups on the sulfur; said radicals Ar and Ar1 and Ar2 are optionally substituted on carbon or on nitrogen, on a ring if the radical is monocyclic, on one or both rings if the radical is bicyclic, or on one, two or three rings if the radical is tricyclic, with up to three substituents per radical independently selected from R3, R4 and R5, wherein R3, R4 and R5 are independently hydroxy, nitro, halogen, carboxy, (C -? - C7) alkoxy, (C1-C4) alkoxy ) (C1-C4) alkyl, (C1-C4) alkoxycarbonyl, (C-? -C) alkyl, (C2-C7) alkenyl, (C2-C) alkynyl, (C3-C7) cycloalkyl, (C3-) cycloalkyl C7) (C1-C4) alkyl, (C3-C7) cycloalkyl (C1-C4) alkanoyl, formyl, alkanoyl (CrC8), alkanoyl (C-pCß) alkyl (Ci-Cß), alkanoylamino (C1-C4), alkoxy (C 1 -C 4) carbonylamino, hydroxysulfonyl, aminocarbonylamino or substituted aminocarbonylamino mono-N, di-N, N-, di-N, N'- or tri-N, N, N'-alkyl (CrC 4), sulfonamido, alkyl (C1-C4) sulfonamido, amino, mono-N- or di-N, N, -alkylamino (C1-C4), carbamoyl, mono-N- or di-N, N-alkyl (CrC4) carbamoyl, cyano, thiol, alkylthio (Ci-Cß), alkyl (Ci-Cß) sulfinyl, alkyl (C 1 -C 4) sulfonyl or mono-N- or di-N, N-C 1 -C 4 alkyl aminosulphinyl, Ar 3, Ar 4 and Ar 5 are each independently a five to eight membered ring partially saturated, fully saturated or fully unsaturated and optionally having from one to four heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two rings of five or six condensed, partially saturated, fully saturated or totally unsaturated, 5 independently considered, and optionally having from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three rings of five or six condensed, partially saturated, fully saturated or totally unsaturated, independently considered, and that

10 optionally have from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen, said ring having, bicyclic ring or tricyclic ring partially or fully saturated, optionally one or two oxo groups substituted on the carbon, or one or two oxo substituted groups on the the sulfur; said radicals Ar3, Ar4 and Ar5 are optionally

15 substituted in carbon or in nitrogen, in a ring if the radical is monocyclic, in one or both rings if the radical is bicyclic, or in one, two or three rings if the radical is tricyclic, with up to three substituents per independently selected from R31, R41 and R51, wherein R31, R41 and R51 are independently hydroxy, nitro, halogen, (C? -C7) alkoxy, alkoxy (d- 20 C4) (C1-C4) alkyl, alkoxy ( C1-C4) carbonyl, (C -? - C7) alkyl, (C2-C) alkenyl, (C2-C7-) alkynyl, (C3-C7) cycloalkyl, (C3-C) cycloalkyl (C1-C4) alkyl, (C3-C7) cycloalkyl (C1-C4) alkanoyl, formyl, (C -? - C8) alkanoyl, (C- C6) alkanoyl, (C-? - C6) alkyl, (C? -C4) amino alkanoyl, alkoxy ( C? -C4) carbonylamino,

hydroxysulfonyl, aminocarbonylamino or aminocarbonylamino substituted with mono N-, di-N, N-, di-N, N'- or tri-N, N, N'-alkyl (CrC4), sulfonamido, alkyl (Cr C4) sulfonamido, amino , mono-N- or di-N, N-C 1 -C 4 alkylamino, carbamoyl, mono-N- or di-N, N-C 1 -C 4 alkylcarbamoyl, cyano, thiol, alkylthio (Ci-Cβ) ), alkyl (CrC6) sulfinyl, alkyl (C1-C4) sulfonyl, alkyl (C1-C4) sulfonyl or mono-N- or di-N, N-alkylamino (C1-C4) sulfinyl; W is oxy, tto, sulfino, sulfonyl, aminosulfonyl-, mono-N-alkylene (C1-C4) aminosulfonyl, sulfonylamino, N-alkylene (C1-C4) alkylsulfonylamino, carboxamido, N-alkylene (C1-C4) carboxamido, carboxiamidoxi, N-alkylene (C1-C4) carboxamidooxí, carbamoyl, -mono-N-alkylene (C? -C4) alkylcarbamoyl, carbamoyloxy, or -mono-N-alkylene (C1-C4) carbamoyloxy, wherein said alkyl W they are optionally substituted on the carbon with one to three fluorine atoms; X is a five or six link aromatic ring optionally having one or two heteroatoms independently selected from oxygen, nitrogen and sulfur; said ring being optionally mono-, di- or trisubstituted independently with halogen, (C 1 -C 3) alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C 1 -C 4) alkoxy or carbamoyl; R1, R2 R3, R4, R5, R11, R31, R41 and R51, when they contain an alkyl, alkylene, alkenylene or alkynylene radical are optionally mono-, di- or trisubstituted on the carbon independently with halogen or hydroxy; and V and V1 are each independently a bond, (C1-C4) thioalkylene, (C1-C4) alkylene, (C1-C4) alkyleneoxy, oxyalkylene (Cr C) or optionally mono (C -? - C3) alkylene. - or di-substituted independently with hydroxy or fluoro; with the condition that: a. when K is alkylene (C2-C4) and M is Ar3 and Ar3 is cyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cyclooct-1-yl, then said cycloalkyl substituents (C5-C8) they are not substituted in a position with hydroxy; and b. when K is a link; G is phenyl, phenylmethyl, substituted phenyl or substituted phenylmethyl; Q is alkylene (C3-C8) and M is Ar3 or Ar4-Ar5, then A is sulfonyl.

2. A compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein B is N; Z is carboxyl, (C 1 -C 2) alkoxycarbonyl or tetrazolyl; Ar is phenyl; furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, midazolilo, pyrazolyl, soxazolilo, isothiazolyl, pyridyl, pyridazinyl, piridímidilo, pyrazinyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1, 3-dioxolanyl, 2H-imidazol¡lo, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, 1, 2,3-oxadiazolyl, 1, 2,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2,3-triazolyl, 1, 2,4-triazolyl, 2H-pyranyl, 4H-pyranyl, pyridyl, piperidinyl, 1, 4-dioxanyl, morpholinyl, 1, 4-dithianyl, thiomorpholinyl, piperazinyl, 1, 3,5-triazinyl, 1, 2,4-triazinyl, azepinyl, oxepinyl, thiepinyl, cyclopentenyl, cyclohexenyl, benzo (b) thienyl, benzoxazolyl, benzimidazolyl, benzatiazolilo, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl and 1,4-benzodioxane; Ar1, Ar2, Ar3, Ar4 and Ar5 are each independently cyclopentyl, ciciohexilo, cicioheptilo, cyclooctyl, phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl , 2H-pyrrolyl, 3H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1, 3-dioxolanyl, 2H-imidazoliIo, 2-¡midazolinilo, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, 1, 2,3- oxadiazolyl, 1, 2,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1, 3,4-oxadiazolyl, 1, 2,3-triazolyl, 1, 2,4-triazolyl, 2H-pyranyl, 4H-pyranyl, pyridyl, piperidinyl, 1, 4-d Ioxa nile, morpholinyl, 1, 4-dithianyl, thiomorpholinyl, piperazinyl, 1, 3,5-triazinyl, 1, 2,4-triazinyl, azepinyl, oxepinyl, thiepinyl, 1, 2, 4-diazepinyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclooctadienyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, 1H-isoindolyl, indolinyl, c¡clopenta (b) pir¡dinilo, p iran (3,4-b) pyrrolyl, benzofuryl, isobenzofuryl, benzo (b) thienyl, benzo (c) thienyl, 1 H-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl, benzatriazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl , cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, 1,4-benzodioxane, pyrid (3,4-b) - pirid¡nilo, pyrido (3,2-b) -pyridinyl, pyrido (4,3-b) -pyridinyl, 2H-1, 3-benzoxazinyl, 2H-1.4-benzoxazinyl, 1H-2,3-benzoxazinyl, 4H -3,1-benzoxazinyl, 2H-1,2-benzoxazinyl and 4H-1,4-benzoxazinyl; and X is tetrahydrofuranyl, phenyl, thiazolyl, thienyl, pyridyl, pyrrazolyl, furanyl or pyrimidyl, wherein X is optionally mono-, di- or trisubstituted independently with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl; and wherein each of said groups Ar, Ar1 and Ar2 are optionally substituted on carbon or on nitrogen with up to three substituents independently selected from R3, R4 and R5; each of said groups Ar, Ar1 and Ar2 are optionally independently substituted on the carbon or on the sulfur with one or two oxo groups; each of said groups Ar3, Ar4 and Ar5 are optionally substituted on the carbon or on the nitrogen independently with up to three R31, R41 and R51 and each of said groups Ar3, Ar4 and Ar5 are optionally independently substituted at carbon or at the sulfur

5 with one or two oxo group.

3. A compound of claim 2, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein A is CO; G is oxyalkylene (C-i-Cß); Q is -alkylene (C2-CβJ-O-(C 1 -C 3) -alkylene, (C 4 -C 8) -alkylene, said (C 4 -C 8) -alkylene being optionally substituted with up to four substituents independently selected from fluoro or alkyl (C1-C4), -X-alkylene (C2-C5) -, -alkylene (CrC5) -X-, -alkylene (C3) -X-alkylene (C3) -, -alkylene (C2-C4) - 0-X-alkylene (Co-C3) -, or -alkylene (Co-C4) -X-0-alkylene (CrC3) -; and X is phenyl, thienyl, furanyl or thiazolyl, wherein X is optionally mono- , it gave

15 trisubstituted with chlorine, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl.

4. A compound of claim 2, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein A is CO; G is Ar, Q is -alkylene (C2-C6) -0-alkylene

(C 1 -C 3) -, (C 4 -C 8) -alkylene, said (C 4 -C 8) -alkylene being optionally substituted with up to four substituents independently selected from fluoro or (C 1 -C 4) alkyl, -X-alkylene (C 2) -C5) -, -alkylene (C? -C5) -X-, -alkylene (C? -C3) -X-alkylene (C? -C3) -, -alkylene (C2-C) -0-X-alkylene (C0-C3) -, or -alkylene (Co-C4) -X-0-alkylene (CrC3) -; and X is phenyl, thienyl, furanyl or thiazolyl, wherein X is optionally mono-, di- or trisubstituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl.

5. A compound of claim 2, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein A is CO; G is R1R2-amino or amino substituted with Ar, or amino substituted with Ar-alkylene (C1-C4) and R11, wherein R11 is H; Q is -alkylene (C2-C6) -0-alkylene (C Cs) -, (C4-C8) -alkylene, said (C-C8) -alkylene being optionally substituted with up to four substituents independently selected from fluoro or alkyl ( C-1-C4), -X-alkylene (C2-C5) -, -alkylene (C5) -X-, -alkylene (CrC3) -X-alkylene (C1-C3) -, -alkylene (C2-C4) ) -0-X-alkylene (C0-C3) -, or -alkylene (Co-C4) -X-0-alkylene (C1-C3) -; and X is phenyl, thienyl, furanyl or thiazolyl, wherein X is optionally mono-, di- or trisubstituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl; and wherein R1 and R2 can be considered separately and are independently selected from H and (C -? - C8) alkyl, or R1 and R2 are independently considered to form a five or six membered azacycloalkyl, said azacycloalkyl optionally containing a oxygen atom.

6. A compound of claim 2, a prodrug thereof to a pharmaceutically acceptable salt of said compound or said prodrug, wherein A is S02; G is R1R2-amino or amino substituted with Ar and R11; Q is -alkylene (C2-C6) -0-alkylene (C1-C3) -, (C4-C8) -alkylene, said (C4-C8) -alkylene being optionally substituted with up to four substituents independently selected from fluoro or alkyl ( C-1-C4), -X-alkylene (C2-C5) -, -alkylene (C? -C5) -X-, -alkylene (CrC3) -X-alkylene (d-C3) -, -alkylene (C2) -C4) -0-X-alkylene (C0-C3) -, or -alkylene (Co-C4) -X-0-alkylene (C Cs) -; and X is phenyl, thienyl, furanyl or thiazolyl, wherein X is optionally mono-, di- or trisubstituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl; and wherein R1 and R2 can be considered separately and independently selected from H and (C? -C8) alkyl, or R1 and R2 are independently considered to form a five or six membered azacycloalkyl, said azacycloalkyl optionally containing one atom of oxygen.

7. A compound of claim 2, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein A is S02; G is Ar, Ar-alkylene (C C2) or A ^ -V-Ar2; Q is (C2-C6) alkylene-0-(C1-C3) alkylene, (C4-C8) alkylene, said (C4-C8) alkylene being optionally substituted with up to four substituents independently selected from fluoro or alkyl (C1 -C4), X-alkylene (C2-C5) -, alkylene (CrC5) -X-, alkylene (C -? - C3) -X-alkylene (C1-C3) -, (C2-C4) alkylene -0- X-alkylene (C0-C3) -, or alkylene (C0-C4) -XO-alkylene (C1-C3) -; and X is phenyl, pyrimidyl, pyridyl, thienyl, tetrahydrofuranyl, furanyl or thiazolyl, wherein X is optionally mono-, di- or trisubstituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl.

8. A compound of claim 7, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein G is Ar or Ar-alkylene- (CrC2); Ar is phenyl, furyl, thienyl pyrrolyl, oxazolyl, thiazolyl, midazolyl, pyrazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazinyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazole, or 1, 3 , 4-thiadiazolyl, wherein each of said Ar groups is optionally substituted on the carbon or on the nitrogen with R1, R2 or R3; Ar 4 is cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, midazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, 1,2,3-triazolyl, 1, 2,4-triazolyl, pyranyl,

Thiomorpholinyl, piperazinyl, 1, 3,5-triazinyl, 1, 2,4-triazinyl, 1,2,3-triazinyl, azepinyl, oxepinyl or tiepinyl, wherein each of said Ar4 groups is optionally mono-, di- - or trisubstituted on carbon or on nitrogen with R31, R41 or R51; Ar5 is cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazole, pyrazolyl, isoxazolyl,

15-isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, 1,2,3-triazoloyl, 1,4-triazolyl, pyranyl, 1,4-dioxanyl, thiomorpholinyl, piperazinyl, 1,3-triazinyl, , 2,4-triazinyl, 1,2,3-triazinyl, azepinyl, oxepinyl or tiepinyl, wherein each of said groups Ar5 is optionally mono-, di- or trisubstituted on carbon or on nitrogen with R31, R41 or R51; Q is -alkylene

20 (C5-C7) -, -alkylene (C? -C2) -X-alkylene (CrC2) -, -alkylene (C? -C2) -X-0- (Cr C2) -, -alkylene (C2-C4) ) -thienyl, -C (C2-C4) -alkylene -furanílo- or (C2-C4) - thiazolyl; X is phenyl, pyridyl, pyrimidyl or thienyl; and said X groups are optionally mono-, di- or trisubstituted with chloro, fluoro, methoxy,

, .- u ^^ í ¿® M * m¡m difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl?!; having said alkylene (C2-C4) -furanyl and (C2-C4) -tienilo- a substitution pattern 2.5, for example,

(C2-C4)

9. A compound of claim 8, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein K is methylene, M is A ^ -Ar5, A ^ -O-Ar5 or A ^ -S- Ar5 and Ar is phenyl, pyridyl, pyrazolyl, imidazolyl, pyrimidyl, thienyl or thiazolyl, wherein A is optionally mono-, di- or trisubstituted on carbon or on nitrogen with R3, R4 or R5.

10. A compound of claim 9, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein M is A ^ -Ar5; Ar is phenyl, pyridyl or imidazolyl; Ar 4 is phenyl, furanyl or pyridyl; and Ar5 is cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, imidazolyl, pyridimidyl, thienyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl or thiazolyl, wherein Ar, Ar4 and Ar5 are optionally mono-, di- or trisubstituted with chlorine, fluoro , methyl, methoxy, difluoromethoxy, trifluoromethyl or trifluoromethoxy.

11. A compound of claim 10, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is -C (C5-C7) -.

12. A compound of claim 10, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is CH2-X-CH2- and X is optionally mono- or disubstituted metaphenylene with chlorine, fluoro, methoxy , difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl.

13. A compound of claim 12 selected from the acid (3 - (((pyridin-3-sulfonyl) - (4-pyrimidin-5-yl-benzyl) -amino) - methyl) -phenyl) -acetic acid (3 - (((5-phenyl-furan-2-ylmethyl) - (pyridin-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid, - (((pyridin-3-sulfonyl) - (4-pyrimidin-2-yl-benzyl) -amino) -methyl) -phenyl] -acetic acid (3 - (((pyridin -3-sulfonyl) - (4-thiazol-2-yl-benzyl) -amino) -methyl) -phenyl) -acetic acid and (3 - (((4-pyrraz-2-yl- benzyl) - (pyridin-3-sulfonyl) -amino) -methyl) -phenyl] -acetic acid.

14. The compound of claim 12, wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar4-Ar5, wherein Ar4 is a furanyl ring and Ar5 is phenyl, wherein said phenyl radical is substituted at the 5-position of said furanyl ring, and Q is -CH2-X-CH2- in the that X is metaphenylene.

15. The compound of claim 12, wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar4-Ar5, where Ar4 is phenyl and Ar5 is pyrimid-2-yl and said pyrimid-2-ylo radical is substituted at the 4-position of said phenyl ring, and Q is -CH2-X-CH2- wherein X is metaphenylene.

16. The compound of claim 12, wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar4-Ar5, wherein Ar4 is phenyl and Ar5 is thiazol-2-yl and said thiazol-2-yl radical is substituted at the 4-position of said phenyl ring, and Q is -CH2-X-CH2- wherein X is metaphenylene.

17. - The compound of claim 12, wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar4-Ar5, where Ar4 is phenyl and Ar5 is pyrimid-5-yl and said pyrimid-5-yl radical is substituted at the 4-position of said phenyl ring, and Q is -CH2-X-CH2- wherein X is metaphenylene. 18. The compound of claim 12, wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar4-Ar5, wherein Ar4 is phenyl and Ar5 is pyrazin-2-yl and said pyrazin-2-yl radical is substituted at the 4-position of said phenyl ring, and Q is -CH2-X-CH2- wherein X is metaphenylene. 19. A compound of claim 10, wherein Q is -alkylene (C2-C) -thiol, -alkylene (C2-C) -furanyl or -alkylene (C2-C) -thiazolyl. 20. The compound of claim 19, which is 5- (3-pyridin-3-sulfonyl) - (4-thiazol-2-yl-benzyl) -amino) -propl) -thiophen-2 acid. -carboxylic 21. The compound of claim 19, wherein Q is n-propylenyl; X is thienyl; Z is carboxy; Ar is 3-pyridyl; Ar 4 is phenyl and Ar 5 is 2-thiazolyl, said 2-thiazolyl being substituted at the 4-position of said phenyl. 22. A compound of claim 10, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is -CH2-X-0-CH2; Ar 4 is phenyl or pyridyl; said phenyl and pyridyl being optionally substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl and methyl and X being metaphenylene. 23. A compound of claim 22 selected from (3 - (((4-cyclohexyl-benzyl) -pyridin-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid, acid (3- (((pyridin-3-sulfonyl) - (4-pyridin-2-yl-benzyl) -amino) -methyl) -phenoxy) -acetic acid (3 - (((pyridin-3) -sulfonyl) - (4-pyridin-3-yl-benzyl) -amino) -methyl) -phenoxy) -acetic acid (3 - (((pyridine-3-sulfonyl) ) - (4-pyridin-4-yl-benzyl) -amino) -methyl) -phenoxy) -acetic acid and (3 - (((pyridin-3-sulfonyl) - (4-thiazole-2-yl- benzyl) -amino) -methyl) -phenoxy) -acetic acid. 24. The compound of claim 22, wherein Ar is pyrid-3-yl; Z is carboxy, Ar4 is phenyl; Ar5 is cyclohexyl and said cyclohexyl radical is substituted at the 4-position of said phenyl ring. 25. The compound of claim 22, wherein Ar is pyrid-3-yl; Z is carboxy, Ar4 is phenyl; Ar5 is thiazol-2-yl and said thiazol-2-yl radical is substituted at the 4-position of said phenyl ring. 26. The compound of claim 22, wherein Ar is pyrid-3-yl; Z is carboxy, Ar4 is phenyl; Ar5 is 2-pyridyl and said 2-pyridyl radical is substituted at the 4-position of said phenyl ring. 27. The compound of claim 22, wherein Ar is pyrid-3-yl; Z is carboxy, Ar4 is phenyl; Ar5 is 3-pyridyl and said 3-pyridyl radical is substituted at the 4-position of said phenyl ring. 28. The compound of claim 22, wherein Ar is pyrid-3-yl; Z is carboxy, Ar4 is phenyl; Ar5 is 4-pyridyl and said 4-pyridyl radical is substituted at the 4-position of said phenyl ring. 29. A compound of claim 8, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein K is methylene, G is Ar; Ar is phenyl, pyridazinyl, pyrazolyl, pyrazinyl, pyridyl, imidazolyl, pyrimidyl, thienyl or thiazolyl, Ar is optionally mono-, di- or trisubstituted with R3, R4 or R5, and M is Ar3, wherein said Ar3 is cyclopentyl, cyclohexyl, phenyl, thienyl, pyridazinyl, pyrimidinyl, pyrazilyl, indolyl, benzofuryl, benzo (b) thienyl, benzoxazolyl, benzathiazolyl, quinolinyl, isoquinolinyl, naphthyl, tetralinyl, 2H-1-benzopyranyl or 1,4-benzodioxane and is optionally mono, di- or trisubstituted with R31, chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethyl or trifluoromethoxy. 30. A compound of claim 29 selected from (3 - (((2,3-dihydro-benzo [1,4] dioxin-6-ylmethyl) - (pyridine-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid and (3 - ((benzofuran-2-ylmethyl) - (pyridin-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid. 31. The compound of claim 29, wherein Ar is pyrid-3-yl; Z is carboxy, M is 6- (1,4-benzodioxane) and Q is -CH 2 -X-CH 2 -, wherein X is metaphenylene. 32. The compound of claim 29, wherein Ar is pyrid-3-yl; Z is carboxy, M is 2-benzofuryl and Q is -CH2-X-CH2-, wherein X is metaphenylene. 33. A compound of claim 29, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Ar is phenyl, pyridyl or imidazolyl, said phenyl, pyridyl or imidazolyl being optionally independently substituted with chlorine, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethyl or trifluoromethoxy; Ar3 is phenyl substituted with R31, wherein R31 is (C-1-C7) alkyl, mono-N- or di-N, N-alkyl- (C? -C4) amine or (C1-C5) alkoxy, said alkyl (CrC7) or (C1-C5) alkoxy optionally mono-, di- or trisubstituted independently with hydroxy or fluoro, wherein Ar3 is optionally mono-, di or trisubstituted with chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl . 34. A compound of claim 33, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is -alkylene (C5-C7) -. 35. A compound of claim 33, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is -CH2-X-CH2- and X is phenyl optionally mono-, di- or tri -substituted with chlorine, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl. 36.- A compound of claim 35, selected from the acid (3 - (((4-butyl-benzyl) - (pyridin-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid, (3- ((Benzenesulfonyl- (4-butyl-benzyl) -amino) -methyl) -phenyl) -acetic acid (3 - (((4-butyl-benzyl) - (1-methyl-1 H-imidazole-4-sulfonyl) ) -amino) -methyl) -phenyl) -acetic acid and (3 - (((4-dimethylamino-benzyl) - (pyridin-3-sulfonyl) -amino) -methyl) -phenyl) -acetic acid. The compound of claim 35, wherein Ar is pyrid-3-yl; Z is carboxy; M is phenyl substituted at the 4-position with n-butyl; and Q is -CH2-X-CH2- wherein X is metaphenylene. 38.- The compound of claim 35, wherein Ar is phenyl; Z is carboxy; M is phenyl substituted at the 4-position with n-butyl; and Q is -CH2-

'+. * .. X-CH2- in which X is metaphenylene. 39.- The compound of claim 35, wherein Ar is 4- (1-methyl-imidazolyl); Z is carboxy; M is phenyl substituted at the 4-position with n-butyl; and Q is -CH2-X-CH2- wherein X is metaphenylene. The compound of claim 35, wherein Ar is pyrid-3-yl; Z is carboxy; M is phenyl substituted at the 4-position with dimethylamino and Q is -CH2-X-CH2- wherein X is metaphenylene. 41. A compound of claim 33, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is -alkylene (C2-C4) -thienyl, -alkylene (C2-C4) -furanyl or alkylene (C2-C4) -thiazolyl. 42. A compound of claim 33, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is -alkylene (C? -C2) -X-0- (CrC2) and X is metaphenylene, said X being optionally mono-, di- or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl. 43.- A compound of claim 42, selected from (3 - (((4-dimethylamino-benzyl) - (pyridin-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid and (3 - (((4-tert-butyl-benzyl) - (pyridin-3-sulfonyl) -amino) -methyl) -phenoxy) -acetic acid. 44. The compound of claim 42, wherein Ar is pyrid-3-ylo; Z is carboxy; M is phenyl substituted at the 4-position with dimethylamino and Q is -CH2-X-CH2- wherein X is metaphenylene.

Í & jhg??

45. The compound of claim 42, wherein Ar is pyrid-3-yl; Z is carboxy; M is phenyl substituted at the 4-position with tert-butyl and Q is -CH2-X-0-CH2-, wherein X is metaphenylene. 46. A compound of claim 8, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein G is Ar; K is (C2-C4) alkylene or n-propenylene; Ar is phenyl, pyrazolyl, pyridazinyl, pyrazinyl, pyridyl, imidazolyl, pyrimidyl, thienyl or thiazolyl, wherein Ar is optionally mono-, di- or trisubstituted with R3, R4 or R5, and M is Ar3 optionally mono-, di or trisubstituted with chlorine, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethoxy and trifluoromethyl. 47. A compound of claim 46, which is trans- (3 - (((3- (3,5-d-chloro-phenyl) -allyl) - (pyridine-3-sulfonyl) -amino acid ) -methyl) -phenyl) -acetic acid. 48. The compound of claim 46, wherein K is trans-n-propenylene, said group M being attached to the 1-position of the n-propenylene and said N atom being attached to the 3-position of the n-propenylene; Ar is pyrid-3-yl; M is 3,5-phenyl disubstituted with chlorine; Z is carboxy and Q is -CH2-X-CH2-, wherein X is metaphenylene. 49. A compound of claim 46, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Ar3 is phenyl optionally substituted by chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl. 50. A compound of claim 49, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is -alkylene (C5-C7) -. 51. A compound of claim 49, wherein Q is -CH2-X-CH2- and X is metaphenylene. 52. A compound of claim 49, a prodrug of the mime or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is -alkylene (C2-C4) -X- and X is furanyl, thienyl or thiazolyl. 53. A compound of claim 49, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is -alkylene (CrC2) -X-0-alkylene (C1-C2) - and X It is metaphenylene. 54. A compound of claim 8, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein G is Ar; K is thioethylene or oxyethylene, Ar is phenyl, pyrazolyl, pyridazinyl, pyrazinyl, pyridyl, imidazolyl, pyrimidyl, thienyl or thiazoloyl, wherein Ar is optionally substituted with up to three R3, R4 or R5, and M is Ar3, optionally, mono-, di- or trisubstituted with chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl. 55. A compound of claim 54, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Ar3 is phenyl. 56. A compound of claim 55, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is (C5-C7) alkylene. 57. A compound of claim 55, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is -CH2-X-CH2- and X is metaphenylene. 58. A compound of claim 55, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is -alkylene (C2-C4) -X- and X is furanyl, thienyl or thiazolyl. 59. A compound of claim 55, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is - (C? -C2) -X-0-alkylene- (CrC2) - and X is metaphenylene. 60.- A compound of claim 59, which is (3 - (((2- (3,5-dichloro-phenoxy) -etl) - (pyridine-3-sulfonyl) -amino) -methyl acid) -phenoxy) -acetic. 61.- A compound of claim 59, wherein K is ethylenyloxy, said group M being linked to the oxygen atom of the ethylenyloxy group and said N atom being attached to the 2-position of the ethylenyloxy group; Ar is pyridi-3-yl; M is 3,5-disubstituted phenyl with chlorine; Z is carboxy and Q is -CH 2 -X-O-CH 2 -, wherein X is a second phenyl ring and said substituents CH and OCH 2 are located in a meta substitution pattern on said second phenyl ring. 62.- A compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein B is CH. 63. A compound of claim 62, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein A is CO; G is Ar; K is methylenyl, propylenyl, propenynyl or oxyethylenyl; M is Ar3 or A ^ -Ar5; Ar3 is phenyl or pyridyl; Ar4 is phenyl, thienyl, pyridyl or furanyl; Ar5 is (C5-C7) cycloalkyl, phenyl, pyridyl, imidazolyl, pyrimidyl, thienyl, pyridyzanyl, pyrazinyl, imidazolyl, pyrazolyl or thiazolyl; Ar is phenyl, pyrazolyl, pyridyzanyl, pyrazinyl, pyridyl, imidazolyl, pyrimidyl, thienyl or thiazolyl; wherein Ar, Ar3, Ar4 and Ar5 are optionally independently substituted with up to three chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl. 64.- A compound of claim 62, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein A is CO; G is Ar; K is methylenyl, propylenyl, propenynyl or oxyethylenyl; M is Ar3 or A ^ -Ar5; Ar3 is phenyl or pyridyl; Ar4 is phenyl, thienyl, pyridyl or furanyl; Ar5 is (C5-C) cycloalkyl, phenyl, pyridyl, imidazolyl, pyrimidyl, thienyl, pyridyzanyl, pyrazinyl, imidazolyl, pyrazolyl or thiazolyl; Ar is phenyl, pyrazolyl, pyridazinyl, pyrazinyl, pyridyl, imidazolyl, pyrimidyl, thienyl or thiazolyl; wherein Ar, Ar3, Ar4 and Ar5 are optionally independently substituted with up to three chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl. The use of a compound as claimed in claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug for the manufacture of said medicament for treating a vertebrate, suffering from a disorder that produces reduction of bone mass. 66. The use as claimed in claim 65, wherein the condition is osteoporosis, osteotomy, childhood idiopathic bone loss or bone loss associated with periodontitis. 67.- The use as claimed in claim 66, wherein the condition is osteoporosis and vertebrateitis in a human subject. 68.- The use as claimed in claim 67, wherein the condition is glucocorticoid-induced osteoporosis, osteoporosis induced by hyperthyroidism, osteoporosis induced by immobilization, osteoporosis induced by heparin or osteoporosis induced by immunosuppression. 69.- The use of a compound as claimed in claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug for the manufacture of a medicament for the augmentation and maintenance of bone mass in a vertebrate. 70. The use as claimed in claim 69, wherein said medicament is useful for bone welding treatments after facial reconstruction, maxillary reconstruction or mandibular reconstruction, inducing vertebral synostosis or improves the extension of long bones, the speed of implantation of a bone graft or prosthetic invagination. 71.- The use as claimed in claim 69, in which the vertebra is a human having a bone fracture. 72. A pharmaceutical composition containing an amount of a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier or diluent. 73.- A pharmaceutical composition of claim 72, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug for the treatment of osteoporosis, wherein the amount is an amount for the treatment of osteoporosis. 74.- A pharmaceutical composition of claim 72 for the increase of bone mass containing an amount for the increase of the bone mass of said compound, a prodrug thereof or a salt

Pharmaceutically acceptable of said compound or said prodrug, and a pharmaceutically acceptable carrier or diluent. 75.- The pharmaceutical composition of claim 74 for the treatment of a bone fracture, containing an amount for the treatment of a bone fracture of said compound, a prodrug of the

20 itself or a pharmaceutically acceptable salt of said compound or said prodrug. 76.- A pharmaceutical composition of claim 72 for the treatment of a disorder that presents reduction of bone mass in a

»** *» *** ** - ^^ faW * «- • - mammal, which contains an amount for the treatment of the disorder having reduced bone mass of said compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier or diluent. 5 77.- A pharmaceutical composition that contains: a. an amount of a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; and b. an amount of an anti-resorption agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said

10 prodrug, and c. a pharmaceutical vehicle or diluent. 78.- A pharmaceutical composition of claim 77, wherein the anti-resorptive agent is: droloxifene, raloxifene, tamoxifen, 4-hydroxy tamoxifen, toremifene, centroman, levormeloxifen, idoxifen, 6- (4-hydroxy-phenol). l) -5- (4- (2-p.peridin-1-yl-ethoxy) -benzyl) -naphthalen-2-ol; (4- (2- (2-aza-bicyclo-15 [2.2.1] hept-2-yl) -ethoxy] -phenyl) - (6-hydroxy-2- (4-hydroxy-phenyl) -benzo [ b] thiophen-3-yl) -metanone 3- (4- (1, 2-diphenyl-but-1-enyl) -phenyl) -acrylic acid 2- (4-methoxy-phenyl) -3 - [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -benzo [b] thiophen-6-ol; c / s-6- (4-fluoro-phenyl) -5- (4- (2 -piperidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalen-2-ol; (-) - c / s-6-phenyl-5- (4- (2-pyrrolidine -1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol; c / s-6-phenyl-5- (4- (2-pyrrolidin-1-yl- ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol; c / s-1 - (ß'-pyrrolidin-ethoxy-3'-pyridinyl) -2-phenyl-6-hydroxy- 1, 2,3,4-tetrahydronaphthalene; 1- (4'-pyrrolidinetoxyphenyl) -2- (4"-fluorophenyl) -6-hydroxy-1, 2,3,4-tetrahydroisoquinoline; c / -s- (6- (4-hydroxyphenyl) -5- (4- (2-piperidin-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-

j ^^ a ^ l ^^^? j | j * & * - ~ ** Mmm¡í M ^ M 2-ol; and 1- (4, -pyrrolidinolethoxyphenyl) -2-pheny1) -6-hydroxy-1, 2,3,4-tetrahydro-isoquinoline, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug. 79.- A pharmaceutical composition of claim 77, wherein the anti-resorption agent is tiludronic acid, alendronic acid, zoledronic acid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid and acid pamidronic acid, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug. 80.- The use of a first compound as claimed in claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; in combination with an anti-resorption agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug for the manufacture of a medicament for the treatment of a vertebrate having a disorder exhibiting reduction of bone mass. 81. The use as claimed in claim 80, wherein the anti-resorption agent is: droloxifene, raloxifene, tamoxifen, 4-hydroxy tamoxifen, toremifene, centroman, levormeloxifen, idoxifen, 6- (4-hydrox) -phenyl) -5- (4- (2-piperidin-1-yl-ethoxy) -benzyl) -naphthalen-2-ol; (4- (2- (2-azabicyclo [2.2.1] hept-2-yl) -ethoxy] -pheny] - (6-hydroxy-2- (4-hydroxy-phenyl) -benzo [b] thiophen -3-yl) -metanone, 3- (4- (1, 2-diphenyl-but-1-enyl) -phenyl) -acrylic acid 2- (4-methoxy-phenyl) -3- [4- ( 2-piperidin-1-yl-ethoxy) -phenoxy] -benzo [b] thiophen-6-ol; c s-6-

^^^^^^^^ JÜ 8g -. * --- *. '.

(4-fluoro-phenyl) -5- (4- (2-piperidin-1-yl-ethoxy) -fenrl) -5,6,7,8-tetrahydro-naphthalene-2-ol; (-) - c / s-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol; c / s-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol; cis-1 - (ß'-pyrrolidinetoxy-S'-pyridyl ^ -phenyl-β-hydroxy-l, 2,3,4-tetrahydronaphthalene; 1 - (4'-pyrrolidinetoxyphenyl) -2- (4"-fluorophenyl) ) -6-hydroxy-1, 2,3,4-tetrahydroisoquinoline; c / -s- (6- (4-hydroxyphenyl) -5- (4- (2-piperidin-1-ethoxy) phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol and l-^ '-pyrrolidinolethoxyphenyl-phenyl-β-hydroxy-l, 2,3,4-tetrahydroisoquinoline, a prodrug thereof or 82. The use as claimed in claim 80, in which the anti-resorptive agent is tiludronic acid, alendronic acid, zoledronic acid, ibandronic acid, and a pharmaceutically acceptable salt of said agent or said prodrug. , risedronic acid, etidronic acid, clodronic acid and pamidronic acid, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug 83.- A test kit containing: a) an amount of a compound of claim 1, a prodrug thereof or a pharmaceutical salt only acceptable of said compound or said prodrug in a first unit dosage form; b. an amount of an anti-resorption agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug, and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and c. a container for containing said first and second dosage form.

84. - A test kit of claim 83, wherein the anti-resorption agent is: droloxifene, raloxifene, tamoxifen, 4-hydroxy tamoxifen, toremifene, centroman, levormeloxifen, idoxyphene, 6- (4-hydroxy-phenol) -5- (4- (2-piperidin-1-yl-ethoxy) -benzyl) -naphthalen-2-ol; (4- (2- (2-aza-bicyclo- [2.2.1] hept-2-yl) -ethoxy] -phenyl) - (6-hydroxy-2- (4-hydroxy-phenyl) -benzo [ b] thiophen-3-yl) -methanone 3- (4- (1, 2-diphenyl-but-1-enyl) -phenyl) -acrylic acid 2- (4-methoxy-phenyl) -3- [4 - (2-piperidin-1-yl-ethoxy) -phenoxy] -benzo [b] thiophen-6-ol; c / s-6- (4-fluoro-phenyl) -5- (4- (2-piperidyl) n-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol; (-) - c / s-6-phenyl-5- (4- (2-pyrrolidin- 1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol; c / s-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol; c / s-1 - (6'-pyrrolidin-ethoxy-S'-pyridyl-phenyl-β-hydroxy-1, 2,3,4-tetrahydronaphthalene; 1- (4'-pyrrolydin-ethoxyphenyl) -2- (4"-fluorophenyl) -6-hydroxy-1, 2,3,4-tetrahydroisoquinoline; c / s- (6- ( 4- hydroxyphenyl) -5- (4- (2-piperidin-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol and 1- (4-pyrrolidinolethoxyphenyl) -2 phenyl) -6-hydroxy-1, 2,3,4-tetrahydroisoquinolone, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug. - A test kit of claim 83, wherein the anti-resorption agent is tiludronic acid, alendronic acid, zoledronic acid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid and pamidronic acid , a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug. 86.- A pharmaceutical composition that contains: a. an amount of a compound of claim 1, a prodrug thereof or

^^ t a pharmaceutically acceptable salt of said compound or said prodrug; b. an amount of a bone anabolic agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug; c. and a pharmaceutical carrier or diluent. 5. The pharmaceutical composition of claim 86, wherein said bone anabolic agent in component b is IGF-1, bone morphogenetic protein, a prostaglandin, a prostaglandin agonist / antagonist, sodium fluoride, parathyroid hormone (PTH), a fragment or active fragments of the parathyroid hormone, a growth hormone

10 or secretagogue of the growth hormone, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug. 88.- The use of a compound as claimed in claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug in combination with another

The bone anabolic agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug for the manufacture of a medicament for the treatment of a mammal exhibiting reduction of bone mass. 89.- The use as claimed in claim 88, in the

20 that said bone anabolic agent in component b is IGF-1, bone morphogenetic protein, a prostaglandin, a prostaglandin agonist / antagonist, sodium fluoride, parathyroid hormone (PTH), a fragment or active fragments of parathyroid hormone , a growth hormone

or secretagogue of the growth hormone, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug. 90.- The use of an effective amount for the renal regeneration of a compound as claimed in claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug for the manufacture of a medicament for the treatment of a mammal that presents renal degeneration. 91.- A test kit containing a. an amount of a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug in a first unit dosage form; b. an amount of another anabolic agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug in a second unit dosage form; and c. a container for containing said first and second dosage form. 92. A test kit of claim 91, wherein said bone anabolic agent in component b is IGF-1, bone morphogenetic protein, a prostaglandin, a prostaglandin agonist / antagonist, sodium fluoride, parathyroid hormone (PTH), a fragment or active fragments of the parathyroid hormone, a growth hormone or secretagogue of the growth hormone, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug. 93.- The use of a compound like the one claimed in the

claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug in combination with an anti-resorptive agent, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug for the manufacture of a medicament for the increase and maintenance of bone mass in a vertebrate. 94. The use as claimed in claim 93, wherein the anti-resorption agent is: droloxifene, raloxifene, tamoxifen, 4-hydroxy tamoxifen, toremifene, centroman, levormeloxifen, idoxifen, 6- (4-hydroxy). - phenyl) -5- (4- (2-p.peridin-1-yl-ethoxy) -benzyl) -naphthalen-2-ol; (4- (2- (2-Azabicyclo [2.2.1] hept-2-yl) -ethoxy) -phenyl) - (6-hydroxy-2- (4-hydroxy-phenyl) -benzo [b] thiophene -3-yl) -metanone; 3- (4- (1, 2-diphenyl-but-1-enyl) -phenyl) -acrylic acid; 2- (4-methoxy-phenyl) -3- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -benzo [b] thiophen-6-ol; c / s-6- (4-fluoro-phenyl) -5- (4- (2-piperidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol; (-) - c / s-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol; c / -s-6-phenyl-5- (4- (2-pyrrolidin-1-yl-ethoxy) -phenyl) -5,6,7,8-tetrahydro-naphthalene-2-ol; cis- 1 - (ß'-pyrrolidinetoxy-S'-pyridyl ^ -phenyl-β-hydroxy-l, 2,3,4-tetrahydronaphthalene; 1- (4'-pyrrolidinetoxyphenyl) -2- (4"-fluorophenyl) ) -6-hydroxy-1, 2,3,4-tetrahydroisoquinoline; c / -s- (6- (4-hydroxyphenyl) -5- (4- (2-piperidin-yl-ethoxy) -phenyl) ) -5,6,7,8-tetrahydro-naphthalene-2-ol and l-^ '-pyrrolidinol-ethoxyphenyl-phenyl-e-hydroxyl, 2,3,4-tetrahydroisoquinoline, a prodrug thereof or a salt pharmaceutically acceptable of said agent or said prodrug 95. The use as claimed in claim 93, in the

< | ^^ that the anti-resorption agent is tiludronic acid, alendronic acid, zoledronic acid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid and pamidronic acid and a prodrug thereof or a pharmaceutically salt acceptable of said agent or said prodrug. 96. The use of a compound as claimed in claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug in combination with another bone anabolic agent, a prodrug thereof or a pharmaceutically acceptable salt thereof. said agent or said prodrug for the manufacture of a medicament for the augmentation and maintenance of bone mass in a vertebrate. 97. The use as claimed in claim 96, wherein said anabolic agent in component b is IGF-1, bone morphogenetic protein, a prostaglandin, a prostaglandin agonist / antagonist, sodium fluoride, parathyroid hormone (PTH), a fragment or active fragments of the parathyroid hormone, a growth hormone or secretagogue of the growth hormone, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug. The use of a compound as claimed in claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug for the manufacture of a medicament for the treatment of glaucoma in a mammal suffering from

The use of a compound such as the one claimed in the claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug for the manufacture of a

5 medicament for the treatment of ocular hypertension in a mammal. 100.- A compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein A is S02, B is N, G is Ar, K is methylene, Z is carboxyl, alkoxy (C6C6) -carbonyl or tetrazolyl; Q is -CH 2 -X-CH 2 -CH 2, CH 2 -X-10 0 -CH 2, CH 2 -X-0-CH- (CH 3), CH 2 -X-CH 2 -CH- (CH 3); and X is metaphenylene; said X being optionally mono- or di-substituted with chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethyl or trifluoromethoxy; M is Ar3 or Ar? Ar5; Ar3 is cyclopentyl, cyclohexyl, phenyl, thienyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuryl, benzo (b) thienyl, benzoxazolyl, benzothiazolyl, quinolinyl,

Isoquinolinyl, naphthyl, tetralinyl, 2H-1-benzopyranyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuryl or 1,4-benzodioxane, optionally being mono-, di- or trisubstituted with R31, chloro, fluoro, methyl, methoxy , difluoromethoxy, trifluoromethyl or trifluoromethoxy; R31 is alkyl (CrC), mono-N, di-N, N-(C1-C4) alkyl amine or (C1-C5) alkoxy, said (C7) alkyl or (C1-C5) alkoxy optionally

20 mono-, di- or trisubstituted independently with hydroxy or fluoro; Ar is phenyl, pyridyl, pyrazolyl, imidazolyl, pyrimidyl, thienyl or thiazolyl, wherein Ar is optionally mono-, di- or tri-substituted on the carbon with chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethyl or trifluoromethoxy, or mono or disubstituted

j * aM > ^^ w < ^. ^, ^^^^ | ^ | ^ l | l1lia¡, nn - iMMMMM? irtiri i líllillli Ti * in nitrogen with methyl or trifluofifietoxi; Ar is phenyl, thienyl, furanyl or pyridyl, wherein Ar4 is optionally mono-, di- or trisubstituted with chloro fluoro, methyl, methoxy, difluoromethoxy, trifluoromethyl or trifluoromethoxy; Ar5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, 5-midazolyl, pyrimidyl, thienyl, pyridazinyl, pyrazinyl or thiazolyl, wherein Ar5 is optionally mono-, di- or trisubstituted with chlorine, fluoro, methyl, methoxy , difluoromethoxy, trifluoromethyl or trifluoromethoxy. 101. The compound of claim 100, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said

Prodrug, wherein Z is carboxyl or (C -? - C3) -carbonyl alkoxy; Q is -CH2-X- CH2-CH2 or CH2-X-0-CH2; Ar is phenyl, 3-fluoro-phenyl, 3-chloro-phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 2-thiazolyl, 2-thienyl, 2- (5-chloro-thienyl), 2-pyridyl, 3-pyridyl or 4- (1-methyl-imidazolyl); M is Ar3; Ar3 is cyclopentyl, cyclohexyl, phenyl, thienyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuryl, benzo (b) thienyl,

Benzoxazole, benzothiazolyl, quinolinyl, isoquinolinyl, naphthyl, tetralinyl, 2H-1-benzopyranyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuryl or 1,4-benzodioxane, optionally being mono-, di- or trisubstituted with R31, chloro , fluoro, methyl, methoxy, difluoromethoxy, trifluoromethyl or trifluoromethoxy; R31 is alkyl (C? -C7) or alkoxy (Ci-Cs), said (C1-C7) alkyl or (C1-C5) alkoxy optionally

20 mono-, di- or trisubstituted independently with hydroxy or fluoro; and X is metaphenylene. 102.- A compound of claim 100, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said

prodrug, wherein Z is carboxyl ^ (C? -C3) alkoxycarbonyl; Ar is phenyl, 3-fluoro-phenyl, 3-chloro-phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 2-thiazolyl, 2-thienyl, 2- (5-chloro-thienyl), 2-pyridyl, 3-pyridyl or 4- (1-methyl-amidazolyl); M is A ^ -Ar5; Ar4 is optionally mono- or disubstituted with chlorine or fluoro and X is metaphenylene. 103. The compound of claim 102, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Ar is 4-chlorophenyl; Q is -CH2-X-0-CH2; X is metaphenylene, Z is carboxyl; Ar4 is para-phenylene and Ar5 is 2-thiazolyl. 10 104.- (3- {[[4-Chloro-benzenesulfonyl) - (4-thiazol-2-yl-benzyl) -amino] -methyl] -phenoxy) -acetic acid. 105. A compound of claim 102, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Z is carboxyl; Q is -CH2-X-CH2-CH2; X is

15 metaphenylene; Ar is phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 2-thiazolyl, 2-thienyl, 2- (5-chloro-thienyl), 2-pyridyl or 3-pyridyl; Ar 4 is phenyl substituted in the para position with Ar 5, said Ar 4 optionally being further substituted with chloro or fluoro; and Ar5 is cyclopentyl, cyclohexyl, phenyl, thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-midazolyl, 2-pyrimidyl, 5-pyrimidyl, 2-thienyl, 6-pyridazanyl, 2-pyrazinyl, -pyrazolyl, 2-thiazoloyl or 5- pyridazinyl optionally mono- or disubstituted on the carbon with chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethyl or trifluoromethoxy. 106.- A compound of claim 105, a prodrug of

same or a salt of said compound or said prodrug selected from the acid 3- (3-pyridin-3-yl-benzyl) -amino acid. ] -methyl.}. -phenyl) -propionic; 3- (3. {[[(4-Chlorobenzenesulfonyl) - (4-pyrazin-2-yl-benzyl) -amino] -methyl] -phenyl) -propionic acid; 3- (3. {[[[4-pyrazin-5-yl-benzyl) - (thiazole-2-sulfonyl) -amino] -methyl} -phenyl) -propionic acid and the acid - (3-. {[[(4-chloro-benzenesulfonyl) - (4-pyrimidin-2-yl-benzyl) -amino] -methyl] -phenyl) -proponic acid. The compound of claim 105, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Ar is 3-pyridyl; Ar4 is paraphenylene and Ar5 is 3-pyridyl. The compound of claim 105, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Ar is 4-chloro-phenyl; Ar 4 is paraphenylene and Ar 5 is 2-pyrazinyl. 109. The compound of claim 105, a prodrug of

15 itself or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Ar is 4-chloro-phenyl; Ar4 is paraphenylene and Ar5 is 2-pyrimidinyl. 110.- The compound of claim 105, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said

Prodrug, wherein Ar is 2-thiazolyl; Ar 4 is paraphenylene and Ar 5 is 2-pyrazinyl.

SUMMARY THE INVENTION

This invention relates to prostaglandin agonists, methods of using said prostaglandin agonists, pharmaceutical compositions containing said prostaglandin agonists, and test kits containing said prostaglandin agonists; Prostaglandin agonists are useful for the treatment of bone disorders, including osteoporosis.

PFIZER / yac * eos * sll * lrb * cgm * abg * mvh * pbg * sff * mmr * xal * aom * jtc * P00 / 310F