Prevention of loss and restoration of bone mass by certain prostaglandin agonists

Description

This invention relates to prostaglandin agonists, pharmaceutical compositions containing pannig agonists, and the use of platelet agonists to prevent bone loss in bone marrow enhancement of bone marrow, bone mass, in combination with the condition of low bone mass in mammals, related to human beings.

Bone edema is a systemic skeletal disease characterized by low bone mass and bone tissue, and a pair of bones increases the risk of bone fracture and risk of fracture. F Bandworms have an effect on more than 25 million people, causing more than 1.3 million injuries per year, with a total of 500,000 spine, 250,000 myeloma and 240,000 myeloma broken annually. Hematopathy is the most severe bone resorption, a pair of 5-20% of patients die within one year, and more than 50% of the survivors are severely impaired.

Older ffllk is at the highest risk of bone dysfunction, and pvf is predicted that the problem increases significantly with the aging of the population. It is projected that outbreaks in the world have increased by threefold over the next 60 years, and one study of the power force will be 4.5 million floridae in the world by 2050.

Women are at greater risk of developing bone dysfunction than men. Women get a high rate of bone loss during the five years after menopause. Cancellation measures that increase the risk include smoking, alcohol abuse, sedation and low calorie intake.

Currently, there are two proliferation inhibitors of the pharmacokinetic drug for bone exchange. The first is the use of anti-absorbed compounds to reduce the absorption of bone tissue.

Estrflgen is dssmi about anti-absorbed material. Known is the force of the violation. Power also clarifies Black, etc. In EP 0605193A1 from the patient, especially when administered by mouth, the amount of LDL in the blood stream decreases and increases the amount of high-density HDL's. However, estrflgen does not support the regeneration of bone back to the level of full full-scale. In a skeleton that causes a haemorrhage of osteoporosis. Furthermore, long-term estrflogen metabolism has averaged the length of a variety of therapies, including the increased risk of cancer in the uterine, cancer of the prostate and possible cancer. In the majority of women, many women suffer from this complication.

Other bacteria for the treatment of osteoporosis is the use of anabolic miflium for proliferation of bone formation and extra bone mass. It is the power of this kind of miflium instrument bone. In a skeleton that has an osteoporosis for bone resorption.

U.S. Pat. 4,112,236 discloses certain interfenylene 8-aza-9-dioxothione-11,12-secoprostaglandin for the treatment of patients with renal failure.

Certain prostaglandin agonists are disclosed in GB 1478281, GB1479156 and U.S. Pat. 4,175,203, 4,055,596, 4,175,203, 3,987,091 and 3,991,106 as useful as, for example, novel micrometers.

U.S. Pat. 4,033,996 discloses the 8-aza-9-oxo (and dioxy) thiophene-11,12-seco prostaglandin useful as novel vasopressors for prophylaxis of thrombosis to induce growth hormone erythema, which adjusts for immune destruction.

French patent no. 897,566 discloses certain amino acid derivatives for the treatment of neurological psychiatric cardiovascular disease.

J. Org. Chem. 26; 1961; 1437 discloses N-acetyl-N-benzyl-p-aminophenylmercaptoacetic acid.

Often, osteoporosis has approximately 20-25 million women, and increased menstrual vertebral fracture as a reduction of bone mass loss, and a further 250,000 myocardial infarction is reported in Amarin one. The later reference is related to 12% mortality in the first two years and 30% of the number of patients in need of a patient reside in a nursing home after breach. As a result, it is estimated that the economic and medical-theoretical implications of the recovery cycle due to the rapid increase in the size of these fractures increased due to the aging of the population. Although there are some promising lymph nodes (bis-phosphonate, etc.) in order to prevent bone loss of age, thus reducing the likelihood of invoking paralysis, these lymph nodes are not given for bone mass rebuilding when breach has occurred.

Verified (Bolander, et al., 38th Annual Meeting Orthopedic Research Society, 1992) has shown that estrogen bsata is a good source of lymph node. Therefore, estrogen replacement therapy may appear to be effective in the treatment of fractures. However, the osteoporosis treatment of patients with estrogen therapy is relatively stable due to its side effects, including reuptake, chest pain, increased risk of uterine cancer, increased levels of breast cancer, and concomitant use of progestins. In addition, men are likely to object to the use of estrogen therapy. Clearly, treatment is required that would be beneficial for patients who suffered from fibrous fracture fractures that have a bone mass and which would increase patient's multiple survival rate.

Although the strength of various osteoporosis disorders, the continuing threats to and continued search in this field provide a wide range of bone dilution therapies. Power increases for bone fractures.

SUMMARY OF INVENTION

This invention relates to a compound of formula I

Formula Propionate Highly Suitable Salad Prepare a pair of such

Bern;

A is (C 1 -C 6)₃alkylsulfonyl which is optionally mono-, di- or tri-substituted on carbon independently with hydroxy, (C1-C4) alkyl or halo;

q

- (C₂-C_e) Alký1en-N- (C₃) Alkylene-,

- (C3-C₈) alkylene, wherein said - (C₃-C_B) alkylene is optionally substituted with up to four substituents independently selected from fluorine or (C1 -C6)₄) Alkyl,

-X-fCrCsjalkýlen-,

- (CrCsJalkýlen-X-,

- (C_a) Alkylene-X- (C-C3) alkylene-,

- (CRC₄) Alkylene-WX- (Co-C3) alkylene-,

- (Co-C ^ alkylene-X-WrfCo-C ^ alkylene,

- (C1 -C6) alkylene-WX-WrfCi-CaJalkylene, wherein the two cases of W are independently;

X is phenyl, thienyl or thiazolyl wherein said phenyl, thienyl or thiazolyt is optionally mono- or di-substituted independently with fluoro, chloro, binuononyl, methoxy, difluoromethoxy or trifluoromethyloxy;

Z is carboxy, (C1-C6) alkoxycarbonyl or tetrazolyl;

K is methylene;

M is -Ar where Ar is phenyl, thiazolyt, pyridyl, thienyl, oxazolyl, furanyl, cyclopentyl or cyclohexyl;

wherein said Ar is optionally substituted on carbon by up to three substituents independently selected from R¹, R² and r³ where Ar is substituted by at least R¹ and where R¹ is (C 1 -C 6) alkyl or (C 1 -C 6) alkoxy, wherein said (C 1 -C 6) alkyl or (C 1 -C 5) -alkoxy means optionally di- or tri-substituted with hydroxy or fluoro; and R² and r³ are each independently chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.

Particularly preferred compounds are 7 - {[4- (1-hydroxy-hexyl) -benzyl] -methanesulfonylamino] -heptanoic acid, 7 - [(4-Butyl-benzyl) methanesulfonic-amide] -heptanoic acid_l7 - {[5- (1-Hydroxy-hexyl) -thiophen-2-ylmethyl] -methanesulfonyl-amino} -heptanoic acid and (3-flu (4-butyl) -benzyl) -methanesulfonyl-amino] -methyl} phenyl) -acetic acid.

A group of compounds which is denoted by the formula, contains those compounds wherein Q is - (C1 -C6 alkylene-WrfCrC2 alkylene; and W is oxy.

A group of compounds which is preferred as the designated F group, contains those compounds wherein

Q is - (C₃-C_B) alkylene, wherein said - (C3-C6) alkylene is optionally substituted with from one to four fluorines.

Particularly preferred compounds in the F group of compounds are chemical compounds in which

a. A is methylsulfonyl;

Q is n-hexylene;

Zerkarboxýl;

K is methylene; and

Methyl 4- (1-hydroxy-n-hexyl-1-yl) phenyl;

b. A is methylsulfonyl;

Q is n-hexylene;

Z is carboxy;

K is methylene; and M is 4- (n-butylene-1-yl) phenyl; and

c. A is methylsulfonyl;

Q is n-hexylene;

Z is carboxy;

K is methylene; and

M is 5- (1-hydroxy-n-hexyl-1-yl) thien-2-yl.

A group of compounds which is highly representative of the G group, contains those compounds wherein Q is -X- (C1 -C6)₅) Akýien-; and

X is thienyl or phenyl; wherein said phenyl and thienyl is optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.

A group of compounds which is the preferred H group, contains those compounds wherein Q is -X- (C1 -C6)_s) Alkylene-; and

X is thienyl or phenyl; wherein said phenyl and thiophenyl is optionally mono- or di-substituted independently with fluorine, chlorine, trifluoromethyl or methoxy.

A group of compounds which is preferred in the group, contains those compounds wherein Q is - (C1- (C1-4) alkylene-X- (C1 -C3) alkylene- and

X is phenyl or phenyl; wherein said phenyl and thienyl is optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.

Particularly preferred compound in the group of compounds is a compound wherein A is methylsulfonyl;

Q is 3-methylenephimethyl;

Z is carboxy;

K is methylene; and

M is 4- (n-butylene-1-yl) phenyl.

A group of compounds which is preferred to represent the J group, contains those compounds wherein Q is - (C_rC₄) Alkylene-WX- (C₀-C₃) Alkylene-;

X is thienyl or phenyl; wherein said phenyl and thienyl is optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and

Weroxý.

A group of compounds which is preferred as a designated K group, contains those compounds wherein Q is - (C₀-C₄) Alkylene-XW- (C, -C₃) Alkylene-;

X is thienyl or phenyl; wherein said phenyl and thienyl is optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and W is oxy.

A group of compounds which is the preferred L-group represented by those compounds wherein Q is - (C1-C6) alkylene-WXW-fCrC1-4alkylene;

Weroxý; and

X is thienyl or phenyl; wherein said phenyl and thienyl is optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.

This invention also relates to the use of a compound of formula I for the production of a medicament for enhancement, and bone mass maintenance and to prevent further bone loss in a mammal.

This invention also relates to the use of a compound of formula I for the manufacture of a medicament for the treatment of a mammal having a low bone mass condition. It is preferable to treat women after menopause and karia over 60 years. Also included are subjects without age to have a significantly lower bone mass, ie8, a 1.5 standard deviation below normal levels of adolescence.

Still another aspect of this invention relates to the use of a compound of formula I for the manufacture of a medicament for the osteoporosis of osteoporosis, fractures, osteoporosis, direct apnea associated with osteoporosis, epidermal vasculitis in a mammal (including human beings).

Still another aspect of this invention relates to the use of a compound of formula I for the manufacture of a medicament for the treatment of osteoporosis in a mammal (including human).

Still another aspect of this invention relates to the use of a compound of Formula I for the manufacture of a medicament for the treatment of direct bone loss in a mammal (including human beings). In one side, the phonogram I is compounded locally on a stack of directions.

Still another aspect of this invention relates to the use of a compound of formula I for the manufacture of a medicament for the treatment of cavity in a mammal (including a human being).

Still another aspect of this invention relates to the use of a compound of Formula I for the manufacture of a medicament for the treatment of direct loss associated with dermatitis in a mammal (including human).

Still another aspect of this invention relates to the use of a compound of formula I for the manufacture of a medicament for the treatment of self-directed bone loss in a male mammal.

Still another aspect of this invention relates to the use of a compound of formula I for the manufacture of a medicament for the treatment of "secondary osteoporosis" comprising glucocorticoid-induced osteoporosis, hyperpigmentation-induced bone dilution, erythropoietin-induced osteoporosis, heparin-induced osteoporosis or immunosuppressive-induced osteoporosis in a mammal (including human).

Still another aspect of this invention relates to the use of a compound of formula I for the delivery of a medicament for the treatment of glucocorticoid-induced bone dilution in a mammal (including a human).

Still another aspect of this invention relates to the use of a compound of formula I for the delivery of a medicament for the treatment of hypercholesterolemia induced osteoporosis in a mammal (including any human).

Another aspect of this invention relates to the use of a compound of formula I for the delivery of a medicament for the treatment of erythropoietin-induced bone dilution in a mammal (including human).

Still another aspect of this invention relates to the use of a compound of formula I for the delivery of a medicament for the treatment of heparin-induced bone dilution in a mammal (including a human).

Still another aspect of this invention relates to the use of a compound of formula I for the delivery of a medicament for the treatment of immunosuppression-induced osteoporosis in a mammal (including human).

Still another aspect of this invention relates to the use of a compound of formula I to the prodrug for use in the treatment of fractures in a mammal (including human). In one aspect of this invention for the metabolism of fractures, Formula I is a compound of a pharmaceutical composition comprising a salt thereof utilized locally at the bone fracture site. In another aspect of this invention, Formula I compounds are pharmaceutically acceptable salt thereof.

Still another aspect of this invention relates to the use of a compound of formula I for the manufacture of a medicament for enhancing the appearance of a recombinant facial enhancement of a laryngeal repair of a mammalian recombinant mammal (including a human being). In one aspect of this invention, Formula I is a compound of Formula III wherein a compound of formula is directly substituted with a salt.

Still another aspect of this invention relates to the use of a compound of formula I for the proliferation of a medicament for inducing vascular growth of arthritis in mammalian (including human).

Still another aspect of this invention relates to the use of a compound of formula I for the proliferation of a medicament for the induction of spinal cord attachment in a mammal (pair of human beings).

Still another aspect of this invention relates to the use of a compound of formula I for the proliferation of a medicament for the purpose of enhancing long-term correction of a mammal (a human being).

Still another aspect of this invention relates to the use of a compound of formula I for the delivery of a medicament for use in the mammalian bone resorber (paired human). In one aspect of this method, Formula I is a compound of a pharmaceutically acceptable salt or parenteral compound. Also, if required, the amount of Formula I compound will be boosted by a pharmacologically active salty pair of on-bone cells to restore bone regeneration.

The preferred dose is about 0.001 to 100 mg / kg / day of Formula I compound to promote pharmaceutically acceptable salt. A particularly preferred dose is about 0.01 to 10 mg / kg / day of Formula I compound to promote pharmaceutically acceptable salts.

This invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I promoting a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

This invention also relates to a pharmaceutical composition for the increase of bone mass comprising bone mass, an increasing amount of a compound of formula I promoting a pharmaceutically acceptable salt! pair of and pharmaceutically acceptable capsules.

This invention also relates to a pharmaceutical composition for the treatment of a condition which results in bone mass in a mammal (a human) comprising amounts of a compound of formula I promoting a pharmaceutically acceptable salt of a low molecular weight state and a pharmaceutically acceptable carrier.

This invention also relates to a pharmaceutical composition for the treatment of osteoporosis, bone fractures, bone fractures, bone resorption, bone loss associated with dental floss, direct stimulation of artificial venous thrombosis in a mammal (human belonging) consisting of an effective amount of a compound of formula I promoting a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

This invention also encompasses pharmaceutical compositions for the control of "secondary bone resorption", which is associated with glucocorticoid-induced bone resorption, shield-induction-induced bone resorption, rigor-inducing bone resorption, heparin-induced bone development, enhancement of transplantation-induced bone dysfunction in a mammal (couple of times human) consisting of "secondary bone mineralization" interfering amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

This invention also relates to a pharmaceutical composition for the treatment of osteoporosis of a mammal (a human being) comprising osteoporosis of a major amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

This invention also relates to a pharmaceutical composition for enhancing bone fracture. In a mammal (including a human) consisting of a fracture therapeutic amount of a compound of formula I promoting a pharmaceutically acceptable salt and a pharmaceutical carrier.

This invention also relates to a pharmaceutical composition for the treatment of bone marrow bone loss in a mammal (a human) consisting of bone-directed bone-directing agents of a compound of Formula I promoting a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.

This invention also relates to a pharmaceutical composition for the treatment of cavity in a mammal (including a human) consisting of a cavity inorganic amount of a compound of formula I promoting a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

This invention also relates to a pharmaceutical composition for the treatment of a self-sustained bone loss comprising a self-sustained bone loss effect of a compound of formula I promoting a pharmaceutically acceptable salt and a pharmaceutical carrier.

This invention also relates to a pharmaceutical composition for enhancing the ability to stimulate postoperative reuptake of a laryngeal repertoire in a mammalian recombinant mammalian recombinant mammalian recombinant body comprising a compound of formula I, a pharmaceutically acceptable carrier, and a pharmaceutically acceptable carrier.

This invention also relates to the pharmaceutical compositions for the treatment of direct therapy associated with dental infusion into a mammal (human-like) consisting of dermatitis associated with a directaneous loss of metabolic amount of a compound of formula I promoting a pharmaceutically acceptable salt! pair of and pharmaceutically acceptable capsules.

This invention also relates to a pharmaceutical composition for the metabolism of the porcine vascular integrity of a mammal (human-like) consisting of a retardation of arthritis with a major amount of a compound of formula I promoting a pharmaceutically acceptable salt and a pharmaceutical carrier.

This invention also relates to the power of pharmaceutical compositions for the induction of spinal cord in a mammal (a human) comprising a highly effective amount of a compound of formula I promoting a pharmaceutically acceptable salt and a pharmaceutical carrier.

This invention also relates to the ability of pharmaceutical formulations to enhance the long-term morbidity of a mammal (a human) comprising bone mass enhancement of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

This invention also relates to pharmaceutical compositions for the treatment of glucocorticoid-induced bone resorption in a mammal (parenteral human) comprising a human therapeutic amount for glucocorticoid-induced bone preparation of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

This invention also relates to pharmaceutical compositions for the treatment of a mammalian-induced mammalian-induced mammalian mammal (human-paired) mammalian mammalian mammalian-induced prodrug of a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.

The present invention also relates to pharmaceutical compositions for the treatment of fibrous-induced bone formation in a mammal (parenteral human) comprising a therapeutically effective amount of bone mineralization of a compound of formula I or a pharmaceutically acceptable peptide salt thereof and a pharmaceutically acceptable carrier.

This invention also relates to pharmaceutical compositions for the treatment of haparin-induced mammalian osteoporosis (human-paired) comprising concomitant levels of heparin-induced bone formation of a compound of formula I, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier agent.

This invention also relates to pharmaceutical compositions for the treatment of immunosuppressive-induced bone donation (human-related) sponges comprising a coagulant amount for dyspnoea-induced bone formation of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Still another aspect of this invention are combinations of the Formula I compounds or pharmaceutically acceptable salts of a pair of & lt; RTI ID = 0.0 & gt; ddrum & lt; tb & gt; ______________________________________ & lt; tb & gt; ______________________________________ & lt; tb & gt;

Still another aspect of this invention relates to pharmaceutical compositions consisting of a compound of formula I, a pharmaceutically acceptable salt and a secondary agent, and to the use of granular formulations for the preparation of a medicament for mediation (e.g., prophylaxis) of low bone mass, a pair of with bone osteoporosis in mammals (eg, humans, especially women), the use of granular formulations for the manufacture of other bone mass supplementary use.

The compositions of this invention comprise a therapeutically effective amount of the first compound, in combination with the first compound, of Formula I compound having a pharmaceutically acceptable salt; and gastrointestinal active amounts of drought compounds, pairs of which other mentioned compounds are antagonized, such as estrogen protectants / antidotes, bisphosphonates

Preferred estrogen agonists / antagonists include dloloxifene, raloxifene, tamoxifen, 4-hydroxy-tamoxifen, tomimifene, centroscane, levormeloxifene, idoxifen, 6- (4-hydroxy-phenyl) -5- [4- (2-piperidin-1-yl -ethoxy) -benzyl] -naphthen-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,

C / s-6- (4-fluoro-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalene-2-ol; (-) - Cts-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydronaphthalene-2-ol; C / s-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydronaphthalene-2-ol;

Cfe-1- [6'-pyrrolodynethoxy-3'-pyridyl] -2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene; 1- (4'-Pyrrolidinoethoxyphenyl) -2- (4 "fluorophenyl) -6-hydroxy-1,2_l3_l4-tetrahydroisoquinoline;

Cis-6- (4-hydroxyphenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalen-2-ol;

- (4'-Pyrrolidinolethoxyphenyl) -2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline and the pharmacologically acceptable salts thereof.

Particularly preferred estigen agonists / antagonists include dróloxifene;

Ci9-6- (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-tetrahydronaphthalene-2-ol; Cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7_I8-tetrahydronaphthalene-2-ol;

Cis-1- [6'-pyrrolodinoethoxy-3'-pyridyl] -2-phenyl-6-hydroxy-1,2,3,4-tetrahydrofuranaphthalene; 1- (4'-Pyrrolidinoethoxyphenyl) -2- (4 "fluorophenyl) -6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

C / s-6- (4-hýdroxýfený1) -5- [4- (2-piperidin-1-y1-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalene-2-ol; 1- (4'-Pyrrolidinolethoxyphenyl) -2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline and pharmacologically acceptable salts thereof.

Preferred bisphosphonates include, tlududic acid, alendronic acid, ibandronic acid, risedronic acid, ethidronic acid, chlorodynus, and pamidronic acid and their pharmaceutically acceptable salts.

Another aspect of this invention is the use of a composition for the delivery of a medicament for the treatment of mammals having low bone mass consisting of

a. effective amount of the first compound, wherein said first compound of Formula I compounds a pharmaceutically acceptable salt thereof; and

b. a highly effective amount of a compound, wherein said compound is an anti-resorptive agent such as an estrogen agonist / antagonist enhancing bisphosphonate.

Such combinations are also used for other bone mass extraction. Preferred estrogen agonists / antagonists in this metabolism include drloloff, raloxifene, tamoxifen, 4-hydroxy-tamoxffen, tremorphen, centroscan, levormeloxifen, idoxifen, 6- (4-hydroxy-phenyl) -5- [4- (2-piperidin- 1-yl-ethoxy) -benzyl] -naphthalen-2-ol, {4- [2- (2-Asa-bicyclo [2.2.1] hept-2-yl) -ethoxy] -phenyl} - [6-hydroxy -2- (4-hydroxy-phenyl) -benzo [b] thiophen-3-yl] -methanone, Cis-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-pyrrólkJ [n-1-yl-ethoxy) -phenyl] -5_l6,7,8-tetrahydronaphthalene-2-ol;

C 2-6 -phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol;

C / s-1- [6'-pyrrolodinoethoxy-3'-pyridyl] -2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene; 1- (4'-Pyrrolidinethoxyphenyl) -2- (4 "-fluorophenyl) -6-hydroxy-1,2,3,4-tetrahydroisoquinoline; Cis-6- (4-hydroxyphenyl) -5- [4- 2-piperidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalen-2-one; 1- (4'-Pyrrolidinoneethoxyphenyl) -2-phenyl-6-hydroxy-1,2 , 3,4-tetrahydroisoquinoline; and the pharmaceuticals of the sweet one.

Poorly preferred estrogen agonists / mopants include drloloxifene; C / s-6- (4-fluoro-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -5_l6,7,8-tetrahydro-naphthalen-2-ol; (-) - C / 's-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydronaphthalene-2-ol; C / s-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydronaphthalene-2-ol;

C / s-1- [6'-pyrrolodinoethoxy-3'-pyridyl] -2-phenyl-6-hydroxy-1,2,3,4-tetrahydroanaphthalene; 1- (4^,-Pyrrolidinoneethoxyphenyl) -2- (4 "-fluorophenyl) -6-hydroxy-1,2,3,4-tetrahydroisoquinoline; Cis-6- (4-hydroxyphenyl) -5- [4- (2-piperidine -1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalen-2-ol; 1- (4'-Pyrrolidinolethoxyphenyl) -2-phenyl-6-hydroxy-1,2,3, 4-tetrahydroisoquinoline and the pharmacologically stable salts thereof.

Preferred bisphosphonic acids include tivadronic acid, alendronic acid, ibandronic acid, risedronic acid, ethidronic acid, clodronic acid, and pamidronic acid and their pharmaceutically acceptable salts.

Preferred aspect of this invention is a pair of conditions that cause low bone mass is osteoporosis.

Another preferred aspect of this invention is wherein the first compound and other compounds are administered almost simultaneously.

Another preferred aspect of this invention is wherein the first compound is administered in a period of from about one week to about a three-year period.

Alternatively, the administration of the first compound is followed by the addition of another compound in which another compound is astromic agonist / antagonist for a period of from about thirty months to approximately one year without the administration of the first compound in the second half of about three months about thirty years old.

Admittedly, the administration of the first compound followed by the administration of the major compound as a secondary compound is an estrogen agonist / antagonist for a period of more than three years without the donation of the first compound over the period after about three years.

Another aspect of this invention is a synthesis consisting of:

a. therapeutically effective amount of Formula I compound administers a pharmaceutically acceptable salt pair of and a pharmacologically acceptable carrier in the first unit dosage form;

b. treated with effective amounts of anti-absorbed agents such as estrogen agonists / antagonists of bisphosphonate and pharmacologically acceptable carrier in a second unit dosage form; and

c. a container for storing said first and second dosage forms.

Preferred estrogen agonists / antagonists In this context, drloloxifene, raloxten, tamoxifen, 4-hydroxy-tamoxifen, tomephen, centroscan, levormeloxyphen, idoxifen, 6- (4-hydroxy-phenyl) -5- [4- (2-piperidin-4-yl) -1-yl-ethoxy) -benzyl] -naphthalen-2-ol, {4- (2- (2Asa-bicyclo [2.2.1] hept-2-yl) -ethoxy] -phenyl) - [6-hydroxy-2- - (4-hydroxy-phenyl) -benzo [bJÞíófen-3-yl] -methanone,

C / s-6- (4-fluoro-phenyl) -5- [4- (2-piperidin-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-tetrahydronaphthalen-2-ol;

Cffi-e-phenyl-S- ^ IZ-pyrrolidin-l-yl-etoxýHenýlJ-S.ej.e-tatrahýdrönaftalen ^ ol;

Cis-1- [6'-pyrrolidinoneethoxy-3'-pyridyl] -2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;

1- {4'-Pyrrolidinoethoxyphenyl) -2- (4 "fluorophenyl) -6-hydroxy-1,2,3,4-tetrahýdróísóklnólln;

C / s-6- (4-hydroxyphenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -5_l6,7,8-tetrahydro-naphthalen-2-ol;

1- (4'-Pyrrolidinolethoxyphenyl) -2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline; and pharmaceutically-acceptable salts thereof.

Particularly preferred estrogen agonists / antagonists include dragloxifene; C / s-6- (4-fluoro-phenyl) -5- [4- (2-piperidin-1-y1-ethoxy) -fený1] -5,6,7,8-tetrahydro-naphthalene-2-ol; (-) - cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydronaphthalene-2-d;

Cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol;

Cts-1- [6'-pyrrolodinoethoxy-3'-pyridyl] -2-phenyl-6-hydroxy-1 ^, 3,4-tetrahydronaphthalene;

- (4-hydroxyphenyl) -5- [4- (2-pyridin-4-yl) phenyl] -5- [4- (2-pyridinoethoxyphenyl) -1-fluorophenyl] -2-hydroxy-1,2,3,4-tetrahydroisoquinoline; 1-yl-eloxý) -phenyl] -5_l6,7,8-tetrahydro-naphthalen-2-ol; 1- (4'-Pyrrolidinolethoxyphenyl) -2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline; and pharmacology20 are the appropriate levels.

Preferred bisphosphonates include tivadronic acid, alendronic acid, ibandronic acid, risadron acid, ethidronic acid, clodronic acid, and pamidronic acid and their pharmaceutically acceptable salts.

Another aspect of this invention relates to a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and another bone resorption medium (although the bone resorption agent may be of formula I compound) and that the use of granular compositions in the preparation of medicaments for treatment low bone mass condition, including bone osteoporosis in mammals (eg humans, especially women) or the use of such combinations for the manufacture of drugs for other bone mass supplementation.

The composition comprises a therapeutically effective amount of the first compound, a pair of said first compound being a compound I or a pharmaceutically acceptable salt pair; and a therapeutically effective amount of a fluorine compound, a pair of said compounds, is another bone tissue enhancer.

Preferred bone resorption agents include IGF-1 optionally with IGF-1 volume 35 protein 3, prostaglandin, prostaglandin garment / antagonist, sodium fluoride, parathyroid hormone (PTH), active fragment of parathyroid hormone, parathyroid hormone associated peptifl and active fractures and analogues of parathyroid hormone related peptides, growth hormone enhances growth hormone secretion and pharmaceuticals rapidly inhibits the salts.

Another aspect of this invention is the use of formulations for the manufacture of a medicament for treating low bone mass mammals consisting of

a. effective amount of the first compound, a pair of said first compound being a compound of formula III, wherein a pharmaceutically acceptable salt is a couple of; and

b. The effective amount of a fluorine compound, a pair of said compounds, is another bone resorption molecule other than Formula I compound.

Such combinations can also be used for other bone mass extraction.

Acceptable bone resorption agents include IGF-1, including IGF-1 volume protein 3, prostaglandin, prostaglandin agonist / metabolite, sodium fluoride, parathyroidism (PTH), active fragment of parathyroid gland, parathyroid gland associated peptide, and active fractures and secretions of parathyroid hormone-related peptides growth hormone enhancing growth hormone secretors and pharmaceutically acceptable fluids.

Preferred alternatives of this invention are a pair of conditions that cause low bone mass is bone mineralization.

Another preferred aspect of this invention is the pair of compounds of the present invention, which are substantially all of the foregoing.

Another aspect of this invention is a synthesis comprising:

a. a therapeutically effective amount of Formula I compound enhancing a pharmacologically acceptable salt pair of and a pharmaceutical carrier in a first unit dosage form;

b. a highly effective amount of fluorine compound, a pair of said compounds, is a bone resorptive agent other than Formula I compound; and

c. dispensed to the forced storage of said first and second dosage forms.

Acceptable bone resorption agents include IGF-1, including IGF-1 binding protein 3, prostaglandin, prostaglandin agonists, sodium fluoride, parathyroid gland, active parathyroid gland, parathyroid gland associated peptide, and active fractures and parathyroid glands associated with peptides growth hormone enhancement of growth hormone secretion and pharmacokinetic hepatitis salts.

The phrase "low bone mass condition" indicates a state of bone mass concentration below age-related levels as defined in the International Health Assessment Institute's Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis (1994). Report of a World Health Organization Study Group. World Health Organization Technical Series 843. "Included in" low bone mass "condition are primary and secondary bone dysfunction. Secondary bone dysfunction involves glucocorticoid-induced bone dysfunction, hypercholesterolemia, bone dyspnoea, rigor-induced bone dysfunction, heparin-induced bone dysfunction and immunosuppression-induced bone dysfunction. Also, the most common is a dental disease, cataracts, osteoporosis and asthmatic bone loss.

The phrase "low bone mass" also indicates a mammal who is known to have a significantly greater than average chance of developing disease as described above including bone dysfunction (eg postmenopausal women older than 60 years of age ).

Other bone mass enhancement or increased use include increasing the rate of fracture fractures, increasing the incidence of effective bone fractures, post-recalcitated postoperative or osteoarthritis or jaw repulsion, arthritis fibroblast retention, vertebrae or longitudinal edema.

Those skilled in the art will understand that the term bone mass actually refers to bone mass on each unit area that sometimes (although the path is not quite correct) is referred to as bone mineral density.

The term "treatment land," treat "or" treatment "as used herein includes prophylaxis (for example, disease-causing) and palliative treatment.

By "pharmacological qualification" means that the carrier, diluent, carrier and / or salt must be compatible with other substances in the composition, and not harmful to the recipient.

Alkyline refers to saturated hydrocarbons (straight chain or branched) as a hydrogen atom is removed from each of the endocoholes. Examples of complex groups (which assume that the designated length covers a particular example) are methylene, ethylene, propylene, butylene, percylene, hexylene, heptylene.

By halo is meant chlorine, bromine, iodine, or fluorine.

By alkyl refers to straight chain saturated hydrocarbons or branched chain saturated hydrocarbons. Examples of such alkyl groups (which assume that the designated length covers a particular example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl , 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.

By alkoxy is straight chain saturated alkyl or branched chain saturated alkyl which is linked to oxo. Examples of such alkoxy groups (pairs of which are meant to include the particular length of a particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, phenoxy, heptoxy and octoxy.

As used herein, the term mono-N- or di-N, N- (C1 -C4)_x) alkyl ... to (C_rC_x) -alkyl moiety which is taken independently when it is df-NN-fCrQJalkyl ... (x refers to the number).

It is understood that if a carbocyclic or heterocyclic moiety may be bonded or otherwise attached to a designated reagent, by different ring atoms without specifying a particular linker, then all possible sites, whether carbon atoms or, for example, a tertiary nitrogen atom . For example, the term "pyridyl 2-, 3-, or 4-pyridyl," pipenet "refers to 2-, or 3-thienyl, and so on.

The term "pharmaceutically acceptable salt" refers to unsaturated anionic anions containing anions such as (but not limited to) chloride, bromide, iodide, sulfate, bisulfate, phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, methanesulfonate and 4-toluene sulfonate. The duke also refers to unsaturated cationic salts such as (but not limited to) sodium, potassium, calcium, magnesium, ammonia or proteinaceous benzadin (N, N'-dibenzylethylenediamine), choline, ethanolamine, diethanolamine, ethylenediamine, methylaminoglycan), benetamine (N-benzythenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanol).

As used herein, the term "inert solvent" and "inert solvent" refers to a solvent that does not interact with the starting material, reagent, intermediates such products in a manner that has a slight effect on the yield of the product desired.

The negligent or corrective symbol in parenthesis used herein in the nouns denotes the directional plane that emits light in a particular stereotype.

Typical chemical agents will see that certain compounds of this invention will contain one or more atoms which may be in a predominantly ambient so-called stereotype configuration, which causes ambient and enantiomeric environments. All of them disappear and mixtures of these are included in this invention. Hydrogenates of the compounds of this invention are also included.

The usual chemical agents will see contemplated combinations of heteroflammatory linkers listed in this invention of the compounds which will be less interfering with physiological factors (e.g., anxiety-enhancing compounds). In combination with these compounds, the compounds are preferred.

DTT means dipffltreitol. DMSO means dimethyl sulfoxide. EDTA means ethylenediamine tetraacetic acid.

The compounds of this invention lead to bone formation which leads to injury injury. This invention substantially adds to the subject, as it provides energy that enhances bone formation that leads to early retention, obstruction, and / or regression of bone dysfunction and related direct disorders.

Other features and advantages will be apparent from the description and the claims describing the invention.

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

Generally, therefore, the compounds of this invention are produced by means of transducers encompassing behaviors that are detected in the chemical layer, particularly in the light of the description herein. Certain deductions for the preparation of the compounds In this invention, the following reactions are shown. Other forces can be described in the experimental section. Some of the schemes, as shown in Formula I compounds, do not cover the synthesis of compounds in accordance with the invention but also show the production of diffusers.

Some connectors (eg carboxy) are best induced by alteration of another functional group (for carboxy examples, hydroxy or carboxaldehyde) at a later stage in the newcomer.

In general, the formula I can be represented by the compounds of which B is a nitrogen atom with a conventional alkylation of a sulfonamide with two hydrocarbon halides or alkylsulfonates; promote reductive amination on amine containing the necessary acidic activity (suitably protected) with aldehyde followed by reaction with sulfonyl chloride followed by hydrolysis.

In general, the yield of the compounds of formula I (pair with B is N 10 (nitrogen) and A, K, M and Q are one and described in the summary) according to the methods described in Schemes 1 and 2 below. Generally, the heterocyclic alkylation of the surfactant formula 1 is the sulfonamide or amide with two suitable alkyl halides or alkyl sulfonates. It is noted that shapes 1 and 2 differ only in terms of the sequence of sequences of the two alkylation moieties. Typically, the alkylation sequence is selected by the high reactivity of the electromagnetic domain. In order to reduce the amount of dichloroalkylation occurring in the first alkylation step, the amount of power less reactive side chain is introduced first. Typically, one of the alkylation agents contains carboxylic acid or acidic electrolyte which is conveniently hid with a residual protective group. In Examples 1 and 2, Formula 3 is a carboxylic acid ester wherein R represents either straight-chain lower alkyl, preferably methyl or ethyl, or tert-butylphenyl. Therefore, using power acid electrophoresis with pvf can be used to change these schemically by force using techniques that are known to those skilled in the art (see Chart 6, which describes tetrazole production for example). Dichloric acylation agents are monovalent, diphthalic, benzylic, allylic, preferably preferred, bromide promoting alkyl iodide. or tert-butylphenyl group. Therefore, using power acid electrophoresis with pvf can be used to change these schemically by force using techniques that are known to those skilled in the art (see Chart 6, which describes tetrazole production for example). Dichloric acylation agents are monovalent, diphthalic, benzylic, allylic, preferably preferred, bromide promoting alkyl iodide. or tert-butylphenyl group. Therefore, using power acid electrophoresis with pvf can be used to change these schemically by force using techniques that are known to those skilled in the art (see Chart 6, which describes tetrazole production for example). Dichloric acylation agents are monovalent, diphthalic, benzylic, allylic, preferably preferred, bromide promoting alkyl iodide.

Formula 1 the sulfonamide is converted into anionic acid with a strong base such as sodium hydride, lithium diisopropylamide, Upturn bis (trifluoromethyl) amide, potassium bis (trimethylsilyl) amide, potassium tert-butoxide, etc. a solvent-like solvent such as dimethylformamide, tetrahydrofuran (THF) or dimethylformamide / benzene at a temperature of -78 ° C to 100 ° C. The resulting anion is alkylated with a leaving formula 2 enhancing the 3-alkyl halide or alkyl sulfonate (pair of which

X is the halide enhancing the succinate) at a temperature of 0 ° C to 100 ° C to give the corresponding alkylated formula 4 a compound. [In some instances, test the different amounts of secretion derived from Malkylation on the sulfonamide, and then remove the power by using chromatography techniques, preferably power, such as flash chromatography (WC Still, M. Kahn, A. Mftra, J. Org. Chem. 43, 2923, 1978). Formulation 4 enhancing the compounds is converted to the anion again using a suitable base such as sodium hydride, lipids bis (trimethylsilyl) amide, liposomes diisopropylamide, potassium bis (trimethylsilyl) amide, potassium tert-butoxide or potassium carbonate an aprotic solvent such as dimethylformamide, THF, dimethylformamide / benzene, or acetylene glycol, temperature of -78 ° C to 100 ° C. Alkylation (as described above) with a secondary secondary alkyl halide enhancing the alkyl sulfonate (Formula 3 or 2 compound) gives the corresponding Formula 6 ester. The Formula 6 ester is hydrolysed to the corresponding Formula I acid (in cases where R represents methyl or ethyl) with dilute aqueous soluble solution (preferably sodium or potassium hydroxide in water-soluble methanol or ethanol), lithium hydroxide in a water-soluble alcohol solvent, water soluble tetrahydropuran at a temperature of 0 ° C to 80 ° C, or using coagulants described in "Protecting Groups in Organic Synthesis", Second Edition, TW Greene and PGM Wuts, John Wiley and Sons, Inc., 1991.

SCHEME 1

1. Basi

A-NH₂₃ 2. X "-KM

1. Basi - »

2. X * -Q-COaR

AN-Q-COaR 1. NaOH

KM

2. HjO +

AN-Q-COfeH

I

KM

I

SKEMA2

A-NH₂

1. Basi

1. Basi

2. X¹-Q-CO2R

AN-Q-CO 2 R H 2. X * -KM

ANQ-COjR 1. NaOH AN-Q-CO2H

KM ^{1 H}3 ° * KM

I

Also, there is a force of formula I compounds of amines (see Examples 3-4 for example). Generally, the residual amine starting materials (Formula 9 and 10 compounds) can be purchased by the use of coagulants 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 this matter, according to Schemes 3 and 4, the high yield of the amine starting materials of the corresponding Formula 7 promotes the 8 nitriles. Nitrile is an indication of whether the power to buy is better force proliferation pauce by force use coagulants which are characterized by peimons that are professional (see Rappaport, "The Chemistry of the Cyano Group," Interscience, New York, 1970, promoting Patai and Rappaport, The Chemistry of Functional Groups, pt. 2 , Wiley, New York, 1983). Formula 7 promotes 8 nitrilifl is a reducing agent with a reducing agent such as boron-tetrahydrofuran complex, boron-methyl sulfide complex, lithium aluminum hydride, promoting hydrogenation in the presence of Raney nickel or platinum propagating palladium catalysts in a polymer solvent such as methanol or ethanol at a temperature of 0 ° C to 50 ° C. The Formula 9 or 10 amine which is released is converted to either Formula 11 or 12 sulfonamide or amphiphilic treatment (acylation) with acid chloride or sulphonyl chloride in a tertiary base such as triethylamine, pyridine, or 4-methyl-morpholine in aprotic solvent like methylene chloride with diethyl ether at a temperature of -20 ° C to 50 ° C. In many ways, it is common practice to execute cloning of amines of formula 9 or 10 to carboxylic acids in an inert solvent such as dichloromethane or N. N-dimethylformamide (DMF) with a coupling reagent such as 1- (310-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) or 1,3-dicyclohexylcarbodiimide (DCC) in the presence of 1-hydroxybenzotriazole hydrate (HOBT) to produce compounds with the formula 11 or 12.1 in case the amine is present as the hydrochloride salt, it is preferable to add one equivalent of a suitable base such as triethylamine to the reaction mixture. For a variety of advantages, the coupling can be performed with a clot substrate such as benzotriazol-1-yloxy-tris (dimethylamino) -phosphonium hexafluorophosphate (BOP) in an inert solvent such as methanol. Thus, coagulant applications are usually carried out at temperatures of -30 ° C to 80 ° C, preferably at 0 ° C to 25 ° C. For discussion of other constituents used for clot peptides see Houben-Weyl, Volume XV, Part II, E. Wunsch, Ed., George Thaime Verlag, 1974, Stuttgart. Alkylation and, upon request, deprotection of the formula 11 or 12 compound as described in Examples 1 and 2 gives the corresponding acidic formula 13 and 14 compound.

Alternatively, formula 9 and 10 amines can be formulated with formula 15 and 16 amine reduction. It is therefore necessary to achieve the reduction by means of reagents such as boron-tetrahydrofuran complex, boron-methyl sulfide complex, or diisobutyl aluminum hydride in aprotic solvent such as tetrahydrofuran or diethyl ether at a temperature of -78 ° C to 60 ° C.

Also, the formula of formula 9 promotes the 10 amines from the corresponding nitro precursors by reducing the nitro group through the use of reducing reagents such as sulfur / HCl, hydrogenation of Raney nickel, palladium, catalytic catalyst, and other reagents as described by PN Rylander In "Hydrogenation Methods," Academic Press, New York, 1985.

SKEMA3

Λ x "h₂nk [ΙΙ [HI

HJN '

AC1

Basi

AN-O-COaH 1. NaH k

I

2. X'-Q-COjR

V

N '' Q '

I

KM

3. Water loss

SKEMA4

2 H

Η? Ν 'Q 15 [H]

HEART Q '

1. NaH

2. X¹-KM

3. Water loss

ACI

Basi

The description, and the production of other amines and alkylation agents useful in the above syntheses is described below in the section referred to as the productions.

Another advantage of the alkylation described above for the production of Formula I compounds refers to reducing amination of amine containing the susceptible acid function (suitably protected) with aldehyde and shown in Scheme

5. Alternatively, the aldehyde may contain the acidic activity to be coupled to amines.

Typically, the reducing amination is carried out with a reducing agent such as sodium cyanoborohydride enhancing sodium triacetoxyborohydride, preferably with a pH between 6 and 8. The reaction is usually carried out in a polymeric solvent such as methanol or ethanol at a temperature of -78 ° C to 40 ° C. ° C (for leading reference see A. Abdel-Magid, C. Maryanoff, K. Carson, Tetrahedron Lett. 39, 31, 5595-5598, 1990). Other herbs refer to the use of fusopropoxid and sodium cyanoborohydride (RJ Mattson et al., J. Org. Chem. 1990, 55, 2552-4) promote the formation of the imine in the event of a dehydrating effluent followed by reduction. Formula 42,

The resulting 42A amine is converted to the sulfonamide with the remaining carbon monoclonal sulfonyl chloride as described in Schemes 3 and 4. If a flask produces hydrolysis corresponding to the acid.

SKEMA5

HgN-Q-COfcR ♦

OHC-K-M m

....................>

HN-Q-CO 2 R 3 K

<img file="IS2389B_D0001.tif" />

N-Q-Coahu

L 'K

I

M 'Q-COgH

<img file="IS2389B_D0002.tif" />

1. NaOH-Q-CO 2 R

2. H3O +

I.NaOH

2. HgO

A ·

<img file="IS2389B_D0003.tif" />

COgR

ACT

Basi

HgN-KM +

OHC-Q-COgR

HN 'CO2R

42A

Description and use of aldehydes useful In Scheme 5 above, see chapter 5 for more detailed information.

The power of other advantages is another process for yielding a particular Formula I compound (i.e., Formula 60 tetrazole pair wherein B is N and A, K, M, and Q are as described above) described in Scheme 6. Initial Formula 4 sulfonamide or the amide is alkylated with the appropriate alkyl halide or sulfonate (where X 'is halide or sulfonate), preferably mono-substituted, benzylic, or allylic alkyl bromide, iodine, or sulfonate containing nitrile to give Formula 59 compounds. The alkylation results in the treatment of the 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 . Alkylation is at a temperature of -78 ° C to 100 ° C.

Chem. 1993,58,4139-4141,1993). For an overview of other tetrazole products, see RN Butler, Tetrazoles, In Comprehensive Heterocyclic Chemistry; Potts, KT Ed .; Pergamon Press: Oxford, 1984, Volume 5, Bis. 791-838.

-NKM

H

Scheme 6 1. NaH

2.

AN-Q-CN

Q-CN

X ·

M 59 (BuaSnfeO

TMSNo toluene

<img file="IS2389B_D0004.tif" />

Alternatively, there is another method for the preparation of certain Formula I compounds described in Scheme 7. The Formula 46 esters can be prepared using the methods described previously (see Box 1 and 2). Repeated Heck conjugation of this intermediate to aryl (preferably aryl bromide or aryl iodide), aryl triflate, or ring ring containing vinyl bromide, iodide, efia triflate with palladium catalysts, such as palladium acetate or tetrakis (triphenylphosphine) palladium (O) in the presence of trialkylamine, such as triethylamine. in some cases, the resulting triaryl phosphide is released into the reaction. Typically, the reaction is carried out in aprotic solvent such as dimethyl methonamide or acetonitrile at a temperature of about 0 ° C to about 150 ° C (see RF Hack in Comp. Org. Syn., Volume 4, Section 4.3, p. 833 or Daves and Hallberg, Chem. Rev. 1989, 89, 1433). If desired, the hydrolysis of Formula 47 compounds (corresponding to the acid) may be hydrogenated. Alternatively, the Formula 47 compounds may be hydrogenated and, if desired, hydrolysis will remain in the corresponding Formula 49 acid. Preferred hydrogenation conditions include the use of palladium or platinum catalyst in an alcohol solvent such as ethanol or methanol at a temperature of about 0 ° C to about 50 ° C. (Cases where M represents a partially saturated ring system will hydrogenation induce a saturated ring system. Preferred hydrogenation conditions include the use of palladium or platinum catalysts in alcoholic solvents such as ethanol or methanol at a temperature of about 0 ° C to about 50 ° C. (cases where M represents a partially saturated ring system will hydrogenation induce a saturated ring system. Preferred hydrogenation conditions include the use of palladium or platinum catalysts in alcoholic solvents such as ethanol or methanol at a temperature of about 0 ° C to about 50 ° C. (cases where M represents a partially saturated ring system will hydrogenation induce a saturated ring system.

<img file="IS2389B_D0005.tif" />

Alternatively, another product for the preparation of certain Formula I compounds (wherein B is N and A, Q, K and M are as described in the Summary and R is as described for Schemes 1 and 2) in Scheme 8. Formula 51 compounds can be prepared as described in Scheme 1 and 2 by alkylation of Formula 5 with an electron of Formula 2 containing the appropriate activity on the M ring for the following change in aldehyde. For example, electrolytes of Formula 2 (Scheme 2) contain protected alcohol on the ring, M, which may be deprotected and oxidized to the aldehyde by using reagents known to those skilled in the art to form Formula 51 compounds. Another method is to alkylate with an electron of formula 2, wherein M contains a vinyl group. After alkylation, oxidation cleavage on the double bond of formula 51 gives the desired aldehyde. The oxidation cleavage may be achieved by converting the double bond to the 1,2-diol with catalytic osmium tetroxide and N-motomorpholine followed by oxidative cleavage in the aldehyde using sodium perodate. Alternatively, ozone depletion oxidation agent followed by reduction by using reagents such as methyl sulfide, tripanylphosphine, acetic acid, or thiourea, will produce the desired Formula 51 aldehyde. Addition of a metal wherein LMálmur represents any metallic reagent which is like lithium or Grignard reagent in an aprotic solvent such as diethyl ether or tetrahydrofuran at a temperature of -7B ° C to 80 ° C, followed by hydrolysis of the ester as described herein above, the formula 50 affords the desired compound.

SCHEME 8

ANQ-COZR | 1. Lemmur

2. Water spray ** M

I

CHO

AN-Q COgH

<img file="IS2389B_D0006.tif" />

Alternatively, another method of preparation of a particular Formula I compound is described in Scheme 9. The corresponding Formula (S) or the compound is alkylated using the constituents described in Schemes 1 and 2 by an electromagnetic device containing aromatic bromide or iodide or ring system which contains vinyl bromide or iodide (Ar,) to give Formula 53 compounds. Suzuki-gerflar clot of Formula 53 compound of aryl boric acid (Ar_z) gives formula 53a compounds (for superseding of the Suzuki reaction see AR Martin and Y. Yang in Acta Chem. Scand., 1993, 47, 221). The quinquency reaction is tested using approximately two equivalents of base, such as sodium carbonate, potassium carbonate, sodium hydroxide, tallium hydroxide, potassium phosphate, or sodium methoxide, in the presence of palladium catalyst, sinatin and tetrakis (trienylphosphine) palladium (0) palladium acetate, palladium chloride, tris (dibenzylidene acetone) dfpalladium (O) or [1,4-bis (d (phenytphosphine) butane] palladium (0). The reaction can be carried out in aqueous alcohols (methanol or ethanol), water-soluble tetra hydrofuran, water soluble acetone, water-soluble glycol dimethyl ether or water-soluble benzene at a temperature ranging from 0 ° C to 120 ° C. When Αη represents a partially saturated ring, it is possible at this point, if applicable, to perform a reduction of the ring to give a saturated ring system. Suitable for accomplishing this change include hydrogenation in the presence of catalysts and palladium of platinum in anhydrous (ethanol or methanol) and / or ethyl acetate. Ester hydrolysis of Formula 53a compounds, if desired, gives the corresponding acid. Outgoing acids may contain functional groups on either of the ring systems (Ar, or Ar) which can be modified using methods known to those of skill in the art.

Examples of such changes are shown in Chart 10.

SCHEME 9

FJ-A-Q each represent a linear

1. NaH

ANQ-CO2R / Pr-fl

Br.l

AraBiOHfe

Pdhvati basi

A-N-Q-CtfcR

<img file="IS2389B_D0007.tif" />

* 2

Accordingly, the preparation of Formula 54 derivative contains an aldehyde functional group using methods described in Scheme 8 and 9. According to Scheme 10, the treatment of Formula 54 provides the compound with a caustic metallic reagent (Mel), such as a lithium or Grignard substrate, in a aprotic solvents and diethyl ether tetrahydropuran at a temperature of -78 ° C to 80 ° C, followed by hydrolysis of the ester of Formula 56 compounds. Alternatively, reduction of the aldehyde results in hydrolysis of Formula 55 compounds.

SKEMA10

ANQ-CO2R

I 1 · [H1

Ar, 2nd VMnsraf

1 CHO

A-N-Q-C H 2 H 2, CH 2 OH

1. Lemmur

2. Water loss _A-_n-_Q-_COfeH

<img file="IS2389B_D0008.tif" />

Alternatively, another method for the production of certain Formula I compounds is described in Scheme 11. The Formula 58 may be prepared from the starting alcohol by the method described in Scheme 1 and 2. Intermediate 58 is coupled to a plurality of aryl alcohols ( M represents an aromatic circle) using Mitsunobu (see Table 5 for Mitsunobu, Synthesis, 1, 1981). Typically, the coupling is accomplished by the addition of a coupling agent such as triphenylphosphine and diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate in inert solvents such as methylene chloride or tetrahydrofuran at a temperature of 0 ° C to 80 ° C. If desired, the following hydrolysis gives the corresponding acid.

SCHEME 11 ^A\

NQ-CO2R

I + M-OH + OH

PPh₃

N-Q-C0₂R

I

DEAD

Alternatively, another derivative for the preparation of certain Formula I compounds (i.e., Formula 106 compound wherein B is N and A, K, and M are as described in the Summary and R is as described in Scheme 1 and 2 and in conjunction with the corresponding acids) described in Scheme 12. Formula 102 compound is biodegradable (Formula 105 compound (wherein X is an aromatic ring such as benzene ring or thiophenic acid) in the presence of Lewis acid eirts and titanium tetrachloride or the nonionic acid like hydrochloric acid. If desired, the formula 106 may be converted to the corresponding acid by hydrolysis to promote deprotection.

SCHEME 12

Μ

102

X / v COJR iodine acid or H * '105' M

106

Alternatively, the formula 104 can be treated with chloromethyl compounds with Lewis acid such as titanium tetrachloride and a suitable substituted vinyl chloride as an ethylene chloride at a temperature of -50 DEG C. to 50 DEG C. to give Phonomel 108 compounds which are then water jelly or dehydrated as described above to give the corresponding acid. If desired, reduce the double bond by using the conditions described in Scheme 7.

ANQ-Coari

<img file="IS2389B_D0009.tif" />

<img file="IS2389B_D0010.tif" />

AN-Q-CO2R

107

Alternatively, another catalyst for the preparation of a particular Formula I compound is described in Scheme 14. Formula 104 chloromethyl compounds are interleaved with Lewis acid such as tetrachlorophyll and appropriately substituted allyl sulfanide in an aprotic solvent such as chloroform in a temperature of 0 ° C to 80 ° C. ° C to yield Formula 109 compounds which are so-called strong hydrothermal or dehydrated as described above.

<img file="IS2389B_D0011.tif" />

Alternatively, there are other processes for the preparation of certain Formula I compounds (i.e., Formula 112 compounds, A pair wherein B is N and A, Q, R and M are as described above, and in combination with that, corresponding acids) are described in Scheme 15. Formula 104 chloromethyl compounds are treated with Formula III sulphonic acid in the presence of a base such as triethylamine in an aprotic solvent such as chloroform at a temperature of -30 ° C to 50 ° C to give Formula 112 compounds which are as far as described above to give the corresponding acid.

SCHEME 15

<img file="IS2389B_D0012.tif" />

CO₂R basitd. E * 3ⁿ

<img file="IS2389B_D0013.tif" />

co₂r

<img file="IS2389B_D0014.tif" />

ho₂s.

111

It is contemplated to prepare Formula I compounds (wherein B is C (H), R 'is a lower alkyl group, and R 1 represents the alkyl groups of A as described in the summary) according to the scheme

16. Formula 113 beta-ketoesters are alkylated sequentially of Formula 114 compounds resulting from alkylation of Formula 116 compounds to give Formula 117 compounds (J. Mad. Chem., 26, 199, pp. 335-41). It is possible to produce alkylations in a suitable solvent such as DMF, THF, ether, or benzene using appropriate bases such as sodium hydride, LDA, or potassium carbonate at a temperature of about -78 ° C to about 80 ° C C. Formula 117 tricyclic ketone esteramides which are released are hydrolysed and decarboxylated to give the corresponding formula 118 the compound using a water-soluble base such as sodium hydroxide to the hydrolysis ester after acidification such as aqueous hydrochloric acid to effect decarboxylation.

SCHEME 16

<img file="IS2389B_D0015.tif" />

Alternatively, formula I compounds can be prepared (a pair of which B is C (H),

R 'is as described above, and R 1 represents the alkyl groups of A as described in the Summary) according to Scheme 17. A randomized alkylation of a malonate derivative of formula 119 gives Formula 121 diacylated species. Deprotection of the ester group by treatment with stearic acid such as TFA or HCl in ethanol at a temperature of about

-20 ° C to about 50 ° C leads to the formula 122 decarboxylated product. Changing the sample into an acid chloride using a thionyl chloride or oxalyl chloride in an aprotic solvent at a temperature of -78 ° C to 50 ° C or a weinreb amphole using methoxymethylamine in a suitable coupling agent such as DCC or DEC in an aprotic solvent at a temperature of about -30 ° C to about 50 ° C gives formula 123 compounds. Formula 123 are suitable substrates for the addition of various metalloelectric species (e.g., Grignard reagents, cadmium-organic reagents) as a hydrolysis of the final estuar to give the keto-acid compounds of formula 118.

In a variety of ways, formula 118 can be formulated by using previously described derivatives (e.g., see shapes 7, 8, 9, 10, and 11) pairs of which either or both of the side chains are activated further after connection.

<img file="IS2389B_D0016.tif" />

SCHEME 17

<img file="IS2389B_D0017.tif" />

120

X * Br. Ο. I, OMs

114

BNL

Ld.NaH

<img file="IS2389B_D0018.tif" />

<img file="IS2389B_D0019.tif" />

FRAMLEIBSLUR

Amine, amide and sulfonamide

It is intended to produce a certain amount of sulfonamide as described by Formulas 21, 22, and 23 according to Scheme 18. Formula 25.26 and 27 alkynyl amides or sulfonamides are prepared by combining formula 24 alkynyl sulfonamide or amide with aromatic or vinyl halide , preferably it is aromatic or vinyl brumide or iodide (pairs of which W and Z are as defined above and wherein X and M represent an aromatic or partially saturated ring system). Typically, the coupling is achieved in the presence of copper iodide, palladium catalysts such as palladium chloride, bis (triphenylphosphine) palladium dichloride, efia tetrakis (trisylphosphine) palladium (0), and amines such as triethylamine, diisopropylamine or butylamine in an aprotic solvent such as acetonitrile at a temperature of 0 ° C to 100 ° C. Formula 25, The 26 and 27 alkynes which are released can be converted to the corresponding formula 21.22 to enhance the alkanes with hydrogenation in the presence of palladium-boosting catalyst and in solvents such as methanol, ethanol and / or ethyl acetate at a temperature of 0 ° C to 50 ° C. The power of many alternatives can change the transformation of the alkyne. In the cis-alken using the force, use the Lindlar catalyst (Pd-CaCO₃-PbO). In the case where M represents the power of a partial circular system, water will change M to a completely mettle ring system. Alkylation and deprotection as described in Examples 1 and 2 give the corresponding Formula I compounds.

SCHEME 18

<img file="IS2389B_D0020.tif" />

<img file="IS2389B_D0021.tif" />

<img file="IS2389B_D0022.tif" />

<img file="IS2389B_D0023.tif" />

According to Scheme 19, there is provided a compound of formula 33 compounds of a suitable formula 32 amines (e.g., methoxyarylalkylamine). In this case, there is a force in the formulation of formula 32, which is obtained by proliferation, by means of effervescent sources known to those skilled in the art (e.g., see Scheme 4), and converted to Formula 31, sulfonamide, enhancing amide, using power, for example, as is described in Schemes 3 and 4. The Formula 31 aromatic methyl ether which is released is desiccant with reactants such as boron tribromide, pyridinium hydrogen chloride, hydrogen bromic / acetic acid, potentiating reagents as described in Protecting Groups in Organic Synthesis, Second Edition, TW Greene and PGM Wilts, John Wiley and Sons, Inc., 1991.

SCHEME 19

<img file="IS2389B_D0024.tif" />

<img file="IS2389B_D0025.tif" />

demethylation

<img file="IS2389B_D0026.tif" />

Ο

<img file="IS2389B_D0027.tif" />

<img file="IS2389B_D0028.tif" />

alkylating agents

There are a large number of new microprocessors for the desired alkali moieties used in the above-mentioned aforementioned processes, and theses are known to those skilled in the art (see The Chemistry of the Carbon-Halogen Bond, Ed P. Patai, J. Wiley, New York, 1973, and The Chemistry of Halides, Pseudo-Halides, and Azides, Eds. S. Patai and Z. Rappaport, J. Wiley, New York, 1983). Some daisies are shown for a period of 20-26. As shown in Scheme 20, power can be converted to a tool or all # substrates with halogenation I benz # promote all # bromide (pairs of Μ, X, W and Z are as described in the summary). This is because of the absence of N-bromosuccinimide (NBS) in the presence of a supported starting material such as AIBN or peroxide, preferably benzoic peroxide. There are many advantages that can be achieved by lightning.

SCHEME 20

HGC-M

BlCffc-M

<img file="IS2389B_D0029.tif" />

promote

BrCHa

NBS Assistance "

starting material

M hype

HsC- * hype

<img file="IS2389B_D0030.tif" />

HAC-X-W

VtiT "2

Scheme 21 illustrates the synthesis of alkylating agents which are useful in the preparation of Formula I compounds wherein M represents a biphenyl or aryl cyclic group. Suzuki-type clot on an aryl glomerulose or bromide promoter ring system containing vinyl bromide or iodide (Ar) with methyllarylboronic acid (An) using the conditions described in Scheme 9 gives Formula 34 a compound. In that case, where vinyl bromide or The iodine used can be reduced by formula 34 to produce a fully saturated broth. The reduction is obtained by hydrogenation in the presence of a palladium or platinum catalyst, typical of a polymeric solvent (methanol or ethanol), tetrahydrofuran, or ethyl acetate. Halogenation of the methyl group by means of using reagent and esterified as described in Scheme 20 gives formula 35 alkylation agents.

SCHEME 21

H₃C-Afi.

\ * ha »-Ar₂

BfOHfe

Pd hvatl basl

HJC-Ar,

NBS \ support 34 ophaMM

Ar_a

Other common power plants to gain access to alkyl halides are by halogenation of alcohol or alcohol residues. Alcohol can be bought or can be produced by using power tools known to those skilled in the art. For example, in Scheme 22, carboxylic acid promotes ester reductions in the alcohol with the use of reagents such as sodium borohydride, alkali metal hydride, boron-tetrahydrofuran complex, boron-methyl sulfide complex, etc. Typical are the corresponding alkyl chlorides produced from the alcohols with reagents such as hydrogen chloride, thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, propagate triphenylphosphine / carbon tetrachloride. For the survival of alkyl bromides, it is common for alkali agents to be treated with reagents such as hydrogen bromide, phosphorus tribromide, triphenylphosphine / bromide, potentiophospholidazole / allyl bromide (Kamijo, T. , Harada, H., Lizuka, K. Chem. Pharm. Bull. 1983,38,4189). For power, the power of the power of alkyl iodides is representative of the reaction of alkali metal compounds with reagents such as triphenylphosphine / iodine / imidazole enhancing hydrogen iodine. Hydrogen chloride can be reacted with a reactive alkyl bromide with an alkylated glycol derivative with an inorganic salt such as sodium bromide, lithium bromide, sodium iodide, or potassium iodide in solvents such as acetone or methyl ethyl ketone. It is possible to use alkyl sulfonates as electromagnetic agents, and can be converted into alkyl halides. Sulphonates are produced from the alcohol using mild bases such as triethylamine or pyridine and sulfonyl chloride in an inert solvent such as methylene chloride or diethyl ether. A change in the halide is achieved by the treatment of inorganic halide (sodium joflide, sodium bromide, potassium iodide, potassium bromide, lithium chloride,

SCHEME 22

Λ / -

R «H, -alkyl-

Generally it is possible to buy amino acids to promote esters, and if forced to change them in formula 37, promote 38 alkylation agents as follows (see Scheme 23). Acetic acid-enhancing aster derivatives are reduced by hydrogenation of palladium-boosting platinum catalysts, including the presence of phthalic solvents (eg, ethanol-enhancing ethanol), tetrahydrofuran, enhancing ethyl acetate. Reduction and alteration of the alkyl halide or the zirconate as described in Scheme 22 gives formula 38. Where appropriate, the amino acids enhance the esters converted directly into the formula

39 alcohols by treatment with reagents such as lithium aluminum hydride in inert solvents such as tetrahydrofuran and diethyl ether. There are many advantages to reducing the acetic acid to enhance the ester of Formula 40 by allyl alkylphosphine, by using reagents such as lithium aluminum hydride / -alcium, diisobutylalcohol, lyophilic butyric acid. A change in the allyl half or the sulfonate as described in Scheme 22 gives Formula 37 a reagent.

<img file="IS2389B_D0031.tif" />

the preparation of Formula 41 alkylation agents (wherein W and M are as described in the above) are described in Scheme 24. Formula 42 compounds are alkylated with a variety of bases, as their selection depends on the nature of W and M. Several Preferred bases are sodium hydroxide, sodium hydride, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide and potassium tert-butoxide, etc. Treatment of the anion which is derived from various dialkyl halides forms the formula 41 alkylation agents as desired. For the precursor of compounds wherein W represents oxygen and M is an aromatic ring, the preferred conditions are for the formation of the alkoxide anion with sodium hydroxide followed by the addition of dialkane, for example dibromoalkane. The reaction is usually carried out in water at 75 ° C to 125 ° C.

SCHEME 24

<img file="IS2389B_D0032.tif" />

X Br, I 41

Xa, Br

You can buy aldans that are useful to the chemistry described in Scheme 5. If you have power, they can be made from available intermediates with the help of methods known to those skilled in the art. Scheme 25 illustrates typical catalysts useful for the preparation of formula 43 hydroxyaldehyde (wherein M in Scheme 5 contains a hydroxy-substituted alkyl group). Diphtheria metabolism, a pair of aldehydes, is a protective component of formula 44 asetal (where OR groups are attached substituents which are used in an ASD), with a metallic reagent (LMálmur), preferably a lithium-organic Grignard substrate, in inert solvent such as tetrahydrofuran or diethyl ether, gives Formula 45 compounds. The following acetic acid hydrolysis inhibits mild acidic conditions, such as dilute hydrogen chloride, Amberiyst-15 resin, kfsilgel,

SCHEME 25

OH

<img file="IS2389B_D0033.tif" />

KLORMETYL MILLIEFNI

It is also possible to produce intermediate chloromethyl compounds as described in Examples 26 and 27. In general, the reactive formula 101 promotes the 103 sulfonamide promotes carboxy compounds with intermediates with formaldehyde equivalents such as paraformaldehyde in an inert organic solvent such as methylene chloride to promote chloroform with suitable catalysts as well as HCl, zinc chloride enhances trimethylsilyl chloride trifluoroacetate from about 0 ° C to 60 ° C to yield Formula 102 and 104 chloromethyl derivatives, as per vial.

SCHEME 26

A-NH

I

K-.

101 (CHO),

HCIedaTMSCI (CHO)_n

<img file="IS2389B_D0034.tif" />

/ ^ OH 'M

<img file="IS2389B_D0035.tif" />

Persons skilled in the art will see that using anti-absorbed agents (such as progestin polyphosphonate, bisphosphonate, estrogen guarantide / antagonist, astrogen, estrogen / progestin combinations, Premarine, estrone, estriol or 17a- or 17β-ethynic estradiol) in combination with the compounds of this invention.

Damaged progestin can be purchased and included: algestone acetophenide, altrenögest, amadinone acetate, anagestone acetate, chloradminone acetate, singel stearate, chlorostatone, clomegestone acetate, delmadinone acetate, desogestrel, dimethisterone, dyestrogesterone, etynnerone, ethynodiol diacetate, etonogestrel, fluorstyrene acetate, gestaclone, gestodene, gestónórún caproate, gestrfnón, halo progesterone, hydroxyprogesterone caproate, Levono-gestrel, lynestrenol, medrogestone, medroxyprogesterone acetate, melengestrol acetate, metýnódlól diacetate, norethindrone, norethindrone acetate, noratýnódrel, norgestimate, nor38 norgestomet, norgestrel, oxógestón fenprúpíónat, progesterone, quinestanol acetate, chinestrone, and telegestol.

Preferred progestins are medroxyprogesterone, norethindrone and noretynodrel.

Typical binder adsorbent polyphosphonates include polyphosphonates of the type disclosed in U.S. Patent 3,683,080, issued August 8, 1972. Preferred polyphosphonates are two dibosphonates (also referred to as bis-phosphonates). Tirudronate disodium is especially palatable polyphosphonate. Ibandronic acid is particularly preferred polyphosphonate. Alendronate is particularly polysaccharide polyphosphonate. Other preferred plyphosphonates are 6-amino-1-hydroxy-hexylidene bisphosphonic acid and 1-hydroxy-3 (methylpentylamino) -propionid-bisphosphonic acid. The polyphosphonates may be administered in the form of the acid, or in the form of a soluble alkali metal salt, to promote the alkaline earth metal salt. Hydrophobic esters of the polyphosphonates are also included. Specific examples include ethane-1-hydroxy, 1,1-diphosphonic acid, methane diphosphonic acid, pentane-1-hydroxy-1,1-diphosphonic acid,

Most preferably, the compounds of this invention combine the mammalian estrogen agonist / antagonist. Power can be used with a catalytic estrogen agonist / antagonist which is an effective compound of this invention. Heitifl estrogen agonist / metabolites refers to compounds that bind the estrflgen receptor, inhibit bone turnover and prevent bone loss. In particular, the oestrogen agonists are defined herein as chemical compounds that are capable of binding the estrogen to the extensive sites in mammalian tissue, and to simulate the effectiveness of estrogen in one enhancement of more tissues. Estrflgen antibiotics are defined herein. As an effective drug capable of binding, the estrogen inhibits the sites in mammalian tissue, and blocks the activity of estrogen in one enhancement of more tissues. Such activity is an apparent choice of subjects skilled in the field of rigorous analyzes, as well as interactions with interferon binding assays, randomized bone marrow modeling, and mutant mutant mutilation, (Eriksen EF et al., Bone Histomorphometry, Raven Press, New York, 1994, bladders 1-74 ; Grier SJ et al., The Use of Dual-Energy X-Ray Absorptiometry In Animals, Inv. Radiol., 1996, 31 (1); 50-62; Wahner HW and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice., Martin Dunltz Ltd., London 1994, ppflsfflur 1-296). Various of these compounds are described as a reference to the power of the nose. leaflets 1-74; Grier SJ et al., The Use of Dual-Energy X-ray Absorptiometry In Animals, Inv. Radiol., 1996, 31 (1); 50-62; Wahner HW and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-ray Absorptiometry in Clinical Practice. Martin Dunltz Ltd., London 1994, ppflsfflur 1-296). Various of these compounds are described as a reference to the power of the nose. leaflets 1-74; Grier SJ et al., The Use of Dual-Energy X-ray Absorptiometry In Animals, Inv. Radiol., 1996, 31 (1); 50-62; Wahner HW and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-ray Absorptiometry in Clinical Practice. Martin Dunltz Ltd., London 1994, ppflsfflur 1-296). Various of these compounds are described as a reference to the power of the nose.

The active ingredient of the active substance is trifluoromene: (phenol, 3- [1- [4- [2- (dimethylamino) ethoxy] phenyl] -2-phenyl-1-butenyl] -, (E) -) and the related compounds as are disclosed in U.S. Patent 5,047,431.

Another preferred estrogen agonist / antidote is tamoxifene: (ethanamine, 2- (4- (1,2-diphenyl-1-butenyl) phenoxy] -N, N-dimethyl, (Z) -2-, 2-hydroxy- 2,3-propanediboxylate (1: 1)) and related compounds disclosed in U.S. Patent 4,536,516 (disclosure of which is incorporated herein by reference).

The other related compound is 4-hydroxy tamoxifene disclosed in U.S. Patent 4,623,660 (disclosure of which is incorporated herein by reference).

Preferred estrogen agonist / mdtlyf is raloxifene: (methane, [6-hydroxy-2- (4-hydroxyphenyl) benzo [b] thien-3-yl] [4- [2- (1-piperidinyl) ethoxy] phenyl] hydrogen chloride is disclosed in U.S. Patent 4,418,066.

Other preferred estrogen agonists / antidotes ar threemifene: (ethanamine, 2- (4- (4-chloro-1,2-diphenyl-1-butenyl) phenoxy] -N, N-dimethyl-, (Z) -, 2-hydroxy -1,2,3-propane rich carboxylate (1: 1) disclosed in U.S. Patent 4,996,225.

Other recommended directives / centrifuges are: 1- [2 - ((4- (methoxy-2,2, dimethyl-3-phenyl-chroman-4-yl) -phenoxy] -ethyl] -pyrrolidine, as disclosed in U.S. Pat. No. 3,822,287. Levormeloxoxen is also desirable.

Other preferred estrogen agonists / antidotes are idoxyphen: pyrrolidin, 1 - (- (4 - ((1- (4-iodophenyl) -2-phenyl-1-butenyl] phenoxy] ethyl] disclosed in U.S. Patent 4,839,155.

Other preferred estrogen agonists is 6- (4-hydroxy-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -naphthalen-2-ol disclosed in U.S. Pat. 5,484,795.

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 disclosed, in addition to the present invention, in PCT publication no. WO 95/10513, which is distributed to Pfizer Inc.

Another preferred estrogen agonist / antidote is GW5638: 3- (4- (1,2-Diphenyl-but-1-enyl) -phenyl] -acrylic acid; see Wilson, TM and colleagues in Endrocrinoiogy 1997, 138, 9, 3901- 3911.

Other preferred agents / agents include compounds as described in commonly assigned U.S. Pat. 5,552,412. Particularly desirable compounds described in par. I are:

Cis-6- (4-fluoro-phenyl) -5- [4- (2-piperidin-1-y1-ethoxy) -fený1] -5,6,7,8-tetrahydro-naphthalene-2-ol;

(-) - Cis-6-phenyl-5- [4- (2-pyrróljdln-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahÝdrdnaftalan-2-d;

Cis-6-phenyl-5- [4- (2-pyrrolidin-1-y1-ethoxy) -phenyl] -5,6,7,8-tetrahydronaphthalene-2-ol;

Cfe-1- [6'-pyrrolodoethoxy-3'-pyridyl] -2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;

- (4'-Pyrrdlid (ndetoxýfenýl) -2- (4 "fluorophenyl) -6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

Cis -6- (4-hydroxyphenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro-naphthalene-2-ol; and

- (4'-Pyrrólidíndletoxýfenýi) -2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline.

Various antiarrhythmic agents / antagonists are disclosed in U.S. Patent 4,133,814. U.S. Patent 4,133,814 discloses derivatives of 2-phenyl-3-aroyl-benzothiophene and 2-phenyl-3-aroylbenzothiophene-1-oxyl.

Those skilled in the art will appreciate the use of bone resorption medium 5 (bone mass enhancing media) in combination with the compounds of this invention. A bone mass enhancer is a compound that increases bone mass, which is above the bone fracture (as is clearly explained in the Survey of the Health Institute, "Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis (1994). Report of a WHO Study Group. World Health

Organization Technical Series 843 ").

Thus, power is used for caffeine prostaglandins, enhancing prostaglandin agonists / antagonists which are as compounds of this invention (this would include force using two different compounds of formula I of this invention). Those skilled in the art will also be able to use the power of IGF-1, inhibitors without the IGF binding factor 3, sodium fluoride, parathyroidism (PTH), active fragment of parathyroid gland, growth hormone enhancing growth hormone secretagogues. The following paragraphs describe typical other compounds of this invention in greater detail.

Thus, power is used for caffeine prostaglandin which is a compound of this invention. Heitifl prostaglandin refers to compounds that are secreted by the natural prostaglandins PGD ,, PGD₂, PGE₂, PGE, and PGF₂ which are useful in the development of online shopping. This compound is bound to prostaglandin vesicles. Permanent binding is an obvious determinant of peers who are professionals according to the standard analyzes (eg, An S. et al., Cloning and Expression of the EP₂ Subtype or Human Receptors for Prostaglandin E &amp; Biochemical and Biophysical Research Communications,

1993, 197 (1): 263-270).

Prostaglandins are alicyclic compounds associated with the basic compound prostanoic acid. Carbonate nitrins in the basic prostaglandin are numbered electrically from the carbocyclic carbonate through the cyclopentyl ring in a single carbon atom on the remaining baffle. Usually, the sideways side chains are in the transistor.

The Nsrvera group of C-9 on the cyclopentyl moiety indicates prostaglandin in the E group of PGE₂ contains trans-dimensional tv link in C₁₃-C₁₄ and cis tv connectors in C₅-C_B stflflunni.

Various prostaglandins are described and shown here, but other prostaglandins will be excreted by professionals who are professionals. Typical prostaglandins are disclosed in U.S. Pat. 4,171,331 and 3,927,197.

Nondin et al., The Role of Prostaglandins in Bone In Vivo, (Prostaglandins

Leukotriene Essential Fatty Acids 41, 139-150, 1990) is overgrowthed of prostaglandin. Jee and Ma, The In Vivo Anabolic Actions of Prostaglandins in Bone. (Bone, 21: 297-304) is a recent overgrowth of prostaglandin prostatic activity.

Thus, the power of the prostaglandin agonist / antagonist is used as a compound of this invention. Heitifl prostaglandin agonist / antagonists indicate compounds that bind prostaglandin receptors (eg, JW Regan et al., Cloning of a Novel Human Prostaglandin Receptor with Characteristics of the Pharmacologically Defined EP₂ Subtype, Molecular Pharmacology, 46: 213-220.1994.) And monitoring the activity of prostaglandins in the liver (eg, stimulate bone formation and increase bone mass and strength). Pannig activity is readily determined by those skilled in the art (Eriksen EF et al., Bone Histomorphometry, Raven Press, New York, 1994, Journal of 1-74; Grier SJ, et al., The Use of Dual- Energy X-Ray Absorptiometry In Animals, Inv. Radiol., 1996, 31 (1): 50-62: Wahner HW and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-ray Absorptiometry in Clinical Practice., Martin Dunitz Ltd ., London 1994, Journal 1-296). Various of these compounds are described and referred to below, however, other prostaglandin agonists / antagonists will be known to those skilled in the art. Typical prostaglandin agonists / antagonists are disclosed in the following.

Generally assigned U.S. Pat. 3,932,389 discloses 2-descarboxyl-2- (fetazol-5-yl) -11-desoxy-15-substituted-omega-pentanorprostaglandin which are useful for bone formation activity.

Generally assigned U.S. Pat. 4,018,692 discloses 16-aryl-13,14-dihydro-PGE₂ p-biphenyl esters which are useful for bone formation activity.

Generally assigned U.S. Pat. 4,219,483 discloses 2,3,6-substituted-4-pyrons useful for bone formation activity.

Generally assigned U.S. Pat. 4,132,847 discloses 2,3,6-substituted-4-pyrons useful for bone formation activity.

U.S. Pat. 4,000,309 discloses 16-aryl-13,14-dihydro-PGE₂ p-biphenyl esters which are useful for bone formation activity.

U.S. Pat. 3,982,016 discloses 16-aryl-13,14-dihydro-PGE₂ p-biphenyl esters which are useful for bone formation activity.

U.S. Pat. 4,621,100 discloses substituted cyclopentane useful for bone formation activity.

U.S. Pat. 5,216,183 discloses cyclopentanone useful for bone formation activity.

It is possible to use sodium fluoride as the second compound of this invention. The name of sodium fluoride refers to sodium fluoride in all its forms (eg, high density sodium fluoride, sodium fluoride with caustic soda). Sodium fluoride with liposuction is disclosed in U.S. Pat. No. 4,904,478. The activity of sodium fluoride is easily determined by those skilled in the field of clinical data (eg, see Eriksen EF et al., Bone Histomorphometry, Raven Press, New York, 1994, Journal of 1-74; Grier SJ et al. The Use of Dual-Energy X-ray Absorptiometry In Animals, Inv. Radiol., 1996, 31 (1): 50-62; Wahner HW and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-ray Absorptiometry in Clinical Practice ., Martin Dunitz Ltd., London 1994, pages 1296).

Any parathyroid hormone (PTH) which is the second compound of this invention may be used. Haitiö parathyroid hormone refers to parathyroid hormone, fractures or metabolites, pairs of and structural analogues that can stimulate bone formation and increased bone mass. Also included are parathyroid hormones associated with peptide and actively abbreviated by parathyroid hormone related peptides, see WO 94/01460. Pannig activity is readily elucidated by arthritis according to the supportive analyzes (eg, Eríksan EF et al., Bone Histomorphometry, Raven Press, New York, 1994, Pages 174; Grier SJ, et al., The Use of Dual -Energy X-Ray Absorptiometry In Animals, Inv. Radiol., 1996, 31 (1): 50-62: Wahner HW and Fogelman I., The Evaluation of Osteoporosis: Dual

Energy X-Ray Absorptiometry in Clinical Practice., Martin Dunitz Ltd., London 1994, pages 1-296). Various of these compounds are described and rejected (here below, on the other hand, other parathyroid hormones will be excreted by skilled workers. Typical parathyroid hormones are published below.

"Human Parathyroid Peptide Treatment or Vertebral Osteoporosis", Osteoporosis

Int., 3, (viflauki 1): 199-203.

"PTH 1-34 Treatment of Osteoporosis with Added Hormone Replacement Therapy: Biochemical, Kinetic and Histological Responses" Osteoporosis Int. 1: 162-170.

Hence, force uses any growth hormone promoting growth hormone secretion which is the second compound of this invention. The term growth hormone secretion refers to compounds that stimulate growth hormone release to hernia following growth hormone activity (eg, increase bone formation leading to increased bone mass). Pannig activity is easily determined by peaks that are professional in accordance with standard analyzes. Various of these compounds are included. In the following published PCT patent applications: WO 95/14666; WO 95113069; WO 94/19367; WO 94/13696; and WO 95/34311. However, other growth hormones or growth hormone secretors will be embarrassed by skilled workers.

Specifically, the preferred growth hormone secretor is N- [1- (R) - [1,2-dihydro-1-methanesulfonylpiro [3H-indole-3,4'-ipiperidin-1-yl] carbonyl] -2- (fený1metýloxý) ethyl] -2-arTiínó-2-methylpropanamide: MK-677.

Other preferred growth hormone secretaries cover

2-Amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2_l3,3a, 4_l6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide or L-tartaric acid salt; 2-Amino-N- {1- (R) -bensýioxýmetýl-2- [3a- (R) - (4-fluoro-benzyl) -2-methyl-3-oxo-2,3,3a, 4,6, 7-hexahydro-pyrazolo [4,3-c] pyridine (n-5-yl] -2-oxo-ethyl) -isobutyramide; and

2-Amino-N- [2- (3a- (R) -benzyl-3-oxo-2,3,3a_l4,6,7-hexahydro-pyrazolo {4_&gt;3-c] pyridin-5-yl) -1- (R) bensýioxýmetýl-2-oxo-ethyl] (sóbútýramíð.

2-Amino-N- {1- (2,4-difluoro-bensýtoxýmetý1) -2-oxo-2- [3-oxo-3a-pyridin-2-ylmethyl-2- (2_l2,2tríflúor-etý1) -2,3,3a, 4,6,7-hexahydro-pyrazolo {4,3-c] pyridin-5-yl] -etý1} -2-methyl-propionamide.

Some of the manufacturing methods useful for the preparation of the compounds described herein may purify the protection of teleprocessing (e.g., single amine, bi-amine amine, carboxyl of Formula I preform). The need for such protection will vary depending on the nature of the opacity and the conditions of the proliferation processes. The need for such vamdun is easily determined by someone skilled in the art. The use of such protection / deprotection forces is also within the art. For a general description of protecting groups and their use, see TW Greene, Protective Groups in Organic Synthesis. John Wiley &amp; Sons, New York, 1991.

The starting materials and reagents for the compounds described above are readily possible, which are easier to obtain, the power produced by those skilled in the art using conventional methods of chemical synthesis. For the sake of the compounds, the use of the compounds is derived from the compounds found in the nets, but there is a great deal of interest here and there, and in combination with this, it is possible to buy more so that the compound is clear from The published content enhances the power produced by a variety of available materials with reference to the published material. Such compounds include, for example, prostaglandin.

Some of the compounds of the present invention have asymmetric carbon atoms, and are therefore enantiomeric compounds of the formula. Preferred compounds are thus capable of separating in their individual enantiomers on the basis of their chemically acceptable derivatives, which are known per se, for example by chromatography and / or enhancing particle chromatography. Hence, it is possible to enantiomize enantiomers with the effect of converting the enantiomeric mixture into a diaromatic reaction with a reaction of a refractory active compound (Ld alcohol), separating the enantiomers and converting the (Ld aqueous) enantiomers into corresponding pure enantiomers. All of these are eliminated, including those enantiomers, enantiomers and mixtures thereof, are included as part of this invention. Also, some of the compounds in the present invention include atropic flavors (Ld.,

Many of the compounds of the present invention are acidic and form salts with a pharmaceutically acceptable carrier. Some of the compounds of this invention are basic and they form a salt with a pharmaceutically acceptable anion. All of the foregoing are within the scope of this invention, and thus the power produced by the mainstream power plants. For this reason, the power produced by the force alone causes the acid and alkaline units to come into contact with each of the forces, usually in proportional proportions, whether or not the water, non-selective force, to a particle of water, such as a crank . It is possible to treat any other functions, with the addition of non-solvent followed by filtration, by evaporation of the solvent, in the case of aqueous solutions, using freeze-drying, as well as a vial.

Additionally, when the compounds of this invention form a hydrotreating solution, they are also within the scope of the invention.

The compounds of this invention are all useful in the use of multifarious applications that enhance bone formation and increase bone mass in mammals, especially humans. A pair of osteoporosis is closely related to the development of osteoporosis and direct disorder, bringing these compounds into action, preventing osteoporosis and / or stopping osteoporosis.

The utility of the compounds of this invention is shown as a therapeutic agent in the moderate condition for low bone mass (eg osteoporosis) in mammals (Lh, especially women) including the activity of the compounds of this invention in conventional measurements, including the measurement in organism, receptor volume measurement, cycling AMP measurement, and transcriptional measurement (all of which are described below). The organism may be used in the measurement (with appropriate changes in the art) to determine the activity of other anabolic agents as well as the prostaglandin agonists of this invention. It is therefore possible to use the estrogen agonist / antagonist tool to determine the activity of estrogen agonists / antagonists separately and also other anti-resorptive agents (with profound changes within the skill). The formulations and the sequential treatment protocol described herein are useful in demonstrating the utility of the formulations of the anabolic agents (e.g., compounds of this invention) and anti-resorptive agents (e.g., estrogen agonists / antagonists) described herein . Such measurements also give rise to a comparison of the activity of the compounds of this invention (or the anabolic agents and the anti-absorption agents described herein) with each other and to the activity of other known compounds. Nitrogen from this comparison are useful for determining the dose levels in mammals, including humans, in the treatment of pannig diseases. chemical compounds of this invention) and anti-resorption agents (e.g., estrogen agonists / antagonists) described herein. Such measurements also give rise to a comparison of the activity of the compounds of this invention (or the anabolic agents and the anti-absorption agents described herein) with each other and to the activity of other known compounds. Nitrogen from this comparison are useful for determining the dose levels in mammals, including humans, in the treatment of pannig diseases. chemical compounds of this invention) and anti-resorption agents (e.g., estrogen agonists / antagonists) described herein. Such measurements also give rise to a comparison of the activity of the compounds of this invention (or the anabolic agents and the anti-absorption agents described herein) with each other and to the activity of other known compounds. Nitrogen from this comparison are useful for determining the dose levels in mammals, including humans, in the treatment of pannig diseases.

Graining f the organism on anabolic medium

It is possible to test the activity of a bipolar disorder to stimulate bone formation and increase bone mass in unmarried cardiac or female rats, sex hormone-free male (prostate) enhancement of female (ovarian cervical) rats.

Hssgt's force uses male enhancement of female rats of different ages (like 3 months old) in the study. Rats are either untouched or ovarian (ovarian or testicular), and are subcutaneously injected with orally administered prostaglandin agonists at different doses (such as 1, 3, or 10 mg / kg / day) for 30 days. In the rat rats, treatment is initiated the day following surgery (for the purpose of preventing belts loss) to promote the peaks that have already occurred (for the purpose of rebuilding bone mass). In the study, all rats have free access to water and cheese on a small-scale brand, which is a powerful buyer (Teklad Rodent Diet # 8064, Harlan Teklad, Madison, Wl) containing 1.46% calcium, 0.99% phosphorus and 4.96 lU / g of vltamini D₃. All rats are subcutaneously injectable with 10 mg / kg of calseini on dflgum

12 and 2 for birth. The rats are faded. The following endpoints are determined:

Lærieoos steinefnamelinaar:

The right leg of each rat is removed by means of an autopsy and screened using the force using dual energy-ray absorption spectrometry (DXA, QDR 1000 / W, Hologic inc.

Waltham, MA), which is equipped with "Regional High Resolution Scan" software (Hologic Inc., Waltham, MA). The screening area is 5.08 x 1.902 cm, the resolution is 0.0254 x 0.0127 cm and the screening speed is 7.25 mm / second. The physiological screening syndromes are analyzed and bone area, BMC, and BMD of WF, DFM, FS, and PF are determined.

Skóflunas web formformelaaraar

The right tibia is a feather at the piercing, flushed clean by the muscles, and cut into the thigh part. The nearest tibia and tibia are attached to 70% ethanol, dehydrated in concentrated concentrations of ethanol, extracted with acetone, then embedded in methyl methacrylate (Eastman Organic Chemicals, Rochester, NY).

Prostheses of short stitching end of the tibia 4 and 10 μm thick are shrunk by using Reichert-Jung Polycut S vein mask. 4 pm snowflakes are colored with modified Massons Trichrome color with 10 pm snowflakes are kept in full color. One 4 pm and one 10 pm cut from each rat are used in the abdominal bone tissue.

Cross-sectional thighs of 10 pm thickness are shrunk by force using Reichert-Jung Polycut S vein mask. Pessar slices are used for tartar tissue formulation.

Bioquant OS / 2 web form measurement system (R &amp; M biometrics, Inc., Nashville, TN) is used for the stationary and motions of the web formulas of the secondary level material at a narrow end, resulting in a dysfunction between 1.2 and 3.6 mm from the growth rate -kasttengingunni. The first 1.2 mm of the end of the end must be omitted so as to isolate the magnitude of the secondary level of magnitude. 4 pm snowflakes are power consumables to determine the amount of bone volume, bone structure, and bone loss, with 10 μm trace amounts, are used to control the bone and bone formation.

I) Mslinoar oo calculations that are used for biobird volume and bvaoinau: (1) Total area of ​​end of the end (TV, mm²): The area of ​​the width of the end between 1.2 and 3.6 mm from the growth of the plunge-throw connection. (2) Curved surface area (BV, mm²): Total area of ​​beam within TV. (3) Polar beam diameter (BS, mm): the length of the total circumference of the beam. (4) Bulk volume (BV / TV.%): BV / TV x 100. (5) Bending cable (TBN, # / mm); 1,199 / 2 x BS / TV. (6) Coefficient of Thickness (TBT, μm): (2000 / 1,199) x (BV / BS). (7) Beam beam power amplifier (TBS, pm): (2000 x 1,199) x (TV - BV).

II) Mallnoar and calculations related to direct search: (1) Bone count (OCN, #): total number of bones within the total area of ​​the end of the end. (2) Amount of odd (OCP, mm): length of beam template, which is accentuated by a straight line. (3) Bone count / mm (OCN / mm, # / mm): OCN / BS. (4) Percentage of bone density (% OCP,%): OCP / BS x 100.

III) Measurements for calculations are calculated as follows: (1) Single-calorie labeled circumference (SLS, mm): total length of beam template labeled with one calsein label. (2) Tvi-calsein marked square (DLS, mm): total length of beam template labeled with two calsein signals. (3) Intermediate width (ILW, μm): mean distance between two calsein signals. (4) Percentage of Mineral Output (PMS,%): (SLS / 2 + DLSJ / BS x 100. (5) Mineral supplemental growth rate (MAR, pm / day): ILW / interval between signs. (6) Bone / surface regeneration BFR / BS, pm²/ d / pm): (SLS / 2 + DLS) x MAR / BS. (η Beinvaltra graph (BTR,% / y): (SLS / 2 + DLS) x MAR / BV x 100.

The Barkarbein Web Formula: Bioquant OS / 2 Web Formulation Scale (R &amp; M Biometrics, Inc., Nashville, TN) is a static and biometric measurements of the vasculature of the larynx. The total area of ​​the site, the area of ​​merghols, the perimeter of the pericardium, the inner circumference, the unlabelled circumference, the two-dimensional circumference, and the interlaced width of both the esophagus and the inner surface of the mucosa are masked), and the area of ​​the corticosteroid (total area of ​​merghols). percentile area of ​​the larynx (corticosteroid area / total area of ​​site x 100), percentage of mergal area (area of ​​merghol / total area of ​​x 100), percent of the peritoneum and inner lumen marked circumference [(single-labeled circumference / 2 + double-labeled circumference) / total circumference x 100], represent the additional growth species (interlaced width / spaces),

Statistics

You can calculate numbers by using StatView 4.0 packages (Abacus Concepts,

Inc., Berkeley, CA). Distribution analysis (ANOVA) prff followed by Fischers PLSD is used for power bars, comparing the differences between groups.

Determination of cAMP elevation in the 293-S cell that restores resented human

EP2 οα EP4 vifltaka.

9 nM for PGE2 (EP4). Unscrambled expression on both sides of the parent 293-S cells is negligible. Cells are retained in RPMI, supplemented with bovine serum serum (10% close) and G418 (700 μg / ml closed).

cAMP responses in the 293-S / EP2 and 293-S / EP4 lines are determined to release cells from culture flasks into 1 ml of Ca ++ and Mg ++ deprived PBS medium potent slice, serum-free RPMI released to a final concentration of 1 x 10⁶ cells / ml, and add 3-isobutyl-1-methylxanithine (IBMX) to a final concentration of 1 mM. One milliliter of cellulose suspension is immediately divided into individual 2 ml vials with screwed stopper and incubated for 10 minutes, unlatched, vial 37 ° C, 5% CO₂, 95% humidity. The compound should then be sampled into cells in 1: 100 dilutions to block DMSO or ethanol concentrations.

1%. Immediately after the compound has been added, the bottles are final, mixed by turning it upside down twice, and stirring at 37 ° C for 12 minutes. The samples are then broken by incubation at 100 ° C for 10 minutes and then immediately chilled on ice for 5 minutes. The primitive source of fermentation to pellets with a loss of 1000 xgf 5 minutes, and the purified suspension is transferred into clean bottles. cAMP concentrations are determined by using a commercially available cAMP spectroscopy sampling kit (NEK-033, NEN / DuPont) after dilution of purified suspensions 1:10 f cAMP RIA assay buffer. Typically, a cell-treated cell with 6-8 concentrations of the compound should be tested for 1 log increase. EC50 razor-sharp construction on the Hewlett Packard 32S11 pocket cartridge by using a slight regression of the final portion of the dose response curves.

references

1. Ragan, JW Bailey, TJ. Pepparl, DJ. Pierce, KL Bogardus, AM Donello, JE Fairbaim, CE. Kedzie, KM Woodward, DF and Gil, DW 1994 Cloning of a Novel Human Prostaglandin Receptor with Characteristics of the Pharmadogically Defined EP_Z Subtype. Mol. Pharmacology 46: 213-220.

2. Basben, L, Sawyer, N "Grygorczyk, R" Matters, K., and Adam, M. 1994 Cloning, Functional Expression, and Characterization of the Human Prostaglandin E2 Receptor EP2 Subtype. J. Biol. Chem. volumes 269.16: 11873-11877.

Feed on bindinou in prostaglandin E2 vifltaka

Framelessness: All power plants are produced by a fan of 4 ° C. Embedded cells expressing prostaglandin E2 transfusions of bacterium 1 (EP1), bacterium 2 (EP2), Fragment 3 (EP3) enhancer 4 (EP4) are harvested and suspended. In 2 million cells in each ml of buffer A [50 mM Tris- HCl (pH 7.4), 10 mM MgCl₂, 1 mM EDTA, 1 mM Pefabloc peptide, (Sigma, St. Louis, MO), 10 μM Phosporamidone peptide, (Sigma, St. Louis, MO), 1 μM Pepstatin A peptide, (Sigma, St. Louis, MO) , 10 μM Elastatininal peptide, (Sigma, St. Louis, MO), 100 μM Antipain peptide, (Sigma, St. Louis, MO)]. They are intermittent with Branson Sonifier (Model # 250, Branson Ultrasonics Corporation, Danbury, CT) for 2 fifteen seconds. Unsorted cells and residues are removed from the spinal cord 100 μg ί 10 min. Celebration is excavated with a spider spider 45,000 xg for 30 minutes. Pellets membranes are resuspended in 3-10 mg pifltine on which ml, the protein concentration levels are determinants. In combination with Bradford's Bradford, Bradford, M., Anal. Biochem., 72, 248 (1976)]. Again 5 suspended membranes are stored in a frozen fan -80 ° C until forced use.

Bindimslino: Frozen membranes produced as the whole of the above is translated and diluted to 1 mg of prduin In each ml of powder A. One volume of membrane suspension is a combined amount of 0.05 volumes of experimental compound boosting ducks and one volume of 3 nM 3H -prostaglandin E2 (#TRK 431, Amersham, Arlington Heights, IL) of Example A. The mixture (205 μL total volume) is grown for 1 hour at 25 ° C. The heavens are required by means of GF / C ferrous fiber (# 1205-401, Wallac, Gaithersburg, MD) using the power of Tomtec Harvester (Model Mach II / 96, Tom Tec, Orange, CT). The membranes of the bound 3H-prostaglandin E2 are bound by the filter, the duodenum and unbound 3H-prostaglandin E2 pass through the strain in the waste. Each sample is swallowed 3 times with 3 ml of [50 mM Tris15 HCl (pH 7.4), 10 mM MgCfe, 1 mM EDTA]. Fill them with a dry cleaner with the power to heat them in a microwave oven. In order to determine the magnitude of the 3 H-prostaglandin bound in the membrane, the dry liquid is placed in a plastic bag with scintillation fluid, and is counted on the LKB 1205 Betaplate reader (Wallac, Gaithersburg, MD). IC50 values ​​are determined by the concentration of the experimental compound required for the production of 50% of the specific bound 3H prostaglandin

E2.

MISCELLANEOUS MEASUREMENTS MEASUREMENT FOR BREAKFAST EFFECT

CONFIDENTIAL DOCUMENT

Breakthrough Rate: 3-month Sprage-Dawfey rats are effective with ketamine. 1 cm scratch is a dandelion on the front of the nose part of a small skull wound strengthening the Isrlegg. The following describes the loss of scab. Skorifl is Through the force of the bone, and the 1 mm hole is drilled 4 mm closer to the outer edge of the skull ring 2 mm by the crank of the front edge. Nailing In the marquee, a 0.8 mm steel steel drum (maximum load 36.3 N, maximum stiffness 61.8 N / mm, power output of the power flap and the bones) is performed. No enlargement of the marrow is performed. Stubbled final break is a force of 2 mm above the connection of the trunk and a column with three points of curvature with force (force use specially adjustable design with adjustable grip.) The force minimizes damage to a soft web. Passive power is not a failure. The hub is the end of a single trumpet nslonsaumi. The force of action is performed in the case of deflisers. Multiple images of all fractures are taken immediately after nail, and expensive trophies other than intermittent nasal congestion enhances the use of nails used are nasal cavity. The remaining animals are divided randomly. In the following groups with 10-12 animals, each substitute is used to force the fracture. The first gallop is administered daily by gastric fluid (water: 100% ethanol = 95: 5) of 1 ml / rats, each day receiving a daily dose of 0.01 to 100 mg / kg / day of the compound at a pressure (1 ml / rat) ί 10,20,40 and 80 days. The remaining animals are divided randomly. In the following groups with 10-12 animals, each substitute is used to force the fracture. The first gallop is administered daily by gastric fluid (water: 100% ethanol = 95: 5) of 1 ml / rats, each day receiving a daily dose of 0.01 to 100 mg / kg / day of the compound at a pressure (1 ml / rat) ί 10,20,40 and 80 days. The remaining animals are divided randomly. In the following groups with 10-12 animals, each substitute is used to force the fracture. The first gallop is administered daily by gastric fluid (water: 100% ethanol = 95: 5) of 1 ml / rats, each day receiving a daily dose of 0.01 to 100 mg / kg / day of the compound at a pressure (1 ml / rat) ί 10,20,40 and 80 days.

At 10,20,40 and 80 days, 10 -12 rats from each group are anesthetized with ketamine and augmented by blood clotting. Both pharyngeal and colon bones are removed by a tissue vein and all soft tissues are removed. Bones from 5 to 6 rats from each group are stored in 70% ethanol for tissue analysis, and bones from other 5 to 6 rats from each group are stored in a doped Ringers solution (+ 4 ° C, pH 7.4) for x-ray and biochemical tests carried out.

The webiaareinina: The bone resorption methods have previously been published by Mosekilde and Bak (The Effects of Growth Hormone on Fracture Healing in Rats: A Histological Description. Bone, 14: 19-27, 1993). (Briefly, the reverse side is scored 8 mm in each direction from the fracture, placed uncircumcised in methyl methacrylate, and shoots a wide range of slices of Reichert-Jung Polycut vein mask (8 μm thick Masson-Trichrome color medium-slice slices (including both tin and column) are used for the visualization of cellular and coronary responses to breakdown with and without treatment. Sirius reddish snails are used to show the characteristics of the bony of the building and to distinguish between the ocular bones and the fly bones at the fracture site. The following measurements are made:

LffafifraBeiiea Graining: The methods for bioavailability analysis have previously been published by Bak and Andreassen (The Effects of Aging on Fracture Healing in Rats. Calcif Tissue Int 45: 292-297, 1989). In summary, transcripts are taken of all violations for the biomedical exam. The extraordinary properties of the healing fragments are analyzed by the deliberate three-step four-point turn method. Maximum load, stiffness, energy at maximum load, side sweep at maximum load, and maximum voltage is determined.

MEASUREMENT FOR AHRIF A BACKGROUND BY BUSINESS

Breach method: About the 2-year female or caricidal dog breeders were used in the study. Transverse radiation fractures are expressed by the continuous load of a three-point turn as described by Lenahan et al. (Lartehan, TM; Balligand, M .; Nunamaker, DM; Wood, FE: Effects of EHDP on Fracture Healing in Dogs. J Orthop Res 3: 499-507; 1985). The virulle is pulled through the fracture site to ensure complete organ damage to the bone. Thus, local delivery of prostaglandin agonists to the fracture is achieved by the immediate release of a compound delivered with low-emission pellets or Alzet pumps for 10,15, or 20 weeks.

Vefiaareinina; The methods for tissue analysis of broken baini have previously been published by Peter et al. (Peter, CP; Cook, WO; Nunamaker, DM; Provost, M. T.; 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 in Rats: A Histological Description. Bone, 14: 19-27, 1993). In short, the brothy sift 3 mm in each direction from the fracture, immersed in methyl methacrylate, and chopped with Reichert-Jung Polycut vein mask in 8 μm thick slices of breadcrumbs. Masson-Trichrome colored mid-latitude slices (including scales and columns) are used for cellular and fibrosis imaging for transplantation with and without treatment. Sirius reddish-brown slices are used to show the characteristics of the bore of the building and to distinguish between ocular bones and fly bones on fractures. The following measurements are performed (1) fracture - measured as the shortest distance between the torso end of the fracture, (2) bony long and bony diameter, (3) total bone volume of the fracture,

Lifafractic Orenine: The fragments for bioavailability analysis have previously been 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, Μ. T .; Seedor, JG; Rodan, GA Effects of Alendronate On Fracture Healing And Bone Remodeling In Dogs. J. Orthop. Res. 14: 74-70, 1996). In summary, rfintgen images are taken from all violations for the bioassay test. The mechanical properties of the healing fragments are analyzed by destructive three-factor quantum-point flexural defects. Maximum intensity, stiffness, energy maximum load, side sweep at maximum load, and maximum voltage are determined.

ESTROGUE MATTER / MULTIPLE STATEMENT

Electrogen agonists / antagonists are a group of compounds that inhibit bone marrow and prevent estrogen deficiency induced bone loss. Beintaps model of rats where the grandfather lives except the ovaries has been a major user who has a direct loss after the menopause. By using this model, the effect of the estrogen agonist / antagonist of the compounds can be tested to prevent bone loss and loss of bone loss.

Notafiar are female Sprague-Dawley rats (Charles River, Wilmington, MA) at different ages (such as 5 months old) in fool studies. Rats are housed separately. In 20 on X 32 cm X 20 cages during the experimental period. All rats have a fertile source of water and a small-sized pellet formulation (Agway ProLab 3000, Agway County Food, Inc., Syracuse, NY) containing 0.97% calcium, 0.85% phosphorus, and 1, 05 IU / g of amphetamine D_a.

Gerf is an arthritis in a group of rats (8 to 10) and treated by mouth with bubbles (10% ethanol and 90% brine, 1 ml / day), on the ovarian ovarian ovarian side, are removed (OVX) from the remaining rats and treated whether or not bending agents (by mouth), 17th-estradiol (Sigma, E-8876, E₂, 30 μg / kg, daily subcutaneous injection), efia estrfigen agonists / antagonists (such as drloxefenium 5.10, efia 20 mg / kg, daily by mouth) for a certain period of time (like 4 weeks). All rats are injected under the cap with 10 mg / kg of calseini (fluorochrome bone marrow) 12 and 2 days of breastfeeding, see the changes in bone tissue. After 4 weeks of intervention, the rats are popped and peer is grown. The following endpoints are determined:

Likamsbvnadar increased: Lfkamweight weight of crawling minus weight of combs with shifting force.

Leabvnod oo tissue science: The leg is removed from each rat, and it is immediately reversed. Next, the leg is able to interfere with fibrosis-like measurements such as perversion of the area's legs, basal thickness, and point thickness.

Total serum cholesterol: Blood is collected by cardiac arrest and allowed to coagulate 4 ° C, and the spinal count is approximately 2,000 g 10 min. A serum sample is a study for the total serum cholesterol levels using power using high-performance cholesterol heaters (Boehringer Mannheim Biochemicals, Indianapolis, IN).

Larieoas steinefnamalinaar: The Hagri larva Or each rat is a distant wavelength of scaling and transplants using the force using a double-stranded magnetic resonance absorbance (DEXA, QDR 1000 / W, Hologic Inc., Waltham, MA), which is equipped with the "Regional High Resolution Scan" software (Hologic Inc., Waltham, MA). The screening fleet is 5.08 x 1.902 cm, the resolution is 0.0254 x 0.0127 cm and the screening bracket is 7.25 mm / second. The larval screen images are analyzed and bone area, bone mineral density (BMC), and bone mineral density (BMD) of the entire larval (WF), four-fold end of the larvae (DFM), larvae (FS), and proximal larvae (PF) are determined. Tissue-shaped malignant nasal scleroderma: The pelvic sclerosis is a fever of craving, cleavage cleansed by muscle, and cut into three parts. The precipitate is subjected to 70% ethanol, dehydrated flask in ethanol, concentrate in acetone, centrifuged in methyl methacrylate (Eastman Organic Chemicals, Rochester, NY). Prosthesis of short stitching end of the tibia at 4 and 10 pm thickness is shrunk by force using Reichert-Jung Polycut S vein mask. One 4 pm and one 10 pm cut from each rat are used in the above-mentioned bone tissue. 4 pm sneiflamar am litafli with changed Massons Trichrome color at 10 pm sneeflamar are hafflarfllflar. One 4 pm and one 10 pm cut from each rat are used in the above-mentioned bone tissue. 4 pm sneiflamar am litafli with changed Massons Trichrome color at 10 pm sneeflamar are hafflarfllflar. One 4 pm and one 10 pm cut from each rat are used in the above-mentioned bone tissue. 4 pm sneiflamar am litafli with changed Massons Trichrome color at 10 pm sneeflamar are hafflarfllflar.

The bioquant OS / 2 web form measurement system (R &amp; M biometrics, Inc., Nashville, TN) is the use of a starboard and the motions of the web form paint on the secondary level of the proximal end of the tibia between 1,2 and 3,6 mm from the growth of the plung-throat connection. The first 1.2 mm of the crunch end of the flange is released to unscramble paintings of the second-grade fracture. 4 pm trampolines are trafficking to determine bone volume, bone structure, and bone resorption, with 10 μm trauma trafficking, trafficking to determine the bone and bone density indicators.

I, the Malinoar and the calculator related to the biálkabine volume and bvqqinqu:

1. Total connection area (TV, mm *): Connection area between 1.2 and 3.6 mm from the growth of the disc-slot connection.

2. Bending Area Area (BV, mm²): Total area of ​​beam within TV.

3. Polar beam circumference (BS, mm): length of total circumference of beam.

4. Bulk volume (BV / TV,%): BV / TV x 100.

5. Bulb number (TBN, # / mm): 1,199 / 2 x BS / TV.

6. Thickness Thickness (TBT, μm): (2000 / 1,199) x (BV / BS).

7. Directional Separation (TBS, μm): (2000 / 1,199) x (TV - BV).

II. Measurement and calculation calculator:

1. Direct number (OCN, #): total number of bone loci within the total area area.

2. Bone circumference (OCP, mm): length of bunch of circumference that is obtuse from the bones.

3. Direction of Fold / mm (OCN / mm, # / mm): OCN / BS.

4. Percentage target circumference (% OCP,%): OCP / BS x 100.

Ill, Measurers, and others, who are responsible for manipulation and turnover:

1. Ein-kalsein-labeled circumference (SLS, mm): total length of beam circumference marked with 20 single calsein signals.

2. Two-calzone labeled circumference (DLS, mm): total length of beam of circumference labeled with two calsein signals.

3. Intermediate marking (ILW, pm): among the distance between two calsein signals.

4. Percentage of Mineral Output (PMS,%): (SLS / 2 + DLS) / BS x 100.

5. Mineral supplemental growth rate (MAR, pm / day): ILW / interval between markers.

6. Bone formation / Surface regeneration (BFR / BS, pm^z/ d / pm): (SLS / 2 + DLS) x MAR / BS.

7. Bone wrap (BTR,% / y): (SLS / 2 + DLS) x MAR / BV x 100.

Tðlfræði

Computer data is calculated by using StatView 4.0 packages (Abacus Concepts, Inc., Berkeley, CA). Distribution analysis (ANOVA), followed by Fischer's PLSD, is the owner of the comparison, comparing the difference between hfipa.

SUMMARY AND RAINBACK MENTAL REPLY

The following descriptions can of course be changed by professionals who are professional. For example, the use of untouched caricine's efia female rats, sex hormone40 deprived karikyn (absenteeism) promotes female (ovarian ovarian) rats. In addition, male or female rats of different ages (ains and 12 months old) may be used in the studies. Rats may be used to prevent unintentional enhancement of bile ductility (proliferation of ovarian hyperplasia of the testosterone), and the delivery of anabolic agents such as the compounds. In this invention, different forms (such as 1, 3, 6 mg / kg / day) for a certain period of time ( ains and twelve weeks to two months) followed by administration of anti-resorptive agents such as drloloxin in different forms (such as 1.5.10 mg / kg / day) for a certain period of time (like twelve weeks to two months) , enhancing the combination of metabolism with anabolic anabolic and anti-absorption molecules in different forms for a certain period of time (such as twelve weeks to two months). In the rat rats, the force may have a major effect on the day after the scar tissue (For the purpose of preventing bone loss), increase the amount of time that blemish has already taken (for the purpose of rebuilding bone mass).

The rats are fused to ketamine. The following points are determined:

Lsrieoos fossil line Hsgri the femur from each rat is a distant wavelength ......... autopsy and transplants with the force of dual-stranded energy-absorption absorption (DXA, QDR 1000 / W, Hologic Inc., Waltham, MA) Regional High Resolution Scan "software (Hologic Inc., Waltham, MA). The screening interval is 5.08 x 1.902 cm, the surface area is 0.0254 x 0.0127 cm and the screening bracket is 7.25 mm / second.

Lsriegg's screening syndromes are diagnosed with bone marrow, bain (BMC), and bone mineral density (BMD) of whole islite (WF), multi-lingual end lsrieggs (DFM), lsrieggs (FS), and nearby lsrieggs (PF).

Lendalifls Mineral Line: Double-stranded energy-efficient absorption spectrometer (QDR 1000 / W, Hologic Inc., Waltham, MA), which is equipped with "Regional High Resolution

Scan * software (Hologic Inc., Waltham, MA) is a benchmark for power determination of bone area, BMC, and BMD on whole lumbar spine and LIFE 6 (LV1-6) in the rotten rat. Rats are swallowed with a syringe (in the abdomen) of 1 ml / kg of ketamine / rumin (ratio 4 to 3), and the sip is placed on the rat. The screening interval is 6 x 1.9 cm, the resolution is 0.0254 x

0.0127 cm, and a screening bracket is 7.25 mm / second. A scan of the lumbar spine is taken and analyzed. Bone area (BA), and bone mineral density (BMC) is determined, and bone mineral density (MBC shared with BA) for the entire tendon back and which of the scalar scales (LV1-6).

The webforms are derived from the following: The precursor flask is attached to 70% ethanol, dehydrated in ethanol concentrations, acetylsalicylate, acetylphosphorylated inoculum (Eastman Organic Chemicals, Rochester, NY). Spikes of narrow stitching end of the tibia at 4 and 10 pm thickness are shrunk with the force of the Reichert-Jung Polycut S vein mask. One 4 pm and one 10 pm cut from each rat are used in the abovementioned bone tissue. The 4 pm slices are colored with modified Massons Trichrome color while the 10 pm slices are left unladen.

The bioquant OS / 2 web form measurement system (R &amp; M biometrics, Inc., Nashville, TN) is used for stationary and motions of the web form measurements of the secondary malignant substance at the near-wide end of the tibia between 1.2 and 3.6 mm from the growth of the plate-to-wall connection . Release the first 1.2 mm of the wide end of the tibia to isolate the measurements of secondary level material. 4 pm sneiflamar aru leaflets to determine bone volume, bone structure, and bone resorption, while the 10 μm slices are used to determine bone and bone formation.

I. Maalinoar οα calculator that consumes a biobond volume of bvoainau:

1. Total area connections (TV, mm^z): Connection area between 1.2 and 3.6 mm from the 15-point Plug-in connection.

2. Bending Area Area (BV, mm²): Total area of ​​beam within TV.

3. Polar beam circumference (BS, mm): length of total circumference of beam.

4. Bulk volume (BV / TV,%): BV / TV x 100.

5. Bulb number (TBN, # / mm): 1,199 / 2 x BS / TV.

6. Thickness Thickness (TBT, μm): (2000 / 1,199) x (BV / BS).

7. Directional Separation (TBS, μm): (2000 / 1,199) x (TV - BV).

II, Maalinoar and the calculator who plays a beinuposoai:

1. Bone number (OCN, #): total number of bone loci within total area area.

2. Bone circumference (OCP, mm): length of bunch of circumference covered by bone.

3. Directional distance / mm (OCN / mm, # / mm): OCN / BS.

4. Promptly set the circumference (% OCP,%): OCP / BS x 100.

III. Paints and counting calculations that are used for the development and delivery of:

1. Ein-kalsein labeled circumference (SLS, mm): total length of beam circumference labeled with one calsein label.

2. Tvi-Calcine Marked Perimeter (DLS, mm): The total length of the bell circumference labeled with two calsein labels.

3. Intermediate Marking (ILW, pm): Meal distance between two calsein markers.

4. Prflsentu Percentage of Mineral Output (PMS,%): (SLS / 2 + DLS) / BS x 100.

5. Mineral growth rate (MAR, pm / day): ILW / interval between markers.

6. Bone formation rate / surface regeneration (BFR / BS, pm^!/ d / pm): (SLS / 2 + DLS) x 40 MAR / BS.

7. Bone velocity (BTR,% / y): (SLS / 2 + DLS) x MAR / BV x 100.

Tðlfræfli

Held is the power of calculating statistics using that force using StatView 4.0 packages (Abacus Concepts, Inc., Berkeley, CA). Distribution analysis (ANOVA) test followed by Fischer's PLSD is used to compare the differences between groups.

Use of prostaglandin receptor agonists

The role of prostaglandin agonist in the novel synthesis was investigated by the ability of PGE_Z enhancing prostaglandin agonist to induce expression of bone marrow protein 7 (BMP-7) in wild-type 293S cells and in 293S cells encapsulated with EP₂vifltakanum.

Coagulants: 293 and EP2 293S cells were recombinant Dulbeccos Modified Egale Miflli (DMEM, Gibco, BRL; Gaithersburg, MD). One day for interference with PGE₂ enhancing prostaglandin agonists, cells were placed at a density of 1.5 x 10^s cells / 10 cm disc. The next day, the cellular enzyme was administered once with OptiMEM (Gibco, BRL) followed by 10 ml OptiMEM / disk prolonged serum boosting the absence of cucumber (DMSO), PGE2 (10⁴ M) promoting prostaglandin agonist (10⁴ M). Cells were up and RNA dropped out after 8, 16 and 24 hours. Norflurblotting analysis of total (20 mg / reindeer) was performed on the force unless the biotransmitter³²P-marked BMP-7 except. Blettimir were stackable for RNA loading by the p-link link with "P-marktum 18s NET RNA except. The power was seen as PGE₂ and the prostaglandin agonist, in a timely manner, induce expression of BMP-7 ί ΕΡ₂ 293S cells, but not in the umbilical cord. BMP-7 secondary function (new generation and prostaglandin agonist effect to induce BMP-7 expression in 293S neonatal cells per hour and fluctuate specific episodes, indicate the role of prostaglandin agonists in newborns.

Thus, power provides the compounds of this invention with a catalytic converter which yields a compound of this invention systematic and / or enhancing pacemaker (e.g., on the pile of bone fracture, the pancreas, enhancing the epileptic curve). These abnormalities include oral, non-gastrointestinal disorders (abdominal cramps, etc. In general, the compounds of this invention are administered by mouth, but there is also force in the use of the uterine parenteral (e.g., intravenously, subcutaneously) , for example, a pair of oral donors is prominent for a significant increase in the patient's ability to absorb a drug.

The compounds are useful in the metabolism and the yield of bone fractures and bone marrows, including the spatial use (e.g., on the bone fracture enhancement) of the ventricles. In this invention, the combination of pairs promotes. The compounds of this invention include the use of a bone fracture enhancing bone bones, such as whether or not injection of the compound into a suitable solvent (e.g., an oleaginous solvent of sintered oil and arachis oil) in the cartilage plate or, in the case of an open cuts, with a pacemaker using such compounds in suitable cavity such as bone wax, precocious bone powder, polymeric bone glue, bone sealants, etc. Alternatively, stacked use may be achieved by using a solution or suspension of the compound in a suitable carrier on the surface of,

Alternatively, the compounds of this invention may be applied to the site of the fracture or bone structure in a suitable vehicle in combination with one or more of the anabolic or direct-absorbed agents described above.

The two different compounds of this invention can be co-administered or sequentially administered in any order, or capable of giving, a single pharmaceutical composition containing the formula I compound as described above and any other compound as described above in a pharmaceutically acceptable excipient.

For example, the use of the intravenous fibromyalgia alone enhances the combination of multiple myelopathy for one week to three years, followed by anti-absorption alone for three months to three years, including multiple repetition of the entire migraine cycle. The power of many benefits is because of the use of the intravenous fibromyalgia alone, the combination of multiple oral absorption for three months to three years, followed by the second-hand absorption of the patient alone, remains the sole responsibility of the patient. For example, in one preferred mode of administration, a strong compound of formula I is described as described above by force once daily and the compound as described above (for example, estrogen agonist / metabolite) can check daily for a single boost in many cases. There are many advantages, for example, In a preferred mode of administration, therefore, the power yields the compounds in a conventional manner, thus providing a formula I compound as described by means of force above once daily in a period of time capable of increasing the bone mass of the force above the fracture threshold (Alzheimer's study Health Organization, Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis (1994). Report of a World Health Organization Study Group. World Health Organization Technical Series 843 ") followed by the use of a multi-functional compound, as described herein above (eg, oestrogen agonists / drugs), daily in a single promotion of multiple sclerosis. Equivalently, the power of the first compound as described above is administered once daily in the form of rapid dialysis such as oral dialysis (e.g.,

In all instances, the magnitude and timing of compounds given, power, see, be the maximum range detected by force, the severity of the mask, the delivery temperature and the scattered evaluation. Therefore, due to variability between patients, the doses given by the majority of patients are non-normative, and the doctor may dose titration of the drug to achieve the metabolic rate (eg, bone mass increase) that the physician considers to be adequate for the patient. Vifl power finds out of the level of interference that is bad

Ignition power includes various factors such as the initial mass of bone mass, the age of the patient, the presence of other diseases, and also other diseases (eg cardiovascular disease).

Generally, a quantity of compound of this invention is used which is sufficient to increase bone mass to a target of bone fracture thresholds (as clearly explained in the WHO study previously referred to).

In general, an effective dose for the anabolic agents described above is from 0.001 to 100 mg / kg / day, preferably at 0.01 to 50 mg / kg / day.

The following paragraphs provide an optimal dose range for various anti-recording media.

The amount of antagonist to be used is determined by its activity as a direct-loss inhibitor. This activity is determined by the pharmacokinetic pharmacology of a single compound and its minimum maximal effective dose inhibitory regimen using a protocol as described above (eg, estrogen agonist / antagonist description).

In general, an effective dose for anti-absorbed medium is about 0.001 mg / kg / day to about 20 mg / kg / day.

In general, an effective dose for progestin is approximately 0.1 to 10 mg daily; The preferred dose is about 0.25 to 5 mg daily.

In general, an effective dose for polyphosphonates is determined by the amount of direct-acting inhibitory multiplier according to standard measurements.

The dose for daily administration of some polyphosphonates is about 0.001 mg / kg / day to about 20 mg / kg / day.

In general, an effective dosage for the treatment of this invention, as for the bone resorption treatment of this invention, for the estrogen agonists / antagonists of this invention ranges from 0.01 to 200 mg / kg / day, preferably from 0.5 to 100 mg / kg / day.

Specifically, an effective dose for droloxifen ranges from 0.1 to 40 mg / kg / day, preferably at 0.1 to 5 mg / kg / day.

Specifically, the effective dose for the raloxifene range is from 0.1 to 100 mg / kg / day, preferably at 0.1 to 10 mg / kg / day.

Specifically, the effective dose for tamoxifen ranges from 0.1 to 100 mg / kg / day, preferably at 0.1 to 5 mg / kg / day.

Special dose effective dose

C / s-6- (4-fluoro-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -fený1] -5,6,7,8-tetrahydro-naphthalene-2-ol;

(-) - C / s-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydronaphthalene-2-ol;

Cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydronaphthalene-2-ol;

C / s-1- [6'-pyrrolodinoethoxy-3'-pyridyl] -2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;

- (4'-Pyrrolidinethoxyphenyl) -2- (4 "-fluorophenyl) -6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

C / s-6- (4-hýdroxýfený1) -5- [4- (2-piperidin-1-yl-ethoxy) -fený1] -5,6,7,8-tetrahydro-naphthalene-2-ol;

or

- (4'-Pyrrolidinoethoxyphenyl) -2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline ranging from 0.0001 to 100 mg / kg / day, preferably 0.001 to 10 mg / kg /day.

Specifically, an effective dose for 4-hydroxy tamoxifen ranges from 0.0001 to 100 mg / kg / day, preferably at 0.001 to 10 mg / kg / day.

The compounds of this invention are usually administered in the form of a pharmaceutical composition containing at least one of the compounds of this invention together with a pharmaceutically acceptable excipient enhancing a promoter. The present invention provides a compound of the invention. In this invention, one enhances the effective administration of a topical oral dosage form of endorphic skin enhancement.

For oral administration, the pharmaceutical composition may be verified in the form of solutions, solutions, tablets, pills, capsules, powders, and pencils. Tablets containing various cuttings, such as sodium citrate, calcium carbonate and calcium phosphate, are used as well as a variety of disintegrating agents such as starch and the preferred source of potato starch and certain complex complexes, together with binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often useful for flotation. Compositions of the same kind are similarly used as fillers in soft and highly filled gelatin capsules; Preferred materials in this connection also cover lactic softening of soft drinks and also polyethylene glycol with high molecular weight.

For gastrointestinal administration, the use of solutions in a sesame stimulant is enhanced by hydrolysis of a water-soluble propylene glycol, as well as a deodorant aqueous solution of corresponding water-soluble results. Such aqueous solutions are suitably effective if the potential is difficult, and fluctuating emollients are first made in the presence of useful saline to promote glucose. Pessar water solutions are especially suitable for injections such as, for example, under the hood and in kviflartiol. In this connection, it is obviously possible to obtain all of the deodorizing water molecules that are used in the field of highly efficient power plants that are well-known by professionals who are skilled in the art.

TH is administered by skin (e.g., pelvic), is prepared for dental sterilization, hydrolysis enhances the proportion of water-soluble solutions (usually about 0.1% to 5% strength), but the majority of the parenteral doses for parenteral use here above.

Coagulation agents for the propagation of various pharmaceutical compositions with a certain amount of active substances are excreted, enhancements will be apparent in this publication, by professionals who are professionals. For examples of drug delivery agents, see Remington's

Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th Ed. (1975).

Pharmaceutical compositions according to the invention may contain from 0.1 to 95% of the compound (s) in this invention, preferably about 1% to 70%. Who's the one?

In addition, the formulations provided by the force will contain an amount of compound (s) according to the invention in an amount effective to treat the disease / condition of the subject being treated, for example, a direct disorder.

In combination with this invention, which relates to the increase and maintenance of bone mass by treatment with a combination of active substances capable of being separated, the invention also contemplates combining separate pharmaceutical compositions in a composite form. The composition consists of two separate pharmaceutical compositions: a compound of formula I and a further compound as described above. The combination contains liquidity containing the separate formulations, such as a flask, to promote a diluted blister pack. It is suggested that the sampler contains a guide for the donation of the separate elements. The consolidated form is particularly advantageous when optimal force is administered in different dosage forms (eg oral and parenteral), given the different dosage parameters,

The resulting mixture is a soiled blister pack. Packaging packages are well known in the packaging industry and are available for use in the collection of unit dose unit dosage forms (capsules, capsules, and pencils). Blister packs generally consist of a relatively rigid material which is comprised of a blister of preferably a gagnamic resin. In the process of processing, there are some images in the plastic blister. Dsldimar has the strength and the suppression of the tablets strengthening the capsules in a force pack. At the top of the tabs, the capsules are placed in the bottom and the layers of tiltable staple material are sealed against the plastic blister on the side of the blister, as opposed to the hinged parts of the blister I. As a result of the forces obtained, the capsules are closed between the blisters between the plastic blister and iagsins. Preferably, the strength of the layer is as strong as it is possible to force the capsules away from the blisters to strengthen the capsules from the blister pack by pushing the blades into the blades and then forming up on the stack of the blister. Then, removing the tablet may increase the capsule of the above openings.

Desirably, the force may have a memory aid in the collapse, for example, in the form of a number of vials next to the tablets, enhancing the capsules in response to the day in the intervening force, increasing the strengths of the capsules so labeled. For example, a memorandum is a calendar printed on a tablet, for example, as follows: "First week, Monday, cleaning day, ..., etc." Second week, Monday, cleaning day, ... "etc. Lost changes to memory support will be helpful. "Daily dose" can confirm one tablet of capsule strengthening a few pillars to strengthen capsules that are consuming on a given day. Alternatively, a daily dose of Formula I compound consisting of a single tablet enhancing capsule may be administered daily dose of the fluorine compound may consist of several types of capsule enhancers and vice versa. The memory device must reflect this.

In another particular embodiment of the invention there is provided a dispenser which is designed to power the daily doses daily one by one in the same manner as their use. Preferably, the dose is prepared by means of a memory card, which further facilitates interferon retention. Such a memory aid is a mechanical counter, indicating the frequent daily doses that have verified dose loss. For this reason, the aid is the battery-operated microplate that is connected to a shadow window, enhancing an audible monument, which read, as a result, the date the last daily dose has been taken and / or reminds you of the time at which the force will take the next dose.

The compounds of this invention, which alone enhance the composition of any multiple compounds, will usually be administered in a suitable form of composition. The following combination agents are illustrative and are not an asthma force limiting the scope of this invention.

In the combinations provided, "active agent" means a compound of this invention.

Composition 1: Gelatin capsule

Hflrfl gelatin capsules are produced using the following uses:

<td>content</td><td>Amount (mg / capsule)</td>

<td>Active substance</td><td>0.25-100</td>

<td>Sterkja, NF</td><td>0-650</td>

<td>Strong flaskable powder</td><td>0-50</td>

<td>Silfkflnvflkvi 350 sentistflk</td><td>0-15</td>

Fluid composition is produced using the following materials:

Composition 2: Tablets

<td>content</td><td>Quantity (mg / tflflu)</td>

<td>Active substance</td><td>0.25-100</td>

<td>Sellulflsi, crystal crystals</td><td>200-650</td>

<td>Kefluxfflff, steam power</td><td>10-650</td>

<td>stearic acid</td><td>5-15</td>

The elements are mixed together and the pressures for power generate a problem.

There are many advantages, each containing 0.25-100 mg of active substances, prepared as follows:

Composition 3: Tablets

<td>content</td><td>Quantity (mg / tflflu)</td>

<td>Active substance</td><td>0.25-100</td>

<td>starch</td><td>45</td>

<td>Sellulflsi, crystal crystals</td><td>35</td>

<td>Polyvinylpyrrolididone (as a 10% solution in water)</td><td>4</td>

<td>Sodium carboxymethyl cellulose</td><td>4.5</td>

<td>Magnesium stearate</td><td>0.5</td>

<td>Talk</td><td>1</td>

Active substances, starch, and cellulose are passed through No. 45 mesh US siu and mixed egg whitish together. The solution of polyvinylpyrrolidone is a mixture of vapor powder which comes out and this is the case. 14 mfiskva US siu. Kymin produced thus are dried at 50 ° C - 60 ° C and passed through 18th grade US siu. Sodium carboxymethyl starch, magnesium sterate, and talc previously used to pass through No. 60 US siu , the figure is placed in the column that, after blindness, are pressed in a tablet machine to give a finger.

Suspensions each containing 0.25-100 mg of active substance for each 5 ml dose prepared as follows:

Composition 4: Suspensions

<td>content</td><td>Quantity (mg / 5 ml)</td>

<td>Active substance</td><td>0.25-100 mg</td>

<td>Sodium carboxymethyl cellulose</td><td>50 mg</td>

<td>syrup</td><td>1.25 mg</td>

<td>Benzoic acid solution</td><td>0.10 mL</td>

<td>Bragfiefni</td><td>qv</td>

<td>Coloring</td><td>qv</td>

<td>Clean water water grandfather</td><td>5 mL</td>

The active substances are allowed to pass through no. 45 mfiskva US Siu and mix together with sodium carboxymethyl cellulose and the syrup to form a smooth paste. The benzoic acid solution, excipients, and dyes are diluted with a little of the water and allowed to dissolve. Available water is available for the required volume. Aerosol solution is manufactured containing the following materials:

Composition 5: Aerosol

<td>content</td><td>Quantity (% mifiafi vifi weight)</td>

<td>Active substance</td><td>0.25</td>

<td>Etanfil</td><td>25.75</td>

<td>Propellant 22 (Chlorodifluoromethane)</td><td>70.00</td>

The active substance is mixed with ethanol and the mixture is concentrated in a portion of the propellant 22, cooled to 30 ° C, and transferred to refill. Magnifi required is a sifian set in stainless steel container and torn with the remaining propellant. The end sections are then attached to the container. Stflar iso manufactured as follows:

Composition 6: Stflar

<td>content</td><td>Quantity (mg / style)</td>

<td>Active substance</td><td>250</td>

<td>Saturated fatty acid glycerin</td><td>2000</td>

The active substance is passed through no. 60 mesh US sfu and suspended in the fat fatty acid glycerides, the shoots have been bombarded using the minimum heat required. The mixture is then poured into a sliced ​​mold with 2 g capacity and allowed to cool.

The composition of the vein is produced as follows:

Composition 7: Solution Γ asht

<td>content</td><td>amount</td>

<td>Active substance Equal pressurized saline</td><td>20 mg 1,000 mL</td>

The solution of the above substances is administered to a patient at a rate of approximately 1 mL per minute.

The active substance above can also verify a combination of media.

GENERAL RUNNING METHODS

NMR rflf were taken on Varian XL-300 (Varian Co., Palo Alto, California), Broker AM-300 Rice Muffler Vial, about 23 ° C at 300 MHz for Proton and 75.4 MHz for Carbon (Broker Co., Billerica , Massachusetts) enhancing the Varian Unity 400 fan 400 MHz for RFID. Chemical gaps are expressed in pairs per million below the trimethylsilane. The top layers are marked as follows: s, simple; d, double; t, triple; q, fourfold; m, multipurpose; bs = wide simple. Hermun which was labeled as interchangeable did not occur in the resistor NMR experiment pair the sample was shaken with a few drops of D₂O In the same solvent. Mass flow rates were the atmospheric pressure (atmospheric pressure) atmospheric pressure (APCI) absorbed on the Fisons Platform II Spectrometer. Ophthalmic mass flow was taken on Hewlett-Packard 5989 tski (Hewlett30 Packard Co., Palo Alto, California) (AMMFIA, PBMS). A pair of concentrations of bromine-containing ions described is seen as the expected ratios ratio (about 3: 1 for Cl / Cl-containing ions and 1: 1 for Br Br-containing ions) and the strength for only the lower mass is given.

Column chromatography was carried out either at Baker kfsilgeli (40 μπι) (JT Baker, Phillipsburg, NJ) efia kfsilgeli 60 (EM Sciences, Gibbstown, NJ) in low pressure nitrile pellets. Gas chromatography was performed using Chromatron (Model 7924T, Harrison Research). Unless otherwise stated, reagents were used as obtained from vendors. Dimethylformamide, 2-propanol, tetrahydrofuran, and dichloromethane used as reactants were of anhydrous class and obtained from Aldrich Chemical Company (Milwaukee, Wisconsin). Microorganisms were performed by Schwarzkopf Microanalytical Laboratory, Woodside, NY. The term "samsafna" and "sampled" visas for removal of water at a water pump pressure at a temperature of about 45 ° C. The reactions are carried out at "0-20 ° C" or "0-25 ° C", the initial cooling of the vessel was carried out in an insulated ice bath which was allowed to warm to room temperature over a few hours. The shortcuts "min" and "kl" represent "minutes" and "hours" as appropriate.

Dami 1

7 - [(4-Butyl-bensý1) -methanesulfony-amino] -heptanoic acid

Step A: Alkvlerinq

Ethyl 7 - [(4-Butyl-benzyl) -methanesulfonamide-amino] -HBDanoate. A solution of ethyl 7-methanesulfonyl-amino-haptanoate (250 mg, 1.0 mmol) in DMF (2 mL) was added dropwise in NaH (48 mg, 1.19 mmol, 60% in oil) DMF at 0 ° C. After stirring for 45 minutes at room temperature, 1-bromomethyl-4-butylbenzene (271 mg, 1.19 mmol) was added dropwise. The reaction was stirred for 2 hours and DMF was removed in vacuo. The residue was diluted with CH 2 Cl 2 and the aqueous solution was washed sequentially with 1N HCl (1x), water (2x), and brine (1x). The lffran solution was dried over MgSO₄, sfufi, and cohabiting in lofttami. The product was purified by chromatography (15% EtOAc / hexane in 40% EtOAc / hexane) to afford the title compound (Step A) (379 mg). 1 H NMR (400 MHz, CDCl 3) δ 7.12-7.30 (m, 4H), 4.35 (s, 2H), 4.12 (q, 2H), 3.10-3.19 (m , 2H), 2.80 (s, 3H), 2.60 (t, 2H), 2.25 (t, 2H), 1.46-1.62 (m, 7H), 1.18-1, 39 (m, 6H), 0.92 (t, 3H); MS415 (M + 18).

Step B: Esther hydrolysis

7- (4-Benzyl-benzyl) -methanesulphonylamino] -heptanoic acid To a solution of the title compound of Step A (379 mg, 0.95 mmol) in MeOH (6 mL) was added NaOH (1.0 mL, 5N) The reaction mixture was stirred at room temperature for 24 h and was acidified with HCl in water (1 N). MeOH was removed in vacuo and the residue was dissolved in CH2 Cl2. The organic solution was washed in turn with HCl (1N, 1x), water 2x), and salt pack (1x). The solution was dried mafi MgSO₄, sfufi, and concentrated in lofttami. Purification by chromatography (CH₂Cl 2 in 6% MaOH / C 2 Cb) gave title compound (356 mg). 1 H NMR (400 MHz, CDCl3)₃) δ 7.30-7.12 (m, 4H), 4.35 (s, 2H), 3.10-3.19 (m, 2H), 2.80 (s, 3H), 2.60 t, 2H), 2.31 (t, 2H), 1.48-1.65 (m, 7H), 1.20-1.40 (m, 6H), 0.97 (t, 3H); MS 387 (M + 18).

Dsmi 2-44

Examples 2-44 were prepared from the secondary starting materials using the coagulant flakes described in Schemes 1 and 2, and in a random manner, such as changes in the reaction temperature and temperature in step A as listed.

Example 2 (3 - {[(4-Butyl-benzyl) -methanesulfonyl-amino] -methyl} -phenyl) -acetic acid 1 H NMR (400 MHz, CDCl3₃) δ 7.32-7.14 (m, 5H), 4.32 (s, 2H), 4.29 (s, 2H), 3.66 (s,

2H), 2.76 (s, 3H), 2.60 (t, 2H), 1.59 (m, 2H), 1.34 (m, 2H), 0.93 (t, 3H); MS 388 (M +).

Dsmi 3 (Viflmiflunardsmi)

7 - {[2- (3,5-Dichloro-phenoxy) -ethyl] -methanesulfonyl-amino} -heptanoic acid

Step A: Reaction time of 24 hours with room temperature. ¹1 H NMR (400 MHz, CDCl 3) δ 7.00 (m, 1H), 6.80 (m, 2H), 4.12 (t, 2H), 3.60 (t, 2H), 3.26 , 2H), 2.90 (s, 3H), 2.37 (t, 2H), 1.65 (m, 4H). 1.39 (m, 4H); MS 412 (M +).

Dsmi 4 (Viflmiflunardsmi)

4- (2 - ((3- (3,5-Dichloro-f0nýi) -allyl] -methanesulfonyl-amino} -ethyl) -benzoic acid ¹1 H NMR (400 MHz, CDCl 3) δ 8.02 (d, 2H), 7.30 (d, 2H), 7.20 (s, 1H), 7.19 (s, 2H),

6.39 (d, 1H), 6.08 (m, 1H), 3.94 (m, 2H), 3.50 (t, 2H), 3.00 (t, 2H), 2.78 , 3H).

Dsmi 5

7- [Methanesulfonyl- (4-trifluoromethyl-bansýl) -amino] -haptansýra ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.60 (d, 2H), 7.48 (d, 2H), 4.41 (s, 2H), 3.16 (t, 2H), 2.87 (s, 3H), 2.29 (t, 2H), 1.40-1.61 (m, 4H), 1.13-1.33 (m, 4H).

Dsmi 6 (Viflmiflunardsmi)

Trans-7- [Matansúlfónýl- (3-phenyl-allyl) -amino] -haptansýra

Step A: Reaction time of 24 hours at 90 ° C. ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.2-7.4 (m, 5H), 6.59 (d, 1H), 6.12-6.21 (m, 1H), 4.0 (d, 2H), 3.21 t, 2H), 2.32 (t, 2H), 1.55-1.70 (m, 4H), 1.27-1.40 (m, 4H); MS 338.1 (M-1).

Case 7 (Violence Disorder)

Tan- (4 - {[3- (3,5-Dichloro-phenyl) -allyl] -methanesulfonylamino} -butoxy) -acetic acid

Step A: Any time of 2 hours at 100 ° C. ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.37 (m, 2H), 7.23 (m, 1H), 6.42-6.52 (m, 1H), 6.15-6.28 (m, 1H), 3.96 m, 4H), 3.52 (m, 2H), 3.23 (m, 2H), 2.66 (s, 3H), 1.55-1.72 (m, 4H); MS 411.5 (M + 1).

Case 8

7 - {[4- (1-Hydroxy-bexý)) - benzyl] -methanesulfonyl-amino] -heptanoic acid

Step A: Reaction time of 24 hours at 90 ° C. Mp. 68-70 ° C;¹1 H NMR (400 MHz, CDCl3)₃) δ 7.20-7.38 (m, 4H), 4.62-4.66 (m, 1H), 4.34 (s, 2H), 3.10-3.18 (m, 2H), 2.94 (s, 1H), 2.83 (s, 3H), 2.17-2.39 (m, 3H), 1.10-1.83 (m, 16H), 0.80-0, 90 (m, 3H).

Example 9 (case study)

7- [Metansúlf6nýl- (2'-trifluoromethyl-b [phenyl-4-ylmethyl) -amino] -heptanoic acid

Step A: Reaction time of 24 hours at room temperature. ¹1 H NMR (CDCl3)₃ 400 MHz) δ 7.75-7.23 (m, 8H), 4.46 (s, 2H), 3.21 (t, 2H), 2.84 (s, 3H), 2.34 (t, 2H), 1.57 (m, 4H), 1.28 (m, 4H).

Case 10 (reference limit)

7 - [(2 '₁6'-dichloro-biphenyl-4-ylmethyl) -methanesulfonyl-amino] -heptanoic acid

Step A: Reaction time of 24 coffin at room temperature. ¹1 H NMR (CDCl3)₃ 400 MHz) δ 7.60-7.20 (m, 7H), 4.41 (s, 2H), 3.21 (t, 2H), 2.82 (s, 3H), 2.30 (t, 2H), 1.56 (m, 4H), 1.27 (m, 4H); MS 458 (M +).

Dami 11 (benchmark)

7- [Methanesulfonyl- (2-phenoxy-ethyl) -amino] -heptanoic acid 1H NMR (400 MHz, CDCl3) δ 7.25-7.36 (m, 2H), 6.85-7.03 (m, 3H), 4.11 (t, 2H), 3.62 (t, 2H), 3.27 (t, 2H), 2.91 (s, 3H), 2.34 (t, 2H), 1 , 72-1.54 (m, 4H), 1.45-1.25 (m, 4H).

Example 12 (Reference Example)

7 - [(Methylsulfonyl) [[4- (2-pyridinyl) phenyl] methyl] amino] -heptanoic acid hydrochloride salt

Wrinkle A: Reaction time of 45 minutes at room temperature. ¹1 H NMR (400 MHz, CDCl 3) δ 8.72 (bs, 1H), 7.64-7.95 (m, 4H), 7.48 (d, 2H), 7.21-7.32 (m, 1H), 4.40 (s, 2H), 3.14 (t, 2H), 2.85 (s, 3H), 2.15-2.35 (m, 2H), 1.40-1.60 (m, 4H), 1.08-1.30 (m, 4H).

Dsmi 13 (reference form)

7- [Metansúlfónýi- (5-phenyl-pentyl) -amino] -heptanoic acid

Step A: Reaction time of 2 hours at room temperature and 18 hours at 70 ° C. ¹1 H NMR δ (400 MHz, CDCl 3) δ 7.28-7.14 (m, 5H), 3.12 (m, 4H), 2.78 (s, 3H), 2.60 (t, 2H), 2.34 (t, 2H),

1.62 (m, 8H), 1.32 (m, 6H).

Example 14 (Reference Example)

7 - ((2- (2,4-Dichloro-phenoxy) -ethyl] -methanesulfonyl-amino} -heptanoic acid

Step A: Reaction time of 20 kfst at 65 ° C. 1 H NMR (400 MHz, CDCl3)₃) δ 7.33 (d, 1H), 7.16 (dd, 1H), 6.83 (d, 1H), 4.13 (t, 2K), 3.62 (t, 2H), 3.31 (t, 2H), 2.94 (s, 3H), 2.31 (m, 2H), 1.61 (m, 4H), 1.33 (m, 4H).

Example 15 (Reference Example)

Trans- [3 - (([3- (3,5-Dichloro-phenyl) -allyl] -methanesulfonyl-amino (amino} -methyl) -phenyl] -acetic acid ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.32-7.13 (m, 7H), 6.33 (d, 1H), 6.09 (m, 1H), 4.38 (s,

2H), 3.91 (d, 2H), 3.61 (s, 2H), 2.89 (s, 3H).

Dasmi 16 (reference example)

7 - {[3- (3,5-dichloro-phenyl) -propyl] -methanesulfonyl-arTiínó} -heptanoic

Step A: Reaction temperature of 60 ° C For 72 hours. ¹1 H NMR (400 MHz, CDCl3)₃) Δ 7.25 (s, 1H),

7.19 (s, 2H), 3.15 (m, 4H), 2.81 (s, 3H), 2.60 (t, 2H), 2.34 (t, 2H), 1.89 , 2H), 1.60 (m, 4H), 1.32 (m, 4H).

Example 17 (vidmidunardami) [3 - ({[3- (3-Chloro-phenyl) -propyl] -methanesulfonyl-amino} -methyl) -phenyl] -acetic acid

Step A: Reaction time of 24 hours at room temperature. 1 H NMR (400 MHz, CDCl3)₃) Δ 7.31-6.91 (m, 8H), 4.34 (s, 2H), 3.64 (s, 2H), 3.18 (t, 2H), 2.81 (s, 3H) , 2.49 (t, 2H), 1.78 (m, 2H); MS 413 (M + 18).

Dami 18 (Maintenance Guide)

7 - [(2-indan-2-yl-aryl) -methanesulfonyl-amino] -heptanoic acid

Step A: Reaction time of 4 hours at room temperature. 1 H NMR (400 MHz, CDCl3)₃) Δ 7.13 (m, 4H), 3.24 (t, 2H), 3.17 (t, 2H), 3.08 (m, 2H), 2.83 (s, 3H), 2.62 (m, 2H), 2.48 (m, 1H), 2.35 (t, 2H), 1.81 (m, 2H), 1.62 (m, 4H), 1.37 (m, 4H) .

Dami 19 (vidmidunardami)

7- [Metansúlfóný1- (4-phenyl-bútý1) -amide [amino] -heptanoic

Step A: Reaction time of 72 hours at 60 ° C. ¹1 H NMR (400 MHz, CDCl 3) δ 7.26 (m, 2H), 7.17 (m, 3H), 3.16 (t, 2H), 3.10 (t, 2H), 2.78 , 3H), 2.63 (t, 2H), 2.34 (t, 2H), 1.701.51 (m, 8H), 1.32 (m, 4H).

Example 20 (Vidamidunardami) [3 - (((2- (3,5-Dichloro-phenoxy) -ethyl] -methanesulfonylamino} -methyl) -phenyl] -acetic acid

Step A: Reaction time of 24 hours at room temperature. ¹1 H NMR (400 MHz, CDCl3)₃) Δ 7.27 (m, 5H), 4.48 (s, 2H), 3.97 (t, 2H), 3.64 (s, 2H), 3.57 (t, 2H), 2.92 (s, 3H).

Dami 21 (vidmidunardami)

4- (4 - {[3- (3-Chloro-fený1) -propyl] -metansúlfóný1-amino} -phenyl) -butyric acid

Step A: Reaction time of 1 hour with room temperature. 1 H NMR (400 MHz, COCl₃) δ

7.32-6.97 (m, 8H), 3.67 (t, 2H), 2.85 (s, 3H), 2.88 (t, 2H), 2.63 (t, 2H), 2 , 40 (t, 2H), 1.97 (m,

2H), 1.77 (m, 2H).

Example 22 (Reference Scheme) [2- (2 - {[3- (3-Chloro-phenyl)) -propyl] -methanesulfonyl-amino} -ethyl) -phenoxy] -acetic acid

Step A: Reaction time of 1 hour with room temperature. ¹1 H NMR (400 MHz, CDCl 3) δ 10 7.29-6.71 (m, 8H), 4.64 (s, 2H), 3.44 (t, 2H), 3.23 (m, 2H), 2.95 (t, 2H), 2.71 (s, 3H), 2.58 (t, 2H), 1.89 (m, 2H).

Example 23 (Reference Example) [3 - ({Methanesulfonyl- [3- (3-trifluoromethyl-phenyl) -propyl] -amino} -methyl) -phenyl] -acetic acid

Step A: Reaction time of 24 hours room temperature. 1 H NMR (CDCl 3₃ 400 MHz) δ 7.42-7.21 (m, 4H), 4.34 (s, 2H), 3.62 (s, 2H), 3.22 (t, 2H), 2.81 (s, 3H), 2.56 (t, 2H), 1.79 (m, 2H); MS447 (M + 18).

Example 24 {4 - [(4-Butyl-benzyl) -methanesulfonylamino] -butoxy} -acetic acid

Step A: Reaction time of 2 hours at 100 ° C. ¹1 H NMR (400 MHz, CDCl 3) δ 7.23 (m,

2H), 7.14 (m, 2H), 4.34 (s, 2H), 4.03 (s, 2H), 3.48 (t, 2H), 3.19 (t, 2H) 79 (s, 3H), 2.59 (t,

2H), 1.57 (m, 6H), 1.32 (m, 2H), 0.91 (t, 3H); MS 370 (M-1).

Dsmi 25 (viflmiflunardsmi)

5- (3 - {[3- (3-chloro-phenyl) -propyl] -matansLitfóný1-amírió} -propyl) -þíófan-2-carboxamide) oxýisýra

Step A: Reaction time of 5 hours at 100 ° C. ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.71 (m, 1H), 7.24-7.15 (m, 3H), 7.03 (m, 1H), 6.83 (m, 1H), 3.19 (m, 4H) , 2.89 (t, 2H), 2.81 (s, 3H),

2.81 (t, 2H), 1.94 (m, 4H).

Dsmi 26

7 - {[5- (1-Hydroxy-hexý1) -thiophene-2-ýimatý1] -methanesulfonyl-amino} -haptansýra ¹1 H NMR (400 MHz, CDCl 3) δ 6.87 (d, 1H), 6.81 (d, 1H), 4.86 (t, 1H), 4.53 (s, 2H),

3.20 (t, 2H), 2.76 (s, 3H), 2.33 (t, 2H), 1.79 (m, 2H), 1.22-1.68 (m, 14H), O , 82-0.92 (m, 3H).

Dami 27

5- {3 - [(4-Butyl-benzyl) -methanesulfonyl-amino] -propyl} -thiophene-2-carboxylic acid

Step A: Reaction time of 4 hours at 100 ° C. ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.65 (s, 1H),

7.20 (m, 4H), 6.68 (s, 1H), 4.33 (s, 2H), 3.22 (m, 2H), 2.81 (m, 5H), 2.59 , 2H), 1.84 (m, 2H), 1.57 (m, 2H), 1.33 (m, 2H), 0.91 (m, 3H); MS 408 (M-1).

Example 28 (Reference Example)

Trans-7 - {[3- (3,5-Difluoro-phenyl) -allyl] -rT, etansútfónýt-amino} -heptanoic acid ¹1 H NMR (400 MHz, CDCl3)₃) δ 6.87 (m, 2H), 6.70 (m, 1H), 6.50 (d, 1H), 6.14-6.25 (m, 1H), 3.98 (d, 2H) , 3.20 (t, 2H), 2.85 (s, 3H), 2.32 (t, 2H), 1.61 (m, 4H), 1.35 (m, 4H).

Dami 29 (benchmark)

7 - {[3- (3-Chloro-fený1) -propyl] -methanesulfonyl-amino} -heptanoic acid

Step A: Reaction time of 24 hours at room temperature. ¹1 H NMR (400 MHz, CDCl 3) δ 7.04-7.30 (m, 4H), 3.15 (m, 4H), 2.80 (s, 3H), 2.62 (t, 2H), 2 , 35 (t, 2H), 1.90 (m, 2H), 1.50

1.67 (m, 4H), 1.25-1.40 (m, 4H).

Dami 30 (benchmark)

Tant-5- (3 - {[3- (3,5-Dichloro-phenyl) -allyl] -methanesulfonylamino} -propyl) -thiophene-2-carboxylic acid

Step A: Reaction time of 4 hours at 100 ° C. ¹1 H NMR (400 MHz, CD₃OD) δ 7.15-7.46 (m, 4H), 6.79 (s, 1H), 6.55 (d, 1H), 6.35 (m, 1H), 3.99 (d, 2H ), 3.29 (m, 2H), 2.91 (m, 5H), 1.99 (m, 2H); MS 447.7 (M-1).

Dami 31

7 - [(4-isobutyl-benzyl) -methanesulfonyl-amino] -heptanoic acid

Step A: Reaction time of 72 hours at room temperature. ¹1 H NMR (400 MHz, CDCl 3) δ

7.24 (d, 2H), 7.12 (d, 2H), 4.32 (s, 2H), 3.12 (t, 2H), 2.79 (s, 3H), 2.45 , 2H), 2.30 (t, 2H),

1.85 (m, 1H), 1.45-1.62 (m, 4H), 1.16-1.32 (m, 4H), 0.90 (d, 6H).

Dasmi 32 fviflmiflunardaemO

7 - {[3- (2-Chloro-phenyl) -propyl] -m0tansúlfónýi-amino) -heptanoic

Step A: Response time of 24 hours to room temperature. ¹1 H NMR (400 MHz, CDCl 3) δ 10 7.10-7.39 (m, 4H), 3.22 (t, 2H), 3.10 (t, 2H), 2.82 (s, 3H), 2.73 (t, 2H), 2.35 (t, 2H), 1.86

2.00 (m, 2H), 1.52-1.70 (m, 4H), 1.28-1.45 (m, 4H); MS 376 (M + 1).

DaBtni33 (symptomatic)

7 - [(2'-Chloro-biphenyl-4-ylmethyl) -methanesulfonyl-amino] -heptanoic acid

Step A: Reaction time of 24 hours with room temperature. 1 H NMR (400 MHz, CDCl3) δ 7.21-7.50 (m, 8H), 4.44 (s, 2H), 3.15-3.26 (m, 2H), 2.86 (s) , 3H), 2.27-2.38 (m, 2H), 1.48

1.68 (m, 5H), 1.20-1.38 (m, 4H).

Case 34 (Viflmiflundeami)

7 - [(4-Benzyl-benzyl) -methanesulfonyl-amino] -heptanoic acid 1H NMR (400 MHz, CDCl3) δ 7.13-7.30 (m, 9H), 4.32 (s, 2H), 3 , 98 (s, 2H), 3.12 (t,

2H), 2.90 (s, 3H), 2.30 (t, 2H), 2.45-2.60 (m, 4H), 1.16-1.32 (m, 4H).

Daami35 (reference example)

Trans- [3 - ({[3- (3,5-Dichloro-phenyl) -allýf] -metansútfónýf-amino) -methyl) -phenoxy] -acetic acid

Step A: Reaction time of 4 hours at 100 ° C. ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.30-7.22 (m, 3H), 7.14 (m, 1H), 6.98-6.82 (m, 3H), 6.34 (d, 1H), 6.09 m, 1H), 4.66 (s, 2H), 4.38 (s, 2H), 3.93 (d, 2H), 2.89 (s, 3H); MS 443.8 (M-1).

Example 36 (4 - {[(4-Butyl-benzyl) -methanesulfonylamino] -methyl} -phenoxy) -acetic acid

Step A: Reaction time of 4 hours at 100 ° C. ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.29-7.13 (m, 5H), 6.98-6.82 (m, 3H), 4.65 (s, 2H), 4.29 (s, 4H), 2.76 S, 3H), 2.58 (t, 2H), 1.57 (m, 2H), 1.33 (m, 2H), 0.91 (t, 3H); MS 405 (M +).

Example 37 (Reference Example)

3- (2 - {[2- (3,5-Dichloro-phenoxy) -atýl] -matansúlfónýl-amino} -ethoxy) -bansósýra

Step A: Reaction time of 4 hours at 100 ° C. ¹1 H NMR (400 MHz, CD₃OD) δ 7.60 (d, 1H), 7.51 (s, 1H), 7.34 (t, 1H), 7.11 (m, 1H), 6.95 (m, 1H) 83 (s, 1H), 4.20 (m, 4H), 3.73 (m, 4H), 3.01 (s, 3H); MS 447.8 (M-1).

Example 38 (Reference Example)

7 - {[2- (3-Chloro-phenoxy) -ethyl] -methanesulfonyl-amino} -heptanoic acid

Step A: Reaction time of 24 hours at 65 ° C. ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.19 (m, 1H), 6.94 (m, 1H), 6.86 (m, 1H), 6.76 (m, 1H), 4.09 (t, 2H), 3.59 (t, 2H), 3.25 (t, 2H), 2.89 (s, 3H), 2.33 (t, 2H), 1.63 (m, 4H), 1.35 (m, 4H) ; MS 395 (M + 18).

Case 39 (viamifiunariaemia)

7 - [(2'-Cyano-biphenyl-4-ylmethyl) -metansiilfónýi-amino] -heptanoic acid

Step A: Reaction time of 6 hours 90 ° C. 1 H NMR (400 MHz, CDCl3)₃) δ 7.75 (d, 1H), 7.65 (t, 1H), 7.40-7.60 (m, 6H), 4.20 (s, 2H), 3.20 (t, 2H) , 2.85 (s, 3H), 2.25 (t, 2H), 1.55 (m, 4H), 1.25 (m, 4H); MS 414 (M + 1).

Dami 40 (vifimifiunardami)

5- (3 - ((2- (3,5-Dfmatýi-phenoxy) -ethyl] -matansúlfónýlamínó} -propyl) -þíáfan-2-carboxylic acid

Step A: Reaction time of 72 hours at the military level. ¹1 H NMR (400 MHz, CDCl3)₃) δ

7.69 (d, 1H), 6.84 (d, 1H), 6.62 (s, 1H), 6.46 (s, 2H), 4.08 (t, 2H), 3.62 , 2H), 3.35 (t, 2H), 2.92 (m, 5H), 2.27 (s, 6H), 2.07 (m, 2H); MS 411 (M +).

Dami 41 (vifimifiunardami)

5- (3 - ((2- (3,5-Dimethoxy-phenoxy) -atýl] -m0tansútfónýl-amino} -propyl) -thiophene-2-carboxylic acid

Step A: Reaction time of 24 hours with room temperature. 1 H NMR (400 MHz, CDCl3)₃) δ

7.69 (d, 1H), 6.84 (d, 1H), 6.09 (m, 1H), 6.01 (m, 2H), 4.08 (t, 2H), 3.74 , 6H), 3.61 (t,

2H), 3.34 (t, 2H), 2.93 (t, 2H), 2.90 (s, 3H), 2.07 (m, 2H); MS 444 (M + 1).

Dami 42 (vifimifiunardami)

5- (3 - {[2- (3,5-Dichloro-phenoxy) -ethyl] -methanesulfony-amino) -propyl) -thiophene-2-carboxylic acid

Step A: Reaction time of 5 hours at 100 ° C. 1 H NMR (400 MHz, CDCl 3) δ 7.70 (d, 1H), 6.97 (m, 1H), 6.84 (d, 1H), 7.22 (d, 2H), 4.08 (t, 2H), 3.59 (t, 2H), 3.33 (t, 2H), 2.92 (t, 2H),

2.89 (s, 3H), 2.06 (m, 2H); MS 452 (M + 1).

Example 43 (vifimifiunardamiami) [3 - ({[3- (3-Chloro-phenyl) -propyl] -methanesulfonyl-amino) -methyl) -phenoxy] -acetic acid

Step A: Reaction time of 5 hours at 100 ° C. 1 H NMR (400 MHz, CDCl3)₃) δ 7.30-6.85 (m, 8H), 4.66 (s, 2H), 4.32 (s, 2H), 3.18 (t, 2H), 2.82 (s, 3H) , 2.49 (t, 2H), 1.76 (m, 2H); MS 412 (M +).

Example 44 (vifimifiunardamiami) [3 - (((2- (3,5-Dichloro-phenoxy) -ethyl] -methanesulfonylamino) -methyl) -phenoxy] -acetic acid

Step A: Reaction time of 5 hours at 100 ° C. 1 H NMR (400 MHz, CD 3 OD) δ 7.24 (t,

1H), 6.98 (m, 3H), 6.84 (m, 1H), 6.78 (d, 2H), 4.60 (s, 2H), 4.44 (s, 2H) 99 (t, 2H), 3.57 (t, 2H), 2.96 (s, 3H); MS 448 (M +).

Dami 45 (vifimifiunardami)

Trans-7 - {[3- (3-Hydroxy-phenyl) -allyl] -methanesulfonyl-amino) -heptanoic acid

Step A: Heck clutch

Trans-Ethyl-7-f [3- (3-Hydroxy-phenyl) -allyl -methanesulfonyl-amino-heDtanóat

To a solution of 7- (allyl-methanesulfonyl-aminoheptanoic acid ethyl ester (250 mg, 0.86 mmol), 1-acetylloxy-3-iodobenzene (225 mg, 0.86 mmol), and triethylamine (139 mL, 1 mmol) in DMF (3 mL) was added palladium acetate (25 mg). The reaction mixture was heated to 80 ° C under nitrogen for 24 h. The mixture was cooled to room temperature and sodium thiosulfate in water and CH2 Cl2 was added. The aqueous solution was extracted out with CH2Cl2 (2x) and the combined organic login was washed with water (1x) and brine (1x). The organic solution was dried with MgSO₄, sifted, and concentrated in a vacuum. The product was purified by chromatography (hexane in 25% EtOAc / hexane) to give the title compound in step A (95 mg).¹1 H NMR (CDCl3)₃ 400 MHz) δ 6.88-7.34 (m, 4H), 6.53-6.60 (m, 1H), 6.13-6.20 (m, 1H), 4.10 (q, 2H ), 3.95 (d, 2H), 3.17-3.21 (m, 2H), 2.85 (s, 3H), 2.24-2.31 (m, 2H), 2.31 s, 3H), 1.56-1.62 (m, 4H), 1.27-1.33 (m, 4H), 1.23 (t, 3H).

Step B: Esther hydrolysis

Trans-7-fí3- (3-Hydroxy-fanvh-allvl1 -methanesulfonyl-amino-1 -heptanoic acid,

In an analogous manner to the method described in Step B of Example 1, the title compound of Step A was hydrolysed to give the title compound (53 mg). ¹1 H NMR (400 MHz, CDCl 3) δ 7.14-7.25 (m, 1H), 6.81-8.89 (m, 2H), 6.74-6.77 (m, 1H) 50 (d, 1H), 6.08-6.15 (m, 1H), 3.95 (d, 2H), 3.16-3.20 (m, 2H), 2.85 (s, 3H) , 2.26-2.33 (m, 2H), 1.50-1.65 (m, 4H), 1.20-1.38 (m, 4H); MS 353.9 (M-1).

Examples 46-50

DSM 46-50 were produced from auxiliary starting materials in a manner similar to that of 45.

Dami46 ​​(hypersensitivity)

Trans-7 - ([3- (2-Hydroxy-phenyl) -allyl] -metansúltónýl-amino} -heptanoic acid ¹1 H NMR (400 MHz, CDCl 3) δ 6.49 (d, 1H), 6.12 (m, 1H), 3.94 (d, 2H), 3.18 (t, 2H), 2.85 , 3H), 2.31 (t, 2H), 1.58 (m, 4H), 1.32 (m, 4H); MS 353.9 (M-1).

Dami 47 (benchmark)

Trans-7 - {[3- (3-Hydroxymethyl-phenyl) -allyl] -methanesulfonyl-amino} -heptanoic acid ¹1 H NMR (400 MHz, CDCl3 δ 7.19-7.41 (m, 4H), 6.58 (d, 1H), 6.13-6.25 (m, 1H),

4.70 (s, 2H), 3.92-4.02 (m, 2H), 3.15-3.25 (m, 2H), 2.85 (s, 3H), 2.29 (t, 2H), 1.52-1.68 (m, 4H), 1.18-1.39 (m, 4H); MS 368 (M-1).

Dami48 (reference example)

Trans-7 - {[3- (3,5-Dichloro-phenyl) -allyl] -methanesulfonyl-amino} -heptanoic acid 1 H NMR (400 MHz, CDCl3) δ 7.25 (m, 3H), 4.80 d, 1H), 6.15-6.28 (m, 1H), 3.98 (m, 2H), 3.22 (t, 2H), 2.87 (s, 3H), 2.35 , 2H), 1.48-1.72 (m, 4H), 1.19-1.42 (m, 4H).

Example 49 (reaction)

Tann-7 - {[3- (3,5-Bis-trifluoromethyl-phenyl) -allyl] -methanesulfonylamino} -heptanoic acid 1 H NMR (400 MHz, CDCl3₃) Δ 7.77 (m, 3H), 6.66 (m, 1H), 6.36 (m, 1H), 4.02 (d,

2H), 3.24 (t, 2H), 2.89 (s, 3H), 2.33 (t, 2H), 1.62 (m, 4H), 1.35 (m, 4H).

Example 50

Tann-7- [Methanesulfonyl- (4-phenyl-but-3-enyl) -amino] -heptanoic acid ¹1 H NMR (400 MHz, CDCl3)₃) Δ 7.23 (m, 5H), 6.46 (d, 1H), 6.13 (m, 1H), 3.31 (t, 2H), 3.19 (t, 2H), 2.83 (s, 3H), 2.52 (m, 2H), 2.34 (m, 2H), 1.62 (m, 4H), 1.35 (m, 4H); MS 353 (M +).

Dami 51 (Immune Disease)

7 - {[3- (3,5-Bis-tríflúormatýl-phenyl) -propyl] -methanesulfonyl-amino} -haptansýra

hydrogenation

A solution of trans-7 - {[3- (3,5-bis-trifluoromethyl-phenyl) -allyl] -methanesulfonylamino} -heptanoic acid (210 mg, 0.44 mmol) in MeOH (10 mL) was added 10% Pd / carbon (200 mg). The mixture was placed on a Pan hydrogenator 50 psi and was watered for 120 hours. The reaction was filtered through selit with the aid of MeOH and the solvent was absent in air. Purification by ring chromatography (2 mm spin plate, 20: 80: 0.1 v / v / v EtOAc / hexane / AcOH) gave the title compound (190 mg). 1 H NMR (CDCl 3 400 MHz) δ 7.69 (s, 1H), 7.63 (s, 2H), 3.20 (t, 2H), 3.14 (t, 2H), 2.81 , 5H), 2.28 (m, 2H), 1.94 (m, 2H), 1.32 (m, 4H); MS 495 (M + 18).

Dami 52-54

Examples 52-54 were prepared from the corresponding starting materials analogously to dami 51.

Dami 52 (benchmark)

7- [Methanesulfonylamino # - (3-phenyl-propyl) -amino] -heptanoic acid ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.10-7.30 (m, 5H), 3.18 (t, 2H), 3.13 (t, 2H), 2.80 (s, 3H), 2.63 (t, 2H) , 2.34 (t, 2H), 1.92 (m, 2H), 1.48-2.72 (m, 4H), 1.09-1.42 (m, 4H).

Example 53 (Comparative Example)

7- [Methanesulfon # - (3-m-tól # -prop #) -amino] -heptanoic acid 1H NMR (400 MHz, CDCl3) δ 6.94-7.21 (m, 4H), 3.18 (t , 2H), 3.13 (t, 2H), 2.80 (s,

3H), 2.59 (t, 2H), 2.34 (t, 2H), 2.32 (s, 3H), 2.85-2.97 (m, 2H), 2.50-2.68 (m, 5H), 1.23-1.40 (m, 5H).

Example 54 (Comparative Example) 7 - {[3- (3,5-Difluoro-phenyl) -propyl] -methanesulfonamide -amino) -heptanoic acid ¹1 H NMR (400 MHz, CDCl 3) δ 6.60-6.78 (m, 3H), 3.12 (m, 4H), 2.82 (s, 3H), 2.64 (t, 2H), 2 , 37 (1.2H), 1.92 (m, 2H), 1.50-1.70 (m, 4H), 1.18-1.42 (m, 4H).

Dami55 (benchmark)

7 - {[4- (1-Hydroxy-3-phenyl-propyl) -benzyl] -matansúlfónýi-amino} -heptanoic acid

Step A: Grianard disappeared

E-7- [4- (1-Hydroxy) -3-phenyl-pyridyl) -benzyl] methanesulfanylamino} -heptanate,

A solution of ethyl 7 - [(4-formyl-benzyl) -methanesulfonyl-amino] -heptanoate (200 mg, 0.54 mmol) in CHgCl₂ (2.5 mL) was cooled to 10 ° C. Phenomagnesium chloride (0.6 mL, 1M in THF, 0.6 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 24 h. Water and HCl (1N) were extracted and the aqueous solution was extracted with CH2Cl2. The solution was washed with water (1x) followed by brine (1x), dried over MgSO₄, filtered, and concentrated in a vacuum. The product was purified by flash chromatography (10% EtOAc / hex at 40%

EtOAc / hex) to give the title compound in Step A (40 mg). ¹H NMR (400 MHz, CDCl3) δ 7.95 (d, 1H), 7.45 (d, 1H), 7.13-7.40 (m, 7H), 4.65-4.73 (m, 1H), 4.32-4.46 (m, 2H), 4.11 (q, 2H), 3.25-3.35 (m, 1H), 3.00-3.22 (m, 2H) , 2.83 (s, 3H), 2.60-2.81 (m, 1H), 1.98-2.34 (m, 4H), 1.15-1.70 (m, 12H); MS 493 (M + 18).

Step B: Esther hydrolysis

7-Π4- (1-ΗνάΓθχν-3-ί6ηνΙ-ΡΓ0ρν8-όβη5νΙίπ6ΐΒη5ύΙίάηνΙ-3ΠΊίηό) -ήθρ {3η5νΓ3.

In an analogous manner to the catalysts described in Step B of Example 1, the title compound of Step A was hydrolysed to give the title compound (11 mg). ¹1 H NMR (400 MHz,

CDCl3) δ 7.93 (d, 1H), 7.48 (d, 1H), 7.15-7.38 (m, 7H), 4.31-4.50 (m, 2H), 3.02 -3.35 (m, 4H), 2.83 (s, 3H), 2.60-2.80 (m, 1H), 1.96-2.33 (m, 4H), 1.12-1 , 61 (m, 8H).

Examples 56-58

Examples 56-58 were prepared from the appropriate starting materials in an analogous manner to Example 55.

Dsmi56

7 - {[4- (1-Hydroxy-pentyl) -benzyl] -methanesulfonyl-amino} -heptanoic acid 1 H NMR (400 MHz, CDCl3) δ 7.35-7.25 (m, 4H), 4.66 t, 1H), 4.34 (s, 2H), 3.15 (t, 2H), 2.82 (s, 3H), 2.25 (t, 2H), 1.85-1.61 , 2H), 1.55-1.12 (m, 13H), 0.90-0.82 (m, 3H); MS 417 (399 + 18).

CamÍSZ (Reference Example)

7 - {[4- (1-Hydroxy-2-phenyl-ethyl) -benzyl] -methanesulfonyl-amino} -heptanoic acid 1 H NMR (400 MHz, CDCl 3) δ 7.15-7.35 (m, 9H), 4.85-4.97 (m, 1H), 4.35 (s, 2H),

3.15 (t, 2H), 2.98-3.05 (m, 2H), 2.82 (s, 3H), 2.28 (t, 2H), 1.40-1.60 (m, 4H), 1.14-1.32 (m, 4H); MS 451 (M + 18).

Example 58 (standard immunodeficiency)

7 - {[2 '- (1-Hydroxy-hexyl) -biphenyl-4-ylmethyl] -methanesulfonyl-amino} -heptanoic acid 1 H NMR (CDCl3 400 MHz) δ 7.55-7.62 (m, 1H), 7.15-7.45 (m, 7H), 4.74 (t, 1H), 4.41 (s, 2H), 3.12-3.28 (m, 2H), 2.88 (s, 3H), 2.30 (t, 3H), 1.43-1.75 (m, 6H), 1.05-1.32 (m,

11H), 0.80 (t, 3H); MS 507 (M + 18).

Dsmi 59 (Reference Example)

Trans-N- [3- (3,5-dichloro-phenyl) -allyl] -N- [6- (1H-tetrazol-5-yl) -hexyl] -methanesulfonamide

Step A: Alkvlerina

Tert-N- (6-Cyano-hexyl) -N- [3- (3,5-dichloro-phenyl) -methyl] -methanesulfonamide

In analogy to the fragment described in Step A of Example 1, trans-N- [3- (3,5-dichloro-phenyl) -allyl] methanesulfonamide (500 mg, 2.45 mmole) was alkylated with 7-bromoheptannitrile (781 mg, 2.94 mmol) at room temperature over 24 h to give the title compound in Step A (760 mg). ¹1 H NMR (CDCl3)₃ 400 MHz) δ 7.26 (m, 3H), 6.49 (d, 1H), 6.22 (m, 1H), 3.98 (m, 2H), 3.22 (t, 2H), 2 , 88 (s, 3H), 2.36 (t, 2H), 1.68-1.35 (m, 8H).

Step B: Tetrasol Mutation

Tert-N - [3- (3,5-Dichloro-phenyl-allyl-N- [6- (1H-tetrazol-5-yl) -hexyl} methanesulfonamide

Trimethylsilyl chloride (0.136 mL, 1.026 mmol) and dibutyl pentoxide (38 mg, 0.15 mmol) were dissolved in a solution of trans-N- (6-cyanohexyl) -N- [3- (3_l5-dichlorophenyl) -allyl] methanesulfonamide (59A) (199 mg, 0.52 mmol) in trifluoroethane (4 mL). There was a heat reversal over the surface. The reaction was diluted with CH₂Cl₂ and the solution was washed with HCI (1N, 1x), water (lx), and brine (1x). The organic solution was dried over MgSO₄, filtered, and compacted into the ceiling.

The product was purified by chromatography (CH2Cl2, 5% MeOH / CH2Cl2) to give title compound (120mg). ¹1 H NMR (CDCl 3 400 MHz) δ 7.26 (m, 3H), 6.50 (d, 1H), 6.22 (m, 1H), 4.00 (m, 2H), 3.23 (t, 2H), 3.02 (t, 2H), 2.90 (s, 3H), 1.83 (t, 2H), 1.62 (t, 2H), 1.38 (m, 4H); MS132 (M +).

Dsmi 60-61

Dsmi 60-61 were produced from auxiliary starting materials in an analogous manner to 59.

Dsmi 60

N- (4-Butyl-benzyl) -N- [6- (2H-tetrasúl · 5-yl) -hθxýl] -metansúlfónamíβ ¹1 H NMR (CDCl 3 400 MHz) δ 7.26-7.17 (m, 4H), 4.36 (s, 2H), 3.17 (t, 2H), 3.00 (t,

2H), 2.81 (s, 3H), 2.59 (t, 2H), 1.88 (t, 2H), 1.54 (m, 6H), 1.15 (m, 4H) 93 (t, 3H); MS

394 (M + 1).

Dsmi 61 (Viflmiflunardsmi)

N- [2- (3,5-Dichloro-phenoxy) -ethyl] -N- [6- (1H-tetrazol-5-yl) -hexyl] -methanesulfonamide 1H NMR (CDCl3 400 MHz) δ 6.99 m, 2H), 6.76 (m, 2H), 4.10 (t, 2H), 3.61 (t, 2H), 3.25 (t, 2H), 3.02 (t, 2H), 2.96 (s, 3H), 1.84 (m, 2H), 1.64 (m, 2H), 1.40 (m, 4H); MS 436 (M +).

Dami 62 (benchmark)

7 - [(2'-Hydroxymethyl-biphen ^ -4-ylmethyl) -metansijlfónýl-amínóJ acid

Step A: Reduction

Ethyl 7- (2'-hydroxymethyl-biphenyl-4-ylmethyl) -methanesulfonyl-amino] -hexanoate

Sodium borohydride (37 mg, 0.95 mmol) was added to a solution of ethyl 7 - {[2 '- (1-phenylmethyl) -biphenyl-4-yl) methyl] -heptanoate (415 mg, 0.95 mmol ) in MeOH (4 mL) at -78 ° C. The reaction was stirred at -20 ° C for 1.5 h and water was added. The reaction was diluted with CH₂Cl2 and the organic solution were washed with water (1x) and brine (1x). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography (10% EtOAc / hexane in 50% EtOAc / hexane) to give the title compound in Step A (397 mg). 1 H NMR (400 MHz, CDCl3 δ 7.55-7.62 (m, 1H), 7.23-7.45 (m, 7H), 4.62 (s, 2H), 4.42 (s,

2H), 4.09 (q, 2H), 3.20 (t, 2H), 2.89 (s, 3H), 2.26 (t, 2H), 1.19-1.70 (m, 11H ); MS 465 (M + 18).

Step B: Water spray

7-ίί2' ^ Η-ΓθχντηΒΐνΙώι1θηνΙ-4-νΙΐ'ηβ {νΙ) -ηΐ6ΐ3η3ύΙ &lt;όην1-8Γηίπό1-ΙΐΒΡΐΗη3νΓ3,

In an analogous manner to the procedure described in Step B of Example 1, the title compound of Step A was hydrolysed to give the title compound (300 mg). 1 H NMR (400 MHz, CDCl 3) δ 7.51-7.59 (m, 1H), 7.22-7.43 (m, 7H), 4.60 (s, 2H), 4.42 , 2H), 3.20 (t,

2H), 2.90 (s, 3H), 2.30 (t, 2H), 1.45-1.62 (m, 4H), 1.20-1.30 (m, 4H); MS 437 (M + 18).

Dami 63 (benchmark)

7- (Biphenyl-4-ylmethyl-methanesulfonyl-amino) -heptanoic

Step A: Suzuki clutch

Etöl7- (Bffenfl-4-ylmethyl-raetansúlf6nfl amín6) -heptanoate

Tetrakis (triphenylphosphine) palladium (0) (102 mg, 0.09 mmol), NaaCO₃ in aqueous solution (0.9 mL, 1M), and phenyl boronic acid (216 mg, 1.77 mmol) was added to a solution of ethyl 7 - {[4-iodobenzyl] methanesulfonylamino-haptanoate (415 mg, 89 mmol) in toluene (37 mL) and EtOH (7 mL). The reaction mixture was heated to reflux for 3 hours. The solution was diluted with EtOAc and washed with water (2x) followed by brine (1x). The organic solution was dried over MgSO₄, filtered, and concentrated in vacuo. Purification by ring chromatography (10% EtOAc / hexane in 30% EtOAc / hexane) gave the title compound in Step A (298 mg).¹1 H NMR (400 MHz, CDCl 3) δ 7.62-7.30 (m, 4H), 4.41 (s, 2H), 4.12 (q, 2H), 3.20 (t, 2H), 2 , 82 (s, 3H), 2.23 (t, 3H), 1.58 (m, 4H), 1.35 (m, 7H); MS 418.3 (M +).

Step B: Water spray

7- (Bífenfl-4-ylmethyl-methanesulfonylamino-amino) -heptanoic acid

In an analogous manner to the solvents described in Step B of Example 1, the title compound of step A (298 mg, 0.71 mmol) hydrolysis to give titled compound (200 mg). ¹1 H NMR (400 MHz, CDCl 3) δ 7.62-7.30 (m, 9H), 4.42 (s, 2H), 3.20 (t, 2H), 2.87 (s, 3H), 2 , 30 (t, 2H), 1.58 (m, 4H); MS 407 (M + 18).

PaBmi 64 fviflmiflunardsmii

7 - [(2'-Formyl-biphenyl-4-ylmethyl) -methanesulfonyl-amino] -heptanoic acid

Step A: Suzuki Cowboy

Ethyl 7 - {[2 '- (1-formyl-biphenyl-4-ylmethyl)} -heptanoate

Tetrakis (triphenylphosphine) palladium (0) (85 mg, 0.07 mmol), NasCO_a (0.8 mL, 1M) and 2-formylbenzene boronic acid were added to a solution of ethyl 7 - {[4-iodobenzyl] methanesulfonyl-amino} -heptanoate (345 mg, 0.74 mmol) in toluene (30 mL ) and EtOH (6 mL). After heating of a reversible flask For 3 hours, the solution was diluted with EtOAc and washed with water (2x) followed by saline (1x). The solution was dried over MgSO4, filtered and concentrated in vacuo. The product was purified by column chromatography to give ethyl 7 - {[2 '- (1-phenylmethyl) -biphenyl-4-ylmethyl]} -heptanoate (320 mL). 1 H NMR (400 MHz, CDCl3)₃) δ 9.95 (s, 1H), 8.05 (d, 1H), 7.35-7.70 (m, 7H), 4.46 (s, 2H), 4.10 (q, 2H) , 3.19-3.28 (m, 2H), 2.90 (s, 3H), 2.28 (1.2H), 1.50-1.62 (m, 5H), 1.201.35 (m , 6H); MS 463 (M + 18).

Step B: Water spray

7-ft2'-Formyl-bffemil-4-methanesulfonyl-Vimetvli-amín61 -heptanoic acid

In an analogous manner to the procedure described in Step B of Example 1, ethyl 7 - {[2 '- (1-formyl) -b (phenyl-4-ylmethyl)} heptanoate (75 mg, 0.172 mmol) was hydrolysed to give give the title compound (55 mg). ¹1 H NMR (400 MHz, CDCl3)₃) Δ 9.93 (s, 1H), 8.04 (d, 1H), 7.63 (m, 1H), 7.52-7.37 (m, 6H), 4.43 (s, 2H) , 3.22 (t, 2H), 2.91 (s, 3H), 2.32 (t, 2H), 1.56 (m, 4H), 1.30 (m, 4H).

Example 65 (reference matrix)

7 - ([4- (3-Hýdraxýnietýl-thiophen-2-yl) -benzyl] -methanesulfonyl-amino) -heptanoic

Skret A: Suzuki koólaun

Ethyl 7- [4- (3-formyl-biphenyl-2-yl) benzyl] methanesulfonyl-amino} -heptanoate

Tetrakis (triphenylphosphine) palladium (0) (91 mg, 0.08 mmol), Na2 CO₃ (0.87 mL, 1M), and

5-formyl-2-thiophenoboronic acid (247 mg, 1.58 mmol) was added to a solution of ethyl 7 - {[4-iodobenzyl] methanesulfonyl-amine heptanoate (371 mg, 0.79 mmol) in toluene mL) and EtOH (6.5 mL). The reaction mixture was heated to reflux for 3 h. The solution was diluted with EtOAc and the organic solution was washed with water (2x) followed by sachet (1x). The solution was dried over MgSO₄. sfufi, and cosmopolitanism in the air. The product was purified by chromatography (25% EtOAc / hexane in 50% EtOAc / hexane) to afford the title compound In Step A (75 mg). 1 H NMR (400 MHz, CDCl3)₃) Δ 9.89 (s, 1H), 7.44-7.60 (m, 5H), 7.21-7.31 (m, 1H), 4.45 (s, 2H), 4.10 q, 2H), 3.20 (t, 2H), 2.90 (s, 3H), 2.25 (t, 3H), 1.58 (m, 4H), 1.35 (m, 7H); MS 452 (M +).

Step B: Reduction

Ethyl 7 - [(4- (3-Hydroxymethyl-biphen-2-yl) -benzenyl-methanesulfonyl-amino) -heptane

Sodium borohydride (6.0 mg, 0.16 mmol) was added to a solution of the title compound of Step A (70 mg, 0.16 mmol) in MeOH (1 mL) at -76 ° C. The reaction was at -20 ° C for 2 hours and water was bumped out in. The reaction was diluted with CH₂Cl₂ and the solution was the pvagin with water (1x) and satis (1x). The solution was a slurry over MgSO₄, sifting, and synergy In the air vent for grandpa give 65B (62 mg) which was used without further purification. 1 H NMR (400 MHz,

CDCl 3) δ 7.15-7.52 (m, 6H), 4.68 (s, 2H), 4.40 (s, 2H), 4.09 (q, 2H), 3.19 (t, 2H) ), 2.86 (s, 3H), 2.24 (t, 2H), 1.82 (bs, 1H), 1.18-1.60 (m, 11H).

Step C: Water spray

7-114- (3-Hydroxymethyl-biphenyl-2-yl) -benzyl] -methanesulfonyl-amino-heptanoic acid

In analogy to the method described in Step B of Example 1, the triplicate compound was removed from Step B (60 mg, 0.13 mmol) to give the title compound (29 mg). ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.15-7.52 (m, 7H), 4.68 (s, 2H), 4.40 (s, 2H), 3.19 (t, 2H), 2.86 (s, 3H) , 2.30 (t, 2H), 1.52 (m, 4H), 1.33 (m, 4H); MS 443 (M + 18).

DamLSS (reference example)

7 - [(4-Hexanoyl-benzyl) -methanesulfonyl-amino] -h0ptansýra

A solution of 7 - ((4- (1-hydroxy-hexyl) -benzyl] methanesulfonyl-amino} -heptane synthesis (88 mg, 0.21 mmol) and Dess-Martin reagent (145 mg, 0.34 mmol) in CH₂Cl₂ (2 mL) was stirred at room temperature for 72 h. Sodium thiosulfate solution was added and the reaction mixture was stirred until all solids were dissolved. The aqueous layer was extracted with CH2Cl2 (2x), and the organic solution was dried over MgSO4₄, filtered, and concentrated in vacuo. Purification by ring chromatography (CH2Cl2) in 5% MeOH / CH₂Cl₂) gave the title compound (93.6 mg). ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.92 (d, 2H), 7.43 (d, 2H), 4.40 (s, 2H), 3.15 (t, 2H), 2.95 (t, 2H), 2.85 (m, 2H), 1.50 (m, 4H), 1.15-1.40 (m, 8H), 0.85- 0.95 (m, 3H).

Example 67 (4- (2 - [(4-Butyl-benzyl) -methanesulfonylamino] -acetyl} -phenyl) -acetic acid

Step A: Alkvlerina (4- {2 - [(4-Butyloxybenzyl)^,N-sulfonyl-amino] ethyl} -phenyl acetic acid methyl ester

A mixture of [4- [2-methanesulfonylamino-ethyl] -phenyl] -acetic acid methyl ester (38 mg, 0.14 mmol), 1-bromomethyl-4-butylbenzene (35 mg, 0.15 mmol), K 25 mg, 0.182 mmol) and acetonitrile was heated at reflux for 1 h. Aqueous solution of HCl (2 mL, 1 N) and EtOAc (30 mL) was added to the reaction. The organic solution was dried with MgSO₄, filtered, and concentrated in vacuo. The product was purified by flash chromatography (30% EtOAc / hexane) to give the title compound in step A.¹1 H NMR (400 MHz, CDCl 3) δ 7.28-7.05 (m, 8H), 4.37 (s, 2H), 3.65 (s, 3H), 3.58 (s, 2H), 3 , 26 (t, 2H), 2.77 (t, 2H), 2.69 (s, 3H), 2.60 (t, 2H), 1.59 (m, 2H), 1.37 (m, 2H), 0.94 (t, 3H).

Step B: Hydrolysis of 4- {2 - [(4-Butyl-benzyl) -methanesulfonyl-amino] -ethyl} -phenyl] -acetic acid

In an analogous manner to Step B of Example 1, the title compound of Step A was hydrolysed to give the title compound. ¹1 H NMR (400 MHz, CDCl3)₃) 7.15 (m, 8H), 4.35 (s, 2H), 3.66 (s, 2H), 3.35 (t, 2H), 2.75 (t, 2H), 2.65 s, 3H), 2.59 (m, 2H), 1.58 (m, 2H), 1.34 (m, 2H), 0.91 (t, 3H).

EXAMPLE 68

7 - [[4- (1-Hydroxy-hexyl) -benzyl] - (propane-1-sulfonyl) -amino] -heptanoic acid

Step A: Reducing amines

7-Methyl-N4-I 1-hydroxy-hexyl) -bBnsvn-aniline) -heptanoate

A solution of 7-aminoheptane methyl ester hydrochloric acid (1.57 g, 8.02 mmol), 4- (1-15 hydroxy-hexyl) benzaldehyde (1.98 g, 9.63 mmol), sodium acetate (1.32 g, 16.05 mmol) and NaBH₃CN (605 mg, 9.63 mmol) in MeOH (50 mL) was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo and diluted with EtOAc. The solution was washed in NaHCOs (1x) rod, water (1x), and brine (1x). The solution was dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography (1% MeOH / CHCl₃ f

5% MeOH / CHCl3) to give 7-methyl - {[4- (1-hydroxy-hexyl) -benzyl] -amino) -heptanoate (1.28

9) Step B: Amide evaluation

7 - [(4- (1-Hydroxy-hexyl) -benzyl] -propane-1-sulfonyl-amino] -heptanoic acid methyl ester

A solution of 7-methyl - {[4- (1-hydroxy-hexyl) -benzyl] -amino} -heptanoate (82.2 mg, 0.235 mmol), 1-propanesulfonyl chloride (29.1 μL, 0.259 mmol) and 4 -metimimorpholine (28.5 μL, 0.259 mmol) in CH₂CI2 (10 mL) was stirred at room temperature for 24 h. More of 1-propanesulfonyl chloride (14.5 μL) and 4-methylmorpholine (14.3 μL) were added, and the reaction was continued for 5 days. The aqueous solution was washed with 5.5% HCl, water, aqueous NaHCO₃, and salt peel. The solution was dried (MgSO4)₄), filtered and concentrated to yield 7 - [[4- (1-hydroxy-hexyl) -benzyl] - (propane-1-sulfonyl) -amino] -heptanoic acid methyl ester used in the next step without further purification.

gkrgtfrVatrW

7- [4- (1-Hydroxy-hexyl) -benzyl] -propano-1-sulfonyl] amino] heptanoic acid

In a similar manner to the coagulants described in Step B of Example 1, 7 - [[4- (1-hydroxy-hexyl) -bansyl] - (propane-1-sulfonyl) -amino] -heptanoic acid methyl ester was hydrolyzed at room temperature at 24 hours to give the title compound (43 mg) as an oil. ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.35-7.22 (d, 2H), 7.11-7.00 (d, 2H), 4.61 (q, 1H), 4.50 (s, 2H), 3.31 t, 2H), 2.402.20 (m, 4H), 2.81-1.43 (m, 10H), 1.41-1.22 (m, 8H), 1.31-0.81 (m, 6H); MS 440 (M-1).

EXAMPLE 69

Example 69 was synthesized from a directing starting material analogously to Example 68.

Example 69 (Alternative Content)

7- [Methanesulfonyl- (4-phenyl-thiophen-2-ylmethyl) -amino] -heptanoic acid 1H NMR (400 MHz, CDCl3) δ 7.55 (d, 1H), 7.40-7.20 (m, 6H), 4.65 (s, 2H), 3.20 (t, 2H), 3.02 (s, 3H), 2.25 (t, 2H), 1.60 (m, 4H) 25 (m, 4H); MS 394 (M-1).

Dami70 (case study)

7 - {[4- (1-Hydroxy-hexyl) -bensýf] -propionyl-amino} -heptanoic acid

Step A: Amalgamation

7-Methyl - ([4- (1-hydroxy-hexyl-benzyl) -thio] -amino] -heptanoate

A solution of 7-methyl-{[4- (1-hydroxy-hexyl) -benzyl] -amino} -heptanoate (314 mg, 0.90 mmol), propionic acid (73.02 mg, 0.99 mmol) and DCC 203.6 mg, 0.99 mmol) in CH₂Cl₂ (20 mL) was stirred at room temperature for 24 h. The solids were removed by filtration and the surface was collected in the air. EtOAc was excreted in the residue and the substances that did not dissolve were removed by filtration. The organic solution was washed successively with aqueous HCl (5.5%, 1x), water (1x), NaHCOa (1x) aqueous solution, and brine (1x). The organic solution was dried (MgSO4)₄), and evaporation to give 7-methyl - {[4- (1-hydroxy-hexyl) -benzyl] -propionyl-amino} -heptanoate (403 mg) as an oil without further purification.

Step B: Water rot

In a similar manner to the catalysts described in Step B of Example 1, the 7-methyl - {[4- (1-hydroxy-hexyl) -benzyl] -propionylamino} -heptanoate (365 mg, 0.90 mmol) was hydrolyzed a ventilator

7- [4- (1-Hydroxy-hexyl) benzyl] -propionyl-amino] heptanoic acid at room temperature for 24 h to give the title compound (254 mg) as an oil. 1 H NMR (300 MHz, CDCl3₃) Δ 7.33-7.11 (m, 4H), 4.43-4.66 (m, 3H), 3.33 (t, 1H), 3.17 (t, 1H), 2,25- 2.47 (m, 4H), 1.02-1.87 (m, 19H), 0.86 (m, 3H); MS 391.4 (M +).

Dami 71-72

Dummies 71-72 were manufactured from video-based starting materials in the elevated position at Dami 70.

Dami 71 (vidmidunardami

7- {Butyryl- [4- (1-hydroxy-hexyl) -benzyl] -amino) -heptanoic acid 1 H NMR (300 MHz, CDCl3₃) Δ 7.32-7.21 (d, 2H), 7.15-7.02 (d, 2H), 4.60 (q, 1H), 4.40 (s, 2H), 3.22 (t, 2H), 2.70 (t, 2H), 2.41-2.20 (t, 2H), 1.85-1.55 (m, 10H), 1.45-1.22 (m ,

BH), 1.01-0.85 (m, 6H); MS 404 (M-1).

Dami 72

7 - [(4-Butyl-benzyl) -propionyl-amino] -heptanoic acid 1H NMR (300 MHz, CDCl3₃) Δ 7.32-7.21 (d, 2H), 7.10-7.00 (d, 2H), 4.50 (s, 2H), 3.30 (t, 2H), 2.50 m, 2H), 2.32 (m, 4H), 1.50 (m, 4H), 1.22 (m, 8H), 1.20 (t, 3H), 0.95 (t, 3H); MS 348 (M +).

Dami 73 (vidmidunardami)

7- [Metansútfónýl- (4-fenatýi-benzyl) -amínóJ-haptansýra

Step A: Alkflerinq

Trans-7-methanesulfonyl- (4-trifluoromethyl) amino] -heptanoic acid ethyl ester

In the manner of the procedure described in Step A of Example 1, ethyl-7-amino-heptanoate (502 mg, 2 mmol) alkylated food trans-4-chloromethylstilbine (502.7 mg, 2.2 mmol) at room temperature every 24 hours trans-7- [methanesulfonyl- (4-styryl-benzyl) -amino] -heptanoic acid ethyl ester (0.90 g). 1 H NMR (400 MHz, CDCl 3) δ 7.50 (m, 4H), 7.40-7.20 (m, 5H), 7.10 (m, 2H), 4.36 (s, 2H), 4.09 (q, 2H), 3.15 (t, 2H), 2.81 (s, 3H), 2.22 (t, 2H), 1.54 (m, 4H), 1.15-1 , 32 (m, 7H).

Step B; hydrogenation

7-methanesulfonyl- (4-phenethyl-benzyl) -amino] -heptanoic acid ester

A solution of trans-7- [methanesulfonyl- (4-styryl-benzyl) -amino] -heptanoic acid ethyl ester (0.60 g) in MeOH (5 mL) and EtOAc (50 mL) was added to 10% Pd / carbon (0.2 g). The reaction mixture was placed on a Parr hydrogenator and hydrogenated for 20 h at 50 psi. The reaction mixture was filtered through celite and concentrated in vacuo to give 7- [methanesulfonyl- (4-phenethyl-benzyl) -amino] -heptanoic acid ethyl ester (0.60 g).¹1 H NMR (400 MHz, CDCl3)₃) δ 7.30-7.10 (m, 9H), 4.32 (s, 2H), 4.10 (q, 2H), 3.12 (t, 2H), 2.90 (s, 4H) , 2.79 (s, 3H), 2.25 (t, 2H), 1.60-1.45 (m, 4H), 1.30-1.19 (m, 7H).

Step C: Esther hydrolysis

7 iMetansúlfónvl-4-phenethyl-berisvB-amino-1 -heptanoic acid

In an analogous manner to the method described in Step B of Example 1, 7- [methanesulfonyl- (4-phenethyl-benzyl) -amino] -heptanoic acid ethyl ester (600 mg) was added to give the title compound. ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.30-7.10 (m, 9H), 4.32 (s, 2H), 3.13 (t, 2H), 2.91 (s, 4H), 2.79 (s, 3H) , 2.30 (t, 2H), 1.61-1.47 (m, 4H), 1.32-1.18 (m, 4H).

Dasmi 74 (Violence Disorder)

Trans-4- {2- [Methanesulfonyl- (3-phenyl-allyl) -amino] -ethoxy} -benzoic acid

Step A: Alkvlerina

Trans -4 - [(2-Methanesulfonyl- (3-phenyl-allyl) -amino-1-ethoxy) -benzoic acid methyl ester

To a solution of 4- (2-methanesulfonylamino-ethoxy) -benzoic acid methyl ester (62 mg, 0.23 mmol) in DMF (10 mL) at 0 ° C was added sodium bis (trimethylsilyl) amide (1.0 M in THF, 0.24 mL, 0.24 mmol) dropwise. After 20 minutes, synamyl bromide (51 mg, 0.26 mmol) was removed and the reaction was stirred at room temperature for 2 h. 1N HCl in water was added and the product was extracted into EtOAc. The organic solution was washed with 1N HCl (3x) followed by brine. The organic solution was dried (Na2 SO4₄), sifted, and conspiracy. Chromatography (20% EtOAc in hexane) gave trans-4- {2- [methanesulfonyl- (3-phenyl-allyl) -amino] -ethoxy) -benzoic acid methyl ester (70 mg).¹1 H NMR (400 MHz, CDCl3)₃) δ 7.97 (d, 2H), 7.35-7.23 (m, 5H), 6.88 (d, 2H), 6.58 (d, 1H), 6.18 (m, 1H) , 4.20 (t, 2H), 4.12 (d, 2H), 3.88 (s, 3H), 3.68 (t, 2H), 2.95 (s, 3H).

Step B: Water spray

Trans-4-2-Methanesulfonyl- (3-phenyl-allyl) -amino-ethoxy) -benzoic acid

In analogy to the method described in Step B of Example 1, trans-4- {2- [methanesulfonyl- (3-phenyl-allyl) -amino] -ethoxy} -benzoic acid methyl ester (60 mg) was hydrolysed to give title compound (35 mg). ¹1 H NMR (300 MHz, CDCl3)₃) δ 8.04 (d, 2H), 7.30 (m, 5H), 6.92 (d, 2H), 6.60 (d, 1H), 6.19 (m, 1H), 4.24 (t, 2H), 4.15 (d, 2H), 3.71 (t, 2H), 2.98 (s, 3H); MS375 (M +).

, PRODUCTION A1

N- (4-Buto-benzyl metansúlfónarnfð

Step A: Nftrfl Reduction

4-Butylbenzamide, A solution of 4-butylbenzonitrile (3.63 g, 22.8 mmol) in THF (10 mL) was added to a three-necked spherical flask equipped with a vigreux column and a short distillation head. The solution was heated to reflux and bra₃-methyl sulfide complex (2.0 M in THF, 15 mL, 30 mmol) was added dropwise over 15 minutes. Methyl nitride was removed from the reaction mixture for 1 h and the solution was cooled to room temperature. HCl in water (6N, 25 mL) was extracted with suction and the mixture was heated at reflux for 30 min. The reaction was cooled to 0 ° C and NaOH (7.0 g) was added in portions. The aqueous solution was extracted with EtOAc (3x) and the organic solution was dried (MgSO₄), filtered, and coincided. The product (4.01 g) was used for the next step without further purification. 1 H NMR (400 MHz, CDCl 3) δ 7.34 (m, 2H), 7.24 (m, 2H), 4.04 (s, 2H), 2.62 (t, 2H), 1.58 m, 2H), 1.34 (m, 2H), 0.92 (t, 3H).

Step B: Sulphonamide reaction

To a solution of 4-buthylbenzylamine (4.01 g, 24.6 mmol) in CH₂Cl₂ (75 mL) was added pyridine (4.0 mL, 49 mmol) after the dropwise precipitation of methanesulfonyl chloride (2.5 mL, 32.3 mmol). The reaction was stirred at room temperature for 24 h and water was added. The product was extracted with CH2 Cl2 (2x) and the organic solution was dried (MgSO4)₄), sifted, and coincided. Flash chromatography (2: 1 in 1: 1 hexane: EtOAc) gave the title compound as a white solid (3.4114 g).¹1 H NMR (400 MHz, CDCl3)_a) δ 7.23 (d, 2H), 7.15 (d, 2H), 4.84 (m, 1H), 4.25 (d, 2H), 2.82 (s, 3H), 2.56 (t, 2H), 1.56 (m, 2H), 1.33 (m, 2H), 0.91 (1.3H).

In a similar manner, the following compounds were prepared from suitable starting materials using the general method of Preparation A1 above.

MANUFACTURE A2

N-í2- (3,5-Dichloro-phenoxy) -etv11-metansúlf6namíð

MANUFACTURE A3

N-2- (3-Chloro-phenoxy) -methanesulfonamide -etvl1

FRAMLEIÐSLAA4

4-methanesulfonamide-Joðbensvi

The title compound was prepared from 4-jobenzylamine in an analogous manner to Step B of Preparation A1.¹1 H NMR (400 MHz, CDCl3)₃) Δ 7.69 (d, 2H), 7.10 (d, 2H), 4.82 (bs, 1H), 4.28 (d, 2H), 2.87 (s, 3H).

FRAMLEIÐSLAA5

N- [3- (2-Chloro-phenyl) -propyl] -methanesulfonamide

FRAMLEIÐSLAB1

Ethyl 7- (R4-iodobenzyl-methanesulfonyl-amino) -heptanoate

In step A of Example 1, 4-iodobenzyl methanesulfonamide (2.67 g, 8.59 mmol) alkylated with ethyl 7-bromoheptanoate (2.00 g, 8.44 mmol) was reported as described in Step A of Example 1. 50 ° C for 12 h and stirring at room temperature for 24 h to give the title compound (3.61 g). 1 H NMR (400 MHz, CDCl3)₃) Δ 7.68 (d, 2H), 7.12 (d, 2H), 7.31 (s, 2H), 4.12 (q, 2H), 3.13 (t, 2H), 2.83 (s, 3H), 2.27 (t, 2H), 1.42-1.65 (m, 5H), 1.15-1.35 (m, 6H); MS 468 (M +).

In an analogous manner, the following condensation compounds were prepared from auxiliary starting materials using the power using the generic yields from residue B1 below above changes in reaction temperature and temperature and precipitation.

FRAMLEIÐSLAB2

ZzíAllílzmeteu ^ úlfónýbamínóizheptansýnj ethyl ester

As described in progress B1: 24 hours, room temperature. ¹1 H NMR (400 MHz, CDCl3)₃) δ 5.71-5.81 (m, 1H), 5.16-5.24 (m, 2H), 4.01-4.10 (m, 2H), 3.70-3.80 (m , 2H), 3.07

3.15 (m, 2H), 2.77 (s, 3H), 2.21 (t, 2H), 1.47-1.58 (m, 4H), 1.22-1.34 (m, 4H), 1.18 (t, 3H).

MANUFACTURE B3

7- (But-3-enyl-methanesulfonyl-amino) -thiotanesyl ethyl ester

As described in framing B1: 90 ° C ί 24 h.

PRODUCTION B4

N- (6-Cyano-hexvB -methanesulfonamide

As described in progress B1: 90 ° C for 24 hours. ¹1 H NMR (400 MHz, CDCl3)₃) δ 4.24 (m, 1H), 3.11 (q, 2H), 2.83 (s, 3H), 2.35 (t, 2H), 1.70-1.37 (m, 8H) ; MS 222 (M + 18).

PREPARATION C1

5- (3-Methanesulfonylamino-propyl) -biphenyl-2-carboxylic acid methyl ester Step A

5- (3-Methanesulfonylamino-prop-1-yl) -biphen-2-carboxylic acid methyl ester. To solution 15 of 5-bromo-thiophen-2-carboxylic acid methyl ester (1.66 g, 8.0 mmol), N-prop-2-ynyl-methanesulfonamide (1.09 g, 8.2 mmol) , EfeN (1.7 mL, 12.1 mmol), and CH₃CN (30 mL) was added Pd (PPh₃)₄ (462 mg, 0.4 mmol) followed by Cul (76 mg, 0.4 mmol). The reaction was heated at the back for 24 hours and was cold at room temperature. The volatiles were removed in vacuo and the residue was purified by trituration (20% EtOAc in hexane 33% EtOAc in hexane) to give 5- (3-methanesulfonylamino-prop-1-yl) -thiophene-2-carboxylic acid methyl ester as Light yellow solid (1.1 g).¹1 H NMR (300 MHz, CDCl 3) δ 7.64 (d, 1H), 7.14 (d, 1H), 4.60 (m, 1H), 4.22 (d, 2H), 3.88 , 3H), 3.10 (s, 3H); MS 274 (M + 1).

Step B: Hydrogenation

A solution of 5- (3-methanesulfonylamino-prop-1-ynyl) -thiophene-2-carboxylic acid methyl ester (3.0 g, 10.9 mmol) in EtOAc (100 mL) and MeOH (50 mL) was hydrogenated with 10 % Pd / C (680 mg) vifl 50 psi for 7 h. The solution was filtered through a self-propellant with the aid of MeOH and was concentrated in vacuo to give the title compound as a direct solid (2.95 g). 1 H NMR (300 MHz, CDCl 3) δ 7.62 (d, 1H), 7.23 (d, 1H), 4.29 (m, 1H), 3.85 (s, 3H), 3.18 q, 2H),

2.93 (m, 5H), 1.96 (m, 2H).

In a secular manner, the following compounds were synthesized from video originating materials using power using the generic generators from residue C1 above.

PRODUCTION C2

N-3- (3-KI6r-fenvB-DróPvi1-metansúltónamíð

MANAGEMENT C3

N-3- (3-trifluoromethyl-fBnvl) -methanesulfonamide -aráDvl1

MANUFACTURE D1 • Bromomethyl-4-buty-benzene

HBr was bulked to a solution of (4-butyl-phenyl) -methanol (10.0 g, 60.9 mmol) in CH₂Cl₂ (100 mL) for 15 minutes. The reaction was continued for another 45 minutes and poured onto ice water. The aqueous solution was extracted with CH₂Cl₂ (2x) and was dried (MgSO4), filtered, and concentrated to give the title compound which was used for further purification. ¹1 H NMR (400 MHz, CDCl3)₃) Δ 7.29 (d, 2H), 7.14 (d, 2H), 4.49 (s, 2H), 2.60 (t, 2H), 1.58 (m, 2H), 1.36 (m, 2H), 0.92 (t, 3H).

In a similar manner, the following compound was prepared from the appropriate starting materials using the general method of production D1.

MANUFACTURE D2

Bromomethyl-4-benzene-ísÓDráDvl ¹1 H NMR (400 MHz, CDCl 3) δ 7.31 (d, 2H), 7.19 (d, 2H), 4.49 (s, 2H), 2.90 (m, 1H), 1.24 , 6H).

MANUFACTURE E1

4'-Bromomethyl-2-chloro-biphenyl

Step A: Suzuki clutch

4'-Methyl-2-chlorobiphenia · Tetrakis (triphenylphosphine) palladium (0) (637 mg, 0.551 mmol), NasCO3 (5 mL, 1M) and 4-methylbenzeneboronic acid (1.5 g, 11.0 mmol) was added to a solution of 2-chloroiodobenzene (1.315 g, 5.514 mmol) in toluene (98 mL) and EtOH (20 mL). The reaction mixture was heated at reflux for 3 h. The cooled solution was diluted with EtOAc, and the organic solution was washed with water (2x) followed by brine (1x). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography (hexane in 10% EtOAc / hexane) to give 4'-methyl-2-chlorobiphenyl (1.08 g).¹1 H NMR (CDCl3)₃ 400 MHz) δ 7.497.21 (m, 8H), 2.39 (s, 3H).

Step B: Benzine bromination

A mixture of 4'-methyl-2-chlorobiphenyl (1.08 g, 5.33 mmol), NBS (1.14 g, 6.40 mmol) and AIBN (175 mg, 1.06 mmol) in CCl4 37 mL) was heated at reflux for 3 h. The reaction mixture was diluted with CH 2 Cl 2 and the organic solution was washed sequentially with saturated aqueous NaHCO₃(2x), water (1x), and salt pack (1x). The organic solution was dried over MgSO₄, filtered and concentrated in a vacuum. The product was purified by flash chromatography (hexane in 5% EtOAc / hexane) to give the title compound (920 mg).¹1 H NMR (CDCl3)₃ 400 MHz) δ 7.63-7.25 (m, BH),

4.56 (s, 2H).

In a similar manner, the following compounds were prepared from the appropriate starting materials using the general method of Preparation E1 above.

MANUFACTURE E2

4'-Bromomethyl-2-trifluoromethyl-biphenyl

FRAMLEIÐSLAE3

4'-Bromomethyl-2,6-dichloro-biphenyl

MANUFACTURE F1 FO-Bromine WI-PhenVh-Ediksfou Methyl Aster

A solution of m-tolyl-acetic acid methyl ester (11.41 g, 69.49 mmol), N-bromosuccinimide (12.59 g, 70.73 mmol), AIBN (100 mg) in CCI₄ (200 mL) was stirred at reflux for 16 h. The reaction mixture was cooled to room temperature and aqueous NaHCO3 (saturated) aqueous solution was added. The aqueous solution was extracted with CH₂Cl₂ (2x) and the aqueous solution was dried (MgSO4)₄), filtered, and sync. Purification by flash chromatography (hexane in 9: 1 hexane: EIOAc) gave the title compound and a colorless liquid (11.99 g).¹1 H NMR (CDCl 3 400 MHz) δ 7.27 (m, 4H), 4.47 (s, 2H), 3.69 (s, 3H), 3.62 (s, 2H).

In a similar manner, the following compound was prepared from the appropriate starting materials using the general procedure of Preparation F1 above.

PRODUCTION F2

2- (4-Bromomethyl-pyridine-fenvB

FRAMLEIÐSLAG1

4-yl] -Abicyclohexyl-benzyl bromide

Step A: Griqnardhvarf and vemdun

4- (1-Acetylethoxy) hexyl] toluene, Pentylmagnesium bromide (2.0 M in Et₂O, 25 mL, 50 mmol) was slowly precipitated in 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 hours. 1N HCl in water was added and the aqueous solution was extracted with EtOAc. The organic solution was washed with brine, dried over MgSO₄, filtered and collected. The residue was dissolved in pyridine (35 mL) and AfcO (10 mL) was added. The reaction was stirred for 24 h and was diluted with water. The product was extracted into EtOAc (3x) and the organic solution was washed with 1N HCl followed by brine, dried over MgSO4₄, filtered, and conspired. The product was purified by flash chromatography (10% EtOAc / hexane) to give 4 - ((1-acetoxy) -hexyl] -toluene (2.082 g).¹1 H NMR (400 MHz, CDCl 3) δ 7.12-7.28 (m,

4H), 5.69 (t, 1H), 2.33 (s, 3H), 2.04 (s, 3H), 1.88 (m, 1H), 1.74 (m, 1H) 27 (m, 6H), 0.86 (m, 3H); MS 252 (M + 18).

Step B: Benzine bromination

A mixture of 4 - ((1-acetyl-oxy) -hexyl] -toluene (2.082 g, 8.89 mmol), NBS (1.58 g, 8.89 mmol), and a catalytic amount of AIBN in CCI₄ (30 mL) was heated to reflux (2 h. The reaction was a catheter and washed with aqueous NaHCO₃ (saturated), dried over MgSO₄, siafl, and samsafnafl. The product was purified by flash chromatography (5% EtOAc / hexane) to give the title compound (2.67 g).¹1 H NMR (400 MHz, CDCl3)₃) δ 7.34-7.40 (m, 4H), 5.70 (t, 1H), 4.47 (s,

2H). 2.06 (s, 3H), 1.86 (m, 1H), 1.73 (m, 1H), 1.27 (m, 6H), 0.85 (m, 3H).

In a similar manner, the following compound was prepared from a refractory starting material by force using the generic generators from preparation G1 above above.

PRODUCTION G2

Ediksvru 1- (5-bromomethyl-blown-2-vh-hexyl ester

MANAGEMENT H1

Tant-1 - (3-Bromopropenyl) -3,5-dichlorobenzene

Step A: Grianardhvarf

- (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 (1M in THF, 48 mL, 48 mmol) was added dropwise. The reaction was stirred at room temperature and was stirred overnight. Aqueous solution of HCl (1N) and EtOAc was added. The aqueous solution was extracted with EtOAc and the resulting solution was dried (MgSO4)₄), filtered, and coincided. The residue was used in the next step without further purification.

Step B: Bromun

The residue produced in step A was dissolved in EfeO and HBr gas was poured into the solution for about 15 minutes. The reaction mixture was stirred at room temperature for 24 hours and water and EtOAc was added. The aqueous solution was extracted with EtOAc and the organic solution was dried (MgSO4)₄), siufi, and social networking. Purification by flash chromatography (hexane) gave the title compound (6.91 g).¹1 H NMR (400 MHz, CDCl 3) δ 7.24 (s, 3H), 6.53 (d, 1H), 6.40 (m, 1H), 4.10 (m, 2H).

In a highly efficient manner, the following compound was prepared from the starting materials, using the general excipient from submerged H1 above.

MANUFACTURE H2

Tant-1 - (3-Bromo-4-oxo-3,5-difluoro-benzene 15 ¹1 H NMR (400 MHz, CDCl3)₃) Δ 6.83-6.95 (m, 2H), 6.65-6.75 (m, 1H), 6.55 (d, 1H), 6.34-6.45 (m, 1H), 4.10 (d, 2H).

FRAMLEIÐSLAI1

4-ísóbútvlbensvlbr6mlð

Step A: Reduction (4-Isobutyl-phenylbibanol) A solution of absolute aluminum hydroxide (30 mL, 1M in THF, 30 mmol) was added dropwise to a solution of 4-isobutylbenzoic acid (5.34 g, 30 mmol) in THF (50 mL) at 0 ° C. The ice-off was removed and the reaction was rapid at room temperature for 11 h. The reaction was poured out of water and aqueous HCl (10 mL, 6N). The product was extracted with EtOAc and the organic solution was dried (MgSO₄), silane, and the like to obtain (4-isobutylphenyl) methanol which was the most useful step without further purification. ¹1 H NMR (400 MHz, CDCl3)₃) Δ 7.26 (d, 2H), 7.13 (d, 2H), 4.65 (s, 2H), 2.46 (d, 2H), 1.85 (m, 1H), 0.89 (d, 6H).

Step B: Brfimun

HBr gas was bullafi through a solution of (4-isobutyl-phenyl) -methanol (5 g, 2B mmol) I

Et2 O (50 mL) for 10-15 minutes. The reaction was rapid for 1 hour and poured onto ice (100 g). et₂O was boiled out and the solution was washed with salt peel (2x). The liver solution was dried (MgSO₄), silica gel, and the title compound gave a title compound (6 g). 1 H NMR (400 MHz, CDCl 3) δ 7.28 (d, 2H), 7.10 (d, 2H), 4.49 (s, 2H), 2.45 (d, 2H), 1.84 m, 1H), 0.89 (d, 6H).

In a similar manner, the following compound was prepared from the appropriate starting materials using the general procedure from subchain 11 high above.

FRAMLEIÐSLAI2

- (bromomethyl) -4- (fenylmetvn-benzene

FRAMLEIÐSLAJ1

7-FÍ4-Formyl-benzyl) -methanesulfonyl-amino -heptanoic

Step A

Bromomethyl-4-vine-benzene. A broth (16.4 g, 103 mmol) was added dropwise to a solution of triphenylphosphine (28.87 g, 110.1 mmol) in CH₂Cl₂ (260 mL) at 0 ° C. After 10 minutes 4-vinyl-benzyl alcohol (12.5 g, 93.3 mmol) was added and the reaction mixture was stirred at 0 ° C for 2 h. The reaction mixture was washed with water (1x) followed by brine (1x). The organic solution was dried over MgSO₄, filtered, and concentrated in vacuo. The product was ground with petroleum ether (3x) and the ether solution was concentrated in vacuo. The residue was purified by flash chromatography (hexane) to give 4-vinyl-benzyl bromide (6.23 g).¹1 H NMR (400 MHz, CDCl3)₃) δ 7.32-7.45 (m, 4H), 6.72 (dd, 1H), 5.77 (d, 1H), 5.28 (d, 1H), 4.50 (s, 2H) .

Step B: Alkvlerina

Ethyl-7- (4-phenyl-benzyl) -methanesulfonyl-amino] -smithanoate Following the procedure described in Preparation B1, ethyl 7-methanesulfonyl-aminoheptanoate (2.30 g, 9.02 mmol) was alkylated with 4- vinylbenzyl bromide (1.77 g, 9.02 mmol) for 3 h at room temperature to give, after flash chromatography (10% EtOAc / hexane in 50% EtOAc / hexane) ethyl 7 - [(4-vinyl-benzyl) methanesulfonyl-amino-heptanoate (2.21 g). 1 H NMR (400 MHz, CDCl 3) δ 7.23-7.45 (m, 4H), 6.72 (dd, 1H), 5.76 (d, 1H), 5.28 (d, 1H), 4.38 (s, 2H), 4.12 (q, 2H), 3.14 (t, 2H), 2.83 (s, 3H), 2.24 (t, 2H), 1.15-1 , 64 (m, 11H); MS 385 (M + 18).

Step C: Oxidation

A solution of ethyl 7 - [(4-vinyl-benzyl) methanesulfonyl-amino] -heptanoate (2.2 g, 6.0 mmol) in dioxane (45 mL) was added to a solution of N-methylmorpholine N- oxide (1.47 g, 12.5 mmol) in water (45 mL). Osmium tetroxide (4.6 mL, 2.5 wt% in 2-methyl-2-propanol) was added and the mixture was stirred at room temperature for 1 h. The reaction was quenched with 1N HCl (50 mL) and the aqueous solution was extracted with CH₂Cl₂. The organic layer was washed with water (1x) followed by saline (1x), dried over MgSO₄, filtered, and concentrated in vacuo. The residue was dissolved in 35% THF in water (100 mL) and NalO4 (1.41 g, 6.59 mmol) was added. The mixture was stirred at room temperature for 2 h and was diluted with EtOAc and water. The aqueous solution was washed with water (1x) followed by brine (1x), powdered over MgSO₄, filtered and concentrated in vacuo to give a title compound (1.9 g) which was a non-purified user. ¹1 H NMR (400 MHz, CDCl3)_a) δ 10.0 (s, 1H), 7.82-7.90 (d, 1H), 7.50-7.59 (d, 2H), 5.30 (s, 2H), 4.45 S,

2H), 4.05-4.18 (m, 2H), 3.12-3.22 (m, 2H), 2.86 (s, 3H), 2.19-2.30 (m, 2H) , 1.42-1.62 (m, 6H), 1.18-1.30 (m, 3H); MS 387 (M + 18).

PREPARATION K1 (4-Methanesulfonylamino-butoxy) acetic acid ethyl ester

Step A: Alkylation (4-Bromo-butoxide) Ethyl acetate, A solution of ethyl glycolate (4.6 g, 44 mmol) in DMF (50 mL) was cooled to 0 ° C and sodium bis (trimethylsilyl) amide THF, 53 mL, 53 mmol) was added dropwise. Reaction time was 115 minutes and 1,4-dibromobutane (5.6 mL, 48.4 mmol) was added. The reaction was warmed to room temperature and stirred 24 hours EtOAc was added and the aqueous solution was washed with HCl (1N, 3x), water (two) and brine (1x). The resulting solution was purrkufi (Na₂SO₄), sfufi, and social networking. Aerosolimitation that was practically absent from the majority was impurities and yielded a mixture of product and 1,4-dibromobutane (3.539 g). Flash chromatography (9: 1 hexane: EtOAc) on this material gave (4-bromo-butoxy) -acetic acid ethyl ester (1.662 g).¹1 H NMR (400 MHz, CDCl3)₃) δ 4.19 (q, 2H), 4.04 (s, 2H), 3.54 (t, 2H), 3.45 (t, 2H), 1.97 (m, 2H), 1.75 (m, 2H), 1.26 (t, 3H); MS 239.1 (M +).

Step B: Alkvlering

Out of NaH (60% in oil, 167 mg, 4.18 mmol) and DMF (10 mL) was added a solution of methanesulfonamide (398 mg, 4.18 mmol) in DMF (5 mL). The mixture was heated to reflux

100 ° C for 1.5 h and was cooled to room temperature. A solution of (4-bromobutoxy) -acetic acid ethyl ester (1.000 g, 4.182 mmol) in DMF (10 mL) was added and the reaction was continued for 100 h for 21 h. Water was added to the reaction mixture and the aqueous solution was acidified to pH = 2 with concentrated HCl. The aqueous solution was extracted with EtOAc (4x) and the resulting solution was purrkufi (MgSO₄), sfufi, and social networking. The product was purified by flash chromatography (60% EtOAc / hexane) to give the title compound (181 mg).¹1 H NMR (400 MHz, CDCl3)₃) δ 4.90 (m, 1H), 4.20 (q, 2H), 4.04 (s, 2H), 3.54 (m, 2H), 3.16 (m, 2H), 2.93 (s, 2H), 1.69 (m, 4H), 1.28 (t, 3H); MS 254.1 (M + 1).

FRAMLEIÐSLAL1

- (2-Br6m-ethoxy) -3,5-benzene-dfklflr

To a solution of NaOH (2.45 g, 61.3 mmol) in water (20 mL) was added 3,5-dichlorophenylphenyl (5 g, 30.7 mmol). The solution was refluxed for 1 h and was cooled to room temperature.

Dibrflmatane (11.52 g, 61.3 mmole) was added color (and the reaction was a reaction temperature of 24 hours. The cooled solution was diluted with EtOAc and the resulting solution was washed with HCl HCI (1N, 1x), water (1x ), and brine (1x). The organic solution was dried (MgSO₄), as well as interactions. Purification by flash chromatography (hexane in 5% EtOAc in hexane) gave the title compound (3.79 g). 1 H NMR (400 MHz, CDCl 3) δ 6.96 (m, 1H), 6.82 (m, 2H), 4.25 (t, 2H), 3.61 (t, 2H).

In a similar manner, the following compounds were prepared from the refractory starting materials by force using the general precipitate from residue L1 above above.

FRAMLEIÐSLAL2

1- (2-Bromo-ethoxy) -3,5-dimethyl-benzene

MANUFACTURE L3

- (2-Bromo-ethoxy-3,5-dimethoxy-benzene

MANUFACTURE M1

4- (1-Hydroxy-hexyl-bansaldehyde

A solution of 4-diethoxymethyl-benzaldehyde (0.300 mL, 1.51 mmol) in THF (3 mL) was cooled to 0 ° C. Pentylmagnesium bromide (3.0 mL, 2.0 μm in THF, 6 mmol) was bubbled out dropwise. The reaction was stirred for 0 ° C for 1 h and the reaction temperature was at room temperature. Water solution of NH₄The mixture was extracted and the aqueous solution was extracted with EtOAc. The organic solution was washed with brine, brine (MgSO4, filtered and concentrated). The residue was dissolved in 10% aqueous water (50 mL) and a wet Amberiyst Residue (1.5 g) was solidified. The mixture was stirred. For 24 hours, the resin was removed by filtration. The solution was concentrated in vacuo. Purification by flash chromatography (4: 1 hexane. EtOAc) gave the title compound (1.15 g).¹1 H NMR (400 MHz, CDCl3)₃) δ 9.99 (s, 1H), 7.86 (d, 2H), 7.51 (d, 2H), 4.77 (m, 1H), 1.89 (m, 1H), 1.74 (m, 2H), 1.48-1.28 (m, 6H), 0.87 (m, 3H).

FRAMLEIÐSLAN1

- (3-Bromo-propyl) -3-chloro-benzene

Step A: Reduction

3- (3-Chloro-phenyl) -propan-1-ol, A slurry of lithium aluminum hydride (2.08 g, 54.7 mmol) in THF (100 mL) was cooled to -78 ° C. A solution of 3-chloroindamic acid (5.00 g, 27.4 mmol) in THF (25 mL) was added dropwise. The cake was removed and the mixture was heated to room temperature. After 6 hours, the reaction was stopped by a branch of sodium sulfate decahydrate and the mixture was stirred overnight. The solids were removed by filtration with EtOAc and the organic solution was concentrated by brine, dried over MgSO₄, filtered and concentrated in vacuo to give 3- (3-chloro-phenyl) -propan-1-ol (5.17 g) as an oil. ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.30-7.07 (m, 4H), 5.06 (bs, 1H), 3.67 (m, 2H), 2.69 (m, 2H), 1.89 (m, 2H) .

Step B: Bromun

A solution of 3- (3-chlorophenyl) propan-1-ol (12.54 g, 73.6 mmol) and N, N'-carbon # diimidazole (13.12 g, 81 mmol) in CH₃The CN was stirred at room temperature for 1 h. All # bromine (53.43 g, 442 mmol) was added and the reaction was heated at reflux for 24 h. The reaction mixture was stirred at room temperature and brine and EtOAc was added. The aqueous solution was extracted with EtOAc and the hepatic solution was dried (MgSO4)₄), sfufl, and samsflfnufl. Flash chromatography gave the title compound in about 85% yield.¹1 H NMR (400 MHz, CDCl3)₃) δ 7.30-7.09 (m, 4H), 3.38 (t, 2H), 2.76 (t, 2H), 2.15 (t, 2H).

FRAMIEIÐ9LAO1

2-indanyl-ethyl bromide

Step A: Reduction

2-indanolethane, lipomal aluminum hydride (1M f et₂0.14 mL, 14 mmol) was poured into a solution of 2-indanone # acetic acid (2.5 g, 14 mmol) in Et₂O. The reaction mixture was heated to reflux for 2 hours and cooled to room temperature. Water and EtOAc were bubbled in and the solution was stirred with water (2x) and brine (1x), dried over MgSO₄, sfufl, and synergy to force give

2-indane # ethanol (2.1 g) which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3) δ 7.08-7.24 (m, 4H), 3.75 (t, 2H), 3.07 (m, 2H), 2.61 (m, 3H), 1.80 (m, 2H); MS 180 (M + 18).

Step B: Brflmun

2-one ## STR3 ## N, N-Carbonidimidazole (2.0g, 12.3mmol) was added to a solution of 2-indane # ethanol (2.0g, 12.3mmol) of asetflnltrili. The reaction mixture was stirred at room temperature for 1 h and all # bromide (8.93 g, 73.8 mm) was replaced by Í. The reaction mixture was heated to 70 ° C for 24 h and poured into water. The aqueous solution was extracted with Et₂The oily solution was washed with water (1x) followed by saline (1x). The organic solution was poured over MgSO_4i and then poured into title compound (2.54 g). ¹1 H NMR (400 MHz, CDCl 3) δ 7.10-7.25 (m, 4H), 3.48 (t, 2H), 3.11 (m, 2H), 2.63 (m, 3H), 2 , 07 (m, 2H).

PREPARATION P1

Trans-3-f (3,5-Dichloro-phenyl) -allvi1-metansúlfánamlð

A mixture of methanesulfonamide (3.27 g, 34.4 mmol), trans- (3,5-dichlorophenyl) -allyl bromide (1.83 g, 6.88 mmol), KgCO₃ (0.95 g, 6.88 mmol) and CH₃CN was at 55 ° C for 24 hours. The reaction mixture was poured into EtOAc and 1N HCl. The solution was urine several times with 1N HCl, dried over MgSO₄, siud, and samsdfnud. Afurdin was sparged with flash chromatography (30% EtOAc / hexane in 40% EtOAc / hexane) to give title compound (1.40 g). 1 H NMR (400 MHz, CDCl 3) δ 7.24 (m, 3H), 6.50 (d, 1H), 6.25 (m, 1H), 4.45 (m, 1H), 3.94 m, 2H), 3.00 (s, 3H).

PREPARATION Q1 (4-Methanesulfonylthio-phenyl) -butyric acid ethyl ester

Step A: Estrun

4- (4-Amino-phenyl) -butyric acid ethyl ester, Sulfuric acid sulfuric acid was added to a solution of 4- (4-aminophenyl) butyric acid (6.0 g, 33.48 mmol) in EtOH. The reaction mixture was stirred at room temperature 124 h HCl (5 mL, 6N) was added and the reaction mixture was heated at reflux for 24 h. The reaction mixture was concentrated in vacuo and CH₂Cl₂ and water was ejected in. The pH was adjusted to 7.0 g aqueous solution of NaHCO3 (mettadri). The organic solution was washed with water (1x) and brine (1x), purrkud over MgSO₄, filtered, and yielding 4- (4-am (naphenyl) -butyric acid ethyl ester (1.53 g) .1 H NMR (400 MHz, CDCl3)?₃) δ 6.95 (d, 2H), 6.61 (d, 2H), 4.10 (q, 2H), 3.66 (bs, 2H), 2.53 (t, 2H), 2.29 (t, 2H), 1.88 (m, 2H), 1.24 (t, 3H).

Step B: Sulphonamide reaction

Pyridine (0.87 mL, 10.9 mmol) was added to a solution of 4- (4-amino-vinyl) -butyric acid ethyl ester (1.50 g, 7.25 mmol) in CH2 Cl2₂Cl₂. The reaction mixture was quenched to 0 ° C and methanesulfonyl chloride (913 mg, 7.97 mmol) was precipitated in. The reaction time was rapid at 0 ° C for 1 hour and at room temperature for 2 hours. The bottle was poured into water and was ejected. The pH was adjusted to 1.0 with the use of 1N HCl. The organic solution was washed with water (1x) and brine (1x), dried over MgSO₄, siud, and samsdfnud in loftsmi. The product was crystallized by evaporation to give the title compound (2.03 g). 1 H NMR (400 MHz, CDCl3)₃) δ 7.09-7.32 (m, 4H), 4.12 (q, 2H), 2.97 (s, 3H), 2.60 (t, 2H), 2.30 (t, 2H) , 1.91 (m, 2H), 1.24 (t, 3H).

PREPARATIONS 1 [2- (2-Methanesulfonylamino) ethyl] phenoxy} -acetic acid ethyl ester

Step A: Sulphonamide reaction

N- (2- (2-Methoxy) methyl) methanesulfonamide, pyridine (12.0 mL, 150 mmol) was added to a solution of 2-methoxyphenethylamine (15.1 g, 100 mmol) in CH2 Cl2₂ (100 mL). The reaction was cooled (O'C and methanesulfonyl chloride) (12.6 g, 110 mmol) was added. The reaction was stirred vifi

0 ° C (0.5 h and at room temperature in 2 coats. Water was added and the aqueous layer was extracted with CH₂Cl₂ (2x). The organic solution was washed with water (1x) and brine (1x), dried over MgSO4₄, filtered and concentrated to give N- [2- (2-methoxy-phenyl) -ethyl] -methanesulfonamide (18.5 9) Step B: Dimethylation

N- [2- (2-Hydroxy-phenyl) -ethyl] -methanesulfonamide, boron trifluoride (1.0 M in CH₂Cl_2l 80.8 mL, 80.8 mmol) was added to a solution of N- [2- (2-methoxy-phenyl) -ethyl] methanesulfonamide (18.5 g, 80.8 mmol) in CH2Cl2 (200 mL) . The reaction was stirred at room temperature for 2 h and poured into water (200 mL). The aqueous layer was extracted with CH2Cl2 (2x) and the organic solution was washed with water (1x) and aqueous NaHCO3 (mettflor, 1x). The organic solution was dried over MgSO₄, filtered, and concentrated to give N- [2- (2-hydroxy-phenyl) -ethyl] methanesulfonamide (16.8 g). ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.11 (m, 2H), 6.86 (m, 1H), 6.80 (m, 1H), 4.79 (m, 1H), 3.39 (t, 2H), 2.88 (t, 2H), 2.77 (s, 3H).

Step C: Alkvterino

A mixture of N- [2- (2-hydroxy-phenyl) -ethyl] -methanesulfonamide (4.3 g, 20 mmol), Na1 (1.2 g, 8.0 mmol), KaCO3 (6.07 g, 44 mmol), ethyl bromate (3.34 g, 20 mmol), and DMF (70 mL) was stirred at room temperature for 24 h. The reaction was poured into water and the aqueous solution was extracted with CH₂Cl₂. The liver solution was washed with water (1x) followed by saline (1x). The liver solution was dried (MgSO4)₄), filtered, and interfacial. Flash chromatography (hexane in 7: 3 hexane: EtOAc) gave the title compound (800 mg).¹1 H NMR (400 MHz, CDCl3 δ 7.18 (m, 2H), 6.93 (t, 1H), 6.71 (d, 1H), 4.97 (m, 1H), 4.65 (s, 2H), 4.24 (q, 2H), 3.42 (m, 2H), 2.94 (t,

2H), 2.75 (s, 3H), 1.27 (t, 3H); MS 319 (M + 18).

FRAMLEIÐSLAS1

1- (3,5-Dichlorophenyl) -prenyl] bromide

Step A

3- (3,5-Dichlorophenyl) -acrylic acid A mixture of 3,5-dichlorobenzaldehyde (15.0 g, 85.7 mmol), matonic acid (12.5 g, 120.2 mmol), and pfperidine (5 mL) was heated fan 100 ° C f2 h and fan 150 ° C for 1 h. The reaction was poured into 3N HCl (200 mL) and the precipitate was distilled off with filtration. The product was purified by recrystallization (100 mL of hot EtOH) to give 3- (3,5-dichlorophenyl) acrylic acid (11.5 g).¹1 H NMR (250 MHz, DMSO-d 6) δ 12.6 (bs, 1H), 7.83 (m, 2H), 7.64-7.51 (m, 2H), 6.72 (d, 1H) .

Step B: Hydrogenation

3- (3,5-Dichlorophenyl) -dioDioic acid · In solution of 10% Pd / C (1.5 g) in THF (200 mL) was added 3- (3,5-dichlorophenyl) -acrylic acid (11.5 g). The reaction was carried out on a Parr shaker vial 50 psi for 3 h. The catalyst was filtered through celite and the resulting solution was concentrated in vacuo to give 3- (3,5-dichlorophenyl) -propionic acid (11.3 g). ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.00-7.35 (m, 3H), 2.89 (t, 2H), 2.66 (t, 2H).

Step C: Reduction

3- (3,5-Dichlorophenyl) -thropanol, LiAlH₄ (1 mL, 10 mL, 10 mmol) was added to a solution of 3- (3,5-dichlorophenyl) -propionic acid (2.19 g, 10 mmol) in EtOAc (50 mL). The reaction was a reversible reversible flap for 2 hours. The reaction was cooled to room temperature and 2N NaOH (1 mL) and aqueous NH2₄CI (mettufl, 3 mL) was added gently to i. The solution was filtered through sealed and flotifl was dry over MgSO₄, siafl, and samsafnafl. The product was purified by flash chromatography (25% EtOAc / hexane) to give 3- (3,5-dichlorophenyl) -propanol (640 mg).¹1 H NMR (400 MHz, CDCl 3) δ 7.17 (m, 1H), 7.07 (m, 2H), 3.64 (m, 2H), 2.65 (t, 2H), 1.84 , 2H).

Step D: Brflmun

Triphenylphosphine (315 mg, 1.20 mmol) was added to a solution of 3- (3,5-dichlorophenyl) -propanol (200 mg, 0.98 mmol) in CH 2 Cl 2 (20 mL). The reaction mixture was cooled to 10 ° C and brine (207 mg, 1.30 mmole) was added dropwise. The shift was faster than the 0^eC for 1 h and heat (room temperature. The reaction was poured into water and the aqueous solution was extracted with CH2 Cl2. The aqueous solution was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The product was purified by flash chromatography (hexane) to power yielding the title compound (134 mg). ¹1 H NMR (400 MHz, CDCl 3) δ 7.21 (m, 1H), 7.08 (m, 2H), 3.37 (t, 2H). 2.74 (t, 2H), 2.13 (m, 2H).

FRAMLEIÐSLAT1

100

4- (2-Methanesulfonylamino-ethoxy) -benzoic acid methyl ester

Step A: Waiver

4- (2-Amino-ethoxy) -benzoic acid methyl ester hydrochloride salt To a solution of 4- (2- (2,2-dimethylpropionylamino) -ethoxy] -benzoic acid methyl ester (350 mg) in EtOH (6 mL) The solution was warmed to room temperature and concentrated in vacuo to give the hydrochloride salt of 4- (2-amino-ethoxy) -benzoic acid methyl ester (266 mg) together with a solid which was used in the next step without further cleaning.

Step B: Sulphonamid reaction

Methanesulfonyl chloride (144 mg, 1.27 mmol) was added to a solution of 4- (2-amino-atoxy) -benzoic acid methyl ester (266 mg, 1.15 mmol) and pyridine (255 mg, 2.52 mmol) in CH₂Cl 2 (10 mL) at 0 ° C. The solution was warmed to room temperature and stirred (24 hours EtOAc was added and the solution was washed with HCl (1N, 2x) followed by brine. The resulting solution was dried (Na2 SO4).₄), filtered, and concentrated to yield the title compound as a white solid (240 mg). ¹1 H NMR (400 MHz, CDCl 3) δ 7.99 (dd, 2H), 6.90 (dd, 2H), 4.77 (m, 1H), 4.15 (t, 2H), 3.88 , 3H), 3.58 (m, 2H), 3.02 (s, 3H); MS 274 (M + 1).

PRODUCTION U1

7- (4-Butyl-phenylamino) -heptanoic acid methyl ester

Following the procedure described in Step A of Example 68, reductive amination of 4-butyl-benzaldehyde (1.50 g, 9.26 mmol) with 7-aminoheptane methyl ester hydrochloride (1.51 g, 7.72 mmol) title compound (955 mg). ¹1 H NMR (300 MHz, CDCl3)₃) δ

7.29 (d, 2H), 7.16 (d, 2H), 3.85 (s, 2H), 3.67 (s, 3H), 3.54 (m, 1H), 2.70 (t, 2H) ), 2.59 (t, 2H),

2.29 (t, 2H), 1.60 (m, 6H), 1.32 (m, 6H), 0.92 (t, 3H); MS 306 (M + 1).

PREPARATION V1 [3- (Methanesulfonylamino-methyl) -phenoxy] -acetic acid

Step A: Sulphonamide reaction

N- (3-Methoxybenzylmethanesulfonamide) Methanesulfonamide chloride (4.170 g, 36.4 mmol) was added to a solution of 3-methoxybenzylamine (5.000 g, 36.4 mmol) and diethylamine (3.946 g, 39.0 mmol ) in THF (100 mL) at room temperature. The mixture was stirred for 18 h, and the insolubles were removed by filtration. The organic solution was concentrated in yellow oil as

101 was purified by flash chromatography (6: 4 hexane: EtOAc in 1: 1 hexane: EtOAc) to give N- (3-methoxybenzyl-methanesulfonamide (7.431 g) .1 H NMR (400 MHz, CDCl3)? 7.26 m, 1H), 6.92-6.82 (m, 3H), 4.62 (m, 1H), 4.28 (d, 2H), 3.80 (s, 3H), 2.87 , 3H); MS 214 (M-1).

Step B: Afmetlerine

N- (3-Hydroxy-benzyl) methanesulfonamide. Solution of BBr₃ (1.0 M, CH₂CI2, 111 mL, 111 mmol) was slowly added to a solution of N- (3-methoxy-benzyl) methanesulfonamide (12,000 g, 55.7 mmol) in CH2 Cl2 (200 mL) at 0 ° C. The reaction was warmed to room temperature and stirred for 4 h. Methanol (100 mL) was added gently and the solution was concentrated in vacuo. Flash chromatography (1: 1 hexane: EtOAc) gave N- (3-hydroxy-benzyl) methanesulfonamide (11.50 g).¹1 H NMR (400 MHz, CDCl 3) δ 7.20 (m, 1H), 6.84 (m, 2H), 6.77 (m, 1H), 4.83 (bs, 1H), 4.24 , 2H), 2.86 (s, 3H); MS 201 (M +).

Step C: Alkvierina

A mixture of N- (3-hydroxy-benzyl) methanesulfonamide (6.000 g, 29.82 mmol), methyl bromoacetate (4.562 g, 29.82 mmol), K₂COg (4.121 g, 29.82 mmol), and acetone (250 mL) was stirred at room temperature for 68 h. The solids were removed by filtration and the solution was combined with air filtration. Purification by flash chromatography (1: 1 hexane: EtOAc) gave the title compound (5.637 g).¹1 H NMR (400 MHz, CDCl3)₃) δ 7.25 (m, 1H), 6.96 (m, 1H), 6.89 (s, 1H), 6.82 (m, 1H), 4.63 (m, 3H), 4.28 (m, 2H), 3.80 (s, 3H), 2.86 (s, 3H); MS 274 (M + 1).

It is understood that the invention is not limited to a particular manifestation described herein, but that it is possible to make various changes and configurations without departing from the spirit and scope of this new concept as defined in the following claims.

PREPARATION W1 [3- (Methanesulfonylamino-methyl-phenyl) -acetic acid ethyl ester

Step A: Estimation (3-Bromo-ethyl) -acetic acid ethyl ester, To a solution of 3-bromophenylacetic acid (10.0 g, 46.5 mmol) in CH₃CN (150 mL) was added K2CO₃ (7.39 g, 53.5 mmol) followed by ethyl iodide (5.6 mL, 70.0 mmol). The mixture was heated at reflux for 2.5 h and cooled to room temperature. The volatiles were removed in air and water was poured out. The aqueous solution was extracted with EtOAc (3x) and the combined organic extracts were washed with brine. The organic solution was dried (MgSO4)₄), filtered, and concentrated to give (3-bromo-phenyl) -acetic acid ethyl ester (9.30 g) as an oil. ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.43 (s, 1H), 7.38 (m, 1H), 7.21-7.16 (m, 2H), 4.14 (q, 2H), 3.56 (s, 2H) , 1.24 (t, 3H).

102

Step B: Nitrile Melting Point (3-Svan6-phenyl) -acetic acid ethyl ester. A mixture of (3-bromo-phenyl) -acetic acid ethyl ester (9.15 g, 37.6 mmol), copper cyanide (5.06 g, 56.5 mmol), and 1-methyl-2-pyrrolidinone (80 mL ) was placed in an oil bath heated to 120 ° C behind a protective cap. The reaction was heated at 200 ° C for 1 hour and more of copper cyanide (spatula buffer) was expired. After heating For 0.5 h, the reaction was cooled to room temperature. The reaction was diluted with EtOAc and the organic solution was washed with water / ammonia hydroxide solution (2: 1 v / v), the aqueous solution was no longer biologically. The organic solution was washed with saline peel, dried (MgSO₄), filtered, and condensed. Flash chromatography (9: 1 hexane: EtOAc) gave (3-cyano-phenyl) -acetic acid ethyl ester (6.31 g) as a clear oil that hardened to stand.¹1 H NMR (400 MHz, CDCl3)₃) δ 7.57-7.50 (m, 3H), 7.42 (m, 1H), 4.15 (q, 2H), 3.63 (s, 2H), 1.24 (t, 3H) .

Step C: Nitrile Acid in 3-Aminomethylphenylacetic Acid Ethyl Ester Hydrochloride A solution of (3-cyano-phenyl) -acetic acid ethyl ester (6.3 g, 33.29 mmol) in EtOH (50 mL) was added to a mixture of 10% Pd / C (1.26 g) in EtOH (50 mL) under nitrogen. More of EtOH (150 mL) was followed by a solution of HCl in dioxane (4 M, 11.4 mL, 45.6 mmol). The mixture was watered on a Parr shaker

45 psi for 20 hours and the catalyst was removed by centrifugation via celite. The solution was concentrated to give (3-aminomethyl-phenyl) -acetic acid ethyl ester as the hydrochloride salt (7.31 g). 1 H NMR (400 MHz, CD 3 OD) δ 7.42-7.32 (m, 4H), 4.12 (q, 2H), 4.09 (s, 2H), 3.68 (s, 2H), 1.23 (t, 3H).

Step D: Sulphonamides yielding 3- (Methanesulfonyl-6-methyl) -phenyl] -acetic acid ethyl ester. Methanesulfonyl chloride (2.6 mL, 34 mmol) was added to a solution of (3-aminomethyl-phenyl) -acetic acid ethyl ester hydrogen chloride (7.31 g, 34 mmol) and triethylamine (9.8 mL, 70 mL) mmol) in CH₂Cl₂ (100 mL) at 0 ° C.

The mixture was stirred for 1 h and 1N aqueous HCl was added. The aqueous solution was extracted with CH₂Cl₂ (3x) and the combined organic extracts were washed with saline peel. The organic solution was dried over MgSO₄, filtered, and coincided. Purification by flash chromatography (1: 1 hexane: EtOAc) gave the title sulfonamide (8.56 g) as a clear and free oil.¹1 H NMR (400 MHz, CDCl 3) δ 7.34-7.21 (m, 4H), 4.70 (br., 1H), 4.29 (d, 2H), 4.12 (q, 2H), 3 , 60 (s, 2 H),

2.86 (s, 3H), 1.24 (t, 3H).

OTHER GENERAL EXPERIENCES

Mean pressure chromatography was performed on the Flash 40 Biotage system (Biotage Inc., Dyax

Corp., Charlottesville, VA).

103

Dami 75-110

Examples 75-110 were prepared analogously to Example 1 starting with a video alkylation ring agent and sulfonamide in alkylation step A followed by ester hydrolysis in step B with changes in reaction temperature and time in step A as noted.

Dami 75 (vifimifiunardami)

5- {3 - [(6-Chloro-2-kihólín ý1metýi) -metansúlfóný1-amino] -propyl} -thiophene-2-carboxylic acid

Step A: Reaction time of 2 hours room temperature and 24 hours vifi 75'C. 1 H NMR (400 MHz, CDCl3)₃) δ 8.01 (d, 1H), 7.80 (d, 1H), 7.70 (s, 1H), 7.52-7.54 (m, 2H), 7.35 (d, 1H) , 6.50 (d, 1H), 4.54 (s, 2H), 4.02 (bs, 1H), 3.19-3.24 (m, 2H), 2.89 (s, 2H), 2.62 (t, 2H), 1.72 (t, 2H); MS453 (M + 14).

Dami 76 (vifimifiunardami)

5- (3-fl2- (3,5-Bis-trlflúonnetýl-phenoxy) -ethyl] -metansLiifónýi-amino} -propyl) -thiophene-2-carboxylic acid

Step A: Reaction time of 24 hours room temperature. ¹1 H NMR (400 MHz, CDCl3)₃) δ

7.69 (d, 1H), 7.48 (s, 1H), 7.25 (s, 2H), 6.84 (d, 1H), 4.22 (t, 2H), 3.63 (t, 2H) ), 3.36 (t, 2H), 2.91-2.96 (m, 5H), 2.10 (t, 2H); MS 519 (M + 1).

Dami 77 (vifimifiunardami)

5- (3- {Methanesulfonyl- [2- (3-methoxy-phenoxy) -ethyl] -amino} -prúpýf) -thiophene-2-carboxylic) oxýisýra

Step A: Reaction time of 30 min room temperature. ¹1 H NMR (400 MHz, CDCl3)₃) S

7.70 (d, 1H), 7.15-7.19 (m, 1H), 6.84 (d, 1H), 6.51-6.54 (m, 1H), 6.39-6.47 m, 2H), 4.10 (t, 2H), 3.77 (s, 3H), 3.62 (t, 2H), 3.35 (t, 2H), 2.91-2.97 (m , 5H), 2.07 (t, 2H); MS 412 (M-1).

Dami 78 (vifimifiunardemiemia)

7 - {[3- (3-Chloro-5-methoxy-phenoxy) -própý1] -methanesulfonyl-amino} -heptanoic acid

Step A: Reaction time of 24 hours room temperature. ¹1 H NMR (400 MHz, CDCl3)₃) δ 6.48-6.51 (m, 2H), 6.32 (s, 1H), 3.97 (t, 2H), 3.76 (s, 3H), 3.33 (t, 2H) , 3.16 (t, 2H), 2.82 (s, 3H), 2.33 (t, 2H), 2.07 (t, 2H), 1.60-1.61 (m, 4H), 1.31-1.33 (m, 4H); MS 420 (M-1).

104

Dami 79 (Reference Example)

5- (3 - {[3- (3-Chloro-5-methoxy-phenoxy) -propyl] -methanesulfonyl-amino} -propyl) -thiophene-2-carboxylic acid

Step A: Reaction time of 24 hours at room temperature. 1 H NMR (400 MHz, CDCl 3)

7.69 (d, 1H), 6.81 (d, 1H), 6.47-6.50 (m, 2H), 6.30-6.31 (m, 1H), 3.97 (t, 2H) , 3.75 (s, 3H),

3.36 (t, 2H), 3.24 (t, 2H), 2.90 (t, 2H), 2.83 (s, 2H), 1.98-2.11 (m, 4H); MS 460 (M-1).

Dami 80 Focus Centers)

5- (3 - ((3- (3,5-Dichloro-phenoxy) -propyl] -matansúlfónýl-amino} -propyl) -thiophene-2-carboxylic acid

Step A: Reaction time of 24 hours with room temperature. ¹1 H NMR (400 MHz, CDCl3)₃) δ 15 7.69 (d, 1H), 6.94 (t, 1H), 6.82 (d, 1H), 6.76 (s, 2H), 3.99 (t, 2H) 35 (t, 2H), 3.24 (t, 2H),

2.90 (t, 2H), 2.84 (s, 3H), 1.98-2.12 (m, 4H); MS 466 (M-1).

Dami 81 (reference date)

5- (3 - {[2- (3-Ethyl-phenoxy) -ethyl] -methanesulfonyl-Amino} -propyl) -thiophene-2-carboxylic acid

Step A: Reaction time of 24 hours with room temperature. ¹1 H NMR (400 MHz, CDCl3) δ

7.70 (d, 1H), 7.19 (t, 1H), 6.81-6.85 (m, 2H), 6.65-6.68 (m, 2H), 4.11 (t, 2H) , 3.64 (t, 2H),

3.36 (t, 2H), 2.91-2.95 (m, 2H), 2.92 (s, 3H), 2.60 (q, 2H), 2.06-2.12 (m, 2H) . 1.19-1.25 (m,

3H); MS 410 (M⁺-1).

Dami 82 (snack cake)

5- (3 - {(2- (3- (isopropyl-phenoxy) -ethyl] -methanesulfonyl-amino} -propyl) -th (thiophen-2-carboxylic acid

Step A: Reaction time of 24 hours at room temperature. ¹1 H NMR (400 MHz, CDCl3)₃) δ

7.70 (d, 1H), 7.20 (t, 1H), 6.84-6.86 (m, 2H), 6.65-6.71 (m, 2H), 4.11 (t, 2H), 3.64 (t, 2H),

3.37 (t, 2H), 2.92-2.95 (m, 2H), 2.92 (s, 3H), 2.82-2.89 (m, 1H), 2.08 (t, 2H) , 1.22 (d, 6H); MS 424 (M⁺-1).

Dami 83 (benchmark)

5- (3- {Metansúlfóný1- [2- (3-trifluoromethyl-phenoxy) -ethyl] -amide (amino} -propyl) -thiophene-2-carboxylic acid

105 '

Step A: Reaction time of 24 hours at room temperature. ¹1 H NMR (400 MHz, CDCl3)₃) Δ 7.68 (d, 1H), 7.37 (t, 1H), 7.21-7.23 (m, 1H), 7.05 (s, 1H), 7.00 (d, 1H) , 6.82 (d, 1H), 4.14 (t, 2H), 3.62 (t, 2H), 3.34 (t, 2H), 2.92 (t, 2H), 2.90 s, 3H), 2.07 (t, 2H); MS 450 (M⁺-1).

Dami 84 (reference case)

2- (3 - ((2- (3,5-Dichloro-phenoxy) -etý1] -methanesulfonyl-amino} -propyl) -th [isothiazole-4-karboxý1sýra

Step A: Reaction time of 5 hours at 100 ° C. 1 H NMR (400 MHz, CDCl3)₃) Δ 8.20 (s, 1H), 6.98 (s, 1H), 6.89 (s, 2H), 4.16 (t, 2H), 3.62 (t, 2H), 3.37 (t, 2H), 3.08 (t, 2H), 2.93 (s, 3H), 2.15 (t, 2H); MS452 (M⁺-1).

Dami 85 (benchmark)

5- {3- [Methanesulfonyl- (3-futile-propyl) -amino] -propyl} -thiophene-2-carboxylic acid

Step A: Reaction time of 5 hours at 100 ° C. 1 H NMR (400 MHz, CDCl3)₃) δ 7.57 (d, 1H), 7.22-7.26 (m, 2H), 7.12-7.18 (m, 3H), 6.86 (d, 1H), 3,16- 3.22 (m, 4H), 2.87 (t, 2H), 2.83 (s, 3H), 2.61 (t, 2H), 1.84-1.97 (m, 4H); MS 380 (M⁺-1).

Dami 86 (benchmark)

7 - ((3- (3,5-Dichloro-phenoxy) -própý1] -metansúlfóný1-amino} -heptanoic acid

Step A: Reaction time of 24 hours at room temperature. ¹1 H NMR (400 MHz, CDCl3)₃) δ

7.70 (d, 1H), 7.19-7.23 (m, 1H), 6.84 (d, 1H), 6.61-6.70 (m, 2H), 6.56 (d, 1H), 4.10 (t, 2H), 3.62 (t, 2H), 3.34 (t, 2H), 2.90 (s, 3H), 2.86-2.95 (m, 2H ), 2.07 (t, 2H); MS 401 (M * -1).

Dami 87 (benchmark)

5- (3- (Methanesulfonyl- [2- (3-fluoro-phenoxy) -0týl] -amino} -propyl) -thiophene-2-carboxylic acid

Step A: Reaction time of 24 hours at room temperature. 1 H NMR (400 MHz, CDCl3)₃) 8

7.70 (d, 1H), 7.19-7.23 (m, 1H), 6.84 (d, 1H), 6.61-6.70 (m, 2H), 6.56 (d, 1H), 4.10 (t, 2H), 3.62 (t, 2H), 3.34 (t, 2H), 2.90 (s, 3H), 2.86-2.95 (m, 2H ), 2.07 (t, 2H); MS 400 (M⁺-1).

Dami 88 (benchmark)

5- (3- {Metansúlfóný1- [3- (3-matoxý-faný1) -própý1] -amino} -própý1) -thiophene-2-carboxylic acid

106

Step A: Reaction time of 2 hours at room temperature. 1 H NMR (400 MHz, CDCl3)₃) δ

7.71 (d, 1H), 7.20 (t, 1H), 6.83 (d, 1H), 6.71-6.78 (m, 3H), 3.78 (s, 3H), 3 , 17-3.22 (m, 4H), 2.89 (t, 2H), 2.81 (s, 3H), 2.61 (t, 2H), 1.88-2.01 (m, 4H ); MS 411 (M +).

Dami 89 (viflmiflunardami)

5- [3- (Benzofuran-2-ýfmetýl-methanesulfonyl-amino) -propyl] -thiophene-2-a ^ karboxýls

Step A: Reaction time of 2 hours with room temperature. ¹1 H NMR (400 MHz, CDCl3)₃) δ 10 7.68 (d, 1H), 7.54 (d, 1H), 7.42 (d, 1H), 7.22-7.32 (m, 2H), 6.82 (d, 1H ). 6.68 (s, 1H), 4.58 (s, 2H), 3.32 (t, 2H), 2.92 (t, 2H), 2.86 (s, 3H), 2.01-2 , Δ (m, 2H); MS 393 (M +).

Dami 90 (viflmiflunardami)

5- (3 - {[2- (3-Chloro-5-m0toxý-phenoxy) -ethyl] -niBtansLilfóný1-amino} -propyl) -thiophene-2-karboxý1sýra

Step A: Reaction time of 24 hours with room temperature. 1 H NMR (400 MHz, CDCl3)₃) δ

7.71 (d, 1H), 6.84 (d, 1H), 8.53 (s, 1H), 6.44 (s, 1H), 6.28 (s, 1H), 4.08 , 2H), 3.75 (s, 3H), 3.60 (t, 2H), 3.34 (t, 2H), 2.90-2.95 (m, 3H), 2.07 (t, 2H); MS 448 (M +).

Dami 91 (viflmiflunardami)

5- (3 - {[2- (3-Ethoxy-phenoxy) -ethyl] -methanesulfonyl-amino) -propyl) -th (thiophen-2-karboxýteýra

Step A: Reaction time of 24 hours with room temperature. 1 H NMR (400 MHz, CDCl3)₃) δ

7.69 (d, 1H), 7.16 (t, 1H), 6.83 (d, 1H), 6.50-6.53 (m, 1H), 6.39-6.44 (m, 1H), 4.10 (t, 2H),

3.98 (q, 2H), 3.62 (t, 2H), 3.35 (t, 2H), 2.86-2.94 (m, 5H), 2.04-2.11 (m, 2H), 1.39 (t, 3H);

MS428 (M +).

Example 92 (Viflmiflunardami) (4 - {[2- (3,5-Dichloro-phenoxy) -ethyl] -methanesulfonyl-amino} -butoxy) -acetic acid

Step A: Reaction time of 2 hours with room temperature. 1 H NMR (400 MHz, CDCl3)₃) δ

6.96 (s, 1H), 6.77 (s, 2H), 4.10 (s, 4H), 3.56-3.60 (m, 4H), 3.30 (t, 2H), 2 , 89 (s, 3H), 1.73

1.80 (m, 2H), 1.63-1.69 (m, 2H); MS 415 (M + 1).

Example 93 (3 - {[(4-Butoxy-benzyl) -methanesulfonyl-amino] -methyl} -phenyl) -acetic acid

107

Step A: Reaction time of 2 hours at room temperature and 3 hours at 70 ° C. 1 H NMR (400 MHz, CDCl 3) δ 7.28-7.33 (m, 1H), 7.17-7.25 (m, 5H), 6.85 (d, 2H), 4.29 (s) , 2H), 4.24 (s, 2H), 3.94 (t, 2H), 3.64 (s, 3H), 2.73 (s, 3H), 1.72-1.79 (m, 2H), 1.44-1.53 ​​(m, 2H), 0.97 (t, 3H); MS 423 (M + 18).

Dami 94

7 - [(4-Butoxy-benzyl) -methanesulfonyl-amino] -heptanoic acid

Step A: Reaction time of 2 hours with room temperature. ¹1 H NMR (400 MHz, CDCl 3) δ 7.23 (d, 2H), 6.85 (d, 2H), 4.29 (s, 2H), 3.94 (t, 2H), 3.11 , 2H), 2.77 (s, 3H), 2.29 (t, 2H), 1.75 (m, 2H), 1.58-1.43 (m, 6H), 1.24 (m, 4H), 0.96 (t, 3H); MS 403 (M + 18).

Dsmi 95 (viflmiflunardami)

7 - [(6-Chloro-quinolin-2-ylmethyl) -methanesulfonyl-amino] -heptanoic acid

Step A: Reaction time of 2 hours with room temperature. ¹1 H NMR (400 MHz, CDCl 3) δ 5.13 (d, 1H), 8.03 (d, 1H), 7.81 (s, 1H), 7.67 (m, 2H), 4.72 , 2H), 3.26 (t, 2H), 2.99 (s, 3H), 2.25 (t, 2H), 1.52 (m, 4H), 1.22 (m, 4H); MS 417 (M + 18).

Example 96 (trifluoromethyl) {3 - [(Benzofuran-2-ylmethyl-methanesulfonyl-amino) -methyl] -phenyl} -acetic acid

Step A: Reaction time of 2 hours with room temperature. ¹1 H NMR (400 MHz, CDCl 3) δ 7.52-7.19 (m, 8H), 4.42 (s, 2H), 4.37 (s, 2H), 3.63 (s, 2H), 2 , 91 (s, 3H).

Example 97 (3 - {[(4-Ethyl-benzyl) -methanesulfonyl-amino] -methyl} -phenyl) -acetic acid

Step A: (3- ({(4-Ethyl-benz-methanesulfonyl-amino) -methyl] -phenyl} -acetic acid methyl ester, reaction to 24 hours at room temperature. ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.29-7.33 (m, 1H), 7.16-7.25 (m, 7H), 4.30 (d, 4H), 3.69 (s, 3H), 3.62 s, 2H), 2.76 (s, 3H), 2.64 (q, 2H), 1.54 (t, 3H); MS376 (M + 1).

Step B: (3-Fluoro-ethyl-benzyl-methanesulfonyl-amino) -methyl) -lenyl) -acetic acid ¹1 H NMR (400 MHz, CDCl 3) δ 7.30-7.34 (m, 1H), 7.15-7.25 (m, 7H), 4.29 (d, 4H), 3.65 (s, 2H), 2.75 (s, 3H), 2.63 (q, 2H), 1.20-1.24 (m, 3H).

108

Example 98 (3 - {[Methanesulfonyl- (4-propyl-benzyl) -amino] -methyl} -phenyl) -acetic acid

Step A: (3-Methanyl) phenyl- (4-propyl-benzyl) -amino] -methyl] -phenyl] -acetic acid methyl ester. Reaction time of 24 hours at room temperature. MS 408 (M + + 18).

Step B: (3-Methanesulfonyl- (4-propyl-benzyl) -amino] -methyl) -phenyl) -acetic acid MS 374 (M * -1).

Example 99 (Compounds) (3 - {[(4-Benzyl-benzyl) -methanesulfonyl-amino] -methyl} -phenyl) -acetic acid

Step A: ί ^ Πί ^ ΒθηβγΚ ^ θηβγΙΙ ^ πτθΙβηΒύΙίόηγυ ^ ιοίπίϊΕπίδΙγϊΙ ^ ΟΙτγΰΞθίίϊΗδίίΙ-Γθθίγί ester, reaction rate of 24 hours at room temperature. 1 H NMR (400 MHz, CDCl 3) δ 7.14-7.29 (m, 13H), 4.28 (d, 4H), 3.95 (s, 2H), 3.67 (s, 3H), 3.59 (s, 2H), 2.75 (s, 3H); MS 456 (M⁺+18).

Step B: [3- (4-Benzyl-benzyl-methanesulfonyl-amino) -methyl) -phenyl] -acetic acid ¹1 H NMR (400 MHz, CDCl 3) δ 7.12-7.29 (m, 13H), 4.27 (d, 4H), 3.94 (s, 2H), 3.61 (s, 2H), 3 , 73 (s, 3H); MS422 (LT-1).

Psmi 109 (3 - {[(4-Butyl-benzyl) - (propane-1-sulfanyl) -amino] -methyl} -phenyl) -acetic acid

Step A: (3-Fluoro-butoxy-1-benzofuran-1-sulfonyl) -amino] -methyl] -phenyl} -acetic acid methyl ester, 1 H NMR (400 MHz, CDCl3)? 4.30 (d, 4H), 3.69 (s, 3H), 3.61 (s, 2H), 2.82-2.86 (m, 2H), 2.59 (t, 2H), 1.78- 1.84 (m, 2H), 1.58 (t, 2H).

Step B: [3- (4-Butyl-benzyl) - (aran-1-sulfonyl) -amino] -methyl] -phenyl-acetic acid 1 H NMR (400 MHz, CDCl3)? 7.12-7.32 (m, 8H) , 4.30 (d, 4H), 3.64 (s, 2H), 2.81-2.90 (m, 2H), 2.59 (t, 2H), 1.74-1.83 (m , 2H), 1.54-1.61 (m, 2H), 1.31-1.40 (m, 2H), 0.87-0.97 (m, 6H); MS

416 (M * -1).

Dami 101 (reference date)

7- {Methanesulfonyl- [3- (5-methyl-thiophen-2-yl) -propyl] -amino} -heptanoic acid

Step A: 7- (Methanesulphonyl- [3- (5-methyl-biphenyl-2-yl) -propyl] amino] -heptanoic acid methyl ester. A reaction time of 1 hour at 60 DEG C. @ 1 H NMR (400 MHz, CDCl3 ) δ 6.55 (d, 2H), 3.66 (s, 2H), 3.12-3.21 (m, 4H), 2.80 (s, 3H), 2.76-2.80 m, 2H), 2.42 (s, 3H), 2.30 (1, 2H), 1.89

1.97 (m, 2H), 1.53-1.65 (m, 4H), 1.31-1.36 (m, 4H); MS 376 (M + + 1), 393 (M + + 18).

109

Step B: 7-Methanesulfonyl-1- [3- (5-methyl-biphen-2-yl) -propyl] -amino) -heptane acid 1 H NMR (400 MHz, CDCl3₃) δ 6.53-6.57 (m, 2H), 3.12-3.21 (m, 4H), 2.80 (s, 3H), 2.78 (t, 2H), 2.42 s, 3H), 2.34 (t, 2H), 1.89-1.97 (m, 2H), 1.54-1.66 (m, 4H), 1.30-1.40 (m, 4H); MS 379 (M⁺+18).

Dsmi 102 (Viflmiflunardsmi)

5- {3 - [(3-Furan-2-yl-propyl) -methanesulfonyl-amino] -própý1} -thiophene-2-carboxylic acid

Step A: 5- [3- (3-Furan-2-fluoro-propyl) -methanesulfonyl-amino] -propyl] -biphenyl-2-carboxylic acid methyl ester, Reaction time of 2 hours at room temperature. 1 H NMR (400 MHz, CDCl3₃) δ 7.62 (d, 1H), 7.29 (d, 1H), 6.80 (d, 1H), 6.26-6.28 (m, 1H), 6.00 (d, 1H) , 3.85 (s, 3H), 3.18-3.23 (m, 4H), 2.88 (t, 2H), 2.81 (s, 3H), 2.66 (1.2H), 1.90-2.03 (m, 4H).

Step B: 5- [3- (3-Furan-2-yl) -propyl-methanesulfonyl-amino-pyridyl) -biphen-2-carboxylic acid, 1 H NMR (400 MHz, CDCl3)? 7.71 (d, 1H), 7 , 29 (d, 1H), 6.84 (d, 1H), 6.26-6.28 (m, 1H), 6.00-6.01 (m, 1H), 3.22 (q, 4H ), 2.90 (t, 2H), 2.82 (s, 3H), 2.67 (t, 2H), 1.88-2.03 (m, 4H); MS 370 (M⁺-1).

Dsmi 103 (Viflmiflunardsmi)

7- {Methanesulfonyl- [3- (3-methoxyphenyl) -propyl] -amino} -heptanoic acid

Step A: 7- (Methanesulphonyl-3- (3-methoxyphenyl) propyl] amino] -pentanoic acid methyl ester, reaction mixture over 2 hours at room temperature. 1 H NMR (400 MHz, CDCl3₃) δ 7.18-7.22 (m, 1H), 6.75-6.78 (m, 2H), 6.73 (s, 1H), 3.79 (s, 3H), 3.66 s, 3H), 3.11-3.20 (m, 4H), 2.80 (s, 3H), 2.61 (t, 2H), 2.29 (t, 2H), 1.88-1 , 95 (m, 2H), 1.52-1.64 (m, 4H), 1.28-1.32 (m, 4H). Step B: 7-Methanesulfone [H3- (3-methoxyphenyl) -propyl] -amine] -heptane89ra.1 H NMR (400 MHz, CDCl3) δ 7.18-7.22 (m, 1H), 6.75-6, 78 (m, 2H), 6.73 (s, 1H), 3.79 (s, 3H), 3.11-3.20 (m, 4H), 2.80 (s, 3H), 2.61 (t, 2H), 2.34 (t, 2H), 1.89-1.95 (m, 2H), 1.53-1.66 (m, 4H), 1.291.36 (m, 4H).

DSMI 104 [3 - ({[4- (1-Hydroxy-hexyl) -benzyl] -methanesulfonyl-amino} -methyl} -phenyl} -acetic acid tertiary ester, Reaction time of 2 hours at room temperature. 1 H NMR (400 MHz, CDCl₃) δ 7.17-7.31 (m, 8H), 5.70 (t, 1H), 4.31 (s, 4H), 4.12-4.17 (m, 4H), 3.60 S, 2H), 2.76 (s, 3H), 2.06 (s, 3H), 1.83-1.88 (m, 1H), 1.57-1.75 (m, 1H), 1 , 20-1.27 (m, 9H), 0.85 (t, 3H); MS 525 (M + + 18).

110

Step B: 1-Hydroxy-hexyl-benzyl] -methanesulfonyl-amino] -methyl} -phenyl] -acetic acid. H

NMR (400 MHz, CDCl3)₃) δ 7.13-7.28 (m, 7H), 7.02 (s, 1H), 4.61 (t, 1H), 4.29 (d, 4H), 3.53 (s, 2H) , 2.79 (s, 3H), 1.60-1.77 (m, 2H), 1.18-1.36 (m, 6H), 0.83 (t, 3H); MS 432 (M * -1).

Dami 105 (viflmiflunardami)

5- (3 - {[2- (3-Chloro-phenoxy) -ethyl] -methanesulfonyl-amino} -propyl) -th (thiophen-2-carboxylic acid

Step A: 5- (3- {2- (3-Chloro-benzyloxy) -ethyl] -methanesulfonyl-amino] -propyl} -biphenyl-210-carboxvic acid methyl ester. Reaction time of 18 hours at 60 ° C.¹1 H NMR (400 MHz, CDCl3)₃) δ 7.60-7.62 (m, 1H), 7.15-7.20 (m, 1H), 6.93-6.95 (m, 1H), 6.79-6.80 (m , 2H), 6.71-6.73 (m, 1H), 4.09 (t, 2H), 3.84 (s, 3H), 3.60 (t, 2H), 3.32 (t, 2H), 2.89 (s, 3H), 2.86-2.94 (m, 2H), 2.01-2.08 (m, 2H).

Step B: 5- (3- {2- (3-Chloro-phenoxy) -ethyl] -methylsulfonyl-amino} -propyl) -biphen-2-carboxylic acid 1H NMR (400 MHz, CDCl3) δ 7.67 (d, 1H), 7.11-7.22 (m, 1H). 6.91-6.93 (m, 1H), 6.81 (s, 2H), 6.69-6.72 (m, 1H), 4.07 (t, 2H), 3.59 (t, 2H), 3.31 (t, 2H), 2.88 (s, 3H), 2.78-2.91 (m, 2H), 2.01-2.05 (m, 2H).

Dami 106 (Viðmiflunaidami)

2- {3- [Methanesulfonyl- (3-phenylpropyl) amino] propyl} -thiazole-4-carboxylic acid

Step A: 2- (3-Methanesulfonyl- (3-phenyl-pyridyl) -amino-1-isoyl) -bisulphol-4-carboxylic acid ethyl ester, Reaction time of 5 hours at 100 DEG C. 1 H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.23

7.27 (m, 2H), 7.13-7.18 (m, 3H), 4.38 (q, 2H), 3.16-3.25 (m, 4H), 3.06 (ζ 2H ), 2.79 (s, 3H),

2.61 (t, 2H), 2.05-2.13 (m, 2H), 1.86-1.94 (m, 2H), 1.37 (t, 3H); MS 411 (M⁺+1).

Step B: 243-Methanesulfonyl- (3-phenyl-propyl) -amino] -propyl] -azole-4-carboxylic acid, 1 H NMR (400 MHz, CDCl3)? 8.20 (s, 1H), 7.10-7, 24 (m, 5H), 3.17-3.28 (m, 4H), 3.04 (t, 2H), 2.83 (s, 3H), 2.61 (t, 2H), 2.02 -2.09 (m, 2H), 1.85-1.92 (m, 2H); MS 381 (M + -1).

Demi 107 (viflmiflunardami)

2- (34 [3- (3-Chloro-phenyl) -propyl] -methanesulfonyl-amino} -propyl) -thiazole-4-kaitioxýisýra

Step A: 2- (3-β3- (3-β-β-3-yl) -propionic acid-3-carboxylic acid ethyl ester, Reaction time of 5 h at 100 DEG C. 1 H NMR (400 MHz, CDCl3₃) δ 8.06 (s, 1H), 7.16-7.23 (m, 3H), 7.05 (d, 1H), 4.40 (q, 2H), 3.09 (t, 2H) , 3.19-3.28 (m, 4H), 2.83 (s, 3H), 2.62 (t, 2H), 2.08-2.17 (m, 2H), 1.87-1 , 95 (m, 2H), 1.39 (t, 3H); MS 445 (MH⁺).

Step B: 2-Chloro-3- (3-Chloropentyl) -propovil-methanesulfonylamino) -propyl) -biazol-4-carboxylic acid,

NMR (400 MHz, CDCl3)₃) δ 8.22 (s, 1H), 7.21-7.25 (m, 2H), 7.12-7.16 (m, 2H), 3.20-3.30

(M, 2H), 1.86 (s, 3H) -1.94 (m, 2H); MS 415 (M⁺-1).

Dsmi 108

2- {3 - [(4-Bttýl-benzyl) -methanesulfonyl-amino] -propyl} -thiazole-4-carboxylic acid

Step A: 2- [3- (4-Butyl-benzyl) -methanesulfonyl-amino] -propyl] -isothiazole-4-carboxylic acid ethyl ester. Reaction time of 5 h at 100 DEG C. @ 1 H NMR (400 MHz, CDCl3) 00 (s, 1H), 7.21 (d, 2H), 7.11 (d, 2H), 4.38 (q, 2H), 4.33 (s, 2H), 3.23 (t, 2H) ), 2.96 (t, 2H), 2.78 (s, 3H), 2.56 (t, 2H), 1.96-2.03 (m, 2H), 1.50-1.58 m, 2H), 1.37 (t, 3H), 1.26-1.33 (m, 2H), 0.89 (t, 3H); MS 439 (M + 1).

Step B: 2- [3- (4-Butyl-benzyl) -methanesulfonyl-amino] -propyl] -isole-4-carboxylic acid ¹1 H NMR (400 MHz, CDCl3)₃) δ 8.15 (s, 1H), 7.25 (d, 2H), 7.12 (d, 2H), 4.32 (s, 2H), 3.22-3.28 (m, 2H) , 2.88-2.91 (m, 2H), 2.88 (s, 3H), 2.57 (t, 2H), 1.87 (m, 2H), 1.54 (m, 2H), 1.27-1.32 (m, 2H), 0.90 (1.3H); MS 409 (M-1).

Example 109 (5 - {[(4-Isobutyl-benzyl) -methanesulfonyl-amino] -phenyl} -thiophen-2-yl) -acetic acid

Step A: (5 - [(4-Isobutyl-bansyl) -methanesulfonyl-amino] -methyl} -biphen-2-yl) -dicarboxylic acid ester. Reaction time of 24 hours at room temperature.

Step B: (5 - [(4-Isobutyl-benzyl) -methanesulfonyl-amino] -methyl} -biphen-2-yl) -acetic acid.1 H NMR (400 MHz, CDCl3)? 6.80-7.32 (m, 6H) , 4.40 (s, 2H), 3.80 (s, 2H), 2.75 (s, 3H), 1.8 O (m, 2H), 0.85 (d, 6H); MS 394 M-1).

Dami 110

2- {3 - [(4-Butyl-benzyl) -methanesulfonyl-amino] -propyl} -thiazole-4-carboxylic acid

Step A: 2- [3- (4-Butyl-benzyl) -methanesulfonyl-amino] -dione} -isothiazole-4-carboxylic acid ethyl ester, reaction mixture over 5 h at 100 ° C. ¹1 H NMR (400 MHz, CDCl 3) δ 8.00 (s, 1H), 7.21 (d, 2H), 7.11 (d, 2H), 4.38 (q, 2H), 4.33 , 2H), 3.23 (t, 2H), 2.96 (t, 2H), 2.78 (s, 3H), 2.56 (t, 2H), 1.96-2.03 (m, 2H), 1.50-1.58 (m, 2H), 1.37 (t, 3H), 1.26-1.33 (m, 2H), 0.89 (t, 3H); MS439 (M + 1).

Step B: 2- [3- (4-Butyl-benzyl) -methanesulfonyl-amino] -diohydryl) -biazole-4-carboxylic acid 1H NMR (400 MHz, CDCl3)? 8.15 (s, 1H) 25 (d, 2H), 7.12 (d, 2H), 4.32 (s, 2H), 3.22-3.28 (m, 2H), 2.88-2.91 (m, 2H) , 2.88 (s, 3H), 2.57 (t, 2H), 1.87 (m, 2H), 1.54 (m, 2H), 1.27-1.32 (m, 2H), 0.90 (t, 3H); MS 409 (M + -1).

112

Dami 111 (case study)

7 - {[2- (3,5-Dichloro-phenoxy) -ethyl] -methanesulfonyl-amino) -heptanoic

Step A: 2- [2- (3,5-Dichloro-phenoxy) -ethyl] -isoquinoline-1,3-dione A solution of 1- (2-bromo-ethoxy) 3,5-dichlorobenzene (2.41 g, 8.93 mmol) and potassium phosphate (2.00 g, 10.64 mmol) in DMF (7.6 mL) was heated at 85 ° C for 1 h. The reaction was cooled to room temperature and the chloroform was poured out. The organic solution was washed with 0.2 N aqueous NaOH followed by water. The organic solution was dried (Na2 O4), filtered and concentrated. The residue was suspended in EtOAc and the solid was collected by filtration to give the title compound (2.21 g) .1 H NMR (400 MHz, CDCl3) δ 7.82 m, 2H), 7.77 (m, 2H), 6.89 (m, 1H), 6.88 (m, 2H), 4.16 (t, 2H), 4.05 (t, 2H); MS 336 (M +).

Step B: 2- (3,5-Dichloro-phenoxyl-etflamine) A solution of 2- (2- (3,5-dichloro-phenoxy) -ethyl] -isoindole-1,3-dione (1.29 g, 3.84 mmol) and hydrazine hydrate (202 mg, 4.05 mmol) in methanol (16 mL) was heated at reflux for 2 h. The mixture was cooled to room temperature and Et₂O was bitten out. The suspension was shaken with 40% aqueous solution of potassium hydroxide. The aqueous solution was extracted with EtgO (3x) and the combined Iffranu login was dried (K₂CO₃), filtered, and concentrated to yield the title compound (870 mg). HNMR (400 MHz, CDCl3) δ 6.95 (m, 1H), 6.80 (m, 2H), 3.95 (m, 2H), 3.07 (t, 2H), 1.70 (bs , 2H).

Step C: N- [2- (3,5-D (Chloro-phenoxy) -ethyl] -methanesulfonamide. The triple compound was prepared from 2- (3,5-dichloro-phenoxy) -ethylamine, E2 N, and methanesulfonyl chloride with using the procedure described in Step 2 of Production A1. Recrystallization from EtOH gave the title compound. 1H NMR (400 MHz, CDCl3) δ 6.93 (m, 1H), 6.74 (m, 2H), 5.09 (m , 1H), 4.01 (t, 2H), 3.47 (q, 2H), 2.96 (s, 3H).

Step D: 7- {2- (3,5-Dichloro-ferroxy) -ethvl-methanesulfonylamino] -titanoic acid ethyl ester, A solution of NaH (60% in oil, 338 mg, 8.45 mmol) in DMF (23 mL) was added cold at 0 ° C followed by extraction of N- [2- (3,5-dichloro-phenoxy) -ethyl] methanesulfonamide (2.0 g, 7.04 mmol). The reaction was stirred at room temperature for 0.5 h and was left cold at 0 ° C followed by the addition of ethyl 7-bromoheptanoate (2.0 g, 8.45 mmol). The reaction was heated at 65 ° C for 3 hours and the cat was at room temperature. EtOAc was extracted and the organic solution was washed sequentially with 1N HCl, water, and brine. The liver solution was dried (MgSO₄), filter, and consolidated. Purification by flash chromatography (4: 1 hexane: EtOAc) gave the title compound (2.84 g). HNMR (400 MHz, CDCl3) δ 6.95 (m, 1H), 6.75 (m, 2H), 4.06 (m, 5H), 3.56 (t, 2H), 3.22 , 2H), 2.86 (s, 3H), 2.26 (t, 2H), 1.60 (m, 4H), 1.32 (m, 4H), 1.22 (t, 3H).

Step E: 7- {2- (3,5-Dichloro-phenoxy) -ethyl] -methanesulfonylamino} -heptanoic acid The title compound was prepared from 7 - {[2- (3,5-dichloro-phenoxy) -ethyl ] -methanesulfonyl-amino} -heptanic acid ethyl ester using the procedure described in Step B of Example 1 with 2N NaOH. Purification by flash chromatography (1% MeOH in CH2) gave the title acid. 1 HNMR (400 MHz, CDCl3)₃) δ 6.95 (m, 1H), 6.75 (m, 2H), 4.07 (t, 2H), 3.56 (t, 2H), 3.23 (t, 2H), 2.86 (s, 3H), 2.33 (t, 2H), 1.61 (m, 4H), 1.33 (m, 4H); MS 411 (M-1).

113

Sample numbers 112-122 are not used in this description.

Examples 123-137

Examples 123-137 were prepared analogously to Example 1 starting with the appropriate alkylation agents and sulfonamides in alkylation step A followed by ester hydrolysis in step B with changes in reaction temperature and time in step A as listed.

Example 123 (5- ({[3- (3-Chloro-phenyl) -propyl] -methanesulfonyl-amino} -methyl) -thiophen-2-yl] -acetic acid

Step A: [5- (3,3-Chloro-phenyl) -propyl] -methanesulfonyl-amino) -methyl] -biphen-2-yl] -acetic acid methyl ester, Reaction time of 24 hours at room temperature.

Step B: R5 - ({[3- (3-Chloro-phenyl) -propyl] -methanesulfonyl-amino) -methyl} -biphen-2-yl-acetic acid 1 H NMR (400 MHz, CDCl3) δ 7.06-7 , 36 (m, 4H), 6.86 (m, 2H), 4.40 (s, 2H), 3.80 (s, 2H), 2.90 (s, 3H), 3.00 (t, 2H, J = 7.0), 2.40 (t, 2H, J = 7.0), 1.70 (m, 2H); MS 399 (M-1).

Example 124 (Compound Methyl) [5 - ({[2- (3,5-Dichloro-phenoxy) -ethyl] -methanesulfonyl-amino} -methyl) -thiophen-2-yl] -acetic acid

Step A: [5- (2- (3,5-Dichloro-phenoxy) -ethyl] -methanesulfonyl-amino) -methyl-biphen-2-yl-acetic acid methyl ester, Reaction time of 24 hours at room temperature.

Step B: [5 - ((2- (3,5-Dichloro-phenoxy) -ethyl] -methanesulfonyl-amino] -methyl} -biphen-2-yl] -acetic acid, 1 H NMR (400 MHz, CDCl3) δ 6.60 -7.60 (m, 5H), 4.60 (s, 2H), 4.10 (m, 2H), 3.80 (s, 2H), 3.60 (m, 2H), 2.90 s, 3H); MS 436 (M-1), 438 (M + 1).

Example 125 (5 - {[(4-Butyl-benzyl) -methanesulfonylamino] -methyl} -thiophen-2-yl) -acetic acid

Step A: (5 - {[(4-Benzyl-benzyl) -methanesulfonylaminol-methyl] -biphen-2-yl) -dicarboxylic acid with a ester, reaction time of 24 hours at room temperature. ,

Step B: (5 - {(4-Butyloxy) -methanesulfonyl-amino] -methyl] -biphen-2-yl] -acetic acid.1 H NMR (400 MHz, CDCl3)? 7.00-7.30 (m, 4H) , 6.80 (d, 1H, J = 4.0), 6.70 (d, 1H, J = 4.0), 4.40 (s, 2H), 4.30 (s, 2H), 3 , 80 (s, 2H), 2.90 (s, 3H), 2.60 (m, 2H), 1.60 (m, 2H), 1.30 (m, 2H), 0.90 (t, 3H, J = 7.0); MS 394 (M-1).

Dami 126 (viflmiflunardami)

114

5- (3 - {[2- (3,5-Dichloro-phenoxy) -ethyl] -metansúlfóný1-amino} -propyl) -furan-2-carboxylic acid

Step A: 5- (3- {2- (3,5-Dichloro-phenoxy) -ethyl] -methanesulfonyl-amino) -propyl) -furan-2-carboxylic acid methyl ester, Reaction time for 72 hours at room temperature; MS 450 (M + 1).

Step B: 5- (3- {2- [3,5-Dichloro-phenoxy-ethyl] -methanesulfonyl-amino] -propyl] -furan-2-carboxylic acid, 1 H NMR (400 MHz, CDCl3) δ 6.80-7 , 70 (m, 5H), 6.19 (d, 1H, J = 3.8), 4.20 (t, 2H, J = 7.0), 3.80 (m, 2H), 3.25 3.40 (m, 4H), 2.95 (s, 3H), 2.65 (m, 2H), 1.80-2.00 (m, 2H); MS 435 (M-1), 436 (M + 1).

Dami 127 (reference date)

Trans-5- (3 - {[3- (3,5-Dichloro-phenyl) -allyl] -methanesulfonyl-amino) -propyl) -furan-2-carboxylic acid

Step A: Trans-5- (3- {3- [3,5-Dichloro-phenyl) -all-1-methanesulfonyl-amino) -propyl] -furanecarboxylic acid methyl ester. Reaction time of 72 hours at room temperature; MS 446 (M +).

Step B; Trans-5-3-ff3- (3.5-Dichloro-phen #) - # 1 all-metansúlfðm? F-amino) -propyl) -furan-2-karboxvjsvra. 1 H NMR (400 MHz, CDCl3)₃) δ 7.00-7.50 (m, 4H), 6.00-6.60 (m, 3H), 4.00 (d, 2H, J = 5.0), 3.20 (m, 2H) ), 2.60-2.70 (m, 2H), 1.70-2.00 (m, 2H); MS 430 (M-1), 432 (M + 1).

Dami 128 (reference date)

3- (2 - ((2- (3,5-Dichloro-phenoxy) -ethyl] -methanesulfonamide -amino} -ethyl) -benzoic acid

Step A; 3- (2- {2- (3,5-Dichloro-phenoxy-ene) -methanesulfamide-1-amino] benzoic acid methyl ester. Reaction time of 2 hours at room temperature; MS 446 (M +).

Step B: 3- {2- [2- (3,5-Dichloro-phenoxy) -ethyl] -methanesulfonyl] -amino] -ethyl} -benzoic acid, 1 H NMR (400 MHz, CDCl3) δ 6.80-7.90 (m, 7H), 4.20 (t, 2H, J = 6.7), 3.20-3.30 (m, 4H), 2.85 (s, 3H), 2.30 (t, 2H, J = 6.8 ); MS 431 (M-1).

Example 129 (Reference Example) [3- (3 - {[3- (3-Chloro-phenyl) -prop #] -methanesulfonamide -amino} -propionic acid #

Step A: [3- (3-Chloro-phenyl) -propyl] -methanesulfonyl-amino] -propyl} -phenylacetic acid methyl ester, Reaction time of 2 hours with room temperature. ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.03-7.29 (m, 8H), 3.68 (s, 3H), 3.59 (s, 2H), 3.15-3.20 (m, 4H), 2.80 s, 3H), 2.58-2.64 (m, 4H), 1.84-1.94 (m, 4H).

Step B: [3- (3-Chloro-3-Chloro-phenoxy) -Drazil-Melanase ############################# ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.02-7.29 (m, 8H), 3.61 (s, 2H), 3.14-3.19 (m, 4H), 2.78 (s, 3H), 2,57- 2.80 (m, 4H), 1.82-1.93 (m, 4H).

115

Dami 130 (vidmidunardami)

5- {3 - [(3-Benzo [1,3] dioxol-5-yl-propyl) -methanesulfonyl-amino] -propyl} -thiophene-2-karboxý1sýra

Step A: 5- [3 - [(3-Benzo [1,3] dioxol-5-yl-propyl) -methanesulfonyl-amino] -propyl} -biphen-2-carboxylic acid methyl ester. Reaction time of 2 hours at room temperature.¹1 H NMR (400 MHz, CDCl 3) δ 7.61 (d, 1H), 6.79 (d, 1H), 6.58-6.72 (m, 3H), 5.91 (s, 2H), 3 , 85 (s, 3H), 3.14-3.21 (m, 4H), 2.87 (t, 2H), 2.80 (s, 3H), 2.55 (t, 2H) 82-1.99 (m, 4H).

Step B: 5- [3 - [(3-Benzo [1,3] doxol-5-yl) -Dimethanesulfonyl-amino] -dione} -biprofen-2-carboxylic acid. 1 H NMR (400 MHz, CDCl3)₃) δ 7.70 (d, 1H), 6.83 (d, 1H), 6.59-6.73 (m, 3H), 5.91 (s, 2H), 3.15-3.22 m, 4H), 2.89 (t, 2H), 2.81 (s, 3H), 2.55 (t, 2H), 1.83-2.01 (m, 4H); MS 424 (M-1).

Example 131 (3 - {[(4-Isobutyl-benzyl) -methanesulfonyl-amino] -methyl} -phenyl) -acetic acid

Step A: (3 - [(4-Isobutyl-benzyl) -methanesulfonyl-amino] -methyl} -phenylacetic acid methyl ester, Reaction time of 2 hours at room temperature. ¹1 H NMR (400 MHz, CDCl 3) δ 7.20-7.32 (m, 6H), 7.11 (d, 2H), 4.30 (d, 4H), 3.69 (s, 3H), 3 , 62 (s, 3H), 3.62 (s, 3H), 2.75 (s, 3H), 2.46 (s, 2H), 1.81-1.88 (m, 1H) 88 (d, 6H); MS 404 (M + 1), 426 (M + 23).

Step B: O-f-isobutylbenzyl-methanesulfonyl-amino-methyl-phenylphenylacetic acid ¹1 H NMR (400 MHz, CDCl 3) δ 7.18-7.31 (m, 6H), 7.10 (d, 2H), 4.29 (d, 4H), 3.63 (s, 2H), 2 , 73 (s, 3H), 2.45 (d, 2H), 1.80-1.87 (m, 1H), 0.88 (d, 6H).

Dsmi 132

7 - [(4- (sóprúpýl-benzyl) -methanesulfonyl-amino] -heptanoic acid

Step A: 7 - [(4-Isopropyl-benzyl) -methanesulfonyl-amino] -heptanoic acid ethyl ester, Reaction time of 24 hours at room temperature. ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.20-7.30 (m, 4H), 4.35 (s, 2H), 4.10 (q, 2H), 3.15 (t, 2H), 2.85-2.95 m, 1H), 2.80 (s, 3H), 2.25 (t, 2H), 1.48-1.62 (m, 4H), 1.18-1.32 (m, 13H); MS 384 (M + 1).

Step B: 7- [(4-Isopropyl-benzyl) -methanesulfonyl-amino] -heptanoic acid MS 356 (M + 1).

Dsmi 133 (vidmidunardami)

7 - {[2- (3,5-Difluoro-phenoxy) -ethyl] -amino} -metansúlfóflý1 -hBptansýra

116

Step A: 7- [2- (3,5-Difluoro-phenoxy) -ethyl] -methan-3-yl} -amino] -heptanoic acid methyl ester. Reaction time of 24 hours at 50 ° C. 1 H NMR (400 MHz, CDCl 3) δ 6.39-6.45 (m, 3H), 4.08 (1, 2H), 3.65 (s, 2H), 3.58 (t, 2H), 3.23-3.27 (m, 2H), 2.88 (s, 3H), 2.30 (t, 2H), 1.571.65 (m, 5H), 1.33-1.35 (m, 4H); MS 394 (M + 1).

Step B: 7- [2- (3,5-Difluoro-phenoxy-ethyl) -methanesulfonyl-amino} -heptanoic acid ¹1 H NMR (400 MHz, CDCl 3) δ 6.39-6.45 (m, 3H), 4.08 (t, 2H), 3.58 (t, 2H), 3.25 (t, 2H), 2 , 35 (t, 2H), 1.64 (m, 5H), 1.24-1.37 (m, 4H); MS 380 (M-1).

Dami 134 (vifimifiunardami)

7 - ((2- (3,5-dimethyl-phenoxy, -ethyl] -amino} -metarisúlfónýl -heptar) acid

Step A: 7 - ([2- (3,5-Dimethyl-tenoxy-ethyl) -methanesulfonyl-amino) -heptanoic acid methyl ester. Reaction time of 24 hours at 50 DEG C. NMR (400 MHz, CDCl3)? 6.61 (s, 1H ), 6.49 (s,

2H), 4.06-4.14 (m, 2H), 3.65 (s, 3H), 3.61 (t, 2H), 3.26 (t, 2H), 2.90 (s, 3H ), 2.27-2.33 (m,

8H), 1.55-1.63 (m, 4H), 1.25 (bs, 4H); MS 385 (M + 1).

Step B: 7- {2- (3,5-Dimethyl-phenoxy) -ethyl] -methanesulfonyl-amino} -heptanoic acid. ¹H NMR (400 MHz, CDCl3) δ 6.61 (s, 1H), 6.49 (s, 2H), 4.06-4.07 (m, 2H), 3.59-3.61 (m, 2H), 3.27 (t, 2H), 2.91 (s, 3H), 2.34 (t, 2H), 2.27 (s, 6H), 1.63-1.65 (m, 4H ), 1.36 (bs, 4H); MS 370 (M-1).

CsamL35 (2- (3 - ((4-Butyl-benzyl) -methanesulfonyl-amino] -propyl} -phenyl) -acetic acid

Step A: (2- (3 - [(4-Butyl-benzyl) -methanesulfonyl-amino] -propyl} -phenyl) -acetic acid methyl ester, 1 H NMR (400 MHz, CDCl3) δ 7.11-7.23 m, 7H), 6.99-7.01 (m, 1H), 4.31 (s, 2H), 3.63 (s, 3H), 3.54 (s, 2H), 3.19 (t , 2H), 2.78 (s, 3H), 2.49-2.59 (m, 4H), 1.72-1.80 (m, 2H), 1.541.59 (m, 2H) 27-1.36 (m, 2H), 0.89 (t, 3H); MS 432 (M + 1).

Step B: (2- (3- (4-Butyl-benzyl-1-methanesulfonyl-amino-propyl) -phenyl) -acetic acid ¹1 H NMR (400 MHz, CDCl 3) δ 7.13-7.27 (m, 7H), 7.02 (d, 1H), 4.32 (s, 2H), 3.59 (s, 2H), 3 , 21 (t, 2H), 2.79 (s, 3H), 2.50-2.61 (m, 4H), 1.73-1.81 (m, 2H), 1.54-1.62 (m, 2H), 1.29-1.38 (m, 2H), 0.92 (t, 3H); MS 416 (M-1).

Dami 136 (vifimifiunardami)

5- (3 - {[2- (Benzo [1,3] dioxol-5-ý1oxý) -ethyl] -methanesulfonyl-amino} -propyl) -thiophene-2-carboxylic acid

117

Step A: 5- [3- (2- (Benzop 1,3-dioxol-5-yloxy) -ethyl] -methanesulfonyl-amino) -propyl} biphene-2-carboxylic acid methyl ester, Reaction time of 24 hours at room temperature. ¹1 H NMR (400 MHz, CDCl 3) δ 7.61 (d, 1H), 6.80 (d, 1H), 6.67-6.70 (m, 1H), 6.41 (d, 1H), 6 , 24-6.27 (m, 1H), 5.91 (s, 2H), 4.03 (t, 2H), 3.85 (s, 3H), 3.59 (t, 2H) 33 (t, 2H), 2.89 (s, 3H), 2.882.92 (m, 2H), 2.01-2.08 (m, 2H); MS 442 (M + 1).

Step B: 5- {3- [2- (Benzol-1,3-dioxol-5-yloxy) ethyl] -methanesulfonylamino} -propyl) -phosphene-2-carboxylic acid, 1 H NMR (400 MHz, CDCl3₃) δ 7.69 (d, 1H), 6.84 (d, 1H), 6.68 (d, 1H), 6.40 (s, 1H), 6.24-6.27 (m, 1H) , 5.91 (s, 2H), 4.03 (t, 2H), 3.60 (t, 2H), 3.34 (t, 2H), 2.90 (s, 3H) 2.94 (m, 2H), 2.02-2.10 (m, 2H); MS 426 (M-1).

Example 137 (Reference Example) [3 - ({[2- (3-Chloro-phenoxy) -ethyl] -methanesulfonyl-amino} -methyl) -phenyl] -acetic acid

Step A: [3- (2 - {(3-Chloro-phenoxy) -ethyl] -methanesulfamide (1-amino) -methyl) -phenyl-acetic acid^lu m aster, ¹1 H NMR (400 MHz, CDCl 3)? 7.15-7.33 (m, 5H), 6.93-6.95 (m, 1H), 6.80-6.81 (m, 1H) 69-6.71 (m, 1H), 4.49 (s, 2H), 3.96-4.02 (m, 2H), 3.67 (s, 2H), 3.54-3.67 m, 4H), 2.94 (s, 3H).

Step B: [3- (2 - {[3-Chloro-phenoxy] -ethyl] -methanesulfamide-1-amino] -methyl} -phenyl) -acetic acid. ¹1 H NMR (400 MHz, CDCl 3) δ 7.13-7.33 (m, 5H), 6.91 (d, 1H), 6.78 (s, 1H), 6.66-6.69 (m, 1H), 4.48 (s, 2H), 3.98 (t, 2H), 3.62 (s, 2H), 3.56 (t, 2H), 2.92 (s, 3H).

Example 138 (Reference Example) [3- (2 - {[3- (3-Chloro-phenyl) -propyl] -methanesulfonyl-amino) -ethyl) -phenyl] -acetic acid

Step A: Alkvlerina [3- (2- {3- (3-Chloro-phenyl) -propyl] -methanesulfonyl-amino] -ethyl} -phenyl) -acetic acid tert-butyl ester, Step A was carried out with appropriate starting materials in an analogous manner AI dami 1 with a reaction time of 24 hours at room temperature; MS 466 (M +).

Step B; Ester hydrolysis of 3- (2- (3- (3-Chloro-phenyl) -amino] -methanesulfonyl-amino) -ethyl] -phenyl] -acetic acid.

A solution of [3- (2 - {[3- (3-chloro-phenyl) -propyl] -methanesulfonyl-amino} -ethyl) -phenyl] -acetic acid tert-butyl ester (170 mg, 0.36 mmol) in HCl / dioxane (5 mL) was stirred for 48 h at room temperature. The reaction mixture was concentrated and the residue was taken up in dilute aqueous NaOH (10 mL, pH = 9.3). The aqueous solution was washed with EtOAc (10 mL) and the login was separated. The aqueous layer

118 after extraction with EtOAc (10 mL) was acidified with dilute aqueous HCl at pH 2.5. After extracting the acidic aqueous layer with EtOAc (10 mL), the liver solution was dried over MgSO4₄, filtered, and intervening to give the title compound as an oil (20 mg). 1 H NMR (400 MHz, CDCl 3) δ 8.90-7.50 (m, 8H), 3.00-3.30 (m, 4H), 2.95 (s, 3H), 2.45-2 , 85 (m, 4H), 1.80 (m,

2H); MS 408 (M-1).

Dami 139-140

Examples 139-140 were produced in a catalytic manner at step 138 starting with appropriate alkylation moieties and sulfonamides in alkylation step A followed by ester hydrolysis in step B with changes in temperature disappearance and time in step A as noted.

Example 139 (trifluoromethyl) [3- (2 - {[2- (3,5-D (chloro-phenoxy) -ethyl] -methanesulfonylamino) -ethyl) -phenyl] -acetic acid

Step A: [3- (2-{[2- (3,5-Dichloro-phenoxy) -1-methyl-1-methanesulfonyl-amino) -ethyl) -phenyl] -acetic acid tert-butyl ester. Reaction time of 4 hours at room temperature.

Step B: [3- (2 - {[2- (3,5-Dichloro-phenoxy) -ethyl] -methanesulfonyl] -amino] -phenyl} -acetic acid, H

NMR (400 MHz, CDCl3) δ 6.70-7.50 (m, 7H), 4.20 (m, 2H). 3.25 (m, 4H), 2.95 (s, 3H), 2.35-2.65 (m, 2H); MS 445 (M-1).

Dami 140 (viflmiflunardami)

5- (3 - {[3- (3-Chloro-phenyl) -propyl] -tríflúorasetý1-amino} -propyl) -th [-thiophene-2-carboxylic acid

Step A: 5- (3- (3- (3-Chloro-phenyl) -dioyl] -trifluoroacetylamino} -propyl) -phenyl-2-carboxylic acid tert-butyl ester, Reaction time of 24 hours at room temperature. MS 508 (M + 18). Step B: 5- (3413- (3-Chloro-phenyl) -bioyl] -trifluoroacetyl-amino] -propyl] -phenyl] -carboxylic acid, 1 H NMR (400 MHz, CDCl3) δ 6.60-7.80 (m, 6H) , 3.22 (m, 4H), 2.80 (m, 2H), 2.63 (m, 2H), 1.60-2.02 (m, 4H); MS 433 (M-1).

Example 141 (Viflmiflunardami) (3 - {[(2,3-Dihydro-benzo [1,4] dioxin-5-ylmethyl) -methanesulfonylamino] -methyl} -phenyl) -acetic acid

Step A: Reducing aminerin (34f (2,3-Dihydro-benzof 1,4] dioxin-5-ylmethyl-amino-1-methyl) -phenyl) -acetic acid ethyl ester To a solution of 1,4-benzodioxan-6-carboxyaldehyde (100 mg, 0.609 mmol) and (32389

119-aminomethyl-phenyl) -acetic acid ethyl ester hydrochloride (148 mg, 0.645 mmol) in MeOH (2.5 mL) was added triethylamine (65 mg, 0.646 mmol). The reaction mixture was stirred for 3 h, cooled to 0 ° C, and NaBH₄ (37 mg, 0.975 mmol) was added. After stirring at room temperature for 10 minutes, a 1: 1 mixture of aq. Aqueous solution of NaHCO3 O was added. The product was extracted into CH₂Cl₂ and the solution was washed with water followed by satin bran. The organic solution was dried over MgSO₄, sulfonitrile, and compound chromatography afforded the title compound (202 mg). ¹1 H NMR (400 MHz, CDCl 3) δ 7.14-7.27 (m, 4H), 6.84 (s, 1H), 6.78 (s, 2H), 4.22 (s, 4H), 4 , 12 (q, 2H), 3.75 (s, 2H), 3.67 (s, 2H), 3.57 (s, 2H); MS 343 (M + 1).

Step B: Sulphonamide Methylation (3 - [(2,3-Dibromo-benzo [1,4] dioxin-5-ylmethane-sulfanylamino-methyl) -phenylacetic acid ethyl ester To a solution of (3 - {[(2,3- dihydro-benzo [1,4] dioxin-5-ylmethyl-amino] -methyl} -phenyl) -acetic acid ethyl ester (200 mg, 0.585 mmole) and triethylamine (71 mg, 0.702 mmole) in CH2Cl2 (10 mL) was added methanesulfonyl chloride (0.05 mL, 0.663 mmole). The reaction mixture was stirred for 16 h and was diluted with CH₂Cl 2. The organic solution was washed with water followed by a brine, dried over MgSO_4L sfufi, and social phenomena. The product was purified by flash chromatography (20% EtOAc in hexane in 40% EtOAc in hexane) to give the title compound (210 mg). 1 H NMR (400 MHz, CDCl3)₃) δ 7.20-7.31 (m, 4H), 6.75-6.62 (m, 3H), 4.30 (s, 2H), 4.24 (s, 4H), 4.20 s, 2H), 4.13 (q, 2H), 3.59 (s, 2H), 2.74 (s, 3H), 1.24 (t, 3H); MS 420 (M +), 437 (M + 17).

Step C: Ester Hydrolysis (3- (R, 2,3-Dihydro-benzyl) -4,4-dioxin-5-ylmethyl] -methanesulfonyl-amino] -methyl} -phenyl) -acetic acid To a solution of (3 - {[(2,3- Hydroxybenzo [1,4] d (oxin-5-ylmethyl) methanesulfonylamino] -methyl} -phenyl) -acetic acid ethyl ester (210 mg, 0.5 mmole) in MeOH (3 mL) at 0 ° C Aqueous aqueous solution of NaOH (2N, 0.5 mL) was stirred at room temperature for 16 h and was diluted with 1N HCl. The product was extracted into CH2 Cl2 and the resulting solution was washed with water followed by brine. The solution was a slurry over MgSO_4L sulfonate, and the resulting compound gave the title compound (165 mg). 1 H NMR (400 MHz, CDCl 3) δ 7.19-7.32 (m, 4H), 6.736.61 (m, 3H), 4.29 (s, 2H), 4.22 (s, 4H), 4.18 (s, 2H), 3.63 (s, 2H), 2.75 (s, 3H).

Dsmi 142-162

Dsmi 142-162 were produced analogously to the 141 par which is the starting point for the appropriate aldehyde and the amine reagents in step A followed by the formation of the sulfonamide to which the fish is left. In step B and ester hydrolysis In step C.

Dsmi 142

120 (3 - ([(5-Ethyl-thiophen-2-ylmethyl, -methanesulfonyl-amino) -methyl} -phenyl) -acetic acid

Step A: (3 - [(5-Ethyl-biphenyl-2-ylmethyl) amino] methyl) -phenyl) -acetic acid ethyl ester. 1 H NMR (400 MHz, CDCl3)₃) δ 7.15-7.29 (m, 4H), 6.70 (d, 1H), 6.59 (d, 1H), 4.11-4.15 (m, 2H),

3.90 (s, 2H), 3.80 (s, 2H), 3.58 (s, 2H), 2.76-2.82 (m, 2H), 1.84 (bs, 1H), 1 , 20-1.29 (m, 6H);

MS316 (M^f+1).

Step B: (3 - {[5-Ethyl-biphen-2-ylmethyl-methanesulfonyl-amino] -methyl} -phenyl) -acetic acid ethyl ester, NMR (400 MHz, CDCl3₃) δ 7.23-7.35 (m, 4H), 6.77 (d, 1H), 6.63-6.64 (m, 1H), 4.40 (s, 2H), 4.38 s, 2H), 4.15 (q, 2H), 3.62 (s, 2H), 2.82 (q, 2H), 2.77 (s, 3H), 1.23-1.31 , 6H); MS413 (M⁺+18).

Step C: (3- {[(5-Ethyl-benzene-2-ylmethyl) -methanesulfonyl-amino] -methyl-thienyl acetic acid ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.23-7.33 (m, 4H), 6.74 (s, 1H), 6.61 (s, 1H), 4.38 (s, 2H), 4.36 (8.2H) , 3.66 (s, 2H), 2.80 (q, 2H), 2.75 (s, 3H), 1.25-1.30 (m, 3H); MS 366 (M⁺-1).

Example 143 (Reference Example) (3 - {[Methanesulfonyl- (5-phenyl-furan-2-ylmethyl) -amino] -methyl} -phenyl) -acetic acid

Step A: [3 - [(5-Phenyl-furan-2-ylmethyl) -amino] -methyl] -phenyl-acetic acid methyl ester. 20¹1 H NMR (400 MHz, CDCl 3) δ 7.62 (d, 2H), 7.34 (t, 2H), 7.14-7.29 (m, 5H), 6.55 (d, 1H),

6.24 (d, 1H), 3.81 (d, 4H), 3.66 (s, 3H), 3.59 (s, 2H), 1.73 (bs, 1H).

Step B: (3- (Methanesulfonyl-5-phenyl-furan-2-ylmethyl) -amino] -methyl] -phenyl-acetic acid methyl ester, ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.62 (d, 2H), 7.38-7.42 (m, 2H), 7.23-7.38 (m, 5H), 6.60-6.61 (m, 1H), 6.34 (d, 1H), 4.37 (d, 4H), 3.69 (s, 3H), 3.63 (s, 2H), 2.89 (s, 3H); MS

436 (M⁺+23).

Step C: (1 H -methanesulphonate- (5-phenyl-furan-2-ylmethyl-amino) methyl) phenyl acetic acid, 1 H NMR (400 MHz, CDCl3) δ 7.60 (d, 2H), 7.37 t, 2H), 7.22-7.33 (m, 5H), 6.57 (d, 1H), 6.31 (d, 1H), 4.36 (s, 2H), 4.33 (s , 2H), 3.64 (s, 2H), 2.67 (s, 3H), 398 MS (M⁺-1).

Example 144 (3 - {[(3-Hydroxy-4-propoxy-benzyl) -methanesulfonyl-amino] -methyl} -phenyl) -acetic acid

Step A: [3- (3-Hydroxy-4-methoxy-benzylamino) -methyl-phenyl) -acetic acid methyl ester. 1 H NMR (400 MHz, CDCl3)_a) δ 7.24-7.30 (m, 3H), 7.16 (d, 1H), 6.91 (s, 1H), 6.79 (s, 2H), 3.98 (t, 2H) , 3.77 (s, 2H), 3.70 (s, 2H), 3.68 (s, 3H), 3.61 (s, 2H), 1.82 (q, 2H), 1.03 t, 3H);

MS 365 (M⁺+22).

Step B: (3-Methanesulfanyl- (3-methanesulfonyloxy-4-propoxy-benzyl) -amine] -methyl} -phenyl) -acetic acid methyl ester, ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.31-7.17 (m, 6H), 6.93 (d, 1H), 4.28 (s,

121

2H), 4.23 (s, 2H), 3.97 (t, 2H), 3.68 (s, 3H), 3.61 (s, 2H), 3.16 (s, 3H) 78 (s, 3H), 1.82 (m, 2H), 1.03 (t, 3H).

Step C: (3- (3-Hydroxy-4-propyl) -benzyl) -methanesulfonyl-amino) -methyl) -phenyl) -acetic acid, ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.34-7.20 (m, 4H), 6.84-6.78 (m, 3H), 4.31 (s, 2H), 4.20 (s,

2H), 3.98 (t, 2H), 3.65 (s, 2H), 2.76 (s, 3H), 1.83 (m, 2H), 1.04 (t, 3H).

Example 145 (Comparative Example) [3 - ({[2- (4-Chloro-phenylsulfanyl) -ethyl] -methanesulfonyl-amino} -methyl) -phenyl] -acetic acid

MS414 (M +).

Example 146 (3 - {[Methanesulphonyl- (4-phenethylsulfanyl-benzyl) -amino] -methyl} -phenyl) -acetic acid

Step A: (3-Fluoro-4-phenethylsulfanyl) -benzyl-amino] -methyl] -phenyl} -benzyl] methyl ester. 1 H NMR (400 MHz, CDCl3₃) δ 7.16-7.33 (m, 13H), 3.78 (d, 4H), 3.68 (s, 3H), 3.61 (s, 2H), 3.12-3.16 m, 2H), 2.89-2.93 (m, 2H); MS 406 (M + 1).

Step B: (3-Dimethanesulfonyl-4-phenethylsulfanyl) benzyl] amino] -methyl] -benzyl} -acetic acid methyl ester, 1 H NMR (400 MHz, CDCl3₃) δ 7.18-7.31 (m, 13H), 4.30 (d, 4H), 3.69 (s, 3H), 3.61 (s, 2H), 3.13-3.19 ( m, 2H), 2.84-2.94 (m, 2H), 2.78 (s, 3H); MS 505 (M + 22).

Step C: (3- (Methanesulfonyl- (4-phenethylsulphanyl-benzyl) -amino] -methyl] -phenyl-acetic acid. 1 H NMR (400 MHz, CDCl3₃) δ 7.13-7.29 (m, 13H), 4.27 (d, 4H), 3.61 (s, 2H), 3.12-3.16 (m,

2H), 2.88-2.92 (m, 2H), 2.76 (s, 3H); MS 468 (M-1).

Example 147 (Reference Example) [3 - ({[3- (3,5-Dichloro-phenoxy) -benzyl] -methanesulfonyl-amino} -methyl) -phenyl] -acetic acid

Step A: [3- (3- (3-Dichloro-phenoxy) -benzyl) -amino} -methyl) -phenyl] -acetic acid methyl ester. 1 H NMR (400 MHz, CDCl3)₃) δ 7.21-7.33 (m, 4H), 7.15 (d, 2H), 7.03-7.04 (m, 2H), 6.88-6.90 (m, 1H), 6.84 (s, 2H), 3.78 (d, 4H), 3.66 (s, 3H), 3.59 (s, 2H), 1.82 (bs, 1H).

Step B: [3- (3,5- Dichloro-phenoxy) -benzyl] methanesulfonyl-amino-methyl-phenyl] -acetic acid methyl ester, 1 H NMR (400 MHz, CDCl3₃) δ 6.81-7.17 (m, 11H), 4.31 (d, 4H), 3.65 (s, 3H), 3.58 (s, 2H), 2.80 (s, 3H) .

Step C: 3- (3,5- (3,5-Dichloro-phenoxy) -benzyl] methanesulfonylamino) -methyl-phenyl] -acetic acid 1 H NMR (400 MHz, CDCl3) δ 7.07-7.35 (m, 8H) , 6.92-6.93 (m, 2H), 6.82 (s, 1H), 4.32 (d, 4H), 3.62 (s, 2H), 2.81 (s, 3H).

122

Example 148 (Reference Example) (3 - {[Methanesulfonyl- (4-pyrimidin-2-yl-benzyl) -amino] -methyl} -phenyl) -acetic acid

Step A: (3 - {[(4-Pyrimidin-2-yl) -benzyl-amino] -methyl] -phenyl} -acetic acid methyl ester.¹H

NMR (400 MHz, CDCl3)₃) δ 8.77 (d, 2H), 8.37 (d, 2H), 7.44 (d, 2H), 7.23-7.29 (m, 3H), 7.147.16 (m, 2H) , 3.86 (s, 2H), 3.79 (s, 2H), 3.66 (s, 2H), 3.60 (s, 2H); MS 348 (M + 1).

Step B: X32] Methylsulfanyl] phenyl] amino] ethyl] amino] ethyl] amino] ester, 1 H NMR (400 MHz, CDCl3)₃) δ 8.83 (s, 2H), 8.43 (s, 2H), 7.44-7.49 (m, 2H), 7.23-7.33 (m, 5H), 4,37- 4.41 (m, 4H), 3.71 (s, 3H), 3.61-3.68 (m, 2H), 2.82 (s, 3H); MS 426 (M + 1).

Step C: (3-Dimethylsulfamoyl-4- (pyrimidin-2-yl) -benzyl) -amino] -methyl} -phenyl) -propionic acid 1H NMR (400 MHz, CDCl3₃) δ 8.82 (d, 2H), 8.15 (d, 2H), 7.30 (d, 2H), 7.24-7.27 (m, 3H), 7.157.17 (m, 1H) , 7.03 (s, 1H), 4.42 (s, 2H), 4.37 (s, 2H), 3.52 (s, 2H), 2.90 (s, 3H).

Example 149 (Reference Example) (3 - {[Methanesulfonyl- (4-thiazol-2-yl-benzyl) -amino] -methyl} -phenyl) -acetic acid

Step A: (3-Fluoro-thiazol-2-yl) -amino] -methyl} -phenyl) -acetic acid methyl ester. H

NMR (400 MHz, CDCl3)₃) δ 7.82-7.91 (m, 3H), 7.38-7.40 (m, 2H), 7.22-7.29 (m, 4H), 7.147.16 (m, 1H), 3.82 (s, 2H), 3.78 (s, 2H), 3.66 (s, 3H), 3.59 (s, 2H); MS 353 (M + 1).

Step B: [3- (1-Methanesulfonyl- (4-bisazol-2-yl-benzyl) -amino] -methyl] -phenyl] -acetic acid methyl ester. 1 H NMR (400 MHz, CDCl3)₃) δ 7.92 (d, 2H), 7.84 (d, 1H), 7.17-7.37 (m, 7H), 4.33 (d, 4H), 3.67 (s, 3H) , 3.59 (s, 2H), 2.80 (s, 3H); MS 431 (M + 1).

Step C: (34-Methanesulfonyl- (4-bisazol-2-yl) -benzyl] -amino] -methyl} -phenylacetic acid 1H NMR (400 MHz, CDCl3)? 6.98-7.85 (m, 10H) 30-4.40 (d, 4H), 3.45 (s, 2H), 2.82 (s, 3H); MS 415 (M-1).

Example 150 (Reference Example) (3 - {[(4-Benzyl-3-hydroxy-benzyl) -methanesulfonyl-amino] -methyl} -phenyl) -acetic acid

Step A: (3-Fluoro-4-benzyl-3-hydroxy-benzyl) -amino] -methyl] -phenyl acetic acid methyl ester, 1 H NMR (400 MHz, CDCl3) δ 7.24-7.43 (m, 11H) , 7.16 (d, 1H), 6.93 (d, 2H), 3.78 (s,

2H), 3.74 (s, 2H), 3.68 (s, 3H), 3.61 (s, 2H); MS 376 (M + 1).

Step B: (3-Fluoro-4-benzyl-3-hydroxybenzyl) methanesulfonyl-amino] methyl} -phenyl) -acetic acid methyl ester, 1 H NMR (400 MHz, CDCl3) δ 7.20-7.43 (m , 12H), 6.94 (d, 2H), 4.30 (s, 2H), 4.26 (s, 2H), 3.69 (s, 3H), 3.62 (s, 2H), 2 , 75 (s, 3H); MS 475 (M + 22).

123

Step C: [3- (4-Benzyl-3-hydroxy-benzyl) -methanesulfonyl-amino] -methyl} -phenyl) -acetic acid. ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.20-7.43 (m, 12H), 6.93 (d, 2H), 4.29 (s, 2H), 4.25 (s, 2H), 3.64 (s, 2H) , 2.74 (s, 3H); MS 438 (M-1).

DSM1 151 (Reference Threshold) (3 - {[Methanesulfonyl- (4-pyrazin-2-yl-benzyl) -amino] -methyl} -phenyl) -acetic acid

Step A: (3 - [[4-Pyridin-2-yl-benzyl] -amino] -methyl] -phenyl acetic acid methyl ester, ¹1 H NMR (400 MHz, CDCl 3) δ 9.00 (s, 1H), 8.60 (s, 1H), 7.96-7.98 (m, 2H), 7.46-7.48 (m, 2H), 7.11-7.30 (m, 4H), 3.77-3.88 (m, 4H), 3.58-3.69 (m, 5H); MS 348 (M + 1).

Step B: (S-Phosphonylphenyl) -pyrazine-3-yl-benzyl] -indan-1-yl] -benzyl acetic acid methyl ester, 1 H NMR (400 MHz, CDCl3₃) δ 9.03 (s, 1H), 8.63-8.64 (m, 1H), 8.52 (d, 1H), 8.00 (d, 2H), 7.46 (d, 2H) , 7.21-7.34 (m, 4H), 4.41 (s, 2H), 4.36 (s, 2H), 3.70 (s, 3H), 3.62 (s, 2H), 2.83 (s, 3H); MS 426 (M + 1).

Step C: [3- (2-Methoxy) -4- (4-Dihrazin-2-yl-benzyl) -amino] -methyl} -phenylacetic acid. 1 H NMR (400 MHz, CDCl 3) δ 8.96 (s, 1H), 8.61-8.62 (m, 1H), 8.56-8.57 (m, 1H), 7.78 , 2H), 7.34 (d, 2H), 7.16-7.30 (m, 3H), 7.05 (s, 1H), 4.42 (s, 2H), 4.38 (s, 2H), 3.52 (s, 2H), 2.91 (s, 3H); MS 410 (M-1).

DSMI 152 (functionalism) (3 - {[Methanesulfonyl- (4-phenoxy-benzyl) -amino] -methyl} -phenyl) -acetic acid

Step A: (3- {[(4-Phenoxy-benzyl) -amino] -methyl} -phenyl) -benzyl] methyl ester, 1 H NMR (400 MHz, CDCl3) δ 7.20-7.34 (m, 7H), 7.17-7.19 (m, 2H), 7.06-7.11 (m, 2H), 6.96-7.00 (m, 4H), 3.79 (d, 4H), 3, 69 (s, 3H), 3.63 (s, 2H); MS 362 (M + 1).

Step B: (3-Dimethanesulfonyl-4-phenoxy-benzyl) -amino] -methyl} -phenyl) -acetic acid methyl ester, 1 H NMR (400 MHz, CDCl3₃) δ 7.20-7.37 (m, 9H), 7.12 (t, 1H), 6.95-7.01 (m, 3H), 4.32 (d, 4H), 3.69 S, 3H), 3.62 (s, 2H), 2.79 (s, 3H); 457 (M + 18).

Step C: (4-Methanesulfonyl- (4-phenoxy-benzyl) -amino-1-methyl) -phenyl] -acetic acid 1 H NMR (400 MHz, CDCl3₃) Δ 7.22-7.36 (m, ΘΗ), 7.12 (t, 1H), 6.94-7.01 (m, 3H), 4.32 (d, 4H), 3.65 s, 2H), 2.79 (s, 3H); MS 424 (M-1).

DSM 153 (Reference Methyl) [3 - ({Methanesulfonyl- [4- (4-methyl- [1,2,3] triazol-1-yl) -benzyl] -amino} -methyl) -phenyl] -acetic acid

Step A: [3- (1,4- (4-Methyl-1,2,3,3-triazol-1-yl) -benzyl-amino) -methyl) -phenylacetic acid methyl ester. 1 H NMR (400 MHz, CDCl3)₃) δ 7.55 (d, 2H), 7.33 (d, 2H), 7.16-7.30 (m, 4H),

124

3.84 (t, 2H), 3.77 (s, 4H), 3.68 (s, 3H), 3.61 (s, 2H), 2.59 (t, 2H), 2.31 , 1H), 2.14 (t, 2H); MS 353 (MH +).

Step B: R 3 - ((Methanesulfonyl-4- (4-methyl-1,2,3-triazol-1-yl) -benzyl] amino) -methyl) -phenylacetic acid methyl ester. 1 H NMR (400 MHz, CDCl3)₃) δ 7.61 (d, 2H), 7.20-7.33 (m, 6H), 4.30 (s,

4H), 3.86 (t, 2H), 3.69 (s, 3H), 3.62 (s, 2H), 2.77 (s, 3H), 2.61 (t, 2H) 17 (t, 2H).

Step C: (3-Dimethanesulfonyl-4- [4-methyl-1,2,3-triazol-1-fluoro-benzyl] -amino] -methyl} -phenyl-acetic acid. ¹1 H NMR (400 MHz, CDCl 3) δ 7.43 (d, 2H), 7.14-7.31 (m, 5H), 7.05 (s, 1H), 4.28 (d, 4H), 3 , 82 (t, 2H), 3.50 (s, 2H), 2.82 (s, 3H), 2.60 (t, 2H), 2.13 (t, 2H).

Example 154 (Reference Example) [3 - ({Methanesulfonyl- [4- (2-oxo-pyrrolidin-1-yl) -benzyl] -amino} -methyl) -phenyl] -acetic acid

Step A: [3- (4 - {2-Oxo-pyrrolidin-1-yl-benzyl) -amide (N-methyl) -phenyl] -acetic acid methyl ester. 1 H NMR (400 MHz, CDCl3)? 7.63-7, 68 (m, 1H), 7.52-7.58 (m, 2H), 7.41-7.47 (m, 2H), 7.17-7.36 (m, 4H), 3.90 s, 2H), 3.83 (s, 2H), 3.69 (s, 3H), 3.63 (s, 2H), 2.34 (s, 3H);

MS 351 (MH +).

Step B: [3- (Methanesulfonyl-4- (2-oxo-pyrrolidin-1-yl) -benzyl] amino) -methyl} -phenyl) -acetic acid methyl ester. 1 H NMR (400 MHz, CDCl3)₃) δ 7.57 (s, 1H). 7.41-7.48 (m, 4H), 7.25-7.30 (m,

1H), 7.17-7.20 (m, 3H), 4.36 (s, 2H), 4.14 (s, 2H), 3.68 (s, 3H), 3.61 (s, 2H ), 2.86 (s, 3H),

2.33 (s, 3H).

Step C: [3- (Methanesulfonyl- [4- (2-oxo-DVTr6idin-1-yl) -benzyl] -amino] methyl} -phenyl] -acetic acid .1 H NMR (400 MHz, CDCl3₃) δ 7.58 (s, 1H), 7.13-7.39 (m, 8H), 4.40 (s, 2H), 4.37 (s, 2H), 3.56 (s, 2H) , 2.91 (s, 3H), 2.29 (s, 3H).

Dami 155 (benchmark)

5- (3 - ((2,3-Dihydro-benzo [1,4] dioxin-6-ylmethyl) -methanesulfonyl-amino] -propyl} -thiophene-2-carboxylic acid

Step A: 5- {3 - [(2,3-Dihydro-benzo [1,4] dioxin-6-ylmethyl-amino] -pyrazol-biphen-2-carboxylic acid methyl ester In step A, triethylamine was replaced with N, N -disopropylethylamine. MS 348 (M + 1).

Step B: 5- [3- (2,3-Dihydro-benzo [1,4] dioxo-6-ylmethyl) -methanesulfonyl-amino] -propyl] biphene-2-carboxylic acid methyl ester. MS 443 (M + 18).

Step C: 5- {3 - [(2,3-Dibromobenzof 1,4-dioxin-6-ylmethyl) -methanesulfonyl-amino] -dioxide-biphen-2-carboxylic acid, 1 H NMR (400 MHz, CDCl3₃) δ 7.70 (d, 1H, J = 3.8), 6.50-6.80 (m, 4H), 4.40 (s, 2H), 3.23 (m, 2H) 80 (m, 2H), 1.70 (m, 2H); MS 400 (M + 1), 398 (M-1).

Dami 156

125 (3 - {[(4-Ethoxy-benzyl) -methanesulfonylamino] -methyl} -phenyl) -acetic acid 1 H NMR (400 MHz, CDCl3₃) δ 7.16-7.31 (m, 6H), 6.83 (d, 2H), 4.27 (s, 2H), 4.22 (s, 2H), 3.99 (q, 2H) , 3.62 (s, 2H), 2.71 (s, 3H), 1.38 (t, 3H); 376 (M-1).

Example 157 (Reference Example) (3 - {[(4-Dimethylamino-benzyl) -methanesulfanyl] -amino] -methyl} -phenyl) -acetic acid 1 H NMR (400 MHz, CDCl3) δ 7.14-7.37 m, 6H), 6.66 (d, 2H), 4.27 (s, 2H), 4.19 (s, 2H), 3.61 (s, 2H), 2.91 (s, 6H), 2.69 (s, 3H); 375 (M-1).

Example 158 (Reference Example) (3 - {[(4-Cyclohexyl-benzyl) -methanesulfonylamino] -methyl} -phenyl) -acetic acid 1 H NMR (400 MHz, CDCl3₃) δ 7.32-7.16 (m, 8H), 4.31 (s, 2H), 4.28 (s, 2H), 3.64 (s, 2H), 2.75 (s, 3H) , 2.48 (m, 1H), 1.63 (m, 5H), 1.38 (m, 5H).

Dami 159 (vifimifiunardami)

5- {3 - [(4-Dimethylamino-benzyl) -methanesulfonyl-amino] -propyl} -thiophene-2-carboxylic acid

Step A: 5- [3- (4-Dichloromethyl-6-benzylamino) -propyl] -phenyl] -2-carboxylic acid methyl ester The title compound In step A was prepared according to the step described in Step A of Example 141 except that triethylamine was replaced out for N, N-diposopropylethylamine.

Step B: 5- (3- (4-Dimethylamino-benzyl) methanesulfonyl-amino-1,3-dihydro-2-carboxyphenyl ester, MS 411 (M + 1).

Step C: 5- {3- [(4-Dimethylamino-benzyl) -methanesulfonyl-amino] -propyl] -biphenyl-2-carboxylic acid. 1 H NMR (400 MHz, CDCl3)₃) δ 7.70 (d, 1H), 7.15 (d, 2H), 6.72 (m, 3H), 4.43 (s, 2H), 3.22 (m, 2H), 2.95 (s, 6H), 2.85 (m, 2H), 2.80 (s, 3H), 1.62 (m, 2H); MS 395 (M-1).

Example 160 (3 - {[Methanesulphonyl- (4-pentyl-benzyl) -amino] -methyl} -phenyl) -acetic acid

Step A: {3 - [(4-Pentyi-benzylamino) -methyl] -phenyl} -acetic acid methyl ester, 1 H NMR (400 MHz, CDCl3₃) δ 7.29-7.12 (m, 8H), 3.78 (s, 2H), 3.76 (s, 2H), 3.68 (s, 3H), 3.61 (s, 2H) , 2.57 (t, 2H), 1.59 (t, 2H), 1.59 (t, 2H), 1.31 (m, 4H), 0.88 (t, 3H); MS 340 (M + 1).

2SC9

126

Step B: (3-Dimethanesulfonyl- (4-Dentyl-benzyl-amino] -methyl) -phenyl) -acetic acid methyl ester. ¹1 H NMR (400 MHz, CDCl 3) δ 7.32-7.14 (m, 8H), 4.31 (s, 2H), 4.29 (s, 2H), 3.69 (s, 3H), 3 , 62 (s, 2H), 2.75 (s, 3H), 2.59 (1.2H), 1.59 (m, 2H), 1.31 (m, 4H), 0.88 (1, 3H).

Step C: [beta] -methanesulfonyl- (4-pentyl-benzyl) -amino] -methyl} -phenyl) -acetic acid. 1 H NMR (400 MHz, CDCl 3) δ 7.34-7.13 (m, 8H), 4.31 (s, 2H), 4.28 (s, 2H), 3.66 (s, 2H) , 2.75 (s, 3H), 2.58 (t, 2H), 1.59 (m, 4H), 1.31 (m, 4H), 0.88 (f, 3H); MS 402 -1).

Example 161 (3 - ([(4-Isopropoxy-benzyl) -methanesulfonyl-amino] -methyl} -phenyl) -acetic acid

Step A: [3- (4-Isopropyl) benzylamino) -methyl] -phenyl} -acetic acid methyl ester, ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.29-7.15 (m, 6H), 6.84 (d, 2H), 4.52 (m, 1H), 3.78 (s, 2H), 3.72 (s, 2H) , 3.68 (s, 3H), 3.61 (s, 2H), 1.32 (d, 6H).

Scheme B: (3- (4-Isopropyl) benzyl] -methanesulfonyl-amino] -methyl} -phenyl) -acetic acid methyl ester. 1 H NMR (400 MHz, CDCl3)₃) δ 7.32-7.19 (m, 6H), 6.84 (d, 2H), 4.53 (m, 1H), 4.30 (s, 2H), 4.25 (s, 2H) , 3.69 (s, 3H), 3.66 (s, 2H), 3.62 (s, 2H), 2.75 (s, 3H), 1.32 (d, 6H).

Scheme C: (3- (4-isopropyl) benzyl-methanesulfonylamino-1-methylphenyl acetic acid. ¹1 H NMR (400 MHz, CDCl 3) δ 7.33-7.17 (m, 6H), 6.83 (d, 2H), 4.52 (m, 1H), 4.29 (s, 2H), 4 , 24 (s,

2H), 3.65 (s, 2H), 2.74 (s, 3H), 1.32 (d, 6H); MS 390 (M-1).

Example 162 (Reference Example) (3 - {[Methanesulfonyl- (4-pyrimidin-5-yl-benzyl) -amino] -methyl} -phenyl) -acetic acid

Scheme A: [3 - [(4-Pyrimidin-5-yl-benzoylamino) -methy] -phenyl) -acetic acid, ¹1 H NMR (400 MHz, CDCl 3) δ 9.19 (s, 1H), 8.95 (s, 2H), 7.52 (m, 4H), 7.32-7.15 (m, 4H), 3 , 88 (s, 2H), 3.82 (s, 2H), 3.69 (s, 3H), 3.63 (s, 2H).

Sketch B: (Β-ίίνθίΒηΒύΚόηνΙ- ρνπιτΜίη-δ-νΙ ^ ηΒνβ-ΒΙηίηόΙ-ΓΒίΒίνβ-ίθηνΒ ^ ΙΙ ^ νπ] met ester, MS 425 (M + k

Step C: (3-Dimethanesulfonyl- (4-pyrimidin-5-yl-benzyl) -amino] -methyl) -phenyl) -acetic acid. ¹1 H NMR (400 MHz, CDCl 3) δ 9.20 (s, 1H), 6.95 (s, 2H), 7.52 (d, 2H), 7.43 (d, 2H), 7.34-7 , 15 (m, 4H), 4.41 (s, 2H), 4.37 (s, 2H), 3.65 (s, 2H), 2.86 (s, 3H); MS 410 (M-1).

Example 163 (3 - {[Methanesulphonyl- (4-methyl-benzyl) -amino] -methyl} -phenyl) -acetic acid

Step A: Reducing amphneria

127 (3 - [(4-Methyl-benzyl) -amino] -methyl] methyl acetic acid ethyl ester A solution of 4-methyl-benzylamine (0.097 mL, 0.76 mmol) and (3-formyl-phenyl) -acetic acid ethyl ester 138 mg, 0.72 mmol) in MeOH (2 mL) was stirred for 3 h at room temperature. The reaction was cooled to 0 ° C and NaBH₄ (43 mg, 1.15 mmol) was added. After stirring at room temperature for 10 minutes, a 1: 1 mixture of aqueous NaHCO₃H₂O bstt ft f. The product was extracted in CH₂Cl₂(3x) and the ice-cream solution was dried over MgSO₄, filtered, and concentrated to afford the title compound (231 mg). ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.13-7.30 (m, 8H), 4.14 (q, 2H), 3.83 (d, 4H), 3.78 (s, 2H), 2.34 (s, 3H) , 1.25 (t, 3H); MS 298 (M + 1).

Step B; Sulphonamide (3-Methanesulfonyl- (4-methyl-benzylamino-methyl) -phenyl) -acetic acid ethyl ester To a solution of (3 - {[(4-methyl-benzyl) -amino] -methyl} -phenyl) -acetic acid ethyl ester (119 mg, 0.401 mmol) and triethylamine (0.61 mL, 0.726 mmol) in CH2 Cl2 (2 mL) at 0 ° C was added methanesulfonyl chloride (0.031 mL, 0.405 mmol). The reaction was a rapid stirrer room temperature ί 2.5 hours and 1N HCI was bsstt ft 1. The product was extracted into CH₂Cl₂ (3x). The resulting solution was dried over MgSO₄, filter, and synergistic in vacuum. The product was purified by chromatography chromatography (3: 1 hexane: EtOAc) to afford titled compound (101.4 mg).¹1 H NMR (400 MHz, CDCl3)₃) δ 7.13-7.36 (m, 8H), 4.27-4.30 (m, 4H), 4.14 (q, 2H), 3.60 (s, 2H), 2.74 s, 3H), 2.33 (s, 3H); MS 376 (M + 1).

Step C: Esther hydrolysis

Step C: (3-Dimethanesulfonyl- (4-methyl-benzylamino-methylphenyl) -acetic acid

A solution of (3 - {[methanesulfonyl- (4-methyl-benzyl) -amino] -methyl} -phenyl) -acetic acid ethyl ester (101.4 mg, 0.27 mmol) of MeOH (3 mL) was bsBtt aqueous solution of NaOH (2N, 0.4 mL). The reaction mixture was stirred at room temperature for 1 hour and was diluted with 1: 1 mixture of 1N HCl and water. The product was extracted into CH2Cl2 (3x) and the resulting solution was dried over MgSO4₄, filtered and concentrated to give title compound (87 mg). ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.137.34 (m, 8H), 4.28 (d, 4H), 3.65 (s, 2H), 2.75 (s, 3H), 2.33 (s, 2H); MS 346 (M-1).

Dssmi 164-170

Dssmi 164-170 were produced analogously to the 163 mole starting from the residual aldehydes and the amine reactants. In step A followed by the formation of the sulfonamide which is left in step B and ester hydrolysis. In step C.

Dsmi 164

128 (3 - {[(4-tert-Butyl-benzyl) -methanesulfonyl-amino] -methyl} -phenyl) -acetic acid

Step A: [3- (4-tert-Butyl-benzyl) -methyl] -phenyl} -acetic acid ethyl ester. 1 H NMR (400 MHz, CDCl 3) δ 7.32-7.34 (m, 2H), 7.24-7.27 (m, 5H), 7.15-7.16 (m, 1H), 4 , 13 (q, 2H),

3.77 (d, 4H), 3.59 (s, 2H), 1.30 (s, 9H), 1.21-1.26 (m, 3H); MS 340 (M * + 1).

Step B: (3- (4-tert-Butyl-benzyl) -methanesulfonyl-amino-1-methyl) -phenyl acetic acid ethyl ester. 1 H NMR (400 MHz, CDCl 3) δ 7.20-7.37 (m, 8H), 4.30 (d, 4H), 4.14 (q, 2H), 3.60 (s, 2H), 2.76 (s, 3H), 1.31 (s.9H), 1.25 (t, 3H).

Step C: (3 - {[(tert-Butyl-benzyl) methanesulfonyl-amino] -methyl] -phenyl} -acetic acid. ¹1 H NMR 10 (400 MHz, CDCl 3) δ 7.20-7.36 (m, 8H), 4.31 (s, 2H), 4.28 (s, 2H), 3.64 (s, 2H), 2.75 (s,

3H), 1.30 (s, 9H); MS 388 (M + -1).

Example 165 (3 - {[(4-tert-Butyl-benzyl) -methanesulfonyl-amino] -methanyl} -phenoxy) -acetic acid

Step A: [3- (4-tert-Butyl-benzylamino) -methyl] -phenoxy) -acetic acid methyl ester.

Step B: (3-tert-Butyl-benzyl) -methanesulfonyl-amino] -methyl) -phenoxy) -acetic acid methyl ester,

Step C: (3- (4-tert-Butyl-benzyl) -methanesulfonamide-1-amino-methyl) -phosphino) -acetic acid. 1 H NMR (400 MHz, CDCl 3) δ 7.20-7.36 (m, 5H), 6.84-6.95 (m, 3H), 4.66 (s, 2H), 4.30 (s , 4H), 2.77 (s, 3H), 1.30 (s, 9H); MS 404 (M-1).

Example 166 (3 - {[Methanesulphonyl- (4-trifluoromethoxy-benzyl) -amino] -methyl} -phenyl) -acetic acid

Step A: (3 - {(4-trifluoromethoxy-benzyl) -amino] -methyl} -phenyl) -acetic acid ethyl ester. ¹1 H NMR (400 MHz, CDCl 3) δ 7.34-7.36 (m, 2H), 7.14-7.16 (m, 3H), 7.21-7.32 (m, 3H) 10

4.16 (m, 2H), 3.77 (d, 4H), 3.60 (s, 2H), 1.21-1.25 (m, 3H); MS 368 (M + 1).

Step B: (3-Dimethanesulfonyl- (4-trifluoromethoxy-benzyl) amino] -methyl} -phenyl) -acetic acid ethyl ester. ¹1 H NMR (400 MHz, CDCl 3) δ 7.15-7.33 (m, 8H), 4.31 (d, 4H), 4.14 (q, 2H), 3.58 (s, 2H), 2 , 81 (s, 3H), 1.25 (t, 3H); MS 446 (M + 1).

Step C: (3-4-Methanesulfonyl) -4-trifluoro-ethoxy-benzyl-amino] -methyl} -phenyl) -acetic acid ¹H

NMR (400 MHz, CDCl 3) δ 7.10-7.32 (m, 8H), 4.30 (s, 4H), 3.62 (s, 2H), 2.80 (s, 3H); MS 416 (M-1).

Example 167 (3 - ({[3- (4-Chloro-phenyl) -propyl] -methanesulfonyl-amino} -methyl) -phenyl] -acetic acid

129

Step A: [3- (3- (4-Chloro-phenyl) -propyl] -amino} -methyl) -phenyl] -acetic acid ethyl ester.

Step B: R3 - [(3- (4-Chloro-phenyl) -propyl] -methanesulfonyl-amino} -methyl) -phenyl] -acetic acid ethyl ester. NMR (400 MHz, CDCl3)₃) δ 7.18-7.31 (m, 6H), 6.95 (d, 2H), 4.34 (s, 2H), 4.11 (q, 2H), 3.59 (s, 2H) , 3.13-3.19 (m, 2H), 2.80 (s, 3H), 2.49 (t, 2H), 1.74-1.82 (m, 2H), 1.23 , 3H); MS 424 (M + 1).

Step C: [3- (4- [4-Chloro-phenyl) -propyl] -methanesulfonyl-amino] -methyl} -phenyl) -acetic acid. MS 393.9 (M-1).

Example 168 (3 - {[Methanesulphonyl- (3-trifluoromethoxy-benzyl) -amino] -methyl} -phenyl) -acetic acid

Step A: (3 - {[(3-trifluoromethoxy-benzyl) -amino] -methyl} -phenyl) -acetic acid ethyl ester. Step B: (3-Dimethanesulfonyl-3-trifluoromethoxy) benzyl) amino] -methyl} -phenyl) -acetic acid ethyl ester. ¹1 H NMR (400 MHz, CDCl 3) δ 7.13-7.40 (m, 8H), 4.33 (d, 4H), 4.14 (q, 2H), 3.59 (s, 2H), 2 , 82 (s, 3H), 1.25 (t, 3H); MS 446 (MH +).

Step C: (3-Methanesulfamyl- (3-trifluoromethoxy-benzylamino-1-methyl) -phenyl) -acetic acid. MS 417 (M-1).

Example 169 (Reference Example) [3 - ({[2- (3-Chloro-phenylsulfanyl) -ethyl] -methanesulfonyl-amino} -methyl) -phenyl] -acetic acid ¹1 H NMR (400 MHz, CDCl3)₃) δ 6.98-7.37 (m, 8H), 4.32 (s, 2H), 3.60 (s, 2H), 3.28 (m, 2H), 2.81-2.93 m, 5H); 412 (M-1).

Example 170 (Reference Example) [3 - ({[4- (2-Benzo [1,3] dioxol-5-yl-vinyl) -benzyl] -methanesulfonyl-amino} -methyl) -phenyl] -acetic acid

MS 478 (M-1).

Example 171 (Reference Example) (3 - {[Methanesulfonyl- (4-thiazol-2-yl-benzyl) -amino] -methyl) -phenoxy) -acetic acid

Step A: Reducing aminerin 3- [4-Thiazol-2-yl-benzylamino) -methyl] -phenoxy} -acetic acid tert-butyl ester, A solution of (3-aminomethyl) phenoxy) acetic acid tert-butyl ester 14 g, 0.59 mmol) and 4-thiazol-2-yl-2389

130 benzaldehyde (0.105 g, 0.55 mmol) in 2 mL at MeOH was stirred at room temperature for 1.5 hours. After cooling to 0 ° C, NaBH was added₄ (0.033 g, 0.88 mmol) was added and the reaction was continued for 10 minutes. The mixture was supported by a satin aqueous NaHCO solution₃H₂O (1: 1) and MeOH were removed in an air atmosphere. The product was extracted into CH₂Cl₂ and the organic solution was purrkud over MgSO₄, filtered and concentrated in vacuo to give brown oil. The product was purified by flash chromatography on silica gel (6/4 EtOAc / hexane) to give title compound In Step A (0.140 g). 1 H NMR (400 MHz, CDCl 3) δ 7.91 (d, 2H), 7.82 (s, 1H), 7.40 (d, 2H), 7.23-7.38 (m, 2H), 6.94 (m, 2H), 6.78 (d, 1H), 4.49 (s, 2H), 3.80 (s, 2H), 3.76 (s, 2H), 1.45 , 9H); MS 411 (M + 1).

Step B: Sulphonamide Preparation (3-Methanesulfonyl- (4-bisazol-2-yl) -phenylamino] -methyl] -phenoxy} -acetic acid tert-butyl ester, A solution of ({3 - [(4-thiazol-2-yl-benzylamino) methyl] -phenoxy} -acetic acid tert-butyl ester (0.045 g, 0.109 mmol), triethylamine (16.8 mL, 0.120 mmol) and methanesulfonyl chloride (8.6 mL,

0.11 mmol) in 2 mL of CH2Cl2 was stirred at room temperature for 12 hours. Hvarfid was quenched with water. The aqueous solution was challenged with CH₂Cl₂ and the solution was purrkud over Na₂SO₄, sfud, and samsdfnud. The product was purified by flash chromatography and silica gel (1/1 EtOAc / hexane) to give the title compound of Step B as tsra oil. 1 H NMR (400 MHz,

CDCl 3) δ 7.97 (d, 2H), 7.85 (s, 1H), 7.35 (m, 3H), 7.32 (m, 1H), 6.80-6.90 (m, 3H ), 4.48 (s, 2H), 4.36 (s, 2H), 4.29 (s, 2H), 2.79 (s, 3H), 1.47 (s, 9H); MS 489 (M + 1).

Step C: Ester hydrolysis of 3- (methanesulfanyl-4-benzazol-2-yl-benzyl) -amino] methyl) -phenoxy) -acetic acid. A solution of (3 - {[methanesulfonyl- (4-piazol-2-yl-benzyl) -amino] -methyl} -phenoxy) -acetic acid tert-butyl ester (0.074 g) in 2 mL of CH 2 was added 10 ° C and 2 mL of trifluoroacetic acid was added. The reaction time was rapid at room temperature for 2 hours. The solvent was removed with Stddug distillation with CH₂C₂ to give the title compound (40 mg). 1 H NMR (400 MHz, CDCl3) δ

9.94 (bs, 1H), 8.14 (s, 1H), 7.81 (d, 2H), 7.55 (s, 1H), 7.37 (d, 2H), 7.18 , 1H), 6.90 (d,

1H), 6.80 (d, 1H), 6.63 (s, 1H), 4.58 (s, 2H), 4.35 (s, 2H), 4.29 (s, 2H) 93 (s, 3H); MS 431 (M-1).

Dsmi 172-178

Dsmi 172-178 were produced in a manner similar to that of 171 pairs which were food-grade aldehyde and amine reagents in step A followed by formation of the desired sulfonamide. In step B and ester hydrolysis In step C.

Dsmi 172 (viMidunardsmi)

131 (3 - {[Methanesulfonyl- (4-pyridin-2-yl-benzyl) -amino] -methyl} -phenoxy) -acetic acid hydrochloride salt

The TFA salt isolated in Step C was converted to HCl salt with addition of 2 equivalents of 1N HCl followed by removal of water and drying in vacuo. MS 427 (M + 1), 425 (M-1).

Example 173 (Reference Example)

5- {3 - [(2-Bensýlsúlfaný1-etý1) -methanesulfonyl-amino] -propyl} -thiophene-2-carboxylic acid

Step A: 5- (3 - [(2-Benzylsulfanyl-ethyl-amino) -propyl) -phosphene-2-carboxylic acid tert-butyl ester, 1 H NMR (400 MHz, CDCl3₃) δ 7.52 (d, 1H), 7.19-7.29 (m, 5H), 6.73 (d, 1H), 3.66 (s, 2H), 2.83 (t, 2H) , 2.71 (t, 2H), 2.53-2.59 (m, 4H), 1.81 (t, 2H), 1.54 (s, 9H); MS 392 (M + 1). Step B: 5- (34 (2-Benzylsulfanyl-ethyl) -methylsulfonyl-amino] -6,6-dihydro-tert-butyl ester,¹1 H NMR (400 MHz, CDCl3)₃) δ 7.52 (d, 1H), 7.22-7.30 (m, 5H), 6.74 (d, 1H). 3.71 (s, 2H), 3.23 (t, 2H), 3.06-3.15 (m, 2H), 2.77-2.82 (m, 5H), 2.58 (t, 2H), 1.54 (s, 9H); MS470 (M + 1).

Step C: 5- [3- (2-Benzylsulfanyl-ethyl) -methanesulfonyl-amino] -propyl} -biphenyl-2-carboxylic acid. MS 412 (M-1).

Example 174 (Reference Example)

5- (3 - {[2- (Biphenyl-2-yloxy) -ethyl] -methanesulfonyl-amino} -propyl) -thiophene-2-carboxylic acid

Step A: 5- (3- {2- (Biphenyl-2-yloxy) -ethyl] -amino] -propyl] -biphenyl-2-carboxylic acid tert-butyl ester, ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.49-7.52 (m, 3H), 7.24-7.39 (m, 5H), 6.90-7.20 (m, 2H), 6.69 (d, 1H), 4.08 (t, 2H), 2.89 (t, 2H), 2.74 (t, 2H), 2.57 (t, 2H), 2.22 (bs, 1H), 1.71-1 , 79 (m, 2H), 1.55 (s, 9H); MS 438 (M + 1).

Step B: 5- (3- {2- (Biphenyl-2-yloxy) -ethyl] -methanesulfonyl-amino] -dioyl} -biphenyl-2-carboxylic acid tert-butyl ester, MS 460 (M-56).

Step C: 5- (3-Dimethyl-biphenyl-2-yloxy) -ethyl] -methanesulfonyl-amino] -propyl} -phosphine-2-carboxylic acid. MS458ÍM-1).

Draft 175 (reference form)

5- (3 - {[3- (1H-indol-3-y1) -propyl] -methanesulfonyl-amino} -própý1) -thiophene-2-karboxý1sýra

Step A: 5- (3- {3- [1H-indol-3-yl) -propyl] -amino} -propyl) -biphen-2-carboxylic acid tert-butyl ester, ¹1 H NMR (400 MHz, CDCl3)₃) δ 8.11 (s, 1H), 7.49-7.57 (m, 2H), 7.32 (d, 1H),

132

7.07-7.18 (m, 2H), 6.96 (s, 1H), 6.71 (d, 1H), 2.66-2.81 (m, 8H), 1.91-2, 06 (m, 4H), 1.54 (s, 9H); MS 399 (M + 1).

Step B: 5- (3- (R3- (1H-Indol-3-yl) -propyl] -methanesulfonyl-amino) -propyl} -biphen-2-carboxylic acid tert-butyl ester, ¹1 H NMR (400 MHz, CDCl3)₃) δ 8.07 (bs, 1H), 7.50-7.55 (m, 2H), 7.34

7.36 (m, 1H), 7.08-7.20 (m, 2H), 6.98-6.99 (m, 1H), 6.70 (d, 1H), 3.66 (s, 2H), 3.15-3.25 (m, 4H), 3.05-3.11 (m, 1H), 2.73-2.85 (m, 6H), 1.88-2.04 ( m, 4H), 1.55 (s, 9H); MS 475 (M-1).

Step C: 5- (3- {3- (1H-Indol-3-yl) -propyl] -methanesulfonyl-amino) -propyl) -biphen-2-carboxylic acid. MS419 (M-1).

Dami 176

5- {3 - [(4-tert-BLrtý) -benzyl) -methanesulfonyl-amino] -propyl} -th [-thiophene-2-carboxylic acid

Step A: 5- [3- (4-tert-Butyl-benzyl-amino] -propyl] -phenyl-2-carboxylic acid tert-butyl ester. 1 H NMR (400 MHz, CDCl3)₃) δ 7.51 (d, 1H), 7.33 (d, 2H), 7.23-7.25 (m, 2H), 6.72 (d, 1H), 3.74 (s, 2H) , 2.87 (t, 2H), 2.69 (t, 2H), 1.90 (t, 2H), 1.54 (s, 9H), 1.29 (s, 9H); MS 388 (M + 1).

Step B: 5- (3- (4-tert-Butyl-benzyl) -methanesulfonyl-amino-1-propyl) -biphenyl-2-carboxylic acid tert-butyl ester, 1 H NMR (400 MHz, CDCl3₃) δ 7.47-7.49 (m, 1H), 7.34-7.36 (m, 2H), 7.237.25 (m, 2H), 6.59 (d, 1H), 4.33 s, 2H), 3.21 (t, 2H), 2.81 (s, 3H), 2.73 (t, 2H), 1.83 (t, 2H), 1.54 (s, 9H), 1.30 (s, 9H); MS 483 (M + 18).

Step C: 5- [3- (4-tert-Butyl-benzyl) -methanesulfonyl-amino] -propyl) -biphen-2-carboxylic acid. 1 H NMR (400 MHz, CDCl 3) δ 7.64 (d, 1H), 7.36 (d, 1H), 7.25-7.26 (m, 2H), 6.66 (d, 1H), 4.34 (s, 2H), 3.23 (t, 2H), 2.82 (s, 3H), 2.77 (t, 2H), 1.79-1.87 (m, 2H), 1 , 30 (s, 9H); MS 408 (M-1).

Dami 177 (viflmiflunardami)

5- (3 - {[2- (3-Chloro-phenylsulfanyl) -ethyl] -methanesulfonyl-amino) -propyl} -thiophene-2-carboxylic acid

Step A: 5- (3 - ((2- (3-Chloro-phenylsulfanyl) -ethyl] -amino) -propyl) -biphenyl-2-carboxylic acid tert-butyl ester, ¹1 H NMR (400 MHz, CDCl3) δ 7.48-7.53 (m, 1H), 7.12-7.31 (m, 4H), 6.74 (d, 1H), 3.06 (t, 2H) ), 2.85 (q, 4H), 2.65 (t, 2H), 1.80-1.87 (m, 2H), 1.55 (s, 9H); MS 412 (MH⁺).

Step B: 5- (3- (2- (3-Chloro-phenylsulfanyl) -ethyl] -methanesulfonylamino} -propyl) -biphen-2-carboxylic acid tert-butyl ester, 1 H NMR (400 MHz, CDCl3) δ 7.52 (d, 1H), 7.14-7.31 (m, 4H), 6.75 (d, 1H), 3.31-3.35 (m, 2H), 3.21 , 2H), 3.11-3.15 (m, 2H), 2.82-2.67 (m, 2H), 2.82 (s, 3H), 1.94 (t, 2H) 54 (s, 9H); MS 508 (M + 18).

Step C: 5- (3- (2- (3-Chloro-phenylsulfanyl) -ethyl-1-methanesulfonyl-amino) -propyl) -biphen-240 carboxyfuran. 1 H NMR (400 MHz, CDCl3)₃) δ 7.72 (d, 1H), 7.31 (s, 1H), 7.15-7.25 (m, 3H),

133

6.97 (d, 1H), 3.34-3.42 (m, 2H), 3.24 (t, 2H), 3.14 (t, 2H), 2.91 (t, 2H), 2 , 85 (s, 3H), 1.932.10 (m, 2H); MS 434 (M + 1).

Example 178 (Reference Example) (3 - {[Methanesulfonyl- (4-pyridin-3-yl-benzyl) -amino] -methyl} -phenoxy) -acetic acid

Step A: [3- (4-Pyridin-3-yl-benzylamino) -methyl} -phenoxy) -acetic acid tert-butyl ester, 1 H NMR (400 MHz, CDCl3₃) δ 8.81 (bs, 2H), 7.59 (d, 2H), 7.47 (m, 2H), 7.41 (m, 2H), 7.22 (t, 1H), 6.94 (m, 2H), 6.78 (m, 1H), 4.50 (s, 2H), 3.82 (s, 2H), 3.78 (s, 2H), 1.45 (s, 9H) ; MS 405 (M + 1).

Step B: (34-Methanesulfonyl-4-pyridin-3-yl-benzyl) -amino] -methyl] -thoxy] -acetic acid tert-butyl ester. ¹1 H NMR (400 MHz, CDCl3)₃) δ 8.83 (bs, 1H). 8.59 (m, 1H), 7.85 (m, 1H), 7.55 (m, 2H), 7.40 (d, 2H), 7.36 (m, 1H), 7.24 , 1H), 6.91 (d, 1H), 6.86 (m, 1H), 6.82 (dd, 1H), 4.49 (s, 2H), 4.39 (s, 2H), 4 , 32 (s, 2H), 2.81 (s, 3H), 1.48 (s, 9H); MS 483 (M + 1).

Step C: (3-Dimethylsulfanyl) -4- (dihydroquinolin-3-yl-benzyl) -amino] -methyl] -phenoxy] -acetic acid. MS 425 (M-1).

Dami 179 (benchmark)

5- (3 - {[3- (3-bromo-phenyl) -propyl] -methanesulfonyl-amino) -propyl) -thiophene-2-carboxylic acid

Step A: Reducing amphneria

5- (3,4-dihydro-3- (3-fluorophenyl) -3-phenyl-2-carboxylic acid tert-butyl ester The title compound was prepared from 5- (3-aminopropyl) -thiophene-2-carboxylic acid tert-butyl ester hydrochloric acid and 3- (3-bromo-phenyl) -propionaldehyde according to the method described in Step A of Example 141. 1 H NMR (400 MHz, CDCl3, δ 7.50 (d, 1H) 26-7.30 (m, 2H), 7.067.14 (m, 2H), 6.75 (d, 1H), 2.85 (t, 2H), 2.65-2.78 (m, 4H) , 2.60 (t, 2H), 1.92-2.04 (m, 4H), 1.52-1.54 (m, 9H); MS 438 (M +).

Step B: Sulphonamides Mwndurt

5- (3- {3- (3-Bromo-phenyl) -propyl] -methanesulfonyl) amino) -propyl} -buten-2-carboxylic acid tert-butyl ester The title compound was prepared from 5- (3 - {[3- 3-bromo-phenyl) -propyl] -amino} -propyl) -thiophene-2-carboxylic acid tert-butyl ester using the procedure described in Step B of Example 141.¹1 H NMR (400 MHz, CDCl3)₃) δ 7.52 (d, 1H), 7.30-7.32 (m, 2H), 7.07-7.16 (m, 2H), 6.74 (d, 1H), 3,15- 3.20 (m, 4H), 2.84 (t, 2H), 2.80 (s, 3H), 2.59 (t, 2H), 1.85-1.98 (m, 4H), 1 , 54 (s, 9H); MS 533 (M + 17).

134

Step C: Esther hydrolysis

The title compound was prepared from 5- (3 - {[3- (3-bromo-phenyl) -propyl] -piperidin-1-yl] -propionamide -methanesulfonyl-amino} -propyl) -thiophene-2-carboxylic acid tert-butyl ester using the method described in Step C of Example 171.¹1 H NMR (400 MHz, CDCl3)₃) Δ 7.71 (d, 1H), 7.31-7.33 (m, 2H), 7.087.17 (m, 2H), 6.84 (d, 1H), 3.11-3.22 m, 4H), 2.90 (t, 2H), 2.81 (s, 3H), 2.60 (t, 2H), 1.821.99 (m, 4H); MS 458 (M-1).

Dasmi 180

Example 180 was prepared in a similar manner to Example 179 starting with a hydrogenated aldehyde and the amine reagents in step A followed by the formation of the nitrophonamide desired step B and ester hydrolysis step C.

Dami 180 (benchmark)

5- (3 - {(Butane-1-sulfonyl) - [3- (3-chloro-phenyl) -propyl] -amino} -propyl) -thiophene-2-carboxylic acid) xýisýra

Step A: 5- (3- {3- [3-Chloro-phenyl] -propyl] -amino] -propyl} -phenylene-2-carboxylic acid tert-butyl ester. The title compound was prepared in accordance with the procedure described in step A, except that diisopropylethylamine was used f the staple for triethylamine.

Step B: 5- (3-Fluorobenz-1-sulfonyl) -3- (3-chloro-phenyl) -propyl] -amino] -propyl] -phen-2-carboxylic acid tert-butyl ester MS 531 (M + 18).

Step C: 5- (3-Cyano-1-sulfonyl) -3- (3-chloro-phenyl) -propion-1-amino) -propyl} -biphen-2-carboxylic acid. ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.72 (d, 1H, J = 4.0), 7.00-7.40 (m, 4H), 6.70 (d, 1H, J = 4.0), 3.25 , 4H), 2.82 (m, 2H), 2.60 (m, 2H), 1.60-2.25 (m, 6H), 1.07 (t, 3H, J = 7.0); MS 457 (M-1).

Dami 181 (viflmiflunardami)

5- {3- [Cyclopropanecarbonyl- (2,3-dihydro-benzo [1,4] díoxln-6-ylmethyl) -amino] -propyl} -þíófen2-carboxylic acid

Step A: Reducing amphnerino

5- [3 - [(2,3-Dihydro-benzo [1,4-d] dioxin-6-ylmethyl) -amino] -propyl} -biphenyl-2-carboxylic acid ester. Step A was performed on the turntable highway step A f dami 163.

Step B: Amffl mndndun

135

5- (3-Cyclopropanecarbonyl- (2,3-dihydroxybenzyl) -1,4-dioxo-6-ylmethyl) -amino] -propyl} -phenyl) -2-carboxylic acid methyl ester A solution of 5- (3 - ((2,3-dihydro- benzo [1,4] dioxin-6-ylmethyl) -amino] -propyl} -thiophene-2-carboxylic acid with # ester (0.435g, 0.125mmf1), DCC (0.0284g, 0.137mmf1) and s # dópopane carbox # acid (0.0119 g, 0.137 mmole) in 10 mL of CH₂Cl₂ The temperature was at room temperature for 16 h. The mixture was filtered and the mother liquor was concentrated in vacuo. The residue was dissolved in 15 mL EtOAc and was sfufl. The solution was washed with water followed by brine, dried over MgSO₄, sulfonyl, and trifluoroacetic acid to give the title compound in Step B as an oil (53 mg). MS 416 (M +).

Step C: Esther hydrolysis

5-β-cyclopropanecarbonyl- (2,3-dihydro-benzo [1,4] dioxin-6-ylmethoxy) -amino] -propyl] -biphen-2-carboxylic acid, Step C was carried out in a stepwise manner to Step C of Example 141. 1 H NMR , CDCI₃) δ 7.70 (bs, 1H), 6.50-7.00 (m, 4H), 4.50 (s, 2H), 4.20 (bs, 4H), 3.32 (m, 2H) , 2.70 (m, 2H), 1.70-1.80 (m, 2H), 1.00-0.70 (m, 4H); MS 402 (M + 1), 400 (M-1).

Dami 182-184

Dummies 182-184 were produced in a mutually exclusive manner, with a combined amount of residual aldehydes and the amine reagents in step A followed by formation of the tributary residue in step B and ester hydrolysis in step C.

Dami 182 (viflmiflunardami)

5- (3- (2- Bensflfúran-record # # # -s dóprúpanlrarbón # -amino) -propionic #] - piófen-2-carboxylic acid # ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.70 (bs, 1H), 7.00-7.60 (m, 4H), 6.60-6.95 (m, 2H), 4.60 (s, 2H), 3.20 m, 2H), 2.70 (m, 2H), 1.80 (m, 2H), 1.00-0.70 (m, 4H); MS 384 (M + 1), 382 (M-1).

Dami 183 (viflmiflunardami)

5- (3 - {[3- (3-Chloro-phen #) - prop #] - propio # -amino} -propionic #) - thiophene-2-carboxylic acid # ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.74 (d, 1H), 7.30-7.00 (m, 4H), 6.73 (d, 1H), 3.20 (m, 4H), 2.92 (m, 2H) , 2.71 (m, 2H), 2.20 (m, 2H), 1.89-1.70 (m, 4H), 1.20 (t, 3H); MS 392 (M-1).

Dami 184 (viflmiflunardami)

136

5- (3- {Acetyl- [3- (3-chloro-fsnýl) -propyl] -amino} -propyl) -thiophene-2-carboxylic acid

Step A: 5- (3- (3- (3-Chloro-phenyl) -propyl) -amino] -propyl} -phophen-2-carboxylic acid methyl ester. MS 352 (M + 1).

Step B: 5- (3- (3-Methyl-2-methylphenyl) -propylcarbonyl-2-methoxyphenyl ester. MS 394 (M + 1).

Step C: 5- (3- (acetyl- [3- (3-chloro-phenyl) -propyl] -amino} -propyl) -biphenyl-2-carboxylic acid. ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.70 (d, 1H, J = 4.0), 7.00-7.60 (m, 4H), 6.80 (d, 1H, J = 4.0), 3.25 , 4H), 2.82 (m, 2H), 2.60 (m, 2H), 2.20 (s, 3H), 1.60-2.00 (m, 2H); MS 378 (M-1), 380 (M + 1).

Dami 185

5- {3 - [(4-Butyl-benzyl) - (propane-1-sulfonyl) -amino] -propyl} -thiophene-2-carboxylic acid

Step A: Reducing aminerin

5- (3 - [(4-Butyl-benzylamino) -propyl] -biphen-2-carboxylic acid methyl ester A mixture of 4-butylbenzaldehyde (250 mg, 1.541 mmol), 5- (3-aminophenyl) 2-carboxylic acid methyl ester hydrochloride (403 mg, 1.695 mmole), and Na2 SO4 (2.189 g, 15.41 mmol) in MeOH (10 mL) was heated to reflux for 4.5 h and more Na2 19 g) was perfectly fit. The reaction was heated to reflux for 1 h and was cooled to room temperature. The solids were filtered off with MeOH and the volatiles were removed in vacuo. The residue was dissolved in THF (10 mL) and CH2 Cl2 mL) and the solution was cooled to 0 DEG C. Acetic acid (185 mg, 3.082 mmole) was followed by sodium triacetoxyborohydride (653 mg, 3.082 mmole) and the reaction was stirred at room temperature for 16 h. The reaction was diluted with EtOAc and The organic solution was washed with aqueous NaHCO3₃ followed by salt peel. The solution was a slurry over MgSO_4L sfufi, and social phenomena. Purification by flash chromatography (99: 1 CHCl₃: MeOH In 97.5: 2.5 CHCl₃: MpOH) gave the title compound (309 mg). MS 346 (MH +).

Step B: Sulphonamide synthesis

5- (3 - [(4-Butyl-benzyl) -propan-1-sulfonyl] amino] -propyl} -biphen-2-carboxylic acid methyl ester The title compound was prepared using the off-balance which is 1 st in step

B According to 141 nsma, N-methylmorpholine was used in the letter for triphenylamine.

Step C: Esther hydrolysis

5- (3-f (4-Bútvbbensvl) - (propane-1-sulfonyl) -amínó1 -propyl) -thiophene-2-carboxylic acid ·

The title compound was prepared with the use of the excipient described in step C (dsmi

137

141. ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.72 (d, 1H, J = 4.0), 7.00-7.40 (m, 4H), 6.70 (d, 1H, J = 4.0), 3.22 , 2H, J = 6.8), 2.65 (t, 2H, J = 6.8), 1.60-2.25 (m, 6H), 1.02-1.10 (m, 6H) ; MS 436 (M-1), 438 (P + 1).

Example 186 (trifluoromethyl) (3 - {[(benzo [1,2,5] oxadiazole-4-sulfonyl) - (4-butyl-benzyl) -amino] -methyl} -phenyl) -acetic acid

STEP A: Sulphonamide reaction (3-chlorobenzo [2,5-oxadiazole-4-sulfonyl) - (4-butyl-benzyl) -amino] -methyl} -phenyl) -acetic acid methyl ester, Benzofuran-4-sulfonyl chloride (109 mg, 0 , 50 mmol) was added to a solution of {3 - [(4-butyl-benzylamino) -methyl] -phenyl} -acetic acid methyl ester (163 mg, 0.50 mmol) and N, N-diposopropylethylamine (65 mg, 0.50 mmol) 1,2-dichloroethane. The reaction mixture was stirred at room temperature for 120 h. The reaction was diluted with EtOAc and the liver solution was washed with water followed by brine. The organic solution was dried over MgSO4, and concentrated to give (3 - {[(benzo [1,2,5] oxadiazole-4-sulfonyl) - (4-butyl-benzyl) -amino] -methyl} phenyl) -acetic acid methyl ester.¹1 H NMR (400 MHz, CDCl3)_a) δ 7.95 (d, 1H), 7.88 (d, 1H), 7.37-7.41 (m, 1H), 7.06-7.10 (m, 2H), 6.90- 6.97 (m, 6H), 4.56 (s, 2H), 4.51 (s, 2H), 3.66 (s, 3H), 3.45 (s, 2H), 2.48 , 2H), 1.45-1.53 ​​(m, 2H), 1.23-1.32 (m, 2H), 0.89 (t, 3H); MS 508 (M + 18).

Step B: Ester Hydrolysis (34ΚΒ6Π8άΗ · 2 · 51οχΒάίΒ8άΙ-4-5ύΙ1άηνΙ) -ί44) ύΝΙ η8ΐ ^) Ι) ^ ^ Ιηό ΒΚ »-ΐ6η ^) ^ ΙΚ--pyridinecarboxylic acid, the title compound was Prepared hydrolysis of (3 - {[ (benzyl [1,2,5] Oxidized (asfll-4-sulfonyl) - (4-butyl-benzyl) -amide [amino] -methyl ester followed aflferflinni described (step C of Example 138.¹1 H NMR (400 MHz, CDCl3)₃) δ 7.93 (d, 1H), 7, B7 (d, 1H), 7.34-7.38 (m, 1H), 7.07-7.09 (m, 2H), 6.90- 6.96 (m, 6H), 4.54 (s, 2H), 4.49 (s, 2H), 3.47 (s, 2H), 2.46 (t, 2H), 1.44-1 , 51 (m, 2H), 1.21-1.31 (m, 2H), 0.88 (t, 3H); MS 492 (M-1).

Dami 187-188

Example 187-188 were prepared in a manner hliflstaflan ventilator Example 186 sets a sulfonamide formation from the appropriate amine in Step A followed by ester hydrolysis in Step B.

Example 187 (3 - {[(4-Butyl-benzyl) - (propane-1-sulfonyl) amino] -methyl} -phenyl) -acetic acid

138

Step A: (341 (4-Butyl-benzyl) - (propan-1-sulfanyl) -amino] -methyl} -phenyl) -acetic acid methyl ester, ¹1 H NMR (400 MHz, CDCl3)₃) δ 4.30 (d, 4H), 3.69 (s, 3H), 3.61 (s, 2H), 2.82-2.86 (m, 2H), 2.59 (t, 2H) , 1.78-1.84 (m, 2H), 1.58 (t, 2H).

Step B: (34r (4-Butyl-benzimidazol-1-sulfonyl) -amino] -methyl] -phenyl} -pentylic acid ¹1 H NMR δ (400 MHz, CDCl 3) δ 7.12-7.32 (m, 8H), 4.30 (d, 4H), 3.64 (s, 2H), 2.61-2.90 (m , 2H), 2.59 (t, 2H), 1.74-1.83 (m, 2H), 1.54-1.61 (m, 2H), 1.31-1.40 (m, 2H ), 0.87-0.97 (m, 6H): MS 416 (M + -1).

Example 188 (viflmiflunardami) (3 - {[(4-Bútý1-benzyl) - (thiophene-2-sulfonyl) -amino] -metý1} -fený1) -acetic acid

Step A: (34K4-Butyl-benzyl) - (biphenyl-2-sulfonyl) -amino] -methyl} -phenyl) -acetic acid methyl ester, 1 H NMR (400 MHz, CDCl3) δ 7.51-7.57 (m , 2H), 7.12-7.20 (m, 2H), 6.95-7.08 (m, 7H), 4.30 (d, 4H), 3.68 (s, 3H) 52 (s, 2H), 2.55 (t, 2H), 1.51-1.58 (m, 2H), 1.27-1.36 (m, 2H), 0.91 (t, 3H) ; MS 472 (M + 1).

Step B: (34í (4-Butyl-benzyl) - (biphenyl-2-sulfonyl) -amino] -methyl} -4-yl) -ecylic acid ¹1 H NMR (400 MHz, CDCl 3) δ 7.50-7.54 (m, 2H), 7.10-7.18 (m, 2H), 6.89-7.05 (m, 7H), 4, 27 (d, 4H), 3.52 (s, 2H), 2.52 (t, 2H), 1.48-1.56 (m, 2H), 1.21-1.34 (m, 2H) , 0.89 (t, 3H); MS 456 (M-1).

Dami 169 (Reference Example)

3- (3 - {[3- (3-Chloro-phenyl) -própý1] amino} -metansúlfóný1--própý1) -benzoic acid

Step A: Sulphonamide reaction

3- (3- {3- (3-Chloro-phenyl) -propyran-methanesulfonyl-amino} -propyl) -benzoic acid methyl ester,

To a solution of 3- (3 - {[3- (3-chloro-phenyl) -propyl] -amino} -propyl) -benzoic acid methyl ester (50.3 mg, 0.145 mmol) and triethylamine (32.4 mg, 0 , 32 mmol) in CH₂Cl₂ (10 mL) was added methanesulfonyl chloride (18.3 mg, 0.16 mmol) at 0 ° C. The reaction mixture was stirred for 24 h at room temperature and was diluted with OH2. The liver solution was washed sequentially with aqueous HCl (5.5%, 1x), HjO (1x), NaHCOg (1x) and brine (1x). The organic solution was dried over MgSO₄, filtered, and concentrated to give the title flask in Step A as an oil (71 mg). MS 424 (M + 1).

Step B: Esther hydrolysis

The title compound was prepared by hydrolysis of 3- (3 - {[3- (3-chloro-phenyl) -propyl] -methanesulfonylamino} -amino} -amino} -amino} -propionyl] -propyl) -benzoic acid methyl ester followed by the yielding step described in step C f

139 Example 141.¹1 H NMR (400 MHz, CDCl 3) δ 7.00-8.00 (m, 8H), 3.19 (m, 4H), 3.00 (s, 3H), 2.70 (m, 2H), 2 , 60 (m, 2H), 1.79-2.03 (m, 4H); MS 408 (M-1), 410 (M + 1).

Dami 190-197

Dams 190-197 were produced in a lateral fashion by way of a sulfonamide formation of the residual amine in Step A followed by ester hydrolysis In step B.

Dami 190 (vifimifiunardami)

5- (3 - {[3- (3-Chloro-phenyl) -propyl] -methanesulfonyl-amino} -propyl) -furan-2-carboxylic acid

Step A: 5- (3 - {[3- (3-Chloro-phenyl) -pyrazol-methane] -phosphine-aminothiourea-furan-2-carboxylic acid methyl ester, MS 414 (M + 1).

Step B: 5- (3 - ((3- (3-Chloro-phenyl) -propyl] -methanesulfonyl-amino} -propyl) -furan-2-carboxylic acid, 1 H NMR (400 MHz, CDCl3) δ 6.75 (M, 2H), 2.65 1.80-2.00 (m, 4H): MS 398 (M-1), 400 (M + 1).

Dami 191 (vifimifiunardami)

5- (3 - ([3- (3-Chloro-phenyl) -propyl] -methanesulfonyl-amino} -propyl) -tetrahydrofuran-2-kartíoxýisýra

Step A: 5- [3- (3- (3-Chloro-phenyl) -propyl) -methanesulfonyl-amino) -propane-tetrahydrofuran-2-carboxylic acid methyl ester, MS 418 (M + 1).

Step Ð: 5- (3- {3- (3-Chloro-1-yl) -propyl] -methanesulfonyl] -amino] -propyl} -tetrahydrofuran-2-carboxylic acid, 1 H NMR (400 MHz, CDCl3) δ 7.00-7 , 30 (m, 14H), 3.20 (t, 2H, J = 6.8), 2.85 (s, 3H), 2.65 (t, 2H, J = 6.7), 1.90 (m, 2H); MS 402 (M-1), 404 (M + 1).

Dami 192 (vifimifiunardami)

5- (3 - {[3- (3-Chloro-phenyl) -propyl] -ethanesulfonyl-amino (amino} -propyl) -furan-2-karbnxýlsýra

Step A: 5- (3 - ((3- (3-Chloro-trifluoro-ethanesulfonylamino) -prop yl-furan-2-carboxylic acid methyl ester. MS 428 (M + 1).

Step B: 5- (3- {3- (3-Chloro-5-yl) -dimethyl-H-ethanesulfonyl-amino) -propyl] -furan-2-carboxylic acid, ¹1 H NMR (400 MHz, CDCl3)₃) δ 6.80-7.70 (m, 5H), 6.21 (d, 1H, J = 4), 3.22 (m, 4H), 2.81 (m, 2H), 2.62 m, 2H), 1.80-2.20 (m, 6H), 1.05 (t, 3H, J = 7); MS 412 (M-1), 414 (M + 1).

Dami 193

140

5- {3 - [(4-Butyl-benzyl) -ethanesulfonyl-amino] -propyl} -thiophene-2-carboxylic acid

Step A: 5- [3- (4-Butyl-benzyl) -ethanesulphonyl-amino-1-propyl] -biphenyl-2-carboxylic acid methyl ester. MS 457 (M + 18).

Step B: 5-13-N4-Butyl-benzyl-ethanesulfonyl-amino-1-propylpropylene-2-carboxylic acid 1H NMR (400 MHz, CDCl3) δ 7.70 (d, 1H, J = 3.9), 7.00-7.40 (m, 4H), 6.72 (d, 1H, J = 3.8), 3.22 (t, 2H, J = 6.9), 2.60 (t, 2H) , J = 7.0), 1.72-2.30 (m, 6H), 1.03-1.09 (m, 6H); MS 422 (M-1).

Case 194 (Reference Day)

5- (3 - {[3- (3-Chloro-phenyl) -própý1] -ethanesulfonyl-amino} -propyl) -thiophene-2-carboxylic acid

Step A: 5- (3- (R3- (3-Chloro-phenyl) -propyl] -ethanesulfanyl] amino] propyl} -phenyl) -2-carboxylic acid methyl ester, MS 461 (M + 18).

Step B: 5- (3- {3- (3-Chloro-phenyl) -propyl] ethanesulfonyl-aminothiopropyl} -blofen-2-carboxylic acid ¹1 H NMR (400 MHz, CDCl 3) δ 6.62-7.71 (m, 6H), 3.26 (m, 4H), 2.83 (m, 2H), 2.63 (m, 2H), 1 , 60-2.25 (m, 6H), 1.06 (t, 3H, J = 7.0); MS 426 (M-1), 429 (M + 1).

Case 195 (Reference Example)

3- (3 - {[3- (3-Kkk-phenyl) -propyl] -etansúltónýl-amino) -propyl) -benzoic acid

Step A: 343- (R3- (3-Chloro-phenyl) -propyl] -ethanesulfonyl-amino) -propyl) -benzoic acid methyl ester, MS 438 (M + 1).

Step B: 3- (3- {3- (3-Chloro-phenyl) -propyl] -ethanesulfonylamino} -propyl) -benzoic acid, ¹1 H NMR (400 MHz, CDCl 3) δ 7.00-8.00 (m, 8H), 3.21 (m, 4H), 2.78 (m, 2H), 2.50 (m, 2H), 1 , 82-2.20 (m, 6H), 1.05 (t, 3H, J = 7.0); MS 422 (M-1), 424 (M + 1).

Case 196 (Reference Day)

5- {3 - [[3- (3-Chloro-phenyl) -propyl] - (propane-1-sulfonyl) -amino] -propyl} -thiophene-2-carboxylic acid

Step A: 5- {β3- (3-Chloro-2-carboxylic acid) (ριύβ3η-1-5βββ-6ηνβ-β-6β-2-carboxylic acid methyl ester, MS 476 (M + 18).

Step Β: 5-ί3-ίΤ3- (3-ΚΙόΓ-ΐ8ηνΙ) -PΓΈρρερος (ριύΡ8η-1-5ύΙί6ηνΙ) ^^ ρι^,1 H-NMR (400 MHz, CDCl 3) δ 7.70 (d, 1H, J = 4.0), 7.00-7.30 (m, 4H), 6, 80 (d, 1H, J = 4.0), 3.20 (m, 4H), 2.70 (m, 4H), 2.50 (m, 2H), 1.70-2.00 (m, 6H), 1.00 (t, 3H, J = 7.0); MS 444 (M + 1), 442 (M-1).

Dami 197 (Reference Day)

141

5- {3 - [[3- (3-Chloro-phenyl) -propyl] - (3-chloro-propane-1-sulfonyl) -amino] -propyl} -thiophene-2karboxýisýra

Step A: Sulphonamide reaction

5- [3- [3- (3-Chloro-phenyl) -propyl] -propan-1-sulfonyl-amino] -propyl] -phenyl-2-carboxylic acid tert-butyl ester The title compound of Step A was prepared from analogous starting materials on the analogue a high pitch of power stations described in step A of this example 189.

Step B: Esther hydrolysis

5- [3- (3- (3-Chloro-phenyl) -piperidin-1-yl] -propan-1-sulfamoyl) -amino] -propyl] -carbophene-2-carboxyphosphine. The title compound was prepared by hydrolysis of 5- {3 - [[ 3- (3-Chloro-phenyl) -propyl] - (3-chloro-propane-1-sulfonyl) -amino] -propyl} -thiophene-2-carboxylic acid tert-butyl ester in a similar manner to the catalysts described in step C19 H171.1 H NMR (400 MHz, CDCl3)₃) δ 6.60-7.72 (m, 6H), 3.19 (m, 4H), 2.79 (m, 2H), 2.60 (m, 2H), 1.60-2.20 ( m, 6H); MS 477 (M-1).

Dami 198 (Viflmiflunardsmi)

5- (3 - {[3- (3-Chloro-phenyl) -propyl] -hydroxyacetyl-amino} -propyl) -thiophene-2-carboxylic acid

Step A: Amffl mndndun

5- (34- [3- (3-Chloro-phenyl) -propyl] -hydroxyethylamino} -DroDyl) -biphen-2-carboxylic acid methyl ester. A solution of 5- (3 - {[3- (3-chloro-phenyl) -propyl] -propyl) -thiophene-2-carboxylic acid methyl ester (80.7 mg, 0.23 mmol), acetoxyacetic acid (30 mg, 0.25 mmole) and DCC (52 mg, 025 mmole) in CH₂Cl_z (10 mL) was stirred for 124 h at room temperature. The reaction mixture was filtered and the flotifl was concentrated. The residue was dissolved in EtOAc (15 mL) and filtered. Flotifl was a mixture of HCI (5.5%, 1x), H_ZO (1x), NaHCO₃ (1x), salt peel (1x). The organic solution was dried over MgSO₄, filtered and concentrated to give the product as an oil (90 mg). MS 452 (M + 1).

Step B: Esther hydrolysis

S ^ S ^ ^ SJO ligk menyana ^ ^ ^ EróEýQjTý OxýasetýkairiínóterÓEýti íóferv ^ ^ JsaTboxýJsýra.

The title compound was prepared by hydrolysis of 5- (3 - {[3- (3-chlorophenyl) -propyl] -hydroxy-acetyl-amino} -propyl) -thiophene-2-carboxylic acid methyl ester in an analogous manner to the yields described in step C in dsmi 141.¹1 H NMR (400 MHz, CDCl3)₃) δ 6.70-7.80 (m, 6H), 3.24 (m, 4H), 2.81 (m, 2H), 2.60 (m, 2H), 1.20-2.02 m, 4H); MS 394 (M-1), 396 (M + 1).

142

Dami 199-205

Examples 199-205 were presented analogously to Example 198 with amide synthesis from video amine in step A followed by ester hydrolysis in step B.

Dami 199 (viflmiflunardami)

5- (3 - {[3- (3-Chloro-phenyl) -propyl] -sýklóprópankarbónýl-amino} -propyl) -thiophene-2-carboxylic acid

Step A: 5- (3- (3- (3-Chloro-phenyl) -propyl] -cyclopropanecarbonylamino} -propyl) -biphenyl-carboxylic acid methyl ester.

Step B: 5- (3- (3- (3-Chloro-phenylbipropyl-1-cyclopropanecarbonyl-amino) -propyl) -biphen-2-carboxylic acid. ¹1 H NMR (400 MHz, CDCl 3) δ 6.60-7.80 (m, 6H), 3.25 (m, 4H), 2.75 (m, 2H), 2.60 (m, 2H), 1 , 80-2.00 (m, 4H), 0.70-1.00 (m, 4H); MS 404 (M-1), 406 (M + 1).

Dami 200 (viflmiflunardami)

5- (3 - {[3- (3-Chloro-fený1) -propyl] -cyclobutanecarbonyl-amino} -propyl) -thiophene-2-carboxylic acid

Step A: 5- (3- (13- (3-Chloro-phenyl) -propyl) -chlorobutanecarbonyl-amino-propyl) -phenyl-2-carboxylic acid methyl ester,

Step B: 5- (3- (3- (3-Chloro-phenyl) -propyl] -cyclopentanecarbonyl-amino) -propyl} -biphen-2-carboxylic acid. ¹1 H NMR (400 MHz, CDCl3)₃) δ 6.60-7.70 (m, 6H), 3.22 (m, 4H), 2.86 (m, 2H), 2.66 (m, 2H), 1.66-1.99 m, 10H); MS 418 (M-1), 420 (M + 1).

Dami 201 (viflmiflunardami)

5- (3 - {[3- (3-Chloro-phenyl) -propyl] -methoxyacetyl-amino) -propyl) -thiophene-2-carboxylic »carboxylic acid

Step A: δζίβζΠΒΗίΒ ^^ ότΤθηγΙΕΕτόΒγίΕίϊΐθίο, ςγββθΙγΙ ^ ΗΓΓίλης Ελληνικής ΙοίθίϊΣ ^ τ.

carboxylic acid.

Step B: 5- (3- (3- (3-Chloro-phenyl) -propyl] -piperazethyl-amino] -propyl) -phosphene-2-carboxylic acid, 1 H NMR (400 MHz, CDCl3₃) δ 6.60-7.82 (m, 6H), 3.25 (m, 4H), 3.20 (s, 3H), 2.80 (t, 2H, J = 7.0), 2, 60 (t, 2H, J = 7.0), 1.60-2.00 (m, 4H); MS 408 (M-1), 410 (M + 1).

Dami 202 (viflmiflunardami)

5- (3- {Butyryl- [3- (3-chloro-phenyl) -propyl] -amino] -propyl) -thiophene-2-carboxylic acid

143

Step A: 5- (3-fluorophenyl) -3- (3-chlorophenyl) -dione-amino] -dioyl) -biphenyl-2-carboxylic acid methyl ester, MS 422 (M + 1).

Step B: 5- [3- (Butyryl- [3- (3-chloro-phenyl) -propyl] -amino} -propyl) -thiophene-2-carboxylic acid. 1 H NMR (400 MHz, CDCl3)₃) δ 6.66-7.70 (m, 6H), 3.20 (m, 4H), 2.81 (m, 2H), 2.62 (m, 2H), 1.70-2.20 ( m, 6H), 1.04 (t, 3H, J = 6.7); MS 408 (M + 1), 406 (M-1).

Example 203 (Reference Example)

5- (3 - {[3- (3-Chloro-phenyl) -própý1] -propionyl-amino [amino} -propyl) -furan-2-carboxylic acid

Step A: 5- (3- {3- (3-Chloro-phenyl) -propyl} -propyl) -amino] -prop-8-furan-2-carboxylic acid methyl ester, MS 392 (M + 1).

Step B: 5- (3- {3- (3-Chloro-phenyl) -propyl] -propanyl-amino) -propyl} -furan-2-carboxylic acid 1H NMR (400 MHz, CDCl3₃) δ 6.80-7.70 (m, 5H), 6.21 (d, 1H, J = 3.9), 3.20 (m, 4H), 2.83 (m, 2H), 2, 60 (m, 2H), 1.80-2.20 (m, 6H), 1.04 (t, 3H, J = 6.8); MS 376 (M-1), 378 (M + 1).

Example 204 (standard immunodeficiency)

5- (3 - {[3- (3-Chloro-fený1) -propyl] -amino} -8ýklóprópankarbóný1 -própý1) -furan-2-karboxý1sýra

Step Α: 5- (3 - ([3- (3-ΙΙά-Σ8ηγΙ1-PΓάλλα-8 ΙάΡΓΡΔηΙ) ή) άηνΙ ^ ίηάΐ-PĂρρρρικής-2-carboxylic acid methyl ester. MS 404 (M + 1).

Step B: 5- (3- {3- (3-Chloro-phenyl) -propyl] -8-propylpropylcarbonylamino} -dio} -furan-2-carboxylic acid. 1 H NMR (400 MHz, CDCl3₃) δ 6.80-7.40 (m, 5H), 6.19 (d, 1H, J = 4.0), 3.25 (m, 4H), 2.61 (m, 2H), 2, 60 (m, 2H), 1.60-2.00 (m, 4H); MS 388 (M-1), 390 (M + 1).

Dami 205 (benchmark)

5- (3- {Acetyl- [3- (3-chloro-phenyl) -propyl] -amino} -propyl) -furan-2-carboxylic acid

Step A: 5- (34-Ethyl-3- (3-chloro-phenyl) -propyl] -amino] -prop-8-furan-2-carboxylic acid methyl ester, MS 378 (M + 1).

Step B: 5- (3-Acetyl) -4- (3-chloro-phenyl) -propyl] -amino] -propane-2-carboxylate [1 H NMR (400 MHz, CDCl3₃) δ 6.82-7.70 (m, 5H), 6.20 (d, 1H, J = 4), 3.20 (m, 4H), 2.80 (m, 2H), 2.60 m, 2H), 2.10 (s, 3H), 1.60-2.04 (m, 4H); MS 362 (M-1), 364 (M + 1).

Dami 206 (reference date)

5- (3 - {[3- (3-Chloro-phenyl) -propyl] -methanesulfonyl-amino} -propyl) -thiophene-2-carboxylic acid sodium salt

144

To a solution of 5- (3 - {[3- (3-chloro-phenyl) -propyl] -methanesulfonyl-amino} -propyl) -thiophene-2-carboxylic acid (7.378 g, 17.74 mmol) of MeOH (325 mL) and water (25 mL) was added NaHCO₃(1.490 g, 17.74 mmol) and reaction was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and the residue was chromatographed on MeOH (2 x 50 mL) followed by CHCl3 (2 x 50 mL) to give sodium salt as a white solid (7.661 g). 1 H NMR (400 MHz,

CDaOD, δ 7.35 (d, 1H), 7.28 (m, 2H), 7.14 (m, 2H), 6.73 (d, 1H), 3.23 (m, 4H) 83 (s, 3H), 2.82 (m, 2H), 2.62 (t, 2H), 1.94 (m, 2H), 1.88 (m, 2H).

Dssmi 207-216

Meff pvf power follows the general yield described for Example 206, the following sodium salts (dsmi 207-216) were produced with the same changes as the recordings.

Example 207 (3 - {[(4-Butyl-benzyl) -methanesulfonyl-amino] -methyl} -phenyl) -acetic acid sodium salt

The effect of the power factor described for Example 206 was the sodium salt produced. Sodium saline was stirred in 3% EtOH / EtOAc vifl 45 ° C for 20 h, cooled to room temperature and yielded a white solid. Bm 158 ° C; 1 H NMR (400 MHz, CD 3 OD) δ 7.26-7.11 (m,

8H), 4.28 (s, 4H), 3.45 (s, 2H), 3.29 (8,2H), 2.80 (s, 3H), 2.58 (t, 2H) 57 (m, 2H), 1.33 (m, 2H), 0.92 (t, 3H).

Example 208 (reversible suspension) [3 - (((3- (3,5-Dichloro-phenyl) -alkyl] -methanesulfonyl-amino} -methyl) -phenoxy] -acetic acid sodium salt 1 H NMR (400 MHz, CDgOD) δ 7.29-7.21 (m, 4H), 6.94 (m, 2H), 6.84 (d, 1H), 6.44 (d, 1H), 6.24 (m, 1H), 4 , 37 (s, 2H), 4.35 (s, 2H), 3.94 (d, 2H), 2.94 (s, 3H).

Example 209 (reversible suspension) [3 - (((2- (3,5-Dichloro-phenoxy) -ethyl] -methanesulfonyl-amino} -methyl) -phenoxy] -acetic acid sodium salt 1 H NMR (400 MHz, CD₃OD) δ 7.21 (m, 1H), 6.96 (m, 3H), 6.83 (m, 3H), 4.44 (s, 2H), 4.35 (s, 2H), 4 , 01 (t, 2H), 3.56 (t, 2H), 2.97 (s, 3H).

Dssmi 210 (Viflmiflunardssmi)

2- (3 - ((2- (3,5-Dichloro-phenoxy) -ethyl] -methanesulfonyl-amino} -propyl) -thiazole-4-carboxylic acid sodium salt

145 ¹1 H NMR (400 MHz, CD₃OD) δ 7.82 (bs, 1H), 6.99 (m, 1H), 6.92 (m, 2H), 4.15 (t, 2H), 3.62 (m, 2H) 36 (m, 2H), 3.03 (m, 2H), 2.94 (s, 3H), 2.14 (m, 2H).

Dsmi 211 (Reference Example)

N- [2- (3,5-Dichloro-phenoxy) -ethyl] -N- [6- (1H-tetrazol-5-yl) -hydroxy] methanesulfonamide sodium salt ¹1 H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 6.93 (s, 2H), 4.14 (t, 2H), 3.58 (t, 2H), 3.23 (t, 2H) 91 (s, 3H), 2.80 (t, 2H), 1.73 (m, 2H), 1.62 (m, 2H), 1.36 (m, 4H).

Dsmi 212 (vidmidunardsmi)

7 - ((2- (3,5-Dichloro-fanoxy) -ethyl] -methanesulfonylamino} -haptanoic acid sodium salt

Following the behavior described for Example 206 sodium salt was produced. Sodium salt was stirred in 2% water in EtOAc at 65 ° C for 20 hours. The mixture was cooled to room temperature and filtered to give a white solid. Bm 166 ° C;¹1 H NMR (400 MHz, CD 3 OD) δ 7.00 (s, 1H), 6.94 (s, 2H), 4.14 (t, 2H), 3.59 (t, 2H), 3.29 , 2H), 2.92 (s, 3H), 2.14 (t, 2H), 1.60 (m, 4H), 1.35 (m, 4H).

Dsmi 213

7 - [(4-Butyl-benzyl) -methanesulfonylamino] -heptanoic acid sodium salt

Following the behavior described for Example 206, sodium salt was produced. Sodium salt was stirred for 10% EtOH in EtOAc at 65 ° C for 20 hours. The mixture was cooled to room temperature and was allowed to give a white solid. Bm 137 ° C; 1 H NMR (400 MHz, CD 3 OD) δ 7.27 (d, 2H), 7.15 (d, 2H), 4.32 (s, 2H), 3.12 (t, 2H), 2.85 s, 3H), 2.60 (t, 2H), 2.09 (t, 2H), 1.60-1.20 (m, 12H), 0.92 (t, 3H).

Example 214 (Compounds) (3 - {[(4-Cyclohexyl-benzyl) -methanesulfonylamino] -methyl} -phenyl) -acetic acid sodium salt 1 H NMR (400 MHz, CD₃OD) δ 7.33-7.15 (m, 8H), 4.31 (s, 2H), 4.28 (s, 2H), 3.64 (s, 2H), 2.74 (s, 3H ), 2.48 (m, 1H), 1.84 (m, 4H), 1.74 (m, 1H), 1.38 (m, 4H), 1.24 (m, 1H).

Example 215 (3 - {[(4-tert-Butyl-benzyl) -methanesulfonyl-amino} -methyl} -phenoxy) -acetic acid sodium salt

146

Following the procedure described for Example 206, sodium saline was produced. Sodium saline was stirred in 2% water in EtOAc at 65 ° C for 20 h. The mixture was cooled to room temperature and was filtered to give a white solid. Mp 184-186 ° C;¹1 H NMR (400 MHz, D₂O) δ 7.19 (d, 2H), 7.04 (m, 3H), 6.71 (d, 1H), 6.63 (d, 1H), 6.49 (s, 1H) 20 (s, 2H),

4.18 (s, 2H), 4.17 (s, 2H), 2.88 (s, 3H), 1.08 (s, 9H).

Example 216 (Case Study)

5- (3 - {[2- (3,5-Dichloro-phenoxy) -ethyl] -methanesulfonylamino) -propyl) -thiophene-2-carboxylic acid sodium salt ¹1 H NMR (400 MHz, CD 3 OD) δ 7.34 (d, 1H), 6.99 (t, 1H), 6.90 (d, 2H), 6.72 (d, 1H), 4.12 , 2H), 3.60 (t, 2H), 3.31 (t, 2H), 2.92 (s, 3H), 2.83 (t, 2H), 2.00 (m, 2H).

FLEXIBILITY C4-C6

The residues C4-C6 were prepared from the residual starting materials in a random manner at residue C1.

PRODUCTION C4

N-3- (5-Methyl-thiophen-2-yl-propyl-metansLilfónamíð ¹1 H NMR (400 MHz, CDCl3)₃) δ 6.57-6.53 (m, 2H), 4.35 (m, 1H), 3.17 (m, 2H), 2.93 (s, 3H), 2.83 (t, 2H) ), 2.42 (s, 3H), 1.90 (m, 2H).

PREPARATION 5 [3- (3-Methanesulfonylamino-propyl) -phenyl] -acetic acid methyl ester 1 H NMR (250 MHz, CDCl 3) δ 7.30-7.06 (m, 4H), 4.34 (m, 1H), 3.70 (s, 3H), 3.61 (s, 2H), 3.27 (m, 2H), 2.94 (s, 3H), 2.72 (t, 2H), 1.93 (m, 2H) .

PREPARATION C6 35 [2- (3-Methanesulfonylamino-propyl) -phenyl] -acetic acid methyl ester 1 H NMR (400 MHz, CDCl3) δ 7.24-7.16 (m, 4H), 4.58 (m, 1H), 3 , 69 (s, 3H), 3.66 (s, 2H), 3.17 (q, 2H), 2.94 (s, 3H), 2.72 (t, 2H), 1.88 (m, 2H).

147 production D3-D4 production D3-D4 were produced from auxiliary starting materials at the yield level of the residual D1.

MANUFACTURE D3

Bromomethyl-4-propyl-benzene ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.30-7.25 (m, 2H), 7.14 (m, 2H), 4.48 (s, 2H), 2.56 (t, 2H), 1.62 (m, 2H) , 0.93 (t, 3H).

MANUFACTURE D4

Bromomethyl-4-ethyl-benzene ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.28 (m, 2H), 7.16 (d, 2H), 4.48 (s, 2H), 2.63 (q, 2H), 1.22 (t, 3H).

The production of F3-F4 products F3-F4 was produced from auxiliary starting materials in a mutually exclusive manner in the yield of F1.

MANUFACTURE F3

2-Bromomethyl-benzofuran

PRODUCTION F4

6-Ktor-2-bromomethyl-quinoline production R L4-L17 productions L4-L17 were prepared from auxiliary starting materials at the yield level of yield L1.

MANUFACTURE L4

- (2-Bromo-ethoxy) -3-ethyl-benzene

148

MANUFACTURE L5

- (2-Brófn-ethoxy) -3-isopropyl-benzene

FRAMLEIÐSLAL6

- (2-Brófn-ethoxy) -3-trifluoromethyl-benzene

FRAMLEIÐSLAL7

(2-Bromo-ethoxy) -3,5-difluoro-benzene 1 H NMR (400 MHz, CDCl3₃) δ 6.42 (m, 3H), 4.24 (t, 2H), 3.62 (t, 2H).

MANUFACTURE L8

- (2-Bromo-ethoxy) -3,5-dichloro-benzene

FRAMLEIÐSLAL9

- (2-Bromo-ethoxide-3-fluoro-benzene

MANUFACTURE L10

1- (2-Bromo-ethoxy) -3-chloro-5-methoxy-benzene

MANUFACTURE L11

- (2-Bromo-ethoxy) -3-ethoxy-benzene 30

MANUFACTURE L12

2-Bromo-ethoxy) -3-chloro-benzene

MANUFACTURE L13

5- (2-Bromo-atoxfl-bens6n, 31di'oxól ¹1 H NMR (400 MHz, CDCl3)_S) δ 6.69 (d, 1H), 6.50 (s, 1H), 6.33 (dd, 1H), 5.91 (s, 2H), 4.20 (t, 2H), 3.59 (t, 2H).

149

MANUFACTURE L14

1- (2-Bromo-ethoxy) -3,5-bis-benzene-tríflúonmetvi

MANUFACTURE L15

1-in 3-Bromo-próooxv) -3-chloro-5-methoxy-benzene

MANUFACTURE L16

- (3-Bromo-propoxy) -3,5-dichloro-benzene

FHAMLEIÐSLAL17

- (2-Bromo-ethoxy) -3-methoxy-benzene

FRAMLEIPSLAW2

5- (3-Oxo-thioyl) -biphene-2-carboxylic acid tert-butyl ester

Step A: Esther Mvndun

5-Bromo-biphene-2-carboxylic acid tert-butyl ester, To a mixture of anhydrous MgSO₄(11.60 g, 96.4 mmol) in 100 mL of CH₂Cl2 was added substantially₂SO₄ (1.45 mL, 24.1 mmol) and the mixture was stirred for 15 minutes after addition of 5-bromo-thiophene-2-carboxylic acid (5.0 g, 24.1 mmol). After stirring for 1 min, tert -butanol (11.6 g, 20 mmol) was added and the reaction was stirred at room temperature for 18 h. The reaction was a staple with saturated NaHCO3. The layers were separated, the water layer was extracted with CH₂Cl₂, and the combined organic login was dried over MgSO₄. The organic solution was concentrated to give a clear oil which was purified by medium pressure chromatography (3% EtOAc in hexane) to give the title compound (4.97 g).¹1 H NMR (400 MHz, CDCl 3) 87.45 (d, 1H), 7.02 (d, 1H), 1.54 (s, 9H).

Step B: Overall Response

5- (3-Oxo-propyl) -biphenyl-2-carboxylic acid tert-butyl ester. To a solution of 5-bromo-thiophene-2-carboxylic acid tert-butyl ester (0.50 g, 1.89 mmol) in 5 mL of DMF was added allyl alcohol (0.51 mL, 7.57 mmol) followed of NaHCO₃ (0.397 g, 4.72 mmol), tetrabutylamine chloride (0.525 g, 1.89 mmol), and palladium acetate (0.021 g, 0.094 mmol). Reaction was placed in an oil bath heated to 65 ° C and heated to 90 ° C for 2 hours. The mixture was diluted with EtOAc and 25 mL of water and the solids were removed by welding through self-contained.

150

Login was separated, and the liver solution was urine with water (4x), dried over MgSO₄ and concentrated in a pale yellow oil which was purified by medium pressure chromatography (7: 1 hexane: EtOAc) to give the title compound (0.190 g). ¹1 H NMR (400 MHz, CDCl3)₃) Δ 9.80 (s, 1H), 7.51 (d, 1H), 6.78 (d, 1H), 3.14 (t, 2H), 2.86 (t, 2H), 1.54 (s, 9H).

FRAMLEIÐSLAX1

3-yl-2-methanesulfonylamino-ethyl-benzoic acid methyl ester

Step A

3-Svanomethyl-benzoic acid methyl ester. A mixture of 3-bifluoromethyl-benzylic acid methyl ester (3.00 g, 13.10 mmol), potassium cyanide (1.02 g, 15.71 mmol) and DMF (25 mL) was heated to 40-45 ° C minute and the room temperature was 118 hours. The reaction was a heat force

40 ° C For 24 hours, cold at room temperature, and more potassium cyanide (1.02 g, 15.71 mmfll) was added. The reaction was a temperature of 40 ° C for 18 hours and was cold at room temperature. Water (25 mL) was added and the residue was extracted with EtOAc (3x25 mL). The combined organic extracts were washed with 1N LiCl followed by brine, dried over MgSO₄, siufl, and samsflfnufl. Flash-chromatography (9: 1 hexane: EtOAc in 4: 1 hexane: EtOAc) gave 3-cyanomethyl-benzoic acid methyl ester (1.36 g). MS 193 (M + 16).

Step B

3- (2-Amino-ethyl) -benzoic acid methyl ester A solution of 3-cyanomethyl-benzylic acid methyl ester (1.36 g) in EtOH (25 mL) was added with HCl (g) and PtO2 (200 mg) ft in The reaction was hydrogenated on a Parr shaker vial 50 psi for 2.5 h. The impulse was removed by self-propagation and the laser was removed from the air. The resulting solid was filtered and the title compound gave title compound as a white solid (1.18 g), MS 180 (M + 1).

Step C

3- (2-Methanesulfonylamino-ethyl) -benzoic acid methyl ester To a solution of 3- (2-aminophenyl) -benzoic acid methyl ester (500 mg) in CH₂Cl₂ (35 mL) at 0 ° C was added methanesulfonyl chloride (292 mg, 2.55 mmol) and triethylamine (1.6 mL, 11.5 mmol). The reaction was stirred at room temperature for 118 hours and was subjected to a mixture of 5.5% HCl, water, NaHCO₃, and salt pack. The liver solution was dried over MgSO₄, filtered and concentrated to give the title compound (522 mg) as a white solid. MS 275 (M + 18).

FRAMLEIÐSLAY1

151 (3-Formyl-phenyl) -acetic acid ethyl ester

STEP A

Method (3-Cyano-ethyl) -acetic acid ethyl ester To a mixture of (3-bromo-phenyl) -acetic acid ethyl ester (15.3 g, 62.9 mmol) and 1-methyl-2-pyrrolidinone (125 mL ) was added copper (I) cyanide (8.46 g, 94.4 mmol). The reaction mixture was stirred in an oil bath at 190 ° C for 1 h. The reaction was cooled to room temperature and diluted with EtOAc and 2: 1 H₂O / NH₄OH. The mixture was stirred for 10 minutes and filtered through self-contained. The aqueous layer was washed with EtOAc (2x). The organic solution was washed with 2: 1 H₂O / NH₄OH until the water extracts were no longer blue. The organic solution was dried over MgSO₄, filtered and concentrated to give (3-cyano-phenyl) -acetic acid ethyl ester (11.95 g). NMR (400 MHz, CDCl3)₃) Δ 7.51-7.58 (m, 3H), 7.43 (t, 1H), 4.16 (q, 2H), 3.63 (s, 2H), 1.25 (t, 3H) .

(3-Bromo-phenyl) -acetic acid ethyl ester (12.38 g, 54.05 mmol), zinc cyanide (4.33 g, 36.9 mmol) , and DMF (150 mL) was distilled off with nitrogen and Pd (PPh₃)₄ (3.10 g, 2.68 mmol) was added. The mixture was heated to a 90 ° C oil bath for 2.5 h and was cooled to room temperature. Water solution of NH₄OH (5%) was added and the product was extracted into Et2 (3x). The combined organic extracts were washed with 5% NH₄OH left by salt broth. The organic solution was dried over MgSO₄, filtered and compacted. Flash chromatography (9: 1 hexane: EtOAc) gave (3-cyano-phenyl) -acetic acid ethyl ester (9.08 g) as a pale yellow liquid which was spherical like that obtained by Note A above.

STEP B (3-Formyl-phenyl) -acetic acid ethyl ester To a solution of (3-cyano-phenyl) -acetic acid ethyl ester (4.8 g, 25.4 mmol) in 75% formic acid in water was a nickel- aluminum alloy (4.6 g). The mixture was heated at reflux (100 ° C) for 2.25 h. The reaction mixture was cooled and filtered through self-propelled boiling EtOH. The flask was diluted with H 2 O and the product was extracted into CHCl₃ (3x). The organic solution was quenched with saturated NaHCO3 solution until a pH of 8 was reached. The organic solution was dried over MgSO₄, then, and coincided. The product was purified by flash chromatography (5: 1 hexane / EtOAc) to afford the title compound (3.33 g).¹1 H NMR (400 MHz, CDCl3)₃) Δ 7.76-7.79 (m, 2H), 7.47-7.57 (m, 2H), 4.15 (q, 2H), 3.69 (s, 2H), 1.25 t, 3H); MS 193 (M + 1).

152

PREPARATIONAZ1 (3-Formyl-phenyl-acetic acid methyl ester

Step A

O-Svano-phenyl) -acetic acid methyl ester, Cooling material was pumped 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 tetrakiphenylphenylphosphine (0) palladium (4.60 g, 3.98 mmol). The mixture was heated for 13 h at 80 DEG C. and cooled to room temperature. 2N aqueous solution of NH₄OH was added and the product was extracted with EtOAc (3x). The liver solution was washed with 2N NH₄OH (2x) followed by salt pack (2x). The liver solution was dried (MgSO₄), siufl, and samsflfnuflί lofami. Purification by flash chromatography (6: 1 hexane: EtOAc) gave the title compound as an oil (15.19 g).¹1 H NMR (400 MHz, CDCl3)₃) δ

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 (1.56 g, 8.91 mmol), aluminum-nickel alloy (1.63 g) and 75 % formic acid (25 mL) was heated to reflux for 1.75 h. The mixture was cooled to room temperature and the solids were removed by filtration through celite with boiling EtOH. Water was extracted and the aqueous solution was stirred with CH₂Cl_Z (3x). An aqueous solution of NaHCOs was carefully added to the Iffranu solution until the pH was approximately 8-9. The liver solution was washed with brine, dried over MgSO₄, and synergy. Purification by flash chromatography (5: 1 hexarcEtOAc) gave the title compound as tan and colorless oil (870 mg). 1 H NMR (400 MHz, CDCl 3) δ 9.98 (s, 1H), 7.77 (m, 2H), 7.55-7.46 (m, 2H), 3.68 (s, 5H).

MANUFACTURE AA1

2- (3-Methanesulfonylamino-6-propyl) -blazole-4-carboxylic acid ethyl ester

STEP

4-Methanesulfonylamino-butyric acid ethyl ester, Methanesulfonyl chloride (4.10 g, 35.8 mmol) was suspended in a suspension of ethyl 4-aminobutyrate hydrochloric acid (6.00 g, 35.8 mmol) and Et2 N (10.8 mL) , 77.4 mmole) in THF (230 mL). The resulting color solution was stirred at room temperature for 43 hours. The reaction mixture was filtered and flocculated. Flash chromatography (1: 1 EtOAc: hexane in EtOAc) gave the title compound (7.08 g).¹1 H NMR (400 MHz, CDCl3)₃) δ

153

4.51 (s, 1H), 4.12 (q, 2H), 3.16 (q, 2H), 2.94 (s, 3H), 2.40 (t, 2H), 1.85-1 , 92 (m, 2H), 1.24 (t, 3H); MS210 (M⁺+1).

£ KBEE_B

4-Methanesulfonylaminobutyramide · A solution of 4-methanesulfonyl-butyric acid ethyl ester (7.08 g, 33.8 mmole) in the majority of NH₄0H (200 mL) was stirred at room temperature for 66 h. The reaction mixture was synthesized to give the title compound as a white solid (6.16 g). The product was used in the next step without further cleaning. 1 H NMR (400 MHz, CDCl3)₃) δ 3.30 (s, 3H), 3.05-3.09 (m, 2H), 2.91 (s, 3H), 2.24-2.30 (m, 2H), 1.80- 1.85 (m, 2H); MS 181 (M + 1).

STEP C

4-Methanesulfonylaminobutylramide, A suspension of 4-methanesulfonylamino-butyric amide (0.50 g, 2.8 mmole) and Lawesson's reagent (0.56 g, 1.4 mmole) in THF (50 mL) was stirred at room temperature f 45 minutes. During this period, all real estate is dissolved. The solution was concentrated and purified by flash chromatography (79: 1 EtOAc: MeOH) to afford the title compound (0.41 g); 1 H NMR (400 MHz, CDCl 3) δ 3.29 (s, 3H), 3.07-3.11 (m, 2H), 2.91 (s, 3H), 2.62-2.66 (m , 2H), 1.93-1.99 (m, 2H); MS 197 (M⁺+1).

STEP D

2- (3-Methanesulfonylamino-dryloxy) -bazole-4-carboxylic acid ethyl ester, A solution of 4-methanesulfonylamino-thiobutylamide (0.35 g, 1.8 mmole) and ethyl bromopyvuvate (0.37 g, 1.9 mmole) in EtOH (50 mL) was stirred at room temperature for 17 h. More ethyl bromopyvuvate (0.05 g, 0.26 mmole) was added and the reaction mixture was stirred at room temperature for 5.5 hours. The reaction mixture was concentrated and purified by flash chromatography (79: 1? 19: 1 EtOAc: MsOH) to give the title compound (0.47 g).¹1 H NMR (400 MHz, CDCl 3) δ 8.05 (s, 1H), 4.40 (q, 2H), 3.24 (t, 2H), 3.17 (t, 2H), 2.96 , 3H), 2.10 (t, 2H), 1.39 (t, 3H); MS 293 (M + +1).

PRODUCTION BB1

N- (4-Butoxy-bensvh-metansijlfánamíð

Step A: Nftrfl Reduction

4-Bútoxvbensviamfn. To a solution of 4-butoxybenzonitrile (4.6 g, 26.25 mmole) in Et₂O (50 mL) was added lithium aluminum hydride (1.0 μm in THF, 26.2 mL, 26.2 mmole) (dropwise. The reaction mixture was heated to reflux for 1 h and was cooled to room temperature. The reaction was poured in water

154 (50 mL) and diluted with EtgO. The solids were removed by decomposition through self-help with Et₂O. The organic solution was washed with water followed by brine, dried (MgSO₄), filtered and concentrated in vacuo to give 4-butoxybenzylamine (2.68 g). ¹1 H NMR (400 MHz, CDCl 3) δ 7.16 (m, 2H), 6.82 (m, 2H), 3.91 (m, 2H), 3.75 (s, 2H), 1.73 , 2H), 1.46 (m, 2H),

1.39 (m, 2H), 0.95 0.3H).

Step B: Sulphonamide synthesis

N-4-Butoxy-benzyl) -methanesulfonamide · The title compound was prepared by the power of the general catalyst described in Step 2 of Preparation A1. ¹1 H NMR (400 MHz, CDCl3) δ 7.24 (d, 2H), 6.86 (d, 2H), 4.76 (bs, 1H), 4.23 (m, 2H), 3.94 , 2H), 2.83 (s, 3H), 1.75 (m, 2H), 1.47 (m, 2H), 0.96 (t, 3H).

FRAMLEIÐSLACC1

3- (3-Chloro-fenvB-DróDÍónaldehvfl

A solution of 1-chloro-3-benzobenzene (9.63 g, 40.38 mmol), allyl alcohol (5.86 g, 100.96 mmol), sodium bicarbonate (8.48 g, 100.96 mmol), tetrabutylammonium chlorophyll (11.22 g,

40.38 mmol), and Pd (OAc)₂ (317 mg, 1.413 mmol) in 25 mL of DMF was stirred at 50 ° C for 18 h. The mixture was cooled to room temperature, diluted with water, and the aqueous solution was washed with EtOAc. The organic solution was washed with water followed by brine, dried over MgSO4_4Lsfufl and interconnectors in aerodynamics. The product was purified by flash chromatography on silica gel (9: 1 hexane: EIOAc) to give the title compound as an oil (5.04 g).

, PRODUCTION CC2

3-13-Bromo-fenvb-própíónaldehvð

The title compound was prepared by force using the yields described below for the reaction of CC1 with a reaction time of 1 hour at 90 ° C.

MANUFACTURE DD1

5- (3-Aminophenyl) -pipera-2-carboxylic acid methyl ester

Step A

5- (3-tert-Butoxycarbonylamino-prop-1-yl) -biphen-2-carboxylic acid methyl ester,

A mixture of ριύρ-2-ynyl-carbamic acid tert-butyl ester (1.67 g, 0.011 mmol), 5-bromo-thiophen-22389

155 carboxylic acid methyl ester (2.50 g, 0.011 mmol), tetrakistiphenylphosphine (0) palladium (0.622 g, 0.0538 mmol), Cul (0.102 g, 0.538 mmol) and triethylamine (1.57 mL, 0.011 mmol) at 50 mL of acetonitrile under nitrogen was heated at reflux for 16 hours. The reaction was cooled to room temperature, diluted with 75 mL EtOAc, purged with 5.5% HCl, water and brine, dried over MgSO4_4L siphon and synergy in the air in oil. The product was purified by flash chromatography (9: 1 (4: 1 hexane: EtOAc) to give title compound as an oil (2.06 g). MS 313 (M + 18).

Step B

5- (3-tert-Butoxycarbonylamino-prop-1-yl) -thiophene-2-carboxylic acid methyl ester (2.06 g) and 10% palladium on carbon (1.03 g) in 50 mL of MeOH was heated on a Parr shaker fan 50 psi H₂ For 16 hours. The reaction was carried out by filtration with MeOH and flotifl was concentrated in vacuo to afford the title compound as a solid (1.93 g). MS 317 (M + 18).

Step C

5- (3-Amino-Diphenyl-biphenyl-2-carboxylic acid methyl ester) A solution of 5- (3-tert-butoxycarbonylamino-propyl) -thiophene-2-carboxylic acid methyl ester (0.118 g, 0.5 mmol) 50 mL of MeOH was added dropwise to 0 ° C and was added with HCl (g). The reaction was stirred at room temperature for 90 minutes. The solution was a combined solid which was partitioned between EtOAc and aq. NaHCO3. The contents were collected and the contents layered was subjected to a salt peel, mashed over MgSO₄, filtered and concentrated in vacuo to give the title compound (399 mg). MS 200 (M + 1).

FARMING DD2

5- (3-Amino-propyl) -furan-2-carboxylic acid methyl ester hydrochloride salt

The title compound was prepared from auxiliary starting materials in a mutually beneficial manner, with the resultant following exceptions. The hydrogenation carried out In step B was carried out for 5.5 hours. In step C, the reaction mixture was heated to room temperature and concentrated in vacuo to afford the title compound as a hydrogen chloride salt.

MANUFACTURE EE1

5- (3-Amino-propyl) -phenyl-2-carboxylic acid tert-butyl ester

Step A

156

Prop-2-yl) -carbamic acid benzyl ester

To a solution of proparglylamine (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 in 0.5 h. The reaction was stirred for 16 hours and the volatiles were removed in an air atmosphere. The residue was dissolved in EtOAc and the solution was washed with water (2x). The solution was stirred with a slurry aqueous HCl followed by saturated NaHCO₃. The solution was purged over MgSO₄, filtered, and concentrated in vacuo to give the title compound (4.43 g).

Step B

5- (3-Benzyloxycarbonylamino-ortho-1-yl) -biphen-2-carboxylic acid tert-butyl ester.

The title compound was prepared or obtained as a starting material in step H at step A in production DD1.

Step C

5- (3-Amino-propyl) -phosphene-2-carboxylic acid tert-butyl ester hydrochloride salt To a solution of 5- (3-benzyloxycarbonylamino-prop-1-ynyl) -piphenyl-2-carboxylic acid tert-butyl ester g, 2.69 mmol) in 15 mL of MeOH and 2.69 mL of 1N HCl (aq) was added Pd (OH)₂ (1 g).

The mixture was shaken in a Parr shaker at 45 psi H? for 16 hours. The impulse was removed by siun through self and more of Pd (OH)₂ (1 g) was bait Ot i. The reaction time was shaken at 45 psi H₂ for 6 hours and the catalyst was removed by filtration through the seal. The solution was consistent with the air max. Leifin was stddugeimud food CCL and was crushed with Et₂To give titilamine (360 mg).

MANUFACTURING FF1

5- [3- [3- (3-Chloro-phenyl) -propamino-1-propyl] -biphenyl-2-carboxylic acid methyl ester

A solution of 5- (3-amino-propyl) -thiophene-2-carboxylic acid methyl ester (0.11 g, 0.5 mmol) and dibsopropylethylamine (0.071 g, 0.55 mmol) in 10 mL of MeOH was stirred at room temperature Temperature For 30 minutes and 3- (3-chloro-phenyl) -propionaldehyde (0.093 g, 0.55 mmdl) was added. The mixture was stirred for 90 minutes. The reaction time was cooled to 0 ° C, NaBH₄ (0.83 mL, 5.98 mmol) was added and the mixture was stirred for 30 min. The reaction was quenched with 1: 1 NaHCO₃H_z0 and was pervid with CH 2 fe. CH2 Cl2 O. The reaction times 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).

production of FF2-FF4

157 preparations of FF2-FF4 were produced from auxiliary starting materials analogously to the production of FF1.

MANUFACTURING FF2

5- [3- (3-Chloro-phenyl) -propylamino] -propyl) -biphen-2-carboxylic acid tert-butyl ester 1H NMR (400 MHz, CDCl3) δ 7.51 (d, 1H), 7.25-7 , 0.5 (m, 4H), 6.74 (d, 1H), 2.83 (t, 2H), 2.72-2.59 (m, 6H), 1.97-1.82 (m, 4H ), 1.53 (s, 9H); MS 394 (M + 1).

MANUFACTURING FF3

5- (3- {3- (3-Chloro-phenyl) -propylamino-propyl} -furan-2-carboxylic acid methyl ester

MS 336 (M + 1).

MANUFACTURING FF4

5_z{3₌I32Í32Kltí ^₌fenýtlj2rÓE »2Í1amínóhBrónýU2tetrahý ^ ^ rófýran222ka oxý1sýnjjTn_istýLester

MS 340 (M + 1).

PRODUCTION GG1

3- (3-Chloro-phenyl--pr6pyiamfn

STEP

3- (3-Chloro-phenyl) -acetic acid A solution of 3- (3-chloro-phenyl) -acrylic acid (15.0 g, 82.15 mmol) in 50 mL of thionyl chloride was heated to reflux for 30 minutes. of thionyl chloride was removed by distillation of atmospheric pressure. The residue was suspended in the ceiling to give 17.288 g of orangeugulary oil. The oil was dissolved in 25 mL of CH₂Cl 2 and the solution was replaced by liquid NH₃ (20 mL, 80.07 mmol) in CHCl3 (50 mL) at -78 ° C. The resulting suspension was heated to room temperature and concentrated in vacuo to yield title compound as a crude solid (19.38 g).¹1 H NMR (400 MHz, CD 3 OD) δ 7.57 (s, 1H), 7.45 (m, 2H), 7.36 (m, 1H), 6.64 (d, 1H); MS 182 (M + 1), 180 (M-1).

STEP B

158

3- (3-Chloro-phenyl) -propylamine · 1.0 M solution of LiAlH₄ THF (6.0 mL, 6.0 mmol) was added dropwise 3- (3-chloro-phenyl) -acrylamide (1.0 g, 5.51 mmol) in 30 mL of THF at 0 ° C. The reaction mixture was heated at reflux temperature and stirred for 5 hours. Other 4 mL of 1 M LiAlH₄ was added in and the reaction was rapid for 18 hours. Other 2 mL of 1 M UAIH4 was added color f and the reaction was fast for 24 hours. The reaction mixture was concentrated in the preparation of a drop of water. The mixture was concentrated under reduced pressure to remove THF and was diluted with water. The aqueous solution was extracted with EtOAc. The organic solution was washed with water, dried over MgSO₄, filtered and compacted in aerodynamics. The residue was dissolved in CHCI₃ and the solution was washed with 1 M HCl. The aqueous solution was evaporated to pH 11 with 1 M NaOH and the product was extracted into CHCl₃. The organic solution was dried over MgSO₄, filtered and concentrated in vacuo to give the title compound as a yellow oil (0.134 g). ¹1 H NMR (400 MHz, CDCl3)₃) δ 7.20-7.22 (m, 3H), 7.16 (m, 1H), 2.74 (t, 2H), 2.61 (t, 2H), 1.74 (m, 2H) ; MS 170 (M + 1).

MANUFACTURE HH1

4-pyrimidin-2-yl-benzaldehyde

A solution of 2-bromopyrimidine (1.00 g, 6.3 mmol) and tetrakistiphenylphosphine (O) palladium (0.218 g, 0.189 mmole) in ethylene glycol dimethyl ether (30 mL) was a high performance resin

10 minutes. A solution of 4-formyl-benzene boronic acid (1.14 g, 7.61 mmol) and sodium bicarbonate (1.58 g, 18.9 mmol) of water was added dropwise and the reaction was heated to reflux for 18 h. The mixture was diluted with water and ΟΗ₃. The residues were separated, and the aqueous solution was washed with CH2Cl2. The combined organic extracts were dried over MgSO4₄, vacuum, and cosmic energy in a vacuum. The residue was purified by flash chromatography (10% in 30% hexane in EtOAc) to give the title compound (0.979 g). 1 H NMR (400 MHz, CDCl 3) δ 10.11 (s, 1H), 8.83 (s, 2H), 8.82 (s, 1H), 7.98 (8.2H), 7.23 s, 2H).

MANUFACTURE HH2-HH7

The prodrugs HH2-HH7 were prepared from the starting materials in the screened-up high-reshape HH1.

MANUFACTURE HH2

4-Pyridin-2-yl-bensaidehvfi ¹1 H NMR (400 MHz, CDCl 3) δ 10.09 (s, 1H), 8.72 (s, 1H), 6.16 (s, 2H), 7.95 (s, 2H), 7.79 , 2H), 7.29 (m, 1H); MS 184 (M + 1).

MANUFACTURE HH3

159

4-Pyridin-3-yl-benzaldehyde ¹1 H NMR (400 MHz, CDCl3)₃) δ 10.04 (s, 1H), 8.88 (s, 1H), 8.64 (s, 1H), 7.97 (s, 2H), 7.91 (m, 1H), 7.75 (m, 2H), 7.39 (m, 1H); MS 184 (M + 1).

MANUFACTURE HH4

4-Pyridin-4-yl-benzaldehyde ¹1 H NMR (400 MHz, CDCl 3) δ 10.03 (s, 1H), 8.70 (8.2H), 7.99 (s, 2H), 7.79 (s, 2H), 7.52 , 2H); MS 184 (M + 1).

MANUFACTURE HH5

ÞíasóF2-4-yl-benzaldehyde

MS189 (M +).

MANUFACTURE HH6

4-PÝrimMío -? - Yi-lwn8aMa) rig ¹1 H NMR (400 MHz, CDCl3)₃) δ 10.03 (s, 1H), 9.26 (s, 1H), 9.00 (s, 2H), 8.03 (m, 2H), 7.76 (m, 2H).

MANUFACTURE HH7

4-pyrazin-2-yl-benzaldehyde ¹1 H NMR (400 MHz, CDCl3)₃) δ 10.03 (s, 1H), 9.10 (s, 1H), 8.69 (s, 1H), 8.59 (s, 1H), 8.21 (d, 2H), 8.03 (d, 2H).

FRAMLEIÐSLA111

5- (3-Oxo-6-yl) -1H-dihydro-3-carboxylic acid ethyl ester

Step A

5- (tert-Butyldimethylsulfanoxid -Dentane-2-6n) A solution of 3-acetyl-1-pyranol (3.000 g, 29.37 mmol), tert -butyldimethylsulfonic acid ( 4.522 g, 30.00 mmol), and imidazole (5.004 g,

160

73.5 mmol) in DMF (40 mL) was heated at 40 ° C for 5 h and the reaction temperature was 66 h. Water (60 mL) was added and the product was extracted into EtOAc (4x50 mL). The combined livestock extracts were washed with water (2x50 mL), dried over MgSO4₄, slaves, and synopsis. Purification by flash chromatography (hexane: EtOAc 9: 1) gave title compound (3.722

g). ¹1 H NMR (400 MHz, CDCl 3) δ 3.59 (t, 2H), 2.49 (t, 2H), 2.13 (s, 3H), 1.76 (m, 2H), 0.86 , 9H), 0.02 (s, 6H); MS 217 (M + 1).

Step B

7- (tert-Butyldimethylsilanyl) oxy) -2,4-dioxo-hexanesyl ethyl ester. Diethyl oxalate (4.048g, 37.7mmol) was added in solid sodium ethoxide (0.472g, 69.3mmol) at 0 ° C followed by the further addition of 5- (tert-butyl-dimethyl-silanyloxy) -pentan-2-one (1.500 g, 69.3 mmole). The orange solution released was a rapid reaction of 0 ° C 10 min and the room temperature for 3 h. Purification by flash chromatography (19: 1 hexane: EtOAc I 9: 1

EtOAc: MeOH) gave title compound (1.982 g); MS 317 (M + 1).

Step C

5- (3- (tert-Butyl-dimethyl-trifluoromethyl) -propyl] -1H-pyrazole-3-carboxylic acid ethyl ester.

A solution of 7- (tert-butyl-dimethyl-silanyloxy) -2,4-dioxo-heptanoic acid ethyl ester (1.627 g, 51.4 mmole) and hydrazine (17 mL, 55 mmol). EtOH was heated to reflux for 6 h . The reaction was concentrated. Purification by flash chromatography (6: 4 hexane: EtOAc) gave the title compound (333 mg). NMR (400 MHz, CDCl3)₃) δ 6.64 (s, 1H), 4.37 (q, 2H), 3.67 (t, 2H), 2.85 (t, 2H), 1.88 (m, 2H), 1.38 (t, 3H), 0.88 (s, 9H), 0.05 (s, 6H); MS 313 (M + 1).

Step D

5- (3-Hydroxy-propyl) -1H-pyrazole-3-carboxylic acid ethyl ester, A solution of 5- [3- (tert-butyl-dimethyl-cyanyloxy) propyl] -1H-pyrazol- 3-carton) xylic acid ethyl ester (327 mg, 1.05 mmole) and tetrabutylammonium fluoride (288 mg, 1.10 mmole) THF (50 mL) was heated at room temperature for 1 h. Flash chromatography (flash chromatography) flash chromatography (EtOAc EtOAc: MeOH 19: 1) gave title compound (165 mg) .1 H NMR (400 MHz, CDCl3)₃) δ 6.58 (s, 1H), 4.35 (q, 2H), 3.71 (t, 2H), 2.84 (t, 2H), 1.91 (m, 2H), 1.36 (t, 3H); MS 199 (M + 1).

Step E

5- (3-Oxo-propyl) -1H-pyrazole-3-carboxylic acid ethyl ester. Dimethylsulfoxide (0.14 mL,

1.9 mmole) was added to a solution of oxalyl chloride (0.137 mg, 1.08 mmol) of CH₂Cl₂ (1 mL) and THF (1 mL) vifl -78 ° C. After stirring, the solution was removed dropwise. In a solution of

5- (3-hydroxy-propyl) -1H-pyrazole-3-carboxylic acid ethyl ester (178 mg, 0.889 mmol) in THF (10

161 μm) v-78 ° C. The reaction mixture was stirred for 0.5 h and triethylamine (0.64 mL) was added. The suspension was stirred for 40 minutes and warmed to room temperature. The reaction was diluted with CH₂Cl₂: hexane (1: 4.40 mL) and the mixture was washed with 10% sodium bisulfate in aqueous solution (15 mL) followed by water (2x10 mL). The organic solution was dried over MgSO₄, siufl, and synergy to force give the title moiety. 1 H NMR (400 MHz, CDCl 3) δ 9.82 (s, 1H), 6.59 (s, 1H), 4.35 (q, 2H), 3.06 (m, 2H), 2.84 t, 2H), 1.91 (m, 2H), 1.34 (t, 3H); MS 197 (M + 1).

PREPARATION JJ1 [5- (Methanesulfonylamino-methyl) -biphen-2-yl-acetic acid methyl ester

Lit in solution of piophen-2-yl-acetic acid methyl ester (2 mL, 12.8 mmol) in 1,4-dioxane (10 mL) was added dropwise HCl (0.4 mL, 4.8 mmol) 10 mins. Zinc chloride flask (78 mg, 0.57 mmole) was added and the reaction mixture was evaporated in a pre-heated hydrolysis buffer at 45 ° C for 15 minutes. HCI (g) was bullaf in solution for 2-3 minutes. The temperature of the reaction is about 60 ° C. The suspension was 37% aqueous formaldehyde solution (1.24 mL, 16 mmol) added dropwise and temperature at 70 ° C. The reaction mixture was cooled to room temperature and methane sulfonamide (1.25 g, 12.8 mmol) was eliminated if administered. The reaction was stirred for 3 h and was poured into EtOAc (60 mL). The organic solution was washed with water and the aqueous solution was washed with EtOAc (60 mL). The combined organic solutions were washed with brine, powders over MgSO_4L siaflar, and samsafnafiar. Purification by flash chromatography (CHCb) gave the title compound (69%) as a golden oil.¹H NMR (400 MHz, CDCl3) δ 6.85 (d, 1H), 6.70 (d, 1H), 5.20 (m, 1H), 4.40 (s, 2H), 3.80 (s, 2H ), 3.70 (s, 3H), 2.80 (s, 3H).

MANUFACTURE KK1

5-13-Bromo-triphenyl] benzo [1,3] dioxole

Step A

3-Benzothiazol-5-yl) -dioxan-1-yl, lithium aluminum hydroxide (1M in THF, 30 mL, 30 mmol) was added dropwise to a solution of 3-benzo [1,3] dioxol-5-yl- propionic acid (5.83 g, 30 mmol) in THF (60 mL) at 0 ° C. The reaction was warmed to room temperature and stirred for 2 h. The solution was poured into portions in the mixture of ice (200 g) and concentrated HCl (2 mL). The effluent was extracted with EtOAc. The organic solution was poured over MgSO₄, siufl, and samsflfnufl. Purification by flash chromatography (hexane: EtOAc 6: 4) gave the title alcohol (4.51 g).¹1 H NMR (400 MHz, CDCl3)₃) δ 6.73-6.62 (m, 3H), 5.91 (s, 2H), 3.66 (t, 2H), 2.63 (t, 2H), 1.84 (m, 2H) .

Step B

162

5- (3-Bromo-propyl) -benzene-1,3-dioxol. According to the force of the step described in step B of step 01, 3-benzo [1,3] dioxol-5-yl-propan-1-one was converted to the title bromide. 1 H NMR (400 MHz, CDCl3)₃) δ 6.74-6.63 (m, 3H), 5.92 (s, 2H), 3.37 (t, 2H), 2.69 (t, 2H), 2.11 (m, 2H) .

MANUFACTURE LL1

2- (3-iodo-pyridyl) furan

To a solution of 3-furan-2-yl-propan-1-ol (6.3 g, 50 mmol) in pyridine (40 mL) at -15 ° C was added p-toluenesulfonyl chloride (11.4 g, 60 mmfll) In a reaction mixture and reaction time, it was 3 hours. Water (10 x 0.5 mL) was extracted and the mixture was poured into concentrated HCl (65 mL) and ice (200 g). Productions were extracted₂The resulting solution was dried over MgSO4₄, and the same to give a yellow oil. The oil was washed with Nal (9 g, 60 mmol) in acetone (70 mL) and the reaction was continued for 15 h. The insoluble materials were removed from the air and flotifl was cohesive in the air. Purification by flash chromatography (hexane) gave the title compound (7.2 g). 1 H NMR (400 MHz, CDCl 3) δ 7.30 (m, 1H), 6.28 (m, 1H), 6.04 (m, 1H), 3.19 (t, 2H), 2.75 t, 2H), 2.14 (m, 2H).

MANUFACTURE MM1

3- [3-amino-proov-benzoic acid methyl ester hydrochloride salt

Skreta

3- (3-tert-Butoxycarbonylamino) -redo-1-yl] -benzoic acid methyl ester, Meff power, follows the general catalyst described in Step A of Preparation C1, Prop-2-ynyl-carbamic acid tert-butyl ester clustered 3- bromomethylbenzoate to give titled compound MS 307 (M + 18).

Step B

3- (3-tert-Butoxycarbonylamino-propyl) -benzoic acid methyl ester. Meff pvf power follows the general activity described in step BI yield C1, 3- (3-tert-butoxycarbonyl-amino-prop-1-ynyl) -benzoic acid methyl ester was hydrogenated to give the title compound. MS 311 (M + 18).

Step C

163

3- (3-Amino-propyl) -benzoic acid methyl ester hydrochloride salt. A solution of 3- (3-tert-butoxycarbonylamino-propyl) -benzoic acid methyl ester (565 mg) in MeOH (25 mL) was cooled to 0 ° C and the solution was treated with HCl (g). The reaction was stirred at room temperature for 1.5 h and the reaction mixture yielded titilaminifl (399 mg). MS 194 (M + 1).

PREPARATION NN1R3- (2-Methanesulfonylamino-benzyl) -phenyl] -acetic acid tert-butyl ester

Step A

3-Bromo-phenyl acetic acid tert-butyl ester A mixture of 3-bromo-phenyl acetic acid (5.00 g, 23.24 mmol), tert-butanol (1.89 g, 25.57 mmol), DMAP 12 g, 25.57 mmol), and DCC (5.27 g, 25.57 mmol) in CH2 Cl2 (150 mL) was stirred for 24 h at room temperature. The reaction was reversible and the float was similar to the ceiling. The residue was dissolved in EtOAc and the mixture was filtered. The solution was urine in a mixture of 5.5% HCl, water, NaHCO_a, and salt peel. The solution was dried over MgSO₄, filtered and concentrated to give title compound (5.64 g).

Step B (2-12- (1,3-D {oxo-1,3-dihydro-2-indol-2-yl) -vinyl] -phenyl] -acetic acid tert-butyl ester.

A mixture of 3-bromo-phenyl acetic acid tert-butyl ester (5.64 g, 20.80 mmol), N-vinyl phthalimide (3.60 g, 20.80 mmol), diisopropylethylamine (3.63 g, 28.08 mmol), palladium acetate (107 mg, 0.478 mmole), and tri-o-tolylphosphine (475 mg, 1.56 mmol) in acetonitrile (10 mL) was stirred at 90 ° C for 20 h. The reaction was concentrated to room temperature and the water (50 mL) was added. EtOAc (50 mL) was added and the aqueous solution was washed with 5.5% HCl followed by brine. The solution was dried over MgSO₄, siufl, and samsflfnufl. Purification by flash chromatography (hexane: EtOAc 9: 1 in 4: 1) gave the title compound (1.95 g). MS 381 (M + 18).

Step C

12-12- (1,3-Dioxo-1,3-dibromo-isoindol-2-yl) -ethyl] -phenyl] -acetic acid tert-butyl ester

To a solution of (2- (2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -vinyl] -phenyl) -acetic acid tert-butyl ester (1.95 g) in THF 50 mL) was basically 10% Pd on a charcoal (1.00 g) and the reaction was hydrogenated Parr shaker vial 50 psi for 24 h. The catalyst was removed by filtration through a solvent using THF. The volatiles were removed. title compound (1.97 g). MS 383 (M + 18).

164

Step D [2- (2-Amino-ethyl) -phenyl] -acetic acid tert-butyl ester A solution of (2- [2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -vinyl ] -phenyl} -acetic acid tert-butyl ester (1.97 g) and hydrazine hydrate (1.97 mL) in EtOH (75 mL) was heated to reflux for 90 minutes. The solids were removed by filtration and the flotifl was concentrated in vacuo The residue was dissolved in EtOAc (50 mL) and the solution was washed with saturated NaHCO3 followed by brine. The solution was dried over MgSO4₄, siufl, and samsöfnufl. Purification by flash chromatography (CHCl3 MeOH 97.5: 2.5 in 95: 5 for 9: 1) gave titile amine (853 mg). MS 236 (M + 1).

[2- (2-amino-ethyl) -phenyl) -acetic acid tert-butyl ester (422.5 mg, 1.795 mmol), triethylamine ( 908 mg,

8.977 mmol), and methanesulfonyl chloride (226.2 mg, 1.975 mmol) in CHgCl3 (20 mL) was concentrated and stirred at 0 ° C for 18 h. The liver solution was washed with stirring dilute HCl, water, m.p. NaHCO3, and brine. The liver solution was dried over MgSO_4L and concentrated to give the titulosulfonamide (535 mg). MS 331 (M + 18).

PRODUCTION OO1

5- (3-Methanesulfonylamino-propyl) -furan-2-carboxylic acid methyl ester

To a solution of 5- (3-aminopropyl) furan-2-carboxylic acid methyl ester hydrochloric acid salt (see prolongation DD2) (150 mg, 0.683 mmol), and triethylamine (0.313 mL, 2.25 mmol) CH₂Cl₂ (15 mL) at 0 ° C was added methanesulfonyl chloride (86 mg, 0.75 mmol). The reaction was stirred at room temperature for 18 hours. The liver solution was washed in a mixture of diluted HCI, water, concentrated NaHCO3, and brine. The liver solution was over MgSO₄, filtered and concentrated to give titulosulfonamide (156 mg). MS 262 (M + 1).

PRODUCTION PP1

5- (3-Amino-propyl) -tetrahydrofuran-2-carboxylic acid methyl ester hydrochloride salt

Step A

5- (3-tert-Butoxycarbonylamino-pyridin-1-yl) -furan-2-carboxylic acid methyl ester,

The title compound was prepared by the use of the yields described. In step A of the prodrug DD1.

165

Step B

5- (3-tert-Butoxycarbonylamino-propyl) -tetrahydrofuran-2-carboxylic acid methyl ester, 5- (3-tert-Butoxycarbonylamino-thioyl) -furan-2-carboxylic acid methyl ester To a solution of 5- (3- tert -butoxycarbonylamino-prop-1-ynyl) -furan-2-carboxylic acid methyl ester (1.69 g) in MeOH (50 mL) was added 10% palladium on carbon (850 mg) and the mixture was hydrogenated on Parr shaker at 50 psi For 18 hours The catalyst was removed by filtration and the volatile materials were co-functional in a preferred embodiment. Flash chromatography (hexane: EtOAc 4: 1) gave 5- (3-tert-butoxycarbonyl-aminopropyl) -furan-2-carboxylic acid methyl ester (422 mg, MS 284 M +) followed by 5- (3-tert-butoxycarbonylaminopropyl) tetrahydrofuran-2-carboxylic acid methyl ester (903 mg).

Step C

5- (3- Amino-propyl) -tetrahydrofuran-2-carboxylic acid methyl ester hydrochloride salt,

The title compound was prepared from 5- (3-tert-butoxycarbonylamino-propyl) -tetrahydrofuran-2-carboxylic acid methyl ester following the procedure described in Step C of Production DD2.

MANUFACTURE QQ1

3-yl] -indole-3-yl} -dione

It is possible to reproduce the title reagent using the method described by Jackson in J. Am. Chem. Soc., 52, 5029-5033, 1930.

PRODUCTION RR1

2- (Biphenyl-2-yloxy) -ethylamine

The title reagent can be reproduced using the method described in GB

521,575.

PRODUCTION SS1

2- (3-Chloro-phenylsulfanyl) -ethylamine

It is possible to produce the title ingredient using the method described in Fed. Rep. Er. Sd. Pharm., 56,4, 229-234, 1988.

166

FRAMLEIÐSLATT1

2- [4-Chloro-phenylsulfanyl] -ethylamine

It is possible to produce the title reagent using the method described in Can. J.

Chem., 37, 325-329, 1959.

ULH FAMILY

3- (4-Chloro-phenyl) -propylamine

The title reagent can be prepared using the method described in J. Med. Chem., 39, 25, 4942-4951, 1996.

FRAMLEIÐSLAW1

4-Fenetvtsúlfanvl-benzaldehyde

The title reagent can be produced using the procedure described in EP

332,331.

PRODUCTION WW1

4- (2-Oxo-pyrrolidin-1-yl) -benzaldehyde 25

The title compound can be prepared using the method described by Kukalenko in Chem. Heterocycl. Compd. (English translation), 8,43,1972.

FRAMLEIÐSLAXX1

4-Cyclohexyl-bensvlamín

It is possible to produce the title compound using the method described by Meglio and colleagues at Farmaco Ed. Sci .; IT; 35,3,191-202,1980.

MANUFACTURE YY1

3-Hydroxy-4-propoxy-benzaldehyde

167

The title compound can be reproduced using power using the coagulation factors described by Beke In Acta Chim. Acad. Sci. Hung., 14,325-6, 1958.

MANUFACTURE ZZ1

5-Phenyl-furan-2-kartoaldefivð

Possible proliferation of the title compounds by force utilizes the degenerators described by D'Auria and colleagues in Heterocycles, 24,6,1575-1578,1986.