MXPA05010967A - Alpha substituted carboxylic acid as ppar modulators. - Google Patents

Alpha substituted carboxylic acid as ppar modulators.

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Publication number
MXPA05010967A
MXPA05010967A MXPA05010967A MXPA05010967A MXPA05010967A MX PA05010967 A MXPA05010967 A MX PA05010967A MX PA05010967 A MXPA05010967 A MX PA05010967A MX PA05010967 A MXPA05010967 A MX PA05010967A MX PA05010967 A MXPA05010967 A MX PA05010967A
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Mexico
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methyl
acid
phenyl
ethoxy
oxazol
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MXPA05010967A
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Spanish (es)
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Stuart Humphries Paul
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Pfizer
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Abstract

wherein R' and R2 are as defined in the specification and R3 is A) formula (II); B) formula (III); C) formula (IV); and D) formula (V); wherein Y, Art, Are, AP, R4, R5, R6, R7, R6, R9, R9a, R10, R", R12, R17, ring A, and p are as defined in the specification; pharmaceutical compositions containing effective amounts of said compounds or their salts are useful for treating PPAR, specifically PPAR alpha/y related disorders, such as diabetes, dyslipidemia, obesity and inflammatory disorders.

Description

ALPHA CARBOXYLIC ACIDS SUBSTITUTED AS PPAR MODULATORS BACKGROUND OF THE INVENTION This invention relates to alpha-substituted carboxylic acids that modulate the activities of peroxisome proliferator-activated receptor (PPAR), preferably two or more of PPAR-a, PPAR-d, or PPAR- ?, allowing them which are useful in the modulation of blood glucose and and the increase in insulin sensitivity in mammals. This invention also relates to the treatment of disorders related to PPAR, such as diabetes, dyslipidemia, obesity and inflammatory disorders. Peroxisome proliferators are a structurally diverse group of compounds that, when administered to rodents, cause dramatic increases in the size and number of hepatic and renal peroxisomes, as well as concomitant increases in the ability of peroxisomes to metabolize fatty acids by increasing of the expression of the enzymes required for the ß-oxidation cycle. The chemical compounds included in this group are the class of fibrates of the hypolipidermic drugs, herbicides, and phthalate plasticizers (Reddy and Lalwani, Crit. Rev. Toxicol., 12: 1-58 (1983)). The proliferation of peroxisomes can also be caused by dietary or physiological factors such as a diet high in fat and cold acclimation. Understanding the mechanism by which peroxisome proliferators exert their pleiotropic effects was provided by identifying a member of the superfamily of nuclear hormone receptors activated by these chemical compounds (Isseman and Green, Nature, 347-645- 650 (1990)). This receptor, called PPAR-a, was subsequently shown to be activated by a variety of meciios and long-chain fatty acids and which stimulates the expression of genes encoding acyl-CoA oxidase and hydratase-dehydrogenase (enzymes required for ß-oxidation of peroxisomes) in rats, as well as cytochrome P450 A46 in rabbits, an O-hydrolase of fatty acids. PPAR-a activates transcription by binding to elements of the DNA sequence, called peroxisome proliferator response elements (abbreviated in English PPRE), as a heterodimer with the retinoid receptor X. The retinoid receptor X is activated by 9-cis retinoic acid (see liewer, et al., Nature, 358: 771-774 (1992), Gearing, et al., Proc. Nati, Acad. Sci. United States, 90: 1440-1444 (1993) , Keller, et al., Proc. Nati, Acad. Sci. United States, 90: 2160-2164 (1993), Heyman, et al., Cell, 68: 397-406 (1992), and Levin, et al. , Nature, 355: 359-361 (1992)). Since the PPAR-a-RXR complex can be activated by peroxisome proliferators and / or 9-cis retinoic acid, the retinoid and fatty acid signaling pathways are seen to converge in the modulation of lipid metabolism. Since the discovery of PPAR-a, additional isoforms of PPAR have been identified, for example PPAR-d, or PPAR- ?, which are differentially expressed spatially. Each PPAR receptor shows a different pattern of tissue expression, and differences in activation by structurally diverse compounds. For example, PPAR-? it is expressed more abundantly in adipose tissue and at lower levels in skeletal muscle, heart, liver, intestine, kidney, vascular endothelial cells and smooth muscles as well as macrophages. There are two isoforms of PPAR- ?, identified as ?? and? 2, respectively. The PPAR-? mediates the signaling of the adipocytes, lipid storage and the metabolism of fats. The evidence accumulated to date supports the conclusion that the PPAR-? it is the main, and perhaps the only, molecular target that mediates the insulin-sensitizing action of a class of antidiabetic agents, thiazolidine 2,4-diones. In a context of monotherapy or combination therapy, the new established oral antidiabetic agents are still considered to have a non-uniform or even limited efficacy. The efficacy of oral antidiabetic therapies may be limited, in part, due to limited or limited glycemic control, or poor patient compliance due to unacceptable side effects. These side effects include edema, weight gain, or even more serious complications. For example, hypoglycaemia is observed in some patients taking sulfonylureas. Metformin, a substituted biguanide, can cause diarrhea and gastrointestinal discomfort. Finally, edema, weight gain, and in some cases, hepatotoxicity, have been associated with the administration of some thiazolidine 2,4-dione antidiabetic agents. Combination therapy that uses two or more of the above agents is common, but generally only leads to incremental improvements in glycemic control. As a result, there is a need for antidiabetic agents that show combined activation of PPAR-a and PPAR-? which should lead to the discovery of effective drugs by reducing glucose and triglycerides that have a great potential in the treatment of type 2 diabetes and the metabolic syndrome (i.e., impaired glucose tolerance, insulin resistance, hypertriglyceridemia and / or obesity).
SUMMARY OF THE INVENTION The present invention provides novel compounds of formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein: The Q ring is aryl (C6-C10) or heterocyclyl of (4-10) links; R1 is H, halo, alkyl (d-C8), alkoxy (d-C8), CN, CF3, -O-CF3, -0-S02-aIlkyl (d-C8), -0-S02- (CR1 R12) t aryl (C6-do), - (CR1 R12) t cycloalkyl (C3-do) - (CRR12) t, - (CR 1R12) t (C3-C10) cycloalkyl- (CR11R1 O -, - (CR11R12), aryl (C6-do) - (CR11R12) t, - (CR1 R12), aryl (C6-C0) t - (CRR12) tO-, - (CR 1R12) t heterocyclyl of (4-10) links - ( CR11R12) t, or - (CR11R12) t heterocyclyl of (4-10) links - (CR R12) t-0-, wherein the ring carbon atoms of R1 are optionally substituted by 1 to 3 R13 groups; the nitrogen atoms in the ring of R1 are optionally substituted with 1 to 3 alkyl (dCe), R2 is H, alkyl (dC8), - (CR1R1) t-cycloalkyl (C3-C10), - ( CR1 R 2) t-aryl (C6-do), or - (CR11R12) t heterocyclyl of (4-10) links, and wherein the carbon atoms of R2 are optionally substituted with 1 to 3 R13 groups; Nitrogen atoms in the ring of R2 are optionally substituted with 1 to 3 alkyl (d - d); R2 is selected from the group consisting of: Y is - (C = 0) - or -SO2-; Y "is NR 0 u -O-; p is 0, 1, or 2, each q, r, and t are independently 0, 1, 2, 3, 4, or 5, each n is independently 0, 1, 2, 3 or 4, each k is independently 1, 2 or 3, each mys is independently 0, 1, 2, or 3, each j is 0, 1, or 2; Each R4 is - (CR11R12) n - - (CR11R12) n -S - (CR11R12) n- - (CR1 R12) n -NR 0-, - (CR1 R12) n -NR10- (CR1 R1z) n -O-, - (CR1 R12) n-0- (CR11R12) k - NR10, - (CR11R12) n-0- (CR11R12) n- - (CR11R12) n-0- (CR11R12) k-0- (CR11R12) n-, - (CR1R1) n -CR11 = CR12 - ( CR11R12n-, or -CH = CH- (CR11R12) -0- (CH2) n-; Each R5 is a bond or - (CR11R1) mZ- (CR11R12) s, where Z is -CR 1R12-, -O - -NR10a - or - (SO) r; Each R6 is - (C = 0) -OH, - (C = 0) -OM +, - (C = 0) - (C1-C8) alkyl, - (C = 0) - O - (Ci-C8) alkyl, - < C = 0) -NRlüR ", - (C = 0) -NR1ü- S02 - R, - S02 - NH - R 0, - NH - S02 - R 0, - (C = 0) - NH - C = N, or R6 has a formula: + is an alkali metal cation or an alkaline earth metal cation; Each R7 and R8 is independently H, alkyl (Ci-Ce), alkoxy (Ci-C8), - (CR1 R 2) t cycloalkyl (C3-C10), - (CR1 R12) t aryl (C6-Cio), - (CR11R12) t aryl (C6-C10) -O-, - (CR 1R12) t heterocyclyl of (4-10) links, or - (CR11R12) t heterocyclyl of (4-10) links -O-; OR R7 and R8 can optionally be taken together with the carbon to which they are attached to form a (C3-C10) cycloalkyl or a (3-10) link heterocycle; Each Ar | \ Ar2, Ar3, and Ar4 represents aryl (C6-C10) or heterocyclyl of (5-10) links; wherein the carbon atoms in the ring of each Ar1, Ar2, Ar3, and Ar4 are optionally substituted with one to three R3 groups; Ring A represents a ring of 3, 4, 5, 6 or 7 links optionally containing 1 to 4 heteroatoms which may be the same or different and which are selected from -N (R10a) -, O, and S (0) j , where j is 0, 1, or 2, with the proviso that the ring does not contain two adjacent O or S (0) j atoms, and in which the carbon atoms of residue A in the ring are optionally substituted with one to three groups R13; R9 is (C1-C8) alkyl, - (CR11R12) t-aryl (C6-C10) or (CR11R12) t -heterocyclyl of (4-10) links, wherein t is independently 0, 1, 2, 3, 4, or 5, wherein said R 9 groups are substituted with 1 to 3 groups independently selected from - (C 1 R 12) q N R 10 11, - (CR 1 R 12) q N R 10 alkanoyl (d - C 6), - (CR11R12) qO (CR11R12) rR10, and - (CR11R12) qR10, and wherein the heterocyclyl, aryl and alkyl moieties of the above groups are optionally substituted with one to three R3 groups; R9A and R10 are independently H or (Ci-C8) alkyl; R11 and R2 are independently H, alkyl (Ci-Ca), hydroxy, or (Ci-C6) alkoxy; R10a is selected from H, alkyl (Ci-Ce), - (C = 0) -R14, -S02NR 5R16, or -S (0) j alkyl (Ci-C6); Each R 3 and R 3a are independently selected from the group consisting of halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, alkoxy (Ci-C6), alkyl (Ci-C10), alkenyl (C2-C6), alkynyl (C2 - (¾), -O- (CR1 R12) k-0- (CR11R2) n- - (C = 0) -R14, - (C = 0) -0-R15, -O- (C = 0) -R15, -NR15 (C = 0) -R16, -NR15 (C = 0) -0-R16, - (C = 0) -NR15R16, -NR15R16_ _NR150R16I _so2R15R16, -S (0) J alkyl (d) - C6), -0-S02-R14, -NR15-S02-R16, R15- (CRR12) t-aryl (C6-Cio), - (CRR12) t heterocyclyl of (4-10) links, - ( CR1 R12) q (C = 0) (CR1 R12) t aryl (C6 - C10), - (CR 1R1) q (C = 0) (CR11R12) t heterocyclyl of (4 - 10) links, - (CR11R12) tO (CR R12) q aryl (C6-C10), - (CR11R 2) tO (CR1 R 2) q heterocyclyl of (4-10) links, - (CR11R12) qS02 (CR 1R12) t aryl (C6-C10), and - (CR 1R12) qS02 (CR11R1) t heterocyclyl of (4-10) links; 1 or 2 carbon atoms in the ring of the heterocyclic moieties of the foregoing groups i3 and i3a are optionally substituted with an oxo moiety (= 0) , and the alkyl, alkenyl, alkynyl, aryl and heterocyclic moieties of the above groups R13 and R13a are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR15, - (C = 0) -R15 , - (C = 0) -0-R15, -O- (C = 0) -R15, -NR15 (C = 0) -R16, - (C = 0) -NR15R16, -NR15R16, -NR15OR16, alkyl ( d - C6), (C2 - C6) alkenyl, (C2 - C6) alkynyl, - (CR11R12) t (C6 - C10) aryl, and - (CR11R2) the theocyclic (4-10) linkers; each R14, R15, and R16 is independently selected from H, alkyl (d-C6), - (CR11R12) t aryl (C6-C10) and - (CR1 R12) t heterocyclyl of (4-10) links; 1 or 2 carbon atoms in the ring of the heterocyclic group are optionally substituted with an oxo moiety (= 0), and the challenges, alkyl, aryl and heterocyclic of the above groups R14, R15 and R6 are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, -NR11R12, trifluoromethyl, trifluoromethoxy, (Ci-C6) alkyl, (C2-C6) alkenyl, (C2-CB) alkynyl, hydroxy, and (Ci-C6) alkoxy; R17 is H, (d-C8) alkyl, -O-alkyl (d-C8), halo, CN, OH, CF3) U -0-CF3; and wherein any of the above-mentioned substituents comprises a group CH3 (methyl), CH2 (methylene), or CH (methino) which is not bonded to a halo, SO or SO2 group or to an N, O or S atom optionally supports on said group a substituent selected from hydroxy, halo, (C1-C4) alkyl, (C1-C4) alkoxy, -NH2, -NH alkyl (Ci-C8), and -N (alkyl (d-C8)) 2 . In one embodiment, the invention relates to the compounds of formula I wherein R3 isl.
In another embodiment, the invention relates to the compounds of formula I in which R3 is Within this embodiment, the -R- and -Y- "- preferred residues are - (CR R 2) n-0- (CR11 R12) n- (C = 0) -NR 0 or - (CR11 R12) n -N R10 - (C = 0) -0- In another embodiment, the invention relates to the compounds of formula I wherein R3 is In another embodiment, the invention relates to the compounds of formula I wherein R3 is In another embodiment, the invention relates to the compounds of formula I wherein the Q ring is selected from the group consisting of In another embodiment, the invention relates to the compounds of formula I wherein R1 is H, halo, (Ci-C8) alkyl, (Ci-C8) alkoxy, CF3, -0-CF3, -O-SO2-alkyl (d-C8), -O-SO2- (CR11R12) t aryl (C6-Cm), or - (CR11R2) t aryl (Ce-C10) -O-, in which the carbon atoms in the ring of R1 are optionally substituted with 1 to 3 R13 groups. In another embodiment, the invention relates to compounds of formula I in which R2 is H, phenyl, H.
CH; N = N In another embodiment, the invention relates to the compounds of Formula 1 in which said is selected from the group consisting of: -11- In another embodiment, the invention relates to the compounds of formula I wherein R4 is -CH2-0-, -CH2-0-CH2-, -CH2-CH2-0-, -CH = CH-CHs-O- , or -CH2-CH2-CH2-O-. In another embodiment, the invention relates to the compounds of formula I wherein R4 is - (CH) n-, wherein n is independently 0, 1, 2 or 3. In another embodiment, the invention relates to compounds of formula I wherein R5 is a bond or - (CR11R12) mZ- (CR11R12) s; wherein Z is -O-, -NR 0a-, or -S (0) j-, wherein each m and s are independently 0, 1, 2, or 3; wherein j is 0, 1, or 2. In another embodiment, the invention relates to compounds of formula I wherein R5 is a bond, -O-, -CH2-, -C (CH3) H-, -C (OH) H-, or -C (0 - (C1-C8) alkyl) H-. In another embodiment, the invention relates to compounds of formula I wherein R6 is - (C = 0) -OH. In another embodiment, the invention relates to the compounds of formula I wherein R6 is - (C = 0) -OM +, wherein M + is selected from the group consisting of Ca ++, Li +, Na + and K +. In another embodiment, the invention relates to compounds of formula I wherein each R7 and R8 is independently H, alkyl (Ci-Ce) or alkoxy (Ci-C8). In another embodiment, the invention relates to the compounds of formula I wherein each R7 and R8 are taken together with the carbon to which they are attached to form a (3-7) link heterocyclyl. In another embodiment, the invention relates to compounds having a formula: In this embodiment, the invention relates to the compounds wherein said -Ar'-Ar2- is selected from the group consisting of: wherein the carbon atoms in the ring of each Ar1 and Ar2 are optionally substituted with 1 to 3 R13 groups selected from the group consisting of halo, (Ci-C8) alkyl and (C-i-C8) alkoxy. Preferably, said-Ar'-Ar2- is selected from the group consisting of: In this embodiment, the specific compounds of the present invention are selected from the group consisting of 2-methyl-2- (. {3 '- [2- (5-methyl-2-phenyl-1,3-oxazole- 4-yl) ethoxy] -1, 1'-biphenyl-3-yl.} Oxy) propanoic acid; 2-Methyl-2 - [(3'- { [4-trifluoromethyl) benzyl] oxy]} -1, '-biphenyl-3-l} oxy] propanoic; 2-Methyl-2 - [(3 '-. {2- 2- [1- (6-methylpyridazin-3-yl) p -peridin-4-yl] ethoxy} - 1,1'-biphenyl-3 acid -yl) oxy] propanoic; 1- ( {3 '- [2- (5-metii-2-phenyl-1) 3-oxazol-4-yl) ethoxy] -1, 1'-biphenyl-3-yl acid} oxy) cyclobutanecarboxylic; 2- (. {3 '- [2- (5-Methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] -1, 1'-biphenyl-3-yl.} Oxy] acid buíanoico; 2- (3- {6- [2- (5-Methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] pyridin-2-yl} phenoxy) butanoic acid; 1- (3- {6- [2- (5-Methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] pyridin-2-ylphenoxy) cyclobutanecarboxylic acid; 2-Methyl-2- (3. {6- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] pyridin-2-yl} acid. phenoxy) propanoic; 2-Methyl-2- (3- {6- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] pyrazin-2-yl} phenoxy) propanoic acid; and the pharmaceutically acceptable salts thereof. Within this embodiment, a specific compound of the present invention is l- ^ S '- ^ - Ib-methyl ^ -phenyl-1 .S-oxazole ^ -i-ethoxyl-1'-biphenyl-3-1I} oxy) cyclobutanecarboxylic acid or the pharmaceutically acceptable salts thereof. Within this embodiment, a specific compound of the present invention is 2- (. {3 '- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] -1 acid, 1'-biphenyl-3-yl}. Oxy) butanoic or the pharmaceutically acceptable salts thereof. Within this embodiment, a specific compound of the present invention is 2- (3- {6- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] pyridine- 2-yl.} Phenoxy) butanoic or the pharmaceutically acceptable salts thereof. Within this embodiment, a specific compound of the present invention is 1- (3. {6- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] pyridine- 2-yl.) Phenoxy) cyclobutanecarboxylic acid or the pharmaceutically acceptable salts thereof. Within this embodiment, a specific compound of the present invention is 1 - [(3'- { [2- (3-fluorophenyl) -5-methyl-1,3-oxazol-4-yl] methoxy acid. .}. biphenyl-3-yl) oxy] cyclobuylenecarboxylic acid or the pharmaceutically acceptable salts thereof. Within this embodiment, a specific compound of the present invention is 1- (. {3 '- [3- (5-methyl-2-phenyl-1,3-oxazol-4-yl) propoxy] biphenyl- acid. 3-yl.) Oxy) cyclobutanecarboxylic acid or the pharmaceutically acceptable salts thereof. Within this embodiment, a specific compound of the present invention is 1 - [(3'-. {[5- (4-methoxyphenyl) -1,2,4-oxadiazol-3-yl] methoxy.] Biphenyl acid -3-yl) oxy] cyclobutanecarboxylic acid or the pharmaceutically acceptable salts thereof. Within this embodiment, a specific compound of the present invention is 2 - [(3 '-. {2- [2- (3-fluorophenyl) -5-methyl-1,3-oxazol-4-yl] ethoxy] acid .}. biphenyl-3-yl) oxy] -2-methylpropanoic acid or the pharmaceutically acceptable salts thereof. Within this embodiment, a specific compound of the present invention is 2-methyl-2- (. {3 '- [(5-methyl-2-phenyl-1,3-oxadiazol-4-yl) methoxy] biphenyl -3-yl.} Oxy) propanoic or pharmaceutically acceptable salts thereof. Within this embodiment, a specific compound of the present invention is 2-ethoxy-3- acid. { 3 '- [2- (5-methyI-2-phenyl-1,3-oxazole-4-y1) ethoxy] b if in i i -3-yl} propanoic or the pharmaceutically acceptable salts thereof. In another embodiment, the invention relates to compounds having a formula: where Y is - (C = 0) - or -S02-; Y "is NR10 and p is 1. Preferably, each R and R12 are independently H. Preferably Ar3 is phenyl In this embodiment, the specific compounds of the present invention are selected from the group consisting of: 1- (3- { [( { 2- [3- (trifluoromethyl) phenyl] ethoxy} carbonyl) amino] methyl} phenoxy) cyclobutanecarboxylic; 2- (3 { [( { 2- [3- (trifluoromethyl) phenyl] ethoxy} carbonyl) amino] methyl} phenoxy) butanoic acid; 2-Methyl-2- (3. {[[( { 2- [3- (trifluoromethyl) phenyl] ethoxy} carbonyl) amino] methyl} phenoxy) propanoic acid; 2-Methyl-2- (3. {[[(. {2- 2- [5-methyl-2-phenyl-1,3-oxazoI-4-yl] ethoxy} carbonyl} amino] methyl ester Phenoxy) propanoic acid 2-methyl-2- (3. {[[( { [4- (5-methyl-1,2,4-oxadiazol-3-yl) benzyl] oxy} carbonyl) amino] methyl) phenoxy) propanoic acid 2- {3 - [( { [2- (5-methyl-2-phenyl-1,3-oxazole-4- il) ethoxy] carbonyl.}. amino) methyl] phenoxy] butanoic acid 1 -. {3 - [( { [2- [5-methyl-2-phenyl-1,3-oxazole- 4-yl] ethoxy] carbonyl.} Amino) methyl] phenoxy.] Cyclobutanecarboxylic acid 1-. {3 - [( { [3- [5-methyl-2-phenyl-1,3-oxazole -4-yl] propoxy] carbonyl.} Amino) methyl] phenoxy.] Cyclobutanecarboxylic acid 2- { 3 - [( { [3- [5-methyl-2-phenyl-1, 3- oxazol-4-yl] propoxy] carbonyl.}. amino) methyl] phenoxy] butanoic acid; 2-methyl-2- acid. { 3 - [( { [3- [5-methyl-2-phenyl-1,3-oxazol-4-yl] propoxy] carbonyl} amino) methylene phenoxy} Propane; and the pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is 2-methyl-2- acid. { 3 - [(. {2- (5-Methyl-2-phenyl-1, 3-oxazol-4-yl) ethoxy] carbonyl}. Amino) methyl] phenoxy} propanoic or pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is 2-methyl-2- (3 - [( { [(5-methyl-2-phenyl-1,3-oxazol-4-yl) methoxy] carbonyl acid. .) .amino) methyl] phenoxy.) propanoic or pharmaceutically acceptable salts thereof In this embodiment, a specific compound of the present invention is 2-methyl-2- { 4 - [( { [ 3- (5-methyl-2-phenyl-1,3-oxazol-4-yl) propoxy] carbonyl, amino) methyl] phenoxy} propanoic acid or the pharmaceutically acceptable salts thereof In this embodiment, a compound Specific to the present invention is 2-. {3-fluoro-4 - [( { [2- (5-methyl-2-phenyl-, 3-oxazol-4-yl) ethoxy] carbonyl}. amino) methyl] phenoxy] -2-methylpropanoic acid or the pharmaceutically acceptable salts thereof In this embodiment, a specific compound of the present invention is 2- {3. [[ { [2- (5 -methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] carbonyl, amino) methyl] phenoxy] butanoic acid or the pharmaceutically acceptable salts thereof. In one embodiment, a specific compound of the present invention is 2- acid. { 3 - [( { [(5-Methyl-2-phenyl-1,3-oxazol-4-yl) methoxy] carbonyl} amino) methyl] phenoxy} butanoic or pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is acid 1-. { 3 - [( { [2- (5-Methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] carbonyl.] Amin) methyl] phenoxy} cyclobutanecarboxylic acid or the pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is 2-methyl-2- (3- {[[( { [2- (5-methyl-2-phenyl-1,3-oxazole-4-acid. il) ethyl] amino.} carbonyl) oxy] methyl.} phenoxy) propanoic or the pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is 2-ethoxy-3- acid. { 3 - [( { [3- (5-Methylene-2-phenyl-1,3-oxazol-4-yl) propoxy] -carbonyl}. Amino) methyl] phenyl} propanoic or pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is 2-ethoxy-3- acid. { 3 - [( { [2- (5-methyl-2-phenyl-1, 3-oxazol-4-yl) ethoxyJ-Jabonyl} amino) methyl} phenyl } propanoic or pharmaceutically acceptable salts thereof. In another embodiment, the invention relates to compounds having a formula: In another embodiment, ring A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In another embodiment, ring A is selected from the group consisting of in which - it is an optional double link. In another embodiment, ring A is selected from the group consisting of in which - it is an optional double link. In another embodiment, ring A is selected from the group consisting of in which - it is an optional double link. In another embodiment, Ar4 is phenyl, naphthiio, pyridinyl, pyrimidinyl, or pyrazinyl. In this embodiment, the specific compounds of the present invention are selected from the group consisting of 1- Acid. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] benzyl} cyclohexanecarboxylic; Acid 1-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] benzyl} cyclopentanecarboxylic; Acid 1-. { 4- [3- (5-methyl-2-phenyl-1,3-oxazol-4-yl) propoxy] benzyl} cyclopentanecarboxylic; 4- Acid. { 4 - [(5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] benzyl} tetrahydro-2H-pyran-4-carboxylic acid 4-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] benzyl} tetrahydro-2H-pyran-4-carboxylic acid; Acid 1 -. { 4- [2- (4'-methoxy-1,1 '-biphenyl-4-ii) ethoxy] benzyl} Cyclobutanecarboxylic; Acid 1-. { 4- [2- (4'-Fluoro-1,1'-biphenyl-4-yl) ethoxy] benzyl} Cyclobutanecarboxylic; Acid 1 -. { 4- [2- (2'-methoxy-1, '-biphenyl-4-yl) ethoxy] benzyl} Cyclobutanecarboxylic; Acid 1 -. { 4- [2- (3 '- (trifluoromethoxy) -1, 1-biphenyl-4-yl) ethoxy] benzyl} Cyclobutanecarboxylic; 1- (4- {2- [4- (6-methoxypyridin-3-yl) phenyl] ethoxy} benzyl) cyclobutanecarboxylic acid; 1 - (4-. {2- [4 '- (Methylsulfonyl) -1, 1'-biphenyl-4-yl] ethoxy} benzyl) cyclobutanecarboxylic acid; 1- (4- {2- (4- (2,3-dihydro-1-benzofuran-6-yl) phenyl] ethoxy} benzyl) cyclobutanecarboxylic acid: 1 - [4- (2-. { 4 '- [(methylsulfonyl) amino] -1,1' -biphenyl-4-yl}. Ethoxy) benzyl] cyclobutanecarboxylic acid 1 -. {4- [3- (5-methyl) -2-phenyl-1,3-oxazol-4-yl) propoxy] benzyl} cyclobutanecarboxylic acid: 1- {4 - [(5-methyl-2-phenyl-1,3-oxazole-4) -yl) methoxy] benzyl] -cyclobutanecarboxylic acid: 1- {3- [2- (5-methyl-2-phenyl-1,3-oxazoI-4-yl) ethoxy] benzyl} - cyclobutanecarboxyl acid CO; 1 -. {4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] benzyl} -cyclobutanecarboxylic acid; [(2,5-diphenyl-1,3-oxazol-4-yl) methoxy] benzyl] cyclobutanecarboxylic acid: 1 -. {4- [3- (2,5-diphenyl-1,3-oxazole- 4-yl) propoxy] benzyl, cyclobutanecarboxylic acid, 1- {4 - [(2,5-diphenyl-1,3-oxazol-4-yl) methoxy] phenoxy] cyclobutanecarboxylic acid; {.4- [3- (2,5-diphenyl-1,3-oxazoI-4-yl) propoxy] phenoxy] -cyclobutanecarboxylic acid 1 - (4- { 2- [2- (, 1 '-biphenyl-4-yl) -5-methyl-1,3-oxazol-4-yl) ethoxy} phenoxy) cyclobutanecarboxylic; Acid 1 -. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] phenoxy} Cyclobutanecarboxylic; Acid 1-. { 4- [3- (5-methyl-2-phenyl-1,3-oxazol-4-yl) propoxy] phenoxy} Cyclobutanecarboxylic; Acid 1 -. { 4 - [(5-methyl-2-phenyI-1, 3-oxazoi-4-yl) methoxy] phenoxy} Cyclobutanecarboxylic; 1 - (. {6- [2- (5-Methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] pyridin-3-yl] methyl] cyclobutanecarboxylic acid; 1 - (Hydroxy- {6- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] pyridin-3-yl} methyl) cyclobutanecarboxylic acid; 1- (. {6- [2- (5-Methyl-2-phenyl-1,3-oxazol-4-yl) -ioxy] -pyridin-3-yl} -methyl) -cydopentanecarboxylic acid; . 1 - (. {6- [2- (5-Methyl-2-phenyl-1,3-oxazol-4-ll) ethoxy] pyridin-3-yl} methyl) cyclohexanecarboxylic acid; 2- (. {6- [2- (5-Methyl-2-phenyl-1,3-oxazol-4-yl) -ioxy] -pyridin-3-yl} -methyl) -tetrahydrofuran-2-acid carboxylic; 2- (. {5- [2- (5-Methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] pyridin-2-yl}. Methyl) tetrahydrofuran-2-carboxylic acid; and the pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is acid 1-. { 4- [3- (5-methyl-2-phenyl-1,3-oxazol-4-yl) propoxy] benzyl !} cyclobutanecarboxylic acid or the pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is acid 1-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] benzyl} cyclobutanecarboxylic acid or the pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is 2- (. {6- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] pyridin-3 acid. -yl.} methyl) tetrahydrofuran-2-carboxylic acid or the pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is 2- (. {5- [2- (5-methyl-2-phenyl-1) acid., 3-oxazol-4-yl) ethoxy] pyridin-2-yl} methyl) tetrahydrofuran-2-carboxylic acid or the pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is 2- (. {6- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] pyridin-3-yl acid. .) methyl) tetrahydro-2H-pyran-2-carboxylic acid or the pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is 2 - [(6- {2- [2- (3-chlorophenyl) -5-methyl-1,3-oxazol-4-yl] ethoxy} acid. pyridin-3-yl) methyl] tetrahydrofuran-2-carboxylic acid or the pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is 2 - [(6- {2- [2- (3-methoxyphenyl) -5-methyl-1,3-oxazol-4-yl] ethoxy} acid. pyridin-3-yl) methyl] tetrahydrofuran-2-carboxylic acid or the pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is 2- acid. { 5- [2- (5-MethyI-2-phenyloxazol-4-yl) ethoxy] pyrazin-2-ylmethyl} tetrahydrofuran-2-carboxylic acid or pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is acid -. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] benzyl} tetrahydrofuran-2-carboxylic acid or pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is 2- acid. { 6- { 2- (5-methyl-2-phenyl-oxazol-4-yl) ethoxy] naphthalene-2-ylmethyl} tetrahydrofuran-2-carboxylic acid or the pharmaceutically acceptable salts thereof. In another embodiment, the invention relates to compounds having a formula: In this embodiment, preferably the invention relates to compounds having the formula: In this embodiment, preferably the invention relates to compounds having the formula: In this embodiment, preferably R9 is methyl, ethyl or benzyl. Preferably R17 is H. In this embodiment, a specific compound of the present invention is 2-ethoxy-3- acid. { 6- { 2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy'i] pyridin-3-yl} propanoic or pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is 2-methoxy-3- (6-. {2- [5-methyl-2- (3-methylphenyl) -1,3-oxazol-4-yl] acid] ethoxy.) pyridin-3-yl) propanoic acid or the pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is 2-methoxy-3- acid. { 6- [2- (4-phenoxyphenyl) ethoxy] pyridin-3-yl} propanoic or pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is 2-ethoxy-3- [6- (2- {4 - [(phenylsulfonyl) oxy] phenyl} ethoxy) pyridin-3-yl] propanoic acid or the pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is 2-ethoxy-3- acid. { 5- [2- (5-Methyl-2-phenyloxazol-4-yl) ethoxy] pyridin-2-yl} propionic or pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is 2-methoxy-2-methyl-3- acid. { 6- [3- (5-methyl-2-phenyloxazol-4-yl) propoxy] pyridin-3-yl} propionic or pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is 2-methoxy-2-methyl-3- acid. { 5- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] pyridin-2-yl} propionic or pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is 3- (6-. {2- [2- (4-chlorophenyl) -5-methyloxazol-4-yl] ethoxy} pyridin-3-yl) -2-methoxy-2-methylpropionic acid or the pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is 2-methoxy-2-methyl-3- acid. { 6- [2- (5-Methyl-2-phenyloxazol-4-yl) ethoxy] p i ri d-n-3-IJpropionic or the pharmaceutically acceptable salts thereof. In this embodiment, a specific compound of the present invention is 2-methoxy-3- (6-. {2- [2- (3-methoxyphenyl) -5-methyloxazol-4-yl] ethoxy} pyridine 3-yl) -2-methylpropionic acid or the pharmaceutically acceptable salts thereof. The present invention also provides a method of treating non-insulin dependent diabetes mellitus in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I). In one embodiment, said mammal has an impaired glucose tolerance.
The present invention also provides a method of treating polycystic ovarian syndrome in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (1). The present invention also provides a method of treating obesity in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I). The present invention also provides a method of treating body weight reduction in an obese mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I). The present invention also provides a method of treating hyperglycemia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I). The present invention also provides a method of treating hyperlipidemia in a mammal comprising administering to the mammal in need thereof a quantity Therapeutically effective of a compound of formula (I). The present invention also provides a method of treating hypercholesterolemia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (1). The present invention also provides a method of treating atherosclerosis in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I). The present invention also provides a method of treating hypertriglyceridemia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I). The present invention also provides a method of treating hyperinsulinemia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I). The present invention also provides a method of treating a patient suffering from insulin disorders and / or abnormal glucose indications associated with circulating glucocorticoids., growth hormone, catecholamines, glucagon, or parathyroid hormone, comprising administering to said patient a therapeutically effective amount of a compound of formula (1). The present invention also provides a method of treating insulin resistance in humans comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (1). The present invention also provides a method of treating disorders relating to PPAR in humans comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I). The present invention also provides a method of modulating PPAR activity in a mammal, comprising administering to a mammal a therapeutically effective amount of a compound of formula (I). The present invention also provides a method of reducing blood glucose in a mammal, comprising administering to a mammal an amount of a compound of formula (I) effective to reduce blood glucose levels. The present invention also provides a method of modulating the differentiation of fat cells in a mammal, comprising administering to a mammal a therapeutically effective amount of a compound of formula (I). The present invention also provides a method of modulation. of the processes mediated by PPAR in a mammal, comprising administering to a mammal a therapeutically effective amount of a compound of formula (I). The present invention also provides a method of increasing insulin sensitivity in mammals, comprising administering to a mammal a therapeutically effective amount of a compound of formula (I). The present invention also provides a method of treating metabolic syndromes selected from the group consisting of gaiactosemia, urine disease in maple syrup, phenylketonuria, hypersarcosinemia, thymine uraciluria, sulfinuria, isovaleric acidemia, saccharinuria, 4-hydroxybutyric aciduria, deficiency of the glucose-6-phosphate dehydrogenase, and deficiency of pyruvate dehydrogenase. The present invention also provides a composition comprising at least one PPAR modulator of formula (I) and a pharmaceutically acceptable carrier thereof. Exemplary pharmaceutically acceptable carriers include vehicles suitable for oral, intravenous, subcutaneous, intramuscular, intracutaneous, and the like administration. Administration is contemplated as creams, lotions, tablets, dispersible powders, granules, elixirs, sterile aqueous or non-aqueous solutions or suspensions or emulsions, and the like. The PPAR agonists of the present invention can be administered in combination with other agents such as a-glucosidase inhibitors, aldosarreductase inhibitors, biguanidine preparations, statin-based compounds, squalene synthesis inhibitors, fibrate-based compounds, LDL catabolism promoters, and enzyme converting enzyme inhibitors. angiotensin In the above description, an α-glucosidase inhibitor is a medicament having action in the inhibition of a digestive enzyme such as amylase, maltase, α-dextrinase or sucrase, thereby retarding the digestion of starch or sucrose. Examples of α-glucosidase inhibitors include acarbose, N- (1,3-dihydroxy-2-propyl) variolamine (common name: voglibose) and miglitol. In the above description, an aldosarreductase inhibitor is a medicament that inhibits an enzyme limiting the speed of the first stage of the polyol pathway, thereby inhibiting diabetic complications. Examples include toirestat, epalrestat, 2,7-difluorospiro (9H-fluoren-9,4'-imidazolidine) -2 ', 5'-dione (common name: mirestat), 3 - [(4-bromo-2-fluorophenyl) methyl] - 7-chloro-3,4-dihydro-2,4-dihydro-2,4-dioxo-1 (2H) -quinozoline acetic acid (common name: zenarestat), 6-fluoro-2,3-dihydro-2,5'- dioxo-spiro [4H-1-benzopyran-4,4'-imidazolidine] -2-carboxyamide (SNK-860), zopolrestat, sorbinyl and 1 - [(3-bromo-2-benzofuranyl) sulfonyl] -2,4- imidazolidinedione (M-16209). In the foregoing description, a biguanide preparation is a medicament having effects on the promotion of anaerobic glycolysis, peripheral insulin boosting, inhibition of intestinal glucose absorption, inhibition of hepatic gluconeogenesis and inhibition of oxidation of fatty acids and examples include phenformin, metformin and buformin. In the above description, a statin-based compound is a medicament that inhibits hydroxymethylglutaryl CoA (abbreviated HG-CoA) reductase, thereby reducing the level of blood cholesterol and examples include pravastatin and the sodium salt of the same, simvastattina, lovastatin, atorvastatin and fluvastataina. In the above description, an inhibitor of squalene synthesis is a medicament that inhibits the synthesis of squalene, thereby reducing the blood cholesterol level and examples include (S) -a- [bis (2,2-dimethyl) Monopotassium-1-oxo-propoxy) methoxy] phosphinyl-3-phenoxybenzene sulphonate (BMS 188494). In the above description, a compound based on fibrates is a drug to inhibit the synthesis and secretion of triglycerides in the liver and activate lipoprotein alipase, therefore reducing the level of triglycerides in the blood. Examples include bezafibrate, beclobrate, binifibrate, ciprofibrate, clinofibrate, clofifrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate, ronififibrate, simfibrate, and theofibrate. In the above description, an LDL catabolism promoter is a medicament for increasing the LDL (low density lipoprotein) receptors, thereby reducing the level of blood cholesterol and examples include the compounds described in the patent application. Japanese Kodai Hei 7-316144 or the salts thereof, more specifically, N- [2- [4-bis (4-fluorophenyl) methyl-1-piperazinyl] ethyl] -7,7-d-phenyl-2, 4,6- heptatrienoicoamide. The statin-based compounds described above, the squalene synthesis inhibitors, the fibrate-based compounds and the LDL catabolism promoters can be replaced with another chemical compound effective to reduce the level of cholesterol or triglycerides in blood. Examples of said medicament include preparations of nicotinic acid derivatives such as nicomol and niceritrol; antioxidants such as probucol; and preparations of ion exchange resins such as coletiramine. In the above description, an angiotensin converting enzyme inhibitor is a medicament for inhibiting the angiotensin converting enzyme, thereby reducing blood pressure and at the same time, partially reducing the blood sugar level of a patient who have diabetes Examples include captopril, enalapril, alacephl, delapril, ramipril, lisinopril, imidapril, benazepril, ceronapril, cilazapril, enalaprilat, fosfinipril, meveltipril, perindopril, quinapril, espirapril, temocapril and trandolapril. For the preparation of oral liquids, suitable carriers include emulsions, solutions, suspensions, syrups, and the like, optionally containing additives such as wetting agents, emulsifying and suspending agents, sweetening agents, flavors and perfumes, and the like. For the preparation of fluids for parenteral administration, suitable carriers include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Said dosage forms may also contain adjuvants such as preservatives, humectants, emulsifiers, and dispersants. They can be sterilized, for example, by filtration through a filter that retains bacteria, by the incorporation of sterilizing agents in the compositions, by irradiation of the compositions, or by heating the compositions. They can also be manufactured in the form of sterile water, or some other sterile injectable medium immediately before use. Definitions For the purposes of the present invention, as described and claimed in this specification, the following terms are defined as follows: The term "halo", as used herein, unless otherwise indicated, means fluorine, chlorine, bromine or iodine. Preferred halo groups are fluoro, chloro and bromo. The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having branched linear or branched moieties. The term "alkenyl", as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond in which alkyl is as defined above and includes the E-isomers and Z of said alkenyl moiety. The term "alkynyl", as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon triple bond in which alkyl is as defined above.
The term "alkoxy," as used herein, unless otherwise indicated, includes O-alkyl groups in which alkyl is as defined above. The term "Me" means methyl, "Et" means ethyl, and "Ac" means acetyl. The term "cycloalkyl", as used herein, unless otherwise indicated, refers to a non-aromatic, saturated or partially saturated, monicyclic or condensed, spiro or non-condensed bicyclic or tricyclic hydrocarbon mentioned in this specification that it contains a total of between 3 and 10 carbon atoms, preferably 5-8 carbon atoms in the ring. Exemplary cycloalkyl include monocyclic rings having between 3 and 7, preferably 3-6, carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Illustrative examples of cycloalkyl are derived from, but are not limited to, the following: The term "aryl" as used in this specification, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by the removal of a hydrogen such as, such as phenyl or nañyl. The term "4-10 link heterocyclic", as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing between one and four heteroatoms each selected from O, S and N, wherein each heterocyclic group has between 4 and 10 atoms in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S atoms. The non-aromatic heterocyclic groups include the groups having only 4 atoms in their ring system, but the aromatic heterocyclic groups must have at least 5 atoms in their ring system. The heterocyclic groups include the benzocondensed ring systems. An example of a 4-membered heterocyclic group is azetidinyl (azetidine derivative). An example of a 5-membered heterocyclic group is thiazolyl and an example of a 10-membered heterocyclic group is quinolinyl. Examples of the non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, tiepanyl, oxazepinyl, diazepinyl, thiazepinyl. , 1, 2,3,6-tetrahydropyridinyl, 2-pyrroinyl, 3-pyrroinyl, indolinyl, 2H-pyridyl, 4H-pyranyl, dioxanyl,, 3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl,. imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl, 3H-indole and quinolizinyl. Examples of the aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naftriridinyl, and furopyridinyl. The previous groups, since they are derived from the groups listed above, can be joined in C or joined in N when possible. For example, a pyrrole derivative group can be pyrrol-1-yl (N-linked) or pyrrole-3-yl (C-linked). In addition, a midazole derivative group can be imidazole-1 - ??? (N-linked) or midazol-3-yl (C-linked). Heterocyclics of 4-10 links can optionally be substituted on any atom (s) of carbon, sulfur or nitrogen in the ring by one to two oxo, per ring. An example of a heterocyclic group in which 2 carbon atoms in the ring are substituted with two oxo moieties is 1,1-dioxothiomorpholinyl. Other illustrative heterocyclic examples of 4-10 links are derived but not limited to the following: Unless otherwise indicated, the term "oxo" refers to = 0. The term "-A ^ -Ar2-" as used in this specification, unless otherwise indicated, includes two rings without any limitation on the order of couplings to R4 and R5. For example, -A ^ -Ar2- is defined as then groups -Ar1-Ar2- can be The phrase "pharmaceutically acceptable salt (s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups that may be present in the compounds of formula (I). The compounds of formula (I) which are basic in nature are capable of forming a wide variety of salts with various organic or inorganic acids. The acids that can be used to prepare the pharmaceutically acceptable acid addition salts of said basic compounds of formula (I) are those which form non-toxic acid addition salts, ie, the salts containing pharmacologically acceptable anions, such as salts acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisilate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate , glycolylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl sulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate, (embonate), palmitate, pantothenate , phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodode, and valerate. In the compounds of formula (I), in which the terms such as (CR11R12) qo (CR 1R12) t, R11 and R12 are used, they may vary with each repetition of qot greater than 1. For example, when qot is 2 the term (CR11R12) qo (CR1 R12) t can be equal to -CH2-CH2-, CH (CH) 3C (CH2CH3) (CH2CH2CH3) -, or any number of similar moieties that fall within the scope of the definitions of R11 and R12 . In addition, as indicated above, any substituent comprising a group CH 3 (methyl), CH 2 (methylene), or CH (methino) that does not bind a halogen, SO or SO 2 group or a N, O or S atom optionally supports on said group a substituent selected from hydroxy, (C 1 -C 4) alkoxy and amines. The term "treat", as used in this specification, unless otherwise indicated, means, reverse, alleviate, inhibit the progress of, or prevent the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used in this specification, unless otherwise indicated, refers to the act of treating as "treating" has been defined immediately before. The term "modulating" or "modulating", as used in this specification, refers to the ability of a modulator for a member of the steroid / thyroid superfamily to bind either directly (by binding to the receptor as a ligand) or indirectly ( as a precursor of a ligand or an inducer that promotes the production of ligand from a precursor) induces the expression of the gene (s) maintained under the control of hormonal expression, or to repress the expression of the the gene (s) maintained under said control. The term "obesity" or "obese", as used in this specification, generally refers to individuals who are at least about 20-30% above the average weight for their age, sex and height. Technically, "obese" is defined, for men, as individuals whose body mass index is greater than 27.8 kg / m2, and for women, such as individuals whose body mass index is greater than 27.3 kg / m2 . Those skilled in the art will readily recognize that the method of the invention is not limited to those that fall within the above criteria. In fact, the method of the invention can also be advantageously implemented in individuals who fall outside of these traditional criteria, for example, by those who are prone to obesity. The term "inflammatory disorders", as used in this specification, refers to disorders such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, chondrocalcinosis, gout, inflammatory bowel disease, ulcerative colitis, Crohn's disease, fibromyalgia and cachexia. The phrase "therapeutically effective amount", as used in this specification, refers to the amount of drug or pharmaceutical agent that will elicit the medical or biological response of a tissue, system, animal or human being that a researcher, veterinarian, seeks. doctor or another. The phrase "amount ... effective to reduce blood glucose levels", as used in this specification, refers to levels of compound sufficient to provide circulating concentrations high enough to achieve the desired effect. Said concentration typically falls in the range of about 10 nM to 2 μ?; with concentrations in the range of about 100 nM to 500 nM being preferred. As indicated above, since the activity of the different compounds falling within the definition of formula (I) as set forth above may vary considerably, and since individual subjects may exhibit a wide variation in the severity of the symptoms, it is the doctor who determines a response of the subject to the treatment and according to the above can vary the dosages. The phrase "insulin resistance", as used in this specification, refers to the reduction of sensitivity to the actions of insulin in the whole body or in individual tissues, such as skeletal muscle tissue, myocardial tissue, fatty tissue or liver tissue. Insulin resistance occurs in many individuals with or without diabetes mellitus. The phrase "insulin resistance syndrome", as used in this specification, refers to the set of manifestations that include insulin resistance, hyperinsulinemia, non-insulin dependent diabetes mellitus (abbreviated in English NIDD), hypertension, central obesity (visceral), and dispilidemia. The phrase "in combination with", as used in this specification, means that the compound of the substituted alpha carboxylic acids of formula (I) can be administered immediately before, immediately after, simultaneously, or any combination of before, after, or simultaneously, with these other agents described in the previous paragraphs. Thus, the compound of the substituted alpha carboxylic acids of formula (I) and the other agents can be administered simultaneously either as a single composition or as two separate compositions or sequentially as two separate compositions. Certain compounds of formula (I) can have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of formula (1), and mixtures thereof, are considered to be within the scope of the invention. With respect to the compounds of formula (I), the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof. The compounds of formula (I) can also exist as tautomers. The invention relates to the use of all these tautomers and mixtures thereof. Certain functional groups contained in the compounds of the present invention can be substituted with bioisostomeric groups, that is, groups having spatial or electronic requirements similar to the precursor group, but exhibiting physicochemical or other, different or improved properties. Suitable examples are well known to those skilled in the art, and include, but are not limited to, the moieties described in Patini et al., Chem. Rev, 1996, 96, 3147-3176 and references cited therein. The subject invention also includes isotope-labeled compounds, which are identical to those reported in formula (I), but by the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the mass Atomic or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2H, 3H, 13C, 4C, 15N, 180, 70, 31 P, 32P, 3S, 18F, and 36CI, respectively. The compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example in which radioactive isotopes such as 3H and 14C are incorporated, are useful in distribution assays in drug tissues and / or substrates. The tritiated isotopes, ie, 3H and carbon 14, ie 14C, are particularly preferred for their easy preparation and detectability. In addition, replacement with heavier isotopes such as deuterium, i.e., 2H, can produce certain therapeutic advantages that result from a greater metabolic stability, for example, increase in half-life in vivo or reduction in dosing requirements, so Therefore, it can be preferred in some circumstances. The isotope-labeled compounds of formula (I) of this invention and prodrugs thereof can generally be prepared by carrying out the procedures described in this specification in the schemes and / or the examples and the preparations below, by replacing a reagent not labeled with isotopes by an available reagent labeled with isotopes. This invention also encompasses pharmaceutical compositions containing them and methods of treating bacterial infections by administration of the compounds of formula 1. Compounds of formula 1 having free amino, amido, hydroxy or carboxylic groups can be converted to prodrugs. Prodrugs include those compounds in which an amino acid residue, or a polypeptide chain of two or more residues (eg, two, three or four) amino acids is covalently linked through an amide or ester linkage to an amino, hydroxy or amino group. carboxylic free of compounds of formula 1. Amino acid residues include but are not limited to the 20 naturally-occurring amino acids commonly designated by three letter symbols and also include 4-hydroxyproline, hydroxylysine, demosin, iso-casein, 3-methylhistidine, norvaline, beta alanine, gammabutyric acid, citrulline, homocysteine, homoserin, ornithine and methionine sulfone. Additional types of prodrugs are also included. For example, free carboxylic groups can be derivatized as amides or alkyl esters. Free hydroxy groups can be derivatized using the groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethoxyloxycarbonyls, as indicated in Advanced Drug Delivery Reviews, 1996, 19, 115. Also included are the carbamate prodrugs of hydroxy and amino groups, such as the carbonate prodrugs, sulfonate esters, and sulfate esters of the hydroxy groups. The derivatization of the hydroxy groups such as (acyloxy) methyl and (acyloxy) ethyl ethers in which the acyl group can be an alkyl ester, optionally substituted with groups including but not limited to the functionalities of ether, amine and carboxylic acid , or when the acyl group is an amino acid ester as described above, they are also included. Prodrugs of this type are described in J. Med. Chem., 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All these prodrug moieties may incorporate may incorporate groups that include but are not limited to the functionalities of ether, amine and carboxylic acid.
Other aspects, advantages, and preferred features of the invention will become apparent from the detailed description below. Detailed Description and Preferred Embodiments of the Invention The following reaction scheme illustrates the preparation of the compounds of the present invention. Unless otherwise indicated, R -R17, Q, Y, Ar1-Ar4, and ring A, in the reaction scheme and description that follows are as defined above.
Esauema 1 Esguema 2 VSlla lXa Vlla Illa Scheme 3 Xla Ha Scheme 4 R5 is - (CR1R2) m -Z- (CR11R12) S; wherein Z is -0-, -NR10a- -S (0) j-; wherein each m and s are independently O, 1, 2 or 3; and in the quej is O, 1, or 2 Esouema 5 R5 is - (CR1R2) m -Z- (CR11R12) S; wherein Z is -O-, -NR10a-, -S (0) j-; wherein each m and s are independently O, 1, 2 or 3; and where j is 0, 1, or 2 Scheme 6 R5 is - (CR11R2) m -Z- (CRR12) S; wherein Z is -CH2-; wherein each m and s are independently 0, 1, 2 or 3; Scheme 7 R5 is - (CR11R12) m -Z- (CR1 R12) S; wherein Z is -CH2-; wherein each m and s are independently 0, 1, 2 or 3; Scheme S PO-Ar4 i R5 is - (CR1 R12) m -Z- (CR1 R12) S; wherein Z is -CH2-; wherein each m and s are independently 0, 1, 2 or 3; Scheme 9 PO-Ar4 Lv9 Xlllc PO-Ar4 R5OH XVc PO-Ar4 R5Lv ' R5 is - (CR11R12) m -Z- (CR11R2) S; wherein Z is -CH2-; wherein each m and s are independently 0, 1, 2 or 3; Scheme 10 PO Ar · -OH R5 is - (CR11R12) m -Z- (CR11R12) S; wherein Z is -O-, -NR 0a-, -S (0) j-; wherein each m and s are independently O, 1, 2 or 3; and where j is O, 1, or 2 Scheme 11 Scheme 12 Scheme 13 With reference to scheme 1 above, the compound of formula la can be prepared by hydrolysis of the compounds lia, in which the group C02R is a hydrolysable ester group such as methyl ester (C02-CH3) or ethyl ester (C02-CH2CH3) , by alkali metal hydroxides (e.g., NaOH, LiOH, KOH) in a suitable solvent (e.g., THF, aqueous methanol or combinations thereof) at a temperature between 0 and 10 degrees centigrade or by heating in a microwave synthesizer . The compounds of formula Ia can be prepared by a coupling reaction of compound IVa, in which Lv1 is Cl, Br, I, or triflate, and an organometallic compound Illa, in which Met = boric acid or ester, stannane, etc. ., and the C02R group is as described above, mediated by a palladium (0) catalyst or other transition metal. Compound IVa can be obtained by alkylation of Compound Va, in which Lv1 is as described above, with Via compounds, wherein Lv2 is Cl, Br, I, or triflate.
With respect to scheme 2 above, the compound of formula Illa, which is used in scheme 1, can be obtained from the compounds Vlla, in which Lv3 is Cl, Br, I, or triflate, by means of coupling reactions mediated by palladium (0) with a reagent such as pinacolatodiborane. The Vlla compounds, in which Lv3 is as described above, can be obtained by alkylation of the Villa compounds, in which Lv3 is as described above, with the compound IXa, wherein Lv 4 is Cl, Br, I, or triflate. With regard to scheme 3 above, the esters lia, which are used in scheme 1, in which the CO2R group is as described above, can also be prepared by alkylation of a compound Xa, in which the group C02R is as described above, with the Via compound, wherein Lv2 is as described above in the description of scheme 1. The Xa compounds can be obtained from the compound Xla, in which the C02R group is as is described above, by reacting the compound Xla with a deprotecting agent, such as with hydrogen gas over a metal catalyst (e.g., palladium on carbon) in a suitable solvent (e.g., THF, methanol, ethanol) at a temperature between 0 degrees Celsius and 100 degrees Celsius. The Xla compounds are commercially available or can be prepared by those skilled in the art. With reference to scheme 4 above, the compounds of formula Ib; wherein R5 is - (CR11R12) m -Z- (CR 1R12) S; wherein Z is -O-, -NH 0a, or -S (0) j "; wherein each mys is independently 0, 1, 2,, or 3, and in which each mys is independently 0, 1 , 2, or 3, and wherein j is 0, 1, or 2, can be prepared by hydrolysis of compounds Ilb, wherein R5 is as described in the compounds of formula Ib and group C02R is as has been described above, by an alkali metal hydroxide (eg, NaOH, LiOH, KOH) in a suitable solvent (eg, aqueous THF, aqueous methanol or combinations thereof) at a temperature of 0 degrees Celsius and 100 degrees Celsius The compounds of formula IIb, wherein R5 is as described in the compounds of formula Ib, can be prepared by the reaction of the compounds of formula IIIb, wherein R5 is as described in the compounds of Hb formula and the CO2R group is as described above, with an activated acylating agent such as Vlb in a suitable solvent (eg, THF, acetyl, tonitrile, dioxane, toluene) at a temperature between 0 degrees Celsius and 100 degrees Celsius. The compounds IVb can be obtained from the compound Vb by the reaction of the compound Vb with the compound Vlb, in which Lv6 is a leaving group. Suitable suitable Vlb compound includes?,? '- carbonyldiimidazole. Compounds Vb and Vlb are commercially available or can be prepared by those skilled in the art. With reference to scheme 5 above, compounds of formula IIIb, which are used in scheme 4, in which R5 is as described in the description of scheme 4 and group C02R is as described above, can be prepared by reacting a compound Vllb wherein R5 is as described in the previous paragraph, with a suitable electrle of formula Lv6 -C (R7R8) -COOR, wherein Lv6 is a leaving group such as halo, in the presence of a base (e.g., cesium carbonate, potassium carbonate) in a suitable solvent (e.g., THF, DMF, acetonitrile, or DMSO) at a temperature between 0 degrees Celsius and 100 degrees Celsius. Suitable electrles of formula Lv6 -C (R7R8) -COOR include methyl 2-bromo-2-methylpropanoate. The Vllb compounds are commercially available or can be prepared by those skilled in the art. The compounds of formula Ib, Ilb, lllb, and Vllb; wherein R5 is - (CR 1R12) m -Z- (CR11R 2) S; wherein Z is -CH2-, and wherein each m and s are as described above; they can be prepared by methods known to those skilled in the art. With respect to scheme 6 above, the compounds of formula le, in which R5 is - (CR1 R12) m -Z- (CR11R12) S; wherein Z is -CH2-, can be prepared by hydrolysis of the compounds He, in which the group C02R is as described above, by means of an alkali metal hydroxide (for example, NaOH, LiOH, KOH) in a suitable solvent (for example, aqueous THF, aqueous methanol or combinations thereof) at a temperature of 0 degrees Celsius and 100 degrees Celsius or by heating in a microwave synthesizer. The compounds 11c can be prepared by alkylation of the lile compound, wherein Lv5 is a leaving group, with the compound IVc (when Lv7 is iodide, bromide, chloride or other leaving group). Various methods can be used to effect this reaction, such as deprotonation of the lile compound (Lv5 = H) with a base for example, sodium bis (trimethylsilyl) amide. The compounds IVc can be prepared from the compounds Ve by a reaction with a halogenating agent or halogenation system, for example, oxalyl chloride and dimethylformamide or from another halide (for example, reaction of the compound IVc, Lv7 = CI with sodium iodide). The Ve compounds can be prepared from the Vlc compounds by reacting the HIVc compounds with a reducing agent, such as sodium borohydride. The Vlc compounds can be obtained from the compound Vllc (Lv 8 = Br or another halogen) by metal-halogen exchange (for example, with butyllithium) followed by reaction with dimethylformamide. As an alternative, in relation to Scheme 7 above, the compounds of the formula lie, in which R5 is - (CR 1R12) m -Z- (CR11R12) S; wherein Z is -CH2-, can be prepared by reductive deoxygenation of the compound Vlllc using a silane and an acid source, typically triethylsilane and trifluoroacetic acid. The Vlllc compounds can be obtained by adding the lile compound to the compound Vlc. Various methods can be used to effect this reaction such as deprotonation of lile (Lv5 = H) with a base for example, lithium diisopropylamide, or Reformatsky type activation of Ule (Lv5 = Br) with a metal or metal salt (e.g. , chromium (II) chloride). The Vlc compounds can be obtained from the compound Vllc (Lv 8 = Br or another halo) by meta exchange. - halogen (for example with butyl lithium) followed by the reaction with dimethylformamide. As an alternative, with respect to scheme 8 above, the compound lie, wherein R5 is - (CR11R12) m -Z- (CR11R12) S; wherein Z is -CH2-, can be obtained by the reaction of compounds IXc with suitable coupling partners of formula Via. These reactions can be performed using the Via electrophiles (eg, Lv2 = hairs, sulfonate esters) in the presence of a base (for example, cesium carbonate) or with alcohols (Lv2 = OH) under conditions of Mitsunobu type (for example, triphenyphosphine and diethyldiazodicarboxylate). The compounds IXc can be prepared by deprotection of the protected compounds Xc. Suitable protecting groups may include allyl, benzyl, etc. Deprotection of Xc (P = allyl) can be achieved by exposure to a soluble transition metal (eg, tetrakis (triphenylphosphine) palladium (0)) in the presence of a base, eg, morpholine. The intermediates Xc-XIHc can be prepared by the procedures described in scheme 6. Alternatively, in relation to scheme 9 above, compound Xc can be prepared by the reaction of compound XIVc (eg, Lv10 = halides, sulfonate esters) with the lile compound, wherein Lv5 is as described above. Compound XIVc can be prepared by reacting compound XVc with (C = 0) Cl 2 in a polar aprotic solvent such as dimethylformamide. Compound XVc can be prepared by the reaction of compound XIIc with a reducing agent, such as sodium borohydride. Compounds XIIIc can be prepared by the procedure outlined in scheme 6. Alternatively, with respect to scheme 10 above, the compound of formula le, "wherein R5 is - (CR 1R12) m -Z- (CR11R12) S where Z is -O-, -NR10a-, or -S (0) j-, where each mys is independently 0, 1, 2, or 3, and where j is 0, 1, or 2, can be prepared by hydrolysis of the compounds lie by alkali metal hydroxides (for example, NaOH, LiOH, OH) in a suitable solvent (for example aqueous THF, aqueous methanol or mixtures thereof) at a temperature between 0 Celsius and 100 degrees Celsius or heating in a microwave synthesizer The compounds of formula He can be obtained by reacting compounds IXc with suitable coupling partners.These reactions can be carried out using electrophiles (eg, Via; Lv2 = halides, sulphonate esters) in the presence of a base (eg, cesium carbonate, carbonate tásico or potassium io-butoxide) or with alcohols (Via; Lv2 = OH) under Mitsunobu-type conditions (for example, triphenylphosphine and diethylazodicarboxylate). The compounds IXc can be prepared by deprotection of compounds Xlc in which P is a protecting group. Suitable protecting groups P may include allyl, benzyl, etc. Deprotection of Xlc (P = allyl) can be achieved by exposure to a soluble transition metal (eg, tetrakis (triphenylphosphine) palladium (0)) in the presence of a base for example morpholine or by reduction (Xlc; P = benzyl) with hydrogen gas on a metal catalyst (eg, palladium on carbon) in a suitable solvent (eg, THF, methanol, ethanol) at a temperature between 0 degrees Celsius and 100 degrees Celsius. The Xlc compounds can be obtained by alkylation of the compounds XlVc with the compound Me (Lv5 = Cl, Br, I, triflate, as described above).
With respect to scheme 11 above, in certain cases the alkylation of an enolate anion of the lile compound with a benzylhalide having the formula XVIc produces the compounds XVc. The XVc compounds can be converted to the compounds by, for example, palladium mediated coupling reaction in a solvent known to those skilled in the art (eg, March, Advanced Organic Chemistry, fourth edition). Referring to scheme 12 above, the compounds of formula Id can be prepared by hydrolysis of the lid compounds by alkali metal hydroxides (eg, NaOH, LiOH, KOH) in a suitable solvent (eg, aqueous THF, aqueous methanol or combinations thereof) at a temperature between 0 degrees Celsius and 100 degrees Celsius. Compounds of the formula lid can be prepared by reacting the Hld compounds with an appropriate hydrogenation agent such as hydrogen gas in a metal catalyst (e.g., palladium or carbon) in a suitable solvent (e.g., THF, methanol, ethanol ) at a temperature between 0 degrees Celsius and 100 degrees Celsius. The compounds of formula Hld can be prepared by the reaction of compounds IVd with an appropriate triphenylphosphine reagent having the formula (C6H5) 3P + -CH (OR9) (COOR) Cl "in a Wittig reaction. Suitable triphenylphosphine reagents include 1,2-dethoxy-2-oxoethyl) (triphenyl) phosphonium chloride The compounds of formula IVd can be prepared by the reaction of compounds Vd as described in scheme 9. Compounds of formula Vd can be prepared by the reaction of the compounds Vid and VHd as described in scheme 9. Alternatively, the compounds of formula lid can be prepared by the procedures of scheme 13. With reference to scheme 13, the alkylation of the enolate anion of 2-methoxypropanoate of methyl with a benzyl halide IXd produces the Vllld products.The HIVd compounds can be made in the compounds lid by, for example, a palladium-mediated coupling reaction. they can also be prepared from the compounds Xd. Compounds Xd can be prepared from compounds Xlld by a sequence of reactions such as (i) palladium mediated coupling reaction to form compounds Xld, and (i) reduction of the ester to alcohol, and (iii) formation of halide to form the compounds lid. Any of the above compounds of formula I and any of the compounds in schemes 1-13 above can be converted to another analogous compound by customary chemical manipulations. These chemical manipulations are known to those skilled in the art and include a) removal of the protecting group by methods indicated in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organics Synthesis", second edition, John Wiley and Sons, New York, 1991; b) displacement of a leaving group (halide, mesylate, tosylate, etc.) with a primary or secondary amine, thiol or alcohol to form a secondary or tertiary amine, thioether or ether, respectively; c) treatment of phenyl carbamates (or substituted phenyl) with primary or secondary amines to form the corresponding ureas as in Thavonekham, B et al., Synyhesis (1997), 10, p. 1189; d) reduction of propargyl or homopropargyl alcohols or primary amines protected with N-BOC to the corresponding E-allyl or E-homoalilic derivatives by treatment with sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al) as in Denmark, S. E .; Jones, T. K. J. Org. Chem. (1982) 47, 4595-4597 or van Benthem, R. A. T. M; Michels, J. J. Speckamp, W. N. Synlett (1994), 368-370; e) reduction of alkynes to the corresponding Z-alkene derivatives by treatment with hydrogen gas and a Pd catalyst as in Tomassy, B. et al. Synth Commun. (1998), 28, p. 1201 f) treatment of primary and secondary amines with an isocyanate, acid chloride (or other activated carboxylic acid derivative), alkyl / aryl chloroformate or sulfonyl chloride to provide the corresponding urea, amide, carbamate or sulfonamide; g) reductive amination of a primary or secondary amine using R1CH (0); and h) treatment of alcohols with an isocyanate, acid chloride (or other activated carboxylic acid derivative), alkyl / aryl chloroformate or sulfonyl chloride to provide the corresponding carbamate, ester, carbonate or sulfonic acid ester. The compounds of the present invention may have asymmetric carbon atoms. The diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical and chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. The enantiomers can be separated by converting the enantiomeric mixtures into a diastereomeric mixture by reaction with an appropriate optically active compound (eg, alcohol), separating the disatherereomers and converting (eg, hydrolyzing) the individual diastereomers into the corresponding pure enantiomers; or by chromatographic separation using a stationary and mobile chiral phase. All these isomers, including the diastereomeric mixtures and pure enantiomers are considered as part of the invention. The compounds of formula (I) which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula (I) from the reaction mixture as a pharmaceutically acceptable salt and then simply convert the latter into the compound of free base by treatment with an alkaline reagent and subsequently converting the last free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention are readily prepared by treating the basic compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. After careful evaporation of the solvent, the desired solid is easily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution. The compounds of formula (I) which are acidic in nature are capable of forming basic salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and particularly, the sodium and potassium salts. All these salts are prepared by conventional techniques. The chemical bases that are used as reagents for preparing the pharmaceutically acceptable salts of this invention are those which form non-toxic base salts with the compounds of formula (I). Said non-toxic basic salts include those derived from said pharmacologically acceptable cations such as sodium, potassium, calcium and magnesium, etc. These salts can be easily prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmaceutically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In any case, stoichiometric amounts of the reactants are preferably employed in order to ensure the completion of the reaction and maximum yield of the desired final product. The compounds of the present invention are PPA modulators, preferably PPA? already. The compounds of the present invention can modulate the procedures mediated by PPAR-?, which refers to biological, physiological, endocrinological and other body processes that are mediated by a receptor or combinations of receptors that are sensitive to the PPAR agonists described herein (eg, diabetes, hyperlipidemia, obesity, glucose tolerance) altered, hypertension, fatty liver, diabetic complications (for example, retinopathy, neuropathy, neurosis, cataracts and diseases of the coronary arteries and the like), arteriesclerosis, pregnancy diabetes, polycystic ovary syndrome, cardiovascular diseases (for example, ischemic heart disease) and the like), cell injury (e.g., brain injury induced by strokes and the like) induced by atherosclerosis or ischemic heart disease, gout, inflammatory diseases (e.g., arthrosteitis, pain, pyrexia, rheumatoid arthritis, inflammatory enteritis, acne, burns solar, psoriasis, eczema, allergosis, asthma, Gl ulcer, cachexia, autoimmune diseases, pancreatitis and the like), cancer, osteoporosis and cataracts. The modulation of such processes can be achieved in vitro or in vivo. In vivo modulation can be carried out in a wide range of subjects, such as, for example, humans, rodents, sheep, pigs, cows, and the like. The compounds of the present invention may also be useful in the treatment of other metabolic syndromes associated with impaired glucose utilization and insulin resistance including late-stage NIDDM complications, such as diabetic angiopathy, atherosclerosis, diabetic nephropathy, diabetic neuropathy, and ocular diabetic complications such as retinopathy, cataract and glaucoma formation, and many other conditions associated with NIDDM, including dyslipidemia, glucocorticoid-induced insulin resistance, dyslipidemia, polycystic ovarian syndrome, obesity, hypergiukaemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperinsulinemia, and hypertension. Brief definitions of these definitions are available in any medical dictionary, for example Stedman's Medical Dictionarv (ed. X). The in vitro activity of the compounds of formula (I) can be determined by the following procedure. Proximity scintillation assay assays (abbreviated in English SPA) In the SPA assay, darglitazone (for PPAR-?) Or GW2331 (for PPAR-a) labeled with 3H binds to the PPAR protein captured on SPA polylysine beads and generates a radioactive counting signal that can be detected by TopCounts (Packard). The 3 H-labeled ligand bound to PPAR can be displaced by an unlabeled compound. The Ki of the compound can then be determined by the degree of displacement at various concentrations of the compound. Reagents: SPA polylysine beads, which can be purchased at Amersham Bioscience. Darglitazone labeled with 3H for PPAR-? GW2331 labeled with 3H for PPAR-a PPAR proteins. Buffer - PBS, 10% glycerol, 14 mM betamercaptoethanol. All the compounds of the present invention that were tested have Ki values in at least one of the above SPA assays of between 0.3 nM to 30 μ ?. Certain preferred groups of the compounds possess differential selectivity towards the various PPARs. A group of the preferred compounds possesses selective activity towards PPAR-a on PPAR- ?. Another preferred group of compounds possesses selective activity towards PPAR-? about PPAR-a. Another preferred group of compounds possesses selective activity toward both PPAR-a and PPAR-? about PPAR-d. Another preferred group of compounds possesses selective activity towards PPAR-d on both PPAR-a and PPAR-β. The alpha-substituted carboxylic acid compounds of formula (I) can be provided in topical, oral and parenteral formulations suitable for use in the treatment of PPAR mediated diseases. The compounds of the present invention can be administered orally in the form of tablets or capsules, in the form of oily or aqueous suspensions, dragees, troches, powders, granules, emulsions, elixir syrups. Compositions for oral use may include one or more agents for flavoring, sweetening, coloring and preserving in order to produce pharmaceutically elegant and palatable preparations. The tablets may contain pharmaceutically acceptable excipients to aid in the manufacture of such tablets. As is conventional in the art these tablets can be coated with a pharmaceutically acceptable enteric coating, such as glyceryl monostearate or glyceryl distearate, to delay disintegration and absorption in the gastrointestinal tract in order to provide a sustained action over a period of time. longer.
Formulations for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, potassium phosphate or kaolin. They can be in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oily medium, such as peanut oil, paraffin oil or olive oil. Aqueous suspensions usually contain active ingredients in admixture with excipients suitable for the manufacture of an aqueous suspension. Said excipients may be a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; a dispersing or wetting agent which may be a naturally occurring phosphatide such as lecithin, a condensation product of ethylene oxide and a long-chain fatty acid, for example polyoxyethylene stearate, a condensation product of ethylene oxide and a long chain aliphatic alcohol, a condensation product of ethylene oxide and a long chain aliphatic alcohol such as heptadecaethylene oxyketanol, a condensation product of ethylene oxide and a partial ester derived from a fatty acid and hexitol such as polyoxyethylenated sorbitol monooleate or a fatty acid hexitol anhydride such as polyoxyethylenated sorbitan monooleate. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. That suspension can be formulated according to known procedures using the dispersing agents or suitable humectants and suspending agents mentioned above. The sterile injectable preparation can also be formulated in the form of a suspension in a non-toxic, parenterally-acceptable diluent or solvent, for example in the form of a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. For this purpose any stable soft oil may be employed including synthetic mono- or diglycerides. In addition to fatty acids such as oleic acid find use in the preparation of injectables. The alpha-substituted carboxylic acid compounds of formula (I) can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at about room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such materials include cocoa butter and other glycerides.
For preparations for topical use, for example, creams, ointments, gelatins, solutions or suspensions containing the compounds of the present invention are used. The alpha-substituted carboxylic acid compounds of formula (I) can also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. The dosage levels of the compounds of the present invention are in the range of about 0.5 mg / kg of body weight to about 100 mg / kg of body weight. A preferred dosage rate is between about 30 mg / kg of body weight and about 100 mg / kg of body weight. However, it will be understood that the specific level of dosage for any particular patient will depend on numerous factors including the activity of the particular compound being administered, age, body weight, general health, sex, diet, time of administration, route of administration , excretion rate, combination of drugs and the severity of the particular disease that undergoes therapy. To enhance the therapeutic activity of the present compounds they can be administered simultaneously with other orally active antidiabetic compounds such as the sulfonylureas, for example, tolbutamide and the like. The methods of preparing various pharmaceutical compositions with a specific amount of active compound are known, or will be apparent to those skilled in the art. For examples, see Reminqton's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., Edition 15 (1975). The examples and preparations provided below further illustrate and exemplify the compounds of the present invention of the present invention and the methods of preparing said compounds. It will be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the following examples, molecules with a single chiral center, unless otherwise indicated, exist as a racemic mixture. Molecules with two or more chiral centers, unless otherwise indicated, exist as a racemic mixture of diastereomers. The individual enantiomers / diastereomers can be obtained by methods known to those skilled in the art. When HPLC chromatography is mentioned in the preparations and examples below, the general conditions used, unless otherwise indicated, are as follows. The column used is a ZORBAX ™ RXC18 column (manufactured by Hewlett Packard) of 150 mm distance and 4.6 mm internal diameter. Samples are processed on a Hewlett Packard-1100 system A system. The gradient solvent process is used using 100 percent ammonium acetate buffer / acetic acid (0.2 M) to 100 percent acetonitrile for 10 minutes. The system then proceeds on a water cycle with 100 percent acetonitrile for 1.5 minutes and then 100 percent buffer solution for 3 minutes. The flow rate during this period is constant at 3 ml / minute. In the following examples and preparations, "Et" means ethyl, "AC" means acetyl, "Me" means methyio, "ETOAC" or "ETOAc" means ethyl acetate, "THF" means tetrahydrofuran, and "BU" means butyl.
Chiral chromatography conditions with chiral supercritical fluid (abbreviated SFC) The individual enantiomers of certain racemic compounds were obtained by SFC using a chiralpak AD-H column at 14,000 kPa and 2.5 mlJmin, chiralpak column AS-H at 14,000 kPa and 2.5 mlJmin, chiralpak column OJ-H at 14,000 kPa and 2.5 mL / min. Throughout the following sections, the compounds of general formula below were prepared by procedures analogous to those described in Heterocycles, 2001, 55 (4), 689-703.
Example A-1 2-Methyl-2-r (3'-f2-f5-methyl-2-phenyl-1,3-oxazole-4-inetoxy1-1.1'-biphenyl-3-doxflpropanoic acid To a solution of 2-methyl-2- (. {3 '- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] -1,1'-biphenyl -3-yl.) Oxy) methyl propanoate (0.89 g, 1.76 mmol) in methanol (20 ml_) was added water (2.6 ml_) and potassium carbonate (0.73 g, 2.0 equiv.). The mixture was then heated to reflux for 5 hours and allowed to cool to room temperature. The solution was then poured into water, acidified to pH 2 with 1N hydrochloric acid and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated to dryness to provide the title compound as a white crystalline solid (0.6 g, 70%). Elemental analysis: calculated for 028? 27 05 C 73.51, H 5.95, N 3.06. Found: C 73.26, H 6.08, N 3.06. LRMS: 458 (M + H) +. H NMR (CDCl 3, 400 MHz): 7.97 (2H, dd, J = 3.0, 6.6 Hz), 7.43 (2H, d, J = 2.8 Hz), 7.41 (1H , s), 7.31 (2H, dd, J = 8.0 Hz), 7.23 (2H, d, J = 8.6 Hz), 7.17 (1H, d, J = 7.6 Hz ), 7.12 (1 H, sa), 6.93 (1H, dd, J = 1.4, 8.2, Hz), 6.87 (1H, dd, J = 2.0, 8.1) Hz), 4.29 (1 H, t, J = 7.7 Hz), 3.07 (2H, t, J = 7.7 Hz), 2.40 (3H, s), 1.63 (6H , s).
Example A-2 2-Methyl-2-r (3'-fr4-ftrifluoromethyl) -benzoxy-V'-biphenyl-3-iPoxflpropanoic acid Following the procedure described in Example A-1, starting with 2-methyl-2 - [(3'-. {[4- (trifluoromethyl) benzyl] oxy] -1, 1'-biphenyl- 3-yl) oxy] propanoate, the title compound was produced. LRMS: 431 (M + H) +.
Example A- 3 2-Methyl-2-f (3 '- (2-f 1- (6-methylDiridazin-3-ylpiDeridin-4-inetoxy) -1,1'-biphenyl-3-D-oxidopropanoic acid Following the procedure described in Example A-1, starting with 2-methyl-2 - [(3'-. {2- 2- [1- (6-methylpyridazin-3-y) piperidin-4-yl] ethoxy. Methyl methyl -1,1'-biphenyl-3-yl) oxy] propane, the title compound was produced as a pale yellow crystalline solid. LRMS: 477 (M + H) +. 1 H NMR (CDCl 3, 400 MHz): 7.27 (2H, c, J = 8.1 Hz), 7.20-7.18 (2H, m), 7.12 (1 H, da, J = 7 , 8 Hz), 7.08-7.06 (2H, m), 6.94-6.93 (1H, m), 6.91-6.90 (1H, m), 6.84 (1 H, dd, J = 2.0, 7.8 Hz), 4.25 (2H, da, J = 13.1 Hz), 4.04 (2H, t, J = 6.1 Hz), 2, 88 (2H, t, J = 13.4 Hz), 2.48 (3H, s), 1.80-1, 70 (5H, m), 1.65 (6H, s), 1, 33-1. , 27 (2H, m).
Example A-4 1- (. {3'-22- (5-Methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy-1-1'-biphenyl-3-yldoX-Cyclobutanecarboxylic acid To a solution of 1- (. {3 '- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] -1,1'-biphenyl-3-yl} oxy) ethyl cyclobutanecarboxylate (0.138 g, 0.278 mmol) in tetrahydrofuran (3 mL) and methanol (1 mL) was added aqueous lithium hydroxide (0.28 mL). The resulting mixture was stirred at room temperature for 16 hours. Water (5 mL) and diethyl ether (10 mL) were added and the resulting solution was stirred for 10 minutes. The ether phase was removed and the aqueous phase was acidified to pH 2 with 1 N hydrochloric acid at 0 ° C and stirred for 20 minutes. The white precipitate was collected by filtration and washed with ice-cold water. After drying at 40 ° C under high vacuum the title compound was produced as a white crystalline solid (0.091 g, 70%). Elemental analysis: calculated for C29H27N05 0.15LiCI C 73.18, H 5.72, N 2.94. Found: C 73.08, H 5.67, N 2.93. LRMS: 471 (M + H) +. 1 H NMR (CDCIs, 400 MHz): 8.03 - 8.00 (2H, m), 7.43 (3H, t, J = 3.3 Hz), 7.30 (2H, t, J = 7.8 Hz ), 7.16 (2H, d, J = 6.8 Hz), 7.09 (1H, t, J = 2.3 Hz), 6.91-6.85 (3H, m), 4.27 (2H, t, J = 7.8 Hz), 3.06 (3H, t, J = 8.1 Hz), 2.83-2.76 (2H, m), 2.53-2.46 ( 2H, m), 2.40 (3H, s), 2.06-1, 97 (2H, m).
Example A-5 to A-28 Examples A-5 to A-28 were prepared using procedures analogous to those described for Example A-4 EM Ex. N. Structure H NMR Analysis (m / z) (BRo AR) (CDCL.3, 400 Hz): 7.95 (2H, dd, J = 2.9, 6.7 Hz), 7.38 - 7.35 Calculated (3H, m), 7.29 - 7.22 for (2H, m), 7.13-7.10 C28H27NO5 (3H, m), 7.07 (1H, t, J = 0.41H20 C 2.3 Hz), 6.91-6.88 for BR 72.34, H A-5 (1H, m), 6.81 (1H, dd, J 458 6.03, N = 1.8, 8.3 Hz), 4.57 (M + H) +. 3.01. (1H, t, J = 6.2 Hz), 4.23 Found: (2H, t, J = 7.7 Hz), 3.05 C 72.33, H - 2.92 (2H, m), 2.34 6.01, N (3H, s), 2.03-1.96 2.95 (2H, m), 1.06 (3H, t, J = 7.5 Hz).
H NMR (400 MHz CDCI3l): 1.97 - 2.07 (m, 2 H), 2.52 (s, 3 H), 2.64 - 2.65 (m, 2 H), 2.74 - 2.82 (m, 2 H), 4.89 (s, LRMS 2 H), 6.68 - 6.70 (m, 1 (m / z) A-20 H), 6.83-6.85 (m, 2 456.2 H), 7.24-7.30 (m, 3 (M + H) +. H), 7.41-7, 47 (m, 3 H), 7.58-7.62 (m, 2 H), 7.66-7.68 (m, 2 H). H NMR (CDCl 3, 400 MHz): 1.56 - 1.65 (m, 6 H), 2.43 (s, 3 H), 3.09 (t, 2 H), 4.33 (t, 2) H), LRMS 6.86 - 6.96 (m, 2 H), (m / z) A-21 7.11-7.19 (m, 2 H), 476 7.20-7.26 (m, 4 H), (M + H) +. 7.32 (t, 2 H), 7.41 (td, 1 H), 7.70 (ddd, 1 H), 7.81 (d, 1 H). 1 H NMR (CDC, 400 MHz): 1.64 (s, 6 H), 2.41 (s, 3 H), 3.06 (t, 2 H EMBR), 4.31 (t, 2 H), 6.88 (m / z) A-22 (dd, 3 H), 7.04-7.13 494 (m, 1 H), 7.14-7.23 (M + H) +. (m, 2 H), 7.23-7.34 (m, 3 H), 7.52 (dd, 2 Hz): 1.56 (s, 6 H), 2.31 (s, 3 H) , 3.11 (t, 2 LRMS H), 4.25 (t, 2 H), 6.81. { mfz) A-26 (m, 2 H), 6.96 (s, 1 H), 458 7.06 (m, 2 H), 7.20 (m, (M + H) +. 4 H), 7, 30 (t, 3 H), 7.82 (d, 2 H). 1 H NMR (CDCl 3, 400 MHz): 1.62 (s, 6 H), 2.07 - 2.15 (m, 2 H), 3.60 - 3.71 (m, 2 H), LRMS 4, 3 (c, 2 H), 4.53 (s, 2 (m / z) A-27 H), 6.83-6.93 (m, 2 421 H), 7.01-7.09 (m, 1 (M + H) +. H), 7.12 (d, 1 H ), 7.14-7.20 (m, 1 H), 7.30 (ddd, 8 H). 1 H NMR (CDC! 3, 400 MHz): 1.18 (t, 3 H), 2.43 (s, 3 H), 2.96 - 3.08 (m, 4 H), 3.32 - EMBR 3.35 (m, 2 H), 3.62 -. { mfz) A -28 3.65 (m, 1 H), 4.24-472.5 4.33 (m, 2 H), 7.07- (M + Hf. 7.19 (m, 2 H), 7 , 23 (t, 1 H), 7.32 (td, 4 H), 7.36-7.47 (m, 4 H), 7.98 (dd, 2 H).
Preparation of starting materials for examples A-1 to A-28 (preparations a-1 to a-11 Preparation a-1 2- (3-vodofenoxiV2-methylpropanoate methyl) To a solution of 3-iodophenol (1.08 g, 4.9 mmol) in N, N-dimethylformamide (10 mL) was added methyl 2-bromo-2-methylpropionate (0.76 mL, 1.2 equiv) and cesium carbonate (3.45 g, 2 equiv). The resulting mixture was heated at 90 ° C for 24 hours and then allowed to cool to room temperature. Water was introduced and the mixture was extracted with diethyl ether (3 x 20 mL). The combined organics were washed with water and saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated. The residue was purified by silica gel chromatography using 0-30% ethyl acetate in hexanes to give the title compound (0.83 g, 53%). LRMS: 321 (M + H) +. 1 H NMR (CDCl 3, 400 MHz): 7.22 (1 H, dt, J = 1, 3, 7.8 Hz), 7.12 (1 H, dd, J = 1.6, 2.4 Hz) , 6.84 (1 H, t, J = 8.1 Hz), 6.66 (1 H, ddd, J = 0.8, 2.5, 8.3 Hz), 3.66 (3H, s ), 1.47 (6H, s). Preparation a - 2 methyl 2- (3-vodophenoxy) butanoate Following the procedure described in preparation a-1, using ethyl 2-bromopropionate in place of methyl 2-bromo-2-methylpropionate at room temperature, the title compound was obtained in 93% yield. LRMS: 321 (M + H) +. 1 H NMR (CDCL-3, 400 Hz): 7.30 (1 H, ddd, J = 1.0, 1.5, 7.8 Hz), 7.24 (1 H, dd, = 1.6, 2 , 4 Hz), 6.97 (1H, dd, J = 7.8, 8.3 Hz), 6.82 (1 H, ddd, J = 1.0, 2.5, 8.6 Hz), 4.53 (1H, dd, J = 5.8, 6.6 Hz), 3.75 (3H, s), 2.00 - 1.93 (2H, m), 1.05 (3H, t, J = 7.15 Hz), Preparation a - 3 1- (Ethyl 3-bromophenoxy-cyclobutanoatocarboxylate) Following the procedure described in preparation a-1, using 3-bromophenol and ethyl 1-bromocyclobutanecarboxylate as starting materials and heating in an acetonitrile solution, the title compound was obtained in 56% yield. LRMS: 300 (M + H) +.
Preparation a - 4 4-í2- (3-vodofenoxi) etn-5-methyl-2-phenyl-1,3-oxazole Following the procedure described in preparation a-1, starting with 3-iodophenol and 2- (5-methyl-2-phenyl-1, 3-oxazoI-4-yl) ethyl-4-methylbenzenesulfonate at room temperature, the compound of the title was obtained with 77% yield in the form of a colorless oil. LRMS: 406 (M + H) +. 1 H NMR (CDCl 3, 400 MHz): 7.87 (2H, dd, J = 1.9, 7.7 Hz), 7.34-7.29 (3H, m), 7.15-7.13 ( 2H, m), 6.86 (1H, t, J = 8.1 Hz), 6.76-6.73 (1H, m), 4.10 (2H, t, J = 6.6 Hz), 2.85 (2H, t, J = 6.6 Hz), 2.26 (3H, s).
Preparation a - 5 2-Bromo-S-r2- (5-methyl-2-phenyl-1,3-oxazole-4-inetoxypyridine To a solution of 2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethanol (1.04 g, 5.1 mmol) and 2,6-dibromopyridine (1.21 g, 5%). , 1 mmole) in anhydrous dioxane (20 mL) at 0 ° C was added sodium hydride (60% in oil, 0.368 g, 3 equiv). The resulting mixture was stirred at room temperature for 16 hours. The mixture was poured into ice water and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated. The residue was purified by silica gel chromatography using 0-50% ethyl acetate in hexanes to give the title compound as a white crystalline solid (1.19 g, 65%). LRMS: 359 (M + H) + 1 H NMR (CDCl 3, 400 MHz): 7.97 (2H, dd, J = 1, 8, 7.8 Hz), 7.44-7.35 (4H, m) , 7.03 (1H, d, J = 7.3 Hz), 6.65 (1H, d, J = 8.1 Hz), 4.55 (2H, t, J = 6.8 Hz), 2 , 97 (2H, t, J = 6.8 Hz), 2.34 (3H, s).
Preparation a - 6 2-Chloro-6-f2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxynpyrazine Following the procedure described in the preparation starting from 2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethanol and 2,6-dichloropyrazine, the title compound was obtained in 64% yield. LRMS: 316 (M + H) +. 1 H NMR (CDCL.3, 400 MHz): 8.11 (2H, d, J = 10.4 Hz), 7.97 (2H, dd, J = 1.9, 7.7 Hz), 7.44. - 7.39 (3H, m), 4.60 (2H, t, J = 6.7 Hz), 2.99 (2H, t, J = 6.7 Hz), 2.35 (3H, s) .
Preparation a - 7 2-r3- (4.4.5.5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxybutanoate methyl To a solution of methyl 2- (3-iodophenoxy) -2-methylpropanoate (preparation a-2) (1.49 g, 4.65 mmol) in dimethyl sulfoxide (40 mL) was added potassium acetate (1.37 g.). g, 3 equiv), bis (pinacolato) diboro and a solution of complex [1, 1'-bis (diphenylphosphino) -ferrocene-dichloropalladium (II) (0.152 g, 0.04 equiv) in dichloromethane. The resulting mixture was heated at 80 ° C for 16 hours and allowed to cool to room temperature. Water was introduced and the mixture was extracted with diethyl ether (3 x 30 mL). The combined organic extracts were washed with 5% aqueous sodium bicarbonate (2 x 50 mL) and saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated. The residue was purified by silica gel chromatography using 0-25% ethyl acetate in hexanes to give the title compound (0.92 g, 62%). LRMS: 321 (+ H) +. 1 H NMR (CDCl 3, 400 MHz): 7.40 (1 H, d, J = 7.3 Hz), 7.32 (1 H, d, J = 2.8 Hz), 7.28 (1 H, d, J = 8.1 Hz), 6.97 (1 H, ddd, J = 1, 0, 2.8, 8.1 Hz), 4.64 (1 H, t, J = 6.3 Hz), 3 , 73 (3H, s), 2.01 - 1.94 (2H, m), 1.32 (12H, s), 1.06 (3H, t, J = 7.5 Hz).
Preparation a - 8 methyl 2-methyl-2-r3-f4.4.5,5-tetramethyl-1,3.2-dioxaborolan-2-infenoxnpropanoate Following the procedure described in preparation a-7, using methyl 2- (3-iodophenoxy) -2-methylpropanoate (preparation 1) as a starting material, the title compound was produced in 75% yield. LRMS: 321 (M + H) +. H NMR (CDCl 3, 400 MHz): 7.42 (1 H, d, J = 7.1 Hz), 7.29 (1 H, d, J = 2.8 Hz), 7.22 (H, t, J = 7.8 Hz), 6.90 (1 H, ddd, J = 0.8, 2.8, 8.1 Hz), 3.75 (3H, s), 1.56 (6H, s) , 1.30 (12 H, s).
Preparation a - 9 1-f3- (4 ^, 5,5-tetramethyl-1,3.2-dioxaborolan-2-ethyl-infenoxyl-cyclobutanecarboxylate) Following the procedure described in the a-7 preparation, using ethyl 1- (3-bromophenoxy) cyclobutanecarboxylate (preparation 3) as the starting material, the title compound was produced in 80% yield. LRMS: 347 (M + H) +.
Preparation a - 10 2-. { f3 '- (Benzyloxy) -1, 1'-biphenyl-3-yl-oxy) -2-methylpropanoate methyl To a solution of methyl 2- (3-iodophenoxy) -2-methylpropanoate (preparation a-1) (1.14 g, 3.56 mmol) in benzene (20 ml_) was added 3-benzyloxyphenylboronic acid (0.89 g). g, 1.1 equiv), 2 M aqueous sodium carbonate (3.56 ml_) and tetrakis (triphenylphosphine) palladium (0) (0.2 g, 0.05 equiv). The resulting mixture was heated to reflux for 2 hours and allowed to cool to room temperature. Water was added and the mixture was extracted with diethyl ether (3 x 20 ml_). The combined organics were washed with 5% aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated. The residue was purified by silica gel chromatography using 0-15% ethyl acetate in hexanes to give the title compound as a colorless oil (1.08 g, 81%). LRMS: 377 (M + H) +. 1 H NMR (CDCl 3, 400 MHz): 7.47-7.45 (2H, m), 7.39 (2H, t, J = 7.3 Hz), 7.33 (2H, t, J = 7, 8 Hz), 7.28 (1 H, t, J = 8.0 Hz), 7.21 (1 H, ddd, J = 1, 0, 1.5, 8.1 Hz), 7.17 ( 1H, dd, J = 1.8, 2.3 Hz), 7.14 (1H, dm, J = 7.6 Hz), 7.08 (1H, dd, J = 1, 8, 2.3 Hz ), 6.96 (1 H, ddd, J = 0.8, 2.5, 8.3 Hz), 6.79 (1 H, ddd, J = 1.0, 2.5, 8.1 Hz) ), 5.11 (2H, s), 3.78 (3H, s), 1.62 (6H, s).
Preparation a - 11 2-methyl-2- ( { 3'-í2- (5-metl-2-phenyl-2H-1,2,3-triazol-4-yl) ethoxy-1-biphenyl-3-yl) oxy) methyl propanoate 2- (5-methyl-2-phenyl-2H-1, 2,3-triazol-4-yl) ethanol (51 mg, 0.25 mmol), 2 - [(3'-hydroxybiphenyl-3-yl) oxy] ] -2-Methylpropanoate methyl (86g mg, 0.30mmol), and ?? ¾? (98 mg, 0.375 mmol) were dissolved in anhydrous THF (1 mL) and followed by the dropwise addition of diethyl azodicarboxylate (65 mg, 0.375 mmol) in anhydrous THF (1 mL) at room temperature via syringe. The solution of the resulting reaction was stirred at room temperature for 18 hours and concentrated. Purification by column of silica gel with 20-40% EtOAc in hexane afforded 69 mg (59%) of light yellow oil. 1 H NMR (CDCl 3, 400 MHz): 1.55 (s, 6 H), 2.31 (s, 3 H), 3.10 (t, 2 H), 3.68 (s, 3 H), 4 , 25 (t, 2 H), 6.70 (m, 1 H), 6.82 (m, 1 H), 7.00 (s, 1 H), 7.05 (d, 1 H), 7 , 20 (m, 4 H), 7.32 (t, 2 H), 7.90 (d, 2 H) LRMS: 472 (M + H) +.
Example B - 1 Acid (trifluoromethylphenylethoxy> carbonylaminolmethyl) phenoxy] cyclobutanecarboxylic acid To a solution of 1 - (3- {[[({2- [3- (trifluoromethyl) phenyl] ethoxy}. Carbonyl) amino] methyl} phenoxy) cyclobutanecarboxylate Ethyl (0.150 g, 0.32 mmol) in tetrahydrofuran (3 mL) and methanol (0.6 mL) at 0 ° C was added 2 M aqueous lithium hydroxide (0.32 mL, 2 equiv). The resulting mixture was stirred at room temperature for 24 hours. Water (10 mL) was added and the mixture was extracted with diethyl ether (1 x 15 mL, discarded). The aqueous phase was adjusted to pH 2 with 1 N hydrochloric acid and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated to dryness to yield the title compound (85%). LRMS: 438 (M + H) +. H NMR (CDCl3, 400 MHz): 7.62 (1H, t, J = 7.8 Hz), 7.46 (1H, t, J = 7.3 Hz), 7.36 (1H, t, J = 7.3 Hz), 7.31 (1H, dd, J = 6.1, 7.6 Hz), 7.18 (1H, t, J = 8.0 Hz), 6.84 (1H, d , J = 7.6 Hz), 6.65 (1H, s), 6.56 (1H, 'd, J = 7.8 Hz), 4.32-4.27 (4H, m), 3, 11 (1H, t, J = 6.8 Hz), 2.79-2.72 (21H, m), 2.49-2.41 (2H, m), 2.09-1.93 (2H, m).
Example B - 2 to B - 29 Examples B-2 to B-29 were prepared by analogous procedures to that used for Example B-1 Example E (m / z) Structure 1HRMN no. (BR or AR) 1H RN (CDCL3, 400 Hz): 7.62 (1H, t, J = 7.8 Hz), 7.46 (1H, t, J = 7.3 Hz), 7.36 (1H, d, J = 7.6 Hz), 7.31 (1H, t, J = 7.6 Hz), 7.22 (1H, t, J = 7 , 8 for BR Hz), 6.88 (1H, d, J = 7.3 Hz), B-2 426 6.83 (1H, s), 6.78 (1H, dd, J = (M + H ) +. 1.9, 8.2 Hz), 4.60 (1H, t, J = 5.8 Hz), 4.36-4.29 (4H, m), 3.11 (2H, t, J = 6.8 Hz), 2.03-1.97 (2H, m), 1.08 (3H, t, J = 7.5 Hz). 1 H NMR (CDCLa, 400 MHz): 7.62 (1H, t, J = 7.8 Hz), 7.46 for BR B-3 (1H, t, J = 7.5 Hz), 7.36 (1H, 426 or § d, J = 7.6 Hz), 7.31 (1H, t, J = (M + H) + .7.6 Hz), 7.21 (1H, t, J = 7.6 Hz), 6.94 (1H, d, J = 7.3 Hz), 6.86 (1H, s), 6 , 81 (1H, d, J = 7.8 Hz), 4.36-4.29 (4H, m), 3.11 (2H, t, J = 7.0 Hz), 1.58 (6H, s). 1 H NMR (CDCLs, 400 MHz): 1.69 (s, 6 H), 4.34 (d, 2 H), 5.05 - 5.17 (m, 1 H), 5.23 (s, EMBR 2 H), 6.71 (dd, 1 H), 6.78 (s, 1 B-4 (m / z) 426.4 H), 6.90 (d, 1 H), 7.18-7 , 23 (M + Hf. (M, 1 H), 7.26-7.33 (m, 1 H), 7.69 (d, 1 H), 7.89 (d, 1 H), 8, 73 (s, 1 H). 1 H NMR (CDCLs, 400 MHz): 7.98-7.92 (2H, m), 7.44-7.38 (3H, m), 7.15 (1H, t , J = for BR B-5 7.7 Hz), 6.87 (1H, s), 6.84-439 6.79 (2H, m), 4.33-4.28 (4H, (M + H) +. ), 2.89 (2H, t, J = 6.8 Hz), 2.32 (3H, s), 1.60 (6H, s). 1 H NMR (CDCLs, 400 MHz): 1.58 (d, 6 H), 2.46 (s, 3 H), 4.32 (d, 2 H), 5.06 (s, 2 H), EMBR B-6 rL S | A v 6.70 - 6.72 (m, 1 H), 6.89 - (m / z) 423.5 6.91 (m, 1 H), 7.23 - 7, 28 (m, (M + H) +. 2 H), 7.39-7.48 (m, 2 H), 7.96-8.05 (m, 2 H). 1 H NMR (CDCl 3, 400 MHz): LRMS B-7 1.63 (m, 6 H), 1.95-2.01 (m, (m / z) 453.5 2 H), 2.34 (s, 3 H), 2.56-2, 58 (M + H) +. (m, 2H), 4.11 -4.13 (m, 2 H), 4.32-4.35 (d, 2 H), 4.89-4.92 (b, 1 H), 6, 82-6.83 (m, 2 H), 7.21-7.27 (m, 3 H), 7.36-7.44 (m, 2 H), 7.93-7.96 (m, 2 H). 1 H NMR (CDCl 3, 400 MHz): 1.59 (s, 6 H), 2.47 (s, 3 H), 4.24 - 4.32 (m, 2 H), 4.99 - EMBR B-8 5.09 (m, 3 H), 6.73-6.80 (m, (m / z) 425.5 2 H), 7.15 (d, 2 H), 7.21-7 , 27 (M + H) +. (m, 1 H), 7.37-7.46 (m, 2 H), 7.96-8.04 (m, 2 H). 1 H NMR (CDCl 3, 400 MHz): 1.64 (m, 6 H), 2.35 (s, 3 H), LRMS 2.82 (t, 2 H), 4.28-4.38 (m, 4 B-9 (m / z) 457.5 H), 6.55 (d, 2 H), 7.17-7.28 (M + H) +. (m, 2 H), 7.36-7.45 (m, 2 H), 7.92 - 8.00 (m, 2 H). 1 H NMR (CDCl 3, 400 MHz): 1.67 (s, 6 H), 4.33 (d, 2 H), 5.03-5.14 (m, 3 H), 6.69 (dd) , EMBR B-10 1 H), 6.78 (s, 1 H), 6.92 (dd, 2 (m / z) 435.5 H), 7.01 (d, 3 H), 7.06 - 7 , 14 (M + H) +. (m, 2 H), 7.18 (t, 1 H), 7.25-7.36 (m, 3 H). 1 H NMR (CDCl 3, 400 MHz): LRMS 1.05-1.16 (m, 3 H), 2.02-B-11 (m / z) 451 or 2.04 (m, 2 H), 4.11 -4.13 (m, (M + H) +. 1 H), 4.48-4.58 (m, 2 H), 4.95-5.96 (m, 1 H), , 11 (s, 2 H), 5.21 (s, 2 H), 6.75 (d, 1 H), 6.83-6.93 (m, 2 H), 7.10 - 7.21 (m, 1 H), 7.30-7.41 (m, 6H), 8.44 (s, 2 H). 1 H NMR (CDCLs, 400 MHz): 8.06-8.00 (1H, m), 8.01 (1H, d, J = 7.6 Hz), 7.47-7.42 (1H, m) , 7.43 (1H, d, J = 7.8 Hz), 7.19 (1H, t, J = 7.8 Hz), for BR 6.87 (1H, d, J = 7.1 Hz) , 6.68 B-12 426 (1H, s), 6.57 (1H, dd, J = 2.3, (M + H) +. 8.1 Hz), 5.17 (2H, s), 4.32 (2H, d, J = 6.1 Hz), 2.80-2.75 (2H, m), 2.65 (3H, s), 2.49-2.41 (2H, m) , 2.03 - 1.97 (2H, s). 1 H NMR (CDCl 400 MHz): 0.85-0.95 (m, 3 H), 1.82 (s, 2 H), 2.13 (s, 3 H), 2.62-2.73 (m, 2 H), 3.85 (d, 1 H), 3.91 EMBR B -13 (s, 1 H), 4.30-4.41 (m, 2 H), (m / z) 439 4.99 (s, 1 H), 6.58 (d, 1 H), (M + H) +. 6.66 (s, 2 H), 6.94 - 7.06 (m, 2 H), 7.22 (s, 3H), 7.70-7.81 (m, 2 H). 1 H NMR (CDCLs, 400 Hz): LRMS 1.93-2.01 (m, 2 H), 2.46 (s, B-14 (m / z) 425.5 3 H), 4.34 (d , 2H), 4.56-4.57 (M + Hf. (M, 1 H), 5.06 (s, 3 H), 6.74-6.76 (m, 1 H), 6.82. - 6.84 (m, 1 H), 6.89 - 6.91 (m, 1 H), 7.19 - 7.28 (m, 2 H), 7.41 - 7.46 (m, 2) H), 7.98 - 8.04 (m, 2 H) for BR B-15 4 5 (M + H) +. 1H RN (CDCL.3, 400 MHz): 7.96-7.94 (2H, m), 7.42-7.40 (3H, m), 7.19 (1H, t, J = 7.7 Hz), 6.79 (2H, t, J = 7.6 for BR Hz), 6.60 (1H, s), 4.32 (1H, d, B-16 465 J = 6.1 Hz), 4.20 (2H, s), 2.81 (M + H) +. - 2.75 (2H, m), 2.62-2.59 (1H, m), 2.49-2.41 (3H, m), 2.32-2.28 (2H, m), 2 , 08 (3H, s), 2.00-1.92 (3H, m). 1 H NMR (CDCl 3, 400 MHz): 1.94-2.05 (m, 2 H), 2.38-2.48 (m, 5 H), 2.68-2.76 (m, 2) H), 4.31 (d, 2 H), 5.06 (s, 3 EMBR B- 17 H), 6.52 - 6.53 (m, 1 H), 6.65 (m / z) 411.4 - 6.67 (m, 1 H), 6.83 - 6.85 ( M + H) +. (m, 1 H), 7.16-7.17 (m, 1 H), 7.41 _ 7.46 (m, 3 H), 7.99-8.03 (m, 2 H). for BR B-18 453 (M + H) +. for BR B-19 453 (M + Hf. 1 H NMR (CDCl 3, 400 MHz): 1.51 (s, 6 H), 4.02 (d, 2 H), 5.12 (s, 1 H), 6, 72 - 6.80 (m, EMBR B-20 2 H), 6.89-6.96 (m, 2 H),. { m / z) 442 6.96-7.02 (m, 2 H), 7.09 (t, 1 (M + H) +. H), 7.29 (s, 2 H), 7.31 - 7.39 (m, 2H), 7.64-7.73 (m, 2 H). H NMR (CDCl 400 MHz): 1.62 (s, 6 H), 2.30 (s, 3 H), 2.69-2.71 (m, 2 H), 3.49 - 3.58 ( m, 2 H), 5.05 (s, 2 H), EMBR B-21 5.36 - 5.38 (m, 1 H), 6.73 - (m / z) 439.5 6.75 (m, 1 H), 6.97 - 6.99 (m, ( M + Hf. 1 H), 7.19-7.28 (m, 3 H), 7.38-7.48 (m, 1 H), 7.96-7.98 (m, 2 H). 1 H NMR (CDCU, 400 MHz): 1.19 - 1.26 (m, 3 H), 2.46 (s, 3 H), 2.93 - 3.02 (m, 2 H), LRMS 3, 26 - 3.29 (m, 2 H), 3.99 - B-22 (m / z) 439.5 4.01 (m, 1 H), 4.36 (d, 2 H), (M + H) +. 5.06 (s, 3 H), 7.15 (m, 3 H), 7.40 - 7.47 (m, 3 H), 7.98 - 8.04 (m, 2 H) ). 1 H NMR (CDCl 3, 400 MHz): 1.21-1.27 (m, 3 H), 1.97-2.06 (m, 2 H), 2.34 (s, 3 H), 2.57 (t, 2 H), 2.95-3.03 (m, 2 LRMS H), 3.34-3.59 (m, 2 H), 4.11 B-23. { miz) 467.5-4.20 (m, 4 H), 4.35 (d, 2 H), (M + H) +. 4.96-4.98 (m, 1 H), 7.11-7.18 (m, 3 H), 7.21-7.27 (m, 3 H), 7.37-7.45 (m, 3 H). m, 2 H), 7.93-7.99 (m2 H). H NMR (CDCl.3, 400 MHz): 1.26-1.28 (m, 3 H), 2.35 (s, 3 H), 2.86-2.88 (m, 2 H), 2.95. - 3.06 (m, 1 H), 3.47 - EMBR 3.52 (m, 2 H), 4.18-4.20 (m, B-24 (miz) 453.5 2 H), 4 , 29-4.40 (m, 4 H), (M + H) +. 4.96-4.99 (m, 1 H), 7.10-7.18 (m, 2 H), 7.19-7.28 (m, 3 H), 7.35-7.46 (m, 2 H), 7.92-7.99 (m, 2 H). 1 H NMR (CDCl a, 400 MHz): 1.07 (t, 3 H), 1.94-2.05 (m, 3 H), 2.17 (s, 3 H), 2.57 (t, 2 H), 4.15 (t, 1 H), 4.17 (d, 2 H), EMBR B-25 4.33 (d, 2 H), 4.58 (m, 1 H), (m / z) 453.5 6.83 (m, 1 H), 6.89 (m, 1 H) , (M + Hf. 6.95 (m, 1 H), 7.21-7.27 (m, 3 H), 7.37-7.44 (m, 2 H), 7.94-7, 99 (m, 1 H). 1 H NMR (CDCl 3, 400 MHz): 1.65 (s, 6 H), 2.88 (d, 2 H), LRMS 3.46 (s, 2 H), 5.03 (d, 3 H) ), B-26 (m / z) 426.4 6.73 (s, 1 H), 6.83 (d, 1 H), (M + H) +. 6.89-7.00 (m, 1 H), 7.19-7.31 (m, 3 H), 7.55 (t, 2 H). 1 H NMR (CDCl 3, 400 MHz): 1.07 (t, 3 H), 1.98 (from, 26 (s, LRMS 2 H), 4.57-4.59 (m, 1 H), (s) , B-27 (m / z) 426.5 2 H), 6.83 (m, 1 H), 6.89 (m, (M + H) +. (T, 1 H), 7.48 ( d, 2 H), 8.06 (d, 2 H), H NMR (CDCL.3, 400 MHz): 1.21 (m, 3 H), 1.57 (s, 6 H), 2.63 - 2.84 (m, 2 H), 4.22 (d, EMBR B-28 2 H), 4.83-4.85 (b, 1 H), 5.23 (m / z) 372.4-5.25 (m, 1 H), 6.84-6.87 (M + H) +. (m, 3H), 7.13 (dt, 2 H), 7.18-7.23 (m, 4 H). 1 H NMR (CDCl 3, 400 MHz): 1.78 (s, 6 H), 2.66 (s, 3 H), 4.34 (d, 2 H), 4.85-4.87 (b, 1 LRMS H), 5.05-5.06 (s, 2H), 6.53- B-29 (m / z) 426.5 6.54 (m, 1 H), 6.67-6.69 (m, (M + H) +. 1 H), 6.83-6.85 (m, 1 H), 7.13 (dt, 1 H), 7.18-7.23 (m, 2H) 7.95-7.97 (m, 2 H).
Preparation of starting materials for examples B-1 to B-29 (preparations b-1 to b-20 ^ Preparation b-1 methyl 2- (3-cyanophenoxy) -2-methylpropanoate To a solution of 3-cyanophenol (5 mmol) in acetonitrile (20 mL) or any polar, aprotic solvent such as dimethyl sulfoxide, N, N-dimethylformamide, etc.) was added methyl 2-bromo-2-methylpropanoate (1.2 equiv) and cesium carbonate (2 equiv). The resulting mixture was heated at 60 ° C for 6 hours and then cooled to room temperature. Water (20 mL) was introduced and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and evaporated to dryness to provide the title compound in 75% yield. LRMS: 220 (M + H) +. 1H RN (CDCl3, 400 MHz): 7.30 (H, t, J = 8.0 Hz), 7.23 (1H, dt, J = 1.3, 7.6 Hz), 7.05 (1 H, dd, J = 1, 3, 2.3 Hz), 7.01 (1 H, ddd, J = 2.3, 2.8, 8.3 Hz), 3.73 (3H, s), 1.57 (6H, s).
Preparation b - 2 a b - 3 Preparations b-2 to b-3 were made using procedures analogous to those described for preparation b-1 Preparation Structure 1H NMR EM (m / z) Preparation b - 4 2- [3- (Aminomethyl-2-phenoxy-2-methylpropanoic acid methyl ester To a solution of methyl 2- (3-cyanophenoxy) -2-methylpropanoate (preparation b-1) (4 mmol) in methanol (20 mL) was added 10% palladium on carbon (20% by weight). The resulting mixture was stirred under a nitrogen atmosphere for 24 hours and filtered through Celite. The filtrate was concentrated and the residue was taken up in ethyl acetate and washed with hydrochloric acid 1 (2 x 20 mL). The combined aqueous washings were adjusted to pH > 10 with 4N aqueous sodium hydroxide and extracted with dichloromethane (3 x 20 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (potassium carbonate), filtered and concentrated to dryness to provide the title compound in 65% yield. LRMS: 224 (M + H) +. Preparation b - 5 a b - 6 Preparations b-5 to b-6 were made using procedures analogous to those described for preparation b-4 Preparation b - 7 H-imidazole-1-carboxylic acid 2- (5-methyl-2-phenyl-1,3-oxazole-4-methyl) To a solution of 2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethanol (1.015 g, 5 mmol) in toluene (25 ml_) was added potassium carbonate (1.38 g, 2%). equiv) and? /,? / '- carbonyldiimidazole (0.97 g, 1.2 equiv). The resulting mixture was stirred at room temperature for 24 hours before water was introduced (20 mL). Extraction with ethyl acetate and washing of the combined organic extracts with aqueous sodium chloride, drying (anhydrous sodium sulfate), filtration and concentration to dryness afforded the title compound (100%). LRMS: 298 (M + Hf. 1 H NMR (CDCL3, 400. Hz): 8.10 (1 H, s), 7.97-7.93 (2H, m), 7.44-7.39 (5H , m), 4.68 (2H, t, J = 6.7 Hz), 2.98 (2H, t, J = 6.7 Hz), 2.34 (3H, s).
Preparation b - 8 a b - 10 Preparations b-8 ab-10 were performed using procedures analogous to those described for preparation b-7 Preparation EM (m / z) Structure 1 H NMR no (BR 0 AR) (CDCL3, 400 MHz): 8.10 (1H, s), 7.68 (1H, d, J '= 7.6 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.40 for BR b-8 (1H, s), 7.38 (1H, s), 7.24 (1H, 285 t, J = 7.3 Hz), 7.17-7.13 (1H, (M + H) + .m), 4 , 63 (2H, t, J = 6.8 Hz), 3.29 (2H, t, J = 6.8 Hz). (CDCl3, 400 MHz): 8.49 (1H, 0-N sa), 8.13 (2H, d, J = 8.3 Hz), for BR b-9 7.57 (1H, s), 7 , 54 (2H, s), 7.26 285-0-7.24 (1H, m), 5.52 (2H, s), (M + H) +. 2.66 (3H, s). for BR b-10 312 or (+ H) +.
Preparation b - 11 2-Methyl-2- (3-r ((r2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy-1-carbonyl) -amino) methyl] phenoxy] methyl propanoate To a solution of 2- (5-methyl-2-phenyl-1,3-oxazole-4-yl) etiol (1-imidazole-1-carboxylate) (preparation 7) (0.48 g, 1.6 mmol) in tetrahydrofuran (3 m! _) Was added methyl 2- [3- (aminomethyl) phenoxy] -2-methylpropanoate (preparation b-4) (0.39 g, 1.1 equiv). The resulting mixture was heated to reflux for 16 hours and then cooled to room temperature. Concentration and purification by chromatography on silica gel using 0-50% ethyl acetate in hexanes gave the title compound (0.39 g, 53%). LRMS: 453 (M + H) +. 1 H NMR (CDCl 3, 400 MHz): 7.96 (2H, dd, J = 1.9, 7.7 Hz), 7.44-7.38 (3H, m), 7.16 (H, t, J = 8.0 Hz), 6.89 (1H, dd, J = 7.3 Hz), 6.77 (1H, s), 6.67 (1 H, dd, J = 2.3, 8, 3 Hz), 4.36 (2H, dd, J = 6.7 Hz), 4.30 (2H, dd, J = 5.8 Hz), 3.75 (3H, s), 2.83 (2H , t, J = 6.7 Hz), 2.32 (3H, s), 1.57 (6H, s).
Preparation b - 12 a b - 20 Preparations b-12 to b-20 were made using procedures analogous to those described for preparation b-11 Preparation EM (m / z) Structure H NMR no (BR or AR) for BR b- 12 440 (M + H) +. (CDCl3, 400 MHz): 7.63 (1 H, for BR d, J = 7.8 Hz), 7.47 (1 H, t, J = b- 13 440 7.5 Hz), 7.38 ( 1 H, d, J = 6.3 (M + Hf. Hz), 7.34-7.28 (1H, m), 7.18 (1H, dd, J = 7.6, 8.1 Hz) , 6.89 (1H, d, J = 7.3 Hz), 6.77 (1H, s), 6.69 (1H, dd, J = 2.3, 8.3 Hz), 4.33 - 4.30 (4H, m), 3.75 (3H, s), 3.13 (2H, t, J = 7.0 Hz), 1.58 (6H, s). (CDCL-3, 400 MHz ): 7.99 (2H, d, J = 8.1 Hz), 7.41 (2H, m), 7.11 (1H, t, J = 8.1 Hz), 6.79 (1H, d) , J = 7.6 Hz), 6.60 (1H, s), 6.46 (1H, dd, J = 2.3, 8.1 for BR b-14 Hz), 5.12 (2H, s ), 4.27 (2H, d, 440 J = 6.1 Hz), 4.12 (2H, c, J = (M + H) +. 7.1 Hz), 2.71-2.60 ( 2H, m), 2.59 (3H, s), 2.42-2.32 (2H, m), 1.98-1.88 (2H, m), 1.09 (3H, t, J = 7.1 Hz) for BR b-15 453 (M + H) *. (CDCL.3, 400 MHz): 7.96 (2H, dd, J = 1.9, 7.7 Hz), 7, 44-7.36 (3H, m), 7.18-7.13 (1H, m), 6.85 (1H, d, J = 7.6 Hz), for BR 6.66 (1H, s) , 6.50 (1H, dt, J = b-16 479 1.3, 8.1 Hz), 4.35 (2H, t, J = (M + H) +, 7.1 Hz), 4, 29 (2H, d, J = 6.1 Hz), 4.11 (2H, c, J = 7.1 Hz), 2.83 (2H, t, J = 6.8 Hz), 2.77-2.69 (2H, m), 2.48-2.38 (2H, m), 2.32 (3H, s), 2, 01-94 (2H, m), 1.16 (3H, t, J = 7.2 Hz). (CDCL 400 MHz): 7.96 (2H, dd, J = 1.8, 7.8 Hz), 7.43-7.38 (3H, m), 7.17 (1H, t, J = 7.8 Hz), 6.85 (1H, d, J = 7.6 Hz), 6.66 (1H, s), 6.50 (1H, dd, J = 2.3, 8.1 Hz), 4.30 (2H, for BR b-17 d, J = 5.8 Hz), 4.19 (2H, c, J = 493 7.3 Hz), 4.18-4.08 (2H, t, J (M + Hf. - 7.5 Hz), 2.77-2.69 (2H, m), 2 , 56 (2H, t, J = 7.5 Hz), 2.48-2.39 (2H, m), 2.30 (3H, s), 2.02-1.94 (4H, m), 1, 16 (3H, t, J = 7.1 Hz). (CDCLs, 400 MHz): 7.96 (2H, dd, J = 1.8, 7.8 Hz), 7.43-7.38 (3H , m), 7.22 (H, t, J = 8.1 Hz), 6.89 (1H, d, J = 7.8 Hz), 6.82 (1H, s), 6.74 (1H , for BR dd, J = 2,2, 8.2 Hz), 4.56 (1H, b-18 467 t, J = 6.2 Hz), 4.32 (2H, d, J = (M + H) +. 5.8 Hz), 4.14 (2H, t, J = 6.3 Hz), 3.74 (3H, s), 2.56 (2H, t, J = 7.3 Hz) , 2.30 (3H, s), 2.03 -1.93 (4H, m), 1.06 (3H, t, J = 7.3 Hz).
Preparation b -21 b-21c Preparation of imidazole b-21c To a solution of the alcohol b-21c (1 mmol) in toluene (5 mL) were added N, NT-carbonyldiimidazole (1.05 mmol) and potassium carbonate (1 mmol). ). The resulting solution was heated to reflux for 3 hours. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to provide the acylimidazole b-21c in quantitative yield. Preparation of imidazole b-21b To a solution of 3-hydroxybenzyl alcohol b-21a (1 mmol) in cesium carbonate (1 mL) in acetonitrile (10 mL) was added methyl 2-bromo-2-methylpropionate (2 mmol) . The mixture was refluxed for 6 hours. After cooling to room temperature, water (50 mL) was introduced and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine, dried over sulfate and evaporated in vacuo. Chromatography on silica gel (abbreviated in English SGC) using 10-30% ethyl acetate-hexane provided the alcohol b-21b. The yields varied between 40 - 85%.
Preparation of the b-21 methyl ester Following the procedures described in b-1, the methyl ester b-21g was prepared by reacting the compound b-21f with the compound b-21c in yields ranging from 60 to 90%. Preparation of the amine b-21f The solution of the azide b-21 e (2 mmol) in ethyl acetate (20 mL) and palladium on carbon (10% by weight, 50 mg) was treated with hydrogen gas at room temperature during 4 hours. Removal of palladium by filtration through a pad of Celite and concentration produced the b-21f amine in quantitative yield. Preparation of the amine b-21 e To a solution of tosylate b-21 d (1 mmol) in D F (5 mL) was added sodium azide (3 mmol). The resulting mixture was stirred at room temperature for 14 hours before water (50 mL) was added. Extraction with ethyl acetate (3 x 20 mL), washing of the combined organic compounds with water, saturated sodium bicarbonate and brine, drying over sodium sulfate and concentration gave the b-21 azide at 85% yield.
Example C-1 1- Acid. { 4-f (5-methyl-2-phenyl-1,3-oxazole-4- iDetoxflbenzD-cyclohexanecarboxylic acid Triethylsilane (1.03 g, 8.86 mmol) was added to a solution of 1-hydroxy. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] pheniI} methyl) cyclohexanecarboxylate (0.797 g, 1.77 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) at room temperature. The resulting mixture was stirred for 1 hour then evaporated in vacuo and azeotropically distilled with heptane. The residue was dissolved in tetrahydrofuran (3 mL) and water (3 mL) and lithium hydroxide monohydrate (0.223 g g, 5.31 mmol) was added. The resulting mixture was stirred at room temperature for 18 hours, acidified to pH 2 with 4N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried (anhydrous magnesium sulfate), filtered and evaporated to yield the title compound (0.332 g, 45%). Elemental analysis: calculated for C26H2gN04 C 74.44, H 6.97, N 3.34. Found: C 74.22, H 6.89, N 3.34. LRMS: 420 (M + H) +. 1 H NMR (DMSO-de, 400 MHz): 7.90 (2H, dd, J = 1.8, 7.8 Hz), 7.51-7.46 (3H, m), 6.98 (2H, d, J = 8.6 Hz), 6.80 (2H, d, J = 8.6 Hz), 4.16 (2H, t, J = 6.6 Hz), 2.90 (2H, d, J = 6.6 Hz), 2.64 (2H, s), 2.34 (3H, s), 1.85 (2H, d, J = 2.6, Hz), 1.53-1.46 (3H, m), 1.29-1.11 (5H, m).
Examples C-2 to C-5 Examples C-2aC-5 were prepared by procedures analogous to those used for Example C-1 with the exception that the final hydrolysis step was carried out by dissolving the crude residue in dimethisulfoxide (75m / ml and sodium hydroxide). 6 N (1 mü v heating at 150 ° C for 10 minutes on a microwave synthesizer MS (m / z) Ex. No. Structure 1H NMR Analysis (BRo AR) (DMSO-de, 400 MHz): 7.90 Calculated (2H, dd, J = 1.9, 7.7 Hz), for 7 , 51-7.44 (3H, m), 7.04 C25H27 O4 (2H, d, J = 8.6 Hz), 6.80 C 74.05, H for BR (2H, d, J = 8, 6 Hz), 4.15 6.71, N C-2 406 (2H, t, J = 6.7 Hz), 2.9 (2H, 3.45 (M + H) + .t, J = 6.6 Hz), 2.79 (2H, s), Found: 2.34 (3H, s), 2.05 - 2.00 C 73.83, H (2H, m), 1.75-1.60 (6H, 6.69, N m) . 3.36 (3H, s), 1.79 (2H, d, J = 3.32, 13.1 Hz), 1.47-1.39 (2H, m).
Example C - 6 1-L4- [2- (4'-methoxy-1,1'-biphenyl-4-yl-ethoxybenzyl) -cyclobutanecarboxylic acid To a solution of 1-. { 4- [2- (4'-methoxy-1,1'-bipheni-4-yl) ethoxy] benzyl} Ethyl cyclobutanecarboxylate (preparation 14) (0.3921 mmol, 1 equiv.) in acetonitrile (2 mL) was added 1N aqueous sodium hydroxide (7.2 mL, 8 equiv.). The resulting mixture was subjected to microwave heating (100 ° C) on a Personal Chemistry Smith synthesizer for 40 minutes. After cooling the reaction mixture, 1 M aqueous hydrochloric acid was added until pH 1 was achieved. The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were then washed with saturated aqueous sodium chloride (100 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to provide the crude product. The residue was purified by trituration with diethyl ether to yield the title compound as a white crystalline solid (0.121 g, 81%). Elemental analysis: calculated for C27H28O4 C 77.86, H 6.78. Found: C 77.65, N 6.85. LRMS: (m / zj 416 (M) -. 1 H NMR (acetone-de, 300 Hz): 7.53 (2H, d, J = 6.1 Hz), 7.66 (2H, d, J = 5 , 1 Hz), 7.46 (2H, d, J = 8.5 Hz), 7.13 (2H, d, J = 8.7 Hz), 7.07 (2H, d, J = 8.7 Hz), 6.85 (2H, d, J = 8.5 Hz), 4.20 (1H, t, J = 6.1 Hz), 3.86 (3H, s), 3.10 (2H, t, J = 7.0 Hz), 3.00 (2H, s), 2.40-2.30 (2H, m), 2.07 - 1.98 (2H, m), 1.92-1 , 80 (2H, m) Examples C - 7 to C - 93 Examples C-7 to C-93 were prepared by procedures analogous to those used for example C-6 or by stirring a solution of the ester with sodium hydroxide or lithium in aqueous methanol. aqueous ethanol, aqueous tetrahydrofuran or mixtures thereof at temperatures between 20 ° C and 75 ° C EM. { miz.) Ex. n ° Structure 1H NMR (BR or AR Analysis) (Acetone-de, 300 MHz): 7.48 (2H, d, J = 8.9 Hz), 7.58 (2H, d, J = 8.7 Hz), Calculated 7.41 (2H, d, J = 8.5 Hz), for 7.13 (2H, t, J = 8.9 Hz), C26H25FO3 for BR 7.07 (2H, t, J = 8.7 Hz), C 77.21, H C-7 404 6.78 (2H, d, J = 8.7 Hz), 6.23. (M + H) 4.14 (2H, t, J = 7.0 Hz), Found: 3.03 (2H, t, J = 7.0 Hz), C 77.13, H 2.97 (2H, s), 2.40-2.30 6.28. (2H, m), 2.01-1, 92 (2H, m), 1.85-1.172 (2H, m). 7.34 (1H, m), 7.37 (2H, d, (M + H) ".78.48, HJ = 8.3 Hz), 7.13 (2H, d, J 6.59. 8.7 Hz), 6.83 (2H, d, J = Found: 8.7 Hz), 6.78 (1H, d, J = C 78.30, H 8.3 Hz), 4.57 ( 2H, t, J = 6.62, 8.7 Hz), 4.18 (2H, t, J = 6.8 Hz), 3.25 (2H, t, J = 8.7 Hz), 3, 08 (2H, t, J = 7.0 Hz), 3.03 (2H, s), 2.40-2.30 (2H, m), 2.07-1.99 (2H, m), 1 , 92-1.79 (2H, m). (Acetone-de, 300 Hz): 7.65 (2H, d, J-8.7 Hz), Calculated 7.59 (2H, d, J = 8, 1 Hz), for 7.42 (4H, dd, J = 1.5, 8.1 Czyh NOsS Hz), 7.13 (2H, d, J = 8.5 C 67.62, H Hz), 6 , 84 (2H, d, J = 8.9 for BR 6.09, N C-13 Hz), 4.20 (2H, t, J = 6.8 479 2.92 Hz), 3.10 (2H, t, J = 6.8 (M + H) \ Found: Hz) , 3.03 (2H, s), 3.01 C 67.36, H (3H, s), 2.40-2.30 (2H, 6.11, N m), 2.07 - 1.99 (2H, m), 2.85. 1.92-1.81 (2H, m). H NMR (CDCIs, 400 MHz): 2.29 (s, 3 H), 2.39 LRMS (m, 2 H), 2.75 (m, 2 H), (m / z): C-14 3 , 00 (c, 2 H), 3.30 (d, 2 390 H), 6.00 (td, 1 H), 6.25 (d, (+ H) +. 1 H), 6.56 ( d, 2 H), 7.08 Calculated (CDCI3, 400 MHz): 8.00 - for 7.97 (2H, m), 7.49 - 7.40 Calculated (3H, m), 7.17 (1 H, d, J = for 0.2 H20 C 7.8 Hz), 7.03 (1H, s), 6.78 C24H2SNO 72.96, H (2H, t, J = 7.1 Hz), 4 , 24 4 C-18 6.48, N (2H, t, J = 8.1 Hz), 3.14 392.1857 3.55. (2H, s), 2.90 (2H, t, J = Found Found: 7.8 Hz), 2.51 - 2.40 (2H, do: C 72.66, H m), 2.36 ( 3H, s), 2.07-392.1859 6.65, N 1.83 (4H, m). 3.47 (DMSO-d6, 400 MHz): Calculated 7.90 (2H, dd, J = 1, 9, 7.7 for Hz), 7.51-7.44 (3H, m), C24H25N04 7, 05 (2H, d, J = 8.6 Hz), C 73.64, H 6.81 (2H, d, J = 8.6 Hz), for BR 6.44, N C-19 4.15 (2H, t, J = 6.7 Hz), 392 3.58. 2.92 (2H, s), 2.90 (2H, t, J (+ H) +. Found: = 6.8 Hz), 2.34 (3H, s), C 73.49, H 2, 25 - 2.18 (2H, m), 1.956.66, N-1, 88 (2H, m), 1.85 - 3.54 1.71 (2H, m). 1 H NMR (D SO-d 6, 400 Calculated MHz): 7.83 (2H, d, J = 9.1 for Hz), 7.06-7.02 (4H, m), CssHza O 6.82 (2H , d, J = 8.6 Hz), C-20 5 -i -. 4.17 (2H, t, J = 6.3 Hz), 422.1962 3.80 (3 H, s), 3.10 (2H, t, J = 6.3 Hz), 2.92 (2 H, s), Found 2.25 - 2.17 (2H, m) 2.08 do: 4.18 (2H, t, J = 6.5 Hz), 4CI 3.03 (2H, s), 2.95 (2H, t, J (M + H) +. = 6.5 Hz), 2 , 44 - 2.41, 426.1467 (2H, m), 2.35 (3H, s), 2.08 Found - 2.01 (2H, m), 1, 90-do: 1.87 (2H, m). 426.1471 For BR 426 (M + H) AR calculated (CDCl3, 400 MHz): 7.92 - for 7.89 (2H, m), 7.10-7.07 C25H27NO (2H, m), 6, 95-6.92 (2H, 5 m), 6.80-6.77 (2H, m), (M + H) +. 4.17 (2H, t, J = 6.5 Hz), C-28 422.1962 3.85 (3H, s), 3.04 (2H, s),? ~ Found 2.95 (2H, t , J = 6.5 Hz), do: 2.48-2.38 (2H, m), 2.34 422.1948 (3H, s), 2.10-2.02 (2H, for BR m) , 1, 94-, 83 (2H, m). 423 (M + H) +. (CDCl 3, 400 MHz): 7.57 - AR 7.55 (1 H, m), 7.51 - 7.49 calculated (1H, m), 7.35 - 7.30 (1H, for m), 7.10 - 7.07 (2H, m), CzsHzr O C-29 6.97 - 6.93 (1 H, m), 6.81 5 - 6.78 (2H, m), 4.19 (2H, (M + H) +. T, J = 6, 5 Hz), 3.87 (3H, 422.1962 s), 3.04 (2H, s), 2.96 (2H, Find t, J = 6.5 Hz), 2.48 - 2.38 C : (2H, m), 2.36 (3H, s), 2.11 422.1947-2.02 (2H, m), 1.94 - For BR 1.85 (2H, m). 422 (M + H) +. Calculated AR (CDCIs, 400 MHz): 8.23 for (1H, s), 8.15 - 8.13 (1H, C25H24NOm), 7.64-7.63 (1H, m), 4F3 7.54 -7.50 (1H, m), 7.07 (M + H) +.
C-30 - 7.05 (2H, m), 6.99 - 460.1730 6.96 (1H, m), 6.77 - 6.75 Find (2H, m), 6.70 - 6.68 (1H, do: m), 4.19 (2H, t, J = 6.5 460.1728 Hz). For BR 460 (+ H) +. AR (CDCl 3, 400 MHz): 7.96 calculated (1H, s), 7.86-7.83 (1H, for m), 7.36-7.33 (2H, m), C24H24NO 7.09 - 7.06 (2H, m), 6.79, 4Cl-6.76 (2H, m), 4.18 (2H, (M + H) +.
C-31 t, J = 6.5 Hz), 3.03 (2H, 426.1467 s), 2.95 (2H, t, J = 6.5 0 Find Hz), 2.47 - 2.38 (2H, m), do: 2.35 (3H, s), 2.08-2.01 426.1465 (2H, m), 1.91-1.84 (2H, for BR m). 426 (CDCI3, 300 MHz): 8.10 - Calculated 8.06 (2H, m), 7.69 - 7.66 Calculated for (2H, m), 7.46 - 7.32 (6H, for CzsHz / NOg m), 6.79-6.66 (4H, m), C29H2BNO C 74.18, H 3.91 (2H, t, J = 6.0 Hz), 4. 5.80, N C-37 2.98 (2H, t, J = 7.3 Hz), 470.1962 2.98. 2.80 - 2.71 (2H, m), 2.50 Found Found: - 2.40 (2H, m), 2.24 - do: C 73.07, H 2.15 (2H, m), 2.06-1, 93-470.1952 6.81, N (2H, m). 2.43 Calculated (CDCl 3) 300 MHz): 8.09 - to 8.07 (2H, m), 7.68 - 7.66 C30H29NO (2H, m), 7.46-7.26 (6H, 4 m), 7.10-6.78 (4H, m), (M + H) + 4.01 (2H, t, J = 5.8 Hz), 468.2107 C-38 3.04-3, 00 (4H, m), 2.49 Found - 2.39 (2H, m), 2.30 - do: 2.21 (2H, m), 2.11 - 2.02 468.2165 (2H, m ), 1.94-1.81 (2H, for BR m). 468 (M + H) + (CDCl 3, 400 MHz): 8,03 Calculated Calculated (2H, d, J = 8.3 Hz), 7.66 for for (2H, d, J = 8.3 Hz), 7.65 C 29 H 28 NO C 29 H 27 NO 5 - 7.60 (2H, m), 7.49 - 5 C 74.18, H C-39 7.32 (3H, m), 6.74-5.63 470.1962 5.80, N (4H, m), 4.03 (2H, t, J = Found 2.98 .6, 6 Hz), 2.96 (2H, t, J = do: Found: 6.6 Hz), 2.81 - 2.70 (2H, 470, 948 C 74.07, H 7.94 (3H, m), 7.49 (1H, dd, J = 2.4, 8.6 Hz), 7.44-7.36 (3H, m), 6.63 (1H, d, J = 8.5 Hz), 4.50 (2H, t, J = 6.7 Hz), 4.00-3.93 for BR C-48 0 (1H, m), 3.89-3.81 (1H, 409 (M) + m), 3.14 (1H, d, J = 14.1 Hz), 2.95 (2H, t, J = 6.7 Hz), 2.85 (1H, d , J = 14.1 Hz), 2.31 (3H, s), 1.99-1.73 (4H, m). (MeOH-d4, 300 MHz): 8.37 (1H, d, J = 2.6 Hz), 8.07 (1H, dd, J = 2.6, 8.9 Calculated Hz), 7.93 - 7.90 (2H, m), for 7.79 (1H, d, J = 8.9 Hz), C23H25 2O5 7.47-7.40 (3H, m), 4.41 Cl C 62.09, (2H, t, J = 6.2 Hz), 3.92 - for BR H 5.66, N C-49 CKXCH3 U OH 3.86 (2H, m), 3.05 (2H, t, 408 (M) -6.30, J = 6.2 Hz), 2.36 (3H, s), Found: 3.50 (1H, d, J = 14.3 Hz), C 61.96, H 3.15 (1H, t, J = 14.3 Hz), 5.75, N 2.31-2 , 23 (1H, m), 2.00-6.18-1.92 (1H, m), 1.89-1.73 (2H, m). (MeOD, 400 MHz): 8.37 for BR (1H, d, J = 2.6 Hz), 8.07 C-50 423 (1H, dd, J = 2.6, 8.9 Hz), ( M + H) + 7.93 - 7.90 (2H, m), 7.79 m). ? NMR (CDCIg, 400 Hz): 8.16 (1? S), 7.88 (2? D, J = 8.6 Hz), 7.81 (1H, d, J = 8.6 Hz) , 7.41 (2H, d, J = 8.6 Hz), 6.87 (1H, d, J = 8.8 Hz), 4.51 for BR C-64 (2H, t, J = 6, 1 Hz), 4.03-443 3.90 (2H, m), 3.23 (1H, d, (M + H) + J = 14.2 Hz), 3.04 (2H, d, J = 6.1 Hz), 2.86 (1H, d, J = 14.2 Hz), 2.42-2.35 (1H, m), 2.37 (3H, s), 2.01 -1, 87 (3H, m). 1 H NMR (DMSO-d 6, 400 MHz): 7.95 (1H, d, J = 2.0 Hz), 7.73 (1H, s), 7.69 Calculated (1H, d, J = 7.3) Hz), 7.51 for (1H, dd, J = 8.6 and 2.3 Hz), Calculated 7.37 (1H, t, J = 7.8 Hz), for .0.4H2O C 7.28 (1H, d, J = 7.1 Hz), C24H27N2 64.23, H 6.69 (1H, d, J = 8.3 Hz), o5 C-65 6.01, N > ?? 4.43 (2H, t, J = 6.8 Hz), 423.1915 6.19. 3.75 (2H, t, J = 6.6 Hz), Found Found: 3.01 (1H, d, J = 14.2 Hz), do: C 64.16, H 2.89 (2H, t , J = 6.8 Hz), 423.1927 6.16, N 2.82 (1H, d, J = 14.2 Hz), 6.01 2.36 (3H, s), 2.30 (3H , s), 2.14-2.08 (1H, m), 1.84-1.60 (3H, m).
H NMR (SO-d6 D, 400 MHz): 7.95 (1H, d, J = 2.3 Hz), 7.79 (2H, d, J = 8.1 Calculated Hz), 7.53 (1H , dd, J = 8.3 for Calculated and 2.5 Hz), 7.29 (2H, d, J = C24H2 N2O5 for 8.1 Hz), 6.68 (1H, d, J = .0.9H2O C 8.3 Hz), 4.43 (2H, t, J = 65.71, H OS C-66 7.1 Hz), 3.75 (2H, t, J = 6.39, N 423.1915 6.8 Hz), 3.01 (1H, d, J = .6.39, 13.9 Hz), 2.88 (2H, t, J = Found: do: 6.8 Hz), 2, 82 (1H, d, J = C 65.61, H 423.1929 13.9 Hz), 2.34 (3H, s), 6.34, N 2.29 (3H, s), 2.14- 2.07 6.20 (1H, m), 1.84-1.60 (3H, m). 1 H NMR (MeOH-d 4, 400 MHz): 8.28 (1 H, s), 7.76 (2 H, dt, J = 7.7, 0.2 Hz), 7.56 (1 H, d) , J = 9.1 Hz), 7.34-7.39 (1 H, m), 7.14-7.20 (2 H, m), 6.28 (1H, EMBR d, J = 9, 2 Hz); 4.12 (2 H, C-67 426 t, J = 8.0 Hz), 3.70 - 3.84 (M + H) + (2 H, m), 3.14-3.20 (1 H, m), 3.00-3.06 (1 H, m), 2.75 (2 H, d, J = 8.0 Hz), 2.34-2.44 (1 H, m), 2.26-2.31 (3 H, m), 1.82-2.05 (3H, m). 1 H NMR (CDCl 3, 400 MHz): 7.98 (1 H, s), 7.48 (1 H, d, J = 9.1 Hz), 7.15-7.30 (4 H, m), 6.65 (2H, C-73 m), 4.37 (2 H, t, J = 6.5 Hz), 3.80 - 4.03 (2 H, m), 2.80 - 3.20 (4 H, m), 2.35 (3 H, m), 1.70-2.05 (3 H, m), 1.50 (9H, s). (Acetone-ds, 300 MHz): 8.37 (1 H, d, J = 1.9 Hz), 7.96 (2 H, m), 7.56 (1 H, dd, J = 7.9 , 2.3 Hz), 7.45 (3 H, m), 7.14 (1 H, t, J = for BR C-74 7.9 Hz), 3.89 (2 H, m), 405 (M) - 3.05 (2 H, m), 2.77 (2 H, m), 2.50 (2 H , t, J = 7.4 Hz), 2.30 (3 H, s), 2.16 (2 H, m), 1.88 (4 H, m). (MeOD, 400 MHz): 8.19 (1 H, s), 7.82-7.80 (2 H, m), 7.61 (1 H, dd, J = 7.8, 1.8 Hz), 7.35-7.33 (3 H, om), 7.15 (1 H, d, J = 8.1 for BR C-75 Hz), 3.83 - 3.73 (2 H, m), 421 3.09 (1 H, d, J = 13.9 Hz), (M + H) + 2.82 (1 H, d , J = 13.9 Hz), 2.69 (2 H, t, J = 7.2 Hz), 2.41 (2 H, t, J = 6.7 Hz), 2.23-2.13 (1 H, m), 2.20 (DMSO-de, 300 MHz): 8.10 (1H, s), 8.03-7.96 (4H, m), 7.48 (1H, s), 7.15-7.12 (2H, m), 6.85-6.83 (2H, m), 4.20 (2H, t, for BR J = 6.5 Hz), 3.76 (2H, t, J · C - 81 451 = 6.5 Hz), 3.04 - 3.00 (M + H) + (1 H, m), 2.95 (2H, t, J = 6.5 Hz) , 2.86-2.82 (1H, m), 2.39 (3H, s), 2.12 (1H, m), 1.83-1.6 (3H, m) (CDCl3, 300 MHz) : 7.85 - calculated 7.77 (2H, m), 7.68 - 7.63 for (1 H, m), 7.15 - 7.12 (2H, C25H23NO m), 6.82 - 6, 80 (2H, m), 4.22 (2H, t, J = 6.5 Hz), (M + H) + 4.01 - 3.96 (1H, m), 3.90 494.1585 C - 82 - 3.85 (1H, m), 3.19 - Found 3.14 (1H, m), 2.97 (2H, t, do: J = 6.5 Hz), 2.90 - 2 , 85 494.1579 (1H, m), 2.39 (3H, s), 2.36 for BR-2.32 (1 H, m), 2.06-494 1.96 (1H, m), 1, 87-1, 77 (M + H) + (2H, m) (CDCl 3, 400 MHz): 7.87-7.84 (2H, d), 7.23-7.21 for BR C-83 (2H, d), 7.14-7.12 (2H, 422 d), 6.82-6.80 (2H, d), (M + H) + 4.19 (2H, t, J = 6.5 Hz), 4.21 (2H, t, J = 6.5 Hz), 5F3 4.00 - 3.81 (2H, m), 3.18 (M + H) + - 3.14 (1H, m), 2 , 97 (2H, 476.1680 t, J = 6.5 Hz), 2.91 - 2.86 Found (1H, m), 2.39 (3H, s), 2.36 C: - 2.30 (1H, m), 2.04 - 476.1661 1.72 (3H, m) for BR 475 (M + H) + (CDCl3, 400 MHz): 7.99-7.97 (2H, m), 7.66 (1 H, d, J = 9.3 Hz), 7.62-7.59 (2H, m), 7.45-7.32 (4H, m), 7.11-7.08 (2H, m), for BR 4.31 (2H, t, J = 6.6 Hz), C-91 458 3.97 - 3.82 (2H, m), 3.34 (+ H) + ( 1H, d, J = 13.9 Hz), 3.08-3.01 (3H, m), 2.39-2.33 (4H, m), 2.08-2.00 (1H, m) , 1.87 - 1.67 (2H, m) (CDCb, 400 MHz): 7.98 (2H, d, J = 5.8 Hz), 7.68 (1H, d, J = 9.1 Hz ), 7.62 - 7.60 (2H, m), 7.42 - 7.33 for BR C-92 (4H, m), 7.14 (1H, dd, J = 472 2.2, 8.8 Hz), 7.07 (1H, s), (M + H) + 4.06 - 3 , 96 (3H, m), 3.87 (1 H, c, J = 7.5 Hz), 3.36 (1H, d, J = 13.9 Hz), 3.08 Alternative preparations of the enantiomers of 2- (. {6-f2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxylpyridin-3-yl> rnetii) tetrahydrofuran-2-carbox (Examples C-48a v C-48b Example C-48a Enantiomer 1 of 2- (. {6-l2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxyflpyridin- 3-yl) methyl) tetrahydrofuran-2-carboxylic acid Lithium hydroxide monohydrate (993 mg, 21.1 mmoi) was added to a solution of (4S) -4-benzyl-3- [2- (. {6- [2- (5-methyl-2- phenyl-1,3-oxazol-4-yl) ethoxy] pyridin-3-yl}. methyl) tetrahydrofuran-2-yl] carbonyl} -1,3-oxazolidin-2-one (600 mg, 1.06 mmol) in a mixture of tetrahydrofuran: methanol: water (1: 1: 1, 12 mL). The mixture was stirred at 50 ° C for 4.5 hours, then cooled to room temperature and stirred for 2 days. The volatile components were removed by evaporation and the residue was diluted with water (5 ml) and extracted with 1: 1 hexanes: ether. The aqueous phase was acidified to pH 5 and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified twice by flash column chromatography (95: 4: 1 dichloromethane: methanol: ammonium hydroxide), yielding the title compound as a colorless oil (72 mg). LRMS (m / z): 409 (M + H) + 1 H NMR (CDCl 3, 300 Hz) 7.99-7.94 (3H, m), 7.49 (1H, dd, J = 2.4, 8 , 6 Hz), 7.44-7.36 (3H, m), 6.63 (1 H, d, J = 8.5 Hz), 4.50 (2H, t, J = 6.7 Hz) , 4.00-3.93 (1 H, m), 3.89-3.81 (1 H, m), 3.14 (1 H, d, J = 14.1 Hz); 2.95 (2H, t, J = 6.7 Hz), 2.85 (1H, d, J = 14.1 Hz), 2.31 (3H, s), 1.99-1, 73 (4H , m). Example C-48b Enantiomer 2 of 2- (. {6-r2- (5-methyl-2-phenyl-, 3-oxazol-4-yl) ethoxylpyridin-3-yl) methyl) tetrahydrofuran-2 carboxylic The enantiomer 2 was prepared using a sequence of reactions similar to those described for enantiomer 1, with the exception that it was split off from (4f?) - 4-benzyl-1,3-oxazolidin-2-one. Example C-94 Acid 1-. { 6- 2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy-1-pyridin-3-ylmethyl) -cyclopropanecarboxylic acid To a solution of 1-tert-butyl ester. { 6- [2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy] -pyridin-3-ylmethyl} Cyclopropanecarboxylic acid (0.2017 g, 0.4642 mmol) in anisole (1.2 mL) was added trifluoroacetic acid (1.2 mL). The resulting solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The crude residue was diluted with ethyl acetate (25 ml) and water (10 ml) and then basified to pH 5-6 by the addition of saturated sodium bicarbonate. The phases were separated and the aqueous phase was extracted with ethyl acetate (3 x 25 mL). The combined organic extracts were then dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to yield the crude product. The pure acid (0.071 g, 40%) was obtained by recrystallization from diethyl ether / hexanes, as a white solid. E BR (m / z): 379 (+ H) +. 1H RN (MeOD, 300 Hz): 7.89-7.83 (3H, m), 7.53 (1H, dd, J = 8.5, 1.9 Hz), 7.37-7.35 (3H, m), 6.60 (1H, d, J = 8.5 Hz), 4.39 (2H, t, J = 6.5 Hz), 2.87 (2H, t, = 6.4) Hz), 2.73 (2H, s), 2.23 (3H, s), 1.14-1.11 (2H, m), 0.77-0.74 (2H, m). EXAMPLE C-95 2- [2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy-5-r2- (1 H-tetrazol-5-yl) -tetrahydrofuran-2-ylmethyl-pyridine A solution of 2-. { 6- [2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy] -pyridin-3-ylmethyl} -tetrahydro-furan-2-carbonitrile (0.11g, 0.27 mmol), sodium azide (0.04 g, 0.54 mmol) and zinc bromide (0.03 g, 0.14 mmol) in water and isopropanol (1: 2, 1.24 ml) was heated to reflux for 23 hours. After cooling to room temperature, the reaction was quenched with 3 N hydrochloric acid (0.14 ml) and ethyl acetate (2.8 ml) and the mixture was stirred until it was completely homogeneous. The aqueous phase was extracted with ethyl acetate (3 x 50 mL) and the combined organic extracts were washed with water (30 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to give the crude product. . The residue was recrystallized with diethyl ether / hexanes to give the title compound (0.052 g, 44%) as a white solid. Elemental analysis: Calculated C22H23 7O3 C 60.96, H 5.35, N 22.62. Found: C 63.50, H 5.62, N 18.80. 1 H R N (CDCl 3, 300 MHz): 6 7.93 (2H, m), 7.86 (1 H, s), 7.40 (3H, m), 7.11 (1H, d, J = 1.7 Hz), 6.49 (1H, d, J = 8.5 Hz), 4.42 (2H, t, J = 6.6 Hz), 3.88 (2H, m), 3.12 (2H, m), 2.92 (2H, t, J = 6.5 Hz), 2.62 (1 H, m), 2.31 (3H, s), 2.23 (1H, m), 1.89 (2H, m). E BR (m / z): 433 (M + H) +. Preparation of starting materials for Examples C- to C-95 (Preparations c- to c- 30) Preparation c-1 4-r2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy-1-benzaldehyde To a solution of 4-hydroxybenzaldehyde (5.05g, 41.4 mmol), 2- (5-methyl-2-phenyl-oxazol-4-yl) -ethan-1-ol (8.39 g, 41.4 mmol) and triphenylphosphine (10.9 g, 41.4 mmol) in anhydrous tetrahydrofuran (165 ml) under a nitrogen atmosphere, diethyl azodicarboxylate (7.21 g, 41.4 mmol) was added dropwise. The resulting solution was stirred at room temperature for 8 hours, then diluted with water and extracted with ethyl acetate. The organic phase was dried (anhydrous magnesium sulfate), filtered and evaporated in vacuo. This residue was then purified by flash column chromatography (hexanes to ethyl acetate) to give the title compound as a white crystalline solid (10.2g, 80%). LRMS (m / z): 308 (M + H) +. Preparation c-2 1- (Hydroxy- {4-f2- (5-methyl-2-phenyl-1,3-oxazole-4-ethoxy-phenyl-methyl) -cyclohexane-methyl-carboxylate) To a suspension of chromium chloride (II) (1.00 g, 8.10 mmol) and lithium iodide (0.087 g, 0.648 mmol) in tetrahydrofuran (20 mL) was added 4- [2- (5-methyl) -2-phenyl-1,3-oxazol-4-yl) ethoxy] benzaldehyde (Preparation 1) (1.00 g, 3.24 mmol) and methyl 1-bromocyclohexanoate (1.07 g, 4.85 mmol) . The resulting mixture was heated to 50 ° C until TLC analysis indicated that the reaction was complete. The mixture was cooled to room temperature and saturated aqueous sodium chloride (15 ml) was added. The resulting mixture was stirred for 15 minutes and then partitioned between water and ethyl acetate. The organic phase was washed with water and dried (anhydrous magnesium sulfate), filtered and evaporated. The residue was purified by flash column chromatography (hexanes to 50% ethyl acetate (hexanes) to give the title compound as a colorless oil (0.797 g, 55%) LRMS (m / z): 450 ( + H) +. Preparation c-3 1- (Hydroxy- {4-r2- (5-methyl-2-phenyl-1,3-oxazole-4-inetoxyphenyl} methyl) cyclobutane carboxylate of ethyl The title compound was obtained as a colorless oil using procedures analogous to those described for Preparation c-2. LRMS (m / z): 436 (M + H) +. Preparation c-4 1 -ff4- (Allyloxy) phenyl-1-methyl-1-methyl-1-cyclopentanecarboxylate To a solution of methyl cyclopentanoate (3.84 g, 30.0 mmol) in tetrahydrofuran (30 mL) at -78 ° C was added dropwise a solution of lithium diisopropylamide (15.0 mL of a 2% solution). M in tetrahydrofuran, 30.0 mmol). The mixture was stirred for two hours and then 4-allyloxybenzaldehyde (2.12 g 13.1 mmol) was added. The mixture was allowed to warm to room temperature and was stirred for 18 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride and dried (anhydrous magnesium sulfate), filtered and evaporated. The residue was purified by flash column chromatography (hexanes to 50% ethyl acetate / hexanes) to give the title compound as a colorless oil (3.67 g, 97%). LRMS (m / z): 273 (-OH) +. Preparation c-5 4-[[4-fBut-3-enyloxy) phenol (hydroxy) methyl methylanthrod-2H-pyran-4-carboxylic acid AND! The title compound was obtained in the form of a colorless oil using procedures analogous to those described for Preparation c-4. LRMS (m / z): 273 (M-OH) +. Preparation c-6 ethyl 1-fr4- (allyloxy) phenin (hydroxy) methyclobutanecarboxylate The title compound was obtained as a colorless oil using procedures analogous to those described for Preparation c-4. LRMS (m / z): 289 (M) +. 1 H NMR (CDCl 3, 300 MHz) 7.22 (2 H, d, J = 8.5 Hz), 6.85 (2 H, d, J = 8.7 Hz), 6, 10-5.98 (1 H , m), 5.39 (1H, ddd, = 1, 5, 3.2, 17.3 Hz), 5.27 (1H, ddd, J = 1, 5, 2.8, 10.4 Hz) , 4.85 (1H, d, J = 6.4 Hz), 4.51 (2H, dt, J = 1, 5, 5.3 Hz), 4.13 (2H, de, J = 0.9) , 7.2 Hz), 3.12 (1 H, d, J = 6.6 Hz), 2.84-2.78 (1 H, m), 2.64-2.58 (1H, m) , 2.35-2.29 (2H, m), 1, 89-1, 83 (1 H, m), 1, 72-1, 66 (1H, m), 1.19 (3H, t, J = 7.0 Hz). Preparation c-7 1-í4-Hydroxybenzyl) cyclopentanecarboxylate methyl Triethylsilane (10.0 mL, 63 mmol) was added to a solution of methyl 1 - [[4- (allyloxy) phenyl] (hydroxy) methyl] cyclopentanecarboxylate (Preparation c-4) (3.66 g, 12%). 6 mmol) in dichloromethane (30 ml) and trifluoroacetic acid at room temperature. The resulting mixture was stirred for 1 hour and then evaporated in vacuo and azeotropically distilled with toluene. The residue was dissolved in tetrahydrofuran (32 ml) and morpholine (3.62 ml, 41.6 mmol) and tetrakis (triphenylphosphine) palladium (0) (1.46 g, 1.26 mmol) were added. The resulting mixture was stirred at room temperature for 18 hours, filtered through Celite and evaporated to dryness. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid and then with a saturated sodium bicarbonate solution. The organic phase was dried (anhydrous magnesium sulfate), filtered and evaporated and the residue was purified by flash column chromatography (hexanes to ethyl acetate) to give the title compound as a white crystalline solid (1, 75 g, 59%). LRMS (m / z): 233 () ". Preparation c-8 4- (4-Hydroxybenzyl) tetrahydro-2H-pyran-4-carboxylic acid methyl ester The title compound was obtained as a white crystalline solid using procedures analogous to those described for Preparation c-7. LRMS (m / z): 249 (M). "Preparation c-9 ethyl 1- (4-hydroxybenzyl) cyclobutanecarboxylate The title compound was obtained as a white crystalline solid using procedures analogous to those described for Preparation c-7. LRMS (m / z): 234 (M). "1 H NMR (CDCl 3, 300 MHz) 6.97 (2H, d, J = 8.5 Hz), 6.68 (2H, d, J = 8.5 Hz), 5.10 (1 H, sa), 4.10 (2H, c, J = 7.2 Hz), 3.00 (2H, s), 2.44-2.35 (2H, m) , 2.07-1, 99 (2H, m), 1.91-1, 80 (2H, m), 1.20 (3H, t, J = 7.2 Hz) Preparation c-10 1- ( Methyl 4-r2-55-ethyl-2-phenyl-1,3-oxazole-4-methoxy-1-benzylcyclopentanecarboxylate The title compound was obtained as a colorless oil using procedures analogous to those described for Preparation c -1 c-7. LRMS (m / z): 249 (M). "Preparation c-1 1- (4-f3- (5-Methyl-2-phenyl-1,3-oxazol-4-yl) propoxflbenzyl-cyclopentanecarboxylate methyl) The title compound was obtained as a colorless oil using procedures analogous to those described for Preparation c -1 c-7. E BR (m / z): 434 (M + H) +. Preparation c- 2 4- (4-22- (5-Methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy-1-benzyl) -tetrahydro-2H-pyran-4-carboxylic acid methyl ester The title compound was obtained as a colorless oil using procedures analogous to those described for Preparation c -1 c-7. LRMS (m / z): 436 (M + H) +. Preparation c-13 1 - (4-r2- (4-Bromophenyl) ethoxybenzyl> ethyl cyclobutanecarboxylate The title compound was obtained as a colorless oil using procedures analogous to those described for Preparation c -1 c-7. LRMS (m / z): 417 (M) +. 1 H NMR (300 MHz CDCI 3l) 7.36 (2H, d, J = 8.3 Hz), 7.08 (2H, d, J = 8.3 Hz), 6.96 (2H, d, J = 8 , 7 Hz), 6.70 (2H, d, J = 8.7 Hz), 4.04 (2H, t, J = 6.8 Hz), 4.03 (2H, c, J = 7.2 Hz), 2.95 (2H, t, J = 6.8 Hz), 2.94 (2H, s), 2.37-2.27 (2H, m), 2.00-1, 91 (2H , m), 1.84-1, 73 (2H, m), 1, 14 (3H, t, J = 7.2 Hz). Preparations c-14 to c-35 Preparations c-14 to c-35 were prepared using procedures analogous to those used for Preparation c-1 c-35 (CDCI3, 300 MHz) 8.09-8.07 (2H, For m), 7.69-7.66 (2H, m), 7.16-7.14 BR 504 (2H, m), 6.81-6.78 (2H, m), 4.21 (M + H) + (2H, t, J = 6.5 Hz), 4.16-4.09 (2H, c, J = 7.1 Hz), 3.95-3.83 (2H, m), 3.15-3.10 (1 H, m), 2.97 (2H, t, J = 6.5 Hz), 2.94-2.89 (1H, m), 2.39 (3H, s) ), 2.27-2.18 (1H, m), 1.92-1.61 (3H, m), 1.21 (3H, t, J = 7.1 Hz).
Preparation c-36 1-. { 4- [2- (4'-Methoxy-1.l'-biphenyl] -i-Detoxylbenzyl ethylcyclobutanecarboxylate To a solution of 1-. { 4- [2- (4-bromophenyl) ethoxy] benzyl} ethyl cyclobutanecarboxylate (Preparation c-13) (0.25 g, 0.5990 mmol), tetrakis (triphenylphosphine) palladium (0) (0.1252 g, 0.6589 mmol), benzene (1.6 ml) and carbonate Aqueous sodium 2 M (0, 8 mL) under a nitrogen atmosphere was added a solution of boric acid (0.8640 mmol, 1.1 equiv.) In ethanol (0.4 mL). The resulting mixture was degassed and then heated to reflux for 16 hours, followed by cooling to room temperature. Then, 30% aqueous hydrogen peroxide (0.04 ml) was added dropwise and the resulting solution was stirred at room temperature for 1 hour. Then the solution was extracted with ethyl acetate (3 x 100 mL) and the combined organic extracts were washed with saturated aqueous sodium chloride 8100 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to yield the gross product. The residue was purified by flash column chromatography (hexanes to 40% ethyl acetate / hexanes) to yield the pure product as a colorless oil. LRMS (m / z): 462 (M + H20) +. H NMR (CDCl 3, 300 Hz) 7.51 (2H, d, J = 5.7 Hz), 7.49 (2H, d, J = 4.7 Hz), 7.32 (2H, d, J = 8.1 Hz), 7.03 (2H, d, J = 8.5 Hz), 6.97 (2H, d, J = 8.9 Hz), 6.80 (2H, d, J = 8, 5 Hz), 4.15 (H, t, J = 7.2 Hz), 4, 10 (2H, c, J = 7.2 Hz), 3.84 (3H, s), 3.10 (2H , t, J = 7.1 Hz), 3.01 (2H, s), 2.43-2.34 (2H, m), 2.07-1.98 (2H, m), 1.90- 1.80 (2H, m), 1, 20 (3H, t, J = 7.2 Hz). Preparations c-37 to c-43 Preparations c-37 to c-43 were prepared using procedures analogous to those used for Preparation c-36 Prep Structure? NMR MS [m / z) No. (B or AR) c-37 (CDCIg, 300 MHz) 7.46 (2H, d, J For BR = 8.9 Hz), 7.41 (2H, d, J = 8.3 433 Hz), 7.27 (2H, d, J = 8.1 Hz), (M + H) + 7.03 (2H, d, J = 8.9 Hz), 6.97 ( 2H, d, J = 8.5 Hz), 6.73 (2H, d, J = 8.7 Hz), 4.09 (2H, t, J = 7.0 Hz), 4.03 (2H, c, J = 7.0 Hz), 3.03 (2H, t, J = 7.0 Hz), 2.94 (2H, s), 2.37-2.27 (2H, m), 2, 00-1, 91 (2H, m), 1.83-1, 72 (2H, m), 1.13 (3H, t, J = 7.1 Hz). c-38 (CDCI3, 300 MHz) 7.48 (2H, d, J for BR = 8.1 Hz), 7, 34-7.29 (4H, m), 467 7.05 (2H, d, J = 8.7 Hz), 6.99 (M + Na) + (2H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.7 Hz), 4.18 (2H , t, J = 7.3 Hz), 4.11 (2H, c, J = 7.0 Hz), 3.81 (3H, s), 3.12 (2H, t, J = 7.3 Hz ), 3.02 (2H, s), 2.44-2.35 (2H, m), 2.08-1, 99 (2H, m), 1.91-1.80 (2H, m), 1.21 (3H, t, J = 7.0 Hz). c-39 (CDCl 3, 300 MHz) 7.53-7.49 (3H, for BR m), 7.44 (2H, t, J = 7.9 Hz), 7.389.499 (2H, t, J = 7.9 Hz), 7.09 (1 H, dm, (M + H) + J = 8.0 Hz), 7.04 (2H, d, J = 8.5 Hz), 6.80 ( 2H, d, J = 8.5 Hz), 4.17 (2H, t, J = 7.0 Hz), 4.10 (2H, c, J = 7.0 Hz), 3.12 (2H, t, J = 7.0 Hz), 3.01 (2H, s), 2.44-2.35 (2H, m), 2.07-1.98 (2H, m), 1, 90- 1 , 83 (2H, m), 1.21 (3H, t, J = 7.2 Hz). c-40 (CDCl 3, 300 MHz) 8.36 (1H, s), For BR 7.77 (1H, dd, J = 2.5 and 8.7 Hz), 446 7, 46 (2H, d, J = 8.1 Hz), 7.35 (M + Hf (2H, d, J = 8.1 Hz), 7.03 (2H, d, J = 8.3 Hz), 6.81 (2H, d , J = 8.3 Hz), 6.79 (2H, d, J = 8.3 Hz), 4.16 (2H, t, J = 6.8 Hz), 4.09 (2H, c, J = 7.2 Hz), 3.97 (3H, s), 3.10 (2H, t, J = 7.0 Hz), 3.00 (2H, s), 2.43-2.33 (2H) , m), 2.06-1, 97 (2H, m), 1.89-1.79 (2H, m), 1.20 (3H, t, J = 7.1 Hz) c-41 ( CDCI3, 300 MHz) 7.99 (2H, d, J For BR = 8.1 Hz), 7.75 (2H, d, J = 8.1 511 Hz), 7.56 (2H, d, J = 8.1 Hz), (M + Na) + 7.40 (2H, d, J = 7.9 Hz), 7.03 (2H, d, J = 8.5 Hz), 6.79 (2H, d, J = 8.5 Hz), 4.17 (2H, t, J = 6.8 Hz), 4.09 (2H, c, J = 7.2 Hz), 3.13 (2H, t, J = 6.9 Hz), 3.08 (3H, s), 3.00 (2H, s), 2.43-2.33 (2H, m), 2.06-1, 97 (2H, m ), 1.90-1.79 (2H, m), 120 (3H, t, J = 7.2 Hz) c-42 (CDCI3, 300 MHz) 7.48 (2H, d, J For BR = 8.3 Hz), 7, 41 (1 H, s), 7.34-47.9 7.31 (1H, m), 7.31 (2H, d, J = 8.3 (+ Na) + Hz) , 7.04 (2H, d, J = 8.7 Hz), 6.85 (1H, d, J = 8.5 Hz), 6.80 (2H, d, J = 8.5 Hz), 4.61 (2H, d, J = 8.7 Hz), 4.16 (2H, t, J = 7.2 Hz) , 4.10 (2H, c, J = 7.2 Hz), 3.27 (2H, t, J = 8.7 Hz), 3.10 (2H, t, J = 7.0 Hz), 3 , 01 (2H, s), 2.44-2.35 (2H, m), 2.07-1.99 (2H, m), 1.91-1.83 (2H, m), 1.21 (3H, t, J = 7.2 Hz). . c-43 300 MHz) 7.57 (2H, d, J For BR = 8.5 Hz), 7.50 (2H, d, J = 8.5 508 (M) + Hz), 7.35 (2H , d, J = 8.5 Hz), 7.27 (2H, d, J = 8.5 Hz), 7.03 (2H, d, J = 8.7 Hz), 6.79 (2H, d, J = 8.7 Hz), 6.37 (1H, sa), 4.16 (2H, t, J = 7.0 Hz), 4.09 (2H, c, J = 7.0 Hz), 3.11 (2H, d, J = 7.0 Hz), 3.04 (3H, s), 3.00 (2H, s), 2.43-2.33 (2H, m), 2.06-1.97 (2H, m), 1.89-1.79 (2H, m), 1.20 (3H, t, J = 7 , 2 Hz).
Preparation c-44 4- (4-f (5-Methyl-2-phenyl-1,3-oxazol-4-yl) methoxy-1-benzyl-tetrahydro-2H-pyran-4-carboxylic acid methyl ester A solution of methyl 4- (4-hydroxybenzyl) tetrahydro-2H-pyran-4-carboxylate (Preparation c-8) (0.500 g, 2.0 mmol), cesium carbonate (1.96 g, 6.0 mmol) ) and chloride (0.458 g, 2.2 mmol) in acetonitrile was heated at 140 ° C in a microwave synthesizer for 10 minutes. The mixture was cooled, filtered and the filtrate was evaporated. The residue was purified by flash column chromatography (hexanes to ethyl acetate) to give the title compound as a crystalline solid (0.827 g, 98%). LRMS (m / z): 422 (+ H) +. Preparation c-45 5-Bromo-2-f2-f5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxypyridine To a solution of 2,5-dibromo-pyridine (5 g, 21, 1060 mmol) and 2- (5-methyl-2-phenyl-oxazol-4-yl) -ethanol (5.1472 g, 25.3271 mmol ) in anhydrous tetrahydrofuran (85 ml) under a nitrogen atmosphere was added potassium tert-butoxide (2.8422 g, 25.3271 mmol). The resulting mixture was heated to reflux for 16 hours and then allowed to cool to room temperature. The mixture was evaporated at about 20 ml and partitioned between saturated aqueous ammonium chloride (50 ml) and ethyl acetate (50 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were then washed with water (2 x 50 mL), saturated aqueous sodium chloride (50 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to yield the crude product. The residue was purified by flash column chromatography (hexanes to 20% ethyl acetate / hexanes) to yield a white crystalline solid (6.3 g, 83%). LRMS (m / z): 359 (M) +. 1H RN (CDCl 3, 400 MHz) 8.17 (1H, d, J = 2.0 Hz), 7.96 (2H, dd, J = 2.0, 8.1 Hz), 7.61 (1H, dd, J = 2.7, 8.7 Hz), 7.43-7.38 (3H, m), 6.62 (1H, d, J = 8.6 HZ), 4.52 (2H, t , J = 6.8 Hz), 2.96 (2H, t, J = 6.8 Hz), 2.32 (3H, s). Preparations c-46 to c-47 Preparations c-46 to c-47 were prepared by the general procedure of Preparation c-45 Preparation c-48 6-r2- (5-Methyl-2-phenyl-1,3-oxazol-4-yl) ethoxynicotinaldehyde To a solution of butyllithium (27.4 ml of a 1.6M solution in hexanes, 43.799 mmol) in anhydrous tetrahydrofuran (200 ml) under a nitrogen atmosphere was added a solution of 5-bromo-2- [ 2- (5-Methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] pyridine (Preparation c-45) (14.31 g, 39.8363 mmol) in anhydrous tetrahydrofuran (170 mL) and ether Anhydrous diethyl ester (170 ml) for a period of 45 minutes. To this solution was then added dropwise? /, / V-dimethylformamide anhydrous (5.7 ml) and the mixture was stirred at 0 ° C for 1 hour. The reaction was stopped by the addition of saturated aqueous ammonium chloride (250 ml) and then ethyl acetate (250 ml). The resulting layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 250 mL). The combined organic extracts were washed with water (2 x 250 mL), saturated aqueous sodium chloride (250 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to yield the crude product. flash column chromatography (hexanes to 50% ethyl acetate / hexanes) to give a pale yellow crystalline solid (7.17 g, 58%) LRMS (m / z): 309 (M + H) +. (CDCl 3, 300 MHz) 9.93 (1H, s), 8.61 (1 H, d, J = 2.3 Hz), 8.04 (1H, dd, J = 2.5, 8.7 Hz ), 7.98-7.95 (2H, m), 7.43-7.39 (3H, m), 6.81 (1H, d, J = 8.7 Hz), 4.68 (2H, t, J = 6.8 Hz), 3.00 (2H, t, J = 6.8 Hz), 2.34 (3H, s) Preparation c-49 1- (Hydroxy- (6-r2- ( Ethyl 5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy-1-pyridin-3-dmethylcyclobutanecarboxylate To a solution of 6- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] nicotinaldehyde (Preparation c-48) (0.65 g, 2.1081 mmol), chloride of chromium (II) (1 g, 8.1367 mmol) and lithium iodide (0.0784 g, 0.5859 mmol) in anhydrous tetrahydrofuran (15 ml) under a nitrogen atmosphere was added dropwise a solution of 1-bromo-cyclobutanecarboxylic acid ethyl ester (0, 79 mL, 4.8821 mmol) in anhydrous tetrahydrofuran (5 mL). The resulting mixture was stirred at 50 ° C for 3 hours and allowed to cool to room temperature. The solution was then quenched by the addition of water (50 ml) and the organic layer was separated and further washed with water (2 x 50 ml), saturated aqueous sodium chloride (50 ml), dried (anhydrous magnesium sulfate). , it was filtered and concentrated in vacuo to yield the crude product. The residue was purified by flash column chromatography (50% ethyl acetate / hexanes to ethyl acetate) to yield a yellow oil (0.3422 g, 37%). LRMS (m / z): 437 (+ H) +. 1 H RN (CDCl 3, 400 MHz) 8.05 (1 H, d, J = 2.3 Hz), 7.98-7.95 (2 H, m), 7.56 (1 H, dd, J = 2 , 5, 8.7 Hz), 7.44-7.37 (3H, m), 6.67 (1 H, d, J = 8.7 Hz), 4.85 (1H, d, J = 6 , 6 Hz), 4.54 (2H, t, J = 6.6 Hz), 4.18-4.07 (2H, m), 3.31 (H, sa), 2.96 (2H, t , J = 6.7 Hz), 2.46-2.30 (2H, m), 2.32 (3H, s), 2.21-2.12 (1H, m), 1.97-1, 85 (1 H, m), 1.79-1.65 (2H, m), 1, 21 (3H, t, J = 7.2 Hz). Preparation c-50 1- (Ethoxy- (6- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy-1-pyridin-3-yl) -methyl) -cyclobutanecarboxylic acid ethyl ester To a 1- (hydroxy- {6- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -pyridin-3-yl} -methyl ethyl ester solution -cyclobutanecarboxylic acid (0.1711 g, 0.3920 mmol) in dry acetonitrile (2 mL) was added with silver oxide (1) (1.8168 g, 7.8396 mmol) and iodoethane (0.64 mL, 7.8396 mmol). The resulting mixture was stirred for 5 days and concentrated under reduced pressure to produce the crude product and the remaining starting material was recovered. The residue was purified by flash column chromatography (hexanes to ethyl acetate) to give the pure ester (0.0474 g, 26%) as a colorless oil. LRMS (m / z): 465 (+ H) +. 1 H NMR (CDCl 3, 400 MHz): 8.05 (1H, d, J = 2.3 Hz), 7.98-7.95 (2H, m), 7.56 (1H, dd, J = 2, 5, 8.7 Hz), 7.44-7.37 (3H, m), 6.67 (H, d, J = 8.7 Hz), 4.65 (1H, m), 4.54 ( 2H, t, J = 6.6 Hz), 4.18-4.07 (2H, m), 4.06 (2H, c, J = 7.1 Hz), 2.96 (2H, t, J = 6.7 Hz), 2.46-2.30 (2H, m), 2.32 (3H, s), 2.21-2.12 (1 H, m), 1.97-1.85 (1H, m), 1.79-1.65 (2H, m), 1.42 (3H, t, J = 7.1 Hz), 1.21 (3H, t, J = 7.2 Hz) . Preparation c-5 (6-r2- (5-Methyl-2-phenyl-1,3-oxazol-4-yl) ethoxylpyridin-3-yl >methanol Sodium borohydride (0.480 g, 12.7 mmol) was added portionwise to a solution of 6- [2- (5-methyl-2-phenyl-, 3-oxazol-4-yl) ethoxy] nicotinaldehyde (Preparation c-48) ) (1.30 g, 4.22 mmol) in methanol (40 ml) at room temperature. The mixture was stirred for 30 minutes and then evaporated. The residue was partitioned between saturated aqueous ammonium chloride and ethyl acetate, the organic phase was washed with saturated aqueous sodium chloride and dried (anhydrous magnesium sulfate), filtered and evaporated to give the title compound as a solid crystalline white (1.24 g, 100%). LRMS (m / z): 3 1 (+ H) +. 1H RN (CDCls, 300 MHz) 8.1 (1 H, d, J = 2.6 Hz), 8.00-7.95 (2H, m), 7.60 (H, dd, J = 2, 5, 8.5 Hz), 7.45-7.38 (3H, m), 6.72 (1H, d, J = 8.5 Hz), 4.61 (2H, sa), 4.56 ( 2H, t, J = 6.8 Hz), 2.98 (2H, t, J = 6.8 Hz), 2.33 (3H, s). Preparation c-52 (2-r2- (5-ethyl-2-phenyl-oxazol-4-yl-ethoxy] -pyrimidin-5-yl-methanol A solution of 5-bromo-2- [2- (5-methyl-2-phenyl-oxazoI-4-yl) -ethoxy] -pyrimidine (1.0 g, 2.7765 mmol), tert-butyl-dimethyl -tribusylstannylmethoxy-silane (1.8 g, 1.1648 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.3209 g, 0.2777 mmol) in 1,4-dioxane (2.8 ml) was heated ( by irradiation with microwaves) at 150 ° C for 2 hours. The resulting solution was allowed to cool to room temperature and saturated aqueous potassium Auroro (10 mL) was added followed by stirring for 30 minutes. Then, the mixture was extracted with ethyl acetate (3 x 25 mL) and the combined organic extracts (anhydrous magnesium sulfate), filtered and concentrated in vacuo to yield the crude product as a yellow oil. To a solution of the crude residue in dry tetrahydrofuran (24 ml) was added tetrabutylammonium fluoride (3.1 ml of a 1.0 M solution in tetrahydrofuran). The resulting mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The residue was purified by flash column chromatography (50% ethyl acetate / hexanes to 10% methanol / ethyl acetate) to yield pure alcohol (0.6137 g, 71% in two steps) as a solid. White. LRMS (m / z): 312 (M + H) +. Preparation c-53 5-Benzyloxy-2-methyl-pyridine To a solution of 5-hydroxy-2-methylpyridine (20 g, 183.2677 mmol) and sodium hydroxide (8.0638 g, 201, 5944 mmol) in acetone (400 mL) and water (120 mL) was added benzyl (24 ml, 201, 5944 mmol). The resulting mixture was heated to reflux for 16 hours and allowed to cool to room temperature. The acetone was removed in vacuo and the mixture was extracted with ethyl acetate (3 x 150 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (200 ml), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to yield the pure product (31.35 g, 86%) as a orange oil LRMS (m / z): 200 (M + H) +. 1H RN (CDCl 3, 300 MHz): 8.25 (1 H, d, J = 2.8 Hz), 7.43-7.31 (5H, m), 7.15 (1 H, dd, J = 8.5, 2.8 Hz), 7.04 (1H, d, J = 8.5 Hz), 5.06 (2H, s), 2.47 (3H, s). Preparation c-54 1-5-Benzyloxy-2-methyl-pyridine oxide To a solution of 5-benzyl-2-methyl-pyridine (31.35 g, 157.34 mmol) in dry chloroform (800 ml) at room temperature was added 3-chloroperoxybenzoic acid (max 77%). ) (38.7888 g, 173.074 mmol). The resulting mixture was stirred for 2 hours and then quenched with a solution of sodium thiosulfate (36.0805 g, 286.5 mmol) in water (500 ml) and stirred for 15 minutes. The phases were separated and the organic layer was washed with water (500 ml) and saturated sodium chloride (500 ml), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to yield the crude product. The residue was recrystallized from acetone / hexanes to yield the crude product. The residue was recrystallized from acetone / hexanes to give the pure product (33.1597 g, 97%) as a white solid. SMI (m / z): 216 (M + H) +. 1H RN (CDCl3, 300 MHz): 8.10-8.09 (1H, ma), 7.38-7.34 (5H, m), 7.10 (1H, d, J = 8.7 Hz) , 6.87 (1H, dd, J = 8.7, 2.3 Hz), 5.04 (2H, s), 2.43 (3H, s). Preparation c-55 (5-Benzyloxy-pyridin-2-yl) -methanol · A solution of 5-benzyloxy-2-methyl-pyridine-1-oxide (0.92 g, 4.2741 mmol) in acetic anhydride (6.5 ml) was heated at 100 ° C for 30 minutes. After cooling to room temperature, the reaction mixture was poured into ethyl acetate (50 ml), washed with saturated aqueous sodium bicarbonate (50 ml) and saturated aqueous sodium chloride (50 ml), dried (anhydrous magnesium sulfate). ), filtered and concentrated in vacuo to yield the crude acetate. To the crude residue in methanol (45 ml) was added potassium carbonate (2.1784 g, 15.7719 mmol) and the solution was allowed to stir at room temperature for 16 hours. The reaction mixture was poured into water (50 ml) and the organic extracts were removed under reduced pressure. The resulting residue was extracted with ethyl acetate (3 x 50 mL) and the combined organic extracts were dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to yield the crude product. The residue was purified by flash column chromatography (hexanes to 20% methanol / ethyl acetate) to yield pure alcohol (0.5719 g, 62% for the two steps) as a white solid. EMBR. { m / z): 216 (+ H) +. H NMR (CDCl 3, 300 MHz): 8.31 (1H, d, J = 2.8 Hz), 7.44-7.31 (5H, m), 7.27 (1 H, dd, J = 8 , 7, 2.8 Hz), 7.17 (1 H, d, J - 8.5 Hz), 5.11 (2 H, s), 4.69 (2 H, s). Preparation c-56 1-2-Methyl-5-f2- (5-methyl-2-phenyl-oxazol-4-yl-ethoxy-1-pyridine oxide) To a solution of 2-methyl-5- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -pyridine (6.793 g, 23.0917 mmol) in dry chloroform (140 ml) ) at room temperature was added 3-chloroperoxybenzoic acid (max 77%) (7.7629 g, 34.6376 mmol). The resulting mixture was stirred for 2 hours and then quenched with a solution of sodium thiosulfate (4.3621 g, 34.6376 mmol) in water (25 mL) and stirred for 15 minutes. The phases were separated and the organic layer was washed with water (50 ml) and saturated sodium chloride (50 ml), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to yield the crude product. The pale yellow oil (7.0689 g, 98%) was used without further purification. Prep Structure? NMR MS (m / z) No. (BR or Preparation c-64 5-FYodomethyl) -2-r2- (5-methyl-2-phenyl-1,3-oxazol-4-inetoxylpyridine Sodium iodide (0.750 g) was added to a solution of 5- (chloromethyl) -2- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] pyridine (Preparation 27) ( 0.690 g, 2.10 mmol) in acetone (5 ml) and the mixture was refluxed for 30 minutes, cooled and evaporated. The residue was suspended in ethyl acetate and filtered through a layer of silica gel. The filtrate was evaporated to give the title compound as a yellow crystalline solid which was used directly in the following reactions. LRMS (m / z): 421 (M + H) +.
Preparations c-65 to c-69 Preparations c-65 to c-69 were prepared by the general procedure of Preparation c-64 Preparation c-70 1- ( {6-r2- (5-Methyl-2-phenyl-1,3-oxazol-4-inetoxnpyridin-3-yl.} Methyl) cyclobutane ethyl carboxylate Sodium (bis) trimethylsilyl amide (3.0 mL of a 1 M solution in tetrahydrofuran, 3.0 mmol) was added dropwise to a solution of ethyl cyclobutanoate (0.41 mL, 3.0 mmol) in anhydrous tetrahydrofuran. (5 mi) at -60 ° C. The mixture was stirred for 1 hour and then a solution of 5- (iodomethyl) -2- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] pyridine was added dropwise. (Preparation 28) (0.271 g, 0.64 mmol) in anhydrous tetrahydrofuran (4 mL). The resulting mixture was stirred at -60 ° C for 1 hour and then quenched with saturated aqueous ammonium chloride and warmed to room temperature. The mixture was extracted with ethyl acetate and the organic phase was dried (anhydrous magnesium sulfate), filtered and evaporated to yield a 1: 1 mixture of the title compound and a dimer (0.160 g) which was used directly in the next stage. LRMS (m / z): 421 (M + H) +. Preparation c-7 2-ff6-r2- (5-Methyl-2-phenyl-1,3-oxazol-4-inetoxy-1-pyridin-3-yl-ethyl-1-tetrahydrofuran-2-carboxylate) Sodium (bis) trimethylsilyl amide (3.18 ml of a 1 M solution in tetrahydrofuran, 3.18 mmol) was added dropwise to a solution of ethyl 2-tetrahydrofuranoate (0.458 g, 3.18 mmol) in anhydrous tetrahydrofuran. (4 mi) at -50 ° C. The mixture was stirred for 45 minutes and then a solution of 5- (iodomethyl) -2- [2- (5-methyl-2-phenol-, 3-oxazol-4-yl) ethoxy] pyridine was added dropwise ( Preparation 28) (0.267 g, 0.64 mmol) in anhydrous tetrahydrofuran (2 mL). The resulting mixture was stirred at -50 ° C for 1.5 hours and then quenched with saturated aqueous ammonium chloride and warmed to room temperature. The mixture was extracted with ethyl acetate and the organic phase was dried (anhydrous magnesium sulfate), filtered and evaporated. The residue was purified by flash column chromatography (25% to 35% ethyl acetate / hexanes) to give the title compound as a colorless oil (0.250 g, 90%). LRMS (? 7 /?): 437 (M + H) +. 1H RN (CDCl 3, 300 MHz) 7.95 (3H, m), 7.51 (1 H, dd, J = 2.5, 8.5 Hz), 7.43-7.36 (3H, m) , 6.61 (1H, d, J = 8.5 Hz), 4.51 (2H, t, J = 6.8 Hz), 4.29.4.18 (1H, m), 4.13 (2H, c, J = 7.2 Hz), 3.95-3.82 (2H, m), 3.10 (1H, d, J = 14.1 Hz), 2.95 (2H, t, J = 6 , 8 Hz), 2.86 (1 H, d, J = 14.1 Hz), 2.31 (3 H, s), 2.26-2.20 (1 H, m), 1.92-1, 77 (2H, m), 1.70-1.61 (1H, m), 1.21 (3H, t, J = 7.2 Hz). Preparations c-72 to c-79 Preparations c-72 to c-79 were prepared by the general procedure of Preparation c-71 Prep Structure? NMR EM No. (m / z) (BR or AR) c-72 (CDCI3, 300 MHz) 8.38 (2H, s), 7.97- for BR 7.94 (2H, m), 7.44-7 , 38 (3H, m), 4.59 438 (2H, t, J = 7.0 Hz), 4.15 (2H, c, J = (M + H) + 7.0 Hz), 3.99 -3.86 (2H, m), 3.13 (1 H, d, J = 14.3 Hz), 3.00 (1 H, t, J = 6.9 Hz), 2.84 (1 H , d, J = 14.3 Hz), 2.35 (3H, s), 2.26-2.20 (1H, m), 1, 91-1, 93 (4H, m), 1, 23 ( 3H, t, J = 7.0 Hz). c-73 (CDCl 3, 300 MHz) 8.27 (1 H, d, J = for BR 2.3 Hz), 7.42-7.32 (5H, m), 7.20-7.13 342 ( 2H, m), 5.06 (2H, s), 4.13 (2H, c, J = (M + H) + 13.9 Hz), 3.33 (1 H, d, J = 13.9 Hz), 3.14 (1 H, d, J = 13.9 Hz), 2.64-2.55 (1 H, m), 2.27-2.20 (1 H, m), 1, 89-1, 63 (4H, m), 1, 24 (3H, t, J = 13.9 Hz). c-74 O (CDCl 3, 300 MHz) 8.27 (1 H, d, J = for BR 2.6 Hz), 7.42-7.29 (5H, m), 7.16 (1H, 316 dd) , J = 8.7, 2.8 Hz), 7.14-7.08 (1 H, (M + H) + m), 5.06 (2H, s), 3.71 (3H, s) , 3.30 (3H, s), 3.16 (2H, s), 1, 40 (3H, s) c-75 (CDCI3, 400 MHz) 8.14 (1 H, d, J = for BR 2 , 3 Hz), 7.41 (1H, dd, J = 8.3, 2.5 289 Hz), 7.36 (1H, dd, J = 8.3, 0.8 Hz), (M + H ) + 3.69 (3H, s), 3.27 (3H, s), 2.99 (1H, d, J = 13.9 Hz), 2.87 (H, d, J = 13.9 Hz ), 1.33 (3H, s) c-76 (CDCl 3, 400 MHz) 8.17 (1H, d, J = for BR 2.3 Hz), 7.96 (2H, dd, J = 7.7 , 1, 9 451 Hz), 7.43-7.38 (3H, m), 7.12 (1H, d, J (M + H) + = 8.1 Hz), 7.09 (1H, dd , J = 8.6, 2.8 Hz), 4.24 (2H, t, J = 6.7 Hz), 4.15 (2H, c, J = 7.2 Hz), 3.88-3 , 84 (1H, m), 3.64 (1 H, dt, J = 11.6, 3.3 Hz), 3.07 (2H, s), 2.96 (2H, t, J = 6, 6 Hz), 2.36 (3H, s), 2.22-2.18 (.1H, m), 1.52- 1.36 (5H, m), 1.20 (3H, t, J = 7.1 Hz). c-77 (CDCl 3, 300 MHz) 8.09 (1H, s), 7.91- for BR 8.01 (3H, m), 7.34-7.45 (3H, m), 438 4.48 -4.64 (2H, m), 3.84-4.24 (2H, (M + H) + m), 3.22 (1 H, d, J = 15.0 Hz), 3.1 ( 1H, d, J = 15.0 Hz), 2.91-3.03 (1H, m), 2.31-2.35 (1H, m), 1.65-2.30 (2H, m) , 1.24 (3H, t, J = 6.6 Hz). c-78 (CDCl 3, 300 MHz) 7.96 (1H, m), 7.92 for BR 0 (2H, d, J = 2.1 Hz), 7.41 (4H, m), 4 1 6, 63 (1H, d, J = 8.5 Hz), 4.52 (2H, t, (M + H) ÷ J = 6.8 Hz), 3.70 (3H, s), 3.30 (3H , m), 2.93 (4H, m), 2.33 (3H, s), 1.33 Preparation c-80 2-bromo-5- (bromomethiupyridine Phosphorus tribromide (100 mmol, 27.1 g, 2.0 equiv.) To 2-cORO-5-hydroxymethyl pyridine (50.0 mmol, 7.18 g, 1.0 equiv.). The pyridine was pooled together and the mixture was heated to 160 degrees C. Within a period of 5 minutes at > 150 ° C, it was observed that the mixture was of a very dark color and that gas evolution occurred. The mixture was stirred at this same temperature for approximately 2.5 hours, at which time it was cooled to room temperature. The mixture was further cooled to 0 ° C after which sodium bicarbonate was added very carefully (high exotherm). As foaming became less vigorous, ice was added to the mixture until foaming was reduced. Then solid sodium bicarbonate was added carefully to achieve a pH of -8-9. The mixture was extracted with ethyl acetate and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. It was concentrated in vacuo to yield a dark solid. This material was dissolved in a minimum amount of DCM and purified using a Biotage Sp4 65i on a gradient of 0-100% ethyl acetate in hexanes to yield the title compound as a pale yellow solid (5.57 g. , 44%). LRMS: 252 (M + H) +. 1 H NMR / DMSO-d 6, 400 MHz): 8.39 (1H, s), 7.59 (1 H, d, J = 8.5 Hz), 7.48 (1H, d, J = 8.5 Hz), 4.46 (2H, s). Preparation c-81 2-f (ethyl 6-Bromopyridin-3-inmetintetrahydrofuran-2-carboxylate) To a solution of ethyl tetrahydrofuran-2-carboxylate (52.9 mmol, 9.10 g,, 5 equiv.) Cooled to -78 ° C in THF (90 mL) was added dropwise a solution of lithium diisopropylamide 2 (52.9 mmol, 1.5 equiv.) In a mixture. of heptane THF / ethylbenzene. The enolate was allowed to form for one hour at the same low temperature, after which a solution of 2-bromo-5- (bromomethyl) pyridine (35.3 mmol, 8.85 g, 1) was added dropwise. , 0 equiv.) In THF. The reaction was allowed to warm gently at room temperature overnight. The reaction was quenched with saturated ammonium chloride. The mixture was extracted with ethyl acetate and the organic extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a yellow oil. This crude product was purified on a Biotage Sp4 65i on a gradient of ethyl acetate of 5% to 95% in hexanes to yield a golden oil (8.70 g, 78%). LRMS: 315 (M + H) +. 1 H NMR (DMSO-d 6, 400 MHz); 8.21 (1H, s), 7.40-7.49 (2H, m), 3.94 (2H, c, J = 7.0 Hz), 3.71-3.85 (2H, m) , 3.05-3.11 (1 H, m), 2.91-2.97 (1H, m), 2.38-2.47 (1H, m), 1.83-2.09 (3H , m), 1.09 (3H, t, J = 7.0 Hz). Preparation c-82 Cyclopropanecarboxylic acid tert-butyl ester Concentrated sulfuric acid (3.45 ml, 62.7832 mmol) was added to a vigorously stirred suspension of anhydrous magnesium sulfate (30.1987 g, 251.1326 mmol) in dichloromethane (250 ml). The mixture was stirred for 15 minutes, after which time cyclopropanecarboxylic acid (5 ml, 62.7832 mmol) and 2-methyl-propan-2-ol (30 ml, 3.995 mmol) were added. The mixture was stopped firmly and stirred at room temperature for 16 hours. Then, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (450 ml) and stirred until all the magnesium sulfate had dissolved. The phases were separated and the organic phase was washed with water (100 ml) and saturated aqueous sodium chloride (100 ml), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to yield the pure ester (8, 3921 g, 59.0162 mmol) in the form of a colorless liquid. H NMR (CDCl 3, 300 MHz): 1.45 (9H, s), 0.93-0.86 (3H, m), 0.79-0.73 (2H, Preparation c-83 1- (6-r2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxyl-pyridin-3-ylmethyl-V-cyclopropanecarboxylic acid tert-butyl ester To a solution of diisopropylamine (0.14 ml, 0.9518 mmol) in dry tetrahydrofuran (2.4 ml) at 0 ° C in a nitrogen atmosphere was added butyllithium (0.38 ml of a 2.5 M solution). in hexanes, 0.9518 mmol). The resulting solution was stirred for 30 minutes and then cooled to -50 ° C. To this was added a solution of tert-butyl ester of cyclopropanecarboxylic acid (0.1269 g, 0.8924 mmol) in dry tetrahydrofuran (1 mL) and stirring was continued for 2 hours. Then a solution of 5-iodomethyl-2- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -pyridine (0.25 g, 0.5949 mmol) was added dropwise dry tetrahydrofuran (1 mL) and the solution was stirred for a further 3 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride (25 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic extracts were then dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to yield the crude product and the remaining starting iodide. The residue was purified by flash column chromatography (hexanes to 60% ethyl acetate / hexanes) to yield the ester (0.0827 g, 32%) partially contaminated with the starting iodide, as a pale yellow solid. LRMS (m / z): 435 (M + H) +. Preparation c-84 2- ( {6-f2- (5-methyl-2-phenyl-1,3-thiazole-4-ii) ethoxy-2-carboxylic acid ethyl ester To a solution purged with argon from bromopyridine (0.636 mmol) in toluene (12 mL) was added palladium (II) acetate (11.4 mg, 0.0508 mmol) and 2- (d, t-butylphosphino). -1, 1'-racemic hydrochloride (25.4 mg, 0.0636 mmol).
The activated complex was allowed to form for approximately ten minutes, at which time cesium carbonate (414 mg, 1.27 mmol) and the appropriate alcohol (0.956 mmol) were added. The mixture was heated to 115 ° C and stirred at this temperature for 12-18 hours. The mixture was cooled to room temperature and filtered through a layer of silica. The filter layer was washed with 2-3 aliquots of ethyl acetate and the organic filtrates were combined and concentrated in vacuo. The resulting residue was purified by flash chromatography or used without further purification. Preparations c-85 to c-88 Preparations c-85 to c-88 were prepared by procedures analogous to those used for Preparation c-84 Preparation c-89 5-fr erc-butyl (diphenylsinoxy) -2- (vodometinpyridine To a solution of 2-bromomethyl-5- (tert-butyl-diferyrylsilanyloxy) -pyridine (Schow, SR; Quinn DeJoy , S .; Wick, M.; Ker ar, SSJ Org. Chem, 1994, 59, 6850-6852) (1.2692 g, 2.9763 mmol) in acetone (15 ml) was added sodium iodide (0.8922 g, 5.9526 mmol) and the resulting heterogeneous mixture was stirred for 3 hours at room temperature, the reaction mixture was concentrated in vacuo and the resulting residue was diluted with ethyl acetate (50 ml) and washed with water (50 ml). The organic layer was further washed with saturated aqueous sodium bicarbonate (50 ml) and saturated aqueous sodium thiosulfate (50 ml) The combined aqueous layers were extracted with ethyl acetate (3 x 50 ml) and the combined organic extracts were dried (sulfate of anhydrous magnesium), filtered and concentrated in vacuo to give the crude product.The residue was purified by flash column chromatography. ida (hexanes to 20% ethyl acetate / hexanes) to yield a pale yellow oil (0.72 g, 51%). This compound was unstable at the time of its concentration, so it was used immediately. LRMS (m / z): 474 (M + H) +. Preparation c-90 Ethyl Tetrahydrofuran-2-carboxylate To a solution of tetrahydrofuran-2-carboxylic acid (20 g, 172.2356 mmol) in anhydrous ethanol (100 mL) was added concentrated sulfuric acid (0.46 mL). The resulting mixture was stirred at reflux for 16 hours and then allowed to cool to room temperature. To this was added water (100 ml) and extracted with diethyl ether (3 x 100 ml). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (2 x 50 ml) and saturated aqueous sodium chloride (100 ml), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to yield the pure product in the form of a colorless liquid (22.5964 g, 91%). LRMS (m / z): 145 (+ H) +. 1 H NMR (CDCl 3, 300 Hz) 4.38 (1 H, dd, J = 4.9, 8, 1 Hz), 4.14 (2 H, c, J = 7.2 Hz), 3.99-3 , 92 (1H, m), 3.88-3.81 (1H, m), 2.24-2, 12 (1H, m), 2.00-1, 79 (3H, m), 1, 22 (3H, t, J = 7.2 Hz). Preparation c-9 Tetrahydro-pyran-2-carboxylic acid ethyl ester The above compound was prepared according to the procedure described in Rychnovsky, S. D .; Hata, T .; Kim, A. I .; Buckmelter, A. J. Org. Lett 2001, 3, 807-810. Preparation c-92 2- (5-. {[[Tert-butyl (diphenyl-phenyl-oxy) > pyridin-2-yl) methyl-1-tetrahydrofuran-2-carboxylate ethyl To a solution of ethyl tetrahydrofuran-2-carboxylate (Preparation 32) (1.065 g, 7.604 mmol) in anhydrous tetrahydrofuran (7 ml) at -50 ° C, under a nitrogen atmosphere was added dropwise ( trimethylsilyl) sodium amide (7.6 ml of a 1.0 M solution in tetrahydrofuran, 7.604 mmol). The reaction mixture was stirred for 1 hour and then a solution of 5- (tert-butyl-diphenyl-silanyloxy) -2-iodomethyl-pyridine (Preparation 31) (0.72 g, 1.5208 mmol) was added dropwise. ) in anhydrous tetrahydrofuran (7 ml). The resulting solution was stirred at -50 ° C for 2 hours and then quenched with saturated aqueous ammonium chloride (25 ml). This was then extracted with ethyl acetate (3 X 25 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to yield the crude product. The residue was purified by flash column chromatography (hexanes to 40% ethyl acetate / hexanes) to yield a colorless oil (0.2438 g, 33%). LRMS (m / z): 490 (M + H) +. 1 H NMR (CDCl 3, 300 MHz) 8.07 (1H, d, J = 2.5 Hz), 7.67-7.63 (4H, m), 7.41-7.31 (6H, m), 6.97 (1H, d, J = 8.5 Hz), 6.86 (1H, dd, J = 2.8, 8.5 Hz), 4.21 (2H, c, J = 7.2 Hz ), 4.09 (2H, c, J = 7.2 Hz), 3.22 (1H, d, J = 13.9 Hz), 3.07 (1 H, d, J = 13.9 Hz) , 2.53-2.44 (1H, m), 2.31-2.15 (1H, m), 1.82-1, 72 (1H, m), 1.60-1.46 (1H, m), 1.25 (3H, t, J = 7.2 Hz), 1.09 (9H, s). Preparation c-93 2-r (ethyl 5-hydroxy-pyridine-2-imethetrahydrofuran-2-carboxylate) To a solution of ethyl 2 - [(5. {[[Ferc-butyl (diphenyl) silyl] oxy} pyridin-2-yl) methyl] tetrahydrofuran-2-carboxylate (Preparation c-92) ( 0, 18 g, 1.1677 mmol) in anhydrous tetrahydrofuran (10 ml) was added tetrabutylammonium fluoride (1.3 ml of a 1.0 M solution in tetrahydrofuran) dropwise. The resulting mixture was stirred at room temperature for 1 hour and the volatiles were removed in vacuo. The residue was purified by flash column chromatography (50% ethyl acetate / hexanes to 10% methanol / ethyl acetate) to yield a colorless oil (0.2321 g, 79%). LRMS (m / z): 252 (M + H) +. H NMR (CDCl 3, 300 MHz) 8.10 (1 H, d, j = 2.3 Hz), 7.20 (1 H, d, J = 8.5 Hz), 7.14 (1 H, dd, J = 2.6, 8.5 Hz), 4.14 (2H, c, J = 7.2 Hz), 3.88 (2H, c, J = 7.8 Hz), 3.35 (1H, d, J = 13.9 Hz), 3.12 (1H, d, J = 13.9 Hz), 2.30-2.21 (1H, m), 2.04-1.94 (1H, m), 1.89-1.76 (1H, m), 1.75-1.63 (1H, m), 1.20 (3H, t, J = 7.2 Hz). Preparation c-93a Alternative preparation of ethyl S-hydroxypyridine ^ -inmethyltetrahydrofuran ^ -carboxylate To a solution of 2- (5-benzyloxy-pyridin-2-ylmethyl) -tetrahydro-furan-2-carboxylic acid ethyl ester ( 0.6065 g, 1.7765 mmol) in dry ethanol (10 mL) was added palladium (0.0607 g, 10% by weight on activated carbon). The resulting solution was heated to 45 ° C in a hydrogen atmosphere for 16 hours. After cooling to room temperature, the solution was filtered through a 7.62 cm bed of Celite and washed with ethanol (100 ml). The filtrate was then concentrated in vacuo to yield the crude product which was used without further purification. LRMS (m / z): 252 (+ H) +. 1 H NMR (CDCl 3, 400 MHz): 8.10 (1 H, d, J = 2.3 Hz), 7.20 (1 H, d, J = 8.5 Hz), 7.14 (1 H, dd, J = 2.6, 8.5 Hz), 4.14 (2H, c, J = 7.2 Hz), 3.88 (2H, c, J = 7.8 Hz), 3.35 (1H, d, J = 13.9 Hz), 3.12 (1H, d, J = 13.9 Hz), 2.30-2.21 (1H, m), 2.04-1.94 (1H, m), 1.89-1, 76 (1H, m), 1.75-1.63 (1H, m), 1.20 (3H, t, J = 7.2 Hz). Preparations c-941 to c-95 Preparations c-94 to c-95 were prepared by the general procedure used for Preparation c-93 Preparation c-96 2- ( {5-r2- (5-ethyl-2-phenyl-1,3-oxazol-4-yl) ethoxy-1-pyridin-2-yl> rnetintetrahydrofuran-2-carboxylic acid ethyl ester To a solution of ethyl 2 - [(5-hydroxypyridin-2-yl) methyl] tetrahydrofuran-2-carboxylate (Preparation c-93) (0.2321 g, 0.9237 mmol), 2- ( 5-methyl-2-phenyl-oxazol-4-yl) -ethanol (0.2065 g, 1.0161 mmol) and triphenylphosphine (0.3634 g, 1.3856 mmol) in anhydrous tetrahydrofuran (10 mL) in an atmosphere of nitrogen was added dropwise a solution of diethyl azodicarboxylate (0.22 ml, 1.3856 mmol) in anhydrous tetrahydrofuran (1 ml). The resulting solution was stirred at room temperature for 16 hours and the volatiles were removed in vacuo. This residue was then purified by flash column chromatography (hexanes to 50% ethyl acetate / hexanes) to yield a pale yellow oil (0.2618 g, 65%). LRMS (m / z): 437 (M + H) +. 1 H NMR (CDCl 3, 300 MHz) 8.20 (1 H, d, J - 2.8 Hz), 7.99 (1 H, d, J = 2.5 Hz), 7.96 (1 H, d , J = 1, 7 Hz), 7.70-7.64 (1 H, m), 7.49-7.39 (2H, m), 7.19 (1 H, d, J = 8.5 Hz), 7, 11 (1 H, dd, J = 3.0, 8.5 Hz), 4.26 (2H, t, J = 6.6 Hz), 4.17 (2H, c, J = 7.2 Hz), 3.95-3.81 (2H, m), 3.33 (1 H, d, J = 13.8 Hz), 3.16 (1 H, d, J = 13.8 Hz), 2.98 (2H, t, J = 6.6 Hz), 2.37 (3H, s), 2.34-2.22 (1H, m), 2.09-2.00 (1 H, m), 1.87-1.76 (1 H, m), 1.72-1.62 (1 H, m), 1.23 (3H, t, J = 7.2 Hz). Preparations c-97 a c-12 Preparations c-97 to c-112 were prepared by the general procedure used for Preparation c-96 Prep No. Structure? NMR MS (m / z) (BR 0 AR) c-97 (CDCl 3, 300 MHz) 8.19 (1H, d, J = 2.8 Hz), for 7.97-7.93 (1H, m) , 7.42-7.39 (3H, m), 7.18 (1H, BR d, J = 8.5 Hz), 7.10 (1H, dd, J = 8.5, 2.8 Hz) , 451 4.16 (2H, c, J = 7.2 Hz), 3.98 (2H, t, J = 6.0 (M + H) + Hz), 3.92-3.82 (2H, m), 3.33 (1H, d, J = 13.8 Hz), 3.14 (H, d, J = 13.9 Hz), 2.67 (2H, t, J = 6.0 Hz) , 2.26 (3H, s), 2.19-2.10 (2H, m), 1.91-1.63 (4H, m), 1.22 (3H, t, J = 7.2 Hz ). c-98 (CDCl 3, 400 MHz) 8.20 (1H, dd, J = 2.0, 1.5 for Hz), 7.95 (2H, dd, J = 7.7, 1.9 Hz), 7.43-7.36 BR (3H, m), 7.10 (2H, d, J = 1.5 Hz), 4.25 (2H, t, J 425 = 6.6 Hz), 4.23 -4.13 (3H, m), 3.63-3.55 (1H, (M + H) + m), 3.37-3.27 (1H, m), 3.15-3.02 (2H, m), 2.97 (2H, t, J = 6.7 Hz), 2.35 (3H, s), 1.21 (3H, t, J = 7.2 Hz), 1.08 (3H, t, J = 7.1 Hz) c-99 0 (CDCl3, 400 MHz) 8.19 (1 H, dd, J = 2.0, 1.5 for Hz), 7.08-7, 07 (2H, m), 4.26-4.23 (3H, m), 4.16 BR (2H, c, J = 7.0 Hz), 3.63-3.56 (1H, m), 3.36- 379 3.28 (1 H, m), 3.15-3.02 (4H, m), 2.58 (3H, s), (+ H) + 2.34 (3H, s) , 1.21 (3H, t, J = 7.1 Hz), 1.08 (3H, t, J = 7.0 Hz) c-100? (CDCI3, 400 Hz) 8.22 (1H, dd, J = 2.4, 1.1 for Hz), 7.86-7.83 (2H, m), 7.42-7.36 (3H, m), BR 7,11-7,10 (2H, m), 4.35 (2H, t, J = 6.8 Hz), 441 4.24 (1H, dd, J = 8.3, 5, 1 Hz), 4.18 (2H, c, J = (M + H) + 7.1 Hz), 3.63-3.56 (1H, m), 3.36-3.28 (1H, m ), 3.18 (2H, t, J = 6.8 Hz), 3.14 (1 H, dd, J = 13.9, 5.1 Hz), 3.05 (1H, dd, J = 13 , 9, 8.3 Hz), 2.45 (3H, s), 1.22 (3H, t, J = 7.1 Hz), 1.09 (3H, t, J = 7.1 Hz) c -101 (CDCI3, 400 MHz) 8.22 (1H, dd, J = 2.0, 1.5 for or Hz), 7.97-7.93 (2H, m), 7.43-7.37 (3H, m), BR 7,11-7,10 (2H, m), 4.25 (1H, dd, J = 8.6, 5.1 439 Hz), 4.18 (2H, C, J = 7.2 Hz), 3.99 (2H, t, J = (M + H) + 6.2 Hz), 3.64-3.56 (1H, m), 3.37-3.29 ( 1H, m), 3.14 (1H, dd, J = 13.9, 5.1 Hz), 3.06 (H, dd, J = 13.9, 8.6 Hz), 2.68 (2H) , t, J = 7.1 Hz), 2.26 (3H, s), 2.18-2.12 (2H, m), 1.22 (3H, t, J = 7.1 Hz), 1 , 09 (3H, t, J = 7.0 Hz) c-102 (CDCl3, 400 MHz) 8.18 (1H, dd, J = 2.3, 1.3 for Hz), 7.96 (2H, dd, J = 7.6, 2.0 Hz), 7.54-7.51 BR (3H, m), 7.10-7.08 (2H, m), 4.25 (2H, t, J = 6.7-411 Hz), 3.29 (3H, s), 3.15 (2H, s), 2.96 (2H, t, J = (+ H) + 6.7 Hz), 2.36 (3H, s), 2.32 (3H, s), 1.38 (3H, s) c-103 0 (CDCl3, 400 MHz) 8.20 (1H, t, J = 7.8 Hz ), for 7.97-7.93 (2H, m), 7.44-7.38 (3H, m), 7.09 (2H, BR d, J = 7.8 Hz), 3.99 ( 2H, t, J = 6.1 Hz), 3.72 425 (4H, m), 7.12-7.08 (2H, m), 4.35 (2H, t, J = 6.8 486 Hz ), 4.16-4.09 (2H, m), 3.96-3.85 (2H, m), 3.32 (+ H) + (1H, d, J = 13.6 Hz), 3.11 (1H, d, J = 13.9 Hz), 3.04 (2H, t, J = 6.8 Hz), 2.40 (3H, s), 2.31-2.24 ( 1H, m), 1, 99-1, 76 (1H, m), 1, 69-1, 60 (1H, m), 1.18 (3H, = 7.1 Hz) C-112 (CDCl3, 400 MHz) 7.99-7.97 (2H, m), 7.67 (1H, for d, J = 8.8 Hz), 7.61-7.59 (2H, m), 7.45-7 , 35 BR (4H, m), 7.12 (1 H, dd, J = 2.3, 8.8 Hz), 7.08-500.07 (1H, d, J = 2.3 Hz) , 4.16-4.06 (4H, m), (M + H) + 3.96-3.86 (2H, m), 3.33 (1H, d, J = 13.6 Hz), 3 , 11 (1H, d, J = 13.6 Hz), 2.74 (2H, t, J = 7.1 Hz), 2.32-2.18 (6H, m), 1.99-1, 91 (1H, m), 1, 86-1, 77 (1H, m), 1.69-1.61 (1H, m), 1.19 (3H, t, J = 7.1 Hz) Preparation c-113 3- (5-Methyl-2-phenyl-oxazol-4-yl> propionaldehyde To a solution of 3- (5-methyl-2-phenyl-oxazol-4-yl) -propan-1-ol (1.0 g, 4.6026 mmol) in dichloromethane (20 mL) was added pyridinium chlorochromate (9.9213 g ~ 20% by weight on SiO2, 9.2051 mmol). The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 16 hours and the volatiles were removed under reduced pressure. The residue was purified by flash column chromatography (hexanes to ethyl acetate) to give the pure aldehyde (0.4752 g, 48%) as a colorless oil. LRMS (m / z): 216 (M + H) +. 1 H NMR (CDCl 3> 300 MHz): 9.84 (1H, s), 7.96-7.93 (2H, m), 7.42-7.37 (3H, m), 2.85 (2H , dd, J = 6.0, 9.0 Hz), 2.80 (2H, d, J = 6.0 Hz), 2.33 (3H, s). Preparation c-114 4-But-3-enyl-5-methyl-2-phenyl-oxazole To a solution of methyl triphenylphosphonium iodide (1.7848 g, 4.41543 mmol) in dry tetrahydrofuran (95 ml) under a nitrogen atmosphere at 0 ° C, butyllithium (1.8 ml of a solution) was added dropwise. 2.5 M in hexanes, 4.4154 mmol). The suspension dissolved and the solution turned orange. After 10 minutes, a solution of 3- (5-methyl-2-phenyl-oxazol-4-yl) -propionaldehyde (0.4752 g, 2.2077 mmol) in dry tetrahydrofuran (15 ml) was added dropwise. and the solution was allowed to warm to room temperature. After 16 hours, hexanes (200 ml) were added and the precipitate was removed by filtration. The filtrate was then extracted with water (200 ml) and the organic phase was dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to yield the crude product. The residue was purified by flash column chromatography (hexanes to ethyl acetate) to give the pure title compound (0.291 g, 62%) as a colorless oil. LRMS (m / z): 214 (M + H) +. 1 H NMR (CDCl 3, 300 MHz): 7.99-7.96 (2H, m), 7.43-7.38 (3H, m), 5.93-5.79 (1H, m), 5, 09-5.02 (H, m), 5.00-4.95 (1H, m), 2.57 (2H, t, J = 7.4 Hz), 2.42 (2H, t, J = 7.4 Hz), 2.31 (3H, s). Preparation c-115 2- Acid ethyl ester. { 6- [4- (5-Methyl-2-phenyl-oxazol-4-yl) -butyn-pyridin-3-ylmethyl-tetrahydro-furan-2-carboxylic acid 9-borabicyclononane (5.5 ml of a 0.5 solution) M in tetrahydrofuran, 2.729 mmol) was added to a yellow solution of 4-but-3-enyl-5-methyl-2-phenyl-oxazole (0.291 g, 1.3645 mmol) in dry tetrahydrofuran (1.3 ml). The mixture was stirred at room temperature for 4 hours and then transferred to another flask containing 2- (6-bromo-pyridin-3-ylmethyl) -tetrahydrofuran-2-carboxylic acid ethyl ester (0.3297 g, 1.0496 mmol), palladium dichloride bis (diphenylphosphino) ferrocene (0.0857 g, 0.1050 mmoi), cesium carbonate (0.9551 g, 2.9389 mmol), triphenylarsine (0.0322 g, 0.1050 mmol) in A / / V-dimethylformamide (2.8 ml) and water (0.23 ml). The dark red mixture was stirred for 16 hours at room temperature under a nitrogen atmosphere. After cooling to 0 ° C, the reaction was quenched with 2M aqueous sodium acetate (5 ml) and 30% aqueous hydrogen peroxide (2 ml). The resulting solution was stirred for 2 hours, diluted with water (25 ml) and extracted with ethyl acetate (4 x 50 ml). The combined organic extracts were washed with water (25 ml), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to give the crude product. The residue was purified by flash column chromatography (hexanes to ethyl acetate) to give the title compound (0.2805 g, 60%) as a pale yellow oil. LRMS (m / z): 449 (M + H) +. H NMR (CDCl 3, 300 MHz): 8.34 (1H, d, J = 1.9 Hz), 7.95 (2H, dd, J = 7.7, 1.9 Hz), 7.52 (1H , dd, J = 8.0, 2.2 Hz), 7.42-7.36 (3H, m), 7.04 (1H, d, J = 7.9 Hz), 4.13 (2H, c, J = 7.2 Hz), 3.96-3.84 (2H, m), 3.16 (1H, d, J = 13.9 Hz), 2.90 (1H, d, J = 13.9 Hz), 2.77 (2H, t, J = 7.3 Hz), 2.50 (2H, t, J 6.9 Hz), 2.31-2.19 (1H, m), 2.28 (3H, s), 1.92-1, 64 (7H, m), 1.20 (3H, t, J = 7, 2 Hz). Preparation c-116 2-f6-f3- (5-methyl-2-phenyl-oxazol-4-in-propyn-pyridin-3-ylmethyl) -tetrahydrofuran-2-carboxylic acid ethyl ester 9-Borabicyclononane (4.2 ml of a 0.5 solution in tetrahydrofuran, 2.07 mmol) was added to a yellow solution of 4-allyl-5-methyl-2-phenyl-oxazole (0.21g, 1%). , 04 mmol) in dry tetrahydrofuran (1 ml). The mixture was stirred at room temperature for 4 hours and then transferred to another flask containing 2- (6-bromo-pyridin-3-ylmethyl) -tetrahydro-furan-2-carboxylic acid ethyl ester (0.25 g, 0.80 mmol), palladium dichloride bis (diphenylphosphino) ferrocene (0.07 g, 0.1 mmol), cesium carbonate (0.72 g, 2.90 mmol), triphenylarsine (0.02 g, 0, 1 mmol) in / V, / V-dimethylformamide: water (4: 1, 2.63 ml). The dark red mixture was stirred for 16 hours at room temperature under a nitrogen atmosphere. After cooling to 0 ° C, the reaction was quenched with 2M aqueous sodium acetate (4.7 ml) and 30% aqueous hydrogen peroxide (1.7 ml). The resulting solution was stirred for 2 hours, diluted with water (20 mL) and extracted with ethyl acetate (4 x 50 mL). The combined organic extracts were washed with water (20 ml), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to give the crude product. The residue was purified by flash column chromatography (40% -90% ethyl acetate / hexanes) to give the title compound (0.20 g, 57%) as a colorless oil.
LRMS (m / z): 435 (M + H) +. 1 H NMR (dimethylformamide-d6, 400 MHz): 8.35 (1H, s), 7.96 (2H, d, J = 7.9 Hz), 7.55 (1H, d, J = 8.3 Hz), 7.39 (3H, t, J = 5.9 Hz), 7.09 (1H, d, J = 8.1 Hz), 3.91 (2H, m), 3.80 (2H, t, J = 10.9 Hz), 3.17 (1H, d, J = 14.0 Hz), 2.91 (1 H, d, J = 13.94 Hz), 2.81 ( 2H, t), 2.53 (2H, t, J = 7.3 Hz), 2.28 (3H, s), 2.09 (2H, d, J = 7.5 Hz), 1.87 ( 4H, d, J = 10.9 Hz), 1.23 (3H, m). Preparation c- 7 1- (4-rfia-3- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethyl Drop-1-en-1-illphenoxycyclobutanecarboxylate A mixture of Pd (OAc) 2 (12 mg, 0.05 mmol) and Ph3P (26 mg, 0.05 mmol) in toluene (2 mL) was stirred under a nitrogen atmosphere at room temperature for 1 hour and continued by the addition of Et ^ N (2 ml) and a solution of 4-allyl-5-methyl-2-phenyl-1,3-oxazole (100 mg, 0.50 mmol) and 1- (4-iodophene) cyclobutanecarboxylate of ethyl (173 mg, 0.50 mmol) in toluene (2 mL). The resulting reaction solution was heated to 80 ° C under a nitrogen atmosphere for 17 hours and cooled to room temperature. After removal of the solvent, the residue was partitioned between EtOAc and brine. The separated organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to give the crude product as a brown oil. Purification by column chromatography on silica gel with 20% EtOAc in hexane gave 85 mg (41%) of a yellow oil. H NMR (400 MHz, CDCl 3) 1.19 (t, 3 H), 1.98 (m, 2 H), 2.38 (s, 3 H), 2.43 (m, 2 H), 2.72 (m, 2H), 3.41 (d, 2H), 4.18 (c, 2H), 6.20 (td, 1 H), 6.40 (d, 1 H), 6.60 (d, 2H), 7.25 (d, 2H), 7.40 (d, 3H), 8.00 (d, 2H). LRMS (m / z): 418 (M + H) +.
Preparation c-118 1-. { Ethyl 4- [3- (5-Methyl-2-phenyl-1, 3-oxazol-4-yl) propynephenoxy) cyclobutanecarboxylate It was dissolved 1-. { 4 - [(1 - =) - 3- (5-methyl-2-phenyl-1,3-oxazol-4-yl) prop-1-en-1-yl] phenoxy} ethyl cyclobutanecarboxylate (85 mg, 0.20 mmol) in MeOH (5 mL) and continued by the addition of 10% Pd / C (5 mg). The mixture was stirred at room temperature for 16 hours with a balloon, filled with hydrogen gas, attached to the flask. The mixture was filtered through a pad of Celite and the cake was rinsed with MeOH. The filtrate was concentrated to give 85 mg (100%) of a yellow oil. 1 H NMR (400 MHz, CDCl 3): 1.19 (t, 3 H), 1, 92-2.02 (m, 4 H), 2.27 (s, 3 H), 2.39-2.51 (m, 4H), 2.60 (t, 2H), 2.66-2.77 (m, 2H), 4.19 (c, 2H), 6.60 (d, 2H), 7.05 (d, 2H) ), 7.36-7.47 (m, 3H), 7.98 (dd, 2H). E BR (m / z): 420 (M + H) +. Preparation c-119 5-Bromo-pyrazin-2-ilamine To a solution of pyrazin-2-ylamine (2.0 g, 21.03 mmol) in dry dichloromethane (120 ml) at 0 ° C was added / V-bromosuccinimide (3.74 g, 21.03 mmol) slowly to keep the internal temperature below 0 ° C. The mixture was stirred at the same temperature for 24 hours and then washed with saturated aqueous sodium bicarbonate (30 ml) and water (30 ml). The combined aqueous extracts were extracted with dichloromethane (3 x 100 mL). The combined organic extracts were dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to produce the crude product. The residue was purified by flash column chromatography (10% to 50% ethyl acetate / hexanes) to give the title compound (2.57 g, 70%) as a yellow solid. LRMS (m / z): 174 (M) ~. 1 NMR (CDCIs, 300 MHz): 8.08 (1 H, d, J = 1.3 Hz), 7.76 (1 H, d, J = 1.3 Hz). Preparation c-120 5-Bromo-pyrazin-2-ol Sodium nitrite (1.35 g, 19.53 mmol) was added portionwise to concentrated sulfuric acid (9.8 ml) at 0 ° C. The mixture was heated to 50 ° C until all the sodium nitrite had dissolved and the mixture was cooled again to 0 ° C. A solution of 5-bromo-pyrazin-2-ylamine (2.57 g, 14.68 mmol) in concentrated sulfuric acid (14.7 ml) was added dropwise to the nitronium solution at 0 ° C. The ice bath was removed, the mixture was warmed to room temperature and stirred for 15 minutes before heating at 45 ° C for seven minutes. After cooling to room temperature, the mixture was slowly poured cautiously into water cooled with crushed ice (100 ml). The aqueous phase was neutralized to pH 4 with 20% aqueous sodium hydroxide and then extracted with ethyl acetate (3 x 00 mL). The combined organic extracts were washed with water (50 ml), dried (anhydrous magnesium sulfate), filtered and evaporated to yield the title compound (1.88 g, 73%) as a yellow solid. 1 H NMR (CDCl 3, 300 MHz): 8.07 (1 H, s), 7.62 (H, d, J = 3.0 Hz). Preparation c-121 2- (tert-Butyl-dimethyl-silanyloxymethyl) -5-f2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy-lycopene To a solution of 2-bromo-5- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -pirazine (0.50 g, 1.39 mmol) and urea-butyl dimethyl-tributylstannylmethoxy-silane (0.91 g, 2.09 mmol) in dry 1,4-dioxane (8 mL) was added tetrakistriphenylphosphine (O) palladium (0.16 g, 0.14 mmol). it was degassed three times and then heated at 120 ° C for 22 hours. After cooling to room temperature, the mixture was diluted with diethyl ether (10 ml) and then quenched with saturated aqueous potassium fluoride (50 ml). The resulting mixture was stirred for 30 minutes and then extracted with ethyl acetate (3 x 50 mL). The organic phase was washed with water (30 ml), dried (anhydrous magnesium sulfate), filtered and evaporated to yield the title compound without further purification.
LRMS (m / z): 426 (+ H) +. 1 H NMR (CDCl 3, 300 MHz): 8.20 (1H, s), 8.09 (1H, s), 7.97 (2H, d, J = 7.4 Hz), 7.41 (3H, d) , J = 5.3 Hz), 4.78 (2H, s), 4.58 (2H, d, J = 6.6 Hz), 2.98 (2H, s), 2.34 (3H, s) ), 0.97 (2H, m), 0.14 (6H, m). Preparation c-122. { 5-f2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxyl-pyrazin-2-yl) -methanol Tetrabutylammonium fluoride (2.8 ml of a 1 M solution in tetrahydrofuran, 2.78 mmol) was added dropwise to a solution of 2- (tert-butyl-dimethyl-silanyloxymethyl) -5- [2- (5- methyl-2-phenyl-oxazol-4-yl) -ethoxy] -p -razine (-1.39 mmol) in dry tetrahydrofuran (20 mL). The mixture was stirred at room temperature for 16 hours and then quenched with water (1 ml) and acidified to pH 5 with a 1 M aqueous solution of acetic acid. The organic extracts were removed in vacuo and the aqueous phase was extracted with dichloromethane (3 x 50 ml). The combined organic extracts were dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to yield the title compound (0.0928 g, 21%). E BR (m / z): 312 (+ H) +. H NMR (CDCl 3, 300 MHz): 8.12 (2H, s), 8.05 (2H, d, J = 6.0 Hz), 7.40 (3H, d, J = 6.0 Hz), 4.72 (2H, s), 4.59 (2H, t, J = 6.0 Hz), 2.99 (2H, t, J = 6.0 Hz), 2.33 (3H, s). Preparation c-123 6-Benzyloxy-naphthalene-2-carboxylic acid benzyl ester The above compound was prepared according to the procedure described in Inui, S .; Suzuki, T .; Limura, N .; Iwane, H .; Nohira, H. Mol. Cryst. Liq. Cryst. Sci. Technol. Sect. A. 1994, 239, 1-10. Preparation c-124 (6-Benzyloxy-naphthalen-2-yl) -methanol To a solution of 6-benzyloxy-naphthalene-2-carboxylic acid benzyl ester (7.09 g, 19.24 mmol) in dry tetrahydrofuran (60 ml) under a nitrogen atmosphere at 0 ° C was added diisobutylaluminum hydride. (58 ml of a 1.0 M solution in tetrahydrofuran, 57.73 mmol). The resulting mixture was allowed to warm to room temperature and was stirred for 16 hours. A solution of citric acid (19 g) in water (40 ml) was added dropwise (CAUTION: Very exothermic). The aqueous layer was then extracted with ethyl acetate (3 x 50 mL) and the combined organic extracts were washed with saturated aqueous sodium chloride (50 mL)., dried (anhydrous magnesium sulfate) and concentrated in vacuo to yield the crude product. The residue was purified by flash column chromatography (hexanes to ethyl acetate) to give the title compound (4.37 g, 86%) as a white solid. LRMS (m / z): 287 (+ Na) +. 1 H NMR (CDCl 3, 400 MHz): 7.76-7.72 (3H, m), 7.50-7.33 (6H, m), 7.25-7.23 (2H, m), 5, 18 (2H, s), 4.82 (2H, d, J = 6.1 Hz). Preparation c- 25 Ethyl 2-f6- (5-methyl-2-phenyl-oxazol-4-ylmethoxy) -naphthalen-2-ylmethyl-tetrahydro-furan-2-carboxylic acid ethyl ester Heterogeneous mixture of 2-phenyl-4- (chloromethyl) -5-methyloxazole (0.133 g, 0.639 mmol), 2- (6-hydroxy-naphthalen-2-ylmethyl) -tetrahydro-furan-2-carboxylic acid ethyl ester ( 0.192 g, 0.639 mmol) and cesium carbonate (0.521 g, 1.59 mmol) in dry acetonitrile (2 mL) was heated (in a microwave) at 140 ° C for 10 minutes. A second portion of 2-phenyl-4- (chloromethyl) -5-methyloxazole (0.5 equiv.) Was added and the mixture was heated at 200 ° C for a further 20 minutes. The reaction mixture was filtered through Celite and washed with acetonitrile (200 ml). The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (hexanes to ethyl acetate) to give the title compound (0.180 g, 60%) as a colorless oil.
Preparation c-126 (4S -4-Benzyl-3- (tetrahydrofuran-2-ylcarbonyl) -1, 3-oxazolidin-2-one N-Butyllithium (22.6 ml of a 2.5M solution in hexanes, 56.4 mmol) was added dropwise to a solution of (4S) -4-benzyl-1,3-oxazolidin-2-one ( 10.0 g, 56.4 mmol) in tetrahydrofuran (200 ml) at -78 ° C. The mixture was stirred for 30 minutes and then a solution of tetrahydrofuran-2-carbonyl chloride (9.12 g, 67.7 mmol) in tetrahydrofuran (25 mL) was added. The mixture was stirred at -78 ° C for 30 minutes, heated at 0 ° C for 1 hour and quenched with a saturated solution of ammonium chloride. The mixture was extracted with ethyl acetate and the organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (1: 3 and then 1: 2 ethyl acetate: hexanes) to yield the title compound as a mixture of about 1: 1 diastereoisomers as a colorless oil (15.0) g, 97%). Preparation c-127 (4S) -4-Benzyl-3- (r2- (. {6-f2- (5-methyl-2-phenyl-1,3-oxazol-4-inetoxy-1-pyridin-3-yl-methyl) ) tetrahydrofuran-2-yl] carbonyl] -1,3-oxazolidin-2-one Sodium (bis) trimethylsilyl amide (3.57 ml of a solution 1 in tetrahydrofuran, 3.57 mmol) was added dropwise to a solution of (4S) -4-benzyl-3- (tetrahydrofuran-2-ylcarbonyl) - 1,3-oxazolidin-2-one (0.983 g, 3.57 mmol) in anhydrous tetrahydrofuran (6 mL) at -50 ° C. The mixture was stirred for 45 minutes and then a solution of 5- (iodomethyl) -2- [2- (5-methyl-2-phenyl-, 3-oxazol-4-yl) ethoxy] pyridine was added dropwise ( Preparation 28) (0.500 g, 1.19 mmol) in anhydrous tetrahydrofuran (6 mL). The resulting mixture was stirred at -50 ° C for 1.5 hours, then quenched with saturated aqueous ammonium chloride and warmed to room temperature. The mixture was extracted with ethyl acetate and the organic phase was dried (anhydrous magnesium sulfate), filtered and evaporated. The residue was purified by flash column chromatography (1: 1 ethyl acetate: hexanes) to yield the title compound as a single diastereomer as a colorless oil (0.617 g, 90%). LRMS (m / z): 568 (+ H) +. H NMR (CDCl 3, 300 MHz) 8.01 (1 H, s), 7.96 (2 H, m), 7.61 (1 H, dd, J = 2.5, 8.5 Hz), 7.40 (3H, m), 7.28 (3H, m), 7.17 (H, m), 6.64 (1H, d, J = 8.6 Hz), 4.55 (3H, m), 4 , 18 (2H, m), 3.90 (1H, m), 3.79 (1 H, m), 3.27 (1 H, d, J = 14 Hz), 3.20 (1H, m) , 3.13 (1H, d, J = 14 Hz), 2.96 (2H, t, J = 6.8 Hz), 2.79 (1H, m), 2.32 (3H, s), 2 , 34 (3H, m), 2.11 (1 H, m), 1.73 (1H, m), 1.54 (1H, m). Preparation c-128 Tetrahydrofuran-2-carboxylic acid amide To a solution of tetrahydrofuran-2-carboxylic acid (2.42 g, 20.82 mmol) in anhydrous tetrahydrofuran (120 mL) under a nitrogen atmosphere at 0 ° C was added triethylamine (8.5 mL, 61%). , 23 mmol) and ethyl chloroformate (2.4 ml, 25.10 mmol). A white precipitate formed after the addition of ethyl chloroformate and the resulting mixture was stirred for 45 minutes at 0 ° C. Ammonia gas was bubbled into the solution for 2 hours and the gas source was removed. The reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. The solution was adjusted to pH 1 by the addition of 1N hydrochloric acid and then extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to give the crude product. The residue was purified by flash column chromatography (hexanes to 10% ethyl acetate / hexanes) to give the title compound (0.97 g, 41%) as a white solid. LRMS (m / z): 116 (+ H) +. 1 H NMR (CDCl 3, 300 MHz): 4.35 (1 H, dd, J = 8.5, 5.8 Hz), 3.92 (2H, m), 2.18 (2H, m), 1, 90 (2H, m). Preparation c- 29 Tetrahydro-furan-2-carbonitrile Trifluoroacetic anhydride (1.55 g, 7.38 mmol) was added slowly, at a rate of one drop every 120 seconds, to an ice-cold (0 ° C) solution of tetrahydrofuran-2-carboxylic acid amide ( 0.77 g, 6.71 mmol) and pyridine (1.06 g, 13.42 mmol) in anhydrous 1,4-dioxane (10 mL). The addition of trifluoroacetic anhydride was controlled to maintain the internal temperature below 5 ° C and was completed after 20 minutes. The resulting mixture was allowed to warm to room temperature and was stirred for 3 hours. Chloroform (100 ml) was added to the mixture and then extracted with water (30 ml) and saturated aqueous sodium chloride (20 ml). The organic extracts were dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to give the crude product. The residue was purified by flash column chromatography (hexanes to 25% ethyl acetate / hexanes) to give the title compound (0.51 g, 62%) as a colorless oil. H NMR (CDCl 3, 300 MHz): 4.70 (1H, m), 3.96 (2H, m), 2.24 (2H, m), 2.08 (2H, m). Preparation c-130 2-f6-r2- (5-Methyl-2-phenyl-oxazol-4-yl) -ethoxy-pyridin-3-ylmethyl > -tetrahydro-furan-2-carbonitrile Sod (bistrimethylsilyl) amide (1.8 mL, 1.79 mmol) was added to a solution of tetrahydro-furan-2-carbonitrile (0.17 g, 1.79 mmol) in anhydrous tetrahydrofuran (6 mL) in a nitrogen atmosphere at -78 ° C. The resulting yellow solution was stirred for 50 minutes and then a solution of 5-iodomethyl-2- [2- (5-methy-2-phenyl-oxazol-4-yl) -ethoxy] -pyr was added to the enolate solution. Dna (0.25 g, 0.596 mmol) in anhydrous tetrahydrofuran (3 mL). The mixture was stirred at -78 ° C for 1.5 hours and quenched with saturated aqueous ammonium chloride (5 ml). The aqueous phase was extracted with ethyl acetate (3 x 50 mL) and the combined organic extracts were washed with water (30 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to give the crude product. . The residue was purified by flash column chromatography (7% to 45% ethyl acetate / hexanes) to give the title compound (0.11 g, 46%) as a white solid. LRMS (m / z): 390 (M + H) +. 1 H NMR (CDCl 3, 300 MHz): 8.03 (1H, d, J = 2.5 Hz), 7.96 (2H, m), 7.56 (1H, dd, J = 8.5, 2, 5 Hz), 7.40 (3H, m), 6.68 (H, d, J = 8.5 Hz), 4.54 (2H, m), 3.96 (2H, m), 3.00 (4H, m), 2.33 (5H, d, J = 3.2 Hz), 1.92 (2H, m). Example D-1 2-Ethoxy-3- Acid. { 6-f2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxylpyridin-3-di-propane Lithium hydroxide monohydrate (80 mg, 4.31 mmol) was added to a solution of 2-ethoxy-3-. { Ethyl 6- [2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] pyridin-3-yl-propaproate (183 mg, 0.431 mmol) in a mixture of tetrahydrofuran: methanol: water (1: 1: 1, 6 mi). The mixture was stirred for 18 hours and then the volatile components were removed by evaporation. The aqueous phase was acidified with 3 M hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified twice by flash column chromatography (98: 2 dichloromethane: methanol) to yield the title compound as a colorless glass (31 mg). LRMS (m / z): 396 () +. 1 H NMR (CDCIs, 300 MHz) 7.99 (3H, m), 7.50 (1H, m), 7.40 (3H, m), 6.65 (1 H, m), 4.50 (2H , t, J = 7 Hz), 4.01 (1 H, m), 3.64 (1 H, m), 3.42 (H, m), 2.98 (4 H, m), 2.34 ( 3H, s), 1, 16 (3H, t, J = 7 Hz). Examples D-2 to D-45 Examples D-2 to D-45 were prepared by procedures analogous to those used for Example D-1 by stirring a solution of the ester with sodium or lithium hydroxide in aqueous methanol, aqueous ethanol. , aqueous tetrahydrofuran or mixtures thereof at temperatures between 20 ° C and 75 ° C.
Ex. N4 Structure? NMR EM (m z) Analysis BR AR D-2? MN (DMSO-dB, 400 MHz): 8.05 for B 408 (2H, d, J = 8.6 Hz), 7.86-7.94 (3H, (M + H) *? M), 7 , 55 (1H, dd, J = 8.3 and 2.3 Hz), 6.70 (1H, d, J = 8.3 Hz), 4.45 (2H, t, J = 6.6 Hz), 3.89 (1H, dd, J = 7.6 and 5.1 Hz), 3.22 (3H, s), 2.95-2.87 (3H, m), 2.80 (1H, dd, J = 14.2 and 7.8 Hz), 2.35 (3H, s) D-3? NMR (DMSO-ds, 400 MHz): 7.96 Calculated Calculated for (1H, d, J = 2.3 Hz), 7.73 (1H, s), 7.69 for 5H20 (1H, d, J = 7.8 Hz), 7.55 (1H, dd, J = C22H25N2O5 C 65.17 H 6.22 N 8.6 and 2.3 Hz), 7.37 (H, t, J = 7, 8 397. 1758. 6.91 Found: C Hz), 7.28 (1H, d, J = 7.1 Hz), 6.70 Found: 65.03 H 6.10 N 7.07 (1H, d , 8.3 Hz), 4.44 (2H, t, J = 6.8 397.1775 Hz), 3.89 (1H, dd, J = 8.1 and 4.8 Hz), 3.22 ( 3H, s), 2.92-2.88 (3H, m), 2.80 (1H, d, J = 14.7 and 8.1 Hz), 2.36 (3H, s), 2.31 (3H, s) D-4? NMR (DMSO-ds, 400 MHz): 7.98 Calculated (1H, d, J = 1.8 Hz), 7.92 (2H, d, J = for 8.6 Hz), 7.58-7, 55 (3H, m), 6.72 (1H, C ^ H ^ CI ^ Os d, J = 8.6 Hz), 4.46 (2H, t, J = 6.6 417.1212.Hz), 3.91 (1H, dd, J = 7.8 and 4.6 Hz), Found: 3.24 (3H, s), 2.94-2.89 (3H, m), 2.82 417.1232 (1H, dd, J = 14.4 and 7.6 Hz), 2.33 (3H, 0-5? R N (DMSO-ds, 400 MHz): 12.71 Calculated for (1H, s), 7.96 (1H, d, J = 2.3 Hz), 7.90 G H. 1H20 ^ i (2H, dd, J = 7.6 and 2.0 Hz), 7.55 (1H, C 65.65 H 5.82 N dd, J = 8.6 and 2.3 Hz), 7 , 51-7.46 (3H, 7.29, Found: C m), 6.71 (1H, d, J = 8.6 Hz), 4.44 65.45 H, 5.92 N (2H, t , J = 6.6 Hz), 3.89 (1H, dd, J = 7.26, 7.6 and 5.1 Hz), 3.22 (3H, s), 2.92-2.88 ( 3H, m), 2.80 (1H, dd, J = 14.2 and 7.6 Hz), 2.32 (3H, s). D-6? NMR (DMSO-d6, 400 MHz): 12.81 Calculated for (1H, s), 7.96 (1H, d, J = 2.0 Hz), 7.90 C2iH22NzO50. 25H20 (2H, dd, J = 7.7 and 1.9 Hz), 7.55 (1H, C 65.19 H 5.86 N dd, J - 8.6 and 2.3 Hz), 7.51 -7.46 (3H, 7.24. Found: C m), 6.70 (1H, d, J = 8.6 Hz), 4.44 65.19 H 5.80 N 7.03 (2H, t, J = 6.8 Hz), 3.88 (1H, dd, J = 7.6 and 4.8 Hz), 3.22 (3H, s), 2.92-2.87 (3H, m ), 2.80 (1H, dd, J = 14.2 and 7.8 Hz), 2.32 (3H, s). D-7? NMR (DMSO-dg, 400 MHz): 12.54 Calculated (1H, s), 7.96 (1H, d, J = 2.0 Hz), 7.83 for (2H, d, J = 9.1 Hz), 7.55 (1H, dd, J = Cz> H 206 8.6 and 2.3 Hz), 7.03 (2H, d, J = 8.8 413.1707. Hz), 6, 70 (1H, d, J = 8.6 Hz), 4.43 Found: (2H, t, J = 6.8 Hz), 3.90 (1H, dd, J 413.1717 = 7.8 and 4 , 8 Hz), 3.80 (3H, s), 3.22 (3H, s), 2.92-2.86 (3H, m), 2.80 (1H, dd, J = 14.7 and 7.6 Hz), 2.29 (3H, s). D-8? NMR (DMSO-ds, 400 MHz): 12.77 Calculated (1H, s), 7.96 (1H, d, J = 2.3 Hz), 7.55 for ^^^ 1 (1H, dd, J = 8.3 and 2.3 Hz), 7.48 (1H, d, J = 7.8 Hz), 7.41 (1H, d, J = 8.1 413.1707, Hz), 7.39 -7.37 (1H, m), 7.04 (1H, dd, Found: J = 8.1 and 2.5 Hz), 6.71 (1H, d, J = 8.6 413.1715 Hz) , 4.44 (2H, t, J = 6.8 Hz), 3.89 (1H, dd, J = 7.8 and 4.8 Hz), 3.81 (3H, s), 3.22 ( 3H, s), 2.92-2.88 (3H, m), 2.80 (H, dd, J = 14.4 and 8.0 Hz), 2.31 (3H, s). D-9? NMR (DMSO-ds, 400 MHz): 12.70 Calculated (1H, s), 8.04 (2H, d, J = 8.1 Hz), 7.91 for (1H, d, J = 2.0 ), 7.80 (2H, d, J = 8.3 CaHsF-jNzOs Hz), 7.49 (1H, dd, J = 8.3 and 2.4 Hz), 451.1476. 6.65 (1H, d, J = 8.3 Hz), 4.40 (2H, t, Found: J = 6.6 Hz), 3.84 (1H, dd, J 451.1474 = 7, and 4.7 Hz), 3.16 (3H, s), 2.90-2.82 (3H, m), 2.74 (1H, dd, J = 14.4 and 7.8 Hz), 2, 29 (3H, s). D-10? NMR (DMSO-ds, 400 MHz): 12.76 Calculated Calculated for (1 H, s), 7.96 (1 H, d, J = 2.3 Hz), 7.79 for 24? 2? 50. 3H20 (2H, d, J = 8.1), 7.55 (1H, dd, J = 8.6 C, 65.75 H, 6.17 N, and 2.5 Hz), 7.29 (2H, d, J = 8.1 Hz), 397. 1758. 6.97. Found: C 6.68 (1H, < ¡, J = 8.3 Hz), 4.43 (2H, t, Found: 65.74 H 6.14 N 6.81 J = 6.8 Hz), 3.89 (1H, dd, J 397.1770 = 7.8 and 4.8 Hz), 3.22 (3H, s), 2.92-2.87 (3H, m), 2.80 (1H , dd, J = 14.2 and 7.8 Hz), 2.34 (3H, s), 2.30 (3H, s).
D-11? M R (MeOH-di, 400 MHz): 8.30 LRMS: 410 (1?, S), 7.58 (1?, D, J = 9.2?), 7.11 (M + H) * (2 ?, d, J = 8.2 ??), 6.71 (2? D, J = 9.2 9.2), 6.31 (1? D, J = 9.2? ), ° 4.57 (2 ?, t, J = 6.5 Hz), 4.18 (1 ?, dd, J = 13.5, 0.2 Hz), 3.98 (2H, c, J) = 7.7 Hz), 3.52 (3H, s), 3.28 (2H, t, J = 6.5 Hz), 3.05-3.11 (1H, m), 2.89-2 , 98 (1 H, m), 1, 44 (3H, t, J = 7.7 Hz) D-12? NMR (MeOH-d4, 400 MHz): 8.30 for BR 39S (1H, s), 7.58 (1H, d, J = 9.2 Hz), 7.10 (M + H) * (2H, d, J = 8.2 Hz), 6.74 (2H, d, J = 8.2 Hz), 6.31 (1H, d, J = 9.2 Hz), 4.57 (2H, t, J = 6.5 Hz), 4.18 (1H, dd, J = 13.5, 0.2 Hz), 3.52 (3H, s), 3.34 (3H, s), 3.28 ( 2H, t, J = 6.5 Hz), 3.06-3.11 (1H, m), 2.89-2.98 (1H, m) D-13? NMR (400 MHz MeOH): 8.30 for BR 394 x?; (1H, s), 7.58 (1H, d, J = 9.2 Hz), (M + Hf 7.31-7.37 (2H, m, J = 8.0, 7.5, 0, 2, 0.2 Hz), 7.06-7.14 (3H, m), 6.96-7.04 (4H, m), 6.31 (1H, d, J = 9.2 Hz), s ° 4.57 (2H, t, J = 6.5 Hz), 4.18 (1H, dd, J = 13.5, 0.2 Hz), 3.52 (3H, s), 3.28 (2H, t, J = 6.5 Hz), 3.06-3.11 (1H, m), 2.89-2.97 (1H, m) D-14? NMR (MeOH-d4, 400 MHz ): 8.28- EMBR 409 8.34 (1H, m), 7.59 (1H, m), 7.31-7.37 (? +? (2H, m), 6.96-7.14 (7H, m), 6.27-6.34 (1H, m), 4.53-4.60 (2H, m), 4.22-4.30 (1H, m), 3.49-3 , 66 (2H, m), 3.25-3.31 (2H, m), 3.05-3.11 (1H, m), 2.89-2.97 (1H, m), 1.19 (3H , t, J = 7.0 Hz) D-15? NMR (MeOH-di, 400 MHz): 8.31 for BR 432 (1H, s), 8.02 (2H, d, J = 8.3 Hz ), 7.5G (M + Hf (1H, d, J = 9, 1 Hz), 7.43 (2H, d, J = 8.3 Hz), 6.31 (1H, d, J = 9.1 Hz) 4.20-4.29 (3H, m) 3, 49-3.66 (2H, m), 3.05-3.11 (1H, m), 2.89-2.97 (1H, m) 2.70 (2H, t, J = 8.0 Hz ), 2.19 (3H, s), 1, 19 (3H, t, J = 7.0 Hz) 3.72 (1H, m), 3.47-3.39 (1H, m), 3, 34 (1H, dd, J = 15.2, 7.1 Hz), 3.20 (1H, dd, J »15.2, 4.3 Hz), 2.67 (2H, t, J = 7, 2 Hz), 2.27 (3H, s), 2.19-2.12 (2H, m), 1.17 (3H, = 7.0 Hz) D-25 (CDCI3, 400 Hz): 8.16 ( 1H, d, J = for B 351 2.3 Hz), 7.24-7.19 (2H, m), 4.27 (2H, (W1 + H t, J = 6.8 Hz), 4, 17 (1H, dd, J = 7.6, 3.8 Hz), 3.79-3.72 (1H, m), 3.47-3.40 (H, m), 3.32 (1H, dd, J = 5.4, 7.6 Hz) 3.18 (1H, dd, J = 15.4, 3.5 Hz), 3.09 (2H, t, J = 6.7 Hz), 2.59 (3H , s), 2.34 (3H, S), 1.17 (3H, t, J = 7.0 Hz) D-26 (MeOD, 400MHZ): 8.01 (1H, d, J = for BR 413 3.0 Hz), 7.74-7.71 (2H, m), 7.34-7.27 (M + Hf (3H, m), 7.24 (1H, dd, J = 8.6 , 2.8 Hz), 7.14 (1H, d, J = 8.6 Hz), 4.27 (2H, t, J = 6.6 Hz) 4.06 (1H, dd, J = 8, 7, 4.7 Hz), 3.51-3.44 (1H, m), 3.22-3.14 (1H, m), 3.08 (2H, = 6.4 Hz), 3.02 (1H, dd, J = 14.2, 4.6 Hz), 2.89 (1H, dd, J = 13.9, 8.6 Hz), 2.34 (3H, s) ), 0.93 (3H, t, J = 7.1 Hz) D-27 (MeOD, 400 MHz): 7.86-7.82 (3H, for BR411 m), 7.47 (1H, dd, J = 8.6, 2.0 Hz), (M + Hf 0 ~ ?? - '"^^' ^ 7,39-7,36 (3H, m), 6,62 (1H, d, J = 8,3 Hz), 4,14 (2H, t, J = 6,2 Hz ), 3.22-3.20 (3H, m), 2.85 (2H, dd, J-22.5, 13.9 Hz) 2.60 (2H, t, J = 7.1 Hz), 2.19 (3H, s), 2.03 (2H, dd, J = 12.9, 6.1 Hz), 1.26 (3H, s) D-28 (MeOD, 400 MHz): 8.02 (1H, d, J = for BR 411 2.5 Hz), 7.85-7.83 (2H, m), 7.39-7.33 (M + H) * (3H, m), 7, 26 (1H, dd, J = 8.6, 2.8 Hz), 7.20 (1H, d, J = 8.6 Hz), 3.96 (2H, t, J = 6.1 Hz) 3 , 20 (3H, s), 3.05 (2H, dd, J = 21.0, 13.9 Hz), 2.61 (2H, t, J = 7.2), 2.20 (3H, s ), 2.07-2.01 (2H, m), 1.24 (3H, s) D-29 (MeOD, 400 MHz): 8.02 (1H, Ü, J = for BR 397 2.6 Hz ), 7.87-7.83 (2H, m), 7.39-7.36 (M + H) * (3H, m), 7.27 (1H, dd, J = 8.6, 2, 8 Hz), 7.19 (1H, d, J = 8.6 Hz), 4.22 (2H, = 6.4 Hz) 3.19 (3H, 3.05 (2H, dd, J = 21, 2, 3.9 Hz), 2.91 (2H, t, = 6.4), 2.29 (3H 1.23 (3H D-30 (MeOD, 400 MHz): 7.87-7.84 ( 3H, for B 431 m), 7.48 (1H, dd, J = 8.6, 2.3 Hz), (M + Hf 7.41 (2H, d, J = 8.6 Hz), 6, 61 (1H, d, J = 8.6 Hz) 4.42 (2H, t, J = 6.6 Hz), 3.22 (3H, s), 2.91 -2.88 (3H, m), 2.83 (1H, d, J = 13.9), 2.27 (3H, s), 1.25 (3H, s) D-31 (MeOD, 400 MHz ): 8.04 (2H, d, J = for BR 465 8.1 Hz), 7.84 (1H, d, J = 2.0 Hz), (M + Hf 7.70 (2H, d, J = 8.3 Hz), 7.46 (1H, dd, J = 8.5, 2.4 Hz), 6.60 (1H, d, J = 8.3 Hz), 4.43 (2H, t , J = 6.6 Hz), 3.22 (3H, s), 2.91 (2H, t, J = 6.4 Hz), 2.88 (1H, d, J = 14.2 Hz) 2 , 82 (1H, d, J = 14.2 Hz), 2.28 (3H, s), 1.25 (3H, s) D-32 (MeOD, 400 MHz): 7.84 (1H, d, J = for BR 403 2.0 Hz), 7.47 (1H, dd, J = 8.5, 2.4 (M + H) * Hz), 6.59 (1H, d, J = 8.6 Hz), 4.32 (2H, t, J = 6.6 Hz), 3.23 (3H, s), 2.89 (1H, d, J = 14.2 Hz), 2.83 (1H, d, J = 13.9 Hz), 2.78 (2H, t, J = 6.7 Hz), 2.64 (1H, tt, J = 11.6, 3.5 Hz) 2, 3 (3H , 1.93-1.89 (2H, m), 1.75-1, 71 (2H, m), 1.65-1.62 (1H, m), 1.50-1.40 (2H, m), 1.37-1.27 (2H, m), 1.26 (3H, s), 1.23-1.19 (1H, m) D-33 (MeOD, 400 MHz): 7.85 (1H, d, J = for BR 413 2.3 Hz), 7.77 (2H, < W, J = 7.6, 1.8 (M + H) + Hz), 7.47 (1H, dd, J = 8.6, 2.3 Hz), 7.39-7.31 (3H, m), 6.61 (1H, d, J = 8.6 Hz), 4.49 (2H, t, J = 6.7 Hz), 3.23 (3H, s), 3, 1 (2H, t, J = 6.7 Hz), 2.89 (1H, d, J = 13.9 Hz), 2.83 (1 H, "d, J = 14.2 Hz) 2.36 (3H, s ), 1.26 (3H, s) D-34 (eOD, 400 MHz): 7.84 (1H, d, J = for BR 386 2.3 Hz), 7.43 (1H, dd, J = 8 , 5, 2.4 (M + Hf Hz), 7.17 (2H, dd, J = 8.1, 0.8 Hz), 7.09-7.05 (1H, m), 6.94 ( 1H, dt, J = 7.8, 1.0 Hz), 6.53 (1H, d, J = 8.3 Hz), 4.49 (2H, t, J = 5.3 Hz), 3, 87 (2H, J = 5.3 Hz), 3.23 (3H, S), 3.18 (3H, s), 2.88 (1H, d, J = 13.9 Hz) 2.82 (1H , d, J = 13.9 Hz), 1.26 (3H, s) D-35 (Dimethyl sulfoxide-de, 300 MHz): 7.91 for B 395 Calculated for (3H, m), 7.49 ( 4H, m), 7.40 (3H, m), (le C 66.65 6.69 (1H, d, J = 8.5 Hz), 4.44 (2H, t, H 6.10 N 7 , 07.J = 6.7 Hz), 3.44 (2H, m), 3.18 (3H, Found: S), 2.89 (2H, m), 2.31 (3H, S), 1 , 19? 22? 24 2? 50.06? 2? (3H, S) C 66.16 H 6.15 N 6.96 D-36 (MeOD, 400 MHz): 7.83 (1H, d, J = for BR 411 1.8 Hz), 7.69 (1H, s), 7.65 (1H, d, J = (M + H) * 7.6 Hz). 7.46 (1H, dd, J = 8.6, 2.3 Hz), 7.25 (1H, t, J = 7.6 Hz), 7.19 (1H, d, J = 7.6 Hz ), 6.59 (1H, d, J = 8.3 Hz), 4.39 (2H, t, J = 6.6 Hz), 3, 9 (3H, s), 2.87 (2H, t , J = 6.4 Hz) 2.87 (1H, d, J = 3.9 Hz), 2.80 (1H, d, J = 13.9 Hz), 2.30 (3H, s), 2 , 24 (3H, s), 1.21 (3H, s) D-37 (MeOD, 400 MHz): 7.83 (1H, d, J = for BR 441 2.3 Hz), 7.79-7 , 76 (2H, m), 7.46 (1H, (M + H) + dd, J = 8.5, 2.4 Hz), 6.90 (2H, d, J = 8.8 Hz), 6.59 (1H, d, J = 8.6 Hz), 4.38 (2H, t, J = 6.7 Hz), 4.00 (2H, c, J = 7.1 Hz), 3, 21 (3H, s), 2.88 (1H, d, J = 13.9 Hz), 2.86 (2H, t, J = 6.6 Hz) 2.81 (1H, d, J = 13, 9 Hz), 2.22 (3H, s), 1.31 (3H, t, J = 7.0 Hz), 1.24 (3H, s) D-38 (CDCIs, 400 MHz): 7.93 (1H, d, J = for BR 363 2.3 Hz), 7.45 (H, dd, J = 8.5, 2.4 (M + H) * Hz), 6.63 (1H, d, J = 8.6 Hz), 4.40 (2H, t, J = 6.8 Hz), 3.37 (3H, s), 3.05-2.96 (1H, m), 2.97 ( 1H, d, J = 14.4 Hz), 2.92 (1H, d, J = 14.4 Hz), 2.86 (2H, t, J = 6.7 Hz), 2.20 (3H, s), 1, 43 (3H, s), 1.30 (3H, s), 1.28 (3H, s) D-39 (MeOD, 400 M Hz): 7.82 (1H, d, J = for BR 415 2.0 Hz), 7.44 (1H, dd, J = 8.6, 2.3 (M + H) * Hz), 6.57 (1H, d, J = 8.6 Hz), 6.45 (1H, s), 4.39 (2H, t, J = 6.4 Hz), 4.00 (3H, s), 3.20 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 2.86 (1H, d, J = 14.2 Hz), 2.80 (1H, d, J = 14.2 Hz), 2.22 (3H, s), 2.14 (3H, s), 1.23 (3H, s) -WO (MeOD, 400 MHz): 7.82 (1 H, d, J = for BR 408 2.3 Hz), 7.44 (1 H, dd, J = 8.0, 1.9 (M + H) + Hz), 7.34-7.29 (2H, m), 7.22 (2H, d, J = 8.6 Hz), 7.09-7.03 (1H, m), 6 , 98-6.91 (4H, m), 6.60 (1H, d, J = 8.6 Hz), 4.33 (2H, t, J = 7.1 Hz), 3.20 (3H, s), 3.00 (2H, t, J = 7.0 Hz), 2.82 (1H, d, J = 14.2 Hz), 2.80 (1H, d, J = 14.2 Hz) 1.23 (3H, s) D-41 (MeOD, 400 MHz): 7.81 (1H, d, J = for BR 400 2.3 Hz), 7.44 (1H, dd, J = 8.6 , 2.3 (M + H) * Hz), 7.27 (2H, d, J = 8.6 Hz), 7.07 (2H, d, J = 7.8 Hz), 6.57 (1H , d, J = 8.6 Hz), 4.33 (2H, t, J = 6.7 Hz), 3.20 (3H, s), 2.97 (2H, t, J = 6.7 Hz ), 2.84 (1H, d, J = 14.2 Hz) 2.82 (1H, d, J = 14.2 Hz), 1.24 (3H, s) D-42 (MeUD, 400 MHz) : 7.83 (1H, d, J = for BR 415 1.8 Hz), 7.65 (1H, d, J = 7.6 Hz ), (M + H) * 7.46 (1H, dd, J = 8.6, 2.3 Hz), 7.29 (1H, s), 7.25 (1H, t, J = 7.6 Hz), 7.19 (1H, d, J = 7.6 Hz), 6.59 (1H, d, J = 8.3 Hz), 4.39 (2H, t, J = 6.6 Hz) , 3.19 (3H, S), 2.87 (2H, t, J = 6.4 Hz) 2.87 (1H, d, J = 13.9 Hz), 2.80 (1H, d, J = 13.9 Hz), 2.24 (3H, s), 1.21 (3H, s) D-43 (MeOD, 400 MHz): 7.81 (1H, d, J = for BR 427 2.3 Hz), 7.45-7.38 (2H, m), 7.32-7.24 (M + H) * (2H, m), 6.91 (1H, dd, J = 8.0, 2 , 4 Hz), 6.58 (1H, d, J = 8.3 Hz), 4.38 (2H, t, J = 6.7 Hz), 3.74 (3H, s), 3.18 ( 3H, s), 2.86 (2H, t, J = 6.7 Hz), 2.85 (1H, d, J = 13.9 Hz), 2.79 (1H, d, J = 3.9 Hz), 2.22 (3H, s), 1.22 (3H, s) Preparations of starting materials for Examples D-1 to D-43 (Preparations d-1 to d-42: Preparation d-1 2-Ethoxy-3- (6-f2-f5-methyl-2-phenyl-1.3- oxazol-4-yl) ethoxypyridin-3-yl) ethyl acrylate Add? /,? /,? / '? /' - tetramethylguanidine (0.305 mL, 2.43 mmol) was added dropwise to a solution of 6- [2- (5-methyl-2-phenyl-1, 3- oxazol-4-yl) ethoxy] nicotinaldehyde (250 mg, 0.811 mmol) and (, 2-diethoxy-2-oxoethyl) (triphenyl) phosphonium chloride (696 mg, 1.62 mmol) in chloroform (4 mL). The mixture was stirred for 16 hours and then partitioned between a saturated solution of ammonium chloride and ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (1: 2 ethyl acetate: hexanes) to give the title compound as a white solid (330 g, 96%). E BR: (m / z): 423 (M + H) +. 1 H NMR (CDCl 3) 300 MHz) 8.42 (1 H, m), 8.10 (1 H, m), 7.97 (1 H, m), 7.40 (2 H, m), 7.28 (3 H , m), 6.90 (1 H, s), 6.73 (1 H, m), 4.60 (2H, t, J = 7 Hz), 4.30 (2H, c, J = 7 Hz ), 4.01 (2H, c, J = 7 Hz), 2.99 (2H, t, J = 7 Hz), 2.34 (3H, s), 1.36 (6H, m). Preparation d-2 2-Ethoxy-3-. { Ethyl 6-í2- (5-methyl-2-phenyl-l, 3-oxazol-4-yl) ethoxy] pyridin-3-yl) propanoate A solution of 2-ethoxy-3-. { 6- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] pyridin-3-yl} Ethyl acrylate (328 mg, 0.776 mmol) in ethanol (10 mL) was hydrogenated at 344.73 kPa on 10% palladium on carbon (33 mg) for 3 hours. The mixture was filtered through celite and the solids were washed with ethyl acetate. The filtrate and washings were evaporated and the residue was purified by flash column chromatography (1: 2 ethyl acetate: hexane) to give the title compound as a colorless oil (183 mg, 56%). LRMS (m / z): 425 (+ H) +. 1 H NMR (CDCl 3, 300 Hz) 7.99 (3H, m), 7.42 (4H, m), 6.65 (1H, m), 4.54 (2H, t, J = 7 Hz), 4 , 18 (2H, c, J = 7 Hz), 3.93 (1 H, m), 3.63 (1H, m), 3.36 (1 H, m), 2, .90 (4H, m ), 2.33 (3H, s), 1.25 (3H, t, J = 7 Hz), 1.16 (3H, t, J = 7 Hz). Preparation d-3 Preparation of 2-β-benzyllox-5-bromopyridine To a solution of 5-bromopyridin-2 (1 H) -one (100 mmol, 17.4 g, 1.0 equiv.) In benzene (170 mL) was added silver (I) carbonate (67.0 mmol). , 18.5 g, 0.67 equiv.). The flask was covered with an aluminum foil and then benzyl bromide (120 mmol, 20.5 g, 1.2 equiv.) Was added via syringe in a stationary stream. The mixture was heated to 50 ° C and stirred in a flask for about 24 hours. The MS / LC of the reaction mixture indicates two peaks with both + H = 265 corresponding to the desired molecular weight. Based on the relative polarities, it was thought that the most polar peak was the N-alkylated product and consisted of approximately 20% of the total. The reaction mixture was allowed to cool to room temperature and the silver salt was removed by filtration of the mixture through a pad of celite. The filter cake was washed with benzene and the organic layer was washed twice with 2% sodium bicarbonate and twice with water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude residue was purified on a Biotage Sp4 65i on a gradient of 5-95% hexanes in ethyl acetate to yield the title compound as a golden oil (25.1 g, 95%). LRMS: 265 (M + H) +. 1 H NMR (DMSO-de, 400 MHz): 8.29 (1H, s), 7.72 (1 H, d, J = 8.5 Hz), 7.31-7.43 (5H, m), 6.54 (1H, d, J = 8.5 Hz), 5.34 (2H, s). Preparation d-4 Preparation of 6-C-benzyloxy) n-ticinaldehyde N-Butyl lithium (2.5 M, 95.9 mmol, 38.4 mL, 1.05 eq.) Was added dropwise via syringe to a stirred solution of 2- (benzyloxy) -5-bromopyridine (91 , 3 mmol, 24.1 g, 1.0 equiv.) In THF (260 ml, c = 0.35) cooled to -78 ° C. After the addition was complete, the solution was allowed to stir at the same low temperature for 1 hour. At this point, V, A -dimethylformamide (183 mmol, 13.4 g, 2.0 equiv.) Was added dropwise as a solution in 5 mL of THF. The stirring was continued at the same low temperature for 30 more minutes, at which time the reaction was interrupted by the addition of 5% sodium bicarbonate. The mixture was transferred to a separatory funnel and extracted with ether (3 x 250 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting yellow oil was purified on a Biotage Sp4 65i on a gradient of 0-50% hexanes in ethyl acetate to yield the title compound (14.1 g, 73%). LRMS: 214 (M + H) +. 1 H NMR (DMSO-de, 400 MHz): 10.02 (1H, s), 8.86 (1H, s), 8.03 (H, d, J = 9.3 Hz), 7.31-7 , 43 (5H, m), 6.50 (1H, d, J = 9.3 Hz), 5.33 (2H, s). Preparation d-5 Preparation of ethyl (2Z) -3- [6- (benzyloxy) pyridin-3-yn-2-ethoxyacrylate] To a solution of 6- (benzyloxy) nicotinaldehyde (1.0 equiv., 33.1 mmol, 7.05 g) and (1,2-diethoxy-2-oxoethyl) (triphenyl) phosphonium chloride (2.0 equiv. ., 66.2 mmol, 28.4 g) in chloroform (165 ml, 0.2 M) was added tetramethylguanidine (3.0 equiv, 99.3 mmol, 11.4 g). The flask was capped with a hollow glass stopper and stirred at room temperature overnight. TLC analysis after approximately 18 hours indicated the presence of a small amount of unreacted starting material. The reaction mixture was heated to reflux and retested by TLC every 2 hours. The reaction was quenched with saturated ammonium chloride. The layers were separated and the organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. A large amount of triphenylphosphine oxide precipitated. The residue was triturated with ether and filtered. The filter cake was washed with ether and concentrated with the combined filtrates in vacuo to yield a pale yellow solid which was dissolved in a minimum amount of DCM and loaded on a Biotage Sp4 65i and eluted on a gradient of 10- hexanes. 100% in ethyl acetate. 12.3 g of a clear colorless oil (37.6 mmol, quant) were obtained. SMI: 328 (M + H) +. 1H RN (DMSO-d6, 400 MHz): 8.33 (1H, s), 7.92 (1H, d, J = 8.0 Hz), 7.31-7.43 (5H, m), 6 , 76 (1H, d, J = 8.1 Hz), 6.60 (1H, s), 5.37 (2H, s), 4.23 (2H, c, J = 7.1 Hz), 3 , 90-3.99 (2H, m), 1.34 (6H, dt, J = 15.8, 7.0 Hz). Preparation d-6 Preparation of ethyl 2-ethoxy-3- (6-oxo-1,6-dihydropyridin-3-yl) propanoate To a Parr agitator vessel containing a solution of (22) -3- [6- (benzyloxy) pyridin-3-yl] -2-ethoxyacrylate in ethanol was added 10% Pd on carbon (~ 1.23). g). The vessel was purged with hydrogen and degassed at reduced pressure three times. The mixture was placed at 344.73 kPa of hydrogen and stirred at room temperature overnight. After ~20 hours, the stirring was stopped and the vessel was degassed in vacuo. Analysis by TLC indicated the consumption of the starting material. The mixture was filtered through a pad of celite to remove the palladium. The filter cake was washed with an additional portion of ethanol. This solution was concentrated in vacuo to yield the reduced and debenzylated pyridone in the form of a golden oil. This oil was purified on a Biotage Sp4, 65i, 80 ml / min over a gradient of 0-10% MeOH in DCM to yield 2.77 g of a clear, colorless oil (1.6 mmol, 31%). LRMS: 240 (M + H) +. 1 H NMR (DMSO-d 6, 400 MHz): 7.29 (1H, d, J = 9.5 Hz), 7.19 (1H, d, J = 5.2 Hz), 6.55 (1H, d, J = 9.5 Hz), 4.20 (2H, c, J = 7.0 Hz), 4.10 (1 H, dd, J = 9.6, 0.3 Hz), 3.59 -3.73 (2H, m), 2.65-2.70 (1H, m), 2.53-2.61 (1H, m), 1.23 (6H, td, J = 7.0, 3.6 Hz).
Preparation d-7 5-Benzyloxy-pyridine-2-carbaldehyde To a solution of (5-benzyloxy-pyridin-2-yl) -methanol (2.3619 g, 10.9728 mrriol) in dichloromethane (120 ml) and pyridine (2.68 ml, 32.9184 mmol) was added. 1, 1, 1-triacetoxy-1,1-dihydro-1,2-benzidioxol-3- (1AV) -one (6.9812 g, 16.4592 mmol). The resulting solution was stirred under a nitrogen atmosphere at room temperature for 16 hours and then diluted with diethyl ether (100 ml) followed by partial concentration under reduced pressure. The residue was taken up in diethyl ether (50 ml) and the precipitates were removed by extraction with 1: 1 of 0% aqueous sodium thiosulfate: saturated aqueous sodium bicarbonate (2 x 100 ml). The organic layer was washed with water (100 ml) and saturated aqueous sodium chloride (100 ml), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to yield the pure title compound (1.1694 g, 50%). ) in the form of a pale yellow oil. E BR (m / z): 214 (M + H) +. 1H RN (CDCl 3, 300 MHz): 9.98 (1 H, d, J = 0.8 Hz), 8.49 (1H, d, J = 2.5 Hz), 7.94 (1H, d, J = 8.7 Hz), 7.44-7.40 (4H, m), 7.38-7.33 (2H, m), 5.19 (2H, s). Preparation d-8 3- (5-Benzyloxy-pyridin-2-yl) -2-ethoxy-acrylic acid ethyl ester To a solution of 5-benzyloxy-pyridine-2-carbaldehyde (1, 1694 g, 5.4842 mmol), (ethoxycarbonyl-methoxy-methyl) -triphenyl-phosphonium chloride (4.7043 g, 10.9684 mmol) in chloroform (30 mL), under a nitrogen atmosphere at room temperature, tetramethylguanidine (2.1 ml, 16.4526 mmol) was added dropwise. The resulting solution was stirred for 16 hours and then quenched with saturated aqueous ammonium chloride (50 ml). The phases were separated and the organic phase was washed with saturated aqueous sodium chloride (50 ml), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to give the crude product. The residue was purified by flash column chromatography (hexanes to ethyl acetate) to give the pure title compound (1.8051 g, 100%) as a yellow oil. E BR (m / z): 328 (+ H) + H NMR (CDCl 3, 300 MHz): 8.37 (1 H, d, J = 2.6 Hz), 8.18 (1H, d, J - 8.9 Hz), 7.44-7.33 (5H, m), 7.25 (1H, dd, J = 8.9.3.0 Hz), 7.13 (1H, s), 5, 13 (2H, s), 4.27 (2H, c, J = 7.2 Hz), 4.05 (2H, c, J = 7.2 Hz), 1.35 (3H, t, J = 7 , 0 Hz), 1.34 (3H, t, J = 7.0 Hz).
Preparation d-9 2-Ethoxy-3-f5-hydroxy-pyridin-2-yl) propionic acid ethyl ester To a solution of the 3- (5-benzyloxy-pyridin-2-yl) -2-ethoxy-acrylic acid ethyl ester (1.8051 g, 5.5144 mmol) in dry ethanol (40 mL) was added palladium ( 0.1805 g, 10% by weight on activated carbon). The resulting solution was stirred at room temperature under a hydrogen atmosphere (344.73 kPa) for 16 hours. The resulting solution was filtered through a 7.62 cm Celite layer and washed with ethanol (200 ml). Then, the filtrate was concentrated in vacuo to yield the pure title compound (1.2231 g, 93%) as a pale yellow oil. LRMS (m / z): 240 (+ H) +. 1 H NMR (CDCl 3, 300 MHz): 8.14 (1H, s), 7.20-7, 11 (2H, m), 4.19-4.10 (3H, m), 3.71 (1H, c, J = 7.0 Hz), 3.63-3.53 (H, m), 3.36-3.26 (1 H, m), 3.18-3.03 (1 H, m) , 1, 18 (3H, t, J = 7.2 Hz), 1.07 (3H, t, J = 7.1 Hz). Preparation d- 0 2-Ethoxy-3-f6-f2- (4-phenoxyphenyl) ethoxylpyridin-3-yl) ethyl propanoate To a solution purged with argon from the appropriate bromopyridine (0.636 mmol) in toluene (12 mL) was added palladium (II) acetate (11.4 mg, 0.0508 mmol) and 2- (di-t-butylphosphino). -1, 1'-racemic binaphthyl (25.4 mg, 0.0636 mmol). The activated complex was allowed to form for approximately ten minutes, at which point cesium carbonate (414 mg, 1.27 mmol) and the appropriate alcohol (0.956 mmol) were added. The mixture was heated to 115 ° C and stirred at this temperature for approximately 12-18 hours. The mixture was cooled to room temperature and filtered through a layer of silica. The filter layer was washed with 2-3 aliquots of ethyl acetate and the combined organic filtrates were combined and concentrated in vacuo. The resulting residue was purified again by flash chromatography or subjected to the general hydrolysis procedure. Preparations d-1 to d-8 Preparations d-11 to d-18 were prepared by procedures analogous to those used for Preparation d-10 Preparation d-19 2-bromo-5- (bromomethyl) pyridine Phosphorus tribromide (100 mmol.27.1 g, 2.0 equiv.) Was carefully added to 2-chloro-5-hydroxymethyl pyridine (50.0 mmol, 7.18 g, 1.0 equiv.). The pyridine was pooled and the mixture was heated to 160 ° C. Within a period of 5 minutes of shaking a > 150 ° C, the mixture turned very dark in color with gas evolution. The mixture was stirred at this same temperature for about 2.5 hours, at which time it was cooled to room temperature. The mixture was further cooled to 0 ° C, after which saturated sodium bicarbonate was added very carefully (very exothermic). As foaming became less vigorous, ice was added to the mixture until the foaming stopped. Then solid sodium bicarbonate was added until a pH of -8-9 was obtained. The mixture was extracted with ethyl acetate and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. It was concentrated in vacuo to yield a dark solid. This material was dissolved in a minimum amount of DC and purified using a Biotage Sp4 65i on a gradient of 0-100% ethyl acetate in hexanes to yield the title compound as a pale yellow solid (5.57 g. , 44%). LRMS: 252 (M + Hf. 1H RN (SO-d6 D, 400 MHz): 8.39 (1 H, s), 7.59 (1H, d, J = 8.5 Hz), 7.48 ( 1H, d, J = 8.5 Hz), 4.46 (2H, s) Preparation d-20 Preparation of dimethyl [(6-bromopyridin-3-ylmethylmethoxy) malonate To a suspension of potassium f-butoxide (46.6 mmol, 5.22 g, 1.3 equiv.) In anhydrous DMF (250 ml) cooled to 0 ° C was added methoxy dimethylmalonate (46.6 mmol, 7.55 g. g, 1, 3 equiv.) by means of a syringe in small portions. The enolate was allowed to warm for about 30 minutes, at which point 2-bromo-5- (bromomethyl) pyridine was added portionwise. The reaction mixture was allowed to warm slowly to room temperature for 3 hours. The reaction mixture was diluted with ethyl ether and transferred to a separatory funnel containing saturated ammonium chloride. The layers were shaken and separated and the organic layer was washed with water. The organic layer was then dried over anhydrous magnesium sulfate and concentrated in vacuo. The yellow oil obtained was purified on a Biotage Sp4 65i on a gradient of 0-100% ethyl acetate in hexanes to produce a colorless oil which solidified upon standing (12)., 1 g, quant). LRMS: 333 (M + H) +. 1 H NMR (DMSO-de, 400 MHz): 8.27 (1 H, s), 7.45-7.55 (2H, m), 3.82 (6H, S), 3.57 (3H, s) ), 3.42 (2H, s). Preparation d-21 Preparation of methyl 3- (6-bromopyridin-3-yl) -2-methoxypropanoate To a solution of dimethyl [(6-bromopyridin-3-yl) methyl] (methoxy) malonate (3.55 mmol, 1.18 g, 1.0 equiv.) In anhydrous DMF (2 mL) was added bromide of lithium (3.20 mmol, 0.278 g, 0.9 equiv.) followed by water (3.55 mmol, 0.064 g, 1.0 equiv.). The solution was placed in an oil bath preheated to 165 ° C. The release of gas began. The bubble formation ceased in 30 minutes and the ME / CL of the reaction mixture at this point indicated that the reaction had been completed. It was cooled to room temperature and diluted with water. The aqueous layer was extracted with diethyl ether (4 x 25 ml). The combined organic layers were washed with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to yield 536 mg of a brown oil that was a single spot by TLC. It was used in the next step without further purification. EMB: 275 (+ H) +. H NMR (DMSO-de, 400 MHz): 8.23 (1H, s), 7.42-7.51 (2H, m), 4.26 (1H, d, J-8.1 Hz), 3 , 79 (3H, s), 3.51 (3H, s), 2.97-3.03 (1H, m), 2.82-2.88 (1H, m). Preparation d-22 3-f6- (2- (4-f (Ethylsulfonyl-oxo-phenyl) -ethoxy) -pyridin-3-yn-2-methoxypropanoate ethyl Preparations d-23 to d-38 Preparations d-23 to d-38 were prepared by analogous procedures dd, J = 8.5, 2.4 Hz), 6.62 (1H, d, J = 8.3 Hz ), 4.52 (2H, t, J = 6.7 Hz), 3.70 (3H, s), 3.28 (3H, s), 2.97 (2H, t, J = 6.7 Hz) ), 2.95 (1H, d, J = 14.2 Hz), 2.86 (1H, d, J = 14.2 Hz), 2.34 (3H, s), 1.33 (3H, s) ) d-28 (CDC13, 400 MHz) 7.90 (1H, d, J = for BR417 2.3 Hz), 7.41 (1H, dd, J = 8.5, 2.4 (M + Hf Hz ), 6.61 (1H, d, J = 8.3 Hz), 4.42 (2H, t, J = 6.8 Hz), 3.71 (3H, s), 3.29 (3H, s) ), 2.95 (1H, d, J = 13.9 Hz), 2.86 (1H, d, J = 14.2 Hz), 2.86 (2H, t, J = 7.1 Hz), 2.67 (1H, tt, J = 1.6, 3.5 Hz), 2.19 (3H, s), 2.02-1.98 (2H, m), 1.81-1.77 ( 2H, m), 1.69-1.65 (1H, m), 1.54-1.46 (2H, m), 1.38-1.31 (2H, m), 1.33 (3H, s), 1.28-1.24 (1H, m) d-29 (CDCI3, 400 MHz) 7.92 (1H, d, J = for BR 427 2.3 Hz), 7.85 (2H, dd , J = 8.0, 1.6 (M + H) + Hz), 7.41 (1H, dd, J = 8.5, 2.4 Hz), 7.39-7.35 (3H, m ), 6.63 (H, d, J = 8.6 Hz), 4.59 (2H, t, J = 7.0 Hz), 3.70 (3H, S), 3.28 (3H, S ), 3.18 (2H, t, J = 7.0 Hz), 2.95 (1 H, d, J = 14.2 Hz), 2.87 (1 H, d, J = 14.2 Hz), 2.42 (3 H, s), 1, 33 (3H, s) d-30 (CDCl 3, 400 MHz) 7.90 (1H, d, J = for BR 400 2.3 Hz), 7.41 (1H, dd, J = 8.5, 2, 4 (M + H) + Hz), 7.33 (1H, d, J = 7.6 Hz), 7.21 (1H, d, J = 7.6 Hz), 7.13 (1H, dt, J = 7.6, 1.0 Hz), 6.97 (1H, dt, J = 7.8, 1.3 Hz), 6.60 (1H, d, J = 8.6 Hz), 4, 56 (2H, t, J = 5.4 Hz), 3.92 (2H, t, J = 5.4 Hz), 3.70 (3H, s), 3.28 (6H, s), 2, 95 (1 H, d, J = 13.9 Hz), 2.86 (1 H, d, J = 14.2 Hz), 1.32 (3 H, s) d-31 (CDCl 3, 400 MHz) 7, 91 (1H, d, J = for BR 425 2.3 Hz), 7.81 (1 H, s), 7.75 (1H, d, (M + H) + J = 7.8 Hz), 7.41 (1H, dd, J = 8.5, 2.4 Hz), 7.29 (1 H, t, J = 7.7 Hz), 7.19 (1H, d, J = 7.6 Hz), 6, 62 (1H, d, J = 8.3 Hz), 4.52 (2H, t, J = 6.8 Hz), 3.70 (3H, S), 3.28 (3H, s), 2, 96 (2H, t, J = 6.8 Hz), 2.95 (1H, d, J = 13.9 Hz), 2.86 (1H, d, J = 13.9 Hz), 2.38 ( 3 H, s), 2.32 (3 H, s), 1.33 (3 H, s) d-32 (CDCl 3, 400 MHz) 7.91 (1 H, d, J for BR 455 O 2.0 Hz), 7.89-7.86 (2H, m), 7.59 (M + H) + (1H, dd, J-8) , 5, 2.2 Hz), 6.92-6.90 (2H, m), 6.62 (1H, d, J = 8.3 Hz), 4.51 (2H, t, J = 6, 8 Hz), 4.06 (2H, c, J = 7.1 Hz), 3.70 (3H, s), 3.28 (3H, s), 2.95 (2H, t, J = 6, 8 Hz), 2.96 (1H, d, J = 13.9 Hz), 2.87 (1H, d, J = 13.9 Hz), 2.30 (3H, s), 1.42 (3H , t, J = 7.1 Hz), 1.33 (3H, s) d-33 (CDCI3, 400 MHz) 7.90 (1H, d, J = for BR 377 2.3 Hz), 7.41 (1H, dd, J = 8.5, 2.4 (M + Hf Hz), 6.61 (1H, d, J = 8.3 Hz), 4.42 (2H, t, J = 6.8 Hz), 3.70 (3H, s), 3.28 (3H, s), 3.00-2.93 (1 H, m), 2.95 (1H, d, J = 14.2 Hz) , 2.86 (2H, t, J = 6.8 Hz), 2.86 (1H, d, J = 14.2 Hz), 2.20 (3H, s), 1.33 (3H, s) , 1, 30 (3H, S), 1, 28 (3H, s) d-34 (CDCI3, 400 MHz) 7.91 (1H, d, J = for BR 429 2.3 Hz), 7.42 ( 1 H, dd, J = 8.5, 2.4 (M + H) + Hz), 6.61 (1H, d, J = 8.3 Hz), 6.48 (1H, s), 4, 51 (2H, t, J = 6.7 Hz), 4.15 (3H, s), 3.71 (3H, s), 3.28 (3H, s), 2.96 (1H, d, J = 13.9 Hz), 2.94 (2H, t, J = 6.6 Hz), 2.87 (1H, d, J = 13.9 Hz), 2.30 (3H, s), 2.27 (3H, s), 1.33 (3H , s) d-35 (CDCl 3, 400 MHz) 7.91 (1 H, d, J = for BR 422 2.3 Hz), 7.42 (1 H, dd, J = 8.0, 1.9 (M + H) + Hz), 7.33-7.28 (2H, m), 7.23 (2H, d, J = 8.6 Hz), 7.08-7.04 (H, m), 6 , 99-6.92 (4H, m), 6.64 (1H, d, J = 8.6 Hz), 4.45 (2H, dt, J = 7.1 Hz), 3.70 (3H , s), 3.20 (3H, s), 3.04 (2H, t, J = 7.0 Hz), 2.92 (H, d, J = 14.2 Hz), 2.87 (1H , d, J = 14.2 Hz), 1.33 (3H, s) d-36 (CDCl3, 400 MHz) 7.90 (1H, d, J = for BR 414 2.3 Hz), 7.42 (1H, dd, J = 8.5, 2.4 (M + H) + Hz), 7.28 (2H, d, J = 8.6 Hz), 7.13 (2H, d, J = 8) , 1 Hz), 6.63 (1H, d, J = 8.3 Hz), 4.46 (2H, t, J = 6.8 Hz), 3.71 (3H, s), 3.28 ( 3H, s), 3.06 (2H, t, J = 6.8 Hz), 2.95 (1 H, d, J = 14.2 Hz), 2.86 (1H, d, J = 13, 9 Hz), 1.33 (3H, s) d-37 (CDCl 3, 400 MHz) 7.91 (1H, d, J = for BR 429 (/? 1 1 or 2.0 Hz), 7J4 (1H, d, J = 7.8 Hz), (M + H) + F 7.41 (1H, dd, J = 8.2, 2.5 Hz), 7.34 (1H, t, J = 7.7 Hz), 7.38 (1H, s), 7.18 ( 1H, d, J = 8.1 Hz), 6.62 (1H, d, J = 8.3 Hz), 4.51 (2H, t, J = 6.7 Hz), 3.70 (3H, s), 3.28 (3H, s), 2.96 (2H, t, J = 6.8 Hz), 2.95 (1H, d, J = 13.9 Hz), 2.86 (1H, d, J = 13.9 Hz), 2.32 (3H, s), 1.32 (3H, s) d-38 (CDCl3, 400 MHz) 7.91 (1H, d, J = for BR 441 2 , 0 Hz), 7.41 (1H, dd, J = 8.5, 2.4 (M + H) + -0 Hz), 7.34-7.29 (2H, m), 6.96-6.93 (2H, m), 6.62 (1H, d, J = 8.5 Hz), 4.52 (2H, t, J = 6.8 Hz), 3.70 (3H, s), 3.28 (3H, s), 2.96 (2H, t, J = 6.8 Hz), 2.95 (1H, d, J = 13.9 Hz), 2.86 (1H, d, J = 13.9 Hz), 2.32 (3H, s), 2, 6 (3H, s), 1.32 (3H, s) The compounds of the invention have been tested for activities against PPAR gamma and PPAR alpha. The activities are tabulated later in Ki (pm) E / M is defined as an enantiomeric mixture, including racemic mixture. S / E is defined as an individual enantiomer.
E / M is defined as an enantiomeric mixture, including racemic mixture. S / E is defined as an individual enantiomer.
E / M is defined as an enantiomeric mixture, including racemic mixture. S / E is defined as an individual enantiomer.
Although the invention has been illustrated by reference to specific and preferred embodiments, those skilled in the art will recognize that variations and modifications can be made by routine experimentation and practice of the invention. Thus, it is not intended to limit the invention by the foregoing description, but is defined by the appended claims and their equivalents.

Claims (15)

    Having described the invention as above, the contents of the following are declared as property CLAIMS
  1. The authors claim 1. A compound of formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein: the Q ring is aryl (C6-C-i0) or heterocyclyl of (4-10) links; R1 is H, halo, (Ci-C8) alkyl, alkoxy (Ci-Ce), CN, CF3, -0-CF3, -0-S02-alkyl (d-C8), -0-S02- (CR1 R12) t aryl (< ¼ -C10), - (CR11R12) t (C3-C10) cycloalkyl- (CR11R12) ,, - (CR11R12) t (C3-C10) cycloalkyl- (CR11R12) t- O - - ( CR11R12) t aryl (C6-C10) - (CR11R12) t, - (CR1 R12) t aryl (C6-Ci0) t - (CR 1R12) t- O - - (CR1 R12) t heterocyclyl of (4-10) links - (CR R12) t, or - (CR11R12), heterococyclyl (4-10) links - (CR 1R12) t -O-; wherein the carbon atoms of the R1 ring are optionally substituted by 1 to 3 R13 groups; and the nitrogen atoms in the ring of R are optionally substituted with 1 to 3 alkyl (C-i-C8); R2 is H, (Ci-C8) alkyl, - (CR11R12) t-cycloalkyl (C3-C10), - (CR11R12) t-aryl (C6-C10) or - (CR11R12) t heterocyclyl of (4-10) links; and wherein the carbon atoms of R2 are optionally substituted with 1 to 3 R13 groups; and the nitrogen atoms in the ring of R2 are optionally substituted with 1 to 3 alkyl (Ci-C8); R2 is selected from the group consisting of: Y is - (C = 0) - or -SO2-; Y "is NR10 or -O-; p is 0, 1, or 2, each q, r, and t are independently 0, 1, 2, 3, 4, or 5, each n is independently 0, 1, 2, 3 or 4, each k is independently 1, 2 or 3, each mys is independently 0, 1, 2, or 3, each j is 0, 1, or 2; Each R4 is - (CR11R2) n -, - (CR11R) n -S - (CR R2) n- - (CR1 R12) n -NR10-, - (CR11R12) n -NR10- (CR11R12) n -O-, - (CR1 2) n-0- (CR11R) k- NR10, - (CR11R2) n-0- (CR11R12) n-, - (CR11R12) n-0- (CR R1VO- (CR1R12) n-, - (CR11R1) n -CR11 = CR12 - (CR11R12) n- or -CH = CH- (CR11R2) -0- (CH2) n-; each R5 is a bond or - (CR1 R1) m- Z- (CR11R12) S, wherein Z is -CR11R12-, -O- NR10a - or - (SO) j; Each R6 is - (C = 0) -OH, - (C = 0) -O +, - (C = 0) - alkyl (C-, - C8), - (C = 0) - O - (Ci-C8) alkyl, - (C = O) -NR10R11, - (C = 0) -NR10-S02-R-S02-NH-R 0, -NH-SOz -R10, - (C = 0) - NH - C = N, or R6 has a formula: M + is an alkali metal cation or an alkaline earth metal cation; Each R7 and R8 is independently H, (C1-C8) alkyl, (C1-C8) alkoxy, - (CR1 R12) t (C3-C10) cycloalkyl, - (CR11R12) t aryl (C6-C10), - (CR11R12) ) t aryl (C6-C10) -O-, - (CR11R12) t heterococlyl of (4-10) links or - (CR1 R12) t heterocyclyl of (4-10) links -O-; Or R7 and R8 can optionally be taken together with the carbon to which they are attached to form a (C3-C-io) cycloalkyl or a (3-10) membered heterocyclyl; Each Ar1, Ar2, Ar3, and Ar4 represents aryl (C6-C10) or heterocyclyl (5-10) links; wherein the carbon atoms in the ring of each Ar1, Ar2, Ar3, and Ar4 are optionally substituted with one to three R3 groups; Ring A represents a ring of 3, 4, 5, 6 or 7 links optionally containing 1 to 4 heteroatoms which may be the same or different and which are selected from ~ N (R10a) -, O, and S (0) j , wherein j is 0, 1, or 2, with the proviso that the ring does not contain two adjacent O or S (0) j atoms, and in which the carbon atoms of residue A in the ring are optionally substituted with one to three R 3 groups; R9 is alkyl (d-C8), - (CR1 R12) t-aryl (C6-C10) or (CR11R12) t -heterocyclyl of (4 - 0) linkages, wherein t is independently 0, 1, 2, 3 , 4, or 5, wherein said R9 groups are substituted with 1 to 3 groups independently selected from - (CR1 R1) qNR10R11, - (CR11R12) qNR10 alkanoyl (d - C6), - (CR11R12) qO (CR1 R12) rR10, and - (CR11R12) qR10; and wherein the heterocyclyl, aryl and alkyl moieties of the above groups are optionally substituted with one to three R13 groups; R9a and R10 are independently H or (Ci-C8) alkyl; R11 and R12 are independently H, (d-C8) alkyl, hydroxy, or alkoxy. { C-i - C6); R10a is selected from H, alkyl (d-C8), - (C = 0) -R14, -S02NR15R16, or - (SO) j alkyl (Ci-C6); Each R13 and R13a are independently selected from the group consisting of halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, alkoxy (Ci-C6), alkyl (Ci-C0), alkenyl (C2-C6), alkynyl ( C2-C6), -O- (CR11R12) k-0- (CR 1R12) n- - (C = 0) -R14, - (C = 0) -0-R15, -O- (C = 0) - R15, -NR15 (C = 0) -R16, -NR15 (C = 0) -0-R16, - (C = 0) -NR15R1s, -NR 5R16, -NR15OR16, -S02R 5R16, -S (0) j alkyl (dC6), -0-S02-R14, -NR15-S02-R16, R15- (CR11R12) t-aryl (C6-C10), - (CR11R12) t heterocyclyl of (4-10) links, - (CR1 R12) q (C = 0) (CR11R12) t aryl (C6 - C10), - (CR1 R) q (C = 0) (CR R 2) t heterocyclyl of (4 - 10) links, - (CR11R12 ) tO (CR11R12) q aryl (C6 - C10), - (CR11R12) tO (CR11R12) q heterocyclyl of (4-10) links, - (CR 1R 2) qS02 (CR R12) t aryl (C6 - C 0) , and - (CR11R12) qS02 (CR11 2) t heterocyclyl of (4-10) links; 1 or 2 carbon atoms in the ring of the heterocyclic moieties of the above groups R13 and R 3a are optionally substituted with an oxo moiety (= 0), and the alkyl, alkenyl, alkynyl, aryl and heterocyclic moieties of the above groups R 3y R13a are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR15, - (C = 0) -R15, - (C = 0) -0-R15, -0- (C = 0) -R15, -NR15 (C = 0) -R16, - (C = 0) -NR15R16, -NR15R16, -NR 5OR16, alkyl (d-C6), alkenyl (C2-C6), alkynyl ( C2-C6), - (CR11R12) t aryl (C6 ~ Cio), and - (CR1R2) theterocyclyl of (4-10) links; each R14, R15, and R16 is independently selected from H, alkyl (d-Ce), - (CR11R12) t aryl (Ce-C10) and - (CR11R12) t heterocyclyl of (4-10) links; 1 or 2 carbon atoms in the ring of the heterocyclic group are optionally substituted with an oxo moiety (= 0), and the challenges, alkyl, aryl and heterocyclic of the above groups R14, R15 and R16 are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, -NR11R12, trifluoromethyl, trifluoromethoxy, alkyl (Ci-Ce), alkenyl (C2-Ce), alkynyl (C2-C6), hydroxy, and (C1-C6) alkoxy; R17 is H, (C1-C8) alkyl, -O-alkyl (Ci-CB), halo, CN, OH, CF3, 0 -O-CF3; and wherein any one of the above-mentioned substituents comprises a CH3 (methyl), CH2 (methylene), or CH (methino) group that is not bonded to a halo, SO or S02 group or to an N, O or S atom optionally supports on said group a substituent selected from hydroxy, halo, (C1-C4) alkyl, (C1-C4) alkoxy, -NH2, -NH alkyl (Ci-C8), and -N (alkyl (d-C8)) 2 .
  2. 2. The compound according to claim 1 wherein R3 is
  3. 3. The compound according to claim 1 wherein R3 is
  4. 4. The compound according to claim 1 wherein R3 is
  5. 5. The compound according to claim 1 wherein R3 is D)
  6. 6. The compound according to claim 2 having a formula which said -Ar1-Ar2- is selected from the group constituted wherein the carbon atoms in the ring of each Ar1 and Ar2 are optionally substituted with 1 to 3 R3 groups selected from the group consisting of halo, (Ci-C8) alkyl and (Ci-C8) alkoxy.
  7. 7. The compound according to claim 2 selected from the group consisting of 1 - (. {3 '- [2- (5-Methyl-2-phenyl-1, 3-oxazol-4-yl) ethoxy] -1,1' -biphenyl-3-yl} oxy} acid ) cyclobutanecarboxylic acid (example A-4); 2- (. {3 '- [2- (5-Methyl-2-phenyl-1, 3-oxazol-4-yl) ethoxy] -1,1'-biphenyl-3-yl} oxy} acid ) butanoic (example A-5); 2- (3- {6- [2- (5-Methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] pyridin-2-yl} phenoxy) butanoic acid (Example A) - 6); 1- (3- {6- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] pyridin-2-yl} phenoxy) cyclobutanecarboxylic acid (Example A - 7); 1 - [(3'- { [2- (3-fluorophenyl) -5-methyl-1,3-oxazol-4-yl] methoxy} biphenyl-3-yl) oxy] cyclobutanecarboxylic acid (Example A) - eleven); 1 - [(3 '- [3- (5-Methyl-2-phenyl-1, 3-oxazol-4-yl) propoxy] biphenyl-3-yl] oxy] cyclobutanecarboxylic acid (Example A-12); 1 - [(3'- { [5- (4-Methoxy-phenyl) -1,2,4-oxadiazol-3-yl] methoxy} biphenyl-3-yl) oxy] cyclobutanecarboxylic acid (Example A) - 17); 2 - [(3'- { 2- [2- (3-fluorophenyl) -5-methyl-1,3-oxazol-4-yl] ethoxy} biphenyl-3-yl) oxy] -2 acid -methylpropanoic acid (example A-21); 2-Methyl-2- (. {3 '- [(5-methyl-2-phenyl-1, 3-oxazol-4-yl) methoxy] biphenyl-3-yl} oxy) propanoic acid (Example A) - 24); 2-ethoxy-3- acid. { 3 '- [2- (5-methyl-2-phenyl-1,3-oxazo] -4-yl) ethoxy] b-phenyl-3-yl} propanoic (example A-28); and the pharmaceutically acceptable salts thereof.
  8. 8. The compound according to claim 3 having a formula where Y is - (C = 0) - or -S02-; Y "is NR10 and p is 1.
  9. 9. The compound according to claim 3 selected from the group consisting of 2-methyl-2- acid. { 3 - [( { [2- (5-methyl-2-phenyl-1, 3-oxazol-4-yl) ethoxy] carbonyl}. Amino) methyl] phenoxy} propanoic (example B-5); 2-methyl-2- acid. { 3 - [( { [(5-Methyl-2-phenyl-1) 3-oxazol-4-yl) methoxy] carbonyl} amino) methyl] phenoxy} propanoic (example B-6); 2-methyl-2- acid. { 4 - [( { [3- (5-methyl-2-phenyl-1, 3-oxazol-4-yl) propoxy] carbonyl.] Amin) methyl] phenoxy} propanoic (example B-7); Acid 2-. { 3-fluoro-4 - [( { [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] carbonyl}. Amino) methyl] phenoxy} -2-methylpropane (example B-9); Acid 2-. { 3 - [( { [2- (5-methyl-2-phenyl-1, 3-oxazol-4-yl) ethoxy] carbonyl}. Amino) methyl] phenoxy} butanoic (example B-13); Acid 2-. { 3 - [( { [(5-Methyl-2-phenyl-1,3-oxazol-4-yl) methoxy] carbonyl} amino) methyl] phenoxy} butanoic (example B-14); Acid 1 -. { 3 - [( { [2- (5-methyl-2-phenyl-1, 3-oxazol-4-yl) ethoxy] carbonyl}. Amino) methyl] phenoxy} cyclobutanecarboxylic (example B-15); 2-Methyl-2- (3. {[[( { [2- (5-methyl-2-phenyl] -1,3-oxazol-4-yl) ethyl] amino} carbon; l) oxy] methyl.} phenoxy) propanoic (example B-21); 2-ethoxy-3- acid. { 3 - [( { [3- (5-methyI-2-phenyl-1,3-oxazol-4-yl) propoxy] carbonyl] amino) methylene] phenyl} propanoic (example B-23); 2-ethoxy-3- acid. { 3 - [( { [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ioxy] -carbonyl} -amino) methyl-3-phenyl} propanoic (example B-24); and the pharmaceutically acceptable salts thereof.
  10. 10. The compound according to claim 4 having a formula wherein said ring A is selected from the group consisting of cyclopropylo, cyclobutyl, cyclopentyl, cyclohexyl, in which - it is an optional double link.
  11. 11. The compound according to claim 4 selected from the group consisting of Acid 1 -. { 4- [3- (5-methyl-2-phenyl-1,3-oxazol-4-yl) propoxy] benzyl} Cyclobutanecarboxylic (example C-16); Acid 1-. { 4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] benzyl} Cyclobutanecarboxylic (example C-19); 2- (. {6- [2- (5-Methyl-2-phenyl] -1,3-oxazol-4-yl) ethoxy] pyridin-3-yl} methyl) tetrahydrofuran-2 acid -carboxylic (example C-48); 2- (. {5- [2- (5-Methyl-2-phenyl-1, 3-oxazol-4-yl) ethoxy] pyridin-2-yl} methyl) tetrahydrofuran-2-carboxylic acid (Example C-49); 2- (. {6- [2- (5-Methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] pyridin-3-yl] methyl) tetra idro-2H-pyran -2-carboxylic acid (example C-56); 2 - [(6- {2- [2- (3-chlorophenyl) -5-methyl-1,3-oxazol-4-yl) ethoxy acid} pyridin-3-yl) methyl] tetrahydrofuran-2-carboxylic acid (example C-59); 2 - [(6- {2- [2- (3-methoxyphenyl) -5-methyl-1,3-oxazol-4-yl] ethoxy} pyridin-3-yl) methyl] tetrahydrofuran-2 acid -carboxy (example C-62); Acid 2-. { 5- [2- (5-Methyl-2-phenyloxazol-4-yl) -ioxy] -pyrazyl-2-ylmethyl} tetrahydrofuran-2-carboxylic acid (example C-77); Acid -. { 4- [2- (5-Methyl-2-phenyl-1,3-oxazol-4-yl) -ioxy] -benzyl} tetrahydrofuran-2-carboxylic acid (example C-78); Acid 2-. { 6- [2- (5-Methyl-2-phenyl-oxazol-4-yl) ethoxy] naphthalen-2-ylmethyl} tetrahydrofuran-2-carboxylic acid (example C-91); or the pharmaceutically acceptable salts thereof.
  12. 12. The compound according to claim 5 having a formula
  13. 13. The compound according to claim 12 selected from the group consisting of 2-ethoxy-3-acid. { 6- { 2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxylpyridin-3-yl} propanoic (example D-1); 2-Methoxy-3- (6-. {2- [5-methyl-2- (3-methylphenyl) -1,3-oxazol-4-yl] ethoxy} pyridin-3-yl) propanoic acid ( example D-3); 2-methoxy-3- acid. { 6- [2- (4-phenoxyphenol) ethoxy] pyridin-3-yl} propanoic (example D-13); 2-Ethoxy-3- [6. { 4 - [(phenylsulfonyl) oxy] phenyl} ethoxy) pyridin-3-ylpropanoic acid (example D-17); 2-ethoxy-3- acid. { 5- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] pyridin-2-yl} propionic (example D-23); 2-methoxy-2-methyl-3- acid. { 6- [3- (5-Methyl-2-phenylisoxazol-4-yl) propoxy] pyridine-3- ii} propionic (example D-27); 2-methoxy-2-methyl-3- acid. { 5- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] pyridin-2-yl} propionic (example D-29); 3- (6- { 2- [2- (4-chlorophenyl) -5-methyloxazol-4-yl) ethoxy acid} pyridin-3-yl) -2-methoxy-2-methylenepropion (example D-30); 2-methoxy-2-methyl-3- acid. { 6- [2- (5-methyl-2-phenyIoxa20l-4-yl) ethoxy] pyridin-3-yl} propionic (example D-35); 2-Methoxy-3- (6- { 2- [2- (3-methoxyphenyl) -5-methyloxazoI-4-yl-p-yl) x-pyridin-3-yl) -2-methylpropionic acid (Example D-43); or the pharmaceutically acceptable salts thereof.
  14. 14. A non-insulin-dependent diabetes mellitus treatment procedure, polycystic ovary syndrome, obesity, hyperglycemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertriglyceridemia, hyperinsulinemia, abnormal insulin disorders and / or glucose evidence, insulin resistance syndrome, and relative disorders a PPAR in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of an alpha-substituted carboxylic acid compound according to claim 1.
  15. 15. A composition comprising at least one compound according to claim 1 and a pharmaceutically acceptable carrier thereof, said compound is optionally in combination with other agents such as a-glucosidase inhibitors, aldosarreductase inhibitors, biguanide preparations, Statin, inhibitors of squalene synthesis, fibrate-based compounds, LDL catabolism promoters and angiotensin converting enzyme inhibitors. SUMMARY Aliphasic carboxylic acids of formula (I): wherein R1 and R2 are as defined in the specification and R3 is wherein Y, Ar1, Ar2, Ar3, R4, R5, R6, R7, R8, R9, R9a, R10, R1, R12, R17, ring A, and p are as defined in the specification; Pharmaceutical compositions containing effective amounts of said compounds or their salts are useful for treating PPAR, specifically disorders related to PPAR a / ?, such as diabetes, dyslipidemia, obesity and inflammatory disorders.
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