MX2012006667A - Novel oxadiazole compounds. - Google Patents

Novel oxadiazole compounds.

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Publication number
MX2012006667A
MX2012006667A MX2012006667A MX2012006667A MX2012006667A MX 2012006667 A MX2012006667 A MX 2012006667A MX 2012006667 A MX2012006667 A MX 2012006667A MX 2012006667 A MX2012006667 A MX 2012006667A MX 2012006667 A MX2012006667 A MX 2012006667A
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Mexico
Prior art keywords
optionally substituted
oxadiazol
chloro
acid
isopropoxyphenyl
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Application number
MX2012006667A
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Spanish (es)
Inventor
Shannon R Fix-Stenzel
Kevin P Cusack
Eric C Breinlinger
Robert H Stoffel
Kevin R Woller
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Abbott Lab
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Publication of MX2012006667A publication Critical patent/MX2012006667A/en

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    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
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    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

Novel oxadiazole compounds, pharmaceutical compositions containing such compounds and the use of those compounds or compositions as agonists or antagonists of the S1P family of G protein-coupled receptors for treating diseases associated with modulation of S1P family receptor activity, in particular by affording a beneficial immunosuppressive effect are disclosed.

Description

NOVEDOUS OXADIAZOL COMPOUNDS Cross-reference to related requests This application claims priority for the Provisional Application E.U.A. Serial No. 61 / 267,679 filed on December 8, 2009, the contents of which are incorporated in this application.
BACKGROUND OF THE INVENTION Sphingosine-1-phosphate (S1P) is part of the sphingomyelin biosynthesis pathway and is known to affect multiple biological processes. S1P is formed through phosphorylation of sphingosine by sphingosine kinases (SK1 and SK2) and is degraded through cleavage by a sphingosine mass to form palmitaldehyde and phosphoethanolamine or through dephosphorylation by phospholipid phosphatases. It is present at high levels (~ 500 nM) in serum and is found in most tissues. This can be synthesized in a wide variety of cells in response to various stimuli, which include cytokines, growth factors and ligands of the G-protein coupled receptor (GPCR). The GPCRs that bind to S1P (currently known as the S1P1-5 receptors of S1P), are coupled via the pertusis toxin sensitive (Gi) routes as well as the pertussis toxin insensitive routes to stimulate a variety of processes. The individual receptors of the S1P family are specific to both tissue and response and therefore are attractive as therapeutic targets.
S1P causes many cell and tissue responses. In particular, S1P has been shown to be an antagonist in all five GPCRs, S1P1 (Edg-1), S1P2 (Edg-5), S1P3 (Edg-3), S1P4 (Edg-6) and S1P5 (Edg-8). The action of S1P in S1P receptors has been linked with resistance to apoptosis, changes in cell morphology, cell migration, growth, differentiation, cell division, angiogenesis and modulation of the immune system through alterations in lymphocyte trafficking. Therefore, S1P receptors are targets for therapy of, for example, neoplastic diseases, autoimmune disorders and tissue rejection in transplantation. These receptors also share 50-55% amino acid identity with three other lysophospholipid receptors, LPA1, LPA2, and LPA3 of structurally related lysophosphatidic acid (LPA).
GPCRs are excellent drug targets with numerous examples of drugs marketed across multiple pathological areas. GPCRs are cell surface receptors that bind hormones on the extracellular surface of the cell and transduce a signal through the cell membrane into the cell. The internal signal is amplified through interaction with the G proteins which in turn interact with several second messenger routes. This transduction path manifests itself in downstream cellular responses that include changes in the cytoskeleton, cell motility, proliferation, apoptosis, secretion and regulation of protein expression to name a few. S 1 P receptors are good drug targets because the individual receptors are expressed in different tissues and signal through different routes making the individual receptors specific to both tissue and response. The tissue specificity of S 1 P receptors is desirable because the development of a selective agonist or antagonist for a receptor localizes the cellular response to the tissues containing said receptor, limiting unwanted side effects. The specificity of response of S1P receptors is also important because it allows the development of agonists or antagonists that initiate or suppress certain cellular responses without affecting other responses. For example, the specificity of response of the S 1 P receptors could allow an S 1 P mimic to initiate platelet aggregation without affecting the morphology of the cell.
The physiological implications of stimulating individual S 1 P receptors are largely unknown, due in part to a lack of selective ligands of the receptor type. The isolation and characterization of S1 P analogs having potent agonist or antagonist activity for S 1 P receptors has been limited.
S 1 P 1 for example is widely expressed and suppression causes embryonic lethality due to rupture of large blood vessel. Adoptive cell transfer experiments using lymphocytes from mice with suppressed S1P1 expression have shown that S1P1 deficient lymphocytes are sequestered in secondary lymphatic organs. In contrast, T cells that overexpress S1P1 are preferentially partitioned into the blood compartment rather than the secondary lymphatic organs. These experiments provide evidence that S1P1 is the main receptor for sphingosine involved in the return and traffic to the secondary lymphoid compartments.
Currently, there is a need for novel, potent, and selective agents that are agonists or antagonists of the individual receptors of the S1P receptor family in order to meet the unmet medical needs associated with receptor agonism or antagonism. Individuals of the S1P receiver family.
BRIEF DESCRIPTION OF THE INVENTION The present invention provides novel compounds described by the general formula (I), (a), (II), (III), (IV), (IVa), (IVb) or (V) as S1P1 receptor agonists coupled to G protein. These compounds reduce the number of circulating and infiltrating T and B lymphocytes, which allows obtaining a beneficial immunosuppressive effect. The compounds also exhibit activity within the S1P receiver family.
In a first embodiment, the invention provides a compound of the formula (I) Formula (I) pharmaceutically acceptable salts, biologically active metabolites, solvates, hydrates, prodrugs racemates, enantiomers or stereoisomers thereof, in which L is a bond or optionally substituted CT-CS alkyl; R 1 is -C (0) -NH-phenyl, -NH-C (0) -furanyl, -NH-S (0) 2 -phenyl optionally substituted, -O-C 1 -C 3 alkyl optionally substituted, -S-alkyl C1-C3 alkyl optionally substituted alkyl of C2-C6, optionally substituted amino, optionally substituted C3-C6 optionally substituted, - (CH2) -alkyl C3, optionally substituted tetrahydrobenzofuranyl, furanyl, optionally substituted tetrahydrofuranyl, optionally substituted 2 3-I dihydroisoindolyl optionally substituted isoindolinyl, optionally substituted imidazolyl, optionally substituted 5,6-dihydroimidazo [1, 2-a] pyrazinyl, optionally substituted imidazo [1,2- a] piraz¡n¡lo optionally substituted, optionally substituted indolyl, optionally substituted isoxazolyl, optionally substituted morpholinyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted -0-CH2-phenyl, optionally substituted -O-phenyl, optionally substituted -O-phenyl, piperidinyl or pcionalmente substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, optionally substituted 1, 2,3,4-tetrahydroisoquinolinyl optionally substituted, optionally substituted quinolinyl, 3,4-dihydroquinolinyl optionally substituted 3,4-dihydroisoquinolinyl optionally substituted , 5,6,7,8-tetrahydro-imidazo [1, 2-a] pyrazinyl, optionally substituted pyrrolyl, optionally substituted pyrrolo [2,3-b] pyridinyl optionally substituted, optionally substituted quinolinyl, optionally substituted thiazolyl or optionally substituted thienyl; R2 is Br, Cl, CF3, CN, or -O-alkyl of d-C2; R3 is -C (C3-C8) optionally substituted, -C (C2-C6) deuterated alkenyl C-C5 alkynyl-C5 C, cycloalkyl, (C3-C6) optionally substituted, -C (C2-C3) optionally substituted-O-alquiloíC ^ -Ca) optionally substituted -alquilíCi-Cs) alkyl optionally substituted imidazolyl, -C (Ci-C3) optionally substituted-morpholinyl, -C (C1-C3) optionally substituted-phenyl, optionally substituted - optionally substituted (Ci-C3) alkyl optionally substituted-piperazinyl, optionally substituted alkyl-pyrrolidinyl, -alkyl-C ^ Cs) optionally substituted- piperidinyl, optionally substituted alkyl (C 1 -C 3) -thienyl, tetrahydrofuranyl or thiazolyl; Y R6 is H; with the condition that R 1 is not substituted by optionally substituted cyclohexyl, -C (0) -cyclohexyl or -N H -cyclohexyl; when L is C 1 -C 3 alkyl, R is not optionally substituted isoxazolyl; when R3 is optionally substituted alkoxy, L-R1 is not cyclohexyl or -CH2-cyclohexyl; Y with the condition that the compound is not In a second embodiment, the invention provides the compound according to the first embodiment wherein R 1 is optionally substituted with one or more substituents that are independently selected from Br, C 1, F, CF 3, CN, oxo , -C (= 0) H, -N (R9) 2, optionally substituted d-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, azabicyclo [2.2.1 optionally substituted Jheptan ilo optionally substituted C3-C6 cycloalkyl, -C (R9) 2-C3-C6 cycloalkyl optionally substituted, -C (R9) 2-azetidinyl optionally substituted, -C R92-piperidyl optionally substituted, -C (R) 2 optionally substituted pyrrolidinyl, -C (R) 2-N (R9) 2, -C (O) - optionally substituted? t-? -alkyl, -C (0) -NR9-d-C6 alkyl, -C (0) -0-optionally substituted Ci-C6 alkyl, -C (R9) 2-C (0) -O-C6-C6 alkyl optionally substituted, -NR9-C3-C6 cycloalkyl optionally substituted, -NR9- azetidinyl optionally substituted, -NR9-furanyl, -NR9-optionally substituted pyrrolidinyl, -NR9-C (0) -0-optionally substituted CrC3 alkyl, -NR9-optionally substituted Ci-C6 alkyl, -NR9-C3-C6 cycloalkyl optionally substituted, -NR9-C (0) -azetidinyl, -NR9-C (0) -furanyl, -NR9-C (0) -pyridinyl, -NR9-C (0) -pyrrolidinyl optionally substituted, -NR9-S (0 ) 2-optionally substituted phenyl, optionally substituted -O-d-Ce alkyl, -O-deuterated-C2-C6 alkyl, optionally substituted-C2-C6-O-alkenyl, optionally substituted -3-C-C6-cycloalkyl , -0-1 H-benzo [d] [1, 2,3] triazolyl, -S (0) 2-N (R9) 2, -S (0) 2-NR9-C-C4 alkyl optionally substituted optionally substituted azetidinyl, optionally substituted piperidinyl, optionally substituted pyridinyl, optionally substituted pyrrolidinyl, optionally substituted 1,2,4-oxadizazolyl, optionally substituted pyrrolidinyl, optionally substituted tetrazolyl, wherein each R is independently selected from H or optionally substituted C ^ C alkyl.
In a third embodiment the invention provides a compound according to any of the foregoing embodiments wherein the compound is a compound of the Formula (Ia) Formula (the) in which L is a link.
In a fourth embodiment the invention provides a compound in accordance with any of the foregoing embodiments wherein R 1 is optionally substituted tetrahydrobenzofu ranyl, optionally substituted ranthyl, optionally substituted 2,3-dihydroisoindolyl, optionally substituted isoindolinyl, optionally substituted imidazolyl, Optionally substituted 5,6-dihydroimidazo [1,2-a] pyrazinyl, optionally substituted imidazo [1,2-a] pyrazinyl, optionally substituted indolyl, optionally substituted isoxazolyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, pyrrolidinyl optionally substituted, 1, 2, 3,4-tetrahydroisoq-quinolinyl optionally substituted, optionally substituted quinolinyl, optionally substituted 3,4-dihydroquinolinyl, optionally substituted 3,4-dihydroquinolinyl, 5,6,7, 8-tetrahydroimidazo [ 1, 2-a] optionally substituted pyrazinyl, pyrrolyl optionally substituted uido, optionally substituted pyrrolo [2, 3-b] pyridinyl, optionally substituted q-quinolinyl, optionally substituted thiazolyl or optionally substituted thienyl.
In a fifth embodiment the invention provides a compound according to any of the above embodiments wherein R 1 is optionally substituted furan or optionally substituted imidazolyl, optionally substituted isoxazolyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, pyrrolidinyl optionally substituted, pyrrolyl optionally substituted, optionally substituted thiazolyl or optionally substituted thienyl.
In a sixth embodiment, the invention provides a compound according to any of the above embodiments wherein R is optionally substituted phenyl or optionally substituted indolyl.
In a seventh embodiment, the invention provides a compound according to any of the preceding claims in which L is optionally substituted C 1 -C 3 alkyl; R1 is -C (0) -N H-phenyl, -N H-C (0) -fu ranyl, -N H-S (0) 2-phenyl optionally substituted, -O-alkoyl of C! C3 optionally substituted, -S-alkyl of (-03, optionally substituted benzyloxy, optionally substituted C3-C6 cycloalkyl, optionally substituted imidazolyl, morpholinyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted piperazinyl, piperidinyl optionally substituted, optionally substituted pyridinyl, optionally substituted pyrrolidinyl or optionally substituted thienyl; R2 is Cl; R3 is isopropyl; Y R6 is H.
In an eighth embodiment the invention provides a compound in accordance with any of the foregoing claims in which L is CH2 and R1 is optionally substituted phenyl 0 C3-C6 cycloalkyl optionally substituted.
In a ninth embodiment the invention provides a compound according to any of the preceding claims wherein the compound is 4- [3- (3-chloro-4-isopropoxy-phenyl) - [1, 2, 4] oxadiazol-5-yl] -3-methyl-pyridine; 3- [3-chloro-4- (1-ethyl-propoxy) -phenyl] -5-o-tolyl- [1, 2, 4] oxadiazole; 3- (3-chloro-4-isopropoxyphenyl) -5- (3-chloropyridin-4-yl) - [1, 2, 4] -oxadiazole; 3-chloro-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzonitrile; 1 - (3-Chloro-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) -3-methylazetidine-3-carboxylic acid; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,4-oxadiazol-5-yl) -1-indol-1-yl) tert-butyl propanoate; 4- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,4-oxadiazol-5-yl) -1 H-indol-1-yl) tert-butyl butanoate; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1 H -indole-1-yl) propane; (1 R, 3 S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenoxy) propane-1,2-diol; (R) -3-. { 3-Chloro-4- [3- (3-chloro-4-isopropoxy-phenyl) - [1, 2,4] -oxadiazol-5-yl] -phenoxy} -propane-1,2-diol; Acid 3-. { 3-Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1,4] oxadiazol-3-yl] -phenoxy} -cyclobutanecarboxylic; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenamino) propi Ifosphonic acid; Ethyl 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzylidene) cyclobutanecarboxylate; Ethyl 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) cyclobutanecarboxylate; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) cyclobutanecarboxylic acid; 5- (3- (3-chloro-4-isopropoxyphenyl) -1,4, 2,4-oxadiazol-5-yl) -1-methyl-1 H -piolzo-3-a-mine; 3- (3-chloro-4-isopropoxyphenyl) -5- (1 H -indol-5-yl) -1,2,4-oxadiazole; 1 - (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) pyrrolidine-3-carboxylic acid; 3-Amino-1- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) pyrrolidine-3-carboxylic acid; (S) -1- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) pyrrolidine-3-carboxylic acid; (R) -1- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) pyrrolidine-3-carboxylic acid; (S) -1- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) benzyl) azetidine-2-carboxylic acid; 4- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1 H -indole-1-yl) butanoic acid; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-i I) -1H-indol-1-yl) -2-fluoropropanoic acid; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1 H -indole-1-yl) -2-methylpropanoic acid; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1 H -indole-1-yl) -2,2-dimethylpropane; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1 H -pyrrolo [2,3-b] pyridin-1-yl) propane acid; Acid (1 R, 3S) -3-. { 4- [3- (5-Chloro-6-isopropoxy-pyridin-3-yl) - [1,4] oxadiazol-5-yl] -3-methyl-phenylamino} -Cyclopentanecarboxylic acid; 4- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) -3,3-dimethylbutanoic acid; 4- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) butanoic acid; 1 - (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) pyrrolidine-3-carboxylic acid; 2- (1- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) pyrrolidin-3-yl) acetic acid; (1R, 3S) -3- (4- (3- (3-Bromo-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; (1 R, 3 S) -3- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; Acid (1 R, 3 S) -3- (4- (3- (5-chloro-6-isopropoxypyridin-3-yl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; (R) -1- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) pyrrolidin-3-amine, acetic acid; Acid (1 R, 2S) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; (1S, 2R) -2- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclohexanecarboxylic acid; (S) -1- (3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) pyrrolidin-1-yl) ethanone; Acid (1 R, 2R) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclohexanecarboxylic acid; Acid (1 R, 2S) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclohexanecarboxylic acid; Acid (1 R, 2S) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclohexanecarboxylic acid; Acid (1 S, 2R) -2- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclohexanecarboxylic acid; Acid (1 R, 2R) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclohexanecarboxylic acid; Acid (1S, 2S) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclohexanecarboxylic acid; (1S, 2R) -2- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; (1S, 2S) -2- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclohexanecarboxylic acid; (S) -N- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) -1 - (methylsulfonyl) pyrrolidin-3- amine; (S) -2- (3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) pyrrolidin-1-yl) acetic acid; Acid (1 R, 3 S) -3- (2-bromo-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; (1 R, 3 S) -3- (2-Bromo-3- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; (1 R, 3 S) -3- (5- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) pyridin-2-ylamino) cyclopentanecarboxylic acid; Acid (1 R, 3S) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-ii) pyridin-2-ylamino) cyclopentanecarboxylic acid; (3S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) -1-methylcyclopentylcarboxylic acid; Acid 2 - ((1 R, 3S) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentyl) acetic acid Acid (1S, 3S) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phen i the min o) - 1 -methylcyclopen tanca rboxíl ico; (1 R, 3 S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,4,4-oxadiazol-5-yl) phenamino) -1-methylcyclopentane rboxylic acid; (3S) -3- (4- (3- (3-Chloro-4-isopropoxyphen-yl) -1,2,4-oxadiazol-5-yl) -phenoxy) -1-fluorocyclopentanecarboxylic acid; (1 R, 3 S) -3- (4- (5- (3-Chloro-4-isopropoxyphenyl) -, 2,4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylic acid; (3S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) -1-hydroxy-cyclopentanecarboxylic acid; Acid (1 R, 3S) -3- (3-Chloro-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid (1 R, 3 S) -3- (4- (3- (3-Bromo-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3-chlorophenylamino) cyclopentanecarboxylic acid; Acid (1 R, 3 S) -3- (3-bromo-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2, 4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; (1 R, 3 S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -2- (trifluoromethyl) phenylamino) cyclopentanecarboxylic acid; (R) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1 H -indole-1-yl) -2-methylpropanoic acid; (S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1 H -indole-1-yl) -2-methylpropanoic acid; 2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-l) phenylamino) cyclopentanecarboxylate of (1 R, 2S) -methyl; 2- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylate of (1 S, 2 R) -methyl; Acid (1 R, 2R) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; Acid (1 S, 2 S) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; 3- (3-chloro-4-isopropoxyphenyl) -5- (1-methyl-1, 2,3,4-tetrahydroquinolin-6-yl) -1, 2,4-oxadiazole; Acid (R) -3- (4- (3- (4- (tetrahydrofuran-3-yloxy) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) -1H-indole- 1-il) propanic; Acid (1 R, 3 S) -3- [4- (5-biphenyl-2-yl- [1, 2,4] oxadiazol-3-yl) -2-methyl-phenylamino] -cyclopentanecarboxylic acid; (1 R, 3S) -3- [4- (5-Biphenyl-3-yl- [1, 2,4] oxadiazol-3-yl) -2-methyl-phenylamino] -cyclopentanecarboxylic acid; Acid (1 R, 3 S) -3- [4- (5-biphenyl-4-yl- [1, 2,4] oxadiazol-3-yl) -2-methyl-phenylamino] -cyclopentanecarboxylic acid; Acid (1 R, 3S) -3-. { 4- [5- (4-cyclohexyl-phenyl) - [1, 2, 4] oxadiazol-3-yl] -2-methyl-phenylamino} -cyclopentanecarboxylic; (1 R, 3 S) -3 - ((4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) (methyl) amino) cyclopentanecarboxylic acid; 3- (5- (3- (3-Chloro-4-isopropoxyphenyl) -1,4,4-oxadiazol-5-yl) -1 H -indol-1-yl) cyclopentanecarboxylic acid methyl ester; 3- (5- (3- (3-Chloro-4-isopropoxyphen-yl) -1,2,4-oxadiazol-5-yl) -1H-indole-1-yl) cyclopentanecarboxyme; (1 R, 3 S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -2-ethynylphenylamino) cyclopentanecarboxylic acid; Acid (1 R, 3 S) -3- (5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxad i azole-5-I) - 1 H -indole-1-yl ) carboxyl tanca rboxilico; (1S, 4R) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3-methoxyphenyl) -2-azabicyclo [2.2.1 ] heptan-3-one; Acid (1 R, 3S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,4,4-oxadiazol-5-yl) -3-methoxife nor the mi no) cyclope n tanca rboxíl ico; (R) -3- (3- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -2-methylphenoxy) propane-1,2-diol; N- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) isonicotinamide; N- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenol) isonotocin; (3S) -3- (4- (3- (3-Chloro-4-isopropoxy-phenyl) -1,2,4-oxadiazol-5-yl) phenylamino) -1-hydroxycyclopentanecarboxylic acid; Acid (1 R, 3 S) -3- (4- (5- (3-chloro-4-isopropoxyphenyl) -1,2, 4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylic acid; 1-amino-3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenoxy) cyclopentanecarboxylic acid; 1-Amino-3- (3-chloro-4- (5- (5-chloro-6-isopropoxypyridin-3-i I) -1,2,4-oxadiazol-3-yl) phenoxy) cyclopentanecarboxylic acid; (1 R, 3 S) -3- (4- (5- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-3-yl) -3-methylphenylamino) cyclopentanecarboxylic acid; (1S, 4R) -2- (4- (5- (5-chloro-6-isopropoxypyridin-3-yl) -1,2,4-oxadiazol-3-yl) -3-methylphenyl) -2-azabicyclo [ 2.2.1] heptan-3-one; (1 R, 3 S) -3- (4- (5- (5-chloro-6-isopropoxypyridin-3-yl) -1,2,4-oxadiazol-3-yl) -3-methylphenylamino) cyclopentanecarboxylic acid; Methyl 2- (5- (3- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) -2H-tetrazol-2-yl) acetate; 3- (3- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) -1,2,4-oxadiazol-5 (2H) -one; (1 R, 3 S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3-ethylphenylamino) cyclopentanecarboxylic acid; Acid (1 R, 3S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2, 4-oxadiazol-5-yl) -3-cyanophenolamine) cyclopentanecarboxylic acid; (2R, 4R) -4- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,2-oxadiazol-5-yl) phenylamino) pyrrolidine-2-carboxylic acid; 2- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenylamino) propan-1-ol; (R) -2- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,4,4-oxadiazol-5-yl) phenoxy) propane acid; (R) -N- (2-hydroxyethyl) -2- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) propanamide; (R) -2- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) propanal; Acid 3-. { 3-Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1, 2, 4] oxadiazol-3-yl] -phenoxy} -cyclobutanecarboxylic; or Acid (1 R, 3S) -3- (4- (5- (5-Chloro-6-isopropoxypyridin-3-yl) -1,2,4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylic acid.
In a tenth embodiment, the invention provides a compound of the Formula (I I) Formula (I I) pharmaceutically acceptable salts, biologically active metabolites, solvates, hydrates, prodrugs enantiomers or stereoisomers thereof, in which And it is a link; L is a bond or CH2; R is optionally substituted Ci-C4 alkyl, optionally substituted indolyl or optionally substituted phenyl; R2 is CF 3.
R3 is H, morpholinyl, optionally substituted piperidine or C3-C5 cycloalkyl; Y R is H.
In a tenth embodiment, the invention provides a compound in accordance with the tenth embodiment in which R1 is optionally substituted with one or more substituents that are independently selected from Cl, F, CN, C: -C3 alkyl optionally substituted, -CH2-azetidinyl optionally substituted, -CH2-pyrrolidinyl optionally substituted, -CH2NRcRd, -NH-C3-C6 cycloalkyl optionally substituted, piperidinyl optionally substituted, in which Rc and Rd are independently H, optionally substituted d-C6 alkyl or optionally substituted C3-C6 cycloalkyl; In a twelfth embodiment the invention provides a compound in accordance with the tenth and eleventh embodiments in which the compound is Acid 1 - ((4- (3- (4- (4-fluoropiperidin-1 -yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) benzylamino) methyl) -cyclopropanecarboxylic acid; Acid (R) -1 - (4- (3- (4- (4-fluoropiperidin-1 -yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) benzyl) pyrrolidin- 3-carboxylic; Acid (S) -1 - (4- (3- (4- (4-fluoropiperidin-1 -yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) benzyl) pyrrolidin- 3-carboxylic; 1 - (4- (3- (4- (4-Fluoroopiperidin-1-yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) benzylamino) -cyclopropanecarboxylic acid; Acid 1 - (4-. {3- [4- (4-Fluoro-piperidin-1-yl) -3-trifluoromethyl-phenyl] - [1,4,2] oxadiazol-5-yl} - benzylamino) -cyclopropanecarboxylic acid; Acid 1 - (4- { 3- [4- (4-Fluoro-piperidin-1-yl) -3-trifluoromethyl-phenyl] - [1,4,2] oxadiazol-5-yl}. -benzyl ) -pyrrolidine-3-carboxylic acid; Acid 1 - (4- { 3- [4- (4-fluoro-piperidin-1-yl) -3-trifluoromethyl-phenyl] - [1, 2,4] oxadiazol-5-yl}. -benzyl ) -4-methyl-pyrrolidine-3-carboxylic acid; 4-Fluoro-piperidin-1-yl) -3-trifluoromethyl-phenyl] - [1, 2, 4] oxadiazol-5-yl acid} -benzylamino) -acetic; Acid [(S) -1 - (4- { 3- [4- (4-fluoro-piperidin-1-yl) -3-trifluoromethyl-phenyl] - [1,4,2] oxadiazol-5-yl .}. -benzyl) -pyrrolidin-2-yl] -acetic; [1 - (4- { 3- [4- (4-Fluoro-piperidin-1-yl) -3-trifluoromethyl-phenyl] - [1,4,2] oxadiazol-5-yl}. benzylamino) -cyclopropyl] -methanol; Acid 1 - (4-. {3- [4- (4-fluoro-piperidin-1-yl) -3-trifluoromethyl-phenyl] - [1,4,2] oxadiazol-5-yl} - benzyl) -4,4-dimethyl-pyrrolidine-3-carboxylic acid; 1 - . 1 - [(4- { 3- [4- (4-Fluoro-piperidin-1-yl) -3-trifluoromethyl-phenyl] - [1,4,2-oxadiazol-5-yl] -benzylamino ) -methyl] -cyclopropanol; (1 R, 3 S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3- (trifluoromethyl) phenylamino) cyclopentanecarboxylic acid; (1 R, 3 S) -3- (4- (3- (3-Chloro-4-isopropoxy-yen-yl) -1,2,4-oxadiazol-5-yl) -3-methylphenylamino) -cyclopentanecarboxylic acid; (1 R, 3 S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -2-methylphenylamino) cyclopentanecarboxylic acid; 4- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) -2-methylbutanoic acid; 2- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) -tert-butyl acetate; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) propane-tert-butyl ester; 1-amino-3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenoxy) cyclopentancarboxylic acid; Acid 3-. { 4- [3- (3-chloro-4-isopropoxy-phenyl) - [1, 2,4] oxadiazol-5-yl] -phenoxy} -cyclobutanecarboxylic; 2- (6- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3,4-dihydroxyquinolin-1 (2H) -yl) acetic acid 3- (6- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3,4-dihydroquinolin-1 (2H) -yl) propane acid; (E) -4- (3- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -2-methylphenoxy) but-2-enoic; 4- (3- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -2-methylphenoxy) butanoic acid; 4- (3- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -4-methylphenoxy) butanoic acid; (3- {4- [3- (3-Chloro-4-isopropoxy-phenyl) - [1,4,4] oxadiazol-5-yl] -phenylamino} -propyl) - diethyl ester - phosphonic; (3- {4- [3- (3-Chloro-4-isopropoxy-phenyl) - [1, 2, 4] oxadiazol-5-yl] -benzylamino} -propyl) -phosphonic acid; Acid (1S, 3R) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentylphosphonic acid; Acid (1 R, 3R) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentylphosphonic acid; Acid (1 R, 3R) -3- (2-Bromo-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentylphosphonic acid; (1 R, 3 S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentylphosphonic acid; Acid (1 R, 3S) -3- (2-bromo-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentylphosphonic acid; (1S, 3S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentylphosphonic acid; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) cyclobutanecarboxylic acid; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) cyclopentanecarboxylic acid; 1 - (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) azetidin-3-carboxylic acid; 2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) propan-2-amines; 3- (2- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) propane-2-ylamino) propanoate methyl; 3- (2- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) propane-2-ylamino) propane acid; 3- (3-chloro-4-isopropoxy-phenyl) -5- (1 H -indol-4-yl) -1,2,4-oxadiazole; (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) methanamine; 3- (3- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) cyclopentylamino) propane acid; 4- (3- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) cyclopentylamino) butanoic acid; (S) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -, 2,4-oxadiazol-5-yl) phenoxy) propane-1,2-diol; 4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzenesulfonamide; 3,3 '- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylsulfonylazand -yl) tert-butyl dipropanoate; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -phenylsulfonamido) tert-butyl propanoate; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylsulfonamido) propane acid; 2, 2 '- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phen i sulphonylazandi-yl) d-acetic acid; 2, 2 '- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylsulfonylazand -yl) tert-butyl diacetate; 2- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylsulfonamido) tert-butyl acetate; 2- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylsulfonamido) acetic acid; 2- (5- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3,4-dihydroisoq-quinolin-2 (1 H) -yl) -acetic acid ester butyl; 5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3,4-dihydroisoquinolin-2 (1 H) -tert-butylcarboxylate; 3- (3-chloro-4-isopropoxyphenyl) -5- (1, 2, 3,4-tetrahydroisoquinolin-5-yl) -1,2,4-oxadiazole; 2- (5- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3,4-dihydroisoquinolin-2 (1 H) -yl) acetic acid; 3- (5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3,4-dihydroisoquinolin-2 (1 H) -yl) tert-butyl propanoate; 3- (5- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3,4-dihydroisoquinolin-2 (1 H) -yl) propane acid; 2- [3- (3-Chloro-4-isopropoxy-phenyl) - [1,4] oxadiazol-5-yl] -3-methyl-1-5,6,7,8-tetrahydro-imidazo [1] 2-a] pyrazine; 1 - . 1 - . 1 - . 1 -. { 2- [3- (3-chloro-4-isopropoxy-phenyl) - [1, 2, 4] oxadiazol-5-yl] -3-methyl-5,6-dihydro-8H-imidazo [1, 2-a] ] pyrazin-7-il} -etanone; Ter-butyl ester of acid. { 2- [3- (3-chloro-4-isopropoxy-phenyl) - [1, 2,4] oxadiazol-5-yl] -3-methyl-5,6-dihydro-8H-imidazo [1, 2 -a] pyrazin-7-il} -acetic; Acid { 2- [3- (3-Chloro-4-isopropoxy-phenyl) - [1,4,2-oxadiazol-5-yl] -3-methyl-5,6-dihydro-8H-imidazo [1,2-a] ] pyrazin-7-il} -acetic; 3- [3- (3-chloro-4-isopropoxy-phenyl) - [1, 2, 4] oxadiazol-5-yl] -2-methyl-imidazo [1, 2-a] pyrazine; 3- (3-Chloro-4-ylpropoxyphen-yl) -5- (4 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) phenyl) -1,2,4-oxadiazole; 2- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenoxy) acetic acid; 1 - (4- (3- (3-Cyano-4-isopropoxyphen-yl) -1,2,4-oxadiazol-5-yl) benzyl) azetidine-3-carboxylic acid; 1 - (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) cyclopropanecarbonitrile; 1- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) cyclopropanecarbaldehyde; 3 - ((1 - (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) cyclopropyl) methylamino) propanoic acid; N- (4- (3- (3-chloro-4-isopropoxyphen-yl) -1,2,4-oxadiazol-5-yl) benzyl) -1 - (2,2-dimethyl-1,3-di-oxo) ? -4-il) methane amine; 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzylamino) propane-1,2-diol; (Z) -methyl-3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2, 4- oxadiazol-5-yl) phenyl) acrylate; trans-methyl-2- (4- (3- (3-chloro-4-ysopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) cyclopropanecarboxylate; Trans-2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) -cyclopropanecarboxylic acid; 5- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazole-5-j |) isoindoline-2-carboxylic acid tert-butyl ester; 3- (3-chloro-4-isopropoxyfen M) -5- (isoindoli n-5-M) -1,2,4-oxadiazole; 3- (5- (3- (3-Chloro-4-isopropoxyphenyl) -1,4,4-oxadiazol-5-yl) isoindolin-2-yl) propanoate methyl; 3- (5- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) isoindolin-2-yl) propane acid; (Z) -methyl-3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) acrylate; (Z) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) acrylic acid; 3- (3-Chloro-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclobutanecarboxylic acid; 3- (4- (3- (3-Chloro-4-isopropoxyphen-yl) -1,2,4-oxadiazol-5-yl) phenylamino) -cyclobutanecarboxylic acid; 1 - (4- (3- (4- (4-fluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) benzyl) azetidine-3-carboxylic acid; of 5 - ((4- (3- (4- (4-fluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) benzylamino) methyl) isoxazole- 3- ol; 2 - ((4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) methyl) morpholine; Acid (1 R, 3S) -3- (4- (3- (4 - ((S) -tetrahydrofuran-3-yloxy) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazole-5- il) phenylamino) cyclopentanecarboxylic; Acid (1R, 3S) -3- (4- (3- (4- (4-fluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenylamino ) cyclopentanecarboxylic; Acid (1R, 3S) -3- (4- (3- (4- (4,4-difluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic; Acid (1S, 3S) -3- (4- (3- (4- (4-fluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -1, 2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic; Acid (1R, 3R) -3- (4- (3- (4- (4-fluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -1, 2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic; Acid (1S, 3R) -3- (4- (5- (3-cyano-4- (4-fluoropiperdin-1-yl) phenyl) -1,2,4-oxadiazol-3-yl) - 2- (trifluoromethyl) phenylamino) cyclopentanecarboxylic; Acid (1S, 3R) -3- (4- (5- (3-Cyano-4- (4-fluoropiperidin-1-yl) phenyl) -1, 2,4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylic acid; 5- [3- (4-Fluoro-phenyl) - [1,2,4] oxadiazol-5-yl] -2- (4-fluoro-piperidin-1-yl) -benzonitrile; 5- [3- (4-fluoro-3-trifluoromethyl-phenyl) - [1, 2, 4] oxadiazol-5-yl] -2- (4-fluoro-piperidin-1-yl) -benzonitrile; Acid (1 R, 3S) -3- [4- (5-biphenyl-2-yl- [1, 2, 4] oxadiazol-3-yl) -2-methy1-phenylalan] - cyclopentanecarboxylic; Acid (1 R, 3 S) -3- [4- (5-biphenyl-3-yl- [1, 2,4] oxadiazol-3-yl) -2-methyl-phenylamino] -cyclopentanecarboxylic acid; Acid (1 R, 3S) -3-. { 4- [5- (4-cyclohexyl-phenyl) - [1, 2, 4] oxadiazol-3-yl] -2-methyl-phenylamino} -cyclopentanecarboxylic; or Acid (1 R, 3S) -3- (4- (5- (4-isobutylphenyl) -1,2,4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylic acid.
In a thirteenth embodiment the invention provides a compound of the Formula (I I I) Formula (I I I) pharmaceutically acceptable salts, biologically active metabolites, solvates, hydrates, prodrugs, enantiomers or stereoisomers thereof, in which E is CH or N; And it's a link; L is a link; R1 is optionally substituted aryl; R2 is H; R3 is H; Y R6 is H or optionally substituted Ci-C3 alkyl.
In a fourteenth embodiment the invention provides a compound of Formula (IV) Formula (IV) or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof, in which: X is N or CR4; L is a bond, -CH2CH2-, C3-C6 cycloalkyl, or -CHR5; Y is -O-, -NR7- or -C (R7) (R7 ') -; R1 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -alkyl (Ci-C6) optionally substituted-O-C-C3 alkyl, -alkyla- Ce) optionally substituted-0-alkyl (Ci-C6) -0 -alkyl Ci-C3, -alkyl-Ce) optionally substituted-O-aryl, alkylsulfanylalkyl, unsubstituted C2-C5 alkyl, substituted Ci-C6 alkyl, -COR11, -O-C1-C3 alkyl optionally substituted , -N (R7) (R8), -N (R7) S02-R1 or optionally substituted C3-C6 cycloalkyl, and in which R1 is not substituted cyclopentathiophen, halogenothiophene, indane substituted or substituted chromenone; R2 and R6 may be the same or different and are independently H, -alkyl of C, -C4, -O-C-C3 alkyl, -CF3, -CN, halogen or -COO-Ci-C4 alkyl; R3 is optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted C3-C6 cycloalkyl, - (CH2) n -R11, -CO-OR11, -CO-R1, -CON (R7) (R11), -N (R7) (R11), -SOR11, -S02R11 and optionally substituted straight or branched C1-CB alkyl chain optionally including the groups -CO-, -COO-, -SO-, -S02-, -CONH- , -NHCO-, -N- or -O- embedded within the alkyl chain; and when Y is O, R3 is not alkyldiazepane, -C (CH3) 2COOCH2CH3 or -CH2CH2N (CH2CH3) 2; and when Y is -CH2-, R3 is not -CH2COOH; or Y is a bond and R3 is optionally substituted morpholino; R 4 is H, -alkyl of -O-alkyl of C! -Ca, -CF 3, -CN or halogen; R 5 is H, O-C 1 -C 3 alkyl or CrC 3 alkyl; each time R7 or R7 occurs is independently H or optionally substituted C ^ -C3 alkyl; R8 is H, optionally substituted CH3, or -COR11; R11 is hydrogen, Ci-C3 alkyl optionally substituted, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl or optionally substituted C3-C6 cycloalkyl; Y n is 1, 2, 3 or 4; with the condition that R1 is not optionally substituted ranyl or optionally substituted -C (O) furanyl; R3 is not an optionally substituted n-butyl group; R 1 is not optionally substituted cyclopropyl, optionally substituted cyclohexyl, optionally substituted franyl, optionally substituted imidazolyl, optionally substituted indolyl, optionally substituted naphthyl, optionally substituted piperazinyl, optionally substituted pyrazolyl, optionally substituted pyridazinyl, or optionally substituted quinolinyl; R1 is not substituted with -C (0) -cyclopentyl, optionally substituted cyclopentyl, -C (0) -cyclobutyl, cyclobutyl, -C (O) -cyclohexyl or optionally substituted cyclohexyl; R3 is not substituted with -C (0) -cyclopropyl; when R3 is CH3 or 4-chlorophenylmethyl, L-R1 is not cyclopropyl, cyclopentyl, optionally substituted cyclohexyl, -C H2-cyclohexyl, -N H -cyclohexyl, -CH2CH2-cyclohexyl or optionally substituted pyrazolyl; when Y is O, R3 is not optionally substituted alkyl (C0-C4) -isoxazolyl or optionally substituted pyrazolyl; when L is C 1 -C 3 alkyl, R 1 is not optionally substituted isoxazolyl; when L is a bond, R1 is not optionally substituted cyclobutyl, optionally substituted cyclohexyl, optionally substituted naphthyl, optionally substituted -CH2-naphthyl, optionally substituted -C H2-0-naphthyl, optionally substituted pyrazolyl or tetrahydro-robofofan; with the condition that the compound is not with the condition that the compound is not wherein R3 is optionally substituted piperazinyl or optionally substituted phenyl; with the condition that the compound is not wherein R1 is optionally substituted pyridine or 3-chlorophenyl and -Y-R3 is -NH-C (0) -phenyl optionally substituted; -O-pyridinyl optionally substituted; -NH-C (0) -OCH3; -CH2-piperazinyl optionally substituted; -O-C ^ -C ^ alkyl optionally substituted; -CH2-morpholinyl; or -0-C (0) -pyridinyl optionally substituted; with the condition that the compound is not L is CH2, CH (CH3) or CH2CH2; And it is O or CH2; R2 is H or OCH3; R3 is CH3 or OCF3; Y R is H or N02; that the compound is not that the compound is not wherein R is phenyl, 4-chlorophenyl, piperidinyl or thienyl.
In a fifteenth embodiment the invention provides a compound in accordance with the fourteenth embodiment in which R1 is optionally substituted phenyl, optionally substituted tetrahydrobenzofuranyl, optionally substituted furanyl, optionally substituted 2,3-dihydroisoindolyl, optionally substituted isoindolinyl, optionally substituted midazolyl, optionally substituted 5,6-dihydroimidazo [1, 2-a] pyrazinyl, imidazo [ 1, 2-a] optionally substituted pyrazinyl, optionally substituted indolyl, optionally substituted isoxazolyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, 1,2, 3,4-tetrahydroisoquinolinyl optionally substituted, q-quinolinyl optionally substituted, optionally substituted 3,4-dihydroquinolinyl, optionally substituted 3,4-dihydroisoquinolinyl, optionally substituted 5,6,7,8-tetrahydroimidazo [1, 2-a] pyrazinyl, optionally substituted pyrrolyl, pyrrolo [2, 3-b] optionally substituted pyridinyl, optionally substituted quinolinyl, optionally substituted thiazolyl, optionally substituted thienyl, -alkyl (C- | -C6) optionally substituted-O-C, -C3 alkyl; -alquila-Ce) optionally substituted-O-alkyHC! -CeJ-O-C1-C3 alkyl, -alkyl-Ce) optionally substituted-O-phenyl, unsubstituted C2-C5 alkyl, substituted C: -C6 alkyl, -COR11, - O-C3-C3 alkyl optionally substituted, -N (R7) (R8), -N (R7) S02-R11 or optionally substituted C3-C6 cycloalkyl; R2 and R6 may be the same or different and are independently H, -alkiltd-C.!), -O-alkyl of (-C3, -CF3, -CN, Cl, or F.
In a sixteenth embodiment the invention provides a compound in accordance with the fourteenth and fifteenth modalities in which L is a bond, -CH2CH2-, or -CHR5; Y is -O-, -NR7- or -C (R7) (R7 ') -; R1 is optionally substituted phenyl, optionally substituted furanyl, optionally substituted isoindolinyl, optionally substituted imidazolyl, optionally substituted imidazo [1,2-a] pyrazinyl, optionally substituted indolyl, optionally substituted isoxazolyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, optionally substituted quinolinyl, optionally substituted pyrrolyl, optionally substituted pyrrolo [2,3-b] pyridinyl, optionally substituted quinolinyl, optionally substituted thiazolyl, thienyl optionally substituted, -alkyl (d-C6) optionally substituted-O-C-C3 alkyl, -alkyl-Ce) optionally substituted-O-phenyl, unsubstituted C2-C5 alkyl, substituted Ci-C6 alkyl, -COR11, -O-C ^ -C3 alkyl optionally substituted, -N (R7) (R8), -N (R7) S02-R1 or cycloalkyl C3-C6 optionally substituted; R 2 and R 6 may be the same or different and are independently H, -C 4 alkyl, -O-C -C 3 alkyl, -CF 3, -CN, Cl or F; R3 is optionally substituted phenyl, optionally substituted piperidinyl, optionally substituted furanyl, optionally substituted pyrimidinyl, optionally substituted pyridinyl, optionally substituted C3-C6 cycloalkyl, - (CH2) n-R11, -CO-OR11, -CO-R11, - CON (R7) (R11), -N (R7) (R11), -SOR11, -S02R11 and optionally substituted straight or branched C ^ C6 alkyl chain.
In a seventeen embodiment the invention provides a compound according to the fourteenth to the sixteenth embodiment in which R1 is optionally substituted phenyl, optionally substituted furanyl, optionally substituted indolyl, optionally substituted isoxazolyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl. , optionally substituted pyrrolyl, unsubstituted C2-C5 alkyl, substituted C6C3 alkyl, -COR11, -N (R7) (R8), optionally substituted -OC-C3 alkyl, or optionally C3-C6 cycloalkyl replaced; R2 and R6 may be the same or different and are independently H, -alkyl (C1-C4), -CF3, Cl or F; R3 is optionally substituted phenyl, optionally substituted pyrimidinyl optionally substituted piperidinyl, optionally substituted pyridinyl, optionally substituted C3-C6 cycloalkyl, - (C H2) n-R1 1, optionally substituted straight or branched C alkylene chain or In a eighteenth embodiment the invention provides a compound according to the fourteenth to seventeen embodiments in which R1 is optionally substituted with one or more substituents that are independently selected from Br, Cl, F, CF3, CN, oxo, -C (= 0) H, -N (R9) 2l optionally substituted d-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, azabicyclo [2.2.1 optionally substituted Jheptanyl, C3 cycloalkyl C6 optionally substituted, -C (R9) 2-cycloalkyl optionally substituted C3-C6, -C (R9) 2-azetidinyl optionally substituted, -CR92-piperidinyl optionally substituted, -C (R9) 2-pyrrolidinyl optionally substituted, - C (R9) 2-N (R9) 2, -C (0) - optionally substituted CrC6 alkyl, -C (0) -NR9-alkyl of (^ -? Β, -C (0) -0-Ci-C6 alkyl optionally substituted, -C (R9) 2-C (0) -0-Ci-C6 alkyl optionally substituted, -NR9-C3-C6 cycloalkyl optionally substituted, - Optionally substituted NR9-azetidinyl, -NR9-furanyl, optionally substituted -NR9-pyrrolidinyl, -NR9-C (0) -O-optionally substituted C1-C3 alkyl, -NR9-optionally substituted Ci-C6 alkyl, -NR9- optionally substituted C3-C6 cycloalkyl, -NR9-C (0) -azetidinyl, -NR9-C (0) -furanyl, -NR9-C (0) -pyridinyl, -NR9-C (0) -opyrrolidinyl optionally substituted, -NR9-S (0) 2-optionally substituted phenyl, -O-C6-C6 alkyl optionally substituted, -O-deuterated-C2-C6 alkyl, -O-C2-C6 alkenyl optionally substituted, -O-cycloalkyl of optionally substituted C3-C6, -0-1 H-benzo [d] [1, 2,3] triazolyl, -S (0) 2- N (R9) 2, -S (0) 2-NR9-alkyl of C ^ -C4 optionally substituted, optionally substituted azetidinyl, optionally substituted piperidinyl, optionally substituted pyridinyl, pyrrolidinyl optionally substituted, optionally substituted 1,2,4-oxadizazolyl, optionally substituted pyrrolidinyl, optionally substituted tetrazolyl, Y wherein each R9 is independently selected from H or optionally substituted Ct-C6 alkyl.
In a nineteenth embodiment the invention provides a compound according to the fourteenth to eighteenth embodiments in which each optional substituent or substituent is independently one or more R 0 groups in which R10 is optionally substituted alkylAlkenyl, optionally substituted alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alcoxicarbonilheterocicloalcoxi, alkyl, alkylamino, alkylcarbonyl, alkylester, alkyl-OC (O) -, alk uil-heterociclilol, alk uil-cycloalkyl, alkyl-nitrile, ylsulphonyl alk, alk uinilo, amido, optionally substituted amino, aminoalkyl, aminoalkoxy, aminocarbonyl, azabicyclo [2.2.1] heptanyl optionally substituted, carbonitrile, carbonylalkoxy, carboxamido, CF3, CN, -C (0) OH, -C (0) H, - C (O) -C (CH 3) 3, -OH, -C (0) 0 -alkyl, -C (0) 0 -cycloalkyl optionally substituted, -C (0) -heterocyclyl, -C (0) - alkyl, -C (0) -cycloalkyl optionally substituted, -C (0) -heterocyclyl, CN, optionally substituted cycloalkyl, dialkylamino, dialq uilaminoalcoxi, dialquilaminocarbon ilalcoxi, dialkylaminocarbonyl, dialkylaminosulfonyl, -C (0) -OR, halogen, heterocyclyl optionally substituted, optionally substituted heterocyclylalkyl, heterocyclyloxy optionally its stituido, hydroxy, hydroxyalkyl, nitro, oxo, optionally substituted phenyl, -S02CH3, -S02C F3, sulfonyl, tetrazolyl, tienilalcoxi, trifluoromethylcarbonylamino, trifluoromethylsulfonamido, heterocyclylalkoxy, heterocyclyl-S (0) p, optionally substituted cycloalkyl-S (0) p , optionally substituted alkyl-S-, optionally substituted heterocyclyl-S, heterocycloalkyl, cycloalkylalkyl, heterocyclic, cycloalkylthio, N-alkylamino and? , β-dialkylamino in which Ra is optionally substituted alkyl, optionally substituted heterocycloalkyl, or optionally substituted heterocyclyl and p is 1 or 2.
In a twentieth embodiment the invention provides a compound in accordance with fourteenth to nineteenth modalities in which -Y-R3 is In a twenty-first embodiment the invention provides a compound according to the fourteenth to twentieth modalities in which the compound is Acid 3-. { 3-Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1, 2, 4] oxadiazol-3-yl] -phenoxy} -Cyclobutanecarboxylic (1 R, 3 S) -3- (4- (5- (5-Chloro-6-isopropoxypyridin-3-yl) -1,2,4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylic acid; (1S, 4R) -2- (3- (3- (5-Chloro-6-isopropoxypyridin-3-yl) -1,2, 4-oxadiazol-5-yl) -2-methylphenyl) -2-azabicyclo [2.2.1] heptan-3-one; Acid (1 R, 3S) -3- (4- (3- (5-chloro-6-isopropoxypyridin-3-yl) -1,2,4-oxadiazol-5-yl) -2-methylphenylamino) cyclopentanecarboxylic acid; Acid (1 R, 3S) -3- (4- (3- (5-chloro-6-isopropoxypyridin-3-yl) -1, 2,4-oxadiazol-5-yl) -3- (trifluoromethyl) phenylamino) cyclopentanecarboxylic; 1-Amino-3- (3-chloro-4- (5- (5-chloro-6-isopropoxypyridin-3-i I) -1,2,4-oxadiazol-3-yl) phenoxy) cyclopentanecarboxylic acid Acid 3-. { 3-Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1,4] oxadiazol-3-yl] -phenoxy} -cyclobutanecarboxylic; Acid 4-. { 3-Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1,4] oxadiazol-3-yl] -phenoxy} -cyclohexanecarboxylic; Acid 3-. { 3-Chloro-4- [3- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1,4] oxadiazol-5-yl] -phenoxy} -cyclobutanecarboxylic; Acid 3-. { 3-Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1,4] oxadiazol-3-yl] -phenoxy} -cyclobutanecarboxylic; Acid 3-. { 3-Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1,4] oxadiazol-3-yl] -phenoxy} -cyclohexanecarboxylic; Acid 4-. { 3-Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1,4] oxadiazol-3-yl] -phenoxy} -cyclohexanecarboxylic; Cis-acid. { 3-Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1,4] oxadiazol-3-yl] -phenoxy} -cyclopentanecarboxylic Trans-3- acid. { 3-Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1,4] oxadiazol-3-yl] -phenoxy} -cyclopentanecarboxylic; or Acid (1 R, 3 S) -3- (4- (5- (5-bromo-6-isopropoxypyridin-3-yl) -1,2,4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylic acid.
In a twenty-second embodiment the invention provides compound in accordance with Formula (V) And it's a link R3 is -3 - ((1aS, 5aR) -1, 1, 2-trimethyl-1, 1 a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalenyl, or optionally substituted thienyl; Ra is H or optionally substituted C ^ C alkyl Rb is H, optionally substituted Ci-C6 alkyl or optionally substituted C3-C6 cycloalkyl.
In a twenty-third embodiment the invention provides a compound according to the twenty-second embodiment in which the compound is Acid (1 R, 3S) -3- (4- (3- (4-phenyl-5- (trifluoromethyl) thiophen-2-yl) -1,2,4-oxadiazole-5-yl) phenol lamino) cyclopentanecarboxylic Acid (S) -3-. { 4- [3 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1, 2, 4] oxadiazol-5-yl] -phenylamino} -cyclopentanecarboxylic. a twenty-fourth embodiment the invention provides a pharmaceutical composition comprising a compound according to any of the above embodiments or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof and a diluent or pharmaceutically acceptable vehicle.
In a twentieth embodiment, the invention provides the use of one or more compounds according to any of the above embodiments or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug or stereoisomer thereof for the manufacture of a medicament for treating an immune disorder In a twenty-sixth embodiment the invention provides use in accordance with the twenty-fifth embodiment in which the immune disorder is active chronic hepatitis, Addison's disease, ankylosing spondylitis, anti-phospholipid syndrome, asthma, atopic allergy, autoimmune atrophic gastritis, autoimmune achlorhid, celiac disease, Crohn's disease, Cushing's syndrome, dermatomyositis, Goodpastu re syndrome, Grave's disease, Hashimoto's thyroiditis, idiopathic adrenal atrophy, idiopathic thrombocytopenia, juvenile rheumatoid arthritis, Lambert-Eaton syndrome, lupoid hepatitis, lupus, mixed connective tissue disease, multiple sclerosis, pemphigoid, pemphigus vulgaris, pernicious anemia, phacogenic uveitis, polyarteritis nodosa, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, Raynauds, sínd rome de Reiter, relapsing polychondritis, Sch midt syndrome, sínd rome de Sjogren, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis, thyrotoxicosis, rheumatoid arthritis, insulin resistance type B, ulcerative colitis, or Wegener's granulomatosis.
In a twenty-seventh embodiment, the invention provides the use of one or more compounds according to any of the above embodiments or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof for the manufacture of a medicament for treating a disorder of the central nervous system.
In a twenty-eighth embodiment the invention provides the use of one or more compounds according to any of the above embodiments or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof for the manufacture of a medicament for treating multiple sclerosis.
In a twenty-ninth embodiment the invention provides the use of one or more compounds according to the claims of any of the above embodiments or pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof for the manufacture of a medicine to treat rheumatoid arthritis.
In a thirtieth embodiment the invention provides a pharmaceutical composition comprising one or more compounds according to Formula (I), (a), (II), (III), (IV), or (V) or pharmaceutically acceptable salts , solvates, hydrates, metabolites, prodrugs or stereoisomers thereof and a pharmaceutically acceptable diluent or vehicle. In a preferred aspect, the invention provides a pharmaceutical composition in which the compound or compounds are present in a quantity Therapeutically effective.
In a thirty-first embodiment the invention provides a packaged pharmaceutical product comprising one or more compounds according to Formula (I), (a), (II), (III), (IV), or (V) or pharmaceutically salts acceptable, solvates, hydrates, metabolites, prodrugs or stereoisomers thereof and instructions for their use. In one embodiment, the invention provides a packaged pharmaceutical product in which the compound or compounds are present in a therapeutically effective amount. In another embodiment, the invention provides a packaged pharmaceutical product in which the compound or compounds are present in a prophylactically effective amount.
DETAILED DESCRIPTION OF THE INVENTION Definitions In this invention, the following definitions are applicable: A "therapeutically effective amount" is an amount of a compound of the formula (I), (II), (III), (IV), or (V) or a combination of two or more of said compounds, which inhibits, total or partially, the advancement of the condition or alleviates, at least partially, one or more symptoms of the condition. A therapeutically effective amount may also be an amount that is prophylactically effective. The amount that is therapeutically Effective will depend on the size and gender of the patient, the condition to be treated, the severity of the condition and the result sought. For a given patient, a therapeutically effective amount can be determined using methods known to those skilled in the art.
"Physiologically acceptable salts" refers to those salts which retain the effectiveness and biological properties of the free bases and which are obtained by reaction with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. or organic acids such as sulfonic acid, carboxylic acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, lactic acid, tartaric acid (e.g. (+) or (-) - tartaric acid or mixtures thereof), amino acids (e.g. (+) or (-) - amino acids or mixtures thereof), and the like. These salts can be prepared using methods known to those skilled in the art.
Some compounds of Formula (I), (I I), (I I I), (IV), or (V) which have acidic substituents may exist as salts with pharmaceutically acceptable bases. The present invention includes said salts. Examples of such salts include sodium salts, potassium salts, salts of Usin and salts of arginine. These salts can be prepared using methods known to those skilled in the art.
Some compounds of Formula (I), (II), (III), (IV), or (V), and their salts may exist in more than one crystalline form and the present invention includes each crystalline form and mixtures thereof .
Some compounds of Formula (I), (II), (III), (IV), or (V) and its salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.
Some compounds of Formula (I), (II), (III), (IV), or (V) may contain one or more chiral centers, and exist in different optically active forms. When the compounds of formula (I), (II), (III), (IV), or (V) contain a chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as racemic mixtures. The enantiomers can be resolved using methods known to those skilled in the art, for example by formation of diastereomeric salts which can be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which can be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of an enantiomer with a specific enantiomer reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. HE it will be appreciated that in cases where the desired enantiomer is converted to another chemical entity by one of the separation methods described above, an additional step can be used to release the desired enantiomeric form. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using reagents, substrates, catalysts or optically active solvents, or by converting one enantiomer into the other by asymmetric transformation.
When a compound of the formula (I), (the), (I I), (I I I), (IV), or (V) contains more than one chiral center, this may exist in diastereomeric forms. The diastereomeric compounds can be separated using methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers can be separated as described above. The present invention includes each diastereomer of the compounds of the formula (I), (la), (I I), (I I I), (IV), or (V) and mixtures thereof.
Some compounds of Formula (I), (a), (II), (III), (IV), and (V) may exist in different tautomeric forms or as different geometric isomers, and the present invention includes each tautomer and / or geometric isomer of the compounds of Formula (I), (II), (III), (IV), and (V) and mixtures thereof.
Some compounds of Formula (I), (la), (I I), (I I I), (IV), and (V) may exist in different stable conformational forms which may be separable. The torsion asymmetry due to the Restricted rotation around a single asymmetric bond, for example due to steric hindrance or deformation of the ring, may allow the separation of different conformers. The present invention includes each conformational isomer of the compounds of Formula (I), (Ia), (I I), (I I I), (IV), and (V), and mixtures thereof.
Some compounds of the Formula (I), (la), (II), (III), (IV), and (V) can exist in zwitterionic form and the present invention includes each zwitterionic form of the compounds of the formula (I) ), (la), (II), (III), (IV), and (V) and mixtures thereof.
As used in the present application, the term "pro-drug" refers to an agent that is converted to the parent drug in vivo by some physiological chemical process (eg, a prodrug to be brought to the physiological pH is converted to the desired drug form). Pro-drugs are often useful because theyIn some situations, these may be easier to administer than the parent drug. These, for example, may be bioavailable by oral administration while the parent drug is not. The prodrug may also have improved solubility in pharmacological compositions with respect to the parent drug. An example, without limitation, of a prodrug could be a compound of the present invention in which it is administered as an ester (the "pro-drug") to facilitate transmission through the cell membrane wherein the solubility in water is not beneficial, but then it is metabolically hydrolyzed to the carboxylic acid once inside the cell where the solubility in water is beneficial.
Pro-drugs have many useful properties. For example, a pro-drug may be more soluble in water than the final drug, thereby facilitating intravenous administration of the drug. A prodrug may also have a higher level of oral bioavailability than that of the final drug. After administration, the prodrug is enzymatically or chemically cut to deliver the final drug in the blood or tissue.
Exemplary prodrugs after being cut off release the corresponding free acid, and said hydrolyzable ester-forming residues of the compounds of this invention include but are not limited to carboxylic acid substituents (e.g., - (CH2) C (0) OH or a portion containing a carboxylic acid) in which the free hydrogen is replaced with C1-C4 alkyl, (C2-Ci2) oxymethyl alkanoyl, 1- (C4-C9 alkanoyl) oxy) ethyl, 1-methyl- 1- (alkanoyloxy) -ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having from 4 to 7 carbon atoms, 1-methyl-1 - (alkoxycarbonyloxy) ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl having from 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl having from 4 to 10 carbon atoms , 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N, N-alkylic-C-C2-C3-Cyanaminoalkyl (such as β-dimethylamino) oethyl), carbamoyl-C1-C2 alkyl, N, N-di (C1-C2) alkyl carbamoyl-d-C2 alkyl and piperidino-C2-C3 alkylsulphyrino-C2-C3 alkyl or morpholino- C2-C3 alkyl.
Other exemplary prodrugs release an alcohol of Formula (I), (a), (II), (III), (IV), and (V) in which the free hydrogen of the hydroxyl substituent (e.g., R1 contains hydroxyl) is replaced with alkanoyl (Ci-C6) oxymethyl, 1- (alkanoiKd-CeJoxOethyl, 1-methyl-1 - (alkanoiC ^ CeJoxiJetilo, alkox ^ d -CeJcarbonyloxymethyl, N-alkoxy (d -d) carbonylamino-methyl, succinoyl, C 1 -C 6 alkanoyl, C 1 -C 4 a-amino-alkanoyl, arylactyl and a-aminoacyl, or a-aminoacyl-a-aminoacyl in which said a-aminoacyl moieties are independently any of the L- amino acids present in Nature found in the proteins, P (0) (OH) 2, -P (0) (0-alkyl (C-C6)) 2 or glycosyl (the radical resulting from the shedding of hydroxyl from the hemiacetal of a carbohydrate).
The term "heterocyclic" or "heterocyclyl", as used in the present application, includes non-aromatic ring systems, including, but not limited to monocyclic, bicyclic and tricyclic rings, which may be completely saturated or which may be contain one or more unsaturation units, to avoid doubt, the degree of unsaturation does not result in an aromatic ring system) and has 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur. For purposes of exemplification, which should not be considered as limiting the scope of this invention, the following are examples of heterocyclic rings: azabicyclo [2.2.1] heptanil, azepinyl, azetidinyl, morpholinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyrrolidinyl, quinicludinyl, thiomorpholinyl, tetrahydropyranyl and tetrahydrofuranyl.
The term "heteroaryl" as used in the present application includes aromatic ring systems, including, but not limited to monocyclic, bicyclic and tricyclic rings, and has 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur. For purposes of exemplification, which should not be construed as limiting the scope of this invention: azaindolyl, benzo (b) thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl , indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, pu-rinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo [2,3-d] pyrimidinyl, pyrazolo [3,4-d-pyrimidinyl, quinolinyl, Nazolinyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazoyl or tropanyl.
When the term "substituted heterocyclic" (or heterocyclyl) or "substituted heteroaryl" or "substituted aryl" is used, what is meant is that the heterocyclic, heteroaryl or aryl group is substituted with one or more substituents that can be made by one skilled in the art and resulting in a molecule which is an agonist or antagonist of the sphingosine receptor family. For purposes of exemplification, which should not be considered as limiting the scope of the invention, preferred substituents for the heterocycle, heteroaryl or aryl group of this invention are each independently selected from the optionally substituted group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylheterocyclealkoxy , alkyl, alkylamino, alkylcarbonyl, alkyl ester, alkyl-N H -alkyl, -alkyl-N H -cycloalkyl, alkyl-OC (O) -, -alkyl-ethercyclyl, -alkyl-cycloalkyl, alkyl-nitrile, alkynyl , amido, amino, aminoalkyl, aminocarbonyl, carbonitrile, carbonylalkoxy, carboxamido, C F3, CN, -C (0) OH, -C (0) H, -C (0) -C (CH3) 3, -OH, -C (0) 0-alkyl, -C (0) 0-cycloalkyl, -C (0) 0-heterocyclyl, -C (0) 0-alkyl-aryl, -C (0) -alkyl, -C (0) -cycloalkyl, -C (0) -heterocyclyl, cycloalkyl, dialkylaminoalkoxy, dialkyl-carbonyl, lalkoxy, dialkylaminocarbonyl, halogen, heterocyclyl, a heterocycloalkyl, heterocyclyloxy, hydroxy, hydroxyalkyl, nitro, OCF3 group, oxo, -O-alkyl, -O-heteroaryl, -O-heterocyclyl, -S02C H3, -S02N H2, -S02N H-alkyl, -S02N (alkyl) 2) tetrazolyl, thienylalkoxy, trifluoromethyl-carbonylamino, trifluoromethylsulfonamido, heterocyclylalkoxy, heterocyclyl-S (0) p, cycloalkyl-S (0) p, alkyl-S-, heterocyclyl-S, heterocycloalkyl, cycloalkylalkyl, heterocyclic, cycloalkylthio, -Z105-C (O) N (R) 2,. -Z105-N (R) -C (O) -Z200, -Z105-N (R) -S (O) 2-Z200, -Z105-N (R) -C (O) -N (R) -Z200 , -N (R), -N (H) -alkyl, -N (H) -cycloalkyl, -C (0) R, -N (R) -C (0) OR, OR-C (0) -heterocyclyl -OR, Rc and -CH2ORc; wherein p is 0, 1 or 2; in which R c for each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted aryl, - (CT -CeJ-N RdRe, -E- (C H2) t- N Rd Re, -E- (CH2 ) t-0-alkyl, -E- (C H2), -S-alkyl, or -E- (C H2), -OH; where t is a whole number of approximately 1 to about 6; Z105 for each time it appears is independently a covalent bond, alkyl, alkenyl or alkynyl; Y Z200 for each occurrence is independently selected from an optionally substituted group that is selected from the group consisting of alkyl, alkenyl, alkynyl, phenyl, alkyl-phenyl, alkenyl-phenyl or alkynyl-phenyl; E is a direct bond, O, S, S (O), S (0) 2, or N Rf, in which Rf is H or alkyl and Rd and Re are independently H, alkyl, alkanoyl or S02-alkyl; or Rd, Re and the nitrogen atom to which these are bound together to form a five or six membered heterocyclic ring.
A "heterocycloalkyl" group, as used in the present application, is a heterocyclic group that is linked to a compound by an aliphatic group having from one to about eight carbon atoms. For example, a morpholinomethyl group is a heterocycloalkyl group.
As used in the present application, "aliphatic" or "an aliphatic group" or notations such as "(C0-C8)" includes straight or branched chain hydrocarbons which are completely saturated or containing one or more units of unsaturation, and, therefore, includes alkyl, alkenyl, alkynyl and hydrocarbons comprising a mixture of single, double and triple bonds. When the group is a C0 it means that the portion is not present or in other words, it is a link. As used in the present application, "alkyl" means Ci-C8 and includes straight or branched chain hydrocarbons, which are completely saturated. Examples of alkyls are methyl, ethyl, propyl, butyl, pentyl, hexyl and isomers thereof. As used in the present application, "alkenyl" and "alkynyl" mean C2-C8 and include straight or branched chain hydrocarbons which contain one or more units of unsaturation, one or more double bonds for alkenyl and one or more triples links for alkynyl.
As used in the present application, aromatic groups (or aryl groups) include aromatic carbocyclic ring systems (for example phenyl and cyclopentyldienyl) and fused polycyclic aromatic ring systems (for example naphthyl, biphenylenyl and 1, 2,3,4 -tetrahydronaphthyl).
As used in the present application, cycloalkyl means monocyclic or C3-C12 monocyclic hydrocarbons (eg, bicyclic, tricyclic, etc.) that are completely saturated or have one or more unsaturated bonds but do not reach an aromatic group. Examples of a cycloalkyl group are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl.
As used in the present application, many portions or substituents are referred to as "substituted" or "optionally substituted." When a portion is modified with one of these terms, unless otherwise indicated, it indicates that any portion of the radical that is known to the person skilled in the art as available for substitution may be substituted, which includes one or more substituents, wherein if there is more than one substituent then each substituent is independently selected. Said means for substitution are well known in the art and / or taught by the present disclosure. For purposes of exemplification, which should not be construed as limiting the scope of the invention, some examples of groups which are substituents are: alkenyl groups, alkoxy group (which itself may be substituted, such as -O- alkyl ^ -Ce) -OR, -0-alkyl (Ci-C6) -N (R) 2, and OCF3), alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylpiperidinyl-alkoxy, alkyl groups (which themselves may also be substituted, such as -alkyl-Ce) -OR, -alkyl (C1-C6) -N (R) 2, COOH, and -CF3), alkylamino, alkylcarbonyl, alkyl ester, alkylnitrile, alkylsulfonyl, amino, aminoalkoxy, C F3, COH , COOH, CN, cycloalkyl, dialkylamino, dialkylaminoalkoxy, dialkylaminocarbonyl, dialkyl aminocarbonylalkoxy, dialkyl aminosulfonyl, esters (-C (O) -OR), in which R is groups such as alkyl, heterocycloalkyl (which may be substituted), heterocyclyl, etc., which may be substituted), halogen group (F, Cl, Br, I), hydroxyl i, morpholinoalkoxy, morpholinoalkyl, -NH-alkyl (Ci-C6) -COOH, nitro, oxo, OCF3, S (0) 2CH3, S (0) 2CF3, and sulfonyl, N-alkylamino or?,? - dialkylamino (in which alkyl groups may also be substituted).
Methods of use The present invention provides compounds described by the general formula (I), (a), (II), (III), (IV), and (V), which are effective as antagonists or agonists of the S1P receptor family coupled to protein G. These compounds reduce the number of circulating and infiltrating T and B lymphocytes, which allows to obtain a beneficial immunosuppressive effect.
The present invention also provides compounds that exhibit activity within the S1P receptor family.
In a related aspect the invention provides a method for modulating the receptors of the S1P family in a human individual suffering from a disorder in which the modulation of S1P activity is beneficial, which comprises administering to the human individual a compound of the formula (I), (a), (II), (III), (IV), and (V) in such a way that the modulation of S1P activity in the human individual is caused and the treatment is achieved.
In another related aspect the invention provides a method for modulating the activity of sphingosine 1-phosphate receptor 1 comprising contacting a cell with one or more compounds of the formula (I), (II), (II), (III) ), (IV), and (V).
A compound of Formula (I), (a), (II), (III), (IV), and (V) or a salt thereof or pharmaceutical compositions containing a therapeutically effective amount thereof is useful in the treatment of a disorder that is selected from the group that comprises disorders of the central nervous system (S NC), arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, juvenile chronic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis and septic arthritis, spondyloarthropathy, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, diabetes mellitus dependent on insulin, thyroiditis, asthma, allergic diseases, psoriasis, scleroderma dermatitis, graft vs. host disease, rejection of organ transplant (including but not limited to rejection of bone marrow and solid organ), acute and chronic immune disease associated with transplantation organ, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki disease, Grave's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Schoenlein purpura, microscopic vasculitis of the kidneys, chronic active hepatitis, uveitis, septic shock , cho syndrome that toxic, sepsis syndrome, cachexia, infectious diseases, parasitic diseases, acquired immunodeficiency syndrome, acute transverse myelitis, chorea H untington, Parkinson's disease, Alzheimer's disease, apoplej ed, primary biliary cirrhosis, hemolytic anemia Notice iPod, malignancies, failure heart, myocardial infarction, of Add ison disease, deficiency poligland ular sporadic type I and polyglandular deficiency type II, Schmidt syndrome, (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthropathy, arthropathy, Reiter's disease , psoriatic arthropathy, ulcerative eolithic arthropathy, enteropathic synovitis, arthropathy associated with Chlamydia, Yersinia and Salmonella, atheromatous disease / arteriosclerosis, atopic allergy, autoimmune blistering disease, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, hemolytic anemia autoinmune, anemia hemol Coombs positive disease, acquired pernicious anemia, juvenile pernicious anemia, myalgic encephalitis / Royal Free disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, Acquired Immunodeficiency Syndrome, I related diseases nmu Acquired deficiency, Hepatitis B, Hepatitis C, common variable immunodeficiency (common variable hypogammaglobulinemia), dilated cardiomyopathy, female infertility, ovarian failure, premature ovarian failure, fibrotic pulmonary disease, chronic wound healing, cryptogenic fibrosing alveolitis, post-interstitial lung disease inflammatory, interstitial pneumonitis, interstitial lung disease associated with connective tissue disease, lung disease associated with mixed connective tissue disease, interstitial lung disease associated with systemic sclerosis, interstitial lung disease associated with rheumatoid arthritis, pulmonary disease associated with systemic lupus erythematosus, pulmonary disease associated with dermatomyositis / polymyositis, lung disease associated with Sjögren's disease, lung disease associated with ankylosing spondylitis, diffuse vasculitic pulmonary disease, lung disease associated with hemosiderosis, drug-induced interstitial lung disease, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonitis, lymphocytic infiltrative lung disease, postinfectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, autoimmune hepatitis type 1 (classic autoimmune or lupoid hepatitis), autoimmune hepatitis ne type 2 (anti-LKM antibody hepatitis), autoimmune mediated hypoglycemia, type B insulin resistance with acanthosis nigricans, hypoparathyroidism, acute immune disease associated with organ transplantation, chronic illness associated with organ transplantation, osteoarthrosis, primary sclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathic leukopenia, autoimmune neutropenia, NOS of renal disease, glomerulonephritis, microscopic vasculitis of the kidneys, Lyme disease, discoid lupus erythematosus, idiopathic male infertility or NOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture syndrome, pulmonary manifestation of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Sjögren's syndrome, Takayasu's disease / arteritis, autoimmune thrombocytopenia, idiopathic thrombocytopenia, autoimmune thyroid disease, hyperthyroidism, autoimmune hypothyroidism, goiter (Hashimoto's disease), autoimmune atrophic hypothyroidism, primary myxoedema, phacogenic uveitis, primary vasculitis, vitiligo, acute liver disease, liver diseases chronic, alcoholic cirrhosis, alcohol-induced liver injury, coleostatis, idiosyncratic liver disease, drug induced hepatitis, nonalcoholic steatohepatitis, allergy and asthma, group B streptococcal (GBS) infection, mental disorders (eg, depression and schizophrenia) ), Th 1 -type and Th2-type mediated diseases, acute and chronic pain (different forms of pain), and cancers such as lung, breast, stomach, urinary bladder, colon, pancreatic, ovarian, prostate and rectal and hemopoietic malignancies (leukemia and lymphoma), Abetalipoprotemia, Acrocyanosis, acute and chronic parasitic or infectious processes, acute leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic bacterial infection, acute pancreatitis, acute renal failure, adenocarcinomas, aerial ectopic beats, dementia complex due to SI DA, alcohol-induced hepatitis, c allergic ophthalmosis, allergic contact dermatitis, allergic rhinitis, allograft rejection, alpha 1 antitrypsin deficiency, amyotrophic lateral sclerosis, anemia, angina pectoris, anterior horn cell degeneration, anti-cd3 therapy, antiphospholipid syndrome, h reactions anti-receptor susceptibility, aortic and peripheral aneurysms, aortic dissection, arterial hypertension, arterysclerosis, arteriovenous fistula, ataxia, atrial fibrillation (sustained or paroxysmal), atrial flutter, atrioventricular block, B-cell lymphoma, bone graft rejection, rejection of bone marrow transplantation (BMT), bundle branch block, Burkitt's lymphoma, burns, cardiac arrhythmias, cardiac stunning syndrome, cardiac tumors, cardiomyopathy, inflammation response by cardiopulmonary bypass, rejection of cartilage transplantation, degeneration Cerebellar cortices, disorders of the cerebellum, atrial tachycardia chaotic or multifocal, disorders associated with chemotherapy, chronic myelocytic leukemia (CM L), chronic alcoholism, chronic inflammatory pathologies, chronic lymphocytic leukemia (C LL), chronic obstructive pulmonary disease (CO PD), chronic salicylate poisoning, colorectal carcinoma, congestive heart failure, conjunctivitis, contact dermatitis, cor pulmonale, coronary artery disease, Creutzfeldt-Jakob disease, negative sepsis in culture, cystic fibrosis, disorders associated with cytokine therapy, pugilistic dementia, demyelinating diseases, dengue hemorrhagic fever , dermatitis, dermatological conditions, diabetes, diabetes mellitus, atherosclerotic diabetic disease, diffuse Lewy body disease, dilated congestive cardiomyopathy, basal ganglia disorders, Down syndrome in middle age, drug-induced drug-induced movement disorders that block the CNS dopamine receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy, epiglottitis, Epstein-Barr virus infection, erythromelalgia, extrapyramidal and cerebellar disorders, familial haematophagocytic lymphohistiocytosis, rejection of fetal thymus implant, Friedreich's ataxia, functional peripheral arterial disorders, fungal sepsis, gas gangrene, gastric ulcer, glomerular nephritis, graft rejection of any organ or tissue, Gram-negative sepsis, Gram-positive sepsis, granulomas due to intracellular organisms, hairy cell leukemia, Hallerrorden-Spatz disease, Hashimoto's thyroiditis, hay fever, transplant rejection of heart, hemachromatosis, hemodialysis, haemolytic uremic syndrome / thrombocytopenic thrombolytic purpura, hemorrhage, hepatitis (A), arrhythmia of His fascicle, infection by VI H / neu VI H clothing, Hodgkin's disease, hyperkinetic movement disorders, hypersensitivity, hypersensitivity pneumonitis, h hypertension, hypokinetic movement disorders, evaluation of the hypothalamic-pituitary-adrenal axis, idiopathic Addison's disease, idiopathic pulmonary fibrosis, antibody-mediated cytotoxicity, asthenia, infantile spinal muscular atrophy, inflammation of the aorta, influenza a, exposure to ionizing radiation, iridocyclitis / uveitis / optic neuritis, ischemia-reperfusion injury, ischemic stroke, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma, rejection of kidney transplantation, legionella, leishmaniasis, leprosy, corticospinal system lesions, lipedema, rejection of liver transplantation, lymphederma, malaria, malignant lymphoma, malignant histiocytosis, malignant melanoma, meningitis, meningococcemia, metabolic / idiopathic, migraine headache, multisystem mitochondrial disorder, mixed connective tissue disease, monoclonal gammopathy, multiple myeloma, system degeneration multiple (Menc Dejerine-Thomas Shi-Drager and Machado-Joseph), myasthenia gravis, Mycobacterium avium intracellulare, Mycobacterium tuberculosis, myelodysplastic syndrome, myocardial infarction, myocardial ischemic disorders, nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrosis, neurodegenerative diseases, neurogenic muscular atrophies I, neutropenic fever, non-Hodgkins lymphoma, occlusion of the abdominal aorta and its ramifications, arterial occlusive disorders, therapy with OKT3, orchitis / epididymitis, orchitis / vasectomy reversal procedures, organomegaly, osteoporosis, transplant rejection of pancreas, pancreatic carcinoma, paraneoplastic syndrome / malignant tumor hypercalcemia, rejection of parathyroid transplantation, pelvic inflammatory disease, perennial rhinitis, pericardial disease, peripheral atherosclerotic disease, peripheral vascular disorders, peritonitis, pernicious anemia, Pneu pneumonia mocystis carinii, pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), post-perfusion syndrome, post-pump syndrome, post-cardiotomy syndrome myocardial infarction (post-M I), pre-eclampsia, progressive supranuclear palsy, primary pulmonary hypertension, radiation therapy, Raynaud's phenomenon and disease, Raynoud's disease, Refsum's disease, narrow QRS tachycardia, renovascular hypertension , reperfusion injury, restrictive cardiomyopathy, sarcomas, scleroderma, senile chorea, senile dementia of Lewy body type, seronegative arthropathies, shock, sickle cell anemia, skin allograft rejection, skin changes syndrome, transplant rejection small bowel, solid tumors, specific arrhythmias, spinal ataxia, spinocerebellar degenerations, streptococcal myositis, structural lesions of the cerebellum, subacute sclerosing panencephalitis, syncope, syphilis of the cardiovascular system, systemic anaphylaxis, systemic inflammatory response syndrome, systemic onset juvenile rheumatoid arthritis , T cell or FAB ALL, Telangie ctasia, thromboangitis obliterans, thrombocytopenia, toxicity, transplants, trauma / hemorrhage, type III hypersensitivity reactions, type IV hypersensitivity, unstable angina, uremia, urosepsis, urticaria, valvular heart disease, varicose veins, vasculitis, venous diseases, venous thrombosis , ventricular fibrillation, viral and fungal infections, vital encephalitis / aseptic meningitis, hemaphagocytic syndrome associated with vital, Wernicke-Korsakoff syndrome, Wilson's disease, rejection of xenograft of any organ or tissue, and diseases involving inadequate vascularization for example diabetic retinopathy retinopathy of premad urez neovascularization of the choroid due to macular degeneration related to age, and infantile hemangiomas in humans. In addition, said compounds may be useful in the treatment of disorders such as edema, ascites, effusions, and exudates, including for example macular edema, cerebral edema, acute lung injury, adult respiratory distress syndrome (ARDS), proliferative disorders such as as restenosis, fibrotic disorders such as liver cirrhosis and atherosclerosis, mesangial cell proliferative disorders such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, syndromes of thrombotic microangiopathy, and glomerulopathies, myocardial angiogenesis, coronary and cerebral collaterals, ischemic extremity angiogenesis, ischemia / reperfusion injury, Helicobacter-related diseases and peptic ulcer, virus-induced angiogenic disorders, Crow-Fukase syndrome (POEMS), preeclampsia, menometrorrhage, cat scratch fever, rubeosis, neovascular glaucoma and retinopathies such as those ociated with diabetic retinopathy, retinopathy of pre-mad urez, age-related macular degeneration or a disorder of the central nervous system. In addition, these compounds can be used as active agents against solid tumors, malignant ascites, von Hippel Lindau disease, hematopoietic cancers and hyperproliferative disorders such as thyroid hyperplasia (especially Grave's disease), and cysts (such as stromal hypervascularization). ovarian characteristic of polycystic ovary syndrome (Stein-Leventhal syndrome) and polycystic kidney disease since these diseases require a proliferation of blood vessel cells for growth and / or metastasis.
Combination therapy The compounds of Formula (I), (Ia), (I I), (I I I), (IV), and (V) of the invention can be used alone or in combination with another therapeutic agent to treat said diseases. It should be understood that the compounds of the invention may be used alone or in combination with an additional agent, for example, a therapeutic agent, said additional agent being selected by the person skilled in the art for its intended purpose. For example, the additional agent may be a therapeutic agent recognized in the art as useful for treating the disease or condition being treated by the compound of the present invention. The additional agent can also be an agent imparting a beneficial attribute to the therapeutic composition, for example, an agent that affects the viscosity of the composition.
It should also be understood that the combinations to be included within this invention are those combinations useful for their intended purpose. The agents indicated below are illustrative for the purposes and are not intended to be limited. The combinations, which are part of this invention, may be the compounds of the present invention and at least one additional agent that is selected from the following lists. The combination may also include more than one additional agent, for example, two or three additional agents if the combination is such that the formed composition can perform its intended function.
Preferred combinations are nonsteroidal anti-inflammatory drugs also referred to as NSAIDS which include drugs such as ibuprofen. Other preferred combinations are corticosteroids including prednisolone; the well-known side effects of the use of steroids can be reduced or even eliminated by decreasing the steroid dose required when treating patients in combination with the S1P receptor agonists or antagonists of this invention. Non-limiting examples of therapeutic agents for rheumatoid arthritis with which a compound of formula (I), (II), (II), (III), (IV), and (V), can be combined of the invention include the following: anti-inflammatory cytokine suppressor drugs (CSAIDs); antibodies to or antagonists of other cytokines or human growth factors, eg, TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL -8, IL-12, IL-15, IL-16, IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF, and PDGF. The S / T kinase inhibitors of the invention can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD28, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86. (B7.2), CD90, CTLA or its ligands including CD 154 (gp39 or CD40L).
Preferred combinations of therapeutic agents may interfere at different points in the autoimmune cascade and subsequent inflammatory cascade; preferred examples include TNF antagonists such as antibodies to chimeric, humanized or human TNFs, D2E7 (HUMIRA ™), (PCT Publication No. WO 97/29131), CA2 (REMICADE ™), CDP 571, and soluble receptors p55 or p75 of TNF, derivatives, thereof, (p75TNFRIgG (ENBREL ™) or p55TNFRIgG (Lenercept), and in addition inhibitors of the TNFa converting enzyme (TACE); similarly inhibitors of IL-1 (inhibitors of the interleukin-1 converting enzyme, IL-IRA, etc.) may be effective for the same reason Other preferred combinations include interleukin 11. Even other preferred combinations are the other key players of the autoimmune response which can act parallel to, dependent on or in concert with the function of IL-18, especially preferred are IL-12 antagonists including antibodies to IL-12 or soluble IL-12 receptors, or IL-12 binding proteins. 12 and IL-18 have n overlapping but different functions and a combination of antagonists for both could be the most effective. Even another preferred combination is non-depleting anti-CD4 inhibitors. Even other preferred combinations include antagonists of the co-stimulatory pathway CD80 (B7.1) or CD86 (B7.2) including antibodies, soluble receptors or antagonist ligands.
A compound of the formula (I), (la), (II), (III), (IV), and (V) of the invention can also be combined with agents, such as methotrexate, 6-MP, azathioprine sulfasalazine, mesalazine, ollalazine, chloroquine / hydroxychloroquine, pencilamine, aurothiomalate (intramuscular and oral), azathioprine, cochicine, corticosteroids (oral, inhaled and local injection), beta-2 adrenoreceptor agonists (salbutamol, terbutaline, salmeteral), xanthines (theophylline, aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium and oxitropium, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adenosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents that interfere with cytokine signaling pro-inflammatory drugs such as TNFa or IL-1 (for example IRAK, NIK, IKK, p38 or MAP kinase inhibitors), inhibitors of the I-L-1β converting enzyme, inhibitors of T-cell signaling such as kinase inhibitors , metalloproteinase inhibitors, sulfasalazine, 6-mercaptopurines, angiotensin-converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (eg soluble p55 or p75 receptors of TNF and the p75TNFRIgG derivatives (Enbrel ™ and p55TNFRIgG (Lenercept)) ), slL-1 Rl, slL-1RII, slL-6R), anti-inflammatory cytokines (eg IL-4, IL-10, IL-11, IL-13 and TGFp), celecoxib, acid fól ico, hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab, naproxen, valdecoxib, sulfasalazine, methylprednisolone, meloxicam, methylprednisolone acetate, sodium aurothiomalate, aspirin, triamcinolone acetonide, propoxyphene napsylate / apap, folate, nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone HCI, hydronodone bitartrate / apap, diclofenac sodium / misoprostol, fentanyl, anakinra, tramadol MCI, salsalate, sulindac, cyanocobalamin / fa / pyridoxine, acetaminophen, alendronate sodium, prednisolone, morphine sulfate, lidocaine hydrochloride, indomethacin, glucosamine sulf / chondroitin, amitriptyline HCl, sulfadiazine, oxycodone HCI / acetaminophen, olopatadine HCI misoprostol, naproxen sodium, omeprazole, cyclophosphamide, rituximab, I L-1 TRAP, M RA, CTLA4-IG, I L-1 8 BP, anti-I L-1 2, Anti-I L1 5, BI RB-796, SCIO-469 , VX-702, AMG-548, VX-740, Roflumilast, IC-485, CDC-801, and mesopram. Preferred combinations include methotrexate or leflunomide and in cases of moderate or severe rheumatoid arthritis, cyclosporine and anti-TNF antibodies as indicated above.
Non-limiting examples of therapeutic agents for inflammatory bowel disease with which a compound of formula (I), (II), (III), (III), (IV), or (V) of the invention can be combined they include the following: budenoside; epidermal growth factor; corticosteroids; cyclosporin, sulfasalazine; aminosalicylates; 6-mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide; antioxidants; thromboxane inhibitors; I L-1 receptor antagonists; anti-l L-1 ß monoclonal antibodies; antibodies monoclonal anti-IL-6; growth factors; elastase inhibitors; pyridinyl imidazole compounds; antibodies to or antagonists of other cytokines or human growth factors, for example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL -16, EMAP-II, GM-CSF, FGF, and PDGF; cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or their ligands; methotrexate; cyclosporin; FK506; rapamycin; mycophenolate mofetil; leflunomide; NSAIDs, for example, ibuprofen; corticosteroids such as prednisolone; phosphodiesterase inhibitors; adenosine agonists; antithrombotic agents; complement inhibitors; adrenergic agents; agents that interfere with signaling by pro-inflammatory cytokines such as TNFa or IL-1 (for example IRAK, NIK, IKK, or AP kinase inhibitors); inhibitors of the IL-1β converting enzyme; inhibitors of the TNFa converting enzyme; inhibitors of T cell signaling such as kinase inhibitors; metalloproteinase inhibitors; sulfasalazine; azathioprine; 6-mercaptopurines; angiotensin-converting enzyme inhibitors; soluble cytokine receptors and derivatives thereof (for example soluble p55 or p75 receptors of TNF, slL-1RI, if L-1 Rl I, slL-6R) and anti-inflammatory cytokines (for example IL-4, IL-10, IL -11, I L-13 t TGF). Preferred examples of therapeutic agents for Crohn's disease with which a compound of formula (I), (a), (II), (III), (IV), or (V) can be combined include the following: antagonists of TNF, for example, anti-TNF antibodies, D2E7 (PCT Publication No. WO 97/29131; HUMIRATM), CA2 (REMICADETM), CDP 571, TNFR-lg constructs, inhibitors of (p75TNFRIgG (ENBRELTM) and p55TNFRIgG (Lenercept ™)) and PDE4 inhibitors. A compound of the formula (I), (a), (II), (III), (IV), or (V) can be combined with corticosteroids, for example, budenoside and dexamethasone; sulfasalazine, 5-aminosalicylic acid; olsalazine; and agents that interfere with the synthesis or action of pro-inflammatory cytokines such as IL-1, for example, inhibitors of the L-1β and IL-Ira converting enzyme; inhibitors of T cell signaling, for example, tyrosine kinase inhibitor 6-mercaptopurines; IL-11; mesalamine; prednisone; azathioprine; mercaptopurine; infliximab; methylprednisolone sodium succinate; diphenoxylate / atrop sulfate; loperamide hydrochloride; methotrexate; Omeprazole; folate; ciprofloxacin / dextrose-water; hydrocodone bitartrate / apap; tetracycline hydrochloride; fluocinonide; metronidazole; thimerosal / boric acid; cholestyramine / sucrose; ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidine hydrochloride; Midazolam hydrochloride; oxycodone HCI / acetaminophen; promethazine hydrochloride; Sodium phosphate; sulfamethoxazole / trimethoprim; celecoxib; polycarbophil; propoxyphene napsylate; hydrocortisone; multivitamins; disodium balsalazide; codeine phosphate / apap; colesevelam HCI; cyanocobalamin; folic acid; levofloxacin; methylprednisolone; natalizumab and interferon-gamma.
Non-limiting examples of therapeutic agents for multiple sclerosis with which a compound can be combined of formula (I), (a), (II), (III), (IV), or (V) include the following: corticosteroids; prednisolone; methylprednisolone; azathioprine; cyclophosphamide; cyclosporin; methotrexate; 4-aminopyridine; tizanidine; interferon-ß? a (Avonex®; Biogen); interferon-β? b (Betaseron®; Chiron / Berlex); interferon a-n3) (Inferieron Sciences / Fujimoto), interferon-a (Alfa Wassermann / J &J), interferon β-IF (Serono / lnhale Therapeutics), Peginterferon a 2b (Enzon / Schering-Plow), Copolymer 1 (Cop-1; Copaxone®; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen; intravenous immunoglobulin; Clabribine; antibodies to or antagonists of other cytokines or growth factors of human and their receptors, for example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL- 23, IL-15, IL-16, EMAP-II, GM-CSF, FGF, and PDGF. A compound of formula (I), (a), (II), (III), (IV), or (V) can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19 , CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands. A compound of formula (I), (a), (II), (III), (IV), or (V) can also be combined with agents such as methotrexate, cyclosporin, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents that interfere with signaling by pro-inflammatory cytokines such as TNFa or IL-1 (by example IRAK, NIK, IKK, p38 or MAP kinase inhibitors), enzyme inhibitors IL-αβ converters, TACE inhibitors, T cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin-converting enzyme inhibitors, soluble cytokine receptors and derivatives of the same (for example soluble p55 or p75 receptors of TNF, slL-1 Rl, slL-1RII, slL-6R) and anti-inflammatory cytokines (for example IL-4, IL-10, IL-13 and TGFP).
Preferred examples of therapeutic agents for multiple sclerosis in which a compound of Formula (I), (a), (II), (III), (IV), or (V) can be combined to include interferon-β, for example, IFNpia and IFN 1b; Copaxone, corticosteroids, caspase inhibitors, for example caspase-1 inhibitors, IL-1 inhibitors, TNF inhibitors, and antibodies to the CD40 and CD80 ligand.
A compound of formula (I), (a), (II), (III), (IV), or (V) can also be combined with agents, such as alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol, a-immunokine NNS03, ABR-215062, AnergiX.MS, chemokine receptor antagonists, BBR-2778, calagualin, CPI-1189, LEM (mitoxantrone encapsulated in liposome), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidone alotrap 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF- beta2, tiplimotide, VLA-4 antagonists (eg, TR-14035, VLA4 Ultrahaler, Antegran-ELAN / Biogen), interferon antagonists gamma and IL-4 agonists.
Non-limiting examples of angina pectoris therapeutic agents with which a compound of the formula (I), (II), (III), (IV), or (V) of the invention can be combined include the following: aspirin, nitroglycerin, isosorbide mononitrate, metoprolol succinate, atenolol, metoprolol tartrate, amlodipine besylate, diltiazem hydrochloride, isosorbide dinitrate, clopidogrel bisulfate, nifedipine, atorvastatin calcium, potassium chloride, furosemide, simvastatin, verapamil HCI, digoxin, propranolol hydrochloride, carvedilol, lisinopril, spironolactone, hydrochlorothiazide, enalapril maleate, nadolol, ramipril, enoxaparin sodium, heparin sodium, valsartan, sotalol hydrochloride, fenofibrate, ezetimibe, bumetanide, losartan potassium, lisinopril / hydrochlorothiazide, felodipine, captopril and bisoprolol fumarate.
Non-limiting examples of therapeutic agents for ankylosing spondylitis with which a compound of the formula (I), (II), (III), (III), (IV), or (V) can be combined include the following: ibuprofen , diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine, minocycline, prednisone, etanercept, and infliximab.
Non-limiting examples of therapeutics for asthma with which a compound of the formula (I), (II), (III), (III), (IV), or (V) can be combined include the following: albuterol, salmeterol / fluticasone, montelukast sodium, fluticasone propionate, budesonide, prednisone, salmeterol xinafoate, levalbuterol HCI, albuterol sulfate / ipratropium, prednisolone sodium phosphate, triamcinolone acetonide, beclomethasone dipropionate, ipratropium bromide, azithromycin, pyrbuterol acetate , pred nisolone, anhydrous theophylline, methylprednisolone sodium succinate, clarithromycin, zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillin trihydrate, flunisolide, injection allergy, cromolyn sodium, fexofenadine hydrochloride, flunisolide / menthol, amoxicillin / clavulanate, levofloxacin, ancillary device of the inhaler, guaifenesin, dexamethasone sodium phosphate, moxifloxacin HCl, doxycycline hyclate, gouanene sina / d-metorfan, p-ephedrine / cod / chlorphenir, gatifloxacin, cetirizine hydrochloride, mometasone roat, salmeterol xinafoate, benzonatate, cephalexin, pe / hydrocodone / chlorphenir, cetirizin HCI / pseudoefed, phenylephrine / cod / promethazine , codeine / promethazine, cefprozil, dexamethasone, guaifenesin / pseudoephedrine, chlorpheniramine / hydrocodone, nedocromil sodium, terbutaline sulfate, epinephrine, methylprednisolone and metaproterenol sulfate.
Non-limiting examples of therapeutic agents for COPD with which a compound of formula (I), (II), (III), (III), (IV), or (V) can be combined include the following: sulfate of albuterol / ipratropium, ipratropium bromide, salmeterol / fluticasone, albuterol, salmeterol xinafoate, fluticasone propionate, prednisone, anhydrous theophylline, methylprednisolone sodium succinate, montelukast sodium, budesonide, formoterol fumarate, acetonide of triamcinolone, levofloxacin, guaifenesin, azithromycin, beclomethasone dipropionate, levalbuterol HCI, flunisolide, ceftriaxone sodium, amoxicillin trihydrate, gatifloxacin, zafirlukast, amoxicillin / clavulanate, flunisolide / menthol, chlorpheniramine / hydrocodone, metaproterenol sulfate, methylprednisolone, mometasone furoate, p-ephedrine / cod / chlorfenir, pyrbuterol acetate, p-ephedrine / loratadine, terbutaline sulfate, tiotropium bromide, (R, R) -formoterol, TgAAT, cilomilast and roflumilast.
Non-limiting examples of therapeutic agents for HCVs with which a compound of the formula (I), (a), (II), (III), (IV), or (V) can be combined include the following: Interferon-alpha-2a, interferon-alpha- 2b, Interferon-alpha con1, Interferon-alpha-n1, interferon-alpha-2a modified with PEG, interferon-alpha-2b modified with PEG, ribavirin, peginterferon alfa-2b + ribavirin, ursodeoxycholic acid, glycyrrhizic acid, timalfasin, Maxamine, VX-497 and any compounds that are used to treat HCV through intervention with the following objectives: HCV polymerase, HCV protease, HCV helicase, and IRES (internal ribosome entry site) of HCV.
Non-limiting examples of therapeutic agents for Idiopathic Pulmonary Fibrosis with which a compound of the formula (I), (II), (III), (IV), or (V) can be combined include the following: prednisone, azathioprine, albuterol, colchicine, albuterol sulfate, digoxin, gamma-interferon, methylprednisolone sod succ, lorazepam, furosemide, Msinopril, nitroglycerin, spironolactone, cyclophosphamide, ipratropium bromide, actinomycin d, alteplase, fluticasone propionate, levofloxacin, metaproterenol sulfate, morphine sulfate, oxycodone HCI, potassium chloride, triamcinolone acetonide, anhydrous tacrolimus, calcium , interferon-alpha, methotrexate, mycophenolate mofetil and interferon-gamma-1 ß.
Non-limiting examples of therapeutic agents for myocardial infarction with which a compound of formula (I), (II), (III), (IV), or (V) can be combined include the following: aspirin, nitroglycerin, metoprolol tartrate, enoxaparin sodium, heparin sodium, clopidogrel bisulfate, carvedilol, atenolol, morphine sulfate, metoprolol succinate, warfarin sodium, lisinopril, isosorbide mononitrate, digoxin, furosemide, simvastatin, ramipril, tenecteplase, maleate of enalapril, torsemide, retavase, losarían potásico, quinapril HCI / mag carb, bumetanide, alteplase, enalaprilat, amiodarone hydrochloride, tirofiban HCI m-hydrate, diltiazem hydrochloride, captopril, irbesartan, valsartan, propranolol hydrochloride, fosinopril sodium, hydrochloride of lidocaine, eptifibatide, cefazolin sodium, atropine sulfate, aminocaproic acid, spironolactone, interferon, sotalol hydrochloride, potassium chloride, docusate sodium, dobutamine HCl, alp razolam, pravastatin sodium, atorvastatin calcium, midazolam hydrochloride, meperidine hydrochloride, isosorbide dinitrate, epinephrine, dopamine hydrochloride, bivalirudin, rosuvastatin, ezetimibe / simvastatin, avasimibe, and cariporide.
Non-limiting examples of therapeutic agents for psoriasis with which a compound of Formula (I), (II), (III), (III), (IV), or (V) can be combined include the following: calcipotriene, clobetasol propionate, triamcinolone acetonide, halobetasol propionate, tazarotene, methotrexate, fluocinonide, increased diprop betamethasone, fluocinolone acetonide, acitretin, tar shampoo, betamethasone valerate, mometasone furoate, ketoconazole, pramoxine / fluocinolone, idrocortisone valerate , Fluoride, urea, betamethasone, clobetasol / emoll propionate, fluticasone propionate, azithromycin, hydrocortisone, humectant formula, folic acid, desonide, pimecrolimus, alkaline ulcer, diflorasone diacetate, etanercept folate, lactic acid, methoxsalen, hc / bismuth subgal / znox / resor, methylprednisolone acetate, prednisone, sunblock, halcinonide, salicylic acid, anthralin, clocortholo pivalate na, coal extract, coal tar / salicylic acid, coal tar / salicylic acid / sulfur, deoximetasone, diazepam, emollient, fluocinonide / emollient, mineral oil / castor oil / na lact, mineral oil / peanut oil, petroleum / isopropyl myristate, psoralen, salicylic acid, soap / tribromsalan, thimerosal / boric acid, celecoxib, infliximab, cyclosporine, alefacept, efalizumab, tacrolimus, pimecrolimus, PUVA, UVB, and sulfasalazine.
Non-limiting examples of therapeutical agents for psoriatic arthritis with which a compound of the formula (I), (II), (III), (III), (IV), or (V) can be combined include the following: methotrexate , etanercept, rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac, betamethasone diprop augmented, infliximab, methotrexate, folate, triamcinolone acetonide, diclofenac, dimethyl sulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone, sodium tolmetin, calcipotriene, cyclosporine, diclofenac sodium / misoprostol, fluocinonide, glucosamine sulfate, sodium aurothiomalate, hydrocodone bitartrate / apap, ibuprofen, risedronate sodium, sulfadiazine, thioguanine, valdecoxib , alefacept and efalizumab.
Non-limiting examples of therapeutic agents for restenosis with which a compound of formula (I), (II), (III), (III), (IV), or (V) can be combined include the following: sirolimus, paclitaxel, everolimus, tacrolimus, ABT-578, and acetaminophen.
Non-limiting examples of sciatica therapeutic agents with which a compound of formula (I), (a), (II), (III), (IV), or (V) may be combined include the following: bitartrate hydrocodone / apap, rofecoxib, cyclobenzaprine HCI, methylprednisolone, naproxen, ibuprofen, oxycodone HCI / acetaminophen, celecoxib, valdecoxib, methylprednisolone acetate, prednisone, codeine / apap phosphate, tramadol hcl / acetaminophen, metaxalone, meloxicam, methocarbamol, lidocaine hydrochloride , diclofenac sodium, gabapentin, dexamethasone, carisoprodol, ketorolac tromethamine, Ndometacin, acetaminophen, diazepam, nabumetone, oxycodone HCI, tizanidine HCI, diclofenac sodium / misoprostol, propoxyphene napsylate / apap, asa / oxycodone / oxycodone ter, ibuprofen / hydrocodone bit, tramadol HCI, etodolac, propoxyphene HCI, amitriptyline HCl, carisoprodol / codeine fos / asa, morphine sulfate, multivitamins, naproxen sodium, orphenadrine citrate, and temazepam.
Preferred examples of therapeutic agents for SLE (Lupus) with which a compound of formula (I), (a), (II), (III), (IV), or (V) can be combined include the following: NSAIDS, for example, diclofenac, naproxen, ibuprofen, piroxicam, ndometacin; COX2 inhibitors, for example, celecoxib, rofecoxib, valdecoxib; anti-malarials, for example, hydroxychloroquine; spheroids, for example, prednisone, prednisolone, budenoside, dexamethasone; cytotoxic, for example, azathioprine, cyclophosphamide, mycophenolate mofetil, methotrexate; PDE4 inhibitors or purine synthesis inhibitor, for example Cellcept®. A compound of formula (I), (a), (II), (III), (IV), or (V) can also be combined with agents such as sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran® and agents which interfere with the synthesis, production or action of pro-inflammatory cytokines such as IL-1, for example, caspase inhibitors such as the inhibitors of the converting enzyme of I L-1β and IL-1ra. A compound of formula (I), (a), (II), (III), (IV), or (V) can also be used with T cell signaling inhibitors, for example, tyrosine kinase inhibitors; or molecules that target the activation molecules of T cell, e.g., CTLA-4-IgG or anti-B7 family antibodies, anti-PD-1 family antibodies. A compound of formula (I), (a), (II), (III), (IV), or (V) can be combined with IL-11 or anti-cytokine antibodies, for example, fonotolizumab (anti-cancer antibody). IFNg), or anti-receptor antibodies, eg, anti-IL-6 receptor antibody and antibodies to B cell surface molecules. A compound of formula (I), (II), (III) , (IV), or (V) can also be used with LJP 394 (abetimus), agents that deplete or inactivate B cells, for example, Rituximab (anti-CD20 antibody), linfostat-B (anti-BlyS antibody), TNF antagonists, eg, anti-TNF antibodies, D2E7 (PCT Publication No. WO 97/29131; HUMIRA ™), CA2 (REMICADE ™), CDP 571, TNFR-lg constructs, (p75TNFRIgG (ENBREL ™) and p55TNFRIgG (LENERCEPT ™)).
In the compositions of the present invention the active compound, if desired, may be associated with other compatible pharmacologically active ingredients. For example, the compounds of this invention can be administered in combination with another therapeutic agent that is known to treat a disease or condition described in the present application. For example, with one or more additional pharmaceutical agents that inhibit or prevent the production of VEGF or angiopoietins, attenuate intracellular responses to VEGF or angiopoietins, block intracellular signal transmission, inhibit vascular hyperpermeability, reduce inflammation, or inhibit or prevent the formation of edema or neovascularization. The compounds of the invention may be administered before, after or concurrently with the additional pharmaceutical agent, whichever is the appropriate administration term. Additional pharmaceutical agents include, but are not limited to, anti-edaemic steroids, NSAI DS, ras inhibitors, anti-TNF agents, anti-L1 agents, antihistamines, PAF antagonists, COX-1 inhibitors, COX inhibitors. -2, NO synthetase inhibitors, Akt / PTB inhibitors, IG F-1 R inhibitors, PKC inhibitors, PI3 kinase inhibitors, calcineurin inhibitors and immunosuppressants. The compounds of the invention and the additional pharmaceutical agents act either additively or synergistically. Therefore, the administration of said combination of substances that inhibits angiogenesisvascular hyperpermeability and / or that inhibits the formation of edema may provide greater relief from the deleterious effects of a hyperproliferative disorder, angiogenesis, vascular hyperpermeability or edema than the administration of any substance alone. In the treatment of malignant disorders, combinations with antiproliferative or cytotoxic chemotherapies or radiation are included in the scope of the present invention.
One or more of the compounds of the invention can be administered to a human patient by themselves or in pharmaceutical compositions in which they are mixed with biologically appropriate carriers or excipients at doses to treat or alleviate a disease or condition as described in the present application.
Mixtures of these compounds can also be administered to the patient as a simple mixture in appropriately formulated pharmaceutical compositions. A therapeutically effective dose refers to the amount of the compound or compounds sufficient to result in the prevention or attenuation of a disease or condition as described in the present application. The techniques for formulation and administration of the compounds of the present application can be found in references well known to the person skilled in the art, such as "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, most recent edition.
Pharmaceutical compositions and modes of administration Appropriate routes of administration may include, for example, oral administration, with ophthalmic, rectal, transmucosal, topical, or intestinal drops; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
Alternatively, the compound can be administered in a local manner rather than systemically, for example, by injection of the compound directly into an edematous site, often in a depot or sustained release formulation.
Also, the drug can be administered in a targeted drug delivery system, for example, in a liposome coated with antibody specific for endothelial cell.
The pharmaceutical compositions of the present invention can be manufactured in a manner that is itself well known, for example, by means of conventional mixing, dissolving, granulating, dragee, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
Therefore, pharmaceutical compositions for use in accordance with the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds as preparations that can be use pharmaceutically The proper formulation is dependent on the chosen route of administration.
For injection, the agents of the invention can be formulated in aqueous solutions, preferably in physiologically compatible buffer solutions such as Hanks' solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, appropriate penetrants are used in the formulation for the barrier to be permeated. Such penetrants are known in general terms in the art.
For oral administration, the compounds can be formulated easily by combining the active compounds with pharmaceutically acceptable carriers known in the art.
Said vehicles allow the compounds of the invention to be formulated as tablets, pills, pills, capsules, liquids, gels, syrups, porridges, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding appropriate auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the interlaced polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
Dragee cores are provided with appropriate coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and appropriate organic solvents or solvent mixtures. Dyes or pigments can be added to tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as sealed, soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The snap closure capsules may contain the active ingredients in intimate admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration must be in appropriate doses for such administration.
For buccal administration, the compositions may take the form of tablets or lozenges formulated in a conventional manner.
For administration by inhalation, the compounds for use in accordance with the present invention are conveniently delivered in the form of an aerosol spray presentation from presumed packs or a nebulizer, with the use of an appropriate propellant, for example, dichlorodifluoromethane. , trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other appropriate gas. In the case of pressurized aerosol the dose unit can be determined by providing a valve to supply a measured quantity. Capsules and cartridges of eg gelatin for use in an inflator or insufflator can be formulated so as to contain a powder mixture of the compound and an appropriate powder base such as lactose or starch.
The compounds can be formulated for parenteral administration by injection, for example bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, for example in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents.
Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable solvents or lipophilic vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain stabilizers or appropriate agents that increase the solubility of the compounds to allow the preparation of highly concentrated solutions.
Alternatively, the active ingredient may be in powder form for constitution with an appropriate vehicle, eg, pyrogen-free, sterile water, before use.
The compounds can also be formulated in rectal compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides.
In addition to the formulations described previously, the compounds can also be formulated as a depot preparation. Such long-acting formulations can be administered by implant, for example subcutaneously or intramuscularly or by intramuscular injection). Thus, for example, the compounds can be formulated with polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as very poorly soluble derivatives, for example, as a very poorly soluble salt .
An example of a pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a non-polar surfactant, an organic polymer miscible in water, and an aqueous phase. The co-solvent system can be the VPD co-solvent system. VPD is a solution of 3% w / v of benzyl alcohol, 8% w / v of the agent non-polar surfactant polysorbate 80, and 65% w / v polyethylene glycol 400, brought to volume in absolute ethanol. The VPD co-solvent system (VPD: 5W) consists of VPD diluted 1: 1 with a 5% solution of dextrose in water. This co-solvent system dissolves hydrophobic compounds well, and by itself produces low toxicity after systemic administration. Naturally, the proportions of a co-solvent system can be varied considerably without destroying its solubility and toxicity characteristics. Also, the identity of the components of the co-solvent can be varied: for example, other non-polar surfactants of low toxicity can be used instead of polysorbate 80; the size of the polyethylene glycol fraction can be varied; other biocompatible polymers can replace polyethylene glycol, for example polyvinylpyrrolidone; and other sugars or polysaccharides can replace dextrose.
Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of carriers or delivery vehicles for hydrophobic drugs. It is also possible to use certain organic solvents such as dimethyl sulfoxide, but usually at higher toxicity costs. Additionally, the compounds can be delivered using a sustained release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Several release materials have been established sustained and are well known to those skilled in the art. Sustained-release capsules, depending on their chemical nature, can release the compounds for a few weeks to more than 1000 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization can be used.
The pharmaceutical compositions may also comprise suitable solid phase or gel carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
Many of the compounds of the invention can be provided as salts with pharmaceutically compatible counterions. The pharmaceutically compatible salts can be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. The salts tend to be more soluble in aqueous solvents or other protonic solvents than the corresponding free base forms.
Pharmaceutical compositions suitable for use in the present invention include compositions in which the active ingredients are contained in an effective amount to achieve their intended purpose. More specifically, a therapeutically effective amount means an effective amount to prevent the development of or to alleviate the existing symptoms of the individual being treated. The determination of the effective amounts is within the ability of those skilled in the art.
Dose For any compound used in a method of the present invention, the therapeutically effective dose can be estimated initially from cellular tests. For example, a dose can be formulated in cellular and animal models to achieve a concentration range in circulation that includes the EC50 as determined in cellular tests (ie, the concentration of the test compound that achieved half the inhibition). maximum activity of a given receiver). In some cases it is appropriate to determine the EC50 in the presence of 3 to 5% of serum albumin because said determination approximates the effects of binding of the plasma protein on the compound. This information can be used to determine more accurately the useful doses in humans. In addition, suitable compounds for systemic administration effectively modulate the receptors of the S 1 P family in intact cells at levels that are obtainable safely in plasma.
A therapeutically effective dose refers to that amount of the compound that results in the improvement of symptoms in a patient. The toxicity and therapeutic efficacy of said compounds can be determined using standard pharmaceutical procedures in cell cultures or animal experimentation, for example, to determine the maximum tolerated dose (MTD) and the ED50 (effective dose for the 50% maximum response). The dose ratio between toxic and therapeutic effects is the therapeutic index and this can be expressed as the relationship between BAT and ED50. Preferred are compounds that exhibit high therapeutic indices. The data obtained from these tests in cell cultures and animal studies can be used to formulate a dosing interval for use in humans. The dosage of said compounds is preferably within a range of circulating concentrations that include ED50 with little or no toxicity. The dose may vary within this range depending on the dosage form used and the route of administration used. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See, for example, Fingí et al., 1975, in "The Pharmacological Basis of Therapeutics," Chapter 1 p1). In the treatment of crisis, the administration of an acute bolus or an infusion that approaches BAT could be convenient to obtain a rapid response.
The amount and range of dosage can be adjusted individually to provide plasma levels of the active portion that are sufficient to modulate the receptors of the S1 P family, or the minimum effective concentration (M EC). The M EC can vary for each compound but can be calculated from in vitro data; for example the concentration necessary to achieve 50-90% inhibition of natural ligand binding using the tests described in the present application. The doses necessary to achieve EC will depend on the individual characteristics and route of administration. However, HPLC tests or bioassays can be used to determine plasma concentrations.
Dose ranges can also be determined using the M EC value. The compounds should be administered using a regimen that maintains plasma levels above the MEC for 1 0-90% of the time, preferably between 30-90% and more preferably between 50-90% until the desired improvement of symptoms. In cases of local administration or selective absorption, the effective local concentration of the drug may not be related to the plasma concentration.
Of course, the amount of composition administered will depend on the individual being treated, the individual's weight, the severity of the condition, the manner of administration and the judgment of the prescribing physician.
If desired, the compositions may be presented in a packaging material or dispensing device which may contain one or more dosage forms containing the active ingredient. The packaging material may, for example, comprise a thin sheet of metal or plastic, such as a bubble packing material. The packaging material or dispensing device may be accompanied by instructions for administration. The compositions comprising a compound of the invention Formulated in a compatible pharmaceutical vehicle can also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
Example formulations In some formulations it may be beneficial to use the compounds of the present invention in the form of very small size particles, for example as obtained by grinding fluid energy.
The use of the compounds of the present invention in the manufacture of pharmaceutical compositions is illustrated by the following description. In this description, the term "active compound" denotes any compound of the invention, particularly any compound which is the final product of one of the preceding Examples. a) Capsules In the preparation of capsules, 1 0 parts by weight of active compound and 240 parts by weight of lactose can be dewatered and combined. The mixture can be used to fill gelatin capsules, each capsule containing a unit dose or part of a unit dose of the active compound. b) Tablets The tablets can be prepared, for example, from the following proteins: Parts by weight Active compound 1 0 Lactose 1 90 Starch of corn 22 Polyvinyl pyrrolidone 1 0 Magnesium stearate 3 The active compound, lactose and some of the starch can be dewatered, combined and the resulting mixture can be granulated with a solution of the polyvinylpyrrolidone in ethanol. The dry granulate can be combined with the magnesium stearate and the rest of the starch. The mixture can then be compacted in a tablet press to obtain tablets in which each contains a unit dose or part of a dosage of the active compound. c) Enteric coated tablets The tablets can be prepared using the method described in (b) above. The tablets can be coated with an enteric coating in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol / dichloromethane (1: 1). d) Suppositories In the preparation of suppositories, for example, 1 00 parts by weight of active compound can be incorporated into 1300 parts by weight of triglyceride base for suppository and the mixture is formed as suppositories each containing a therapeutically effective amount of active ingredient.
The present invention also comprises the use of a compound of Formula (I), (Ia), (I I), (I I I), (IV), or (V) as a medicament.
A further aspect of the present invention provides the use of a compound of Formula (I), (a), (II), (III), (IV), or (V) or a salt thereof in the manufacture of a medicament for treating vascular hyperpermeability, angiogenesis-dependent disorders, proliferative diseases and / or immune system disorders in mammals, particularly humans.
The present invention also provides a method for treating vascular hyperpermeability, appropriate neovascu larization, diseases and / or proliferative disorders of the immune system which comprises the administration of a therapeutically effective amount of a compound of the Formula (I), (a), (II), (III), (IV), or (V) to a mammal, particularly a human being, in need thereof.
The teachings of all references, including articles of periodical publications, patents and published patent applications, are incorporated in the present application for reference in its entirety.
GTPyS tests of the S1P receiver The [35S] GTPyS binding test can be run using both the scintillation proximity test (SPA) as well as filtration methods. Both formats are in 96-well plates and use membranes from stable or transient CHO human cell lines that over-express SIP ^ S1P3, S1P4 or S1P5. The reserve solutions of the compounds are brought to 10 mM using DMSO and the serial dilutions are carried out using 100% DMSO. Compounds are transferred to 96-well plates to obtain a final DMSO concentration of 1% for all tests (1 ul for a test volume of 100 μ?). The thawed membranes are thawed and diluted in buffer for test containing 20 mM HEPES pH 7.4, 0.1% fatty acid free BSA, 100 mM NaCl, 5 mM MgCl2 and 10 μM. of GDP. For the SPA test the membranes are previously mixed with WGA-SPA globules to obtain a final concentration per cavity of 5 pg of membranes and 500 pg of globules. For the filtration test, the membranes are added directly to the incubation plate at 5 ug per cavity. The test begins with the addition of 50 μ? of the membrane or membrane / globule mixture to each cavity of the test plate. Then, 50 μ? of [35 S] GTPyS 0.4 nM to each well and incubated for 30 minutes. The non-specific binding is measured using GTPyS 10 μ? not marked. For the SPA test, the plates are centrifuged and then read in the Topcount. For the filtration test, the plate is harvested on GF-C filtration plates using a Packard 96-well harvester.
Inhibition of binding of T33P1S1P to S1P receptors The radioligand binding is performed using membranes from transiently transfected HEK cells that overexpress SIP ^ S1P3, S1P4 or S1P5. All compounds are dissolved in DMSO and serial dilutions are carried out in DMSO before addition to the test buffer. The final DMSO concentrations of the test are 1% (v / v). [33P] S1P is purchased from Perkin Elmer and is used at 50 pM in all tests. The frozen membranes are thawed and resuspended in test buffer containing 50 mM HEPES pH 7.4, 100 mM NaCl, 10 mM MgCl 2 and 0.1% fatty acid free BSA. The membrane is added to obtain 5-10 pg of membrane per cavity. The non-specific binding is determined in the presence of S1P 1 μ? cold Incubations are performed at room temperature for 45-60 minutes before filtering into the filter plates using a Packard 96-well harvester. The plates are dried before adding Microscint to each cavity, sealed and counted in a Topcount.
Abbreviations ACN acetonitrile Binap 2,2'-bis (diphenylphosphino) -1, 1'-biphenyl C H 2C 12 dichloromethane C HCl3 Chloroform C02 Carbon dioxide DAST Diethylaminosulfur trifluoride DBAD Di-tert-butyl azodicarboxylate DBU 1, 8-Diazabicyclo (5.4.0) undec-7-ene DCC N, N'-dicyclohexylcarbodi-imide DCE Dichloroethane DCM Dichloromethane DIAD Di-isopropyl azodicarboxylate Dibal-H Di-isobutylaluminum hydride DIC N, N'-di-isopropylcarbodi-imide DI EA N, N-di-isopropileti lamina DMA N, N-dimethylacetamide DM E 1, 2-dimethoxyethane DM F N, N-dimethylformamide DMSO Dimethyl sulfoxide EA Acetate of ethyl EDC 1, 2-dichloroethane EDC I 1 - (3-dimethylaminopropyl) -3-ethylcarbodiimide EtOH Ethanol EtOAc Ethyl acetate Et3N Triethylamine FCC Cromatog instant vaporization column li hour (s) HBTU O-benzotriazol-1 -li?,?,? ',?' - tetramethyluronium hexafluorophosphate HATU 0- (7-Azabenzotriazole-1-N-N-N'-N-tetramethyluronium hexafluorophosphate HCI Hydrochloric acid HOBt 1 -Hydroxybenzotriazole HOAT 1-Hydroxy-7-azabenzotriazole HPLC High Performance Liquid Chromatography KHMDS Hexamethyldisilazide Potassium MeOH Methanol Min Minutes MW Microwave NaOH Sodium hydroxide NIS N-iodosuccinimide NMP 1-methyl-2-pyrrolidone PS-DCC Carbodi-imide supported on polymer PS-PPh3 Trifenilfosfina supported in polymer RBF Round bottom flask RP Reverse phase Rt Retention time TA Ambient temperature THF Tetrahydrofuran i-PrOH 2-Propanol PPh3 Triphenylphosphine SFC Supercritical fluid chromatography SOCI2 Thionyl chloride Analytical methods The analytical data are defined either within the general procedures or in the tables of the examples. Unless otherwise stated, all 1H or 13C NMR data is collected on a Varian Mercury Plus 400 MHz instrument or a Bruker DRX 400 MHz instrument; Chemical shifts are quoted in parts per million (ppm). The analytical data of high pressure liquid chromatography (HPLC) are detailed either within the experiments or are referred to the table of HPLC conditions, using the letter of the method in lowercase, in Table 1.
TABLE 1 List of HPLC methods TABLE 1 (cont.) TABLE 1 (with TABLE 1 (cont.) TABLE 1 (conU TABLE 1 (cont.) TABLE 1 (cont.
Purification methods For general procedures, the final compounds can be purified using any technique or combination of techniques known to the person skilled in the art. Some non-limiting examples include flash chromatography with a solid phase (eg, silica gel, alumina, etc.) and a solvent (or combination of solvents) that elutes the desired compounds (eg, heptane, EtOAc, DCM, MeOH, MeCN, water, etc.); Preparative TLC with a solid phase (eg, silica gel, alumina, etc.) and a solvent (or combination of solvents) that elutes the desired compounds (e.g., heptane, EtOAc, DCM, MeOH, MeCN, water, etc.); Reverse phase HPLC (see Table 1 for some non-limiting conditions); recrystallization with an appropriate solvent (for example MeOH, EtOH, IPA, EtOAc, toluene, etc.) or combination of solvents (for example EtOAc / heptane, EtOAc / MeOH, etc.); Chiral LC with a solid phase and an appropriate solvent (see Table 2 for some non-limiting conditions) to elute the desired compound; Chiral SFC with a solid phase and C02 with an appropriate modifier (for example MeOH, EtOH, IPA with or without additional modifier such as diethylamine, TFA, etc.); precipitation with a combination of solvents (for example DMF / water, DMSO / DCM, EtOAc / heptane, etc.); trituration with a suitable solvent (for example EtOAc, DCM, MeCN, MeOH, EtOH, IPA, n-IPA, etc.); extractions by dissolving a compound in a liquid and washing with an appropriate immiscible liquid (eg DCM / water, EtOAc / water, DCM / saturated aqueous NaHCO3, EtOAc / saturated aqueous NaHC03, DCM / 10% aqueous HCl, EtOAc / aqueous HCl 10%, etc.); distillation (eg simple, fractional, Kugelrohr, etc.); gas chromatography using an appropriate temperature, carrier gas and flow rate; sublimation at an appropriate temperature and pressure; filtration through a medium (for example Florosil®, alumina, Celita®, silica gel, etc.) with a solvent (for example heptane, hexanes, EtOAc, DCM, MeOH, etc.) or combination of solvents; salt formation with solid support (based on resin, for example ion exchange) or without support. Some descriptions of these techniques can be found in the following references: Gordon, A. J. and Ford, R. A. "The Chemist's Companion", 1972; Palleros, D. R. "Experimental Organic Chemistry", 2000; Still, W. C, Kahn and M. Mitra, A. J. Org.
Chem. 1978, 43, 2923; Yan, B. "Analysis and Purification Methods in Combinatorial Chemistry", 2003; Harwood, L.M., Moody, C.J. and Percy, J.M. "Experimental Organic Chemistry: Standard and Microscale, 2nd Edition", 1999; Stichlmair, J. G. and Fair, J. R. "Distillation, Principles and Practices", 1998; Beesley, T. E. and Scott, R. P. W. "Chiral Chromatography", 1999; Landgrebe, J. A. "Theory and Practice in the Organic Laboratory, 4th Ed.", 1993; Skoog, D. A. and Leary, J. J. "Principies of Instrumental Analysis, 4th Ed.", 1992; G. Subramanian, "Chiral Separation Techniques, 3rd Edition", 2007; Y. Kazakevich, R. Lobrutto, "HPLC for Pharmaceutical Scientists," 2007.
REACTION SCHEME A A method for preparing disubstituted oxadiazole compounds of the invention is illustrated in the reaction scheme A (X = CR3 or N). In reaction scheme A, step i, a suitably substituted nitrile 1 compound (commercially available or made through General Procedure A or B) is reacted with hydroxylamine to obtain compound 2. This type of reactions are well established in the literature (see, for example, Yan, et al., Bioorg &Med Chem Lett 2006, 16 (14), 3679-3683). This reaction is typically carried out in a protic solvent (such as MeOH or EtO H) at or below the reflux temperature (such as 60 ° C). The product 2 is typically isolated from the reaction mixture as a solid by concentration of the mixture. The compound 2 can be used as such. Coupling of compound 2 with an appropriate acid or acid chloride followed by ring closure to produce compound 3 is shown in step ii. The coupling reaction is typically carried out with carboxylic acids in the presence of a coupling reagent (such as HOBt, DCC) or with acid chlorides in the presence of an organic base (such as DI EA, Et 3 N) at room temperature or elevated temperature (e.g., 20-180 ° C) in a solvent such as DM F or DMA. The subsequent ring closure reaction is completed in situ at elevated temperature (for example 1 60 ° C) (see, for example, Wang, et al., Org Lett 2005 7 (5), 925-928). The compounds 3 can then be isolated and purified using standard techniques (such as reverse phase liquid chromatography or SFC).
General schemes of synthesis The general synthetic schemes that are used to construct the majority of compounds described in this application are described below in (Reaction Schemes 1-3).
Reaction scheme 1. General synthesis route for 4-alkoxy-benzonitrile (general procedure A, B) Reaction scheme 2. General synthesis route for 3,5-disubstituted oxadiazole (general procedure C, D, and E) Scheme of reaction 3. General route of synthesis for an acid chloride (general procedure F) LIST OF GENETICAL MECHANICAL PROCEEDS General Procedure A: Preparation of 4-alkoxy-benzonitrile using triphenylphosphine General Procedure B: Preparation of 4-alkoxybenzoyl itryl using polymer-bound triphenylphosphine General procedure C: Preparation of hydroxyamidine General procedure D: Oxadiazole formation from an acid General procedure E: Oxadiazole formation from an acid chloride General procedure F: Formation of an acid chlorine from a carboxylic acid General procedure G Formation of aldehyde from nitrile General procedure H: Almination of aldehido General procedure I: Alkylation of indole with acrylate General procedure J: Alkylation of indole with an alkyl halogen General procedure K: Deprotection of tert-butyl ester or ether General procedure L: Amino halogen amination General procedure M Alkylation of phenol with an alkyl halogen General procedure N De-benzylation General procedure O Deprotection of protected 1,2-diol General procedure P Nucleophilic displacement of an aryl fluoride General procedure Q Hydrolysis of an ester General procedure R Copulation of M itsunobu to a phenol General procedure S: Deprotection of phosphonate ester with or without bromination General procedure T: Preparation of benzylic olefin from ketone General procedure U: Benzyl olefin reduction General procedure V: H ester hydrolysis General procedure W: Alkylation of a phenol Example of use of general procedures The letter codes of the general procedure constitute a synthesis route to the final product. An example worked out in the way in which the route is determined is given below using Example A.33 as a non-limiting illustration. Example A.33, 4- [3- (3-chloro-4-isopropoxy-phenyl) - [1, 2, 4] oxadiazol-5-yl] -pyridine is prepared from 3-chloro-N-hydroxy-4-isopropoxy -benzamidine using general procedure D, as shown in the following synthesis scheme: The precursor for Example A.33, 3-chloro-N-hydroxy-4-isopropoxy-benzamidine is prepared using the route (A, C). This is translated in the following synthesis sequence, in which the hydroxyamidine starting material used in the general process D is the product by means of the following procedure A and C, in the given order.
Preparations and examples The general methods of synthesis used in each general procedure follow and include an illustration of a compound that is synthesized using the designated general procedure. None of the specific conditions and reagents indicated in the present application should be considered as limiting the scope of the invention and are provided for illustrative purposes only. All starting materials can be obtained commercially from Sigma-Aldrich (including Fluka and Discovery CPR) unless otherwise indicated after the chemical name. The given reagent / reactant names are as those named on the commercial bottle or as generated by the conventions of IU PAC, CambridgeSoft® ChemDraw Ultra 9.0.7, CambridgeSoft® Chemistry E-Notebook 9.0.1 27, or AutoNom 2000.
General Procedure A: Preparation of 4-alkoxy-benzonitrile using triphenylphosphine Triphenylphosphine (1-3 equivalents, preferably 1.6 equivalents) and 4-hydroxybenzonitrile (1-3 equivalents, preferably 1 equivalent) are dissolved in an anhydrous organic solvent such as dichloromethane, toluene, or tetrahydrofuran (preferably tetrahydrofuran) under a nitrogen atmosphere. After briefly stirring, an azodicarboxylate such as ditalty azodicarboxylate, di-isopropyl azodicarboxylate, or di-tert-butyl azodicarboxylate (preferably di-tert-butyl azodicarboxylate) (1-3 equivalents, preferably 1.6 equivalents) and the mixture is stirred for a few minutes before the addition of an anhydrous alcohol (1-3 equivalents, preferably 1.25 equivalents). The reaction mixture is stirred at 0-100 ° C (preferably about 23 ° C) under a nitrogen atmosphere for a period of about 2-24 hours (preferably 1 6 hours). The solvent is removed under red pressure. The crude product can be further purified by flash column chromatography.
Eiemplification of general procedure A: Preparation of 3-chloro-4-isopropoxy-benzonitrile In a round bottom flask containing triphenylphosphine (27.3 g, 104 mmol) and 3-chloro-4-hydroxy-benzonitrile (10 g, 65 mmol) is added anhydrous tetrahydrofuran (600 ml). The mixture is stirred briefly under nitrogen, then di-tert-butyl azodicarboxylate (24 g, 104 mmol) is added. The mixture is stirred for a few minutes, followed by the addition of anhydrous isopropanol (6.23 ml, 81.4 mmol). The reaction mixture is stirred at room temperature overnight under nitrogen. The crude product is purified by flash chromatography using ethyl acetate / heptane 1: 4 (v / v) as eluent. The fractions are dried to obtain 3-chloro-4-isopropoxy-benzonitrile (12.2 g, 91%) as a red-orange semi-solid.
LC / MS (Table 1, Method d) Rt = 2.36 minutes, m / z 152.1 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d 7.74 (d, 1 H), 7.61 (dd, 1H), 7.14 (d, 1H), 4.75 (septet, 1H), 1.34 (d, 6H).
General Procedure B: Preparation of 4-alkoxy-benzonitrile using polymer-bound triphenylphosphine To an alcohol (1-3 equivalents, preferably 1 equivalent) and 4-hydroxy-benzonitrile (1-3 equivalents, preferably 1 equivalent) dissolved in a suitable solvent such as dichloromethane, dichloroethane, tetrahydrofuran, or 1,4-dioxane (preferably tetrahydrofuran) is added triphenylphosphine bound to polymer (1-3 equivalents, preferably 2 equivalents) and a azodicarboxylate such as diethyl azodicarboxylate, DIAD, or di-tert-butyl azodicarboxylate (preferably DIAD) (1-2 equivalents, preferably 1.5 equivalents). The mixture is stirred at about 0-100 ° C (preferably about 23 ° C) for a period of 4-24 hours (preferably 16 hours). The crude mixture is filtered and the resin is washed with an appropriate solvent such as dichloromethane, dichloroethane, THF, or 1,4-dioxane (preferably TH F). The filtrate is concentrated to dryness under reduced pressure and the residue is subjected to General Procedure C.
Exemplification of general procedure B: Preparation of 3-chloro-4- (1-ethyl-propoxy) -benzonitrile In a scintillation vial containing a solution of pentan-3-ol (22 mg, 0.25 mmol) dissolved in TH F (2 mL) is added to a solution of 3-chloro-4-hydroxy-benzonitrile (38 mg, 0.25). mmoles) in TH F (2 ml) followed by PS-PPh3 resin (357 mg, 0.5 mmol, loading 1.4 mmol / g) and a solution of DIAD (76 mg, 0.375 mmol) in TH F (2 ml). The vial is capped and agitated at room temperature overnight. The reaction mixture is filtered and the resin is washed with THF (4 ml). The filtrate is concentrated to dryness to obtain 3-chloro-4- (1-ethyl-propoxy) -benzonitrile.
General Procedure C: Preparation of Hydroxyamidine To a solution of benzonitrile (1-3 equivalents, preferably 1 equivalent) in a suitable solvent such as methanol, ethanol, isopropanol, or water (preferably ethanol) is added (1-50 equivalents, preferably 1.1 equivalents). The reaction mixture is heated to about 25-100 ° C (preferably 60 ° C) for a period of about 2-24 hours (preferably 16 hours). The solvents are removed under reduced pressure. The crude product is dried under vacuum and then subjected to General Procedure D or E.
Eiemplification of general procedure C: Preparation of 3-chloro-N-hydroxy-4-isopropoxy-benzamidine In a round-bottomed flask are added 3-chloro-4-isopropoxy-benzonitrile (5.00 g, 25.6 mmol), hydroxylamine (50% by weight in water, 1.86 ml, 28.1 mmol) and ethanol (150 ml). The mixture is heated to approximately 60 ° C overnight. After the reaction is complete, the mixture is concentrated to dryness under reduced pressure to obtain 3-chloro-N-hydroxy-4-isopropoxy-benzamidine (5.76 g, 94%) as a light yellow solid.
LC / MS (Table 1, Method a) Rt = 2.09 minutes, m / z 229 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d 9.58 (s, 1 H), 7.70 (d, 1 H), 7.59 (dd, 1 H), 7.15 (d, 1 H), 5.81 (s, 2 H), 4.69 (septet, 1H), 1.29 (d, 6H).
General procedure D: Oxadiazole formation from an acid To a reaction vial is added a hydroxyamidine (0.9-1.5 equivalents, preferably 1.1 equivalent), an acid (0.9-1.5 equivalents, preferably 1 equivalent), a coupling reagent such as HBTU, HATU, HOBt, or HOBt bound to polymer (preferably HOBt) (1-2 equivalents, preferably 1 equivalent), a carbodiimide such as PS, EDCI, DIC, DCC or DCC bound to polymer (preferably DCC bound to polymer) (1.5-3 equivalents) , preferably 3 equivalents), a base such as di-isopropylethylamine, triethylamine, or N-methylmorpholine (preferably di-isopropylamine) (1-3 equivalents, preferably 3 equivalents) and an appropriate solvent such as DMF, DMA, or ACN (preferably ACN). The reaction vial is capped and heated (conventional heating or microwave heating, preferably microwave heating) to 100-200 ° C (preferably 160 ° C) for a period of 15-45 minutes (preferably 30 minutes) . After cooling to room temperature, the crude reaction mixture is filtered, washed with an appropriate solvent such as DMF, DMA, or ACN (preferably ACN), and the filtrate is concentrated to dryness under reduced pressure. The crude product is further purified by chromatography.
Eiemplification of the general procedure D: Preparation of 4- [3- (3-chloro-4-isopropoxy-phenyl) - [1,4] oxadiazol-5-yl] -3-methyl-pyridine To a microwave vial loaded with 3-chloro-N-hydroxy-4-isopropoxy-benzamidine (75 mg, 0.328 mmol), 3-methyl-isonicotinic acid (41 mg, 0.298 mmol), HOBt (46 mg, 0.298 mmol) , PS-carbodi-imide (720 mg, 0.894 mmol, loading 1.24 mmol / g) is added ACN (3.5 ml) and di-isopropylethylamine (156 μ ?, 0.894 mmol). The reaction vial is capped and heated to approximately 160 ° C for approximately 30 minutes in a Biotage microwave. The reaction mixture is filtered and the resin is washed with ACN (4 mL). The filtrate is concentrated to dryness. The crude product is purified by reverse phase HPLC (30-90% ACN, 30 minute ramp) to obtain 10.2 mg (10%) of 4- [3- (3-chloro-4-isopropoxy-phen M) - [1, 2,4] oxadiazol-5-yl] -3-methyl-pyridine.
LC / MS (Table 1, Method c) Rt = 2.70 minutes, m / z 330 (M + H) +.
H NMR (400 MHz, DMSO-d6) d 8.77 (s, 1H), 8.69 (d, 1H), 8.06 (d, 1H), 8.01 (dd, 2H), 7.39 (d, 1H), 4.83 (septet, 1H), 2.70 (s, 3H), 1.35 (d, 6H).
General procedure E: Oxadiazole formation from an acid chloride To a solution of a 3-chloro-N-hydroxy-4-alkoxybenzamidine (1-3 equivalents, preferably 1 equivalent) in pyridine is added a solution of an acid chloride (1-3 equivalents, preferably 2 equivalent ) in pyridine. The reaction mixture is heated to 60-100 ° C (preferably 100 ° C) for a period of 8-24 hours (preferably 20 hours). The solvent is removed under reduced pressure and the residue is further purified by chromatography.
Eiemplification of the general procedure E: Preparation of 3- [3-chloro-4- (1-ethyl-propoxy) -phenyl] -5-o-tolyl- [1, 2,4] oxadiazole To a solution of 3-chloro-4- (1-ethyl-propoxy) ÷ N-hydroxybenzamidine (64 mg, 0.25 mmol) (prepared by General Procedure B) in pyridine (1 mL) is added a chloride solution of 2-methylbenzoyl (77 mg, 0.5 mmol) in pyridine (1 mL). The mixture is heated to approximately 100 ° C overnight. The solvent is removed under reduced pressure and the crude product is purified by SFC (pure G02 / MeOH, gradient: 5% retention for 0.5 minutes, increase to 7.3% up to 50% in the course of 6.5 minutes, hold at 50% for 1 minute) to obtain 3- [3-chloro-4- (1-ethyl-propoxy) -phenyl] -5-o-tolyl- [1, 2,4] oxadiazole (16.5 mg, 18.5%).
LC / MS (Table 1, Method b) Rt = 3.18 minutes, m / z 356.13 (M-H) \ 1 H NMR (400 MHz, CHCl 3) d 8.19 (d, 1 H), 8.16 (dd, 1 H), 8. 01 (dd, 1H), 7.48 (m, 1H), 7.37 (d, 1H), 7.01 (d, 1H), 4.28 (m, 1H), 1.77 (m, 4H), 1.01 (t, 6H).
Preparation of 3- (3-chloro-4-isopropoxyphenyl) -5- (3-chloropyridin-4-yl) - [1,4] -oxadiazole To a solution of 3-chloroisonicotinoyl chloride (approximately 2.6 mmol) (prepared by General Procedure F) in pyridine (5 mL) is added 3-chloro-4-isopropoxy-N-hydroxy-benzamidine (300 mg, 1.31 mmol) (prepared by General Procedure B). The mixture is heated to approximately 100 ° C overnight. The solvent is removed under reduced pressure and the crude product is purified by chromatography on silica gel in normal phase (gradient of 0-50% ethyl acetate / heptane in the course of 30 minutes) to obtain 3- (3-chloro) -4-isopropoxyphenyl) -5- (3-chloropyridin-4-yl) - [1,4] -oxadiazole (323 mg, 70.3%).
LC / MS (Table 1, Method b) R, = 3.88 minutes, m / z 349.04 (M-H) -. 1 H NMR (400 MHz, CHCl 3) d = 8.84 (d, 1H), 8.69 (d, 1H), 8.11 (d, 1H), 8.02 (d, 1H), 7.99 (dd, 1H), 7.02, (d, 1H), 4.69 (m, 1H), 1.44 (d, 6H).
General procedure F: Formation of an acid chloride from a carboxylic acid To an acid (preferably 1 equivalent) in an appropriate solvent, such as DCM or dichloroethane (preferably DCM) is added a reagent for chlorination such as thionyl chloride or oxalyl chloride (preferably thionyl chloride) (1-100) equivalents, preferably 3 equivalents). The reaction mixture is stirred at 20-80 ° C (preferably about 23 ° C) for a period of 1- 24 hours (preferably 3 hours). The solvent is removed under reduced pressure. The crude product is dried under vacuum and then subjected to General Procedure E.
Exemplification of the general procedure F: Preparation of 3-methyl-isonicotinoyl chloride 3-Methylisonicotinic acid (1000 mg, 0.729 mmol) suspended in DCM (2.5 ml) is added thionyl chloride (260 mg, 2.1 88 mmol). The reaction mixture is stirred at room temperature for about 3 hours. The solvent is removed under reduced pressure and the residue is dried under high vacuum for 1 hour to obtain 3-methyl-isonicotinoyl chloride.
Preparation of 3-chloro-isonicotinoyl chloride To 3-chloroisonicotinic acid (41 3 mg, 2.62 mmol) thionyl chloride (5 ml, 68.5 mmol) is added. The reaction mixture is stirred at room temperature for about 20 hours. The solution is concentrated under reduced pressure and the residue is dried under high vacuum for 1 hour to obtain 3-chloro-isonicotinoyl chloride.
General procedure G: Formation of aldehyde from nitrile A mixture of a nitrile in a round bottom flask containing (0.9-1.2 equivalents, preferably 1.0 equivalents) in an appropriate solvent such as dichloromethane or dichloroethane (preferably dichloromethane) is cooled between 0 ° C and -60 ° C ( preferably -40 ° C). A Dibal-H solution is added dropwise (0.9-2.5 equivalents, preferably 2.0 equivalents) and then the solution is stirred for 15-240 minutes (preferably 120 minutes), quenched with methanol, warmed to room temperature and it is treated with a 10% solution of Rochelle salt. After extraction with DCM, the combined organic layers are stirred with dilute aqueous acid (preferably aqueous 1M HCl). The layers are separated and the aqueous layer is extracted with DCM. The combined organic layers are washed with brine, dried with MgSO4 or Na2SO4, filtered and evaporated to dryness. The crude product is further purified by chromatography.
Eiemplification of the general procedure G: Preparation of 3-chloro-4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) benzonitrile A 100 ml round bottom flask fitted with a septa cap equipped with a nitrogen exit needle is charged with 3-chloro-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazole -5-yl) benzonitrile (1529 g, 3.27 mmol) in DCM (65.4 mL) to obtain an orange solution. The reaction mixture is cooled to about -40 ° C by an ACN-dry ice bath. Then Dibal-H (3.60 ml, 3.60 mmol) is added by dripping at approximately -40 ° C. The resulting mixture is stirred for about 2 hours at about -40 ° C. Then methanol (0.5 ml, 12.36 mmol) is added dropwise to the reaction mixture at about -40 ° C. The ice bath is removed and the reaction is allowed to warm to room temperature, then Rochelle's salt solution (60 ml) is added. The resulting mixture is stirred vigorously for about 3 hours. The aqueous layer is separated. The organic phase is washed with brine, dried (MgSO 4) and concentrated to obtain crude yellow oil. The residue is purified by the Analogix® FCC system using a 120 g RediSep ™ RS column, with a gradient of 0-15% EtOAc / Heptane in the course of 40 minutes at 40 ml / minute then it is maintained at 15% until all peaks elute. The fractions containing the product are combined and concentrated to produce 3-chloro-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzonitrile (0.791 g, 2.09 mmol. ). 1 H NMR (400 MHz, CDCl 3) d ppm 10.09 (s, 1H), 8.35 (d, J = 8.02 Hz, 1H), 8.21 (d, J = 1.90 Hz, 1H), 8.09 (s, 1H), 8.03 ( dd, J = 8.56, 1.86 Hz, 1H), 7.94 (dd, J = 8.04, 0.79 Hz, 1H), 7.05 (d, J = 8.62 Hz, 1H), 4.69 (td, J = 12.05, 6.04 Hz, 1H ), 1.45 (t, J = 6.80 Hz, 6H).
General Procedure H: Aldehyde Amination A mixture of an amine (0.9-1.2 equivalents, preferably 1.1 equivalents), an aldehyde (0.9-1.2 equivalents, preferably 1.0 equivalents), an appropriate reducing agent, such as sodium cyanoborohydride or cyanoborohydride sodium supported in polymer (preferably sodium cyanoborohydride supported on polymer) (1.5-3.0 equivalents, preferably 2.0 equivalents), acetic acid (2-24 drops, preferably 6 drops) and an appropriate solvent such as DCM or methanol ( preferably DCM) is stirred at room temperature for 4-72 hours, preferably 17 hours. The crude product is further purified by chromatography.
General procedure H alternative In a microwave vial of 2.5, add a solution of aldehyde (25 mg, 1 equivalent) dissolved in DCM: methanol 1: 1 (1.5 ml), followed by the addition of amine (35 mg, 1.2 eq.) Also dissolved in 1: 1 solution of DCM: methanol (1.0 ml), followed by resin-linked cyanoborohydride (3 eq.) and acetic acid (10 eq.). The microwave vial is capped and heated at 90 ° C for 600 seconds by reaction in Biotage parallel microwave optimizer. The reaction is verified by LC / MS (Table 1, method m) and concentrated to dryness. The residue dissolves in DMSO / MeOH 1: 1 and purified by reverse phase HPLC (Table 1, method L).
Exemplification of the general procedure H: Preparation of 1 - (3-chloro-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) -3-methylazetidin-3-carboxylic acid A 500 ml round bottom flask is charged with 3- chloro-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzaldehyde (0.745 g, 1.975 mmol) , Ethyl 3-methylazetidin-3-carboxylate (0.566 g, 3.95 mmol) (Tetrahedron Letters 1991, 32, 36, 4795-4798) and methanol (197 ml). To this is added acetic acid (0.904 ml, 15.80 mmol). The resulting mixture is stirred at room temperature for about 1 hour then sodium cyanoborohydride (0.095 g, 1512 mmoles) is added in one portion. The reaction is stirred for approximately 17 hours at room temperature. The progress of the reaction is monitored by LC / MS. The reaction is concentrated in vacuo to obtain crude dark yellow oil. The residue is purified by Analogix® FCC system using 120 g Redi-Sep column, with a gradient of 0-40% EtOAc / Heptane in the course of about 45 minutes at 50 ml / minute then it is maintained at 40% EtOAc until all peaks elute. The fractions containing the product are combined and concentrated to yield 0.820 g (1626 mmol) of colorless oil. The material is dissolved in THF (80 ml). To this is added NaOH (9.0 ml, 9.00 mmol) as a 1N solution, followed by MeOH (apr 25 ml). The reaction is stirred at room temperature for about 3 hours, after which LC / MS shows that the hydrolysis is complete. To the reaction mixture is added HCl (9.0 ml, 9.00 mmol) as a 1N solution by dripping to neutralize the pH. The reaction mixture is concentrated in vacuo then lyophilized to dryness. The crude white solid is triturated in diethyl ether and DCM is then filtered. The resulting solid is washed with water then oven dried overnight to obtain 1 - (3-chloro-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazole-5- acid. il) benzyl) -3-methylazetidine-3-carboxylic acid (0.377 g, 0.75 mmol) as a white solid.
LC / MS (Table 1, Method a) Rt = 1.81 minutes; MS m / z: 476.15 (M + H) +.
H NMR (400 MHz, DMSO) d ppm 12.67-12.25 (m, 1H), 8.24-7.93 (m, 3H), 7.73-7.32 (m, 3H), 4.90-4.76 (m, 1H), 3.69 (s, 2H), 3.43 (d, J = 6.51 Hz, 2H), 3.09 (d, J = 6.43 Hz, 2H), 1.45 (s, 3H), 1.35 (d, J = 5.75 Hz, 6H).
General procedure I: Algallation of indole with acrylate To a solution of an indole (0.9-1.2 equivalents, preferably 1.0 equivalents) in an appropriate solvent such as ACN at about 60 ° C is added an acrylate (1.0-2.0 equivalents, preferably 1.5 equivalents) and a base such as DBU (0.3-1.0 equivalents, preferably 0.5 equivalents). The mixture is stirred at approximately 50 ° C overnight. The solvent is removed under reduced pressure and the crude product is dissolved in DCM, washed with brine, dried with MgSO4 or Na2SO4, filtered and the solvent is removed under reduced pressure. The crude product is further purified by chromatography or recrystallization.
Eiemplification of general procedure I: «Preparation of tert-butyl 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) -1 H -indole-1-yl) propanoate To a solution of approximately 3- (3-chloro-4-isopropoxyphenyl) -5- (1 H -indol-4-yl) -1,2,4-oxadiazole (5.6 g, 15.83 mmol) in ACN (55.9 ml) at 60 ° C tert-butyl acrylate (3.45 ml, 23.74 mmol) is added dropwise, followed by DBU (1193 ml, 7.91 mmol). The mixture is stirred at approximately 50 ° C overnight. The solvent is removed under reduced pressure and the crude product is dissolved in DCM (150 ml), washed with brine (3 x 100 ml), dried with MgSO 4, filtered and the solvent is removed under reduced pressure. Recrystallization with petroleum ether 30-60 ° C prod uce 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) -1 H-indole-1 -yl) tert-butyl propanoate (5.42 g, 69.6%).
LC / MS (Table 1, Method b) Rt = 3.03 minutes, m / z 482.26 (M + H) +.
General procedure J: Alkylation of indole with an alkyl halogen To a solution of an indole (0.9-1.2 equivalents, preferably 1.0 equivalent) in an appropriate solvent such as DM F is added NaH (0.9-1.2 equivalents, preferably 1.1 equivalents). After about 15 minutes, an alkyl halide (0.9-2.0 equivalents, preferably 1.5 equivalents) is added and the reaction mixture is heated to about 50 ° C. After about 24 hours the reaction mixture is cooled to room temperature, evaporated to dryness and the crude product is further purified by chromatography.
Eiemplification of the general procedure J: Preparation of tert-butyl 4- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1 H -indole-1-yl) butanoate To a solution of 3- (3-chloro-4-isopropoxyphenyl) -5- (1 H -indol-4-yl) -1,2,4-oxadiazole (0.100 g, 0.283 mmol) in DM F (0.999 ml) NaH is added (0.01 2 g, 0.31 1 mmol). After about 15 minutes, tert-butyl 4-bromobutanoate (0.095 g, 0.424 mmol) is added and the reaction mixture is heated to about 50 ° C. After about 24 hours the reaction mixture is cooled to room temperature, concentrated in vacuo and purified by chromatography on silica gel (eluting with EtOAc / Hep) to provide 4- (4- (3- (3-chloro- 4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1 H-indol-1-yl) tert-butyl butanoate (0.1 35 g, 93%) as a colorless oil that solidifies on standing.
LC / M S (Table 1, Method c) Rt = 3.50 minutes, m / z 496 (M + H) +.
General procedure K: Deprotection of tert-butyl ester or ether To a solution of a tert-butyl ester (0.9-1.2 equivalents, preferably 1.0 equivalent) in a suitable solvent such as DCM is added trifluoroacetic acid (15-25 equivalents, preferably 20 equivalents. it is stirred at room temperature for about 1 -1 0 hours (preferably 8 hours) The solvent is removed under reduced pressure and the crude product is further purified by chromatography or recrystallization.
Exemplification of the general procedure K: Preparation of 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1 H -indole-1-yl) propanoic acid To a solution of 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -, 2,4-oxadiazol-5-yl) -1 H-indol-1 -i I) butyl-oxadiazole (5.25 g, 10.89 mmol) in DCM (136 mL) was added trifluoroacetic acid (16.78 mL, 218 mmol). The mixture is stirred at room temperature for about 8 hours. The solvent is removed under reduced pressure and the solid residue is triturated with ether to obtain 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1H acid. -indol-1-yl) propanoic (4.35 g, 93.0%).
LC / MS (Table 1, Method b) R, = 3.03 minutes, m / z 356.13 (M-H) -.
H NMR (400 MHz, DMSO) d 12.39 (s, 1H), 8.13 (m, 1H), 8.07 (m, 1H), 8.00 (d, 1H), 7.94 (d, 1H), 7.7 (d, 1H) , 7.41 (m, 2H), 7.18 (d, 1H), 4.84 (s, 1H), 4.53 (td, 2H), 2.82 (td, 2H), 1.36 (d, 6H).
General procedure L: Amino acid halide To a reaction vessel is added an aryl fluoride or bromide (preferably fluoride) (0.9-1.2 equivalents, preferably 1.0 equivalents), an amine (0.9-1.5 equivalents, preferably 1.1 equivalents) potassium carbonate (0.9-3.0) equivalents, preferably 2.0 equivalents) and an appropriate solvent such as DMF, DMA or DMSO (preferably DMF). The reaction vial is capped and heated either through microwaves with cooling or in an oil bath (preferably by microwave) at 110-200 ° C (preferably 160 ° C) for 15 minutes to 4 days (preferably 30 minutes). The crude product is optionally isolated from the reaction mixture by dilution with water followed by filtration or neutralization at pH = 3 and extraction with an appropriate organic solvent (ethyl acetate, dichloromethane, diethyl ether - preferably dichloromethane). The product can be further purified by chromatography or crystallization.
Eiemplification of the general procedure L: Preparation of (1 R, 3S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid 3- (3-Chloro-4-isopropoxyphenyl) -5- (4-fluorophenyl) -1,2,4-oxadiazole (360 mg, 1082 mmol), (1R, 3S) -3-aminocyclopentanecarboxylic acid (154 mg) are heated. , 1,190 mmole), potassium carbonate (329 mg, 2380 mmol) and DMF (2 ml) with cooling at approximately 160 ° C in the Biotage microwave during approximately 30 minutes. The mixture is diluted with DMSO (6 ml) and ACN (8 ml), filtered and divided into 8 aliquots for purification by LC / MS directed to molecular ion. The fractions are combined and evaporated to obtain a pale brown solid which is vacuum dried at about 60 ° C for about 3 hours. This produces (1 R, 3S) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid (212 mg, 0.480 mmol, 44.3% yield) as a pale brown solid.
LC / MS (Table 1, Method a) R, = 3.49 minutes, m / z 440.20 (M-H) -. 1 H NMR (400 MHz, DMSO) d ppm 4.81 (s, 1 H), 3.96-3.76 (m, 1 H), 2.78 (s, 1 H), 2.42-2.25 (m, 1 H), 2.12-1.95 (m, 1 H) , 1.89 (d, J = 7.72 Hz, 2H), 1.73-1.61 (m, 1H), 1.61-1.48 (m, 1H), 1.39-1.30 (m, 7H), 12.22-12.07 (m, 1H), 6.73 (d, J = 8.82 Hz, 2H), 6.87-6.79 (m, 1H), 7.36 (d, J = 8.63 Hz, 1H), 7.87 (d, J = 8.59 Hz, 2H), 7.98 (ddd, J = 9.78, 1.97, 1.06 Hz, 2H).
General procedure M: Alkylation of phenol with an alkyl halide A phenol such as benzyl 4-hydroxybenzoate (0.9-1.2 equivalents, preferably 1 equivalent) and an appropriate base (such as potassium carbonate (1-5 equivalents, preferably 5 equivalents)) are combined in an organic solvent (such as as acetone (approximately 100 ml)). An alkyl bromide (such as tert-butyl 2-bromoacetate (0.9-1.2 equivalents, preferably 1 equivalent)) is added dropwise. The solution is stirred at about 60-70 ° C, preferably about 65 ° C for 1-2-24 hours, preferably about 18 hours. The solution is cooled and the reaction mixture is filtered through a sintered glass funnel. The filtrate is concentrated in vacuo to obtain a crude product which can be further purified by chromatography or crystallization.
Exemplification of the general procedure M: Preparation of benzyl 4- (2-tert-butoxy-2-oxoethoxy) benzoate In a 1 00 ml round-bottom flask, benzyl 4-hydroxybenzoate (1.445 g, 6.33 mmol) and potassium carbonate (4.17 g, 30.1 mmol) in acetone (1000 ml) are combined. Tert-butyl 2-bromoacetate (0.908 mL, 6.03 mmol) is added dropwise. The solution is stirred at approximately 65 ° C overnight. The solution is cooled and the reaction mixture is filtered through a sintered glass funnel. The filtrate is concentrated to obtain pale yellow oil, which is purified by chromatography on silica gel (40 g, 30% EtOAc: heptane) to obtain 4- (2-tert-butoxy-2-oxoethoxy) benzoate. benzyl (2.06 g, 5.90 mmol, 98% yield) as a colorless oil.
LC / MS (Table 1, Method a) Rt = 4.31 minutes.
General procedure N: De-benzylation A high pressure flask is charged with 5-20% (preferably 10%) of palladium on carbon (0.9-1.2 equivalents, preferably 1.0 equivalent), an appropriate solvent such as MeOH (200 ml) is added. , then a benzoate ester (50-70 equivalents, preferably 60 equivalents). The resulting suspension is allowed to stir under a hydrogen atmosphere at about 0.703-4.921 kg / cm2 (preferably 3.304 kg / cm2) at room temperature for about 2 hours. The mixture is filtered through Celite® and the colorless filtrate is concentrated to obtain the product.
Exemplification of the general procedure N: Preparation of 4- (2-tert-butoxy-2-oxoethoxy) benzoic acid A 500 ml high pressure flask is charged with benzyl 4- (2-tert-butoxy-2-oxoethoxy) benzoate (2.06 g, 6.02 mmol) in methanol (100 ml). 10% Palladium on carbon (0.320 g, 0.301 mmol) is added, the resulting suspension is allowed to stir under a hydrogen atmosphere (about 3030 kg / cm2) at room temperature for about 6 hours. The mixture is filtered through Celite®, and the colorless filtrate is concentrated to obtain 4- (2-tert-butoxy-2-oxoethoxy) benzoic acid (1.5 g, 5.95 mmol, 99% yield) as a yellow solid. pale.
LC / MS (Table 1, Method a) Rt = 3.03 minutes; MS m / z: 251.30 (M-H) -. 1 H NMR (400 MHz, d-DMSO) ppm 7.88 (d, J = 8.99 Hz, 2H), 6.98 (d, J = 9.00 Hz, 2H), 4.75 (s, 2H), 1.43 (s, 9H).
General procedure O: Deprotection of a protected 1.2 diol To a solution of protected diol (0.9-1.2 equivalents, preferably 1.0 equivalents) in an appropriate solvent such as THF is added a solution of 1 M HCl (1.5-2.5 equivalents, preferably 2.0 equivalents). The mixture is heated to approximately 70 ° C for about 2 hours. After cooling to room temperature, a solution of an aqueous base such as 1 M NaOH is added and the reaction mixture is concentrated in vacuo. The resulting solid is washed with water and dried under vacuum to obtain the product.
Eiemplification of the general procedure O: Preparation of 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenoxy) propane-1,2-diol 3- (3-Chloro-4-isopropoxyphenyl) -5- (4 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) phenyl) -1,2,4-oxadiazole ( 0.1 g, 0.225 mmol) and p-toluenesulfonic acid monohydrate (8.55 mg, 0.045 mmol) in methanol (2.4 ml). The reaction mixture is heated to about 70 ° C for about 16 hours. The solution is cooled, methanol (1.5 ml) is added to the mixture and recrystallized, the resulting suspension is filtered, the solid is washed with water to obtain 3- (4- (3- (3-chloro-4-isopropoxyphenyl) ) -1, 2,4-oxadiazol-5-yl) phenoxy) propane-1,2-diol (0.08 g, 0.198 mmol, 88% yield) as a white solid.
LC / MS (Table 1, method g) Rt = 2.97 minutes; MS m / z: 405.18 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 8.16-8.09 (m, 2H), 8.05 (d, J = 2.13 Hz, 1H), 7.99 (dd, J = 8.64, 2.15 Hz, 1H), 7.38 (d , J = 9.05 Hz, 1H), 7.25-7.16 (m, 2H), 5.03 (d, J = 5.19 Hz, 1H), 4.87-4.78 (m, 1H), 4.72 (t, J = 5.68 Hz, 1H) , 4.15 (dd, J = 3.97, 10.01 Hz, 1H), 4.01 (dd, J = 6.20, 10.03 Hz, 1H), 3.84 (dt, J = 4.04, 5.69, 5.91 Hz, 1H), 3.47 (t, J = 5.84 Hz, 2H), 1.35 (d, J = 6.03 Hz, 6H).
General procedure P: Nucleophilic displacement of an aryl fluoride A solution of an aryl fluoride in a dry aprotic solvent such as DM F, TH F, toluene or 1,4-dioxane (preferably TH F) is treated with a base such as sodium hydride (1.0 to 3.0 equivalents) , preferably about 1.1 equivalents) at 0-50 ° C (preferably room temperature). The mixture is treated by dropping with a solution of an alcohol (1-150 equivalents, preferably 1.1-10.1 equivalents) and then the reaction is stirred at 20-150 ° C (preferably about 40 ° C). ) until the aryl fluoride is consumed. The reaction is then cooled and concentrated then purified by extractive work-up, crystallization or chromatography. Optionally, when a component of the coupling is protected, the crude material can be deprotected by hydrolysis during the extractive treatment.
Eiemplification of the general procedure P: Preparation of (R) -3-. { 3-Chloro-4- [3- (3-chloro-4-isopropoxy-phenyl) - [1, 2,4] oxadiazol-5-yl] -phenoxy} -propane-1, 2-diol A solution of 5- (2-chloro-4-fluorophenyl) -3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazole (6.25 g, 17.02 mmol) in dry THF (75.00 ml) is treated. with NaH (1225 g, 20.42 mmol) at room temperature. Add (undiluted (2,2-dimethyl-1,3-dioxolan-4-yl) methanol (2,330 ml, 18.72 mmoles) by dropping at room temperature and the reaction is heated to about 40 ° C for about 4 hours. The reaction is cooled to room temperature and treated with 2N HCl (75 ml) and allowed to stir 3 days at room temperature. The mixture is diluted with ethyl acetate (200 ml) and washed with saturated NaCl solution (3 x 100 ml), dried over sodium sulfate, filtered and concentrated. Further purification by crystallization with ethyl acetate and heptane produces (R) -3-. { 3-Chloro-4- [3- (3-chloro-4-isopropoxy-phenyl) - [1, 2,4] oxadiazol-5-yl] -phenoxy} -propane-1,2-diol (5.94 g, 79%) as a white solid.
LC / MS (Table 1, Method A) Rt = 2.60 minutes; MS m / z: 498 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d 8.15 (d, J = 8.8, 1H), 8.05 (d, J = 1.3, 1H), 8.08-7.95 (m, 1H), 7.39 (d, J = 8.7, 1H), 7.33 (d, J = 2.2, 1H), 7.19 (dd, J = 8.9, 2.4, 1H), 5.05 (d, J = 5.2, 1H), 4.87 -4.78 (m, 1H), 4.72 (t , J = 5.7, 1H), 4.20-4.02 (m, 2H), 3.83 (m, 1H), 3.46 (m, 2H), 1.35 (d, J = 6.0, 6H).
General Procedure Q: Hydrolysis of an ester A solution of an ester in an organic solvent such as THF, MeOH, 1,4-dioxane, methanol, ethanol, DMF or DMSO (from preferably THF, MeOH or 1,4-dioxane) is treated with an aqueous base (1-10 equivalents, preferably about 1 equivalent) such as NaOH, LiOH or KOH and the mixture is stirred at 20-100 ° C (preferably room temperature) until the reaction is complete. The reaction is neutralized with an acid such as HCl, H2SO4, or acetic acid (preferably HCl), cooled, concentrated and purified by extractive workup, crystallization or chromatography.
Eiemplification of the general procedure Q: Preparation of acid 3-. { 3-Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1,4] oxadiazol-3-yl] -phenoxy} -cyclobutanecarboxylic To a solution of (1 r, 3 r) -ethyl-3- (3-chloro-4- (5- (5-chloro-6-isopropoxypyridin-3-yl) -1, 2,4-oxadiazol-3-yl ) phenoxy) cyclobutanecarboxylate (118 mg, 0.240 mmol) in 1,4-dioxane (2.00 ml) is added 2N NaOH (0.359 ml, 0.719 mmol) and the mixture is stirred at room temperature for about 3 hours. The reaction is neutralized by addition of 2N HCl (360 μ) and the mixture is concentrated. Re-crystallization with ACN and water produces 3- acid. { 3- Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1,4] oxadiazol-3-yl] -phenoxy-cyclobutanecarboxylic acid (72 mg, 65%) as a solid White color.
LC / MS (Table 1, Method a) Rt = 3.13 minutes; MS m / z: 465/467/469 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d 12.38 (bs, 1H), 8.91 (d, J = 2.2, 1H), 8.53 (d, J = 2.2, 1H), 7.99-7.92 (m, 1H), 7.15 - 7.10 (m, 1H), 7.08 - 7.01 (m, 1H), 5.48-5.42 (m, 2H), 5.01-4.94 (m, 2H), 3.17 -3.05 (m, 1H), 2.74 - 2.66 (m, 3H), 2.46-2.28 (m, 2H), 1.42-1.32 (d, 6H).
Exemplification of the general procedure Q: Preparation of deuterated methyl 5-chloro-6-isopropoxynicotinate Dissolve methyl 5-chloro-6-hydroxynicotinate (3.86 g) in approximately 21 ml of methanol and add approximately 2.1 ml of water. 1.74 g of sodium hydroxide are added to the solution. The mixture is heated to about 50 ° C and mixed well to dissolve all the NaOH and the solution is stirred for about 1 hour at the same temperature. The aqueous methanol solution is extracted with hexane (2 x 10 mL) and the aqueous layer is adjusted to pH 4 using 6N HCl. The methanol is then removed by concentration and the aqueous suspension is adjusted to pH ~ 1 using HCl in an ice bath. The resulting suspension is stirred for about 30 minutes then filtered and washed with water. The product is further purified by vacuum drying. Performance 3.64 g. Purity H PLC 98%, 9,404 min. HPLC (Table 1, Method q) General procedure R: Mitsu nobu coupling to a phenol A solution of a phenol and alcohol (1-3 equivalents, preferably about 1.1 equivalents) in a solvent such as THF or 1,4-dioxane (preferably THF) is treated with a phosphine (1-5 equivalents) ) such as triphenylphosphine or triphenylphosphine bound to resin (preferably triphenylphosphine bound to resin) and optionally with 4 A molecular sieves and the mixture is cooled to approximately 0 ° C. A solution of an alkyl azodicarboxylate (1-2 equivalents, preferably about 1.1 equivalents) such as diethylazodicarboxylate, di-isopropylazodicarboxylate, or di-tert-butylazodicarboxylate (preferably di-tert-butylazodicarboxylate) in a solvent such as TH F or 1,4-dioxane (preferably TH F) and then the reaction is heated to 20-70 ° C (preferably room temperature) with stirring for 1-24 hours (preferably about 18 hours). The reaction is filtered, concentrated and purified by chromatography on silica gel or crystallization.
Preparation of 3- (3-chloro-4-cia non-p-n-oxy) -cyclobucarboxylic acid tert-butyl ester A solution of 2-chloro-4-hydroxybenzonitrile (5.00 g, 32.6 mmol) and (1 s, 3 s) -tert-butyl-3-hydroxycyclobutanecarboxylate (6.1 7 g, 35.8 mmol) in TH F (220 ml) is treated with molecular sieves of 4 A (10 g) and Ph3P bound to resin (32.6 ml, 98 mmoles) for about 20 minutes at room temperature, then cooled to about 0 ° C. A solution of di-tert-butyl azodicarboxylate (8.25 g, 35.8 mmol) in THF (30 ml) is added dropwise while maintaining the reaction temperature below about 4 ° C. The reaction is stirred about 15 minutes at about 0 ° C and then allowed to warm to room temperature for about 18 hours. The reaction is filtered and the solids are rinsed with methanol (3 x 50 mL) and the combined organic solutions are concentrated. The residue is purified on a column of silica gel using a gradient of 1 0-30% ethyl acetate in heptane. The product fractions are combined and concentrated to a clear, colorless oil which solidifies on standing to obtain the 3- (3-chloro-4-cyano-phenoxy) -cyclobutanecarboxylic acid tert-butyl ester.
LC / MS (Method a) Rt = 2.75 minutes; 1 H NMR (400 MHz, DMSO-d 6) d 7.87 (d, J = 8.7, 1 H), 7.19 (d, J = 2.4, 1H), 6.99 (dd, J = 8.7, 2.4, 1H), 4.99-4.92 (m, 1H), 3.11-3.04 (m, 1H), 2.69-2.63 (m, 2H), 2.40 - 2.28 (m, 2H), 1.44 (s, 9H).
General procedure S: Deprotection of phosphonate ester with or without bromination To a solution of phosphonate ester (0.9-1.2 equivalents, preferably 1.0 equivalents) in an anhydrous organic solvent such as DCM, or THF (preferably DCM) is added bromotrimethylsilane (1-20 equivalents, preferably 10 equivalents). The reaction mixture is stirred for about 2-72 hours (preferably 2-16 hours). The reaction mixture is concentrated under reduced pressure. The intermediates and final compounds prepared by this general procedure can optionally be purified using one or more of the Purification Methods described above.
Eiemplification of the general procedure S Example S.1 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) propylphosphonic acid To a solution of diethyl 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) propylphosphonate (Table D, # 50, 0.060 g, 0.12 mmoles) in DCM (1.2 mL) is added bromotrimethylsilane (0.15 mL, 1.18 mmol). The reaction mixture is stirred at room temperature for about 16 hours. The reaction mixture is concentrated under reduced pressure. The material is purified by RP-HPLC (A = 50 mM ammonium acetate, B = ACN, 5-100% B over the course of approximately 30.0 minutes (flow rate 21.0 ml / minute), Thermo Hyperprep C18 column 21.2 ? 250 mm, particles of 8 μ? T?) To obtain 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenamino) propylphosphon acid ico (0.035 g, 65%).
LC / MS (Table 1, Method b) Rt = 1.83 minutes; MS m / z 452 (M + H) +.
General procedure T: Preparation of benzylic olefin from ketone A suspension of 1-3 equivalents of sodium hydride (60% in mineral oil, preferably 1.6 equivalents) in approximately 5 ml of DMSO is heated to approximately 80- 100 ° C (preferably about 80 ° C) for about 1 5-30 minutes (preferably 1 5 minutes). The mixture is cooled to about 0-5 ° C in an ice bath, (4- (3- (3-chloro-4-isopropoxyphen-yl) -1,2,4-oxadiazol-5-yl chloride is added) benzyl) triphenylphosphonium (preferably 1 eq uivalent) in one portion, the reaction mixture is stirred at room temperature for 30 minutes. A ketone solution (preferably 1.2 equivalents) in DMSO is added dropwise. The reaction mixture is heated to about 80 ° C for about 1 2-1 20 hours (preferably 64 hours). After cooling, the mixture is poured into ice water, acidified with HCl (6N), extracted with DCM or ethyl acetate, the organic layer is washed with HCl (1 N) and brine, dried with sulfate of magnesium, filtration and concentration allows to obtain a crude product, which is further purified by chromatography.
Eiemplification of the general procedure T: Preparation of ethyl 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,2-oxadiazol-5-yl) benzylidene) cyclobutanecarboxylate Sodium hydride (0.036 g, 0.900 mmol) in DMSO (5.6 ml) is added under nitrogen to obtain a color suspension.
White. The mixture is heated to approximately 80 ° C for approximately 18 minutes. This is cooled to room temperature, then the reaction mixture is cooled to about 0-5 ° C by an ice bath. (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) triphenylphosphonium chloride (0.422 g, 0.675 mmol) is added in one portion, the bath is removed of ice and DMSO (2 ml) is added. This is stirred at room temperature for about 30 minutes, a solution of ethyl 3-oxocyclobutanecarboxylate (0.08 g, 0.563 mmol) in DMSO (1.0 ml) is added by dripping over the course of about 5 minutes. The reaction mixture is heated to about 80 ° C for about 64 hours. The mixture is cooled, poured into ice water with stirring (60 ml), HCl (6N, 20 ml) is added, the mixture is extracted with DCM (2 x 75 ml), the combined layer of DCM is washed with HCl ( 1N, 40 mL), water (50 mL), brine (30 mL), dried over magnesium sulfate, filtered and concentrated to obtain 505 mg of orange oil, which was purified by Analogix ™ FCC (0%). % 5 minutes, 0-10% over the course of 10 minutes, 10-15% over the course of 15 minutes, 15% over the course of 5 minutes, EtOAc / Heptane, Redi-Sep® silica gel column 80 g) to obtain ethyl 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzylidene) cyclobutanecarboxylate (0.106 g, 0.234 mmol, 41.6% yield) ) as white solid.
LC / MS (Table 1, Method g) R, = 2.07 minutes, m / z 453.12 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 8.10 (d, J = 8.41 Hz, 2H), 8.04 (d, J = 2.10 Hz, 1H), 7.98 (dd, J = 8.63, 2.12 Hz, 1H), 7.46 (d, J = 8.46 Hz, 2H), 7.37 (s, 1H), 6.31 (d, J = 2.27 Hz, 1H), 4.81 (dt, J = 6.0, 12.0 Hz, 1H), 4.11 (q, J = 7.10 Hz, 2H), 3.41-3.22 (m, 3H), 3.17-3.03 (m, 2H), 1.34 (d, J = 6.02 Hz, 6H), 1.20 (t, J = 7.10 Hz, 3H).
General Procedure U: Benzyl Olefin Reduction A high pressure flask is charged with a benzylic olefin (1 equivalent) and palladium on carbon (preferably 0.25 equivalents in ethyl acetate). The resulting suspension is stirred under a hydrogen atmosphere (0.984 kg / cm2) at room temperature for about 30-90 minutes (preferably 60 minutes). The mixture is filtered through Celite® and the colorless filtrate is concentrated to obtain the product.
Eiemplification of the general procedure U: Preparation of ethyl 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) cyclobutanecarboxylate Ethyl 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzylidene) cichlobutanecarboxylate (0.08 g, 0.177 mmol) and 10% palladium are added. % on charcoal (0.047 g, 0.044 mmol) in EtOAc (8.83 ml) to obtain a black suspension. The reaction mixture is allowed to stir under a balloon atmosphere of hydrogen at room temperature for about 1 hour. The reaction mixture is diluted with ethyl acetate and filtered, the filtrate is concentrated and the residue is used as such in the next step.
LC / MS (Table 1, Method i) R, = 2.08 minutes, m / z 455.14 (M + H) +.
General procedure V: Ester hydrolysis A solution of the ester (1 equivalent) in ethyl alcohol / 1,4-dioxane is combined with a solution of potassium hydroxide / sodium (1-10 equivalents, preferably 10 equivalents) in water, the mixture is heated to approximately 100 °. C for approximately 16 hours. The reaction mixture is cooled, partitioned between aqueous ammonium chloride (1.0 M) and ethyl acetate, the organic layers are washed with water and concentrated in vacuo, which results in the crude product which is further purified by chromatography Exemplification of the general procedure V: Preparation of 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) cyclobutanecarboxylic acid Ethyl 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) cyclobutanecarboxylate (0.08 g, 0.176 mmol) in EtOH (5 mL) is added. to obtain a colorless solution. A solution of potassium hydroxide (0.099 g, 1758 mmol) in water (2.5 ml) is added while stirring. The reaction mixture is heated to approximately 100 ° C for about 16 hours. The reaction mixture is cooled, partitioned between aqueous ammonium chloride (1M, 40 mL) and EtOAc (2 x 35 mL), the combined organic layers are washed with water (2 x 30 mL), concentrated to obtain 80 mg. of oil of gray color, which is purified by RP-HPLC (A = 50 mM ammonium acetate, B = ACN, 30-100% B in the course of 30.0 minutes (flow rate 21.0 ml / minute); Hyperprep C18 of 21.2 x 250 mm, particles of 8 μ ??) to obtain acid 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) benzyl) Cyclobutanecarboxylic (0.049 g, 0.112 mmol, 64% yield) as a white solid.
LC / MS (Table 1, Method g) Rt = 3.13 minutes, m / z 427.24 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 8.12-8.03 (m, 2H), 8.00 (dd, J = 8.6, 2.1, 1H), 7.46 (t, J = 8.4, 1H), 7.39 (d, J = 8.9, 1H), 4.88 - 4.77 (m, 1H), 3.13 - 3.02 (m, 1H), 2.97 - 2.82 (m, 1H), 2.77 (d, J = 7.5, 1H), 2.70 - 2.55 (m, 0H), 2.27-2.14 (m, 1H), 2.00-1.83 (m, 1H), 1.35 (d, J = 6.0, 6H).
General procedure W: Alchelation of a phenol A solution of the ester (1 equivalent) in ethyl alcohol / 1,4-dioxane or toluene is combined with a solution of potassium hydroxide / sodium or Ag2C03 (1-10 equivalents, preferably 10 equivalents) in water, the mixture is heated approximately at 60-100 ° C for approximately 16-20 hours. The reaction mixture is cooled, and the resulting crude product mixture can be further purified by extractive treatment and / or chromatography.
Eiemplification of the general procedure W: Preparation of methyl 5-chloro-6-isopropoxynicotinate Combine methyl 5-chloro-6-hydroxynicotinate (8.91 g, 47.5 mmol) and 2-iodo-propane (7.12 mL, 71.2 mmol) in toluene (202 ml) under nitrogen to obtain a colorless solution. Silver carbonate (19.65 g, 71.2 mmol) is added and the reaction is heated to approximately 60 ° C for about 4 hours. TLC in EtOAc / heptane 1: 1 shows that (visualization with UV light) the reaction is not over yet. The temperature is reduced to about 50 ° C and the reaction is stirred for an additional 16 hours. The reaction is allowed to cool to room temperature. The mixture is filtered through a buchner funnel and washed thoroughly with ethyl acetate. The solvents are removed under reduced pressure. The residue is purified by flash column chromatography (120 g Redi-Sep column) eluting with 5% ethyl acetate / heptane and the product fractions are combined. Solvents are removed under reduced pressure to provide methyl 5-chloro-6-isopropoxynicotinate (10.539 g, 45.9 mmol, 97% yield) as a colorless oil which solidifies in vacuo to a white solid: LC / MS (Method g) R, = 2.84 minutes; MS m / z: 230.05 (M + H) +. 1 H NMR (400 MHz, CDCl 3) d ppm 8.71 (d, J = 2.02 Hz, 1H), 8.22 (d, J = 1.93 Hz, 1H), 5.53-5.42 (m, 1H), 3.94 (s, 3H), 1.44 (d, J = 6.20 Hz, 6H).
Exemplification of the general procedure W Preparation of methyl 5-chloro-6-deutero-isopropoxynicotinate Methyl-5-chloro-6-hydroxynicotinate (3.15 g), toluene (70 ml) and deuterated isopropyl iodide (4445 g) are added together at room temperature. Then Ag2CO3 (6.95 g) is added and the reaction mixture is heated to approximately 60 ° C for about 20 hours. The solids are removed by filtration and washed with toluene (2 x 20 ml). The filtrate is concentrated to dryness and redissolved in methanol followed by concentration each time (3 x 2.0 ml). Purity HPLC 98%, 14,031 minutes. HPLC (Table 1, Method q) Tables that use the General Procedures TABLE A Examples that are developed using the Procedures General C, D, E (Reaction scheme 2) The letter in parentheses below the nitrite precursors indicates the General Procedure by which the nitrile precursor is prepared.
Acid or chloride NH2OH ^ RIL "acid Procedure General General Procedure C D or E TABLE B Examples that are prepared using the Procedures General C. Do E. G and H C DoE TABLE B fcont.) TABLE B (cont.) TABLE B (cont.) TABLE B (cont.) TABLE C Examples that are elaborated using the Procedures General C. Do E. I or J and K Acid? TABLE C (cont.) TABLE D Examples that are developed using the Procedures General C. Do E, and L Acid or C DoE TABLE D ícont.) TABLE D (cont.
TABLE D ícont.) TABLE D (cont.) TABLE D (cont'i) TABLE D (cont.) TABLE D (cont.) TABLE D (cont.) TABLE D (cont.l) TABLE D (cont.
TABLE D (cont.) TABLE D fcont.) TABLE E Examples that are developed using the Procedures General R. K. D? V TABLE F Examples that are developed using the Procedures General R, C, D v K TABLE F (cont.) TABLE G Examples that are developed using the Procedures General C, D or E, L v K Acid or NH2OH chloride N N-OH acid Procedure Procedure General General C DoE enera L Process general K TABLE H Examples that are prepared using the Procedures Generals P. C. D v K or Q TABLE H (cont.) Note H See the section Preparation of Examples Adiciona is for modification of the benzonitrile intermediate TABLE I Examples that are developed using the Procedures General C. D or E. P, K, R and K or Q Acid or C DoE enera P K TABLE I (cont.l) TABLE I (cont.) Note F: Mix of isomers Note G: The crude mixture of 4 isomers is separated using two orthogonal preparative chromatographic methods. Method A: Socratic elution using 0.1 2% trifluoroacetic acid in heptane (solvent B) and isopropanol (solvent A) in a ratio of 20% solvent A: 80% solvent B in a Daicel ADH column (20 x 250 mm) in the course of 16.5 minutes, monitoring with UV (280 nm). Method B: Elution with gradient using 0.12 of trifluoroacetic acid in heptane (solvent B) and ethanol: methanol 1: 1 (solvent A), 20-60% of solvent A on a Daicel ADH column (20 x 250 mm) in the course of 19.5 minutes, monitoring with UV (280 nm).
TABLE J Examples that are developed using the Procedures General C, D or E, l or J and Q C DoE TABLE J (cont.) TABLE K Examples that are prepared using Preparations # 61.62 and 63 The letter in parentheses below the phenol precursors indicates the General Procedure by which the phenol precursor is made TABLE K (cont.) TABLE L Examples that are developed using the Procedures General C v D or E ^ TABLE M Examples that are prepared using General Procedure S TABLE M (cont.
TABLE N Examples that are prepared using the Procedures General T, U and V TABLE P The following deuterated compounds can be prepared by those skilled in the art: Preparation of Additional Examples Preparation # 1: Preparation of 3-chloro-4-isopropoxy-benzoic acid In a round-bottomed flask is added triphenylphosphine (62 g, 0.263 mol), 3-chloro-4-hydroxy-benzoic acid methyl ester (10 g), 0.0535 moles) and anhydrous THF (500 ml). The mixture is briefly stirred under nitrogen, then DBAD (19.75 g, 0.0858 moles) is added. The mixture is stirred for a few minutes before adding anhydrous isopropanol (5.125 ml, 0.067 moles). After the reaction mixture is stirred at room temperature under a nitrogen atmosphere for about 3 hours, DBAD (19.75 g, 0.0858 moles) and anhydrous isopropanol (5.125 ml, 0.067 moles) are added and the mixture is allowed to stir at room temperature during the night. The solvent is removed under reduced pressure. The residue is dissolved in a minimum amount of ethyl acetate. Heptane is added and the precipitate is removed by filtration. The filtrate is dissolved in methanol. Water is added until the solution becomes cloudy. The precipitate is removed by filtration. The methanol / water precipitation procedure is repeated twice more. The filtrate is dissolved in THF (200 mL) and 5M NaOH (200 mL). The mixture is stirred at room temperature overnight. The organic solvent is removed under reduced pressure. The aqueous layer is extracted three times with ethyl acetate. The aqueous layer is further acidified to pH 1-2 with 2M HCl. The cloudy suspension is then extracted with ethyl acetate three times. The organic layers are combined, dried with magnesium sulfate, and concentrated to dryness to obtain 3-chloro-4-isopropoxy-benzoic acid (8.4 g, 71.4%) as a white solid.
LC / MS (Table 1, Method b) Rt = 2.42 minutes, m / z (M-H) " 213. 1 H NMR (400 MHz, DMSO-d 6) d 12.95 (s, 1 H), 7.87 (m, 2H), 7.25 (d, 1H), 4.79 (m, 1H), 1.32 (d, 6H).
Preparation # 2: 4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-iPbenzonitrile 3-Chloro-N-hydroxy-4-isopropoxybenzimidamide (10 g, 43.7 mmol) is dissolved in DMF (219 mL) under nitrogen. The mixture is heated to approximately 110 ° C for about 10 minutes. A solution of 4-cyanobenzoyl chloride (7.24 g, 43.7 mmol) dissolved in DMF (30 mL) is added dropwise over the course of about 20 minutes and the reaction heated to approximately 110 ° C for about 4 hours until LC / MS shows that the reaction was completed. The reaction is cooled in an ice bath and poured into rapidly stirred water (1000 ml). The resulting white precipitate is collected by vacuum filtration and washed with water. The precipitate is dissolved in methylene chloride and washed with 1 N HCl and then brine. The methylene chloride is dried with sodium sulfate, filtered, and evaporated. Heptane and DCM are added to the residue and the mixture is heated until the DCM boils after which the mixture is allowed to cool. The solids do not dissolve in hot heptane. The resulting solid is collected by vacuum filtration and washed with heptane to provide 4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzonitrile (12.568 g, 37.0 mmol , 85% yield) as a tan solid.
LC / M S (Table 1, Method a) Rt = 4.58 minutes; MS m / z: 340.20 (M + H) +.
Preparation # 3: 4- (3- (3-chloro-4-isopropoxyphenyl) -1 .2,4-oxadiazol-5-yl) benzaldehyde 4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,2-oxadiazol-5-yl) benzonitrile (1.0 g, 29.4 mmol) is dissolved in dichloromethane (535 ml) under nitrogen. The reaction is cooled to approximately -40 ° C in a dry ice bath / AC N measuring the temperature internally. A solution of Dibal-H (58.9 ml, 58.9 mmol) is added dropwise and the reaction is stirred for approximately 30 minutes, and then quenched with methanol. The mixture is stirred until the bubbles cease. The mixture is then heated to room temperature and stirred rapidly with a 1 0% solution of Rochelle's salt. The separated layers are extracted with DC M (3 x 1 00 ml). The combined extracts are stirred rapidly with approximately 1 00 ml of 1 N HCl and the solution changes from orange to colorless. CCF indicates that the mixture has been cleaned to only one spot with some baseline material. The layers are separated and the aqueous layer is extracted with DCM (2 x 1000 mL). The combined organic extracts are washed with brine, dried with sodium sulfate, filtered, and evaporated to dryness to obtain an off-white solid. The solid is stirred with heptane and the solvent carefully removed by pipette. The solid is dried in vacuo to obtain 4- (3- (3-chloro-4-isopropoxyphen-yl) -1,2,4-oxadiazol-5-yl) benzaldehyde (9.1 5 g, 26.7 mmol, 91% yield ) as white solid.
LC / MS (Table 1, Method a) Rt = 4.59 minutes; MS m / z: 343. 26, 345.1 8 (M + H) +.
EXAMPLE 1 Acid 1 - (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazole-5 il) benz l) azetidine-3-carboxylic acid Azetidine-3-carboxylic acid (3.72 g, 36.8 mmol) (Synchem) is dissolved in acetic acid (16.03 ml, 280 mmol) and methanol (2 ml). This is added to a stirred suspension of 4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzaldehyde (12 g, 35.0 mmol) in MeOH (600 mL). The reaction is stirred for about 18 hours. Sodium cyanoborohydride (5.50 g, 88 mmol) is added and the reaction is stirred for about 4 hours. The reaction is cooled with an ice bath and the precipitate is collected by vacuum filtration and washed with ice-cold methanol and then ether. CCF shows that impurities are still present. The crude solid is dissolved in EtOAc / (CHCl3 / MeOH / NH4OH 6: 3: 1) 1: 1 with a little additional NH4OH added. Chromatography with silica gel in a mixture of EtOAc / (CHCl3 / MeOH / NH4OH 6: 3: 1) 1: 1 increasing to CHCl3 / MeOH / NH4OH 6: 3: 1 elutes the product. The fractions are evaporated to dryness to obtain a colorless film / oil. The mixture is dissolved in methanol and evaporated to dryness. The residue is resuspended in the minimum amount of methanol, water is added and the mixture is filtered, washed with water and then ether. The residue is dried under vacuum at room temperature and then under vacuum at approximately 60 ° C to remove traces of methanol to obtain 1- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4 acid. -oxadiazol-5-yl) benzyl) azetidine-3-carboxylic acid (8.3 g, 19.40 mmol, 55.4% yield) as a white solid.
LC / MS (Table 1, Method a) Rt = 2.94 minutes; MS m / z: 428.31, 430.27 (M + H) +. p.f. 194.8-195.9 ° C.
H NMR (400 MHz, DMSO-d) d ppm 8.12 (d, J = 8.34 Hz, 2H), 8.06 (d, J = 2.13 Hz, 1H), 8.00 (dd, J = 8.67, 2.15 Hz, 1H), 7.54 (d, J = 8.36 Hz, 2H), 7.39 (d, J = 9.06 Hz, 1H), 4.88-4.77 (m, 1H), 3.67 (s, 2H), 3.48-3.38 (m, 2H), 3.29 -3.19 (m, 3H), 1.35 (d, J = 6.02 Hz, 6H).
Preparation # 4: Preparation of 3- (3-chloro-4-isopropoxyphenyl) -5- (4-fluorophenyl) -1,2,4-oxadiazole Charge (Z) -3-chloro-N'-hydroxy-4-isopropoxybenzimidamide (2.0 g, 8.75 mmol), 4-fluorobenzoyl chloride (2.1 g, 13.12 mmol) and pyridine (12 ml) in a microwave vial. of 20 mi equipped with a stir bar. The vessel is sealed and the reaction is heated to about 200 ° C with cooling for about 25 minutes. The mixture is purified using normal phase chromatography to obtain a pale brown solid. Analysis by LC / MS shows that this is a 35:30:21 mixture of 3- (3-chloro-4-) Sopropoxyphenyl) -5- (4-fluorophenyl) -1,2,4-oxadiazole, 2-chloro-4- (5- (4-fluorophenyl) -1,2,4-oxadiazol-3-yl) phenol and 4-fluorobenzoic acid. The mixture is purified a second time using normal phase chromatography to obtain 5 fractions. Fractions 1, 2 and 3 are combined and evaporated to dryness to obtain 3- (3-chloro-4-isopropoxyphenyl) -5- (4-fluorophenyl) -1,2,4-oxadiazole (420 mmol, 14%) as a white solid.
LC / MS (Table 1, Method a) Rt = 2.85 minutes, m / z 333.1 0 (M-H) +.
Preparation # 5: Preparation of 3-chloro-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzonitrile To a 250 ml round bottom flask equipped with a stir bar and charged with 2-chloro-4-cyanobenzoic acid (3.0 g, 16.52 mmol), DC M anhydrous (80 ml) was added, and DM F (0.064 ml, 0.826 mmol). Oxalyl chloride (8.26 ml, 1.65 mmoles) (2M solution in DCM) is then added slowly and the mixture is stirred under nitrogen at room temperature. After adding the oxalyl chloride, the gas evolution begins and the suspended solid begins to dissolve. After about 2-3 hours, the reaction becomes translucent. The mixture is concentrated in vacuo. The resulting crude material is dissolved in pyridine (50 ml). To this is added (Z) -3-chloro-N'-hydroxy-4-isopropoxybenzamidedam (1258 g, 5.50 mmol). The mixture is heated to about 100 ° C under a nitrogen atmosphere for about 16 hours. The resulting mixture is cooled to room temperature. The pyridine is removed under reduced pressure and the resulting material is triturated as a mixture of DCM and MeOH (approximately 1: 1). The resulting precipitate is allowed to stand for a few minutes at room temperature then is collected by filtration, washed with a DCM / MeOH 1: 1 mixture, and then with direct MeOH and dried in a vacuum oven for about 48 hours to obtain 3-chloro-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzonitrile (1529 g, 4.09 mmol, 25%) as a beige solid. 1 H NMR (400 MHz, DMSO) d ppm 8.39 (d, J = 1.53 Hz, 1H), 8.35 (d, J = 8.15 Hz, 1H), 8.09 (dd, J = 8.14, 1.53 Hz, 1H), 8.05 ( d, J = 2.11 Hz, 1H), 8.00 (dd, J = 8.63, 2.12 Hz, 1H), 7.39 (d, J = 8.82 Hz, 1H), 4.82 (septet, J = 6.04 Hz, 1H), 1.35 ( d, J = 6.01 Hz, 6H).
EXAMPLE # 2 Preparation of 2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) propan-2-amine Cerium chloride (I I I) is added to nhydro (5.57 g, 22.60 mmol) and tetrahydrofuran anhydride (20 ml) to a dry 2-neck round bottom flask under nitrogen. The resulting suspension is subjected to sonic energy for a few minutes and then stirred at room temperature for about 90 minutes. The mixture is then cooled to about -50 ° C, and methyllithium (14.13 mL, 22.60 mmol) is slowly added. After approximately 60 minutes, and to warm to about 0 ° C, the reaction is cooled to about -50 ° C and 4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazole-5- is added dropwise. il) benzonitrile (2.4g, 7.06 mmol) in 8 ml of THF anhydrous, to maintain the reaction temperature at about -50 ° C. The reaction is maintained at about -50 ° C for about 1 hour, then allowed to warm to room temperature overnight. The next day the reaction is cooled to about -50 ° C, and quenched by the addition of 21 ml of 35% N H4OH. The quenched reaction is allowed to warm to room temperature in the past approximately two hours. The mixture is filtered through Celite® and washed with DC M (4 x 60 mL). The filtrate is collected and then washed with water and dried with gS04. He solvent is removed under reduced pressure and the crude material is purified by RP-HPLC (A = 50 mM ammonium acetate, B = ACN, 30-70% B over the course of 30.0 minutes (flow rate 21.0 ml / minute) Thermo Hyperprep C18 column 21.2 x 250 mm, particles of 8 μ ??) to obtain 2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) phenyl) propan-2-amine as the acetic acid salt (309 mg, 10.1%).
LC / MS (Table 1, Method a) Rt = 2.61 minutes. 1 H NMR (400 MHz, DMSO-d 6) d ppm 8.14-7.94 (m, 4H), 7.80 (d, J = 8.43 Hz, 2H), 7.37 (d, J = 8.81 Hz, 1H), 4.80 (septet, J = 6.04 Hz, 1H), 1.85 (s, 3H), 1.39 (s, 6H), 1.36-1.31 (d, J = 6.04 Hz, 6H).
EXAMPLE # 3 Preparation of methyl 3- (2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -phenpropan-2-ylamino) propanoate 2- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) phenyl) propan-2-amine and acetic acid (132 mg, 0.306 mmol) are added to a 5 ml microwave vial equipped with a stir bar. Methyl acrylate (52.6 mg, 0.611 mmol), and MeOH (3.0 ml) are added, the vial is capped, and the reaction is heated to about 120 ° C for about 90 minutes under microwave irradiation (Biotage Optimizer ™, 300 W). After approximately 90 minutes another aliquot of methyl acrylate (52.6 mg, 0.611 mmol) is added and the reaction heated for approximately another 60 minutes at approximately 120 ° C. The reaction is cooled and the solvent is removed under reduced pressure. The raw material is purified by RP-HPLC (A = 50 mM ammonium acetate, B = ACN, 30-70% B over the course of 30.0 minutes (flow rate 21.0 ml / minute), Thermo Hyperprep C18 column 21.2 x 250 mm, particles of 8 μ? t?) to obtain 3- (2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) phenyl) propan -2-ylamino) methyl propanoate (83.5 mg, 59.7%).
LC / MS (Table 1, Method a) R, = 2.78 minutes, m / z = 458.29 (M = H) +.
EXAMPLE # 4: Preparation of 3- (2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) ropan-2-ylamino) propane acid Dissolve methyl 3- (2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) propane-2-ylamino) propanoate (83 mg, 0.181 mmol) in ethanol (4 ml) and NaOH (4 ml, 8.00 g. mmoles). The mixture is stirred at room temperature under nitrogen. After approximately 20 minutes the reaction is neutralized by dropwise addition of acetic acid. The aqueous mixture is then frozen and lyophilized. DCM is added to the solid, filtered, and washed with DCM. The filtrate is concentrated and ether is added to obtain a slightly cloudy solution. 1 N HCl in ether is added by dropping until a white precipitate forms. The material is collected by filtration, washed with ether, and dried in a vacuum oven to obtain 3- (2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4- oxadiazol-5-yl) phenyl) propan-2-ylamino) propane as the hydrochloric acid salt (61.5 mg, 70.6%) LC / MS (Table 1, Method a) Rt = 1.98 minutes, m / z = 444.29 (M = H) +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 8.32 (d, J = 8.57 Hz, 2H), 8.12 (d, J = 2.08 Hz, 1H), 8.03 (dd, J = 8.64, 2.10 Hz, 1H), 7.85 (d, J = 8.59 Hz, 2H), 7.25 (d, J = 8.78 Hz, 1H), 4.79 (septet, J = 6.11 Hz, 1H), 2.95 (t, J = 6.20 Hz, 2H), 2.44 ( t, J = 6.17 Hz, 2H), 1.84 (s, 6H), 1.40 (d, J = 6.04 Hz, 6H).
EXAMPLE # 5 Preparation of 3- (3-chloro-4-isopropoxyphenyl) -5- (1 H -indol-4-yl) -1, 2,4-oxadiazole A mixture of 1 H-indole-4-carboxylic acid (3.88 g, 24.05 mmol), (3-dimethylamino-propyl) -ethyl-carbodi-imide hydrochloride (4.61 g, 24.05 mmol) and benzotriazole-1-ol hydrate (3.68 g, 24.05 mmol) in anhydrous DMF (61.4 ml) is stirred under a nitrogen atmosphere at room temperature for about 1 hour. A solution of 3-chloro-N-hydroxy-4-isopropoxybenzamidine (5.0 g, 21.87 mmol) in DMF (11.51 ml) is added to the reaction mixture. The mixture is stirred and heated to approximately 140 ° C for about 2 hours. The mixture is cooled to room temperature and poured into water (1L). The product is partitioned between ethyl acetate and the aqueous phase. The organic layer is washed with 1N HCl (4 x 150 ml), NaOH 1N (2 x 150 ml) and water (2 x 300 ml), dried with MgSO 4 and filtered. The solvent is removed under reduced pressure and the crude product is purified by elution through Florisil with heptane / ethyl acetate (2: 1) to obtain 3- (3-chloro-4-isopropoxyphenyl) -5- (1 H-). indole-4-yl) -1, 2,4-oxadiazole (2.76 g, 35.7%).
LC / MS (Table 1, Method b) Rt = 2.69 minutes, m / z 354.17 (M + H) +.
Preparation # 6: Preparation of (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) phenyl) methanol To a suspension of 4- (hydroxymethyl) benzoic acid (0.220 g, 1443 mmol) in DMF (1640 ml) is added EDC (0.277 g, 1443 mmol) followed by hydrated HOBT (0.195 g, 1443 mmol). After about 45 minutes, a solution of (Z) -3-chloro-N'-hydroxy-4-isopropoxybenzimidamide (0.300 g, 1.31 mmol) in DMF (1640 ml) is added and the reaction mixture is heated to about 140 ° C for about 2 hours. After cooling to room temperature the reaction mixture is concentrated in vacuo and purified by chromatography on silica gel (eluting with EtOAc / Hep) to provide (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) phenyl) methanol (0.336 g, 71%) as an off-white solid.
LC / MS (Table 1, Method c) R, = 2.80 minutes, m / z 345 (M + H) +.
Preparation # 7: Preparation of 5- (4- (azidomethyl) phenyl) -3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazole To a solution of (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenol) methanol (0.100 g, 0.290 mmol) in TH F ( .5 ml) is added DBU (0.048 ml, 0.31 9 mmol) followed by diphenyl phosphorazidate (0.069 ml, 0.31 9 mmol). After about 15 hours the reaction mixture is poured into ether and saturated NaHCO 3. The organic layer is separated, washed with brine, dried (MgSO 4), concentrated in vacuo and purified by chromatography on silica gel (eluting with EtOAc / Hep) to provide 5- (4- (azidomethyl) phenyl) -3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazole (0.066g, 60%) as a colorless solid.
LC / MS (Table 1, Method c) Rt = 3.22 minutes, m / z 370 (M + H) +.
EXAMPLE # 6 Preparation of (4- (3- (3-chloro-4-isopropoxyphenyl) -, 2,4-oxadiazol-5-yl) phenyl) methanamine To a solution of 5- (4- (azidomethyl) phenyl) -3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazole (0.066 g, 0.178 mmol) in THF (3.40 ml) and water (0.170 ml) is added triphenylphosphine supported on polymer (0.237 g, 0.711 mmoles). After about 2 hours the reaction mixture is heated to about 60 ° C. After about 1 hour the reaction mixture is cooled to room temperature, filtered, concentrated in vacuo and purified by chromatography on silica gel (eluting with MeOH: DCM) to provide (4- (3- (3-chloro) -4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) phenyl) methanamine (40 mg, 64%) as a colorless solid.
LC / MS (Table 1, Method c) Rt = 1.97 minutes, m / z 344 (M + H) +.
Preparation # 8: 3- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) c-cyclopentanone To a suspension of 3-oxocyclopentanecarboxylic acid (0.123 g, 0.962 mmol) in DMF (1.0 mL) was added EDC (0.184 g, 0.962 mmol) followed by hydrated HOBT (0.130 g, 0.962 mmol). After about 1 hour a solution of (Z) -3-chloro-N'-hydroxy-4-isopropoxybenzimidamide (0.2 g, 0.875 mmole) in DMF (0.5 ml) is added and the reaction mixture is heated to about 140 ° C for about 45 minutes. After cooling to room temperature the reaction mixture is concentrated in vacuo and purified by chromatography on silica gel (eluting with EtOAc / Hep) to provide 3- (3- (3-chloro-4-isopropoxyphenyl) -1,2. , 4-oxadiazol-5-yl) cyclopentanone (0.156 g, 56%) as a yellow oil.
LC / MS (Table 1, Method c) Rt = 2.75 minutes, m / z 321 (M + H) +.
EXAMPLE # 7 3- (3- (3- (3-Chloro-4-isopropoxyphenyl) -1.2.4-oxadiazol-5-yl) cyclopentylamino) propane acid To a suspension of 3- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) cyclopentanone (0.178 g, 0.555 mmol) in MeOH (6.94 ml) and DCE (6.94 ml) ) add acetic acid (0.254 ml, 4.44 mmol) followed by 3-aminopropanoic acid (0.494 g, 5.55 mmol). After about 1 hour sodium cyanoborohydride (0.017 g, 0.277 mmol) is added to the reaction mixture. After about 15 hours the reaction mixture is filtered, rinsed with MeOH. The filtrate is concentrated in vacuo and purified by RP HPLC to provide 3- (3- (3- (3-chloro-4-isopropoxyphenyl) -1,2, 4-oxadiazol-5-yl) cyclopentylamino) propanoic acid.
LC / MS (Table 1, Method c) Rt = 1.64 minutes, m / z 394 (M + H) +.
EXAMPLE # 8 4- (3- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5- i I) c i clopenti lamino) butano ico acid 3- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) cyclopentanone (0.078 g, 0.243 mmol) is suspended in a mixture of MeOH (3.04 ml) and DCE (3.04 ml). ). To this is added acetic acid (0.111 ml, 1945 mmol) followed by 4-aminobutanoic acid (0.251 g, 2.432 mmol) as a solid. The solution is stirred at room temperature for 0.5-1 hour. Then add sodium cyanoborohydride (7.64 mg, 0.122 mmol) in one portion. The reaction is stirred at room temperature overnight and LC / MS indicates that the reaction was complete. The excess amino acid is removed by filtration and the filtrate is concentrated in vacuo. The crude oil is partitioned between ethyl acetate and brine. The organic layer is dried (MgSO4) and concentrated to obtain a residue that is purified in a Prep HPLC system using 30-100% ACN in 50 mM NH4OAc buffer at 21 ml / minute. Fractions 12-14 are combined and concentrated in vacuo. The resulting material is subjected to sonic energy in MeOH. The suspended precipitate is filtered, rinsed with cold MeOH and dried to obtain 4- (3- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) cyclopentylamino) butanoic acid. , (11 mg, 0.025 mmol) as a white solid.
LC / MS (Table 1, Method c) R, = 1.72 minutes, m / z 408.22 (M-H) +. 1 H NMR (400 MHz, DMSO) d ppm 8.06-7.94 (d, 2H), 7.89 - 7.79 (dd, J = 1.99, 8.66 Hz, 1H), 7.14 - 7.06 (d, J = 8.68 Hz, 1H), 4.78 - 4.65 (td, J = 6.08, 12.13 Hz, 1H), 4.09 - 3.96 (dd) , J = 5.94, 10.14 Hz, 1H), 3.91 - 3.79 (m, 1H), 3.38 - 3.24 (t, J = 7.26 Hz, 2H), 2.73 - 2.65 (dd, J = 4.81 11.44 Hz, 2H), 2.65 - 2.56 (m, 1H), 2.53-2.37 (m, 2H), 2.37 - 2.28 (m, 1H), 2.28 - 2.22 (m, 1H), 2.22 - 2.20 (s, 1H), 2.20 - 2.10 (m, 2H), [2.10 - 1.96 (m, 1H) and 1.48 - 1.38 (d, J = 6.05 Hz, 6H).
Preparation # 9: (R) -benzyl-4 - ((2,2-dimethyl-1,3-dioxolan-4-dimethoxybenzoate In a 250 ml round bottom flask, triphenylphosphine (6.54 g, 24.92 mmol) in THF (79 ml) was added to obtain a clear, colorless solution. The solution is cooled to approximately 0 ° C by means of an ice bath. After stirring for about 15 minutes, di-isopropyl azodicarboxylate (5.1 ml, 24.96 mmol) (orange liquid) is added dropwise over the course of about 5 minutes. In the process, the reaction mixture becomes a white suspension. The reaction mixture is stirred at about 0 ° C for about 30 minutes. A colorless solution of benzyl 4-hydroxybenzoate (5.69 g, 24.92 mmol) and (R) - (2,2-dimethyl-1,3-dioxolan-4-yl) methanol (3.00 ml, 23.73 g) is then added to the mixture. mmoles) in TH F (39.5 ml), maintaining the temperature at or below approximately 0 ° C. The solution turns clear light yellow. The solution is stirred for approximately 2 hours at 0 ° C then slowly warmed to room temperature and stirred over the weekend. The mixture is concentrated in vacuo to obtain crude yellow oil (~ 27 g). The crude oil is dissolved in ether. Then heptane is added. The resulting precipitate is subjected to sonic energy and filtered. The filtrate is concentrated and purified by the Analogix® system using the RediSep ™ RS column of 1 20 g, with a gradient of 0-20% EtOAc / heptane over the course of 10 minutes at 50 ml / minute after which it is maintained. to 20% ethyl acetate for 20 minutes. The fractions containing the product are combined and concentrated to obtain (R) -benzyl-4 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) benzoate as a white solid ( 6.17 g, 23.73 mmoles).
LC / MS (Table 1, Method c) Rt = 2.89 minutes, m / z 343.20 (M + H) +.
Preparation # 10: (R) -4 - ((2,2-Dimethyl-1,3-dioxolan-4-yl) methoxy) benzoic acid A 500 ml high pressure flask is loaded with palladium on carbon (0.300 g, 0.282 mmol), then MeOH (200 ml) is added, followed by (R) -benzyl-4 - ((2,2-dimethyl-1) , 3-dioxolan-4-yl) methoxy) benzoate (6.17 g, 18.02 mmol). The resulting suspension is allowed to stir under a hydrogen atmosphere (2.47 kg / cm2) at room temperature for about 2 hours. The mixture is filtered through Celite® and the colorless filtrate is concentrated to obtain (R) -4 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) benzoic acid as a white solid. (4.45 g, 17.64 mmol).
LC / MS (Table 1, Method c) Rt = 2.15 minutes, m / z 253.14 (M + H) +.
Preparation # 11: (R) -3- (3-Chloro-4-isopropoxyphenin-5- (4 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) phenyl) -1,2,4-oxadiazole suspension of (R) -4 - ((2,2-dimethyl-1, 3-dioxolan-4-yl) methoxy) benzoic acid (0.303 g, 1,203 mmol) in DMF (1367 mL) is added EDC (0.231 g, 1,203 mmoles) followed by hydrated HOBT (0.163 g, 1,203 mmoles). After about 1.5 hours a solution of (Z) -3-chloro-N'-hydroxy-4-isopropoxybenzimidamide (0.250 g, 1.09 mmol) in DMF (1367 ml) is added. The reaction mixture is heated to about 140 ° C for about 2 hours. After cooling to room temperature the reaction mixture is concentrated in vacuo and purified by chromatography on silica gel (eluting with EtOAc / Hep) to provide (R) -3- (3-chloro-4-isopropoxyphenyl) -5- (4 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) phenyl) -1,2,4-oxadiazole (0.339 g, 70%) as a colorless solid.
LC / MS (Table 1, Method c) Rt = 3.36 minutes, m / z 445 (M + H) +.
EXAMPLE # 9 Preparation of (S) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-tl) phenoxypropane-1,2-diol To a solution of (R) -3- (3-chloro-4-isopropoxyphenyl) -5- (4 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) phenyl) - 1, 2, 4-oxadiazole (0.339 g, 0.762 mmol) in TH F (1 5.24 ml) was added a solution of 1 N HCl (1.524 ml, 1.524 mmol). After about 48 hours additional 1 N HCl (2286 ml, 2286 mmol) is added and the reaction mixture is heated to about 70 ° C for about 2 hours. After cooling to room temperature, a solution of 1 N NaOH (3.81 ml, 3.81 mmol) is added and the reaction mixture is concentrated in vacuo. The resulting solid is washed with water and dried under vacuum to provide (S) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenoxy) propane-1,2-diol (0.294 g, 94%) as a colorless solid.
LC / M S (Table 1, Method c) Rt = 2.73 minutes, m / z 405 (M + H) +.
EXAMPLE # 10 Preparation of 4- (3- (3-chloro-4-isopropoxyphenyl) -1,4, 2,4-oxadiazol-5-D-benzenesulfonamide To a suspension of 4-sulfamoylbenzoic acid (1452 g, 7.22 mmol) in DMF (8.20 ml) is added EDC (1383 g, 7.22 mmol) followed by hydrated HOBT (0.975 g, 7.22 mmol). After about 30 minutes a solution of (Z) -3-chloro-N'-hydroxy-4-isopropoxybenzimidamide in DMF (8.20 ml) is added. The reaction mixture is heated to about 140 ° C for about 2 hours. After cooling to room temperature the reaction mixture is concentrated in vacuo and purified by chromatography on silica gel (eluting with EtOAc / Hep) to provide 4- (3- (3-chloro-4-isopropoxyphenyl) -1,2. , 4- oxadiazol-5-yl) benzenesulfonamide (1.28 g, 50%) as a colorless solid.
LC / MS (Table 1, Method c) R, = 2.74 minutes, m / z 392 (M-H) -.
Preparation # 12a: Preparation of 3.3 '- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-i-phenylsulfonylazandi-tert-butyl y-diphenylpropanoate and 3- (4- (3- ( 3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylsulfonamido) propane tert-butyl ester To a solution of 4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzenesulfonamide (0.500 g, 1270 mmol) in DMF (3.17 ml) is added NaH (0.056). g, 1396 mmol). After approximately 10 minutes, tert-butyl 3-bromopropanoate (0.233 ml) is added1,396 mmoles) and the reaction mixture is heated to about 60 ° C. After about 48 hours the reaction mixture is cooled to room temperature and purified by chromatography on silica gel (eluting with EtOAc / Hep) to provide 3.3 '- (4- (3- (3-chloro-4-) isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) phenylsulfonylanediyl-yl) dipropanoate (0.24 g, 29%) as a colorless solid. LC / S (Table 1, Method c) Rt = 3.43 minutes, m / z 667 (M + NH4) +, in addition to 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2, 3-Oxadiazol-5-yl) phenylsulfonamido) tert-butyl propanoate (0.28 g, 42%) as a colorless solid. LC / MS (Table 1, Method c) Rt = 3.13 minutes, m / z 521 (M-H) ".
EXAMPLE # 13 Preparation of 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylsulfonamido) propane acid To a solution of tert-butyl 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylsulfonamido) propanoate (0.28 g, 0.536 mmol) in dichloromethane (6.0 mi) TFA (2.0 ml, 26.0 mmol) is added. After about 3 hours the reaction mixture is concentrated in vacuo and the resulting solid is triturated with ether, filtered and dried to provide 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1 acid, 2,4-oxadiazol-5-yl) phenylsulfonamido) propane (0.176 g, 70%) as a colorless solid.
LC / MS (Table 1, Method c) R, = 2.54 minutes, m / z 466 (M + H) +.
EXAMPLE # 14 Preparation of 2,2 '- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylsulfonylazandi-1) diacetic acid TFA (1.0 ml, 12.98 mmol) is added to a stirred mixture of 2,2 '- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylsulfonylazole. il) tert-butyl diacetate (0.106 g, 0.170) mmoles), dichlorom and then concentrated in vacuo. The resulting residue is triturated with diethyl ether, filtered and dried to obtain 2, 2 '- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) acid. phenylsulfonylazandi-yl) diacetic (63 mg, 0.1 22 mmol) as a white solid.
LC / MS (Table 1, Method c) R, = 1.84 minutes, m / z 508.38 (M-H) \ Preparation # 1 2b: Preparation of 2,2 '- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-M) phenylsulfonylazand-yl) tert-butyl diacetate and 2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylsulfonamido) tert-butyl acetate K2C03 powder (0.1 90 g, 1373 mmol) is added dropwise to a stirred mixture of 4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl. ) benzenesulfonamide (0.492 g, 1, 249 mmoles) in anhydrous ACN (6.25 ml) under N2. Then tert-butyl 2-bromoacetate (0.203 ml, 3774 mmol) is added and the mixture is heated to about 80 ° C for about 3 hours. The reaction mixture (suspension) is concentrated in vacuo and the resulting material is triturated in DCM and filtered. The filtrate is concentrated and purified directly by the Analogix® system using the RediSep ™ RS 40 g column, with a gradient of 0- 40% EtOAc / heptane over the course of 40 minutes, at 30 ml / minute. The fractions containing the product are combined and concentrated. This produces 2,2 '- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylsulfonylandi-2-yl) tert-butyl diacetate (249 mg, 0.400 mmol) ) as a white sticky solid, LC / MS (Table 1, Method c) Rt = 3.1 7 minutes, m / z 639 (M + N H4) + and 2- (4- (3- (3-chloro- 4-isopropoxyphenyl) -, 2,4-oxadiazol-5-yl) phenylsulfonamido) tert-butyl acetate (1 21 mg, 0.238 mmol) as a white solid, LC / MS (Table 1, Method c) R, = 2.81 minutes, m / z 508 (M + H) +.
EXEM PLO # 1 6 Preparation of 2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylsulphonamido) acetic acid TFA (2.0 mL, 26.0 mmol) is added dropwise to a stirred mixture of 2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,2-oxadiazol-5-yl) phenylsulfonamido) acetate. of tert-butyl (0.121 g, 0.238 mmol), DCM (5.0 ml) under N2. The mixture is stirred at room temperature for about 3 hours then concentrated in vacuo. The resulting solid is triturated in ether, filtered and dried to obtain 2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylsulfonamido) acetic acid ( 46 mg, 0.1 02 mmoles) as a white solid.
LC / MS (Table 1, Method c) Rt = 2.14 minutes, m / z 450.34 Preparation # 12c: Preparation of 2- (5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3,4-dihydroisoa-quinolin-2 (1 H) -i-Diacetate of ter -butyl To a solution of 3- (3-chloro-4-isopropoxyphenyl) -5- (1, 2,3,4-tetrahydroisoquinolin-5-yl) -1, 2,4-oxadiazole (0.0726 g, 0.196 mmol) DMF (1963 ml) was added K2C03 (0.054 g, 0.393 mmol) followed by tert-butyl bromoacetate (0.030 ml, 0.206 mmol). After about 48 hours the reaction mixture is filtered, concentrated in vacuo and purified by chromatography to provide 2- (5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazole-5 -yl) -3,4-dihydroisoquinolin-2 (1 H) -yl) tert-butyl acetate as a colorless oil that solidifies on standing.
LC / MS (Table 1, Method c) Rt = 3.41 minutes, m / z 486 (M + H) +.
Preparation # 12d: Preparation of 5- (3- (3-chloro-4-isopropoxyphenyl) -1,4-oxadiazol-5-yl) -3,4-dihydroisoquinolin-2 (1 H) -tert-butylcarboxylate To a suspension of 2- (tert-butoxycarbonyl) -1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid (0.380 g, 1371 mmol) in DMF (1662 ml) is added EDC (0.263 g, 1.371 mmol) followed by HOBT hydrated. After about 1 hour a solution of (Z) -3-chloro-N'-hydroxy-4-isopropoxybenzimidamide (0.285 g, 1.246 mmol) in DMF (0.831 ml) is added and the reaction mixture is heated to about 140 °. C for about 1 hour. The reaction mixture is concentrated in vacuo and purified by chromatography on silica gel to provide 5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3,4 -dihydroisoquinolin-2 (1 H) -tert-butylcarboxylate (0.403 g, 69%) as a colorless oil.
LC / MS (Table 1, Method c) Rt = 3.43 minutes, m / z 471 (M + H) +.
EXAMPLE # 19 Preparation of 3- (3-chloro-4-isopropoxy-phenyl) -5- (1.2.3.4-tetrahydroisoquinolin-5-yl) -1,2,4-oxadiazole To a solution of 5- (3- (3-chloro-4-isopropoxyphenyl) -1,4,4-oxadiazol-5-yl) -3,4-dihydro-5-quinolin-2 (1 H) -carboxylate of tert-butyl (0.403 g, 0.858 mmol) in dioxane (17.15 mL) is added a 4N solution of HCl in 1,4-dioxane (3.86 mL, 15.44 mmol). After about 15 hours, the reaction mixture is filtered. The resulting solid is partitioned between EtOAc and saturated NaHCO 3. The organic layer is separated, dried (MgSO.sub.4), filtered and concentrated in vacuo to provide 3- (3-chloro-4-isopropoxyphenyl) -5- (1, 2,3,4-tetrahydro-5-quinoline-5-yl). ) -1, 2,4-oxadiazole (0.230 g, 73%) as a colorless solid.
LC / MS (Table 1, Method c) Rt = 2.00 minutes, m / z 372 (M + H) +.
EXAMPLE # 20 Preparation of 2- (5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3,4-dihydroisoquinolin-2 (1 H) -yl) acetic acid To a solution of 2- (5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3,4-dihyd-r-isoquinolin-2. (1 H) -il ) tert-butyl acetate (0.1 31 9 g, 0.273 mmole) in dichloromethane (10 mL) was added tri-isopropylsilane (0.056 mL, 0.273 mmol) followed by TFA (2 mL). The resulting solid is triturated in ether, filtered and dried to provide 2- (5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazole acid. -5-yl) -3,4-dihydroisoquinolin-2 (1 H) -yl) acetic acid (0.1 38 g, 93%) as an off-white solid.
LC / MS (Table 1, Method c) Rt = 2.00 minutes, m / z 428 (M + H) +.
Preparation # 1 2e: Preparation of 3- (5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3,4-dihydroisoquinolin-2 (1 H) - Tert-butyl dpropanoate A 3- (3-Chloro-4-isopropoxyphenyl) -5- (1, 2, 3,4-tetrahydroisoquinolin-5-yl) -1,2,4-oxadiazole (0.1088 g, 0.294 mmol) in DM F (2.94 ml) (briefly warmed to approximately 40 ° C for complete dissolution) is added K2C03 (0.081 g, 0.588 mmol) and tert-butyl 3-bromopropanoate (0.046 ml, 0.276 mmol) and the mixture is stirred at room temperature during approximately 2 hours. Additional tert-butyl-3-bromopropanoate (0.053 ml, 0.31 5 mmol) is added and the reaction is stirred at approximately 60 ° C over the weekend. Additional tert-butyl 3-bromopropanoate (0.053 ml, 0.315 mmol) is added and the reaction is continued heating at about 60 ° C overnight. Additional K2C03 (0.041 g, 0.294 mmol) is added, followed by tert-butyl 3-bromopropanoate (0.053 mL, 0.31 5 mmol). The reaction is heated to approximately 60 ° C overnight. The reaction mixture is filtered and the filtrate is concentrated in vacuo to obtain ~1 79 mg of crude yellow oil. The crude residue is purified by the Analogix® system using the RediSep ™ RS column of 1 2 g, with a gradient of 0-45% EtOAc / heptane over the course of 35 minutes, at 15 ml / minute. Fractions 23-28 are combined and concentrated to obtain 3- (5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3,4-dihydroisoquinolin-2 (1 H) -yl) tert-butyl propanoate (91 mg, 0.1 83 mmol) as light yellow oil.
LC / MS (Table 1, Method c) Rt = 3.39 minutes, m / z 500.72 (M + H) +.
EJ EM PLO # 22 Preparation of 3- (5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3,4-dihydroisoq-quinolin-2 (1 H) -yl) propanic, salt TFA A 3- (5- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3,4-dihydroxyquinolin-2 (1 H) -yl) propanoate tert-butyl (0.091 g, 0.183 mmol) in dichloromethane (6.0 mL) is added TFA (1.5 mL) and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo and the resulting crude product is dissolved in a small amount of DCM. Ether is added until a solid precipitates. The mixture is filtered, rinsed with ether and dried to obtain 3- (5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3,4- dihydroisoquinolin-2 (1 H) -yl) propane, TFA salt (74.7 mg, 0.134 mmol) as light yellow solid.
LC / MS (Table 1, Method c) Rt = 2.04 minutes, m / z 442.25 (M + H) +.
H NMR (400 MHz, DMSO) d ppm 8.18 - 8.11 (dd, J = 2.07 6.76 Hz, 1H), 8.11 - 8.06 (d, J = 2.01 Hz, 1H), 8.06 - 7.99 (J = 2.02, 8.64 Hz, 1H), 7.61 - 7.53 (J = 6.58, 6.58 Hz, 1H), 7.45 - 7.37 (J = 8.8 Hz, 1H), 4.90 - 4.78 (m, 1H), 4.65 - 4.46 (s, 2H), 3.71 - 3.51 (s, 3H), 3.51 - 3.38 (J = 6.87, 6.87 Hz, 3H), 2.91 - 2.81 (t, J = 7.32, 7.32 Hz, 2H) and 1.39 - 1.33 (d, 6H).
Preparation # 12: 4-isopropoxy-3- (trifluoromethyl) benzonitrile A mixture of 4-hydroxy-3- (trifluoromethyl) benzonitrile (5.89 g, 31.5 mmol) and triphenylphosphine (13.21 g, 50.4 mmol) in anhydrous THF (200 mL) is stirred under a nitrogen atmosphere for about 5 minutes at room temperature . DBAD (11.60 g, 50.4 mmol) is added to the solution, it is stirred approximately 5 minutes before the addition of 2-propanol (3.03 ml, 39.3 mmol). The mixture is stirred at room temperature for about 72 hours. The solvent is removed under reduced pressure. The resulting oil is triturated with pet ether 30-60 ° C (200 ml), filtered to remove the phosphine oxide and the crude product is further purified by elution through silica with heptane / ethyl acetate (4: 1). ). The isolated oil is dissolved in dichloromethane (200 ml) and stirred with TFA (4.85 ml, 63.0 mmol) for about 90 minutes at room temperature. The solution is basified with 2.5 N NaOH (30 ml) and the product is partitioned between DCM and the basic aqueous phase to obtain crude 4-isopropoxy-3- (trifluoromethyl) benzonitrile (6.56, 91%).
LC / MS (Table 1, Method a) Rt = 2.32 minutes. 1 H NMR (400MHz, CDCl 3) 7.85 (d, 1H), 7.75 (dd, 1H), 7.06 1H), 4.73 (m, 1H), 1.41 (dd, 6H).
Preparation # 13: (Z) -N'-hydroxy-4-isopropoxy-3- (trifluoromethyl) benzimidamide Under a nitrogen atmosphere, 4-isopropoxy-3- (trifluoromethyl) benzonitrile (6.5 g, 28.4 mmol) and 50% aqueous hydroxylamine (5.21 mL, 85 mmol) in EtOH (20.0 mL) are heated at 60 ° C for approximately 18 hours. The solvents are removed in vacuo and the residue is azeotropically distilled with MeOH. The residual solid is purified by precipitation with a mixture of ethyl acetate / pet / ether 30-60 ° C (1: 2) to obtain (Z) -N'-hydroxy-4-isopropoxy-3- (trifluoromethyl) benzim damida (2.51g, 33.8%).
LC / MS (Table 1, Method b) Rt = 1.89 minutes, m / z 263.13 (M + H) +.
Preparation # 14: (S) -3-chloro-4- (tetrahydrofuran-3-yloxybenzonitrile Under a nitrogen atmosphere, a mixture of 3-chloro-4-hydroxybenzonitrile (8.70 g, 56.7 mmol) and triphenylphosphine (23.77 g, 91 mmol) in anhydrous THF (21 8 ml) is stirred for approximately 5 minutes at room temperature. ambient. DBAD (20.87 g, 91 mmol) is added to the solution, it is stirred approximately 5 minutes before the addition of (S) - (+) - 3-hydroxytetrahydrofuran (3.87 ml, 56.7 mmol) in TH F (10 ml). ). The mixture is stirred at room temperature for approximately 24 hours. The solvent is removed under reduced pressure. The residue is dissolved in dichloromethane (200 ml) and stirred with TFA (21.82 ml., 283 mmoles) for approximately 90 minutes at room temperature. The solution is basified with aqueous sodium hydroxide and the product is partitioned between DC M and the basic aqueous phase. The DCM is dried with magnesium sulfate, filtered and the solvent is removed under red pressure to obtain an oil. The oil is stirred with hot pet / ether 30-60 ° C (200 ml), cooled and filtered. The solvent is removed under reduced pressure to obtain the crude (S) -3-chloro-4- (tetrahydrofuran-3-yloxy) benzonitrile (1.1 g). R, 2.06 minutes, m / z 378.2 (M + H) +.
Preparation # 15: (S.Z) -3-chloro-N'-hydroxy-4- (tetrahydrofuran-3-yloxy) benzimidamide Under a nitrogen atmosphere, it is heated to approximately 60 ° C (S) -3-chloro-4- (tetrahydrofuran-3-yloxy) benzonitrile (11.2 g, 50.1 mmol) and 50% aqueous hydroxylamine (3.31 g). , 50.1 mmole) in EtOH (50.0 ml) for about 1 8 hours. The solvents are removed in vacuo and the residue is azeotropically distilled with MeOH. The residual solid is purified by precipitation with a mixture of ethyl acetate / pet / ether 30-60 ° C (1: 2) to obtain (S, Z) -3-chloro-N'-hydroxy-4- (tetrahydrofuran- 3-yloxy) benzimidamide (5.3 g).
LC / MS (Table 1, Method b) Rt = 1.52 minutes, m / z 257.09 (M + H) +.
Preparation # 16: 4-morpholino-3- (trifluoromethyl) benzonitrile To a solution of 4-fluoro-3- (trifluoromethyl) benzonitrile (15 g, 79 mmol) in dimethyl sulfoxide (160 ml) is added morpholine (13.8 ml, 159 mmol) and potassium carbonate (16.4 g, 119 mmol). . The mixture is heated to approximately 90 ° C for about 18 hours. The mixture is cooled to room temperature and the solid is removed by filtration. The filtrate is partitioned between ethyl acetate (1.8 L) and water (1.5 L). The organic layer is washed with water (1.0 L) and brine (1.0 L) and dried with anhydrous magnesium sulfate. The solvent is removed under vacuum to obtain 4-morpholino-3- (trifluoromethyl) benzonitrile (17.25 g, 85%). 1 H NMR (DMSO-d 6, 400MHz) d ppm 8.18 (d, J = 2.05 Hz, 1H), 8.09 (dd, J = 8.51, 2.06 Hz, 1H), 7.60 (d, J = 8.52 Hz, 1H), 3.69-3.75 (m, 4H), 2.97-3.04 (m, 4H).
Preparation # 17: N'-hydroxy-4-morpholino-3- (trifluoromethyl) benzimidamide To a solution of 4-morpholino-3- (trifluoromethyl) benzonitrile (17.3 g, 67.3 mmol) in ethanol (400 mL) is added a 50% aqueous solution of hydroxylamine (4.9 mL, 74.1 mmol) by trickling. The mixture is heated to approximately 65 ° C for approximately 24 hours. The mixture is cooled to room temperature and the solid is removed by filtration. The filtrate is partitioned between ethyl acetate (1.8 L) and water (1.5 L). The organic layer is washed with water (1.0 L) and brine (1.0 L) and dried with anhydrous magnesium sulfate. The solvent is removed under vacuum to obtain N'-hydroxy-4-morpholino-3- (trifluoromethyl) benzimidamide (8.6 g, 91%) as a mixture of syn / anti isomers.
LC / MS (Table 1, Method b) R, = 1.85 minutes, m / z 290.15 (M + H) *. 1 H NMR (DMSO-d 6, 400MHz) d ppm 9.75 (s, 1H), 8.09-8.16 (m, 1H), 7.89-7.96 (m, 1H), 7.52-7.58 (m, 1H), 3.66-3.72 (m , 4H), 2.83-2.93 (m, 4H).
Preparation # 18: 5-Methoxy-3,6-dihydro-2H-pyrazin-1-carboxylic acid benzyl ester A solution of benzyl 3-oxopiperazine-1-carboxylate (2.50 g, 10.67 mmol) in CH2Cl2 (100 mL) is cooled to about 0 ° C and treated with Na2CO3 (23.0 g, 217 mmol) for about 10 minutes. Pure trimethyloxonium tetrafluoroborate (5.50 g, 37.2 mmol) is added in one portion, then the reaction is allowed to warm to room temperature for about 6 hours. The reaction is poured into water (100 ml), and the layers are separated. The aqueous layer is back extracted with 50 ml of CH 2 Cl 2 and the combined organic layers are washed with brine (100 ml). The organic layer is dried with sodium sulfate, filtered and concentrated to obtain the 5-methoxy-3,6-dihydro-2H-pyrazin-1-carboxylic acid benzyl ester (2.51g, 95%) as an oil. .
LC / MS (Table 1, Method a) Rt = 3.00 minutes, m / z 249.24 (? +?) + ·.
H NMR (400 MHz, DMSO-d6) d ppm 7.36 (m, 5H), 5.16 (s, 2H), 3.96 (s, 2H), 3.68 (s, 3H), 3.54 (s, 2H), 3.47 (m , 2H).
Preparation # 19: 3-Methyl-5,6-dihydro-8H-imidazori. 2-alpyrazine-7-carboxylic acid benzyl ester To a solution of 3-methoxy-5,6-dihydropyrazin-1 (2H) -carboxylate (4.48 g, 18.03 mmol) in MeOH (200 mL) is added propargylamine (6.18 mL, 90 mmol) at room temperature. The mixture is heated to reflux for about 5 hours, then cooled to room temperature and concentrated. The residue is dissolved in 1N HCl (100 mL) and washed with 3 x 75 mL of ethyl acetate. The aqueous solution is neutralized with solid Na 2 CO 3 and extracted with 2 x 100 ml of ethyl acetate. The combined extracts are washed with 100 ml of saturated NaCl solution, filtered and concentrated. The residue is triturated with ether, filtered and dried under reduced pressure to obtain the benzyl ester of 3-methyl-5,6-dihydro-8H-imidazo [1,2-a] pyrazine-7-carboxylic acid ester (2.91 g. , 60%) as a whitish solid.
LC / MS (Table 1, Method a) Rt = 3.07 minutes, m / z 272.11 (M + H) + \ 1 H NMR (400 MHz DMSO-d 6) d ppm 7.30 (m, 5H), 6.58 (q, 1H), 5.13 (s, 2H), 4.55 (s, broad, 2H), 3.84 (s, 4H), 2.10 ( s, 3H).
Preparation # 20: 2-iodo-3-methyl-5,6-dihydro-8H-imidazof1, 2-alpyrazine-7-carboxylic acid benzyl ester To a solution of benzyl-3-methyl-5,6-dihydroimidazo [1,2-a] pyrazin-7 (8H) -carboxylate (1085 g, 4.00 mmol) in 1,2-dichloroethane (60 ml) was add NIS (4.50 g, 20.00 mmol) and the reaction is refluxed for about 1 hour. The reaction is cooled to room temperature and poured into 100 ml of saturated 5% sodium thiosulfate solution. The layers are separated and the aqueous layer is extracted again with 1,2-dichloroethane (40 ml). The combined organic layers are washed with water (100 ml), dried over sodium sulfate, filtered and concentrated. The product is extracted from the residue by trituration with 3 x 50 ml portions of ether. The extract is filtered and concentrated to obtain the ester 2-iodo-3-methyl-5,6-dihydro-8H-imidazo [1, 2-a] pyrazine-7-carboxylic acid benzyl ester (1.42 g, 89%) as a pale yellow oil.
LC / MS (Table 1, Method a) Rt = 3.32 minutes, m / z 398.59 (+ H) + \ 1 H NMR (400 MHz, CHCl 3) d ppm 7.35 (m, 5 H), 5.13 (s, 2 H), 4.56 (s, broad, 2 H), 4.38 (t, 2 H), 3.82 (s, broad, 2 H), 2.09 (s, 3H).
Preparation # 21: 7-Benzyl 3-methyl-5,6-dihydro-8H-imidazof 1,2-a1pyrazine-2,7-dicarboxylic acid ester A solution of benzyl 2-iodo-3-methyl-5,6-dihydroimidazo [1,2-a] pyrazin-7 (8H) -carboxylate (900 mg, 2266 mmol) in dry THF (25 mL) is cooled to about 0 ° C and ethylmagnesium bromide (1888 ml, 5.66 mmol) is added at a rate such as to maintain the reaction temperature below about 2.5 ° C. The reaction is stirred under nitrogen at about 0 ° C for about 15 minutes, then the reaction is quenched with a flow of carbon dioxide. The reaction is concentrated to solids and acetic acid (0.60 mL, 10.48 mmol) ethyl acetate (50 mL) is added and the suspension is stirred vigorously at room temperature for approximately 15 minutes. The resulting solid is filtered and washed with an additional 15 ml of ethyl acetate. The residue is dissolved in 10 ml of water plus 2N HCl until pH 4, then washed twice with 10 ml of ether and then extracted with 4 x 20 ml of CH2Cl2. The combined organic extracts are dried with sodium sulfate, filtered and evaporated under reduced pressure to obtain the 7-benzyl ester of 3-methyl-5,6-dihydro-8H-imidazo [1,2-a] pyrazine. 2,7-dicarboxylic (374 mg, 52%) as a foam.
LC / MS (Table 1, Method a) Rt = 2.28 minutes, m / z 316.10 (M + H) + \ 1 H NMR (400 MHz, DMSO-d 6) d ppm 7.35 (m, 5H), 5.11 (s, 2H), 4.56 (s, broad, 2H), 3.88 (m, 2H), 3.83 (s, broad, 2H) , 2.36 (s, 3H).
Preparation # 22: Preparation of the benzyl ester of 2-f3- (3-chloro-4-isopropoxy-phenyl) -ri, 2,41-oxadiazol-5-H-3-methyl-5,6-dihydro-8H-imidazori. -alpyrazine-7-carboxylic acid To a solution of 7- (benzyloxycarbonyl) -3-methyl-5,6,7,8-tetrahydroimidazo [1, 2-a] pyrazine-2-carboxylic acid (370 mg, 1173 mmol) in DCM (10 mL) was added. add oxalyl chloride (2054 mi, 23.47 mmol) and DMF (5 μ?). The reaction is stirred for about 1 hour and concentrated. A solution of (E) -3-chloro-N'-hydroxy-4-isopropoxybenzimidamide (268 mg, 1173 mmol) in pyridine (10.00 ml) is added and the reaction is stirred at room temperature for about 30 minutes. The reaction is treated with acetyl chloride (0.092 ml, 1291 mmol) and then heated at 115 ° C under nitrogen for about 4 hours. The reaction is cooled, concentrated and partitioned between saturated Na 2 CO 3 and methylene chloride. The organic layer is washed with water, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue is purified on silica gel using 80:20 / methylene chloride: ethyl acetate as the eluent to obtain the benzyl ester of 2- [3- (3-chloro-4-isopropoxy-phenyl) - [1, 2,4] oxadiazol-5-yl] -3-methyl-5,6-dihydro-8H-imidazo [1, 2-a] pyrazine-7-carboxylic acid (173 mg, 29%) as an off-white solid.
LC / MS (Table 1, Method a) Rt = 4.34 minutes, m / z 508.24 (M + H) + \ 1 H NMR (400 MHz, DMSO-d 6) d ppm 7.98 (d, 1 H), 7.93 (d, d, 1 H), 7.35 (m, 6 H), 5.12 (s, 2 H), 4.78 (m, 1 H), 4.66 (s, width, 2H), 3.99 (m, 2H), 3.88 (s, width, 2H), 2.57 (s, 3H), 1.31 (d, 6H).
EXAMPLE # 23 Preparation of 2-r3- (3-chloro-4-isopropoxy-phenyl) -H .2.41-oxadiazol-5-yl-3-methyl-5,6,7,8-tetrahydro-imidazoH .2-alpyrazine A solution of 2- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3-methyl-5,6-dihydroimidazo [1,2-a] pyrazin-7 (8H) -Benzyl carboxylate (160 mg, 0.315 mmol) in 33% HBr solution in acetic acid (2.00 ml) containing triisopropylsilane (0.065 ml, 0.315 mmol)) is stirred at room temperature under nitrogen for approximately 10 minutes . Ether (20 ml) is added to precipitate the product. The resulting solid is removed by filtration, treated with saturated bicarbonate solution (10 ml) and extracted with methylene chloride (2 x 10 ml). The combined organic layers are dried with sodium sulfate, filtered, concentrated to solids and dried under reduced pressure to obtain 2- [3- (3-chloro-4-isopropoxy-phenyl) - [1,2,4] oxadiazol-5-yl] -3-methyl-5,6,7,8-tetrahydro-imidazo [1, 2-a] pyrazine (113 mg, 96%) as an off-white solid.
LC / MS (Table 1, Method a) R, = 3.14 minutes, m / z 374.24 (M + H) + \ H NMR (400 MHz, DMSO-d6) d ppm 8.01 (d, 1H), 7.97 (d, d, 1H), 7.36 (d, 1H), 4.81 (m, 1H), 4.66 (s, 2H), 3.90 (s, 2H), 3.87 (t, 2H), 3.12 (t, 2H), 2.60 (s, 3H), 1.34 (d, 6H).
EXAMPLE # 24 Preparation of 1 - (2-f3- (3-chloro-4-isopropoxy-phenyl) -G1.2.41 oxadiazol-5-iH-3-methyl-5,6-dihydro-8H-imidazori, 2-alpyrazin-7-yl) -etanone To a solution of 2- (3-chloro-4-isopropoxyphenyl) -3-methyl-5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine (32 mg, 0.105 mmol) in methylene chloride (2.0 mi) acetyl chloride (7.50 μ ?, 0.105 mmol) is added at room temperature. The mixture is stirred at room temperature for 4 hours and concentrated. The residue is purified by reverse phase HPLC to obtain 1 -. { 2- [3- (3-chloro-4-isopropoxy-phenyl) - [1,4] oxadiazol-5-yl] -3-methyl-5,6-dihydro-8H-imidazo [1, 2-a] ] pyrazin-7-il} -ethanone (31 mg, 86%) as a whitish solid.
LC / MS (Table 1, Method a) Rt = 3.46 minutes, m / z 416.20 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 8.02 (d, 1 H), 8.97 (d, d, 1 H), 7.37 (d, 1 H), 4.81 (m, 2 H), 4.70 (s, 2 H), 3.90 (s, 2H), 4.07 (tOm, 1H), 3.95 (m, 3H), 2.62 (s, 3H), 2.14 (m, 3H), 1.34 (d, 6H).
Preparation # 22a: Preparation of the tert-butyl ester of the acid. { 2-r3- (3-Chloro-4-isopropoxy-phenyl) -M, 2.41-oxadiazol-5-yn-3-methyl-5,6-dihydro-8H-imidazori, 2-a1pyrazin-7-yl) -acetic To a solution of 3- (3-chloro-4-isopropoxyphenyl) -5- (3-methyl-5,6,7,8-tetrahydroimidazo [1, 2-a] pyrazin-2-yl) -1, 2, 4-Oxadiazole (50.0 mg, 0.1 34 mmol) in DM F (1.0 ml) at room temperature is added sodium carbonate (28.4 mg, 0.267 mmol) and tert-butyl bromoacetate (0.021 ml, 0.140 mmol) at room temperature. ambient. The reaction is continued overnight. The reaction is filtered and concentrated. The residue is dissolved in ethyl acetate (10 mL), washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to obtain tert-butyl ester of the acid. { 2- [3- (3-chloro-4-isopropoxy-phenyl) - [1, 2,4] oxadiazol-5-yl] -3-methyl-5,6-dihydro-8H-imidazo [1, 2- a] pyrazin-7- il} -acetic (35 mg, 54%) as a white foam which is used in the next step without further purification.
LC / MS (Table 1, Method a) Rt = 4.32 minutes, m / z 488.29 (M + H) +.
EXAMPLE # 26 Preparation of acid (2-r3- (3-chloro-4-isopropoxy-phenyl) -G1.2,41-oxadiazol-5-iH-3-methyl-5,6-dihydro-8H-imidazoH .2-a1pyrazin-7-yl- acetic, trifluoroacetic acid salt To a solution of 2- (2- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3-methyl-5,6-dihydroimidazo [1,2-a] ] tert-butyl pyrazin-7 (8H) -yl) acetate (32 mg, 0.066 mmol) and triisopropylsilane (0.013 mL, 0.066 mmol) in methylene chloride (2.0 mL) is added TFA (2.0 mL) at room temperature environment for about 3 hours. The reaction is diluted with ether (20 mL) and the product is removed by filtration and dried under reduced pressure.
LC / MS (Table 1, Method a) R, = 2.99 minutes, m / z 432.23 (? +?) + ·. 1 H NMR (400 MHz, DMSO-d 6) d 8.0 (m, 2 H), 7.36 (m, 1 H), 4.81 (m, 1 H), 3.97 (m, 2 H), 3.84 (m, 2 H), 3.46 (m, 2H), 3.09 (m, 2H), 2.59 (s, 3H), 1.33 (d, 6H).
Preparation # 23: 2-Methyl-imidazo-2, 2-alpyrazine-3-carboxylic acid ethyl ester A solution of pyrazin-2-amine (3.6 g, 37.9 mmol) and 2-chloro-3-oxobutanoate (5.24 mi, 37.9 mmol) in ethanol (30 ml) is refluxed d uring about 9 hours. A 1 N solution of HCl in ether is added and the mixture is concentrated under a reddish pressure. The residue is triturated with 3 x 50 ml of AC N and filtered to obtain the crude ethyl 2-methyl-imidazo [1,2-a] pyrazine-3-carboxylic acid ester (4.5 g, 58%) as a Amorphous solid which is used in the next step without further purification.
Preparation # 24: 2-methyl-imidazof 1,2-a1pyrazine-3-carboxylic acid A sodium hydroxide solution (1 .754 g, 43. 9 mmol) in water (25 ml) was added to crude ethyl 2-methylimidazo [1,2-a] pyrazine-3-carboxylate (4.5 g, 21.93 mmol). The reaction is exothermic and ends in minutes without additional heating. The mixture is acidified with concentrated HCl to about pH 5. The solution is injected onto a preparative C 1 8 column and washed with water and then eluted with 20% CH 3 CN / water. The product fractions are combined and concentrated to obtain 2-methyl-imidazo [1,2-a] pyrazine-3-carboxylic acid (250 mg, 6%) as a tan solid.
LC / MS (Table 1, Method a) R, = 0.84 minutes, m / z 176.18 (M-H) -. 1 H R N (400 MHz, DMSO-d 6) d 9.12 (m, 2 H), 8.12 (m, 1 H), 2.66 (s, 3 H).
EXAMPLE # 27 Preparation of 3-r3- (3-chloro-4-isopropoxy-phenyl) -H .2.4Toxadiazol-5-yn-2-methyl-methyldazole, 2-aT irazine A solution of 2-methyl-1,4-azo [1,2-a] pyrazine-3-carboxylic acid (250 mg, 1411 mmol) in DCE (5 mL) is treated with Hunig's Base (0.542 mL, 3.10 mmol) and HATU (590 mg, 1552 mmol) at room temperature for about 15 minutes and about 40 ° C for about 30 minutes. The reaction is concentrated and the residue is dissolved in acetic acid (10 mL) and heated to approximately 100 ° C for about 45 minutes. The reaction is cooled to room temperature and concentrated under reduced pressure. The residue is partitioned between saturated sodium carbonate solution (10 ml) and methylene chloride (2 x 10 ml). The organic layers are dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified on silica gel using 9: 1 / CH2Cl2: MeOH. The product fractions are combined and concentrated under reduced pressure to obtain 3- [3- (3-chloro-4-isopropoxy-phenyl) - [1,4] oxadiazol-5-yl] -2-methyl-imidazole. [1, 2- a] pyrazine (133 mg, 25%) as a tan solid.
LC / MS (Table 1, Method a) Rt = 4.31 minutes, m / z 370.25 (M + H) +.
H NMR (400 MHz, DMSO-d6) d 9.43 (d.d, 1H), 9.26 (d, 1H), 8.30 (d, 1H), 8.21 (d, 1H), 8.10 (d, d, 1H), 7.40 (d, 1H), 4.84 (m, 1H), 2.84 (s, 3H), 1.36 (d , 6H).
Preparation # 24a: Preparation of 3- (3-chloro-4-isopropoxypheniU-5- (4 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy-enyl) -2,4-oxadiazole In a 25 ml microwave tube combine 4 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) benzoyl chloride (0.483 g, 1784 mmol) and (Z) -3-chloro -N'-hydroxy-4-isopropoxybenzimidamide (0.272 g, 1189 mmol) in pyridine (15 mL) to obtain an orange solution. The container is closed and the reaction is heated at approximately 200 ° C for approximately 20 minutes under microwave irradiation (Biotage Optimizer ™, 300 W). The mixture is cooled, the solvent is removed to obtain a yellow solid, which is partitioned between water (100 ml) and EtOAc (50 ml), extracted with EtOAc (2 x 30 ml), the EtOAC layer combined it is washed with water (2 x 30 ml), and concentrated to obtain a yellow solid, which is purified by chromatography on silica gel (40 g, 30% EtOAc: Heptane) to obtain 3- (3- chloro-4-isopropoxyphenyl) -5- (4 - ((2,2-dimethyl-1, 3-dioxolan-4-yl) methoxy) phenyl) -1, 2,4-oxadiazole (0.3 g, 0.674 mmol, 56.7 % yield) as white solid.
LC / MS (30_95 NH40Ac 4m GC8.olp) Rt = 3.22 minutes; MS m / z: 445.31 (M + H) +. 1 H NMR (400 MHz, d-DMSO) d ppm 8.17-8.09 (m, 2H), 8. 05 (d, J = 2.13 Hz, 1H), 7.99 (dd, J = 8.64, 2.15 Hz, 1H), 7.38 (d, J = 9.01 Hz, 1H), 7.26-7.19 (m, 2H), 4.88-4.77 (m, 1H), 4.45 (s, 1H), 4.23-4.07 (m, 3H), 3.79 (dd, J = 8.42, 6.29 Hz, 1H), 1.35 (m, 12H).
Preparation # 25: 2- (4- (chlorocarbonyl) phenoxy) tert-butyl acetate Into a 1000 ml round bottom flask was 4- (2-tert-butoxy-2-oxoethoxy) benzoic acid (0.76 g, 3.01 mmol) in dichloromethane (30.1 ml) to obtain a colorless suspension. Five drops of DMF are added to the solution. The reaction mixture is cooled by an ice bath. Oxalyl chloride (0.396 ml, 4.52 mmol) was added dropwise. The ice bath is removed, and the solution is stirred at room temperature for about 40 minutes. The reaction mixture is concentrated to obtain tert-butyl 2- (4- (chlorocarbonyl) phenoxy) acetate (0.86 g, 3.1 8 mmol, 105% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3) d ppm 8.1 0 (d, 2H), 6.95 (d, 2H), 4.61 (s, 2H), 1.49 (s, 9H).
EXAMPLE # 29 Preparation of 2- (4- (3- (3-chloro-4-isopropoxypheni-1, 2,4-oxadiazol-5-l) phenoxy) acetic acid A 25 ml microwell reaction vial is charged with 2- (4- (chlorocarbonyl) phenoxy) tert-butyl acetate (0.81 5 g, 3.01 mmol) and pyridine (1.5 ml), ag rega (Z) - 3-chloro-N'-hydroxy-4-isopropoxybenzimidamide (0.459 g, 2007 mmole). The vessel is closed and the reaction is heated to approximately 200 ° C for approximately 20 minutes under microwave irradiation (Biotage Optimizer, 300 W). The mixture is cooled, the reaction mixture is poured into HCl with stirring (10%, 100 ml), the resulting suspension is filtered, the solid is washed with HCl (5%, 20 ml) and dried to obtain solid. gray color, which is purified by RP-HPLC (A = 50 mM ammonium acetate, B = ACN, 30-95% B over the course of 25.0 minutes (flow rate 21.0 ml / minute); Thermo Hyperprep C18 column of 21.2 x 250 mm, 8 pm particles) to obtain 2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) phenoxy) acetic acid (0.246 g) , 0.633 mmole, 31.5% yield) as a white solid.
LC / MS (Table 1, Method f) Rt = 2.08 minutes; MS m / z: 389.14 (M + H) +. 1 H NMR (400 MHz, d-DMSO) d ppm 13.28-13.07 (m, 1H), 8.13 (d, J = 9.03 Hz, 2H), 8.05 (d, J = 2.13 Hz, 1H), 7.99 (dd, J = 8.64, 2.15 Hz, 1H), 7.38 (d, J = 9.04 Hz, 1H), 7.18 (d, J = 9.06 Hz, 2H), 4.85 (s, 3H), 1.35 (d, J = 6.03 Hz, 6H ).
Preparation # 26: Preparation of 5- (6- (1 H-benzofdyl, 2,31-triazo-1-1-yloxy) pyridin-3-y-3- (3-chloro-4-isopropoxypheni-1, 2,4-oxadiazole A 25 ml microwave reaction vial is loaded with (Z) -3-chloro-N'-hydroxy-4-isopropoxybenzimidamide (0.1 g, 0.437 mmol), 6-bromonicotinic acid (0.097 g, 0.481 mmol), and DCC (0.099 g, 0.481 mmoles) in ACN (2,403 mi). HOBT (0.074 g, 0.481 mmol) is added in one portion, the resulting suspension is allowed to stir at room temperature for about 10 minutes. DIEA (0.168 mL, 0.962 mmol) is added dropwise, the reaction mixture is heated to approximately 120 ° C for approximately 30 minutes under microwave irradiation (Biotage Optimizer, 300 W). The solution is cooled, the reaction mixture is partitioned between EtOAc (50 ml) and water (50 ml), the organic layer is washed with water (2 x 50 ml), and concentrated to obtain yellow solid, which is purify by chromatography on silica gel (12 g, 20% EtOAc: Heptane) to obtain 5- (6- (1H-benzo [d] [1,2] triazol-1-yloxy) pyridin-3-yl ) -3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazole (0.128 g, 0.285 mmol, 65.2% yield) as a white solid.
LC / MS (Table 1, Method a) R, = 3.74 minutes; MS m / z: 449.18 (M + H) +.
H NMR (400 MHz, d-DMSO) ppm 8.88 (dd, J = 2.25, 0.65 Hz, 1H), 8.62 (dd, J = 8.68, 2.27 Hz, 1H), 8.15 (t, J = 5.28 Hz, 2H), 7.97 (dd, J = 8.62, 2.14 Hz, 1H), 7.55 (d, J = 0.96 Hz, 1H), 7.52-7.44 (m, 2H), 7.36 (dd, J = 8.68, 0.70 Hz, 1H), 7.03 (d, J = 8.87 Hz, 1H), 4.73-4.61 (m, 1H) , 1.46-1.40 (m, 6H).
Preparation # 27: (Z) -3-bromo-N'-hydroxy-4-isopropoxybenzimidamide Combine 3-bromo-4-isopropoxybenzonitrile (0.68 g, 2.83 mmol) and hydroxylamine (0.208 ml, 3.1 2 mmol) in EtO H (20 ml). The reaction mixture is heated to about 65 ° C for about 16 hours. The reaction mixture is concentrated to obtain (Z) -3-bromo-N'-hydroxy-4-isopropoxybenzimidamide (0.76 g, 2.78 mmol, 98% yield) as pale yellow solid.
LC / MS (Table 1, Method a) Rt = 2.89 minutes; MS m / z: 275.00 (M + H) +.
Preparation # 28: Preparation of 4- (3- (3-bromo-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzonitrile A 25 ml microwave vial equipped with a stir bar is charged with 4-cyanobenzoyl chloride (0.4 g, 2.416 mmol), (Z) -3-bromo-N'-hydroxy-4-isopropoxybenzimidamide (0.5 g, 1831 mmoles) and pyridine (15 ml) to obtain an orange solution. The vessel is closed and the reaction is heated to approximately 200 ° C for approximately 20 minutes under microwave irradiation (Biotage Optimizer, 300 W). The solution is cooled, the reaction mixture is partitioned between aqueous HCI mixture (10%, 150 ml) and DCM (40 ml), the DCM layer is drained, and the aqueous layer is extracted with DCM (2x20 ml). The combined DCM layers are washed with water (2 x 20 mL) and concentrated to obtain white solid, which is purified by chromatography on silica gel (40 g, 40% EtOAc: Heptane) to obtain 4- (3- (3-bromo-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzonitrile (0.638 g, 1660 mmol, 91% yield) as a white solid.
LC / MS (Method c) Rt = 3.17 minutes; MS m / z: 386.19 (M + H) +. 1 H NMR (400 MHz, d-DMSO) ppm 8.40-8.32 (m, 2H), 8.23 (d, J = 2.13 Hz, 1H), 8.14 (dd, J = 8.14, 0.61 Hz, 2H), 8.05 (dd, J = 8.65, 2.15 Hz, 1H), 7.36 (d, J = 9.12 Hz, 1H), 4.89-4.77 (m, 1H), 1.35 (d, J = 6.03 Hz, 6H).
Preparation # 29: Preparation of 4- (3- (3-bromo-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) benzaldehyde A 1000 ml round bottom flask equipped with a septa cap equipped with a nitrogen inlet needle is charged with 4- (3- (3-bromo-4-isopropoxyphenyl) -1,2,4-oxadiazole-5- il) benzonitrile (0.64 g, 1666 mmol) in DCM (33.3 ml) to obtain a colorless solution. The reaction mixture is cooled to about -40 ° C by dry ice-ACN bath and this becomes a white suspension. Dibal-H (3.33 mL, 3.33 mmol) is added dropwise over the course of approximately 10 minutes. This is stirred for approximately an additional 60 minutes at -40 ° C. Methanol (0.1 35 ml, 3.33 mmol) is added by dripping to quench the reaction. Then the whole mixture was poured into Rochelle's salt (200 ml) with stirring. This is stirred at room temperature for 4 hours, then partitioned, the aqueous layer is extracted with DCM (2 x 50 ml), the combined DCM layers are washed with water (60 ml), dried with MgSC. Filtration and concentration allow to obtain 1 .04 g of orange oil, which is purified by chromatography on silica gel (40 g, 40% EtOAc: Heptane) to obtain 4- (3- (3-bromo-4-isopropoxyphenyl) ) -1, 2, 4-oxadiazol-5-yl) benzaldehyde (0.551 g, 1.423 mmol, 85% yield) as a pale yellow solid.
LC / MS (Method c) R, = 3.1 7 minutes; MS m / z: 388.94 (M + H) +. 1 H NMR (400 MHz, d-DMSO) ppm 10.15 (s, 1H), 8.41 (d, J = 8.20 Hz, 2H), 8.24 (d, J = 2.13 Hz, 1H), 8.20-8.14 (m, 2H) , 8.06 (dd, J = 8.64, 2.15 Hz, 1H), 7.37 (d, J = 9.11 Hz, 1H), 4.89-4.78 (m, 1H), 1.36 (d, J = 6.03 Hz, 6H).
Preparation # 30: Preparation of 3- (3-bromo-4-isopropoxyphenyl) -5- (4- (dimethoxymethyl) phenyl) -1,2,4-oxadiazole 4- (3- (3-Bromo-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) benzaldehyde (0.551 g, 1423 mmol), molecular sieve (4A, 8-12 mesh, 130 mg) are added. ) and p-toluenesulfonic acid monohydrate (0.037 g, 0.195 mmol) in trimethyl orthoformate (4 mL, 36.2 mmol) and methanol (6 mL), the reaction mixture is heated to approximately 80 ° C for about 16 hours. The solution is cooled, the reaction mixture is concentrated to obtain a gray solid, which is purified by chromatography on silica gel (12 g, 20% EtOAc: Heptane) to obtain 3- (3-bromo-4-). iso propoxyphen il) -5- (4- (di methoxymethyl) phen il) -1, 2,4-oxadiazole (0.61 g, 1366 mmol, 96% yield) as a white solid.
LC / MS (Table 1, Method a) Rt = 3.31 minutes; MS m / z: 435.03 (M + H) +. 1 H NMR (400 MHz, d-DMSO) ppm 8.25-8.19 (m, 3H), 8.05 (dd, J = 8.63, 2.14 Hz, 1H), 7.67 (d, J = 8.18 Hz, 2H), 7.35 (d, J = 9.02 Hz, 1H), 5.52 (s, 1H), 4.86-4.78 (m, 1H), 3.30 (s, 6H), 1.35 (d, J = 6.02 Hz, 7H).
Preparation # 31: Preparation of 5- (5- (4- (dimethoxymethyl) phenyl) -1,2,4-oxadiazol-3-yl) -2-isopropoxybenzonitrile A 25 ml microwave vial equipped with a stir bar is charged with 3- (3-bromo-4-isopropoxyphenyl) -5- (4- (dimethoxymethyl) phenyl) -1,2,4-oxadiazole (0.25 g, 0.577 mmole), copper cyanide (l) (0.133 g, 1485 mmole) and pyridine (15 ml). The vessel is covered and the reaction is heated to approximately 230 ° C for approximately 30 minutes under microwave irradiation (Biotage Optimizer, 300 W). The solution is cooled and the reaction mixture is concentrated. To the residue is added hydrated ferric chloride (0.8 g), concentrated hydrochloric acid (2 ml) and water (12 ml). The solution is heated to about 65 ° C for about 20 minutes, the aqueous mixture is extracted with DCM (3 x 30 ml), the combined DCM layers are washed with FeCl 3 solution (2 x 20 ml), then water (2 ml). x 20 ml), dried (brine, MgSO4) and concentrated to obtain a yellow solid, which was purified by chromatography on silica gel (40 g, 20% EtOAc: Heptane) to obtain 5- (5- (4- (dimethoxymethyl) phenyl) -1,2,4-oxadiazol-3-yl) -2-isopropoxybenzonitrile (0.086 g, 0.227 mmol, 39.3% yield) as a pale yellow solid which is used in the following step without further purification.
Preparation # 32: Preparation of 5- (5- (4-formylphen) -1, 2,4-oxadiazol-3-yl) -2-isopropoxybenzonitrile 5- (5- (4- (Dimethoxymethyl) phenyl) -1,2,4-oxadiazol-3-yl) -2-isopropoxybenzonitrile (0.086 g, 0.227 mmol) and p-toluenesulfonic acid monohydrate (0.043 g, 0.227) are added. mmoles) in acetone (10 mL) to obtain a colorless solution. The reaction mixture is heated to approximately 60 ° C for approximately 2 hours. The solution is cooled, the reaction mixture is concentrated, the residue is purified by chromatography on silica gel (1 2 g, 50% EtOAc: Heptane) to obtain 5- (5- (4-formylphenyl) -1,2. , 4-oxadiazol-3-yl) -2-isopropoxybenzonitrile (0.077 g, 0.231 mmol, 1% yield) as a white solid.
LC / M S (Table 1, Method f) R, = 2.88 minutes; MS m / z: 334.08 (M + H) +.
EXAMPLE # 30 Preparation of 1- (4- (3- (3-cyano-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) azetidine-3-carboxylic acid 5- (5- (4-Formylphenyl) -1,4,4-oxadiazol-3-yl) -2-isopropoxybenzonitrile (0.077 g, 0.231 mmol) and azetidine-3-carboxylic acid (0.028 g, 0.277 mmol) are combined . in methanol (11.55 ml) and DCE (11.55 ml) in a sealed vial. Acetic acid (0.066 ml, 1155 mmol) is added. The reaction mixture is stirred at room temperature for about 2 hours. P-cyanoborohydride (0.265 g, 0.570 mmol) is added and the reaction is stirred for approximately 24 hours. The solution is filtered, the solid is washed with methylene chloride and methanol, and the filtrate is concentrated to obtain a white solid, which is recrystallized from methanol (5 ml) to obtain 1 - (4- (3- (3-cyano-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) azetidine-3-carboxylic acid (0.025 g, 0.060 mmol, 25.9% yield) as a white solid.
LC / S (Table 1, Method a) Rt = 2.10 minutes; MS m / z: 420.26 (M + H) +. 1 H NMR (400 MHz, d-DMSO) ppm 8.35-8.28 (m, 2H), 8.17-8.11 (d, J = 8.00 Hz, 2H), 7.56-7.50 (m, 8.69 Hz, 3H), 4.98-4.89 ( m, 1H), 3.68 (s, 2H), 3.43 (s, 2H), 3.25-3.23 (m, 3H), 1.38 (d, J = 6.03 Hz, 6H).
EXAMPLE # 31 Preparation of 1- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) cyclopropanecarbonitrile A 20 ml microwave vial is charged with 4- (1-cyanocyclopropyl) benzoic acid (720 mg, 3.85 mmol), (Z) -3-chloro-N'-hydroxy-4-isopropoxybenzimidamide (880 mg, 3.85 mmol), DCC (873 mg, 4.23 mmol), HOBT (648 mg, 4.23 mmol), ACN (10 mL), and DIEA (1478 mL, 8.46 mmol). The vial is capped and heated to approximately 160 ° C by microwave irradiation for approximately 25 minutes (300 W max.). The solvent is removed under reduced pressure and the crude oil is purified by flash chromatography (Analogix® system, heptane / ethyl acetate, 0-45% ethyl acetate over the course of 30 minutes; 80 g column, flow rate 60 ml / minute). The fractions containing the product are combined, subjected to rotary evaporation, and dried in a vacuum oven overnight to obtain 1- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2, 4-oxadiazol-5-yl) phenyl) cyclopropanecarbonitrile (347 mg, 23.8%) as a yellow solid.
LC / MS (Table 1, Method c) Rt = 3.19 minutes, m / z 380.43 (+ H) +. 1 H NMR (400 MHz, DMSO)) d ppm 8.22-8.12 (m, 2H), 8.05 (d, 1H), 7.99 (dd, 2.14 Hz, 1H), 7.62-7.55 (m, 2H), 7.38 (d, 1H), 4.82 (td, 1H), 1.90 (q, 2H), 1.67 (q, 2H), 1.38-1.33 (m, 6H).
Preparation # 32a: Preparation of 1- (4- (3- (3-chloro-4-isoproDQxyphenyl) -1,2,4-oxadiazole-5-M) phenyl) cyclopropanecarbaldehyde A 100 ml round bottom flask is charged with 1- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) cyclopropanecarbonitrile (300 mg, 0.790 mmol) ) and dichloromethane (8 ml) and then cooled to about -40 ° C. Dibal-H (0.869 mL, 0.869 mmol) is added via syringe and the reaction mixture is allowed to warm to room temperature overnight. The reaction is quenched by addition of MeOH (4 mL), and aqueous Rochelle's salt (4 mL). The layers are separated and the aqueous layer is extracted with DCM (3 x 25ml). The organic layers are washed with saturated sodium bicarbonate solution, then dried with MgSO 4, and concentrated. To a solution of the crude material in 3 ml of THF are added 3 ml of 1N HCl. The mixture is stirred room temperature for about 1 hour. The mixture is subjected to rotary evaporation to remove the THF. The material is then purified by flash column chromatography (Analogix®, 40 g column, 0-40% ethyl acetate in heptane over the course of 30 minutes, flow rate 30 ml / minute). The fractions containing product are combined and concentrated to obtain 1- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) cyclopropancarbaldehyde (144 mg, 48 %) as a yellow sticky solid.
LC / S (Table 1, Method c) R, = 3.11 minutes, m / z 383.50 (M + H) +.
EXAMPLE # 33 Preparation of 3 - ((1- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) cyclopropyl) methylamino) propane acid, acid trifluoroacetic A 20 ml vial is loaded with 1- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) cyclopropanecarbaldehyde (46 mg, 0.120 mmol), methanol (2.5 ml), 3-aminopropanoic acid (10.70 mg, 0.120 mmol) and acetic acid (0.034 ml, 0.601 mmol).
The vial is capped and the mixture is stirred for approximately 30 minutes at room temperature. Then, sodium cyanoborohydride (7.55 mg, 0.120 mmol) is added in an aliquot and the reaction is stirred overnight at room temperature. The solvents are removed under reduced pressure and the crude material is purified by RP-HPLC (A = 0.1% TFA, B = ACN, 30% to 95% B over the course of 30 minutes at 21.0 ml / minute, UV? = 254 nm; Thermo Hyperprep HS C18 column, 8 pm, 250 x 21.2 mm). The fractions containing the product are subjected to rotary evaporation and lyophilized to obtain 3 - ((1- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) acid. ) phenyl) cyclopropyl) methylamino) propane (27 mg, 40%) as the trifluoroacetic acid salt.
LC / MS (Table 1, Method c) Rt = 2.07 minutes, m / z 456.25 (M + H) +.
H NMR (400 MHz, methanol) d ppm 8.22 (d, 2H), 8.11 (d, 1H), 8.03 (dd, 1H), 7.69 (d, J = 8.19 Hz, 2H), 7.24 (d, 1H), 4.80-4.76 (m.H.), 3.36 (s, 2H), 3.13 (t "2H), 2.44 (t, 2H), 1.40 (d, 6H), 1.17 (d, 4H).
EXAMPLE # 34 Preparation of N- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) -1 - (2, 2-di metí 1-1, 3-d) oxolan-4-l) methanamine Charge 4- (3- (3-chloro-4-isopropoxyphenyl) -1,4,4-oxadiazol-5-yl) benzaldehyde (150 mg, 0.438 mmol), (2,2-dimethyl-1,3-dioxolan) -4-μl) methanamine (0.057 ml, 0.438 mmol), methanol (4 ml), and acetic acid (0.125 ml, 2.188 mmol) in a 25 ml flask equipped with a stir bar. The mixture is stirred for about 10 minutes at room temperature under nitrogen. Sodium cyanoborohydride (27.5 mg, 0.438 mmol) is added in one portion, and the reaction mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the crude material is purified by RP-HPLC (A = 50 mM ammonium acetate, B = ACN; 40% to 80% of B over the course of 30 minutes at 21.0 ml / min; UV? = 254 nm; Thermo Hyperprep HS C18 column, 8 pm, 250 x 21.2 mm). The fractions containing the product are combined, rotated and lyophilized to obtain N- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl. ) -1 - (2,2-dimethyl-1,3-dioxolan-4-yl) methanamine (130.9 mg, 64.7%) as a white solid.
LC / MS (Table 1, Method c) R, = 2.59 minutes, m / z 458.62 (M + H) +. 1 H NMR (400 MHz, DMSO) d ppm 8.13 (d, 2H), 8.06 (d, 1H), 8.00 (dd, 1H), 7.61 (d, 2H), 7.39 (d, 1H), 4.82 (septet, 1H) ), 4.15 (p, 1H), 3.99 (dd, 1H), 3.84 (s, 2H), 3.63 (dd, 1H), 2.61 (ddd, 2H), 1.86 (s, 4H), 1.35 (d, 6H) 1.26 (s, 3H).
EXAMPLE # 35 Preparation of 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzylamino) propane-1,2-diol To a solution of N- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) -1- (2,2-dimethyl-1, 3- dioxolan-4-yl) methanamine (108 mg, 0.236 mmol) in THF (4 mL) is added aqueous 1N HCl (0.778 mL, 0.778 mmol). The reaction is heated to about 65 ° C under nitrogen for about 90 minutes. The heating is stopped and the reaction is neutralized by addition of aqueous 1 N NaOH (0.778 ml, 0.778 mmol). The THF is removed under reduced pressure and the remaining aqueous solution is basified (pH approx. 9) by the addition of 0.1 N NaOH, at which point a white precipitate forms. The solid is collected by vacuum filtration, and washed with 0.1N NaOH (3 x 10 ml). The solid is dried in a vacuum oven overnight to obtain 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -, 2,4-oxadiazol-5-yl) benzylamino) propane-1, 2 -diol (31.7mg, 32%) as a solid whitish LC / MS (Table 1, Method c) Rt = 1.90 minutes, m / z 418.47 (M + H) +. 1 H NMR (400 MHz, methanol) d ppm 7.22 (d, J = 8.68 Hz, 1H), 7.60 (d, 2H), 8.01 (dd ,, 1H), 8.10 (d, 1H), 8.16 (d, 2H) , 4.78 (septet, 1H), 2.76 (dd, 1H), 2.63 (dd, 1H), 3.52 (d, 2H), 3.90 (d, 2H), 3.78 (m, 1H), 1.40 (d, 6H).
Preparation # 33: Preparation of (Z) -methyl-3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) acrylate A two-neck round bottom flask is charged with methyl 2- (bis (2,2,2-trifluoroethoxy) phosphoryl) acetate (0.235 ml, 1109 mmol), 18-crown-6 (1465 mg, 5.54 mmol) and THF (15 mi). The mixture is then cooled to about -78 ° C under a nitrogen atmosphere. Potassium bis (trimethylsilyl) amide (221 mg, 1,109 mmol) is added and the mixture is stirred for a few minutes. 4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzaldehyde (380 mg, 1,109 mmol) is added and the mixture is stirred at about -78 ° C for approximately 90 minutes and then let it warm up to room temperature during the night. The reaction is quenched by the addition of saturated NH 4 Cl (aqueous). The mixture is separated and the aqueous layer extracted with ether (3 x 10 ml). The combined organics are dried with MgSO 4 and concentrated to obtain an off-white solid. The solid is triturated with MeOH and collected by vacuum filtration and washed with MeOH (3 x 10 mL). The collected solid is dried overnight in a vacuum oven to obtain (Z) -methyl-3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl. ) pheny1) acrylate (325 mg, 73.5%).
LC / MS (Table 1, Method c) Rt = 3.22 minutes, m / z 399.16 (M + H) +. 1 H NMR (400 MHz, DMSO) d ppm 8.18 (d, 2H), 8.06 (d, 1H), 8.01 (dd, 1H), 7.79 (d, 2H), 7.40 (d, 1H), 7.18 (d, 1H) ), 6.84 (d, 1H), 6.20 (d, 1H), 4.83 (septet, 1H), 3.67 (s, 3H), 1.35 (d, 6H).
EXAMPLE # 36 Preparation of methyl trans-2- (4- (3- (3-chloro-4-isopropoxyphertyl) -1,2,4-oxadiazol-5-yl) phenycyclopropanecarboxylate To a stirred suspension of trimethylsulfoxonium iodide (234 mg, 1065 mmol) in DMSO (5.0 ml) under nitrogen, add NaH in portions (42.6 mg, 1065 mmol) in a water bath to maintain the reaction between approximately 25 g. -30 ° C. After the evolution of hydrogen is complete, a solution of (Z) -methyl-3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl is added. ) acrylate (386 mg, 0.968 mmol) in DMSO (5.00 ml) by dropping, keeping the reaction temperature at or below about 35 ° C. After the addition is complete, the reaction is stirred at room temperature for about an hour and a half and then heated to about 50 ° C for about 2 hours. Then 50 ml of water is added to the reaction, and the reaction is allowed to stir at room temperature overnight. The reaction mixture is diluted with saturated aqueous sodium chloride, and the aqueous layer is extracted 3 x with 75 ml of EtOAc. The organic layers are combined, dried with MgSO 4, and concentrated. The crude material is purified by RP-HPLC (A = 50 mM ammonium acetate, B = ACN; 30% to 100% B over the course of 30 minutes at 21.0 ml / min; UV? = 254 nm; Thermo Hyperprep HS C18 column, 8 pm, 250 x 21.2 mm). The fractions containing the product are combined, concentrated and lyophilized to obtain trans-2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) Methyl cyclopropancarboxylate (155 mg, 39%) as a white solid.
LC / MS (Table 1, Method c) R, = 3.27 minutes, m / z 413.17 (M + H) +. 1 H NMR (400 MHz, DMSO) d ppm 8.08 (d, 2H), 8.06 (d, 1H), 7.99 (dd, 1H), 7.47 (d, 2H), 7.39 (d, 1H), 4.82 (septet, 1H) ), 3.66 (s, 3H), 2.59 (ddd, 1H), 2.12 (ddd, 1H), 1.58 (ddd, 1H), 1.53 (ddd, 1H), 1.35 (d, 6H).
EXAMPLE # 37 Preparation of trans-2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) cyclopropanecarboxylic acid To a suspension of (1S, 2S) -methyl-2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) phenyl) cyclopropanecarboxylate (111 mg, 0.269 mmole) in ethanol (5 mL) is added 2N NaOH (5 mL, 10.00 mmol). The mixture is stirred under nitrogen at room temperature overnight. The reaction mixture is neutralized by the addition of acetic acid, and then acidified with a few drops of aqueous 1N HCl (pH about 2). A white solid is precipitated and collected by filtration, washed with 0.1 N HCl (3 x 5 mL), and dried under vacuum to obtain trans-2- (4- (3- (3-chloro-4) acid. isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) phenyl) cyclopropanecarboxylic acid (64 mg, 59%).
LC / MS (Table 1, Method f) Rt = 2.99 minutes, m / z 399.16 (M + H) +. 1 H NMR (400 MHz, DMSO) d ppm 8.07 (d, 2H), 8.05 (d, 1H), 7.99 (dd, 1H), 7.45 (d, 2H), 7.38 (d, 1H), 4.82 (septet, 1H), 2.54 (m, 1H), 1.97 (m, 1H), 1.53 (td, 1H) ), 1.46 (ddd, 1H), 1.35 (d, 6H).
EXAMPLE # 38 Preparation of 5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) isoindoline-2-carboxylic acid tert-butyl ester To a solution of 2- (tert-butoxycarbonyl) isoindoline-5-carboxylic acid (190 mg, 0.722 mmol) in ACN (3 mL) in a 5 mL microwave vial is added HOBT (330 mg, 2.16 mmol), DCC (298 mg, 2.16 mmol), and DIEA (0.115 ml, 0.656 mmol). The mixture is stirred at room temperature for approximately 16 hours. Then (Z) -3-chloro-N'-hydroxy-4-isopropoxybenzimidamide (150 mg, 0.656 mmol) (prepared by General Procedure B) is added and the reaction is heated to about 150 ° C under microwave irradiation (300 W max.) For approximately 20 minutes. After cooling, the reaction mixture is filtered, concentrated, and purified by Analogix® FCC system using the 40 g RediSep ™ column, with a gradient of 0-40% EtOAc / heptane over the course of 30 minutes at a time. Flow rate of 30 ml / minute. Fractions containing the product are combined, evaporated rotating, and dried in a vacuum oven to obtain 5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) isoindoline-2-carboxylic acid tert-butyl ester (46.2 mg, 15.5%).
LC / MS (Table 1, Method c) R, = 3.40 minutes, m / z 456.22 (M + H) +. 1 H NMR (400 MHz, DMSO) d ppm 8.16 (d, 1H), 8.10 (s, 1H), 8.05 (d, 1H), 7.61 (m, 1H), 7.39 (d, 1H), 4.82 (septet, 1H) ), 4.70 (d, 4H), 1.48 (s, 9H), 1.35 (d, 6H).
EXAMPLE # 39 Preparation of 3- (3-chloro-4-isopropoxyphenyl) -5- (isoindolin-5-iM-1, 2,4-oxadiazole, Trifluoroacetic acid To a solution of tert-butyl 5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) isoindoline-2-carboxylate (41 mg, 0.090 mmol) in DCM ( 2 ml) TFA (0.5 ml, 6.49 mmol) is added. The mixture is stirred at room temperature under nitrogen for about 30 minutes. After 30 minutes, ether is added slowly to the mixture, until it becomes turbid and a white precipitate forms. The solid is collected by filtration and washed with ether (3 x 10 mL). The collected solid is then dried in a vacuum oven to obtain 3- (3-chloro-4-isopropoxyphenyl) -5- (isoindolin-5-yl) -1, 2,4-oxadiazole as the TFA salt (26.7 mg , 62.6%).
LC / MS (Table 1, Method c) Rt = 2.29 minutes, m / z 356.17 (M + H) \ 1 H NMR (400 MHz, DMSO) d ppm 9.46 (s, 2H), 8.27 (s, 1H), 8.20 (d, 1H), 8.00 (d, 1H), 7.70 (d, 1H), 7.41 (d, 1H) ), 4.83 (septet, 1H), 4.64 (d, 4H), 1.35 (d, 6H).
Preparation # 34: Preparation of methyl 3- (5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) isoindolin-2-yl) propanoate 3- (3-Chloro-4-isopropoxyphenyl) -5- (isoindolin-5-yl) -1,2,4-oxadiazole (16.7 mg, 0.047 mmol) is added to a 2 ml microwave vial equipped with a bar of agitation. Methyl acrylate (8.45 μ ?, 0.094 mmol), and methanol (1.0 ml) are added, the vial is capped, and the reaction is heated to about 90 ° C for about 20 minutes under microwave irradiation (300 W). After about 20 minutes, another aliquot of methyl acrylate (8.45 μ ?, 0.094 mmol) is added, the vial is resealed, and heated to approximately 110 ° C for approximately 40 minutes under microwave irradiation (300 W) . The reaction is then concentrated and dried in vacuo overnight to obtain 3- (5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) isoindolin-2-yl. ) crude methyl propanoate as a yellow oil (21.6 mg, 104%). The product is used without further purification.
LC / MS (Table 1, Method c) R, = 2.85 minutes, m / z 442.45 (M + H) + EJ EM PLO # 41 Preparation of 3- (5- (3- (3-chloro-4-isopropoxypheni-1 .2.4 oxadiazol-5-yl) isoindolin-2-yl) propane acid, Hydrochloric Acid To a solution of methyl 3- (5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) isoindolin-2-yl) propanoate (21 mg, 0.048 mmol) in ethanol (1 ml), 2 M aqueous NaOH (1 ml, 2,000 mmol) was added. The reaction is stirred at room temperature under a nitrogen atmosphere for about 4 hours. The reaction mixture is then acidified to approximately pH of 1 by addition of 2 N HCl, at which time a precipitate is formed. The solid is collected by filtration and washed with water (3 x 5 ml). The solid is then dried in a vacuum oven overnight to obtain 3- (5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) isoindolin-2-acid. il) propanic as the hydrochloride salt (1 0.2 mg, 46.2%).
LC / MS (Table 1, Method c) R, = 1.86 minutes, m / z 428.20 (M + H) +. 1 H NMR (400 MHz, DMSO) d ppm 12.12 (m, 1H), 8.23 (s, 1H), 8.19 (d, 1H), 8.07 (d, 1H), 8.01 (dd, 1H), 7.68 (d, 1H) ), 7.41 (d, 1H), 4.83 (septet, 1H), 4.72 (s, 4H), 3.58 (t, 2H), 2.84 (t, 2H), 1.36 (d, 6H) EXAMPLE # 42 Preparation of (Z) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1.2.4-oxadiazol-5-yl) phenyl) acrylic acid To a solution of (Z) -methyl-3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) acrylate (30 mg, 0.075 mmol) in EtOH (2 mL) is added 2N aqueous NaOH (2 mL). The reaction is stirred at room temperature, under nitrogen, for about 2 hours. The reaction is acidified by the addition of 1N HCl, until a precipitate forms. The solid is collected by filtration, washed with 0.2 N HCl, and dried in a vacuum oven to obtain (Z) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2 acid. , 4-oxadiazol-5-yl) phenyl) acrylic (8.2 mg, 28.3%).
LC / MS (Table 1, Method c) Rt = 2.64 minutes, m / z 385.12 (M + H) +. 1 H NMR (400 MHz, DMSO) d ppm 13.11-12.20 (m, 1H), 8.15 (d, 2H), 8.04 (d, 1H), 7.99 (dd "1H), 7.78 (d, 2H), 7.37 (d , 1H), 7.03 (d, 1H), 6.12 (d, 1H), 4.81 (septet, 1H), 1.33 (d, 6H) Preparation # 35: Preparation of 3-chloro-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) aniline (Z) -3-chloro-N'-hydroxy-4-isopropoxybenzimidamide (0.5 g, 2187 mmol), 4-amino-2-chlorobenzoic acid (0.413 g, 2,405 mmol), DCC (0.496 g, 2,405 mmol) are placed. , HOBT (0.368 g, 2.405 mmol) in an 80 ml microwave vial and ACN (12.01 ml) is added. The reaction mixture is stirred for about 5 minutes at room temperature before the addition of DIEA (0.840 ml, 4.81 mmol). The reaction mixture is heated to about 120 ° C for about 30 minutes in a microwave. CCF (50% EA / Hept) indicates 4 spots Rf 0.8, 0.6, 0.5 and 0.3. LC / MS (2007_9349) indicated by UV of 16% (2.61 minutes) to (M + H) 364.31. The solvent is removed and the crude material is purified by FCC (50% EA / Hept) to obtain 3-chloro-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazole-5 - il) aninine (534 mg, 1466 mmoles, 67.1% yield).
LC / MS (Table A, Method b) indicates 99% by UV (3.10 minutes) and 92% by ELSD (3.06 minutes) (M + H) + 364.12 EXAMPLE # 43 Preparation of 3- (3-chloro-4- (3- (3-chloro-4-isopropoxy-phenyl) -1,2,4-oxadiazol-5-yl-phenylamino) -cyclobutanecarboxylic acid 3-chloro-4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-i) ani Ine (200 mg, 0.549 mmol) and 3-oxocyclobutanecarboxylic acid (62.7 mg) , 0.549 mmol) in methanol (1280 [mu] g) at room temperature is added acetic acid (842 [mu], 14.72 mmol). The reaction mixture is stirred at room temperature for about 10 minutes before the addition of sodium cyanoborohydride (17.25 mg, 0.275 mmole) as a single portion. The reaction mixture is stirred at room temperature overnight. The solvent is removed and the crude material is purified by FCC (50% EA / Hept) to obtain 3- (3-chloro-4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4 acid. -oxadiazol-5-yl) phenylamino) cyclobutanecarboxylic (135 mg, 0.292 mmol, 53.2% yield) as a white solid.
LC / MS (Table A, Method b) indicates 100% by UV (3.06 minutes) to (M + H) + 364.12.
Preparation # 36: 4- (3- (3-chloro-4-isopropoxyphenyl) -, 2,4-oxadiazol-5-yl) aniline Combine (Z) -3-chloro-N'-hydroxy-4-isopropoxybenzimidamide (1 g, 4.37 mmole), 4-aminobenzoic acid (0.660 g, 4.81 mmole), HOBT (0.737 g, 4.81 mmole), DCC (0.992) g, 4.81 mmol) and DI EA (1680 ml, 9.62 mmol) in a microwave vial. The reaction mixture is heated in the microwave for about 20 minutes at about 50 ° C. The reaction mixture is filtered to remove the urea formed in the reaction and the solvent is removed in vacuo. The crude material is purified by FCC (50% ethyl acetate / heptane) to obtain 4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) aniline (729 mg , 2.21 1 mmole, 50.6% yield) as a whitish solid: LC / M S (Table A, Method b) 3.00 minutes, (M + H) + 330.1 3.
EJ EM PLO # 44 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclobutanecarboxylic acid 4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) aninyl (250 mg, 0.531 mmol) in methanol (1478 μl) at room temperature was added 3-oxocyclobutanecarboxylic acid (60.5 mg, 0.531 mmol) followed by acetic acid (81 4 μ ?, 14.22 mmol). The reaction mixture is stirred at room temperature for approximately 5 minutes before the addition of sodium cyanoborohydride (1 6.67 mg, 0.265 mmol). The reaction mixture is stirred overnight at room temperature. The solvent is removed and the crude material is purified by FCC (50% ethyl acetate / heptane) to obtain 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazole acid. -5-yl) phenylamino) cyclobutanecarboxylic acid (139 mg, 0.302 mmol, 56.9% yield) as a white solid.
LC / MS (Table A, Method b) 2.89 minutes, (M + H) + 428.20.
Preparation # 37: 3-Hydroxy-cyclobutanecarboxylic acid tert-butyl ester A solution of tert-butyl 3-oxocyclobutanecarboxylate (prepared in accordance with RP Lemieux, J. Org. Chem. (1993), Vol. 58, No. 1, pp. 100-110) (10.5 g, 61.7 mmol) in EtOH (110 mL) is treated with sodium borohydride (2173 mL, 61.7 mmol) in portions at room temperature (cold water bath is used to maintain the reaction temperature below about 30 ° C) and the reaction is stirred at room temperature. room temperature for about 2 hours. The reaction is diluted with saturated NaCl solution (300 mL) and extracted with EtOAc (300 mL). The EtOAc layer is washed with saturated salt solution (3 x 200 ml), dried over sodium sulfate, filtered and concentrated. The crude product is further purified by distillation, taking the boiling fraction at about 88-90 ° C at 3 Torr to obtain 3-hydroxy-cyclobutanecarboxylic acid tert-butyl ester (7.37 g, 70%) as a colorless oil.
LC / MS (Table 1, Method a), Rt = no peak, no parent ion. 1 H NMR (400 MHz, DMSO-d 6) d ppm 5.12 (d, J = 6.9, 1H), 3.97-3.88 (m, 1H), 2.46-2.29 (m, 3H), 1.94-1.86 (m, 2H), 1.39 (s, 9H).
Preparation # 38: 4-hydroxy-cyclohexanecarboxylic acid tert-butyl ester To a suspension of trans-4- acid hydroxycyclohexanecarboxylic acid (3.25 g, 22.54 mmol) in dichloroethane (150 ml) is added tert-butyl 2,2,2-trichloroacetimidate (16.15 ml, 90 mmol) and the mixture is heated to approximately 80 ° C under nitrogen for about 4 days . The reaction is cooled to room temperature, filtered and the white solid is rinsed with 10 ml of methylene chloride. The organic layer is washed with saturated sodium bicarbonate solution (100 ml), filtered and concentrated. The residue is triturated twice with 10 ml of 80:20 / heptane: ethyl acetate and filtered. The filtrate is injected onto a column of silica gel and eluted with a gradient of 20% to 60% ethyl acetate in heptane over the course of about 40 minutes. The combined product fractions are concentrated to an oil which solidifies upon drying to constant vacuum weight to obtain 4-hydroxy-cyclohexanecarboxylic acid tert-butyl ester (1.95 g, 45%) as a white solid.
LC / MS (Table 1, Method f) Rt = no peak, no parent ion. H NMR (400 MHz, DMSO-d6) d ppm 4.52 (d, J = 4.3, 1H), 3.38-3.29 (m, 1H), 2.10-2.02 (m, 1H), 1.82-1.79 (m, 4H), 1.38 (s, 9H), 1.34-1.24 (m, 2H), 1.18-1.08 (m, 2H).
Preparation # 39: 3-hydroxy-cyclopentanecarboxylic acid ethyl ester A solution of ethyl 3-oxocyclopentanecarboxylate (2.00 g, 12.81 mmol) in EtOH (20 mL) is treated with sodium borohydride (0.451 mL, 12.81 mmol) in portions at room temperature (water bath at room temperature to control the exotherm ) and the reaction is stirred overnight. The reaction is quenched with 2N HCl to approximately pH = 2 and extracted with CH 2 Cl 2, washed with water, dried with sodium sulfate, filtered and concentrated to oil. The crude product is further purified on silica gel using a gradient of 20-40% ethyl acetate in heptane. The fractions of pure and concentrated product are combined until constant weight. NMR indicates an isomer ratio of approximately 3: 7. 1 H NMR (400 MHz, DMSO-d 6) d ppm 4.52-4.50 (m, 1H), 4.19-4.15 (m, 0.3H), 4.08-4.02 (m, 2.7H), 2.94-2.86 (m, 0.3H) , 2.74-2.66 (m, 0.7H), 2.08-1.46 (m, 6H), 1.19-1.15 (m, 3H).
Preparation # 40: Acid (1R. 3S) -3- (4-cyano-phenylamino) -cyclopentanecarboxylic acid To a round-bottomed flask is added 4-fluorobenzonitrile (1705 g, 14.08 mmol), (1R, 3S) -3-aminocyclopentanecarboxylic acid (2 g, 15.49 mmol), potassium carbonate (4.28 g, 31 mmol), DMSO ( 45 mi) and water (1 ml). The mixture is heated to approximately 100 ° C for about 16 hours. The mixture is then cooled to room temperature and partitioned between water (250 ml) and EtOAc (250 ml). The aqueous layer is extracted with EtOAc (2 x 100 mL). The combined organic layers are dried with Na 2 SO 4, filtered and concentrated to dryness to obtain (1R, 3S) -3- (4-cyano-phenylamino) -cyclopentanecarboxylic acid (1.83 g, 7.87 mmol, 55.9%) as an off-white solid.
LC / MS (Table 1, Method b) R, = 1.94 minutes, m / z 231 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 12.1 (s, 1H), 7.44- 7.42 (d, 2H), 6.74-6.72 (d, 1H), 6.63-6.61 (d, 2H), 3.81-3.74 ( m, 1H), 2.79-2.71 (m, 1H), 2.37-2.27 (m, 1H), 2.01-1.93 (m, 1H), 1.89-1.83 (m, 2H), 1.65-1.58 (m, 1H), 1.54-1.45 (m, 1H).
Preparation # 41: Preparation of (1R. 3S) -ethyl 3- (4-cyanophenylamino) cyclopentanecarboxylate A solution of (1 R, 3S) -3- (4-cyano-phenylamino) -cyclopentanecarboxylic acid (1.83 g, 7.87 mmol) in DMF (79 ml) is treated with DIEA (2.78 ml, 15.89 mmol) and HATU (3.63 g, 9.54 mmol) at room temperature. Then EtOH (0.696 mL, 11.92 mmol) is added and the reaction is stirred for about 16 hours.
The reaction is concentrated under reduced pressure and the residue is partitioned between saturated sodium carbonate solution (100 ml) and EtOAc (2 x 100 ml). The organic layers are dried with Na 2 SO 4, filtered and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (120 g, 0-60% EtOAc: Heptane) to obtain (1R, 3S) -ethyl 3- (4-cyanophenylamino) -cyclopentanecarboxylate (1.66 g, 6.43 mmol, 81% ) as an oil.
LC / MS (Table 1, Method b) R, = 2.38 minutes, m / z 259 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 7.44-7.42 (d, 2H), 6. 74-6.72 (d, 1H), 6.63-6.61 (d, 2H), 4.08-4.03 (q, 2H), 3.82-3.77 (m, 1H), 2.87-2.79 (m, 1H), 2.35-2.28 (m , 1H), 2.03-1.94 (m, 1H), 1.90-1.85 (m, 2H), 1.63-1.59 (m, 1H), 1.53-1.47 (m, 1H), 1.18-1.14 (t, 3H).
Preparation # 42: (1 R.3S) -ethyl 3- (2-bromo-4-cyanofen Mam ino) -cyclopentanecarboxylate Sodium perborate monohydrate (0.353 g, 3.54 mmol) is added dropwise to a suspension of KBr (0.481 g, 4.04 mmol), (1R, 3S) -ethyl 3- (4-cyanophenylamino) cyclopentanecarboxylate (0.870 g, 3.37 mmol) and ammonium molybdate tetrahydrate (0.017 ml, 0.034 mmol) in acetic acid (11.2 ml). The reaction is stirred for about 16 hours at room temperature and then concentrated acetic acid is removed under reduced pressure. Saturated NaC03 solution (50 ml) is added and the residue is extracted with EtOAc (100 ml). The organic layer is washed with a saturated Na 2 CO 3 solution, dried with Na 2 SO 4, filtered and concentrated under reduced pressure to obtain (1R, 3S) -ethyl 3- (2-bromo-4-cyanophenylamino) -cyclopentanecarboxylate (1112 g , 3.30 mmoles, 98%) as a cinnamon oil.
LC / MS (Table 1, Method b) R, = 2.64 minutes, m / z 337 (M + H) \ 1 H NMR (400 MHz, DMSO-d 6) d ppm 7.89 (d, 1H), 7.61-7.58 (dd, 1H), 6.85-6.82 (d, 1H), 5.77-5.75 (d, 1H), 4.10-4.05 ( q, 2H), 4.04-395 (m, 1H), 2.94-2.86 (m, 1H), 2.29-2.24 (m, 1H), 2.02-1.80 (m, 4H), 1.71-1.63 (m, 1H), 1.19-1.16 (t, 3H).
Preparation # 43: Preparation of (1R.3S) -ethyl 3- (4-cyano-2-methylphenylamino) -cyclopentanecarboxylate A solution of (1R, 3S) -ethyl 3- (2-bromo-4-cyanophenylamino) cyclopentanecarboxylate (1.12 g, 3.32 mmol), cesium carbonate (3.25 g, 9.96 mmol), trimethylboroxin (1668 g, 6.64 mmol) and bis (triphenylphosphine) palladium (ll) chloride (0.117 g, 0.166 mmol) in DME (16.6 ml) and water (5.5 ml) is purged with nitrogen for approximately 15 minutes. The reaction is stirred at about 90 ° C and after about 4 hours the reaction is cooled to room temperature. DME is removed under reduced pressure and the residue is partitioned between EtOAc (25 mL) and saturated NaC03 solution (25 mL). The aqueous layer is extracted again with EtOAc (50 ml) and the combined organic layers are dried with Na 2 SO 4, filtered and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (120 g, 0-40% EtOAc: Heptane) to obtain (1R, 3S) -ethyl 3- (4-cyano-2-methylphenylamino) cyclopentanecarboxylate (0.66 g, 2.42 mmol , 73%) as an oil.
LC / MS (Table 1, Method b) Rt = 2.61 minutes, m / z 273 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 7.43-7.40 (dd, 1H), 7.33 (s, 1H), 6.66-6.63 (d, 1H), 5.55-5.53 (d, 1H), 4.09-4.04 ( q, 2H), 3.95-3.87 (m, 1H), 2.82-2.90 (m, 1H), 2.31-2.24 (m, 1H), 2.08 (s, 3H), 2.00-1.87 (m, 3H), 1.85- 1.77 (m, 1H), 1.68-1.61 (m, 1H), 1.19-1.15 (t, 3H).
Preparation # 44: Preparation of 4- (4-fluoropiperidin-1 -iO-3- (trifluoromethyl) benzonitrile In a 200 ml round bottom flask, 4-fluoro-3-trifluoromethyl-benzonitrile (5.43 g, 28.7 mmol), 4-fluoropiperidine hydrochloride (4.407 g, 31.6 mmol), and carbonate are added. of potassium (9.92 g, 71.7 mmoles) in DMF (50 ml) to obtain a tan suspension. The mixture is heated to approximately 90 ° C for about 40 hours. After cooling to room temperature, the reaction mixture is partitioned between water (75 ml) and ethyl acetate (75 ml). The organic layer is washed with water (50 ml) and brine (50 ml). The organic layer is dried with anhydrous magnesium sulfate and the solvent is removed in vacuo. The crude material is purified by normal phase chromatography with gradient on silica gel (0% to 100% ethyl acetate in heptane through 6 column volumes) to obtain 4- (4-fluoropiperidin-1-yl) - 3- (trifluoromethyl) benzonitrile (4.87 g, 17.9 mmol, 62% yield).
LC / MS Rf = 7.51 minutes; MS m / z: (M + H + AcOH) +. (Table 1, Method n). 1 H NMR (400 MHz, DMSO-d 6) ppm 8.17 (d, J = 1.98, 1H), 8.06 (dd, J = 2.01, 8.51, 1H), 7.59 (d, J = 8.53, 1H), 4.87 (tdd, J = 3.26, 6.66, 48.35, 1H), 3.13 (t, J = 10.01, 2H), 3.02-2.92 (m, 2H), 2.07-1.78 (m, 4H).
Preparation # 45: Preparation of (Z) -4- (4-fluoropiperidin-1-yl) -N'-hydroxy-3- (trifluoromethyl) benzimidamide 4- (4-f Ioro-piperidin-1-yl) -N-hydroxy-3-trifluoromethyl-benzamidine Prepared using General Procedure C.
LC / MS Rf = 5.53 minutes; MS m / z: 306.17 (M + H) +. (Table 1, Method n) 1 H NMR (400 MHz, DMSO-d 6) d 9.74 (s, 1 H), 7.95 (d, J = 1.8, 1 H), 7.91 (d, J = 1.8, 8.4, 1 H), 7.53 (d, J = 8.4, 1H), 5.93 (s, 2H), 4.94-4.74 (m, 1H), 3.01 (t, J = 9.2, 2H), 2.88-2.78 (m, 2H), 2.06 - 1.90 (m, 2H), 1.84 ( dqd, J = 3.7, 6.8, 13.5, 2H).
Preparation # 46: Preparation of 4- (3- (4- (4-fluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -1, 2,4-oxadiazol-5-iDbenzonitrile 4-. { 3- [4- (4-fl uoro-piperidin-1-yl) -3-trifluoromethyl-phenyl] - [1,4] oxadiazol-5-yl} -benzonitrile Prepared using General Procedure E.
LC / MS Rf = 2.26 minutes; MS m / z: 417.18 (M + H) + (Table 1, Method o) 1 H NMR (400 MHz, DMSO-d 6) d 8.38 (d, J = 8.3, 2H), 8.32 (dd, J = 1.9, 8.4, 1H), 8.29 (d, J = 1.9, 1H), 8.14 (d, J = 8.3, 2H), 7.72 (d, J = 8.4, 1H), 4.98 - 4.78 (m, 1H), 3.19 - 3.05 (m, 2H), 3.02 - 2.90 (m, 2H), 2.02 (dddd, J = 3.6, 6.3, 11.5, 13.4, 2H), 1.94 - 1.81 (m, 2H).
Preparation # 47: Reaction to produce 4- (3- (4- (4-fluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazole-5-d-benzaldehyde 4-. { 3- [4- (4-Fluoro-piperidin-1-yl) -3-trifluoromethyl-phenyl] - [1,4] oxadiazol-5-yl} -benzaldehyde Prepared using General Procedure G.
LC / MS Rf = 4.20 minutes; MS m / z: 421.15 (M + H) + (Table 1, Method p) 1 H NMR (400 MHz, DMSO-d 6) d 10.16 (s, 1 H), 8.42 (d, J = 8.2, 2 H), 8.33 (dd, J = 2.0, 8.4, 1 H), 8.30 (d, J = 2.0, 1H), 8.17 (d, J = 8.6, 2H), 7.72 (d, J = 8.4, 1H), 4.88 (dtt, J = 3.3, 6.6, 48.4, 1H), 3.16 - 3.06 (m, 2H), 3.01 - 2.91 (m, 2H), 2.10 - 1.94 (m, 2H), 1.94 - 1.80 (m, 2H).
EXAMPLE # 45 Preparation of 1 - (4- (3- (4- (4-fluoropiperidin-1-i I - 3 - (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) benzyl) azetidin-3 acid - carboxylic acid ammonium acetate salt 1- (4-. {3- [4- (4-Fluoro-piperidin-1-yl) -3-trifluoromethyl-phenyl] - [1,4] oxadiazol-5-yl} acid. -benzyl) -zetidine-3-carboxylic acid Prepared using General Procedure H.
LC / MS Rt = 2.07 minutes; MS m / z: 505.19 (M + H) +, (Table 1, Method g). 1 H NMR (400 MHz, DMSO-d 6) d ppm 8.33-8.26 (m, 2H), 8.15 (d, J = 8.35 Hz, 2H), 7.71 (d, J = 8.43 Hz, 1H), 7.55 (d, J = 8.43 Hz, 2H), 4.88 (dddd, J = 17.52, 10.37, 6.67, 3.53 Hz, 1H), 3.68 (s, 2H), 3.47-3.16 (m, 12H), 3.16-3.06 (m, 2H), 2.98-2.90 (m, 2H), 2.09-1.81 (m, 1H), 1.91 (s, 3H).
EXAMPLE # 46 Preparation of 5 - ((4- (3- (4- (4-fluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) benzylamino) methyl) -soxazole -3-ol Prepared using General Procedure H.
LC / MS Rt = 2.69 minutes; MS m / z: 516.18 (M-H) \ Table 1, method g. 1 H NMR (400 MHz, CDCl 3) d ppm 8.50-8.42 (m, 1H), 8.28 (d, J = 1.11 Hz, 1H), 8.19 (d, J = 8.14 Hz, 2H), 7.55 (d, J = 8.25 Hz, 3H), 7.44 (d, J = 8.32 ??, 1H), 5.89 (s, 1H), 4.96-4.74 (m, 1H), 3.94 (s, 2H), 3.86 (s, 2H), 3.25- 3.09 (m, 2H), 3.00-2.87 (m, 2H), 2.05 (m, 4H).
EXAMPLE # 47 Preparation of 2 - ((4- (3- (4-α-Propoxy-3- (trifluoromethyl) phenyl) - .2,4-oxadiazol-5-yl) phenoxy) methyl) morpholine In a 25 ml round bottom flask, add 2-hydroxymethylmorpholine (0.096 g, 0.819 mmol) (TYGER) in THF (10 mL) to obtain a colorless solution. Sodium hydride (0.020 g, 0.819 mmol) is added and the mixture is stirred until the evolution of hydrogen ceases. 5- (4-Fluorophenyl) -3- (4-isopropoxy-3- (trifluoromethyl) pheny1), 2,4-oxadiazole (0.300 g, 0.819 mmol) is added and the mixture is stirred at room temperature under a nitrogen atmosphere is then heated to reflux for about 4 days. The solvent is removed in vacuo. The crude material is purified by normal phase chromatography with gradient using 0-10% methanol in dichloromethane as an eluent to obtain 2 - ((4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1, 2,4-oxadiazol-5-yl) phenoxy) methyl) morpholine (0.032 g, 0.068 mmol, 8.4% yield).
LC / MS R, = 2.29 minutes; MS m / z: 464.15 (M + H) +. (Table 1, Method j). 1 H NMR (400 MHz, DMSO) d ppm 8.27 (dd, J = 8.78, 2.11 Hz, 1H), 8.19 (d, J = 2.06 Hz, 1H), 8.11 (d, J = 8.95 Hz, 2H), 7.51 ( d, J = 8.93 Hz, 1H), 7.18 (d, J = 8.98 Hz, 2H), 4.90 (td, J = 12.15, 6.07 Hz, 1H), 4.09-4.02 (m, 2H), 3.76-3.67 (m , 2H), 3.49-3.42 (m, 1H), 3.15 (d, J = 5.20 Hz, 1H), 2.86 (dd, J = 12.11, 2.23 Hz, 1H), 2.71-2.59 (m, 2H), 2.55- 2.45 (m, 1H), 1.33 (d, J = 6.02 Hz, 6H).
Preparations # 48 and 49: Preparation of (R) - v (S) -4- (tetrahydrofuran-3-yloxy) -3- (trifluoromethylbenzonitrile in accordance with Reaction Scheme AA AA REACTION SCHEME 4-methoxy-3- (trifluoromethyl) benzonitrile mixture (AA1, 24.88 g, 0.124 mol) and pyridine hydrochloride (29.04 g, 0.251 mol) is stirred and heated to approximately 200 ° C for about 40 minutes. The mixture is cooled to room temperature before the addition of water and the resulting precipitate is filtered and dried to obtain 21.1 g of 4-hydroxy-3- (trifluoromethyl) benzonitrile (AA2) which is used without further purification. Yield: 91%.
To a stirred mixture of 4-hydroxy-3- (trifluoromethyl) benzonitrile (AA2, 9.9 g, 53 mmol) and PPh3 (23.6 g, 90 mmol) in THF (250 ml) at about 0 ° C, DIAD (17.7 g) is added. mi, 90 mmol) The mixture is stirred for approximately 10 minutes at approximately 0 ° C before adding (R) - (-) - 3-hydroxytetrahydrofuran (5 g, 56.7 mmol) in THF (20 mL). The mixture is stirred at room temperature overnight under a nitrogen atmosphere. The solvent is removed in vacuo and the residue is purified by flash chromatography (EA / petroleum ether = 10-20%) to obtain (R) -4- (tetrahydrofuran-3-yloxy) -3- ( trifluoromethyl) benzonitrile (AA5, 8.8g, 65% yield) which is used without further purification. 19 ml (96 mmol) of diisopropyl azodicarboxylate are added to the mixture of 4-hydroxy-3- (trifluoromethyl) benzonitrile (AA2.1 1 g, 59 mmol) and triphenylphosphine (25.3 g, 96 mmol) in THF ( 250 ml) at approximately 0 ° C. The mixture is stirred for approximately 10 minutes at approximately 0 ° C. Add (S) - (+) - 3-hydroxytetrahydrofuran (5 g, 56.7 mmol) in TH F (20 mL). The mixture is stirred at room temperature overnight under nitrogen. The solvent is removed in vacuo and the residue is purified by flash chromatography (ethyl acetate / petroleum ether = 10-20%) to obtain (S) -4- (tetrahydrofuran-3-yloxy) -3 - (trifluoromethyl) benzonitrile. (AA3, 9.2 g, yield: 63%) which is used without further purification.
A solution of (R) -4- (tetrahydrofu ran-3-yloxy) -3- (trifluoromethyl) benzonitrile (AA5, 8.6 g, 33 mmol) in ethanol (80 ml) is treated with 50% aqueous hydroxylamine ( 8.1 mi). The mixture is stirred and heated to approximately 60 ° C for about 1 8 hours. The solvents are removed in vacuo and the residue is purified by flash chromatography (methanol / chloroform = 5-1 5%) to obtain (R) -N'-hydroxy-4- (tetrahydrofuran-3-yloxy) -3- (trifluoromethyl) benzimidamide (AA6, 5.4 g, yield: 56%) LC / MS (Table 1, Method c) Rt = 2.48 minutes, m / z 290.0 (M + H) +. 1 H NMR (400 MHz, DMSO-de) d 9.64 (s, 1 H), 7.89 (m, 2 H), 7. 27 (d, 1H), 5.91 (s, 2H), 5.24 (m, 1H), 3.95 (dd, 1H), 3.79 (ddd, 3H), 2.24 (dtd, 1H), 1.98 (td, 1H).
A solution of (S) -4- (tetrahydrofuran-3-yloxy) -3- (trifluoromethyl) benzonitrile (AA3, 9 g, 35 mmol) in ethanol (80 ml) is tapped with 50% aqueous hydroxylamine (8.5 ml) . The mixture is stirred and heated to approximately 60 ° C overnight. The solvents are removed in vacuo and the residue is purified by flash chromatography (methanol / chloroform = 5-15%) to obtain N-hydroxy-4 - [(S) - (tetrahydro-furan-3-yl) oxy] -3-trifluoromethyl-benzamidine. (AA4, 5.6 g, yield: 55%) which is used without further purification.
Preparation # 50: (S) -5- (4-fluorophenyl) -3- (4- (tetrahydrofuran-3-yloxy) -3- (trifluoromethyl) phenyl) -1, 2,4-oxadiazole Charge (S, Z) -N'-hydroxy-4- (tetrahydrofuran-3-yloxy) -3 (trifluoromethyl) benzimidamide (500 mg, 1723 mmoles fluorobenzoyl (0.207 ml, 1723 mmol) and pyridine (5 ml) in a microwave vial equipped with a stir bar. The vessel is sealed and the reaction is heated to about 160 ° C with cooling for about 25 minutes. The mixture is diluted with DMSO (2 mL) and analyzed by LC / MS. MeCN (6 mL) is added and the mixture is subjected to purification by LC / MS directed to molecular ion to obtain (S) -5- (4-fluorophenyl) -3- (4- (tetrahydrofuran-3-yloxy) -3 - (trifluoromethyl) phenyl) -1, 2,4-oxadiazole (413 mg, 1047 mmol, 60.8% yield) as an off-white solid.
LC / MS (Table 1, Method g) Rt = 3.15 minutes; MS m / z: does not ionize. 1 H NMR (400 MHz, DMSO) d ppm 8.42-8.14 (m, 4H), 7.60-7.43 (m, 3H), 5.35 (t, J = 5.02 Hz, 1H), 3.98 (dd, J = 10.49, 4.40 Hz , 1H), 3.91-3.76 (m, 3H), 2.30 (dd, J = 13.95, 5.75 Hz, 1H), 2.11-1.96 (m, 1H).
EXAMPLE # 48 Acid (1R.3S) -3- (4- (3- (4 - ((S) -tetrahydrofuran-3-yloxy) -3- (trifluoromethyl) phenyl) -1.2.4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic Heat (S) -5- (4-fluorophenyl) -3- (4- (tetrahydrofuran-3-yloxy) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazole (350 mg, 0.888 mmol), (1 R, 3S) -3-aminocyclopentanecarboxylic acid (115 mg, 0.888 mmol), potassium carbonate (270 mg, 1953 mmol) and DMF (2 mL) with cooling at approximately 160 ° C in the Biotage microwave for approximately 30 minutes . The mixture is diluted with DMSO (6 mL) and MeCN (8 mL), filtered and divided into 8 aliquots for purification by LC / MS directed to molecular ion. The fractions are combined and evaporated to obtain a pale brown solid which is vacuum dried at about 60 ° C for about 3 hours to obtain acid (1 R, 3S) -3- (4- (3- (4- ((S) -tetrahydrofuran-3-yloxy) -3- (trifluoromethyl) phenyl) -1, 2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid (43 mg, 0.083 mmol, 9.33% yield) as a solid pale brown. NMR shows the presence of ammonium acetate and therefore the compound is dried under vacuum at approximately 100 ° C for about 3 hours to obtain acid (1 R, 3S) -3- (4- (3- (4 - (( S) -tetrahydrofuran-3-yloxy) -3- (trifluoromethyl) phenyl) -1, 2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid (43 mg, 0.083 mmol, 9.33% yield) as an off-white solid.
LC / MS (Table 1, Method g) Rt = 2.61 minutes; MS m / z: 504.2 (M + H) +. 1 H NMR (400 MHz, DMSO) d ppm 7.48 (d, J = 8.85 Hz, 1H), 7.03-6.89 (m, 1H), 6.72 (d, J = 8.94 Hz, 2H), 7.87 (d, J = 8.88 Hz, 2H), 8.20 (d, J = 2.03 Hz, 1H), 8.27 (dd, J = 8.73, 2.06 Hz, 1H), 5.37-5.27 (m, 1H), 3.98 (dd, J = 10.41, 4.47 Hz , 1H), 3.90-3.74 (m, 4H), 2.75 (t, J = 8.31 Hz, 1H), 2.30 (td, J = 11.68, 6.98 Hz, 2H), 2.10- 1.92 (m, 2H), 1.92- 1.81 (m, 2H), 1.68 (dd, J = 7.98, 4.74 Hz, 1H), 1.55 (dd, J = 12.18, 6.65 Hz, 1H).
EXAMPLE # 49 Acid (1R.3S) -3- (4- (3- (4- (4-fluoropiperidin-1-M) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid 5- (4-Fluorophenyl) -3- (4- (4-fluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazole (420 mg, 1026 mmol), acid ( 1R, 3S) -3-aminocyclopentanecarboxylic acid (146 mg, 1129 mmol), potassium carbonate (312 mg, 2257 mmol) and DMF (2 mL) with cooling at approximately 160 ° C in the Biotage microwave for approximately 30 minutes. The mixture is diluted with DMSO (6 mL) and MeCN (8 mL), filtered and divided into 8 aliquots for purification by LC / MS directed to molecular ion. The fractions are combined and evaporated to obtain a pale brown solid which is vacuum dried at about 60 ° C for about 3 hours to obtain acid (1 R, 3S) -3- (4- (3- (4- (4-fluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid (122 mg, 0.235 mmol, 22.93% yield) as a whitish solid.
LC / MS (Table 1, Method f) R, = 3.05 minutes; MS miz: 517.17 (M-H) \ 1 H NMR (400 MHz, DMSO) d ppm 6.83 (d, J = 6.67 Hz, 1H), 6.72 (d, J = 8.92 Hz, 2H), 8.28-8.21 (m, 2H), 7.87 (d, J = 8.86 Hz, 2H), 7.67 (d, J = 8.40 Hz, 1H), 12.16- 12.05 (m, 1H), 4.97-4.75 (m, 1H), 3.84 (d, J = 6.98 Hz, 1H), 3.08 (t, J = 9.04 Hz, 2H), 1.65 (d, J = 12.27 Hz, 1H ), 1.52 (s, 1H), 2.31 (s, 1H), 2.11-1.92 (m, 3H), 1.92-1.79 (m, 4H), 2.97-2.85 (m, 2H), 2.83-2.69 (m, 1H) ).
EXAMPLE # 50 Acid acetate salt (1 R.3S) -3- (4- (3- (4- (4,4-difluoropiperidin-1 -yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazole-5-l ) phenylamino) cyclopentanecarboxylic 3- (4- (4,4-difluoropiperidin-1-yI> - 3 - (trifluoromethyl) phenyl) -5- (4-fluorophenyl) -1,2,4-oxadiazole (503 mg, 1177 mg) are heated. mmoles), (1 R, 3S) -3-aminocyclopentanecarboxylic acid (167 mg, 1295 mmol), potassium carbonate (358 mg, 2.59 mmol) and DMF (2 mL) with cooling at approximately 160 ° C in the Biotage microwave for about 30 minutes The mixture is diluted with DMSO (6 ml) and MeCN (8 ml), is filtered and divided into 8 aliquots for purification by LC / MS directed to molecular ion. The fractions are combined and evaporated to obtain a pale brown solid which is vacuum dried at about 60 ° C for about 3 hours to obtain acid (1 R, 3S) -3- (4- (3- (4- (4,4-difluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -1, 2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid (243 mg, 0.453 mmol, 38.5% yield) as a solid whitish like acetate salt.
LC / MS (Table 1, Method g) R, = 3.06 minutes; MS m / z: 535.2 (M-H). " H NMR (400 MHz, DMSO) d ppm 7.73 (d, J 1H), 7.86 (d, J = 8.85 Hz, 2H), 8.29-8.21 (m, 2H), 2.81-2.68 (m, 1H), 2.30 (d, J = 12.64 Hz, 1H), 2.10 (ddd, J = 13.96, 10.71, 5.50 Hz, 4H), 1.98 (s, 1H), 1.92-1.81 (m, 2H), 1.66 (d, J = 12.66 Hz, 1H), 1.52 (s, 1H), 3.09-3.04 ( m, 4H), 3.87-3.79 (m, 1H), 2.52 (s, 3H).
EXAMPLE # 51 Acetate salt (1S, 3S) -3- (4- (3- (4- (4-fluoropiperidin-1 -ih-3- (trifluoromethylphenyl) -1,2,4-oxadiazole-5) - l) phenylamino) cyclopentanecarboxylic 5- (4-Fluorophenyl) -3- (4- (4-fluoropiperidin-1 -yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazole (576 mg, 1,408 mmol), acid ( 1S, 3S) -3-aminocyclopentanecarboxylic acid (200 mg, 1549 mmol, Afid Therapeutics), potassium carbonate (428 mg, 3.10 mmol) and DMF (2 mL) with cooling at approximately 160 ° C in the Biotage microwave for approximately 30 minutes. minutes The mixture is diluted with DMSO (6 mL) and MeCN (8 mL), filtered and divided into 8 aliquots for purification by LC / MS directed to molecular ion. The fractions are combined and evaporated to obtain a pale brown solid which is vacuum dried at about 60 ° C for about 3 hours to obtain acid (1S, 3S) -3- (4- (3- (4- (4-fluoropiperidin-1 -yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid (47 mg, 0.082 mmol, 5.80% yield) as a solid of color pale coffee like acetate salt.
LC / MS (Table 1, Method, g) Rt = 3.03 minutes; MS m / z: 517.2 (M-H) \ 1 H NMR (400 MHz, DMSO) d ppm 8.23 (td, J = 5.39, 1.81 Hz, 2H), 7.65 (d, J = 8.39 Hz, 1H), 6.69 (dd, J = 9.02, 2.47 Hz, 2H), 6.79 (d, J = 6.44 Hz, 1H), 7.86 (d, J = 8.88 Hz, 2H), 4.97-4.87 (m, 1H), 4.83-4.74 (m, 1H), 3.96-3.79 (m, 2H) , 3.07 (s, 2H), 2.97-2.85 (m, 2H), 2.85-2.72 (m, 1H), 2.20-1.43 (m, 13H).
EXAMPLE # 52 Acid acetate salt (1 R.3R) -3- (4- (3- (4- (4-fluoropiperidin-1-yl) -3- (trifl uoromethyl) phenyl) -1,4, 2,4-oxadiazole - 5- il) phenylamino) cyclopentanecarboxylic acid 5- (4-Fluorophenyl) -3- (4- (4-fluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazole (576 mg, 1,408 mmol), acid ( 1R, 3R) -3-aminocyclopentanecarboxylic acid (200 mg, 1549 mmol, Afid Therapeutics), potassium carbonate (428 mg, 3.10 mmol) and DMF (3 mL) with cooling at approximately 160 ° C in the Biotage microwave for approximately 30 minutes. minutes The mixture is diluted with DMSO (6 ml) and MeCN (8 ml), it is filtered and divided into 8 aliquots for purification by LC / MS directed to molecular ion. The fractions are combined and evaporated to obtain a pale brown solid which is vacuum dried at about 60 ° C for about 3 hours to obtain acid (1 R, 3R) -3- (4- (3- (4- (4-fluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid (43 mg, 0.075 mmol, 5.30% yield) as a solid of color pale coffee like acetate salt.
LC / MS (Table 1, Method g Rt = 3.03 minutes; MS m / z: 517.2 (M-H) -. 1 H NMR (400 MHz, DMSO) d ppm 8.27-8.18 (m, 2H), 7.85 (dd, J = 8.88, 3.58 Hz, 2H), 7.65 (d, J = 8.35 Hz, 1H), 6.79 (d, J = 6.47 Hz, 1H), 6.70 (d, J = 8.94 Hz, 2H), 4.91 (dd, J = 6.64, 3.30 Hz, 1H), 4.82-4.73 (m, 1H), 3.87 (d, J = 5.83 Hz , 1H), 3.06 (t, J = 8.93 Hz, 2H), 2.96-2.76 (m, 3H), 2.28-1.39 (m, 13H).
EXAMPLE # 53 Acid acetate (1S.3R) -3- (4- (5- (3-cyano-4- (4-fluoropiperidin-1-yl) phenih-1.2.4-oxadiazol-3-n-2- ( trifluoromethyl) phenylamino) cyclopentanecarboxylic acid 5- (3- (4-Fluoro-3- (trifluoromethyl) phenol) -1,2,4-oxadiazol-5-yl) -2- (4-fluoropiperidin-1-yl) benzonitrile (500 mg , 1151 mmol), (1S, 3R) -3-aminocyclopentanecarboxylic acid (164 mg, 1266 mmol), potassium carbonate (350 mg, 2.53 mmol) and DMF (3 mL) with cooling to approximately 160 ° C in the microond Biotage for approximately 30 minutes. The mixture is diluted with DMSO (12 mL) and ACN (9 mL), filtered and divided into 8 aliquots for purification by LC / MS directed to molecular ion. The fractions are combined and evaporated to obtain a pale brown solid which is vacuum dried at about 60 ° C for about 7 hours to obtain acid (1S, 3R) -3- (4- (5- (3- cyano-4- (4-fluoropiperidin-1-yl) phenyl) -1, 2,4-oxadiazol-3-yl) -2- (trifluoromethyl) phenylamino) cyclopentanecarboxylic acid (153 mg, 0.267 mmol, 23.23% yield) as a pale brown solid like the acetate salt.
LC / MS (Table 1, Method g) Rt = 2.93 minutes; MS m / z: 542.1 (M-H) \ d? (400 ??, DMSO) 8.32 (1?, S), 8.19 (1?, D, J 8.9), 8.01 (2?, D, J 7.8), 7.31 (1?, D, J 8.9), 7.03 ( 1?, D, J 9.2), 5.96 (1?, S), 5.05 - 4.79 (1?, M), 4.12 - 3.97 (1?, M), 3.44 (4?, D, J 29.9), 2.84 ( 1?, S), 1.97 (11?, D, J 73.3).
EXAMPLE # 54 Acid salt of (1S, 3R) -3- (4- (5- (3-cyano-4- (4-f luoropiperidin-1-yl) phenyl) -1,2,4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylic 5- (3- (4-fluorophenyl) -1,2,4-oxadiazol-5-yl) -2- (4-fluoropiperidin-1-yl) benzonitrile (500 mg, 1365 mmol), acid (1 S) is heated. , 3R) -3-aminocyclopentanecarboxylic acid (194 mg, 1,501 mmol), potassium carbonate (415 mg, 3.00 mmol) and DMF (3 mL) with cooling at approximately 160 ° C in the Biotage microwave for approximately 30 minutes. The mixture is diluted with DMSO (12 mL) and MeCN (9 mL), filtered and divided into 12 aliquots for purification by LC / MS directed to molecular ion. The fractions are combined and evaporated to obtain a pale brown solid which is vacuum dried at about 60 ° C for about 7 hours to obtain acid (1S, 3R) -3- (4- (5- (3- cyano-4- (4-fluoropiperidin-1-yl) phenyl) -1, 2,4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylic acid (23 mg, 0.046 mmol, 3.40% of yield) as a pale yellow solid such as acetate salt.
LC / MS (Table 1, Method g) Rt = 2.59 minutes; MS m / z: 474.2 (M-H) \ d H (400 Hz, DMSO) 8.33 (1 H, s), 8.24 - 8.17 (1 H, m), 7. 75 (2 H, d, J 8.6), 7.34 (1 H, d, J 8.9), 6.65 (2 H, d, J 8.7), 5.03 - 4.83 (2 H, m), 3.84 - 3.72 (2 H, m), 3.55 - 3.32 (6 H, m), 2.75 - 2.58 (2 H, m), 1.83 (15 H, s).
Preparations # 51 v 52: 5-r3- (4-fluoro-phenyl) -G1.2,41-oxadiazol-5-yl1-2- (4-fluoro-piperidin-1-β-benzonitrile and 5-f3- (4 - fluoro-3-trifluoromethyl-phenyl) -ri .2,41-oxadiazol-5-yl1-2- (4-fluoro-piperidin-1-yl) -benzonitrile according to Reaction Scheme BB REACTION SCHEME BB REACTION SCHEME BB (cont.) Preparation of BB2: 4-fluoro-piperidin-1-carboxylic acid tert-butyl ester BB1 The solution of 4-hydroxy-piperidin-1-carboxylic acid tert-butyl ester (BB 1, 20.0 g, 99.4 mmol) in DC M (400 ml) is cooled to about -78 ° C and DAST is added slowly (31.65 ml) by dripping over the course of about 30 minutes. The mixture is stirred at about -78 ° C for about 0.5 hour and about 0 ° C for about 0.5 hour. The analysis by TLC shows the formation of the desired product which is then quenched by the addition of saturated aqueous NaHCO 3 and chloroform. Separate the organic layer, dry with Na 2 SO 4, and concentrate under reduced pressure. The crude product is further purified by silica gel column chromatography to obtain the 4-fluoro-piperidin-1-carboxylic acid tert-butyl ester as a colorless oil (BB2, 8.0 g).
Preparation of BB3: 4-fluoro-piperidine hydrochloride BB2 BB3 To a solution of the 4-fluoro-piperidine-1-carboxylic acid tert-butyl ester 2 (BB2, 23.0 g, 113.2 mmol) in DCM (460 ml) is slowly added the solution of HCl / 1,4-dioxane (2). N, 200 ml) by dripping at approximately 0 ° C. The mixture is stirred at approximately 25 ° C overnight. Analysis by TLC indicates the termination of the reaction. The solution is concentrated under reduced pressure. The residue is washed with DCM, dried under vacuum to obtain 4-fluoro-piperidine as the white hydrochloride salt (BB3, 13.3 g).
Preparation of BB4: 2-fluoro-5-formyl-benzonitrile 3-Bromo-4-fluoro-benzaldehyde (1 5.0 g, 74 mmol) and CuCN (7.6 g, 84.4 mmol) were mixed with NM P (27 ml) under vigorous stirring at approximately 25 ° C. The mixture is heated slowly over several hours to approximately 70 ° C and stirred for approximately 24 hours. The analysis by CC F shows the complete consumption of the starting material and the formation of new product. The temperature is cooled to about 80 ° C and EtOAc (250 ml) and water (150 ml) are added. The organic layer is separated and the aqueous layer is extracted with EtOAc (150 ml x 2). The combined organic layers are dried with NaSO4 and concentrated. The residue is purified by column chromatography with silica gel to obtain 2-fluoro-5-formyl-benzonitrile as a white solid (BB4, 9.0 g).
Preparation of BB5: 3-cyano-4-fluoro-benzoic acid To a solution of 2-fluoro-5-formyl-benzonitrile BB4 in mixed solvent of H20 / t-BuOH (48 ml / 201 ml), add NaCl02 (28.2 g, 223.5 mmol) and NaH2P04 (22.2 g, 142.6 mmol). ). The mixture is stirred vigorously at approximately 25 ° C and left to stand overnight. The analysis by CC F indicates the complete consumption of the starting material. The solution is adjusted to pH = 3.5 by addition of aqueous 1 N HCl and extracted with DCM / i-Propanol (10: 1, 200 ml x 3). The combined organic layer is dried with Na 2 SO 4 and concentrated in vacuo. The residue is redissolved in aqueous NaHCO 3 and extracted with DC M. The aqueous layer is acidified; the white precipitate is extracted with DCM, dried with Na2SO4 and concentrated under reduced pressure to obtain 3-cyano-4-fluoro-benzoic acid as a white solid (BB5, 9.5 g).
Preparation of BB8: 4-fluoro-N-hid roxy-benzamidine BB8 To a solution of 4-fluoro-benzonitrile (1 0.0 g, 52.9 mmol) in ethanol (200 ml), the solution of N H 2 O HCl (4.0 g, 58.2 mmol) in H2O (4 ml) was added dropwise. . The mixture is stirred vigorously at approximately 65 ° C and left to stand overnight. The analysis by TLC indicates the complete consumption of the starting material. The solution is concentrated to remove the solvent. The residue is dissolved in DC M and washed with water, Brine, dry with Na 2 SO and concentrate in vacuo to obtain 4-fluoro-N-hldroxl-benzamidine as pale yellow solid (BB8).
Preparation of BB6: 3-cyano-4- (4-fluoro-piperidin-1-yl) -benzoic acid To a solution of 3-cyano-4-fluoro-benzoic acid BB5 (14.3 g, 86.9 mmol) and K2CO3 (36.3 g, 26.1 mmol) in DMF (150 mL) was added 4-fluoro-piperidinium hydrochloride BB3 (1 3.3 g, 95.6 mmol) undiluted at approximately 25 ° C. The mixture is heated to about 90 ° C and stirred overnight. After approximately 24 hours, analysis by HPLC indicates that starting material still remains. The solution is stirred for another 24 hours. The solution is quenched by the addition of EtOAc and (300 ml) 1 N HCl. The organic layer is washed with brine, dried with Na 2 SO 4, concentrated under reduced pressure. The residue is further purified by column chromatography with silica gel to obtain 3-cyano-4- (4-fluoro-piperidin-1-yl) -benzoic acid as a white solid (BB6).
Preparation of 5-r3- (4-fluoro-phenyD-M .2.41-oxadizol-5-ill-2- (4-fluoro-piperidin-1-yl) -benzonitrile Prepare a solution of 3-cyano-4- (4-fluoro-piperidin-1-yl) -benzoic acid BB6 (0.5 g x 18, 2 mmoles) and CCI3CN (0.44 g x 18, 3 mmoles) in dry THF (15 ml). ) and Ph3P (1.58 g * 18.6 mmoles) is added under nitrogen protection at approximately 25 ° C. The mixture is reacted in the microwave added to the list of abbreviations at approximately 100 ° C for about 5 minutes, then a solution of 4-fluoro-N-hydroxy-benzamidine BB8 (0.34 g x 18, 2.2 mmol) and DIEA is added. (0.52 g x 18, 4 mmoles). The mixture is reacted in MW at approximately 150 ° C for about 15 minutes. Analysis by TLC shows the formation of the desired product, which is purified by column chromatography with silica gel to obtain 5- [3- (4-fluoro-phenyl) - [1,4] oxadiazol-5-yl. ] -2- (4-Fluoro-piperidin-1-yl) -benzonitrile as a white solid (BB9). 1 H NMR (400 MHz, DMSO) d ppm 8.31 (1H, m), 8.19-8.17 (1H, m), 8.08-8.05 (2H, m), 7.41-7.36 (2H, m), 7.32-7.30 (1H, m), 4.97 - 4.85 (1H, m), 3.50 - 3.35 (4H, m), 2.07 - 1.91 (2H, m) and .89 - 1.85 (2H, m).
Preparation of BB7: 4-fluoro-N-hydroxy-3-trifluoromethyl-benzamidine To a solution of 4-fluoro-3-trifluoromethyl-benzonitrile (20.0 g, 105.8 mmol) in ethanol (400 mL) is added a solution of NH2OH HCl (8.0 g, 116.4 mmol) which is adjusted to pH = 7.0 by addition NaOH in H20 (8 ml). The mixture is vigorously stirred and heated to about 65 ° C for about 16 hours. Analysis by TLC indicates the conclusion of the reaction; it is concentrated to eliminate the solvent. The residue is redissolved in DCM (200 ml) and washed with water, brine and dried with Na 2 SO 4, concentrated in vacuo to obtain 4-fluoro-N-hydroxy-3-trifluoromethyl-benzamidine (BB 7) as a pale yellow color. 1 H NMR (400 MHz, DMSO) d ppm 9.83 (1H, s), 8.00-7.98 (2H, m), 7.50 (1H, t) and 6.00 (2H, s).
Preparation of BB10: 5-r3- (4-fluoro-3-trifluoromethyl-phenyl) - H l, 2,4-oxadiazol-5-ill-2- (4-fluoro-p-perpent-1-yl) -benzonitrile To a solution of compound BB6 (20 g, 80.6 mmol) in DMF (385 ml), add HATU (36.5 g, 96.7 mmol), 4-fluoro-N-hydroxy-3-trifluoromethyl-benzamidine (21.5 g, 96.7 g). mmoles) and DIPA (29.3 g, 227 mmol). Analysis by HPLC indicates that there is no change in the starting material. The solution is cooled to approximately 25 ° C and quenched by the addition of H20 / DCM (200 ml / 500 ml). The organic layer is separated, washed with saturated NaHCO 3; Brine (200 ml x 2) is dried with NaSO 4 and concentrated. The crude product is isolated by pre-HPLC to obtain the product as a white solid (BB10) H NMR (400 MHz, DMSO) d ppm 8.42 - 8.38 (2H, m), 8.32 - 8.30 (1H, m), 8.25 - 8.22 (1H, m), 7.75 (1H, t), 7.35 (1H, d) , 5.01 - 4.87 (1H, m), 3.59 - 3.36 (4H, m), 2.12 - 2.02 (2H, m) and 1.92 - 1.74 (2H, m).
Preparations # 53 and 54: Preparation of 5- (4-fluoropheni0-3- (4- (4-fluoropiperidin-1 -yl) -3- (trifluoromethyl) phenyl) -1, 2,4-oxadiazole and 3- (4 - (4,4-difluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -5- (4-fluorophenyl) -1.2.4-oxadiazole Preparation of 4- (4-fluoropiperidin-1-yl) -3- (trifluoromethyl) benzonitrile (compound-2) To a stirred solution of compound 1 (5.0 g, 0.026 mmol) and 4-fluoropiperidine HCI (4.05 g, 0.029 mmol) in DMSO (50 mL) was added K2C03 (9.1 2 g, 0.066 mmol) at room temperature. The reaction mixture is heated to approximately 100 ° C for approximately 12 hours. After the starting material is completely consumed, the reaction mixture is cooled to room temperature and poured into crushed ice. The aqueous layer is extracted with hexane (2 x 50 mL), washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain a crude compound which is purified by column chromatography using 2-hydroquinone. % EtOAc / Hexane to obtain compound 2 as a colorless liquid (4.75 g, 67%). 1 H NMR (200 MHz, CDCl 3): d 1.94-2.01 (m, 2H), 2.04-2.12 (m, 2H), 2.92-3.03 (m, 2H), 3.13-3.25 (m, 2H), 4.70-5.10 ( m, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.75 (dd, J = 8.4, 2.2 Hz, 1H), 7.89 (d, J = 2.2 Hz, 1H).
MS (ESI): 273 (M + + H).
Preparation of 4- (4-fluoropiperidin-1-M) -N'-hydroxy-3- (trifluoromethyl) benzimidamide (compound-3) A stirred solution of compound 2 (4.75 g, 0.017 mmol) in EtOH (50 mL), hydroxylamine (50% in water, 1.26 mL, 0.019 mmol) is added at room temperature. The reaction mixture is heated to about 65 ° C for about 4 hours. After the starting material is completely consumed, the volatiles are removed under reduced pressure to obtain crude 4- (4-fluoropiperidin-1-yl) -N'-hydroxy-3- (trifluoromethyl) benzimidamide 3 (5.4 g) which It is used for the next step without further purification.
Preparation of 5- (4-fluorophenyl) -3- (4- (4-fluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazole A stirred solution of compound 3 (5.4 g, 0.017 mmol) in toluene (50 ml), 4-fluorobenzoyl chloride (2.33 ml, 0.019 mmol) and pyridine (1.56 ml, 0.019 mmol) is added at room temperature. The reaction mixture is heated to approximately 130 ° C for about 10 hours. After the starting material is completely consumed, the toluene is removed and the crude product is dissolved in EtOAc (100 ml). The organic layer is washed with water (50 ml), brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure to obtain the crude compound which is purified by column chromatography using 1% EtOAc / Hexane. to obtain 5- (4-fluorophenyl) -3- (4- (4-fluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -1, 2,4-oxadiazole as a white solid (5.0 g, 69 %). 1 H NMR (500 MHz, DMSO-d 6): d 1.83-1.90 (m, 2H), 1.95-2.04 (m, 2H), 2.49-2.94 (m, 2H), 3.07-3.11 (m, 2H), 4.80- 4.92 (m, 1H), 7.49 (t, J = 8.5 Hz, 2H), 7.68 (d, J = 8.5 Hz, 1H), 8.24-8.29 (m, 4H). 13C R N (125 MHz, DMSO-d6): d 174.7, 166.9, 165.9, 163. 9, 154.8, 131.8, 130.8, 125.8, 125.1, 124.8, 122.5, 121.8, 119.8, 116.8, 116.7, 88.2, 86.9, 49.4, 49.3, 31.5, 31.4.
Preparation of 4- (4.4-difluoropiperidin-1 -yl) -3- (trifluoromethyl) benzonitrile (compound-4) A stirred solution of compound 1 (5.0 g, 0.026 mmol) and 4,4-difluoropiperidine HCI (4.58 g, 0.029 mmol) in DMSO (50 mL), K2C03 (9.12 g, 0.066 mmol) is added at room temperature. The reaction mixture is heated to approximately 100 ° C for approximately 12 hours. After the starting material is completely consumed, the reaction mixture is cooled to room temperature and poured into crushed ice. The aqueous layer is extracted with EtOAc (2 x 100 mL), washed with water (60 mL), brine (60 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain the crude compound which is purified. by column chromatography using 2% EtOAc / Hexane to obtain compound 4 as a white solid (3.2 g, 42%).
H NMR (200 MHz, CDCl 3): d 2.06-2.25 (m, 4H), 3.13 (t, J = 5.4 Hz, 4H), 7.36 (d, J = 8.4 Hz, 1H), 7.78 (dd, J = 8.4 , 2.2 Hz, 1H), 7.92 (d, J = 2.2 Hz, 1H).
MS (ESI): 290 (M + + H).
Preparation of 4- (4.4-difluoropiperidin-1-yl) -N'-hydroxy-3- (trifluoromethyl) benzimidamide (compound-5) A stirred solution of compound 4 (3.4 g, 0.011 mmol) in EtOH (65 mL), hydroxylamine (50% in water, 0.85 mL, 0.025 mmol) is added at room temperature. The reaction mixture heat to approximately 65 ° C for about 3 hours. After the starting material is completely consumed, the volatiles are removed under reduced pressure to obtain the crude compound 5 (3.7T g) which is used for the next step without further purification.
Preparation of 3- (4- (4,4-difluoropiperidin-1-i) - 3 - (trifluoromethyl) phenyl) -5- (4-fluorophenyl) -1,2,4-oxadiazole A stirred solution of compound 5 (3.78 g, 0.011 mmol) in toluene (115 ml), 4-fluorobenzoyl chloride (1.54 ml, 0.013 mmol) and pyridine (1.03 ml, 0.013 mmol) are added at room temperature. The reaction mixture is heated to approximately 120 ° C for about 10 hours. After the starting material is completely consumed, the toluene is removed and the crude mass is dissolved in EtOAc (150 ml). The organic layer is washed with water (50 ml), brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure to obtain the crude compound which is purified by column chromatography using 1% EtOAc / Hexane. to obtain 3- (4- (4,4-difluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -5- (4-fluorophen-yl) -1,2,4-oxadiazole as a white solid (2.5 g, 50%). 1 H NMR (500 MHz, CDCl 3): d 2.13-2.20 (m, 4 H), 3.11 (m, 4 H), 7.23-7.44 (m, 2 H), 7.48 (d, J = 8.5 Hz, 1 H), 8.22-8.26. (m, 2H), 8.30 (dd, J = 8.5 Hz, 2.0 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H) 13 C NMR (125 MHz, CDCl 3): d 175.1, 167.7, 166.6, 164.5, 154. 2, 131.6, 130.7, 130.6, 127.4, 127.1, 127.0, 126.9, 126.8, 124.7, 124.2, 123.6, 123.4, 122.5, 121.5, 120.4, 119.6, 116.6, 116.4, 50.5, 50.48, 50.4, 34.7, 34.6, 34.4.
EXAMPLE # 55 Preparation of 1- (4- (3- (3-chloro-4-isopropoxyphenin-1,2,4-oxadiazol-5-yl) benzyl) -5-oxopyrrolidine-3-carboxylic acid To a solution of (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) phenyl) methanamine (27 mg, 0.079 mmol) (EXAMPLE # 6) in MeOH ( 1 ml) is added dimethyl 2-methylensuccinate (12.42 mg, 0.079 mmol). After approximately 4 hours, add additional dimethyl-2-methylene succinate (124 mg, 0.79 mmol) and the reaction mixture is heated to about 50 ° C. After about 20 hours the reaction mixture is cooled to room temperature and lithium hydroxide monohydrate (9.89 mg, 0.236 mmol) is added. After about 30 minutes a 1 N solution of HCl (10 mL) and DCM (10 mL) is added to the reaction mixture. The organic layer is removed, dried (Na2SO4), filtered and concentrated in vacuo. The oily residue is suspended in Et20 (30 mL). After standing for approximately 30 minutes the resulting solid is collected by filtration and dried under vacuum to provide 1 - (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) -5-oxopyrrolidine-3-carboxylic acid (30 mg, 84%) as a colorless solid.
LC / M S (Table 1, Method a) R, = 2.38 minutes, m / z 456 (M + H) +.
EJ EM PLO # 56 Separation of (R) -3- (4- (3- (3-Chloro-4-isopropoxypheni I) -1,2,4-oxadiazol-5-yl) -1 H -indole-1-yl) -2 acid -methylpropanoic acid and (S) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1 .2,4-oxadiazol-5-tl) -1 H -indole-1 -iO-2- methyl propane The enantiomers of 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1H-indol-1-yl) -2-methylpropanoic acid (example # C .3) are separated by chiral chromatography using a Daicel AD-H column (20 x 250 mm, 5 m particle) at a flow rate of 25 ml / minute, elution in g radient with 2-1 6% of ethanol in heptane with 0.2% diethylamine modifier in the course of 26 minutes. The elution of the compounds is monitored by UV detection at 254 nm with a column temperature of about 25 ° C. Samples for injection are prepared by dissolving the racemic acid in 80% heptane: 20% ethanol: 0.2% diethylamine. The concentration of the fractions containing the Desired products provide the acid ((R) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1 H-indol-1-yl ) -2-methylpropanoic (the stereochemistry is assigned arbitrarily) LC / MS (Table 1, Method a) Rt = 3.05 minutes, m / z 440 (M + H) +, or = neg. Followed by the acid ((S) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1 H- indol-1-yl) -2-methylpropanoic acid ( stereochemistry is assigned arbitrarily) LC / MS (Table 1, Method a) Rt = 3.05 minutes, m / z 440 (M + H) + Preparation # 57: Preparation of (1 R. 2 S) -methyl-2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylate mixed with (1 S.2R) -methyl-2- (4- (3- (3-chloro-4-ylpropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylate (1: 1) A 20 ml reaction vial is charged with acid (1 R.2S) 2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid mixed with acid (1 S, 2 R) -2- (4 (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazole-5- il) phenollamine) cyclopentanecarboxylic acid (1: 1) (0.265 g, 0.300 mmol) in methanol (1934 ml) to obtain a cloudy suspension. To the reaction mixture thionyl chloride (0.044 ml, 0.600 mmol) is added dropwise. The resulting solution is stirred at about 60 ° C for about 15 hours. The mixture is cooled to about room temperature. The resulting white precipitate is filtered, it is rinsed with water (5 ml) and dried in an oven to provide (1 R, 2 S) -methyl-2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxad Azol-5-yl) phenylamino) cyclopentanecarboxylate mixed with (1S, 2R) -methyl-2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylate (1: 1) (0.165 g, 0.181 mmol, 60.3% yield) as a white solid.
LC / MS (Table 1, Method a) Rt = 3.11 minutes, m / z 456 (M + H) +.
EXAMPLE # 58 Preparation of acid (1 R, 2R) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic mixed with acid (1 S, 2S) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1.2.4-oxadiazol-5-yl) phenylamino) cyclocarboxylic acid (1: 1) A 25 ml flask purged with nitrogen is charged with sodium (0.398 mg, 0.017 mmol). The flask is cooled to about 0 ° C and methanol (5 ml) is added. The mixture is stirred until all the metal dissolves. A solution of (1 R, 2S) -methyl-2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylate mixed with ( 1 S, 2R) -methyl-2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylate (1: 1) (0.158 g, 0.173 mmole) in methanol (10 mL) and DCM (3 mL) to the reaction mixture. After stirring at room temperature for approximately 48 hours water (2 ml) is added to the reaction mixture. The mixture is concentrated in vacuo and the residue partitioned between EtOAc (10 mL) and water (10 mL). The organic phase is dried (Na 2 SO 4) filtered and concentrated. The crude material is purified by RP-HPLC on a Hyperprep HS C18 column using 0-95% ACN / Water (NH OAc buffer) in the course of 30 minutes at 21 ml / minute. The fractions are concentrated in vacuo to provide the acid (1R, 2R) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid mixed with (1S, 2S) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid (1: 1) (0.0336) g, 0.038 mmole, 21.94% yield) as a white solid.
LC / MS (Table 1, Method a) Rt = 2.76 minutes, m / z 442 (M + H) +.
EXAMPLE # 59 Preparation of 3- (3-chloro-4-isopropoxyphen-5- (1-methyl-1,2,3,4-tetrahydroquinolin-6-yl) -1,2,4-oxadiazole To a solution of 2- (6- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3,4-dihydroquinolin-1 (2H) -yl) acetate of tert-butyl (0.117 g, 0.242 mmol) in DCM (2.015 mL) was added TFA (0.403 mL) by dripping. After about 24 hours the reaction mixture is concentrated in vacuo and the crude material is purified by chromatography on silica gel (12 g) eluting with EtOAc / Heptane (0-15%). The fractions containing the product are combined and concentrated to obtain 3- (3-chloro-4-isopropoxyphenyl) -5- (1-methyl-1, 2,3,4-tetrahydroquinolin-6-yl) -1, 2 , 4-oxadiazole (0.0405 g, 0.106 mmol, 43.6% yield) as light yellow powder. 1 H NMR (400 MHz, D SO) d 8.00 (s, 1H), 7.94 (d, J = 8.7, 1H), 7.77 (d, J = 8.7, 1H), 7.66 (s, 1H), 7.34 (d, J = 8.7, 1H), 6.69 (d, J = 8.8, 1H), 4.84 - 4.75 (m, 1H), 3.40 - 3.32 (m, 2H), 2.96 (s, 3H), 2.77 (t, J = 6.1 , 2H), 1.89 (s, 2H), 1.33 (d, J = 6.0, 6H).
LC / MS (Table 1, Method a) R, = 3.26 minutes, m / z 384 (M + H) +.
Preparation # 58: Preparation of (R) -5- (1 H -indol-4-yl) -3- (4- (tetrahydrofuran-3-yloxy) -3- (trifluoromethyl) phenyl) -1, 2.4 -oxadiazole A mixture of 1 H-indole-4-carboxylic acid (0.61 1 g, 3.79 mmol), EDCI hydrochloride (0.727 g, 3.79 mmol) and hydrated HOBT (0.580 g, 3.79 mmol) in anhydrous DMF (9.66 ml) it is stirred at room temperature for about 1 hour under a nitrogen atmosphere. A solution of (R) -N'-hydroxy-4- (tetrahydrofuran-3-yloxy) -3- (trifluoromethyl) benzimidamide (1.00 g, 3.45 mmol) in anhydrous DMF (1.823 ml) is added. ) and the reaction mixture is stirred at approximately 140 ° C for about 2 hours. The reaction is cooled to room temperature and poured into water (200 ml). The crude product is partitioned between EA and the aqueous phase. The combined organic extracts are washed with 20% brine solution and 1 N HCl (2 x 50 mL), 1 N NaOH (3 x 50 mL) and water (3 x 50 mL), then dried with MgSO 4, filtered and the solvent is removed to obtain a pale brown solid 1.23 g of (R) -5- (1 H -indol-4-yl) -3- (4- (tetrahydrofuran-3-yloxy) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazole LC / MS (Table 1, Method c) Rt = 2.36 minutes, m / z 416.1 (M + H) +.
H NMR (400 MHz, DMSO-d6) d 11.7 (d, 1H), 8.39 (dd, 1H), 8.31 (d, 1H), 8.15 (s, 1H), 7.99 (dd, 1H), 7.79 (td, 1H), 7.69 (m, 1H), 7.53 (d, 1H), 7.35 (m, 1H), 7.18 (ddd, 1H), 5.36 (m, 1H), 3.82 (m, 4H), 2.31 (dd, 2H) ), 1.99 (s, 2H).
Preparation # 59: Preparation of (R) -tert-butyl-3- (4- (3- (4- (tetrahydrofuran-3-yloxy) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazole-5 -iD-1 H-indol-1-iQpropanoate To a stirred solution of (R) -5- (1 H -indol-4-yl) -3- (4- (tetrahydrofuran-3-yloxy) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazole (0.4 g, 0.963 mmol) in ACN (5.0 ml) (which is heated to about 60 ° C until complete dissolution), tert-butyl acrylate (0.212 ml, 1445 mmol) is added dropwise, followed by DBU (0.072 ml). , 0.482 mmol). The solution is stirred at approximately 50 ° C for about 18 hours. The solvent is removed and the yellow solid is dissolved in EtOAc (150 ml), washed with saturated brine (3 x 100 ml), dried with MgSO 4, filtered and the solvent is removed to obtain a gum / solid of yellow color (0.59 g). The gum / solid is triturated with EtOAc (5 mL), cooled to approximately 0-5 ° C and the solid The resulting pale yellow color is collected, washed with ice-cold EtOAc (2 x 1 ml) and cold 30-60 ° C petroleum ether (2 x 1 ml) and dried to obtain (R) -ter-butyl-3- ( 4- (3- (4- (tetrahydrofuran-3-yloxy) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazole-5-M) -1 H -indole-1-yl) propanoate. (0.27 g, 52% yield).
LC / MS (Table 1, Method c) Rt = 2.76 minutes, m / z 544.22 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d 8.39 (dd, 1 H), 8.3 (d, 1 H), 8.01 (dd, 1 H), 7.94 (d, 1 H), 7.7 (d, 1 H), 7.53 (d, 1H), 7.4 (m, 1H), 7.12 (dd, 1H), 5.36 (d, 1H), 4.52 (t, 2H), 3.99 (dd, 1H), 3.84 (ddd, 3H), 2.81 (t, 2H) ), 2.31 (dd, 1H), 2.07 (s, 1H), 1.31 (s, 9H).
EXAMPLE # 60 Preparation of (R) -3- (4- (3- (4- (tetrahydrofuran-3-yloxy) -3- (trifluoromethyl) phenyl) -1.2.4-oxadiazol-5-yl) -1 H-indole acid -1 -il) propanoic A stirred solution of (R) -ter-butyl-3- (4- (3- (4- (tetrahydrofuran-3-yloxy) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl ) -1 H-indol-1-yl) propanoate (0.25 g, 0.460 mmol) in DCM (23 mL) is treated with trifluoroacetic acid (0.709 mL, 9.20 mmol) at room temperature. The reaction mixture is stirred for about 20 hours. The solvent is removed and the residue is diluted with water (50 ml). The product is partitioned between EtOAc (4 x 2 mL) and the acidic aqueous phase. The extracts are combined and washed with saturated brine (4 x 30 ml) and dried with MgSO 4, filtered and the solvent removed in vacuo to obtain a pale yellow solid (0.24 g). The solid is recrystallized with can (8 ml), cooled to room temperature before collecting the solid, washed with ACN (2 x 2 ml), petroleum ether 30-60 ° C (2 x 2 ml) and dried to obtain a pale yellow powdery solid of (R) -3- (4- (3- (4- (tetrahydrofuran-3-yloxy) -3- (trifluoromethyl) phenyl) -1, 2,4-oxadiazole- 5-yl) -1H-indol-1-yl) propane. (0.155g, 69%) LC / MS (Table 1, Method c) Rt = 2.12 minutes, m / z 486.11 (M-H) -. 1 H NMR (400 MHz, DMSO-d 6) d 12.48 (m, 1), 8.38 (dd, 1H), 8.3 (d, 1H), 8.01 (dd, 1H), 7.95 (d, 1H), 7.71 (d, 1H), 7.53 (d, 1H), 7.4 (m, 1H), 7.16 (dd, 1H), 5.36 (dt, 1H), 4.53 (t, 2H), 3.99 (dd, 1H), 3.84 (ddd, 3H) ), 2.81 (t, 2H), 2.31 (m, 1H), 2.05 (m, 1H).
EXAMPLES # 61.62.63 v 64 Preparation of (1 R.3S) -3-r4- (5-biphenyl-2-yl-ri, 2,41-oxadiazol-3-yl) -2-methyl-phenylamino-1-cyclopentanecarboxylic acid, acid (1R, 3S) ) -3- r4- (5-Biphenyl-3-yl-H .2,41-oxadiazol-3-yl) -2-methyl-phenylamino-1-cyclopentanecarboxylic acid. acid (1 R.3S) -3-f4- (5-biphenyl-4- »i-G1.2.41 oxa di azol-3-yl) -2-m etM-f in i lamino! -cyclopentancarboxylic ico acid (1 R.3S) -3- (4-r5- (4-cyclohexyl-phenyl) -ri.2.41-oxadiazol-3-in-2-methylene-phenylamino) -c clopentancarboxylic ?? Synthesis of DD2: acid (1 R.3S) -3- (4-cyano-2-methyl-phenylamino) -cyclopentanecarboxylic acid DD1 DD2 A solution of DD1 (1 R, 3S) -3-amino-cyclopentanecarboxylic acid (5.89 g, 45.6 mmol) and 4-fluoro-3-methylbenzonitrile (5.60 g, 41.4 mmol) in DMSO (140 ml) and water (11.67 ml) ) is treated with potassium carbonate (12.60 g, 91 mmol) and the mixture is heated to about 110 ° C under nitrogen overnight. The solution is cooled to room temperature and diluted with water, washed with ether then acidified to pH = 2 with concentrated HCl. The product is extracted with ethyl acetate, the combined ethyl acetate layers are washed with saturated NaCl solution, dried with sodium sulfate, filtered and concentrated to about 100 ml. Hexane (100 ml) is added and the solution is concentrated until the product leaves the solution. The solids are filtered and the filtrate is concentrated to a gum which is dissolved in 40 ml of methanol, and water and concentrated until the crystals are formed. A second crop of solids is removed by filtration, combined with the first crop, then vacuum dried overnight to obtain 5.78 g of (1R.3S) -3- (4-cyano-2-methyl-phenylamino) -cyclopentanecarboxylic acid. (DD2, 57% yield) LC / MS (ESI): m / z 245.2 (M + H), R ,: 0.78 minutes.
Synthesis of DD3: (1 R, 3S) -3- (4-cyano-2-methyl-phenylamino) -cyclopentanecarboxylic acid ethyl ester DD2 DD3 In a 500 ml round bottom flask, (1R, 3S) -3- (4-cyano-2-methyl-phenylamino) -cyclopentanecarboxylic acid (DD2, 5.78 g, 23.7 mmole) in DMF (200 ml) is added. to get orange solution. Molecule sieve (4A, 8-12 mesh, 4.4 g) is added. HATU (10.8 g, 28.4 mmoles) is added in one portion, ethanol is added (2.08 ml, 35.6 mmol). The solution is stirred at room temperature for about 30 minutes, then the mixture is cooled to about 0 ° C in an ice bath. N, N-cyanopropylethylamine (8.27 ml, 47.4 mmol) was added dropwise over the course of about 10 minutes. The ice bath is removed, and the solution is stirred at room temperature overnight. The reaction mixture is filtered, washed with DMF, the combined filtrate is concentrated, the residue is partitioned between EtOAc and saturated ammonium chloride, the organic layer is washed with saturated ammonium chloride, water, saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated to obtain 8.1 g of brown oil, which is purified by means of gel chromatography (0-30% EtOAc / petroleum ether) to obtain the ester. Ethyl (1R, 3S) -3- (4-cyano-2-methyl-phenylamino) -cyclopentanecarboxylic acid (DD3, 5.48 g, 20.1 mmol, 85% yield) as an orange oil.
LC / MS (ESI): m / z 273.3 (M + H), R ,: 0.928 min.
Synthesis of D D4: Ethyl ester of (1 R.3S) -3-β4- (N-hydroxycarbamimidodo) -2-methylene-phenylamino-cyclopentanecarboxylic acid In a 250 ml round bottom flask, (1 R, 3S) -3- (4-cyano-2-methyl-phenylamino) -cyclopentanecarboxylic acid ethyl ester (DD3, 5.48 g, 20.1 mmol) and hydroxylamine are added. (4.92 mL, 80.4 mmol) in EtOH (86 mL) to obtain a pale yellow solution. The solution is heated to approximately 50 ° C overnight. The reaction mixture is almost colorless solution, which is concentrated, the residue is loaded in a silica gel cartridge with the help of EtOAc, purified by reverse phase HPLC (0% in the trans- verse of 3 minutes, 0- 95% MeOH / H20 over the course of 30 minutes, silica gel column 220 g) to obtain the ethyl ester of (1 R, 3S) -3- [4- (N-hydroxycarbamimidoyl) -2- methyl-phenylamino] -cyclopentanecarboxylic acid (DD4, 4 g, 1 3.1 mmol, 65% yield) as a slightly waxy, white solid.
LC / MS (ESI): m / z 306 (M + H), Rt: 1.80 minutes.
Synthesis of DD5: (1 R.3S) -3-β4- (5-biphenyl-2-yl-n, 2, 41-oxadiazol-3-yl) -2-methyl-phenylamino-1-cyclopentanecarboxylic acid ethyl ester In a 250 mL round bottom flask, 2-biphenylcarboxylic acid (340 mg, 1.72 mmol) and HOBT (300 mg, 1.997 mmol) in DCM (5 mL) are added to obtain white suspension. EDC-HCl (377 mg, 1.97 mmoles) is added in one portion, the reaction mixture becomes mostly clear, then it rapidly becomes a turbid suspension. After about 1 hour, the reaction mixture is a cloudy, pale yellow suspension. The ethyl ester of (1R, 3S) -3- [4- (N-hydroxycarbamimidoyl) -2-methyl-phenylamino] -cyclopentanecarboxylic acid (DD4, 500 mg, 1.64 mmol) is added with the aid of 5 ml of DC M, and the reaction mixture becomes deep blue solution immediately. This is stirred at room temperature for about 1 50 minutes. The reaction mixture is diluted with DCM, washed with brine, dried over sodium sulfate overnight, filtered and concentrated to obtain a yellow waxy solid, which is dissolved in 1,4-dioxane (1). 0 ml) to form a deep red solution, molecular sieves are added (4Á, 8-1 2 mesh, globules, 300mg). The solution is heated to approximately 10 ° C for about 2 hours. The solution is cooled, the reaction mixture is a black solution, it is concentrated, the residue is purified by chromatography on silica gel (6/1 petroleum ether to EtOAc) to obtain 10 mg (14.4% of yield) of (1 R, 3S) -3- [4- (5-biphenyl-2-yl- [1, 2,4] oxadiazol-3-yl) -2-methyl-phenylamino] -cyclopentanecarboxylic acid ethyl ester DD5.
LC / MS (ESI): m / z 468.2 (M + H), Rt: 2.49 minutes.
Synthesis of DD6: M ethylic acid ester R.3S) -3-f4- (5-biphenyl-3-yl-n, 2,41-oxadiazol-3-yl) -2-methyl-phenylamino-cyclopentanecarboxylic acid In a 250 ml round bottom flask, 3-biphenylcarboxylic acid (340 mg, 1.72 mmol) and HOBT (300 mg, 1.97 mmol) in DCM (5 mL) are added to obtain a white suspension. EDC-HCl (377 mg, 1.97 mmol) is added in one portion, the reaction mixture becomes mostly clear, then it quickly becomes a cloudy suspension. After about 1 hour, the reaction mixture is a cloudy, pale yellow suspension. The ethyl ester of the acid (1R, 3S) -3- [4- (N-hydroxycarbamimidoyl) -2-methyl-1-faith or lame-1-cyclopentanecarboxylic acid (DD10, 500 mg, 1.64 mmol) is added with the aid of anhydrous. my DCM The reaction mixture becomes a deep blue solution immediately, this is stirred at room temperature for about 150 minutes. The reaction mixture is diluted with DCM, washed with brine, dried over sodium sulfate overnight, filtered and concentrated to obtain a yellow waxy solid, which is dissolved in 1,4-dioxane (10 ml). mi) to form a deep red solution, add MS (4Á, 8-12 mesh, globules, 300 mg). The solution heats up about 1 1 0 ° C for about 2 hours. The solution is cooled, the reaction mixture is a black solution, it is concentrated, the residue is purified by chromatography on silica gel (6/1 petroleum ether to EA) to obtain 280 mg (36.6% yield) of compound DD6: (1R, 3S) -3- [4- (5-biphenyl-3-yl- [1, 2,4] oxadiazol-3-yl) -2-methyl-phenylamino acid ethyl ester ] -cyclopentanecarboxylic acid LC / MS (ESI): m / z 468.2 (M + H), Rt: 2.57minutes.
Synthesis of DD9: Ethyl ester of (1 R.3S) -3-f4- (5-biphenyl'-4-yl-n, 2.41-oxadiazol-3-yl) -2-methyl-phenylamino-1-cyclopentanecarboxylic acid ester In a 250 ml round bottom flask, 4-biphenylcarboxylic acid (340 mg, 1.72 mmol) and HOBT (300 mg, 1.997 mmol) in DCM (5 ml) are added to obtain a white suspension. . EDC-HCl (377 mg, 1.97 mmoles) is added in one portion, the reaction mixture becomes mostly clear, then it quickly becomes a turbid suspension. After about 1 hour, the reaction mixture is a cloudy, pale yellow suspension. The ethyl ester of (1 R, 3S) -3- [4- (N-hydroxycarbamimidoyl) -2-methyl-phenylamino] is added.
Cyclopentanecarboxylic acid (DD4, 500 mg, 1.64 mmol) is added with the aid of 5 ml DCM. The reaction mixture becomes a deep blue solution immediately, this is stirred at room temperature for about 1 50 minutes. The reaction mixture is diluted with DCM, washed with brine, dried over sodium sulfate overnight, filtered and concentrated to obtain a yellow waxy solid, which is dissolved in 1,4-dioxane (1). 0 ml) to form a deep red solution, MS (4Á, 8-1 2 mesh, globules, 300 mg) is added. The solution is heated to approximately 1 1 0 ° C for about 2 hours. The solution is cooled, the reaction mixture is a black solution, it is concentrated, the residue is purified by chromatography on silica gel (6/1 petroleum ether to EA) to obtain 320 mg (41.8%). of yield) of the ethyl ester of the acid (1 R, 3S) -3- [4- (5-biphenyl-4-yl- [1, 2, 4] oxadiazol-3-yl) -2-methyl-phenylamino] - DD9 cyclopentanecarboxylic LC / MS (ES I): m / z 468.2 (M + H), Rt: 2.57 minutes.
Synthesis of DD 10: Ethyl ester of (1 R.3S) -3-H-r5- (4-cyclohexyl-phenyl) -M .2, 41-oxadiazol-3-ill-2-methyl-phenylamino > -cyclopentanecarboxylic In a 250 ml round bottom flask, add 4-cyclohexyl-benzoic acid (340 mg, 1.72 mmol) and HOBt (300 mg, 1.97 mmol) in DC (5 m ") to obtain a white suspension. EDC-HCI (377 mg, 1.97 mmol) in one portion, the reaction mixture becomes mostly clear, then it quickly becomes a turbid suspension, after about 1 hour, the reaction mixture is a cloudy suspension pale yellow colored acid ethyl ester (1 R, 3S) -3- [4- (N-hydroxycarbamimidoyl) -2-methyl-phenylamino] -cyclopentanecarboxylic acid (DD4, 500 mg, 1.64 mmole) is added with the aid of 5 ml DCM The reaction mixture becomes a deep blue solution immediately, it is stirred at room temperature for about 150 minutes The reaction mixture is diluted with DCM, washed with brine, dried with sodium sulfate overnight, filter and concentrate to obtain a yellow waxy solid , which is dissolved in 1,4-dioxane (10 ml) to form a deep red solution, MS (4Á, 8-12 mesh, globules, 300 mg) is added. The solution is heated to approximately 110 ° C for about 2 hours. The solution is cooled, the reaction mixture is a black solution, it is concentrated, the residue is purified by chromatography on silica gel (6/1 petroleum ether to EA) to obtain 91 mg (11.3% yield) of the compound DD10: ethyl ester of (1R, 3S) -3- acid. { 4- [5- (4-cyclohexyl-phenyl) - [, 2,4] oxadiazol-3-yl] -2-methyl-phenylamino} -cyclopentanecarboxylic LC / MS (ESI): m / z 474.2 (M + H), Rt: 2.75 minutes.
EXAMPLE # 61 Preparation of DD7: acid (1 R.3S) -3-r4- (5-biphenyl-2-yl-ri.2.41-oxadiazol-3-yl) -2-methyl-phenylamino-1-cyclopentanecarboxylic acid A solution of DD5: (1 R, 3S) -3- [4- (5-biphenyl-2-yl- [1, 2,4] oxadiazol-3-yl) -2-methyl-phenylamino] ethyl ester] -cyclopentanecarboxylic acid (110 mg, 0.235 mmol) in 1,4-dioxane (10 ml) with LiOH (1M, 4 ml), is stirred at room temperature for about 4 hours, then the mixture is acidified by 1.0 M HCl, diluted with EtOAc, wash with brine to pH = 6 approximately, dry with Na 2 SO 4, and concentrate. Reverse phase purification of HPLC yields 48.5 mg (47% yield) of DD7 acid (1 R, 3S) -3- [4- (5-biphenyl-2-yl- [1, 2,4] oxadiazole-3 -yl) -2-methyl-phenylamino] -cyclopentanecarboxylic acid. 1 H NMR (500 MHz, CDCl 3l d) 8.06 (d, 1 H, J = 7.6 Hz), 07.78 (d, 1 H, J = 8.4 Hz), 7.73 (s, 1 H), 7.61 (t, 1 H, J = 7.0 Hz) , 7.52-7.48 (m, 2H), 7.36-7.35 (m, 3H), 7.29-7.26 (m, 2H), 6.65 (d, 1H, J = 8.4 Hz), 5.17 (br, 1H), 4.05-4.03 (m, 1H), 3.01-2.99 (m, 1H), 2.38-2.29 (m, 1H), 2.14 (s, 3H), 2.10-1.85 (m, 5H).
EXAMPLE # 62 Preparation of DD8: acid (1 R.3S) -3-r4- (5-biphenyl-3-yl-G1.2.41 oxadiazol-3-yl) -2-methyl-phenylamino-1-cyclopentanecarboxylic acid A solution of DD6: (1 R, 3S) -3- [4- (5-bif in l-3-yl- [1, 2,4] oxadiazol-3-yl) -2-methyl ethyl ester phenylamino] -cyclopentanecarboxylic acid (280 mg, 0.599 mmol) in 1,4-dioxane (3 mL) with LiOH (1M, 2.4 mL), is stirred at room temperature for approximately 4 hours, then the mixture is acidified by 1.0 M HCl. , it is diluted with EtOAc, washed with brine to approximately pH 6, dried with Na 2 SO 4, and concentrated. Reverse phase purification of HPLC yields 144.9 mg (55.1% yield) of compound DD8: (1 R, 3S) -3- [4- (5-biphenyl-3-yl- [1, 2,4] oxadiazole] -3-yl) -2-methyl-phenylamino] -cyclopentanecarboxylic acid. 1 H NMR (500 MHz, CDCl 3, d) 8.43 (s, 1 H), 8.18 (d, 1 H, J = 8.4 Hz), 7.95 (d, 1H, J = 8.4 Hz), 7.88 (s, 1H), 7.81 (d, 1H, J = 8.0 Hz), 7.68 (d, 2H, J = 7.2 Hz), 7.61 (t, 1H, J = 7.8 Hz), 7.50 (t, 2H, J = 7.6 Hz), 7.41 (t, 1H, J = 7.4 Hz), 6.70 (d, 1H, J = 4.4 Hz), 3.07-3.00 (m, 1H), 2.42-2.33 (m, 1H), 2.19 (s, 3H), 2.14-1.88 (m, 5H).
EXAMPLE # 63 Preparation of DD11: (1 R, 3S) -3-r4- (5-biphenyl-4-yl-G1.2,41-oxadiazol-3-yl) -2-methyl-phenylamino-cyclopentanecarboxylic acid A solution of (1R, 3S) -3- [4- (5-biphenyl-4-yl- [1, 2,4] oxadiazol-3-yl) -2-methyl-phenylamino] -cyclopentanecarboxylic acid ethyl ester DD9 (105 mg, 0.225 mmol) in 1,4-dioxane (3 mL) with LiOH (1M, 0.9 mL) is stirred at room temperature for approximately 4 hours, then the mixture is acidified by 1.0 M HCl, diluted with EA, washed with brine until approximately pH = 6, dried with Na 2 SO 4, concentrated. Reverse phase purification of HPLC yields 90.9 mg (92% yield) of compound DD11: (1 R, 3S) -3- [4- (5-biphenyl-4-yl- [1, 2,4] oxadiazole] -3-yl) -2-methyl-phenylamino] -cyclopentanecarboxylic acid. 1 H NMR (500 MHz, CDCl 3, d) 8.26 (d, 1 H, J = 8.4 Hz), 7.96 (d, 1 H, J = 8.4 Hz), 7.89 (s, 1 H), 7.75 (d, 2 H, J = 8.4 Hz ), 7.65 (d, 2H, J = 7.2 Hz), 7.48 (t, 1H, J = 7.4 Hz), 7.41 (t, 2H, J = 7.4 Hz), 6.76 (d, 1H, J = 8.8 Hz), 6.16 (br, 1H), 4.13-4.05 (m, 1H), 3.07-3.00 (m, 1H), 2.40-2.33 (m, 1H), 2.22 (s, 3H), 2.15-1.88 (m, 5H).
EXAMPLE # 64 Preparation of DD12: (1 R, 3S) -3-f4-r5- (4-cyclohexyl-phenyD-G1.2,41-oxadiazol-3-yl-2-methyl-phenylamino) -cyclopentanecarboxylic acid A solution of DD10: ethyl ester of (1R, 3S) -3- acid. { 4- [5- (4-cyclohexylcyclohexyl-phenyl) - [1, 2,4] oxadiazol-3-yl] -2-methyl-phenylamino} -cyclopentanecarboxylic acid (129 mg, 0.272 mmol) in dioxane (10 mL) with LiOH (1M, 1.1 mL), stirred at room temperature for approximately 4 hours, then the mixture was acidified by 1.0 M HCl, diluted with EtOAc, Wash with brine until pH = 6 approximately, dry with Na 2 SO 4, and concentrate. Reverse phase purification of HPLC yields 97.1 mg (80% yield) of compound DD12: (1 R, 3S) -3- acid. { 4- [5- (4-cyclohexyl-phenyl) - [1,4] oxadiazol-3-yl] -2-methyl-phenylamino} -cyclopentanecarboxylic. 1 H NMR (500 MHz, CDCl 3, d) 8.10 (d, 1 H, J = 8.4 Hz), 7.93 (d, 1 H, J = 7.6 Hz), 7.89 (s, 1 H), 7.36 (d, 2 H, J = 8.4 Hz ), 6.82 (d, 1H, J = 8.0 Hz), 6.62 (br, 1H), 4.13-4.04 (m, 1H), 3.10-2.97 (m, 1H), 3.61-2.56 (m, 1H), 2.38- 2.31 (m, 1H), 2.24 (s, 3H), 2.11-1.75 (m, 10H), 1.50-1.25 (m, 1H).
EXAMPLE # 65 Preparation of acid f 1 R.3S) -3 - ((4- (3- (3-chloro-4-isopropoxypheni I) -1,2,4-oxadiazol-5-yl) phenyl) (methyl) amino) cyclopentanecarboxylic A 20 ml reaction vial equipped with a septa cap equipped with a nitrogen inlet needle is charged with acid (1 R, 3S) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid (0.469 g, 1.061 mmol) and formaldehyde solution (0.398 ml, 5.31 mmol) in acetic acid (0.61 ml) to obtain a colorless suspension. Sodium triacetoxyborohydride (0.675 g, 3.1 8 mmol) is added in one portion. The resulting suspension is allowed to stir at room temperature for 1 day. The reaction mixture is concentrated. The sample is diluted with water and the resulting solid is collected by filtration and dried open in air. The sample is further purified by automated silica gel chromatography (5% eOH: CH 2 Cl 2, EA column -40 g, 1 8 x 1 50 mm test tubes). The fractions containing product are concentrated to obtain (1 R, 3S) -3 - ((4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl acid ) (methyl) amino) cyclopentanecarboxylic acid (101 mg, 21%) as a white solid.
LC / MS (Table 1, Method g) Rt = 3.08 min utes, m / z 456 (M + H) +. 1 H NMR (400 MHz, DMSO) d 8.04-7.82 (m, 4H), 7.35 (d, J = 8.9, 1H), 6.96 (d, J = 9.2, 2H), 4.80 (dt, J = 12.2, 6.0, 1H), 4.46 (dd, J = 17.1, 7.4, 1H), 2.87 (s, 3H), 2.84-2.74 (m, 1H), 2.16 - 2.05 (m, 1H), 2.05 - 1.60 (m, 6H), 1.33 (d, J = 6.0, 6H) Preparation # 60a: Preparation of 3- (5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1H-indole-1- methyl Q-cyclopentanecarboxylate A 100 ml round bottom flask equipped with rubber septum and needle for nitrogen inlet is charged with 3- (3-chloro-4-isopropoxyphenyl) -5- (1 H -indol-5-yl) -1,2. , 4-oxadiazole (0.144 g, 0.407 mmol) in DMF (4.07 ml) to obtain a tan solution. The reaction mixture is cooled to approximately 0 ° C for about 10 minutes. Sodium hydride dispersion in mineral oil (0.020 g, 0.488 mmol) is added in one portion. The resulting suspension is allowed to stir at about 0 ° C for about 20 minutes. Methyl 3-bromocyclopentanecarboxylate (0.101 g, 0.488 mmol) is added in one portion. The resulting yellow solution is allowed to stir at room temperature for 1 day. 3- are added Methyl bromocyclopentanecarboxylate (0.1 69 g, 0.814 mmol) and additional sodium iodide (0.031 g, 0.204 mmol) each sequentially in one portion. The resulting solution is allowed to stir at room temperature for an additional 8 hours. The reaction mixture is concentrated and the sample is transferred in solution to a preparative H PLC column and eluted with 60% -100% MeC N: water (N H OAc buffer) over the course of 30 minutes. The fractions containing product are combined and concentrated to obtain 3- (5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1 H -indole-1- il) methyl cyclopentanecarboxylate (11 mg, 6%).
LC / MS (Table 1, Method g) Rt = 3.55 minutes, m / z 480 (M + H) \ EXAMPLE # 67 Preparation of 3- (5- (3- (3-chloro-4-isopropoxypheni) -1 .2.4-oxadiazole-5-l) -1 H -indole-1-cyclopentanecarboxylic acid A 25 ml round bottom flask equipped with rubber septum and needle for nitrogen inlet is charged with 3- (5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazole-5. -yl) -1 H-indol-1-yl) cyclopentanecarboxylic acid (0.01 1 g, 0.023 mmol) in (1, 4?) Dioxane (2292 ml) to obtain a colorless solution. Sodium hydroxide solution (0.229 ml, 0.229 mmole) is added by dripping through syringe. The resulting solution is allowed to stir at room temperature for about 2 hours. The pH of the solution is adjusted to pH = 1 approximately by drip addition of 1N HCl solution. The mixture is diluted with DCM and the solution is washed with H20 (1 x 10 mL). The organic phase is dried with MgSO 4, filtered and concentrated to obtain 3- (5- (3- (3-chloro-4-isopropoxyphenyl) -, 2,4-oxadiazol-5-yl) -1 H-indole. -1-yl) cyclopentanecarboxylic acid (10 mg, 90%) as a colorless oil.
LC / S (Table 1, Method g) R, = 3.12 minutes, m / z 466 (M + H) +. 1 H NMR (400 MHz, DMSO) d 8.47 (d, J = 1.7, 1H), 8.10 -7.92 (m, 3H), 7.79 (dd, J = 11.9, 8.6, 1H), 7.72 (dd, J = 7.8, 3.2, 1H), 7.40 (d, J = 8.8, 1H), 6.73 (t, J = 2.6, 1H), 5.14 - 5.00 (m, 1H), 4.88 -4.78 (m, 1H), 3.13 - 2.93 (m , 2H), 2.31 - 2.08 (m, 4H), 2.10 - 1.94 (m, 2H), 1.39 - 1.33 (m, 6H).
Preparation # 60: Preparation 3- (3-Chloro-4-ylpropoxyphenyl) -5- (4-fluoro-3 - ((trimethylsilyl) ethylene) phenyD-1.2.4-oxadiazole 25 ml round bottom flask equipped with Reflux condenser equipped with a nitrogen inlet adapter is charged with 5- (3-bromo-4-fluorophenyl) -3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazole (0.608 g, 1 .477 mmoles), bis (triphenylphosphine) palladium chloride (ll) (0.052 g, 0.074 mmol), copper iodide (l) (0.014 g, 0.074 mmol), is emptied and filled with nitrogen (three cycles), and then TH F is added to obtain a yellow solution. Ethynyltrimethylsilane (0.307 ml, 2.21 mmol) and triethylamine (0.61 ml, 4.43 mmol) are added sequentially in one portion. The reaction mixture is heated to approximately 60 ° C for approximately 6 hours. The reaction mixture is allowed to cool to room temperature and concentrated. The sample is deposited on silica gel and purified by automated silica gel chromatography (2% EtOAc: Heptane; EA column -40g, 1 8 x 1 50 mm test tubes). The product-containing fractions are combined and concentrated to obtain 3- (3-chloro-4-isopropoxyphenyl) -5- (4-fluoro-3- ((trimethylsilyl) ethynyl) phenyl) -1,2,4-oxadiazole ( 321 mg, 51%) as a solid.
LC / MS (Table 1, Method g) Rt = 2.43 min utes, m / z 429 (M + H) +.
Preparation # 60b: Preparation of acid (1 R, 3S) -3- (4- (3- (3-chloro-4-isopropoxy-phenyl-1, 2,4-oxadiazol-5-yl) -2-ethynylphenylamino) cyclopentanecarboxylic acid A 20 ml microwave reaction vial equipped with septa cap for pressure release is loaded with 3- (3-chloro-4-isopropoxyphenyl) -5- (4-fluoro-3 - ((trimethylsilyl) ethynyl) phenyl) -1,2,4-oxadiazole (0.295 g, 0.688 mmol), (1 R, 3S) -3-aminocyclopentanecarboxylic acid (0.098 g, 0.756 mmol), and potassium carbonate (0.209 g, 1.51 3 mmol) in water (0.344 ml) and DMSO (3.09 ml) to obtain a cinnamon suspension. The reaction mixture is heated to about 70 ° C for about 1 hour using simultaneous heating while cooling. The reaction mixture is diluted with 10 mL of water and diluted with EtOAc. The solution is washed with 1 M HCl solution (3 x 50 mL) and saturated NaCl solution (1 x 50 mL). The organic phase is dried with MgSO 4, filtered and concentrated to obtain a solid which is triturated with MeOH, filtered, and dried open in air to obtain 256 mg of a solid which is suspended in DMSO and filtered. Wash with 1N HCl solution and dry open in air to obtain (1 R, 3S) -3 - ((4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazole- 5-yl) phenyl) (methyl) amino) cyclopentanecarboxylic acid (220 mg, 64%) as a white solid.
LC / M S (Table 1, Method g) Rt = 1 .63 min utes, m / z 466 (M + H) +.
EXAMPLE # 69 Preparation of (1 R, 3S) -3- (5-f 3- (3-chloro-4-isopropoxyphenyl) -1,4-oxadiazol-5-yl) -1H-indol-1-yl) cyclopentanecarboxylic acid A 50 ml reaction vial equipped with a septa cap equipped with a nitrogen inlet needle is charged with (1 R, 3S) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1) acid, 2,4-oxadiazol-5-yl) -2-ethynylphenylamino) cyclopentanecarboxylic acid (0.220 g, 0.113 mmol) and gold chloride (l) (2.63 mg, 0.011 mmol) in DCE (1133 ml) to obtain a solution of cinnamon colour. The reaction mixture is heated to about 80 ° C for about 14 hours. The reaction mixture is placed on silica gel and loaded onto a column of silica gel and eluted with 40% -80% EtOAc: Heptane. The fractions containing product are combined and concentrated to obtain (1 R, 3S) -3- (5- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) acid. -1 H -indo 1-1 -yl) cyclopentanecarboxylic acid (5 mg, 2%) as a solid.
LC / MS (Table 1, Method g) Rt = 3.12 minutes, 466 miz (M + H) +. 1 H NMR (400 MHz, DMSO) d 8.47 (d, J = 1.7, 1H), 8.10 - 7. 92 (m, 3H), 7.79 (del, J = 11.9, 8.6, 1H), 7.72 (dd, J = 7.8, 3.2, 1H), 7.40 (d, J = 8.8, 1H), 6.73 (t, J = 2.6, 1H), 5.14 - 5.00 (m, 1H), 4.88 - 4.78 (m, 1H), 3.13 - 2.93 (m, 2H), 2.31 - 2.08 (m, 4H), 2.10 - 1.94 (m, 2H), 1.39-1.33 (m, 6H).
Preparation # 61: Preparation of (E) -ethyl-4- (3- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -2-methylphenoxy) but-2 -enoato A 50 ml reaction vial equipped with a septa cap equipped with a nitrogen inlet needle is charged with 3- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) - 2-methylphenol (0.350 g, 1015 mmole) and potassium carbonate (0.351 g, 2.54 mmole) in acetone (5.08 ml) to obtain a colorless suspension. (E) -ethyl-4-bromobut-2-enoate (0.275 ml, 2030 mmol) is added by dripping through a syringe. The resulting suspension is allowed to stir at room temperature for about 2 days. The reaction mixture is diluted with EtOAc and the solution is washed with 1 M HCl solution (1 x 50 mL), saturated NaHCO 3 solution (1 x 50 mL), and saturated NaCl solution (1 x 50 mL). The organic phase is dried with MgSO 4, filtered and concentrated to obtain 540 mg of a solid. The sample is purified by automated silica gel chromatography (10% -20% EtOAc: Heptane, EA column -40 g, tubes of test 18 x 1 50 mm). The fractions containing product are combined and concentrated to obtain (E) -ethyl-4- (3- (3- (3-chloro-4-isopropoxyphenyl) -, 2,4-oxadiazol-5-yl) -2 -methylphenoxy) but-2-enoate (353 mg, 76%) as a solid.
LC / M S (Table 1, Method k) Rt = 1.98 minutes, m / z 457 (M + H) +.
Preparation # 62: Preparation of ethyl 4- (3- (3- (3-chloro-4-isopropoxyphenyl) -. 2, 4-oxadiazol-5-yl) -2-methylphenoxybutanoate A 1000 ml round bottom flask equipped with rubber septum and needle for nitrogen inlet is charged with (E) -ethyl-4- (3- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) -2-methylphenoxy) but-2-enoate (0.336 g, 0.735 mmol), copper chloride (l) (3.64 mg, 0.037 mmol), p-Tol-Binap (0.050 g) , 0.074 mmol), sodium tert-butoxide (3.53 mg, 0.037 mmol), it is drained and filled with nitrogen (three cycles), and then toluene (2.94 ml) is added to obtain a yellow solution. Poly (methylhydrosiloxane) (0.1 76 ml, 2.94 mmol) is added in one portion. The resulting solution is allowed to stir at room temperature for about 3 days. EtOH (approximately 10 mL) is added dropwise. The solution is diluted with EtOAc. The solution is washed with saturated NaHC03 solution (1 x 50 ml), H20 (1 x 50 ml), and saturated NaCl solution (1 x 50 ml). The organic phase is dried with MgSO 4, filtered and concentrated to obtain 590 mg of a solid. The sample is purified by automated silica gel chromatography (10% -40% EtOAc.Heptane, column EA-40g, test tubes 18 x 150 mm). The fractions containing product are combined and concentrated to obtain ethyl 4- (3- (3- (3-chloro-4-isopropoxy-phenyl) -1,2,4-oxadiazol-5-yl) -2-methylphenoxy) butanoate (178 mg, 53%) as an oil.
LC / MS (Table 1, Method g) Rt = 3.74 minutes, m / z 459 (M + H) +.
Preparation # 63: Preparation of (E) -4- (3- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -2-methylphenoxy) but-2- acid enoic A 25 ml round bottom flask equipped with rubber septum and needle for nitrogen inlet is charged with (E) -ethyl-4- (3- (3- (3-chloro-4-isopropoxyphenyl) -1,2, 4-oxadiazol-5-yl) -2-methylphenoxy) but-2-enoate (0.255 g, 0.407 mmol) in (1.4%) dioxane (2.037 ml) to obtain a colorless solution. Sodium hydroxide solution (1222 mL, 1222 mmol) is added in one portion. The resulting solution is allowed to stir at room temperature during approximately 16 hours. The pH is adjusted to pH = 4 approximately by drip addition of acetic acid. The solution is concentrated and triturated with water (1 x 20 ml). The solid is filtered through a sintered glass funnel, washed with water, and dried under vacuum to obtain (E) -4- (3- (3- (3-chloro-4-isopropoxyphenyl) -1) acid, 2,4-oxadiazol-5-yl) -2-methylphenoxy) but-2-enoic (39 mg, 22%) as a white solid.
LC / MS (Table 1, Method g) Rt = 3.05 minutes, m / z 429 (M + H) +. 1 H NMR (400 MHz, DMSO) d 8.04 (d, J = 2.0, 1H), 8.00 (d, J = 8.6, 1H), 7.77 (d, J = 7.7, 1H), 7.48 - 7.33 (m, 4H), 6.74 (d, J = 5.8, 1H), 5.07 (dd, J = 13.2, 7.1, 1H) , 4.86 - 4.75 (m, 1H), 3.19 (d, J = 7.0, 2H), 2.58 (s, 3H), 1.33 (d, J = 6.0, 6H).
Preparation # 64: Preparation of methyl 4-vodo-2-methoxybenzoate A 250 ml round bottom flask equipped with nitrogen inlet adapter is charged with 4-iodo-2-methoxybenzoic acid (5.0 g, 17.98 mmol) in MeOH (36.0 ml) to obtain a colorless solution. The reaction mixture is cooled to approximately 0 ° C for about 20 minutes. HE add thionyl chloride (3.94 ml, 53.9 mmol) slowly through syringe. The resulting solution is allowed to stir at room temperature for about 18 hours. The solution is concentrated and dissolved in EtOAc. The solution is washed with saturated NaHCO 3 solution (1 x 200 ml) and saturated NaCl solution (1 x 200 ml). The organic phase is dried with MgSO 4, filtered and concentrated to obtain methyl 4-iodo-2-methoxybenzoate (5.2 g, 99%) as an oil.
LC / MS (Table 1, Method g) R, = 2.43 minutes. 1 H NMR (400 MHz, DMSO) d 7.47 (s, 1 H), 7.38 (s, 2 H), 3. 81 (s, 3H), 3.75 (s, 3H).
Preparation # 65: Preparation of methyl 2-methoxy-4 - ((1 R.4S) -3-oxo-2-azabicyclo2.2.11hept-5-en-2-yl) benzoate A 50 ml round bottom flask equipped with a reflux condenser equipped with a nitrogen inlet adapter is charged with (1 R, 4S) -2-azabicyclo [2.2.1] hept-5-en-3-one (1480 g, 13.56 mmol), copper iodide (l) (0.129 g, 0.678 mmol), tribasic potassium phosphate (5.76 g, 27.1 mmol), is emptied and filled with nitrogen (three cycles), and then toluene is added ( 27.1 mi) to obtain a white suspension. Methyl 4-iodo-2-methoxybenzoate (4.95 g, 16.95 mmol) and N1, N2-dimethyletan-1,2-diamine (0.146 ml, 1356 mmol) are added each sequentially in one portion. The reaction mixture is heated to approximately 110 ° C for about 18 hours. The reaction mixture is filtered and deposited on silica gel. The crude material is purified by automated silica gel chromatography (10% -50% EtOAc: Heptane, column EA-80g, test tubes 18 x 150 mm). The product-containing fractions are combined and concentrated to obtain 2-methoxy-4 - ((1 R, 4S) -3-oxo-2-azabicyclo [2.2.1] hept-5-en-2-yl) benzoate. methyl (2.69 g, 74%) as a solid.
LC / MS (Table 1, Method g) Rt = 1.95 minutes, m / z 274 (M + H) +.
Preparation # 66: Preparation of methyl 2-methoxy-4 - ((1 S.4R) -3-oxo-2-azabicycloi2.2.11heptan-2-yl) benzoate A 250 ml round bottom flask is charged with methyl 2-methoxy-4 - ((1 R, 4S) -3-oxo-2-azabicyclo [2.2.1] hept-5-en-2-yl) benzoate (2.70 g, 9.88 mmol) in ethyl acetate (99 ml) to obtain a brown solution. Palladium on charcoal (0.210 g, 0.198 mmol) is added in one portion. The resulting suspension is left stir under a hydrogen atmosphere (balloon) at room temperature for about 6 hours. The suspension is filtered through a Celita® pad. The filtrate is concentrated to obtain methyl 2-methoxy-4 - ((1 S, 4R) -3-oxo-2-azabicyclo [2.2.1] heptan-2-yl) benzoate (2.73 g, 100%) as a solid.
LC / MS (Table 1, Method g) Rt = 1.91 minutes, m / z 276 (M + H) +.
Preparation # 67: Preparation of 2-methoxy-4 - ((1 S.4R) -3-oxo-2-azabicyclo [2.2.11heptan-2-yl] benzoic acid A 25 ml round bottom flask equipped with rubber septum and needle for nitrogen inlet is charged with 2-methoxy-4 - ((1 S, 4R) -3-oxo-2-azabicyclo [2.2.1] heptan- 2-yl) methyl benzoate (0.61 g, 2.21 6 mmoles) in EtOH (8.86 ml) to obtain a colorless solution. Barium hydroxide solution (8.1 ml, 2.437 mmol) was added dropwise. The resulting suspension is allowed to stir at room temperature for about 1 6 hours. The pH is adjusted to pH = 5 approximately by drip addition of acetic acid. The solution is concentrated. The solid is triturated with EtOAc (1 x 25 mL). The solid is removed by filtration through a sintered glass funnel, and the filtrate is dried under vacuum to obtain 2-methoxy-4 - ((1S, 4R) -3-oxo-2-azabicyclo [2.2.1] acid. ] heptan-2-yl) benzoic acid (378 mg, 65%) as an oil.
LC / MS (Table 1, Method k) R, = 1.71 minute. 1 H NMR (400 MHz, DMSO) d 7.67 (t, J = 7.8, 1H), 7.42 (dd, J = 5.5, 1.9, 1H), 7.14 - 7.06 (m, 1H), 4.71 (s, 1H), 3.79 (s, 3H), 2.83 (s, 1H), 1.95 (m, 3H), 1.69 (dd, J = 17.7, 12.0, 1H), 1.52 (dd, J = 17.4, 10.9, 2H).
Preparation # 67a: Preparation of (1 S, 4R) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazole-5-M) -3-methoxyphenyl) -2 -azabicichlor2.2.1 lheptan-3-one 2-Methoxy-4 - ((1 S, 4R) -3-oxo-2-azabicyclo [2.2.1] heptan-2-yl) benzoic acid (0.340 g, 1301 mmol), HOBt (0.299 g, 1952) are suspended. mmoles), EDC (0.374 g, 1952 mmol) in DMF (2169 ml) under nitrogen. The solution is stirred at room temperature for approximately 30 minutes. (Z) -3-Chloro-N'-hydroxy-4-isopropoxybenzimidamide (0.446 g, 1952 mmol) is added as a solution in DMF (0.434 ml) and heated to about 140 ° C for about 4 hours. The solution is allowed to cool to room temperature and is precipitated with water. The solids are filtered and then dissolved in EtOAc. The organic phase is washed with 1N HCl solution (1 x 200 mL), saturated NaHCO 3 solution (1 x 200 mL), saturated NaCl solution (1 x 200 mL), dried over MgSO 3, filtered and concentrated to obtain (1S, 4R) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) -3-methoxyphenyl) -2-azabicyclo [2.2 .1] heptan-3-one (290 mg, 44%) as a solid.
LC / MS (Table 1, Method g) Rt = 3.18 minutes, m / z 454 (M + H) +.
EXAMPLE # 71 Preparation of acid (1 R.3S) -3- (4- (3- (3-chloro-4-isopropoxyphenih-1,2,4-oxadiazol-5-yl) -3-methoxyphenylamino) cyclopentanecarboxylic acid A 75 ml reaction vial equipped with a septa cap equipped with a nitrogen inlet needle is charged with (1 S, 4R) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2 , 4-oxadiazol-5-yl) -3-methoxyphenyl) -2-azabicyclo [2.2.1] heptan-3-one (0.290 g, 0.639 mmol) in THF (6.39 ml) to obtain a colorless solution. Sodium hydroxide solution (6.39 ml, 6.39 mmol) is added by dripping through a syringe. The reaction mixture is heated to about 60 ° C for about 16 hours. The pH is adjusted to pH = 2 approximately by drip addition of 1N HCl solution. The aqueous suspension is extracted with EtOAc (2 x 50 mL) and washed with saturated NaCl solution (1 x 50 mL). The organic phase is dried with MgSO 4, filtered and concentrated to obtain an oil. The sample is purified by automated silica gel chromatography (0% -5% MeOH: CH2Cl2, column EA-40g, test tubes 18 x 150 mm). The fractions containing product are combined and concentrated to obtain 204 mg of a solid. The sample is recrystallized from ether, the solvent is decanted, and the solid is collected and washed with ether, then dried in vacuo to obtain acid (1 R, 3S) -3- (4- (3- (3-chloro) -4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) -3-methoxyphenylamino) cyclopentanecarboxylic acid (120 mg, 39%) as a solid.
LC / MS (Table 1, Method g) R, = 2.85 minutes, m / z 472 (M + H) +. 1 H NMR (400 MHz, DIVISO) d 7.98 (d, J = 2.1, 1H), 7.92 (dd, J = 8.6, 2.1, 1H), 7.82 (d, J = 8.7, 1H), 7.34 (d, J = 9.0, 1H), 6.79 (d, J = 6.9, 1H), 6.33 (dd, J) = 8.8, 2.0, 1H), 6.29 (d, J = 1.8, 1H), 4.85 - 4.73 (m, 1H), 3.95 - 3.83 (m, 4H), 2.82 - 2.71 (m, 1H), 2.40 - 2.29 ( m, 1H), 2.01 (dd, J = 12.3, 7.0, 1H), 1.87 (dd, J = 15.3, 7.5, 2H), 1.70 - 1.60 (m, 1H), 1.53 (m, 1H), 1.33 (d , J = 6.0, 6H).
EXAMPLE # 72 Preparation of (R) -3- (3- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -2-methyloxy) propane-1,2-diol A 50 ml reaction vial equipped with a septa cap equipped with a nitrogen inlet needle is charged with 3- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) - 2-methylphenol (0.350 g, 1.01 mmol), (S) - (2,2-dimethyl-1,3-dioxolan-4-yl) methanol (0.1 39 mL, 1.1 mmol / L), and PS-triphenylphosphine (0.406 g, 1.21 8 mmol) in TH F (5.08 ml) to obtain a tan suspension. 4A molecular sieves are added in one portion. The resulting suspension is allowed to stir at room temperature for about 2 days. The reaction mixture is diluted with approximately 20 ml of ether and HCl (0.508 ml, 6.09 mmol) is added dropwise. The resulting suspension is allowed to stir at ambient temperature for about 6 hours. The suspension is filtered through a Celita® pad with the aid of EtOAc. The filtrate is concentrated and the resulting oil is diluted with DCM (5.08 ml). TFA (0.782 ml, 10.1 5 mmol) is added by dripping. The resulting solution is allowed to stir at ambient temperature for about 8 hours. The mixture is concentrated and the sample is purified by automated silica gel chromatography (5% -20% EtOAc: Heptane, RS-40g column, 1 8 x 1 50 mm test tubes). The product-containing fractions are combined and concentrated and then dissolved in MeOH. 1000 mg of K2C03 is added and the suspension is allowed to stir room temperature for about 6 hours. The solution is concentrated and triturated with water (2 x 50 mL), filtered and washed with water, then dried under vacuum to obtain (R) -3- (3- (3- (3-chloro-4-) isopropoxyphenyl) -1,4,4-oxadiazol-5-yl) -2-methylphenoxy) propane-1,2-diol (142 mg, 33%) as a white solid.
LC / MS (Table 1, Method g) R, = 3.35 minutes, m / z 457 (M + H) +.
H NMR (400 MHz, DMSO) d 8.04 (d, J = 2.1, 1H), 7.99 (dd, J = 8.6, 2.1, 1H), 7.61 (d, J = 7.3, 1H), 7.39 (dd, J = 8.5, 5.8, 2H), 7.28 (d, J = 8.0, 1H), 4.98 (d, J = 5.1, 1H), 4.82 (d, J = 6.0, 1H), 4.68 (s, 1H), 4.06 (d , J = 4.5, 1H), 3.98 (d, J = 5.7, 1H), 3.84 (d, J = 5.1, 1H), 3.50 (d, J = 2.7, 2H), 2.54 (s, 3H), 1.34 ( d, J = 6.0, 6H).
Preparation # 68: Preparation of diethyl (1 R.3R) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentylphosphonate, (1S. 3R) -3- (4- (3- (3-Chloro-4-isopropoxy-phenoxy-1,2-4,4-oxadiazol-5-yl) phenylamino) -cyclopentylphosphonate diethyl ester (1 R.3S) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) -cyclopentylphosphonate diethyl and (1 S, 3S) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentylphosphonate diethyl A solution of 4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) aniline (0.430 g, 1.30 mmol, 4- (3- (3-chloro-4) isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) aniline is prepared from 3-chloro-4-isopropoxybenzonitrile and 4-aminobenzoic acid following General Procedures C and D.), diethyl 3-oxocyclopentylphosphonate ( 0.861 g, 3.91 mmol, prepared according to Journal of Medicinal Chemistry (1986), 29 (10), 1988-95.), Acetic acid (1.50 ml, 26.1 mmol), 4 A molecular sieves (1.5 g) in DCM (6.5 mL) and MeOH (6.52 mL) is heated at about 40 ° C for about 6 hours, then NaCNBH3 (0.041 g, 0.65 mmol) is added. The reaction mixture is stirred at room temperature for about 16 hours. Water (20 ml) is added to the reaction mixture. After filtration, the filtrate is concentrated under reduced pressure and purified on silica gel (80 g) using (1-5% MeOH in DCM) followed by chiral chromatography (The gradient is 0-40% of A in 19 minutes. (flow rate 20 ml / minute) Mobile phase A is absolute ethanol, mobile phase B is HPLC grade heptane with 0.1% added diethylamine The column used for chromatography is a Daicel OD-H column, 20 x 250 mm (particles of 5 μ ??). The detection methods are UV detection (330 nm) as well as optical rotation) to obtain (1 R, 3R) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazole -5-yl) phenylamino) cyclopentylphosphonate diethyl [Rt 12.3 minutes, optical rotation = positive] (0.060 g, 9%): LC / MS (Table 1, Method b) R, = 2.87 min; MS m / z: 534 (M + H) +. (1S, 3R) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) diethyl cyclopentylphosphonate [Rt 13.4 minutes, optical rotation = negative] (0.065 g, 9%): LC / MS (Table 1, Method b) R, = 2.82 min; MS m / z: 534 (M + H) +. (1 R, 3S) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) diethyl cyclopentylphosphonate [Rt 15.4 minutes, optical rotation = positive] (0.149 g, 21%): LC / MS (Table 1, Method b) R, = 2.87 min; MS m / z: 534 (M + H) +. (1S, 3S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentylphosphonate diethylate [Table 3, Method 9, Rt 13.4 minutes, optical rotation = negative] (0.052 g, 7%): LC / MS (Table 1, Method b) R, = 2.82 min; MS m / z: 534 (M + H) \ EXAMPLE # 73 Preparation of N- (4- (3- (3-chloro-4-isopropoxy-phenyl) -1,2,4-oxadiazole-5-p-phenyl) isonicotinamide 4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) aniline is prepared from 3-chloro-4-isopropoxybenzonitrile and 4-aminobenzoic acid following General Procedures C and D. Isonicotinic acid (0.1 1 2 g, 0.91 mmol) is dissolved in thionyl chloride (5 ml, 68.5 mmol) to obtain a colorless solution. DM F (3 drops) is added, the reaction mixture is heated to about 70 ° C for about 16 hours. After cooling, the solvent is removed to obtain almost 0.2 g of pale yellow solid. Dissolve 4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) aniline (0.1 5 g, 0.455 mmol) in DCM (5 mL) to obtain a colorless solution, The reaction mixture is cooled to about 0-5 ° C in an ice bath. The cloudy suspension of 0.2 g of pale yellow solid in DCM (5 ml) is added dropwise to the solution. The ice bath is removed, the reaction mixture is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo, the yellow residue is triturated with methanol (3 mL) and DMSO (3 mL).The resulting suspension is filtered, the solid is washed with methanol (2 x 5 ml). It is dried in the oven overnight to obtain 0.1 8 g of solid, to which DMSO (2 ml) and methanol (2 ml) are added, heated at approximately 80 ° C for approximately 30 minutes. The solution is cooled, the mixture is filtered, the solid is collected and washed with methanol (5 ml) and water (2 x 5 ml), and dried to obtain N- (4- (3- (3-chloro-4). -isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) phenyl) isonicotinamide (0.12 g, 0.276 mmol, 60.7% yield) as a yellow powder.
LC / MS (Table 1, Method a) Rt = 4.39 minutes; MS m / z: 435.19 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 11.17 (s, 1H), 8.96 (dd, J = 4.84, 1.50 Hz, 2H), 8.26-8.20 (m, 2H), 8.17 (dd, J = 4.82, 1.54 Hz, 2H), 8.14-8.09 (m, 2H), 8.06 (d, J = 2.11 Hz, 1H), 8.00 (dd, J = 8.63, 2.13 Hz, 1H), 7.40 (d, J = 8.88 Hz, 1H), 4.91-4.75 (m, 1H), 1.36 (d, J = 6.02 Hz, 6H).
EXAMPLE # 74 Preparation of 3-amino-1- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) pyrrolidine-3-carboxylic acid 3-Amino-1- (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) benzyl) pyrrolidine-3-carboxylic acid is made by the General Procedures H and K.
LC / MS (Table 1, Method g) R, = 1.94 minutes, m / z 457.14 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 8.12 (d, J = 8.29 Hz, 2H), 8.05 (d, J = 2.11 Hz, 1H), 7.99 (dd, J = 8.64, 2.12 Hz, 1H), 7.65 (d, J = 8.28 Hz, 2H), 7.38 (d, J = 8.97 Hz, 1H), 4.81 (dt, J = 6.0, 12.0 Hz, 1H), 3.73 (dd, J = 24.40, 10.0 Hz, 2H ), 2.96-2.90 (m, 1H), 2.75 (dd, J = 34.80, 10.0 Hz, 2H), 2.37-2.27 (m, 2H), 1.80-1.72 (m, 1H), 1.34 (d, J = 6.02 Hz, 6H).
Preparation # 69: Preparation of (1 R.3S) -methyl-3- (d i benci lamin o) cyclopen tanca rboxylate Step 1 (1R, 3S) -methyl-3-aminociclopen tanca rboxylate hydrochloride A solution of (1R, 3S) -3-aminocyclopentanecarboxylic acid (0.115 g, 0.890 mmol) (PepTech) in MeOH (1.5 ml) is cooled to about 0 ° C in an ice bath. Thionyl chloride (0.130 ml, 1781 mmol) is added dropwise. The reaction mixture is stirred at about 0 ° C for about 2 hours, then the reaction mixture is heated to about 65 ° C for about 18 hours until CCF in (3: 1: 1 n-BuOH / AcOH / water) sample (ninhydrin visualization / EtOH) less polar spot formation (product Rf = 0.428, SM's Rf = 0.345). The reaction mixture is cooled and concentrated to obtain (1R, 3S) -methyl-3-aminocyclopentanecarboxylate hydrochloride (0.16 g, 0.89 mmol, 100% yield) as a pale green solid.
Step 2 (1 R, 3S) -methyl-3- (dibenzylamino) cyclopentanecarboxylate A solution of sodium carbonate (0.296 g, 2.79 mmol) in water (0.840 ml) is added DCM (1680 ml). Hydrochloric acid (1R, 3S) -methyl-3-aminociclopentancarboxylate (0.125 g, 0.698 mmol) is added, then benzyl bromide (0.170 mL, 1431 mmol) is added. The reaction mixture is heated to about 40 ° C for about 7 hours. The reaction mixture is cooled, partitioned between EtOAc (30 mL) and water (30 mL), the organic layer is washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to obtain 237 mg. of pale yellow oil, which is purified by Analogix® (0-25% EtOAc / heptane over the course of 20 minutes; 12 g Redi-Sep® silica gel column) to obtain (1 R, 3S ) -methyl-3- (dibenzylamino) cyclopentanecarboxylate (0.195 g, 0.603 mmol, 86% yield) as a colorless oil.
LC / MS (Table 1, Method g) Rt = 2.89 minutes, m / z 324.19 (M + H) +.
Preparation # 70: Preparation of (3S) -methyl-3-amino-1-fluorocyclopentanecarboxylate Step 1 (3S) -methyl-3- (dibenzylamide i) - 1-fluorocyclopentanecarboxylate A solution of (1R, 3S) -methyl-3- (dibenzylamino) cyclopentanecarboxylate (0.139 g, 0.430 mmol) in TH F (1.433 ml) is cooled to about -78 ° C in a dry ice bath. /acetone. Potassium hexamethyldisiazide (0.945 ml, 0.473 mmol) (0.5 in toluene) is added dropwise over the course of about 5 minutes, the reaction mixture is stirred at about -78 ° C for about 50 minutes. A solution of N-fluoro-N- (phenylsulfonyl) benzenesulfonamide (0.163 g, 0.51 6 mmol) in THF (0.71 ml) was added dropwise over the course of about 1 minute, then the water bath was removed. cooling, the reaction mixture is heated to room temperature. Hydrochloric acid (0.1 M, 4.30 mL, 0.430 mmol) is added to quench the reaction. The mixture is partitioned between water (30 ml) and ether (30 ml), the aqueous layer is extracted with ether (2 x 1.5 ml), the combined ether layer is washed with brine (20 ml), dried with sulfate of sodium, filtered and concentrated to obtain 198 mg of yellow oil, which is purified by Analogix® (0-30% EtOAc / heptane in the course of 20 min.; silica gel column of 1 2 g Redi-Sep®) to obtain (3S) -methyl-3- (dibenzylamino) -1-fluorocyclopentanecarboxylate (0.098 g, 0.287 mmol, 66.8% yield) as a colorless oil.
LC / MS (Table 1, Method g) R, = 3.1 1 minutes, m / z 342.1 5 (M + H) +.
Step 2 (3S) -methyl-3-amino-1-fluorocyclopentanecarboxylate elaborated by General Procedure N and used in the next step without further purification.
Preparation # 71: Preparation of (3S) -methyl-3-amino-1-methylcyclopentanecarboxylate Step 1 (3S) -methyl-3- (dibenzylamino) -1-methylcyclopentanecarboxylate A solution of diisopropylamine (0.521 ml, 3.65 mmol) in TH F (2.77 ml) is cooled to about 0 ° C in an ice bath, n-butyllithium (2.075 ml, 3.32 mmol) is added (1. 6 M in hexane) by dripping over the course of about 2 minutes. The solution is stirred at approximately 0 ° C for about 1 5 minutes. The reaction mixture is then cooled to about -78 ° C in a dry ice / acetone bath. A solution of (1R, 3S) -methyl-3- (dibenzylamino) cyclopentanecarboxylate (0.358 g, 1 .107 mmol) in TH F (1384 ml) is added dropwise over the course of about 8 minutes. This is stirred at -78 ° C for approximately 80 minutes. A colorless solution of methyl iodide (0.41 5 ml, 6.64 mmol) in TH F (1384 ml) is added dropwise over the course of about 1 3 minutes. The reaction mixture is stirred at about -78 ° C for about 24 minutes. The cooling bath is removed, the The reaction mixture is warmed to room temperature and stirred at room temperature overnight. The crude mixture is poured into saturated ammonium chloride (25 ml), rinsed with some water, extracted with EtOAc (50 ml), the organic layer is washed with water (20 ml) and brine (20 ml), it is dried with sodium sulfate, filtered and concentrated to obtain 390 mg of orange oil, which is purified by Analogix® (0-25% EtOAc / heptane in the course of 20 min; 40 g Redi-Sep®) to obtain (3S) -methyl-3- (dibenzylamino) -1-methylcyclopentanecarboxylate (0.34 g, 1,008 mmol, 91% yield) as an orange oil.
LC / MS (Table 1, Method g) R, = 3.1 1 minutes, m / z 338.1 9 (M + H) +.
Step 2 (3S) -methyl-3-amino-1-methylcyclopentanecarboxylate (3S) -methyl-3-amino-1-methylcyclopentanecarboxylate is made using General Procedure N. CC F Rf = 0.545 in 3: 1: 1 n-BuOH / AcO H / water (visualization with KMn04).
Preparation # 72: Preparation of (3S) -methyl-3-amino-1-hydroxycycloethanecarboxylate Step 1 A solution of KHM DS (0.557 ml, 0.278 mmol) in TH F (2441 ml) is cooled to about -78 ° C in a dry ice / acetone bath. A solution of (1 R, 3S) -methyl-3- (dibenzylamino) cyclopentanecarboxylate (0.06 g, 0.1 86 mmol) in TH F (1 .953 mL) is added dropwise over the course of about 3 minutes. The reaction mixture gradually turns orange-pink in the addition process. The solution is stirred at about -78 ° C for about 70 minutes. A solution of (R) -3-phenyl-2- (phenylsulfonyl) -1,2-oxaziridine (0.073 g, 0.278 mmol) is added. { Organic Syntheses, 1 988, 66, 203) in TH F (4.88 ml) by dripping over the course of about 3 minutes. The solution is stirred at about -78 ° C for about 70 minutes, then saturated N H CI (0.5 ml) is added to quench the reaction and the reaction mixture is warmed to room temperature. The reaction mixture is concentrated in vacuo, to the aqueous residue is added EtOAc (1.5 mL) and water (5 mL), the aqueous layer is removed, the organic layer is washed with water (10 mL) and brine (10 mL). ), dried over sodium sulfate, filtered and concentrated to obtain 140 mg of yellow solid, which was purified by Analogix® (0-50% EtOAc / heptane over the course of 20 minutes; of 40 g Red-Sep® silica) to obtain 20 mg of yellow oil. LC / MS shows a mixture of (3S) -methyl-3-amino-1-hydroxycyclopentanecarboxylate and N-oxide, LC / MS (Table 1, Method h) R, = 2.09; 2.57 minutes, m / z 340.2; 356.2 (M + H) +. (3S) -methyl-3-amino-1-hydroxycyclopentanecarboxylate is used without further purification in the next step.
The (S) -3-amino-1-hydroxy-cyclopentanecarboxylic acid methyl ester is made using General Procedure E.
LC / MS (Table 1, Method h) Rt = 0.46 minutes, m / z 1 60.09 (M + H) +.
EXAMPLE # 75 Preparation of (3S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazole-5-l) phenylamino) -1-hydroxycyclopentanecarboxylic acid (3S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1, 2,4-oxadia-2-yl-5-yl) phenylamino) -1-hydroxycyclopentanecarboxylic acid is made using the General Procedures P and Q LC / MS (Table 1, Method g) Rt = 2.39 minutes, m / z 458.09 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 8.02 (d, J = 1.9, 1H), 7. 96 (dd, J = 8.7, 2.0, 1H), 7.87 (dd, J = 8.9, 2.9, 2H), 7.36 (d, J = 8.8, 1H), 6.93-6.86 (m, 1H), 6.82 (d, J = 6.9, 1H), 6.72 (d, J = 8.8, 2H), 4.88 - 4.74 (m, 1H), 4.11 - 3.87 (m, 2H), 2.59 - 2.52 (m, 1H), 2.31 - 2.08 (m , 2H), 2.05 - 1.89 (m, 1H), 1.89 - 1.67 (m, 2H), 1.68 - 1.50 (m, 1H), 1.35 (d, J = 6.0, 6H).
Preparation # 73: Preparation of 3- (3-chloro-4-isopropoxyphenyl) -5- (4- (chloromethyl) phenyl) -1, 2,4-oxadiazole 3- (3-Chloro-4-isopropoxyphenyl) -5- (4- (chloromethyl) phenyl) -1,2,4-oxadiazole is made using General Procedure E.
LC / MS (Table 1, Method h) Rt = 3.15 minutes, m / z 365.09 (+ H) +. 1H RN (400 MHz, DMSO-d6) d ppm 8.25-8.17 (m, 2H), 8.07 (d, J = 2.12 Hz, 1H), 8.01 (dd, J = 8.65, 2.13 Hz, 1H), 7.73 (d , J = 8.26 Hz, 2H), 7.40 (d, J = 8.87 Hz, 1H), 4.90 (s, 2H), 4.83 ((dt, J = 6.0, 12.0 Hz, 1H), 1.35 (d, J = 6.02 Hz, 6H).
Preparation # 74: Preparation of (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-ylbenzyl) triphenylphosphonium chloride 3- (3-Chloro-4-isopropoxyphenyl) -5- (4- (chloromethyl) phenyl) -1, 2,4-oxadiazole (1653 g, 4.55 mmol) and triphenylphosphine (1790 g, 6.83 mmol) in xylene are added. (30.3 ml) to obtain a cloudy colorless solution. The solution is heated to approximately 140 ° C for approximately 18 hours. The solution is cooled, the suspension is filtered white, washed with heptane (3 x 8 ml), dried under vacuum (about 60 ° C) for about 3 hours to obtain (4- (3- ( 3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) benzyl) triphenylphosphonium (1812 g, 2.90 mmol, 63.7% yield) as a white solid.
LC / MS (Table 1, Method g) Rt = 2.89 minutes, m / z 589.11 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 8.06-8.02 (m, 3H), 8.00-7.86 (m, 4H), 7.78-7.67 (m, 12H), 7.38 (d, J = 8.97 Hz, 1H) , 7.23 (dd, J = 8.44, 2.35 Hz, 2H), 5.32 (d, J = 16.30 Hz, 2H), 4.81 (dt, J = 6.0, 12.0 Hz, 1H), 1.33 (d, J = 6.02 Hz, 6H).
EXAMPLE # 76 Preparation of acid (1 R.3S) -3- (4- (5- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxad-1-azole-3-yl) phenyl aminoprethylpentanecarboxylic acid The acid (1 R, 3S) -3- (4- (5- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylic acid is prepared using the General Procedure Q LC / MS (Table 1, Method g) R, = 2.94 minutes, m / z 442.27 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 12.10 (s, 1 H), 8.14 (d, J = 2.09 Hz, 1H), 8.07 (dd, J = 8.67, 2.16 Hz, 1H), 7.78 (d, J = 8.68 Hz, 2H), 7.42 (d, J = 8.90 Hz, 1H), 6.69 (d, J = 8.77 Hz, 2H), 6.40 (d, J = 6.66 Hz, 1H), 4.87 (dt, J = 6.0 , 12.0 Hz, 1H), 3.86-3.77 (m, 1H), 2.83-2.72 (m, 1H), 2.37-2.30 (m, 1H), 2.05-1.96 (m, 1H), 1.93-1.82 (m, 2H ), 1.69-1.61 (m, 1H), 1.57-1.49 (m, 1H), 1.36 (d, J = 6.01 Hz, 6H).
EJ EM PLO # 77 Preparation of 1-amino-3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-l) phenoxy) cyclopentanecarboxylic acid Step 1 4- (3- (ter-bu toxica rbonilam no) -3- (ethoxycarbonyl) cyclopentenyloxy) benzoate benzyl Benzyl 4- (3- (tert-butoxycarbonylamino) -3- (ethoxycarbonyl) cyclopentenyloxy) benzoate is prepared using General Procedure R.
LC / MS (Table 1, Method g) R, = 3.05 minutes, m / z 484.14 (M + H) +.
Step 2 4- (3- (tert-butoxycarbonylamino) -3- (ethoxycarbonyl) -cyclopentyloxy) benzoic acid The 4- (3- (tert-butoxycarbonylamino) -3- (ethoxycarbonyl) -cyclopentyloxy) benzoic acid is prepared using General Procedure N.
LC / M S (Table 1, Method g) Rt = 2.1 6 minutes, m / z 394.1 5 (M + H) +.
Step 3 1 - . 1 - . 1 - . 1- (tert-butoxycarbonylamino) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenoxy) cyclopentanecarboxylate ethyl The ethyl 1- (tert-butoxycarbonylamino) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenoxy) cyclopentanecarboxylate is prepared using the General Procedure D.
LC / M S (Table 1, Method g) Rt = 3.78 minutes, m / z 586.22 (M + H) +.
Step 4 1-amino-3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenoxy) ethyl cyclopentanecarboxylate The ethyl 1-amino-3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-M) phenoxy) cyclopentanecarboxylate is prepared using General Procedure K.
LC / MS (Table 1, Method g) R, = 2.57 minutes, miz 486.10 (M + H) +.
Step 5 Acid 1 -amino-3-. { 4- [3- (3-chloro-4-isopropoxy-phenyl) - [1, 2,4] oxadiazol-5-yl] -phenoxy} -cyclopentanecarboxylic The acid 1-amino-3-. { 4- [3- (3-chloro-4-isopropoxy-phenyl) - [1, 2,4] oxadiazol-5-yl] -phenoxy} -cyclopentanecarboxylic is prepared using the General Procedure P.
LC / MS (Table 1, Method g) Rt = 2.08 minutes, m / z 458.11 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 8.70-8.20 (brs, 2H), 8.13 (d, J = 8.9, 2H), 8.04 (d, J = 2.1, 1H), 7.98 (dd, J = 8.6 , 2.1, 1H), 7.38 (d, J = 9.0, 1H), 7.21 (d, J = 8.9, 2H), 5.16 - 5.09 (m, 1H), 4.82 (hept, J = 6.1, 1H), 2.77 ( dd, J = 14.7, 6.4, 1H), 2.44-2.19 (m, 2H), 2.20-2.02 (m, 3H), 1.35 (d, J = 6.0, 6H).
EXAMPLE # 78 Preparation of 1-amino-3- (3-chloro-4- (5- (5-chloro-6-isopropoxypyridin-3-yl) -1,2,4-oxadiazol-3-yl) phenoxy) cyclopentanecarboxylic acid Step 1 1- (tert-butoxycarbonylamino) -3- (3-chloro-4- (5- (5-chloro-6-) -propoxypyridin-3-M) -1, 2,4-oxadiazol-3-yl) phenoxy) ethyl cyclopentane carboxylate 1- (tert-butoxylcarbonylamino) -3- (3-chloro-4- (5- (5-chloro-6-isopropoxypyridin-3-yl) -1,2,4-oxadiazol-3-yl) phenoxy ethyl cyclopentanecarboxylate is prepared using General Procedure M.
LC / MS (Table 1, Method i) Rt = 2.10 minutes, m / z 621.20 (M + H) +.
Step 2 1-amino-3- (3-chloro-4- (5- (5-chloro-6-isopropoxypyridin-3-yl) -1,2,4-oxadiazol-3-yl) phenoxy) ethyl cyclopentanecarboxylate The ethyl 1-amino-3- (3-chloro-4- (5- (5-chloro-6-isopropoxypyridin-3-yl) -1,2,4-oxadiazol-3-yl) phenoxy) cyclopentanecarboxylate is prepared using General Procedure K.
LC / MS (Table 1, Method g) Rt = 2.90 minutes, m / z 521 .09 (M + H) +.
Step 3 1-amino-3- (3-chloro-4- (5- (5-chloro-6-isopropoxypyrid in) -1, 2,4-oxadiazol-3-yl) phenoxy) cyclopentanecarboxylic acid 1-amino-3- (3-chloro-4- (5- (5-chloro-6-isopropoxypyridin-3-yl) -1,2, 4-oxadiazol-3-yl) phenoxy) cyclopentanecarboxylic acid prepare using the General Procedure P.
LC / MS (Table 1, Method g) R, = 2.14 minutes, m / z 493.10 (M + H) +.
H NMR (400 MHz, DMSO-d6) d ppm 8.91 (d, J = 2.1, 1H), 8.53 (d, J = 2.1, 1H), 7.97 (d, J = 8.7, 1H), 7.89-7.60 (brs) , 2H), 7.25 (d, J = 2.4, 1H), 7.15 (dd, J = 8.8, 2.4, 1H), 5.51 - 5.39 (m, 1H), 5.14 - 5.05 (m, 1H), 2.65 (dd, J = 14.1, 6.1, 1H), 2.33 - 2.18 (m, 1H), 2.18 - 2.05 (m, 1H), 1.99 - 1.80 (m, 3H), 1.39 (d, J = 6.2, 6H).
EXAMPLE # 79 Preparation of acid (1 R, 3S) -3- (4- (5- (3-chloro-4-isopropoxyphenih-1,2,4-oxadiazol-3-yl) -3-methylphenylamino cyclopentanecarboxylic acid Step 1 2-methyl-4 - ((1 R, 4S) -3-oxo-2-azabicyclo [2.2.1] hept-5-en-2-yl) benzonitrile 4-Bromo-2-methylbenzonitrile (10 g, 51.0 mmol) and (1 R, 4 S) -2-azabicyclo [2.2.1] hept-5-en-3-one (4.64 g, 42.5 mmol) in toluene are added. (85 ml) to obtain a pale yellow suspension. Add N1, N2-dimethyletan-1, 2-diamine (0.458 ml, 4.25 mmol), add the ground tribasic potassium phosphate (18.05 g, 85 mmol). The reaction mixture is drained and refilled with nitrogen three times. Copper iodide (l) is added (0.405 g2,125 mmole). The reaction mixture is drained and refilled with nitrogen three times, a condenser is placed under nitrogen. The resulting green suspension is heated to approximately 130 ° C for about 16 hours. The reaction mixture is cooled and diluted with EtOAc (250 mL), washed with water (3 x 100 mL), HCl (1 N, 2 x 100 mL), and water (100 mL), the organic layer is filtered through Celita®, and concentrated to obtain 10.7 g of yellow solid, which is purified by Analogix® (10% -50% EtOAc / heptane over the course of 30 minutes; 120 g Redi-Sep® silica gel column) to obtain 2-methyl-4 - ((1 R, 4S) -3-oxo-2-azabicyclo [2.2.1] hept-5-en-2-yl ) benzonitrile (4.12 g, 18.37 mmol, 43.2% yield) as a white solid.
LC / MS (Table 1, Method g) R, = 2.10 minutes, m / z 225.12 (M + H) +.
H NMR (400 MHz, CDCl 3) d ppm 7.55 (d, J = 8.53 Hz, 1H), 7.44 (d, J = 2.00 Hz, 1H), 7.31 (dd, J = 8.53, 2.22 Hz, 1H), 7.02 ( dd, J = 5.28, 1.91 Hz, 1H), 6.73 (ddd, J = 4.96, 3.23, 1.43 Hz, 1H), 4.85 (dd, J = 3.78, 1.88 Hz, 1H), 3.56-3.50 (m, 1H) , 2.53 (s, 3H), 2.47 (td, J = 8.24, 1.63 Hz, 1H), 2.33 (td, J = 8.24, 1.54 Hz, 1H).
Step 2 Preparation of 2-methyl-4 - ((1 S, 4R) -3-oxo-2-azabicyclo [2.2.1] heptan-2-yl) benzonitrile 2-methyl-4 - ((1S, 4R) -3-oxo-2-azabicyclo [2.2.1] heptan-2-yl) benzonitrile is prepared using General Procedure N.
LC / MS (Table 1, Method h) R, = 2.10 minutes, m / z 227.13 (M + H) +.
Step 3 Preparation of (Z) -N'-hydroxy-2-methyl-4 - ((1 S, 4R) -3-oxo-2-azabicyclo [2.2.1] heptan-2-yl) benzimidamide (Z) -N'-hydroxy-2-methyl-4 - ((1S, 4R) -3-oxo-2-azabicyclo [2.2.1] heptan-2-yl) benzimidazole is prepared using the General Procedure C.
LC / MS (Table 1, Method g) R, = 1.33 minutes, m / z 260.17 Step 4 (1S, 4R) -2- (4- (5- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-3-yl) -3-methylphenyl) -2-azab cycle [2.2.1] heptan-3-one (1S, 4R) -2- (4- (5- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-3-yl) -3-methylphenyl) -2-azab Cycle [2.2.1] heptan-3-one is prepared using General Procedure D.
LC / MS (Table 1, Method g) R, = 3.45 minutes, m / z 438.14 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 8.17 (d, J = 2.17 Hz, 1H), 8.10 (dd, J = 8.69, 2.17 Hz, 1H), 8.02 (d, J = 8.39 Hz, 1H), 7.66-7.60 (m, 2H), 7.44 (d, J = 8.96 Hz, 1H), 4.88 (td, J = 6.0, 1H), 4.73 (brs, 1H), 2.88-2.83 (m, 1H), 2.61 ( s, 3H), 2.02-1.90 (m, 3H), 1.79- 1.68 (m, 1H), 1.61-1.54 (m, 2H), 1.36 (d, J = 6.01 Hz, 6H), 1.29-1.20 (m, 1H), 0.89-0.83 (m, 1H).
Step 5 Acid (1 R, 3S) -3- (4- (5- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadia-2-yl-3-yl) -3-methylphenylamino) cyclopentanecarboxylic acid (1 R, 3S) -3- (4- (5- (3-Chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-3-yl) -3-methylphenylamino) cyclopentanecarboxylic acid is prepared using the procedure General P.
LC / MS (Table 1, Method g) Rt = 3.08 minutes, m / z 456.44 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 12.13 (brs, 1H), 8.14 (d, J = 2.16 Hz, 1H), 8.07 (dd, J = 8.70, 2.17 Hz, 1H), 7.82 (d, J = 8.52 Hz, 1H), 7.43 (d, J = 9.03 Hz, 1H), 6.55 (d, J = 7.93 Hz, 2H), 6.28 (d, J = 6.84 Hz, 1H), 4.87 (td, J = 6.0 Hz, 1H), 3.81 (sextet, J, = 6.8 Hz, J2 = 7.2 Hz, 1H), 2.77 (quintet, J = 8.2 Hz, 1H), 2.51 (s, 7H), 2.38-2.28 (m, 1H) , 2.05-1.94 (m, 1H), 1.92-1.83 (m, 2H), 1.69-1.58 (m, 1H), 1.58-1.45 (m, 1H), 1.36 (d, J = 6.02 Hz, 6H).
EXAMPLE # 80 Preparation of (1S.4R) -2- (4- (5- (5-chloro-6-isopropoxypyrid8n-3-in- 1.2.4-oxadiazol-3-yl-3-methylphenyl) -2-azabicyclo2.2. nheptan-3-one (1S, 4R) -2- (4- (5- (5-chloro-6-isopropoxypyridin-3-M) -1, 2,4-oxadia-2-yl-3-yl) -3-methylphenyl) -2- azabicyclo [2.2.1] heptan-3-one is prepared using General Procedure D.
LC / MS (Table 1, Method g) Rt = 3.61 minutes, m / z 439.18 (M + H) +.
H NMR (400 MHz, CDCl 3) d ppm 8.86 (d, J = 2.12 Hz, 1H), 8.38 (d, J = 2.12 Hz, 1H), 8.09 (d, J = 8.60 Hz, 1H), 7.56 (d, J = 2.18 Hz, 1H), 7.47 (dd, J = 8.58, 2.26 Hz, 1H), 5.49 (td, J = 6.0, 1H), 4.57-4.52 (m, 1H), 3.02-2.97 (m, 1H), 2.69 (s, 3H), 2.13-1.86 (m, 4H), 1.84 -1.73 (m, 1H), 1.60-1.54 (m, 1H), 1.45 (d, J = 6.21 Hz, 6H).
EXAMPLE # 81 Preparation of acid (1 R.SSi-S- -fS-fS-chloro-e-isopropoxypyridin-S-in-l .2.4-oxadiazol-3-yl) -3-methylphenylamino) cyclopentanecarboxylic acid The acid (1 R, 3S) -3- (4- (5- (5-chloro-6-isopropoxypyridin-3-yl) -1,2,4-oxadiazol-3-yl) -3-methylphenylamino) cyclopentanecarboxylic acid prepare using the General Procedure P.
LC / MS (Table 1, Method g) Rt = 3.23 minutes, m / z 457.15 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 12.08 (brs, 1H), 8.88 (d, J = 2.10 Hz, 1H), 8.50 (d, J = 2.09 Hz, 1H), 7.83 (d, J = 8.66 Hz, 1H), 6.61-6.51 (m, 2H), 6.28 (d, J = 6.32 Hz, 1H), 5.44 (td, J = 6.0 Hz, 1H), 3.88-3.74 (m, 1H), 2.83-2.70 (m, 1H), 2.52 (s, 3H), 2.38-2.27 (m, 1H) ), 2.05-1.94 (m, 1H), 1.87 (dd, J = 15.25, 7.64 Hz, 2H), 1.68- 1.58 (m, 1H), 1.58-1.46 (m, 1H), 1.39 (d, J = 6.19 Hz, 6H).
EXAMPLE # 82 Preparation of 5- (3- (2H-tetrazol-5-yl) phenyl) -3- (3-chloro-4-isopropoxyphenyl) -1.2.4-oxadiazole A mixture of 3- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) benzonitrile Table A, entry A.4), sodium azide (0.036 g, 0.554 mmol) , zinc bromide (0.074 g, 0.329 mmol), water (2.83 mL) and THF (0.944 mL) is heated with stirring in a CEM microwave at approximately 120 ° C for approximately 105 minutes. The resulting suspension is acidified to a pH of about 1 using aqueous 1 N HCl. HE add acetic acid and ethanol, after which the mixture is stirred overnight. The solution is then diluted with water and stirred to obtain a white precipitate and the resulting solid is collected by vacuum filtration and washed with water to provide a white solid. The crude solid is further purified by automated flash chromatography (0-10% MeOH in DCM) to obtain the product, 5- (3- (2H-tetrazol-5-yl) phenyl) -3- (3-chloro) -4-isopropoxyphenyl) -1, 2,4-oxadiazole (0.090 g, 78%).
LC / MS (Table 1, Method g) Rt = 2.14 minutes, m / z 383 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d 8.84 (s, 1 H), 8.42 - 8.35 (m, 2 H), 8.10 (d, J = 2.1, 1 H), 8.04 (dd, J = 2.1, 8.6, 1 H) , 7.90 (t, J = 7.9, 1H), 7.41 (d, J = 8.8, 1H), 4.91-4.76 (m, 1H), 1.36 (d, J = 6.0, 6H).
EXAMPLE # 83 Preparation of 2- (5- (3- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) -2H-tetrazol-2-yl) methyl acetate A mixture of 5- (3- (2H-tetrazol-5-yl) phenyl) -3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazole (0.114 g, 0.299 mmol), methyl bromoacetate (0.06 ml, 0.651 mmol) and carbonate of Potassium (0.061 g, 0.441 mmol) in DMF (2.3 ml) is stirred overnight at room temperature. The mixture is then concentrated to dryness and the residue triturated with water (10 ml). The resulting suspension is filtered through a sintered glass funnel and the resulting solid is washed with water (3 x 15 ml), dried in air, and resuspended in dichloromethane / MeOH (9: 1; 5 ml). . The suspension is filtered through a sintered glass funnel and the filtrate is then concentrated under reduced pressure. The residue is purified by automated flash chromatography (0-25% EtOAc / heptane) to obtain the product as a white solid: 2- (5- (3- (3- (3-chloro-4-isopropoxyphenyl) ) -, methyl 2,4-oxadiazol-5-yl) phenyl) -2H-tetrazol-2-yl) acetate (0.082 g, 60.3%).
LC / MS (Table 1, Method g) Rt = 3.10 minutes, m / z 455 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d 8.82 (s, 1H), 8.40 (dd, J = 7.8, 19.8, 2H), 8.10 (d, J = 2.1, 1H), 8.05 (dd, J = 2.1, 8.6, 1H), 7.90 (t, J = 7.9, 1H), 7.40 (d, J = 8.8, 1H), 5.99 (s, 2H), 4.84 (dt, J = 6.2, 12.2, 1H), 3.78 (s) , 3H), 1.36 (d, J = 6.0, 6H).
Preparation # 85: Preparation of 3- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -N-hydroxybenzimidamide A mixture of 3- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzonitrile (0.1 01 g, 0.298 mmol), hydroxylamine hydrochloride (0.031 g) , 0.445 mmol) and triethylamine (0.095 mL, 0.684 mmol) in ethanol (2.98 mL) is heated to reflux for approximately 20 hours in a 1 0 mL round bottom flask. The reaction mixture is concentrated under reduced pressure to provide a crude solid, which is then triturated with water (5 ml) and then isolated by vacuum filtration, rinsed with water and air dried to obtain 3- (3 - (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -N-hydroxybenzimidamide (0.098 g, 88%), which is used without further purification.
LC / M S (Table 1, Method j) Rt = 1.45 minutes, m / z 373 (M + H) +.
EXAMPLE # 84 Preparation of 3- (3- (3- (3-chloro-4-isopropoxypheni) -1, 2,4-oxadiazol-5-yl) phenyl] -1), 2,4-oxadiazol-5 (2H) -one To a mixture of 3- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -N-hydroxybenzimidamide (0.098 g, 0.263 mmol) and 1,1 '-carbonyldi imidazole (0.058 g, 0.345 mmol) in 1,4-dioxane (0.263 mL) was added DBU (0.042 mL, 0.281 mmol). The solution The resulting heat is heated to approximately 105 ° C for about 4 hours and monitored by LC / MS (Table 1, method j). Additional 1, 1 '-carbonyldi-imidazole (0.021 g) and DBU (0.025 ml) are added and heating is continued for an additional 0.5 hours, after which LC / MS (Table 1, method j) indicates complete conversion to the product . The reaction mixture is diluted with water (6 ml), extracted with ethyl acetate (50 ml), acidified to a pH of about 2 with aqueous 4 N HCl, and extracted again with ethyl acetate (2 ×). 5 mi). The two organic layers are combined, concentrated under reduced pressure, and the resulting semi-solid is redissolved in dichloromethane and filtered to remove a white solid. The filtrate is concentrated and then purified by preparative HPLC (Varian ProStar with UV-Visible detector) using a Thermo Electron Hyperprep HS C18 column and the following gradient: A: Water; B: Acetonitrile; 30% B to 70% B over the course of 45 minutes to obtain the product: 3- (3- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) -1, 2,4-oxadiazol-5 (2H) -one (0.030 g, 28.6% yield).
LC / MS (Table 1, Method g) Rt = 2.61 minutes, m / z 397 (M-H) \ 1 H NMR (400 MHz, DMSO-d 6) d 13.42-13.04 (m, 1H), 8.62 (s, 1H), 8.40 (d, J = 8.0, 1H), 8.15 (d, J = 8.0, 1H), 8.09 (d, J = 1.9, 1H), 8.03 (dd, J = 2.0, 8.6, 1H), 7.87 (t, J = 7.9, 1H), 7.41 (d, J = 8.6, 1H), 4.92 - 4.74 (m , 1H), 1.36 (d, J = 6.0, 6H).
Preparation # 76: Preparation of 3- (4-fluorophenyl) -5- (4-isobutylphenyl) -1,2,4-oxadiazole 3- (4-fluorophenyl) -5- (4-isobutylphenyl) -1,2,4-oxadiazole is prepared from 4-isobutylbenzoyl chloride (prepared from 4-isobutylbenzoic acid [TCI] in accordance with the Procedure General F) and 4-fluorobenzamidoxime in accordance with General Procedure E.
LC / MS (Table 1, Method h) Rt = 3.32 minutes, m / z 297 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d 8.25 - 8.06 (m, 4 H), 7.52 - 7.39 (m, 4 H), 2.59 (d, J = 7.2, 2 H), 1.92 (dt, J = 6.8, 13.6, 1H), 0.89 (t, J = 8.5, 6H).
EXAMPLE # 85 Preparation of acid (1 R, 3S) -3- (4- (5- (4-isobuti If eni h-1, 2.4 oxadiazol-3-yl) phenylamino) cyclopentanecarboxylic acid (1R, 3S) -3- (4- (5- (4-Isobutylphenyl) -1,2,4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylic acid is prepared from 3- (4-fluorophenyl) - 5- (4-isobutylphenyl) -1, 2,4-oxadiazole and (1R, 3S) -3-aminocyclopentanecarboxylic acid (Acros) in accordance with General Procedure L.
LC / S (Table 1, Method g) R, = 3.09 minutes, m / z 406 (M + H) +. 1 H NMR (400 MHz, CDCl 3) d 8.13-8.07 (m, 2H), 8.00 -7.93 (m, 2H), 7.31 (s, 1H), 7.29 (s, 1H), 6.66 (d, J = 8.5, 2H ), 3.99 (p, J = 5.5, 1H), 3.03 - 2.91 (m, 1H), 2.56 (d, J = 7.2, 2H), 2.38 (ddd, J = 6.6, 9.1, 13.6, 1H), 2.12 - 1.87 (m, 5H), 1.80 (dd, J = 5.9, 11.6, 1H), 0.93 (d, J = 6.6, 6H).
Preparation # 77: Preparation of 3- (3-chloro-4-isopropoxypheni0-5- (2-ethyl-4-fluorophenyl) -1, 2,4-oxadiazole A 5 ml microwave reaction vial equipped with septa cap for pressure release is loaded with 5- (2-bromo-4-fluorophenyl) -3- (3-chloro-4-isopropoxyphenyl) -1, 2.4 -oxadiazole (0.500 g, 1215 mmole, prepared from 3-chloro-N-hydroxy-4-isopropoxy-benzamidine and 2-bromo-4-fluorobenzoyl chloride in accordance with General Procedure E), ethylboronic acid (0.179 g) , 2,429 mmoles, Alfa Aesar), tetrakis (triphenylphosphine) palladium (0) (0.140 g, 0.121 mmol), and tribasic potassium phosphate (0.516 g, 2.429 mmol) in 1,2-dimethoxyethane (13.35 ml) to obtain an orange suspension. The mixture is heated in a Biotage microwave at approximately 150 ° C for about 45 minutes. The reaction is concentrated to dryness to obtain an orange residue, which is purified by automated flash chromatography (0-10% EtOAc / heptane) to obtain 3- (3-chloro-4-isopropoxyphenyl) -5- (2-ethyl-4-fluorophenyl) -1,2,4-oxadiazole (0.224 g, 51.1% yield).
LC / MS (Table 1, Method h) Rt = 3.33 minutes, m / z 361 (M + H) +.
H NMR (400 MHz, CDCl 3) d 8.18 (d, J = 1H), 8.13 (dd, J = 5.8, 8.7, 1H), 8.01 (dd, J = 2.1, 8.5, 1H), 7.15 - 7.02 (m, 3H), 4.73 - 4.63 (m, 1H), 3.23 - 3.14 (m, 2H) ), 1.44 (d, J = 6.0, 6H), 1.32 (t, J = 7.5, 3H).
EXAMPLE # 86 Preparation of (1 R.3S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3-ethylphenylamino) cyclopentanecarboxylic acid The acid (1 R, 3S) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-M) -3-ethylphen-phenylane) c Clopentancarboxylic acid is prepared from 3- (3-chloro-4-isopropoxyphenyl) -5- (2-ethyl-4-fluorophenyl) -1, 2,4-oxadiazole and (1R, 3S) -3- aminocyclopentanecarboxylic acid (Acros) in accordance with General Procedure L.
LC / MS (Table 1, Method g) Rt = 3.14 minutes, m / z 470 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d 12.32-11.86 (m, 1H), 8. 01 (d, J = 2.1, 1H), 7.96 (dd, J = 2.1, 8.6, 1H), 7.89-7.82 (m, 1H), 7.38 (d, J = 8.7, 1H), 6.61 - 6.55 (m, 2H), 4.81 (p, J = 6.0, 1H), 3.91 - 3.80 (m, 1H), 3.04 (q, J = 7.4, 2H), 2.75 (s, 1H), 2.33-2.23 (m, 1H), 2. 02 - 1.92 (m, 1H), 1.92 - 1.82 (m, 2H), 1.72 - 1.60 (m, 1H), 1.60 - 1.48 (m, 1H), 1.35 (d, J = 6.0, 6H), 1.21 (d , J = 7.4, 4H).
Preparation # 78: Preparation of 2- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -5-fluorobenzonitrile A suspension of 5- (2-bromo-4-fluorophenyl) -3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazole (0.500 g, 1.215 mmol) and copper cyanide (1) (0.163) g, 1822 mmol) in N-methyl-2-pyrrolidinone (5.65 ml) is heated in a Biotage microwave at approximately 150 ° C. for about 15 minutes. The reaction is diluted with ethyl acetate (90 ml) and water (90 ml) is added. After separating the layers, the aqueous phase is extracted with ethyl acetate (2 x 25 mL) and the combined organic phases are washed with brine, dried with MgSO4 > they are filtered, and concentrated under reduced pressure. The crude material is purified automated flash chromatography (0-15% EtOAc / Heptane) to obtain the product, 2- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazole-5- il) -5-fluorobenzonitrile (0.220 g, 50.6% yield).
LC / MS (Table 1, Method g) R, = 3.06 minutes, m / z 358 (M + H.) +. 1 H NMR (400 MHz, CDCl 3) d 8.35 (dd, J = 5.2, 8.8, 1H), 8.20 (d, J = 2.1, 1H), 8.05 (dd, J = 2.1, 8.6, 1H), 7.66 - 7.48 ( m, 2H), 7.05 (d, J = 8.6, 1H), 4.68 (dt, J = 6.0, 12.1, 1H), 1.45 - 1.38 (m, 6H).
EXAMPLE # 87 Preparation of (1 R, 3S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3-cyano-phenylamino) -cyclopentanecarboxylic acid The acid (1 R, 3S) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3-cyano-phenylamino) -cyclopentanecarboxylic acid is prepared from 2- (3- (3-chloro-4-isopropoxyphenyl) -1,4,4-oxadiazol-5-yl) -5-fluorobenzonitrile and (1 R, 3S) -3-aminocyclopentanecarboxylic acid (Acros) in accordance with General Procedure L.
LC / MS (Table 1, Method g) R, = 2.85 minutes, m / z 467 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d 12.31-12.02 (m, 1H), 8.04 (d, J = 6.8, 2H), 7.98 (dd, J = 2.1, 8.6, 1H), 7.43-7.3 (m, 1H), 7.38-7.30 (m, 1H), 7.15 (d, J = 2.4, 1H), 7.00 (dd, J = 2.4, 9.0, 1H), 4.82 (p, J = 6.0, 1H), 3.92 (q , J = 6.8, 1H), 2.82-2.72 (m, 1H), 2.38-2.28 (m, 1H), 2.03 (s, 1H), 1.94 - 1.84 (m, 2H), 1.68 (s, 1H), 1.55 (d, J = 7.1, 1H), 1.35 (d, J = 6.0, 6H).
Preparation # 79: Preparation of (E) -ethyl-4- (1,3-dioxoisoindolin-2-M) -2-methylbut-2-enoate A 200 ml round-bottomed flask equipped with a reflux condenser equipped with a nitrogen inlet adapter is charged with ethyl tiglate (16.13 ml, 117 mmol), N-bromosuccinimide (10.72 ml, 126 mmol), and benzoyl peroxide. (0.012 g, 0.051 mmol) in carbon tetrachloride (58.5 ml) to obtain a yellow color suspension. The reaction mixture is heated to reflux for about 1 day. The mixture of The reaction is concentrated under reduced pressure by rotary evaporation to obtain a reddish-brown oil. The reaction flask is then equipped with a reflux condenser and adapter for nitrogen inlet, and then loaded with potassium phthalimide (19.82 g, 107 mmol) and DMF (86 ml) to obtain a purple solution. The mixture is heated in an oil bath at approximately 140 ° C for about 18 hours. The bath is removed and the reaction is cooled to room temperature, filtered through a sintered glass funnel, and concentrated under reduced pressure to about half of its original volume. The resulting dark brown solution is diluted with EtOAc (450 mL) and extracted with water (2 x 400 mL), saturated aqueous 50% NaCl (2 x 400 mL) and brine (400 mL). The organic phase is dried with MgSO 4, filtered and concentrated to obtain a brown oil. The crude material is purified by automated flash chromatography (10-50% EtOAc / heptane) to obtain a yellow semi-solid, from which the product is isolated by crystallization with cyclohexane: (E) -ethyl-4- (1,3-dioxoisoindolin-2-yl) -2-methylbut-2-enoate (4.0 g, 13.68% yield). 1 H NMR (400 MHz, CDCl 3) d 7.90-7.83 (m, 2H), 7.77 -7.70 (ra, 2H), 6.69-6.61 (m, 1H), 4.44 (d, J = 6.8, 2H), 4.22-4.13. (m, 2H), 1.27 (td, J = 0.8, 7.1, 3H).
Preparation # 80: Preparation of ethyl 4- (1,3-dioxoiso-indolin-2-yl) -2-methylbutanoate A solution of (E) -eti l-4- (1, 3-dioxoisoindolin-2-yl) -2-methylbut-2-enoate (4.0 g, 14.64 mmol) in methanol (150 ml) is passed through a H-Cube hydrogenation apparatus containing a 10% palladium on carbon cartridge at 1.5 ml / minute under a hydrogen atmosphere (approximately 20 bar) at approximately 20 ° C for approximately 90 minutes. The catalyst cartridge is replaced with a new one and the procedure is repeated, after which the resulting solution is concentrated by rotary evaporation to obtain ethyl 4- (l, 3-dioxoisoindolin-2-yl) -2-methylbutanoate (4.03 g, 100% yield), as a colorless oil. The material is used directly in the next step without further purification.
LC / MS (Table 1, Method h) Rt = 2.00 minutes, m / z 276 (M + H) +. 1 H NMR (400 MHz, CDCl 3) d 7.92 - 7.79 (m, 2 H), 7.77 - 7.64 (m, 2 H), 4.12 (q, J = 7.2, 2 H), 3.75 (t, J = 7.1, 2 H), 2.47 (h, J = 7.1, 1H), 2.16 - 2.02 (m, 1H), 1.79 (dq, J = 6.9, 13.7, 1H), 1.34 - 1.13 (m, 6H).
Preparation # 81: Preparation of 4-methyl-2-aminobutanoic acid A 500 ml round bottom flask equipped with a reflux condenser equipped with a nitrogen inlet adapter is charged with ethyl 4- (1, 3-dioxoisoindolin-2-yl) -2-methylbutanoate (4.03 g, 14.64 mmol) in acetic acid (1 1 3 ml) and HCl. 6 N (227 ml) to obtain a colorless solution. The solution is heated to approximately 35 ° C for approximately 24 hours. After cooling to room temperature, a white precipitate forms and is removed by vacuum filtration. The filtrate is concentrated under reduced pressure, filtered again to remove more solid, and further concentrated to obtain a slightly yellow residue. The residue is purified by ion exchange chromatography (Dowex 8 x 50 w H + form), rinsed with deionized water, prepared and charged with 1 N aqueous HCl, eluting sequentially with deionized water followed by aqueous 1 M aqueous solution. pyridine). The collection and evaporation of the appropriate fractions (identified using ninhydrin stain) allows the product, 4-amino-2-methylbutanoic acid (1.526 g,, 89% yield), to be obtained as a slightly yellow solid. The material is used directly in the next step without further purification. 1 H NMR (400 MHz, D20) d 3.10-2.95 (m, 2H), 2.47-2.35 (m, 1H), 1.98-1.84 (m, 1H), 1.82-1.69 (m, 1H), 1.16 (dd, J = 1.1, 7.0, 3H).
Preparation # 82: Preparation of 4-phenyl-5- (trifluoromethyl) thiophene-2-carboxamide Step 1 Combine 4-phenyl-5- (trifluoromethyl) thiophene-2-carboxylic acid (5 g, 18.37 mmol) (Maybridge) and DMF (0.071 mL, 0.918 mmol) in dichloromethane (184 mL) under nitrogen to obtain a colorless solution. Oxalyl chloride (1768 ml, 20.20 mmol) is added slowly and then the reaction is stirred for about 5 hours. The solvents are removed under reduced pressure. Toluene is added and the solvents are removed. The residue is dissolved in ethyl acetate (10 ml) and added dropwise to a rapidly stirred mixture of ethyl acetate (150 ml) and concentrated ammonium hydroxide (100 ml). The mixture is stirred for 1 hour. The layers are separated and the aqueous layer is extracted with ethyl acetate (50 ml). The combined extracts are washed with brine, dried over sodium sulfate, filtered, and evaporated to a white solid.
LC / M S (Method g) R, = 2.24 minutes; MS m / z: 270.06 (M-H) -. 1 H NMR (400 MHz, DMSO-d6) d ppm 8.24 (s, 1 H), 7.90- 7.87 (m, 1 H), 7.80 (s, 1 H), 7.52-7.42 (m, 5H) Step 2 Preparation of 4-phenyl-5- (trifluoromethyl) thiophene-2-carbonitrile 4-Phenyl-5- (trifluoromethyl) thiophene-2-carboxamide is dissolved (1.400 g, 5.1.6 mmol) in 1,2-dichloroethane (51 ml) under nitrogen to obtain a colorless solution. Burgess reagent (4.92 g, 20.64 mmol) (Acros) is added and the reaction heated to approximately 60 ° C for approximately 4 hours. The reaction is allowed to cool to room temperature. Methylene chloride (50 ml) and water (50 ml) are added and the layers are separated. The aqueous layer is extracted with methylene chloride (1 x 25 ml). The combined extracts are washed with brine, dried over sodium sulfate, filtered, and evaporated to a colorless solid. The residue is purified by flash chromatography (40 g.
Redi-Sep) eluting with 20-50% ethyl acetate / heptane and the product fractions are combined. The solvents are removed under reduced pressure to provide 4-phenyl-5- (trifluoromethyl) thiophene-2-carbonitrile (1.227 g, 4.85 mmol, 94% yield) as a white solid.
LC / MS (Method H) R, = 2.74 minutes. 1 H NMR (400 MHz, DMSO-d6) d ppm 8.27-8.1 7 (m, 1 H), 7.55-7.40 (m, 6H).
Step 3 Preparation of (Z) -N'-hydroxy-4-phenyl-5- (trifluoromethyl) thiophene-2-carboximidamide 4-Phenyl-5- (trifluoromethyl) thiophene-2-carbonitrile (1.22 g, 4.82 mmol) is dissolved in ethanol (48 ml) under nitrogen to obtain a colorless suspension. Hydroxylamine (0.947 ml, 1.297 mmol) is added and the reaction is heated to approximately 60 ° C for about 5 hours. CC F in EtOAc / heptane 1: 1 sample (visualization with uv light) that the reaction was complete. The reaction is allowed to cool to ambient temperature. The solvents are removed under reduced pressure. The residue is purified by flash chromatography (column 40 g Redi-Sep) eluting with 20-50% ethyl acetate / heptane and the product fractions are combined. The solvents are removed under reduced pressure to provide (Z) -N'-hydroxy-4-phenyl-5- (trifluoromethyl) thiophene-2-carboximidamide (1397 g, 4.88 mmol, 101% yield) as a white solid .
LC / MS (Method g) R, = 2.19 minutes; MS m / z: 287.08 (M + H) +. 1 H NMR (400 MHz, DMSO) d ppm 9.98 (s, 1 H), 7.65-7.63 (m, 1 H), 7.51-7.41 (m, 5 H), 6.15 (s, 2 H).
Preparation # 83: Preparation of the acid amide (1aS, 5aR) -1.1.2-trimethyl-1.1 a.5.5a-tetrahydro-3-thia-cyclopropafalpentalene-4-carboxylic acid Step 1 Combine (1 aS, 5aR) -1, 1, 2-trimethyl-1, 1 a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-carboxylic acid (0.39 g, 1754 mmoles) ( prepared in accordance with WO2006 / 010379) and DMF (6.79 μ ?, 0.088 mmol) in dichloromethane (17 ml) under nitrogen to obtain an orange solution. Oxalyl chloride (0.169 ml, 1930 mmol) is added and the reaction is stirred for about 4 hours. The solvents are removed under reduced pressure and the residue is dried under vacuum for about 30 minutes. The residue is dissolved in ethyl acetate (15 ml). Concentrated ammonium hydroxide (10 ml) is added with rapid stirring and the mixture is stirred for about 45 minutes. The layers are separated and the aqueous layer is extracted with ethyl acetate (15 ml). The combined organic extracts are washed with brine, dried over sodium sulfate, filtered, and evaporated to an orange oil. The residue is purified by flash chromatography (column 40 g Redi-Sep) eluting with EtOAc / heptane 1: 1 and the product fractions are combined. The solvents are removed under reduced pressure to provide the acid amide (1aS, 5aR) -1, 1, 2-trimethyl-1, 1 aSSa-tetrahydro-S-thia-cyclopropata-pentalene -carboxylic acid (0.324 g, 1464 mmoles, 83% yield) as an orange oil.
LC / MS (Method g) Rt = 2.12 minutes; MS m / z: 222.12 (M + H) +.
Step 2 Preparation of (1aS, 5aR) -1, 1, 2-trimethyl-1, 1-tetrahydro-3-thia-cyclopropa [a] pentalen-4-carbonitrile The amide of the acid is dissolved (1 aS, 5aR) -1, 1, 2-trimethyl-1, 1 a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-carboxylic acid (0.324 g, 1,464 mmole) in 1, 2- dichloroethane (14 ml) under nitrogen to obtain an orange solution. Burgess reagent (0.698 g, 2.93 mmol) (Acros) is added and the reaction is stirred for about 1 8 hours. Methylene chloride (20 ml) and water (15 ml) are added and the layers are separated. The aqueous layer is extracted with methylene chloride (1 x 10 mL). The combined extracts are washed with salt water, dried over sodium sulfate, decanted, and evaporated to an orange oil. The oil is purified by flash chromatography (40 g Redi-Sep) eluting with 0-1 0% ethyl acetate / heptane and the product fractions are combined. The solvents are removed under reduced pressure to provide (1 aS, 5aR) -1, 1, 2-trimethyl-1, 1 a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-carbonitrile ( 0.26 g, 1.279 mmol, 87% yield) as a colorless oil.
LC / MS (Method h) Rt = 2.84 minutes; MS m / z: 204.09 (M + H) +.
Step 3 Preparation of (1 aS, 5aR) -N-hydroxy-1,2, trimethyl-1, 1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-carboxamidine Combine (1 aS, 5aR) -1, 1, 2-trimethyl-1, 1 a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-carbonitrile (0.26 g, 1279 mmole) and hydroxylamine (50% solution in water) (0.302 ml, 5.12 mmol) in ethanol (12.8 ml) under nitrogen to obtain a colorless solution. The mixture is heated to approximately 60 ° C for about 5 hours. TLC in EtOAc / heptane 1: 1 sample (visualization with uv light) that the reaction was complete. The solvents are removed under reduced pressure. The residue is purified by flash chromatography (40 g Redi-Sep column) eluting with 20-50% ethyl acetate / heptane and the product fractions are combined. Solvents are removed under reduced pressure to provide (1 aS, 5aR) -N-hydroxy-1,2, trimethyl-1, 1 a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4 -carboxamidine (0.284 g, 1,202 mmol, 94% yield) as a white sticky solid LC / MS (Method g) Rt = 2.16 minutes; MS m / z: 237.09 (M + H) +.
Preparation # 84: Preparation of (2 R.4R) -1-tert-butyl-2-methyl-4- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazole-5 -yl) phenylamino) pyrrolidin-1,2-dicarboxylate Step 1 3- (3-Chloro-4-isopropoxyphenyl) -5- (4-fluorophenyl) -1,2,4-oxadiazole (0.4 g, 1,202 mmol), hydrochloride of (2 R, 4R) -1- are combined tert-butyl-2-methyl-4-aminopyrrolidin-1,2-dicarboxylate (0.506 g, 1,803 mmol) (Acesys Pharmatech), and potassium carbonate (0.498 g, 3.61 mmol) in DMSO (4.01 ml) in a sealed vial to obtain a white suspension. The mixture is heated to approximately 1000 ° C for approximately 20 hours. Ethyl acetate (20 ml) and water (20 ml) are added and the layers separated. The ethyl acetate layer is washed with water (2 x 10 ml). The ethyl acetate layer is washed with brine, dried with sodium sulfate, filtered, and evaporated to a yellow oil. The residue is purified by flash chromatography (column 40 g Redi-Sep) eluting with 10-50% ethyl acetate / heptane and the product fractions are combined. The solvents are removed under reduced pressure to provide (2R, 4R) -1-tert-butyl-2-methyl 4- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazole- 5- l) phenylamino) pyrrolidin-1,2-dicarboxylate (0.085 g, 0.153 mmol, 12.69% yield) as an off-white solid.
LC / MS (Method h) R, = 3.10 minutes; MS m / z: 557.24 (M + H) +.
NMR (400 MHz,) d 8.21 (d, J = 2.0, 1 H), 8.08 - 7.99 (m, 3 H), 7.05 (d, J = 8.7, 1 H), 6.75 - 6.66 (m, 2 H), 4.75 - 4.63 (m, 1H), 4.41 (dd, J = 8.6, 35.3, 1H), 4.31 - 4.19 (m, 1H), 3.90 - 3.54 (m, 5H), 2.66 - 2.42 (m, 1H), 2.26 - 2.10 ( m, 1H), 1.47 (t, J = 12.3, 16H).
Step 2 Preparation of (2R, 4R) -1- (tert-butoxycarbonyl) -4- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) pyrrolidin -2-carboxylic Dissolve (2R, 4R) -1-tert-butyl-2-methyl-4- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) pyrrolidin-1, 2-dicarboxylate (0.085 g, 0.153 mmol) in a mixture of THF (2.0 ml) and water (1.0 ml) under nitrogen to obtain a colorless solution. Lithium hydroxide (15 mg, 0.626 mmol) is added and the reaction is stirred for approximately 48 hours. The solvents are removed under reduced pressure. Ethyl acetate (15 ml) and 1N HCl (3 ml) are added and the layers separated. The aqueous layer is extracted with acetate ethyl (1 x 10 ml). The combined extracts are washed with brine, dried over sodium sulfate, filtered, and evaporated to a white solid. The residue is purified by flash chromatography (column 40 g Redi-Sep) eluting with 50-100% ethyl acetate / heptane and the product fractions are combined. The solvents are removed under reduced pressure to provide (2R, 4R) -1- (tert-butoxycarbonyl) -4- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazole- 5-yl) phenylamino) pyrrolidine-2-carboxylic acid (0.036 g, 0.066 mmol, 43.4% yield) as an off-white solid.
LC / MS (Method g) R, = 2.71 minutes; MS m / z: 543.15 (M + H) +, NMR (400 MHz,) d 8.21 (d, J = 1.6, 1H), 8.08 - 7.98 (m 3H), 7.05 (d, J = 8.6, 1H), 6.63 (d, J = 8.5, 2H), 4.76-4.64 (m, 1H), 4.59 (d, J = 8.8, 1H), 4.28 - 4.17 (m , 1H), 3.68 - 3.46 (m, 2H), 2.73 (d, J = 13.4, 1H), 2.50 - 2.36 (m, 1H), 1.53 (s, 9H), 1.50 (m, darkened, 1 H), 1.45 (d, J = 6.0, 6H).
EXAMPLE # 88 Acid (2R.4R) -4- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) phenylamino) pyrrolidine-2-carboxylic acid Dissolve (2R, 4R) -1 - (tert-butoxycarbonyl) -4- (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) phenylamino) pyrrolidine -2-carboxylic acid (0.036 g, 0.066 mmol) in dichloromethane (0.663 ml) under nitrogen to obtain a colorless solution. Trifluoroacetic acid (0.663 ml) is added and the reaction is stirred for about 18 hours. The solvents are removed under reduced pressure. The residue is purified by flash chromatography (4 g Redi-sep) eluting with EtOAc / (CHCl 3 / MeOH / NH 4 OH 6: 3: 1) 1: 1 and the product fractions are combined. The solvents are removed under reduced pressure. Ether is added and the resulting solid is collected by vacuum filtration and washed with ether to provide (2R, 4R) -4- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4 acid. -oxadiazol-5-yl) phenylamino) pyrrolidine-2-carboxylic acid (0.043 g, 0.097 mmol, quantitative yield) as a white solid when dried under vacuum at 55 ° C.
LC / MS (Method g) R, = 2.00 minutes; MS m / z: 443.11 (M + H) +. 1 H NMR (400 MHz, DMSO) d ppm 8.00-7.95 (m, 1H), 7.95-7.89 (m, 1H), 7.86 (d, J = 8.41 Hz, 2H), 7.33 (d, J = 8.58 Hz, 1H ), 6.86 (d, J = 6.34 Hz, 1H), 6.72 (d, J = 6.34 Hz, 2H), 4.84-4.72 (m, 1H), 4.19-4.08 (m, 1H), 3.81 (t, J = 8.15 Hz, 1H), 3.47-3.39 (m, 1H), 3.13-3.06 (m, 1H), 2.62-2.51 (m, 1H), 1.96-1.85 (m, 1H), 1.33 (d, J = 5.81 Hz , 6H).
Preparation # 85: Preparation of methyl 5-chloro-6-hydroxynicotinate Step 1 5-Chloro-6-hydroxynicotinic acid (10.2 g, 58.8 mmol) (Alfa Aesar) is dissolved in methanol (102 ml) under nitrogen to obtain a white suspension. Sulfuric acid (15.66 ml, 294 mmol) is added by dripping (exotherm is observed) and the reaction is heated to about 65 ° C for about 6 hours. The reaction is cooled to about room temperature and stirred overnight. The resulting solid is collected by vacuum filtration and washed with methanol (2 x 10 mL) and ether (2 x 10 mL) to provide methyl 5-chloro-6-hydroxynicotinate (8.911 g, 47.5 mmol, 81% yield). ) as a white solid when dried under vacuum at 60 ° C.
LC / MS (Method g) Rt = 1.45 minutes; MS m / z: 188.00 (M + H) \ H NMR (400 MHz, CDCl 3) d ppm 12.71 (s, 1H), 8.06-8.03 (m, 1H), 8.00-7.98 (m, 1H), 3.76 (s, 3H) Preparation of methyl 5-chloro-6-isopropoxynicotinate Combine methyl 5-chloro-6-hydroxynicotinate (8.91 g, 47.5 mmol) and 2-iodo-propane (7.1.2 mL, 71.2 mmol) in toluene (202 mL) under nitrogen to obtain a colorless solution. Silver carbonate (1 9.65 g, 71.2 mmol) is added and the reaction is heated to about 60 ° C for about 4 hours. CC F in EtOAc / heptane 1: 1 sample (visualization with uv light) that the reaction is not yet complete. The temperature is adjusted to approximately 50 ° C and the reaction is stirred for an additional 1 6 hours. The reaction is allowed to cool to room temperature. The mixture is filtered through a buchner funnel and washed with ethyl acetate. The solvents are removed under reduced pressure. The residue is purified by flash chromatography (column 1 20 g Redi-Sep) eluting with 5% ethyl acetate / heptane and the product fractions are combined. The solvents are removed under reduced pressure to provide methyl 5-chloro-6-isopropoxynicotinate (0.539 g, 45.9 mmol, 97% yield) as a colorless oil which solidifies in vacuo to a white solid.
LC / MS (Method g) Rt = 2.84 minutes; MS m / z: 230.05 (M + H) +. 1 H NMR (400 MHz, CDCl 3) d ppm 8.71 (d, J = 2.02 Hz, 1H), 8.22 (d, J = 1.93 Hz, 1H), 5.53-5.42 (m, 1H), 3.94 (s, 3H), 1.44 (d, J = 6.20 Hz, 6H).
Step 3 Preparation of 5-chloro-6-isopropoxynicotinamide Methyl 5-chloro-6-isopropoxynicotinate (5.19 g, 22.60 mmol) in ammonia (7 M in methanol) (75 mL, 525 mmol) is stirred in a pressure vessel (with release valve) to obtain a color suspension. White. The mixture is heated to approximately 60 ° C for about 48 hours. The reaction is cooled to about 0-5 ° C in an ice bath and the reaction vessel is opened. The solvents are removed under reduced pressure. The resulting white solid is dissolved in water (100 ml) and stirred rapidly for about 2 hours. The resulting solid is collected by vacuum filtration and washed with water and then pentane to provide 5-chloro-6-isopropoxynicotinamide (4.45 g, 20.73 mmol, 92% yield) as a white solid.
LC / MS (Method g) Rt = 1.91 minutes; MS m / z: 215.04 (M + H) +.
NMR (400 MHz,) d 8.58 (d, J = 2.2, 1H), 8.24 (d, J = 2.2, 1H), 8.00 (s, 1H), 7.48 (s, 1H), 5.42 - 5.27 (m, 1H) ), 1.32 (d, J = 6.2, 6H).
Step 4 Preparation of 5-chloro-6-isopropoxynicotinonitrile 5-Chloro-6-isopropoxynicotinamide (6 g, 28.0 mmol) is dissolved in 1,2-dichloroethane (140 ml) under nitrogen to obtain a white suspension. Burgess reagent (13.32 g, 55.9 mmol) (Alfa Aesar) is added and the reaction is stirred for approximately 16 hours. As the reaction progresses all the solids dissolve (within one or two hours). The solvents are removed under reduced pressure. The residue is purified by flash chromatography (column 80 g Redi-Sep) eluting with 10% ethyl acetate / heptane and the product fractions are combined. The solvents are removed under reduced pressure to provide 5-chloro-6-isopropoxynicotinonitrile (5.36 g, 27.3 mmol, 98% yield) as a white solid.
LC / MS (Method g) Rt = 2.60 minutes; MS m / z: 196.07 (M + H) +. 1 H NMR (400 MHz, DMSO) d ppm 8.63 (d, J = 2.03 Hz, 1 H), 8.45 (d, J = 2.04 Hz, 1 H), 5.41 -5.31 (m, 1 H), 1. 33 (d, J = 6.17 Hz, 6H) Step 5 Preparation of (Z) -5-chloro-N'-hydroxy-6-isopropoxynicotinimidamide 5-Chloro-6-isopropoxynicotinonitrile (5.36 g, 27.3 mmoles) is dissolved in ethanol (1 36 ml) under nitrogen to obtain a colorless solution. Hydroxylamine (50% in water) (6.43 mL, 109 mmol) is added and the reaction is heated to approximately 60 ° C for about 3 hours. TLC in EtOAc / heptane 1: 1 sample (visualization with uv light) that the reaction was complete. The reaction is concentrated in vacuo to a colorless, thick oil. Heptane is added to obtain a biphasic system. The oil is sown with previously prepared product and the crystallization forms an intense precipitate. The precipitate is collected by vacuum filtration and washed with heptane. The mother solution is more product than the one that precipitated. The brown solution is concentrated, heptane is added, and it is sown to obtain a second crop. The harvests look the same through TLC and combine to obtain (Z) -5-chloro-N'- hydroxy-6-isopropoxynicotinimidamide (6.108 g, 26.6 mmol, 98% yield) as a white solid by drying under vacuum at approximately 60 ° C with phosphorus pentoxide.
LC / MS (Method g) R, = 1.89 minutes; MS m / z: 230.05 (M + H) +. 1 H NMR (400 MHz, DMSO) d = 9.71 (s, 1 H), 8.36 (d, J = 2.1, 1 H), 8.02 (d, J = 2.1, 1 H), 5.91 (s, 2 H), 5.37 - 5.24 ( m, 1H), 1.31 (d, J = 6.2, 6H).
EXAMPLE # 89 2- (4- (3- (4-isopropoxy-3- (trifluoromethylphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) propan-1-ol Step 1 Preparation of N- (1 - (benzyloxy) propan-2-yl) -4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) aniline 5- (4-fluorophenyl) -3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazole (1794 g, 4.90 mmol), 1- (benzyloxy) propan-2-amine are combined (0.890 g, 5.39 mmol), and potassium carbonate (1489 g, 10.77 mmol) in DMSO (17 mL) and water (1.4 mL) under nitrogen to obtain a white suspension. The mixture is heated to approximately 110 ° C during approximately 72 hours. TLC in EtOAc / heptane 1: 1 sample (visualization with uv light) slow conversion to a more polar spot. The reaction is allowed to cool to room temperature. Ethyl acetate (75 ml) and water (50 ml) are added and the layers separated. The ethyl acetate is washed with water (2 x 25 ml). The combined extracts are washed with brine, dried over sodium sulfate, filtered, and evaporated to an off-white solid. This mixture is transferred to a vial of vial microwaves and 2 equivalents of the amine (1.9 g) are added. DMSO (15 ml) and water (1.2 ml) are added and the vial is capped. The reaction is heated in a Biotage microwave (heating with cooling) at about 80 ° C for about 30 minutes. CCF shows better progress towards the product. Heating for approximately 30 additional minutes gives approximately 50% conversion as judged by TLC. The reaction is heated for an additional 60 minutes. The reaction is poured into water (50 ml) and ethyl acetate (150 ml). The ethyl acetate is washed with water (2 x 50 ml). The ethyl acetate is washed with brine, dried over sodium sulfate, filtered, and evaporated to a brown oil. Using a small amount of methylene chloride, the oil is transferred to a column and purified by flash chromatography (column 80 g Redi-Sep) eluting with 1-0-40% ethyl acetate / heptane and the product fractions. The solvents are removed under reduced pressure to provide N- (1 - (benzyloxy) propan-2-yl) -4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazole- 5-yl) aniline (1475 g, 2.88 mmol, 58.9% yield) as an orange oil.
LC / MS (Method g) R, = 3.75 minutes; MS m / z: 512.14 (M + H) +. 1 H NMR (400 MHz, CDCl 3) d = 8.39 (s, 1H), 8.27 (d, J = 8.7, 1H), 8.02 (d, J = 8.6, 2H), 7.43-7.30 (m, 5H), 7.12 ( d, J = 8.8, 1H), 6.68 (d, J = 8.7, 2H), 4.82 - 4.70 (m, 1H), 4.59 (s, 2H), 4.43 (d, J = 8.0, 1H), 3.88 - 3.76 (m, 1H), 3.57 (d, J = 4.6, 2H), 1.44 (d, J = 6.0, 6H), 1.33 (d, J = 6.5, 3H).
Step 2 Preparation of 2- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,4-oxadiazol-5-yl) phenylamino) propan-1-ol N- (1 - (benzyloxy) propan-2-yl) -4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) aniline is dissolved (1,111 g, 2172 mmol) in dichloromethane (145 ml) under nitrogen to obtain a colorless solution. The reaction is cooled to about 0-5 ° C in an ice bath. A solution of boron tribromide (1.0 M in dichloromethane) (4.34 ml, 4.34 mmol) is added slowly and the reaction is stirred for about 30 minutes. TLC in EtOAc / heptane 1: 1 sample (visualization with UV light) complete reaction having formed a more polar spot. The reaction extinguish by addition of 1N HCl (10 ml). The cooling is removed and the reaction is stirred for about 30 minutes. Saturated sodium bicarbonate (30 ml) is added and the layers are separated. The aqueous layer is extracted with methylene chloride (1 x 30 mL). The combined extracts are washed with brine, dried with sodium sulfate, filtered, and evaporated to a yellow / tan solid. The residue (dissolved in methylene chloride) is purified by flash chromatography (column 40 g Redi-Sep) eluting with 20-60% ethyl acetate / heptane and the product fractions are combined. The solvents are removed under reduced pressure. Pentane is added and the solid is scraped from the sides of the flask. The resulting solid is collected by vacuum filtration and washed with pentane to provide 2- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenylamino ) propan-1 -ol (0.771 g, 1.830 mol, 84% yield) as a white solid by drying under vacuum at about 70 ° C with phosphorus pentoxide.
LC / MS (Method g) Rt = 2.95 minutes; MS m / z: 422.14 (M + H) +. 1 H NMR (400 MHz, DMSO) d = 8.24 (dd, J = 2.1, 8.8, 1H), 8. 17 (d, J = 2.1, 1H), 7.85 (d, J = 8.8, 2H), 7.49 (d, J = 8.9, 1H), 6.73 (d, J = 8.9, 2H), 6.52 (d, J = 7.9, 1H), 4.97 - 4.81 (m, 1H), 4.76 (t, J = 5.6, 1H), 3.62 - 3.49 (m, 1H), 3.49 - 3.40 (m, 1H), 3.36 - 3.30 (m, 1H ), 1.32 (d, J = 6.0, 6H), 1.14 (d, J = 6.4, 3H).
EXAMPLE # 90 Acid (R) -2- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1 .2,4-oxadiazol-5-yl) phenoxy) propane Step 1 Preparation (R) -benzyl-4- (1-ethoxy-1-oxopropan-2-yloxy) benzoate Combine benzyl 4-hydroxybenzoate (10 g, 43.8 mmol), (S) -ethyl-2-hydroxypropanoate (6.21 g, 52.6 mmol), and triphenylphosphine (14.36 g, 54.8 mmol) in tetrahydrofuran (11). 0 ml) under nitrogen to obtain a colorless solution. Globules of 4A molecular sieves (4-8 mesh) (5 g) are added and the reaction is stirred for about 30 minutes. The reaction is cooled to about 0-5 ° C in an ice bath. Di- tert butyl azodicarboxylate (1.62 g, 54.8 mmol) is added (exotherm is observed) and the reaction is stirred for about 1 8 hours. CC F in EtOAc / heptane 1: 1 sample (visualization with uv light) that the reaction was complete. The mixture is filtered through Celite® and washed with ethyl acetate. The solvents are removed under reduced pressure. Heptane is added and the sides scraped to induce the crystallization of triphenylphosphine oxide and reduced di-tert-butyl azodicarboxylate. The flask is stirred with stirring until a thick precipitate has formed. After standing overnight the solids are removed by vacuum filtration and the solid is washed with heptane until no additional product elutes as judged by TLC. The solvents are removed under reduced pressure. The residue is purified by flash chromatography (column 120 g Redi-Sep) eluting with 10-20% ethyl acetate / heptane and the product fractions are combined. The product fractions are concentrated to provide (R) -benzyl-4- (1-ethoxy-1-oxopropan-2-yloxy) benzoate (16.3 g, 49.6 mmol, 113% yield) as a colorless oil.
LC / MS (Method g) Rt = 2.83 minutes; MS m / z: 329.15 (M + H) +. 1 H NMR (400 MHz, CDCl 3) d 8.05 (d, J = 8.9, 2H), 7.60-2.21 (m, 5H), 6.91 (d, J = 8.8, 2H), 5.36 (s, 2H), 4.84 (q , J = 6.8, 1H), 4.24 (q, J = 7.1, 2H), 1.67 (d, J = 6.8, 3H), 1.27 (t, J = 7.1, 3H).
(R) -4- (1-ethoxy-1-oxopropan -2- acid) (R) -benzyl-4- (1-ethoxy-1-oxopropan-2-yloxy) benzoate (14.39 g, 43.8 mmol) was dissolved in methanol (438 ml). Palladium hydroxide on carbon (20%) (3.08 g, 4.38 mmol) is added, the reaction is purged with hydrogen, and hydrogenated at atmospheric pressure for about 3 hours. TLC in EtOAc / heptane 1: 1 sample (visualization with uv light) that the reaction was complete. The reaction is purged with nitrogen. The mixture is filtered through Celite® and washed with methanol. The solvents are removed under reduced pressure. Ethyl acetate is added and the solvents are removed again to remove any remaining methanol which provides a white solid. Heptane is added and the solid is scraped off the sides of the flask. The resulting solid is collected by vacuum filtration and washed with heptane to provide (R) -4- (1-ethoxy-1-oxopropan-2-yloxy) benzoic acid (8.83 g, 37.1 mmol, 85% yield) as a solid of white color.
LC / MS (Method g) Rt = 1.88 minutes; MS m / z: 237.08 (M + H) +. 1 H NMR (400 MHz, DMSO) d 12.67 (m, 1H), 7.85 (d, J = 8.9, 2H), 6.94 (d, J = 8.9, 2H), 5.06 (d, J = 6.8, 1H), 4.13 (q, J = 7.1, 2H), 1.51 (d, J = 6.8, 3H), 1.15 (t, J = 7.1, 3H).
Step 3 Preparation of (R) -ethyl-2- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) propanoate Combine (R) -4- (1-ethoxy-1-oxopropan-2-yloxy) benzoic acid (1 g, 4.20 mmol) and HOBt (0.884 g), 4.62 mmole) in methylene chloride (20.99 ml) under nitrogen to obtain a white suspension. EDC (0.885 g, 4.62 mmol) is added and the reaction is stirred for approximately 4 hours. TLC in EtOAc / heptane 1: 1 sample (visualization with uv light) that has formed a less polar spot. Methylene chloride (20 ml) and water (20 ml) are added and the layers are separated. The methylene chloride is washed with water (2 x 15 mL). The combined extracts are washed with brine, dried over sodium sulfate, filtered, and evaporated to a white solid. The solid is dissolved in DM F (20 ml) and (Z) -N'-hydroxy-4-isopropoxy-3- (trifluoromethyl) benzimidamide (1,101 g, 4.20 mmol) is added. The reaction is heated to about 60 ° C for about 72 hours. CC F shows formation of an intermediate spot and a non-polar spot. LC / MS shows that this is the non-cyclized intermediate and the oxadiazole product. The reaction temperature increases to approximately 90 ° C and the reaction proceeds more rapidly. A further increase to approximately 1 10 ° C for about 4 hours terminates the reaction. The reaction is cooled to room temperature and poured into water (approximately 200 ml). The aqueous mixture is extracted with ethyl acetate (3 x 50 mL). The combined ethyl acetate extracts are washed with 5% lithium chloride solution (3 x 30 ml). The ethyl acetate is then washed with brine, dried with its sodium phosphate, filtered and evaporated. The resulting residue is purified by flash chromatography (column 80 g Redi-sep) eluting with ethyl acetate / heptane and the product fractions are combined. The solvents are removed under reduced pressure to provide (R) -ethyl-2- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) propanoate (1373 g, 2.96 mmol, 70.4%) as an off-white solid.
LC / MS (Method g) Rt = 3.50 minutes; MS m / z: 465.15 (M + H) +.
H NMR (400 MHz, CDCl 3) d 8.40 (s, 1H), 8.28 (d, J = 8.7, 1H), 8.18 (d, J = 7.7, 2H), 7.13 (d, J = 8.6, 1H), 7.04 (d, J = 7.8, 2H), 4.89 (dd, J = 6.7, 13.5, 1H), 4.83 - 4.70 (m, 1H), 4.28 (q, J = 7.1, 2H), 1.71 (d, J = 5.8, 3H), 1.45 (d, J = 4.9, 6H), 1.30 (t, J = 7.1, 3H ).
Step 4 Preparation of (R) -2- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) acid Dissolve (R) -ethyl-2- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) propanoate (0.5 g, 1.077 mmol) ) in ethanol (10 ml) open to the air to obtain a white suspension. Sodium hydroxide (1 M) is added (2.153 ml, 2.153 mmol) and the reaction is stirred for about 2 hours. The starting material is not very soluble. Tetrahydrofuran (5 ml) is added and the reaction is subjected to sonic energy. All the material is dissolved and the reaction is stirred for about 30 additional minutes. TLC in EtOAc / heptane 1: 1 sample (visualization with uv light) that the reaction was complete. The solvents are removed under reduced pressure. HCl 1N (2.5 mL) is added and the aqueous layer is extracted with ethyl acetate (2 x 10 mL). The combined extracts are washed with brine, dried over sodium sulfate, filtered, and evaporated to a white solid. The residue is purified by flash chromatography (column 40 g Redi-Sep) eluting with 5-10% methanol in methylene chloride and the product fractions are combined. Solvents are removed under reduced pressure to provide (R) -2- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) propanoic acid (0.286 g, 0.655 mmol, 60.9% yield) as a white solid upon drying under vacuum at approximately 60 ° C.
LC / MS (Method g) Rt = 2.31 minutes; MS m / z: 437.11 (M + H) +. 1 H NMR (400 MHz, DMSO) d 13.16 (s, OH), 8.26 (dd, J = 2.1, 8.8, 1H), 8.19 (d, J = 2.1, 1H), 8.11 (d, J = 8.9, 2H) , 7.51 (d, J = 8.9, 1H), 7.11 (d, J = 9.0, 2H), 5.02 (q, J = 6.7, 1H), 4.96 - 4.85 (m, 1H), 1.54 (d, J = 6.8 , 3H), 1.32 (d, J = 6.0, 6H).
EXAMPLE # 91 (R) -N- (2-hydroxyethyl) -2- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) propanamide Combine (R) -2- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) propane (0.05 g, 0.115 mmol) and HOBT (0.021 g, 0.115 mmol) in dichloromethane (2.29 ml) in a sealed vial to obtain a colorless solution. EDC (0.022 g, 0.115 mmol) is added and the reaction is stirred for approximately 30 minutes. Ethanolamine (30 μ ?, 0.496 mmol) is added and the reaction is stirred for about 30 minutes. TLC in EtOAc shows (visualization with UV light) that the reaction was complete. Methylene chloride (5 ml) and water (5 ml) are added and the layers are separated. The methylene chloride is washed with 1 N HCl (1 x 5 mL). The methylene chloride is washed with brine, dried over sodium sulfate, filtered, and evaporated to a colorless oil. The residue is purified by flash chromatography (column 40 g Redi-Sep) eluting with 50-80% ethyl acetate / heptane and the product fractions are combined. The solvents are removed under reduced pressure. The residue is triturated with pentane and the resulting solid is collected by vacuum filtration and washed with pentane to provide (R) -N- (2-hydroxyethyl) -2- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) propanamide (0.043 g, 0.090 mmol, 78% yield) as a white solid.
LC / MS (Method g) R, = 2.64 minutes; MS m / z: 480.17 (M + H) +. 1 H NMR (400 MHz, DMSO) d 8.27 (dd, J = 2.1, 8.8, 1H), 8.22 - 8.18 (m, 1H), 8.15 (t, J = 5.9, 1H), 8.13 - 8.09 (m, 1H) , 7.56 -7.46 (m, 1H), 7.19 - 7.11 (m, 2H), 4.96 - 4.84 (m, 2H), 4.67 (q, J = 5.4, 1H), 3.42 - 3.33 (m, 2H), 3.20 - 3.11 (m, 2H), 1.46 (d, J = 6.6, 3H), 1.32 (d, J = 6.0, 6H).
EXAMPLE # 92 Acid (1 R, 3S) -3- (4- (5- (5-bromo-6-isopropoxypyridin-3-yl) -1.2.4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylic acid Step 1 Preparation of methyl 5-bromo-6-hydroxynicotinate 5-Bromo-6-hydroxynicotinic acid (4.9 g, 22.48 mmol) (Combi-Blocks) in methanol (39.0 ml) is stirred under nitrogen to obtain a whitish suspension. Sulfuric acid (5.99 ml, 112 mmol) is added slowly and the reaction heated to approximately 60 ° C for about 20 hours. The The reaction is allowed to cool to room temperature. The resulting solid is collected by vacuum filtration and washed with methanol and then ether to provide methyl 5-bromo-6-hydroxynicotinate (4.041 g, 17.42 mmol, 77% yield) as an off white solid under vacuum drying at 50 ° C. ° C.
LC / MS (Method g) R, = 1.55 minutes; MS m / z: 233.95 (M + H) \ 1 H NMR (400 MHz, DMSO) d 12.66 (s, 1 H), 8.16 (d, J = 2.4, 1 H), 8.07 (d, J = 2.4, 1 H), 3.76 (s, 3 H).
Step 2 Preparation of methyl 5-bromo-6-isopropoxynicotinate Combine methyl 5-bromo-6-hydroxynicotinate (4 g, 17.24 mmol) and 2-iodopropane (2.58 mL, 25.9 mmol) (Alfa Aesar) in toluene (73 mL) and equip with a reflux condenser under nitrogen to get a white suspension. Silver carbonate (7.13 g, 25.9 mmol) (Alfa Aesar) is added and the reaction is heated to approximately 60 ° C for about 24 hours. The mixture is filtered through Celite® and washed with ethyl acetate until no further product is released as judged by TLC. The solvents are removed under reduced pressure to provide methyl 5-bromo-6-isopropoxynicotinate (4,809 g, 17.54 mmol, 102% yield) as a white solid.
LC / MS (Method g) Rt = 2.92 minutes; MS m / z: 274.00, 276.00 (M + H) +.
H NMR (400 MHz, DMSO) d 8.67 (d, J = 2.1, 1H), 8.35 (d, J = 2.1, 1H), 5.42-5.30 (m, 1H), 3.83 (s, 3H), 1.33 (d , J = 6.2, 6H).
Step 3 Preparation of 5-bromo-6-isopropoxynicotinic acid Combine methyl 5-bromo-6-isopropoxynicotinate (4.8 g, 17.51 mmol) and sodium hydroxide (1,401 g, 35.0 mmol) in methanol (31 ml) and water (3.5 ml) under nitrogen to obtain a cloudy colorless solution. The mixture is heated to approximately 50 ° C for about 6 hours. The reaction is allowed to cool to room temperature. The solvents are removed under reduced pressure. The residue is dissolved in water. The mixture is acidified to approximately pH = 1 with 1 N HCl which causes a thick white precipitate to form. The resulting solid is collected by vacuum filtration and washed with water to provide 5-bromo-6-isopropoxynicotinic acid (4.155 g, 15.98 mmol, 91% yield) as a white solid upon drying under vacuum at about 50 °. C with phosphorus pentoxide.
LC / MS (Method g) Rt = 1.92 minutes; MS m / z: 257.98, 259. 97 (? -?) '. 1? NMR (400 ???, DMSO) d 13.26 (s, 1?), 8.65 (d, J = 2.0, 1?), 8.31 (d, J = 2.1, 1H), 5.35 (dt, J = 6.2, 12.4 , 1H), 1.33 (d, J = 6.2, 6H).
Step 4 Preparation of (1 R, 3S) -ethyl-3- (4- (5- (5-bromo-6-isopropoxypyridin-3-yl) -1, 2,4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylate Combine 5-bromo-6-isopropoxynicotinic acid (0.1 g, 0.384 mmol), HOBt (0.081 g, 0.423 mmol), and 4A molecular sieves (4-8 mesh globules) (0.5 g) in DMF (1922 ml) under nitrogen to obtain a colorless suspension. EDC (0.081 g, 0.423 mmol) and N, N-di-isopropylethylamine (0.074 mL, 0.423 mmol) are added and the reaction is stirred for approximately 30 minutes. Add (1R, 3S) -ethyl-3- (4 - ((Z) -N'-hydroxycarbamimidoyl) -phenylamino) cyclopentanecarboxylate (0.101 g, 0.346 mmol) and the reaction is heated to about 100 ° C for about 6 hours. hours. Ethyl acetate (15 ml) and water (10 ml) are added and the layers separated. The ethyl acetate is washed with water (2 x 5 ml). The combined extracts are washed with brine, dry with sodium sulfate, filter, and evaporate to a brown oil. The residue is purified by flash chromatography (40 g Redi-Sep) eluting with 10-20% ethyl acetate / heptane and the product fractions are combined. The solvents are removed under reduced pressure to provide (1R.3S) -ethyl-3- (4- (5- (5-bromo-6-isopropoxypyridin-3-yl) -1,2,4-oxadiazol-3-yl. ) phenylamino) cyclopentanecarboxylate (0.023 g, 0.045 mmol, 11.6% yield).
LC / MS (Method g) Rt = 3.94 minutes; MS m / z: 515.11, 517.11 (M + H) +. 1 H NMR (400 MHz, DMSO) d 8.89 (d, J = 2.1, 1H), 8.60 (d, J = 2.1, 1H), 7.77 (d, J = 8.6, 2H), 6.68 (d, J = 8.7, 2H), 6.41 (d, J = 6.7, 1H), 5.47 - 5.35 (m, 1H), 4.05 (dd, J = 7.1, 14.2, 2H), 3.87 - 3.75 (m, 1H), 2.89 - 2.76 (m , 1H), 2.38-2.28 (m, 1H), 2.06 - 1.94 (m, 1H), 1.88 (dd, J = 7.6, 15.2, 2H), 1.69 - 1.59 (m, 1H), 1.58 - 1.47 (m, 1H), 1.36 (d, J = 6.2, 6H), 1.15 (t, J = 7.1, 3H).
Step 5 Preparation of (1 R, 3S) -3- (4- (5- (5-bromo-6-isopropoxypyridin-3-yl) -1, 2,4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylic acid It is dissolved (1R, 3S) -ethyl-3- (4- (5- (5-bromo-6-isopropoxypyridin-3-yl) -1, 2,4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylate (0.023) g, 0.045 mmole) in ethanol (0.446 ml) in a sealed vial to obtain a white suspension. A solution of sodium hydroxide (1 M) (0.179 ml, 0.179 mmol) is added in one portion and the reaction is stirred for about 4 hours. THF (1 mL) is added and the reaction is clarified. LC / MS indicates that the reaction was completed. The solvents are removed under reduced pressure. The residue is dissolved in water (approximately 3 ml) and 1N HCl (0.2 ml) is added with rapid stirring which causes a white precipitate to form. The mixture is stirred for about 1 hour to ensure complete precipitation. The resulting solid is collected by vacuum filtration and washed with water and pentane to provide acid (1R, 3S) -3- (4- (5- (5-bromo-6-isopropoxypyridin-3-yl) -1, 2,4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylic acid (0.02 g, 0.041 mmol, 92% yield) as an off-white solid by drying under vacuum at 50 ° C with phosphorus pentoxide.
LC / MS (Method g) Rt = 3.14 minutes; MS m / z: 487.1 (M + H) +. 1 H NMR (400 MHz, DMSO) d 12.03 (s, 1 H), 8.89 (d, J = 2.1, 1 H), 8.60 (d, J = 2.1, 1 H), 7.77 (d, J = 8.6, 2 H), 6.68 (d, J = 8.7, 2H), 6.41 (d, J = 6.6, 1H), 5.46 - 5.34 (m, 1H), 3.86 - 3.74 (m, 1H), 2.81 - 2.70 (m, 1H), 2.38 - 2.26 (m, 1H), 2.06 - 1.92 (m, 1H), 1.86 (dd, J = 7.6, 15.2, 2H), 1.71 - 1.57 (m, 1H), 1.57 - 1.46 (m, 1H), 1.36 (d , J = 6.2, 6H).
EXAMPLE # 93 Preparation of (R) -2- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) 1 .2.4-oxadiazol-5-yl) phenoxy) pro anal Step 1 (R) -ethyl-2- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) propanoate (0.608 g, 1. 309 mmole) in tetrahydrofuran (1.09 ml) under nitrogen to obtain a colorless solution. The reaction is cooled to about 0-5 ° C in an ice bath. A solution of lithium aluminum hydride (2 M in TH F) (1 .309 mL, 2.62 mmol) is added dropwise and the reaction is stirred for about 30 minutes. TLC in EtOAc / heptane 1: 1 sample (visualization with UV light) conversion to a more polar spot. The reaction is quenched by the addition of water (1000 ul) and the reaction is stirred for about 15 minutes. Add 10% NaO H (300 ul) is added and the reaction is stirred for about 30 minutes. Water (1000 μ?) Is added and the reaction is stirred for about 30 minutes. The mixture is filtered through Celite® and washed with ethyl acetate. The solution is then dried with Sodium sulfate, filtered and concentrated. The residue is dissolved in dichloromethane (13.09 ml). Dessinin's periodinane (1111 g, 2.62 mmol) is added and the reaction is stirred for about 5 hours. The reaction is quenched by the addition of saturated sodium bicarbonate (1 mL) and methylene chloride (5 mL). The layers are separated. The aqueous layer is extracted with methylene chloride (1 x 2 mL). The combined extracts are washed with brine, they are dried with sodium sulfate, filtered, and evaporated to a colorless oil. The residue is purified by flash chromatography (40 g Redi-Sep column) eluting with 20-40% ethyl acetate / heptane and the product fractions are combined. The solvents are removed under reduced pressure to provide (R) -2- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) propanal ( 0.281 g, 0.668 mmole, 51.1% yield) as an off-white solid.
LC / MS (Method g) R, = 2.77 minutes; MS m / z: 439.14 (M + H20) +. 1 H NMR (400 MHz, DMSO) d 9.68 (s, 1H), 8.26 (dd, J = 2.0, 8.8, 1H), 8.19 (d, J = 2.0, 1H), 8.11 (d, J = 8.8, 2H) , 7.50 (d, J = 8.9, 1H), 7.19 (d, J = 8.8, 2H), 5.23 (q, J = 7.0, 1H), 4.96 - 4.85 (m, 1H), 1.46 (d, J = 7.0 , 3H), 1.32 (d, J = 6.0, 6H).
Step 2 Preparation of (R, E) -ethyl-4- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) -2- methylpent-2-enoate Dissolve (R) -2- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) propanal (0.281 g, 0.668 mmol) in dichloromethane (6.68 ml) under nitrogen to obtain a colorless solution. Ethyl 2- (triphenylphosphoranylidene) propionate (0.266 g, 0.735 mmol) is added and the reaction is stirred for about 18 hours. The solvents are removed under reduced pressure. The residue is purified by flash chromatography (40 g Redi-Sep column) eluting with 20-40% ethyl acetate / heptane and the product fractions are combined. The solvents are removed under reduced pressure to provide (R, E) -ethyl-4- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) -2-methylpent-2-enoate (0.281 g, 0.557 mmol, 83% yield) as a white solid.
LC / S (Method g) Rt = 3.93 minutes; MS m / z: 505.17 (M + H) +.
H NMR (400 MHz, DIVISO) d 8.26 (dd, J = 2.1, 8.7, 1H), 8. 19 (d, J = 2.0, 1H), 8.11 (d, J = 8.8, 2H), 7.50 (d, J = 8.9, 1H), 7.11 (d, J = 8.9, 2H), 6.56 (dd, J = 1.3, 7.9, 1H), 5.52 - 5.42 (m, 1H), 4.96 - 4.84 (m, 1H), 4.10 (qd, J = 1.6, 7.1, 2H), 1.94 (d, J = 1.0, 3H), 1.42 (d, J = 6.3, 3H), 1.32 (d, J = 6.0, 6H), 1.19 (t, J = 7.1, 3H).
Step 3 Preparation of (R, E) -ethyl-4- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) -2-methylpentyl 2-enoate (R, E) -ethyl-4- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) -2-methylpentyl is dissolved. 2-enoate (0.281 g, 0.557 mmol) in ethyl acetate (11.1 ml). Palladium on carbon (1.0%) (0.059 g, 0.056 mmol) is added, the reaction is purged with hydrogen, and hydrogenated at atmospheric pressure for about 4 hours. LC / MS shows product and oxadiazole opening. The mixture is filtered through a syringe filter and washed with ethyl acetate. The solvents are removed under reduced pressure. The residue is purified by flash chromatography (column 40 g Redi-Sep) eluting with 20-40% ethyl acetate / heptane and the product fractions are combined. Solvents are removed under reduced pressure to provide (4R) -ethyl-4- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) -2-methylpentanoate (0.1 05 g, 0.207 mmol, 37.2% yield) as a colorless oil.
LC / MS (Method i) R, = 2.1 7 minutes; MS m / z: 507.1 8 (M + H) +. 1 H NMR (400 MHz, DMSO) d 8.26 (dd, J = 2.1, 8.8, 1 H), 8.19 (d, J = 2.0, 1H), 8.09 (d, J = 8.9, 2H), 7.50 ( d, J = 8.9, 1H), 7.12 (d, J = 8.9, 2H), 4.95 - 4.84 (m, 1H), 4.69 - 4.56 (m, 1H), 4.10 - 3.92 (m, 2H), 2.68 - 2.50 (m, 2H), 2.11 - 2.02 (m, 1H), 1.97 - 1.76 (m, 2H), 1.69 - 1.61 (m, 1H), 1.32 (d, J = 6.0, 6H), 1.26 (d, J = 6.0, 3H), 1.15 -1.01 (m, 3H) greater diastereomer, the smaller diastereomer is observed at d 8.10 (d, J = 9.0, 2H), 7.14 (d, J = 8.9, 2H).
Step 4 Preparation of (R) -4- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) -2-methylpentanoic acid Dissolve (4R) -ethyl-4- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) -2-methylpentanoate (0.105 g) , 0.207 mmole) in ethanol (2.073 ml) under nitrogen to obtain a colorless solution. A solution of sodium hydroxide (1 M) (0.829 ml, 0.829 mmol) is added in one portion and the reaction is stirred for about 20 hours. When the sodium hydroxide is added, the reaction becomes cloudy but it becomes homogeneous after reacting overnight. The solvents are removed under reduced pressure. The residue is dissolved in water (approximately 5 ml) with application of sonic energy. HCl 1N (900 uL) is added to bring the mixture to pH = 1 approximately. A form is formed precipitate white and stir for about 2 hours. The resulting solid is collected by vacuum filtration and washed with water and a small amount of pentane to provide (R) -4- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1 acid, 2,4-oxadiazol-5-yl) phenoxy) -2-methylpentanoic acid (0.081 g, 0.169 mmol, 82% yield) as a white solid.
LC / MS (Method g) R, = 3.24 minutes; MS m / z: 479.16 (M + H) + (higher diastereomer) and Rt = 3.20 minutes; MS m / z: 479.16 (M + H) + (minor diastereomer). 1 H NMR (400 MHz, DMSO) d 12.10 (s, 1 H), 8.27 (dd, J = 1. 9, 8.7, 1H), 8.19 (d, J = 1.9, 1H), 8.10 (d, J = 8.8, 2H), 7.51 (d, J = 8.9, 1H), 7.19 - 7.09 (m, 2H), 4.97 - 4.84 (m, 1H), 4.69 - 4.57 (m, 1H), 2.59 - 2.50 (m, 1H), 1.97 - 1.84 (m, 1H), 1.75 (d, J = 19.4, 1H), 1.33 (d, J = 6.0, 6H), 1.27 (d, J = 6.0, 3H), 1.10 (d, J = 7.1, 3H). Minor diastereomer observed at 2.13 - 2.02 (m, 1H), 1.66 - 1.53 (m, 1H), 1.31 (d, J = 6.0, 6H), 1.08 (d, J = 7.1, 3H).
Preparation # 86: Preparation of 5-chloro-6-isopropoxynicotinic acid Methyl 5-chloro-6-isopropoxynicotinate (24 g, 105 mmol) in methanol (190 ml) and water (19.00 ml) are stirred under nitrogen to obtain a colorless solution. Sodium hydroxide (5.43 g, 136 mmol) is added and the reaction heated to approximately 60 ° C for about 6 hours. TLC in EtOAc shows (visualization with uv light) that the reaction was complete. The reaction is allowed to cool to room temperature. The solvents are removed under reduced pressure. The white residue is redissolved in water (approximately 250 ml) to obtain a cloudy solution. The mixture is filtered through Celite and washed with water (approximately 200 ml). The clear aqueous solution is acidified to approximately pH 2 with 1N HCl (140 ml) which causes a white-colored precipitate to form. The resulting solid is collected by vacuum filtration and washed with water and then pentane to provide 5-chloro-6-isopropoxynicotinic acid (21,946 g, 102 mmol, 97% yield) as a white solid upon drying under vacuum at 50 ° C with phosphorus pentoxide.
LC / S (Table 1, Method g) Rt = 1.91 minutes; MS m / z: 214.02, 216.04 (M-H) \ 1 H NMR (400 MHz, DMSO) d ppm 13.29 (s, 1 H), 8.62 (d, J = 2.0, 1 H), 8.18 (d, J = 2.0, 1 H), 5.44 - 5.31 (m, 1 H), 1.33 ( d, J = 6.2, 6H).
Preparation # 87: 3- (3-chloro-4-cyano-phenoxy) -cyclobutanecarboxylic acid tert-butyl ester A solution of 2-chloro-4-hydroxybenzonitrile (5.00 g, 32.6 mmol) and (1 s, 3 s) -tert-butyl-3-hydroxycyclobutanecarboxylate described in WO20070607 (6.1 7 g, 35.8 mmol) in TH F (220 ml) it is treated with 4A molecular sieves (1.0 g) and bound to Ph3P-resin (32.6 ml, 98 mmoles) for 20 minutes at room temperature, then cooled to about 0 ° C. A solution of di-tert-butyl azodicarboxylate (8.25 g, 35.8 mmol) in THF (30 ml) is added dropwise while maintaining the reaction temperature below 4 ° C. The reaction is stirred about 1 5 minutes at 0 ° C and then allowed to warm to room temperature for about 1 8 hours. The reaction is filtered and the solids are quenched with methanol (3 x 50 ml) and the combined organic solutions are concentrated. The residue is purified on a silica gel column using a gradient of 10-30% ethyl acetate in heptane. The product fractions are combined and concentrated to a clear, colorless oil which solidifies on standing to obtain the 3- (3-chloro-4-cyano-phenoxy) -cyclobutanecarboxylic acid tert-butyl ester (6.03 g, 60%). %) as a white solid.
LC / S (Table 1, Method a) Rt = 2.75 minutes; MS m / z: Without progenitor mass. 1 H NMR (400 MHz, DMSO) d ppm 7.87 (d, J = 8.7, 1H), 7.19 (d, J = 2.4, 1H), 6.99 (dd, J = 8.7, 2.4, 1H), 4.99-4.92 (m , 1H), 3.11-3.04 (m, 1H), 2.69-2.63 (m, 2H), 2.40-2.28 (m, 2H), 1.44 (s, 9H).
Preparation # 88: tert-butyl ester of 3-r3-chloro-4- (N-hydroxycarbamimidyl) -phenoxyl cyclocarboxylic acid ester Into a round-bottomed flask are (1r, 3r) -tert-butyl-3- (3-chloro-4-cyanophenoxy) -cyclobutanecarboxylate (5.98 g, 19.43 mmol), hydroxylamine (50% by weight in water, 6.88 g. mi, 117 mmoles) and ethanol (50 ml). The mixture is heated at 60 ° C overnight. After the reaction is complete, the mixture is cooled to room temperature, diluted with 150 ml of water and extracted with 150 ml of ethyl acetate. The organic layer is washed with saturated NaCl solution (100 ml), dried over sodium sulfate, filtered and concentrated to solids. The crude product is triturated with ether to obtain the 3- [3-chloro-4- (N-hydroxycarbamimidoyl) -phenoxy] -cyclobutanecarboxylic acid tert-butyl ester (5.43 g, 82%) as a white solid.
LC / MS (Table 1, Method a) R, = 2.15 minutes, m / z 341 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 9.37 (s, 1H), 7.30 (d, J = 8.5, 1H), 6.89 (d, J = 2.5, 2H), 6.81 (dd, J = 8.5, 2.5 , 1H), 5.71 (s, 2H), 4.91 - 4.81 (m, 1H), 3.12 - 3.01 (m, 1H), 2.63 (m, 2H), 2.37 - 2.26 (m, 2H), 1.44 (s, 9H ).
Preparation # 89: 3- tert.-butyl ester. { 3-chloro-4- f5- (5-chloro-6-isopropoxy-pindin-3-yl) -n, 2.41-oxadiazol-3-ill-phenoxy > - cyclob uta ncarbox Mico A solution of 5-chloro-6-isopropoxynicotinic acid (3.42 g, 15.87 mmol) and 1 H-benzo [d] [1,2,3] triazol-1-ol hydrate (2.430 g, 15.87 mmol) in CH2Cl2 ( 100 ml) is treated with EDC (3.04 g, 15.87 mmol) and the reaction is stirred at room temperature for 2 hours. The mixture is washed twice with water (50 ml), dried over sodium sulfate, filtered and concentrated. The residue is dissolved in NMP (100 mL) and (1 r, 3 r) -tert-butyl-3- (3-chloro-4 - ((Z) -N'-hydroxycarbamimidoyl) phenoxy) cyclobutanecarboxylate (5.23 g, 14.43 mmoles) and the mixture is heated to approximately 110 ° C for about 18 hours. The reaction is cooled to room temperature, diluted with water (200 ml) and extracted with ethyl acetate (200 ml). The ethyl acetate layer is washed with saturated sodium bicarbonate solution (100 ml), saturated ammonium (100 ml) and saturated NaCl solution (100 ml). The organic layer is dried with sodium sulfate, filtered and concentrated. The residue is further purified on silica gel using a gradient of 10% to 20% ethyl acetate / heptane. The product fractions are concentrated to approximately 100 ml and filtered to obtain the 3- tert-butyl ester. { 3-Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1,4] oxadiazol-3-yl] -phenoxy-cyclobutanecarboxylic acid (6.52 g, 87%) as whitish solid product.
LC / MS (Table 1, Method c) R, = 3.30 minutes, m / z 520 (M + H) +.
H NMR (400 MHz, DMSO-d6) d ppm 8.91 (d, J = 2.1, 1H), 8. 53 (d, J = 2.1, 1H), 7.95 (d, J = 8.7, 1H), 7.12 (d, J = 2.5, 1H), 7.03 (dd, J = 8.8, 2.5, 1H), 5.50-5.40 ( m, 1H), 5.02 - 4.90 (m, 1H), 3.13-3.06 (m, 1H), 2.73 - 2.63 (m, 2H), 2.43 - 2.32 (m, 2H), 1.45 (s, 9H), 1.39 ( d, J = 6.2, 6H).
EXAMPLE # 94 3- (3-Chloro-4-r5- (5-chloro-6-isopropoxy-pyridin-3-yl) - G .2.41 oxadiazol-3-H-phenoxy) -cyclobutanecarboxylic acid A solution of (1 r, 3 r) -ter-butyl-3- (3-chloro-4- (5- (5-chloro-6-isopropoxypyridin-3-yl) -1, 2,4-oxadiazole-3 il) phenoxy) cyclobutanecarboxylate (6.42 g, 12.34 mmol) in DCM (100.0 ml) is treated with tri-isopropylsilane (2.53 ml, 12.34 mmol) and then TFA (100 ml) at room temperature for about 45 minutes. The mixture is concentrated to obtain an oil and purified on silica gel using a gradient of 0-10% MeOH. The product fractions are combined and concentrated. The residue is triturated with 1: 1 / MeOH water (50 ml), filtered, washed with water and dried under vacuum to obtain 3- acid. { 3-Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1,4] oxadiazol-3-yl] -phenoxy} -cyclobutanecarboxylic acid (5.26 g, 92%) as a white solid.
LC / MS (Table 1, Method c) Rt = 2.70 minutes, m / z 464 (M + H) +.
H NMR (400 MHz, DMSO-d6) d ppm 12.36 (s, 1H), 8.88 (d, J = 2.1, 1H), 8.50 (d, J = 2.1, 1H), 7.94 (d, J = 8.7, 1H ), 7.11 (d, J) 2. 5, 1H), 7.03 (dd, J = 8.8, 2.5, 1H), 5.50 - 5.38 (m, 1H), 5.03 - 4 n, 1H), 3.12 (m, 1H), 2.71 (m, 2H), 2.43 - 2.32 (m, 2H), 1.39 (d, .2, 6H).
Preparation # 90: MR.3S) -ethyl-3- (4 - ((Z) -N'-hydroxycarbamimidoiO-phenylamino) cyclopentanecarboxylate In a round-bottomed flask is added (1R, 3S) -ethyl-3- (4-cyanophen-lamino) -cyclopentanecarboxylate (0.5 g, 1936 mmol), hydroxylamine (50% by weight in water, 0.457 ml, 7.74 mmoles) and ethanol (6 ml). The mixture is heated to approximately 60 ° C for about 16 hours. After the reaction is complete, the mixture is concentrated to dryness under reduced pressure to obtain (1R, 3S) -ethyl-3- (4 - ((Z) -N'-hydroxycarbamimidoyl) phenylamino) -cyclopentanecarboxylate (0.506 g, 1.737 mmoles, 90%) as an oil.
LC / MS (Table 1, Method b) Rt = 1.62 minutes, m / z 292 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 9.18 (s, 1H), 7.39-7.37 (d, 2H), 6.53-6.50 (d, 2H), 5.84-5.83 (d, 1H), 5.52 (s, 2H), 4.08-4.03 (q, 2H), 3.79-3.71 (m, 1H), 2.86-277 (m, 1H), 2.35-2.28 (m, 1H), 2.01-1.93 (m, 1H), 1.89- 1.84 (m, 2H), 1.64-1.56 (m, 1H), 1.54-1.47 (m, 1H), 1.18-1.15 (t, 3H).
Preparation # 91: (1 R.3S) -ethyl-3- (4- (5- (5-chloro-6-isopropoxypyridin-3-yl) -1, 2,4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylate To a solution of (1 R, 3 S) -ethyl-3- (4 - ((Z) -N'-hydroxycarbamimidoyl) phenylamino) cyclopentanecarboxylate (0.506 g, 1.737 mmol), EDC (0.366 g, 1910 mmol), DIEA ( 0.334 ml, 1.910 mmol) and HOBT (0.293 g, 1.910 mmol) in DF (10 ml) is added 5-chloro-6-isopropoxynicotinic acid in solution (0.412 g, 1.910 mmol) and the reaction is stirred at room temperature under nitrogen for about 1 hour and then heated to approximately 100 ° C for about 16 hours. The reaction is cooled and concentrated under reduced pressure and the residue is dissolved in EtOAc (25 mL) and sequentially washed with a saturated NH4Cl solution (20 mL), a saturated Na2CO3 solution (20 mL) and water ( 20 mi). The organic layer is dried with Na 2 SO 4, filtered and concentrated under reduced pressure. The residue is purified on silica gel using a gradient of 15-50% EtOAc in Heptane to obtain (1 R, 3S) -ethyl-3- (4- (5- (5-chloro-6-isopropoxypyridin-3) il) -1, 2,4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylate (0.170 g, 0.361 mmol, 20.8%) as a pale yellow solid.
LC / MS (Table 1, Method b) R, = 3.21 minutes, m / z 471 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 8.88 (d, 1H), 8.50 (d, 1H), 7.80-7.78 (d, 2H), 6.71-6.69 (d, 2H), 6.43-6.42 (d, 1H), 5.48-5.41 (m, 1H), 4.09-4.04 (q, 2H), 3.87-3.78 (m, 1H), 2.89-2.81 (m, 1H), 2.39-2.32 (m, 1H), 2.06- 1.97 (m, 1H), 1.92-1.87 (m, 2H), 1.70-1.62 (m, 1H), 1.57-1.50 (m, 1H), 1.39-1.38 (d, 6H), 1.19-1.15 (t, 3H) ).
EXAMPLE # 95 Acid (1 R, 3S) -3- (4- (5- (5-chloro-6-isopropoxypyridin-3-yl) -1,2,4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylic acid To a solution of (1 R, 3S) -ethyl-3- (4- (5- (5-chloro-6-isopropoxypyridin-3-yl) -1, 2,4-oxadiazol-3-yl) phenylamino Cyclopentanecarboxylate (170 mg, 0.361 mmol) in dioxane (3.6 mL) is added 2 M potassium hydroxide (0.722 mL, 1444 mmol) and the mixture is stirred at room temperature for approximately 16 hours. The reaction is neutralized by addition of 2M HCl (750 μ) and the mixture is concentrated. The residue is triturated with water and aqueous ammonium acetate solution. The resulting solid is filtered and washed with water and dried to obtain (1 R, 3S) -3- (4- (5- (5-chloro-6-isopropoxypyridin-3-yl) -1, 2,4 acid. -oxadiazol-3-yl) phenylamino) cyclopentanecarboxylic acid (141.6 mg, 0.317 mmol, 88%) as a tan solid.
LC / MS (Table 1, Method b) Rt = 2.81 minutes, m / z 433 (M + H) +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 8.88-87 (d, 1H), 8.50-8.49 (d, 1H), 7.81-7.79 (d, 2H), 6.74-6.71 (d, 2H), 5.49- 5.40 (m, 1H), 3.85-3.78 (m, 1H), 2.82-2.73 (m, 1H), 2.37-2.30 (m, 1H), 2.05-1.96 (m, 1H), 1.91-1.85 (m, 2H) ), 1.69-1.62 (m, 1H), 1.58-1.50 (m, 1H), 1.39-1.38 (d, 6H).
Preparation # 1-1: Isomerization N-BuLi (approximately 1 equivalent) is added to approximately 20 ml of THF at 0 ° C, followed by ethanol and trans-tert-butyl-3- (4- (5- (5-chloro-6-isopropoxypyridine). 3-yl) -1, 2,4-oxadiazol-3-yl) phenoxy) cyclobutanecarboxylate. It is heated to about room temperature in the course of about 5 hours, then it is stirred for about 8 hours. NaOH is added (4 eq, 5% in water). The reaction is stirred for about 4 hours at room temperature and the pH is adjusted to about 2 with about 1 2 N HCl. The precipitate is filtered, washed with water and ethanol, water 1: 1 then dried. Yield 1.32 g. of cis / trans 82: 14 products identical to those described above (74% yield).

Claims (1)

  1. CLAIMS 1. - A compound of the formula (I) Formula (I) pharmaceutically acceptable salts, biologically active metabolites, solvates, hydrates, prodrugs, racemates, enantiomers or stereoisomers thereof, in which L is a bond or optionally substituted CT-CS alkyl; R 1 is -C (0) -NH-phenyl, -NH-C (0) -furanyl, -NH-S (0) 2 -phenyl optionally substituted, -O-C 1 -C 3 alkyl optionally substituted, -S-alkyl optionally substituted CT-C3, optionally substituted C2-C6 alkyl, optionally substituted amino, optionally substituted C3-C6 cycloalkyl, - (CH2) -C3 alkyl, optionally substituted tetrahydrobenzofuranyl, optionally substituted furanyl, optionally substituted tetrahydrofuranyl, 2, 3-optionally substituted 3-dihydroisoindolyl, optionally substituted isoindolinyl, optionally substituted imidazolyl, optionally substituted 5,6-dihydro-midazo [1,2-a] pyrazinyl, optionally substituted imidazo [1,2-a] pyrazinyl, indolyl optionally substituted, optionally substituted isoxazolyl, optionally substituted morpholinyl, optionally substituted naphthyl, optionally substituted phenyl, -0-CH2-optionally substituted phenyl, optionally substituted -O-phenyl, optionally substituted -O-phenyl, optionally substituted piperidinyl, optionally substituted pyrazolyl, pyridinyl optionally substituted, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, 1, 2,3,4-tetrahydroisoquinolinyl optionally substituted, optionally substituted quinolinyl, optionally substituted 3,4-dihydroquinolinyl, optionally substituted 3,4-dihydroisoquinolinyl, 5,6,7,8 optionally substituted tetrahydroimidazo [1, 2-a] pyrazinyl, optionally substituted pyrrolyl, optionally substituted pyrrolo [2,3-b] pyridinyl, optionally substituted quinolinyl, optionally substituted thiazolyl or optionally substituted thienyl; R2 is Br, Cl, CF3, CN, or -O-Ci-C2 alkyl; R3 is optionally substituted (C3-C8) alkyl, deuterated (C2-C6) alkyl, C4-C5 alkenyl, C4-C5 alkynyl, optionally substituted-C3-C6-cycloalkyl, -alkyl (C2-C3) optionally substituted -O-alkyloxyC ^ Cs) optionally substituted, -alkyl C ^ Ca) optionally substituted-imidazolyl, -alkyl (Ci-C3) optionally substituted-morpholinyl, -alkyl (Ci-C3) optionally substituted-optionally substituted phenyl, alkyl ^ -Cs) optionally substituted-piperazinyl optionally substituted, -alkyl Ci-Cs) optionally substituted-pyrrolidinyl, -alkyl (Ci-C3) optionally substituted-piperidinyl, alkyl (d-C3) -thienyl optionally substituted, optionally substituted tetrahydrofuranyl or thiazolyl; Y R6 is H; with the condition that R is not substituted by optionally substituted cyclohexyl, -C (0) -cyclohexyl or -N H -cyclohexyl; when L is C 1 Cs alkyl, R is not optionally substituted isoxazolyl; when R3 is optionally substituted d-alkyl, L-R1 is not cyclohexyl or -C H2-cyclohexyl; Y with the condition that the compound is not 2. The compound according to claim 1, wherein R1 is optionally substituted with one or more substituents that are independently selected from Br, C l, F, C F3, CN, oxo, -C (= 0 ) H, -N (R9) 2, optionally substituted d-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted azabicyclo [2.2.1] heptanyl, C3-C6 cycloalkyl optionally substituted, -C (R9) 2-C3-C6 cycloalkyl optionally substituted, -C (R9) 2-azetidinyl optionally substituted, -CR92-piperidinyl optionally substituted, -C (R9) 2-pyrrolidinyl optionally substituted, -C (R9) ) 2-N (R9) 2, -C (0) -alkyl of optionally substituted C, -C (0) -NR -alkyl of C ^ Ce, -C (0) -0-C ^ -C6 alkyl optionally substituted, -C (R9) 2-C (0) -0-C- -Ce alkyl optionally substituted, -NR9-C3-C6 cycloalkyl optionally substitutedOptionally substituted -NR9-azetidinyl, -NR9-furanyl, optionally substituted -NR9-pyrrolidinyl, -NR9-C (0) -0-optionally substituted d-C3 alkyl, -NR9-optionally substituted Ci-C6 alkyl, - NR9-C3-C6 cycloalkyl optionally substituted, -NR9-C (0) -azetidinyl, -NR9-C (0) -furanyl, -NR9-C (0) -pyridinyl, -NR9-C (0) -pyrrolidinyl optionally substituted, -NR9-S (0) 2-optionally substituted phenyl, -O-C6-C6 alkyl optionally substituted, -O-deuterated-C2-C6 alkyl, -O-C2-C6 alkenyl optionally substituted, -O optionally substituted C3-C6 cycloalkyl, -0-1 H-benzo [d] [1, 2,3] triazolyl, -S (0) 2-N (R) 2, -S (0) 2-NR9- optionally substituted C ^ -C4 alkyl, optionally substituted azetidinyl, optionally substituted piperidinyl, optionally substituted pyridinyl, optionally substituted pyrrolidinyl, optionally substituted 1,2,4-oxadizazolyl, optionally substituted pyrrolidinyl, optionally substituted tetrazolyl, wherein each R is independently selected from H or optionally substituted C 1 -Ce alkyl. 3. - The compound according to claim 1, wherein the compound is a compound of the Formula (Ia) Formula (the) where L is a link. 4. The compound according to claim 3, wherein R1 is optionally substituted tetrahydrobenzofu ranyl, optionally substituted furanyl, optionally substituted 2,3-diisocyanoindolyl, optionally substituted isoindolinyl, optionally substituted imidazolyl, 5,6-dihydroimidazo [1, 2-a] optionally substituted pyrazinyl, optionally substituted imidazo [1, 2-a] pyrazinyl, optionally substituted indolyl, optionally substituted isoxazolyl, optionally substituted p-razolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrimidinyl, , 2, optionally substituted 3,4-tetrahydroquinolinolinyl, optionally substituted quinolinyl, optionally substituted 3,4-dihydroquinolinyl, optionally substituted 3,4-diisocyanoquinolinyl, 5,6,7,8-tetrahydroimidazo [1,2-a] optionally substituted pyrazinyl, optionally substituted pyrrolyl, optionally substituted pyrrolo [2, 3-b] pyridinyl, optionally substituted uinolinyl, optionally substituted thiazolyl or optionally substituted thienyl. 5. The compound according to claim 4, wherein R1 is optionally substituted furanyl, optionally substituted imidazolyl, optionally substituted isoxazolyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, optionally substituted pyrrolyl, optionally substituted thiazolyl or optionally substituted thienyl. 6. - The compound according to claim 1, wherein R1 is optionally substituted phenyl or indolyl optionally substituted. 7. - The compound according to claim 1, wherein L is optionally substituted C-C3 alkyl; R1 is -C (0) -N H-phenyl, -N H-C (0) -furanyl, -N H-S (0) 2-phenyl optionally substituted, -O-alkyl of?! -03 optionally substituted, -S-C 1 -C 3 alkyl, optionally substituted benzyloxy, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted imidazolyl, morpholinyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted pyridinyl, optionally substituted pyrrolidinyl or optionally substituted thienyl; R2 is Cl; R3 is isopropyl; Y R6 is H. 8. The compound according to claim 1, wherein L is CH2 and R1 is optionally substituted phenyl or optionally substituted C3-C6 cycloalkyl. 9. - The compound according to claim 1, wherein the compound is 4- [3- (3-chloro-4-isopropoxy-phenyl) - [1, 2, 4] oxadiazol-5-yl] -3-methyl-pyridine; 3- [3-chloro-4- (1-ethyl-propoxy) -phenyl] -5-o-tolyl- [1, 2, 4] oxadiazole; 3- (3-chloro-4-isopropoxyphenyl) -5- (3-chloropyridin-4-yl) - [1, 2, 4] -oxadiazole; 3-chloro-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzonitrile; 1 - (3-Chloro-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) -3-methylazetidine-3-carboxylic acid; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1 H-indole-1-l) tert-butyl propanoate; 4- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1H-indole-1-l) tert-butyl butanoate; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1H-indole-1-yl) propane acid; (1 R, 3 S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenoxy) propane-1,2-diol; (R) -3-. { 3-Chloro-4- [3- (3-chloro-4-isopropoxy-phenyl) - [1, 2, 4] -oxadiazol-5-yl] -phenoxy} -propa no-1, 2-diol; Acid 3-. { 3-Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1, 2, 4] oxadiazol-3-yl] -phenoxy} -cyclobutanecarboxylic; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) propylphosphonic acid; Ethyl 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzylidene) cyclobutanecarboxylate; Ethyl 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) -cyclobutanecarboxylate; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazole-5-i-1-amino acid) n-cyclocarboxylic acid cycle; 5- (3- (3-chloro-4-isopropoxyphenyl) -1,4,4-oxadiazol-5-yl) -1-methyl-1 H-pyrazole-3-amino; 3- (3-chloro-4-isopropoxyphenyl) -5- (1 H -indol-5-yl) -1,2,4-oxadiazole; 1- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) pyrrolidine-3-carboxylic acid; 3-Amino-1- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) pyrrolidine-3-carboxylic acid; (S) -1- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) pyrrolidine-3-carboxylic acid; (R) -1- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) pyrrolidine-3-carboxylic acid; (S) -1- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) azetidine-2-carboxylic acid; 4- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1H-indol-1-yl) butanoic acid; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1 H -indole-1-yl) -2-fluoropropanoic acid; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-i I) -1H-indol-1-yl) -2-methylpropanoic acid; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1H-indole-1-yl) -2,2-d-methyl ester lpropanoic; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1 H -pyrrolo [2,3-b] pyridin-1-yl) propane acid; Acid (1 R, 3S) -3-. { 4- [3- (5-Chloro-6-isopropoxy-pyridin-3-yl) - [1, 2, 4] oxadiazol-5-yl] -3-methyl-phenylamino} -cyclopentanecarboxylic; 4- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) -3,3-dimethylbutanoic acid; 4- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) butanoic acid; 1 - (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) pyrrolidine-3-carboxylic acid; 2- (1 - (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) pyrrolidin-3-yl) acetic acid; (1 R, 3 S) -3- (4- (3- (3-Bromo-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; Acid (1 R, 3S) -3- (4- (3- (4-α-Propoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; (1 R, 3 S) -3- (4- (3- (5-Chloro-6-isopropoxypyridin-3-yl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; (R) -1 - (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) pyrrolidin-3-amine, acetic acid; Acid (1 R, 2S) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; Acid (1 S, 2 R) -2- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclohexanecarboxylic acid; (S) -1 - (3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) pyrrolidin-1-yl) ethanone; Acid (1 R, 2R) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenamino) hexancarboxylic acid cycle; Acid (1 R, 2S) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) fe or the non-hexancarboxylic ring; Acid (1 R, 2S) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxad azo-l-5-yl) faith nor the mi no) hexancarboxylic acid cycle; Acid (1S, 2R) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phen i lamino) hexancarboxylic acid cycle; Acid (1 R, 2R) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclohexanecarboxylic acid; Acid (1S, 2S) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclohexanecarboxylic acid; Acid (1 S, 2 R) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -, 2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; Acid (1S, 2S) -2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclohexanecarboxylic acid; (S) -N- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) -1- (methylsulfonyl) pyrrolidin-3-amine; (S) -2- (3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) pyrrolidin-1-yl) acetic acid; Acid (1 R, 3S) -3- (2-Bromo-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; Acid (1 R, 3S) -3- (2-bromo-3- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; (1 R, 3 S) -3- (5- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) pyridin-2-ylamino) cyclopentanecarboxylic acid; (1 R, 3 S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) pyridin-2-ylamino) cyclopentanecarboxylic acid; (3S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) -1-methylcyclopentanecarboxylic acid; 2 - ((1 R, 3 S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentyl) acetic acid; Acid (1S, 3S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxad-1-azole-5-yl) phen i the min o) -1-methylcyclopentanecarboxylic acid; (1 R, 3 S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phen i my no) -1-methylcyclopentanecarboxylic acid; (3S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenamino) -1-fluorocyclopentanecarboxylic acid; (1 R, 3 S) -3- (4- (5- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylic acid; (3S) -3- (4- (3- (3-Chloro-4-y-propoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) -1-hydroxycyclopentanecarboxylic acid; (1 R, 3 S) -3- (3-Chloro-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; (1 R, 3 S) -3- (4- (3- (3-Bromo-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3-chlorophenylamino) cyclopentanecarboxylic acid; Acid (1 R, 3S) -3- (3-bromo-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; Acid (1 R, 3S) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -2- (trifluoromethyl) phenylamino) cyclopentanecarboxylic acid; (R) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1 H -indole-1-yl) -2-methylpropanoic acid; Acid (S) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1 H -indole-1-yl) -2-methylp nó ico; 2- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylate of (1 R, 2S) -methyl; 2- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylate of (1S, 2R) -methyl; (1 R, 2R) -2- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; Acid (1 S, 2S) -2- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; 3- (3-chloro-4-isopropoxyphenyl) -5- (1-methyl-1, 2,3,4-tetrahydroquinolin-6-yl) -1,2,4-oxadiazole; Acid (R) -3- (4- (3- (4- (tetrahydrofuran-3-yloxy) -3- (trifluoromethyl) phenyl) -1, 2,4-oxadiazol-5-yl) -1H-indole 1 -il) propanic; Acid (1 R, 3 S) -3- [4- (5-biphenyl-2-yl- [1, 2,4] oxadiazol-3-yl) -2-methyl-phenylamino] -cyclopentanecarboxylic acid; Acid (1 R, 3 S) -3- [4- (5-biphenyl-3-yl- [1, 2,4] oxadiazol-3-yl) -2-methyl-phenylamino] -cyclopentanecarboxylic acid; (1R, 3S) -3- [4- (5-Biphenyl-4-yl- [1,2,4] oxadiazol-3-yl) -2-methyl-phenylamino] -cyclopentanecarboxylic acid; Acid (1R, 3S) -3-. { 4- [5- (4-cyclohexyl-phenyl) - [1,2,4] oxadiazol-3-yl] -2-methyl-phenylamino} -cyclopentanecarboxylic; (1 R, 3S) -3 - ((4- (3- (3-Chloro-4-isopropoxy-phenyl) -1,2,4-oxadiazol-5-yl) phenyl) (methyl) amino) cyclopentanecarboxylic acid; 3- (5- (3- (3-Chloro-4-ylpropoxyphenyl) -1,4,4-oxadiazol-5-yl) -1 H -indol-1-yl) cyclopentanecarboxylic acid methyl ester; 3- (5- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1H-indole-1-yl) -cyclopentanecarboxylic acid; (1 R, 3 S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -2-ethynylphenylamino) cyclopentanecarboxylic acid; Acid (1 R, 3S) -3- (5- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -1 H -indole-1-yl) cyclopentanecarboxyme; (1S, 4R) -2- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3-methoxyphenyl) -2-azabicyclo [2.2.1 ] hepta n-3-one; (1 R, 3 S) -3- (4- (3- (3-Chloro-4-isopropoxy-yen-yl) -1,2,4-oxadiazol-5-yl) -3-methoxyphenylamino) -cyclopentanecarboxylic acid; (R) -3- (3- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -2-methylphenoxy) propane-1,2-diol; N- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) isonicotinamide; N- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) isonicotinamide; (3S) -3- (4- (3- (3-Chloro-4-isopropoxyphen-yl) -1,2,4-oxadiazol-5-yl) phenylamino) -1-hydroxycyclopentanecarboxylic acid; (1 R, 3 S) -3- (4- (5- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylic acid; 1-amino-3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenoxy) cyclopentanecarboxylic acid; 1-amino-3- (3-chloro-4- (5- (5-chloro-6-isopropoxypyridin-3-yl) -1,2,4-oxadiazol-3-yl) phenoxy) -cyclopentanecarboxylic acid; Acid (1 R, 3S) -3- (4- (5- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-3-yl) -3-methylphenylamino) cyclopentanecarboxylic acid; (1S, 4R) -2- (4- (5- (5-chloro-6-isopropoxypyridin-3-yl) -1,2,4-oxadiazol-3-yl) -3-methylphenyl) -2-azabicyclo [2.2.1] heptan-3-one; (1 R, 3 S) -3- (4- (5- (5-chloro-6-isopropoxypyridin-3-yl) -1,2,4-oxadiazol-3-yl) -3-methylphenylamino) cyclopentanecarboxylic acid; Methyl 2- (5- (3- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) -2H-tetrazol-2-yl) acetate; 3- (3- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) -1,2,4-oxadiazol-5 (2H) -one; (R, 3S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3-ethylphenylamino) cyclopentane carboxylic acid; (1 R, 3 S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3-cyano-phenylamino) -cyclopentanecarboxylic acid; (2R, 4R) -4- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) pyrrolidine-2-carboxylic acid; 2- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenylamino) propan-1-ol; Acid (R) -2- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) propane; (R) -N- (2-hydroxyethyl) -2- (4- (3- (4-isopropoxy-3-) (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) propanamide; (R) -2- (4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) propanal; Acid 3-. { 3-Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1, 2, 4] oxadiazol-3-yl] -phenoxy} -cyclobutanecarboxylic; or (1 R, 3 S) -3- (4- (5- (5-Chloro-6-isopropoxypyridin-3-yl) -1,2,4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylic acid. 1 0.- A compound of the formula (I I) Formula (I I) pharmaceutically acceptable salts, biologically active metabolites, solvates, hydrates, prodrugs enantiomers or stereoisomers thereof, in which And it is a link; L is a bond or C H2; R1 is optionally substituted C 1 -C 4 alkyl, optionally substituted indolyl or optionally substituted phenyl; R2 is CF3, R3 is H, morpholinyl, optionally substituted piperidine or C3-C5 cycloalkyl; Y R6 is H. The compound according to claim 10, wherein R1 is optionally substituted with one or more substituents that are independently selected from Cl, F, CN, optionally substituted C 1 -C 3 alkyloyl Optionally substituted -C-H2-azetidinyl, optionally substituted -CH2-pyrrolidinyl, -CH2N-RcRd, -N-C-C6-optionally substituted-cycloalkyl, optionally substituted piperidinyl, wherein R ° and Rd are independently H, optionally substituted (--Ce alkyl or optionally substituted C3-C6 cycloalkyl. 1 2. The compound according to claim 1 wherein the compound is 1 - ((4- (3- (4- (4-fluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) benzylamino) methyl) -cyclopropanecarboxylic acid; Acid (R) -1 - (4- (3- (4- (4-fluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) benzyl) pyrrolidin- 3-carboxylic; Acid (S) -1 - (4- (3- (4- (4-fluoropiperidin-1 -yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) benzyl) pyrrolidin- 3-carboxylic; Acid 1 - (4- (3- (4- (4-fluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) benzylamino) -cyclopropanecarboxylic acid; Acid 1 - (4- { 3- [4- (4-fluoro-piper-dine-1-yl) -3-trifluoromethyl-phenyl] - [1,2,4] oxadiazole-5- il.}. -benzylamino) -cyclopropanecarboxylic acid; Acid 1 - (4-. {3- [4- (4-Fluoro-piperidin-1-yl) -3-trifluoromethyl-phenyl] - [1,4,2] oxadiazol-5-yl} - benzyl) -pyrrolidine-3-carboxylic acid; Acid 1 - (4- { 3- [4- (4-Fluoro-piperidin-1-yl) -3-trifluoromethyl-phenyl] - [1,4,2] oxadiazol-5-yl}. -benzyl -4-methyl-pyrrolidine-3-carboxylic acid 4-Fluoro-piperidin-1-yl) -3-trifluoromethyl-phenyl] - [1, 2, 4] oxadiazol-5-yl acid} -benzylamino) -acetic; Acid [(S) -1 - (4- { 3- [4- (4-fluoro-piperidin-1-yl) -3-trifluoromethyl-phenyl] - [1,4] oxadiazol-5-yl .}. -benzyl) -pyrrolidin-2-yl] -acetic; [1 - (4- { 3- [4- (4-fluoro-piperidin-1-yl) -3-trtf luoromethyl-phenyl] - [1, 2, 4] oxadiazol-5-yl.} - benzylamino) -cyclopropyl] -methanol; Acid 1 - (4- { 3- [4- (4-fluoro-piperidin-1-yl) -3-trifluoromethyl-phenyl] - [1, 2,4] oxadiazol-5-yl}. -benzyl 4,4-dimethyl-pyrrolidine-3-carboxylic acid; 1 - . 1 - [(4- { 3- [4- (4-Fluoro-piperidin-1-yl) -3-trifluoromethyl-phenyl] - [1,4,2-oxadiazol-5-yl] -benzylamino ) -methyl] -cyclopropanol; (1 R, 3 S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3- (trifluoromethyl) phenylamino) cyclopentanecarboxylic acid; (1 R, 3 S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3-methylphenylamino) -cyclopentanecarboxylic acid; (1 R, 3 S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -2-methylphenylamino) cyclopentanecarboxylic acid; 4- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) -2-methylaltatanoic acid; 2- (4- (3- (3-Chloro-4-isopropoxy-phenyl) -1,2,4-oxadiazol-5-yl) -phenylamino) -tert-butyl acetate; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) propane-tert-butyl ester; 1-amino-3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenoxy) cyclopentanecarboxylic acid; Acid 3-. { 4- [3- (3-chloro-4-isopropoxy-phenyl) - [1, 2, 4] oxadiazol-5-yl] -phenoxy} -cyclobutanecarboxylic; 2- (6- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3,4-dihydroquinoline-1 (2 H) -yl) acetic acid; 3- (6- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3,4-dihydroq-quinolin-1 (2H) -yl) propane acid; (E) -4- (3- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -2-methylphenoxy) but-2-enoic; 4- (3- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -2-methylphenoxy) butanoic acid 4- (3- (3- (3-Chloro-4-isopropoxyphenyl) -, 2,4-oxadiazol-5-yl) -4-methylphenoxy) butanoic acid; (3- {4- [3- (3-Chloro-4-isopropoxy-phenyl) - [1,4,4] oxadiazol-5-yl] -phenylamino} -propyl) -phosphonic acid diethyl ester; (3- {4- [3- (3-Chloro-4-isopropoxy-phenyl) - [1, 2, 4] oxadiazol-5-yl] -benzylamino} -propyl) -phosphonic acid; Acid (1S, 3R) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,2-oxadiazol-5-yl) phenylamino) cyclopentylphosphonic acid; Acid (1 R, 3R) -3- (4- (3- (3-Chloro-4-ylpropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentylphosphonic acid; Acid (1 R, 3R) -3- (2-Bromo-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentylphosphonic acid; (1 R, 3 S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentylphosphonic acid; Acid (1 R, 3S) -3- (2-bromo-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentylphosphonic acid; (1S, 3S) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentylphosphonic acid; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) cyclobutanecarboxylic acid; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) cyclopentanecarboxylic acid; 1 - (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) azetidine-3-carboxylic acid; 2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1, 2,4-oxadiazol-5-yl) phenyl) propan-2-amine; 3- (2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) propane-2-ylamino) propanoate methyl; 3- (2- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) propane-2-ylamino) propane acid; 3- (3-chloro-4-isopropoxyphenyl) -5- (1 H -indol-4-yl) -1,2,4-oxadiazole; (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) pheny1) methanamine; 3- (3- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) cyclopentylamino) propane acid; 4- (3- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) cyclopentylamino) butanoic acid; (S) -3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenoxy) propane-1,2-diol; 4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzenesulfonamide; 3,3 '- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylsulfonylazand -yl) tert-butyl dipropanoate; 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylsulfonamido) tert-butyl propanoate; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylsulfonamido) propane acid; 2, 2 '- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -phenylsulfonyl-n-yl) -acetic acid; 2, 2 '- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylsulfonylazand i -yl) tert-butyl diacetate; 2- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylsulfonamido) tert-butyl acetate; 2- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylsulphonido) acetic acid; 2- (5- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3,4-dihydroisoq-quinolin-2 (1 H) -yl) -acetic acid ester butyl; 5- (3- (3-chloro-4-isopropoxyphenyl) -1,4,4-oxadiazol-5-yl) -3,4-dihydroisoquinolin-2 (1 H) -tert-butylcarboxylate; 3- (3-chloro-4-isopropoxyphenyl) -5- (1, 2, 3,4-tetrahydroisoquinolin-5-yl) -1,2,4-oxadiazole; 2- (5- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3,4-dihydroisoq-quinolin-2 (1 H) -yl) acetic acid; 3- (5- (3- (3-Chloro-4-isopropoxyphenyl) -1,4,4-oxadiazol-5-yl) -3,4-d-hydroxyisoquinolin-2 (1 H) -yl) propanoate of ter- butyl; 3- (5- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) -3,4-dihydroisoquinolin-2 (1 H) -yl) propane; 2- [3- (3-chloro-4-isopropoxy-phenyl) - [1, 2,4] oxadiazol-5-yl] -3-methyl-5,6,7,8-tetrahydro-imidazo [1, 2 -a] pyrazine; 1 - . 1 - . 1 - . 1 -. { 2- [3- (3-chloro-4-isopropoxy-phenyl) - [1, 2, 4] oxadiazol-5-yl] -3-methyl-5,6-dihydro-8 H-imidazo [1, 2- a] pyrazin-7-il} -etanone; Ter-butyl ester of acid. { 2- [3- (3-chloro-4-isopropoxy-phenyl) - [1,4] oxadiazol-5-yl] -3-methyl-5,6-dihydro-8 H-imidazo [1, 2- a] pyrazin-7-il} -acetic; Acid { 2- [3- (3-chloro-4-isopropoxy-pheny] - [1, 2, 4] oxadiazol-5-yl] -3-methyl-5,6-dihydro-8H-imidazo [1, 2 -a] pyrazin-7-il} -acetic; 3- [3- (3-chloro-4-isopropoxy-phenyl) - [1,4] oxadiazol-5-yl] -2-methyl-imidazo [1,2-a] pyrazine; 3- (3-chloro-4-isopropoxyphenyl) -5- (4 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) phenyl) -1,2,4-oxadiazole; 2- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenoxy) acetic acid; 1- (4- (3- (3-Cyano-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) azetidyl-3-carboxylic acid; 1- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) cyclopropanecarbonitrile; 1- (4- (3- (3-chloro-4-isopropoxy-phenyl) -1,2,4-oxadiazol-5-yl) phenyl) -cyclopropanecarbamide; 3 - ((1 - (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) cyclopropyl) methylamino) propanoic acid; N- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzyl) -1 - (2,2-dimethyl-, 3-dioxolan-4-yl) ) methanamine; 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) benzylamino) propane-1,2-diol; (Z) -methyl 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) acrylate; trans-methyl 2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) cyclopropanecarboxylate; Trans-2- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) -cyclopropanecarboxylic acid; 5- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) isoindoline-2-carboxylic acid tert -butyl ester; 3- (3-chloro-4-isopropoxyphenyl) -5- (isoindolin-5-yl) -1,2,4-oxadiazole; 3- (5- (3- (3-Chloro-4-isopropoxyphenyl) -1,4,4-oxadiazol-5-yl) isoindolin-2-yl) propanoate methyl; 3- (5- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) isoindolin-2-yl) -proparoic acid; (Z) -methyl 3- (4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) acrylate; (Z) -3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenyl) acrylic acid; 3- (3-Chloro-4- (3- (3-chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclobutanecarboxylic acid; 3- (4- (3- (3-Chloro-4-isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclobutanecarboxylic acid; 1 - (4- (3- (4- (4-fluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) benzyl) azetidine-3-carboxylic acid; of 5 - ((4- (3- (4- (4-fluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) benzylamino) methyl) isoxazole-3 -ol; 2 - ((4- (3- (4-isopropoxy-3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenoxy) methy1) morpholine; Acid (1 R, 3S) -3- (4- (3- (4 - ((S) -tetrahydrofu ran-3-yloxy) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazole-5- il) phenylamino) cyclopentanecarboxylic; Acid (1 R, 3S) -3- (4- (3- (4- (4-fluoropiperidin-1 -yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenylamino ) cyclopentanecarboxylic; Acid (1 R, 3S) -3- (4- (3- (4- (4,4-difluoropiperidin-1 -yl) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl ) phenylamino) cyclopentanecarboxylic; Acid (1S, 3S) -3- (4- (3- (4- (4-fluoropiperidin-1-M) -3- (trifluoromethyl) phenyl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; Acid (1R, 3R) -3- (4- (3- (4- (4-fluoropiperidin-1-yl) -3- (trifluoromethyl) phenyl) -1, 2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic; Acid (1S, 3R) -3- (4- (5- (3-cyano-4- (4-fluoropiperidin-1-yl) phenyl) -1,2,4-oxadiazol-3-yl) -2- ( trifluoromethyl) phenylamino) cyclopentanecarboxylic; Acid (1S, 3R) -3- (4- (5- (3-cyano-4- (4-fluoropiperidin-1-yl) phenyl) -1,2,4-oxadiazol-3-yl) phenylamino) cyclopentane carboxylic; 5- [3- (4-Fluoro-phenyl) - [1,2,4] oxadiazol-5-yl] -2- (4-fluoro-p-peridin-1-yl) -benzonitrile; 5- [3- (4-fluoro-3-trifluoromethyl-phenyl) - [1,4] oxadiazol-5-yl] -2- (4-fluoro-piperidin-1-yl) -benzonitrile; Acid (1 R, 3 S) -3- [4- (5-biphenyl-2-yl- [1, 2,4] oxadiazol-3-yl) -2-methyl-phenylamino] -cyclopentanecarboxylic acid; Acid (1 R, 3 S) -3- [4- (5-biphenyl-3-yl- [1, 2,4] oxadiazol-3-yl) -2-methyl-phenylamino] -cyclopentanecarboxylic acid; Acid (1 R, 3S) -3-. { 4- [5- (4-cyclohexyl-phenyl) - [1, 2,4] oxadiazol-3-yl] -2-m etyl-phenamide} -cyclopene so carboxylic; or Acid (1R, 3S) -3- (4- (5- (4-isobutylphenyl) -1,2,4-oxadiazole-3-yl) fe n i lam i) o) cycle so carboxylic. 13. - A compound of the formula (III) Formula (I I I) pharmaceutically acceptable salts, biologically active metabolites, solvates, hydrates, prodrugs, enantiomers or stereoisomers thereof, wherein E is CH or N; And it is a link; L is a link; R1 is optionally substituted aryl; R2 is H; R3 is H; Y R6 is H or optionally substituted 0 to 03 alkyl. 14. - A compound of the formula (IV): Formula (IV) or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof, in which: X is N or CR4; L is a bond, -CH2CH2-, C3-C6 cycloalkyl, or -CHR5; Y is -O-, -NR7- or -C (R7) (R7 ') -; R is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -alkyl (Ci-C6) optionally substituted-O-C 1 Ca alkyl, -alkyl C 5 -C 6) optionally substituted-O-alkyld-CeJ-O- C1-C3 alkyl, -alkyl (Ci-C6) optionally substituted-O-aryl, alkylsulfanylalkyl, unsubstituted C2-C5 alkyl, substituted C-alkyl, -COR11, -O-C-C3 alkyl optionally substituted , -N (R7) (R8), -N (R7) S02-R11 or optionally substituted C3-C6 cycloalkyl, and wherein R1 is not substituted cyclopentathiophen, halogenothiophene, substituted indan or substituted chromenone; R 2 and R 6 may be the same or different and are independently H, -alkyl of C 4 -C 4, -O-alkyl of C 1 Ca, -CF 3) -CN, halogen or -COO-Ci-C alkyl; R3 is optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted C3-C6 cycloalkyl, - (CH2) n -R11, -CO-OR1, -CO-R1, -CON (R7) (R11), -N (R7) (R11), -SOR11, -S02R11 and optionally substituted straight or branched Ci-C8 alkyl chain optionally including the groups -CO-, -COO-, -SO-, -S02-, -CONH- , -NHCO-, -N- or -O- embedded within the alkyl chain; and when Y is O, R3 is not alkyldiazepane, -C (CH3) 2COOCH2CH3 or -CH2CH2N (CH2CH3) 2; and when Y is -CH2-, R3 is not -CH2COOH; or Y is a bond and R3 is optionally substituted morpholino; R 4 is H, -C 1 -C 4 alkyl, -O-Ci-C 3 alkyl, -CF 3, -CN or halogen; R5 is H, O-C1-C3 alkyl or C1-C3 alkyl; each time R7 or R7 occurs is independently H or optionally substituted C- | -C3 alkyl; R8 is H, optionally substituted CH3, or -COR11; R11 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl or optionally substituted C3-C6 cycloalkyl; Y n is 1, 2, 3 or 4; with the condition that R is not optionally substituted furanyl or optionally substituted -C (O) furanyl; R3 is not optionally substituted quinolinyl; R11 is not optionally substituted cyclopropyl, optionally substituted cyclohexyl, optionally substituted furanyl, optionally substituted imidazolyl, optionally substituted indolyl, optionally substituted naphthyl, optionally substituted piperazinyl, optionally substituted pyrazolyl, optionally substituted pyridazinyl, or optionally substituted quinolinyl; R1 is not substituted with -C (0) -cyclopentyl, optionally substituted cyclopentyl, -C (0) -cyclobutyl, cyclobutyl, -C (O) -cyclohexyl or optionally substituted cyclohexyl; R3 is not substituted with -C (0) -cyclopropyl; when R3 is CH3 or 4-chlorophenylmethyl, L-R1 is not cyclopropyl, cyclopentyl, optionally substituted cyclohexyl, -CH2-cyclohexyl, -NH-cyclohexyl, -CH2CH2-cyclohexyl or optionally substituted pyrazolyl; when Y is O, R3 is not optionally substituted alkyl (C0-C) -isoxazolyl or optionally substituted pyrazolyl; when L is C 1 -C 3 alkyl, R 1 is not optionally substituted isoxazolyl; when L is a bond, R is not optionally substituted cyclobutyl, optionally substituted cyclohexyl, optionally substituted naphthyl, optionally substituted -CH2-naphthyl, optionally substituted -CH2-0-naphthyl, optionally substituted pyrazolyl or tetrahydrobenzofuranyl; with the condition that the compound is not with the condition that the compound is not wherein R3 is optionally substituted piperazinyl or optionally substituted phenyl; with the condition that the compound is not wherein R1 is optionally substituted pyridine or 3-chlorophenyl and -Y-R is -NH-C (0) -optionally substituted phenyl; -O-pyridinyl optionally substituted; -NH-C (0) -OCH3; -CH2-piperazinyl optionally substituted; -O-C-Cg alkyl optionally substituted; -CH2-morpholinyl; or -0-C (0) -pyridinyl optionally substituted; with the condition that the compound is not in which L is CH2, CH (CH3) or CH2CH2; And it is O or CH2; R2 is H or OCH3; R3 is CH3 or OCF3; Y R is H or N02; the condition that the compound is not the condition that the compound is not wherein R 1 is phenyl, 4-chlorophenyl, piperidinyl or thienyl. 15. - The compound according to claim 14, wherein R1 is optionally substituted phenyl, optionally substituted tetrahydrobenzofuranyl, optionally substituted furanyl, optionally substituted 2,3-dihydroisoindolyl, optionally substituted isoindolinyl, optionally substituted imidazolyl, optionally substituted 5,6-dihydroimidazo [1, 2-a] pyrazinyl, imidazo [1, 2-a] optionally substituted pyrazinyl, optionally substituted indolyl, optionally substituted isoxazolyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, optionally substituted 1,2,3,4-tetrahydroisoquinolinyl, optionally substituted quinolinyl, 3, Optionally substituted 4-dihydroquinolinyl, optionally substituted 3,4-dihydroisoquinolinyl, optionally substituted 5,6,7,8-tetrahydroimidazo [1,2-a] pyrazinyl, optionally substituted pyrrolyl, optionally substituted pyrrolo [2,3-b] pyridinyl, optionally substituted quinolinyl, optionally substituted thiazolyl, optionally substituted thienyl, -alkyl (d-C6) optionally substituted-O-CrC3 alkyl, -alkyl (Ci-C6) optionally substituted -0-alkyl (Ci-C6) -0-C-C3 alkyl, -alkyla-Ce) optionally substituted-O-phenyl, unsubstituted C2-C5 alkyl, substituted? -β3 alkyl, -COR11 , -O-optionally substituted C1-C3 alkyl, -N (R7) (R8), -N (R7) S02-R11 or optionally substituted C3-C6 cycloalkyl; R2 and R6 may be the same or different and are independently H, -alkylCi), -O-C -C3 alkyl, -CF3, -CN, Cl, or F. 16. - The compound in accordance with the claim 15, where L is a bond, -CH2CH2-, or -CHR5; Y is -O-, -NR7- or -C (R7) (R7 ') -; R1 is optionally substituted phenyl, optionally substituted furanyl, optionally substituted isoindolinyl, optionally substituted imidazolyl, optionally substituted imidazo [1, 2-a] pyrazinyl, optionally substituted indolyl, optionally substituted isoxazolyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, optionally substituted quinolinyl, optionally substituted pyrrolyl, optionally substituted pyrrolo [2,3-b] pyridinyl, optionally substituted quinolinyl, optionally substituted thiazolyl, optionally substituted thienyl, -alkyl C ^ Ce) optionally substituted-O-Ci alkyl -C3, -alkyl-Ce) optionally substituted-O-phenyl, unsubstituted C2-C5 alkyl, substituted Ci-C6 alkyl, -COR11, -O-optionally substituted C-C3 alkyl, -N (R7) ( R8), -N (R7) S02-R11 or optionally substituted C3-C6 cycloalkyl; R2 and R6 may be the same or different and are independently H, -Ci-C4 alkyl, -O-Ci-Ca alkyl, -CF3, -CN, Cl or F; R3 is optionally substituted phenyl, optionally substituted piperidinyl, optionally substituted furanyl, optionally substituted pyrimidinyl, optionally substituted pyridinyl, optionally substituted C3-C6 cycloalkyl, - (CH2) n-R1, -CO-OR11, -CO-R1, -CON (R7) (R11), -N (R7) (R11), -SOR11, -S02R11 and optionally substituted straight or branched Ci-Ce alkyl chain. 17. The compound according to claim 16, wherein R is optionally substituted phenyl, furanyl optionally substituted, optionally substituted indolyl, optionally substituted isoxazolyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolyl, unsubstituted C2-C5 alkyl, substituted Ci-C6 alkyl, -COR11, -N (R7) (R8), -O-optionally substituted C1-C3 alkyl, or optionally substituted C3-C6 cycloalkyl; R2 and R6 may be the same or different and are independently H, -alkyl (C -C4), -CF3, Cl or F; R 3 is optionally substituted phenyl, optionally substituted pyrimidinyl optionally substituted piperidinyl, optionally substituted pyridinyl, optionally substituted C 3 -C 6 cycloalkyl, - (CH 2) n-R 11, optionally substituted straight or branched C 1 -C 4 alkyl chain or 1 8. The compound according to claim 1, wherein R 1 is optionally substituted with one or more substituents which are independently selected from Br, Cl, F, C F 3, CN, oxo, - C (= 0) H, -N (R9) 2, optionally substituted d-Cg alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, azabicyclo [2.2. 1 optionally substituted Jheptanil, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6-C (R9) cycloalkyl, optionally substituted-C (R9) 2-azetidinyl, optionally substituted -CR92-piperidinyl, -C ( R9) optionally substituted 2-pyrrolidinyl, -C (R9) 2 -N (R9) 2, -C (0) -alkyl of C i -Ce optionally substituted, -C (0) -N R 9 -alkyl of CrC 6 , -C (0) -0-C-Ce alkyl optionally substituted, -C (R9) 2-C (0) -0- optionally substituted d-C6 alkyl, -NR-C3-C6 cycloalkyl optionally substituted Optionally substituted -NR9-azetidinyl, -NR9-furanyl, optionally substituted -NR9-pyrrolidinyl, -NR9-C (0) -O-optionally substituted C-C3 alkyl, -NR9-optionally substituted Ci-C6 alkyl, -NR9-C3-C6 cycloalkyl optionally substituted, -NR9-C (0) -azetidinyl, -NR9-C (0) -furanyl, -NR9-C (0) -pyridinyl, -NR9-C (0) -pyrrolidinyl optionally substituted, -NR9-S (0) 2-optionally substituted phenyl, -O-alkyl optionally substituted, -O-deuterated-C2-C6 alkyl, -O-C2-C6 alkenyl optionally substituted, - Optionally substituted C3-C6-cycloalkyl, -0-1 H-benzo [d] [1, 2,3] triazolyl, -S (0) 2-N (R9) 2, -S (0) 2-NR9 optionally substituted Ci-C4 alkyl, optionally substituted azetidinyl, optionally substituted piperidinyl, optionally substituted pyridinyl, optionally substituted pyrrolidinyl, optionally substituted 1,2,4-oxadizazolyl, optionally substituted pyrrolidinyl, optionally substituted tetrazolyl, Y wherein each R9 is independently selected from H or optionally substituted Ci-C6 alkyl. 9. The compound according to claim 18, wherein each optional substituent or substituent is independently or not or more groups R10 wherein R10 is optionally substituted alkenyl, alkenyl, optionally substituted alkoxy groups, alkoxyalkoxy, alkoxyalkyl , alkoxycarbonyl, alkoxycarbonylheterocyclealkoxy, alkyl, alkylamino, alkylcarbonyl, alkyl ester, alkyl-OC (O) -, alkylene-heterocyclyl, alkyl-cycloalkyl, alkyl-nitrile, alkylsulfonyl, alkynyl, amido groups, non-optionally substituted ami, aminoalkyl, aminoalkoxy , aminocarbonyl, optionally substituted azabicyclo [2.2.1] heptanil, carbonitrile, carbonylalkoxy, carboxamido, CF3, CN, -C (0) OH, -C (0) H, -C (O) -C (CH3) 3, - OH, -C (0) 0-alkyl, -C (0) 0-cycloalkyl optionally substituted, -C (0) 0-heterocyclyl, -C (0) -alkyl, -C (0) -cycloalkyl optionally substituted, -C (0) -heterocyclyl, CN, optionally substituted cycloalkyl, dialkylamino, dialkylaminoalkoxy, dial quilaminocarbonylalkoxy, dialkylaminocarbonyl, dialkylaminosulfonyl, -C (0) -ORa, halogen, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyloxy, hydroxy, hydroxyalkyl, nitro, oxo, optionally substituted phenyl, -S02CH3, -S02C F3, sulfonyl, tetrazolyl , thienylalkoxy, trifluoromethylcarbonylamino, trifluoromethylsulfonamido, heterocyclylalkoxy, heterocyclyl-S (0) p, optionally substituted cycloalkyl-S (0) p, optionally substituted alkyl-S-, optionally substituted heterocyclyl-S, heterocycloalkyl, cycloalkylalkyl, heterocyclic, cycloalkylthio, N-alkylamino and? , β-dialkylamino in which Ra is optionally substituted alkyl, optionally substituted heterocycloalkyl, or optionally substituted heterocyclyl and p is 1 or 2. 20. - The compound according to claim 1 9, wherein -Y-R3 is compound in accordance with the claim 20, where the compound is Acid 3-. { 3-Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1, 2, 4] oxadiazol-3-yl] -phenoxy} -Cyclobutanecarboxylic Acid (1 R, 3S) -3- (4- (5- (5-chloro-6-isopropoxypyridin-3-yl) -1, 2,4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylic acid (1S, 4R) -2- (3- (3- (5-Chloro-6-isopropoxypyridin-3-yl) -1,2,4-oxadiazol-5-yl) -2-methylphenyl) -2-azabicyclo [2.2.1] heptan-3-one; (1 R, 3 S) -3- (4- (3- (5-Chloro-6-isopropoxypyridin-3-yl) -1,2,4-oxadiazol-5-yl) -2-methylphenylamino) cyclopentanecarboxylic acid; Acid (1 R, 3S) -3- (4- (3- (5-chloro-6-isopropoxypyridin-3-yl) -1,2,4-oxadiazol-5-yl) -3- (trifluoromethyl) phenylamino) cyclopentanecarboxylic; 1-amino-3- (3-chloro-4- (5- (5-chloro-6-isopropoxypyridin-3-yl) -1,2,4-oxadiazol-3-yl) phenoxy) -cyclopentanecarboxylic acid; Acid 3-. { 3-Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1, 2, 4] oxadiazol-3-yl] -phenoxy} -cyclobutanecarboxylic; Acid 4-. { 3-Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1, 2, 4] oxadiazol-3-yl] -phenoxy} -cyclohexanecarboxylic; Acid 3-. { 3-Chloro-4- [3- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1, 2, 4] oxadiazol-5-yl] -phenoxy} -cyclobutanecarboxylic; Acid 3-. { 3-Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1, 2, 4] oxadiazol-3-yl] -phenoxy} -cyclobutanecarboxylic; Acid 3-. { 3-Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1, 2, 4] oxadiazol-3-yl] -phenoxy} -cyclohexanecarboxylic; Acid 4-. { 3-Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1,4] oxadiazol-3-yl] -phenoxy} -cyclohexanecarboxylic acid; Cis-acid. { 3-Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-i I) - [1, 2,4] oxadiazol-3-yl] -phenoxy} -cyclopentanecarboxylic; Trans-3- acid. { 3-Chloro-4- [5- (5-chloro-6-isopropoxy-pyridin-3-yl) - [1,4] oxadiazol-3-yl] -phenoxy} -cyclopentanecarboxylic; or Acid (1 R, 3S) -3- (4- (5- (5-bromo-6-isopropoxypyridin-3-yl) -1, 2,4-oxadiazol-3-yl) phenylamino) cyclopentanecarboxylic acid. 22. - A compound according to Formula (V) Formula (V) And it's a link R3 is -3 - ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalenyl, or optionally substituted thienyl; Ra is H or optionally substituted C ^ C alkyl R b is H, optionally substituted C 1 -C e alkyl or optionally substituted C 3 -C 6 cycloalkyl. 23. - The compound according to claim 22, wherein the compound is Acid (1 R, 3 S) -3- (4- (3- (4-phenyl-5- (trifluoromethyl) thiophen-2-yl) -1,2,4-oxadiazol-5-yl) phenylamino) cyclopentanecarboxylic acid; or Acid (S) -3-. { 4- [3 - ((1aS, 5aR) -1,1,2-Trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl) - [1, 2,4] oxadiazol-5-yl] -phenylamino} -cyclopentanecarboxylic. 24 -. 24 - A pharmaceutical composition comprising a compound according to claims 1 or 14 or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof and a pharmaceutically acceptable diluent or carrier. 25. The use of one or more compounds according to claims 1 or 14 or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug or stereoisomer thereof for the manufacture of a medicament for treating an immune disorder. 26. The use according to claim 25, wherein the immune disorder is active chronic hepatitis, Addison's disease, ankylosing spondylitis, anti-phospholipid syndrome, asthma, atopic allergy, autoimmune atrophic gastritis, acyclohydrate autoimmune, celiac disease, disease of Crohn's disease, Cushing's syndrome, dermatomyositis, Goodpastu re syndrome, Grave's disease, Hashimoto's thyroiditis, idiopathic adrenal atrophy, idiopathic thrombocytopenia, juvenile rheumatoid arthritis, Lambert-Eaton syndrome, lupoid hepatitis, lupus, tissue disease mixed connective, multiple sclerosis, pemphigoid, pemphigus vulgaris, pernicious anemia, phacogenic uveitis, polyarteritis nodosa, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, Raynauds, Reiter syndrome, relapsing polychondritis, Schmidt s snd rome, Sínd rome de Sjogren, Sympathetic ophthalmia, Takayasu arteritis, temporal arteritis, thyrotoxicosis, arthritis rheumatoid, Insulin resistance type B, ulcerative colitis, or Wegener's granulomatosis. 27. The use of one or more compounds according to claims 1 or 14 or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof for the manufacture of a medicament for treating a disorder of the central nervous system. 28. The use of one or more compounds according to claim 1 or 14 or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof for the manufacture of a medicament for treating multiple sclerosis. 29. The use of one or more compounds according to claims 1 or 14 or a pharmaceutically acceptable salt, solvate, h idrate, metabolite, prodrug, enantiomer or stereoisomer thereof for the manufacture of a medicament for treating rheumatoid arthritis. 30. - A pharmaceutical composition comprising one or more compounds according to Formula (I), (a), (II), (III), (IV), or (V) or pharmaceutically acceptable salts, solvates, hydrates , metabolites, prodrugs or stereoisomers thereof and a pharmaceutically acceptable diluent or carrier. In a preferred aspect, the invention provides a pharmaceutical composition wherein the compound or compounds are present in a therapeutically effective amount. 31 .- A packaged pharmaceutical product comprising one or more compounds according to Formula (I), (a), (II), (III), (IV), or (V) or pharmaceutically acceptable salts, solvates, hydrates, metabolites, prodrugs or stereoisomers thereof and instructions for its use. In one embodiment, the invention provides a packaged pharmaceutical product in which the compound or compounds are present in a therapeutically effective amount. In another embodiment, the invention provides a packaged pharmaceutical product wherein the compound or compounds are present in a prophylactically effective amount.
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