MX2008010534A - Hydantoin based kinase inhibitors - Google Patents
Hydantoin based kinase inhibitorsInfo
- Publication number
- MX2008010534A MX2008010534A MX/A/2008/010534A MX2008010534A MX2008010534A MX 2008010534 A MX2008010534 A MX 2008010534A MX 2008010534 A MX2008010534 A MX 2008010534A MX 2008010534 A MX2008010534 A MX 2008010534A
- Authority
- MX
- Mexico
- Prior art keywords
- phenyl
- fluoro
- ethoxy
- dioxo
- imidazolidin
- Prior art date
Links
Abstract
The present invention relates to compounds of the formula (I), pharmaceutical compositions containing said compounds, methods for the preparation thereof, and methods for their use. The compounds are useful in treating diseases characterized by the hyperactivity of MEK. Accordingly the compounds are useful in the treatment of diseases, such as cancer, cognitive and CNS disorders, and inflammatory/autoimmune diseases.
Description
INHIBITORS OF KINASE BASED ON HIDANTOIN FIELD OF THE INVENTION The present invention relates to hydantoin derivatives and their use as inhibitors. of two protein kinases commonly known as MEK1 and MEK2 for the treatment of human diseases, such as cancer. The EK is the abbreviation normally used for the MAP kinase / ERK kinase, which in turn are the abbreviation of mitogen / kinase-activated protein regulated by extracellular signals. MEK is also called MAPK kinase or MAP kinase-kinase. BACKGROUND OF THE INVENTION Cancer is a disease characterized by the proliferation of malignant cells and tumors, which have an unlimited potential for growth, local expansion and systemic metastasis. This uncontrolled growth is derived from abnormality in the mechanisms of signal transduction and the response to several growth factors, which differs from those found in normal cells. Abnormalities include changes in the intrinsic activity or cellular concentration of one or more proteins within the signaling cascade. These changes are often caused by intrinsic mutations or overexpression of intracellular signaling proteins, which leads to spurious mitogenic signals within the cells. The trajectory of the protein kinase activated by Ref. 1954
mitogen (MAP) is one of the best characterized signaling mechanisms, which intervene in the development and progress of human malignant tumors. This trajectory, through the Ras / Raf / MEK / ERK signaling cascade, allows the transmission and amplification of mitogenic signals from the cell surface to the nucleus, where activated transcription factors regulate gene expression and determine the destiny of the cell. The constitutive activation of this path is sufficient to induce cell transformation. The deregulated activation of the MAP kinase mechanism, due to an aberrant activation of receptor tyrosine kinase, RAS mutations or Raf mutations, has been observed frequently in human malignant tumors and constitutes an important factor to determine the control of a growth abnormal. In malignant diseases, Ras mutations are frequent and have been detected in 30% of malignant tumors. The Ras group of protein-GTPases (proteins that convert guanosine triphosphate into guanosine diphosphate) emit signals of activated growth factor receptors in the direction of their cellular partners. Among the targets recruited by the active Ras fixed on membrane are the serine / threonine-protein-kinases of the Raf group. The Raf group consists of three related kinases (the A-Raf, B-Raf and C-
Raf), which act in the direction of the effectors of the Ras. The activation of Raf mediated by Ras in turn triggers the activation of MEK1 and MEK2 (MAP / ERK-kinases 1 and 2), which in turn phosphorylate ERK1 and ERK2 (kinases 1 and 2 regulated by extracellular signals ) both tyrosine-185 and threonine-183. The activated ERK1 and ERK2 change location and accumulate in the nucleus, where they can phosphorylate a large number of substrates, including the transcription factors that control cell growth and survival. Given the importance of the Ras / Raf / MEK / ERK mechanism in the development of human cancer, the kinase components of the signaling cascade are emerging as potentially important targets for modulating the progress of the pathological state, either in cancer, or in other proliferating diseases. MEK1 and MEK2 are components of a larger group of dual specificity kinases (MEK1-7), which phosphorylate the threonine and tyrosine moieties of several MAP kinases. MEK1 and MEK2 are encoded with different genes, but share a high homology (80%) not only with the catalytic kinase domains of the C-terminus, but also with most of the N-terminal regulatory region. The oncogenic forms of MEK1 and MEK2 have been detected in human malignant tumors, but the constitutive activation of MEK has been found to cause a transformation
cell phone. In addition to Raf, MEK can also be activated by the action of other oncogenes. So far, the only known substrates of MEK1 and MEK2 are ERK1 and ERK2. This unusual substrate specificity and also the unique ability to phosphorylate both tyrosine and threonine residues, converts MEK1 and MEK2 into critical points within the signal transduction cascade, which allow many extracellular signals to be integrated into the MAPK mechanism. In previously published studies on an MEK inhibitor, 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-benzamide, also known as Cl-1040 (PCT publication no. O 99/01426), it is evident that MEK1 and MEK2 constitute an attractive target for pharmacological intervention in cancer or in other human diseases, characterized by the hyperactivity of MEK and diseases regulated by the MAPK mechanism. Substituted hydantoins have been previously reported as glucokinase activators (PCT publication No. WO 01/83478). BRIEF DESCRIPTION OF THE INVENTION This invention relates to compounds of the formula I:
or their pharmaceutically acable salts, wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7 and R 8 have the meanings defined in this application. These compounds inhibit the enzymes MEK1 and MEK2, protein kinases that are components of the signal transduction mechanism of the
MAP kinase and, as such, these compounds will have anti-hyperproliferating cellular activity. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds of the formula I:
wherein: R 1 is selected from the group consisting of bromine, iodine, ethynyl, cycloalkyl, alkoxy, azetidinyl, acetyl, heterocyclyl, cyano, straight chain alkyl and branched chain alkyl; R2 is selected from the group consisting of hydrogen, chlorine, fluorine and alkyl; R3 is selected from the group consisting of hydrogen, chlorine and fluorine; R4 is selected from the group consisting of hydrogen, optionally substituted aryl, alkyl and
cycloalkyl; R5 is selected from the group consisting of hydrogen and
wherein R6 is selected from the group consisting of hydroxyl, alkoxy, cycloalkyl, optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl; R7 and R8 are independently selected from the group consisting of hydrogen and optionally substituted alkyl; or R6 and R7 can together form a cycloalkyl group and R8 is hydrogen; and their pharmaceutically acable salts or esters. In one aspect, the invention relates to compounds of the formula I, wherein R 1 is iodo, ethynyl or cyclopropyl. In another aspect, the invention relates to compounds of the formula I, wherein R 2 is hydrogen, chlorine or fluorine. In another aspect, the invention relates to compounds of the formula I, wherein R3 is hydrogen. In another aspect, the invention relates to compounds of the formula I, wherein R8 is hydrogen or methyl. In another aspect, the invention relates to
compounds of formula I, wherein R 4 is substituted aryl. In another aspect, the invention relates to compounds of formula I, wherein R 1 is iodo, ethynyl or cyclopropyl, R 2 is hydrogen, fluorine, chlorine or methyl, R 3 is hydrogen, R 4 is optionally substituted aryl, R 5 is
R6 is alkoxy, cycloalkyl or optionally substituted aryl, R7 is hydrogen and R8 is hydrogen or methyl. In another aspect, the invention relates to compounds of formula I, wherein R 1 is iodo, ethynyl or cyclopropyl, R 2 is hydrogen, fluorine or chlorine, R 3 is hydrogen, R 4 is optionally substituted phenyl, R 5 is R 6 -C 8 , R1 R6 is optionally substituted phenyl, R7 is hydrogen and R8 is methyl. In another aspect, the invention relates to compounds of the formula I, wherein R 1 is iodo, R 2 is fluorine or chlorine, R 3 is hydrogen, R 4 is phenyl substituted by alkoxy, R 5 is
I R6 is phenyl, R7 is hydrogen and R8 is methyl. In another aspect, the invention relates to
compounds of formula I, wherein R 1 is iodine, R 2 is fluorine
0 chlorine, R3 is hydrogen, R4 is phenyl substituted by 2,3-dihydroxy-propoxy or 2-hydroxy-ethoxy, R5 is
R6 is phenyl, R7 is hydrogen and R8 is methyl. In a preferred embodiment of the present invention, there is provided the compound of the formula I, wherein R 4 is phenyl, which is unsubstituted or substituted
1 or 2 times by a substituent independently selected from -halogen, -P (0) (0-CH 3) 2, -P (0) (0H) 2, -S (0) 2- (C 1 -C 6 alkyl), - (0-CH2-CH2) 2-0-CH3 and -0- (C1-C6 alkyl), wherein the alkyl group is unsubstituted or substituted 1 or 2 times by a substituent independently selected from -OH, -oxo , -C3-C6 cycloalkyl, -0- (C1-C6 alkyl), -NH- (C1-C6 alkyl) or -N (Cl-C6 alkyl) 2,
wherein the alkyl groups are unsubstituted or substituted by -OH, or a 4- to 6-membered heterocycle, whose heteroatoms are selected from N, S and 0; and the other substituents have the meanings defined above. In still another preferred embodiment of the present invention, there is provided the compound of formula I, wherein R 4 is phenyl, which is unsubstituted or substituted
1 or 2 times by a substituent independently selected from -halogen, -P (O) (0-CH 3) 2, -P (0) (0H) 2, -S (O) 2- (C 1 -C 6 alkyl), - (0-CH2-CH2) 2-O-CH3 and -O- (C1-C6 alkyl), said alkyl group is unsubstituted or substituted 1 or 2 times by a substituent independently selected from -OH, -oxo, - C3-C6 cycloalkyl, -0- (C1-C6 alkyl), -NH- (C1-C6 alkyl) or -N (C1-C6 alkyl) 2, alkyl groups are unsubstituted
0 substituted by -OH, or a 4- to 6-membered heterocycle, whose heteroatoms are selected from N, S and O; R5 is 1-phenyl-ethyl; and "the other substituents have the meanings defined above." In yet another preferred embodiment of the present invention, there is provided the compound of the formula I, wherein R 1 is iodo, R 2 is hydrogen or fluoro, R 3 is hydrogen or fluoro; phenyl, which is unsubstituted or substituted
1 or 2 times by a substituent independently selected from -halogen, -P (O) (0-CH 3) 2, -P (O) (OH) 2, -S (O) 2- (C 1 -C 6 alkyl), - (0-CH2-CH2) 2-0-CH3 and -O- (C1-C6 alkyl), said alkyl group is unsubstituted or substituted 1 or 2 times by a substituent independently selected from -OH, -oxo,
-C3-C6-cycloalkyl, -0- (C1-C6 alkyl), -NH- (C1-C6 alkyl) or -N (C1-C6 alkyl) 2, the alkyl groups are unsubstituted
0 substituted by -OH, or - a 4- to 6-membered heterocycle, whose heteroatoms are selected from N, S and 0; and R5 is 1-phenyl-ethyl. In still another preferred embodiment of the present invention, there is provided the compound of formula I, wherein R 4 is phenyl, which is unsubstituted or substituted
1 or 2 times by a substituent independently selected from -halogen, -P (0) (0-CH 3) 2, -P (O) (OH) 2, -S (O) 2- (C 1 -C 6 alkyl), - (0-CH2-CH2) 2-O-CH3 and -0- (C1-C6 alkyl), said alkyl group is unsubstituted or substituted 1 or 2 times by a substituent independently selected from -OH, -oxo, - C3-C6 cycloalkyl, -0- (C1-C6 alkyl), -NH- (C1-C6 alkyl) or
-N (Cl-C6 alkyl) 2 / alkyl groups are unsubstituted
0 substituted by -OH, or a 4- to 6-membered heterocycle, whose heteroatoms are selected from N, S and 0; R5 is benzyl, said benzyl is unsubstituted or substituted once by -C1-C6 alkyl, -fluoro or chloro, -CN, -0-C1-C6 alkyl and -CF3; and the other substituents have the meanings defined above. In still another preferred embodiment of the present invention, there is provided the compound of formula I, wherein R 4 is phenyl, which is unsubstituted or substituted
1 or 2 times by a substituent independently selected from -halogen, -P (0) (0-CH 3) 2, -P (0) (0H) 2, -S (0) 2- (C 1 -C 6 alkyl), - (0-CH2-CH2) 2-O-CH3 and -0- (C1-C6 alkyl), said alkyl group is without
substituted or substituted 1 or 2 times by a substituent independently selected from -OH, -oxo, -C3-C6-cycloalkyl, -0- (C1-C6 alkyl), -NH- (C1-C6 alkyl) or -N (Cl-C6 alkyl) 2, the alkyl groups are unsubstituted or substituted by -OH, or a heterocycle of from 4 to 6 members, whose heteroatoms are selected from N, S and 0; R5 is C1-C6 alkyl, which is unsubstituted or substituted 1 or 2 times by a substituent independently selected from -naphthyl, pyridinyl, thiazolyl, thiophenyl which is optionally substituted by bromine, imidazolyl which is optionally substituted by methyl; or C3-C6 cycloalkyl; -CF3; -0-C1-C6 alkyl; -0-CH2-phenyl; -S (0) 2-methyl; -oxo; or -NH2; and the other substituents have the meanings defined above.
Preferred compounds of the invention are: (2S, 3S) -N- (4-bromo-phenyl) -2- [(R) -4- (4-methoxy-phenyl) -2,5-dioxo-imidazolidin-1- il] -3-phenyl-butyramide; (2S, 3S) -N- (4-iodo-phenyl) -2- [(R) -4- (4-methoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl] -3-phenyl- Butyramide; (2S, 3S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} 3-phenyl-butyramide; (2S, 3S) -N- (4-ethynyl-2-fluoro-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} 3-phenyl-butyramide; (2R, 3S) -N- (-etinyl-2-fluoro-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} 3-phenyl-butyramide; (2S, 3S) -N- (2-chloro-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} 3-phenyl-butyramide; (2S, 3S) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (4-iodo-2-methyl-phenyl) -3-phenyl-butyramide; (2S, 3S) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4- [4 - ((R) -2,3-dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} 3-phenyl-butyramide; (2S, 3S) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4- [4 - ((S) -2,3-dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-
phenylbutyramide; (2S, 3S) -2-. { (R) -2,5-dioxo-4- [4- (2-oxo-2-pyrrolidin-1-yl-ethoxy) -phenyl] -imidazolidin-1-yl} -N- (2-fluoro-4-iodo-phenyl) -3-phenyl-butyramide; (2S, 3S) -2- ((R) -2,5-dioxo-4-thiophen-3-yl-imidazolidin-1-yl) -N- (4-iodo-phenyl) -3-phenyl-butyramide; (S) -2 - [(R) -4- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -2,5-dioxo-imidazolidin-1-yl] -N- (2 -fluoro-4-iodo-phenyl) -3-phenyl-propionamide; (S) -2 - [(R) -4- (4-acetylamino-phenyl) -2,5-dioxo-imidazolidin-1-yl] -N- (2-fluoro-4-iodo-phenyl) -3- phenyl-propionamide; (4- { (R) -1 - [(1S, 2S) -1- (2-fluoro-4-iodo-phenylcarbamoyl) -2-phenyl-propyl] -2,5-dioxo-imidazolidin-4- il.}. phenoxymethyl) -phosphonate dimethyl; (2S, 3S) -N- (2-fluoro-4-iodo-phenyl) -2- ((R) -4-isopropyl-2,5-dioxo-imidazolidin-1-yl) -3-phenyl-butyramide; (S) -N- (2-fluoro-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-methyl-butyramide; (S) -N- (2-fluoro-4-iodo-phenyl) -2- [(R) -4- (4-methoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl] -3- o-tolyl-propionamide; (S) -N- (2-fluoro-4-iodo-phenyl) -2- [(R) -4- (4-methoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl] -3- m-tolyl-propionamide; (S) -N- (2-fluoro-4-iodo-phenyl) -2- [(R) -4- (4-methoxy)
phenyl) -2,5-dioxo-imidazolidin-1-yl] -3-p-tolyl-propionamide; Y
(S) -N- (4-cyclopropyl-2-fluoro-phenyl) -3- (4-fluoro-phenyl) -2-. { (R) -4- [4- (2-hydroxy-l-hydroxymethyl-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -propionamide. "Alkyl" denotes a saturated aliphatic hydrocarbon, straight chain, branched or cyclic. Alkyl preferably denotes a lower alkyl group, ie, a C 1 -C 6 alkyl group and includes methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 2-butyl, pentyl, hexyl and the like. Lower alkyl is more preferably C 1 -C 4 alkyl and with special preference C 1 -C 3 alkyl. Most preferred is isopropyl or 2-propyl. Examples of "cycloalkyl" groups as used herein are moieties having from 3 to 10 carbon atoms, preferably from 3 to 7, including the cyclopropyl, cyclopentyl and cyclohexyl groups. "Halogen" means fluorine, chlorine, bromine or iodine. "Trihaloalkyl" means an alkyl group, in which three hydrogen atoms of the terminal carbon atoms have been replaced by halogen, preferably by fluorine. Examples of such groups are trifluoromethyl, trichloromethyl, 1,1-trifluoroethyl, 1,1-trichloropropyl and the like. "Lower trihaloalkyl" means a trihaloalkyl group having one to six carbon atoms, preferably one to three carbon atoms.
"Aryl" means a carbocyclic or heterocyclic, monocyclic or bicyclic, monovalent aromatic radical, preferably an aromatic ring system composed of 6-10 members. An "aryl" group containing one or more heteroatoms, preferably selected from N, S and O, can also be called a "heteroaryl" group. Preferred aryl and heteroaryl groups include, but are not limited to: phenyl, naphthyl, tolyl, xylyl, thienyl, furyl, indolyl, pyrrolyl, pyridinyl, oxy-pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazole and tetrazolyl. The aryl groups may be optionally mono-, di- or tri- substituted by for example lower alkyl, cycloalkyl, for example, cyclopropyl, trihalo lower alkyl, for example, trifluoromethyl, hydroxyl, alkoxy, especially lower alkoxy, mono- or disubstituted alkoxy. by hydroxy; acetamido, methoxyacetamido, dimethylaminoacetamido, halogen, for example, fluoro, chloro or bromo, aniline derivatives, amide derivatives of the aniline and methanesulfonyl derivatives. When two or more substituents are present in the aryl or heteroaryl ring, then they may also be present in the fused ring form. The fused rings include, but are not limited to: 3,4-methylenedioxyphenyl and 3,4-ethylenedioxyphenyl. "Heteroatom" means an atom selected from N, O and S.
"Heterocyclyl" means a non-aromatic monocyclic hydrocarbon radical, having from four to six carbon atoms, and at least one heteroatom, preferably one or two heteroatoms. Azetidinyl, oxetanyl, pyrrolidinyl, morpholino and the like are examples of such heterocyclyl groups. "Alkoxy or lower alkoxy" means any of the lower alkyl groups mentioned above, which are linked through an oxygen atom. Typical lower alkoxy groups include methoxy, ethoxy, isopropoxy or propoxy, butyloxy, cyclopropyl-methoxy and the like. Included within the meaning of alkoxy are the multiple alkoxy side chains, for example ethoxy-ethoxy, methoxy-ethoxy, methoxy-ethoxy-ethoxy, methyl-oxetanyl-methoxy and the like. Also included are the side chains substituted by alkoxy, for example, hydroxyethoxy, dihydroxypropoxy, dimethylamino-ethoxy, diethylamino-ethoxy, phosphoryl-methoxy, dimethoxy-phosphoryl-methoxy, carbamoyl-methoxy, methyl- and dimethyl-carbamoyl-methoxy, carbamoyl- ethoxy, methyl- and dimethyl-carbamoyl-ethoxy, azetidinyl-carbamoyl-ethoxy, oxopyrrolidinyl-ethoxy, bishydroxyethylcarbamoyl-methoxy, morpholinyl-methoxy, morpholinyl-ethoxy, piperazinyl-methoxy, piperazinyl-ethoxy, lower alkyl-piperazine-ethoxy, oxo- pyrrolidinyl-ethoxy and the like. "Pharmaceutically acceptable ester" means a
composed of formula I esterified in conventional manner, having a carboxyl group, the esters retain the biological efficacy and properties of the compounds of formula I and decompose in vivo (in the organism), to regenerate the original active carboxylic acid . Information regarding esters and the use of esters to generate pharmaceutical compounds can be found in Design of Prodrugs, Bundgaard, Hans (coord.), (Elsevier, 1985). See also Ansel et al., Pha rma ce u t i ca 1 Dosage Forms and Drug Delivery Systems (6th ed., 1995) on pp. 108-109; Krogsgaard-Lar sen et al., Textbook of Drug Design and Development (2nd ed., 1996) on pp. 152-191. "Pharmaceutically acceptable salt" means the acid addition salts and the conventional base addition salts, which retain the efficacy and biological properties of the compounds of the present invention and are formed from suitable, non-toxic inorganic or organic acids. , or of inorganic or organic bases. Examples of acid addition salts include salts derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid and
those derived from organic acids, such as p-1 or 1 acid, salicilic acid, methansulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, trifluoric acid 1 uo r oa cé ti co and similar. Examples of base addition salts include those derived from ammonium, potassium, sodium and quaternary ammonium hydroxides, for example, from tetramethyl ammonium hydroxide. The chemical modification of a pharmaceutical compound (ie, of a drug) to convert it into a salt is a technique that pharmaceutical chemists know well and use to obtain better physical and chemical properties in the compounds, for example better stability, hygroscopicity, fluidity and solubility. See for example Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th ed., 1995) on pp. 196 and 1456-1457. "Pharmaceutically acceptable", for example a carrier, excipient, etc. "Pharmaceutically acceptable" means that it is pharmacologically acceptable and substantially non-toxic to the subject, to which the subject compound is administered. "Substituted", for example in aryl or substituted heteroaryl, means that the substitution may take place in one or more positions and, unless stated otherwise,
that the substituents of each substitution position are selected independently of the specified options. "Therapeutically effective amount or effective amount" means an amount of at least one designated compound that significantly inhibits proliferation and / or prevents differentiation of a human neoplastic cell, including human neoplastic cell lines. The compounds of the general formula I can also be referred to in this application as compounds of the formula I. The compounds of the present invention are useful for treating or controlling cell proliferation disorders, such as inflammatory / autoimmune disorders, for example restenosis, cognitive disorders, for example dementia and Alzheimer's disease, CNS disorders, for example neuropathic pain and, in particular, oncological disorders. These compounds and formulations containing the compounds may be useful for the treatment or control of solid tumors, for example, breast, colon, lung and prostate tumors. Accordingly, the present invention also provides a compound of formula I, as defined above, for use as a medicament.
Another object of the present invention is a compound of formula I, as defined above, for use as a medicament for the treatment of cancer, in particular of solid tumors, more particularly of lung, breast, colon or Prostate Still another object of the present invention is the use of a compound of formula I, as defined above, for the manufacture of a medicament for the treatment of cancer, in particular of solid tumors, more particularly of lung tumors, of breast , colon or prostate. The compounds of the formula I and their salts have at least one asymmetric carbon atom and, therefore, may be present in the form of mixtures of different stereoisomers. The various isomers can be isolated by known separation methods, for example by chromatography. A therapeutically effective amount of a compound according to this invention means an amount of compound that is effective to prevent, alleviate or ameliorate the symptoms of the disease or to prolong the survival of the treated subject. The determination of the therapeutically effective amount is part of the technical knowledge.
The therapeutically effective amount or dosage of a compound of this invention can vary within wide limits and can be determined in a manner known in the art. Such dosage should be adjusted to the individual requirements in each particular case, including (s) the specific compound (s) to be administered, the route of administration, the pathological condition to be treated, as well as the general condition of the patient to be treated. In general, in the case of oral or parenteral administration to adult humans, weighing approximately 70 kg, a daily dosage of 10 mg to 10 000 mg, preferably 200 mg to 1,000 mg, may be appropriate, although the upper limit may be appropriate. indicated may be exceeded, if it is considered indicated. The daily dose may be administered as a single dose or divided into sub-doses or, in the case of parenteral administration, may be given as a continuous infusion. The compounds claimed in the present invention (compounds of the general formula I) can be obtained by applying the general reaction order described in reaction scheme 1, in which all the substituents have the meanings defined above, unless explicitly stated otherwise. contrary.
Reaction Scheme 1
6
Step 1: A compound having an α-amino acid functional group of the general formula 2 is converted into a
reactive acylating species of general formula 3, which is suitable for use in step 2 of the synthesis sequence. Step 1 is conveniently carried out in an α-amino acid carrying a protecting group (PG1) on the nitrogen of the α-amine. The appropriate choice of the protecting group PG1 is that which converts the a-amine nitrogen inert to the reaction conditions applied during steps 1 and 2 of the synthesis sequence, but which can be eliminated during step 3 of the sequence of synthesis without causing annoying modifications in the rest of the compound, when exposed to the conditions necessary for the removal of the protective group. The suitable choice of the protective group PG1 can be carried out according to the organic chemistry manuals (for example Protective Groups in Organic Synthesis, Theodora, Greene et al.), The original chemical bibliography or it will be carried out according to the general knowledge that the experts in organic synthesis. Particularly preferred are carbamate-type protecting groups, for example tert-butyloxycarbonyl and 9H-fluoren-9-ylmethoxycarbonyl, but other amine protecting groups may also be effective. The choice of the reactive acylating agent of the general formula 3 to be formed will depend as much on the compatibility with the potentially reactive functional groups, existing in other positions of the molecule of
the general formula 3, as well as the reactivity and the selectivity of the acylating agent of the formula 3 for the acylation of the aniline derivative of the formula 4. This reaction leads to the formation of the desired amide bond, existing in the compounds of the formula 5. Typical reactive acylating agents, which may be employed in step 2, are acyl halides (compound 3, X = halogen) and acid anhydrides (compound 3, X = 0-C (O) R). The preferred choice of acylating agents of the general formula 3 will be the acyl halides, in particular the acyl fluorides (compound 3, X = F), the acyl chlorides (3, X = chlorine) and the acyl bromides (3). , X = bromine). Other additional options of acylating agents of general formula 3 may also be suitable for use in step 2 and those skilled in organic synthesis already know them perfectly. In the case, in which the compounds of the general formula 2 contain a chiral center on carbon a, the preferred stereochemistry will be S. Step 2: An aniline derivative of the general formula 4 is reacted with an acylating agent formed previously of the general formula 3 to form an amide derivative of the general formula 5. The experts in organic synthesis know well that applying the condensation techniques, already known from the
For the chemistry of the peptides, it is possible to directly obtain compounds of the general formula 5 from the compounds of the general formula 2 and of the general formula 4 without the need to previously obtain the reactive acylating agent of the general formula 3. The condensation agents Typical of the peptides, which can be used for the direct conversion of the compounds of the general formula 2 and of the general formula 4 to compounds of the general formula 5 include the diimide base reagents for example dicyclohexylcarbodiimide, hydrochloride (3 -dimethylamino-propyl) -ethyl-carbodiimide; or the uronium-based reagents, for example O-benzotriazole-1-yl-N, N ',' -tetramethyluronium hexafluorophosphate or 0-benzotriazol-1-yl-N, N, N ',' - hexafluorophosphate bis (tetramethylene) uronium. Alternative peptide condensation reagents can also be effective in carrying out this conversion. The choice of alternative peptide condensation reagents can be made with reference to the original chemical literature or according to the knowledge already possessed by the experts in organic synthesis. Step 3: This step in the synthesis sequence includes the removal of the protecting group PG1 from the compounds of the general formula 5 to form the amine-containing compounds of the general formula 6 with a view to their further transformation. As has been said before, the
The choice of the PGl protecting group and the conditions applied in step 3 for the removal of the PGI will depend on other potentially reactive functional groups that are present in the compounds of the general formula 5 and the need to avoid annoying reactions in other positions of the starting material or the product of the reaction, ie the compounds of the general formulas 5 and 6, respectively. In the case where the PGl protecting group present in the compounds of the general formula 5 is tert-butyloxycarbonyl, this protecting group can be removed under acidic conditions, for example by treatment with trifluoroacetic acid in dichloromethane or hydrochloric acid in p- dioxane The removal of the tert-butyloxycarbonyl group under acidic conditions initially liberates the corresponding salt of the compound of the general formula 6, from which the free amine of the general formula 6 can be liberated by treatment with a base. In the case in which the amine protecting group PGl present in the compounds of the general formula 5 is 9H-fluoren-9-ylmethoxycarbonyl, said protecting group may be removed under basic conditions, for example by treatment with piperidine in dichloromethane. Step 4: The compounds of the general formula 8 are obtained by reaction of amines of the general formula 6 with a compound containing α-amino acid functional groups. Is
It is very convenient to carry out step 4 in compounds of the general formula 7 which contain an α-amino acid carrying a protective group (PG2) of the nitrogen of the α-amine. The criteria for the choice of the protecting group PG2 are the same as those described for the choice of the protecting group PG1 in step 1. Particularly preferred are carbamate-type protective groups, for example tert-butyloxycarbonyl, but they can also be effective other amine protecting groups. In the case that the compounds of the general formula 7 have a chiral group on carbon a, the preferred stereochemistry will be R. Step 5: This step of the synthesis sequence includes the removal of the protective group PG2 from the compounds of the general formula 8 for forming amine-containing compounds of the general formula 9, before the end of the synthesis sequence. The choice of the conditions for the effective removal of the protective group PG2 from the compounds of the general formula 8 is based both on the reactivity of the protective group PG2 and on the nature and reactivity of the other functional groups present in the starting material and in the product of the reaction performed in step 5, ie, the compounds of the general formulas 8 and 9, respectively. In the case, that the amine protecting group PG2, present in the compounds
of the general formula 8, ie tert-butyloxycarbonyl, this protective group may be removed under acidic conditions, for example by treatment with trifluoroacetic acid in dichloromethane, hydrochloric acid in p-dioxane or with formic acid as such. The removal of the tert-butyloxycarbonyl group under acidic conditions initially liberates the corresponding salt of the compound of the general formula 9, from which the free amine of the general formula 9 can be liberated by treatment with a base. Step 6: The compounds of the general formula I claimed in the present invention can be obtained from the compounds of the general formula 9 by cyclization in the presence of phosgene or an equivalent reagent, that is, by direct condensation of a carbonyl group on two. scrollable groups. A preferred reagent for effecting the cyclization of compounds of the general formula 9 in compounds of the general formula I is trichloromethyl chloroformate, which acts in the reaction mixture as two equivalents of phosgene. Cyclization of compounds of the general formula 9 with trichloromethyl chloroformate is generally rapid and is usually carried out at low temperatures (<0 ° C) and in the presence of a carefully controlled amount of a base to neutralize the acid formed during the cyclization and to avoid unnecessary isomerization of the existing potentially labile chiral center
in the newly formed hydantoin ring. Experts in organic synthesis will readily understand that, when one or more of the substitutes marked from R1 to R5 or of the substitutes and nt is included in their definitions, of the compounds represented in reaction scheme 1, they are in groups that by they themselves are chemically reactive or contain reactive groups, then a further modification of the compounds of the general formula I by compound 9, which contains the reactive groups, will be possible. The point of the synthesis sequence, in which the modification of the chemically reactive groups takes place, can be chosen so that the newly generated group is chemically inert with respect to the reagents that will be used in the subsequent steps of the synthesis sequence and it will not interfere with the subsequent steps of the synthesis sequence, represented in scheme 1. Alternatively, if the newly generated group is not inert chemistry or can interfere with the remaining steps of the synthesis sequence, it may be necessary to temporarily mask the group functionally reactive with a suitable protective group or derivat ive it in a residue, which is stable during the subsequent transformations of the sequence of
synthesis and may be present in the final product of the sequence of reactions. If a protective group is introduced, which is not necessary in the final compound of the general structure I, then this group can be removed under the conditions of the remaining reactions of the synthesis sequence shown in scheme 1 or by introduction of an additional step. of deprotection within the synthesis sequence, depending on the nature of the protecting group employed. The conditions of the above reactions may vary to some degree. The methods for carrying out the reactions and processes just described are obvious to those skilled in the organic synthesis, based on the present invention or by deduction and similarity to the examples. The starting materials are commercial products or compounds obtainable by methods similar to those described in the examples. The following examples illustrate the preferred embodiments of the present invention, but they are not intended to limit the scope of the invention in any way.
Example 1 (2S, 3S) -N- (4-bromo-phenyl) -2- [(R) -4- (4-methoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl] -3- phenylbutyramide
Step 1: To a solution of (2S, 3S) -2-tert-butoxycarbonylamino-3-phenyl-butyric acid (838 mg, 3.0 mmol) in dichloromethane (10 mL) is added at -35 ° C dry pyridine (255 μ ?, 3.15 mmoles) and cyanuryl fluoride (375 μ ?, 4.5 mmoles) under dry argon atmosphere. The mixture is stirred for 1.5 hours maintaining the temperature between -35 and -25 ° C. A small amount of ice is added to the reaction mixture and the mixture is stirred vigorously for 15 minutes. The organic phase is separated by decanting the aqueous solution and the aqueous phase is extracted with dichloromethane (2 x 10 ml). The combined organic layers are washed with ice water (15 ml), dried over sodium sulfate, filtered and the vacuum concentrated, yielding (1-fluorocarbonyl-2-phenyl-propyl) -carbamic acid tert-butyl ester, used in the next step without further purification. Step 2: To a solution of 4-bromoaniline (purity 97%) (177 mg, 1.0 mmol) and N-methyl-morpholine (220 μ ?, 2.0 mmol) in dry tetrahydrofuran (3 ml) is added a
solution of (1-fluorocarbonyl-2-phenyl-propyl) -carbamic acid tert -butyl ester (* 1.5 mmol) in dry tetrahydrofuran (2 ml + 1 ml to rinse the funnel, which is added to the reaction mixture) and an amount catalytically sufficient dimethyl-pyridin-4-yl-amine. The mixture is heated under reflux under a dry argon atmosphere for 3 hours and then cooled to room temperature. The reaction mixture is concentrated in vacuo and the residue is taken up in ethyl acetate. The organic solution is washed successively with water (once), a 1.5 M aqueous solution of potassium hydrogen sulfate (one time), water (three times), brine (one time), dried over sodium sulfate, filtered and Concentrate the vacuum to obtain (1S, 2S) -1- (-bromo-phenylcarbamoyl) -2-phenyl-propyl] -carbamic acid tert-butyl ester, which is used in the next step without further purification (530 mg). LC-MS, observed mass (M + H +) = 433/435; calculated mass = 433/435 for the C2iH26BrN20 +. Step 3: To a solution of (1S, 2S) -1- (4-bromo-phenylcarbamoyl) -2-phenyl-propyl] -carbamic acid tert -butyl ester (530 mg, ¾1 mmol) in dichloromethane (12 ml) was trifluoroacetic acid (8 ml, 108 mmol) is added at 0 ° C under a dry argon atmosphere and the mixture is stirred at 0 ° C for 1.5 hours. The reaction mixture is concentrated in vacuo and the residue is suspended in ice water. The aqueous suspension is neutralized with a saturated aqueous solution of sodium hydrogen carbonate
(12 ml), then extracted with dichloromethane (three times). The combined organic extracts are dried with sodium sulfate, filtered and the vacuum concentrated, obtaining (2S, 3S) -2-amino-N- (-bromo-phenyl) -3-phenyl-butyramide, which is used in the Next step without further purification (334 mg). LC-MS, observed mass (M + H +) = 333/335; calculated mass = 333/335 for the Ci6Hi8BrN20 +. Step 4: To a solution of (2S, 3S) -2-amino-N- (4-bromo-phenyl) -3-phenyl-butyramide (167 mg, "0.5 mol) in N, N-dimethylformamide (3 ml) 0 (R) -ter-butyloxycarbonylamino-4-methoxyphenylglycine (155 mg, 0.55 mol) (obtained according to the procedure of Hyun, MH et al., J. Liq. Chrom. &Re. Technol. 25, 573-588, 2002), N, N-diisopropylethylamine (350 μ ?, 2.0 mmol), N-hydroxybenzotriazole (82 mg, 0.6 mmol), O-benzotriazole-1-yl-N-hexafluorophosphate , N, N ', N' -tetramethyluronium (227 mg, 0.6 mmol) and a catalytically sufficient amount of dimethyl-pyridin-4-yl-amine and the mixture is stirred under a dry argon atmosphere and allowed to warm to room temperature. one night. The reaction mixture is poured into water / ice (20 ml), extracted with ethyl acetate (2 x 10 ml), the combined organic extracts are washed with water (3 x 10 ml), brine (10 ml), Dry with sodium sulfate, filter and concentrate the vacuum. The crude product is purified by chromatography through silica gel eluting
with a 2: 1 v / v mixture of hexanes / ethyl acetate, thereby obtaining [[(1S, 2S) -1- (4-bromo-phenylcarbamoyl) -2-phenyl-propylcarbamoyl] - ((R ) -4-methoxy-phenyl) -methyl] -carbamic acid tert-butyl ester as a colorless solid (154 mg, 52%). LC-MS, observed mass (M-H ~) = 594/596; calculated mass = 594/596 for C3oH33BrN305 ~ · Step 5: To a solution of [[(1S, 2S) -1- (4-bromo-phenylcarbamoyl) -2-phenyl-propylcarbamoyl] - ((R) -4- methoxy-phenyl) -methyl] -carbamic acid tert-butyl ester (150 mg, 0.25 mmol) in dichloromethane (10 ml) is added at 0 ° C under a dry argon atmosphere, trifluoroacetic acid (6 ml, 81 mmol) and stir the mixture at 0 ° C for 1.5 hours. The reaction mixture is concentrated in vacuo and the residue is suspended in ice water. The aqueous suspension is neutralized with a saturated aqueous sodium hydrogen carbonate solution (12 ml), then extracted with dichloromethane (three times). The combined organic extracts are dried with sodium sulfate, filtered and the vacuum concentrated, yielding (2S, 3S) -2- [(R) -2-amino-2- (4-methoxy-phenyl) -acetylamino] - N- (4-bromo-phenyl) -3-phenyl-butyramide, which is used in the next step without further purification (124 mg). LC-MS, observed mass (M + H +) = 496/498; calculated mass = 496/498 for the C25H26BrN303 +. Step 6: To a difosgen solution (20 μ ?, 0.17 mmol) in a 1: 1 v / v mixture of toluene / tetrahydrofuran (16
total) are added at -35 ° C by dripping for 10 min and with stirring under a dry argon atmosphere a solution of (2S, 3S) -2- [(R) -2-amino-2- (4 -methoxy-phenyl) -acetylamino] -N- (4-bromo-phenyl) -3-phenyl-butyramide (120 mg, 0.24 mmole) and N, N-diisopropylethylamine (210 μ ?, 1.2 mmole) in tetrahydrofuran (8 ml ). After a further 45 minutes, add ice and stir the reaction mixture vigorously and allow it to warm to room temperature. The reaction mixture is poured into water, extracted with ethyl acetate (twice), the combined organic layers are washed successively with water (twice), a 0.1 M aqueous solution of hydrochloric acid, water, a saturated aqueous solution of sodium hydrogen carbonate, water and brine, then dried with sodium sulfate, filtered and the vacuum concentrated. The crude product is purified by chromatography through silica gel eluting with a 2: 1 v / v hexanes / ethyl acetate mixture. The isolated product is dissolved in a small volume of dichloromethane and then precipitated by dropping over a large volume and stirring petroleum ether. The precipitated solid is isolated by filtration and the vacuum is dried, yielding (2S, 3S) -N- (4-bromo-phenyl) -2- [(R) -4- (4-methoxy-phenyl) -2, 5-dioxo-imidazolidin-1-yl] -3-phenyl-butyramide as a colorless solid (87 mg, 69%). HR-HR, observed mass (M + H +) = 522.1021; calculated mass = 522.1023 for the C26H25Br 304+.
Example 2 (2S, 3S) -N- (4-bromo-2-fluoro-phenyl) -2-. { (R) -4- [4- ((R) -2,3-Dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
It is obtained by the same method as described in Example 1, except that (i) 4-bromo-2-fluoraniline is used in place of 4-bromoaniline in step 2 and (ii) acid (R) -ter-butoxycarbonylamino- [4- ((S) -2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -phenyl] -acetic acid in place of (R) -tert-butyloxycarbonylamino-4-methoxyphenylglycine in step 4. The (R) -ter-butoxycarbonylamino- [4- ((S) -2,2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -phenyl] -acetic acid is obtained and used in the manner described in Example 114. HR-HR, observed mass (M + H +) = 600.1137; calculated mass = 600.1140 for the C28H28BrFN306 +. Example 3 (2S, 3S) -N- (4-bromo-2-chloro-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl butyra ida
Step 1: The 4-bromo-2-chloro is cooled to -30 ° C.
aniline (325 mg, 1.58 mmol) and (S, S) -2-tert-butoxycarbonylamino-3-phenyl-butyric acid (440 mg, 1.58 mmol) in pyridine (5 ml). Phosphorus oxychloride (0.158 mL, 1.7 mmol) is added and stirred at -20 ° C for 2 hours. The mixture is poured into ice water and extracted with ethyl acetate (3 x). The combined organic extracts are washed with water, brine, dried with sodium sulfate and the vacuum concentrated. The residue was dissolved in dichloromethane (5 ml) at 0 ° C and trifluoroacetic acid (3 mol) was added. Stirring is continued at 0 ° C for 2 hours. The mixture is concentrated by evaporation and the residue is dissolved in ether. The ether solution is made basic with a saturated aqueous solution of sodium bicarbonate and extracted with ether. The organic extracts are washed with brine, dried over sodium sulfate and concentrated to give (2S, 3S) -2-amino-N- (4-bromo-2-chloro-phenyl) -3-phenyl-butyramide (325 mg, 55%). Step 2: To a solution of (2S, 3S) -2-amino-N- (-bromo-2-chloro-phenyl) -3-phenyl-butyramide (320 mg, 0.87 mmol) in N, N-dimethylformamide ( 3 ml) is added at 0 ° C (R) -tert-butoxycarbonylamino- [4- (2-tert-butoxy-ethoxy) -phenyl] -acetic acid (320 mg, 0.87 mmol) (obtained in the manner described in Example 48 for the preparation of (R) -tert-butoxycarbonylamino-, {4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic acid, except that the - (2-bromo-ethoxy) -2-methyl-propane instead of 2- (2-bromo-ethoxy) -
tetrahydropyran), N-diisopropylethylamine (0.71 ml, 2.0 mmol), N-hydroxybenzotriazole (82 mg, 0.6 mmol), O-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium hexafluorophosphate (227 mg , 0.6 mmol). After 30 minutes, pour the reaction mixture over water / ice (20 ml), extract with ethyl acetate (2 x 10 ml), combine the combined organic extracts with water (3 x 10 ml), brine (10 ml). ), dried over sodium sulfate, filtered and concentrated in vacuo to obtain [[(1S, 2S) -1- (4-bromo-2-chloro-phenylcarbamoyl) -2-phenyl-butylcarbamoyl] - ((R ) -4- (tert-butoxy-ethoxy) -phenyl) -methyl] -carbamic acid tert-butyl ester as a white solid (560 mg). The ester is suspended in acetonitrile (5 ml) in an ice bath. 4M Hydrogen chloride in p-dioxane (2 ml) is added and the mixture is stirred for 1.5 hours. The mixture is concentrated by evaporation and triturated with ether / hexanes. The solid is filtered and partitioned between a saturated aqueous solution of sodium bicarbonate and dichloromethane. The organic phase is separated, washed with brine and dried with sodium sulfate. Evaporation of the solvents gives the acid [[(1S, 2S) -1- (4-bromo-2-chloro-phenylcarbamoyl) -2-phenyl-butylcarbamoyl] - ((R) -4- (tert-butoxy) ethoxy) -phenyl) -methyl] -carbamic acid as a white solid (346 mg, 72%). Step 3: To the acid [[(1S, 2S) -1- (4-bromo-2-chloro-phenylcarbamoyl) -2-phenyl-butylcarbamoyl] - ((R) -4- (tert-butoxy)
ethoxy- (phenyl) -methyl] -carbamic acid (344 mg, 0.56 mmol) and diisopropyl-ethyl-amine (0.40 ml), 2.25 mmol) were added at -78 ° C the diphosgene (47 μ ?, 0.39 mmol) in tetrahydrofuran (5 ml) and toluene (5 ml). The mixture is stirred and heated slowly from -78 to -30 ° C for 1.5 hours, then diluted with ethyl acetate and washed with water. The organic phase is washed with brine, dried with sodium sulfate and concentrated. The residue is triturated with hexanes, obtaining N- (-bromo-2-chloro-phenyl) -2-. { 4- [4- (2-tert-butoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} 3-phenyl-butyramide (300 mg, 84%). Step 4: N- (4-bromo-2-chloro-phenyl) -2- is dissolved. { - [4- (2-tert-butoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} 3-phenyl-butyramide (300 mg) in dichloromethane (2 ml) and acetonitrile (2 ml) in an ice bath. Trimethylsilyl chloride (0.36 ml, 2.8 mmol) is added and then sodium iodide (352 mg, 2.35 mmol). The mixture is stirred at 0 ° C for 1.5 hours and then diluted with ethyl acetate. The mixture is washed with aqueous sodium bisulfite, washed with brine, dried with sodium sulfate and concentrated in vacuo. The N- (4-bromo-2-chloro-phenyl) -2- is obtained by trituration of the residue with hexanes. { 4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} 3-phenyl-butyramide (210 mg, 76%). HR-HR, observed mass (M + H +) = 586.0739; calculated mass = 586.0739 for the C27H26BrCl 305+.
Example 4 (S) -N- (4-iodo-phenyl) -2- [(R) -4- (4-methoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl] -3-phenyl- propionamide
It is obtained by the same method as described in Example 1, except that (i) (S) -2-1 -butyl ox i ca rbon i 1 amino-3-pheny1-propionic acid is used instead of the acid (2S, 3S) -2-tert-but ox i ca rbon i 1 ami no - 3 - f in i 1 -but í ri co in step 1, (ii) -yodoani 1 ina instead of the - bromoani 1 ina in step 2 and (iii) the salt of t-fluorouracetic acid is isolated from (S) -2-ami not -N- (4-iodo-f in i 1) -3-f 1 -pr op i onami da in step 3 and is used directly in step 4 with 1.0 equivalent of triethylamine and (3-dimethyl ti 1 ami non-propyl) -ethexyl carbodiimide hydrochloride as condensation reagent instead of 0-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate. HR-HR, observed mass (M + H +) = 556.0726; calculated mass = 556.0728 for the C25H2 3 IN304 +. Example 5 (2S, 3S) -N- (4-iodo-phenyl) -2- [(R) -4- (4-methoxy-phenyl) -
2,5-dioxo-imidazolidin-l-yl] -3-phenyl-butyramide
It is obtained by the same method as described in Example 1, except that 4-iodoaniline is used in place of 4-bromoaniline in step 2 and (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride. as a condensation reagent in place of O-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium hexafluorophosphate in step 4. HR-HR, observed mass (M + H +) = 570.0883; calculated mass = 570.0884 for the C26H25l 304+. Example 6 (2S, 3S) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (-iodo-phenyl) -3-phenyl-butyramide
It is obtained by the same method as described in example 48, except that (i) 4-iodoaniline is used instead of 2-fluoro-4-iodoaniline in step 2 and (ii) hydrochloride ( 3-dimethylamino-propyl) -ethyl-carbodiimide as a condensation reagent instead of hexafluorophosphate
of O-benzotriazol-l-yl-N, N, ', N' -tetramethyluronium in step 4. HR-HR, observed mass (M + H +) = 600.0987 calculated mass = 600.0990 for C27H27lN305 +. Example 7 (2S, 3S) -2-. { (R) -4 - [4 - (2-Ethoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (4-iodo-phenyl) -3-phenyl-butyramide
It is obtained by the same method as described in Example 1, except that (i) 4-iodoaniline is used in place of 4-bromoaniline in step 2 and (ii) (R) -tert-butoxycarbonylamino acid -. { 4-ethoxy-ethoxy] -phenyl} -acetic in place of the (R) -ter-butyloxycarbonylamino-4-methoxyphenyl-glycine in step 4. The (R) -tert-butoxycarbonylamino- acid is obtained. { 4-ethoxy-ethoxy] -phenyl} -acetic in the manner described in example 48, except that 1-bromo-2-ethoxy-ethane is used in place of 2- (2-bromo-ethoxy) -tetrahydropyran. HR-HR, observed mass (M + H +) = 628.1305; calculated mass = 628.1303 for the C29H3iI 305+. Example 8 (2S, 3S) -N- (4-iodo-phenyl) -2- ((R) -4- { 4- [2- (2-methoxy-
ethoxy) -ethoxy] -phenyl} -2, 5-dioxo-imidazolidin-1-yl) -3-phenyl-butyramide
It is obtained by the same method as described in Example 7, except that (R) -tert-butoxycarbonylamino- acid is used. { 4- [2- (2-methoxy-ethoxy) -ethoxy] -phenyl} -acetic instead of (R) -ter-butoxycarbonylamino- acid. { 4-ethoxy-ethoxy] -phenyl} -acetic. The (R) -ter-butoxycarbonylamino- acid is obtained. { 4- [2- (2-methoxy-ethoxy) -ethoxy] -phenyl} -acetic in the manner described in example 48, except that 1- (2-bromo-ethoxy) -2-methoxy-ethane is used in place of 2- (2-bromo-ethoxy) -tetrahydropyran. HR-HR, observed mass (M + H +) = 658.1410; calculated mass =
658. 1409 for the C30H33IN3CV. Example 9 (2S, 3S) -N- (4-iodo-phenyl) -2- [(R) -4- (4-methylcarbamoylmethoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl] -3- phenylbutyramide
It is obtained by the same method as described in example 5, except that the acid (R) -ter-
butoxycarbonylamino- (-methylcarbamoylmethoxy-phenyl) -acetic acid in place of (R) -tert-butyloxycarbonylamino-4-methoxyphenylglycine in step 4. The (R) -tert-butoxycarbonylamino- (4-methylcarbamoylmethoxy-phenyl) - acid is obtained acetic acid by a method similar to that described for the preparation of (R) -tert-butyloxycarbonylamino-4-methoxyphenylglycine in Example 1, except that 2-chloro-N-methyl-acetamide is used instead of iodomethane. HR-HR, observed mass (M + H +) = 627.1096; calculated mass = 627.1099 for the C28H28l 405+. Example 10 (2S, 3S) -2-. { (R) -4- [4- (2-azetidin-1-yl-2-oxo-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (-iodo-phenyl) -3-phenyl-butyramide
It is obtained by the same method as described in example 1, except that (i) 4-iodoaniline is used instead of 4-bromoaniline in step 2 and (ii) (R) - [4- (2-azetidin-l-yl-2-oxo-ethoxy) -phenyl] -ter-butoxycarbonylamino-acetic acid in place of (R) -tert-butyloxycarbonylamino-4-methoxyphenylglycine. The (R) - [4- (2-azetidin-1-yl-2-oxo-ethoxy) -phenyl] -ter-butoxycarbonylamino-acetic acid is obtained by a method similar to that described
for the preparation of (R) -ter-butyloxycarbonylamino-4-methoxyphenylglycine in Example 1, except that l-azetidin-l-yl-2-chloro-ethanone is used in place of iodomethane. E -HR, observed mass (M + H +) = 653.1258; calculamass = 658.1256 for the C3oH30IN 05+. Example 11 (2S, 3S) -N- (4-iodo-phenyl) -2-. { (R) -4- [4- (2-morpholin-4-yl-2-oxo-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
It is obtained by the same method as described in Example 1, except that (i) 4-iodoaniline is used instead of 4-bromoaniline in step 2 and (ii) (R) -tert-butoxycarbonylamino acid - [4- (2-morpholin-4-yl-2-oxo-ethoxy) -phenyl] -acetic acid in place of (R) -tert-butyloxycarbonylamino-4-methoxyphenylglycine. The (R) -ter-butoxycarbonylamino- [4- (2-morpholin-4-yl-2-oxo-ethoxy) -phenyl] -acetic acid is obtained by a method similar to that described for obtaining the (R) - tert-butyloxycarbonylamino-4-methoxyphenylglycine in example 1, except that 2-chloro-l-morpholin-4-yl-ethanone is used in place of iodomethane. HR-HR, observed mass (M + H +) = 683.1363; dough
calcula= 683.1361 for the C3iH32lN406 +. Example 12 (2S, 3S) -2- [4- (3-fluoro-4-methoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl] -N- (4-iodo-phenyl) -3- phenyl-butyramide, isomer 1
It is obtained by the same method as described in Example 1, except that (i) 4-iodoaniline is used in place of 4-bromoaniline in step 2, (ii) tert-butoxycarbonylamino- [3-] fluoro-4-methoxy-phenyl] -acetic in place of the (R) -ter-butyloxycarbonylamino-4-methoxyphenylglycine in step 4 and (iii) after step 5 the 2 diastereomers are separaby chromatography through silica gel with a methanol gradient of 0.2 and 1.5% v / v in dichloromethane. The fractions containing the second elucomponent are collecand used in step 6. The tert-butoxycarbonylamino- [3-fluoro-4-methoxy-phenyl] -acetic acid is obtained in the manner described in WO 2006/029862. HR-HR, observed mass (M + H +) = 588.0790; calculamass = 588.0790 for the
. Example 13 (2S, 3S) -2- [4- (3-fluoro-4-methoxy-phenyl) -2,5-dioxo-
imidazolidin-1-yl] -N- (4-iodo-phenyl) -3-phenyl-butyramide, isomer 2
It is obtained by the same method as described in Example 12, except that during the chromatographic separation of the diastereomers after step 5 the first elucomponent is collecand used in step 6. HR-HR, mass observed (M + H +) = 588.0785; calculamass = 588.0790 for the C26H2 FIN304 +. Example 14 (2S, 3S) -2- ((R) -2,5-dioxo-4-thiophen-3-yl-imidazolidin-1-yl) -N- (4-iodo-phenyl) -3-phenyl- butyramide
It is obtained by the same method as described in example 5, except that (R) -tert-butoxycarbonylamino-thiophen-3-yl-acetic acid is used instead of (R) -tert-butyloxycarbonylamino-4- methoxyphenylglycine. HR-HR, observed mass (M + H +) = 546.0339; calculamass = 546.0343 for the C23H2iI 303S +.
Example 15 (S) -2- (2,5-dioxo-imidazolidin-1-yl) -N- (2-fluoro-4-iodo-phenyl) -3-p-tolyl-propionamide
It is obtained by the same method as described in Example 1, except that (i) (S) -2-tert-butoxycarbonylamino-3-p-tolyl-propionic acid is used instead of (2S, 3S) acid -2-tert-butoxycarbonylamino-3-phenyl-butyric in step 1, (ii) 2-fluoro-4-iodoaniline in place of 4-bromoaniline in step 2 and (iii) tert-butyloxycarbonyl-amino- glycine in place of the (R) -ter-butyloxycarbonylamino-4-methoxyphenylglycine in step 4. HR-HR, observed mass (M + H +) = 482.0372; calculamass = 482.0372 for the Ci9H18FIN303 +. Example 16 (S) -2- (2,5-dioxo-imidazolidin-1-yl) -N- (2-fluoro-4-iodo-phenyl) -3- (4-flunamide)
It is obtained by the same method as described in Example 1, except that (i) (S) -2- is used
tert-butoxycarbonylamino-3- (4-fluoro-phenyl) -propionic acid in place of (2S, 3S) -2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 1, (ii) 2-fluoro-4 -iodoaniline in place of 4-bromoaniline in step 2 and (iii) tert-butyloxycarbonylamino-glycine in place of (R) -tert-butyloxycarbonylamino-4-methoxyphenylglycine in step 4. HR-HR, observed mass ( M + H +) = 486.0116; calculated mass = 486.0121 for the Ci8H15F2IN303 +. Example 17 (S) -2- (2,5-dioxo-imidazolidin-1-yl) -N- (2-fluoro-4-iodo-phenyl) -3-o-tolyl-propionamide
It is obtained by the same method as described in Example 1, except that (i) (S) -2-tert-butoxycarbonylamino-3-o-tolyl-propionic acid is used instead of (2S, 3S) acid -2-tert-butoxycarbonylamino-3-phenyl-butyric in step 1, (ii) 2-fluoro-4-iodoaniline in place of 4-bromoaniline in step 2 and (iii) tert-butyloxycarbonyl-amino- glycine in place of the (R) -ter-butyloxycarbonylamino-4-methoxyphenylglycine in step 4. HRMS, observed mass (M + Na +) = 504.0190; calculated mass = 504.0191 for the Ci9H17FI 3Na03 +.
Example 18 (S) -N- (2-fluoro-4-iodo-phenyl) -2- [(R) -4- (-methoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl] -3 -phenyl-propionamide
It is obtained by the same method as described in Example 4, except that 2-fluoro-4-iodoaniline is used instead of 4-iodoaniline in step 2. HR-HR, observed mass (M + H +) = 574.0629; calculated mass = 574.0634 for the C25H22FI 304+. Example 19 (S) -2- [(R) -4- (4-ethoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl] -N- (2-fluoro-4-iodo-phenyl) - 3-phenyl-propionamide
It is obtained by the same method as described in Example 1, except that (i) (S) -2-tert-butoxycarbonylamino-3-phenyl-propionic acid is used instead of (2S, 3S) -2 -ter-butoxycarbonylamino-3-phenyl-butyric in step 1, (ii) 2-fluoro-4-iodoaniline instead of 4-bromoaniline in step 2 and (iii) (R) -term
butyloxycarbonylamino-4-ethyloxyphenylglycine in place of (R) -tert-butyloxycarbonylamino-4-methoxyphenylglycine in step 4. The (R) -tert-butyloxycarbonylamino-4-ethyloxyphenylglycine is obtained in the manner described in Example 48, except that employs ethyl iodide in place of 2- (2-bromo-ethoxy) -tetrahydropyran. HR-HR, observed mass (M + Na +) = 610.0605; calculated mass = 610.0609 for C26H23FIN3Na04 +. Example 20 (S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-propionamide
It is obtained by the same method as described in Example 18, except that (R) -tert-butoxycarbonylamino- acid is used. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic in place of the (R) -ter-butyloxycarbonylamino-4-methoxyphenylglycine in step 4. HR-HR, observed mass (M + H +) = 604.0738; calculated mass = 604.0739 for the C26H24FIN305 +. Example 21 (S) -N- (2-fluoro-iodo-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-
propionamide
It is obtained in a manner similar to that described in Example 1, except that (i) (S) -2-tert-butoxycarbonylamino-3-phenyl-propionic acid is used in place of (2S, 3S) -2-tertiary acid. butoxycarbonylamino-3-phenyl-butyric in step 1, (ii) 2-fluoro-4-iodoaniline instead of 4-bromoaniline in step 2 and (iii) (R) -tert-butoxycarbonylamino- [4] acid - (methoxy-ethoxy) -phenyl] -acetic acid in place of (R) -ter-butoxycarbonylamino- [4-methoxy-phenyl] -acetic acid in step 4. The (R) -tert-butoxycarbonylamino- [-] acid is obtained 4- (methoxy-ethoxy) -phenyl] -acetic acid in the manner described in Example 80. HR-HR, observed mass (M + H +) = 618.0896; calculated mass = 618.0896 for the C27H26FIN305 +. Example 22 (S) -2-. { (R) -4- [4- (2-Ethoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (2-fluoro-4-iodo-phenyl) -3-phenyl-propionamide
obtained by the same method as described
in Example 18, except that (R) -tert-butoxycarbonylamino- [4- (2-ethoxy-ethoxy) -phenyl] -acetic acid is used in place of (R) -tert-butyloxycarbonylamino-4-methoxyphenylglycine in step 4. HR-HR, observed mass (M + Na +) = 654.0874; calculated mass = 654.0871 for the C28H27 IN3Na05 +. Example 23 (S) -N- (2-Fluoro-4-iodo-phenyl) -2 - ((R) -4- { 4- [2- (2-hydroxy-ethoxy) -ethoxy] -phenyl} -2, 5-dioxo-imidazolidin-1-yl) -3-phenyl-propionamide
It is obtained by the same method as that described in Example 18, except that (R) -tert-butoxycarbonylamino- (4. {2- [2- (tetrahydro-pyran-2-yloxy) - ethoxy] -ethoxy.} - phenyl) -acetic acid in place of (R) - 1 e r-but i 1 ox i ca rbon i 1 amino-4-methoxy-enylglycine in step 4. HR-HR, observed mass (M + Na +) = 670.0819; calculated mass = 670.0821 for the C28H27 FIN3Na06 +. Example 24 (S) -N- (2-fluoro-4-iodo-phenyl) -2- ((R) -4- { 4- [2- (2-methoxy-ethoxy) -ethoxy] -phenyl} -2, 5-dioxo-imidazolidin-1-yl) -3-
phenyl-propionamide
It is obtained by the same method as that described in Example 1, except that (i) the acid (S) -2-1 -butyl ox i ca rbon i 1 amino-3-f is used in i 1 -propionic acid instead of the acid (2S, 3S) -2-tert-bu t ox i ca rbon i 1 ami no - 3 - f in i 1 -bu tiri co in step 1, (ii) the 2 - f 1 uo ro - 4 - iodoan i 1 ina in place of 4-bromoaniline in step 2 and (iii) (R) -tert-butoxycarbonylamino- [4- (methoxy-ethoxy-ethoxy) -phenyl] -acetic acid instead of acid (R) -ter-bu t ox i ca rbon i 1 ami no- [4 -me t ox i - f in i 1] - a cé th co in step 4. You get acid (R) -ter -butoxycarbonylamino- [4- (methoxy-ethoxy-ethoxy) -phenyl] -acetic acid in the manner described in Example 48, except that 1 - (2-bor orno -et ox i) - 2 -me t ox i is used - et ano instead of 2 - (2 -br orno- et ox i) - 1 et rahi drop ir ano. LC-MS, observed mass (M + H +) = 662.13; calculated mass = 662.12 for the C29H3oFI 306+. Example 25 (S) -2-. { (R) -4- [4- ((R) -2,3-Dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (2-fluoro--iodo-phenyl) -3-
phenyl-propionamide
It is obtained by the same method as described in example 2, except that (i) 2-fluoro-4-iodoaniline is used instead of 4-bromo-2-fluoroaniline and (ii) the ((S) -2-tert-butoxycarbonylamino-3-phenyl-propionic acid in place of (2S, 3S) -2-tert-butoxycarbonylamino-3-phenyl-butyric acid EM-HR, observed mass (M + H +) = 634.0839, calculated mass = 634.0845 for C27H26FIN306 + Example 26 (S) -2- [(R) -4- (4-acetylamino-phenyl) -2,5-dioxo-imidazolidin-1-yl] -N- ( 2-fluoro-4-iodo-phenyl) -3-phenyl-propionamide
It is obtained by the same method as described in Example 29, except that (2R) - (4-acetylamino-phenyl) -ter-butoxycarbonylamino-acetic acid is used in place of (2R) -tert-butoxycarbonylamino- (2,3-dihydro-benzo [1.4] dioxin-6-yl) -acetic acid. The acid (2R) - (4-
acetylamino-phenyl) -ter-butoxycarbonylamino-acetic acid as follows: (1) To a suspension of (2R) -amino-phenyl-acetic acid (10.0 g, 66.2 mmol) in water (300 ml) is added sodium hydroxide ( 2.65 g, 66.3 mmoles). After stirring for 2 minutes, acetic anhydride (12.5 ml, 132.2 mmol) was added and the mixture was stirred at room temperature for 15 minutes. The reaction mixture is acidified to pH = 1 with 1M aqueous hydrochloric acid and the colorless precipitate of (2R) -acetylamino-phenyl-acetic acid is collected by filtration and dried (10.24 g, 80%). LC-LC, obs mass = 194; calculated mass = 194 for C10H12NO3 +. (2) (2R) -acetylamino-phenyl-acetic acid (9.7 g, 50.5 mmol) is dissolved in concentrated sulfuric acid
(25 ml) at -10 ° C and the concentrated nitric acid (4.2 ml, 100 mmol) is added dropwise and with stirring keeping the temperature below 0 ° C. After stirring for 30 minutes at -10 ° C, the reaction mixture is poured onto ice (150 g) and after thawing, filtering and drying, the (2R) -acetylamino- (4-nitro-phenyl) -acetic acid is obtained as a colorless solid (8.75 g, 73%). LC-LC, obs mass = 239; calculated mass = 194 for the CioHnN205 +. (3) The mixture is heated to boiling under reflux at 100 [deg.] C.
(2R) -acetylamino- (4-nitro-phenyl) -acetic acid (500 mg, 2.10 mmol) in 2M aqueous hydrochloric acid for 3.5 hours. The reaction mixture is cooled to room temperature and half of the reaction mixture is dried by lyophilization. The freeze-drying residue was suspended in water (2 ml) and treated with a saturated aqueous solution of sodium carbonate, obtaining a solution of pH = 10. The p-dioxane (6 ml) was added to the aqueous mixture and then the solution was added. add di-tert-butyl dicarbonate (368 μ ?, 1.6 mmol) and stir the mixture at room temperature for 3 hours. The reaction mixture is acidified with an aqueous solution of citric acid at 20% w / v, then extracted with ethyl acetate (three times), the organic phases are combined, dried over sodium sulphate, filtered and the empty. The residue is purified by chromatography on silica gel, eluting with a methanol gradient of 0 to 10% v / v in dichloromethane, yielding (2R) -tert-butoxycarbonylamino- (4-nitro-phenyl) -acetic acid. in the form of a colorless oil (372 mg,> 100%). LC-LC, obs mass = 297; calculated mass = 297 for the Ci3Hi7N206 +. To a solution of (2R) -ter-butoxycarbonylamino- (4-nitro-phenyl) -acetic acid (350 mg, <1.18 mmol) in absolute ethanol (15 ml) is added a small amount of 10% palladium on carbon and the mixture is stirred under a hydrogen atmosphere for 16 hours. The
Reaction mixture through a pad of Celite and rinse the Celite with absolute ethanol. The filtrate is concentrated in vacuo and then purified by chromatography through silica gel, eluting with a gradient of 0 to 7% v / v in dichloromethane. The (2R) - (4-amino-phenyl) -tert-butoxycarbonylaminoacetic acid is obtained in the form of a yellow oil (146 mg, 46%). LC-LC, obs mass = 267; calculated mass = 267 for the Ci3H19N204 +. (4) To a solution of (2R) - (4-amino-phenyl) -ter-butoxycarbonylamino-acetic acid (100 mg, 0.376 mmol) in dichloromethane (2 ml) is added pyridine (36 μ ?, 0.45 mmol) and acetic anhydride (42 μ ?, 0.44 mmol) and the mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with dichloromethane, washed with a 1M aqueous citric acid solution, brine, dried over sodium sulfate, filtered and the vacuum concentrated. The residue is purified by silica gel chromatography, eluting with a methanol gradient of 0 to 10% v / v in dichloromethane, yielding (2R) - (4-acetylamino-phenyl) -tert-butoxycarbonylamino-acetic acid. in the form of a yellow solid (59 mg, 51%). LC-LC, obs mass = 307; calculated mass = 307 for the C15H19N205".
LC-MS, observed mass (M + H) = 601; calculated mass
Example 27 (S) -N- (2-fluoro-iodo-phenyl) -2-. { (R) -4- [4- (2-methoxy-acetylamino) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-propionamide
It is obtained by the same method as described in Example 1, except that (i) 2-fluoro-4-iodoaniline is used in place of the -bromoaniline in step 2, (ii) O-hexafluorophosphate is used. -benzotriazole-l-yl-N,, N ',' -bis (tetramethylene) uronium as condensation reagent in place of 0-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium hexafluorophosphate in the step 4 and (iii) (R) -ter-butoxycarbonylamino- [4- (2-methoxy-acetylamino) -phenyl] -acetic acid in place of (R) -tert-butyloxycarbonylamino-4-methioxyphenyl-glycine in the step 4. The (R) -ter-butoxycarbonylamino- [4- (2-methoxy-acetylamino) -phenyl] -acetic acid is obtained by the same method described for the preparation of (R) - (4-acetylamino-phenyl) acid ) -ter-butoxycarbonyl-amino-acetic acid in Example 26, except that methoxy-acetyl chloride is used in place of the anhydride
acetic in step 5. LC-MS, observed mass (M + H +) = 631; calculated mass = 631 for the C27H25FIN405 +. Example 28 (S) -2-. { (R) -4- [4- (2-dimethylamino-acetylamino) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (2-fluoro-4-iodo-phenyl) -3-phenyl-propionamide
It is obtained by the same method as described in Example 1, except that (i) 2-fluoro-4-iodoaniline is used instead of 4-bromoaniline in step 2, (ii) it is used as a reagent condensation O-benzotriazole-l-yl-N, N, N ', N' -bis (tetramethylene) uronium hexafluorophosphate in place of O-benzotriazole-l-yl-N, N, N ', N' - hexafluorophosphate tetramethyluronium in step 4 and (iii) and (R) -tert-butoxycarbonylamino- [4- (2-dimethylamino-acetylamino) -phenyl] -acetic acid in place of (R) -tert-butyloxycarbonylamino-4-methyloxyphenyl -glycine in step 4. The (R) -ter-butoxycarbonylamino- [4- (2-dimethylamino-acetylamino) -phenyl] -acetic acid is obtained by the same method described for the preparation of the acid (R) - (4) -acetylamino-phenyl) -tert-butoxycarbonyl-amino-acetic acid in Example 26, except that the
2-dimethylamino-acetyl instead of acetic anhydride in step 5. LC-MS, observed mass (M + H +) = 644; calculated mass = 644 for the C28H28FIN504 +. Example 29 (S) -2 - [(R) -4- (2,3-Dihydro-benzo [1,4] dioxin-6-yl) -2,5-dioxo-imidazolidin-1-yl] -N- (2-fluoro-4-iodo-phenyl) -3-phenyl-propionamide
It is obtained by the same method as described in Example 18, except that (i) (2S) -2-tert-butoxycarbonylamino-3-phenyl-propionic acid is used instead of (2S, 3S) -2 -ter-butoxycarbonylamino-3-phenyl-butyric acid in step 1 and (ii) (2R) -tert-butoxycarbonylamino- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -acetic acid (obtained from according to the procedure of Bohme, EH, et al., J. Med. Chem. 23, 405-412, 1980), in place of (R) -tert-butoxycarbonylamino- acid. { 4 - [2- (Tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic in step 4. HR-HR, observed mass (M + H +) = 602.0587; calculated mass = 602.0583 for the C26H22EIN305 +.
Example 30 (S) -N- (2-f luoro-4-iodo-phenyl) -2- [(R) -4- (4-methoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl] -3-p-tolyl-propionamide
It is obtained by the same method as described in Example 1, except that (i) (S) -2-tert-butoxycarbonylamino-3-p-tolyl-propionic acid is used instead of (2S, 3S) acid -2- tert-butoxycarbonylamino-3-phenyl-butyric in step 1 and (ii) 2-fluoro-4-iodoaniline instead of 4-bromoaniline in step 2. HR-HR, observed mass (M + Na + ) = 610.0613; calculated mass = 610.0609 for the CsffeFINsNaC. Example 31 (S) -N- (2-f luoro-4-iodo-phenyl) -3- (4-f luoro-phenyl) -2- [(R) -4- (4-methoxy-f-enyl) - 2,5-dioxo-imidazolidin-1-yl] -
It is obtained by the same method as described in Example 4, except that (i) (S) -2-tert-butoxycarbonylamino-3- (4-f luoro-phenyl) -propionic acid is used instead of the acid (S) -2-tert-butoxycarbonylamino-3-phenyl-propionic in step 1 and (ii) the
2-f luoro-4-iodoaniline in place of 4-iodoaniline in step 2. HR-HR, observed mass (M + H +) = 592.0539; calculated mass = 592.0540 for the Czflz &TÑ & t. Example 32 (S) -3- (4-Chloro-phenyl) -N- (2-fluoro-4-iodo-phenyl) -2- [(R) -4- (4-methoxy-phenyl) -2,5 -dioxo-imidazolidin-l-yl] -propionamide
It is obtained by the same method as described in Example 1, except that (i) (S) -2-tert-butoxycarbonylamino-3-p-chloro-propionic acid is used instead of (2S, 3S) acid -2-tert-butoxycarbonylamino-3-phenyl-butyric in step 1 and (ii) 2-fluoro-4-iodoaniline instead of 4-bromoaniline in step 2. HR-HR, observed mass (M + H + ) = 608.0241; calculated mass = 608.0244 for C25H21CIFIN3O. Example 33 (S) -3- (4-Cyano-phenyl) -N- (2-f luoro-4-iodo-f-enyl) -2- [(R) -4- (4-methoxy-phenyl) - 2,5-dioxo-imidazolidin-1-yl] -propionamide I
obtained by the same method as described
in Example 1, except that (i) (S) -2-tert-butoxycarbonylamino-3- (-cyano-phenyl) -propionic acid is used in place of (2S, 3S) -2-tert-butoxycarbonylamino- 3-phenyl-butyric in step 1 and (ii) 2-fluoro-4-iodoaniline instead of 4-bromoaniline in step 2. HR-HR, observed mass (M + H +) = 599.0575; calculated mass = 599.0586 for the C26H2iFIN404 +. Example 34 (S) -N- (2-fluoro-4-iodo-phenyl) -3- (-methoxy-phenyl) -2- [(R) -4- (4-methoxy-phenyl) -2,5- dioxo-imidazolidin-l-yl] -propionamide
It is obtained by the same method as described in example 1, except that (i) (S) -2-tert-butoxycarbonylamino-3- (4-methoxy-phenyl) -propionic acid is used instead of the acid ( 2S, 3S) -2-tert-butoxycarbonylamino-3-phenyl-butyric in step 1 and (ii) 2-fluoro-4-iodoaniline instead of 4-bromoaniline in step 2. HR-HR, mass observed (M + H +) = 604.0739; calculated mass = 604.0739 for the C26H2 FIN305 +. Example 35 (S) -N- (2-fluoro-4-iodo-phenyl) -2- [(R) -4- (4-methoxy)
phenyl) -2,5-dioxo-imidazolidin-1-yl] -3- (4-trifluoromethyl-phenyl) -propionamide
It is obtained by the same method as described in Example 1, except that (i) (S) -2-tert-butoxycarbonylamino-3- (4-trifluoromethyl-phenyl) -propionic acid is used in place of the acid ( 2S, 3S) -2-tert-butoxycarbonylamino-3-phenyl-butyric in step 1 and (ii) 2-fluoro-4-iodoaniline instead of 4-bromoaniline in step 2. HR-HR, mass observed (M + H +) = 642.0507; calculated mass = 642.0508 for the C26H2iF4IN304 +. Example 36 (S) -N- (2-Fluoro-4-iodo-phenyl) -3- (3-fluoro-phenyl) -2- [(R) -4- (4-methoxy-phenyl) -2,5 -dioxo-imidazolidin-l-il] -
It is obtained by the same method as described in Example 1, except that (i) (S) -2-tert-butoxycarbonylamino-3- (3-fluoro-phenyl) -propionic acid is used instead of the acid ( 2S, 3S) -2-tert-butoxycarbonylamino-3-phenyl-
butyric in step 1 and (ii) 2-fluoro-4-iodoaniline instead of 4-bromoaniline in step 2. HR-HR, observed mass (M + Na +) = 614.0350; calculated mass =
Example 37 (S) -N- (2-fluoro-4-iodo-phenyl) -2- [(R) -4- (4-methoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl] - 3-m-tolyl-propionamide
It is obtained by the same method as described in Example 1, except that (i) (S) -2-tert-butoxycarbonylamino-3-m-tolyl-propionic acid is used instead of (2S, 3S) acid -2-tert-butoxycarbonylamino-3-phenyl-butyric in step 1 and (ii) 2-fluoro-4-iodoaniline instead of 4-bromoaniline in step 2. EM-HR, observed mass (M + Na + ) = 610.0607; calculated mass = 610.0609 for C26H23FIN3Na04 +. Example 38 (S) -N- (2-fluoro-4-iodo-phenyl) -2- [(R) -4- (4-methoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl] - 3-o-tolyl-propionamide
It is obtained by the same method as described in Example 1, except that (i) (S) -2-tert-butoxycarbonylamino-3-o-tolyl-propionic acid is used instead of (2S, 3S) acid -2-tert-butoxycarbonylamino-3-phenyl-butyric in step 1 and (ii) 2-fluoro-4-iodoaniline in place of 4-bromoaniline in step 2. HR-HR, observed mass (M + H + ) = 588.0791; calculated mass = 588.0790 for C26H24FIN3O4. "Example 39 (S) -N- (2-fluoro-4-iodo-phenyl) -3- (2-methoxy-phenyl) -2- [(R) -4- (4 -methoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl] -propionamide
It is obtained by the same method as described in example 4, except that (i) (S) -2-tert-butoxycarbonylamino-3- (2-methoxy-phenyl) -propionic acid is used instead of the acid ( S) -2-tert-butoxycarbonylamino-3-phenyl-propionic in step 1 and (ii) 2-fluoro-4-iodoaniline instead of 4-iodoaniline in step 2. HR-HR, observed mass (M) + H +) = 604.0745 calculated mass = 604.0739 for the C26H24 IN305 +.
Example 40 (S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3- (2-methoxy-phenyl) -propionamide
It is obtained by the same method as described in Example 39, except that (i) (R) -tert-butoxycarbonylamino- acid is used. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic (obtained in the manner described in example 48) in place of the (R) -ter-butyloxycarbonylamino-4-methoxyphenyl-glycine in step 4 and (ii) step 6 is carried out as described in example 48. HR-HR, observed mass (M + H +) = 634.0842 calculated mass = 634.0845 for C27H26F, IN306 +. Example 41 N- (2-Fluoro-4-iodo-phenyl) -2- [(R) -4- (4-methoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl] -3- (2 -trifluoromethyl-phenyl) -propionamide, isomer 1
It is obtained by the same method as described in example 4, except that (i) (S) -2-tert-butoxycarbonylamino-3- (2-trifluoromethyl-phenyl) -propionic acid is used. instead of (S) -2-tert-butoxycarbonylamino-3-phenyl-propionic acid in step 1, (ii) 2-fluoro-4-iodoaniline instead of 4-iodoaniline in step 2, (iii) the trifluoroacetic acid salt of (S) -2-amino-N- (2-fluoro-4-iodo-phenyl) -3- (2-trifluoromethyl-phenyl) -propionamide is isolated in step 3 and used directly in step 4 with 1.0 equivalent of triethylamine and, as a condensation reagent, (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride in place of O-benzotriazol-1-yl-N, N, N 'hexafluorophosphate , N'-tetramethyluronium and (iv) after performing step 5, the diastereomers (resulting from the racemisation of step 2) are separated from 2- [(R) -2-amino-2- (4-methoxy-phenyl)] -acetylamino] -N- (2-fluoro-4-iodo-phenyl) -3- (2-trifluoromethyl-phenyl) -propionamide by chromatography on silica gel, eluting with a gradient of ethyl acetate from 40 to 60 % v / v in hexane. The slower moving component is collected and after concentrating the vacuum is used in step 6. HR-HR, observed mass (M + H +) = 642.0502 calculated mass = 642.0508 for C26H2iF4I 304 + - Example 42 N- (2 -fluoro-4-iodo-phenyl) -2- [(R) -4- (4-methoxy-
phenyl) -2,5-dioxo-imidazolidin-1-yl] -3- (2-trifluoromethyl-phenyl) -propionamide, isomer 2
It is obtained by the same method as described in Example 41, except that the fastest moving component of the chromatography separation of the diastereomers of the 2- [(R) -2-amino-2- (4- methoxy-phenyl) -acetylamino] -N- (2-fluoro-4-iodo-phenyl) -3- (2-trifluoromethyl-phenyl) -propionamide and after concentrating the vacuum is used in step 6. EM-HR, observed mass (M + Na +) = 664.0327 calculated mass = 664.0327 for C26H2oE4IN3Na04 +. Example 43 (S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3- naphthalen-2-yl-propionamide
It is obtained by the same method as described in Example 48, except that (i) steps 1-2 are performed
newly described in place of steps 1-3 described in example 48 and (ii) is used as the condensation reagent the hexafluorophosphate of O-benzotriazol-l-il-N, N, ', N' -bis (tetramethylene) uronium instead of 0-benzotriazole-1-yl-N, N, N ', N' -tetramethyluronium hexafluorophosphate in step 4. Step 1: To a solution of (S) -2- (9H-fluoren-9- illmethoxycarbonylamino) -3-naphthalen-2-yl-propionic acid (1.0 g, 2.30 mmol) and 2-fluoro-4-iodoaniline (434 mg, 1.84 mmol), triphenylphosphine (0.94 g, 3.45 mmol) and pyridine (0.39 mL, 4.60 mmoles) in dichloromethane (10 ml) is added at 0 ° C N-bromosuccinimide (0.61 mg, 3.45 mmol) in two portions under an atmosphere of dry nitrogen. The mixture is stirred at 0 ° C for 2 hours. The reaction mixture is purified by chromatography on silica gel, eluting with a gradient of 100% dichloromethane to 10% methanol and 90% dichloromethane in 30 minutes. By concentration of the product-containing fractions, [9 S-fluoren-9-ylmethyl] - (2-fluoro-4-iodo-phenylcarbamoyl) -2-naphthalen-2-yl-ethyl] -carbamate is obtained. in the form of yellow solid foam (1.05 g, 70%). LC-MS, observed mass (M + H +) = 657; calculated mass = 657 for the C34H27FIN203 +. Step 2: To a solution of [9 (S) -1- (2-fluoro-4-iodo-phenylcarbamoyl) -2-naphthalen-2-yl-ethyl] -carbamic acid 9H-fluoren-9-ylmethyl ester (1.05 g, 1.60 mmoles) in dichloromethane (24
mi) piperidine (6 ml) is added and the mixture is stirred at room temperature for 1 hour. After removing the solvent, the residue is purified by chromatography on silica gel, eluting with a gradient of 100% hexane to 40% ethyl acetate and 60% hexane in 30 minutes. By concentration of the fractions containing product, (S) -2-amino-N- (2-fluoro-iodo-phenyl) -3-naphthalen-2-yl-propionamide is obtained as a yellow solid (390 mg, 56%). LC-MS, observed mass (M + H +) = 435; calculated mass
= 435 for the Ci9Hi7FIN20 +. LC-MS, observed mass (M + H +) = 654; calculated mass = 654 for the C3oH26FIN305 +. Example 44 (2S, 3S) -2- ((R) -2,5-dioxo-4-phenyl-imidazolidin-1-yl) -N- (2-fluoro-4-iodo-phenyl) -3-phenyl- butyramide
It is obtained by the same method as described in example 1, except that (i) 2-fluoro-4-iodoaniline is used instead of 4-bromoaniline in step 2 and (ii) acid (R) -ter-butoxycarbonylamino-phenyl-acetic acid in place of (R) -tert-butoxycarbonylamino- [4-methoxy-phenyl] -acetic acid in step
HR-HR, observed mass (M + Na) = 580.0492; calculated mass = 580.0504 for C25H2iFIN3Na03 +. Example 45 (2S, 3S) -N- (2-fluoro-4-iodo-phenyl) -2- [(R) -4- (4-methoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl ] -3-phenyl-butyramide)
It is obtained by the same method as described in Example 1, except that 2-fluoro-4-iodoaniline is used in place of 4-bromoaniline in step 2. HR-HR, observed mass (M + H +) = 588.0791; calculated mass = 588.0790 for the C26H24FIN30 +. Example 46 (2S, 3S) -2- [(R) -4- (4-ethoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl] -N- (2-fluoro-4-iodo- phenyl) -3-phenyl-butyramide
It is obtained by the same method as described in example 44, except that (R) -tert-butoxycarbonylamino- (-ethoxy-phenyl) -acetic acid is used instead of
(R) -ter-butoxycarbonylamino-phenyl-acetic acid in step 4. The (R) -tert-butoxycarbonylamino- (4-ethoxy-phenyl) -acetic acid is obtained in the manner described in example 1, step 4, for the preparation of (R) -tert-butoxycarbonylamino- (4-methoxy-phenyl) -acetic acid, except that ethyl iodide is used instead of methyl iodide. HR-HR, observed mass (M + H +) = 602.0944; calculated mass = 602.0947 for the C27H26FIN304 +. Example 47 (2S, 3S) -2- [(R) -4- (4-cyclopropylmethoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl] -N- (2-fluoro-4-iodo-phenyl) -3-phenyl-butyramide
It is obtained by the same method as described in example 46, except that (R) -tert-butoxycarbonylamino- (4-cyclopropylmethoxy-phenyl) -acetic acid is used instead of (R) -tert-butoxycarbonylamino- (4-ethoxy-phenyl) -acetic. The (R) -tert-butoxycarbonylamino- (4-cyclopropylmethoxy-phenyl) -acetic acid is obtained in the manner described in Example 46, except that bromomethylcyclopropane is used in place of ethyl iodide. HR-HR, observed mass (M + H +) = 628.1094; calculated mass = 628.1103 for the C29H28 FI N3O4".
Example 48 (2S, 3S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
It is obtained by the same method as described in Example 1, except that (i) 2-fluoro-4-iodoaniline is used instead of 4-bromoaniline in step 2, (ii) acid (R) -ter-butoxycarbonylamino-. { - [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic (obtained in the manner described below) in place of the (R) -ter-butyloxycarbonylamino-4-methoxyphenylglycine in step 4 and (iii) step 6 is carried out as described below. Obtaining (R) -ter-butoxycarbonylamino- acid. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic: (R) -tert-butoxycarbonylamino- (4-hydroxy-phenyl) -acetic acid (2.67 g, 10 turnols) is dissolved (Salituro, GM, Townsend, CA; J. Am. Chem. Soc. 112, 760-770, 1990) in N, N-dimethylformamide (70 ml) in an ice bath. Sodium hydride (0.88 g, 60% in mineral oil, 22 mmol) is added in small portions. The mixture is heated at 10 ° C for 1 hour. The 2- (2-bromo-ethoxy) -tetrahydropyran (1.7 ml, 11 mmol) in N, -dimethylformamide is added dropwise.
(20 mi). The reaction mixture is stirred for 24 hours and then diluted with water / ice. The mixture is extracted with ethyl acetate. The aqueous phase is cooled in an ice bath and acidified with a 1.5 M aqueous solution of potassium acid sulfate to pH = 2-3. The resulting mixture is extracted with ethyl acetate (5?), washed with water (5 x), brine and dried with sodium sulfate. Filtration and evaporation of the solvents yields (R) -tert-butoxycarbonylamino- acid. { 4- [2- (tetrahydropyran-2-yloxy) -ethoxy] -phenyl} -acetic in the form of white solid foam (3.2 g, 82%). Step 6: To a difosgen solution (21.1 μ ?, 0.173 min) in a 1: 1 v / v mixture of toluene / tetrahydrofuran (20 ml total) a mixture of (2S, 3S) is added at -40 ° C. )-2-. { (R) -2-amino-2- [4- (2-hydroxy-ethoxy) -phenyl] -acetylamino} -N- (2-fluoro-4-iodo-phenyl) -3-phenyl-butyramide (180 mg, 0.289 mmole) and N, -diisopropylethylamine (154 μ ?, 0.867 mmole) in dry dichloromethane (40 ml) for 5 minutes and a small amount of dry dichloromethane is added to the reaction mixture. After 20 minutes at -40 ° C the temperature is raised to -20 ° C for a further 15 minutes to complete the reaction. The colorless solution is diluted with ethyl acetate (100 ml) and washed successively with a 1.5 M aqueous solution of potassium hydrogen sulfate (twice), an aqueous 5% w / v sodium hydrogen carbonate solution (once). ) and brine (once). The aqueous phases are extracted again with ethyl acetate
ethyl (2 x 50 ml). The ethyl acetate extracts are combined, diluted with an equal volume of dichloromethane and passed through a sodium sulphate column, placed on the top of a flash column of 4"silica gel. a pale yellow residue (177 mg) The residue is triturated with dichloromethane (5 ml), the organic solutions are combined, purified by chromatography on silica gel (deactivated with methanol before use), eluting with a gradient that progresses in steps of 1% from 100% dichloromethane to 3% methanol and 97% dichloromethane.At the concentration of the fractions containing product, a vitreous type residue (98 mg) is obtained. the residue in a small volume of dichloromethane is diluted with diethyl ether (1 ml) and the product is precipitated by the addition of hexanes (10 ml), the product is isolated by filtration, washed with hexanes and the vacuum dried. obtaining the ( 2S, 3S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide as a colorless solid (81 mg). HR-HR, observed mass (M + Na +) = 640.0713; calculated mass = 640.0715 for the C27H25FIN3Na05 +. LC- S (HPLC in reverse phase, column C18, water / acetonitrile gradient): Rt = 2.29 minutes, mass observed
(M + Na +) = 640; calculated mass = 640 for the C27H25FIN3Na05 +. R N-H1 (DMSO-d6, 300 MHz) d? = 10.11 (s, 1H), 8.53 (s, 1H), 5.02 (d, J = 11.8 Hz, 1H) ppm (characteristic resonances). Example 49 (2S, 3S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (S) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
A solution of (2S, 3S) -N- (2-fluoro-4-iodo-phenyl) -2- is dissolved. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} 3-phenyl-butyramide (obtained as described in example 48) (50 mg, 0.081 mmol) in methanol (3 ml) and stirred at room temperature for 4 days. The resulting mixture of isomers is concentrated in vacuo and purified by supercritical fluid chromatography using a Chiracel OJ column eluting with carbon dioxide at 100 bar and 30 ° C, modified with 35% v / v ethanol in acetonitrile with a flow rate of 2 ml / minute. The eluted compound is collected first and the vacuum concentrated, yielding (2S, 3S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (S) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
(9.1 mg, 18%). The compound eluted in the second place is identical to (2S, 3S) -N- (2-f luor o- 4 -iodo-f eni 1) -2-. { (R) -4 - [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide (19.9 mg, 40%). LC-MS (HPLC in reverse phase, column C18, water / acetonitrile gradient): Rt = 2.34 minutes, mass observed (M + Na +) = 640; calculated mass = 640 for the C27H25FIN3Na05 +. NMR-H1 (DMS0-d6, 300 MHz) d? = 10.18 (s, 1H), 8.57 (s, 1H), 4.84 (s, 1H) ppm (characteristic resonances). E j empyl 50 (2S, 3S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-f-enyl-butyramide
It is obtained by the same method as described in Example 1, except that (i) the 2-f luo ro-iodoani 1 ina is used instead of the 4-bromoaniline in step 2 and (ii) the acid (R) -ter-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic in place of (R) -1-butyloxycarbonyl 1 amino acid-
[-me t ox i-feni 1] - a cé ti co in step 4. The (R) -ter-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid is obtained in the manner described in Example 80. HR-HR, observed mass (M + H +) = 632.1053; calculated mass = 632.1052 for the C28H28FIN305 +. Example 51 (2S, 3S) -2-. { (R) -4- [4- (2-Ethoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (2-fluoro-4-iodo-phenyl) -3-phenyl-butyramide
It is obtained in a manner similar to that described in example 1, except that (i) 2-fluoro-4-iodoaniline is used in place of 4-bromoaniline in step 2 and (ii) acid (R) -ter -butoxycarbonylamino- [4- (2-ethoxy-ethoxy) -phenyl] -acetic acid in place of (R) -tert-butoxycarbonylamino- [4-methoxy-phenyl] -acetic acid in step 4. The acid is obtained (R ) -ter-butoxycarbonylamino- [4- (2-ethoxy-ethoxy) -phenyl] -acetic acid as described in example 48except that l-bromo-2-ethoxyethane is used in place of 2- (2-bromo-ethoxy) -tetrahydropyran. HR-HR, observed mass (M + H +) = 646.1192; calculated mass = 646.1209 for the C29H3oFIN305 +.
Example 52 (2S, 3S) -N- (2-fluoro-iodo-phenyl) -2-. { (R) -4- [4- (3-hydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
It is obtained by the same method as described in example 48, except that (R) -tert-butoxycarbonylamino- acid is used. { 4- [3- (tetrahydro-p i r an- 2 - i 1 ox i) -pr opox i] - f eni 1} - a cé t i co instead of the acid (R) -ter-butoxycarbonylamino-. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic The (R) -ter-butoxycarbonylamino- acid is obtained. { - [3- (tetrahydro-pi r an- 2 -i 1 ox i) -propox i] - phen i 1} - a cé t i co in the manner described in example 48, except that 2- (3-bromo-propoxy) -tetrahydropyran is used in place of 2- (2-bromo-ethoxy) -tetrahydropyran. HR-HR, observed mass (M + H +) = 632.1055; calculated mass = 632.1052 for the C28H28FIN305 +. Example 53 (2S, 3S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (4-hydroxy-butoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-
butyramide
It is obtained by the same method as described in example 48, except that (R) -tert-butoxycarbonylamino- acid is used. { 4- [4- (tetrahydro-pyran-2-yloxy) -butoxy] -phenyl} -acetic instead of (R) -ter-butoxycarbonylamino- acid. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic. The (R) -ter-butoxycarbonylamino- acid is obtained. { 4- [4- (tetrahydro-pyran-2-yloxy) -butoxy] -phenyl} -acetic in the manner described in example 48, except that 2- (4-bromo-butoxy) -tetrahydropyran is used in place of 2- (2-bromo-ethoxy) -tetrahydropyran. HR-HR, observed mass (M + H +) = 646.1208; calculated mass = 646.1209 for the C29H3oFI 305+. Example 54 (2S, 3S) -N- (2-fluoro-4-iodo-phenyl) -2 - ((R) -4- { 4- [2- (2-hydroxy-ethoxy) -ethoxy] - phenyl.} -2, 5-dioxo-imidazolidin-1-yl) -3-phenyl-butyramide
It is obtained by the same method as described in Example 48, except that (R) -tert-butoxycarbonylamino- (-. {2- [2- (tetrahydro-pyran-2-yloxy) -
ethoxy] -ethoxy} phenyl) -acetic in place of (R) -tert-butoxycarbonylamino- acid. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic The (R) -tert-butoxycarbonylamino- (4. {2- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -ethoxy} -phenyl) -acetic acid is obtained in the manner described in Example 48, except that 2- [2- (2-chloro-ethoxy) -ethoxy] -tetrahydropyran is used in place of 2- (2-bromo-ethoxy) -tetrahydropyran. HR-HR, observed mass (M + H +) = 662.1158; calculated mass = 662.1158 for the C29H30 FI N3C. Example 55 (2S, 3S) -N- (2-fluoro-4-iodo-phenyl) -2- ((R) -4- { 4- [2- (2-methoxy-ethoxy) -ethoxy] - phenyl.} -2, 5-dioxo-imidazolidin-1-yl) -3-phenyl-butyramide
It is obtained by the same method as described in example 1, except that (i) 2-fluoro-4-iodoaniline is used instead of 4-bromoaniline in step 2 and (ii) acid (R) -tert-butoxycarbonylamino- [4- (2-. {2-methoxy-ethoxy.] -ethoxy) -phenyl] -acetic acid in place of (R) -tert-butoxycarbonylamino- [4-methoxy-phenyl] - acetic acid in step 4. The (R) -ter-butoxycarbonylamino- [4- (2-. {2-methoxy-) acid is obtained
ethoxy} -ethoxy) -phenyl] -acetic acid in the manner described in Example 48, except that 1- (2-bromo-ethoxy) -2-methoxy-ethane is used in place of 2- (2-bromo-ethoxy) -tetrahydropyran . HR-HR, observed mass (M + H +) = 676.1306; calculated mass = 676.1315 for the C3oH32FIN306 +. Example 56 (2S, 3S) -2-. { (R) -4- [4 - ((R) -2,3-dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (2-fluoro-4-iodo-phenyl) -3-phenyl-butyramide
It is obtained by the same method as described in Example 114, except that 2-fluoro-4-iodoaniline is used in place of 2-chloro-4-iodoaniline in step 2. HR-HR, mass observed ( M + H +) = 648.0995; calculated mass = 648.1002 for the C28H28FI 306+. LC-MS (HPLC in reverse phase, column C18, water / acetonitrile gradient): Rt = 3.55 minutes, mass observed (M + H +) = 648; calculated mass = 648 for the C28H28FIN306 +. NMR-H1 (DMSO-d6, 300 MHz) d? = 10.11 (s, 1H), 8.52 (s, 1H), 5.02 (d, J = 11.5 Hz, 1H) ppm (characteristic resonances).
Example 57 (2S, 3S) -2-. { (S) -4- [4 - ((R) -2,3-dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (2-fluoro-4-iodo-phenyl) -3-phenyl-butyramide
The (2S, 3S) -2- is dissolved. { (R) -4- [4- ((R) Dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (2-fluoro-4-iodo-phenyl) -3-phenyl-butyramide (obtained in the manner described in example 56) (160 mg, 0.25 mmol) in methanol (10 ml) and kept stirring at room temperature environment for 48 hours and then heated to 50 ° C for 6 more hours. The solvent is removed in the vacuum and the residue is purified by supercritical fluid chromatography using a Chiracel OD column, eluting with carbon dioxide at 100 bar and 30 ° C containing 35% methanol in acetonitrile with a flow rate of 2 ml / minute. The eluted compound was collected in second place and the vacuum concentrated, obtaining (2S, 3S) -2-. { (S) -4- [4- ((R) -2,3-Dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (2-fluoro-4-iodo-phenyl) -3-phenyl-butyramide as a colorless solid (35 mg, 44%). The compound eluted in the first place is identical to (2S, 3S) -2-. { (R) -4- [4- ((R) -2,3-dihydroxy-propoxy) -phenyl] -2,5-dioxo-
imidazolidin-l-il} -N- (2-fluoro-4-iodo-phenyl) -3-phenyl-butyramide. HR-HR, observed mass (M + H +) = 648.0995; calculated mass = 648.1002 for the C28H28FIN306 +. LC-MS (HPLC in reverse phase, column C18, water / acetonitrile gradient): Rt = 3.13 minutes, mass observed (M + H +) = 648; calculated mass = 648 for the C28H28FIN306 +. NMR-H1 (DMSO-d6, 300 ??) d? = 10.18 (s, 1H), 8.57 (s, 1H), 4.84 (s, 1H) ppm (characteristic resonances). Example 58 (2S, 3S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-l-hydroxymethyl-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
It is obtained by the same method as described in Example 1, except that (i) 2-fluoro-4-iodoaniline is used instead of 4-bromoaniline in step 2, (ii) acid (R) -ter-butoxycarbonylamino- [4- (2-hydroxy-1-hydroxymethyl-ethoxy) -phenyl] -acetic acid (obtained as described in example 160) in place of (R) -tert-butoxycarbonylamino- (4-methoxy) -phenyl) -acetic in step 4, (iii) the diol functional group is provisionally protected
existing in (2S, 3S) -2-. { (R) -2-amino-2- [4- (2-hydroxy-l-hydroxymethyl-ethoxy) -phenyl] -acetylamino} -N- (2-fluoro-4-iodo-phenyl) -3-phenyl-butyramide in the form of bis-trimethylsilyl ether (protection carried out in the manner described in example 114) before carrying out step 6 and (iv) performs an acid-catalyzed hydrolysis of (2S, 3S) -2-. { (R) -2,5-dioxo-4- [4- (2-trimethylsilanyloxy-1-trimethylsilanyloxymethyl-ethoxy) -phenyl] -imidazolidin-1-yl} -N- (2-fluoro-4-iodo-phenyl) -3-phenyl-butyramide in the manner described in Example 114 before proceeding to the purification and isolation of (2S, 3S) -N- (2-fluoro- 4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-l-hydroxymethyl-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide in step 6. HR-HR, observed mass (M + H +) = 648.0991 calculated mass = 648.1002 for C28H28FIN306 +. Example 59 (2S, 3S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (3-Methyl-oxetan-3-ylmethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
It is obtained by the same method as described in example 48, except that the acid (R) -term is used.
butoxycarbonylamino- [4- (3-methyl-oxetane-3-ylmethoxy) -phenyl] -acetic acid in place of (R) -tert-butoxycarbonylamino- acid. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic The (R) -tert-butoxycarbonylamino- [4- (3-methyl-oxetan-3-ylmethoxy) -phenyl] -acetic acid is obtained in the manner described in example 48, except that 3-bromomethyl-3 is used methyl-oxetane in place of 2- (2-bromo-ethoxy) -tetrahydropyran. HR-HR, observed mass (M + H +) = 658.1202; calculated mass = 658.1209 for the C30H3oFIN305 +. Example 60 (2R, 3S) -N- (2-fluoro-4-iodo-phenyl) -2- [(R) -4- (4-methylcarbamoylmethoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl ] -3-phenyl-butyramide
It is obtained by the same method as described in Example 48, except that (R) -tert-butoxycarbonylamino- (4-methylcarbamoylmethoxy-phenyl) -acetic acid is used in place of (R) -tert-butoxycarbonylamino- . { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic The (R) -tert-butoxycarbonylamino- (4-methylcarbamoylmethoxy-phenyl) -acetic acid is obtained in the manner described in example 48, except that 2-chloro-N-methyl-acetamide is used instead of 2-
(2-bromo-ethoxy) -tetrahydropyran. HR-HR, observed mass (M + Na +) = 667.0820; calculated mass = 667.0824 for the C28H26FIN4Na05 +. Example 61 (2S, 3S) -2-. { (R) -2,5-dioxo-4- [4- (2-oxo-2-pyrrolidin-1-yl-ethoxy) -phenyl] -imidazolidin-1-yl} -N- (2-fluoro-4-iodo-phenyl) -3-phenyl-butyramide
It is obtained by the same method as described in example 48, except that (R) -tert-butoxycarbonylamino- [4- (2-oxo-2-pyrrolidin-1-yl-ethoxy) -phenyl acid is used] -acetic instead of (R) -ter-butoxycarbonylamino- acid. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic The (R) -ter-butoxycarbonylamino- [4- (2-oxo-2-pyrrolidin-1-yl-ethoxy) -phenyl] -acetic acid is obtained by a method similar to that described for obtaining the (R) - tert-butyloxycarbonylamino-4-methoxyphenylglycine in Example 1, except that 2-chloro-l-pyrrolidin-1-yl-ethanone is used in place of iodomethane. LC-MS, observed mass (M + H +) = 685/687; calculated mass = 685/687 for the C3iH3iFIN405 +.
Example 62 (2S, 3S) -2- [(R) -4 - (4- { [Bis- (2-hydroxy-ethyl) -carbamoyl] -methoxy.} - phenyl) -2,5-dioxo -imidazolidin-l-yl] -N- (2-fluoro-4-iodo-phenyl) -3-phenyl-butyramide
It is obtained by the same method as that described in example 48, except that (R) - [4- (2-. {Bis- [2- (tert-butyl-dimethyl-silanyloxy) -ethyl ester is used. ] -amino.}. -acetoxy) -phenyl] -ter-butoxycarbonylamino-acetic acid instead of (R) -tert-butoxycarbonylamino- acid. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic The acid (R) - [4- (2-. {Bis- [2- (tert-butyl-dimethyl-silanyloxy) -ethyl] -amino}. -acetoxy) -phenyl] -ter-butoxycarbonylamino- is obtained. acetic acid as described in Example 48, except that N, N-bis- [2- (tert-butyl-dimethyl-silanyloxy) -ethyl] -2-chloroacetamide is used instead of 2- (2-bromine) -ethoxy) -tetrahydropyran. HR-HR, observed mass (M + Na +) = 741.1194; calculated mass = 741.1192 for the C3iH32FIN4 a07 +. Example 63 (4- { (R) -1- [(1S, 2S) -1- (2-fluoro-4-iodo-phenylcarbamoyl) -2-phenyl-propyl] -2,5-dioxo-imidazolidin- 4-il.}. -
diramethyl phenoxymethyl) -phosphonate
It is obtained by the same method as described in example 48, except that (R) -tert-butoxycarbonylamino- [4- (dimethoxy-phosphorylmethoxy) -phenyl] -acetic acid is used instead of (R) - tert-butoxycarbonylamino-. { 4 - [2- (Tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic The (R) -tert-butoxycarbonylamino- [4- (dimethoxy-phosphorylmethoxy) -phenyl] -acetic acid is obtained in the following manner: (1) Dimethyl phosphite (2.0 g, 18.2 mmol), paraformaldehyde (574) are mixed. mg, 19.1 mmol) and triethylamine (0.25 mL, 1.8 mmol) and heated to 70 ° C, obtaining a clear solution. After 1 hour the reaction mixture was cooled and the vacuum was concentrated overnight, obtaining the crude dimethyl hydroxymethyl phosphonate (2.5 g). (2) To a solution of the dimethyl hydroxymethyl phosphonate (2.0 g, 14.5 mmol) in anhydrous dichloromethane (50 ml) is added at -20 ° C the pyridine (1.4 ml, 16.7 mmol) and then the trifluoromethanesulfonic anhydride (2.7 g). me, 15.9 mmoles). After stirring at 0 ° C for 0.5 hours the mixture is filtered through Celite with a thin layer of gel
silica. The filtrate is washed with cold 1.0 N aqueous hydrochloric acid, water, a saturated aqueous sodium bicarbonate solution and dried with sodium sulfate. The solvents are removed, obtaining trifluoro-methanesulfonate of dimethoxy-phosphorylmethyl in the form of an oil (2.1 g., 53%). (3) Sodium hydride (18.9 mg, 0.79 thymols) is added to the (R) -ter-butoxycarbonylamino- (4-hydroxy-phenyl) -acetic acid (100 mg, 0.37 mmol) in anhydrous dimethylformamide (2.5 ml) in a bath of ice. The mixture is allowed to warm to room temperature and dimethoxy phosphorylmethyl trifluoro-methanesulfonate (122 mg, 0.45 mmol) is added. Stirring is continued at room temperature overnight. The reaction mixture was poured into 0.2 M aqueous hydrochloric acid (10 mL) and the mixture was extracted with ethyl acetate. The extracts are combined, washed with a saturated aqueous solution of sodium bicarbonate, brine and dried with sodium sulfate. Evaporation of the solvents gave tert-butoxycarbonylamino- [(R) -4- (dimethoxy-phosphorylmethoxy) -phenyl] -acetic acid (120 mg, yield = 83%). HR-HR, observed mass (M + H +) = 696.0766; calculated mass = 696.0767 for the C28H29FI 307P +. Example 64 Acid (4- { (R) -l - [(lS, 2S) -l- (2-fluoro-4-iodo-phenylcarbamoyl) -2-phenyl-propyl] -2,5-dioxo-imidazolidin -4-il.}. -
phenoxymethyl) -phosphonic
To a solution of (4 - { (R) -1- [(1S, 2S) -1- (2-fluoro-4-iodo-phenylcarbamoyl) -2-phenyl-propyl] -2,5-dioxo- dimethyl imidazolidin-4-yl.} - phenoxymethyl) -phosphonate
(obtained in the manner described in example 63) (79 mg, 0.11 mmol) in dichloromethane (2.0 ml) was added bromotrimethylsilane (0.12 ml, 0.88 mmol) at room temperature. After 4 hours the reaction mixture was concentrated in vacuo and diluted with water (5 ml). The precipitated solid is filtered and dried, yielding (4- ({(R) -1- [(1S, 2S) -1- (2-fluoro-4-iodo-phenylcarbamoyl) -2-phenyl-propyl) acid. -2,5-dioxo-imidazolidin-4-yl.} - phenoxymethyl) -phosphonic acid (51 mg, 68%). HR-HR, observed mass (M + H +) 668.0453; calculated mass = 668.0454 for the C26H25FIN307P +. Example 65 (2S, 3S) -N- (2-fluoro-4-iodo-phenyl) -2- ((R) -4-isopropyl-2, 5-dioxo-imidazolidin-1-yl) -3-phenyl- butyramide
obtained by the same method as described
in Example 48, except that (R) -2-tert-butoxycarbonylamino-3-methyl-butyric acid is used in place of (R) -tert-butoxycarbonylamino- acid. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic HR-HR, observed mass (M + H +) = 524.0840; calculated mass = 524.0841 for the C22H24 I 303+. Example 66 (2S, 3S) -2- [4- (4-cyclopropyl-phenyl) -2,5-dioxo-imidazolidin-1-yl] -N- (2-fluoro-4-iodo-phenyl) -3- phenyl-butyramide, isomer 1
It is obtained by the same method as that described in example 48, except that tert-butoxycarbonylamino- (4-cyclopropyl-phenyl) -acetic acid is used instead of (R) -tert-butoxycarbonylamino- acid. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic The tert-butoxycarbonylamino- (4-cyclopropyl-phenyl) -acetic acid is obtained in the following manner: (i) The p-cyclopropylbenzaldehyde (840 mg, 5.68 mmol) is dissolved in dry dichloromethane (2.5 ml) and treated with cyanide. trimethylsilyl (756 mg, 7394 mmol) and 5 crystals of zinc iodide and heated at 40 ° C for 15 minutes. The reaction mixture is concentrated in vacuo.
(ii) Treat the concentrated orange solution of step (i) with 7N ammonia in methanol (7.1 ml, 14.22 mmol) and heat in a sealed tube and argon atmosphere at 40 ° C for 20 h. The solution is concentrated, obtaining a yellow residue (1.08 g). (iii) The yellow residue from step (ii) is dissolved in 6N HC1 in water (4.18 ml, 25.08 mmol) and heated at 100 ° C for 5 h. The solution is concentrated to a volume of about 3 ml and adjusted with concentrated aqueous NaOH to pH 8.0, obtaining a gummy residue (0.41 g). (Iv) The residue from step (iii) is dissolved in 1 N aqueous sodium hydroxide ( 2.1 ml, 2.1 mmol), water (2.14 ml) and p-dioxane (7.1 ml) and cooled in an ice bath. To this mixture is added di-tert-butyl dicarbonate (661 mg, 3,002 mmol), the mixture is stirred and allowed to warm to room temperature for 2 h. The solution is concentrated to remove the p-dioxane, diluted with water (25 ml), washed with diethyl ether (3? 25 ml) and extracted again with a saturated aqueous solution of sodium bicarbonate (25 ml). The combined aqueous phases are adjusted to pH 2-3 with a 1.5 N aqueous solution of potassium acid sulfate and extracted with ethyl acetate (3? 50 mL). The combined organic extracts are dried with sodium sulfate, filtered and the vacuum concentrated, obtaining the ter-
butoxycarbonylamino- (4-cyclopropyl-phenyl) -acetic acid (70 mg, yield = 11%). The diastereomers are separated from (2S, 3S) -2- [4- (4-cyclopropyl-phenyl) -2,5-dioxo-imidazolidin-1-yl] -N- (2-fluoro-4-iodo-phenyl) ) -3-phenyl-but-iramide by chromatography through silica gel eluting with a gradient of ethyl acetate of 5 to 20% v / v in hexanes. The fractions containing the fastest moving component are collected and the vacuum is concentrated. The residue is precipitated from ether / hexanes, yielding (2S, 3S) -2- [4- (4-cyclopropyl-phenyl) -2,5-dioxo-imidazolidin-1-yl] -N- (2-fluoro- 4-iodo-phenyl) -3-phenyl-butyramide, isomer 1. HR-HR, observed mass (M + H +) = 598.0998; calculated mass = 598.0998 for the Cze ^ eFI ^ Os "". Example 67 (2S, 3S) -2 - [(S) -4- (4-cyclopropyl-phenyl) -2,5-dioxo-imidazolidin-1-yl] -N- (2-fluoro-4-iodo-phenyl) ) -3-phenyl-butyramide, isomer 2
It is obtained by the same method as described in example 66. The diastereomers are separated from (2S, 3S) -2- [4-
(4-cyclopropyl-phenyl) -2,5-dioxo-imidazolidin-1-yl] -N- (2-fluoro-4-iodo-phenyl) -3-phenyl-butyramide by chromatography through silica gel, eluting with a gradient of ethyl acetate of 5 to 20% v / v in hexanes. The fractions containing the slower moving component are collected and the vacuum concentrated, obtaining (2S, 3S) -2- [4 - (4-cyclopropyl-phenyl) -2,5-dioxo-imidazolidin-1-yl. ] -N- (2-fluoro-4-iodo-phenyl) -3-phenyl-butyramide, isomer 2. HR-MS, observed mass (M + H +) = 598.0994; calculated mass = 598.0998 for the C28H26FIN303 +. Example 68 (2S, 3S) -2- ((R) -4-cyclohexyl-2,5-dioxo-imidazolidin-1-yl) -N- (2-fluoro-4-iodo-phenyl) -3-phenyl- butyramide
It is obtained by the same method as described in example 48, except that (R) -tert-butoxycarbonylamino-cyclohexyl-acetic acid is used in place of (R) -tert-butoxycarbonylamino- acid. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic HR-HR, observed mass (M + H +) = 564.1156; calculated mass = 564.1154 for the
.
Example 69 (2S, 3S) -N- (2-fluoro-4-iodo-phenyl) -2-. { 4- [4- (2-methanesulfonyl-ethyl) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide, diastereomer 1
It is obtained by the same method as described in Example 1, except that (i) 2-fluoro-4-iodoaniline is used instead of 4-bromoaniline in step 2, (ii) tert-butoxycarbonylamino acid - [4- (2-methanesulfonyl-ethyl) -phenyl] -acetic (obtained as described below) in place of the (R) -tert-butyloxycarbonylamino-4-methoxyphenylglycine in step 4 and (iii) an Supercritical fluid chromatography to separate the diastereomers of the (2S, 3S) -N- (2-fluoro-4-iodo-phenyl) -2-. { 4 - [4- (2-methanesulfonyl-ethyl) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide after performing step 6. The separation by chromatography of supercritical fluids is carried out using a Chiracel OJ column and eluting with carbon dioxide at 100 bar and 30 ° C modified with 25% ethanol in acetonitrile with a flow rate of 2 ml / minute. The eluted compound is collected first and the vacuum concentrated, yielding (2S, 3S) -N- (2-fluoro-4-iodo-phenyl) -2-. { 4- [4- (2-
methanesulfonyl-ethyl) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide, diastereomer 1. Preparation of tert-butoxycarbonylamino- [4- (2-methanesulfonyl-ethyl) -phenyl] -acetic acid: (1) To a mixture of amino- (4-bromo-phenyl) acid -acetic (543 mg, 2.4 mmol), triethylamine (822 μ ?, 5.9 mmol), 4- (dimethylamino) pyridine (29 mg, 0.24 mmol) in dioxane / water (2: 1, 12 ml) is added dicarbonate of di-tert-butyl (1.1 g, 5.0 mmol) and the resulting solution is maintained under stirring for 3 hours. The reaction mixture is diluted with ethyl acetate (50 ml), washed with 0.2 N aqueous hydrochloric acid (10 ml), water (20 ml), brine and the organic phase is dried with sodium sulfate and filtered. The solvent is removed in vacuo, obtaining (4-bromo-phenyl) -ter-butoxycarbonylamino-acetic acid (780 mg, 100%) (2) (4-bromo-phenyl) -tert-butoxycarbonylamino-acetic acid is dissolved (780 mg, 2.4 mmol) in N, N-dimethylformamide (15 ml), potassium carbonate (260 mg, 2.6 mmol) and then benzyl bromide (281 μ ?, 2.4 mmol) are added and stirring is continued at room temperature for 6 hours. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2 x 60 ml). The organic extracts are washed with water (2 x 20 ml), brine, dried over sodium sulfate and filtered through a layer of silica gel. The liquid is concentrated
The vacuum was filtered and the residue was crystallized in 100% hexane to obtain (4-bromo-phenyl) -ter-butoxycarbonylamino-benzyl acetate (500 mg, 50%). (3) The (4-bromo-phenyl) -ter-butoxycarbonylamino-benzyl acetate (1.5 g) is mixed., 3.6 mmol), methyl vinyl sulfone (406 μ ?, 4.6 mmol), palladium (II) acetate (80 mg, 10 mol%), tri-o-tolylphosphine (217 mg, 20 mol%) and triethylamine ( 2.0 ml, 14.3 mmol) in acetonitrile (18 ml) are degassed and refluxed for 8 hours. More palladium (II) acetate (80 mg, 10 mol%) and tri-o-tolylphosphine (217 mg, 20 mol%) are added and the reflux is continued overnight. The reaction mixture is cooled, the solvent is removed in vacuo and the residue is purified by chromatography through silica gel, eluting with a gradient of ethyl acetate of 20 to 90% v / v in hexane, obtaining the ter- butoxycarbonylamino- [4- ((E) -2-methanesulfonyl-vinyl) -phenyl] -benzyl acetate (1.2 g, 75%). (4) A hydrogenation reactor containing the tert-butoxycarbonylamino- [4- ((E) -2-methanesulfonyl-vinyl) -phenyl] -acetic acid benzyl ester (1.1 g, 2.5 mmol) in methanol / acetate is purged with nitrogen. of ethyl (3: 1, 50 ml) and 10% palladium on carbon (200 mg) is added. The atmosphere is changed over the organic solution to hydrogen and the reaction mixture is stirred vigorously at room temperature for 3 hours. The reaction mixture is filtered through
a Celite bed and the vacuum concentrated, obtaining tert-butoxycarbonylamino- [4- (2-methanesulfonyl-ethyl) -phenyl] -acetic acid (800 mg, 94%). HR-HR, observed mass (M + H +) = 664.0778; calculated mass = 664.0773 for the C28H28FIN305S +. NMR-H1 (DMSO-de, 300 MHz) d? = 10.11 (s, 1H), 8.56 (s, 1H), 5.02 (d, J = 11.7 Hz, 1H), 4.41 (s, 1H) ppm (characteristic resonances). Example 70 (2S, 3S) -N- (2-fluoro-4-iodo-phenyl) -2-. { 4- [4- (2-methanesulfonyl-ethyl) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide, diastereomer 2
Obtained in the manner described in Example 69, except that the eluted compound is collected in second place and the vacuum concentrated, obtaining (2S, 3S) -N- (2-fluoro-4-iodo-phenyl) -2- ( 4- [4- (2-methanesulfonyl-ethyl) -phenyl] -2,5-dioxo-imidazolidin-1-yl] -3-phenyl-butyramide, diastereomer 2. HR-HR, observed mass (M + H + ) = 664.0763, calculated mass = 664.0773 for C28H28FIN305S + LC-EM: RMN-H1 (DMSO-d6, 300 MHz) d? = 10.18 (s, 1H), 8.61
(s, 1H), 4.93 (s, 1H), 4.87 (d, J = 11.4 Hz, 1H) ppm
(characteristic resonances). Example 71 (2S, 3S) -N- (2,6-Difluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
It is obtained by the same method as described in example 48, except that (i) 2,6-difluoro-4-iodoaniline is used in place of 2-fluoro-4-iodoaniline and (ii) acid (R) -ter-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid in place of (R) -tert-butoxycarbonylamino- acid. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic The (R) -tert-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid is obtained in the manner described in example 48, except that l-bromo-2-methoxyethane is used instead of the 2- (2-bromo-ethoxy) -tetrahydropyran. HR-HR, observed mass (M + H +) = 650.0952; calculated mass = 650.0958 for the C28H27F2IN305 +. Example 72 (S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-thiophene-
2-yl-propionamide
It is obtained by the same method as described in example 48, except that (i) step 1 is carried out as described below and (ii) O-benzotriazole-1-yl-N, N hexafluorophosphate is used. , N ', N' -bis (tetramethylene) uronium as condensation reagent in place of O-benzotriazol-1-yl-N, N, ',' -tetramethyluronium hexafluorophosphate in step 4. Step 1: To a solution of (S) -2-tert-butoxy-carbonylamino-3-thiophen-2-yl-propionic acid (1.1 g, 4.06 mmol) and 2-fluoro-4-iodoaniline (800 mg, 3.38 mmol) in pyridine (15 ml) phosphorus oxychloride (0.35 ml, 3.72 mmol) is added slowly at -10 ° C under a dry nitrogen atmosphere. The mixture is stirred at -10 ° C for 2 hours. After removing the solvent and the excess reagent in a rotary evaporator, ice water is added. The mixture is extracted with dichloromethane, the organic phase is washed with aqueous citric acid 1, brine, a saturated aqueous solution of sodium carbonate, brine and dried with sodium sulfate. The solvents are removed, yielding [(S) -1- (2-fluoro-4-iodo-phenylcarbamoyl) -2-thiophen-2-yl-ethyl] -carbamate ter-
butyl in the form of yellow viscous oil which is used in the next step (1.52 g, 92%). LC-MS, observed mass (M + H +) = 491; calculated mass = 491 for the Ci8H2oFIN203S +. LC-MS, observed mass (M + H +) = 610; calculated mass
= 610 for the C24H22FIN305S +. Example 73 (S) -3- (5-Bromo-thiophen-2-yl) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -propionamide
It is obtained by the same method as described in Example 72, except that (S) -3- (5-bromo-thiophen-2-yl) -2-tert-butoxycarbonylamino-propionic acid is used instead of the acid (S) -2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionic in step 1. LC-MS, observed mass (M + H +) = 688; calculated mass = 688 for the C24H2iBrFIN305S +. Example 74 (S) -2-. { (R) -4- [4- ((R) -2,3-Dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (2-fluoro-4-iodo-phenyl) -3-
thiophen-2-yl-propionamide
It is obtained by the same method as described in example 114, except that (i) step 1 is carried out in the manner described in example 72 and (ii) O-benzotriazole-1-yl-N hexafluorophosphate is used. , N, NT, N'-bis (tetramethylene) uronium as condensation reagent in place of O-benzotriazole-l-yl-N, N, N ',' -tetramethyluronium hexafluorophosphate in step 4. EM-LC, mass observed (M + H +) = 640; calculated mass = 640 for the C25H24FI 306S +. Example 75 (S) -3- (5-bromo-thiophen-2-yl) -2-. { (R) -4- [4- ((R) -2,3-Dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (2-fluoro--iodo-phenyl) -propionamide
It is obtained by the same method as described in example 114, except that (i) step 1 is carried out in the manner described in example 73 and (ii) O-benzotriazole-1-yl-N hexafluorophosphate is used. ,, N ', N' -
bis (tetramethylene) uronium as a condensation reagent in place of O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate in step 4. LC-MS, mass observed (M + JT) = 718; calculated mass = 718 for the C25H23BrFIN306S +. Example 76 (S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-pyridin-2-yl-propionamide
It is obtained by the same method as described in Example 43, except that (i) (S) -2-tert-butoxycarbonylamino-3-pyridin-2-yl-propionic acid is used in place of the acid (S) -2- (9H-Fluoren-9-ylmethoxycarbonylamino) -3-naphthalen-2-yl-propionic acid in step 1 and (ii) step 3 is carried out as described below. Step 3: To a solution of (S) - [1- (2-fluoro-4-iodo-phenylcarbamoyl) -2-pyridin-2-yl-ethyl] -carbamic acid tert -butyl ester (1.2 g, 2.47 mmole) in dichloromethane (5 ml) is added at 0 ° C trifluoroacetic acid (5 ml) and the mixture is stirred at 0 ° C for 1 hour. The reaction mixture is concentrated in vacuo and the residue is suspended in ice water. The aqueous suspension is neutralized with a saturated aqueous solution of
sodium carbonate to a basic pH, then extracted with dichloromethane (three times). The combined organic extracts are dried with sodium sulfate, filtered and the vacuum concentrated. The residue is purified by chromatography through silica gel, eluting with a gradient of 100% hexane to 100% ethyl acetate in 40 minutes. By concentration of the fractions containing product, (S) -2-amino-N- (2-fluoro-4-iodo-phenyl) -3-pyridin-2-yl-propionamide is obtained as a yellow solid (806 mg , 85%). LC-MS, observed mass (M + H +), 386; calculated mass =
386 for the Ci4Hi3FIN30 +. LC-MS, observed mass (M + H +) = 605; calculated mass = 605 for the C25H23FIN405 +. Example 77 (S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3- (1-oxy-pyridin-2-yl) -propionamide
To a solution of (S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} 3-pyridin-2-yl-propionamide (obtained in the manner described in Example 76) (50 mg, 0.083 mmol) in dichloromethane (4
mi) is added 3-chloroperbenzoic acid (77%, 28 mg, 0.12 mmol) and the mixture is stirred for 5 hours. The reaction mixture is concentrated in vacuo and the residue is purified by chromatography on silica gel, eluting with a gradient of 100% dichloromethane to 10% methanol / 90% dichloromethane in 30 minutes. The concentration of the fractions containing product yields (S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3- (l-oxy-pyridin-2-yl) -propionamide as a white solid (40 mg, 78%). LC-MS observed mass (M + H +) = 621; calculated mass = 621 for the C25H23FIN406 +. Example 78 (S) -2-. { (R) -4- [4- ((R) -2,3-Dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (2-fluoro-4-iodo-phenyl) -3- pyridin-2-yl-propionamide
It is obtained by the same method as described in example 114, except that (i) steps 1-3 are carried out in the manner described in example 76 and (ii) 0-benzotriazole hexafluorophosphate is used as the condensation reagent. -l-il-N, N, N ', N' -bis (tetramethylene) uronium instead
of the hexaf luorof osf ato of O-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium in step 4. E-LC, observed mass (M + H +) = 635; calculated mass = 635 for the C26H25FIN406 +. Example 79 (S) -N- (2-f luoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-thiazole-
It is obtained by the same method as described in Example 1, except that 2-fluoro-4-iodoaniline is used instead of 4-bromoaniline and (S) -2-tert-butoxycarbonylamino-3-thiazole acid 4-yl-propionic acid in place of (2S, 3S) -2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 2 and (R) -tert-butoxycarbonylamino- acid. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic in place of the (R) -ter-butoxycarbonylamino- [4-methoxy-phenyl] -acetic acid in step 4. The (R) -tert-butoxycarbonylamino- acid is obtained. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic in the manner described in example 48. HR-HR, observed mass (M + H +) = 611.0253; calculated mass = 611.0256 for the C23H2iFIN405S +. Example 80 (S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-thiazole-4-
il-propionamide
It is obtained by the same method as described in Example 79, except that (R) -tert-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid is used in place of the acid (R ) -ter-butoxycarbonylamino-. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic. The (R) -tert-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid is obtained in the manner described in example 48, except that l-bromo-2-methoxyethane is used instead of the 2- (2-bromo-ethoxy) -tetrahydropyran. HR-HR, observed mass (M + H +) = 625.0403; calculated mass = 625.0413 for the C24H23FIN405S +. Example 81 (S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4 - (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3- (3-methyl-3H-imidazol-4-yl) -propionamide
It is obtained by the same method as described in Example 3, except that (i) 2-fluoro-4-iodoaniline is used instead of 2-chloro-4-bromoaniline and (ii)
(2S) -2-tert-butoxycarbonylamino-3- (3-methyl-3H-imidazol-4-yl) -propionic acid in place of (2S, 3S) -2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 1. HR-HR, observed mass (M + H +) = 608.0798; calculated mass = 608.0801 for the C24H24FIN505 +. Example 82 N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -acetamide
obtained by the same method as described in example 48, except that ter-butoxycarbonylaminoacetic acid is used in place of (2S, 3S) -2-tert-butoxycarbonylamino-3-phenyl-butyric acid. HRMS, observed mass (M + Na +) = 536.0088; calculated mass = 536.0089 for the Ci9Hi7FIN3Na05 +. Example 83 (S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-methyl-butyramide
obtained by the same method as described
in Example 48, except that (S) -2-tert-butoxycarbonylamino-3-methyl-butyric acid is used in place of (2S, 3S) -2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 1. EM-LC, obs mass = 556; calculated mass = 556 for the C22H24FI 305+. Example 84 (S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-methyl-butyramide
It is obtained by the same method as described in Example 21, except that (i) (S) -2-tert-butoxycarbonylamino-3-methyl-butyric acid is used instead of (S) -2-ter -butoxycarbonylamino-3-phenyl-propionic in step 1 and (ii) O-benzotriazol-1-yl-N, N, N ', N'-bis (tetramethylene) uronium hexafluorophosphate as a condensation reagent instead of hexafluorophosphate of O-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium in step 4. LC-MS, observed mass (M + H +) = 570; calculated mass = 570 for the C23H26FIN305 +. Example 85 (S) -2-. { (R) -4- [4- ((R) -2,3-Dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (2-fluoro-4-iodo-phenyl) -3-
methyl-butyramide
It is obtained by the same method as described in example 114, except that (i) step 1 is carried out in the manner described in example 83 and (ii) O-benzotriazole-1-yl-N hexafluorophosphate is used. , N, N ', N' -bis (tetramethylene) uronium as condensation reagent in place of O-benzotriazole-l-yl-N, N, N ', N' -tetramethyluronium hexafluorophosphate in step 4. EM-LC , observed mass (M + H +) = 586; calculated mass = 586 for the C23H26FIN306 +. Example 86 (S) -N- (2-fluoro-4-iodo-phenyl) -3-methyl-2-. { - [4- (2-morpholin-4-yl-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -butyramide; composed with acetic acid
It is obtained by the same method as described in Example 1, except that (i) (S) -2-tert-butoxycarbonylamino-3-methyl-butyric acid is used instead of (2S, 3S) -2 -ter-butoxycarbonylamino-3-phenyl-butyric in the
step 1, (ii) 2-fluoro-4-iodoaniline instead of 4-bromoaniline in step 2 and (iii) (R, S) -tert-butoxycarbonylamino- [4- (2-morpholin-4) acid -yl-ethoxy) -phenyl] -acetic acid in place of (R) -ter-butyloxycarbonylamino-4-methoxyphenylglycine in step 4. The (R, S) -tert-butoxycarbonylamino- [4- (2- morpholin-4-yl-ethoxy) -phenyl] -acetic as follows: (1) To a solution of (R) -tert-butoxy-carbo-nylamino- [4- (2-hydroxy-ethoxy) -phenyl] -acetic (1.0 g, 3.21 mmol) in methanol (10 ml) is added a catalytically sufficient amount of concentrated sulfuric acid. The reaction mixture is stirred under reflux for 3 hours. The solvent is evaporated and the crude (R) -ter-butoxycarbonylamino- [4- (2-hydroxy-ethoxy) -phenyl] -acetic acid methyl ester (0.836 g, yield = 80%) is used in the next step without further ado. purification. (2) To a stirred solution of methyl (R) -ter-butoxycarbonylamino- [4- (2-hydroxy-ethoxy) -phenyl] -acetate (80 mg, 0.25 mmol) in pyridine (1.5 ml) is added by drip methanesulfonyl chloride (0.023 ml, 0.30 mmol). The reaction mixture is stirred at room temperature for 3 hours. The solvent is evaporated and the crude product is purified by chromatography through silica gel, eluting with a 3: 1 v / v mixture of hexanes / ethyl acetate, thereby obtaining the (R) -ter-butoxycarbonylamino - [4- (2-Methanesulfonyloxy-ethoxy) -phenyl] -acetic acid methyl ester (50 mg,
yield = 50%) in the form of a colorless oil. (3) To a stirred solution of methyl (R) -ter-butoxycarbonylamino- [4- (2-methanesulfonyloxy-ethoxy) -phenyl] -acetate (50 mg, 0.12 mmol) in ethanol (1 ml) morpholine (0.043 ml, 0.49 mmol) is added at room temperature. The reaction mixture is boiled under reflux for 1 hour. The solvent is evaporated and the crude product is purified by chromatography through silica gel, eluting with a 1: 1 v / v hexanes / ethyl acetate mixture, thereby obtaining the (R) -ter-butoxycarbonylamino - [4- (2-morpholin-4-yl-ethoxy) -phenyl] -acetic acid methyl ester (45 mg, yield = 92%) as a colorless oil. (4) To a stirred solution of methyl (R) -ter-butoxycarbonylamino- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -acetate (45 mg, 0.11 mmol) in methanol (0.6 ml) and water (0.2 ml) is added lithium hydroxide monohydrate (14.3 mg, 0.34 mmol) at room temperature. The reaction mixture is stirred at room temperature for 3 hours. The solvent is evaporated and the crude product, (R, S) -tert-butoxycarbonylamino- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -acetic acid (43 mg, yield = 99) is used. %), in the next step without further purification. HR-HR, observed mass (M + H +) = 625.1318; calculated mass = 625.1318 for the C26H3iFIN405 +.
Example 87 (S) -N- (2-Fluoro-4-iodo-phenyl) -3-methyl-2- (4- { 4- [2- (-methyl-piperazin-1-yl) -ethoxy] -phenyl.} -2,5-dioxo-imidazolidin-1-yl) -butyramide; composed with acetic acid
It is obtained by the same method as described in Example 86, except that (i) the acid (R, S) -1 er-bu t oxi ca rboni 1 amino- is used. { 4 - [2 - (4-methyl-piperazin-1-yl) -ethoxy] -phenyl} -acetic instead of acid (R, S) - 1-er-but oxica rbon i lamino- [4 - (2-morpholin-4-yl-ethoxy) -phenyl] -acetic in step 4. The acid (R, S) - 1 er is obtained - but ox i ca rboni 1 ami no -. { - [2 - (4-methyl-piperazin-1-yl) -ethoxy] -phenyl} -acetic using the same method described for the acid (R, S) -ter-butoxycarbonylamino- [4- (2-morpholin-4-yl-e t ox i) - f in i 1] - a cé ti co in the Example 86, except that 1-me ti 1 -p ipe ra zi na is used in place of morpholine in step 3. HR-HR, observed mass (M + H +) = 638.1633; calculated mass = 638.1637 for the C27H3 FIN504 +. Example 88 (S) -2- (2,5-dioxo-4-pyridin-3-yl-imidazolidin-1-yl) -
N- (2-fluoro-4-iodo-phenyl) -3-methyl-butyramide
It is obtained by the same method as described in Example 1, except that (i) (S) -2-tert-butoxycarbonylamino-3-methyl-butyric acid is used instead of (2S, 3S) -2 -ter-butoxycarbonylamino-3-phenyl-butyric in step 1, (ii) 2-fluoro-4-iodoaniline instead of 4-bromoaniline in step 2 and (iii) acid (R, S) -ter -butoxycarbonylamino-pyridin-3-yl-acetic acid in place of (R) -tert-butyloxycarbonylamino-4-methoxyphenylglycine in step 4. HR-HR, observed mass (M + H +) = 497.0476; calculated mass = 497.0481 for the Ci9Hi9FIN403 +. Example 89 4.4, 4-trifluoro-N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-methyl-butyramide
It is obtained by the same method as that described in example 72, except that (±) -2-tert-butoxycarbonylamino-4,4,4-trifluoro-3-methyl-butyric acid is used instead of the acid (S). ) -2-tert-butoxycarbonylamino-3-thiophene-2-yl-
propionic in step 1. LC-MS, observed mass (M + H +) = 610; calculated mass = 610 for the C22H2iF4I 305+. Example 90 (2S, 3S) -2- (2-fluoro-4-iodo-phenyl) -amide. { (R) -4- [4- ((R) -2,3-Dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-methyl-pentanoic
It is obtained by the same method as described in Example 74 except that (2S, 3S) -2-tert-butoxycarbonylamino-3-methyl-propionic acid is used in place of (S) -2-tert-butoxycarbonylamino acid -3-thiophene-2-yl-propionic in step 1. LC-MS, observed mass (M + H +) = 600; calculated mass = 600 for the C24H28FIN306 +. Example 91 4.4, 4-trifluoro-N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-trifluoromethyl-butyramide
obtained by the same method as described
in Example 72, except that (±) -2-tert-butoxycarbonyl-amino-4, 4 -trifluoro-3-trifluoromethyl-butyric acid is used in place of (S) -2-tert-butoxycarbonylamino-3 -thiophen-2-yl-propionic acid in step 1. 2-tert-butoxycarbonyl-amino-4, 4-trifluoromethyl-3-trifluoromethyl-butyric acid is obtained in the manner described below. Obtaining 2-tert-butoxycarbonyl-amino-4,4, 4-trifluoro-3-trifluoromethyl-butyric acid: To a solution of 4, 4, 4, 4 ',', 4 '-hexafluoro-DL-valine (1.0 g, 4.4 mraole) and sodium carbonate (933 mg, 8.8 mmol) in dioxane (10 ml) and water (10 ml) is slowly added at 0 ° C di-tert-butyl dicarbonate. After the addition is complete, the mixture is stirred at room temperature for 12 hours. The reaction mixture is partitioned between water and ethyl acetate and the organic phase is discarded. The organic phase is adjusted to pH > 4 with a 1M aqueous solution of citric acid, washed with brine, dried with sodium sulfate and concentrated, yielding 2-tert-butoxycarbonyl-amino-4,4,4-trifluoro-3-trifluoromethyl-butyric acid in yellow solid form (1.34 g, 96%). LC-MS, observed mass (M-H +) = 324; calculated mass = 324 for Ci0H12F6NO4. "EM-LC, observed mass (M + H +) = 664, calculated mass = 664 for C22Hi8F7I 305+.
Example 92 (S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3.3-dimethyl-butyramide
It is obtained by the same method as described in example 43, except that (S) -2- (9H-fluoren-9-ylmethoxycarbonylamino) -3.3-dimethyl-2-yl-butyric acid is used instead of the acid (S) -2- (9H-Fluoren-9-ylmethoxycarbonylamino) -3-naphthalen-2-yl-propionic in step 1. LC-MS, observed mass (M + H +) = 570; calculated mass
= 570 for the C23H26FIN305 +. Example 93 (2-Fluoro-4-iodo-phenyl) -amide of (S) -2- acid. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} - .4-dimethyl-pentanoic
It is obtained by the same method as described in example 43, except that (i) (S) -2- (9H-fluoren-9-ylmethoxycarbonylamino) -4,4-dimethyl-2-yl-pentanoic acid is used in Place of (S) -2- (9H-fluoren-9-) acid
ilmethoxycarbonylamino.no) -3-naphthalen-2-yl-propanoic acid in step 1 and (ii) steps 4 to 7 are carried out as described below: Step 4: To the solution of (2-fluoro-4) 2-amino-4,4-dimethyl-pentanoic acid-2-phenyl) -amide (364 mg, 1 mmol), (R) -tert-butoxycarbonylamino- [4- (2-tert-butoxy-ethoxy) -phenyl acid] -acetic (1M in DMF, 1.1 ml, 1.1 mmol), 1-hydroxybenzotriazole (168 mg, 1.1 mmol) and diisopropylethylamine (0.53 ml, 3.3 mmol) in N, N-dimethylformamide (5 ml) is added dropwise to the O-benzotriazol-1-yl-N, N, N ', N' -bis (tetramethylene) uronium hexafluorophosphate solution (474 mg, 1.1 mmol). The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate and washed with water and brine. The organic phases are washed successively with a 1 M aqueous solution of citric acid, brine, a saturated aqueous solution of sodium carbonate, brine, dried over sodium sulfate, filtered and concentrated to obtain the. { (R) - [4- (2-tert-Butoxy-ethoxy) -phenyl] - [(S) -1- (2-fluoro-4-iodo-phenylcarbamoyl) -3,3-dimethyl-butylcarbamoyl] -methyl} - tert-butyl carbamate (652 mg, 91%) as a white solid. LC-MS, observed mass (M + H +) = 714; calculated mass = 714 for the C32H45FIN306 +. Step 5: To a solution of. { (R) - [4- (2-tert-butoxy-
ethoxy) -phenyl] - [(S) -1- (2-fluoro-4-iodo-phenylcarbamoyl) -3,3-di-methyl-butylcarbamoyl] -methyl} tert-butyl carbamate (652 mg, 0.91 mmol) in acetonitrile (6 ml) was added 4 N hydrogen chloride in dioxane (1 ml, 4 mmol) and the mixture was stirred at 40 ° C for 30 minutes. The reaction mixture is concentrated in vacuo and the residue is suspended in ice water. The aqueous suspension is neutralized to basic pH with a saturated aqueous solution of sodium carbonate, then extracted with dichloromethane (three times). The combined organic extracts are dried with sodium sulfate, filtered, the vacuum is concentrated and the residue is purified by chromatography through silica gel, eluting with a gradient of 100% dichloromethane to 10% methanol / 90% strength. dichloromethane in 30 minutes. The (2-fluoro-4-iodo-phenyl) -amide of the (S) -2- acid is obtained by concentration of the product-containing fractions. { (R) -2-amino-2- [4- (2-tert-butoxy-ethoxy) -phenyl] -acetylamino} -4.4-dimethyl-pentanoic acid (490 mg, 87%). LC-MS, observed mass (M + H +) = 614; calculated mass = 614 for the C27H38FIN304 +. Step 6: To a solution of diphosgene (41 μ ?, 0.34 mmol) in a 1: 1 v / v mixture of toluene / tetrahydrofuran (18 ml total) is added dropwise at -35 ° C for 10 min and with stirring in a dry argon atmosphere a solution of the (S) -2- (2-fluoro-4-iodo-phenyl) -amide. { (R) -2-amino-2- [4-
(2-tert-butoxy-ethoxy) -phenyl] -acetylamino} -4.4-dimethyl-pentanoic acid (300 mg, 0.49 mmol) and N, N-diisopropylethylamine (260 μ ?, 1.47 mmol) in tetrahydrofuran (9 ml). After an additional 45 minutes, add ice, stir the reaction mixture vigorously and heat to room temperature. The reaction mixture is poured into water, extracted with ethyl acetate (twice), the combined organic layers are washed successively with water (twice), a 0.1 M aqueous solution of hydrochloric acid, water, a saturated aqueous solution of sodium hydrogen carbonate, water and brine, then dried with sodium sulfate, filtered and the vacuum concentrated, yielding (S) -2- (2-fluoro-4-iodo-phenyl) -amide. { (R) -4- [4- (2-tert-Butoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolium-din-l-yl} -4.4-dimethyl-pentanoic in the form of yellow sticky solid (295 mg, 95%), which is used in the next step without further purification. LC-MS, observed mass (M + H +) = 640; calculated mass = 640 for the C28H36FIN305 +. Step 7: To a solution of the (S) -2- (2-fluoro-4-iodo-phenyl) -amide. { (R) -4- [4- (2-tert-Butoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -4.4-dimethyl-pentanoic acid (295 mg, 0.46 mmol) in dichloromethane (3 mL) was slowly added at 0 ° C and under a dry argon atmosphere a solution of trimethylsilyl iodide (183 μ ?, 1.3 mmol) in dichloromethane (1 ml). The reaction mixture is stirred at
room temperature for 2 hours. Methanol (0.5 ml) is added to interrupt the reaction. The reaction mixture is extracted with dichloromethane and the organic phase is washed successively with a saturated aqueous solution of sodium carbonate, 5% aqueous sodium thiosulfate, brine, then dried with sodium sulfate, filtered and the vacuum concentrated. The residue is purified by chromatography on silica gel, eluting with a gradient of 100% hexane to 50% ethyl acetate / 50% hexane in 30 minutes. The (2-fluoro-4-iodo-phenyl) -amide of the (S) -2- acid is obtained by concentration of the fractions containing product. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -4.4-dimethyl-pentanoic acid as a white solid (126 mg, 47%). LC-MS, observed mass (M + H +) = 584; calculated mass
= 584 for the C24H28FIN305 +. Example 94 (S) -2-cyclopropyl-N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -
It is obtained by the same method as described in Example 48, except that (i) (S) -tert-butoxycarbonylamino-cyclopropyl-acetic acid is used instead of the acid
(2S, 3S) -2-tert-butoxycarbonylamino-3-phenyl-butyric in step 1 and (ii) O-benzotriazol-1-yl-N, N, N ', N'-bis (tetramethylene) uronium hexafluorophosphate as a condensation reagent in place of the 0-benzotriazol-1-yl-N, N ', N' -tetramethyluronium hexafluorophosphate in step 4. LC-MS, mass observed (M + H +) = 554; calculated mass = 554 for C22H22FIN3O5"". Example 95 (S) -3-Cyclopropyl-N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-etho i) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -propionamide
It is obtained by the same method as described in example 48, except that (i) (S) -2-tert-butoxycarbonylamino-3-cyclopropyl-propionic acid is used instead of (2S, 3S) -2 -ter-butoxycarbonylamino-3-phenyl-butyric acid in step 1 and (ii) O-benzotriazol-1-yl-N, N, N ', N'-bis (tetramethylene) uronium hexafluorophosphate as condensation reagent instead of O-benzotriazole-1-yl-N, N, N ',' -tetramethyluronium hexafluorophosphate in step 4. LC-MS, observed mass (M + H +) = 568; calculated mass = 568 for the C23H24FIN305 +.
Example 96 (S) -3-Cyclohexyl-N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -propionamide
It is obtained by the same method as described in example 48, except that (i) (S) -2-tert-butoxycarbonylamino-3-cyclohexyl-propionic acid is used instead of (2S, 3S) -2 -ter-butoxycarbonylamino-3-phenyl-butyric acid in step 1 and (ii) O-benzotriazol-1-yl-N, N, N ', N'-bis (tetramethylene) uronium hexafluorophosphate as condensation reagent instead of O-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium hexafluorophosphate in step 4. LC-MS, observed mass (M + H +) = 610; calculated mass = 610 for the C26H3oFIN305 +. Example 97 (2S, 3R) -N- (2-fluoro-4-iodo-phenyl) -2- [(R) -4- (4-hydroxy-phenyl) -2,5-dioxo-imidazolidin-1-yl ] -3-methoxy-butyramide
obtained by the same method as described
in Example 1, except that (i) (2S, 3R) -2-tert-butoxycarbonylamino-3-methoxy-butyric acid is used in place of (2S, 3S) -2-tert-butoxycarbonylamino-3-phenyl acid -butyric in step 1, (ii) 2-fluoro-4-iodoaniline instead of 4-bromoaniline in step 2, (iii) 0-benzotriazol-1-yl-N, N ', hexafluorophosphate , N'-bis (tetramethylene) uronium as a condensation reagent in place of the 0-benzotriazol-1-yl-N, N ',' -tetramethyluronium hexafluorophosphate in step 4 and (iv) the (R) -term butyloxycarbonylamino-4-hydroxyphenylglycine in place of (R) -tert-butyloxycarbonylamino-4-methoxyphenylglycine in step 4. LC-MS, observed mass (+ H +) = 528; calculated mass = 528 for C2oH2oFIN305 +. Example 98 (2S, 3R) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-methoxy-butyramide
It is obtained by the same method as described in example 48, except that (i) (2S, 3R) -2-tert-butoxycarbonylamino-3-methoxy-butyric acid is used instead of (2S, 3S) acid -2-tert-butoxycarbonylamino-3-phenyl-butyric in step 1 and (ii) the hexafluorophosphate of O-benzotriazole-1-yl-
N, N, N ',' -bis (tetramethylene) uronium as a condensation reagent in place of the 0-benzotriazol-1-yl-N, N ', N' -tetramethyluronium hexafluorophosphate in step 4. EM-LC, observed mass (M + H +) = 572; calculated mass = 572 for the C22H24FIN306 +. Example 99 (2S, 3R) -2-. { (R) -4- [4- ((R) -2,3-Dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (2-fluoro-4-iodo-phenyl) -3-methoxy-butyramide
It is obtained by the same method as described in example 114, except that (i) (2S, 3R) -2-tert-butoxycarbonylamino-3-methoxy-butyric acid is used instead of (2S, 3S) acid -2-tert-butoxycarbonylamino-3-phenyl-butyric in step 1, (ii) 2-fluoro-4-iodoaniline instead of 2-chloro-4-iodoaniline in step 2 and (iii) hexafluorophosphate in O-benzotriazol-1-yl-N, N, N ', N' -bis (tetramethylene) uronium as a condensation reagent in place of 0-benzotriazol-1-yl-N, N, N ', N' - hexafluorophosphate tetramethyluronium in step 4. LC-MS, observed mass (M + H +) = 602; calculated mass = 602 for the C23H26FIN307 +. Example 100 (2S, 3R) -3-benzyloxy-2-. { (R) -4- [4 - ((R) -2, 3-dihydroxy-
propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (2-fluoro-4-iodo-phenyl) -butyramide
It is obtained by the same method as described in example 43, except that (i) (2S, 3R) -3-benzyloxy-2- (9H-fluoren-9-ylmethoxycarbonylamino) -butyric acid is used instead of (S) -2- (9H-Fluoren-9-ylmethoxycarbonylamino) -3-naphthalen-2-yl-propionic acid in step 1 and (ii) the steps are carried out after step 3 in the manner described in example 114. LC-MS, observed mass (M + H +) = 678; calculated mass = 678 for the C29H3oFIN307 +. Example 101 (2S, 3R) -2-. { (R) -4- [4- ((R) -2,3-dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (2-fluoro-4-iodo-phenyl) -3-hydroxy-butyramide
It is obtained by the same method as described in Example 43, except that (i) (2S, 3R) -3-tert-butoxy-2- (9H-fluoren-9-ylmethoxycarbonylamino) -butyric acid is used in place of (S) -2- (9H-fluoren-9-ylmethoxycarbonylaiTU.no) -3-naphthalen-2-yl-propionic acid in step 1 and (ii) the steps following step 4 are carried out in the manner
described in Example 114. LC-LC, observed mass (+ H +) = 588; calculated mass = 588 for the C22H24FIN307 +. Example 102 (S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -4-phenyl-butyramide
It is obtained by the same method as described in example 72, except that (S) -2-tert-butoxycarbonylamino-4-phenyl-2-yl-butyric acid is used instead of (S) -2- tert-butoxycarbonylamino-3-thiophen-2-yl-propionic acid in step 1. LC-MS, observed mass (M + H +) = 618; calculated mass
= 618 for the C27H26FIN305 +. Example 103 (S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -4-methanesulfonyl-butyramide
It is obtained by the same method that has been described
in Example 43, except that (S) -2- (9H-fluoren-9-ylmethoxycarbonylamino) -4-methanesulfonyl-butyric acid is used in place of (S) -2- (9H-fluoren-9-ylmethoxycarbonylamino ) -3-naphthalen-2-yl-propionic in step 1. LC-MS, observed mass (M + H +) = 620; calculated mass
= 620 for the C22H24FIN307S +. Example 104 5-amide 1- [(2-fluoro-4-iodo-phenyl) -amide] of (S) -2- acid. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -pentanodioic
It is obtained by the same method as described in example 72, except that (S) -2-tert-butoxycarbonylamino-4-carbamoyl-butyric acid is used in place of (S) -2-tert-butoxycarbonylamino- 3-thiophene-2-yl-propionic in step 1. LC-MS, observed mass (M + H +) = 585; calculated mass = 585 for the C22H23FIN406 +. Example 105 (S) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-
propionamide
It is obtained by the same method as described in Example 3, except that (i) 2-chloro-4-iodo-aniline is used in place of 4-bromo-2-chloroaniline in step 1 and (ii) (S) -2-tert-butoxycarbonylamino-3-phenyl-propionic acid in place of (S, S) -2-tert-butoxycarbonyl-amino-3-phenyl-butyric acid in step 1. EM- HR, observed mass (M + H +) = 620.0442; calculated mass = 620.0444 for the Cze ^ ClI ^ Os "". Example 106 (S) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-propionamide
It is obtained by the same method as described in Example 3, except that (i) 2-chloro-4-iodo-aniline is used in place of 4-bromo-2-chloroaniline in step 1, (ii) (S) -2-tert-butoxycarbonylamino-3-phenyl-propionic acid in place of (S, S) -2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 1 and (iii) the
(R) -ter-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid in place of (R) -tert-butoxycarbonylamino- [4- (2-tert-butoxy-ethoxy) -phenyl acid ] -acetic in step 2. The (R) -ter-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid is obtained in the manner described in example 80. E -HR, observed mass ( M + H +) = 634.0602; calculated mass = 634.0600 for the C27H26C1IN305 +. Example 107 (S) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4- [4- ((R) -2,3-Dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-propionamide
It is obtained by the same method as described in Example 3, except that (i) 2-chloro-4-iodo-ani-i-na is used instead of -br-2-c-1 or in step 1, (ii) the acid (S) -2-tert-but ox i ca rbon i 1 ami no- 3-pheny1-pr opy ion instead of the acid (S) , S) - 2 - 1 er -but ox i ca rbon i 1 ami no- 3 - phen i 1 -butyric in step 1 and (iii) (R) - tert-butoxycarbonylamino- [4- ((S) acid) ) -2, 2-dimethyl- [1, 3] dioxolan-4-ylme t oxy) -pheni 1] -acetyl co instead of (R) -tert-butoxycarbonylamino- [4- (2-ter- butoxy-ethoxy) -f eni 1] - acé ti co in step 2. The acid is obtained (R) -
ter-butoxycarbonylamino- [4- ((S) -2,2-dimethyl- [1, 3] di oxo 1 to n- 4 - i lme t ox i) - f in i 1] - a cé ti co and used in the manner described in Example 114. HR-HR, observed mass (M + H +) = 650.0541; calculated mass = 650.0550 for the C27H26 1 IN306 +. Example 108 (2S, 3S) -N- (2-chloro-4-iodo-phenyl) -2- [(R) -4- (4-methoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl -3-phenyl-but i ramida
It is obtained in the manner described in example 1, except that (i) 2-c 1 oro-4-iodoan i 1 i na is used instead of 4-bromoani 1 ina in step 2 and (ii) is used As the condensation reagent, the hydrochloride of the (3-dimethyl ti 1 ami non-pr op i 1) - eti 1-ca rbodi imi da in place of the hexafluorophosphate of O-ben zotriazo 1 - 1 - i 1 -N,, ' , N '- 1 etr ame ti 1 u ron io in step 4. HR-HR, observed mass (M + H +) = 604.0496; calculated mass = 604.0495 for the C26H24C I I 3C. Example 109 (2S, 3S) -N- (2-chloro-4-iodo-phenyl) -2- [(R) -4- (4-cyclopropylmethoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl ] -3-
phenylbutyramide
It is obtained by the same method as described in Example 3, except that 2-chloro-4-iodoaniline is used in place of 2-chloro-4-bromoaniline in step 1 and acid (R) -ter -butoxycarbonylamino- (4-cyclopropylmethoxy-phenyl) -acetic acid in place of -tert-butoxycarbonylamino- [4- (2-tert-butoxy-ethoxy) -phenyl] -acetic acid in step 2. The (R) - acid is obtained tert-butoxycarbonylamino- [4- (2-tert-butoxy-ethoxy) -phenyl] -acetic acid by a method similar to that described for the preparation of (R) -tert-butoxycarbonylamino- acid. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic in example 48, except that cyclopropylmethyl bromide is used in place of 2- (2-bromo-ethoxy) -tetrahydropyran. HR-HR, observed mass (M + H +) = 644.0799; calculated mass = 644.0808 for the C29H28CIIN3O. Example 110 (2S, 3S) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
It is obtained by the same method as described in Example 48, except that 2-chloro-4-iodoaniline is used in place of 2-fluoro-4-iodoaniline in step 2. HR-HR, mass observed ( M + H +) = 634.0597; calculated mass = 634.0600 for the C27H26C1I 305+. LC-MS (HPLC in reverse phase, column C18, water / acetonitrile gradient): Rt = 2.36 minutes, mass observed (M + Na +) = 656; calculated mass = 640 for C27H25ClIN3Na05 +. NMR-H1 (DMSO-d6, 300 Hz) d? = 9.85 (s, 1H), 8.56
(s, 1H), 4.95 (d, J = 11.5 Hz, 1H) ppm (characteristic resonances). Example 111 (2S, 3S) -N- (2-chloro-4-iodo-phenyl) -2-. { (S) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide |
A solution of (2S, 3S) -N- (2-chloro-4-iodo-phenyl) -2- is dissolved. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} 3-phenyl-butyramide (obtained as described in example 110) (50 mg, 0.079 mmol) in methanol (3 ml) and stirred at room temperature for 4 days. The mixture of isomers is concentrated in vacuo and
purify by supercritical fluid chromatography using a Chiracel OJ column and eluting with carbon dioxide at 100 bar and 30 ° C modified with 35% v / v ethanol in acetonitrile with a flow rate of 2 ml / minute. The eluted compound is collected first and the vacuum concentrated, yielding (2S, 3S) -N- (2-chloro-4-iodo-phenyl) -2-. { (S) -4 - [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide (14.6 mg, 29%). The compound eluted in the second place is identical to (2S, 3S) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4 - [- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} 3-phenyl-butyramide (18.1 mg, 36%). LC-MS (HPLC in reverse phase, column C18, water / acetonitrile gradient): Rt = 2.40 minutes, mass observed (M + Na +) = 656; calculated mass = 640 for C27H25ClIN3Na05 +. NMR-H1 (DMSO-d6, 300 MHz) d? = 9.98 (s, 1H), 8.61
(s, 1H), 4.81 (d, J = 11.8 Hz, 1H) ppm (characteristic resonances). Example 112 (2S, 3S) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4- [4 - ((R) -2-hydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
obtained by the same method as described
in Example 3, except that (i) 2-chloro-4-iodo-aniline is used in place of 4-bromo-2-chloroaniline in step 1 and (ii) (R) -ter acid -butoxycarbonylamino- [4- ((R) -2-hydroxy-propoxy) -phenyl] -acetic acid in place of (R) -tert-butoxy-carbonylamino- [4- (2-tert-butoxy-ethoxy) -phenyl acid ] -acetic in step 2. The (R) -ter-butoxycarbonylamino- [4- ((R) -2-hydroxy-propoxy) -phenyl] -acetic acid is obtained in the manner described in example 48, except that it is used (R) -2-methyl-oxirane in place of 2- (2-bromo-ethoxy) -tetrahydropyran. HR-HR, observed mass (M + H +) = 648.0755; calculated mass = 648.0757 for the C28H28C1IN305 +. Example 113 (2S, 3S) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
obtained by the same method as described in Example 3, except that (i) 2-chloro-4-iodo-aniline is used in place of 4-bromo-2-chloroaniline in step 1 and ( ii) (R) -tert-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid in place of (R) -tert-butoxycarbonylamino- [4- (2-tert-butoxy-ethoxy)] ) -phenyl] -acetic in step 2. The (R) -ter-butoxycarbonylamino- [4-] acid is obtained
(2-methoxy-ethoxy) -phenyl] -acetic acid in the manner described in Example 80. HR-HR, observed mass (M + H +) = 648.0746; calculated mass = 648.0757 for the C28H28C I I N3O5"". Example 114 (2S, 3S) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4- [4 - ((R) -2,3-dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
It is obtained by the same method as described in Example 110, except that (i) (R) -tert-butoxycarbonylamino- [4 - ((S) -2,2-dimethyl- [1,3]) is used. dioxolan-4-ylmethoxy) -phenyl] -acetic acid (obtained as described below) in place of (R) -tert-butoxycarbonylamino- acid. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic in step 4, (ii) temporarily protects (2S, 3S) -2-. { (R) -2-amino-2- [4- ((R) -2,3-dihydroxy-propoxy) -phenyl] -acetylamino} -N- (2-chloro-4-iodo-phenyl) -3-phenyl-butyramide in the form of (2S, 3S) -2-. { (R) -2-amino-2- [4- ((S) -2, 3-bis-trimethylsilanyloxy-propoxy) -phenyl] -acetylamino} -N- (2-chloro-4-iodo-phenyl) -3-phenyl-butyramide (in the manner described below) before carrying out step 6 and (iii) an acid-catalyzed hydrolysis of the (2S) is carried out , 3S) -2-. { (R) -4- [4- ((S) -2, 3-bis-
trimethylsilanyloxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (2-chloro-4-iodo-phenyl) -3-phenyl-butyramide (as indicated below) before purification and isolation of (2S, 3S) -N- (2-eloro- -yodo-phenyl) -2-. { (R) -4- [4- ((R) -2,3-Dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide in step 6. Obtaining (R) -tert-butoxycarbonylamino- [4- ((S) -2, 2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -phenyl acid] -acetic: (1) To a solution of (S) -2,2-dimethyl-l, 3-dioxolane-4-methanol (5.22 g, 39.5 rotaols) in dichloromethane (60 ml) is added at 0 ° C in dry argon atmosphere triethylamine (11 ml, 79 mmol) and 2,5-dichlorosulfonyl chloride (10.18 g, 41.5 mmol), the mixture is kept under stirring and left to warm slowly at room temperature overnight. The reaction mixture is diluted with dichloromethane and washed with water. The aqueous phase is separated and washed once with dichloromethane. The combined organic layers are washed with a saturated aqueous solution of sodium hydrogen carbonate (one time), brine (one time), dried over sodium sulfate, filtered and the vacuum concentrated, obtaining an oily residue. The residue is purified by chromatography through silica gel, eluting with a gradient of ethyl acetate of 0 to 40% v / v in hexanes, obtaining 2, 5-dichloro-benzenesulfonate of (R) -2, 2- dimethyl- [1, 3] dioxolan-4-ylmethyl as a solid
colorless (11.06 g, 82%). (2) To a stirred solution of (R) -ter-butoxycarbonylamino- (4-hydroxy-phenyl) -acetic acid (1.4 g, 5.24 mmol) in dry N, N-dimethylformamide (25 ml) is added at 0 °. C in a dry argon atmosphere, sodium hydride (60% suspension in mineral oil) (290 mg, 0.12 mmol) and the mixture is stirred at 0 ° C for 15 minutes. The (R) -2,2-dimethyl- [1, 3] dioxolan-4-ylmethyl (2.14 mmol, 6.29 mmol) 2,5-dichloro-benzenesulfonate is added to the reaction mixture, forming a yellow solution, which it is stirred at room temperature for 5 minutes, then it is heated at 100 ° C for 10 minutes. The reaction mixture, which already contains a coarse precipitate, is cooled to room temperature, diluted with ethyl acetate, cooled to 0 ° C and treated with an equal volume of water. The stirred mixture is acidified to pH ¾ 4 with 1 M aqueous hydrochloric acid. The organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic layers are washed with water (three times), dried over sodium sulfate, filtered through a thin layer of silica gel and the vacuum concentrated to give the (R) -tert-butoxycarbonylamino- [4] acid. - ((S) -2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -phenyl] -acetic acid in the form of pale yellow solid foam, having a purity suitable for later use in step 4 without further purification (1.96 g, 96%).
Obtaining the (2S, 3S) -2-. { (R) -2-amino-2- [4 - ((S) -2, 3-bis-trimethylsilanyloxy-propoxy) -phenyl] -acetylamino} -N- (2-chloro-4-iodo-phenyl) -3-phenyl-butyramide: To a solution of (2S, 3S) -2-. { (R) -2-amino-2- [4- ((R) -2,3-dihydroxy-propoxy) -phenyl] -acetylamino} -N- (2-chloro-4-iodo-phenyl) -3-phenyl-butyramide (330 mg, 0.44 mmol) in dry and degassed tetrahydrofuran (5 ml) is added triethylamine (277 μ ?, 1.98 mmol) and Chlorotrimethylsilane (230 μ ?, 1.76 mmol) and the mixture is stirred at room temperature for 30 minutes. The resulting suspension is diluted with ethyl acetate (50 ml) and washed with brine (2 x 50 ml). The brine phases are combined, extracted again with ethyl acetate (2 x 50 ml), the organic phases are combined, dried over sodium sulfate, filtered and the vacuum concentrated, obtaining (2S, 3S) - 2- . { (R) -2-amino-2- [4- ((S) -2, 3-bis-trimethylsilanyloxy-propoxy) -phenyl] -acetylamino} -N- (2-chloro-4-iodo-phenyl) -3-phenyl-butyramide crude, having a purity suitable for use in the subsequent step 6 without further purification (330 mg, 96%). Hydrolysis of (2S, 3S) -2-. { (R) -4- [4- ((S) -2, 3-bis-trimethylsilanyloxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (2-chloro-4-iodo-phenyl) -3-phenyl-butyramide: After the delation of (2S, 3S) -2-. { (R) -2-amino-2- [4- ((S) -2, 3-bis-trimethylsilanyloxy-propoxy) -phenyl] -acetylamino} -N- (2-chloro-4-iodo-phenyl) -3-phenyl-butyramide
applying a method similar to that described in example 6, (2S, 3S) -2- is dissolved. { (R) -4- [4- ((S) -2, 3-bis-trimethylsilanyloxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (2-chloro-4-iodo-f-enyl) -3-f in i-1-butyamy crude in ethyl acetate (50 ml) and mix vigorously at room temperature with a 1: 1 mixture. v / v aqueous lM hydrochloric acid / brine for 15 minutes to remove the trimethylsilyl protecting groups. The phases are separated and the aqueous phase is extracted with ethyl acetate (2 x 50 ml). The ethyl acetate phases are combined, dried over sodium sulfate, filtered and the vacuum concentrated before the final purification is carried out by chromatography on silica gel, eluting with a gradient that progresses in steps of 1% v / v. between 100% dichloromethane and 3% methanol in dichloromethane. After concentrating the vacuum the fractions containing product dissolve the vitreous-like residue in dichloromethane (0.5 ml), dilute with diethyl ether (2 ml) and add hexanes (15 ml) to precipitate (2S, 3). S) -N- (2 - the gold-4-iodo-phenyl) -2-. { (R) -4- [4 - ((R) -2,3-dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide which is obtained as a colorless solid after filtering and drying the vacuum (72 mg, 25%).
HR-HR, observed mass = 664.0703; calculated mass = 664.0706 for the C28H28 1IN306 +. Example 115 (2S, 3S) -N- (2-chloro-4-iodo-phenyl) -2-. { (S) -4- [4 - ((R) -2,3-dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
The filtered liquid is enriched with the final purification step of obtaining (2S, 3S) -N- (2-chloro-iodo-phenyl) -2-. { (R) -4- [4- ((R) -2,3-Dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} 3-phenyl-butyramide (obtained in the manner described in Example 114) in (2S, 3S) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4- [4 - ((R) -2,3-dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide. The diastereomers are separated by supercritical liquid chromatography, using a Daicel OD column, eluting with 45% v / v acetonitrile in a 1: 1 mixture of ethanol in carbon dioxide. HR-HR, observed mass (M + H +) = 664.0706; calculated mass = 664.0706 for the C28H28C1IN306 +. Example 116 (2S, 3S) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4- [4 - ((S) -
2, 3-dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
It is obtained by the same method as described in example 114, except that (R) -tert-butoxycarbonylamino- [4- ((R) -2,2-dimethyl- [1, 3] dioxolan- 4-ylmethoxy) -phenyl] -acetic acid in place of (R) -tert-butoxycarbonylamino- [4 - ((S) -2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -phenyl] - acetic acid in step 4. The (R) -tert-butoxycarbonylamino- [4- ((R) -2,2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -phenyl] -acetic acid is obtained by the same method that has been described for the preparation of (R) -tert-butoxycarbonylamino- [4- ((S) -2, 2-dimethyl- [1, 3] di oxo 1 an - 4 - i lme t ox i ) - f in i 1] -a cé ti co in example 114, except that (R) -2,2-dime ti 1 - 1, 3 -di oxo 1 ano - 4 -me ta no 1 is used in Place of (S) -2,2-dimethyl-1,3-dioxolane-4-methanol. HR-HR, observed mass (M + H +) = 664.0710; calculated mass = 664.0706 for the C28H28C1 IN306 +. Example 117 (2S, 3S) -2- [(R) -4- (4- { [Bis- (2-hydroxy-ethyl) -carbamoyl] -methoxy.} - phenyl) -2,5-dioxo -imidazolidin-1-yl] -N- (2-
chloro-4-iodo-phenyl) -3-phenyl-butyramide
It is obtained by the same method as described in Example 109, except that (R) - [4- (2- { Bis- [2- (tert-butyl-dimethyl-silanyloxy) -ethyl ester is used. ] -amino.}. -acetoxy) -phenyl] -ter-butoxycarbonylamino-acetic acid in place of (R) -tert-butoxycarbonylamino- (4-cyclopropylmethoxy-phenyl) -acetic acid. The acid (R) - [4- (2-. {Bis- [2- (tert-butyl-dimethyl-silanyloxy) -ethyl] -amino}. -acetoxy) -phenyl] -ter-butoxycarbonylamino- is obtained. acetic acid as described in Example 48, except that N, N-bis- [2- (tert-butyl-dimethyl-silanyloxy) -ethyl] -2-chloroacetamide is used instead of 2- (2-bromine) -ethoxy) -tetrahydropyran. HR-HR, observed mass (M + Na +) = 757.0898; calculated mass = 757.0896 for C3iH32ClIN4Na07 +. Example 118 (S) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-thiazol-4-yl-propionamide
obtained by the same method as described
in Example 3, except that (i) 2-chloro-4-iodo-aniline is used in place of 4-bromo-2-chloroaniline in step 1 and (ii) (S) -2 acid -ter-butoxycarbonylamino-3-thiazol-4-yl-propionic acid in place of (2S, 3S) -2-tert-butoxycarbonyl-amino-3-phenyl-butyric acid in step 1. HR-HR, observed mass (M + H +) = 626,994; calculated mass = 626.9961 for the C23H2iClI 405S +. Example 119 (S) -N- (2-Chloro-4-iodo-phenyl) -2- [(R) -4- (4-cyclopropylmethoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl] - 3-methyl-butyramide
obtained by the same method as described in Example 3, except that (i) 2-chloro-4-iodo-aniline is used in place of 4-bromo-2-chloroaniline in step 1, ( ii) (S) -2-tert-butoxycarbonylamino-3-methyl-butyric acid in place of (S, S) -2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 1 and (iii) the acid (R) -ter-butoxycarbonylamino- (4-cyclopropylmethoxy-phenyl) -acetic acid (obtained in the manner described in example 109) in place of (R) -tert-butoxycarbonylamino- [4- (2-ter -butoxy-ethoxy) -phenyl] -acetic in step 2. HR-HR, observed mass (M + H +) = 582.0655; dough
calculated = 582.0651 for the C24H26 1IN304 +. Example 120 (S) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-methyl-butyramide
It is obtained by the same method as described in Example 119, except that (R) -tert-butoxycarbonylamino- acid is used. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic instead of (R) -tert-butoxycarbonylamino- (4-cyclopropylmethoxy-phenyl) -acetic acid. The (R) -ter-butoxycarbonylamino- acid is obtained. { - [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic in the manner described in Example 48. HR-HR, observed mass (M + H +) = 572.0433; calculated mass = 572.0444 for the C22H24C1IN305 +. Example 121 (S) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-methyl-butyramide
obtained by the same method as described
in Example 119, except that (R) -tert-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid is used in place of (R) -tert-butoxycarbonylamino- (4-cyclopropylmethoxy) acid -phenyl) -acetic. The (R) -ter-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid is obtained in the manner described in Example 80. HR-HR, observed mass (M + H +) = 586.0586; calculated mass = 586.0600 for the C23H26C1IN305 +. Example 122 (S) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4- [4 - ((R) -2,3-Dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-methyl-butyramide
It is obtained by the same method as described in Example 3, except that (i) 2-chloro-4-iodoaniline is used in place of 4-bromo-2-chloroaniline in step 1, (ii) (S) -2-tert-butoxycarbonylamino-3-methyl-butyric acid in place of (2S, 3S) -2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 1 and (iii) (R) acid -ter-butoxycarbonylamino- [4- ((S) -2,2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -phenyl] -acetic acid in place of (R) -tert-butoxycarbonylamino- [4-] (2-tert-butoxy-ethoxy) -phenyl] -acetic acid in step 2. The acid (R) -ter
butoxycarbonylamino- [4- ((S) -2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -phenyl] -acetic acid and used as described in Example 114. HR-HR, observed mass ( M + Na +) = 624.0367; calculated mass = 624.0369 for C23H25ClIN3Na06 +. Example 123 (S) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4 - [4 - ((S) -2,3-dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-methyl-butyramide
It is obtained by the same method as described in Example 3, except that (i) 2-chloro-4-iodoaniline is used in place of 4-bromo-2-chloroaniline in step 1, (ii) (S) -2-tert-butoxycarbonylamino-3-methyl-butyric acid in place of (2S, 3S) -2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 1 and (iii) the acid (R) -ter-butoxycarbonylamino- [4- ((R) -2,2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -phenyl] -acetic acid in place of (R) -tert-butoxycarbonylamino- [4-] (2-tert-butoxy-ethoxy) -phenyl] -acetic acid in step 2. The (R) -tert-butoxycarbonylamino- [4- ((R) -2, 2-dimethyl- [1,3]] acid is obtained dioxolan-4-ylmethoxy) -phenyl] -acetic acid and is used in the manner described in Example 116.
HR-HR, observed mass (M + H +) = 602.0541; calculated mass = 602.0550 for the C23H26C1IN306 +. Example 124 (S) -N- (2-chloro-4-iodo-phenyl) -2- [(R) -4- (2,3-dihydro-benzo [1.4] dioxin-6-yl) -2,5 -dioxo-imidazolidin-l-yl] -3-methyl-butyramide
It is obtained by the same method as described in Example 119, except that (R) -tert-butoxycarbonylamino- (2,3-dihydro-benzo [1.4] dioxin-6-yl) -acetic acid is used instead of (R) -tert-butoxycarbonylamino- (4-cyclopropylmethoxy-phenyl) -acetic acid. The (R) -tert-butoxycarbonylamino- (2,3-dihydro-benzo [1.4] dioxin-6-yl) -acetic acid is obtained in the manner described in Example 29. HR-HR, observed mass (M + H +) = 570.0277; calculated mass = 570.0287 for the C22H22C1I 305+. Example 125 (S) -N- (2-chloro-4-iodo-phenyl) -2- [(R) -4- (4-dimethylcarbamoylmethoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl] - 3-methyl-butyramide
It is obtained by the same method as described in Example 119, except that (R) -tert-butoxycarbonylamino- (-dimethylcarbamoylmethoxy-phenyl) -acetic acid is used in place of (R) -tert-butoxycarbonylamino- ( 4-cyclopropylmethoxy-phenyl) -acetic. The (R) -tert-butoxycarbonylamino- (4-dimethylcarbamoylmethoxy-phenyl) -acetic acid is obtained by the same method that has been applied for the preparation of the (R) -ter-butyloxycarbonylamino-4-methoxyphenylglycine in Example 1, except that 2-chloro-N, N-dimethyl acetamide is used in place of iodomethane. HR-HR, observed mass (M + H +) = 613.0703; calculated mass = 613.0709 for the C24H27C1IN405 +. Example 126 (S) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -2,5-dioxo-4- [- (2-oxo-2-pyrrolidin-1-yl-ethoxy) -phenyl] -imidazolidin-1-yl} -3-methyl-butyramide
Obtained by the same method as described in Example 119, except that (R) -tert-butoxycarbonylamino- [4- (2-oxo-2-pyrrolidin-1-yl-ethoxy) -phenyl acid is used] -acetic instead of (R) -tert-butoxycarbonylamino- (4-cyclopropylmethoxy-phenyl) -acetic acid. The (R) -ter-butoxycarbonylamino- [4- (2-oxo-2-) acid is obtained
pyrrolidin-1-yl-ethoxy) -phenyl] -acetic acid by the same method that has been applied for the preparation of the (R) -ter-butyloxycarbonylamino-4-methoxy-trifluorine in Example 1, except that 2- chloro-l-pyrrolidin-1-yl-ethanone instead of iodomethane. E -HR, observed mass (M + H +) = 639.0864; calculated mass = 639.0866 for 026? 29? 1 ?? 405+. Example 127 (S) -2- [(R) -4- (4- { [Bis- (2-hydroxy-ethyl) -carbamoyl] -methoxy.} - phenyl) -2,5-dioxo-imidazolidin -l-il] -N- (2-chloro-4-iodo-phenyl) -3-methyl-butyramide
It is obtained by the same method as described in Example 119, except that the acid (R) - [4- (2-. {Bis- [2- (tert-butyl-dimethyl-silanyloxy) -ethyl) is used. ] -amino.}. -acetoxy) -phenyl] -ter-butoxycarbonylamino-acetic acid in place of (R) -tert-butoxycarbonylairu.no- (4-cyclopropylmethoxy-phenyl) -acetic acid. The acid (R) - [4- (2-. {Bis- [2- (tert-butyl-dimethyl-silanyloxy) -ethyl] -amino}. -acetoxy) -phenyl] -ter-butoxycarbonylamino- is obtained. acetic acid in the manner described in Example 62. HR-HR, observed mass (M + Na +) = 695.0739; calculated mass = 695.0740 for the C26H3oClIN4 a07 +.
Example 128 (2S, 3S) -2- (2-chloro-4-iodo-phenyl) -amide. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-methyl-pentanoic
It is obtained by the same method as described in Example 3, except that 2-chloro-4-iodoaniline is used instead of 4-bromo-2-chloroaniline and (2S, 3S) -2-ter -butoxycarbonylamino-3-methyl-pentanoic acid in place of (2S, 3S) -2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 1. HR-HR, observed mass (M + H +) = 586.0603; calculated mass = 586.0600 for the C23H26C1I 305+. Example 129 (2S, 3S) -2- [(R) -4- (2,3-dihydro-benzo [1.4] dioxin-6-yl) - (2-chloro-4-iodo-phenyl) -amide - 2,5-dioxo-imidazolidin-1-yl] -3-methyl-pentanoic acid
It is obtained by the same method as described in Example 128, except that (R) -tert-butoxycarbonylamino- (2,3-dihydro-benzo [1.4] dioxin-6-yl) - acid is used.
acetic acid in place of (R) -tert-butoxycarbonylamino- [4- (2-tert-butoxy-ethoxy) -phenyl] -acetic acid. The (R) -tert-butoxycarbonylamino- (2,3-dihydro-benzo [1.4] dioxin-6-yl) -acetic acid is obtained in the manner described in Example 29. HR-HR, observed mass (M + H +) = 584.0438; calculated mass = 584.0444 for the C23H24C1IN305 +. Example 130 (2S, 3R) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-methoxy-butyramide
It is obtained by the same method as described in Example 72, except that 2-fluoro-4-iodoaniline is used in place of 2-chloro-4-iodoaniline and (2S, 3R) -2-ter -butoxycarbonylamino-3-methoxy-butyric acid in place of (S) -2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionic acid in step 1. E-LC, observed mass (M + H +) = 588; calculated mass = 588 for 022? 24? 1 ?? 306+. Example 131 (2S, 3S) -2- (2-chloro-4-iodo-phenyl) -amide. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-
il} -3-methyl-pentanoic
It is obtained by the same method as described in Example 3, except that (i) 2-chloro-4-iodoaniline is used in place of 4-bromo-2-chloroaniline in step 1, (ii) (2S, 3S) -2-tert-butoxycarbonylamino-3-methyl-pentanoic acid in place of (2S, 3S) -2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 1 and (iii) the acid ( R) -ter-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid in place of (R) -tert-butoxycarbonylamino- [4- (2-tert-butoxy-ethoxy) -phenyl] - acetic in step 2. The (R) -ter-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid is obtained in the manner described in Example 80. HR-HR, observed mass (M + H +) = 600.0758; calculated mass = 600.0757 for the C24H28C1IN305 +. Example 132 (2S, 3R) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4- [4- ((R) -2,3-Dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-methoxy-butyramide
It is obtained by the same method that has been described
in Example 114, except that (i) (2S, 3R) -2-tert-butoxycarbonylamino-3-methoxy-butyric acid is used in place of (2S, 3S) -2-tert-butoxycarbonylamino-3-phenyl acid -butyric. LC-MS, observed mass (M + H +) = 618; calculated mass = 618 for the C23H26C1IN307 +. Example 133 (2S, 3S) -N- (4-iodo-2-methyl-phenyl) -2 - [(R) -4- (4-methoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl ] -3-phenyl-butyramide
It is obtained by the same method as described in Example 1, except that 4-iodo-2-methyl-aniline is used instead of 4-bromoaniline in step 2. observed mass (M + H) = 584.1042; calculated mass = 584.1041 for the C27H27IN304.
Example 134 (2S, 3S) -2-. { (R) -4- [4- (2-Hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (4-iodo-2-methyl-phenyl) -3-phenyl-
It is obtained by the same method that has been described
in Example 48, except that 4-iodo-2-methylaniline is used in place of 2-fluoro-4-iodoaniline in step 2. HR-HR, observed mass (M + H +) = 614.1135; calculated mass = 614.1147 for the C28H29lN305 +. Example 135 (2S, 3S) -N- (4-iodo-2-methyl-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
It is obtained by the same method as described in example 48, except that (i) 4-iodo-2-methylaniline is used in place of 2-fluoro-4-iodoaniline in step 2 and (ii) (R) -ter-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid in place of (R) -tert-butoxycarbonylamino- acid. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic The (R) -tert-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid is obtained in the manner described in Example 80. HR-HR, observed mass (M + H +) = 628.1293; calculated mass = 628.1303 for the C29H3iIN305 +.
Example 136 (2S, 3S) -N- (4-iodo-2-methyl-phenyl) -2- ((R) -4- { 4- [2- (2-methoxy-ethoxy) -ethoxy] - phenyl.} -2, 5-dioxo-imidazolidin-1-yl) -3-phenyl-butyramide
It is obtained by the same method as described in example 48, except that (i) 4-iodo-2-methylaniline is used in place of 2-fluoro-4-iodoaniline in step 2 and (ii) (R) -tert-butoxycarbonylamino- [4- ( 2- (2-methoxy-ethoxy.) -ethoxy) -fen i 1] - a cé ti co in place of the acid (R) -tert-butoxycarbonylamino-. {- - [2- (tetrahydro-pyran-2- iloxy) -et ox i] - f in i 1.) - a cé ti co. (R) -ter-butoxycarbonylamino- [4- (2- (2-methoxy-ethoxy) -ethoxy) - f-enyl] -acetic as described in example 48, except that 1 - (2 -brorno-et oxy) -2-methoxy-ethane is used in place of 2 - (2-boron-ethoxy) ) -tetrahydropyran HR-HR, observed mass (M + H +) = 672.1556; calculated mass = 672.1565 for the C3iH35IN306 +. Example 137 (2S, 3S) -N- (4-ethynyl-phenyl) -2- [(R) -4- (4-methoxy-
phenyl) -2,5-dioxo-imidazolidin-1-yl] -3-phenyl-butyramide
It is obtained by the same method as described in example 1, except that (i) 4-ethylaniline is used in place of 4-bromoaniline in step 2, (ii) as condensation reagent, the hydrochloride of (3-dimethylamino-propyl) -ethyl-carbodiimide in place of O-benzotriazole-1-yl-N, N, N ', N' -tetramethyluronium hexafluorophosphate in step 4 and (iii) formic acid is used to removing the tert-butyloxycarbonyl protecting group in steps 3 and 5 in the manner described below. Obtaining (2S, 3S) -2-amino-N- (4-ethynyl-phenyl) -3-phenyl-butyramide: A suspension of [(1S, 2S) -1- is heated at 50 ° C for 1 hour. (4-ethynyl-phenylcarbamoyl) -2-phenyl-propyl] -carbamic acid tert -butyl ester (300 mg, 0.79 mmole) in formic acid (5 ml). The reaction mixture is concentrated in vacuo, made basic with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate (2 x 20 mL). The combined organic extracts are washed with water, brine, dried with sodium sulfate, filtered and
Concentrate the vacuum to obtain (2S, 3S) -2-amino-N- (4-ethynyl-phenyl) -3-phenyl-butyramide as a foam (214 mg, 92%). HR-HR, observed mass (M + Na +) = 490.1731; calculated mass = 490.1737 for the C28H25N3Na04 +. Example 138 (S) -N- (4-ethynyl-2-fluoro-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-propionamide
It is obtained by the same method as described in example 140, except that (2S) -2-tert-butoxycarbonylamino-3-phenylpropanoic acid is used in place of (2S, 3S) -2-tertiary acid. butoxycarbonylamino-3-phenyl-butyric acid and (R) -tert-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid in place of (R) -tert-butoxycarbonylamino- acid. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic The (R) -ter-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid is obtained in the manner described in Example 80. HR-HR, observed mass (M + H +) - 516.1932; calculated mass = 516.1929 for the C29H27 305+.
Example 139 (2S, 3S) -2- ((R) -2,5-dioxo-4-phenyl-imidazolidin-1-yl) -N- (4-ethynyl-2-fluoro-phenyl) -3-phenyl- butyramide
It is obtained by the same method as described in example 140, except that (R) -ter-butoxycarbonylamino-phenyl-acetic acid is used in place of (R) -tert-butoxycarbonylamino- acid. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic. HR-HR, observed mass (M + Na +) = 478.1529; calculated mass = 478.1537 for C27H22FN3Na03 +. Example 140 (3S) -N- (-etinyl-2-fluoro-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide, isomer 1
It gets
it has been described in example 48, except that (i) after step 3 and before step 4 the (2S, 3S) -2-amino-N- (2-fluoro-4-iodo-phenyl) -3 is converted -phenyl-butyramide in (2S, 3S) -2-amino-N- (2-
fluoro-4-trimethylsilanylethynyl-phenyl) -3-phenyl-butyramide under the conditions described below and (ii) after the initial purification of step 6 the product is subjected to a chiral HPLC separation in the manner described above. continuation. The trimethylsilyl group is introduced in step 3 and is subsequently removed, in step 5 of the synthesis, at the same time that the tert-butyloxycarbonyl protecting group is removed. Obtaining (2S, 3S) -2-amino-N- (4-ethynyl-2-fluoro-phenyl) -3-phenyl-butyramide: A solution with argon is degassed with a solution of (2S, 3S) -2 -amino-N- (2-fluoro-4-iodo-phenyl) -3-phenyl-butyramide (1.00 g, 2.51 mmole) in triethylamine (1.5 ml, 10.8 mmol), is added bis-dichlorotriphenylphosphine palladium (II ) (20.3 mg, 0.05 mmol) and then copper iodide (9.8 mg, 0.05 mmol) and trimethylsilylacetylene (277 mg, 2.77 mmol) and the mixture is stirred at room temperature and under an argon atmosphere for 3 hours. More triethylamine (1.5 ml, 10.8 mmol) is added to obtain a stirrable mixture and stirring is continued for a further 20 hours. The reaction mixture is diluted with diethyl ether and a small amount of Celite is added before filtering through Celite. The Celite is rinsed with diethyl ether (4 x 20 mL), the organic filtered liquids are combined and the vacuum concentrated. The resulting green oil is dissolved
in a small amount of diethyl ether and diluted with hexanes (10 ml) to induce crystallization. The product is isolated by filtration, washed with hexanes and the vacuum dried, yielding (2S, 3S) -2-amino-N- (2-fluoro-4-trimethylsilanylethynyl-phenyl) -3-phenyl-butyramide in the form of solid gray (610 mg, 66%). A second product collection is achieved by repeating the process with the mother liquors of the first crystallization (168 mg, 18%). HR-HR, observed mass = 369.1793; calculated mass = 369.1793 for the C2iH26FN2OSi +. Cleavage by chiral HPLC: A sample of (3S) -N- (4-ethynyl-2-fluoro-phenyl) -2- is purified. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide (22 mg, 0.43 mmol) by chiral HPLC using a 2.0 cm x 25 cm Daicel OD column and eluting with a 1: 1 v / v mixture of hexanes and absolute ethanol with a flow rate of 5 ml per minute, using UV detection at 260 nm to monitor the presence of the product in the eluent. The eluted product is collected in the first place and the vacuum is concentrated, obtaining (3S) -N- (4-ethynyl-2-fluoro-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide, isomer 1, as a white solid (6.1 mg, 28%). HR-HR, observed mass (M + H +) = 516.1926; calculated mass = 516.1929 for the C29H27F 305+.
Example 141 (3S) -N- (4-etinyl-2-fluoro-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide, isomer 2
It is obtained by the same method as described in example 140, except that the product eluted in the second step is collected in the purification step by chiral HPLC and the vacuum is concentrated, obtaining the (3S) -N- (4 -etinyl-2-fluoro-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide, isomer 2, as a colorless solid (7 mg, 32%). HR-HR, observed mass (+ H +) = 516.1931; calculated mass = 516.1929 for the C29ti21FN305 +. Example 142 (3S) -N- (4-etinyl-2-fluoro-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide, isomer 1
It is obtained by the same method as described in example 140, except that the acid (R) -ter
butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid in place of (R) -tert-butoxycarbonylamino- acid. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic The (R) -tert-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid is obtained in the manner described in Example 80. The purification of the final product is carried out by chromatography through silica gel. , eluting with a gradient of ethyl acetate from 0 to 30% v / v in hexanes. The eluted product is collected first and the vacuum concentrated, then precipitated with ethyl ether (100 ml) containing a small amount of dichloromethane with hexanes (10 ml). The precipitated solid is collected by filtration and dried, yielding (3S) -N- (4-ethynyl-2-fluoro-phenyl) -2-. { (R) -4- [4 - (2-Methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide, isomer 1, as a colorless solid (19%). HRMS, observed mass (M + Na +) = 552.1905; calculated mass = 552.1905 for the C3oH28FN3Na05 +. Example 143 (3S) -N- (-etinyl-2-fluoro-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide, isomer 2
It is obtained by the same method that has been described
in Example 142, except that the product eluted in the second place is collected in the chromatographic purification of the final reaction product. The eluted product is collected in second place and the vacuum is concentrated, then it is precipitated with ethyl ether (1 ml) containing a small amount of dichloromethane with hexanes (10 ml). The precipitated solid is collected by filtration and dried, yielding (3S) -N- (4-ethynyl-2-fluoro-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide, isomer 2, as a colorless solid (10%). HRMS, observed mass (M + Na +) = 552.1906; calculated mass = 552.1905 for C30H28FN3NaO5 +. Example 144 (S) -N- (4-ethynyl-2-fluoro-phenyl) -2- ((R) -4- { 4- [2- (2-methoxy-ethoxy) -ethoxy] -phenyl} -2, 5-dioxo-imidazolidin-1-yl) -3-phenyl-butyramide
It is obtained by the same method as described in Example 140, except that (R) -tert-butoxy-carbonylamino- acid is used. { 4- [2- (2-methoxy-ethoxy) -ethoxy] -phenyl} -acetic instead of (R) -ter-butoxycarbonylamino- acid. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic. The (R) -ter-butoxycarbonylamino- acid is obtained. { 4- [2- (2-methoxy-ethoxy) -ethoxy] -phenyl} -acetic as described in
Example 48, except that 1- (2-bromo-ethoxy) -2-methoxy-ethane is used in place of 2- (2-bromo-ethoxy) -tetrahydropyran. HR-HR, observed mass (M + Na +) = 596.2168; caated mass = 596.2167 for C32H32FN3Na06 +. Example 145 (2S, 3S) -2-. { (R) -2,5-dioxo-4- [4- (2-oxo-2-pyrrolidin-1-yl-ethoxy) -phenyl] -imidazolidin-1-yl} -N- (4-ethynyl-2-fluoro-phenyl) -3-phenyl-butyramide
Obtained by the same method as described in Example 140, except that (R) -tert-butoxycarbonylamino- [4- (2-oxo-2-pyrrolidin-1-yl-ethoxy) -phenyl acid is used] -acetic instead of (R) -ter-butoxycarbonylamino- acid. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic The (R) -ter-butoxycarbonylamino- [4- (2-oxo-2-pyrrolidin-1-yl-ethoxy) -phenyl] -acetic acid is obtained in the manner described in Example 126. HR-HR, observed mass ( M + H +) = 583.2352; caated mass = 583.2351 for the C33H32FN405 +. Example 146 (S) -N- (2-chloro-4-ethynyl-phenyl) -2-. { 4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-
propionamide, isomer 1
It is obtained in the manner described below from (S) -2-amino- (2-chloro-4-iodo-phenyl) -3-phenyl-propionamide. The (S) -2-amino- (2-chloro-4-iodo-phenyl) -3-phenyl-propionamide is obtained by the same method as described in step 1 of example 3, except that the -chloro-4-iodo-aniline instead of 4-bromo-2-chloroaniline and (S) -2-tert-butoxycarbonylamino-3-phenyl-propionic acid instead of (S, S) -2 -ter-butoxycarbonylamino-3-phenyl-butyric acid. Step 2: The (S) -2-amino- (2-chloro-4-iodo-phenyl) -3-phenyl-propionamide (980 mg, 2.44 min), the bis-dichlorotriphenylphosphine-palladium ( 19.8 mg, 0.0489 mmol) and copper iodide (9.5 mg, 0.049 mmol). To this mixture is added trimethylsilylacetylene (269.7 mg, 2.69 mmoles) in dry triethylamine (1.46 ml). After 30 minutes, dry dichloromethane (1 ml) was added. After 3 hours more bis-dichlorotriphenylphosphine palladium (40 mg, 0.099 mmol) and copper iodide (20 mg, 0.099 mmol) are added. After 1 hour the reaction mixture is diluted with a 1: 1 v / v mixture of diethyl ether / dichloromethane and passed through a pad of silica gel and the gel is eluted.
silica with a 2: 3 v / v mixture of diethyl ether / dichloromethane. The eluent is concentrated in vacuo and the crude residue is purified by chromatography through silica gel, eluting with a gradient of diethyl ether of 5 to 30% v / v in hexanes. The fractions containing product were combined and concentrated, yielding (S) -2-amino-N- (2-chloro-4-trimethylsilanylethynyl-phenyl) -3-phenyl-propionamide as a white solid (820 mg, yield). = 90%). Step 3: (S) -2-amino-N- (2-chloro-4-trimethylsilanylethynyl-phenyl) -3-phenyl-propionamide is condensed with the (R) -tert-butoxycarbonylamino- acid. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic (obtained in the manner described in example 48) by applying the same method described in step 4 of example 1, thereby obtaining ((S) - [(S) -1- (2-chloro-4- trimethylsilanylethynyl-phenylcarbamoyl) -2-phenyl-ethyl-carbamoyl] -. {4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl] -methyl) -carbamic acid tert-butyl ester. Step 4: Dissolve ((S) - [(S) -1- (2-chloro-4-trimethylsilanylethynyl-phenylcarbamoyl) -2-phenyl-ethylcarbamoyl] -. {4- [2- (tetrahydro-pyran 2-yloxy) -ethoxy] -phenyl.}. Methyl-tert-butylcarbamate (491 mg, 0.656 mmol) in formic acid (7.1 ml) and heated at 40 ° C for 30 minutes. The temperature is increased to between 50 and 55 ° C for 3 hours. The reaction mixture is concentrated in vacuo,
Collect the residue in dichloromethane, carefully neutralize with a saturated aqueous solution of sodium bicarbonate and then extract with dichloromethane. The combined organic extracts are dried with sodium sulfate, the vacuum is concentrated and the crude product is purified by chromatography through silica gel, eluting with a gradient of methanol of 0.5 to 5% v / v in dichloromethane. The fractions containing product are concentrated, obtaining a white residue which is triturated in a 1: 1 mixture of ether / hexanes (20 ml), filtered and dried, obtaining the (S) -2-. { (S) -2-amino-2- [4 - (2-hydroxy-ethoxy) -phenyl] -acetylamino} -N- [2-Chloro-4- (3-oxo-prop-1-ynyl) -phenyl] -3-phenyl-propionamide (240 mg, 70%). Step 5: Diphosgene cyclization is carried out applying the same method described in step 6 of example 1, except that after isolation of the material (250 mg), it is dissolved in methanol (11.3 ml), cooled in a ice bath and treated with sodium borohydride (123 mg, 3.28 mmol). After 15 minutes, the reaction mixture is treated with a 1.5 N aqueous solution of potassium hydrogen sulfate and extracted with ethyl acetate (3? 50 ml). The combined organic extracts are washed with a 1.5 N aqueous solution of potassium acid sulfate (2? 50 ml) and water (2? 50 ml). The organic solution is dried with sodium sulfate, filtered and concentrated, obtaining a mixture of diastereomers in
stupid . Step 6: The crude diastereomer mixture is purified by chromatography using a Daicel OD column and eluting with 50% v / v methanol in 10 mmol of an aqueous solution of ammonium acetate. The elution component is concentrated in a vacuum, dissolved in ethyl acetate (100 ml), the organic solution is washed with an aqueous solution of sodium bicarbonate at 5% w / v (3? 50 ml), the aqueous layers and extracted again with ethyl acetate (2 x 50 ml). The combined organic extracts are dried with sodium sulfate and concentrated, yielding (S) -N- (2-chloro-4-ethynyl-phenyl) -2-. { 4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} 3-phenyl-propionamide, isomer 1 (64 mg, yield = 25.5%). HR-HR, observed mass (M + H +) = 518.1477; calculated mass = 518.1477 for the C28H25C1N305 +. Example 147 (S) -N- (2-chloro-4-ethynyl-phenyl) -2-. { 4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-propionamide, isomer 2
It is obtained by the same procedure described in example 146, except that in step 6 the slower elution component is collected, obtaining after washing and drying the (S) -N- (2-
chloro-4-ethynyl-phenyl) -2-. { 4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} 3-phenyl-propionamide, isomer 2 (42 mg, yield = 18.5%). HR-HR, observed mass (M + H +) = 518.1472; calculated mass = 518.1477 for the C28H25C1N305 +. Example 148 (S) -N- (2-chloro-4-ethynyl-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-propionamide
obtained by the same method as described in example 146 except that (i) in step 3 the (R) -tert-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid is used in Place of (R) -tert-butoxycarbonylamino- acid. { 4 - [2- (Tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic The (R) -tert-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid is obtained in the manner described in Example 80, (ii) no formyl group is present after the treatment with diphosgene in step 5 and therefore treatment with sodium borohydride is no longer necessary and (iii) no diastereomer is detected after step 5 and therefore no separation of diastereomers is required by supercritical fluid chromatography (step 6 of the example
146). HR-HR, observed mass (+ H +) = 532.1634; calculated mass = 532.1634 for the C29H27C1N305 +. Example 149 (2S, 3S) -N- (2-chloro-4-ethynyl-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide)
It is obtained by the same method as described in Example 146, except that (2S, 3S) -2-tert-butoxycarbonylamino-3-phenyl-butyric acid is used in place of (S) -2-ter- butoxycarbonylamino-3-phenyl-propionic acid. HR-HR, observed mass (M + H +) = 532.1637; calculated mass = 532.1634 for the C29H27C1 305+. Example 150 (2S, 3S) -N- (2-chloro-4-ethynyl-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
It is obtained by the same method as described in Example 149, except that (R) -tert-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid is used in place of the acid (R ) -ter-butoxycarbonylamino-. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic The (R) -ter-butoxycarbonylamino- [4 - (2-methoxy-ethoxy) -phenyl] -acetic acid is obtained in the manner described in Example 80. HR-HR, observed mass (M + H +) = 546.1785; calculated mass = 546.1790 for the C30H29CIN3O5"". Example 151 (2S, 3S) -N- (2-chloro-4-ethynyl-phenyl) -2 - ((R) -4- { 4- [2- (2-methoxy-ethoxy) -ethoxy] - phenyl.} -2, 5-dioxo-imidazolidin-1-yl) -3-phenyl-butyramide
It is obtained by the same method as described in example 150, except that (R) -tert-butoxycarbonylamino- acid is used. { 4- [2- (2-methoxy-ethoxy) -ethoxy] -phenyl} -acetic in place of (R) -tert-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid. The (R) -ter-butoxycarbonylamino- acid is obtained. { 4- [2- (2-methoxy-ethoxy) -ethoxy] -phenyl} -acetic in the manner described in example 48, except that 1- (2-bromo-ethoxy) -2-methoxy-ethane is used in place of 2- (2-
bromo-ethoxy) -tetrahydropyran. HR-HR, observed mass (M + H +) = 590,2053; calculated mass = 590,2053 for the C32H33CIN3C. Example 152 (S) -N- (2-chloro-4-ethynyl-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-methyl-butyramide
It is obtained by the same method as that described in Example 150, except that (S) -2-tert-butoxycarbonylamino-3-methyl-butyric acid is used in place of (2S, 3S) -2-ter- butoxycarbonylamino-3-phenyl-butyric acid. HR-HR, observed mass (M + Na +) = 506.1455; calculated mass = 506.1453 for C25H26Cl 3Na05 +. Example 153 (2S, 3S) -2- (2-Chloro-4-ethynyl-phenyl) -amide. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-methyl-pentanoic
It is obtained by the same method as described in Example 150, except that the acid (2S, 3S) -2- is used.
tert-butoxycarbonylamino-3-methyl-pentanoic acid instead of (2S, 3S) -2-tert-butoxycarbonylamino-3-phenyl-butyric acid. HR-HR, observed mass (M + Na +) = 520.1612; calculated mass = 520.1609 for the C26H28 lN3Na05 +. Example 154 (2S, 3S) -N- (-etinyl-2-methyl-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
It is obtained by the same method as described in Example 150, except that 4-iodo-2-methylaniline is used in place of 2-chloro-4-iodomomethylaniline. HR-HR, observed mass (M + Na +) = 548.2154; calculated mass = 548.2156 for C31H31N3Na05 +. Example 155 (2S, 3S) -N- (4-ethynyl-2-methyl-phenyl) -2- ((R) -4- { 4- [2- (2-methoxy-ethoxy) -ethoxy] - phenyl.} -2, 5-dioxo-imidazolidin-1-yl) -3-phenyl-butyramide
It is obtained by the same method as described in Example 151, except that 4-iodo-2-methylaniline is used instead
of 2-chloro-4-yodomethylaniline. HR-HR, observed mass (M + Na +) = 592.2411; calculated mass = 592.2418 for C33H35N3Na06 +. Example 156 (2S, 3S) -N- (4-cyclopropyl-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
It is obtained by the same method as described in Example 48, except that 4-cyclopropyl-aniline is used in place of 2-fluoro-4-iodoaniline. HR-HR, observed mass (M + H +) = 514.2333; calculated mass = 514.2337 for the C3oH32N305 +. HR-HR, observed mass (M + Na +) = 536.2153; calculated mass = 536.2156 for C3oH3iN3Na05 +. Example 157 (S) -N- (4-cyclopropyl-2-fluoro-phenyl) -3- (4-fluoro-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -propionamide
It is obtained by the same method as described in example 160, except that (R) -tert-butoxycarbonylamino- acid is used. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic in place of (R) -tert-butoxycarbonyl-amino- [4- (2-hydroxy-l-hydroxymethyl-ethoxy) -phenyl] -acetic acid. The (R) -ter-butoxycarbonylamino- acid is obtained. { 4- [2- (tetra-hi-dro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic in the manner described in example 48. HR-HR, observed mass (M + H +) = 536.1986; calculated mass = 536.1992 for the C29H28 2N305 +. Example 158 (S) -N- (4-cyclopropyl-2-fluoro-phenyl) -2-. { (R) -4- [4- ((R) -2,3-Dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3- (4-fluoro-phenyl) -propionamide
It is obtained by the same method as described in Example 160, except that (R) -tert-butoxycarbonylamino- [4- ((R) -2,2-dimethyl- [1, 3] dioxolan- 4-ylmethoxy) -phenyl] -acetic acid in place of (R) -tert-butoxycarbonylamino- [4- (2-hydroxy-l-hydroxymethyl-ethoxy) -phenyl] -acetic acid. The (R) -tert-butoxycarbonylamino- [4- ((R) -2, 2-dimethyl- [1,3] dioxolan-4-) acid is obtained
ylmetoxy) -phenyl] -acetic acid and used in the manner described in Example 114. HR-HR, observed mass (+ H +) = 566.2099; calculated mass = 566.2097 for the C3oH3oF2N306 +. Example 159 (S) -N- (4-cyclopropyl-2-fluoro-phenyl) -2-. { (R) -4- [4- ((S) -2,3-dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3- (4-fluoro-phenyl) -propionamide
It is obtained by the same method as that described in example 160, except that (R) -tert-butoxycarbonylamino- [4- ((S) -2,2-dimethyl- [1,3] dioxolan- 4-ylmethoxy) -phenyl] -acetic acid in place of (R) -tert-butoxycarbonylamino- [4- ((R) -2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -phenyl] - acetic The (R) -ter-butoxycarbonylamino- [4- ((S) -2,2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -phenyl] -acetic acid is obtained and used in the manner described in example 116. HR-HR, observed mass (M + Na +) = 588.1912; calculated mass = 588.1916 for C3oH29F2N3Na06 +. Example 160 (S) -N- (4-cyclopropyl-2-fluoro-phenyl) -3- (4-fluoro-
phenyl) -2-. { (R) -4- [4- (2-hydroxy-l-hydroxymethyl-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -propionamide
It is obtained by the same method as described in Example 3, except that (i) (S) -2-tert-butoxycarbonylamino-3- (4-fluoro-phenyl) -propionic acid is used instead of the acid ( 2S, 3S) -2-tert-butoxycarbonylamino-3-phenyl-butyric in step 1, (ii) converts (S) - [1- (2-fluoro-4-iodo-phenylcarbamoyl) -2- (4) -fluoro-phenyl) -ethyl] -carbamate of tert-butyl in the (S) - [1- (4-cyclopropyl-2-fluoro-phenylcarbamoyl) -2- (-fluoro-phenyl) -ethyl] -carbamate ter - butyl after step 2 and before step 3 (applying the conditions described below), (iii) (R) -tert-butoxycarbonylamino- [4- (2-hydroxy-l-hydroxymethyl-ethoxy) is used ) -phenyl] -acetic (obtained as described below) in place of (R) -tert-butoxycarbonylamino- acid. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic in step 4 and (iv) the diol functional group of (S) -2- is temporarily protected. { 2-amino-2- [4- (2-hydroxy-l-hydroxymethyl-ethoxy) -phenyl] -acetylamino} -N- (-cyclopropyl-2-fluoro-phenyl) -3- (4-fluoro-phenyl) -propionamide in the form of bis-trimethylsilyl ether during step 6 by the same
method as described in Example 114. Obtaining (S) - [1- (4-cyclopropyl-2-fluoro-phenylcarbamoyl) -2- (4-fluoro-phenyl) -ethyl] -carbamic acid-tert-butyl ester: Al (S) - [1- (2-fluoro-4-iodo-phenylcarbamoyl) -2- (4-fluoro-phenyl) -ethyl] -carbamic acid tert -butyl ester (4.5 g, 9.0 mmol) and cyclopropylboronic acid (1.0 g, 11.7 mmoles) in a mixture of toluene (40 ml) and water (2 ml) is added tribasic potassium phosphate (6.68 g, 31.5 mmol), tricyclohexylphosphine (0.50 g, 1.8 mmol) and palladium acetate (0.20 g, 0.89 mmoles). The mixture is heated at 100 ° C for 3 hours, then more tricyclohexylphosphine (0.25 g, 0.89 mmol) and palladium acetate (0.10 g, 0.45 mmol) are added. The heating is continued at 100 ° C for 3 more hours and then the cyclopropylboronic acid (0.2 g, 2.33 mmol) is added and the heating is continued at 100 ° C for a final period of 3 hours. The reaction mixture is diluted with ethyl acetate, washed with water (twice), brine (once), dried with sodium sulfate, filtered and the vacuum concentrated. The residue is purified by chromatography through silica gel eluting with a 9: 1 v / v mixture of dichloromethane and hexanes, obtaining (S) - [1- (4-cyclopropyl-2-fluoro-phenylcarbamoyl) -2- (4-fluoro-phenyl) -ethyl] -carbamic acid tert-butyl ester in the form of a colorless solid (2.0 g, 53%).
LC-LC, obs mass = 417; calculated mass = 417 for C23H27F2 203+. Preparation of (R) -ter-butoxycarbonylamino- [4- (2-hydroxy-l-hydroxymethyl-ethoxy) -phenyl] -acetic acid: (1) 2,5-dichloro-benzenesulfonate is obtained from
2-benzyloxy-1-benzyloxymethyl-ethyl from 1,3-bis-benzyloxy-propan-2-ol according to the procedure of Shimizu, M. et al. (J. Chem. Soc. Chem. Commun. 867, 1986). (2) To a solution of (R) -ter-butoxycarbonylamino- (4-hydroxy-phenyl) -acetic acid (1.0 g, 3.74 mmol) in dry N, N-dimethylformamide (50 ml) is added sodium hydride (suspension to 60% in mineral oil) (328 mg, 8.2 mmol) and the mixture is stirred at room temperature under a dry argon atmosphere for 15 minutes. Add 2-benzyloxy-1-benzyloxymethyl-ethyl 2,5-dichloro-benzenesulfonate (2.2 g, 4.57 mmol) dissolved in dry N, N-dimethylformamide (25 ml) and stir the mixture placed on an oil bath. at 110 ° C for 10 minutes. The reaction mixture is cooled to room temperature and 0.5 M aqueous hydrochloric acid (16.5 ml, 8.3 mmol) is added. The reaction mixture is extracted with ethyl acetate (2 x 250 mL), the combined organic layers are washed with water (2 x 250 mL), brine (250 mL), dried over sodium sulfate, filtered and concentrated by evaporation. empty. The residue is purified by chromatography through silica gel, eluting with a 49: 1 v / v mixture
of dichloromethane / methanol containing 0.2% v / v of acetic acid, obtaining (R) - [4- (2-benzyloxy-l-benzyloxymethyl-ethoxy) -phenyl] -ter-butoxycarbonylamino-acetic acid as a solid colorless (1.2 g, 80%). HR-HR, observed mass = 544.2307; calculated mass =
544. 2306 for the C3oH35N a07 +. (3) A hydrogenation reactor is purged, into which a solution of (R) - [4- (2-benzyloxy-1-benzyloxymethyl-ethoxy) -phenyl] -tert-butoxycarbonylamino-acetic acid (1.86 g) has been introduced. , 3.57 mol) in methanol (50 ml), with nitrogen and 10% palladium on carbon (100 mg) is introduced. The atmosphere is changed above the methanolic solution to hydrogen and the reaction mixture is stirred vigorously for 30 minutes at room temperature. The reaction mixture was filtered through a pad of Celite and the vacuum concentrated, yielding (R) -tert-butoxycarbonylamino- [4- (2-hydroxy-l-hydroxymethyl-ethoxy) -phenyl] -acetic acid, which has a sufficient purity for subsequent use without further purification (0.88 g, 73%). HR-HR, observed mass = 364.1368; calculated mass =
364. 1367 for the Ci6H23NNa07 +. HR-HR, observed mass = 566,2100; calculated mass =
Example 161 (S) -N- (4-cyclopropyl-2-fluoro-phenyl) -2-. { (R) -4- [4-
(2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3- (4-methoxy-phenyl) -propionamide
It is obtained by the same method as described in Example 160, except that (i) (S) -2-tert-butoxycarbonylamino-3- (4-methoxy-phenyl) -propionic acid is used instead of the acid ( S) -2-tert-butoxycarbonylamino-3- (4-fluoro-phenyl) -propionic and (ii) (R) -tert-butoxycarbonylamino- acid. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic in place of (R) -tert-butoxycarbonylamino- [4- (2-hydroxy-l-hydroxymethyl-ethoxy) -phenyl] -acetic acid. The (R) -ter-butoxycarbonylamino- acid is obtained. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -phenyl} -acetic as described in Example 48. HR-HR, observed mass (M + H +) = 548.2180; calculated mass = 548.2192 for the C3oH3iFN306 +. Example 162 (S) -N- (4-cyclopropyl-2-fluoro-phenyl) -2-. { (R) -4- [4- ((S) -2,3-dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3- (4-methoxy-phenyl) -propionamide
It is obtained by the same method as described in Example 160, except that (i) (S) -2-tert-butoxycarbonylamino-3- (4-methoxy-phenyl) -propionic acid is used instead of the acid ( S) -2-tert-butoxycarbonylamino-3- (4-fluoro-phenyl) -propionic and (ii) (R) -tert-butoxycarbonylamino- [4- ((S) -2, 2-dimethyl- [1] acid , 3] dioxolan-4-ylmethoxy) -phenyl] -acetic acid (obtained as described in example 116) in place of (R) -tert-butoxycarbonylamino- [4- (2-hydroxy-l-hydroxymethyl-ethoxy)] -phenyl] -acetic. HR-HR, observed mass (M + Na +) = 600.2112 / calculated mass - 600.2116 for C3iH32FN3Na07 +. Example 163 (2S, 3S) -N- (4-cyclopropyl-2-fluoro-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
It is obtained by the same method as described in example 48, except that (i) 4-cyclopropyl-2-fluoraniline (obtained as described below) is used in place of 2-fluoro-4-iodoaniline and (ii) the modified procedure described below is applied to perform step 6.
Obtaining 4-cyclopropyl-2-fluoraniline: (According to the procedure of D. Wallace and C. Chen, Tetrahedron Lett. 4_3, 6987, 2002) 4-bromo-2-fluoraniline is reacted (19. Og, 100 mmole) with cyclopropyl boronic acid (11.3 g, 131 mmol), palladium (II) acetate (1.12 g, 4.79 mmol), tricyclohexyl phosphine (2.80 g, 13.2 mmol) and potassium phosphate (74.2 g, 265 mmole) in toluene (400 ml) and water (30 ml). The mixture is heated on an oil bath at 100 ° C for 2 days, cooled and the liquid is filtered through a pad of Celite. The residual solid from the reactor is triturated with water (200 ml) and the suspension is filtered through Celite. The aqueous filtered liquid is extracted once with hexanes (100 ml), the organic phases are combined and dried with anhydrous magnesium sulfate. Dry the organic phases through a pad of silica gel and wash the bed with 80% v / v dichloromethane in hexanes (250 ml). The vacuum filtrate is concentrated, obtaining a red oil, which is subjected to fractional distillation (Vigreux column, 6 plates). The fraction distilling between 65 and 73 ° C is collected at 6-7 mbar, obtaining 6.8 g (45 mmol, 45%) of 4-cyclopropyl-2-fluoraniline as a pale yellow liquid. NMR-H1 (300 MHz, CDC13) d = 6.69 (m, 3H), 3.57 (br.s, 2H), 1.79 (m, 1H), 0.87 (m, 2H), 0.57 (m, 2H). Step 6: the 2- dissolves. { 2-amino-2- [4- (2-
trimethylsilanyloxy-ethoxy) -phenyl] -acetylamino} -N- (4-cyclopropyl-2-fluorophenyl) -3-phenyl-butyramide (680 mg, 1.2 mmol) and pyridine (3 ml) in dichloromethane (60 ml) at -78 ° C. To this mixture is added dropwise a solution of triphosgene (296 mg, 1 mmol) in dichloromethane (15 ml). The mixture is slowly allowed to warm to room temperature and is stirred at room temperature overnight. The mixture is cooled in an ice bath, 3 M HC1 (60 ml) is added slowly and stirring is continued at 0 ° C for 30 minutes. The organic phase is separated and dried with anhydrous sodium sulfate. By concentration 150 mg of an oily solid is obtained, which is chromatographed through silica gel (65% ethyl acetate v / v in hexanes), obtaining N- (4-cyclopropyl-2-fluoro-phenyl) - 2-. { 4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidinyl} -3-phenyl-butyramide as a yellow solid (70 mg, 0.13 mmol, 13%). HR-HR, observed mass (M + H +) = 532.2244; calculated mass = 532.2242 for the C3oH3iFN305 +. Example 164 (S) -N- (4-cyclopropyl-2-fluoro-phenyl) -2-. { (R) -4- [4- (2-hydroxy-l-hydroxymethyl-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3- (4-methoxy-phenyl) -propionamide
obtained by the same method as described
in Example 160, except that (i) (S) -2-tert-butoxycarbonylamino-3- (4-methoxy-phenyl) -propionic acid is used in place of (S) -2-tert-butoxycarbonylamino-3 - (4-fluoro-phenyl) -propionic in step 1 and (ii) as condensation reagent, the hydrochloride of (3-dimethylaminopropyl) -ethyl-carbodiimide is used in place of the hexafluorophosphate of
0-benzotriazole-1-yl-N, N, N ', N' -tetramethyluronium in step 4. HR-HR, observed mass (M + H +) = 578.2295 calculated mass = 578.2297 for C3iH33FN307 +. Example 165 (2S, 3S) -N- (4-cyclopropyl-2-fluoro-phenyl) -2-. { (R) -4- [4- ((R) -2,3-Dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
It is obtained by the same method as described in example 160, except that (i) (2S, 3S) -2-tert-butoxycarbonylamino-3-phenyl-butyric acid is used instead of (S) -2 -ter-butoxycarbonylamino-3- (4-fluoro-phenyl) -propionic in step 1 and (ii) (R) -tert-butoxycarbonylamino- [4- ((R) -2, 2-dimethyl- [1 , 3] dioxolan-4-ylmethoxy) -phenyl] -acetic acid in place of (R) -tert-butoxycarbonylamino- acid. { 4- [2- (tetrahydro-pyran-2-yloxy) -ethoxy] -
phenyl } -acetic in step 4. The (R) -ter-butoxycarboni acid lamino- [4- ((R) -2, 2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -phenyl] -acetic is obtained and used in the manner described in Example 114. HR-HR, observed mass (M + H +) = 562.2349; calculated mass = 562.2348 for the C3iH33FN306 +. Example 166 (2S, 3S) -N- (4-cyclopropyl-2-fluoro-phenyl) -2- ((R) -4- { 4- [2- (2-hydroxy-ethoxy) -ethoxy] - phenyl.} -2-, 5-dioxo-imidazolidin-1-yl) -3-phenyl-butyramide
It is obtained by the same method as described in Example 165, except that (R) -tert-butoxycarbonylamino- (-. {2- 2- (tetrahydro-pyran-2-yloxy) -ethoxy) acid is used. ] -ethoxy.}.-phenyl.} -acetic acid in place of (R) -tert-butoxycarbonylamino- [4- ((S) -2, 2-dimethyl- [1,3] dioxolan-4-ylmethoxy) phenyl] -acetic HR-HR, observed mass (M + H +) = 576.2504, calculated mass = 576.2505 for C32H35FN306 + Example 167 (2S, 3S) -N- (4-cyclopropyl-2-fluoro-phenyl) - 2- ((R) -4- { 4- [2- (2-methoxy-ethoxy) -ethoxy] -phenyl} -2-, 5-dioxo-imidazolidin-
1-yl) -3-phenyl-butyramide
It is obtained by the same method as described in Example 165, except that (R) -tert-butoxycarbonylamino- acid is used. { 4- [2 - (2-methoxy-ethoxy) -ethoxy] -phenyl} -acetic in place of (R) -tert-butoxycarbonylamino- [4 - ((S) -2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -phenyl] -acetic acid. HR-HR, observed mass (M + H +) = 590.2656; calculated mass = 590.2661 for the C33H37 FN306 +. HR-HR, observed mass (M + Na +) = 612.2475; calculated mass = 612.2480 for C33H36FN3Na06 + · E j usb 168 (2S, 3S) -N- (4-cyclopropyl-2-fluoro-phenyl) -2- [(R) -4- (4-methylcarbamoylmethoxy-phenyl) -2 , 5-dioxo-imidazolidin-l-yl] -3-phenyl-butyramide
It is obtained by the same method as described in Example 165, except that the
(R) -tert-butoxycarbonylamino- (4-methylcarbamoylmethoxy-f-enyl) -acetic acid in place of (R) -tert-butoxycarbonylamino- [4- ((S) -2, 2-dimethyl- [1, 3]] dioxolan-4-ylmethoxy) -phenyl] -acetic acid. The (R) -tert-butoxycarbonylamino- (4-methylcarbamoylmethoxy-phenyl) -acetic acid is obtained in the manner described in Example 9. HR-HR, observed mass (M + H +) = 559.2354; calculated mass = 559.2351 for the C3iH32FN405 +. Example 169 (4-cyclopropyl-2-fluoro-phenyl) -amide of (S) -2-. { (R) -4- [4- ((R) -2,3-Dihydroxy-propoxy) -phenyl] -2,5-dioxo-imi-dazolidin-1-yl} -4-methyl-pentanoic
It is obtained by the same method as that described in Example 165, except that (S) -2-tert-butoxycarbonylamino-4-methyl-pentanoic acid is used in place of (2S, 3S) -2-tert. butoxycarbonylamino-3-phenyl-butyric acid. HR-HR, observed mass (M + H +) = 514.2349; calculated mass = 514.2348 for the C27H33FN306 +. Example 170 (4-cyclopropyl-2-fluoro-phenyl) -amide of (S) -2- acid. { (R) -4- [4- ((S) -2,3-dihydroxy-propoxy) -phenyl] -2,5-dioxo-
imidazolidin-l-il} -4-methyl-pentanoic
It is obtained by applying the same method as described in Example 169, except that the acid (R) -t er-but-oxy-carboni lamino- [4 - ((R) -2,2-dimethyl- [1, 3] dioxolan-4-ylmethoxy) -phenyl] -acetic acid in place of (R) -te r-butyloxycarbonyl lamino- [4 - ((S) -2,2-dimethyl- [1, 3] dioxolan- 4-ylmethoxy) -phenyl] -acetic acid in step 4. The (R) -t er-but-o-xicarbonylamino- [4 - ((R) -2, 2-dimethyl- [1, 3] dioxolan acid is obtained -4-ylmethoxy) -phenyl] -acetic by the same method as described for the preparation of (R) -ter-butoxycarbonylamino- [4 - ((S) -2, 2-dimethyl- [1, 3]] dioxolan-4-ylmethoxy) -phenyl] -acetic in Example 114, except that (R) -2,2-dimethyl-1,3-dioxolane-4-methanol is used instead of (S) -2.2 -dimethyl-1, 3-dioxolane-4-methanol. HR-HR, observed mass (M + Na +) = 536.2164; calculated mass = 536.2167 for C27H32FN3Na06 +. Example 171 (S) -2- (4-cyclopropyl-2-fluoro-phenyl) -amide. { (R) -4- [4- (2-hydroxy-l-hydroxymethyl-ethoxy) -phenyl] -2, 5-
dioxo-imidazolidin-l-il} -4-methyl-pentanoic
It is obtained by the same method as described in Example 160, except that (i) (S) -2-tert-butoxycarbonylamino-4-methyl-pentanoic acid is used in place of (S) -2-tert-butoxycarbonylamino-3- (4-fluoro-phenyl) -propionic acid in step 1 and (ii) as condensation reagent, the hydrochloride of (3-dimethylamino-propyl) -ethyl-carbodiimide is used in place of the O-benzotriazol-1-yl-N, N, N 'hexafluorophosphate. , N '-tetramethyluronium in step 4. HR-HR, observed mass (M + H +) = 514.2347 calculated mass = 514.2348 for C27H33FN3C. · Example 172 (2S, 3S) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-N-p-tolyl-butyramide
It is obtained by the same method as described in Example 1, except that (i) 4-methyl-aniline is used in place of 4-bromoaniline in step 2 and (ii) the acid
(R) -ter-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid in place of (R) -tert-butoxycarbonylamino- (4-methoxy-phenyl) -acetic acid in step 4. obtains (R) -tert-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid in the manner described in Example 80. HR-HR, observed mass (M + H +) = 502.2332; calculated mass = 502.2337 for the C29H32N305 +. Example 173 (2S, 3S) -N- (4-ethyl-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
It is obtained by applying the same method described in Example 1, except that (i) 4-ethyl-aniline is used in place of 4-bromoaniline in step 2 and (ii) (R) -tert-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid in place of (R) -tert-butoxycarbonylamino- (-methoxy-phenyl) -acetic acid in step 4. The (R) -terminic acid is obtained bu-toxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid in the manner described in Example 80. HR-HR, observed mass (M + H +) = 516.2489; calculated mass = 516.2493 for C30H34N3O5 +.
Example 174 (2S, 3S) -N- (4-Isopropyl-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
It is obtained by the same method described in Example 1, except that (i) 4-isopropyl-aniline is used in place of 4-bromoaniline in step 2 and (ii) (R) -tert-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid in place of (R) -tert-butoxycarbonylamino- (4-methoxy-phenyl) -acetic acid in step 4. The (R) -teric acid is obtained -butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid in the manner described in Example 80. HR-HR, observed mass (M + H +) = 530.2646; calculated mass = 530.2650 for the C3iH36N305 +. Example 175 (2S, 3S) -N- (2-fluoro-4-methyl-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
It is obtained by applying the same method as described in Example 1, except that (i) 2-fluoro-4-methyl-aniline is used instead of 4-bromoaniline in step 2 and (ii) the acid ( R) -ter-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid in place of (R) -tert-butoxycarbonylamino- (4-methoxy-phenyl) -acetic acid in step 4. Obtained the (R) -tert-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid in the manner described in Example 80. HR-HR, observed mass (M + Na +) = 542.2056; calculated mass = 542.2061 for CzgHsoF ^ NaC ^. Example 176 (S) -N- (4-tert-butyl-2-chloro-phenyl) -2-. { (R) -4- [4 - ((R) -2,3-dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-methyl-butyramide
It is obtained by the same method as described in example 43, except that (i) (S) -2- (9H-fluoren-9-ylmethoxycarbonylamino) -3-methyl-butyric acid is used instead of the acid ( S) -2- (9H-fluoren-9-ylmethoxycarbonylamino) -3-naphthalen-2-yl-propionic acid in step 1, (ii) 4-tert-butyl-2-chloro-phenylamine instead of 2- fluoro-4-iodoaniline in step 1 and (iii) the steps subsequent to step 3 are carried out in the manner described in example 114. MS-LC, observed mass (M + H +) = 532; calculated mass = 532
Example 177 (2S, 3S) -N- (4-ethoxy-2-fluoro-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-inddazolidin-1-yl} -3-phenyl-butyramide
It is obtained by applying the same method as described in Example 1, except that (i) 4-ethoxy-2-fluoro-aniline is used in place of 4-bromoaniline in step 2 and (ii) the acid ( R) -ter-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid in place of (R) -tert-butoxycarbonylamino- (4-methoxy-phenyl) -acetic acid in step 4. Obtained the (R) -tert-butoxycarbonylamino- [4- (2-methoxy-ethoxy) -phenyl] -acetic acid in the manner described in Example 80. HR-HR, observed mass (M + H +) = 550.2352; calculated mass = 550.2348 for the C3oH33F 306+. Example 178 (2S, 3S) -N- (2-fluoro-4-isopropoxy-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
obtained by the same method as described
in Example 50, except that 2-fluoro-4-isopropyloxyaniline hydrochloride is used in place of 2-fluoro-4-iodoaniline. HR-HR, observed mass (M + H +) = 564.2498; calculated mass = 564.2505 for the C3iH35FN306 +. Example 179 (2S, 3S) -N- (4-azetidin-1-yl-2-fluoro-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
It is obtained by the same method as described in Example 50, except that 4-azetidin-1-yl-2-fluoro-phenylamine is used in place of 2-fluoro-4-iodoaniline. 4-Azetidin-1-yl-2-fluoro-phenylamine is obtained as follows: To a mixture of 2-fluoro-4-iodoaniline (1 g, 4.14 mmol), copper iodide (304 mg, 0.21 mmol) and Potassium phosphate (1.75 g, 8.27 mmol) in ethylene glycol (465 μ ?, 8.27 mmol) and isopropanol (4 ml) in a pump-type flask was added azetidine (304 mg, 5.17 mmol). The flask is sealed and heated at 80 ° C for 24 hours. The reaction mixture was dissolved in ethyl acetate (50 ml), washed with water (3 ml).
? 50 ml), brine (50 ml) and the brine phase is extracted again with ethyl acetate (2? 50 ml). The combined organic extracts are dried with sodium sulfate, filtered and the vacuum concentrated, obtaining a brown oil. The oil is purified by chromatography through silica gel, eluting with 40% v / v ethyl acetate in hexanes. The fractions containing product were combined and concentrated, yielding 4-azetidin-1-yl-2-fluoro-phenylamine as an orange oil (555 mg, yield = 81%). HR-HR, observed mass (M + H +) = 561.2501; calculated mass = 561.2508 for the C3iH34F 405+. Example 180 (2S, 3S) -N- (4-Cyano-2-fluoro-phenyl) -2-. { (R) -4- [4- (2-methoxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide
It is obtained by the same method as described in example 50, except that before carrying out step 4 of the series of reactions, the transformation described below is carried out (step 3a). Step 3a: Insert into a degassed flask
with argon and dry (2S, 3S) -2-araino-N- (2-fluoro-4-iodo-phenyl) -3-phenyl-butyramide (796 mg, 1.99 mmol), zinc cyanide (352 mg, 2.99 g) mmoles), tetrakis-triphenylphosphine palladium (0) (116 mg, 0.1 mmol) and dry tetrahydrofuran (4 mL). After heating at 80 ° C for 8 hours no reaction is observed. The mixture is cooled, 2-dicyclohexylphosphino-2'-6'-dimethoxybiphenyl (42 mg, 0.1 mmol) is added and the reaction mixture is again heated at 80 ° C for 90 minutes, again no reaction is observed. The mixture is cooled, triethylamine (840 μ ?, 5.99 mmol) is added and the reaction mixture is heated at 80 ° C for 2 hours, also no reaction is observed now. The mixture is cooled, 2-dicyclohexylphosphino-2'-6'-dimethoxybiphenyl (84 mg, 0.2 mmol) is added and no reaction is observed after 2 hours at 85 ° C. The mixture is cooled, rac-2-2 '-bis (diphenylphosphino) -1-1' -bubfethyl (125.6 mg, 0.2 mmol) and dry toluene (2 ml) are added. The reaction mixture is heated at 85 ° C for 40 hours, dissolved in ethyl acetate (50 ml) and washed with a 1.5 N aqueous solution of potassium hydrogen sulfate, a saturated aqueous solution of sodium bicarbonate and extracted from water. The aqueous phases were back-washed with ethyl acetate (2 * 50 ml). The organic phases are combined, dried over sodium sulfate and concentrated. The crude residue is purified by chromatography on silica gel, eluting with a gradient of ethyl acetate
from 5 to 15% v / v in hexanes, obtaining (2S, 3S) -2-amino-N- (-ciano-2-fluoro-phenyl) -3-phenyl-butyramide as a yellow residue after concentrating the fractions containing product (120 mg, yield = 20.2%). HR-HR, observed mass (M + H +) = 531.2035; calculated mass = 531.2038 for the C29H28FN405 +. Example 181 (S) -N- (4-Cyano-2-fluoro-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-methyl-butyramide
It is obtained by the same method as described in example 43, except that step 1 is carried out in the manner described below. Step 1: To a solution of (S) -2- (9H-fluoren-9-ylmethoxycarbonylamino) -3-methyl-butyric acid (2.5 g, 7.37 mmol) and a few drops of N, -dimethylformamide in dichloromethane (20 ml) Oxalyl chloride (1.3 ml, 14.74 mmol) was slowly added at 0 ° C under a dry nitrogen atmosphere. The mixture is stirred at 0 ° C for 15 minutes and at room temperature for 2 hours. After removing the solvent, the residue is dissolved in dichloromethane (20 ml) and 4-amino-3- is added to the resulting solution at 0 ° C.
f 1 uo r o -ben z on i t r i 1 (840 mg, 6.14 mmol), 4-dime t i 1 ami nop i r i d i na (150 mg, 1.2 mmol) and pyridine (0.78 ml, 9.21 mmol). The mixture is stirred at 0 ° C for 2 h and at room temperature overnight. The reaction is quenched with a 1 M aqueous solution of citric acid and then extracted with dichloromethane (three times). The combined organic extracts are washed with a 1 M aqueous solution of citric acid, brine, a saturated aqueous solution of sodium carbonate, brine, dried over sodium sulfate, filtered and the vacuum concentrated. The residue is purified by chromatography on silica gel, eluting with a gradient of 100% dichloromethane to 10% methanol / 90% dichloromethane in 30 minutes. By concentration of the fractions containing product, the [(S) - 1 - (4-cyano-2-fluoro-phenylcarbamoyl) -2-methyl-propyl] -carbamate of 9H-f luo is obtained in-9-i. lme ti 1 or as a white solid (2.15 mg, 11%). LC-MS, observed mass (M + H +) = 458; calculated mass
= 548 for C27H2sFN303 +. LC-MS, observed mass (M + H +) = 455; calculated mass = 455 for the C23H24FN405 +.
Example 182 (2S, 3S) -N- (4-acetyl-2-fluoro-phenyl) -2-. { (R) -2,5-dioxo-4- [4- (2-oxo-2-pyrrolidin-1-yl-ethoxy) -phenyl] -imidazolidin-1-yl} -3-phenyl-butyramide
Obtained by the same method as described in Example 145, this compound is obtained as a secondary product in the purification of step 6. HR-HR, observed mass (+ H +) = 601.2454; calculated mass = 601.2457 for the C33H34FN406 +. Example 183 Determination of the IC 50 of the compounds in an MEK cascade assay The compounds are evaluated as MEK inhibitors in a pear-based FP assay, called an IMAP assay with MEK cascade components. Briefly, the assay is performed in a reaction solution containing 10 mM HEPES, pH 7.0, 10 mM MgCl2, 50 mM NaCl, 0.1 mM NaV04 and 1 mM DTT in the presence of 50 μM. of ATP, 0.45 nM of c-RAF, 11.25 nM of MEK, 90.5 nM of ERK and 0.5 μ? of ERK labeled with FITC (FITC-Aca-Ala-Ala-Ala-Thr-Gly-Pro-Leu-Ser-Pro-Gly-Pro-Phe-Ala-NH2). They are added
successively the peptide substrates C-RAF, MEK, ERK and ERK to the reaction buffer. Activated c-Raf phosphorylates MEK, activated MEK phosphorylates ERK and subsequently activated ERK phosphorylates its peptide substrate. Peptide substrates labeled with FITC, when phosphorylated by a kinase, are fixed on nanoparticles derivatized with trivalent metal cations thanks to the metal-phosphorylated interaction. The result of this fixation is a phosphorylated product with fluorescein that presents an increase in polarization signal, due to a decrease in the molecular mobility of the fixed product. A series of ten dilutions of the compounds that are added to the MEK cascade assays are performed before mixing them with the ERK and the ERK peptide substrates. The reaction mixture is incubated at 37 ° C for 20 minutes to activate the MEK, 20 minutes to activate the ERK, 30 minutes to phosphorylate the ERK peptide substrate, then incubated overnight at room temperature to be fixed on the mats. IMAP. The IMAP test is done in a 384-hole plate format. Changes in fluorescence polarization are measured with an LJL instrument at 485 nm for excitation and 530 nm for emission. The polarization value (MP) is calculated as follows: (MP) = 1000 x (vertical intensity - horizontal intensity) / (vertical intensity + horizontal intensity) -
The values of the IC50 are generated using the Excel XLfit3 program. The percentage of activity and the percentage of inhibition of reactions in the presence of a compound are calculated by comparing their MP values with those obtained in the absence of the compound (as 100% activity). In the previous test, the compounds of the formula I have IC5o values of less than 10 micromolar, as can be seen from the following specific data:
Example n ° Chemical structure IC50 / pM
??
Example n ° Chemical structure ?? 50 / μ?
??
??
??
??
??
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Claims (25)
- CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of the formula I: characterized in that Rl is selected from the group consisting of bromine, iodine, ethynyl, cycloalkyl, alkoxy, azetidinyl, acetyl, heterocyclyl, cyano, straight chain alkyl and branched chain alkyl; R2 is selected from the group consisting of hydrogen, chloro, fluoro and alkyl; R3 is selected from the group consisting of hydrogen, chlorine and fluoro; R 4 is selected from the group consisting of hydrogen, optionally substituted aryl, alkyl and cycloalkyl; R5 is selected from the group consisting of hydrogen and R6-C-R8 wherein R6 is selected from the group consisting of hydroxyl, alkoxy, cycloalkyl, trihaloalkyl, alkyl, optionally substituted aryl and optionally substituted heteroaryl; R7 and R8 are independently selected from the group consisting of hydrogen, alkyl and trihaloalkyl; or R6 and R7 can together form a cycloalkyl group and R8 is hydrogen; and their pharmaceutically acceptable salts or esters. 2. The compound according to claim 1, characterized in that it has the formula: where R 1 is selected from the group consisting of bromine, iodine, ethynyl, cycloalkyl, alkoxy, acetyl, alkylthio, heterocyclyl, cyano, straight-chain lower alkyl and branched-chain lower alkyl; R2 is selected from the group consisting of hydrogen, chloro, fluoro and lower alkyl; R3 is selected from the group consisting of hydrogen and fluoro; R 4 is selected from the group consisting of optionally substituted aryl, lower alkyl and cycloalkyl;
- R5 is selected from the group consisting of hydrogen and wherein R6 is selected from the group consisting of hydroxyl, alkoxy, cycloalkyl, trihalo-lower alkyl, lower alkyl, optionally substituted aryl, and optionally substituted heteroaryl; R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl and trihalo-lower alkyl; or R6 and R7 can together form a cycloalkyl group and R8 is hydrogen; and their pharmaceutically acceptable salts or esters.
- 3. The compound according to claim 2, characterized in that Rl is selected from the group consisting of iodine, ethynyl and cyclopropyl.
- 4. The compound according to claim 3, characterized in that R2 is selected from the group consisting of hydrogen, chlorine and fluoro.
- 5. The compound according to claim 4, characterized in that R3 is hydrogen.
- 6. The compound according to claim 5, characterized in that R5 is R6-C-R8 R7 and R7 and R8 are independently selected from the group consisting of hydrogen and methyl.
- 7. The compound according to claim 6, characterized in that R4 is optionally substituted aryl.
- 8. The compound according to claim 7, characterized in that Rl is selected from the group consisting of iodine, ethynyl and cyclopropyl, R2 is selected from the group consisting of hydrogen, fluoro and chloro, R3 is hydrogen, R4 is phenyl optionally substituted, R5 is R6-C-R8 R7 R6 is optionally substituted phenyl, R7 is methyl and R8 is hydrogen.
- 9. The compound according to claim 8, characterized in that R4 is phenyl substituted with alkoxy.
- 10. The compound according to claim 9, characterized in that Rl is iodine and R2 is selected from the group consisting of chlorine and fluoro.
- 11. The compound according to claim 10, characterized in that R6 is phenyl and R4 is phenyl substituted with a member selected from a 2,3-dihydroxy-propoxy group and a 2-hydroxy-ethoxy group.
- 12. - The compound according to the rei indication 1 or 2, characterized in that R4 is phenyl, which is unsubstituted or substituted 1 or 2 times by a substituent independently selected from -halogen, -P (0) (0-CH 3) 2, -P (O) (OH) 2, -S (O) 2- (C 1 -C 6 alkyl), - (0-CH 2 -CH 2) 2-O- CH3, and -O- (C1-C6 alkyl), wherein the alkyl group is unsubstituted or substituted 1 or 2 times by a substituent independently selected from -OH, -oxo, -C3-C6 cycloalkyl, -O- (C 1 -C 6 alkyl), -NH- (C 1 -C 6 alkyl) or -N (Cl-C 6 alkyl) 2, wherein the alkyl groups are unsubstituted or substituted by -OH, or - a heterocycle of 4 to 6 members, wherein the heteroatoms are selected from N, S and 0.
- 13. The compound according to claim 12, characterized in that R5 is 1-phenyl-ethyl.
- 14. - The compound according to claim 13, characterized in that Rl is iodine; R2 is hydrogen or fluoro; and R3 is hydrogen or fluoro.
- 15. The compound according to claim 12, characterized in that R5 is benzyl, whose benzyl is unsubstituted or substituted once by -C1-C6 alkyl, -fluoro or chloro, -CN, -O-C1- alkyl C6 or -CF3.
- 16. The compound according to claim 12, characterized in that R5 is Cl-C6 alkyl, which is unsubstituted or substituted 1 or 2 times by a substituent independently selected from -naphthyl, pyridinyl, thiazolyl, thiophenyl which is optionally substituted by bromine, imidazolyl which is optionally substituted by methyl; or C3-C6 cycloalkyl; -CF3; -O-C1-C6 alkyl; -0-CH2-phenyl; -S (O) 2-methyl; -oxo; or -NH2.
- 17. A compound according to claim 1 or 2, characterized in that it is selected from the group consisting of: (2S, 3S) -N- (4-bromo-phenyl) -2- [(R) -4- (4 -methoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl] -3-phenyl-butyramide; (2S, 3S) -N- (4-iodo-phenyl) -2- [(R) -4- (4-methoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl] -3-phenyl- Butyramide; (2S, 3S) -N- (4-ethynyl-2-fluoro-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} 3-phenyl-butyramide; (2R, 3S) -N- (4-etinyl-2-fluoro-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} 3-phenyl-butyramide; (2S, 3S) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} 3-phenyl-butyramide; (2S, 3S) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (4-iodo-2-methyl-phenyl) -3-phenyl-butyramide; (2S, 3S) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4- [4 - ((R) -2,3-dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} 3-phenyl-butyramide; (2S, 3S) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4- [4 - ((S) - 2, 3-dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-i1} 3-phenyl-butyramide; (2S, 3S) -2-. { (R) -2,5-dioxo-4- [4- (2-oxo-2-pyrrolidin-1-yl-ethoxy) -phenyl] -imidazolidin-1-yl} -N- (2-fluoro-4-iodo-phenyl) -3-phenyl-butyramide; (2S, 3S) -2 - ((R) -2,5-dioxo-4-thiophen-3-yl-imidazolidin-1-yl) -N- (4-iodo-phenyl) -3-phenyl-butyramide; (S) -2- [(R) -4- (2,3-dihydro-benzo [1.4] dioxin-6-yl) -2,5-dioxo-imidazolidin-1-yl] -N- (2-fluoro) -4-iodo-phenyl) -3-phenyl-propionamide; (S) -2- [(R) -4- (4-acetylamino-phenyl) -2,5-dioxo-imidazolidin-1-yl] -N- (2-fluoro-4-iodo-phenyl) -3- phenyl-propionamide; (4- { (R) -1- [(1S, 2S) -1- (2-fluoro-4-iodo-phenylcarbamoyl) -2-phenyl-propyl] -2,5-dioxo-imidazolidin-4- il.}. phenoxymethyl) -phosphonate dimethyl; (2S, 3S) -N- (2-fluoro-4-iodo-phenyl) -2- ((R) -4-isopropyl-2,5-dioxo-imidazolidin-1-yl) -3-phenyl-butyramide; (S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-methyl-butyramide; (S) -N- (2-fluoro-4-iodo-phenyl) -2- [(R) -4- (4-methoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl] -3- o-tolyl-propionamide; (S) -N- (2-fluoro-4-iodo-phenyl) -2- [(R) -4- (4-methoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl] -3- m-tolyl-propionamide; (S) -N- (2-fluoro-4-iodo-phenyl) -2- [(R) -4- (4-methoxy-phenyl) -2,5-dioxo-imidazolidin-1-yl] -3- p-tolyl-propionamide; Y (S) -N- (-cyclopropyl-2-fluoro-phenyl) -3- (4-fluoro-phenyl) -2-. { (R) -4- [4- (2-hydroxy-l-hydroxymethyl-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -propionamide.
- 18. A compound according to claim 1 or 2, characterized in that it is selected from the group consisting of: (2S, 3S) -N- (2-fluoro-4-iodo-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} 3-phenyl-butyramide; (2S, 3S) -2-. { (R) -4- [4 - ((R) -2,3-dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -N- (2-fluoro-4-iodo-phenyl) -3-phenyl-butyramide; (2S, 3S) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4- [4 - ((R) -2,3-Dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} 3-phenyl-butyramide; (2S, 3S) -N- (2-chloro-4-iodo-phenyl) -2-. { (R) -4- [4 - ((S) -2,3-dihydroxy-propoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} 3-phenyl-butyramide; and (2S, 3S) -N- (4-cyclopropyl-2-fluoro-phenyl) -2-. { (R) -4- [4- (2-hydroxy-ethoxy) -phenyl] -2,5-dioxo-imidazolidin-1-yl} -3-phenyl-butyramide.
- 19. - A pharmaceutical composition, characterized in that it contains a compound in accordance with the claim 1 or 2 and a pharmaceutically acceptable diluent, excipient or adjuvant.
- 20. - A pharmaceutical composition, characterized in that it contains a compound according to claim 11 or 14 and a pharmaceutically acceptable diluent, excipient or adjuvant.
- 21. - A pharmaceutical composition, characterized in that it contains a compound according to claim 18 and a pharmaceutically acceptable diluent, excipient or adjuvant.
- 22. A compound according to claim 1 or 2, characterized in that it is for use as a medicament.
- 23. - A compound according to claim 1 or 2, characterized in that it is for use as a medicament for the treatment of cancer, in particular of solid tumors, more particularly of lung, breast, colon or prostate tumors. .
- 24. The use of a compound according to claim 1 or 2, wherein it is for the manufacture of a compound for the treatment of cancer, in particular solid tumors, more particularly lung, breast, colon or of prostate.
- 25. - A process for the synthesis of compounds of the formula I according to claim 1 or 2, characterized in that it consists in reacting a compound of the formula 9 in the presence of phosgene or trichloromethyl chloroformate at temperatures below 0 ° C and in the presence of a base, to obtain the corresponding compounds of the formula I, wherein all the substituents from R1 to R5 have the meanings according to the claim 1.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60/775,658 | 2006-02-22 | ||
US60/861,105 | 2006-11-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
MX2008010534A true MX2008010534A (en) | 2008-10-03 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1989186B1 (en) | Hydantoin based kinase inhibitors | |
EP2291369B1 (en) | Benzodioxinyl substituted indazole derivatives | |
RU2442779C2 (en) | Derivants of 2, 4, 5-triphenylimidazoline as inactivators of interaction between p53 and mdm2 proteins designed for application as anticancer drugs | |
ES2313389T3 (en) | SUBSTITUTED HYDANTOINS. | |
RU2326117C2 (en) | 2,5-dioxoimidazolin-4-yl methylcarbonyl compounds, method of obtaining them, pharmaceutical mixtures containg them and thir use in medicine preparation | |
SK48499A3 (en) | Heteroaryl succinamides and their use as metalloproteinase inhibitors | |
NO302948B1 (en) | Pyrrolidine and piperidine derivatives with anticoagulant activity, and agents containing such derivatives | |
KR20090083408A (en) | Substituted dihydroimidazoles and their use in the treatment of tumors | |
HU226645B1 (en) | Certain cyclic thio substituted acylaminoacid amide derivatives | |
KR20110073580A (en) | Sphingosine-1-phosphate receptor antagonists | |
JP2007501267A (en) | Novel imidazole derivatives, their production and their use as pharmaceuticals | |
WO2008101840A1 (en) | Combination of erlotinib and mek-inhibitors for inhibiting proliferation of tumor cells | |
MX2008010534A (en) | Hydantoin based kinase inhibitors | |
ES2354916T3 (en) | QUINASA INHIBITORS BASED ON HYDANTOINE. | |
EP1283825B1 (en) | N-substituted peptidyl nitriles as cysteine cathepsin inhibitors | |
CA2277105A1 (en) | C-terminal ketone hydroxamic acid inhibitors of matrix metalloproteinases and tnfa secretion | |
KR20110118157A (en) | Substituted 3-benzofuranyl-indol-2-one-3-acetamidopiperazine derivatives, preparation thereof, and therapeutic use thereof | |
FR2941947A1 (en) | 3-BENZOFURANYL-INDOL-2-ONE 3-DERIVED DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION | |
JP2007506690A (en) | Bicyclic imino acid derivatives used as inhibitors of matrix metalloproteinases | |
WO2005013909A2 (en) | Novel cathepsin k inhibitors |