MXPA05009241A - Phosphate/sulfate ester compounds and pharmaceutical compositions for inhibiting protein interacting nima (pin1). - Google Patents

Phosphate/sulfate ester compounds and pharmaceutical compositions for inhibiting protein interacting nima (pin1).

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MXPA05009241A
MXPA05009241A MXPA05009241A MXPA05009241A MXPA05009241A MX PA05009241 A MXPA05009241 A MX PA05009241A MX PA05009241 A MXPA05009241 A MX PA05009241A MX PA05009241 A MXPA05009241 A MX PA05009241A MX PA05009241 A MXPA05009241 A MX PA05009241A
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crdre
mmol
aryl
alkyl
nrbrc
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MXPA05009241A
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Anthony Margosiak Stephen
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Pfizer
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Abstract

Phosphate/sulfate ester compounds that modulate and/or inhibit the activity of protein interacting NIMA (PIN1), and to pharmaceutical compositions containing such compounds are described. The invention is also directed to the therapeutic or prophylactic use of such compounds and compositions, and to methods of treating disorders characterized by hypertension, inappropriate cell proliferation, infectious diseases, and neurodegenerative brain disorders, by administering effective amounts of such compounds.

Description

CO STERES ESTER PHOSPHATE / SULPHATE AND COMPOSITIONS PHARMACEUTICALS TO INHIBIT INTERACTIVE PROTEIN WITH NIMA (PIN1) FIELD OF THE INVENTION This invention is directed to phosphate / sulfate ester compounds that modulate and / or inhibit the activity of the protein that interacts with NIMA (PIN1), and to pharmaceutical compositions containing said compounds. The invention is also directed to the therapeutic or prophylactic use of said compounds and compositions, and to methods for treating disorders characterized by hypertension, inappropriate cell proliferation, infectious diseases, and neurodegenerative brain disorders, by administering effective amounts of said compounds.
BACKGROUND OF THE INVENTION PIN1 is a member of the parvulin family of peptidyl-prolyl isomerases (PPIase) and catalyzes the rotation on the peptide bond preceding a proline residue. PIN1 is a regulator of Cdc25, which dephosphorylates Cdc2 / cyclin B to direct cells towards mitosis. PIN1 has been identified in all eukaryotic organisms examined, including plants, yeasts, insects, and mammals. The orthologs of yeast PIN1 (£ ss1) and Dorosophilla (dodo) present a high identity with respect to the sequence labels expressed in humans, which has allowed the cloning of the human dodo gene called PIN1. It has been reported that the dodo gene of Dorosophilia is 45% identical to the yeast gene, Ess1. Using a two-hybrid screening of a human cDNA library, human PIN1 was identified as a binding protein of the NIMA protein of the fungus Aspergillus nidulens. NIMA is a kinase that directs cells towards mitosis and has been reported to be negatively regulated by PIN1. It has been reported that NIMA deletion in A. nidulans cells results in cell cycle arrest in G2 while overexpression promotes premature mitosis. The Ser / Thr Cdc2 / cyclin B kinase may be the analogous NIMA kinase in human cells although it has been postulated that there is another NIMA-like pathway in human cells. It has been reported that the modulation of PIN1 activity results in dramatic cellular morphological phenotypes. For example, it has been reported that overexpression of PIN1 in Hela cells produces a stop in G2 while elimination produces mitotic arrest-the opposite phenotypes compared to those observed with NIMA modulation. Additionally, it has been reported that decreasing the expression of the PIN1 protein by full-length antisense expression causes the cells to progress to mitosis prematurely, that contain aberrant nuclei due to premature chromosomal condensation and that Induce apoptosis. These data indicate that PIN1 is a negative regulator of mitosis through interactions with a functional NIMA homolog of mammals and that. it is required for progression through mitosis. In addition, it is also postulated that the elimination of PIN1 plays a role in Alzheimer's disease. Lu et al., Nature, 380, 544-547 (1996). It has been reported that \ n vitro, PIN1 interacts with mitotic proteins that are also recognized by the MPM-2 antibody. The monoclonal antibody MPM-2 recognizes a phospho-Ser / Thr-Pro epitope in approximately 50 proteins associated with mitosis, including important mitotic regulators, such as Cdc25, Wee1, Cdc27, Map 4, and NIMA. See, for example, Davis et al., Proc. Nati Acad. Sci. U.S.A. 80, 2926 (1983). It has also been reported that PI 1 interacts with important high regulators of Cdc2 / cyclin B, including Cdc25 and its known regulator, Plx1. See Shen et al., Genes Dev. 12, 706 (1998). PIN1, due to its enzymatic action, can eliminate the action of Cdc25 and Plx1 by causing its degradation in the cell. Studies indicate that the biological function of PIN1 depends on a functional active site of PPIase. Lu et al., Science, 283, 1325-1328 (1999). Studies also indicate that PIN1 recognizes its substrates (specific phosphoproteins of mitosis) through the WW domain. The WW domain is a protein recognition residue that is common in biology. However, the WW domain of PIN1 is unique in the sense that it requires its ligand protein to contain a phosphorylated serine. As in the case of PPlasa domain, it has been published that a functional WW domain is essential for the biological functions of PIN1. This is consistent with the model in which PIN1 recognizes its substrates through the WW domain followed by the completion of its essential catalytic role. The full-length PIN1 protein and the nucleotide sequence encoding full length PIN1 are described in U.S. Patent Nos. 5,952,467 and 5,972,697. Additionally, the PIN1 sequences have been deposited in GenBank with the registration numbers NM006221 (mRNA) and S68520 (protein). The sequence of dodo mRNA is deposited in GenBank under registration number U35140. The mouse PIN1 mRNA sequence is deposited in GenBank with the registration number NM023371. The crystal structure of full-length PIN1 has been published in Ranganathan, R. et al., Cell, 89, 875-886 (1997) and in International Publication No. WO 99/63931. Zhang et al, provide further analysis of the crystal structure of PIN1 in complex with Ala-Pro. { Biochemistry, 41:39 11868-77 (2002)). Lu et al. (International Publication No. WO 01/38878) and Wulf et al. (EMBO J. 20, 3459-3472 (2001)) describe that PIN1 is upregulated in human tumors and that it is a biomarker of cell proliferation. In the literature, inhibitors of PIN1 have been described. For example, Hennig et al. (Biochemistry, 37, 5953-5960 (1998)) publish that juglone (5-hydroxy-1,4-naphthoquinone) selectively inhibits many parvulinas, including human PIN1. Noel et al. in U.S. Patent Application No. 20010016346, using data based on the crystal structure obtained from full-length human PIN1, describe compounds that are postulated to be inhibitors of PIN1. Lu et al. in International Publication No. WO 99/12962 disclose inhibitors that mimic the phospho-Ser / Thr moiety of the phosphoserine or phosphothreonine-proline substrate of the peptidyl prolyl isomerase. Due to the important role that PIN1 plays in cell cycle regulation, additional compounds that inhibit PIN1 are needed. These compounds, together with pharmaceutical compositions thereof, can serve as effective chemotherapeutic agents for the treatment of different disorders characterized by hypertension, inappropriate cell proliferation, including cancer, infectious diseases, and neurodegenerative brain disorders. The invention provides said compounds that inhibit PIN1.
SUMMARY OF THE INVENTION Accordingly, an object of the invention is to discover compounds and methods for modulating or inhibiting PIN1. Another object of the invention is to provide compounds and methods for modulating or inhibiting PIN1 that can be used in pharmaceutical compositions for the treatment of disorders characterized by hypertension, inappropriate cell proliferation, infectious diseases, and neurodegenerative brain disorders. These and other objects of the invention, which will become apparent from the following description, have been achieved by the discovery of phosphate / sulfate ester compounds, pharmaceutically acceptable prodrugs, active metabolites from a pharmaceutical point of view, and pharmaceutically acceptable salts thereof (reference is made to said compounds, prodrugs, metabolites and salts collectively as "agents") described below, which inhibit PIN1. Pharmaceutical compositions containing said agents are useful for treating diseases characterized by hypertension, inappropriate cell proliferation, infectious diseases, and neurodegenerative brain disorders. In a general aspect, the invention relates to compounds of Formula I: Formula I in which: n is 1 or 2; A is a -CH = CH-, - (alkyl-Ci-C7 -) - Y-, -NRd (CH2) tY-, -Y- (alkyl-C1-C7) -, -Y- (alkyl-CrC7) -, -Y-NH-, -Y-NRd (alkyl-Ci-C6) -, -S-, -S (0) 2-, -OY-, - Y-0-, -YS-, or -SY-divalent, wherein Rd is H or C1-C6 alkyl, t is an integer from 0 to 5, Y is C (O), C (S), S (O), S (0) 2, or a link; X is a direct bond, CH2, CF2, O, S, NH, C (O), or C (S); R1 is a C3-Ci0 cycloalkyl group, 4- to 10-membered heterocydoalkyl, C6-C10 aryl, or 4- to 10-membered heteroaryl, wherein R1 is unsubstituted or substituted by 1 to 4 R10 groups; R2 is -S (0) 2OH, -S (0) 2NRdRe, or -P (0) (OR4) 2l wherein R4 is an H, C1-C10 alkyl group, C6-Ci0 aryl, or -CH2-0 -C (0) ReCH3, Rd and Re are each independently an H or a Ci-C6 alkyl group, and R4 is unsubstituted or is substituted with 1 to 4 R10 groups; and R3 is OH, C1-C7 alkyl, C1-C7 alkoxy, C6-Ci0 aryl, 4- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocydoalkyl, -NH (R5), or -N (R5 ) 2, wherein R5 is independently selected from H, C1-C7 alkyl, C6-C10 aryl, or wherein ring B is a 5- or 6-membered heterocyclealkyl group, Z is a C (0) Z ', heteroaryl or heterocyclealkyl divalent group in which Z' is an O, S, NH, N (CH3), C02 , or divalent CH2, and R6 is H, C1-C10 alkyl group, aryl, Ci-C6 alkyl aryl, or arylalkyl, wherein R3, R5, B and R5 are unsubstituted or substituted with 1 to 4 R10 groups; wherein each R is independently selected from halo, amino, = 0, = S, = NH, cyano, nitro, hydroxyl, -SH, haloalkyl, heteroalkyl of 2 to 10 members, Ci-C6 alkoxy, Ci-alkyl C, C2-C6 alkenyl, C2-C6 alkynyl, -C (0) jRa, -OC (0) jRd, -OC (0) OC (0) Rd, -OOH, -C (NRd) NRbR °, -NRdC (NRe) NRbR °, -NRdC (0) jRb, -C (0) NRbR °, -C (0) NRdCORb, -OC (0) NRbRc, -NRbRc, -NRdORc, -C (S) NRbRc, -NRdC (S) NRbRc, -NRdC (0) NRbR °, -OSH, -S (0) jRb, -OS (0) jRb, -SC (0) Rb, -S (0) jC (0) ORb, -SCORd , -NRdSRc, -SRb, -NHS (0) jRb, -COSRb, -C (0) S (0) jRb, -CSRb, -CS (0) jRb, -C (SO) OH, -C (SO) 2OH, -NRdC (S) Rc, -OC (S) Rb, -OC (S) OH, -OC (SO) 2R, -S (0) jNRbRc, -SNRbR °, -S (0) NRbR °, - NRdCS (0) jR °, -C (0) j (CH2) tNRd- (4- to 10-membered heteroaryl), -C (0) j (CH2) tNRd (4- to 10-membered heterocycloalkyl), - (CRdRe) tCN, - (CRdRe) t (C3-Ci0 cycloalkyl), - (CRdRe) t (arylC6-Cio), - (CRdRe) t (heterocycle-alkyl of 4 to 10 members), - (CRdRe) t (heteroaryl of 4) to 10 members), - (CRdRe) qC (0) (CRdRe) t (C3-Cio cycloalkyl), - (CRdRe) qC (0) (CRdRe) t (C6- aryl) C10), - (CRdRe) qC (0) (CRdRe) t (4 to 10 membered heterocycloalkyl), - (CRdRe) qC (0) (CRdRe) t (4 to 10 membered heteroaryl), (CRdRe) tO ( CRdRe) q (C3-C10 cycloalkyl),. - (CRdRe) tO (CRdRe) q (C6-C10 aryl), - (CRdRe) tO (CRdRe) q (4 to 10 membered heterocycloalkyl), (CRdRe) tO (CRdRe) q (4 to 10 membered heteroaryl) , (CRdRe) qS02 (CRdRe) t (C3-C 0 cycloalkyl), - (CRdRe) qS02 (CRdRe) t (C6-Ci0 aryl), - (CRdRe) qS02 (CRdRe) t (4- to 10-membered heterocycloalkyl) , and - (CRdRe) qS02 (CRdRe) t (4 to 10 membered heteroaryl), wherein Ra is selected from the group consisting of halo, hydroxyl, -NRdRe, C1-C10 alkyl, haloalkyl, C1-C6 alkoxy, Rb and R ° are independently selected from H, d-C10 alkyl, - (CRdRe) t (C3-C10 cycloalkyl), - (CRdRe) t (C6-C10 aryl), - (CRdRe) t (4- to 10-membered heterocycloalkyl), and - (CRdRe) t (4- to 10-membered heteroaryl), Rd and Re are independently H or Ci-C6 alkyl, j is an integer of 0 to 2, q and t are each independently an integer from 0 to 5, and 1 or 2 ring carbon atoms of the cyclic moieties of the above R10 groups are unsubstituted or substituted with = 0, and the alkyl moieties are , alkenyl, alkynyl, aryl and cyclics of the Ri0 groups above are unsubstituted or substituted with 1 to 3 substituents independently selected from halo, = 0, cyano, nitro, - (CRdRe) tCN, haloalkyl, heteroalkyl of 2 to 10 members, -OR, -C (0) jRb, -NRdC (0) Rb, -C (0) NRbRc, -NRbRc, -NRbORc, -NRdC (0) jNRbRc, -NRdC (0) jRbR °, -OC (0) jRb, -OC (0) NRbRc, -SRd, C1-C10 alkyl, C2-C6 alkenyl, C2- alkynyl C6, - (CRdRe) t (C3-C 0 cycloalkyl), - (CRdRe) t (C6-C10 aryl), - (CRdRc) l (4- to 10-membered heterocycloalkyl), - (CRdRe) t (heteroaryl 4 to 10 members), - (CRdRe) t (C6-C10 aryl) - (CrC6 alkyl); where t, Rb, Rc, Rd, Re are as defined above. The invention is also directed to pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of the compounds of Formula I and their active metabolites from a pharmaceutical point of view. Advantageous methods for preparing the compounds of Formula I are also described.
In a preferred embodiment, the invention relates to compounds of Formula I, wherein n is 1 or 2; A is a -NH-Y-, -NRd (CH2) t-Y-, or -O-Y- divalent, and Y is C (O) or S (0) 2; X is a direct link, CH2, O, or S; R1 is a C6-C10 aryl or 4 to 10-membered heteroaryl group unsubstituted or substituted with 1 to 4 R10 groups; R2 is -S (0) 2OH, or -P (0) (OR4) 2, wherein R4 is an H, C1-C10 alkyl group, or C6-C10 aryl, and is unsubstituted or substituted by 1 to 4 groups R10; and R3 is a C6-C10 aryl, 4- to 10-membered heteroaryl, -NH (C6H5), or wherein ring B is a 5- or 6-membered heterocycloalkyl group, Z is a C (0) Z ', heteroaryl or heterocycloalkyl divalent group in which Z' is an O, S, NH, N (CH3), C02 , or divalent CH2, and R6 is H or a C1-C10 alkyl group, wherein R3, B, and R6 are unsubstituted or substituted with 1 to 4 R10 groups; and wherein R10 is as defined above. In an especially preferred embodiment, the invention relates to compounds of Formula I, wherein n is 1; A is a -NH-Y- or -O-Y-divalent, in which Y is C (O); X is a direct link, CH2, or O; R1 is a Ce-C-io aryl group unsubstituted or substituted with 1 to 4 R10 groups; R2 is -P (0) (OR4) 2, wherein R4 is an H, C1-C10 alkyl group, or C6-C10 aryl, and is unsubstituted or substituted with 1 to 4 R10 groups; and R3 is a C6-C10 aryl, heteroaryl from 4 to 10 members, or wherein ring B is an unsubstituted 6-membered heterocycloalkyl, Z a divalent C (0) Z ', Z' is a divalent O, S, or CH2, and R6 is a Ci-C-io alkyl group, that R3, B and R6 are unsubstituted or substituted with 1 to 4 R10 groups; and wherein R10 is as defined above. In a particularly preferred additional embodiment, the invention relates to compounds of Formula I, wherein n is 1; A is -NH-Y- or -O-Y-, wherein Y is C (O); X is a direct link, CH2, or O; R1 is a C6-C10 aryl group unsubstituted or substituted by 1 to 4 R0 groups; R2 is -P (0) (OR4) 2, wherein R4 is an H or a C1-C10 alkyl group which is unsubstituted or substituted by 1 to 4 R10 groups; and R3 is a C6-Cio aryl or 4- to 10-membered heteroaryl group unsubstituted or substituted with 1 to 4 R0 groups; and wherein R10 is as defined above. Preferably, the invention includes compounds, and pharmaceutically acceptable salts thereof, selected from the following group: -12- -13- The invention also relates to a method for inhibiting PIN1 by administering a compound of Formula I or a pharmaceutically acceptable prodrug, a pharmaceutically active metabolite, or a pharmaceutically acceptable salt. of said compound or of a metabolite thereof. The invention also relates to pharmaceutical compositions, comprising a therapeutically effective amount of an agent selected from compounds, prodrugs, metabolites, and salts of compounds of Formula I, and a carrier for said agent acceptable from a point of view. pharmaceutical view The invention further provides methods for treating conditions associated with mammalian diseases mediated by PIN1 activity, by administration to a mammal in the need for a therapeutically effective amount of a compound, prodrug, active metabolite or salt of a compound of Formula I. Conditions associated with diseases of mammals that are treated according to the invention are associated with hypertension, inappropriate cell proliferation (e.g., cancer), infectious diseases (e.g., bacterial and fungal infections), and neurodegenerative brain disorders (e.g., Alzheimer's disease). The compounds of Formula I are useful for modulating or inhibiting PIN1. More especially, the compounds are useful in modulating or inhibiting the activity of PIN1, thereby providing treatments for hypertension, infectious diseases, neurodegenerative disorders, and cancer or other diseases associated with cell proliferation. The terms "comprising" and "including" are used herein in their broadest and non-limiting sense. Used as described herein, "inappropriate cell proliferation" includes diseases or disorders associated with uncontrolled or abnormal cell proliferation. Such diseases and disorders include, but are not limited to, the following: - different cancers, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous melanoma or intraocular, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, cancer uterine, fallopian tube carcinoma, endometrial carcinoma, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland , cancer of the parathyroid gland, cancer of the adrenal gland, soft tissue sarcoma, cancer of the urethra, cancer of the penis, cancer of the prostate, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, kidney or kidney cancer urethra, renal cell carcinoma, renal pelvis carcinoma, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal cord tumors, brainstem glioma, pituitary adenoma, or a combination of one or more of the previous cancers; a process of a disease exhibiting an abnormal cell proliferation, for example, benign prostatic hyperplasia, familial adenomatous polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic formation of scars, inflammatory bowel disease, rejection of transplants, endotoxic shock, and fungal infections; and conditions associated with defective apoptosis, such as cancers (including, but not limited to, the types mentioned hereinabove), viral infections (including, but not limited to, HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of the development of AIDS in HIV-infected individuals, autoimmune diseases (including, but not limited to, systemic lupus erythematosus) , rheumatoid arthritis, psoriasis, autoimmune-mediated glomerulonephritis, inflammatory bowel disease, and autoimmune diabetes mellitus), neurodegenerative disorders (including, but not limited to, Alzheimer's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, Parkinson's disease, dementia related to AIDS, spinal muscular atrophy, and degeneration of the cerebellum), myelodysplastic syndromes, aplastic anemia, ischemic damage associated with myocardial infarctions, vascular damage due to stroke and reperfusion, arrhythmia, atherosclerosis, toxin-induced or alcohol-related liver diseases, hematological (including, but not limited to, ane chronic myelitis and aplastic anemia), degenerative diseases of the musculoskeletal system (including, but not limited to, osteroporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases, and pain associated with cancer. The term "alkyl" used as described herein refers to a linear or branched chain, saturated or partially unsaturated, alkyl group having from one to twelve carbon atoms. The Preferred alkyl groups have from 1 to 10, and more preferably from 1 to 7, carbon atoms. Exemplary alkyl groups include methyl (Me, which may also be structurally described by "/"), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tere-butyl (tBu), pentyl, isopentyl , tert-pentyl, hexyl, isohexyl, and the like. The term "lower alkyl" designates an alkyl having 1 to 6 carbon atoms (a C 1 -C-alkyl). The term "aryl" (Ar) refers to an aromatic, monocyclic, or fused or spiro-cyclic carbocycle (ring structure having ring atoms that are all carbons) having from three to twelve ring atoms per ring, preferably 6 to 10 atoms in the ring and more preferably 5 to 7 atoms in the ring. Illustrative examples of aryl groups include the following moieties: The term "heteroaryl" (heteroAr) refers to a monocyclic, or fused or spiro-cyclic aromatic heterocycle (ring structure having ring atoms selected from carbon atoms as well as nitrogen, oxygen, and sulfur heteroatoms) having from three to twelve atoms in the ring per ring, preferably 4 to 10 atoms in the ring and more preferably 5 to 7 atoms in the ring. Illustrative examples of aryl groups include the following moieties: The term "cycloalkyl" refers to a monocyclic, or fused or spiropyclic, saturated or partially saturated carbocycle, having from three to twelve ring atoms per ring, preferably 3 to 10 carbon atoms and more preferably 5 to 7 carbon atoms. carbon. Illustrative examples of cycloalkyl groups include the following moieties: Co.co.co, and similar.
A "heterocycloalkyl" refers to a monocyclic, or fused or spiro polycyclic ring structure, which is saturated or partially saturated and has from three to twelve atoms in the ring selected from C atoms and heteroatoms N, O and S, preferably 4 to 10 atoms in the ring and more preferably 5 to 7 atoms in the ring. Illustrative examples of heterocycloalkyl groups include: The term "alkoxy" refers to -O-alkyl. Illustrative examples include methoxy, ethoxy, propoxy, and the like. The term "halogen" represents chlorine, fluorine, bromine or iodine. The term "halo" represents chlorine, fluorine, bromine or iodine. Used as described herein, "haloalkyl" refers to a lower alkyl radical in which one or more of the hydrogen atoms are replaced by halogen including, but not limited to, chloromethyl, trifluoromethyl, 1-chloro-2 -fluoroethe and similar. "Heteroalkyl" is an alkyl group (as defined herein) in which at least one of the carbon atoms is replaced by a heteroatom. The preferred heteroatoms are nitrogen, oxygen, sulfur, and halogen. A heteroatom may have, although it typically does not have, the same number of valence sites as carbon. Therefore, when a carbon is replaced by a heteroatom, it may be necessary to increase or decrease the number of hydrogens bound to the heteroatom in order to conform to the valence sites of the heteroatom. For example, if the carbon (valence four) is replaced by nitrogen (valence three), one of the hydrogens initially attached to the replaced carbon must be removed. Similarly, if the carbon is replaced by halogen (valence one), three hydrogens (that is, all) bound initially to the replaced carbon must be eliminated. As another example, trifluoromethyl is a heteroalkyl group in which the three methyl groups of a t-butyl group are replaced by fluorine. Preferred heteroalkyls of the invention have 2 to 10 member atoms, including both heteroatoms and carbon atoms. The term "substituted" means that the group or the specified moiety supports one or more substituents. The term "unsubstituted" means that the specified group does not support substituents. The compounds of the invention may exhibit the phenomenon of tautomerism. Although Formula I can not expressly describe all possible tautomeric forms, it should be understood that Formula I is intended to represent any tautomeric form of the described compound and that it is not limited merely to a specific form of the compound described by the drawings of the formula. The compounds of Formula I may have one or more asymmetric centers indicated by an asterisk as shown below in Formula I. Additional asymmetric centers may be present in the molecule depending on the nature of the various substituents in the molecule.
Formula As a consequence of these asymmetric centers, the compounds of Formula I can exist as unique stereoisomers (ie, essentially without other stereoisomers), racemates, and / or mixtures of enantiomers and / or diastereomers. It is intended that all single stereoisomers, racemates, and mixtures thereof be within the scope of the present invention. Preferably, the compounds of the invention which are optically active are used in optically pure form.
In accordance with an agreement used in the art, it is used in structural formulas herein to describe the bond that is the point of attachment of the moiety or substituent to the central or main structure. As generally understood by those skilled in the art, an optically pure compound having a chiral center (i.e., an asymmetric carbon atom) is one that consists essentially of one of the two possible enantiomers (ie, is enantiomerically pure) , and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure. Preferably, the compounds of the present invention are used in a form that is at least 90% optically pure, that is, a form that contains at least 90% of a single isomer (80% enantiomeric excess ("ee") or excess diastereomeric ("from")), more preferably at least 95% (ee or from 90%), even more preferably at least 97.5% (ee or from 95%), and most preferably at least 99% ( ee or of 98%). Additionally, it is intended that Formula I encompasses both solvated and unsolvated forms of the identified structures. For example, Formula I includes compounds of the structure indicated in both hydrated and non-hydrated forms. Other examples of solvates include structures in combination with isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine. In addition to the compounds of Formula I, the invention includes pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of said compounds and metabolites. "A pharmaceutically acceptable prodrug" is a compound that can be converted to physiological conditions or by solvolysis in the specified compound or in a salt of said pharmaceutically acceptable compound. "An active metabolite from a pharmaceutical point of view" is meant to mean an active product from a pharmaceutical point of view produced by the metabolism in the body of a specified compound or a salt thereof. Prodrugs and active metabolites of a compound can be identified using routine techniques known in the art. See, for example, Bertolini et al., J. Med. Chem., 40, 2011-2016 (1997); Shan, et al., J. Pharm. Sci., 86 (7), 765-767; Bagsha e, Drug Dev. Res., 34, 220-230 (1995); Bodor, Advances in Drug Res., 13, 224-331 (1984); Bundgaard, Design of Prodrugs (Elsevier Press 1985); Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., Eds., Harwood Academic Publishers, 1991); Dear et al., J. Chromatogr. 8, 748, 281-293 (2000); Spraul et al., J. Pharmaceutical & Biomedical Analysis, 10, 601-605 (1992); and Prox et al., Xenobiol., 3, 103-112 (1992). "A pharmaceutically acceptable salt" is meant to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not undesirable from a biological point of view or from any other. A compound of the invention may possess a sufficiently acidic group, a sufficiently basic group, or both functional groups, and thereby react with any inorganic or organic base and with inorganic and organic acids to form an acceptable salt from a pharmaceutical point of view. . Exemplary pharmaceutically acceptable salts include salts prepared by reaction of the compounds of the present invention with an inorganic or organic acid or an inorganic base, such as salts that include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites. , phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formats, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacate, fumarates, maleates , butin-, 4-dioates, hexin-1, 6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylene sulphonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates,? -hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates. If the inventive compound is a base, the desired salt from a desired pharmaceutical standpoint can be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, acid sulfuric acid, nitric acid, phosphoric acid and the like or with an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid , such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like. If the inventive compound is an acid, the desired salt from a desired pharmaceutical standpoint can be prepared by any suitable method, for example, by treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary). ), an alkali metal hydroxide or an alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts from amino acids, such as glycine and arginine, ammonia, primary, secondary and tertiary amines and cyclic amines such such as piperidine, morpholine and piperazine and inorganic salts from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium. In the case of agents that are solid, it is understood by those skilled in the art that the compounds and inventive salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and the specified formulas . Lu et al. (International Publication No. WO 01/38878, incorporated herein by reference in its entirety) discloses that PIN1 is overexpressed in different cancers, including breast, colon, and prostate. Additionally, the authors describe that PIN1 is overexpressed in proliferating cells. Therefore, the agents of the invention can be useful for treating different cell proliferation diseases associated with overexpression of PIN1. Therapeutically effective amounts of the agents of the invention can be used to treat diseases mediated by the modulation or regulation of PIN1. An "effective amount" is intended to mean the amount of an agent that, when administered to a mammal in need of such treatment, is sufficient to carry out the treatment of a disease modulated or inhibited by PIN1 activity. Therefore, for example, a therapeutic effective amount of a compound of Formula I, salt, active metabolite or prodrug thereof is an amount sufficient to modulate, regulate or inhibit the activity of PIN1 in a manner that reduces or alleviates a condition that is associated with a disease that is mediated by that activity. The amount of a particular agent that will correspond to said amount will vary depending on factors such as the particular compound, condition associated with the disease and its severity, identity (e.g., weight) of the mammal in need of treatment, but can be determined routinely by an expert in the art. The term "treat" refers to: (i) preventing the occurrence of a disease, disorder, or condition in an animal that may be predisposed to the disease, disorder, and / or condition, but has not yet been diagnosed as having it; (ii) inhibit the disease, disorder, or condition, that is, slow down its development; and (ii) mitigate the disease, disorder, or condition, i.e., bring about the regression of the disease, disorder and / or condition.
DETAILED DESCRIPTION OF THE INVENTION AND THE PREFERRED MODALITIES The active agents of the invention can be formulated in pharmaceutical compositions as described below. The pharmaceutical compositions of this invention comprise an amount of a compound of Formula I that modulates, regulates or inhibits effectively and an inert vehicle or diluent acceptable from a pharmaceutical standpoint. In In an embodiment of the pharmaceutical compositions, effective levels of the inventive agents are provided to provide therapeutic benefits involving the modulation of PIN1. By "effective levels" is meant levels at which the effects of PIN 1 activity are, at a minimum, regulated. These compositions are prepared in unit dose form appropriate for the route of administration, for example, parenteral or oral administration. An inventive agent can be administered in conventional dosage form prepared by combining a therapeutic effective amount of an agent (e.g., a compound of Formula I) as an active ingredient with vehicles or diluents suitable from a pharmaceutical point of view. according to conventional procedures. These methods may involve mixing, granulating and compressing or dissolving the ingredients as appropriate for the desired preparation. The pharmaceutical carrier used can be a solid or a liquid. Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary liquid vehicles are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include controlled release or retarding material known in the art, such as glycerol monostearate or glycerol distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methyl methacrylate and the like.
Different pharmaceutical forms can be used. Therefore, if a solid carrier is used, the preparation can be compressed, put into a hard gelatin capsule in the form of powder or granules or in the form of a tablet or tablet. The amount of solid carrier may vary, but will generally be from about 25 mg to about 1 g. If a liquid vehicle is used, the preparation will be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in a vial or vial or non-aqueous liquid suspension. To obtain a stable water-soluble dosage form, a salt of a pharmaceutically acceptable inventive agent can be dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3 M solution of succinic acid or citric acid. If a soluble salt form is not available, the agent can be dissolved in a suitable co-solvent or co-solvent combinations. Examples of suitable co-solvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0-60% of the total volume. In an exemplary embodiment, a compound of Formula I is dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution. It will be appreciated that the actual doses of the agents used in the compositions of this invention will vary according to the complex particular that is being used, the particular composition formulated, the route of administration and the particular site, host and disease being treated. Optimal dosages for a given set of conditions can be determined by those skilled in the art using conventional dose determination assays, in view of the experimental data for an agent. For oral administration, an exemplary daily dose generally employed is from about 0.001 to about 1000 mg / kg body weight, with evolution of the treatment repeated at appropriate intervals. Prodrug administration is typically dosed at weight levels, which are chemically equivalent to the weight levels of the fully active form. The compositions of the invention can be manufactured in manners generally known in the preparation of pharmaceutical compositions, for example, using conventional techniques such as mixing, dissolving, granulating, dragee-making, levigating, trapping, emulsifying, encapsulating, or lyophilizing. The pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, which can be selected from excipients and adjuvants that facilitate processing of the active compounds into preparations, which can be used pharmaceutically. The appropriate formulation depends on the chosen route of administration. For injection, the agents of the invention can be formulated in aqueous solutions, preferably in compatible buffers from a physiological point of view such as Hanks solution, Ringer's solution or physiological saline buffer. For transmucosal administration, appropriate penetrating fluids are used in the formulation to the barrier that has to be permeated. Such penetrating fluids are generally known in the art. For oral administration, the compounds can be easily formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art. Said vehicles make it possible for the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, mixtures, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture and treating the mixture of granules after adding suitable adjuvants, if desired, to obtain tablets or dragee cores. . Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate.
Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which optionally may contain gum arabic, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents. Pharmaceutical preparations that can be used orally include snap-fit capsules made of gelatin, as well as soft sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Pressure-adjusting capsules may contain the active ingredients in admixture with fillers such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active agents can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration should be in doses suitable for said administration. For sublingual administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. For administration intranasally or by inhalation, the compounds for use according to the present invention are conveniently administered in the form of an aerosol spray presentation from pressurized packages or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or another suitable gas. In the case of a pressurized aerosol the dose unit can be determined by providing a valve for dispensing a measured quantity. Capsules and gelatin cartridges for use in an inhaler or insufflator and the like can be formulated containing a powder mixture of the compound and a suitable powder base such as lactose or starch. The compounds can be formulated for parenteral administration by injection, for example, by rapid intravenous injection or by continuous infusion. Formulations for injection can be presented in unit dose form, for example, in ampoules or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents can be prepared as appropriate injection oily suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as Sesame oil or esters of synthetic fatty acids such as ethyl oleate or triglycerides, or liposomes. Aqueous suspensions for injection may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain stabilizers or suitable agents, which increase the solubility of the compounds to allow the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for reconstitution before use with a suitable vehicle, for example, sterile, pyrogen-free water. The compounds can also be formulated in rectal compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described above, the compounds can also be formulated as a slow release drug preparation. Such long acting formulations can be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins or poorly soluble derivatives, for example, as a poorly soluble salt. An exemplary pharmaceutical vehicle for hydrophobic compounds is a co-solvent system comprising benzyl alcohol, a non-polar surfactant, an organic water-miscible polymer and an aqueous phase. The co-solvent system can be a co-solvent system of VPD. VPD is a solution of benzylic alcohol at 3% w / v, non-polar surfactant polysorbate 80 at 8% w / v and polyethylene glycol 300 at 65% w / v, completing up to the final volume with absolute ethanol. The VPD co-solvent system (VPD: 5W) contains VPD diluted 1: 1 with a 5% dextrose solution in water. This co-solvent system dissolves hydrophobic compounds well and produces low toxicity by itself after systemic administration. Naturally, the proportions of a co-solvent system can be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components can be varied: for example, other non-polar surfactants with low toxicity can be used instead of polysorbate 80; the size of the polyethylene glycol fraction can be varied; other biocompatible polymers can replace polyethylene glycol, for example, polyvinylpyrrolidone; and other sugars or polysaccharides can be substituted for dextrose. Alternatively, other administration systems for the hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles for hydrophobic drugs. Certain organic solvents can also be used, such as dimethylsulfoxide, but usually at the expense of greater toxicity. Additionally, the compounds can be released using a prolonged release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various prolonged release materials have been established and are known to those skilled in the art. Prolonged-release capsules may, depending on their chemical nature, release the compounds for a few weeks to over 100 days. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed. The pharmaceutical compositions may also comprise suitable vehicles or excipients, in solid phase or in gel phase. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols. Some of the compounds of the invention can be provided as salts with compatible counterions from a pharmaceutical point of view. Compatible salts from a pharmaceutical point of view can be formed with numerous acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. The salts tend to be more soluble in aqueous solvents or other protonic solvents than the corresponding free base forms. The inventive agents can be prepared using reaction routes and synthesis schemes as described below, using general techniques known in the art using starting materials that can be easily obtained. The preparation of the preferred compounds of the present invention is described in detail in the following examples, although one skilled in the art will recognize that the described chemical reactions can easily be adapted to prepare other inhibitors of PIN1 than the invention. For example, the synthesis of non-exemplified compounds according to the invention can be carried out by modifications apparent to those skilled in the art, for example, by adequately protecting the interfering groups, switching to other suitable reagents known in the art, or making routine modifications of the reaction conditions. Alternatively, it will be recognized that other reactions described herein or generally known in the art have applicability to prepare other compounds of the invention.
EXAMPLES In the examples described below, unless otherwise stated, all temperatures are shown in degrees Celsius (° C) and all parts and percentages are by weight. Reagents were obtained from commercial distributors, such as Aldrich Chemical Company or Lancaster Synthesis Ltd. and used without further purification unless otherwise indicated. Tetrahydrofuran and?,? - dimethylformamide were obtained from Aldrich in bottles with safety closure and were used when they were received. All solvents were purified using standard methods known to those skilled in the art, unless otherwise indicated. The reactions described below were generally carried out under a positive argon pressure at room temperature (unless otherwise specified) in anhydrous solvents, and the reaction flasks were equipped with rubber septum for the introduction of substrates and reagents by a syringe. The glass material was dried in oven and / or with heat. Analytical thin-layer chromatography (TLC) was performed on 60 F 254 plates of Analtech (0.25 mm) of silica gel fired on glass, eluted with the appropriate proportions of solvent (v / v), and indicated when It was appropriate. The reactions were tested by TLC and terminated when judged by the consumption of the starting material. Visualization of the TLC plates was performed with iodine vapor, ultraviolet illumination, 2% Ce (NH4) (S04) 4 in 20% aqueous sulfuric acid, or vaporized p-anisaldehyde reagent, and activated with heat when It was appropriate. The final treatments were typically done by doubling the reaction volume with the reaction solvent or extraction solvent and then washing with the indicated aqueous solutions using 25 volume% of the extraction volume unless otherwise indicated. The product solutions were dried over Na2SO4 and / or anhydrous Mg2SO4 before filtration and evaporation of the solvents under reduced pressure in a rotary evaporator and scored as solvents removed in vacuo. Flash column chromatography (Still et al., J. Org. Chem., 43, 2923 (1978)) was carried out using silica gel of Merck (47-61 Dm) with a proportion of silica gel and crude material of approximately 20: 1 to 50: 1, unless otherwise indicated. The hydrogenolysis was carried out at the pressure indicated in the examples or at atmospheric pressure. All melting points (mp) are uncorrected. The 1H-NMR spectra were recorded in an instrument Bruker or Varian that worked at 300 MHz and the 3C-NMR spectra were recorded operating at 75 MHz. The NMR spectra were obtained as CDC solutions (indicated in ppm), using chloroform as reference standard (7.27 ppm and 77 ppm). , 00 ppm) or CD3OD (3.4 and 4.8 ppm and 49.3 ppm), or an internal standard of tetramethylsilane (0.00 ppm) when appropriate. Other solvents were used for NMR when necessary. When multiplicities of the peaks are indicated, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (widened), dd (doublet of doublets), dt (doublet of triplets) . Coupling constants, when they appear, are indicated in Hertz (Hz). The infrared (IR) spectra were recorded on a Perkin-Elmer FT-IR spectrometer as pure oils, as KBr sediments or as CDCI3 solutions, and when shown are indicated in wave numbers (cm-1). Mass spectrometry (MS) was carried out with different techniques. Mass spectra were obtained using liquid chromatograph mass spectrometry with electrospray ionization, MS (ESP). Mass Spectrometry with Fourier Transform with Matrix Assisted Laser Desorption / Allocation (MALDI) was performed on a lonSpec FTMS mass spectrometer. The following compounds of the invention were prepared according to the general synthetic routes shown in Schemes 1 to 10 and to the detailed experimental processes appearing after them. These synthetic routes and experimental processes use many common chemical abbreviations, such as THF (tetrahydrofuran), DMF (?,? - dimethylformamide), EtOAc (ethyl acetate), DBU (1,8-diazacyclo [5.4.0] undec-7). -one), TMSCI (trimethylsilyl chloride), MCPBA (3-chloroperoxybenzoic acid), EDC (1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride), HOBT (hydrate-hydroxybenzotriazole), DMAP (4- dimethylaminopyridine), TBDPSCI (t-butyldiphenylchlorosilane), TMSBr (bromo-trimethylsilane), DIEA (diisopropylethylamine), TBAI (tetrabutylammonium iodide), and the like.
SCHEME 1 CiSOsH a3N 5b1 m = 2 Re- (CH ^ Pii Z-C (0) 0- Alcohol 2a: To a solution of pyridine (1 ml_) of sulfamoyl chloride 1a (0.14 g, 0.5 mmoles, preparation described in International Publication No. WO 0140185) was added D-phenylalaninol (0.151 g, 1 mmol) at 25 ° C. After 12 h, the reaction mixture was concentrated in vacuo. The yellow rest was purified by flash column chromatography (25% ethyl acetate (EtOAc) in hexanes) followed by preparative TLC to yield 70 mg (33% yield) of compound 2a. 1 H NMR (CDCl 3): d 7.24-7.0 (10H, m), 4.89 (2H, AB), 4.70 (1 H, d, J = 8.7 Hz), 4.25 ( 1H, dd, J = 8.7, 3.6 Hz), 3.54 (2H, m), 3.28 (1 H, m), 3.04 (2H, m), 2.66 (2H, d, J = 6.6 Hz), 2.33 (1 H, m), 2.01 (1 H, m); HRMS (FAB) for C21 H27N2O5S (M + H +) 419.1641; Found 419.1629.
Example 3a: 1- (2-phenyl-1-sulfooxymethyl-ethylsulfamoyl) -pyrrolidine-2S-carboxylic acid benzyl ester At -70 ° C, triethylamine (EI3, 0.05 mL) and chlorosulfonic acid (8 mg, 5 μ ?, 0.068) were added to a solution of methylene chloride (2 mL) of the alcohol 2a (10 mg, 0.024 mmol). mmoles). The cooling bath was then removed and the reaction mixture was allowed to warm to 25 ° C for 3 h. All the solvent was evaporated in vacuo. The residue was purified by column chromatography (3% methanol (MeOH) in EtOAc) to yield 8 mg (67% yield) of the major compound 3a. 1 H NMR (CD 3 OD): d 7.4-7.15 (10H, m), 5.16 (2H, AB), 4.22 (1 H, dd, J = 8.7, 3.9 Hz), 4.04 (1 H, dd, J = 10.2, 4.8 Hz), 3.91 (1 H, dd, J = 10.2, 4.5 Hz), 3.77 (1 H, m) , 3.38 (1 H, m), 3.14 (1H, m), 2.93 (1H, dd, J = 14.1, 9.1 Hz), 2.81 (1H, dd, J = 14.1, 6.6 Hz), 2.18 (1 H, m), 1.97-7.73 (3H, m); MS (ESP): 497 (-H +); HRMS (FAB) for CarH sI ^ OsSaNa (M + Na +) 521, 1028; Found 521,1010.
Alcohol 2b1: Prepared as described in the synthesis of 2a using the n-butyl-phenyl ester of sulfamoyl chloride 1a (0.15 g, 0.42 mmol, preparation described in International Publication No. WO 0140185) and D-phenylalaninol ( , 18 g, 1.2 mmol). After purification by flash column chromatography (25% EtOAc in hexanes), compound 2b1 (62 mg) was obtained in 31% yield. 1 H NMR (CDCl 3): d 7.4-7.1 (10H, m), 5.17 (1H, d, J = 8.1 Hz), 4.68 (1 H, d, J = 4.5 Hz), 4.20 (2H, m), 3.75 (2H, m), 3.55 (1H, m), 3.35 (1H, br d, J = 12.1 Hz), 2.95 -2.73 (3H, m), 2.67 (2H, m), 2.45 (1H, br s), 2.24 (1 H, d, J = 13.1 Hz); HRMS (FAB) for C 25 H 34 N 205SNa (M + Na 4) 497,2086; found 497,2079.
Example 3b1: 1- (2-phenyl-1-sulfooxymethyl-ethylsulfamoyl) -piperidine-2S-carboxylic acid 4-phenyl-butyl ester Prepared as described in the synthesis of 3a using alcohol 2b1 (10 mg, 0.021 mmol), chlorosulfonic acid (6 mg, 4 μ ?, 0.055 mmol) and triethylamine (0.015 mL). The reaction mixture was diluted with EtOAc (20 mL) and washed with 5% hydrochloric acid (HCl) solution cooled on ice (1x20 mL). Column chromatography (8% MeOH in EtOAc) yielded 10 mg (85% yield) of the main compound 3b1. 1 H NMR (CDCl 3): 5 7.3-6.9 (10H, m), 6.03 (1H, br s), 4.26 (2H, m), 4.05 (2H, m), 3, 93 (1 H, br s), 3.58 (1 H, br s), 3.13 (1 H, m), 2.79 (3 H, m), 2.48 (2 H, m), 2.30 ( 1 H, m), 1.88 (1 H, m); HRMS (FAB) for C25H33N2O8S2CS2 (M-H ++ 2Cs +) 818.9787; found 818.9756.
Alcohol 2b2: Prepared as described in the synthesis of 2a using the sulfamoyl chloride 1b2 (0.15 g, 0.47 mmol, preparation described in International Publication No. WO 0140185) and D-phenylalaninol (0.214 g, 1.4 mmol). After purification by flash column chromatography (25% to 30% EtOAc in hexanes), compound 2b2 (66 mg) was obtained in 33% yield. 1 H NMR (CDCl 3): d 7.4-7.17 (10H, m), 5.19 (2H, AB), 5.03 (1 H, d, J = 8.4 Hz), 4.71 ( 1 H, br d, J = 4.8 Hz), 3.8-3.6 (2H, m), 3.48 (1H, m), 3.31 (1 H, br d, J = 12, 6 Hz), 2.88-2.74 (3H, m), 2.34 (1 H, br t, J = 5.1 Hz), 2.25 (1H, m).
Example 3b2: 1- (1-Benzyl-2-sulfooxy-ethylsulfamoyl) -piperidine-2S-carboxylic acid benzyl ester Prepared as described in the synthesis of 3a using alcohol 2b2 (30 mg, 0.069 mmol), chlorosulfonic acid (16 mg, 10 μ ?, 0.13 mmol) and triethylamine (0.05 ml_). The reaction mixture was diluted with EtOAc (20 mL) and washed with a 5% HCl solution cooled on ice (1x20 mL). Purification by column chromatography (5% MeOH in EtOAc) yielded 25 mg (70% yield) of the major compound 3b2. 1 H NMR (CDCl 3): d 7.31-7.01 (10H, m), 6.03 (1 H, br d, J = 9 Hz), 5.16 (1H, d, J = 12.3 Hz), 5.00 (1H, d, J = 12.3 Hz), 4.43-4.30 (2H, m), 4.1 (1H, m), 3.66 (1H, m), 3.37 (3H, m), 3.14 (1H, m), 2.80 (3H, m), 1.98 (1H, br d); HRMS (FAB) for CazHayNaOsSaNaa (M-H ++ 2Na +) 557.1004; found 557,1019.
Alcohol 2b3: Prepared as described in the synthesis of 2a using sulfamoyl chloride 1b3 (0.05 g, 0.105 mmol, preparation described in International Publication No. WO 0140185) and D-phenylalaninol (0.026 g, 0.17 mmol) ). After purification by flash column chromatography (25% to 30% EtOAc in hexanes), compound 2b3 (30 mg) was obtained in 48% yield. H NMR (CDCl 3): d 7.35-7.09 (15H, m), 5.07 (1 H, d, J = 7.8 Hz), 5.02 (1H, m), 4.64 ( 1H, br d, J = 4.5 Hz), 3.69 (2H, m), 3.47 (1H, m), 3.30 (1 H, br d, J = 12.6 Hz), 2 , 84 (2H, d, J = 7.2 Hz), 2.80 (1 H, td, J = 13.5, 3.9 Hz), 2.67-2.51 (4H, m), 2 , 26-2.08 (2H, m).
Example 3b3: 1- (2-Phenyl-1-sulfooxylmethyl-ethylsulfamoin-p-peridin-2S-carboxylic acid 4-phenyl-1- (3-phenyl-propyl) -butyl ester) Prepared as described in the synthesis of 3a using alcohol 2b3 (10 mg, 0.0169 mmol), chlorosulfonic acid (8 mg, 5 μ ?, 0.068 mmol) and triethylamine (0.05 mL). The reaction mixture was diluted with EtOAc (20 mL) and washed with a 5% HCl solution cooled on ice (1x20 mL). Purification by column chromatography (5% MeOH in EtOAc) yielded 8 mg (70% yield) of the major compound 3b3. 1 H NMR (CDCIs): d 7.36-7.00 (15H, m), 6.06 (1H, br d, J = 7.5 Hz), 4.90 (H, m), 4.31 ( 1H, br d), 4.20 (1H, br s), 4.06 (1H, m), 3.66 (1H, m), 3.34 (1H, br d, J = 11, 1 Hz) , 2.85 (3H, m), 2.51 (4H, m); HRMS (FAB) for C34H43N2O8S2CS2 (M-H ++ 2Cs +) 937.0570; found 937.0557.
Synthesis of Benzyl Ester To a mixture of L-penicillamine (14.92 g), 2-dichloroethane (300 mL) and DMF (2 mL) at 0 ° C was added 1,8-diazacyclo [5.4.0] undec-7-ene ( DBU, 22.4 mL), followed by trimethyl silyl chloride (TMSCI, 19 mL). After stirring for 3 h, the solution was warmed to 25 ° C, followed by the slow addition of DBU (29.9 mL). The reaction mixture was stirred for 17 h at 25 ° C. Methanol (10 mL) was added and a precipitate formed. The precipitate was collected by filtration and washed with a minimum amount of methanol. The solid was dried under vacuum at 50 ° C for 6 h to yield 3 (R) -2,2-dimethyl-tetra idro-2H-1,4-thiazine-3-carboxylic acid as a white powder (16 g). At 0 ° C, a portion of the thiazine (0.4 g, 2.3 mmol) was dissolved in a solution of NaOH (1 N, 12 mL). To the resulting mixture was added benzyl chloroformate (1.4 mL, 9.2 mmol). After 15 h at 25 ° C, the solution was diluted with water (20 mL) and extracted with EtOAc (2x25 mL). The extracts were dried (MgSO 4) and concentrated in vacuo. Purification by flash column chromatography (5-20% EtOAc in hexanes) yielded 0.63 g of the main compound 3b3. 1 H NMR (CDCl 3): (mixture of two rotamers) d 7.3 (0H, m), 7.11 (4H, br s), 4.87 and 4.70 (1H, s), 4.40 and 4 , 28 (1H, d, J = 6.7 Hz), 3.72 and 3.60 (1 H, m), 2.94 (1H, m), 2.37 (1H, t, J = 3, 9 Hz), 1.45 (3H, s), 1.34 (3H, s); MS (ESP) 400 (M + H +).
Sulfamoyl Chloride 1b4: CfSOsH To a solution of methylene chloride (2 mL) of the benzyl ester (0.6 g, 1.5 mmol) at 0 ° C were added methyl sulfide (1 mL) and BF3 · Et20 (0.2 mL). After 16 h, saturated NaHCO 3 solution (5 mL) was added to the reaction mixture and extracted with methylene chloride (2 x 20 mL). The combined organic layers were washed with concentrated saline (1x25 mL) and dried (Na2SO). All the solvent was removed in vacuo to give a light yellow oil (0.35 g), which was dissolved in methylene chloride (8 mL). To the resulting solution were slowly added triethylamine (1 mL) and CIS03H (0.23 g, 1.97 mmol). The mixture was allowed to warm to about 25 ° C and was stirred at that temperature for about 2 h. Then, the solution was concentrated in vacuo after which benzene (2x15 mL) was added and evaporated to remove trace amounts of Et3N and water. To the rest were added benzene (20 mL) and PCI5 (0.41 g, 1.97 mmol). The suspension was heated to reflux for about 30 minutes, then cooled to about 25 ° C and poured into an ice-cold NaOH solution (5%, 40 mL). Then, the aqueous mixture was extracted with CH2Cl2 (3x30 mL), dried over sodium sulfate and concentrated. The remainder was purified by flash column chromatography (3% EtOAc in hexanes) yielding 0.355 g (74%) of compound 1b4. Amine: 1 H NMR (CDCl 3): d 7,4-7,3 (5H, m), 5,14 (2H, AB), 3.75 (1H, s), 3.38 (1 H, m), 2.92 (2H, m), 2.27 (1H, m), 1.40 (3H, s), 1.26 (3H, s); Sulfamoyl Chloride 1b4: 1 H NMR (CDCl 3): d 7.43-7.29 (5H, m), 5.22 (2H, AB), 4.53 (1H, s), 4.24-4.05 (2H, m), 3.17 (1H, dd, J = 1, 7, 4 , 5 Hz), 3.13 (1 H, dd, J = 11.7, 4.8 Hz), 2.56 (1 H, dt, J = 14.1, 2.7 Hz), 1.58 ( 3H, s), 1, 29 (3H, s).
Alcohol 2b4: Prepared as described in the synthesis of 2a using sulfamoyl chloride 1b4 (0.2 g, 0.55 mmole) and D-phenylalaninol (0.166 g, 1.1 mmole). After purification by flash column chromatography (25% to 30% EtOAc in hexanes), compound 2b4 (10 mg) was obtained in 4% yield. 1H RN (CDCl3): d 7.42-7.12 (10H, m), 5.18 (2H, AB), 4.46 (2H, m), 3.68-3.59 (3H, m) , 3.48 (1H, m), 3.39 (1 H, m), 2.95 (1H, m), 2.76 (2H, d, J = 7.2 Hz), 2.32 (1H , dt, J = 13.5, 2.1 Hz), 1.87 (3H, s), 1.34 (3H, s).
Example 3b4: Benzyl ester of 3,3-dimethyl-1- (2-phenyl-1-sulfooxamethyl-ethylsulfamoyl) -piperidine-2R-carboxylic acid Prepared as described in the synthesis of 3a using alcohol 2b4 (6 mg, 0.0126 mmol), chlorosulfonic acid (6 mg, 4 μ ?, 0.04 mmol) and triethylamine (0.04 mL). The reaction mixture was diluted with EtOAc (20 mL) and washed with a 5% HCl solution cooled on ice (1x20 mL). Purification by column chromatography (5% MeOH in EtOAc) yielded 3 mg (43% yield) of the main compound 3b4. 1 H NMR (CDCl 3): d 7.34-7.06 (10H, m), 5.04 (2H, s), 4.23 (1H, s), 3.89 (1 H, dd, J = 9 , 9, 4.2 Hz), 3.82 (1 H, dd, J = 9.9, 5.1 Hz), 3.59 (1 H, td, J = 12.9, 3 Hz), 3, 52-3.33 (2H, m), 2.88 (1H, dd, J = 14.1, 6.8 Hz), 2.64 (1 H, dd, J = 14.1, 7.5 Hz) ), 2.53 (1H, td, J = 12.8, 4.2 Hz), 2.13 (1 H, dt, J = 14.1, 2.4 Hz), 1.37 (3H, s) ), 1, 09 (3H, s); MS (ESP) 557 (M-H ").
To a solution of acetonitrile (7 ml_) of the 2b1 alcohol (25 mg, 0.0527 mmol) and 1H-tetrazole (7.4 mg, 0.105 mmol) was added dibenzyl N, N-dusopropylphosphoramidite (27.3 mg, 0.079 mmol). ) at 25 ° C. After 1 h, 3-chloroperoxybenzoic acid (CPBA, 34 mg, 70% pure, 0.139 mmol) was added to the suspension. The solution was diluted with ether (40 mL), washed with concentrated NaHSÜ3 solution (2x30 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC to yield 29.5 mg of compound 4b1 in 76% yield. 1 H NMR (CDCl 3): d 7.30-7.05 (20H, m), 5.09 (1H, d, J = 9.3 Hz), 4.99 (4H, m), 4.52 (1H , m), 4.14-3.83 (4H, m), 3.68 (1H, m), 3.20 (1H, d, J = 12.9 Hz), 2.75 (2H, d, J = 7.2 Hz), 2.72 (1H, m), 2.54 (2H, m), 2.10 (1H, d, J = 13.5 Hz); HRMS (FAB) for C39H47N208PSCs (M + Cs +) 867.1845; found 867, 868.
Example 5b1: 1- (2-Phenyl-1-phosphonooxymethyl-ethylsulfamoyl) -piperidin-2S-carboxylic acid 4-phenyl-butyl ester To a methanol solution of the benzyl phosphate ester 4 -1 (29.5 mg, 0.0402 mmol) was added palladium on carbon (10%, 5 mg). The suspension was kept under hydrogen (1 atm) for 1.5 h. After filtration, the filtrate was concentrated to dryness, yielding 22.6 mg of the compound Main 5b1 with 100% performance. HRN (CDCl 3): d 7.34-6.95 (10H, m), 4.47 (1H, s), 4.17-3.82 (4H, m), 3.62 (1H, br s), 3.20 (1 H, br d), 3.28 (3 H, m), 2.53 (2 H, m), 1, 21 (1 H, br d); HRMS (FAB) for CasHssNaOsPSNa (M + Na +) 577.1749; found 577.1769.
Ester Bencil Phosphate 4b2: Prepared as described in the synthesis of 4b1 using alcohol 2b2 (240 mg, 0.554 mmol), 1H-tetrazole (77 mg, 1.11 mmol), dibenzyl?,? - diisopropylphosphoramidite (249 mg, 0.72 mmol). For oxidation, hydrogen peroxide (30%, 2 mL) was used instead of MCPBA. Purification by column chromatography (30% EtOAc in hexanes) gave 300 mg of compound 4b2 in 83% yield. 1 H NMR (CDCl 3): d 7.41-7.10 (20H, m), 5.11-5.00 (6H, m), 4.66 (1H, J = 4.5 Hz), 4.07 (1 H, m), 3.89 (1 H, m), 3.72 (1 H, m), 3.26 (1 H, br d, J = 13.2 Hz), 2.85-2.71 (3H, m), 2.22 (1 H, d, J = 12.9 Hz).
Example 5b2: 1- (2-Phenyl-1-phosphonooxymethyl-ethylsulfamoyl) -piperidine-2-carboxylic acid Prepared as described in the synthesis of 5b1 from the benzyl phosphate ester 4b2 (300 mg, 0.457 mmol). The benzylic ester of the carboxylate was also broken down to carboxylic acid during hydrogenation. The main compound 5b2 was obtained with a yield of 68% (119 mg). 1 H NMR (CD 3 OD): d 7.37-7.13 (5H, m), 4.46 (1 H, d, J = 2.1 Hz), 4.05 (2H, m), 3.64 ( 1H, m), 3.28 (1H, m), 3.05 (1H, m), 3.00 (1H, dd, J = 13.8, 6.8 Hz), 2.82 (1H , dd, J = 13.8, 7.5 Hz), 2.15 (1 H, d, J = 12.9 Hz); LCMS: 423 (M + H +); HRMS (FAB) for C15H24N2O8PS (M + H +) 423.0991; found 423.0995.
Alcohol 2b5: Prepared as described in the synthesis of 2a using sulfamoyl chloride 1b5 (0.07 g, 0.205 mmol, preparation described in International Publication No. WO 0140185) and D-phenylalaninol (0.1 g, 0.662 g) mmoles). 3,5-lutidine was used as the reaction solvent in place of pyridine. After purification by flash column chromatography (50% EtOAc in hexanes), compound 2b5 (28 mg) was obtained in 30% yield. 1 H NMR (CDCl 3): d 7,43-7,13 (10H, m), 5.53 (1H, d, J = 8.4 Hz), 5.27 (H, br d, J = 3.3 Hz), 4.19 (2H, AB), 3.71 (2H, m), 3.48 (1H, m), 3.35 (1H, dt, J = 12.9, 3.3 Hz) , 2.91-2.74 (3H, m), 2.53 (1H, t, J = 6.3 Hz), 2.19 (1H, dq, J = 13.5, 3 Hz), 1, 94 (1H, tdd, J = 13.6, 5.3, 3.8 Hz).
Ester Bencil Phosphate 4b5: Prepared as described in the synthesis of 4b1 using alcohol 2b5 (28 mg, 0.061 mmol), 1H-tetrazole (8 mg, 0.12 mmol), dibenzyl N, N-diisopropylphosphoramidite (25 mg, 0.072 mmol) and MCPBA ( 33 mg, 70% pure, 0.13 mmol). Purification by column chromatography (30 to 60% EtOAc in hexanes) followed by purification by preparative TLC (50% EtOAc in hexanes) gave 30 mg of compound 4b5 in 69% yield. 1 H NMR (CDCl 3): d 7.44-7.07 (20H, m), 5.57 (1H, d, J = 8.4 Hz), 5.19 (1H, br d, J = 3 Hz) , 5.13-4.97 (4H, m), 4.13 (2H, AB), 4.04 (1H, m), 3.91 (1H, m), 3.75 (1H, m), 3.26 (1H, dt, J = 12.6, 3 Hz), 2.89-2.59 (3H, m), 2.15 (1 H, dq, J = 13.8, 3 Hz), 1.89 (1H, m), 1.74 (1H, br s), 1.64 (1H, dt, J = 13.2, 3.3 Hz).
Example 5b5: Mono-f (R) -2-r (S) -2- (5-benzyl-ri.3,41-oxadiazol-2-yl) -piperidin-1-sulfonylamino-3-phenyl-propyl ester > of phosphoric acid Prepared as described in the synthesis of 5b1 using benzyl phosphate ester 4b5 (30 mg, 0.042 mmol) and 10% palladium on carbon (5 mg). The main compound 5b5 was obtained with a quantitative yield (28 mg). H NMR (CD3OD): d 7.32-7.01 (10H, m), 4.95 (1H, m), 4.12 (2H, AB), 3.92-3.76 (2H, m) , 3.51 (1H, m), 3.24 (1H, br d), 2.93-2.76 (2H, m), 2.67 (1H, dd, J = 13.8, 7.8 Hz), 1.92 (1H, br d), 1.79 (1H, m); S (ESP): 559 (M + Na +); 535 (? -? - G).
Scheme 2 16d Ri = -P (OJ (OH); Rí = H 1 * 0 t * < F (PXOtqgR ** JjHfPh 16d ifH Alcohol 9: To a solution of DMF (5 ml_) of 3-amino-1-propanol (0.207 g, 0.21 rriL, 2.75 mmole) were added triethylamine (0.42 mL, 3 mmol) and 4-chloro-7-. Nitrobenzofurazane (0.5 g, 2.5 mmol) at 25 ° C. After 20 h, the reaction mixture was poured into water (100 mL). The precipitate was collected by filtration. Recrystallization from warm methanol yielded 150 mg (25% yield) of compound 9 as a yellow solid. 1 H NMR (CD 3 OD): d 9.49 (1 H, s), 8.51 (1 H, d, J = 8.7 Hz), 6.41 (1 H, d, J = 8.7 Hz), 4.65 (1H, m), 3.62-3.44 (4H, m), 1.84 (2H, p, J = 6.6 Hz); MS (ESP positive): 239 (M + H +); MS (negative ESP): 237 (M-H) ".
Esther 11: To a solution of DMF (2 mL) of alcohol 9 (0.08 g, 0.336 mmol) and N-Boc-pipecolinic acid 10 (0.115 g, 0.504 mmol, preparation described in International Publication No. WO 0140185) were added. triethylamine (0.2 mL), EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodumide hydrochloride) (0.097 g, 0.504 mmol) and HOBT (1-hydroxybenzotriazole hydrate) (0.068 g, 0.0504 mmol) a 25 ° C. After 20 h, the reaction mixture was diluted with EtOAc (50 mL), washed with concentrated saline (3x50 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (20-25% EtOAc in hexanes) yielding 150 mg (100% yield) of compound 11. 1 H NMR (CDCl 3): (mixture of two rotamers) d 8.48 (1 H , d, J = 8.7 Hz), 7.11-6.94 (1 H, br s), 6.26 (1 H, d, J = 8.7 Hz), 4.85 (1 H, br s), 4.36 (2H, m), 4.06-3.86 (2H, m), 3.67 (2H, m), 3.12-2.81 (1H, m), 2, 26-2.12 (3H, m), 1.46 (9H, s).
Amina 6b To a solution of methylene chloride (5 mL) of ester 11 (150 mg, 0.5 mmol) at -30 ° C was added trifluoroacetic acid (1 mL). The solution was heated to 25 ° C for 3 h. All the solvent was removed in vacuo to yield 125 mg (100%) of compound 6b. 1 H NMR (CDCl 3): d 8.45 (1 H, d, J = 8.4 Hz), 6.18 (1 H, d, J = 8.4 Hz), 4.35 (2 H, t, J = 6.3 Hz), 3.66 (2H, t, J = 6 Hz), 3.43 (1 H, dd, J = 9.9, 3.3 Hz), 3.13 (1 H, br d ), 2.70 (1 H, br t), 2.19 (2H, p, J = 6.3 Hz).
Urea 12b To a solution of DMF (5 mL) of D-phenylalaninol (1 g, 6.6 mmol) were added midazole (0.494 g, 7.27 mmol) and t-butyldimethylchlorosilane (1 g, 7.27 mmol). After 40 h, the mixture was diluted with ether (20 mL), washed with concentrated saline (3x50 mL) and dried (Na 2 SO 4). All the solvent was removed in vacuo to yield the amine 8b (1.85 g) as an oil drop. At -40 ° C, a portion of amine 8b (0.265 g, 1 mmol) was added to a solution of methylene chloride (5 mL) of phosgene (0.544 mL, 20% in toluene, 1.1 mmol) and triethylamine. (0.5 mL). The solution was heated slowly to 25 ° C for 30 min, and cooled to 0 ° C again. The pipecoat ester 6b (0.05 g, 0.143 mmol) was introduced immediately. The mixture was stirred at 25 ° C for 20 h, diluted with EtOAc (50 mL), washed with concentrated NaHCO 3 solution (1x50 mL), dried (Na 2 SO 4) and concentrated. The remainder was purified by column chromatography (50% EtOAc in hexanes) to yield 20 mg (22% yield) of compound 12b. 1 H NMR (CDCl 3): d 8.42 (1H, d, J = 8.7 Hz), 7.30-7.07 (5H, m), 6.17 (1H, d, J = 8.7 Hz ), 5.11 (1H, d, J = 8.7 Hz), 4.83 (1H, dd, J = 6, 3.3 Hz), 4.37 (1H, m), 4.15 (1H, m), 4.02 (1H, m), 3.66-3.28 (4H, m), 3.19 ( 1H, td, J = 11, 7, 3.6 Hz), 2.81 (3H, m), 2.07 (3H, m), 0.88 (9H, s), 0.01 (3H, s ), 0.0 (3H, s).
Alcohol 13b: To a THF solution (4 mL) of the silyl ether (20 mg, 0.0313 mmol) was added tetrabutylammonium fluoride (1 mL, 1 in THF, 1 mmol). After 1 h at 25 ° C, the solution was concentrated. The resulting residue was purified by column chromatography (75% EtOAc in hexanes) to yield 18 mg (100%) of compound 13b. 1H RN (CD3OD): d 8.49 (1 H, d, J = 9 Hz), 7.3-7.1 (5H, m), 6.35 (1H, d, J = 9 Hz), 4 , 38 (1H, m), 4.05 (1H, m), 3.92 (1 H, dd, J = 13.2, 4.8 Hz), 3.84-3.59 (6H, m) , 3.13 (1H, m), 3.00 (1 H, dd, J = 13.8, 5.4 Hz), 2.78 (1 H, m), 1.99 (3H, m).
Example 14b: 1- (2-phenyl-1-sulfooxymethyl-ethylcarbamoyl) -pperidyl-2-carboxylic acid ester 3-f7-nitro-benzon, 2-51-oxadiazol-4-ylamino) -propyl acid At -70 ° C, triethylamine (0.05 ml_) and chlorosulfonic acid (8 mg, 5 μ ?, 0.068 mmol) were added to a solution of methylene chloride (2 mL) of alcohol 13b (10 mg, 0.019 mmol). . The cooling bath was then removed and the reaction mixture was allowed to warm to 25 ° C for 3 h. All the solvent was evaporated in vacuo. The residue was purified by column chromatography (10% MeOH in EtOAc) to give 5 mg (42% yield) of the main compound 14b. 1 H NMR (CD 3 OD): d 8.63 (1H, d, J = 9 Hz), 7.37-7.18 (5H, m), 6.49 (1H, d, J = 9 Hz), 4, 71-4.53 (2H, m), 4.33-4.15 (3H, m), 3.98 (1H, dd, J = 12.6, 4.5 Hz), 3.84-3 , 71 (4H, m), 3.36-3.11 (2H, m), 2.85 (1H, td, J = 12.6, 4.5 Hz).
Alcohol 13a: Method A: To a solution of methylene chloride (4 mL) of the picolacolate ester 6a (0.2 g, 0.528 mmol) and triethylamine (1 mL) was added a solution of methylene chloride (1 mL) of triphosgene (0.052 g, 0.176 mmol. ). After 10 min, the solution was heated to reflux for 1 h, and then cooled to 25 ° C. A solution of methylene chloride (1 mL) of D-phenylalaninol (0.0798 g, 0.528 mmol) was added. After 2 h, the reaction solution was diluted with Et20 (50 mL), washed with concentrated saline (2x70 mL), dried (Na2SO4) and concentrated in vacuo. The remainder was purified by flash column chromatography (20% EtOAc in hexanes) to yield 80 mg (27% yield) of compound 13a. 1 H NMR (CDCl 3): d 7.38-7.10 (15H, m), 4.96 (2H, m), 4.70 (1H, d, J = 6.9 Hz), 4.01 (1H , m), 3.67 (1H, br d), 3.51 (1H, dd, J = 10.8, 5.1 Hz), 3.25 (2H, br t), 3.04 (1 H , td, J = 12.3, 3.33 Hz), 2.84 (2H, m), 2.58 (4H, m), 2.18 (1H, br d, J = 12.6 Hz); MS (ESP positive): 557 (M + H +); 555 (M-H) \ Method B: Silyl ether 17: To a solution of DMF (7 mL) of (R) - (+) - 2- (t-Boc) -amino-3-phenyl-1-propanol (4.15 g, 16.5 mmol) were added imidazole ( 2.24 g, 33 mmoles) and t-butylchlorodiphenylsilane (5.15 mL, 19.8 mmol). After 15 h at 25 ° C, the mixture was diluted with ether (50 mL), washed with saturated NH 4 Cl solution (3x50 mL), dried (Na 2 SO 4) and concentrated in vacuo. The residue was purified by column chromatography (2-4% EtOAc in hexanes) to yield 9.19 g (100%) of compound 17 as a white solid. MS (ESP): 512 (M + Na +).
Amina 7a To a solution of methylene chloride (60 mL) of silyl ether 17 (9.19 g, 16.5 mmol) at 0 ° C was added trifluoroacetic acid (20 mL). The reaction solution was stirred at 0 ° C for 1 h and then warmed to 25 ° C for 30 min. The mixture was concentrated in vacuo and redissolved in methylene chloride (50 mL). The resulting solution was washed with saturated NaHCO 3 solution (2x50 mL), dried (Na 2 SO 4) and concentrated. The residue was purified by column chromatography (97.5 / 2.5 / 0.25 CH2Cl2 / MeOH / NH4OH) to yield 5.97 g (78% yield) of compound 7a as a light yellow oil. 1H RN (CDCl3): d 7.56 (4H, br d), 7.36-7.23 (6H, m), 7.20-7.13 (2H, m), 7.12-7.02 (3H, m), 3.52 (1H, dd, J = 9.9, 4.5 Hz), 3.43 (1H, dd, J = 10.2, 6.3 Hz), 3.10- 2.99 (1H, m), 2.71 (1H, dd, J = 13.2, 4.8 Hz), 2.41 (1H, dd, J = 13.5, 8.4 Hz), 0.97 (9H, s); MS (ESP): 390 (M + H +).
Urea 12a: To a solution of methylene chloride (20 mL) of the amine 7a (3.44 g, 7.04 mmol) and triethylamine (2 mL) was added a solution of methylene chloride (1 mL) of triphosgene (0.613 g, 2.07 mmol). After 2 h, the solution was heated to reflux for 1.5 h, and then cooled to 25 ° C. A solution of methylene chloride (40 mL) of amine 6a (2.67 g, 7.04 mmol) was added (the preparation of 6a is described in Guo et al in International Publication No. WO 01/40183) . After 15 h, the reaction solution was diluted with CH2Cl2 (100 mL), washed with concentrated saline (2x80 mL), dried (Na2SO4) and concentrated in vacuo. The remainder was purified by flash column chromatography (5-20% EtOAc in hexanes) to yield 4.85 g (77% yield) of compound 12a. 1H RN (CDCl 3): (mixture of two rotamers) d 7.6-7.5 (4H, m), 7.39-7.23 (7H, m), 7.22-6.99 (14H, m ), 5.00-4.80 (2H, m), 4.16 and 4.01 (1 H, m), 3.51 (3H, m), 3.30 (1H, m), 3.07 -2.74 (4H, m), 2.55-2.43 (2H, m), 1, 04 and 1, 03 (9H, s); MS (ESP): 817 (M + Na +).
Alcohol 13a: To a THF solution (30 mL) of silyl ether 12a (4.83 g, 6.08 mmol) at 0 ° C was added hydrogen fluoride-pyridine (8 mL). After 30 min at 0 ° C, the mixture was heated to 25 ° C for 1 h. All the solvent was removed in vacuo. The residue was dissolved in methylene chloride (50 mL) and the solution was washed with ice-cold HCl solution (2x40 mL), dried (Na2SO4) and concentrated. Purification by flash column chromatography afforded 1.96 g (58% yield) of compound 13a as a white solid.
Example 14a: 1- (2-Phenyl-1-sulfooxymethyl-ethylcarbamoyl) -piperidine-2S-carboxylic acid 4-phenyl-1- (3-phenyl-propy-butyl) ester Prepared as described in the synthesis of 14b using alcohol 13a (17 mg, 0.0306 mmol), chlorosulfonic acid (11 mg, 8 μ ?, 0.011 mmol) and triethylamine (0.05 mL). The reaction mixture was diluted with EtOAc (20 mL) and washed with a 5% HCl solution cooled on ice (1x20 mL). Column chromatography (8% MeOH in EtOAc) yielded 12 mg (62% yield) of the main compound 14a. 1 H NMR (CD 3 OD): d 7.36-7.06 (15H, m), 6.55 (1H, d, J = 7.8 Hz), 4.99 (1H, m), 4.11 ( 1 H, m), 3.97 (2H, m), 3.74 (1 H, m), 2.99 (1H, br t), 2.87 (2H, m), 2.60 (4H, m), 2.20 (1H, br d); S (negative ESP): 635 (M-H) "; HR S (FAB) cale for C35H43N2O7S (M-H) 635.2791, found 635.2815.
To a solution of acetonitrile (10 mL) of alcohol 13a (73 mg, 0.131 mmol) and 1H-tetrazole (15 mg, 0.21 mmol) was added dibenzyl N, N-diisopropylphosphoramidite (68 mg, 0.198 mmol) at 25 ° C. C. After 1 h, MCPBA (102 mg, 70% pure, 0.4 mmol) was added to the suspension. The solution was diluted with ether (50 mL), washed with concentrated NaHS03 solution (2x30 mL), dried over MgSO4 and concentrated in vacuo. He The residue was purified by column chromatography (20-25% EtOAc in hexanes) to yield 70 mg of compound 15a in 65% yield. H NMR (CDCl 3): d 7.40-7.07 (25H, m), 5.67 (1 H, d, J = 7.8 Hz), 5.10-4.89 (6H, m), 4.14 (1 H, m), 3.90 (2H, m), 3.53 (1 H, br d), 3.09 (1H, br t), 2.97 (1H, dd, J = 13.2, 4.8 Hz), 2.69 (1 H, dd, J = 13.2, 9 Hz), 2.56 (4H, m), 2.18 (1 H, br d).
Example 16a: 1- (2-Phenyl-1-phosphonooxymethyl-ethylcarbamoyl) -piperdin-2S-carboxylic acid 4-phenyl-1- (3-phenyl-propyl) -butyl ester To a methanol solution of the benzyl phosphate ester 15a (50 mg, 0.061 mmol) was added palladium on carbon (10%, 6 mg). The suspension was kept under hydrogen (1 atm) for 5 h. After filtration, the filtrate was concentrated to dryness, yielding 40 mg of the main compound 16a in 100% yield. H NMR (CDCl 3): d 7.36-7.07 (15H, m), 5.02 (1H, m), 4.86 (1 H, br d), 4.12 (1 H, m), 3.92 (2H, m), 3.70 (1 H, br d), 3.09-2.88 (2H, m), 2.83 (1H, dd, J = 13.8, 7.8 Hz), 2.60 (4H, m), 2.18 (1H, br d); HRMS (ALDI) for C35H44N207P a2 (M-H ++ 2Na +) 681.2681; found 681, 2691.
Alcohol 3c: To a solution of methylene chloride (10 mL) of the picolacolate ester 6c (0.5 g, 1.92 mmol, preparation described in International Publication No. WO 0140185) and triethylamine (2 mL) at -40 ° C was added. a solution of toluene (1.04 mL) of phosgene (20%, 0.208 g, 0.176 mmol). The solution was heated to 25 ° C for 1 h and then D-phenylalaninol (0.29 g, 1.92 mmol) was added. After 10 h, the reaction mixture was diluted with Et.20 (100 mL), washed with 5% HCl solution cooled on ice (1x50 mL) and concentrated saline (1x50 mL), dried (Na2SO4) and He concentrated in vacuum. The remainder was purified by flash column chromatography (20% EtOAc in hexanes) to yield 100 mg (12% yield) of compound 13c. 1 H NMR (CDCl 3): d 7.31-7.03 (10H, m), 4.85 (1 H, br d), 4.1-3.9 (2H, m), 3.64 (1 H , dd, J = 10.8, 3.3 Hz), 3.50 (1 H, dd, J = 11, 4, 5.7 Hz), 3.25 (1 H, br d), 2.99 (1 H, td, J = 12.6, 3 Hz), 2.79 (2H, m), 2.56 (2H, m).
Ester Bencil Phosphate 15c: Prepared as described in the 15a synthesis using alcohol 13c (60 mg, 0.137 mmol), 1H-tetrazole (19.2 mg, 0.274 mmol), dibenzyl N, N-diisopropylphosphoramidite (0.069 mL, 71 mg, 0.205 mmol) and MCPBA (115 mg, 60% pure, 0.4 mmol). Purification by preparative TLC (30% EtOAc in hexanes) provided 20 mg of compound 15c in 21% yield. H NMR (CDCl 3): d 7.43-7.1 (20H, m), 5.64 (1 H, d, J = 7.5 Hz), 5.1-5.0 (4H, m), 4.97 (1H, br d), 4.21-3.82 (5H, m), 3.54 (1H, br d), 3.09 (1H, td, J = 12.6, 3.3 Hz), 2.97 (1H, dd, J = 13.5, 5.7 Hz), 2.70 (1H, dd, J = 13.8, 9.6 Hz), 2.60 (2H, m ), 2.19 (1 H, d, J = 13.5 Hz).
Example 16c: 1- (2-Phenyl-1-phosphonooxymethyl-ethylcarbamoin-Diperidine-28-carboxylic acid 4-phenyl-1-butyl ester Prepared as described in the synthesis of 16a from benzyl phosphate ester 15c (20 mg, 0.457 mmol). Ethanol was used as the reaction solvent instead of methanol. The main compound 16c was obtained with a yield of 88% (13 mg). H NMR (CD3OD): d 7.25-6.99 (10H, m), 4.01 (3H, m), 3.83 (2H, m), 3.62 (1H, br d), 2, 94-2.66 (3H, m), 2.53 (2H, m), 2.08 (H, d, J = 12.9 Hz); HRMS (MALDI) for C 26 H 35 N 207 PNa (M + Na +) 541, 2080; found 541, 2106.
Alcohol 13d: Prepared as described in the synthesis of 13c using the piketcolate ester 6d (0.78 g, 3.56 mmol, preparation described in International Publication No. WO 0140185), triethylamine (2 ml), phosgene (20% in toluene, 2.4 ml_, 4.45 mmole) and D-phenylalaninol (1.35 g, 8.9 mmole). Purification by flash column chromatography (50% EtOAc in hexanes) to give 60 mg (4.4% yield) of compound 13d. 1 H NMR (CDCl 3): d 7.31-7.16 (5H, m), 4.42 (1H, m), 4.06 (1H, dd, J = 13.2, 4.8 Hz), 3 , 97-3.81 (2H, m), 3.58 (1 H, dd, J = 12, 4.2 Hz), 3.39 (1H, dd, J = 9.66 Hz), 3 , 14 (2H, m), 2.75 (1H, td, J = 13.8, 3.9 Hz), 2.09 (1H, m), 1.91 (1 H, m), 1.67 (1 H, m); MS (ESP): 397 (M + H +).
Ester Bencil Phosphate 15d: Prepared as described in the 15a synthesis using alcohol 13d (89 mg, 0.225 mmol), 1 H-tetrazole (32 mg, 0.45 mmol), dibenzyl N, N-diisopropylphosphoramidite (0.113 mL, 0.337 mmol) and MCPBA (136 mg, 60% pure, 0.45 mmol). Purification by column chromatography (30% EtOAc in hexanes) provided 71 mg of compound 15d in 48% yield. 1 H NMR (CDCl 3): d 7.31-7.06 (20H, m), 5.62 (H, d, J = 7.8 Hz), 5.11-4.92 (2H, m), 4 , 13 (1 H, m), 3.99-3.79 (2H, m), 3.49 (1 H, br d), 3.01 (1 H, td, J = 12.3, 2, 7 Hz), 2.89 (1H, dd, J = 13.5, 5.4 Hz), 2.63 (1 H, dd, J = 13.8, 9.3 Hz), 2.15 (1H , br d, J = 13.8 Hz); MS (ESP positive): 657 (M + H +), 679 (M + Na +).
Example 16d: 1- (2-Phenyl-1-phosphonooxymethyl-ethylcarbamoyl) -piperidine-2-carboxylic acid Prepared as described in the synthesis of 16a from benzyl phosphate ester 15d (48 mg, 0.073 mmol). Ethanol was used as the reaction solvent instead of methanol. The benzylic ester of the carboxylate was also broken down to carboxylic acid during hydrogenation. After purification by HPLC, the main compound 16d was obtained in a yield of 4% (1 mg). 1 H NMR (CD 3 OD): d 7.46-7.11 (5H, m), 4.71-4.45 (2H, m), 4.19 (1H, m), 3.93 (1H, dd, J = 13.2, 4.8 Hz), 3.69 (1H, dd, J = 12, 4.2 Hz), 3.26-3.0 (2H, m), 2.79 (1H , td, J = 13.2, 3.6 Hz), 2.00 (1H, m).
Scheme 3 Route I to Aminophosphate 21: Route II to Aminophosphate 21: The following is a list of the compounds prepared using the synthetic routes indicated in Scheme 3, and then the detailed experimental processes.
Prepared Compounds Using Scheme 3 Alcohol 19a To a solution of methylene chloride (80 mL) of D-phenylalaninol 18a (1.15 g, 7.61 mmol) were added triethylamine (1.59 mL, 11.4 mmol) and benzyl chloroformate (1.19 mL). , 8.37 mmol). The mixture was stirred for 3 h and then concentrated. The residue was dissolved in methylene chloride (50 mL) and washed with concentrated saline (1x50 mL). The solution was dried (Na2SO4) and concentrated. After purification by column chromatography (10 to 30% EtOAc in hexanes), compound 19a was obtained in 73% yield (1.59 g). 1H RN (CDCl3): d 7.46-7.15 (10H, m), 5.11 (2H, s), 4.96 (1H, m), 3.98 (1H, m), 3.72. (1H, m), 3.63 (1H, m), 2.89 (1H, d, J = 7.2 Hz); MS (ESP): 286 (M + H +); 284 (M-H) _.
Alcohol 19b: Prepared as described in the synthesis of alcohol 19a using L-phenylalaninol 18b (2.59 g, 17.1 mmol), triethylamine (2.6 g, 3.58 g) ml_, 25.7 mmoles) and chloroformate-benzyl (2.69 mL, 18.8 mmoles). After purification by column chromatography (20 to 40% EtOAc in hexanes), compound 19b was obtained in 55% yield (2.61 g). 1 H NMR (CDCl 3): d 7.43-7.13 (10H, m), 5.09 (2H, s), 4.94 (1 H, m), 3.95 (1 H, m), 3 , 69 (1H, m), 3.58 (1H, m), 2.87 (1H, d, J = 7.2 Hz); MS (ESP): 286 (M + H +); 284 (M-H) ~.
Ester Bencil Phosphate 20a: To a solution of acetonitrile (40 mL) of alcohol 19a (1.58 g, 5.54 mmol) and 1 H-tetrazole (1.05 g, 15 mmol) was added dibenzyl N, N-düsopropylphosphoramidite (3.72 mL). 11, 1 mmol) at 25 ° C. After 3 h, MCPBA (4.19 g, 70% pure, 13.85 mmol) was added to the suspension. The solution was diluted with EtOAc (100 mL), washed with concentrated NaHSÜ3 solution (2x80 mL), dried over MgSO4 and concentrated in vacuo. The remainder was purified by column chromatography (10-30% EtOAc in hexanes) to yield 2.88 g of compound 20a in 95% yield. 1 H NMR (CDCl 3): d 7.47-7.05 (20H, m), 5.19-4.96 (7H, m), 4.09-3.83 (3H, m), 2.93- 2.67 (2H, m); MS (ESP positive): 568 (M + Na +); MS (negative ESP): 580 (M + CI) -.
Ester Bencil Phosphate 20b: Prepared as described in the synthesis of 20a using alcohol 19a (2.61 g, 9.16 mmol), 1H-tetrazole (1.73 g, 24.7 mmol), dibenzyl N, N-diisopropylphosphoramidite (6). , 15 ml_, 18.3 mmoles) and MCPBA (6.26 g, 77% pure, 27.5 mmoles). Purification by column chromatography (15-30% EtOAc in hexanes) yielded 4.1 g of compound 20b in 82% yield. 1 H NMR (CDCl 3): d 7.42-7.1 (20H, m), 5.16-5.0 (7H, m), 4.09-3.84 (3H, m), 2.9- 2.69 (2H, m); S (ESP): 546 (M + H ÷); 580 (M + CI) -.
Aminophosphate 21a: To an ethanol solution of the benzyl phosphate ester 20a (2.88 g, 5.28 mmoles) was added palladium on carbon (10%, 300 mg). The suspension was kept under a hydrogen atmosphere (1 atm) for 4 h, and then filtered through celite. The collected solid was washed with methylene chloride. The mixture of the solid and celite was suspended in 5% HCl solution and stirred for 20 min. After filtration, the filtrate was concentrated to dryness, yielding 1.2 g of compound 21a in 86% yield. H NMR (CD3OD): d 7.49-7.25 (5H, m), 4.22-4.08 (1 H, m), 4.0 (1H, m), 3.72 (H, m ), 3.03 (2H, d, J = 7.5 Hz); LCMS: 232 (M + H +); 230 (M-H) -; HRMS (MALDI) was calcined for C 9 H 15 NO 4 P (M + H +) 232.0733; Found 232.0736.
Aminophosphate 21b: Prepared as described in the synthesis of 21a using the benzyl phosphate ester 20b (4.1 g, 7.5 mmol) and palladium on carbon (10%, 410 mg). After filtration and evaporation, compound 21b was obtained with a quantitative yield (2.29 g). 1 H NMR (CD 3 OD): d 7.48-7.24 (5H, m), 4.14 (1 H, m), 3.98 (1 H, m), 3.69 (1H, m), 3 , 00 (2H, d, J = 7.4 Hz); LCMS: 232 (M + H +).
Example 23a: Mono-3-phenyl-2- (3-phenyl-ureido) -propyl ester of phosphoric acid To a solution of sodium carbonate (1 M, 1 mL) were added aminophosphate 21a (53 mg, 0.198 mmol) and phenylisocyanate (0.023 mL, 0.208 mmol). After 15 h, it was acidified to pH ~ 1 by the addition of concentrated HCl solution at 0 ° C. Purification by preparative HPLC yielded 27 mg (42% yield) of the main compound 23a. 1 H NMR (CD 3 OD): d 7.36-7.17 (9H, m), 6.97 (1H, t, J = 7.8 Hz), 4.19 (1H, m), 3.98 (2H , m), 2.98 (1 H, dd, J = 13.9, 7.1 Hz), 2.88 (1H, dd, J = 13.8, 7.7 Hz); HRMS (MALDI) for C 5 H i 9 N 205 PNa (M + Na +) 373.0924; found 373.0934.
Example 23b: Mono- (2- [3- (2-phenoxy-phenyl) -ureidol-3-phenyl-propyl) ester of phosphoric acid Prepared as described in the synthesis of 23a using 21a (82 mg, 0.307 mmol), 1-isocyanato-2-phenoxybenzene (67.8 mg, 0.058 mL, 0.322 mmol) and 1 M sodium carbonate solution (1 mL). Purification by preparative HPLC yielded 36 mg (27% yield) of the main compound 23b. 1 H NMR (CD 3 OD): d 8.05 (1H, d, J = 8.4 Hz), 7.36 (2H, t, J = 8.1 Hz), 7.30-7.02 (7H, m), 7.02-6.91 (3H, m), 6.83 (H, d, J = 8 , 1 Hz), 4.18 (1H, m), 3.95 (2H, m), 2.95 (1H, dd, J = 13.8, 6.9 Hz), 2.81 (1H, dd , J = 13.8, 7.8 Hz); MS (ESP): 443 (+ H +), 465 (M + Na +); 441 (M-H) ".
Example 23c: Mono- ester. { 2-f3- (3-Methoxy-5-methyl-phenol-ureido-3-phenylpropyl) phosphoric acid Prepared as described in the synthesis of 23a using 21a (62 mg, 0.232 mmol), 2-methoxy-5-methylphenylisocyanate (40 mg, 0.243 mmol) and 1 M sodium carbonate solution (1 mL). Purification by preparative HPLC yielded 50 mg (55% yield) of the main compound 23c. 1H RN (CD3OD): d 7.76 (1H, d, J = 1.8 Hz), 7.33-7.27 (4H, m), 7.22 (1H, m), 6.81 (1H , d, J = 8.1 Hz), 6.74 (H, br d), 4.19 (H, m), 3.97 (2H, m), 2.98 (1H, dd, J = 13 , 9, 7.0 Hz), 2.83 (1H, dd, J = 14, 8.1 Hz); HR S (MALDI) for C 18 H 24 N 2 O 6 P (M + H +) 395.1372; found 395.1383.
Example 23d: Mono-ester. { 2-f3- (3,5-dimethoxy-phenyl) -ureidol-3-phenyl-propyl} of phosphoric acid Prepared as described in the synthesis of 23a using 21a (71 mg, 0.265 mmol), 2,4-dimethoxy-phenylisocyanate (50 mg, 0.279 mmol) and 1 M sodium carbonate solution (1 mL). Purification by preparative HPLC yielded 29 mg (27% yield) of the main compound 23d. 1 H NMR (CD 3 OD): d 7.76 (1 H, d, J = 9 Hz), 7.46-7.29 (5 H, m), 6.66 (1 H, d, J = 2.6 Hz ), 6.56 (1 H, dd, J = 9, 2.8 Hz), 4.30 (1H, m), 4.08 (2H, m), 3.95 (3H, s), 3, 88 (3H, s), 3.09 (1 H, dd, J = 13.8, 6.6 Hz), 2.96 (1H, dd, J = 13.8, 7.7 Hz); MS (ESP) 411 (M + H +), 433 (M + Na +); 409 (M-H) ~.
Example 23e: Mono- (2-benzenesulfonylamino-3-phenol-propyl) ester of phosphoric acid To a sodium carbonate solution (1.1 mL) were added aminophosphate 21a (66 mg, 0.246 mmol) and phenylsulfonyl chloride (0.047). mL, 0.369 mmol). After 15 h, it was acidified to pH ~ 1 by the addition of concentrated HCl solution at 0 ° C. Purification by preparative HPLC yielded 35 mg (38% yield) of the major compound 23e. 1 H NMR (CD 3 OD): d 7.67 (2H, d, J = 7.5 Hz), 7.54 (1H, t, J = 7.2 Hz), 7.42 (1H, t, J = 7 , 8 Hz), 7.21-7.11 (3H, m), 7.09-7.03 (2H, m), 3.95 (1H, m), 3.84 (1H, m), 3.61 (1H, m), 2.94 (1 H, dd, J = 13.8, 6.6 Hz), 2.59 (1H, dd, J = 13.5, 7.8 Hz); LCMS: 372 (M + H +), 394 (M + Na +); 370 (M-H) "; HRMS (MALDI) cale for Ci5Hi8N06PSNa (M + Na +) 394.0485, found 394.0487.
Example 25-1: Mono- (3-phenyl-2-r (1-phenyl-methanoyl) -amino-1-propyl) ester of phosphoric acid To a solution of sodium carbonate (1 M, 1 mL) were added aminophosphate 21a (70 mg, 0.242 mmol) and benzoyl chloride (0.028 mL, 0.238 mmol). After 15 h, it was acidified to pH ~ 1 by the addition of concentrated HCl solution at 0 ° C. Purification by preparative HPLC yielded 20 mg (23% yield) of the main compound 25-. 1 H NMR (CD 3 OD): d 8.04 (1H, br d), 7.76 (2H, br d), 7.76 (2H, br d), 7.64-7.16 (9H, m), 4.52 (1H, m), 4.09 (2H, m), 3.08 (1 H, dd, J = 13.6, 6.8 Hz), 2.96 (1 H, dd, J = 13.5, 8.1 Hz); MS (ESP): 336 (M + H +); 334 (M-H) ".
Example 25-2: Ester mono-. { (R) -2-f (1-benzoybltiophen-2-l-methanoyl) -amino-1,3-phenyl-propyl) of phosphoric acid Prepared as described in the synthesis of 25-1 using 21a (48 mg, 0.179 mmol), benzothiophene-2-carbonyl chloride (35 mg, 0.79 mmol) and 1 M sodium carbonate solution (1 mL). Purification by preparative HPLC yielded 34 mg (48% yield) of the main compound 25-2. 1 H NMR (CD 3 OD): d 7.96 (1H, s), 7.90 (2H, m), 7.43 (2H, m), 7.37-7.17 (5H, m), 4.50 (1H, m), 4.10 (2H, m), 3.09 (1H, dd, J = 13.9, 6.6 Hz), 3.00 (1H, dd, J = 13.9, 7 8 Hz); HRMS (MALDI) for C ^ H ^ NOgPSNa (M + Na +) 414.0550; found 414.0536.
Example 25-2 ': Ester mono- (2- { N- (1-oxo-benzofb1tiofen-2-ylV methanoin-amino) -3-phenyl-propyl) of phosphoric acid To a solution of trifluoroacetic acid (1 mL) of 25-2 (9 mg, 0.023 mmoles) at 0 ° C was added 30% hydrogen peroxide (0.0244 mL). The solution was concentrated in vacuo. The remainder was purified by preparative HPLC to yield 1 mg (10% yield) of the major compound 25-2 '. 1 H NMR (CD 3 OD): S 8.01-7.93 (2H, m), 7.78-7.6 (3H, m), 7.36-7.26 (4H, m), 7.25- 7.17 (1 H, m), 4.44 (1 H, m), 4.04 (2 H, m), 3.02 (2 H, m); MS (ESP): 408 (M + H +), 430 (M + Na +).
Example 25-3: Mono - ((R) -2-r (1-naphthalen-2-yl-methanoyl) -aminol-3-phenyl-propyl) ester of phosphoric acid Prepared as described in the synthesis of 25-1 using 21a (50 mg, 0.187 mmol), 2-naphthoyl chloride (36 mg, 0.187 mmol) and 1 M sodium carbonate solution (1 mL). Purification by preparative HPLC yielded 29 mg (40% yield) of the major compound 25-3. H NMR (CD3OD): S 8.32 (1 H, s), 8.1-7.88 (3H, m), 7.83 (1 H, dd, J = 8.4, 1.8 Hz) , 7.64-7.53 (2H, m), 7.39-7.18 (5H, m), 4.57 (1H, m), 4.12 (2H, m), 3.12 (1 H, dd, J = 13.7, 6.8 Hz), 3.02 (1 H, dd, J = 13.7, 8.1 Hz); LCMS (ESP): 386 (M + H +), 408 (M + Na +); 384 (M-H) "; HRMS (MALDI) cale for CzoHzoNOsPNa (M + Na +) 408.0971; found 408.0986.
Example 25-4: Ester mono-r2- ( { 1-r5- (3,5-dichloro-phenox0-furan-2-iri-methanoyl) -amino) -3-phenol-propyl1 of phosphoric acid Prepared as described in the synthesis of 25-1 using 21a (76 mg, 0.284 mmol), 5- (3,5-dichlorophenoxy) -2-furoyl chloride (83 mg, 0.284 mmol) and 1 M sodium carbonate solution (1 mL). Purification by preparative HPLC yielded 46 mg (33% yield) of the main compound 25-4. H NMR (CD3OD): d 7.21 (1 H, t, J = 1.7 Hz), 7.17-7.03 (5H, m), 7.00 (2H, d, J = 1.8) Hz), 6.99 (1 H, d, J = 3.6 Hz), 5.79 (1 H, d, J = 3.9 Hz), 4.35 (1 H, m), 3.92 ( 2H, m), 2.91 (1H, dd, J = 13.6, 6 Hz), 2.78 (1H, dd, J = 13.8, 8.7 Hz); S (ESP): 508 (M + Na +); 484 (M-H) ".
Example 25-5: Mono- (2- { R - (3,4-dichloro-phenan-methanoin-amino) -3-phenyl-propyl ester) phosphoric acid Prepared as described in the synthesis of 25-1 using 21a (56 mg, 0.209 mmol), 3,4-dichlorobenzoyl chloride (44 mg, 0.209 mmol) and 1 M sodium carbonate solution (1 mL). Purification by preparative HPLC yielded 20 mg (24% yield) of the main compound 25-5. 1 H NMR (CD 3 OD): d 7.91 (1 H, d, J = 2.1 Hz), 7.68 (1 H, dd, J = 8.4, 1.8 Hz), 7.60 (1 H, d , J = 8.4 Hz), 7.35-7.16 (5H, m), 4.50 (1H, m), 4.08 (2H, m), 3.07 (1H, dd, J = 13.9, 6.8 Hz), 2.94 (1 H, dd, J = 13.9, 8.4 Hz); LCMS (ESP): 404 (M + H +), 426 (M + Na +); 402 (M-H) '.
Example 25-6: Ester mono- (2- (n- (5-chloro-4-methoxy-thiophen-3-iD-methanoyl-1-amino-3-phenyl-propyl) ester of phosphoric acid Prepared as described in the synthesis of 25-1 using 21a (63 mg, 0.236 mmol), 2-chloro-3-methoxythiophen-4-carbonyl chloride (50 mg, 0.236 mmol) and 1 M sodium carbonate solution (1 mL). Purification by preparative HPLC yielded 37 mg (38% yield) of the main compound 25-6. 1 H NMR (CD 3 OD): d 7.86 (1H, s), 7.38-7.19 (5H, m), 4.51 (1H, m), 4.09 (2H, m), 3.93. (2H, m), 3.04 (2H, m); LCMS (ESP): 406 (M + H +), 428 (M + Na +); 404 (M-H) '.
Example 25-7: Ester mono- (2- { H- (5-methyl-2-phenyl-2H-n.2.31triazol-4-yl-methanoyl-1-amino) -3-phenyl-propyl) of phosphoric acid Prepared as described in the synthesis of 25-1 using 21a (46 mg, 0.172 mmol), 4-methyl-2-phenyl-1,2,3-triazole-5-carbonyl chloride (38 mg, 0.172 mmol) and 1 M sodium carbonate solution (1 mL). Purification by preparative HPLC yielded 36 mg (50% yield) of the main compound 25-7. 1 H NMR (CD 3 OD): d 7.98 (1 H, d, J = 8.1 Hz), 7.43 (2 H, br t), 7.31 (1 H, br t), 7.25-7, 04 (5H, m), 4.40 (1H, m), 3.98 (2H, m), 2.96 (1H, dd, J = 13.7, 6.8 Hz), 2.87 (1 H, dd, J = 13.9, 7.9 Hz); LC S (ESP): 417 (M + H +), 439 (+ Na +); 415 (-H) -.
Example 25-8: Mono- (2- (ri- (3-chloro-phenyl) -methanoyl-amino-3-phenyl-propyl) ester of phosphoric acid Prepared as described in the synthesis of 25-1 using 21a (45 mg, 0.168 mmol), 3-chlorobenzoyl chloride (29 mg, 0.168 mmol) and sodium carbonate solution 1 (1 mL). Purification by preparative HPLC yielded 5 mg (8% yield) of the main compound 25-8. 1 H NMR (CD 3 OD): d 7.64 (1 H, s), 7.57 (1 H, d, J = 7.5 Hz), 7.39 (1 H, d, J = 9 Hz), 7.30 (1 H, t, J = 7.8 Hz), 7.23-7.01 (5H, m), 4.33 (1 H, m), 3.91 (2H, m), 2.94 ( 1H, dd, J = 13.5, 6.9 Hz), 2.83 (1H, dd, J = 13.8, 8.1 Hz); LCMS (ESP): 392 (M + Na +); 368 (M-H) -.
Example 25-9: Prepared as described in the synthesis of 25-1 using 21a (46 mg, 0.172 mmol), nicotinoyl chloride hydrochloride (31 mg, 0.172 mmol) and 1 M sodium carbonate solution (1 mL). Purification by preparative HPLC yielded 3 mg (2% yield) of the main compound 25-9. 1 H NMR (CD 3 OD): d 8.89 (1 H, s), 8.68 (1 H, d, J = 5.1 Hz), 8.36 (1 H, dt, J = 7.5, 1, 8 Hz), 7.68 (1H, dd, J = 7.8, 5.4 Hz), 7.22-7.05 (5H, m), 4.42 (1 H, m), 3.98 (2H, m), 2.96 (H, dd, J = 13.5, 6.6 Hz), 2.85 (1H, dd, J = 13.5, 8.1 Hz); LCMS (ESP): 337 (M + H +), 359 (M + Na +); 335 (M-H) ".
Example 25-10: Monster Ester. { 2 - [(1-naphthalen-1-yl-methanoyl) Vannino-3-phenyl-propyl of phosphoric acid Prepared as described in the synthesis of 25-1 using 21a (62 mg, 0.232 mmol), 1-naphthoyl chloride (0.035 mL, 0.232 mmol) and 1 M sodium carbonate solution (1 mL). Purification by preparative HPLC yielded 8 mg (yield 9%) of the major compound 25-10. 1 H NMR (CD 3 OD): d 7.93 (1H, m), 7.88 (1H, d, J = 7.8 Hz), 7.77 (1 H, d, J = 8.4 Hz), 7 , 55-7.24 (9H, m), 4.70 (1 H, m), 4.16 (2H, m), 3.14 (1 H, dd, J = 14.1, 5.8 Hz ), 2.91 (1H, dd, J = 13.9, 9.4 Hz); LCMS (ESP): 408 (M + Na +), 430 (-H + 2Na +); 384 (M-H) \ Example 25-11: Mono- (3-phenyl-2-f (1-quinoxalin-2-yl-methanoiD-aminol-propyl) ester of phosphoric acid Prepared as described in the synthesis of 25-1 using 21a (68 mg, 0.254 mmole), quinoxaloyl chloride (50 mg, 0.254 mmole) and 1 M sodium carbonate solution (1 mL). Purification by preparative HPLC yielded 17 mg (17% yield) of the major compound 25-11. 1 H NMR (CD 3 OD): d 9.44 (1H, s), 8.24 (1H, m), 8.17 (1H, m), 8.01-7.90 (2H, m), 7.4 -7.14 (5H, m), 4.62 (1H, m), 4.17 (2H, m), 3.10 (2H, m); LCMS (ESP): 388 (M + H +), 410 (+ Na +); 386 (M-H) \ Example 25-12: Prepared as described in the synthesis of 25-1 using 2 a (63 mg, 0.236 mmol), 3-chloro-thiophene-2-carbonyl chloride (43 mg, 0.236 mmol) and 1 M sodium carbonate solution (1 mL) ). Purification by preparative HPLC yielded 26 mg (30% yield) of the major compound 25-12. 1 H NMR (CD 3 OD): d 7.67 (1 H, d, J = 5.1 Hz), 7.37-7.18 (5 H, m), 7.05 (1 H, d, J = 5.4 Hz ), 4.50 (1H, m), 4.09 (2H, m), 3.08 (1 H, dd, J = 13.9, 6.9 Hz), 2.99 (1H, dd, J = 13.9, 8.5 Hz); HRMS (MALDI) for C14H16N05PSCI (M + H +) 376.0175; found 376.0158.
Example 25-13: Ester mono- (2- { Ri- (2-hydroxy-phenyl-methanoyl- amino -3-phenyl-propyl) of phosphoric acid Prepared as described in the synthesis of 25-1 using 21a (187 mg, 0.699 mmol), acetylsalicyloyl chloride (139 mg, 0.699 mmol) and 1 M sodium carbonate solution (2 mL). Purification by preparative HPLC yielded 25 mg (10% yield) of the major compound 25-13. 1 H NMR (CD 3 OD): d 7.79 (1 H, dd, J = 8.1, 1.8 Hz), 7.41-7.2 (7H, m), 6.89 (2H, m), 4.53 (1 H, m), 4.08 (2H, m), 3.07 (1 H, dd, J = 13.6, 6.8 Hz), 2.99 (1H, dd, J = 13.6, 6.7 Hz); HRMS (MALDI) for C 6 H 9 N 0 6 P (M + H +) 352.0950; found 352.0960.
Example 25-14: Ester mono-l2-f (1-furan-2-yl-methanoyl-Vinylin-3-phenyl-propyl) of phosphoric acid Prepared as described in the synthesis of 25-1 using 21a (85 mg, 0.318 mmol), 2-furoyl chloride (0.032 mL, 0.318 mmol) and 1 M sodium carbonate solution (1 mL). Purification by preparative HPLC yielded 86 mg (83% yield) of the major compound 25-14. 1 H NMR (CD 3 OD): d 7.65 (1H, br d), 7.33-7.17 (5H, m), 7.08 (1 H, d, J = 3.6 Hz), 6.57 (1 H, dd, J = 3.3, 1.5 Hz), 4.48 (1 H, m), 4.05 (2 H, m), 3.05 (1 H, dd, J = 13.6 , 6.4 Hz), 2.94 (1H, dd, J = 13.6, 8.1 Hz); HRMS (MALDI) for C14H17N06P (+ H +) 326.0794; found 326.0801.
Example 25-15: To a solution of sodium carbonate (1 M, 1 mL) were added aminophosphate 21a (106 mg, 0.397 mmol) and 2-methylpropanoic anhydride (0.16 mL, 153 mg, 0.966 mmol). After 15 h, it was acidified to pHDl by the addition of concentrated HCl solution at 0 ° C. Purification by preparative HPLC yielded 110 mg (92% yield) of the main compound 25-15. H NMR (CD3OD): d 7.29-7.08 (5H, m), 6.94 (1 H, br d), 4.34 (1H, br s), 4.10 (H, m), 3.96 (1H, m), 2.82 (2H, m), 2.41 (1H, heat, J = 7.2 Hz), 1.00 (3H, d, J = 7 Hz), 0, 97 (3H, d, J = 7 Hz); LCMS (ESP): 302 (+ H +); 300 (-H) ".
Example 25-16: Mono-r (R) -2- (2,2-dimethyl-propane -lamino) -3- ester phenyl-propylicol of phosphoric acid Prepared as described in the synthesis of 25-15 using 21a (110 mg, 0.412 mmol), 2,2-dimethylpropanoic anhydride (0.16 mL, 147 mg, 0.79 mmol) and 1 M sodium carbonate solution (1 mL). Purification by preparative HPLC yielded 130 mg (100% yield) of the major compound 25-16. 1 H NMR (CD 3 OD): d 7.32-7.11 (5H, m), 6.25 (1H, br d, J = 8.7 Hz), 4.37 (1H, m), 4.13 ( 1H, m), 3.98 (1H, m), 2.93 (1H, dd, J = 14.1, 6.6 Hz), 2.80 (1H, dd, J = 14.1, 8, 5 Hz), 1.06 (9H, s); LCMS (ESP): 316 (M + H +); 314 (M-H) -.
Example 25-40: Phosphoric acid mono- (2-acetylamino-3-phenylpropyl) ester Prepared as described in the synthesis of 25-15 using 21a (120 mg, 0.45 mmol), acetic anhydride (0.1 mL, 108 mg, 1.0 mmol) and sodium carbonate solution 1 (1 mL). Purification by HPLC preparation yielded 50 mg (40% yield) of the main compound 25-40. H NMR (CD3OD): d 7.64-7.30 (5H, m), 4.47 (1H, m), 4.16 (2H, m), 3.16 (1H, dd, J = 14, 1, 6.6 Hz), 2.99 (1H, dd, J = 13.9, 8.7 Hz), 2.10 (3H, s); LCMS (ESP): 274 (M + H +), 296 (M + Na +); 272 (-H) ".
Example 25-17: Ester mono-f2-f (1-cyclohexyl-methanoyl) -aminol-3-phenyl-propylic acid phosphoric acid To a solution of ether (5 mL) of cyclohexanecarboxylic acid (250 mg, 1.95 mmol) were added pyridine (0.5 mL) and cyclohexanecarbonyl chloride (286 mg, 0.261 mL, 1.95 mmol). After 10 h, the suspension was diluted with ether (20 mL), washed with 5% HCl solution cooled on ice (1x50 mL) and concentrated NaHCO 3 solution (1x50 mL) and dried over Na 2 SO 4. All the solvent was removed in vacuo to give 350 mg of cyclohexanecarboxylic anhydride as a colorless oil. A portion of the cyclohexanecarboxylic anhydride (226 mg, 0.948 mmol) was added to a solution of sodium carbonate (1 M, 2 mL) of aminophosphate 21a (110 mg, 0.412 mmol). After 15 h, it was acidified to pHDl by the addition of concentrated HCl solution at 0 ° C. Purification by HPLC preparation yielded 50 mg (36% yield) of the main compound 25-17. 1 H NMR (CD 3 OD): d 7.27-7.1 (5H, m), 6.67 (1H, br d), 4.34 (1 H, br s), 4.08 (1 H, m) , 3.96 (1H, m), 2.90 (1 H, dd, J = 14.4, 6.6 Hz), 2.78 (1H, dd, J = 14.9, 9 Hz), 2 , 10 (1 H, br t), 1, 79-1, 51 (5H, m), 1.33-1, 02 (5H, m); LCMS (ESP): 342 (M + H +); 340 (M-H) ~.
Example 25-18: Ester mono- (2-f (1-1H-tndol-2-yl-methanoyl) -L-3-phenyl-propyl) -amino of the phosphoric acid To a solution of DMF (1 mL) of aminophosphate 21a (78 mg, 0.292 mmol) were added imidazole (65 mg, 0.962 mmol) and t-butyldimethylchlorosilane (110 mg, 0.730 mmol). After 3.5 h, indole-2-carboxylic acid (49 mg, 0.307 mmol), EDC (70 mg, 0.365 mmol), DMAP (4-dimethylaminopyridine) (7 mg, 0.058 mmol) were added to the reaction. The mixture was stirred for 15 h and acidified to pHDl by the addition of concentrated HCl solution at 0 ° C. Purification by preparative HPLC yielded 1 mg (1% yield) of the major compound 25-18. 1 H NMR (CD 3 OD): d 7.48 (1 H, d, J = 8.5 Hz), 7.30 (1 H, d, J = 8.4 Hz), 7.25-6.89 (7H, m ), 4.36 (1H, m), 3.93 (2H, m), 2.92 (2H, m); LCMS (ESP): 373 (M-H). " Example 25-19: Ester mono-. { 2 - [(1-benzofuran-2-yl-methanoyl) -amino-3-phenyl-propyl] -phosphoric acid Prepared as described in the synthesis of 25-18 using aminophosphate 21a (94 mg, 0.351 mmol), imidazole (79 mg, 1.16 mmol), t-butyldimethylchlorosilane (132 mg, 0.878 mmol), 1-benzofuran- 2-carboxylic acid (60 mg, 0.369 mmol), EDC (84 mg, 0.439 mmol) and DMAP (9 mg, 0.07 mmol). Purification by preparative HPLC yielded 16 mg (12% yield) of the major compound 25-19. 1H RN (CD3OD): d 7.59 (1H, d, J = 7.8 Hz), 7.47 (1H, d, J = 8.1 Hz), 7.39-7.29 (2H, m ), 7.25-7.03 (6H, m), 4.43 (1H, m), 3.98 (2H, m), 2.96 (1 H, dd, J = 13.8, 6, 2 Hz), 2.87 (1H, dd, J = 13.8, 8.1 Hz); LCMS (ESP): 374 (M-H) ".
Example 25-20: Mono- (2- (H- (6-hydroxy-naphthalen-2-in-methanoin-amino) -3-phenyl-propyl) ester of phosphoric acid Prepared as described in the synthesis of 25-18 using aminophosphate 21a (152 mg, 0.568 mmol), imidazole (155 mg, 2.27 mmol), t-butyldimethylchlorosilane (214 mg, 1.42 mmol), 6-8 (acetyloxy) -2-naphthoic acid (131 mg, 0.569 mmol), EDC (136 mg, 0.71 mmol) and DMAP (14 mg, 0.114 mmol). Purification by preparative HPLC yielded 25 mg (11% yield) of the major compound 25-20. H NMR (CD3OD): d 8.21 (1 H, s), 7.9-7.6 (4H, m), 7.4-7.05 (6H, m), 4.57 (1H, m) ), 4.12 (2H, m), 3.00 (2H, m); LCMS: 400 (M-H) ~.
Example 25-21: Prepared as described in the synthesis of 25-18 using aminophosphate 21a (94 mg, 0.351 mmol), imidazole (96 mg, 1.4 mmol), t-butyldimethylchlorosilane (132 mg, 0.878 mmol), 1-hydroxy acid. 2-naphthoic acid (66 mg, 0.351 mmol), EDC (84 mg, 0.439 mmol) and DMAP (9 mg, 0.07 mmol). Purification by preparative HPLC yielded 7 mg (yield 5%) of the main compound 25-21. 1 H NMR (CD 3 OD): d 8.24 (1 H, d, J = 8.1 Hz), 7.70 (1 H, d, J = 7.8 Hz), 7.64 (1 H, d, J = 9 Hz), 7.49 (1H, t, J = 7.2 Hz), 7.41 (1H, d, J = 8.1 Hz), 7.3-7.05 (6H, m), 4 , 50 (1H, m), 4.04 (2H, m), 2.98 (2H, m); HRMS (MALDI) for C2oH2iN06P (+ H +) 402.1107; found 402,1099.
Example 25-22: Ester mono-f2- (1 - (3-hydroxy-naphthalen-2-yl) -methane-n-amino -3-phenyl-propyl) phosphoric acid Prepared as described in the synthesis of 25-18 using aminophosphate 21a (98 mg, 0.366 mmol), imidazole (100 mg, 1.46 mmol), t-butyldimethylchlorosilane (138 mg, 0.915 mmol), 3-hydroxy acid. 2-naphthoic acid (69 mg, 0.366 mmol), EDC (88 mg, 0.458 mmol) and DMAP (9 mg, 0.0732 mmol). Purification by preparative HPLC yielded 2 mg (1% yield) of the major compound 25-22. 1 H NMR (CD 3 OD): d 8.31 (1 H, s), 7.72 (1 H, d, J = 8.4 Hz), 7.55 (1 H, d, J = 8.7 Hz), 7 , 36 (1 H, t, J = 7.8 .Hz), 7.28-7.02 (7H, m), 4.47 (1 H, m), 4.00 (2H, m), 2 96 (2H, m); LCMS (ESP): 402 (M + H +), 424 (M + Na +).
Example 25-23: Mono- ester. { (R) -2-f (1 H-benzoimidazole-5-carbonyl) -aminol-3-phenyl-propyl-yl) of phosphoric acid Prepared as described in the synthesis of 25-18 using aminophosphate 21a (100 mg, 0.374 mmol), imidazole (76 mg, 1.12 mmol), t-butyldimethylchlorosilane (141 mg, 0.935 mmol), 6- (acetyloxy) acid ) -2-naphthoic (72.7 mg, 0.499 mmol), EDC (86 mg, 0.449 mmol) and DMAP (10 mg, 0.081 mmol). Before acidification the reaction mixture was treated with 10% NaOH solution (1 mL) for 10 h. Purification by preparative HPLC yielded 30 mg (21% yield) of the major compound 25-23. 1 H NMR (CD 3 OD): d 9.44 (1H, s), 8.23 (1H, s), 7.99 (1H, d, J = 8.7 Hz), 7.87 (1H, d, J = 8.7 Hz), 7.37-7.13 (5H, m), 4.55 (1 H, m), 4.13 (2H, m), 3.09 (1H, dd, J = 13 , 5.6.9 Hz), 2.99 (1H, dd, J = 13.5, 8.1 Hz); LCMS (ESP): 376 (M + H +); 374 (M-H) -.
Example 25-24: Ester mono- (2- (f1- (1-bromo-naphthalen-2-iD-methanoyl-amino) -3-phenyl-propyl) of phosphoric acid To a solution of methylene chloride (2 mL) of 1-bromo-2-naphthoic acid (182 mg, 0.725 mmol) were added oxalyl chloride (0.19 mL, 2.18 mmol) and 2 drops of DMF. The mixture was stirred for 2 h and concentrated in vacuo. To the rest was added sodium carbonate solution (1 M, 2 mL), aminophosphate 21a (194 mg, 0.725 mmol) and 1 mL of acetonitrile. After 15 h, it was acidified to pH ~ 1 by the addition of concentrated HCl solution at 0 ° C. Purification by preparative HPLC yielded 103 mg (31% yield) of the major compound 25-24. 1 H NMR (CD 3 OD): d 8.32 (1 H, d, J = 8.7 Hz), 7.92 (2 H, m), 7.65 (2 H, m), 7.41-7.20 ( 6H, m), 4.60 (1H, m), 4.14 (2H, m), 3.12 (1H, dd, J = 13.9, 6 Hz), 2.94 (1H, dd, 13.8, 8.7 Hz); HRMS (MALDI) for C2oH2oN05PBr (M + H +) 464.0262; found 464.0271.
Example 25-25: Ester mono- (2-fri- (6-methoxy-naphthalen-2-yl) -methanoin-amino) -3-phenyl-propyl) of phosphoric acid Prepared as described in the 25-24 synthesis using 6-methoxy-2-naphthoic acid (255 mg, 1.26 mmol), oxalyl chloride (0.33 mL, 3.78 mmol), DMF (2 drops) , sodium carbonate solution (1 M, 2 mL) and the aminophosphate 21a (337 mg, 1.26 mmol). Purification by preparative HPLC yielded 44 mg (13% yield) of the major compound 25-25. H NMR (CD3OD): d 8.24 (1 H, s), 7.86 (1H, d, J = 9.3 Hz), 7.81 (2H, m), 7.41 (7H, m) , 4.56 (1H, m), 4.13 (2H, m), 3.95 (3H, s), 3.11 (1H, dd, J = 14.1, 7.2 Hz), 3 , 01 (1H, dd, J = 13.6, 8.5 Hz); LCMS (ESP): 414 (M-H) -; Elemental Analysis for (C2iH22NO6P0,25H2O) cale: C 60.07, H 5.40, N 3.34; found: C 59.66, H 5.33, N 3.74.
Example 25-26: Ester mono-. { 2 - [(1-Benzo [b] thiophen-2-yl-methanoyl) -amino] -3-phenyl-propyl} of phosphoric acid To a solution of sodium carbonate (1 M, 1 mL) were added aminophosphate 21b (68 mg, 0.254 mmol) and benzothiophene-2-carbonyl chloride (50 mg, 0.254 mmol). After 15 h, it was acidified to pH ~ 1 by the addition of concentrated HCl solution at 0 ° C. Purification by preparative HPLC yielded 20 mg (20% yield) of the main compound 25-26. 1 H NMR (CD 3 OD): d 7.99-7.86 (3H, m), 7.53-7.15 (7H, m), 4.49 (1H, m), 4.10 (2H, m) 3.04 (2H, m); LCMS (ESP): 414 (+ Na +); 390 (M-H) ".
Example 25-27: Mono- ester. { 2-f (1-naphthalen-2-yl-methanoyl) -aminol-3-phenyl-propyl} of phosphoric acid Prepared as described in the synthesis of 25-26 using 21b (70 mg, 0.262 mmol), 2-naphthoyl chloride (50 mg, 0.262 mmol) and 1 M sodium carbonate solution (1 mL). Purification by preparative HPLC yielded 20 mg (20% yield) of the main compound 25-27. 1 H NMR (CD 3 OD): d 8.32 (1 H, s), 8.08-7.78 (4H, m), 7.66-7.5 (2H, m), 7.39-7.17 (5H, m), 4.56 (1 H, m), 4.11 (2H, m), 3.12 (1H, dd, J = 13.7, 6.8 Hz), 3.02 (1 H, dd, J = 13.8, 7.7 Hz); LCMS (ESP): 386 (M + H +), 408 (+ Na +); 384 (M-H) ".
Aminoalcohol 18c: To a THF solution (30 mL) of D-3-fluorophenylalanine (5 g, 27.3 mmol) at 0 ° C was added borane in THF (1 M, 68.3 mL, 68.3 mmol). After 5 h at 25 ° C, saturated NaHCO3 solution (10 mL) was added to the solution, and stirred for 15 h. The mixture was concentrated and extracted with methylene chloride (3x50 mL). The combined organic layers were dried (Na2SO4) and concentrated. The remainder was purified by column chromatography (CH2Cl2 / MeOH / NH4OH 95/5 / 0.5 to 90/10/1) to yield 1.94 g (42% yield) of compound 18c as a white solid. 1 H NMR (CD 3 OD): d 7.32-7.21 (1H, m), 7.00-6.98 (3H, m), 3.63 (1H, dd, J = 11.1, 4.2 Hz), 3.38 (1H, dd, J = 10.5, 6.9 Hz), 3.12 (1H, m), 2.79 (1H, dd, J = 13.5, 5.1 Hz) ), 2.54 (1 H, dd, J = 13.5.8.4 Hz); LCMS (ESP): 170 (M + H +).
Alcohol 19c: To a solution of methylene chloride (30 mL) of aminoalcohol 18c (1.94 g, 11.5 mmol) were added triethylamine (2.8 mL, 20 mmol) and benzyl chloroformate (2.05 mL, 14.3 mL). mmoles). The mixture was stirred for 15 h and then diluted with methylene chloride (50 mL). The solution was washed with concentrated saline (1x50 mL), dried (a2SO4) and concentrated. After purification by column chromatography (20 to 30% EtOAc in hexanes), compound 19c was obtained in 64% yield (2.22 g). H NMR (CDCl 3): d 7.4-7.19 (6H, m), 7.02-6.86 (3H, m), 5.08 (2H, s), 4.95 (1H, br s ), 3.93 (1H, m), 3.69 (1 H, dd, J = 10.2, 3 Hz), 3.58 (1 H, dd, J = 11.4, 4.8 Hz) , 2.87 (2H, d, J = 7.5 Hz); LCMS (ESP): 326 (M + Na +); Elemental Analysis for (Ci7Hi8FN03) cale: C 67.31, H 5.98, N 4.62; found: C 67.31, H 5.98, N 4.62.
Ester Bencil Phosphate 20c: To a solution of acetonitrile (40 mL) of alcohol 19c (2.21 g, 7.29 mmol) and 1 H-tetrazole (1.37 g, 19.6 mmol) was added dibenzyl N, N-diisopropylphosphoramidite (4.9 mL). 14.6 mmole) at 25 ° C. After 5 h, MCPBA (5.72 g, 77% pure, 25.5 mmol) was added to the suspension. The solution was diluted with methylene chloride (100 mL), washed with concentrated NaHS03 solution (2x80 mL), dried over MgSO4 and concentrated in vacuo. The remainder was purified by column chromatography (15-30% EtOAc in hexanes) to yield 4.39 g of compound 20c in 100% yield. 1H RN (CDCl3): d 7.44-7.12 (16H, m), 6.96-6.76 (3H, m), 5.18-4.96 (7H, m), 4.04- 3.78 (3H, m), 2.87-2.63 (2H, m).
Aminophosphate 21c: 21C To an ethanol solution of the benzyl phosphate ester (20c, 4.37 g, 7.76 mmol) was added palladium on carbon (10%, 870 mg). The suspension was kept under a hydrogen atmosphere (1 atm) for 15 h and then 5% HCl solution (10 mL) was added. The mixture was filtered through celite. The filtrate was concentrated to dryness, yielding 2.30 g of a yellowish solid. Purification by preparative HPLC yielded 1.2 g (62% yield) of compound 21c as a white solid. 1 H NMR (CD 3 OD): d 7.45-7.35 (1 H, m), 7.18-7.01 (3 H, m), 4.10 (1 H, m), 3.94 (1 H, m), 3.70 (1 H, m), 3.03 (2H, m); LCMS (ESP): 250 (M + H +); 248 (M-H) ".
Example 25-28: Mono-f3- (3-fluoro-phenyl) -2-r (1-naphthalen-2-yl-methanoiD-aminol-propylic acid ester of phosphoric acid To a solution of sodium carbonate (1 M, 1 mL) were added aminophosphate 21c (110 mg, 0.385 mmol) and 2-naphthoyl chloride (1.0 mg, 0.578 mmol). After 15 h, it was acidified to pH ~ 1 by the addition of concentrated HCl solution at 0 ° C. Purification by preparative HPLC yielded 160 mg (100% yield) of the major compound 25-28. * H NMR (CD3OD): d 8.31 (1H, s), 8.0-7.88 (3H, m), 7.82 (1 H, dd, J = 8.7, 1.8 Hz), 7.58 (2H, m), 7.31 (1H, m), 7.14 (2H, m), 6.95 (1H, br td), 4.59 (H, m ), 4.14 (2H, m), 3.13 (1 H, dd, J = 13.8, 6 Hz), 3.02 (1 H, dd, J = 13.9, 8.7 Hz); HRMS (MALDI) stained for C20H20NO5PF (M + H +) 404.1063; found 404,1078.
Example 25-29: Prepared as described in the synthesis of 25-28 using 21c (110 mg, 0.386 mmol), 1-benzothiophen-2-carbonyl chloride (114 mg, 0.578 mmol) and 1 M sodium carbonate solution (1 ml). Purification by preparative HPLC yielded 145 mg (92% yield) of the major compound 25-29. 1 H NMR (CD 3 OD): d 7.95 (1H, s), 7.93-7.85 (2H, m), 7.4 (2H, m), 7.30 (1H, m), 7.2 -7.04 (2H, m), 6.94 (1H, br td), 4.51 (1H, m), 4.2-4.0 (2H, m), 3.11 (1H, dd, J = 13.9, 6.4 Hz), 3.01 (1H, dd, J = 13.9, 8.3 Hz); HRMS (MALDI) for Ci8Hi8N05PFS (M + H +) 410.0627; Found 410.0639.
Example 25-30: Mono-r (R) -2- (2,2-dimethyl-propanoylamino) -3- (3-fluorophenyl) -propylene glycol ester of phosphoric acid To a solution of sodium carbonate (1 M, 1 mL) were added aminophosphate 21c (65 mg, 0.228 mmol) and 2,2-dimethylpropanoic anhydride (0.08 mL, 0.392 mmol). After 15 h, it was acidified to pH ~ 1 by the addition of concentrated HCl solution at 0 ° C. Purification by preparative HPLC yielded 43 mg (57% yield) of the major compound 25-30. 1 H NMR (CD 3 OD): d 7.19 (1 H, m), 7.0-6.77 (3 H, m), 4.23 (1 H, m), 3.89 (2 H, m), 2 , 91 (1 H, dd, J = 13.8, 5.5 Hz), 2.74 (1 H, dd, J = 13.8, 9.2 Hz), 1.00 (9H, s); HRMS (MALDI) stained for C 14 H 22 NO 5 PF (M + H +) 334.1220; found 334,1223.
Example 25-31: Ester mono-f (RV2- { F1- (1-bromo-naphthalen-2-yl-methanoyl-amino> -3- (3-fluoro-phenyl-propyl-T-phosphoric acid To a solution of methylene chloride (3 mL) of acid 1- bromo-2-naphthoic acid (161 mg, 0.643 mmol) oxalyl chloride (0.168 mL, 1.93 mmol) and 2 drops of DMF were added. The mixture was stirred for 2 h and concentrated in vacuo. To the rest was added sodium carbonate solution (1 M, 2 mL), aminophosphate 21c (80 mg, 0.28 mmol) and 1 mL of acetonitrile. After 15 h, it was acidified to pH ~ 1 by the addition of concentrated HCl solution at 0 ° C. Purification by preparative HPLC yielded 70 mg (52% yield) of the main compound 25-31. 1 H NMR (CD 3 OD): d 8.22 (1H, d, J = 8.7 Hz), 7.84 (1H, m), 7.56 (2H, m), 7.27 (1H, m), 7.18 (1H, d, J = 8.7 Hz), 7.09 (1H, d, J = 7.8 Hz), 7.03 (1H, m), 6.91 (1H, td, J = 8.7, 3 Hz), 4.51 (1 H, m), 4.04 (2H, m), 3.05 (1 H, dd, J = 14.1, 5.7 Hz), 2 84 (1 H, dd, 14.1, 9.3 Hz); LCMS (ESP): 481 (MH) "; Elemental Analysis for (C2oH18BrFN05P) cale: C 49.81, H 3.76, N 2.90, found: C 49.63, H 3.73, N 2.92 .
Example 25-32: Ester mono- ((R) -3- (3-fluoro-phenD-2 - ((1- (6-methoxy-naphthalen-2-yD-methanoyl-1-a) -propyl) of phosphoric acid Prepared as described in the synthesis of 25-31 using 6-methoxy-2-naphthoic acid (143 mg, 7.07 mmol), oxalyl chloride (0.185 mL, 2.12 mmol), DMF (2 drops), solution of sodium carbonate (1 M, 2 mL) and aminophosphate 21c (88 mg, 0.353 mmol). Purification by preparative HPLC yielded 50 mg (39% yield) of the main compound 25-32. 1 H NMR (CD 3 OD): d 8.25 (1H, s), 7.9-7.73 (3H, m), 7.37-7.06 (5H, m), 6.95 (1H, t, J = 8.1 Hz), 4.57 (1 H, m), 4.12 (2 H, m), 3.95 (3 H, s), 3.13 (1 H, dd, J = 13.8, 6.6 Hz), 3.01 (1H, dd, J = 14.3, 7.7 Hz); LCMS (ESP): 432 (MH) "; Elemental Analysis for (C2iH2iFN06P 0.25H2O) cale: C 57.60, H 4.95, N 3.20, found: C 57.58, H 4.97, N 3,27.
Aminoalcohol 18d: To a THF solution (10 mL) of D-3-methylphenylalanine (1 g, 5.58 mmoles) at 0 ° C borane was added in THF (1 M, 22.4 mL, 22.4 mmol). After 48 h at 25 ° C, saturated NaHCO 3 solution (2 mL) was added to the solution, and stirred for 3 h. The mixture was concentrated and extracted with methylene chloride (3x20 mL). The combined organic layers were dried (Na2SO4) and concentrated. The remainder was purified by column chromatography (CH2Cl2 / eOH / NH4OH 95/5 / 0.5 to 90/10/1) to yield 490 mg (53% yield) of compound 18d as a white solid. 1 H NMR (CD 3 OD): d 7.20 (1H, t, J = 7.8 Hz), 7.08-6.94 (3H, m), 3.63 (1 H, dd, J = 10.5 , 3.9 Hz), 3.37 (1 H, dd, J = 10.5, 7.5 Hz), 3.11 (1H, m), 2.76 (1H, dd, J = 13.5 , 5.7 Hz), 2.49 (1H, dd, J = 13.8, 8.4 Hz), 2.34 (3H, s); LCMS (ESP): 166 (M + H +).
Alcohol 19d: To a solution of methylene chloride (5 mL) of the aminoalcohol 18d (150 mg, 0.909 mmol) were added triethylamine (0.3 mL) and benzyl chloroformate (0.21 mL, 1.5 mmol). The mixture was stirred for 15 h and then diluted with methylene chloride (20 mL). The solution was washed with concentrated saline (1x20 mL), dried (Na2SO4) and concentrated. After purification by column chromatography (15 to 30% EtOAc in hexanes), compound 19d was obtained in 63% yield (170 mg). 1 H NMR (CDCl 3): d 7.40-7.27 (5H, m), 7.18 (1H, t, J = 7.8 Hz), 7.08-6.95 (3H, m), 5 , 09 (2H, s), 4.94 (1H, br s), 3.94 (1 H, m), 3.69 (1H, br d), 3.58 (H, dd, J = 14, 5, 5.4 Hz), 2.82 (2H, d, J = 6.9 Hz), 2.32 (3H, s); LCMS (ESP): 322 (M + Na +).
Ester Bencil Phosphate 20d: To a solution of acetonitrile (8 mL) of alcohol 19d (160 mg, 0.535 mmol) and 1H-tetrazole (101 mg, 1.44 mmol) was added dibenzyl N, N-diisopropylphosphoramidite (0.36 mL, 1.07 mmol) at 25 ° C. After 5 h, MCPBA (0.42 g, 77% pure, 1.87 mmol) was added to the suspension. The solution was diluted with methylene chloride (35 mL), washed with concentrated NaHSÜ3 solution (2x25 mL), dried over gS04 and concentrated in vacuo. The residue was purified by column chromatography (15-30% EtOAc in hexanes) to yield 0.287 g of compound 20d in 96% yield. 1 H NMR (CDCl 3): d 7.39-7.2 (15H, m), 7.12 (1H, t, J = 7.8 Hz), 7.01 (1 H, d, J = 7.8. Hz), 6.93 (2H, m), 5.14-4.98 (7H, m), 4.05-3.82 (3H, m), 2.78 (1H, br dd), 2, 69 (1H, dd, J = 13.8, 7.8 Hz), 2.27 (3H, s).
Aminophosphate 21 d: To an ethanol solution of the benzyl phosphate ester 20d (0.287 g, 0.5 3 mmol) was added palladium on carbon (10%, 58 mg). The suspension was kept under a hydrogen atmosphere (1 atm) for 15 h and then 5% HCl solution (5 mL) was added. The mixture was filtered through celite. The filtrate was concentrated to dryness yielding 134 mg (92% yield) of 21d yellowish solid. 1 H NMR (CD 3 OD): d 7.26 (1 H, t, J = 7.5 Hz), 7.18- 7.06 (3H, m), 4.12 (1H, br d), 3.99 (1H, m), 3.68 (1H, m), 2.98 (2H, d, J = 7, 8 Hz), 2.36 (3H, s).
Example 25-33: Mono-r (R) -2- (f1- (d.ethylammonoxy-2H-chromen-3-in-methanoyl-1-amino-V3- (3-fuoro-phenin-propylene glycol) phosphoric acid ester To a solution of sodium carbonate (1 M, 2 mL) were added aminophosphate 21c (50 mg, 0.176 mmol) and 7-diethylamino-cumarin-3-carboxylic acid succinimidyl ester (50 mg)., 0.140 mmol). After 15 h, it was acidified to pHDl by the addition of concentrated 1 M HCl solution at 0 ° C. Purification by preparative HPLC yielded 43 mg (57% yield) of the main compound 25-33. 1 H NMR (CD 3 OD): 8 8.69 (1 H, s), 7.54 (1 H, d, J = 9.04 Hz), 7.31 (1 H, dd, J = 14.22, 7 , 91 Hz), 7.12 (2H, dd, J = 17.33, 9.80 Hz), 6.94 (1H, t, J = 8.86 Hz), 6.83 (1 H, dd, J = 9.04, 2.44 Hz), 6.95 (1 H, d, J = 2.26 Hz), 4.50 (1 H, m), 4.07 (2H, t, J = 4 , 71 Hz), 3.54 (4H, m), 3.14-2.92 (2H, m), 1.25 (6H, t, J = 7.16 Hz); HRMS (MALLD) cale for C 23 H 26 FN 2 O 7 PH (M + H +) 493.1549; found 493.1540.
Example 25-34: Mono- ((R) -2-fn- (1-bromo-naphthalen-2-ylV methano-n-amino) -3-m-tolyl-propyl) ester of phosphoric acid To a solution of methylene chloride (3 mL) of 1-bromo-2-naphthoic acid (123 mg, 0.49 mmol) were added oxalyl chloride (0.128 mL, 1.47 mmol) and 2 drops of DMF. The mixture was stirred for 3.5 h and concentrated in vacuo. To the rest was added sodium carbonate solution (1 M, 2 mL), 21 d-aminophosphate (69 mg, 0.245 mmol) and 2 mL of acetonitrile. After 15 h, it was acidified to pH ~ 1 by the addition of concentrated HCl solution at 0 ° C. Purification by preparative HPLC yielded 32 mg (27% yield) of the main compound 25-34. 1 H NMR (CD 3 OD): d 8.22 (1 H, d, J = 8.4 Hz), 7.82 (2 H, m), 7.76-7.46 (2 H, m), 7.2-6 , 9 (5H, m), 4.48 (1H, m), 4.03 (2H, m), 2.98 (1H, dd, J = 13.9, 6.2 Hz), 2.80 ( 1H, dd, J = 13.9, 8.7 Hz), 2.26 (3H, s); HRMS (ALDI) for C2iH22N05PBr (M + H +) 478.0414; found 478.0438.
Example 25-35: Mono (-) (R) -2- { Ri- (6-methoxy-naphthalen-2-yl) -methane-amino) -3-m-tolyl-propyl) ester of phosphoric acid Prepared as described in the synthesis of 25-32 using 6-methoxy-2-naphthoic acid (99 mg, 0.49 mmol), oxalyl chloride (0.128 mL, 1.47 mmol), DMF (2 drops), solution of sodium carbonate (1 M, 2 mL) and aminophosphate 21 d (69 mg, 0.245 mmol). Purification by preparative HPLC yielded 76 mg (51% yield) of the major compound 25-35. 1 H NMR (CD 3 OD): d 8.24 (1 H, s), 7.86 (1 H, d, J = 8.7 Hz), 7.82 (2 H, m), 7.30 (1 H, d , J = 2.4 Hz), 7.24-7.09 (4H, m), 7.03 (1H, d, J = 7.5 Hz), 4.53 (1H, m), 4.10 (2H, m), 3.95 (3H, s), 3.06 (1 H, dd, J = 13.9, 6.8 Hz), 2.96 (1 H, dd, J = 14, 8 , 3 Hz), 2.31 (3H, s); HRMS (MALDI) for C22H25NO6P (M + H +) 430.1420; Found 430.1436.
Alcohol 26a: To a solution of sodium carbonate (1 M, 2 mL) were added acetonitrile (1 mL), the amino alcohol 18d (180 mg, 1.09 mmol) and 2-chloro Naphthoyl (250 mg, 1.31 mmol). After 10 h, the mixture was extracted with methylene chloride (2x20 mL). The combined organic layers were dried (MgSO4) and concentrated. The remainder was purified by column chromatography (40% EtOAc in hexanes) to yield 350 mg (100% yield) of compound 26a. 1 H NMR (CD 3 OD): d 8.07 (1H, s), 7.82-7.73 (3H, m), 7.65 (1H, dd, J = 9, 1.5 Hz), 7.54 -7.41 (2H, m), 7.16 (1H, t, J = 7.2 Hz), 7.08-6.97 (3H, m), 6.46 (1H, br d, J = 7.2 Hz), 4.33 (1H, m), 3.77 (1H, dd, J = 11.1, 3.3 Hz), 3.68 (1H, dd, J = 11, 1, 5 , 1 Hz), 2.93 (2H, d, J = 7.2 Hz), 2.27 (3H, s).
Alcohol 26b: Prepared as described in the synthesis of the alcohol 26a using the amino alcohol 18d (131 mg, 0.794 mmole), 1-benzothiophene-2-carbonyl chloride (195 mg, 0.992 mmol) in a co-solvent of sodium carbonate solution (1 M, 1.5 mL) and acetonitrile (1.5 mL). Purification by column chromatography (50% EtOAc in hexanes) yielded 230 mg (89% yield) of compound 26b. 1 H NMR (CD 3 OD): d 7.96-7.81 (3H, m), 7.50-7.36 (21 H, m), 7.21-7.04 (3H, m), 7.01 (1H, d, J = 7.5 Hz), 4.32 (1H, m), 3.67 (1H, d, J = 5.4 Hz), 3.00 (1H, dd, J = 13, 1, 6.6 Hz), 2.87 (1H, dd, J = 13.1, 8.7 Hz), 2.29 (3H, s); LCMS (ESP): 326 (M + H +), 348 (+ Na +); 324 (M-H) \ Ester Bencil Phosphate 27a: To a solution of acetonitrile (0 mL) of alcohol 26a (348 mg, 1.09 mmol) and 1 H-tetrazole (191 mg, 2.728 mmol) was added dibenzyl N, N-diisopropylphosphoramidite (0.92 mL, 941 mg, 2.728 mmol) at 25 ° C. After 5 h, MCPBA (0.938 g, 60% pure, 3.27 mmol) was added to the suspension. The solution was diluted with methylene chloride (35 mL), washed with concentrated NaHSÜ3 solution (2x25 mL), dried over MgSO4 and concentrated in vacuo. The remainder was purified by column chromatography (30% EtOAc in hexanes) to yield 0.400 g of compound 27a in 63% yield. 1 H NMR (CDCl 3): d 8.34 (1 H, s), 7.95-7.82 (3 H, m), 7.55 (2 H, m), 7.41-7.28 (11 H, m ), 7.17 (1 H, t, J = 7.5 Hz), 7.10-6.99 (3H, m), 5.15-4.97 (5H, m), 4.50 (1 H, m), 4.17-3.96 (2H, m), 3.04 (1 H, dd, J = 13.5.5.4 Hz), 2.81 (1H, dd, J = 13 , 5, 9 Hz), 2.31 (3H, s).
Ester Bencil Phosphate 27b: Prepared as described in the synthesis of 27a using alcohol 26b (221 mg, 0.68 mmol), 1 H-tetrazole (129 mg, 1.84 mmol), dibenzyl?,? - düsopropylphosphoramidite (0.46 mL, 1 , 36 mmole) and MCPBA (0.533 g, 77% pure, 2.38 mmole). Purification by column chromatography (30% EtOAc in hexanes) yielded 0.50 g of compound 27b in 100% yield. 1 H NMR (CDCl 3): d 7.89-7.78 (3H, m), 7.5-7.29 (13H, m), 7.16 (1H, t, J = 7.8 Hz), 7 , 08-6.95 (3H, m), 5.16-4.97 (4H, m), 4.41 (1H, m), 4.04 (2H, m), 3.05 (1H, dd, J = 13.5, 5.4 Hz), 2.77 (1H, dd, J = 13.5, 9.6 Hz), 2.31 (3H, s).
Example 25-36: Mono- (2-r (1-naphthalen-2-yl-methanoin-amino-3-m-tolyl-propyl) ester of phosphoric acid To an ethanol solution of benzyl phosphate ester 27a (0.35 g, 0.604 mmol) was added palladium on carbon (10%, 35 mg). The suspension was kept under a hydrogen atmosphere (1 atm) for 15 h, and then filtered through celite. All the solvent was removed in vacuo. The remainder was purified by preparative HPLC to yield 45 mg (19% yield) of the major compound 25-36. 1 H NMR (CD 3 OD): d 8.21 (1 H, s), 7.9-7.76 (3 H, m), 7.72 (1 H, dd, J = 8.4, 8.1 Hz) , 7.48 (2H, m), 7.13-7.0 (3H, m), 6.93 (1H, d, J = 6.9 Hz), 4.45 (1H, m), 4, 03 (2H, m), 2.97 (1H, dd, J = 13.7, 6.8 Hz), 2.87 (1H, dd, J = 13.5, 8.1 Hz); HRMS (MALDI) stained for C21H23NO5P (M + H +) 400.1314; Found 400.1314.
Example 25-37: Mono-1,2-r (1-benzorb-thiophen-2-yl-methanoyl) -aminol-3-m-tolyl-propyl ester) of phosphoric acid Prepared as described in the synthesis of 25-36 using benzyl phosphate ester (27b, 0.398 g, 0.68 mmol) and palladium on carbon (10%, 100 mg). The suspension was kept under a hydrogen atmosphere (1 atm) for 72 h, and then filtered through celite. All the solvent was removed in vacuo. The remainder was purified by preparative HPLC to yield 120 mg (44% yield) of the major compound 25-37. 1 H NMR (CD 3 OD): d 8.0-7.8 (3H, m), 7.44 (2H, m), 7.23-7.0 (4H, m), 4.47 (1H, m) 4.09 (2H, m), 3.04 (1H, dd, J = 13.8, 6.8 Hz), 2.95 (1H, dd, J = 14.1, 7.7 Hz), 2.30 ( 3H, s); LCMS (ESP): 404 (MH) "; Elemental Analysis for (C 9H2oN05PS) cale: C 56.29, H 4.97, N 3.46, found: C 56.03, H 4.94, N 3, 39 Alcohol 28: To a THF solution (10 mL) of Boc-D-Ala (3-pyridyl) -OH (4.39 g, 16.5 mmol) at 0 ° C borane was added in THF (1 M, 40 mL, 40 mmol). After 20 h at 25 ° C, saturated NaHCO 3 solution (5 mL) was added to the solution, and stirred for 3 h. The mixture was concentrated and extracted with methylene chloride (3x50 mL). The combined organic layers were dried (Na2SO4) and concentrated. The remainder was purified by column chromatography (50% to 100% EtOAc in hexanes) to yield 1.51 g (36% yield) of compound 28 as a white solid. 1 H NMR (CDCl 3): δ 8.47 (2H, s), 7.84 (1H, d, J = 7.8 Hz), 7.44 (1H, dd, J = 7.8, 5.7 Hz ), 4.82 (1 H, m), 3.87 (1 H, m), 3.72 (1 H, dd, J = 10.5, 3.6 Hz), 3.62 (1H, dd) , J = 10.5, 4.2 Hz), 2.95 (2H, m), 1.39 (9H, m); LCMS (ESP): 253 (M + H +), 275 (M + Na +); HRMS (MALDI) stained for C 13 H 21 N 2 O 3 (M + H +) 253.1552; found 253.1564.
Ester Bencil Phosphate 29: To a solution of acetonitrile (15 mL) of alcohol 28 (997 mg, 3.96 mmol) and 1 H-tetrazole (1.11 g, 15.8 mmol) was added dibenzyl N, N-diisopropylphosphoramidite (2.66 mL). , 7.91 mmol) at 25 ° C. After 3 h, MCPBA (2.67 g, 77% pure, 11.9 mmol) was added to the suspension. The solution was diluted with methylene chloride (60 mL), washed with IMaHSC solution > 3 concentrated (2x25 mL), dried over MgSO4 and concentrated in vacuo. The remainder was purified by column chromatography (50% to 100% EtOAc in hexanes) to yield 0.481 g of compound 29 in 24% yield. 1 H NMR (CDCl 3): d 8.46 (1 H, br d), 8.39 (1 H, br s), 7.48 (1 H, d, J = 6.6 Hz), 7.36 (11 H , m), 5.06 (4H, m), 4.81 (1H, m), 4.0-3.80 (2H, m), 2.72 (2H, d, J = 6.3 Hz) , 1, 37 (9H, s); LCMS (ESP): 513 (M + H +); 535 (M + Na +).
Example 30: (1-Phosphonooxymethyl-2-pyridin-3-yl-ethyl) -carbamic acid tert-butyl ester To a solution of ethanol (3 mL) of the benzyl ester 29 (48 mg, 0.094 mmol) was added palladium on carbon (10%, 15 mg). The suspension it was kept under a hydrogen atmosphere (1 atm) for 15 h. After filtration, the filtrate was concentrated to dryness, yielding 36 mg (100% yield) of the main compound 30. 1 H NMR (CD3OD): d 8.58 (1H, s), 8.49 (1H, br d) , 8.19 (1 H, d, J = 7.5 Hz), 7.69 (1 H, br t), 3.87 (1 H, m), 3.79 (2 H, m), 3.06 (1 H, dd, J = 13.9, 5.3 Hz), 2.82 (1H, dd, J = 13.8, 8.5 Hz), 1.23 (9H, s); HRMS (ALDI) for C13H22N206P (M + H +) 333.1216; found 333,1218.
Aminophosphate 21e: To a solution of methylene chloride (2.5 mL) of the benzyl ester 29 (278 mg, 0.543 mmol) at 0 ° C was added trifluoroacetic acid (0.75 mL). After 45 min, the solution was concentrated in vacuo to yield 385 mg of the amine 31 as a colorless oil. The crude amine 31 was dissolved in ethanol (5 mL) and palladium on carbon (10%, 75 mg) was added. The suspension was kept under a hydrogen atmosphere (1 atm) for 48 h. After filtration, the filtrate was concentrated to dryness, yielding compound 21e as a solid (225 mg, 100%). 1 H NMR (CD 3 OD): d 8.68 (1 H, br s), 8.27 (1 H, br s), 7.48 (1 H, m), 7.25 (1 H, m), 4, 83 (1 H, d), 4.0-3.6 (2H, m), 3.26-3.01 (2H, m); LCMS (ESP): 233 (M + H +), 465 (2M + H +); 231 (M-H) ~.
Example 25-38: Ester mono- (2-K1-benzo [b iofen-2-yl-methanoyl-V-amino1-3-pyridin-3-yl-propyl]) of phosphoric acid To a solution of sodium carbonate (1 M, 1 ml_) was added 21 aminophosphate (110 mg, 0.474 mmol), 1-benzothiophen-2-carbonyl chloride (93 mg, 0.474 mmol). After 15 h, it was acidified to pH ~ 1 by the addition of concentrated HCl solution at 0 ° C. Purification by preparative HPLC yielded 25 mg (14% yield) of the main compound 25-38. 1 H NMR (CD 3 OD): d 8.83 (1 H, s), 8.71-8.63 (1 H, m), 8.58-8.46 (10H, m), 8.02-7, 83 (4H, m), 7.44 (2H, m), 4.60 (1H, m), 4.17 (2H, m), 3.42-3.13 (2H, m); HRMS (MALDI) for C17H18N2O5PS (M + H +) 393.0674; found 393.0681.
Example 25-39: Ester mono-f2-f (1-naphthalen-2-yl-methanoyl) -amino-1-3-pyridyl-3-yl-propyl > of phosphoric acid Prepared as described in the synthesis of 25-34 using 21 e (97 mg, 0.418 mmol), 2-naphthoyl chloride (80 mg, 0.418 mmol) and 1 M sodium carbonate solution (2 mL). Purification by preparative HPLC yielded 25 mg (16% yield) of the major compound 25-39. 1 H NMR (CD 3 OD): d 8.85 (1H, s), 8.70 (1H, m), 8.58 (1 H, d, J = 8.4 Hz), 8.323 (1H, s), 8 , 0-7.85 (4H, m), 7.79 (1 H, dd, J = 8.4, 1.8 Hz), 7.58 (2H, m), 4.71 (1H, m) , 4.22 (2H, m), 3.40 (1 H, dd, J = 14.0, 5.3 Hz), 3.22 (1 H, dd, J = 14.3, 9.6 Hz ); HRMS (MALDI) for C19H20N2O5P (M + H +) 387.1110; found 387,1117.
Example 33: Mono-ester. { (R) -3-Cyclohexyl-2-r (1-naphthalen-2-yl-methanoiD-aminol-propyl) of phosphoric acid To a solution of aminophosphate 21a (540 mg, 2.02 mmol) in acetic acid (70% aqueous solution, 7 mL) was added 5% rhodium on alumina (306 mg). The suspension was maintained under a hydrogen atmosphere (60 psi) for 15 h. After filtration, the filtrate was concentrated to dryness to yield 500 mg of compound 32. A part of 32 (96 mg, 0.416 mmol) was dissolved in 1 M sodium carbonate solution (2 mL). 2-Naphthoyl chloride (79 mg, 0.416 mmol) was added to the solution. After 15 hours, acidified to pH ~ 1 by the addition of concentrated HCl solution at 0 ° C. Purification by preparative HPLC yielded 4 mg (2% yield) of the major compound 33. 1 H NMR (CD3OD): d 8.40 (1H, s), 8.09-7.87 (4H, m), 7, 60 (2H, m), 4.48 (1H, m), 4.06 (2H, m), 1.93 (1H, m); LCMS (ESP): 390 (M-H) -.
Aminoalcohol 34: To a THF solution (30 mL) of D-homophenylalanine (5 g, 27.9 mmol) at 0 ° C was added borane in THF (1 M, 55.8 mL, 55.8 mmol). After 48 h at 25 ° C, saturated NaHCC solution (5 mL) was added to the solution, and stirred for 4 h. The mixture was concentrated and extracted with methylene chloride (3x50 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by column chromatography (CH2Cl2 / MeOH / NH40H 95/5 / 0.5) to yield 1.2 g (26% yield) of compound 34 as a yellowish oil. 1 H NMR (CDCIs): d 7.39-7.13 (5H, m), 4.01 (1H, dd, J = 11.4, 3.8 Hz), 3.69 (1H, dd, J = 11.7, 6.3 Hz), 2.94 (1H, m), 2.71 (2H, t, J = 7.8 Hz), 2.09 (1H, m), 1.89 (1H, m); LCMS (ESP): 166 (M + H +).
Alcohol 35: To a solution of sodium carbonate (1 M, 2 mL) were added acetonitrile (2 mL), aminoalcohol 34 (300 mg, 1.82 mmol) and 2-naphthoyl chloride (347 mg, 1.82 mmol). After 10 h, the mixture was extracted with methylene chloride (3x20 mL). The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by column chromatography (50% EtOAc in hexanes) to yield 220 mg (38% yield) of compound 35. 1 H NMR (CDCl 3): d 8.16 (1 H, s), 7.93 -7.82 (3H, m), 7.74 (1H, dd, J = 8.1, 1.8 Hz), 7.55 (2H, m), 7.34-7.15 (5H, m) ), 6.40 (1 H, d, J = 7.2 Hz), 4.29 (1H, m), 3.87 (1 H, dd, J = 11, 1, 3.9 Hz), 3 , 78 (1H, dd, J = 1, .8, 5.1 Hz), 2.81 (2H, t, J = 7.5 Hz), 2.11-2.0 (2H, m); LCMS (ESP): 342 (M + Na +); 318 (-H) -; Elemental Analysis for (C21H21NO2) cale: C 78.97, H 6.63, N 4.39; found: C 79.07, H 6.62, N 4.20.
Ester Bencil Phosphate 36: To a solution of acetonitrile (6 mL) of alcohol 35 (206 mg, 0.646 mmol) and 1 H-tetrazole (122 mg, 1.74 mmol) was added dibenzyl N, N-diisopropylphosphoramidite (0.433 mL, 1.29 mmol) at 25 ° C. After 5 h, MCPBA (0.3 g, 77% pure, 2.26 mmol) was added to the suspension. The solution was diluted with methylene chloride (35 mL), washed with concentrated NaHS03 solution (2x25 mL), dried over MgSO4 and concentrated in vacuo. The remainder was purified by column chromatography (30% EtOAc in hexanes) to yield 0.311 g of compound 36 in 83% yield. 1 H NMR (CDCl 3): d 8.28 (1 H, s), 7.95-7.78 (4H, m), 7.55 (2H, m), 7.37-7.13 (16H, m ), 6.92 (1H, d, J = 8.1 Hz), 5.11-4.93 (4H, m), 4.41 (1H, m), 4.21-4.07 (1H , m), 2.72 (2H, t, J = 7.8 Hz), 1.97 (2H, m).
Example 37: Ester mono-. { 2-f (1-naphthalen-2-yl-methanoyl) -amino-1-4-phenyl-butyl) of phosphoric acid To an ethanol solution of benzyl phosphate ester 36 (0.305 g, 0.527 mmol) was added 10% palladium on carbon (60 mg). The suspension was kept under a hydrogen atmosphere (1 atm) for 15 h, and then filtered through celite. All the solvent was removed in vacuo to yield 210 mg (100%) of the major compound 37. 1 H NMR (CD3OD): d 8.39 (1H, s), 8.1-7.9 (4H, m), 7 , 59 (2H, m), 7.3-7.18 (5H, m), 4.37 (1H, m), 4.12 (2H, m), 2.79 (2H, m), 2, 06 (2H, m); HR S (ALDI) for C27H23NO5P (M + H +) 400.1314; Found 400.1312.
To a solution of methylene chloride (8.5 mL) of D-3-fluorophenylalanine (0.5 g, 2.73 mmol) were added triethylamine (1 mL) and dansyl chloride (0.737 g, 2.73 mmol). . After 12 h, the mixture was concentrated in vacuo. The remainder was dissolved in EtOAc (10 mL) and added to a 5% solution of HCl (10 mL). The resulting precipitate 38 was collected by filtration. The solid 38 was dissolved in MeOH (15 mL). After cooling the solution to -20 ° C, thionyl chloride (1.5 mL) was added. After 15 h at 25 ° C, the solution was concentrated in vacuo and the remainder was dissolved in EtOAc (50 mL). The EtOAc solution was washed with ice cold saturated carbonate solution (1x50 mL), and dried over MgSO4 and concentrated to dryness yielding 506 mg of methyl ester 39. The solid 39 was dissolved in THF (10 mL) and LiBH 4 (76 mg, 3.5 mmol) was added. After 15 h, the reaction was stopped by the slow addition of saturated NH 4 Cl solution (1.5 mL). The mixture was extracted with EtOAc (3x25 mL), washed with concentrated saline (1x20 mL), dried (MgSO4) and concentrated. The remainder was purified by column chromatography (50% EtOAc in hexanes) to yield 308 mg (28% yield for .3 steps) of the desired compound 40. 1 H NMR (CDCl 3): d 8.43 (1 H, d , J = 8.4 Hz), 8.14 (1 H, dd, J = 7.8, 0.9 Hz), 8.04 (1 H, d, J = 8.7 Hz), 7.40 (2H, m), 7.07 (1H, d, J = 7.5 Hz), 6.78 (1H, m), 6.55-6.46 (2H, m), 6.38 (1H , dt, J = 9, 1, 2 Hz), 5.25 (1 H, d, J = 10.5 Hz), 3.56 (1 H, dd, J = 10.8, 3.9 Hz) , 3.47-3.31 (3H, m), 2.81 (6H, s), 2.61 (1H, dd, J = 13.8, 6.6 Hz), 2.49 (1H, dd) , J = 13.8, 7.8 Hz).
Ester Bencil Phosphate 41: To a solution of acetonitrile (1 mL) of alcohol 35 (53 mg, 0.132 mmol) and 1H-tetrazole (28 mg, 0.394 mmol) was added dibenzyl N, N-diisopropylphosphoramidite (91.2 mg, 0.244 mmol) at 25 ° C. After 4 h, 50% hydrogen peroxide (1 mL) was added to the suspension at 0 ° C. The solution was diluted with methylene chloride (25 mL), washed with concentrated NaHS03 solution (2x25 mL), dried over MgSO4 and concentrated in vacuo. The remainder was purified by column chromatography (35% EtOAc in hexanes) to yield 0.06 g of compound 41 in 69% yield. 1 H NMR (CDCIs): d 8.48 (1H, d, J = 8.4 Hz), 8.15 (1H, dd, J = 7.5, 0.9 Hz), 8.11 (1H, d , J = 8.7 Hz), 7.45 (2H, m), 7.38-7.30 (10H, m), 7.12 (1H, d, J = 7.5 Hz), 6.83 (1 H, m), 6.59 (1H, td, J = 8.7, 2.7 Hz), 6.51 (1H, d, J = 7.5 Hz), 6.42 (1H, dt , J = 9.6, 1.8 Hz), 5.42 (1H, d, J = 8.1 Hz), 5.08-4.94 (4H, m), 3.95-3.84 ( 2H, m), 3.50 (1H, m), 2.86 (6H, s), 2.59 (1H, dd, J = 13.8, 7.2 Hz), 2.46 (1H, dd) , J = 13.8, 7.2 Hz).
Example 42: Mono-r (R) -2- (5-dimethylamino-naphthalene-1-sulfonylamino) -3- (3-fluoro-phenyl) -propyl ester of phosphoric acid To an ethanol solution of benzyl phosphate ester 41 (0.06 g, 0.0906 mmol) was added 10% palladium on carbon (10 mg). The suspension was kept under a hydrogen atmosphere (1 atm) for 15 h, and then filtered through celite. The filtrate was concentrated in vacuo. The remainder was purified by HPLC to yield 20 mg (46% yield) of the major compound 42. 1H RN (CD3OD): d 8.46 (1H, d, J = 8.7 Hz), 8.39 (1H, d, J = 9 Hz), 8.20 (1H, d, J = 7.5 Hz), 7.77 (1H, d, J = 7.5 Hz), 7.72-7.59 (2H, m), 6.69 (1H, m), 6.59 (1H, d, J = 8.1 Hz), 6.48-6.34 (2H, m), 4.14 (1 H, m) , 3.97 (1H, m), 3.62 (1H, m), 3.32 (6H, s), 2.90 (1 H, dd, J = 14.4, 3.9 Hz), 2 , 49 (1H, dd, J = 10.2, 14.1 Hz); LCMS (ESP): 483 (M + H +) Alcohol 43: To a sodium carbonate solution (1.5 mL) were added acetonitrile (5 mL), ethanolamine (0.173 mL, 3.12 mmol) and 2-naphthoyl chloride (594 mg, 3.12 mmol). After 15 h, the mixture was extracted with methylene chloride (3x50 mL). The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by column chromatography (EtOAc) to yield 386 mg (58% yield) of compound 43. H NMR (CDCl 3): d 8.31 (1H, s), 7.96-7.78 (4H , m), 7.55 (2H, m), 6.76 (1H, br s), 3.89 (2H, t, J = 5.7 Hz), 3.70 (2H, q, J = 5.4 Hz); LCMS (ESP): 2115 (M + H +), 238 (M + Na +); Elemental Analysis for (C13H13N02) cale: C 72.54, H 6.09, N 6.51; found: C 72.68, H 6.09, N 6.51.
Ester Bencil Phosphate 44: To a solution of acetonitrile (10 mL) of alcohol 43 (321 mg, 1.49 mmol) and 1 H-tetrazole (282 mg, 4.02 mmol) was added dibenzyl N, N-diisopropylphosphoramidite (1 mL, 2.99 mmol). ) at 25 ° C. After 3 h, MCPBA (77% pure, 900 mg, 5.22 mmol) was added to the suspension at 0 ° C. The solution was diluted with methylene chloride (75 mL), washed with concentrated NaHSC-3 solution (2x50 mL), dried over MgSC and concentrated in vacuo. The residue was purified by column chromatography (50% to 75% EtOAc in hexanes) to yield 0.699 g of compound 44 in 99% yield. HRN (CDCl 3): d 8.34 (1 H, s), 7.96-7.81 (4H, m), 7.55 (2H, m), 7.37-7.15 (11 H, m ), 5.04 (4H, m), 4.19 (2H, m), 3.73 (2H, q, J = 5.1 Hz); LCMS (ESP): 498 (M + Na +).
Phosphoric Acid 45 To an ethanol solution of the benzyl phosphate ester 44 (0.672 g, 1.41 mmol) was added 10% palladium on carbon (134 mg). The suspension was kept under a hydrogen atmosphere (1 atm) for 2.5 h, and then filtered through celite. The filtrate was concentrated to dryness in vacuo to yield 415 mg (100% yield) of compound 45 as a white solid. 1 H NMR (CD 3 OD): d 8.42 (1 H, s), 8.03-7.87 (4 H, m), 7.59 (2 H, m), 4.20 (2 H, q, J = 5 , 7 Hz), 3.73 (2H, t, J = 5.4 Hz); LCMS (ESP): 296 (+ H +), 318 (M + Na +); 294 (M-H) ', 589 (2M-H)'; Elemental Analysis for (C13Hi4N05P 0.2H2O) cale: C 52.25, H 4.86, N 4.69; found: C 52.21, H 4.95, N 4.60.
To a solution of methylene chloride (5 mL) of D-phenylactic acid (0.5 g, 3 mmol) at 0 ° C were added triethylamine (1 mL) and 2-naphthoyl chloride (0.629 g, 3.3 mmol). ). After 12 h, the mixture was diluted with EtOAc (80 mL), washed with 5% HCl solution cooled on ice (1x50 mL), dried and concentrated. The remainder 46 (0.9 g) was dissolved in THF (10 mL). The solution was cooled to -20 ° C and 1 borane in THF solution (3 mL, 3 mmol) was added. After the mixture was stirred at 25 ° C for 6.5 h, MeOH (15 mL) was added. After 15 min, all the solvent was removed in vacuo. The residue was dissolved in MeOH (15 mL) and stirred for 1 h. The solution was diluted with EtOAc (100 mL), washed with 1M a2C03 solution cooled on ice (2x50 mL) and concentrated saline (1x50 mL), dried and concentrated. The residue was purified by column chromatography (35% EtOAc in hexanes) to yield 300 mg (33% yield) of compound 47. 1 H NMR (CDCl 3): d 8.57 (H, s), 8.02 ( H, dd, J = 8.7, 1.8 Hz), 7.94 (1H, br d, J = 7.8 Hz), 7.90-7.79 (2H, m), 7.57 ( 2H, m), 7.35-7.18 (5H, m), 5.41 (1H, m), 3.90 (1H, dd, J = 12.3, 3.3 Hz), 3.80 (1H, dd, J = 12.3, 3.6 Hz), 3.12 (2H, m); LCMS (ESP): 329 (M + Na +); 305 (M-H) ".
To a solution of acetonitrile (10 ml_) of alcohol 43 (60 mg, 0.196 mmol) and 1 H-tetrazole (70 mg, 1 mmol) was added dibenzyl N, N-diisopropylphosphoramidite (260 mg, 0.75 mmol) at 25 ° C. ° C. After 3 h, MCPBA (77% pure, 570 mg, 3 mmol) was added to the suspension at 0 ° C. The solution was diluted with methylene chloride (30 ml_), washed with concentrated NaHS03 solution (2x30 ml), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1% THF in methylene chloride) to yield 80 mg of compound 48 in 73% yield. H NMR (CDCl 3): d 8.57 (1 H, s), 8.02 (1 H, dd, J = 8.4, 1.2 Hz), 7.93-7.77 (3H, m) , 7.63-7.46 (2H, m), 7.40-7.17 (15H, m), 5.48 (1H, m), 5.10-4.93 (4H, m), 4.19 (2H, m), 3.11 (1 H, dd, J = 13.5, 6.3 Hz), 3.01 (1 H, dd, J = 13.5, 7.2 Hz) .
Example 49: Naphthalene-2-carboxylic acid (R) -2-phenyl-1-phosphonooxymethyl-ethyl ester To an ethanol solution of the benzyl phosphate ester 48 (80 mg, 0.141 mmol) was added 10% palladium on carbon (25 mg). The suspension was kept under a hydrogen atmosphere (1 atm) for 15 h, and then filtered through celite. The filtrate was concentrated in vacuo. The rest it was purified by HPLC to give 30 mg (55% yield) of the main compound 49. 1 H NMR (CD3OD): d 8.53 (1H, s), 7.99-7.80 (4H, m), 7, 53 (2H, p, J = 6.9 Hz), 7.31-7.08 (5H, m), 5.44 (1H, m), 4.24-4.05 (2H, m), 3 , 08 (2H, d, J = 6.9 Hz); LCMS (ESP): 385 (M-H) "; HRMS (MALDI) cale for C20H2oO6P (M + H +) 387.0998, found 387.1016.
Hydroxycarboxylic acid: D-3-fluorophenylalanine (7.98 g, 43.8 mmol) was dissolved in 1 M sulfuric acid solution (140 mL). To the solution, 6 M NaN02 (36 mL, 216 mmol) and 3.2 M sulfuric acid (36 mL) were slowly added at 0 ° C. The mixture was stirred at 0 ° C for 3 h and then at 25 ° C for 0.5 h. The solution was extracted with EtOAc (7x75 mL). The combined organic layers were dried and concentrated. Recrystallization from EtOAc / hexanes yielded 5.36 g (67% yield) of the cc-hydroxycarboxylic acid compound. 1 H NMR (CDCl 3): d 7.29 (1H, m), 7.13-7.0 (2H, m), 6.95 (1H, td, J = 8.4, 2.4 Hz), 4 , 36 (1H, dd, J = 7.8, 4.2 Hz), 3.12 (1H, dd, J = 14.1, 4.5 Hz), 2.93 (1H, dd, J = 13 , 8, 7.8 Hz); LCMS (ESP): 183 (M-H) ".
Diol 51: To a THF solution (15 mL) of α-hydroxycarboxylic acid 50 (2.04 g, 1.1 mmol) was added 1 M borane in THF solution (16.6 mL, 16.6 mmol). The mixture was stirred at 25 ° C for 16 h. The reaction was stopped by the addition of MeOH (15 mL). After 1 h, all the solvent was removed in vacuo. The remainder was dissolved in methylene chloride (15 mL). Saturated NaHCO 3 solution (15 mL) was added to the solution, which was stirred vigorously for 3 h. The mixture was extracted with methylene chloride (2x50 mL). The combined organic layers were dried over a2SO4 and concentrated. The residue was purified by column chromatography (35% to 50% EtOAc in hexanes) to yield 969 mg (51% yield) of compound 51. 1 H NMR (CDCl 3): d 7.34-7.22 (1 H , m), 7.05-6.89 (3H, m), 3.96 (1H, m), 3.71 (1H, dd, J = 11, 1, 3.3 Hz), 3.53 (1H, dd, J = 1, 7, 6.9 Hz), 2.78 (2H, m).
Ester Bencil Phosphate 52: To a solution of methylene chloride (4 mL) of diol 51 (215 mg, 1.26 mmol) were added pirdine (1 mL), 4-dimethylaminopyridine (DMAP) (10 mg) and 10% dibenzyl phosphoryl chloride in benzene. (8.8 mL, 2.78 mmol). After 17 h, the solution was diluted with methylene chloride (25 mL), washed with 5% HCl solution (1x30 mL), dried and concentrated. The residue was purified by column chromatography (35% EtOAc in hexanes) to yield 68 mg (13% yield) of compound 52. 1 H NMR (CDCl 3): d 7.43-7.29 (10H, m), 7.28 (1H, m), 7.00-6.84 (2H, m), 5.15-4.98 (4H, m), 4.03-3.78 (3H, m), 2, 71 (2H, m); LCMS (ESP): 431 (M + H +), 453 (M + Na +).
Ester 53: To a solution of methylene chloride (2 mL) of alcohol 52 (67 mg, 0.158 mmol) were added triethylamine (1 mL) and 1-benzothiophen-2-carbonyl chloride (62 mg, 0.316 mmol). After 3 h, the mixture was concentrated in vacuo. The remainder was dissolved in methylene chloride (20 mL). The solution was washed with concentrated saline (1x20 mL), dried over Na2SO4 and concentrated. The rest was purified by chromatography on column (5 to 15% EtOAc in hexanes) yielding 23 mg (24% yield) of compound 53. 1 H NMR (CDCl 3): d 8.01 (1H, s), 7.84 (2H, d, J = 8.4 Hz), 5.43 (2H, m), 7.33-7.17 (12H, m), 7.03-6.85 (3H, m), 5.37 (1H, m), 5.02 (4H, m), 4.12 (2H, m), 3.04 (1 H, dd, J = 13.8, 6.9 Hz), 2.96 (1H, dd, J = 14 , 1, 6.6 Hz).
Example 54: Mono-r (R) -2-f (1-benzofb1thiophen-2-yl-methanoyl-V-amino1-3- (3-fluoro-phenyl-V-phenyl glycol) ester of phosphoric acid 53 54 To an ethanol solution of benzyl phosphate ester 53 (23 mg, 0.038 mmol) was added 10% palladium on carbon (5 mg). The suspension was kept under a hydrogen atmosphere (1 atm) for 15 h, and then filtered through celite. The filtrate was concentrated in vacuo. The residue was purified by HPLC to yield 10 mg (64% yield) of compound 54. 1 H NMR (CD3OD): d 8.17 (1H, s), 8.00 (2H, m), 7.53 (2H , m), 7.35 (1H, m), 7.24-7.11 (2H, m), 7.01 (1H, td, J = 8.7, 2.7 Hz), 5.53 ( 1H, m), 4.24 (2H, m), 3.20 (2H, m); HRMS (MALDI) for C18Hi706PS (M + H +) 411, 0468; found 411, 0480.
Aminoalcohol 55: To a THF solution (20 mL) of N-methyl-D-phenylalanine (2.5 g, 14 mmol) was added 1M borane solution in THF (20.9 mL, 20.9 mmol). After 15 h, saturated NaHCO 3 solution (5 mL) was added to the solution. The mixture was stirred vigorously for 48 h and then extracted with methylene chloride (3x25 mL). The combined organic layers were dried over MgSO4 and concentrated. The remainder was purified by column chromatography (95/5 / 0.5 to 90/10/1 CH2Cl2 / CH3OH / NH4OH) to yield 710 mg (31% yield) of compound 55. H NMR (CDCl3): d 7 , 41-7.09 (5H, m), 3.64 (1H, dd, J = 10.8, 3.6 Hz), 3.34 (1H, dd, J = 10.8, 4.5 Hz) ), 2.86-2.68 (3H, m), 2.41 (3H, s).
Alcohol 56: To a sodium carbonate solution (1M, 4 mL) were added acetonitrile (4 mL), aminoalcohol 55 (377 mg, 2.28 mmol) and 2-naphthoyl chloride (435 mg, 2.28 mmol). After 15 h, the mixture was extracted with methylene chloride (3x25 mL). The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by column chromatography (50-100% EtOAc in hexanes) to yield 574 mg (79% yield) of compound 56. 1 H NMR (CD3OD): (mixture of two rotamers)? 3.16 and 2.81 (3H, s); LCMS (ESP): 320 (M + H +), 342 (M + Na +); Elemental Analysis for (C21H21NO2) cale: C 78.97, H 6.63, N 4.39; found: C 79.00, H 6.76, N 4.47.
Ester Bencil Phosphate 57: To a solution of acetonitrile (8 mL) of alcohol 56 (322 mg, 1.01 mmol) and 1H-tetrazole (191 mg, 2.72 mmol) was added dibenzyl N, N-diisopropylphosphoramidite (0.678 mL, 2.02 mmol). ) at 25 ° C. After 3 h, MCPBA (0.523 g, 77% pure, 3.03 mmol) was added to the suspension. The solution was diluted with methylene chloride (35 mL), washed with concentrated NaHSÜ3 solution (2x25 mL), dried over MgSO4 and concentrated in vacuo. The remainder was purified by column chromatography (30% to 50% EtOAc in hexanes) to yield 0.23 g of compound 57 in 40% yield. 1 H NMR (CDCl 3): (mixture of two rotamers) d 5.06 (4H, m), 3.06 and 2.72 (3H, s); LCMS (ESP): 602 (M + Na +).
Example 58: Ester mono- (rrnethyl- (1-naphthalen-2-yl-methanoyl-1-phenyl-1-phenyl-propyl) phosphoric acid To an ethanol solution of the benzyl phosphate ester 57 (224 mg, 0.387 mmol) was added 10% palladium on carbon (45 mg). The suspension was kept under a hydrogen atmosphere (1 atm) for 3 h, and then filtered through celite. The filtrate was concentrated to dryness in vacuo yielding 155 mg (100% yield) of the major compound 58. 1 H NMR (CD3OD): (mixture of two rotamers) d 3.18 and 2.87 (3H, s); LCMS (ESP): 398 (M-H). "Scheme 4 Alcohol 59: To a solution of 3-fluorophenylalanine (2.2 g, 12 mmol) in methanol (12 mL) at -30 ° C was added thionyl chloride (1 mL). After stirring at 25 ° C for 15 h, the reaction mixture was concentrated in vacuo to yield 2.2 g of a solid, which was dissolved in DMF (25 mL). To the solution were added benzimidazole-6-carboxylic acid (2.18 g, 13.44 mmol), EDC (3.22 g, 16.8 mmol), and DMAP (0.237 g, 2.24 mmol). After 15 h, the mixture was diluted with EtOAc (100 mL), washed with 5% ice cold NaOH solution (1x80 mL) and concentrated saline (3x 80 mL), dried (MgSO 4) and concentrated. The resulting crude oil (2 g) was dissolved in THF (10 mL) and the solution was slowly added to UBH4 (0.52 g, 24 mmol). After 15 h at 25 ° C, a solution of NH 4 Cl (1 mL) was added slowly to stop the reaction. The suspension was extracted with EtOAc (3x20 mL). The combined organic phases were washed with concentrated saline (2x40 mL), dried (MgSO4) and concentrated. The residue was purified by column chromatography (5% MeOH in CH 2 Cl 2) to give 400 mg (11% yield) of compound 59. LCMS: 314 (M + H +, ESP Positive); 312 (M-hT, negative ESP).
Ester Bencil Phosphate 60: To a solution of acetonitrile (6 mL) of alcohol 59 (188 mg, 0.601 mmol) and 1 H-tetrazole (84 mg, 1.20 mmol) was added dibenzyl N, N-diisopropylphosphoramidite (0.302 mL, 0.901 mmol) at 25 ° C. ° C. After 3 h, MCPBA (404 mg, 77% pure, 1.80 mmol) was added to the suspension. The solution was diluted with EtOAc (20 mL), washed with 5% NaHS03 solution (1x20 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (98/2 / 0.2 CH2Cl2 / CH3OH / NH4OH) and further purified by preparative HPLC to yield 132 mg of compound 60 in 38% yield. 1 H RN (CDCl 3): d 8.82 (1 H, s), 7.89 (1 H, d, J = 8.10 Hz), 7.75 (1 H, d, J = 7.54 Hz), 7.47 (1 H, d, J = 8.67 Hz), 7.37-7.19 (1 H, m), 7.00 (H, d, J = 7.35 Hz), 6.91 (2H, d, J = 8.85 Hz), 5.14-5.00 (4H, m), 4.53 (1H, m), 4.23-4.01 (2H, m), 3, 08-2.96 (1H, dd, J = 13.76, 6.97 Hz), 2.91-2.80 (1 H, dd, J = 13.94, 8.86 Hz); LCMS: 574 (+ H +); 596 (M + Na +).
Example 61: Ester mono-f (R) -2-IY1-3H-benzoamidazol-5-yl-methanoiD-amino1-3-f3-fluoro-phenyl) -propyl 1 of phosphoric acid To a methanol solution of the benzyl phosphate ester 60 (132 mg, 0.230 mmol) was added palladium on carbon (10%, 26 mg). The suspension was kept under a hydrogen atmosphere (1 atm) overnight, and then filtered through celite. Purification by preparative HPLC yielded 1 mg (12% yield) of the major compound 61. 1 H RN (CD3OD): 5 9.46 (1 H, s), 8.26 (1 H, s), 8.06-7 , 86 (1 H, dd, J = 38.24, 8.85 Hz), 7.30 (1 H, m), 7.20-7.04 (2H, m), 6.95 (1H, t , J = 10.36 Hz), 4.57 (1 H, m), 4.13 (2H, m), 3.18-2.94 (2H, m); LCMS: 394 (M + H +); 392 (M-H) "; HRMS (MALDI) cale for C 7Hi7FN305PH (M + H +) 394.0962; found 394.0968.
Esauema 5 2,3-Difluoro-DL- 62 63 phenylalanine 65 To a solution of tetrahydrofuran (25 mL) of 2,3-difluoro-DL-phenylalanine (2.93 g, 14.6 mmol) was slowly added 1 M borane in tetrahydrofuran (36.5 mL, 36.5 mmol) to 0 ° C. The mixture was warmed to room temperature and stirred overnight. Methanol (20 mL) was added and the solution was stirred vigorously for 1 h. The solvent was evaporated and the process repeated. The residue was dissolved in methylene chloride (50 mL) and stirred vigorously with 1 M NaHCC >; 3 (30 mi) all night. The mixture was extracted with methylene chloride (3x50 mL). The combined methylene chloride extract was washed with concentrated saline (50 mL), dried with Na2SO4, and concentrated. After purification by column chromatography (95/5 / 0.5 CH2Cl2 / CH3OH / NH4OH), compound 62 was obtained in 47% yield (1.28 g). 1 H NMR (CH 3 OD): d 7.20-7.02 (3H, m), 3.54 (1H, dd, J = 10.93, 4.52 Hz), 3.44-3.35 (1 H , m), 3.14-3.05 (1 H, m), 2.93-2.84 (H, m), 2.75-2.65 (1H, m); LCMS: 18 8.0 (M + H +).
Alcohol 63: 63 To a solution of methylene chloride (30 mL) of 62 (1.28 g, 6.84 mmol) were added triethylamine (1.9 mL, 13.7 mmol) and benzyl chloroformate (1.47 mL, 10%). 3 mmoles). The mixture was stirred overnight and then he concentrated. The residue was dissolved in methylene chloride (30 mL) and washed with concentrated saline (1x30 mL). The solution was dried (Na2SO4) and concentrated. After purification by column chromatography (10 to 30% EtOAc in hexane), compound 63 was obtained in 59% yield (1.30 g). H NMR (CDCl 3): d 7.27 (5H, m), 7.03-6.86 (3H, m), 5.00 (2H, s), 3.90 (H, m), 3.70. -3.47 (2H, m), 2.88 (1H, d, J = 6.80 Hz); S (ESP): 322.1 (M + H +); 344.1 (M + Na +).
Ester Bencil Phosphate 64: To a solution of acetonitrile (20 mL) of alcohol 63 (1.30 g, 4.05 mmol) and 1 H-tetrazole (765 mg, 10.9 mmol) was added dibenzyl N, N-diisopropylphosphoramidite (2.72 mL). , 8.10 mmol) at 25 ° C. After 3 h, MCPBA (3.18 g, 77% pure, 14.2 mmol) was added to the suspension. The solution was diluted with EtOAc (80 mL), washed with 5% NaHS03 solution (2x80 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (10-30% EtOAc in hexane) to yield 2.16 g of compound 64 in 92% yield. 1 H NMR (CDCl 3): d 7.51-7.38 (15H, m), 7.18-6.93 (3H, m), 5.18-5.08 (6H, m), 4.21- 3.93 (3H, m), 2.95 (2H, d, J = 6.42 Hz); LCMS: 604.2 (M + Na +).
Amino Phosphate 65: HCI To a methanol solution of the benzyl phosphate ester 64 (2.16 g, 3.72 mmoles) palladium on carbon (10%, 300 mg) was added. The suspension was kept under a hydrogen atmosphere (1 atm) for 4 h, and then filtered through celite. The collected solid was washed with methylene chloride. The mixture of the solid and celite was suspended in 5% HCl solution and stirred for 20 min. After filtration, the filtrate was concentrated to dryness, yielding 910 mg of compound 65 in 92% yield. 1H RN (SO): d 6.48-6.32 (3H, m), 3.38-3.28 (1H, m), 3.24-3.13 (1H, m), 3, 00-2.88 (1H, m), 2.32 (2H, d, J = 7.18 Hz); LC S: 268.0 (M + H +); 266.1 (-H) '.
Example 66: Mono- (3- (2,3-difluoro-phenin-2-f (1-naphthalen-2-yl-methanoi-O-aminol-propyl) ester of phosphoric acid To a solution of sodium carbonate (1 M, 5 ml_) were added aminophosphate 65 (226 mg, 0.745 mmol) and 2-naphthyl chloride (142 mg, 0.745 mmol). After 15 h, it was acidified to pH ~ 1 by the addition of 1 M HCl solution at 0 ° C. Purification by preparative HPLC yielded 135 mg (43% yield) of the major compound 66. 1 H NMR (CD3OD): d 8.31 (1H, 3), 7.98-7.91 (3H, m), 7, 82 (1H, d, J = 1.72 Hz), 7.60 (2H, m), 7.20-7.06 (3H, m), 4.82 (1H, m), 4.18 (2H , m), 3.24 (1H, dd, J = 13.93, 5.49 Hz), 3.07 (1 H, dd, J = 13.69, 8.84 Hz); LCMS: 420.2 (M-H) "; Elemental Analysis for (C20H18F2NO5P) cale: C 57.01, H 4.31, N 3.32, found: C 56.80, H 4.55, N 3.27.
Example 67: Ester mono-r2-r (1-benzorb1tiofen-2-yl-methanoyl) -amino1-3- (2,3-difluoro-phenin-propyl) phosphoric acid To a solution of sodium carbonate (1 M, 5 mL) were added aminophosphate 65 (199 mg, 0.656 mmol) and benzo [b] thiophene-2-carbonyl chloride (129 mg, 0.656 mmol). After 15 h, it was acidified to pH ~ 1 by the addition of 1 M HCl solution at 0 ° C. Purification by preparative HPLC yielded 75 mg (27% yield) of the main compound 67. 1 H NMR (CD 3 OD): d 7.73-7.62 (3? M), 7.23-7.15 (2? M), 6.95-6.78 (3H, m), 4, 42-4.29 (1H, m), 3.97-3.82 (2H, m), 2.98 (1 H, dd, J = 13.97, 4.91 Hz), 2.80 (H , dd, J = 3.98, 10.20 Hz); LCMS: 426.0 (M-H); Elemental Analysis for (C 8H16F2N05PS, 0.20H2O) cale: C 50.16, H 3.84, N 3.25; found: C 50.04, H 3.85, N 3.32.
Scheme 6 (R) -3-amino4- (3-fIuoro-phenyl) -8-butyric acid, hydrochloride To a stirring solution of lithium borohydride (3 eq) in THF (45 mL) was added chlorotrimethylsilane (10.09 mL, 0.080 mol, 6 eq). The solution was stirred five minutes at room temperature. Acid was added (R) -3-amino-4- (3-fluoro-phene) -butyric acid, hydrochloride (3.10 g, 13.24 mmol), and the reaction was stirred overnight at room temperature. The reaction was stopped with methanol, and the solvents were removed in vacuo. The remainder was diluted with H2O, and the pH was brought to 12 with aqueous NaOH. The product was extracted with chloroform, and the organic phase was separated, washed sequentially with water and concentrated saline, dried (MgSC), and the solvent was evaporated to yield 2.21 g (91%) of an oil. transparent 68. H NMR (benzene-de): d 1, 10-1.30 (m, 2H), 1, 20-1, 60 (br, 3H), 1.91 (dd, 1 H, J = 8 , 3, 13.3 Hz), 2.18 (dd, 1 H, J = 5.2, 13.3 Hz), 2.54-2.62 (m, 1H), 3.62-3.70 (m, 1H), 3.73-3.79 (m, 1 H), 6.48 (d, 1H, J = 7.5 Hz), 6.55-6.59 (m, 1 H), 6.69-6.76 (m, 1 H), 6.83-6.90 (m, 1 H); IR (pure) 1588, 1487, 1449, 1251, 1141, 1065, 783 cm "1, Rf = 0.18 (5% methanolic ammonia / CHCl3), LCMS 184 (M + H).
Alcohol 69: The amine 68 (1.05 g, 5.72 mmol) was dissolved in CH2Cl2 (60 mL). Triethylamine (0.88 mL, 6.30 mmol) was added followed by benzo [b] thiophene-2-carbonyl chloride (1.12 g, 5.72 mmol). The reaction was stirred at room temperature for one hour, and the solvent was removed in vacuo. He The product was purified by flash column chromatography eluting with a gradient of 30-60% EtOAc / hexanes (Rf = 0.24 (50% EtOAc / hexanes) to yield 1.87 g (91%) of a solid. white 69. 1 H NMR (D SO-cfe): d 1.68-1, 75 (m, 2H), 2.87 (d, 2H, J = 7.0 Hz), 3.43-3.52 ( m, 2H), 4.20-4.27 (m, 1 H), 4.42 (t, 1 H, J = 5.1 Hz), 6.94-7.00 (m, 1 H), 7.03-7.08 (m, 2H), 7.25-7.32 (m, 1H), 7.39-7.46 (m, 2H), 7.90-8.01 (m, 2H) ), 8.05 (s, 1H), 8.50 (d, 1 H, J = 8.5 Hz); LCMS 344 (M + H).
Bromide 70: Alcohol 69 (1.77 g, 5.14 mmol) was partially dissolved in CH2CI2 (50 mL) and cooled to 0 ° C. Triethyl phosphite (1.77 ml_, 10.29 mmole) was added, followed by CBr4 (3.41 g, 10.29 mmole). The ice bath was removed and the reaction was allowed to warm to room temperature for 5 hours. The reaction was poured into CH2Cl2 / H2O. The organic phase was separated, washed with concentrated saline, dried (MgSO 4) and evaporated. The crude product was purified by flash column chromatography eluting with a gradient of 3-50% EtOAc / hexanes (Rf = 0.18 (10% EtOAc / hexanes) to yield 0.45 g (21%) of a white solid 70. 1 H NMR (DMSO-de): d 2.05-2.16 (m, 2H), 2.88 (d, 2H, J = 6.9 Hz), 3.50-3.59 (m, 2H) , 4.25-4.29 (m, 1 H), 6.96-7.08 (m, 3H), 7.26-7.33 (m, 1 H), 7.40-7.47 ( m, 2H), 7.92-8.01 (m, 2H), 8.06 (s, 1 H), 8.57 (d, 1 H, J = 8.5 Hz); LCMS 406, 408 (M + H).
Example 71: (Acidof (R) -3-I (benzofb1tiofen-2-carbonylVamino1-4- (3-fluoro-phenyD-butin-phosphonic): Bromide 70 (0.38 g, 0.93 mmol) was suspended in triethyl phosphite (5 mL) and placed in a microwave apparatus for 15 minutes at 150 ° C after which the reaction became clear. The solvent was removed in vacuo. The crude product was chromatographed by flash chromatography on silica gel eluting with a gradient of 0-2% MeOH / CHC yielding 0.11 g of the diethyl phosphonate as a clear oil (Rf = 0.24, 3% MeOH / CHCl3). The oil was dissolved in CH2Cl2 (3 mL) and treated with bromotrimethylsilane (0.15 mL, 1.2 mmol). The reaction was stirred overnight at room temperature. The solvent was removed, and the rest was triturated with water. The resulting white precipitate was filtered, washed with Water, and dried to yield 0.07 g (17%) of the main compound as a white solid 71. 1 H NMR (DMSO-d 6): d 1, 49-1, 80 (m, 4H), 2.80- 2.93 (m, 2H), 4.14-4.19 (m, 1H), 6.94-7.00 (m, 1 H), 7.07-7.09 (m, 2H), 7 , 24-7.32 (ra, 1 H), 7.40-7.46 (m, 2H), 7.91-8.00 (m, 2H), 8.08 (s, 1 H), 8 , 60 (d, 1H, J = 8.5 Hz); HRMS calculated for C19H2oN04PSF 408.0835 (M + H), found 408.0830; Anal. (C19H19N04PSF) C, H, N.
Scheme 7 Synthesis of Examples 72 and 73 Synthesis of Example 74 19a To a solution of CH2Cl2 (40 mL) of D-phenylalaninol (2.26 g, 14.9 mmoles) at 0 ° C were added triethylamine (3.11 mL, 22.4 mmol) and 2-naphthoyl chloride (3.13 g, 16.4 mmol). After 15 to 25 ° C, the mixture was diluted with CH2Cl2 (50 mL), washed with concentrated saline (3x50 mL), dried and concentrated. The residue was purified by column chromatography (2% MeOH in CH 2 Cl 2) to yield 1.33 g (30% yield) of compound 19a as a white solid. 1 H NMR (CDCl 3): d 8.16 (1 H, 8), 7.93-7.83 (3H, m), 7.73 (1 H, dd, J = 8.5, 1.7 Hz), 7.55 (2H, m), 7.39-7.23 (5H, m), 6.48 (1H, d, J = 9 Hz), 4.43 (1H, m), 3.86 (1H , dd, J = 11.1, 3.6 Hz), 3.77 (1H, dd, J = 11, 4.9 Hz); Elemental Analysis for (C20H19NO2) cale: C 78.66, H 6.27, N 4.59; found: C 78.41, H 6.37, N 4.52.
Example 72: 2-R (1-naphthalen-2-yl-methanoyl) -aminol-3-phenyl-propyl ester of sulfamic acid To a solution of acetonitrile (1 mL) of chlorosulfonyl isocyanate (136 μ ?, 1.57 mmol) at 0 ° C was added water (28 μ ?, 1.57 mmol). After stirring for 1.5 h at 0 ° C, acetonitrile (1 mL), pyridine (149 μ ?, 1.57 mmol), and alcohol (255 mg, 0.836 mmol) were added to the solution. The mixture was stirred at 25 ° C for 15 h, diluted with EtOAc (20 mL), and washed with 2% HCl solution cooled on ice (1x20 mL). Purification by column chromatography (30-50% EtOAc in hexanes) yielded 19 mg (yield 6%) of the major compound 72. H NMR (CD3OD): d 8.29 (1H, S), 8.0- 7.89 (3H, M), 7.80 (1H, dd, J = 8.7, 1.7 Hz), 7.58 (2H, m), 7.4-7.18 (5H, m) , 4.66 (1H, m), 4.29 (2H, m), 3.08 (2H, m); LCMS (ESP): 385 (M + H +), 407 (M + Na +).
Example 73: Ester mono-f2-K1-naphthalen-2-yl-methanoyl-anrímol-3-phenyl-propyl) of sulfuric acid.
To a solution of CH2Cl2 (5 mL) of the alcohol (105 mg, 0.344 mmol) at -30 ° C were added triethylamine (0.5 mL) and chlorosulfonic acid (116 mg, 90 DI, 1 mmol). After stirring at 25 ° C for 15 h, the mixture was diluted with EtOAc (10 mL), washed with 2% HCl solution cooled on ice (1x15 mL), dried and concentrated. The remainder was purified by column chromatography to yield 131 mg (87% yield) of the major compound 73 as a white solid. H NMR (CD3OD): d 8.34 (1H, s), 7.91 (4H, m), 7.58 (2H, m), 7.4-7.15 (5H, m), 4.59 (1H, m), 4.23 (1H, dd, J = 10.5, 4.3 Hz), 4.13 (1H, dd, J = 10.6, 5.5 Hz), 3.07 ( 2H, m); HRMS (MALDI) cale for C2oH18N05SNa2 (M-H ++ 2Na +) 430.0695; found 430.0676.
Alcohol 47a was prepared as described in the synthesis of compound 47. In the first step (preparation of 46a), hydroxyl carboxylic acid (760 mg, 4.13 mmol), 2-naphthoyl chloride (866 mg, 4 mg) was used. , 54 mmole), and trlethylamine (2.9 mL). In the second stage, 1 M borane in THF (4.73 mL) was used. After purification by column chromatography (40% EtOAc in hexanes), compound 47a was obtained as a crude oil (137 mg). LCMS: 325 (M + H +). 48a Benzyl Ester 48a was prepared as described in the synthesis of 48 using alcohol 47a (137 mg, 0.423 mmol), 1H-tetrazole (68 mg, 0.973 mmol), dibenzyl N, N-diisopropylphosphoramide (0.213 mL, 0.634) mmoles) and MCPBA (380 mg, 77% pure, 1.69 mmol). After purification by column chromatography (10% to 20% EtOAc in hexanes), compound 48a was obtained as a crude oil (330 mg), which was taken to the next step.
Example 74: Naphthalene-2-carboxylic acid (R) -H 3 -fluoro-benzyl-2-phosphonooxyethyl ester Example 74 was prepared as described in the synthesis of 49 using crude benzyl ester (330 mg) and 10% palladium on carbon (70 mg). Purification by preparative HPLC yielded 70 mg of the major compound 74 (31% yield from alcohol). 1 H NMR (CD 3 OD): d 8.56 (1 H, s), 8.02-7.8 (4H, m), 7.53 (2H, m), 7.23 (1H, m), 7, 06 (2H, m), 6.89 (1 H, m), 4.40 (1 H, dd, J = 12, 3 Hz), 4.26 (1H, dd, J = 11, 8, 6 Hz ), 3.12 (2H, m); LCMS (ESP Negative): 403 (M-H). HRMS (MALDI): cale for C2oHi906FP (M + H +) 405.0903; found 405.0902.
Scheme 8 D-Phenylalanine 18c: 18c To a solution of tetrahydrofuran (30 mL) of D-3-Fluorophenylalanine (5.00 g, 27.3 mmol) was slowly added 1 M borane in tetrahydrofuran (68.3 mL, 68.3 mmol) at 0 ° C. The mixture heated up room temperature and stirred overnight. Methanol (40 mL) was added and stirred vigorously for 1 h. The solvent was evaporated and the process repeated. The residue was dissolved in methylene chloride (100 mL) and stirred vigorously with 1 M NaHCO3 (50 mL) overnight. The mixture was extracted with methylene chloride (3x50 mL). The combined methylene chloride extract was washed with concentrated saline (50 mL), dried with NaaSC, and concentrated. After purification by column chromatography (95/5 / 0.5 CH2Cl2 / CH3OH / NH4OH), compound 18c was obtained in 28% yield (1.29 g). 1 H NMR (CD 3 OD): d 7.34 (1 H, m), 7.09-6.92 (3 H, m), 3.54 (1 H, dd, J = 10.74.4.33 Hz), 3.39 (1 H, dd, J = 10.74, 6.60 Hz), 3.13-3.02 (1H, m), 2.83 (1 H, dd, J = 13.37, 6 , 21 Hz), 2.62 (1 H, dd, J = 13.38, 7.73 Hz); LCMS: 170.1 (M + H +).
To a solution of DMF (10 mL) of D-phenylalaninol 18c (1.30 g, 7.70 mmol) were added imidazole (1.05 g, 15.4 mmol) and t-butyldiphenylchlorosilane (TBDPSCI) (2.40). mL, 9.24 mmol). After stirring overnight, the mixture was diluted with ether (80 mL), washed with saturated ammonium chloride (1x50), concentrated saline (1x50 mL) and dried (Na2S04). The solvent was removed in vacuo. The residue was purified by column chromatography (95/5 CH2CI2 / CH3OH) to yield 2.35 g (74% yield) of compound 75. 1 H NMR (CDCl 3): d 7.87 (4H, d, J = 6 , 22 Hz), 7.47-7.34 (6H, m), 7.21 (1H, t, J = 7.35 Hz), 6.91 (3H, dd, J = 16.58, 9, 42 Hz), 3.61 (2H, dd, J = 9.98, 4.71 Hz), 3.52 (1 H, dd, J = 9.98, 6.22 Hz), 3.17-3 , 08 (1 H, m), 2.80 (1 H, dd, J = 13.56, 5.27 Hz), 2.52 (1H, dd, J = 13.38, 8.29 Hz), 2.52 (1H, dd, J = 13.38, 8.29 Hz), 1.08 (9H, s); LCMS: 408.2 (M + H +), 430.2 (M + Na +).
Silil Ether 76: 76 To a solution of methylene chloride (15 mL) of amine 75 (2.35 g, 5.77 mmol) and triethylamine (1.53 mL, 11.0 mmol) was added a solution of methylene chloride (2 mL). ) of triphosgene (1.03 g, 3.46 mmol). After 2 h, the solution was heated to reflux for 1.5 h, and then cooled to 25 ° C. A solution of methylene chloride (25 mL) of amine 6a (2.19 g, 5.77 mmol) was added. After 15 h, the reaction solution was diluted with CH 2 Cl 2 (80 mL), washed with concentrated saline (2x80 mL), dried (Na 2 SO 4) and concentrated in vacuo. The rest was purified by flash column chromatography (5-20% EtOAc in hexane) to yield 3.92 g (79% yield) of compound 76. 1 H NMR (CDCl 3): d 7.65-7.58 (4H, m ), 7.47-7.33 (6H, m), 7.25-7.18 (4H, m), 7.17-7.07 (7H, m), 6.88-6.82 (3H , m), 5.06 (1 H, d, J = 8.29 Hz), 5.01-4.94 (1 H, m), 4.93-4.88 (1H, m), 4, 11-3.97 (1 H, m), 3.55 (2H, d, J = 3.02 Hz), 3.42-3.30 (1H, m), 3.15-2.81 (3H) , m), 2.63-2.49 (4H, m), 2.23-2.13 (1H, m), 1.72-1.46 (10H, m), 1.34-1.20 (4H, m), 1.10 (9H, s).
Alcohol 77: To a THF solution (30 mL) of silyl ether 76 (3.92 g, 4.80 mmol) was added 1 M HF / pyridine (7 mL) at 0 ° C. The reaction mixture was heated to 25 ° C after 30 minutes and stirred overnight. The THF was removed by vacuum. The remainder was dissolved in methylene chloride (50 mL) and washed with 1 M cold HCl (2x50 mL). The solution was concentrated. The resulting residue was purified by column chromatography (30% EtOAc in hexane) to yield 2.26 g (82% yield) of compound 77. 1 H NMR (CDCl 3): d 7.33-7.23 (4H, m), 7.22-7.12 (6H, m), 7.06-6.89 (3H, m), 4.99 (H, m), 4.90 (H, m), 4.05 -3.94 (1H, m), 3.72 (1 H, d, J = 3.20 Hz), 3.68 (1H, d, J = 3.02 Hz), 3.60-3.50 (1H, m), 3.39 (1H, d, J = 11, 68 Hz), 3.18-3.05 (1H, m), 2.99-2.78 (3H, m), 2.60 (5H, m), 2.21 (1H, d, J = 12.81 Hz), 1.81-1, 51 (9H, m ), 1, 50-1, 36 (1 H, m), 1.33-1, 20 (1H, m).
Ester Bencil Phosphate 78: To a solution of acetonitrile (35 mL) of alcohol 77 (2.26 g, 3.94 mmol) and 1 H-tetrazole (552 mg, 7.88 mmol) was added dibenzyl N, N-diisopropylphosphoramidite (1.98 mL, 5.91 mmol) at 25 ° C. After 3 h, MCPBA (2.65 g, 77% pure, 11.8 mmol) was added to the suspension. The solution was diluted with EtOAc (100 mL), washed with concentrated NaHSÜ3 solution (2x80 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (10-30% EtOAc in hexane) to yield 2.23 g of compound 78 in 68% yield. 1 H NMR (CDCIs): d 7.18 (12H, m), 7.09-7.03 (3H, m), 7.03-6.91 (6H, m), 6.81-6.67 ( 3H, m), 5.57-5.45 (1 H, m), 4.95-4.84 (5H, m), 4.84-4.73 (2H, m), 4.00-3 , 91 (2H, m), 3.81-3.58 (2H, m), 3.43-3.30 (1 H, m), 3.00-2.87 (1 H, m), 2 , 83-2.73 (1 H, m), 2.54-2.35 (5H, m), 2.08-1, 97 (1 H, m), 1.55-1, 32 (5H, m), 1, 13-1, 06 (6H, m).
Example 79: 4-phenyl-1- (3-phenyl-propyl) -butyl ester of (S) -1-f (RV2- (3-fluoro-phenyl-1-phosphonooxymethyl-ethylcarbamoin-piperidine-2-carboxylic acid) To a methanol solution of the benzyl phosphate ester 78 (400 mg, 0.479 mmoles) palladium on carbon (10%, 80 mg) was added. The suspension was kept under a hydrogen atmosphere (1 atm) overnight, and then filtered through celite. The filtrate was purified by preparative HPLC, yielding 160 mg of compound 79 in 51% yield. 1 H NMR (CD 3 OD): d 7.34-7.19 (5H, m), 7.19-7.09 (6H, m), 7.09-6.88 (3H, m), 5.05- 4.95 (1H, m), 4.87-4.81 (1H, m), 4.17-4.06 (1H, m), 3.93 (2H, t, J = 5.09 Hz) , 3.75-3.65 (1 H, m), 3.07-2.90 (2H, m), 2.88-2.76 (1 H, m), 2.69-2.51 ( 4H, m), 2.18 (1H, d, J = 13.56 Hz), 1.72-1.51 (11H, m), 1.45-1.14 (2H, m); HRMS (MALDl) for C9Hi5N04P (M + H +) 655.2954; found 655,2958.
Scheme 9: Synthetic Routes to Prodrugs 1. Synthesis of Acetoxymethyl Phosphate Ester: ° ~ ^ 0_ ^ 2. Synthesis of Ester Phenyl Phosphate: Example 80: 4-Phenyl-1- (3-phenyl-propyl) -butyl-1-phenyl ester of 1-α- (bis-acetoxymethoxy-phosphoryloxymethin-2-phenyl-ethylcarbamoyl-1-piperidine-2S-carboxylic acid To an acetonitrile solution of phosphate 16a (10 mg, 0.0158 mmol) at 0 ° C were added bromomethyl acetate (15.4 μm, 24.2 mg, 0.158 mmol) and diisopropylethylamine (0.1 mL). . After 2 h at 20 ° C, the solution was concentrated in vacuo. The remainder was purified by column chromatography (deactivated with 1% Et3N in hexanes, eluted with 30% EtOAc in hexanes) to yield 5 mg (41% yield) of the major compound 80. 1 H NMR (CDCl 3): d 7 , 36-7.06 (15H, m), 5.64 (4H, m), 5.45 (1H, d, J = 8.4 Hz), 4.96 (2H, m), 4.22 ( 1H, m), 4.03 (2H, m), 3.58 (1H, br d), 3.12 (1H, td, J = 12.8, 3.3 Hz), 2.99 (1H, dd, J = 13.8, 5.7 Hz), 2.79 (1H, dd, J = 13.5, 9 Hz), 2.59 (4H, m), 2.19 (1H, br d) , 2.13 (3H, s), 2.11 (3H, s); HRMS (MALDI) stained for C41H53N2O11P (M + H +) 803.3279; found 803.3258.
Example 81: Acetoxymethoxy- (2-fri- (1-bromo-naphthalen-2-yl) -methanoin-amino-3-phenyl-propoxy) -phosphoryloxymethyl acetic acid ester Example 81 was prepared as described in the synthesis of Example 80 using 25-24 (23 mg, 0.05 mmol), bromomethyl acetate (24.5 μl, 38.2 mg, 0.25 mmol) and diisopropylethylamine (0.1 ml). Purification by column chromatography quenched with EI3N (30% EtOAc in hexanes) yielded 3 mg (10% yield) of the major compound 81. 1 H NMR (CDCl 3): d 8.33 (1H, d, J = 8, 4 Hz), 7.83 (2H, m), 7.61 (2H, m), 7.41 (1H, dd, J = 8.7 Hz), 7.38-7.21 (5H, m) , 6.52 (1H, br d, J = 9 Hz), 5.64 (4H, m), 4.68 (1 H, m), 4.33 (1H, m), 4.18 (1 H , m), 3.13 (1 H, dd, J = 13.8, 6.9 Hz), 3.02 (1 H, dd, J = 13.5, 8.4 Hz), 2.06 ( 3H, s), 2.05 (3H, s).
Example 82: Acetoxymethoxy - ((R) -2-t3- (2-phenoxy-phenyl) -ureido-3-phenyl-propoxyphosphoryloxymethyl acetic acid ester Example 82 was prepared as described in the synthesis of Example 80 using 23b (22 mg, 0.0498 mmol), bromomethyl acetate (24 μm), 0.249 mmole) and diisopropylethylamine (0.05 ml_). Purification by column chromatography deactivated with Et3N (50% EtOAc in hexanes) yielded 9 mg (31% yield) of the major compound 82. 1 H NMR (CDCl 3): d 8.22 (1H, dd, J = 8, 1, 1, 5 Hz), 7.36-7.17 (5H, m), 7.14-7.06 (3H, m), 7.01-6.88 (4H, m), 6.82 (1 H, dd, J = 8.4, 1.8 Hz), 5.65-5.49 (5H, m), 4.28 (1 H, m), 4.17 (1 H, m) , 4.02 (1 H, m), 3.01 (1 H, dd, J = 13.2, 5.7 Hz), 2.81 (1 H, dd, J = 13.5, 9 Hz) , 2.05 (3H, s), 2.04 (3H, s); LCMS (ESP): 609 (M + Na +).
Example 83: Acetoxymethoxy-r2 - ((1-r5- (3,5-dichloro-phenoxy) -furan-2-l-1-methanoyl) -amino) -3-phenyl-propoxy-phosphoryloxymethyl acetic acid ester Example 83 was prepared as described in the synthesis of Example 80 using 25-4 (23 mg, 0.0473 mmol), bromomethyl acetate (23 μ! _, 0.237 mmol) and diisopropylethylamine (0.049 ml_). Purification by column chromatography deactivated with Et3N (50% EtOAc in hexanes) yield 6 mg (20% yield) of compound 83. 1 H NMR (CDCl 3): d 7.37-7.17 (6H, m), 7.11 (1 H, d, J = 3.3 Hz), 7.00 (2H, d, J = 1.5 Hz), 6.67 (1H, br D = 8.7 Hz), 5.76 (1H, d, J = 3.3 Hz), 5 , 62 (4H, m), 4.5 (1H, m), 4.19 (1H, m), 4.09 (1H, m), 3.02 (1H, dd, J = 13.5, 6 , 3 Hz), 2.93 (1H, dd, J = 13.8, 8.1 Hz), 2.11 (3H, s), 2.09 (3H, s).
Example 84: Acetoxymethoxy- ester. { (R) -3- (3-Fluoro-phenan-2-f (1-naphthalen-2-yl-methanoin-amnol-propoxyl-phosphoryloxymethyl) acetic acid Example 84 was prepared as described in the synthesis of Example 80 using 25-28 (50 mg, 0.124 mmol), bromomethyl acetate (61 μ? _, 0.620 mmol) and diisopropylethylamine (0.13 mL). Purification by column chromatography deactivated with Et ^ N (30-50% EtOAc in hexanes) yielded 17 mg (25% yield) of compound 84. 1 H NMR (CDCIs): d 8.39 (1 H, s) , 8.00-7.81 (4H, m), 7.56 (1H, m), 7.37-7.23 (2H, m), 7.11 (1H, d, J = 7.8 Hz ), 7.05 (1H, d, J = 9.9 Hz), 6.95 (1H, td, J = 8.7, 2.7 Hz), 5.75-5.57 (4H, m) , 4.63 (1H, m), 4.30 (1H, m), 4.16 (1H, td, J = 10.8, 3.9 Hz), 3.15 (1H, dd, J = 13.5, 6 Hz), 2.99 (13.5, 8.7 Hz), 2.12 (3H, s), 2.06 (3H, s); LCMS (ESP): 548 (M + H +), 570 (M + Na +); HR S (ALD1) for C28H28NO9FP (M + H +) 548.1486; found 548.1489.
Example 85: Acetoxymethoxy-f (R) -2-r (1-benzorb] thiophen-2-yl-methanoyl) -aminol-3- (3-fluoro-phenin-propoxy-phosphoryloxymethyl) acetic acid ester Example 85 was prepared as described in the synthesis of Example 80 using 25-29 (45 mg, 0.11 mmol), bromomethyl acetate (55 μ ?, 0.55 mmol) and diisopropylethylamine (0.115 mL). Purification by column chromatography deactivated with E.3N (30-50% EtOAc in hexanes) yielded 39 mg (64% yield) of the main compound 85. 1 H NMR (CDCl 3): d 7.92-7.81 ( 3H, m), 7.48-7.27 (3H, m), 7.09 (1H, br d, J = 7.5 Hz), 7.03 (1H, br d, J = 9.6 Hz ), 6.95 (1H, dd, J = 8.7, 2.4 Hz), 5.78-5.59 (4H, m), 4.54 (1H, m), 4.27 (1H, m), 4.13 (1H, td, J = 11.1, 3.9 Hz), 3.14 (1 H, dd, J = 13.8, 6 Hz), 2.96 (1H, dd, J = 13.5, 9.3 Hz), 2.15 (3H, s), 2.09 (3H, s); LCMS (ESP): 576 (M + Na +); HRMS (MALDl) for C 24 H 26 NO 9 FPS (M + H +) 554.1050; found 554,1044.
Example 86: Ester (RV2- (5-dimethylamino-naphthalene-1-sulfonylane) -3- (3-fluoro-phenyl) -propyl diphenyl ester of phosphoric acid To a THF solution (10 mL) of alcohol 40 (300 mg, 0.746 mmol) were added EI N (0.5 mL), DMAP (30 mg) and diphenyl chlorophosphate (0.23 mL, 301 mg, 1 mg). , 12 mmol). After 15 h, the solution was diluted with EtOAc (50 mL), washed with concentrated saline (2x50 mL), dried and concentrated. The residue was purified by column chromatography to yield 310 mg (66% yield) of the main compound 86. H NMR (CDCl 3): d 8.49 (1H, d, J = 8.7 Hz), 8.18 ( 1H, dd, J = 7.5, 1.2 Hz), 8.06 (1H, d, J = 8.7 Hz), 7.45 (2H, m), 7.40-7.30 (4H , m), 7.25-7.16 (6H, m), 7.12 (1H, d, J = 7.5 Hz), 6.85 (1H, m), 6.60 (1H, td , J = 8.4, 2.4 Hz), 6.50 (1H, d, J = 7.5 Hz), 6.40 (1 H, dt, J = 12.3, 1.5 Hz), 5.21 (1H, d, J = 8.4 Hz), 4.19 (2H, m), 3.59 (1H, m), 2.87 (6H, s), 2.69 (1H, dd , J = 13.5, 7.2 Hz), 2.51 (1H, dd, J = 13.8, 7.2 Hz).
Alcohol 88: To a 1 M solution of Na 2 CO 3 (5 mL) at 0 ° C were added D-3-fluorophenylalanine (0.5 g, 2.73 mmol) and 1-benzothiophene-2-carbonyl chloride (62 mg, 0.316 mmol) . After 15 h at 20 ° C, the mixture was acidified by the addition of 5% HCl solution cooled on ice (10 mL). The suspension was extracted with methylene chloride (3x25 mL). The combined organic layers were dried over MgSO4 and concentrated to yield 0, 6 g of 87 as a white solid. The carboxylic acid 87 was dissolved in THF (5 mL). To the THF solution at 0 ° C was added 1 M borane in THF (1.31 mL). After 15 h at 25 ° C, a solution of saturated NaHCO 3 (15 mL) was introduced. The suspension was stirred for 3 h and then extracted with methylene chloride (3x25 mL). The combined organic layers were washed with concentrated saline (2x25 mL), dried over Na2SO4, and concentrated. Purification by column chromatography (35% EtOAc in hexanes) yielded 200 mg (22.5% yield) of compound 88. 1 H NMR (CDCl 3): d 7.84 (2H, m), 7.72 (1H , s), 7.41 (2H, m), 7.34-7.25 (1H, m), 7.11-6.89 (3H, m), 6.41 (1H, br d, J = 7.5 Hz), 4.37 (1 H, m), 3.77 (2 H, m), 3.03 (2 H, AB), 2.33 (1 H, br s).
Example 89: Ester 2-f (1-benzorbltiophen-2-yl-methanoyl aminol-3- (3-fluoro-phenyo-propyl) diphenyl ester of phosphoric acid Example 89 was prepared as described in the synthesis of Example 86 using alcohol 88 (40 mg, 0.122 mmol), Et3N (0.1 mL), DMAP (4 mg) and diphenyl chlorophosphate (0.29 μ? _, 37 , 6 mg, 0.14 mmol). Purification by column chromatography (40% EtOAc in hexanes) yielded 62 mg (97% yield) of the major compound 89. 1 H NMR (CDCIs): d 7.84 (1H, d, J = 7.5 Hz) , 7.76 (1 H, m), 7.66 (1H, s), 7.45-7.32 (5H, m), 7.30-7.13 (8H, m), 7.11- 6.98 (2H, m), 6.93 (2H, m), 4.52 (1 H, m), 4.40 (1 H, m), 4.25 (1 H, td, J = 11 , 4, 4.8 Hz), 3.11 (1 H, dd, J = 13.5, 5.7 Hz), 2.85 (1H, dd, J = 13.5, 9.3 Hz); HRMS (MALDI) for C3oH26N05FPS (M + ") 562.1253, found 562.1279.
Example 90: 4-phenyl-butyl ester of 1-f1-bis-acetoxymethoxy-phosphoryloxymethin-2-phenyl-ethylsulphamem-piperidine-2S-carboxylic acid Example 90 was prepared as described in the synthesis of Example 80 using 5b1 (20 mg, 0.036 mmol), bromomethyl acetate (36 μ ?, 0.36 mmol) and diisopropylethylamine (0.1 mL). Purification by column chromatography deactivated with EtaN (40% EtOAc in hexanes) yielded 25 mg (100% yield) of the main compound 90. 1 H RN (CDCl 3): d 7.35-7.12 (10H, m) , 5.68 (2H, d, J = 3 Hz), 5.64 (2H, d, J = 2.7 Hz), 5.23 (1H, d, J = 9 Hz), 4.61 (1H , d, J = 3.9 Hz), 4.26-4.01 (4H, m), 3.81 (1H, m), 3.31 (1H, br d), 2.92 (2H, AB ), 2.80 (1H, td, J = 12.9, 3.6 Hz), 2.65 (2H, m), 2.20 (1 H, br d), 2.13 (6H, s); MS (ESP): 721 (M + Na +); 733 (M + CI) '.
Example 91: (S) -1-i (R) -1- (Bis-acetoxy-methoxy-phosphoryloxymethyl) -2-phenyl-ethylcarbamoyl-p-peridin-2-carboxylic acid Example 91 was prepared as described in the synthesis of Example 80 using 16d (60 mg, 0.155 mmol), bromomethyl acetate (0.15 μl, 1.55 mmol) and diisopropylethylamine (0.4 ml_, 2, 33 mmoles). Purification by column chromatography deactivated with Et3N (40% EtOAc in hexanes) yielded 45 mg (55% yield) of the major compound 91. 1 H NMR (CDCl 3): d 7.32-7.07 (5H, m) , 5.58 (2H, d, J = 1.8 Hz), 5.54 (2H, d, J = 1.8 Hz), 4.68-4.50 (2H, m), 4.22 ( 1H, m), 3.98 (1H, dd, J = 13.8, 5.1 Hz), 3.55 (1H, dd, J = 12, 4.2 Hz), 3.16 (1H, dd , J = 13.8, 9.3 Hz), 3.02 (1H, dd, J = 13.8, 6 Hz), 2.69 (1H, td, J = 13.2, 3.3 Hz) , 2.10 (3H, s), 2.10 (3H, s).
Example 92: Acetoxymethoxy-1 (R) -2-r (7-diethylamino-2-oxo-2H-chromen-3-carbonyl) -amino-3- (3-fluoro-phenyl) -propoxyl-phosphoryloxymethyl ester acetic Example 92 was prepared as described in the synthesis of Example 80 using Example 25-33 (18 mg, 0.0366 mmole), bromomethyl acetate- (0.03 mL, 0.3 mmole) and diisopropylethylamine (0, 1 mL, 0.6 mmol). Purification by column chromatography deactivated with Et3N (100%) EtOAc in hexanes) yielded 5 mg (25% yield) of the Main compound 92. * H NMR (CDCl 3): d 9.05 (1H, d, J = 8.3 Hz), 8.64 (1 H, s), 7.41 (1 H, t, J = 9 , 1 Hz), 7.26 (1 H, m), 7.08 (1 H, d, J = 7.5 Hz), 7.02 (1 H, br d, J = 9.8 Hz), 6.92 (1 H, td, J = 8.3, 2.1 Hz), 6.64 (1 H, dd, J = 9.3, 2.7 Hz), 6.49 (1 H, d , J = 2.2 Hz), 5.67 (1 H, dd, J = 13.6, 0.9 Hz), 4.55 (1 H, br s), 4.17 (2 H, m), 3.46 (4H, q, J = 7 Hz), 3.01 (1 H, d, J = 7.3 Hz), 2.13 (6H, s), 1.24 (6H, t, J = 7.2 Hz).
Example 93: Acetoxymethoxy-r3-f (benzo ["b1-tofen-2-carboni0-amino-1-4- (3-fluoro-phenyl) -butyl-1-phosphinoyloxymethyl) acetic acid ester Example 93 was prepared as described in the synthesis of Example 80 using Example 71 (22 mg, 0.0541 mmol), bromomethyl acetate (0.05 mL, 0.52 mmol) and diisopropylethylamine (0.13 mL, 0.77 mmol). Purification by flash column chromatography (100% EtOAc in hexanes) yielded 23 mg (77% yield) of the major compound 93. 1 H NMR (CDCl 3): d 7.88-7.79 (3H, m) , 7.41 (2H, m), 7.27 (1 H, m), 7.02 (1 H, d, J = 7.6 Hz), 6.94 (2H, m), 6.80 ( 1 H, d, J = 8.6 Hz), 5.71-5.55 (4H, m), 4.38 (1 H, br t, J = 7.3 Hz), 3.05 (1H, dd, J = 13.7, 6.1 Hz), 2.87 (1 H, dd, J = 13.7, 7.1 Hz), 2.12 (3H, s), 2.05 (3H, s).
Scheme 10 Synthesis of Examples 98 and 99 Ester Phosphonate 95: To a dry suspension of CH2Cl2 (20 mL) of polymer-supported triphenylphosphine (1.69 g, 4.53 mmol) was added iodine (1.15 g, 4.53 mmol). After 15 min, imidazole (0.33 g, 5.15 mmol) was added. The suspension was stirred for another 15 min. A solution of CH2Cl2 was added (8 mL) of 19c (600 mg, 2.06 mmol). The mixture was refluxed for 1 h. After cooling the mixture to 25 ° C, the polymeric solid was removed by filtration. The filtrate was washed with Na 2 S 2 O 3 solution (concentrated, 2 x 30 mL), water (1 x 25 mL) and concentrated saline (1 x 25 mL). All the solvent was removed in vacuo, yielding 914 mg (100%) of the iodide 94 as a yellow solid. A portion of the iodide 94 (420 mg) was mixed with triethyl phosphite (2.5 mL) in a sealed tube. The suspension was heated at 150 ° C for 30 min by microwave radiation. The triethyl phosphite was removed in vacuo. The residue was purified by column chromatography (30-50% EtOAc in hexanes) to yield 80 mg (19% yield) of the phosphonate 95 as a colorless oil. H NMR (CDCl 3): d 7.32-7.10 (5H, m), 6.95-6.82 (4H, m), 5.43 (1H, d, J = 6 Hz), 5.01 (2H, s), 4.12-3.92 (4H, m), 3.01-2.75 (2H, m), 1.92 (2H, m), 1, 28-1, 13 (6H , m); LCMS (APCI positive): 424 (M + H +), 446 (M + Na +).
Amina 96: To a solution of ethanol (5 mL) of compound 95 (235 mg, 0.556 mmol) was added palladium on carbon (10%, 40 mg). The suspension was kept under hydrogen (1 atm) for 15 h. After filtering, the filtering He concentrated. The remainder was purified by column chromatography (MeOH / CH2Cl2 5/95) to yield 148 mg (92% yield) of compound 96 as an oil. 1 H NMR (SO-D 6 D): d 7.4-7.0 (4H, m), 4.05-3.90 (4H, m), 3.25 (1H, m), 2.78 ( 1H, dd, J = 13.4, 6.1 Hz), 2.69 (1 H, dd, J = 12.2, 6.1 Hz), 2.06 (2H, br s), 1.9 -1, 70 (2H, m). LCMS (APCI positive): 290 (M + H +), 312 (M + Na +).
Amida 97: To a solution of methylene chloride (5 mL) of amine 96 (144 mg, 0.498 mmol) were added triethylamine (0.139 mL, 0.996 mmol), 4- (dimethylamino) pyridine (6 mg, 0.0498 mmol), and 1-benzothiophen-2-carbonyl chloride (123 mg, 0.623 mmol) at 0 ° C. After 15 h at 25 ° C, the mixture was diluted with methylene chloride (20 mL), washed with ice-cold HCl solution (1 M, 1x20 mL), sodium carbonate solution (1 M, 1x20 mL), and concentrated saline solution (1x20 mL). Then, the solution was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (30-50% EtOAc in hexanes) to yield 150 mg (67% yield) of compound 97 as a white solid. H NMR (CDCl 3): d 7.85-7.65 (3H, m), 7.33 (2H, m), 7.21-7.15 (1 H, m), 7.03 (1H, d) , J = 7.7 Hz), 6.96 (1 H, br d, J = 9.9 Hz), 6.88 (1 H, td, J = 8.1, 1.9 Hz), 4.51 (1H, d, J = 2.1 Hz), 4.16 -3.97 (4H, m), 3.17 (1 H, dd, J = 12, 5.1 Hz), 2.91 (1H, dd, J = 13.4, 8.9 Hz), 2 , 02 (1H, d, J = 4.7 Hz), 1.98 (1H, d, J = 5.3 Hz), 1.33 (3H, t, J = 6.9 Hz), 1.73 (3H, t, J = 7.1 Hz); LCMS (ESP): 450 (M + H +), 472 (M + Na +); 448 (M-H).
Example 98: f2-f (b8nzofaltofen-2-carbonin-amino-3- (3-fluoro-phenyl) -propi-phosphonic acid 98 To a solution of methylene chloride (2 mL) of the phosphonate ester 97 (140 mg, 0.31 mmol) was added bromotrimethylsilane (1 mL). After 15 h, the solution was concentrated in vacuo. The oily residue was triturated with water (3x2 mL). In the process, a white solid 98 (110 mg, 89% yield) was obtained by filtration. 1 H NMR (DMSO-d 6): d 8.66 (1 H, d, J = 8.4 Hz), 8.1-7.92 (3H, m), 7.45 (2H, m), 7, 32 (1H, q, J = 8 Hz), 7.12-7.0 (3H, m), 4.42 (1H, m), 3.14 (1H, dd, J = 13.7, 2, 1 Hz), 2.94 (1H, dd, J = 13.4, 8.1 Hz), 1.92 (2H, m); LCMS (APCI positive): 394 (M + H +), 416 (M + Na +); Elemental Analysis for (C18H17N04PFS 0.3H2O) cale: C 54.21, H 4.45, N 3.51; found: C 54.15, H 4.47, N 3.47.
Example 99: Acetoxymethoxy-r 2 -benzoro-1-thiophen-2-carbonyl) -aminol-3- (3-fluoro-phenyl-propane-phosphinoyloxymethyl) acetic acid ester To a solution of acetonitrile (1 ml_) of the phosphonate acid 98 (31.8 mg, 0.0809 mmol) were added diisopropylethylamine (0.127 ml_, 0.728 mmole) and bromomethyl acetate (60 μ ?, 0.607 mmole) at 0 ° C. . After 15 h at 25 ° C, the solution was concentrated and the resulting residue was purified by column chromatography (50-70% EtOAc in hexanes), yielding 26 mg (59% yield) of the main compound 99 as a white solid . 1 H NMR (CD 3 OD): d 7.85-7.75 (3H, m), 7.33 (2H, m), 7.19 (1 H, q, J = 8 Hz), 6.99 (1 H , d, J = 7.5 Hz), 6.94 (1 H, dt, J = 7.6, 2.2 Hz), 6.84 (1 H, td, J = 8.3, 2.5 Hz), 5.6-5.45 (4H, m), 4.50 (1H, m), 2.93 (2H, m), 2.35-2.16 (2H, m), 1, 94 (3H, s), 1, 94 (2H, s); HRMS (MALDI) for CMHMNOBFPS (M + H +) 538.1129; found 538,1101 Example 100: Ester fS-ríbenzofáltiofen ^ -carboniD-aminol ^ -O-fluoro-phenyl) -butyl-1- (2,2-dimethyl-propionyloxymethoxy) -phosphinoyloxymethyl acid ester 2,2-dimethyl-propionic To a solution of acetonitrile (5 ml_) of Example 71 (50 mg, 0.123 mmol) were added tetrabutylammonium iodide (5 mg), diopropylethylamine (0.2 ml), and chloromethyl pivalate (132 μm, 0.92). mmoles) at 0 ° C. The solution was heated at 60 ° C for 4 h and concentrated in vacuo. The remainder was purified by column chromatography (35% EtOAc in hexanes) yielding 20 mg (26% yield) of the major compound 100. 1 H NMR (CD3OD): d 7.81-7.75 (3H, m), 7.32 (2H, m), 7.16 (1H, q, J = 8 Hz), 6.97 (1H, d, J = 7.8 Hz), 6.92 (1H, dt, J = 10 , 1, 2.3 Hz), 6.81 (1H, td, J = 8.3, 2Hz), 5.6-5.48 (4H, m), 4.24 (1H, m), 2, 84 (2H, m), 1.95-1.7 (4H, m), 1.09 (9H, s), 1, 04 (9H, s); LCMS (APCI positive): 636 (M + H +); HRMS (MALDI) for C3iH4oN08FPS (M + H +) 636.2196; Found 636.2182.
Biological Test: Peptidyl-Prolyl Isomerase Test Pin1 PIN1 is a peptidyl-prolyl isomerase-dependent phosphorylation. The PIN 1 test is a spectrophotometric assay based on the coupled break catalyzed by chymotrypsin or subtilisin, dependent on the cis-trans conformation of a peptide substrate containing para-nitroaniline. This improves the general trial of rotamase described for the first time once by Kofron, et al. (Biochemistry, 30, 6217-6134 (1991)) and applied to the isomerase activity of PIN1 by Yaffe, et al. [Science, 278, 1957-1960 (1997)). Breakage of the isomerized peptide releases para-nitroanaline, which can be determined by an increase in absorbance at 390 nm. The peptide substrate of PIN1, succinyl-leucine-proline-phenylalanine-paranitroaniline (Suc-AEPF-p A) (Bachem), is predominantly maintained in a cis conformation with an anhydrous TFE / LiCI solvent mixture. After being diluted in an aqueous test mixture containing PIN1, the peptide substrate undergoes PIN1-catalyzed isomerization to the trans conformation. Chymotrypsin or subtilisin (Carlsberg subtilisin protease, available from Sigma, catalog number P-5380) breaks the trans product to form free para-nitroanaline. To minimize the spontaneous isomerization of the peptide substrate, the reactions are carried out at 15 ° C. A typical reaction contains 25 mM MOPS pH 7.5, 0.5 mM TCEP, 2% DMSO, 5 Di of a 25 mg / ml solution of Carlsberg subtilisin, 50 nM PIN1-PPiase, and 100 μ? of Suc-AEPF-pNA peptide substrate. The reactions are cooled to 15 ° C and initiated by the addition of Suc-AEPF-pNA. The absorbance at 390 nm is determined continuously until all the substrate has become the degraded product. These data, the progress curve, fit an exponential equation to determine a constant of velocity k for the reaction. The rate constant k is proportional linearly to the concentration of the active enzyme present in the test mixture once the speed constant of the spontaneous isomerization. The Km for this substrate is much greater than 100 μ? ([S] «Km). Therefore, during the inhibition experiments, the IC50, for inhibitors that bind weakly, is essentially the inhibition constant K ,. In Table 1, the data of K, shown under the heading PIN1-CD correspond to the test with the peptide PIN1 containing the catalytic domain peptidyl-prolyl, but lacking the WW domain of PIN1. Similarly, the data of the dissociation constant (Kd) under PIN1-CD refers to the assay with a peptide that contains the catalytic domain of PIN1 but lacks the WW domain of PIN1.
Table 1 Example No PIN1-CD PIN1-CD Kd (μ?) K¡ (μ?) 25-23 < 1 < 1 25-24 < 1 25-25 < 1 25-26 < 10 25-27 < 10 25-28 < 1 < 1 25-29 < 1 25-30 < 1 < 1 25-31 < 1 < 1 25-32 < 1 < 1 25-33 < 1 25-34 < 1 < 1 25-35 < 1 < 1 25-36 < 1 < 1 25-37 < 1 < 1 25-38 30 < 10 < 100 25-39 33 < 10 37 < 2 < 10 42 < 10 49 < 1 < 1 54 < 1 < 1 58 < 10 61 < 1 66 < 1 67 < 1 71 < 1 72 < 100 73 74 < 1 < 1 79 < 1 82 83 85 < 100 86 < 100 89 20% at 20 mM 91 0% at 100 mM 98 < 1 The exemplary compounds described above can be formulated into pharmaceutical compositions according to the following general examples.
Example 1: Parenteral Composition To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a water soluble salt of a compound of Formula I are dissolved in DMSO and then mixed with 10 ml_ of 0.9% saline. sterile. The mixture is incorporated into a suitable dosage unit form for administration by injection.
Example 2: Oral Composition To prepare a pharmaceutical composition for oral administration, 100 mg of a compound of Formula I is mixed with 750 mg of lactose. The mixture is incorporated in a unit oral dosage form, such as a hard gelatin capsule, which is suitable for oral administration.

Claims (9)

REIVINPICATIONS
1. - A compound of Formula I: Formula I wherein: n is 1 or 2; A is -CH = CH-, - (alkyl-dd-) - Y- -NRd (CH2) tY-, -Y- (alkyl-dd) -, -Y- (alkyl-dd) -, -Y- NH-, -Y-NRd (alkyl-Ci-C6) -, -S-, -S (0) 2-, -OY- -YO- -YS-, or -SY-divalent, in which Rd is H or alkyl dC6, t is an integer from 0 to 5, Y is C (O), C (S), S (O), S (0) 2, or a bond; X is a direct bond, CH2, CF2, O, S, NH, C (O), or C (S); R1 is a C3-C10 cycloalkyl group, 4 to 10 membered heterocycloalkyl, C6-d0 aryl, 4 to 10 membered heteroaryl, wherein R is unsubstituted or substituted by 1 to 4 R10 groups; R2 is -S (0) 2OH, -S (0) 2NRdRe, or -P (0) (OR4) 2, wherein R4 is an H, alkyl group d-dc an an C6-Ci0, or -CH2 -0-C (0) ReCH3, Rd and Re are each independently an H or C1-C6 alkyl group, and R4 is unsubstituted or substituted with 1 to 4 R10 groups; and R3 is OH, d-C7 alkyl, d-d alkoxy. C6-C10 aryl, 4-heteroaryl 10 members, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, -NH (R5), or -N (R5) 2, wherein R5 is independently selected from H, Ci-C7 alkyl) C6-Cio aryl , or wherein ring B is a 5- or 6-membered heterocycloalkyl group, Z is a divalent group C (0) Z ', heteroaryl or heterocycloalkyl wherein Z' is an O, S, NH, N (CH3), C02 , or divalent CH2, and R6 is H, C1-C-10 alkyl, aryl, Ci-C6-aryl, or arylalkyl, wherein R3, R5, B and R6 are unsubstituted or substituted. to 4 groups R 0; wherein each R10 is independently selected from halo, amino, = 0, = S, = NH, cyano, nitro, hydroxyl, -SH, haloalkyl, heteroalkyl of 2 to 10 members, Ci-C6 alkoxy, Ci_Cio alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C (0) jRa, -OC (0) jRd, -OC (0) OC (0) Rd, -OOH, -C (NRd) NRbRc, -NRdC (NRe) NRbRc, -NRdC (0) jRb, -C (0) NRbRc, -C (0) NRdCORb, -OC (0) NRbRc, -NRbR °, -NRdOR °, -C (S) NR Rc, -NRdC (S) ) NR R °, -NRdC (0) NRbRc, -OSH, -S (0) jRb, -OS (0) jRb, -SC (0) R, -S (0) jC (0) ORb, -SCORd, -NRdSR °, -SRb, -NHS (0) jRb, -COSRb, -C (0) S (0) jRb, -CSRb, -CS (0) jRb, -C (SO) OH, -C (SO) 2OH, -NRdC (S) R °, -OC (S) Rb, -OC (S) OH, -OC (SO) 2Rb, -S (0) jNRbRc, -SNRbRc, -S (0) NRbRc, -NRdCS (0) jRc, -C (0) j (CH2) tNRd- (4- to 10-membered heteroaryl), -C (0) j (CH2) tNRd (4- to 10-membered heterocycloalkyl), - (CRdRe) tCN, - (CRdRe) t (C3-C10 cycloalkyl), - (CRdRe) t (C6-Ci0 aryl), - (CRdRe) t (4 to 10 membered heterocycloalkyl), - (CRdRe) t (4 to 10 heteroaryl) members), - (CRdRe) qC (0) (CRdRe) t (C3-C10 cycloalkyl), - (CRdRe) qC (0) (CRdRe) t (C6-C10 aryl), - (CRdRe) qC (0) ( CRdRe) t (4 to 10 membered heterocycloalkyl), - (CRdRe) qC (0) (CRdRe) t (4 to 10 membered heteroaryl), (CRdRe) tO (CRdRe) q (C3-C10 cycloalkyl), - ( CRdRe) tO (CRdRe) q (aryl C6-Ci0), - (CRdRe) tO (CRdRe) q (heterocycloalkyl of 4 to 10 members), (CRdRe) tO (CRdRe) q (heteroaryl of 4 to 10 members), ( CRdRe) qS02 (CRdRe) t (C3-C10 cycloalkyl), - (CRdRe) qS02 (CRdRe) t (C6-C10 aryl), - (CRdRe) qS02 (CRdRe) t (4- to 10-membered heterocycloalkyl), and - (CRdRe) qS02 (CRdRe) t (4 to 10 membered heteroaryl), wherein Ra is selected from the group consisting of halo, hydroxyl, -NRdRe, C1-C10 alkyl, haloalkyl, Ci-C6 alkoxy, Rb and R ° are independently selected from H, C Cι alkyl, - (CRdRe) t (C3-C10 cycloalkyl), - (CRdRe) t (C6-C10 aryl), - (CRdRe) t (heterocycloalkyl) uilo of 4 to 10 members), and - (CRdRe) t (heteroaryl of 4 to 10 members), Rd and Re are independently H or Ci-C6 alkyl, j is an integer from 0 to 2, q and t are each one independently an integer from 0 to 5, and 1 or 2 ring carbon atoms of the cyclic moieties of the above R10 groups are unsubstituted or substituted with = 0, and the alkyl, alkenyl, alkynyl, aryl moieties and cyclics of the above R10 groups are unsubstituted or substituted with 1 to 3 substituents independently selected from halo, = 0, cyano, nitro, - (CRdRe) tCN, haloalkyl, heteroalkyl of 2 to 10 members, -ORb, -C (0) jRb, - NRdC (0) Rb, -C (0) NRbRc, -NRbRc, -NR ORc, -NRdC (0) jNRbR °, -NRdC (0) jRbR °, -OC (0) ¡Rb, -OC (0) NRbRc , -SRd, C C10 alkyl, C2-C6 alkenyl, C2-C2 alkynyl, - (CRdRe) t (C3-C10 cycloalkyl), - (CRdRe) t (C6-C10 aryl), (CRdRc) t (4 to 4-heterocycloalkyl) 10 members), - (CRdRe) t (heteroaryl of 4 to 10 members), - (CRdRe) t (C6-C10 aryl) - (C ^ Ce alkyl); where t, Rb, Rc, Rd, Re are as defined above; or a prodrug of said pharmaceutically acceptable compound, metabolite of said active compound from a pharmaceutical point of view, or salt of said pharmaceutically acceptable compound or metabolite.
2. - An acceptable salt from a pharmaceutical point of view according to claim 1.
3. - A compound or pharmaceutically acceptable salt according to claim 1, wherein: n is 1 or 2; A is a -NH-Y-, -NRd (CH2) t-Y-, or -O-Y- divalent, and Y is C (O) or S (0) 2; X is a direct link, CH2, O, or S; R1 is a C6-Ci0 aryl or 4 to 10-membered heteroaryl group unsubstituted or substituted with 1 to 4 R10 groups; R2 is -S (0) 2OH, or -P (0) (OR) 2, wherein R4 is an H, Cr C10 alkyl group, or C6-Cio aryl, and is unsubstituted or substituted by 1 to 4 R10 groups; and R3 is a C6-C10 aryl, 4- to 10-membered heteroaryl, -NH (C6H5), or wherein ring B is a 5- or 6-membered heterocycloalkyl group, Z is a C (0) Z? heteroaryl or heterocycloalkyl divalent group wherein Z 'is an O, S, NH, N (CH3), C02, or divalent CH2, and R6 is H or a C1-C10 alkyl group, wherein R3, B, and R6 are unsubstituted or substituted with 1 to 4 R0 groups; wherein each R10 is independently selected from halo, amino, = 0, = S, = NH, cyano, nitro, hydroxyl, -SH, haloalkyl, heteroalkyl of 2 to 10 members, C1-C6 alkoxy, C1-6 alkyl C10, C2-C6 alkenyl, C2-C6 alkynyl, -C (0) jRa, -OC (0) jRd, -OC (0) OC (0) Rd, -OOH, -C (NRd) NRbR °, -NRdC (NRe) NRbRc, -NRdC (0) jRb, -C (0) NR Rc, -C (0) NRdCORb, -OC (0) NR R °, -NRbRc, -NRdORc, -C (S) NRbRc, - NRdC (S) NRbRc, -NRdC (0) NRbRc, -OSH, -S (0) jRb, -OS (0) jR, -SC (0) Rb, -S (0) jC (0) ORb, -SCORd , -NR SRc, -SR, -NHS (0) jRb, -COSRb, -C (0) S (0) jRb, -CSRb, -CS (0) jRb, -C (SO) OH, -C (SO) ) 2OH, -NRdC (S) Rc, -OC (S) R, -OC (S) OH, -OC (SO) 2Rb, -S (0) jNRbRc, -SNRbR °, -S (0) NR R ° , -NRdCS (0) jRc, -C (0) j (CH2) tNRd- (4- to 10-membered heteroaryl), -C (0) j (CH2) tNRd (4- to 10-membered heterocycloalkyl), - (CRdRe ) tCN, - (CRdRe) t (C3-C10 cycloalkyl), - (CRdRe) t (C6-Ci0 aryl), - (CRdRe) t (hetero- 4 to 10 membered cycloalkyl), - (CRdRe) t (4 to 10 membered heteroaryl), - (CRdRe) qC (0) (CRdRe) t (C3-C10 cycloalkyl), - (CRdRe) qC (0 ) (CRdRe) t (aryl Cedo), - (CRdRe) qC (0) (CRdRe) t (heterocycloalkion of 4 to 10 members), - (CRdRe) qC (0) (CRdRe) t (heteroaryl of 4 to 10 members) ), (CRdRe) tO (CRdRe) q (C3-C10 cycloalkyl), - (CRdRe) tO (CRdRe) q (C6-C10 aryl), - (CR Re) tO (CRdRe) q (4- to 10-membered heterocycloalkyl) ), (CRdRe) tO (CRdRe) q (4 to 10 membered heteroaryl), (CRdRe) qS02 (CRdRe) t (C3-C10 cycloalkyl), - (CRdRe) qS02 (CRdRe) t (C6-C10 aryl) ), - (CRdRe) qS02 (CR Re) t (4 to 10 membered heterocycloalkyl), and - (CRaRe) qS02 (CRdRe) t (4 to 10 membered heteroaryl), wherein Ra is selected from the group consisting of in halo, hydroxyl, -NRdRe, C1-C10 alkyl, haloalkyl, C1-C6 alkoxy, Rb and Rc are independently selected from H, C1-C10 alkyl, - (CRdRe) t (C3-C10 cycloalkyl), - (CRdRe ) t (C6-Ci0 aryl), - (CRdRe) t (4- to 10-membered heterocycloalkyl), and - (CRdRe) t (4- to 10-membered heteroaryl), Rd and Re are independently H or C1-C6 alkyl, j is an integer from 0 to 2, q and t are each independently an integer from 0 to 5, and 1 or 2 carbon atoms of the ring of the residues cyclics of the above R10 groups are unsubstituted or substituted with = 0, and the alkyl, alkenyl, alkynyl, aryl and cyclic moieties of the above R10 groups are unsubstituted or substituted with 1 to 3 substituents selected independently of halo , = 0, cyano, nitro, - (CRdRe) tCN, haloalkyl, 2- to 10-membered heteroalkyl, -ORb, -C (0) jRb, -NRdC (0) Rb, -C (0) NRbRc, -NRbRc, -NRbORc, -NRdC (0) jNRbRc, -NRdC (0) jRbR °, -OC (0) jRb, -OC (0) NRbRc, -SRd, Ci-C 0 alkyl, C 2 -C 6 alkenyl, C 2 -C 8 alkynyl, - (CRdRe) t (C 3 -C 10 cycloalkyl), - (CRdRe) t (C6-Ci0 aryl), (CRdRc) t (4- to 10-membered heterocycloalkyl), - (CRdRe) t (4- to 10-membered heteroaryl), - (CRdRe) t (C6-Ci0 aryl) - (CrC6 alkyl); and in which t, Rb, Rc, Rd, Re are as defined above.
4. - A compound or pharmaceutically acceptable salt according to claim 3, wherein: n is 1; A is a -NH-Y- or -O-Y- divalent, in which Y is C (O); X is a direct link, CH2, or O; R1 is a C6-C10 aryl group unsubstituted or substituted with 1 to 4 groups R10; R2 is -P (0) (OR4) 2, wherein R4 is an H, C1-C10 alkyl group, or C6-C10 aryl, and is unsubstituted or substituted with 1 to 4 R0 groups; and R3 is a C6-C10 aryl, 4- to 10-membered heteroaryl, or wherein ring B is an unsubstituted 6-membered heterocycloalkyl, Z a divalent C (0) Z ', Z' is a divalent O, S, or CH2, and R6 is a C1-C10 alkyl group, wherein R3, B and R6 are not replaced or are substituted with 1 to 4 R groups; wherein each R10 is independently selected from halo, amino, = 0, = S, = NH, cyano, nitro, hydroxyl, -SH, haloalkyl, heteroalkyl of 2 to 10 members, C1-C6 alkoxy, C1-6 alkyl C10, C2-C6 alkenyl, C2-C6 alkynyl, -C (0) jRa, -OC (0) jRd, -OC (0) OC (0) Rd, -OOH, -C (NRd) NRbRc, -NRdC ( NRe) NRbRc, -NRdC (0) jRb, -C (0) NRbRc, -C (0) NRdCORb, -OC (0) NRbRc, -NRbR °, -NRdOR °, -C (S) NRbR °, -NRdC (S) NRbRc, -NRdC (0) NRbRc, -OSH, -S (0) jRb, -OS (0) jRb, -SC (0) Rb, -S (0) jC (0) ORb, -SCORd, -NRdSR °, -SRb, -NHS (0) jRb, -COSRb, -C (0) S (0) jRb, -CSRb, -CS (0) jR, -C (SO) OH, -C (SO) 2OH, -NRdC (S) Rc, -OC (S) Rb, -OC (S) OH, -OC (SO) 2Rb, -S (0) jNRbRc, -SNRbR °, -S (0) NRbRc, -NRdCS (0) jR °, -C (0) j (CH2) tNRd- (4- to 10-membered heteroaryl), -C (0) j (CH2) tNRd (4- to 10-membered heterocycloalkyl), - (CRdRe) tCN , - (CRdRe) t (C3-C10 cycloalkyl), - (CRdRe) t (C6-Ci0 aryl), - (CRdRe) t (4- to 10-membered heterocycloalkyl), - (CRdRe) t (heteroaryl of 4) to 10 members), - (CRdRe) qC (0) (CRdRe) t (C3-C10 cycloalkyl), - (CRdRe) qC (0) (CRdRe) t (aryl C 6-C10), - (CRdRe) qC (0) (CRdRe) t (heterocycloalkyl of 4 to 10 members), - (CRdRe) qC (0) (CRdRe) t (heteroaryl of 4 to 10 members), ( CRdRe) tO (CRdRe) q (C3-C10 cycloalkyl), - (CRdRe) tO (CRdRe) q (C6-C10 aryl), - (CRdRe) tO (CRdRe) q (4- to 10-membered heterocycloalkyl), - ( CRdRe) tO (CRdRe) q (heteroaryl of 4 to 10 members), (CRdRe) qS02 (CRdRe), (C3-C10 cycloalkyl), - (CRdRe) qS02 (CRdRe) t (aryl C6-Ci0), - (CRdRe) qS02 (CRdRe) t (heterocycloalkyl from 4 to 10 members), and - (CRdRe) qS02 (CRdRe) t (heteroaryl of 4 to 10 members), in which Ra is selected from the group consisting of halo, hydroxyl, -NRdRe, C1-C10 alkyl, haloalkyl, Ci-C6 alkoxy, Rb and R ° are independently selected from H, C1-C10 alkyl, - (CRdRe) t (C3 cycloalkyl) -C10), - (CRdRe) t (aryl C6-Ci0), - (CRdRe) t (heterocycloalkyl of 4 to 10 members), and - (CRdRe) t (heteroaryl of 4 to 10 members), Rd and Re are of independently H or C-1-Ce alkyl, j is an integer from 0 to 2, q and t are each independently an integer from 0 to 5, and 1 or 2 ring carbon atoms of the cyclic moieties of the above R10 groups are unsubstituted or substituted with = 0, and the alkyl, alkenyl, alkynyl, aryl and cyclic moieties of the above R10 groups are unsubstituted or substituted with 1 to 3 substituents independently selected from halo, = 0, cyano, nitro, - (CRdRe) tCN, haloalkyl, 2- to 10-membered heteroalkyl, -ORb, -C (0) jRb, -NRdC (0) Rb, -C (0) NRbRc, -NRbRc, -NRbOR °, -NRdC (0) jNRbRc, -NRdC (0) jRb Rc, -OC (0) jRb, -OC (0) NRbRc, -SRd, C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, - (CRdRe) t (C3-C10 cycloalkyl), - (CRdRe) t (aryl C6-Cio), (CRdRc) t (4- to 10-membered heterocycloalkyl), - (CRdRe) t (4 to 10 membered heteroaryl), - (CRdRe) t (C6-Cio aryl) - (C6-C6 alkyl); and in which t, Rb, Rc, Rd, Re are as defined above.
5. - A compound or pharmaceutically acceptable salt according to claim 4, wherein: n is 1; A is -NH-Y- or -O-Y-, wherein Y is C (O); X is a direct link, CH2, or O; R1 is a C6-C10 aryl group unsubstituted or substituted with 1 to 4 groups R10; R2 is -P (0) (OR4) 2, wherein R4 is an H, or a C1-C10 alkyl group which is unsubstituted or substituted by 1 to 4 R10 groups; and R3 is a C6-C10 aryl or 4- to 10-membered heteroaryl group unsubstituted or substituted with 1 to 4 R10 groups; wherein each R 0 is independently selected from halo, amino, = 0, = S, = NH, cyano, nitro, hydroxyl, -SH, haloalkyl, heteroalkyl of 2 to 10 members, C1-C6 alkoxy, Ci-Cio alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C (0) jRa, -OC (0) jRd, -OC (0) OC (0) Rd, -OOH, - C (NRd) NRbR °, -NRdC (NRe) NRbRc, -NRdC (0) jRb, -C (0) NRbRc, -C (0) NRdCOR, -OC (0) NRbRc, -NRbRc, -NRdORc, -C (S) NRbRc, -NRdC (S) NRbRc, -NRdC (0) NRbRc, -OSH, -S (0) jRb, -OS (0) jRb, -SC (0) Rb, -S (0) jC ( 0) ORb, -SCORd, -NRdSRc, -SR, -NHS (0) jRb, -COSR, -C (0) S (0) jR, -CSR, -CS (0) jR, -C (SO) OH , -C (SO) 2 OH, -NRdC (S) Rc, -OC (S) Rb, -OC (S) OH, -OC (SO) 2Rb, -S (0) jNR Rc, -SNRbRc, -S ( 0) NRbR °, -NRdCS (0) jRc, -C (0) j (CH2) tNRd- (4- to 10-membered heteroaryl), -C (0) j (CH2) tNRd (4- to 10-membered heterocycloalkyl) , - (CRdRe) tCN, - (CRdRe) t (C3-C10 cycloalkyl), - (CRdRe) t (C6-Cio aryl), (CRdRe) t (4- to 10-membered heterocycloalkyl), - (CRdRe) t ( 4 to 10 membered heteroaryl), - (CRdRe) qC (0) (CRdRe) t (C3-Ciocycloalkyl), (CRdRe) qC (0) (CRdRe) t (C6-C10 aryl), - (CRdRe ) qC (0) (CRdRe) t (4 to 10 membered heterocycloalkyl), - (CRdRe) qC (0) (CRdRe) t (4 to 10 membered heteroaryl), - (CRdRe) tO (CRdRe) q (C3-C10 cycloalkyl), - (CRdRe) tO (CRdRe) q (C6-C10 aryl), - (CRdRe) tO (CRdRe) q (4- to 10-membered heterocycloalkyl) ), (CRdRe) tO (CRdRe) q (4 to 10 membered heteroaryl), (CRdRe) qS02 (CRdRe) t (C3-C10 cycloalkyl), - (CRdRe) qS02 (CRdRe) t (C6-C10 aryl), - (CRdRe) qS02 (CRdRe) t (4 to 10 membered heterocycloalkyl), and - (CRdRe) qS02 (CRdRe) t (4 to 10 membered heteroaryl), wherein Ra is selected from the group consisting of halo, hydroxyl, -NRdRe, C1-C10 alkyl, haloalkyl, CrC6 alkoxy, R and Rc are independently selected from H, C C10 alkyl, - (CRdRe) t (C3-C10 cycloalkyl), - (CRdRe) t (C6- aryl) C10), - (CRdRe) t (4- to 10-membered heterocycloalkyl), and - (CRdRe) t (4- to 10-membered heteroaryl), Rd and Re are independently H or Ci-C6 alkyl, j is a number integer from 0 to 2, q and t are each independently an integer from 0 to 5, and 1 or 2 ring carbon atoms of the cyclic moieties of the above R10 groups are unsubstituted or are are substituted with = 0, and the alkyl, alkenyl, alkynyl, aryl and cyclic moieties of the above R10 groups are unsubstituted or substituted with 1 to 3 substituents independently selected from halo, = 0, cyano, nitro, - ( CRdRe) tCN, haloalkyl, 2- to 10-membered heteroalkyl, -ORb, -C (0) jRb, -NRdC (0) Rb, -C (0) NRbRc, -NRbR °, -NR OR °, -NRdC (0 ) jNRbRc, -NRdC (0) jRbRc, -OC (0) jRb, -OC (0) NRbR °, -SR, C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, - (CRdRe) t (cycloalkyl) C3-C10), - (CRdRe) t (aryl Ce-Cio), (CRdRc) t (heterocycloalkyl of 4 to 10 members), - (CRdRe) t (heteroaryl of 4 to 10 members), - (CRdRe) t ( C6-Ci0 aryl) - (Ci-C6 alkyl); and where t, Rb, Rc, Rd, Re are as defined above.
6. A compound selected from the group consisting of: -206- or a salt of these acceptable from a pharmaceutical point of view.
7. - A pharmaceutical composition comprising: a therapeutic effective amount of an agent selected from the group consisting of compounds, prodrugs, metabolites, and salts as defined in claim 1; and an acceptable vehicle from a pharmaceutical point of view.
8. - A method for treating a condition associated with a mammalian disease mediated by PIN1 activity, which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound, acceptable prodrug from a point of view pharmaceutical, pharmaceutically active metabolite, or pharmaceutically acceptable salt as defined in claim 1.
9. - A method according to claim 8, wherein the condition associated with a mammalian disease is associated with hypertension, inappropriate cell proliferation, infectious diseases, or neurodegenerative brain disorders.
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Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005080406A2 (en) * 2003-12-19 2005-09-01 Jerini Ag Compounds for the inhibition of undesired cell proliferation and use thereof
US7795448B2 (en) 2004-05-06 2010-09-14 Cytokinetics, Incorporated Imidazoyl-benzamide anti-cancer agents
US7618981B2 (en) 2004-05-06 2009-11-17 Cytokinetics, Inc. Imidazopyridinyl-benzamide anti-cancer agents
US7504413B2 (en) 2004-05-06 2009-03-17 Cytokinetics, Inc. N-(4-(imidazo[1,2A]pyridin-YL)phenethyl)benzamide inhibitors of the mitotic kinesin CENP-E for treating certain cellular proliferation diseases
WO2006040646A1 (en) * 2004-10-14 2006-04-20 Pfizer, Inc. Benzimidazole or indole amides as inhibitors of pin1
EP2845588A1 (en) * 2013-09-09 2015-03-11 Centre National de la Recherche Scientifique (C.N.R.S.) PIN1 inhibitors for use in the prevention and/or treatment of theileriosis, and related applications
BR112017006669B1 (en) 2014-10-03 2023-04-18 Ucb Biopharma Sprl fused IMIDAZOLE PENTACYCLIC DERIVATIVES, PHARMACEUTICAL COMPOSITION INCLUDING THEM AND USE THEREOF
WO2017063757A1 (en) 2015-10-12 2017-04-20 Polyphor Ag Conformationally constrained macrocyclic compounds
WO2017063755A1 (en) 2015-10-12 2017-04-20 Polyphor Ag Conformationally constrained macrocyclic compounds
WO2017063756A1 (en) * 2015-10-12 2017-04-20 Polyphor Ag Conformationally constrained macrocyclic compounds as pin1 modulators
WO2017063754A1 (en) 2015-10-12 2017-04-20 Polyphor Ag Conformationally constrained macrocyclic compounds as pin1 modulators
US10654861B2 (en) 2016-04-01 2020-05-19 UCB Biopharma SRL Fused pentacyclic imidazole derivatives as modulators of TNF activity
CN109219608B (en) 2016-04-01 2021-12-21 Ucb生物制药私人有限公司 Fused pentacyclic imidazole derivatives as modulators of TNF activity
CN109195969B (en) 2016-04-01 2021-12-21 Ucb生物制药私人有限公司 Fused pentacyclic imidazole derivatives as modulators of TNF activity
BR112018069937A2 (en) 2016-04-01 2019-02-05 Sanofi Sa fused hexacyclic imidazole derivatives as modulators of tnf activity
ES2954968T3 (en) 2016-11-29 2023-11-27 Univ Hiroshima Novel ester compound and Pin1 inhibitor, inflammatory disease therapy and colon cancer therapy using said ester compound
TW202402300A (en) * 2017-01-31 2024-01-16 美商基利科學股份有限公司 Crystalline forms of tenofovir alafenamide
CA3055863A1 (en) 2017-03-15 2018-09-20 Ucb Biopharma Sprl Fused pentacyclic imidazole derivatives as modulators of tnf activity
US11504379B2 (en) 2017-08-07 2022-11-22 Hiroshima University Amide compound, and Pin1 inhibitor, therapeutic agent for inflammatory diseases and therapeutic agent for cancer that use the same
CN111183129A (en) 2017-08-07 2020-05-19 国立大学法人广岛大学 Novel anthranilic acid compound, Pin1 inhibitor using same, and therapeutic agent for inflammatory disease and cancer
EP3679930A4 (en) 2017-08-07 2021-11-17 Hiroshima University Therapeutic agent for fatty liver diseases and therapeutic agent for adiposity
KR20220152535A (en) 2020-03-12 2022-11-16 고쿠리츠다이가쿠호진 히로시마다이가쿠 Novel 3,5-diaminobenzoic acid compounds, and Pin1 inhibitors using the same and therapeutic agents for inflammatory diseases
WO2022032179A1 (en) * 2020-08-07 2022-02-10 The Regents Of The University Of California Pin1 inhibitors and uses thereof
JP2022080079A (en) 2020-11-17 2022-05-27 国立大学法人広島大学 Covid-19 therapeutic or prophylactic agent
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