JP2006523669A - Phosphate / sulfate compounds and pharmaceutical compositions for inhibiting NIMA regulatory protein (PIN1) - Google Patents

Abstract

Phosphate / sulfate compounds that modulate and / or inhibit the activity of NIMA regulatory protein (PIN1) and pharmaceutical compositions containing such compounds have been described. The invention also provides therapeutic or prophylactic use of such compounds and compositions, and diseases characterized by hypertension, abnormal cell proliferation, infections, and neurodegenerative brain diseases by administering an effective amount of such compounds. It also relates to the treatment method.

Description

  The present invention relates to phosphate / sulfate compounds that modulate and / or inhibit the activity of protein interacting NIMA (PIN1) and pharmaceutical compositions containing such compounds. The invention also provides therapeutic or prophylactic use of such compounds and compositions, and diseases characterized by hypertension, abnormal cell proliferation, infections, and neurodegenerative brain diseases by administering an effective amount of such compounds. It also relates to the treatment method.

  PIN1 is one member of the parvulin family of peptidylprolyl isomerases (PPIases) and catalyzes the rotation of peptide bonds located in front of proline residues. PIN1 is a regulator of Cdc25 and dephosphorylates Cdc2 / cyclin B leading to cells in mitosis. PIN1 has been identified in all eukaryotes examined, including plants, yeast, insects, and mammals. The PIN1 orthologue of yeast (Ess1) and Drosophila (dodo) showed high homology with the human-expressed sequence tag, which ultimately resulted in the cloning of a human dodo gene called PIN1. . The Drosophila dodo gene has been reported to be 45% identical to the yeast gene Ess1.

Using yeast two-hybrid screening of human cDNA libraries, human PIN1 was first identified as a binding protein of the fungus Aspergillus nidulens protein NIMA. NIMA is a kinase that leads cells to mitosis and is reported to be negatively regulated by PIN1. Deletion of NIMA in Aspergillus nidulans cells, cell cycle arrest brought in G _2, whereas, overexpression has been reported to mitotic immature is promoted. Ser / Thr kinase Cdc2 / cyclin B may be a similar NIMA kinase in human cells, but it is envisioned that other NIMA-like pathways in human cells exist.

It has been reported that modulation of PIN1 activity results in a dramatic morphological cell phenotype. For example, overexpression of PIN1 in HeLa cells, resulted in _{G 2} phase stopped, while the deletion of PIN1 has been reported to result in a mitotic stop (phenotype opposite to that observed with NIMA Modulation) It was. In addition, reduction of PIN1 protein expression due to full-length antisense expression results in immature mitotic progression in cells, abnormal nuclei due to immature chromosomal condensation, and apoptosis. These data indicate that PIN1 is a negative regulator of mitosis through interaction with mammalian functional homologues of NIMA and is required to promote mitosis. Moreover, PIN1 deletion is also claimed to play a role in Alzheimer's disease (Lu et al., Nature, 380, 544-547 (1996)).

In vitro, PIN1 has been reported to interact with cell division proteins recognized by MPM-2 antibodies. The MPM-2 monoclonal antibody recognizes phospho-Ser / Thr-Pro epitopes on approximately 50 proteins associated with mitosis, including important cell division regulators such as Cdc25, Wee1, Cdc27, Map4, NIMA . See, for example, Davis et al., Proc. Natl. Acad. Sci. USA 80, 2926 (1983). PIN1 has also been reported to interact with important upstream regulators of Cdc2 / cyclin B, including Cdc25 and its known regulator, Plx1. Shen et al., Genes
See Dev. 12, 706 (1998). PIN1 can remove the role of Cdc25 and Plx1 by degrading in cells using its enzymatic action.

  Studies have shown that the biological function of PIN1 depends on the functional PPIase active site (Lu et al., Science, 283, 1325-1328 (1999)). Studies have also shown that PIN1 recognizes its substrate (mitosis specific phosphoprotein) via the WW domain. The WW domain is a protein recognition motif widely present in the living world. However, the PIN1 WW domain is characterized in that its ligand protein requires phosphorylated serine. Similar to the PPIase domain, a functional WW domain has been reported to be essential for the biological function of PIN1. This is consistent with the model that PIN1 recognizes its substrate through the WW domain and then plays its essential catalytic role.

  Nucleotide sequences encoding full length PIN1 protein and full length PIN1 are disclosed in US Pat. Nos. 5,952,467 and 5,972,697. Furthermore, the sequence of PIN1 is registered in GenBank as accession numbers NM006221 (mRNA) and S68520 (protein). The mRNA sequence of dodo is registered in GenBank as accession number U35140. The mRNA sequence of mouse PIN1 is registered under the accession number NM023371.

The crystal structure of full-length PIN1 is Ranganathan, R. et al., Cell, 89,
875-886 (1997) and International Publication No. WO99 / 63931. Zhang et al. Provide further analysis of the crystal structure of PIN1 complexed 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)) discloses that PIN1 is upregulated in human cancer and is a biomarker for cell proliferation.

PIN1 inhibitors are described in the literature. For example, Hennig et al. (Biochemistry,
37, 5953-5960 (1998)) report that juglone (5-hydroxy-1,4-naphthoquinone) selectively inhibits several perbulins including human PIN1. Noel et al., In US Patent Application No. 2001016346, discloses a compound that is believed to be PIN1 using data based on the crystal structure derived from full-length human PIN1. Lu et al., In International Publication No. WO 99/12962, report inhibitors that mimic the phospho-Ser / Thr moiety of phosphoserine or phosphothreonine-proline peptidylprolyl isomerase substrates.

  Considering that PIN1 plays an important role in cell cycle control, other compounds that inhibit PIN1 are sought. These compounds, together with their pharmaceutical compositions, can be used as effective chemotherapeutic agents for the treatment of various diseases characterized by hypertension, abnormal cell proliferation, including cancer, infections, and neurodegenerative brain diseases. The present invention provides compounds that inhibit PIN1.

  Accordingly, it is an object of the present invention to find compounds and methods for modulating or inhibiting PIN1.

  Another object of the present invention is to modulate or inhibit PIN1 which can be used in a pharmaceutical composition for the treatment of diseases characterized by hypertension, cell overgrowth, infections, and neurodegenerative brain diseases. The compounds and methods are provided.

  These and other objects of the present invention will become apparent from the following description, but include the phosphate / sulfate compounds described below, pharmaceutically acceptable prodrugs, pharmaceutically active metabolites that inhibit PIN1. And their pharmaceutically acceptable salts (collectively termed such compounds, prodrugs, metabolites and salts as drugs). Pharmaceutical compositions containing such agents are useful for the treatment of diseases characterized by hypertension, abnormal cell proliferation, infections, and neurodegenerative brain diseases.

［式中：
ｎは１または２であり；
Ａは２価の−ＣＨ＝ＣＨ−、−（Ｃ_１−Ｃ_７−アルキル）−Ｙ−、−ＮＲ^ｄ（ＣＨ_２）_ｔ−Ｙ−、−Ｙ−（Ｃ_１−Ｃ_７−アルキル）−、−Ｙ−（Ｃ_１−Ｃ_７アルキル）−、−Ｙ−ＮＨ−、−Ｙ−ＮＲ^ｄ（Ｃ_１−Ｃ_６−アルキル）−、−Ｓ−、−Ｓ（Ｏ）_２−、−Ｏ−Ｙ−、−Ｙ−Ｏ−、−Ｙ−Ｓ−、または−Ｓ−Ｙ−であり、ここでＲ^ｄはＨまたはＣ_１−Ｃ_６アルキルであり、ｔは０〜５の整数であり、ＹはＣ（Ｏ）、Ｃ（Ｓ）、Ｓ（Ｏ）、Ｓ（Ｏ）_２、または単結合であり；
Ｘは直接結合、ＣＨ_２、ＣＦ_２、Ｏ、Ｓ、ＮＨ、Ｃ（Ｏ）、またはＣ（Ｓ）であり；
Ｒ^１はＣ_３−Ｃ_１０シクロアルキル、４〜１０員ヘテロシクロアルキル、Ｃ_６−Ｃ_１０アリール、または４〜１０員ヘテロアリール基であり、ここでＲ^１は置換されていないかまたは１〜４個のＲ^１０基で置換されており；
Ｒ^２は−Ｓ（Ｏ）_２ＯＨ、−Ｓ（Ｏ）_２ＮＲ^ｄＲ^ｅ、または−Ｐ（Ｏ）（ＯＲ^４）_２であり、ここでＲ^４はＨ、Ｃ_１−Ｃ_１０−アルキル、Ｃ_６−Ｃ_１０アリール、または−ＣＨ_２−Ｏ−Ｃ（Ｏ）Ｒ^ｅＣＨ_３基であり、Ｒ^ｄおよびＲ^ｅは、それぞれ独立して、ＨまたはＣ_１−Ｃ_６アルキル基であり、そしてＲ^４は置換されていないかまたは１〜４個のＲ^１０基で置換されており；そして
Ｒ^３はＯＨ、Ｃ_１−Ｃ_７−アルキル、Ｃ_１−Ｃ_７−アルコキシル、Ｃ_６−Ｃ_１０アリール、４〜１０員ヘテロアリール、Ｃ_３−Ｃ_１０シクロアルキル、３〜１０員ヘテロシクロアルキル、−ＮＨ（Ｒ^５）、または−Ｎ（Ｒ^５）_２基であり、ここでＲ^５は、独立して、Ｈ、Ｃ_１−Ｃ_７アルキル、Ｃ_６−Ｃ_１０アリール、または

から選択され、
ここで環Ｂは５または６員のヘテロシクロアルキル基であり、Ｚは２価のＣ（Ｏ）Ｚ’、ヘテロアリールまたはヘテロシクロアルキル基であり、ここでＺ’は２価のＯ、Ｓ、ＮＨ、Ｎ（ＣＨ_３）、ＣＯ_２、またはＣＨ_２であり、そしてＲ^６はＨ、Ｃ_１−Ｃ_１０アルキル、アリール、Ｃ_１−Ｃ_６アルキル−アリール、またはアリールアルキル基であり、ここでＲ^３、Ｒ^５、ＢおよびＲ^６は１〜４個のＲ^１０基で置換されていないかまたは置換されており；
ここで各Ｒ^１０は独立してハロ、アミノ、＝Ｏ、＝Ｓ、＝ＮＨ、シアノ、ニトロ、ヒドロキシル、−ＳＨ、ハロアルキル、２〜１０員ヘテロアルキル、Ｃ_１−Ｃ_６アルコキシ、Ｃ_１−Ｃ_１０アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、−Ｃ（Ｏ）_ｊＲ^ａ、−ＯＣ（Ｏ）_ｊＲ^ｄ、−ＯＣ（Ｏ）ＯＣ（Ｏ）Ｒ^ｄ、−ＯＯＨ、−Ｃ（ＮＲ^ｄ）ＮＲ^ｂＲ^ｃ、−ＮＲ^ｄＣ（ＮＲ^ｅ）ＮＲ^ｂＲ^ｃ、−ＮＲ^ｄＣ（Ｏ）_ｊＲ^ｂ、−Ｃ（Ｏ）ＮＲ^ｂＲ^ｃ、−Ｃ（Ｏ）ＮＲ^ｄＣＯＲ^ｂ、−ＯＣ（Ｏ）ＮＲ^ｂＲ^ｃ、−ＮＲ^ｂＲ^ｃ、−ＮＲ^ｄＯＲ^ｃ、−Ｃ（Ｓ）ＮＲ^ｂＲ^ｃ、−ＮＲ^ｄＣ（Ｓ）ＮＲ^ｂＲ^ｃ、−ＮＲ^ｄＣ（Ｏ）ＮＲ^ｂＲ^ｃ、−ＯＳＨ、−Ｓ（Ｏ）_ｊＲ^ｂ、−ＯＳ（Ｏ）_ｊＲ^ｂ、−ＳＣ（Ｏ）Ｒ^ｂ、−Ｓ（Ｏ）_ｊＣ（Ｏ）ＯＲ^ｂ、−ＳＣＯＲ^ｄ、−ＮＲ^ｄＳＲ^ｃ、−ＳＲ^ｂ、−ＮＨＳ（Ｏ）_ｊＲ^ｂ、−ＣＯＳＲ^ｂ、−Ｃ（Ｏ）Ｓ（Ｏ）_ｊＲ^ｂ、−ＣＳＲ^ｂ、−ＣＳ（Ｏ）_ｊＲ^ｂ、−Ｃ（ＳＯ）ＯＨ、−Ｃ（ＳＯ）_２ＯＨ、−ＮＲ^ｄＣ（Ｓ）Ｒ^ｃ、−ＯＣ（Ｓ）Ｒ^ｂ、−ＯＣ（Ｓ）ＯＨ、−ＯＣ（ＳＯ）_２Ｒ^ｂ、−Ｓ（Ｏ）_ｊＮＲ^ｂＲ^ｃ、−ＳＮＲ^ｂＲ^ｃ、−Ｓ（Ｏ）ＮＲ^ｂＲ^ｃ、−ＮＲ^ｄＣＳ（Ｏ）_ｊＲ^ｃ、−Ｃ（Ｏ）_ｊ（ＣＨ_２）_ｔＮＲ^ｄ−（４〜１０員ヘテロアリール）、−Ｃ（Ｏ）_ｊ（ＣＨ_２）_ｔＮＲ^ｄ（４〜１０員ヘテロシクロアルキル）、−（ＣＲ^ｄＲ^ｅ）_ｔＣＮ、−（ＣＲ^ｄＲ^ｅ）_ｔ（Ｃ_３−Ｃ_１０シクロアルキル）、−（ＣＲ^ｄＲ^ｅ）_ｔ（Ｃ_６−Ｃ_１０アリール）、−（ＣＲ^ｄＲ^ｅ）_ｔ（４〜１０員ヘテロシクロアルキル）、−（ＣＲ^ｄＲ^ｅ）_ｔ（４〜１０員ヘテロアリール）、−（ＣＲ^ｄＲ^ｅ）_ｑＣ（Ｏ）（ＣＲ^ｄＲ^ｅ）_ｔ（Ｃ_３−Ｃ_１０シクロアルキル）、−（ＣＲ^ｄＲ^ｅ）_ｑＣ（Ｏ）（ＣＲ^ｄＲ^ｅ）_ｔ（Ｃ_６−Ｃ_１０アリール）、−（ＣＲ^ｄＲ^ｅ）_ｑＣ（Ｏ）（ＣＲ^ｄＲ^ｅ）_ｔ（４〜１０員ヘテロシクロアルキル）、−（ＣＲ^ｄＲ^ｅ）_ｑＣ（Ｏ）（ＣＲ^ｄＲ^ｅ）_ｔ（４〜１０員ヘテロアリール）、−（ＣＲ^ｄＲ^ｅ）_ｔＯ（ＣＲ^ｄＲ^ｅ）_ｑ（Ｃ_３−Ｃ_１０シクロアルキル）、−（ＣＲ^ｄＲ^ｅ）_ｔＯ（ＣＲ^ｄＲ^ｅ）_ｑ（Ｃ_６−Ｃ_１０アリール）、−（ＣＲ^ｄＲ^ｅ）_ｔＯ（ＣＲ^ｄＲ^ｅ）_ｑ（４〜１０員ヘテロシクロアルキル）、−（ＣＲ^ｄＲ^ｅ）_ｔＯ（ＣＲ^ｄＲ^ｅ）_ｑ（４〜１０員ヘテロアリール）、−（ＣＲ^ｄＲ^ｅ）_ｑＳＯ_２（ＣＲ^ｄＲ^ｅ）_ｔ（Ｃ_３−Ｃ_１０シクロアルキル）、−（ＣＲ^ｄＲ^ｅ）_ｑＳＯ_２（ＣＲ^ｄＲ^ｅ）_ｔ（Ｃ_６−Ｃ_１０アリール）、−（ＣＲ^ｄＲ^ｅ）_ｑＳＯ_２（ＣＲ^ｄＲ^ｅ）_ｔ（４〜１０員ヘテロシクロアルキル）、および−（ＣＲ^ｄＲ^ｅ）_ｑＳＯ_２（ＣＲ^ｄＲ^ｅ）_ｔ（４〜１０員ヘテロアリール）から選択され、ここでＲ^ａはハロ、ヒドロキシル、−ＮＲ^ｄＲ^ｅ、Ｃ_１−Ｃ_１０アルキル、ハロアルキル、Ｃ_１−Ｃ_６アルコキシルからなるグループから選択され、Ｒ^ｂおよびＲ^ｃは、独立して、Ｈ、Ｃ_１−Ｃ_１０アルキル、−（ＣＲ^ｄＲ^ｅ）_ｔ（Ｃ_３−Ｃ_１０シクロアルキル）、−（ＣＲ^ｄＲ^ｅ）_ｔ（Ｃ_６−Ｃ_１０アリール）、−（ＣＲ^ｄＲ^ｅ）_ｔ（４〜１０員ヘテロシクロアルキル）、および−（ＣＲ^ｄＲ^ｅ）_ｔ（４〜１０員ヘテロアリール）、から選択され、Ｒ^ｄおよびＲ^ｅは独立してＨまたはＣ_１−Ｃ_６アルキルであり、ｊは０〜２の整数であり、ｑおよびｔは、それぞれ独立して、０〜５の整数であり、そして前記Ｒ^１０基の環部分の１または２個の環炭素原子は、置換されていないかまたは＝Ｏで置換されており、そしてアルキル、アルケニル、アルキニル、アリールおよび前記Ｒ^１０基の環部分は、置換されていないかまたはハロ、＝Ｏ、シアノ、ニトロ、−（ＣＲ^ｄＲ^ｅ）_ｔＣＮ、ハロアルキル、２〜１０員ヘテロアルキル、−ＯＲ^ｂ、−Ｃ（Ｏ）_ｊＲ^ｂ、−ＮＲ^ｄＣ（Ｏ）Ｒ^ｂ、−Ｃ（Ｏ）ＮＲ^ｂＲ^ｃ、−ＮＲ^ｂＲ^ｃ、−ＮＲ^ｂＯＲ^ｃ _、−ＮＲ^ｄＣ（Ｏ）_ｊＮＲ^ｂＲ^ｃ、−ＮＲ^ｄＣ（Ｏ）_ｊＲ^ｂＲ^ｃ、−ＯＣ（Ｏ）_ｊＲ^ｂ、−ＯＣ（Ｏ）ＮＲ^ｂＲ^ｃ、−ＳＲ^ｄ、Ｃ_１−Ｃ_１０アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、−（ＣＲ^ｄＲ^ｅ）_ｔ（Ｃ_３−Ｃ_１０シクロアルキル）、−（ＣＲ^ｄＲ^ｅ）_ｔ（Ｃ_６−Ｃ_１０アリール）、−（ＣＲ^ｄＲ^ｅ）_ｔ（４〜１０員ヘテロシクロアルキル）、−（ＣＲ^ｄＲ^ｅ）_ｔ（４〜１０員ヘテロアリール）、−（ＣＲ^ｄＲ^ｅ）_ｔ（Ｃ_６−Ｃ_１０アリール）−（Ｃ_１−Ｃ_６アルキル）から独立して選択される１〜３個の置換基で置換されており；ここでｔ、Ｒ^ｂ、Ｒ^ｃ、Ｒ^ｄ、Ｒ^ｅは上記で定義したものである］。 In a general aspect, the invention relates to compounds of formula (I):

[Where:
n is 1 or 2;
A is divalent —CH═CH—, — (C ₁ -C ₇ -alkyl) -Y—, —NR ^d (CH ₂ ) _t —Y—, —Y— (C ₁ -C ₇ -alkyl) — , -Y- (C ₁ -C ₇ alkyl)-, -Y-NH-, -Y-NR ^d (C ₁ -C ₆ -alkyl)-, -S-, -S (O) _2- , -O —Y—, —Y—O—, —Y—S—, or —S—Y—, wherein R ^d is H or C ₁ -C ₆ alkyl, and t is an integer from 0 to 5. , Y is C (O), C (S), S (O), S (O) ₂ or a single bond;
X is a direct bond, CH ₂ , CF ₂ , O, S, NH, C (O), or C (S);
R ¹ is a C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 4-10 membered heteroaryl group, wherein R ¹ is unsubstituted or 1- Substituted with 4 R ¹⁰ groups;
R ² is —S (O) ₂ OH, —S (O) ₂ NR ^d R ^e , or —P (O) (OR ⁴ ) ₂ , where R ⁴ is H, C ₁ -C ₁₀ -alkyl. , C ₆ -C ₁₀ aryl, or —CH ₂ —O—C (O) R ^e CH ₃ group, wherein R ^d and ^Re are each independently H or a C ₁ -C ₆ alkyl group And R ⁴ is unsubstituted or substituted with 1 to 4 R ¹⁰ groups; and R ³ is OH, C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkoxyl, C _6- C ₁₀ aryl, 4-10 membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocycloalkyl, —NH (R ⁵ ), or —N (R ⁵ ) ₂ groups, wherein R ⁵ It is independently, _H, C 1 -C _{7 alkyl,} C 6 _{-C 10} aryl Or

Selected from
Wherein ring B is a 5- or 6-membered heterocycloalkyl group, Z is a divalent C (O) Z ′, heteroaryl or heterocycloalkyl group, where Z ′ is a divalent O, S , NH, N (CH ₃ ), CO ₂ , or CH ₂ , and R ⁶ is H, C ₁ -C ₁₀ alkyl, aryl, C ₁ -C ₆ alkyl-aryl, or arylalkyl group, where In which R ³ , R ⁵ , B and R ⁶ are unsubstituted or substituted with 1 to 4 R ¹⁰ groups;
Wherein each R ¹⁰ is independently halo, amino, ═O, ═S, ═NH, cyano, nitro, hydroxyl, —SH, haloalkyl, 2-10 membered heteroalkyl, C ₁ -C ₆ alkoxy, C ₁ — C _{10 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 ^{alkynyl, -C (O) j R a}} , -OC (O) j R d, -OC (O) OC (O) R d, -OOH , -C (NR ^d ) NR ^b R ^c , -NR ^d C (NR ^e ) NR ^b R ^c , -NR ^d C (O) _j R ^b , -C (O) NR ^b R ^c , -C (O ) NR ^d COR ^b , —OC (O) NR ^b R ^c , —NR ^b R ^c , —NR ^d OR ^c , —C (S) NR ^b R ^c , —NR ^d C (S) NR ^b R ^c , ^{-NR d C (O) NR b} R c, -OSH, -S (O) j R b, -OS (O) j R b ^{_{-SC (O) R b, -S}} (O) j C (O) OR b, -SCOR d, -NR d SR c, -SR b, -NHS (O) j R b, -COSR b, -C (O) S (O) _j R ^b , —CSR ^b , —CS (O) _j R ^b , —C (SO) OH, —C (SO) ₂ OH, —NR ^d C (S) R ^c , — ^{_{OC (S) R b, -OC}} (S) OH, -OC (SO) 2 R b, -S (O) j NR b R c, -SNR b R c, -S (O) NR b R c, —NR ^d CS (O) _j R ^c , —C (O) _j (CH ₂ ) _t NR ^d — (4 to 10-membered heteroaryl), —C (O) _j (CH ₂ ) _t NR ^d (4 to 10-membered _{^{heterocycloalkyl), - (CR d R e}} ) t CN, - (CR d R e) t (C 3 -C 10 cycloalkyl), - ^(CR d R ) _{T (C} 6 _{-C 10 ^{aryl), - (CR d R e}} ) t (4~10 membered _{^{heterocycloalkyl), - (CR d R e}} ) t (4~10 membered heteroaryl), - (CR ^d R ^e ) _q C (O) (CR ^d R ^e ) _t (C ₃ -C ₁₀ cycloalkyl), — (CR ^d R ^e ) _q C (O) (CR ^d R ^e ) _t (C ₆ -C ₁₀ Aryl), — (CR ^d R ^e ) _q C (O) (CR ^d R ^e ) _t (4 to 10-membered heterocycloalkyl), — (CR ^d R ^e ) _q C (O) (CR ^d R ^e ) _t (4 to 10 membered heteroaryl),-(CR ^d R ^e ) _t O (CR ^d R ^e ) _q (C ₃ -C ₁₀ cycloalkyl),-(CR ^d R ^e ) _t O (CR ^d R ^e ) _{q (C} 6 _{-C 10 ^{aryl), - (CR d R e}} ) t O (CR d R e) q (4-10 membered ^{_{heterocycloalkyl), - (CR d R e}} ) t O (CR d R e) q (4~10 membered ^{_{heteroaryl), - (CR d R e}} ) q SO 2 (CR d R e ) _T (C ₃ -C ₁₀ cycloalkyl), — (CR ^d R ^e ) _q SO ₂ (CR ^d R ^e ) _t (C ₆ -C ₁₀ aryl), — (CR ^d R ^e ) _q SO ₂ (CR ^d R ^e ) _t (4-10 membered heterocycloalkyl), and — (CR ^d R ^e ) _q SO ₂ (CR ^d R ^e ) _t (4-10 membered heteroaryl), wherein R ^a Selected from the group consisting of halo, hydroxyl, —NR ^d R ^e , C ₁ -C ₁₀ alkyl, haloalkyl, C ₁ -C ₆ alkoxyl, wherein R ^b and R ^c are independently H, C ₁ -C ₁₀ alkyl, - ^(CR d R ) _{T (C} 3 _{-C 10 ^{cycloalkyl), - (CR d R e}} ) t (C 6 -C 10 _{^{aryl), - (CR d R e}} ) t (4~10 membered heterocycloalkyl), and - ( CR ^d R ^e ) _t (4 to 10 membered heteroaryl), wherein R ^d and R ^e are independently H or C ₁ -C ₆ 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 ring portion of the R ¹⁰ group are unsubstituted or substituted with ═O; And alkyl, alkenyl, alkynyl, aryl and the ring portion of the R ¹⁰ group is unsubstituted or halo, ═O, cyano, nitro, — (CR ^d R ^e ) _t CN, haloalkyl, 2-10 membered hetero Alkyl, -OR ^{_{b, -C (O) j R}} b, -NR d C (O) R b, -C (O) NR b R c, -NR b R c, -NR b OR c, -NR d C (O) ^{_{j NR b R c, -NR d}} C (O) j R b R c, -OC (O) j R b, -OC (O) NR b R c, -SR d, C 1 -C 10 alkyl, C ₂ -C _{6 alkenyl,} C 2 -C _{6 ^{alkynyl, - (CR d R e)}} t (C 3 -C 10 _{^{cycloalkyl), - (CR d R e}} ) t (C 6 -C 10 aryl), - ( CR ^d R ^e) _t (4~10 membered _{^{heterocycloalkyl), - (CR d R e}} ) t (4~10 membered _{^{heteroaryl), - (CR d R e}} ) t (C 6 -C 10 aryl) - is substituted with 1-3 substituents independently selected from _(C 1 -C ₆ alkyl); where t ^{R b, R c, R d} , ^{R e} is as defined above].

  The present invention also relates to pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of the compounds of Formula I and pharmaceutically active metabolites thereof. An advantageous process for preparing the compounds of formula I has also been described.

であり、
ここで環Ｂは５または６員のヘテロシクロアルキル基であり、Ｚは２価のＣ（Ｏ）Ｚ’、ヘテロアリールまたはヘテロシクロアルキル基であり、ここでＺ’は２価のＯ、Ｓ、ＮＨ、Ｎ（ＣＨ_３）、ＣＯ_２、またはＣＨ_２であり、そしてＲ^６はＨまたはＣ_１−Ｃ_１０アルキル基であり、ここでＲ^３、Ｂ、およびＲ^６は置換されていないかまたは１〜４個のＲ^１０基で置換されており；
そしてここでＲ^１０は上記で定義したものである］に関する。 In preferred embodiments, the present invention provides compounds of formula I wherein n is 1 or 2; A is divalent —NH—Y—, —NR ^d (CH ₂ ) _t —Y—, or —O -Y- and Y is C (O) or S (O) ₂ ; X is a direct bond, CH ₂ , O, or S; R ¹ is unsubstituted or 1-4 be a _C 6 _{-C 10} aryl or 4-10 membered heteroaryl group is substituted with ^{R 10} groups; ^{R 2} is -S _(O) 2 OH or _{^{-P (O) (oR 4)}} 2, Where R ⁴ is H, a C ₁ -C ₁₀ alkyl, or a C ₆ -C ₁₀ aryl group and is unsubstituted or substituted with 1 to 4 R ¹⁰ groups; ³ _C 6 _{-C 10} aryl, 4-10 membered _{heteroaryl, -NH (C 6 H 5)} , or It is

And
Wherein ring B is a 5- or 6-membered heterocycloalkyl group, Z is a divalent C (O) Z ′, heteroaryl or heterocycloalkyl group, where Z ′ is a divalent O, S , NH, N (CH ₃ ), CO ₂ , or CH ₂ , and R ⁶ is H or a C ₁ -C ₁₀ alkyl group, where R ³ , B, and R ⁶ are unsubstituted Or substituted with 1 to 4 R ¹⁰ groups;
And here R ¹⁰ is as defined above].

であり、
ここで環Ｂは置換されていない６員ヘテロシクロアルキルであり、Ｚは２価のＣ（Ｏ）Ｚ’であり、Ｚ’は２価のＯ、Ｓ、またはＣＨ_２であり、そしてＲ^６はＣ_１−Ｃ_１０アルキル基であり、ここでＲ^３、ＢおよびＲ^６は置換されていないかまたは１〜４個のＲ^１０基で置換されており；そしてここでＲ^１０は上記で定義したものである］に関する。 In a particularly preferred embodiment, the present invention provides a compound of formula I wherein n is 1; A is divalent —NH—Y— or —O—Y—, wherein Y is C (O) There; X is a direct bond, be CH ₂ or O,; ^{R 1} is an _C 6 _{-C 10} aryl group substituted with unsubstituted or 1-4 ^{R 10} groups; ^{R 2} is -P (O) a ^(oR _{4) 2,} wherein ^{R 4} is _H, C 1 _{-C 10} alkyl or _C 6 _{-C 10} aryl group, and, or 1-4 unsubstituted of which is substituted with ^{R 10} groups; and ^{R 3} is _C 6 _{-C 10} aryl, 4-10 membered heteroaryl or,

And
Where Ring B is an unsubstituted 6-membered heterocycloalkyl, Z is divalent C (O) Z ′, Z ′ is divalent O, S, or CH ₂ , and R ⁶ Is a C ₁ -C ₁₀ alkyl group, wherein R ³ , B and R ⁶ are unsubstituted or substituted with 1 to 4 R ¹⁰ groups; and wherein R ¹⁰ is as defined above Is].

In a further particularly preferred embodiment, the present invention provides a compound of formula I wherein n is 1; A is —NH—Y— or —O—Y—, wherein Y is C (O);
X is a direct bond, CH ₂ , or O; R ¹ is a C ₆ -C ₁₀ aryl group that is unsubstituted or substituted with 1 to 4 R ¹⁰ groups; R ² is —P (O) (OR ⁴ ) ₂ , wherein R ⁴ is H or a C ₁ -C ₁₀ alkyl group that is unsubstituted or substituted with 1 to 4 R ¹⁰ groups; and R ³ is a C ₆ -C ₁₀ aryl or 4-10 membered heteroaryl group which is unsubstituted or substituted with 1 to 4 R ¹⁰ groups; and wherein R ¹⁰ is as defined above Is].

のグループから選択される化合物およびその薬学的に許容できる塩を含む。 Preferably, the present invention

And a pharmaceutically acceptable salt thereof.

  The present invention also provides for the administration of PIN1 by administering a compound of formula I or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt of such a compound or a metabolite thereof. It also relates to the inhibition method.

  The present invention also includes a therapeutically effective amount of a compound of formula I selected from compounds, prodrugs, metabolites and salts, and a medicament each comprising a pharmaceutically acceptable carrier or vehicle for such drug. Relates to the composition. The present invention is further a method of treating a mammalian disease state mediated by PIN1 activity, wherein a therapeutically effective amount of a compound, prodrug, active metabolite, or salt of a compound of formula I is required for such treatment. And a method comprising administering to the mammal. The pathology of mammals treated by the present invention is associated with hypertension, abnormal cell growth (eg, cancer), infections (eg, bacterial and fungal infections), and neurodegenerative brain diseases (eg, Alzheimer's disease).

  The compounds of formula I are useful for modulating or inhibiting PIN1. More particularly, the compounds are useful as providing treatment for hypertension, infections, neurodegenerative diseases, and diseases associated with cancer or cell proliferation by modulating or inhibiting PIN1 activity. .

  The terms “including” and “containing” are used herein in an unlimited and non-limiting sense.

As used herein, “abnormal cell growth” includes diseases or disorders that are not controlled, ie, associated with abnormal cell growth. Such diseases / disorders include, but are not limited to: lung cancer, osteosarcoma, pancreatic cancer, skin cancer, head or neck cancer, skin melanoma or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, Anal cancer, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, vice Thyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphoma, bladder cancer, renal cancer or ureteral cancer, renal cell cancer, renal pelvis cancer, central nervous system (CNS) new Various cancers including but not limited to organisms, primary central nervous system malignant lymphomas, spinal vertebral tumors, brainstem gliomas, pituitary adenomas, or combinations of one or more of the foregoing cancers;
Benign prostatic hypertrophy, familial adenomatosis, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis after angioplasty or vascular surgery, hypertrophic scar formation, inflammation Disease processes characterized by abnormal cell growth, such as sexual bowel disease, transplant rejection, endotoxic shock, fungal infections; and diseases associated with apoptotic abnormalities such as, but not limited to, the types listed above Viral infection (including but not limited to HIV, human papillomavirus, herpes virus, poxvirus, EB virus, Sindbis virus and adenovirus), prevention of AIDS in HIV-infected patients, autoimmune disease ( Without limitation, systemic lupus erythematosus, rheumatoid arthritis, psoriasis, autoimmune glomerulonephritis, Intestinal diseases and autoimmune diabetes), neurodegenerative diseases (including but not limited to Alzheimer's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, Parkinson's disease, AIDS-related dementia, spinal muscle Atrophy and cerebellar degeneration), myelodysplastic syndrome, aplastic anemia, ischemic injury associated with myocardial infarction, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxicogenic or alcoholic liver disease , Blood disorders (including but not limited to chronic anemia and aplastic anemia), musculoskeletal degenerative disorders (including but not limited to osteoporosis and arthritis), aspirin-sensitive nasal accessory Includes rhinitis, cystic fibrosis, multiple sclerosis, kidney disease, and cancer pain.

As used herein, the term “alkyl” refers to a linear or branched, saturated or partially unsaturated alkyl group having 1 to 12 carbon atoms. Preferred alkyl groups have 1 to 10 and more preferred alkyl groups have 1 to 7 carbon atoms. Typical alkyl groups are methyl (Me, which can also be represented by “/” in the structural formula), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu). , Pentyl, isopentyl, tert-pentyl, hexyl, isohexyl and the like. The term “lower alkyl” refers to an alkyl having 1 to 6 carbon atoms (C ₁ -C ₆ alkyl).

  The term “aryl” (Ar) is monocyclic or fused or spiro having 3 to 12 ring atoms, preferably 6 to 10 ring atoms, and more preferably 5 to 7 ring atoms per ring. Polycyclic aromatic carbocycles (ring structures having ring atoms that are all carbon).

Specific examples of aryl groups include the following moieties:

The term “heteroaryl” (heteroAr) is monocyclic or fused cyclic having from 3 to 12 ring atoms per ring, preferably 4 to 10 ring atoms, and more preferably 5 to 7 ring atoms. Alternatively, it refers to a spiro polycyclic aromatic heterocycle (a ring structure containing a carbon atom and a ring atom selected from nitrogen, oxygen and sulfur heteroatoms). Specific examples of aryl groups include the following moieties:

The term “cycloalkyl” is a saturated or partially unsaturated monocyclic or fused ring having 3 to 12 ring atoms, preferably 3 to 10 carbon atoms, and more preferably 5 to 7 carbon atoms per ring. Refers to a formula or spiro polycyclic carbocycle. Specific examples of cycloalkyl groups include the following moieties:

“Heterocycloalkyl” is a saturated or partially unsaturated monocyclic, or fused or spiro polycyclic ring structure, 3 per ring selected from C atoms and N, O, and S heteroatoms. Refers to those having ~ 12 atoms, preferably 4-10 ring atoms, and more preferably 5-7 ring atoms. Specific examples of heterocycloalkyl groups include:

  The term “alkoxy” refers to —O-alkyl. Specific examples include methoxy, ethoxy, propoxy.

  The term “halogen” refers to chlorine, fluorine, bromine or iodine. The term “halo” represents chloro, fluoro, bromo or iodo.

  As used herein, “haloalkyl” refers to a lower alkyl group in which one or more hydrogen atoms have been replaced by a halogen, including but not limited to chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl, and the like. .

  “Heteroalkyl” is an alkyl group (as described herein) in which at least one of the carbon atoms has been replaced by a heteroatom. Preferred heteroatoms are nitrogen, oxygen, sulfur and halogen. Although not common, heteroatoms can have as many valence sites as carbon. Thus, when the carbon is replaced by a heteroatom, the number of hydrogens attached to the heteroatom may need to be increased or decreased to match the number of valence sites on the heteroatom. For example, if carbon (valence 4) is replaced by nitrogen (valence 3), one of the hydrogens attached to the carbon to be replaced must be removed. Similarly, when a carbon is substituted with a halogen (valence 1), the three (ie, all) hydrogens attached to the substituted carbon must be removed. As another example, trifluoromethyl is a heteroalkyl group in which three methyl groups of a t-butyl group are substituted with fluorine. Preferred heteroalkyls of the present invention have 2 to 10 membered atoms including both heteroatoms and carbon atoms.

  The term “substituted” means that the specified group or moiety bears one or more substituents. The term “unsubstituted” means that the specified group has no substituent.

The compounds of the present invention may exhibit a tautomeric phenomenon. Although Formula I cannot clearly depict all possible tautomers, Formula I represents all tautomers of the depicted compounds and is intended to illustrate certain compounds depicted by the structural formula It should be construed that it is not limited to types only. A compound of formula I can have one or more asymmetric centers designated by an asterisk, as shown in formula I below. Based on the nature of various substituents on the molecule, there can be additional asymmetric centers on the molecule.

  As a result of these asymmetric centers, the compounds of formula I are single stereoisomers (ie essentially free of other stereoisomers), racemates, and / or enantiomers and / or diastereomers. It can exist as a mixture. All such single stereoisomers, racemates and mixtures thereof are within the scope of the invention. Preferably, the optically active compounds of the present invention are used in optically pure form.

は、中心部または骨格構造への部分または置換基の結合個所である結合を描くために用いられている。 Based on convention in the art, in the structural formulas herein

Is used to describe a bond that is the point of attachment of a moiety or substituent to a central or skeletal structure.

  As is generally understood by those skilled in the art, an optically pure compound having one chiral center (ie, one asymmetric carbon atom) is essentially one of two possible enantiomers. An optically pure compound consisting of (ie enantiomerically pure) and having two or more chiral centers is a diastereomerically pure and enantiomerically pure compound. Preferably, the compounds of the invention are in at least 90% optically pure form, i.e. containing at least 90% of a single isomer (80% enantiomeric excess ("ee")) or diastereomers Excess ("de")), more preferably at least 95% (90% ee or de), even more preferably at least 97.5% (95% e) Ee) or most preferably at least 99% (98% ee or de).

  Furthermore, Formula I is directed to solvated forms as well as unsolvated forms of the specified structure. For example, Formula I includes compounds of the structure shown in 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 compounds of Formula I, the present invention includes such compounds, pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts and metabolites.

  A “pharmaceutically acceptable prodrug” is a compound that can be converted into a specific compound or a pharmaceutically acceptable salt of such a compound by transformation or solvolysis under physiological conditions.

  “Pharmaceutically active metabolite” means a pharmacologically active product produced by metabolism in the body of a specific compound or salt thereof.

Prodrugs and active metabolites of the compounds can be identified using conventional methods known in the art. For example, Bertolini et al., J. Med. Chem., 40,
2011-2016 (1997); Shan et al., J. Pharm. Sci., 86 (7), 765-767; Bagshawe, Drug Dev.
Res., 34, 220-230 (1995); Bodor, Advances in Drug Res., 13, 224-331 (1984);
Bundgaard, Design of Prodrug (Elsevier Press 1985); Larsen, Design and
Application of Prdrugs, Drug Design and Development (Krogsgaard-Larsen et al., Eds., Harwood Academic Publishers,
1991); Dear et al., J. Chromatogr. B, 748, 281-293 (2000); Spraul et al., J. Pharmaceutical
& Biomedical Analysis, 10, 601-605 (1992); and Prox et al., Xenobiol., 3, 103-112
(1992).

  "Pharmaceutically acceptable salt" means a salt that retains the biological effectiveness of the free acids and free bases of a particular compound and does not have biologically or otherwise undesirable properties. The compounds of the present invention can have sufficiently acidic, sufficiently basic or both functional groups and thus react with many inorganic or organic bases and any of inorganic and organic acids and pharmaceutically acceptable salts. Can be formed. Exemplary pharmaceutically acceptable salts include those prepared by reaction of a compound of the present invention with an inorganic or organic acid or inorganic base, such as sulfate, pyrosulfate, bisulfate, Sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, Caprylate, acrylate, formate, isobutyrate, caprate, heptanoic acid, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, Maleate, Butyne-1,4-Diate, Hexin-1,6-Diate, Benzoate, Chlorobenzoate, Methylbenzoate, Dinitrobenzoate, Hydroxybenzoate, Methoxybenzoate Acid salt, phthalic acid , Sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, g-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propane Sulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate are included.

  When the compound of the present invention is a base, the desired pharmaceutically acceptable salt can be prepared using any suitable method available in the art, including, for example, the free base and an inorganic acid (eg, hydrochloric acid, odor Hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or organic acids (eg acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, glucuronic acid or galacturonic acid Such as pyranosidic acid, α-hydroxy acids such as citric acid or tartaric acid, amino acids such as aspartic acid or glutamic acid, aromatic acids such as benzoic acid or cinnamic acid, sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid) It can manufacture by processing with.

  When the compound of the present invention is an acid, the desired pharmaceutically acceptable salt can be prepared using any suitable method available in the art, but free acids and inorganic or organic bases such as amines (primary, (Secondary or tertiary), alkali metal hydroxide, alkaline earth metal hydroxide, or the like. Specific examples of suitable salts include amino acids (such as glycine and arginine), ammonia, primary, secondary, and tertiary amines, and cyclic amines (such as piperidine, morpholine, and piperazine), and sodium, calcium, potassium, magnesium, Contains inorganic salts derived from manganese, iron, copper, zinc, aluminum and lithium.

  In the case of a drug that is a solid, it will be appreciated by those skilled in the art that the compounds and salts of the present invention can exist in various crystalline or polymorphic forms, all of which are within the scope and specific formula of the present invention. .

  Lu et al. (International Publication No. WO01 / 38878; all incorporated herein by reference) discloses that PIN1 is overexpressed in various cancers including breast cancer, colon cancer, and prostate cancer. . In addition, the authors disclose that PIN1 is overexpressed in proliferating cells. Therefore, the agent of the present invention is considered useful for the treatment of various cell proliferative diseases associated with overexpression of PIN1.

  A therapeutically effective amount of an agent of the invention can be used to treat a disease mediated by PIN1 modulation or control. “Effective amount” means an amount of an agent that, when administered to a mammal in need of such treatment, is sufficient to effect treatment of a disease that is modulated or inhibited by PIN1 activity. Thus, for example, a therapeutically effective amount of a compound of formula I, salt, active metabolite or prodrug thereof modulates, regulates or inhibits PIN1 activity to reduce or alleviate the pathology mediated by PIN1 activity. Say enough amount to.

The amount of a given agent corresponding to such an amount will vary depending on the compound used, the condition and its severity, and the individual data (eg, body weight) of the mammal in need of treatment, but can be routinely determined by one skilled in the art. The term “treatment” is:
(I) preventing the occurrence of the disease, disorder and / or condition in an animal that may be susceptible to the disease, disorder and / or condition but has not yet been diagnosed;
(Ii) suppression of the disease, disorder, or condition, ie, suppression of its onset; and (iii) alleviation of the disease, disorder, or condition, ie, regression of the disease, disorder, and / or condition;
Means.
Detailed Description of the Invention and Preferred Embodiments

  The active ingredients of the present invention can be formulated into pharmaceutical compositions as described below. The pharmaceutical compositions of the invention comprise an effective amount of a compound of formula I that modulates, regulates or inhibits, and an inert, pharmaceutically acceptable carrier or diluent. In one embodiment of the pharmaceutical composition, an effective level of an agent of the present invention is provided such that a therapeutic benefit comprising a modulation of PIN1 is obtained. “Effective level” means a level at which the effect of PIN1 activity is controlled to a minimum. These compositions can be produced in unit dosage forms suitable for administration methods such as parenteral or oral administration.

  Inventive agents are prepared by conventional procedures, by mixing a therapeutically effective amount of the agent as an active ingredient (eg, a compound of formula I) with a suitable pharmaceutical carrier or diluent by conventional procedures. Can be administered in formulation. These procedures can include mixing, granulating and compressing or dissolving the ingredients, depending on the desired formulation.

  The pharmaceutical carrier used may be either solid or liquid. Typical examples of solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid and the like. Typical examples of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may be a time delay or time release material known in the art using glyceryl monostearate or glyceryl distearate, alone or in combination with wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate, and the like. Can be included.

  Various pharmaceutical dosage forms can be used. Thus, if a solid carrier is used, the preparation can be tableted, powdered or pelleted in a hard gelatin capsule, or in the form of a troche or lozenge. The amount of solid carrier can vary, but generally will be from about 25 mg to about 1 g. When a liquid carrier is used, the formulation can be in the form of a syrup, emulsion, soft gelatin capsule, sterile injection solution or suspension in an ampoule or vial, or a non-aqueous liquid suspension.

  In order to obtain a stable, water-soluble dosage form, a pharmaceutically acceptable salt of the inventive agent is dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3 M solution of succinic acid or citric acid. If a soluble salt form is not obtained, the drug can be dissolved in a suitable co-solvent or combination of co-solvents. Examples of suitable co-solvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like at concentrations ranging from 0-60% of the total volume. In an exemplary embodiment, the compound of formula I is dissolved in DMSO and diluted with water. The composition can also be in the form of a salt form solution of the active ingredient in a suitable aqueous vehicle such as water or isotonic saline or dextrose solution.

  The actual dosage of agents used in the compositions of the invention will vary according to the particular complex used, the particular composition formulated, the method of administration and the particular site, host and disease being treated. It will be understood that One of ordinary skill in the art can ascertain the optimal dosage for a particular set of diseases using routine dosage determination studies in view of experimental data regarding the drug. For oral administration, a typical daily dose commonly used is from about 0.001 to about 1000 mg / kg body weight (kg) with repeated courses of treatment at appropriate intervals. Prodrug administration is generally administered at a weight level that is chemically equivalent to the fully active form of the body weight level.

  The compositions of the present invention are generally known methods for the manufacture of pharmaceutical compositions using conventional techniques such as, for example, mixing, dissolving, granulating, sugar-coating, grinding, emulsifying, incorporating or lyophilizing. Can be manufactured. The pharmaceutical composition can be formulated in a conventional manner using one or more physiologically acceptable carriers, which can be selected from excipients and co-agents that facilitate the processing of the active compound into a pharmaceutically acceptable formulation. .

  Proper formulation is dependent upon the route of administration chosen. For injection, the agents of the invention can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be passed are used in the formulation. Such penetrants are generally known in the art.

  For oral administration, the compounds can be formulated readily by mixing the active compound with a pharmaceutically acceptable carrier known in the art. Such carriers enable the compounds of the present invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral intake by the patient being treated. Formulations for oral administration can be obtained using solid excipients mixed with an active ingredient (drug). If desired, the resulting mixture is pulverized and, if necessary, an appropriate auxiliary agent is added, and then the mixture of granules is processed to obtain a tablet or dragee core. Suitable excipients are: fillers such as sugars including lactose, sucrose, mannitol, or sorbitol; and corn starch, wheat starch, rice starch, potato starch, gelatin, gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose Cellulose products such as, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents can be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

  Dragee cores can be provided with suitable coatings. For this purpose, a concentrated sugar solution can be used, if desired, such as gum arabic, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer liquid, and appropriate Various organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active ingredients.

  Formulations that can be used for oral administration include push-fit capsules made of gelatin and soft sealed capsules made of gelatin, as well as a plasticizer, such as glycerol or sorbitol. Push-in capsules can contain active ingredients mixed with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active ingredient can be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers can be added. All formulations for oral administration should be used in dosages suitable for such administration. For buccal administration, the composition can take the form of tablets or lozenges formulated in conventional manner.

  For intranasal or inhalation administration, the compounds for use according to the invention use a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas Conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Gelatin capsules and cartridges for use in inhalers or insufflators can be formulated to contain a powder mixture of the compound and a suitable powder base, such as lactose or starch.

  The compounds can be formulated for parenteral administration, eg, by injection such as bolus injection or continuous infusion. Injectable preparations may be presented in unit dosage form, eg, in ampoules or multi-dose containers, with an added preservative. The composition can take the form of a suspension, solution or emulsion in an oily or aqueous vehicle and can contain pharmaceutical 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. Furthermore, the active ingredient suspension can be formulated as an oily injection suspension, if desired. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. If desired, the suspension can also include suitable stabilizers or agents that allow for the preparation of highly concentrated solutions by increasing the solubility of the compound.

  Alternatively, the active ingredient can be in powder form for reconstitution with a suitable vehicle, such as sterile pyrogen-free water, before use. The compounds can also be formulated in rectal compositions such as suppositories or retention enemas, eg containing conventional suppository bases such as cocoa butter or other glycerides.

  In addition to the aforementioned formulations, the present compounds can also be formulated as a depot formulation. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated using suitable polymers or hydrophobic substances (eg, as acceptable emulsions in oil) or ion exchange resins, or as slightly soluble derivatives such as slightly soluble salts.

  A typical pharmaceutical carrier for hydrophobic compounds is a co-solvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous layer. The co-solvent system can be a VPD co-solvent system. VPD is a solution made up to absolute volume in absolute ethanol in 3% w / v benzyl alcohol, 8% w / v nonpolar surfactant polysorbate 80, and 65% w / v polyethylene glycol 300. The VPD co-solvent system (VPD: 5W) contains VPD diluted with a 5% aqueous solution of dextrose. This co-solvent system dissolves hydrophobic compounds well and itself exhibits low toxicity upon systemic administration. Of course, the ratio of the co-solvent system can be varied greatly without changing the solubility and toxicity characteristics. In addition, the type of co-solvent component can be changed: for example, other low toxicity non-polar surfactants can be used in place of polysorbate 80; the fraction size of polyethylene glycol can be changed; Can be replaced with polyethylene glycol; dextrose can be replaced with other sugars or polysaccharides.

  Alternatively, other delivery systems for hydrophobic drugs can be used. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethyl sulfoxide can also be used, but are usually associated with greater toxicity. Additionally, the compounds can be delivered using sustained release systems, such as semi-permeable matrices of solid hydrophobic polymers containing therapeutic agents. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained release capsules can release compounds over several weeks up to over 100 days, depending on their chemical nature. Depending on the chemical and biological properties of the therapeutic agent, additional strategies for protein stabilization can be used.

  The pharmaceutical composition can also include a suitable solid or gel phase carrier or excipient. Examples of such carriers or excipients include polymers such as calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives, gelatin, and polyethylene glycol.

  Some of the compounds of the present invention can be provided as salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts can be formed with many acids, including hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid and the like. Salts tend to be more soluble in aqueous or other protic solvents than their corresponding free base forms.

  The agents of the present invention can be prepared using readily available starting materials and the general reaction techniques known in the art using the following reaction pathways and synthetic schemes. The preparation of the preferred compounds of the present invention is described in detail in the examples below, but it should be noted that the described chemical reactions are readily applicable to the manufacture of many other PIN1 inhibitors of the present invention. Those skilled in the art will understand. For example, the synthesis of unillustrated compounds according to the present invention may involve, for example, appropriately protecting interfering groups, changing to other suitable reagents known in the art, or routine modification of reaction conditions, etc. Can be successfully implemented with modifications apparent to those skilled in the art. Alternatively, it will be appreciated that other reactions described herein or known in the art have applicability in the preparation of other compounds of the invention.

  In the following examples, all temperatures are given in degrees Celsius (° C.) and all parts and percentages are given by weight unless otherwise specified. Reagents are available from Aldrich Chemical Company or Lancaster Synthesis Ltd. Unless otherwise specified, it was used without further purification. Tetrahydrofuran and N, N-dimethylformamide were purchased from Aldrich in Sure Seal bottles and used as received. Unless otherwise noted, all solvents were purified using standard methods known to those skilled in the art.

  In general, reactions were conducted in anhydrous solvents at ambient temperature (unless otherwise noted) and under a positive pressure of argon, and the reaction flask was equipped with a rubber septum for introducing substrate and reagents via a syringe. Glassware was oven dried and / or heat dried. Thin layer chromatography (TLC) analysis was performed using Analtech glass-lined silica gel 60F254 plates (0.25 mm) and eluted at the appropriate solvent ratio (v / v) (shown where appropriate). The reaction was analyzed by TLC and completed as judged by consumption of starting material.

Visualization of the TLC plate was carried out using iodine vapor, ultraviolet irradiation, 2% Ce (NH ₄ ) ₄ (SO ₄ ) ₄ in 20% sulfuric acid aqueous solution, or p-anisaldehyde spray reagent and heat-activated as necessary. went. The post-treatment was generally doubled with the reaction solvent or extraction solvent and then washed with the indicated aqueous solution at a volume of 25% of the extraction volume unless otherwise stated. The product solution was filtered and dried over anhydrous Na ₂ SO ₄ and / or Mg ₂ SO ₄ before the solvent was distilled off using a rotary evaporator under reduced pressure and the solvent was noted removed under reduced pressure. . Unless otherwise stated, flash column chromatography (Still et al., J. Org. Chem., 43, 2923) using Merck silica gel (47-61 μm) at a silica gel to crude product ratio of about 20: 1 to 50: 1. 1978)). Hydrocracking was carried out at the pressure described in the examples or at ambient pressure. All melting points (mp) are uncorrected.

¹ H-NMR spectra were measured and recorded at 300 MHz using a Bruker or Varian instrument, and ¹³ C-NMR spectra were measured and recorded at 75 MHz. NMR spectra are based on chloroform (7.27 ppm and 77.00 ppm) or CD ₃ OD (3.4 and 4.8 ppm and 49.3 ppm) reference standards, or, where appropriate, tetramethylsilane (0.00 ppm). Was used as an internal standard and was obtained with CDCl ₃ solution (recorded in ppm). Other NMR solvents were used as needed. The following abbreviations are used to indicate peak multiplicity: s (single line), d (double line), t (triple line), q (quadruple line), m (multiple line), br (spread) ), Dd (double double line), dt (triple double line). The resulting coupling constant is shown in hertz (Hz).

Infrared (IR) spectra were recorded using a Perkin-Elmer FT-IR spectrometer with neat oil, KBr pellets, or CDCl ₃ solution. The obtained spectrum is indicated by wave number (cm ⁻¹ ).

  Mass spectrometry (MS) was performed using various techniques. Mass spectra were obtained using liquid chromatography / electrospray ionization mass spectrometry MS (ESP). Matrix-assisted laser desorption / ionization (MALDI) Fourier transform mass spectrometry was performed using an IonSpec FTMS mass spectrometer.

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The following compounds of the present invention were prepared according to the general synthetic routes shown in Schemes 1-10 and the detailed experimental procedures that follow. These synthetic routes and experimental procedures include THF (tetrahydrofuran), DMF (N, N-dimethylformamide), EtOAc (ethyl acetate), DBU (1,8-diazacyclo [5.4.0] undec-7-ene. ), TMSCl (trimethylsilyl chloride), MCPBA (3-chloroperbenzoic acid), EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), HOBT (1-hydroxybenzotriazole hydrate), Uses many common abbreviations such as DMAP (4-dimethylaminopyridine), TBDPSCl (t-butyldiphenylchlorosilane), TMSBr (bromotrimethylsilane), DIEA (diisopropylethylamine), TBAI (tetrabutylammonium iodide) .

Alcohol 2a

D-phenylalaninol (0.151 g, 1 mmol) was added to a pyridine solution (1 mL) of sulfamoyl chloride 1a (0.14 g, 0.5 mmol, the production method is described in International Publication No. WO01414085) at 25 ° C. It was. After 12 hours, the reaction mixture was concentrated under reduced pressure. The yellow residue was purified by flash column chromatography (25% ethyl acetate (EtOAc) in hexane) and then purified by preparative TLC to give 70 mg (33% yield) of compound 2a. ¹ H NMR (CDCl ₃ ): δ 7.24-7.0 (10H, m), 4.89 (2H, AB), 4.70 (1H, d, J = 8.7 Hz), 4.25 (1H , Dd, J = 8.7, 3.6 Hz), 3.54 (2H, m), 3.28 (1H, m), 3.04 (2H, m), 2.66 (2H, d, J = 6.6 Hz), 2.33 (1H, m), 2.01 (1 H, m); HRMS (FAB): calculated as C ₂₁ H ₂₇ N ₂ O ₅ S (M + H ⁺ ) 419.1642; Value 419.1629.
(Example 3a)
1- (2-Phenyl-1-sulfooxymethyl-ethylsulfamoyl) -pyrrolidine-2S-carboxylic acid benzyl ester

At −70 ° C., triethylamine (Et ₃ N, 0.05 mL) and chlorosulfonic acid (8 mg, 5 μl, 0.068 mmol) were added to a solution of alcohol 2a (10 mg, 0.024 mmol) in methylene chloride (2 mL). The cooling bath was then removed and the reaction mixture was warmed to 25 ° C. over 3 hours. All solvents were distilled off under reduced pressure. The residue was purified by column chromatography (3% methanol (MeOH) in EtOAc) to give 8 mg (67% yield) of the title compound 3a. ¹ H NMR (CD ₃ OD): δ 7.4-7.15 (10H, m), 5.16 (2H, AB), 4.22 (1H, dd, J = 8.7, 3.9 Hz), 4.04 (1H, dd, J = 10.2, 4.8 Hz), 3.91 (1H, dd, J = 10.2, 4.5 Hz), 3.77 (1H, m), 3.38 (1H, 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 (1H, m), 1.97-1.73 (3H, m); MS (ESP): 497 (M−H ⁺ ); HRMS (FAB): C ₂₁ H ₂₆ N ₂ O Calculated 521.1028 as ₈ S ₂ Na (M + Na ⁺ ); found 521.010.
Alcohol 2b1

Synthesis of 2a using n-butyl-phenyl ester of sulfamoyl chloride 1a (0.15 g, 0.42 mmol, production method described in International Publication No. WO0141405) and D-phenylalaninol (0.18 g, 1.2 mmol) And was prepared as described in After purification by flash column chromatography (25% EtOAc in hexane), compound 2b1 (62 mg) was obtained in 31% yield. ¹ H NMR (CDCl ₃ ): δ 7.4-7.1 (10H, m), 5.17 (1H, d, J = 8.1 Hz), 4.68 (1H, d, J = 4.5 Hz) 4.20 (2H, m), 3.75 (2H, m), 3.55 (1H, m), 3.35 (1H, brd, J = 12.1 Hz), 2.95-2. 73 (3H, m), 2.67 (2H, m), 2.45 (1H, br s), 2.24 (1H, d, J = 13.1 Hz); HRMS (FAB): C ₂₅ H _{34 N 2 O 5 SNa (M +} Na +) calculated 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 μl, 0.055 mmol) and triethylamine (0.015 mL). The reaction mixture was diluted with EtOAc (20 mL) and washed with ice-cold 5% hydrochloric acid (HCl) solution (1 × 20 mL). Column chromatography (8% MeOH in EtOAc) gave 10 mg (85% yield) of the title compound 3b1. ¹ H NMR (CDCl ₃ ): δ 7.3-6.9 (10H, m), 6.03 (1H, brs), 4.26 (2H, m), 4.05 (2H, m), 3 .93 (1H, br s), 3.58 (1H, br s), 3.13 (1H, m), 2.79 (3H, m), 2.48 (2H, m), 2.30 ( _{1H, m), 1.88 (1H} , m); HRMS (FAB): C 25 H 33 N 2 O 8 S 2 Cs 2 (M-H + + 2Cs +) calculated 818.9787; found 818. 9756.
Alcohol 2b2

As described in the synthesis of 2a using sulfamoyl chloride 1b2 (0.15 g, 0.47 mmol, production method described in International Publication No. WO0141405) and D-phenylalaninol (0.214 g, 1.4 mmol). Manufactured. After purification by flash column chromatography (25% -30% EtOAc in hexane), compound 2b2 (66 mg) was obtained in 33% yield. ¹ H NMR (CDCl ₃ ): δ 7.4-7.17 (10H, m), 5.19 (2H, AB), 5.03 (1H, d, J = 8.4 Hz), 4.71 (1H , Br d, J = 4.8 Hz), 3.8-3.6 (2H, m), 3.48 (1H, m), 3.31 (1H, br d, J = 12.6 Hz), 2 88-2.74 (3H, m), 2.34 (1 H, br t, J = 5.1 Hz), 2.25 (1 H, 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 μl, 0.13 mmol) and triethylamine (0.05 mL). The reaction mixture was diluted with EtOAc (20 mL) and washed with ice-cold 5% HCl solution (1 × 20 mL). Column chromatography purification (5% MeOH in EtOAc) gave 25 mg (70% yield) of the title compound 3b2. ¹ H NMR (CDCl ₃ ): δ 7.31-7.01 (10H, m), 6.03 (1H, 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): C 22 H 27 N 2 O 8 S 2 Na 2 Calculated 557.1004 as (M−H ⁺ + 2Na ⁺ ); found 557.1019.
Alcohol 2b3

Use sulfamoyl chloride 1b3 (0.05 g, 0.105 mmol, production method described in International Publication No. WO0141405) and D-phenylalaninol (0.026 g, 0.17 mmol) as described in the synthesis of 2a. Manufactured. After purification by flash column chromatography (25% -30% EtOAc in hexane), compound 2b3 (30 mg) was obtained in 48% yield. ¹ H NMR (CDCl ₃ ): δ 7.35-7.09 (15 H, m), 5.07 (1 H, d, J = 7.8 Hz), 5.02 (1 H, m), 4.64 (1 H , Br d, J = 4.5 Hz), 3.69 (2H, m), 3.47 (1 H, m), 3.30 (1 H, br d, J = 12.6 Hz), 2.84 (2H , D, J = 7.2 Hz), 2.80 (1H, 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-sulfooxymethyl-ethylsulfamoyl) -piperidine-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 μl, 0.068 mmol) and triethylamine (0.05 mL). The reaction mixture was diluted with EtOAc (20 mL) and washed with ice-cold 5% HCl solution (1 × 20 mL). Column chromatography purification (5% MeOH in EtOAc) gave 8 mg (70% yield) of the title compound 3b3. ¹ H NMR (CDCl ₃ ): δ 7.36-7.00 (15H, m), 6.06 (1H, br d, J = 7.5 Hz), 4.90 (1H, m), 4.31 ( 1H, br d), 4.20 (1 H, br s), 4.06 (1 H, m), 3.66 (1 H, m), 3.34 (1 H, br d, J = 11.1 Hz), 2.85 (3H, m), 2.51 (4H, m); HRMS (FAB): calculated as C ₃₄ H ₄₃ N ₂ O ₈ S ₂ Cs ₂ (M−H ⁺ + 2Cs ⁺ ) 937.0570; Found 937.0557.
Synthesis of benzyl esters

To a mixture of L-penicillamine (14.92 g), 1,2-dichloroethane (300 mL) and DMF (2 mL) at 0 ° C., 1,8-diazacyclo [5.4.0] undec-7-ene (DBU, 22.4 mL) was added followed by trimethylsilyl chloride (TMSCl, 19 mL). After stirring for 3 hours, the solution was warmed to 25 ° C. and then DBU (29.9 mL) was added slowly. The reaction mixture was stirred at 25 ° C. for 17 hours. Methanol (10 mL) was added to form a precipitate. The precipitate was collected by filtration and washed with a minimum amount of methanol. The solid was dried at 50 ° C. under reduced pressure for 6 hours to obtain 3 (R) -2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxylic acid as a white powder (16 g). At 0 ° C., a portion of thiazine (0.4 g, 2.3 mmol) was dissolved in NaOH solution (1N, 12 mL). To the resulting mixture was added benzyl chloroformate (1.4 mL, 9.2 mmol). After 15 hours at 25 ° C., the solution was diluted with water (20 mL) and extracted with EtOAc (2 × 25 mL). The extract was dried (MgSO ₄ ) and concentrated under reduced pressure. Purification by flash column chromatography (15-20% EtOAc in hexane) gave 0.63 g of the title compound 3b3. ¹ H NMR (CDCl ₃ ): (mixture of two rotamers) δ 7.3 (10H, 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 (1H, 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

To a methylene chloride solution (2 mL) of benzyl ester (0.6 g, 1.5 mmol), methyl sulfide (1 mL) and BF ₃ .Et ₂ O (0.2 mL) were added at 0 ° C. After 16 hours, saturated NaHCO ₃ solution (5 mL) was added to the reaction mixture and extracted with methylene chloride (2 × 20 mL). The combined organic layers were washed with brine (1 × 25 mL) and dried (Na ₂ SO ₄ ). All solvent was removed under reduced pressure to give a pale yellow oil (0.35 g), which was dissolved in methylene chloride (8 mL). To the resulting solution, triethylamine (1 mL) and ClSO ₃ H (0.23 g, 1.97 mmol) were slowly added. The mixture was allowed to reach about 25 ° C. and stirred at that temperature for about 2 hours. The solution was then concentrated under reduced pressure, after which benzene (2 × 15 mL) was added and distilled off to remove traces of Et ₃ N and water. To the residue was added benzene (20 mL) and PCl ₅ (0.41 g, 1.97 mmol). The suspension was heated under reflux conditions for about 30 minutes, then cooled to about 25 ° C. and poured into ice-cold NaOH solution (5%, 40 mL). The aqueous mixture was extracted with CH ₂ Cl ₂ (3 × 30 mL), dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (3% EtOAc in hexane) to give 0.355 g (74%) of compound 1b4. Amine: ¹ H NMR (CDCl ₃ ): δ 7.4-7.3 (5H, m), 5.14 (2H, AB), 3.75 (1H, s), 3.38 (1H, 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 ): δ7. 43-7.29 (5H, m), 5.22 (2H, AB), 4.53 (1H, s), 4.24-4.05 (2H, m), 3.17 (1H, dd, J = 11.7, 4.5 Hz), 3.13 (1H, dd, J = 11.7, 4.8 Hz), 2.56 (1H, 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 mmol) and D-phenylalaninol (0.166 g, 1.1 mmol). After purification by flash column chromatography (25% -30% EtOAc in hexane), compound 2b4 (10 mg) was obtained in 4% yield. ¹ H NMR (CDCl ₃ ): δ 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 (1H, 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)
3,3-Dimethyl-1- (2-phenyl-1-sulfooxymethyl-ethylsulfamoyl) -piperidine-2R-carboxylic acid benzyl ester

Prepared as described in the synthesis of 3a using alcohol 2b4 (6 mg, 0.0126 mmol), chlorosulfonic acid (6 mg, 4 μl, 0.04 mmol) and triethylamine (0.04 mL). The reaction mixture was diluted with EtOAc (20 mL) and washed with ice-cold 5% HCl solution (1 × 20 mL). Column chromatography purification (5% MeOH in EtOAc) gave 3 mg (43% yield) of the title compound 3b4. ¹ H NMR (CDCl ₃ ): δ 7.34-7.06 (10H, m), 5.04 (2H, s), 4.23 (1H, s), 3.89 (1H, dd, J = 9) .9, 4.2 Hz), 3.82 (1H, dd, J = 9.9, 5.1 Hz), 3.59 (1H, td, J = 12.9, 3 Hz), 3.52-3. 33 (2H, m), 2.88 (1H, dd, J = 14.1, 6.8 Hz), 2.64 (1H, dd, J = 14.1, 7.5 Hz), 2.53 (1H , Td, J = 12.8, 4.2 Hz), 2.13 (1H, dt, J = 14.1, 2.4 Hz), 1.37 (3H, s), 1.09 (3H, s) ; MS (ESP): 557 ( M-H -).
Phosphoric acid benzyl ester 4b1

Dibenzyl N, N-diisopropyl phosphoramidite (27.3 mg, 0.079 mmol) was added to a solution of alcohol 2b1 (25 mg, 0.0527 mmol) and 1H-tetrazole (7.4 mg, 0.105 mmol) in acetonitrile (7 mL) at 25 ° C. ) Was added. After 1 hour, 3-chloroperbenzoic acid (MCPBA, 34 mg, 70% purity, 0.139 mmol) was added to the suspension. The solution was diluted with ether (40 mL), washed with concentrated NaHSO ₃ solution (2 × 30 mL), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC to give 29.5 mg of compound 4b1 in 76% yield. ¹ H NMR (CDCl ₃ ): δ 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 (1 H, m), 2.54 (2 H, m), 2.10 (1 H, d, J = 13.5 Hz); HRMS (FAB): C ₃₉ H ₄₇ N ₂ Calculated 867.1845 as O ₈ PSCs (M + Cs ⁺ ); found 867. 1868.
(Example 5b1)
1- (2-Phenyl-1-phosphonooxymethyl-ethylsulfamoyl) -piperidine-2S-carboxylic acid 4-phenyl-butyl ester

Palladium / carbon (10%, 5 mg) was added to a methanol solution of phosphoric acid benzyl ester 4b1 (29.5 mg, 0.0402 mmol). The suspension was placed under hydrogen (1 atm) for 1.5 hours. After filtration, the filtrate was concentrated to remove the solvent to give 22.6 mg of the title compound 5b1 in 100% yield. ¹ H NMR (CDCl ₃ ): δ 7.34-6.95 (10H, m), 4.47 (1H, s), 4.17-3.82 (4H, m), 3.62 (1H, br) s), 3.20 (1H, br d), 3.28 (3H, m), 2.53 (2H, m), 1.21 (1H, br d); HRMS (FAB): C ₂₅ H ₃₅ Calcd for N ₂ O ₈ PSNa (M + Na ⁺ ) 577.1749; found 577.1769.
Phosphoric acid benzyl ester 4b2

Alcohol 2b2 (240 mg, 0.554 mmol), 1H-tetrazole (77 mg, 1.11 mmol), dibenzyl N, N-diisopropyl phosphoramidite (249 mg, 0.72 mmol) were used as described in the synthesis of 4b1. Manufactured. Hydrogen peroxide (30%, 2 mL) was used instead of MCPBA for oxidation. Column chromatography purification (30% EtOAc in hexane) gave 300 mg of compound 4b2 in 83% yield. ¹ H NMR (CDCl ₃ ): δ 7.41-7.10 (20H, m), 5.11-5.00 (6H, m), 4.66 (1H, J = 4.5 Hz), 4.07 (1H, m), 3.89 (1H, m), 3.72 (1H, m), 3.26 (1H, br d, J = 13.2 Hz), 2.85-2.71 (3H, m), 2.22 (1H, d, J = 12.9 Hz).
(Example 5b2)
1- (2-Phenyl-1-phosphonooxymethyl-ethylsulfamoyl) -piperidine-2-carboxylic acid

Prepared from phosphate benzyl ester 4b2 (300 mg, 0.457 mmol) as described in the synthesis of 5b1. The benzyl ester of carboxylic acid was also degraded by hydrogenation to carboxylic acid. The title compound 5b2 was obtained in 68% yield (119 mg). ¹ H NMR (CD ₃ OD): δ 7.37-7.13 (5H, m), 4.46 (1H, 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 (1H, d, J = 12.9 Hz); LCMS: 423 (M + H ⁺ ); HRMS (FAB): C ₁₅ H ₂₄ N ₂ O ₈ PS (M + H) ⁺ ) Calculated value 423.0991; found value 423.0995.
Alcohol 2b5

Using sulfamoyl chloride 1b5 (0.07 g, 0.205 mmol, production method described in International Publication No. WO0141405) and D-phenylalaninol (0.1 g, 0.662 mmol) as described in the synthesis of 2a. Manufactured. Instead of pyridine, 3,5-lutidine was used as a reaction solvent. After purification by flash column chromatography (50% EtOAc in hexane), compound 2b5 (28 mg) was obtained in 30% yield. ¹ H NMR (CDCl ₃ ): δ 7.43-7.13 (10H, m), 5.53 (1H, d, J = 8.4 Hz), 5.27 (1H, 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).
Benzyl phosphate 4b5

Alcohol 2b5 (28 mg, 0.061 mmol), 1H-tetrazole (8 mg, 0.12 mmol), dibenzyl N, N-diisopropyl phosphoramidite (25 mg, 0.072 mmol) and MCPBA (33 mg, 70% purity, 0.13 mmol) Was prepared as described in the synthesis of 4b1. Purification by column chromatography (30-60% EtOAc in hexane) followed by preparative TLC (50% EtOAc in hexane) gave 30 mg of compound 4b5 in 69% yield. ¹ H NMR (CDCl ₃ ): δ 7.44-7.07 (20H, m), 5.57 (1H, d, J = 8.4 Hz), 5.19 (1H, br d, J = 3 Hz), 5.13-4.47 (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 (1H, 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-{(R) -2-[(S) -2- (5-benzyl- [1,3,4]] oxadiazol-2-yl) -piperidine-1-sulfonylamino] -3-phenyl phosphate -Propyl} ester

アルコール９

Prepared as described in the synthesis of 5b1 using phosphoric acid benzyl ester 4b5 (30 mg, 0.042 mmol) and 10% palladium / carbon (5 mg). The title compound 5b5 was obtained in quantitative yield (28 mg). ¹ H NMR (CD ₃ OD): δ 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 (1 H, m); MS (ESP): 559 (M + Na ⁺ ); 535 (M−H) ⁻ .

Alcohol 9

To a DMF solution (5 mL) of 3-amino-1-propanol (0.207 g, 0.21 mL, 2.75 mmol) at 25 ° C., triethylamine (0.42 mL, 3 mmol) and 4-chloro-7-nitrobenzofura Zan (0.5 g, 2.5 mmol) was added. After 20 hours, the reaction mixture was poured into water (100 mL). The precipitate was collected by filtration. Recrystallization from warm methanol gave 150 mg (25% yield) of compound 9 as a yellow solid. ¹ H NMR (CD ₃ OD): δ 9.49 (1H, s), 8.51 (1H, d, J = 8.7 Hz), 6.41 (1H, d, J = 8.7 Hz); 65 (1H, m), 3.62-3.44 (4H, m), 1.84 (2H, p, J = 6.6 Hz); MS (positive ion ESP): 239 (M + H ⁺ ); MS ( Negative ion ESP): 237 (M−H) ⁻ .
Ester 11

To a DMF solution (2 mL) of alcohol 9 (0.08 g, 0.336 mmol) and N-Boc-pipecolic acid 10 (0.115 g, 0.504 mmol, production method described in International Publication No. WO0141405) at 25 ° C., Triethylamine (0.2 mL), EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) (0.097 g, 0.504 mmol) and HOBT (1-hydroxybenzotriazole hydrate) (0. 068 g, 0.0504 mmol) was added. After 20 hours, the reaction mixture was diluted with EtOAc (50 mL), washed with brine (3 × 50 mL), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by column chromatography (20-25% EtOAc in hexane) to give 150 mg (yield 100%) of compound 11. ¹ H NMR (CDCl ₃ ): (mixture of two rotamers) δ 8.48 (1H, d, J = 8.7 Hz), 7.11-6.94 (1H, br s), 6.26 ( 1H, d, J = 8.7 Hz), 4.85 (1H, br s), 4.36 (2H, m), 4.06 to 3.86 (2H, m), 3.67 (2H, m) ), 3.12-2.81 (1H, m), 2.6-2.12 (3H, m), 1.46 (9H, s).
Amine 6b

To a methylene chloride solution (5 mL) of ester 11 (150 mg, 0.5 mmol), trifluoroacetic acid (1 mL) was added at −30 ° C. The solution was brought to 25 ° C. over 3 hours. All solvents were removed under reduced pressure to give 125 mg (100%) of compound 6b. ¹ H NMR (CDCl ₃ ): δ 8.45 (1H, d, J = 8.4 Hz), 6.18 (1H, d, J = 8.4 Hz), 4.35 (2H, t, J = 6. 3 Hz), 3.66 (2 H, 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 DMF solution (5 mL) of D-phenylalaninol (1 g, 6.6 mmol), imidazole (0.494 g, 7.27 mmol) and t-butyldimethylchlorosilane (1 g, 7.27 mmol) were added. After 40 hours, the mixture was diluted with ether (20 mL), washed with brine (3 × 50 mL) and dried (Na ₂ SO ₄ ). All solvent was removed under reduced pressure to give amine 8b (1.85 g) as a colorless oil. At −40 ° C., a portion of amine 8b (0.265 g, 1 mmol) was added to a solution of phosgene (0.544 mL, 20% toluene solution, 1.1 mmol) and triethylamine (0.5 mL) in methylene chloride (5 mL). It was. The solution was slowly warmed to 25 ° C. over 30 minutes and cooled again to 0 ° C. Pipecolic ester 6b (0.05 g, 0.143 mmol) was added in one portion. The mixture was stirred at 25 ° C. for 20 h, diluted with EtOAc (50 mL), washed with concentrated NaHCO ₃ solution (1 × 50 mL), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by column chromatography (50% EtOAc in hexane) to give 20 mg (22% yield) of compound 12b. ¹ H NMR (CDCl ₃ ): δ 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 (1 H, m), 4.15 (1 H, 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

Tetrabutylammonium fluoride (1 mL, 1M THF solution, 1 mmol) was added to a THF solution (4 mL) of silyl ether (20 mg, 0.0313 mmol). After 1 hour, the solution was concentrated at 25 ° C. The resulting residue was purified by column chromatography (75% EtOAc in hexane) to give 18 mg (100%) of compound 13b. ¹ H NMR (CD ₃ OD): δ 8.49 (1H, d, J = 9 Hz), 7.3-7.1 (5H, m), 6.35 (1H, d, J = 9 Hz); 38 (1H, m), 4.05 (1H, m), 3.92 (1H, dd, J = 13.2, 4.8 Hz), 3.84-3.59 (6H, m), 3. 13 (1H, m), 3.00 (1H, dd, J = 13.8, 5.4 Hz), 2.78 (1 H, m), 1.99 (3H, m).
(Example 14b)
1- (2-Phenyl-1-sulfooxymethyl-ethylcarbamoyl) -piperidine-2-carboxylic acid 3- (7-nitro-benzo [1,2,5] oxadiazol-4-ylamino) -propyl ester

At −70 ° C., a solution of alcohol 13b (10 mg, 0.019 mmol) in methylene chloride (2 mL) was added to triethylamine (0.05 mL) and chlorosulfonic acid (8 mg, 5 μl, 0.068 mmol). The cooling bath was then removed and the reaction mixture was warmed to 25 ° C. over 3 hours. All solvents were distilled off under reduced pressure. The residue was purified by column chromatography (10% MeOH in EtOAc) to give 5 mg (42% yield) of the title compound 14b. ¹ H NMR (CD ₃ OD): δ 8.63 (1H, d, J = 9 Hz), 7.37-7.18 (5H, m), 6.49 (1H, d, J = 9 Hz); 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 methylene chloride solution (4 mL) of pipecolic ester 6a (0.2 g, 0.528 mmol) and triethylamine (1 mL) was added a solution of triphosgene (0.052 g, 0.176 mmol) in methylene chloride (1 mL). After 10 minutes, the solution was heated under reflux for 1 hour and then cooled to 25 ° C. A solution of D-phenylalaninol (0.0798 g, 0.528 mmol) in methylene chloride (1 mL) was added. After 2 hours, the reaction solution was diluted with Et ₂ O (50 mL), washed with brine (2 × 70 mL), dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The residue was purified by flash column chromatography (20% EtOAc in hexane) to give 80 mg (27% yield) of compound 13a. ¹ H NMR (CDCl ₃ ): δ 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 (1H, td , J = 12.3, 3.3 Hz), 2.84 (2H, m), 2.58 (4H, m), 2.18 (1H, br d, J = 12.6 Hz); MS (positive ion) ESP): 557 (M + H ⁺ ); 555 (M−H) ⁻ .
Method B
Silyl ether 17

(R)-(+)-2- (t-Boc) -amino-3-phenyl-1-propanol (4.15 g, 16.5 mmol) in DMF solution (7 mL) was added imidazole (2.24 g, 33 mmol). And t-butylchlorodiphenylsilane (5.15 mL, 19.8 mmol) were added. After 15 hours at 25 ° C., the mixture was diluted with ether (50 mL), washed with saturated NH ₄ Cl solution (3 × 50 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (2-4% EtOAc in hexane) to give 9.19 g (100%) of compound 17 as a white solid. MS (ESP): 512 (M + Na ^< + ^> ).
Amine 7a

To a methylene chloride solution (60 mL) of silyl ether 17 (9.19 g, 16.5 mmol) was added trifluoroacetic acid (20 mL) at 0 ° C. The reaction solution was stirred at 0 ° C. for 1 hour and then warmed to 25 ° C. over 30 minutes. The mixture was concentrated under reduced pressure and redissolved in methylene chloride (50 mL). The resulting solution was washed with saturated NaHCO ₃ solution (2 × 50 mL), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by column chromatography (97.5 / 2.5 / 0.25 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to obtain 5.97 g (yield 78%) of compound 7a as a pale yellow oil. It was. ¹ H NMR (CDCl ₃ ): δ 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 amine 7a (3.44 g, 7.04 mmol) and triethylamine (2 mL) in methylene chloride (20 mL) was added a solution of triphosgene (0.613 g, 2.07 mmol) in methylene chloride (1 mL). After 2 hours, the solution was heated under reflux conditions for 1.5 hours and then cooled to 25 ° C. Methylene chloride solution (40 mL) of amine 6a (2.67 g, 7.04 mmol) (the method for preparing 6a is described in International Publication No. WO01 / 40183 by Guo et al.) Was added. After 15 hours, the reaction solution was diluted with CH ₂ Cl ₂ (100 mL), washed with brine (2 × 80 mL), dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The residue was purified by flash column chromatography (5-20% EtOAc in hexane) to give 4.85 g (77% yield) of compound 12a. ¹ H NMR (CDCl ₃ ): (mixture of two rotamers) δ 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 (1H, 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

Hydrogen fluoride-pyridine (8 mL) was added to a THF solution (30 mL) of silyl ether 12a (4.83 g, 6.08 mmol) at 0 ° C. After 30 minutes at 0 ° C., the mixture was brought to 25 ° C. over 1 hour. All solvents were removed under reduced pressure. The residue was dissolved in methylene chloride (50 mL) and the solution was washed with ice-cold HCl solution (2 × 40 mL), dried (Na ₂ SO ₄ ) and concentrated. Purification by flash column chromatography gave 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-propyl) -butyl ester

Prepared as described in the synthesis of 14b using alcohol 13a (17 mg, 0.0306 mmol), chlorosulfonic acid (11 mg, 8 μL, 0.011 mmol) and triethylamine (0.05 mL). The reaction mixture was diluted with EtOAc (20 mL) and washed with ice-cold 5% HCl solution (1 × 20 mL). Column chromatography (8% MeOH in EtOAc) gave 12 mg (62% yield) of the title compound 14a. ¹ H NMR (CD ₃ OD): δ 7.36-7.06 (15H, m), 6.55 (1H, d, J = 7.8 Hz), 4.99 (1H, m), 4.11 ( 1H, m), 3.97 (2H, m), 3.74 (1H, m), 2.99 (1H, brt), 2.87 (2H, m), 2.60 (4H, m) , 2.20 (1H, br d); MS (negative ion ESP): 635 (M−H) ⁻ ; HRMS (FAB): calculated as C ₃₅ H ₄₃ N ₂ O ₇ S (M−H) 2791; found 633.5815.
Phosphoric acid benzyl ester 15a

Dibenzyl N, N-diisopropyl phosphoramidite (68 mg, 0.198 mmol) was added to an acetonitrile solution (10 mL) of alcohol 13a (73 mg, 0.131 mmol) and 1H-tetrazole (15 mg, 0.21 mmol) at 25 ° C. It was. After 1 hour, MCPBA (102 mg, 70% purity, 0.4 mmol) was added to the suspension. The solution was diluted with ether (50 mL), washed with concentrated NaHSO ₃ solution (2 × 30 mL), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (20-25% EtOAc in hexane) to give 70 mg of compound 15a in 65% yield. ¹ H NMR (CDCl ₃ ): δ 7.40-7.07 (25H, m), 5.67 (1H, d, J = 7.8 Hz), 5.10-4.89 (6H, m), 4 .14 (1H, m), 3.90 (2H, m), 3.53 (1H, br d), 3.09 (1H, br t), 2.97 (1H, dd, J = 13.2) , 4.8 Hz), 2.69 (1H, dd, J = 13.2, 9 Hz), 2.56 (4H, m), 2.18 (1H, br d).
Example 16a
1- (2-Phenyl-1-phosphonooxymethyl-ethylcarbamoyl) -piperidine-2S-carboxylic acid 4-phenyl-1- (3-phenyl-propyl) -butyl ester

Palladium / carbon (10%, 6 mg) was added to a methanolic solution of benzyl phosphate 15a (50 mg, 0.061 mmol). The suspension was placed under hydrogen (1 atm) for 5 hours. After filtration, the filtrate was concentrated to remove the solvent to give 40 mg of the title compound 16a in 100% yield. ¹ H NMR (CDCl ₃ ): δ 7.36-7.07 (15H, m), 5.02 (1 H, m), 4.86 (1 H, br d), 4.12 (1 H, m), 3 .92 (2H, m), 3.70 (1H, br d), 3.09-2.88 (2H, m), 2.83 (1H, dd, J = 13.8,7.8 Hz), 2.60 (4H, m), 2.18 (1 H, br d); HRMS (MALDI): calculated as C ₃₅ H ₄₄ N ₂ O ₇ PNa ₂ (M−H ⁺ + 2Na ⁺ ) 681.2681; Value 681.2691.
Alcohol 13c

Pipecolic acid ester 6c (0.5 g, 1.92 mmol, production method described in International Publication No. WO0141405) and triethylamine (2 mL) in methylene chloride (10 mL) at −40 ° C. at phosgene (20%, 0.208 g) , 0.176 mmol) in toluene (1.04 mL) was added. The solution was warmed to 25 ° C. over 1 hour, then D-phenylalaninol (0.29 g, 1.92 mmol) was added. After 10 hours, the reaction mixture was diluted with Et ₂ O (100 mL), washed with ice-cold 5% HCl solution (1 × 50 mL) and brine (1 × 50 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. . The residue was purified by flash column chromatography (20% EtOAc in hexane) to give 100 mg (12% yield) of compound 13c. ¹ H NMR (CDCl ₃ ): δ 7.31-7.03 (10H, m), 4.85 (1H, br d), 4.1-3.9 (2H, m), 3.64 (1H, dd, J = 10.8, 3.3 Hz), 3.50 (1H, dd, J = 11.4, 5.7 Hz), 3.25 (1H, br d), 2.99 (1H, td, J = 12.6, 3 Hz), 2.79 (2H, m), 2.56 (2H, m).
Phosphoric acid benzyl ester 15c

Alcohol 13c (60 mg, 0.137 mmol), 1H-tetrazole (19.2 mg, 0.274 mmol), dibenzyl N, N-diisopropyl phosphoramidite (0.069 mL, 71 mg, 0.205 mmol) and MCPBA (115 mg, purity 60 %, 0.4 mmol) and was prepared as described in the synthesis of 15a. Preparative TLC purification (30% EtOAc in hexane) gave 20 mg of compound 15c in 21% yield. ¹ H NMR (CDCl ₃ ): δ 7.43-7.1 (20H, m), 5.64 (1H, d, J = 7.5 Hz), 5.1-5.0 (4H, m), 4 .97 (1H, br d), 4.21-3.82 (5 H, m), 3.54 (1 H, br d), 3.09 (1 H, 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 (1H, d, J = 13.5 Hz).
(Example 16c)
1- (2-Phenyl-1-phosphonooxymethyl-ethylcarbamoyl) -piperidine-2S-carboxylic acid 4-phenyl-1-butyl ester

Prepared from phosphate benzyl ester 15c (20 mg, 0.457 mmol) as described in the synthesis of 16a. As a reaction solvent, ethanol was used instead of methanol. The title compound 16c was obtained in 88% yield (13 mg). ¹ H NMR (CD ₃ OD): δ 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 (1H, d, J = 12.9 Hz); HRMS (MALDI): C ₂₆ H ₃₅ N ₂ O ₇ Calculated 541.2080 as PNa (M + Na ⁺ ); found 541.2106.
Alcohol 13d:

Pipecolic acid ester 6d (0.78 g, 3.56 mmol, production method described in International Publication No. WO0141405), triethylamine (2 mL), phosgene (20% toluene solution, 2.4 mL, 4.45 mmol) and D-phenylalaninol (1.35 g, 8.9 mmol) was prepared as described in the synthesis of 13c. Purification by flash column chromatography (50% EtOAc in hexanes) gave 60 mg (yield 4.4%) of compound 13d. ¹ H NMR (CDCl ₃ ): δ 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 (1H, dd, J = 12, 4.2 Hz), 3.39 (1 H, dd, J = 9.6, 3.6 Hz), 3. 14 (2H, m), 2.75 (1H, td, J = 13.8,3.9 Hz), 2.09 (1H, m), 1.91 (1H, m), 1.67 (1H, m); MS (ESP): 397 (M + H ^< + ^> ).
Phosphoric acid benzyl ester 15d

Alcohol 13d (89 mg, 0.225 mmol), 1H-tetrazole (32 mg, 0.45 mmol), dibenzyl N, N-diisopropyl phosphoramidite (0.113 mL, 0.337 mmol) and MCPBA (136 mg, purity 60%,. 45 mmol) and was prepared as described in the synthesis of 15a. Column chromatography purification (30% EtOAc in hexanes) gave 71 mg of compound 15d in 48% yield. ¹ H NMR (CDCl ₃ ): δ 7.31-7.06 (20H, m), 5.62 (1H, d, J = 7.8 Hz), 5.11-4.92 (2H, m), 4 .13 (1H, m), 3.99-3.79 (2H, m), 3.49 (1H, br d), 3.01 (1H, td, J = 12.3, 2.7 Hz), 2.89 (1H, dd, J = 13.5, 5.4 Hz), 2.63 (1H, dd, J = 13.8, 9.3 Hz), 2.15 (1H, br d, J = 13) .8 Hz); MS (positive ion ESP): 657 (M + H ⁺ ), 679 (M + Na ⁺ ).
(Example 16d)
1- (2-Phenyl-1-phosphonooxymethyl-ethylcarbamoyl) -piperidine-2-carboxylic acid

Prepared from phosphate benzyl ester 15d (48 mg, 0.073 mmol) as described in the synthesis of 16a. As a reaction solvent, ethanol was used instead of methanol. The benzyl ester of the carboxylic acid also replaced the carboxylic acid upon decomposition during hydrogenation. After purification by HPLC, the title compound 16d was obtained in 4% yield (1 mg). ¹ H NMR (CD ₃ OD): δ 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).

アルコール１９ａ

The following is a list of compounds prepared using the synthetic route outlined in Scheme 3, followed by a detailed experimental procedure.

Alcohol 19a

To a methylene chloride solution (80 mL) of D-phenylalaninol 18a (1.15 g, 7.61 mmol) was added triethylamine (1.59 mL, 11.4 mmol) and benzyl chloroformate (1.19 mL, 8.37 mmol). . The mixture was stirred for 3 hours and then concentrated. The residue was dissolved in methylene chloride (50 mL) and washed with brine (1 × 50 mL). The solution was dried (Na ₂ SO ₄ ) and concentrated. After column chromatography purification (10-30% EtOAc in hexane), compound 19a was obtained in 73% yield (1.59 g). ¹ H NMR (CDCl ₃ ): δ 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 (MH) ⁻ .
Alcohol 19b

Synthesis of alcohol 19a using L-phenylalaninol 18b (2.59 g, 17.1 mmol), triethylamine (2.6 g, 3.58 mL, 25.7 mmol) and benzyl chloroformate (2.69 mL, 18.8 mmol) And was prepared as described in After column chromatography purification (20-40% EtOAc in hexane), compound 19b was obtained in 55% yield (2.61 g). ¹ H NMR (CDCl ₃ ): δ 7.43-7.13 (10H, m), 5.09 (2H, s), 4.94 (1H, m), 3.95 (1H, m), 3. 69 (1 H, m), 3.58 (1 H, m), 2.87 (1 H, d, J = 7.2 Hz); MS (ESP): 286 (M + H ⁺ ); 284 (M−H) ⁻ .
Phosphoric acid benzyl ester 20a

To a solution of alcohol 19a (1.58 g, 5.54 mmol) and 1H-tetrazole (1.05 g, 15 mmol) in acetonitrile (40 mL) at 25 ° C., dibenzyl N, N-diisopropyl phosphoramidite (3.72 mL, 11. 1 mmol) was added. After 3 hours, MCPBA (4.19 g, 70% purity, 13.85 mmol) was added to the suspension. The solution was diluted with EtOAc (100 mL), washed with concentrated NaHSO ₃ solution (2 × 80 mL), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (10-30% EtOAc in hexane) to give 2.88 g of compound 20a in 95% yield. ¹ H NMR (CDCl ₃ ): δ 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 (positive ion ESP): 568 (M + Na ⁺ ); MS (negative ion ESP): 580 (M + Cl) ⁻ .
Phosphoric acid benzyl ester 20b

Alcohol 19a (2.61 g, 9.16 mmol), 1H-tetrazole (1.73 g, 24.7 mmol), dibenzyl N, N-diisopropyl phosphoramidite (6.15 mL, 18.3 mmol) and MCPBA (6.26 g, (77% purity, 27.5 mmol) and was prepared as described in the synthesis of compound 20a. Purification by column chromatography (15-30% EtOAc in hexane) gave 4.1 g of compound 20b in 82% yield. ¹ H NMR (CDCl ₃ ): δ 7.42-7.1 (20H, m), 5.16-5.0 (7H, m), 4.09-3.84 (3H, m), 2.9 -2.69 (2H, m); MS (ESP): 546 (M + H ⁺ ); 580 (M + Cl) ^- .
Aminophosphate 21a

Palladium / carbon (10%, 300 mg) was added to a solution of benzyl phosphate ester 20a (2.88 g, 5.28 mmol) in ethanol. The suspension was placed under a hydrogen atmosphere (1 atm) for 4 hours and then filtered through a celite pad. The collected solid was washed with methylene chloride. The mixture of solid and celite was suspended in 5% HCl solution and stirred for 20 minutes. After filtration, the filtrate was concentrated to remove the solvent, yielding 1.2 g of compound 21a in 86% yield. ¹ H NMR (CD ₃ OD): δ 7.49-7.25 (5H, m), 4.22-4.08 (1H, m), 4.0 (1H, m), 3.72 (1H, m), 3.03 (2H, d, J = 7.5 Hz); LCMS: 232 (M + H ⁺ ); 230 (M−H) ⁻ ; HRMS (MALDI): C ₉ H ₁₅ NO ₄ P (M + H ⁺ ) As calculated value 232.0733; actually measured value 232.0733.
Aminophosphate ester 21b

Prepared as described in the synthesis of 21a using phosphoric acid benzyl ester 20b (4.1 g, 7.5 mmol) and palladium / carbon (10%, 410 mg). After filtration and distillation, compound 21b was obtained in quantitative yield (2.29 g). ¹ H NMR (CD ₃ OD): δ 7.48-7.24 (5H, m), 4.14 (1H, m), 3.98 (1H, m), 3.69 (1H, m), 3 .00 (2H, d, J = 7.4 Hz); LCMS: 232 (M + H ⁺ ).
(Example 23a)
Phosphoric acid mono- [3-phenyl-2- (3-phenyl-ureido) -propyl] ester

To a sodium carbonate solution (1 M, 1 mL) was added aminophosphate 21a (53 mg, 0.198 mmol) and phenyl isocyanate (0.023 mL, 0.208 mmol). After 15 hours, at 0 ° C., it was acidified to pH˜1 by adding concentrated hydrochloric acid solution. Preparative HPLC purification gave 27 mg (42% yield) of the title compound 23a. ¹ H NMR (CD ₃ OD): δ 7.36-7.17 (9H, m), 6.97 (1H, t, J = 7.8 Hz), 4.19 (1H, m), 3.98 ( 2H, m), 2.98 (1H, dd, J = 13.9, 7.1 Hz), 2.88 (1H, dd, J = 13.8, 7.7 Hz); HRMS (MALDI): C ₁₆ Calc'd for H ₁₉ N ₂ O ₅ PNa (M + Na ⁺ ) 373.0924; found 373.0934.
(Example 23b)
Phosphoric acid mono- {2- [3- (2-phenoxy-phenyl) -ureido] -3-phenyl-propyl} ester

21a (82 mg, 0.307 mmol), 1-isocyanato-2-phenoxybenzene (67.8 mg, 0.058 mL, 0.322 mmol) and 1M sodium carbonate solution (1 mL), described in the synthesis of 23a It was manufactured as described above. Preparative HPLC purification gave 36 mg (27% yield) of the title compound 23b. ¹ H NMR (CD ₃ OD): δ 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 (1H, 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 (M + H ⁺ ), 465 (M + Na ⁺ ); 441 (M−H) ⁻ .
(Example 23c)
Phosphoric acid mono- {2- [3- (3-methoxy-5-methyl-phenyl) -ureido] -3-phenyl-propyl} ester

Prepared as described in the synthesis of 23a using 21a (62 mg, 0.232 mmol), 2-methoxy-5-methylphenyl isocyanate (40 mg, 0.243 mmol) and 1M sodium carbonate solution (1 mL). Preparative HPLC purification gave 50 mg (55% yield) of the title compound 23c. ¹ H NMR (CD ₃ OD): δ 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 (1H, br d), 4.19 (1H, m), 3.97 (2H, m), 2.98 (1H, dd, J = 13) .9, 7.0 Hz), 2.83 (1H, dd, J = 14, 8.1 Hz); HRMS (MALDI): Calculated 395.1372 as C ₁₈ H ₂₄ N ₂ O ₆ P (M + H ⁺ ); Found 395.1383.
(Example 23d)
Phosphoric acid mono- {2- [3- (3,5-dimethoxy-phenyl) -ureido] -3-phenyl-propyl} ester

Prepared as described in the synthesis of 23a using 21a (71 mg, 0.265 mmol), 2,4-dimethoxy-phenyl isocyanate (50 mg, 0.279 mmol) and 1M sodium carbonate solution (1 mL). Preparative HPLC purification gave 29 mg (27% yield) of the title compound 23d. ¹ H NMR (CD ₃ OD): δ 7.76 (1H, d, J = 9 Hz), 7.46-7.29 (5H, m), 6.66 (1H, d, J = 2.6 Hz), 6.56 (1H, dd, J = 9, 2.8 Hz), 4.30 (1H, m), 4.08 (2H, m), 3.95 (3H, s), 3.88 (3H, s), 3.09 (1H, 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)
Phosphoric acid mono- (2-benzenesulfonylamino-3-phenyl-propyl) ester

To a sodium carbonate solution (1M, 1 mL) was added aminophosphate 21a (66 mg, 0.246 mmol) and phenylsulfonyl chloride (0.047 mL, 0.369 mmol). After 15 hours, concentrated hydrochloric acid solution was added at 0 ° C. to acidify to pH˜1. Preparative HPLC purification gave 35 mg (38% yield) of the title compound 23e. ¹ H NMR (CD ₃ OD): δ 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 (1H, 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): calculated as C ₁₅ H ₁₈ NO ₆ PSNa (M + Na ⁺ ) 394.0485; found 34.0487.
(Example 25-1)
Phosphoric acid mono- {3-phenyl-2-[(1-phenyl-methanoyl) -amino] -propyl} ester

To a sodium carbonate solution (1M, 1 mL) was added aminophosphate 21a (70 mg, 0.262 mmol) and benzoyl chloride (0.028 mL, 0.238 mmol). After 15 hours, concentrated hydrochloric acid solution was added at 0 ° C. to acidify it to pH˜1. Preparative HPLC purification gave 20 mg (23% yield) of the title compound 25-1. ¹ H NMR (CD ₃ OD): δ 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 (1H, dd, J = 13.6, 6.8 Hz), 2.96 (1H, dd, J = 13) .5, 8.1 Hz); MS (ESP): 336 (M + H ⁺ ); 334 (M−H) ⁻ .
(Example 25-2)
Phosphoric acid mono-{(R) -2-[(1-benzo [b] thiophen-2-yl-methanoyl) -amino] -3-phenyl-propyl} ester

Prepared as described in the synthesis of 25-1 using 21a (48 mg, 0.179 mmol), benzothiophene-2-carbonyl chloride (35 mg, 0.179 mmol) and 1 M sodium carbonate solution (1 mL). Preparative HPLC purification gave 34 mg (48% yield) of the title compound 25-2. ¹ H NMR (CD ₃ OD): δ 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): Calculated 414.0540 as C ₁₈ H ₁₈ NO ₅ PSNa (M + Na ⁺ ); found 414.0536.
(Example 25-2 ′)
Phosphoric acid mono- (2-{[1- (1-oxo-benzo [b] thiophen-2-yl) -methanoyl] -amino} -3-phenyl-propyl) ester

To a trifluoroacetic acid solution (1 mL) of 25-2 (9 mg, 0.023 mmol), 30% hydrogen peroxide (0.0244 mL) was added at 0 ° C. The solution was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 1 mg (yield 10%) of the title compound 25-2 ′. ¹ H NMR (CD ₃ OD): δ 8.01-7.93 (2H, m), 7.78-7.6 (3H, m), 7.36-7.26 (4H, m), 7. 25-7.17 (1H, m), 4.44 (1H, m), 4.04 (2H, m), 3.02 (2H, m); MS (ESP): 408 (M + H ⁺ ), 430 (M + Na ⁺ ).
(Example 25-3)
Phosphoric acid mono-{(R) -2-[(1-naphthalen-2-yl-methanoyl) -amino] -3-phenyl-propyl} ester

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). Preparative HPLC purification gave 29 mg (40% yield) of the title compound 25-3. ¹ H NMR (CD ₃ OD): δ 8.32 (1H, s), 8.1-7.88 (3H, m), 7.83 (1H, 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 (1H, m) dd, J = 13.7, 6.8 Hz), 3.02 (1H, dd, J = 13.7, 8.1 Hz); LCMS (ESP): 386 (M + H ⁺ ), 408 (M + Na ⁺ ); 384 (M−H) ⁻ ; HRMS (MALDI): Calculated as C ₂₀ H ₂₀ NO ₅ PNa (M + Na ⁺ ) 408.0971; found 408.0986.
(Example 25-4)
Phosphoric acid mono- [2-({1- [5- (3,5-dichloro-phenoxy) -furan-2-yl] -methanoyl} -amino) -3-phenyl-propyl] ester

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). As manufactured. Preparative HPLC purification gave 46 mg (33% yield) of the title compound 25-4. ¹ H NMR (CD ₃ OD): δ 7.21 (1H, t, J = 1.7 Hz), 7.17-7.03 (5H, m), 7.00 (2H, d, J = 1.8 Hz) ), 6.99 (1H, d, J = 3.6 Hz), 5.79 (1H, d, J = 3.9 Hz), 4.35 (1H, m), 3.92 (2H, m), 2.91 (1H, dd, J = 13.6, 6 Hz), 2.78 (1H, dd, J = 13.8, 8.7 Hz); MS (ESP): 508 (M + Na ⁺ ); 484 (M -H) ^- .
(Example 25-5)
Phosphoric acid mono- (2-{[1- (3,4-dichloro-phenyl) -methanoyl] -amino} -3-phenyl-propyl) ester

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). Preparative HPLC purification gave 20 mg (24% yield) of the title compound 25-5. ¹ H NMR (CD ₃ OD): δ 7.91 (1H, d, J = 2.1 Hz), 7.68 (1H, dd, J = 8.4, 1.8 Hz), 7.60 (1H, d , J = 8.4 Hz), 7.35-7.16 (5H, m), 4.501H, m), 4.08 (2H, m), 3.07 (1H, dd, J = 13.9). , 6.8 Hz), 2.94 (1H, dd, J = 13.9, 8.4 Hz); LCMS (ESP): 404 (M + H ⁺ ), 426 (M + Na ⁺ ); 402 (M−H) ⁻ .
(Example 25-6)
Phosphoric acid mono- (2-{[1- (5-chloro-4-methoxy-thiophen-3-yl) -methanoyl] -amino} -3-phenyl-propyl) ester

21a (63 mg, 0.236 mmol), 2-chloro-3-methoxythiophene-4-carbonyl chloride (50 mg, 0.236 mmol) and 1M sodium carbonate solution (1 mL) are described in the synthesis of 25-1. It was manufactured as described above. Preparative HPLC purification gave 37 mg (38% yield) of the title compound 25-6. ¹ H NMR (CD ₃ OD): δ 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)
Phosphoric acid mono- (2-{[1- (5-methyl-2-phenyl-2H- [1,2,3] triazol-4-yl) -methanoyl] -amino} -3-phenyl-propyl) ester

21a (46 mg, 0.172 mmol), 4-methyl-2-phenyl-1,2,3-triazole-5-carbonyl chloride (38 mg, 0.172 mmol) and 1M sodium carbonate solution (1 mL) were used. As described in the synthesis of Preparative HPLC purification gave 36 mg (50% yield) of the title compound 25-7. ¹ H NMR (CD ₃ OD): δ 7.98 (1H, d, J = 8.1 Hz), 7.43 (2H, 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 (1H, dd, J = 13.9, 7.9 Hz); LCMS (ESP): 417 (M + H ⁺ ), 439 (M + Na ⁺ ); 415 (M−H) ⁻ .
(Example 25-8)
Phosphoric acid mono- (2-{[1- (3-chloro-phenyl) -methanoyl] -amino} -3-phenyl-propyl) ester

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 1 M sodium carbonate solution (1 mL). Preparative HPLC purification gave 5 mg (8% yield) of the title compound 25-8. ¹ H NMR (CD ₃ OD): δ 7.64 (1H, s), 7.57 (1H, d, J = 7.5 Hz), 7.39 (1H, d, J = 9 Hz), 7.30 ( 1H, t, J = 7.8 Hz), 7.23-7.01 (5H, m), 4.33 (1H, 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 (MH) ⁻ .
(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). Preparative HPLC purification gave 3 mg (2% yield) of the title compound 25-9. ¹ H NMR (CD ₃ OD): δ 8.89 (1H, s), 8.68 (1H, d, J = 5.1 Hz), 8.36 (1H, 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 (1H, m), 3.98 (2H, m) ), 2.96 (1H, 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)
Phosphoric acid mono- {2-[(1-naphthalen-1-yl-methanoyl) -amino] -3-phenyl-propyl} ester

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). Preparative HPLC purification gave 8 mg (9% yield) of the title compound 25-10. ¹ H NMR (CD ₃ OD): δ 7.93 (1H, m), 7.88 (1H, d, J = 7.8 Hz), 7.77 (1H, d, J = 8.4 Hz), 7. 55-7.24 (9H, m), 4.70 (1H, m), 4.16 (2H, m), 3.14 (1H, dd, J = 14.1, 5.8 Hz), 2. 91 (1H, dd, J = 13.9, 9.4 Hz); LCMS (ESP): 408 (M + Na ⁺ ), 430 (M−H + 2Na ⁺ ); 384 (M−H) ⁻ .
(Example 25-11)
Phosphoric acid mono- {3-phenyl-2-[(1-quinoxalin-2-yl-methanoyl) -amino] -propyl} ester

Prepared as described in the synthesis of 25-1 using 21a (68 mg, 0.254 mmol), quinoxaloyl chloride (50 mg, 0.254 mmol) and 1 M sodium carbonate solution (1 mL). Preparative HPLC purification gave 17 mg (17% yield) of the title compound 25-11. ¹ H NMR (CD ₃ OD): δ 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 (M + Na ⁺ ); 386 (M−H) ⁻ .
(Example 25-12)

21a (63 mg, 0.236 mmol), 3-chloro-thiophene-2-carbonyl chloride (43 mg, 0.236 mmol) and 1 M sodium carbonate solution (1 mL) as described in the synthesis of 25-1. Manufactured. Preparative HPLC purification gave 26 mg (30% yield) of the title compound 25-12. ¹ H NMR (CD ₃ OD): δ 7.67 (1H, d, J = 5.1 Hz), 7.37-7.18 (5H, m), 7.05 (1H, d, J = 5.4 Hz) ), 4.50 (1H, m), 4.09 (2H, m), 3.08 (1H, dd, J = 13.9, 6.9 Hz), 2.99 (1H, dd, J = 13) HRMS (MALDI): Calculated as C ₁₄ H ₁₆ NO ₅ PSCl (M + H ⁺ ) 376.0175; found 376.0158.
(Example 25-13)
Phosphoric acid mono- (2-{[1- (2-hydroxy-phenyl) -methanoyl] -amino} -3-phenyl-propyl) ester

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). Preparative HPLC purification gave (yield 10%) of the title compound 25-13. ¹ H NMR (CD ₃ OD): δ 7.79 (1H, dd, J = 8.1, 1.8 Hz), 7.41-7.2 (7H, m), 6.89 (2H, m), 4.53 (1H, m), 4.08 (2H, m), 3.07 (1 H, dd, J = 13.6, 6.8 Hz), 2.99 (1 H, dd, J = 13.6) , 6.7 Hz); HRMS (MALDI): Calculated as C ₁₆ H ₁₉ NO ₆ P (M + H ⁺ ) 352.0950; found 352.0960.
(Example 25-14)
Phosphoric acid mono- {2-[(1-furan-2-yl-methanoyl) -amino] -3-phenyl-propyl} ester

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). Preparative HPLC purification gave 86 mg (83% yield) of the title compound 25-14. ¹ H NMR (CD ₃ OD): δ 7.65 (1H, br d), 7.33-7.17 (5H, m), 7.08 (1H, d, J = 3.6 Hz), 6.57 (1H, dd, J = 3.3, 1.5 Hz), 4.48 (1H, m), 4.05 (2H, m), 3.05 (1H, dd, J = 13.6, 6.. 4 Hz), 2.94 (1 h, dd, J = 13.6, 8.1 Hz); HRMS (MALDI): calculated as C ₁₄ H ₁₇ NO ₆ P (M + H ⁺ ) 326.0794; found 326.0801 .
(Example 25-15)

To the sodium carbonate solution (1M, 1 mL) was added aminophosphate ester 21a (106 mg, 0.397 mmol) and 2-methylpropanoic anhydride (0.16 mL, 153 mg, 0.966 mmol). After 15 hours, concentrated hydrochloric acid solution was added at 0 ° C. to acidify it to pH˜1. Preparative HPLC purification gave 110 mg (92% yield) of the title compound 25-15. ¹ H NMR (CD ₃ OD): δ 7.29-7.08 (5H, m), 6.94 (1 H, br d), 4.34 (1 H, br s), 4.10 (1 H, m) 3.96 (1H, m), 2.82 (2H, m), 2.41 (1H, heating, J = 7.2 Hz), 1.00 (3H, d, J = 7 Hz), 0.97 (3H, d, J = 7 Hz); LCMS (ESP): 302 (M + H ⁺ ); 300 (M−H) ⁻ .
(Example 25-16)
Phosphoric acid mono-[(R) -2- (2,2-dimethyl-propanoylamino) -3-phenyl-propyl] ester

21a (110 mg, 0.412 mmol), 2,2-dimethylpropanoic anhydride (0.16 mL, 147 mg, 0.79 mmol) and 1M sodium carbonate solution (1 mL), described in the synthesis of 25-15 Was manufactured as described above. Preparative HPLC purification gave 130 mg (100% yield) of the title compound 25-16. ¹ H NMR (CD ₃ OD): δ 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) ⁻ .
(Examples 25-40)
Phosphoric acid mono- (2-acetylamino-3-phenyl-propyl) 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 1M sodium carbonate solution (1 mL). Preparative HPLC purification gave 50 mg (40% yield) of the title compound 25-40. ¹ H NMR (CD ₃ OD): δ 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 (M−H) ⁻ .
(Examples 25-17)
Phosphoric acid mono- {2-[(1-cyclohexyl-methanoyl) -amino] -3-phenyl-propyl} ester

To an ether solution (5 mL) of cyclohexanecarboxylic acid (250 mg, 1.95 mmol), pyridine (0.5 mL) and cyclohexanecarbonyl chloride (286 mg, 0.261 mL, 1.95 mmol) were added. After 10 hours, the suspension was diluted with ether (20 mL), washed with ice-cold 5% HCl solution (1 × 50 mL) and concentrated NaHCO ₃ solution (1 × 50 mL), and dried over Na ₂ SO ₄ . All solvents were removed under reduced pressure to give 350 mg of cyclohexanecarboxylic anhydride as a colorless oil. A portion of cyclohexanecarboxylic anhydride (226 mg, 0.948 mmol) was added to a sodium carbonate solution (1M, 2 mL) of aminophosphate ester 21a (110 mg, 0.412 mmol). After 15 hours, concentrated hydrochloric acid solution was added at 0 ° C. to acidify it to pH˜1. Preparative HPLC purification gave 50 mg (36% yield) of the title compound 25-17. ¹ H NMR (CD ₃ OD): δ 7.27-7.1 (5H, m), 6.67 (1 H, 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 (1 H, dd, J = 14.9, 9 Hz), 2.10 ( 1H, brt), 1.79-1.51 (5H, m), 1.33-1.02 (5H, m); LCMS (ESP): 342 (M + H ⁺ ); 340 (M−H) ⁻ .
(Examples 25-18)
Phosphoric acid mono- {2-[(1-1H-indol-2-yl-methanoyl) -amino] -3-phenyl-propyl} ester

Imidazole (65 mg, 0.962 mmol) and t-butyldimethylchlorosilane (110 mg, 0.730 mmol) were added to a DMF solution (1 mL) of aminophosphate 21a (78 mg, 0.292 mmol). After 3.5 hours, 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 hours and acidified to pH˜1 by adding concentrated hydrochloric acid solution at 0 ° C. Preparative HPLC purification gave 1 mg (1% yield) of the title compound 25-18. ¹ H NMR (CD ₃ OD): δ 7.48 (1H, d, J = 8.5 Hz), 7.30 (1H, 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) ⁻ .
(Examples 25-19)
Phosphoric acid mono- {2-[(1-benzofuran-2-yl-methanoyl) -amino] -3-phenyl-propyl} ester

Aminophosphate ester 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), Prepared as described in the synthesis of 25-18 using EDC (84 mg, 0.439 mmol) and DMAP (9 mg, 0.07 mmol). Preparative HPLC purification gave 16 mg (12% yield) of the title compound 25-19. ¹ H NMR (CD ₃ OD): δ 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 (1H, dd, J = 13.8, 6.2 Hz) ), 2.87 (1H, dd, J = 13.8, 8.1 Hz); LCMS (ESP): 374 (M−H) ⁻ .
(Examples 25-20)
Phosphoric acid mono- (2-{[1- (6-hydroxy-naphthalen-2-yl) -methanoyl] -amino} -3-phenyl-propyl) ester

Aminophosphate ester 21a (152 mg, 0.568 mmol), imidazole (155 mg, 2.27 mmol), t-butyldimethylchlorosilane (214 mg, 1.42 mmol), 6- (acetyloxy) -2-naphthoic acid (131 mg, 0. 569 mmol), EDC (136 mg, 0.71 mmol) and DMAP (14 mg, 0.114 mmol) were prepared as described in the synthesis of 25-18. Preparative HPLC purification gave 25 mg (11% yield) of the title compound 25-20. ¹ H NMR (CD ₃ OD): δ 8.21 (1H, 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)

Aminophosphate ester 21a (94 mg, 0.351 mmol), imidazole (96 mg, 1.4 mmol), t-butyldimethylchlorosilane (132 mg, 0.878 mmol), 1-hydroxy-2-naphthoic acid (66 mg, 0.351 mmol), Prepared as described in the synthesis of 25-18 using EDC (84 mg, 0.439 mmol) and DMAP (9 mg, 0.07 mmol). Preparative HPLC purification gave 7 mg (5% yield) of the title compound 25-21. ¹ H NMR (CD ₃ OD): δ8.24 (1H, d, J = 8.1 Hz), 7.70 (1H, d, J = 7.8 Hz), 7.64 (1H, 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): calculated as C ₂₀ H ₂₁ NO ₆ P (M + H ⁺ ) 402.1107; found 402.1099 .
(Examples 25-22)
Phosphoric acid mono- (2-{[1- (3-hydroxy-naphthalen-2-yl) -methanoyl] -amino} -3-phenyl-propyl) ester

Aminophosphate ester 21a (98 mg, 0.366 mmol), imidazole (100 mg, 1.46 mmol), t-butyldimethylchlorosilane (138 mg, 0.915 mmol), 3-hydroxy-2-naphthoic acid (69 mg, 0.366 mmol), Prepared as described in the synthesis of 25-18 using EDC (88 mg, 0.458 mmol) and DMAP (9 mg, 0.0732 mmol). Preparative HPLC purification gave 2 mg (1% yield) of the title compound 25-22. ¹ H NMR (CD ₃ OD): δ 8.31 (1H, s), 7.72 (1H, d, J = 8.4 Hz), 7.55 (1H, d, J = 8.7 Hz), 7. 36 (1H, t, J = 7.8 Hz), 7.28-7.02 (7H, m), 4.47 (1H, m), 4.00 (2H, m), 2.96 (2H, m); LCMS (ESP): 402 (M + H ⁺ ), 424 (M + Na ⁺ ).
(Examples 25-23)
Phosphoric acid mono-{(R) -2-[(1H-benzimidazol-5-carbonyl) -amino] -3-phenyl-propyl} ester

Aminophosphate ester 21a (100 mg, 0.374 mmol), imidazole (76 mg, 1.12 mmol), t-butyldimethylchlorosilane (141 mg, 0.935 mmol), 6- (acetyloxy) -2-naphthoic acid (72.7 mg, 0.449 mmol), EDC (86 mg, 0.449 mmol) and DMAP (10 mg, 0.081 mmol) were prepared as described in the synthesis of 25-18. Prior to acidification, the reaction mixture was treated with 10% NaOH solution (1 mL) for 10 hours. Preparative HPLC purification gave 30 mg (21% yield) of the title compound 25-23. ¹ H NMR (CD ₃ OD): δ 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 (1 H, 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) ⁻ .
(Examples 25-24)
Phosphoric acid mono- (2-{[1- (1-bromo-naphthalen-2-yl) -methanoyl] -amino} -3-phenyl-propyl) ester

To a solution of 1-bromo-2-naphthoic acid (182 mg, 0.725 mmol) in methylene chloride (2 mL) was added oxalyl chloride (0.19 mL, 2.18 mmol) and 2 drops of DMF. The mixture was stirred for 2 hours and concentrated under reduced pressure. To the residue was added sodium carbonate solution (1M, 2 mL), aminophosphate 21a (194 mg, 0.725 mmol) and 1 mL of acetonitrile. After 15 hours, concentrated hydrochloric acid solution was added at 0 ° C. to acidify to pH˜1. Preparative HPLC purification gave 103 mg (yield 31%) of the title compound 25-24. ¹ H NMR (CD ₃ OD): δ 8.32 (1H, d, J = 8.7 Hz), 7.92 (2H, m), 7.65 (2H, 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. _{8,8.7Hz); HRMS (MALDI):} C 20 H 20 NO 5 PBr (M + H +) calculated 464.0262; found 464.0271.
(Examples 25-25)
Phosphoric acid mono- (2-{[1- (6-methoxy-naphthalen-2-yl) -methanoyl] -amino} -3-phenyl-propyl) ester

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 aminophosphate 21a (337 mg, 1.26 mmol) and was prepared as described in the synthesis of 25-24. Preparative HPLC purification (13% yield) gave the title compound 25-25. ¹ H NMR (CD ₃ OD): δ 8.24 (1H, 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 (1 H, dd, J = 14.1, 7.2 Hz), 3.01 (1H, dd, J = 13.6, 8.5 Hz); LCMS (ESP): 414 (M−H) ⁻ ; calculated as elemental analysis (C ₂₁ H ₂₂ NO ₆ P 0.25H ₂ O): C60 .07, H5.40, N3.34; Found: C59.66, H5.33, N3.74.
(Examples 25-26)
Phosphoric acid mono- {2-[(1-benzo [b] thiophen-2-yl-methanoyl) -amino] -3-phenyl-propyl} ester

To a sodium carbonate solution (1M, 1 mL) was added aminophosphate 21b (68 mg, 0.254 mmol) and benzothiophene-2-carbonyl chloride (50 mg, 0.254 mmol). After 15 hours, concentrated hydrochloric acid solution was added at 0 ° C., which was acidified to pH˜1. Preparative HPLC purification gave 20 mg (20% yield) of the title compound 25-26. ¹ H NMR (CD ₃ OD): δ 7.9-7.86 (3H, m), 7.53-7.15 (7H, m), 4.49 (1H, m), 4.10 (2H, m), 3.04 (2H, m); LCMS (ESP): 414 (M + Na ^< + ^> ); 390 (M-H) < ^{- >} .
(Examples 25-27)
Phosphoric acid mono- {2-[(1-naphthalen-2-yl-methanoyl) -amino] -3-phenyl-propyl} ester

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). Preparative HPLC purification gave 20 mg (20% yield) of the title compound 25-27. ¹ H NMR (CD ₃ OD): δ 8.32 (1H, s), 8.08-7.78 (4H, m), 7.66-7.5 (2H, m), 7.39-7. 17 (5H, m), 4.56 (1H, m), 4.11 (2H, m), 3.12 (1H, dd, J = 13.7, 6.8 Hz), 3.02 (1H, dd, J = 13.8, 7.7 Hz); LCMS (ESP): 386 (M + H ⁺ ), 408 (M + Na ⁺ ); 384 (M−H) ⁻ .
Amino alcohol 18c

To a THF solution (30 mL) of D-3-fluorophenylalanine (5 g, 27.3 mmol) at 0 ° C. was added a THF solution of borane (1M, 68.3 mL, 68.3 mmol). After 5 hours at 25 ° C., saturated NaHCO ₃ solution (10 mL) was added to the solution, which was stirred for 15 hours. The mixture was concentrated and extracted with methylene chloride (3 × 50 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by column chromatography (CH ₂ Cl ₂ / MeOH / NH ₄ OH 95/5 / 0.5 to 90/10/1), and 1.94 g (42% yield) of compound 18c was obtained as a white solid. Obtained. ¹ H NMR (CD ₃ OD): δ 7.32-7.21 (1H, m), 7.00-6.98 (3H, m), 3.63 (1H, dd, J = 11.1, 4) .2 Hz), 3.38 (1 H, dd, J = 10.5, 6.9 Hz), 3.12 (1 H, m), 2.79 (1 H, dd, J = 13.5, 5.1 Hz) 2.54 (1H, dd, J = 13.5, 8.4 Hz); LCMS (ESP): 170 (M + H ^< + ^> ).
Alcohol 19c

To a solution of amino alcohol 18c (1.94 g, 11.5 mmol) in methylene chloride (30 mL) were added triethylamine (2.8 mL, 20 mmol) and benzyl chloroformate (2.05 mL, 14.3 mmol). The mixture was stirred for 15 hours and then diluted with methylene chloride (50 mL). The solution was washed with brine (1 × 50 mL), dried (Na ₂ SO ₄ ) and concentrated. After column chromatography purification (20-30% EtOAc in hexane), compound 19c was obtained in 64% yield (2.22 g). ¹ H NMR (CDCl ₃ ): δ 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 (1H, dd, J = 10.2, 3 Hz), 3.58 (1H, dd, J = 11.4, 4.8 Hz), 2. 87 (2H, d, J = 7.5 Hz); LCMS (ESP): 326 (M + Na ⁺ ); calculated as elemental analysis (C ₁₇ H ₁₈ FNO ₃ ): C67.31, H5.98, N4.62; Found: C67.31, H5.98, N4.62.
Phosphoric acid benzyl ester 20c

To a solution of alcohol 19c (2.21 g, 7.29 mmol) and 1H-tetrazole (1.37 g, 19.6 mmol) in acetonitrile (40 mL) at 25 ° C. was added dibenzyl N, N-diisopropyl phosphoramidite (4.9 mL, 14 .6 mmol) was added. After 5 hours, MCPBA (5.72 g, purity 77%, 25.5 mmol) was added to the suspension. The solution was diluted with methylene chloride (100 mL), washed with concentrated NaHSO ₃ solution (2 × 80 mL), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (15-30% EtOAc in hexane) to give 4.39 g of compound 20c in 100% yield. ¹ H NMR (CDCl ₃ ): δ 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

Palladium / carbon (10%, 870 mg) was added to an ethanol solution of phosphoric acid benzyl ester (20c, 4.37 g, 7.76 mmol). The suspension was placed under a hydrogen atmosphere (1 atm) for 15 hours, then 5% HCl solution (10 mL) was added. The mixture was filtered through a celite pad. The filtrate was concentrated to remove the solvent and 2.30 g of a yellowish solid was obtained. Preparative HPLC purification gave 1.2 g (62% yield) of compound 21c as a white solid. ¹ H NMR (CD ₃ OD): δ 7.45-7.35 (1H, m), 7.18-7.01 (3H, m), 4.10 (1H, m), 3.94 (1H, m), 3.70 (1H, m), 3.03 (2H, m); LCMS (ESP): 250 (M + H ⁺ ); 248 (M−H) ⁻ .
(Examples 25-28)
Phosphoric acid mono- {3- (3-fluoro-phenyl) -2-[(1-naphthalen-2-yl-methanoyl) -amino] -propyl} ester

To a sodium carbonate solution (1M, 1 mL) was added aminophosphate 21c (110 mg, 0.385 mmol) and 2-naphthoyl chloride (110 mg, 0.578 mmol). After 15 hours, concentrated hydrochloric acid solution was added at 0 ° C. to acidify it to pH˜1. Preparative HPLC purification gave 160 mg (100% yield) of the title compound 25-28. ¹ H NMR (CD ₃ OD): δ 8.31 (1H, s), 8.0-7.88 (3H, m), 7.82 (1H, 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 (1H, m), 4.14 ( 2H, m), 3.13 (1H, dd, J = 13.8, 6 Hz), 3.02 (1H, dd, J = 13.9, 8.7 Hz); HRMS (MALDI): C ₂₀ H ₂₀ Calculated 404.1063 as NO ₅ PF (M + H ⁺ ); found 404.1078.
(Examples 25-29)

Prepared as described in the synthesis of 25-28 using 21c (110 mg, 0.386 mmol), 1-benzothiophene-2-carbonyl chloride (114 mg, 0.578 mmol) and 1 M sodium carbonate solution (1 mL). did. Preparative HPLC purification gave 145 mg (92% yield) of the title compound 25-29. ¹ H NMR (CD ₃ OD): δ 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): calculated as C ₁₈ H ₁₈ NO ₅ PFS (M + H ⁺ ) Value 410.0627; measured value 410.0639.
(Examples 25-30)
Phosphoric acid mono-[(R) -2- (2,2-dimethyl-propanoylamino) -3- (3-fluoro-phenyl) -propyl] ester

To the sodium carbonate solution (1M, 1 mL) was added aminophosphate 21c (65 mg, 0.228 mmol) and 2,2-dimethylpropanoic anhydride (0.08 mL, 0.392 mmol). After 15 hours, concentrated hydrochloric acid solution was added at 0 ° C. to acidify it to pH˜1. Preparative HPLC purification gave 43 mg (57% yield) of the title compound 25-30. ¹ H NMR (CD ₃ OD): δ 7.19 (1H, m), 7.0-6.77 (3H, m), 4.23 (1H, m), 3.89 (2H, m), 2 .91 (1H, dd, J = 13.8, 5.5 Hz), 2.74 (1H, dd, J = 13.8, 9.2 Hz), 1.00 (9H, s); HRMS (MALDI) _{: C 14 H 22 NO 5 PF} (M + H +) calculated 334.1220; found 334.1223.
(Examples 25-31)
Phosphoric acid mono-[(R) -2-{[1- (1-bromo-naphthalen-2-yl) -methanoyl] -amino} -3- (3-fluoro-phenyl) -propyl] ester

To a solution of 1-bromo-2-naphthoic acid (161 mg, 0.643 mmol) in methylene chloride (3 mL) was added oxalyl chloride (0.168 mL, 1.93 mmol) and 2 drops of DMF. The mixture was stirred for 2 hours and concentrated under reduced pressure. To the residue was added sodium carbonate solution (1M, 2 mL), aminophosphate 21c (80 mg, 0.28 mmol) and 1 mL acetonitrile. After 15 hours, concentrated hydrochloric acid solution was added at 0 ° C. to acidify it to pH˜1. Preparative HPLC purification gave 70 mg (52% yield) of the title compound 25-31. ¹ H NMR (CD ₃ OD): δ 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 (2 H, 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 (M−H) ⁻ ; calculated as elemental analysis (C ₂₀ H ₁₈ BrFNO ₅ P): C49.81, H3.76, N2.90 Measured values: C49.63, H3.73, N2.92.
(Examples 25-32)
Phosphoric acid mono-((R) -3- (3-fluoro-phenyl) -2-{[1- (6-methoxy-naphthalen-2-yl) -methanoyl] -amino} -propyl) ester

6-methoxy-2-naphthoic acid (143 mg, 7.07 mmol), oxalyl chloride (0.185 mL, 2.12 mmol), DMF (2 drops), sodium carbonate solution (1 M, 2 mL) and aminophosphate 21c (88 mg, 0.353 mmol) and was prepared as described in the synthesis of 25-31. Preparative HPLC purification gave 50 mg (39% yield) of the title compound 25-32. ¹ H NMR (CD ₃ OD): δ 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 (1H, m), 4.12 (2H, m), 3.95 (3H, s), 3.13 (1H, dd, J = 13.8, 6.6 Hz), 3.01 (1H, dd, J = 14.3, 7.7 Hz); LCMS (ESP): 432 (M−H) ⁻ ; Elemental analysis (C ₂₁ H ₂₁ FNO ₆ P 0.25H) Calculated as ₂ O): C57.60, H4.95, N3.20; Found: C57.58, H4.97, N3.27.
Amino alcohol 18d

Borane in THF (1M, 22.4 mL, 22.4 mmol) was added to a THF solution (10 mL) of D-3-methylphenylalanine (1 g, 5.58 mmol) at 0 ° C. After 48 hours at 25 ° C., saturated NaHCO ₃ solution (2 mL) was added to the solution and stirred for 3 hours. The mixture was concentrated and extracted with methylene chloride (3 × 20 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by column chromatography _{(CH 2 Cl 2 / MeOH /} NH 4 OH 95/5 / 0.5~90 / 10/1), to give the compound 18d of 490 mg (53% yield) of a white solid . ¹ H NMR (CD ₃ OD): δ 7.20 (1H, t, J = 7.8 Hz), 7.08-6.94 (3H, m), 3.63 (1H, dd, J = 10.5) , 3.9 Hz), 3.37 (1H, 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 amino alcohol 18d (150 mg, 0.909 mmol) in methylene chloride (5 mL) were added triethylamine (0.3 mL) and benzyl chloroformate (0.21 mL, 1.5 mmol). The mixture was stirred for 15 hours and then diluted with methylene chloride (20 mL). The solution was washed with brine (1 × 20 mL), dried (Na ₂ SO ₄ ) and concentrated. After column chromatography purification (15-30% EtOAc in hexane), compound 19d was obtained in 63% yield (170 mg). ¹ H NMR (CDCl ₃ ): δ 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 (1H, m), 3.69 (1H, br d), 3.58 (1H, dd, J = 14.5) , 5.4 Hz), 2.82 (2H, d, J = 6.9 Hz), 2.32 (3H, s); LCMS (ESP): 322 (M + Na ⁺ ).
Phosphoric acid benzyl ester 20d

Dibenzyl N, N-diisopropyl phosphoramidite (0.36 mL, 1.07 mmol) was added to an acetonitrile solution (8 mL) of alcohol 19d (160 mg, 0.535 mmol) and 1H-tetrazole (101 mg, 1.44 mmol) at 25 ° C. added. After 5 hours, MCPBA (0.42 g, purity 77%, 1.87 mmol) was added to the suspension. The solution was diluted with methylene chloride (35 mL), washed with concentrated NaHSO ₃ solution (2 × 25 mL), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (15-30% EtOAc in hexane) to give 0.287 g of compound 20d in 96% yield. ¹ H NMR (CDCl ₃ ): δ 7.39-7.2 (15H, m), 7.12 (1H, t, J = 7.8 Hz), 7.01 (1H, 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 21d

Palladium / carbon (10%, 58 mg) was added to an ethanol solution of phosphoric acid benzyl ester 20d (0.287 g, 0.513 mmol). The suspension was placed under a hydrogen atmosphere (1 atm) for 15 hours and then 5% HCl solution (5 mL) was added. The mixture was filtered through a celite pad. The filtrate was concentrated to remove the solvent to give 134 mg (92% yield) of 21d as a yellowish solid. ¹ H NMR (CD ₃ OD): δ 7.26 (1H, 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).
(Examples 25-33)
Phosphoric acid mono-[(R) -2-{[1- (diethylamino-oxo-2H-chromen-3-yl) -methanoyl] -amino} -3- (3-fluoro-phenyl) -propyl] ester

To a sodium carbonate solution (1M, 2 mL) was added aminophosphate 21c (50 mg, 0.176 mmol) and 7-diethylaminocoumarin-3-carboxylic acid succinimidyl ester (50 mg, 0.140 mmol). After 15 hours, 1M HCl solution was added at 0 ° C. to acidify it to pH˜1. Preparative HPLC purification gave 43 mg (57% yield) of the title compound 25-33. ¹ H NMR (CD ₃ OD): δ 8.69 (1H, s), 7.54 (1H, d, J = 9.04 Hz), 7.31 (1H, dd, J = 14.12, 7.91 Hz) ), 7.12 (2H, dd, J = 17.33, 9.80 Hz), 6.94 (1H, t, J = 8.86 Hz), 6.83 (1H, dd, J = 9.04, 2.44 Hz), 6.95 (1 H, d, J = 2.26 Hz), 4.50 (1 H, m), 4.07 (2 H, t, J = 4.71 Hz), 3.54 (4 H, m), 3.14-2.92 (2H, m ), 1.25 (6H, t, J = 7.16Hz); HRMS (MALDI): as _{C 23 H 26 FN 2 O 7} PH (M + H +) Calculated value 493.1549;
(Examples 25-34)
Phosphoric acid mono-((R) -2-{[1- (1-bromo-naphthalen-2-yl) -methanoyl] -amino} -3-m-tolyl-propyl) ester

To a solution of 1-bromo-2-naphthoic acid (123 mg, 0.49 mmol) in methylene chloride (3 mL) was added oxalyl chloride (0.128 mL, 1.47 mmol) and 2 drops of DMF. The mixture was stirred for 3.5 hours and concentrated under reduced pressure. To the residue was added sodium carbonate solution (1M, 2 mL), aminophosphate 21d (69 mg, 0.245 mmol) and 2 mL of acetonitrile. After 15 hours, concentrated hydrochloric acid solution was added at 0 ° C. to acidify it to pH˜1. Preparative HPLC purification gave 32 mg (27% yield) of the title compound 25-34. ¹ H NMR (CD ₃ OD): δ 8.22 (1H, d, J = 8.4 Hz), 7.82 (2H, m), 7.7.6-7.46 (2H, 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 (MALDI): Calculated value 478.0419 as C ₂₁ H ₂₂ NO ₅ PBr (M + H ⁺ ); Value 478.0438.
(Examples 25-35)
Phosphoric acid mono-((R) -2-{[1- (6-methoxy-naphthalen-2-yl) -methanoyl] -amino} -3-m-tolyl-propyl) ester

6-methoxy-2-naphthoic acid (99 mg, 0.49 mmol), oxalyl chloride (0.128 mL, 1.47 mmol), DMF (2 drops), sodium carbonate solution (1 M, 2 mL) and aminophosphate 21d (69 mg, 0.245 mmol) and was prepared as described in the synthesis of 25-32. Preparative HPLC purification gave 76 mg (51% yield) of the title compound 25-35. ¹ H NMR (CD ₃ OD): δ8.24 (1H, s), 7.86 (1H, d, J = 8.7 Hz), 7.82 (2H, m), 7.30 (1H, 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 (1H, dd, J = 13.9, 6.8 Hz), 2.96 (1H, dd, J = 14, 8.3 Hz), 2. 31 (3H, s); HRMS (MALDI): calcd _{C 22 H 25 NO 6 P (} M + H +) 430.1420; Found 430.1436.
Alcohol 26a

Acetonitrile (1 mL), aminoalcohol 18d (180 mg, 1.09 mmol) and 2-naphthoyl chloride (250 mg, 1.31 mmol) were added to a sodium carbonate solution (1 M, 2 mL). After 10 hours, the mixture was extracted with methylene chloride (2 × 20 mL). The combined organic layers were dried (MgSO ₄ ) and concentrated. The residue was purified by column chromatography (40% EtOAc in hexane) to give 350 mg (yield 100%) of compound 26a. ¹ H NMR (CD ₃ OD): δ 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 (1 H, m), 3.77 (1 H, dd, J = 11.1, 3.3 Hz), 3.68 (1 H, dd, J = 11.1, 5.1 Hz) ), 2.93 (2H, d, J = 7.2 Hz), 2.27 (3H, s).
Alcohol 26b

Amino alcohol 18d (131 mg, 0.794 mmol), 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). And was prepared as described in the synthesis of alcohol 26a. Purification by column chromatography (50% EtOAc in hexane) gave 230 mg (89% yield) of compound 26b. ¹ H NMR (CD ₃ OD): δ 7.96-7.81 (3H, m), 7.50-7.36 (2H, m), 7.21-7.04 (3H, m), 7. 01 (1 H, d, J = 7.5 Hz), 4.32 (1 H, m), 3.67 (1 H, d, J = 5.4 Hz), 3.00 (1 H, 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 (M + Na ⁺ ) 324 (M−H) ⁻ .
Phosphoric acid benzyl ester 27a

Dibenzyl N, N-diisopropyl phosphoramidite (0.92 mL, 941 mg, 2.728 mmol) was added to an acetonitrile solution (10 mL) of alcohol 26a (348 mg, 1.09 mmol) and 1H-tetrazole (191 mg, 2.728 mmol) at 25 ° C. ) Was added. After 5 hours, MCPBA (0.938 g, purity 60%, 3.27 mmol) was added to the suspension. The solution was diluted with methylene chloride (35 mL), washed with concentrated NaHSO ₃ solution (2 × 25 mL), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc in hexane) to give 0.400 g of compound 27a in 63% yield. ¹ H NMR (CDCl ₃ ): δ 8.34 (1H, s), 7.95-7.82 (3H, m), 7.55 (2H, m), 7.41-7.28 (11H, m ), 7.17 (1H, t, J = 7.5 Hz), 7.10-6.99 (3H, m), 5.15-4.97 (5H, m), 4.50 (1H, m) ), 4.17-3.96 (2H, m), 3.04 (1H, dd, J = 13.5, 5.4 Hz), 2.81 (1H, dd, J = 13.5, 9 Hz) 2.31 (3H, s).
Phosphoric acid benzyl ester 27b

Alcohol 26b (221 mg, 0.68 mmol), 1H-tetrazole (129 mg, 1.84 mmol), dibenzyl N, N-diisopropyl phosphoramidite (0.46 mL, 1.36 mmol) and MCPBA (0.533 g, purity 77%, 2.38 mmol) and was prepared as described in the synthesis of compound 27a. Purification by column chromatography (30% EtOAc in hexane) gave 0.50 g of compound 27b in 100% yield. ¹ H NMR (CDCl ₃ ): δ 7.89-7.78 (3H, m), 7.5-7.29 (13 H, m), 7.16 (1 H, 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).
(Examples 25-36)
Phosphoric acid mono- {2-[(1-naphthalen-2-yl-methanoyl) -amino] -3-m-tolyl-propyl} ester

Palladium / carbon (10%, 35 mg) was added to an ethanol solution of phosphoric acid benzyl ester 27a (0.35 g, 0.604 mmol). The suspension was placed under a hydrogen atmosphere (1 atm) for 15 hours and then filtered through a celite pad. All solvents were removed under reduced pressure. The residue was purified by preparative HPLC to give 45 mg (19% yield) of the title compound 25-36. ¹ H NMR (CD ₃ OD): δ 8.21 (1H, s), 7.9-7.76 (3H, m), 7.72 (1H, dd, J = 8.4, 1.8 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): C ₂₁ calculated _{H 23 NO 5 P (M +} H +) 400.1314; Found 400.1314.
(Examples 25-37)
Phosphoric acid mono- {2-[(1-benzo [b] thiophen-2-yl-methanoyl) -amino] -3-m-tolyl-propyl} ester

Prepared as described in the synthesis of 25-36 using benzyl phosphate ester (27b, 0.398 g, 0.68 mmol) with the addition of palladium / carbon (10%, 100 mg). The suspension was placed in a hydrogen atmosphere (1 atm) for 72 hours and then filtered through a celite pad. All solvents were removed under reduced pressure. The residue was purified by preparative HPLC to give 120 mg (44% yield) of the title compound 25-37. ¹ H NMR (CD ₃ OD): δ 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 (M−H) ⁻ ; calculated as elemental analysis (C ₁₉ H ₂₀ NO ₅ PS): C56.29, H4.97, N3.46; Value: C56.03, H4.94, N3.39.
Alcohol 28

To a THF solution (10 mL) of Boc-D-Ala (3-pyridyl) -OH (4.39 g, 16.5 mmol) at 0 ° C. was added a THF solution of borane (1M, 40 mL, 40 mmol). After 20 hours at 25 ° C., saturated NaHCO ₃ solution (5 mL) was added to the solution and stirred for 3 hours. The mixture was concentrated and extracted with methylene chloride (3 × 50 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by column chromatography (50% -100% EtOAc in hexane) to give 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 (1H, m), 3.87 (1H, m), 3.72 (1H, dd, J = 10.5, 3.6 Hz), 3.62 (1H, dd, J = 10. 5, 4.2 Hz), 2.95 (2H, m), 1.39 (9 H, m); LCMS (ESP): 253 (M + H ⁺ ), 275 (M + Na ⁺ ); HRMS (MALDI): C ₁₃ H Calc'd for ₂₁ N ₂ O ₃ (M + H ⁺ ) 253.1552; found 253.1564.
Benzyl phosphate 29

Dibenzyl N, N-diisopropyl phosphoramidite (2.66 mL, 7.91 mmol) was added to a solution of alcohol 28 (997 mg, 3.96 mmol) and 1H-tetrazole (1.11 g, 15.8 mmol) in acetonitrile (15 mL) at 25 ° C. ) Was added. After 3 hours, MCPBA (2.67 g, purity 77%, 11.9 mmol) was added to the suspension. The solution was diluted with methylene chloride (60 mL), washed with concentrated NaHSO ₃ solution (2 × 25 mL), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (50% -100% EtOAc in hexane) to give 0.481 g of compound 29 in 24% yield. ¹ H NMR (CDCl ₃ ): δ 8.46 (1H, 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

Palladium / carbon (10%, 15 mg) was added to an ethanol solution (3 mL) of benzyl ester 29 (48 mg, 0.094 mmol). The suspension was placed under a hydrogen atmosphere (1 atm) for 15 hours. After filtration, the filtrate was concentrated to remove the solvent, and 36 mg (yield 100%) of the title compound 30 was obtained. ¹ H NMR (CD ₃ OD): δ 8.58 (1H, s), 8.49 (1 H, br d), 8.19 (1 H, d, J = 7.5 Hz), 7.69 (1 H, br) t), 3.87 (1H, m), 3.79 (2H, m), 3.06 (1H, dd, J = 13.9, 5.3 Hz), 2.82 (1H, dd, J = 13.8,8.5Hz), 1.23 (9H, s ); HRMS (MALDI): calcd _{C 13 H 22 N 2 O 6} P (M + H +) 333.1216; Found 333.1218.
Aminophosphate 21e

To a methylene chloride solution (2.5 mL) of benzyl ester 29 (278 mg, 0.543 mmol) was added trifluoroacetic acid (0.75 mL) at 0 ° C. After 45 minutes, the solution was concentrated under reduced pressure to give 385 mg of amine 31 as a colorless oil. The crude amine 31 was dissolved in ethanol (5 mL) and palladium / carbon (10%, 75 mg) was added. The suspension was placed in a hydrogen atmosphere (1 atm) for 48 hours. After filtration, the filtrate was concentrated to remove the solvent, and compound 21e was obtained as a solid (225 mg, 100%). ¹ H NMR (CD ₃ OD): δ 8.68 (1H, br s), 8.27 (1 H, br s), 7.48 (1 H, m), 7.25 (1 H, m), 4.83 (1H, d), 4.0-3.6 (2H, m), 3.26-3.01 (2H, m); LCMS (ESP): 233 (M + H ⁺ ), 465 (2M + H ⁺ ); 231 (M−H) ⁻ .
(Examples 25-38)
Phosphoric acid mono- {2-[(1-benzo [b] thiophen-2-yl-methanoyl) -amino] -3-pyridin-3-yl-propyl} ester

Aminophosphate ester 21e (110 mg, 0.474 mmol) and 1-benzothiophene-2-carbonyl chloride (93 mg, 0.474 mmol) were added to a sodium carbonate solution (1M, 1 mL). After 15 hours, concentrated hydrochloric acid solution was added at 0 ° C. to acidify it to pH˜1. Preparative HPLC purification gave 25 mg (14% yield) of the title compound 25-38. ¹ H NMR (CD ₃ OD): δ 8.83 (1H, s), 8.71-8.63 (1H, 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 ): Calculated as C ₁₇ H ₁₈ N ₂ O ₅ PS (M + H ⁺ ) 393.0674; found 393.0681.
(Examples 25-39)
Phosphoric acid mono- {2-[(1-naphthalen-2-yl-methanoyl) -amino] -3-pyridin-3-yl-propyl} ester

Prepared as described in the synthesis of 25-34 using 21e (97 mg, 0.418 mmol), 2-naphthoyl chloride (80 mg, 0.418 mmol) and 1 M sodium carbonate solution (2 mL). Preparative HPLC purification gave 25 mg (16% yield) of the title compound 25-39. ¹ H NMR (CD ₃ OD): δ 8.85 (1H, s), 8.70 (1H, m), 8.58 (1H, d, J = 8.4 Hz), 8.323 (1H, s) 8.0-7.85 (4H, m), 7.79 (1H, 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): calcd _{C 19 H 20 N 2 O 5} P (M + H +) 387.1110; Found 387.1117.
(Example 33)
Phosphoric acid mono-{(R) -3-cyclohexyl-2-[(1-naphthalen-2-yl-methanoyl) -amino] -propyl} ester

To a solution of aminophosphate 21a (540 mg, 2.02 mmol) in acetic acid (70% aqueous solution, 7 mL) was added 5% rhodium / alumina (306 mg). The suspension was placed under a hydrogen atmosphere (60 psi) for 15 hours. After filtration, the filtrate was concentrated to remove the solvent, and 500 mg of compound 32 was obtained. A portion of 32 (96 mg, 0.416 mmol) was dissolved in 1M sodium carbonate solution (2 mL). To the solution was added 2-naphthoyl chloride (79 mg, 0.416 mmol). After 15 hours, concentrated hydrochloric acid solution was added at 0 ° C. to acidify it to pH˜1. Preparative HPLC purification gave 4 mg (2% yield) of the title compound 33. ¹ H NMR (CD ₃ OD): δ 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) ⁻ .
Amino alcohol 34

Borane in THF (1M, 55.8 mL, 55.8 mmol) was added to a THF solution (30 mL) of D-homophenylalanine (5 g, 27.9 mmol) at 0 ° C. After 48 hours, saturated NaHCO ₃ solution (5 mL) was added to the solution at 25 ° C. and stirred for 4 hours. The mixture was concentrated and extracted with methylene chloride (3 × 50 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by column chromatography (CH ₂ Cl ₂ / MeOH / NH ₄ OH 95/5 / 0.5) to obtain 1.2 g (yield 26%) of Compound 34. ¹ H NMR (CDCl ₃ ): δ 7.39-7.13 (5H, m), 4.01 (1H, dd, J = 11.4, 3.6 Hz), 3.69 (1H, dd, J = 11.7, 6.3 Hz), 2.94 (1 H, m), 2.71 (2 H, t, J = 7.8 Hz), 2.09 (1 H, m), 1.89 (1 H, m) LCMS (ESP): 166 (M + H ^< + ^> ).
Alcohol 35

To a sodium carbonate solution (1M, 2 mL) was added acetonitrile (2 mL), amino alcohol 34 (300 mg, 1.82 mmol) and 2-naphthoyl chloride (347 mg, 1.82 mmol). After 10 hours, the mixture was extracted with methylene chloride (3 × 20 mL). The combined organic layers were dried (MgSO ₄ ) and concentrated. The residue was purified by column chromatography (50% EtOAc in hexane) to give 220 mg (38% yield) of compound 35. ¹ H NMR (CDCl ₃ ): δ 8.16 (1H, 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 (1H, d, J = 7.2 Hz), 4.29 (1H, m), 3.87 (1H) , Dd, J = 11.1, 3.9 Hz), 3.78 (1H, dd, J = 10.8, 5.1 Hz), 2.81 (2H, t, J = 7.5 Hz), 2. 11-2.0 (2H, m); LCMS (ESP): 342 (M + Na ⁺ ); 318 (M−H) ⁻ ; calculated as elemental analysis (C ₂₁ H ₂₁ NO ₂ ): C78.97, H6. 63, N4.39; Found: C79.07, H6.62, N4.20.
Phosphoric acid benzyl ester 36

Dibenzyl N, N-diisopropyl phosphoramidite (0.433 mL, 1.29 mmol) was added to an acetonitrile solution (6 mL) of alcohol 35 (206 mg, 0.646 mmol) and 1H-tetrazole (122 mg, 1.74 mmol) at 25 ° C. added. After 5 hours, MCPBA (0.3 g, purity 77%, 2.26 mmol) was added to the suspension. The solution was diluted with methylene chloride (35 mL), washed with concentrated NaHSO ₃ solution (2 × 25 mL), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc in hexane) to give 0.311 g of compound 36 in 83% yield. ¹ H NMR (CDCl ₃ ): δ 8.28 (1H, 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)
Phosphoric acid mono- {2-[(1-naphthalen-2-yl-methanoyl) -amino] -4-phenyl-butyl} ester

10% Palladium / carbon (60 mg) was added to an ethanol solution of phosphoric acid benzyl ester 36 (0.305 g, 0.527 mmol). The suspension was placed under a hydrogen atmosphere (1 atm) for 15 hours and then filtered through a celite pad. All solvents were removed under reduced pressure to give 210 mg (100%) of the title compound 37. ¹ H NMR (CD ₃ OD): δ 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); HRMS (MALDI): C ₂₁ H ₂₃ NO ₅ Calculated value 400.1314 as P (M + H ⁺ );
Carboxylic acid 38

To a methylene chloride solution (8.5 mL) of D-3-fluorophenylalanine (0.5 g, 2.73 mmol), triethylamine (1 mL) and dansyl chloride (0.737 g, 2.73 mmol) were added. After 12 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (10 mL) and added to 5% HCl solution (10 mL). The resulting precipitate 38 was collected by filtration. Solid 38 was dissolved in MeOH (15 mL). After the solution was cooled to −20 ° C., thionyl chloride (1.5 mL) was added. After 15 hours, at 25 ° C., the solution was concentrated under reduced pressure and the residue was dissolved in EtOAc (50 mL). The EtOAc solution was washed with ice-cold saturated sodium carbonate solution (1 × 50 mL), dried over MgSO ₄ and concentrated to remove the solvent to give 506 mg of methyl ester 39. Solid 39 was dissolved in THF (10 mL) and LiBH ₄ (76 mg, 3.5 mmol) was added. After 15 hours, the reaction was quenched by slow addition to saturated NH ₄ Cl solution (1.5 mL). The mixture was extracted with EtOAc (3 × 25 mL), washed with brine (1 × 20 mL), dried (MgSO ₄ ) and concentrated. The residue was purified by column chromatography (50% EtOAc in hexanes) to give 308 mg (28% yield over 3 steps) of the desired compound 40. ¹ H NMR (CDCl ₃ ): δ 8.43 (1H, d, J = 8.4 Hz), 8.14 (1H, dd, J = 7.8, 0.9 Hz), 8.04 (1H, d, J = 8.7 Hz), 7.40 (2H, m), 7.07 (1H, d, J = 7.5 Hz), 6.78 (1 H, m), 6.55-6.46 (2H, m), 6.38 (1H, dt, J = 9, 1.2 Hz), 5.25 (1H, d, J = 10.5 Hz), 3.56 (1H, dd, J = 10.8, 3) 0.9 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).
Benzyl phosphate 41

Dibenzyl N, N-diisopropyl phosphoramidite (91.2 mg, 0.264 mmol) was added to an acetonitrile solution (1 mL) of alcohol 35 (53 mg, 0.132 mmol) and 1H-tetrazole (28 mg, 0.394 mmol) at 25 ° C. added. After 4 hours, 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 NaHSO ₃ solution (2 × 25 mL), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (35% EtOAc in hexane) to give 0.06 g of compound 41 in 69% yield. ¹ H NMR (CDCl ₃ ): δ 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 (10 H, m), 7.12 (1 H, 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)
Phosphoric acid mono-[(R) -2- (5-dimethylamino-naphthalene-1-sulfonylamino) -3- (3-fluoro-phenyl) -propyl] ester

10% Palladium / carbon (10 mg) was added to an ethanol solution of phosphoric acid benzyl ester 41 (0.06 g, 0.0906 mmol). The suspension was placed under a hydrogen atmosphere (1 atm) for 15 hours and then filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by HPLC to give 20 mg (46% yield) of the title compound 42. ¹ H NMR (CD ₃ OD): δ 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 (1H, m), 3.97 (1H, m), 3.62 (1H, m), 3.32 (6H, s), 2.90 (1H, 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 M, 5 mL), acetonitrile (5 mL), ethanolamine (0.173 mL, 3.12 mmol) and 2-naphthoyl chloride (594 mg, 3.12 mmol) were added. After 15 hours, the mixture was extracted with methylene chloride (3 × 50 mL). The combined organic layers were dried (MgSO ₄ ) and concentrated. The residue was purified by column chromatography (EtOAc) to obtain 386 mg (yield 58%) of compound 43. ¹ H NMR (CDCl ₃ ): δ 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): 216 (M + H ⁺ ), 238 (M + Na ⁺ ); Elemental analysis (C ₁₃ H ₁₃ NO ₂ ) Calculated: C72.54, H6.09, N6.51; Found: C72.68, H6.09, N6.51.
Phosphoric acid benzyl ester 44

To an acetonitrile solution (10 mL) of alcohol 43 (321 mg, 1.49 mmol) and 1H-tetrazole (282 mg, 4.02 mmol) was added dibenzyl N, N-diisopropyl phosphoramidite (1 mL, 2.99 mmol) at 25 ° C. . After 3 hours, MCPBA (purity 77%, 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 NaHSO ₃ solution (2 × 50 mL), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (50% -75% EtOAc in hexane) to give 0.699 g of compound 44 in 99% yield. ¹ H NMR (CDCl ₃ ): δ 8.34 (1H, s), 7.96-7.81 (4H, m), 7/55 (2H, m), 7.37-7.15 (11H, m ), 5.04 (4H, m), 4.19 (2H, m), 3.73 (2H, q, J = 5.1 Hz); LCMS (ESP): 498 (M + Na ⁺ ).
Phosphate ester 45

To an ethanol solution of benzyl phosphate 44 (0.672 g, 1.41 mmol) was added 10% palladium / carbon (134 mg). The suspension was placed under a hydrogen atmosphere (1 atm) for 2.5 hours and then filtered through a celite pad. The filtrate was concentrated under reduced pressure to remove the solvent, and 415 mg (yield 100%) of compound 45 was obtained as a white solid. ¹ H NMR (CD ₃ OD): δ 8.42 (1H, s), 8.03-7.87 (4H, m), 7.59 (2H, m), 4.20 (2H, q, J = 5.7 Hz), 3.73 (2H, t, J = 5.4 Hz); LCMS (ESP): 296 (M + H ⁺ ), 318 (M + Na ⁺ ); 294 (M−H) ⁻ , 589 (2M−H) ) ^-; elemental analysis _{(C 13 H 14 NO 5 P} 0.2H 2 O) calculated: C52.25, H4.86, N4.69; Found: C52.21, H4.95, N4.60.
Alcohol 47

Triethylamine (1 mL) and 2-naphthoyl chloride (0.629 g, 3.3 mmol) were added to a (0.5 g, 3 mmol) methylene chloride solution (5 mL) of D-phenyllactic acid at 0 ° C. After 12 hours, the mixture was diluted with EtOAc (80 mL), washed with ice-cold 5% HCl solution (1 × 50 mL), dried and concentrated. Residue 46 (0.9 g) was dissolved in THF (10 mL). The solution was cooled to −20 ° C. and 1M borane in THF (3 mL, 3 mmol) was added. The mixture was stirred at 25 ° C. for 6.5 hours before MeOH (15 mL) was added. After 15 minutes, all solvent was removed under reduced pressure. The residue was dissolved in MeOH (15 mL) and stirred for 1 hour. The solution was diluted with EtOAc (100 mL), washed with ice-cold 1M Na ₂ CO ₃ solution ( ₂ × 50 mL) and brine (1 × 50 mL), dried and concentrated. The residue was purified by column chromatography (35% EtOAc in hexane) to give 300 mg (33% yield) of Compound 47. ¹ H NMR (CDCl ₃ ): δ 8.57 (1H, s), 8.02 (1H, 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) ⁻ .
Benzyl phosphate 48

Dibenzyl N, N-diisopropyl phosphoramidite (260 mg, 0.75 mmol) was added to a solution of alcohol 43 (60 mg, 0.196 mmol) and 1H-tetrazole (70 mg, 1 mmol) in acetonitrile (10 mL) at 25 ° C. After 3 hours, MCPBA (purity 77%, 570 mg, 3 mmol) was added to the suspension at 0 ° C. The solution was diluted with methylene chloride (30 mL), washed with concentrated NaHSO ₃ solution (2 × 30 mL), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (1% THF in methylene chloride) to give 80 mg of compound 48 in 73% yield. ¹ H NMR (CDCl ₃ ): δ 8.57 (1H, s), 8.02 (1H, 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 (1H, dd, J = 13.5, 6.3 Hz), 3.01 (1H, dd, J = 13.5, 7.2 Hz).
(Example 49)
Naphthalene-2-carboxylic acid (R) -2-phenyl-1-phosphonooxymethyl-ethyl ester

10% Palladium / carbon (25 mg) was added to an ethanol solution of phosphoric acid benzyl ester 48 (80 mg, 0.141 mmol). The suspension was placed under a hydrogen atmosphere (1 atm) for 15 hours and then filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by HPLC to give 30 mg (55% yield) of the title compound 49. ¹ H NMR (CD ₃ OD): δ 8.53 (1H, s), 7.9-7.80 (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): calculated as C ₂₀ H ₂₀ O ₆ P (M + H ⁺ ) 387.0998; found 387.10.16.
α-hydroxycarboxylic acid

D-3-fluorophenylalanine (7.98 g, 43.8 mmol) was dissolved in 1M sulfuric acid solution (140 mL). To the solution was slowly added 6M NaNO ₂ solution (36 mL, 216 mmol) and 3.2 M sulfuric acid (36 mL) at 0 ° C. The mixture was stirred at 0 ° C. for 3 hours and then at 25 ° C. for 0.5 hour. The solution was extracted with EtOAc (7 × 75 mL). The combined organic layers were dried and concentrated. Recrystallization from EtOAc / hexane gave 5.36 g (yield 67%) of compound α-hydroxycarboxylic acid. ¹ H NMR (CDCl ₃ ): δ 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, 11.1 mmol) was added 1M borane in THF (16.6 mL, 16.6 mmol). The mixture was stirred at 25 ° C. for 16 hours. MeOH (15 mL) was added to quench the reaction. After 1 hour, all solvents were removed under reduced pressure. The residue was dissolved in methylene chloride (15 mL). To 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 (2 × 50 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (35% -50% EtOAc in hexane) to give 969 mg (51% yield) of compound 51. ¹ H NMR (CDCl ₃ ): δ 7.34-7.22 (1H, 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 = 11.7, 6.9 Hz), 2.78 (2H, m).
Phosphoric acid benzyl ester 52

Diol 51 (215 mg, 1.26 mmol) in methylene chloride (4 mL) was added to pyridine (1 mL), 4-dimethylaminopyridine (DMAP) (10 mg) and 10% chloride in benzene (8.8 mL, 2.78 mmol). Dibenzylphosphoryl was added. After 17 hours, the solution was diluted with methylene chloride (25 mL), washed with 5% HCl solution (1 × 30 mL), dried and concentrated. The residue was purified by column chromatography (35% EtOAc in hexane) to give 68 mg (13% yield) of compound 52. ¹ H NMR (CDCl ₃ ): δ 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 alcohol 52 (67 mg, 0.158 mmol) in methylene chloride (2 mL) were added triethylamine (1 mL) and 1-benzothiophene-2-carbonyl chloride (62 mg, 0.316 mmol). After 3 hours, the mixture was concentrated under reduced pressure. The residue was dissolved with methylene chloride (20 mL). The solution was washed with brine (1 × 20 mL), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (5-15% EtOAc in hexane) to give 23 mg (yield 24%) of compound 53. ¹ H NMR (CDCl ₃ ): δ 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 (1H, dd, J = 13.8, 6.9 Hz), 2.96 (1H, dd, J = 14.1, 6.6 Hz).
(Example 54)
Phosphoric acid mono-[(R) -2-[(1-benzo [b] thiophen-2-yl-methanoyl) -amino] -3- (3-fluoro-phenyl) -propyl] ester

To an ethanol solution of benzyl phosphate 53 (23 mg, 0.038 mmol), 10% palladium / carbon (5 mg) was added. The suspension was placed under a hydrogen atmosphere (1 atm) for 15 hours and then filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by HPLC to give 10 mg (yield 64%) of compound 54. ¹ H NMR (CD ₃ OD): δ 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): Calculated as C ₁₈ H ₁₇ O ₆ PS (M + H ⁺ ) 411.0468; found 411.0480.
Amino alcohol 55

To a THF solution (20 mL) of N-methyl-D-phenylalanine (2.5 g, 14 mmol) was added 1M borane in THF (20.9 mL, 20.9 mmol). After 15 hours, saturated NaHCO ₃ solution (5 mL) was added to the solution. The mixture was stirred vigorously for 48 hours and then extracted with methylene chloride (3 × 25 mL). The combined organic layers were dried over MgSO ₄ and concentrated. The residue was purified by column chromatography (95/5 / 0.5 to 90/10/1 CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH) to obtain 710 mg (yield 31%) of Compound 55. ¹ H NMR (CDCl ₃ ): δ 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 (1 M, 4 mL) was added acetonitrile (4 mL), amino alcohol 55 (377 mg, 2.28 mmol), and 2-naphthoyl chloride (435 mg, 2.28 mmol). After 15 hours, the mixture was extracted with methylene chloride (3 × 25 mL). The combined organic layers were dried (MgSO ₄ ) and concentrated. The residue was purified by column chromatography (50-100% EtOAc in hexane) to give 574 mg (yield 79%) of Compound 56. ¹ H NMR (CD ₃ OD): (mixture of two rotamers) δ 3.16 and 2.81 (3H, s); LCMS (ESP): 320 (M + H ⁺ ), 342 (M + Na ⁺ ); elemental analysis Calculated as (C ₂₁ H ₂₁ NO ₂ ): C78.97, H6.63, N4.39; Found: C79.00, H6.76, N4.47.
Phosphoric acid benzyl ester 57

Dibenzyl N, N-diisopropyl phosphoramidite (0.678 mL, 2.02 mmol) was added to an acetonitrile solution (8 mL) of alcohol 56 (322 mg, 1.01 mmol) and 1H-tetrazole (191 mg, 2.72 mmol) at 25 ° C. added. After 3 hours, MCPBA (0.523 g, purity 77%, 3.03 mmol) was added to the suspension. The solution was diluted with methylene chloride (35 mL), washed with concentrated NaHSO ₃ solution (2 × 25 mL), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (30-50% EtOAc in hexane) to give 0.23 g of compound 57 in 40% yield. _{^{1 H NMR (CDCl 3) :(}} 2 one, mixture of rotamers) δ5.06 (4H, m), 3.06 and 2.72 (3H, s); LCMS (ESP): 602 (M + Na +).
(Example 58)
Phosphoric acid mono-{[methyl- (1-naphthalen-2-yl-methanoyl) -amino] -phenyl-propyl} ester

アルコール５９

10% Palladium / carbon (45 mg) was added to an ethanol solution of phosphoric acid benzyl ester 57 (224 mg, 0.387 mmol). The suspension was placed under a hydrogen atmosphere (1 atm) for 3 hours and then filtered through a celite pad. The filtrate was concentrated under reduced pressure to remove the solvent to give 155 mg (yield 100%) of the title compound 58. ¹ H NMR (CD ₃ OD): (mixture of two rotamers) δ 3.18 and 2.87 (3H, s); LCMS (ESP): 398 (M−H) ⁻ .

Alcohol 59

To a solution of 3-fluorophenylalanine (2.2 g, 12 mmol) in methanol (12 mL) was added thionyl chloride (1 mL) at 30 ° C. After stirring at 25 ° C. for 15 hours, the reaction mixture was concentrated under reduced pressure to give 2.2 g of solid, which was then dissolved in DMF (25 mL). To the solution was 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 hours, the mixture was diluted with EtOAc (100 mL), washed with ice-cold 5% NaOH solution (1 × 80 mL) and brine (3 × 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 LiBH ₄ (0.52 g, 24 mmol). After 15 hours at 25 ° C., NH ₄ Cl (1 mL) was added slowly to quench the reaction. The suspension was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 40 mL), dried (MgSO ₄ ) and concentrated. The residue was purified by column chromatography (5% MeOH in CH ₂ Cl ₂ ) to give 400 mg (yield 11%) of compound 59. LCMS: 314 (M + H ^< + ^> , cation ESP); 312 (M-H < ^{- >} , anion ESP).
Phosphoric acid benzyl ester 60

Dibenzyl N, N-diisopropyl phosphoramidite (0.302 mL, 0.901 mmol) was added to an acetonitrile solution (6 mL) of alcohol 59 (188 mg, 0.601 mmol) and 1H-tetrazole (84 mg, 1.20 mmol) at 25 ° C. added. After 3 hours, MCPBA (404 mg, purity 77%, 1.80 mmol) was added to the suspension. The solution was diluted with EtOAc (20 mL), washed with 5% NaHSO ₃ solution (1 × 20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (98/2 / 0.2 CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH) and further purified by preparative HPLC to give 132 mg of compound 60 in 38% yield. It was. ¹ H NMR (CDCl ₃ ): δ 8.82 (1H, s), 7.89 (1H, d, J = 8.10 Hz), 7.75 (1H, d, J = 7.54 Hz), 7.47 (1H, d, J = 8.67 Hz), 7.37-7.19 (1H, m), 7.00 (1H, 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 (1H, dd, J = 13.94, 8.86 Hz); LCMS: 574 (M + H ⁺ ); 596 (M + Na ⁺ ).
(Example 61)
Mono-[(R) -2-[(1-3H-benzimidazol-5-yl-methanoyl) -amino] -3- (3-fluoro-phenyl) -propyl] ester of phosphoric acid

アルコール６２

Palladium / carbon (10%, 26 mg) was added to a methanol solution of phosphoric acid benzyl ester 60 (132 mg, 0.230 mmol). The suspension was placed under a hydrogen atmosphere (1 atm) overnight and then filtered through a celite pad. Preparative HPLC purification gave 11 mg (12% yield) of the title compound 61. ¹ H NMR (CD ₃ OD): δ 9.46 (1H, s), 8.26 (1H, s), 8.06-7.86 (1H, dd, J = 38.24, 8.85 Hz), 7.30 (1H, m), 7.20-7.04 (2H, m), 6.95 (1H, t, J = 10.36 Hz), 4.57 (1H, m), 4.13 ( 2H, m), 3.18-2.94 (2H, m); LCMS: 394 (M + H ⁺ ); 392 (M−H) ⁻ ; HRMS (MALDI): C ₁₇ H ₁₇ FN ₃ O ₅ PH (M + H ⁺ ) Calculated value 394.0962; found value 394.0968.

Alcohol 62

To a tetrahydrofuran solution (25 mL) of 2,3-difluoro-DL-phenylalanine (2.93 g, 14.6 mmol), 1 M borane-tetrahydrofuran (36.5 mL, 36.5 mmol) was slowly added at 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 hour. The solvent was distilled off and this procedure was repeated. The residue was dissolved in methylene chloride (50 mL), 1M NaHCO ₃ (30 ml) was added and stirred vigorously overnight. The mixture was extracted with methylene chloride (3 × 50 mL). The combined methylene chloride extracts were washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated. After column chromatography purification (95/5 / 0.5 CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH), compound 62 was obtained in 47% yield (1.28 g). ¹ H NMR (CH ₃ OD): δ 7.20-7.02 (3H, m), 3.54 (1H, dd, J = 10.93, 4.52 Hz), 3.44-3.35 (1H , M), 3.14-3.05 (1H, m), 2.93-2.84 (1H, m), 2.75-2.65 (1H, m); LCMS: 188.0 (M + H) ⁺ ).
Alcohol 63

To a methylene chloride solution (30 mL) of 62 (1.28 g, 6.84 mmol), triethylamine (1.9 mL, 13.7 mmol) and benzyl chloroformate (1.47 mL, 10.3 mmol) were added. The mixture was stirred overnight and then concentrated. The residue was dissolved in methylene chloride (30 mL) and washed with brine (1 × 30 mL). The solution was dried (Na ₂ SO ₄ ) and concentrated. After column chromatography purification (10-30% EtOAc in hexane), compound 63 was obtained in 59% yield (1.30 g). ¹ H NMR (CDCl ₃ ): δ 7.27 (5H, m), 7.03-6.86 (3H, m), 5.00 (2H, s), 3.90 (1H, m), 3. 70-3.47 (2H, m), 2.88 (1H, d, J = 6.80 Hz); MS (ESP): 322.1 (M + H ⁺ ); 344.1 (M + Na ⁺ ).
Phosphoric acid benzyl ester 64

Dibenzyl N, N-diisopropyl phosphoramidite (2.72 mL, 8.10 mmol) was added to an acetonitrile solution (20 mL) of alcohol 63 (1.30 g, 4.05 mmol) and 1H-tetrazole (765 mg, 10.9 mmol) at 25 ° C. ) Was added. After 3 hours, MCPBA (3.18 g, purity 77%, 14.2 mmol) was added to the suspension. The solution was diluted with EtOAc (80 mL), washed with 5% NaHSO ₃ solution (2 × 80 mL), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (10-30% EtOAc in hexane) to give 2.16 g of compound 64 in 92% yield. ¹ H NMR (CDCl ₃ ): δ 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 ⁺ ).
Aminophosphate 65

Palladium / carbon (10%, 300 mg) was added to a methanolic solution of benzyl phosphate 64 (2.16 g, 3.72 mmol). The suspension was placed in a hydrogen atmosphere (1 atm) for 4 hours and then filtered through a celite pad. The collected solid was washed with methylene chloride. The mixture of solid and celite was suspended in 5% HCl solution and stirred for 20 minutes. After filtration, the filtrate was concentrated to remove the solvent, yielding 910 mg of compound 65 in 92% yield. ¹ H NMR (DMSO): δ 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); LCMS: 268.0 (M + H ⁺ ); 266.1 (M−H) ⁻ .
Example 66
Phosphoric acid mono- {3- (2,3-difluoro-phenyl) -2-[(1-naphthalen-2-yl-methanoyl) -amino] -propyl} ester

To a sodium carbonate solution (1M, 5 mL) was added aminophosphate 65 (226 mg, 0.745 mmol) and 2-naphthyl chloride (142 mg, 0.745 mmol). After 15 hours, 1M HCl solution was added at 0 ° C. to acidify it to pH˜1. Preparative HPLC purification gave 135 mg (43% yield) of the title compound 66. ¹ H NMR (CD ₃ OD): δ 8.31 (1H, s), 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 (1H, dd, J = 13.69, 8.84 Hz); LCMS: 420.2 (M−H) ⁻ ; as elemental analysis (C ₂₀ H ₁₈ F ₂ NO ₅ P) Calculated values: C57.01, H4.31, N3.32; found values: C56.80, H4.55, N3.27.
(Example 67)
Phosphoric acid mono- [2-[(1-benzo [b] thiophen-2-yl-methanoyl) -amino] -3- (2,3-difluoro-phenyl) -propyl] ester

アミン６８

To a sodium carbonate solution (1M, 5 mL) was added aminophosphate 65 (199 mg, 0.656 mmol) and benzo [b] thiophene-2-carbonyl chloride (129 mg, 0.656 mmol). After 15 hours, it was acidified to pH˜1 by adding 1M HCl solution at 0 ° C. Preparative HPLC purification gave 75 mg (27% yield) of the title compound 67. ¹ H NMR (CD ₃ OD): δ 7.73-7.62 (3H, m), 7.23-7.15 (2H, m), 6.95-6.78 (3H, m), 4. 42-4.29 (1H, m), 3.97-3.82 (2H, m), 2.98 (1H, dd, J = 13.97, 4.91 Hz), 2.80 (1H, dd) , J = 13.98, 10.20 Hz); LCMS: 426.0 (M−H ⁻ ); calculated as elemental analysis (C ₁₈ H ₁₆ F ₂ NO ₅ PS 0.20H ₂ O): C50.16, H3.84, N3.25; found: C50.04, H3.85, N3.32.

Amine 68

Chlorotrimethylsilane (10.09 mL, 0.080 mol, 6 equivalents) was added to a solution of lithium borohydride (3 equivalents) in THF (45 mL) with stirring. The solution was stirred at room temperature for 5 minutes. (R) -3-Amino-4- (3-fluoro-phenyl) -butyric acid hydrochloride (3.10 g, 13.24 mmol) was added in portions and the reaction was stirred at room temperature overnight. The reaction was quenched with methanol and the solvent was distilled off under reduced pressure. The residue was diluted with H ₂ O and the pH was adjusted to 12 with aqueous NaOH. The product was extracted with chloroform, the organic layer was separated, washed sequentially with water and brine, dried (MgSO ₄ ) and evaporated to give 2.21 g (91%) of clear oil 68. ¹ H NMR (benzene-d ₆ ): δ 1.10-1.30 (m, 2H), 1.20-1.60 (br, 3H), 1.91 (dd, 1H, J = 8.3, 13.3 Hz), 2.18 (dd, 1H, J = 5.2, 13.3 Hz), 2.54-2.62 (m, 1H), 3.62-3.70 (m, 1H), 3.73-3.79 (m, 1H), 6.48 (d, 1H, J = 7.5 Hz), 6.55-6.59 (m, 1H), 6.69-6.76 (m , 1H), 6.83-6.90 (m, 1H); IR (neat) 1588, 1487, 1449, 1251, 1141, 1065, 783 cm ⁻¹ ; R _f = 0.18 (5% methanolic ammonia / _{CHCl 3); LCMS: 184 (} M + H).
Alcohol 69

Amine 68 (1.05 g, 5.72 mmol) was dissolved in CH ₂ Cl ₂ (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 1 hour and the solvent was removed under reduced pressure. The product was purified by flash column chromatography using a gradient elution of 30-60% EtOAc / hexane (R _f = 0.24 (50% EtOAc / hexane) to give 1.87 g (91%) of white solid 69. ¹ H NMR (DMSO-d ₆ ): δ 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, 1H), 4.42 (t, 1H, J = 5.1 Hz), 6.94-7.00 (m, 1H), 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, 1H, J = 8.5 Hz); LCMS: 344 (M + H).
Bromide 70:

Partially dissolved in CH ₂ Cl ₂ (50 mL) in alcohol 69 (1.77 g, 5.14 mmol) and cooled to 0 ° C. Triethyl phosphite (1.77 mL, 10.29 mmol) was added, followed by CBr ₄ (3.41 g, 10.29 mmol). The ice bath was removed and the reaction was allowed to warm to room temperature over 5 hours. The reaction was poured into CH ₂ Cl ₂ / H ₂ O. The organic layer was separated, washed with brine, dried (MgSO ₄ ) and evaporated. The crude product was purified by flash column chromatography using gradient elution of 3-50% EtOAc / hexanes (R _f = 0.18 (10% EtOAc / hexanes) to give 0.45 g (21%) of white solid 70. ¹ H NMR (DMSO-d ₆ ): δ 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, 1H), 6.96-7.08 (m, 3H), 7.26-7.33 (m, 1H), 7.40-7.47. (M, 2H), 7.92-8.01 (m, 2H), 8.06 (s, 1H), 8.57 (d, 1H, J = 8.5 Hz); LCMS: 406, 408 (M + H ).
(Example 71)
([(R) -3-[(Benzo [b] thiophene-2-carbonyl) -amino] -4- (3-fluoro-phenyl) -butyl] -phosphonic acid)

アルコール１９ａ

Bromide 70 (0.38 g, 0.93 mmol) was suspended in triethyl phosphite (5 mL), placed in a microwave apparatus and treated at 150 ° C. for 15 minutes, which made the reaction clear. The solvent was removed under reduced pressure. The crude product was chromatographed on flash silica gel chromatography using a gradient elution of 0-2% MeOH / CHCl ₃ and 0.11 g of diethyl phosphonate was purified as a clear oil (R _f = 0.24, 3% MeOH / CHCl 3). ₃ ). The oil was dissolved in CH ₂ Cl ₂ (3 mL) and treated with bromotrimethylsilane (0.15 mL, 1.2 mmol). The reaction was stirred at room temperature overnight. The solvent was removed and the residue was triturated with water. The resulting white precipitate was filtered, washed with water and dried to give 0.07 g (17%) of the title compound as a white solid 71. ¹ H NMR (DMSO-d ₆ ): δ 1.49-1.80 (m, 4H), 2.80-2.93 (m, 2H), 4.14-4.19 (m, 1H), 6 .94-7.00 (m, 1H), 7.07-7.09 (m, 2H), 7.24-7.32 (m, 1H), 7.40-7.46 (m, 2H) , 7.91-8.00 (m, 2H), 8.08 (s, 1H), 8.60 (d, 1H, J = 8.5Hz); HRMS: C 19 H 20 NO 4 calculated as PSF value 408.0835 (M + H), Found 408.0830; elemental analysis _{(C 19 H 19 NO 4 PSF} ): C, H, N.

Alcohol 19a

To a CH ₂ Cl ₂ solution (40 mL) of D-phenylalaninol (2.26 g, 14.9 mmol) at 0 ° C., triethylamine (3.11 mL, 22.4 mmol) and 2-naphthoyl chloride (3.13 g, 16. 4 mmol) was added. After 15 hours at 25 ° C., the mixture was diluted with CH ₂ Cl ₂ (50 mL), washed with brine (3 × 50 mL), dried and concentrated. The residue was purified by column chromatography (2% MeOH in CH ₂ Cl ₂ ) to give 1.33 g (yield 30%) of compound 19a as a white solid. ¹ H NMR (CDCl ₃ ): δ 8.16 (1H, s), 7.93-7.83 (3H, m), 7.73 (1H, 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 = 11.1,3.6Hz), 3.77 ( 1H, dd, J = 11,4.9Hz); elemental analysis _{(C 20 H} 19 NO ₂₎ as calculated: C78.66, H6. 27, N4.59; Found: C78.41, H6.37, N4.52.
(Example 72)
Sulfamic acid 2-[(1-naphthalen-2-yl-methanoyl) -amino] -3-phenyl-propyl ester

Water (28 μL, 1.57 mmol) was added to a solution of chlorosulfonyl isocyanate (136 μL, 1.57 mmol) in acetonitrile (1 mL) at 0 ° C. After stirring at 0 ° C. for 1.5 hours, acetonitrile (1 mL), pyridine (149 μL, 1.57 mmol), and alcohol (255 mg, 0.836 mmol) were added to the solution. The mixture was stirred at 25 ° C. for 15 hours, diluted with EtOAc (20 mL) and washed with ice-cold 2% HCl solution (1 × 20 mL). Purification by column chromatography (30-50% EtOAc in hexane) gave 19 mg (6% yield) of the title compound 72. ¹ H NMR (CD ₃ OD): δ 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)
Sulfuric acid mono- {2-[(1-naphthalen-2-yl-methanoyl) -amino] -3-phenyl-propyl} ester.

To a solution of alcohol (105 mg, 0.344 mmol) in CH ₂ Cl ₂ (5 mL) was added triethylamine (0.5 mL) and chlorosulfonic acid (116 mg, 90 μL, 1 mmol) at −30 ° C. After stirring at 25 ° C. for 15 hours, the mixture was diluted with EtOAc (10 mL), washed with ice-cold 2% HCl solution (1 × 15 mL), dried and concentrated. The residue was purified by column chromatography to obtain 131 mg (yield 87%) of the title compound 73 as a white solid. ¹ H NMR (CD ₃ OD): δ 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} ): C 20 H 18 NO 5 SNa 2 (M-H + + 2Na +) calculated 430.0695; found 430.0676.
Alcohol 47a

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, 4.54 mmol), and triethylamine (2.9 mL) were used. In the second step, 1M borane in THF (4.73 mL) was used. After purification by column chromatography (40% EtOAc in hexane), compound 47a was obtained as a crude oil (137 mg). LCMS: 325 (M + H ^< + ^> ).
Benzyl ester 48a

Alcohol 47a (137 mg, 0.423 mmol), 1H-tetrazole (68 mg, 0.973 mmol), dibenzyl N, N-diisopropyl phosphoramidite (0.213 mL, 0.634 mmol), and MCPBA (380 mg, purity 77%, 1 Benzyl ester 48a was prepared as described in the synthesis of 48. After column chromatography purification (10% -20% EtOAc in hexane), compound 48a was obtained as a crude oil (330 mg), which was used in the next step.
(Example 74)
Naphthalene-2-carboxylic acid (R) -1- (3-fluoro-benzyl) -2-phosphonooxy-ethyl ester

Ｄ−フェニルアラニノール１８ｃ

Example 74 was prepared as described in the synthesis of 49 using the crude benzyl ester (330 mg) and 10% palladium / carbon (70 mg). Preparative HPLC purification gave 70 mg of the title compound 74 (31% yield from alcohol). ¹ H NMR (CD ₃ OD): δ 8.56 (1H, 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 (1 H, dd, J = 11.8, 6 Hz), 3. LCMS (negative ion ESP): 403 (MH); HRMS (MALDI): calculated as C ₂₀ H ₁₉ O ₆ FP (M + H ⁺ ) 405.0903; found 405.0902.

D-Phenylalaninol 18c

To a tetrahydrofuran solution (30 mL) of D-3-fluorophenylalanine (5.00 g, 27.3 mmol), a tetrahydrofuran solution of 1M borane (68.3 mL, 68.3 mmol) was slowly added at 0 ° C. The mixture was warmed to room temperature and stirred overnight. Methanol (40 mL) was added and stirred vigorously for 1 hour. The solvent was distilled off and this procedure was repeated. The residue was dissolved in methylene chloride (100 mL) and stirred vigorously with 1M NaHCO ₃ (50 ml) overnight. The mixture was extracted with methylene chloride (3 × 50 mL). The combined methylene chloride extracts were washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated. After column chromatography purification (95/5 / 0.5 CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH), compound 18c was obtained in 28% yield (1.29 g). ¹ H NMR (CD ₃ OD): δ 7.34 (1H, m), 7.09-6.92 (3H, m), 3.54 (1H, dd, J = 10.74, 4.33 Hz), 3.39 (1H, dd, J = 10.74, 6.60 Hz), 3.13-3.02 (1 H, m), 2.83 (1 H, dd, J = 13.37, 6.21 Hz) 2.62 (1H, dd, J = 13.38, 7.73 Hz); LCMS: 170.1 (M + H ⁺ ).
Amine 75

To a DMF solution (10 mL) of D-phenylalaninol 18c (1.30 g, 7.70 mmol), imidazole (1.05 g, 15.4 mmol) and t-butyldiphenylchlorosilane (TBDPSCl) (2.40 mL, 9.24 mmol). ) Was added. After stirring overnight, the mixture was diluted with ether (80 mL), washed with saturated ammonium chloride (1 × 50) and brine (1 × 50 mL), and dried (Na ₂ SO ₄ ). The solvent was removed under reduced pressure. The residue was purified by column chromatography (95/5 CH ₂ Cl ₂ / CH ₃ OH) to obtain 2.35 g (yield 74%) of Compound 75. ¹ H NMR (CDCl ₃ ): δ 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 (1H, 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 (1 H, dd, J = 13.38, 8.29 Hz), 2.52 (1H, dd, J = 13.38, 8.29 Hz), 1.08 (9 H, s); LCMS: 408.2 (M + H ⁺ ), 430.2 (M + Na ⁺ ).
Silyl ether 76

To a solution of amine 75 (2.35 g, 5.77 mmol) and triethylamine (1.53 mL, 11.0 mmol) in methylene chloride (15 mL) was added a solution of triphosgene (1.03 g, 3.46 mmol) in methylene chloride (2 mL). It was. After 2 hours, the solution was heated under reflux conditions for 1.5 hours and then cooled to 25 ° C. A solution of amine 6a (2.19 g, 5.77 mmol) in methylene chloride (25 mL) was added. After 15 hours, the reaction solution was diluted with CH ₂ Cl ₂ (80 mL), washed with brine (2 × 80 mL), dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The residue was purified by flash column chromatography (5-20% EtOAc in hexane) to give 3.92 g (79% yield) of compound 76. ¹ H NMR (CDCl ₃ ): δ 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 (1H, d, J = 8.29Hz), 5.01-4.94 (1H, m) 4.93-4.88 (1H, m), 4.11-3.97 (1H, 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 1M HF / pyridine (7 mL) at 0 ° C. The reaction mixture was warmed to 25 ° C. after 30 minutes and stirred overnight. THF was removed under reduced pressure. The residue was dissolved in methylene chloride (50 mL) and washed with cold 1M HCl (2 × 50). The solution was concentrated. The obtained residue was purified by column chromatography (30% EtOAc in hexane) to obtain 2.26 g (yield 82%) of Compound 77. ¹ H NMR (CDCl ₃ ): δ 7.33-7.23 (4H, m), 7.22-7.12 (6H, m), 7.06-6.89 (3H, m), 4.99 (1H, m), 4.90 (1H, m), 4.05-3.94 (1H, m), 3.72 (1H, d, J = 3.20 Hz), 3.68 (1H, d) , J = 3.02 Hz), 3.60-3.50 (1 H, m), 3.39 (1 H, d, J = 11.68 Hz), 3.18-3.05 (1 H, 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 (1H, m), 1.33-1.20 (1H, m).
Phosphoric acid benzyl ester 78

To a solution of alcohol 77 (2.26 g, 3.94 mmol) and 1H-tetrazole (552 mg, 7.88 mmol) in acetonitrile (35 mL) at 25 ° C. was added dibenzyl N, N-diisopropyl phosphoramidite (1.98 mL, 5.91 mmol). ) Was added. After 3 hours, MCPBA (2.65 g, purity 77%, 11.8 mmol) was added to the suspension. The solution was diluted with EtOAc (100 mL), washed with concentrated NaHSO ₃ solution (2 × 80 mL), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (10-30% EtOAc in hexane) to give 2.23 g of compound 78 in 68% yield. ¹ H NMR (CDCl ₃ ): δ 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 (1H, 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 (1H, m), 3.00-2.87 (1H, m), 2.83 -2.73 (1H, m), 2.54-2.35 (5H, m), 2.08-1.97 (1H, m), 1.55-1.32 (5H, m), 1 .13-1.06 (6H, m).
(Example 79)
(S) -1-[(R) -2- (3-Fluoro-phenyl) -1-phosphonooxymethyl-ethylcarbamoyl] -piperidine-2-carboxylic acid 4-phenyl-1- (3-phenyl-propyl) ) -Butyl ester

（実施例８０）
１−［１−（ビス−アセトキシメトキシ−ホスホリルオキシメチル）−２−フェニル−エチルカルバモイル］−ピペリジン−２Ｓ−カルボン酸４−フェニル−１−（３−フェニル−プロピル）−ブチルエステル

Palladium / carbon (10%, 80 mg) was added to a methanol solution of benzyl phosphate 78 (400 mg, 0.479 mmol). The suspension was placed under a hydrogen atmosphere (1 atm) overnight and then filtered through a celite pad. The filtrate was purified by preparative HPLC to give 160 mg of compound 79 in 51% yield. ¹ H NMR (CD ₃ OD): δ 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 (1H, m), 3.07-2.90 (2H, m), 2.88-2.76 (1H, 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 (MALDI): Calc'd for C ₉ H ₁₅ NO ₄ P (M + H ⁺ ) 655.22954; found 6555.2958.

(Example 80)
1- [1- (Bis-acetoxymethoxy-phosphoryloxymethyl) -2-phenyl-ethylcarbamoyl] -piperidine-2S-carboxylic acid 4-phenyl-1- (3-phenyl-propyl) -butyl ester

Bromomethyl acetate (15.4 μL, 24.2 mg, 0.158 mmol) and diisopropylethylamine (0.1 mL) were added to a solution of phosphate ester 16a (10 mg, 0.0158 mmol) in acetonitrile at 0 ° C. After 2 hours at 20 ° C., the solution was concentrated under reduced pressure. The residue was purified by column chromatography (inactivated with 1% Et ₃ N in hexane and eluted with 30% EtOAc in hexane) to give 5 mg (41% yield) of the title compound 80. ¹ H NMR (CDCl ₃ ): δ 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): calculated as C ₄₁ H ₅₃ N ₂ O ₁₁ P (M + H ⁺ ) 803.3279; Value 803.3258.
(Example 81)
Acetic acid acetoxymethoxy- (2-{[1- (1-bromo-naphthalen-2-yl) -methanoyl] -amino} -3-phenyl-propoxy) -phosphoryloxymethyl ester

25-24 (23 mg, 0.05 mmol), bromomethyl acetate (24.5 μL, 38.2 mg, 0.25 mmol) and diisopropylethylamine (0.1 mL) were used as described in the synthesis of Example 80. Example 81 was prepared. Purification by Et ₃ N inactivated column chromatography (30% EtOAc in hexane) afforded 3 mg (10% yield) of the title compound 81. ¹ H NMR (CDCl ₃ ): δ 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 (5 H, m), 6.52 (1 H, br d, J = 9 Hz), 5.64 (4 H, 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)
Acetic acid acetoxymethoxy-{(R) -2- [3- (2-phenoxy-phenyl) -ureido] -3-phenyl-propoxy} -phosphoryloxymethyl ester

Example 82 was prepared as described in the synthesis of Example 80 using 23b (22 mg, 0.0498 mmol), bromomethyl acetate (24 μL, 0.249 mmol) and diisopropylethylamine (0.05 mL). Purification by Et ₃ N inactivated column chromatography (50% EtOAc in hexane) gave 9 mg (31% yield) of the title compound 82. ¹ H NMR (CDCl ₃ ): δ 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 (1H, dd, J = 8.4, 1.8 Hz), 5.65-5.49 (5H, m). 28 (1H, m), 4.17 (1H, m), 4.02 (1H, m), 3.01 (1H, dd, J = 13.2, 5.7 Hz), 2.81 (1H, dd, J = 13.5, 9 Hz), 2.05 (3H, s), 2.04 (3H, s); LCMS (ESP): 609 (M + Na ⁺ ).
(Example 83)
Acetic acid acetoxymethoxy- [2-({1- [5- (3,5-dichloro-phenoxy) -furan-2-yl] -methanoyl} -amino) -3-phenyl-propoxy] -phosphoryloxymethyl ester

Example 83 was prepared as described in the synthesis of Example 80 using 25-4 (23 mg, 0.0473 mmol), bromomethyl acetate (23 μL, 0.237 mmol) and diisopropylethylamine (0.049 mL). . Purification by Et ₃ N inactivated column chromatography (50% EtOAc in hexane) afforded 6 mg (20% yield) of the title compound 83. ¹ H NMR (CDCl ₃ ): δ 7.37-7.17 (6H, m), 7.11 (1H, d, J = 3.3 Hz), 7.00 (2H, d, J = 1.5 Hz) 6.67 (1H, br d.J = 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 (1 H, m), 3.02 (1 H, dd, J = 13.5, 6.3 Hz), 2.93 (1 H, dd, J = 13.8) , 8.1 Hz), 2.11 (3H, s), 2.09 (3H, s).
(Example 84)
Acetic acid acetoxymethoxy-{(R) -3- (3-fluoro-phenyl) -2-[(1-naphthalen-2-yl-methanoyl) -amino] -propoxy} -phosphoryloxymethyl ester

Example 84 was prepared as described in the synthesis of Example 80 using 25-28 (50 mg, 0.124 mmol), bromomethyl acetate (61 μL, 0.620 mmol) and diisopropylethylamine (0.13 mL). . Et ₃ N inactivated column chromatography (30-50% EtOAc in hexane) afforded 17 mg (25% yield) of the title compound 84. ¹ H NMR (CDCl ₃ ): δ 8.39 (1H, 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 +); HRMS (MALDI): calcd _{C 26 H 28 NO 9 FP (} M + H +) 548.148 ; Found 548.1489.
(Example 85)
Acetoxymethoxyacetate-[(R) -2-[(1-benzo [b] thiophen-2-yl-methanoyl) -amino] -3- (3-fluoro-phenyl) -propoxy] -phosphoryloxymethyl ester

Example 85 was prepared as described in the synthesis of Example 80 using 25-29 (45 mg, 0.11 mmol), bromomethyl acetate (55 μL, 0.55 mmol) and diisopropylethylamine (0.115 mL). . Et ₃ N inactivated column chromatography (30-50% EtOAc in hexane) afforded 39 mg (64% yield) of the title compound 85. ¹ H NMR (CDCl ₃ ): δ 7.92-7.81 (3H, m), 7.48-7.27 (3H, m), 7.09 (1 H, 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), 5.76-5.59 (4H, m), 4. 54 (1 H, m), 4.27 (1 H, m), 4.13 (1 H, 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 (MALDI): C 24 H} 26 NO 9 calculated for ^{FPS (M + H +) 554.1050} ; Found 554.1044.
(Example 86)
Phosphoric acid (R) -2- (5-dimethylamino-naphthalene-1-sulfonylamino) -3- (3-fluoro-phenyl) -propyl ester diphenyl ester

To a THF solution (10 mL) of alcohol 40 (300 mg, 0.746 mmol), Et ₃ N (0.5 mL), DMAP (30 mg) and diphenylchlorophosphate (0.23 mL, 301 mg, 1.12 mmol) were added. After 15 hours, the solution was diluted with EtOAc (50 mL), washed with brine (2 × 50 mL), dried and concentrated. The residue was purified by column chromatography to give 310 mg (yield 66%) of the title compound 86. ¹ H NMR (CDCl ₃ ): δ 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 (1 H, m), 6.60 (1 H, td, J = 8.4, 2.4 Hz), 6.50 (1 H, d, J = 7.5 Hz), 6.40 (1H, 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 1M Na ₂ CO ₃ solution (5 mL), D-3-fluorophenylalanine (0.5 g, 2.73 mmol) and 1-benzothiophene-2-carbonyl chloride (62 mg, 0.316 mmol) were added at 0 ° C. After 15 hours at 20 ° C., the mixture was acidified by adding ice-cold 5% HCl solution (10 mL). The suspension was extracted with methylene chloride (3 × 25 mL). The combined organic layers were dried over MgSO ₄ and concentrated to give 0.6 g of 87 as a white solid. Carboxylic acid 87 was dissolved in THF (5 mL). To the THF solution was added 1M borane in THF (1.31 mL) at 0 ° C. After 15 hours at 25 ° C., saturated NaHCO ₃ solution (15 mL) was added. The suspension was stirred for 3 hours and then extracted with methylene chloride (3 × 25 mL). The combined organic layers were washed with brine (2 × 25 mL), dried over Na ₂ SO ₄ and concentrated. Purification by column chromatography (35% EtOAc in hexane) gave 200 mg (yield 22.5%) of compound 88. ¹ H NMR (CDCl ₃ ): δ 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, brd, J = 7.5 Hz), 4.37 (1H, m), 3.77 (2H, m), 3.03 (2H , AB), 2.33 (1H, br s).
Example 89
2-[(1-Benzo [b] thiophen-2-yl-methanoyl) -amino] -3- (3-fluoro-phenyl) -propyl ester diphenyl ester of phosphoric acid

Described in the synthesis of Example 86 using alcohol 88 (40 mg, 0.122 mmol), Et ₃ N (0.1 mL), DMAP (4 mg) and diphenyl chlorophosphate (0.29 μL, 37.6 mg, 0.14 mmol). Example 89 was prepared as described. Column chromatography purification (40% EtOAc in hexane) gave 62 mg (97% yield) of the title compound 89. ¹ H NMR (CDCl ₃ ): δ 7.84 (1H, d, J = 7.5 Hz), 7.76 (1H, 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 (1H, 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 (1 H , Dd, J = 13.5, 9.3 Hz); HRMS (MALDI): Calculated as C ₃₀ H ₂₆ NO ₅ FPS (M + H ⁺ ) 562.1253; found 562.1279.
(Example 90)
1- [1-bis-acetoxymethoxy-phosphoryloxymethyl) -2-phenyl-ethylsulfamoyl)]-piperidine-2S-carboxylic acid 4-phenyl-butyl ester

Example 90 was prepared as described in the synthesis of Example 80 using 5b1 (20 mg, 0.036 mmol), bromomethyl acetate (36 μL, 0.36 mmol) and diisopropylethylamine (0.1 mL). Purification by Et ₃ N inactivated column chromatography (40% EtOAc in hexane) gave 25 mg (100% yield) of the title compound 90. ¹ H NMR (CDCl ₃ ): δ 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 ( 1H, br d), 2.13 (6H, s); MS (ESP): 721 (M + Na ⁺ ); 733 (M + Cl) ⁻ .
(Example 91)
(S) -1-[(R) -1- (bis-acetoxymethoxy-phosphoryloxymethyl) -2-phenyl-ethylcarbamoyl] -piperidine-2-carboxylic acid

Example 16d (60 mg, 0.155 mmol), bromomethyl acetate (0.15 μL, 1.55 mmol) and diisopropylethylamine (0.4 mL, 2.33 mmol) were used as described in the synthesis of Example 80. 91 was produced. Purification by Et ₃ N inactivated column chromatography (40% EtOAc in hexane) afforded 45 mg (55% yield) of the title compound 91. ¹ H NMR (CDCl ₃ ): δ 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 (1 H, m), 3.98 (1 H, dd, J = 13.8, 5.1 Hz), 3.55 (1 H, dd, J = 12, 4.2 Hz), 3.16 (1 H, dd, J = 13.8, 9.3 Hz), 3.02 (1 H, dd, J = 13.8, 6 Hz), 2.69 (1 H , Td, J = 13.2, 3.3 Hz), 2.10 (3H, s), 2.10 (3H, s).
(Example 92)
Acetic acid acetoxymethoxy-[(R) -2-[(7-diethylamino-2-oxo-2H-chromene-3-carbonyl) -amino] -3- (3-fluoro-phenyl) -propoxy] -phosphoryloxymethyl ester

Example 25-33 (18 mg, 0.0366 mmol), bromomethyl acetate (0.03 mL, 0.3 mmol) and diisopropylethylamine (0.1 mL, 0.6 mmol) were used as described in the synthesis of Example 80. Example 92 was produced as described above. Purification by Et ₃ N inactivated column chromatography (100% EtOAc in hexane) gave 5 mg (25% yield) of the title compound 92. ¹ H NMR (CDCl ₃ ): δ 9.05 (1H, d, J = 8.3 Hz), 8.64 (1H, s), 7.41 (1H, t, J = 9.1 Hz), 7.26 (1H, m), 7.08 (1H, d, J = 7.5 Hz), 7.02 (1H, brd, J = 9.8 Hz), 6.92 (1H, td, J = 8.3) 2.1 Hz), 6.64 (1H, dd, J = 9.3, 2.7 Hz), 6.49 (1H, d, J = 2.2 Hz), 5.67 (1H, dd, J = 13.6, 0.9 Hz), 4.55 (1 H, br s), 4.17 (2 H, m), 3.46 (4 H, 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)
Acetic acid acetoxymethoxy- [3-[(benzo [b] thiophene-2-carbonyl) -amino] -4- (3-fluoro-phenyl) -butyl] -phosphinoyloxymethyl ester

実施例１００の合成

ホスホン酸エステル９５：

Example 71 (22 mg, 0.0541 mmol), bromomethyl acetate (0.05 mL, 0.52 mmol) and diisopropylethylamine (0.13 mL, 0.77 mmol) were used as described in the synthesis of Example 80. Example 93 was prepared. Purification by flash column chromatography (100% EtOAc in hexane) gave 23 mg (77% yield) of the title compound 93. ¹ H NMR (CDCl ₃ ): δ 7.88-7.79 (3H, m), 7.41 (2H, m), 7.27 (1H, m), 7.02 (1H, d, J = 7) .6 Hz), 6.94 (2 H, m), 6.80 (1 H, d, J = 8.6 Hz), 5.71-5.55 (4 H, m), 4.38 (1 H, br t, J = 7.3 Hz), 3.05 (1H, dd, J = 13.7, 6.1 Hz), 2.87 (1H, dd, J = 13.7, 7.1 Hz), 2.12 (3H) , S), 2.05 (3H, s).

Synthesis of Example 100

Phosphonate 95:

To a suspension of polymer-supported triphenylphosphine (1.69 g, 4.53 mmol) in dry CH ₂ Cl ₂ (20 mL), iodine (1.15 g, 4.53 mmol) was added. After 15 minutes, imidazole (0.33 g, 5.15 mmol) was added. The suspension was stirred for an additional 15 minutes. A solution of 19c (600 mg, 2.06 mmol) in CH ₂ Cl ₂ (8 mL) was added. The mixture was heated under reflux conditions for 1 hour. After the mixture was cooled to 25 ° C., the polymer solid was removed by filtration. The filtrate was washed with Na ₂ S ₂ O ₃ solution (concentrated solution, 2 × 30 mL) water (1 × 25 mL) and brine (1 × 25 mL). All solvents were removed under reduced pressure to give 914 mg (100%) of iodide 94 as a yellow solid. A portion of iodide 94 (420 mg) was mixed with triethyl phosphite (2.5 mL) in a sealed tube. The suspension was heated by microwave irradiation at 150 ° C. for 30 minutes. Triethyl phosphite was removed under reduced pressure. The residue was purified by column chromatography (30-50% EtOAc in hexane) to give 80 mg (19% yield) of phosphonic acid ester 95 as a colorless oil. ¹ H NMR (CDCl ₃ ): δ 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 (cationic APCI): 424 (M + H ⁺ ), 446 (M + Na ⁺ ).
Amine 96

Palladium / carbon (10%, 40 mg) was added to an ethanol solution (5 mL) of compound 95 (235 mg, 0.556 mmol). The suspension was placed in a hydrogen (1 atm) atmosphere for 15 hours. After filtration, the filtrate was concentrated. The residue was purified by column chromatography (MeOH / CH ₂ Cl ₂ 5/95) to give 148 mg (yield 92%) of compound 96 as an oil. ¹ H NMR (DMSO-d ₆ ): δ 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 (1H, dd, J = 12.2, 6.1 Hz), 2.06 (2H, br s), 1.9-1.70. (2H, m). LCMS (cationic APCI): 290 (M + H ^< + ^> ), 312 (M + Na ^< + ^> ).
Amide 97

A solution of amine 96 (144 mg, 0.498 mmol) in methylene chloride (5 mL) at 0 ° C. with triethylamine (0.139 mL, 0.996 mmol), 4- (dimethylamino) pyridine (6 mg, 0.0498 mmol), and chloride 1 -Benzothiophene-2-carbonyl (123 mg, 0.623 mmol) was added. After 15 hours at 25 ° C., the mixture was diluted with methylene chloride (20 mL) and washed with ice-cold HCl solution (1M, 1 × 20 mL), sodium carbonate solution (1M, 1 × 20 mL), and brine (1 × 20 mL). The solution was then dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by column chromatography (30-50% EtOAc in hexane) to give 150 mg (67% yield) of compound 97 as a white solid. ¹ H NMR (CDCl ₃ ): δ 7.85-7.65 (3H, m), 7.33 (2H, m), 7.21-7.15 (1H, m), 7.03 (1H, d , J = 7.7 Hz), 6.96 (1H, br d, J = 9.9 Hz), 6.88 (1H, td, J = 8.1, 1.9 Hz), 4.51 (1H, d , J = 2.1 Hz), 4.16-3.97 (4H, m), 3.17 (1H, 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)
[2-[(Benzo [b] thiophene-2-carbonyl) -amino] -3- (3-fluoro-phenyl) -propyl] -phosphonic acid

Bromotrimethylsilane (1 mL) was added to a methylene chloride solution (2 mL) of phosphonate ester 97 (140 mg, 0.31 mmol). After 15 hours, the solution was concentrated under reduced pressure. The oily residue was triturated with water (3 × 2 mL). In the process, filtration gave white solid 98 (110 mg, 89% yield). ¹ H NMR (DMSO-d ₆ ): δ 8.66 (1H, 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 (positive ion APCI): 394 (M + H ⁺ ), 416 (M + Na ⁺ ); elemental analysis _{(C 18 H 17 NO 4 PFS} 0.3H 2 O) calculated: C54.21, H4.45, N3.51; Found: C54.15, H4.47, N3.47.
Example 99
Acetic acid acetoxymethoxy- [2- [benzo [b] thiophene-2-carbonyl) -amino] -3- (3-fluoro-phenyl) -propyl] -phosphinoyloxymethyl ester

To an acetonitrile solution (1 mL) of phosphonic acid 98 (31.8 mg, 0.0809 mmol), diisopropylethylamine (0.127 mL, 0.728 mmol) and bromomethyl acetate (60 μL, 0.607 mmol) were added at 0 ° C. After 15 hours at 25 ° C., the solution was concentrated and the resulting residue was purified by column chromatography (50-70% EtOAc in hexane) to afford 26 mg (59% yield) of the title compound 99 as a white solid. Obtained. ¹ H NMR (CD ₃ OD): δ 7.85-7.75 (3H, m), 7.33 (2H, m), 7.19 (1H, q, J = 8 Hz), 6.99 (1H, d, J = 7.5 Hz), 6.94 (1H, dt, J = 7.6, 2.2 Hz), 6.84 (1H, 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): calcd _{C 24 H 26 NO 8 FPS (} M + H +) 538.1129; Found 538.1101.
(Example 100)
2,2-Dimethyl-propionic acid [3-[(benzo [b] thiophen-2-carbonyl) -amino] -4- (3-fluoro-phenyl) -butyl]-(2,2-dimethyl-propionyloxymethoxy ) -Phosphinoyloxymethyl ester

Example 71 (50 mg, 0.123 mmol) in acetonitrile (5 mL) at 0 ° C. with tetrabutylammonium iodide (5 mg), diisopropylethylamine (0.2 mL), and chloromethyl pivalate (132 μL, 0.92 mmol). Was added. The solution was heated at 60 ° C. for 4 hours and concentrated under reduced pressure. The residue was purified by column chromatography (35% EtOAc in hexane) to give 20 mg (yield 26%) of the title compound 100. ¹ H NMR (CD ₃ OD): δ 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, 2 Hz), 5.6-5 .48 (4H, m), 4.24 (1H, m), 2.84 (2H, m), 1.95-1.7 (4H, m), 1.09 (9H, s), LCMS (positive ion APCI): 636 (M + H ⁺ ); HRMS (MALDI): calculated as C ₃₁ H ₄₀ NO ₈ FPS (M + H ⁺ ) 636.2196; found 636.2182.
Biological test: Pin1 peptidylprolyl isomerase assay

PIN1 is a phosphorylation-dependent peptidylprolyl isomerase. The PIN1 assay is a spectrophotometric assay based on cis-trans conformation dependent cleavage of p-nitroanaline-containing peptide substrates coupled with chymotrypsin or subtilisin catalysis. This improved general rotamase assay was first described by Kofron et al. (Biochemistry, 30, 6217-6134 (1991)) and Yaffe et al. (Science,
278, 1957-1960 (1997)) applied to PIN1 isomerase activity. Cleavage of the isomerized peptide releases p-nitroanaline, which can be monitored by an increase in absorbance at 390 nm. The PIN1 peptide substrate, succinyl-leucine-proline-phenylalanine-p-nitroaniline (Suc-AEPF-pNA) (Bachem), is mainly maintained in cis conformation in anhydrous TFE / LiCl solvent mixture. .

By diluting in an aqueous assay mixture containing PIN1, the peptide substrate is catalyzed by PIN1 and isomerizes to the trans conformation. With chymotrypsin or subtilisin (available from subtilisin Carlsberg protease, Sigma (catalog no. P-5380)), the trans product is cleaved to produce free p-nitroanaline. In order to minimize the natural isomerization of the peptide substrate, the reaction is carried out at 15 ° C. A typical reaction contains 25 mM MOPS pH 7.5, 0.5 mM TCEP, 2% DMSO, 5 μl of a 25 mg / ml solution of subtilisin Carlsberg, 50 nM PIN1-PPiase, and 100 μM Suc-AEPF-pNA peptide substrate. The reaction is cooled to 15 ° C. and Suc-AEPF-pNA is added to initiate the reaction. Absorbance at 390 nm is continuously monitored until all substrate has been converted to degradation products. This data (progress curve) is then fitted to an exponential equation to determine the rate constant k for the reaction. Subtracting the rate constant for spontaneous isomerization, the rate constant k is linearly proportional to the concentration of active enzyme present in the assay mixture. The K _m for this substrate is much greater than 100 μM ([S] << K _m ). Thus, during an inhibition experiment, the IC ₅₀ for an inhibitor that exhibits weak binding is essentially the inhibition constant K _i .

Table 1, under the heading PIN1-CD, have a peptidyl prolyl isomerase catalytic domain reports a _{K i} data by test using PIN1 peptides lacking PIN1 WW domain. Similarly, the dissociation constant (K _d ) data under PIN1-CD represents testing with peptides that have the PIN1 catalytic domain but lack the PIN1WW domain.

The foregoing exemplary compounds can be formulated into pharmaceutical compositions according to the following general examples.
Example 1
Parenteral composition

To produce a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of the water-soluble salt of the compound of formula I are dissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline. This mixture is incorporated into a unit dosage form suitable for injection administration.
(Example 2)
Oral composition

  To produce a pharmaceutical composition for oral delivery, 100 mg of a compound of formula I is mixed with 750 mg lactose. This mixture is incorporated into an oral dosage unit form such as a hard gelatin capsule suitable for oral administration.

Claims (9)

Compound of formula (I):

[Where:
n is 1 or 2;
A is divalent —CH═CH—, — (C ₁ -C ₇ -alkyl) -Y—, —NR ^d (CH ₂ ) _t —Y—, —Y— (C ₁ -C ₇ -alkyl) — , -Y- (C ₁ -C ₇ alkyl)-, -Y-NH-, -Y-NR ^d (C ₁ -C ₆ -alkyl)-, -S-, -S (O) _2- , -O —Y—, —Y—O—, —Y—S—, or —S—Y—, wherein R ^d is H or C ₁ -C ₆ alkyl, and t is an integer from 0 to 5. , Y is C (O), C (S), S (O), S (O) ₂ or a single bond;
X is a direct bond, CH ₂ , CF ₂ , O, S, NH, C (O), or C (S);
R ¹ is a C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 4-10 membered heteroaryl group, wherein R ¹ is unsubstituted or 1- Substituted with 4 R ¹⁰ groups;
R ² is —S (O) ₂ OH, —S (O) ₂ NR ^d R ^e , or —P (O) (OR ⁴ ) ₂ , where R ⁴ is H, C ₁ -C ₁₀ -alkyl. , C ₆ -C ₁₀ aryl, or —CH ₂ —O—C (O) R ^e CH ₃ group, wherein R ^d and ^Re are each independently H or a C ₁ -C ₆ alkyl group And R ⁴ is unsubstituted or substituted with 1 to 4 R ¹⁰ groups; and R ³ is OH, C ₁ -C ₇ -alkyl, C ₁ -C ₇ -alkoxyl, C _6- C ₁₀ aryl, 4-10 membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocycloalkyl, —NH (R ⁵ ), or —N (R ⁵ ) ₂ groups, wherein R ⁵ It is independently, _H, C 1 -C _{7 alkyl,} C 6 _{-C 10} aryl Or

Selected from
Wherein ring B is a 5- or 6-membered heterocycloalkyl group, Z is a divalent C (O) Z ′, heteroaryl or heterocycloalkyl group, where Z ′ is a divalent O, S , NH, N (CH ₃ ), CO ₂ , or CH ₂ and R ⁶ is H, C ₁ -C ₁₀ alkyl, aryl, C ₁ -C ₆ alkyl-aryl, or arylalkyl group, wherein In which R ³ , R ⁵ , B and R ⁶ are unsubstituted or substituted with 1 to 4 R ¹⁰ groups;
Wherein each R ¹⁰ is independently halo, amino, ═O, ═S, ═NH, cyano, nitro, hydroxyl, —SH, haloalkyl, 2-10 membered heteroalkyl, C ₁ -C ₆ alkoxy, C ₁ — C _{10 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 ^{alkynyl, -C (O) j R a}} , -OC (O) j R d, -OC (O) OC (O) R d, -OOH , -C (NR ^d ) NR ^b R ^c , -NR ^d C (NR ^e ) NR ^b R ^c , -NR ^d C (O) _j R ^b , -C (O) NR ^b R ^c , -C (O ) NR ^d COR ^b , —OC (O) NR ^b R ^c , —NR ^b R ^c , —NR ^d OR ^c , —C (S) NR ^b R ^c , —NR ^d C (S) NR ^b R ^c , ^{-NR d C (O) NR b} R c, -OSH, -S (O) j R b, -OS (O) j R b ^{_{-SC (O) R b, -S}} (O) j C (O) OR b, -SCOR d, -NR d SR c, -SR b, -NHS (O) j R b, -COSR b, -C (O) S (O) _j R ^b , —CSR ^b , —CS (O) _j R ^b , —C (SO) OH, —C (SO) ₂ OH, —NR ^d C (S) R ^c , — ^{_{OC (S) R b, -OC}} (S) OH, -OC (SO) 2 R b, -S (O) j NR b R c, -SNR b R c, -S (O) NR b R c, —NR ^d CS (O) _j R ^c , —C (O) _j (CH ₂ ) _t NR ^d — (4 to 10-membered heteroaryl), —C (O) _j (CH ₂ ) _t NR ^d (4 to 10-membered _{^{heterocycloalkyl), - (CR d R e}} ) t CN, - (CR d R e) t (C 3 -C 10 cycloalkyl), - ^(CR d R ) _{T (C} 6 _{-C 10 ^{aryl), - (CR d R e}} ) t (4~10 membered _{^{heterocycloalkyl), - (CR d R e}} ) t (4~10 membered heteroaryl), - (CR ^d R ^e ) _q C (O) (CR ^d R ^e ) _t (C ₃ -C ₁₀ cycloalkyl), — (CR ^d R ^e ) _q C (O) (CR ^d R ^e ) _t (C ₆ -C ₁₀ Aryl), — (CR ^d R ^e ) _q C (O) (CR ^d R ^e ) _t (4 to 10-membered heterocycloalkyl), — (CR ^d R ^e ) _q C (O) (CR ^d R ^e ) _t (4 to 10 membered heteroaryl),-(CR ^d R ^e ) _t O (CR ^d R ^e ) _q (C ₃ -C ₁₀ cycloalkyl),-(CR ^d R ^e ) _t O (CR ^d R ^e ) _{q (C} 6 _{-C 10 ^{aryl), - (CR d R e}} ) t O (CR d R e) q (4-10 membered ^{_{heterocycloalkyl), - (CR d R e}} ) t O (CR d R e) q (4~10 membered ^{_{heteroaryl), - (CR d R e}} ) q SO 2 (CR d R e ) _T (C ₃ -C ₁₀ cycloalkyl), — (CR ^d R ^e ) _q SO ₂ (CR ^d R ^e ) _t (C ₆ -C ₁₀ aryl), — (CR ^d R ^e ) _q SO ₂ (CR ^d R ^e ) _t (4-10 membered heterocycloalkyl), and — (CR ^d R ^e ) _q SO ₂ (CR ^d R ^e ) _t (4-10 membered heteroaryl), wherein R ^a Selected from the group consisting of halo, hydroxyl, —NR ^d R ^e , C ₁ -C ₁₀ alkyl, haloalkyl, C ₁ -C ₆ alkoxyl, wherein R ^b and R ^c are independently H, C ₁ -C ₁₀ alkyl, - ^(CR d R ) _{T (C} 3 _{-C 10 ^{cycloalkyl), - (CR d R e}} ) t (C 6 -C 10 _{^{aryl), - (CR d R e}} ) t (4~10 membered heterocycloalkyl), and - ( CR ^d R ^e ) _t (4 to 10 membered heteroaryl), wherein R ^d and R ^e are independently H or C ₁ -C ₆ 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 ring portion of the R ¹⁰ group are unsubstituted or substituted with ═O; And alkyl, alkenyl, alkynyl, aryl and the ring portion of the R ¹⁰ group is unsubstituted or halo, ═O, cyano, nitro, — (CR ^d R ^e ) _t CN, haloalkyl, 2-10 membered hetero Alkyl, -OR ^{_{b, -C (O) j R}} b, -NR d C (O) R b, -C (O) NR b R c, -NR b R c, -NR b OR c, -NR d C (O) ^{_{j NR b R c, -NR d}} C (O) j R b R c, -OC (O) j R b, -OC (O) NR b R c, -SR d, C 1 -C 10 alkyl, C ₂ -C _{6 alkenyl,} C 2 -C _{6 ^{alkynyl, - (CR d R e)}} t (C 3 -C 10 _{^{cycloalkyl), - (CR d R e}} ) t (C 6 -C 10 aryl), - ( CR ^d R ^e) _t (4~10 membered _{^{heterocycloalkyl), - (CR d R e}} ) t (4~10 membered _{^{heteroaryl), - (CR d R e}} ) t (C 6 -C 10 aryl) - is substituted with 1-3 substituents independently selected from _(C 1 -C ₆ alkyl); where t ^{R b, R c, R d} , R ^e is as hereinbefore defined above, or a pharmaceutically acceptable prodrug of said compound, pharmaceutically active metabolite of said compound or said compound or said metabolite, Pharmaceutically acceptable salt of A pharmaceutically acceptable salt according to claim 1. A compound or pharmaceutically acceptable salt according to claim 1, wherein:
n is 1 or 2;
A is divalent —NH—Y—, —NR ^d (CH ₂ ) _t —Y—, or —O—Y—, and Y is C (O) or S (O) ₂ ;
X is a direct bond, CH ₂ , O, or S;
R ¹ is a C ₆ -C ₁₀ aryl or 4-10 membered heteroaryl group that is unsubstituted or substituted with ¹ to 4 R ¹⁰ groups;
R ² is —S (O) ₂ OH, or —P (O) (OR ⁴ ) ₂ , where R ⁴ is H, C ₁ -C ₁₀ alkyl, or C ₆ -C ₁₀ aryl group And unsubstituted or substituted with 1 to 4 R ¹⁰ groups); and R ³ is C ₆ -C ₁₀ aryl, 4 to 10 membered heteroaryl, —NH (C ₆ H ₅ ), Or

And
Wherein ring B is a 5- or 6-membered heterocycloalkyl group, Z is a divalent C (O) Z ′, heteroaryl or heterocycloalkyl group, where Z ′ is a divalent O, S , NH, N (CH ₃ ), CO ₂ , or CH ₂ , and R ⁶ is H or a C ₁ -C ₁₀ alkyl group, where R ³ , B, and R ⁶ are unsubstituted Or substituted with 1 to 4 R ¹⁰ groups;
Where each R ¹⁰ is independently halo, amino, ═O, ═S, ═NH, cyano, nitro, hydroxyl, —SH, haloalkyl, 2-10 membered heteroalkyl, C ₁ -C ₆ alkoxy, C ₁ -C _{10 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 ^{alkynyl, -C (O) j R a}} , -OC (O) j R d, -OC (O) OC (O) R d, ^{-OOH, -C (NR d) NR} b R c, -NR d C (NR e) NR b R c, -NR d C (O) j R b, -C (O) NR b R c, -C (O) NR ^d COR ^b , —OC (O) NR ^b R ^c , —NR ^b R ^c , —NR ^d OR ^c , —C (S) NR ^b R ^c , —NR ^d C (S) NR ^b R ^{c, -NR d C (O)} NR b R c, -OSH, -S (O) j R b, -OS (O) j R ^{_{b, -SC (O) R b}} , -S (O) j C (O) OR b, -SCOR d, -NR d SR c, -SR b, -NHS (O) j R b, -COSR b, ^{_{-C (O) S (O)}} j R b, -CSR b, -CS (O) j R b, -C (SO) OH, -C (SO) 2 OH, -NR d C (S) R c ^{_{, -OC (S) R b,}} -OC (S) OH, -OC (SO) 2 R b, -S (O) j NR b R c, -SNR b R c, -S (O) NR b R ^{_{c, -NR d CS (O)}} j R c, -C (O) j (CH 2) t NR d - (4~10 membered _{heteroaryl), - C (O) j} (CH 2) t NR d ( 4-10 membered heterocycloalkyl),-(CR ^d R ^e ) _t CN,-(CR ^d R ^e ) _t (C ₃ -C ₁₀ cycloalkyl),-(CR ^d R ^e ) _t (C ₆ -C ₁₀ aryl), — (CR ^d R ^e ) _t (4-10 membered heterocycloalkyl), — (CR ^d R ^e ) _t (4-10 membered heteroaryl), — ( CR ^d R ^e ) _q C (O) (CR ^d R ^e ) _t (C ₃ -C ₁₀ cycloalkyl), — (CR ^d R ^e ) _q C (O) (CR ^d R ^e ) _t (C ₆ − C ₁₀ aryl), — (CR ^d R ^e ) _q C (O) (CR ^d R ^e ) _t (4-10 membered heterocycloalkyl), — (CR ^d R ^e ) _q C (O) (CR ^d R ^e) _t (4 to 10 membered ^{_{heteroaryl), - (CR d R e}} ) t O (CR d R e) q (C 3 -C 10 _{^{cycloalkyl), - (CR d R e}} ) t O (CR d ^{_{R e) q (C 6 -C}} 10 _{^{aryl), - (CR d R e}} ) t O (CR d R e _q (4 to 10 membered ^{_{heterocycloalkyl), - (CR d R e}} ) t O (CR d R e) q (4~10 membered ^{_{heteroaryl), - (CR d R e}} ) q SO 2 (CR d R ^e) _{t (C} 3 _{-C 10 ^{cycloalkyl), - (CR d R e}} ) q SO 2 (CR d R e) t (C 6 -C 10 _{^{aryl), - (CR d R e}} ) q SO 2 ( CR ^d R ^e ) _t (4-10 membered heterocycloalkyl), and — (CR ^d R ^e ) _q SO ₂ (CR ^d R ^e ) _t (4-10 membered heteroaryl), wherein R ^a Is selected from the group consisting of halo, hydroxyl, —NR ^d R ^e , C ₁ -C ₁₀ alkyl, haloalkyl, C ₁ -C ₆ alkoxyl, wherein R ^b and R ^c are independently H, C ₁ -C ₁₀ alkyl,-(CR ^d R ^e ) _t (C ₃ -C ₁₀ cycloalkyl), — (CR ^d R ^e ) _t (C ₆ -C ₁₀ aryl), — (CR ^d R ^e ) _t (4-10 membered heterocycloalkyl), and -(CR ^d R ^e ) _t (4-10 membered heteroaryl), R ^d and R ^e are independently H or C ₁ -C ₆ alkyl, j is an integer from 0 to 2, q and t are each independently an integer of 0 to 5, and 1 or 2 ring carbon atoms of the ring portion of the R ¹⁰ group are unsubstituted or substituted with ═O. And the alkyl, alkenyl, alkynyl, aryl and ring moieties of said R ¹⁰ group are unsubstituted or halo, ═O, cyano, nitro, — (CR ^d R ^e ) _t CN, haloalkyl, 2-10 members Heteroalkyl, -O ^{_{b, -C (O) j R}} b, -NR d C (O) R b, -C (O) NR b R c, -NR b R c, -NR b OR c, -NR d C (O) ^{_{j NR b R c, -NR d}} C (O) j R b R c, -OC (O) j R b, -OC (O) NR b R c, -SR d, C 1 -C 10 alkyl, C ₂ -C _{6 alkenyl,} C 2 -C _{6 ^{alkynyl, - (CR d R e)}} t (C 3 -C 10 _{^{cycloalkyl), - (CR d R e}} ) t (C 6 -C 10 aryl), - ( CR ^d R ^e) _t (4~10 membered _{^{heterocycloalkyl), - (CR d R e}} ) t (4~10 membered _{^{heteroaryl), - (CR d R e}} ) t (C 6 -C 10 aryl) - It is substituted with 1-3 substituents independently selected from _(C 1 -C ₆ alkyl); and ^T In ^{this, R b, R c, R} d, ^{R e} is as defined above]. A compound or pharmaceutically acceptable salt according to claim 3, wherein:
n is 1;
A is divalent —NH—Y— or —O—Y—, wherein Y is C (O);
X is a direct bond, CH ₂ , or O;
R ¹ is a C ₆ -C ₁₀ aryl group that is unsubstituted or substituted with ¹ to 4 R ¹⁰ groups;
R ² is —P (O) (OR ⁴ ) ₂ , where R ⁴ is an H, C ₁ -C ₁₀ alkyl, or C ₆ -C ₁₀ aryl group and is unsubstituted or 1 And substituted with 4 R ¹⁰ groups); and R ³ is C ₆ -C ₁₀ aryl, 4 to 10 membered heteroaryl, or

And
Where Ring B is an unsubstituted 6-membered heterocycloalkyl, Z is divalent C (O) Z ′, Z ′ is divalent O, S, or CH ₂ , and R ⁶ Is a C ₁ -C ₁₀ alkyl group, wherein R ³ , B and R ⁶ are unsubstituted or substituted with 1 to 4 R ¹⁰ groups;
Where each R ¹⁰ is independently halo, amino, ═O, ═S, ═NH, cyano, nitro, hydroxyl, —SH, haloalkyl, 2-10 membered heteroalkyl, C ₁ -C ₆ alkoxy, C ₁ -C _{10 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 ^{alkynyl, -C (O) j R a}} , -OC (O) j R d, -OC (O) OC (O) R d, ^{-OOH, -C (NR d) NR} b R c, -NR d C (NR e) NR b R c, -NR d C (O) j R b, -C (O) NR b R c, -C (O) NR ^d COR ^b , —OC (O) NR ^b R ^c , —NR ^b R ^c , —NR ^d OR ^c , —C (S) NR ^b R ^c , —NR ^d C (S) NR ^b R ^{c, -NR d C (O)} NR b R c, -OSH, -S (O) j R b, -OS (O) j R ^{_{b, -SC (O) R b}} , -S (O) j C (O) OR b, -SCOR d, -NR d SR c, -SR b, -NHS (O) j R b, -COSR b, ^{_{-C (O) S (O)}} j R b, -CSR b, -CS (O) j R b, -C (SO) OH, -C (SO) 2 OH, -NR d C (S) R c ^{_{, -OC (S) R b,}} -OC (S) OH, -OC (SO) 2 R b, -S (O) j NR b R c, -SNR b R c, -S (O) NR b R ^{_{c, -NR d CS (O)}} j R c, -C (O) j (CH 2) t NR d - (4~10 membered _{heteroaryl), - C (O) j} (CH 2) t NR d ( 4-10 membered heterocycloalkyl),-(CR ^d R ^e ) _t CN,-(CR ^d R ^e ) _t (C ₃ -C ₁₀ cycloalkyl),-(CR ^d R ^e ) _t (C ₆ -C ₁₀ aryl), — (CR ^d R ^e ) _t (4-10 membered heterocycloalkyl), — (CR ^d R ^e ) _t (4-10 membered heteroaryl), — ( CR ^d R ^e ) _q C (O) (CR ^d R ^e ) _t (C ₃ -C ₁₀ cycloalkyl), — (CR ^d R ^e ) _q C (O) (CR ^d R ^e ) _t (C ₆ − C ₁₀ aryl), — (CR ^d R ^e ) _q C (O) (CR ^d R ^e ) _t (4-10 membered heterocycloalkyl), — (CR ^d R ^e ) _q C (O) (CR ^d R ^e) _t (4 to 10 membered ^{_{heteroaryl), - (CR d R e}} ) t O (CR d R e) q (C 3 -C 10 _{^{cycloalkyl), - (CR d R e}} ) t O (CR d ^{_{R e) q (C 6 -C}} 10 _{^{aryl), - (CR d R e}} ) t O (CR d R e _q (4 to 10 membered ^{_{heterocycloalkyl), - (CR d R e}} ) t O (CR d R e) q (4~10 membered ^{_{heteroaryl), - (CR d R e}} ) q SO 2 (CR d R ^e) _{t (C} 3 _{-C 10 ^{cycloalkyl), - (CR d R e}} ) q SO 2 (CR d R e) t (C 6 -C 10 _{^{aryl), - (CR d R e}} ) q SO 2 ( CR ^d R ^e ) _t (4-10 membered heterocycloalkyl), and — (CR ^d R ^e ) _q SO ₂ (CR ^d R ^e ) _t (4-10 membered heteroaryl), wherein R ^a Is selected from the group consisting of halo, hydroxyl, —NR ^d R ^e , C ₁ -C ₁₀ alkyl, haloalkyl, C ₁ -C ₆ alkoxyl, wherein R ^b and R ^c are independently H, C ₁ -C ₁₀ alkyl,-(CR ^d R ^e ) _t (C ₃ -C ₁₀ cycloalkyl), — (CR ^d R ^e ) _t (C ₆ -C ₁₀ aryl), — (CR ^d R ^e ) _t (4-10 membered heterocycloalkyl), and -(CR ^d R ^e ) _t (4-10 membered heteroaryl), R ^d and R ^e are independently H or C ₁ -C ₆ alkyl, j is an integer from 0 to 2 There, q and t are each independently an integer of 0 to 5, and wherein 1 or 2 ring carbon atoms of the ring portion of R ¹⁰ groups is substituted with unsubstituted or = O And the alkyl, alkenyl, alkynyl, aryl and ring moieties of the R ¹⁰ group are unsubstituted or halo, ═O, cyano, nitro, — (CR ^d R ^e ) _t CN, haloalkyl, 2-10 members Heteroalkyl, -O ^{_{b, -C (O) j R}} b, -NR d C (O) R b, -C (O) NR b R c, -NR b R c, -NR b OR c, -NR d C (O) ^{_{j NR b R c, -NR d}} C (O) j R b R c, -OC (O) j R b, -OC (O) NR b R c, -SR d, C 1 -C 10 alkyl, C ₂ -C _{6 alkenyl,} C 2 -C _{6 ^{alkynyl, - (CR d R e)}} t (C 3 -C 10 _{^{cycloalkyl), - (CR d R e}} ) t (C 6 -C 10 aryl), - ( CR ^d R ^e) _t (4~10 membered _{^{heterocycloalkyl), - (CR d R e}} ) t (4~10 membered _{^{heteroaryl), - (CR d R e}} ) t (C 6 -C 10 aryl) - It is substituted with 1-3 substituents independently selected from _(C 1 -C ₆ alkyl); and ^T In ^{this, R b, R c, R} d, ^{R e} is 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 bond, CH ₂ , or O;
R ¹ is a C ₆ -C ₁₀ aryl group that is unsubstituted or substituted with ¹ to 4 R ¹⁰ groups;
R ² is —P (O) (OR ⁴ ) ₂ , wherein R ⁴ is H or a C ₁ -C ₁₀ alkyl group that is unsubstituted or substituted with 1 to 4 R ¹⁰ groups. And R ³ is a C ₆ -C ₁₀ aryl or 4-10 membered heteroaryl group that is unsubstituted or substituted with 1 to 4 R ¹⁰ groups;
Where each R ¹⁰ is independently halo, amino, ═O, ═S, ═NH, cyano, nitro, hydroxyl, —SH, haloalkyl, 2-10 membered heteroalkyl, C ₁ -C ₆ alkoxy, C ₁ -C _{10 alkyl,} C 2 -C _{6 alkenyl,} C 2 -C _{6 ^{alkynyl, -C (O) j R a}} , -OC (O) j R d, -OC (O) OC (O) R d ^{, -OOH, -C (NR d)} NR b R c, -NR d C (NR e) NR b R c, -NR d C (O) j R b, -C (O) NR b R c, - C (O) NR ^d COR ^b , —OC (O) NR ^b R ^c , —NR ^b R ^c , —NR ^d OR ^c , —C (S) NR ^b R ^c , —NR ^d C (S) NR ^{b R c, -NR d C (O} ) NR b R c, -OSH, -S (O) j R b, -OS (O) j ^{_{R b, -SC (O) R}} b, -S (O) j C (O) OR b, -SCOR d, -NR d SR c, -SR b, -NHS (O) j R b, -COSR b ^{_{, -C (O) S (O}} ) j R b, -CSR b, -CS (O) j R b, -C (SO) OH, -C (SO) 2 OH, -NR d C (S) R ^{_{c, -OC (S) R b}} , -OC (S) OH, -OC (SO) 2 R b, -S (O) j NR b R c, -SNR b R c, -S (O) NR b ^{_{R c, -NR d CS (O}} ) j R c, -C (O) j (CH 2) t NR d - (4~10 membered _{heteroaryl), - C (O) j} (CH 2) t NR d (4-10 membered _{^{heterocycloalkyl), - (CR d R e}} ) t CN, - (CR d R e) t (C 3 -C 10 cycloalkyl), - (CR ^{_{R e) t (C 6 -C}} 10 _{^{aryl), - (CR d R e}} ) t (4~10 membered _{^{heterocycloalkyl), - (CR d R e}} ) t (4~10 membered heteroaryl), - ( CR ^d R ^e ) _q C (O) (CR ^d R ^e ) _t (C ₃ -C ₁₀ cycloalkyl), — (CR ^d R ^e ) _q C (O) (CR ^d R ^e ) _t (C ₆ − C ₁₀ aryl), — (CR ^d R ^e ) _q C (O) (CR ^d R ^e ) _t (4-10 membered heterocycloalkyl), — (CR ^d R ^e ) _q C (O) (CR ^d R ^e) _t (4 to 10 membered ^{_{heteroaryl), - (CR d R e}} ) t O (CR d R e) q (C 3 -C 10 _{^{cycloalkyl), - (CR d R e}} ) t O (CR d R ^e ) _q (C ₆ -C ₁₀ aryl), — (CR ^d R ^e ) _t O (CR ^d R ^e ) _Q (4 to 10 membered ^{_{heterocycloalkyl), - (CR d R e}} ) t O (CR d R e) q (4~10 membered _{^{heteroaryl), - (CR d R e}} ) q SO 2 (CR d R ^e ) _t (C ₃ -C ₁₀ cycloalkyl), — (CR ^d R ^e ) _q SO ₂ (CR ^d R ^e ) _t (C ₆ -C ₁₀ aryl), — (CR ^d R ^e ) _q SO ₂ Selected from (CR ^d R ^e ) _t (4-10 membered heterocycloalkyl) and — (CR ^d R ^e ) _q SO ₂ (CR ^d R ^e ) _t (4-10 membered heteroaryl), wherein R ^a is selected from the group consisting of halo, hydroxyl, —NR ^d R ^e , C ₁ -C ₁₀ alkyl, haloalkyl, C ₁ -C ₆ alkoxyl, R ^b and R ^c are independently H, C ₁ -C ₁₀ alkyl, - (CR ^{d e)} _{t (C} 3 _{-C 10 ^{cycloalkyl), - (CR d R e}} ) t (C 6 -C 10 _{^{aryl), - (CR d R e}} ) t (4~10 membered heterocycloalkyl), and - (CR ^d R ^e ) _t (4-10 membered heteroaryl) is selected, R ^d and R ^e are independently H or C ₁ -C ₆ alkyl, and j is an integer from 0 to 2 , Q and t are each independently an integer from 0 to 5 and one or two ring carbon atoms of the ring portion of the R ¹⁰ group are unsubstituted or substituted with ═O. And the alkyl, alkenyl, alkynyl, aryl and ring moieties of said R ¹⁰ group are unsubstituted or halo, ═O, cyano, nitro, — (CR ^d R ^e ) _t CN, haloalkyl, 2-10 Membered heteroalkyl,- ^{_{R b, -C (O) j}} R b, -NR d C (O) R b, -C (O) NR b R c, -NR b R c, -NR b OR c, -NR d C (O ^{_{) j NR b R c, -NR}} d C (O) j R b R c, -OC (O) j R b, -OC (O) NR b R c, -SR d, C 1 -C 10 alkyl, C ₂ -C _{6 alkenyl,} C 2 -C _{6 ^{alkynyl, - (CR d R e)}} t (C 3 -C 10 _{^{cycloalkyl), - (CR d R e}} ) t (C 6 -C 10 aryl), - (CR ^d R ^e ) _t (4 to 10 membered heterocycloalkyl), — (CR ^d R ^e ) _t (4 to 10 membered heteroaryl), — (CR ^d R ^e ) _t (C ₆ -C ₁₀ aryl) - it is substituted with 1-3 substituents independently selected from _(C 1 -C ₆ alkyl); and Wherein ^{t, R b, R c,} R d, ^{R e} is as defined above].

A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a therapeutically effective amount of a drug selected from the group consisting of the compound, prodrug, metabolite and salt of claim 1 and a pharmaceutically acceptable carrier. A method for the treatment of a mammalian medical condition mediated by PIN1 activity, comprising treating the compound of claim 1, a pharmaceutically acceptable prodrug, a pharmaceutically active metabolite, or a pharmaceutically acceptable salt. Administering the effective amount to a mammal in need of such treatment. 9. The method of claim 8, wherein the mammalian condition is associated with hypertension, cell overgrowth, infection, or neurodegenerative brain disease.