# Patent

## Title
Substituted polycyclic carbamoylpyridone derivative

## Abstract

This invention provides compounds having antiviral activities especially inhibiting activity for influenza virus, more preferably provides substituted 3-hydroxy-4-pyridone derivatives having cap-dependent endonuclease inhibitory activity.

## Background
This is a division of application No. 13/378,334, filed Dec. 14, 2011,which is the U.S. national stage application of International Application No. PCT/JP2010/060006,filed on Jun. 14, 2010, which claims the benefit of priority from Japanese Application No. 2009-142166, filed on Jun. 15, 2009. All of these application are herein incorporated by reference in their entireties.


TECHNICAL FIELD
This invention relates to substituted polycyclic carbamoylpyridone derivatives having cap-dependent endonuclease inhibitory activity, and pharmaceutical compositions including thereof.
BACKGROUND ART
Influenza is an acute respiratory infectious disease caused by infection with an influenza virus. In Japan, there is a report of a few millions of influenza-like patients every winter, and influenza is accompanied with high morbidity and mortality. Influenza is a particularly important disease in a high risk population such as baby and elderly, a complication rate with pneumonia is high in elderly, and death with influenza is occupied with elderly in many cases.
As anti-influenza drugs, Symmetrel (trade name: Amantadine) and Flumadine (trade name: Rimantadine) which inhibit the denucleation process of a virus, and Oseltamivir (trade name: Tamiflu) and Zanamivir (trade name: Relenza) which are neuraminidase inhibitors suppressing virus budding and release from a cell are known. However, since problems of appearances of resistant strains and side effects, and worldwide epidemic of a new-type influenza virus having high pathogenicity and mortality are feared, development of an anti-influenza drug having a novel mechanism has been desired.
Since a cap-dependent endonuclease which is an influenza virus-derived enzyme is essential for virus proliferation, and has the virus-specific enzymatic activity which is not possessed by a host, it is believed that the endonuclease is suitable for a target of an anti-influenza drug. The cap-dependent endonuclease has a host mRNA precursor as a substrate, and has the endonuclease activity of producing a fragment of 9 to 13 bases including a cap structure (not including the number of bases of the cap structure). This fragment functions as a primer of a virus RNA polymerase, and is used in synthesizing mRNA encoding a virus protein. That is, it is believed that a substance which inhibits the cap-dependent endonuclease inhibits synthesis of a virus protein by inhibiting synthesis of virus mRNA and, as a result, inhibits virus proliferation.
As the substance which inhibits the cap-dependent endo nuclease, flutimide (Patent Document 1 and Non-Patent Documents 1 and 2) and 4-substituted 2,4-dioxobutanoic acid (Non-Patent Documents 3 to 5) are reported, but they have not yet led to clinical use as anti-influenza drugs. In addition, Patent Documents 2 to 9 and Non-Patent Document 6 describe compounds having a similar structure to that of this invention, however, the documents do not describe cap-dependent endonuclease.
PRIOR ART DOCUMENTS
Patent Documents


    [Patent Document 1] GB No. 2280435 specification
    [Patent Document 2] International Publication No. 2007/049675pamphlet
    [Patent Document 3] International Publication No. 2006/088173pamphlet
    [Patent Document 4] International Publication No. 2006/066414pamphlet
    [Patent Document 5] International Publication No. 2005/092099pamphlet
    [Patent Document 6] International Publication No. 2005/087766pamphlet
    [Patent Document 7] International Publication No. 2005/016927pamphlet
    [Patent Document 8] International Publication No. 2004/024078pamphlet
    [Patent Document 9] International Publication No. 2006/116764pamphlet


Non-Patent Documents


    [Non-Patent Document 1] Tetrahedron Lett 1995, 36(12), 2005
    [Non-Patent Document 2] Tetrahedron Lett 1995, 36(12), 2009
    [Non-Patent Document 3] Antimicrobial Agents And Chemotherapy, December 1994, p. 2827-2837
    [Non-Patent Document 4] Antimicrobial Agents And Chemotherapy, May 1996, p. 1304-1307
    [Non-Patent Document 5] J. Med. Chem. 2003, 46, 1153-1164
    [Non-Patent Document 6] Bioorganic & Medicinal Chemistry Letters 17 (2007)5595-5599


SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
An object of the present invention is to provide compounds having antiviral activities especially inhibiting growth activity of influenza virus. More preferably, this invention provides compounds and medicament containing the same which inhibit increase of influenza virus by exhibiting cap-dependent endonuclease inhibitory activity.
Means for Solving the Problems
[Item 1′]
A CAP dependent endonuclease inhibitor containing a compound represented by formula (I), a pharmaceutically acceptable salt, or a solvate thereof:




    (wherein
    R1 is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, lower alkyloxy optionally substituted by substituent group A, lower alkenyloxy optionally substituted by substituent group A, lower alkylcarbonyl optionally substituted by substituent group A, lower alkyloxycarbonyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, carbocyclecarbonyl optionally substituted by substituent group A, carbocycleoxy optionally substituted by substituent group A, carbocycleoxycarbonyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A, heterocyclecarbonyl optionally substituted by substituent group A, heterocycleoxy optionally substituted by substituent group A, heterocycleoxycarbonyl optionally substituted by substituent group A,
    —Z—N(RX1)(RX2),
    —Z—N(RX3)—SO2—(RX4),
    —Z—C(═O)—N(RX5)—SO2—(RX6),
    —Z—N(RX7)—C(═O)—RX8,
    —Z—C(═O)—N(RX9)(RX10),
    —Z—S—RX11,
    —Z—SO2—RX12,
    —Z—S(═O)—RX13,
    —Z—N(RX14)—C(═O)—O—RX15,
    —Z—N(RX16)—C(═O)—N(RX17)(RX18),
    —Z—C(═O)—N(RX19)—C(═O)—N(RX20)(RX21), or
    —Z—N(RX22)—C(═O)—C(═O)—RX23 
    (wherein RX1, RX2, RX3, RX5, RX7, RX8, RX9, RX10, RX11, RX14, RX15, RX16, RX17, RX18, RX19, RX20, RX21, RX22, and RX23 are each independently selected from a substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A, RX4, RX6, RX12, and RX13 are each independently selected from a substituent group consisting of, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A,
    RX1 and RX2, RX9 and RX10, RX17 and RX18, and RX20 and RX21 each may be taken together with an adjacent atom to form heterocycle, and
    Z is a bond or straight or branched lower alkylene);
    R2 is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, lower alkyloxy optionally substituted by substituent group A, lower alkenyloxy optionally substituted by substituent group A, lower alkylcarbonyl optionally substituted by substituent group A, lower alkyloxycarbonyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, carbocyclecarbonyl optionally substituted by substituent group A, carbocycleoxy optionally substituted by substituent group A, carbocycleoxycarbonyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A, heterocyclecarbonyl optionally substituted by substituent group A, heterocycleoxy optionally substituted by substituent group A, heterocycleoxycarbonyl optionally substituted by substituent group A,
    —Z—N(RY1)—SO2—RY2,
    —Z—N(RY3)—C(═O)—RY4,
    —Z—N(RY5)—C(═O)—O—RY6,
    —Z—C(═O)—N(RY7)(RY8),
    —Z—N(RY9)(RY10), or
    —Z—SO2—RY11 
    (wherein RY1, RY3, RY4, RY5, RY6, RY7, RY8, RY9, and RY10 are each independently selected from a substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A, RY2 and RY11 are each independently selected from a substituent group consisting of lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A,
    RY7 and RY8, and RY9 and RY10 may be taken together with an adjacent atom to form heterocycle and
    Z is a bond or straight or branched lower alkylene);
    R3 is hydrogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, lower alkyloxy optionally substituted by substituent group A, lower alkenyloxy optionally substituted by substituent group A, lower alkylcarbonyl optionally substituted by substituent group A, lower alkyloxycarbonyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, carbocycleoxy lower alkyl optionally substituted by substituent group A, carbocyclecarbonyl optionally substituted by substituent group A, carbocycleoxy optionally substituted by substituent group A, carbocycleoxycarbonyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A, heterocycleoxy lower alkyl optionally substituted by substituent group A, heterocyclecarbonyl optionally substituted by substituent group A, heterocycleoxy optionally substituted by substituent group A, heterocycleoxycarbonyl optionally substituted by substituent group A,
    —Z—N(RZ1)—SO2—RZ2,
    —Z—N(RZ3)—C(═O)—RZ4,
    —Z—N(RZ5)—C(═O)—O—RZ6,
    —Z—C(═O)—N(RZ7)(RZ8),
    —Z—N(RZ9)(RZ10),
    —Z—SO2—RZ11, or
    —Z—N(RZ12)—O—C(═O)—RZ13 
    (wherein RZ1, RZ3, RZ4, RZ5, RZ6, RZ7, RZ8, RZ9, RZ10, RZ12, and RZ13 are each independently selected from a substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A,
    RZ2 and RZ11 are each independently selected from a substituent group consisting of lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A,
    RZ7 and RZ8, and RZ9 and RZ10 each may be taken together with an adjacent atom to form heterocycle, and
    Z is a bond or straight or branched lower alkylene) and;
    a) either A1 or A2 is CR5R6, and the other is NR7, or
    b) A1 is CR8R9, and A2 is CR10R11,
    R5, R6, R7, R8, R9, R10, and R11 are each independently selected from a substituent group consisting of hydrogen, carboxy, cyano, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, lower alkyl carbonyl optionally substituted by substituent group A, lower alkyl oxycarbonyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, carbocycleoxy lower alkyl optionally substituted by substituent group A, carbocyclecarbonyl optionally substituted by substituent group A, carbocycleoxycarbonyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A, heterocycleoxy lower alkyl optionally substituted by substituent group A, heterocyclecarbonyl optionally substituted by substituent group A, heterocycleoxycarbonyl optionally substituted by substituent group A,
    —Z—S—RV1,
    —Z—S(═O)—RV2,
    −Z−SO2—RV3,
    —C(═O)—C(═O)—RV4,
    —C(═O)—N(RV5)(RV6)
    —Z—N(RV7)—C(═O)—O—RV8, or
    —Z—N(RV9)—C(═O)—RV10 
    (wherein RV1, RV4, RV5, RV6, RV7, RV8, RV9 and RV10 are each independently selected from a substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A,
    RV2 and RV3 are each independently selected from a substituent group consisting of lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A, RV5 and RV6 may be taken together with an adjacent atom to form heterocycle, and
    Z is a bond or straight or branched lower alkylene), and
    R5 and R6 may be taken together with an adjacent atom to form carbocycle;
    1) when A1 is CR5R6 and A2 is NR7,
    R3 and R7 may be taken together with an adjacent atom to form heterocycle optionally substituted by substituent group B or may form a condensed ring,
    2) when A1 is NR7 and A2 is CR5R6,
    R3 and R6 may be taken together with an adjacent atom to form heterocycle optionally substituted by substituent group B or may form condensed ring, or
    3) when A1 is CR8R9, and A2 is CR10R11,
    R8 and R10 may be taken together with an adjacent atom to form a bond, and R8 and R10 may be taken together with an adjacent atom to form carbocycle or heterocycle, or
    R3 and R11 may be taken together with an adjacent atom to form heterocycle optionally substituted by substituent group B or may form condensed ring;

with a proviso that the following case of c) and d) are excluded;

    c) R5, R6, and R7 are all hydrogens
    d) R8, R9, R10, and R11 are all hydrogens;
    Substituent group A: halogen, cyano, hydroxy, carboxy, formyl, amino, oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy, lower alkylthio, hydroxy lower alkyl, carbocyclic group, heterocyclic group, heterocyclic group substituted by oxo, carbocycle lower alkyloxy, carbocycleoxy lower alkyl, carbocycle lower alkyloxy lower alkyl, heterocycle lower alkyloxy, heterocycleoxy lower alkyl, heterocycle lower alkyloxy lower alkyl, halogeno lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, lower alkylcarbonyloxy, lower alkyloxycarbonyl, lower alkylamino, lower alkylcarbonylamino, halogeno lower alkyl carbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, lower alkylsulfinyl, and lower alkylsulfonylamino;
    Substituent group B: halogen, cyano, hydroxy, carboxy, formyl, amino, oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy, carbocycle lower alkyloxy, heterocycle lower alkyloxy, halogeno lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, lower alkyloxycarbonyl, lower alkylamino, lower alkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, lower alkylsulfonylamino, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A).

[Item 2′]



A CAP dependent endonuclease inhibitor according to item 1′, wherein

    R1 is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, lower alkyloxy optionally substituted by substituent group A, lower alkenyloxy optionally substituted by substituent group A, lower alkylcarbonyl optionally substituted by substituent group A, lower alkyloxycarbonyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, carbocyclecarbonyl optionally substituted by substituent group A, carbocycleoxy optionally substituted by substituent group A, carbocycleoxycarbonyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A, heterocyclecarbonyl optionally substituted by substituent group A, heterocycleoxy optionally substituted by substituent group A, heterocycleoxycarbonyl optionally substituted by substituent group A,
    —Z—N(RX1)(RX2),
    —Z—N(RX3)—SO2—(RX4),
    —Z—C(═O)—N(RX5)—SO2—(RX6),
    —Z—N(RX7)—C(═O)—RX8,
    —Z—S—RX11,
    —Z—SO2—RX12,
    —Z—S(═O)—RX13,
    —Z—N(RX14)—C(═O)—O—RX15,
    —Z—N(RX16)—C(═O)—N(RX17)(RX18), or
    —Z—N(RX22)—C(═O)—C(═O)—RX23 
    (Substituent group A, RX1, RX2, RX3, RX4, RX5, RX6, RX7, RX8, RX11, RX12, RX13, RX14, RX15, RX16, RX17, RX18, RX22, RX23, and
    Z are same meaning as those of item 1′).

[Item 3′]



A CAP dependent endonuclease inhibitor according to item 1′, wherein

    R1 is hydrogen, halogen, hydroxy, carboxy, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkyloxy optionally substituted by substituent group A, lower alkylcarbonyl optionally substituted by substituent group A, lower alkyloxycarbonyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A,
    —Z—N(RX1)(RX2),
    —Z—N(RX7)—C(═O)—RX8, or
    —Z—N(RX14)—C(═O)—O—RX15 
    (Substituent group A, RX1, RX2, RX7, RX8, RX14, RX15, and Z are same meaning as those of item 1′).

[Item 4′]



A CAP dependent endonuclease inhibitor according to item 1′, wherein

    R1 is hydrogen, halogen, hydroxy, carboxy, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkyloxy optionally substituted by substituent group A, lower alkyl carbonyl optionally substituted by substituent group A, lower alkyloxycarbonyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, or
    —Z—N(RX1)(RX2)
    (Substituent group A, RX1, RX2, and Z are same meaning as those of item 1′).

[Item 5′]



A CAP dependent endonuclease inhibitor according to item 1′, wherein R1 is hydrogen or carboxy.
[Item 6′]
A CAP dependent endonuclease inhibitor according to any one of items 1′ to 5′, wherein

    R2 is hydrogen, lower alkyl optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A, or
    —Z—N(RY9)(RY10)
    (Substituent group A, RY9, RY10, and Z are same meaning as those of item 1′).

[Item 7′]



A CAP dependent endonuclease inhibitor according to any one of items 1′ to 5′, wherein

    R2 is hydrogen or lower alkyl optionally substituted by substituent group A
    (Substituent group A is same meaning as that of item 1′).

[Item 8′]



A CAP dependent endonuclease inhibitor according to any one of items 1′ to 7′, wherein

    R3 is hydrogen, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, carbocycleoxy lower alkyl optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A,
    —Z—N(RZ1)—SO2—RZ2,
    —Z—N(RZ3)—C(═O)—RZ4,
    —Z—N(RZ5)—C(═O)—O—RZ6,
    —Z—C(═O)—N(RZ7)(RZ8), or
    —Z—N(RZ9)(RZ10)
    (Substituent group A, RZ1, RZ2, RZ3, RZ4, RZ5, RZ6, RZ7, RZ8, RZ9, RZ10, and Z are same meaning as those of item 1′).

[Item 9′]



A CAP dependent endonuclease inhibitor according to any one of items 1′ to 8′, wherein

    A1 is CR8R9, A2 is CR10R11,
    R9, R10, and R11 are hydrogen or lower alkyl optionally substituted by substituent group A, and
    R8 is lower alkyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, carbocycleoxy lower alkyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A, heterocycleoxy lower alkyl optionally substituted by substituent group A,
    —Z—S—RV1,
    —Z—S(═O)—RV2, or
    —Z—SO2—RV3 
    (Substituent group A, RV1, RV2, RV3, and Z are same meaning as those of item 1′).

[Item 10′]



A CAP dependent endonuclease inhibitor according to any one of items 1′ to 8′, wherein

    A1 is CR8R9, A2 is CR10R11,
    R8, R9, and R11 are hydrogen, or lower alkyl optionally substituted by substituent group A, and
    R10 is lower alkyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, carbocycleoxy lower alkyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A, heterocycleoxy lower alkyl optionally substituted by substituent group A,
    —Z—S—RV1,
    —Z—S(═O)—RV2, or
    —Z—SO2—RV3 
    (Substituent group A, RV1, RV2, RV3, and Z are same meaning as those of item 1′).

[Item 11′]



A CAP dependent endonuclease inhibitor according to any one of items 1′ to 8′, wherein

    A1 is CR8R9, A2 is CR10R11,
    R9 and R11 are hydrogen,
    i) either R8 or R10 is a group shown below:






    (wherein RE6 is selected from substituent group A,
    m is an integer of 0 or more, and substituent group A is same meaning as those of item 1′)

and;

    ii) the other of R8 or R10 is hydrogen, or lower alkyl optionally substituted by substituent group A;

[Item 12′]

    CAP dependent endonuclease inhibitor according to item 11′, wherein
    A1 is CR6R9, A2 is CR10R11,
    R9 and R11 are hydrogen,
    i) either R8 or R10 is a group shown below:






    (wherein RE6 is selected from substituent group A,
    m is an integer of 0 or more, substituent group A is same meaning as that of item 1′)

and;

    ii) the other of R8 or R10 is hydrogen or lower alkyl optionally substituted by substituent group A.

[Item 13′]



A compound represented by formula (II), or a pharmaceutically acceptable salt thereof or a solvate thereof:




    (wherein
    R1a is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, lower alkyloxy optionally substituted by substituent group C, lower alkenyloxy optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocycleoxy optionally substituted by substituent group C, carbocycleoxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocycleoxy optionally substituted by substituent group C, heterocycleoxycarbonyl optionally substituted by substituent group C,
    —Z—N(RA1)(RA2),
    —Z—N(RA3)—SO2— (RA4),
    —Z—C(═O)—N(RA5)—SO2—(RA6),
    —Z—N(RA7)—C(═O)—RA8,
    —Z—S—RA9,
    —Z—SO2—R10,
    —Z—S(═O)—RA11,
    —Z—N(RA12)—C(═O)—O—RA13,
    —Z—N(RA14)—C(═O)—N(RA15)(RA16),
    —Z—C(═O)—N(RA17)C(═O)—N(RA18)(RA19), or
    —Z—N(RA20)—C(═O)—C(═O)—RA21,
    (wherein RA1, RA2, RA3, RA4, RA5, RA7, RA8, RA9, RA12, RA13, RA14, RA15, RA16, RA17, RA18, RA19, R20, and RA21 are each independently selected from substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C, RA4, RA6, RA10, and RA11 are each independently selected from substituent group consisting of, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C,
    RA1 and RA2, RA15 and RA16, and RA18 and RA19 each may be taken together with an adjacent atom to form heterocyce, and
    Z is a bond or straight or branched lower alkylene);
    R2a is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, lower alkyloxy optionally substituted by substituent group C, lower alkenyloxy optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocyclecarbonyl optionally substituted by substituent group C, carbocycleoxy optionally substituted by substituent group C, carbocycleoxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocyclecarbonyl optionally substituted by substituent group C, heterocycleoxy optionally substituted by substituent group C, heterocycleoxycarbonyl optionally substituted by substituent group C,
    —Z—N(RB1)—SO2—RB2,
    —Z—N(RB3)—C(═O)—RB4,
    —Z—N(RB5)—C(═O)—O—RB6,
    —Z—C(═O)—N(RB7)(RB8),
    —Z—N(RB9)(RB10), or
    —Z—SO2—RB11 
    (wherein RB1, RB3, RB4, RB5, RB6, RB7, RB8, RB9, and RB10 are each independently selected from a substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C, RB2 and RB11 are each independently selected from a substituent group consisting of lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C,
    RB7 and RB8, and RB9 and RB10 each may be taken together with an adjacent atom to form heterocycle, and
    Z is a bond or straight or branched lower alkylene);
    R3a is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, lower alkyloxy optionally substituted by substituent group C, lower alkenyloxy optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C, carbocyclecarbonyl optionally substituted by substituent group C, carbocycleoxy optionally substituted by substituent group C, carbocycleoxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocycleoxy lower alkyl optionally substituted by substituent group C, heterocyclecarbonyl optionally substituted by substituent group C, heterocycleoxy optionally substituted by substituent group C, heterocycleoxycarbonyl optionally substituted by substituent group C,
    —Z—N(RC1)—SO2—RC2,
    —Z—N(RC3)—C(═O)—RC4,
    —Z—N(RC5)—C(═O)—O—RC6,
    —Z—C(═O)—N(RC7)(RC8),
    —Z—N(RC9)(RC10),
    —Z—SO2—RC11, or
    —Z—N(RC12)—O—C(═O)—RC13 
    (wherein RC1, RC3, RC4, RC5, RC6, RC7, RC8, RC9, RC10, RC12 and, RC13 are each independently selected from a substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C,
    RC2, and RC11 are each independently selected from a substituent group consisting of lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C,
    RC7 and RC8, and RC9 and RC10 each may be taken together with an adjacent atom to form heterocycle, and
    Z is a bond or straight or branched lower alkylene) and;
    a) either B1 or B2 is CR5aR6a, and the other is NR7a,

or

    b) B1 is CR8aR9a and B2 is CR10aR11a,
    R5a, R6a, R7a, R8a, R9a, R10a and R11a are each independently selected from a substituent group consisting of hydrogen, carboxy, cyano, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, lower alkyl carbonyl optionally substituted by substituent group C, lower alkyl oxycarbonyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C, carbocyclecarbonyl optionally substituted by substituent group C, carbocycleoxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocycleoxy lower alkyl optionally substituted by substituent group C, heterocyclecarbonyl optionally substituted by substituent group C, heterocycleoxycarbonyl optionally substituted by substituent group C,
    —Y—S—RD1,
    —Z—S(═O)—RD2,
    —Z—SO2—RD3,
    —C(═O)—C(═O)—RD4,
    —C(═O)—N(RD5)(RD6),
    —Z—C(RD7)(RD8)(RD9),
    —Z—CH2—RD10,
    —Z—N(RD11)—C(═O)—O—RD12, or
    —Z—N(RD13)—C(═O)—RD14 
    (wherein RD1, RD4, RD5, RD6, RD9, RD11, RD12, RD13, and RD14 are each independently selected from a substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C,
    RD2 and RD3 are each independently selected from a substituent group consisting of lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C,
    RD7, RD8, and RD10 are each independently selected from a substituent group consisting of carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C,
    RD5 and RD6 may be taken together with an adjacent atom to form heterocycle,
    Y is straight or branched lower alkylene, and
    Z is a bond or straight or branched lower alkylene);
    RD5 and RD6 may be taken together with an adjacent atom to form carbocycle;
    1) when B1 is CR5aR6a and B2 is NR7a,
    R3a and R7a may be taken together with an adjacent atom to form heterocycle optionally substituted by substituent group D,
    2) when B1 is NR7a and B2 is CR5aR6a,
    R3a and R6a may be taken together with an adjacent atom to form heterocycle optionally substituted by substituent group D, or
    3) when B1 is CR8aR9a and B2 is CR10aR11a,
    R8a and R10a may be taken together with an adjacent atom to form carbocycle or heterocycle optionally substituted by substituent group D, or
    R3a and R11a may be taken together with an adjacent atom to form heterocycle optionally substituted by substituent group D,

wherein

    when B1 is CR8aR9a, and B2 is CR10aR11a, and R9a is hydrogen, and R11a is hydrogen,
    i) either R8a or R10a is
    —Z—C(RE1)(RE2)(RE3)
    —Y—S—RE4,
    —Z—CH2—RE5, or
    a group shown below:






    (wherein RE1 and RE2 are each independently, carbocycle optionally substituted by substituent group C, and heterocycle optionally substituted by substituent group C,
    RE3 is selected from a substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C,
    RE4 is selected from a substituent group consisting of carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C,
    RE5 is aromatic heterocycle optionally substituted by substituent group C,
    RE6 is selected from a substituent group C,
    m is an integer of 0 or more,
    provided that
    m of RE6s is same or different groups selected from substituent group C
    Y is straight or branched lower alkylene, and
    Z is a bond or straight or branched lower alkylene); and
    ii) the other of R8a or R10a is
    hydrogen, carboxy, cyano, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C, carbocyclecarbonyl optionally substituted by substituent group C, carbocycleoxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocycleoxy lower alkyl optionally substituted by substituent group C, heterocyclecarbonyl, heterocycleoxycarbonyl optionally substituted by substituent group C,
    —Y—S—RF1,
    —C(═O)—C(═O)—RF2, or
    —C(═O)—N(RF3)(RF4)
    (wherein RF1, RF2, RR3, and RF4 are each independently, hydrogen, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C, and Y is straight or branched lower alkylene);

with a proviso that the following c) and d) are excluded

    c) R5a, R6a, and R7a are all hydrogens
    d) R8a, R9a, R10a, and R11a are all hydrogens;
    Substituent group C: halogen, cyano, hydroxy, carboxy, formyl, amino, oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy, lower alkylthio, hydroxy lower alkyl, carbocyclic group, heterocyclic group, heterocyclic group substituted by oxo, carbocycle lower alkyloxy, carbocycleoxy lower alkyl, carbocycle lower alkyloxy lower alkyl, heterocycle lower alkyloxy, heterocycleoxy lower alkyl, heterocycle lower alkyloxy lower alkyl, halogeno lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, lower alkylcarbonyloxy, lower alkyloxycarbonyl, lower alkylamino, lower alkylcarbonylamino, halogeno lower alkyl carbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, lower alkylsulfinyl, and lower alkylsulfonylamino;
    Substituent group D: halogen, cyano, hydroxy, carboxy, formyl, amino, oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy, carbocycle lower alkyloxy, heterocycle lower alkyloxy, halogeno lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, lower alkyloxycarbonyl, lower alkylamino, lower alkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, lower alkylsulfonylamino, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C).

[Item 14′]



The compound according to item 13′, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein R1a is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, lower alkyloxy optionally substituted by substituent group C, lower alkenyloxy optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocyclecarbonyl optionally substituted by substituent group C, carbocycleoxy optionally substituted by substituent group C, carbocycleoxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocyclecarbonyl optionally substituted by substituent group C, heterocycleoxy optionally substituted by substituent group C, heterocycleoxycarbonyl optionally substituted by substituent group C,
    —Z—N(RA1)(RA2),
    —Z—N(RA3)—SO2—(RA4),
    —Z—N(RA7)—C(═O)—RA8,
    —Z—S—RA9,
    —Z—SO2—RA10,
    —Z—N(RA12)—C(═O)—O—RA13, or
    —Z—N(RA20)—C(═O)—C(═O)—RA21 
    (substituent group C, RA1, RA2, RA3, RA4, RA7, RA8, RA9, RA10, RA12, RA13, RA20, RA21, and Z are same meaning as those of item 13).

[Item 15′]



The compound according to item 13′, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein R1a is hydrogen, halogen, hydroxy, carboxy, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkyloxy optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C,
    —Z—N(RA1)(RA2),
    —Z—N(RA7)—C(═O)—RA8, or
    —Z—N(RA12)—C(═O)—O—RA13 
    (substituent group C, RA1, RA2, RA7, RA8, RA12, RA13, and Z are same as those of item 13′).

[Item 16′]



The compound according to item 13′, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein R1a is hydrogen, halogen, hydroxy, carboxy, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkyloxy optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, or
    —Z—N(RA1)(RA2)
    (substituent group C, RA1, RA2, and Z are same as those of item 13′).

[Item 17′]



The compound according to item 13′, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein R1a is hydrogen, or carboxy.

[Item 18′]



The compound according to any one of items 13′ to 17′, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein R2a is hydrogen, lower alkyl optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, or
    —Z—N(RB9)(RB10)
    (substituent group C, RB9, RB10, and Z are same as those of item 13′).

[Item 19′]



The compound according to any one of items 13′ to 17′, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein R2a is hydrogen or lower alkyl optionally substituted by substituent group C
    (substituent group C is same as that of item 13′).

[Item 20′]



The compound according to any one of items 13′ to 19′, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein R3a is hydrogen, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C,
    —Z—N(RC1)—SO2—RC2,
    —Z—N(RC3)—C(═O)—RC4,
    —Z—N(RC5)—C(═O)—O—RC6,
    —Z—C(═O)—N(RC7)(RC8), or
    —Z—N(RC9)(RC10)
    (substituent group C, RC1, RC2, RC3, RC4, RC5, RC6, RC7, RC8, RC9, RC10, and Z are same as those of item 13′).

[Item 21′]



The compound according to any one of items 13′ to 19′, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein R3a is hydrogen, lower alkyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C,
    (substituent group C, is same as that of item 13′).

[Item 22′]



The compound according to any one of items 13′ to 21′, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein B1 is NR7a, and B2 is CR5aR6a, and
    R5a, R6a and R7a are each independently hydrogen, carboxy, cyano, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, lower alkyl carbonyl optionally substituted by substituent group C, lower alkyl oxycarbonyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C, carbocyclecarbonyl optionally substituted by substituent group C, carbocycleoxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocycleoxy lower alkyl optionally substituted by substituent group C, heterocyclecarbonyl optionally substituted by substituent group C, heterocycleoxycarbonyl optionally substituted by substituent group C,
    —Y—S—RD1,
    —Z—S(═O)—RD2,
    —Z—SO2—RD3,
    —C(═O)—C(═O)—RD4,
    —C(═O)—N(RD8)(RD6),
    —Z—C(RD7)(RD8)(RS9)
    —Z—N(RD11)—C(═O)—O—RD12, or
    —Z—N(RD13)—C(═O)—RD14 
    (substituent group C, RD1, RD2, RD3, RD4, RD5, RD6, RD7, RD8, RD9, RD11, RD12, RD13, RD14, Y, and Z are same as those of item 13).

[Item 23′]



The compound according to any one of items 13′ to 21′, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein B1 is NR7a, and B2 is CR5aR6a,
    R5a is hydrogen,
    R6a is hydrogen, or lower alkyl optionally substituted by substituent group C, and
    R7a is lower alkyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, or
    —Z—C(RD7)(RD8)(RD9)
    (substituent group C, RD7, RD8, RD9, and Z are same as item 13′)

[Item 24′]



The compound according to any one of items 13′ to 21′, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein B1 is CR5aR6a, and B2 is NR7a,
    R5a is hydrogen,
    R6a is hydrogen, or lower alkyl optionally substituted by substituent group C, and
    R7a is lower alkyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, or
    —Z—C(RD7)(RD8)(RD9)
    (Substituent group C, RD7, RD8, RD9, and Z are same as item 13′).

[Item 25′]



The compound according to items 23′ or 24′, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein R7a is a group shown below:






    (wherein RE6 and m are same as those of item 13′).

[Item 26′]



The compound according to items 13′ or 21′, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein
    B1 is CR8aR9a, and B2 is CR10aR11a,
    R9a is hydrogen, and R11a is hydrogen, and
    i) either R8a or R10a is a group shown below:






    (wherein RE6, and m are same as those of item 13′); and
    ii) the other of R8a or R10a is
    hydrogen, or lower alkyl optionally substituted by substituent group C,
    (Substituent group C is same as those of item 13′).

[Item 27′]



The compound according to any one of items 13′ to 19′, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein B1 is CR5aR6a, and B2 is NR7a,
    R6a is hydrogen,
    R3a and R7a may be taken together with an adjacent atom to form heterocycle optionally substituted by substituent group D, and
    R5a is hydrogen, lower alkyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocycleoxy lower alkyl optionally substituted by substituent group C,
    —Y—S—RD1,
    —C(═O)—C(═O)—RD2, or
    —C(═O)—N(RD3)(RD4)
    (wherein RD1, RD2, RD3, RD4, Y, substituent group C and substituent group D are the same as item 13′).

[Item 28′]



The compound according to item 27′, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein R5a is hydrogen, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, or heterocycle lower alkyl optionally substituted by substituent group C
    (wherein Substituent group C is same as item 13′).

[Item 29′]



The compound according to any one of items 13′ to 19′, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein B1 is CR8aR9a, and B2 is CR10aR11a,
    R9a is hydrogen, and R10a is hydrogen,
    R3a and R11a are taken together with an adjacent atom to form heterocycle optionally substituted by substituent group D, and
    R8a is hydrogen, lower alkyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocycleoxy lower alkyl optionally substituted by substituent group C,
    —Y—S—RD1,
    —C(═O)—C(═O)—RD2, or
    —C(═O)—N(RD3)(RD4)
    (wherein RD1, RD2, RD3, RD4, Y, substituent group C and substituent group D is same as item 13′).

[Item 30′]



The compound according to item 29′, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein R8a is hydrogen, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, or heterocycle lower alkyl optionally substituted by substituent group C
    (wherein substituent group C is same as that of item 13′).

[Item 31′]



The compound according to any one of items 27′ to 30′, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein substituent group D is carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, or heterocycle lower alkyl optionally substituted by substituent group C
    (wherein substituent group C is same as that of item 13′).

[Item 32′]



A pharmaceutical composition containing a compound according to any one of items 13′ to 31′, or a pharmaceutically acceptable salt thereof or a solvate thereof.
[Item 33′]
The pharmaceutical composition according to item 32′ which exhibits anti influenza activity.
[Item 34′]
The compound according to any one of items 13′ to 31′ for treating and/or preventing influenza infectious disease.
[Item 35′]
The compound according to any one of items 13′ to 31′, or the pharmaceutically acceptable salt thereof or the solvate thereof, for treating and/or preventing influenza infectious disease.
[Item 36′]
The pharmaceutical composition according to item 32′ which exhibits CAP dependent endonuclease inhibitory activity.

    This invention provides following items as another aspect.

[Item 1]



A CAP dependent endonuclease inhibitor containing a compound represented by formula (I), a pharmaceutically acceptable salt, or a solvate thereof:




    (wherein
    R1 is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, lower alkyloxy optionally substituted by substituent group A, lower alkenyloxy optionally substituted by substituent group A, lower alkylcarbonyl optionally substituted by substituent group A, lower alkyloxycarbonyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, carbocyclecarbonyl optionally substituted by substituent group A, carbocycleoxy optionally substituted by substituent group A, carbocycleoxycarbonyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A, heterocyclecarbonyl optionally substituted by substituent group A, heterocycleoxy optionally substituted by substituent group A, heterocycleoxycarbonyl optionally substituted by substituent group A,
    —Z—N(RX1)(RX2),
    —Z—N(RX3)—SO2—(RX4)
    —Z—C(═O)—N(RX5)—SO2—(RX6),
    —Z—N(RX7)—C(═O)—RX8,
    —Z—C(═O)—N(RC9)(RX10),
    —Z—S—RX11,
    —Z—SO2—RX12,
    —Z—S(═O)—RX13,
    —Z—N(RX14)—C(═O)—O—RX15,
    —Z—N(RX6)—C(═O)—N(RX17)(RX18),
    —Z—C(═O)—N(RX19)—C(═O)—N(RX20)(RX21), or
    —Z—N(RX22)—C(═O)—C(═O)—RX23 
    (wherein RX1, RX2, RX3, RX5, RX7, RX8, RX9, RX10, RX11, RX14, RX15, RX16, RX17, RX18, RX19, RX20, RX21, R22 and R23 are each independently selected from a substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A,
    RX4, RX6, RX12, and RX13 are each independently selected from a substituent group consisting of, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A,
    RX1 and RX2, RX9 and RX10, RX17 and RX18, and RX20 and RX21 each may be taken together with an adjacent atom to form heterocycle, and
    Z is a bond or straight or branched lower alkylene);
    R2 is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, lower alkyloxy optionally substituted by substituent group A, lower alkenyloxy optionally substituted by substituent group A, lower alkylcarbonyl optionally substituted by substituent group A, lower alkyloxycarbonyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, carbocyclecarbonyl optionally substituted by substituent group A, carbocycleoxy optionally substituted by substituent group A, carbocycleoxycarbonyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A, heterocyclecarbonyl optionally substituted by substituent group A, heterocycleoxy optionally substituted by substituent group A, heterocycleoxycarbonyl optionally substituted by substituent group A,
    —Z—N(RY1)—SO2—RY2,
    —Z—N(RY3)—C(═O)—RY4,
    —Z—N(RY5)—C(═O)—O—RY6,
    —Z—C(═O)—N(RY7)(RY8),
    —Z—N(RY9)(RY10), or
    —Z—SO2—RY11 
    (wherein RY1, RY3, RY4, RY5, RY6, RY7, RY8, RY9, and RY10 are each independently selected from a substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A,
    RY2 and RY11 are each independently selected from a substituent group consisting of lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A,
    RY7 and RY8, and RY9 and RY10 each may be taken together with an adjacent atom to form heterocycle and
    Z is a bond or straight or branched lower alkylene);
    R3 is hydrogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, lower alkyloxy optionally substituted by substituent group A, lower alkenyloxy optionally substituted by substituent group A, lower alkylcarbonyl optionally substituted by substituent group A, lower alkyloxycarbonyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, carbocycleoxy lower alkyl optionally substituted by substituent group A, carbocyclecarbonyl optionally substituted by substituent group A, carbocycleoxy optionally substituted by substituent group A, carbocycleoxycarbonyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A, heterocycleoxy lower alkyl optionally substituted by substituent group A, heterocyclecarbonyl optionally substituted by substituent group A, heterocycleoxy optionally substituted by substituent group A, heterocycleoxycarbonyl optionally substituted by substituent group A,
    —Z—N(RZ1)—SO2—RZ2,
    —Z—N(RZ3)—C(═O)—RZ4,
    —Z—N(RZ5)—C(═O)—O—RZ6,
    —Z—C(═O)—N(RZ7)(RZ8),
    —Z—N(RZ9)(RZ10),
    —Z—SO2—RZ11, or
    —Z—N(RZ12)—O—C(═O)—RZ13 
    (wherein RZ1, RZ3, RZ4, RZ5, RZ6, RZ7, RZ8, RZ9, RZ10, RZ12 and RZ13 are each independently selected from a substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A,
    RZ2 and RZ11 are each independently selected from a substituent group consisting of lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A,
    RZ7 and RZ8, and RZ9 and RZ10 each may be taken together with an adjacent atom to form heterocycle, and
    Z is a bond or straight or branched lower alkylene) and;
    a) either A1 or A2 is CR5R6, and the other is NR7, or A1 is CR8R9, and A2 is CR10R11,
    b) R5, R6, R7, R8, R9, R10, and R11 are each independently selected from a substituent group consisting of hydrogen, carboxy, cyano, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, lower alkyl carbonyl optionally substituted by substituent group A, lower alkyl oxycarbonyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, carbocycleoxy lower alkyl optionally substituted by substituent group A, carbocyclecarbonyl optionally substituted by substituent group A, carbocycleoxycarbonyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A, heterocycleoxy lower alkyl optionally substituted by substituent group A, heterocyclecarbonyl optionally substituted by substituent group A, heterocycleoxycarbonyl optionally substituted by substituent group A,
    —Z—S—RV1,
    —Z—S(═O)—RV2,
    —Z—SO2—RV3,
    —C(═O)—C(═O)—RV4, or
    —C(═O)—N(RV5)(RV6),
    (wherein RV1, RV4, Rv5, and RV6 are each independently selected from a substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A,
    RV2 and RV3 are each independently selected from a substituent group consisting of lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A,
    RV5 and RV6 may be taken together with an adjacent atom to form heterocycle, and
    Z is a bond or straight or branched lower alkylene);
    1) when A1 is CR5R6 and A2 is NR7,
    R3 and R7 may be taken together with an adjacent atom to form heterocycle optionally substituted by substituent group B or may form condensed ring,
    2) when A1 is NR7 and A2 is CR5R6,
    R3 and R6 may be taken together with an adjacent atom to form heterocycle optionally substituted by substituent group B or may form condensed ring,

or

    3) when A1 is CR8R9 and A2 is CR10R11,
    R8 and R10 may be taken together with an adjacent atom to form a bond, and R8 and R10 may be taken together with an adjacent atom to form carbocycle or heterocycle, or
    R3 and R11 may be taken together with an adjacent atom to form heterocycle optionally substituted by substituent group B or may form condensed ring;
    Substituent group A: halogen, cyano, hydroxy, carboxy, formyl, amino, oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy, carbocyclic group, heterocyclic group, carbocycle lower alkyloxy, heterocycle lower alkyloxy, halogeno lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, lower alkyloxycarbonyl, lower alkylamino, lower alkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, and lower alkylsulfonylamino;
    Substituent group B: halogen, cyano, hydroxy, carboxy, formyl, amino, oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy, carbocyclic group, heterocyclic group, carbocycle lower alkyloxy, heterocycle lower alkyloxy, halogeno lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, lower alkyloxycarbonyl, lower alkylamino, lower alkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, lower alkylsulfonylamino, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A).

[Item 2]



A CAP dependent endonuclease inhibitor according to item 1, wherein

    R1 is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, lower alkyloxy optionally substituted by substituent group A, lower alkenyloxy optionally substituted by substituent group A, lower alkylcarbonyl optionally substituted by substituent group A, lower alkyloxycarbonyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, carbocyclecarbonyl optionally substituted by substituent group A, carbocycleoxy optionally substituted by substituent group A, carbocycleoxycarbonyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A, heterocyclecarbonyl optionally substituted by substituent group A, heterocycleoxy optionally substituted by substituent group A, heterocycleoxycarbonyl optionally substituted by substituent group A,
    —Z—N(RX1)(RX2),
    —Z—N(RX3)—SO2—(RX4),
    —Z—C(═O)—N(RX5)—SO2—(RX6),
    —Z—N(RX7)—C(═O)—RX8,
    —Z—S—RX11,
    —Z—SO2—RX12,
    —Z—S(═O)—RX13,
    —Z—N(RX14)—C(═O)—O—RX15,
    —Z—N(RX16)—C(═O)—N(RX17)(RX18), or
    —Z—N(RX22)—C(═O)—C(═O)—RX23 
    (Substituent group A, RX1, RX2, RX3, RX4, RX5, RX6, RX7, RX8, RX11, RX12, RX13, RX14, RX15, RX16, RX17, RX18, RX22, RX23, and Z are same meaning as those of item 1).

[Item 3]



A CAP dependent endonuclease inhibitor according to item 1, wherein

    R1 is hydrogen, halogen, hydroxy, carboxy, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkyloxy optionally substituted by substituent group A, lower alkylcarbonyl optionally substituted by substituent group A, lower alkyloxycarbonyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A,
    —Z—N(RX1)(RX2),
    —Z—N(RX7)—C(═O)—RX8, or
    —Z—N(RX14)—C(═O)—O—RX15 
    (Substituent group A, RX1, RX2, RX7, RX8, RX14, RX15, and Z are same meaning as those of item 1).

[Item 4]



A CAP dependent endonuclease inhibitor according to item 1, wherein

    R1 is hydrogen, halogen, hydroxy, carboxy, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkyloxy optionally substituted by substituent group A, lower alkyl carbonyl optionally substituted by substituent group A, lower alkyloxycarbonyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, or
    —Z—N(RX1)(RX2)
    (Substituent group A, RX1, RX2, and Z are same meaning as those of item 1).

[Item 5]



A CAP dependent endonuclease inhibitor according to item 1, wherein R1 is hydrogen or carboxy.
[Item 6]
A CAP dependent endonuclease inhibitor according to any one of items 1 to 5, wherein

    R2 is hydrogen, lower alkyl optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A, or
    —Z—N(RY9)(RY10)
    (Substituent group A, RY9, RY10, and Z are same meaning as those of item 1).

[Item 7]



A CAP dependent endonuclease inhibitor according to any one of items 1 to 5, wherein

    R2 is hydrogen or lower alkyl optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A,
    (Substituent group A is same meaning as that of item 1).

[Item 8]



A CAP dependent endonuclease inhibitor according to any one of items 1 to 7, wherein

    R3 is hydrogen, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, carbocycleoxy lower alkyl optionally substituted by substituent group A,
    —Z—N(RZ1)—SO2—RZ2,
    —Z—N(RZ3)—C(═O)—RZ4,
    —Z—N(RZ5)—C(═O)—O—RZ6,
    —Z—C(═O)—N(RZ7)(RZ8), or
    —Z—N(RZ9)(RZ10)
    (Substituent group A, RZ1, RZ2, RZ3, RZ4, RZ5, RZ6, RZ7, RZ8, RZ9, RZ10, and Z are same meaning as those of item 1).

[Item 9]



A CAP dependent endonuclease inhibitor according to any one of items 1 to 8, wherein

    A1 is NR7,
    A is CHR6, and
    R6 and R7 are each independently hydrogen, lower alkyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, carbocycleoxy lower alkyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A, heterocycleoxy lower alkyl optionally substituted by substituent group A,
    —Z—S—RV1,
    —Z—S(═O)—RV2, or
    —Z—SO2—RV3 
    (Substituent group A, RV1, RV2, RV3, and Z are same meaning as those of item 1).

[Item 10]



A CAP dependent endonuclease inhibitor according to any one of items 1 to 8, wherein

    A1 is CHR9,
    A2 is CHR11, and
    R9 and R11 are each independently hydrogen, lower alkyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, carbocycleoxy lower alkyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A, heterocycleoxy lower alkyl optionally substituted by substituent group A,
    —Z—S—RV1,
    —Z—S(═O)—RV2, or
    —Z—SO2—RV3 
    (Substituent group A, RV1, RV2, Rv3, and Z are same meaning as those of item 1).

[Item 11]



A CAP dependent endonuclease inhibitor according to any one of items 1 to 7, wherein

    A1 is CHR9,
    A2 is CHR11,
    R3 and R11 may be taken together with an adjacent atom to form heterocycle optionally substituted by substituent group B, and
    R9 is hydrogen, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A,
    (Substituent group A and substituent group B are same meaning as those of item 1).

[Item 12]



A CAP dependent endonuclease inhibitor according to any one of items 1 to 7, wherein

    A1 is CHR6,
    A2 is NR7,
    R3 and R7 may be taken together with an adjacent atom to form heterocycle optionally substituted by substituent group B,
    R6 is hydrogen, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A,
    (Substituent group A and substituent group B are same meaning as those of item 1).

[Item 13]



A compound represented by formula (II), or a pharmaceutically acceptable salt thereof or a solvate thereof:




    (wherein
    R1a is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, lower alkyloxy optionally substituted by substituent group C, lower alkenyloxy optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocyclecarbonyl optionally substituted by substituent group C, carbocycleoxy optionally substituted by substituent group C, carbocycleoxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocyclecarbonyl optionally substituted by substituent group C, heterocycleoxy optionally substituted by substituent group C, heterocycleoxycarbonyl optionally substituted by substituent group C,
    —Z—N(RA1)(RA2),
    —Z—N(RA3)—SO2—(RA4),
    —Z—C(═O)—N(RA5)—SO2— (RA6),
    —Z—N(RA7)—C(═O)—RA8,
    —Z—S—RA9,
    —Z—SO2—RA10,
    —Z—S(═O)—RA11,
    —Z—N(RA12)—C(═O)—O—RA13,
    —Z—N(RA14)—C(═O)—N(RA15)(RA16),
    —Z—C(═O)—N(RA17)—C(═O)—N(RA18)(RA19), or
    —Z—N(RA20)—C(═O)—C(═O)—RA21 
    (wherein RA1, RA2, RA3, RA5, RA7, RA8, RA9, RA12, RA13, RA14, RA15, RA16, RA17, RA18, RA19, RA20, and RA21 are each independently selected from substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C,
    RA4, RA6, RA10, and RA11 are each independently selected from substituent group consisting of, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C,
    RA1 and RA2, RA15 and RA16 and RA18 and R19 may be taken together with an adjacent atom to form heterocycle, and
    Z is a bond or straight or branched lower alkylene);
    R2a is hydrogen, halogen, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, lower alkyloxy optionally substituted by substituent group C, lower alkenyloxy optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocyclecarbonyl optionally substituted by substituent group C, carbocycleoxy optionally substituted by substituent group C, carbocycleoxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocyclecarbonyl optionally substituted by substituent group C, heterocycleoxy optionally substituted by substituent group C, heterocycleoxycarbonyl optionally substituted by substituent group C,
    —Z—N(RB1)—SO2—RB2 
    —Z—N(RB3)—C(═O)—RB4,
    —Z—N(RB5)—C(═O)—O—RB6,
    —Z—C(═O)—N(RB7)(RB8),
    —Z—N(RB9)(RB10), or
    —Z—SO2—RB11 
    (wherein RB1, RB3, RB4, RB5, RB6, RB7, RB8, RB9, and RB10 are each independently selected from a substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C,
    RB2 and RB11 are each independently selected from a substituent group consisting of lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C,
    RB7 and RB8, and RB9 and RB10 may be taken together with an adjacent atom to form heterocycle, and
    Z is a bond or straight or branched lower alkylene);
    R3a is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, lower alkyloxy optionally substituted by substituent group C, lower alkenyloxy optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C, carbocyclecarbonyl optionally substituted by substituent group C, carbocycleoxy optionally substituted by substituent group C, carbocycleoxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocycleoxy lower alkyl optionally substituted by substituent group C, heterocyclecarbonyl optionally substituted by substituent group C, heterocycleoxy optionally substituted by substituent group C, heterocycleoxycarbonyl optionally substituted by substituent group C,
    —Z—N(RC1)—SO2—RC2,
    —Z—N(RC3)—C(═O)—RC4,
    —Z—N(RC5)—C(═O)—O—RC6,
    —Z—C(═O)—N(RC7)(RC8)
    —Z—N(RC9)(RC10),
    —Z—SO2—RC11, or
    —Z—N(RC12)—O—C(═O)—RC13 
    (wherein RC1, RC3, RC4, RC5, RC6, RC7, RC8, RC9, RC10, R12 and, RC13 are each independently selected from a substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C,
    RC2, and RC11 are each independently selected from a substituent group consisting of lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C,
    RC7 and RC8, and RC9 and RC10 may be taken together with an adjacent atom to form heterocycle, and
    Z is a bond or straight or branched lower alkylene) and;
    a) either B1 or B2 is CR5aR6a, and the other is NR7a,

ors

    b) B1 is CR8aR9a and B2 is CR10aR11a,
    R5a, R6a, R7a, R8a, R9a, R10a and R11a are each independently selected from a substituent group consisting of hydrogen, carboxy, cyano, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, lower alkyl carbonyl optionally substituted by substituent group C, lower alkyl oxycarbonyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C, carbocyclecarbonyl optionally substituted by substituent group C, carbocycleoxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocycleoxy lower alkyl optionally substituted by substituent group C, heterocyclecarbonyl optionally substituted by substituent group C, heterocycleoxycarbonyl optionally substituted by substituent group C,
    —Y—S—RD1,
    —Z—S(═O)—RD2,
    —Z—SO2—RD3,
    —C(═O)—C(═O)—RD4,
    —C(═O)—N(RD8)(RD9),
    —Z—C(RD7)(RD8)(RD9) or
    —Z—CH2—RD10,
    (wherein RD1, RD4, RD5, RD6, and RD9 are each independently selected from a substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C,
    RD2, and RD3 are each independently selected from a substituent group consisting of lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C,
    RD7, RD8, and RD10 are each independently selected from a substituent group consisting of carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C,
    RD5 and RD6 may be taken together with an adjacent atom to form heterocycle,
    Y is straight or branched lower alkylene, and
    Z is a bond or straight or branched lower alkylene);
    1) when B1 is CR5aR6a and B2 is NR7a,
    R3a and R7a may be taken together with an adjacent atom to form heterocycle optionally substituted by substituent group D,
    2) when B1 is NR7a and B2 is CR5aR6a,
    R3a and R6a may be taken together with an adjacent atom to form heterocycle optionally substituted by substituent group D, or
    3) when B1 is CR8aR9a and B2 is CR10aR11a,
    R8a and R10a may be taken together with an adjacent atom to form carbocycle or heterocycle optionally substituted by substituent group D, or
    R3a and R11a may be taken together with an adjacent atom to form heterocycle optionally substituted by substituent group D,

wherein

    when B1 is CR8aR9a, and B2 is CR10aR11a, and R9a is hydrogen, and R11a is hydrogen,
    i) either R8a or R10a is
    —Z—C(RE1)(RE2)(RE3)
    —Y—S—RE4,
    —Z—CH2—RE5, or
    a group shown below:






    (wherein RE1 and RE2 are each independently, carbocyclic group optionally substituted by substituent group C, and heterocyclic group optionally substituted by substituent group C,
    RE3 is selected from a substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C,
    RE4 is selected from a substituent group consisting of carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C,
    RE5 is aromatic heterocyclic group optionally substituted by substituent group C,
    RE6 is selected from a substituent group C,
    m is an integer of 0 or more,

provided that

    m of RE6s is same or different groups selected from a substituent group C
    Y is straight or branched lower alkylene, and
    Z is a bond or straight or branched lower alkylene); and
    ii) the other of R8a or R10a is,
    hydrogen, carboxy, cyano, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C, carbocyclecarbonyl optionally substituted by substituent group C, carbocycleoxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocycleoxy lower alkyl optionally substituted by substituent group C, heterocyclecarbonyl, heterocycleoxycarbonyl optionally substituted by substituent group C,
    —Y—S—RF1,
    —C(═O)—C(═O)—RF2, or
    —C(═O)—N(RF3)(RF4)
    (wherein RF1, RF2, RF3, and RF4 are each independently, hydrogen, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C, and

Y is straight or branched lower alkylene);

    Substituent group C: halogen, cyano, hydroxy, carboxy, formyl, amino, oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy, carbocyclic group, heterocyclic group, carbocycle lower alkyloxy, heterocycle lower alkyloxy, halogeno lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, lower alkyloxycarbonyl, lower alkylamino, lower alkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, and lower alkylsulfonylamino;
    Substituent group D: halogen, cyano, hydroxy, carboxy, formyl, amino, oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy, carbocyclic group, heterocyclic group, carbocycle lower alkyloxy, heterocycle lower alkyloxy, halogeno lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, lower alkyloxycarbonyl, lower alkylamino, lower alkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, lower alkylsulfonylamino, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C).

[Item 14]



The compound according to item 13, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein R1a is hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, lower alkyloxy optionally substituted by substituent group C, lower alkenyloxy optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocyclecarbonyl optionally substituted by substituent group C, carbocycleoxy optionally substituted by substituent group C, carbocycleoxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocyclecarbonyl optionally substituted by substituent group C, heterocycleoxy optionally substituted by substituent group C, heterocycleoxycarbonyl optionally substituted by substituent group C,
    —Z—N(RA1)(RA2),
    —Z—N(RA3)—SO2—(RA4),
    —Z—N(RA7)—C(═O)—RA8,
    —Z—S—RA9,
    —Z—SO2—RA10,
    —Z—N(R12)—C(═O)—O—RA13, or
    —Z—N(RA20)—C(═O)—C(═O)—RA21 
    (substituent group C, RA1, RA2, RA3, RA4, RA7, RA8, RA9, RA10, RA12, RA13, RA20, RA21, and Z are same meaning as those of item 13).

[Item 15]



The compound according to item 13, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein R1a is hydrogen, halogen, hydroxy, carboxy, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkyloxy optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C,
    —Z—N(RA1)(RA2),
    —Z—N(RA7)—C(═O)—RA8, or
    —Z—N(RA12)—C(═O)—O—RA13 
    (substituent group C, RA1, RA2, RA7, RA8, RA12, RA13, and Z are same as those of item 13).

[Item 16]



The compound according to item 13, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein R1a is hydrogen, halogen, hydroxy, carboxy, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkyloxy optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, or
    —Z—N(RA1)(RA2)
    (substituent group C, RA1, RA2, and Z are same as those of item 13).

[Item 17]



The compound according to item 13, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein R1a is hydrogen, or carboxy.

[Item 18]



The compound according to any one of items 13 to 17, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein R2a is hydrogen, lower alkyl optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, or
    —Z—N(RB9)(RB10)
    (substituent group C, RB9, RB10, and Z are same as those of item 13).

[Item 19]



The compound according to any one of items 13 to 17, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein R2a is hydrogen, lower alkyl optionally substituted by substituent group C, or heterocycle lower alkyl optionally substituted by substituent group C
    (substituent group C is same as that of item 13).

[Item 20]



The compound according to any one of items 13 to 19, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein R3a is hydrogen, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C,
    —Z—N(RC1)—SO2—RC2,
    —Z—N(RC3)—C(═O)—RC4,
    —Z—N(RC5)—C(═O)—O—RC6,
    —Z—C(═O)—N(RC7)(RC8), or
    —Z—N(RC9)(RC10)
    (substituent group C, RC1, RC2, RC3, RC4, RC5, RC6, RC7, RC8, RC9, RC10, and Z are same as those of item 13).

[Item 21]



The compound according to any one of items 13 to 20, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein B1 is NR7a, and B2 is CR5aR6a, and
    R5a, R6a and R7a are each independently hydrogen, carboxy, cyano, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, lower alkyl carbonyl optionally substituted by substituent group C, lower alkyl oxycarbonyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C, carbocyclecarbonyl optionally substituted by substituent group C, carbocycleoxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocycleoxy lower alkyl optionally substituted by substituent group C, heterocyclecarbonyl optionally substituted by substituent group C, heterocycleoxycarbonyl optionally substituted by substituent group C,
    —Y—S—RD1,
    —Z—S(═O)—RD2,
    —Z—SO2—RD3,
    —C(═O)—C(═O)—RD4,
    —C(═O)—N(RD5)(RD6), or
    —Z—C(RD7)(RD8)(R9)
    (substituent group C, RD1, RD2, RD3, RD4, RD5, RD6, RD7, RD8, RD9, Y, and Z are same as those of item 13).

[Item 22]



The compound according to any one of items 13 to 20, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein B1 is NR7a, and B2 is CR5aR6a,
    R6a is hydrogen, and
    R5a and R7a are each independently hydrogen, lower alkyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycleoxy lower alkyl optionally substituted by substituent group C,
    —Z—S—RD1, or
    —Z—C(RD7)(RD8)(RD9)
    (substituent group C, RD1, RD7, RD8, RD9 and Z are same as item 13).

[Item 23]



The compound according to any one of items 13 to 20, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein B1 is NR7a, and B2 is CR5aR6a,
    R5a is hydrogen, R6a is hydrogen, and
    R7a is lower alkyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, or
    —Z—C(RD7)(RD8)(RD9)
    (substituent group C, RD7, RD8, RD9, and Z are same as item 13).

[Item 24]



The compound according to any one of items 13 to 20, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein B1 is NR7a, and B2 is CR5aR6a,
    R5a is hydrogen, R6a is hydrogen, and
    R7a is a group shown below:






    (wherein RE6 and m are same as those of item 13).

[Item 25]



The compound according to items 13 or 20, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein
    B1 is CR8aR9a, and B2 is CR10aR11a,
    R9a is hydrogen, and R11a is hydrogen, and
    i) either R8a or R10a is
    —Z—C(RE1)(RE2)(RE3)
    —Y—S—RE4 
    —Z—CH2—RE5,
    or a group shown below:






and,

    ii) the other of R8a or R10a is
    hydrogen, or lower alkyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocycleoxy lower alkyl optionally substituted by substituent group C,
    (Substituent group C is same as that of item 13).
    —Z—S—RF1,
    —C(═O)—C(═O)—RF2, or
    —C(═O)—N(RF3)(RF4)
    (substituent group C, RE1, RE2, RE3, RE4, RE5, RF1, RF2, RF3, RF4, RE6, m, Z, and Y are same as those of item 13).

[Item 26]



The compound according to any one of items 13 to 20, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein B1 is CR8aR9a, and B2 is CR10aR11a,
    R9a is hydrogen, R10a is hydrogen, and R11a is hydrogen,
    R8a is —Z—CH(RE1)(RE2)
    (RE1, RE2, and Z are same as those of item 13).

[Item 27]



The compound according to any one of items 13 to 20, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein B1 is CR8aR9a and B2 is CR10aR11a,
    R8a is hydrogen, R9a is hydrogen, and R11a is hydrogen, and
    R10a is —Z—CH(RE1)(RE2)
    (RE1, RE2, and Z are same as those of item 13).

[Item 28]



The compound according to any one of items 13 to 20, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein B1 is CR8aR9a, and B2 is CR10aR11a,
    R9a is hydrogen, R10a is hydrogen, and R11a is hydrogen, and
    R8a is a group shown below:






    (wherein, RE6 and m are same as those of item 13).

[Item 29]



The compound according to any one of items 13 to 20, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein B1 is CR8aR9a and B2 is CR10aR11a,
    R9a is hydrogen, and R11a is hydrogen,
    R8a and R10a may be taken together with an adjacent atom to form carbocycle or heterocycle optionally substituted by substituent group D,
    (wherein substituent group D is same as that of item 13)

[Item 30]



The compound according to any one of items 13 to 19, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein B1 is CR5aR6a, and B2 is NR7a,
    R6a is hydrogen,
    R3a and R7a may be taken together with an adjacent atom to form heterocycle optionally substituted by substituent group D, and
    R5a is hydrogen, lower alkyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocycleoxy lower alkyl optionally substituted by substituent group C,
    —Y—S—RD1,
    —C(═O)—C(═O)—RD2, or
    —C(═O)—N(RD3)(RD4)
    (wherein, RD1, RD2, RD3, and RD4 are each independently selected from a substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C,
    Y is straight or branched lower alkylene, and
    Substituent group C and substituent group D are same as those of item 13).

[Item 31]



The compound according to item 30, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein B1 is CR5aR6a, and B2 is NR7a,
    R6a is hydrogen,
    R3a and R7a may be taken together with an adjacent atom to form heterocycle optionally substituted by substituent group D, and
    R5a is hydrogen, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, or heterocycle lower alkyl optionally substituted by substituent group C (wherein substituent group C and substituent group D are same as those of item 13).

[Item 32]



The compound according to any one of items 13 to 19, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein B1 is CR8aR9a, and B2 is CR10aR11a,
    R9a is hydrogen, and R10a is hydrogen,
    R3a and R11a may be taken together with an adjacent atom to form heterocycle optionally substituted by substituent group D, and
    R8a is hydrogen, lower alkyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocycleoxy lower alkyl optionally substituted by substituent group C,
    —Y—S—RD1,
    —C(═O)—C(═O)—RD2, or
    —C(═O)—N(RD3)(RD4)
    (wherein, RD1, RD2, RD3, and RD4 are each independently selected from a substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, and heterocycle lower alkyl optionally substituted by substituent group C,
    Y is straight or branched lower alkylene, and substituent group C and substituent group D are same as those of item 13).

[Item 33]



The compound according to item 32, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein B1 is CR8aR9a, and B2 is CR10aR11a,
    R9a is hydrogen, R10a is hydrogen,
    R3a and R11a may be taken together with an adjacent atom to form heterocycle optionally substituted by substituent group D, and
    R8a is hydrogen, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, or heterocycle lower alkyl optionally substituted by substituent group C)
    (wherein, substituent group C and substituent group D are same as those of item 13).

[Item 34]



The compound according to any one of items 29 to 33, or the pharmaceutically acceptable salt thereof or the solvate thereof,

    wherein substituent group D is carbocyclic group optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, or heterocycle lower alkyl optionally substituted by substituent group C

[Item 35]



A pharmaceutical composition containing a compound according to any one of items 13 to 34, or a pharmaceutically acceptable salt thereof or a solvate thereof.
[Item 36]
The pharmaceutical composition according to item 35 which exhibits CAP dependent endonuclease inhibitory activity.
[Item 37]
The pharmaceutical composition according to item 35 which exhibits anti influenza activity.
[Item 38]
A method for treating influenza infectious disease characterized in administering the compound shown by formula (II) according to above item 13, or the pharmaceutically acceptable salt thereof or the solvate thereof.
[Item 39]
Use of the compound shown by formula (II) according to above item 13, or the pharmaceutically acceptable salt thereof or the solvate thereof, for manufacturing a therapeutic agent for influenza infectious disease.
[Item 40]
The compound shown by formula (II) according to above item 13, or the pharmaceutically acceptable salt thereof or the solvate thereof, for treating influenza infectious disease.
[Item 41]
A method of producing a compound shown by formula (X4) or a salt thereof, comprising the steps of:
(Step B)
reacting a compound shown by formula (X2):




    (wherein R1d is hydrogen, halogen, lower alkyloxy optionally substituted by substituent E, carbocyclic group lower alkyloxy optionally substituted by substituent E, heterocycle lower alkyloxy optionally substituted by substituent E, or
    —OSi(R1e)3,


R1es are each independently lower alkyl optionally substituted by substituent E, carbocyclic group optionally substituted by substituent E, heterocyclic group optionally substituted by substituent E, carbocycle lower alkyl optionally substituted by substituent E or heterocycle lower alkyl optionally substituted by substituent E,
R2d is hydrogen, lower alkyl optionally substituted by substituent E, carbocycle lower alkyl optionally substituted by substituent E, or heterocycle lower alkyl optionally substituted by substituent E,
R3d is hydrogen, lower alkyl optionally substituted by substituent E, —N(R3e)2, or —OR3e,

    R3es are each independently lower alkyl optionally substituted by substituent E,
    wavy line is E form and/or Z form
    Substituent E: halogen, cyano, hydroxy, carboxy, formyl, amino, oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy, carbocyclic group, heterocyclic group, carbocyclic group lower alkyloxy, heterocyclic group lower alkyloxy, halogeno lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, lower alkyloxycarbonyl, lower alkylamino, lower alkylcarbonylamino, lower alkylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, and lower alkylsulfonylamino;)

with a compound shown by formula (V2):







    (wherein R4d is lower alkyl optionally substituted by substituent E, carbocycle lower alkyl optionally substituted by substituent E, or heterocycle lower alkyl optionally substituted by substituent E,
    R5d is hydrogen, halogen, lower alkyloxy optionally substituted by substituent E, —O—SO2—R5e, —O—SO2—R5f, or —O—SO2—R5g,
    R5e is lower alkyl optionally substituted by substituent E,
    R5f is carbocycle lower alkyl optionally substituted by substituent E, and
    R5g is carbocycle lower alkyl optionally substituted by substituent E, and
    substituent E is defined above)

to obtain a compound shown by formula (X3):







    (wherein each symbol is defined above); and

(Step C)



reacting a compound shown by formula (X3) with a compound shown by formula (V3):

[Chemical formula 17]

H2N—R6d   (V3)

    (wherein R6d is lower alkyl optionally substituted by substituent E, or lower alkenyl optionally substituted by substituent E, and
    substituent E is defined above)

to obtain a compound shown by formula (X4):







    (wherein each symbol is defined above).

[Item 42]



A method according to item 41, wherein Step B and Step C are continuously performed.
[Item 43]
A method of producing a compound shown by formula (X3), or a salt thereof:




    (wherein each symbol is defined in item 41)

reacting a compound shown by formula (X2):







(wherein each symbol is defined in item 41)

with a compound shown by formula (V2):





    (wherein each symbol is defined in item 41).

[Item 44]



A method of producing a compound shown by formula (X4), or a salt thereof:




    (wherein each symbol is defined in item 41)

reacting a compound shown by formula (X3):







    (wherein each symbol is defined in item 41); and
    with a compound shown by formula (V3):

[Chemical formula 23]

H2N—R6d   (V3)

    (wherein symbol is defined in item 41).

[Item 45]



A method of producing a compound shown by formula (X4′), or a salt thereof:




    (wherein each symbol is defined in item 41)

comprising a step of:

reacting a compound shown by formula (X2):







    (wherein each symbol is defined in item 41)

a compound shown by formula (V2):







    (wherein each symbol is defined in item 41)
    and a compound shown by formula:

[Chemical formula 27]

NH4+Xd−

    (wherein Xd is halogen, CH3COO, or HSO4)

[Item 46]



A method of producing a compound shown by formula (X4), or a salt thereof:




    (wherein each symbol is defined above)

comprising the step of:

    reacting the compound shown by formula (X4′):






    (wherein each symbol is defined above)
    obtained in the production method as defined in item 45, with a compound shown by formula (V3′):

[Chemical formula 30]

R6d-Ld  (V3′)

    (wherein R6d is defined above,
    Ld is halogen, —O—SO2—CH3, or —O—SO2-Ph-CH3, and Ph is a phenyl group).

[Item 47]



A method according to any one of items 41, 43, and 45, wherein the compound shown by formula (X2) is obtained by reacting a compound shown by formula (X1):




    (wherein each symbol is defined above)

with a compound shown by formula (VI):







    (wherein Pd is lower alkyl optionally substituted by substituent E, and substituent E is defined in item 41).

[Item 48]



A compound shown by formula (X3):




    (wherein each symbol is defined above),
    or a pharmaceutically acceptable salt thereof or solvate thereof.

[Item 49]



A compound shown by formula (X4):




    (wherein each symbol is defined above),
    or a pharmaceutically acceptable salt thereof or solvate thereof.


Effect of the Invention
The compounds of this invention, having inhibitory activities to cap-dependent endonuclease, are effective as therapeutic agents and/or preventive agents for influenza infectious disease.


BEST MODE FOR CARRYING OUT THE INVENTION
The meaning of each term used in the present description is explained below. Each term is used in a unified sense, and is used in the same sense when used alone, or when used in combination of other term.
“Optionally substituted by substituent group A” means that an arbitrary position may be substituted by one, two or more same or different substituents selected from substituent group A.
“Optionally substituted by substituent group B”, “optionally substituted by substituent group C”, “optionally substituted by substituent group D”, and “optionally substituted by substituent group E” are also as described above.
“Halogen” includes fluorine, chlorine, bromine and iodine. Preferable is fluorine, chlorine and bromine.
“Lower alkyl” includes straight or branched alkyl of a carbon number of 1 to 15, preferably a carbon number of 1 to 10, more preferably a carbon number of 1 to 6, further preferably a carbon number of 1 to 4, and examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl and n-decyl etc. Examples of a preferable embodiment of “lower alkyl” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. Examples of a further preferable embodiment include methyl, ethyl, n-propyl, isopropyl, and tert-butyl.
“Lower alkenyl” includes straight or branched alkenyl of a carbon number of 2 to 15, preferably a carbon number of 2 to 10, more preferably a carbon number of 2 to 6, further preferably a carbon number of 2 to 4, having one or more double bonds at an arbitrary position. Specifically, lower alkenyl includes vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl etc. Examples of a preferable embodiment of “lower alkenyl” include vinyl, allyl, propenyl, isopropenyl, and butenyl.
“Lower alkynyl” includes straight or branched alkynyl of a carbon number of 2 to 10, preferably a carbon number of 2 to 8, further preferably a carbon number of 3 to 6, having one or more triple bonds at an arbitrary position. Specifically, lower alkynyl includes ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl etc. These may further have a double bond at an arbitrary position. Examples of a preferable embodiment of “lower alkynyl” include ethynyl, propynyl, butynyl, and pentynyl.
A lower alkyl part of “lower alkyloxy”, “lower alkylcarbonyl”, “lower alkyloxycarbonyl”, “carbocycle lower alkyl”, “heterocycle lower alkyl”, “carbocycleoxy lower alkyl”, “heterocycleoxy lower alkyl”, “halogeno lower alkyl”, “carbocycle lower alkyloxy”, “heterocycle lower alkyloxy”, “halogeno lower alkyloxy”, “lower alkyloxy lower alkyl”, “lower alkyloxy lower alkyloxy”, “lower alkylcarbonyl”, “lower alkyloxycarbonyl”, “lower alkylamino”, “lower alkylcarbonylamino”, “lower alkylaminocarbonyl”, “lower alkylsulfonyl”, “lower alkylsulfonylamino”, “lower alkylthio”, “hydroxy lower alkyl”, “carbocycle lower alkyloxy lower alkyl”, “heterocycle lower alkyloxy lower alkyl”, “lower alkylcarbonyloxy”, “halogeno lower alkylcarbonylamino”, and “lower alkylsulfinyl” is the same as the “lower alkyl” as described above.
A lower alkenyl part of “lower alkenyloxy” is the same as the “lower alkenyl” as described above.
A halogen part of “halogeno lower alkyl”, “halogeno lower alkyloxy”, and “halogeno lower alkylcarbonylamino” is the same as the “halogen”. Herein, an arbitrary position on an alkyl group of “lower alkyl”, “lower alkyloxy”, and “lower alkylcarbonylamino” may be substituted by same or different one or plural halogen atoms, respectively.
“Carbocyclic group” or “carbocycle” means carbocyclic group of a carbon number of 3 to 20, preferably a carbon number of 3 to 16, more preferably a carbon number of 4 to 12, and includes cycloalkyl, cycloalkenyl, aryl and a non-aromatic condensed carbocyclic group, etc.
Specifically, “cycloalkyl” is carbocyclic group of a carbon number of 3 to 16, preferably a carbon number of 3 to 12, more preferably a carbon number of 4 to 8, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl, etc.
Specifically, “cycloalkenyl” includes cycloalkenyl having one or more double bonds at an arbitrary position in the cycloalkyl ring, and examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptynyl, cyclooctynyl and cyclohexadienyl, etc.
Specifically, “aryl” includes phenyl, naphthyl, anthryl and phenanthryl, etc. and, particularly, phenyl is preferable.
Specifically, “non-aromatic condensed carbocyclic group” includes a group in which two or more cyclic groups selected from the “cycloalkyl”, the “cycloalkenyl” and the “aryl” are condensed, and examples include indanyl, indenyl, tetrahydronaphthyl, fluorenyl, adamantyl, and a group shown below:




etc.

Examples of a preferable embodiment of “carbocyclic group” or “carbocycle” include cycloalkyl, aryl and a non-aromatic condensed carbocyclic group, specifically examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, naphthyl, and a group shown below:




etc.

A carbocyclic part of “carbocycle lower alkyl”, “carbocycle lower alkyloxy”, “carbocycleoxy lower alkyl”, “carbocyclecarbonyl”, “carbocycleoxy”, “carbocycleoxycarbonyl” and “carbocycle lower alkyloxy lower alkyl” is the same as the “carbocyclic group” or the “carbocycle” as described above.
“Heterocyclic group” or “heterocycle” includes heterocyclic group such as heteroaryl, a non-aromatic heterocyclic group, a bicyclic condensed heterocyclic group, a tricyclic condensed heterocyclic group, etc., having one or more same or different hetero atoms arbitrarily selected from O, S and N in a ring.
Specifically, “heteroaryl” includes a 5- to 6-membered aromatic cyclic group such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isooxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, etc.
Specifically, “non-aromatic heterocyclic group” includes a 4- to 8-membered non-aromatic heterocyclic group such as dioxanyl, thiiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydrofuryl, tetrahydropyranyl, dihydrothiazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl, tetrahydrodiazepinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxolanyl, etc.
Specifically, “bicyclic condensed heterocyclic group” includes a cyclic group including at least one 4- to 8-membered aromatic or non-aromatic heterocyclic group such as indolyl, isoindolyl, indazolyl, indolizinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzotriazolyl, benzisooxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, thienopyridyl, thienopyrrolyl, thienopyrazolyl, thienopyrazinyl, furopyrrolyl, thienothienyl, imidazopyridyl, pyrazolopyridyl, thiazolopyridyl, pyrazolopyrimidinyl, pyrazolotrianizyl, pyridazolopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl, naphthyridinyl, dihydrothiazolopyrimidinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrobenzofuryl, dihydrobenzoxazinyl, dihydrobenzimidazolyl, tetrahydrobenzothienyl, tetrahydrobenzofuryl, benzodioxolyl, benzodioxonyl, chromanyl, chromenyl, octahydrochromenyl, dihydrobenzodioxynyl, dihydrobenzooxezinyl, dihydrobenzodioxepinyl, dihydrothienodioxynyl, etc.
Specifically, “tricyclic condensed heterocyclic group” includes a cyclic group including at least one 4- to 8-membered aromatic or non-aromatic heterocyclic group such as carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl, imidazoquinolyl, tetrahydrocarbazolyl, and a group shown below:




etc.

Examples of a preferable embodiment of “heterocyclic group” include 5- to 6-membered heteroaryl, a non-aromatic heterocyclic group and a tricyclic condensed heterocyclic group.
A heterocyclic part of “heterocycle lower alkyl”, “heterocycle lower alkyloxy”, “carbocycleoxy lower alkyl”, “heterocyclecarbonyl”, “heterocycleoxy”, “heterocycleoxycarbonyl”, and “heterocycle lower alkyloxy lower alkyl” is the same as the “heterocyclic group” or the “heterocycle” as described above.
“Heterocyclic group substituted by oxo” means the “heterocyclic group” as described above, substituted by oxo as shown below. A group shown below:




is exemplified.

“Straight or branched lower alkylene” is divalent “lower alkyl” as described above, and includes, for example, methylene, ethylene, propylene, butylene, isobutylene, pentylene, heptylene, dimethylmethylene, ethylmethylmethylene, 1,2-dimethylethylene, etc.
Examples of “lower alkyloxy” include methoxy, ethoxy, propyloxy, isopropyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy, etc. Examples of a preferable embodiment include methoxy, ethoxy, propyloxy, isopropyloxy, and tert-butyloxy.
Examples of “lower alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl, etc. Examples of a preferable embodiment include methylcarbonyl, ethylcarbonyl, and propylcarbonyl.
Examples of “lower alkyloxycarbonyl” include methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl, etc. Examples of a preferable embodiment include methyloxycarbonyl, ethyloxycarbonyl, and propyloxycarbonyl.
“Carbocycle lower alkyl” represents lower alkyl substituted by one, two or more carbocyclic groups, and examples of “carbocycle lower alkyl” include benzyl, phenethyl, phenylpropynyl, benzhydryl, trityl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, naphthylmethyl, a group shown below:




etc. Examples of a preferable embodiment include benzyl, phenethyl, and benzhydryl.

“Heterocycle lower alkyl” represents lower alkyl substituted by one, two or more heterocyclic groups, and also includes heterocycle lower alkyl in which an alkyl part is substituted by carbocyclic group. Examples of “heterocycle lower alkyl” include pyridylmethyl, tetrahydropyranylmethyl, furanylmethyl, morpholinylethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isooxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benzoxazolylmethyl, piperidinylmethyl, piperazinylmethyl, a group shown below:




etc. Examples of a preferable embodiment include pyridylmethyl, tetrahydropyranylmethyl, furanylmethyl, and morpholinylethyl.

Examples of “carbocycleoxy lower alkyl” include phenyloxymethyl, phenyloxyethyl, cyclopropyloxymethyl, cyclopropyloxyethyl, cyclobutyloxymethyl, cyclobutyloxyethyl, cyclohexyloxymethyl, cyclohexyloxyethyl, etc. Examples of a preferable embodiment include phenyloxymethyl, and phenyloxyethyl.
Examples of “heterocycleoxy lower alkyl” include pyridyloxymethyl, pyridyloxyethyl, morpholinyloxymethyl, morpholinyloxyethyl, benzoxazolyloxymethyl, etc. Examples of a preferable embodiment include pyridyloxymethyl, morpholinyloxymethyl, etc.
“Carbocycle lower alkyloxy” represents lower alkyloxy in which an alkyl part is substituted by one, two or more carbocyclic groups, and examples of “carbocycle lower alkyloxy” include phenylmethyloxy, phenylethyloxy, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, etc. Examples of a preferable embodiment include phenylmethyloxy, cyclopropylmethyloxy, etc.
“Heterocycle lower alkyloxy” represents lower alkyloxy in which an alkyl part is substituted by one, two or more heterocyclic groups, and also includes heterocycle lower alkyloxy in which an alkyl part is substituted by carbocyclic group. Examples of “heterocycle lower alkyloxy” include pyridylmethyloxy, pyridylethyloxy, imidazolylmethyloxy, imidazolylethyloxy, benzoxazolylmethyloxy, benzoxazolylethyloxy, etc.
Examples of “lower alkyloxy lower alkyl” include methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxypropyl, methoxybutyl, ethoxypropyl, ethoxybutyl, isopropyloxymethyl, tert-butyloxymethyl, etc. Examples of a preferable embodiment include methoxymethyl, methoxyethyl, ethoxymethyl, and ethoxyethyl.
Examples of “lower alkyloxy lower alkyloxy” include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy, methoxypropyloxy, methoxybutyloxy, ethoxypropyloxy, ethoxybutyloxy, isopropyloxymethyloxy, tert-butyloxymethyloxy, etc. Examples of a preferable embodiment include methoxymethoxy, methoxyethoxy, ethoxymethoxy, and ethoxyethoxy.
Examples of “lower alkylamino” include methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, N,N-diisopropylamino, N-methyl-N-ethylamino, N-isopropyl-N-ethylamino, etc. Examples of a preferable embodiment include methylamino, dimethylamino, ethylamino, and diethylamino.
Examples of “lower alkylcarbonylamino” include methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino, etc. Examples of a preferable embodiment include methylcarbonylamino, and ethylcarbonylamino.
Examples of “lower alkylaminocarbonyl” include methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, isopropylaminocarbonyl, N,N-diisopropylaminocarbonyl, N-methyl-N-ethylaminocarbonyl, N-isopropyl-N-ethylaminocarbonyl, etc. Examples of a preferable embodiment include methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, and diethylaminocarbonyl.
Examples of “lower alkylsulfonyl” include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, etc. Examples of a preferable embodiment include methylsulfonyl, and ethylsulfonyl.
Examples of “lower alkylsulfonylamino” include methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino, etc. Examples of a preferable embodiment include methylsulfonylamino, and ethylsulfonylamino.
Examples of “lower alkenyloxy” include ethylenyloxy, 1-propylenyloxy, 2-propylenyloxy, 1-butylenyloxy, 2-butylenyloxy, 3-butylenyloxy, etc.
Examples of “halogeno lower alkyl” include monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl, etc. Examples of a preferable embodiment include trifluoromethyl, trichloromethyl, 1,1,1-trifluoropropan-2-yl.
Examples of “halogeno lower alkyloxy” include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, trichloroethoxy, etc. Examples of a preferable embodiment include trifluoromethoxy, and trichloromethoxy.
Examples of “lower alkylthio” include methylthio, ethylthio, propylthio, etc.
Examples of “hydroxy lower alkyl” include hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.
Examples of “carbocycle lower alkyloxy lower alkyl” include benzyloxymethyl, benzyloxyethyl, benzhydryloxymethyl, etc.
Examples of “heterocycle lower alkyloxy lower alkyl” include pyridylmethyloxymethyl, pyridylmethyloxyethyl, etc.
Examples of “lower alkylcarbonyloxy” include methylcarbonyloxy, ethylcarbonyloxy, etc.
Examples of “halogeno lower alkylcarbonylamino” include trifluoromethylcarbonylamino, 2,2,3,3,3-pentafluoropropylcarbonylamino, etc.
Examples of “lower alkylsulfinyl” include methylsulfinyl, ethylsulfinyl, etc.
Examples of “carbocyclecarbonyl” include phenylcarbonyl, naphthylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.
Examples of “carbocycleoxy” include phenyloxy, naphthyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.
Examples of “carbocycleoxycarbonyl” include phenyloxycarbonyl, naphthyloxycarbonyl, cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, etc.
Examples of “heterocyclecarbonyl” include pyridylcarbonyl, benzoxazolylcarbonyl, morpholinylcarbonyl, tetrahydropyranylcarbonyl, etc.
Examples of “heterocycleoxy” include pyridyloxy, benzoxazolyloxy, morpholinyloxy, tetrahydropyranyloxy, etc.
Examples of “heterocycleoxycarbonyl” include pyridyloxycarbonyl, benzoxazolyloxycarbonyl, morpholinyloxycarbonyl, tetrahydropyranyloxycarbonyl, etc.

    “RX1 and RX2, RX9 and RX10, RX17 and RX18 as well as RX20 and RX21, each may be taken together with an adjacent atom to form a heterocycle”,
    “RY7 and RY8, as well as RY9 and RY10, each may be taken together with an adjacent atom to form a heterocycle”,
    “RZ7 and RZ8, as well as RZ9 and RZ10, each may be taken together with an adjacent atom to form a heterocycle”, and
    “RV5 and RV6 may be taken together with an adjacent atom to form a heterocycle” in item 1′ and item 1; and
    “RA1 and RA2, RA15 and RA16, as well as RA19 and RA20, each may be taken together with an adjacent atom to form a heterocycle”,
    “RB7 and RB8, as well as RB9 and RB10, each may be taken together with an adjacent atom to form a heterocycle”,
    “RC7 and RC8, as well as RC9 and RC10, each may be taken together with an adjacent atom to form a heterocycle”, and
    “RD5 and RD6 may be taken together with an adjacent atom to form a heterocycle” in item 13′ and item 13 mean a heterocycle having N atom, and include, for example, a group shown below:






etc.

In the present description, (RE6)m in the formula shown below:




    means that an arbitrary carbon atom or nitrogen atom which can chemically have a substituent on a ring is substituted by m of RE6s which are same or different.


For example, in the formula below:




as shown by a substituent below:





    (wherein ma+mb+mc=m, and RE6 is as defined above),
    it is meant that any hydrogen atom on two benzene rings and a 7-membered ring containing a sulfur atom may be substituted by RE6, and respective RE6s may be the same or different.


And, ma is preferably an integer of 0 to 3, mb is preferably an integer of 0 to 3, and mc is preferably an integer of 0 or 1. And, ma is more preferably an integer of 0 or 1, mb is more preferably an integer of 0 or 1, and mc is more preferably 0.
For example, in the formula below:




substituents shown below:





    (wherein RE6, and m are as defined in item 13′)

etc. are included.



“When A1 is CR5R6, and A2 is NR7, R3 and R7 may be taken together with an adjacent atom to form a heterocycle optionally substituted by substituent group B” in the formula (I) in item 1′ and item 1 represents the formula (I′) shown below:




    (wherein R1, R2, R5 and R6 are as defined in item 1′ and item 1), and indicates that the “ring” may be substituted by one, two or more same or different substituents selected from substituent group B at an arbitrary position. The heterocycle is preferably a 5- to 7-membered ring. In addition, “the heterocycle may form a condensed ring” indicates that the ring in the formula (I′) may be further condensed with a ring, and indicates that substituent group B may be bound to any of the ring in the formula (I′) or the ring which is condensed with a ring. Examples of the formula (I′) include compounds shown by the following formulae:






    (wherein Rx, and Ry are a substituent selected from substituent group B, and R1, R2, R5, and R6 are as defined in item 1′ and item 1) etc.


“When form a heterocycle” in “when A1 is NR7, and A2 is CR5R6, R3 and R6 may be taken together with an adjacent atom to form a heterocycle optionally substituted by substituent group B” in the formula (I) in item 1′ and item 1 represents the formula (I′′) shown below:




    (wherein R1, R2, R5, and R6 are as defined in item 1′ and item 1), and indicates that a part of a ring may be substituted by one, two or more same or different substituents selected from substituent group B at an arbitrary position. The heterocycle is preferably a 5- to 7-membered ring. In addition, “the heterocycle may form a condensed ring” indicates that the ring in the formula (I′′) may be further condensed with a ring, and indicates that one, two or more of substituent group B may be bound to any of the ring in the formula (I′′) or the ring which is condensed with a ring. Examples of the formula (I′′) include compounds shown in the following formula:






    (wherein Rx an Ry are a substituent selected from substituent group B, and R1, R2, R5 and R7 are as defined in item 1′ and item 1) etc.


“When form a bond” in “when A1 is CR8R9, and A2 is CR10R11, R8 and R10 may be taken together with an adjacent atom to form a bond” in the formula (I) of item 1′ and item 1 represents the formula (I′′′) shown below:




    (wherein R1, R2, R3, R9 and R11 are as defined in item 1′ and item 1).


In addition, “when form a bond” in “R8 and R10 may be taken together with an adjacent atom to form a carbocycle or a heterocycle optionally substituted by substituent group B′′ represents the formula (I′′′′) shown below:




    (wherein R1, R2, R3, R9 and R11 are as defined in item 1′ and item 1), and indicates that a part of a ring may be substituted by one, two or more same or different substituents selected from substituent group B at an arbitrary position. The carbocycle or the heterocycle is preferably a 5- to 7-membered ring. Examples of the formula (I′′′′) include a compound shown in the following formula:






    (wherein Rx and Ry are a substituent selected from substituent group B, and R1, R2, R3, R9 and R11 are as defined in item 1′ and item 1) etc.


Further, “R3 and R11 may be taken together with an adjacent atom to form a heterocyle optionally substituted by substituent group B, and the heterocycle may form a condensed ring” represents the formula (I′′′′′) shown below:




    (wherein R1, R2, R8, R9 and R10 are as defined in item 1′ and item 1), and indicates that a part of a ring may further form a condensed ring, and the same or different substituents selected from substituent group B may be bound to any of the ring in the formula (I′′′′′) or the ring which is condensed with a ring at an arbitrary position. The heterocycle is preferably a 5- to 7-membered ring. Examples of the formula (I′′′′′) include compounds shown by the following formula:






    (wherein Rx and Ry are a substituent selected from substituent group B, and R1, R2, R8, R9 and R10 are as defined in item 1′ and item 1) etc.


“When form a heterocyle” in “when B1 is CR5aR6a, and B2 is NR7a, R3a and R7a may be taken together with an adjacent atom to form a heterocycle optionally substituted by substituent group D” in the formula (II) in item 13 represents the formula (II′) shown below:




    (wherein R1a, R2a, R5a and R6a are as defined in item 13′ and item 13).


“When form a heterocycle” in “when B1 is NR7a, and B2 is CR5aR6a, R3a and R6a may be taken together with an adjacent atom to form a heterocycle optionally substituted by substituent group D” represents the formula (II′′) shown below:




    (wherein R1a, R2a, R5a and R7a are as defined in item 13′ and item 13). The heterocycle is preferably a 5- to 7-membered ring.


“When form a heterocycle” in “when B1 is CR8aR9a, and B2 is CR10aR11a, R8a and R10a may be taken together with an adjacent atom to form a carbocycle or a heterocycle, optionally substituted by substituent group D” represents the formula (II′′′) shown below:




    (wherein R1a, R2a, R3a, R9a and R11a are as defined in item 13′ and item 13). The carbocycle or the heterocycle is preferably a 5- to 7-membered ring.


“When form a heterocycle” in “when B1 is CR8aR9a, and B2 is CR10aR11a, R3a and R11a may be taken together with an adjacent atom to form a heterocycle optionally substituted by substituent group D” represents the formula (II′′′′) shown below:




    (wherein R1a, R2a, R8a, R9a and R10a are as defined in item 13′ and an item 13). The heterocycle is preferably a 5- to 7-membered ring.


“Solvate” includes, for example, a solvate with an organic solvent, a hydrate, etc. When a hydrate is formed, the compound may be coordinated with an arbitrary number of water molecules.
The compound of the present invention includes a pharmaceutically acceptable salt. Examples include salts with an alkali metal (lithium, sodium or potassium, etc.), an alkaline earth metal (magnesium or calcium, etc.), ammonium, an organic base and an amino acid, or salts with an inorganic acid (hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid or hydroiodic acid, etc.), and an organic acid (acetic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid, etc.). These salts can be formed by the method which is usually performed.
In addition, the compound of the present invention is not limited to a particular isomer, but includes all possible isomers (keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer and rotation isomer, etc.) and racemic bodies.
The formula (I) and the formula (II) in the present invention are not limited to a particular isomer, but include all possible isomers and racemic bodies. For example, they contain a tautomer and a steric isomer as follows.




Further in the formula (I) and the formula (II) of the present invention, one or more hydrogen atoms, carbon atoms or other atoms can be substituted by an isotope of a hydrogen atom, a carbon atom or other atoms, respectively.
In addition, the compounds of the formulae (I) and (II) include all radioactive labeled bodies thereof. Such the “radioactive labeling” and “radioactive labeled form” of the compounds of the formulae (I) and (II) are included in the present invention, respectively, and are useful as a study and/or diagnostic tool in metabolized drug dynamic state study and binding assay.
Examples of an isotope which can be incorporated into the compounds of the formulae (I) and (II) of the present invention include a hydrogen atom, a carbon atom, a nitrogen atom, an oxygen atom, a phosphorus atom, a sulfur atom, a fluorine atom and a chlorine atom, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl.
A particularly preferable example of an isotope which can be incorporated into the compounds of the formulae (I) and (II) of the present invention is 2H (i.e. heavy hydrogen atom), and can be prepared by the method shown in Examples of the present description, or the method well-known in the art. In addition, a heavy hydrogen atom is expressed as “D” in Examples of the present description. Compounds of the formulae (I) and (II) of the present invention in which a hydrogen atom has been converted into a heavy hydrogen atom are excellent in respect of bioavailability, metabolism safety, drug efficacy, and toxicity as compared with unconverted forms, in some cases, and can be useful as medicaments.
“step B and step C are continuously performed” refers to execution of step C after reaction of step B without isolation operation and column chromatography purification of product generated in step B. A reaction container for step B and a reaction container for step C may be the same or different.
Examples of “lower alkyl optionally substituted by substituent group A” and “lower alkyl optionally substituted by substituent group C” include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, pentan-2-yl, hydroxymethyl, hydroxyethyl, carboxymethyl, carboxyethyl, carboxypropyl, ethoxycarbonylpropyl, cyanomethyl, cyanoethyl, fluoromethyl, fluoroethyl, fluoropropyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, ethyloxycarbonylethyl, methoxymethyl, dimethoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, 1-methyl-1-methoxymethyl, propyloxymethyl, aminopropyl, dimethylaminomethyl, aminomethyl, aminoethyl, dimethylaminoethyl, diethylaminomethyl, diethylaminoethyl, dimethylaminopropyl, cyclopropylmethyloxymethyl, methylsulfonylaminomethyl, methylaminocarbonylethyl, 1,1,1-trifluoropropan-2-yl, 1,1-difluoroethyl, 1,1,1-trifluoroethyl, 1,1,1-trifluoropropyl, trifluoromethyloxyethyl, trifluoromethylcarbonylaminomethyl, methylsulfonylethyl, methylcarbonyloxyethyl, and groups shown below:




etc.

Examples of “lower alkenyl optionally substituted by substituent group A” and “lower alkenyl optionally substituted by substituent group C” include ethylenyl, 3-methylbuten-2-yl, carboxyethylenyl, hydroxyethylenyl, difluoroethylenyl, 1-propen-2-yl, etc.
Examples of “lower alkynyl optionally substituted by substituent group A” and “lower alkynyl optionally substituted by substituent group C” include 1-propynyl, 1-butynyl, 3,3,3-trifluoromethylpropynyl, 3-hydroxy-propynyl, etc.
Examples of “lower alkyloxy optionally substituted by substituent group A” and “lower alkyloxy optionally substituted by substituent group C” include methyloxy, ethyloxy, trifluoromethyloxy, trichloromethyloxy, hydroxymethyloxy, hydroxyethyloxy, carboxymethyloxy, carboxyethyloxy, etc.
Examples of “lower alkenyloxy optionally substituted by substituent group A” and “lower alkenyloxy optionally substituted by substituent group C” include 3-fluoro-1-propenyloxy, ethylenyl, carboxyethylenyl, hydroxyethylenyloxy, difluoroethylenyloxy, etc.
Examples of “lower alkylcarbonyl optionally substituted by substituent group A” and “lower alkylcarbonyl optionally substituted by substituent group C” include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl, trifluoromethylcarbonyl, 2,2,2-trifluoromethylcarbonyl, carboxymethylcarbonyl, etc.
Examples of “lower alkyloxycarbonyl optionally substituted by substituent group A” and “lower alkyloxycarbonyl optionally substituted by substituent group C” include methyloxycarbonyl, ethyloxycarbonyl, trifluoromethyl oxycarbonyl, trichloromethyloxycarbonyl, hydroxymethyloxycarbonyl, hydroxyethyloxycarbonyl, carboxymethyloxycarbonyl, etc.
Examples of “carbocyclic group optionally substituted by substituent group A” and “carbocyclic group optionally substituted by substituent group C” include phenyl, naphthyl, anthracenyl, phenanthracenyl, adamantyl, 1-hydroxyadamantyl, 2-hydroxyadamantyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, fluorocyclopropyl, difluorocyclobutanyl, difluorocyclohexyl, and groups shown below:




    (wherein RE6 represents a group selected from substituent group A or substituent group C, and m of RE6s may be the same or different) etc.


Examples of “carbocycle lower alkyl optionally substituted by substituent group A” and “carbocycle lower alkyl optionally substituted by substituent group C” include cyclopropylmethyl, 4-hydroxybenzyl, cyclopentylmethyl, benzyl, 2-aminobenzyl, 2-cyanobenzyl, 2-fluorobenzyl, 4-fluorobenzyl, 2-trifluoromethylbenzyl, 1,3,5-trifluorobenzyl, 3,4,5-trifluorobenzyl, 4-methoxybenzyl, 2,4-difluorobenzyl, 2-fluoro-3-chlorobenzyl, benzhydryl, 4-phenylbenzyl, phenethyl, phenylpropyl, 4-methylcarbonylaminobenzyl, 3,4-dichlorobenzyl, 4-chloro-2-fluorobenzyl, 3,5-dihydroxybenzyl, and groups shown below:










etc.

Examples of “carbocycric oxy lower alkyl optionally substituted by substituent group A” and “carbocycleoxy lower alkyl optionally substituted by substituent group C” include 4-hydroxyphenyloxymethyl, 4-hydroxyphenyloxyethyl, cyclopropyloxymethyl, cyclopentyloxymethyl, 4-fluorophenyloxymethyl, 4-fluorophenyloxyethyl, 4-trifluoromethylphenyloxymethyl, 4-trifluoromethylphenyloxyethyl, 4-methoxyphenyloxymethyl, 4-methoxyphenyloxyethyl, etc.
Examples of “carbocyclecarbonyl optionally substituted by substituent group A” and “carbocyclecarbonyl optionally substituted by substituent group C” include phenylcarbonyl, 4-fluorophenylcarbonyl, 4-trifluoromethylphenylcarbonyl, 4-methoxyphenylcarbonyl, cyclopropylcarbonyl, etc.
Examples of “carbocycleoxy optionally substituted by substituent group A” and “carbocycleoxy optionally substituted by substituent group C” include phenyloxy, cyclopropyloxy, cyclopentyloxy, 4-fluorophenyloxy, 4-trifluoromethylphenyloxy, 4-methoxyphenyloxy, etc.
Examples of “carbocycleoxycarbonyl optionally substituted by substituent group A” and “carbocycleoxycarbonyl optionally substituted by substituent group C” include phenyloxycarbonyl, cyclopropyloxycarbonyl, cyclopentyloxycarbonyl, 4-fluorophenyloxycarbonyl, 4-trifluoromethylphenyloxycarbonyl, 4-methoxyphenyloxycarbonyl, etc.
Examples of “heterocyclic group optionally substituted by substituent group A” and “heterocyclic group optionally substituted by substituent group C” include pyrimidinyl, pyridyl, benzoxazolyl, morpholinyl, tetrahydropyranyl, furyl, thiophenyl, oxazolyl, thiazolyl, pyrazolyl, methylpyrrolidinyl, isopropylpyrrolidinyl, methylsulfonylpyrrolidinyl, hydroxyethylpyrrolidinyl, methylpiperidinyl, methylpiperazinyl, tetrahydrofuryl, and groups shown below:




    (wherein RE6 represents a group selected from substituent group A or substituent group C, and m of RE6s may be the same or different) etc.


Examples of “heterocycle lower alkyl optionally substituted by substituent group A” and “heterocycle lower alkyl optionally substituted by substituent group C” include tetrahydropyranylmethyl, pyridylmethyl, isoxazolylmethyl, 5-methyl-isoxazolylmethyl, 3-methyl-oxadiazolylmethyl, indolylmethyl, benzothiophenylmethyl, 5-chlorobenzothiophenylmethyl, thiazolylmethyl, 2-methylthiazolylmethyl, pyrazolylmethyl, 2-methylpyrazolylmethyl, dithiophenylmethyl, tetrazolylmethyl, quinazolylmethyl, and groups shown below:




etc.

Examples of “heterocycleoxy lower alkyl optionally substituted by substituent group A” and “heterocycleoxy lower alkyl optionally substituted by a substituent group C” include tetrahydropyranyloxymethyl, pyridyloxymethyl, isoxazolyloxymethyl, 5-methyl-isoxazolyloxymethyl, indolyloxymethyl, benzothiophenyloxymethyl, 5-chlorobenzothiophenyloxymethyl, thiazolyloxymethyl, 2-methylthiazolyloxymethyl, pyrazolyloxymethyl, 2-methylpyrazolyloxymethyl, etc.
Examples of “heterocyclecarbonyl optionally substituted by substituent group A” and “heterocyclecarbonyl optionally substituted by substituent group C” include tetrahydropyranylcarbonyl, pyridylcarbonyl, isoxazolylcarbonyl, 5-methyl-isoxazolylcarbonyl, indolylcarbonyl, benzothiophenylcarbonyl, 5-chlorobenzothiophenylcarbonyl, thiazolylcarbonyl, 2-methylthiazolylcarbonyl, pyrazolylcarbonyl, 2-methylpyrazolylcarbonyl, etc.
Examples of “heterocycleoxy optionally substituted by substituent group A”, and “heterocycleoxy optionally substituted by substituent C” include tetrahydropyranyloxy, pyridyloxy, isoxazolyloxy, 5-methyl-isoxazolyloxy, indolyloxy, benzothiophenyloxy, 5-chlorobenzothiophenyloxy, thiazolyloxy, 2-methylthiazolyloxy, pyrazolyloxy, 2-methylpyrazolyloxy, etc.
Examples of “heterocycleoxycarbonyl optionally substituted by substituent group A”, and “heterocycleoxycarbonyl optionally substituted by substituent group C” include tetrahydropyranyloxycarbonyl, pyridyloxycarbonyl, isoxazolyloxycarbonyl, 5-methyl-isoxazolyloxycarbonyl, indolyloxycarbonyl, benzothiophenyloxycarbonyl, 5-chlorobenzothiophenyloxycarbonyl, thiazolyloxycarbonyl, 2-methylthiazolyloxycarbonyl, pyrazolyloxycarbonyl, 2-methylpyrazolyloxycarbonyl, etc.
Examples of a preferable substituent in R1 and R1a include hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, lower alkyloxy optionally substituted by substituent group C, lower alkenyloxy optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocyclecarbonyl optionally substituted by substituent group C, carbocycleoxy optionally substituted by substituent group C, carbocycleoxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocyclecarbonyl optionally substituted by substituent group C, heterocycleoxy optionally substituted by substituent group C, heterocycleoxycarbonyl optionally substituted by substituent group C,

    —Z—N(RA1)(RA2),
    —Z—N(RA3)—SO2—(RA4),
    —Z—C(═O)—N(RA5)—SO2—(RA6),
    —Z—N(RA7)—C(═O)—RA8,
    —Z—S—RA9,
    —Z—SO2—RA10,
    —Z—S(═O)—RA11,
    —Z—N(RA12)—C(═O)—O—RA13,
    —Z—N(RA14)—C(═O)—N(RA15)(RA16),
    —Z—C(═O)—N(RA17)—C(═O)—N(RA18)(RA19), or
    —Z—N(RA20)—C(═O)—C(═O)—RA21 

(substituent group C, RA1, RA2, RA3, RA5, RA7, RA8, RA9, RA10, RA11, RA12, RA13, RA14, RA15, RA16, RA17, RA18, RA19, RA20, RA21, and Z are as defined in item 13′ or item 13)



Examples of a more preferable substituent in R1 and R1a include hydrogen, halogen, hydroxy, carboxy, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkyloxy optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C,

    —Z—N(RA1)(RA2),
    —Z—N(RA7)—C(═O)—RA8, or
    —Z—N(RA12)—C(═O)—O—RA13 

(Substituent group C, RA1, RA2, RA7, RA8, RA12, RA13 and Z are as defined in item 13′ or item 13).



Examples of a further preferable substituent in R1 and R1a include hydrogen, halogen, hydroxy, carboxy, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkyloxy optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, or

    —Z—N(RA1)(RA2)

(substituent group C, RA1, RA2, and Z are as defined in item 13′ or item 13).



Examples of another embodiment of a preferable substituent in R1 and R1a include hydrogen, carboxy, hydroxymethyl, methoxy, chlorine atom, bromine atom, ethoxymethyl, dimethylamino, hydroxy, —C(═O)—NH—S(═O)2-Me, amino, methylamino, methylaminomethyl, —NH—C(═O)—CF3, pyrazolyl, —NH—C(═O)-Me, —C(═O)N-Me2, tetrazolyl, —NH—C(═O)-Ph, —C(═O)NH-Me, —C(═O)NH-Et, —C(═O)NH-cyclopropyl, methoxycarbonyl, methyl, propenyl, propyl, isopropyl, fluoromethyl
(Me represents a methyl group, Ph represents a phenyl group, and Et represents an ethyl group) etc.
Examples of another embodiment of a more preferable substituent in R1 and R1a include hydrogen, carboxy, hydroxymethyl, methoxy, bromine atom, ethoxymethyl, dimethylamino, hydroxy, —C(═O)—NH—S(═O)2-Me, amino, methylamino, methyl, propenyl
(Me represents a methyl group) etc.
Examples of another embodiment of a further preferable substituent in R1 and R1a include hydrogen, and carboxy.
Examples of a preferable substituent in R2 and R2a include hydrogen, halogen, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, lower alkyloxy optionally substituted by substituent group C, lower alkenyloxy optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocyclecarbonyl optionally substituted by substituent group C, carbocycleoxy optionally substituted by substituent group C, carbocycleoxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocyclecarbonyl optionally substituted by substituent group C, heterocycleoxy optionally substituted by substituent group C, heterocycleoxycarbonyl optionally substituted by substituent group C,

    —Z—N(RB1)—SO2—RB2,
    —Z—N(RB3)—C(═O)—RB4,
    —Z—N(RB5)—C(═O)—O—RB6,
    —Z—C(═O)—N(RB7)(R8),
    —Z—N(RB9)(RB10), or
    —Z—SO2—RB11 

(substituent group C, RB1, RB2, RB3, RB4, RB5, RB6, RB7, RB8, RB9, RB10, RB11 and Z are as defined in item 13′ or item 13).



Examples of a more preferable substituent in R2 and R2a include hydrogen, lower alkyl optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, or

    —Z—N(RB9)(RB10)

(a substituent group C, RB9, RB10, and Z are as defined in item 13′ or item 13).



Examples of a further preferable substituent in R2 and R2a include hydrogen, or lower alkyl optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C
(substituent group C is as defined in item 13′ or item 13).
Examples of another embodiment of a preferable substituent in R2 and R2a include hydrogen, hydroxymethyl, amino, methoxymethyl, methoxymethylcyclopropylmethyloxymethyl, cyanomethyl, aminomethyl, propyloxymethyl, —CH2—NH—C(═O)-Me, methylaminomethyl, imidazolyl, dimethylaminomethyl, pyrrolidinyl, fluoromethyl, —CH2—NH—C(═O)H
(Me represents a methyl group) etc.
Examples of another embodiment of a more preferable substituent in R2 and R2a include hydrogen, hydroxymethyl, methoxymethylcyclopropylmethyloxymethyl, aminomethyl, propyloxymethyl, etc.
Examples of another embodiment of a further preferable substituent in R2 and R2a include hydrogen.
Examples of a preferable substituent in R3 and R3a include hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, lower alkyloxy optionally substituted by substituent group C, lower alkenyloxy optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C, carbocyclecarbonyl optionally substituted by substituent group C, carbocycleoxy optionally substituted by substituent group C, carbocycleoxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocycleoxy lower alkyl optionally substituted by substituent group C, heterocyclecarbonyl optionally substituted by substituent group C, heterocycleoxy optionally substituted by substituent group C, heterocycleoxycarbonyl optionally substituted by substituent group C,

    —Z—N(RC1)—SO2—RC2,
    —Z—N(RC3)—C(═O)—RC4,
    —Z—N(RC5)—C(═O)—O—RC6,
    —Z—C(═O)—N(RC7)(RC8),
    —Z—N(RC9)(RC10), or
    —Z—SO2—RC11 

(substituent group C, RC1, RC2, RC3, RC4, RC5, RC6, RC7, RC8, RC9, RC10, RC11, and Z are as defined in item 13′ or item 13).



Examples of a more preferable substituent in R3 and R3a include hydrogen, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C,

    —Z—N(RC1)—SO2—RC2,
    —Z—N(RC3)—C(═O)—RC4,
    —Z—N(RC5)—C(═O)—O—RC6,
    —Z—C(═O)—N(RC7)(RC8), or
    —Z—N(RC9)(RC10)

(substituent group C, RC1, RC2, RC3, RC4, RC5, RC6, RC7, RC8, RC9, RC10, and Z are as defined in item 13).



Examples of a further preferable substituent in R3 and R3a include hydrogen, lower alkyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, or carbocycle lower alkyl optionally substituted by substituent group C
(substituent group C is as defined in item 13′ or item 13).
Examples of another embodiment of a preferable substituent in R3 and R3a include hydrogen, ethoxyethyl, methyl, ethyl, propyl, 2,4-difluorobenzyl, methoxyethyl, cyanomethyl, cyanoethyl, 3-chloro-2-fluorobenzyl, 1-methoxypropyl, pyridylmethyl, isopropyl, tetrahydropyranylmethyl, cyclopropylmethyl, benzyl, methylisoxazolylmethyl, methyloxadiazolyl, isopropyloxyethyl, hydroxyethyl, 4-fluorobenzyl, cyclopropyl, ethoxycarbonylethyl, —CH(Me)CH2OMe, carboxyethyl, —CH2CH2C(═O)—N(Me)2, —CH2CH2N(Me)-S(═O)-2-Ph, —CH2CH2—N(Me)-S(═O)2-Me, —CH2CH2—NHC(═O)-Ph, —CH(Me)-CH2—OMe, —CH2CH2—NH—S(═O)2-Ph, —CH2CH2—NH—C(═O)—O—CH(Me)2, —CH2CH2—C(═O)—NH-Ph, —CH2CH2—N(Me)C(═O)-Ph, —CH2CH2—NH—C(═O)-Me, —CH2CH2—NH—S(═O)2-Me, aminoethyl, —CH2CH2—N(Me)-C(═O)-Me, —CH2CH2—C(═O)—N(Me)-Ph, —CH2CH2—NH—C(═O)—O-tBu, piperidinylcarbonylethyl, dimethylaminoethyl, cyclopropylmethyl, methylaminoethyl, furanylmethyl, morpholinylcarbonylethyl, sec-butyl, pentan-2-yl, carboxypropyl, ethoxycarbonylpropyl, phenylpropyl, propyloxyethyl, aminopropyl, dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl, diethylaminoethyl, dimethylaminopropyl, methylaminocarbonylethyl, 1,1,1-trifluoropropan-2-yl, 1,1-difluoroethyl, 1,1,1-trifluoroethyl, 1,1,1-trifluoropropyl, trifluoromethyloxyethyl, trifluoromethylcarbonylaminomethyl, methylsulfonylethyl, methylcarbonyloxyethyl, methylcarbonyloxypropyl, 1-fluoropropyl, fluorocyclopropyl, difluorocyclopropyl, 3,3-dimethylbutan-2-yl, 1-fluoroethyl, 1-methoxypropan-2-yl, amino, thiazolylmethyl, methylsulfonylethyl, 4-fluorophenyloxyethyl, pyridyl, pentan-2-yl, butan-2-yl, 3-methylbuten-2-yl, as well as groups shown below:







    (Me represents a methyl group, Ph represents a phenyl group, and tBu represents a tert-butyl group) etc.


Examples of another embodiment of a more preferable substituent in R3 and R3a include ethoxyethyl, methyl, ethyl, 2,4-difluorobenzyl, methoxyethyl, cyanomethyl, 3-chloro-2-fluorobenzyl, methoxypropyl, pyridylmethyl, isopropyl, tetrahydropyranylmethyl, cyclopropylmethyl, benzyl, methylisoxazolylmethyl, 4-fluorobenzyl, cyclopropyl, ethoxycarbonylethyl, —CH(Me)CH2OMe, carboxyethyl, —CH2CH2C(═O)—N(Me)2, —CH2CH2N(Me)-S(═O)-2-Ph, —CH2CH2—N(Me)—S(═O)2-Me, —CH2CH2—NHC(═O)-Ph, —CH(Me)-CH2—OMe, —CH2CH2—NH—S(═O)2-Ph, —CH2CH2—NH—C(═O)—O—CH(Me)2, —CH2CH2—C(═O)—NH-Ph, —CH2CH2—N(Me)C(═O)-Ph, —CH2CH2—NH—C(═O)-Me, —CH2CH2—NH—S(═O)2-Me, aminoethyl, 1,1,1-trifluoropropan-2-yl, propyl, methylthiomethyl, hydrogen, fluorocyclopropyl, trifluoromethoxyethyl, 1-fluoropropyl, 1-fluoroethyl, methylcarbonyloxymethyl, 1,1-difluoromethyl, and groups shown below:




    (Me represents methyl group, and Ph represents phenyl group) etc.


Examples of another embodiment of a further preferable substituent in R3 and R3a include ethoxyethyl, methyl, ethyl, 2,4-difluorobenzyl, methoxyethyl, cyanomethyl, 3-chloro-2-fluorobenzyl, methoxypropyl, pyridylmethyl, isopropyl, tetrahydropyranylmethyl, cyclopropylmethyl, benzyl, 4-fluorobenzyl, cyclopropyl, ethoxycarbonylethyl, —CH(Me)CH2OMe, carboxyethyl, 1,1,1-trifluoropropan-2-yl, hydroxyethyl, 1-fluoroethyl
(Me represents methyl group) etc.
Examples of another embodiment of a most preferable substituent in R3 and R3a include 1,1,1-trifluoropropan-2-yl.
Examples of a preferable substituent in R5, R6, R7, R8, R9, R10, and R11, as well as R5a, R6a, R7a, R8a, R9a, R10a, and R11a include hydrogen, carboxy, cyano, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C, carbocyclecarbonyl optionally substituted by substituent group C, carbocycleoxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocycleoxy lower alkyl optionally substituted by substituent group C, heterocyclecarbonyl optionally substituted by substituent group C, heterocycleoxycarbonyl optionally substituted by substituent group C,

    —Y—S—RD1,
    —Z—S(═O)—RD2,
    —Z—SO2—RD3,
    —C(═O)—C(═O)—RD4,
    —C(═O)—N(RD5)(RD6),
    —Z—C(RD7)(RD8)(RD9), or
    —Z—CH2—RD10 

(substituent group C, RD1, RD2, RD3, RD4, RD5, RD6, RD7, RD8, RD9, RD10 and Z are as defined in item 13′ or item 13).



Examples of a more preferable substituent in R5, R6, R7, R8, R9, R10 and R11, as well as R5a, R6a, R7a, R8a, R9a, R10a, and R11a include hydrogen, lower alkyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycleoxy lower alkyl optionally substituted by substituent group C,

    —Y—S—RD1, or
    —Z—C(RD7)(RD8)(RD9)

(substituent group C, RD1, RD7, RD8, RD9, Y, and Z are as defined in item 13′ or item 13).



Examples of another embodiment of a preferable substituent in R5, R6, R7, R8, R9, R10, and R11, as well as R5a, R6a, R7a, R8a, R9a, R10a, and R11a include hydrogen, benzhydryl, benzyl, indolylmethyl, cyclohexylmethyl, phenethyl, benzylthiomethyl, 3,5-dimethylisoxazolyl, 5-chloro-3-ethylbenzothiophenyl, 4-fluorobenzyl, methylthiazolylmethyl, cyclopentylmethyl, 4-methoxybenzyl, 3-fluorobenzyl, naphthylmethyl, methyl, 3-trifluoromethylbenzyl, pyridylmethyl, 4-methylcarbonylaminobenzyl, pyrimidinyl, isobutyl, phenoxyethyl, methoxypropyl, phenylpropyl, as well as the following groups:










    (wherein RE6 represents a group selected from substituent group A or substituent group C, and m of RE6s may be the same or different) etc.


Examples of another embodiment of a more preferable substituent in R5, R6, R7, R8, R9, R10, and R11, as well as R5a, R6a, R7a, R8a, R9a, R10a, and R11a include hydrogen, benzhydryl, benzyl, indolylmethyl, cyclohexylmethyl, phenethyl, 3,5-dimethylisoxazolyl, 5-chloro-3-ethylbenzothiophenyl, biphenylmethyl, 4-fluorobenzyl, methylthiazolylmethyl, cyclopentylmethyl, 4-methoxybenzyl, 3-fluorobenzyl, naphthylmethyl, methyl, 3-trifluoromethylbenzyl, pyridylmethyl, 4-methylcarbonylaminobenzyl, pyrimidinyl, and the following groups:




    (wherein RE6 represents a group selected from substituent group A or substituent group C, and m of RE6s may be the same or different).

etc.

    1) Examples of a preferable embodiment when A1 is CR5R6, and A2 is NR7 include the case where R3 and R7 are taken together with an adjacent atom to form a heterocycle optionally substituted by substituent group B.
    2) Examples of a preferable embodiment when A1 is NR7, and A2 is CR5R6 include the case where R3 and R6 are taken together with an adjacent atom to form a heterocycle optionally substituted by substituent group B.
    3) Examples of a preferable embodiment when A1 is CR8R9, and A2 is CR10R11 include the case where R8 and R10 are taken together with an adjacent atom to form a carbocycle or a heterocycle optionally substituted by substituent group B.
    4) Examples of another preferable embodiment when A1 is CR8R9, and A2 is CR10R11 include the case where R3 and R11 are taken together with an adjacent atom to form a heterocycle optionally substituted by substituent group B.
    1) Examples of a preferable embodiment when B1 is CR5aR6a, and B2 is NR7a include the case where R3a and R7a are taken together with an adjacent atom to form a heterocycle optionally substituted by substituent group D.
    2) Examples of a preferable embodiment when B1 is NR7a, and B2 is CR5aR6a include the case where R3a and R6a are taken together with an adjacent atom to form a heterocycle optionally substituted by substituent group D.
    3) Examples of a preferable embodiment when B1 is CR8aR9a, and B2 is CR10aR11a include the case where R8a and R10a are taken together with an adjacent atom to form a carbocycle or a heterocycle optionally substituted by substituent group D.
    4) Examples of another preferable embodiment when B1 is CR8aR9a, and B2 is CR10aR11a include the case where R3a and R11a are taken together with an adjacent atom to form a heterocycle optionally substituted by substituent group D.


When any one of A1 and A2 is CR5R6, and the other is NR7, the case where A1 is NR7, and A2 is CR5R6 is more preferable.
When any one of B1 and B2 is CR5aR6a, and the other is NR7a, the case where B1 is NR7a, and B2 is CR5aR6a is more preferable.
When any one of A1 and A2 is CR5R6, and the other is NR7, it is preferable that at least any one of R5 or R6 is hydrogen. A more preferable embodiment is such that R5 is hydrogen, and R6 is hydrogen. In this case, R7 is not a hydrogen atom.
When any one of B1 and B2 is CR5aR6a, and the other is NR7a, it is preferable that at least any one of R5a or R6a is hydrogen. A more preferable embodiment is such that R5a is hydrogen, and R6a is hydrogen. In this case, R7a is not a hydrogen atom.
A preferable embodiment of R7 and R7a is carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, and heterocyclic lower alkyl optionally substituted by substituent group A.
A more preferable embodiment of R7 and R7a is cycloalkyl, cycloalkenyl, aryl, non-aromatic condensed carbocyclic group, heteroaryl, non-aromatic heterocyclic group, bicyclic condensed heterocyclic group, tricyclic condensed heterocyclic group, lower alkyl substituted by one or two carbocyclic groups, and lower alkyl substituted by one or two heterocyclic groups.
A further preferable embodiment of R7 and R7a is benzyl, benzhydryl, 4-fluorobenzyl, p-methoxybenzyl, and the following groups:




    (wherein RE6, and m are as defined in item 13′).


A most preferable embodiment of R7 and R7a is the following groups:




    (wherein RE6, and m are as defined in item 13′).


When A1 is CR8R9, and A2 is CR10R11, it is preferable that R9 and R11 are hydrogen. A preferable embodiment of R8 and R10 is such that any one of them is hydrogen.
When R9 and R11 are hydrogen, and any one of R8 and R10 is hydrogen, a preferable embodiment of the other of R8 and R10 is carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A.
When B1 is CR8aR9a, and B2 is CR10aR11a, it is preferable that R9a and R11a are hydrogen. A preferable embodiment of R8a and R10a is such that any one of them is hydrogen.
When R9a and R11a are hydrogen, and any one of R8a and R10a is hydrogen, a preferable embodiment of the other of R8a and R10a is the following groups

    —Z—C(RE1)(RE2)(RE3) or






    (wherein Z, RE1, RE2, RE3, RE6, and m are as defined in item 13 or item 13′).


When R9a and R11a are hydrogen, and any one of R8a and R10a is hydrogen, a further preferable embodiment of the other of R8a and R10a is the following groups:




    (wherein RE6 and m are as defined in item 13 or item 13′).


Examples of a preferable substituent in substituent group B and substituent group D include carbocyclic group optionally substituted by substituent group A or substituent group C, heterocyclic group optionally substituted by substituent group A or substituent group C, carbocycle lower alkyl optionally substituted by substituent group A or substituent group C, and heterocycle lower alkyl optionally substituted by substituent group A or substituent group C.
Examples of another embodiment of a preferable substituent in substituent group B and substituent group D include benzyl, benzhydryl, 4-fluorobenzyl, p-methoxybenzyl,




    (wherein RE6 represents a group selected from substituent group A or substituent group C, and m of RE6s may be the same or different) etc.


Examples of a preferable substituent of RE6 include halogen, cyano, hydroxy, carboxy, formyl, amino, oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy, halogeno lower alkyloxy, etc.
Examples of a more preferable substituent of RE6 include fluorine atom, chlorine atom, bromine atom, cyano, methyl, hydroxymethyl, isopropyl, methoxy, trifluoromethyl, oxo, carboxy, etc.
A preferable embodiment of m is an integer of 0 to 6, further preferably an integer of 0 to 3, most preferably an integer of 0 to 2.
Examples of a preferable substituent of R1d include hydrogen, halogen, lower alkyloxy optionally substituted by substituent group E, carbocycle lower alkyloxy optionally substituted by substituent group E, and —OSi(R1e)3.
Examples of R1es each include independently lower alkyl optionally substituted by substituent group E, and carbocyclic group optionally substituted by substituent group E.
Examples of a preferable substituent of R2d include lower alkyl optionally substituted by substituent group E.
Examples of a preferable embodiment of R3d include —N(R3e)2, or —OR3e.
R3es are each independently lower alkyl optionally substituted by substituent group E.
Examples of a preferable substituent of R4d include lower alkyl optionally substituted by substituent group E, and carbocycle lower alkyl optionally substituted by substituent group E.
Examples of a preferable substituent of R5d include halogen, and lower alkyloxy optionally substituted by substituent group E.
Examples of a preferable substituent of R6d include lower alkyl optionally substituted by substituent group E, and lower alkenyl optionally substituted by substituent group E.
Examples of a preferable substituent of Pd include lower alkyl optionally substituted by substituent group E.
Examples of another embodiment of a preferable substituent of R1d include hydrogen, chlorine atom, bromine atom, methoxy, ethoxy, tert-butyloxy, trifluoromethoxy, benzyloxy, p-methoxybenzyloxy, trimethylsilyloxy, triethylsilyloxy, tert-butyldimethylsilyloxy, diisopropylsilyloxy, triphenylsilyloxy, etc.
Examples of another embodiment of a preferable substituent of R2d include methyl, ethyl, isopropyl, tert-butyl, p-methoxybenzyl, and p-nitrobenzyl.
Examples of another embodiment of a preferable substituent of R3d include methoxy, ethoxy, isopropyloxy, benzyloxy, —N(Me)2, —N(Et)2, —N(iPr)2 (Me represents methyl group, Et represents ethyl group, and iPr represents isopropyl group) etc.
Examples of another embodiment of a preferable substituent of R4d include methyl, ethyl, isopropyl, tert-butyl, p-methoxybenzyl, and p-nitrobenzyl, etc.
Examples of another embodiment of a preferable substituent of R5d include hydrogen, chlorine atom, bromine atom, methoxy, ethoxy, tert-butyloxy, trifluoromethoxy, —O—SO2—CH3, —O—SO2-Ph-CH3 (Ph represents phenyl group) etc.
Examples of another embodiment of a preferable substituent of R6d include methyl, ethyl, isopropyl, allyl, —CH2—CH(OMe)2, —CH2—CH(OEt)2,




etc.

Examples of another embodiment of a preferable substituent of Pd include methyl, ethyl, isopropyl, etc.
One of characteristics of the compound in the present invention is in that a polycyclic carbamoylpyridone derivative, in which two or more rings are condensed, such as shown in the formula (I) in item 1′ and item 1 and/or the formula (II) in item 13′ and item 13 and/or a composition including them, has high inhibitory activity on cap-dependent endonuclease.
Another characteristic of the compound in the present invention is that cap-dependent endonuclease inhibitory activity was improved, by applying a functional group as shown below to R1 in the formula (I) and/or R1a in the formula (II). Functional group: hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkynyl optionally substituted by substituent group C, lower alkyloxy optionally substituted by substituent group C, lower alkenyloxy optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocyclecarbonyl optionally substituted by substituent group C, carbocycleoxy optionally substituted by substituent group C, carbocycleoxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocyclecarbonyl optionally substituted by substituent group C, heterocycleoxy optionally substituted by substituent group C, heterocycleoxycarbonyl optionally substituted by substituent group C,

    —Z—N(RA1)(RA2),
    —Z—N(RA3)—SO2—(RA4),
    —Z—C(═O)—N(RA5)—SO2—(RA6),
    —Z—N(R7)—C(═O)—RA8,
    —Z—S—RA9,
    —Z—SO2—RA10,
    —Z—S(═O)—RA11,
    —Z—N(RA12)—C(═O)—O—RA13,
    —Z—N(RA1)—C(═O)—N(RA15)(RA16),
    —Z—C(═O)—N(RA17)—C(═O)—N(RA18)(RA19), or
    —Z—N(RA20)—C(═O)—C(═O)—RA21 

(substituent group C, RA1, RA2, RA3, RA5, RA7, RA8, RA9, RA12, RA13, RA14, RA15, RA16, RA17, RA18, RA19, RA20 and RA21 are as defined in item 13′ or item 13).



The characteristic of a more preferable compound in the present invention is that cap-dependent endonuclease inhibitory activity is improved, by applying a functional group shown below to R1 in the formula (I) and/or R1a in the formula (II).
Functional group: hydrogen, halogen, hydroxy, carboxy, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkyloxy optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group A,

    —Z—N(RA1)(RA2),
    —Z—N(RA7)—C(═O)—RA8, or
    —Z—N(RA2)—C(═O)—O—RA13 

(substituent group C, RA1, RA2, RA7, RA8, RA12, RA13, and Z are as defined in item 13′ or item 13).



The characteristic of a further preferable compound in the present invention is that cap-dependent endonuclease inhibitory activity is improved, by applying a functional group shown below to R1 in the formula (I) and/or R1a in the formula (II).
Functional group: hydrogen, halogen, hydroxy, carboxy, lower alkyl optionally substituted by substituent group C, lower alkenyl optionally substituted by substituent group C, lower alkyloxy optionally substituted by substituent group C, lower alkylcarbonyl optionally substituted by substituent group C, lower alkyloxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group A, or

    —Z—N(RA1)(RA2)

(substituent group C, RA1, RA2 and Z are as defined in item 13′ or item 13).



The characteristic of a particularly preferable compound in the present invention is that cap-dependent endonuclease inhibitory activity is improved, by applying a functional group shown below to R1 in the formula (I) and/or R1a in the formula (II).
Functional group: hydrogen, or carboxy
Other characteristic of the compound in the present invention is that cap-dependent endonuclease inhibitory activity was improved, by introducing one, two or more of lipid-soluble functional groups shown below on carbon atom or on nitrogen atom of A1 and/or A2 in the formula (I), as well as of B1 and/or B2 in the formula (II).
Lipid-soluble functional group: carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C, carbocycleoxycarbonyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C, heterocycleoxy lower alkyl optionally substituted by substituent group C, heterocycleoxycarbonyl optionally substituted by substituent group C

(substituent group C is as defined in item 13′ or item 13).

Other characteristic of a more preferable compound in the present invention is that cap-dependent endonuclease inhibitory activity is improved, by introducing one lipid-soluble functional group shown below on carbon atom or on nitrogen atom of A1 and/or A2 in the formula (I), as well as of B1 and/or B2 in the formula (II).
Lipid-soluble functional group: carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, carbocycleoxy lower alkyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C

(substituent group C is as defined in item 13′ or item 13).

Other characteristic of a particularly preferable compound in the present invention is that cap-dependent endonuclease inhibitory activity was improved, by introducing one lipid-soluble functional group shown below on carbon atom or on nitrogen atom of A1 and/or A2 in the formula (I), as well as of B1 and/or B2 in the formula (II).
Lipid-soluble functional group: carbocyclic group optionally substituted by substituent group C, carbocycle lower alkyl optionally substituted by substituent group C, heterocyclic group optionally substituted by substituent group C, heterocycle lower alkyl optionally substituted by substituent group C,

(substituent group C is as defined in item 13′ or item 13).

A preferable embodiment of the present invention will be exemplified below.
In the formula (III), the formula (III′), the formula (III′′), the formula (III′′′), the formula (III′′′′), the formula (III′′′′′):




1)

    a compound in which R1b is hydrogen (hereinafter, R1b is R1-1),
    a compound in which R1b is carboxy (hereinafter, R1b is R1-2)
    a compound in which R1b is halogen (hereinafter R1b is R1-3),
    a compound in which R1b is hydroxy (hereinafter, R1b is R1-4),
    a compound in which R1b is lower alkyl optionally substituted by substituent group C (hereinafter, R1b is R1-5),
    a compound in which R1b is lower alkylcarbonyl optionally substituted by substituent group C (hereinafter, R1b is R1-6),
    a compound in which R1b is lower alkyloxycarbonyl optionally substituted by substituent group C (hereinafter, R1b is R1-7),
    a compound in which R1b is amino (hereinafter, R1b is R1-8),

2)

    a compound in which R2b is hydrogen (hereinafter, R2b is R2-1),
    a compound in which R2b is lower alkyl optionally substituted by substituent group C (hereinafter, R2b is R2-2),

3)

    a compound in which R3b is lower alkyl optionally substituted by substituent group C (hereinafter, R3b is R3-1),
    a compound in which R3b is carbocycle lower alkyl optionally substituted by substituent group C (hereinafter, R3b is R3-2),
    a compound in which R3b is heterocycle lower alkyl optionally substituted by substituent group C (hereinafter, R3b is R3-3),
    a compound in which R3b is carbocyclic group optionally substituted by substituent group C (hereinafter, R3b is R3-4),
    a compound in which R3b is heterocyclic group optionally substituted by substituent group C (hereinafter, R3b is R3-5),

in the formula (III′),

1)

    a compound in which R7b is carbocyclic group optionally substituted by substituent group C, and R5b and R6b are hydrogen (hereinafter, R7-1),
    a compound in which R7b is heterocyclic group optionally substituted by substituent group C, and R5b and R6b are hydrogen (hereinafter, R7-2),
    a compound in which R7b is carbocycle lower alkyl optionally substituted by substituent group C, and R5b and R6b are hydrogen (hereinafter, R7-3),

2)

    a compound in which R6b is carbocyclic group optionally substituted by substituent group C, and R5b and R7b are hydrogen (hereinafter, R6-1),
    a compound in which R6b is heterocyclic group optionally substituted by substituent group C, and R5b and R7b are hydrogen (hereinafter, R6-2),
    a compound in which R6b is carbocycle lower alkyl optionally substituted by substituent group C, and R5b and R7b are hydrogen (hereinafter, R6-3),

in the formula (III),

    a compound in which R9b is carbocyclic group optionally substituted by substituent group C, and R8b, R10b and R11b are hydrogen (hereinafter, R9-1),
    a compound in which R9b is heterocyclic group optionally substituted by substituent group C, and R8b, R10b and R11b are hydrogen (hereinafter, R9-1),
    a compound in which R9b is carbocycle lower alkyl optionally substituted by substituent group C, and R8b, R10b, and R11b are hydrogen (hereinafter, R9-1).


Herein, the substituent group C is at least one selected from a substituent group consisting of halogen, cyano, hydroxy, carboxy, formyl, amino, oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy, carbocyclic group, heterocyclic group, carbocycle lower alkyloxy, heterocycle lower alkyloxy, halogeno lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, lower alkyloxycarbonyl, lower alkylamino, lower alkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, and lower alkylsulfonylamino.
Compounds in which, in the formula (III′), a combination of R1b, R2b, R3b, as well as (R5b, R6b, and R7b) is as follows.

    (R1-1, R2-1, R3-1, R7-1), (R1-1, R2-1, R3-1, R7-2), (R1-1, R2-1, R3-1, R7-3), (R1-1, R2-1, R3-2, R7-1), (R1-1, R2-1, R3-2, R7-2), (R1-1, R2-1, R3-2, R7-3), (R1-1, R2-1, R3-3, R7-1), (R1-1, R2-1, R3-3, R7-2), (R1-1, R2-1, R3-3, R7-3), (R1-1, R2-1, R3-4, R7-1), (R1-1, R2-1, R3-4, R7-2), (R1-1, R2-1, R3-4, R7-3), (R1-1, R2-1, R3-5, R7-1), (R1-1, R2-1, R3-5, R7-2), (R1-1, R2-1, R3-5, R7-3), (R1-1, R2-2, R3-1, R7-1), (R1-1, R2-2, R3-1, R7-2), (R1-1, R2-2, R3-1, R7-3), (R1-1, R2-2, R3-2, R7-1), (R1-1, R2-2, R3-2, R7-2), (R1-1, R2-2, R3-2, R7-3), (R1-1, R2-2, R3-3, R7-1), (R1-1, R2-2, R3-3, R7-2), (R1-1, R2-2, R3-3, R7-3), (R1-1, R2-2, R3-4, R7-1), (R1-1, R2-2, R3-4, R7-2), (R1-1, R2-2, R3-4, R7-3), (R1-1, R2-2, R3-5, R7-1), (R1-1, R2-2, R3-5, R7-2), (R1-1, R2-2, R3-5, R7-3), (R1-2, R2-1, R3-1, R7-1), (R1-2, R2-1, R3-1, R7-2), (R1-2, R2-1, R3-1, R7-3), (R1-2, R2-1, R3-2, R7-1), (R1-2, R2-1, R3-2, R7-2), (R1-2, R2-1, R3-2, R7-3), (R1-2, R2-1, R3-3, R7-1), (R1-2, R2-1, R3-3, R7-2), (R1-2, R2-1, R3-3, R7-3), (R1-2, R2-1, R3-4, R7-1), (R1-2, R2-1, R3-4, R7-2), (R1-2, R2-1, R3-4, R7-3), (R1-2, R2-1, R3-5, R7-1), (R1-2, R2-1, R3-5, R7-2), (R1-2, R2-1, R3-5, R7-3), (R1-2, R2-2, R3-1, R7-1), (R1-2, R2-2, R3-1, R7-2), (R1-2, R2-2, R3-1, R7-3), (R1-2, R2-2, R3-2, R7-1), (R1-2, R2-2, R3-2, R7-2), (R1-2, R2-2, R3-2, R7-3), (R1-2, R2-2, R3-3, R7-1), (R1-2, R2-2, R3-3, R7-2), (R1-2, R2-2, R3-3, R7-3), (R1-2, R2-2, R3-4, R7-1), (R1-2, R2-2, R3-4, R7-2), (R1-2, R2-2, R3-4, R7-3), (R1-2, R2-2, R3-5, R7-1), (R1-2, R2-2, R3-5, R7-2), (R1-2, R2-2, R3-5, R7-3), (R1-3, R2-1, R3-1, R7-1), (R1-3, R2-1, R3-1, R7-2), (R1-3, R2-1, R3-1, R7-3), (R1-3, R2-1, R3-2, R7-1), (R1-3, R2-1, R3-2, R7-2), (R1-3, R2-1, R3-2, R7-3), (R1-3, R2-1, R3-3, R7-1), (R1-3, R2-1, R3-3, R7-2), (R1-3, R2-1, R3-3, R7-3), (R1-3, R2-1, R3-4, R7-1), (R1-3, R2-1, R3-4, R7-2), (R1-3, R2-1, R3-4, R7-3), (R1-3, R2-1, R3-5, R7-1), (R1-3, R2-1, R3-5, R7-2), (R1-3, R2-1, R3-5, R7-3), (R1-3, R2-2, R3-1, R7-1), (R1-3, R2-2, R3-1, R7-2), (R1-3, R2-2, R3-1, R7-3), (R1-3, R2-2, R3-2, R7-1), (R1-3, R2-2, R3-2, R7-2), (R1-3, R2-2, R3-2, R7-3), (R1-3, R2-2, R3-3, R7-1), (R1-3, R2-2, R3-3, R7-2), (R1-3, R2-2, R3-3, R7-3), (R1-3, R2-2, R3-4, R7-1), (R1-3, R2-2, R3-4, R7-2), (R1-3, R2-2, R3-4, R7-3), (R1-3, R2-2, R3-5, R7-1), (R1-3, R2-2, R3-5, R7-2), (R1-3, R2-2, R3-5, R7-3), (R1-4, R2-1, R3-1, R7-1), (R1-4, R2-1, R3-1, R7-2), (R1-4, R2-1, R3-1, R7-3), (R1-4, R2-1, R3-2, R7-1), (R1-4, R2-1, R3-2, R7-2), (R1-4, R2-1, R3-2, R7-3), (R1-4, R2-1, R3-3, R7-1), (R1-4, R2-1, R3-3, R7-2), (R1-4, R2-1, R3-3, R7-3), (R1-4, R2-1, R3-4, R7-1), (R1-4, R2-1, R3-4, R7-2), (R1-4, R2-1, R3-4, R7-3), (R1-4, R2-1, R3-5, R7-1), (R1-4, R2-1, R3-5, R7-2), (R1-4, R2-1, R3-5, R7-3), (R1-4, R2-2, R3-1, R7-1), (R1-4, R2-2, R3-1, R7-2), (R1-4, R2-2, R3-1, R7-3), (R1-4, R2-2, R3-2, R7-1), (R1-4, R2-2, R3-2, R7-2), (R1-4, R2-2, R3-2, R7-3), (R1-4, R2-2, R3-3, R7-1), (R1-4, R2-2, R3-3, R7-2), (R1-4, R2-2, R3-3, R7-3), (R1-4, R2-2, R3-4, R7-1), (R1-4, R2-2, R3-4, R7-2), (R1-4, R2-2, R3-4, R7-3), (R1-4, R2-2, R3-5, R7-1), (R1-4, R2-2, R3-5, R7-2), (R1-4, R2-2, R3-5, R7-3),
    (R1-5, R2-1, R3-1, R7-1), (R1-5, R2-1, R3-1, R7-2), (R1-5, R2-1, R3-1, R7-3), (R1-5, R2-1, R3-2, R7-1), (R1-5, R2-1, R3-2, R7-2), (R1-5, R2-1, R3-2, R7-3), (R1-5, R2-1, R3-3, R7-1), (R1-5, R2-1, R3-3, R7-2), (R1-5, R2-1, R3-3, R7-3), (R1-5, R2-1, R3-4, R7-1), (R1-5, R2-1, R3-4, R7-2), (R1-5, R2-1, R3-4, R7-3), (R1-5, R2-1, R3-5, R7-1), (R1-5, R2-1, R3-5, R7-2), (R1-5, R2-1, R3-5, R7-3), (R1-5, R2-2, R3-1, R7-1), (R1-5, R2-2, R3-1, R7-2), (R1-5, R2-2, R3-1, R7-3), (R1-5, R2-2, R3-2, R7-1), (R1-5, R2-2, R3-2, R7-2), (R1-5, R2-2, R3-2, R7-3), (R1-5, R2-2, R3-3, R7-1), (R1-5, R2-2, R3-3, R7-2), (R1-5, R2-2, R3-3, R7-3), (R1-5, R2-2, R3-4, R7-1), (R1-5, R2-2, R3-4, R7-2), (R1-5, R2-2, R3-4, R7-3), (R1-5, R2-2, R3-5, R7-1), (R1-5, R2-2, R3-5, R7-2), (R1-5, R2-2, R3-5, R7-3), (R1-6, R2-1, R3-1, R7-1), (R1-6, R2-1, R3-1, R7-2), (R1-6, R2-1, R3-1, R7-3), (R1-6, R2-1, R3-2, R7-1), (R1-6, R2-1, R3-2, R7-2), (R1-6, R2-1, R3-2, R7-3), (R1-6, R2-1, R3-3, R7-1), (R1-6, R2-1, R3-3, R7-2), (R1-6, R2-1, R3-3, R7-3), (R1-6, R2-1, R3-4, R7-1), (R1-6, R2-1, R3-4, R7-2), (R1-6, R2-1, R3-4, R7-3), (R1-6, R2-1, R3-5, R7-1), (R1-6, R2-1, R3-5, R7-2), (R1-6, R2-1, R3-5, R7-3), (R1-6, R2-2, R3-1, R7-1), (R1-6, R2-2, R3-1, R7-2), (R1-6, R2-2, R3-1, R7-3), (R1-6, R2-2, R3-2, R7-1), (R1-6, R2-2, R3-2, R7-2), (R1-6, R2-2, R3-2, R7-3), (R1-6, R2-2, R3-3, R7-1), (R1-6, R2-2, R3-3, R7-2), (R1-6, R2-2, R3-3, R7-3), (R1-6, R2-2, R3-4, R7-1), (R1-6, R2-2, R3-4, R7-2), (R1-6, R2-2, R3-4, R7-3), (R1-6, R2-2, R3-5, R7-1), (R1-6, R2-2, R3-5, R7-2), (R1-6, R2-2, R3-5, R7-3), (R1-7, R2-1, R3-1, R7-1), (R1-7, R2-1, R3-1, R7-2), (R1-7, R2-1, R3-1, R7-3), (R1-7, R2-1, R3-2, R7-1), (R1-7, R2-1, R3-2, R7-2), (R1-7, R2-1, R3-2, R7-3), (R1-7, R2-1, R3-3, R7-1), (R1-7, R2-1, R3-3, R7-2), (R1-7, R2-1, R3-3, R7-3), (R1-7, R2-1, R3-4, R7-1), (R1-7, R2-1, R3-4, R7-2), (R1-7, R2-1, R3-4, R7-3), (R1-7, R2-1, R3-5, R7-1), (R1-7, R2-1, R3-5, R7-2), (R1-7, R2-1, R3-5, R7-3), (R1-7, R2-2, R3-1, R7-1), (R1-7, R2-2, R3-1, R7-2), (R1-7, R2-2, R3-1, R7-3), (R1-7, R2-2, R3-2, R7-1), (R1-7, R2-2, R3-2, R7-2), (R1-7, R2-2, R3-2, R7-3), (R1-7, R2-2, R3-3, R7-1), (R1-7, R2-2, R3-3, R7-2), (R1-7, R2-2, R3-3, R7-3), (R1-7, R2-2, R3-4, R7-1), (R1-7, R2-2, R3-4, R7-2), (R1-7, R2-2, R3-4, R7-3), (R1-7, R2-2, R3-5, R7-1), (R1-7, R2-2, R3-5, R7-2), (R1-7, R2-2, R3-5, R7-3), (R1-8, R2-1, R3-1, R7-1), (R1-8, R2-1, R3-1, R7-2), (R1-8, R2-1, R3-1, R7-3), (R1-8, R2-1, R3-2, R7-1), (R1-8, R2-1, R3-2, R7-2), (R1-8, R2-1, R3-2, R7-3), (R1-8, R2-1, R3-3, R7-1), (R1-8, R2-1, R3-3, R7-2), (R1-8, R2-1, R3-3, R7-3), (R1-8, R2-1, R3-4, R7-1), (R1-8, R2-1, R3-4, R7-2), (R1-8, R2-1, R3-4, R7-3), (R1-8, R2-1, R3-5, R7-1), (R1-8, R2-1, R3-5, R7-2), (R1-8, R2-1, R3-5, R7-3), (R1-8, R2-2, R3-1, R7-1), (R1-8, R2-2, R3-1, R7-2), (R1-8, R2-2, R3-1, R7-3), (R1-8, R2-2, R3-2, R7-1), (R1-8, R2-2, R3-2, R7-2), (R1-8, R2-2, R3-2, R7-3), (R1-8, R2-2, R3-3, R7-1), (R1-8, R2-2, R3-3, R7-2), (R1-8, R2-2, R3-3, R7-3), (R1-8, R2-2, R3-4, R7-1), (R1-8, R2-2, R3-4, R7-2), (R1-8, R2-2, R3-4, R7-3), (R1-8, R2-2, R3-5, R7-1), (R1-8, R2-2, R3-5, R7-2), (R1-8, R2-2, R3-5, R7-3),
    (R1-1, R2-1, R3-1, R6-1), (R1-1, R2-1, R3-1, R6-2), (R1-1, R2-1, R3-1, R6-3), (R1-1, R2-1, R3-2, R6-1), (R1-1, R2-1, R3-2, R6-2), (R1-1, R2-1, R3-2, R6-3), (R1-1, R2-1, R3-3, R6-1), (R1-1, R2-1, R3-3, R6-2), (R1-1, R2-1, R3-3, R6-3), (R1-1, R2-1, R3-4, R6-1), (R1-1, R2-1, R3-4, R6-2), (R1-1, R2-1, R3-4, R6-3), (R1-1, R2-1, R3-5, R6-1), (R1-1, R2-1, R3-5, R6-2), (R1-1, R2-1, R3-5, R6-3), (R1-1, R2-2, R3-1, R6-1), (R1-1, R2-2, R3-1, R6-2), (R1-1, R2-2, R3-1, R6-3), (R1-1, R2-2, R3-2, R6-1), (R1-1, R2-2, R3-2, R6-2), (R1-1, R2-2, R3-2, R6-3), (R1-1, R2-2, R3-3, R6-1), (R1-1, R2-2, R3-3, R6-2), (R1-1, R2-2, R3-3, R6-3), (R1-1, R2-2, R3-4, R6-1), (R1-1, R2-2, R3-4, R6-2), (R1-1, R2-2, R3-4, R6-3), (R1-1, R2-2, R3-5, R6-1), (R1-1, R2-2, R3-5, R6-2), (R1-1, R2-2, R3-5, R6-3), (R1-2, R2-1, R3-1, R6-1), (R1-2, R2-1, R3-1, R6-2), (R1-2, R2-1, R3-1, R6-3), (R1-2, R2-1, R3-2, R6-1), (R1-2, R2-1, R3-2, R6-2), (R1-2, R2-1, R3-2, R6-3), (R1-2, R2-1, R3-3, R6-1), (R1-2, R2-1, R3-3, R6-2), (R1-2, R2-1, R3-3, R6-3), (R1-2, R2-1, R3-4, R6-1), (R1-2, R2-1, R3-4, R6-2), (R1-2, R2-1, R3-4, R6-3), (R1-2, R2-1, R3-5, R6-1), (R1-2, R2-1, R3-5, R6-2), (R1-2, R2-1, R3-5, R6-3), (R1-2, R2-2, R3-1, R6-1), (R1-2, R2-2, R3-1, R6-2), (R1-2, R2-2, R3-1, R6-3), (R1-2, R2-2, R3-2, R6-1), (R1-2, R2-2, R3-2, R6-2), (R1-2, R2-2, R3-2, R6-3), (R1-2, R2-2, R3-3, R6-1), (R1-2, R2-2, R3-3, R6-2), (R1-2, R2-2, R3-3, R6-3), (R1-2, R2-2, R3-4, R6-1), (R1-2, R2-2, R3-4, R6-2), (R1-2, R2-2, R3-4, R6-3), (R1-2, R2-2, R3-5, R6-1), (R1-2, R2-2, R3-5, R6-2), (R1-2, R2-2, R3-5, R6-3), (R1-3, R2-1, R3-1, R6-1), (R1-3, R2-1, R3-1, R6-2), (R1-3, R2-1, R3-1, R6-3), (R1-3, R2-1, R3-2, R6-1), (R1-3, R2-1, R3-2, R6-2), (R1-3, R2-1, R3-2, R6-3), (R1-3, R2-1, R3-3, R6-1), (R1-3, R2-1, R3-3, R6-2), (R1-3, R2-1, R3-3, R6-3), (R1-3, R2-1, R3-4, R6-1), (R1-3, R2-1, R3-4, R6-2), (R1-3, R2-1, R3-4, R6-3), (R1-3, R2-1, R3-5, R6-1), (R1-3, R2-1, R3-5, R6-2), (R1-3, R2-1, R3-5, R6-3), (R1-3, R2-2, R3-1, R6-1), (R1-3, R2-2, R3-1, R6-2), (R1-3, R2-2, R3-1, R6-3), (R1-3, R2-2, R3-2, R6-1), (R1-3, R2-2, R3-2, R6-2), (R1-3, R2-2, R3-2, R6-3), (R1-3, R2-2, R3-3, R6-1), (R1-3, R2-2, R3-3, R6-2), (R1-3, R2-2, R3-3, R6-3), (R1-3, R2-2, R3-4, R6-1), (R1-3, R2-2, R3-4, R6-2), (R1-3, R2-2, R3-4, R6-3), (R1-3, R2-2, R3-5, R6-1), (R1-3, R2-2, R3-5, R6-2), (R1-3, R2-2, R3-5, R6-3), (R1-4, R2-1, R3-1, R6-1), (R1-4, R2-1, R3-1, R6-2), (R1-4, R2-1, R3-1, R6-3), (R1-4, R2-1, R3-2, R6-1), (R1-4, R2-1, R3-2, R6-2), (R1-4, R2-1, R3-2, R6-3), (R1-4, R2-1, R3-3, R6-1), (R1-4, R2-1, R3-3, R6-2), (R1-4, R2-1, R3-3, R6-3), (R1-4, R2-1, R3-4, R6-1), (R1-4, R2-1, R3-4, R6-2), (R1-4, R2-1, R3-4, R6-3), (R1-4, R2-1, R3-5, R6-1), (R1-4, R2-1, R3-5, R6-2), (R1-4, R2-1, R3-5, R6-3), (R1-4, R2-2, R3-1, R6-1), (R1-4, R2-2, R3-1, R6-2), (R1-4, R2-2, R3-1, R6-3), (R1-4, R2-2, R3-2, R6-1), (R1-4, R2-2, R3-2, R6-2), (R1-4, R2-2, R3-2, R6-3), (R1-4, R2-2, R3-3, R6-1), (R1-4, R2-2, R3-3, R6-2), (R1-4, R2-2, R3-3, R6-3), (R1-4, R2-2, R3-4, R6-1), (R1-4, R2-2, R3-4, R6-2), (R1-4, R2-2, R3-4, R6-3), (R1-4, R2-2, R3-5, R6-1), (R1-4, R2-2, R3-5, R6-2), (R1-4, R2-2, R3-5, R6-3),
    (R1-5, R2-1, R3-1, R6-1), (R1-5, R2-1, R3-1, R6-2), (R1-5, R2-1, R3-1, R6-3), (R1-5, R2-1, R3-2, R6-1), (R1-5, R2-1, R3-2, R6-2), (R1-5, R2-1, R3-2, R6-3), (R1-5, R2-1, R3-3, R6-1), (R1-5, R2-1, R3-3, R6-2), (R1-5, R2-1, R3-3, R6-3), (R1-5, R2-1, R3-4, R6-1), (R1-5, R2-1, R3-4, R6-2), (R1-5, R2-1, R3-4, R6-3), (R1-5, R2-1, R3-5, R6-1), (R1-5, R2-1, R3-5, R6-2), (R1-5, R2-1, R3-5, R6-3), (R1-5, R2-2, R3-1, R6-1), (R1-5, R2-2, R3-1, R6-2), (R1-5, R2-2, R3-1, R6-3), (R1-5, R2-2, R3-2, R6-1), (R1-5, R2-2, R3-2, R6-2), (R1-5, R2-2, R3-2, R6-3), (R1-5, R2-2, R3-3, R6-1), (R1-5, R2-2, R3-3, R6-2), (R1-5, R2-2, R3-3, R6-3), (R1-5, R2-2, R3-4, R6-1), (R1-5, R2-2, R3-4, R6-2), (R1-5, R2-2, R3-4, R6-3), (R1-5, R2-2, R3-5, R6-1), (R1-5, R2-2, R3-5, R6-2), (R1-5, R2-2, R3-5, R6-3), (R1-6, R2-1, R3-1, R6-1), (R1-6, R2-1, R3-1, R6-2), (R1-6, R2-1, R3-1, R6-3), (R1-6, R2-1, R3-2, R6-1), (R1-6, R2-1, R3-2, R6-2), (R1-6, R2-1, R3-2, R6-3), (R1-6, R2-1, R3-3, R6-1), (R1-6, R2-1, R3-3, R6-2), (R1-6, R2-1, R3-3, R6-3), (R1-6, R2-1, R3-4, R6-1), (R1-6, R2-1, R3-4, R6-2), (R1-6, R2-1, R3-4, R6-3), (R1-6, R2-1, R3-5, R6-1), (R1-6, R2-1, R3-5, R6-2), (R1-6, R2-1, R3-5, R6-3), (R1-6, R2-2, R3-1, R6-1), (R1-6, R2-2, R3-1, R6-2), (R1-6, R2-2, R3-1, R6-3), (R1-6, R2-2, R3-2, R6-1), (R1-6, R2-2, R3-2, R6-2), (R1-6, R2-2, R3-2, R6-3), (R1-6, R2-2, R3-3, R6-1), (R1-6, R2-2, R3-3, R6-2), (R1-6, R2-2, R3-3, R6-3), (R1-6, R2-2, R3-4, R6-1), (R1-6, R2-2, R3-4, R6-2), (R1-6, R2-2, R3-4, R6-3), (R1-6, R2-2, R3-5, R6-1), (R1-6, R2-2, R3-5, R6-2), (R1-6, R2-2, R3-5, R6-3), (R1-7, R2-1, R3-1, R6-1), (R1-7, R2-1, R3-1, R6-2), (R1-7, R2-1, R3-1, R6-3), (R1-7, R2-1, R3-2, R6-1), (R1-7, R2-1, R3-2, R6-2), (R1-7, R2-1, R3-2, R6-3), (R1-7, R2-1, R3-3, R6-1), (R1-7, R2-1, R3-3, R6-2), (R1-7, R2-1, R3-3, R6-3), (R1-7, R2-1, R3-4, R6-1), (R1-7, R2-1, R3-4, R6-2), (R1-7, R2-1, R3-4, R6-3), (R1-7, R2-1, R3-5, R6-1), (R1-7, R2-1, R3-5, R6-2), (R1-7, R2-1, R3-5, R6-3), (R1-7, R2-2, R3-1, R6-1), (R1-7, R2-2, R3-1, R6-2), (R1-7, R2-2, R3-1, R6-3), (R1-7, R2-2, R3-2, R6-1), (R1-7, R2-2, R3-2, R6-2), (R1-7, R2-2, R3-2, R6-3), (R1-7, R2-2, R3-3, R6-1), (R1-7, R2-2, R3-3, R6-2), (R1-7, R2-2, R3-3, R6-3), (R1-7, R2-2, R3-4, R6-1), (R1-7, R2-2, R3-4, R6-2), (R1-7, R2-2, R3-4, R6-3), (R1-7, R2-2, R3-5, R6-1), (R1-7, R2-2, R3-5, R6-2), (R1-7, R2-2, R3-5, R6-3), (R1-8, R2-1, R3-1, R6-1), (R1-8, R2-1, R3-1, R6-2), (R1-8, R2-1, R3-1, R6-3), (R1-8, R2-1, R3-2, R6-1), (R1-8, R2-1, R3-2, R6-2), (R1-8, R2-1, R3-2, R6-3), (R1-8, R2-1, R3-3, R6-1), (R1-8, R2-1, R3-3, R6-2), (R1-8, R2-1, R3-3, R6-3), (R1-8, R2-1, R3-4, R6-1), (R1-8, R2-1, R3-4, R6-2), (R1-8, R2-1, R3-4, R6-3), (R1-8, R2-1, R3-5, R6-1), (R1-8, R2-1, R3-5, R6-2), (R1-8, R2-1, R3-5, R6-3), (R1-8, R2-2, R3-1, R6-1), (R1-8, R2-2, R3-1, R6-2), (R1-8, R2-2, R3-1, R6-3), (R1-8, R2-2, R3-2, R6-1), (R1-8, R2-2, R3-2, R6-2), (R1-8, R2-2, R3-2, R6-3), (R1-8, R2-2, R3-3, R6-1), (R1-8, R2-2, R3-3, R6-2), (R1-8, R2-2, R3-3, R6-3), (R1-8, R2-2, R3-4, R6-1), (R1-8, R2-2, R3-4, R6-2), (R1-8, R2-2, R3-4, R6-3), (R1-8, R2-2, R3-5, R6-1), (R1-8, R2-2, R3-5, R6-2), (R1-8, R2-2, R3-5, R6-3).


Compounds in which, in the formula (III), a combination of R1b, R2b, R3b, as well as (R8b, R9b, R10b, and R11b) is as follows.

    (R1-1, R2-1, R3-1, R9-1), (R1-1, R2-1, R3-1, R9-2), (R1-1, R2-1, R3-1, R9-3), (R1-1, R2-1, R3-2, R9-1), (R1-1, R2-1, R3-2, R9-2), (R1-1, R2-1, R3-2, R9-3), (R1-1, R2-1, R3-3, R9-1), (R1-1, R2-1, R3-3, R9-2), (R1-1, R2-1, R3-3, R9-3), (R1-1, R2-1, R3-4, R9-1), (R1-1, R2-1, R3-4, R9-2), (R1-1, R2-1, R3-4, R9-3), (R1-1, R2-1, R3-5, R9-1), (R1-1, R2-1, R3-5, R9-2), (R1-1, R2-1, R3-5, R9-3), (R1-1, R2-2, R3-1, R9-1), (R1-1, R2-2, R3-1, R9-2), (R1-1, R2-2, R3-1, R9-3), (R1-1, R2-2, R3-2, R9-1), (R1-1, R2-2, R3-2, R9-2), (R1-1, R2-2, R3-2, R9-3), (R1-1, R2-2, R3-3, R9-1), (R1-1, R2-2, R3-3, R9-2), (R1-1, R2-2, R3-3, R9-3), (R1-1, R2-2, R3-4, R9-1), (R1-1, R2-2, R3-4, R9-2), (R1-1, R2-2, R3-4, R9-3), (R1-1, R2-2, R3-5, R9-1), (R1-1, R2-2, R3-5, R9-2), (R1-1, R2-2, R3-5, R9-3), (R1-2, R2-1, R3-1, R9-1), (R1-2, R2-1, R3-1, R9-2), (R1-2, R2-1, R3-1, R9-3), (R1-2, R2-1, R3-2, R9-1), (R1-2, R2-1, R3-2, R9-2), (R1-2, R2-1, R3-2, R9-3), (R1-2, R2-1, R3-3, R9-1), (R1-2, R2-1, R3-3, R9-2), (R1-2, R2-1, R3-3, R9-3), (R1-2, R2-1, R3-4, R9-1), (R1-2, R2-1, R3-4, R9-2), (R1-2, R2-1, R3-4, R9-3), (R1-2, R2-1, R3-5, R9-1), (R1-2, R2-1, R3-5, R9-2), (R1-2, R2-1, R3-5, R9-3), (R1-2, R2-2, R3-1, R9-1), (R1-2, R2-2, R3-1, R9-2), (R1-2, R2-2, R3-1, R9-3), (R1-2, R2-2, R3-2, R9-1), (R1-2, R2-2, R3-2, R9-2), (R1-2, R2-2, R3-2, R9-3), (R1-2, R2-2, R3-3, R9-1), (R1-2, R2-2, R3-3, R9-2), (R1-2, R2-2, R3-3, R9-3), (R1-2, R2-2, R3-4, R9-1), (R1-2, R2-2, R3-4, R9-2), (R1-2, R2-2, R3-4, R9-3), (R1-2, R2-2, R3-5, R9-1), (R1-2, R2-2, R3-5, R9-2), (R1-2, R2-2, R3-5, R9-3), (R1-3, R2-1, R3-1, R9-1), (R1-3, R2-1, R3-1, R9-2), (R1-3, R2-1, R3-1, R9-3), (R1-3, R2-1, R3-2, R9-1), (R1-3, R2-1, R3-2, R9-2), (R1-3, R2-1, R3-2, R9-3), (R1-3, R2-1, R3-3, R9-1), (R1-3, R2-1, R3-3, R9-2), (R1-3, R2-1, R3-3, R9-3), (R1-3, R2-1, R3-4, R9-1), (R1-3, R2-1, R3-4, R9-2), (R1-3, R2-1, R3-4, R9-3), (R1-3, R2-1, R3-5, R9-1), (R1-3, R2-1, R3-5, R9-2), (R1-3, R2-1, R3-5, R9-3), (R1-3, R2-2, R3-1, R9-1), (R1-3, R2-2, R3-1, R9-2), (R1-3, R2-2, R3-1, R9-3), (R1-3, R2-2, R3-2, R9-1), (R1-3, R2-2, R3-2, R9-2), (R1-3, R2-2, R3-2, R9-3), (R1-3, R2-2, R3-3, R9-1), (R1-3, R2-2, R3-3, R9-2), (R1-3, R2-2, R3-3, R9-3), (R1-3, R2-2, R3-4, R9-1), (R1-3, R2-2, R3-4, R9-2), (R1-3, R2-2, R3-4, R9-3), (R1-3, R2-2, R3-5, R9-1), (R1-3, R2-2, R3-5, R9-2), (R1-3, R2-2, R3-5, R9-3), (R1-4, R2-1, R3-1, R9-1), (R1-4, R2-1, R3-1, R9-2), (R1-4, R2-1, R3-1, R9-3), (R1-4, R2-1, R3-2, R9-1), (R1-4, R2-1, R3-2, R9-2), (R1-4, R2-1, R3-2, R9-3), (R1-4, R2-1, R3-3, R9-1), (R1-4, R2-1, R3-3, R9-2), (R1-4, R2-1, R3-3, R9-3), (R1-4, R2-1, R3-4, R9-1), (R1-4, R2-1, R3-4, R9-2), (R1-4, R2-1, R3-4, R9-3), (R1-4, R2-1, R3-5, R9-1), (R1-4, R2-1, R3-5, R9-2), (R1-4, R2-1, R3-5, R9-3), (R1-4, R2-2, R3-1, R9-1), (R1-4, R2-2, R3-1, R9-2), (R1-4, R2-2, R3-1, R9-3), (R1-4, R2-2, R3-2, R9-1), (R1-4, R2-2, R3-2, R9-2), (R1-4, R2-2, R3-2, R9-3), (R1-4, R2-2, R3-3, R9-1), (R1-4, R2-2, R3-3, R9-2), (R1-4, R2-2, R3-3, R9-3), (R1-4, R2-2, R3-4, R9-1), (R1-4, R2-2, R3-4, R9-2), (R1-4, R2-2, R3-4, R9-3), (R1-4, R2-2, R3-5, R9-1), (R1-4, R2-2, R3-5, R9-2), (R1-4, R2-2, R3-5, R9-3),
    (R1-5, R2-1, R3-1, R9-1), (R1-5, R2-1, R3-1, R9-2), (R1-5, R2-1, R3-1, R9-3), (R1-5, R2-1, R3-2, R9-1), (R1-5, R2-1, R3-2, R9-2), (R1-5, R2-1, R3-2, R9-3), (R1-5, R2-1, R3-3, R9-1), (R1-5, R2-1, R3-3, R9-2), (R1-5, R2-1, R3-3, R9-3), (R1-5, R2-1, R3-4, R9-1), (R1-5, R2-1, R3-4, R9-2), (R1-5, R2-1, R3-4, R9-3), (R1-5, R2-1, R3-5, R9-1), (R1-5, R2-1, R3-5, R9-2), (R1-5, R2-1, R3-5, R9-3), (R1-5, R2-2, R3-1, R9-1), (R1-5, R2-2, R3-1, R9-2), (R1-5, R2-2, R3-1, R9-3), (R1-5, R2-2, R3-2, R9-1), (R1-5, R2-2, R3-2, R9-2), (R1-5, R2-2, R3-2, R9-3), (R1-5, R2-2, R3-3, R9-1), (R1-5, R2-2, R3-3, R9-2), (R1-5, R2-2, R3-3, R9-3), (R1-5, R2-2, R3-4, R9-1), (R1-5, R2-2, R3-4, R9-2), (R1-5, R2-2, R3-4, R9-3), (R1-5, R2-2, R3-5, R9-1), (R1-5, R2-2, R3-5, R9-2), (R1-5, R2-2, R3-5, R9-3), (R1-6, R2-1, R3-1, R9-1), (R1-6, R2-1, R3-1, R9-2), (R1-6, R2-1, R3-1, R9-3), (R1-6, R2-1, R3-2, R9-1), (R1-6, R2-1, R3-2, R9-2), (R1-6, R2-1, R3-2, R9-3), (R1-6, R2-1, R3-3, R9-1), (R1-6, R2-1, R3-3, R9-2), (R1-6, R2-1, R3-3, R9-3), (R1-6, R2-1, R3-4, R9-1), (R1-6, R2-1, R3-4, R9-2), (R1-6, R2-1, R3-4, R9-3), (R1-6, R2-1, R3-5, R9-1), (R1-6, R2-1, R3-5, R9-2), (R1-6, R2-1, R3-5, R9-3), (R1-6, R2-2, R3-1, R9-1), (R1-6, R2-2, R3-1, R9-2), (R1-6, R2-2, R3-1, R9-3), (R1-6, R2-2, R3-2, R9-1), (R1-6, R2-2, R3-2, R9-2), (R1-6, R2-2, R3-2, R9-3), (R1-6, R2-2, R3-3, R9-1), (R1-6, R2-2, R3-3, R9-2), (R1-6, R2-2, R3-3, R9-3), (R1-6, R2-2, R3-4, R9-1), (R1-6, R2-2, R3-4, R9-2), (R1-6, R2-2, R3-4, R9-3), (R1-6, R2-2, R3-5, R9-1), (R1-6, R2-2, R3-5, R9-2), (R1-6, R2-2, R3-5, R9-3), (R1-7, R2-1, R3-1, R9-1), (R1-7, R2-1, R3-1, R9-2), (R1-7, R2-1, R3-1, R9-3), (R1-7, R2-1, R3-2, R9-1), (R1-7, R2-1, R3-2, R9-2), (R1-7, R2-1, R3-2, R9-3), (R1-7, R2-1, R3-3, R9-1), (R1-7, R2-1, R3-3, R9-2), (R1-7, R2-1, R3-3, R9-3), (R1-7, R2-1, R3-4, R9-1), (R1-7, R2-1, R3-4, R9-2), (R1-7, R2-1, R3-4, R9-3), (R1-7, R2-1, R3-5, R9-1), (R1-7, R2-1, R3-5, R9-2), (R1-7, R2-1, R3-5, R9-3), (R1-7, R2-2, R3-1, R9-1), (R1-7, R2-2, R3-1, R9-2), (R1-7, R2-2, R3-1, R9-3), (R1-7, R2-2, R3-2, R9-1), (R1-7, R2-2, R3-2, R9-2), (R1-7, R2-2, R3-2, R9-3), (R1-7, R2-2, R3-3, R9-1), (R1-7, R2-2, R3-3, R9-2), (R1-7, R2-2, R3-3, R9-3), (R1-7, R2-2, R3-4, R9-1), (R1-7, R2-2, R3-4, R9-2), (R1-7, R2-2, R3-4, R9-3), (R1-7, R2-2, R3-5, R9-1), (R1-7, R2-2, R3-5, R9-2), (R1-7, R2-2, R3-5, R9-3), (R1-8, R2-1, R3-1, R9-1), (R1-8, R2-1, R3-1, R9-2), (R1-8, R2-1, R3-1, R9-3), (R1-8, R2-1, R3-2, R9-1), (R1-8, R2-1, R3-2, R9-2), (R1-8, R2-1, R3-2, R9-3), (R1-8, R2-1, R3-3, R9-1), (R1-8, R2-1, R3-3, R9-2), (R1-8, R2-1, R3-3, R9-3), (R1-8, R2-1, R3-4, R9-1), (R1-8, R2-1, R3-4, R9-2), (R1-8, R2-1, R3-4, R9-3), (R1-8, R2-1, R3-5, R9-1), (R1-8, R2-1, R3-5, R9-2), (R1-8, R2-1, R3-5, R9-3), (R1-8, R2-2, R3-1, R9-1), (R1-8, R2-2, R3-1, R9-2), (R1-8, R2-2, R3-1, R9-3), (R1-8, R2-2, R3-2, R9-1), (R1-8, R2-2, R3-2, R9-2), (R1-8, R2-2, R3-2, R9-3), (R1-8, R2-2, R3-3, R9-1), (R1-8, R2-2, R3-3, R9-2), (R1-8, R2-2, R3-3, R9-3), (R1-8, R2-2, R3-4, R9-1), (R1-8, R2-2, R3-4, R9-2), (R1-8, R2-2, R3-4, R9-3), (R1-8, R2-2, R3-5, R9-1), (R1-8, R2-2, R3-5, R9-2), (R1-8, R2-2, R3-5, R9-3).

(Method for Producing Compound of the Present Invention)



A general method for producing the compound of the present invention will be exemplified below. And, as extraction and purification, treatment which is performed in a normal experiment of organic chemistry may be conducted.
Synthesis of the compound of the present invention can be carried out referring to the procedures known in the art.
As a raw material compound, commercially available compounds, compounds described in the present description, compounds described in the references cited in the present description, and other known compounds can be utilized.
Among the compounds of the present invention, there are compounds in which a tautomer can be present, and the present invention includes all possible isomers and a mixture thereof, including them.
When one wants to obtain a salt of the compound of the present invention, in the case where the compound of the present invention is obtained in a form of a salt, it may be purified as it is and, in the case where the compound of the present invention is obtained in a free form, a salt may be formed by a normal method by dissolving or suspending the compound in a suitable organic solvent, and adding an acid or a base.
In addition, the compound of the present invention and a pharmaceutically acceptable salt thereof are present in a form of adducts with water or various solvents (hydrate or solvate) in some cases, and these adducts are included in the present invention.
In a general synthesis method as well as Examples and Reference Examples, the meaning of each abbreviation is as follows.

    DMF: N,N-dimethylformamide
    DMA: N,N-dimethylacetamide,
    NMP: N-methylpyrrolidone
    DMI: dimethylimidazolidinone
    THF: tetrahydrofuran
    Ms: methanesulfonyl
    Ts: paratoluenesulfonyl
    Boc: tert-butoxycarbonyl
    DIBALH: diisobutylaluminum hydride
    WSC or EDCI: N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide
    HOBt: 1-hydroxybenzotriazole
    HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
    NBS: N-bromosuccinimide
    NCS: N-chlorosuccinimide
    TEMPO: 2,2,6,6-tetramethylpiperidine-1-oxyl radical
    PDC: pyridinium dichloromate
    DEAD: diethyl azodicarboxylate
    DIAD: diisopropyl azodicarboxylate
    DMAP: 4-dimethylaminopyridine
    mCPBA: m-chloroperbenzoic acid
    DBU: 1,8-diazabicyclo[5.4.0]-7-undecene
    DIPEA: diisopropylethylamine
    TBAF: tetrabutylammonium fluoride
    IBX: 2-iodoxybenzoic acid
    DMSO: dimethyl sulfoxide
    NaHMDS: sodium hexamethyldisilazide
    TFA: trifluoroacetic acid


Synthesis of Objective Compound aj (See: Example 1)







    (wherein R is carboxy protective group, P1 is hydroxyl protective group, R2, R3, R8, R9, R10 and R11 are as defined in item 1′ or item 1, R and P1 may be a group which can be protected and/or deprotected by the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc. and, for example, R is lower alkyl etc., and P1 is arylalkyl etc.)

First Step



A compound ab can be obtained by reacting a compound aa which is commercially available or can be prepared by the known method at −20° C. to 30° C., preferably 0° C. to 20° C. for 0.1 hour to 24 hours, preferably 0.5 hour to 12 hours in a solvent such as dichloromethane, toluene, THF etc. or a mixed solvent thereof, by adding dropwise tertiary amine such as pyridine, trimethylamine, N-methylmorpholine, 4-dimethylaminopyridine etc. and benzyloxyacetyl chloride.
Second Step
A compound ac can be obtained by adding an organometallic base such as lithium hexamethyldisilazane, lithium diisopropylamide, butyllithium, tert-butyllithium etc. to the compound ab in a solvent such as ether, dichloromethane, THF etc. or a mixed solvent thereof, in the presence of cinnamoyl chloride, and performing a reaction at −80° C. to 0° C., preferably −80° C. to −40° C. for 1 minute to 2 hours, preferably 10 minutes to 1 hour.
Third Step
A compound ad can be obtained by adding a catalytic amount of an oxidizing agent such as ruthenium chloride and sodium periodate, TEMPO, manganese dioxide, as well as PDC etc. to the compound ac in a solvent such as ether, dichloromethane, THF, acetonitrile etc. or a mixed solvent thereof, and performing a reaction at −40° C. to 80° C., preferably 0° C. to 40° C. for 0.1 hour to 24 hours, preferably 0.2 hour to 3 hours.
Fourth Step
Concentrated sulfuric acid and an aqeuous solution of amidosuluflic acid are added to the compound ad at 0° C. to 60° C., preferably 10° C. to 40° C. in the presence of a solvent such as ether, dichloromethane, THF, acetonitrile, acetone, water etc. or in a mixed solvent thereof. An aqueous sodium chlorite solution is added dropwise thereto at the same temperature to perform a reaction for 1 minute to 3 hours, preferably 5 minutes to 1 hour, thereby, a compound ae can be obtained.
Fifth Step
A compound af can be obtained by adding a compound R3—NH2 having a substituent corresponding to an objective compound to the compound ae in a solvent such as DMF, THF, dichloromethane, acetonitrile etc. in the presence of a dehydration-condensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimido-N-hydroxybenzotriazole, 4-(4,6-dimethoxy-1,3,5,-triazin-2-yl)-4-methylmorpholinium chloride, hexafluorophosphoric acid 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, WSC.HCl, HATU etc., and performing a reaction at −20° C. to 60° C., preferably −10° C. to 40° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Sixth Step
A compound ah can be obtained by adding a compound ag to the compound af in the presence of a solvent such as toluene, xylene, THF, dioxane etc. or in a mixed solvent thereof, and performing a reaction for 0.1 hour to 12 hours, preferably 0.2 hour to 6 hours under the heat-refluxing condition.
Seventh Step
A compound ai can be obtained by adding triphenylphosphine and a condensation agent such as DEAD, DIAD etc. to the compound ah in the presence of a solvent such as THF, dioxane, ethyl acetate, acetonitrile etc. or in a mixed solvent thereof, and performing a reaction at 0° C. to 60° C., preferably 10° C. to 40° C. for 0.1 hour to 12 hours, preferably 0.2 hour to 6 hours.
Eighth Step
By subjecting the compound ai to the known general deprotecting reaction of a carboxyl protective group and a hydroxyl protective group, a compound aj can be obtained.
Synthesis of Compound bk (See: Example 12)







    (wherein P2 is amino protective group, P2 may be a group which can be protected and/or deprotected by the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc. and, for example, P2 is arylalkyloxycarbonyl, lower alkyloxycarbonyl, etc. Other each symbol is as defined above)

First Step



A compound bb can be obtained by adding a base such as potassium carbonate, sodium carbonate, cesium carbonate etc. and a compound P2-L (wherein L is a leaving group such as halogen, OMs etc.) having a substituent corresponding to an objective compound to a compound ba in the presence of a solvent such as DMF, THF, dioxane, acetonitrile etc. or in a mixed solvent thereof, and performing a reaction at −20° C. to 80° C., preferably 0° C. to 50° C. for 0.1 hour to 6 hours, preferably 0.2 hour to 6 hours.
Second Step
A compound bc can be obtained by adding triphenylphosphine and phthalimide to the compound bb in the presence of a solvent such as DMF, THF, dioxane, acetonitrile etc. or in a mixed solvent thereof, adding a dehydration-condensation reagent such as DIAD, DEAD etc., and performing a reaction at −10° C. to 60° C., preferably 0° C. to 50° C. for 0.1 hour to 24 hours, preferably 0.2 hour to 12 hours.
Third Step
A compound bd can be obtained by adding hydrazine hydrate or methylhydrazine to the compound bc in the presence of a solvent such as methanol, THF, dioxane, acetonitrile, etc. or in a mixed solvent thereof, and performing a reaction at −10° C. to 80° C., preferably 10° C. to 60° C. for 0.5 hour to 24 hours, preferably 1 to 12 hours.
Fourth Step
A compound be can be obtained by adding Boc2O to the compound bd in the presence of a solvent such as THF, dioxane, acetonitrile etc. or in a mixed solvent thereof, and performing a reaction at −10° C. to 80° C., preferably 10° C. to 60° C. for 0.5 hour to 24 hours, preferably 1 to 12 hours.
Fifth Step
A compound bf can be obtained by subjecting the compound be to the known general deprotecting reaction of an amino protective group.
Sixth Step
A compound bh can be obtained by adding a compound bg to the compound bf in the presence of a solvent such as toluene, THF, dioxane, acetonitrile etc. or in a mixed solvent thereof, and performing a reaction at 20° C. to 110° C., preferably 40° C. to under heat-refluxing for 0.5 hour to 24 hours, preferably 1 hour to 12 hours.
Seventh Step
HCl-ethyl acetate, HCl-dioxane, formic acid etc. is added to the compound bh, and they are reacted at 0° C. or 40° C., preferably 0° C. to 20° C. for 0.5 hour to 12 hours, preferably 1 hour to 6 hours. After the solvent is distilled off under reduced pressure, an aqueous saturated sodium bicarbonate solution is added, and the mixture is stirred, thereby, a compound bi can be obtained.
Eighth Step
A compound bj can be obtained by adding a base such as potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate etc. and a compound R3-L (L is a leaving group such as halogen, OMs etc.) to the compound bi in the presence of a solvent such as DMF, THF, DMA, NMP etc. or in a mixed solvent thereof, and performing a reaction at 0° C. to 60° C., preferably 10° C. to 30° C. for 0.5 hour to 12 hours, preferably 1 hour to 6 hours.
Ninth Step
A compound bk can be obtained by subjecting the compound bj to the known general deprotecting reaction of a carboxyl protective group and a hydroxyl protective group.
Synthesis of Compound cd (See: Examples 28 and 43)




    (wherein each symbol is as defined above)

First Step



A compound cb can be obtained by adding tertiary amine such as triethylamine, DMAP, morpholine etc. or a base such as sodium carbonate, sodium bicarbonate etc. to a compound ca in the presence of a solvent such as THF, dioxane, acetonitrile, water etc. or in a mixed solvent thereof, adding Boc2O, and performing a reaction at −10° C. to 80° C., preferably 10° C. to 60° C. for 0.5 hour to 24 hours, preferably 1 to 12 hours.
Second Step
A compound cc can be obtained by adding triphenylphosphine and phthalimide to the compound cb in the presence of a solvent such as DMF, THF, dioxane, acetonitrile etc. or in a mixed solvent thereof, adding a dehydration-condensation reagent such as DIAD, DEAD etc., and performing a reaction at −10° C. to 60° C., preferably 0° C. to 50° C. for 0.1 hour to 24 hours, preferably 0.2 hour to 12 hours.
Third Step
A compound cd can be obtained by adding hydrazine hydrate to the compound cc in the presence of a solvent such as methanol, THF, dioxane, acetonitrile etc. or in a mixed solvent thereof, and performing a reaction at −10° C. to 80° C., preferably 10° C. to 60° C. for 0.5 hour to 24 hours, preferably 1 to 12 hours.
Synthesis of Compound dg (See: Examples 36, 41 and 46)




    (wherein B1 and B2 are as defined in item 13′ or item 13, and other each symbol is as defined above).

First Step



A compound db can be obtained by subjecting the compound da obtained by the same method as the synthesis method of bi to the known general carboxyl deprotecting reaction.
Second Step
A decarbonized compound dc can be obtained by reacting the compound db for 1 minute to 2 hours under microwave irradiation in a solvent such as diphenyl ether etc. And, a decarbonized compound dc can be obtained by adding copper in a quinoline solvent, and performing a reaction at 180° C. for 2 to 48 hours.
Third Step
A compound dd can be obtained by adding a base such as potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate etc. and a compound R3-L (L is a leaving group such as halogen, OMs etc.) to the compound da obtained by the method described in Example 12 in the presence of a solvent such as DMF, THF, DMA, NMP etc. or in a mixed solvent thereof, and performing a reaction at 0° C. to 60° C., preferably 10° C. to 30° C. for 0.5 hour to 12 hours, preferably 1 hour to 6 hours.
Fourth Step
A compound de can be obtained by the same method as that of the first step.
Fifth Step
A compound df can be obtained by the same method as that of the second step.
Sixth Step
A compound df can be obtained by the same method as that of the third step.
Seventh Step
A compound dg can be obtained by subjecting the compound df to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound ec (See: Example 48)




    (wherein each symbol is as defined above)

First Step



A base such as triethylamine, N-methylmorpholine, diisopropylethylamine etc. and ethyl chloroformate are added to a compound ea in the presence of a solvent such as THF, dioxane, dichloromethane, toluene etc. or in a mixed solvent thereof. A reducing agent having a low reducing power such as sodium borohydride etc. is added thereto, and a reaction is performed at −20° C. to 60° C., preferably −10° C. to 20° C. for 0.2 hour to 12 hours, preferably 0.5 hour to 6 hours, thereby, a compound eb can be obtained.
Second Step
A compound ec can be obtained by subjecting the compound eb to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound fh (See: Example 50)







    (wherein each symbol is as defined above)

First Step



A compound fb and triphenylphosphine are added to a compound fa in the presence of a solvent such as THF, dichloromethane, dioxane, acetonitrile etc. or in a mixed solvent thereof. DIAD is added thereto, and a reaction is performed at 0° C. to 60° C., preferably 10° C. to 30° C. for 0.5 hour to 12 hours, preferably 1 hour to 12 hours, thereby, a compound fc can be obtained.
Second Step
A compound fd can be obtained by adding a base such as potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate etc. and thiol such as benzenethiol etc. to the compound fc in the presence of a solvent such as THF, dioxane, acetonitrile etc. or in a mixed solvent thereof, and performing a reaction at 0° C. to 60° C., preferably 10° C. to 30° C. for 0.5 hour to 12 hours, preferably 1 hour to 12 hours.
Third Step
A compound ff can be obtained by adding a compound fe having a substituent corresponding to an objective compound to the compound fd in a solvent such as DMF, THF, dichloromethane, acetonitrile etc. in the presence of a dehydration-condensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimido-N-hydroxybenzotriazole, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, hexafluorophosphoric acid 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, WSC.HCl etc., and performing a reaction at 0° C. to 60° C., preferably 10° C. to 40° C. for 1 hour to 48 hours, preferably 2 hours to 24 hours.
Fourth Step
A compound fg can be obtained by subjecting the compound ff to the known general deprotecting reaction concerning a P2 group on an amino group, subsequently, adding a base such as an aqueous sodium carbonate solution, an aqueous potassium carbonate solution etc. in a solvent such as water, ethanol, methanol, acetonitrile etc. or in a mixed solvent thereof, and performing a reaction at 20° C. to 80° C., preferably 20° C. to 70° C. for 0.5 hour to 24 hours, preferably 1 hour to 6 hours.
Fifth Step
A compound fh can be obtained by subjecting the compound fd to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound ga (See: Example 51)




    (wherein each symbol is as defined above)

First Step



A compound ga can be obtained by subjecting a compound dd to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound hh (See: Example 52)




    (wherein each symbol is as defined above)

First Step



A compound hb can be obtained by adding O,N-dimethylhydroxylamine hydrochloride to a compound ha in a solvent such as DMF, THF, dichloromethane, acetonitrile etc. in the presence of a dehydration-condensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimido-N-hydroxybenzotriazole, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, hexafluorophosphoric acid 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, WSC.HCl, HATU etc., adding a tertiary base such as triethylamine, diisopropylethylamine, N-methylmorpholine etc., and performing a reaction at 0° C. to 60° C., preferably 10° C. to 40° C. for 1 hour to 24 hours, preferably 1 hour to 12 hours.
Second Step
A compound he can be obtained by adding a Grignard reagent (R-MgBr) to the compound hb at −80° C. to −40° C. in the presence of a solvent such as THF, ether, dichloromethane, dioxane etc. or in a mixed solvent thereof, and performing a reaction at −80° C. to 0° C., preferably −60° C. to −20° C. for 0.5 hour to 24 hours, preferably 0.5 hour to 6 hours.
Third Step
A compound hd can be obtained by adding mCPBA to the compound hc in the presence of a solvent such as chloroform and dichloromethane, and performing a reaction at −20° C. to 30° C., preferably 10° C. to 30° C. for 0.1 hour to 12 hours, preferably 0.5 hour to 6 hours.
Fourth Step
A compound he can be obtained by adding an aqueous sodium hydroxide solution to the compound hd in the presence of a solvent such as ethanol etc., and performing a reaction at 0° C. to 120° C., preferably 30° C. to 90° C. for 1 minute to 10 hours, preferably 30 minutes to 120 minutes.
Fifth Step
A compound hf can be obtained by subjecting the compound he to the known general hydroxyl group deprotecting reaction.
Sixth Step
A compound hg can be obtained by adding a compound R-Br etc. corresponding to an objective compound to a compound he in the presence of a solvent such as chloroform, dichloromethane, THF, toluene etc. or in a mixed solvent thereof, adding a metal base such as sodium hydride, sodium methylate, n-butyllithium etc., and performing a reaction at −20° C. to 120° C., preferably 0° C. to 30° C. for 0.5 hour to 12 hours, preferably 1 hour to 6 hours.
Seventh Step
A compound hh can be obtained by subjecting the compound hg to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound ic (See: Example 53)




First Step

Tertiary amine such as triethylamine, diisopropylethylamine, N-methylmorpholine etc., and a chlorinating reagent such as ethyl chlorocarbonate, and ethyl chloroformate are added to a compound ia in the presence of a solvent such as DMF, DMA, NMP, THF etc. or in a mixed solvent thereof, and the mixture is stirred at 0° C. to 30° C. for 0.1 hour to 1 hour. A compound R—SO2—NH2 (e.g.: methanesulfonylamide) corresponding to an objective substance and DMAP are added thereto, and a reaction is performed at 40° C. to 100° C., preferably 40° C. to 80° C. for 0.5 hour to 12 hours, preferably 1 hour to 6 hours, thereby, a compound ib can be obtained.
Second Step
A compound ic can be obtained by subjecting the compound ib to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound je (See: Example 54)




    (wherein each symbol is as defined above)

First Step



Tertiary amine such as triethylamine, N-methylmorpholine, diisopropylethylamine etc. and ethyl chloroformate or ethyl chlorocarbonate are added to a compound ja in the presence of a solvent such as THF, dioxane, dichloromethane, toluene, DMF etc. or in a mixed solvent thereof. A reducing agent having low reactivity such as sodium borohydride etc. is added thereto, and a reaction is performed at −20° C. to 40° C., preferably −10° C. to 20° C. for 0.2 hour to 12 hours, preferably 0.5 hour to 6 hours to obtain an alcohol intermediate. This intermediate is dissolved in dichloromethane, chloroform, etc., an oxidizing agent such as TEMPO, manganese dioxide, PDC etc. is added, and a reaction is performed at −40° C. to 30° C., preferably 0° C. to 30° C. for 0.1 hour to 24 hours, preferably 0.5 hour to 12 hours, thereby, a compound jb can be obtained.
Second Step
A compound jc can be obtained by adding 28% aqueous ammonia and iodine to the compound jb in the presence of a solvent such as THF, dioxane, dichloromethane etc., and performing a reaction at 0° C. to 40° C., preferably 10° C. to 30° C. for 0.5 hour to 24 hours, preferably 1 hour to 6 hours.
Third Step
A compound jd can be obtained by adding sodium azide, and tertiary amine such as triethylamine, diisopropylethylamine, N-methylmorpholine etc. to the compound jc in the presence of a solvent such as toluene, xylene, THF, dioxane etc. or in a mixed solvent thereof, and performing a reaction at 0° C. to 60° C., preferably 10° C. to 40° C. for 0.5 hour to 24 hours, preferably 1 hour to 12 hours.
Fourth Step
A compound je can be obtained by subjecting the compound jd to the known general hydroxyl group deprotecting reaction.
Synthesis of Compounds kd and kf (See: Example 56 and Derivative Thereof)




    (wherein Rm is lower alkyl, R is a substituent corresponding to an objective compound, W is —C(═O)— or —SO2—, and other each symbol is as defined above)

First Step



Tertiary amine such as triethylamine, N-methylmorpholine, diisopropylethylamine etc. and ethyl chloroformate or ethyl chlorocarbonate are added to a compound ka in the presence of a solvent such as THF, dioxane, dichloromethane, toluene, DMF etc. or in a mixed solvent thereof. Sodium azide is added thereto to perform a reaction at 0° C. to 40° C., preferably 10° C. to 30° C. for 0.5 hour to 24 hours, preferably 1 hour to 12 hours. Thereafter, an alcohol (Rm—OH) is added, and a reaction is performed at 20° C. to 60° C., preferably 20° C. to 50° C. for 0.5 hour to 24 hours, preferably 1 hour to 12 hours, thereby, a compound kb can be obtained.
Second Step
A compound kc can be obtained by adding a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution etc. to the compound kb in a solvent such as ethanol, methanol, water etc. or in a mixed solvent thereof, and performing a reaction at 20° C. to 80° C., preferably 40° C. to 60° C. for 0.5 hour to 24 hours, preferably 1 hour to 12 hours.
Third Step
A compound kd can be obtained by subjecting the compound kc to the known general hydroxyl group deprotecting reaction.
Fourth Step
A compound ke can be obtained by adding acid chloride (R—CO—Cl) or sulfonyl chloride (R—SO2—Cl) corresponding to an objective substance to a compound kc in a solvent such as THF, dioxane, toluene, dichloromethane etc., adding tertiary amine such as pyridine, triethylamine, N-methylmorpholine etc. as necessary, and performing a reaction at −20° C. to 40° C., preferably 0° C. to 30° C. for 0.1 hour to 12 hours, preferably 0.2 hour to 6 hours.
Fifth Step
A compound kf can be obtained by subjecting the compound ke to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound lc (See: Example 60)




    (wherein R is a substituent corresponding to an objective compound, and other each symbol is as defined above)

First Step



Sodium hydride is added to a compound la in a solvent such as THF, dichloromethane, DMF etc. R-L (L is a leaving group such as halogen, OMs etc.) corresponding to an objective substance is added thereto, and a reaction is performed at −20° C. to 40° C., preferably 0° C. to 30° C. for 0.1 hour to 12 hours, preferably 0.2 hour to 6 hours, thereby, a compound 1b can be obtained.
Alternatively, a compound lb can be obtained by adding formaldehyde to a compound la in a solvent of formic acid, and performing a reaction at 70° C. to 110° C. for 0.5 hour to 24 hours, preferably 1 hour to 12 hours.
Second Step
A compound lc can be obtained by subjecting the compound lb to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound md (See: Example 61)




    (wherein R is a substituent corresponding to an objective compound, and other each symbol is as defined above)

First Step



An amino-protected body mb can be obtained by adding Boc2O etc. to a compound ma in a solvent such as THF, dioxane, acetonitrile, water etc. or in a mixed solvent thereof, and subjecting this to an amine protecting reaction.
Second Step
Sodium hydride is added to a compound mb in a solvent such as THF, dichloromethane, DMF etc. R-L (L is a leaving group such as halogen, OMs etc.) corresponding to an objective substance is added thereto, and a reaction is performed at −20° C. to 40° C., preferably 0° C. to 30° C. for 0.1 hour to 12 hours, preferably 0.2 hour to 6 hours, thereby, a compound mc can be obtained.
Third Step
A compound md can be obtained by subjecting the compound mc to the known general amino group and hydroxyl group deprotecting reaction.
Synthesis of Compound nc and Compound ne (See: Examples 63 and 64)




    (wherein X is halogen, M is boronic acid ester such as B(O-phenyl)3 etc., and other each symbol is as defined above)

First Step



A compound nb can be obtained by adding a halogenating reagent (e.g. NBS, NCS, bromine etc.) to a compound na in a solvent such as dichloromethane, toluene, THF, dioxane etc., and performing a reaction for 0.1 hour to 12 hours, preferably 0.2 hour to 6 hours under the overheating refluxing condition.
Second Step
A compound nc can be obtained by subjecting the compound nb to the known general hydroxyl group deprotecting reaction.
Third Step
Boronic acid ester (R-M) corresponding to an objective substance is added to a compound nb in a solvent such as toluene, THF, DMF etc. or in a mixed solvent thereof, and a base such as potassium carbonate, sodium carbonate, sodium hydroxide etc. is added. A 0-valent palladium catalyst (e.g.: Pd(PPh3)4) is added thereto under nitrogen stream, and a reaction is performed at 60° C. to 120° C., preferably 80° C. to 110° C. for 1 hour to 48 hours, preferably 2 hours to 24 hours, thereby, a compound nd can be obtained.
Fourth Step
A compound ne can be obtained by subjecting the compound nd to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound oh (See: Example 65)







    (wherein R is a carboxyl protective group such as lower alkyl etc., R7 is as defined in item 1′ or item 1, L1 is a leaving group such as halogen, OMs, OTs etc., and other symbol is as defined above)

First Step



A compound ob can be obtained by adding sodium chlorite and amidosulfuric acid to a compound oa in the presence of a solvent such as THF, dioxane, dichloromethane, acetonitrile etc., and performing a reaction at 0° C. to 40° C., preferably 0° C. to 30° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Second Step
A compound oc can be obtained by adding a condensation agent such as HATU, WSC.HCl etc. to the compound ob in the presence of a solvent such as DMF, DMA, NMP, THF etc., adding amine (R3—NH2) corresponding to an objective substance, and tertiary amine such as triethylamine, N-methylmorpholine, pyridine etc., and performing a reaction at 10° C. to 60° C., preferably 20° C. to 40° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Third Step
A compound od can be obtained by adding potassium carbonate, sodium carbonate, and O-(2,4-dinitrophenyl)hydroxylamine to the compound oc in the presence of a solvent such as DMF, DMA, NMP, THF etc., and performing a reaction at 10° C. to 60° C., preferably 20° C. to 40° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Fourth Step
A compound oe can be obtained by adding R5—C(═O)—R6 and acetic acid to the compound od in the presence of a solvent such as toluene, DMF, DMA, NMP, THF etc., and performing a reaction at 60° C. to 120° C., preferably 80° C. to 110° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Fifth Step
A compound of can be obtained by adding a compound R7-L1 corresponding to an objective substance, and a base such as sodium carbonate, potassium carbonate, cesium carbonate etc. to the compound oe in the presence of a solvent such as DMF, DMA, NMP, THF etc., and performing a reaction at 0° C. to 60° C., preferably 10° C. to 40° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Sixth Step
A compound og can be obtained by subjecting the compound of to the known general carboxyl group deprotecting reaction.
Seventh Step
A compound oh can be obtained by subjecting the compound og to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound pg (See: Example 95)




    (wherein each symbol is as defined above)

First Step



A compound pb can be obtained by adding aqueous ammonia to a compound pa, and performing a reaction at 0° C. to 30° C., preferably 10° C. to 30° C. for 0.5 hour to 48 hours, preferably 1 hour to 24 hours.
Second Step
A compound pc can be obtained by adding a condensation agent such as HATU, WSC.HCl etc. to the compound pb in the presence of a solvent such as DMF, DMA, NMP, THF etc. or in a mixed solvent thereof, adding amine (R3—NH2) corresponding to an objective substance and, if necessary, tertiary amine such as triethylamine, N-methylmorpholine etc., and performing a reaction at 10° C. to 60° C., preferably 20° C. to 40° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Third Step
A compound pd can be obtained by adding potassium carbonate, sodium carbonate, and O-(2,4-dinitrophenyl)hydroxylamine to the compound pc in the presence of a solvent such as DMF, DMA, NMP, THF etc., and performing a reaction at 10° C. to 60° C., preferably 20° C. to 40° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Fourth Step
A compound pe can be obtained by adding R5—C(═O)—R6 and acetic acid to the compound pd in the presence of a solvent such as toluene, DMF, DMA, NMP, THF etc., and performing a reaction at 60° C. to 120° C., preferably 80° C. to 110° C. for 0.1 hour to 12 hours, preferably 0.2 hour to 6 hours.
Fifth Step
A compound pf can be obtained by adding a compound R7-L1 corresponding to an objective substance, and a base such as sodium carbonate, potassium carbonate, cesium carbonate etc. to the compound pe in the presence of a solvent such as DMF, DMA, NMP, THF etc., and performing a reaction at 0° C. to 60° C., preferably 10° C. to 40° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Sixth Step
A compound pg can be obtained by subjecting the compound pf to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound qg, Compound qi, and Compound qk (See: Example 128)




    (wherein R represents a carboxyl protective group, n represents an integer of 0 to 6, RZ7 and RZ8 are as defined in item 1′ or item 1, and other each symbol is as defined above)

First Step



A compound qc can be obtained by adding a condensation agent such as HATU, WSC.HCl etc. to a compound qa in the presence of a solvent such as pyridine, DMF, DMA, NMP, THF etc. or in a mixed solvent thereof, adding a compound qb and, if necessary, tertiary amine such as triethylamine, N-methylmorpholine etc., and performing a reaction at 10° C. to 60° C., preferably 20° C. to 40° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Second Step
A compound qd can be obtained by adding potassium carbonate, sodium carbonate, and O-(2,4-dinitrophenyl)hydroxylamine to the compound qc in the presence of a solvent such as DMF, DMA, NMP, THF etc. or in a mixed solvent thereof, and performing a reaction at 10° C. to 60° C., preferably 20° C. to 40° C. for 0.1 hour to 48 hours, preferably 1 hour to 24 hours.
Third Step
A compound pe can be obtained by adding R5—C(═O)—R6 and acetic acid to the compound qd in the presence of a solvent such as toluene, DMF, DMA, NMP, THF etc. or in a mixed solvent thereof, and performing a reaction at 60° C. to 120° C., preferably 80° C. to 110° C. for 0.1 hour to 12 hours, preferably 0.2 hour to 6 hours.
Alternatively, a compound qe can be obtained by performing a reaction at 100° C. to 200° C. for 5 minutes to 1 hour under microwave irradiation condition in a solvent such as ethanol, isopropyl alcohol etc.
Fourth Step
A compound qf can be obtained by adding a compound R7-L1 corresponding to an objective substance, and a base such as sodium carbonate, potassium carbonate, cesium carbonate etc. to the compound qe in the presence of a solvent such as DMF, DMA, NMP etc. or in a mixed solvent thereof, and performing a reaction at 0° C. to 60° C., preferably 10° C. to 40° C. for 0.1 hour to 48 hours, preferably 1 hour to 24 hours.
Fifth Step
A compound qg can be obtained by subjecting the compound qf to the known general hydroxyl group deprotecting reaction.
Sixth Step
A compound qh can be obtained by subjecting the compound qf to the known general carboxyl group deprotecting reaction.
Seventh Step
A compound qi can be obtained by subjecting the compound qh to the known general hydroxyl group deprotecting reaction.
Eighth Step
A compound qj can be obtained by adding a condensation agent such as HATU, WSC.HCl etc. to a compound qh in the presence of a solvent such as pyridine, DMF, DMA, NMP, THF etc. or in a mixed solvent thereof, adding a compound HNRZ7RZ8 and, if necessary, tertiary amine such as triethylamine, diisopropylethylamine, N-methylmorpholine etc., and performing a reaction at 10° C. to 60° C., preferably 20° C. to 40° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Ninth Step
A compound qk can be obtained by subjecting the compound qj to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound qq, Compound qs, Compound qu, and Compound qw (See: Example 128)




    (wherein RZ2, RZ4, RZ9, RZ10, and RZ13 are as defined in item 1′ or item 1, and other each symbol is as defined above)

Step 1



A compound qm can be obtained by adding a condensation agent such as HATU, WSC.HCl, etc. to a compound qa in the presence of a solvent such as pyridine, DMF, DMA, NMP etc. or in a mixed solvent thereof, adding a compound ql and, if necessary, tertiary amine such as triethylamine, diisopropylethylamine, N-methylmorpholine, etc., and performing a reaction at 10° C. to 60° C., preferably 20° C. to 40° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Second Step
A compound qn can be obtained by adding potassium carbonate, sodium carbonate, and O-(2,4-dinitrophenyl)hydroxylamine to the compound qm in the presence of a solvent such as DMF, DMA, NMP, THF etc., and performing a reaction at 10° C. to 60° C., preferably 20° C. to 40° C. for 0.1 hour to 48 hours, preferably 1 hour to 24 hours.
Third Step
A compound pe can be obtained by adding R5—C(═O)—R6 and acetic acid to the compound qn in the presence of a solvent such as toluene, DMF, DMA, NMP, THF etc. or in a mixed solvent thereof, and performing a reaction at 60° C. to 120° C., preferably 80° C. to 110° C. for 0.1 hour to 12 hours, preferably 0.2 hour to 6 hours.
Alternatively, a compound qo can be obtained by performing a reaction at 100° C. to 200° C. for 5 minutes to 1 hour under microwave irradiation condition in a solvent such as ethanol etc.
Fourth Step
A compound qp can be obtained by adding a compound R7-L1 corresponding to an objective substance, and a base such as sodium carbonate, potassium carbonate, cesium carbonate, etc. to the compound qo in the presence of a solvent such as DMF, DMA, NMP, THF, etc. or in a mixed solvent thereof, and performing a reaction at 0° C. to 60° C., preferably 10° C. to 40° C. for 0.1 hour to 48 hours, preferably 1 hour to 24 hours.
Fifth Step
A compound qq can be obtained by subjecting the compound qp to the known general hydroxyl group deprotecting reaction.
Sixth Step
A compound qr can be obtained by subjecting the compound qp to the known general amino group deprotecting reaction.
Seventh Step
A compound qs can be obtained by subjecting the compound qr to the known general hydroxyl group deprotecting reaction.
Eighth Step
A compound qt can be obtained by adding a compound RZ10-L1 corresponding to an objective substance, and a base such as sodium carbonate, potassium carbonate, cesium carbonate, etc. to the compound qr in the presence of a solvent such as DMF, DMA, NMP, THF, etc. or in a solvent thereof, and performing a reaction at 0° C. to 60° C., preferably 10° C. to 40° C. for 0.1 hour to 48 hours, preferably 1 hour to 24 hours.
Ninth Step
A compound qu can be obtained by subjecting the compound qt to the known general hydroxyl group deprotecing reaction.
Tenth Step
A base such as sodium carbonate, potassium carbonate, cesium carbonate etc. is added to the compound qr in the presence of a solvent such as THF, dioxane, dichloromethane, acetonitrile, etc. A compound (RZ4COCl, RZ2SO2Cl, or RZ13OCOCl) corresponding to an objective substance is added thereto, and a reaction is performed at −20° C. to 60° C., preferably 0° C. to 30° C. for 0.1 hour to 48 hours, preferably 1 hour to 24 hours, thereby, a compound qv can be obtained.
Eleventh Step
A compound qw can be obtained by subjecting the compound qv to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound rb (See: Example 155)




    (wherein each symbol is as defined above)


A compound rb can be obtained by adding a compound R3NH2 having a substituent corresponding to an objective compound to a compound ra in the presence of a dehydration-condensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimido-N-hydroxybenzotriazole, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, hexafluorophosphoric acid 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, WSC.HCl, HATU, etc. in a solvent such as DMF, THF, dichloromethane, acetonitrile, etc. or in a mixed solvent thereof, and performing a reaction at −20° C. to 60° C., preferably −10° C. to 40° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Alternatively, a compound rb can be obtained by adding an acylating reagent such as diphenylchlorophosphate, thionyl chloride, oxalyl chloride, etc. to a compound ra in the presence or absence of a base such as pyridine, triethylamine, diisopropylethylamine, 1-methylimidazole, etc. in the presence of a solvent such as THF, dioxane, dichloromethane, DMF, etc. to generate acid chloride, adding a compound R3—NH2 having a substituent corresponding to an objective compound, and performing a reaction at −20° C. to 60° C., preferably −10° C. to 40° C. for 0.1 hour to 24 hours, preferably 0.5 hour to 12 hours.
Synthesis of Compound sl (See: Example 49)




    (wherein P3 is an amino protective group, and may be a group which can be protected and/or deprotected by the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc. and, for example, P3 is aryl lower alkyloxycarbonyl, lower alkylcarbonyl, etc. B is as defined in item 1′ or item 1, and other each symbol is as defined above.)

First Step



A compound sb can be obtained by adding an oxidizing reagent such as Dess Martin Periodinane, manganese dioxide, PDC, etc, to a compound sa in the presence of a solvent such as dichloromethane, THF, dioxane, toluene etc., and performing a reaction at −20° C. to 60° C., preferably 0° C. to 40° C. for 0.1 hour to 24 hours, preferably 0.5 hour to 12 hours.
Second Step
A compound sd can be obtained by adding sodium sulfate and an aminoalcohol sc corresponding to an objective substance to the compound sb in the presence or absence of a solvent such as toluene, THF etc., and performing a reaction at 0° C. to 80° C., preferably 20° C. to 60° C. for 0.1 hour to 24 hours, preferably 0.5 hour to 12 hours.
Third Step
A compound se can be obtained by subjecting the compound sd to the known general amino group deprotecting reaction.
Fourth Step
A compound sg can be obtained by adding a compound sf to the compound se in the presence of a solvent such as toluene, THF, dioxane etc., and performing a reaction at 40° C. to 110° C., preferably 60° C. to 100° C. for 0.5 hour to 24 hours, preferably 1 hour to 12 hours.
Fifth Step
A compound sh can be obtained by subjecting the compound sg to the known general amino group deprotecting reaction and, thereafter, performing a reaction at 40° C. to 110° C., preferably 60° C. to 100° C. for 0.1 hour to 12 hours, preferably 0.2 hour to 6 hours in the presence of a solvent such as toluene, THF, dioxane, etc.
Sixth Step
A compound si can be obtained by subjecting the compound sh to the known general carboxyl group deprotecting reaction.
Seventh Step
A compound sj can be obtained by subjecting the compound si to the known general hydroxyl group deprotecting reaction.
Eighth Step
A decarbonized compound sk can be obtained by reacting the compound si for 1 minute to 2 hours under microwave irradiation in a solvent such as diphenyl ether etc.
Ninth Step
A compound sl can be obtained by subjecting the compound sk to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound un (See: Example 177)




    (wherein L1 represents a leaving group such as halogen, OMs, OTs etc., and other each symbol is as defined above)

First Step



A compound ub can be obtained by subjecting a compound ua to a secondary amino group protecting reaction.
Second Step
A compound uc can be obtained by subjecting the compound ub to a general amino group protecting reaction.
Third Step
A compound ue can be obtained by adding a compound R7-L1 corresponding to an objective compound to the compound uc in the presence of a solvent such as DMF, DMA, NMP, etc. and a base such as NaH etc., and performing a reaction at 0° C. to 80° C., preferably 20° C. to 60° C. for 0.5 hour to 12 hours, preferably 1 hour to 6 hours.
Fourth Step, Fifth Step


    (wherein R3 and R7 may be bound adjacently and, in this case, a fourth step and a fifth step are performed simultaneously).


A compound ue can be obtained by reacting a compound ud sequentially with compounds corresponding to an objective compound, R3-L1 and R7-L1 in the presence of a solvent such as DMF, DMA, NMP etc. and a base such as NaH etc.
Sixth Step
A compound ug can be obtained by subjecting a compound uf to a secondary amino group protecting reaction.
Seventh Step
A compound uh can be obtained by subjecting the compound ug to a secondary amino group protecting reaction.
Eighth Step
A compound ue can be obtained by adding a base such as NaH etc. to the compound uh in the presence of a solvent such as DMF, DMA, NMP, acetonitrile etc. or in a mixed solvent thereof, and performing a reaction with a compound R3-L1 corresponding to an objective compound.
Ninth Step
A compound uj can be obtained by subjecting the compound ue to a general secondary amine deprotecting reaction.
Tenth Step
A compound ul can be obtained by adding a condensation agent such as HATU, WSC.HCl etc. to a compound uk in the presence of a solvent such as DMF, DMA, THF, etc., adding amine uj corresponding to an objective substance, and tertiary amine such as pyridine, triethylamine, N-methylmorpholine etc., and performing a reaction at 10° C. to 60° C., preferably 20° C. to 40° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Eleventh Step
A compound um can be obtained by subjecting the compound ul to a general amino group protecting reaction.
Twelfth Step
A compound un can be obtained by adding R5—C(═O)—R6′ tertiary amine such as, triethylamine, diisopropylethylamine, N-methylmorpholine, etc. to the compound um in the presence of a solvent such as toluene, DMF, DMA, NMP etc., and performing a reaction at 60° C. to 120° C., preferably 80° C. to 100° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Synthesis of Compound te




    (wherein R′ may be a group which can be protected and/or deprotected by the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc. and, for example, R′ is lower alkyl etc. X is halogen, and other each symbol is as defined above.)

First Step



An alcohol (P1—OH) corresponding to an objective substance is added to an organometallic base such as sodium tert-pentoxide, n-butyllithium, tert-butyllithium etc. in a solvent such as THF, ether, dichloromethane, DMI, DMF, DMA, etc. or in a mixed solution thereof. A solution of a compound ta is added dropwise thereto, and a reaction is performed at −20° C. to 40° C., preferably 0° C. to 30° C. for 0.1 hour to 12 hours, preferably 0.5 hour to 6 hours, thereby, a compound tb can be obtained.
Second Step
A compound tc can be obtained by adding N,N-dimethylformamidodimethylacetal to the compound tb in a solvent such as THF, dioxane, toluene, ethyl acetate etc. or in a mixed solvent thereof, or without a solvent, and performing a reaction at 0° C. to 80° C., preferably 20° C. to 40° C. for 0.5 hour to 24 hours, preferably 1 hour to 12 hours.
Third Step
A compound td corresponding to an objective substance is added to an organometallic base such as sodium tert-pentoxide, n-butyllithium, tert-butyllithium, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide etc. in a solvent such as THF, ether, DMI, methanol, ethanol, etc. or in a mixed solvent thereof. A solution of the compound tc is added dropwise thereto, a reaction is performed at −20° C. to 60° C., preferably 0° C. to 30° C. for 0.5 hour to 24 hours, preferably 1 hour to 12 hours and, thereafter, an acid such as hydrochloric acid, sulfuric acid etc. is added to perform a reaction at −20° C. to 60° C., preferably 0° C. to 30° C. for 0.5 hour to 24 hours, preferably 1 hour to 12 hours, thereby, a compound te can be obtained.
Synthesis of Compound tm and Compound tp (See: Examples 165, and 169)




    (wherein RP may be an acetal protective group which can protect and/or can be deprotected by the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc. and, for example, RP is lower alkyl etc. Other each symbol is as defined above.)

First Step



A compound th can be obtained by adding allylamine to a compound tf which can be synthesized by the same method as that of a compound te in the presence of a solvent such as ethanol, THF, dioxane, acetonitrile, etc. or in a mixed solvent thereof, and performing a reaction at 0° C. to 80° C., preferably 20° C. to 60° C. for 0.5 hour to 48 hours, preferably 1 hour to 24 hours.
Second Step
A compound ti can be obtained by adding a compound tg to a compound tf in the presence of a solvent such as ethanol, THF, dioxane, acetonitrile etc. or in a mixed solvent thereof, and performing a reaction at 0° C. to 80° C., preferably 20° C. to 60° C. for 0.5 hour to 48 hours, preferably 1 hour to 24 hours.
Third Step
A compound tj can be obtained by adding potassium osmate dihydrate, sodium periodate, and water to the compound th in the presence of a solvent such as THF, ethyl acetate, dioxane, etc. or in a mixed solvent thereof, and performing a reaction at 0° C. to 60° C., preferably 10° C. to 40° C. for 0.5 hour to 24 hours, preferably 1 hour to 12 hours.
Alternatively, a compound tj can be obtained by introducing ozone into the compound th at −10° C. to 20° C. in the presence of a solvent such as THF, ethyl acetate, dioxane etc. or in a mixed solvent thereof and, subsequent to completion of the reaction, adding zinc-acetic acid, (EtO)3P, or dimethyl sulfide.
Fourth Step
A compound tk can be obtained by adding an acid such as formic acid, trifluoroacetic acid, paratoluenesulfonic acid, etc. to the compound ti in a solvent such as acetone, acetonitrile, ethanol, water, etc. or in a mixed solvent thereof, or adding sulfuric acid in a formic acid solvent, and performing a reaction at 0° C. to 90° C., preferably 20° C. to 80° C. for 0.5 hour to 24 hours, preferably 1 hour to 12 hours.
Fifth Step
A compound tm can be obtained by adding a compound tl and acetic acid to the compound tj or the compound tk in the presence of a solvent such as chloroform, dichloromethane, THF, etc., and performing a reaction at 0° C. to 40° C., preferably 10° C. to 30° C. for 0.5 hour to 24 hours, preferably 1 hour to 12 hours.
Sixth Step
A compound to can be obtained by adding a compound tn and acetic acid to the compound tj or the compound tk in the presence of a solvent such as chloroform, dichloromethane, THF, etc., and performing a reaction at 0° C. to 40° C., preferably 10° C. to 30° C. for 0.5 hour to 24 hours, preferably 1 hour to 12 hours.
Seventh Step
A compound tp can be obtained by adding a compound B-L1 corresponding to an objective compound to the compound to in the presence of a solvent such as DMF, DMA, NMP, THF, etc. or in a mixed solvent thereof, and performing a reaction at 0° C. to 80° C., preferably 20° C. to 60° C. for 0.5 hour to 12 hours, preferably 1 hour to 6 hours.
Synthesis of Compound vf (See: Examples 583 and 584)







    (wherein Y1 is a substituent corresponding to R3 or R3a, and Y2 is a substituent corresponding to R11 or R11a. Other each symbol is as defined above.)

First Step



A compound vc can be obtained by adding a compound vb having a substituent corresponding to an objective compound to a compound va in the presence of a dehydration-condensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimido-N-hydroxybenzotriazole, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, hexafluorophosphoric acid 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, WSC.HCl, HATU, etc. in a solvent such as DMF, THF, dichloromethane, acetonitrile etc. or in a mixed solvent thereof, and performing a reaction at −20° C. to 60° C., preferably −10° C. to 40° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Alternatively, a compound vc can be obtained by adding an acylating reagent such as diphenylchlorophosphate, thionyl chloride, oxalyl chloride etc. to a compound va in the presence or absence of a base such as pyridine, triethylamine, diisopropylethylamine, 1-methylimidazole, etc. in the presence of a solvent such as THF, dioxane, dichloromethane, DMF etc., thereby, generating acid chloride, and adding a compound vb having a substituent corresponding to an objective compound, and performing a reaction at −20° C. to 60° C., preferably −10° C. to 40° C. for 0.1 hour to 24 hours, preferably 0.5 hour to 12 hours.
Second Step
A compound vd can be obtained by adding potassium carbonate, sodium carbonate, and O-(2,4-dinitrophenyl)hydroxylamine to the compound vc in the presence of a solvent such as DMF, DMA, NMP, THF, etc., and performing a reaction at 10° C. to 60° C., preferably 20° C. to 40° C. for 0.1 hour to 48 hours, preferably 1 hour to 24 hours.
Third Step
A deprotecting reaction of an acetal protective group of the compound vd can be performed by the general method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc. Thereafter, a generated aldehyde group is subjected to an intramolecular reaction, thereby, a compound ve can be obtained.
For example, a compound ve can be obtained by adding acetic acid and/or paratoluenesulfonic acid to the compound vd in the presence of a solvent such as DMF, toluene, THF, etc., and performing a reaction at 10° C. to 80° C., preferably 30° C. to 60° C. for 0.5 hour to 12 hours, preferably 1 hour to 6 hours.
Fourth Step
A compound vf can be obtained by adding a compound R7-L1 corresponding to an objective substance, and a base such as sodium carbonate, potassium carbonate, cesium carbonate, etc. to the compound ve in the presence of a solvent such as DMF, DMA, NMP, THF, etc. or in a mixed solvent thereof, and performing a reaction at 0° C. to 60° C., preferably 10° C. to 40° C. for 0.1 hour to 48 hours, preferably 1 hour to 24 hours.
The present invention will be explained in more detail below by way of Examples and Reference Examples, as well as Test Examples of the present invention, but the present invention is not limited by them.
EXAMPLE 1







First Step

A dichloromethane (90 mL) solution of compound 1A (12.8 g, 89.4 mmol) and pyridine (8.50 g, 107 mmol) was cooled to 1 to 3° C., and a dichloromethane (90 mL) solution of benzyloxyacetyl chloride (19.8 g, 107 mmol) was added dropwise over 50 minutes while the same temperature was retained. After the reaction solution was stirred at the same temperature for 30 minutes, temperature was gradually raised to 15° C. over 60 minutes, and ice water was added. The dichloromethane layer was separated, and the aqueous layer was extracted with dichloromethane once. The combined extracts were washed with water three times, washed with an aqueous saturated sodium chloride solution, and dried. The solvent was distilled off, and the resulting oil was purified by silica gel column chromatography. The materials were eluted firstly with n-hexane and, then, with n-hexane-ethyl acetate (1:1, v/v). Concentration of objective fraction afforded 22.2 g of compound 1B as an oil.
1H-NMR (CDCl3) δ: 1.25 (3H, t, J=7.2 Hz), 2.90 (3H, brs), 3.24 (3H, brs), 4.15 (2H, q, J=7.2 Hz), 4.45 (2H, s), 4.58 (2H, s), 7.25-7.38 (5H, m), 7.72 (1H, s).
Second Step
A 1N lithiumhexamethyldisilazane THF solution (4.29 ml, 4.29 mmol) was cooled to −78° C., and a THF solution (4 ml) of compound 1B (500 mg, 1.72 mmol) and cinnamoyl chloride (343.2 mg, 2.06 mmol) were added dropwise thereto over 3 minutes while the same temperature was retained. After the reaction solution was stirred at the same temperature for 25 minutes, 2N hydrochloric acid (10 ml) was added, and the mixture was further stirred at room temperature for 10 minutes. To the reaction solution was added ethyl acetate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate three times. The combined extracts were dried with sodium sulfate. The solvent was distilled off, and the resulting oil was purified by silica gel column chromatography. From fraction eluted with n-hexane-ethyl acetate (1:1, v/v), 364.3 mg (yield 56%) of compound 1C was obtained as a solid.
1H-NMR (CDCl3) δ: 1.40 (3H, t, J=7.2 Hz), 4.39 (2H, q, J=7.2 Hz), 5.27 (2H, s), 6.99 (1H, d, J=16.2 Hz), 7.23 (1H, d, J=16.2), 7.26-7.48 (10H, m), 8.45 (1H, s).
Third Step
To a MeCN (5 ml) solution of compound 1C and ruthenium chloride (2.76 mg, 0.0133 mmol) was added dropwise an aqueous solution (8 ml) of sodium periodate (625.8 mg, 2.93 mmol) and 96% sulfuric acid (287.4 mg, 2.93 mmol) over 10 minutes at room temperature under nitrogen stream. After the reaction solution was stirred at the same temperature for 5 minutes, ethyl acetate was added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate two times. The combined extracts were dried with sodium sulfate. The solvent was distilled off, and the resulting oil was purified by silica gel column chromatography. From fraction eluted with n-hexane-ethyl acetate (1:1, v/v), 303.2 mg (yield 75%) of compound 1D was obtained as an oil.
1H-NMR (CDCl3) δ: 1.39 (3H, t, J=6.9 Hz), 4.40 (2H, q, J=6.9 Hz), 5.54 (2H, s), 7.37 (5H, s), 8.48 (1H, s), 9.85 (1H, s).
Fourth Step
To a MeCN (15 ml) solution of compound 1D (1.00 g, 3.31 mmol) was added an aqueous solution (10 ml) of 96% sulfuric acid (421.7 mg, 4.30 mmol) and amidosululic acid (642.7 mg, 6.62 mmol) at room temperature, the mixture was stirred, and an aqueous solution (10 ml) of sodium chlorite (388.9 mg, 4.30 mmol) was added dropwise over 5 minutes while the same temperature was retained. After the reaction solution was stirred at the same temperature for 5 minutes, an aqueous saturated sodium chloride solution was added, and the mixture was extracted with ethyl acetate three times. The combined extracts were dried with sodium sulfate. The solvent was distilled off, and the resulting oil was purified by silica gel column chromatography. The materials were eluted firstly with chloroform and, then, with chloroform-MeOH (7:3, v/v). Concentration of objective fraction afforded 748.8 mg (yield 71%) of compound 1E as an oil.
1H-NMR (CDCl3) δ: 1.40 (3H, t, J=7.2 Hz), 3.93 (1H, br s), 4.40 (2H, q, J=7.2 Hz), 5.61 (2H, s), 7.38-7.44 (10H, m), 8.52 (1H, s).
Fifth Step
To a DMF (10 ml) solution of compound 1E (1.00 g, 3.14 mmol) were added WSC HCl (1.20 g, 6.28 mmol) and HOBt (551.6 mg, 4.08 mmol) at room temperature, and the mixture was stirred at the same temperature for 90 minutes. The reaction solution was cooled to 0° C., and a DMF (2 ml) solution of 2-methoxyethanamine (236.0 mg, 3.14 mmol) was added dropwise over 3 minutes. The reaction solution was stirred at the same temperature for 1 hour, water was added, and the mixture was extracted with ethyl acetate three times. The extract was washed with water three times, and dried with sodium sulfate. The solvent was distilled off, and the resulting oil was purified by silica gel chromatography. The materials were eluted firstly with n-hexane-ethyl acetate (1:1, v/v) and, then, with n-hexane-ethyl acetate (1:9, v/v). Concentration of objective fraction afforded 928.5 mg (yield 79%) of compound 1F as an oil.
1H-NMR (CDCl3) δ: 1.39 (3H, t, J=7.2 Hz), 3.29 (3H, s), 3.41 (2H, t, J=5.4 Hz), 3.47-3.53 (2H, m), 4.39 (2H, q, J=7.2 Hz), 5.44 (2H, s), 7.36 (3H, m), 7.44-7.47 (2H, m), 8.07 (1H, br s), 8.54 (1H, s).
Sixth Step
A xylene (2 ml) solution of compound 1F (500 mg, 1.33 mmol) and (S)-2-amino-3-phenylpropan-1-ol (604.2 mg, 4.0 mmol) was heated to 120° C., and stirred for 30 minutes. After the reaction solution was cooled to room temperature, and the solvent was distilled off, the resulting oil was purified by silica gel chromatography. The materials were eluted firstly with chloroform and, then, with chloroform-MeOH (9:1, v/v). Concentration of objective fraction afforded 487 mg (yield 72%) of compound 1G as an oil.
1H-NMR (CDCl3) δ: 1.41 (3H, t, J=6.9 Hz), 2.24-2.34 (1H, m), 2.24-3.00 (1H, m), 3.03-3.16 (1H, m), 3.05 (3H, m), 3.25-3.32 (2H, m), 4.13-4.19 (1H, m), 4.17-4.30 (1H, m), 4.36-4.47 (1H, m), 4.51-4.54 (1H, m), 4.55 (1H, d, J=10.5 Hz), 5.78 (1H, t, J=6.9 Hz), 7.17-7.26 (4H, m), 7.28-7.35 (5H, m), 7.49 (1H, t, J=5.4 Hz), 6.32 (1H, s).
Seventh Step
To a THF (6 ml) solution of compound 1G (2.86 g, 5.63 mmol) and triphenylphosphine (2.21 g, 8.45 mmol) was added dropwise a DEAD 40 wt % toluene solution (3.68 g, 8.45 mmol) at room temperature over 3 minutes. The reaction solution was stirred at the same temperature for 30 minutes, the solvent was distilled off, and the resulting oil was purified by silica gel chromatography. From a fraction eluted with ethyl acetate-MeOH (9:1, v/v), 1.37 g (yield 50%) of compound 1H was obtained as an oil.
1H-NMR (CDCl3) δ: 1.31 (3H, t, J=7.2 Hz), 3.07 (2H, d, J=6.9 Hz), 3.33 (3H, s), 3.57-3.80 (4H, m), 3.95 (1H, dd, J=3.0 Hz, 6.6 Hz), 4.01-4.14 (1H, m), 4.16-4.34 (2H, m), 5.24 (1H, d, J=9.9 Hz), 5.51 (1H, d, J=9.9 Hz), 7.01-7.03 (2H, m), 7.21-7.37 (5H, m), 7.41-7.58 (1H, m), 7.64-7.69 (2H, m).
Eighth Step
To an EtOH (6 ml) solution of compound 1H (1.0 g, 2.04 mmol) was added a 2N aqueous sodium hydroxide solution (6 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was neutralized with 2N hydrochloric acid, and the precipitated solid was filtered, and dried to obtain 754 mg (yield 80%) of compound 11.
1H-NMR (CDCl3) δ: 3.10 (2H, d, J=7.8 Hz), 3.33 (3H, s), 3.57-3.69 (4H, m), 3.82-3.90 (1H, m), 3.95 (1H, dd, J=3.3 Hz, 13.8 Hz), 4.36 (1H, dd, J=6.3 Hz, 7.5 Hz), 5.36 (1H, d, J=10.2 Hz), 5.45 (1H, d, J=10.2 Hz), 6.98-7.01 (2H, m), 7.28-7.39 (6H, m), 7.59 (2H, dd, J=1.8 Hz, 8.1 Hz), 7.87 (1H, s).
Ninth Step
Compound 1I (1.0 g, 2.16 mmol) was dissolved in THF (10 ml), 10% Pd—C (200 mg) was added, and the mixture was subjected to a catalytic reduction under hydrogen stream. The catalyst was removed by filtration, and the filtrate was concentrated. The resulting residue was washed with ether to obtain 512 mg (yield 64%) of compound 1.
1H-NMR (CDCl3) δ: 6.24 (2H, d, J=6.3 Hz), 3.36 (3H, s), 3.60-3.86 (5H, m), 4.14 (1H, d, J=12.9 Hz), 4.47 (1H, s), 7.03-7.05 (2H, m), 7.30-7.35 (3H, m), 7.88 (1H, s), 12.68 (1H, s), 14.83 (1H, s).
EXAMPLE 2







First Step

To (S)-tert-butyl 3-hydroxy-1,1-diphenylpropan-2-ylcarbamate (5.00 g, 15.3 mmol) was added trifluoroacetic acid (40 ml), and the mixture was stirred for 1 hour under ice-cooling. After trifluoroacetic acid was distilled off, toluene was added, and distilled off again under reduced pressure to obtain crude (S)-2-amino-3,3-diphenylpropan-1-ol. To the resulting (S)-2-amino-3,3-diphenylpropan-1-ol were added compound 1F (5.73 g, 15.3 mmol), toluene (50 ml), and triethylamine (6.4 ml, 45.8 mmol), the mixture was stirred at 90° C. for 1 hour, and cooled to room temperature and, thereafter, the solvent was distilled off. To the resulting residue was added dichloromethane, and the mixture was washed with 2N hydrochloric acid, an aqueous saturated sodium bicarbonate solution, and an aqueous saturated sodium chloride solution. After separation of the organic layer, after magnesium sulfate was added, the mixture was filtered with celite, and the filtrate was distilled off to obtain candy-like compound 2A (9.12 g).
MS: m/z=585.2 [M+H]+.
Second Step
The compound 2A (8.60 g, 14.7 mmol) and triphenylphosphine (7.72 g, 29.4 mmol) were dissolved in tetrahydrofuran (90 ml), and a 2.2M toluene solution of diethyl azodicarboxylate (10.0 ml, 22.0 mmol) was added dropwise under ice-cooling. After the mixture was stirred for 2 hours under ice-cooling, and for 18 hours under room temperature, the solvent was distilled off. The resulting residue was purified by silica gel column chromatography to obtain foamy compound 2B (3.88 g, 6.85 mmol).
1H-NMR (DMSO-d6) δ: 1.18 (3H, m), 3.11 (3H, s), 3.16 (1H, m), 3.28 (1H, m), 3.76 (1H, m), 3.97-4.13 (3H, m), 4.31 (1H, d, J=11.3 Hz), 5.08 (2H, s), 5.52 (1H, d, J=12.0 Hz), 7.18-7.25 (6H, m), 7.25-7.45 (6H, m), 7.55-7.66 (6H, m).
MS: m/z=567.7 [M+H]+.
Third Step
To compound 2B (3.4 g, 6.0 mmol) were added ethanol (36 ml), water (12 ml), and a 2N aqueous sodium hydroxide solution (4.5 ml, 9.0 mmol), and the mixture was stirred at room temperature for 40 minutes, thereafter, ethanol (10 ml) and water (10 ml) were added, and the mixture was further stirred for 30 minutes. Ethanol was distilled off, ethyl acetate and water were added, and the mixture was stirred vigorously and, thereafter, layers were separated. The ethyl acetate layer was washed with 2N sodium hydroxide three times, and the aqueous layers were combined into one aqueous layer. To the aqueous layer was added ethyl acetate, the mixture was neutralized using 2N hydrochloric acid, then the mixture was stirred vigorously and, thereafter, the ethyl acetate layer was separated. To the ethyl acetate layer was added magnesium sulfate, the mixture was filtered with celite, and the filtrate was distilled off. The resulting residue was dissolved in MeOH, and the solvent was distilled off to obtain a solid of compound 2C (3.0 g, 5.64 mmol).
1H-NMR (DMSO-d6) δ: 3.11 (3H, s), 3.16 (1H, m), 3.25 (1H, m), 3.75 (1H, m), 4.11 (1H, m), 4.36 (1H, d, J=11.6 Hz), 5.18 (2H, dd, J=15.7 Hz, 10.4 Hz), 5.71 (1H, d, J=11.6 Hz), 7.08-7.20 (5H, m), 7.29-7.45 (6H, m), 7.55 (2H, d, J=6.7 Hz), 7.61 (2H, d, J=7.5 Hz), 7.98 (1H, s).
MS: m/z=539.4 [M+H]+.
Fourth Step
To compound 2C (1.50 g, 2.79 mmol) were added methanol (22 ml), and 10% palladium carbon-50% wet (150 mg), and the mixture was stirred for 1 hour under hydrogen atmosphere. Ethyl acetate (44 ml) was added, the mixture was filtered with celite, and the filtrate was distilled off. The resulting residue was dissolved in methanol (20 ml), water (10 ml) was added, and methanol was distilled off. The precipitate was filtered, and dried to obtain compound 2 (1.15 g, 2.56 mmol).
1H-NMR (DMSO-d6) δ: 3.15 (3H, s), 3.50-3.70 (5H, m), 4.19 (1H, dd, J=13.8 Hz, 3.1 Hz), 4.49 (1H, d, J=11.6 Hz), 5.78 (1H, d, J=9.6 Hz), 7.10-7.27 (6H, m), 7.34 (1H, m), 7.46 (2H, t, J=7.5 Hz), 7.63 (2H, t, J=7.7 Hz), 7.94 (1H, s), 12.94 (1H, s), 15.08 (1H, s).
MS: m/z=449.4 [M+H]+.
EXAMPLE 3




According to Example 2, compound 3 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 3.15 (1H, m), 3.26 (3H, s), 3.52-3.70 (4H, m), 3.70-3.80 (2H, m), 4.10 (1H, d, J=12.9 Hz), 4.92 (1H, brs), 6.98 (1H, t, J=7.4 Hz), 7.03 (1H, brs), 7.08 (1H, t, 7.6 Hz), 7.34 (1H, d, J=7.8 Hz), 7.47 (1H, d, J=7.3 Hz), 7.80 (1H, s), 10.94 (1H, brs), 15.38 (1H, brs).
MS: m/z=412.4 [M+H]+.
EXAMPLE 4




According to Example 2, compound 4 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 3.13 (3H, s), 3.46-3.72 (5H, m), 4.16 (1H, d, J=12.6 Hz), 4.48 (1H, d, J=10.9 Hz), 5.77 (1H, d, J=11.6 Hz), 7.10-7.27 (6H, m), 7.32 (1H, m), 7.44 (2H, m), 7.61 (2H, m), 7.93 (1H, s), 15.04 (1H, s).
MS: m/z=449.3 [M+H]+.
EXAMPLE 5




According to Example 2, compound 5 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 3.28 (3H, s), 3.52-3.68 (4H, m), 4.06 (1H, m), 4.25 (2H, m), 4.41 (1H, brs), 4.56 (1H, d, J=13.6 Hz), 4.82 (1H, d, J=13.9 Hz), 6.74 (2H, d, J=7.6 Hz), 6.92 (1H, t, J=7.20 Hz), 7.25 (2H, t, J=7.8 Hz), 8.58 (1H, s), 12.48 (1H, brs), 15.55 (1H, brs).
MS: m/z=389.4 [M+H]+.
EXAMPLE 6




According to Example 2, compound 6 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 3.16 (1H, m), 3.26 (3H, s), 3.50-3.70 (4H, m), 3.70-3.80 (2H, m), 4.10 (1H, d, J=13.4 Hz), 4.92 (1H, brs), 6.98 (1H, t, J=7.1 Hz), 7.03 (1H, brs), 7.08 (1H, t, J=7.3 Hz), 7.34 (1H, d, J=7.8 Hz), 7.48 (1H, d, J=7.3 Hz), 7.81 (1H, s), 12.91 (1H, s), 15.36 (1H, s).
MS: m/z=412.4 [M+H]+.
EXAMPLE 7




According to Example 2, compound 7 was synthesized by the same method.
1H-NMR (DMSO-d6) δ: 0.85-0.95 (2H, m), 1.05-1.25 (5H, m), 1.45-1.80 (8H, m), 3.28 (3H, s), 3.46 (1H, m), 3.58 (1H, m), 3.72 (1H, d, J=13.9 Hz), 3.93 (1H, m), 4.04 (1H, d, J=13.1 Hz), 4.88 (1H, s), 8.56 (1H, s), 12.80 (1H, s), 15.51 (1H, s).
MS: m/z=379.3 [M+H]+.
EXAMPLE 8




According to Example 2, compound 8 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 2.07 (2H, m), 2.55 (1H, m), 2.74 (1H, m), 3.17 (1H, s), 3.23 (3H, s), 3.48-3.65 (4H, m), 3.79 (1H, d, J=13.6 Hz), 3.87 (1H, m), 4.09 (1H, d, J=13.6 Hz), 4.80 (1H, s), 7.10-7.29 (5H, m), 8.59 (1H, s), 12.77 (1H, s), 15.49 (1H, s).
MS: m/z=387.3 [M+H]+.
EXAMPLE 9




According to Example 2, compound 9 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 2.80 (1H, dd, J=14.5 Hz, J2=8.5 Hz), 2.93 (1H, dd, J=14.4 Hz, 5.6 Hz), 3.21 (3H, s), 3.40-3.55 (4H, m), 3.77 (2H, s), 3.82 (1H, d, J=13.1 Hz), 3.88 (1H, m), 4.13 (1H, d, J=13.6 Hz), 4.85 (1H, s), 7.20-7.35 (5H, m), 8.61 (1H, s), 12.79 (1H, s), 15.43 (1H, s).
MS: m/z=419.3 [M+H]+.
EXAMPLE 10




According to Example 2, compound 10 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 1.22 (3H, d, J=6.2 Hz), 3.29 (3H, s), 3.43 (1H, m), 3.58 (2H, m), 3.94 (1H, m), 4.12 (1H, brs), 4.41 (1H, d, J=13.6 Hz), 4.49 (1H, d, J=13.1 Hz), 8.59 (1H, s), 12.65 (1H, s), 15.53 (1H, s).
MS: m/z=297.2 [M+H]+.
EXAMPLE 11




According to Example 2, compound 11 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 1.46 (4H, brs), 1.76-1.90 (2H, m), 2.22 (1H, brs), 3.27 (3H, s), 3.57 (1H, d, J=5.3 Hz), 4.07 (1H, m), 4.69 (1H, m), 8.47 (1H, s), 13.04 (1H, s), 15.52 (1H, s).
MS: m/z=337.2 [M+H]+.
EXAMPLE 12







First Step

Compound 12A (1.53 g, 5.80 mmol) were dissolved in THF (6 ml) and water (6 ml), potassium carbonate (2.41 g, 17.4 mmol) was added, the mixture was stirred, and benzyl chloroformate (1.09 g, 6.38 mmol) was added dropwise at 0° C. After stirring at 0° C. for 10 minutes, the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into sodium bicarbonate water, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and an aqueous saturated sodium chloride solution, and dried with sodium sulfate. The solvent was distilled off to obtain 2.32 g of compound 12B as a colorless gummy solid.
1H-NMR (CDCl3) δ: 1.98 (1H, brs), 3.55 (1H, m), 3.75 (1H, m), 4.20 (1H, d, J=10.5 Hz), 4.58 (1H, m), 4.83 (1H, brs), 5.07 (2H, s), 7.16-7.39 (15H, m).
Second Step
The compound 12B (1.94 g, 5.37 mmol), triphenylphosphine (2.11 g, 8.05 mmol) and phthalimide (948 mg, 6.44 mmol) were added to THF (20 ml), and diisopropyl azodicarboxylate (2.2M in toluene, 3.66 ml, 8.05 mmol) was added dropwise at room temperature. After stirring at room temperature for 4 hours, the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (n-hexane-ethyl acetate, 1:1, v/v) to obtain 2.39 g of compound 12C as a colorless solid.
1H-NMR (CDCl3) δ: 3.73 (2H, m), 4.05 (1H, d, J=10.1 Hz), 4.70 (1H, d, J=9.6 Hz), 4.77 (2H, d, J=7.2 Hz) 5.02 (1H, m), 7.03-7.42 (15H, m), 7.68 (2H, dd, J=5.7, 2.1 Hz), 7.78 (2H, dd, J=5.7, 2.1 Hz).
Third Step
The compound 12C (2.39 g, 4.87 mmol) was added to THF (20 ml) and methanol (20 ml), hydrazine hydrate (4.88 g, 97.4 mmol) was added, and the mixture was stirred at 50° C. for 4 hours. The white precipitate was removed by filtration, and washed with methanol. After the filtrate was distilled off under reduced pressure, the resulting crude product was purified by amino column chromatography (chloroform-methanol, 99:1, v/v) to obtain 1.41 g of compound 12D as a colorless solid.
1H-NMR (CDCl3) δ: 2.63 (1H, dd, J=13.2, 5.8 Hz), 2.86 (1H, d, J=9.9 Hz), 4.07 (1H, d, J=10.4 Hz), 4.53 (1H, m), 4.81 (1H, m), 5.00 (2H, d, 8.4 Hz), 7.20-7.36 (10H, m).
Fourth Step
Compound 12D (1.41 g, 3.91 mmol) was dissolved in THF (15 ml), and Boc2O (896 mg, 4.11 mmol) was added at room temperature. After stirring for 1.5 hours, the solvent was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (n-hexane-ethyl acetate, 1:1, v/v) to obtain 1.77 g of compound 12E as a colorless solid.
1H-NMR (CDCl3) δ: 1.41 (9H, s), 3.23 (2H, brm), 3.97 (1H, d, J=9.8 Hz), 4.58-4.80 (3H, m), 5.00 (2H, d, J=9.8 Hz), 7.15-7.29 (10H, m).
Fifth Step
Compound 12E (1.73 g, 3.76 mmol) and palladium-active carbon (10%, wet, 200 mg) were added to methanol (20 ml), and the mixture was stirred at room temperature for 1 hour under hydrogen atmosphere. After filtration with celite, the solvent was concentrated under reduced pressure to obtain 1.01 g of a colorless oily substance 12F.
1H-NMR (CDCl3) δ: 1.44 (9H, s), 2.82 (1H, m), 3.31 (1H, m), 3.73 (2H, d, J=6.9 Hz), 4.98 (1H, s), 7.18-7.39 (10H, m).
Sixth Step
Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (974 mg, 3.06 mmol) obtained by the method shown in Reference Example 1, and 12F (999 mg, 3.06 mmol) were added to toluene (10 ml), and the mixture was stirred at 110° C. for 5 hours. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 98:2, v/v) to obtain 1.51 g of compound 12G as a pale yellow solid.
1H-NMR (CDCl3) δ: 1.36 (9H, s), 3.40 (1H, m), 3.53 (1H, m), 3.82 (3H, s), 3.91 (3H, s), 4.29 (1H, d, J=11.3 Hz), 4.78 (1H, m), 4.82 (1H, m), 5.11 (1.9H, d, J=7.5 Hz), 7.10-7.38 (10H, m), 8.27 (1H, s).
Seventh Step
To compound 12G (1.45 g, 2.31 mmol) was added 4N HCl (ethyl acetate solution, 20 ml), and the mixture was stirred at room temperature for 1.5 hours. After the solvent was distilled off under reduced pressure, sodium bicarbonate water was added, and the mixture was stirred at room temperature for 1.5 hours. This was extracted with chloroform, and dried with sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 95:5, v/v) to obtain 1.01 g of compound 12H as a colorless solid.
1H-NMR (CDCl3) δ: 3.40 (1H, dd, J=13.6, 6.6 Hz), 3.78 (3H, s), 3.80 (1H, m), 4.37 (1H, d, J=11.6 Hz), 4.59 (1H, d, J=11.0 Hz), 5.43 (2H, d, J=10.2 Hz), 5.93 (1H, d, J=5.8 Hz), 7.03-7.21 (5H, m), 7.37 (9H, m), 7.63 (2H, m).
Eighth Step
Compound 12H (50 mg, 0.10 mmol) was dissolved in DMF (1 ml), and cesium carbonate (165 mg, 0.50 mmol) was added. After stirring at room temperature for 30 minutes, iodomethane (0.032 ml, 0.50 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate, and dried with sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 95:5, v/v) to obtain 49 mg of compound 12I as a colorless solid.
Ninth Step
Compound 12I (49 mg, 0.096 mmol) was dissolved in THF (0.5 ml) and methanol (0.5 ml), a 2N aqueous sodium hydroxide solution (0.24 ml, 0.48 mmol) was added at room temperature, and the mixture was stirred for 1.5 hours. After 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate, the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, 54 mg of compound 12J was obtained as a colorless solid.
MS: m/z=481 [M+H]+.
Tenth Step
To compound 12J obtained in the ninth step was added trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, pH was adjusted to 3 with sodium bicarbonate water and 2N hydrochloric acid, and the mixture was extracted with chloroform, and dried with sodium sulfate. After the solvent was distilled off under reduced pressure, chloroform-methanol-ethyl ether were added, and the precipitated solid was filtered to obtain 26 mg of compound 12 as a colorless solid.
1H-NMR (DMSO-d6) δ: 3.01 (3H, s), 3.26 (1H, t, J=14.4 Hz), 4.23 (1H, dd, J=13.5, 3.8 Hz), 4.57 (1H, d, J=11.6 Hz), 5.78 (1H, d, J=11.3 Hz), 7.16-7.70 (10H, m), 8.00 (1H, s), 13.00 (1H, s), 15.10 (1H, s).
MS: m/z=405 [M+H]+.
EXAMPLE 13




According to Example 12, compound 13 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 1.05 (3H, t, J=6.9 Hz), 3.43-3.65 (3H, m), 4.22 (1H, d, J=10.6 Hz), 4.55 (1H, d, J=11.6 Hz), 5.81 (1H, d, J=10.1 Hz), 7.15-7.68 (10H, m), 7.97 (1H, s), 12.96 (1H, s), 15.07 (1H, s).
MS: m/z=463 [M+H]+.
EXAMPLE 14




According to Example 12, compound 14 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 0.98 (3H, t, J=7.17 Hz), 3.44-3.64 (3H, m), 4.15 (1H, dd, J=13.7, 3.5 Hz), 4.45 (1H, d, J=11.6 Hz), 5.79 (1H, d, J=12.2 Hz), 7.08-7.63 (10H, m), 7.89 (1H, s), 13.01 (1H, s), 15.06 (1H, s).
MS: m/z=419 [M+H]+.
EXAMPLE 15




According to Example 12, compound 15 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 3.22 (1H, s), 3.47 (1H, d, J=13.3 Hz), 4.17 (2H, m), 4.44 (2H, dd, J=16.7, 3.0 Hz), 5.79 (1H, d, J 12.2 Hz), 7.10-7.64 (10H, m), 7.98 (1H, s), 12.56 (1H, s), 15.05 (1H, brs).
EXAMPLE 16




According to Example 12, compound 16 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 3.24 (1H, d, J=13.2 Hz), 4.23 (1H, m), 4.25 (1H, d, J=14.7 Hz), 4.40 (1H, d, J=14.8 Hz), 4.92 (1H, d, J=15.4 Hz), 5.79 (1H, m), 7.03-7.48 (10H, m), 7.93 (1H, s), 12.82 (1H, s), 15.06 (1H, s).
EXAMPLE 17




According to Example 12, compound 17 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 3.23 (1H, d, J=13.4 Hz), 4.22 (1H, m), 4.25 (1H, d, J=12.0 Hz), 4.45 (1H, d, J=14.9 Hz), 4.93 (1H, d, J=15.3 Hz), 5.77 (1H, d, J=11.6 Hz), 7.09-7.56 (10H, m), 7.92 (1H, s), 12.74 (1H, s), 15.06 (1H, s).
EXAMPLE 18




According to Example 12, compound 18 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 1.63 (2H, m), 3.20 (3H, s), 3.44 (5H, m), 4.19 (1H, d, J=10.2 Hz), 4.51 (1H, d, J=11.8 Hz), 5.80 (1H, d, J=11.0 Hz), 7.13-7.65 (10H, m), 7.93 (1H, s), 13.02 (1H, s).
MS: m/z=463 [M+H]+.
EXAMPLE 19




According to Example 12, compound 19 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 3.15 (1H, d, J=9.5 Hz), 3.95 (1H, dd, J=13.5, 3.4 Hz), 4.51 (1H, d, J=11.6 Hz), 5.74 (1H, d, J=11.1 Hz), 7.11-7.62 (10H, m), 7.93 (1H, s), 9.34 (1H, s), 12.97 (1H, s), 15.07 (1H, brs).
MS: m/z=391 [M+H]+.
EXAMPLE 20




According to Example 12, compound 20 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 3.26 (1H, m), 4.24 (1H, m), 4.27 (1H, d, J=12.0 Hz), 4.41 (1H, d, J=14.8 Hz), 4.87 (1H, d, J=14.9 Hz), 5.75 (1H, d, J=7.6 Hz), 7.09-7.77 (12H, m), 7.93 (1H, s), 8.52 (2H, m), 12.79 (1H, s), 15.07 (1H, brs).
MS: m/z=482 [M+H]+.
EXAMPLE 21




According to Example 12, compound 21 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 0.62 (3H, d, J=6.9 Hz), 0.82 (3H, d, J=6.6 Hz), 3.18 (1H, m), 3.75 (1H, d, J=10.2 Hz), 4.25 (1H, d, J=11.8 Hz), 4.58 (1H, m), 5.65 (1H, d, J=11.3 Hz), 6.89-7.43 (10H, m), 7.67 (1H, s), 12.94 (1H, s).
MS: m/z=433 [M+H]+.
EXAMPLE 22




According to Example 12, compound 22 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 1.07-1.70 (5H, m), 3.04-3.34 (5H, m), 3.82 (2H, dm), 4.18 (1H, d, J=10.2 Hz), 4.42 (1H, d, J=12.0 Hz), 5.81 (1H, d, J=11.7 Hz), 7.11-7.59 (10H, m), 7.86 (1H, s), 12.96 (1H, s), 15.07 (1H, brs).
MS: m/z=489 [M+H]+.
EXAMPLE 23




According to Example 12, compound 23 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 0.01-0.79 (5H, m), 3.05 (1H, dd, J=14.1, 7.5 Hz), 3.49-3.59 (2H, m), 4.16 (1H, dd, J=14.0, 3.3 Hz), 4.50 (1H, d, J=11.9 Hz), 5.82 (1H, d, J=11.1 Hz), 7.11-7.62 (10H, m), 7.89 (1H, s), 12.99 (1H, s), 15.07 (1H, brs).
MS: m/z=445 [M+H]+.
EXAMPLE 24




According to Example 12, compound 24 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 3.23 (1H, d, J=13.7 Hz), 4.16 (1H, dd, J=13.2, 3.3 Hz), 4.19 (2H, d, J=12.0 Hz), 4.38 (1H, d, J=14.6 Hz), 4.84 (1H, d, J=14.6 Hz), 5.72 (1H, d, J=11.4 Hz), 7.08-7.33 (15H, m), 7.98 (1H, s), 12.88 (1H, s), 15.07 (1H, s).
MS: m/z=481 [M+H]+.
EXAMPLE 25




According to Example 12, compound 25 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 2.39 (3H, s), 3.37 (1H, m), 4.21 (1H, dd, J=14.4, 3.9 Hz), 4.40 (1H, dd, J=11.7 Hz), 4.45 (1H, d, J=15.3 Hz), 4.81 (1H, d, J=15.4 Hz), 5.78 (1H, d, J=12.0 Hz), 6.30 (1H, s), 7.09-7.42 (10H, m), 7.95 (1H, s), 12.65 (1H, s), 15.07 (1H, s).
MS: m/z=486 [M+H]+.
EXAMPLE 26




According to Example 12, compound 26 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 1.20-1.77 (6H, m), 3.11-3.61 (6H, m), 4.21 (1H, d, J=9.9 Hz), 4.53 (1H, d, J=11.7 Hz), 5.80 (1H, d, J=11.8 Hz), 7.14-7.65 (10H, m), 7.95 (1H, s), 12.95 (1H, brs), 15.06 (1H, brs).
MS: m/z=489 [M+H]+.
EXAMPLE 27




According to Example 12, compound 27 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 3.36 (1H, m), 4.28 (1H, d, J=12.0 Hz), 4.54 (1H, d, J=11.4 Hz), 4.62 (1H, d, J=15.3 Hz), 4.79 (1H, d, J=15.4 Hz), 5.77 (1H, d, J=9.9 Hz), 7.09-7.79 (13H, m), 7.98 (1H, s), 8.46 (1H, d, J=4.6 Hz), 12.82 (1H, brs), 15.06 (1H, brs).
MS: m/z=482 [M+H]+.
EXAMPLE 28







First Step

Compound 28A (3.20 g, 17.1 mmol) was added to THF (20 ml), triethylamine (2.60 ml, 18.8 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. After Boc2O (4.09 g, 18.8 mmol) was added at room temperature, the mixture was stirred for 2 hours. The solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, and dried with sodium sulfate. The solvent was distilled off under reduced pressure to obtain 5.17 g of compound 28B as a colorless solid.
1H-NMR (CDCl3) δ: 1.52 (9H, s), 2.77 (2H, m), 3.03-3.12 (1H, m), 3.38 (1H, m), 3.90-3.98 (1H, m), 4.93 (1H, brs), 7.20-7.35 (5H, m).
Second Step
Compound 28B (4.29 g, 17.1 mmol), triphenylphosphine (5.37 g, 20.5 mmol) and phthalimide (2.76 g, 18.8 mmol) were added to THF (60 ml), and diethyl azodicarboxylate (2.2M in toluene, 11.6 ml, 25.6 mmol) was added dropwise at room temperature. After the mixture was stirred at room temperature for 1 hour, the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (n-hexane-ethyl acetate, 2:1, v/v) to obtain 6.13 g of compound 28C as a colorless solid.
1H-NMR (CDCl3) δ: 1.30 (9H, s), 3.14 (1H, dd, J=13.8, 6.2 Hz), 3.39 (2H, m), 3.87 (1H, m), 4.67 (1H, m), 4.81 (1H, brs), 7.16-7.19 (5H, m), 7.66 (2H, dd, J=5.3, 3.1 Hz), 7.75 (2H, dd, J=5.7, 3.0 Hz).
Third Step
Compound 28C (1.00 g, 2.63 mmol) was added to THF (7 ml) and methanol (7 ml), hydrazine hydrate (2.63 g, 52.6 mmol) was added, and the mixture was stirred at 50° C. for 2 hours. The white precipitate was removed by filtration, and washed with methanol. After the filtrate was distilled off under reduced pressure, the resulting crude product was purified by amino column chromatography (chloroform-methanol, 99:1, v/v) to obtain 249 mg of compound 28D as a colorless solid.
1H-NMR (CDCl3) δ: 1.44 (9H, s), 1.95 (2H, brs), 2.55-3.31 (5H, m), 5.06 (1H, brs), 7.18-7.33 (5H, m).
Fourth Step
Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (313 mg, 0.983 mmol) and 28D (246 mg, 0.983 mmol) were added to toluene (3 ml), and the mixture was stirred at 100° C. for 2.5 hours. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 98:2, v/v) to obtain 320 mg of compound 28E as a pale yellow gummy substance.
1H-NMR (CDCl3) δ: 1.42 (9H, s), 3.07 (2H, m), 3.56 (2H, m), 3.68 (3H, s), 3.95 (3H, s), 4.26 (1H, s), 4.86 (1H, s), 5.18 (1H, d, J=10.8 Hz), 5.22 (1H, d, J=10.8 Hz), 7.01 (2H, m), 7.24-7.38 (8H, m), 8.22 (1H, s).
MS: m/z=551 [M+H]+.
Fifth Step
To compound 28E (315 mg, 0.572 mmol) was added 4N HCl (ethyl acetate solution, 5 ml), and the mixture was stirred at room temperature for 30 minutes. After the solvent was distilled off under reduced pressure, aqueous sodium bicarbonate water was added, and the mixture was extracted with chloroform, and dried with sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 95:5, v/v) to obtain 210 mg of compound 28F as a colorless solid.
1H-NMR (CDCl3) δ: 3.07-3.15 (2H, m), 3.34 (1H, dd, J=13.2, 6.0 Hz), 3.74 (2H, m), 3.86 (3H, s), 4.12 (1H, m), 5.27 (1H, d, J=10.1 Hz), 5.47 (1H, d, J=10.1 Hz), 6.76 (1H, d, J=6.4 Hz), 7.04 (2H, m), 7.32 (6H, m), 7.62 (2H, dd, J=7.7, 1.4 Hz), 7.70 (1H, s).
MS: m/z=419 [M+H]+.
Sixth Step
Compound 28F (50 mg, 0.12 mmol) was dissolved in DMF (1 ml), and cesium carbonate (195 mg, 0.597 mmol) was added. After the mixture was stirred at room temperature for 30 minutes, iodoethane (0.048 ml, 0.60 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate, and dried with sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 95:5, v/v) to obtain 47 mg of compound 28G as a colorless solid.
1H-NMR (CDCl3) δ: 1.22 (3H, t, J=7.2 Hz), 3.00-3.15 (2H, m), 3.28 (1H, dd, J=13.6, 1.6 Hz), 3.48 (1H, m), 3.75 (1H, m), 3.85 (3H, s), 3.88 (1H, dd, J=13.3, 3.2 Hz), 4.15 (1H, m), 5.25 (1H, d, J=9.9 Hz), 5.50 (1H, d, J=9.9 Hz), 7.04 (2H, m), 7.29-7.38 (6H, m), 7.60 (1H, s), 7.68 (2H, m).
MS: m/z=447 [M+H]+.
Seventh Step
Compound 28G (47 mg, 0.11 mmol) was dissolved in THF (0.5 ml) and methanol (0.5 ml), a 2N aqueous sodium hydroxide solution (0.26 ml, 0.53 mmol) was added at room temperature, and the mixture was stirred for 1 hour. After 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate, the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, 40 mg of compound 28H was obtained as a colorless solid.
MS: m/z=433 [M+H]+.
Eighth Step
To compound 28H obtained in the seventh step was added trifluoroaceteic acid (1 ml), and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, pH was adjusted to 3 with sodium bicarbonate water and 2N hydrochloric acid, the mixture was extracted with chloroform, and the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, chloroform-methanol-ethyl ether were added, and the precipitated solid was filtered to obtain 17 mg of compound 28 as a colorless solid.
1H-NMR (DMSO-d6) δ: 1.17 (3H, t, J=7.2 Hz), 3.08 (2H, m), 3.51-3.63 (3H, m), 4.08 (1H, dd, J=13.6, 3.9 Hz), 5.03 (1H, brs), 7.21 (5H, m), 8.07 (1H, s), 12.98 (1H, s), 15.07 (1H, brs).
MS: m/z=343 [M+H]+.
EXAMPLE 29




According to Example 28, compound 29 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 2.96 (2H, d, J=7.6 Hz), 3.46 (1H, d, J=13.3 Hz), 4.06 (1H, dd, J=13.6, 3.8 Hz), 4.64 (1H, d, J=14.9 Hz), 4.89 (1H, d, J=14.6 Hz), 4.98 (1H, m), 6.97 (2H, m), 7.10-7.37 (5H, m), 7.57 (1H, m), 8.12 (1H, s), 12.75 (1H, s), 15.07 (1H, brs).
EXAMPLE 30




According to Example 28, compound 30 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 2.99 (2H, dd, J=7.5, 3.6 Hz), 3.48 (1H, d, J=13.4 Hz), 4.09 (1H, dd, J=13.4, 4.0 Hz), 4.73 (1H, d, J=15.1 Hz), 4.92 (1H, d, J=15.1 Hz), 4.99 (1H, m), 6.97 (2H, m), 7.18-7.29 (4H, m), 7.49 (1H, m), 7.61 (1H, m), 8.15 (1H, s), 12.69 (1H, s), 15.06 (1H, brs).
EXAMPLE 31




According to Example 28, compound 31 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 2.91 (2H, m), 3.45 (1H, d, J=13.1 Hz), 4.02 (1H, dd, J=13.6, 4.0 Hz), 4.57 (1H, d, J=14.6 Hz), 4.91 (1H, d, J=14.6 Hz), 4.93 (1H, m), 6.89 (2H, m), 7.18 (3H, m), 7.40 (5H, m), 8.16 (1H, s), 12.86 (1H, brs), 15.06 (1H, brs).
MS: m/z=405 [M+H]+.
EXAMPLE 32




According to Example 28, compound 32 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 3.10 (2H, m), 3.39 (1H, d, J=13.6 Hz), 3.84 (1H, dd, J=13.6, 4.0 Hz), 4.94 (1H, m), 7.23 (5H, m), 8.19 (1H, s), 9.44 (1H, brs), 12.97 (1H, s), 15.06 (1H, brs).
MS: m/z=315 [M+H]+.
EXAMPLE 33




According to Example 28, compound 33 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 1.09 (3H, t, J=6.9 Hz), 3.10 (2H, m), 3.42-3.50 (2H, m), 3.71 (5H, m), 4.11 (1H, dd, J=13.6, 3.8 Hz), 4.99 (1H, brs), 7.11-7.29 (5H, m), 7.99 (1H, s), 12.88 (1H, s), 15.06 (1H, brs).
MS: m/z=387 [M+H]+.
EXAMPLE 34




According to Example 28, compound 34 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 1.16 (3H, d, J=6.9 Hz), 1.21 (3H, d, J=6.9 Hz), 2.98 (1H, dd, J=13.6, 9.8 Hz), 3.13 (1H, dd, J=13.7, 5.8 Hz), 3.68 (1H, d, J=12.8 Hz), 3.87 (1H, dd, J=13.6, 3.7 Hz), 4.83 (1H, quin, J=6.8 Hz), 5.07 (1H, brs), 7.19 (5H, m), 7.90 (1H, s), 13.09 (1H, s), 15.08 (1H, brs).
MS: m/z=357 [M+H]+.
EXAMPLE 35




According to Example 28, compound 35 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 3.07 (3H, s), 3.14 (2H, m), 3.49 (1H, d, J=13.3 Hz), 4.08 (1H, dd, J=13.7, 4.0 Hz), 4.99 (1H, m), 7.13-7.31 (5H, m), 8.18 (1H, s), 12.95 (1H, s), 15.06 (1H, brs).
MS: m/z=329 [M+H]+.
EXAMPLE 36




First Step

Compound 12H (460 mg, 0.930 mmol) was dissolved in THF (2.5 ml) and methanol (2.5 ml), a 2N aqueous sodium hydroxide solution (2.33 ml, 4.65 mmol) was added at room temperature, and the mixture was stirred for 1.5 hours. After 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate, the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, 405 mg of compound 36A was obtained as a colorless solid.
1H-NMR (CDCl3) δ: 3.45 (1H, ddd, J=13.8, 6.9, 1.3 Hz), 3.80 (1H, dd, J=13.5, 2.1 Hz), 4.35 (1H, d, J=11.6 Hz), 4.77 (1H, d, J=11.3 Hz), 5.46 (1H, d, J=10.5 Hz), 5.52 (1H, d, J=10.5 Hz), 6.11 (1H, d, J=5.8 Hz), 6.94-6.98 (2H, m), 7.17 (3H, m), 7.31-7.46 (8H, m), 7.58 (3H, m).
Second Step
Compound 36A (402 mg, 0.837 mmol) was added to diphenyl ether (5 ml), and the mixture was stirred at 245° C. for 1 hour under microwave irradiation. The reaction solution was poured into n-hexane, and the precipitated solid was filtered. The resulting crude product was purified by amino column chromatography (chloroform-methanol, 99:1, v/v) to obtain 164 mg of compound 36B as a colorless solid.
1H-NMR (CDCl3) δ: 3.36 (1H, dd, J=13.0, 7.0 Hz), 3.72 (1H, d, J=11.1 Hz), 4.35 (1H, d, J=11.4 Hz), 4.49 (1H, d, J=10.2 Hz), 5.38 (1H, d, J=10.5 Hz), 5.43 (1H, d, J=10.4 Hz), 5.94 (1H, d, J=7.2 Hz), 6.29 (1H, d, J=6.6 Hz), 6.38 (1H, d, J=7.5 Hz), 6.99 (2H, m), 7.17 (3H, m), 7.36 (8H, m), 7.60 (2H, m).
Third Step
Compound 36B (40 mg, 0.092 mmol) was dissolved in DMF (1 ml), and cesium carbonate (179 mg, 0.55 mmol) was added. After stirring at room temperature for 30 minutes, iodomethane (0.029 ml, 0.46 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours. After the reaction solution was poured into water, and the mixture was extracted with ethyl acetate, the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 95:5, v/v) to obtain 44 mg of compound 36C as a colorless gummy substance.
Fourth Step
To compound 36C obtained in the third step was added trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, pH was adjusted to 6 with sodium bicarbonate water and 2N hydrochloric acid, the mixture was extracted with chloroform, and the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, chloroform-ethyl ether were added, and the precipitated solid was filtered to obtain 24 mg of compound 36 as a colorless solid.
1H-NMR (DMSO-d6) δ: 2.93 (3H, s), 3.17 (1H, d, J=13.0 Hz), 4.13 (1H, dd, J=13.6, 3.4 Hz), 4.47 (1H, d, J=11.4 Hz), 5.52 (1H, dd, J=9.3, 3.4 Hz), 5.99 (1H, d, J=7.3 Hz), 7.18 (4H, m), 7.30 (3H, m), 7.41 (2H, t, J=7.5 Hz), 7.60 (2H, d, J=7.2 Hz).
MS: m/z=361 [M+H]+.
EXAMPLE 37




According to Example 36, compound 37 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 3.16 (2H, d, J=13.3 Hz), 4.05 (1H, d, J=10.5 Hz), 4.15 (1H, d, J=11.7 Hz), 4.38 (1H, d, J=14.9 Hz), 4.74 (1H, d, J=14.5 Hz), 5.35 (1H, d, J=11.4 Hz), 5.65 (1H, d, J=7.3 Hz), 6.99 (1H, d, J=7.5 Hz), 7.21 (15H, m).
MS: m/z=437 [M+H]+.
EXAMPLE 38




According to Example 36, compound 38 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 1.57 (2H, m), 3.17 (3H, s), 3.21-3.31 (5H, m), 4.07 (1H, dd, J=13.5, 3.7 Hz), 4.36 (1H, d, J=11.6 Hz), 5.42 (1H, d, J=9.2 Hz), 5.61 (1H, d, J=7.3 Hz), 6.89 (1H, d, J=7.5 Hz), 7.13-7.31 (6H, m), 7.40 (2H, t, J=6.3 Hz), 7.57 (2H, d, J=7.3 Hz), 12.31 (1H, brs).
MS: m/z=419 [M+H]+.
EXAMPLE 39




According to Example 36, compound 39 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 3.12 (1H, dd, J=13.6, 5.5 Hz), 3.87 (1H, d, J=9.5 Hz), 4.44 (1H, d, J=11.7 Hz), 5.45 (1H, d, J=10.4 Hz), 5.83 (1H, d, J=7.5 Hz), 7.04 (1H, d, J=7.2 Hz), 7.14-7.31 (6H, m), 7.40 (2H, t, J=7.5 Hz), 7.58 (2H, d, J=7.5 Hz), 9.09 (1H, d, J=5.2 Hz).
MS: m/z=347 [M+H]+.
EXAMPLE 40




According to Example 36, compound 40 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 2.88-3.15 (2H, m), 3.27 (3H, s), 3.53-3.73 (5H, m), 3.99 (1H, dd, J=13.27, 3.97 Hz), 4.56-4.60 (1H, m), 5.89 (1H, d, J=7.32 Hz), 7.08-7.30 (6H, m).
EXAMPLE 41




First Step

Compound 41A (290 mg, 0.555 mmol) synthesized according to Example 12 was added to diphenyl ether (5 ml), and the mixture was stirred at 245° C. for 1 hour under microwave irradiation. The reaction solution was poured into n-hexane, and the precipitated solid was filtered. The resulting crude product was purified by amino column chromatography (chloroform-methanol, 99:1→97:3, v/v) to obtain 86 mg of compound 41B as a colorless solid.
1H-NMR (CDCl3) δ: 0.76 (3H, d, J=6.7 Hz), 0.98 (3H, d, J=6.9 Hz), 3.43-3.52 (2H, m), 3.62 (1H, dd, J=13.6, 3.5 Hz), 4.22 (1H, d, J=11.6 Hz), 4.52 (1H, d, J=11.6 Hz), 4.86-4.95 (1H, m), 5.37 (1H, d, J=10.2 Hz), 5.45 (1H, d, J=10.2 Hz), 5.90 (1H, d, J=7.5 Hz), 6.22 (1H, d, J=7.5 Hz), 6.89 (2H, m), 7.15 (3H, m), 7.36 (8H, m), 7.67 (2H, m).
Second Step
To compound 41B obtained in the first step was added trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, pH was adjusted to 6 with sodium bicarbonate water and 2N hydrochloric acid, the mixture was extracted with chloroform, and the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, methylene chloride-ethyl ether were added, and the precipitated solid was filtered to obtain 45 mg of compound 41 as a colorless solid.
1H-NMR (DMSO-d6) δ: 0.82 (3H, d, J=6.7 Hz), 1.05 (3H, d, J=6.7 Hz), 3.90 (1H, dd, J=13.6, 3.4 Hz), 4.39 (1H, d, J=11.9 Hz), 4.77-4.86 (1H, m), 5.50 (1H, d, J=8.6 Hz), 5.69 (1H, d, J=7.4 Hz), 6.92 (1H, d, J=7.4 Hz), 7.15-7.48 (8H, m), 7.63 (2H, d, J=7.7 Hz) 12.51 (1H, Brs).
MS: m/z=389 [M+H]+.
EXAMPLE 42




According to Example 41, compound 42 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 3.12 (3H, s), 3.51 (5H, m), 4.05 (1H, dd, J=13.9, 3.5 Hz), 4.37 (1H, d, J=11.4 Hz), 5.38 (1H, d, J=11.6 Hz), 5.60 (1H, d, J=7.3 Hz), 6.90 (1H, d, J=7.5 Hz), 7.22 (6H, m), 7.40 (2H, t, J=7.5 Hz), 7.56 (2H, d, J=7.2 Hz).
MS: m/z=405 [M+H]+.
EXAMPLE 43







First Step

Compound 43A (2.00 g, 6.11 mmol), triphenylphosphine (2.40 g, 9.16 mmol) and phthalimide (1.08 g, 7.33 mmol) were added to THF (20 ml), and diethyl azodicarboxylate (2.2M in toluene, 4.16 ml, 9.16 mmol) was added dropwise at room temperature. After stirring at room temperature for 3 hours, the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (n-hexane-ethyl acetate, 1:1, v/v) to obtain 2.39 g of compound 43B as a colorless solid.
1H-NMR (DMSO-d6) δ: 1.00 (9H, s), 3.30 (1H, m), 3.61 (1H, dd, J=13.4, 10.2 Hz), 4.15 (1H, d, J=12.2 Hz), 4.75 (1H, m), 6.79 (1H, d, J=9.5 Hz), 7.25 (15H, m), 7.76-7.89 (4H, m).
Second Step
Compound 43B (2.06 g, 4.51 mmol) was added to THF (20 ml) and methanol (20 ml), hydrazine hydrate (4.52 g, 90.2 mmol) was added, and the mixture was stirred at 60° C. for 5 hours. The white precipitate was removed by filtration, and washed with methanol. After the filtrate was distilled off under reduced pressure, the resulting crude product was purified by amino column chromatography (chloroform-methanol, 99:1, v/v), n-hexane was added, and the precipitated solid was filtered to obtain 1.25 g of compound 43C as a colorless solid.
1H-NMR (CDCl3) δ: 1.32 (9H, s), 2.55 (1H, dd, J=13.3, 6.0 Hz), 2.80 (1H, dd, J=13.3, 3.5 Hz), 3.99 (1H, d, J=10.1 Hz), 4.47 (2H, m), 7.13-7.33 (10H, m).
Third Step
Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (488 mg, 1.53 mmol) and 43C (500 mg, 1.53 mmol) were added to toluene (8 ml), and the mixture was stirred at 110° C. for 1 hour. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 97:3→96:4→94:6, v/v) to obtain 667 mg of compound 43D as a pale yellow gummy substance.
1H-NMR (CDCl3) δ: 1.28 (9H, s), 3.63 (3H, s), 3.80 (1H, m), 3.87 (3H, s), 4.02 (1H, dd, J=14.5, 10.1 Hz), 4.21 (1H, d, J=10.4 Hz), 4.47 (2H, m), 5.20 (1H, d, J=10.8 Hz), 5.26 (1H, d, J=10.7 Hz), 7.30 (15H, m), 8.05 (1H, s).
MS: m/z=627 [M+H]+.
Fourth Step
To compound 43D (664 mg, 1.06 mmol) was added 4N HCl (ethyl acetate solution, 10 ml), and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, THF and saturated sodium bicarbonate water were added, and the mixture was stirred for 2.5 hours. This was extracted with chloroform, and the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, methylene chloride-ethyl ether were added, and the precipitated solid was filtered to obtain 458 mg of compound 43E as a colorless solid.
1H-NMR (CDCl3) δ: 3.86 (3H, m), 3.92 (3H, s), 4.41-4.48 (1H, m), 5.32 (1H, d, J=10.8 Hz), 5.42 (1H, d, J=10.1 Hz), 5.92 (1H, s), 7.21-7.39 (13H, m), 7.59 (2H, m), 7.89 (1H, s).
MS: m/z=495 [M+H]+.
Fifth Step
Compound 43E (50 mg, 0.10 mmol) was dissolved in DMF (1 ml), and cesium carbonate (165 mg, 0.51 mmol) was added. After the mixture was stirred at room temperature for 30 minutes, iodomethane (0.025 ml, 0.40 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was poured into water, and the mixture was extracted with ethyl acetate, the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 97:3→95:5, v/v) to obtain 60 mg of compound 43F as a colorless solid.
1H-NMR (CDCl3) δ: 2.57 (3H, s), 3.75 (2H, d, J=11.3 Hz), 3.93 (3H, s), 4.20-4.29 (2H, m), 5.25 (1H, d, J=9.9 Hz), 5.57 (1H, d, J=9.9 Hz), 7.15-7.41 (13H, m), 7.63 (1H, s), 7.72-7.76 (2H, m).
Sixth Step
Compound 43F obtained in the fifth step was dissolved in THF (0.5 ml) and methanol (0.5 ml), a 2N aqueous sodium hydroxide solution (0.25 ml, 0.50 mmol) was added at room temperature, and the mixture was stirred for 1 hour. After 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate, the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, a colorless gummy compound 43G was obtained.
Seventh Step
To compound 43G obtained in the sixth step was added trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, pH was adjusted to 3 with sodium bicarbonate water and 2N hydrochloric acid, the mixture was extracted with chloroform, and the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, chloroform-ethyl ether were added, and the precipitated solid was filtered to obtain 27 mg of compound 43 as a colorless solid.
1H-NMR (DMSO-d6) δ: 2.53 (3H, s), 4.26 (1H, d, J=10.9 Hz), 4.35 (1H, d, J=13.3 Hz), 4.58 (1H, dd, J=13.8, 3.5 Hz), 5.06 (1H, d, J=10.9 Hz), 7.36 (10H, m), 8.36 (1H, s), 12.58 (1H, s), 15.62 (1H, s).
MS: m/z=405 [M+H]+.
EXAMPLE 44




According to Example 43, compound 44 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 4.19 (2H, m), 4.42 (1H, dd, J=13.3, 3.8 Hz), 4.90 (1H, d, J=9.2 Hz), 7.17-7.41 (10H, m), 8.40 (1H, s), 9.66 (1H, s), 12.70 (1H, s), 15.60 (1H, s).
MS: m/z=391 [M+H]+.
EXAMPLE 45




According to Example 43, compound 45 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 2.17-2.26 (1H, m), 3.22 (3H, s), 3.39 (2H, m), 3.58-3.67 (1H, m), 4.19 (1H, d, J=10.7 Hz), 4.38 (2H, m), 4.95 (1H, d, J=10.8 Hz), 7.20-7.44 (10H, m), 8.28 (1H, s), 12.40 (1H, s), 15.60 (1H, s).
MS: m/z=449 [M+H]+.
EXAMPLE 46




First Step

Compound 43E (289 mg, 0.584 mmol) obtained in Example 35 was dissolved in THF (3 ml) and methanol (3 ml), a 2N aqueous sodium hydroxide solution (1.46 ml, 2.92 mmol) was added at room temperature, and the mixture was stirred for 1.5 hours. After 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate, the extract was dried with sodium sulfate. After the solvent was distilled off, 342 mg of compound 46A was obtained as a colorless solid.
1H-NMR (CDCl3) δ: 3.72-4.04 (3H, m), 4.46 (1H, m), 5.39 (1H, d, J=10.4 Hz), 5.44 (1H, d, J=10.4 Hz), 6.04 (1H, brs), 7.19-7.60 (15H, m), 8.10 (1H, s).
Second Step
Compound 46A (402 mg, 0.837 mmol) was added to diphenyl ether (5 ml), and the mixture was stirred at 245° C. for 1 hour under microwave irradiation. The reaction solution was poured into n-hexane, and the precipitated solid was filtered. The resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 97:3→95:5→92:8, v/v) to obtain 85 mg of compound 46B as a colorless solid.
1H-NMR (CDCl3) δ: 3.86 (3H, m), 4.45 (1H, m), 5.35 (1H, d, J=10.5 Hz), 5.41 (1H, d, J=10.4 Hz), 5.94 (1H, brs), 6.48 (1H, d, J=7.4 Hz), 7.00 (1H, d, J=7.4 Hz), 7.25-7.44 (13H, m), 7.62 (2H, m).
Third Step
Compound 46B (39 mg, 0.089 mmol) was dissolved in DMF (1 ml), and cesium carbonate (145 mg, 0.445 mmol) was added. After stirring at room temperature for 30 minutes, 1-bromo-2-methoxyethane (0.033 ml, 0.36 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours. After the reaction solution was poured into water, and the mixture was extracted with ethyl acetate, the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 97:3→95:5→92:8, v/v) to obtain 66 mg of compound 46C as a colorless gummy substance.
Fourth Step
To compound 46C obtained in the third step was added trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, pH was adjusted to 6 with sodium bicarbonate water and 2N hydrochloric acid, the mixture was extracted with chloroform, and the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, methylene chloride-ethyl ether were added, and the precipitated solid was filtered to obtain 21 mg of compound 46 as a colorless solid.
1H-NMR (DMSO-d6) δ: 2.12-2.21 (1H, m), 3.20 (3H, s), 3.55-3.64 (3H, m), 3.81 (1H, d, J=13.0 Hz), 3.99 (1H, d, J=11.0 Hz), 4.22 (1H, dd, J=13.3, 3.1 Hz), 4.86 (1H, d, J=11.0 Hz), 6.11 (1H, d, J=7.2 Hz), 7.18-7.45 (11H, m).
MS: m/z=405 [M+H]+.
EXAMPLE 47




According to Example 46, compound 47 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 3.70 (1H, d, J=12.2 Hz), 4.02 (1H, d, J=10.7 Hz), 4.17 (1H, dd, J=13.2, 3.6 Hz), 4.79 (1H, t, J=3.4 Hz), 6.11 (1H, d, J=7.3 Hz), 7.18-7.44 (11H, m), 9.23 (1H, d, J=4.3 Hz).
MS: m/z=347 [M+H]+.
EXAMPLE 48




First Step

Compound 41A (400 mg, 0.743 mmol) was dissolved in DMF (5 ml), triethylamine (0.21 ml, 1.5 mmol) and ethyl chloroformate (0.143 ml, 1.49 mmol) were added at 0° C., and the mixture was stirred for 20 minutes. Sodium borohydride (70.2 mg, 1.86 mmol) was added at 0° C., and the mixture was stirred at room temperature for 30 minutes. Sodium borohydride (70.2 mg, 1.86 mmol) was further added at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water, the mixture was extracted with ethyl acetate, and the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 97.3, v/v) to obtain 160 mg of compound 48A as a colorless solid.
1H-NMR (CDCl3) δ: 3.19 (3H, s), 3.37-3.54 (3H, m), 3.65-3.73 (1H, m), 3.87 (1H, m), 4.06 (2H, d, J=13.9 Hz), 4.31 (1H, d, J=11.2 Hz), 4.39 (1H, d, J=13.8 Hz), 4.77 (1H, d, J=11.2 Hz), 5.36 (1H, d, J=10.1 Hz), 5.41 (1H, d, J=10.1 Hz), 6.65 (1H, brs), 7.00 (2H, m), 7.19 (3H, m), 7.33-7.49 (8H, m), 7.70 (2H, m).
Second Step
To compound 48A (50 mg, 0.095 mmol) was added trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, pH was adjusted to 6 with sodium bicarbonate water and 2N hydrochloric acid, the mixture was extracted with chloroform, and the extract was dried with sodium sulfate. The solvent was distilled off under reduced pressure, chroloform-ethyl ether were added, and the precipitated solid was filtered to obtain 3.5 mg of compound 48 as a colorless solid.
1H-NMR (DMSO-d6) δ: 3.12 (3H, s), 3.51 (5H, m), 3.71 (1H, d, J=13.7 Hz), 4.02 (1H, d, J=9.9 Hz), 4.09 (1H, d, J=12.0 Hz), 4.36 (1H, d, J=11.6 Hz), 4.73 (1H, brs), 5.45 (1H, d, J=12.5 Hz), 7.00 (1H, s), 7.15 (5H, m), 7.28 (1H, t, J=7.2 Hz), 7.40 (2H, t, J=7.5 Hz), 7.59 (2H, d, J=7.6 Hz).
MS: m/z=435 [M+H]+.
EXAMPLE 49







First Step

To Dess-Martin Periodinane (0.3M, methylene chloride solution, 52.0 ml, 15.6 mmol) was added dropwise a methylene chloride solution (20 ml) of compound 49A (2.97 g, 10.4 mmol) at 0° C. After stirring at room temperature for 3 hours, the reaction mixture was poured into a 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl ether. The organic layer was washed with a 1N aqueous sodium hydroxide solution and an aqueous saturated sodium chloride solution, and dried with magnesium sulfate. After the solvent was distilled off under reduced pressure, 2.08 g of compound 49B was obtained as a white solid.
1H-NMR (CDCl3) δ: 3.13 (2H, d, J=6.6 Hz), 4.53 (1H, q, J=6.7 Hz), 5.12 (2H, s), 5.28 (1H, brs), 7.26 (10H, m), 9.64 (1H, s).
Second Step
Compound 49B (700 mg, 2.47 mmol), 2-aminoethanol (166 mg, 2.72 mmol) and sodium sulfate (1.76 g, 12.4 mmol) were added to toluene (20 ml), and the mixture was stirred at room temperature for 1 hour. Boc2O (0.631 ml, 2.72 mmol) was added at room temperature, and the mixture was stirred for 18 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (n-hexane-ethyl acetate, 1:1, v/v) to obtain 893 mg of 49C as a colorless gummy substance.
Third Step
Compound 49C (890 mg, 2.09 mmol) and palladium-active carbon (10% wet, 200 mg) were added to ethanol (20 ml), and the mixture was stirred at room temperature for 2 hours under hydrogen atmosphere. After filtration with celite, the solvent was concentrated under reduced pressure to obtain 656 mg of a colorless oily substance 49D.
1H-NMR (CDCl3) δ: 1.40 (9H, s), 2.65-2.86 (2H, m), 3.32 (2H, m), 3.80 (2H, m), 4.03-4.12 (1H, m), 4.86 (1H, brs), 7.22 (5H, m).
Fourth Step
Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (610 mg, 2.09 mmol) and 49D (664 mg, 2.09 mmol) were added to toluene (6 ml), and the mixture was stirred at 100° C. for 4 hours. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (n-hexane-ethyl acetate, 1:1, v/v) to obtain 884 mg of compound 49E as a pale yellow gummy substance.
MS: m/z=593 [M+H]+.
Fifth Step
To compound 49E (860 mg, 1.45 mmol) was added 4N HCl (ethyl acetate solution, 10 ml). After stirring at room temperature for 30 minutes, the solvent was distilled off under reduced pressure. Subsequently, toluene (10 ml) and 2-aminoethanol (0.175 ml, 2.90 mmol) were added, and the mixture was stirred at 80° C. for 30 minutes. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 99:1→95:5→90:10, v/v) to obtain 157 mg of compound 49F as a colorless gummy substance and 217 mg of compound 49G as a yellow solid.
49F: 1H-NMR (CDCl3) δ: 2.48 (1H, dd, J=14.0, 11.4 Hz), 3.22 (1H, dd, J=14.1, 3.3 Hz), 3.69 (1H, m), 3.77 (3H, s), 3.83-3.95 (1H, m), 4.08 (1H, m), 4.29 (1H, m), 4.41 (1H, m), 5.34 (2H, m), 5.48 (1H, d, J=10.1 Hz), 6.86 (2H, m), 7.20-7.39 (7H, m), 7.64 (2H, m)
49G: 1H-NMR (DMSO-d6) δ: 3.70 (2H, t, J=5.3 Hz), 3.73 (3H, s), 3.86 (2H, t, J=5.3 Hz), 4.14 (2H, s), 4.98 (1H, t, J=5.0 Hz), 5.06 (2H, s), 6.98 (1H, s), 7.35 (8H, m), 7.62 (2H, d, J=7.1 Hz), 8.34 (1H, d, J=0.8 Hz).
Sixth Step
The compound 49G (214 mg, 0.465 mmol) was dissolved in THF (4 ml), ethanol (2 ml) and methylene chloride (2 ml), a 2N aqueous sodium hydroxide solution (1.16 ml, 2.32 mmol) was added at room temperature, and the mixture was stirred for 2.5 hours. After 1N hydrochloric acid was added, and the mixture was extracted with chloroform, the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, 158 mg of compound 49H was obtained as a yellow solid.
1H-NMR (DMSO-d6) δ: 3.70 (2H, q, J=5.2 Hz), 3.89 (2H, t, J=5.3 Hz), 4.22 (2H, s), 4.97 (1H, t, J=5.6 Hz), 5.12 (2H, s), 7.23-7.41 (9H, m), 7.60 (2H, m), 8.54 (1H, s).
Seventh Step
Compound 49H (50.0 mg, 0.112 mmol) and palladium-active carbon (10%, wet, 12 mg) were added to methanol (1 ml) and DMF (3 ml), and the mixture was stirred at room temperature for 5 hours under hydrogen atmosphere. After filtration with celite, the solvent was concentrated under reduced pressure, chloroform-methanol-ethyl ether were added, and the precipitated solid was filtered to obtain 9.0 mg of compound 49 as a colorless solid.
1H-NMR (DMSO-d6) δ: 3.10 (2H, m), 3.51-3.69 (4H, m), 4.10 (1H, d, J=10.7 Hz), 4.94 (2H, m), 7.11-7.26 (5H, m), 8.03 (1H, s), 12.94 (1H, brs), 15.30 (1H, brs).
MS: m/z=359 [M+H]+.
EXAMPLE 50




First Step

Compound 50A (1.00 g, 3.98 mmol), triphenylphosphine (1.15 g, 4.48 mmol) and N-methyl-2-nitrobenzenesulfonamide (860 mg, 3.98 mmol) were added to THF (10 ml), diethyl azodicarboxylate (2.2M in toluene, 1.99 ml, 4.38 mmol) was added dropwise at room temperature. After stirring at room temperature for 3 hours, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (n-hexane-ethyl acetate, 1; 1, v/v) to obtain 710 mg of compound 50B as a colorless gummy substance.
Second Step
Compound 50B (458 mg, 1.02 mmol) was dissolved in acetonitrile, potassium carbonate (422 mg, 3.06 mmol) and benzenethiol (0.126 ml, 1.22 mmol) were added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into a 1N aqueous sodium hydroxide solution, the mixture was extracted with methylene chloride, and the extract was dried with sodium sulfate. The resulting crude product was purified by amino column chromatography (chloroform-methanol, 95:5, v/v) to obtain 147 mg of compound 50C as a colorless oily substance.
1H-NMR (CDCl3) δ: 1.36 (9H, s), 2.40 (3H, s), 2.51-2.89 (4H, m), 3.90 (1H, s), 4.69 (1H, s), 7.17-7.31 (5H, m).
Third Step
Compound 50C (140 mg, 0.530 mmol) and 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (WO 2006/116764, 119 mg, 0.482 mmol) were added to THF (3 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (111 mg, 0.578 mmol) and 1-hydroxybenzotriazole (65.1 mg, 0.482 mmol) were added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was poured into sodium bicarbonate water, the mixture was extracted with ethyl acetate, and the extract was dried with sodium sulfate. The resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 97:3, v/v) to obtain 219 mg of compound 50D as a colorless solid.
MS: m/z=493 [M+H]+.
Fourth Step
To compound 50D (216 mg, 0.439 mmol) was added 4N HCl (ethyl acetate solution, 3 ml). After the mixture was stirred at room temperature for 1 hour, the solvent was distilled off under reduced pressure. Subsequently, ethanol (4 ml) and an aqueous saturated sodium carbonate solution (3 ml) were added, and the mixture was stirred at 60° C. for 2 hours. After water was added, and the mixture was extracted with ethyl acetate, the extract was dried with sodium sulfate. The resulting crude product was purified by amino column chromatography (chloroform-methanol, 95:5, v/v) to obtain 108 mg of compound 50E as a pale yellow gummy substance.
1H-NMR (CDCl3) δ: 3.00 (2H, m), 3.13 (3H, s), 3.18 (1H, m), 3.88 (1H, dd, J=13.5, 3.4 Hz), 4.00-4.07 (1H, m), 5.26 (1H, d, J=10.2 Hz), 5.46 (1H, d, J=10.1 Hz), 6.25 (1H, d, J=7.5 Hz), 6.73 (1H, d, J=7.5 Hz), 6.99-7.02 (2H, m), 7.28-7.37 (6H, m), 7.63-7.67 (2H, m).
Fifth Step
To compound 50E (105 mg, 0.280 mmol) was added trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 30 minutes. After concentration under reduced pressure, pH was adjusted to 6 with sodium bicarbonate water and 2N hydrochloric acid, the mixture was extracted with chloroform, and the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, methylene chloride-methanol-ethyl ether were added, and the precipitated solid was filtered to obtain 29 mg of compound 50 as a colorless solid.
1H-NMR (DMSO-d6) δ: 2.99 (3H, s), 3.26-3.47 (3H, m), 4.07 (1H, d, J=11.1 Hz), 4.80 (1H, m), 6.43 (1H, d, J=6.9 Hz), 7.11-7.29 (5H, m), 7.50 (1H, d, J=6.9 Hz).
MS: m/z=285 [M+H]+.
EXAMPLE 51




First Step

Compound 1D (60 mg, 0.11 mmol) was dissolved in trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was distilled off, and the resulting residue was purified by LC/MS to obtain compound 51 (43 mg, 0.09 mmol).
1H-NMR (DMSO-d6) δ: 1.17 (3H, t, J=6.9 Hz), 3.11 (3H, s), 3.48-3.58 (2H, m), 3.95-4.12 (3H, m), 4.40 (1H, d, J=11.4 Hz), 5.59 (1H, d, J=11.4 Hz), 7.11 (1H, d, J=7.3 Hz), 7.17 (2H, t, J=7.2 Hz), 7.26 (2H, d, J=7.1 Hz), 7.30 (1H, t, J=7.3 Hz), 7.42 (2H, t, J=7.2 Hz), 7.60 (3H, m), 12.55 (1H, brs).
MS: m/z=477.2 [M+H]+.
EXAMPLE 52




First Step

To a DMF (10 ml) solution of compound 1I (2.0 g, 4.32 mmol) were added WSC HCl (1.24 g, 6.49 mmol) and HOBt (876.9 mg, 6.49 mmol) at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction solution were added O,N-dimethylhydroxylamine hydrochloride (842.7 mg, 8.64 mmol) and triethylamine (2.19 g, 21.6 mmol), the mixture was stirred at the same temperature for 3 hours, thereafter, water was added, and the mixture was extracted with ethyl acetate three times. After the extract was washed with water three times, and dried with sodium sulfate, the solvent was distilled off, and the resulting oil was purified by silica gel chromatography. The materials were eluted firstly with n-hexane-ethyl acetate (7; 3, v/v) and, then, with only ethyl acetate. Concentration of an objective fraction afforded 543 mg (yield 25%) of compound 52A as an oil.
MS: m/z=506 [M+H]+.
Second Step
A THF (5 ml) solution of compound 52A (543 mg, 1.07 mmol) was cooled to −78° C., a methylmagnesium bromide 0.97M THF solution (1.66 ml, 1.61 mmol) was added, and temperature was raised up to −20° C. over 2 hours. To the reaction solution was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate three times. After the extract was dried with sodium sulfate, the solvent was distilled off, and the resulting oil was purified by silica gel chromatography. The materials were eluted firstly with n-hexane-ethyl acetate (7:3, v/v) and, then, with only ethyl acetate. Concentration of an objective fraction afforded 256.8 mg (yield 52%) of compound 52B as an oil.
1H-NMR (CDCl3) δ: 2.65 (3H, s), 3.08 (2H, d, J=7.5 Hz), 3.12 (3H, s), 3.53-3.68 (4H, m), 3.79-3.95 (1H, m), 3.92 (1H, dd, J=3.3 Hz, 13.5 Hz), 4.10-4.16 (1H, m), 5.30 (1H, d, J=10.2 Hz), 5.45 (1H, d, J=10.2 Hz), 6.99-7.02 (2H, m), 7.25-7.38 (6H, m), 7.49 (1H, s), 7.63-7.66 (2H, m).
Third Step
To a dichloromethane (4 ml) solution of compound 52B (256 mg, 0.558 mmol) was added mCPBA (144.3 mg, 0.836 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added an aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate three times. After the extract was washed with saturated sodium bicarbonate water two times, and dried with sodium sulfate, the solvent was distilled off, the resulting oil was dissolved in ethanol (4 ml), and a 2N-aqueous sodium hydroxide solution (1 ml) was added, followed by refluxing for 1 hour. After the solvent was distilled off, the precipitated solid was washed with diisopropyl ether to obtain 242 mg (yield 100%) of compound 52C.
1H-NMR (CDCl3) δ: 3.09 (2H, d, J=6.9 Hz), 3.32 (3H, s), 3.54 (1H, d, J=14.1 Hz), 3.59-3.71 (2H, m), 3.76-3.85 (1H, m), 3.92 (1H, dd, J=3.6 Hz, 13.5 Hz), 4.03 (1H, brt), 5.28 (1H, d, J=10.2 Hz), 5.47 (1H, d, J=10.2 Hz), 6.68 (1H, s), 7.00-7.04 (2H, m), 7.23-7.37 (6H, m), 7.64 (2H, d, J=6.3 Hz).
Fourth Step
To a THF (3 ml) solution of compound 52C (242 mg, 0.558 mmol) was added 10% Pd—C (50 mg), and the mixture was subjected to a catalytic reduction under hydrogen stream. The catalyst was removed by filtration, and the filtrate was concentrated. To the resulting residue was added diisopropyl ether, and the precipitated solid was filtered to obtain 60 mg (yield 31%) of compound 52.
1H-NMR (CDCl3) δ: 3.05 (2H, brs), 3.36 (3H, s), 3.58 (1H, d, J=12 Hz), 3.66-3.68 (2H, m), 3.74-3.75 (2H, m), 4.11-4.19 (2H, m), 6.80 (1H, brs), 6.90-7.04 (2H, m), 7.30 (3H, brs).
EXAMPLE 53




First Step

To a DMF (10 ml) solution of compound 1I(1.0 mg, 2.23 mmol) were added triethylamine (677 mg, 6.69 mmol) and ethyl chlorocarbonate (729 mg, 6.69 mmol) under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. To the reaction solution were added methanesulfonamide (1.06 g, 11.15 mmol) and DMAP (272.4 mg, 2.23 mmol), and the mixture was heated to stir at 80° C. for 2 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate three times. After the extract was washed with water three times, and dried with sodium sulfate, the solvent was distilled off, and the resulting oil was purified by silica gel chromatography. The materials were eluted firstly with only chloroform and, then, with chloroform-MeOH (9; 1, v/v). Concentration of an objective fraction afforded 535 mg (yield 46%) of compound 53A as an oil.
MS: m/z=463 [M+H]+.
Second Step
To a THF (5 ml) solution of compound 53A (535 mg, 0.991 mmol) was added 10% Pd—C (218 mg), and the mixture was subjected to a catalytic reduction under hydrogen stream. The catalyst was removed by filtration, and the filtrate was concentrated. To the resulting residue was added diisopropyl ether, and the precipitated solid was filtered to obtain 235 mg (yield 53%) of compound 53.
1H-NMR (DMSO-d6) δ: 2.99-3.17 (2H, m), 3.27 (3H, s), 3.33 (3H, s), 3.53-3.76 (5H, m), 4.06 (1H, dd, J=3.6 Hz, 13.8 Hz), 4.98 (1H, brs), 7.14 (2H, d, J=6.6 Hz), 7.19-7.30 (3H, m), 8.07 (1H, s), 12.84 (1H, s), 13.24 (1H, s).
EXAMPLE 54




First Step

To a DMF (10 ml) solution of compound 1I (1.0 mg, 2.23 mmol) were added triethylamine (677 mg, 6.69 mmol) and ethyl chlorocarbonate (729 mg, 6.69 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. The reaction solution was added dropwise to an ice-cooled solution of sodium borohydride (441 mg, 11.7 mmol) in water (5 ml), and the mixture was stirred at the same temperature for 2 hours. To the reaction solution was added 2N hydrochloric acid to stop the reaction, and the mixture was neutralized with a 2N aqueous sodium hydroxide solution, and extracted with ethyl acetate three times. After the extract was washed with water three times, and dried with sodium sulfate, the solvent was distilled off, and the resulting crude product was dissolved in dichloromethane (5 ml).
To the dichloromethane solution was added manganese dioxide (2.1 g, 24.15 mmol), and the mixture was stirred at room temperature for 6 hours. After the reaction solution was filtered, and the solvent was distilled off, the resulting oil was purified by silica gel chromatography. Elution with ethyl acetate-MeOH (9; 1, v/v) and concentration of an objective fraction afforded 188 mg (yield 19%) of compound 54A.
MS: m/z=447 [M+H]+.
Second Step
Compound 54A (188 mg, 0.422 mmol) was dissolved in THF (6 ml), 28% aqueous ammonia and iodine (117.7 mg, 0.464 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction solution was added an aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate three times. After the extract was dried with sodium sulfate, the solvent was distilled off, and the resulting oil was purified by silica gel chromatography. Elution with ethyl acetate-MeOH (9:1, v/v) and concentration of an objective fraction afforded 54.7 mg (yield 29%) of compound 54B.
1H-NMR (CDCl3) δ: 3.05 (2H, d, J=7.5 Hz), 3.33 (3H, s), 3.56-3.79 (5H, m), 3.99 (1H, dd, J=3.6 Hz, 13.8 Hz), 4.08 (1H, brt), 5.33 (1H, d, J=10.2 Hz), 5.46 (1H, d, J=10.2 Hz), 6.83 (1H, s), 6.93-6.97 (2H, m), 7.25-7.37 (5H, m), 7.58-7.62 (2H, m).
Third Step
To a toluene (2 ml) solution of compound 54B (216 mg, 0.487 mmol) were added sodium azide (95 mg, 1.46 mmol) and triethylamine (201 mg, 1.46 mmol), and the mixture was stirred at room temperature for 6 hours. The reaction solution was extracted with a 2N aqueous sodium hydroxide solution two times, and the extract was neutralized with 2N hydrochloric acid, and extracted with ethyl acetate three times. After drying of the organic layer with sodium sulfate, the solvent was distilled off to obtain 65 mg (yield 27%) of compound 54C.
1H-NMR (CDCl3) δ: 3.08-3.21 (2H, m), 3.33 (3H, s), 3.55-3.70 (4H, m), 3.81-3.90 (1H, m), 3.96-4.01 (1H, m), 4.51 (1H, brt), 5.31 (1H, d, J=10.2 Hz), 5.42 (1H, d, J=10.2 Hz), 7.03-7.05 (2H, m), 7.18-7.37 (6H, m), 7.58-7.61 (2H, m), 8.33 (1H, s).
Fourth Step
To a THF (2 ml)-MeOH (2 ml) solution of compound 54C (500 mg, 1.03 mmol) was added 10% Pd—C (100 mg), and the mixture was subjected to a catalytic reduction under hydrogen stream. The catalyst was removed by filtration, and the filtrate was concentrated. The resulting residue was dissolved in dichloromethane (10 ml), and the solution was extracted with a 2N aqueous sodium hydroxide solution two times. After the extract was neutralized with 2N hydrochloric acid, the mixture was extracted with ethyl acetate three times. The organic layer was dried with sodium sulfate, the solvent was distilled off, and the resulting solid was washed with diisopropyl ether, and filtered to obtain 55 mg (yield 14%) of compound 54.
1H-NMR (DMSO-d6) δ: 3.01-3.19 (2H, m), 3.28 (3H, s), 3.51-3.79 (5H, m), 4.09 (1H, dd, J=3.9 Hz, 13.5 Hz), 4.95 (1H, brs), 7.13-7.26 (5H, m), 8.20 (1H, s), 12.23 (1H, s).
EXAMPLE 55




First Step

To a THF (5 ml) solution of compound 1I (500 mg, 1.08 mmol) was added a trimethylsilyldiazomethane 2M hexane solution (1 ml, 2.0 mmol) at room temperature, and the mixture was heated to 50° C., and stirred. After the solvent was distilled off, the resulting oil was purified by silica gel chromatography. Elution with n-hexane-ethyl acetate (1; 1, v/v) and concentration of objective fraction afforded 115 mg (yield 22%) of compound 55A.
1H-NMR (CDCl3) δ: 3.06 (2H, d, J=7.5 Hz), 3.31 (3H, s), 3.51-3.72 (5H, m), 3.81 (3H, s), 3.98 (1H, dd, J=3.6 Hz), 13.5 Hz), 4.11 (1H, brt), 5.22 (1H, d, J=9.6 Hz), 5.46 (1H, d, J=9.6 Hz), 6.99-7.02 (2H, m), 7.26-7.37 (6H, m), 7.46 (1H, s), 7.65-7.69 (2H, m).
Second Step
Compound 55A (210 mg, 0.441 mmol) was dissolved in THF (2 ml), 10% Pd—C (85.7 mg) was added, and the mixture was subjected to a catalytic reduction under hydrogen stream. The catalyst was removed by filtration, and the filtrate was concentrated. The resulting residue was washed with diisopropyl ether to obtain 50 mg (yield 23%) of compound 55.
1H-NMR (CDCl3) δ: 1.55 (2H, d, J=7.5 Hz), 3.37 (3H, s), 3.59-3.84 (5H, m), 4.23-4.32 (2H, m), 7.00 (2H, dd, J=1.5 Hz, 6.9 Hz), 7.23-7.32 (3H, m), 7.39 (1H, s), 12.31 (1H, brs).
EXAMPLE 56




First Step

A DMF (5 ml) solution of compound 2D (424 mg, 0.787 mmol) was ice-cooled, and triethylamine (327 ul, 2.36 mmol) and, subsequently, ethyl chloroformate (150 ul, 1.57 mmol) were added. After the reaction solution was stirred at room temperature for 10 minutes, it was ice-cooled again, sodium azide (154 mg, 2.36 mmol) was added, and the mixture was stirred for 1 hour. To the reaction solution were added dichloromethane, water and a small amount of methanol, the dichloromethane layer was separated, and the aqueous layer was extracted with dichloromethane once. The combined extracts were concentrated, methanol (8 ml) was added to the resulting residue, the mixture was stirred at 50° C. for 3 hours, and the solvent was distilled off. The resulting oil was purified by silica gel column chromatography. The materials were eluted firstly with n-hexane-ethyl acetate (1:1, v/v) and, then, with only ethyl acetate. Concentration of objective fraction afforded 160 mg of compound 56A as a white solid.
1H-NMR (CDCl3) δ: 3.08-3.18 (4H, m), 3.35-3.49 (3H, m), 3.68 (3H, s), 3.98 (2H, dt, J=23.1, 5.6 Hz), 4.32 (1H, d, J=11.3 Hz), 4.59 (1H, d, J=11.3 Hz), 5.37 (2H, dd, J=12.0, 10.4 Hz), 6.98-7.70 (15H, m).
MS: m/z=568.25 [M+H]+.
Second Step
Compound 56A (160 mg, 0.102 mmol) was dissolved in EtOH (10 mL), a 2N aqueous sodium hydroxide solution (14 ml) was added, and the mixture was stirred at 60° C. for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was distributed between dichloromethane and water. The dichloromethane layer was separated, and the aqueous layer was extracted with dichloromethane three times. The solvent was distilled off to obtain compound 56B.
1H-NMR (CDCl3) δ: 2.97-3.06 (1H, m), 3.15 (3H, s), 3.38-3.44 (3H, m), 3.71 (2H, s), 3.93-3.99 (2H, m), 4.35 (2H, dd, J=19.3, 11.1 Hz), 5.37 (2H, dd, J=31.6, 10.1 Hz), 6.04 (1H, s), 6.98 (2H, dd, J=6.4, 2.9 Hz), 7.17 (4H, t, J=3.3 Hz), 7.28-7.69 (12H, m).
MS: m/z=509.23 [M+H]+.
Third Step
Compound 56B (56 mg, 0.11 mmol) was dissolved in TFA (3 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was subjected to toluene azeotropy, and the resulting residue was purified using a LCMS fractionation device. The eluted solvent was distilled off, isopropyl ether was added to the residue, and the precipitated solid was filtered. Washing with isopropyl ether and drying afforded 7 mg of compound 56.
MS: m/z=420.07 [M+H]+.
EXAMPLE 57




First Step

To a THF (1 mL) solution of compound 56B (25 mg, 0.049 mmol) were added triethylamine (20 ul, 0.015 mmol) and, subsequently, acetic acid anhydride (7.0 ul, 0.074 mmol) under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. Then, 4-fluorobenzyl amine (330 mg, 1.75 mmol) was added, and the mixture was stirred for 7 hours. Further, triethylamine (20 uL, 0.15 mmol) and, subsequently, acetic acid anhydride (7.0 ul, 0.074 mmol) were added, and the mixture was stirred overnight. To the reaction solution were added water, ethyl acetate, and brine, the ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. To the combined extracts was added sodium sulfate, and filtration and concentration afforded 18 mg of compound 57A as a white solid.
1H-NMR (CDCl3) δ: 2.05 (3H, s), 3.09-3.14 (4H, m), 3.41-3.45 (3H, m), 3.95-4.02 (2H, m), 4.31 (1H, d, J=11.4 Hz), 4.59 (1H, d, J=12.4 Hz), 5.36 (2H, s), 7.00 (2H, d, J=4.0 Hz), 7.11-7.16 (3H, m), 7.36 (7H, tt, J=14.5, 5.1 Hz), 7.62 (2H, t, J=7.3 Hz), 8.02 (1H, s), 8.18 (1H, s).
MS: m/z=552.20 [M+H]+.
Second Step
Compound 57A (21 mg, 0.038 mmol) was dissolved in TFA (3 mL), and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was subjected to toluene azeotropy, isopropyl ether was added to the resulting residue, and the precipitated solid was filtered. Washing with isopropyl ether, and drying afforded 10 mg of compound 57.
1H-NMR (CDCl3) δ: 2.12 (3H, s), 3.20 (3H, s), 3.39-3.60 (4H, m), 3.76-3.86 (1H, m), 4.08 (1H, dd, J=13.7, 3.7 Hz), 4.31 (1H, d, J=11.5 Hz), 4.68 (1H, dd, J=8.5, 4.3 Hz), 6.96-7.19 (4H, m), 7.30-7.44 (6H, m), 8.11 (1H, s).
MS: m/z=462.20 [M+H]+.
EXAMPLE 58




According to Example 57, compound 58 was synthesized by the same procedure.
1H-NMR (CDCl3) δ: 3.20 (3H, s), 3.41-3.54 (3H, m), 3.60-3.68 (2H, m), 3.73-3.85 (1H, m), 4.12 (1H, dt, J=14.0, 3.5 Hz), 4.31 (1H, d, J=11.4 Hz), 4.68 (1H, dd, J=11.4, 2.6 Hz), 6.95-7.21 (5H, m), 7.39 (5H, dt, J=26.9, 7.6 Hz), 7.94 (1H, s), 8.88 (1H, s).
MS: m/z=516.10 [M+H]+.
EXAMPLE 59




According to Example 57, compound 59 was synthesized by the same procedure.
1H-NMR (CDCl3) δ: 3.21 (3H, s), 3.43-3.63 (4H, m), 3.82 (1H, d, J=14.0 Hz), 4.12 (1H, dd, J=8.3, 4.2 Hz), 4.35 (1H, d, J=11.2 Hz), 4.74 (1H, d, J=8.3 Hz), 6.90-7.18 (5H, m), 7.34-7.60 (8H, m), 7.82 (2H, d, J=6.8 Hz), 8.34 (1H, s), 8.89 (1H, s).
MS: m/z=523.21 [M+H]+.
EXAMPLE 60




To compound 56B (30 mg, 0.059 mmol) were added formic acid (1.0 mL, 26 mmol) and, subsequently, a 37% formaldehyde solution (0.5 mL, 6.7 mmol), and the mixture was stirred at 100° C. for 7 hours. The reaction solution was subjected to toluene azeotropy, DMSO was added, insolubles were filtered and, thereafter, purification was performed using a LCMS fractionating device. The eluted solvent was distilled off, isopropyl ether was added to the residue, and the precipitated solid was filtered. Washing with isopropyl ether, and drying afforded 3 mg of compound 60.
1H-NMR (CDCl3) δ: 2.37 (6H, s), 3.18 (3H, s), 3.29-3.66 (4H, m), 3.82 (1H, d, J=12.5 Hz), 4.06-4.15 (1H, m), 4.31 (1H, d, J=11.7 Hz), 4.54 (1H, d, J=8.1 Hz), 5.97 (1H, s), 7.01 (2H, dd, J=6.4, 2.8 Hz), 7.17 (3H, t, J=2.9 Hz), 7.32-7.45 (6H, m).
MS: m/z=448.15 [M+H]+.
EXAMPLE 61




First Step

Compound 56B (50 mg, 0.098 mmol) was dissolved in THF (1 mL), Boc2O (0.068 mL, 0.29 mmol) and, subsequently, DMAP (6.0 mg, 0.049 mmol) were added, and the mixture was stirred at room temperature for 5 hours. To the reaction solution were added water and ethyl acetate, the ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. To the combined extracts was added sodium sulfate, the mixture was filtered, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography. Concentration of an objective fraction afforded 20 mg of compound 61A as a colorless transparent oil.
MS: m/z=610.50 [M+H]+.
Second Step
Compound 61A (20 mg, 0.033 mmol) was dissolved in DMF (1 mL), sodium hydride (2.6 mg, 0.066 mmol) was added under ice-cooling, the mixture was stirred for 10 minutes, methyl iodide (4.1 uL, 0.066 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. Ice water, ethyl acetate and brine were added, the ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. To the combined extracts was added sodium sulfate, the mixture was filtered, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography. Concentration of an objective fraction afforded 13 mg of compound 61B as a white solid.
MS: m/z=624.25 [M+H]+.
Third Step
Compound 61B (13 mg, 0.021 mmol) was dissolved in TFA (3 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was subjected to toluene azeotropy, and the resulting residue was purified using a LCMS fractionating device. The eluted solvent was distilled off, isopropyl ether-hexane were added to the residue, and the precipitated solid was filtered. Washing with isopropyl ether, and drying afforded 7.5 mg of compound 61.
1H-NMR (CDCl3) δ: 2.19 (3H, s), 3.26 (3H, s), 3.46-3.70 (4H, m), 4.23 (1H, d, J=11.0 Hz), 4.58-4.60 (1H, br m), 5.41-5.44 (1H, br m), 6.28 (1H, br s), 6.99 (2H, br s), 7.13 (3H, br s), 7.31-7.46 (6H, m).
MS: m/z=434.10 [M+H]+.
EXAMPLE 62







First Step

Compound 2D (112 mg, 0.208 mmol) was dissolved in DMF (2 mL), triethylamine (0.144 ml, 1.04 mmol) and, subsequently, ethyl chloroformate (0.040 mL, 0.42 mmol) were added under ice-cooling, the mixture was stirred at room temperature for 10 minutes, thereafter, N,O-dimethylhydroxyamine hydrochloride (41 mg, 0.42 mmol) and, subsequently, DMAP (3 mg, 0.02 mmol) were added, and the mixture was stirred at room temperature for 1 hour. To the reaction solution were added water, and ethyl acetate, the ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. To the combined extracts was added sodium sulfate, the mixture was filtered, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography. Concentration of an objective fraction afforded 127 mg of crude purified product 62A as a yellow oil.
MS: m/z=582.20 [M+H]+.
Second Step
Compound 62A (137 mg, 0.236 mmol) was dissolved in THF (8 mL), a 2M THF solution of methylmagnesium bromide (0.444 ml, 0.471 mmol) was added at −78° C. under nitrogen stream, and the mixture was stirred for 30 minutes while temperature was raised to −50° C. To the reaction solution was added 1M hydrochloric acid (4 ml), the mixture was stirred at 0° C. for 20 minutes, ethyl acetate was added, the ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined extracts were neutralized with an aqueous saturated sodium bicarbonate solution, sodium sulfate was added to the organic layer, the mixture was filtered, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography. Concentration of an objective fraction afforded 67 mg of compound 62B as a yellow oil.
1H-NMR (CDCl3) δ: 2.55 (3H, s), 3.01-3.14 (1H, m), 3.16 (3H, s), 3.37-3.54 (3H, m), 3.91-4.07 (2H, m), 4.28 (1H, d, J=11.3 Hz), 4.50-4.60 (1H, m), 5.42 (2H, d, J=1.2 Hz), 6.97-6.99 (2H, m), 7.14-7.17 (4H, m), 7.31-7.45 (8H, m), 7.65 (2H, d, J=6.5 Hz).
MS: m/z=537.20 [M+H]+.
Third Step
Compound 62B (67 mg, 0.13 mmol) was dissolved in dichloromethane (4 mL), mCPBA (32 mg, 0.19 mmol) was added at 0° C. under nitrogen stream, and the mixture was stirred at room temperature for 3 hours. The reaction solution was ice-cooled, an aqueous sodium thiosulfate solution, and ethyl acetate were added, the ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined extracts were neutralized with an aqueous saturated sodium bicarbonate solution, sodium sulfate was added to the organic layer, the mixture was filtered, and the solvent was distilled off to obtain 64 mg of compound 62C.
MS: m/z=553.23 [M+H]+.
Fourth Step
Compound 62C (64 mg, 0.12 mmol) was dissolved in ethanol (8 mL), and the solution was heated to reflux for 4 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography. Concentration of an objective fraction afforded 42 mg of compound 62D.
1H-NMR (CDCl3) δ: 2.93-3.09 (1H, m), 3.16 (3H, s), 3.33-3.53 (4H, m), 3.90-4.07 (2H, m), 4.29-4.47 (2H, m), 5.41 (2H, q, J=10.4 Hz), 6.34 (1H, s), 6.95-6.99 (2H, m), 7.12-7.21 (4H, m), 7.33-7.42 (8H, m), 7.64 (2H, d, J=6.9 Hz).
MS: m/z=511.21 [M+H]+.
Fifth Step
Compound 62D (41 mg, 0.080 mmol) was dissolved in DMF (1 mL), sodium hydride (6.4 mg, 0.16 mmol) was added under ice-cooling, the mixture was stirred for 10 minutes, methyl iodide (0.010 ml, 0.16 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. To the reaction solution were added ice water and ethyl acetate, the ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. To the combined extracts was added sodium sulfate, the mixture was filtered, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography. Concentration of an objective fraction afforded 41 mg of compound 62E as a white solid.
1H-NMR (CDCl3) δ: 2.99-3.09 (1H, m), 3.16 (3H, s), 3.25 (3H, s), 3.32-3.38 (1H, m), 3.42-3.50 (2H, m), 3.94-4.03 (2H, m), 4.28 (1H, d, J=11.3 Hz), 4.43 (1H, br s), 5.40 (2H, dd, J=28.3, 10.2 Hz), 6.01 (1H, s), 6.90-7.19 (5H, m), 7.28-7.44 (8H, m), 7.66 (2H, d, J=6.4 Hz).
MS: m/z=525.21 [M+H]+.
Sixth Step
Compound 62E (40 mg, 0.076 mmol) was dissolved in TFA (3 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was subjected to toluene azeotropy, and the resulting residue was purified using a LCMS fractionating device. The eluted solvent was distilled off, ethyl acetate-isopropyl ether-hexane were added to the residue, and the precipitated solid was filtered. Washing with isopropyl ether, and drying afforded 7.1 mg of compound 62 as a pink solid.
1H-NMR (CDCl3) δ: 3.17 (3H, s), 3.22 (3H, s), 3.40-3.53 (4H, m), 3.63-3.71 (1H, m), 4.24 (1H, d, J=11.5 Hz), 4.45 (1H, d, J=13.3 Hz), 4.60 (1H, d, J=11.2 Hz), 6.08 (1H, d, J=11.7 Hz), 6.96-6.99 (2H, br m), 7.13-7.17 (3H, m), 7.30-7.43 (5H, m).
MS: m/z=435.15 [M+H]+.
EXAMPLE 63




First Step

Compound 2D (164 mg, 0.304 mmol) was dissolved in diphenyl ether (1 mL), the mixture was stirred at 245° C. for 1 hour using a microwave apparatus and, thereafter, the reaction solution was purified by silica gel column chromatography. Concentration of an objective fraction afforded 72 mg of compound 63A as a brown solid.
1H-NMR (CDCl3) δ: 2.92-3.01 (1H, m), 3.16 (3H, s), 3.32-3.50 (3H, m), 3.90-4.46 (4H, m), 5.42 (2H, dd, J=26.1, 10.3 Hz), 5.94 (1H, d, J=7.4 Hz), 6.28 (1H, d, J=7.5 Hz), 6.96-6.99 (2H, m), 7.15-7.19 (3H, m), 7.28-7.44 (8H, m), 7.62-7.65 (2H, m).
MS: m/z=495.21 [M+H]+.
Second Step
To a dichloromethane (4 mL) solution of compound 63A (21 mg, 0.042 mmol) was added NBS (11 mg, 0.062 mmol), and the mixture was heated to reflux for 1 hour. The reaction solution was allowed to cool, and purified by silica gel column chromatography. Concentration of an objective fraction afforded 26 mg of compound 63B as a white solid.
1H-NMR (CDCl3) δ: 3.01-3.09 (1H, m), 3.16 (3H, s), 3.35-3.53 (3H, m), 3.92-4.47 (4H, m), 5.41 (2H, dd, J=32.6, 10.0 Hz), 6.72 (1H, s), 6.97-7.00 (2H, br m), 7.20-7.22 (3H, m), 7.30-7.46 (8H, m), 7.66-7.70 (2H, m).
MS: m/z=573.20 [M+H]+.
Third Step
Compound 63B (10 mg, 0.017 mmol) was dissolved in TFA (3 mL), and the mixture was stirred at room temperature for 50 minutes. The reaction mixture was subjected to toluene azeotropy, isopropyl ether was added to the resulting residue, and the precipitated solid was filtered. Washing with isopropyl ether, and drying afforded 1.4 mg of compound 63 as an orange solid.
MS: m/z=483.15 [M+H]+.
EXAMPLE 64




First Step

To a DMF solution (2 mL) of compound 63B (20 mg, 0.035 mmol) were added pyrazole-4-boronic acid pinacol ester (36 mg, 0.19 mmol) and, subsequently, potassium carbonate (29 mg, 0.21 mmol) and, thereafter, tetrakistriphenylphosphinepalladium (24 mg, 0.021 mmol) was added under nitrogen atmosphere, and the mixture was stirred at 110° C. for 8.5 hours. After the reaction solution was concentrated, ethyl acetate and methanol were added, and insolubles were removed. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography. Concentration of an objective fraction afforded 18 mg of compound 64A as a white solid.
MS: m/z=561.30 [M+H]+.
Second Step
Compound 64A (14 mg, 0.025 mmol) was dissolved in TFA (2 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was subjected to toluene azeotropy, and the resulting residue was purified using a LCMS fractionating device. The eluted solvent was distilled off, isopropyl ether was added to the residue, and the precipitated solid was filtered. Washing with isopropyl ether, and drying afforded 1.1 mg of compound 64 as an orange solid.
MS: m/z=471.20 [M+H]+.
EXAMPLE 65




First Step

A THF (1.1 L) solution of compound 65A (WO 2006/088173, 20.0 g, 69.6 mmol) was retained at 25° C. n DMF water bath, an aqueous (378 mL) solution of sodium chlorite (25.2 g, 278 mmol) and amidosulfuric acid (27.0 g, 278 mmol) was added dropwise over 30 minutes. The reaction solution was stirred at the same temperature for 1 hour, and concentrated under reduced pressure. To the residue were added ice water (100 mL) and diethyl ether (100 mL), and the precipitated solid was filtered. The resulting crude purified product was washed with water and diethyl ether to obtain 20.3 g of compound 65B as a white solid.
1H-NMR (DMSO-d6) δ: 3.74 (3H, s), 5.11 (2H, s), 7.31-7.38 (3H, m), 7.48 (2H, d, J=7.2 Hz), 8.11 (1H, s), 12.07 (1H, brs).
Second Step
Compound 65B (2.0 g, 6.59 mmol) was dissolved in DMF (340 mL), HATU (2.76 g, 7.25 mmol), methylamine (2 mol/L, THF solution, 3.63 mL, 7.25 mmol) and triethylamine (9.89 mmol) were added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was distributed between ethyl acetate and water, the ethyl acetate layer was separated. and the aqueous layer was extracted with ethyl acetate once. The combined extracts were washed with water and an aqueous saturated sodium chloride solution, and dried. The solvent was distilled off to obtain 1.66 g of a crude purified product of compound 65C as a white solid.
1H-NMR (DMSO-d6) δ: 3.38 (3H, brs), 3.75 (3H, s), 5.37 (2H, s), 7.34-7.44 (5H, m), 8.10 (1H, s), 8.38 (1H, s), 11.84 (1H, brs).
Third Step
To a DMF (20 mL) solution of compound 65C (1.2 g, 3.79 mmol) were added potassium carbonate (1.04 g, 7.59 mmol) and O-(2,4-dinitrophenyl)hydroxylamine (831 mg, 4.17 mmol), and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added water, and the precipitated solid was filtered, and washed with water to obtain 1.0 g of a crude purified product of compound 65D.
1H-NMR (DMSO-d6) δ: 3.74 (3H, s), 3.83 (3H, brs), 5.05 (2H, s), 6.46 (2H, brs), 7.31-7.38 (5H, m), 8.20 (1H, s), 8.52 (1H, brs).
Fourth Step
To a DMF (10 mL) solution of compound 65D (1.0 g, 3.02 mmol) were added paraformaldehyde (109 mg, 3.62 mmol) and acetic acid (0.017 ml, 0.302 mmol) at room temperature, and the mixture was stirred at 105° C. for 2 hours. The reaction solution was cooled to 0° C., cesium carbonate (3.44 g, 10.6 mmol) was added, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added water, and the mixture was distributed between ethyl acetate and water. The organic layer was washed with an aqueous saturated sodium chloride solution, and dried. The solvent was distilled off to obtain 120 mg of compound 65E.
MS: m/z=344 [M+H]+.
Fifth Step
To a DMF (1 mL) solution of compound 65E (17.0 mg, 0.05 mmol) were added cesium carbonate (81.4 mg, 0.25 mmol) and methylamine (2 mol/L THF solution, 0.125 ml, 0.25 mmol), and the mixture was stirred at room temperature for 5 hours. The reaction solution was filtered, and the filtrate was fractionated and purified by LCMS to obtain compound 65F.
MS: m/z=358 [M+H]+.
Sixth Step
To a DMF (0.5 mL) solution of compound 65F was added a 2N aqueous sodium hydroxide solution (0.2 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added ion-exchange resin DOWEX (50W-X8), and the mixture was filtered, and washed with DMF. After concentration of the filtrate, trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at 80° C. for 4 hours. After concentration of the reaction solution, water and chloroform were added, and the organic layer was separated. The organic layer was concentrated, and fractionation-purified by LCMS to obtain 6.47 mg of compound 65.
MS: m/z=254 [M+H]+.
According to Example 65, the following compounds were synthesized by the same procedure.









TABLE 1





Exam-




ple
Structure
MS







Exam- ple 66




348


 


Exam- ple 67




296


 


Exam- ple 68




340


 


Exam- ple 69




348


 


Exam- ple 70




442


 


Exam- ple 71




318


















TABLE 2





Exam-




ple
Structure
MS







Exam- ple 72




362


 


Exam- ple 73




388


 


Exam- ple 74




438


 


Exam- ple 75




298


 


Exam- ple 76




430


 


Exam- ple 77




442


















TABLE 3





Exam-




ple
Structure
MS







Exam- ple 78




442


 


Exam- ple 79




454


 


Exam- ple 80




438


 


Exam- ple 81




492


 


Exam- ple 82




443


















TABLE 4





Exam-




ple
Structure
MS







Exam- ple 83




513


 


Exam- ple 84




500


 


Exam- ple 85




454


 


Exam- ple 86




452


 


Exam- ple 87




480


















TABLE 5





Example
Structure
MS







Exam- ple 88




406


 


Exam- ple 89




445


 


Exam- ple 90




500


 


Exam- ple 91




416


 


Exam- ple 92




450













According to Example 65, compound 93 was synthesized by the same procedure.
1H-NMR (CDCl3) δ: 3.34 (3H, s), 3.57-3.68 (2H, m), 3.73 (2H, br s), 4.18 (2H, s), 4.75 (2H, br s), 7.06-7.12 (2H, m), 7.21-7.24 (2H, m), 8.10 (1H, s), 11.96 (1H, br s), 14.52 (1H, brs).
EXAMPLE 94




First Step

Using compound 94A (WO 2007/049675), and according to the same procedure as that of the fifth step of Example 65, compound 94B was synthesized.
1H-NMR (CDCl3) δ: 3.00-3.09 (1H, m), 3.18 (3H, s), 3.44 (2H, dd, J=7.55, 2.82 Hz), 4.02-4.08 (1H, m), 4.44-4.59 (3H, m), 4.86 (1H, d, J=13.57 Hz), 5.25 (1H, s), 5.36 (2H, dd, J=14.87, 9.99 Hz), 6.74-6.84 (2H, m), 7.09-7.60 (16H, m), 7.90 (1H, s), 10.07 (1H, t, J=5.87 Hz).
Second Step
To a MeCN (20 ml) solution of compound 94B (1.1 g, 1.655 mmol) were added DMAP (202 mg, 1.655 mmol) and Boc2O (20 ml, 86 mmol) at room temperature under nitrogen stream, and the mixture was heated to reflux for 5 hours. Further, Boc2O (20 ml, 86 mmol) was added, and the mixture was heated to reflux for 5 hours. After concentration under reduced pressure, to the residue were added ethanol (20.00 ml) and an aqueous sodium hydroxide solution (40%, 25 ml), and the mixture was stirred at room temperature for 5 hours. To the reaction mixture were added ethyl acetate-water to make the aqueous layer acidic. After extraction with ethyl acetate (2×200 mL), the organic layer was washed with an aqueous saturated sodium chloride solution. After drying with magnesium sulfate, the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography (CHCl3/MeOH 20:1) to obtain compound 94C. (750 mg, 63%)
1H-NMR (DMSO-d6) δ: 3.13 (3H, s), 3.25-3.34 (3H, m), 3.79 (1H, d, J=13.73 Hz), 4.42 (1H, d, J=14.03 Hz), 5.11-5.27 (3H, m), 5.48 (1H, s), 7.18-7.21 (5H, m), 7.33-7.49 (6H, m), 7.56-7.58 (2H, m), 7.74 (2H, d, J=7.32 Hz), 8.01 (1H, s).
Third Step
Using compound 94C, and according to the same procedure as that of the tenth step of Example 12, compound 94 was synthesized.
1H-NMR (DMSO-d6) δ: 3.13 (3H, s), 3.41-3.56 (4H, m), 4.50 (1H, d, J=13.57 Hz), 5.21 (1H, d, J=13.42 Hz), 5.58 (1H, s), 7.16-7.50 (8H, m), 7.72 (2H, d, J=7.32 Hz), 7.93 (1H, s), 12.12 (1H, s).
EXAMPLE 95




First Step

Compound 95A (WO 2006/116764, 1 g, 4.06 mmol) was dissolved in 28% aqueous ammonia, and the solution was stirred at room temperature for 12 hours. After concentration of the reaction solution, the resulting residue was neutralized with 2N hydrochloric acid, and the precipitated solid was suspended in ethyl acetate, filtered, and dried to obtain 1.14 g (yield 100%) of compound 95B.
1H-NMR (DMSO-d6) δ: 5.14 (2H, s), 7.31 (1H, d, J=6.6 Hz), 7.34-7.41 (3H, m), 7.45-7.51 (2H, m), 8.17 (1H, d, J=6.6 Hz).
Second Step
To a DMF (10 ml) solution of compound 95B (3.00 g, 10.65 mmol) were added WSC HCl (3.06 g, 15.98 mmol) and HOBt (1.58 g, 11.7 mmol) at room temperature, the mixture was stirred for 10 minutes, and a methylamine 33 wt % ethanol solution (1.50 g, 15.98 mmol) was added dropwise. After the reaction solution was stirred at the same temperature for 2 hours, water was added, and the mixture was extracted with chloroform five times. The extract was dried with sodium sulfate, the solvent was distilled off, and the resulting oil was purified by silica gel chromatography. From a fraction eluted with ethyl acetate-MeOH (6:4, v/v), 2.62 g (yield 95%) of compound 95C was obtained as a solid.
1H-NMR (CDCl3) δ: 2.77 (3H, d, J=4.8 Hz), 5.49 (2H, s), 6.57 (1H, d, J=6.9 Hz), 7.25-7.43 (5H, m), 7.48 (1H, t, J=6.0 Hz), 8.23 (1H, brs), 9.77 (1H, brs).
Third Step
Into a DMF (10 ml) solution of compound 95C (2.62 g, 10.14 mmol) was suspended potassium carbonate (4.20 g, 30.42 mmol) at room temperature, the suspension was stirred for 5 minutes, O-(2,4-dinitrophenyl)hydroxylamine (3.03 g, 15.21 mmol) was added, and the mixture was stirred at the same temperature for 3 hours. To the reaction solution was added water, the mixture was extracted with chloroform five times, and the extract was dried with sodium sulfate. After the solvent was distilled off, the resulting oil was purified by silica gel chromatography. From a fraction eluted with ethyl acetate-MeOH (6:4, v/v), 1.41 g (yield 51%) of compound 95D was obtained as a solid.
1H-NMR (CDCl3) δ: 2.62 (3H, d, J=5.1 Hz), 5.06 (2H, s), 5.22 (2H, s), 6.18 (1H, d, J=7.8 Hz), 7.25-7.36 (5H, m), 5.89 (1H, d, J=7.8 Hz), 7.57 (1H, q, J=5.1 Hz).
Fourth Step
A toluene (10 ml) solution of compound 95D (1.0 g, 3.66 mmol) were added paraformaldehyde (109.9 mg, 3.66 mmol) and acetic acid (22 mg, 0.37 mmol), and the mixture was heated to stir at 100° C. for 40 minutes. After cooling, the solvent was distilled off, the residue was dissolved in DMF (10 ml) without purification, cesium carbonate (3.58 g, 10.98 mmol) was added under ice-cooling, and the mixture was stirred for 10 minutes. To the reaction solution was added benzohydryl bromide (1.36 g, 5.49 mmol), the mixture was stirred at room temperature for 3 hours, water was added, and the mixture was extracted with ethyl acetate three times. The extract was washed with water three times, and dried with sodium sulfate. The solvent was distilled off, and the resulting oil was purified by silica gel chromatography. From a fraction eluted with ethyl acetate-MeOH (9:1, v/v), 1.26 g (yield 71%) of compound 95E was obtained as a solid.
1H-NMR (CDCl3) δ: 2.91 (3H, s), 4.26 (1H, d, J=13.2 Hz), 4.77 (1H, d, J=13.2 Hz), 5.12 (1H, s), 5.42 (1H, J=13.2 Hz), 5.45 (1H, d, J=13.2 Hz), 5.82 (1H, J=7.5 Hz), 6.71 (1H, d, J=7.5 Hz), 7.10-7.23 (5H, m), 7.27-7.46 (6H, m), 7.52 (2H, d, J=6.9 Hz), 7.60-7.64 (2H, m).
Fifth Step
Compound 95E (100 mg, 0.221 mmol) was dissolved in trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, the residue was dissolved in dichloromethane (2 ml), and the solution was neutralized with saturated sodium bicarbonate water. The resulting solution was made acidic with an aqueous citric acid solution, and the organic layer was separated. The aqueous layer was extracted with dichloromethane once, and the combined organic layers were washed with water, and dried with sodium sulfate. After the solvent was distilled off, the resulting solid was washed with diisopropyl ether to obtain 50 mg (yield 63%) of compound 95.
1H-NMR (CDCl3) δ: 2.95 (3H, s), 4.36 (1H, d, J=13.2 Hz), 4.95 (1H, d, J=13.2 Hz), 5.22 (1H, s), 5.71 (1H, d, J=7.8 Hz), 6.75 (1H, d, J=7.8 Hz), 7.21 (5H, br s), 7.33-7.47 (4H, m), 7.55 (2H, d, J=6.6 Hz).
According to Example 95, the following compounds were synthesized by the same procedure.
EXAMPLE 96




1H-NMR (CDCl3) δ: 3.12-3.18 (1H, m), 3.21 (3H, s), 3.38-3.52 (2H, m), 3.81 (1H, ddd, J=3.3 Hz, 4.2 Hz, 14.1 Hz), 4.52 ( 1H, d, J=13.2 Hz), 5.00 (1H, d, J=13.2 Hz), 5.28 (1H, s), 5.71 (1H, d, J=7.8 Hz), 6.74 (1H, d, J=7.8 Hz), 7.14-7.21 (5H, m), 7.32-7.46 (3H, m), 7.53 (2H, d, J=7.5 Hz).
EXAMPLE 97




1H-NMR (CDCl3) δ: 2.99-3.06 (0.54H, m), 3.18-3.23 (3.9H, m), 3.42-3.54 (2.5H, m), 3.86-3.91 (0.42H, m), 4.03-4.08 (0.58H, m), 4.37 (0.58H, d, J=13.5 Hz), 4.54 (0.42H, d, J=13.8 Hz), 4.98 (0.58H, d, J=13.5 Hz), 5.08 (0.42H, d, J=13.8 Hz), 5.36 (0.58H, s), 5.43 (0.42H, s), 5.70-5.77 (1H, m), 6.77 (0.42H, d, J=7.5 Hz), 6.94 (0.58H, d, J=7.8 Hz), 7.08-7.53 (6H, m), 7.60-7.78 (2H, m), 8.55 (0.58H, d, J=4.2 Hz), 8.72 (0.42H, d, J=3.9 Hz).
EXAMPLE 98




1H-NMR (CDCl3) δ: 0.930 (3H, d, J=6.9 Hz), 1.09 (3H, d, J=6.9 Hz), 4.58 (1H, d, J=12.6 Hz), 4.79 (1H, d, J=12.6 Hz), 4.83-4.90 (1H, m), 5.20 (1H, s), 5.67 (1H, d, J=7.5 Hz), 6.66 (1H, d, J=7.5 Hz), 7.07-7.09 (2H, m), 7.13-7.19 (3H, m), 7.34-7.46 (3H, m), 7.52 (1H, d, J=7.5 Hz).
EXAMPLE 99




1H-NMR (CDCl3) δ: 3.30 (3H, s), 3.49 (1H, brs), 3.54-3.56 (2H, m), 3.73 (1H, brs), 4.11 (2H, brs), 4.25 (1H, brs), 4.78 (1H, brs), 6.00 (1H, d, J=7.5 Hz), 8.33 (1H, d, J=7.5 Hz), 7.19-7.24 (3H, m), 7.34-7.37 (2H, m), 7.38-7.48 (4H, m).
EXAMPLE 100




1H-NMR (CDCl3) δ: 4.32 (1H, d, J=14.7 Hz), 4.41 (1H, d, J=12.9 Hz), 4.69 (1H, d, J=14.7 Hz), 4.88 (1H, d, J=12.9 Hz), 4.97 (1H, s), 5.68 (1H, d, J=7.5 Hz), 6.70 (1H, d, J=7.5 Hz), 6.91-6.98 (2H, m), 7.05-7.08 (2H, m), 7.12-7.20 (7H, m), 7.30-7.32 (4H, m).
EXAMPLE 101




1H-NMR (CDCl3) δ: 3.35 (3H, s), 3.66-3.69 (3H, m), 3.89 (1H, brs), 4.51 (1H, brs), 4.64 (2H, brs), 5.05 (1H, brs), 5.89 (1H, d, J=7.5 Hz), 6.58 (1H, d, J=7.5 H), 7.11 (1H, d, J=7.2 Hz), 7.26-7.40 (1H, m), 7.54-7.62 (2H, m), 7.86-7.93 (2H, m), 8.13 (1H, d, J=8.4 Hz).
EXAMPLE 102




1H-NMR (CDCl3) δ: 4.54 (1H, d, J=12.9 Hz), 4.56 (2H, s), 4.94 (1H, d, J=12.9 Hz), 5.14 (1H, s), 5.68 (1H, d, J=7.8 Hz), 6.20 (1H, d, J=3.0 Hz), 6.25-6.27 (1H, m), 6.72 (1H, d, J=7.8 Hz), 7.10-7.37 (11H, m).
EXAMPLE 103




1H-NMR (CDCl3) δ: 3.33 (3H, s), 3.63-3.66 (2H, m), 3.75 (2H, brs), 4.27 (2H, brs), 4.67 (1H, brs), 5.00 (1H, brs), 6.09 (1H, d, J=7.8 Hz), 6.99 (1H, d, J=7.8 Hz), 7.18 (1H, d, J=7.8 Hz), 7.27-7.32 (1H, m), 7.66-7.71 (1H, m), 8.63-8.65 (1H, m).
EXAMPLE 104




1H-NMR (CDCl3) δ: 3.12-3.22 (1H, m), 3.21 (3H, m), 3.38-3.55 (3H, m), 3.74-3.80 (0.55H, m), 3.87-3.94 (0.44H, m), 4.46-4.54 (1H, m), 5.00-5.07 (1H, m), 5.30-5.39 (1H, m), 5.70 (0.55H, d, J=7.5 Hz), 5.77 (0.45H, d, J=7.5 Hz), 6.74 (0.55H, d, J=7.8 Hz), 6.81 (0.45H, d, J=7.8 Hz), 7.11-7.54 (7.45H, m), 7.90 (0.55H, d, J=7.8 Hz), 8.459-8.783 (2H, m).
EXAMPLE 105




1H-NMR (CDCl3) δ: 3.34 (3H, s), 3.65-3.70 (4H, m), 4.18 (1H, brs), 4.21 (1H, brs), 4.48 (1H, brs), 4.98 (1H, brs), 6.12 (1H, d, J=7.8 Hz), 6.97 (1H, d, J=7.8 Hz), 7.36 (1H, d, J=7.5 Hz), 7.49 (1H, t, J=7.8 Hz), 7.61-7.66 (2H, m).
EXAMPLE 106




1H-NMR (CDCl3) δ: 2.54 (2H, t, J=7.5 Hz), 3.01 (2H, t, J=7, 5 Hz), 4.38 (2H, brs), 4.77 (2H, brs), 6.27 (1H, d, J=7.5 Hz), 6.96-7.00 (2H, m), 7.04-7.09 (3H, m), 7.19-7.33 (5H, m).
EXAMPLE 107




First Step

To a DMF (30 ml) solution of compound 107A (3.0 g, 9.96 mmol) synthesized according to the method of synthesizing compound 95D were added paraformaldehyde (299 mg, 9.96 mmol) and acetic acid (1 ml), and the mixture was heated to stir at 120° C. for 4 hours. After the solvent was distilled off, to the residue were added ethyl acetate-diisopropyl ether, and the precipitated solid was filtered to obtain 2.85 g (yield 91%) of compound 107B.
1H-NMR (CDCl3) δ: 1.19 (6H, J=6.6 Hz), 4.34 (2H, J=7.5 Hz), 4.72-4.86 (1H, m), 5.30 (2H, s), 5.49 (1H, t, J=7.5 Hz), 6.36 (1H, d, J=7.8 Hz), 7.26-7.35 (4H, m), 7.37 (1H, d, J=7.8 Hz), 7.55-7.58 (2H, m).
Second Step
To an acetic acid (2 ml) solution of compound 107B (100 mg, 0.319 mmol) were added 96% sulfuric acid (0.5 ml) and bis(3-chlorophenyl)methanol (242.3 mg, 0.957 mmol) at room temperature, and the mixture was stirred at 80° C. for 2 hours. After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate three times. The organic layer was washed with water once, and dried with sodium sulfate. After the solvent was distilled off, to the residue was added diisopropyl ether, and the precipitated solid was filtered to obtain 42 mg (yield 29%) of compound 107.
1H-NMR (CDCl3) δ: 0.953 (3H, d, J=3.9 Hz), 1.12 (3H, d, J=4.2 Hz), 4.51 (1H, 13.5 Hz), 4.83 (1H, d, J=13.5 Hz), 4.83-4.92 (1H, m), 5.18 (1H, s), 5.74 (1H, d, J=7.8 Hz), 6.73 (1H, d, J=7.8 Hz), 6.90 (1H, d, J=7.5 Hz), 7.12 (2H, dd, J=7.2 Hz, 8.1 Hz), 7.19-7.22 (1H, m), 7.37-7.41 (3H, m), 7.55 (1H, s).
According to Example 107, the following compounds were synthesized by the same procedure.
EXAMPLE 108




1H-NMR (CDCl3) δ: 0.465-0.549 (1H, m), 0.642-0.738 (1H, m), 0.754-0.907 (2H, m), 2.71-2.79 (1H, m), 2.86 (1H, ddd, J=4.8 Hz, 5.7 Hz, 14.7 Hz), 3.01 (2H, ddd, J=4.2 Hz, 16.0 Hz, 16.8 Hz), 3.88 (1H, ddd, J=4.8 Hz, 5.1 Hz, 16.8 Hz), 4.08-4.14 (1H, m), 4.16 (1H, d, J=12.9 Hz), 4.70 (1H, d, J=12.9 Hz), 4.96 (1H, s), 5.75 (1H, d, J=7.8 Hz), 6.58 (1H, d, J=7.8 Hz), 6.61 (1H, d, J=7.5 Hz), 6.92 (1H, dd, J=6.0 Hz, 7.5 Hz), 7.11-7.80 (6H, m).
EXAMPLE 109




1H-NMR (CDCl3) δ: 1.14 (3H, d, J=6.9 Hz), 1.18 (3H, d, J=6.9 Hz), 2.82 (1H, ddd, J=4.5 Hz, 4.8 Hz, 14.1 Hz), 3.08 (1H, ddd, J=4.2 Hz, 13.2 Hz, 17.7 Hz), 3.53 (1H, ddd, J=4.2 Hz, 4.5 Hz, 17.7 Hz), 4.27 (1H, d, J=12.9 Hz), 4.26-4.37 (1H, m), 4.62-4.71 (1H, m), 4.68 (1H, d, J=12.9 Hz), 5.05 (1H, s), 5.71 (1H, d, J=7.5 Hz), 6.63 (2H, d, J=7.2 Hz), 6.90 (1H, t, J=7.5 Hz), 7.08-7.63 (6H, m).
EXAMPLE 110




1H-NMR (CDCl3) δ: 3.16-3.28 (1H, m), 3.22 (3H, s), 3.46-3.50 (2H, m), 3.86 (1H, ddd, J=3.6 Hz, 3.6 Hz, 14.4 Hz), 4.47 (1H, d, J=13.2 Hz), 5.01 (1H, d, J=13.2 Hz), 5.30 (1H, s), 5.76 (1H, d, J=7.5 Hz), 6.72 (1H, d, J=7.5 Hz), 6.90 (2H, t, J=8.4 Hz), 7.06-7.18 (4H, m), 7.51 (2H, dd, J=5.4 Hz, 8.7 Hz).
EXAMPLE 111




1H-NMR (CDCl3) δ: 0.903 (1.3H, d, J=6.9 Hz), 0.982 (1.5H, d, J=6.6 Hz), 1.08-1.14 (3.2H, m), 4.55 (1H, dd, J=13.2 Hz, 16.5 Hz), 4.78-4.93 (2H, m), 5, 20 (1H, s), 5.66 (0.58H, d, J=7.5 Hz), 5.75 (0.42H, d, J=7.5 Hz), 6.67 (0.55H, d, J=7.5 Hz), 6.73 (0.45H, d, J=7.5 Hz), 6.92 (0.45H, d, J=7.2 Hz), 7.04-7.59 (8.6H, m).
EXAMPLE 112




1H-NMR (CDCl3) δ: 3.22 (3H, s), 3.24-3.32 (1H, m), 3.47-3.50 (2H, m), 3.84 (1H, ddd, J=3.3 Hz, 3.9 Hz, 14.4 Hz), 4.51 (1H, d, J=13.5 Hz), 5.03 (1H, d, J=13.5 Hz), 5.32 (1H, s), 5.77 (1H, d, J=7.8 Hz), 6.80 (1H, d, J=7.8 Hz), 6.84 (1H, d, J=7.8 Hz), 6.93 (2H, t, J=8.4 Hz), 7.06-7.20 (2H, m), 7.25-7.29 (2H, m), 7.39-7.47 (1H, m).
EXAMPLE 113




1H-NMR (CDCl3) δ: 0.88 (3H, d, J=6.9 Hz), 1.10 (3H, d, J=6.6 Hz), 2.10 (3H, s), 4.62-4.69 (1H, m), 4.79-4.92 (2H, m), 5.32 (1H, s), 5.64 (0.74H, 7.5 Hz), 5.72 (0.26H, d, J=7.5 Hz), 6.61 (0.74H, d, J=7.8 Hz), 6.82 (0.26H, d, J=7.8 Hz), 6.96-7.52 (8.26H, m), 7.48 (0.74H, d, J=7.5 Hz).
EXAMPLE 114




1H-NMR (CDCl3) δ: 0.976 (2H, d, J=6.9 Hz), 1.09-1.14 (3H, m), 5.63 (0.74H, d, J=7.8 Hz), 5.65 (0.74H, s), 5.73 (0.26H, d, J=7.8 Hz), 6.20 (0.26H, s), 6.65 (0.74H, d, J=7.8 Hz), 6.79 (0.26H, d, J=7.8 Hz), 7.05-7.24 (4.26H, m), 7.31-7.56 (4H, m), 8.02 (0.74H, d, J=6.3 Hz).
EXAMPLE 115




1H-NMR (CDCl3) δ: 0.893 (1.2H, d, J=6.6 Hz), 0.958 (1.8H, d, J=6.9 Hz), 1.09-1.13 (3H, m), 4.44 (0.56H, d, J=13.2 Hz), 4.63 (0.44H, d, J=13.5 Hz), 4.81-4.93 (2H, m), 5.35 (1H, m), 5.67 (0.56H, d, J=7.8 Hz), 5.72 (0.44H, d, J=7.8 Hz), 6.67-6.73 (1H, m), 7.03 (1H, d, J=6.6 Hz), 7.20-7.51 (5H, m), 7.75 (1H, d, 8.4 Hz), 8.06 (0.88H, d, J=8.7 Hz), 8.33 (1.1H, d, J=8.7 Hz).
EXAMPLE 116




1H-NMR (CDCl3) δ: 0.91-0.0.948 (3H, m), 1.10-1.14 (3H, m), 3.61-3.68 (1H, m), 4.44 (0.56H, d, J=12.9 Hz), 4.59 (0.44H, d, J=12.9 Hz), 4.79-4.91 (2H, m), 5.29 (1H, s), 5.67-5.69 (1H, m), 6.63-6.70 (2H, m), 6.90-7.81 (8H, m).
EXAMPLE 117




1H-NMR (CDCl3) δ: 3.19-3.28 (1H, m), 3.22 (3H, s), 3.46-3.50 (2H, m), 3.85 (1H, ddd, J=3 Hz, 4.2 Hz, 14.4 Hz), 4.47 (1H, d, J=13.2 Hz), 5.01 (1H, d, J=13.2 Hz), 5.28 (1H, s), 5.78 (1H, d, J=7.8 Hz), 6.73 (1H, d, J−=7.8 Hz), 7.04 (2H, d, J=8.4 Hz), 7.19 (2H, d, 8.4 Hz), 7.36-7.50 (4H, m).
EXAMPLE 118




1H-NMR (CDCl3) δ: 0.914-0.957 (3H, m), 1.08-1.14 (3H, m), 2.20 (1.4H, s), 2.39 (1.6H, s), 4.56 (0.48H, d, J=4.5 Hz), 4.60 (0.52H, d, J=4.2 Hz), 4.77-4.89 (2H, m), 5.16 (1H, s), 5.66-5.70 (1H, m), 6.65-6.69 (1H, m), 6.85-6.91 (1H, m), 6.98-7.10 (2H, m), 7.14-7.19 (2H, m), 7.30-7.39 (2H, m), 7.44 (1H, t, J=6.9 Hz), 7.51 (1H, d, J=6.9 Hz).
EXAMPLE 119




1H-NMR (CDCl3) δ: 0.893-0.982 (3H, m), 1.08-1.14 (3H, m), 4.49-4.60 (1H, m), 4.78-4.90 (2H, m), 5.20 (1H, s), 5.65 (0.57H, J=7.5 Hz), 5.76 (0.43H, d, J=7.8 Hz), 6.64-6.70 (1H, m), 7.03 (2H, d, J=8.1 Hz), 7.10-7.20 (3H, m), 7.28-7.51 (4H, m).
EXAMPLE 120




1H-NMR (CDCl3) δ: 0.526 (3H, d, J=6.9 Hz), 1.01 (3H, d, J=6.6 Hz), 4.69 (1H, d, J=13.8 Hz), 4.75-4, 83 (1H, m), 4.86 (1H, d, J=13.8 Hz), 5.69 (1H, d, J=7.8 Hz), 6.03 (1H, s), 6.70 (1H, d, J=7.8 Hz), 7.16 (5H, s), 7.40-7.48 (2H, m), 7.67 (1H, t, J=7.8 Hz), 7.81-7.91 (3H, m), 8.16 (1H, d, J=7.2 Hz).
EXAMPLE 121




1H-NMR (CDCl3) δ: 0.947 (3H, d, J=6.9 Hz), 1.09 (3H, d, J=7.2 Hz), 2.22 (3H, s), 2.37 (3H, s), 4.58 (1H, d, J=12.9 Ha), 4.76 (1H, d, J=12.9 Hz), 4.78-4.88 (1H, m), 5.13 (1H, s), 5.72 (1H, d, J=7.8 Hz), 6.67 (1H, d, J=7.8 Hz), 6.72 (1H, s), 6.90-6.98 (4H, m), 7.22 (2H, d, J=7.8 Hz), 7.38 (2H, d, J=7.8 Hz).
EXAMPLE 122




1H-NMR (CDCl3) δ: 0.932 (3H, d, J=6.6 Hz), 1.12 (3H, d, J=6.9 Hz), 4.44 (1H, d, J=13.2 Hz), 4.86 (1H, d, J=13.2 Hz), 4.87-4.93 (1H, m), 5.38 (1H, s), 5.67 (1H, d, J=7.8 Hz), 6.67 (1H, d, J=7.8 Hz), 7.21-7.24 (1H, m), 7.32-7.40 (2H, m), 7.52 (1H, d, J=7.5 Hz), 7.60-7.72 (2H, m), 7.77- 7.79 (2H, m).
EXAMPLE 123




1H-NMR (CDCl3) δ: 3.08-3.17 (1H, m), 3.23 (3H, s), 3.40-3.54 (2H, m), 3.71 (3H, s), 3.82 (3H, s), 3.95 (1H, ddd, J=3.3 Hz, 3.9 Hz, 14.4 Hz), 4.48 (1H, d, J=13.5 Hz), 4.96 (1H, d, J=13.5 Hz), 5.16 (1H, s), 5.76 (1H, d, J=7.5 Hz), 6.70 (2H, d, J=9.0 Hz), 6.73 (1H, d, J=7.5 Hz), 6.94 (2H, d, J=8.7 Hz), 7.03 (2H, d, J=8.7 Hz), 7.42 (2H, d, J=8.7 Hz).
EXAMPLE 124




1H-NMR (CDCl3) δ: 0.966 (3H, d, J=6.9 Hz), 1.10 (3H, d, J=6.9 Hz), 3.67 (3H, s), 3.83 (3H, s), 4.60 (1H, d, J=12.9 Hz), 4.78 (1H, d, J=12.9 Hz), 4.80-4.90 (1H, m), 5.13 (1H, m), 5.23 (1H, d, J=7.8 Hz), 6.66 (2H, d, J=7.2 Hz), 6.72-6.87 (2H, m), 6.87-6.90 (1H, m), 7.06-7.11 (3H, m), 7.34 (1H, t, J=8.1 Hz).
EXAMPLE 125




1H-NMR (DMSO-d6) δ: 1.05 (2H, d, J=7.0 Hz), 1.15 (1H, d, J=7.5 Hz), 2.73-3.63 (8H, m), 4.20-4.93 (4H, m), 5.25 (0.4H, s), 5.30 (0.6H, s), 5.46 (1H, d, J=7.8 Hz), 6.68-7.46 (11H, m).
MS: m/z=446 [M+H]+.
EXAMPLE 126




First Step

Compound 95B (1.00 g, 3.55 mmol) and cyclopropanamine (0.492 ml, 7.10 mmol) were added to pyridine (20 ml), 1-hydroxybenzotriazole (544 mg, 3.55 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.36 g, 7.10 mmol) were sequentially added, and the mixture was stirred at room temperature for 18 hours. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 95:5, v/v) and, subsequently, amino column chromatography (chloroform-methanol, 99:1, v/v) to obtain 1.19 g of compound 126A as a colorless solid.
1H-NMR (CDCl3) δ: 0.22 (1H, m), 0.70 (2H, m), 2.76-2.83 (1H, m), 5.50 (2H, s), 6.59 (1H, dd, J=7.0, 1.9 Hz), 7.44 (5H, d, J=0.7 Hz), 7.53 (1H, dd, J=6.9, 6.2 Hz), 8.30 (1H, brs), 9.71 (1H, brs).
Second Step
Compound 126A (1.19 g, 4.19 mmol) was dissolved in DMF (15 ml), potassium carbonate (2.90 g, 20.1 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. O-(2,4-dinitrophenyl)hydroxylamine (1.67 g, 8.38 mmol) was added, and the mixture was stirred at room temperature for 18 hours. To the reaction solution was added chloroform, the precipitated yellow precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by amino column chromatography (chloroform-methanol, 97:3→95:5, v/v) to obtain 851 mg of compound 126B as a yellow solid.
1H-NMR (CDCl3) δ: 0.41-0.46 (2H, m), 0.76 (2H, m), 2.73-2.81 (1H, m), 5.19 (2H, s), 5.61 (2H, s), 6.26 (1H, d, J=7.2 Hz), 7.38 (5H, s), 7.44 (1H, d, J=7.8 Hz), 7.70 (1H, s).
Third Step
Compound 126B (847 mg, 2.83 mmol) and paraformaldehyde (255 mg, 8.49 mmol) were added to ethanol (12 ml), and the mixture was stirred at 140° C. for 30 minutes under microwave irradiation. The reaction solution was concentrated under reduced pressure, the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 97:3→95:5→90:10, v/v) and, subsequently, amino column chromatography (chloroform-methanol, 97:3, v/v), methylene chloride-ethyl ether were added, and the precipitated solid was filtered to obtain 665 mg of compound 126C as a colorless solid.
1H-NMR (CDCl3) δ: 0.61-0.66 (2H, m), 0.87 (2H, m), 2.68-2.76 (1H, m), 4.32 (2H, d, J=7.9 Hz), 5.28 (2H, s), 6.33 (1H, d, J=7.7 Hz), 6.45 (1H, t, J=7.7 Hz), 7.33 (3H, m), 7.38 (1H, d, J=7.7 Hz), 7.52 (2H, m).
Fourth Step
Compound 126C (100 mg, 0.321 mmol) was dissolved in DMF (0.5 ml), cesium carbonate (314 mg, 0.964 mmol) and (bromomethylene)dibenzene (119 mg, 0.482 mmol) were added at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water, the mixture was extracted with ethyl acetate, and the organic layer was washed with water, and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 97:3→95:5, v/v) to obtain 124 mg of compound 126D as a colorless gummy substance.
1H-NMR (CDCl3) δ: 0.37-0.47 (2H, m), 0.74 (2H, m), 2.63-2.68 (1H, m), 4.35 (1H, d, J=13.4 Hz), 4.65 (1H, d, J=13.4 Hz), 5.07 (1H, s), 5.40 (1H, d, J=10.7 Hz), 5.47 (1H, d, J=10.5 Hz), 5.79 (1H, d, J=7.6 Hz), 6.67 (1H, d, J=7.8 Hz), 7.04-7.62 (15H, m).
Fifth Step
To compound 126D obtained in the fourth step was added trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 1.5 hours. After concentration under reduced pressure, pH was adjusted to 6 with sodium bicarbonate water and 2N hydrochloric acid, and the mixture was extracted with chloroform, and dried with sodium sulfate. After the solvent was distilled off under reduced pressure, methylene chloride-ethyl ether were added, and the precipitated solid was filtered to obtain 52 mg of compound 126 as a colorless solid.
1H-NMR (DMSO-d6) δ: —0.19--0.06 (1H, m), 0.44-0.54 (1H, m), 0.82 (2H, m), 2.62-2.69 (1H, m), 4.21 (1H, d, J=13.3 Hz), 5.11 (1H, d, J=13.1 Hz), 5.32 (1H, s), 5.47 (1H, t, J=11.1 Hz), 7.13 (1H, d, J=7.6 Hz), 7.23 (3H, m), 7.28-7.47 (8H, m), 7.69 (2H, t, J=8.5 Hz).
MS: m/z=388 [M+H]+.
EXAMPLE 127




According to Example 126, compound 127 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 0.86 (1.5H, d, J=7.0 Hz), 1.04 (1.5H, d, J=7.2 Hz), 3.08 (1.5H, s), 3.16 (1.5H, s), 4.52-5.05 (3H, m), 5.48 (2H, m), 7.31-7.47 (9H, m), 7.66 (2H, t, J=8.4 Hz).
MS: m/z=420 [M+H]+.
EXAMPLE 128




First Step

Compound 95B (2.40 g, 8.52 mmol) and ethyl 3-aminopropanoate hydrochloride (2.62 g, 17.0 mmol) were added to pyridine (30 ml), 1-hydroxybenzotriazole (1.31 g, 8.52 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.27 g, 17.0 mmol) were sequentially added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by amino column chromatography (chloroform-methanol, 95:5, v/v) to obtain 1.90 g of compound 128A as a colorless solid.
1H-NMR (CDCl3) δ: 1.29 (3H, t, J=7.1 Hz), 2.48 (2H, t, J=6.4 Hz), 3.58 (2H, q, J=6.3 Hz), 4.17 (2H, q, J=7.1 Hz), 5.59 (2H, s), 6.57 (1H, dd, J=7.1, 1.6 Hz), 7.37-7.52 (6H, m), 8.73 (1H, brs), 9.72 (1H, brs).
Second Step
Compound 128A (2.58 g, 7.49 mmol) was dissolved in DMF (30 ml), potassium carbonate (5.18 g, 37.5 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. O-(2,4-dinitrophenyl)hydroxylamine (2.98 g, 15.0 mmol) was added, and the mixture was stirred at room temperature for 20 hours. To the reaction solution was added chloroform, the precipitated yellow precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by amino column chromatography (chloroform-methanol, 97:3→95:5, v/v) and, subsequently, silica gel column chromatography (chloroform-methanol, 95:5→0.92:8, v/v) to obtain 1.67 g of compound 128B as a yellow solid.
1H-NMR (CDCl3) δ: 1.26 (3H, t, J=7.2 Hz), 2.42 (2H, t, J=6.6 Hz), 3.43 (2H, q, J=6.4 Hz), 4.12 (2H, q, J=7.1 Hz), 5.13 (2H, s), 5.53 (2H, s), 6.21 (1H, d, J=7.6 Hz), 7.33 (5H, s), 7.39 (1H, d, J=7.6 Hz), 7.85 (1H, t, J=5.6 Hz).
Third Step
Compound 128B (1.66 g, 4.62 mmol) and paraformaldehyde (416 mg, 13.9 mmol) were added to ethanol (20 ml), and the mixture was stirred at 140° C. for 30 minutes under microwave irradiation. The reaction solution was concentrated under reduced pressure, the resulting crude product was purified by amino column chromatography (chloroform-methanol, 99:1→0.95:5, v/v) to obtain 1.57 g of compound 128C as a colorless solid.
1H-NMR (CDCl3) δ: 1.27 (3H, t, J=7.2 Hz), 2.70 (2H, t, J=5.7 Hz), 3.57 (2H, t, J=5.8 Hz), 4.13 (2H, q, J=7.1 Hz), 4.50 (2H, d, J=7.9 Hz), 5.27 (2H, s), 5.87 (1H, t, J=7.8 Hz), 6.32 (1H, d, J=7.6 Hz), 7.31 (4H, m), 7.54 (2H, m).
Fourth Step
Compound 128C (1.00 g, 2.69 mmol) was dissolved in DMF (10 ml), cesium carbonate (2.63 g, 8.08 mmol) and (bromomethylene)dibenzene (998 mg, 4.04 mmol) were added at 0° C., and the mixture was stirred at room temperature for 18 hours. The reaction solution was poured into water, the mixture was extracted with ethyl acetate, and the organic layer was washed with water, and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (chloroform/methanol, 98:2, v/v) to obtain 500 mg of compound 128D as a colorless gummy substance.
1H-NMR (CDCl3) δ: 1.25 (3H, t, J=7.3 Hz), 2.46 (1H, m), 2.70-2.80 (1H, m), 2.87-2.96 (1H, m), 4.11 (2H, q, J=7.3 Hz), 4.12 (1H, m), 4.48 (1H, d, J=13.7 Hz), 4.85 (1H, d, J=13.7 Hz), 5.10 (1H, s), 5.47 (2H, s), 5.83 (1H, d, J=8.0 Hz), 6.73 (1H, d, J=8.0 Hz), 7.37 (15H, m).
Fifth Step
To compound 128D (40 mg, 0.074 mmol) was added trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, pH was adjusted to 6 with sodium bicarbonate water and 2N hydrochloric acid, and the mixture was extracted with chloroform, and dried with sodium sulfate. After the solvent was distilled off under reduced pressure, methylene chloride-ethyl ether were added, and the precipitated solid was filtered to obtain 20 mg of compound 128 as a colorless solid.
1H-NMR (DMSO-d6) δ: 1.16 (3H, t, J=7.1 Hz), 2.45-2.58 (3H, m), 3.70 (1H, m), 4.02 (2H, q, J=7.1 Hz), 4.39 (1H, d, J=13.4 Hz), 5.09 (1H, d, J=13.3 Hz), 5.48 (1H, d, J=3.2 Hz), 5.51 (1H, s), 7.19-7.38 (7H, m), 7.45 (2H, t, J=7.3 Hz), 7.69 (2H, d, J=7.2 Hz).
MS: m/z=448 [M+H]+.
EXAMPLE 129




First Step

Compound 128D (426 mg, 0.792 mmol) was dissolved in ethanol (3 ml) and THF (3 ml), a 2N aqueous sodium hydroxide solution (1.19 ml, 2.38 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. To the reaction solution was added 2N hydrochloric acid, and the mixture was extracted with chloroform, and dried with sodium sulfate. To the resulting crude product were added methylene chloride-ethyl ether, and the precipitated solid was filtered to obtain 359 mg of compound 129A as a colorless solid.
Second Step
To compound 129A (40 mg, 0.079 mmol), was added trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, pH was adjusted to 3 with sodium bicarbonate water and 2N hydrochloric acid, and the mixture was extracted with chloroform, and dried with sodium sulfate. After the solvent was distilled off under reduced pressure, chloroform-methanol-ethyl ether were added, and the precipitated solid was filtered to obtain 25 mg of compound 129 as a colorless solid.
1H-NMR (DMSO-d6) δ: 2.31-2.41 (1H, m), 2.57 (1H, m), 3.63-3.72 (1H, m), 4.37 (1H, d, J=13.3 Hz), 5.09 (1H, d, J=13.3 Hz), 5.47 (1H, s), 5.50 (1H, d, J=7.8 Hz), 7.28 (7H, m), 7.44 (2H, t, J=7.5 Hz), 7.69 (2H, d, J=7.2 Hz), 12.40 (1H, brs).
MS: m/z=420 [M+H]+.
EXAMPLES 130




First Step

Compound 129A (50 mg, 0.098 mmol) was added to DMF (1 ml), 1-hydroxybenzotriazole (14 mg, 0.098 mmol), dimethylamine hydrochloride (24 mg, 0.29 mmol), triethylamine (0.048 ml, 0.34 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28 mg, 0.15 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate, washed with sodium bicarbonate water, and dried with sodium sulfate. The solvent was distilled off under reduced pressure to obtain compound 130A as a colorless gummy substance.
Second Step
To compound 130A obtained in the first step was added trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, pH was adjusted to 6 with sodium bicarbonate water and an aqueous ammonium chloride solution, and the mixture was extracted with chloroform, and dried with sodium sulfate. The solvent was distilled off under reduced pressure, chloroform-ethyl ether were added, and the precipitated solid was filtered to obtain 25 mg of compound 130 as a colorless solid.
1H-NMR (DMSO-d6) δ: 2.33-2.43 (1H, m), 2.66 (1H, m), 2.78 (3H, s), 2.89 (3H, s), 3.56 (2H, m), 4.45 (1H, d, J=13.6 Hz), 5.05 (1H, d, J=13.6 Hz), 5.47 (s, 1H), 5.49 (1H, d, J=7.5 Hz), 7.27 (7H, m), 7.44 (2H, t, J=7.3 Hz), 7.69 (2H, d, J=7.3 Hz).
EXAMPLE 131




According to Example 130, compound 131 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 2.60-2.77 (3H, m), 3.94 (1H, m), 4.42 (1H, d, J=13.4 Hz), 5.15 (1H, d, J=13.4 Hz), 5.49 (1H, s), 5.55 (1H, d, J=7.2 Hz), 7.07 (1H, t, J=7.3 Hz), 7.12-7.49 (13H, m), 7.73 (2H, d, J=7.2 Hz), 10.01 (1H, s).
MS: m/z=495 [M+H]+.
EXAMPLE 132




According to Example 130, compound 132 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 3.14 (3H, s), 3.65 (4H, m), 4.34 (1H, d, J=13.6 Hz), 5.06 (1H, d, J=13.6 Hz), 5.42 (1H, s), 5.53 (1H, d, J=7.5 Hz), 7.42-7.58 (16H, m).
MS: m/z=509 [M+H]+.
EXAMPLE 133




According to Example 130, compound 133 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 1.08-1.55 (8H, m), 2.33 (1H, m), 2.68 (1H, m), 4.45 (1H, d, J=13.6 Hz), 5.05 (1H, d, J=13.6 Hz), 5.50 (2H, brs), 7.46-7.68 (11H, m).
MS: m/z=487 [M+H]+.
EXAMPLE 134




According to Example 130, compound 134 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 2.34-2.40 (1H, m), 2.61-2.77 (1H, m), 3.51-3.69 (10H, m), 4.44 (1H, d, J=13.4 Hz), 5.03-5.11 (1H, d, J=13.4 Hz), 5.51 (2H, s), 7.18-7.52 (9H, m), 7.69-7.75 (2H, m).
EXAMPLE 135




First Step

Compound 95B (1.50 g, 5.32 mmol) and tert-butyl 2-aminoethyl(methyl)carbamate (1.86 g, 10.7 mmol) were added to pyridine (20 ml), 1-hydroxybenzotriazole (815 mg, 5.32 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.04 g, 10.7 mmol) were sequentially added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into 1N hydrochloric acid, and the mixture was extracted with ethyl acetate, and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by amino column chromatography (chloroform-methanol, 95:5, v/v) and, subsequently, silica gel column chromatography (chloroform-methanol, 95:5, v/v) to obtain 1.63 g of compound 135A as a colorless gummy substance.
1H-NMR (CDCl3) δ: 1.44 (9H, s), 2.82 (3H, s), 3.28 (4H, m), 5.59 (2H, s), 6.57 (1H, d, J=6.0 Hz), 7.46 (6H, m), 8.46 (1H, m), 9.68 (1H, brs).
Second Step
Compound 135A (1.05 g, 2.62 mmol) was dissolved in DMF (15 ml), potassium carbonate (1.81 g, 13.1 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. O-(2,4-dinitrophenyl)hydroxylamine (1.04 g, 5.23 mmol) was added, and the mixture was stirred at room temperature for 18 hours. To the reaction solution was added chloroform, the precipitated yellow precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by amino column chromatography (chloroform-methanol, 97:3→95:5, v/v) to obtain 887 mg of compound 135B as a pale yellow solid.
1H-NMR (CDCl3) δ: 1.44 (9H, s), 2.84 (3H, s), 3.38 (4H, m), 5.33 (2H, s), 5.68 (1H, brs), 5.80 (1H, brs), 6.35 (1H, d, J=7.6 Hz), 6.74 (1H, brs), 7.39 (5H, brm), 7.52 (1H, t, J=9.5 Hz).
Third Step
Compound 135B (880 mg, 2.11 mmol) and paraformaldehyde (190 mg, 6.34 mmol) were added to ethanol (18 ml), and the mixture was stirred at 140° C. for 30 minutes under microwave irradiation. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 97:3→95:5→90:10 v/v) and, subsequently, amino column chromatography (chloroform-methanol, 97:3, v/v) to obtain 721 mg of compound 135C as a colorless solid.
1H-NMR (CDCl3) δ: 1.29 (9H, s), 2.95 (3H, s), 4.38 (2H, brs), 5.33 (2H, brs), 6.36 (1H, d, J=7.6 Hz), 6.85 (1H, t, J=7.4 Hz), 7.33 (4H, m), 7.55 (2H, m).
MS: m/z=429 [M+H]+.
Fourth Step
Compound 135C (720 mg, 1.68 mmol) was dissolved in DMF (3.5 ml), cesium carbonate (1.64 g, 5.04 mmol) and (bromomethylene)dibenzene (623 mg, 2.52 mmol) were added at 0° C., and the mixture was stirred at room temperature for 18 hours. The reaction solution was poured into water, the mixture was extracted with ethyl acetate, and the organic layer was washed with water, and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 97:3→95:5 v/v) to obtain 732 mg of compound 135D.
Fifth Step
To compound 135D (727 mg, 1.22 mmol) was added 4N HCl (ethyl acetate solution, 10 ml). After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. Saturated sodium bicarbonate water was added, the mixture was extracted with chloroform, and the extract was dried with sodium sulfate. The solvent was distilled off under reduced pressure, to the resulting crude product were added methylene chloride-ethyl ether, and the precipitated solid was filtered to obtain 575 mg of compound 135E as a colorless solid.
Sixth Step
To compound 135E (50 mg, 0.10 mmol) was added trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 1.5 hours. After concentration under reduced pressure, pH was adjusted to 6 with sodium bicarbonate water and an aqueous ammonium chloride solution, the mixture was extracted with chloroform, and the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, ethylene chloride-ethyl ether were added, and the precipitated solid was filtered to obtain 15 mg of compound 135 as a colorless solid.
1H-NMR (DMSO-d6) δ: 2.40 (3H, s), 2.80 (1H, s), 3.12 (3H, m), 3.87 (1H, m), 4.37 (1H, d, J=13.6 Hz), 5.10 (1H, d, J=13.4 Hz), 5.52 (1H, s), 5.53 (1H, d, J=5.5 Hz), 7.15-7.70 (11H, m).
MS: m/z=405 [M+H]+.
EXAMPLE 136




First Step

Compound 135E (50 mg, 0.10 mmol) was dissolved in methylene chloride (1 ml), triethylamine (0.042 ml, 0.30 mmol) and acetyl chloride (0.011 ml, 0.15 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 97:3→95:5, v/v) and, subsequently, amino column chromatography (chloroform-methanol, 97:3, v/v) to obtain 72 mg of compound 136A as a colorless solid.
Second Step
To compound 136A obtained in the first step was added trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 1.5 hours. After concentration under reduced pressure, pH was adjusted to 6 with sodium bicarbonate water and an aqueous ammonium chloride solution, the mixture was extracted with chloroform, and the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, methylene chloride-ethyl ether were added, and the precipitated solid was filtered to obtain 23 mg of compound 136 as a colorless solid.
1H-NMR (DMSO-d6) δ: 1.89 (2H, s), 1.92 (1H, s), 2.73 (1H, s), 2.95 (2H, s), 3.00-3.06 (1H, m), 3.43 (2H, m), 3.80 (1H, m), 4.34 (0.7H, d, J=13.3 Hz), 4.45 (0.3H, d, J=13.1 Hz), 5.11 (1H, m), 5.49 (2H, m), 7.20-7.73 (11H, m).
EXAMPLE 137




According to Example 136, compound 137 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 2.95 (3H, s), 3.13-4.07 (4H, m), 4.46 (1H, d, J=13.2 Hz), 5.16 (1H, d, J=13.0 Hz), 5.51 (1H, d, J=7.3 Hz), 5.62 (1H, s), 7.17-7.78 (16H, m).
MS: m/z=509 [M+H]+.
EXAMPLE 138




According to Example 136, compound 138 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 2.62 (3H, s), 3.03-3.22 (4H, m), 3.72 (2H, d, J=13.3 Hz), 4.39 (1H, d, J=13.3 Hz), 5.08 (1H, d, J=13.3 Hz), 5.53 (1H, d, J=7.8 Hz), 5.55 (1H, s), 7.19-7.79 (16H, m).
MS: m/z=545 [M+H]+.
EXAMPLE 139




According to Example 136, compound 139 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 2.72 (3H, s), 2.88 (3H, s), 3.12-3.24 (3H, m), 3.75-3.80 (1H, m), 4.37 (1H, d, J=13.0 Hz), 5.10 (1H, d, J=13.4 Hz), 5.51 (1H, d, J=7.6 Hz), 5.54 (1H, s), 7.19-7.46 (19H, m), 7.72 (2H, d, J=7.0 Hz).
MS: m/z=483 [M+H]+.
EXAMPLE 140




According to Example 136, compound 140 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 2.88 (3H, s), 2.98-3.12 (3H, m), 3.77 (1H, m), 4.31 (1H, d, J=13.3 Hz), 5.13 (1H, d, J=13.3 Hz), 5.51 (1H, s), 5.52 (1H, d, J=7.6 Hz), 7.13-7.46 (9H, m), 7.71 (2H, d, J=7.2 Hz).
MS: m/z=469 [M+H]+.
EXAMPLE 141




According to Example 136, compound 141 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 1.07 (9H, s), 2.84 (1H, m), 3.19 (2H, d, J=3.9 Hz), 3.96 (1H, d, m), 4.28 (1H, d, J=13.1 Hz), 5.21 (1H, d, J=13.1 Hz), 5.52 (1H, s), 5.56 (1H, t, J=4.2 Hz), 7.25-7.59 (10H, m), 7.75 (2H, d, J=7.7 Hz).
MS: m/z=475 [M+H]+.
EXAMPLE 142




According to Example 136, compound 142 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 1.10 (6H, m), 2.98 (3H, m), 3.78 (1H, m), 4.27 (1H, d, J=13.6 Hz), 4.68 (1H, m), 5.11 (1H, d, J=12.8 Hz), 5.51 (2H, m), 7.07-7.46 (10H, m), 7.70 (2H, d, J=7.2 Hz).
MS: m/z=477 [M+H]+.
EXAMPLE 143




According to Example 136, compound 143 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 2.89 (3H, m), 3.62 (1H, m), 4.17 (1H, d, J=13.1 Hz), 4.99 (1H, d, J=13.1 Hz), 5.45 (1H, s), 5.51 (1H, d, J=7.8 Hz), 7.18-7.77 (17H, m).
MS: m/z=531 [M+H]+.
EXAMPLE 144




First Step

To compound 144A synthesized according to the first to fifth steps of Example 135 were added formic acid and formalin, and the mixture was stirred at 80 degree for 1.5 hours. The solvent was distilled off under reduced pressure, saturated sodium bicarbonate water was added, then the mixture was extracted with chloroform, and the extract was dried with sodium sulfate. The solvent was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 95:5→0.92:8, v/v) to obtain 26 mg of compound 144B.
1H-NMR (CDCl3) δ: 2.06 (6H, s), 2.18-2.26 (1H, m), 2.36-2.45 (1H, m), 2.89-2.98 (1H, m), 3.91 (1H, dt, J=14.1, 5.9 Hz), 4.43 (1H, d, J=13.6 Hz), 4.82 (1H, d, J=13.4 Hz), 5.20 (1H, s), 5.41 (1H, d, J=10.8 Hz), 5.46 (1H, d, J=10.7 Hz), 5.80 (1H, d, J=7.8 Hz), 6.69 (1H, d, J=7.8 Hz), 7.05-7.64 (15H, m).
Second Step
To compound 144B obtained in the first step was added trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, pH was adjusted to 6 with sodium bicarbonate water and an aqueous ammonium chloride solution, then the mixture was extracted with chloroform, and the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, methylene chloride-ethyl ether were added, and the precipitated solid was filtered to obtain 13 mg of compound 144 as a colorless solid.
1H-NMR (DMSO-d6) δ: 2.17 (6H, s), 2.38-2.46 (3H, m), 3.59 (1H, m), 4.41 (1H, d, J=13.1 Hz), 5.09 (1H, d, J=13.3 Hz), 5.50 (1H, d, J=6.4 Hz), 5.51 (1H, s), 7.19-7.47 (9H, m), 7.66 (2H, d, J=7.3 Hz).
MS: m/z=419 [M+H]+.
EXAMPLE 145




First Step

To a dichloromethane (5 ml) solution of compound 95E (300 mg, 0.664 mmol) was added NBS (130 mg, 0.731 mmol) under ice-cooling, temperature was raised to room temperature and, thereafter, the mixture was refluxed for 1 hour. After the solvent was distilled off, the resulting residue was purified by silica gel chromatography. The materials were eluted firstly with n-hexane-ethyl acetate (1:1, v/v) and, then, with ethyl acetate. Concentration of an objective fraction afforded 326.7 mg (yield 93%) of compound 145A as a solid.
1H-NMR (CDCl3) δ: 2.93 (3H, s), 4.27 (1H, d, J=13.5 Hz), 4.82 (1H, d, J=13.5 Hz), 5.13 (1H, s), 5.41 (2H, s), 5.41-7.12 (2H, m), 7.15 (1H, s), 7.17-7.28 (3H, m), 7.31-7.47 (6H, m), 7.52 (2H, d, J=6.6 Hz), 7.63-7.67 (2H, m).
Second Step
To a DMF (3 ml) solution of compound 145A (100 mg, 0.189 mmol) were added a solution of potassium carbonate (78.4 mg, 0.567 mmol) in water (0.5 ml), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (47.6 mg, 0.284 mmol) and tetakistriphenylphosphinepalladium (21.8 mg, 0.189 mmol), and the mixture was heated to stir at 80° C. for 4 hours. After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate three times. The extract was washed with water three times, and dried with sodium sulfate and, thereafter, the resulting oil was purified by silica gel chromatography. Elution with only ethyl acetate, and concentration of an objective fraction afforded 42.0 mg (yield 45%) of compound 145B as an oil.
1H-NMR (CDCl3) δ: 1.73 (3H, s), 2.92 (3H, s), 4.29 (1H, d, J=13.5 Hz), 4.83 (1H, d, J=13.5 Hz), 4.96-4.97 (1H, m), 5.15 (1H, s), 5.21-5.21 (1H, m), 5.37 (1H, d, J=10.8 Hz), 5.40 (1H, d, J=10.8 Hz), 6.82 (1H, s), 7.15-7.21 (5H, m), 7.27-7.47 (6H, m), 7.54 (2H, d, J=6.9 Hz), 7.64-7.69 (2H, m).
Third Step
To a THF (2 ml) solution of compound 145B (40 mg, 0.081 mmol) was added 10% Pd—C (8 mg), and the mixture was subjected to a catalytic reduction under hydrogen stream. The catalyst was removed by filtration, and the filtrate was concentrated. The resulting residue was washed with ether to obtain 6.8 mg (yield 21%) of compound 145.
1H-NMR (CDCl3) δ: 0.629 (3H, d, J=6.9 Hz), 0.900 (3H, d, J=6.9 Hz), 2.87-3.00 (1H, m), 2.94 (3H, s), 4.37 (1H, d, J=13.2 Hz), 4.93 (1H, d, J=13.2 Hz), 5.21 (1H, s), 6.69 (1H, s), 7.21 (5H, s), 7.35-7.47 (3H, m), 7.57 (2H, d, J=7.5 Hz).
EXAMPLE 146




According to Example 145, compound 146 was synthesized by the same procedure.
1H-NMR (CDCl3) δ: 0.738 (3H, t, J=7.2 Hz), 1.05-1.18 (2H, m), 2.01-2.18 (2H, m), 2.94 (3H, s), 4.35 (1H, d, J=13.2 Hz), 4.95 (1H, d, J=13.2 Hz), 5.22 (1H, s), 6.71 (1H, s), 7.20 (5H, s), 7.35-7.47 (3H, m), 7.55 (2H, d, J=6.9 Hz).
EXAMPLE 147




First Step

Compound 145A (60 mg, 0.113 mg) was dissolved in trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, the residue was dissolved in dichloromethane (2 ml), and the solution was neutralized with saturated sodium bicarbonate water. The resulting solution was made acidic with an aqueous citric acid solution, and the organic layer was separated. The aqueous layer was extracted with dichloromethane once, and the combined organic layers were washed with water, and dried with sodium sulfate. After the solvent was distilled off, the resulting solid was washed with diisopropyl ether to obtain 30 mg (yield 60%) of compound 147.
1H-NMR (CDCl3) δ: 2.97 (3H, s), 4.36 (1H, d, J=13.2 Hz), 5.01 (1H, d, J=13.2 Hz), 5.21 (1H, s), 7.14 (1H, s), 7.17-7.25 (5H, m), 7.36-7.48 (3H, m), 7.54 (2H, d, J=7.2 Hz).
EXAMPLE 148




Compound 145B (41 mg, 0.083 mg) was dissolved in trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, the residue was dissolved in dichloromethane (2 ml), and the solution was neutralized with saturated sodium bicarbonate water. The resulting solution was made acidic with an aqueous citric acid solution, and the organic layer was separated. The aqueous layer was extracted with dichloromethane once, and the combined organic layers were washed with water, and dried with sodium sulfate. After the solvent was distilled off, the resulting solid was washed with diisopropyl ether to obtain 12 mg (yield 36%) of compound 148.
1H-NMR (CDCl3) δ: 1.70 (3H, s), 2.95 (3H, s), 4.36 (1H, d, J=12.9 Hz), 4.95 (1H, d, J=12.9 Hz), 4.96-4.98 (1H, m), 5.23 (1H, s), 5.32-5.33 (1H, m), 6.86 (1H, s), 7.21 (5H, s), 7.35-7.48 (3H, m), 7.56 (2H, d, J=7.2 Hz).
EXAMPLE 149




To a THF (2 ml) solution of compound 145A (100 mg, 0.189 mg) were added a 2N methylzinc chloride THF solution (0.377 ml, 0.754 mmol) and tetrakistriphenylphosphinepalladium (10.9 mg, 0.0945 mmol) at room temperature, and the mixture was heated to stir at 60° C. for 4 hours. After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with chloroform three times. After the extract was dried with sodium sulfate, the solvent was distilled off, and the resulting oil was purified by a MS trigger reverse layer column to obtain 9.6 mg (yield 14%) of compound 149.
1H-NMR (CDCl3) δ: 1.63 (3H, s), 2.95 (3H, s), 4.34 (1H, d, J=12.9 Hz), 4.68 (1H, d, J=12.9 Hz), 5.21 (1H, s), 6.70 (1H, s), 7.18 (5H, s), 7.37-7.47 (3H, m), 7.54 (2H, d, J=6.9 Hz).
EXAMPLE 150




First Step

Compound 150A (465 mg, 0.801 mmol) synthesized according to the first to fourth step of Example 135 was dissolved in a 4N hydrochloric acid dioxane solution (5 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was neutralized with saturated sodium bicarbonate water, and was extracted with dichloromethane three times. After the extract was dried with sodium sulfate, the solvent was distilled off, and 100 mg of the resulting oil was dissolved in dichloromethane (2 ml). To the dichloromethane solution were added triethylamine (63.2 mg, 0.624 mmol) and benzoyl chloride (31.9 mg, 0.312 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added water, and the mixture was extracted with dichloromethane three times. After the extract was dried with sodium sulfate, the solvent was distilled off, and the resulting residue was washed with diethyl ether to obtain 68 mg (yield 56%) of compound 150B.
1H-NMR (CDCl3) δ: 3.05-3.12 (1H, m), 3, 38-3.45 (1H, m), 3.64-3.70 (1H, m), 3.93-3.99 (1H, m), 4.22 (1H, d, J=13.2 Hz), 5.04 (1H, s), 5.07 (1H, d, J=13.2 Hz), 5.22 (1H, d, J=10.2 Hz), 5.31 (1H, d, J=10.2 Hz), 5.70 (1H, d, J=7.8 Hz), 6.55 (1H, d, J=7.8 Hz), 6.98 (2H, d, J=6.6 Hz), 7.08-7.19 (4H, m), 7.29-7.46 (5H, m), 7.49-7.53 (2H, m), 7.87 (2H, d, J=7.2 Hz), 8.06 (1H, brs).
Second Step
Compound 150B (30 mg, 0.051 mg) was dissolved in trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, the residue was dissolved in dichloromethane (2 ml), and the solution was neutralized with saturated sodium bicarbonate water. The resulting solution was made acidic with an aqueous citric acid solution, and the organic layer was separated. The aqueous layer was extracted with dichloromethane once, and the combined organic layers were washed with water, and dried with sodium sulfate. After the solvent was distilled off, the resulting solid was washed with diisopropyl ether to obtain 15 mg (yield 59%) of compound 150.
1H-NMR (CDCl3) δ: 2.91-2.98 (1H, m), 3.54-3.66 (1H, m), 3.76-3.84 (1H, m), 4.13-4.18 (1H, m), 4.28 (1H, d, J=12.9 Hz), 5.11 (1H, s), 5.43 (1H, d, J=12.9 Hz), 5.45 (1H, d, J=7.5 Hz), 6.68 (1H, d, J=7.5 Hz), 7.10-7.18 (4H, m), 7.35-7.47 (8H, m), 7.89 (2H, d, J=7.2 Hz), 8.41 (1H, s).
EXAMPLE 151




According to Example 150, compound 151 was synthesized by the same procedure.
1H-NMR (CDCl3) δ: 2.02 (3H, s), 2.69 (1H, br t, J=10.8 Hz), 3.40-3.49 (1H, m), 3.06-3.74 (1H, m), 4.12-4.22 (1H, m), 4.20 (1H, d, J=12.9 Hz), 5.08 (1H, s), 5.47 (1H, d, J=7.8 Hz), 5.50 (1H, d, J=12.9 Hz), 6.67 (1H, d, J=7.8 Hz), 7.12-7.21 (5H, m), 7.28-7.46 (5H, m), 8.31 (1H, brs).
EXAMPLE 152




First Step

Compound 150A (50 mg, 0.801 mmol) was dissolved in a 4N hydrochloric acid dioxane solution (5 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was neutralized with saturated sodium bicarbonate water, and was extracted with dichloromethane three times. After the extract was dried with sodium sulfate, the solvent was distilled off, and 50 mg of the resulting oil was dissolved in methanol (2 ml). To the methanol solution was added 10% Pd—C (10 mg), and the mixture was subjected to a catalytic reduction under hydrogen stream. The catalyst was removed by filtration, and the filtrate was concentrated. To the resulting residue was added diisopropyl ether, and the precipitated solid was filtered to obtain 10 mg (yield 25%) of compound 152.
1H-NMR (DMSO-d6) δ: 2.74-2.78 (2H, m), 3.00-3.07 (1H, m), 3.78-3.85 (1H, m), 4.34 (1H, d, J=13.5 Hz), 5.13 (1H, d, J=13.5 Hz), 5.48-5.54 (1H, m), 5.10 (1H, s), 7.20-7.47 (9H, m), 7.63-7.71 (2H, m).
EXAMPLE 153




First Step

To a THF (3 ml) solution of compound 150A (30 mg, 0.052 mmol) was added 10% Pd—C (10 mg), and the mixture was subjected to a catalytic reduction under hydrogen stream. The catalyst was removed by filtration, and the filtrate was concentrated. To the resulting residue was added diisopropyl ether, and the precipitated solid was filtered to obtain 20 mg (yield 79%) of compound 153.
1H-NMR (CDCl3) δ: 1.34 (9H, s), 2.84-2.91 (1H, m), 3.18-3.25 (2H, m), 4.03-4.11 (1H, m), 4.35 (1H, d, J−=13.2 Hz), 5.20 (1H, s), 5.24 (1H, d, J=13.2 Hz), 5.49 (1H, brs), 5.70 (1H, d, J=7.8 Hz), 6.73 (1H, d, J=7.8 Hz), 7.16-7.20 (5H, m), 7.32-7.46 (3H, m), 7.53 (2H, d, J=7.2 Hz).
EXAMPLE 154




First Step

To a DMF (10 ml) solution of compound 154A (539 mg, 1.01 mmol) synthesized according to the synthesis method of Example 65 were added triethylamine (615.7 mg, 6.08 mmol) and ethyl chlorocarbonate (328.8 mg, 3.03 mmol) under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. To the reaction solution were added O,N-dimethylhydroxylamine hydrochloride (295.0 mg, 3.03 mmol) and DMAP (12.3 mg, 0.101 mmol), the mixture was stirred at the same temperature for 2 hours, water was added, and was extracted with ethyl acetate three times. After the extract was washed with water three times, and dried with sodium sulfate, the solvent was distilled off, and the resulting oil was purified by silica gel chromatography. The materials were eluted firstly with n-hexane-ethyl acetate (7:3, v/v) and, then, with only ethyl acetate. Concentration of an objective fraction afforded 445.4 mg (yield 76%) of compound 154B as an oil.
1H-NMR (DMSO-d6) δ: 3.09 (3H, s), 3.52 (3H, s), 3.94 (2H, s), 4.40 (1H, brs), 4.64 (2H, s), 4.96 (1H, brs), 5.15 (2H, s), 7.06-7.15 (4H, m), 7.21 (2H, t, J=8.7 Hz), 7.28-7.38 (3H, m), 7.43 (2H, dd, J=5.7 Hz, 8.4 Hz), 7.52-7.54 (2H, m), 7.66 (1H, s).
Second Step
A THF (5 ml) solution of compound 154B (250 mg, 0.435 mmol) was cooled to −78° C., a methylmagnesium bromide 0.97M THF solution (0.673 ml, 0.653 mmol) was added, and temperature was raised to −20° C. over 2 hours. To the reaction solution was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate three times. After the extract was dried with sodium sulfate, the solvent was distilled off, and the resulting oil was purified by silica gel chromatography. The materials were eluted firstly with only chloroform and, then, with chloroform-methanol (7:3, v/v). Concentration of an objective fraction afforded 117.0 mg (yield 51%) of compound 154C as an oil.
1H-NMR (CDCl3) δ: 2.68 (3H, s), 3.80 (2H, brs), 4.29 (2H, brs), 4.71 (2H, brs), 5.45 (2H, brs), 6.83 (2H, m), 6.92-6.98 (2H, m), 7.03-7.10 (2H, m), 7.28-7.39 (5H, m), 7.90 (1H, s).
Third Step
To a dichloromethane (2 ml) solution of compound 154C (117 mg, 0.221 mmol) was added mCPBA (52.7 mg, 0.332 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added an aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate three times. After the extract was washed with saturated sodium bicarbonate water two times, and dried with sodium sulfate, the solvent was distilled off, the resulting oil was dissolved in ethanol (2 ml), and the solution was refluxed for 1 hour. After the solvent was distilled off, the precipitated solid was washed with diisopropyl ether to obtain 54 mg (yield 49%) of compound 154D.
1H-NMR (CDCl3) δ: 3.74 (1H, brs), 3.85 (1H, brs), 4.20 (2H, brs), 4.61 (1H, brs), 4.93 (1H, brs), 5, 41 (2H, brs), 6.79-6.86 (2H, m), 6.91-6.96 (2H, m), 7.02-7.09 (2H, m), 7.15-7.16 (1H, m), 7.26-7.34 (5H, m), 7.56-7.65 (2H, m).
Fourth Step
To a THF (3 ml) solution of compound 154D (54 mg, 0.107 mmol) was added 10% Pd—C (20 mg), and the mixture was subjected to a catalytic reduction under hydrogen stream. The catalyst was removed by filtration, and the filtrate was concentrated. To the resulting residue was added diisopropyl ether, and the precipitated solid was filtered to obtain 21 mg (yield 47%) of compound 154.
1H-NMR (DMSO-d6) δ: 3.90 (2H, brs), 3.95 (2H, s), 4, 66 (2H, brs), 7.07-7.12 (4H, m), 7.22 (2H, t, J=8.7 Hz), 7.29 (1H, s), 7.43-7.47 (2H, m).
EXAMPLE 155







First Step

To a toluene (150 ml) solution of compound 155A (WO 2006/066414, 15.0 g, 38.4 mmol) were sequentially added N,N-diisopropylethylamine (16.1 mL, 92.0 mmol), 1-methylimidazole (3.70 mL, 46.4 mmol) and 2-methoxyethylamine (4.05 mL, 46.4 mmol) under ice-cooling and, thereafter, diphenyl chlorophosphate (9.60 mL, 46.1 mmol) was further added dropwise over 10 minutes. After the reaction solution was stirred for 20 minutes under ice-cooling, acetonitrile (50 mL) was added, and the mixture was further stirred for 2 hours. To the reaction solution was added an aqueous acetic acid solution (10%, 100 mL) under ice-cooling and, thereafter, the mixture was extracted with ethyl acetate. The extract was sequentially washed with water (100 mL), saturated sodium bicarbonate water (150 mL) and an aqueous saturated sodium chloride solution (100 ml) and, thereafter, dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=25%→50%) to obtain compound 155B (7.86 g, 46%) as a colorless oil.
1H-NMR (CDCl3) δ: 0.10 (6H, s), 0.93 (9H, s), 3.29 (3H, s), 3.39 (2H, m), 3.47 (2H, m), 4.56 (2H, d, J=1.2 Hz), 5.41 (2H, s), 6.60 (1H, s), 7.35-7.42 (5H, m), 8.11 (1H, brt).
Second Step
To an ethanol (80 mL) solution of compound 155B (7.70 g, 17.2 mmol) was added aqueous ammonia (40 mL) at room temperature, and the mixture was stirred for 18 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=75%→100%) to obtain compound 155C (7.15 g, 93%) as a colorless oil.
1H-NMR (CDCl3) δ: 0.14 (6H, s), 0.97 (9H, s), 3.28 (3H, s), 3.38 (2H, m), 3.49 (2H, m), 4.64 (2H, s), 5.53 (2H, s), 6.31 (1H, s), 7.34-7.49 (5H, m), 8.61 (1H, brs), 9.94 (1H, brs).
Third Step
To a DMF (125 mL) solution of compound 155C (7.15 g, 16.0 mmol) and potassium carbonate (6.64 g, 48.0 mmol) was added O-(2,4-dinitrophenyl)hydroxylamine (7.97 g, 40.0 mmol) at room temperature, and the mixture was stirred for 2 days. To the reaction solution was added water (250 mL) under ice-cooling and, thereafter, the mixture was extracted with ethyl acetate (300 mL×2). After the extract was sequentially washed with water (300 mL), saturated sodium bicarbonate water (300 mL×2) and an aqueous saturated sodium chloride solution (150 mL), the mixture was dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol/chloroform=0%→0.10%) to obtain compound 155D (6.47 g, 88%) as a pale yellow solid.
1H-NMR (CDCl3) δ: 0.11 (6H, s), 0.94 (9H, s), 3.26 (3H, s), 3.35 (4H, m), 4.66 (2H, s), 5.16 (2H, s), 5.24 (2H, s), 6.43 (1H, s), 7.31-7.40 (5H, m), 7.59 (1H, brs).
Fourth Step
To a toluene (100 mL) solution of compound 155D (6.47 g, 14.0 mmol) and acetic acid (0.080 mL, 1.4 mmol) was added paraformaldehyde (0.422 g, 14.1 mmol) at room temperature, and the mixture was stirred at 80° C. for 2 hours. The solvent was distilled off under reduced pressure, and the resulting crude product of compound 155E was utilized in a next step without purification.
Fifth Step
To a DMF (100 mL) solution of the crude product of compound 155E obtained in the fourth step was added cesium carbonate (22.7 g, 69.8 mmol) under ice-cooling, and the mixture was stirred for 1 hour. Under ice-cooling, bromodiphenylmethane (5.20 g, 21.0 mmol) was added, and the mixture was stirred at room temperature for 19 hours. To the reaction solution was added water (200 mL) under ice-cooling and, thereafter, the mixture was extracted with ethyl acetate (200 mL×3). The extract was sequentially washed with water (200 mL×2) and an aqueous saturated sodium chloride solution (100 mL), and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product of compound 155F was utilized in a next step without purification.
MS: m/z=640 [M+H]+.
Sixth Step
To a methanol (100 mL) solution of the crude product of compound 155F obtained in the fifth step was added hydrogen chloride (4N ethyl acetate solution, 40 mL) at room temperature, and the mixture was stirred for 2.5 hours. To the reaction solution was added an aqueous sodium hydroxide solution (2N, 75 mL) to perform neutralization (pH=6) under ice-cooling, and the mixture was extracted with chloroform (200 mL×3). The extract was dried with sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol/chloroform=5%→40%) to obtain compound 155G (5.18 g, 3 step 70%) as an orange oil.
1H-NMR (CDCl3) δ: 3.16 (3H, s), 3.18-3.43 (3H, m), 3.60-3.74 (2H, m), 4.06 (1H, d, J=13.5 Hz), 4.19 (1H, brs), 4.58 (1H, d, J=14.7 Hz), 5.00 (1H, d, J=13.5 Hz), 5.24 (1H, s), 5.27 (2H, s), 5.96 (1H, s), 6.78 (2H, m), 6.98-7.10 (3H, m), 7.30-7.42 (8H, m), 7.72 (2H, m).
Seventh Step
To a THF (2 mL) solution of compound 155G (100 mg, 0.190 mmol), (bromomethyl)cyclopropane (0.110 mL, 1.12 mmol) and sodium iodide (5.0 mg, 0.033 mmol) was added potassium tert-butoxide (78.0 mg, 0.695 mmol) at room temperature, the mixture was stirred at room temperature for 22 hours and, thereafter, the mixture was stirred at 100° C. for 10 minutes under microwave irradiation. To the reaction solution were added water and hydrochloric acid (2N) (pH=1), the mixture was extracted with chloroform, and the extract was dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product of compound 155H was utilized in a next step without purification.
MS: m/z=580 [M+H]+.
Eighth Step
To a DMF (2 mL) solution of the crude product of compound 155H obtained in the seventh step was added lithium chloride (35.0 mg, 0.826 mmol) at room temperature, and the mixture was stirred at 150° C. for 15 minutes under microwave irradiation. The reaction solution was purified by preparative LCMS to obtain compound 155 (4.3 mg, 2 step 5%) as a white solid.
1H-NMR (CDCl3) δ: 0.16 (2H, m), 0.52 (2H, m), 0.98 (1H, m), 3.08 (3H, m), 3.20 (3H, s), 3.46 (2H, m), 3.68 (1H, dd, J=0.6, 14.1 Hz), 3.90 (1H, m), 4.52 (1H, d, J=13.2 Hz), 4.58 (1H, d, J=14.1 Hz), 4.93 (1H, d, J=13.2 Hz), 5.38 (1H, s), 6.01 (1H, s), 6.98 (2H, m), 7.11-7.48 (8H, m).
MS: m/z=490 [M+H]+.
EXAMPLE 156




According to Example 155, compound 156 was synthesized by the same procedure.
1H-NMR (CDCl3) δ: 0.88 (3H, t, J=7.4 Hz), 1.51 (2H, m), 3.15-3.23 (6H, m), 3.46 (2H, m), 3.69 (1H, dd, J=0.6, 14.1 Hz), 3.88 (1H, m), 4.54 (2H, d, J=14.1 Hz), 4.58 (1H, d, J=14.1 Hz), 4.93 (1H, d, J=13.5 Hz), 5.39 (1H, s), 6.12 (1H, s), 6.97 (2H, m), 7.12-7.47 (8H, m).
MS: m/z=478 [M+H]+.
EXAMPLE 157




According to Example 155, compound 157 was synthesized by the same procedure.
1H-NMR (CDCl3) δ: 3.13-3.22 (1H, m), 3.18 (3H, s), 3.20 (3H, s), 3.41-3.51 (2H, m), 3.60 (1H, d, J=13.8 Hz), 3.89 (1H, ddd, J=3.3 Hz, 4.2 Hz, 14.4 Hz), 4.52 (1H, d, J=13.2 Hz), 4.53 (1H, d, J=13.8 Hz), 4.92 (1H, d, J=13.2 Hz), 5.38 (1H, s), 5.98 (1H, s), 6.98 (2H, d, J=8.4 Hz), 7.11-7.22 (3H, m), 7.36-7.48 (5H, m).
EXAMPLE 158




First Step

To a THF (100 mL) solution of compound 155G (960 mg, 1.83 mmol) was added manganese dioxide (2.06 g, 92.0 mmol) at room temperature, and the mixture was stirred for 2 days. After the reaction solution was filtered, the filtrate was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=60%→100%) to obtain compound 158A (554 mg, 58%) as a pale yellow foam.
1H-NMR (CDCl3) δ: 2.96 (1H, m), 3.18 (3H, s), 3.44 (2H, m), 4.18 (1H, m), 4.56 (1H, d, J′=13.8 Hz), 4.98 (1H, d, J=13.8 Hz), 5.28 (1H, s), 5.54 (1H, d, J=10.5 Hz), 5.64 (1H, d, J=10.5 Hz), 6.35 (1H, s), 6.85 (2H, m), 7.03 (2H, m), 7.18 (1H, m), 7.26-7.48 (8H, m), 7.64 (2H, m), 10.10 (1H, s).
Second Step
To a methylene chloride (4 mL) solution of compound 158A (83.0 mg, 0.159 mmol), pyrrolidine (0.0400 mL, 0.484 mmol) and acetic acid (0.100 ml) was added sodium triacetoxyborohydride (136 mg, 0.642 mmol) at room temperature, and the mixture was stirred for 28 hours. To the reaction solution was added water, the mixture was extracted with chloroform, and the extract was dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product of compound 158B was utilized in a next step without purification.
MS: m/z=579 [M+H]+.
Third Step
To a DMF (2 mL) solution of the crude product of compound 158B obtained in the second step was added lithium chloride (39.2 mg, 0.925 mmol) at room temperature, and the mixture was stirred at 150° C. for 15 minutes under microwave irradiation. The reaction solution was distilled off under reduced pressure, and the resulting residue was purified by preparative LCMS to obtain compound 158 (8.8 mg, 2 step 11%) as a yellow oil.
1H-NMR (CDCl3) δ: 1.84 (4H, m), 2.70-2.85 (5H, m), 3.19 (3H, s), 3.20-3.47 (3H, m), 3.80 (1H, m), 4.25 (1H, d, J=14.7 Hz), 4.57 (1H, d, J=13.5 Hz), 5.07 (1H, d, J=13.5 Hz), 5.39 (1H, s), 6.06 (1H, s), 6.97 (2H, m), 7.12-7.54 (8H, m), 8.29 (1H, s).
MS: m/z=489 [M+H]+.
EXAMPLE 159




First Step

To a methylene chloride (20 mL) solution of compound 155G (950 mg, 1.81 mmol) and N,N-diisopropylethylamine (0.380 mL, 2.18 mmol) was added dropwise methanesulfonyl chloride (0.148 mL, 1.90 mmol) under ice-cooling, and the mixture was stirred for 90 minutes. To the reaction solution was added water (20 mL), the mixture was extracted with chloroform (50 mL), and the extract was dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product (1.06 g) of compound 159A was utilized in a next step without purification.
MS: m/z=604 [M+H]+.
Second Step
To the crude product (161 mg) of compound 159A obtained in the first step was added dimethylamine (2M THF solution, 2.00 mL, 4.00 mmol) at room temperature, and the mixture was stirred for 3 days. To the reaction solution was added an aqueous saturated sodium chloride solution (2 mL), the mixture was extracted with ethyl acetate, and the extract was dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product of compound 159B was utilized in a next step without purification.
MS: m/z=553 [M+H]+.
Third Step
To a DMF (2 mL) solution of the crude product of compound 159B obtained in the second step was added lithium chloride (56.0 mg, 1.32 mmol) at room temperature, and the mixture was stirred at 150° C. for 30 minutes under microwave irradiation. The reaction solution was distilled off under reduced pressure, and the resulting residue was purified by preparative LCMS to obtain compound 159 (33.6 mg, 3 step 27%) as a white solid.
1H-NMR (CDCl3) δ: 2.37 (6H, s), 2.69 (1H, d, J=14.4 Hz), 3.19 (3H, s), 3.30-3.46 (3H, m), 3.76 (1H, m), 4.00 (1H, d, J=14.4 Hz), 4.60 (1H, d, J=13.5 Hz), 5.20 (1H, d, J=13.5 Hz), 5.40 (1H, s), 6.01 (1H, s), 6.97 (2H, m), 7.11-7.42 (8H, m).
MS: m/z=463 [M+H]+.
EXAMPLE 160




First Step

To a crude product (95.8 mg) of compound 159A was added methylamine (2M THF solution, 2.00 mL, 4.00 mmol) at room temperature, and the mixture was stirred for 3 days. The reaction solution was filtered, the solvent was distilled off under reduced pressure, and the resulting crude product of compound 160A was utilized in a next step without purification.
MS: m/z=539 [M+H]+.
Second Step
To an acetonitrile (3 mL) suspension of the crude product of compound 160A and sodium iodide (100 mg, 0.667 mmol) was added chlorotrimethylsilane (0.0850 mL, 0.665 mmol) at room temperature, and the mixture was stirred for 5 hours. To the reaction solution was added water (1 mL), the solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative LCMS to obtain compound 160 (59.8 mg, 3 step 84%) as a white solid.
1H-NMR (CDCl3) δ: 2.75 (3H, s), 3.08 (1H, d, J=13.5 Hz), 3.24 (3H, s), 3.30-3.40 (3H, m), 3.75 (1H, m), 4.32 (1H, d, J=13.8 Hz), 4.66 (1H, d, J=13.8 Hz), 5.33 (1H, s), 5.58 (1H, d, J=13.5 Hz), 6.40 (1H, s), 6.98 (2H, m), 7.12-7.25 (3H, m), 7.40-7.51 (2H, m), 7.60 (2H, m).
MS: m/z=449 [M+H]+.
EXAMPLE 161




First Step

After a DMF (2 mL) suspension of a crude product (156 mg) of compound 159A, imidazole (19.5 mg, 0.286 mmol) and potassium carbonate (37.7 mg, 0.273 mmol) was stirred at room temperature for 4 hours, sodium hydride (60%, 11.7 mg, 0.293 mmol) was added, and the mixture was stirred for 3 days. To the reaction solution was added an aqueous acetic acid solution (10%), the mixture was extracted with chloroform, and the extract was dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product of compound 161A was utilized in a next step without purification.
MS: m/z=576 [M+H]+.
Second Step
To the crude product of compound 161A was added trifluoroacetic acid (1 mL) at room temperature, and the mixture was stirred for 18 hours and, thereafter, the mixture was stirred at 60° C. for 3 hours. The reaction solution was distilled off under reduced pressure, and the resulting residue was purified by preparative LCMS to obtain compound 161 (19.8 mg, 3 step 16%) as a pale orange amorphous substance.
1H-NMR (CDCl3) δ: 3.17-3.25 (1H, m), 3.21 (3H, s), 3.38-3.47 (2H, m), 3.82 (1H, m), 4.40 (1H, d, J=16.5 Hz), 4.54 (1H, d, J=13.5 Hz), 5.02 (1H, d, J=13.5 Hz), 5.09 (1H, s), 5.32 (1H, d, J=16.5 Hz), 5.40 (1H, s), 6.65 (1H, brs), 7.03 (2H, m), 7.15-7.49 (8H, m), 8.08 (1H, brs).
MS: m/z=486 [M+H]+.
EXAMPLE 162




First Step

To a DMF (2 mL) solution of a crude product (192 mg) of compound 159A was added sodium azide (24.2 mg, 0.372 mmol) at room temperature, and the mixture was stirred at 60° C. for 2 hours. The reaction solution was distilled off under reduced pressure, and the resulting crude product of compound 162A was utilized in a next step without purification.
MS: m/z=551 [M+H]+.
Second Step
To a THF (4 mL) solution of the crude product of compound 162A were sequentially added water (0.200 mL) and triphenylphosphine (83.0 mg, 0.316 mmol) at room temperature, and the mixture was stirred at 60° C. for 1 hour. The reaction solution was distilled off under reduced pressure, and the resulting residue was purified by preparative LCMS to obtain compound 162B (110 mg, 3 step 66%) as a colorless oil.
MS: m/z=525 [M+H]+.
Third Step
To an acetonitrile (1 mL) suspension of compound 162B (50.0 mg, 0.0950 mmol) and sodium iodide (56.2 mg, 0.375 mmol) was added chlorotrimethylsilane (0.0490 mL, 0.381 mmol) at room temperature, and the mixture was stirred for 6 hours. To the reaction solution was added water (0.5 mL), the solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative LCMS to obtain compound 162 (25.9 mg, 63%) as a pale orange solid.
1H-NMR (CDCl3) δ: 3.12 (1H, d, J=14.7 Hz), 3.27 (3H, s), 3.35-3.48 (3H, m), 3.81 (1H, m), 4.65 (1H, d, J=13.5 Hz), 5.31 (1H, s), 5.59 (1H, d, J=13.5 Hz), 6.40 (1H, s), 6.98 (2H, m), 7.19 (3H, m), 7.40 (1H, m), 7.50 (2H, m), 7.62 (2H, m), 8.11 (1H, s).
MS: m/z=435 [M+H]+.
EXAMPLE 163




First Step

To an acetonitrile (3 mL) solution of compound 162B (50.0 mg, 0.0950 mmol) and N,N-diisopropylethylamine (0.0366 mL, 0.210 mmol) was added acetic anhydride (0.0100 mL, 0.106 mmol) at room temperature, and the mixture was stirred for 6 hours. The reaction solution was distilled off under reduced pressure, and the resulting crude product of compound 163A was utilized in a next step without purification.
MS: m/z=567 [M+H]+.
Second Step
To an acetonitrile (5 mL) suspension of the crude product of compound 163A and sodium iodide (59.2 mg, 0.395 mmol) was added chlorotrimethylsilane (0.0487 mL, 0.381 mmol) at room temperature, and the mixture was stirred for 16 hours. To the reaction solution was added water (0.5 mL), the solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative LCMS to obtain compound 163 (28.1 mg, 2 step 62%) as a pale orange foam.
1H-NMR (CDCl3) δ: 2.07 (3H, s), 3.24 (3H, s), 3.27-3.52 (4H, m), 3.67 (1H, m), 4.54 (1H, d, J=13.5 Hz), 4.78 (1H, dd, J=6.5, 14.9 Hz), 5.17 (1H, d, J=13.5 Hz), 5.28 (1H, s), 5.61 (1H, s), 7.01 (2H, m), 7.01-7.58 (9H, m).
MS: m/z=477 [M+H]+.
EXAMPLE 164




First Step

Compound 155G (43.3 mg, 0.221 mmol) was dissolved in trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, the residue was dissolved in dichloromethane (2 ml), and the solution was neutralized with saturated sodium bicarbonate water. The resulting solution was made acidic with an aqueous citric acid solution, and the organic layer was separated. The aqueous layer was extracted with dichloromethane once, and the combined organic layers were washed with water, and dried with sodium sulfate. After the solvent was distilled off, the resulting solid was washed with diisopropyl ether to obtain 22 mg (yield 61%) of compound 164.
1H-NMR (CDCl3) δ: 1.13 (6H, d, J=6.0 Hz), 3.18-3.77 (7H, m), 3.26 (3H, s), 4.49 (1H, d, J=12.3 Hz), 4.76 (1H, d, J=12.3 Hz), 5.27 (2H, brs), 5.89 (1H, s), 6.90 (2H, d, J=7.2 Hz), 6.98-7.14 (3H, m), 7.315-7.50 (5H, m).
EXAMPLE 165







First Step

To a DMF (370 mL) solution of compound 165A (WO 2006/088173, 37.0 g, 108 mmol) were sequentially added potassium carbonate (17.9 mg, 129 mmol) and methyl iodide (8.03 mL, 129 mmol) at room temperature, and the mixture was stirred for 1.5 hours. The reaction solution was added to a solution of ammonium chloride (20.8 g, 390 mmol) in water (1110 mL) under ice-cooling, and the precipitated solid was filtered, and washed with water to obtain a crude product (33 g). In addition, the aqueous layer was salted out with sodium chloride, and the mixture was extracted with ethyl acetate, and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and a crude product (9 g) was obtained from the resulting residue. The crude products were combined and purified by silica gel column chromatography (ethyl acetate/n-hexane=50%→100%) to obtain compound 165B (36.5 g, 95%) as a white solid.
Second Step
To a 1,4-dioxane (548 mL) solution of compound 165B (36.5 g, 102 mmol) were sequentially added potassium osmate dihydrate (1.13 g, 3.06 mmol), sodium periodate (87.3 g, 408 mmol) and water (365 mmol) at room temperature, and the mixture was stirred for 6 hours. The reaction solution was extracted with methylene chloride, and the extract was dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=50%→100%) to obtain compound 165C (33.0 g, 90%) as a bronzed foam.
Third Step
To a toluene (25 mL) suspension of compound 165C (1.38 g, 3.66 mmol) were sequentially added ethylenediamine (0.247 mL, 3.66 mmol) and acetic acid (0.0210 mL, 0.366 mmol) at room temperature and, thereafter, the mixture was stirred for 1 hour, and further stirred at 50° C. for 17 hours. The precipitated solid was filtered, and washed with ether to obtain compound 165D (1.11 g, 100%) as a pale yellow solid.
1HNMR (DMSO-d6) δ: 3.05 (2H, m), 3.26 (1H, m), 3.63 (2H, m), 3.75 (3H, s), 3.87 (1H, m), 4.52 (1H, dd, J=3.3, 12.6 Hz), 4.69 (1H, m), 4.99 (1H, d, J=10.4 Hz), 5.15 (1H, d, J=10.4 Hz), 7.35 (3H, m), 7.54 (2H, m), 8.41 (1H, s).
Fourth Step
To an acetonitrile (30 mL) suspension of compound 165D (2.77 g, 7.50 mmol), potassium carbonate (2.23 g, 16.1 mmol) and sodium iodide (102 mg, 0.680 mmol) was added bromodiphenylmethane (2.26 g, 9.14 mmol) at room temperature, and the mixture was stirred at 90° C. for 7 hours. The reaction solution was poured into hydrochloric acid (2N, 10 mL) and an ice (20 g), the mixture was extracted with chloroform (100 mL×2), and the extract was dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=0%→5%) to obtain compound 165E (2.72 g, 68%) as a pale yellow solid.
Fifth Step
To an ethanol (30 mL) solution of compound 165E (2.72 g, 5.08 mmol) was added an aqueous sodium hydroxide solution (2N, 10 mL) at room temperature, and the mixture was stirred for 3 days. To the reaction solution was added hydrochloric acid (1N, 20 mL) (pH=1) at room temperature, the mixture was extracted with chloroform (100 mL×2), and the extract was dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol=0%→10%) to obtain compound 165F (1.77 g, 67%) as a pale yellow solid.
1HNMR (DMSO-d6) δ: 2.63 (1H, m), 3.16 (1H, m), 3.49 (1H, m), 3.73 (1H, m), 4.12 (2H, m), 4.56 (1H, m), 5.04 (1H, s), 5.09 (1H, d, J=10.7 Hz), 5.19 (1H, d, J=10.7 Hz), 7.28-7.53 (15H, m), 8.32 (1H, s), 8.39 (1H, s).
Sixth Step
A N,N′-dimethylimidazolidinone (20 mL) solution of compound 165F (1.77 g, 3.39 mmol) and lithium chloride (0.515 g, 12.2 mmol) was stirred at 90° C. for 1 hour. To the reaction solution were sequentially added water (10 mL), hydrochloric acid (2N, 10 mL) and water (10 mL) at room temperature. The precipitated solid was filtered, and washed with ether, DMF-water were added, and the precipitated solid was filtered to obtain compound 165 (599 mg, 41%) as a white solid.
1HNMR (DMSO-d6) δ: 2.60 (1H, m), 3.20 (1H, m), 3.64 (2H, m), 4.00 (2H, m), 4.55 (1H, m), 5.01 (1H, s), 7.28-7.47 (10H, m), 8.16 (1H, s), 11.97 (1H, brs).
MS: m/z=432 [M+H]+.
EXAMPLE 166




According to Example 165, following compound 166 was synthesized by the same procedure.
1HNMR (DMSO-d6) δ: 1.54 (1H, d, J=12.6 H), 1.66-1.78 (1H, m), 2.60 (1H, t, J=9.9 Hz), 2.83 (1H, d, J=11.7 Hz), 3.01 (1H, t, J=11.7 Hz), 3.34-3.38 (1H, m), 3.94 (1H, d, J=13.8 Hz), 4.44-4.59 (3H, m), 4.82 (1H, d, J=14.7 Hz), 7.06 (2H, t, J=8.7 Hz), 7.18-7.23 (2H, m), 8.27 (1H, s), 12.84 (1H, brs).
EXAMPLE 167




First Step

To a xylene (30 ml) solution of compound 167A (WO 2006/11674, 3.58 g, 7.61 mmol) were added (S)—N1-benzyl-3-phenylpropane-1,2-diamine (Journal of the American Chemical Society; English; 127; 30; 2005; 10504, 1.83 g, 7.61 mmol) and acetic acid (0.5 ml), and the mixture was refluxed for 2 hours. After cooling to room temperature, the solvent was distilled off, and the resulting oil was purified by silica gel chromatography. The materials were eluted firstly with n-hexane-ethyl acetate (9:1, v/v) and, then, with n-hexane-ethyl acetate (1:1, v/v). Concentration of an objective fraction afforded 349 mg (yield 7%) of compound 167B as an oil.
1HNMR (CDCl3) δ: 2.54 (1H, t, J=9.6 Hz), 2.77 (1H, dd, J=9.0 Hz, 13.2 Hz), 3.31 (1H, dd, J=6.9 Hz, 9.6 Hz), 3.43-3.78 (5H, m), 4.04-4.15 (1H, m), 4.42-4.48 (1H, m), 4.62 (2H, d, J=6.0 Hz), 5.29 (1H, d, J=10.5 Hz), 5.43 (1H, d, J=10.5 Hz), 6.77-6.85 (2H, m), 7.19-7.39 (14H, m), 7.60 (2H, d, J=6.3 Hz), 8.05 (1H, s).
Second Step
To a MeCN (10 ml) solution of compound 167B (968 mg, 1.47 mmol) were added Boc2O (3 ml) and DMAP (180 mg, 1.47 mmol), and the mixture was heated to reflux for 5 hours. To the reaction solution was added a 2N aqueous sodium hydroxide solution to stop the reaction, the reaction solution was neutralized using 2N hydrochloric acid and, thereafter, the mixture was extracted with ethyl acetate three times. After the extract was washed with an aqueous saturated sodium chloride solution, the solvent was distilled off, and the resulting oil was purified by silica gel chromatography. The materials were eluted firstly with n-hexane-ethyl acetate (6:4, v/v) and, then, only with ethyl acetate. Concentration of an objective fraction afforded 349 mg (yield 45%) of compound 167C.
1HNMR (CDCl3) δ: 2.54 (1H, t=9.0 Hz), 2.76 (1H, dd, J=9.3 Hz, 16.5 Hz), 3.31 (1H, dd, J=6.9 Hz, 9.6 Hz), 3.45 (1H, dd, J=3.3 Hz, 12.6 Hz), 3.51-3.78 (4H, m), 4.04-4.13 (1H, m), 4.42-4.52 (1H, m), 4.61 (2H, d, J=6.0 Hz), 2.79 (1H, d, J=10.2 Hz), 5.29 (1H, d, J=10.2 Hz), 5.43 (1H, d, J=10.2 Hz), 6.76-7.39 (11H, m), 7.60 (2H, d, J=6.6 Hz), 8.05 (1H, s), 10.42 (1H, t, J=5.7 Hz).
Third Step
Compound 167C (150 mg, 0.280 mmol) was dissolved in trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, the residue was dissolved in dichloromethane (2 ml), and the solution was neutralized with saturated sodium bicarbonate water. The resulting solution was made acidic with an aqueous citric acid solution, and the organic layer was separated. The aqueous layer was extracted with dichloromethane once, and the combined organic layers were washed with water, and dried with sodium sulfate. After the solvent was distilled off, the resulting solid was washed with diisopropyl ether to obtain 71 mg (yield 57%) of compound 167.
1HNMR (CDCl3) δ: 2.65 (1H, dd, J=8.4 Hz, 9.6 Hz), 2.97 (1H, dd, J=9 Hz, 13.5 Hz), 3.43 (1J, dd, J=7.2 Hz, 9.6 Hz), 3.55 (1H, dd, J=3.0 Hz, 13.2 Hz), 3.61-3.80 (4H, m), 4.15 (1H, dd, J=4.2 Hz, 9.9 Hz), 4.51-4.60 (1H, m), 7.15-7.18 (2H, m), 7.28-7.38 (8H, m), 8.02 (1H, s), 12.04 (1H, s).
EXAMPLE 168




First Step

To a DMF (3 mL) solution of compound 168A (WO 2006/116764, 400 mg, 0.840 mmol) were added cesium carbonate (821 mg, 2.52 mmol) and, subsequently, bromomethylenedibenzene (311 mg, 1.26 mmol), and the mixture was stirred at 100° C. for 5 hours. To the reaction solution were added 2N hydrochloric acid, water and ethyl acetate, the ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate once. The combined extracts were washed with an aqueous saturated sodium bicarbonate solution and brine, dried with magnesium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography. Concentration of an objective fraction afforded 100 mg of compound 168B as a yellow oil.
1H-NMR (CDCl3) δ: 1.79-1.84 (2H, m), 2.67-2.77 (1H, m), 2.84-3.05 (2H, m), 4.03 (1H, dd, J=13.0, 4.2 Hz), 4.28 (1H, dd, J=13.6, 6.5 Hz), 4.49 (1H, dd, J=6.4, 3.8 Hz), 4.57 (2H, d, J=5.7 Hz), 4.78 (1H, dd, J=13.4, 5.7 Hz), 4.93 (1H, s), 5.27 (2H, s), 7.00 (2H, t, J=8.8 Hz), 7.15-7.37 (14H, m), 7.57-7.63 (2H, m), 7.76 (1H, s), 10.44 (1H, t, J=5.9 Hz).
MS: m/z=643.20 [M+H]+.
Second Step
Compound 168B (100 mg, 0.156 mmol) was dissolved in acetonitrile (3 mL), Boc2O (4.0 mL, 17.3 mmol) and, subsequently, DMAP (84 mg, 0.69 mmol) were added, and the mixture was stirred at 80° C. for 6 hours. The reaction solution was allowed to cool, a 2N aqueous sodium hydroxide solution (8 mL) and, subsequently, ethanol (3 mL) were added, and the mixture was stirred at 60° C. for 2 hours. To the reaction solution were added 2N hydrochloric acid and ethyl acetate, the ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. The solvent was distilled off, and the resulting residue was purified by silica gel chromatography. Elution with ethyl acetate-methanol, and concentration of an objective fraction afforded 84 mg of compound 168C.
MS: m/z=536.25 [M+H]+.
Third Step
To a DMI (2 mL) solution of compound 168C (80 mg, 0.15 mmol) was added lithium chloride (19 mg, 0.45 mmol), and the mixture was stirred at 90° C. for 2 hours. To the reaction mixture were added water and 2N hydrochloric acid, the precipitated solid was filtered, and the resulting solid was purified using a LCMS fractionating device. The eluted solvent was distilled off, to the residue was added isopropyl ether, and the precipitated solid was filtered. Washing with isopropyl ether and drying afforded 12 mg of compound 168.
MS: m/z=446.05 [M+H]+.
EXAMPLE 169




First Step

To an ethanol (5 mL) solution of compound 95A (WO 2006/116764, 500 mg, 2.03 mmol) was added 2,2-dimethoxyethanamine (0.49 ml, 4.47 mmol), and the mixture was stirred at 80° C. for 3 hours. After the reaction solution was allowed to cool, acetic acid (0.27 ml, 4.69 mmol) was added at room temperature, and the mixture was concentrated under reduced pressure. The resulting residue was dissolved in DMF (5 mL), DBU (0.66 mL, 4.4 mmol) and, subsequently, methyl iodide (1.02 mL, 16.2 mmol) were added under nitrogen atmosphere, and the mixture was stirred at room temperature for 3 hours. To the reaction solution were added an aqueous saturated sodium bicarbonate solution and ethyl acetate, the ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. To the combined extracts was added sodium sulfate, the mixture was filtered and concentrated, and the resulting residue was purified by silica gel chromatography. Elution with chloroform-methanol (9:1) and concentration of an objective fraction afforded 258 mg of compound 169A as a brown oil.
1H-NMR (CDCl3) δ: 3.37 (6H, s), 3.80 (3H, s), 3.87 (2H, d, J=4.8 Hz), 4.46 (1H, t, J=4.8 Hz), 5.30 (2H, s), 6.75 (1H, d, J=6.0 Hz), 7.30-7.41 (6H, m).
Second Step
To compound 169A (1.00 g, 2.88 mmol) were added formic acid (31 mL) and, subsequently, water (5 mL), and the mixture was stirred at 70° C. for 6.5 hours. To the reaction mixture were added water and ethyl acetate, the ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. After the combined extracts were washed with an aqueous saturated sodium bicarbonate solution, and sodium sulfate was added, then the mixture was filtered and concentrated, and the resulting residue was purified by silica gel chromatography. Elution with ethyl acetate-methanol, and concentration of an objective fraction afforded a mixture of aldehyde hydride and methylacetal as a colorless transparent oil. The resulting oil was dissolved in dichloromethane (5 mL), 1,3-diaminopropane dihydrochloride (354 mg, 2.41 mmol) and, subsequently, acetic acid (0.069 ml, 1.2 mmol) were added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with dichloromethane, insolubles were filtered and, thereafter, the mixture was concentrated under reduced pressure to obtain a crude purified product of compound 169B.
MS: m/z=326.20 [M+H]+.
Third Step
To an acetonitrile (4 mL) solution of compound 168B (391 mg, 1.20 mmol) were added potassium carbonate (498 mg, 3.61 mmol) and, subsequently, bromomethylenedibenzene (890 mg, 3.61 mmol). After the reaction solution was stirred at 90° C. for 2 hours, to the reaction solution were added water, ethyl acetate and brine, the ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate once. After the combined extracts were dried with magnesium sulfate, then the mixture was filtered and concentrated. The resulting residue was purified by silica gel column chromatography. Elution with ethyl acetate-methanol, and concentration of an objective fraction afforded 106 mg of compound 169C as an orange solid.
MS: m/z=492.15 [M+H]+.
Fourth Step
To a DMI (2 mL) solution of compound 169C (105 mg, 0.214 mmol) was added lithium chloride (27.2 mg, 0.641 mmol), and the mixture was stirred at 90° C. for 3 hours. Further, lithium chloride (27.2 mg, 0.641 mmol) was added, and the mixture was stirred at 90° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified using a LCMS fractionating device. The eluted solvent was distilled off, to the residue was added diethyl ether, and the precipitated solid was filtered. Washing with diethyl ether, and drying afforded 27 mg of compound 169.
1H-NMR (CD3 OD) δ: 1.63 (1H, dd, J=13.4, 2.8 Hz), 1.84 (1H, br s), 2.55-2.64 (1H, m), 2.90-3.10 (2H, m), 4.30 (1H, dd, J=14.5, 4.0 Hz), 4.52 (4H, dd, J=14.5, 3.8 Hz), 4.63-4.75 (4H, m), 5.16 (1H, s), 6.16 (1H, d, J=7.2 Hz), 6.78 (1H, d, J=7.2 Hz), 7.16-7.32 (10H, m).
MS: m/z=402.10 [M+H]+.
EXAMPLE 170




First Step

Compound 49F (87 mg, 0.19 mmol) was dissolved in ethanol (1 ml) and THF (1 ml), a 2N aqueous sodium hydroxide solution (0.47 ml, 0.95 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. To the reaction solution was added 2N hydrochloric acid, the mixture was extracted with ethyl acetate, and the extract was dried with sodium sulfate. The resulting crude product was purified by silica gel column chromatography (chloroform-methanol 95:5→90:10, v/v) to obtain 60 mg of compound 170A.
1H-NMR (CDCl3) δ: 2.48 (1H, dd, J=13.8, 11.8 Hz), 3.27 (1H, dd, J=14.2, 3.4 Hz), 3.73-3.80 (1H, m), 3.92 (1H, m), 4.16 (1H, m), 4.45 (2H, m), 5.34 (1H, d, J=3.5 Hz), 5.47 (1H, d, J=10.4 Hz), 5.52 (1H, d, J=10.7 Hz), 6.73 (2H, d, J=6.9 Hz), 7.18-7.42 (7H, m), 7.60 (2H, d, J=6.9 Hz), 14.63 (1H, s).
Second Step
To compound 170A (57 mg, 0.13 mmol) was added trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, pH was adjusted to 3 with sodium bicarbonate water and 2N hydrochloric acid, then the mixture was extracted with chloroform, and the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, chloroform-ethyl ether were added, and the precipitated solid was filtered to obtain 19 mg of compound 170 as a colorless solid.
1H-NMR (DMSO-d6) δ: 2.74 (1H, t, J=12.1 Hz), 3.10-3.22 (1H, m), 3.76 (2H, m), 4.12 (1H, q, J=8.0 Hz), 4.44 (1H, m), 5.35 (1H, m), 5.49 (1H, d, J=3.4 Hz), 7.05 (5H, m), 7.77 (1H, s), 12.05 (1H, brs).
EXAMPLE 171







First Step

Compound 49B (950 mg, 3.35 mmol), 3-aminopropan-1-ol (277 mg, 3.69 mmol) and sodium sulfate (1.91 g, 13.4 mmol) were added to toluene (25 ml), and the mixture was stirred at room temperature for 1 hour. Boc2O (0.856 ml, 3.69 mmol) was added at room temperature, and the mixture was stirred for 18 hours. Further, Boc2O (0.400 ml, 1.72 mmol) was added at room temperature, and the mixture was stirred for 60 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (n-hexane-ethyl acetate, 1:1, v/v) to obtain 1.02 g of compound 171A as a colorless gummy substance.
Second Step
Compound 171A (1.01 g, 2.29 mmol) and palladium-active carbon (10%, wet, 200 mg) were added to ethanol (20 ml), and the mixture was stirred at room temperature for 1.5 hours under hydrogen atmosphere. After filtration with celite, the solvent was concentrated under reduced pressure to obtain 755 mg of a colorless oily substance 171B.
1H-NMR (CDCl3) δ: 1.42 (5H, s), 1.49 (4H, s), 1.56-1.92 (2H, m), 2.49 (0.4H, dd, J=13.6, 9.8 Hz), 2.62 (0.6H, dd, J=13.6, 8.5 Hz), 2.81 (0.4H, dd, J=13.5, 3.6 Hz), 3.16 (1.6H, m), 3.60-4.14 (4H, m), 5.13 (0.6H, d, J=8.8 Hz), 5.19 (0.4H, d, J=8.5 Hz), 7.22-7.37 (5H, m).
Third Step
Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (660 mg, 1.99 mmol) and compound 171B (609 mg, 1.99 mmol) were added to toluene (8 ml), and the mixture was stirred at 100° C. for 1.5 hours. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 99:1, v/v) to obtain 1.02 g of compound 171C as a pale yellow gummy substance.
Fourth Step
To compound 171C (991 mg, 1.60 mmol) was added 4N HCl (ethyl acetate solution, 12 ml). After the mixture was stirred at room temperature for 1 hour, the solvent was distilled off under reduced pressure. Subsequently, toluene (12 ml) and 3-aminopropan-1-ol (0.244 ml, 3.19 mmol) were added, the mixture was stirred at 80° C. for 10 minutes. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 99:1→95:5→90:10, v/v) to obtain 341 mg of compound 171D as a yellow gummy substance and 338 mg of compound 171E as a colorless solid.
171D: 1H-NMR (CDCl3) δ: 1.29 (3H, t, J=7.1 Hz), 1.51 (1H, d, J=13.7 Hz), 1.97 (1H, m), 2.91 (1H, dd, J=13.8, 9.8 Hz), 2.99-3.10 (2H, m), 3.90 (1H, td, J=12.1, 2.5 Hz), 4.12 (2H, m), 4.25 (2H, m), 4.83 (2H, m), 5.33 (1H, d, J=10.1 Hz), 5.51 (1H, d, J=10.1 Hz), 6.88 (2H, m), 7.23-7.40 (7H, m), 7.68 (2H, m)
171E: 1H-NMR (CDCl3) δ: 1.19 (3H, t, J=7.2 Hz), 1.82-1.99 (2H, m), 2.73 (1H, dd, J=14.0, 11.3 Hz), 3.13 (1H, m), 3.35 (1H, dd, J=14.0, 3.4 Hz), 3.63 (1H, m), 3.90-4.26 (4H, m), 4.43 (1H, d, J=13.6 Hz), 5.27 (1H, t, J=3.5 Hz), 5.31 (2H, s), 6.78 (2H, dd, J=6.3, 3.2 Hz), 7.01 (1H, d, J=7.0 Hz), 7.18 (3H, t, J=3.1 Hz), 7.28-7.39 (3H, m), 7.67 (2H, m).
Fifth Step
Compound 171D (329 mg, 0.673 mmol) was dissolved in ethanol (2 ml) and THF (4 ml), a 2N aqueous sodium hydroxide solution (1.69 ml, 3.38 mmol) was added, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added 2N hydrochloric acid, the mixture was extracted with ethyl acetate, and the extract was dried with sodium sulfate. The solvent was concentrated under reduced pressure to obtain 215 mg of compound 171F as a colorless solid.
MS: m/z=461 [M+H]+.
Sixth Step
To compound 171F (50 mg, 0.11 mmol) was added trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, pH was adjusted to 6 with sodium bicarbonate water and 2N hydrochloric acid, the mixture was extracted with chloroform, and the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, chloroform-methanol-ethyl ether were added, and the precipitated solid was filtered to obtain 24 mg of compound 171 as a colorless solid.
1H-NMR (DMSO-d6) δ: 1.63 (1H, d, J=12.6 Hz), 1.83 (1H, m), 2.96-3.29 (3H, m), 4.05 (2H, m), 4.55 (1H, dd, J=13.2, 4.4 Hz), 5.08 (1H, dd, J=9.2, 5.4 Hz), 5.30 (1H, s), 7.19 (5H, m), 8.09 (1H, s), 12.84 (1H, brs).
MS: m/z=371 [M+H]+.
EXAMPLE 172




According to Example 171, using compound 171E, compound 172 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 1.91 (2H, m), 2.94 (1H, dd, J=14.0, 10.8 Hz), 3.11-3.21 (3H, m), 3.71 (1H, m), 4.19 (1H, m), 4.29-4.35 (1H, m), 5.08-5.14 (1H, m), 5.47 (1H, d, J=4.0 Hz), 6.92-7.22 (5H, m), 7.71 (1H, s), 12.80 (1H, brs), 15.06 (1H, brs).
MS: m/z=371 [M+H]+.
EXAMPLE 173




First Step

Compound 171F (159 mg, 0.345 mmol) was added to diphenyl ether (2.5 ml), and the mixture was stirred at 245° C. for 1 hour under microwave irradiation. The reaction solution was poured into n-hexane, and the precipitated solid was filtered. The resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 95:5→90:10, v/v) to obtain compound 173A.
Second Step
To compound 173A obtained in the first step was added trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, pH was adjusted to 6 with sodium bicarbonate water and 2N hydrochloric acid, the mixture was extracted with chloroform, and the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, methylene chloride-ethyl ether were added, and the precipitated solid was filtered to obtain 10 mg of compound 173 as a colorless solid.
1H-NMR (DMSO-d6) δ: 1.55-1.86 (2H, m), 2.84-3.26 (3H, m), 3.92-4.09 (2H, m), 4.55 (2H, m), 5.15 (1H, s), 5.89 (1H, d, J=7.5 Hz), 7.17 (6H, m), 12.11 (1H, brs)
MS: m/z=327 [M+H]+.
EXAMPLE 174




According to Example 173, compound 174 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 1.86 (2H, m), 2.87 (1H, t, J=12.3 Hz), 3.18 (2H, m), 3.68 (1H, t, J=10.4 Hz), 4.16 (1H, d, J=10.1 Hz), 4.29 (1H, d, J=12.4 Hz), 4.71 (1H, d, J=9.2 Hz), 5.37 (1H, d, J=3.5 Hz), 5.75 (1H, d, J=7.5 Hz), 7.00 (6H, m), 12.51 (1H, brs).
MS: m/z=327 [M+H]+.
EXAMPLE 175







First Step

To Dess-Martin Periodinane (0.3M, methylene chloride solution, 25.0 ml, 7.50 mmol) was added dropwise a methylene chloride solution (10 ml) of compound 2B (1.98 g, 5.48 mmol) at 0° C. After the mixture was stirred at room temperature for 3 hours, the mixture was poured into a 1N aqueous sodium hydroxide solution, and extracted with ethyl ether. The organic layer was washed with a 1N aqueous sodium hydroxide solution and an aqueous saturated sodium chloride solution, and dried with magnesium sulfate. After the solvent was distilled off under reduced pressure, purification was performed by silica gel column chromatography (n-hexane-ethyl acetate, 2:1, v/v) to obtain 1.73 g of compound 175A as a white solid.
1H-NMR (CDCl3) δ: 4.55 (1H, d, J=7.3 Hz), 5.09 (2H, s), 5.14 (2H, m), 7.22-7.35 (15H, m), 9.62 (1H, s).
Second Step
Compound 175A (1.30 g, 4.59 mmol), 3-aminopropan-1-ol (379 mg, 5.05 mmol) and sodium sulfate (3.26 g, 22.4 mmol) were added to toluene (40 ml), and the mixture was stirred at room temperature for 1 hour. Boc2O (1.17 ml, 5.05 mmol) was added at room temperature, and the mixture was stirred for 18 hours. Boc2O (1.17 ml, 5.05 mmol) and sodium sulfate (3.26 g, 22.4 mmol) were added, and the mixture was stirred for 60 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (n-hexane-ethyl acetate, 1:1, v/v) to obtain 635 mg of compound 175B as a colorless solid.
Third Step
Compound 175B (632 mg, 1.22 mmol) and palladium-active carbon (10%, wet, 100 mg) were added to ethanol (10 ml) and THF (5 ml), and the mixture was stirred at room temperature for 3 hours under hydrogen atmosphere. After filtration with celite, the solvent was concentrated under reduced pressure to obtain 502 mg of a colorless oily substance 175C.
1H-NMR (CDCl3) δ: 1.45 (9H, s), 1.77 (2H, m), 3.18-3.27 (1H, m), 3.43-3.51 (1H, m), 4.04 (4H, m), 4.92 (1H, d, J=4.7 Hz), 7.28 (10H, m).
Fourth Step
Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (390 mg, 1.22 mmol) and compound 175C (468 mg, 1.22 mmol) were added to toluene (5 ml), and the mixture was stirred at 100° C. for 2 hours. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (n-hexane-ethyl acetate, 1:1, v/v) to obtain 391 mg of compound 175D as a pale yellow gummy substance.
Fifth Step
To compound 175D (388 mg, 0.568 mmol) was added 4N HCl (ethyl acetate solution, 4 ml). After the mixture was stirred at room temperature for 1 hour, the solvent was distilled off under reduced pressure. Subsequently, toluene (4 ml) and 3-aminopropan-1-ol (0.0870 ml, 1.14 mmol) were added, and the mixture was stirred at 80° C. for 5 hours. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 98:2, v/v) to obtain 57 mg of compound 175E as a yellow gummy substance and 44 mg of compound 175F as a brown gummy substance.
175E: 1H-NMR (CDCl3) δ: 1.91-2.00 (2H, m), 2.87 (1H, m), 3.78 (3H, s), 3.87-4.15 (3H, m), 4.61 (1H, d, J=12.1 Hz), 4.78 (2H, m), 5.33 (1H, d, J=10.2 Hz), 5.63 (1H, d, J=10.2 Hz), 6.95 (2H, m), 7.13-7.53 (12H, m), 7.76 (2H, m)
175F: 1H-NMR (CDCl3) δ: 1.83-1.97 (2H, m), 3.12-3.22 (1H, m), 3.50 (1H, m), 3.85 (3H, s), 3.90 (1H, m), 4.34-4.40 (1H, m), 4.74 (1H, d, J=8.6 Hz), 4.84-4.89 (1H, m), 5.09 (1H, d, J=3.3 Hz), 5.15 (1H, d, J=9.9 Hz), 5.26 (1H, d, J=9.6 Hz), 7.08-7.50 (13H, m), 7.65-7.77 (3H, m).
Sixth Step
Compound 175E (57 mg, 0.10 mmol) was dissolved in THF (0.5 ml) and ethanol (0.5 ml), a 2N aqueous sodium hydroxide solution (0.25 ml, 0.50 mmol) was added at room temperature, and the mixture was stirred for 1 hour. After 1N hydrochloric acid was added, and the mixture was extracted with chloroform, the extract was dried with sodium sulfate. The solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 98:2, v/v) to obtain compound 175G.
Seventh Step
To compound 175G obtained in the sixth step was added trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, pH was adjusted to 3 with sodium bicarbonate water and 2N hydrochloric acid, then the mixture was extracted with chloroform, and the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, chloroform-methanol-ethyl ether were added, and the precipitated solid was filtered to obtain 11 mg of compound 175 as a colorless solid.
1H-NMR (DMSO-d6) δ: 1.50 (1H, d, J=13.1 Hz), 1.79 (1H, m), 3.17 (1H, m), 3.86 (1H, t, J=11.0 Hz), 4.03 (1H, dd, J=10.8, 4.1 Hz), 4.46 (1H, d, J=12.0 Hz), 4.53 (1H, dd, J=12.7, 4.2 Hz), 4.84 (1H, s), 5.85 (1H, d, J=11.7 Hz), 7.22 (7H, m), 7.44 (2H, t, J=7.6 Hz), 7.65 (2H, d, J=7.3 Hz), 8.14 (1H, s), 12.75 (1H, s), 15.33 (1H, brs).
MS: m/z=447 [M+H]+.
EXAMPLE 176




According to Example 175, using compound 175F, compound 176 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 1.75 (2H, m), 3.17 (2H, m), 3.43 (1H, m), 3.60 (1H, d, J=10.7 Hz), 4.31 (1H, d, J=12.7 Hz), 4.73 (1H, d, J=9.8 Hz), 5.52 (1H, d, J=3.4 Hz), 5.87 (1H, dd, J=9.9, 3.4 Hz), 7.10 (7H, m), 7.29 (2H, t, J=7.5 Hz), 7.58 (2H, d, J=7.3 Hz), 8.37 (1H, s), 12.65 (1H, brs).
MS: m/z=447 [M+H]+.
EXAMPLE 177




First Step

Tert-butyl pyrazolidine-1-carboxylate (275 mg, 1.60 mmol) synthesized according to the method of the reference (Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1975, p. 1712), and compound 95B (409 mg, 1.45 mmol) were dissolved in pyridine (5 ml), HATU (607 mg, 1.60 mmol) was added at room temperature, and the mixture was stirred for 18 hours. The reaction solution was poured into 1N hydrochloric acid, then the mixture was extracted with ethyl acetate, and the extract was dried with sodium sulfate The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 97:3→95:5, v/v) to obtain 529 mg of compound 177A as a yellow solid.
1H-NMR (CDCl3) δ: 1.35 (9H, s), 1.88-2.10 (2H, m), 3.04 (1H, s), 3.31 (1H, s), 3.86 (2H, m), 4.96 (1H, d, J=9.3 Hz), 5.45 (1H, d, J=11.0 Hz), 6.56 (1H, d, J=6.7 Hz), 7.29-7.43 (6H, m).
Second Step
To compound 177A (525 mg, 1.31 mmol) was added 4N HCl (dioxane solution, 6 ml). After the mixture was stirred at room temperature for 1.5 hours, the solvent was distilled off under reduced pressure to obtain 413 mg of compound 177B as a colorless solid.
1H-NMR (DMSO-d6) δ: 1.95-2.05 (2H, m), 2.78 (2H, t, J=6.6 Hz), 3.41-3.54 (2H, m), 5.11 (2H, s), 7.38 (5H, m), 7.46 (1H, d, J=6.6 Hz), 8.36 (1H, d, J=6.7 Hz).
Third Step
Compound 177B (100 mg, 0.298 mmol) was added to ethanol (2 ml), 2,2-diphenylacetaldehyde (58 mg, 0.30 mmol), triethylamine (0.083 ml, 0.596 mmol) and acetic acid (0.051 ml, 0.89 mmol) were added, and the mixture was stirred at 80° C. for 3 hours. The reaction solution was poured into water, the mixture was extracted with chloroform, and the extract was dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 97:3→95:5→93:7→90:10, v/v) to obtain 106 mg of compound 177C as a yellow gummy substance.
MS: m/z=478 [M+H]+.
Fourth Step
To compound 177C obtained in the third step was added trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, pH was adjusted to 6 with sodium bicarbonate water and 2N hydrochloric acid, the mixture was extracted with chloroform, and the extract was dried with sodium sulfate. After the solvent was distilled off under reduced pressure, methylene chloride-ethyl ether were added, and the precipitated solid was filtered to obtain 7 mg of compound 177 as a colorless solid.
1H-NMR (DMSO-d6) δ: 1.95 (2H, m), 2.76 (1H, m), 2.96-3.17 (2H, m), 4.04 (1H, m), 4.68 (1H, d, J=10.4 Hz), 5.66 (1H, d, J=7.3 Hz), 6.56 (1H, d, J=10.5 Hz), 7.03 (1H, d, J=7.2 Hz), 7.17 (6H, m), 7.34 (2H, t, J=7.3 Hz), 7.55 (2H, d, J=7.5 Hz).
MS: m/z=388 [M+H]+.
EXAMPLE 178




According to Example 177, compound 178 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 1.55 (4H, m), 2.35-7.49 (1H, m), 2.39 (1H, t, J=12.6 Hz), 2.77 (1H, t, J=10.0 Hz), 3.09 (1H, d, J=11.4 Hz), 4.34 (1H, d, J=12.8 Hz), 4.55 (1H, d, J=10.8 Hz), 5.71 (1H, d, J=7.0 Hz), 6.17 (1H, d, J=10.8 Hz), 6.82 (1H, d, J=7.3 Hz), 7.13-7.40 (8H, m), 7.48 (2H, d, J=7.3 Hz).
MS: m/z=402 [M+H]+.
EXAMPLE 179




According to Example 177, compound 179 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 1.31 (6H, m), 2.68 (2H, m), 3.21 (1H, m), 4.04 (1H, m), 4.40 (1H, d, J=10.8 Hz), 5.77 (1H, t, J=5.2 Hz), 6.26 (1H, d, J=10.8 Hz), 6.78 (1H, d, J=7.3 Hz), 7.27 (8H, m), 7.53 (2H, d, J=7.2 Hz).
MS: m/z=416 [M+H]+.
EXAMPLE 180




According to Example 177, compound 180 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 2.78-3.74 (7H, m), 4.17 (1H, m), 4.49 (1H, d, J=10.8 Hz), 5.79 (1H, d, J=7.2 Hz), 6.32 (1H, d, J=10.8 Hz), 6.79 (1H, d, J=7.2 Hz), 7.28 (8H, m), 7.55 (2H, d, J=7.6 Hz).
MS: m/z=418 [M+H]+.
Using amines which are commercially available or known in the references and halides which are commercially available or known in the references, and according to the method of Example 12, Examples 181 to 187 were synthesized.
EXAMPLE 181




MS: m/z=433 [M+H]+.
EXAMPLE 182




MS: m/z=459 [M+H]+.
EXAMPLE 183




MS: m/z=529 [M+H]+.
EXAMPLE 184




MS: m/z=477 [M+H]+.
EXAMPLE 185




MS: m/z=473 [M+H]+.
EXAMPLE 186




MS: m/z=447 [M+H]+.
EXAMPLE 187




MS: m/z=461 [M+H]+.
EXAMPLE 188




According to Example 12 and Example 129, compound 188 was synthesized by the same procedure.
MS: m/z=449 [M+H]+.
Using amines which are commercially available or known in the references and halides which are commercially available or known in the references, and according to the method of Example 95, Examples 189 to 229 were synthesized.
EXAMPLE 189




MS: m/z=399 [M+H]+
EXAMPLE 190




MS: m/z=488 [M+H]+
EXAMPLE 191




MS: m/z=470 [M+H]+
EXAMPLE 192




MS: m/z=422 [M+H]+
EXAMPLE 193




MS: m/z=422 [M+H]+
EXAMPLE 194




MS: m/z=486 [M+H]+
EXAMPLE 195




MS: m/z=365 [M+H]+
EXAMPLE 196




MS: m/z=418 [M+H]+
EXAMPLE 197




MS: m/z=339 [M+H]+
EXAMPLE 198




MS: m/z=344 [M+H]+
EXAMPLE 199




MS: m/z=383 [M+H]+
EXAMPLE 200




MS: m/z=339 [M+H]+
EXAMPLE 201




MS: m/z=440 [M+H]+
EXAMPLE 202




MS: m/z=365 [M+H]+
EXAMPLE 203




MS: m/z=396 [M+H]+
EXAMPLE 204




MS: m/z=370 [M+H]+
EXAMPLE 205




MS: m/z=390 [M+H]+
EXAMPLE 206




MS: m/z=420 [M+H]+
EXAMPLE 207




MS: m/z=350 [M+H]+
EXAMPLE 208




MS: m/z=428 [M+H]+
EXAMPLE 209




MS: m/z=386 [M+H]+
EXAMPLE 210




MS: m/z=378 [M+H]+
EXAMPLE 211




MS: m/z=366 [M+H]+
EXAMPLE 212




MS: m/z=362 [M+H]+
EXAMPLE 213




MS: m/z=358 [M+H]+
EXAMPLE 214




MS: m/z=350 [M+H]+
EXAMPLE 215




MS: m/z=350 [M+H]+
EXAMPLE 216




MS: m/z=411 [M+H]+
EXAMPLE 217




MS: m/z=445 [M+H]+
EXAMPLE 218




MS: m/z=366 [M+H]+
EXAMPLE 219




MS: m/z=354 [M+H]+
EXAMPLE 220




MS: m/z=368 [M+H]+
EXAMPLE 221




MS: m/z=314 [M+H]+
EXAMPLE 222




MS: m/z=330 [M+H]+
EXAMPLE 223




MS: m/z=346 [M+H]+
EXAMPLE 224




MS: m/z=418 [M+H]+.
EXAMPLE 225




MS: m/z=445 [M+H]+.
EXAMPLE 226




MS: m/z=473 [M+H]+.
EXAMPLE 227




MS: m/z=444 [M+H]+.
EXAMPLE 228




MS: m/z=434 [M+H]+.
EXAMPLE 229




MS: m/z=443 [M+H]+.
EXAMPLE 230




According to Example 128, compound 230 was synthesized by the same procedure.
MS: m/z=461 [M+H]+.
EXAMPLE 231




According to Example 129, compound 231 was synthesized by the same procedure.
MS: m/z=420 [M+H]+.
EXAMPLE 232




According to Example 129, compound 232 was synthesized by the same procedure.
MS: m/z=434 [M+H]+.
EXAMPLE 233




According to Example 130, compound 233 was synthesized by the same procedure.
MS: m/z=433 [M+H]+.
EXAMPLE 234




According to Example 130, compound 234 was synthesized by the same procedure.
MS: m/z=447 [M+H]+.
EXAMPLE 235




According to Example 130, compound 235 was synthesized by the same procedure
MS: m/z=473 [M+H]+.
EXAMPLE 236




According to Example 130, compound 236 was synthesized by the same procedure.
MS: m/z=447 [M+H]+.
EXAMPLE 237




According to Example 130, compound 237 was synthesized by the same procedure.
MS: m/z=487 [M+H]+.
EXAMPLE 238




According to Example 130, compound 238 was synthesized by the same procedure.
MS: m/z=509 [M+H]+.
EXAMPLE 239




MS: m/z=376 [M+H]+
According to Example 157, compound 239 was synthesized by the same procedure.
Using amines which are commercially available or known in the references and alcohols which are commercially available or known in the references, and according to the method of Example 107, Examples 240 to 245 were synthesized.
EXAMPLE 240




1H-NMR (CDCl3) δ: 1.05 (3H, d, J=6.9 Hz), 1.04-1.14 (4H, m), 4.49 (1H, d, J=13.2 Hz), 4.83 (1H, d, J=13.2 Hz), 4.91-4.99 (1H, m), 5.73 (1H, d, J=7.8 Hz), 6.50 (1H, s), 6.70 (1H, d, J=7.8 Hz), 7.12-7.30 (4H, m), 7.33-7.43 (2H, m), 7.46-7.54 (1H, m), 8.06 (1H, d, J=7.5 Hz).
EXAMPLE 241




MS: m/z=478 [M+H]+
EXAMPLE 242




MS: m/z=478 [M+H]+
EXAMPLE 243




MS: m/z=478 [M+H]+
EXAMPLE 244




1H-NMR (CDCl3) δ: 1.14 (6H, d, J=6.9 Hz), 4.59 (1H, d, J=12.6 Hz), 4.77 (1H, d, J=12.6 Hz), 4.81-4.91 (1H, m), 5.82 (1H, d, J=7.5 Hz), 5.82 (1H, s), 6.71 (1H, brs), 6.78 (1H, brs), 6.87 (1H, d, J=7.5 Hz), 7.05 (1H, brs), 7.16 (1H, brs), 7.25 (1H, brs), 7.41 (1H, brs).
EXAMPLE 245




MS: m/z=490 [M+H]+.
EXAMPLE 246







First Step

To a dimethylformamide (20 ml) solution of compound 246A (5.30 g, 18.76 mmol) and potassium carbonate (5.19 g, 27.53 mmol) was added benzyl bromide (3.21 g, 18.76 mmol), and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added ethyl acetate (80 ml), insolubles were filtered off, and 1N hydrochloric acid was added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate two times. The combined organic layers were washed with water once and, further, washed with sodium bicarbonate water once, and with an aqueous saturated sodium chloride solution once. The resulting solution was dried with sodium sulfate, and the solvent was distilled off to obtain 6.98 g of compound 246B as an oil.
1H-NMR (CDCl3) δ: 5.36 (2H, s), 7.35-7.47 (6H, m), 7.78 (1H, d, J=8.4 Hz), 8.01 (1H, d, J=2.1 Hz).
Second Step
To a dimethylformamide (15 ml) solution of compound 246B (3 g, 8.05 mmol) and 1-chloro-3-ethynylbenzene (1.32 g, 9.66 mmol) and triethylamine (4.07 g, 40.25 mmol) were added copper chloride (76.6 mg, 0.403 mmol) and dichlorobis(triphenylphosphine)palladium (282.5 mg, 0.403 mmol) under nitrogen atmosphere, and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with water, and the mixture was extracted with ethyl acetate three times. The combined extracts were washed with water three times, and dried with sodium sulfate, then the solvent was distilled off. The resulting oil was purified by silica gel column chromatography. The material were eluted firstly with hexane and, then, with hexane-ethyl acetate (7:3, v/v). Concentration of an objective fraction afforded 3.10 g of compound 246C as an oil.
1H-NMR (CDCl3) δ: 5.39 (2H, s), 7.21-7.46 (9H, m), 7.62 (1H, d, J=2.1 Hz), 7.98 (1H, d, J=8.4 Hz).
Third Step
To a methanol (30 ml) solution of compound 246C (3.10 g, 8.05 mmol) was added 10% palladium carbon (620 mg, 20 wt %), and the mixture was stirred at room temperature under 1 atm hydrogen atmosphere. The reaction solution was filtered with celite, the solvent was distilled off, to the resulting crude product were added ethyl acetate-diisopropyl ether, and the precipitated residue was filtered to obtain 618 mg of compound 246D as a solid.
1H-NMR (CDCl3) δ: 2.90 (2H, dd, J=7.8 Hz, 10.8 Hz), 3.29 (2H, dd, J=7.5 Hz, 10.5 Hz), 7.06-7.09 (1H, m), 7.18-7.25 (4H, m), 7.31 (1H, dd, J=2.1 Hz, 8.7 Hz), 8.05 (1H, d, J=8.4 Hz).
Fourth Step
To compound 246D (2.20 g, 7.45 mmol) was added polyphosphoric acid (20 g), and the mixture was stirred at 200° C. for 1 hour. After cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate three times. The combined extracts were washed with saturated sodium bicarbonate water, and dried with sodium sulfate and, thereafter, the solvent was distilled off. The resulting oil was purified by silica gel column chromatography. The materials were eluted firstly with hexane and, then, with hexane-ethyl acetate (7:3, v/v). Concentration of an objective fraction afforded 1.05 g of compound 246E as an oil.
1H-NMR (CDCl3) δ: 3.17 (4H, s), 7.24 (2H, d, J=2.1 Hz), 7.32 (2H, dd, J=2.1 Hz, 8.4 Hz, 8.00 (2H, d, J=8.4 Hz).
Fifth Step
A methanol (10 ml) suspension of sodium borohydride (409 mg, 10.82 mmol) was cooled to 1 to 3° C., and compound 246E (1.0 g, 3.61 mmol) was added while the same temperature was retained. After the reaction solution was stirred at the same temperature for 30 minutes, water was added. The precipitated solid was filtered to obtain 968 mg of compound 246F.
1H-NMR (CDCl3) δ: 2.25 (1H, d, J=3.0 Hz), 3.05-3.16 (2H, m), 3.27-3.38 (2H, m), 5.95 (1H, d, J=3.0 Hz), 7.14-7.17 (4H, m), 7.39 (2H, d, J=8.1 Hz).
Sixth Step
According to Example 107, compound 246 was synthesized by the same procedure.
1H-NMR (CDCl3) δ: 1.14 (3H, d, J=6.9 Hz), 1.20 (3H, d, J=6.9 Hz), 2.79 (1H, ddd, J=4.5 Hz, 4.5 Hz, 14.4 Hz), 2.99-3.11 (1H, m), 3.50 (1H, ddd, J=4.8 Hz, 4.8 Hz), 17.7 Hz), 4.21-4.33 (1H, m), 4.23 (1H, d, J=12.9 Hz), 4.62-4.74 (2H, m), 5.04 (1H, s), 5.84 (1H, d, J=7.8 Hz), 6.57 (1H, d, J=8.1 Hz), 6.65-6.72 (2H, m), 6.89-6.92 (1H, m), 7.11-7.30 (4H, m).
Using amines which are commercially available or known in the references and intermediates corresponding to compound 246A to compound 246F which are commercially available or known in the references, and according to the method of Example 246, compounds 247 to 284 were synthesized.
EXAMPLE 247




MS: m/z=457 [M+H]+.
EXAMPLE 248




MS: m/z=485 [M+H]+.
EXAMPLE 249




MS: m/z=471 [M+H]+.
EXAMPLE 250




MS: m/z=457 [M+H]+.
EXAMPLE 251




MS: m/z=521 [M+H]+.
EXAMPLE 252




MS: m/z=485 [M+H]+.
EXAMPLE 253




MS: m/z=471 [M+H]+.
EXAMPLE 254




MS: m/z=487 [M+H]+.
EXAMPLE 255




MS: m/z=469 [M+H]+.
EXAMPLE 256




MS: m/z=470 [M+H]+.
EXAMPLE 257




MS: m/z=434 [M+H]+.
EXAMPLE 258




1H-NMR (DMSO-d6) δ: 2.88 (3H, m), 3.43 (2H, m), 3.69 (1H, dt, J=16.9, 5.1 Hz), 4.01 (1H, d, J=13.4 Hz), 4.07-4.17 (2H, m), 4.97 (1H, d, J=13.4 Hz), 5.24 (1H, s), 5.50 (1H, d, J=7.6 Hz), 6.73 (1H, d, J=7.2 Hz), 6.85-6.94 (2H, m), 7.14-7.41 (6H, m), 11.73 (1H, s).
MS: m/z=432 [M+H]+.
EXAMPLE 259




1H-NMR (DMSO-d6) δ: 2.80 (1H, td, J=9.6, 4.5 Hz), 2.86-2.99 (1H, m), 3.00-3.18 (1H, m), 3.67 (1H, dt, J=17.1, 5.0 Hz), 4.03-4.19 (2H, m), 4.32-4.52 (1H, m), 5.05 (1H, d, J=13.3 Hz), 5.26 (1H, s), 5.53 (1H, d, J=7.6 Hz), 6.17 (1H, tt, J=55.0, 3.5 Hz), 6.72 (1H, d, J=7.5 Hz), 6.87-6.94 (2H, m), 7.12-7.27 (3H, m), 7.30-7.43 (3H, m).
MS: m/z=438 [M+H]+.
EXAMPLE 260




MS: m/z=460 [M+H]+.
EXAMPLE 261




MS: m/z=474 [M+H]+.
EXAMPLE 262




1H-NMR (DMSO-d6) δ: 2.80 (1H, dt, J=14.2, 5.1 Hz), 2.86-2.99 (1H, m), 3.00-3.18 (1H, m), 3.68 (1H, dt, J=16.9, 5.3 Hz), 4.05 (1H, d, J=13.3 Hz), 4.07-4.32 (2H, m), 4.37-4.52 (1H, m), 4.53-4.67 (1H, m), 5.02 (1H, d, J=13.0 Hz), 5.26 (1H, s), 5.50 (1H, d, J=7.8 Hz), 6.73 (1H, d, J=7.6 Hz), 6.85-6.94 (2H, m), 7.12-7.27 (3H, m), 7.30-7.43 (3H, m).
MS: m/z=420 [M+H]+.
EXAMPLE 263




1H-NMR (DMSO-d6) δ: 2.76-3.00 (2H, m), 3.46-3.73 (2H, m), 4.06-4.22 (2H, m), 4.77-4.91 (1H, m), 5.15 (1H, d, J=12.9 Hz), 5.24 (1H, s), 5.56 (1H, d, J=7.7 Hz), 6.72 (1H, d, J=7.1 Hz), 6.88-6.95 (1H, m), 6.96 (1H, d, J=7.7 Hz), 7.09-7.41 (7H, m).
MS: m/z=456 [M+H]+
EXAMPLE 264




1H-NMR (DMSO-d6) δ: 2.74-2.99 (2H, m), 3.62-3.73 (1H, m), 4.01-4.20 (3H, m), 5.12 (1H, d, J=13.2 Hz), 5.15 (1H, d, J=15.7 Hz), 5.34 (1H, s), 5.52 (1H, d, J=7.7 Hz), 6.78 (1H, d, J=8.0 Hz), 6.89-6.96 (2H, m), 7.10-7.23 (5H, m), 7.27-7.35 (3H, m), 7.43 (1H, d, J=7.7 Hz), 7.79 (1H, td, J=7.6, 1.8 Hz), 8.45-8.50 (1H, m).
MS: m/z=465 [M+H]+.
EXAMPLE 265




1H-NMR (DMSO-d6) δ: 1.32 (9H, s), 2.76-2.86 (1H, m), 2.87-3.01 (1H, m), 3.59-3.70 (1H, m), 4.12-4.25 (1H, m), 4.29 (1H, d, J=13.5 Hz), 4.90 (1H, d, J=13.2 Hz), 5.20 (1H, s), 5.49 (1H, d, J=7.4 Hz), 6.75 (1H, d, J=8.0 Hz), 6.81 (1H, d, J=7.4 Hz), 6.91 (1H, t, J=6.6 Hz), 7.12-7.21 (2H, m), 7.22-7.30 (1H, m), 7.33-7.38 (2H, m), 7.46 (1H, d, J=7.4 Hz).
MS: m/z=430 [M+H]+.
EXAMPLE 266




1H-NMR (DMSO-d6) δ: 1.05 (3H, t, J=7.2 Hz), 2.80 (1H, dt, J=14.4, 5.1 Hz), 2.85-2.99 (2H, m), 3.68 (1H, dt, J=16.8, 5.0 Hz), 3.74-3.87 (1H, m), 4.02 (1H, d, J=13.3 Hz), 4.06-4.19 (1H, m), 4.98 (1H, d, J=13.1 Hz), 5.22 (1H, s), 5.48 (1H, d, J=7.6 Hz), 6.73 (1H, d, J=7.5 Hz), 6.83-6.94 (2H, m), 7.12-7.40 (6H, m).
MS: m/z=402 [M+H]+.
EXAMPLE 267




1H-NMR (CDCl3) δ: 1.74-1.86 (2H, m), 2.71-2.82 (1H, m), 2.83-2.93 (1H, m), 2.98-3.11 (1H, m), 3.25 (3H, s), 3.39 (2H, t, J=5.4 Hz), 3.62-3.74 (1H, m), 4.02-4.14 (2H, m), 4.16-4.28 (1H, m), 4.82 (1H, d, J=13.2 Hz), 5.03 (1H, s), 5.76 (1H, d, J=7.7 Hz), 6.58 (1H, d, J=7.7 Hz), 6.64 (1H, d, J=7.4 Hz), 6.89-6.97 (1H, m), 7.12-7.39 (6H, m).
MS: m/z=446 [M+H]+.
EXAMPLE 268




1H-NMR (CDCl3) δ: 1.09 (3H, t, J=7.0 Hz), 2.65-2.77 (1H, m), 2.83-2.94 (1H, m), 2.97-3.10 (1H, m), 3.40 (2H, q, J=7.0 Hz), 3.45-3.52 (1H, m), 3.55-3.64 (1H, m), 3.65-3.76 (1H, m), 4.00-4.15 (2H, m), 4.36-4.45 (1H, m), 4.90 (1H, d, J=13.5 Hz), 5.02 (1H, s), 5.79 (1H, d, J=7.7 Hz), 6.59 (1H, d, J=7.7 Hz), 6.63 (1H, d, J=7.4 Hz), 6.90-6.97 (1H, m), 7.13-7.39 (6H, m).
MS: m/z=446 [M+H]+.
EXAMPLE 269




MS: m/z=480 [M+H]+.
EXAMPLE 270




1H-NMR (DMSO-d6) δ: 2.33 (3H, s), 2.85 (2H, m), 3.68 (1H, m), 4.16 (1H, m), 4.29 (1H, d, J=13.3 Hz), 4.45 (1H, d, J=17.1 Hz), 5.12 (1H, d, J=13.1 Hz), 5.26 (1H, d, J=17.4 Hz), 5.36 (1H, s), 5.55 (1H, d, J=7.6 Hz), 6.74 (1H, d, J=7.6 Hz), 6.89-7.38 (8H, m).
MS: m/z=470 [M+H]+.
EXAMPLE 271




1H-NMR (DMSO-d6) δ: 2.87 (2H, m), 3.61-3.69 (1H, m), 4.15 (1H, m), 4.18 (1H, d, J=13.2 Hz), 4.51 (1H, d, J=15.9 Hz), 5.08 (1H, d, J=13.1 Hz), 5.21 (1H, s), 5.22 (1H, d, J=15.6 Hz), 5.52 (1H, d, J=7.6 Hz), 6.72 (1H, d, J=7.5 Hz), 6.89-7.32 (8H, m), 7.76 (2H, s).
MS: m/z=471 [M+H]+.
EXAMPLE 272




MS: m/z=476 [M+H]+.
EXAMPLE 273




1H-NMR (CDCl3) δ: 2.84-2.93 (1H, m), 2.98 (3H, s), 2.98-3.09 (1H, m), 3.66-3.75 (1H, m), 3.99-4.15 (1H, m), 4.06 (1H, d, J=12.9 Hz), 4.80 (1H, d, J=13.2 Hz), 5.03 (1H, s), 5.74 (1H, d, J=7.5 Hz), 6.56 (1H, d, J=7.5 Hz), 6.63 (1H, d, J=6.6 Hz), 6.90-6.96 (1H, m), 7.14-7.37 (6H, m).
EXAMPLE 274




MS: m/z=470 [M+H]+.
EXAMPLE 275




MS: m/z=470 [M+H]+.
EXAMPLE 276




MS: m/z=460 [M+H]+
EXAMPLE 277




MS: m/z=486 [M+H]+.
EXAMPLE 278




MS: m/z=446 [M+H]+
EXAMPLE 279




1H-NMR (CDCl3) δ: 1.08-1.21 (6H, m), 2.84 (1H, ddd, J=4.8 Hz, 4.8 Hz, 14.4 Hz), 2.97-3.08 (1H, m), 3.54 (1H, ddd, J=4.8 Hz, 6.6 Hz, 17.1 Hz), 4.09-4.26 (1H, m), 4.24 (1H, d, J=13.2 Hz), 4.64-4.74 (m, 1H), 4.70 (1H, d, J=13.2 Hz), 4.94 (1H, s), 5.81 (1H, d, J=7.8 Hz), 6.42 (1H, dd, J=2.7 Hz, 9.0 Hz), 6.67 (1H, d, J=7.8 Hz), 6.89-7.12 (4H, m), 7.19-7.36 (1H, m).
EXAMPLE 280




1H-NMR (CDCl3) δ: 1.15 (3H, d, J=6.9 Hz), 1.20 (3H, d, J=6.9 Hz), 2.84 (1H, ddd, J=4.8 Hz, 5.1 Hz, 14.4 Hz), 2.96-3.07 (1H, m), 3.55 (1H, ddd, J=4.8 Hz, 5.1 Hz, 17.4 Hz), 4.11-4.23 (1H, m), 4.21 (1H, d, J=12.9 Hz), 4.65-4.74 (1H, m), 4.70 (1H, d, J=12.9 Hz), 4.95 (1H, s), 5.78 (1H, d, J=7.8 Hz), 6.63 (1H, d, J=7.8 Hz), 6.69 (1H, d, J=2.1 Hz), 7.06 (1H, d, J=8.4 Hz), 7.18 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.23-7.26 (2H, m), 7.24 (1H, dd, J=2.1 Hz, 8.1 Hz).
EXAMPLE 281




1H-NMR (CDCl3) δ: 1.13 (3H, d, J=6.6 Hz), 1.20 (3H, d, J=6.9 Hz), 2.90-3.32 (1H, m), 3.36 (1H, ddd, J=4.5 Hz, 4.5 Hz, 9.6 Hz), 3.42-3.51 (1H, m), 3.95-4.02 (1H, m), 4.28 (1H, d, J=12.9 Hz), 4.64-4.75 (1H, m), 1.89 (1H, d, J=12.9 Hz), 5.15 (1H, s), 5.80 (1H, d, J=7.5 Hz), 6.46-6.49 (1H, m), 6.70 (1H, d, J=7.8 Hz), 6.88-7.00 (2H, m), 7.03-7.06 (1H, m), 7.11-7.22 (2H, m).
EXAMPLE 282




1H-NMR (CDCl3) δ: 1.09-1.19 (6H, m), 2.80-3.10 (2H, m), 3.40-3.60 (1H, m), 4.16-4.41 (2H, m), 4.61-4.47 (2H, m), 5.06-5.10 (1H, m), 5.71 (0.45H, d, J=7.5 Hz), 5.74 (0.55H, d, J=7.8 Hz), 6.60-6.72 (2H, m), 6.86-6.94 (1H, m), 7.10-7.46 (6H, m).
EXAMPLE 283




1H-NMR (CDCl3) δ: 1.10-1.21 (6H, m), 2.75-2, 86 (1H, m), 2.99-3.14 (1H, m), 4.23-4.37 (2H, m), 4, 59-4.74 (2H, m), 5.04 (1H, s), 5.67-5.80 (1H, m), 6.58-6.67 (2H, m), 6.88-7.08 (1H, m), 7.11-7.38 (5H, m).
EXAMPLE 284




1H-NMR (CDCl3) δ: 1.15 (3H, d, J=6.9 Hz), 1.20 (3H, d, J=6.9 Hz), 2.80 (1H, ddd, J=4.5 Hz, 4.5 Hz, 9.9 Hz), 3.07 (1H, t, J=3.9 Hz, 13.2 Hz, 13.2 Hz), 3.50 (1H, ddd, J=4.2 Hz, 4.2 Hz, 18.0 Hz), 4.24 (1H, 6.9 Hz), 4.34 (1H, ddd, J=4.2 Hz, 13.5 Hz, 13.5 Hz), 4.63-4.74 (2H, m), 5.06 (1H, s), 5.81 (1H, d, J=7.8 Hz), 6.57-6.64 (2H, m), 6.65 (1H, d, J=7.5 Hz), 6.82 (1H, d, J=9.3 Hz), 6.90 (1H, ddd, J=2.7 Hz, 8.4 Hz, 8.4 Hz), 7.02 (1H, dd, J=2.7 Hz, 9.0 Hz), 7.19-7.26 (2H, m).
Example 285







First Step

Compound 285A (5.00 g, 29.3 mmol) was dissolved in dimethylformamide (150 ml), potassium carbonate (14.2 mmol) and iodoethane (7.11 ml, 88.0 mmol) were added, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added hexane, and the mixture was washed with water and an aqueous saturated sodium chloride solution. The organic layer was dried with sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a colorless oily substance 285B.
1H-NMR (CDCl3) δ: 1.40 (3H, t, J=7.2 Hz), 2.60 (3H, s), 4.37 (2H, q, J=7.1 Hz), 7.17 (1H, td, J=7.9, 0.6 Hz), 7.49 (1H, ddd, J=8.0, 1.4, 0.4 Hz), 7.68 (1H, ddd, J=7.8, 1.4, 0.3 Hz).
Second Step
Compound 285B (5.63 g, 28.3 mmol) obtained in the first step was dissolved in carbon tetrachloride (150 ml), N-bromosuccinimide (5.55 g, 31.2 mmol) was added, and the mixture was stirred at 100° C. for 18 hours. The reaction solution was cooled to room temperature, and washed with water and an aqueous saturated sodium chloride solution. The organic layer was dried with sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 8.08 g of an orange oily substance 285C.
1H-NMR (CDCl3) δ: 1.43 (3H, t, J=7.6 Hz), 4.42 (2H, q, J=7.1 Hz), 5.10 (2H, s), 7.31 (1H, t, J=8.6 Hz), 7.57 (1H, d, J=8.1 Hz), 7.84 (1H, d, J=8.1 Hz).
Third Step
Compound 285C (2.17 g, 7.8 mmol) obtained in the second step was dissolved in acetone (25 ml), 4-fluorobenzenethiol (1.00 g, 7.80 mmol) and potassium carbonate (1.62 g, 11.7 mmol) were added, and the mixture was stirred at 80° C. for 18 hours. After cooled to room temperature, the reaction solution was poured into water, the mixture was extracted with ethyl acetate, the extract was washed with an aqueous saturated sodium chloride solution, and the organic layer was dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography and eluted with n-hexane-ethyl acetate (4:1, v/v) to obtain 2.20 g of a colorless oily substance 285D.
1H-NMR (CDCl3) δ: 1.35 (3H, t, J=7.2 Hz), 4.25 (2H, d, J=7.5 Hz), 4.65 (2H, s), 6.91 (2H, t, J=8.8 Hz), 7.19-7.31 (3H, m), 7.48 (1H, dd, J=8.2, 1.4 Hz), 7.70 (1H, dd, J=7.6, 1.5 Hz).
Fourth Step
Compound 285D (2.20 g, 6.77 mmol) obtained in the third step was dissolved in ethanol (20 ml), a 2N aqueous sodium hydroxide solution (16.9 ml, 33.8 mmol) was added, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added water, the mixture was made acidic with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, and dried with sodium sulfate, and the solvent was distilled off under reduced pressure. To the resulting compound was added n-hexane, and the precipitated residue was filtered to obtain 1.81 g of a white solid 285E.
1H-NMR (CDCl3) δ: 4.74 (2H, s), 6.95 (2H, t, J=8.8 Hz), 7.34 (3H, m), 7.59 (1H, dd, J=7.9, 1.5 Hz), 7.92 (1H, dd, J=7.9, 1.3 Hz).
Fifth Step
To compound 285E (1.81 g, 6.10 mmol) obtained in the fourth step was added polyphosphoric acid (10.0 g), and the mixture was stirred at 120° C. for 5 hours. After cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried with sodium sulfate, the solvent was concentrated under reduced pressure, to the resulting compound were added n-hexane-ethyl acetate, and the precipitated residue was filtered to obtain 1.18 g of a white solid 285F.
1H-NMR (CDCl3) δ: 4.28 (2H, s), 7.18 (1H, ddd, J=9.3, 6.6, 2.3 Hz), 7.33 (2H, m), 7.46 (1H, dd, J=7.7, 1.5 Hz), 7.59 (1H, dd, J=7.9, 1.3 Hz), 7.91 (1H, dd, J=10.1, 2.9 Hz).
Sixth Step
To compound 285F (1.17 g, 4.20 mmol) was added methanol (15 ml), sodium borohydride (191 mg, 5.04 mmol) was added at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water, the mixture was extracted with dichloromethane, the organic layer was dried with sodium sulfate, and the solvent was distilled off. To the resulting compound were added n-hexane-dichloromethane, and the precipitated residue was filtered to obtain 945 mg of a white solid 285G.
1H-NMR (CDCl3) δ: 2.58 (1H, d, J=3.2 Hz), 4.46 (1H, d, J=14.3 Hz), 4.58 (1H, d, J=14.6 Hz), 6.33 (1H, d, J=3.7 Hz), 6.82 (1H, td, J=8.3, 2.9 Hz), 7.07 (1H, dd, J=8.5, 5.4 Hz), 7.20 (1H, t, J=7.9 Hz), 7.33 (2H, m), 7.44 (1H, d, J=6.9 Hz).
Seventh Step According to the same procedure as that of Example 107, compound 285 was synthesized.
MS: m/z=486 [M+H]+
Using amines which are commercially available or known in the references and intermediates corresponding to compound 285A to compound 285G which are commercially available or known in the references. Then according to the method of Example 285, compounds 286 to compound 359 were synthesized.
EXAMPLE 286




MS: m/z=595 [M+H]+.
EXAMPLE 287




MS: m/z=475 [M+H]+.
EXAMPLE 288




1H-NMR (DMSO-d6) δ: 1.57 (1H, brs), 1.84-1.99 (2H, m), 2.68 (3H, d, J=4.6 Hz), 3.08-3.17 (2H, m), 3.39 (3H, brs), 3.89 (1H, d, J=13.4 Hz), 4.16 (1H, d, J=13.3 Hz), 4.54 (1H, brs), 5.10 (1H, d, J=12.7 Hz), 5.50 (1H, s), 5.63 (1H, d, J=13.4 Hz), 5.73 (1H, d, J=7.8 Hz), 6.82-7.94 (9H, m).
MS: m/z=489 [M+H]+.
EXAMPLE 289




MS: m/z=503 [M+H]+.
EXAMPLE 290




MS: m/z=505 [M+H]+.
EXAMPLE 291




MS: m/z=517 [M+H]+.
EXAMPLE 292




MS: m/z=503 [M+H]+.
EXAMPLE 293




MS: m/z=489 [M+H]+.
EXAMPLE 294




MS: m/z=456 [M+H]+.
EXAMPLE 295




MS: m/z=488 [M+H]+.
EXAMPLE 296




MS: m/z=498 [M+H]+
EXAMPLE 297




1H-NMR (DMSO-d6) δ: 3.21 (1H, m), 3.85 (1H, d, J=13.4 Hz), 4.08-4.18 (3H, m), 4.28 (1H, d, J=13.4 Hz), 5.10 (1H, d, J=13.7 Hz), 5.45 (1H, s), 5.57-5.64 (2H, m), 6.82-7.50 (10H, m).
MS: m/z=504 [M+H]+.
EXAMPLE 298




According to Example 107, compound 298 was synthesized by the same procedure.
MS: m/z=452 [M+H]+.
EXAMPLE 299




MS: m/z=450 [M+H]+.
EXAMPLE 300




MS: m/z=464 [M+H]+.
EXAMPLE 301




1H-NMR (DMSO-d6) δ: 1.00 (3H, d, J=6.9 Hz), 1.06 (3H, d, J=6.9 Hz), 3.88 (1H, d, J=13.4 Hz), 4.32 (1H, d, J=13.3 Hz), 4.67 (1H, m), 4.97 (1H, d, J=13.4 Hz), 5.43 (1H, s), 5.59 (2H, m), 6.84-7.45 (9H, m), 11.90 (1H, brs).
MS: m/z=434 [M+H]+.
EXAMPLE 302




1H-NMR (DMSO-d6) δ: 0.11 (1H, m), 0.54-0.92 (3H, m), 2.71 (1H, m), 3.85 (1H, d, J=13.7 Hz), 4.06 (1H, d, J=13.1 Hz), 5.06 (1H, d, J=13.1 Hz), 5.35 (1H, s), 5.57 (2H, m), 7.15 (9H, m), 11.66 (1H, brs).
MS: m/z=432 [M+H]+.
EXAMPLE 303




1HNMR (CDCl3) δ: 1.14 (1H, m), 1.54 (2H, m), 1.67 (1H, m), 3.60 (1H, d, J=13.5 Hz), 4.39 (1H, d, J=12.6 Hz), 5.02 (1H, s), 5.07 (1H, d, J=12.6 Hz), 5.60 (1H, d. J=13.5 Hz), 5.77 (1H, d, J=7.7 Hz), 6.69 (1H, d, J=7.7 Hz), 7.07-7.13 (3H, m), 7.25-7.44 (4H, m).
MS: m/z=457.10 [M+H]+.
EXAMPLE 304




1H-NMR (DMSO-d6) δ: 3.33-3.42 (1H, m), 3.84 (1H, d, J=13.1 Hz), 3.90-4.10 (1H, m), 4.24 (1H, d, J=13.4 Hz), 4.35-4.66 (2H, m), 5.13 (1H, d, J=13.4 Hz), 5.43 (1H, s), 5.54-5.64 (2H, m), 6.80-6.95 (2H, m), 7.04-7.50 (8H, m).
MS: m/z=438 [M+H]+.
EXAMPLE 305




MS: m/z=487 [M+H]+.
EXAMPLE 306




1H-NMR (DMSO-d6) δ: 3.69-3.82 (1H, m), 3.89 (1H, d, J=13.6 Hz), 4.40 (1H, d, J=12.9 Hz), 4.60-4.77 (1H, m), 5.27 (1H, d, J=13.3 Hz), 5.43 (1H, s), 5.60 (1H, d, J=13.6 Hz), 5.70 (1H, d, J=7.7 Hz), 6.84-6.95 (1H, m), 7.08-7.55 (9H, m).
MS: m/z=474 [M+H]+.
EXAMPLE 307




1H-NMR (DMSO-d6) δ: 3.81 (1H, d, J=13.5 Hz), 4.29 (1H, d, J=13.5 Hz), 4.33 (1H, d, J=16.2 Hz), 4.96 (1H, d, J=16.2 Hz), 5.23 (1H, d, J=13.5 Hz), 5.49 (1H, s), 5.59 (1H, d, J=13.2 Hz), 5.64 (1H, d, J=7.7 Hz), 6.82-6.97 (2H, m), 7.05-7.41 (10H, m), 7.80 (1H, td, J=7.6, 1.7 Hz), 8.47 (1H, d, J=4.9 Hz).
MS: m/z=483 [M+H]+.
EXAMPLE 308




1H-NMR (DMSO-d6) δ: 1.28 (9H, s), 3.86 (1H, d, J=13.6 Hz), 4.42 (1H, d, J=13.3 Hz), 4.99 (1H, d, J=13.4 Hz), 5.32 (1H, s), 5.53 (1H, d, J=13.3 Hz), 5.60 (1H, d, J=7.6 Hz), 6.81-7.63 (10H, m).
MS: m/z=448 [M+H]+.
EXAMPLE 309




1H-NMR (DMSO-d6) δ: 1.03 (3H, t, J=7.4 Hz), 3.12-3.26 (1H, m), 3.43-3.58 (1H, m), 3.85 (1H, d, J=13.6 Hz), 4.21 (1H, d, J=13.4 Hz), 5.07 (1H, d, J=13.4 Hz), 5.40 (1H, s), 5.57 (1H, d, J=13.1 Hz), 5.59 (1H, d, J=7.3 Hz), 6.80-6.88 (1H, m), 6.91 (1H, d, J=7.9 Hz), 7.03-7.55 (8H, m).
MS: m/z=420 [M+H]+.
EXAMPLE 310




MS: m/z=498 [M+H]+.
EXAMPLE 311




1H-NMR (CDCl3) δ: 1.73-1.85 (2H, m), 2.96-3.07 (1H, m), 3.27 (3H, s), 3.42 (2H, t, J=5.6 Hz), 3.56 (1H, d, J=13.5 Hz), 3.93-4.04 (1H, m), 4.25 (1H, d, J=13.2 Hz), 4.95 (1H, d, J=12.9 Hz), 5.13 (1H, s), 5.65 (1H, d, J=13.2 Hz), 5.82 (1H, d, J=7.7 Hz), 6.69 (1H, d, J=7.7 Hz), 6.78-6.86 (1H, m), 7.03-7.15 (3H, m), 7.17-7.47 (5H, m).
MS: m/z=464 [M+H]+.
EXAMPLE 312




1H-NMR (CDCl3) δ: 1.10 (3H, t, J=6.9 Hz), 2.79-2.91 (1H, m), 3.41 (2H, q, J=7.1 Hz), 3.46-3.69 (3H, m), 4.30 (1H, d, J=13.5 Hz), 5.01 (1H, d, J=13.5 Hz), 5.12 (1H, s), 5.65 (1H, d, J=13.5 Hz), 5.83 (1H, d, J=7.7 Hz), 6.68 (1H, d, J=7.7 Hz), 6.77-6.86 (1H, m), 7.03-7.12 (3H, m), 7.16-7.46 (5H, m).
MS: m/z=464 [M+H]+.
EXAMPLE 313




1H-NMR (CDCl3) δ: 1.30-1.47 (1H, m), 1.49-1.67 (1H, m), 1.73-2.02 (4H, m), 2.09-2.23 (2H, m), 3.60 (1H, d, J=13.5 Hz), 4.39 (1H, d, J=12.9 Hz), 4.45-4.64 (1H, m), 4.93 (1H, d, J=12.6 Hz), 5.10 (1H, s), 5.65 (1H, d, J=13.5 Hz), 5.87 (1H, d, J=7.4 Hz), 6.67 (1H, d, J=8.0 Hz), 6.76-6.85 (1H, m), 7.08 (2H, d, J=3.8 Hz), 7.16 (2H, d, J=7.7 Hz), 7.23-7.31 (1H, m), 7.34-7.48 (2H, m).
MS: m/z=510 [M+H]+.
EXAMPLE 314




MS: m/z=476 [M+H]+.
EXAMPLE 315




MS: m/z=488 [M+H]+.
EXAMPLE 316




1H-NMR (DMSO-d6) δ: 3.83 (1H, d, J=13.4 Hz), 4.34 (1H, d, J=13.1 Hz), 4.67 (1H, d, J=15.9 Hz), 5.05 (1H, d, J=15.9 Hz), 5.20 (1H, d, J=13.4 Hz), 5.33 (1H, s), 5.60 (1H, d, J=13.8 Hz), 5.64 (1H, d, J=7.8 Hz), 6.87 (3H, m), 7.05-7.19 (4H, m), 7.35-7.44 (2H, m), 7.74 (1H, d, 3.3 Hz), 7.77 (1H, d, 3.3 Hz).
EXAMPLE 317




MS: m/z=464 [M+H]+l 
EXAMPLE 318




MS: m/z=494 [M+H]+
EXAMPLE 319




1H-NMR (CDCl3) δ: 3.18-3.35 (1H, m), 3.60 (1H, d, J=13.7 Hz), 4.37 (1H, d, J=13.2 Hz), 4.75-4.95 (1H, m), 5.07-5.15 (2H, m), 5.60 (1H, d, J=13.7 Hz), 5.85 (1H, d, J=7.7 Hz), 6.68 (1H, d, J=7.7 Hz), 6.79-6.88 (1H, m), 7.09-7.14 (3H, m), 7.16 (1H, d, J=7.7 Hz), 7.29-7.36 (1H, m), 7.36-7.41 (1H, m), 7.42-7.50 (1H, m).
MS: m/z=524 [M+H]+.
EXAMPLE 320




1H-NMR (CDCl3) δ: 0.89 (9H, s), 0.97 (3H, d, J=7.1 Hz), 3.61 (1H, d, J=13.2 Hz), 4.43 (1H, d, J=13.2 Hz), 4.84-4.92 (2H, m), 5.11 (1H, s), 5.70 (1H, d, J=13.2 Hz), 5.83 (1H, d, J=7.7 Hz), 6.72 (1H, d, J=7.4 Hz), 6.79-6.85 (1H, m), 7.03-7.09 (2H, m), 7.16-7.24 (3H, m), 7.29-7.44 (2H, m).
MS: m/z=476 [M+H]+.
EXAMPLE 321




1H-NMR (CDCl3) δ: 2.87 (0.75H, s), 3.01 (2.25H, s), 3.55 (1.5H, d, J=10.2 Hz), 3.62 (0.5H, 13.5 Hz), 4.17 (0.5H, d, J=13.2 Hz), 4.22 (1.5 Hz, J=12.9 Hz), 4.97 (1H, d, J=12.9 Hz), 5.02 (0.25H, s), 5.11 (0.75H, s), 5.63 (0.75H, d, J=13.5 Hz), 5.77-5.83 (1.25H, m), 6.64-6.68 (1H, m), 6.76-6.85 (1H, m), 7.01 (1H, d, J=7.5 Hz), 7.05-7.13 (2H, m), 7.17-7.45 (3H, m).
EXAMPLE 322




1H-NMR (CDCl3) δ: 3.63 (1H, d, J=13.4 Hz), 4.51-4.59 (2H, m), 4.68-4.98 (4H, m), 5.13 (1H, d, J=12.9 Hz), 5.28 (1H, s), 5.71 (1H, d, J=13.3 Hz), 5.85 (1H, d, J=7.7 Hz), 6.77 (1H, d, J=7.4 Hz), 6.82-6.89 (1H, m), 7.12 (2H, d, J=3.5 Hz), 7.24 (1H, d, J=7.6 Hz), 7.33 (2H, d, J=4.4 Hz), 7.39 (1H, d, J=7.1 Hz), 7.42-7.50 (1H, m).
MS: m/z=470 [M+H]+.
EXAMPLE 323




MS: m/z=450 [M+H]+
EXAMPLE 324




MS: m/z=482 [M+H]+
EXAMPLE 325




1H-NMR (DMSO-d6) δ: 1.93 (3H, s), 3.13 (1H, m), 3.86 (1H, d, J=13.6 Hz), 4.06 (3H, m), 4.26 (1H, d, J=13.3 Hz), 5.14 (1H, d, J=13.6 Hz), 5.44 (1H, s), 5.60 (2H, m), 6.82-7.49 (10H, m).
MS: m/z=478 [M+H]+.
EXAMPLE 326




1H-NMR (CDCl3) δ: 1.07 (3H, d, J=6.6 Hz), 1.10 (3H, d, J=6.9 Hz), 3.70 (1H, d, J=13.5 Hz), 4.37 (1H, d, J=12.9 Hz), 4.75-4.85 (2H, m), 5.18 (1H, s), 5.76 (1H, d, J=13.2 Hz), 5.82 (1H, d, J=7.8 Hz), 6.67 (1H, dd, J=1.2 Hz, 7.8 Hz), 6.77 (1H, t, J=7.8 Hz), 7.07 (1H, d, J=7.5 Hz), 7.18-7.30 (3H, m), 7.35-7.46 (2H, m).
EXAMPLE 327




1H-NMR (CDCl3) δ: 1.06 (3H, d, J=6.9 Hz), 1.15 (3H, d, J=7.2 Hz), 3.60 (H, d, J=13.5 Hz), 4.36 (1H, d, J=12.9 Hz), 4.75-4.83 (2H, m), 5.10 (1H, s), 5.67 (1H, d, J=13.2 Hz), 5.86 (1H, d, J=7.5 Hz), 6.65 (1H, d, J=8, 1 Hz), 6.78 (1H, dd, J=1.8 Hz, 8.1 Hz), 7.08-7.18 (2H, m), 7.13 (1H, d, J=8.1 Hz), 7.24-7.30 (1H, m), 7.33-7.36 (1H, m), 7.39-7.45 (1H, m).
EXAMPLE 328




1H-NMR (CDCl3) δ: 0.98 (0.4H, d, J=7.2 Hz), 1.07 (2.6H, d, J=6.6 Hz), 1.15 (2.6H, d, J=6.9 Hz), 1.27 (0.4H, d, J=0.6 Hz), 3.62 (0.9H, d, J=13.2 Hz), 3.73 (0.1H, d, J=13.8 Hz), 4.36 (1H, d, J=12.9 Hz), 4.77-4.88 (1H, m), 4.83 (1H, d, J=12.9 Hz), 5.07 (1H, s), 5.62 (1H, d, J=13.2 Hz), 5.77 (0.1H, d, J=7.5 Hz), 5.85 (0.9H, d, J=7.8 Hz), 6.69-6.83 (1H, m), 6.98-7.07 (2H, m), 7.18 (2H, d, J=7.8 Hz), 7.25-7.35 (2H, m), 7.40-7.45 (1H, m).
EXAMPLE 329




1H-NMR (CDCl3) δ: 1.07 (3H, d, J=6.6 Hz), 1.15 (3H, d, J=6.9 Hz), 3.63 (1H, d, J=13.2 Hz), 4.37 (1H, d, J=12.9 Hz), 4.77-4.8 (1H, m), 4.82 (1H, d, J=12.6 Hz), 5.06 (1H, s), 5.60 (1H, d, J=12.9 Hz), 5.85 (1H, d, J=7.8 Hz), 6.53 (1H, dd, J=3.0 Hz, 9.0 Hz), 6.80-6.86 (1H, m), 7.03 (1H, dd, J=4.2 Hz, 9.0 Hz), 7.16-7.30 (3H, m), 7.35 (1H, d, J=6.3 Hz), 7.40-7.45 (1H, m).
EXAMPLE 330




1H-NMR (DMSO-d6) δ: 1.02 (3H, t, J=7.2 Hz), 3.07-3.22 (1H, m), 3.44-3.59 (1H, m), 4.00 (1H, d, J=13.4 Hz), 4.21 (1H, d, J=13.4 Hz), 5.06 (1H, d, J=13.3 Hz), 5.47-5.76 (3H, m), 6.84-6.92 (1H, m), 6.92-6.99 (1H, m), 7.04 (1H, d, J=7.6 Hz), 7.10-7.52 (6H, m).
MS: m/z=454 [M+H]+.
EXAMPLE 331




1H-NMR (CDCl3) δ: 2.96 (0.79H, s), 3.00 (2.2H, s), 3.59 (0.75H, d, J=13.2 Hz), 3.62 (0.25H, d, J=13.8 Hz), 4.15 (0.25H, d, J=13.2 Hz), 4.21 (0.75H, d, J=12.9 Hz), 4.95-5.01 (2H, m), 5.07 (1H, s), 5.56 (1H, d, J=13.5 Hz), 5.75-5.79 (1H, m), 5.88 (1H, d, J=7.8 Hz), 6.63 (0.36H, d, J=7.8 Hz), 6.73 (1H, d, J=1.8 Hz), 6.83 (0.39H, d, J=7.2 Hz), 7.01-7.46 (7.25H, m).
EXAMPLE 332




MS: m/z=484 [M+H]+
EXAMPLE 333




MS: m/z=484 [M+H]+.
EXAMPLE 334




1H-NMR (DMSO-d6) δ: 3.01-3.10 (1H, m), 3.16 (3H, s), 3.40 (2H, m), 3.89 (2H, d, J=13.4 Hz), 4.19 (1H, d, J=13.4 Hz), 5.06 (1H, d, J=13.6 Hz), 5.49 (1H, s), 5.58 (1H, d, J=13.4 Hz), 5.70 (1H, d, J=7.8 Hz), 6.89-7.48 (8H, m), 11.36 (1H, s).
EXAMPLE 335




1H-NMR (DMSO-d6) δ: 3.00-3.09 (1H, m), 3.15 (3H, s), 3.39 (2H, m), 3.94 (1H, m), 4.00 (1H, d, J=13.2 Hz), 4.20 (1H, d, J=13.4 Hz), 5.06 (1H, d, J=13.4 Hz), 5.54 (1H, s), 5.65 (2H, m), 6.86-7.50 (8H, m), 11.54 (1H, brs).
EXAMPLE 336




1H-NMR (DMSO-d6) δ: 3.01-3.09 (1H, m), 3.15 (3H, s), 3.40 (2H, m), 3.87-3.94 (1H, m), 3.98 (1H, d, J=13.6 Hz), 4.20 (1H, d, J=13.6 Hz), 5.06 (1H, d, J=13.4 Hz), 5.54 (1H, s), 5.62 (1H, d, J=13.6 Hz), 5.67 (1H, d, J=7.6 Hz), 6.78-7.50 (8H, m).
MS: m/z=468 [M+H]+.
EXAMPLE 337




1H-NMR (DMSO-d6) δ: 3.07 (1H, m), 3.16 (3H, s), 3.41 (2H, s), 3.89 (1H, d, J=13.7 Hz), 3.91 (1H, m), 4.19 (1H, d, J=13.6 Hz), 5.06 (1H, d, J=13.6 HZ), 5.48 (1H, s), 5.61 (1H, d, J=13.3 Hz), 5.69 (1H, d, J=7.6 Hz), 6.70-7.48 (9H, m).
MS: m/z=468 [M+H]+
EXAMPLE 338




MS: m/z=468 [M+H]+.
EXAMPLE 339




1H-NMR (DMSO-d6) δ: 3.14 (3H, s), 3.18 (s, 3H), 3.50 (4H, m), 4.00 (1H, d, J=13.1 Hz), 4.49 (1H, d, J=13.3 Hz), 4.77 (1H, m), 4.95 (1H, d, J=13.3 Hz), 5.56 (1H, s), 5.68 (2H, m), 7.14 (8H, m).
MS: m/z=512 [M+H]+
EXAMPLE 340




1H-NMR (DMSO-d6) δ: 3.12 (3H, s), 3.20 (3H, s), 3.51 (4H, m), 3.96 (1H, d, J=13.3 Hz), 4.53 (1H, d, J=13.4 Hz), 4.75 (1H, m), 4.97 (1H, d, J=13.1 Hz), 5.50 (1H, d, J=13.3 Hz), 5.54 (1H, s), 5.67 (1H, d, J=7.8 Hz), 6.87-7.54 (8H, m).
MS: m/z=530 [M+H]+
EXAMPLE 341




MS: m/z=466 [M+H]+
EXAMPLE 342




MS: m/z=506 [M+H]+
EXAMPLE 343




MS: m/z=522 [M+H]+
EXAMPLE 344




MS: m/z=506 [M+H]+
EXAMPLE 345




MS: m/z=506 [M+H]+
EXAMPLE 346




MS: m/z=470 [M+H]+.
EXAMPLE 347




1H-NMR (CDCl3) δ: 2.88 (0.60H, s), 2.99 (2.40H, s), 3.67 (0.80H, d, J=13.8 Hz), 3.73 (0.20H, d, J=14.1 Hz), 4.16 (0.20H, d, J=11.1 Hz), 4.20 (0.80H, d, J=12.9 Hz), 4.97 (0.80H, d, J=12.9 Hz), 4.99 (0.20H, d, J=15 Hz), 5.10 (0.20H, s), 5.18 (0.80H, s), 5.69 (0.80H, d, J=13.5 Hz), 5.79 (0.20H, d, J=7.8 Hz), 5.85 (0.80H, d, J=7.5 Hz), 5.88 (0.20H, J=13.5 Hz), 6.62-6.66 (1H, m), 6.75-6.85 (1H, m), 6.98 (1H, d, J=7.5 Hz), 7.03-7.16 (0.5H, m), 7.19 (1H, d, J=6.9 Hz), 7.24-7.39 (2.5H, m), 7.43-7.48 (1H, m).
EXAMPLE 348




1H-NMR (CDCl3) δ: 2.91 (0.75H, s), 2.99 (2.25H, s), 3.57 (0.75H, d, J=13.8 Hz), 3.63 (0.25H, d, 13.8 Hz), 4.17 (0.25H, d, J=12.9 Hz), 4.10 (0.75H, d, J=12.9 Hz), 4.99 (0.75H, d, J=12.9 Hz), 5.00 (0.25H, s), 5.01 (0.25H, d, J=12.3 Hz), 5.10 (0.75H, s), 5.61 (0.75H, d, J=13.5 Hz), 5.78 (0.25H, J=7.5 Hz), 5.80 (0.25H, J=15 Hz), 5.89 (0.75H, d, J=7.5 Hz), 6.60 (0.75H, d, J=8.4 Hz), 6.64 (0.25H, d, J=7.8 Hz), 6.78 (1H, dd, J=2.1 Hz, 8.1 Hz), 7.03 (1H, d, J=7.8 Hz), 7.04-7.21 (2H, m), 7.26-7.36 (2H, m), 7.41-7.47 (1H, m).
EXAMPLE 349




1H-NMR (CDCl3) δ: 2.94 (0.66H, s), 3.00 (2.34H, s), 3.60 (0.78H, d, J=13.5 Hz), 3.65 (0.22H, d, J=3.8 Hz), 4.22 (1H, d, J=12.9 Hz), 4.94-5.00 (1H, m), 5.06 (1H, s), 5.54 (0.78H, d, J=13.2 Hz), 5.71 (0.22H, d, J=13.8 Hz), 5.78 (0.22H, d, J=7.5 Hz), 5.88 (0.78H, d, J=7.8 Hz), 6.49 (1H, dd, J=3.0 Hz, 9.0 Hz), 6.66 (0.22H, d, J=7.8 Hz), 6.82-6.88 (1H, m), 6.97-7.13 (2H, m), 7.16-7.21 (1H, m), 7.29-7.36 (2H, m), 7.41-7.46 (1H, m).
EXAMPLE 350




1H-NMR (CDCl3) δ: 1.08 (3H, d, J=6.9 Hz), 1.16 (3H, d, J=6.9 Hz), 3.63 (1H, d, J=13.2 Hz), 4.37 (1H, d, J=12.6 Hz), 4.78-4.87 (1H, m), 5.10 (1H, s), 5.67 (1H, d, J=13.2 Hz), 5.82 (1H, d, J=7.8 Hz), 6.65 (1H, d, J=2.1 Hz), 6.96-6.99 (1H, m), 7.08-7.12 (2H, m), 7.17 (1H, d, J=13.5 Hz), 7.25-7.32 (1H, m), 7.35-7.37 (1H, m), 7.42-7.47 (1H, m).
EXAMPLE 351




1H-NMR (CDCl3) δ: 1.08 (3H, d, J=6.9 Hz), 1.16 (3H, d, J=6.9 Hz), 3.68 (1H, d, J=13.2 Hz), 4.37 (1H, d, J=12.9 Hz), 4.76-4.84 (2H, m), 5.18 (1H, s), 5.72 (1H, d, J=13.5 Hz), 5.81 (1H, dd, J=0.9 Hz, 7.5 Hz), 6.56 (1H, d, J=7.2 Hz), 6.76-6.83 (1H, m), 6.90 (1H, t, J=9.0 Hz), 7.07-7.11 (1H, m), 7.19 (1H, d, J=7.5 Hz), 7.25-7.30 (1H, m), 7.35-7.45 (2H, m).
EXAMPLE 352




1H-NMR (CDCl3) δ: 1.07 (3H, d, J=6.9 Hz), 1.15 (3H, d, J=7.1 Hz), 3.59 (1H, d, J=13.2 Hz), 4.36 (1H, d, J=9.9 Hz), 4.75-4.85 (2H, m), 5.11 (1H, s), 5.70 (1H, d, J=13.2 Hz), 5.84 (1H, d, J=7.8 Hz), 6.48-6.55 (1H, m), 6.71 (1H, dd, J=5.4 Hz, 8.4 Hz), 6.80 (1H, dd, J=2.4 Hz, 9.3 Hz), 7.11 (1H, d, J=7.8 Hz), 7.18 (1H, dd, J=0.9 Hz), 7.5 Hz), 7.25-7.30 (1H, m), 7.32-7.36 (1H, m), 7.39-7.45 (1H, m).
EXAMPLE 353




1H-NMR (CDCl3) δ: 2.92 (0.66H, s), 3.01 (2.34H, s), 3.59 (0.78H, d, J=13.5 Hz), 3.67 (0.22H, d, J=13.8 Hz), 4.18 (0.22H, d, J=13.2 Hz), 4.21 (0.78H, d, J=12.9 Hz), 5.03 (1H, J=12.9 Hz), 5.05 (0.22H, s), 5.10 (0.78H, s), 5.62 (0.78H, d, J=13.5 Hz), 5.76-5.82 (0.44H, m), 5.87 (0.78H, d, J=7.8 Hz), 6.62 (0.78H, brs), 6.68 (0.22H, d, J=8.1 Hz), 6.85 (0.22H, d, J=7.8 Hz), 6.98-7.04 (1.56H, m), 7.11-7.39 (3H, m), 7.44-7.49 (1H, m).
EXAMPLE 354




1H-NMR (CDCl3) δ: 2.89 (0.48H, s), 3.00 (2.52H, s), 3.64 (0.84H, d, J=13.5 Hz), 3.71 (0.16H, d, J=13.8 Hz), 4.21 (1H, d, J=12.9 Hz), 4.94 (0.84H, d, J=12.9 Hz), 4.98 (0.16H, d, J=12.9 Hz), 5.10 (0.16H, s), 5.19 (0.84H, s), 5.65 (0.84H, d, J=7.5 Hz), 5.77-5.85 (1.32H, m), 6.52 (0.84H, d, J=7.8 Hz), 6.64 (0.16H, d, J=7.8 Hz), 6.77-6.84 (1H, m), 6.89-6.95 (1H, m), 6.99 (1H, d, J=7.8 Hz), 7.07-7.25 (1H, m), 7.29-7.38 (2H, m), 7.42-7.47 (1H, m).
EXAMPLE 355




1H-NMR (CDCl3) δ: 2.91 (0.48H, s), 3.00 (2.52H, s), 3.56 (d, J=13.8 Hz), 3.62 (0.16H, d, J=13.8 Hz), 4.18 (0.16H, d, J=12.9 Hz), 4.20 (0.84H, d, J=12.9 Hz), 4.96 (0.84H, d, J=12.9 Hz), 4.98 (0.16H, d, J=13.8 Hz), 5.03 (0.16H, s), 5.12 (0.84H, s), 5.64 (0.84H, d, J=13.5 Hz), 5.78-5.87 (0.32H, m), 5.89 (0.84H, d, J=7.8 Hz), 6.50-6.56 (0.84H, m), 6.63-6.69 (1.16H, m), 6.84 (1H, dd, J=2.4 Hz, 9.3 Hz), 6.94-6.97 (0.16H, m), 7.02 (0.84H, d, J=7.5 Hz), 7.13-7.23 (1H, m), 7.33-7.38 (2H, m), 7.42-7.47 (1H, m).
EXAMPLE 356




1H-NMR (CDCl3) δ: 1.08 (3H, d, J=6.9 Hz), 1.15 (3H, d, J=6.9 Hz), 2.24 (3H, s), 3.68 (1H, d, J=13.2 Hz), 4.38 (1H, d, J=13.2 Hz), 4.76-4.85 (1H, m), 4.80 (1H, d, J=12.6 Hz), 5.14 (1H, s), 5.72 (1H, d, J=12.9 Hz), 5.76 (1H, d, J=7.8 Hz), 6.59 (1H, d, J=7.5 Hz), 6.72 (1H, t, J=7.5 Hz), 6.99 (1H, d, J=6.9 Hz), 7.07 (1H, d, J=7.8 Hz), 7.17-7.27 (2H, m), 7.33-7.42 (2H, m).
EXAMPLE 357




1H-NMR (CDCl3) δ: 1.10 (3H, d, J=6.9 Hz), 1.16 (3H, d, J=6.9 Hz), 3.58 (1H, d, J=13.2 Hz), 4.37 (1H, d, J=12.9 Hz), 4.76-4.87 (1H, m), 4.85 (1H, d, J=12.6 Hz), 5.06 (1H, s), 5.65 (1H, d, J=13.2 Hz), 5.79 (1H, d, J=7.5 Hz), 6.54 (1H, s), 6.89 (1H, dd, J=1.5 Hz, 8.4 Hz), 6.95 (1H, d, J=7.8 Hz), 7.14-7.19 (1H, m), 7.22-7.28 (1H, m), 7.33-7.43 (2H, m).
EXAMPLE 358




1H-NMR (CDCl3) δ: 1.07 (3H, d, J=6.9 Hz), 1.16 (3H, d, J=6.9 Hz), 2.20 (3H, s), 2.23 (3H, s), 3.77 (1H, d, J=12.6 Hz), 4.47 (1H, d, J=12.9 Hz), 4.78-4.86 (1H, m), 4.88 (1H, 12.9 Hz), 5.49 (1H, d, J=12.9 Hz), 5.83 (1H, d, J=11.1 Hz), 5.85 (1H, d, J=9.0 Hz), 6.64 (1H, d, J=7.8 Hz), 6.86 (1H, J=7.8 Hz), 7.16-7.40 (5H, m).
EXAMPLE 359




1H-NMR (DMSO-d6) δ: 1.94 (3H, s), 3.07 (1H, m), 3.98-4.12 (4H, m), 4.25 (2H, d, J=13.4 Hz), 5.13 (2H, d, J=13.3 Hz), 5.56 (1H, s), 5.66 (1H, d, J=13.5 Hz), 5.68 (1H, t, J=7.8 Hz), 6.87-7.51 (8H, m).
EXAMPLE 360




Compound 325 (46.0 mg, 0.0960 mmol) was dissolved in methanol (0.5 ml) and tetrahydrofuran (0.5 ml), a 2N aqueous sodium hydroxide solution (0.241 ml, 0.482 mmol) was added, and the mixture was stirred for 30 minutes. To the reaction solution was added dilute hydrochloric acid to make the solution acidic, and the mixture was extracted with chloroform. The organic layer was dried with sodium sulfate, and the reaction solution was concentrated under reduced pressure. To the resulting compound 360 were added n-hexane-diethyl ether, and the precipitated residue was filtered to obtain 33 mg of a white solid.
1H-NMR (DMSO-d6) δ: 2.85-2.94 (1H, m), 3.52 (2H, m), 3.89 (1H, d, J=13.4 Hz), 3.98 (1H, td, J=9.1, 4.5 Hz), 4.24 (1H, d, J=13.6 Hz), 4.84 (1H, brs), 5.16 (1H, d, J=13.6 Hz), 5.48 (1H, s), 5.65 (2H, m), 6.86-7.55 (9H, m).
MS: m/z=436 [M+H]+
Using ester bodies synthesized according to Examples 107, 246 and 285, and according to the method of Example 320, compounds 361 to 382 were synthesized.
EXAMPLE 361




1H-NMR (DMSO-d6) δ: 2.82 (3H, m), 3.49 (1H, brs), 3.71 (1H, dt, J=16.7, 5.0 Hz), 4.03 (1H, t, J=7.8 Hz), 4.08-4.15 (2H, m), 4.79 (1H, brs), 5.01 (1H, d, J=13.4 Hz), 5.25 (1H, s), 5.51 (1H, d, J=7.6 Hz), 6.72-7.41 (9H, m).
EXAMPLE 362




MS: m/z=432 [M+H]+.
EXAMPLE 363




MS: m/z=450 [M+H]+.
EXAMPLE 364




MS: m/z=448 [M+H]+.
EXAMPLE 365




MS: m/z=466 [M+H]+.
EXAMPLE 366




MS: m/z=466 [M+H]+.
EXAMPLE 367




MS: m/z=512 [M+H]+.
EXAMPLE 368




MS: m/z=406 [M+H]+.
EXAMPLE 369




MS: m/z=420 [M+H]+.
EXAMPLE 370




1H-NMR (CDCl3) δ: 1.23 (3H, s), 1.24 (3H, s), 2.43 (1H, d, J=13.7 Hz), 2.81-2.91 (1H, m), 2.96-3.10 (1H, m), 3.61-3.72 (1H, m), 4.02-4.14 (1H, m), 4.15 (1H, d, J=13.7 Hz), 4.42 (1H, d, J=14.0 Hz), 4.95 (1H, s), 5.15 (1H, d, J=13.5 Hz), 5.74 (1H, d, J=7.7 Hz), 6.54-6.61 (2H, m), 6.86-6.94 (1H, m), 7.11-7.39 (8H, m).
MS: m/z=446 [M+H]+.
EXAMPLE 371




1H-NMR (CDCl3) δ: 1.24 (3H, s), 1.26 (3H, s), 2.52 (1H, d, J=14.0 Hz), 3.56 (1H, d, J=13.7 Hz), 4.34 (1H, d, J=13.5 Hz), 4.36 (1H, d, J=13.5 Hz), 5.04 (1H, s), 5.23 (1H, d, J=13.7 Hz), 5.63 (1H, d, J=13.5 Hz), 5.84 (1H, d, J=7.7 Hz), 6.65 (1H, d, J=7.7 Hz), 6.76-6.84 (1H, m), 7.03-7.18 (5H, m), 7.27-7.47 (4H, m).
MS: m/z=464 [M+H]+.
EXAMPLE 372




1H-NMR (CDCl3) δ: 1.21-1.68 (10H, m), 2.47 (1H, d, J=13.7 Hz), 3.55 (1H, d, J=13.5 Hz), 4.34 (1H, d, J=13.6 Hz), 4.35 (1H, d, J=13.6 Hz), 5.03 (1H, s), 5.25 (1H, d, J=13.5 Hz), 5.63 (1H, d, J=13.5 Hz), 5.79 (1H, d, J=7.7 Hz), 6.64 (1H, d, J=7.4 Hz), 6.76-6.84 (1H, m), 7.03 (1H, d, J=7.7 Hz), 7.06-7.10 (2H, m), 7.15 (1H, d, J=7.1 Hz), 7.28-7.37 (2H, m), 7.37-7.46 (1H, m).
MS: m/z=504 [M+H]+.
EXAMPLE 373




MS: m/z=450 [M+H]+.
EXAMPLE 374




MS: m/z=492 [M+H]+.
EXAMPLE 375




MS: m/z=445 [M+H]+.
EXAMPLE 376




MS: m/z=512 [M+H]+.
EXAMPLE 377




MS: m/z=492 [M+H]+.
EXAMPLE 378




MS: m/z=478 [M+H]+
EXAMPLE 379




MS: m/z=478 [M+H]+
EXAMPLE 380




MS: m/z=492 [M+H]+
EXAMPLE 381




MS: m/z=492 [M+H]+
EXAMPLE 382




1H-NMR (DMSO-d6) δ: 2.76-2.85 (1H, m), 3.58 (2H, m), 3.92 (1H, m), 3.98 (1H, d, J=13.5 Hz), 4.18 (1H, d, J=13.6 Hz), 4.80 (1H, brs), 5.10 (1H, t, J=8.8 Hz), 5.50-5.68 (3H, m), 6.87-7.52 (8H, m).
EXAMPLE 383




First Step

Compound 383A (1.00 g, 4.42 mmol) was dissolved in dichloromethane (50 ml), mCPBA (2.67 g, 15.5 mmol) was added at 0° C., and the mixture was stirred at room temperature for 4 hours. To the reaction solution was added an aqueous sodium sulfite solution, and the mixture was extracted with dichloromethane. The organic layer was washed with an aqueous sodium bicarbonate solution, and dried with sodium sulfate, and the solvent was distilled off. To the resulting compound were added n-hexane-dichloromethane, and the precipitated residue was filtered to obtain 1.06 g of a white solid 383B.
1H-NMR (CDCl3) δ: 4.81 (2H, s), 7.29-8.12 (6H, m).
Second Step
To compound 383B (1.05 g, 4.07 mmol) was added methanol (11 mm), sodium borohydride (185 mg, 4.88 mmol) was added at 0° C., and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into water, the mixture was extracted with dichloromethane, the organic layer was dried with sodium sulfate, and the solvent was distilled off. To the resulting compound were added n-hexane-dichloromethane, and the precipitated residue was filtered to obtain 1.01 g of a white solid 383C.
1H-NMR (CDCl3) δ: 2.84 (1H, d, J=3.7 Hz), 4.76 (1H, d, J=14.6 Hz), 5.25 (1H, d, J=14.6 Hz), 6.23 (1H, d, J=3.7 Hz), 7.28-7.96 (8H, m).
Third Step
According to Example 107, compound 383 was synthesized by the same procedure.
MS: m/z=466 [M+H]+.
Using intermediates corresponding to 383A to 383C which are commercially available or known in the references, and according to the method of Example 383, compounds 384 to 389 were synthesized.
EXAMPLE 384




1H-NMR (CDCl3) δ: 1.12-1.25 (6H, m), 2.87-3.26 (3H, m), 3.42-3.67 (1H, m), 4.00-4.08 (1H, m), 4.28-4.35 (1H, m), 4.56-4.83 (3H, m), 5.10-5.30 (1H, m), 5.89-6.11 (1H, m), 6.55-6.63 (0.5H, m), 6.71-6.75 (0.5H, m), 6.84-6.94 (1H, m), 7.03-7.47 (4H, m), 8.18-8.20 (0.5H, m), 8.48-8.49 (0.5H, m).
EXAMPLE 385




1H-NMR (CDCl3) δ: 0.59 (3H, d, J=6.6 Hz), 1.07-1.14 (4H, m), 1.19-1.28 (1H, m), 2.22-2.32 (1H, m), 2.73-3.12 (3H, m), 4.71-4.81 (1H, m), 4.83 (1H, d, J=12.9 Hz), 4.96 (1H, d, J=12.9 Hz), 5.88 (1H, d, J=7.5 Hz), 5.89 (1H, s), 6.89 (1H, m), 7.00-7.04 (2H, m), 7.08-7.18 (2H, m), 7.22-7.27 (1H, m), 7.38 (1H, d, J=7.5 Hz), 7.58-7.61 (1H, m), 7.79 (1H, d, J=7.5 Hz).
EXAMPLE 386




1H-NMR (CDCl3) δ: 0.95 (3H, d, J=6.9 Hz), 1.17 (3H, d, 6.9 Hz), 3.34 (2H, d, J=12.3 Hz), 4.39 (1H, d, J=12.9 Hz), 4.56-4.65 (1H, m), 4.85 (1H, d, J=12.9 Hz), 4.93 (1H, m), 5.77 (1H, d, J=7.5 Hz), 6.77-6.81 (1H, m), 6.79 (1H, d, J=7.5 Hz), 7.00-7.05 (1H, m), 7.21-7.29 (2H, m), 7.32-7.42 (3H, m).
EXAMPLE 387




1H-NMR (CDCl3) δ: 1.06-1.17 (6H, m), 4.02-4.17 (1H, m), 4.61-4.78 (2H, m), 5.16 (1H, d, J=5.1 Hz), 5.72 (1H, t, J=8.1 Hz), 6.54 (0.5H, d, J=7.8 Hz), 6.84 (0.5H, d, J=7.8 Hz), 6.91-7.08 (2H, m), 7.16-7.47 (4H, m), 7.56-7.59 (1H, m), 8.00 (0.5H, J=6.3 Hz), 8.09-8.12 (0.5H, m), 8.51 (0.5H, s), 8.68 (0.5H, s).
EXAMPLE 388




1H-NMR (CDCl3) δ: 1.19 (3H, d, J=6.9 Hz), 1.25 (3H, d, J=6.9 Hz), 2.76-2.91 (2H, m), 3.23-3.31 (1H, m), 4.17-4.33 (2H, m), 4, 54-4.84 (2H, m), 5.18 (1H, s), 5.87 (1H, d, J=7.8 Hz), 6.70 (1H, d, J=5.1 Hz), 6.86 (1H, d, J=7.8 Hz), 7.04 (1H, d, J=5.1 Hz), 7.19-7.25 (2H, m), 7.32-7.38 (2H, m).
EXAMPLE 389




1H-NMR (DMSO-d6) δ: 1.04-1.20 (6H, m), 2.83-3.02 (1H, m), 3.46-3.57 (1H, m), 3.75-3.85 (1H, m), 4.13-4.26 (1H, m), 4.32-4.50 (1H, m), 4.56-4.62 (1H, m), 4.89 (1H, d, J=13.2 Hz), 5.36 (1H, s), 5.44-5.50 (1H, m), 6.73 (1H, d, J=7.8 Hz), 6.86 (1H, t, J=7.5 Hz), 6.95-6.98 (1H, m), 7.09-6.54 (5H, m).
EXAMPLE 390




First Step

Compound 390A (14.8 g, 115 mmol) was added to methanol (200 ml), sodium methoxide (28% methanol solution, 22.2 g, 115 mmol) was added at room temperature, and the mixture was stirred for 1 hour. The solvent was distilled off under reduced pressure to obtain 17.3 g of a white solid. To 5.61 g of it was added phthalide (5.00 g, 37.3 mmol), and the mixture was stirred at 200° C. for 1 hour. The reaction solution was poured into water, the mixture was made acidic with hydrochloric acid, and the generated white precipitate was filtered. This was dissolved in chloroform, the solution was dried with sodium sulfate, and the solvent was distilled off. To the resulting compound were added n-hexane-chloroform-diisopropyl ether, and the precipitated residue was filtered to obtain 2.44 g of a pale brown solid 390B.
1H-NMR (CDCl3) δ: 5.61 (2H, s), 6.92 (1H, td, J=7.6, 1.4 Hz), 7.01 (1H, dd, J=8.3, 1.3 Hz), 7.21 (1H, ddd, J=8.7, 7.0, 1.2 Hz), 7.32-7.54 (2H, m), 7.66 (1H, td, J=7.6, 1.4 Hz), 7.92-7.99 (1H, m), 8.17 (1H, dd, J=7.9, 1.3 Hz).
Second Step
Compound 390B (2.44 g, 9.29 mmol) was dissolved in dichloromethane (30 ml), trifluoroacetic acid anhydride (1.44 ml, 10.2 mmol) and boron trifluoride etherate (0.235 ml, 1.86 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into water, the mixture was extracted with dichloromethane, the organic layer was washed with 1N hydrochloric acid and an aqueous saturated sodium chloride solution, and the solvent was distilled off. The resulting crude product was purified by silica gel column chromatography, and eluted with n-hexane-ethyl acetate (4:1, v/v) to obtain 1.76 g of a pale yellow solid 390C.
1H-NMR (CDCl3) δ: 5.36 (2H, s), 7.11 (1H, t, J=8.0 Hz), 7.43-7.66 (4H, m), 7.93 (1H, d, J=6.5 Hz), 8.19 (1H, dd, J=8.1, 1.8 Hz).
Third Step
To compound 390C (1.76 g, 7.19 mmol) was added methanol (20 ml), sodium borohydride (327 mg, 8.63 mmol) was added at 0° C., and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into water, the mixture was extracted with dichloromethane, the organic layer was dried with sodium sulfate, and the solvent was distilled off. To the resulting compound were added n-hexane-dichloromethane, and the precipitated residue was filtered to obtain 1.44 g of a white solid 390D.
1H-NMR (CDCl3) δ: 2.75 (1H, d, J=5.0 Hz), 5.18 (1H, d, J=13.6 Hz), 5.69 (1H, d, J=5.0 Hz), 5.89 (1H, d, J=13.6 Hz), 6.93 (1H, t, J=7.9 Hz), 7.19-7.43 (6H, m).
Fourth Step
Compound 390 was synthesized by the same procedure as that of Example 107.
MS: m/z=452 [M+H]+
Using amines which are commercially available or known in the references and intermediates corresponding to 390A to 390D which are commercially available or known in the references, and according to the method of Example 390, compounds 391 to 412 were synthesized.
EXAMPLE 391




MS: m/z=418 [M+H]+.
EXAMPLE 392




MS: m/z=416 [M+H]+.
EXAMPLE 393




MS: m/z=458 [M+H]+.
EXAMPLE 394




MS: m/z=434 [M+H]+.
EXAMPLE 395




MS: m/z=390 [M+H]+.
EXAMPLE 396




MS: m/z=468 [M+H]+
EXAMPLE 397




MS: m/z=452 [M+H]+
EXAMPLE 398




1H-NMR (CDCl3) δ: 1.12-1.32 (6H, m), 4.25 (0.52H, d, J=12.9 Hz), 4.41 (0.48H, d, J=13.2 Hz), 4.58-4.79 (2H, m), 4.92-5.03 (2H, m), 5.73 (0.48H, d, J=7.8 Hz), 5.89 (0.52H, d, J=7.8 Hz), 6.12 (0.48H, d, J=12 Hz), 6.46-6.58 (1.52H, m), 6.74-6.78 (1H, m), 6.98 (1H, t, J=7.5 Hz), 7.10-7.14 (1H, m), 7.20-7.50 (4H, m).
EXAMPLE 399




1H-NMR (CDCl3) δ: 1.12-1.31 (6H, m), 4.25 (0.75H, d, J=12.9 Hz), 4.43 (0.25H, d, J=12.9 Hz), 4.53-4.60 (0.50H, m), 4.67-4.78 (1.5H, m), 4.90-5.05 (2H, m), 5.70 (0.25H, d, J=7.8 Hz, 5.86 (0.75H, d, J=7.5 Hz), 6.18 (0.25H, d, J=13.5 Hz), 6.36-6.42 (0.75H, m), 6.49-6.56 (2H, m), 6.69-6.80 (1H, m), 6.94 (1H, d, J=7.8 Hz), 7.10-7.19 (0.25H, m), 7.21-7.50 (3.75H, m).
EXAMPLE 400




MS: m/z=452 [M+H]+
EXAMPLE 401




MS: m/z=452 [M+H]+
EXAMPLE 402




MS: m/z=470 [M+H]+
EXAMPLE 403




MS: m/z=436 [M+H]+
EXAMPLE 404




MS: m/z=452 [M+H]+
EXAMPLE 405




MS: m/z=452 [M+H]+
EXAMPLE 406




MS: m/z=490 [M+H]+
EXAMPLE 407




MS: m/z=436 [M+H]+
EXAMPLE 408




MS: m/z=452 [M+H]+
Example 409




MS: m/z=452 [M+H]+
EXAMPLE 410




MS: m/z=490 [M+H]+
EXAMPLE 411




MS: m/z=506 [M+H]+
EXAMPLE 412




1H-NMR (CDCl3) δ: 1.13-1.31 (12H, m), 3.28-3.37 (0.50H, m), 3.44-3.53 (0.50H, m), 4.29-4.36 (1H, m), 4.65-4.76 (2H, m), 4.98-5.05 (2H, m), 6.37 (0.5H, d, J=12.9 Hz), 6.45 (0.5H, d, J=7.5 Hz), 6.67 (0.5H, t, J=7.8 Hz), 6.81 (0.5H, 7.8 Hz), 6.98-7.08 (2H, m), 7.14 (0.5Hm d, J=7.8 Hz), 7.22-7.45 (2.5H, m).
EXAMPLE 413
Example 414




First Step

Compound 413A (200 mg, 0.544 mmol) obtained by the same procedure as that of Example 95, and 6,11-dihydrodibenzo[b,e]thiepin-11-ol (124 mg 0.554 mmol) were dissolved in acetic acid (8 ml), and concentrated sulfuric acid (2 ml) was added dropwise under water-cooling. After the mixture was stirred at room temperature for 30 minutes, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried with sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product of 413B.
Second Step
Compound 413B obtained in the first step was dissolved in dichloromethane (2 ml), acetic acid anhydride (0.154 ml, 1.63 mmol), triethylamine (0.226 ml, 1.63 mmol) and 4-(dimethylamino)pyridine (cat.) were added, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off, the resulting crude product was purified by silica gel column chromatography, and eluted with chloroform-methanol (97:3, v/v), and diastereomers were resolved. They were dissolved in methanol (1 ml) and tetrahydrofran (1 ml), respectively, a 2N aqueous sodium hydroxide solution (0.198 ml, 0.397 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into water, and the mixture was made acidic with hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried with sodium sulfate, and the solvent was distilled off under reduced pressure. To the resulting compound were added ethyl acetate-diethyl ether, and the fractionation-precipitated residue was filtered to obtain compound 413 (22 mg) and compound 414 (20 mg), respectively.
EXAMPLE 413
1H-NMR (DMSO-d6) δ: 1.20 (3H, d, J=7.4 Hz), 3.92 (1H, d, J=13.6 Hz), 4.45 (1H, d, J=13.4 Hz), 5.12 (1H, d, J=12.8 Hz), 5.60 (4H, m), 6.87-7.60 (9H, m).
MS: m/z=488 [M+H]+
EXAMPLE 414
MS: m/z=488 [M+H]+
According to Example 413, compounds 414 to 475 were synthesized using the same procedure.
EXAMPLE 415




1H-NMR (DMSO-d6) δ: 1.16 (3H, d, J=7.3 Hz), 3.88 (1H, d, J=13.3 Hz), 4.41 (1H, d, J=13.3 Hz), 5.07 (1H, d, J=13.0 Hz), 5.42-5.52 (1H, m), 5.62 (3H, m), 6.82-7.56 (9H, m).
MS: m/z=488 [M+H]+
EXAMPLE 416




1H-NMR (DMSO-d6) δ: 1.35 (3H, d, J=7.3 Hz), 3.88 (1H, d, J=13.3 Hz), 4.44 (1H, d, J=12.7 Hz), 5.15 (1H, d, J=12.5 Hz), 5.16 (1H, m), 5.29 (1H, s), 5.57 (1H, d, J=13.4 Hz), 5.64 (1H, d, J=7.8 Hz), 6.81-7.45 (9H, m).
MS: m/z=488 [M+H]+
EXAMPLE 417




1H-NMR (CDCl3) δ: 1.22 (3H, d, J=7.2 Hz), 4.32 (1H, d, J=13.9 Hz), 4.49 (1H, d, J=13.1 Hz), 4.90 (1H, d, J=13.3 Hz), 5.15 (1H, s), 5.47-5.65 (2H, m), 5.83 (1H, d, J=8.1 Hz), 6.69 (1H, d, J=6.5 Hz), 6.80-6.87 (1H, m), 7.07-7.24 (5H, m), 7.54 (1H, d, J=7.9 Hz).
MS: m/z=522 [M+H]+.
EXAMPLE 418




1H-NMR (CDCl3) δ: 1.48 (3H, d, J=7.1 Hz), 3.63 (1H, d, J=13.2 Hz), 4.49 (1H, d, J=12.6 Hz), 5.03 (1H, s), 5.28-5.45 (2H, m), 5.53 (1H, d, J=13.5 Hz), 5.73 (1H, d, J=7.7 Hz), 6.50 (1H, dd, J=8.7, 2.6 Hz), 6.79-6.86 (1H, m), 6.90 (1H, d, J=9.1 Hz), 7.02 (1H, dd, J=8.8, 5.2 Hz), 7.10 (1H, ddd, J=8.1, 2.5, 1.2 Hz), 7.25 (1H, d, J=7.7 Hz), 7.30 (1H, dd, J=8.5, 5.5 Hz).
MS: m/z=524 [M+H]+.
EXAMPLE 419




1H-NMR (CDCl3) δ: 1.50 (3H, d, J=7.1 Hz), 4.28 (1H, d, J=13.7 Hz), 4.50 (1H, d, J=12.4 Hz), 5.17 (1H, s), 5.26-5.44 (2H, m), 5.60-5.69 (2H, m), 6.65 (1H, d, J=7.4 Hz), 6.73-6.80 (1H, m), 7.01-7.21 (5H, m), 7.48 (1H, d, J=8.0 Hz).
MS: m/z=522 [M+H]+.
EXAMPLE 420




1H-NMR (CDCl3) δ: 1.49 (3H, d, J=7.4 Hz), 3.51 (1H, d, J=13.5 Hz), 4.48 (1H, d, J=12.6 Hz), 5.12 (1H, s), 5.28-5.44 (2H, m), 5.60-5.70 (2H, m), 6.65 (1H, d, J=7.4 Hz), 6.73-6.80 (1H, m), 7.00-7.06 (2H, m), 7.10 (1H, d, J=8.5 Hz), 7.14 (1H, d, J=8.0 Hz), 7.23 (1H, dd, J=8.2, 2.2 Hz), 7.31 (1H, d, J=1.9 Hz).
MS: m/z=522 [M+H]+.
EXAMPLE 421




1H-NMR (CDCl3) δ: 1.53 (3H, d, J=7.4 Hz), 3.59 (1H, d, J=13.4 Hz), 4.51 (1H, d, J=12.6 Hz), 5.12 (1H, s), 5.30-5.48 (2H, m), 5.62-5.70 (2H, m), 6.71 (1H, d, J=7.7 Hz), 6.80-6.83 (1H, m), 7.07-7.11 (2H, m), 7.18 (1H, d, J=7.7 Hz), 7.22 (1H, s), 7.28 (1H, d, J=8.4 Hz), 7.39 (1H, d, J=8.1 Hz).
MS: m/z=522 [M+H]+.
EXAMPLE 422




1H-NMR (CDCl3) δ: 1.49 (3H, d, J=7.4 Hz), 3.59 (1H, d, J=13.5 Hz), 4.48 (1H, d, J=12.4 Hz), 5.12 (1H, s), 5.29-5.39 (2H, m), 5.66 (1H, d, J=13.5 Hz), 5.73 (1H, d, J=7.7 Hz), 6.61 (1H, d, J=8.2 Hz), 6.73 (1H, dd, J=8.2, 2.2 Hz), 7.04 (1H, d, J=2.2 Hz), 7.12-7.20 (2H, m), 7.23-7.27 (1H, m), 7.31 (1H, d, J=6.3 Hz), 7.36-7.44 (1H, m).
MS: m/z=522 [M+H]+.
EXAMPLE 423




1H-NMR (CDCl3) δ: 1.47 (3H, d, J=7.1 Hz), 3.69 (1H, d, J=13.5 Hz), 4.49 (1H, d, J=12.6 Hz), 5.21 (1H, s), 5.27 (1H, d, J=12.6 Hz), 5.30-5.40 (1H, m), 5.70 (1H, d, J=7.7 Hz), 5.75 (1H, d, J=13.5 Hz), 6.65 (1H, dd, J=7.8, 1.5 Hz), 6.73 (1H, t, J=7.7 Hz), 7.13 (1H, d, J=7.7 Hz), 7.15-7.22 (2H, m), 7.25-7.29 (1H, m), 7.32 (1H, d, J=8.0 Hz), 7.37-7.45 (1H, m).
MS: m/z=522 [M+H]+.
EXAMPLE 424




MS: m/z=490 [M+H]+.
EXAMPLE 425




MS: m/z=490 [M+H]+.
EXAMPLE 426




MS: m/z=490 [M+H]+.
EXAMPLE 427




1HNMR (CDCl3) δ: 1.14 (3H, d, J=6.9 Hz), 3.64 (1H, d, J=13.5 Hz), 4.48 (1H, d, J=12.8 Hz), 4.88 (1H, d, J=12.8 Hz), 5.08 (1H, s), 5.51 (1H, m), 5.60 (1H, d, J=13.5 Hz), 5.93 (1H, d, J=8.1 Hz), 6.58 (1H, d, J=8.1 Hz), 6.95 (1H, dd, J=2.0, 8.1 Hz), 7.18 (2H, m), 7.29 (1H, m), 7.37-7.45 (2H, m).
EXAMPLE 428




1HNMR (CDCl3) δ: 1.41 (3H, d, J=7.5 Hz), 3.61 (1H, d, J=13.4 Hz), 4.55 (1H, d, J=12.5 Hz), 5.06 (1H, d, J=12.5 Hz), 5.16 (1H, s), 5.34 (1H, m), 5.63 (1H, d, J=13.4 Hz), 5.87 (1H, d, J=8.1 Hz), 6.61 (1H, d, J=8.1 Hz), 6.93 (1H, dd, J=1.8, 8.1 Hz), 7.16-7.41 (5H, m).
EXAMPLE 429




1H-NMR (CDCl3) δ: 1.15 (3H, d, J=7.4 Hz), 3.64 (1H, d, J=13.5 Hz), 4.44 (1H, d, J=13.2 Hz), 4.87 (1H, d, J=13.2 Hz), 5.44-5.57 (1H, m), 5.68 (1H, d, J=13.2 Hz), 5.83 (1H, d, J=7.7 Hz), 5.94 (1H, s), 6.78-6.91 (2H, m), 7.08-7.18 (3H, m), 7.28-7.38 (3H, m).
MS: m/z=522 [M+H]+.
EXAMPLE 430




MS: m/z=522 [M+H]+.
EXAMPLE 431




MS: m/z=522 [M+H]+.
EXAMPLE 432




1H-NMR (CDCl3) δ: 1.21 (3H, d, J=7.4 Hz), 3.70 (1H, d, J=13.5 Hz), 4.43 (1H, d, J=13.2 Hz), 4.93 (1H, d, J=13.2 Hz), 5.21 (1H, s), 5.46-5.60 (1H, m), 5.70 (1H, d, J=13.5 Hz), 5.84 (1H, d, J=7.7 Hz), 6.73 (1H, d, J=7.1 Hz), 6.82-6.89 (1H, m), 7.08-7.17 (2H, m), 7.22 (1H, d, J=7.7 Hz), 7.35 (1H, d, J=8.0 Hz), 7.55 (1H, d, J=8.0 Hz), 7.67 (1H, s).
MS: m/z=071 [M+H]+.
EXAMPLE 433




1H-NMR (CDCl3) δ: 1.22 (3H, d, J=7.1 Hz), 3.56 (1H, d, J=13.5 Hz), 4.48 (1H, d, J=13.2 Hz), 4.90 (1H, d, J=13.2 Hz), 5.09 (1H, s), 5.46-5.60 (1H, m), 5.62 (1H, d, J=13.2 Hz), 5.82 (1H, d, J=7.7 Hz), 6.69 (1H, d, J=7.4 Hz), 6.84 (1H, dt, J=10.0, 3.5 Hz), 7.04-7.14 (3H, m), 7.17 (1H, d, J=7.7 Hz), 7.42 (1H, dd, J=8.0, 1.6 Hz), 7.55 (1H, d, J=1.9 Hz).
MS: m/z=433 [M+H]+.
EXAMPLE 434




1H-NMR (CDCl3) δ: 1.44 (3H, d, J=7.3 Hz), 3.54 (1H, d, J=13.4 Hz), 4.54 (1H, d, J=12.5 Hz), 5.10 (1H, d, J=12.5 Hz), 5.16 (1H, s), 5.31-5.45 (1H, m), 5.65 (1H, d, J=13.3 Hz), 5.73 (1H, d, J=7.8 Hz), 6.71 (1H, d, J=7.8 Hz), 6.77-6.84 (1H, m), 7.03-7.11 (3H, m), 7.22 (1H, d, J=7.6 Hz), 7.40 (1H, dd, J=8.2, 2.0 Hz), 7.48 (1H, d, J=2.0 Hz).
MS: m/z=433 [M+H]+.
EXAMPLE 435




1H-NMR (CDCl3) δ: 1.14 (3H, d, J=7.3 Hz), 3.70 (1H, d, J=13.4 Hz), 4.51 (1H, d, J=13.1 Hz), 4.90 (1H, d, J=12.8 Hz), 5.19 (1H, s), 5.44-5.58 (1H, m), 5.62 (1H, d, J=13.3 Hz), 5.87 (1H, d, J=7.6 Hz), 6.86 (1H, d, J=7.9 Hz), 7.07 (1H, dd, J=8.2, 1.4 Hz), 7.15-7.22 (2H, m), 7.27-7.51 (4H, m).
MS: m/z=433 [M+H]+.
EXAMPLE 436




1H-NMR (CDCl3) δ: 1.48 (3H, d, J=7.4 Hz), 3.71 (1H, d, J=13.3 Hz), 4.60 (1H, d, J=12.6 Hz), 5.21 (1H, d, J=12.6 Hz), 5.29 (1H, s), 5.32-5.46 (1H, m), 5.70 (1H, d, J=13.3 Hz), 5.80 (1H, d, J=7.7 Hz), 6.91 (1H, d, J=7.9 Hz), 7.08 (1H, d, J=7.4 Hz), 7.20-7.29 (2H, m), 7.33-7.51 (4H, m).
MS: m/z=433 [M+H]+.
EXAMPLE 437




1H-NMR (CDCl3) δ: 1.21 (3H, d, J=7.3 Hz), 3.60 (1H, d, J=13.6 Hz), 4.46 (1H, d, J=13.1 Hz), 4.90 (1H, d, J=12.8 Hz), 5.15 (1H, s), 5.47-5.59 (1H, m), 5.68 (1H, d, J=13.4 Hz), 5.83 (1H, d, J=7.6 Hz), 6.70 (1H, d, J=7.3 Hz), 6.80-6.88 (1H, m), 7.07-7.26 (6H, m).
MS: m/z=433 [M+H]+.
EXAMPLE 438




1H-NMR (CDCl3) δ: 1.42 (3H, d, J=7.3 Hz), 3.57 (1H, d, J=13.3 Hz), 4.55 (1H, d, J=12.5 Hz), 5.05 (1H, d, J=12.5 Hz), 5.23 (1H, s), 5.32-5.47 (1H, m), 5.70 (1H, d, J=13.4 Hz), 5.77 (1H, d, J=7.6 Hz), 6.74 (1H, d, J=7.8 Hz), 6.79-6.87 (1H, m), 7.04-7.26 (6H, m).
MS: m/z=433 [M+H]+.
EXAMPLE 439




1H-NMR (CDCl3) δ: 1.20 (3H, d, J=7.2 Hz), 2.29 (3H, s), 3.76 (1H, d, J=13.3 Hz), 4.54 (1H, d, J=13.1 Hz), 4.92 (1H, d, J=13.1 Hz), 5.18 (1H, s), 5.50-5.62 (1H, m), 5.71 (1H, d, J=13.4 Hz), 5.84 (1H, d, J=7.7 Hz), 6.63 (1H, d, J=7.4 Hz), 6.78 (1H, t, J=7.6 Hz), 7.06 (1H, d, J=7.6 Hz), 7.17 (1H, d, J=7.7 Hz), 7.23 (1H, d, J=7.6 Hz), 7.28-7.34 (1H, m), 7.39-7.51 (2H, m).
MS: m/z=433 [M+H]+.
EXAMPLE 440




1H-NMR (CDCl3) δ: 1.45 (3H, d, J=7.2 Hz), 2.27 (3H, s), 3.74 (1H, d, J=13.3 Hz), 4.61 (1H, d, J=12.4 Hz), 5.07 (1H, d, J=12.4 Hz), 5.27 (1H, s), 5.31-5.44 (1H, m), 5.75 (1H, d, J=13.3 Hz), 5.80 (1H, d, J=7.7 Hz), 6.67 (1H, d, J=7.1 Hz), 6.77 (1H, t, J=7.6 Hz), 7.04 (1H, d, J=7.1 Hz), 7.21-7.47 (5H, m).
MS: m/z=433 [M+H]+.
EXAMPLE 441




1H-NMR (DMSO-d6) δ: 1.22 (3H, d, J=7.2 Hz), 3.94 (1H, d, J=13.3 Hz), 4.45 (1H, d, J=13.4 Hz), 5.08 (1H, d, J=12.8 Hz), 5.56 (4H, dm), 6.84-7.54 (8H, m).
EXAMPLE 442




1H-NMR (DMSO-d6) δ: 1.37 (3H, d, J=7.2 Hz), 3.98 (1H, d, J=13.4 Hz), 4.48 (1H, d, J=13.1 Hz), 5.21 (1H, d, J=12.9 Hz), 5.22 (1H, m), 5.38 (1H, s), 5.52 (1H, d, J=13.4 Hz), 5.67 (1H, d, J=7.6 Hz), 6.87-7.57 (8H, m).
EXAMPLE 443




1H-NMR (DMSO-d6) δ: 1.19 (3H, d, J=7.2 Hz), 3.92 (1H, d, J=13.4 Hz), 4.43 (1H, d, J=13.1 Hz), 5.05 (1H, d, J=13.0 Hz), 5.54 (4H, m), 7.29 (8H, m).
MS: m/z=522 [M+H]+
EXAMPLE 444




1H-NMR (DMSO-d6) δ: 1.13 (3H, d, J=7.0 Hz), 4.00 (1H, d, J=14.2 Hz), 4.40 (1H, d, J=13.3 Hz), 5.05 (1H, d, J=13.3 Hz), 5.44 (1H, m), 5.62-5.71 (3H, m), 6.82-7.56 (8H, m).
MS: m/z=506 [M+H]+
EXAMPLE 445




1H-NMR (DMSO-d6) δ: 1.23 (3H, d, J=7.2 Hz), 4.14 (1H, d, J=13.8 Hz), 4.60 (1H, d, J=13.6 Hz), 5.10 (1H, d, J=13.3 Hz), 5.48 (1H, d, J=15.6 Hz) 5.49 (1H, m), 5.69 (1H, d, J=7.9 Hz), 5.70 (1H, s), 6.89-7.47 (8H, m).
MS: m/z=506 [M+H]+
EXAMPLE 446




1H-NMR (DMSO-d6) δ: 1.22 (3H, d, J=6.9 Hz), 3.93 (1H, d, J=13.1 Hz), 4.49 (1H, d, J=13.4 Hz), 5.05 (1H, d, J=13.7 Hz), 5.57 (4H, m), 6.87-7.61 (8H, m).
MS: m/z=522 [M+H]+
EXAMPLE 447




1H-NMR (DMSO-d6) δ: 1.41 (3H, d, J=7.2 Hz), 3.98 (1H, d, J=13.3 Hz), 4.48 (1H, d, J=12.9 Hz), 5.21 (1H, d, J=14.4 Hz), 5.22 (1H, m), 5.39 (1H, s), 5.52 (1H, d, J=13.6 Hz), 5.67 (1H, d, J=7.6 Hz), 6.88-7.57 (8H, m).
MS: m/z=506 [M+H]+.
EXAMPLE 448




1H-NMR (DMSO-d6) δ: 1.19 (3H, d, J=7.2 Hz), 3.94 (1H, d, J=13.3 Hz), 4.44 (1H, d, J=13.3 Hz), 5.12 (1H, d, J=13.1 Hz), 5.46-5.68 (3H, m), 5.76 (1H, d, J=7.6 Hz), 7.27 (8H, m).
MS: m/z=506 [M+H]+
EXAMPLE 449




1H-NMR (DMSO-d6) δ: 1.14 (3H, d, J=7.2 Hz), 3.93 (1H, d, J=13.3 Hz), 4.40 (1H, d, J=13.1 Hz), 5.07 (1H, d, J=13.0 Hz), 5.46 (1H, m), 5.62 (1H, d, J=15.6 Hz), 5.64 (1H, s), 5.75 (1H, d, J=7.6 Hz), 6.94-7.55 (8H, m).
MS: m/z=522 [M+H]+
EXAMPLE 450




1H-NMR (DMSO-d6) δ: 1.14 (3H, d, J=7.2 Hz), 4.03 (1H, d, J=13.3 Hz), 4.41 (1H, d, J=13.3 Hz), 5.06 (1H, d, J=13.0 Hz), 5.46 (1H, m), 5.69 (3H, m), 6.88-7.57 (8H, m).
MS: m/z=522 [M+H]+
EXAMPLE 451




1H-NMR (DMSO-d6) δ: 1.35 (3H, d, J=7.2 Hz), 4.03 (1H, d, J=13.3 Hz), 4.43 (1H, d, J=13.0 Hz), 5.14 (1H, t, J=12.6 Hz), 5.15 (1H, m), 5.42 (1H, s), 5.63 (1H, d, J=13.5 Hz), 5.65 (1H, d, J=7.8 Hz), 6.88-7.44 (8H, m).
MS: m/z=522 [M+H]+
EXAMPLE 452




1H-NMR (DMSO-d6) δ: 1.42 (3H, d, J=7.2 Hz), 4.14 (1H, d, J=13.9 Hz), 4.57 (1H, d, J=13.1 Hz), 5.14 (1H, d, J=13.0 Hz), 5.15 (1H, m), 5.30 (1H, d, J=13.0 Hz), 5.40 (1H, s), 5.68 (1H, d, J=7.7 Hz), 6.89-7.38 (8H, m).
MS: m/z=506 [M+H]+
EXAMPLE 453




1H-NMR (DMSO-d6) δ: 1.40 (3H, d, J=7.4 Hz), 4.05 (1H, d, J=13.4 Hz), 4.47 (1H, d, J=13.1 Hz), 5.18 (1H, m), 5.19 (1H, d, J=13.2 Hz), 5.46 (1H, s), 5.65 (1H, d, J=13.4 Hz), 5.74 (1H, d, J=7.6 Hz), 6.89-7.52 (8H, m).
MS: m/z=506 [M+H]+
EXAMPLE 454




1H-NMR (DMSO-d6) δ: 1.20 (3H, d, J=7.2 Hz), 3.89 (1H, d, J=13.4 Hz), 4.46 (1H, d, J=13.4 Hz), 5.05 (1H, d, J=13.4 Hz), 5.44-5.66 (4H, m), 6.83-7.63 (8H, m).
MS: m/z=506 [M+H]+
EXAMPLE 455




1H-NMR (DMSO-d6) δ: 1.16 (3H, d, J=7.3 Hz), 3.92 (1H, d, J=13.3 Hz), 4.39 (1H, d, J=13.1 Hz), 5.07 (1H, d, J=13.3 Hz), 5.47 (1H, m), 5.60 (1H, d, J=13.3 Hz), 5.68 (1H, s), 5.72 (1H, d, J=7.6 Hz), 7.07-7.54 (8H, m).
MS: m/z=522 [M+H]+
EXAMPLE 456




1H-NMR (DMSO-d6) δ: 1.13 (5H, d, J=6.3 Hz), 4.00 (1H, d, J=13.4 Hz), 4.52 (1H, d, J=13.6 Hz), 5.09 (1H, d, J=13.3 Hz), 5.49-5.69 (4H, m), 6.84-7.51 (8H, m).
MS: m/z=506 [M+H]+
EXAMPLE 457




1H-NMR (DMSO-d6) δ: 1.40 (3H, d, J=7.2 Hz), 4.02 (1H, d, J=13.1 Hz), 4.53 (1H, d, J=13.3 Hz), 5.20 (1H, d, J=12.9 Hz), 5.26 (1H, m), 5.67 (3H, m), 7.18 (8H, m).
MS: m/z=506 [M+H]+
EXAMPLE 458




1H-NMR (DMSO-d6) δ: 1.15 (3H, d, J=7.3 Hz), 3.91 (1H, d, J=13.4 Hz), 4.39 (1H, d, J=13.3 Hz), 5.06 (1H, d, J=13.3 Hz), 5.45 (1H, m), 5.62 (1H, s), 5.63 (1H, t, J=13.5 Hz), 5.74 (1H, d, J=7.6 Hz), 6.71-7.55 (8H, m).
MS: m/z=506 [M+H]+
EXAMPLE 459




1H-NMR (DMSO-d6) δ: 1.39 (3H, d, J=7.4 Hz), 3.95 (1H, d, J=13.4 Hz), 4.46 (1H, d, J=12.9 Hz), 5.19 (1H, d, J=13.1 Hz), 5.20 (1H, m), 5.41 (1H, s), 5.62 (1H, d, J=13.4 Hz), 5.76 (1H, d, J=7.7 Hz), 6.72-7.50 (8H, m).
MS: m/z=506 [M+H]+
EXAMPLE 460




1H-NMR (DMSO-d6) δ: 1.42 (3H, d, J=7.2 Hz), 3.94 (1H, d, J=13.3 Hz), 4.50 (1H, d, J=13.1 Hz), 5.17 (1H, d, J=12.4 Hz), 5.18 (1H, m), 5.39 (1H, s), 5.60-5.69 (2H, m), 6.87-7.42 (8H, m).
MS: m/z=506 [M+H]+
EXAMPLE 461




1H-NMR (DMSO-d6) δ: 1.35 (3H, d, J=7.2 Hz), 3.91 (1H, d, J=13.0 Hz), 4.43 (1H, d, J=13.1 Hz), 5.15 (1H, d, J=12.8 Hz), 5.16 (1H, m), 5.41 (1H, s), 5.47 (1H, d, J=13.0 Hz), 5.69 (1H, d, J=7.6 Hz), 7.00-7.45 (8H, m).
MS: m/z=506 [M+H]+
EXAMPLE 462




1H-NMR (DMSO-d6) δ: 1.21 (3H, d, J=7.3 Hz), 3.97 (1H, d, J=13.3 Hz), 4.46 (1H, d, J=13.1 Hz), 5.09 (1H, d, J=13.6 Hz), 5.50 (1H, m), 5.51 (1H, d, J=12.8 Hz), 5.65 (1H, s), 5.72 (1H, d, J=7.6 Hz), 6.85-7.55 (7H, m).
MS: m/z=524 [M+H]+
EXAMPLE 463




MS: m/z=568 [M+H]+
EXAMPLE 464




MS: m/z=502 [M+H]+
EXAMPLE 465




MS: m/z=502 [M+H]+
EXAMPLE 466




MS: m/z=540 [M+H]+
EXAMPLE 467




MS: m/z=540 [M+H]+
EXAMPLE 468




1HNMR (CDCl3) δ: 1.13 (3H, d, J=5.8 Hz), 4.20 (1H, d, J=13.6 Hz), 4.58 (1H, d, J=12.7 Hz), 4.99 (1H, d, J=12.7 Hz), 5.29-5.42 (3H, m), 5.84 (1H, d, J=7.8 Hz), 6.60 (1H, m), 6.79-7.01 (3H, m), 7.19-7.28 (4H, m).
MS: m/z=524 [M+H]+.
EXAMPLE 469




1HNMR (CDCl3) δ: 1.19 (3H, d, J=7.6 Hz), 4.21 (1H, d, J=13.9 Hz), 4.48 (1H, d, J=13.3 Hz), 4.89 (1H, d, J=13.3 Hz), 5.22 (1H, s), 5.37 (1H, dd, J=2.1, 13.9 Hz), 5.52 (1H, m), 5.86 (1H, d, J=7.6), 6.55 (1H, m), 6.83 (1H, m), 6.96 (1H, m), 7.14 (1H, d, J=7.6 Hz), 7.19-7.30 (4H, m).
MS: m/z=524 [M+H]+.
EXAMPLE 470




1HNMR (CDCl3) δ: 1.19 (3H, d, J=7.3 Hz), 3.65 (1H, d, J=13.5 Hz), 4.47 (1H, d, J=13.0 Hz), 4.87 (1H, d, J=13.0 Hz), 5.18 (1H, s), 5.50 (1H, m), 5.69 (1H, d, J=13.5 Hz), 5.85 (1H, d, J=7.8 Hz), 6.53 (1H, m), 6.83 (1H, m), 6.91-7.01 (2H, m), 7.11 (1H, d, J=7.6 Hz), 7.10-7.20 (3H, m).
MS: m/z=524 [M+H]+.
EXAMPLE 471




1HNMR (CDCl3) δ: 1.13 (3H, d, J=6.1 Hz), 3.63 (1H, d, J=13.5 Hz), 4.56 (1H, d, J=12.5 Hz), 5.02 (1H, d, J=12.5 Hz), 5.26 (1H, s), 5.38 (1H, m), 5.71 (1H, d, J=13.5 Hz), 5.81 (1H, d, J=7.8 Hz), 6.57 (1H, m), 6.81 (1H, m), 6.91 (1H, m), 6.99 (1H, dd, J=2.6, 8.2 Hz), 7.05 (1H, dd, J=2.6, 8.7 Hz), 7.17 (2H, m), 7.19 (1H, d, J=7.6 Hz).
MS: m/z=524 [M+H]+.
EXAMPLE 472




1HNMR (CDCl3) δ: 1.21 (3H, d, J=7.4 Hz), 3.66 (1H, d, J=13.5 Hz), 4.47 (1H, d, J=13.3 Hz), 4.88 (1H, d, J=13.3 Hz), 5.17 (1H, s), 5.52 (1H, m), 5.66 (1H, d, J=13.5 Hz), 5.85 (1H, d, J=7.7 Hz), 6.54 (1H, m), 6.83 (1H, m), 6.95 (1H, m), 7.11-7.14 (2H, m), 7.23-7.29 (2H, m), 7.41 (1H, d, J=2.0 Hz).
MS: m/z=540 [M+H]+.
EXAMPLE 473




1HNMR (CDCl3) δ: 1.13 (3H, d, J=6.2 Hz), 3.63 (1H, d, J=13.5 Hz), 4.55 (1H, d, J=12.6 Hz), 5.04 (1H, d, J=12.6 Hz), 5.25 (1H, s), 5.38 (1H, m), 5.69 (1H, d, J=13.5 Hz), 5.80 (1H, d, J=7.7 Hz), 6.58 (1H, m), 6.82 (1H, m), 6.92 (1H, m), 7.13 (1H, m), 7.19 (1H, d, J=7.7 Hz), 7.24-7.29 (2H, m), 7.34 (1H, d, J=2.2 Hz).
MS: m/z=540 [M+H]+.
EXAMPLE 474




1HNMR (CDCl3) δ: 1.19 (3H, d, J=7.3 Hz), 4.40 (1H, d, J=13.9 Hz), 4.59 (1H, d, J=13.0 Hz), 5.02 (1H, d, J=13.0 Hz), 5.31 (1H, s), 5.39 (1H, m), 5.66 (1H, d, J=13.9 Hz), 5.84 (1H, d, J=7.8 Hz), 6.58 (1H, m), 6.82 (1H, m), 6.92 (1H, m), 7.10 (1H, m), 7.19 (1H, dd, J=3.7, 7.9 Hz), 7.20-7.26 (2H, m), 7.51 (1H, m).
MS: m/z=540 [M+H]+.
EXAMPLE 475




MS: m/z=522 [M+H]+.
EXAMPLE 476




First Step

Compound 476A (3.00 g, 9.83 mmol) synthesized by the same procedure as that of Example was dissolved in dimethylformamide (30 ml), copper (I) cyanide (2.64 g, 29.5 mmol) was added, and the mixture was stirred at 150° C. for 7 hours. The reaction solution was cooled to room temperature, and filtered with celite. To the filtrate was added water, the mixture was extracted with ethyl acetate, and the organic layer was washed with water. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography, and eluted with n-hexane-ethyl acetate (1:1, v/v). To the resulting compound was added n-hexane, and the precipitated residue was filtered to obtain 1.81 g of a white solid 476B.
1H-NMR (CDCl3) δ: 4.29 (2H, s), 7.28-7.48 (4H, m), 7.78 (2H, t, J=7.5 Hz), 8.20 (1H, dd, J=8.1, 1.5 Hz).
Second Step
Compound 476 was synthesized by the same procedure as that of Example 107.
1H-NMR (DMSO-d6) δ: 1.16 (3H, d, J=7.0 Hz), 4.01 (1H, d, J=14.0 Hz), 4.65 (1H, d, J=13.7 Hz), 5.04 (1H, d, J=13.3 Hz), 5.45 (1H, t, J=8.1 Hz), 5.66 (1H, d, J=7.6 Hz), 5.74 (1H, s), 5.84 (1H, d, J=14.0 Hz), 6.87-7.93 (7H, m).
MS: m/z=513 [M+H]+
EXAMPLE 477




First Step

To compound 476B (859 mg, 3.42 mmol) was added concentrated sulfuric acid (13 ml), and the mixture was stirred at room temperature for 18 hours, and at 60° C. for 2 hours. The reaction solution was added to water, the mixture was extracted with ethyl acetate, and the organic layer was dried with sodium sulfate. The solvent was concentrated under reduced pressure to obtain 387 mg of a pale yellow solid. To the resulting compound was added methanol (10 ml), a 10N aqueous sodium hydroxide solution (6 ml) was added, and the mixture was stirred at 90° C. for 5 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was washed with dichloromethane. To the aqueous layer was added dilute hydrochloric acid, the mixture was extracted with ethyl acetate, and the organic layer was dried with sodium sulfate. The solvent was concentrated under reduced pressure to obtain 296 mg of a yellow solid 477A.
Second Step
Compound 477A (179 mg, 0.662 mmol) obtained in the first step was dissolved in dichloromethane (4 ml), dimethylamine hydrochloride (108 mg, 1.32 mmol), EDCI (190 mg, 0.993 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (89.0 mg, 0.662 mmol) and triethylamine (0.3 ml) were added, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added water, the mixture was extracted with ethyl acetate, and the organic layer was washed with an aqueous sodium bicarbonate solution, and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography, and eluted with n-hexane-ethyl acetate (1:1, v/v), to obtain 170 mg of a colorless gummy substance 477B.
1H-NMR (CDCl3) δ: 2.99 (3H, s), 3.23 (3H, s), 4.08 (2H, s), 7.28-7.44 (5H, m), 7.58 (1H, t, J=4.4 Hz), 8.22 (1H, dd, J=8.1, 1.5 Hz).
Third Step
Compound 477 was synthesized by the same procedure as that of Example 107.
MS: m/z=559 [M+H]+
EXAMPLE 478







First Step

Compound 277 (971 mg, 2.11 mmol) was dissolved in dimethylformamide (10 ml), cesium carbonate (2.75 g, 8.45 mmol) and benzyl bromide (0.753 ml, 6.34 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into water, then extracted with ethyl acetate, and the organic layer was washed with water, and dried with sodium sulfate. The solvent was distilled off under reduced pressure, to the resulting compound were added dichloromethane-diethyl ether, and the precipitated residue was filtered to obtain 740 mg of a white solid 478A.
Second Step
Compound 478A (740 mg, 1.35 mmol) was dissolved in tetrahydrofuran (7 ml) and methanol (7 ml), a 2N aqueous sodium hydroxide solution (3.37 ml, 6.73 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added dilute hydrochloric acid to make the solution acidic, the mixture was extracted with chloroform, and the organic layer was dried with sodium sulfate. The solvent was concentrated under reduced pressure to obtain 618 mg of a white solid 478B.
MS: m/z=508 [M+H]+
Third Step
Compound 478B (505 mg, 0.995 mmol) was dissolved in tetrahydrofuran (10 ml), triphenylphosphine (391 mg, 1.49 mmol), phthalimide (220 mg, 1.49 mmol) and azodicarboxylic acid diisopropyl ester (0.290 ml, 1.49 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography, and eluted with chloroform-methanol (97:3, v/v). To the resulting compound were added dichloromethane-diethyl ether, and the precipitated residue was filtered to obtain 578 mg of a white solid 478C.
MS: m/z=637 [M+H]+
Fourth Step
To compound 478C (667 mg, 1.05 mmol) was added ethanol (10 ml), hydrazine hydrate (0.254 ml, 5.24 mmol) was added, and the mixture was stirred at 90° C. for 2 hours. The reaction solution was cooled to room temperature, chloroform was added, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by amino column chromatography, and eluted with chloroform-methanol (97:3, v/v). To the resulting compound were added dichloromethane-diethyl ether, and the precipitated residue was filtered to obtain 462 mg of a white soled 478D.
MS: m/z=507 [M+H]+
Fifth Step
To compound 478D (100 mg, 0.197 mmol) were added formic acid (1.0 ml) and an aqueous formalin solution (1.0 ml), and the mixture was stirred at 80° C. for 1 hour. To the reaction solution was added a 1N aqueous sodium hydroxide solution, the mixture was extracted with dichloromethane, and the organic layer was dried with sodium sulfate. The resulting crude product was purified by amino column chromatography, and eluted with chloroform-methanol (97:3, v/v), to obtain 56 mg of a colorless oily substance. This compound was dissolved in acetic acid (2.0 ml), concentrated sulfuric acid (0.5 ml) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into an aqueous sodium bicarbonate solution, and was extracted with chloroform, and the organic layer was dried with sodium sulfate. The solvent was distilled off under reduced pressure, to the resulting crude product were added dichloromethane-ethyl acetate-diethyl ether, and the precipitated residue was filtered to obtain 12 mg of a white solid 478.
MS: m/z=445 [M+H]+
EXAMPLE 479




First Step

To a dichloromethane (50 ml) solution of compound 479A (5.25 g, 11.8 mmol) synthesized according to Example 95, DIPEA (6.20 mL, 35.5 mmol) and Boc2O (5.17 g, 23.7 mmol) was added DMAP (434 mg, 3.55 mmol), and the mixture was stirred at room temperature for 4 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate. The solution was sequentially washed with 0.5N hydrochloric acid and an aqueous saturated sodium chloride solution, and dried with sodium sulfate. The solvent was distilled off, and the resulting oil was purified by silica gel chromatography. The materials were eluted firstly with chloroform and, then, with chloroform-methanol (97:3, v/v). Concentration of an objective fraction afforded 5.22 g of compound 479B as an oil.
MS: m/z=544 [M+H]+.
Second Step
To a THF (340 mL) solution of compound 479B (29.7 g, 102 mmol) and acetic acid (29.7 g, 102 mmol) was added TBAF (1M THF solution, 23.6 g, 310 mmol) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. To the reaction solution were added ethyl acetate and water, and the ethyl acetate layer was separated, washed with water, and dried with sodium sulfate. The solvent was distilled off, and the resulting oil was solidified by adding dichloromethane-ether, to obtain 2.76 g of compound 479C.
MS: m/z=430 [M+H]+.
Third Step
To an ethyl acetate (20 mL) suspension of compound 479C (500 mg, 1.16 mmol) was added IBX (652 mg, 2.33 mmol), and the mixture was heated to stir for 3 hours. After the reaction solution was diluted with ethyl acetate, insolubles were filtered, and the resulting filtrate was sequentially washed with a 1N aqueous sodium hydroxide solution and water, and dried with sodium sulfate. After the solvent was distilled off, and the resulting oil was dissolved in THF (5 mL), dimethylamine (2M THF solution, 0.873 mL, 1.75 mmol) and NaBH(OAc)3 (370 mg, 1.75 mmol) were added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. After 2N hydrochloric acid was added to the reaction solution under ice-cooling, the mixture was made basic with an aqueous sodium bicarbonate solution. This was extracted with chloroform, and dried with sodium sulfate. The solvent was distilled off, and the resulting oil was purified by silica gel chromatography. The materials were eluted first with chloroform and, then, with chloroform-methanol (93:7, v/v). Concentration of an objective fraction afforded 437 mg of compound 479D as an amorphous substance.
MS: m/z=457 [M+H]+.
Fourth Step
Compound 479D (430 mg, 0.942 mmol) was dissolved in acetic acid (10 mL), and the solution was heated to stir for 1 hour. The solvent was distilled off, and the resulting oil was purified by silica gel chromatography. The materials were eluted firstly with chloroform and, then, with chloroform-methanol (95:5, v/v). Concentration of an objective fraction afforded 330 mg of compound 479E as an oil.
MS: m/z=357 [M+H]+.
Fifth Step
To an acetic acid (2 mL) solution of compound 479E (50 mg, 0.140 mmol) and dibenzosuberol (29.5 mg, 0.140 mmol) was added dropwise sulfuric acid (0.5 mL), and the mixture was stirred for 30 minutes. To the reaction solution were added ethyl acetate and water, thereafter, the aqueous layer was separated, and neutralized with an aqueous sodium bicarbonate solution. Extraction was performed using the ethyl acetate layer, and the extract was washed with water, and dried with sodium sulfate. The solvent was distilled off, and the resulting oil was solidified by adding ether, to obtain 17.0 mg of compound 479.
MS: m/z=354 [M+H]+.
According to Example 478 or Example 479, Examples 480 to 490 were synthesized using the same procedure.
EXAMPLE 480




MS: m/z=477 [M+H]+.
EXAMPLE 481




MS: m/z=512 [M+H]+.
EXAMPLE 482




MS: m/z=501 [M+H]+.
EXAMPLE 483




MS: m/z=519 [M+H]+.
EXAMPLE 484




MS: m/z=514 [M+H]+.
EXAMPLE 485




MS: m/z=532 [M+H]+.
EXAMPLE 486




MS: m/z=499 [M+H]+.
EXAMPLE 487




MS: m/z=517 [M+H]+.
EXAMPLE 488




MS: m/z=517 [M+H]+.
EXAMPLE 489




MS: m/z=535 [M+H]+.
EXAMPLE 490




MS: m/z=473 [M+H]+
EXAMPLE 491




According to Example 65 and Example 107, compound 491 was synthesized by the same procedure.
1H-NMR (DMSO-d6) δ: 1.10 (3H, d, J=4.0 Hz), 1.12 (3H, d, J=4.6 Hz), 2.82-3.06 (2H, m), 3.56 (1H, d, J=17.8 Hz), 4.26 (1H, d, J=13.2 Hz), 4.31 (1H, m), 4.51-4.60 (1H, m), 4.97 (1H, d, J=13.1 Hz), 5.39 (1H, s), 6.74-7.52 (8H, m).
MS: m/z=460 [M+H]+
EXAMPLE 492




According to Example 65 and Example 107, compound 492 was synthesized by the same procedure.
MS: m/z=478 [M+H]+
EXAMPLE 493




First Step

A dichloromethane (5 mL) solution of compound 493A (258 mg, 1.30 mmol) was cooled to −50° C., and a toluene solution (1M, 1.96 mL) of DIBAL-H was added dropwise over 5 minutes while the same temperature was retained. After the reaction solution was stirred at the same temperature for 1 hour, temperature was raised to room temperature, and the mixture was stirred for 2.5 hours. To the reaction solution was added an aqueous saturated ammonium chloride solution, thereafter, the mixture was stirred at room temperature for 1 hour, and insolubles were removed by filtration. The dichloromethane layer was separated, and the aqueous layer was extracted with dichloromethane once. The combined extracts were washed with water three times, washed with an aqueous saturated sodium chloride solution, and dried. The solvent was distilled off, and the resulting oil was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate. Concentration of an objective fraction afforded 148 mg of compound 493B as an oil.
1HNMR (CDCl3) δ: 1.03-1.44 (5H, m), 1.63-1.83 (5H, m), 2.05-2.13 (1H, m), 3.25 (1H, dd, J=9.5 Hz, 3.4 Hz), 7.16-7.19 (2H, ms), 7.27-7.38 (3H, m), 9.69 (1H, d, J=3.5 Hz).
Second Step
According to Example 177, compound 493 was synthesized by the same procedure.
MS: m/z=410 [M+H]+
Using aldehydes which are commercially available or known in the references and hydrazines which are commercially available or known in the references, and according to Example 493, compounds 494 to 505 were synthesized.
EXAMPLE 494




MS: m/z=428 [M+H]+
EXAMPLE 495




MS: m/z=420 [M+H]+.
EXAMPLE 496




MS: m/z=376 [M+H]+.
EXAMPLE 497




MS: m/z=500 [M+H]+.
EXAMPLE 498




MS: m/z=404 [M+H]+.
EXAMPLE 499




MS: m/z=382 [M+H]+.
EXAMPLE 500




MS: m/z=382 [M+H]+.
EXAMPLE 501




MS: m/z=368 [M+H]+.
EXAMPLE 502




1H-NMR (CDCl3) δ: 0.94 (3H, t, J=7.2 Hz), 1.26 (3H, t, J=7.3 Hz), 2.87-2.94 (2H, m), 3.10-3.22 (1H, m), 3.79-3.89 (1H, m), 3.98 (1H, d, J=16.9 Hz), 4.17 (1H, d, J=16.8 Hz), 4.28 (1H, d, J=9.8 Hz), 6.04 (1H, d, J=7.2 Hz), 6.54 (2H, t, J=8.1 Hz), 6.73 (1H, d, J=9.8 Hz), 6.95-7.33 (6H, m), 7.66 (1H, dd, J=5.3, 3.6 Hz).
MS: m/z=448 [M+H]+.
EXAMPLE 503




MS: m/z=374 [M+H]+.
EXAMPLE 504




MS: m/z=374 [M+H]+.
EXAMPLE 505




MS: m/z=342 [M+H]+.
EXAMPLE 506




According to Example 177, using compound 65B, compound 506 was synthesized by the same procedure.
MS: m/z=470 [M+H]+.
EXAMPLE 507




According to Example 65, using compound 506, compound 507 was synthesized by the same procedure.
MS: m/z=446 [M+H]+.
EXAMPLE 508




First Step

Compound 508A (261 mg, 0.475 mmol) which is a synthetic intermediate of Example 491 was dissolved in dimethyformamide (3 ml), triethylamine (0.132 ml, 0.950 mmol) and ethyl chloroformate (0.0910 ml, 0.950 mmol) were added at 0° C., and the mixture was stirred at room temperature for 20 minutes. An aqueous solution (0.5 ml) of sodium borohydride (71.9 mg, 1.90 mmol) was added at 0° C., and the mixture was stirred for 30 minutes. The reaction solution was poured into water, the mixture was extracted with ethyl acetate, and the organic layer was dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography, and eluted with chloroform-methanol (97:3, v/v). Diethyl ether was added, and the precipitated residue was filtered to obtain 107 mg of a white solid 508B.
MS: m/z=536 [M+H]+
Second Step
Compound 508B (100 mg, 0.187 mmol) obtained in the first step was dissolved in dichloromethane (1 ml), DAST (33.1 mg, 0.205 mmol) was added at 0° C., and the mixture was stirred for 30 minutes. The reaction solution was poured into water, the mixture was extracted with chloroform, and the organic layer was dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography, and eluted with chloroform-methanol (97:3, v/v), to obtain 28 mg of a pale yellow gummy substance 508C.
MS: m/z=538 [M+H]+
Third Step
To compound 508C obtained in the second step were added acetic acid (2 ml) and concentrated sulfuric acid (0.5 ml), and the mixture was stirred at room temperature for 20 minutes. The reaction solution was poured into water, the mixture was extracted with ethyl acetate, and the organic layer was dried with sodium sulfate. Diethyl ether was added, and the precipitated residue was filtered to obtain 4.5 mg of a white solid 508.
MS: m/z=448 [M+H]+.
EXAMPLE 509




According to Example 508, compound 509 was synthesized by the same procedure.
MS: m/z=466 [M+H]+
EXAMPLE 510










First Step

Compound 510A (36.8 g, 259 mmol) was dissolved in dimethylformamide (380 ml), potassium carbonate (39.3 g, 285 mmol) and benzyl bromide (30.7 ml, 259 mmol) were added, and the mixture was stirred at 80° C. for 8 hours. The reaction was cooled to room temperature, insolubles were removed by filtration, and the solvent was distilled off under reduced pressure. Water was added, and the precipitated residue was filtered, and dried under reduced pressure to obtain 46.21 g of a pale brown solid 510B.
Second Step
To compound 510B (4.79 g, 20.6 mmol) obtained in the first step was added dichloromethane (70 ml), triethylamine (4.29 ml, 30.9 mmol) and methanesulfonyl chloride (1.93 ml, 24.8 mmol) were added at 0° C., and the mixture was stirred for 30 minutes. The reaction solution was poured into an aqueous saturated sodium chloride solution, the mixture was extracted with dichloromethane, the extract was dried with sodium sulfate, and the solvent was distilled off under reduced pressure. To the resulting compound were added n-hexane-dichloromethane, and the precipitated residue was filtered to obtain 6.56 g of a white solid. This compound was dissolved in acetonitrile (40 ml), tetrabutylammonium fluoride (75% aqueous solution, 21.6 g, 61.9 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added, and the mixture was washed with an aqueous sodium bicarbonate solution. The organic layer was dried with sodium sulfate, and distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography, and eluted with n-hexane-ethyl acetate (1:1, v/v), to obtain 2.51 g of a white solid 510C.
1H-NMR (DMSO-d6) δ: 4.96 (3H, s), 5.30 (3H, d, J=46.4 Hz), 6.56 (1H, d, J=1.8 Hz), 7.39 (5H, m), 8.30 (1H, s).
Third Step
Compound 510C (2.40 g, 10.3 mmol) obtained in the second step was dissolved in dichloromethane (40 ml), boron tribromide (1M dichloromethane solution, 10.3 ml, 10.3 mmol) was added dropwise at 0° C., and the mixture was stirred for 30 minutes. Methanol was added, the solvent was distilled off under reduced pressure, ethyl acetate was added, and the mixture was washed with an aqueous saturated sodium chloride solution. The organic layer was dried with sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting solid was washed with diethyl ether to obtain 940 mg of 510D.
1H-NMR (CDCl3) δ: 5.20 (2H, d, J=46.3 Hz), 6.40 (1H, s), 6.62 (1H, s), 7.91 (1H, s).
Fourth Step
Compound 510D (940 mg, 6.52 mmol) obtained in the third step was dissolved in methanol (8 ml), a 2N aqueous sodium hydroxide solution (3.26 ml, 6.52 mmol) and a 37% aqueous formaldehyde solution (1.46 ml, 19.6 mmol) were added at 0° C., and the mixture was stirred at room temperature for 20 hours. To the reaction solution was added an aqueous saturated ammonium chloride solution, and the solvent was distilled off under reduced pressure. Hydrochloric acid was added, the mixture was extracted with chloroform, and the organic layer was dried with sodium sulfate. The solvent was distilled off under reduced pressure, to the resulting compound were added n-hexane-dichloromethane-ethyl acetate, and the precipitated residue was filtered to obtain 858 mg of a pale yellow solid 510E.
1H-NMR (CDCl3) δ: 4.73 (2H, s), 5.19 (2H, d, J=46.1 Hz), 6.55 (1H, s).
Fifth Step
Compound 510E (855 mg, 4.91 mmol) obtained in the fourth step was dissolved in dimethylformamide (10 ml), potassium carbonate (746 mg, 5.40 mmol) and benzyl bromide (0.583 ml, 4.91 mmol) were added, and the mixture was stirred at 80° C. for 5 hours. Insolubles were removed by filtration, and the filtrate was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography, and eluted with chloroform-methanol (97:3, v/v), to obtain 887 mg of a pale orange solid 510F.
1H-NMR (CDCl3) δ: 1.39 (1H, t, J=7.1 Hz), 4.31 (2H, d, J=7.2 Hz), 5.12 (2H, dd, J=46.3, 0.7 Hz), 5.23 (2H, s), 6.50 (1H, s), 7.33-7.43 (5H, m).
Sixth Step
Compound 510F (887 mg, 3.36 mmol) obtained in the fifth step was dissolved in chloroform, manganese dioxide (2.00 g, 23.0 mmol) was added, and the mixture was stirred at 80° C. for 2 hours. After cooled to room temperature, the mixture was filtered with celite, and the solvent was distilled off under reduced pressure to obtain 812 mg of a white solid 510G.
1H-NMR (CDCl3) δ: 5.18 (2H, dd, J=45.8, 0.8 Hz), 5.52 (2H, s), 6.60 (1H, d, J=0.8 Hz), 7.32-7.38 (5H, m), 9.86 (1H, s).
Seventh Step
To compound 510G (884 mg, 3.37 mmol) obtained in the sixth step were added acetonitrile and water, monosodium dihydrogen phosphate (809 mg, 6.74 mmol) and sodium hypochlorite (1.01 g, 11.1 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, pH was adjusted to 3 with hydrochloric acid, the mixture was extracted with chloroform, and the extract was dried with sodium sulfate. The solvent was distilled off under reduced pressure to obtain 404 mg of a white solid 510H.
1H-NMR (DMSO-d6) δ: 5.17 (2H, s), 5.38 (2H, d, J=46.2 Hz), 6.73 (1H, d, J=1.5 Hz), 7.34-7.51 (5H, m).
Eighth Step
Compound 510H (402 mg, 1.45 mmol) obtained in the seventh step was dissolved in dimethylformamide, N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (554 mg, 2.89 mmol) and 1H-benzo [d][1,2,3]triazol-1-ol (195 mg, 1.45 mmol) were added, and the mixture was stirred at room temperature for 5 minutes. After propan-2-amine (0.149 ml, 1.73 mmol) was added, the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water was added, the mixture was extracted with ethyl acetate, and the organic layer was washed with an aqueous sodium bicarbonate solution, and dried with sodium sulfate. The reaction solution was distilled off under reduced pressure, to the resulting compound was added n-hexane, and the precipitated residue was filtered to obtain 3.56 g of a white solid 510I.
1H-NMR (CDCl3) δ: 0.98 (6H, d, J=6.6 Hz), 4.05 (1H, m), 5.24 (2H, dd, J=45.9, 0.9 Hz), 5.41 (2H, s), 6.59 (1H, q, J=0.9 Hz), 7.40 (5H, m), 7.56 (1H, brs).
Ninth Step
Compound 510I (392 mg, 1.23 mmol) obtained in the eighth step was dissolved in ethanol (6 ml), aqueous ammonia (4 ml) was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography, and eluted with chloroform-methanol (97:3, v/v), to obtain 333 mg of a white solid 510J.
MS: m/z=319 [M+H]+
Tenth Step
Compound 510 was synthesized by the same procedure as that of Example 95.
MS: m/z=422 [M+H]+
EXAMPLE 511




First Step

A dichloromethane (90 mL) solution of compound 511A (200 mg, 0.664 mmol) and 1,1,3-trimethoxypropane (178.2 mg, 1.33 mmol) was cooled to 1 to 3° C., and a boron trifluoride diethyl ether complex (113 mg, 0.797 mmol) was added dropwise while the same temperature was retained. After the reaction solution was stirred at the same temperature for 30 minutes, saturated sodium bicarbonate water was added. The dichloromethane layer was separated, and the aqueous layer was extracted with dichloromethane three times. After the combined extracts were dried with sodium sulfate, the solvent was distilled off, and the resulting oil was purified by silica gel column chromatography. The materials were eluted firstly with ethyl acetate and, then, with ethyl acetate-methanol (3:2, v/v). Concentration of an objective fraction afforded 179.2 mg of compound 511B as an oil.
1H-NMR (CDCl3) δ: 1.14 (6H, d, J=6.3 Hz), 2.71 (2H, dd, J=6.0 Hz), 3.34 (3H, s), 3.64 (2H, t, J=6.0 Hz), 4.06-4.17 (1H, m), 5.23 (2H, s), 6.34 (1H, brs), 6.37 (1H, d, J=7.8 Hz), 7.26-7.43 (6H, m), 7.90 (1H, t, J=5.4 Hz).
Second Step
A dimethylformamide (3 ml) solution of compound 511B (179.2 mg, 0.482 mmol) was cooled to 1 to 3° C., cesium carbonate (786 mg, 2.41 mmol) was added while the same temperature was retained, and the mixture was stirred at the same temperature for 15 minutes. The reaction solution was diluted with water, and extracted with chloroform three times. After the combined extracts were dried with sodium sulfate, the solvent was distilled off to obtain 130 mg of compound 511C as a solid.
1H-NMR (CDCl3) δ: 1.22 (3H, d, J=6.9 Hz), 1.28 (3H, d, J=6.9 Hz), 1.59 (2H, brs), 3.22-3.41 (2H, m), 3.12 (3H, s), 4.57-4.70 (2H, m), 5.19 (1H, d, J=10.5 Hz), 5.38 (1H, brs), 5.54 (1H, d, J=10.5 Hz), 6.34 (1H, d, J=7.8 Hz), 7.26-7.32 (4H, m), 7.49-7.52 (2H, m).
Third Step
To an acetic acid (2 ml) solution of compound 511C (130 mg, 0.350 mmol) and dibenzosuberol (368 mg, 1.75 mmol) was added dropwise sulfuric acid (0.4 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was diluted with water, and extracted with ethyl acetate three times. The extract was washed with water once, and dried with sodium sulfate, thereafter, the solvent was distilled off, and the resulting solid was washed with diisopropyl ether to obtain 65 mg of compound 511 as a solid.
1H-NMR (CDCl3) δ: 1.27 (3H, d, J=6.9 Hz), 1.49 (3H, d, J=6.6 Hz), 1.64-1.74 (1H, m), 1.88-1.99 (1H, m), 2.83 (1H, d, J=4.5 Hz, 4.5 Hz, 9.3 Hz), 3.06 (1H, ddd, J=5.6 Hz, 13.2 Hz, 13.2 Hz), 3.19 (3H, s), 3.30-3.44 (1H, m), 3.50-3.57 (1H, m), 3.78-3.92 (1H, m), 4.28 (1H, ddd, J=4.2 Hz, 13.5 Hz, 13.5 Hz), 4.53 (1H, dd, J=3.3 Hz, 10.8 Hz), 4.96 (1H, s), 5.73 (1H, d, J=7.5 Hz), 6.61 (1H, d, J=7.5 Hz), 6.65 (1H, d, J=7.5 Hz), 6.89-6.93 (1H, m), 7.08-7.36 (6H, m).
Using amines which are commercially available or known in the references and acetals which are commercially available or known in the references, and according to Example 511, compounds 512 to 515 were synthesized.
EXAMPLE 512




MS: m/z=528 [M+H]+
EXAMPLE 513




MS: m/z=528 [M+H]+
EXAMPLE 514




1H-NMR (CDCl3) δ: 1.27 (1H, 3H, d, J=6.9 Hz), 1.48 (3H, d, J=6.6 Hz), 1.95 (3H, s), 2.63-2.68 (2H, m), 2.84 (1H, ddd, J=4.8 Hz, 9.3 Hz, 9.3 Hz), 3.05 (1H, ddd, J=4.2 Hz, 13.2 Hz, 13.2 Hz), 3.60 (1H, ddd, J=4.8 Hz, 4.8 Hz, 17.4 Hz), 3.87-3.98 (1H, m), 4.42 (1H, dd, J=6.6 Hz, 8.1 Hz), 4.59 (1H, ddd, J=4.2 Hz, 13.5 Hz, 13.5 Hz), 4.93 (1H, s), 5.77 (1H, d, J=7.8 Hz), 6.64 (1H, d, J=6.9 Hz), 6.69 (1H, d, J=7.8 Hz), 6.91 (1H, t, J=6.0 Hz), 7.09-7.38 (6H, m).
EXAMPLE 515




1H-NMR (CDCl3) δ: 1.20 (3H, d, J=6.9 Hz), 1.44 (3H, d, J=6.9 Hz), 2.80 (1H, ddd, J=4.5 Hz, 4.5 Hz, 9.3 Hz), 3.07 (1H, ddd, J=4.5 Hz, 13.5 Hz, 13.5 Hz), 3.25 (3H, s), 3.22-3.43 (2H, m), 3.55 (1H, ddd, J=4.2 Hz, 4.2 Hz, 8.7 Hz), 3.85-3.94 (1H, m), 4.36 (1H, dd, J=5.1 Hz, 14.1 Hz), 4.42-4.48 (1H, m), 4.92 (1H, s), 5.78 (1H, d, J=7.5 Hz), 6.59 (1H, d, J=7.8 Hz), 6.64 (1H, d, J=7.5 Hz), 6.91 (1H, t, J=6.9 Hz), 7.09-7.36 (6H, m).
EXAMPLE 516




First Step

To a toluene (3 ml) solution of compound 516A (100 mg, 0.332 mmol) and 3-(methylthio)propanal (52 mg, 0.498 mmol) was added acetic acid (30 mg, 0.500 mmol), and the mixture was refluxed for 30 minutes. After cooled to room temperature, the solvent was distilled off, and the resulting crude product was dissolved in dimethylformamide (3 ml). The solution was cooled to 1 to 3° C., cesium carbonate (541 mg, 1.66 mmol) was added while the same temperature was retained, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was diluted with water, and extracted with ethyl acetate three times. The combined extracts were washed with water three times, and dried with sodium sulfate, and the solvent was distilled off. The resulting oil was purified by silica gel column chromatography. The materials were eluted firstly with ethyl acetate and, then, with ethyl acetate-methanol (7:3, v/v). Concentration of an objective fraction afforded 84.7 mg of compound 516B as an oil.
1H-NMR (CDCl3) δ: 1.21 (3H, J=6.9 Hz), 1.28 (3H, d, J=6, 9 Hz), 1.31-1.56 (2H, m), 2.05 (3H, s), 2.46 (2H, dd, J=5.4 Hz, 7.8 Hz), 4.57-4.71 (2H, m), 5.18 (1H, d, J=10.5 Hz), 5.51 (1H, d, J=10.5 Hz), 5.66 (1H, brs), 6.33 (1H, d, J=7.8 Hz), 7.19-7.35 (4H, m), 7.46-7.49 (2H, m).
Second Step
Compound 516 was synthesized by the same procedure as that of Example 511.
1H-NMR (CDCl3) δ: 1.29 (3H, d, J=6.9 Hz), 1.49 (3H, d, J=6.6 Hz), 1.82-1.89 (2H, m), 1.99 (3H, s), 2.41-2.58 (2H, m), 2.86 (1H, ddd, J=4.5 Hz, 4.5 Hz, 14.1 Hz), 2.99-3.11 (1H, m), 3.53 (1H, ddd, J=4.5 Hz, 4.5 Hz, 17.7 Hz), 4.87-3.96 (1H, m), 4.21 (1H, ddd, J=3.9 Hz, 12.9 Hz, 12.9 Hz), 4.53 (1H, dd, J=5.1 Hz, 8.7 Hz), 4.96 (1H, s), 5.74 (1H, d, J=7.5 Hz), 6.62 (1H, d, J=7.5 Hz), 6.64 (1H, d, J=9.0 Hz), 6.89-6.94 (1H, m), 7.07-7.37 (6H, m).
Using amines which are commercially available or known in the references and aldehydes which are commercially available or known in the references, and according to Example 516, compounds 517 to 526 were synthesized.
EXAMPLE 517




MS: m/z=500 [M+H]+
EXAMPLE 518




1H-NMR (CDCl3) δ: 1.78 (3H, t, J=6.9 Hz), 1.19-1.30 (1H, m), 1.29 (3H, d, J=6.9 Hz), 1.43-1.62 (3H, m), 1.50 (3H, d, J=6.9 Hz), 2.84 (1H, ddd, J=4.5 Hz, 4.5 Hz, 14.1 Hz), 3.00-3.11 (1H, ddd, J=3.9 Hz, 12.9 Hz, 12.9 Hz), 3.52 (1H, ddd, J=4.5 Hz, 4.5 Hz, 17.4 Hz), 3.79-3.88 (1H, m), 4.23-4.35 (2H, m), 4.96 (1H, s), 5.74 (1H, d, J=7.8 Hz), 6.61 (1H, d, J=7.5 Hz), 6.65 (1H, dd, J=1.2 Hz, 7.8 Hz), 6.91 (1H, ddd, J=1.5 Hz, 7.5 Hz, 7.5 Hz), 7.08-7.37 (6H, m).
EXAMPLE 519




1H-NMR (CDCl3) δ: 1.44 (3H, d, J=6.9 Hz), 1.54 (3H, d, J=6.6 Hz), 1.88 (1H, ddd, J=3.9 Hz, 3.9 Hz, 14.4 Hz), 2.72 (1H, ddd, J=3.6 Hz, 14.1 Hz, 14.1 Hz), 3.15 (1H, ddd, J=4.2 Hz, 4.2 Hz, 16.5 Hz), 3.54 (1H, dd, J=3.0 Hz, 14.4 Hz), 3.66 (1H, ddd, J=3.9 Hz, 13.8 Hz, 13.8 Hz), 4.03 (1H, dd, J=10.5 Hz, 14.1 Hz), 4.27-4.26 (1H, m), 4.64 (1H, dd, J=2.7 Hz, 10.5 Hz), 4.92 (1H, s), 5.80 (1H, d, J=7.8 Hz), 6.62-6.70 (2H, m), 6.69 (1H, d, J=7.8 Hz), 6.89 (1H, t, J=7.5 Hz), 6.96 (1H, d, J=7.5 Hz), 7.09-7.25 (4H, m), 7.77-7.89 (4H, m).
EXAMPLE 520




1H-NMR (CDCl3) δ: 1.30 (3H, d, J=6.6 Hz), 1.54 (3H, d, J=6.6 Hz), 2.83 (1H, ddd, J=4.8 Hz, 4.8 Hz, 14.1 Hz), 3.03-3.14 (1H, m), 3.21 (3H, s), 3.30 (3H, s), 3.53 (1H, ddd, J=4.5 Hz, 4.5 Hz, 17.7 Hz), 3.61-3.70 (1H, m), 4.18 (1H, d, J=5.4 Hz), 4.26 (1H, d, J=5.4 Hz), 4.45 (1H, ddd, J=4.5 Hz, 13.8 Hz, 13.8 Hz), 4.92 (1H, s), 5.72 (1H, d, J=7.8 Hz), 6.63 (1H, d, J=7.8 Hz), 6.65 (1H, d, J=6.6 Hz), 6.91 (1H, t, J=6.0 Hz), 7.08-7.36 (6H, m).
EXAMPLE 521




1H-NMR (CDCl3) δ: 1.30 (2.52H, d, J=6.9 Hz), 1.36 (0.48H, d, J=6.9 Hz), 1.42 (0.48H, d, J=6.9 Hz), 1.50 (2.52H, d, J=6.9 Hz), 1.74-1.98 (1H, m), 2.00-2.12 (1H, m), 2.16-2.35 (1H, m), 2.89 (1H, ddd, J=5.1 Hz, 5.1 Hz, 13.5 Hz), 3.06 (1H, ddd, J=3.9 Hz, 12.9 Hz, 12.9 H), 3.52 (1H, d, J=4.2 Hz, 4.2 Hz, 17.4 Hz), 3.86-3.96 (1H, m), 4.15 (1H, ddd, J=3.9 Hz, 13.5 Hz, 13.5 Hz), 4.32 (1H, dd, J=3.9 Hz, 10.8 Hz), 4.48-4.64 (1H, m), 4.97 (0.84H, s), 5.30 (0.16H, s), 5.73 (0.84H, d, J=7.8 Hz), 6.20 (0.16H, d, J=7.5 Hz), 6.45 (0.16H, brs), 6.61 (1H, d, J=7.5 Hz), 6.64 (0.84H, d, J=8.7 Hz), 6.92 (1H, t, J=6.3 Hz), 7.10 (1H, d, J=7.5 Hz), 7.15-7.39 (3H, m).
EXAMPLE 522




1H-NMR (CDCl3) δ: 1.28 (3H, d, J=6.9 Hz), 1.49 (3H, d, J=6.9 Hz), 1.54-1.79 (4H, m), 2.84 (1H, ddd, J=4.8 Hz, 4.8 Hz, 14.1 Hz), 3.05 (1H, ddd, J=4.2 Hz, 13.5 Hz, 13.5 Hz), 3.17 (3H, s), 3.17-3.21 (2H, m), 3.52 (1H, ddd, J=4.2 Hz, 4.2 Hz, 17.7 Hz), 3.83-3.92 (1H, m), 4.22-4.32 (2H, m), 4.96 (1H, s), 5.73 (1H, d, J=7.5 Hz), 6.62 (1H, d, J=7.8 Hz), 6.65 (1H, d, J=8.1 Hz), 6.92 (1H, t, J=7.2 Hz), 7.07-7.37 (6H, m).
EXAMPLE 523




1H-NMR (CDCl3) δ: 1.19-1.28 (1H, m), 1.28 (3H, d, J=6.9 Hz), 1.40-1.82 (4H, m), 1.48 (3H, d, J=6.6 Hz), 2.89-3.00 z81H, m), 3.17 (3H, s), 3.20-3.27 (2H, m), 3.31-3.40 (1H, m), 3.44-3.53 (1H, m), 3.86-3.98 (2H, m), 4.38 (1H, dd, J=3.6 Hz, 10.5 Hz), 5.05 (1H, s), 5.84 (1H, d, 7.5 Hz), 6.48-6.50 (1H, m), 6.66-6.69 (1H, m), 6.89-7.00 (2H, m), 7.05 (1H, d, 7.2 Hz), 7.11-7.24 (2H, m).
EXAMPLE 524




1H-NMR (CDCl3) δ: 1.29 (3H, d, J=6.9 Hz), 1.42-1.83 (4H, m), 1.48 (3H, d, J=6.6 Hz), 2.80 (1H, ddd, J=4.5 Hz, 4.5 Hz), 14.4 H), 2.94-3.11 (1H, m), 3.18 (3H, s), 3.21-3.26 (2H, m), 3.49 (1H, ddd, J=4.2 Hz, 4.2 Hz, 18.0 Hz), 3.82-3.91 (1H, m), 4.20-4.33 (2H, m), 5.83 (1H, s), 5.84 (1Hm d, J=7.8 Hz), 6.58-6.72 (2H, m), 6.91-6.94 (1H, m), 7.11-7.30 (4H, m).
EXAMPLE 525




1H-NMR (CDCl3) δ: 1.29 (3H, d, J=6.9 Hz), 1.47 (3H, d, J=6.6 Hz), 2.10 (3H, s), 2.78 (1H, ddd, J=4.2 Hz, 4.2 Hz, 13.8 Hz), 2.97 (3H, s), 3.01-3.13 (2H, m), 3.47 (1H, ddd, J=4.2 Hz, 4.2 Hz, 17.7 Hz), 3.65 (1H, dd, J=3.3 Hz, 14.1 Hz), 3.99-4.23 (2H, m), 4.70 (1H, dd, J=3.3 Hz, 10.2 Hz), 4.95 (1H, s), 5.78 (1H, d, J=7.8 Hz), 6.61 (1H, d, J=7.8 Hz), 6.65 (1H, d, J=7.5 Hz), 6.93 (1H, t, J=6.6 Hz), 7.09 (1H, d, J=7.5 Hz), 7.15-7.27 (4H, m), 7.30-7.37 (1H, m).
EXAMPLE 526




1H-NMR (CDCl3) δ: 1.57-1.34 (1H, m), 1.29 (3H, d, J=6.9 Hz), 1.41-1.52 (1H, m), 1.48 (3H, d, J=6.6 Hz), 1.59-1.81 (2H, m), 2.80 (1H, ddd, 4.5 Hz, 4.5 Hz, 14.4 Hz), 3.04 (1H, ddd, J=4.2 Hz, 13.2 Hz, 13.2 Hz), 3.14-3.26 (2H, m), 3.18 (3H, s), 3.49 (1H, ddd, J=4.8 Hz, 4.8 Hz, 17.7 Hz), 3.84-3.93 (1H, m), 4.23-4.34 (2H, m), 4.96 (1H, s), 5.81 (1H, d, J=7.5 Hz), 6.60-6.79 (3H, m), 6.81 (1Hm d, J=9.3 Hz), 6.92 (1H, ddd, J=2.7 Hz, 8.4 Hz, 8.4 Hz), 7.19-7.24 (1H, m).
EXAMPLE 527




First Step

A DMF (0.2 mL) solution of compound 527A (36 mg, 0.09 mmol) synthesized according to the method of synthesizing compound 516 was cooled to 1 to 3° C., 5-chlorodibenzosuberane (97 mg, 0.43 mmol) and cesium carbonate (138 mg, 0.43 mmol) were added, and the mixture was stirred at room temperature overnight. To the reaction solution was added water, and the mixture was distributed between ethyl acetate and water. The organic layer was washed with an aqueous saturated sodium chloride solution, and dried. The solvent was distilled off, and the resulting oil was subjected to silica gel column chromatography, and eluted with chloroform-methanol. Concentration of an objective fraction afforded 19 mg of compound 527B as an oil.
MS: m/z=616 [M+H]+.
Second Step
Compound 527B (19 mg, 0.03 mmol) was dissolved in MeOH (0.6 mL), 10% Pd—C (3 mg) was added, and the mixture was subjected to a catalytic reduction under hydrogen stream. The catalyst was removed by filtration, and the filtrate was concentrated. The resulting oil was subjected to diol silica gel column chromatography, and eluted with chloroform-methanol. Concentration of an objective fraction afforded 7 mg of compound 527 as an oil.
MS: m/z=526 [M+H]+.
Using halides which are commercially available or known in the references and aldehydes which are commercially available or known in the references, and according to the method of Example 527, compounds 528 to 531 were synthesized.
EXAMPLE 528




MS: m/z=418 [M+H]+
EXAMPLE 529




MS: m/z=432 [M+H]+
EXAMPLE 530




MS: m/z=459 [M+H]+.
EXAMPLE 531




MS: m/z=466 [M+H]+
EXAMPLE 532




First Step

To a methanol (5 ml) solution of compound 519 (440 mg, 0.766 mmol) was added hydrazine hydrate (383 mg, 7.66 mmol), and the mixture was refluxed for 1 hour. After cooled to room temperature, the precipitated insolubles were filtered off. After the solvent was distilled off, the residue was suspended in ethyl acetate, the insolubles were filtered off, and the solvent was distilled off. The resulting crude product was suspended in chloroform, and insolubles were filtered off. The solvent was distilled off, and the resulting crude product was washed with ethyl acetate-diisopropyl ether to obtain 190 mg of compound 532 as a solid.
1H-NMR (CDCl3) δ: 1.24 (3H, d, J=6.9 H), 1.46 (3H, d, J=6.6 Hz), 2.73-2.90 (3H, m), 3.08 (1H, ddd, J=4.2 Hz, 12.9 Hz, 12.9 Hz), 3.54 (1H, ddd, J=4.5 Hz, 4.5 Hz, 17.7 Hz), 3.85-3.94 (1H, m), 4.19 (1H, dd, J=7.2 Hz, 11.1 Hz), 4.35 (1H, ddd, J=4.5 Hz, 13.8 Hz, 13.8 Hz), 4.97 (1H, s), 5.74 (1H, d, J=7.5 Hz), 6.60 (1H, d, J=7.8 Hz), 6.65 (1H, d, J=7.2 Hz), 6.92 (1H, t, J=6.3 Hz), 7.09-7.45 (6H, m).
EXAMPLE 533




Compound 533 was synthesized by the same procedure as that of Example 532.
1H-NMR (DMSO-d6) δ: 1.22 (3H, d, J=6.6 Hz), 1.40 (3H, d, J=6.6 Hz), 1.45-1.58 (1H, m), 1.62-1.75 (1H, m), 2.61-2.69 (1H, m), 2.71-2.84 (1H, m), 2.88-2.95 (1H, m), 3.16-3.34 (1H, m), 3.60-3.64 (1H, m), 3.92-4.00 (1H, m), 4.24-4.33 (1H, m), 4.42-4.46 (1H, dd, J=3.3 Hz, 10.8 Hz), 5.10 (1H, s), 5.47 (1H, d, J=7.5 Hz), 6.70 (1H, d, J=7.5 Hz), 6.88 (1H, t, J=7.5 Hz), 7.02 (1H, d, J=10.8 Hz), 7.09-7.16 (2H, m), 7.19-7.25 (1H, m), 7.33 (2H, d, 4.2 Hz), 7.42 (1H, d, J=7.5 Hz).
EXAMPLE 534




Compound 534 was synthesized by the same procedure as that of Example 532.
1H-NMR (DMSO-d6) δ: 1.25 (3H, d, J=6.9 Hz), 1.44 (3H, d, J=6.6 Hz), 1.32-1.58 (2H, m), 1.77-1.79 (2H, m), 2.64-2.73 (1H, m), 2.79-3.00 (2H, m), 3.88-3.97 (2H, m), 4.19-4.28 (2H, m), 5.15 (1H, s), 5.67 (1H, d, J=7.5 Hz), 5.73 (1H, d, J=7.5 Hz), 6.90 (1H, t, J=6.6 Hz), 7.03 (1H, d, J=7.5 Hz), 7.13-7.32 (3H, m), 7.36 (2H, d, J=4.2 Hz), 7.44 (1H, J=7.2 Hz), 7.75 (1H, brs).
EXAMPLE 535




Compound 535 was synthesized by the same procedure as that of Example 532.
1H-NMR (DMSO-d6) δ: 1.40-1.52 (1H, m), 1.61-1.72 (1H, m), 2.40-2.49 (1H, m), 2.58-2.62 (1H, m), 2.78-2.86 (1H, m), 2.89-2.95 (1H, m), 2.95 (3H, m), 3.66-3.74 (1H, m), 4.01-4.13 (1H, m), 4.28-4.32 (1H, m), 5.14 (1H, m), 5.51 (1H, d, J=7.8 Hz), 6.72 (1H, d, J=7.5 Hz), 6.91-6.94 (2H, m), 7.14-7.40 (6H, m).
EXAMPLE 536




First Step

A dichloromethane (1 ml) solution of compound 532 (30 mg, 0.0675 mmol) and a 38% aqueous formalin solution (53.5 mg, 0.675 mmol) was cooled to 1 to 3° C., sodium triacetoxyhydroborate (42.9 mg, 0.293 mmol) and acetic acid (10 mg, 0.166 mmol) were added while the same temperature was retained. After the reaction solution was stirred at the same temperature for 30 minutes, saturated sodium bicarbonate water was added, and the mixture was extracted with ethyl acetate three times. The combined extracts were washed with water once, and dried with sodium sulfate, and the solvent was distilled off. The resulting crude product was washed with ethyl acetate-diisopropyl ether to obtain 20 mg of compound 536 as a solid.
1H-NMR (CDCl3) δ: 1.22 (3H, d, J=6.6 Hz), 1.44 (3H, d, J=6.9 Hz), 2.06 (6H, s), 2.29 (1H, dd, J=4.5 Hz, 13.2 Hz), 4.23 (1H, dd, J=8.4 Hz, 13.2 Hz), 2.78 (1H, ddd, J=4.5 Hz, 4.5 Hz, 14.1 Hz, 3.06 (1H, J=4.2 Hz, 13.5 Hz, 13.5 Hz), 3.55 (1H, ddd, J=4.2 Hz, 4.2 Hz, 17.7 Hz), 3.83-3.92 (1H, m), 4.34 (1H, dd, J=4.5 Hz, 8.4 Hz), 4.54 (1H, ddd, J=4.5 Hz, 13.8 Hz, 13.8 Hz), 4.91 (1H, s), 5.74 (1H, d, J=7.5 Hz), 6.63 (1H, d, J=7.8 Hz), 6.64 (1H, d, J=7.8 Hz), 6.88-6.93 (1H, m), 7.08-7.45 (6H, m).
EXAMPLE 537




Compound 537 was synthesized by the same procedure as that of Example 536.
1H-NMR (DMSO-d6) δ: 1.25 (3H, d, J=6.6 Hz), 1.40 (3H, d, J=6.6 Hz), 1.46-1.57 (1H, m), 1.68-1.79 (1H, m), 1.98 (6H, s), 2.04-2.11 (1H, m), 2.27-2.41 (1H, m), 2.72-2.94 (2H, m), 3.55-3.64 (1H, m), 3.91-4.00 (1H, m), 4.29-4.44 (2H, m), 5.10 (1H, s), 5.48 (1H, d, J=7.8 Hz), 6.71 (1H, d, J=7.8 Hz), 6.86-6.90 (1H, m), 7.05-7.24 (4H, m), 7.33 (2H, d, J=4.2 Hz), 7.40 (1H, d, J=7.5 Hz).
EXAMPLE 538




Compound 538 was synthesized by the same procedure as that of Example 536.
1H-NMR (DMSO-d6) δ: 0.75 (6H, t, J=6.6 Hz), 1.28 (3H, d, J=6.6 Hz), 1.41 (3H, d, J=6.6 Hz), 1.45-1.56 (1H, m), 1.67-1.78 (1H, m), 2.22-2.49 (4H, m), 2.74-2.97 (2H, m), 3.94-4.03 (1H, m), 4.29-4.41 (2H, m), 5.11 (1H, s), 5.48 (1H, d, J=7.8 Hz), 6.71 (1H, d, J=6.9 Hz), 6.87 (1H, t, J=7.2 Hz), 7.06-7.25 (4H, m), 7.33 (2H, d, J=7.2 Hz), 7.35 (1H, m).
EXAMPLE 539




Compound 539 was synthesized by the same procedure as that of Example 536.
1H-NMR (DMSO-d6) δ: 1.25 (3H, d, J=6.6 Hz), 1.44 (3H, d, J=6.6 Hz), 1.42-1.51 (2H, m), 1.75-1.91 (2H, m), 2.62-2.67 (1H, m), 2.65 (6H, s), 2.74-2.97 (3H, m), 3.57-3.63 (1H, m), 3.91-3.26 (4H, m), 5.16 (1H, s), 5.73 (1H, d, J=7.5 Hz), 6.71 (1H, d, J=7.2 Hz), 6.89 (1H, t, J=6.9 Hz), 7.12-7.28 (4H, m), 7.33-7.45 (3H, m).
EXAMPLE 540




Compound 540 was synthesized by the same procedure as that of Example 536.
1H-NMR (CDCl3) δ: 1.58-1.78 (2H, m), 2.06 (6H, s), 2.15-2.35 (2H, m), 2.84-2.93 (1H, m), 2.96-3.11 (1H, m), 3.00 (3H, s), 3.65-3.74 (1H, m), 3.99-4.14 (1H, m), 4.28-4.33 (1H, m), 4.94 (1H, s), 5.78 (1H, d, J=7.5 Hz), 6.56 (1H, d, J=7.8 Hz), 8.66 (1H, d, J=7.2 Hz), 6.95 (t, J=7.2 Hz), 7.13-7.38 (6H, m).
EXAMPLE 541




Compound 541 was synthesized by the same procedure as that of Example 536.
1H-NMR (CDCl3) δ: 0.846 (6H, t, J=7.2 Hz), 1.49-1.75 (2H, m), 2.30-2.41 (5H, m), 2.43-2.53 (1H, m), 2.85-2.93 (1H, m), 2, 98-3.08 (1H, m), 3.01 (3H, s), 3.63-3.74 (1H, m), 3.97-4.07 (1H, m), 4.30 (1H, dd, J=5.1 Hz, 8.1 Hz), 4.95 (1H, s), 5.77 (1H, d, J=6.0 Hz), 6.56 (1H, d, J=7.8 Hz), 6.65 (1H, d, J=7.8 Hz), 6.95 (1H, t, J=6.3 Hz), 7.13-7.38 (6H, m).
EXAMPLE 542




First Step

A dichloromethane (1 ml) solution of compound 532 (30 mg, 0.0675 mmol) and triethylamine (20.5 mg, 0.202 mmol) was cooled to 1 to 3° C., and acetic acid anhydride (10.3 mg, 0.101 mmol) was added while the same temperature was retained. After the reaction solution was stirred at the same temperature for 30 minutes, water was added, and the mixture was extracted with ethyl acetate three times. The combined extracts were washed with water once, and dried with sodium sulfate, and the solvent was distilled off. The resulting crude product was washed with ethyl acetate-diisopropyl ether to obtain 15 mg of compound 542 as a solid.
1H-NMR (CDCl3) δ: 1.30 (3H, d, J=6.9 Hz), 1.47 (3H, d, J=6.6 Hz), 2.00 (3H, s), 2.78-2.94 (2H, m), 3.04 (1H, ddd, J=4.2 Hz, 13.5 Hz, 13.5 Hz), 3.48-3.60 (1H, m), 3.98-3.07 (1H, m), 4.36 (1H, ddd, J=4.2 Hz, 13.5 Hz, 13.5 Hz), 4.64 (1H, dd, J=3.9 Hz, 9.3 Hz), 4.87 (1H, s), 5.43 (1H, d, J=7.5 Hz), 6.57 (1H, d, J=7.5 Hz), 6.68 (1H, d, J=7.5 Hz), 6.85 (1H, t, J=6.0 Hz), 7.09-7.36 (6H, m), 7.41 (1H, brs).
EXAMPLE 543




Compound 543 was synthesized by the same procedure as that of Example 542.
1H-NMR (CDCl3) δ: 1.32 (3H, d, J=6.9 Hz), 1.50 (3H, d, J=6.9 Hz), 2.79 (1H, ddd, J=4.2 Hz, 4.2 Hz, 14.4 Hz), 3.01 (1H, ddd, J=3.9 Hz, 13.5 Hz, 13.5 Hz), 3.18-3.28 (1H, m), 3.46-3.59 (2H, m), 4.04-4.18 (1H, m), 4.27 (1H, ddd, J=3.9 Hz, 13.5 Hz, 13.5 Hz), 4.69 (1H, dd, J=3.3 Hz, 9.9 Hz), 4.87 (0.9H, s), 5.17 (0.1H, s), 5.37 (0.9H, d, J=7.8 Hz), 4.50 (0.1H, d, J=7.8 H), 6.32 (0.1H, d, J=7.8 Hz), 6.54 (1H, d, J=7.5 Hz), 6.78 (0.9H, d, J=7.5 Hz), 6.84 (1H, t, J=6.6 Hz), 6.91 (0.1H, d, J=6.0 Hz), 7.06-7.51 (6H, m), 9.29 (1H, brs).
EXAMPLE 544




Compound 544 was synthesized by the same procedure as that of Example 542.
1H-NMR (CDCl3) δ: 1.29 (3H, d, J=6.9 Hz), 1.46 (3H, d, J=6.3 Hz), 2.78 (1H, ddd, J=4.5 Hz, 4.5 Hz, 15.9 Hz), 2.94-3.10 (2H, m), 3.19-3.54 (2H, m), 3.64 (3H, s), 3.96-3.11 (1H, m), 4.28 (1H, ddd, J=4.2 Hz, 13.5 Hz, 13.5 Hz), 4.57 (1H, dd, J=3.3 Hz, 9.9 Hz), 4.91 (1H, s), 5.57 (1H, brs), 5.70 (1H, d, J=7.5 Hz), 6.60 (1H, d, J=7.5 Hz), 6.66 (1H, d, J=7.8 Hz), 6.89 (1H, t, J=7.2 Hz), 7.08-7.47 (6H, m).
EXAMPLE 545




First Step

A dichloromethane (1 ml) solution of compound 532 (30 mg, 0.0675 mmol) and pyridine (16 mg, 0.203 mmol) was cooled to 1 to 3° C., and 2-methoxyacetyl chloride (11 mg, 0.101 mmol) was added while the same temperature was retained. After the reaction solution was stirred at the same temperature for 30 minutes, water was added, and the mixture was extracted with ethyl acetate three times. The combined extracts were washed with water once, and dried with sodium sulfate, and the solvent was distilled off. The resulting crude product was washed with ethyl acetate-diisopropyl ether to obtain 22 mg of compound 545 as a solid.
1H-NMR (CDCl3) δ: 1.31 (3H, d, J=6.9 Hz), 1.49 (3H, d, J=6.9 Hz), 2.77 (1H, ddd, J=4.8 Hz, 4.8 Hz, 14.1 Hz), 2.99-3.11 (2H, m), 3.47 (3H, s), 3.47-3.55 (1H, m), 3.64-3.72 (1H, m), 3.77-3.88 (2H, m), 4.02-4.11 (1H, m), 4.23 (1H, ddd, J=4.2 Hz, 13, 8 Hz, 13.8 Hz), 4.47 (1H, dd, J=3.3 Hz, 9.9 Hz), 4.94 (1H, s), 5.75 (1H, d, J=7.8 Hz), 6.64 (1H, d, J=9.0 Hz), 6.67 (1H, 7.8 Hz), 6.80 (1H, brt), 6.91 (1H, t, J=7.5 Hz), 7.08-7.23 (5H, m), 7.29-7.36 (1H, m).
EXAMPLE 546




First Step

To a dimethylformamide (1 ml) solution of 2-(methylthio)acetic acid (15.7 mg, 0.148 mmol) were added EDCI (28.5 mg, 0.148 mmol) and 1-hydroxy benzotriazole (11.4 mg, 0.0742 mmol) at room temperature, the mixture was stirred at the same temperature for 5 minutes, and compound 532 was added. The reaction solution was stirred at room temperature for 1 hour, and diluted with methanol (3 ml). The solution was cooled to 1 to 3° C., a 2N aqueous sodium hydroxide solution (1 ml) was added, the mixture was stirred at the same temperature for 30 minutes, and the mixture was neutralized with 2N hydrochloric acid (1 ml). The reaction solution was extracted with ethyl acetate three times, the combined extracts were washed with water once, and dried with sodium sulfate, and the solvent was distilled off. The resulting crude product was washed with ethyl acetate-diisopropyl ether to obtain 15 mg of compound 546 as a solid.
1H-NMR (CDCl3) δ: 1.32 (3H, d, J=6.9 Hz), 1.50 (3H, J=6.6 Hz), 2.11 (3, s), 2.79 (1H, ddd, J=4.2 Hz, 4.2 Hz, 14.1 Hz), 2.99-3.16 (4H, m), 3.50 (1H, ddd, J=4.5 Hz, 4.5 Hz, 12.9 Hz), 3.68 (1H, d, J=10.2 Hz), 3.97-4.11 (1H, m), 4.26 (1H, ddd, J=4.5 Hz, 13.8 Hz, 13.8 Hz), 4.94 (3H, s), 5.69 (1H, d, J=7.5 Hz), 6.63 (1H, d, J=7.5 Hz), 6.70 (1H, d, J=7.8 Hz), 6.90 (1H, t, J=6.0 Hz), 7.09 (1H, d, J=7.5 Hz), 7.20-7.25 (3H, m), 7.29-7.36 (1H, m), 7.36-7.49 (1H, m).
EXAMPLE 547




First Step

To an acetic acid (3 ml) solution of compound 547A (367 mg, 0.812 mmol) synthesized by the same procedure as that of Example 516 and dibenzosuberol (205 mg, 0.974 mmol) was added dropwise sulfuric acid (0.6 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was diluted with water, and extracted with ethyl acetate three times. The extract was washed with water once, and dried with sodium sulfate, and the solvent was distilled off. The resulting crude product was dissolved in methanol (3 ml), a 2N aqueous sodium hydroxide solution (1 ml) was added at room temperature, and the mixture was stirred for 30 minutes. The reaction solution was neutralized with 2N hydrochloric acid (1 ml), and extracted with ethyl acetate three times. The combined extracts were dried with sodium sulfate, and the solvent was distilled off. The resulting crude product was washed with ethyl acetate-diisopropyl ether to obtain 75 mg of compound 547 as a solid.
1H-NMR (CDCl3) δ: 1.22 (3H, d, J=6.9 Hz), 1.45 (3H, d, J=6.3 Hz), 2.80 (1H, ddd, J=4.5 Hz, 4.5 Hz, 14.1 Hz), 2.99-3.11 (1H, m), 3.53 (1H, ddd, J=3.9 Hz, 3, 9 Hz, 17.7 Hz), 3.64 (1H, dd, J=6.9 Hz), 12.3 Hz), 3.82 (1H, dd, J=3.3 Hz, 12.3 Hz), 3.86-3.97 (1H, m), 4.34-4.44 (2H, m), 4.88 (1H, s), 5.35 (1H, d, J=7.5 Hz), 6.52-6.58 (2H, m), 6.82 (1H, dt, J=1.8 Hz, 7.2 Hz), 7.06-7.35 (6H, m).
EXAMPLE 548




Compound 548 was synthesized by the same procedure as that of Example 547.
1H-NMR (CDCl3) δ: 1.29 (3H, d, J=6.6 Hz), 1.50 (3H, d, J=6.6 Hz), 1.70-1.81 (1H, m), 1.88-2.00 (1H, m), 2.85 (1H, ddd, J=4.5 Hz, 4.5 Hz, 14.1 Hz), 2.99-3.11 (1H, m), 3.48-3.57 (1H, m), 3.68-3.73 (2H, m), 3.83-3.92 (1H, m), 4.30 (1H, ddd, J=4.2 Hz, 13.8 Hz, 13.8 Hz), 4.54 (1H, dd, J=3.6 Hz, 11.1 Hz), 4.67 (1H, s), 5.69 (1H, d, J=7.8 Hz), 6.62 (1H, d, J=7.5 Hz), 6.64 (1H, d, J=5.7 Hz), 6.90 (1H, t, J=6.9 Hz), 7.07-7.36 (6H, m).
EXAMPLE 549




First Step

To an acetic acid (3 ml) solution of compound 549A (997 mg, 1.69 mmol) synthesized by the same procedure as that of Example 516 and dibenzosuberol (1.07 g, 5.08 mmol) was added dropwise sulfuric acid (0.6 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was diluted with water, and extracted with ethyl acetate three times. The extract was washed with water once, and dried with sodium sulfate, and the solvent was distilled off. The resulting crude product was washed with ethyl acetate-diisopropyl ether to obtain 513 mg of compound 549B.
1H-NMR (CDCl3) δ: 2.09 (3H, s), 2.71 (1H, ddd, J=3.6 Hz, 13.5 Hz, 13.5 Hz), 3.18-3.27 (1H, m), 3.42-3.56 (2H, m), 3.80 (1H, dd, J=2.7 Hz, 14.1 Hz), 4.03 (1H, dd, J=10.2 Hz, 14.1 Hz), 4.15 (1H, ddd, J=4.2 Hz, 4.2 Hz, 9.3 Hz), 4.32-4.40 (1H, m), 4.49-4.53 (2H, m), 4.94 (1H, s), 5/83 (1H, d, J=7.8 Hz), 6.63 (1H, d, J=7.5 Hz), 6.69 (1H, d, J=7.8 Hz), 6.76 (1H, d, J=6.6 Hz), 6.91 (1H, t, J=7.5 Hz), 7.00 (1H, d, J=8.1 Hz), 7.12-7.17 (2H, m), 7.20-7.32 (2H, m), 7.82-7.89 (4H, m).
Second Step
To a methanol (5 ml) solution of compound 549B (513 mg, 0.829 mmol) was added hydrazine hydrate (124.5 mg, 2.49 mmol), and the mixture was refluxed for 2 hours. After cooled to room temperature, to the reaction solution were added 2N hydrochloric acid (30 ml) and ethyl acetate (30 ml). After the layers were separated, the organic layer was extracted with 2N hydrochloric acid two times. The combined aqueous layers were neutralized with sodium bicarbonate water, and extracted with chloroform-methanol three times. The combined organic layers were dried with sodium sulfate, and the solvent was distilled off. The resulting crude product was washed with ethyl acetate-diisopropyl ether to obtain 135 mg of compound 549.
1H-NMR (DMSO-d6) δ: 2.40-2.50 (1H, m), 2.72-2.80 (1H, m), 2.83-2.98 (2H, m), 3.03-3.66 (4H, m), 3.79-3.87 (1H, m), 4.11 (1H, 4.2 Hz), 4.32-4.44 (1H, m), 5.12 (1H, s), 5.51 (1H, 7.5 Hz), 6.69 (d, J=7.5 Hz), 6.84-6.90 (1H, m), 7.07-7.24 (4H, m), 7.30-7.34 (2H, m), 7.39-7.42 (1H, m).
EXAMPLE 550




According to Example 536, compound 550 was synthesized from compound 549 by the same procedure.
1H-NMR (DMSO-d6) δ: 0.77 (6H, t, 6.9 Hz), 1.99-2.36 (3H, m), 2.38-2.56 (1H, m), 2.64 (1H, dd, J=3.9 Hz, 14.1 Hz), 2.75 z81H, ddd, J=4.5 Hz, 4.5 Hz, 14.4 Hz), 2.89-3.00 (1H, m), 3.09-3.68 (4H, m), 3.74-3.82 (1H, m), 4.09 (1H, brs), 4.17 (1H, dd, J=3.6 Hz, 8.4 Hz), 5.03 (1H, brs), 5.17 (1H, s), 5.53 (1H, d, J=7.5 Hz), 6.73 (1H, d, J=7.5 Hz), 6.84 (1H, d, J=7.8 Hz), 6.91 (1H, t, J=7.2 Hz), 7.12-7.26 (4H, m), 7.31-7.44 (4H, m), 7.45 (1H, d, J=7.2 Hz).
EXAMPLE 551




According to Example 536, compound 551 was synthesized from compound 549 by the same procedure.
1H-NMR (DMSO-d6) δ: 1.99 (6H, s), 2.27 (1H, brs), 2.51-2.27 (3H, m), 3.56-3.70 (4H, m), 4.03 (2H, brs), 4.36 (1H, brs), 4.94 (2H, brs), 5.29 (1H, brs), 6.54-6.83 (3H, m), 7.11-7.33 (6H, m).
EXAMPLE 552




First Step

To an acetic acid (2 ml) solution of compound 552A (137 mg, 0.367 mmol) synthesized by the same procedure as that of Example 516 and dibenzosuberol (386 mg, 1.83 mmol) was added dropwise sulfuric acid (0.4 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was diluted with water, and extracted with ethyl acetate three times. The extract was washed with water once, and dried with sodium sulfate, and the solvent was distilled off. The resulting crude product was dissolved in methanol (5 ml), a 2N aqueous sodium hydroxide solution (2 ml) was added at room temperature, and the mixture was stirred for 30 minutes. The reaction solution was neutralized with 2N hydrochloric acid (2 ml), and extracted with ethyl acetate two times. The combined extracts were dried with sodium sulfate, and the solvent was distilled off. The resulting crude product was washed with ethyl acetate to obtain 62 mg of compound 552.
1H-NMR (CDCl3) δ: 1.71-1.82 (1H, m), 2.09-2.21 (1H, m), 2.82-2.90 (1H, m), 3.06 (1H, ddd, J=4.2 Hz, 13.2 Hz, 13.2 Hz), 3.19 (3H, s), 3.22-3.43 (3H, m), 3.60 (1H, ddd, J=10.5 Hz, 10.5 Hz, 17.4 Hz), 3.79-3.96 (3H, m), 4.12-4.21 (1H, m), 4.46 (1H, dd, J=3.3 Hz, 10.2 Hz), 4.98 (1H, s), 5.89 (1H, d, J=7.5 Hz), 6.62 (1H, d, J=6.9 Hz), 6.64 (1H, d, J=7.5 Hz), 6.88-6.93 (1H, m), 7.11-7.37 (6H, m).
EXAMPLE 553




Compound 553 was synthesized by the same procedure as that of Example 552.
1H-NMR (CDCl3) δ: 0.80 (3H, d, J=6.6 Hz), 0.94 (3H, d, J=6.9 Hz), 1.94-2.00 (1H, m), 2.82-2.90 (1H, m), 3.00-3.11 (1H, m), 5.31-3.59 (2H, m), 3.64-3.74 (1H, m), 3.94-4.04 (3H, m), 4.25-4.36 (1H, m), 5.04 (1H, s), 5.87 (1H, d, J=7.2 Hz), 6.65 (1H, d, J=7.2 Hz), 7.12 (1H, d, J=7.5 Hz), 6.92 (1H, t, J=8.1 Hz), 7.10 (1H, d, J=7.2 Hz), 7.15-7.38 (5H, m).
EXAMPLE 554




First Step

To an acetic acid (2 ml) solution of compound 554A (100 mg, 0.177 mmol) synthesized by the same procedure as that of Example 516 and dibenzosuberol (186 mg, 0.885 mmol) was added dropwise sulfuric acid (0.4 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was diluted with water, and extracted with ethyl acetate three times. The extract was washed with water once, and dried with sodium sulfate, and the solvent was distilled off. The resulting crude product was dissolved in methanol (5 ml), a 2N aqueous sodium hydroxide solution (2 ml) was added at room temperature, and the mixture was stirred for 30 minutes. The reaction solution was neutralized with an aqueous citric acid solution, and extracted with ethyl acetate two times. The combined extracts were washed with sodium bicarbonate water, and dried with sodium sulfate, and the solvent was distilled off. The resulting crude product was washed with ethyl acetate to obtain 24 mg of compound 554.
1H-NMR (CDCl3) δ: 2.81-2.91 (2H, m), 2.98-3.09 (1H, m), 3.60-3.75 (2H, m), 3.91-4.04 (2H, m), 4.08-4.17 (2H, m), 4.22-4.33 (2H, m), 4.80 (1H, s), 5.69 (1H, d, J=7.8 Hz), 6.48 (1H, d, J=7.5 Hz), 6.59 (1H, d, J=7.5 Hz), 6.80-6.85 (1H, m), 7.13-7.35 (6H, m).
EXAMPLE 555




To an acetic acid (4 ml) solution of compound 555A (380 mg, 1.11 mmol) synthesized according to Example 516 and dibenzosuberol (1.16 g, 5.52 mmol) was added dropwise sulfuric acid (0.8 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was diluted with water, and extracted with ethyl acetate three times. The extract was washed with water once, and dried with sodium sulfate, and the solvent was distilled off. The resulting crude product was dissolved in methanol (5 ml), a 2N aqueous sodium hydroxide solution (2 ml) was added at room temperature, and the mixture was stirred for 30 minutes. The reaction solution was neutralized with an aqueous citric acid solution, and extracted with ethyl acetate three times. The combined extracts were dried with sodium sulfate, and the solvent was distilled off. To the resulting crude product were added ethyl acetate-diisopropyl ether, and the precipitated residue was filtered to obtain 22 mg of compound 555.
1H-NMR (CDCl3) δ: 1.62 (3H, d, J=6.9 Hz), 2.81 (1H, ddd, J=4.2 Hz, 4.2 Hz, 14.4 Hz), 3.09 (1H, ddd, J=4.5 Hz, 13.8 Hz, 13.8 Hz), 3.37 (3H, s), 3.37-3.53 (2H, m), 3.70 (1H, d, J=5.4 Hz), 4.23-4.30 (2H, m), 4.33-4.44 (1H, m), 4.94 (1H, s), 5.70 (1H, d, J=7.8 Hz), 6.59 (1H, d, J=7.5 Hz), 6.64 (1H, d, J=7.8 Hz), 6.88-6.92 (1H, m), 7.08-7.37 (6H, m).
EXAMPLE 556




Compound 556 was synthesized by the same procedures as those of Example 65 and Example 516.
1H-NMR (CDCl3) δ: 1.66-1.78 (2H, m), 1.97 (3H, s), 2.19-2.31 (1H, m), 2.35-2.44 (1H, m), 2.49-2.57 (1H, m), 2.85-2.93 (1H, m), 3.06 (1H, J=3.9 Hz, 12.9 Hz, 12.9 Hz), 3.27-3.39 (2H, m), 3.34 (3H, s), 3.58-3.73 (3H, m), 3.96-4.04 (1H, m), 4.08-4.18 (1H, m), 4.60 (1H, dd, J=3.0 Hz, 11.1 Hz), 4.96 (1H, s), 6.52 (1H, d, J=7.5 Hz), 6.87-6.92 (1H, m), 7.18-7.28 (4H, m), 7.31-7.40 (2H, m), 7.65 (1H, s), 12.04 (1H, s), 14.33 (1H, s).
EXAMPLE 557




Compound 557 was synthesized by the same procedure as that of Example 149.
MS: m/z=419 [M+H]+.
EXAMPLE 558




To a DMSO (2 mL) solution of compound 63B (68.8 mg, 0.120 mmol) was added copper chloride (39.2 mg, 0.396 mmol), and the mixture was stirred at 110 degree for 2 hours and, further, at 120 degree for 1 hour. Thereafter, copper chloride (50.0 mg, 0.505 mmol) was added, and the mixture was stirred at 200 degree for 1 hour. The reaction solution was purified using a LCMS fractionating device, the eluted solvent was distilled off, to the concentrated residue was added diethyl ether, and the precipitated white solid was filtered. Washing with diethyl ether, and drying afforded 20.9 mg of compound 558.
MS: m/z=439 [M+H]+.
EXAMPLE 559




First Step

Compound 48A (43 mg, 0.083 mmol) was dissolved in dichloromethane (6.0 mL), manganese dioxide (120 mg, 1.38 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction solution was filtered with celite, the filtrate was concentrated to obtain 22.3 mg of compound 559B as a pale yellow solid.
1HNMR (CDCl3) δ: 3.17 (3H, s), 3.41-3.55 (4H, m), 3.95-4.07 (2H, m), 4.28 (1H, d, J=16.1 Hz), 4.53 (1H, d, J=11.8 Hz), 5.49 (2H, d, J=2.0 Hz), 6.97-7.66 (16H, m), 10.07 (1H, s).
Second Step
Compound 559B (22 mg, 0.043 mmol) was dissolved in THF (6.0 mL), a 40% methanamine methanol solution (6.5 ul, 0.064 mmol) and acetic acid (3.7 ul, 0.064 mmol) were added, and the mixture was stirred at room temperature for 5 minutes. The reaction solution was ice-cooled, NaBH(OAc)3 (14 mg, 0.064 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction solution were added water and chloroform, and the chloroform layer was separated. The aqueous layer was extracted with chloroform, and sodium sulfate was added to the combined extracts to dry them. The solvent was distilled off to obtain 24 mg of compound 559C as a pale yellow solid.
MS: m/z=538 [M+H]+.
Third Step
Compound 559 was synthesized by the same procedure as that of Example 1.
MS: m/z=448 [M+H]+.
EXAMPLE 560










First Step

A dioxane (20 mL) mixed solution of (methoxymethyl)triphenylphosphonium chloride (6.73 g, 19.0 mmol) was cooled to 0° C., and a 1.06M NaHMDS toluene solution (18.0 ml, 19.0 mmol) was added dropwise while the same temperature was retained. After the reaction solution was stirred at the same temperature for 30 minutes, compound 383A was added, and the mixture was refluxed for 1 hour and 30 minutes. The reaction solution was returned to room temperature, and water and ethyl acetate were added. The ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. To the combined extracts was added sodium sulfate to dry them. The solvent was distilled off, and the resulting oil was purified by silica gel column chromatography, and eluted with n-hexane-ethyl acetate (95:5, v/v). Concentration of an objective fraction afforded 2.22 g of compound 560B as an oil.
1H-NMR (CDCl3) δ: 3.68 (3H, s), 3.73 (3H, s), 4.20 (4H, brs), 6.17 (1H, s), 6.39 (1H, s), 6.96-7.07 (6H, m), 7.18-7.32 (9H, m), 7.32-7.46 (1H, m).
Second Step
Compound 560B (1.98 g, 7.78 mmol) was dissolved in dichloromethane (30 mL), a 70% aqueous perchloric acid solution (8.0 ml, 93 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction solution was added an aqueous saturated sodium carbonate solution, and the dichloromethane layer was separated. The aqueous layer was extracted with dichloromethane, and magnesium sulfate was added to the combined extracts to dry them. The solvent was distilled off, and the resulting oil was purified by silica gel column chromatography, and eluted with n-hexane-ethyl acetate (90:10, v/v). Concentration of an objective fraction afforded 1.80 g of compound 560C as an oil.
1H-NMR (CDCl3) δ: 3.93 (1H, d, J=16.1 Hz), 4.06 (1H, d, J=16.1 Hz), 4.53 (1H, s), 7.11-7.50 (8H, m), 9.89 (1H, s).
MS: m/z=241 [M+H]+.
Third Step
To a dichloromethane (30 mL) solution of compound 560C (2.87 g, 11.9 mmol) were added tetraisopropoxytitanium (17.5 mL, 59.7 mmol) and (S)-4-methylbenzenesulfinamide (2.27 g, 14.3 mmol) at room temperature, then the mixture was refluxed for 3 hours and 30 minutes. The reaction solution was ice-cooled, ice water (30 ml) was added, the mixture was stirred for 1 hour while temperature was retained at the same temperature, and the precipitated solid was filtered using celite. The resulting filtrate was extracted with dichloromethane, and magnesium sulfate was added to the combined extracts to dry them. The solvent was distilled off, and the resulting oil was purified by silica gel column chromatography, and eluted with n-hexane-ethyl acetate (70:30, v/v). Concentration of an objective fraction afforded 3.16 g of compound 560D as a yellow solid.
1H-NMR (CDCl3) δ: 2.39 (6H, s), 3.60 (1H, d, J=15.2 Hz), 3.68 (1H, d, J=14.9 Hz), 3.97 (1H, d, J=15.0 Hz), 4.07 (1H, d, J=15.0 Hz), 4.90 (1H, d, J=2.7 Hz), 4.92 (1H, d, J=2.9 Hz), 7.08-7.26 (20H, m), 7.46-7.51 (4H, m), 8.62 (1H, d, J=2.8 Hz), 8.65 (1H, d, J=2.7 Hz).
MS: m/z=378 [M+H]+.
Fourth Step
A THF (30 mL) suspension of a 1M cyanodiethylaluminum toluene solution (16.7 mL, 16.7 mmol) was cooled to 0 degree, 2-propanol (1.29 mL, 16.7 mmol) was added and, thereafter, the mixture was stirred for 1 hour while temperature was retained at the same temperature. Thereafter, the reaction solution was cooled to −60 degree, a THF (12 mL) solution of compound 560D (3.16 g, 8.37 mmol) was added dropwise, the mixture was stirred for 15 minutes while temperature was retained at the same temperature, thereafter, temperature was raised to room temperature, and the mixture was stirred overnight. The reaction solution was ice-cooled, an aqueous saturated ammonium chloride solution was added, the mixture was stirred at room temperature for 1 hour and 30 minutes and, thereafter, the precipitated solid was filtered using celite, and washed with dichloromethane. The dichloromethane layer of the filtrate was separated, and the aqueous layer was extracted with dichloromethane and, thereafter, sodium sulfate was added to the combined extracts to dry them. The solvent was distilled off, and the resulting oil was purified by silica gel column chromatography, and eluted with chloroform-methanol (97:3, v/v). Concentration of an objective fraction afforded 1.88 g of compound 560E.
MS: m/z=427 [M+Na]+.
Fifth Step
A methanol (4 mL) solution of compound 560E (235 mg, 0.581 mmol) was cooled to 0 degree, cobalt (II) chloride hexahydrate (55.3 mg, 0.232 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Thereafter, the reaction solution was ice-cooled, a DMF (4 mL) solution of sodium borohydride (88 mg, 2.3 mmol) was added dropwise, and the mixture was stirred at the same temperature for 5 minutes, and at room temperature for 1 hour. Then, Boc2O (0.674 mL, 2.90 mmol) was added, and the mixture was stirred for 30 minutes. To the reaction solution was added water, the mixture was extracted with ethyl acetate, and sodium sulfate was added to the combined extracts to dry them. The solvent was distilled off, and the resulting oil was subjected to silica gel column chromatography, and eluted with chloroform-methanol (98:2, v/v). Concentration of an objective fraction afforded a crude product (211 mg) of compound 560F.
MS: m/z=509 [M+Na]+.
Sixth Step
To a methanol (6 mL) solution of the crude product (211 mg) of compound 560F was added TFA (0.128 mL, 1.66 mmol), and the mixture was stirred at room temperature for 2.5 hours. To the reaction solution was added triethylmine (0.230 mL, 1.66 mmol), the solvent was distilled off, and the resulting crude product of compound 560G was used in a next reaction without purification.
MS: m/z=371 [M+H]+.
Seventh Step
To a toluene (4 mL) solution of the crude product of compound 560G was added dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (132 mg, 0.416 mmol), and the mixture was refluxed for 1 hour and 30 minutes. The reaction solution was subjected to silica gel column chromatography, and eluted with chloroform-methanol (100:0→90:10, v/v). Concentration of an objective fraction afforded a crude product (287 mg) of compound 560H.
MS: m/z=671 [M+H]+.
Eighth Step
To the crude product of compound 560H obtained in the seventh step was added a 4N hydrochloric acid ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off, to the resulting concentrated residue were added THF (2 mL) and an aqueous saturated sodium bicarbonate solution (2 mL), and the mixture was stirred at room temperature for 45 minutes. To the reaction solution was added water, the mixture was extracted with chloroform, and sodium sulfate was added to the combined extracts to dry them. The solvent was distilled off, and the resulting oil was subjected to silica gel column chromatography, and eluted with chloroform-methanol (100:0→94:6, v/v). Concentration of an objective fraction afforded 27 mg of compound 5601 as a yellow solid.
MS: m/z=539 [M+H]+.
Ninth Step
Compound 560I (27 mg, 0.050 mmol) was dissolved in DMF (2 mL), cesium carbonate (82 mg, 0.25 mmol) and methyl iodide (0.010 mL, 0.16 mmol) were added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. To the reaction solution was added water, the mixture was extracted with ethyl acetate, and sodium sulfate was added to the combined extracts to dry them. The solvent was distilled off, and the resulting oil was subjected to silica gel column chromatography, and eluted with chloroform-methanol (100:0→94:6, v/v). Concentration of an objective fraction afforded a crude product of compound 560J.
MS: m/z=553 [M+H]+.
Tenth Step
To an EtOH (2 mL) solution of the crude product of compound 560J obtained in the ninth step was added 2N NaOH (1 mL), and the mixture was stirred at room temperature for 40 minutes. To the reaction solution was added a 2N aqueous HCl solution, the mixture was extracted with ethyl acetate, and sodium sulfate was added to the combined extracts to dry them. The solvent was distilled off to obtain 17 mg of compound 560K as a white oil.
MS: m/z=539 [M+H]+.
Eleventh Step
To compound 560K (17 mg, 0.032 mmol) was added TFA (2.0 mL), and the mixture was stirred at room temperature for 35 minutes. The reaction solution was subjected to toluene azeotropy, to the resulting concentrated residue was added isopropyl ether, and the precipitated solid was filtered and washed to obtain 7.1 mg of compound 560 as a pink solid.
MS: m/z=449 [M+H]+.
EXAMPLE 561







First Step

To a crude product (433 mg) of compound 560H was added a 4N hydrochloric acid ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, to a THF (2 mL) solution of the resulting residue was added acetone (2 mL), the mixture was stirred at room temperature for 20 minutes, NaBH(OAc)3 (70 mg, 0.32 mmol) was added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Thereafter, to the reaction solution was added an aqueous saturated sodium bicarbonate solution (3 mL), and the mixture was stirred at room temperature overnight. To the reaction solution was added water, the mixture was extracted with chloroform, and sodium sulfate was added to the combined extracts to dry them. The solvent was distilled off, and the resulting oil was subjected to silica gel column chromatography, and eluted with chloroform-methanol (100:0→94:6, v/v). Concentration of an objective fraction afforded a crude product (79 mg) of compound 561A.
MS: m/z=581 [M+H]+.
Second Step
To an EtOH (4 mL) solution of the crude product (79 mg) of compound 561A was added 2N NaOH (2 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added a 2N aqueous HCl solution, the mixture was extracted with ethyl acetate, and sodium sulfate was added to the combined extracts to dry them. The solvent was distilled off, and the resulting oil was subjected to silica gel column chromatography, and eluted with chloroform-methanol (100:0→94:6, v/v). Concentration of an objective fraction afforded compound 561B (53 mg).
MS: m/z=567 [M+H]+.
Third Step
A DMF (2 mL) solution of compound 5618 (53 mg, 0.093 mmol) was cooled to 0 degree, triethylamine (0.039 mL, 0.28 mmol) and ethyl chloroformate (0.018 mL, 0.187 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. Thereafter, the reaction solution was cooled to 0 degree, sodium azide (18 mg, 0.28 mmol) was added, and the mixture was stirred for 50 minutes while temperature was retained at the same temperature. To the reaction solution was added water, the mixture was extracted with dichloromethane, and the combined extracts were concentrated to obtain a crude product of compound 561C.
MS: m/z=592 [M+H]+.
Fourth Step
The crude product (55 mg) of compound 561C was dissolved in methanol (2 mL), and the mixture was stirred at 50° C. for 1 hour. The reaction solution was subjected to silica gel column chromatography, and eluted with chloroform-methanol (100:0→94:6, v/v). Concentration of an objective fraction afforded a crude product (43 mg) of compound 561D.
MS: m/z=596 [M+H]+.
Fifth Step
To an EtOH (2 mL) solution of the crude product (43 mg) of compound 561D was added 2N NaOH (4 mL), and the mixture was stirred at 60 degree for 1 hour. The solvent was distilled off, water was added, the mixture was extracted with ethyl acetate and, thereafter, sodium sulfate was added to the combined extracts to dry them. The solvent was distilled off, the resulting oil was subjected to amino column chromatography, and eluted with chloroform-methanol (100:0→0.80:20, v/v). Concentration of an objective fraction afforded 16 mg of compound 561E as a pale yellow solid.
MS: m/z=538 [M+H]+.
Sixth Step
Compound 561E (16 mg, 0.029 mmol) was dissolved in EtOH (1 mL) and a 48% aqueous tetrafluoroboric acid (1 mL), the reaction solution was cooled to 0 degree, sodium nitrite (15 mg, 0.22 mmol) was added, and the mixture was stirred for 1 hour and 30 minutes while temperature was retained at the same temperature and, further, at room temperature for 2 hours and 30 minutes. To the reaction solution was added water, the mixture was extracted with chloroform, and sodium sulfate was added to the combined extracts to dry them. The solvent was distilled off, to the resulting concentrated residue were added ethyl acetate and isopropyl ether, and the precipitated solid was filtered and washed to obtain 5 mg of compound 561 as a white solid.
1H-NMR (CDCl3) δ: 0.96 (3H, d, J=6.9 Hz), 1.17 (3H, d, J=6.8 Hz), 3.37 (1H, d, J=13.3 Hz), 3.88 (1H, dd, J=13.4, 4.3 Hz), 3.99 (1H, d, J=14.9 Hz), 4.08 (1H, d, J=11.3 Hz), 4.52 (1H, d, J=14.9 Hz), 4.81-4.90 (1H, m), 5.67 (1H, dd, J=11.3, 3.1 Hz), 5.94 (1H, d, J=7.4 Hz), 6.59 (1H, d, J=6.4 Hz), 6.72 (1H, d, J=7.3 Hz), 6.86 (1H, t, J=7.1 Hz), 7.09 (1H, t, J=7.6 Hz), 7.16-7.31 (5H, m).
EXAMPLE 562




Compound 562 was synthesized by the same procedure as that of Example 561.
1H-NMR (CDCl3) δ: 3.07 (3H, s), 3.21 (1H, d, J=12.3 Hz), 4.00-4.31 (4H, m), 5.78 (1H, d, J=10.5 Hz), 5.94 (1H, d, J=7.4 Hz), 6.54 (1H, d, J=7.3 Hz), 6.69 (1H, d, J=7.5 Hz), 6.98 (1H, t, J=7.6 Hz), 7.14-7.41 (6H, m).
MS: m/z=405 [M+H]+.
EXAMPLE 563







First Step

Compound 563A (Tetrahedron Letters, 34, 953-956, 1993, 41.1 g, 154 mmol) was dissolved in THF (300 mL), 1M BH3-THF (770 mL) was slowly added at room temperature, and the mixture was stirred for 18 hours. 3N hydrochloric acid (513 mL) was slowly added, and the mixture was refluxed for 1 hour, and was progressed to a next step without purification.
LC-MS: m/z=254 [M+H]+.
Second Step
Using a solution containing compound 563B, according to Example 12, compound 563C was synthesized.
LC-MS: m/z=353 [M+H]+.
1H-NMR (DMSO-d6): 1.40 (9H, s), 2.65-2.72 (1H, m), 2.86-2.92 (3H, m), 3.47-3.56 (3H, m), 3.56-3.69 (1H, m), 6.63 (1H, s), 7.11-7.26 (8H, m).
Third Step
A toluene (30 mL) solution of compound 563C (2.16 g, 6.79 mmol) and dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (2.38 g, 6.75 mmol) was stirred at 100° C. for 4 hours. The reaction solution was distilled off under reduced pressure, and the resulting crude product of compound 563D was used in a next reaction without purification.
MS: m/z=653.05 [M+H]+.
Fourth Step
To an ethyl acetate (20 mL) solution of the crude product of compound 563D was added hydrogen chloride (4N ethyl acetate solution, 20 mL) at room temperature, and the mixture was stirred for 30 minutes. The reaction solution was distilled off under reduced pressure, and the resulting crude product of compound 563E was used in a next reaction without purification.
MS: m/z=553.05 [M+H]+.
Fifth Step
To a tetrahydrofuran (40 mL) solution of the crude product of compound 563E was added saturated sodium bicarbonate water (5 mL) at room temperature, and the mixture was stirred for 16 hours. To the reaction solution was added water (50 mL), the mixture was extracted with chloroform three times, and the extracts were combined, and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and diethyl ether and chloroform were added to the resulting residue to covert them into a powder, to obtain compound 563F (2.90 g, 70.2%) as a white solid.
MS: m/z=521.05 [M+H]+.
Sixth Step
To a methanol (7.5 mL) suspension of compound 563F (523 mg, 1.01 mmol) was added an aqueous sodium hydroxide solution (2 M, 1.5 mL) at room temperature, and the mixture was stirred for 3 hours. To the reaction solution were added hydrochloric acid (2N, 1.5 mL) and water (3 mL) at room temperature and, thereafter, the mixture was stirred at 0° C. for 15 minutes. The precipitated solid was filtered, and washed with water and diethyl ether to obtain compound 563G (418 mg, 82.0%) as a white solid.
MS: m/z=507.00 [M+H]+.
Seventh Step
A diphenyl ether (5 mL) suspension of compound 563G (107 mg, 0.211 mmol) was stirred at 240° C. for 1 hour under microwave irradiation. The reaction solution was purified by silica gel column chromatography (methanol/chloroform=0%→5%) to obtain compound 563H (64.4 mg, 65.9%) as a white solid.
MS: m/z=463.05 [M+H]+.
Eighth Step
A methanol (30 mL) solution of compound 563H (64.4 mg, 0.139 mmol) was hydrogenated by passing through 10% Pd—C CatCart (H-cube, Full-H2 mode, 25° C.) for 3 hours. The reaction solution was distilled off under reduced pressure, and ethyl acetate and methanol were added to the resulting residue to convert it into a powder, to obtain compound 563 (31.1 mg, 60.0%) as a gray white solid.
1HNMR (DMSO-d6) δ: 2.50-3.03 (3H, m), 3.50-3.72 (3H, m), 4.29 (1H, d, J=11.4 Hz), 5.12 (1H, m), 5.69 (1H, d, J=7.2 Hz), 6.50 (1H, d, J=7.7 Hz), 6.75 (1H, d, J=7.7 Hz), 6.84 (1H, m), 7.14-7.30 (6H, m), 9.16 (1H, d, J=4.8 Hz).
MS: m/z=372.90 [M+H]+.
EXAMPLE 564




First Step

To a dimethylformamide (2 mL) suspension of compound 563H (64.2 mg, 0.139 mmol) and cesium carbonate (220 mg, 0.675 mmol) was added methyl iodide (0.0430 mL, 0.688 mmol) at room temperature, and the mixture was stirred for 3 hours. To the reaction solution was added water (10 mL) at room temperature, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with water (10 mL) and an aqueous saturated sodium chloride solution (10 mL), and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/chloroform=2.5%→10%) to obtain compound 564A (56.0 mg, 85.0%) as a colorless gummy substance.
MS: m/z=477.00 [M+H]+.
Second Step
A solution of compound 564A (56.0 mg, 0.118 mmol) in methanol (10 mL), ethyl acetate (5 mL) and tetrahydrofran (5 mL) was hydrogenated by passing through 10% Pd—C CatCart (H-cube, Full-H2 mode, 25° C.) for 75 minutes. The reaction solution was distilled off under reduced pressure, and ethyl acetate and methanol were added to the resulting residue to convert it into a powder, to obtain compound 564 (22.0 mg, 48.4%) as a gray white solid.
1HNMR (DMSO-d6) δ: 2.86-2.98 (6H, m), 3.51-3.58 (2H, m), 3.94 (1H, m), 4.30 (1H, d, J=11.1 Hz), 5.19 (1H, d, J=10.2 Hz), 5.79 (1H, d, J=6.9 Hz), 6.49 (1H, d, J=7.4 Hz), 6.74 (1H, d, J=7.4 Hz), 6.85 (1H, m), 7.14 (2H, m), 7.25 (4H, m), 12.50 (1H, brs).
MS: m/z=387.05 [M+H]+.
EXAMPLE 565




Compound 565 was synthesized by the same procedure as that of Example 564.
MS: m/z=443.95 [M+H]+.
EXAMPLE 566




First Step

A dimethylformamide (2 mL) suspension of compound 563H (75.4 mg, 0.163 mmol), 3-iodobenzonitrile (124 mg, 0.541 mmol), copper (I) iodide (33.2 mg, 0.174 mmol), potassium carbonate (74.7 mg, 0.540 mmol) and N,N′-dimethylethylenediamine (0.0200 ml, 0.186 mmol) was stirred at 140° C. for 2 hours under microwave irradiation. To the reaction solution were added water (10 mL) and hydrochloric acid (2M, 2 mL) at room temperature, and the mixture was extracted with ethyl acetate. The extract was filtered with celite, and the filtrate was washed with water (10 mL×2) and an aqueous saturated sodium chloride solution (10 mL), and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product of compound 566A was used in a next reaction without purification.
MS: m/z=564.05 [M+H]+.
Second Step
To a methylene chloride (10 mL) solution of the crude product of compound 566A obtained in the first step was added trifluoroacetic acid (2 mL) at room temperature, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative LCMS to obtain compound 566 (30.3 mg, 39.3%) as a yellow solid.
1HNMR (DMSO-d6) δ: 2.81-2.94 (2H, m), 3.38-3.58 (2H, m), 4.54 (1H, d, J=10.5 Hz), 4.64 (1H, d, J=10.5 Hz), 5.35 (1H, d, J=10.5 Hz), 5.76 (1H, m), 6.66-6.71 (3H, m), 6.90 (1H, m), 7.06-7.15 (6H, m), 7.76 (2H, m), 7.90 (2H, m).
MS: m/z=473.90 [M+H]+.
EXAMPLE 567




Compound 567 was synthesized by the same procedure as that of Example 566.
1HNMR (DMSO-d6) δ: 2.80-3.00 (2H, m), 3.40-3.70 (2H, m), 4.52 (1H, m), 4.64 (1H, m), 5.38 (1H, m), 5.76 (1H, m), 6.60-7.20 (10H, m), 7.60-7.90 (3H, m), 8.11 (1H, m).
MS: m/z=474.00 [M+H]+.
EXAMPLE 568




Compound 568 was synthesized by the same procedure as that of Example 566.
1HNMR (DMSO-d6) δ: 2.87-2.96 (2H, m), 3.34-3.73 (2H, m), 4.64 (2H, m), 5.33 (1H, m), 5.71 (1H, d, J=7.2 Hz), 6.61 (1H, d, J=7.8 Hz), 6.87-6.95 (3H, m), 7.00-7.27 (6H, m), 7.62 (2H, m), 7.86 (1H, m), 8.07 (1H, m).
MS: m/z=474.00 [M+H]+.
EXAMPLE 569




Compound 569 was synthesized by the same procedure as that of Example 566.
MS: m/z=449.95 [M+H]+.
EXAMPLE 570




Compound 570 was synthesized by the same procedure as that of Example 566.
1HNMR (DMSO-d6) δ: 2.83-2.97 (3H, m), 3.16-3.62 (2H, m), 3.56 (1H, m), 3.66 (1H, d, J=11.1 Hz), 5.35 (1H, d, J=11.1 Hz), 5.73 (1H, d, J=7.4 Hz), 6.68 (1H, d, J=7.4 Hz), 6.92 (1H, m), 7.06-7.21 (5H, m), 7.49 (1H, m), 7.97 (1H, d, J=8.4 Hz), 8.14 (1H, s), 8.50 (1H, d, J=3.6 Hz), 8.81 (1H, d, J=2.1 Hz).
MS: m/z=449.95 [M+H]+.
EXAMPLE 571




First Step

To a DMF (1 mL) solution of compound 563H (50.0 mg, 0.108 mmol) was added cesium carbonate (176 mg, 0.540 mmol), and the mixture was stirred at room temperature for 10 minutes. To the reaction solution was added O-(2,4-dinitrophenyl)hydroxylamine (64.6 mg, 0.324 mmol), and the mixture was stirred at room temperature for 9 hours. To the reaction solution was added chloroform, and the mixture was washed with water, and dried with sodium sulfate. The solvent was distilled off, and the resulting oil was purified by silica gel column chromatography. The materials were eluted firstly with chloroform and, then, with chloroform-methanol (98:2, v/v). Concentration of an objective fraction afforded 28.3 mg of compound 571A as an amorphous substance.
MS: m/z=478 [M+H]+.
Second Step
Compound 571A (27.0 g, 0.057 mmol) was dissolved in a THF-methanol (1 mL, 1:1, v/v) solution, 10% palladium carbon (15.0 mg) was added, and the mixture was stirred at room temperature for 2 hours under hydrogen atmosphere. After dilution with chloroform, insolubles were removed by celite filtration. After the filtrate was concentrated under reduced pressure, the residue was solidified with dichloromethane-ether to obtain 12.0 mg of compound 571.
MS: m/z=388 [M+H]+.
EXAMPLE 572




Using compound 12H, and according to Example 571, compound 572 was synthesized by the same procedure.
MS: m/z=420 [M+H]+.
EXAMPLE 573




First Step

To a dimethylformamide (1.5 mL) solution of compound 563H (83.2 mg, 0.160 mmol) was added sodium hydride (60%, 13.2 mg, 0.330 mmol) under ice-cooling, the mixture was stirred for 30 minutes, thereafter, bromoacetonitrile (0.0190 mL, 0.270 mmol) was added, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added an aqueous ammonium chloride solution (10%, 3 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with water (10 mL) and an aqueous saturated sodium chloride solution (10 mL), and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product of compound 573A was used in a next reaction without purification.
MS: m/z=502.00 [M+H]+.
Second Step
To an acetonitrile (4 mL) suspension of the crude product of compound 573A obtained in the first step and sodium iodide (111 mg, 0.741 mmol) was added chlorotrimethylsilane (0.0920 mL, 0.720 mmol) at room temperature, and the mixture was stirred for 24 hours. To the reaction solution was added an aqueous sodium hydrogen sulfite solution (10%, 10 mL) and, thereafter, the mixture was extracted with chloroform. After the extracts were combined, and dried with sodium sulfate, the solvent was concentrated under reduced pressure, and the resulting residue was purified by preparative LCMS to obtain compound 573 (22.0 mg, 29.7%) as a gray white solid.
1H-NMR (DMSO-d6) δ: 2.86-2.95 (2H, m), 3.45-3.63 (2H, m), 4.01 (1H, m), 4.30 (1H, d, J=10.8 Hz), 4.35 (1H, d, J=17.4 Hz), 4.74 (1H, d, J=17.4 Hz), 5.20 (1H, m), 5.66 (1H, d, J=7.5 Hz), 6.52 (1H, d, J=7.8 Hz), 6.73 (1H, d, J=7.5 Hz), 6.83 (1H, m), 7.11-7.28 (6H, m).
MS: m/z=502.00 [M+H]+.
EXAMPLE 574




Compound 574 was synthesized by the same procedure as that of Example 573.
1H-NMR (DMSO-d6) δ: 4.16 (1H, dd, J=13.26, 3.53 Hz), 4.36 (1H, d, J=11.58 Hz), 4.52 (2H, dd, J=20.73, 17.54 Hz), 5.44 (1H, d, J=11.41 Hz), 5.65 (1H, d, J=7.39 Hz), 6.99 (1H, d, J=7.55 Hz), 7.11-7.32 (6H, m), 7.36-7.45 (2H, m), 7.58 (2H, d, J=7.39 Hz).
EXAMPLE 575




Compound 575 was synthesized by the same procedure as that of Example 573.
MS: m/z=425.95 [M+H]+.
EXAMPLE 576










First Step

A dichloromethane (30 mL) solution of compound 576A (Bioorg. Med. Chem., 2003, 11, 197-206) (2.26 g, 10.2 mmol) were added tetraisopropoxytitanium (10.0 mL, 33.1 mmol) and (S)-4-methylbenzenesulfinamide (1.29 g, 8.13 mmol) at room temperature, and the mixture was refluxed for 2 hours. The reaction solution was ice-cooled, ice water (40 ml) was added, the mixture was stirred for 1 hour while temperature was retained at the same temperature, and the precipitated solid was filtered using celite. The resulting filtrate was extracted with dichloromethane, and magnesium sulfate was added to the combined extracts to dry them. The solvent was distilled off, and the resulting oil was purified by silica gel column chromatography, and eluted with n-hexane-ethyl acetate (100:0→70:30, v/v). Concentration of an objective fraction afforded 1.35 g of compound 576B as a yellow solid.
1H-NMR (CDCl3) δ: 2.32 (3H, s), 2.72-2.85 (2H, m), 3.03-3.16 (2H, m), 4.89 (1H, d, J=3.5 Hz), 7.09-7.25 (10H, m), 7.39-7.42 (2H, m), 8.49 (1H, d, J=3.6 Hz).
MS: m/z=360 [M+H]+.
Second Step
A THF (20 mL) solution of a 1M cyanodiethylaluminum toluene solution (7.51 mL, 7.51 mmol) was cooled to 0 degree, 2-propanol (0.579 mL, 7.51 mmol) was added and, thereafter, the mixture was stirred for 1 hour while temperature was retained at the same temperature. Thereafter, the reaction solution was cooled to −60 degree, a THF (14 mL) solution of compound 576B was added dropwise, the mixture was stirred for 15 minutes while temperature was retained at the same temperature, thereafter, temperature was raised to room temperature, and the mixture was stirred overnight. The reaction solution was ice-cooled, an aqueous saturated ammonium chloride solution was added, the mixture was stirred at room temperature for 1 hour and 30 minutes and, thereafter, the precipitated solid was filtered using celite, and washed with dichloromethane. The dichloromethane layer of the filtrate was separated, the aqueous layer was extracted with dichloromethane, and sodium sulfate was added to the combined extracts to dry them. The solvent was distilled off, to the resulting oil were added ethyl acetate and hexane, and the precipitated solid was filtered and washed to obtain 976 mg of compound 576C as a white solid.
1H-NMR (CDCl3) δ: 2.38 (3H, s), 2.92-3.055 (2H, m), 3.41-3.52 (2H, m), 4.25 (1H, d, J=10.8 Hz), 4.28 (1H, d, J=5.6 Hz), 4.94 (1H, dd, J=10.6, 5.7 Hz), 7.14-7.41 (12H, m).
Third Step
A methanol (8 mL) suspension of compound 576C (500 mg, 1.29 mmol) was cooled to 0 degree, cobalt (II) chloride hexahydrate (123 mg, 0.517 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added chloroform (5 mL), thereafter, the mixture was ice-cooled, a DMF (4 mL) solution of sodium borohydride (196 mg, 5.17 mmol) was added dropwise, and the mixture was stirred at the same temperature for 5 minutes, and at room temperature for 2 hours. Then, Boc2O (1.0 mL, 4.3 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction solution was added water, the mixture was extracted with ethyl acetate, and sodium sulfate was added to the combined extracts to dry them. The solvent was distilled off, and the resulting oil was subjected to silica gel column chromatography, and eluted with chloroform-methanol (100:0→98:2, v/v). Concentration of an objective fraction afforded a crude product (200 mg) of compound 576D.
MS: m/z=491 [M+Na]+.
Fourth Step
To a methanol (6 mL) solution of the crude product (200 mg) of compound 576D obtained in the third step was added TFA (0.188 mL, 2.45 mmol), and the mixture was stirred at room temperature for 2.5 hours. To the reaction solution was added triethylamine (0.399 mL, 2.45 mmol), the solvent was distilled off, and the resulting crude product of compound 576E was used in a next reaction without purification.
MS: m/z=353 [M+H]+.
Fifth Step
To a toluene (4 mL) solution of the crude product of compound 576E obtained in the fourth step was added dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (130 mg, 0.409 mmol), and the mixture was refluxed for 2 hours. The reaction solution was subjected to silica gel column chromatography, and eluted with chloroform-methanol (100:0→90:10, v/v). Concentration of an objective fraction afforded a crude product (268 mg) of compound 576F.
MS: m/z=653 [M+H]+.
Sixth Step
To the crude product (263 mg) of compound 576F obtained in the fifth step was added a 4N hydrochloric acid ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1 hour and 30 minutes. The solvent was distilled off, to a THF (4 mL) solution of the resulting concentrated residue was added acetone (1 mL), the mixture was stirred at room temperature for 25 minutes, thereafter, NaBH(OAc)3 (180 mg, 0.807 mmol) was added, and the mixture was stirred at room temperature for 1 hour and 15 minutes. Thereafter, to the reaction solution was added an aqueous saturated sodium bicarbonate solution (7 mL), and the mixture was stirred at room temperature overnight. To the reaction solution was added water, the mixture was extracted with chloroform, and sodium sulfate was added to the combined extracts to dry them. The solvent was distilled off, and the resulting oil was subjected to silica gel column chromatography, and eluted with chloroform-methanol (100:0→94:6, v/v). Concentration of an objective fraction afforded a crude product (160 mg) of compound 576G.
MS: m/z=563 [M+H]+.
Seventh Step
To an EtOH (4 mL) solution of the crude product (160 mg) of compound 576G obtained in the sixth step was added 2N NaOH (2 mL), and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added a 2N aqueous HCl solution, the mixture was extracted with ethyl acetate, and sodium sulfate was added to the combined extracts to dry them. The solvent was distilled off, and the resulting oil was subjected to silica gel column chromatography, and eluted with chloroform-methanol (100:0→94:6, v/v). Concentration of an objective fraction afforded 78 mg of compound 576H as a yellow solid.
MS: m/z=549 [M+H]+.
Eighth Step
To compound 576H (78 mg, 0.14 mmol) was added diphenyl ether (3 mL), and the mixture was stirred at 245 degree for 1 hour under microwave irradiation. The reaction solution was subjected to silica gel column chromatography, and eluted with chloroform-methanol (100:0→90:10, v/v). Concentration of an objective fraction afforded 43 mg of compound 5761 as a bronzed oil.
MS: m/z=505 [M+H]+.
Ninth Step
To compound 576I (42 mg, 0.083 mmol) was added TFA (1.0 mL), and the mixture was stirred at room temperature for 35 minutes. The reaction solution was subjected to toluene azeotropy, to the resulting concentrated residue was added an aqueous saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. Sodium sulfate was added to the combined extracts to dry them. The solvent was distilled off, to the resulting oil were added ethyl acetate and isopropyl ether, and the precipitated solid was filtered and washed to obtain 14 mg of compound 576 as a pale brown solid.
1H-NMR (CDCl3) δ: 1.13 (3H, d, J=6.7 Hz), 1.20 (3H, d, J=6.7 Hz), 2.95-3.13 (2H, m), 3.28 (1H, d, J=13.1 Hz), 3.37-3.59 (2H, m), 3.75 (1H, d, J=10.3 Hz), 4.10 (1H, d, J=10.8 Hz), 4.80-4.87 (2H, m), 5.91 (1H, d, J=5.8 Hz), 6.41 (2H, t, J=6.5 Hz), 6.85 (1H, t, J=6.4 Hz), 7.05-7.35 (6H, m).
MS: m/z=415 [M+H]+.
EXAMPLE 577




First Step

To a dimethylformamide (3 mL) solution of a crude product (140 mg) of compound 159A was added potassium cyanide (21.0 mg, 0.323 mmol) at room temperature, and the mixture was stirred at 80° C. for 30 minutes, and at 100° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=80%→100%) to obtain compound 577B (41.5 mg, 33.5%) as a pale orange foam.
MS: m/z=535.25 [M+H]+.
Second Step
To an acetonitrile (4 mL) solution of compound 577B (41.5 mg, 0.078 mmol) and sodium iodide (45.5 mg, 0.304 mmol) was added chlorotrimethylsilane (0.0400 mL, 0.313 mmol) at room temperature, and the mixture was stirred for 2 hours. To the reaction solution was added water (1 mL), the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative LCMS. Diethyl ether was added to the resulting residue to convert it into a powder, to obtain compound 577 (20.7 mg, 60.0%) as a gray white solid.
1HNMR (DMSO-d6) δ: 3.10 (3H, s), 3.51 (2H, m), 3.70 (1H, d, J=18.9 Hz), 4.03 (1H, d, J=18.9 Hz), 4.46 (1H, d, J=13.4 Hz), 5.04 (1H, d, J=13.4 Hz), 5.56 (1H, s), 5.69 (1H, s), 7.09-7.21 (5H, m), 7.39-7.63 (3H, m), 7.64 (2H, m).
MS: m/z=445.20 [M+H]+.
EXAMPLE 578




Compound 578 was synthesized by the same procedure as that of Example 157.
1HNMR (CDCl3) δ: 0.97 (3H, d, J=6.6 Hz), 1.19 (3H, d, J=6.9 Hz), 3.29 (3H, s), 3.97 (1H, d, J=16.1 Hz), 4.56 (1H, d, J=13.7 Hz), 4.82 (1H, m), 4.96 (1H, d, J=16.1 Hz), 5.34 (1H, s), 5.97 (1H, d, J=13.7 Hz), 6.78 (2H, m), 7.12 (2H, m), 7.44-7.51 (6H, m).
MS: m/z=434.10 [M+H]+.
EXAMPLE 579




Compound 579 was synthesized by the same procedure as that of Example 163.
MS: m/z=477.25 [M+H]+.
EXAMPLE 580










First Step

To a solution of compound 155A (10.5 g, 26.9 mmol), diisopropylethylamine (11.0 mL, 63.0 mmol), 1-methylimidazole (2.60 mL, 32.6 mmol) and isopropylamine (2.80 mL, 32.7 mmol) in toluene (100 mL) and acetonitrile (20 mL) was added dropwise diphenylphosphoric acid chloride (6.80 mL, 32.7 mmol) over 5 minutes under ice-cooling, and the mixture was stirred under ice-cooling for 90 minutes, at room temperature for 90 minutes. To the reaction solution were added tert-butyldimethylsilyl chloride (4.05 g, 26.9 mmol) and triethylamine (4.10 mL, 29.6 mmol) under ice-cooling, the mixture was stirred at room temperature for 80 minutes, 4-dimethylaminopyridine (164 mg, 1.35 mmol) and methylene chloride (100 mL) were added at room temperature, and the mixture was stirred for 15.5 hours. To the reaction solution was added tert-butyldimethylsilyl chloride (2.04 g, 26.9 mmol) at room temperature, and the mixture was stirred for 24 hours. To the reaction solution was added a 10% aqueous acetic acid solution (100 mL) at room temperature, and the mixture was extracted with chloroform, the extracts were combined, washed with saturated sodium bicarbonate water (100 mL), and dried with sodium sulfate. The solvent was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=15%→40%) to obtain compound 580B (6.96 g, 59.9%) as a pale yellow oil.
MS: m/z=432.25 [M+H]+.
Second Step
To an ethanol (50 mL) solution of compound 580B (6.96 g, 16.1 mmol) was added aqueous ammonia (35 mL) at room temperature, and the mixture was stirred for 4 days. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=75%→100%, methanol/chloroform=0%→15%) to obtain compound 580C (4.50 g, 64.8%) as a pale orange gummy substance.
MS: m/z=431.25 [M+H]+.
Third Step
To a dimethylformamide (90 mL) solution of compound 580C (4.50 g, 10.5 mmol) and potassium carbonate (7.27 g, 52.6 mmol) was added O-(2,4-dinitrophenyl)hydroxylamine (6.29 g, 31.6 mmol) at room temperature, and the mixture was stirred for 2 days. To the reaction solution was added chloroform (180 mL) at room temperature, the precipitated insolubles were filtered off, the filtrated was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol/chloroform=0%→10%) to obtain compound 580D (5.28 g, quant) as a yellow solid.
MS: m/z=446.25 [M+H]+.
Fourth Step
To an ethanol (15 ml) solution of compound 580D (1.29 g, 2.89 mmol) was added paraformaldehyde (261 mg, 8.68 mmol) at room temperature, and the mixture was stirred at 140° C. for 3 hours under microwave irradiation. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=50%→100%) to obtain compound 580E (2.47 g, 93.0%) as a pale orange solid.
MS: m/z=458.20 [M+H]+.
Fifth Step
To a DMF (25 mL) solution of compound 580E (2.47 g, 5.40 mmol) were added cesium carbonate (5.28 g, 16.2 mmol) and bromodiphenylmethane (4.02 g, 16.3 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 days. To the reaction solution was added water (50 mL) under ice-cooling and, thereafter, the mixture was extracted with ethyl acetate (150 mL×2). The extracts were combined, sequentially washed with water (50 mL×2) and an aqueous saturated sodium chloride solution (50 mL), and dried with sodium sulfate. The solvent was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=50%→100%, methanol/chloroform=10%→20%) to obtain compound 580F (1.60 g, 47.5%) as a yellow form.
MS: m/z=624.30 [M+H]+.
Sixth Step
To a methanol (40 mL) solution of compound 580F (1.60 g, 2.56 mmol) was added hydrogen chloride (4N ethyl acetate solution, 20 mL) at room temperature, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, to the resulting residue was added saturated sodium bicarbonate water (20 mL) at room temperature and, thereafter, the mixture was extracted with chloroform three times. The extracts were combined, and dried with sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain compound 580G (920 mg, 70.4%) as a white foam.
MS: m/z=510.25 [M+H]+.
Seventh Step
To a THF (80 mL) solution of compound 580G (816 mg, 1.60 mmol) was added manganese dioxide (2.39 g, 27.5 mmol) at room temperature, and the mixture was stirred for 19 hours. After the reaction solution was filtered, the filtrate was distilled off under reduced pressure, and the resulting crude product (785 mg) of compound 580H was used in a next reaction without purification.
MS: m/z=508.20 [M+H]+.
Eighth Step
To a solution of the crude product (635 mg, 1.25 mmol) of compound 580H obtained in the seventh step and amidosulfuric acid (425 mg, 4.38 mmol) in methanol (30 mL) and water (10 mL) was added dropwise a solution of sodium chlorite (396 mg, 4.38 mmol) in water (4 mL) over 10 minutes under ice-cooling, the mixture was stirred at room temperature for 30 minutes, and a 5% aqueous sodium hydrogen sulfite solution (10 mL) was added. Methanol was distilled off under reduced pressure, and the resulting residue was extracted with ethyl acetate two times. The extracts were combined, washed with an aqueous saturated sodium chloride solution (10 mL), and dried with sodium sulfate. The filtrated was distilled off under reduced pressure, and the resulting crude product of compound 580I was used in a next reaction without purification.
MS: m/z=524.25 [M+H]+.
Ninth Step
To a methylene chloride (20 mL) solution of the crude product (164 mg, 0.313 mmol) of compound 580I obtained in the eighth step, diisopropylethylamine (0.131 mL, and 0.751 mmol), 1-methylimidazole (0.0300 mL, 0.376 mmol) and methylamine (2.0M tetrahydrofuran solution, 0.188 mL, 0.376 mmol) was added diphenylphosphoric acid chloride (0.0780 mL, 0.375 mmol) at room temperature, the mixture was stirred for 3.5 hours, methylamine hydrochloride (25.0 mg, 0.370 mmol) was added, and the mixture was stirred for 6 days. The reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=75%→100%) to obtain compound 580J (45.7 mg, 27.2%) as a white foam.
MS: m/z=537.30 [M+H]+.
Tenth Step
To an acetonitrile (4 mL) solution of compound 580J (45.7 mg, 0.0850 mmol) and sodium iodide (103 mg, 0.687 mmol) was added chlorotrimethylsilane (0.0870 mL, 0.681 mmol) at room temperature, and the mixture was stirred for 20 hours. To the reaction solution was added a 5% aqueous sodium hydrogen sulfite solution (4 mL), and the mixture was extracted with chloroform two times. After the extracts were combined, and dried with sodium sulfate, the residue obtained by concentration under reduced pressure was purified by preparative LCMS. Diethyl ether and n-hexane were added to the resulting residue to convert it into a powder, to obtain compound 580 (17.1 mg, 45.0%) as a white solid.
1HNMR (CDCl3) δ: 0.93 (3H, d, J=6.9 Hz), 1.11 (3H, d, J=6.9 Hz), 2.83 (3H, d, J=4.8 Hz), 4.53 (1H, d, J=13.4 Hz), 4.85 (1H, m), 4.97 (1H, d, J=13.4 Hz), 5.07 (1H, brd), 5.25 (1H, s), 5.86 (1H, s), 6.97 (2H, m), 7.15-7.24 (2H, m), 7.38-7.46 (6H, m).
MS: m/z=447.20 [M+H]+.
EXAMPLE 581




First Step

To a tert-butanol (4 mL) solution of compound 5801 (398 mg, 0.760 mmol) were added triethylamine (0.158 mL, 1.14 mmol) and diphenylphosphoric acid azide (0.196 mL, 0.912 mmol) at room temperature, and the mixture was heated to reflux for 20 hours. To the reaction solution was added water (20 mL) at room temperature, and the mixture was extracted with chloroform three times. The extracts were combined, and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol/chloroform=0%→10%) to obtain compound 581A (167 mg, 36.9%) as a gray white solid.
MS: m/z=595.10 [M+H]+.
Second Step
To a methylene chloride (2 mL) solution of compound 581A (167 mg, 0.281 mmol) was added trifluoroacetic acid (2 mL) at room temperature, and the mixture was stirred for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative LCMS. Ethyl acetate, diethyl ether, and methanol were added to the resulting residue to convert it into a powder, to obtain compound 581 (29.4 mg, 25.9%) as a white solid.
1HNMR (DMSO-d6) δ: 0.81 (3H, d, J=6.5 Hz), 0.98 (3H, d, J=6.5 Hz), 4.35 (1H, d, J=12.6 Hz), 4.63 (1H, m), 4.68 (1H, d, J=12.6 Hz), 4.80 (1H, s), 5.28 (1H, s), 6.34 (2H, s), 7.10-7.43 (8H, m), 7.81-7.83 (2H, m).
MS: m/z=404.95 [M+H]+.
EXAMPLE 582




First Step

To an ethanol (4 mL) solution of compound 582A (200 mg, 0.470 mmol) synthesized according to the synthesis method of Example 65 was added paraformaldehyde (14.8 mg, 0.493 mmol) at room temperature, and the mixture was stirred at 140° C. for 45 minutes under microwave irradiation. The reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=90%→100%) to obtain compound 582B (173 mg, 84.0%) as a white solid.
MS: m/z=438.15 [M+H]+.
Second Step
To a methylene chloride (4 mL) solution of compound 582B (173 mg, 0.396 mmol), 4-dimethylaminopyridine (5.6 mg, 0.046 mmol) and triethylamine (0.164 mL, 1.18 mmol) was added 2-fluorobenzenesulfonyl chloride (0.0790 mL, 0.597 mmol) at room temperature, and the mixture was stirred for 3 days. The reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=60%→80%) to obtain compound 582C (199 mg, 84.0%) as a white solid.
MS: m/z=596.15 [M+H]+.
Third Step
To an acetic acid (2 mL) solution of compound 582C (162 mg, 0.272 mmol) was added 48% aqueous hydrogen bromide (2 mL) at room temperature, and the mixture was stirred at 100° C. for 20 minutes under microwave irradiation. The solvent was distilled off under reduced pressure, and diethyl ether and methanol were added to the resulting residue to convert it into a powder, to obtain compound 582 (160 mg, quant) as a yellow solid.
1HNMR (DMSO-d6) δ: 4.34 (1H, d, J=14.7 Hz), 4.59 (1H, d, J=14.7 Hz), 5.50 (1H, d, J=14.3 Hz), 5.81 (1H, d, J=14.3 Hz), 7.15-7.21 (2H, m), 7.35-7.40 (2H, m), 7.45-7.61 (2H, m), 7.78 (1H, m), 7.93 (1H, m), 8.42 (1H, s).
MS: m/z=492.10 [M+H]+.
EXAMPLE 583, Example 584




First Step

Compound 583A (3.0 g, 0.99 mmol) synthesized according to Example 95 was added to toluene (300 ml) and acetic acid (30.0 ml) to dissolve, and TsOH H2O (0.1 g, 0.526 mmol) was added at room temperature. The reaction mixture was stirred for 3 hours under heat-refluxing. After concentration under reduced pressure, the residue was purified by amino silica gel column chromatography (CHCl3/MeOH 50:1) to obtain compound 583B (1.8 g, 72.4%).
MS: m/z=312 [M+H]+.
Second Step
Compound 583B (233 mg, 0.748 mmol) and compound 583C (197 mg, 0.8 mmol) were suspended in THF (7.5 ml), and NaHMDS (1.123 ml, 1.123 mmol, 1M-THF solution) was added at room temperature under nitrogen stream. After stirring at room temperature for 3 hours, water was added, and the mixture was extracted with ethyl acetate (2×30 mL). The ethyl acetate layer was washed with an aqueous saturated sodium chloride solution, and dried with sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3/MeOH 20:1) to obtain compound 583D (90 mg, 23.1%).
MS: m/z=522 [M+H]+.
Third Step
Compound 583D (90 mg, 0.173 mmol) was dissolved in a mixed solvent of MeOH (3 ml) and THF (3.00 ml), and 10% palladium-carbon (90 mg, 0.846 mmol) was added. The mixture was stirred for 24 hours under hydrogen (2 atm) stream, and insolubles were filtered. The residue was purified using HPLC (MeCN—H2O), and diastereomers were resolved.
First fraction (compound 583)
(15 mg, 20.1%)
MS: m/z=432 [M+H]+.
Second fraction (compound 584)
(45 mg, 60.4%)
MS: m/z=432 [M+H]+.
EXAMPLE 585




Compound 585 was synthesized by the same procedure as that of Example 403.
1H-NMR (DMSO-d6) δ: 1.87-2.28 (4H, m), 3.40-3.80 (3H, m), 4.32 (1H, d, J=12.96 Hz), 5.34 (1H, t, J=7.32 Hz), 5.65 (1H, d, J=7.63 Hz), 6.90 (1H, d, J=7.78 Hz), 7.10-7.35 (5H, m).
MS: m/z=312 [M+H]+.
EXAMPLE 586










First Step

Compound 95B (2.29 g, 8.12 mmol) was dissolved in pyridine (10 ml), iso-propyl-D7-amine hydrochloride (1.00 g, 9.75 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (1.10 g, 8.12 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (3.11 g, 16.2 mmol) were added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate, and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography, and eluted with chloroform-methanol (97:3, v/v). To the resulting compound was added diethyl ether, and the precipitated residue was filtered to obtain 1.36 g of a white solid 586B.
Second Step
Compound 586B (1.36 g, 4.64 mmol) obtained in the first step was dissolved in dimethylformamide (20 ml), potassium carbonate (3.20 g, 23.2 mmol) was added, and the mixture was stirred at room temperature for 50 minutes. O-(2,4-dinitrophenyl)hydroxylamine (1.85 g, 9.27 mmol) was added, and the mixture was stirred at room temperature for 18 hours. To the reaction solution was added chloroform, the generated precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by amino column chromatography, and eluted with chloroform-methanol (97:3, v/v) to obtain 835 mg of a colorless solid 586C.
1H-NMR (CDCl3) δ: 5.28 (2H, s), 5.63 (2H, s), 6.32 (1H, d, J=7.7 Hz), 7.10 (1H, brs), 7.42 (6H, m).
Third Step
Compound 586C (581 mg, 1.88 mmol) obtained in the second step and paraformaldehyde-D2 (181 mg, 5.65 mmol) were added to ethanol (12 ml), and the mixture was stirred at 140° C. for 30 minutes under microwave irradiation. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by amino column chromatography, and eluted with chloroform-methanol (97:3, v/v). To the resulting compound was added diethyl, ether, and the precipitated residue was filtered to obtain 140 mg of white solid 586D.
1H-NMR (CDCl3) δ: 4.39 (2H, d, J=8.1 Hz), 5.36 (2H, s), 5.42 (1H, t, J=8.0 Hz), 6.37 (1H, d, J=7.6 Hz), 7.48 (6H, m).
Fourth Step
Compound 586E (972 mg, 5.78 mmol) was dissolved in tetrahydrofuran (10 ml), sodium hydride (60%, 231 mg, 5.78 mmol) and benzyl bromide-D2 (1.00 g, 5.78 mmol) were added at 0° C., and the mixture was stirred at 60° C. for 30 minutes. The reaction solution was added to dilute hydrochloric acid, the mixture was extracted with ethyl acetate, and the organic layer was washed with an aqueous sodium bicarbonate solution. The solvent was distilled off under reduced pressure to obtain 1.48 g of a white solid 586F.
1H-NMR (CDCl3) δ: 3.95 (3H, s), 7.17-7.48 (8H, m), 8.00 (1H, dd, J=7.8, 1.3 Hz).
Fifth Step
Compound 586F (1.50 g, 5.76 mmol) obtained in the fourth step was dissolved in methanol (20 ml) and tetrahydrofuran (20 ml), a 2N aqueous sodium hydroxide solution (14.4 ml, 28.8 mmol) was added, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added dilute hydrochloric acid to make the solution acidic, the mixture was extracted with ethyl acetate, and the organic layer was washed with an aqueous saturated sodium chloride solution, and dried with sodium sulfate. The solvent was distilled off under reduced pressure, to the resulting compound were added n-hexane-ethyl acetate, and the precipitated residue was filtered to obtain 1.17 g of a white solid 586G.
1H-NMR (CDCl3) δ: 7.18-7.48 (8H, m), 8.11 (1H, dd, J=7.9, 1.6 Hz).
Sixth Step
To compound 586G (1.15 g, 4.67 mmol) obtained in the fifth step was added toluene (10 ml), dimethylformamide (0.100 ml, 1.29 mmol) and thionyl chloride (0.410 ml, 5.60 mmol) were added, and the mixture was stirred at 130° C. for 1.5 hours. After cooled to room temperature, the reaction solution was concentrated under reduced pressure. To the resulting compound was added n-hexane, and the precipitated residue was filtered to obtain 1.16 g of a white solid. To aluminum chloride (718 mg, 5.38 mmol) were added dichloromethane (10 ml) and nitromethane (0.5 ml), a dichloromethane solution (5 ml) of 500 mg of the compound obtained above was added at 0° C., and the mixture was stirred at room temperature for 5 hours. To the reaction solution was added an aqueous sodium hydroxide solution, and the mixture was extracted with methylene chloride, and the organic layer was dried with sodium sulfate. The solvent was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography, and eluted with n-hexane-ethyl acetate (4:1, v/v). To the resulting compound was added n-hexane, and the precipitated residue was filtered to obtain 155 mg of a pale yellow solid 586H.
1H-NMR (CDCl3) δ: 7.21-7.39 (6H, m), 7.46 (1H, td, J=7.5, 1.4 Hz), 7.59 (1H, dd, J=7.5, 1.4 Hz), 8.21 (1H, dd, J=8.0, 1.0 Hz).
Seventh Step
Compound 586H (150 mg, 0.657 mmol) obtained in the sixth step was dissolved in tetrahydrofuran (3 ml), lithium aluminum hydride-D4 (13.8 mg, 0.329 mmol) was added at 0° C., and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added dilute hydrochloric acid, the mixture was extracted with ethyl acetate, and dried with sodium sulfate, and the solvent was distilled off under reduced pressure. To the resulting compound were added n-hexane-dichloromethane, and the precipitated residue was filtered to obtain 114 mg of a white solid 5861.
1H-NMR (CDCl3) δ: 7.17 (6H, m), 7.40-7.52 (2H, m).
Eighth Step
Compound 586D (76.0 mg, 0.236 mmol) and 5861 (54.5 mg, 0.235 mmol) were dissolved in acetic acid (3.2 ml), and concentrated sulfuric acid (0.8 ml) was added dropwise under water-cooling. After the mixture was stirred at room temperature for 30 minutes, the mixture was poured into water, and extracted with ethyl acetate. The organic layer was dried with sodium sulfate, the solvent was distilled off under reduced pressure, to the resulting crude product were added ethyl acetate-diethyl ether, and the precipitated residue was filtered to obtain 32 mg of a white solid 586.
1H-NMR (DMSO-d6) δ: 5.57 (1H, d, J=7.3 Hz), 6.82-7.44 (9H, m).
MS: m/z=446 [M+H]+
Using a commercially available heavy hydrogen reagent, and according to Example 586, compounds 587 to 591 were synthesized.
EXAMPLE 587




EXAMPLE 588




1H-NMR (DMSO-d6) δ: 3.87 (1H, d, J=13.4 Hz), 5.58 (1H, d, J=7.8 Hz), 5.60 (1H, d, J=12.6 Hz), 6.81-7.48 (9H, m).
EXAMPLE 589




MS: m/z=441 [M+H]+
EXAMPLE 590




MS: m/z=435 [M+H]+
EXAMPLE 591




MS: m/z=436 [M+H]+
The following EX-1 to EX-29 can be also synthesized like the Examples, and are a preferable embodiment of the present invention.






















Further, the following combinations of substituents can be also synthesized like the above Examples, and are a preferable embodiment of the present invention.
Compounds in which, in the following formula (I) or (II):




combinations of R3 or R3a, as well as R7 or R7a of the following formula (I′) or (II′):





are selected from the following Tables 6 to 10 and Table 11, respectively.

Combinations of (R3, R7) or (R3a, R7a)=

    (R3-1, R7-1), (R3-1, R7-2), (R3-1, R7-3), (R3-1, R7-4), (R3-1, R7-5), (R3-1, R7-6), (R3-1, R7-7), (R3-1, R7-8), (R3-1, R7-9), (R3-1, R7-10), (R3-1, R7-11), (R3-1, R7-12), (R3-1, R7-13), (R3-1, R7-14), (R3-1, R7-15), (R3-1, R7-16), (R3-1, R7-17), (R3-1, R7-18), (R3-1, R7-19), (R3-1, R7-20), (R3-1, R7-21), (R3-1, R7-22), (R3-1, R7-23), (R3-1, R7-24), (R3-1, R7-25), (R3-1, R7-26), (R3-1, R7-27), (R3-1, R7-28), (R3-1, R7-29), (R3-1, R7-30), (R3-1, R7-31), (R3-1, R7-32), (R3-1, R7-33), (R3-1, R7-34), (R3-1, R7-35), (R3-1, R7-36), (R3-1, R7-37), (R3-1, R7-38), (R3-1, R7-39), (R3-1, R7-40), (R3-1, R7-41), (R3-1, R7-42), (R3-1, R7-43), (R3-1, R7-44), (R3-1, R7-45), (R3-1, R7-46), (R3-1, R7-47), (R3-1, R7-48), (R3-1, R7-49), (R3-1, R7-50), (R3-1, R7-51), (R3-1, R7-52), (R3-1, R7-53), (R3-1, R7-54), (R3-1, R7-55), (R3-1, R7-56), (R3-1, R7-57), (R3-1, R7-58), (R3-1, R7-59), (R3-1, R7-60), (R3-1, R7-61), (R3-1, R7-62), (R3-1, R7-63), (R3-1, R7-64), (R3-1, R7-65), (R3-1, R7-66), (R3-1, R7-67), (R3-1, R7-68), (R3-1, R7-69), (R3-1, R7-70), (R3-1, R7-71), (R3-1, R7-72), (R3-1, R7-73), (R3-1, R7-74), (R3-1, R7-75), (R3-1, R7-76), (R3-1, R7-77),
    (R3-2, R7-1), (R3-2, R7-2), (R3-2, R7-3), (R3-2, R7-4), (R3-2, R7-5), (R3-2, R7-6), (R3-2, R7-7), (R3-2, R7-8), (R3-2, R7-9), (R3-2, R7-10), (R3-2, R7-11), (R3-2, R7-12), (R3-2, R7-13), (R3-2, R7-14), (R3-2, R7-15), (R3-2, R7-16), (R3-2, R7-17), (R3-2, R7-18), (R3-2, R7-19), (R3-2, R7-20), (R3-2, R7-21), (R3-2, R7-22), (R3-2, R7-23), (R3-2, R7-24), (R3-2, R7-25), (R3-2, R7-26), (R3-2, R7-27), (R3-2, R7-28), (R3-2, R7-29), (R3-2, R7-30), (R3-2, R7-31), (R3-2, R7-32), (R3-2, R7-33), (R3-2, R7-34), (R3-2, R7-35), (R3-2, R7-36), (R3-2, R7-37), (R3-2, R7-38), (R3-2, R7-39), (R3-2, R7-40), (R3-2, R7-41), (R3-2, R7-42), (R3-2, R7-43), (R3-2, R7-44), (R3-2, R7-45), (R3-2, R7-46), (R3-2, R7-47), (R3-2, R7-48), (R3-2, R7-49), (R3-2, R7-50), (R3-2, R7-51), (R3-2, R7-52), (R3-2, R7-53), (R3-2, R7-54), (R3-2, R7-55), (R3-2, R7-56), (R3-2, R7-57), (R3-2, R7-58), (R3-2, R7-59), (R3-2, R7-60), (R3-2, R7-61), (R3-2, R7-62), (R3-2, R7-63), (R3-2, R7-64), (R3-2, R7-65), (R3-2, R7-66), (R3-2, R7-67), (R3-2, R7-68), (R3-2, R7-69), (R3-2, R7-70), (R3-2, R7-71), (R3-2, R7-72), (R3-2, R7-73), (R3-2, R7-74), (R3-2, R7-75), (R3-2, R7-76), (R3-2, R7-77),
    (R3-3, R7-1), (R3-3, R7-2), (R3-3, R7-3), (R3-3, R7-4), (R3-3, R7-5), (R3-3, R7-6), (R3-3, R7-7), (R3-3, R7-8), (R3-3, R7-9), (R3-3, R7-10), (R3-3, R7-11), (R3-3, R7-12), (R3-3, R7-13), (R3-3, R7-14), (R3-3, R7-15), (R3-3, R7-16), (R3-3, R7-17), (R3-3, R7-18), (R3-3, R7-19), (R3-3, R7-20), (R3-3, R7-21), (R3-3, R7-22), (R3-3, R7-23), (R3-3, R7-24), (R3-3, R7-25), (R3-3, R7-26), (R3-3, R7-27), (R3-3, R7-28), (R3-3, R7-29), (R3-3, R7-30), (R3-3, R7-31), (R3-3, R7-32), (R3-3, R7-33), (R3-3, R7-34), (R3-3, R7-35), (R3-3, R7-36), (R3-3, R7-37), (R3-3, R7-38), (R3-3, R7-39), (R3-3, R7-40), (R3-3, R7-41), (R3-3, R7-42), (R3-3, R7-43), (R3-3, R7-44), (R3-3, R7-45), (R3-3, R7-46), (R3-3, R7-47), (R3-3, R7-48), (R3-3, R7-49), (R3-3, R7-50), (R3-3, R7-51), (R3-3, R7-52), (R3-3, R7-53), (R3-3, R7-54), (R3-3, R7-55), (R3-3, R7-56), (R3-3, R7-57), (R3-3, R7-58), (R3-3, R7-59), (R3-3, R7-60), (R3-3, R7-61), (R3-3, R7-62), (R3-3, R7-63), (R3-3, R7-64), (R3-3, R7-65), (R3-3, R7-66), (R3-3, R7-67), (R3-3, R7-68), (R3-3, R7-69), (R3-3, R7-70), (R3-3, R7-71), (R3-3, R7-72), (R3-3, R7-73), (R3-3, R7-74), (R3-3, R7-75), (R3-3, R7-76), (R3-3, R7-77).












TABLE 6








R3 or R3a









R3-1







 



R3-2







 



R3-3
























TABLE 7








R7 or R7a









R7-1 







 



R7-2 







 



R7-3 







 



R7-4 







 



R7-5 







 



R7-6 







 



R7-7 







 



R7-8 







 



R7-9 







 



R7-10







 



R7-11







 



R7-12







 



R7-13







 



R7-14







 



R7-15







 



R7-16







 



R7-17







 



R7-18
























TABLE 8








R7 or R7a









R7-19







 



R7-20







 



R7-21







 



R7-22







 



R7-23







 



R7-24







 



R7-25







 



R7-26







 



R7-27







 



R7-28







 



R7-29







 



R7-30







 



R7-31







 



R7-32







 



R7-33







 



R7-34







 



R7-35







 



R7-36
























TABLE 9








R7 or R7a









R7-37







 



R7-38







 



R7-39







 



R7-40







 



R7-41







 



R7-42







 



R7-43







 



R7-44







 



R7-45







 



R7-46







 



R7-47







 



R7-48







 



R7-49







 



R7-50







 



R7-51







 



R7-52







 



R7-53







 



R7-54
























TABLE 10








R7 or R7a









R7-55







 



R7-56







 



R7-57







 



R7-58







 



R7-59







 



R7-60







 



R7-61







 



R7-62







 



R7-63







 



R7-64







 



R7-65







 



R7-66







 



R7-67







 



R7-68







 



R7-69







 



R7-70







 



R7-71







 



R7-72
























TABLE 11








R7 or R7a









R7-73







 



R7-74







 



R7-75







 



R7-76







 



R7-77














As Reference Examples, a method for synthesizing intermediates useful for carrying out the present application is shown below.
REFERENCE EXAMPLE 1




First Step

A solution of benzyl alcohol (1.00 g, 9.25 mmol) in THF (3 ml) was added to a suspension of sodium tert-pentoxide (2.55 g, 23.2 mmol) in THF (4 ml) at room temperature under nitrogen atmosphere, and the mixture was stirred at 40° C. for 2 hours. This reaction solution was cooled in an ice bath, and a solution of compound 1a (1.53 g, 10.2 mmol) in THF (3 ml) was added dropwise at 0 to 10° C. After the reaction solution was stirred at room temperature for 2 hours, 2 N hydrochloric acid (15 ml) was added, followed by extraction with ethyl acetate two times. The combined extracts were washed sequentially with water, saturated sodium bicarbonate water, water and saturated sodium chloride water, and then dried with anhydrous sodium sulfate. The solvent was distilled off, and the resulting oil was purified by silica gel column chromatography (n-hexane-ethyl acetate 4:1, v/v) to obtain 1.89 g (yield 92%) of compound 1b as an oil product.
1H-NMR (CDCl3) δ: 3.56 (2H, s), 3.71 (3H, s), 4.14 (2H, s), 4.59 (2H, s), 7.27-7.42 (5H, m).
Second Step
Compound 1b (1.80 g, 8.1 mmol) was dissolved in 1,4-dioxane (18 mL), N,N-dimethylformamide dimethyl acetal (1.45 g, 12.2 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate 1:4, v/v) to obtain 1.77 g (yield 79%) of compound 1c as an oil product.
1H-NMR (CDCl3) δ: 2.90 (3H, br), 3.25 (3H, br), 3.69 (3H, s), 4.45 (2H, s), 4.59 (2H, s), 7.24-7.40 (5H, m), 7.73 (s, 1H).
Third Step
Sodium tert-butoxide (2.55 g, 23.2 mmol), dimethyl oxalate (639 mg, 5.41 mmol) and DMI (3 ml) were added to a three-neck flask under nitrogen atmosphere, and a solution of compound 1c (0.50 g, 1.80 mmol) in DMI (2 ml) was added dropwise thereto at 25 to 30° C. After stirring at room temperature for 7 hours, 2N hydrochloric acid (10 ml) was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was extracted with ethyl acetate two times, and the combined extracts were washed sequentially with water, saturated sodium bicarbonate water, water and saturated sodium chloride water, and then dried with anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate 2:1 to 1:1, v/v) to obtain 488 mg (yield 85%) of compound 1d as a white crystal.
1H-NMR (CDCl3) δ: 3.89 (3H, s), 3.93 (3H, s), 5.34 (2H, s), 7.32-7.40 (3H, m), 7.45-7.49 (2H, m), 8.50 (1H, s).
REFERENCE EXAMPLE 2




First Step

A solution of benzyl alcohol (0.66 g, 6.1 mmol) in DMI (3 ml) was added to a suspension of sodium tert-pentoxide (1.67 g, 15.2 mmol) in DMI (4 ml) at room temperature under nitrogen atmosphere, and the mixture was stirred at 40° C. for 2 hours. This reaction solution was cooled in an ice bath, and a solution of compound 2a (1.10 g, 6.68 mmol) in DMI (3 ml) was added dropwise at 0 to 10° C. The reaction solution was stirred at 0 to 5° C. for 2 hours, and at room temperature for 3 hours, and 2N hydrochloric acid (15 ml) was added, followed by extraction with ethyl acetate two times. The combined extracts were washed sequentially with water, saturated sodium bicarbonate water, water and saturated sodium chloride water, and then dried with anhydrous sodium sulfate. The solvent was distilled off, and the resulting oil product was purified by silica gel column chromatography (n-hexane-ethyl acetate 4:1, v/v) to obtain 1.29 g (yield 90%) of compound 2b as an oil product.
1H-NMR (CDCl3) δ: 1.25 (3H, t, J=7.2 Hz), 3.54 (2H, s), 4.14 (2H, s), 4.17 (2H, q, J=7.2 Hz), 4.59 (2H, s), 7.28-7.40 (5H, m).
Second Step
Compound 2b (9.73 g, 41.2 mmol) was dissolved in toluene (45 ml), N,N-dimethylformamide dimethyl acetal (7.36 g, 61.8 mmol) was added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate two times. The combined extracts were washed sequentially with water, and saturated sodium chloride water, and then dried with anhydrous magnesium sulfate. The solvent was distilled off, and the resulting oil product was purified by silica gel column chromatography (n-hexane-ethyl acetate 1:1 to 3:7, v/v) to obtain 7.90 g (yield 66%) of compound 2c as an oil product.
1H-NMR (CDCl3) δ: 1.25 (3H, t, J=7.2 Hz), 2.95 (3H, br), 3.22 (3H, br), 4.15 (2H, q, J=7.2 Hz), 4.45 (2H, s), 4.59 (2H, s), 7.22-7.40 (5H, m), 7.73 (1H, s).
Third Step
Sodium tert-butoxide (495 mg, 5.15 mmol) and DMI (2 ml) were added to a three-neck flask under nitrogen atmosphere, and dimethyl oxalate (608 mg, 5.15 mmol) and a solution of compound 2c (0.50 g, 1.72 mmol) in DMI (3 ml) was added dropwise at 25 to 30° C. After stirring at room temperature for 4 hours, 2N hydrochloric acid (10 ml) was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was extracted with toluene two times, and the combined extracts were washed sequentially with water, saturated sodium bicarbonate water, water and saturated sodium chloride water, and then dried with anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate 2:1, v/v) to obtain 420 mg (yield 74%) of compound 2d as a white crystal.
1H-NMR (CDCl3) δ: 1.39 (3H, t, J=7.2 Hz), 3.88 (3H, s), 4.39 (2H, q, J=7.2 Hz), 5.34 (2H, s), 7.30-7.41 (3H, m), 7.45-7.50 (2H, m), 8.48 (1H, s).
REFERENCE EXAMPLE 3




First Step

N,N-dimethylformamide dimethyl acetal (4.9 ml, 36.5 mmol) was added dropwise to compound 3a (5.0 g, 30.4 mmol) at 0° C. under cooling. After stirring at 0° C. for 1 hour, 100 ml of ethyl acetate was added to the reaction solution, followed by washing with 0.5N hydrochloric acid (50 ml). The aqueous layer was separated, and extracted with ethyl acetate (50 ml). The organic layers were combined, washed sequentially with saturated sodium bicarbonate water and saturated sodium chloride water, and then dried with anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate 1:1 (v/v)→ethyl acetate) to obtain 4.49 g (yield 67%) of compound 3b as an oil product.
1H-NMR (CDCl3) δ:1.32 (3H, t, J=7.1 Hz), 2.90 (3H, br s), 3.29 (3H, br s), 4.23 (2H, q, J=7.1 Hz), 4.54 (2H, s), 7.81 (1H, s).
Second Step
Lithium hexamethyldisilazide (1.0 M toluene solution, 49 ml, 49.0 mmol) was diluted with tetrahydrofuran (44 ml), a solution of compound 3b (4.49 g, 20.4 mmol) in tetrahydrofuran (10 ml) was added dropwise thereto at −78° C. under cooling, and a solution of ethyl oxalyl chloride (3.35 g, 24.5 mmol) in tetrahydrofuran (10 ml) was added dropwise. After stirring at −78° C. for 2 hours, temperature was raised to 0° C. After 2N hydrochloric acid was added to the reaction solution, and the mixture was stirred for 20 minutes, the solution was extracted with ethyl acetate (200 ml×2), and the organic layer was washed with saturated sodium bicarbonate water and saturated sodium chloride water and then dried with anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate 7:3→5:5→0:10 (v/v)) to obtain 1.77 g (yield 31%) of compound 3c as a white solid.
1H-NMR (CDCl3) δ:1.36-1.46 (6H, m), 4.35-4.52 (8H, m), 8.53 (1H, s).
Third Step
Aminoacetaldehyde dimethyl acetal (0.13 ml, 1.20 mmol) was added to a solution of compound 3c (300 mg, 1.09 mmol) in ethanol (6 ml) at 0° C., and the mixture was stirred at 0° C. for 1 hour and 30 minutes, at room temperature for 18 hours and, then, at 60° C. for 4 hours. After the solvent was distilled off from the reaction solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate 5:5→0:10 (v/v)) to obtain 252 mg (yield 64%) of compound 3d as an oil product.
1H-NMR (CDCl3) δ:1.36-1.47 (6H, m), 3.42 (6H, s), 3.90 (2H, d, J=5.2 Hz), 4.37 (3H, q, J=7.2 Hz), 4.50 (2H, q, J=7.2 Hz), 8.16 (1H, s).
REFERENCE EXAMPLE 4




First Step

N,N-dimethylformamide dimethyl acetal (12.2 ml, 92.2 mmol) was added dropwise to compound 4a (10.0 g, 76.8 mmol) at 0° C. under cooling. After stirring at 0° C. for 1 hour and 30 minutes and, then, at room temperature for 2 hours and 30 minutes, 100 ml of ethyl acetate was added to the reaction solution, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate 5:5→0:10 (v/v)) to obtain 12.45 g (yield 88%) of compound 4b as an oil product.
1H-NMR (CDCl3) δ:1.32 (3H, t, J=7.1 Hz), 2.33 (3H, s), 3.04 (6H, br s), 4.23 (2H, q, J=7.2 Hz), 7.68 (1H, s).
Second Step
Lithium hexamethyldisilazide (1.0M toluene solution, 24 ml, 24.0 mmol) was diluted with tetrahydrofuran (20 ml), a solution of compound 4b (1.85 g, 10.0 mmol) in tetrahydrofuran (5 ml) was added dropwise thereto at −78° C. under cooling, and a solution of ethyl oxalyl chloride (1.34 ml, 12.0 mmol) in tetrahydrofuran (5 ml) was added dropwise. After stirring at −78° C. for 2 hours, 2N-hydrochloric acid was added to the reaction solution, and the mixture was stirred at room temperature for 20 minutes. The solution was extracted with ethyl acetate, and the organic layer was washed sequentially with saturated sodium bicarbonate water and saturated sodium chloride water, and then dried with anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate 75:25→455:5 (v/v)) to obtain 1.03 g (yield 43%) of compound 4c as a brown oil product.
1H-NMR (CDCl3) δ:1.38 (3H, t, J=7.1 Hz), 1.42 (3H, t, J=7.4 Hz), 4.33-4.47 (4H, m), 7.19 (1H, s), 8.54 (1H, s).
Third Step
Aminoacetaldehyde dimethyl acetal (0.34 ml, 3.11 mmol) was added to a solution of compound 4c (680 mg, 2.83 mmol) in ethanol (6.8 ml) at 0° C., and it was allowed to stand at room temperature for 16 hours. After the solvent was distilled off from the reaction solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate 90:10 (v/v)) to obtain 875 mg (yield 94%) of compound 4d as an oil product.
1H-NMR (CDCl3) δ:1.38 (3H, t, J=7.1 Hz), 1.39 (3H, t, J=7.1 Hz), 3.40 (6H, s), 4.33 (2H, d, J=4.7 Hz), 4.37 (4H, q, J=7.1 Hz), 4.49 (1H, t, J=4.7 Hz), 7.06 (1H, s), 8.17 (1H, s).
Fourth Step
N-bromosuccinimide (1.46 g, 8.18 mmol) was added to a solution of compound 4d (2.68 g, 8.18 mmol) in N,N-dimethylformamide (10 ml), and the mixture was stirred at room temperature for 48 hours. After saturated sodium bicarbonate water was added to the reaction solution, the solution was extracted with ethyl acetate, and the organic layer was washed sequentially with water and saturated sodium chloride water, and then dried with anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate 90:10 (v/v)) to obtain 2.83 g (yield 85%) of compound 4e as an oil product.
1H-NMR (CDCl3) δ: 1.41 (3H, t, J=7.1 Hz), 1.48 (3H, t, J=7.1 Hz), 3.42 (6H, s), 3.90 (2H, d, J=5.0 Hz), 4.39 (2H, q, J=7.1 Hz), 4.53 (3H, q, J=14.3 Hz), 4.54 (3H, s), 4.57 (3H, t, J=5.4 Hz), 8.19 (1H, s).
REFERENCE EXAMPLE 5




First Step

Compound 5a (598 mg, 4.09 mmol) and N,N-dimethylformamide dimethyl acetal (488 mg, 4.09 mmol) were dissolved in toluene (1 ml), and the mixture was stirred at room temperature for 11 hours. The solvent was distilled off from the reaction solution under reduced pressure, and the resulting residue (containing compound 5b) was used in Second step without purification.
Second Step
Sodium tert-butoxide (400 mg, 4.16 mmol) was suspended in dimethyl imidazolidinone (5 ml), a solution of the crude product obtained in First step in dimethylimidazolidinone (5 ml) was added thereto, a solution of dimethyl oxalate (983 mg, 8.32 mmol) in THF (10 ml) was added dropwise, and the mixture was stirred at room temperature for 45 minutes. The reaction solution was poured into 2N hydrochloric acid-methanol (20 ml), and the mixture was stirred at 0° C. for 20 minutes. Water was added, the solution was extracted with ethyl acetate, and the organic layer was washed sequentially with water, saturated sodium bicarbonate water, and saturated sodium chloride water, and dried with anhydrous sodium sulfate. After the solvent was distilled off, the resulting residue was purified by silica gel column chromatography to obtain 222 mg (yield: 22% from 5a) of compound 5c.
REFERENCE EXAMPLE 6




First Step

Lithium hexamethyldisilazide (1.0M toluene solution, 12 ml, 12.0 mmol) was diluted with tetrahydrofuran (11 ml), a solution of compound 6a (1.46 g, 5.0 mmol) in tetrahydrofuran (2 ml) was added dropwise thereto at −78° C. under cooling, and a solution of ethyl oxalyl chloride (0.67 ml, 6.0 mmol) in tetrahydrofuran (2 ml) was added dropwise. After stirring at −78° C. for 2 hours, ammonium acetate (500 mg) and acetic acid (10 ml) were added to the reaction solution, and the mixture was stirred at 65° C. for 1 hour and 30 minutes. Water was added to the reaction solution, the solvent was extracted with ethyl acetate, and the organic layer was washed sequentially with water, and saturated sodium bicarbonate water, and dried with anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (N-hexane-ethyl acetate 55:45→45:55 (v/v)) to obtain 505.1 mg of compound 6B as a yellow solid. It was washed with isopropyl ether-hexane (1:2), and dried under reduced pressure to obtain 416.8 mg (yield 24%) of Compound 6b as a yellow crystal.
1H-NMR (CDCl3) δ:1.35 (3H, t, J=7.1 Hz), 1.46 (3H, t, J=7.1 Hz), 4.40 (2H, q, J=7.2 Hz), 4.50 (2H, q, J=7.1 Hz), 5.20 (2H, s), 7.33-7.41 (3H, m), 7.49-7.52 (2H, m), 8.76 (1H, s), 11.61 (1H, br s).
Second Step
Cesium carbonate (73.3 mg, 0.23 mmol) and bromoacetaldehyde dimethyl acetal (38.0 mg, 0.23 mmol) were added to a solution of compound 6b (51.8 mg, 0.15 mmol) in N,N-dimethylformamide (1 ml), and the mixture was stirred at room temperature overnight. Cesium carbonate (73.3 mg, 0.23 mmol) and bromoacetaldehyde dimethyl acetal (38.0 mg, 0.23 mmol) were further added, and the mixture was further stirred at 100° C. for 20 minutes. After water was added to the reaction solution, the solution was extracted with ethyl acetate, and the organic layer was washed sequentially with water and saturated sodium chloride water, and dried with anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate 50:50→30:70 (v/v)) to obtain 35.3 mg (yield 54%) of compound 6c as a colorless oil product.
1H-NMR (CDCl3) δ:1.26 (3H, t, J=7.1 Hz), 1.40 (3H, t, J=7.1 Hz), 3.39 (6H, s), 3.91 (2H, d, J=5.0 Hz), 4.29 (2H, q, J=7.1 Hz), 4.40 (2H, q, J=7.2 Hz), 4.50 (1H, t, J=5.0 Hz), 5.30 (2H, s), 7.31-7.37 (3H, m), 7.43-7.46 (2H, m), 8.12 (1H, s).
REFERENCE EXAMPLE 7




First Step

Aminoacetaldehyde dimethyl acetal (7.80 mmol) was added to a solution of compound 7a (900 mg, 2.60 mmol) in ethanol (5 ml), and the mixture was stirred at room temperature for 22 hours. Ethyl acetate (5 ml) and water (5 ml) were added to the reaction solution, followed by extraction with ethyl acetate (5 ml). After the organic layer was washed with water (10 ml), the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate 2:1) to obtain 0.37 g (yield 33%) of compound 7b as a colorless oil product.
1H-NMR (CDCl3) δ: 7.90 (1H, s), 7.45-7.43 (5H, m), 5.30 (2H, s), 4.51 (1H, t, J=5.1 Hz), 4.40 (2H, q, J=7.1 Hz), 4.30 (2H, q, J=7.1 Hz), 3.91 (2H, d, J=5.1 Hz), 3.46 (6H, s), 1.40 (3H, t, J=7.1 Hz), 1.26 (3H, t, J=7.1 Hz).
The compounds in connection with the present invention are useful for symptoms and/or diseases which are induced by influenza virus. For example, they are useful for treating and/or preventing, or improving symptoms of, cold-like symptoms accompanying fever, algor, headache, muscular pain, general malaise etc., airway inflammation symptoms such as pharyngalgia, nasal secretion, nasal congestion, cough, sputum etc., gastrointestinal symptoms such as abdominal pain, vomitus, diarrhea etc. and, further, complications accompanying secondary infection such as acute encephalopathy and pneumonia.
Since the compounds in connection with the present invention have the effects such as inhibitory activity on high cap structure-dependent endonuclease, and high selectivity due to a virus-specific enzyme, they can be medicaments having reduced side effects. Further, since the compounds in connection with the present invention have advantages that metabolism stability is high, solubility is high, oral absorbability is high, good bioavailability is exhibited, good clearance is exhibited, pulmonary transitivity is high, a half life is long, a non-protein binding rate is high, hERG channel inhibition is low, CYP inhibition is low, CPE (CytoPathic Effect) inhibiting effect is recognized, and/or negativity is exhibited in a phototoxicity test, an Ames test and a gene toxicity test, they can be excellent medicaments.
The compounds in connection with the present invention can be administered orally or parenterally. In the case of oral administration, the present compounds can be also used as a normal preparation, for example, as any dosage form of solid preparations such as tablets, powders, granules, capsules etc.; solutions; oleaginous suspensions; or liquid preparations such as syrups or elixirs etc. In the case of parenteral administration, the compounds in connection with the present invention can be used as aqueous or oleaginous suspension injectables, or nose drops. Upon preparation of them, conventional excipients, binders, lubricants, aqueous solvents, oleaginous solvents, emulsifiers, suspending agents, preservatives, stabilizers etc. can be arbitrarily used. The pharmaceutical composition of the present invention can be produced by combining (for example, mixing) a therapeutically effective amount of the present compound with pharmaceutically acceptable carriers or diluents.
A dose of the compounds in connection with the present invention is different depending on an administration method, an age, a weight and the state of a patient, and a kind of a disease and, usually, in the case of oral administration, about 0.05 mg to 3000 mg, preferably about 0.1 mg to 1000 mg per adult a day may be administered, if necessary, by division. In addition, in the case of parenteral administration, about 0.01 mg to 1000 mg, preferably about 0.05 mg to 500 mg per adult a day is administered.
TEST EXAMPLE 1
Measurement of Cap-Dependant Endonuclease (CEN) Inhibitory Activity
1) Preparation of Substrate
30merRNA (5′-pp-[m2′-O]GAA UAU(-Cy3) GCA UCA CUA GUA AGC UUU GCU CUA-BHQ2-3′:manufactured by Japan Bioservice) in which G at a 5′ end is diphosphate-modified, a hydroxy group at 2′ position is methoxylation-modified, U sixth from a 5′ end is labelled with Cy3, and a 3′ end is labelled with BHQ2 was purchased, and a cap structure was added using ScriptCap system manufactured by EPICENTRE (a product was m7G [5′]-ppp-[5′][m2′-O]GAA UAU(-Cy3) GCA UCA CUA GUA AGC UUU GCU CUA(-BHQ2)-3′). This was separated and purified by denatured polyacrylamide gel electrophoresis, and used as a substrate.
2) Preparation of Enzyme
RNP was prepared from a virus particle using standard method (Reference Document: VIROLOGY (1976) 73, p 327-338 OLGA M. ROCHOVANSKY). Specifically, A/WSN/33 virus (1×103 PFU/mL, 200 μL) was innoculated in a 10 days old embryonated chicken egg. After incubation at 37° C. for 2 days, the allantoic fluid of the chicken egg was recovered. A virus particle was purified by ultracentrifugation using 20% sucrose, solubilized using TritonX-100 and lysolecithin, and an RNP fraction (50-70% glycerol fraction) was collected by ultracentrifugation using a 30-70% glycerol density gradient, and was used as an enzyme solution (containing approximately 1 nM PB1•PB2•PA complex).
3) Enzymatic Reaction
An enzymatic reaction solution (2.5 μL) (composition: 53 mM Tris-hydrochloride (pH 7.8), 1 mM MgCl2, 1.25 mM dithiothreitol, 80 mM NaCl, 12.5% glycerol, enzyme solution 0.15 μL) was dispensed into a 384-well plate made of polypropylene. Then, 0.5 μL of a test substance solution which had been serially diluted with dimethyl sulfoxide (DMSO) was added to the plate. As a positive control (PC) or a negative control (NC), 0.5 μL of DMSO was added to the plate respectively. Each plate was mixed well. Then, 2 μL of a substrate solution (1.4 nM substrate RNA, 0.05% Tween20) was added to initiate a reaction. After room temperature incubation for 60 minutes, 1 μL of the reaction solution was collected and added to 10 μL of a Hi-Di formamide solution (containing GeneScan 120 Liz Size Standard as a sizing marker: manufactured by Applied Biosystem (ABI)) in order to stop the reaction. For NC, the reaction was stopped in advance by adding EDTA (4.5 mM) before initiation of the reaction (all concentrations described above are final concentrations).
3) Measurement of Inhibition Ratio (IC50 Value)
The solution for which the reaction was stopped was heated at 85° C. for 5 minutes, rapidly cooled on ice for 2 minutes, and analyzed with an ABI PRIZM 3730 genetic analyzer. A peak of the cap-dependent endonuclease product was quantitated by analysis software ABI Genemapper, a CEN reaction inhibition ratio (%) of a test compound was obtained by setting fluorescent intensities of PC and NC to be 0% inhibition and 100% inhibition, respectively, an IC50 value was obtained using curve fitting software (XLfit2.0:Model 205 (manufactured IDBS etc.)). The IC50 values of test substances are shown in Table 12-21.
TEST EXAMPLE 2
CYP Inhibition Test
Using commercially available pooled human hepatic microsome, and employing, as markers, 7-ethoxyresorufin O-deethylation (CYP1A2), tolbutamide methyl-hydroxylation (CYP2C9), mephenyloin 4′-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenedine hydroxylation as typical substrate metabolism reactions of human main five CYP enzyme forms (CYP1A2, 2C9, 2C19, 2D6, 3A4), an inhibitory degree of each metabolite production amount by a test compound was assessed.
The reaction conditions were as follows: substrate, 0.5 μmol/L ethoxyresorufin (CYP1A2), 100 μmol/L tolbutamide (CYP2C9), 50 μmol/L S-mephenitoin (CYP2C19), 5 μmol/L dextromethorphan (CYP2D6), 1 μmol/L terfenedine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37° C.; enzyme, pooled human hepatic microsome 0.2 mg protein/mL; test drug concentration, 1, 5, 10, 20 μmol/L (four points).
Each five kinds of substrates, human hepatic microsome, or a test drug in 50 mM Hepes buffer as a reaction solution was added to a 96-well plate at the composition as described above, NADPH, as a cofactor was added to initiate metabolism reactions as markers and, after the incubation at 37° C. for 15 minutes, a methanol/acetonitrile=1/1 (v/v) solution was added to stop the reaction. After the centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant was quantified by a fluorescent multilabel counter and tributamide hydroxide (CYP2CP metabolite), mephenyloin 4′ hydroxide (CYP2C19 metabolite), dextromethorphan (CYP2D6 metabolite), and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC/MS/MS.
Addition of only DMSO being a solvent dissolving a drug to a reaction system was adopted as a control (100%), remaining activity (%) was calculated at each concentration of a test drug added as the solution and IC50 was calculated by reverse presumption by a logistic model using a concentration and an inhibition rate.
TEST EXAMPLE 3
Solubility Test
The solubility of each compound is determined under 1% DMSO addition conditions. A 10 mM solution of the compound is prepared with DMSO, and 6 μL of the compound solution is added to 594 μL of an artificial intestinal juice (water and 118 mL of 0.2 mol/L NaOH reagent are added to 250 mL of 0.2 mol/L potassium dihydrogen phosphate reagent to reach 1000 mL) with pH of 6.8. The mixture is left standing for 16 hours at 25° C., and the mixture is vacuum-filtered. The filtrate is two-fold diluted with methanol/water=1/1, and the compound concentration in the filtrate is measured with HPLC or LC/MS/MS by the absolute calibration method.
TEST EXAMPLE 4
Metabolism Stability Test
Using a commercially available pooled human hepatic microsomes, a test compound was reacted for a constant time, a remaining rate was calculated by comparing a reacted sample and an unreacted sample, thereby, a degree of metabolism in liver was assessed.
A reaction was performed (oxidative reaction) at 37° C. for 0 minute or 30 minutes in the presence of 1 mmol/L NADPH in 0.2 mL of a buffer (50 mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/L magnesium chloride) containing 0.5 mg protein/mL of human liver microsomes. After the reaction, 50 μL of the reaction solution was added to 100 μL of a methanol/acetonitrile=1/1 (v/v), mixed and centrifuged at 3000 rpm for 15 minutes. The test compound in the supernatant was quantified by LC/MS/MS, and a remaining amount of the test compound after the reaction was calculated, letting a compound amount at 0 minute reaction time to be 100%. Hydrolysis reaction was performed in the absence of NADPH and glucuronidation reaction was in the presence of 5 mM UDP-glucuronic acid in place of NADPH, followed by similar operations.
Test Example 5
hERG Test
For the purpose of assessing risk of an electrocardiogram QT interval prolongation, effects on delayed rectifier K+ current (IKr), which plays an important role in the ventricular repolarization process, was studied using HEK293 cells expressing human ether-a-go-go related gene (hERG) channel.
After a cell was retained at a membrane potential of −80 mV by whole cell patch clamp method using an automated patch clamp system (PatchXpress 7000A, Axon Instruments Inc.), IKr induced by depolarization pulse stimulation at +40 mV for 2 seconds and, further, repolarization pulse stimulation at −50 mV for 2 seconds was recorded. After the generated current was stabilized, extracellular solution (NaCl: 135 mmol/L, KCl: 5.4 mmol/L, NaH2PO4: 0.3 mmol/L, CaCl2.2H2O: 1.8 mmol/L, MgCl2. 6H2O: 1 mmol/L, glucose: 10 mmol/L, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol/L, pH=7.4) in which the test compound had been dissolved at an objective concentration was applied to the cell under the room temperature condition for 10 minutes. From the recording IKr, an absolute value of the tail peak current was measured based on the current value at the resting membrane potential using an analysis software (DataXpress ver. 1, Molecular Devices Corporation). Further, the % inhibition relative to the tail peak current before application of the test substance was calculated, and compared with the vehicle-applied group (0.1% dimethyl sulfoxide solution) to assess influence of the test substance on IKr.
Test Example 6
CPE Inhibitory Effect Confirming Assay
<Material>


    2% FCS E-MEM (prepared by adding kanamycin and FCS to MEM (Minimum Essential Medium) (Invitrogen))
    0.5% BSA E-MEM (prepared by adding kanamycin and BSA to MEM (Minimum Essential Medium) (Invitrogen))
    HBSS (Hanks' Balanced Salt Solution)
    MDBK Cell


Cells were adjusted to the appropriate cell number (3×105/mL) with 2% FCS E-MEM.
MDCK Cell
After washing with HBSS two times, cells were adjusted to the appropriate cell number (5×105/mL) with 0.5% BSA E-MEM.
Trypsin Solution
Trypsin from porcine pancreas (SIGMA) was dissolved in PBS(−), and filtrated with a 0.45 μm filter.

    EnVision (Perkin Elmer)
    WST-8 Kit (Kishida Chemical Co., Ltd.)
    10% SDS solution

<Operation Procedure>

Dilution and Dispensation of Test Sample



As a culture medium, 2% FCS E-MEM was used at the use of MDBK cells, and 0.5% BSA E-MEM was used at the use of MDCK cells. Hereinafter, for diluting virus, cells and a test sample, the same culture medium was used.
A test sample was diluted with a culture medium to a appropriate concentration in advance, and then 2 to 5-fold serial dilution on a 96 well plate (50 μL/well) was prepared. Two plate, one for measuring anti-Flu activity and the other for measuring cytotoxity, were prepared. Each assay was performed triplicate for each drug.
At the use of MDCK cells, trypsin was added to the cells to be a final concentration of 3 μg/mL only for measuring anti-Flu activity.
Dilution and Dispensation of Influenza Virus
An influenza virus was diluted with a culture medium to a appropriate concentration in advance, and each 50 μL/well was dispensed on a 96-well plate containing a test substance. Each 50 μL/well of a culture medium was dispensed on a plate containing a test substance for measuring cytotoxity.
Dilution and Dispensation of Cell
Each 100 μL/well of cells which had been adjusted to the appropriate cell number was dispensed on a 96 well plate containing a test substance. This was mixed with a plate mixer, and incubated in a CO2 incubator for 3 days for measuring anti-Flu activity and measuring cytotoxity.
Dispensation of WST 8
The cells in 96-well plate which had been incubated for 3 days was observed visually under a microscope, and appearance of the cells, the presence or absence of a crystal of test substance were checked. The supernatant was removed so that the cells were not absorbed from the plate.
WST-8 Kit was diluted 10-fold with a culture medium, and each 100 μL was dispensed into each well. After mixing with a plate mixer, cells were incubated in a CO2 incubator for 1 to 3 hours.
After incubation, regarding the plate for measuring anti-Flu activity, each 10 μL/well of a 10% SDS solution was dispensed in order to inactivate a virus.
Measurement of Absorbance
After the 96-well plate was mixed, absorbance was measured with EnVision at two wavelengths of 450 nm/620 nm.
<Calculation of Each Measurement Item Value>
The value was calculated using Microsoft Excel or a program having the equivalent calculation and processing ability, based on the following calculation equation. Calculation of effective concentration to achieve 50% CPE inhibition (EC50)

EC50=10^Z 

Z=(50%−High %)/(High %−Low %)×{log (High conc.)−log (Low conc.)}+log(High conc.)

IC50 values of test substances are shown in Table 12-21.









TABLE 12






CEN IC50
CPE EC50


Example No.
(μM)
(μM)

















2
0.048
0.293


14
0.043
0.313


16
0.065
0.632


26
0.108
0.547


37
0.101
0.318


43
0.078
1.410


48
0.087
10.90


56
0.358
3.860


62
0.110
1.680


63
0.170
2.000


94
0.096
1.470


99
0.341
2.000


108
0.037
0.019


128
0.063
0.416


138
0.166
0.100


139
0.189
0.741


143
0.224
0.333


150
0.193
0.553


175
0.132
0.102


178
0.061
0.075


















TABLE 13






CEN IC50
CPE EC50


Example No.
(μM)
(μM)







181
0.049
0.349


182
0.099
0.562


183
0.074
2.370


184
0.055
0.403


185
0.132
1.920


186
0.085
0.159


187
0.085
0.282


190
0.143
2.640


191
0.238
2.820


199
0.236
2.720


204
0.299
2.360


224
0.276
0.119


225
0.283
0.663


228
0.243
0.141


230
0.282
0.525


233
0.228
2.240


238
0.101
0.440


240
0.037
0.048


241
0.197
0.063


242
0.114
0.059


243
0.076
0.020


244
0.249
0.108


246
0.082
0.026


247
0.282
2.260


248
0.103
0.489


249
0.151
1.890


250
0.113
0.476


251
0.058
0.157


252
0.107
0.454


253
0.235
0.280


254
0.135
0.564


255
0.052
0.319


256
0.038
0.400


















TABLE 14






CEN IC50
CPE EC50


Example No.
(μM)
(μM)







257
0.041
0.055


258
0.042
0.028


259
0.066
0.026


260
0.091
0.065


261
0.058
0.047


262
0.032
0.038


263
0.085
0.075


264
0.064
0.128


265
0.172
0.036


266
0.043
0.085


267
0.029
0.063


268
0.018
0.074


269
0.073
0.417


270
0.058
0.129


271
0.073
0.102


272
0.082
0.030


273
0.016
0.084


274
0.038
0.016


274
0.157
0.056


276
0.053
0.089


277
0.039
0.071


278
0.205
0.074


279
0.056
0.119


280
0.068
0.145


281
0.026
0.018


282
0.036
0.029


283
0.028
0.021


284
0.042
0.019


285
0.044
0.017


286
0.161
0.121


287
0.154
0.268


288
0.299
0.085


289
0.031
0.419


















TABLE 15






CEN IC50
CPE EC50


Example No.
(μM)
(μM)







290
0.067
0.492


292
0.155
2.230


293
0.290
0.437


294
0.035
0.018


295
0.052
0.334


296
0.130
0.397


297
0.045
0.033


298
0.044
0.012


299
0.050
0.015


300
0.058
0.021


301
0.062
0.017


302
0.035
0.014


304
0.018
0.015


305
0.059
0.103


306
0.076
0.021


307
0.052
0.095


308
0.072
0.019


309
0.040
0.013


310
0.108
0.522


311
0.040
0.026


312
0.019
0.029


313
0.189
0.050


314
0.149
0.026


315
0.057
0.115


316
0.069
0.083


317
0.048
0.017


318
0.130
0.015


320
0.045
0.011


321
0.019
0.019


322
0.113
0.028


323
0.077
0.019


324
0.107
0.035


325
0.032
0.025


















TABLE 16






CEN IC50
CPE EC50


Example No.
(μM)
(μM)







326
0.043
0.005


327
0.092
0.024


328
0.029
0.168


329
0.058
0.023


330
0.026
0.019


331
0.045
0.335


332
0.048
0.020


333
0.021
0.425


334
0.075
0.032


335
0.019
0.016


336
0.051
0.070


337
0.058
0.028


338
0.074
0.085


339
0.183
0.040


340
0.101
0.027


341
0.016
0.027


342
0.099
0.026


343
0.122
0.018


344
0.050
0.009


345
0.097
0.008


346
0.028
0.018


347
0.014
0.017


348
0.054
0.080


349
0.053
0.075


351
0.091
0.019


352
0.067
0.020


354
0.025
0.083


355
0.040
0.075


356
0.066
0.020


357
0.138
0.386


358
0.051
0.069


359
0.037
0.080


360
0.042
0.087


















TABLE 17






CEN IC50
CPE EC50


Example No.
(μM)
(μM)







361
0.039
0.145


362
0.084
0.067


363
0.058
0.067


364
0.112
0.515


365
0.041
2.250


366
0.090
0.838


368
0.140
0.470


369
0.294
0.434


370
0.113
0.061


371
0.161
0.074


372
0.164
0.146


373
0.065
0.050


374
0.137
0.154


375
0.037
0.073


376
0.063
0.092


377
0.024
0.022


378
0.047
0.022


380
0.123
0.018


381
0.200
0.034


382
0.032
0.094


384
0.153
0.293


386
0.075
0.096


387
0.300
1.150


388
0.133
0.063


390
0.095
0.029


391
0.264
0.071


392
0.153
0.025


394
0.087
0.064


395
0.043
0.089


396
0.056
0.060


397
0.055
0.077


398
0.034
0.118


399
0.105
0.061


















TABLE 18






CEN IC50
CPE EC50


Example No.
(μM)
(μM)







400
0.067
0.079


401
0.089
0.133


402
0.085
0.081


403
0.090
0.070


404
0.084
0.063


405
0.074
0.051


406
0.119
0.022


407
0.035
0.017


408
0.135
0.061


409
0.093
0.029


410
0.265
0.014


411
0.046
0.014


412
0.292
0.203


413
0.050
0.005


414
1.890
0.131


415
0.285
0.022


416
0.112
0.019


417
0.030
0.003


418
0.121
0.072


419
0.124
0.019


420
0.058
0.021


423
0.280
0.019


425
0.183
0.047


429
0.016
0.004


430
0.168
0.029


431
0.097
0.011


432
0.155
0.062


433
0.014
0.017


441
0.044
0.005


443
0.166
0.004


444
0.066
0.003


445
0.013
0.004


446
0.007
0.011


















TABLE 19






CEN IC50
CPE EC50


Example No.
(μM)
(μM)







447
0.096
0.018


448
0.039
0.008


449
0.062
0.021


450
0.023
0.014


452
0.177
0.016


453
0.186
0.049


454
0.012
0.004


455
0.025
0.071


456
0.032
0.004


457
0.242
0.014


458
0.048
0.014


459
0.287
0.048


460
0.085
0.009


461
0.255
0.074


462
0.069
0.011


463
0.012
0.005


464
0.024
0.014


469
0.016
0.004


470
0.008
0.003


475
0.164
0.441


476
0.031
0.014


478
0.088
0.129


479
0.117
0.064


480
0.151
0.084


481
0.114
0.086


482
0.103
0.031


483
0.101
0.027


485
0.221
0.424


486
0.140
0.072


487
0.091
0.026


488
0.151
0.027


489
0.133
0.014


490
0.212
0.468


















TABLE 20






CEN IC50
CPE EC50


Example No.
(μM)
(μM)







491
0.069
0.099


492
0.121
0.160


493
0.112
0.101


495
0.277
0.310


496
0.170
0.177


497
0.215
0.511


498
0.161
0.351


502
0.042
0.142


506
0.247
1.620


507
0.063
0.197


508
0.036
0.056


509
0.015
0.014


511
0.175
0.015


514
0.049
0.018


515
0.197
0.019


516
0.039
0.017


518
0.049
0.024


520
0.212
0.017


521
0.191
0.015


522
0.039
0.014


523
0.035
0.014


524
0.057
0.026


525
0.141
0.090


526
0.044
0.019


527
0.127
0.088


532
0.098
0.075


533
0.065
0.391


534
0.165
1.200


536
0.071
0.027


537
0.152
0.022


538
0.196
0.030


544
0.168
0.051


546
0.202
0.124


















TABLE 21






CEN IC50
CPE EC50


Example No.
(μM)
(μM)







547
0.032
0.027


548
0.086
0.038


549
0.076
2.100


550
0.042
0.042


551
0.041
0.107


552
0.230
0.085


553
0.028
0.030


554
0.065
0.465


555
0.023
0.012


556
0.023
0.412


557
0.281
2.470


558
0.114
0.541


560
0.027
0.173


561
0.073
0.008


562
0.022
0.062


563
0.049
0.464


564
0.088
0.136


565
0.154
0.726


568
0.264
2.810


569
0.138
1.010


570
0.081
2.050


571
0.065
0.320


573
0.055
0.158


574
0.165
0.442


575
0.058
0.087


576
0.063
0.027


577
0.233
0.337


581
0.083
0.480









Test Example 7
Influenza Virus-Infected Mouse Lethality Inhibitory Test
<Mouse>
BALB/cAnNCrlCrlj (female, 5-week-old; CHARLES RIVER LABORATORIES JAPAN, INC.) was purchased, and 6- to 7-week-old mice were used in the test.
<Preparation of Virus Solution>
A/Victoria/3/75 or B/Maryland/1/59(ATCC) was passaged in mouse lung to make a mouse-acclimatized virus. A freezing-stored mouse-acclimatized virus solution was rapidly thawed, and diluted with DPBS to an infectivity titer to be used (in the case of A/Victoria/3/75: 750 TCID50/mouse, in the case of B/Maryland/1/59: 100 TCID50/mouse).
<Infection>
Under anesthesia with ketamine*xylazine, 100 ul of the prepared virus solution was nasally inoculated to directly infect mouse lung.
<Preparation of Test Sample>
A test sample was dissolved in a 5% DMAA/20% HP-β-CD aqueous solution to a suitable concentration.
<Administration of Test Sample to Infected Mouse>
A suitably diluted test sample was intravenously administered at 200 ul to a mouse immediately after virus infection, by a single dose.
<Drug Efficacy Assessment>
The mouse was reared for 14 days after virus infection, and a necessary dose per day for 50% lethality inhibition, ED50 (mg/kg/day), a lethality inhibition rate at a maximum dose (% survival), or days during which the mouse survives 50% as compared with a control at a maximum dose (50% life extension days) was calculated.
<Euthanasia>
The mouse after completion of the test was euthanized by carbon dioxide or halothane excessive administration.
The present compound exhibits the effect of inhibiting lethality of an influenza virus-infected mouse in the above test. Therefore, the present compound is effective in treating and/or preventing an influenza infectious disease.
Formulation Example 1
A granule containing the following ingredients is manufactured.

















Ingredient
A compound shown by formula (I)
 10 mg




lactose
700 mg




cornstarch
274 mg




HPC-L
 16 mg





1000 mg 










A compound shown by formula (I) and lactose are passed through a 60 mesh sieve. Corn starch is passed through a 120 mesh sieve. These are mixed with V-type blendor. To the mixture, aqueous HPC-L (low viscosity of hydroxypropylcellulose) is added, then the mixture is kneaded together, granulated (extrusive granulation pore diameter 0.5 ̃1 mm), and dried. The obtained dried granule is passed through vibrating sieve (12/60 mesh) to obtain a granule.
Formulation Example 2
A granule for encapsulation containing the following ingredients is manufactured.

















Ingredient
A compound shown by formula (I)
15 mg




lactose
90 mg




cornstarch
42 mg




HPC-L
 3 mg





150 mg 










A compound shown by formula (I) and lactose are passed through a 60 mesh sieve. Corn starch is passed through a 120 mesh sieve. These are mixed and aqueous HPC-L (low viscosity of hydroxypropylcellulose) is added thereto, then the mixture is kneaded together, granulated, and dried. The obtained dried granule is trimmed and 150 mg thereof is filled into a No. 4 hard gelatin capsule.
Formulation Example 3
A tablet containing the following ingredients is manufactured.

















Ingredient
A compound shown by formula (I)
10 mg




lactose
90 mg




microcrystal cellulose
30 mg




CMC-Na
15 mg




Magnesium stearate
 5 mg





150 mg 










A compound shown by formula (I), lactose, and microcrystal cellulose, CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60 mesh sieve and mixed. Magnesium stearate is added to the mixed powder to obtain a mixture for tablet. The mixture is tabletted directly to obtain a 150 mg tablet.
Formulation Example 4
An injectable solution is manufactured by mixing the following ingredients under warming, followed by sterilization.

















Ingredient
A compound shown by formula (I)
 3 mg




non-ion surfactant
15 mg 




Water for injection
1 ml










INDUSTRIAL APPLICABILITY
The compound of the present invention has cap-dependent endonuclease (CEN) inhibitory activity. The compound of the present invention can be a useful agent for treatment and/or prevention of symptom and/or disease induced by infection with influenza virus.

## Claims

1. A method for treating influenza infectious disease, the method comprising administering a compound represented by formula (I), a pharmaceutically acceptable salt, or a solvate thereof, to a subject in need of said treating:



wherein:
R1 is chosen from hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, lower alkyloxy optionally substituted by substituent group A, lower alkenyloxy optionally substituted by substituent group A, lower alkylcarbonyl optionally substituted by substituent group A, lower alkyloxycarbonyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, carbocyclecarbonyl optionally substituted by substituent group A, carbocycleoxy optionally substituted by substituent group A, carbocycleoxycarbonyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A, heterocyclecarbonyl optionally substituted by substituent group A, heterocycleoxy optionally substituted by substituent group A, heterocycleoxycarbonyl optionally substituted by substituent group A,

—Z—N(Rx1)(Rx2),
—Z—N(Rx3)—SO2—(Rx4),
—Z—C(═O)—N(Rx5)—SO2—(Rx6),
—Z—N(Rx7)—C(═O)—Rx8,
—Z—C(═O)—N(Rx9)(Rx10),
—Z—S—Rx11,
—Z—SO2—Rx12,
—Z—S(═O)—Rx13,
—Z—N(Rx14)—C(═O)—O—Rx15,
—Z—N(Rx16)—C(═O)—N(Rx17)(RX18),
—Z—C(═O)—N(Rx19)—C(═O)—N(Rx20)(Rx21), and
—Z—N(Rx22)—C(═O)—C(═O)—Rx23,
wherein:
Rx1, Rx2, Rx3, Rx5, Rx7, Rx8, Rx9, Rx10, Rx11, Rx14, Rx15, Rx16, Rx17, Rx18, Rx19, Rx20, Rx21, Rx22, and Rx23 are each independently selected from a substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A,
Rx4, Rx6, Rx12, and Rx13 are each independently selected from a substituent group consisting of, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A,
Rx1 and Rx2, Rx9 and Rx10, Rx17 and Rx18, and Rx20 and Rx21 each may be taken together with an adjacent atom to form heterocycle, and
Z is a bond or straight or branched lower alkylene;

R2 is chosen from hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, lower alkyloxy optionally substituted by substituent group A, lower alkenyloxy optionally substituted by substituent group A, lower alkylcarbonyl optionally substituted by substituent group A, lower alkyloxycarbonyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, carbocyclecarbonyl optionally substituted by substituent group A, carbocycleoxy optionally substituted by substituent group A, carbocycleoxycarbonyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A, heterocyclecarbonyl optionally substituted by substituent group A, heterocycleoxy optionally substituted by substituent group A, heterocycleoxycarbonyl optionally substituted by substituent group A,

—Z—N(Ry1)—SO2—Ry2,
—Z—N(Ry3)—C(═O)—Ry4,
—Z—N(Ry5)—C(═O)—O—Ry6,
—Z—C(═O)—N(Ry7)(Ry8),
—Z—N(Ry9)(Ry10), and
—Z—SO2—Ry11,
wherein:
RY1, RY3, RY4, RY5, RY6, RY7, RY8, RY9, and RY10 are each independently selected from a substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A,
RY2 and RY11 are each independently selected from a substituent group consisting of lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A,
RY7 and RY8, and RY9 and RY10 may be taken together with an adjacent atom to form heterocycle, and
Z is a bond or straight or branched lower alkylene;

R3 is chosen from_hydrogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, lower alkyloxy optionally substituted by substituent group A, lower alkenyloxy optionally substituted by substituent group A, lower alkylcarbonyl optionally substituted by substituent group A, lower alkyloxycarbonyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, carbocycleoxy lower alkyl optionally substituted by substituent group A, carbocyclecarbonyl optionally substituted by substituent group A, carbocycleoxy optionally substituted by substituent group A, carbocycleoxycarbonyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A, heterocycleoxy lower alkyl optionally substituted by substituent group A, heterocyclecarbonyl optionally substituted by substituent group A, heterocycleoxy optionally substituted by substituent group A, heterocycleoxycarbonyl optionally substituted by substituent group A,
—Z—N(Rz1)—SO2—Rz2,
—Z—N(Rz3)—C(═O)—Rz4,
—Z—N(Rz5)—C(═O)—O—Rz6,
—Z—C(═O)—N(Rz7)(Rz8),
—Z—N(Rz9)(Rz10),
—Z—SO2—Rz11, and
—Z—N(Rz12)—O—C(═O)—Rz13 
wherein:
Rz1, Rz3, Rz4, Rz5, Rz6, Rz7, Rz8, Rz9, Rz10, Rz12, and Rz13 are each independently selected from a substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A,
Rz2 and Rz11 are each independently selected from a substituent group consisting of lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A,
Rz7 and Rz8, and Rz9 and Rz10 each may be taken together with an adjacent atom to form heterocycle, and
Z is a bond or straight or branched lower alkylene, and;

wherein:
a) either A1 or A2 is CR5R6, and the other is NR7 
wherein:
R5, R6, R7, R8, R9, R10, and R11 are each independently selected from a substituent group consisting of hydrogen, carboxy, cyano, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, lower alkyl carbonyl optionally substituted by substituent group A, lower alkyl oxycarbonyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, carbocycleoxy lower alkyl optionally substituted by substituent group A, carbocyclecarbonyl optionally substituted by substituent group A, carbocycleoxycarbonyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A, heterocycleoxy lower alkyl optionally substituted by substituent group A, heterocyclecarbonyl optionally substituted by substituent group A, heterocycleoxycarbonyl optionally substituted by substituent group A,

—Z—S—Rv1,
—Z—S(═O)—Rv2,
—Z—SO2—Rv3,
—C(═O)—C(═O)—Rv4,
—C(═O)—N(Rv5)(Rv6),
—Z—N(Rv7)—C(═O)—O—Rv8, and
—Z—N(Rv9)—C(═O)—Rv10 
wherein:
Rv1, Rv4, Rv5, Rv6, Rv7, Rv8, Rv9, and Rv10 are each independently selected from a substituent group consisting of hydrogen, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A,
Rv2 and Rv3 are each independently selected from a substituent group consisting of lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A,
Rv5 and Rv6 may be taken together with an adjacent atom to form heterocycle, and
Z is a bond or straight or branched lower alkylene, and
R5 and R6 may be taken together with an adjacent atom to form carbocycle;

wherein:
1) when A1 is CR5R6 and A2 is NR7,
R3 and R7 may be taken together with an adjacent atom to form heterocycle optionally substituted by substituent group B or may form a condensed ring,
2) when A1 is NR7 and A2 is CR5R6,
R3 and R6 may be taken together with an adjacent atom to form heterocycle optionally substituted by substituent group B or may form condensed ring,
with a proviso that:
c) R5, R6, and R7 are not all hydrogens and
d) R8, R9, R10, and R11 are not all hydrogens; and
wherein
Substituent group A is chosen from halogen, cyano, hydroxy, carboxy, formyl, amino, oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy, lower alkylthio, hydroxy lower alkyl, carbocyclic group, heterocyclic group, heterocyclic group substituted by oxo, carbocycle lower alkyloxy, carbocycleoxy lower alkyl, carbocycle lower alkyloxy lower alkyl, heterocycle lower alkyloxy, heterocycleoxy lower alkyl, heterocycle lower alkyloxy lower alkyl, halogeno lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, lower alkylcarbonyloxy, lower alkyloxycarbonyl, lower alkylamine, lower alkylcarbonylamino, halogeno lower alkyl carbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, lower alkylsulfinyl, and lower alkylsulfonylamino; and
Substituent group B is chosen from halogen, cyano, hydroxy, carboxy, formyl, amino, oxo, nitro, lower alkyl, halogeno lower alkyl, lower alkyloxy, carbocycle lower alkyloxy, heterocycle lower alkyloxy, halogeno lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, lower alkyloxycarbonyl, lower alkylamine, lower alkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, lower alkylsulfonylamino, carbocyclic group optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, and heterocycle lower alkyl optionally substituted by substituent group A.

2. The method according to claim 1, wherein
R1 is chosen from hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, lower alkyloxy optionally substituted by substituent group A, lower alkenyloxy optionally substituted by substituent group A, lower alkylcarbonyl optionally substituted by substituent group A, lower alkyloxycarbonyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, carbocyclecarbonyl optionally substituted by substituent group A, carbocycleoxy optionally substituted by substituent group A, carbocycleoxycarbonyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A, heterocyclecarbonyl optionally substituted by substituent group A, heterocycleoxy optionally substituted by substituent group A, heterocycleoxycarbonyl optionally substituted by substituent group A,
—Z—N(Rx1)(Rx2),
—Z—N(Rx3)—SO2—(Rx4),
—Z—C(═O)—N(Rx5)—SO2—(Rx6),
—Z—N(Rx7)—C(═O)—Rx8,
—Z—C(═O)—N(Rx9)(Rx10),
—Z—S—Rx11,
—Z—SO2—Rx12,
—Z—S(═O)—Rx13,
—Z—N(Rx14)—C(═O)—O—Rx15,
—Z—N(Rx16)—C(═O)—N(Rx17)(RX18), and
—Z—N(Rx22)—C(═O)—C(═O)—Rx23 
(Substituent group A, Rx1, Rx2, Rx3, Rx4, Rx5, Rx6, Rx7, Rx8, Rx11, Rx12, Rx13, Rx14, Rx15, Rx16, Rx17, Rx18, Rx22, Rx23, and
z are same meaning as those of claim 1).

3. The method according to claim 1, wherein
R1 is chosen from hydrogen, halogen, hydroxy, carboxy, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkyloxy optionally substituted by substituent group A, lower alkylcarbonyl optionally substituted by substituent group A, lower alkyloxycarbonyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A,
—Z—N(Rx1)(Rx2),
—Z—N(Rx7)—C(═O)—Rx8, and
—Z—N(Rx14)—C{═O)—O—Rx15 
(Substituent group A, Rx1, Rx2, Rx7, Rx8, Rx14, Rx15, and Z are same meaning as those of claim 1).

4. The method according to claim 1, wherein
R1 is chosen from hydrogen, halogen, hydroxy, carboxy, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkyloxy optionally substituted by substituent group A, lower alkyl carbonyl optionally substituted by substituent group A, lower alkyloxycarbonyl optionally substituted by substituent group A, heterocyclic group optionally substituted by substituent group A, and
—Z—N(Rx1)(Rx2)
(Substituent group A, Rx1, Rx2, and Z are same meaning as those of claim 1).

5. The method according to claim 1, wherein R1 is hydrogen or carboxy.

6. The method according to claim 1, wherein
R2 is chosen from hydrogen, lower alkyl optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A, and
—Z—N(RY9)(RY10)
(Substituent group A, RY9, RY10, and z are same meaning as those of claim 1).

7. The method according to claim 1, wherein R2 is chosen from hydrogen and lower alkyl optionally substituted by substituent group A (Substituent group A is same meaning as that of claim 1).

8. The method according to claim 1, wherein
R3 is chosen from hydrogen, lower alkyl optionally substituted by substituent group A, lower alkenyl optionally substituted by substituent group A, lower alkynyl optionally substituted by substituent group A, carbocyclic group optionally substituted by substituent group A, carbocycle lower alkyl optionally substituted by substituent group A, carbocycleoxy lower alkyl optionally substituted by substituent group A, heterocycle lower alkyl optionally substituted by substituent group A,
—Z—N(Rz1)—SO2—Rz2,
—Z—N(Rz3)—C(═O)—Rz4,
—Z—N(Rz5)—C(═O)—O—Rz6,
—Z—C(═O)—N(Rz7)(Rz8), and
—Z—N(Rz9)(Rz10)
(Substituent group A, Rz1, Rz2, Rz3, Rz4, Rz5, Rz6, Rz7, Rz8, Rz9, Rz10, and Z are same meaning as those of claim 1).