# Patent

## Title
Compound having heterocyclic ring

## Abstract

The invention provides a novel oxazolidinone derivative represented by the formula (I):




wherein

    
    
        Ring A is optionally substituted or fused and represents
    
    
    (A-1) at least 7-membered monocyclic hetero ring containing at least three N atoms; (A-2) at least 6-membered monocyclic hetero ring containing at least two N atoms and at least one O atom; or (A-3) at least 7-membered monocyclic hetero ring containing at least two N atoms and at least one S atom;
    
        X1 is a single bond, —O—, —S—, —NR2—, —CO—, —CS—, —CONR3—, —NR4CO—, —SO2NR5—, and —NR6SO2— (wherein R2-R6 are independently hydrogen or lower alkyl), or lower alkylene or lower alkenylene in which one of the preceding groups may intervene;
        Ring B is optionally substituted carbocycle or optionally substituted heterocycle;
        R1 is hydrogen, or an organic residue which is able to bind to the 5-position of oxazolidinone ring in oxazolidinone antimicrobial agent,

and an antibacterial agent containing the same.

## Background
FIELD OF INVENTION
The invention relates to a novel compound having a heterocyclic ring, preferably triazepane derivatives and oxadiazepane derivatives having 7-membered heterocycle. The invention also relates to oxazolidinone derivatives having such 7-membered heterocycle, a pharmaceutical composition (e.g., antimicrobial) comprising the same, and synthetic intermediates thereof.
BACKGROUND ART
Various oxazolidinone derivatives having antimicrobial activity were known in the art, as disclosed, for example, in U.S. Pat. No. 6,255,304 (Patent Document 1), U.S. Pat. No. 6,218,413 (Patent Document 2), U.S. Pat. No. 6,362,189 (Patent Document 3), U.S. Pat. No. 6,342,513 (Patent Document 4), U.S. Pat. No. 6,537,986 (Patent Document 5), WO2000/032599 (Patent Document 6), WO99/24428 (Patent Document 7), WO97/10223 (Patent Document 8), WO97/09328 (Patent Document 9), U.S. Pat. No. 5,523,403 (Patent Document 10), WO95/07271 (Patent Document 11), WO2004/014392 (Patent Document 12), U.S. Pat. No. 6,956,040 (Patent Document 13), U.S. Pat. No. 6,734,307 (Patent Document 14), WO2002/006278 (Patent Document 15), WO2003/008389 (Patent Document 16), WO2003/007870 (Patent Document 17), WO2005/058888 (Patent Document 18), WO2004/096221 (Patent Document 19), EP Patent No. Publication EP697412A (Patent Document 20), WO2000/027830 (Patent Document 21), Japanese Patent Publication 11-322729 (Patent Document 22), Japanese Patent Publication 9-221476 (Patent Document 23), WO95/34540 (Patent Document 24), WO002560 (Patent Document 25), WO99/64417 (Patent Document 26), EP Patent No. 657440B (Patent Document 27), WO2005/019213 (Patent Document 28), Japanese Patent Publication 2005-524660 (Patent Document 29), U.S. Pat. No. 6,239,152 (Patent Document 30), U.S. Application Publication 2005/4174A1 (Patent Document 31), Japanese Patent Publication 2003-513885 (Patent Document 32), WO99/37630 (Patent Document 33), Japanese Patent Publication 2003-519141 (Patent Document 34), Japanese Patent Publication 2000-204084 (Patent Document 35), Japanese Patent Publication 11-322729 (Patent Document 36), Japanese Patent Publication 11-158164 (Patent Document 37), WO2004/101552 (Patent Document 38), WO2004/026848 (Patent Document 39), WO2003/11859 (Patent Document 40), WO2004/002967 (Patent Document 41).
Particularly, (S)—N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (“linezolid”), as disclosed in WO95/07271 (Patent Document 11), has a potent antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) and it has been approved and marketed as a VRE anti-infectious drug.
Triazacycloheptane derivative was also known (Patent Document 42, Patent Document 43, Patent Document 44, Non-patent Document 1) but its antimicrobial activity was not disclosed.
Additionally, various quinolone or newquinolone antimicrobial agents were known as an antimicrobial drug. However, such a compound attached via its side chain with a triazacycloheptane derivative has not been reported.

    [Patent Document 1] U.S. Pat. No. 6,255,304
    [Patent Document 2] U.S. Pat. No. 6,218,413
    [Patent Document 3] U.S. Pat. No. 6,362,189
    [Patent Document 4] U.S. Pat. No. 6,342,513
    [Patent Document 5] U.S. Pat. No. 6,537,986
    [Patent Document 6] WO2000/032599
    [Patent Document 7] WO99/24428
    [Patent Document 8] WO97/10223
    [Patent Document 9] WO97/09328
    [Patent Document 10] U.S. Pat. No. 5,523,403
    [Patent Document 11] WO95/07271
    [Patent Document 12] WO2004/014392
    [Patent Document 13] U.S. Pat. No. 6,956,040
    [Patent Document 14] U.S. Pat. No. 6,734,307
    [Patent Document 15] WO2002/006278
    [Patent Document 16] WO2003/008389
    [Patent Document 17] WO2003/007870
    [Patent Document 18] WO2005/058888
    [Patent Document 19] WO2004/096221
    [Patent Document 20] EP Patent No. Publication EP697412A
    [Patent Document 21] WO2000/027830
    [Patent Document 22] Japanese Patent Publication 11-322729
    [Patent Document 23] Japanese Patent Publication 9-221476
    [Patent Document 24] WO95/34540
    [Patent Document 25] WO002560
    [Patent Document 26] WO99/64417
    [Patent Document 27] EP Patent No. 657440B
    [Patent Document 28] WO2005/019213
    [Patent Document 29] Japanese Patent Publication 2005-524660
    [Patent Document 30] U.S. Pat. No. 6,239,152
    [Patent Document 31] US Application Publication 2005/4174A1
    [Patent Document 32] Japanese Patent Publication 2003-513885
    [Patent Document 33] WO99/37630
    [Patent Document 34] Japanese Patent Publication 2003-519141
    [Patent Document 35] Japanese Patent Publication 2000-204084
    [Patent Document 36] Japanese Patent Publication 11-322729
    [Patent Document 37] Japanese Patent Publication 11-158164
    [Patent Document 38] WO2004/101552
    [Patent Document 39] WO2004/026848
    [Patent Document 40] WO2003/11859
    [Patent Document 41] WO2004/002967
    [Patent Document 42] UK Patent No. 1543081
    [Patent Document 43] EP Patent No. 358749
    [Patent Document 44] U.S. Pat. No. 4,801,706

[Non-patent Document 1] Dissertationes Pharmaceuticae et Pharmacologicae (1972), 24 (4), 385-390



DISCLOSURE OF THE INVENTION
Problems to be Resolved by the Invention
There is still need for developments in antimicrobial agent that has strong antimicrobial activity against wide range of microorganisms. Additionally, there is need for a novel antimicrobial agent which is effective against resistant strains to currently used antimicrobials. The invention provides a novel oxazolidinone derivative and pharmaceutically acceptable salts thereof useful as an antimicrobial agent, and an antimicrobial drug comprising the same as an active ingredient. More preferably, the invention provides a compound having good solubility and pharmacokinetics, etc. Still more preferably, the invention provides a compound with reduced side effect, compared with conventional antimicrobial agents.
The invention also provides a novel quinolone antimicrobial agent. The invention further provides a novel compound useful as a medicament. Also, the invention provides synthetic intermediates of such compound.
Means of Solving the Problems
The inventors have discovered novel oxazolidinone derivatives having antimicrobial activity. Also, the inventor has discovered novel compounds having a heterocycle such as triazacycloheptane derivative, oxadiazepane derivative and the like, which have antimicrobial activity, and intermediates thereof. The invention has been accomplished on the basis of the above discoveries.
(1) A compound of the formula:




or a pharmaceutically acceptable salt or solvate thereof

    wherein
    Y1 is NP2 or O;
    P1 and P2 are independently hydrogen, a substituent selected from Substituent Group S1 or an amino protecting group, or P1 and P2 may be taken together with N atom to which they are attached to form optionally substituted heterocycle;
    Substituent Group S1 consists of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted formyl, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted lower alkyloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted carbamoyl, lower alkylthio, cycloalkylthio, arylthio, optionally substituted lower alkylsulfonyl, optionally substituted phenylsulfonyl, optionally substituted aromatic heterocycle(lower)alkyl, optionally substituted aryl, and optionally substituted heterocyclic group;
    Ring B is optionally substituted and optionally condensed benzene ring or optionally substituted heterocycle;
    with the proviso that the compound is not the following compounds:






wherein Ph is phenyl.

(2) The compound according to (1) or a pharmaceutically acceptable salt or solvate thereof, wherein the substituent of Ring B optionally substituted is one or more substituent selected from the group consisting of halo, nitro, amino, amino protected with an amino protecting group, optionally substituted amide, formyl, carboxyl, carboxamide, optionally substituted alkyl, lower alkoxy, hydroxyimino, optionally substituted oxazolidinone, optionally substituted isoxazole, and optionally substituted heterocyclic group (preferably 5- or 6-membered).
(3) The compound according to (1) represented by the formula:




or a pharmaceutically acceptable salt or solvate thereof

    wherein
    P1 and P2 are hydrogen, a substituent selected from Substituent Group S1 or an amino protecting group, or P1 and P2 may be taken together with N atom to which they are attached to form optionally substituted heterocycle;
    Ring B1 is a benzene ring optionally substituted with one or more halogen atom;
    R10 is —NO2 or —NHP3;
    P3 is hydrogen or an amino protecting group.


(4) The compound according to (1) represented by the formula:




or a pharmaceutically acceptable salt or solvate thereof,

    wherein
    P1 is hydrogen, a substituent selected from substituent Group S1 or an amino protecting group;
    Substituent Group S1 consists of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted formyl, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted lower alkyloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted carbamoyl, lower alkylthio, cycloalkylthio, arylthio, optionally substituted lower alkylsulfonyl, optionally substituted phenylsulfonyl, optionally substituted aromatic heterocycle(lower)alkyl, optionally substituted aryl, and optionally substituted heterocyclic group;
    Ring B is optionally substituted and optionally condensed benzene ring or optionally substituted heterocycle.


(5) The compound according to any one of (1), (2) or (4) wherein Ring B is a substituted quinoline ring.
(6) The compound according to (5) wherein Ring B is a residue of a quinolone antimicrobial compound or a newquinolone antimicrobial compound and connected at 7-position.
(7) A compound of the formula:




or a pharmaceutically acceptable salt or solvate thereof

    wherein
    Y1 is NP2 or O;
    P1 and P2 are independently hydrogen, a substituent selected from Substituent Group S1 or an amino protecting group, or P1 and P2 may be taken together with N atom to which they are attached to form optionally substituted heterocycle;
    R10, R11, R12, R13, R14 and R15 are independently hydrogen, lower alkyl, cycloalkyl, cycloalkyl lower alkyl, halo, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, lower alkylamino, optionally substituted aryl, or optionally substituted heterocyclic group, or R12 and R13 are taken together with their neighboring atom(s) to form optionally substituted heterocycle.


(8) The compound according to (7) or a pharmaceutically acceptable salt or solvate thereof, wherein R10 is hydrogen, R11 is halo, R12 is lower alkoxy, R13 is cycloalkyl, R14 is hydrogen, R15 is carboxy or lower alkoxycarbonyl.
(9) A compound of the formula:




or a pharmaceutically acceptable salt or solvate thereof,

    wherein
    Y1 is NP2 or O;
    P1 and P2 are independently hydrogen, acyl group or an amino protecting group;
    R11 is hydrogen, acyl group or an amino protecting group, provided that —CO(CH2)3—CO2H, -Ph and —CH2Ph (Ph: phenyl) are excluded.


(10) The compound according to (9) represented by the formula:




or a pharmaceutically acceptable salt or solvate thereof,

    wherein
    P1 and P2 are independently hydrogen, acyl group or an amino protecting group;
    R11 is hydrogen, acyl group or an amino protecting group, provided that —CO(CH2)3—CO2H, -Ph and —CH2Ph (Ph: phenyl) are excluded.


(11) The compound according to (9) wherein P1 and P2 are independently an amino protecting group and R11 is hydrogen.
(12) A compound of the formula:




or a pharmaceutically acceptable salt or solvate thereof,

    wherein
    Ring A is
    (A-1) at least 7-membered monocyclic hetero ring containing at least three N atoms;
    (A-2) at least 6-membered monocyclic hetero ring containing at least two N atoms and at least one O atom; or
    (A-3) at least 7-membered monocyclic hetero ring containing at least two N atoms and at least one S atom, wherein said monocyclic hetero ring is optionally substituted, and said monocyclic hetero ring is optionally condensed with another ring,
    X1 is a single bond, or a hetero atom-containing group selected from the group consisting of —O—, —S—, —NR2—, —CO—, —CS—, —CONR3—, —NR4CO—, —SO2NR5—, and —NR6SO2—, wherein R2, R3, R4, R5 and R6 are independently hydrogen or lower alkyl, or lower alkylene or lower alkenylene each optionally interrupted by said hetero atom-containing group;
    Ring B is optionally substituted carbocycle or optionally substituted heterocycle;
    R1 is hydrogen, or an organic residue which is able to bind to the 5-position of oxazolidinone ring in oxazolidinone antimicrobial agent.


(13) The compound according to (12) or a pharmaceutically acceptable salt or solvate thereof wherein Ring A is (A-1) at least 7-membered monocyclic hetero ring containing at least three N atoms.
(14) The compound according to (12) or a pharmaceutically acceptable salt or solvate thereof wherein Ring A is (A-2) at least 6-membered monocyclic hetero ring containing at least two N atoms and at least one O atom.
(15) The compound according to (12) or a pharmaceutically acceptable salt or solvate thereof wherein Ring A is (A-3) at least 7-membered monocyclic hetero ring containing at least two N atoms and at least one S atom.
(16) The compound according to (12) represented by the formula:




or a pharmaceutically acceptable salt or solvate thereof,

    wherein
    Y1 is NRb, O or S;
    Rb and Ra are independently hydrogen or a substituent selected from Substituent Group S1, said Substituent Group S1 consists of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted formyl, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted lower alkyloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted carbamoyl, lower alkylthiocarbonyl, cycloalkylthiocarbonyl, arylthiocarbonyl, optionally substituted lower alkylsulfonyl, optionally substituted phenylsulfonyl, optionally substituted aromatic heterocyclic group sulfonyl, optionally substituted aminosulfonyl, optionally substituted aryl, and optionally substituted heterocyclic group, or
    Ra and Rb are taken together with N atom to which they are attached to form optionally substituted heterocycle;
    Ring A1 may be substituted with a substituent other than Ra and Rb;
    p, q and r are independently an integer from 0 to 3, provided that p+q+r≧4 when Y1 is NRb or S, p+q+r≧3 when Y1 is O;
    X1 is a single bond, or a hetero atom-containing group selected from the group consisting of —O—, —S—, —NR2—, —CO—, —CS—, —CONR5—, —NR4CO—, —SO2NR5—, and —NR6SO2— (wherein R2, R3, R4, R5 and R6 are independently hydrogen or lower alkyl), or lower alkylene or lower alkenylene each optionally interrupted by said hetero atom-containing group;
    Ring B is optionally substituted carbocycle or optionally substituted heterocycle;
    R1 is hydrogen, or an organic residue which is able to bind to the 5-position of oxazolidinone ring in oxazolidinone antimicrobial agent.


(17) The compound according to (16) or a pharmaceutically acceptable salt or solvate thereof wherein Y1 is NRb, Rb is hydrogen or a substituent selected from Substituent Group S1 as defined above.
(18) The compound according to (16) or a pharmaceutically acceptable salt or solvate thereof wherein Ra is hydrogen, Y1 is NRb, Rb is hydrogen or a substituent selected from Substituent Group S1 as defined above.
(19) The compound according to (16) or a pharmaceutically acceptable salt or solvate thereof wherein Ra is hydrogen or lower alkyl; Y1 is NRb, Rb is hydrogen, optionally substituted lower alkyl, optionally substituted formyl, optionally substituted lower alkylcarbonyl, or optionally substituted carbamoyl.
(20) The compound according to (16) or a pharmaceutically acceptable salt or solvate thereof wherein p is 0; Y1 is NRb; Ra and Rb are taken together with their neighboring N atom to form optionally substituted heterocycle.
(21) The compound according to (16) or a pharmaceutically acceptable salt or solvate thereof wherein Y1 is O.
(22) The compound according to (16) or a pharmaceutically acceptable salt or solvate thereof wherein Ra is hydrogen, optionally substituted lower alkyl, optionally substituted formyl, optionally substituted lower alkylcarbonyl, or optionally substituted carbamoyl; Y1 is O.
(23) The compound according to (16) or a pharmaceutically acceptable salt or solvate thereof wherein Y1 is S.
(24) The compound according to (16) or a pharmaceutically acceptable salt or solvate thereof wherein Ra is hydrogen or acyl; Y1 is S.
(25) The compound according to (16) or a pharmaceutically acceptable salt or solvate thereof wherein p is 0; q+r=4.
(26) The compound according to (16) or a pharmaceutically acceptable salt or solvate thereof wherein p is 0; q=r=2.
(27) The compound according to (12) or (16) or a pharmaceutically acceptable salt or solvate thereof wherein X1 is a single bond.
(28) The compound according to (12) or (16) or a pharmaceutically acceptable salt or solvate thereof wherein Ring B is optionally substituted benzene ring or optionally substituted 5- to 7-membered aromatic heterocycle.
(29) The compound according to (12) or (16) or a pharmaceutically acceptable salt or solvate thereof wherein Ring B is optionally substituted benzene ring.
(30) The compound according to (12) or (16) or a pharmaceutically acceptable salt or solvate thereof wherein Ring B is a benzene ring substituted with one or two halogen.
(31) The compound according to (12) or (16) or a pharmaceutically acceptable salt or solvate thereof wherein R1 is optionally substituted aminomethylene or optionally substituted hydroxymethylene.
(32) The compound according to (12) or (16) or a pharmaceutically acceptable salt or solvate thereof wherein R1 is substituted aminomethylene.
(33) The compound according to (12) or (16) or a pharmaceutically acceptable salt or solvate thereof wherein R1 is —CH2NHCOR7 (wherein R7 is optionally substituted lower alkyl, optionally substituted lower alkyloxy, cycloalkyl, optionally substituted heterocycle, lower alkylamino or optionally substituted phenyl), or —CH2NHCSR8 (wherein R8 is optionally substituted lower alkyl, optionally substituted lower alkyloxy, cycloalkyl, optionally substituted heterocycle, lower alkylamino or optionally substituted phenyl).
(34) The compound according to (16) or a pharmaceutically acceptable salt or solvate thereof wherein Y1 is NRb; Rb is hydrogen or a substituent selected from Substituent Group S1 as defined above; p is 0; q+r=4; X1 is a single bond; Ring B is optionally substituted benzene ring or optionally substituted 5- to 7-membered aromatic heterocycle; R1 is —CH2NHCOR7 wherein R7 is optionally substituted lower alkyl or —CH2NHCSR8 wherein R8 is optionally substituted lower alkyloxy; Ring A1 may be substituted further with a substituent other than Ra and Rb.
(35) The compound according to (16) or a pharmaceutically acceptable salt or solvate thereof wherein Ra is hydrogen or lower alkyl; Y1 is NRb, Rb is hydrogen or optionally substituted lower alkyl, optionally substituted formyl, optionally substituted lower alkylcarbonyl or optionally substituted carbamoyl; p is 0; q=r=2; X1 is a single bond; Ring B is optionally substituted benzene ring; R1 is —CH2NHCOR7 wherein R7 is optionally substituted lower alkyl or —CH2NHCSR8 wherein R8 is optionally substituted lower alkyloxy; Ring A1 may be substituted further with a substituent other than Ra and Rb.
(36) The compound according to (16) or a pharmaceutically acceptable salt or solvate thereof wherein Ra is hydrogen or lower alkyl; Y1 is NRb, Rb is optionally substituted lower alkyl, optionally substituted lower alkylcarbonyl or optionally substituted carbamoyl; p is 0; q=r=2; X1 is a single bond; Ring B is optionally substituted benzene ring with one or two halogen; R1 is —CH2NHCOR7 wherein R7 is optionally substituted lower alkyl or —CH2NHCSR8 wherein R8 is optionally substituted lower alkyloxy.
(37) The compound according to (36) or a pharmaceutically acceptable salt or solvate thereof wherein Rb is —COCH2OH, or —CONH— (optionally substituted heterocyclic group).
(38) The compound according to (16) or a pharmaceutically acceptable salt or solvate thereof wherein p is 0; q=r=2; Y1 is NR1, Ra and Rb are taken together with their neighboring N atom to form optionally substituted heterocycle; X1 is a single bond; Ring B is optionally substituted benzene ring; R1 is —CH2NHCOR7 wherein R7 is optionally substituted lower alkyl, optionally substituted lower alkyloxy, cycloalkyl, optionally substituted heterocycle, lower alkylamino or optionally substituted phenyl or —CH2NHCSR8 wherein R8 is optionally substituted lower alkyl, optionally substituted lower alkyloxy, cycloalkyl, optionally substituted heterocycle, lower alkylamino or optionally substituted phenyl; Ring A1 may be substituted further with a substituent other than Ra and Rb.
(39) The compound according to (16) or a pharmaceutically acceptable salt or solvate thereof wherein p is 0; q=r=2; Y1 is NRb, Ra and Rb are taken together with their neighboring N atom to form 5- or 6-membered optionally substituted heterocycle with oxo, and the other position on said heterocycle is optionally substituted or condensed; X1 is a single bond; Ring B is optionally substituted benzene ring with one or two halogen; R1 is —CH2NHCOR7 wherein R7 is optionally substituted lower alkyl or —CH2NHCSR8 wherein R8 is optionally substituted lower alkyloxy.
(40) The compound according to (39) or a pharmaceutically acceptable salt or solvate thereof wherein Ring A1 is represented by the formula:




wherein Ring H is optionally substituted monocyclic heterocycle.

(41) The compound according to (16) or a pharmaceutically acceptable salt or solvate thereof wherein Y1 is O; p is 0; q+r=4; X1 is a single bond; Ring B is optionally substituted benzene ring or optionally substituted 5- to 7-membered aromatic heterocycle; R1 is —CH2NHCOR7 wherein R7 is optionally substituted lower alkyl, optionally substituted lower alkyloxy, cycloalkyl, optionally substituted heterocycle, lower alkylamino or optionally substituted phenyl or —CH2NHCSR8 wherein R8 is optionally substituted lower alkyl, optionally substituted lower alkyloxy, cycloalkyl, optionally substituted heterocycle, lower alkylamino or optionally substituted phenyl; Ring A1 may be substituted further with a substituent other than Ra and Rb.
(42) The compound according to (16) or a pharmaceutically acceptable salt or solvate thereof wherein Y1 is O; Ra is hydrogen, optionally substituted lower alkyl, optionally substituted formyl, optionally substituted lower alkylcarbonyl, optionally substituted carbamoyl; p is 0; q=r=2; X1 is a single bond; Ring B is optionally substituted benzene ring with one or two halogen; R1 is —CH2NHCOR7 wherein R7 is optionally substituted lower alkyl or —CH2NHCSR8 wherein R8 is optionally substituted lower alkyloxy.
(43) The compound according to (42) or a pharmaceutically acceptable salt or solvate thereof wherein Ra is —COCH2OH, —CONH— (optionally substituted heterocyclic group), or —CONHC(═NH)N(CH3)2.
(44) A pharmaceutical composition comprising the compound according to any one of (1) to (43) or a pharmaceutically acceptable salt or solvate thereof.
(45) An antimicrobial agent comprising the compound according to any one of (1) to (43) or a pharmaceutically acceptable salt or solvate thereof.
As presented by the formula (I), the oxazolidinone derivative is structurally characterized in that Ring A, which is at least 6-membered or 7-membered, preferably 7-membered heterocycle, binds to the N atom at position 3 of oxazolidinone ring via one carbocycle or heterocycle and an optional spacer.
In another preferred embodiment, the compound of the invention is characterized in that it has triazacycloheptane skeleton.
In further embodiment, the compound of the invention is characterized in that it has oxadiazepane skeleton wherein one N atom in the triazacycloheptane skeleton is replaced with O atom.
EFFECT OF THE INVENTION
The oxazolidinone derivative, triazacycloheptane derivative or oxadiazepane derivative of the invention is useful as a pharmaceutical active ingredient (e.g., antimicrobial) or a synthetic intermediate thereof. Also, the oxazolidinone derivative of the invention has a potent antimicrobial activity against gram-positive bacteria and gram-negative bacteria. Especially, the compound exhibits antimicrobial activity with wide spectrum against drug-resistant gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin resistant enterococcus (VRE), penicillin resistant pneumococcus (PRSP). More preferably, the compound of the invention is effective against linezolid resistant (LZD-R) organisms. The compound of the invention more preferably shows good solubility or absorbability, which allows administration by injection. Still more preferably, the compound of the invention reduces the side-effects concerned in conventional antimicrobial agents (e.g., linezolid), such as bone marrow suppression, monoamine oxidase (MAO) inhibiting activity, neurotoxicity. Decreased MAO inhibition is preferred because side-effects such as metabolism suppression of dopamine, serotonin, etc., blood pressure elevation, agitation, etc. are concerned by such inhibition. Additionally, preferred compound of the invention also shows good profiles in pharmacokinetics such as CYP inhibition, PK profile, plasma stability.
Also, the compound of the invention, wherein triazacycloheptane skeleton or oxadiazepane skeleton is connected to quinolone skeleton, shows a potent antimicrobial activity against various bacteria. Especially, the compound shows antimicrobial activity equal to or more (e.g., more than 4 times) than commercial newquinolone antimicrobial drug (e.g., ciprofloxacin, gatifloxacin, moxifloxacin) against various bacteria including VRE (vancomycin resistant enterococcus), MRSA (methicillin-resistant Staphylococcus aureus).
Thus, by having triazacycloheptane skeleton, oxadiazepane skeleton or similar structure thereof as a partial structure, the compound of the invention remarkably improves its pharmaceutical activity, pharmacokinetics and/or side-effects and very useful as a pharmaceutical compound.
Also, a synthetic intermediate of the invention having triazacycloheptane skeleton, oxadiazepane skeleton is useful for the production of various pharmaceutical compounds including antimicrobial agent.


BEST MODE FOR CARRYING OUT THE INVENTION
The terms as used herein are described bellow. Each term, alone or in combination with another term, has the following meaning unless otherwise specifically indicated.
The substituent for the term “optionally substituted” in Substituent Group S1 is selected from amino, optionally substituted lower alkylamino, optionally substituted lower alkylcarbonylamino, halo, halogenated lower alkyl, halogenated lower alkoxy, lower alkyl, optionally substituted lower alkoxy, carboxy, oxo, hydroxy, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkylcarbonylamino, optionally substituted phenylcarbonylamino, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylcarbonyl, optionally substituted aralkyl, optionally substituted aralkyloxy, optionally substituted heterocyclic group, optionally substituted heterocyclic lower alkyl, optionally substituted heterocyclecarbonyl, carbamoyl, lower alkyl carbamoyl, nitro, cycloalkyl and the like. Examples of the substituent for optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylcarbonyl, optionally substituted aralkyl, optionally substituted aralkyloxy, optionally substituted heterocyclic group, optionally substituted heterocyclic lower alkyl, and optionally substituted heterocyclecarbonyl include amino, nitro, lower alkylamino, halo, halogenated lower alkyl, halogenated lower alkoxy, lower alkyl, lower alkoxy, carboxy, oxo, hydroxy, lower alkylcarbonyl, lower alkoxycarbonyl, morpholino, carbamoyl, lower alkyl carbamoyl and the like.
The term “lower alkyl” refers to C1-C6 straight or branched monovalent hydrocarbon radical. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl and the like.
The term “lower alkylene” refers to straight or branched C1-C6 alkylene and includes methylene, ethylene, trimethylene, propylene, tetramethylene, ethyl ethylene, pentamethylene, hexamethylene and the like.
The term “lower alkenylene” refers to straight or branched chain group of 2 to 6 carbon atoms having one or more double bond in the “lower alkylene” as defined above and includes, for example, vinylene, propenylene, butenylene and the like.
The term “carbocycle” refers to aryl, cycloalkyl or cycloalkenyl and includes cyclobutane, cyclopentane, cyclohexane, cycloheptane, benzene, naphthalene and the like. 5- to 7-membered ring is preferable, and 6-membered ring is especially preferable.
The term “heterocycle” and “heterocyclic group”, as used herein, refers to a ring wherein a carbon atom in the above “carbocycle” is replaced with at least one hetero atom independently selected from N atom, oxygen atom or sulphur atom. For example, heteroaryl, heteroring, etc. are exemplified for this term.
The term “monocyclic heterocycle” refers to aromatic cyclic group or non-aromatic cyclic group containing at least one hetero atom selected from N atom, oxygen atom or sulphur atom in its ring.
The term “heteroaryl” refers to monocyclic aromatic heterocyclic group or condensed aromatic heterocyclic group. The monocyclic aromatic heterocyclic group refers to a group induced from a 5- to 8-membered aromatic ring that contains optionally one to four O, S, P and/or N atom in Ring And has a binding position at any substitutable position. The condensed aromatic heterocyclic group refers to a group wherein a 5- to 8-membered aromatic ring, which contains optionally one to four O, S, P and/or N atom in the ring, is condensed with one to four 5- to 8-membered aromatic carbocycle(s) or other 5- to 8-membered aromatic heteroring(s) and has a binding position at any substitutable position. Examples of “heteroaryl” include furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazolyl-3-yl, 1,2,4-triazol-4-yl), tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), furazanyl (e.g., 3-furazanyl), pyrazinyl (e.g., 2-pyrazinyl), oxadiazolyl (e.g., 1,3,4-oxadiazole-2-yl), benzofuryl (e.g., 2-benzo[b]furyl, 3-benzo[b]furyl, 4-benzo[b]furyl, 5-benzo[b]furyl, 6-benzo[b]furyl, 7-benzo[b]furyl), benzothienyl (e.g., 2-benzo[b]thienyl, 3-benzo[b]thienyl, 4-benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzo[b]thienyl, 7-benzo[b]thienyl), benzimidazolyl (e.g., 1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl), dibenzofuryl, benzoxazolyl (e.g., 2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 7-benzoxazolyl, 8-benzoxazolyl), quinoxalyl (e.g., 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl), cinnolinyl (e.g., 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), quinazolyl (e.g., 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl), quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), phthalazinyl (e.g., 1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), puryl, pteridinyl (e.g., 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl), carbazolyl, phenanthridinyl, acridinyl (e.g., 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), isoindolyl, phenazynyl (e.g., 1-phenazinyl, 2-phenazinyl) or phenothiazinyl (e.g., 1-phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl, 4-phenothiazinyl), etc.
The term “heteroring” refers to a non-aromatic heterocyclic group which has at least one N, O and/or S atom in Ring And has a binding position at any substitutable position.
The term “non-aromatic heterocyclic group” refers to a group containing one or more O, S or N atom, induced from a 5- to 7-membered non-aromatic ring or a condensed ring thereof wherein two or more such rings are condensed. Examples of “heterocycle” include 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidino, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, piperazino, 2-piperazinyl, 2-morpholinyl, 3-morpholinyl, morpholino, tetrahydropyranyl, etc. The term “non-aromatic heterocyclic group” may be saturated or unsaturated as far as it is non-aromatic. The term “cycloalkyl” includes cycloalkyl of three to eight carbon atoms. Examples of “cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylyl, cycloheptyl and cyclooctyl.
The term “aryl” refers to monocyclic or condensed aromatic hydrocarbon. Examples of “aryl” include phenyl, 1-naphthyl, 2-naphthyl, anthryl and the like.
The term “an organic residue which is able to bind to the 5-position of oxazolidinone ring in oxazolidinone antimicrobial agent” for R1 refers to any organic residue that can bind to the 5-position of the oxazolidinone ring of the oxazolidinone antimicrobial compound, which is known as disclosed in the patents listed above in the section “Background Art”, capable of synthesis by those skilled in the art, or may be disclosed in the future. Examples of such organic residue include optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, optionally substituted carbamoyl, optionally substituted lower alkoxycarbonyl, optionally substituted amino and the like. Examples of the substituent for “optionally substituted” include optionally substituted amino, optionally substituted hydroxy, lower-alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkylcarbonyl, lower alkylsulfonyloxy, halo, carboxy, halogenated lower alkyl, halogenated lower alkoxy, lower alkylcarbonyl, lower alkoxycarbonyl, carbamoyl, lower alkyl carbamoyl. Examples of the substituent for optionally substituted amino include —COR7 or —CSR8, lower alkylsulfonyl, lower alkylaminosulfonyl, lower alkyl, lower alkylcarbonylamino, as described bellow.
Preferably, R1 is optionally substituted alkyl (substituents: optionally substituted amino, optionally substituted hydroxy, azido, halo, —NCS, etc.), more preferably, optionally substituted aminomethylene or optionally substituted hydroxymethylene, still more preferably, substituted aminomethylene, even more preferably —CH2NHCOR7 or —CH2NHCSR8. R7 may be optionally substituted lower alkyl, optionally substituted lower alkoxy, cycloalkyl, optionally substituted heterocycle (preferably nitrogen-containing 5- to 7-membered ring), lower alkylamino, lower alkylsulfonyl or optionally substituted phenyl, preferably optionally substituted lower alkyl. Preferable substituent for said amino, lower alkyl, heterocycle or phenyl include halo, hydroxy, lower alkoxy, optionally substituted phenyl, optionally substituted phenyloxy, lower alkyl, carboxy, lower alkoxycarbonyl, lower alkylsulfonyl, preferably halo, hydroxy, lower alkoxy, more preferably halogen (e.g., F). Particular preferably, R7 is lower alkyl optionally substituted with halogen (e.g., —CH3, —CHF2).
R8 may be optionally substituted lower alkyl, optionally substituted lower alkyloxy, cycloalkyl, optionally substituted heterocycle (preferably nitrogen-containing 5- to 7-membered ring), lower alkylamino or optionally substituted phenyl, preferably, optionally substituted lower alkyloxy. Preferable substituent for said lower alkyloxy is halo, hydroxy, lower alkoxy, optionally substituted phenyl, optionally substituted phenyloxy, preferably halogen (e.g., F). More preferably, R8 is lower alkyloxy (e.g., —OCH3).
Examples of the substituent for optionally substituted hydroxymethylene include R7.
Examples of “lower alkylcarbonyl” include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, octanoyl, methoxyethylcarbonyl, 2,2,2-trifluoroethylcarbonyl, ethoxycarbonylmethylcarbonyl and the like.
Examples of “cycloalkylcarbonyl” include cyclopropylcarbonyl, cyclohexylylcarbonyl and the like.
Examples of “lower alkyloxycarbonyl” include methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, t-butyloxycarbonyl, n-pentyloxycarbonyl and the like.
Examples of “arylcarbonyl” include benzoyl, naphthylcarbonyl and the like.
In case where “optionally substituted carbocycle”, “optionally substituted heterocycle”, “optionally substituted lower alkyl”, “optionally substituted lower alkylcarbonyl”, “optionally substituted cycloalkylcarbonyl”, “optionally substituted lower alkyloxy carbonyl”, “optionally substituted arylcarbonyl”, “optionally substituted heterocyclecarbonyl”, “optionally substituted carbamoyl”, etc. are substituted, it may be substituted at any position with same or different substituent selected from the following Substituent Group B. Substituent Group B includes, for example, hydroxy, carboxy, halogen (F, Cl, Br, I), haloalkyl (e.g., CF3, CH2CF3, CH2CCl3, etc.), haloalkoxy (e.g., CF3), alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl, etc.), alkenyl (e.g., vinyl), alkynyl (e.g., ethynyl), cycloalkyl (e.g., cyclopropyl), cycloalkenyl (e.g., cyclopropenyl), alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, etc.), alkenyloxy (e.g., vinyloxy, allyloxy, etc.), alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), carboxy, carboxamide, nitro, nitroso, optionally substituted amino (e.g., alkylamino (e.g., methylamino, ethylamino, dimethylamino, amino protected with amino protecting group, etc.), acylamino (e.g., acetylamino, benzoylamino, etc.), optionally substituted amide, aralkylamino (e.g., benzylamino, tritylamino), hydroxyamino, etc.), azido, aryl (e.g., phenyl, etc.), aralkyl (e.g., benzyl, etc.), cyano, isothiocyano, isocyanato, thiocyanato, isothiocyanato, mercapto, alkylthio (e.g., methylthio, etc.), alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl), optionally substituted carbamoyl (e.g., alkylcarbamoyl such as methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, etc.), sulfamoyl, acyl (e.g., formyl, acetyl, etc.), formyl, formyloxy, haloformyl, oxalo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino, hydrazino, azido, ureido, amidino, guanidino, phthalimido, oxo, optionally substituted alkyl, lower alkoxy, optionally substituted oxazolidinone, and optionally substituted isoxazole or the substituents as disclosed in the following examples.
For “amino protecting groups”, any amino protecting group well known in the art can be used, and preferably, it can be lower alkoxycarbonyl (e.g., t-butoxycarbonyl), optionally substituted aralkyloxy carbonyl (e.g., benzyl oxycarbonyl, p-nitrobenzyl oxycarbonyl), lower alkyl.
The first embodiment of the invention relates to a novel compound of the following formula, having 7-membered monocyclic hetero ring structure, preferably 1,2,5-triazacycloheptane (hereinafter referred to as “triazepane”) or 1-oxa-2,5-diazacycloheptane (hereinafter referred to as “oxadiazepane”), i.e., triazepane derivative and oxadiazepane derivative:




wherein

    Y1 is NP2 or O, preferably N;
    P1 and P2 are independently hydrogen, a substituent selected from Substituent Group S1 or an amino protecting group, or P1 and P2 are taken together with N atom to which they are attached to form optionally substituted heterocycle. P1 and P2 are preferably Ra and Rb as defined bellow for Compound (I).


Substituent Group S1 consists of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted formyl, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted lower alkyloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted carbamoyl, lower alkylthio, cycloalkylthio, arylthio, optionally substituted lower alkylsulfonyl, optionally substituted phenylsulfonyl, optionally substituted aromatic heterocyclic group, optionally substituted aryl, and optionally substituted heterocyclic group.
Examples of each group are as described bellow for Compound (I).
Ring B is benzene ring optionally substituted or condensed, or optionally substituted heterocycle. The heterocycle means the heterocycle as defined above and may be monocyclic or condensed ring. When Ring B is benzene ring, it is represented preferably by the formula:




The substituents Rb1 to Rb5 are preferably selected from the group consisting of hydrogen, halo, nitro, amino, amino protected with an amino protecting group, optionally substituted amide, formyl, carboxyl, carboxamide, optionally substituted alkyl, lower alkoxy, optionally substituted oxazolidinone, optionally substituted isoxazole, lower alkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkoxycarbonyl, lower alkylamino, optionally substituted aryl, and optionally substituted heterocyclic group.

In one preferred embodiment, any one or two of Rb1, Rb2, Rb and Rb5 is halogen.
In one preferred embodiment, Rb4 is nitro, amino, amino protected with an amino protecting group, or optionally substituted oxazolidinone.
In one preferred embodiment, Rb5, Rb1 and Rb2 are R10, R11 and R12 as defined bellow, respectively.
In one preferred embodiment, two substituents next to each other, such as Rb1 and Rb5′ Rb5 and Rb4′ Rb4 and Rb3 or Rb3 and Rb2, are taken together with neighboring carbon atoms to form optionally substituted monocyclic, preferably 4- to 7-membered, carbocycle or heterocycle. Said heterocycle has preferably one to three O, S, and/or N atom. More preferably, it has at least one N atom. Examples of the substituent for said carbocycle or heterocycle include substituents as described for Rb1 to Rb5, oxo, and substituents as described bellow for R13, R14 and R15.
In one preferred embodiment, Ring B is the main backbone of the antimicrobial compound and includes, for example, quinoline ring, quinolone skeleton, β-lactams skeleton (e.g., cephem ring, cepham ring, carbapenem ring, carbapenam ring), glycopeptide skeleton (e.g., vancomycin, teicoplanin), macrolide skeleton (e.g., erythromycin, serotomycin, telithromycin), tetracycline skeleton, and benzene ring that binds to the oxazolidinone ring of oxazolidinone antimicrobial drugs (e.g., linezolid). By the connection of the 7-membered heterocycle structure to the main backbone of the compound, the antimicrobial compound of the invention can be improved in its antimicrobial activity and pharmacokinetics and reduced in its side-effect.
One preferred embodiment of the compound is represented by the following formula:




wherein

    P1 and P2 are hydrogen, a substituent selected from Substituent Group S1 or an amino protecting group, or P1 and P2 are taken together with N atom to which they are attached to form optionally substituted heterocycle;
    Ring B1 is optionally substituted benzene ring with one or more halogen atom;
    R10 is —NO2, —NHP3, or other reactive functional group (e.g., —OH, —COOR wherein R is hydrogen or a carboxy protecting group, —SH);
    P3 is hydrogen or an amino protecting group.


The above compound is useful as an intermediate for the production of oxazolidinone antimicrobial agent, particularly Compound (I) as described bellow.
When Ring B is a substituted quinoline ring, preferably a residue of quinolone antimicrobial compounds or newquinolone antimicrobial compounds, the compound is as represented bellow. Example of such quinolone or newquinolone antimicrobial compound include, for example, norfloxacin (NFLX), ofloxacin (OFLX), tosufloxacin (TFLX), fleroxacin (FLRX), ciprofloxacin (CPFX), sparfloxacin (SPFX), levofloxacin (LVFX), gatifloxacin (GFLX), pazufloxacin (PFLX). In this case, Ring B preferably binds at 7-position to the quinoline ring.




wherein

    Y1 is NP2 or O, preferably NP2;
    P1 and P2 are independently hydrogen, a substituent selected from Substituent Group S1 or an amino protecting group, or P1 and P2 are taken together with N atom to which they are attached to form optionally substituted heterocycle.
    More preferably, P2 is hydrogen, P1 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkylcarbonyl (Examples of substituent: hydroxy, lower alkoxy, acetyl, amino, lower alkylamino, halo, carboxy, carbamoyl, lower alkyl carbamoyl, heterocycle).
    R10 to R15 are independently hydrogen, lower alkyl, cycloalkyl, cycloalkyl lower alkyl, halo, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, lower alkylamino, optionally substituted aryl, or optionally substituted heterocyclic group; or R12 and R13 are taken together with adjacent atoms to form optionally substituted heterocycle preferably 5- or 6-membered (Example of substituent: lower alkyl, hydroxy, lower alkoxy, amino, lower alkylamino, cycloalkyl).


More preferably, R10 is hydrogen, R11 is halo, R12 is lower alkoxy, R13 is cycloalkyl, R14 is hydrogen, R15 is carboxy or lower alkoxycarbonyl.
The present invention also relates to a compound of the formula:




wherein

    Y1 is NP or O;
    P1 and P are independently hydrogen, acyl group or an amino protecting group;
    R11 is hydrogen, acyl group or an amino protecting group, provided that —CO(CH2)3—CO2H, -Ph and —CH2Ph (Ph: phenyl) are excluded.


Such compound is useful as an intermediate for the production of various compounds (e.g., antimicrobial agent, antivirus agent, antiobesity agent, CNS disease therapeutic agent, anti-inflammatory agent) that have 7-membered heterocycle moiety of the formula:




In another embodiment, the invention provides oxazolidinone derivatives of the formula:




(Embodiment 1)

In one embodiment of the invention, Ring A of the formula I is at least 7-membered monocyclic heterocycle containing at least three nitrogen atoms, preferably a 7-membered monocyclic heterocycle containing three nitrogen atoms. The positions of these nitrogen atoms are not limited, and preferably, two N atoms are located in adjacent positions. Also, Ring A and X1 may bind to each other at any position, and preferably, one N atom at Ring A connects to X1. More preferably, following groups are exemplified.




Y1 is NRb.

    p, q and r are independently an integer from 0 to 3; p+q+r≧4 and preferably p+q+r=4. More preferably, p=0, q=r=2.
    Ring A1 may be substituted further with a substituent other than Ra and Rb (e.g., hydroxy, lower alkyl, lower alkoxy, halogen).


Still more preferably, Ring A1 is represented by the formula:




Rb and Ra are independently hydrogen or a substituent selected from Substituent Group S1, and preferably, one of which is hydrogen and the other is a substituent selected from Substituent Group S1, or both of which are substituent selected from Substituent Group S1.

Substituent Group S1 consists of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted formyl, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted lower alkyloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted carbamoyl, lower alkylthiocarbonyl, cycloalkylthiocarbonyl, arylthiocarbonyl, optionally substituted lower alkylsulfonyl, optionally substituted phenylsulfonyl, optionally substituted aromatic heterocyclic group sulfonyl and optionally substituted aminosulfonyl.
Substituents for “optionally substituted” in Substituent Group S1 can be selected from amino, optionally substituted lower alkylamino, optionally substituted lower alkylcarbonylamino, halo, halogenated lower alkyl, lower alkyl, optionally substituted lower alkoxy (e.g., halogenated lower alkoxy), carboxy, oxo, hydroxy, lower alkoxycarbonyl, lower alkylcarbonyloxy, optionally substituted phenylcarbonylamino, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylcarbonyl, optionally substituted aralkyl, optionally substituted aralkyloxy, optionally substituted heterocyclic group, optionally substituted heterocyclic lower alkyl, optionally substituted heterocyclecarbonyl, carbamoyl, lower alkyl carbamoyl, nitro, cycloalkyl, etc.
Examples of the substituent for said optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylcarbonyl, optionally substituted aralkyl, optionally substituted aralkyloxy, optionally substituted heterocyclic group, optionally substituted heterocyclic lower alkyl, optionally substituted heterocyclecarbonyl include amino, nitro, lower alkylamino, halo, halogenated lower alkyl, halogenated lower alkoxy, lower alkyl, lower alkoxy, carboxy, oxo, hydroxy, lower alkylcarbonyl, lower alkoxycarbonyl, morpholino and the like.
Ra is preferably hydrogen or lower alkyl (e.g., methyl).
Rb is preferably hydrogen, optionally substituted lower alkyl, optionally substituted formyl, optionally substituted lower alkylcarbonyl or optionally substituted carbamoyl, more preferably, optionally substituted lower alkyl, optionally substituted lower alkylcarbonyl, or optionally substituted carbamoyl.
Examples of the substituent for said optionally substituted lower alkyl include, preferably, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkylcarbonyloxy, amino, optionally substituted lower alkylamino, lower alkylcarbonylamino, cycloalkylcarbonylamino, hydroxyamino, lower alkoxyamino, halo, carbamoyl, lower alkyl carbamoyl, nitro, cycloalkyl, optionally substituted phenyl, optionally substituted phenyloxy, optionally substituted phenyl carbonyl, optionally substituted heterocyclic group (preferably 5- to 6-membered aromatic heterocyclic group), optionally substituted heterocycleoxy, optionally substituted heterocyclecarbonyl and oxo. Examples of the substituent for said optionally substituted lower alkylamino include halo, hydroxy, lower alkoxy, amino, carboxy, optionally substituted heterocyclic group (preferably 5- to 6-membered aromatic heterocyclic group) and phenyl. Examples of the substituent for said optionally substituted phenyl or heterocyclic group include amino, halo, hydroxy, lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkylcarbonyloxy, nitro, and morpholino.
Examples of the substituent for said optionally substituted formyl include, preferably, optionally substituted amino, optionally substituted lower alkyloxy, optionally substituted lower alkyloxycarbonyl, carboxy, optionally substituted phenyl, optionally substituted phenyloxy, optionally substituted heterocyclic group (preferably 5- to 6-membered), optionally substituted heterocycleoxy (preferably 5- to 6-membered) and optionally substituted cycloalkyl. Examples of the substituent for said optionally substituted amino include hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkyl, optionally substituted heterocyclic group (substituents: lower alkyl, lower alkoxy, hydroxy, carboxy, amino, nitro, lower alkylamino, hydroxy lower alkyl; heterocyclic group is preferably 5- to 6-membered, more preferably aromatic heterocyclic group (e.g., triazole, tetrazole, pyridyl)), optionally substituted heterocyclic lower alkyl, mono- or di-lower alkylamino, —C(═NH)N(CH3)2. Examples of the substituent for said optionally substituted lower alkyloxy include optionally substituted aryl (e.g., phenyl). Examples of the substituent for said optionally substituted phenyl or heterocyclic group include amino, halo, hydroxy, lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkylcarbonyloxy, nitro and morpholino. Examples of the substituent for said optionally substituted cycloalkyl include lower alkylcarbonyl, lower alkoxycarbonyl.
Examples of the substituent for said optionally substituted lower alkylcarbonyl include preferably hydroxy, optionally substituted lower alkoxy (substituents: halo, carboxy, hydroxy, optionally substituted phenyl or heterocyclic group (preferably 5- to 6-membered aromatic heterocyclic group)), cyano, amino, hydroxyamino, lower alkoxyamino, optionally substituted lower alkylamino (substituents: halo, carboxy, hydroxy, optionally substituted phenyl or heterocyclic group (preferably 5- to 6-membered aromatic heterocyclic group)), cycloalkylamino, lower alkylcarbonyloxy, lower alkoxycarbonyl, optionally substituted lower alkylcarbonylamino, optionally substituted phenylcarbonylamino, carboxy, halo, optionally substituted phenyl, optionally substituted phenyloxy, optionally substituted heterocyclic group (preferably 5- to 6-membered heterocyclic group), optionally substituted heterocycleoxy, carbamoyl, lower alkyl carbamoyl, lower alkylsulfonylamino and oxo, and preferably, hydroxy, amino, lower alkylcarbonylamino and optionally substituted phenylcarbonylamino. More preferably, examples of the substituent for said optionally substituted lower alkylcarbonyl include —COCH3, —COCH2CH3, —COCH2OH, —COCH2NH2, particular preferably —COCH2OH. Examples of the substituent for said optionally substituted phenyl and optionally substituted heterocyclic group include amino, halo, hydroxy, lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkylcarbonyloxy, nitro, and morpholino.
Examples of the substituent for said “optionally substituted isoxazole”, “optionally substituted heterocyclic group (preferably 5- or 6-membered)” include the groups as defined for R1 in compound (I).
Ra and Rb can be taken together with N atom to which they are attached to form optionally substituted heterocycle, preferably 5- to 7-membered ring. Said heterocycle may be a condensed ring. Examples of substituents on such heterocycle include optionally substituted amino (e.g., lower alkylamino, acetylamino), halo, halogenated lower alkyl, halogenated lower alkoxy, lower alkyl, lower alkoxy, carboxy, oxo, hydroxy, optionally substituted, phenyl or heterocyclic group and the like. Ra and Rb are preferably taken together with N atom to which they are attached to form one or two 5- or 6-membered heterocycle D optionally substituted with oxo, wherein said heterocycle D is optionally substituted with the substituent R at another position. Said substituent R is selected from lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, cycloalkyl, optionally substituted, phenyl or heterocyclic group (preferably 5- to 6-membered aromatic heterocyclic group; examples of substituents: carboxy, amino, halo, lower alkoxy, halogenated lower alkyl), optionally substituted phenyl lower alkyl, optionally substituted heterocyclic lower alkyl, acyl, carboxy, lower alkoxycarbonyl, lower alkylsulfonyl, hydroxy, halo, amino, lower alkylamino, carbamoyl, lower alkyl carbamoyl, etc. Said heterocycle D is also optionally condensed with 5- to 6-membered carbocycle optionally substituted or heterocycle optionally substituted (e.g., Ring H as follows). Preferably, Examples of the substituent for said carbocycle or said heterocycle include carboxy, amino, optionally substituted acetylamino (substituents: carboxy, hydroxy, amino, morpholino), halogen. Preferably, in this case, Ring A1 forms a condensed ring as follows:




wherein Ring D is as defined above; Ring H is independently monocyclic heterocycle optionally substituted; R is a substituent as defined above; N is 1 or 2.

Preferably, Ring H is optionally substituted 5- to 6-membered ring, more preferably, aromatic hetero ring, still more preferably, a nitrogen-containing aromatic heterocycle (e.g., pyridine ring, pyrimidine ring, pyrazine ring). Examples of the substituent for said Ring H include lower alkyl, hydroxy, carboxy, lower alkoxy, amino, lower alkylamino, optionally substituted acetylamino (substituents: hydroxy, carboxy, amino, lower alkoxy), heterocyclic group carbonylamino (heterocycle is preferably 5- to 6-membered aliphatic ring).
(Embodiment 2)
In one embodiment of the invention, Ring A of the formula I is at least 6-membered monocyclic hetero ring that contains at least two nitrogen atoms and at least one oxygen atom, and preferably, 6-membered or 7-membered monocyclic hetero ring containing two nitrogen atoms and one oxygen atom. The positions of the nitrogen atom and oxygen atom are not limited, and preferably, one nitrogen atom and oxygen atom are located in adjacent positions. Also, Ring A may be connected to X1 at any position, and preferably, one N atom at Ring A is connected to X1. More preferably, following groups are exemplified.




Y1 is O, and the other variables are as defined above in Embodiment 1.

p, q and r are independently an integer from 0 to 3, p+q+r≧3, preferably p+q+r=3 or 4, more preferably 4. Still more preferably, p=0 and q=r=2.
Ring A1 may be substituted further with a substituent other than Ra (e.g., hydroxy, lower alkyl, lower alkoxy, halogen).
Preferably, Ring A1 is represented by the formula:




More preferably, Ra is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted formyl, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted lower alkylthio, optionally substituted phenylthiourea, optionally substituted heterocyclic group thio (preferably 5- to 6-membered ring), optionally substituted lower alkylsulfonyl, optionally substituted phenylsulfonyl, —C(═NH)NH2, optionally substituted aminothiocarbonyl, aminosulfonyl, or lower alkylaminosulfonyl, and preferably hydrogen or optionally substituted formyl.

Preferably, substituent for “optionally substituted” in Ra is hydroxy, optionally substituted amino, carboxy, halo, optionally substituted lower alkoxy (substituents: hydroxy, carboxy, lower alkoxy, amino, halogen), cycloalkyl, lower alkylcarbonyl, lower alkoxycarbonyl, lower alkylcarbonylamino, optionally substituted or condensed heterocyclic group (preferably 5- to 6-membered cyclic group), optionally substituted or condensed heterocyclic group carbonyl, optionally substituted or condensed phenyl, optionally substituted or condensed phenylcarbonyl, optionally substituted or condensed phenyloxy. Examples of the substituent for said optionally substituted amino include optionally substituted lower alkyl (substituents: halo, carboxy, hydroxy, lower alkoxy, amino, imino, optionally substituted heterocyclic group (preferably 5- to 6-membered ring)), cycloalkyl, optionally substituted or condensed heterocyclic group (preferably 5- to 6-membered ring, condensed ring such as benzene ring), hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkylcarbonyl, optionally substituted phenyl carbonyl, and optionally substituted heterocyclecarbonyl. Examples of the substituent for said optionally substituted phenyl, optionally substituted heterocyclic group include hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkenyloxy, lower alkenyloxycarbonyl, amino, lower alkylamino, halo, carboxy, nitro, phenyl, heterocyclic group (preferably 5- to 6-membered ring), optionally substituted lower alkyl (substituents: hydroxy, amino, halo, carboxy).
(Embodiment 3)
In one embodiment of the invention, Ring A of the formula I is at least 7-membered monocyclic hetero ring containing at least two nitrogen atoms and at least one sulphur atom, preferably 7-membered monocyclic hetero ring containing two nitrogen atoms and one sulphur atom. The positions of these nitrogen atoms and sulphur atom are not limited, and preferably, one N atoms and S atom are located in adjacent positions. Also, Ring A may be connected to X1 at any position, and preferably, one N atom at Ring A is connected to X1. More preferably, following groups are exemplified.




wherein Y1 is S, and the other variables are as defined above in Embodiment 1.

p, q and r are independently an integer from 0 to 3, p+q+r≧4, preferably p+q+r=4. More preferably, p=0 and q=r=2.
Ring A1 may be substituted further with a substituent other than Ra (e.g., hydroxy, lower alkyl, lower alkoxy, halogen).
Preferably, Ring A1 is represented by the following formula:




Examples of Ra include groups as defined above in Embodiment 2, and more preferably, hydrogen, optionally substituted lower alkyl, or acyl (e.g., optionally substituted lower alkylcarbonyl; substituents is preferably hydroxy).

Further, the Ring A as defined above may be condensed with another ring.
In case where said Ring A is a condensed ring, it can be condensed with one to four 5- to 8-membered carbocycle (5- to 8-membered aromatic carbocycle) and/or other 5- to 8-membered heterocycle (optionally containing one to four O, S and/or N atom in the ring). For the ring to be condensed with Ring A, 5- or 6-membered ring is preferred.
Examples of the substituent for said condensed ring include amino, lower alkylamino, halo, halogenated lower alkyl, halogenated lower alkoxy, lower alkyl, lower alkoxy, carboxy, oxo, hydroxy and the like.
More preferably, Compound (I) includes the following compounds.




Ring A1 is as defined above in Embodiments 1-3.

The followings describe about other variables in the structure.
X1 is a single bond or any spacer moiety. Examples for such spacer include a hetero atom-containing group selected from the group consisting of —O—, —S—, —NR2—, —CO—, —CS—, —CONR3—, —NR4CO—, —SO2NR5— and —NR6SO2— (wherein R2 to R6 are independently hydrogen or lower alkyl), or lower alkylene or lower alkenylene each optionally interrupted with said hetero atom-containing group. The position interrupted in said hetero atom-containing group is not limited, but it may be between carbon atoms that forms lower alkylene or lower alkenylene. Also, it may be interrupted between carbon atoms of lower alkylene or lower alkenylene and Ring A1 or Ring B. The length of said hetero atom-containing group is not limited and preferably 1-3 atoms. More preferably, X1 is a single bond. The lower alkylene is preferably C1-C3, the lower alkenylene is preferably C2-C3.
Ring B is optionally substituted carbocycle or optionally substituted heterocycle. Preferably, it can be optionally substituted carbocycle, more preferably 5- to 7-membered ring, particular preferably 6-membered ring, still more preferably optionally substituted benzene ring.
Examples of substituents for Ring B include amino, lower alkylamino, halo, halogenated lower alkyl, halogenated lower alkoxy, lower alkyl, lower alkoxy, carboxy, oxo, hydroxy and the like, and preferably halogen. Number of such substituent is preferably one to four, more preferably one to two.
In case where said Ring B is a heterocycle, it is preferably 5- to 7-membered ring, more preferably aromatic heterocycle (e.g., pyridine).
Preferably, Ring B is represented by the following formula:




wherein Y2 and Y3 are independently hydrogen or halogen, preferably at least one of which is halo, more preferably both of which are halogen (e.g., F).

R1 is as defined above, more preferably substituted aminomethylene, but various substituents other than these specific groups are promising in terms of the antimicrobial activity of the compound.
Preferred embodiments of Compound (I-1) are described bellow.

    (1) Y1 is NRb; Rb is hydrogen or a substituent selected from Substituent Group S1 as defined above; p is 0; q+r=4; X1 is a single bond; Ring B is optionally substituted benzene ring or optionally substituted 5- to 7-membered aromatic heterocycle; R1 is —CH2NHCOR7 (R7 is optionally substituted lower alkyl) or —CH2NHCSR8 (R8 is optionally substituted lower alkyloxy); Ring A1 may be substituted with a substituent other than Ra and Rb.


More preferably,

    (2) Ra is hydrogen or lower alkyl; Y1 is NRb, Rb is hydrogen or optionally substituted lower alkyl, optionally substituted formyl or optionally substituted lower alkylcarbonyl; p is 0; q=r=2; X1 is a single bond; Ring B is optionally substituted benzene ring (substituent is preferably one or two halogen); R1 is —CH2NHCOR7 (wherein R7 is optionally substituted lower alkyl) or —CH2NHCSR8 (wherein R8 is optionally substituted lower alkyloxy); Ring A1 may be substituted with a substituent other than Ra and Rb.


More preferably, examples of Rb include hydrogen, optionally substituted lower alkyl (preferably, substituent is selected from hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, optionally substituted lower alkylamino, halo, carbamoyl, lower alkyl carbamoyl, nitro, cycloalkyl, optionally substituted phenyl or optionally substituted heterocyclic group, and more preferably, hydroxy, lower alkoxy, carboxy, and still more preferably, hydroxy), and optionally substituted formyl (preferably, substituent is optionally substituted amino, optionally substituted lower alkyloxy, carboxy, optionally substituted phenyl, or optionally substituted heterocyclic group (preferably 5- to 6-membered; such as oxadiazol, isoxazole, triazole, tetrazole)).
Still more preferably,

    (3) Rb is —COCH2OH, —CONH— (optionally substituted heterocyclic group, preferably 5- to 6-membered ring), or optionally substituted lower alkyloxy carbonyl.


In another preferred embodiment,

    (4) Ra and Rb are taken together with N atom to which they are attached to form optionally substituted or condensed heterocycle, preferably 5- to 7-membered ring; p is 0; q+r=4; X1 is a single bond; Ring B is optionally substituted benzene ring or optionally substituted 5- to 7-membered aromatic heterocycle, preferably optionally substituted benzene ring (substituent: halogen); R1 is —CH2NHCOR7 (wherein R7 is optionally substituted lower alkyl), or —CH2NHCSR8 (wherein R8 is optionally substituted lower alkyloxy); Ring A1 may be substituted with a substituent other than Ra and Rb.


More preferably, Ra and Rb are, as defined above, taken together with their neighboring N atoms to form 5- or 6-membered heterocycle D optionally substituted with one or two oxo, wherein said heterocycle D is optionally substituted at other position. In this case, Ring A1 forms a heterocycle as represented above by the formulae (A-1) to (A-6), more preferably the formula (A-1). Ring H is, as defined above, preferably optionally substituted 5- to 6-membered ring, more preferably aromatic hetero ring, still more preferably nitrogen-containing aromatic hetero ring (e.g., pyridine ring, pyrimidine ring, pyrazine ring).
In still another preferred embodiment,

    (5) Y1 is O; p is 0; q+r=4; X1 is a single bond; Ring B is optionally substituted benzene ring or optionally substituted 5- to 7-membered aromatic heterocycle, more preferably optionally substituted benzene ring; R1 is —CH2NHCOR7 wherein R7 is optionally substituted lower alkyl or —CH2NHCSR8 wherein R8 is optionally substituted lower alkyloxy; Ring A1 may be substituted with a substituent other than Ra and Rb.
    (6) Y1 is O; Ra is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted formyl, optionally substituted lower alkylcarbonyl; p is 0; q=r=2; X1 is a single bond; Ring B is benzene ring optionally substituted with one or two halogen; R1 is —CH2NHCOR7 wherein R7 is optionally substituted lower alkyl or —CH2NHCSR8 wherein R8 is optionally substituted lower alkyloxy.


Preferably, substituent for optionally substituted formyl is optionally substituted amino. Substituent for optionally substituted lower alkylcarbonyl is preferably hydroxy.
More preferably, Ra is —COCH2OH, —CONH— (optionally substituted heterocyclic group, preferably 5- to 6-membered ring), —CONHC(═NH)N(CH3)2, or optionally substituted lower alkyloxy carbonyl.
Compound (I) is particularly characterized in Ring A, which can contributes to improvement of antimicrobial activity, water solubility, pharmacokinetics, safety, etc.
The compound s of the invention can be prepared according to the procedure as shown in Scheme I and II. Reagents and conditions used in the reaction can be selected appropriately by those skilled in the art, for example, according to the description in Japanese Patent Publication NO. 7-508665.




wherein Ring A, X1 and Ring B are as defined above, Ph is phenyl group, MS is methanesulfonyl group, Z is benzyloxycarbonyl group.

In Step 1, the nitro group of Compound a is reduced to obtain Compound b according to an appropriate reduction method such as for example hydrogenation reduction with a catalyst such as platinum oxide, Raney nickel, palladium carbon or the like, or a reaction method using iron powder with hydrochloric acid, acetic acid or the like. Compound a is commercially available or can be prepared easily by those skilled in the art from reagent commercially available.
In Step 2, Compound b is urethanated in an appropriate organic solvent with di-tert-butyl dicarbonate or urethanated with benzyloxycarbonyl chloride in the presence of a base such as triethylamine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, etc., in water or an organic solvent such as acetone, methanol, tetrahydrofuran or a combined solvent thereof. Then, it is treated with a base such as n-butyllithium in an appropriate aprotic organic solvent, such as tetrahydrofuran, N,N-dimethylformamide,
at a temperature in a range from −78° C. to the reflux temperature of the solvent, and followed by reacted with glycidyl butyrate to obtain Compound C.
Additionally, Compound C obtained in the above Scheme I may be further converted to Compound g according to the following Scheme II.




In Step 3, Compound c is reacted with methanesulfonyl chloride in the presence of a base such as triethylamine in an organic solvent, such as dichloromethane, tetrahydrofuran, etc., at a temperature in a range of under ice cooling to the reflux temperature of the solvent to obtain Compound d.
In Step 4, Compound d is reacted with sodium azide in an organic solvent, such as tetrahydrofuran, N,N-dimethylformamide, etc., at a temperature in a range of under ice cooling to the reflux temperature of the solvent to obtain Compound e.
In Step 5, the azido group of Compound e is reduced according to an appropriate reduction method, for example a hydrogenation reduction method using a catalyst such as platinum oxide, palladium carbon or the like, to obtain Compound f.
In Step 6, Compound f is acylated with an appropriate anhydrous acid such as acetic anhydride in a basic solvent such as pyridine to obtain Compound g.
Optionally, the compound as obtained above may further be modified with any substituent at 5-position of the oxazolidinone ring to obtain various oxazolidinone derivatives. Also, Ring A, Ring B, and X1 moiety may further be modified. Such modification is within a level of those skilled in the art and is readily practiced by those skilled in the art.
In case where any intermediate has a group reactive during reaction (e.g., —OH, —NH2, —COOH) in the above synthesis, such group can be protected appropriately before the reaction. For example, it may be protected with an appropriate protecting group, such as t-butoxycarbonyl group, benzyloxycarbonyl group, and then readily removed thereafter at an appropriate time, according to Greene, T. W., Wuts, P.G.M., “Protective Groups in Organic Synthesis”, 2nd ed; John Wiley & Sons: New York (1991).
The present invention also provides a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. Based on the antimicrobial activity of the compound, examples of such pharmaceutical composition include antimicrobial drugs. When the compound of the invention is used in a treatment, the compound, a salt thereof or solvate thereof is administered to an animal, including human, which is affected with infection in a therapeutically effective amount. Route for administration may be oral or parenteral. For this purpose, the compound of the invention or a salt thereof is combined with a pharmaceutically acceptable carrier, diluent or excipient and incorporated into a capsule or compressed to a tablet. Alternatively, the composition may be in a dosage form such as powder or granule. For parenteral administration, it is formulated into an aqueous solution or suspension suitable for subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, etc. Also, the composition can be provided as suppositories, topical formulations, eye-drops and the like. Examples of pharmaceutically acceptable salts of the compound of the invention include salt or intra-molecular salts with inorganic bases, ammonia, organic bases, inorganic acids, organic acids, basic amino acids, halogen ions, etc. Examples of said inorganic base include alkali metals (Na, K, etc.), alkaline earth metals (Ca, Mg, etc.). Examples of the organic base include trimethylamine, triethylamine, choline, procaine, ethanolamine, etc. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid and the like. Examples of organic acid include p-toluenesulphonic acid, methanesulphonic acid, formic acid, trifluoro acetate, maleic acid and the like. Examples of basic amino acid include lysine, arginine, ornithine, histidine and the like. The above salts may be a solvate.
Oral administration can be practiced in a solid or liquid dose form prepared according to a conventional method, such as tablet, powder, capsule, granule, suspension, solution, syrup, lozenge, sublingual tablet and other dosage forms. If necessary, unit dosage form for oral administration can be microcapsulated. Also, such formulation can be applied with a coating or embedded into polymer or wax, in order to prolong the duration of activity or provide sustained release.
Parenteral administration can be practiced in a liquid dosage form prepared according to a conventional method, such as an injectable solution and suspension. Among others, oral administration and intravenous administration by injection are preferred. For administration, of course, it should be practiced in a dosage form suitable for such administration.
Preferable dose for oral administration is generally about 10 mg to 4000 mg, preferably 100 mg to 2000 mg per day. For parenteral administration, preferable dose is about 10 mg to 4000 mg, preferably 50 mg to 2000 mg per day.
While the following Examples, Test Examples and Formulation Examples describe further the present invention, the invention should not be limited to these Examples, Test Examples and Formulation Examples. Accordingly, one skilled in the art could readily prepare any compound of the invention by selecting appropriately starting materials, reagents and conditions in a reaction, with referring to, and with any modification if necessary, to the above general description and the following Examples.
Abbreviations used in Preparations and Examples have the following meanings.
Ac=acetyl group, Et=ethyl group, Me=methyl group, Ph=phenyl group, Boc=t-butoxycarbonyl group, Cbz=benzyloxycarbonyl group, Bn=benzyl group.
EXAMPLE 1
Preparation of Compounds 12 and 13







a. Compound 3

An eggplant-shape flask was charged with NaH (60% in mineral oil; 1.2714 g, 31.79 mmol) and washed three times with n-hexane (5 cm3×3). After residual n-hexane was removed under reduced pressure, dimethylformamide (50 cm3) was added. Compound 1 (3.6313 g, 13.64 mmol) was added at room temperature and then stirred for 30 minutes at this temperature. Compound 2 (5.6310 g, 15.22 mmol) was then added dropwise at room temperature and stirred for 20 minutes at this temperature. The mixture was poured into water (200 cm3), followed by added with ethyl acetate (100 cm3) for separation, and extracted twice with ethyl acetate, washed once with water and once with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. After the drying reagent was filtered out, solvent was concentrated in vacuo. The residue was purified by silica gel column chromatography (BW-200, 120 g, eluant: from 20%→40% ethyl acetate/n-hexane) to afford Compound 3 (4.9678 g, 10.47 mmol). Yield: 77%.
1H NMR (CDCl3) δ=1.32-1.48 (9H, t-Bu), 3.21-4.32 (8H), 5.03-5.25 (2H, m, CH2Ph), 6.74-6.85 (1H, m), 7.22-7.42 (5H, m), and 7.84-7.95 (2H, m).
b. Compound 4
Compound 3 (4.9678 g, 10.47 mmol) was dissolved in ethanol (200 cm3), SnCl2.2H2O (13.0278 g, 57.73 mmol) was added. The mixture was heated to 80-90° C. and stirred for two hours. At the same temperature, NaBH4 (0.2778 g, 7.34 mmol) was dissolved in ethanol (10 cm3), and the solution was added slowly dropwise and stirred for additional one hour. After about two-thirds of ethanol was removed, saturated aqueous sodium hydrogen carbonate was added carefully until any effervescent is not occurred. The mixture was extracted four time with ethyl acetate, washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The drying reagent was filtered out, solvent was concentrated in vacuo. The residue was purified by silica gel column chromatography (BW-200.80 g, eluant: 10%→20%→50%→100% ethyl acetate/n-hexane) to afford Compound 4 (1.6021 g, 3.60 mol). Also, the compound, wherein the Boc-group has been removed, was obtained (M=344.38, 1.6304 g, 4.73 mmol, 45%). Yield: 34%.
1H NMR (CDCl3) δ=1.32-1.50 (9H, Boc), 3.00-3.58 (8H, m), 3.90-4.24 (2H, m), 5.05-5.30 (2H, m, CH2Ph), 6.30-6.45 (2H, m), 6.72-6.82 (1H, m), and 7.28-7.37 (5H, m, CH2Ph).
c. Compound 5
Compound 4 (1.6021 g, 3.60 mmol) was dissolved in methanol (20 cm3), and sodium carbonate (0.5856 g, 5.53 mmol) and Boc2O (1.1708 g, 5.36 mmol) was added. The mixture was stirred for 17 hours at room temperature. The mixture was separated with addition of Water (30 cm3) and ethyl acetate (50 cm3), followed by washed twice with ethyl acetate, and dried over anhydrous sodium sulfate. The drying reagent was filtered out, solvent was concentrated in vacuo. The residue was purified by silica gel column chromatography (BW-200, 50 g, eluant: 10%→20%→30% ethyl acetate/n-hexane) to afford Compound 5 (1.8683 g, 3.43 mmol). Yield: 95%.
1H NMR (CDCl3) δ=1.34-1.52 (18H, Boc), 3.10-3.52 (6H, m), 3.95-4.28 (2H, m), 5.05-5.29 (2H, m, CH2Ph), 6.38 (1H, brs, NHBoc), 6.77-6.89 (2H, m), and 7.21-7.36 (6H, m).
d. Compound 6
Compound 5 (1.8683 g, 3.43 mmol) in dried tetrahydrofuran (20 cm3) was subjected to aryl substitution and cooled to −78° C. To this solution, n-BuLi (1.54 M in n-hexane; 2.5 cm3, 3.85 mmol) was added slowly dropwise, and then stirred at the temperature for 10 min. (R)-glycidylbutyrate (0.6084 g, 4.22 mmol) dissolved in dried tetrahydrofuran (3 cm3) was added slowly dropwise, and the mixture was cooled to room temperature and stirred for 20 minutes. water (30 cm3) was added, and the mixture was extracted five times with ethyl acetate and dried over anhydrous sodium sulfate. After filtration, solvent was removed to obtain the residue (2.2370 g). The residue was dissolved in methanol (20 cm3), added with potassium carbonate (5.0776 g, 36.74 mmol) and stirred for 6 hours at room temperature. Water (30 cm3) was added, and the mixture was extracted five times with ethyl acetate and dried over anhydrous sodium sulfate. The drying reagent was filtered out, and solvent was concentrated in vacuo. The residue was purified by silica gel column chromatography (BW-200.30 g, eluant: 50%→100% ethyl acetate/n-hexane→2% methanol/dichloromethane) to afford Compound 6 (1.5838 g, 3.01 mmol). Yield: 88%.
1H NMR (CDCl3) δ=1.34-1.47 (9H, Boc), 2.59 (1H, br, OH), 3.16-3.40 (6H, m), 3.70-3.82 (1H, m), 3.89-4.27 (5H, m), 4.68-4.78 (1H, m, CH2CHCH2OH), 5.06-5.30 (2H, m, CH2Ph), 6.83-6.93 (1H, m), 7.02-7.13 (1H, m), and 7.27-7.46 (6H, m).
e. Compound 7
A solution of Compound 6 (1.5834 g, 3.01 mmol), triethylamine (0.65 cm3, 4.62 mmol) and dried dichloromethane (30 cm3), which has been cooled to 0° C. and diluted with dried dichloromethane (3 cm3), was added dropwise with methanesulfonyl chloride (0.3 cm3, 3.88 mmol) and stirred for 20 minutes at 0° C. Saturated aqueous NaHCO3 (50 cm3) was added, and the mixture was extracted three times with trichloromethane and dried over anhydrous sodium sulfate. After filtration, solvent was removed to obtain the residue (1.9525 g). The residue was dissolved in dimethylformamide (15 cm3), which was added with sodium azide (0.5870 g, 9.03 mmol) and stirred for two hours at 80 to 90° C. Water (50 cm3) was added, the mixture was extracted three times with ethyl acetate. The organic layer was washed sequentially with water and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. After filtration, After filtration, solvent was removed to obtain the residue. Purification by silica gel column chromatography (BW-200.40 g, eluant: 25%→30%→50% ethyl acetate/n-hexane) afforded Compound 7 (1.5894 g, 2.79 mmol). Yield: 93%.
1H NMR (CDCl3) δ=1.34-1.47 (9H, Boc), 3.18-4.28 (12H, m), 4.73-4.83 (1H, m, CH2CHCH2N3), 5.06-5.28 (2H, m, CH2Ph), 6.85-6.93 (1H, m), 7.02-7.13 (1H, m), and 7.28-7.45 (6H, m)
f. Compound 8
Compound 7 (1.5894 g, 2.79 mmol) was dissolved in tetrahydrofuran (20 cm3), followed by added with triphenylphosphine (1.1128 g, 4.240 mmol) and water (1 cm3) at room temperature, and the mixture was stirred for 16 hours at room temperature and for two hours at about 60° C. After confirming the consumption of the starting material, Solvent was removed, and the residue was then purified by silica gel column chromatography (BW-200, 30 g, eluant: ethyl acetate→5%→15% methanol/trichloromethane) to afford Compound 8 (1.4394 g, 2.65 mmol). Yield: 95%.
1H NMR (CDCl3) δ=1.34-1.48 (9H, Boc), 2.95 (1H, dd, J=5.8, 13.7 Hz), 3.11 (1H, dd, J=4.0, 13.7 Hz), 3.16-3.59 (6H, m), 3.76-3.84 (1H, m), 3.94-4.27 (3H, m), 4.62-4.72 (1H, m, CH2CH CH2N3), 5.06-5.29 (2H, m, CH2Ph), 6.84-6.92 (1H, m), 7.03-7.14 (1H, m), and 7.25-7.48 (6H, m).
g. Compound 9
Compound 8 (1.4394 g, 2.65 mmol) was dissolved in pyridine (20 cm3), and followed by added with acetic anhydride (2.0 cm3) and stirred for 1 hour at room temperature. Solvent was removed, and the residue was purified by silica gel column chromatography (BW-200.30 g, eluant: 0%→3%→5% methanol/trichloromethane) to afford Compound 9 (1.4769 g, 2.52 mmol). Yield: 95%.
h. Compound 10
Compound 9 (1.1139 g, 1.902 mmol) was dissolved in 5% ethanol (50 cm3), followed by added with 10% Pd/C (0.2073 g) for H2 Substitution carefully, and then the mixture was stirred at room temperature for 90 hours. After filtration through celite, Solvent was removed, and the residue was then purified by silica gel column chromatography (BW-200.30 g, eluant: 0%→2%→4% methanol/trichloromethane) to afford Compound 10 (0.8159 g, 1.807 mmol). Yield: 95%
1H NMR (CDCl3) δ=1.38 (9H, brs, Boc), 2.03 (3H, s, ac), 3.08-3.16 (2H, m), 3.40-3.48 (2H, m), 3.53-3.77 (8H, m), 4.00 (1H, t, J=9.0 Hz), 4.72-4.81 (1H, m), 6.45 (1H, brs, NHAc), 6.87 (1H, t, J=9.0 Hz), 6.99 (1H, dd, J=2.4, 9.0 Hz), and 7.36 (1H, dd, J=2.4, 15.1 Hz).
i. Compound 11
Compound 10 (0.2016 g, 0.477 mmol) was dissolved in pyridine (5 cm3), followed by added with acetic anhydride (3 cm3) and stirred for 18 hours at room temperature. Solvent was removed, and the residue was then purified by silica gel column chromatography (BW-200, 15 g, eluant: 50%→100% ethyl acetate/n-hexane→4% methanol/trichloromethane) to afford Compound 11 (0.2055 g, 0.416 mmol). Yield: 93%.
1H NMR (CDCl3) δ=1.48 (9H, s, Boc), 2.03 (3H, s, NHAc), 2.05 (3H, s, NNAc), 3.08-3.78 (10H, m), 4.01 (1H, dt, J=3.0, 9.1 Hz), 4.25-4.40 (1H, m), 4.72-4.82 (1H, m), 6.08 (1H, t, J=6.0 Hz, NHAc), 6.89 (1H, t, J=9.1 Hz), 7.05 (1H, br d, J=9 Hz), and 7.40 (1H, dd, J=2.5, 14.6 Hz).
j. Compound 12
Compound 11 (0.1462 g, 0.296 mmol) was dissolved in dichloromethane (5 cm3), followed by added with trifluoroacetic acid (1 cm3) and stirred at room temperature for two hours. Saturated aqueous potassium carbonate was added to adjust to neutral pH, and followed by extracted five times with trichloromethane. After dryness over anhydrous sodium sulfate, the drying reagent was filtered out and solvent was remove. The residue was purified by silica gel column chromatography (BW-200, 15 g, eluant: 0%→5% →10% methanol/trichloromethane) to afford Compound 12 (0.1034 g, 0.263 mmol). Yield: 89%.
1H NMR (CDCl3) δ=1.97 (3H, s, NNAc), 2.03 (3H, s, NHAc), 3.06-3.14 (1H, m), 3.16-3.23 (1H, m), 3.34-3.44 (3H, m), 3.54-3.80 (6H, m), 3.88-3.94 (1H, m), 4.01 (1H, t, J=8.8 Hz), 4.72-4.81 (1H, m), 6.08-6.16 (1H, br), 6.84-6.93 (1H, m), 6.96-6.75 (1H, m), and 7.37-7.48 (1H, m).
k. Compound 13
2-aminothiazole (135.6 mg, 1.354 mmol) was dissolved in dichloromethane (10 cm3), followed by added with triphosgene (138.1 mg, 0.465 mmol) at 0° C. After dropwise addition of triethylamine (0.4 cm3, 2.846 mmol), Compound 10 (154.4 mg, 0.342 mmol) was added. The mixture was cooled to room temperature and stirred for 75 hours. 10% citric acid aqueous solution (20 cm3) was added and extracted twice with trichloromethane. After dryness over anhydrous sodium sulfate, the drying reagent was filtered out. Solvent was removed, and the residue was then dissolved in dichloromethane (10 cm3), followed by added with trifluoroacetic acid (1.0 cm3) and stirred at room temperature for 24 hours. The mixture was neutralized with saturated aqueous sodium carbonate and extracted five times with 10% methanol/trichloromethane. After dryness over anhydrous sodium sulfate, the drying reagent was filtered out. Solvent was removed, and the residue was then purified by silica gel column chromatography (BW-200, 10 g, eluant: 1%→3%→5% methanol/trichloromethane) to afford Compound 13 (80.0 mg, 0.168 mmol). Yield: 49%.
1H NMR (CDCl3) δ=2.02 (3H, s, ac), 3.22-4.25 (12H, m), 4.70-4.81 (1H, m), 6.73 (1H, t, J=6.1 Hz, NHAc), 6.84-7.03 (3H, m), 7.33-7.43 (2H, m), and 9.84 (1H, s, N═C—NHC═O).
EXAMPLE 2
Preparation of Compound 24




a. Compound 16

To a suspension of commercially available bis(chloroethyl)amine monohydrate (5.7974 g, 32.48 mmol) and sodium carbonate (3.6300 g, 34.25 mmol) in methanol (80 cm3) and water (40 cm3), benzyl chloroformate (6.0 cm3, 33.77 mmol) was added slowly dropwise at 0° C., and the mixture was stirred for 3 hours at this temperature. Methanol was removed by half, water (50 cm3) was added, followed by extracted for times with dichloromethane, washed with saturated aqueous sodium chloride. After dryness over sodium sulfate, filtration and concentration to obtain the residue containing Compound 14 as a main product (10.674 g). Another eggplant-shape flask was charged with NaH (60% in mineral oil; 2.0544 g, 51.36 mmol) and washed with n-hexane (5 cm3×3). Residual n-hexane was removed under reduced pressure, dimethylformamide (80 cm3) was added and aryl substituted. After cooling to 0° C., Compound 15 (4.1983 g, 18.07 mmol) was added and stirred for 10 min. at this temperature. The above residue containing Compound 14 (10.674 g) was dissolved in dimethylformamide (20 cm3) and added dropwise to the mixture and stirred gently for 41 hours with cooling to room temperature. The mixture was poured into water (400 cm3), and extracted three times with ethyl acetate and once with water, washed with saturated aqueous sodium chloride. Purification by silica gel column chromatography (BW-200, 150 g, eluant: 15%→20%→30% ethyl acetate/n-hexane) afforded 7.1642 g of desired residue containing 7-membered ring compound (5-Cbz derivative) as a main product. The residue was dissolved in methanol (120 cm3) and dichloromethane (40 cm3), followed by added with 10% Pd/C (0.7241 g) for H2 substitution and stirred at room temperature for 23 hours. After celite filtration, filtrate was concentrated, and the residue was purified by silica gel column chromatography (BW-200, 100 g, eluant:ethyl acetate→methanol:triethylamine:dichloromethane=10:2:88) to afford Compound 16 (3.4838 g, 11.56 mmol). Yield: 64%
1H NMR (CDCl3) δ=1.43-1.51 (18H, Boc×2), 2.96-3.54 (6H, m), and 3.98-4.26 (2H, m), and 6.62 (1H, brs, NH).
b. Compound 17
Compound 16 (5.6532 g, 18.76 mmol) was dissolved in CH3CN (40 cm3), followed by added with potassium carbonate (2.8864 g, 20.88 mmol) and 2-chloro-5-nitro pyridine (3.5675 g, 22.50 mmol), and the mixture was heated under reflux for 19 hours. Water (50 cm3) was added to the mixture, which was then extracted four times with ethyl acetate. After dryness over anhydrous sodium sulfate, the drying reagent was filtered out. Solvent was removed, and the residue was then purified by silica gel column chromatography (BW-200, 120 g, eluant: 10%→20%→30% ethyl acetate/n-hexane) to afford solid Compound 17 (5.0881 g, 12.02 mmol). Yield: 64%
1H NMR (CDCl3) δ=1.43 (18H, s, Boc×2), 3.12-3.45 (2H, m), 3.66-4.31 (6H, m), 6.53 (1H, d, J=9.6 Hz), 8.23 (1H, dd, J=2.8, 9.6 Hz), and 9.04 (1H, m)
c. Compound 18
Compound 17 (5.2346 g, 12.36 mmol) was dissolved in ethanol (100 cm3), followed by added with 10% Pd/C (1.4253 g) to obtain a suspension. The suspension was subjected to hydrogen substitution and stirred at room temperature for 3.5 hours.
After filtration through celite, solvent was removed. The residue (0.8354 g) was purified by silica gel column chromatography (BW-200, 80 g, eluant: 30%→50%→100% ethyl acetate/n-hexane) to afford Compound 18 (4.7463 g, 12.06 mmol). Yield: 98%
d. Compound 19
Compound 18 (4.7463 g, 12.06 mmol) was dissolved in acetone (40 cm3) and water (20 cm3), followed by added with sodium carbonate (1.7605 g, 16.61 mmol) and benzyl chloroformate (2.60 cm3, 14.63 mmol), and stirred at room temperature for 1 hour. Acetone was removed, and ethyl acetate (100 cm3) was added to separate the phase. After dryness over anhydrous sodium sulfate, the drying reagent was filtered out. Solvent was removed, and the residue was then purified by silica gel column chromatography (BW-200, 90 g, eluant: 10%→35% ethyl acetate/n-hexane) to afford Compound 19 (6.2841 g, 11.91 mmol).
e. Compound 20
Compound 19 (6.2841 g, 11.91 mmol) was dissolved in dried tetrahydrofuran (50 cm3), followed by subjected to aryl substitution and cooled to −78° C. To this solution, n-BuLi (1.58 M in n-hexane; 8.0 cm3, 12.64 mmol) was added slowly dropwise, followed by stirring at this temperature for 5 min. (R)-glycidyl butyrate (1.9001 g, 13.18 mmol) in dried tetrahydrofuran (2 cm3) was added slowly dropwise, and cooled to room temperature and stirred for 21 hour. Water (50 cm3) was added and the mixture was extracted four times with ethyl acetate, washed once with saturated aqueous sodium chloride. After dryness over anhydrous sodium sulfate, the drying reagent was filtered out. Solvent was removed, and the residue was then purified by silica gel column chromatography (BW-200, 80 g, eluant: 50%→100% ethyl acetate/n-hexane) to afford Compound 20 (4.0759 g, 8.258 mmol). Yield: 69%.
1H NMR (CDCl3) δ=1.43 (18H, s, Boc×2), 2.75 (1H, brs, OH), 3.10-4.26 (12H, m), 4.69-4.79 (1H, m), 6.53 (1H, d, J=9.3 Hz), 7.82-7.92 (1H, m), and 8.07-8.12 (1H, m).
f. Compound 21
To the mixture of Compound 20 (4.0759 g, 8.26 mmol), triethylamine (1.8 cm3, 12.81 mmol) and dried dichloromethane (80 cm3) at 0° C., methanesulfonyl chloride (0.8 cm3, 10.34 mmol) was added dropwise and stirred at 0° C. for 20 min. Saturated aqueous sodium hydrogen carbonate (50 cm3) was added to the mixture to separate the phase, and aqueous layer was extracted twice with trichloromethane. The organic layer was combined and dried over anhydrous sodium sulfate. After filtration, solvent was removed. The residue (4.8528 g) was dissolved in dimethylformamide (40 cm3), followed by added with sodium azide (1.0125 g, 15.57 mmol) and stirred at 40 to 50° C. for 15 hours. Water (150 cm3) was added and extracted three times with ethyl acetate, washed once with saturated aqueous sodium chloride. After dryness over anhydrous sodium sulfate, the drying reagent was filtered out, and solvent was removed. The residue (4.4467 g) was dissolved in tetrahydrofuran (40 cm3), followed by added with triphenylphosphine (3.2983 g, 12.58 mmol) and water (2.0 cm3) at room temperature, and the mixture was stirred for two hours at 50° C. Solvent was removed, and the residue was purified by silica gel column chromatography (BW-200, 100 g, eluant: ethyl acetate→15% methanol/trichloromethane) to afford Compound 21 (3.8884 g, 7.89, mmol). Yield: 96%.
1H NMR (CDCl3) δ=1.43 (18H, s, Boc×2), 2.88-4.26 (12H, m), 4.63-4.75 (1H, m), 6.55 (1H, d, J=9.3 Hz), 7.86-7.96 (1H, m), and 8.06-8.12 (1H, m).
g. Compound 22
Compound 21 (1.0932 g, 2.219 mmol) in dichloromethane (10 cm3) was added with pyridine (1.0 cm3) and acetic anhydride (1.0 cm3), and the mixture was stirred at room temperature for 25 hours. Solvent was removed, and the residue was purified by silica gel column chromatography (BW-200, 40 g, eluant: 50% ethyl acetate/n-hexane→3% methanol/ethyl acetate→3% methanol/trichloromethane) to afford Compound 22 (0.9087 g, 1.700 mmol). Yield: 77%.
1H NMR (CDCl3) δ=1.43 (18H, s, Boc×2), 2.03 (3H, s, ac), 3.10-4.26 (12H, m), 4.73-4.82 (1H, m), 6.02 (1H, t, J=6.2 Hz, NHAc), 6.55 (1H, d, J=9.3 Hz), 7.76-7.83 (1H, m), and 8.07-8.11 (1H, m).
h. Compound 23
Compound 22 (0.2444 g, 0.457 mmol) in dichloromethane (10 cm3) was added with trifluoroacetic acid (1.0 cm3), and the mixture was stirred at room temperature for 3 hours. Solvent was removed, and the residue was dissolved in dichloromethane (10 cm3), followed by added with BnOCH2COCl (0.1293 g, 0.700 mmol) in triethylamine (0.5 cm3) and dichloromethane (2 cm3) and stirred at room temperature for 21 hours. Water (20 cm3) was added and extracted five times with 10% methanol/trichloromethane. After dryness over anhydrous sodium sulfate, the drying reagent was filtered out. Solvent was removed, and the residue was purified by silica gel column chromatography (BW-200, 10 g, eluant: 3% methanol/trichloromethane) to afford Compound 23 (0.1010 g, 0.209 mmol). Yield: 46%.
i. Compound 24
Compound 23 (0.1010 g, 0.209 mmol) in ethanol (5 cm3) was added with 10% Pd/C (0.0981 g) to obtain a suspension. The suspension was subjected to hydrogen substitution, and stirred at room temperature for 64 hours. After filtration through celite, solvent was removed. The residue (0.8354 g) was purified by silica gel column chromatography (BW-200, 80 g, eluant: 3%→10% methanol/trichloromethane) to afford Compound 24 (0.0190 g, 0.0484 mmol). Yield: 23%.
1H NMR (CDCl3) δ=2.03 (3H, s, ac), 3.00-4.04 (12H, m), 4.33 (2H, s, CH2OH), 4.73-4.83 (1H, m), 6.37 (1H, t, J=6.0 Hz, NHAc), 6.51-6.57 (1H, m), 7.75-7.82 (1H, m), and 8.09-8.12 (1H, m).
EXAMPLE 3
Preparation of Compounds 35 and 36







a. Compound 26

3,4,5-trifluoro nitro benzene (25) (3.6970 g, 23.32 mmol) in diethanolamine (19.40 g, 184.5 mmol) was stirred at 110-120° C. for two hours. Water (50 cm3) was added and extracted five times with ethyl acetate. After dryness over anhydrous sodium sulfate, the drying reagent was filtered out. Solvent was removed, and the residue was purified by silica gel column chromatography (BW-200,150 g, eluant: 1%→2%→5%→10% methanol/trichloromethane) to afford Compound 26 (7.5182 g, 28.67 mmol). Yield: 87%.
1H NMR (CDCl3) δ=2.41 (2H, brs, OH×2), 3.47-3.58 (4H, m), 3.69-3.81 (4H, m), and 7.80 (2H, d, J=9.1 Hz).
b. Compound 27
To a solution of Compound 26 (7.5182 g, 28.67 mmol), triethylamine (10.0 cm3, 71.15 mmol) and dried dichloromethane (10.0 cm3) at 0° C., methanesulfonyl chloride (5.0 cm3, 64.60 mmol) was added dropwise and stirred at 0° C. for 1 hour. Saturated aqueous sodium hydrogen carbonate (100 cm3) was added to separate the phase. The aqueous layer was extracted three times with trichloromethane, and the organic layer was combined and dried over anhydrous sodium sulfate. After filtration, solvent was removed, and the residue (4.8528 g) was purified by silica gel column chromatography (BW-200, 150 g, eluant: 20%→50% ethyl acetate/n-hexane→1%→2% methanol/trichloromethane) to afford Compound 27 (11.9906 g, 28.66 mmol). Yield: 100%.
1H NMR (CDCl3) δ=3.00 (6H, s, Ms×2), 3.71-3.76 (4H, m), 4.29-4.34 (4H, m), and 7.83 (2H, d, J=9.1 Hz).
c. Compound 28
An eggplant-shape flask was charged with NaH (60% in mineral oil; 2.4320 g, 60.80 mmol) and washed with n-hexane (5 cm3×3). Residual n-hexane was removed under reduced pressure, and dimethylformamide (80 cm3) was added. Compound 1 (7.5056 g, 28.19 mmol) was added at room temperature, and the mixture was stirred at this temperature for 30 minutes. Compound 27 (11.9906 g, 28.66 mmol) in dimethylformamide (30 cm3) was added dropwise at room temperature, and the mixture was stirred for 20 minutes at this temperature. The mixture was poured into water (400 cm3), followed by extracted four times with ethyl acetate, twice with water, and washed once with saturated aqueous sodium chloride. After dryness over anhydrous sodium sulfate, the drying reagent was filtered out, and solvent was concentrated in vacuo. The residue was purified by silica gel column chromatography (BW-200, 150 g, eluant: 10%→20%→50% ethyl acetate/n-hexane) to afford Compound 28 (6.3121 g, 12.82 mmol). Yield: 45%.
1H NMR (CDCl3) δ=1.36 (9H, s, Boc), 3.23-3.77 (6H, m), 3.96-4.25 (2H, m), 5.08-5.31 (2H, m, OCH2Ph), 7.30-7.39 (5H, m), and 7.77 (2H, d, J=9.9 Hz).
d. Compound 29
Compound 28 (6.3121 g, 12.82 mmol) was dissolved in a combined solution of ethanol (100 cm3) and water (1 cm3). To the solution, 10% Pd/C (0.6837 g) was added to obtain a suspension. The suspension was subjected to hydrogen substitution and stirred at room temperature for 41 hour. After filtration through celite, solvent was removed. The residue (0.8354 g) was dissolved in acetone (60 cm3) and water (30 cm3), and the mixture was added with sodium carbonate (3.2019 g, 30.21 mmol) and benzyl chloroformate (5.0 cm3, 28.14 mmol). The mixture was stirred at room temperature for 1 hour. Acetone was removed, water (100 cm3) and ethyl acetate (100 cm3) were added to separate the phase. After dryness over anhydrous sodium sulfate, the drying reagent was filtered out, and solvent was removed. The residue was purified by silica gel column chromatography (BW-200, 120 g, eluant: 10%→15%→30% ethyl acetate/n-hexane) to afford Compound 29 (7.2419 g, 12.14 mmol). Yield: 95%.
e. Compound 30
Compound 29 (7.2419 g, 12.14 mmol) in dried tetrahydrofuran (60 cm3) was subjected to aryl substitution and cooled to −78° C. To this solution, n-BuLi (1.54 M in n-hexane; 8.8 cm3, 13.55 mmol) was added slowly dropwise, and followed by stirred for 5 min. at this temperature. (R)-glycidyl butyrate (1.9622 g, 13.61 mmol) in dried tetrahydrofuran (2 cm3) was then added slowly dropwise, and cooled to room temperature and stirred for 20 minutes. Water (50 cm3) was added to the mixture, which was extracted five times with ethyl acetate, and dried over anhydrous sodium sulfate. The drying reagent was filtered out, and solvent was removed. The residue (8.9592 g) was dissolved in methanol (50 cm3) and added with potassium carbonate (5.0460 g, 36.51 mmol). The mixture was stirred at room temperature for 1 hour. Methanol was removed, and water (50 cm3) was added and extracted five times with ethyl acetate. After dryness over anhydrous sodium sulfate, the drying reagent was filtered out, and solvent was removed. Purification by silica gel column chromatography (BW-200,120 g, eluant: 50%→1% methanol/ethyl acetate) afforded Compound 30 (5.5651 g, 9.89 mmol). Yield: 81%.
1H NMR (CDCl3) δ=1.36 (9H, s, Boc), 2.81 (1H, t, J=6.3 Hz, CH2OH), 3.03-4.16 (12H, m), 4.68-4.78 (1H, m), 5.07-5.32 (2H, m, OCH2Ph), 7.12 (2H, br d, J=9 Hz), and 7.28-7.40 (5H, m).
f. Compound 31
To a solution of Compound 30 (5.5651 g, 9.89 mmol), triethylamine (2.0 cm3, 14.23 mmol) and dried dichloromethane (50 cm3) at 0° C., methanesulfonyl chloride (1.0 cm3, 12.92 mmol) was added dropwise and stirred at 0° C. for 15 minutes. Methanol (1 cm3) and saturated aqueous sodium hydrogen carbonate (30 cm3) were added to separate the phase. The aqueous layer was extracted twice with trichloromethane, and the organic layer was combined and dried over anhydrous sodium sulfate. After filtration, solvent was removed. The residue was dissolved in dimethylformamide (50 cm3), and sodium azide (1.0848 g, 16.69 mmol) was added and stirred at 40-50° C. for 16 hours. Water (100 cm3) was added to the mixture, which was extracted three times with ethyl acetate, washed once with saturated aqueous sodium chloride. After dryness over anhydrous sodium sulfate, the drying reagent was filtered out, and solvent was removed. The residue was purified by silica gel column chromatography (BW-200, 100 g, eluant: 20→30→50% ethyl acetate/n-hexane) to afford Compound 31 (5.7033 g, 9.71 mmol). Yield: 98%.
1H NMR (CDCl3) δ=1.37 (9H, s, Boc), 3.05-4.20 (12H, m), 4.74-4.84 (1H, m), 5.08-5.33 (2H, m, OCH2Ph), 7.12 (2H, br d, J=9 Hz), and 7.30-7.40 (5H, m).
g. Compound 32
Compound 31 in tetrahydrofuran (50 cm3) was added with triphenylphosphine (3.9751 g, 15.16 mmol) and water (1.0 cm3) at room temperature and stirred at 50° C. for 16 hours. Solvent was removed, and the residue was purified by silica gel column chromatography (BW-200, 120 g, eluant: ethyl acetate→10% methanol/trichloromethane) to afford Compound 32 (5.0795 g, 9.05 mmol). Yield: 93%.
1H NMR (CDCl3) δ=1.37 (9H, s, Boc), 2.88-4.18 (12H, m), 4.63-4.73 (1H, m), 5.08-5.33 (2H, m, OCH2Ph), 7.13 (2H, br d, J=9 Hz), and 7.30-7.40 (5H, m).
h. Compound 33
Compound 32 (0.9751 g, 1.736 mmol) in pyridine (5 cm3) was added with acetic anhydride (3.0 cm3) and stirred at room temperature for 1 hour. Solvent was removed, and the residue was dissolved in a combined liquid of ethanol (20 cm3) and water (2 cm3), and followed by added with 10% Pd/C (0.5584 g) to obtain a suspension. The suspension was subjected to hydrogen substitution and stirred at room temperature for 44 hours. After filtration through celite, solvent was removed. The residue was purified by silica gel column chromatography (BW-200.30 g, eluant: 1%→3% methanol/trichloromethane) to afford Compound 33 (0.7821 g, 1.666 mmol). Yield: 96%.
1H NMR (CDCl3) δ=1.49 (9H, s, Boc×2), 2.03 (3H, s, ac), 3.02-3.08 (2H, m), 3.23-3.30 (2H, m), 3.37-3.44 (2H, m), 3.57-3.75 (5H, m), 3.99 (1H, t, J=9.1 Hz), 4.73-4.82 (1H, m), 6.12 (1H, t, J=6.0 Hz, NHAc), and 7.08 (2H, d, J=10.7 Hz).
i. Compound 34
Compound 32 (0.9751 g, 1.736 mmol) in methanol (5 cm3) was added with triethylamine (1.0 cm3) and (1.0 cm3), and the mixture was stirred at room temperature for 1 hour. Solvent was removed, and the residue was dissolved in a combined liquid of ethanol (20 cm3) and water (4 cm3), and added with 10% Pd/C (0.4436 g) to obtain a suspension. The suspension was subjected to hydrogen substitution, and stirred at room temperature for 42 hours. After filtration through celite, solvent was removed. The residue was purified by silica gel column chromatography (BW-200.30 g, eluant: 2%→3% methanol/trichloromethane) to afford Compound 34 (0.7005 g, 1.386 mmol). Yield: 93%.
1H NMR (CDCl3) δ=1.49 (9H, s, Boc×2), 3.02-3.08 (2H, m), 3.23-3.30 (2H, m), 3.37-3.45 (2H, m), 3.57-3.73 (4H, m), 3.79-3.90 (1H, m), 4.05 (1H, t, J=9.1 Hz), 4.77-4.87 (1H, m), 5.94 (1H, t, J=54.0 Hz, CHF2), and 6.99-7.12 (3H, m).
j. Compound 35
3-amino-5-methyl isoxazole (103.5 mg, 1.06 mmol) in dichloromethane (10 cm3) was added with triphosgene (104.5 mg, 0.352 mmol) at 0° C. and then with triethylamine (0.4 cm3, 2.85 mmol) dropwise, and the mixture was stirred at this temperature for 10 min. At this temperature, Compound 33 (87.4 mg, 0.187 mmol) was added, and cooled to room temperature and stirred for 24 hours. 10% citric acid aqueous solution (20 cm3) was added to the mixture, which was extracted three times with trichloromethane. After dryness over anhydrous sodium sulfate, the drying reagent was filtered out. Solvent was removed, and the residue was dissolved in dichloromethane (5 cm3), followed by added with trifluoroacetic acid (0.5 cm3), and the mixture was stirred at room temperature for 16 hours. The mixture was neutralized with 10% sodium carbonate aqueous solution (20 cm3), and extracted four times with 10% methanol/trichloromethane. After dryness over anhydrous sodium in dichloromethane (5 cm3), followed by added with trifluoroacetic acid (0.5 cm3) and stirred at room temperature for 21 hours. The mixture was neutralized with 10% sodium carbonate aqueous solution (30 cm3), and extracted four times with 10% methanol/trichloromethane. After dryness over anhydrous sodium sulfate, the drying reagent was filtered out, and solvent was removed. The residue was purified by silica gel column chromatography (BW-200, 8 g, eluant: 1%→2%→5% methanol/trichloromethane) to afford Compound 36 (61.2 mg, 0.132 mmol). Yield: 85%.
1H NMR (CDCl3) δ=3.11-3.19 (2H, m), 3.26-3.42 (4H, m), 3.63-3.90 (5H, m), 4.06 (1H, t, J=9.1 Hz), 4.39 (2H, s, CH2OH), 4.79-4.90 (1H, m), 5.95 (1H, t, J=54.1 Hz, CHF2), 7.08 (2H, d, J=10.7 Hz), and 7.45 (1H, t, J=6.2 Hz, NHC═O).
The compounds of Examples 4-103, which structures and physical data are as follows, were prepared according to the procedures in Examples as described above.
EXAMPLE 4




1H NMR (CDCl3) δ 2.03 (1H, s, Ac), 2.53 (6H, s, Me×2), 3.15-3.21 (4H, m), 3.36-3.43 (4H, m), 3.61-3.68 (2H, m), 3.75 (1H, dd, J=6.6, 9.1 Hz), 4.01 (1H, t, J=9.1 Hz), 4.73-4.82 (1H, m, CH2CHCH2NHAc), 6.74-6.82 (1H, br, NHAc), 6.80-6.87 (1H, m), 6.96-7.03 (1H, m), and 7.31-7.38 (1H, m)
EXAMPLE 5




1H NMR (CDCl3) δ 1.09 (3H, t, J=7.1 Hz, NCH2CH3), 2.03 (3H, s, Ac), 2.53 (3H, s, NMe), 2.72 (2H, q, J=7.1 Hz), 3.12-3.27 (4H, m), 3.34-3.42 (4H, m), 3.55-3.76 (3H, m), 4.01 (1H, t, J=9.1 Hz), 4.71-4.81 (1H, m, CH2CHCH2NHAc), 6.25 (1H, t, J=6.2 Hz, NHAc), 6.82-6.90 (1H, m), 6.98-7.04 (1H, m), and 7.32-7.40 (1H, m).
EXAMPLE 6




1H NMR (CDCl3) δ 2.03 (3H, s, NHAc), 2.19 (3H, s, NAc), 2.57 (3H, NMe), 2.84-2.99 (2H, m), 3.16-3.77 (8H, m), 4.01 (1H, t, J=9.1 Hz), 4.24-4.34 (1H, m), 4.69-4.82 (1H, m, CH2CHCH2NHAc), 6.28 (1H, br, NHAc), 6.85-6.93 (1H, m), 6.97-7.03 (1H, m), and 7.38-7.47 (1H, m).
EXAMPLE 7




1H NMR (CDCl3) δ 2.02 (3H, s, Ac), 2.51 (3H, s, NMe), 2.92 (1H, dd, J=7.8, 12.5 Hz), 3.12 (1H, dd, J=8.2, 14.0 Hz), 3.28-3.53 (5H, m), 3.60 (1H, dt, J=6.1, 14.6 Hz), 3.68 (1H, dd, J=3.3, 6.1 Hz), 3.74 (1H, dd, J=6.9, 9.1 Hz), 4.02 (1H, t, J=9.1 Hz), 4.44-4.53 (1H, m), 4.72-4.82 (1H, m, CH2CHCH2NHAc), 6.19 (1H, t, J=6.1 Hz, NHAc), 6.90-6.98 (1H, m), 7.00-7.06 (1H, m), and 7.33-7.58 (1H, m)
EXAMPLE 8




1H NMR (CDCl3) δ 2.17 (3H, s, Ac), 2.51 (3H, s, NMe), 2.87-2.97 (1H, m), 3.06-3.16 (1H, m), 3.28-3.52 (5H, m), 3.70 (1H, dd, J=6.1, 9.1 Hz), 4.03-4.24 (3H, m), 4.45-4.55 (1H, m), 4.89-4.99 (1H, m, CH2CHCH2NHAc), 6.89-7.08 (2H, m), and 7.33-7.71 (11H, m).
EXAMPLE 9




1H NMR (CDCl3) δ 2.02 (3H, s, Ac), 2.64 (1.5H, s, NMe), 2.77 (1.5H, s, NMe), 2.82-3.77 (11H, m), 3.94-4.05 (2H, m), 4.70-4.81 (1H, m, CH2CHCH2NHAc), 5.09-5.29 (2H, m, CH2Ph), 6.14 (1H, t, J=6.0 Hz, NHAc), 6.81-6.92 (1H, m), 6.97-7.04 (1H, m), and 7.2@5-7.44 (6H, m).
EXAMPLE 10




1H NMR (CDCl3) δ 1.34 (9H, s, Boc), 2.02 (3H, s, Ac), 3.18-3.76 (9H, m), 3.95-4.27 (3H, m), 4.71-4.81 (1H, m), 5.06-5.28 (2H, m, CH2Ph), 6.13 (1H, br t, J=6 Hz, NHAc), 6.87 (1H, t, J=9.1 Hz), 6.98-7.07 (1H, m), and 7.30-7.44 (6H, m).
EXAMPLE 11




1H NMR (CDCl3) δ 1.38 (9H, br s, Boc), 2.03 (3H, s, Ac), 3.08-3.16 (2H, m), 3.40-3.48 (2H, m), 3.53-3.77 (8H, m), 4.00 (1H, t, J=9.0 Hz), 4.72-4.81 (1H, m), 6.45 (1H, br s, NHAc), 6.87 (1H, t, J=9.0 Hz), 6.99 (1H, dd, J=2.4, 9.0 Hz), and 7.36 (1H, dd, J=2.4, 15.1 Hz).
EXAMPLE 12




1H NMR (CDCl3) δ 2.01 (3H, s, Ac), 3.20-3.79 (11H, m), 4.01 (1H, t, J=9.1 Hz), 4.77 (1H, br), 5.95 (1H, br, NNH), 6.39 (1H, br, NHAc), 6.84-6.95 (1H, m), 6.98-7.15 (2H, m), and 7.2@5-7.41 (5H, m).
EXAMPLE 13




1H NMR (CDCl3) δ 2.02 (3H, s, NHAc), 3.10-3.77 (9H, m), 3.95-4.26 (5H, m), 4.39-4.69 (4H, m), 4.71-4.81 (1H, m), 6.10-6.25 (1H, br, NHAc), 6.97 (1H, t, J=9.1 Hz), 7.03 (1H, br d, J=9 Hz), 7.30-7.39 (5H, m, CH2Ph), and 7.41 (1H, br d, J=15 Hz).
EXAMPLE 14




1H NMR (CDCl3) δ 2.02 (3H, s, Ac), 3.02 (2H, t, J=4.7 Hz), 3.14-3.78 (9H, m), 3.97-4.26 (5H, m), 4.49-4.63 (2H, m), 4.72-4.82 (1H, m), 6.06 (1H, t, J=6.0 Hz, NHAc), 6.90 (1H, t, J=9.1 Hz), 7.02-7.09 (1H, m), and 7.4@2-7.50 (1H, m)
EXAMPLE 15




1H NMR (CDCl3) δ 2.52 (6H, s, Me×2), 3.12-3.20 (4H, m), 3.34-3.43 (4H, m), 3.59-3.78 (3H, m), 4.01 (1H, t, J=9.0 Hz), 4.11 (2H, s, CH2OH), 4.73-4.83 (1H, m), 6.82 (1H, t, J=9.1 Hz), 7.01 (1H, dd, J=2.4, 9.1 Hz), 7.31 (1H, dd, J=2.4, 14.8 Hz), and 7.35 (1H, br s, NH)
EXAMPLE 16




1H NMR (CDCl3) δ 3.10-3.62 (9H, m), 3.74-4.30 (10H, m), 4.68-4.79 (1H, m), 5.05 (1H, t, J=6.0 Hz), 5.60 (1H, t, J=6.0 Hz, NH), 7.04-7.16 (2H, m), 7.40-7.50 (1H, m), and 8.08 (1H, t, J=6.0 Hz)
EXAMPLE 17




1H NMR (CDCl3) δ 2.02 (3H, s, Ac), 3.12-3.78 (9H, m), 3.91-4.05 (3H, m), 4.37 (2H, br s, CH2OH), 4.72-4.81 (1H, m), 6.27 (1H, br s, NHAc), 6.89 (1H, t, J=9.1 Hz), 6.98-7.06 (1H, m), and 7.37-7.46 (1H, m).
EXAMPLE 18




1H NMR (CDCl3) δ 2.94-3.52 (9H, m), 3.58-4.16 (8H, m), 4.37 (2H, br s), 4.74-4.84 (1H, m), 6.89 (1H, t, J=9.1 Hz), 6.99-7.16 (2H, m), and 7.3@6-7.45 (1H, m).
EXAMPLE 19




1H NMR (CDCl3) δ 2.02 (3H, s, Ac), 3.17-3.23 (2H, m), 3.35-3.42 (4H, m), 3.55-3.77 (3H, m), 3.81-3.89 (2H, m), 4.00 (1H, t, J=9.1 Hz), 4.71-4.81 (1H, m), 5.61 (1H, br s, NHH), 6.38 (1H, br, s, NHH), 6.89 (1H, t, J=9.1 Hz), 7.02 (1H, ddd, J=0.8, 2.5, 9.1 Hz), and 7.2@8-7.42 (2H, m).
EXAMPLE 20




1H NMR (CDCl3) δ 2.02 (3H, s, Ac), 3.12-3.78 (11H, m), 3.81-4.01 (2H, m), 4.00 (1H, t, J=9.1 Hz), 4.42 (2H, AB), 4.71-4.81 (1H, m), 6.14 (1H, br), 6.76 (1H, br t, J=5.5 Hz), 6.86-6.93 (1H, m), 6.98-7.07 (1H, m), and 7.2@2-7.46 (6H, m).
EXAMPLE 21




1H NMR (DMSO-d6+CDCl3) δ 2.02 (3H, s, Ac), 2.94-4.12 (20H, m), 4.66-4.86 (1H, m), 6.85-7.08 (2H, m), 7.35-7.45 (1H, m), and 7.95-8.10 (1H, br, NHAc).
EXAMPLE 22




1H NMR (CDCl3) δ 2.02 (3H, s, Ac), 3.13-3.76 (19H, m), 4.00 (1H, t, J=8.9 Hz), 4.71-4.81 (1H, m, CH2CHCH2), 6.19 (1H, br s, NHAc), 6.90 (1H, t, J=9.1 Hz), 7.01 (1H, br d, J=9 Hz), and 7.39 (1H, dd, J=2.6, 14.8 Hz).
EXAMPLE 23




EXAMPLE 24




1H NMR (CDCl3) δ 2.02 (3H, s, NHAc), 2.80 (3H, d, J=4.8 Hz, MeNH—C═O), 3.10-4.04 (12H, m), 4.71-4.81 (1H, m, CH2CHCH2), 6.26-6.42 (2H, br, MeNH—C═O and NHAc), 6.88 (1H, t, J=9.1 Hz), 6.96-7.04 (1H, m), and 7.3@5-7.45 (1H, m).
EXAMPLE 25




1H NMR (CDCl3) δ 2.02 (3H, s, Ac), 2.86 (6H, s, NMe2), 3.12-4.06 (12H, m), 4.71-4.81 (1H, m, NCH2CHCH2), 6.25 (1H, br s, NHAc), 6.90 (1H, t, J=9.1 Hz), 7.01 (1H, br d, J=9 Hz), and 7.38 (1H, dd, J=2.5, 14.6 Hz).
EXAMPLE 26




1H NMR (CDCl3) δ 2.02 (3H, s, Ac), 3.05-3.11 (4H, m), 3.43-3.50 (4H, m), 3.61-3.68 (2H, m), 3.75 (1H, dd, J=6.6, 9.1 Hz), 4.00 (1H, t, J=9.1 Hz), 4.72-4.82 (1H, m), 6.89 (1H, t, J=9.1 Hz), 6.89-6.99 (1H, br, NHAc), 7.01 (1H, dd, J=2.5, 9.1 Hz), and 7.34 (1H, dd, J=2.5, 15.1 Hz).
EXAMPLE 27




1H NMR (CDCl3) δ 1.46 (18H, S, Boc×2), 3.17-3.78 (9H, m), 3.92-4.23 (5H, m), 4.55 (2H, s, CH2Ph), 4.69-4.80 (1H, m), 6.88 (1H, t, J=9.1 Hz), 6.98-7.14 (2H, m), and 7.2@6-7.42 (6H, m).
EXAMPLE 28




1H NMR (CDCl3) δ 2.40 (1H, br s, OH), 3.10-4.04 (10H, m), 4.15-4.36 (2H, m), 4.65-4.78 (1H, m), 4.95-5.20 (4H, m, CH2Ph×2), 6.68 (1H, d, J=7.8 Hz), and 7.15-7.45 (2H, m).
EXAMPLE 29




1H NMR (CDCl3) δ 1.99 (s, Ac, a1), 2.00 (s, Ac, a2), 3.22-4.34 (m, b1), 4.66-4.77 (m, b2), 4.96-5.18 (m, b3), 6.63-6.71 (m, c1), 7.17-7.34 (m, c2). integral ratio; a1+a2:b1:b2:b3:c1:c2+c3=3:13:1:4:3:11.
EXAMPLE 30




1H NMR (CDCl3) δ 2.03 (3H, s, Ac), 3.44-3.51 (4H, m), 3.57-3.80 (3H, m), 4.03 (1H, t, J=8.9 Hz), 4.13-4.18 (4H, m), 4.73-4.82 (1H, m, CH2CHCH2), 5.99 (1H, t, J=6.3 Hz, NHAc), 7.00 (1H, t, J=9.1 Hz), 7.11 (1H, br d, J=9 Hz), 7.49 (1H, dd, J=2.6, 14.0 Hz), 7.76-7.80 (2H, m), and 8.69-8.73 (2H, m).
EXAMPLE 31




1H NMR (DMSO-d6) δ 1.83 (6H, s, Ac×2), 3.05-3.14 (2H, m), 3.28-3.48 (6H, m), 3.68 (1H, dd, J=6.3, 9.2 Hz), 3.73-3.82 (2H, m), 4.06 (1H, t, J=9.1 Hz), 4.64-4.74 (1H, m), 4.98 (2H, d, J=6.3 Hz, NCH2N), 5.36 (1H, t, J=6.1 Hz), 7.00-7.15 (2H, m), 7.44 (1H, dd, J=2.5, 15.6 Hz), 7.57-7.66 (4H, m), 8.23 (1H, t, J=6.0 Hz), 8.79 (1H, s, N—CH═C), 8.88 (1H, t, J=6.0 Hz), and 9.07 (1H, s).
EXAMPLE 32




1H NMR (DMSO-d6) δ 1.83 (6H, s, Ac×2), 3.00-4.15 (16H, m), 4.64-4.76 (2H, m), 5.49 (1H, t, J=6.1 Hz), 7.00-7.24 (3H, m), 7.40-7.63 (2H, m), 7.98 (1H, t, J=9.1 Hz), 8.23 (2H, br s), and 8.84 (1H, s).
EXAMPLE 33




1H NMR (CDCl3) δ 2.00 (3H, s, Ac), 3.08-3.76 (9H, m), 3.92-4.21 (5H, m), 4.38-4.80 (7H, m), 6.52 (1H, br s, NHAc), 6.84 (1H, t, J=9.1 Hz), 6.97-7.05 (1H, m), and 7.25-7.43 (11H, m).
EXAMPLE 34




1H NMR (CDCl3) δ 2.02 (3H, s, Ac), 2.38 (3H, s, Aryl-Me), 3.22-4.04 (12H, m), 4.71-4.81 (1H, m), 6.20 (1H, br s, NHAc), 6.63 (1H, s, CH═CMe), 6.90 (1H, t, J=9.1 Hz), 7.03 (1H, br d, J=9 Hz), 7.41 (1H, dd, J=2.5, 14.6 Hz), and 9.10 (1H, s, Aryl-NHC═O).
EXAMPLE 35




1H NMR (CDCl3) δ 2.03 (3H, s, NHAc), 3.10-3.16 (1H, m), 3.23-3.29 (1H, m), 3.34-3.39 (1H, m), 3.41-3.45 (2H, m), 3.55-3.86 (6H, m), 3.96-4.05 (1H, m), 4.71-4.82 (1H, m, CH2CHCH2), 6.32 (1H, br s, NHAc), 6.81-6.93 (1H, m), 6.97-7.06 (1H, m), 7.36-7.43 (1H, m), 7.89 (0.5H, s, CHO) and 8.33 (0.5H, s, CHO).
EXAMPLE 36




1H NMR (CDCl3) δ 2.03 (3H, s, Ac), 3.23-3.45 (6H, m), 3.56-3.78 (4H, m), 3.91-4.05 (2H, m), 4.44 (2H, s, CH2Cl), 4.72-4.82 (1H, m, CH2CHCH2), 6.30 (1H, br s, NHAc), 6.85-6.93 (1H, m), 6.98-7.06 (1H, m), and 7.38-7.46 (1H, m).
EXAMPLE 37




1H NMR (CDCl3) δ 2.02 (3H, s, Ac), 3.09-3.22 (2H, m), 3.32-3.44 (4H, m), 3.52-3.77 (6H, m), 3.89-3.94 (1H, m), 3.97-4.04 (1H, m), 4.72-4.81 (1H, m, CH2CHCH2), 6.34 (1H, br t, J=6 Hz, NHAc), 6.83-6.92 (1H, m), 6.98-7.06 (1H, m), and 7.40 (1H, dd, J=2.4, 14.6 Hz).
EXAMPLE 38




1H NMR (DMSO-d6) δ 1.83 (3H, s, Ac), 2.92-3.72 (11H, m), 4.06 (1H, t, J=9.1 Hz), 4.64-4.74 (1H, m, CH2CHCH2), 4.96 (1H, t, J=6.1 Hz), 6.99 (1H, t, J=9.1 Hz), 7.10 (1H, dd, J=2.5, 9.1 Hz), 7.41 (1H, dd, J=2.5, 15.7 Hz), and 8.24 (1H, t, J=6.1 Hz).
EXAMPLE 39




1H NMR (CDCl3) δ 2.03 (3H, s, Ac), 2.59 (6H, s, NMe2), 3.11-3.19 (2H, m), 3.34-3.41 (4H, m), 3.52-3.78 (5H, m), 4.00 (1H, t, J=9.1 Hz), 4.72-4.82 (1H, m, CH2CHCH2), 6.46 (1H, t, J=6.0 Hz, NHAc), 6.89 (1H, t, J=9.1 Hz), 7.01 (1H, br d, J=9 Hz), 7.17 (1H, s, NHNMe2), and 7.39 (1H, dd, J=2.5, 14.6 Hz).
EXAMPLE 40




EXAMPLE 41




1H NMR (CDCl3) δ 0.68-0.96 (4H, m), 1.62-1.67 (1H, m), 2.03 (3H, s, Ac), 3.06-3.44 (5H, m), 3.55-3.95 (6H, m), 4.01 (1H, t, J=9.1 Hz), 4.72-4.81 (1H, m, CH2CHCH2), 6.18 (1H, br, NHAc), 6.89 (1H, br t, J=9 Hz), 7.01 (1H, br t, J=9 Hz), and 7.41 (1H, br t, J=15 Hz).
EXAMPLE 42




1H NMR (CDCl3) δ 1.99 (3H, s, Ac), 3.09-3.17 (2H, m), 3.33-3.42 (2H, m), 3.50-3.91 (8H, m), 3.96 (1H, t, J=8.9 Hz), 4.30 (2H, d, J=6.0 Hz, NH CH2-Aryl), 4.68-4.77 (1H, m, CH2CHCH2), 6.53-6.67 (3H, m), 6.75 (1H, t, J=6.1 Hz), 6.83-6.91 (2H, m), 6.99 (1H, br d, J=9 Hz), 7.04-7.11 (1H, m), and 7.37 (1H, dd, J=2.8, 14.8 Hz).
EXAMPLE 43




1H NMR (CDCl3) δ 3.17-3.25 (2H, m), 3.32-3.47 (4H, m), 3.57-4.00 (5H, m), 4.07 (1H, t, J=9.1 Hz), 4.37 (2H, s, CH2OH), 4.76-4.86 (1H, m), 5.94 (1H, t, J=54.1 Hz, CHF2), 6.86-7.07 (3H, m), and 7.36-7.44 (1H, m).
EXAMPLE 44




1H NMR (DMSO-d6) δ 2.97-3.76 (11H, m), 4.06 (1H, t, J=8.8 Hz), 4.19 (2H, s, CH2OH), 4.62-4.75 (1H, m), 7.02 (1H, t, J=9.9 Hz), 7.11 (1H, dd, J=2.5, 9.9 Hz), 7.43 (1H, dd, J=2.5, 15.7 Hz), 8.24 (1H, t, J=5.8 Hz), and 8.32 (1H, s).
EXAMPLE 45




EXAMPLE 46




1H NMR (CDCl3) δ 2.02 (3H, s, Ac), 2.09 (6H, s, AcN-NAc), 3.14-3.26 (4H, m), 3.43-3.54 (2H, m), 3.56-3.78 (3H, m), 3.79-4.05 (1H, m), 4.48-4.60 (2H, m), 4.72-4.82 (1H, m), 6.25 (1H, t, J=6.0 Hz, NHAc), 6.89 (1H, t, J=9.1 Hz), 7.05 (1H, br d, J=9 Hz), and 7.41 (1H, dt, J=14.6, 2.5 Hz).
EXAMPLE 48




1H NMR (CDCl3) δ 1.40-1.52 (18H, Boc×2), 3.05-4.36 (20H, m), 4.68-4.78 (1H, m), 4.96-5.20 (5H, m), 6.67 (2H, br d, J=8.8 Hz), and 7.17-7.35 (12H, m).
EXAMPLE 49




1H NMR (CDCl3) δ 1.36-1.43 (18H, Boc×2), 3.12-4.36 (16H, m), 4.69-4.79 (1H, m), 4.96-5.20 (4H, m), 5.34-5.52 (1H, m) 6.60-6.70 (5H, m), and 7.02-7.38 (14H, m).
EXAMPLE 50




EXAMPLE 51




EXAMPLE 52




1H NMR (CDCl3) δ 1.31 (3H, t, J=7.2 Hz, OCH2CH3), 1.99 (3H, s, Ac), 3.15-3.25 (2H, m), 3.28-3.35 (2H, m), 3.38-3.45 (2H, m), 3.57-3.85 (5H, m), 3.98 (1H, t, J=8.8 Hz), 4.29 (2H, q, J=7.2 Hz, OCH2CH3), 4.69-4.79 (1H, m), 6.72 (1H, t, J=6.1 Hz, NHAc), 6.86 (1H, t, J=9.1 Hz), 6.94-7.03 (1H, m), and 7.37 (1H, dd, J=2.5, 14.6 Hz).
EXAMPLE 53




1H NMR (CDCl3) δ 1.34 (3H, t, J=7.1 Hz), 1.37 (3H, t, J=7.1 Hz), 2.47 (3H, s, Ac), 3.20-3.47 (6H, m), 3.70-4.20 (6H, m), 4.32 (2H, q, J=7.1 Hz), 4.37 (2H, q, J=7.1 Hz), sulfate, the drying reagent was filtered out, and solvent was removed. The residue was purified by silica gel column chromatography (BW-200, 8 g, eluant: 2%→5% methanol/trichloromethane) to afford Compound 35 (81.5 mg, 0.165 mmol). Yield: 88%.
1H NMR (CDCl3) δ=2.03 (3H, s, ac), 2.38 (3H, s, C═C-Me), 3.16-3.24 (2H, m), 3.29-3.42 (4H, m), 3.62-4.03 (6H, m), 4.77-4.88 (1H, m), 6.21-6.33 (1H, br, NHC═O), 6.65 (1H, s, Me-C═CH), 7.10 (2H, d, J=10.7 Hz), and 9.14 (1H, s, NH Ar).
k. Compound 36
Compound 34 (78.9 mg, 0.156 mmol) in dichloromethane (3 cm3) was added with triethylamine (0.05 cm3, 0.356 mmol) at room temperature, and BnOCH2COCl (36.5 mg, 0.198 mmol) in dichloromethane (1 cm3) was added and stirred for 1 hour. A small amount of methanol was added, and then water (20 cm3) was added and extracted twice with trichloromethane. After dryness over anhydrous sodium sulfate, the drying reagent was filtered out, and solvent was removed. The residue was dissolved in ethanol (5 cm3), followed by added with 10% Pd/C (88.9 mg) and subjected to H2 substitution and stirred at room temperature for 122 hours. After celite filtration, solvent was removed. The residue was dissolved 4.80-4.91 (1H, m), 6.91 (1H, t, J=9.1 Hz), 6.99-7.08 (1H, m), and 7.40 (1H, dd, J=2.5, 14.6 Hz).
EXAMPLE 54




1H NMR (CDCl3) δ 2.02 (3H, s, Ac), 3.20-3.76 (10H, m), 3.95-4.15 (2H, m), 4.70-4.81 (1H, m), 6.30-6.40 (1H, br), 6.48 (1H, dd, J=1.7, 3.6 Hz), 6.86-7.03 (2H, m), 7.38 (1H, dd, J=2.6, 14.8 Hz), and 7.53 (1H, s).
EXAMPLE 55




1H NMR (CDCl3) δ 2.01 (3H, s, Ac), 3.02-4.12 (12H, m), 4.72-4.82 (1H, m), 6.38 (1H, br s, NHAc), and 6.82-7.44 (7H, m).
EXAMPLE 56




1H NMR (CDCl3) δ 1.96 (3H, s, Ac), 3.16-3.76 (11H, m), 3.97 (1H, t, J=8.8 Hz), 4.69-4.79 (1H, m), 5.87 (1H, br s), and 6.81-7.38 (7H, m).
EXAMPLE 57




1H NMR (CDCl3) δ 2.03 (3H, s, Ac), 3.38-3.50 (4H, m), 3.65-3.69 (2H, m), 3.79 (1H, dd, J=6.5, 9.1 Hz), 4.03 (1H, t, J=9.1 Hz), 4.38-4.47 (4H, m), 4.75-4.85 (1H, m), 6.82 (1H, t, J=6.1 Hz, NHAc), 6.99 (1H, t, J=9.1 Hz), 7.05-7.11 (2H, m), 7.46 (1H, dd, J=2.5, 14.0 Hz), 8.16 (1H, dd, J=1.7, 8.0 Hz), and 8.53 (1H, dd, J=1.7, 5.0 Hz).
EXAMPLE 58




1H NMR (CDCl3) δ 2.03 (3H, s, Ac), 2.24 (3H, s, Aryl-Me), 3.24-4.05 (12H, m), 4.72-4.82 (1H, m), 6.03 (1H, s), 6.35 (1H, t, J=6.0 Hz, NHAc), 6.90 (1H, t, J=9.0 Hz), 7.00-7.06 (1H, m), 7.41 (1H, dd, J=2.5, 14.6 Hz), and 9.29 (1H, s, Aryl-NHC═O).
EXAMPLE 59




1H NMR (CDCl3) δ 2.02 (3H, s, Ac), 2.37 (3H, s, Aryl-Me), 3.23-4.03 (12H, m), 4.71-4.80 (1H, m), 6.42 (1H, t, J=6.0 Hz, NHAc), 6.48 (1H, s), 6.88 (1H, t, J=9.2 Hz), 7.00 (1H, br dd, J=3, 9 Hz), 7.40 (1H, dd, J=2.5, 14.6 Hz), and 9.33 (1H, s, Aryl-NHC═O).
EXAMPLE 60




1H NMR (CDCl3) δ 2.02 (3H, s, Ac), 2.37 (3H, s, Aryl-Me), 3.24-4.04 (12H, m), 4.70-4.81 (1H, m), 6.40 (1H, t, J=6.0 Hz, NHAc), 6.48 (1H, s), 6.88 (1H, t, J=9.2 Hz), 7.00 (1H, br dd, J=3, 9 Hz), 7.40 (1H, dd, J=2.7, 14.4 Hz), and 9.33 (1H, s, Aryl-NHC═O).
EXAMPLE 61




1H NMR (CDCl3) δ 2.02 (3H, s, Ac), 3.26-4.08 (12H, m), 4.71-4.81 (1H, m), 6.16 (1H, t, J=6.0 Hz), 6.87-7.81 (5H, m), 7.68-7.81 (2H, m), and 9.96 (1H, s, Aryl-NHC═O).
EXAMPLE 62




1H NMR (CDCl3) δ 3.11-3.18 (2H, m), 3.35-3.43 (4H, m), 3.53-3.78 (6H, m), 3.84-4.02 (2H, m), 4.41 (2H, AB), 4.68-4.78 (1H, m), 6.76 (1H, t, J=6.0 Hz, CHCH2NHC═O), 6.84-7.05 (2H, m), 7.20-7.45 (6H, m), and 7.74 (1H, t, J=6.3 Hz, NH CH2Ph).
EXAMPLE 63




EXAMPLE 64




1H NMR (DMSO-d6) δ 2.95-4.11 (13H, m), 4.20 (2H, s), 4.63-4.74 (1H, m), 6.98-7.14 (2H, m), 7.44 (1H, br d, J=16 Hz), and 8.26 (1H, br t, J=6 Hz).
EXAMPLE 65




1H NMR (CDCl3) δ 2.16 (3H, s, Ac), 3.13-4.10 (12H, m), 4.78-4.88 (1H, m), 4.93 (2H, s, CH2OAC), 6.04 (1H, s, CHCl2), 6.50-6.57 (1H, m), 7.52 (1H, t, J=6.1 Hz, NHC═O), 7.73 (1H, dd, J=2.8, 9.1 Hz), and 8.09 (1H, d, J=2.8 Hz).
EXAMPLE 66




1H NMR (CDCl3) δ 3.00-4.10 (12H, m), 4.34 (2H, AB, CH2OH), 4.79-4.88 (1H, m), 5.98 (1H, s, CHCl2), 6.52-6.58 (1H, m), 7.11 (1H, t, J=6.0 Hz, NHC═O), 7.77-7.82 (1H, m), and 8.08-8.11 (1H, m).
EXAMPLE 67




1H NMR (CDCl3) δ 1.43 (18H, s, Boc×2), 2.88-4.26 (12H, m), 4.63-4.75 (1H, m), 6.55 (1H, d, J=9.3 Hz), 7.86-7.96 (1H, m), and 8.06-8.12 (1H, m).
EXAMPLE 68




1H NMR (CDCl3) δ 1.43 (18H, s, Boc×2), 2.03 (3H, S, Ac), 3.10-4.26 (12H, m), 4.73-4.82 (1H, m), 6.02 (1H, t, J=6.2 Hz, NHAc), 6.55 (1H, d, J=9.3 Hz), 7.76-7.83 (1H, m), and 8.07-8.11 (1H, m).
EXAMPLE 69




1H NMR (CDCl3) δ 1.43 (18H, s, Boc×2), 3.10-4.26 (12H, m), 4.79-4.89 (1H, m), 5.98 (1H, s, CHCl2), 6.55 (1H, d, J=9.3 Hz), 7.28 (1H, br s, NHC═O), 7.72-7.81 (1H, m), and 8.06-8.11 (1H, m).
EXAMPLE 70




1H NMR (CDCl3) δ 2.03 (3H, s, NHAc), 2.10 (3H, s, OAC), 3.06-3.52 (6H, m), 3.63-3.78 (3H, m), 3.99 (1H, t, J=9.1 Hz), 4.19 (2H, AB, CH2 OAC), 4.40-4.50 (2H, m), 4.74-4.84 (1H, m), 6.34 (1H, br t, J=6 Hz, NHAc), and 7.11 (2H, d, J=10.7 Hz).
EXAMPLE 71




1H NMR (CDCl3) δ 2.10 (3H, s, OAC), 3.06-3.52 (6H, m), 3.62-3.74 (2H, m), 3.79-3.89 (1H, m), 4.06 (1H, t, J=9.1 Hz), 4.19 (2H, AB, CH2 OAC), 4.40-4.50 (2H, m), 4.78-4.89 (1H, m), 5.94 (1H, t, J=54.1 Hz, CHF2), 6.97-7.10 (1H, br, NHC═O), and 7.10 (2H, d, J=10.7 Hz).
EXAMPLE 72




1H NMR (CDCl3) δ 1.02-1.15 (3H, m, CH3 CH2C═O), 2.02 (3H, s, Ac), 2.20 (1H, q, J=7.6 Hz, CH3CHHC═O), 2.58 (1H, q, J=7.6 Hz, CH3CHHC═O), 3.05-3.13 (1H, m), 3.16-3.22 (1H, m), 3.30-3.45 (3H, m), 3.56-3.78 (5H, m), 3.86-4.05 (2H, m), 4.72-4.82 (1H, m), 6.64-6.76 (1H, br, NHAc), 6.87 (1H, t, J=9.1 Hz), 6.96-7.04 (1H, m), and 7.34-7.45 (1H, m).
EXAMPLE 73




1H NMR (CDCl3) δ 2.01 (3H, s, Ac), 3.04-3.39 (6H, m), 3.54-4.05 (6H, m), 3.92 (2H, s, CH2Ph), 4.70-4.81 (1H, m), 6.28 (1H, br t, J=6 Hz, NHAc), 6.78-7.05 (2H, m), and 7.13-7.42 (6H, m).
EXAMPLE 74




1H NMR (CDCl3) δ 2.02 (3H, s, Ac), 3.16-3.21 (2H, m), 3.32-3.41 (4H, m), 3.45 (3H, s, OMe), 3.60-4.02 (6H, m), 4.35 (2H, s, CH2OMe), 4.71-4.82 (1H, m), 6.70 (1H, t, J=6.1 Hz, NHAc), 6.87 (1H, t, J=9.1 Hz), 7.01 (1H, dd, J=2.5, 9.1 Hz), and 7.39 (1H, dd, J=2.5, 14.6 Hz).
EXAMPLE 75




1H NMR (CDCl3) δ 1.99 (3H, s, Ac), 3.21-3.28 (2H, m), 3.33-3.44 (4H, m), 3.56-4.01 (6H, m), 4.68-4.79 (1H, m), 4.94 (2H, s, CH2OPh), 6.70-7.03 (6H, m), 7.22-7.29 (2H, m), and 7.39 (1H, dd, J=2.5, 14.6 Hz).
EXAMPLE 76




1H NMR (CDCl3) δ 1.25 (3H, t, J=7.5 Hz, CH3 CH2O), 2.03 (3H, s, Ac), 2.45-2.93 (4H, m), 3.06-3.78 (10H, m), 3.86-3.92 (1H, m), 4.01 (1H, t, J=9.1 Hz), 4.13 (2H, q, J=7.5 Hz, CH3 CH2O), 4.72-4.82 (1H, m), 6.56 (1H, br s, NHAc), 6.88 (1H, t, J=9.1 Hz), 6.97-7.05 (1H, m), and 7.34-7.45 (1H, m).
EXAMPLE 77




1H NMR (CDCl3) δ 2.38 (3H, s, Aryl-Me), 3.16-3.24 (2H, m), 3.29-3.42 (4H, m), 3.62-3.76 (2H, m), 3.78-3.91 (2H, m), 3.98 (1H, t, J=6.0 Hz), 4.06 (1H, t, J=9.1 Hz), 4.79-4.89 (1H, m), 5.94 (1H, t, J=54.1 Hz, CHF2), 6.64 (1H, s, Me-C═CH), 7.09 (2H, d, J=10.7 Hz), and 9.15 (1H, s, Aryl-NHC═O).
EXAMPLE 78




1H NMR (CDCl3) δ 3.44-3.50 (4H, m), 3.61-3.77 (2H, m), 3.87 (1H, ddd, J=3.3, 6.6, 14.6 Hz), 4.10 (1H, t, J=9.1 Hz), 4.13-4.19 (4H, m), 4.78-4.88 (1H, m), 5.94 (1H, t, J=54.1 Hz, CHF2), 6.84 (1H, br t, J=6 Hz, NHC═O), 7.00 (1H, t, J=9.0 Hz), 7.10 (1H, dd, J=2.5, 9.0 Hz), 7.46 (1H, dd, J=2.5, 13.9 Hz), 7.78 (2H, d, J=4.7 Hz,), and 8.71 (2H, d, J=4.7 Hz).
EXAMPLE 79




1H NMR (CDCl3) δ 3.41-3.50 (4H, m), 3.63-3.76 (2H, m), 3.84 (1H, ddd, J=3.3, 6.3, 14.6 Hz), 4.07 (1H, t, J=9.1 Hz), 4.10-4.16 (4H, m), 4.79-4.89 (1H, m), 5.94 (1H, t, J=54.1 Hz, CHF2), 7.07-7.15 (1H, br, NHC═O), 7.14 (2H, d, J=10.7 Hz), 7.78 (2H, d, J=4.7 Hz), and 8.71 (2H, d, J=4.7 Hz).
EXAMPLE 80




1H NMR (CDCl3) δ 3.39-3.51 (4H, m), 3.60-3.77 (2H, m), 3.86 (1H, ddd, J=3.2, 6.6, 14.2 Hz), 4.10 (1H, t, J=9.1 Hz), 4.39-4.48 (4H, m), 4.78-4.88 (1H, m), 5.94 (1H, t, J=54.1 Hz, CHF2), 6.90-7.02 (1H, br, NHAc), 7.00 (1H, t, J=9.1 Hz), 7.06-7.11 (2H, m), 7.46 (1H, dd, J=2.5, 13.7 Hz), 8.18 (1H, dd, J=1.7, 7.7 Hz), and 8.55 (1H, dd, J=1.7, 4.7 Hz).
EXAMPLE 81




1H NMR (CDCl3) δ 2.04 (3H, s, Ac), 3.38-3.50 (4H, m), 3.64-3.71 (2H, m), 3.78 (1H, dd, J=6.9, 9.1 Hz), 4.01 (1H, t, J=9.1 Hz), 4.35-4.50 (4H, m), 4.76-4.86 (1H, m), 6.71 (1H, t, J=6.0 Hz, NHAc), 7.07 (1H, dd, J=4.8, 7.8 Hz), 7.13 (2H, d, J=10.7 Hz), 8.16 (1H, dd, J=1.7, 7.8 Hz), and 8.53 (1H, dd, J=1.7, 4.8 Hz).
EXAMPLE 82




1H NMR (CDCl3) δ 3.38-3.49 (4H, m), 3.65-3.80 (2H, m), 3.83 (1H, ddd, J=3.9, 6.3, 14.6 Hz), 4.07 (1H, t, J=9.1 Hz), 4.35-4.49 (4H, m), 5.96 (1H, t, J=54.1 Hz, CHF2), 7.07 (1H, dd, J=4.7, 8.0 Hz), 7.12 (2H, d, J=10.5 Hz), 7.53 (1H, br t, J=6 Hz, NHC═O), 8.16 (1H, dd, J=1.6, 8.0 Hz), and 8.53 (1H, dd, J=1.6, 4.7 Hz).
EXAMPLE 83




1H NMR (CDCl3) δ 2.03 (3H, s, Ac), 3.17-3.26 (2H, m), 3.29-3.36 (2H, m), 3.37-3.44 (2H, m), 3.62-3.70 (2H, m), 3.72 (1H, dd, J=6.5, 9.1 Hz), 3.84-3.95 (1H, m), 3.96 (1H, t, J=9.1 Hz), 4.14 (1H, br t, J=6 Hz), 4.74-4.84 (1H, m), 6.52 (1H, t, J=6.1 Hz, NHAc), 6.87 (1H, d, J=3.6 Hz), 7.09 (2H, d, J=10.7 Hz), 7.37 (1H, d, J=3.6 Hz), and 9.87 (1H, br s, Aryl-NHC═O).
EXAMPLE 84




1H NMR (CDCl3) δ 3.18-3.26 (2H, m), 3.30-3.37 (2H, m), 3.37-3.45 (2H, m), 3.62-3.74 (2H, m), 3.78-3.96 (2H, m), 4.02-4.10 (2H, m), 4.78-4.88 (1H, m), 5.94 (1H, t, J=54.1 Hz, CHF2), 6.88 (1H, d, J=3.6 Hz), 7.09 (2H, d, J=10.7 Hz), 7.19 (1H, br t, J=6 Hz, NHC═O), 7.37 (1H, d, J=3.6 Hz), and 9.85 (1H, s, Aryl-NHC═O).
EXAMPLE 85




1H NMR (CDCl3) δ 2.03 (3H, s, Ac), 3.19-3.27 (2H, m), 3.32-3.44 (4H, m), 3.62-3.70 (3H, m), 3.74 (1H, dd, J=6.8, 9.1 Hz), 3.95-4.04 (2H, m), 4.73-4.83 (1H, m), 6.43 (1H, t, J=6.2 Hz, NHAc), 7.11 (2H, d, J=10.7 Hz), 7.44 (2H, d, J=4.8 Hz), and 8.42 (2H, d, J=4.8 Hz).
EXAMPLE 86




1H NMR (CDCl3) δ 3.19-3.28 (2H, m), 3.33-3.44 (4H, m), 3.61-3.74 (3H, m), 3.84 (1H, ddd, J=3.5, 6.3, 14.6 Hz), 3.96 (1H, t, J=6.3 Hz), 4.06 (1H, t, J=9.1 Hz), 4.78-4.88 (1H, m), 5.94 (1H, t, J=54.1 Hz, CHF2), 7.07-7.14 (1H, br, Aryl-NHC═O), 7.10 (2H, d, J=10.7 Hz), 7.44 (2H, d, J=5.0 Hz), and 8.43 (2H, d, J=5.0 Hz).
EXAMPLE 87




1H NMR (CDCl3) δ 2.02 (3H, s, Ac), 3.18-3.30 (2H, m), 3.36-3.46 (4H, m), 3.55-3.77 (3H, m), 3.87-4.05 (3H, m), 4.71-4.81 (1H, m), 6.28 (1H, br t, J=6 Hz, NHAc), 6.91 (1H, t, J=9.1 Hz), 7.00 (1H, d, J=1.6 Hz), 7.03 (1H, dd, J=2.5, 9.1 Hz), 7.41 (1H, dd, J=2.5, 14.6 Hz), 8.23 (1H, d, J=1.6 Hz), and 9.22 (1H, s, Aryl-NHC═O).
EXAMPLE 88




1H NMR (CDCl3) δ 2.03 (3H, s, Ac), 3.17-3.26 (2H, m), 3.30-3.42 (4H, m), 3.63-3.69 (2H, m), 3.74 (1H, dd, J=6.9, 9.1 Hz), 3.82-3.94 (1H, m), 3.96-4.04 (2H, m), 4.74-4.84 (1H, m), 6.36 (1H, t, J=6.1 Hz, NHAc), 7.02 (1H, d, J=1.7 Hz), 7.10 (2H, d, J=10.7 Hz), 8.24 (1H, d, J=1.7 Hz), and 9.26 (1H, s, Aryl-NHC═O).
EXAMPLE 89




1H NMR (CDCl3) δ 2.03 (3H, s, Ac), 2.25 (3H, s, Aryl-Me), 3.18-3.26 (2H, m), 3.29-3.42 (4H, m), 3.62-3.70 (2H, m), 3.74 (1H, dd, J=6.6, 9.1 Hz), 3.80-3.94 (1H, m), 4.00 (1H, t, J=9.1 Hz), 4.07 (1H, t, J=6.1 Hz), 4.74-4.84 (1H, m), 6.03 (1H, s, O—C═CH), 6.48 (1H, t, J=6.3 Hz, NHAc), 7.10 (2H, d, J=10.7 Hz), and 9.34 (1H, s, Aryl-NHC═O).
EXAMPLE 90




1H NMR (CDCl3) δ 2.26 (3H, s, Aryl-Me), 3.20-3.27 (2H, m), 3.30-3.43 (4H, m), 3.61-4.09 (6H, m), 4.78-4.88 (1H, m), 5.94 (1H, t, J=54.1 Hz), 6.24 (1H, s, O—C═CH), 6.96 (1H, br t, J=6 Hz, NHC═O), 7.10 (2H, d, J=10.7 Hz), and 9.34 (1H, s, Aryl-NHC═O).
EXAMPLE 91




1H NMR (CDCl3) δ 2.03 (3H, s, Ac), 3.10-3.22 (2H, m), 3.25-3.31 (2H, m), 3.34-3.42 (2H, m), 3.63-3.70 (2H, m), 3.75 (1H, dd, J=6.6, 9.1 Hz), 3.88-3.93 (2H, m), 4.01 (1H, t, J=9.1 Hz), 4.39 (2H, s, CH2OH), 4.75-4.85 (1H, m), 6.77 (1H, t, J=6.1 Hz, NHAc), and 7.09 (2H, d, J=10.7 Hz).
EXAMPLE 92




1H NMR (CDCl3) δ 2.01 (3H, s, Ac), 2.84-2.92 (1H, m), 3.26-3.32 (1H, m), 3.36-3.41 (1H, m), 3.49-3.54 (1H, m), 3.58-3.86 (6H, m), 3.95-4.08 (2H, m), 4.71-4.81 (1H, m), 6.73-6.82 (1H, m, NHAc), 6.84-7.04 (2H, m), 7.27-7.85 (3H, m), and 8.55 (1H, br d, J=5 Hz).
EXAMPLE 93




1H NMR (CDCl3) δ 2.01 (3H, s, Ac), 3.46-3.82 (9H, m), 3.96-4.15 (2H, m), 4.46-4.57 (1H, m), 4.72-4.82 (1H, m), 6.54 (1H, t, J=6.0 Hz, NHAc), and 6.91-8.58 (9H, m).
EXAMPLE 94




1H NMR (CDCl3) δ 2.03 (3H, s, Ac), 2.32 (3H, s, N-Me), 2.54-2.68 (4H, m), 2.76-2.93 (4H, m), 3.12-3.20 (2H, m), 3.33-3.40 (4H, m), 3.56-3.88 (5H, m), 4.00 (1H, t, J=9.1 Hz), 4.72-4.82 (1H, m), 6.54 (1H, t, J=6.1 Hz, NHAc), 6.88 (1H, t, J=9.1 Hz), 7.01 (1H, dd, J=2.4, 9.1 Hz), 7.19 (1H, s, N—NHC═O), and 7.39 (1H, dd, J=2.4, 14.6 Hz).
EXAMPLE 95




1H NMR (CDCl3) δ 2.02 (3H, S, Ac), 3.17-3.26 (2H, m), 3.36-3.44 (4H, m), 3.54-3.77 (4H, m), 3.84-3.93 (1H, m), 4.00 (1H, t, J=9.1 Hz), 4.54 (2H, AB, Ar CH2N), 4.71-4.81 (1H, m), 6.38 (1H, t, J=6.2 Hz, NHAc), 6.89 (1H, t, J=9.1 Hz), 7.01 (1H, dd, J=2.2, 9.1 Hz), 7.16 (1H, dd, J=4.9, 7.8 Hz), 7.24 (1H, t, J=5.8 Hz, CH2NHC═O), 7.30 (1H, d, J=7.8 Hz), 7.39 (1H, dd, J=2.2, 14.6 Hz), 7.64 (1H, dt, J=1.9, 7.8 Hz), and 8.54 (1H, br d, J=5 Hz).
EXAMPLE 96




1H-NMR in CDCl3: δ 2.02 (3H, s), 3.22 (2H, t, 6 Hz), 3.56 (1H, m), 3.68 (2H, t, 6 Hz), 3.74 (1H, m), 3.78 (2H, t, 6 Hz), 4.00 (1H, t, 9 Hz), 4.74 (1H, m), 6.07 (1H, bt), 6.73 (2H, d, 9 Hz), 7.31 (2H, d, 9 Hz)
EXAMPLE 97




1H-NMR in CDCl3: δ 2.03 (3H, s), 3.58 (1H, m), 3.76 (5H, m), 4.01 (3H, m), 4.12 (2H, t, 6 Hz), 4.29 (2H, bs), 4.75 (1H, m), 5.97 (1H, bt), 6.72 (2H, d, 9 Hz), 7.36 (2H, d, 9 Hz)
EXAMPLE 98




1H-NMR in CDCl3: δ 3.22 (2H, t, 6 Hz), 3.60-3.84 (2H, m), 3.68 (2H, t, 6 Hz), 3.78 (2H, t, 6 Hz), 4.06 (1H, t, 9 Hz), 4.78 (1H, m), 5.95 (1H, s), 6.73 (2H, d, 9 Hz), 7.00 (1H, bt), 7.30 (2H, d, 9 Hz)
EXAMPLE 99




EXAMPLE 100




1H-NMR in CDCl3: δ 2.03 (3H, s), 3.27 (2H, t, 6 Hz), 3.56 (2H, t, 6 Hz), 3.57-3.74 (4H, m), 3.93 (2H, t, 6 Hz), 4.01 (1H, t, 9 Hz), 4.75 (1H, m), 5.79 (1H, bs), 5.93 (1H, bt), 6.91 (1H, t, 9 Hz), 7.03 (1H, dd, 3, 9 Hz), 7.86 (1H, dd, 3, 9 Hz)
EXAMPLE 101




1H-NMR in CDCl3: δ 2.03 (3H, s), 3.08 (1H, bs), 3.52 (4H, m), 3.58-3.76 (2H, m), 4.01 (3H, m), 4.13 (2H, t, 6 Hz), 4.33 (2H, s), 4.75 (1H, m), 5.96 (1H, bs), 6.90 (1H, t, 9 Hz), 7.05 (1H, dd, 3, 9 Hz), 7.43 (1H, dd, 3, 9 Hz)
EXAMPLE 102




1H-NMR in CDCl3: δ 2.03 (3H, s), 2.59 (3H, s), 2.93 (2H, t, 6 Hz), 3.55-3.69 (3H, m), 3.73 (4H, t, 6 Hz), 3.95 (2H, t, 6 Hz), 4.01 (1H, t, 9 Hz), 4.73 (1H, m), 6.00 (1H, bt), 6.73 (2H, d, 10 Hz), 7.31 (2H, d, 10 Hz)
EXAMPLE 103




1H-NMR in CDCl3: δ 2.03 (3H, s), 2.65 (3H, s), 2.96 (2H, t, 6 Hz), 3.55 (3H, t, 6 Hz), 3.61 (2H, t, 6 Hz), 3.69-3.75 (3H, m), 3.94 (2H, t, 6 Hz), 4.00 (1H, t, 9 Hz), 4.74 (1H, m), 5.93 (1H, bt), 6.89 (1H, t, 10 Hz), 7.02 (1H, dd, 10, 4 Hz), 7.35 (1H, dd, 10, 4 Hz)
EXAMPLE 104




EXAMPLE 105




EXAMPLE 106




EXAMPLE 107




EXAMPLE 108




EXAMPLE 109




EXAMPLE 110




EXAMPLE 111




EXAMPLE 112




EXAMPLE 113




EXAMPLE 114




EXAMPLE 115




EXAMPLE 116




EXAMPLE 117




EXAMPLE 118




EXAMPLE 119




EXAMPLE 120




EXAMPLE 121




EXAMPLE 122




EXAMPLE 123




EXAMPLE 124




EXAMPLE 125




EXAMPLE 126




EXAMPLE 127




EXAMPLE 128




EXAMPLE 129




EXAMPLE 130




EXAMPLE 131




EXAMPLE 132




EXAMPLE 133




EXAMPLE 134a




EXAMPLE 134b




EXAMPLE 135




EXAMPLE 136




EXAMPLE 137




EXAMPLE 138




EXAMPLE 139




EXAMPLE 140




EXAMPLE 141




EXAMPLE 142




EXAMPLE 143




EXAMPLE 144




EXAMPLE 145




EXAMPLE 146




EXAMPLE 147




EXAMPLE 148




EXAMPLE 149




EXAMPLE 150




EXAMPLE 151




EXAMPLE 152




EXAMPLE 153




EXAMPLE 154




EXAMPLE 155




EXAMPLE 156




EXAMPLE 157




EXAMPLE 158




EXAMPLE 159




EXAMPLE 160




EXAMPLE 161




EXAMPLE 162




EXAMPLE 163




EXAMPLE 164




EXAMPLE 165




EXAMPLE 166




EXAMPLE 167




EXAMPLE 168




EXAMPLE 169




EXAMPLE 170




EXAMPLE 171




EXAMPLE 172




EXAMPLE 173




EXAMPLE 174




EXAMPLE 175




EXAMPLE 176




EXAMPLE 177




EXAMPLE 178




EXAMPLE 179




EXAMPLE 180




EXAMPLE 181




EXAMPLE 182




EXAMPLE 183




EXAMPLE 184




EXAMPLE 185




EXAMPLE 186




EXAMPLE 187




EXAMPLE 188




EXAMPLE 189




EXAMPLE 190




EXAMPLE 191




EXAMPLE 192




EXAMPLE 193




EXAMPLE 194




EXAMPLE 195




EXAMPLE 196




EXAMPLE 197




EXAMPLE 198




EXAMPLE 199




EXAMPLE 200




EXAMPLE 201




EXAMPLE 202




EXAMPLE 203




EXAMPLE 204




EXAMPLE 205




EXAMPLE 206




EXAMPLE 207




EXAMPLE 208




EXAMPLE 209




EXAMPLE 210




EXAMPLE 211




EXAMPLE 212




EXAMPLE 213




EXAMPLE 214




EXAMPLE 215




EXAMPLE 216




EXAMPLE 217




EXAMPLE 218




EXAMPLE 219




EXAMPLE 220




EXAMPLE 221




EXAMPLE 222




EXAMPLE 223




EXAMPLE 224




EXAMPLE 225




EXAMPLE 226




EXAMPLE 227




EXAMPLE 228




EXAMPLE 229




EXAMPLE 230




EXAMPLE 231




EXAMPLE 232




EXAMPLE 233




EXAMPLE 234




EXAMPLE 235




EXAMPLE 236




EXAMPLE 237




EXAMPLE 238




EXAMPLE 239




EXAMPLE 240




EXAMPLE 241




EXAMPLE 242




EXAMPLE 243




EXAMPLE 244




EXAMPLE 245




EXAMPLE 246




EXAMPLE 247




EXAMPLE 248




EXAMPLE 249




EXAMPLE 250




EXAMPLE 251




EXAMPLE 252




EXAMPLE 253




EXAMPLE 254




EXAMPLE 255




EXAMPLE 256




EXAMPLE 257




EXAMPLE 258




EXAMPLE 259




EXAMPLE 260




EXAMPLE 261




EXAMPLE 262




EXAMPLE 263




EXAMPLE 264




EXAMPLE 265




EXAMPLE 266




EXAMPLE 267




EXAMPLE 268




EXAMPLE 269




EXAMPLE 270




EXAMPLE 271




EXAMPLE 272




EXAMPLE 273




EXAMPLE 274




EXAMPLE 275




EXAMPLE 276




EXAMPLE 277




EXAMPLE 278




EXAMPLE 279




EXAMPLE 280




EXAMPLE 281




EXAMPLE 282




EXAMPLE 283




EXAMPLE 284




EXAMPLE 285




EXAMPLE 286




EXAMPLE 287




EXAMPLE 288




EXAMPLE 289




EXAMPLE 290




EXAMPLE 291




EXAMPLE 292




EXAMPLE 293




EXAMPLE 294




EXAMPLE 295




EXAMPLE 296




EXAMPLE 297




EXAMPLE 298




EXAMPLE 299




EXAMPLE 300




EXAMPLE 301




EXAMPLE 302




EXAMPLE 303




EXAMPLE 304




EXAMPLE 305




EXAMPLE 306




EXAMPLE 307




EXAMPLE 308




EXAMPLE 309




EXAMPLE 310




EXAMPLE 311




EXAMPLE 312




EXAMPLE 313




EXAMPLE 314




EXAMPLE 315




EXAMPLE 316




EXAMPLE 317




EXAMPLE 318




EXAMPLE 319




EXAMPLE 320




EXAMPLE 321




EXAMPLE 322




EXAMPLE 323




EXAMPLE 324




EXAMPLE 325




EXAMPLE 326




EXAMPLE 327




EXAMPLE 328




EXAMPLE 329




EXAMPLE 330




EXAMPLE 331




EXAMPLE 332




EXAMPLE 333




EXAMPLE 334




EXAMPLE 335




EXAMPLE 336




EXAMPLE 337




EXAMPLE 338




EXAMPLE 339




EXAMPLE 340




EXAMPLE 341




EXAMPLE 342




EXAMPLE 343




EXAMPLE 344




EXAMPLE 345




EXAMPLE 346




EXAMPLE 347




EXAMPLE 348




EXAMPLE 349




EXAMPLE 350




EXAMPLE 351




EXAMPLE 352




EXAMPLE 353




EXAMPLE 354




EXAMPLE 355




EXAMPLE 356




EXAMPLE 357




EXAMPLE 358




EXAMPLE 359




EXAMPLE 360




EXAMPLE 361




EXAMPLE 362




EXAMPLE 363




EXAMPLE 364




EXAMPLE 365




EXAMPLE 366




EXAMPLE 367




EXAMPLE 368




EXAMPLE 369




EXAMPLE 370




EXAMPLE 371




EXAMPLE 372




EXAMPLE 373




EXAMPLE 374




EXAMPLE 375




EXAMPLE 376




EXAMPLE 377




EXAMPLE 378




EXAMPLE 379




EXAMPLE 380




EXAMPLE 381




EXAMPLE 382




EXAMPLE 383




EXAMPLE 384




EXAMPLE 385




EXAMPLE 386




EXAMPLE 387




EXAMPLE 388




EXAMPLE 389




EXAMPLE 390




EXAMPLE 391




EXAMPLE 392




EXAMPLE 393




EXAMPLE 394




EXAMPLE 395




EXAMPLE 396




EXAMPLE 397




EXAMPLE 398




EXAMPLE 399




EXAMPLE 400




EXAMPLE 401




EXAMPLE 402




EXAMPLE 403




EXAMPLE 404




EXAMPLE 405




EXAMPLE 406




EXAMPLE 407




EXAMPLE 408




EXAMPLE 409




EXAMPLE 410




EXAMPLE 411




EXAMPLE 412




EXAMPLE 413




EXAMPLE 414




EXAMPLE 415




EXAMPLE 416




EXAMPLE 417




EXAMPLE 418




EXAMPLE 419




EXAMPLE 420




EXAMPLE 421




EXAMPLE 422




EXAMPLE 423




EXAMPLE 424




EXAMPLE 425




EXAMPLE 426




EXAMPLE 427




EXAMPLE 428




EXAMPLE 429




EXAMPLE 430




EXAMPLE 431




EXAMPLE 432




EXAMPLE 433




EXAMPLE 434




EXAMPLE 435




EXAMPLE 436




EXAMPLE 437




EXAMPLE 438




EXAMPLE 439




EXAMPLE 440




EXAMPLE 441




EXAMPLE 442




EXAMPLE 443




EXAMPLE 444




EXAMPLE 445




EXAMPLE 446




EXAMPLE 447




EXAMPLE 448




EXAMPLE 449




EXAMPLE 450




EXAMPLE 451




EXAMPLE 452




EXAMPLE 453




EXAMPLE 454




EXAMPLE 455




EXAMPLE 456




EXAMPLE 457




EXAMPLE 458




EXAMPLE 459




EXAMPLE 460




EXAMPLE 461




EXAMPLE 462




EXAMPLE 463




EXAMPLE 464




EXAMPLE 465




EXAMPLE 46.6




EXAMPLE 467




EXAMPLE 468




EXAMPLE 469




EXAMPLE 470




EXAMPLE 471




EXAMPLE 472




EXAMPLE 473




EXAMPLE 474




EXAMPLE 475




EXAMPLE 476




EXAMPLE 477




EXAMPLE 478




EXAMPLE 479




EXAMPLE 480




EXAMPLE 481




EXAMPLE 482




EXAMPLE 483




EXAMPLE 484




EXAMPLE 485




EXAMPLE 486




EXAMPLE 487




EXAMPLE 488




EXAMPLE 489




EXAMPLE 490




EXAMPLE 491




EXAMPLE 492




EXAMPLE 493




EXAMPLE 494




EXAMPLE 495




EXAMPLE 496




EXAMPLE 497




EXAMPLE 498




EXAMPLE 499




EXAMPLE 500




EXAMPLE 501




EXAMPLE 502




EXAMPLE 503




EXAMPLE 504




EXAMPLE 505




EXAMPLE 506




EXAMPLE 507




EXAMPLE 508




EXAMPLE 509




EXAMPLE 510




EXAMPLE 511




EXAMPLE 512




EXAMPLE 513




EXAMPLE 514




EXAMPLE 515




EXAMPLE 516




EXAMPLE 517




EXAMPLE 518




EXAMPLE 519




EXAMPLE 520




EXAMPLE 521




EXAMPLE 522




EXAMPLE 523




EXAMPLE 524




EXAMPLE 525




EXAMPLE 526




EXAMPLE 527




EXAMPLE 528




EXAMPLE 529




EXAMPLE 530




EXAMPLE 531




EXAMPLE 532




EXAMPLE 533




EXAMPLE 534




EXAMPLE 535




EXAMPLE 536




EXAMPLE 537




EXAMPLE 538




EXAMPLE 539




EXAMPLE 540




EXAMPLE 541




EXAMPLE 542




EXAMPLE 543




EXAMPLE 544




EXAMPLE 545




EXAMPLE 546




EXAMPLE 547




EXAMPLE 548




EXAMPLE 549




EXAMPLE 550




EXAMPLE 551




EXAMPLE 552




EXAMPLE 553




EXAMPLE 554




EXAMPLE 555




EXAMPLE 556




EXAMPLE 557




EXAMPLE 558




EXAMPLE 559




EXAMPLE 560




EXAMPLE 561




EXAMPLE 562




EXAMPLE 563




EXAMPLE 564




EXAMPLE 565




EXAMPLE 566




EXAMPLE 567




EXAMPLE 568




EXAMPLE 569




EXAMPLE 570




EXAMPLE 571




EXAMPLE 572




EXAMPLE 573




EXAMPLE 574




EXAMPLE 575




EXAMPLE 576




EXAMPLE 577




EXAMPLE 578




EXAMPLE 579




EXAMPLE 580




EXAMPLE 581




EXAMPLE 582




EXAMPLE 583




EXAMPLE 584




EXAMPLE 585




EXAMPLE 586




EXAMPLE 587




EXAMPLE 588




EXAMPLE 589




EXAMPLE 590




EXAMPLE 591




EXAMPLE 592




EXAMPLE 593




EXAMPLE 594




EXAMPLE 595




EXAMPLE 596




EXAMPLE 597




EXAMPLE 598




EXAMPLE 599




EXAMPLE 600




EXAMPLE 601




EXAMPLE 602




EXAMPLE 603




EXAMPLE 604




EXAMPLE 605




EXAMPLE 606




EXAMPLE 607




EXAMPLE 608




EXAMPLE 609




EXAMPLE 610




EXAMPLE 611




EXAMPLE 612




EXAMPLE 613a




EXAMPLE 613b




EXAMPLE 614




EXAMPLE 615




EXAMPLE 616




EXAMPLE 617




EXAMPLE 618




EXAMPLE 619




EXAMPLE 620




EXAMPLE 621




EXAMPLE 622




EXAMPLE 623




EXAMPLE 624




EXAMPLE 625




EXAMPLE 626




EXAMPLE 627




EXAMPLE 628




EXAMPLE 629




EXAMPLE 630




EXAMPLE 631




EXAMPLE 632




EXAMPLE 633




EXAMPLE 634




EXAMPLE 635




EXAMPLE 636




EXAMPLE 637a




EXAMPLE 637b




EXAMPLE 638




EXAMPLE 639




EXAMPLE 640




EXAMPLE 641




EXAMPLE 642




EXAMPLE 643




EXAMPLE 644




EXAMPLE 645




EXAMPLE 646




EXAMPLE 647




EXAMPLE 648




EXAMPLE 64.9




EXAMPLE 650




EXAMPLE 651




EXAMPLE 652




EXAMPLE 653




EXAMPLE 654




EXAMPLE 655




EXAMPLE 656




EXAMPLE 657




EXAMPLE 658




EXAMPLE 659




EXAMPLE 660




EXAMPLE 661




EXAMPLE 662




EXAMPLE 663




EXAMPLE 664




EXAMPLE 665




EXAMPLE 666




EXAMPLE 667




EXAMPLE 668




EXAMPLE 669




EXAMPLE 670




EXAMPLE 671




EXAMPLE 672




EXAMPLE 673




EXAMPLE 674




EXAMPLE 675




EXAMPLE 676




EXAMPLE 677




EXAMPLE 678




EXAMPLE 679




EXAMPLE 680




EXAMPLE 681




EXAMPLE 682




EXAMPLE 683




EXAMPLE 684




EXAMPLE 685




EXAMPLE 686




EXAMPLE 687




EXAMPLE 688




EXAMPLE 689




EXAMPLE 690




EXAMPLE 691




EXAMPLE 692




EXAMPLE 693




EXAMPLE 694




EXAMPLE 695




EXAMPLE 696




EXAMPLE 697




EXAMPLE 698




EXAMPLE 699




EXAMPLE 700




EXAMPLE 701




EXAMPLE 702




EXAMPLE 703




EXAMPLE 704




EXAMPLE 705




EXAMPLE 706




EXAMPLE 707




EXAMPLE 708




EXAMPLE 709




EXAMPLE 710




EXAMPLE 711




EXAMPLE 712




EXAMPLE 713




EXAMPLE 714




EXAMPLE 715




EXAMPLE 716




EXAMPLE 717




EXAMPLE 718




EXAMPLE 719




EXAMPLE 720




EXAMPLE 721




EXAMPLE 722




EXAMPLE 723




EXAMPLE 724




EXAMPLE 725




EXAMPLE 726




EXAMPLE 727




EXAMPLE 728




EXAMPLE 729




EXAMPLE 730




EXAMPLE 731




EXAMPLE 732




EXAMPLE 733




EXAMPLE 734




EXAMPLE 735




EXAMPLE 736




EXAMPLE 737




EXAMPLE 738




EXAMPLE 739




EXAMPLE 740




EXAMPLE 741 TO 743




Synthesis of Compound (44)

To a solution of hydroxylamine-BOC compound (4.01 g) in DMF (40 ml), 60% NaH (2.61 g) is added portionwise at room temperature, and effervescence occurs simultaneously. After 15 minutes, mesyl compound (11.59 g) in DMF (40 ml) is dropped slowly, and stirred at room temperature for 15 minutes. The temperature is raised to 100-110° C. and continued stirring carefully for additional 15 minutes. After the reaction, under reduced pressure, solvent is removed and NH4Cl aqueous solution is added and extracted with ethyl acetate. After dryness (Na2SO4), solvent is removed, and the residue is purified by silica gel chromatography (hexane-ethyl acetate (2:1)) to afford Compound (44) (6.11 g, 62%) as a colorless oil.
44: colorless oil; 1H-NMR (300 MHz, CDCl3) δ 1.48 (s, 9H), 3.56-3.75 (m, 6H), 3.94-4.05 (m, 2H), 5.14 (s, 2H), 7.32 (s, 5H); IR (CHCl3) νmax 1693 cm−1; MS e/m 277 (3), 206 (3), 115 (10), 101 (29), 91 (99), 57 (100).
Synthesis of Compound (45)
To a solution of oxadiazepane compound (44, 6.84 g) in methanol (70 ml), 10% Pd—C (1.01 g) is added to subject to hydrogenation for 6 hours. After the reaction, the mixture is filtered, and solvent is removed. The residue is purified by silica gel chromatography (chloroform-methanol (9:1)). Recrystallization from ethanol affords a colorless amorphous Compound (45) (2.80 g, 68%)
45: colorless amorphous mp: 156.5-157.5° C. (EtOH) (decomp.); 1H-NMR (300 MHz, CDCl3) δ 1.51 (s, 9H), 3.41-3.53 (m, 4H), 3.99 (t, 6, 2H), 4.32 (t, 5, 2H)); IR (KBr) νmax 1705, 1667 cm−1; MS e/m 202 (M+, 1), 129 (9), 99 (12), 72 (17), 57 (100), 43 (86).
Synthesis of Compound (46)
To a solution of amine compound (45, 6.84 g) and 3,4,5-trifluoronitro benzene (3.11 g) in acetonitrile (60 ml), potassium carbonate (3.19 g) is added, and the mixture is heated at reflux for 15 hours. After the reaction, NH4Cl aqueous solution is added mad extracted with chloroform-methanol (9:1). After dryness (Na2SO4), solvent is removed, and the residue is purified by silica gel chromatography (hexane-ethyl acetate (2:1)). Recrystallization from hexane affords 3.31 g (52%) of Compound (46) as yellow needle-like crystal.
46: yellow needle-like crystal mp: 87-88° C. (Hexane); 1H-NMR (300 MHz, CDCl3) δ 1.51 (s, 9H), 3.63-3.71 (m, 4H), 3.84 (t, 6, 2H), 4.13 (t, 5, 2H), 7.72-7.84 (m, 2H); IR (KBr) νmax 1678 cm−1; MS e/m 359 (M+, 0.3), 303 (1), 286 (1), 256 (4), 201 (7), 172 (7), 57 (100).
Synthesis of Compound (47)
To a solution of the nitro compound (46, 2.90 g) in methanol (40 ml), 10% Pd—C (646 mg) is added, and the mixture is subjected to hydrogenation for 2 hours. After the reaction, the mixture is filtered, and solvent is removed. After dryness, potassium carbonate (4.6 g) is added to a solution of the residue and carbobenzoxy chloride (3.0 ml) in THF (50 ml), and the solution is stirred for 15 hours. After the reaction, ice-cold water is added and extracted with chloroform. After dryness (Na2SO4), solvent is removed. The residue is purified by silica gel chromatography (hexane-ethyl acetate (2:1)). Recrystallization from chloroform-hexane affords 3.19 g (85%) of colorless prismatic Compound (47).
47: colorless prismatic mp: 100-101° C. (CHCl3-Hexane); 1H-NMR (300 MHz, CDCl3) δ 1.51 (s, 9H), 3.63-3.71 (m, 4H), 3.84 (t, 6, 2H), 4.13 (t, 5, 2H), 7.72-7.84 (m, 2H); IR (KBr) νmax 1731, 1687 cm−1; MS e/m 463 (M+, 4), 334 (4), 305 (4), 225 (6), 197 (6), 165 (14), 108 (10), 91 (91), 79 (12), 57 (100).
Synthesis of Compound (48)
To a solution of carbobenzoxy compound (47, 363 mg) in THF (10 ml), 1.54M BuLi hexane solution (0.60 ml) is added and stirred under argon atmosphere at −78°. After 10 minutes, (R)-glycidyl butyrate (241 mg) in THF (2 ml) is added and stirred at the temperature for 10 min. and additional 19 hours at room temperature. After the reaction, NH4Cl aqueous solution is added and extracted with chloroform-methanol (9:1). After dryness (Na2SO4), solvent is removed. The residue in methanol (10 ml) is added with potassium carbonate (173 mg) and stirred for 15 minutes. NH4Cl aqueous solution is added and extracted with chloroform-methanol (9:1). After dryness (Na2SO4), solvent is removed. The residue is purified by silica gel chromatography (chloroform-methanol (9:1)) to afford 291 mg (87%) of Compound (48) as colorless syrup.
48: colorless syrup; 1H-NMR (300 MHz, CDCl3) δ 1.51 (s, 9H), 3.33-3.43 (m, 4H), 3.71-3.82 (m, 3H), 3.90-4.02 (m, 3H), 4.07 (t, 5, 2H), 4.70-4.79 (m, 1H), 7.06-7.17 (m, 2H); IR (CHCl3) νmax 1752, 1705, 1690 cm−1; MS e/m 429 (M+, 6), 326 (5), 299 (9), 271 (17), 242 (11), 168 (10), 154 (8), 57 (100).
Synthesis of Compound (49)
To a colorless solution of the hydroxy compound (48, 364 mg) and triethylamine (0.5 ml) in chloroform (10 ml), methanesulfonyl chloride (0.2 ml) is added and stirred under ice-cooling for 15 minutes. After the reaction, NaHCO3 aqueous solution is added and extracted with chloroform-methanol (9:1). After dryness (Na2SO4), solvent is removed. The residue is purified by silica gel chromatography (chloroform-methanol (19:1)) to afford 409 mg (95%) of Compound (49) as colorless syrup.
49: colorless syrup; 1H-NMR (300 MHz, CDCl3) δ 1.51 (s, 9H), 3.11 (s, 3H), 3.33-3.45 (m, 4H), 3.77 (t, 6, 2H), 3.89 (dd, 9, 6, 1H), 4.07 (t, 5, 2H), 4.13 (dd, 9, 9, 1H), 4.43 (dd, 12, 3.5, 1H), 4.53 (dd, 12, 3, 1H), 4.96 (dddd, 9, 6, 3.5, 3, 1H), 7.07-7.18 (m, 2H); IR (CHCl3) νmax 1760, 1702, 1688 cm−1; MS e/m 507 (M+, 6), 404 (4), 378 (10), 349 (10), 335 (16), 320 (10), 180 (12), 79 (9), 57 (100).
Synthesis of Compound (50)
To a solution of the mesyl compound (49, 406 mg) and 18-Crown-6 (77 mg) in DMF (3 ml), NaN3 (213 mg) is added and heated to 100-110° C. After 1 hour, solvent is removed. Water is added, and the mixture is extracted with chloroform. After dryness (Na2SO4), solvent is removed. The  residue is purified by column chromatography (chloroform-methanol (19:1)) to afford 360 mg (99%) of colorless gummy Compound (50).
50: colorless gum; 1H-NMR (300 MHz, CDCl3) δ 1.51 (s, 9H), 3.34-3.44 (m, 4H), 3.60 (dd, 13.5, 4, 1H), 3.71-3.85 (m, 4H), 4.01-4.13 (m, 3H), 4.78-4.88 (m, 1H), 7.08-7.19 (m, 2H); IR (CHCl3) νmax 2105, 1757, 1690 cm−1; MS e/m 454 (M+, 5), 404 (4), 325 (4), 267 (5), 154 (11), 57 (100).
Synthesis of Compound (51)
A combined solution of the azido compound (50, 101 mg) and triphenylphosphine (123 mg) in THF (5 ml) and water (0.5 ml) is heated at reflux. After 1 hour, solvent is removed. The dried residue and triethylamine (1 ml) in chloroform (10 ml) is added dropwise with acetic anhydride (0.25 ml) and stirred for 1 hour. After the reaction, NaHCO3 aqueous solution is added and the mixture is extracted with chloroform-methanol (9:1). After dryness (Na2SO4), solvent is removed. The residue is purified by preparative thin-layer chromatography (chloroform-methanol (19:1)) to afford 101 mg (97%) of colorless gummy compound (51).
51: colorless gum; 1H-NMR (300 MHz, CDCl3) δ 1.51 (s, 9H), 2.03 (s, 3H), 3.34-3.43 (m, 4H), 3.60-3.71 (m, 2H), 3.72-3.81 (m, 3H), 4.01 (dd, 9, 9, 1H), 4.07 (t, 5, 2H), 4.76-4.85 (m, 1H), 6.99 (br t, 6, NH), 7.04-7.15 (m, 2H)); IR (CHCl3) νmax 1750, 1673 cm−1; MS e/m 470 (M+, 14), 367 (6), 341 (9), 312 (10), 298 (10), 239 (14), 183 (9), 180 (13) 154 (9), 57 (100).
Synthesis of Compound (52)
A combined solution of the azido compound (50, 633 mg) and triphenylphosphine (579 mg) in THF (10 ml) and water (1 ml) is heated at reflux. After 30 minutes, solvent is removed. The dried residue and triethylamine (2 ml) in methanol (10 ml) is added dropwise with CHF2COOEt (1 ml) and stirred for 3 hours. After the reaction, solvent is removed. The residue is purified by column chromatography (chloroform-methanol (19: 1)) to afford 587 mg (83%) of colorless gummy compound (52).
52: colorless gum; 1H-NMR (300 MHz, CDCl3) δ 1.51 (s, 9H), 3.33-3.43 (m, 4H), 3.63-3.82 (m, 5H), 4.02-4.11 (m, 3H), 4.80-4.90 (m, 1H), 5.96 (t, 54, 1H), 7.02-7.14 (m, 2H), 7.65-7.84 (br, NH); IR (CHCl3) νmax 1758, 1706 cm−1; MS e/m 506 (M+, 5), 403 (4), 377 (9), 348 (9), 334 (12), 319 (7), 180 (11), 57 (100).
EXAMPLE 741
Synthesis of Compound (53)




To a solution of BOC compound (51, 73 mg) in chloroform (10 ml), trifluoro acetic acid (0.5 ml) is added dropwise and stirred for 15 hours at room temperature. After the reaction, saturated aqueous NaHCO3 is added, and the mixture is extracted with methanol-chloroform (1:9). After washing with water and dryness (Na2SO4), solvent is removed. The residue is purified by preparative thin-layer chromatography (methanol-chloroform (1:9)) to afford 41 mg (71%) of colorless glassy Compound (53).
53: colorless glass; 1H-NMR (300 MHz, CDCl3) δ 2.03 (s, 3H), 3.22 (t, 6, 2H), 3.40 (br t, 6, 2H), 3.49 (t, 5.5, 2H), 3.66 (dd, 6, 4.5, 2H), 3.74 (dd, 9, 6.5, 1H), 3.90 (t, 5.5, 2H), 4.00 (dd, 9, 9, 1H), 4.79 (dddd, 9, 6.5, 4.5, 4.5, 1H), 6.68 (br t, 6, NH), 7.01-7.12 (m, 2H); IR (CHCl3) νmax 1749, 1669 cm−1; MS e/m 370 (M+, 17), 341 (11), 312 (18), 298 (15), 256 (11), 239 (21), 195 (14), 183 (16), 180 (25), 168 (14), 126 (8), 85 (11), 56 (100), 43 (72).
EXAMPLE 742
Synthesis of Compound (54)




BOC Compound (52, 36 mg) in chloroform (5 ml) was added dropwise with trifluoro acetic acid (0.3 ml) and stirred for 15 hours at room temperature. After the reaction, saturated NaHCO3 aqueous solution was added, ant the mixture is extracted with methanol-chloroform (1:9). After washing with water and dryness (Na2SO4), solvent is removed. The residue is purified by preparative thin-layer chromatography (methanol-chloroform (1:9)) and triturated with ether to afford 22 mg (76%) of Compound (54) as colorless powder.
54: colorless powders; 1H-NMR (300 MHz, CDCl3) δ 3.22 (t, 5, 2H), 3.40 (br t, 5, 2H), 3.49 (t, 5.5, 2H), 3.66 (ddd, 14.56.5, 6.5, 1H), 3.70 (dd, 9, 6.5, 1H), 3.83 (ddd, 14.5, 6.5, 3, 1H), 3.90 (t, 5.5, 2H), 4.05 (dd, 9, 9, 1H), 4.78-4.88 (m, 1H), 5.94 (t, 54, 1H), 7.26 (br t, 6, NH), 7.00-7.11 (m, 2H); IR (CHCl3) νmax 1755, 1706 cm−1; MS e/m 406 (M+, 13), 388 (8), 377 (22), 361 (10), 348 (27), 334 (31), 319 (14), 195 (14), 180 (25), 168 (20), 154 (21), 56 (100).
EXAMPLE 743
Synthesis of Compound (55)




To a solution of amino compound (53, 41 mg) and triethylamine (0.3 ml) in chloroform (5 ml), acetoxy acetyl chloride (0.1 ml) is added, and the mixture is stirred under ice-cooling for 20 min. After the reaction, NaHCO3 aqueous solution is added, and the mixture is extracted with methanol-chloroform (1:9). After washing with water and dryness, solvent is removed. The residue in methanol solution (5 ml) is added with K2CO3 (99 mg), and the mixture is stirred for 30 min. After the reaction, NH4Cl aqueous solution is added, and the mixture is extracted with methanol-chloroform (1:9). After washing with water and dryness, solvent is removed. The residue is purified by preparative thin-layer chromatography (methanol-chloroform (1:9)) and triturated with ether to afford 18 mg (38%) of Compound (55) as colorless powders.
55: colorless powders; 1H-NMR (300 MHz, CDCl3) δ 2.03 (s, 3H), 3.41 (t, 5, 2H), 3.47 (t, 5.5, 2H), 3.61-3.71 (m, 2H), 3.75 (dd, 9, 6.5, 1H), 3.95 (t, 5.5, 2H), 4.00 (dd, 9, 9, 1H), 4.12 (t, 5, 2H), 4.36 (s, 2H), 4.74-4.84 (m, 1H), 6.39 (br t, 6, NH), 7.06-7.17 (m, 2H); IR (CHCl3) νmax 1753, 1662 cm−1; MS e/m 428 (M+, 9), 384 (23), 323 (10), 309 (15), 298 (13), 239 (12), 213 (12), 183 (16), 180 (14), 169 (23), 85 (26), 56 (100), 44 (28), 43 (33).
EXAMPLE 744




1H NMR (CDCl3) δ=0.13-0.19 (2H, m), 0.44-0.54 (2H, m), 0.84-0.96 (1H, m), 2.62 (3H, s, N—N—CH3), 2.67 (2H, d, J=6.6 Hz, cyclopropyl-CH2N—N), 3.12-3.17 (2H, m), 3.20-3.26 (2H, m), 3.29-3.38 (4H, m), 3.77-4.13 (4H, m), 4.01 (3H, s, CH3OC═S), 4.87-4.97 (1H, m), 6.78 (1H, t, J=5.9 Hz), and 7.07 (2H, d, J=10.7 Hz).
EXAMPLE 745




1H NMR (CDCl3) δ=2.63 (3H, s, N—N—CH3), 3.02-3.08 (2H, m), 3.12-3.17 (2H, m), 3.25-3.31 (2H, m), 3.33-3.40 (2H, m), 3.91 (2H, s, heterocycle-CH2N), 3.92 (3H, s, heterocycle-OCH3), 4.01 (3H, s, CH3OC═S), 4.88-4.97 (1H, m), 6.71 (1H, d, J=8.5 Hz), 6.83 (1H, t, J=6.0 Hz), 7.09 (2H, d, J=10.7 Hz), 7.64 (1H, dd, J=2.4, 8.5 Hz), and 8.10 (1H, d, J=2.4 Hz).
EXAMPLE 746




1H NMR (CDCl3) δ=0.01-0.07 (2H, m), 0.35-0.42 (2H, m), 0.68-0.80 (1H, m), 2.68 (2H, d, J=6.5 Hz, cyclopropyl-CH2N—N), 3.15-3.21 (2H, m), 3.26-3.41 (6H, m), 3.78-4.14 (4H, m), 4.01 (3H, s, CH3OC═S), 4.05 (2H, s, heterocycle-CH2N), 4.88-4.98 (1H, m), 6.67 (1H, br t, J=6 Hz), 7.09 (2H, d, J=10.7 Hz), 7.20-7.25 (1H, m), 7.90 (1H, br d, J=7 Hz), and 8.27 (1H, m).
EXAMPLE 747




1H NMR (CDCl3) δ=2.61 (3H, s, N—N—CH3), 3.09-3.14 (2H, m), 3.17-3.22 (2H, m), 3.32-3.39 (4H, m), 3.60-4.14 (4H, m), 4.01 (3H, s, CH3OC═S), 4.05 (2H, s, heterocycle-CH2N), 4.88-4.98 (1H, m), 6.52 (1H, d, J=3.6 Hz), 6.76 (1H, t, J=6.1 Hz), 7.10 (2H, d, J=10.7 Hz), and 7.29 (1H, d, J=3.6 Hz).
EXAMPLE 748




1H NMR (CDCl3) δ=2.63 (3H, s, N—N—CH3), 3.14-3.43 (8H, m), 3.61-4.15 (4H, m), 4.01 (3H, s, CH3OC═S), 4.50 (2H, s, heterocycle-CH2N), 4.87-4.97 (1H, m), 6.73 (1H, br t, J=6 Hz), 7.10 (2H, d, J=10.7 Hz), and 8.49 (1H, s, S—CH═C)
EXAMPLE 749




1H NMR (CDCl3) δ=2.53 (6H, s, CH3N—NCH3), 3.15-3.21 (4H, m), 3.37-3.43 (4H, m), 3.60-3.86 (2H, m), 3.91-4.11 (2H, m), 4.00 (3H, s, CH3OC═S), 4.87-4.97 (1H, m), 6.85 (1H, t, J=9.3 Hz), 7.02 (1H, br d, J=9 Hz), 7.17 (1H, t, J=6.1 Hz, NHC═S), and 7.34 (1H, br d, J=15 Hz).
EXAMPLE 750




1H NMR (CDCl3) δ=2.60 (6H, s, CH3N—NCH3), 3.10-3.16 (4H, m), 3.32-3.38 (4H, m), 3.60-3.85 (2H, m), 3.94-4.13 (2H, m), 4.01 (3H, s, CH3OC═S), 4.87-4.97 (1H, m), 6.81 (1H, t, J=6.1 Hz, NHC═S), and 7.08 (2H, d, J=10.7 Hz).
EXAMPLE 751




1H NMR (CDCl3) δ=2.94-3.52 (9H, m), 3.58-4.16 (8H, m), 4.37 (2H, br s), 4.74-4.84 (1H, m), 6.89 (1H, t, J=9.1 Hz), 6.99-7.16 (2H, m), and 7.36-7.45 (1H, m)
EXAMPLE 752




1H NMR (CDCl3) δ=2.03 (3H, s, CH3C═O), 3.00-4.04 (12H, m), 4.33 (2H, s, CH2OH), 4.73-4.83 (1H, m), 6.37 (1H, t, J=6.0 Hz, NHC═O), 6.51-6.57 (1H, m), 7.75-7.82 (1H, m), and 8.09-8.12 (1H, m).
EXAMPLE 753




1H NMR (CDCl3) δ=3.11-3.19 (2H, m), 3.26-3.42 (4H, m), 3.63-3.90 (5H, m), 4.06 (1H, t, J=9.1 Hz), 4.39 (2H, s, CH2OH), 4.79-4.90 (1H, m), 5.95 (1H, t, J=54.1 Hz, CHF2), 7.08 (2H, d, J=10.7 Hz), and 7.45 (1H, t, J=6.2 Hz, NHC═O)
EXAMPLE 754




1H NMR (CDCl3) δ=3.12-3.48 (6H, m), 3.64-3.73 (2H, m), 3.81 (1H, dd, J=7.2, 9.1 Hz), 3.90-4.15 (3H, m) 4.01 (3H, s, CH3OC═S), 4.37 (2H, br s, CH2OH), 4.85-4.96 (1H, m), 6.73 (1H, br t, J=6 Hz, NHC═S), 6.90 (1H, t, J=9.1 Hz), 7.05 (1H, dd, J=2.5, 9.1 Hz), and 7.41 (1H, dd, J=2.5, 14.6 Hz).
EXAMPLE 755




1H NMR (CDCl3) δ=3.12-3.18 (2H, m), 3.26-3.32 (2H, m), 3.35-3.41 (2H, m), 3.69-4.14 (6H, m), 4.01 (3H, s, CH3OC═S), 4.39 (2H, s, CH2OH), 4.88-4.98 (1H, m), 6.76 (1H, br t, J=6 Hz, NHC═S), and 7.11 (2H, d, J=10.7 Hz).
EXAMPLE 756




1H NMR (CDCl3) δ=2.05 (3H, s, CH3C═O), 3.17-3.25 (2H, m), 3.43-3.54 (4H, m), 3.62-3.71 (3H, m), 3.73 (1H, dd, J=6.3, 9.1 Hz), 3.93-3.99 (1H, m), 4.01 (1H, t, J=9.1 Hz), 4.37 (2H, s, CH2OH), 4.76-4.86 (1H, m), 6.17 (1H, br t, J=6 Hz, NHC═O), 6.64 (1H, br t, J=9 Hz), and 7.05 (1H, br t, J=9 Hz).
EXAMPLE 757




1H NMR (CDCl3) δ=1.76-1.88 (2H, m, NHCH2CH2CH2C═O), 1.93 (3H, s, CH3C═O), 1.99 (3H, s, CH3C═O), 2.36 & 2.65 (2H, t, J=6.9 Hz, NHCH2CH2CH2C═O), 2.92-3.82 (13H, m), 3.96 (1H, t, J=9.1 Hz), 4.71-4.81 (1H, m), 6.40-6.55 (1H, br, NHC═O), 6.88 (1H, t, J=6.1 Hz, NHC═O), and 7.06 (2H, d, J=10.7 Hz).
EXAMPLE 758




1H NMR (CDCl3) δ=1.82-1.97 (2H, m, NHCH2CH2CH2C═O), 2.02 (3H, s, CH3C═O), 2.39 & 2.68 (2H, t, J=7.1 Hz, NHCH2CH2CH2C═O), 2.96-4.10 (16H, m), 4.74-4.84 (1H, m), 6.54 (1H, br t, J=6 Hz, NHC═O), and 7.08 (2H, d, J=10.7 Hz).
EXAMPLE 759




1H NMR (CDCl3) δ=1.84-1.98 (2H, m, NHCH2CH2CH2C═O), 2.00 (3H, s, CH3C═O), 2.42 & 2.71 (2H, t, J=6.9 Hz, NHCH2CH2CH2C═O), 2.93 (3H, s, CH3SO2), 2.93-3.85 (13H, m), 3.97 (1H, t, J=9.1 Hz), 4.72-4.81 (1H, m), 5.38 & 5.40 (1H, t, J=5.8 Hz, NHCH2CH2CH2C═O), 6.59 (1H, t, J=6.1 Hz, NHC═O), and 7.06 (2H, d, J=10.7 Hz).
EXAMPLE 760




1H NMR (CDCl3) δ=1.78-1.92 (2H, m, NHCH2CH2CH2C═O), 2.02 (3H, s, CH3C═O), 2.35-2.65 (6H, m), 2.96-3.85 (17H, m), 4.00 (1H, t, J=9.1 Hz), 4.74-4.83 (1H, m), 6.78 (1H, br t, J=6 Hz, NHC═O), and 7.08 (2H, d, J=10.7 Hz).
EXAMPLE 761




1H NMR (CDCl3) δ=2.02 (3H, s, CH3C═O), 2.60-2.67 (1H, m), 2.90-3.86 (14H, m), 3.99 (1H, t, J=9.0 Hz), 4.73-4.83 (1H, m), 6.44 (1H, t, J=5.9 Hz, NHC═O), 7.08 (2H, d, J=10.7 Hz), 7.21 (1H, dd, J=4.7, 7.8 Hz), 7.58 (1H, br d, J=8 Hz), 8.44 (1H, d, J=4.7 Hz), and 8.50 (1H, br s).
EXAMPLE 762




1H NMR (CDCl3) δ=2.03 (3H, s, CH3C═O), 2.52-2.64 (4H, m, O[CH2CH2]2N), 2.98-3.84 (17H, m), 3.99 (1H, t, J=9.1 Hz), 4.74-4.83 (1H, m), 6.38 (1H, br t, J=6 Hz, NHC═O), and 7.10 (2H, d, J=10.7 Hz).
EXAMPLE 763




1H NMR (CDCl3) δ=2.03 (3H, s, CH3C═O), 2.33 & 2.36 & 2.40 (3H, s, CH3N), 2.51-2.75 (8H, m, CH3N[CH2CH2]2N), 2.98-3.83 (13H, m), 3.99 (1H, t, J=9.1 Hz), 4.74-4.83 (1H, m), 6.59 (1H, br t, J=6 Hz, NHC═O), and 7.08 (2H, d, J=10.7 Hz).
EXAMPLE 764




1H NMR (CDCl3) δ=0.37-0.48 (4H, m), 2.03 (3H, s, CH3C═O), 2.18-2.27 (1H, m), 2.99-3.87 (13H, m), 3.99 (1H, t, J=9.1 Hz), 4.74-4.83 (1H, m), 6.79 (1H, br t, J=6 Hz, NHC═O), and 7.09 (2H, d, J=10.7 Hz).
EXAMPLE 765




EXAMPLE 766




1H NMR (CDCl3) δ=2.02 (3H, s, CH3C═O), 2.30-2.39 (1H, m), 2.53 (1H, t, J=6.6 Hz), 2.62-2.68 (1H, m), 2.91-2.97 (1H, m), 3.18-4.05 (12H, m), 4.71-4.81 (1H, m), 6.29 (1H, t, J=6.0 Hz, NHC═O), 6.81-7.04 (2H, m), and 7.37-7.45 (1H, m)
EXAMPLE 767




1H NMR (CD3OD) δ=3.13 (2H, m), 3.39 (2H, m), 3.46 (4H, m), 3.60 and 3.95 (2H, m, N—CH2CH—O), 3.85 (2H, m, O—CHCH2NH), 4.01 (3H, s, CH3O), 4.09 and 4.11 (4H, m, NH3CH2CO), 4.78 (1H, m, O—CHCH2), 6.61 (1H, s, NHCS), 7.21 (1H, s, aromatic-CFCH), and 7.25 (1H, s, aromatic-CFCH).
EXAMPLE 768




1H NMR (DMSO-d6) δ=3.01 (2H, m), 3.21 (2H, m), 3.27 (2H, m), 3.60 (2H, m), 3.71 and 3.83 (2H, m, N—CH2CH—O), 3.75 (2H, m, O—CHCH2NH), 3.88 (3H, s, CH3O), 4.12 (2H, m, NH3CH2CO), 4.90 (1H, m, O—CHCH2), 6.56 (3H, s, NH3Cl), 7.26 (1H, s, aromatic-CFCH), 7.30 (1H, s, aromatic-CFCH), 8.09 (2H, br, NH2Cl) and 9.59 (1H, br, NHCS).
EXAMPLE 769




1H NMR (CDCl3+DMSO-d6) δ=3.08-3.17 (2H, m), 3.24-3.32 (2H, m), 3.36-3.42 (2H, m), 3.83-4.20 (6H, m), 4.38 (2H, AB, HOCH2C═O), 4.82-4.93 (1H, m), 6.61 (2H, br s, NH2), 7.13 (2H, d, J=10.7 Hz), and 8.12 (1H, br t, J=6 Hz, CH2NHC═S).
EXAMPLE 770




1H NMR (CD3OD) δ=1.42 (1H, s, NH2), 1.47 (1H, s, NH2), 3.05 (2H, m), 3.26 (2H, m), 3.31 (2H, m), 3.83 (2H, m), 3.63 and 4.10 (2H, m, N—CH2CH—O), 3.90 (2H, m, O—CHCH2NH), 3.95 (3H, s, CH3b), 4.95 (1H, m, O—CHCH2), 5.48 (1H, s, NHCS), 7.18 (1H, s, aromatic-CFCH), and 7.22 (1H, s, aromatic-CFCH).
EXAMPLE 771




1H NMR (CDCl3) δ=1.14 & 1.17 (3H, t, J=7.4 Hz, CH3CH2C═O, two conformers), 2.35 & 2.60 (2H, q, J=7.4 Hz, CH3CH2C═O, two conformers), 2.96-4.12 (12H, m), 4.00 (3H, s, CH3OC═S), 4.88-4.98 (1H, m, NCH2CHCH2NHC═O), 7.05 (1H, br t, J=6 Hz, NHC═S), and 7.09 (2H, d, J=10.7 Hz).
EXAMPLE 772




1H NMR (CD3OD) δ=2.95-3.15 (2H, dd, C6H5CH2), 3.06 (2H, m), 3.25 (2H, m), 3.40 (2H, m), 3.50-3.80 (2H, m), 3.90 (2H, m, O—CHCH2NH), 3.90-4.00 and 4.10 (2H, m, N—CH2CH—O), 3.95 (3H, s, CH3O), 4.77-4.90 (1H, m, NH2CH—CO), 4.95-5.00 (1H, m, O—CHCH2), 7.20-7.40 (5H, m, C6H5), 7.30 (1H, s, aromatic-CFCH) and 7.34 (1H, s, aromatic-CFCH).
EXAMPLE 773




1H NMR (CD3OD) δ=1.00-1.20 (6H, d+d, CH3CH), 1.52-1.54 (1H, m, CH3CH), 3.17 (2H, m), 3.30 (2H, m), 3.42 (4H, m), 3.89 (2H, m, O—CHCH2NH), 3.95 (3H, s, CH3O), 3.96 and 4.14 (2H, m, N—CH2CH—O), 4.80-4.85 (1H, m, NH3CHCO), 4.95-5.00 (1H, m, O—CHCH2), 7.21 (1H, s, aromatic-CFCH) and 7.25 (1H, s, aromatic-CFCH).
EXAMPLE 774




1H NMR (CD3OD) δ=1.96 (3H, s, CH3CONH), 3.30-3.32 (2H, m), 3.35-3.43 (4H, m), 3.55 (2H, d, COCH2CN), 3.79 and 4.11 (2H, dd+dd, N—CH2CH—O), 3.94 (4H, m), 4.52 (2H, m, NHCO), 4.70-4.90 (1H, m, O—CHCH2), 7.05-7.20 (2H, m, aromatic-CHCH), and 7.50 (1H, dd, aromatic-CFCH).
N-08
EXAMPLE 775




1H NMR (CDCl3) δ=2.03 (3H, s, CH3C═O), 3.03-3.10 (2H, m), 3.24-3.31 (2H, m), 3.38-3.45 (2H, m), 3.58-3.76 (5H, m), 3.77 (3H, s, CH3O), 3.99 (1H, t, J=8.8 Hz), 4.73-4.83 (1H, m), 6.32 (1H, t, J=6.0 Hz, NHC═O), and 7.07 (2H, d, J=10.7 Hz).
EXAMPLE 776




1H NMR (CDCl3) δ=1.29 (3H, t, J=7.1 Hz, CH3CH2O), 2.03 (3H, s, CH3C═O), 3.04-3.09 (2H, m), 3.25-3.30 (2H, m), 3.39-3.45 (2H, m), 3.58-3.76 (5H, m), 3.99 (1H, t, J=9.0 Hz), 4.21 (2H, q, J=7.1 Hz, CH3CH2O), 4.73-4.83 (1H, m), 6.33 (1H, t, J=6.0 Hz, NHC═O), and 7.07 (2H, d, J=10.7 Hz).
EXAMPLE 777




1H NMR (CDCl3) δ=2.02 (3H, s, CH3C═O), 3.10-3.90 (11H, m), 3.99 (1H, t, J=9.0 Hz), 4.73-4.83 (1H, m), 6.22 (1H, t, J=6.0 Hz, NHC═O), 6.97-7.08 (1H, br s, NHC═O), 7.12 (2H, d, J=10.7 Hz), 7.34 (1H, dd, J=4.7, 8.2 Hz), 7.56 (1H, br d, J=8 Hz), and 8.44-8.50 (2H, m).
EXAMPLE 778




1H NMR (CDCl3) δ=3.10-3.90 (12H, m), 4.77-4.88 (1H, m), 5.94 (1H, t, J=54.1 Hz, CHF2C═O), 6.97-7.08 (1H, br s, NHC═O), 7.11 (2H, d, J=10.6 Hz), 7.36 (1H, dd, J=5.0, 8.0 Hz), 7.56 (1H, br d, J=8 Hz), and 8.43-8.51 (2H, m).
EXAMPLE 779




1H NMR (CDCl3) δ=3.08-4.14 (12H, m), 4.01 (3H, s, CH3OC═S), 4.88-4.98 (1H, m), 6.90 (1H, t, J=6.0 Hz, NHC═S), 7.12 (2H, d, J=10.5 Hz), 7.35 (1H, dd, J=4.7, 8.3 Hz), 7.56 (1H, br d, J=8 Hz), and 8.43-8.52 (2H, m).
EXAMPLE 780




1H NMR (CDCl3) δ=3.10-3.17 (2H, m), 3.40-3.45 (2H, m), 3.54-3.75 (6H, m), 3.68 (3H, s, CH3OC═O), 3.83 (1H, ddd, J=3.3, 6.3, 14.6 Hz), 4.06 (1H, t, J=9.1 Hz), 4.80 (1H, ddt, J=3.3, 9.1, 6.3 Hz, CHCH2NHC═O), 5.94 (1H, t, J=54.1 Hz, CHF2), 6.87 (1H, t, J=9.2 Hz), 7.00 (1H, dd, J=1.8, 9.2 Hz), 7.22 (1H, br t, J=6 Hz, NHC═O), and 7.32 (1H, dd, J=1.8, 14.8 Hz).
EXAMPLE 781




1H NMR (CD3OD) δ=3.13-3.18 (2H, m), 3.34-3.39 (2H, m), 3.48-3.54 (2H, m), 3.70-3.97 (6H, m), 3.86 (3H, s, CH3OC═O), 4.14 (1H, t, J=9.1 Hz), 4.75-4.85 (1H, m, NCH2CHCH2NHC═O), 5.94 (1H, t, J=54.0 Hz, CHF2), 7.04 (2H, d, J=10.7 Hz), and 7.24 (1H, br t, J=6 Hz, NHC═O).
EXAMPLE 782




1H NMR (CDCl3) δ=3.04-3.09 (2H, m), 3.25-3.30 (2H, m), 3.38-3.45 (2H, m), 3.62-3.69 (2H, m), 3.77 (3H, s, CH3OC═O), 3.77-4.12 (4H, m), 4.01 (3H, s, CH3OC═S), 4.88-4.98 (1H, m, NCH2CHCH2NHC═O), 6.96 (1H, br t, J=8 Hz), and 7.08 (2H, d, J=10.7 Hz).
EXAMPLE 783




1H NMR (CDCl3) δ=3.02-3.08 (2H, m), 3.24-3.30 (2H, m), 3.37-3.45 (2H, m), 3.57-3.63 (2H, m), 3.81 (1H, dd, J=7.1, 9.1 Hz), 3.93-4.14 (3H, m), 4.01 (3H, s, CH3OC═S), 4.87-4.97 (1H, m, NCH2CHCH2NHC═O), 6.72 (1H, br t, J=6 Hz, NHC═S), and 7.08 (2H, d, J=10.7 Hz).
EXAMPLE 784




1H NMR (CDCl3) δ=2.02 (3H, s, CH3C═O), 2.93-4.11 (12H, m), 4.74-4.85 (1H, m), 6.42-6.53 (1H, m, NHC═O), 7.06-7.15 (2H, m), 7.54-7.62 (1H, m), and 8.13-8.21 (2H, m).
EXAMPLE 785




1H NMR (CDCl3) δ=2.00 (3H, s, CH3C═O), 2.97 (6H, s, CH3NCH3), 3.18-3.24 (2H, m), 3.44-3.50 (2H, m), 3.53-3.82 (7H, m), 3.98 (1H, t, J=9.1 Hz), 4.69-4.79 (1H, m), 6.55-6.65 (4H, m), 6.89 (1H, t, J=9.1 Hz), 6.99 (1H, dd, J=2.5, 9.1 Hz), 7.20 (1H, br s, NHC═O), and 7.38 (1H, dd, J=2.5, 14.6 Hz).
EXAMPLE 786




1H NMR (CDCl3) δ=2.01 (3H, s, CH3C═O), 3.10-3.17 (2H, m), 3.29-3.35 (2H, m), 3.46-3.52 (2H, m), 3.61-3.67 (2H, m), 3.72 (1H, dd, J=6.6, 9.1 Hz), 3.90-4.02 (3H, m), 4.72-4.83 (1H, m, NCH2CHCH2NHC═O), 6.48 (1H, br t, J=6 Hz, NHC═O), 6.85 (1H, br t, J=8 Hz), 6.97 (1H, br d, J=8 Hz), 7.09 (2H, d, J=10.7 Hz), 7.33 (1H, br t, J=8 Hz), and 7.76 (1H, br s).
EXAMPLE 787




1H NMR (CDCl3) δ=3.10-3.17 (2H, m), 3.29-3.36 (2H, m), 3.47-3.53 (2H, m), 3.60-3.73 (2H, m), 3.79-4.00 (3H, m), 4.0.5 (1H, t, J=9.1 Hz), 4.72-4.83 (1H, m, NCH2CHCH2NHC═O) 5.93 (1H, t, J=53.8 Hz, CHF2), 6.85 (1H, br t, J=8 Hz), 6.98 (1H, br d, J=8 Hz), 7.09 (2H, d, J=10.7 Hz), 7.34 (1H, br t, J=8 Hz), and 7.78 (1H, br s).
EXAMPLE 788




1H NMR (CDCl3) δ=2.03 (3H, s, CH3C═O), 3.08-3.14 (2H, m), 3.29-3.35 (2H, m), 3.40-3.46 (2H, m), 3.50-3.88 (13H, m), 4.00 (1H, t, J=9.0 Hz), 4.75-4.85 (1H, m), 6.51 (1H, t, J=4.7 Hz), 6.58 (1H, t, J=6.0 Hz, NHC═O), 7.09 (2H, d, J=10.7 Hz), and 8.32 (2H, d, J=4.7 Hz).
EXAMPLE 789




1H NMR (CDCl3) δ=2.00 & 2.01 (3H, two singlet peaks, CH3C═O), 3.04-4.02 (19H, m), 4.36-4.46 (1H, m), 4.71-4.81 (1H, m), 6.13-6.23 (1H, m, NHC═O), 6.79-7.15 (3H, m), and 7.47-8.54 (2H, m).
EXAMPLE 790




1H NMR (CDCl3) δ=1.94 & 1.95 (3H, two singlet peaks, CH3C═O), 2.25 & 2.28 (3H, two singlet peaks, CH3—N), 2.35-2.50 (4H, m), 2.96-3.93 (15H, m), 4.65-4.76 (1H, m), 6.29-6.39 (1H, m, NHC═O), 6.72 & 6.85 (1H, two dd peaks, J=4.4, 7.4 Hz), 6.96-7.05 (2H, m), 7.42 & 7.62 (1H, two dd peaks, J=1.9, 7.4 Hz), and 8.16 & 8.23 (1H, two dd peaks, J=1.9, 4.4 Hz).
EXAMPLE 791




1H NMR (CDCl3) δ=2.02 (3H, s, CH3C═O), 2.35 (3H, s, CH3N), 2.51 (4H, t-like, J=5 Hz), 3.10-3.18 (2H, m), 3.28-3.35 (2H, m), 3.43-3.49 (2H, m), 3.56-3.75 (9H, m), 3.98 (1H, t, J=9.0 Hz), 4.72-4.82 (1H, m), 6.16 (1H, t, J=6.0 Hz, NHC═O), 6.62 (1H, d, J=8.8 Hz), 7.09 (2H, d, J=10.7 Hz), 7.70-7.85 (1H, br), and 8.51 (1H, br s).
EXAMPLE 792




1H NMR (CDCl3) δ=3.08-3.15 (2H, m), 3.30-3.37 (2H, m), 3.40-3.46 (2H, m), 3.51-3.57 (4H, m), 3.63-3.69 (2H, m), 3.78-4.13 (8H, m), 4.01 (3H, s, CH3OC═S), 4.88-4.98 (1H, m), 6.51 (1H, t, J=4.7 Hz), 6.86 (1H, t, J=6.0 Hz, NHC═S), 7.10 (2H, d, J=10.7 Hz), and 8.32 (2H, d, J=4.7 Hz).
EXAMPLE 793




1H NMR (CDCl3+DMSO-d6) δ=2.01 (3H, s, NHC═O), 3.28-3.42 (4H, m), 3.46-3.53 (2H, m), 3.58-3.66 (2H, m), 3.74 (1H, dd, J=7.1, 9.1 Hz), 4.00 (1H, t, J=9.1 Hz), 4.02-4.10 (2H, m), 4.71-4.81 (1H, m), 6.80 (1H, br t, J=6 Hz, NHC═O), 6.91 (1H, t, J=9.1 Hz), 7.03 (1H, br d, J=9 Hz), 7.07 (1H, t, J=4.5 Hz), 7.42 (1H, br d, J=15 Hz), 7.51 (1H, d, J=4.5 Hz), and 8.05 (1H, br s).
EXAMPLE 794




1H NMR (CDCl3) δ=1.60-1.74 (1H, m), 1.98-2.12 (1H, m), 2.86 (2H, br S, NH2), 3.06-3.13 (2H, m), 3.23-3.39 (5H, m), 3.50-3.85 (8H, m), 3.93-4.14 (2H, m), 4.01 (3H, s, CH3OC═S), 4.88-4.98 (1H, m), 6.72 (1H, br t, J=6 Hz, NHC═S), and 7.07 (2H, d, J=10.7 Hz).
EXAMPLE 795




1H NMR (CD3OD) δ=3.14 (4H, m), 3.49 (4H, m), 3.89 (2H, m, O—CHCH2NH), 3.94 (3H, s, CH3O), 4.10 (2H, m, N—CH2CH—O), 4.93 (1H, m, O—CHCH2), 6.70 (1H, s, NHCS), 7.01 (1H, br, aromatic-N—CHCH—), 7.21 (2H, s+s, aromatic-CFCH) and 7.66 (1H, br, aromatic-N—CHCH—)
EXAMPLE 796




1H NMR (CDCl3) δ=2.03 (3H, s, CH3C═O), 3.20-3.46 (6H, m), 3.63-3.71 (2H, m), 3.73 (1H, dd, J=6.8, 9.1 Hz), 3.86-3.96 (1H, m), 3.99 (1H, t, J=9.1 Hz), 4.14 (1H, t, J=6.0 Hz), 4.73-4.84 (1H, m), 6.37 (1H, t, J=6.3 Hz, NHC═O), 7.11 (2H, d, J=10.7 Hz), and 8.75 (1H, s, N═CH—S).
EXAMPLE 797




1H NMR (CDCl3) δ=2.02 (3H, s, CH3C═O), 3.24-3.31 (2H, m), 3.39-3.47 (4H, m), 3.56-3.77 (3H, m), 3.83-4.04 (3H, m), 3.92 (3H, s, OMe), 4.72-4.81 (1H, m), 6.13 (1H, t, J=6.0 Hz, NHC═O), 6.78 (1H, d, J=11.3 Hz), 6.91 (1H, t, J=9.1 Hz), 7.03 (1H, dd, J=2.0, 9.1 Hz), 7.23-7.31 (1H, m), 7.42 (1H, dd, J=2.5, 14.6 Hz), 7.64 (1H, br d, J=11 Hz), and 8.71 (1H, s, NH-tropolone).
EXAMPLE 798




1H NMR (CDCl3) δ=2.02 (3H, s, CH3C═O), 3.23-3.48 (6H, m), 3.56-3.78 (3H, m), 3.90-4.05 (3H, m), 4.71-4.81 (1H, m), 6.47 (1H, t, J=6.3 Hz, NHC═O), 6.86-7.05 (3H, m), 7.39 (1H, dd, J=2.5, 14.6 Hz), 7.64 (1H, ddd, J=1.9, 7.7, 8.5 Hz), 8.11 (1H, d, J=8.5 Hz), 8.22 (1H, br d, J=5 Hz), and 9.22 (1H, s, NH-heterocycle).
EXAMPLE 799




1H NMR (CDCl3) δ=3.24-3.31 (2H, m), 3.38-3.46 (4H, m), 3.59-4.10 (6H, m), 4.00 (3H, s, CH3OC═S), 4.85-4.96 (1H, m), 6.90 (1H, t, J=8.8 Hz), 7.02 (1H, br d, J=9 Hz), 7.32 (1H, t, J=6.5 Hz, NHC═S), 7.36-7.44 (4H, m) 8.41 (2H, d-like, J=5 Hz), and 8.84 (1H, s, NH-heterocycle).
EXAMPLE 800




1H NMR (CDCl3) δ=3.19-3.27 (2H, m), 3.33-3.43 (4H, m), 3.61-4.13 (6H, m), 4.01 (3H, s, CH3OC═S), 4.88-4.98 (1H, m), 6.85 (1H, br t, J=6 Hz, NHC═S), 7.11 (2H, d, J=10.7 Hz), 7.44 (2H, br d, J=5 Hz), 8.43 (2H, br d, J=5 Hz), and 8.87 (1H, s, NH-heterocycle).
EXAMPLE 801




1H NMR (CDCl3) δ=3.22-3.31 (2H, m), 3.34-3.48 (4H, m), 3.59-4.12 (6H, m), 4.00 (3H, s, CH3OC═S), 4.85-4.96 (1H, m), 6.86 (1H, d, J=3.6 Hz), 6.90 (1H, t, J=8.8 Hz), 7.00-7.10 (2H, m), 7.36 (1H, d, J=3.6 Hz), 7.40 (1H, dd, J=2.5, 14.3 Hz), and 9.85 (1H, br s, NH-heterocycle).
EXAMPLE 802




1H NMR (CDCl3) δ=3.19-3.26 (2H, m), 3.31-3.37 (2H, m), 3.38-3.44 (2H, m), 3.82 (1H, dd, J=7.1, 9.1 Hz), 3.86-4.16 (5H, m), 4.01 (3H, s, CH3OC═S), 4.87-4.97 (1H, m), 6.71 (1H, br t, J=6 Hz, NHC═S), 6.88 (1H, d, J=3.6 Hz), 7.11 (2H, d, J=10.7 Hz), 7.37 (1H, d, J=3.6 Hz), and 9.83 (1H, br s, NH-heterocycle).
EXAMPLE 803




1H NMR (CDCl3) δ=3.22-3.34 (2H, m), 3.38-3.44 (2H, m), 3.45-3.50 (2H, m), 3.82 (1H, dd, J=7.1, 9.1 Hz), 3.90-4.14 (5H, m), 4.00 (3H, s, CH3OC═S), 4.85-4.95 (1H, m), 6.70 (1H, br t, J=6 Hz, NHC═S), 6.92 (1H, t, J=8.8 Hz), 7.05 (1H, br d, J=9 Hz), 7.21-7.33 (1H, m), 7.37-7.46 (2H, m), 7.71 (1H, d, J=8.0 Hz), 7.79 (1H, d, J=8.0 Hz), and 9.95 (1H, br s, NH-heterocycle).
EXAMPLE 804




1H NMR (CDCl3) δ=3.20-3.29 (2H, m), 3.31-3.38 (2H, m), 3.39-3.47 (2H, m), 3.81 (1H, dd, J=7.1, 9.1 Hz), 3.86-4.15 (5H, m), 4.01 (3H, s, CH3OC═S), 4.88-4.97 (1H, m), 6.80 (1H, br t, J=6 Hz, NHC═S), 7.11 (2H, d, J=10.7 Hz), 7.21-7.33 (1H, m), 7.40 (1H, br t, J=8 Hz), 7.71 (1H, d, J=8.0 Hz), 7.79 (1H, d, J=8.0 Hz), and 10.00 (1H, br s, NH-heterocycle).
EXAMPLE 805




1H NMR (CDCl3) δ=3.20-3.47 (6H, m), 3.59-4.13 (6H, m), 4.01 (3H, s, CH3OC═S), 4.87-4.98 (1H, m), 6.74 (1H, br t, J=6 Hz, NHC═S), 7.12 (2H, d, J=10.5 Hz), 8.74 (1H, s, N═CH—S), and 10.09 (1H, s, NH-heterocycle).
EXAMPLE 806




1H NMR (CDCl3) δ=3.12-3.19 (2H, m), 3.28-3.36 (4H, m), 3.72-4.10 (6H, m), 4.01 (3H, s, CH3OC═S), 4.88-4.98 (1H, m), 5.42 (2H, br s, H2C═O), 7.05 (1H, t, J=6.0 Hz, NHC═S), and 7.11 (2H, d, J=10.7 Hz).
EXAMPLE 807




1H NMR (CDCl3) δ=2.30 (6H, s, CH3NCH3), 2.48 (2H, t, J=6.3 Hz, Me2NCH2), 3.07-3.15 (2H, m), 3.26-3.38 (6H, m), 3.64-4.10 (6H, m), 4.00 (3H, s, CH3OC═S), 4.88-4.98 (1H, m), 6.72 (1H, t, J=5.5 Hz), 7.09 (2H, d, J=10.7 Hz), and 7.29 (1H, br t, J=6 Hz).
EXAMPLE 808




1H NMR (CDCl3) δ=3.20-4.11 (12H, m), 4.00 (3H, s, CH3OC═S), 4.34-4.47 (1H, m, CHNHC═O), 4.88-4.98 (1H, m), 7.07 (1H, t-like, J=6 Hz, NHC═S), 7.09 (2H, d, J=10.7 Hz), 7.23 (1H, dd, J=4.7, 8.4 Hz), 8.14 (1H, br d, J=8 Hz), 8.24 (1H, br d, J=5 Hz), 8.51 (1H, br s), and 8.74 (1H, s, heteroaryl-NHC═O).
EXAMPLE 809




1H NMR (CDCl3) δ=1.69-1.84 (1H, m), 2.00-2.58 (3H, m), 2.47 (3H, s, N—CH3), 2.68-2.86 (2H, m), 3.00-3.15 (2H, m), 3.25-3.36 (4H, m), 3.61-4.14 (6H, m), 4.01 (3H, s, CH3OC═S), 4.34-4.47 (1H, m, CHNHC═O), 4.87-4.97 (1H, m), 6.81 (1H, d, J=7.7 Hz, CHNHC═O), 6.94 (1H, t-like, J=6 Hz, NHC═S), and 7.09 (2H, d, J=10.7 Hz).
EXAMPLE 810




1H NMR (CDCl3) δ=3.12-3.20 (2H, m), 3.28-3.36 (4H, m), 3.75-4.08 (6H, m), 3.99 (3H, s, CH3OC═S), 4.55 (2H, d, J=5.9 Hz, heteroaryl-CH2NHC═O), 4.88-4.98 (1H, m), 7.09 (2H, d, J=10.7 Hz), 7.17 (1H, ddd, J=1.1, 4.9, 7.5 Hz), 7.27 (1H, t, J=5.8 Hz), 7.32 (1H, d, J=7.5 Hz), 7.48 (1H, t, J=6.2 Hz), 7.65 (1H, dt, J=1.9, 7.5 Hz), and 8.54 (1H, ddd, J=1.1, 1.9, 4.9 Hz).
EXAMPLE 811




1H NMR (CDCl3) δ=3.07-3.14 (2H, m), 3.28-3.37 (4H, m), 3.59-4.16 (6H, m), 4.00 (3H, s, CH3OC═S), 4.34 (2H, d, J=5.8 Hz, aryl-CH2NHC═O), 4.86-4.96 (1H, m), 6.55-6.92 (5H, m), and 7.03-7.14 (3H, m).
EXAMPLE 812




1H NMR (CDCl3) δ=2.75-2.87 (4H, m), 3.08-3.15 (2H, m), 3.25-3.32 (4H, m), 3.64-4.12 (10H, m), 4.00 (3H, s, CH3OC═S), 4.90-5.00 (1H, m), 7.09 (2H, d, J=10.7 Hz), 7.31 (1H, s, N—NHC═O), and 7.45 (1H, t, J=5.9 Hz, NHC═S).
EXAMPLE 813




1H NMR (CDCl3) (=3.08-3.15 (2H, m), 3.30-3.37 (2H, m), 3.40-3.46 (2H, m), 3.51-3.57 (4H, m), 3.63-3.69 (2H, m), 3.78-4.13 (8H, m), 4.01 (3H, s, CH3OC═S), 4.88-4.98 (1H, m), 6.51 (1H, t, J=4.7 Hz), 6.86 (1H, t, J=6.0 Hz, NHC═S), 7.10 (2H, d, J=10.7 Hz), and 8.32 (2H, d, J=4.7 Hz).
EXAMPLE 814




1H NMR (CDCl3) δ=2.47 (3H, s, CH3-heteroaryl), 3.05-3.14 (2H, m), 3.25-3.36 (4H, m), 3.60-4.13 (6H, m), 4.01 (3H, s, CH3OC═S), 4.26 (2H, d, J=6.9 Hz, heteroaryl-CH2NHC═O), 4.88-4.98 (1H, m), 6.21 (2H, br s, heteroaryl-NH2), 6.82 (1H, t, J=6.0 Hz), 7.10 (2H, d, J=10.7 Hz), 7.14 (1H, t, J=6.0 Hz), and 7.96 (1H, s).
EXAMPLE 815




1H NMR (CDCl3) δ=2.56 (3H, s, CH3-heteroaryl), 3.10-3.19 (2H, m), 3.29-3.37 (4H, m), 3.63-4.13 (6H, m), 4.00 (3H, s, CH3OC═S), 4.56 (2H, d, J=5.9 Hz, heteroaryl-CH2NHC═O), 4.87-4.97 (1H, m), 6.92 (1H, t, J=6.0 Hz), 7.10 (2H, d, J=10.7 Hz), 7.16 (1H, t, J=6.0 Hz), 8.39 (1H, s), and 8.52 (1H, s).
EXAMPLE 816




1H NMR (CDCl3) δ=2.23 (3H, s, CH3—C═C—), 3.05-3.14 (2H, m), 3.27-3.36 (4H, m), 3.62-4.12 (6H, m), 3.73 (3H, CH3—N—N═C), 4.00 (3H, s, CH3OC═S), 4.35 (2H, d, J=5.9 Hz, heterocycle-CH2NHC═O), 4.87-4.97 (1H, m), 5.98 (1H, s, Me-C═CH—C), 6.80 (1H, t, J=6.0 Hz), 6.89 (1H, t, J=6.0 Hz), and 7.09 (2H, d, J=10.7 Hz).
EXAMPLE 817




1H NMR (CDCl3) δ=3.07-3.15 (2H, m), 3.27-3.38 (4H, m), 3.62-4.13 (6H, m), 4.00 (3H, s, CH3OC═S), 4.42 (2H, d, J=6.3 Hz, heteroaryl-CH2NHC═O), 4.87-4.97 (1H, m), 6.86 (1H, t, J=6.0 Hz), 6.88 (1H, t, J=6.0 Hz), 7.10 (2H, d, J=10.7 Hz), 7.29 (1H, d, J=8.0 Hz), 7.66 (1H, dd, J=2.5, 8.0 Hz), and 8.33 (1H, d, J=2.5 Hz).
EXAMPLE 818




1H NMR (CDCl3) δ=3.09-3.16 (2H, m), 3.29-3.38 (4H, m), 3.60-4.13 (6H, m), 4.01 (3H, s, CH3OC═S), 4.52 (2H, d, J=6.1 Hz, heteroaryl-CH2NHC═O), 4.87-4.97 (1H, m), 6.81 (1H, t, J=6.0 Hz), 6.94 (1H, t, J=6.0 Hz), 7.10 (2H, d, J=10.7 Hz), 7.65 (1H, d, J=8.2 Hz), 7.87 (1H, br d, J=8 Hz), and 8.67 (1H, br s).
EXAMPLE 819




1H NMR (CDCl3) δ=3.08-3.17 (2H, m), 3.30-3.41 (4H, m), 3.65-4.13 (6H, m), 4.01 (3H, s, CH3OC═S), 4.51 (2H, d, J=6.0 Hz, aryl-CH2NHC═O), 4.87-4.97 (1H, m), 6.77 (1H, t, J=6.0 Hz), 6.93 (1H, t, J=6.0 Hz), 7.10 (2H, d, J=10.7 Hz), 7.40 (2H, d, J=8.5 Hz), and 8.02 (2H, d, J=8.5 Hz).
EXAMPLE 820




1H NMR (CDCl3) δ=2.93 (6H, S, CH3NCH3), 3.04-3.12 (2H, m), 3.26-3.37 (4H, m), 3.58-4.09 (6H, m), 3.99 (3H, s, CH3OC═S), 4.32 (2H, d, J=5.8 Hz, aryl-CH2NHC═O), 4.86-4.96 (1H, m), 6.67 (1H, t, J=6.0 Hz), 6.71 (2H, d, J=8.8 Hz), 7.06 (1H, t, J=6.0 Hz), 7.09 (2H, d, J=10.7 Hz), and 7.20 (2H, d, J=8.8 Hz).
EXAMPLE 821




1H NMR (CDCl3) δ=3.09-3.18 (2H, m), 3.29-3.41 (4H, m), 3.60-4.10 (6H, m), 3.99 (3H, s, CH3OC═S), 4.87-4.97 (1H, m), 4.93 (2H, d, J=6.0 Hz, heteroaryl-CH2NHC═O), 6.94 (1H, t, J=6.0 Hz), 7.01 (1H, t, J=6.0 Hz), 7.10 (2H, d, J=10.7 Hz), 7.39 (1H, d, J=4.4 Hz), 7.60 (1H, t-like, J=8 Hz), 7.73 (1H, t-like, J=8 Hz), 8.07 (1H, br d, J=8 Hz), 8.11 (1H, br d, J=8 Hz), and 8.88 (1H, d, J=4.4 Hz).
EXAMPLE 822




1H NMR (CDCl3) δ=3.09-3.17 (2H, m), 3.30-3.39 (4H, m), 3.62-4.10 (6H, m), 4.01 (3H, s, CH3OC═S), 4.50 (2H, d, J=6.0 Hz, aryl-CH2NHC═O), 4.87-4.97 (1H, m), 6.90 (1H, t, J=6.0 Hz), 6.97 (1H, t, J=6.0 Hz), 7.09 (2H, d, J=10.7 Hz), 7.46 (2H, d, J=8.3 Hz), 8.00 (2H, d, J=8.3 Hz), and 8.64 (1H, s).
EXAMPLE 823




1H NMR (CDCl3) δ=3.08-3.15 (2H, m), 3.27-3.37 (4H, m), 3.60-4.12 (6H, m), 4.01 (3H, s, CH3OC═S), 4.42 (2H, d, J=6.0 Hz, heterocycle-CH2NHC═O), 4.87-4.97 (1H, m), 6.21 (1H, d, J=3.0 Hz), 6.32 (1H, dd, J=1.9, 3.0 Hz), 6.76 (2H, br t, J=6 Hz), 7.09 (2H, d, J=10.7 Hz), and 7.36 (1H, d, J=1.9 Hz).
EXAMPLE 824




1H NMR (CDCl3) δ=3.07-3.15 (2H, m), 3.27-3.38 (4H, m), 3.65-4.12 (6H, m), 4.00 (3H, s, CH3OC═S), 4.60 (2H, d, J=6.0 Hz, heterocycle-CH2NHC═O), 4.87-4.97 (1H, m), 6.77-6.86 (2H, m), 6.92-7.00 (2H, m), 7.10 (2H, d, J=10.7 Hz), and 7.20 (1H, dd, J=1.4, 4.9 Hz).
EXAMPLE 825




1H NMR (CDCl3) δ=2.00 (1H, s, CH3C═O), 3.10-3.20 (2H, m), 3.34-3.43 (4H, m), 3.55-3.92 (5H, m), 3.99 (1H, t, J=9.1 Hz), 4.42 (2H, d, J=6.2 Hz, heteroaryl-CH2NHC═O), 4.73-4.83 (1H, m), 6.84-6.93 (2H, m), 7.01 (1H, br d, J=9 Hz), 7.22-7.26 (1H, m), 7.06 (1H, t, J=6.1 Hz), 7.24 (1H, dd, J=5.0, 7.4 Hz), 7.38 (1H, br d, J=15 Hz), 7.64 (1H, br d, J=7 Hz), 8.48 (1H, br d, J=5 Hz), and 8.54 (1H, br s).
EXAMPLE 826




1H NMR (CDCl3) (=3.12-3.20 (2H, m), 3.36-3.45 (4H, m), 3.57-3.94 (5H, m), 4.07 (1H, t, J=9.1 Hz), 4.43 (2H, d, J=6.3 Hz, heteroaryl-CH2NHC═O), 4.75-4.86 (1H, m), 5.93 (1H, t, J=54.0 Hz, CHF2), 6.83 (1H, t, J=6.1 Hz, NHC═O), 6.90 (1H, t, J=9.1 Hz), 7.01 (1H, dd, J=2.8, 9.1 Hz), 7.22-7.26 (1H, m), 7.38 (1H, dd, J=2.8, 14.6 Hz), 7.65 (1H, br d, J=7 Hz), 8.50 (1H, dd, J=1.4, 4.7 Hz), and 8.55 (1H, d, J=1.4 Hz).
EXAMPLE 827




1H NMR (CDCl3) δ=2.01 (1H, s, CH3C═O), 3.08-3.15 (2H, m), 3.27-3.37 (4H, m), 3.60-3.85 (5H, m), 3.98 (1H, t, J=9.1 Hz), 4.44 (2H, d, J=6.2 Hz, heteroaryl-CH2NHC═O), 4.73-4.82 (1H, m), 6.89 (1H, t, J=6.1 Hz), 6.91 (1H, t, J=6.1 Hz), 7.08 (2H, d, J=10.6 Hz), 7.26 (1H, dd, J=4.9, 7.6 Hz), 7.68 (1H, br d, J=8 Hz), 8.49 (1H, br d, J=5 Hz), and 8.56 (1H, br s).
EXAMPLE 828




1H NMR (CDCl3) δ=3.08-3.15 (2H, m), 3.28-3.38 (4H, m), 3.60-3.87 (5H, m), 4.05 (1H, t, J=9.1 Hz), 4.45 (2H, d, J=6.3 Hz, heteroaryl-CH2NHC═O), 4.77-4.87 (1H, m), 5.93 (1H, t, J=54.0 Hz, CHF2), 6.87 (1H, t, J=6.1 Hz, NHC═O), 6.90 (1H, t, J=9.1 Hz), 7.08 (2H, d, J=10.6 Hz), 7.22-7.40 (2H, m), 7.67 (1H, br d, J=8 Hz), 8.50 (1H, dd, J=1.5, 4.7 Hz), and 8.57 (1H, d, J=1.5 Hz).
EXAMPLE 829




1H NMR (CDCl3) δ=3.07-3.15 (2H, m), 3.28-3.38 (4H, m), 3.60-3.87 (5H, m), 4.05 (1H, t, J=9.1 Hz), 4.41 (2H, d, J=6.3 Hz, heteroaryl-CH2NHC═O), 4.77-4.84 (1H, m), 5.93 (1H, t, J=54.0 Hz, CHF2), 6.88 (1H, t, J=6.1 Hz, NHC═O), 7.08 (2H, d, J=10.6 Hz), 7.29 (1H, d, J=8.2 Hz), 7.66 (1H, dd, J=2.5, 8.2 Hz), and 8.33 (1H, d, J=2.5 Hz).
EXAMPLE 830




1H NMR (CDCl3) δ=3.05-4.12 (2H, m), 4.35 (2H, d, J=6.0 Hz, aryl-CH2NHC═O), 4.86-4.97 (1H, m), 6.71 (1H, t, J=6.0 Hz), 6.79 (1H, t, J=6.0 Hz), 6.88 (2H, d, J=8.9 Hz), 7.10 (2H, d, J=10.7 Hz), and 7.24 (2H, d, J=8.9 Hz).
EXAMPLE 831




1H NMR (CDCl3) δ=3.05-3.13 (2H, m), 3.27-3.36 (4H, m), 3.63-4.11 (6H, m), 4.00 (3H, s, CH3OC═S), 4.27 (2H, d, J=6.0 Hz, heterocycle-CH2NHC═O), 4.87-4.97 (1H, m), 6.40 (1H, br s), 6.63 (1H, t, J=6.1 Hz), 6.97 (1H, t, J=6.1 Hz), 7.09 (2H, d, J=10.7 Hz), and 7.37 (2H, br s).
EXAMPLE 832




1H NMR (CDCl3) δ=2.02 (3H, s, CH3C═O), 3.02-3.13 (2H, m), 3.08 (6H, s, CH3NCH3), 3.26-3.38 (4H, m), 3.56-3.85 (5H, m), 3.98 (1H, t, J=9.8 Hz), 4.28 (2H, d, J=5.8 Hz, NHCH2-heterocycle), 4.72-4.83 (1H, m, NCH2CHCH2NHC═O), 6.24 (1H, t, J=6.0 Hz), 6.51 (1H, d, J=8.8 Hz), 6.65 (1H, t, J=5.8 Hz), 7.09 (2H, d, J=10.7 Hz), 7.48 (1H, dd, J=2.5, 8.8 Hz), and 8.10 (1H, d, J=2.5 Hz).
EXAMPLE 833




1H NMR (CD3OD) δ=2.38 (3H, s, heterocycle-CH3), 2.55 (3H, s, heterocycle-CH3), 3.26-3.40 (6H, m), 3.81-3.92 (5H, m), 3.94 (3H, s, CH3OC═S), 4.10 (1H, t, J=9.1 Hz), 4.26 (2H, s, NHCH2-heterocycle), 4.90-5.00 (1H, m, NCH2CHCH2NHC═O), and 7.23 (2H, d, J=11.0 Hz).
EXAMPLE 834




1H NMR (CDCl3) δ=3.18-3.25 (2H, m), 3.32-3.38 (4H, m), 3.75-4.14 (6H, m), 4.01 (3H, s, CH3OC═S), 4.72 (2H, d, J=5.8 Hz, NHCH2-heterocycle), 4.87-4.97 (1H, m, NCH2CHCH2NHC═O), 6.74 (1H, t, J=5.8 Hz), 7.10 (2H, d, J=10.4 Hz), 7.19 (1H, t, J=5.0 Hz), 7.38 (1H, t, J=6.0 Hz), and 8.72 (2H, d, J=5.0 Hz).
EXAMPLE 835




1H NMR (CDCl3) δ=1.97-2.03 (4H, m, NCH2CH2CH2CH2N), 3.09-3.17 (2H, m), 3.30-3.38 (4H, m), 3.42-3.50 (4H, m, NCH2CH2CH2CH2N), 3.65-4.14 (6H, m), 4.01 (3H, s, CH3OC═S), 4.37 (2H, d, J=6.1 Hz, NHCH2-heterocycle), 4.87-4.97 (1H, m, NCH2CHCH2NHC═O), 6.30 (1H, s), 6.48 (1H, d, J=5.2 Hz), 6.81 (2H, br t, J=6 Hz), 7.10 (2H, d, J=10.7 Hz), and 8.09 (1H, d, J=5.2 Hz).
EXAMPLE 836




1H NMR (CDCl3) δ=3.09-3.17 (2H, m), 3.30-3.39 (4H, m), 3.46-3.54 (4H, m, NCH2CH2OCH2CH2N), 3.65-4.12 (6H, m), 3.78-3.86 (4H, m, NCH2CH2OCH2CH2N), 4.01 (3H, s, CH3OC═S), 4.36 (2H, d, J=6.2 Hz, NHCH2-heterocycle), 4.87-4.97 (1H, m, NCH2CHCH2NHC═O), 6.59 (1H, s), 6.62 (1H, d, J=5.2 Hz), 6.76 (1H, br t, J=6 Hz), 6.84 (1H, br t, J=6 Hz), 7.09 (2H, d, J=10.7 Hz), and 8.14 (1H, d, J=5.2 Hz).
EXAMPLE 837




1H NMR (CDCl3) δ=2.43 (3H, s, heterocycle-CH3), 3.01-3.08 (2H, m), 3.24-3.38 (4H, m), 3.40 (3H, s, heterocycle-CH2OCH3), 3.60-4.14 (6H, m), 4.01 (3H, s, CH3OC═S), 4.27 (2H, br s, hererocycle-NH2), 4.41 (2H, d, J=5.5 Hz, NHCH2-heterocycle), 4.60 (2H, s, heterocycle-CH2OCH3), 4.88-4.97 (1H, m, NCH2CHCH2NHC═O), 6.57 (1H, br t, J=6 Hz), 6.87 (1H, br t, J=6 Hz), 7.10 (2H, d, J=10.7 Hz), and 7.88 (1H, s).
EXAMPLE 838




1H NMR (CDCl3) δ=3.08-3.20 (2H, m), 3.32-3.41 (4H, m), 3.72-4.14 (6H, m), 4.01 (3H, s, CH3OC═S), 4.70 (2H, d, J=6.0 Hz, NHCH2-heterocycle), 4.88-4.98 (1H, m, NCH2CHCH2NHC═O), 6.75 (1H, br t, J=6 Hz), 7.05 (1H, br t, J=6 Hz), 7.11 (2H, d, J=10.7 Hz), 7.78 (1H, br d, J=9 Hz), 8.00 (1H, s), 8.09 (1H, d, J=8.6 Hz), and 8.82-8.86 (2H, m).
EXAMPLE 839




1H NMR (CDCl3) δ=2.97-3.05 (2H, m), 3.22-3.33 (4H, m), 3.48-4.12 (6H, m), 4.00 (3H, s, CH3OC═S), 4.40 (2H, d, J=6.0 Hz, NHCH2-heterocycle), 4.87-4.97 (1H, m, NCH2CHCH2NHC═O), 6.69-6.80 (2H, m), 7.06 (1H, br t, J=6 Hz), 7.09 (2H, d, J=10.7 Hz), 7.28-7.38 (2H, m), 7.49 (1H, dd, J=1.7, 7.4 Hz), 8.08 (1H, br s), 8.26 (1H, d, J=2.8 Hz), and 8.47 (1H, br s).
EXAMPLE 840




1H NMR (CDCl3) δ=3.08-3.15 (2H, m), 3.29-3.38 (4H, m), 3.64-4.16 (6H, m), 4.00 (3H, s, CH3OC═S), 4.29 (3H, s, N═N—N—CH3), 4.60 (2H, br d, J=6 Hz, NHCH2-heterocycle), 4.88-4.98 (1H, m, NCH2CHCH2NHC═O), 6.88-6.98 (2H, m), 7.10 (2H, d, J=10.5 Hz), 7.44-7.54 (2H, m), and 7.94 (1H, s).
EXAMPLE 841




1H NMR (CDCl3) δ=3.08-3.15 (2H, m), 3.29-3.39 (4H, m), 3.60-4.16 (6H, m), 4.01 (3H, s, CH3OC═S), 4.46 (2H, d, J=6.0 Hz, NHCH2-heterocycle), 4.87-4.97 (1H, m, NCH2CHCH2NHC═O), 6.46 (1H, dd, J=1.7, 2.5 Hz), 6.75 (1H, br t, J=6 Hz), 6.85 (1H, br t, J=6 Hz), 7.10 (2H, d, J=10.7 Hz), 7.41 (2H, d, J=8.5 Hz), 7.65 (2H, d, J=8.5 Hz), 7.72 (1H, d, J=1.7 Hz), and 7.911H, d, J=2.5 Hz).
EXAMPLE 842




1H NMR (CDCl3) δ=2.28 (3H, s, CH3N), 2.08-2.80 (8H, m), 3.06-3.20 (2H, m), 3.26-3.38 (4H, m), 3.49 (2H, br s, NCH2Ph), 3.66-3.12 (6H, m), 3.99 (3H, s, CH3OC═S), 4.41 (2H, br s, NHCH2-heterocycle), 4.87-4.97 (1H, m, NCH2CHCH2NHC═O), 6.79 (1H, br t, J=6 Hz), 7.10 (2H, d, J=10.7 Hz), and 7.26 (1H, br t, J=6 Hz).
EXAMPLE 843




1H NMR (CDCl3) δ=2.40 (3H, s, heterocycle-CH3), 3.08-3.15 (2H, m), 3.26-3.37 (4H, m), 3.65-4.16 (6H, m), 4.01 (3H, s, CH3OC═S), 4.44 (2H, d, J=6.0 Hz, NHCH2-heterocycle), 4.87-4.97 (1H, m, NCH2CHCH2NHC═O), 6.01 (1H, s), 6.81 (1H, br t, J=6 Hz), 6.90 (1H, br t, J=6 Hz), and 7.10 (2H, d, J=10.7 Hz).
EXAMPLE 844




1H NMR (CDCl3+DMSO-d6) δ=2.97 (3H, d, J=4.0 Hz, NHCH3), 3.15-3.29 (4H, m), 3.34-3.41 (2H, m), 3.76-3.82 (2H, m), 3.82-4.04 (4H, m), 4.00 (3H, s, CH3OC═S), 4.88-4.98 (1H, m, NCH2CHCH2NHC═O), 7.12 (2H, d, J=10.5 Hz), 8.16 (1H, br t, J=6 Hz), and 9.85 (1H, br s).
EXAMPLE 845




1H NMR (CDCl3) δ=2.40 (3H, s, heterocycle-CH3), 3.03-3.11 (2H, m), 3.21-3.28 (2H, m), 3.31-3.37 (2H, m), 3.68-4.12 (6H, m), 4.00 (3H, s, CH3OC═S), 4.90-5.00 (1H, m, NCH2CHCH2NHC═O), 4.99 (2H, d, J=6.2 Hz, NHCH2-heterocycle), 6.87 (1H, br t, J=6 Hz), 7.09 (2H, d, J=10.7 Hz), 7.11 (1H, br t, J=6 Hz), 7.25-7.36 (2H, m), 7.73 (1H, br d, J=10 Hz), and 8.59 (1H, br d, J=7 Hz).
EXAMPLE 846




1H NMR (CDCl3) δ=2.95-3.02 (4H, m, NCH2CH2OCH2CH2N), 3.11-3.18 (2H, m), 3.30-3.39 (4H, m), 3.64-4.12 (6H, m), 3.71-3.78 (4H, m, NCH2CH2OCH2CH2N), 4.00 (3H, s, CH3OC═S), 4.52 (2H, d, J=6.2 Hz, NHCH2-heterocycle), 4.88-4.98 (1H, m, NCH2CHCH2NHC═O), 6.93-7.00 (2H, m), 7.10 (2H, d, J=10.7 Hz), 7.50 (2H, br d, J=8 Hz), and 7.70 (2H, br d, J=8 Hz).
EXAMPLE 847




1H NMR (CDCl3) δ=3.16-3.24 (2H, m), 3.31-3.38 (4H, m), 3.65-4.10 (6H, m), 3.93 & 3.95 (6H, s, heterocycle-OCH3×2, two conformers), 4.01 (3H, s, CH3OC═S), 4.50 & 4.51 (2H, d, J=5.5 Hz, NHCH2-heterocycle, two conformers), 4.89-4.99 (1H, m, NCH2CHCH2NHC═O), 5.73 & 7.18 (1H, br t, J=6 Hz, two conformers), 5.91 (1H, br s), 7.10 (2H, d, J=10.7 Hz), and 7.45 (1H, br t, J=6 Hz).
EXAMPLE 848




1H NMR (CDCl3) δ=3.19-3.26 (2H, m), 3.37-3.43 (4H, m), 3.59-3.67 (2H, m), 3.78-4.14 (4H, m), 4.00 (3H, s, CH3OC═S), 4.59 (2H, d, J=5.6 Hz, NHCH2-heteroaryl), 4.86-4.96 (1H, m, NCH2CHCH2NHC═O), 6.79 (1H, br t, J=6 Hz, NHC═S), 6.90 (1H, t, J=9.1 Hz), 7.02 (1H, br d, J=9 Hz), 7.14-7.30 (2H, m), 7.39 (1H, dd, J=2.8, 14.7 Hz), and 8.26-8.30 (1H, m).
EXAMPLE 849




1H NMR (CDCl3) δ=2.45 (6H, s, CH3-heteroaryl×2), 3.24-3.32 (2H, m), 3.39-3.47 (4H, m), 3.61-3.68 (2H, m), 3.78-4.14 (4H, m), 4.00 (3H, s, CH3OC═S), 4.60 (2H, d, J=5.4 Hz, NHCH2-heteroaryl), 4.85-4.95 (1H, m, NCH2CHCH2NHC═O), 6.72 (1H, br t, J=6 Hz, NHC═S), 6.89 (1H, s), 6.91 (1H, t, J=9.1 Hz), 7.02 (1H, dd, J=2.5, 9.1 Hz), 7.38 (1H, t, J=5.4 Hz, NHCH2-heteroaryl), and 7.40 (1H, dd, J=2.5, 14.6 Hz).
EXAMPLE 850




1H NMR (CDCl3) δ=3.15-3.23 (2H, m), 3.35-3.45 (4H, m), 3.62-3.71 (2H, m), 3.78-4.11 (4H, m), 4.00 (3H, s, CH3OC═S), 4.50 (2H, d, J=6.2 Hz, NHCH2-aryl), 4.86-4.96 (1H, m, NCH2CHCH2NHC═O), 6.85-6.95 (2H, m), 7.02 (1H, dd, J=2.5, 9.1 Hz), 7.17 (1H, t, J=6.2 Hz), 7.32-7.49 (3H, m), 7.55 (1H, br d, J=8 Hz), 7.64 (1H, s), 8.09 (1H, s), and 8.57 (1H, s).
EXAMPLE 851
Chemical Formula 882




1H NMR (CDCl3) δ=2.39 (3H, s, CH3-heteroaryl), 3.14-3.22 (2H, m), 3.35-3.42 (4H, m), 3.63-3.75 (2H, m), 3.78-4.12 (4H, m), 4.00 (3H, s, CH3OC═S), 4.55 (2H, d, J=6.1 Hz, NHCH2-heteroaryl), 4.86-4.97 (1H, m, NCH2CHCH2NHC═O), 6.88 (1H, t, J=9.1 Hz), 6.94 (1H, br t, J=6 Hz, NHC═S), 7.01 (1H, dd, J=2.5, 9.1 Hz), 7.11 (1H, t, J=6.1 Hz, NHCH2-heteroaryl), and 7.38 (1H, dd, J=2.5, 14.6 Hz).
EXAMPLE 852




1H NMR (CDCl3) δ=3.43-3.50 (4H, m), 3.85 (1H, dd, J=7.1, 9.1 Hz), 3.91-4.21 (7H, m), 4.01 (3H, s, OMe), 4.87-4.98 (1H, m), 6.96-7.13 (3H, m), 7.48 (1H, dd, J=2.5, 15.0 Hz), 7.78 (2H, d, J=4.7 Hz), and 8.70 (2H, d, J=4.7 Hz).
EXAMPLE 853




1H NMR (CDCl3) δ=3.42-3.49 (4H, m), 3.84 (1H, dd, J=7.1, 9.1 Hz), 3.90-4.19 (7H, m), 4.01 (3H, s, OMe), 4.88-4.99 (1H, m), 6.79 (1H, t, J=6.3 Hz, NHC═S), 7.16 (2H, d, J=10.7 Hz), 7.79 (2H, d, J=4.7 Hz), and 8.71 (2H, d, J=4.7 Hz).
EXAMPLE 854




1H NMR (CDCl3) δ=3.41-3.50 (4H, m), 3.63-3.76 (2H, m), (1H, ddd, J=3.3, 6.3, 14.6 Hz), 4.07 (1H, t, J=9.1 Hz), 4.10-4.16 (4H, m), 4.79-4.89 (1H, m), 5.94 (1H, t, J=54.1 Hz, CHF2), 7.07-7.15 (1H, br, NHC═O), 7.14 (2H, d, J=10.7 Hz), 7.78 (2H, d, J=4.7 Hz), and 8.71 (2H, d, J=4.7 Hz).
EXAMPLE 855




1H NMR (CDCl3) δ=3.38-3.50 (4H, m), 3.62-4.14 (4H, m), (3H, s, CH3OC═S), 4.37-4.48 (4H, m), 4.88-4.98 (1H, m), (1H, t, J=6.0 Hz, NHC═S), 7.00 (1H, t, J=9.1 Hz), 7.05-7.12 (2H, m), 7.47 (1H, dd, J=2.5, 14.0 Hz), 8.18 (1H, dd, J=1.7, 7.7 Hz), and 8.54 (1H, dd, J=1.7, 4.7 Hz).
EXAMPLE 856




1H NMR (CDCl3) δ=3.35-3.50 (4H, m), 3.62-4.14 (4H, m), 4.00 (3H, s, CH3OC═S), 4.34-4.49 (4H, m), 4.88-5.01 (1H, m), 7.02-7.19 (4H, m), 8.17 (1H, dd, J=1.7, 7.7 Hz), and 8.53 (1H, dd, J=1.7, 4.7 Hz)
EXAMPLE 857




1H NMR (CDCl3) δ=2.55 (1H, br t, J=6 Hz, OH), 3.38-3.50 (4H, m), 3.77 (1H, ddd, J=3.6, 7.1, 12.6 Hz), 3.95-4.06 (3H, m), 4.37-4.48 (4H, m), 4.72-4.81 (1H, m), 7.07 (1H, dd, J=4.7, 7.7 Hz), 7.17 (2H, d, J=10.8 Hz), 8.18 (1H, dd, J=1.7, 7.7 Hz), and 8.53 (1H, dd, J=1.7, 4.7 Hz).
EXAMPLE 858




1H NMR (CDCl3) δ=3.02 (3H, S, CH3SO2), 3.38-3.52 (4H, m), 3.84-3.95 (1H, m), 4.11 (1H, t, J=9.1 Hz), 4.37-4.54 (6H, m), 4.89-4.99 (1H, m), 7.07 (1H, dd, J=4.7, 7.7 Hz), 7.17 (2H, d, J=10.8 Hz), 8.18 (1H, dd, J=1.7, 7.7 Hz), and 8.53 (1H, dd, J=1.7, 4.7 Hz).
EXAMPLE 859




1H NMR (CDCl3) δ=3.39-3.51 (4H, m), 3.58 (1H, dd, J=7.1, 10.7 Hz, CHHBr), 3.65 (1H, dd, J=3.8, 10.7 Hz, CHHBr), 3.83 (1H, dd, J=5.8, 9.1 Hz), 4.12 (1H, t, J=9.1 Hz), 4.37-4.48 (4H, m), 4.84-4.95 (1H, m), 7.07 (1H, dd, J=4.7, 7.7 Hz), 7.18 (2H, d, J=10.7 Hz), 8.18 (1H, dd, J=1.7, 7.7 Hz), and 8.53 (1H, dd, J=1.7, 4.7 Hz).
EXAMPLE 860




1H NMR (CDCl3) δ=3.39-3.51 (4H, m), 3.87-4.15 (4H, m), 4.37-4.52 (4H, m), 4.85-4.95 (1H, m), 7.11 (1H, dd, J=4.7, 7.7 Hz), 7.17 (2H, d, J=10.7 Hz), 8.18 (1H, dd, J=1.6, 7.7 Hz), and 8.53 (1H, dd, J=1.6, 4.7 Hz).
EXAMPLE 861




1H NMR (CDCl3) δ=2.02 (3H, s, CH3C═O), 3.36-3.48 (4H, m), 3.61-3.77 (3H, m), 3.99 (1H, t, J=9.1 Hz), 4.35-4.45 (4H, m), 4.73-4.83 (1H, m, NCH2CHCH2NHC═O), 6.11 (1H, br t, J=6 Hz), 7.13 (2H, d, J=10.7 Hz), 8.12 (1H, dd, J=1.4, 2.5 Hz), and 8.45 (1H, dd, J=1.4, 2.5 Hz).
EXAMPLE 862




1H NMR (CDCl3) δ=3.30-3.40 (4H, m), 3.54-3.83 (3H, m), 4.00 (1H, t, J=9.1 Hz), 4.28-4.39 (4H, m), 4.72-4.82 (1H, m, NCH2CHCH2NHC═O), 5.87 (1H, t, J=59.0 Hz, CHF2), 6.96 (1H, br t, J=6 Hz, NHC═O), 7.07 (2H, d, J=10.7 Hz), 8.06 (1H, dd, J=1.4, 2.5 Hz), and 8.39 (1H, dd, J=1.4, 2.5 Hz).
EXAMPLE 863




1H NMR (CDCl3) δ=2.03 (3H, s, CH3C═O), 3.37-3.49 (4H, m), 3.63-3.82 (3H, m), 4.00 (1H, t, J=9.1 Hz), 4.35-4.46 (4H, m), 4.74-4.84 (0.1H, m, NCH2CHCH2NHC═O), 6.38 (1H, br t, J=6 Hz, NHC═O), 7.13 (2H, d, J=10.7 Hz), 8.26 (1H, br s), and 8.54 (1H, br s)
EXAMPLE 864




1H NMR (CDCl3) δ=2.03 (3H, s, CH3C═O), 2.98 (6H, s, CH3NCH3), 3.35-3.52 (4H, m), 3.63-3.79 (3H, m), 4.00 (1H, t, J=9.1 Hz), 4.20-4.35 (4H, m), 4.75-4.84 (1H, m, NCH2CHCH2NHC═O), 6.32 (1H, br t, J=6 Hz, NHC═O), 7.13 (2H, d, J=10.7 Hz), 7.45 (1H, d, J=3.0 Hz), and 8.24 (1H, d, J=3.0 Hz).
EXAMPLE 865




1H NMR (CDCl3) δ=2.03 (3H, s, CH3C═O), 3.35-3.52 (4H, m), 3.61-3.79 (3H, m), 4.00 (1H, t, J=9.1 Hz), 4.20-4.35 (4H, m), 4.75-4.84 (1H, m, NCH2CHCH2NHC═O), 6.19 (1H, br t, J=6 Hz, NHC═O), 7.13 (2H, d, J=10.7 Hz), 7.46 (1H, d, J=2.2 Hz), and 8.13 (1H, d, J=2.2 Hz).
EXAMPLE 866




1H NMR (CDCl3) δ=3.35-3.52 (4H, m), 3.61-3.90 (3H, m), 4.07 (1H, t, J=9.1 Hz), 4.20-4.35 (4H, m), 4.79-4.88 (1H, m, NCH2CHCH2NHC═O), 5.94 (1H, t, J=54.0 Hz, CHF2), 7.01 (1H, br t, J=6 Hz, NHC═O), 7.13 (2H, d, J=10.7 Hz), 7.46 (1H, d, J=2.8 Hz), and 8.13 (1H, d, J=2.8 Hz).
EXAMPLE 867




1H NMR (CDCl3) δ=2.05 (3H, s, CH3C═O), 3.40-3.52 (4H, m), 3.68 (2H, dd, J=4.7, 6.1 Hz), 3.79 (1H, dd, J=6.7, 9.1 Hz), 4.00 (1H, t, J=9.1 Hz), 4.44-4.50 (4H, m), 4.75-4.85 (1H, m, NCH2CHCH2NHC═O), 6.47 (1H, br t, J=6 Hz, NHC═O), 7.14 (2H, d, J=10.7 Hz), 8.47 (1H, d, J=8.8 Hz), and 8.48 (1H, d, J=8.8 Hz).
EXAMPLE 868




1H NMR (CDCl3) δ=2.03 (3H, s, CH3C═O), 3.44-3.52 (4H, m), 3.62-3.78 (3H, m), 4.00 (1H, t, J=9.1 Hz), 4.40-4.45 (2H, m), 4.61-4.66 (2H, m), 4.74-4.84 (1H, m, NCH2CHCH2NHC═O), 5.93 (1H, br t, J=6 Hz, NHC═O), 7.16 (2H, d, J=10.7 Hz), and 7.92 (1H, s).
EXAMPLE 869




1H NMR (CDCl3) δ=2.02 (3H, s, CH3C═O), 3.30-4.01 (12H, m), 4.72-4.82 (1H, m), 6.10 (1H, t, J=6.0 Hz, NHC═O), 7.08 (2H, d, J=10.7 Hz), 7.49 (1H, br s), 7.60 (1H, br d, J=8 Hz), 7.76 (1H, dt, J=1.7, 7.7 Hz), and 8.53 (1H, br d, J=8 Hz).
EXAMPLE 870




1H NMR (CDCl3) δ=2.03 (3H, s, CH3C═O), 3.05-3.13 (2H, m), 3.25-3.32 (2H, m), 3.40-3.47 (2H, m), 3.64-3.79 (3H, m), 3.93-4.04 (3H, m), 4.75-4.85 (1H, m, NCH2CHCH2NHC═O), 6.36 (1H, br t, J=6 Hz, NHC═O), 7.09 (2H, d, J=10.7 Hz), 7.29 (1H, s), and 11.46 (1H, br s, CO2H).
EXAMPLE 871




1H-NMR (300 MHz, CDCl3) δ 3.22 (br t, 5.5, 2H), 3.39 (br t, 5, 2H), 3.48 (br t, 5, 2H), 3.52-3.62 (m, 2H), 3.68 (s, 3H), 3.75 (dd, 9, 7.5, 1H), 3.90 (t, 5.5, 2H), 4.00 (dd, 9, 9, 1H), 4.72-4.82 (m, 1H), 5.65 (br t, 6, NH), 7.01-7.14 (m, 2H)
EXAMPLE 872




1H-NMR (300 MHz, CDCl3) δ 3.22 (t, 5.5, 2H), 3.40 (br t, 5.5, 2H), 3.49 (t, 5.5, 2H), 3.80 (dd, 9, 7, 1H), 3.90 (t, 5.5, 2H), 3.94-4.12 (m, 3H), 4.00 (s, 3H), 4.88-4.98 (m, 1H), 7.00 (br t, 6, NH), 7.02-7.13 (m, 2H)
EXAMPLE 873




1H-NMR (300 MHz, CDCl3-CD3OD (9:1)) δ 3.00 (s, 3H), 3.19-3.30 (m, 2H), 3.30-3.46 (m, 2H), 3.46-3.56 (m, 3H), 3.92 (t, 5.5, 2H), 3.92 (dd, 9, 6.5, 1H), 4.03 (dd, 9, 9, 1H), 4.75-4.84 (m, 1H), 7.06-7.17 (m, 2H)
EXAMPLE 874




1H-NMR (300 MHz, CDCl3) δ 3.22 (t, 5.5, 2H), 3.40 (t, 5.5, 2H), 3.49 (t, 5.5, 2H), 3.64-3.81 (m, 2H), 3.75 (dd, 9, 7, 1H), 3.90 (t, 5.5, 2H), 4.01 (dd, 9, 9, 1H), 4.77-4.86 (m, 1H), 5.79 (br s, NH), 6.65 (br t, 6, NH), 7.02-7.12 (m, 2H), 8.28 (d, 2, 1H)
EXAMPLE 875




1H-NMR (300 MHz, CDCl3) δ 2.73 (d, 5, 3H), 3.22 (br t, 5, 2H), 3.39 (br t, 5, 2H), 3.48 (br t, 5.5, 2H), 3.56 (ddd, 15, 6, 3, 1H), 3.70 (ddd, 15, 6, 4.5, 1H), 3.83-3.92 (m, 3H), 3.99 (dd, 9, 9, 1H), 4.75-4.84 (m, 1H), 5.51 (br q, 5, NH), 5.98 (br t, 6, NH), 7.01-7.12 (m, 2H);
EXAMPLE 876




1H-NMR (300 MHz, CDCl3) δ 3.22 (t, 5.5, 2H), 3.40 (t, 5.5, 2H), 3.49 (t, 5.5, 2H), 3.58 (dd, 12, 7, 1H), 3.64 (dd, 12, 4, 1H), 3.84 (dd, 9, 6, 1H), 3.90 (t; 5.5, 2H), 4.11 (dd, 9, 9, 1H), 4.88 (dddd, 9, 7, 6, 4, 1H), 5.74 (br s, NH), 7.05-7.16 (m, 2H)
EXAMPLE 877




1H-NMR (300 MHz, CDCl3) δ 2.81 (s, 6H), 3.22 (br t, 5.5, 2H), 3.40 (br t, 5, 2H), 3.43-3.54 (m, 4H), 3.88 (dd, 9, 6, 1H), 3.90 (t, 5.5, 2H), 4.01 (dd, 9, 9, 1H), 4.76-4.86 (m, 1H), 5.44 (br s, NH), 7.03-7.14 (m, 2H)
EXAMPLE 878




1H-NMR (300 MHz, CDCl3) δ 3.11 (s, 3H), 3.23 (t, 5, 2H), 3.41 (t, 5, 2H), 3.50 (t, 5, 2H), 3.85-3.93 (m, 3H), 4.10 (dd, 9, 9, 1H), 4.42 (dd, 12, 4, 1H), 4.51 (dd, 12, 3.5, 1H), 4.89-4.98 (m, 1H), 7.04-7.15 (m, 2H);
EXAMPLE 879




1H-NMR (300 MHz, CDCl3-CD3OD (9:1)) δ 3.21 (t, 5, 2H), 3.39 (br t, 5, 2H), 3.47 (br t, 5.5, 2H), 3.90 (t, 5.5, 2H), 3.74-3.88 (m, 3H), 4.07 (dd, 9, 9, 1H), 4.85-4.94 (m, 1H), 6.88 (ddd, 8, 8, 1, 1H), 6.94 (dd, 8, 1, 1H), 7.01-7.12 (m, 2H), 7.39 (ddd, 8, 8, 1.5, 1H), 7.68 (dd, 8, 1.5, 1H);
EXAMPLE 880




1H-NMR (300 MHz, CDCl3) δ 2.02 (s, 3H), 3.06 (t, 5.5, 2H), 3.54-3.78 (m, 9H), 3.72 (s, 3H), 3.99 (dd, 9, 9, 1H), 4.00 (t, 6, 2H), 4.70-4.80 (m, 1H), 6.41 (br t, 6, NH), 6.89 (dd, 9, 9, 1H), 7.01 (br dd, 9, 2.5, 1H), 7.34 (dd, 15.5, 2.5, 1H)
EXAMPLE 881




1H-NMR (300 MHz, CDCl3) δ 2.02 (s, 3H), 3.14 (br t, 5.5, 2H), 3.55-3.71 (m, 6H), 3.73 (dd, 9, 7, 1H), 3.88 (br t, 5.5, 2H), 3.99 (dd, 9, 9, 1H), 4.16 (br s, 2H), 4.71-4.81 (m, 1H), 6.47 (br t, 6, NH), 6.88 (dd, 9, 9, 1H), 7.01 (br dd, 9, 2.5, 1H), 7.33 (dd, 15.5, 2.5, 1H), 7.44 (dd, 7.5, 7.5, 2H), 7.56 (dddd, 7.5, 7.5, 1, 1, 1H), 7.96 (dd, 7.5, 1, 2H);
EXAMPLE 882




1H-NMR (300 MHz, CDCl3) δ 2.94 (s, 6H), 2.96 (t, 5.5, 2H), 3.37 (br t, 5, 2H), 3.45 (br t, 5.5, 2H), 3.76 (br t, 5.5, 2H), 3.81 (s, 2H), 3.91-4.12 (m, 4H), 4.00 (s, 3H), 4.86-4.95 (m, 1H), 6.70 (A2B2, J=9, 2H), 6.84 (br t, 6, NH), 6.99-7.11 (m, 2H), 7.24 (A2B2, J=9, 2H);
EXAMPLE 883




1H-NMR (300 MHz, CDCl3) δ 3.11 (t, 5.5, 2H), 3.40-3.50 (m, 4H), 3.80 (dd, 9, 7, 1H), 3.90 (br t, 5.5, 2H), 3.94-4.14 (m, 4H), 4.00 (s, 3H), 4.10 (s, 2H), 4.86-4.96 (m, 1H), 6.79-6.94 (m, 3H), 7.00-7.15 (m, 2H+NH), 7.20 (ddd, 8.5, 8.5, 1.5, 1H), 9.29 (br s, OH);
EXAMPLE 884




1H-NMR (300 MHz, CDCl3) δ 3.06 (t, 5.5, 2H), 3.38-3.48 (m, 4H), 3.65 (t, 5.5, 2H), 3.80 (dd, 9, 7, 1H), 3.88 (s, 2H), 3.91-4.12 (m, 3H), 4.03 (s, 3H), 4.87-4.97 (m, 1H), 7.00-7.14 (m, 2H+NH), 7.27 (dd, 7.5, 5, 1H), 7.74 (ddd, 7.5, 1.5, 1.5, 1H), 8.52 (dd, 5, 1.5, 1H), 8.62 (d, 1.5, 1H);
EXAMPLE 885




1H-NMR (300 MHz, CDCl3) δ 3.02 (t, 5.5, 2H), 3.36-3.46 (m, 4H), 3.67 (br t, 5.5, 2H), 3.80 (dd, 9, 7, 1H), 3.80 (s, 2H), 3.93 (s, 3H), 3.96-4.11 (m, 3H), 4.00 (s, 3H), 4.87-4.97 (m, 1H), 6.72 (d, 8.5, 1H), 6.99-7.11 (m, 2H+NH), 7.64 (dd, 8.5, 2.5, 1H), 8.12 (d, 2.5, 1H)
EXAMPLE 886




1H-NMR (300 MHz, CDCl3) δ 2.98 (t, 5, 2H), 3.37 (br t, 5, 2H), 3.42 (br t, 5.5, 2H), 3.74-3.86 (m, 3H), 3.92-4.10 (m, 3H), 3.95 (s, 2H), 4.00 (s, 3H), 4.88-4.98 (m, 1H), 6.99 (d, 0.5, 1H), 6.98-7.09 (m, 2H), 7.48 (br t, 6, NH), 7.64 (d, 0.5, 1H);
EXAMPLE 887




1H-NMR (300 MHz, CDCl3) δ 3.03 (t, 5, 2H), 3.37 (br t, 5, 2H), 3.45 (br t, 5.5, 2H), 3.67 (s, 3H), 3.76-3.87 (m, 3H), 3.92-4.10 (m, 3H), 3.90 (s, 2H), 4.00 (s, 3H), 4.88-4.98 (m, 1H), 6.86 (d, 1, 1H), 6.98-7.10 (m, 2H), 7.39 (d, 1, 1H), 7.50 (br t, 6, NH);
EXAMPLE 888




1H-NMR (300 MHz, CDCl3) δ 3.07 (t, 5.5, 2H), 3.40-3.50 (m, 4H), 3.76-3.85 (m, 3H), 3.94-4.12 (m, 3H), 3.98 (s, 2H), 4.00 (s, 3H), 4.88-4.98 (m, 1H), 6.57 (d, 3.5, 1H), 6.95 (br t, 6, NH), 7.01-7.13 (m, 2H), 7.30 (d, 3.5, 1H), 7.50 (br t, 6, NH);
EXAMPLE 889




1H-NMR (300 MHz, CDCl3) δ 2.03 (s, 3H), 2.59 (s, 3H), 2.93 (t, 6, 2H), 3.55-3.69 (m, 3H), 3.73 (t, 6, 4H,), 3.95 (t, 6, 2H), 4.01 (t, 9, 1H), 4.73 (m, 1H), 6.00 (bt, NH), 6.73 (d, 10, 2H), 7.31 (d, 10, 2H);
EXAMPLE 890




1H-NMR (300 MHz, CDCl3) δ 2.03 (s, 3H), 2.65 (s, 3H), 2.96 (t, 6, 2H), 3.55 (t, 6, 3H), 3.61 (t, 6, 2H), 3.69-3.75 (m, 3H), 3.94 (t, 6, 2H), 4.00 (t, 9, 1H), 4.74 (m, 1H), 5.93 (bt, NH), 6.89 (t, 10, 1H), 7.02 (dd, 10, 4, 1H), 7.35 (dd, 10, 4, 1H)
EXAMPLE 891




1H-NMR (300 MHz, CDCl3) δ 2.68 (s, 3H), 2.93 (t, 5.5, 2H), 3.40 (br t, 5, 2H), 3.45 (br t, 5, 2H), 3.80 (dd, 9, 7, 1H), 3.91 (t, 5.5, 2H), 3.95-4.12 (m, 3H), 4.01 (s, 3H), 4.88-4.98 (m, 1H), 6.99 (br s, NH), 7.00-7.12 (m, 2H);
EXAMPLE 892




1H-NMR (300 MHz, CDCl3) δ 1.34 (t, 7, 3H), 2.02 (s, 3H), 3.48-3.57 (m, 4H), 3.57-3.72 (m, 2H), 3.76 (dd, 9, 6.5, 1H), 3.98 (t, 6, 2H), 4.02 (dd, 9, 9, 1H), 4.22 (t, 5, 2H), 4.36 (q, 7, 2H), 4.73-4.82 (m, 1H), 6.47 (br t, 6, NH), 6.91 (dd, 9, 9, 1H), 7.05 (br dd, 9, 3, 1H), 7.42 (dd, 15, 3, 1H);
EXAMPLE 893




1H-NMR (300 MHz, CDCl3) δ 1.28 (t, 7, 3H), 2.02 (s, 3H), 3.46-3.55 (m, 4H), 3.55-3.71 (m, 2H), 3.56 (s, 2H), 3.75 (dd, 9, 6.5, 1H), 4.01 (t, 5.5, 2H), 4.01 (dd, 9, 9, 1H), 4.16 (t, 5, 2H), 4.20 (q, 7, 2H), 4.72-4.82 (m, 1H), 6.37 (br t, 6, NH), 6.90 (dd, 9, 9, 1H), 7.04 (br dd, 9, 2.5, 1H), 7.41 (dd, 15, 2.5, 1H);
EXAMPLE 894




1H-NMR (300 MHz, CDCl3) δ 1.26 (t, 7, 3H), 2.02 (s, 3H), 2.65 (br t, 7, 2H), 2.79 (br t, 7, 2H), 3.45-3.56 (m, 4H), 3.56-3.71 (m, 2H), 3.75 (dd, 9, 7, 1H), 3.97 (t, 6, 2H), 4.01 (dd, 9, 9, 1H), 4.14 (q, 7, 2H), 4.18 (t, 5.5, 2H), 4.72-4.82 (m, 1H), 6.67 (br t, 6, NH), 6.89 (dd, 9, 9, 1H), 7.03 (br dd, 9, 2.5, 1H), 7.39 (dd, 15, 2.5, 1H);
EXAMPLE 895




1H-NMR (300 MHz, CDCl3-CD3OD (9:1)) δ 2.19 (s, 3H), 3.48-3.58 (m, 4H), 3.62 (dd, 14.5, 6.5, 1H), 3.73 (dd, 14.5, 4, 1H), 3.75 (dd, 9, 6.5, 1H), 3.97 (t, 5.5, 2H), 4.08 (dd, 9, 9, 1H), 4.22 (t, 5, 2H), 4.81 (dddd, 9, 6.5, 6.5, 4, 1H), 4.88 (s, 2H), 5.95 (t, 54, 1H), 6.93 (dd, 9, 9, 1H), 7.05 (br dd, 9, 2.5, 1H), 7.39 (dd, 15, 2.5, 1H);
EXAMPLE 896




1H-NMR (300 MHz, CDCl3) δ 2.01 (s, 3H), 3.41-3.50 (m, 4H), 3.73 (dd, 9, 7, 1H), 3.81 (s, 2H), 3.95-4.05 (m, 5H), 4.71-4.80 (m, 1H), 6.38 (br t, 6, NH), 6.85 (dd, 9, 9, 1H), 7.02 (br dd, 9, 2.5, 1H), 7.20-7.34 (m, 5H), 7.39 (dd, 15, 2.5, 1H);
EXAMPLE 897




1H-NMR (300 MHz, CDCl3) δ 2.19 (s, 3H), 3.67 (ddd, 14.5, 6, 6, 1H), 3.72 (dd, 9, 6, 1H), 3.81 (ddd, 14.5, 6, 3.5, 1H), 3.90 (t, 5.5, 2H), 4.05 (dd, 9, 9, 1H), 4.18 (t, 5, 2H), 4.79-4.91 (m, 1H), 4.89 (s, 2H), 5.95 (t, 54, 1H), 7.46 (br t, 6, NH), 7.03-7.14 (m, 2H);
EXAMPLE 898




1H-NMR (300 MHz, CDCl3-CD3OD (9:1)) δ 2.01 (s, 3H), 3.38-3.48 (m, 4H), 3.54-3.68 (m, 4H), 3.73 (dd, 9, 6.5, 1H), 3.92 (t, 5.5, 2H), 4.01 (dd, 9, 9, 1H), 4.11 (t, 5, 2H), 4.72-4.82 (m, 1H), 7.07-7.17 (m, 2H);
EXAMPLE 899




1H-NMR (300 MHz, CDCl3) δ 3.36-3.47 (m, 4H), 3.62-3.85 (m, 2H), 3.65 (br s, 2H), 3.72 (dd, 9, 6.5, 1H), 3.90 (t, 5.5, 2H), 4.05 (dd, 9, 9, 1H), 4.11 (t, 5, 2H), 4.79-4.89 (m, 1H), 5.94 (t, 54, 1H), 7.03-7.14 (m, 2H), 7.83 (br s, NH);
EXAMPLE 900




1H-NMR (300 MHz, CDCl3-CD3OD (9:1)) δ 2.74 (t, 6, 2H), 3.06 (t, 6, 2H), 3.37-3.47 (m, 4H), 3.64 (dd, 14.5, 6, 1H), 3.69-3.78 (m, 4H), 3.90 (t, 5.5, 2H), 4.05 (dd, 9, 9, 1H), 4.13 (t, 5, 2H), 4.77-4.87 (m, 1H), 5.93 (t, 54, 1H), 7.05-7.16 (m, 2H).
EXAMPLE 901




1H-NMR (300 MHz, CDCl3) δ 1.46 (s, 9H), 3.37-3.47 (m, 4H), 3.67 (ddd, 14.5, 6, 6, 1H), 3.72 (dd, 9, 6.5, 1H), 3.82 (ddd, 14.5, 6, 3.5, 1H), 3.90 (t, 5.5, 2H), 4.06 (dd, 9, 9, 1H), 4.11-4.18 (m 4H), 4.79-4.89 (m, 1H), 5.35 (br s, NH), 5.94 (t, 54, 1H), 7.07-7.17 (m, 2H), 7.34 (br t, 6, NH);
EXAMPLE 902




1H-NMR (300 MHz, CDCl3) δ 1.43 (s, 9H), 2.71 (t, 5.5, 2H), 3.36-3.48 (m, 6H), 3.68 (ddd, 14.5, 6, 6, 1H), 3.74 (dd, 9, 6, 1H), 3.81 (ddd, 14.5, 6, 3.5, 1H), 3.89 (t, 5.5, 2H), 4.06 (dd, 9, 9, 1H), 4.10 (t, 5, 2H), 4.80-4.90 (m, 1H), 5.28 (br s, NH), 5.95 (t, 54, 1H), 7.03-7.14 (m, 2H), 7.60 (br t, 6, NH);
EXAMPLE 903




1H-NMR (300 MHz, CDCl3) δ 3.37-3.48 (m, 4H), 3.66 (br s, 2H), 3.83 (dd, 9, 7, 1H), 3.92 (t, 5.5, 2H), 3.96-4.07 (m, 3H), 4.00 (s, 3H), 4.11 (t, 5, 2H), 4.88-4.98 (m, 1H), 7.05-7.16 (m, 2H), 7.18 (br s, NH);
EXAMPLE 904




1H-NMR (300 MHz, CDCl3) δ 2.07 (s, 3H), 3.41 (br t, 5, 2H), 3.45 (br t, 5, 2H), 3.83 (dd, 9, 7, 1H), 3.95-4.12 (m, 3H), 4.00 (s, 3H), 4.14 (t, 5, 2H), 4.17 (br t, 5, 2H), 4.25 (d, 4.5, 2H), 4.89-4.99 (m, 1H), 6.45 (br s, NH), 7.02 (br t, 6, NH), 7.06-7.17 (m, 2H)
EXAMPLE 905




1H-NMR (300 MHz, CDCl3) δ 2.69 (t, 6, 2H), 3.06 (t, 6, 2H), 3.37-3.46 (m, 4H), 3.83 (dd, 9, 7, 1H), 3.91 (t, 5.5, 2H), 3.94-4.10 (m, 3H), 4.00 (s, 3H), 4.12 (t, 5, 2H), 4.88-4.98 (m, 1H), 7.03-7.14 (m, 2H);
EXAMPLE 906




1H-NMR (300 MHz, CDCl3) δ 3.41-3.53 (m, 4H), 3.82 (dd, 9, 7, 1H), 3.94-4.12 (m, 5H), 4.00 (s, 3H), 4.21 (t, 5, 2H), 4.42 (d, 4, 2H), 4.88-4.97 (m, 1H), 6.85 (br t, 6, NH), 6.87 (ddd, 8, 8, 1, 1H), 6.98 (dd, 8, 1, 1H), 7.06-7.17 (m, 2H), 7.37 (br s, NH), 7.40 (ddd, 8, 8, 1.5, 1H), 7.52 (dd, 8, 1.5, 1H);
EXAMPLE 907




1H-NMR (300 MHz, CDCl3) δ 2.20 (s, 3H), 3.39-3.48 (m, 4H), 3.54 (ddd, 15, 6.5, 5.5, 1H), 3.63 (ddd, 15, 6.5, 4, 1H), 3.69 (s, 3H), 3.75 (dd, 9, 7, 1H), 3.92 (m, 2H), 3.99 (dd, 9, 9, 1H), 4.18 (t, 5, 2H), 4.78 (dddd, 9, 7, 5.5, 4, 1H), 4.89 (s, 2H), 5.20 (br t, 6.5, NH), 7.07-7.18 (m, 2H);
EXAMPLE 908




1H-NMR (300 MHz, CDCl3) δ 3.37-3.47 (m, 4H), 3.49-3.72 (m, 2H), 3.64 (br s, 2H), 3.69 (s, 3H), 3.76 (dd, 9, 7, 1H), 3.99 (dd, 9, 9, 1H), 4.11 (br t, 5, 2H), 4.72-4.82 (m, 1H), 5.49 (br t, 6, NH), 7.06-7.17 (m, 2H);
EXAMPLE 909




1H-NMR (300 MHz, CDCl3-CD3OD (9:1)) δ 201 (s, 3H), 3.40-3.53 (m, 4H), 3.53-3.67 (m, 2H), 3.73 (dd, 9, 6.5, 1H), 3.96 (t, 6, 2H), 4.02 (dd, 9, 9, 1H), 4.24 (t, 5, 2H), 4.43 (s, 2H), 4.72-4.82 (m, 1H), 6.91 (br dd, 8, 8, 1H), 6.97 (br d, 8, 1H), 7.08-7.19 (m, 2H), 7.41 (ddd, 8, 8, 1.5, 1H), 7.65 (dd, 8, 1.5, 1H);
EXAMPLE 910




1H-NMR (300 MHz, CDCl3-CD3OD (9:1)) δ 3.41-3.63 (m, 6H), 3.68 (s, 3H), 3.77 (dd, 9, 7, 1H), 3.97 (t, 6, 2H), 4.02 (dd, 9, 9, 1H), 4.24 (t, 5, 2H), 4.43 (s, 2H), 4.72-4.82 (m, 1H), 6.91 (ddd, 8.5, 8, 1, 1H), 6.97 (dd, 8.5, 1, 1H), 7.09-7.19 (m, 2H), 7.41 (ddd, 8.5, 8, 1.5, 1H), 7.64 (dd, 8, 1.5, 1H);
EXAMPLE 911




1H-NMR (300 MHz, CDCl3) δ 2.02 (s, 3H), 2.16 (s, 3H), 3.45-3.56 (m, 4H), 3.58-3.71 (m, 2H), 3.75 (dd, 9, 6, 1H), 3.98 (t, 5, 2H), 4.01 (dd, 9, 9, 1H), 4.14 (t, 5, 2H), 4.72-4.82 (m, 1H), 6.47 (br t, 6, NH), 6.89 (dd, 9, 9, 1H), 7.03 (br dd, 9, 2.5, 1H), 7.40 (dd, 15, 2.5, 1H);
EXAMPLE 912




EXAMPLE 913




1H-NMR (300 MHz, CDCl3) δ 1.24 (ddd, 8.5, 8.5, 5, 1H), 1.73 (ddd, 6.5, 6.5, 5, 1H), 2.02 (s, 3H), 2.10 (ddd, 8.5, 8.5, 6.5, 1H), 2.47 (ddd, 8.5, 8.5, 6.5, 1H), 3.38-3.71 (m, 6H), 3.64 (s, 3H), 3.75 (dd, 9, 6.5, 1H), 3.87-4.08 (m, 2H), 4.01 (dd, 9, 9, 1H), 4.19 (t, 5, 2H), 4.72-4.82 (m, 1H), 6.57 (br t, 6, NH), 6.88 (dd, 9, 9, 1H), 7.03 (br dd, 9, 2.5, 1H), 7.40 (dd, 15, 2.5, 1H);
EXAMPLE 914




1H-NMR (300 MHz, CDCl3) δ 0.79-0.88 (m, 2H) 0.96-1.03 (m, 2H), (s, 3H), 2.12-2.23 (m, 1H), 3.49 (t, 6, 2H), 3.56 (t, 5, 2H), 3.58-3.71 (m, 2H), 3.75 (dd, 9, 6.5, 1H), 3.96-4.05 (m, 3H), 4.72-4.82 (m, 1H), 6.52 (br t, 6, NH), 6.90 (dd, 9, 9, 1H), 7.03 (br dd, 9, 2.5, 1H), 7.40 (dd, 15, 2.5, 1H);
EXAMPLE 915




1H-NMR (300 MHz, CDCl3) δ 2.03 (s, 3H), 3.36-3.47 (m, 4H), 3.60-3.70 (m, 2H), 3.74 (dd, 9, 6, 1H), 3.80 (s, 3H), 3.83 (t, 5.5, 2H), 3.97 (dd, 9, 9, 1H), 4.74-4.83 (m, 1H), 6.36 (br t, 6, NH), 7.04-7.15 (m, 2H);
EXAMPLE 916




1H-NMR (300 MHz, CDCl3-CD3OD (9:1) 50° C.) δ 1.99 (s, 3H), 3.46-3.59 (m, 5H), 3.63 (dd, 14.5, 3.5, 1H), 3.74 (dd, 9, 6.5, 1H), 3.96 (br s, 2H), 4.02 (dd, 9, 9, 1H), 4.11 (br s, 2H), 4.70-4.79 (m, 1H), 6.90-7.23 (m, 4H), 7.25-7.47 (m, 3H);
EXAMPLE 917




1H-NMR (300 MHz, CDCl3) δ 2.29 (s, 3H), 3.36 (br s, 2H), 3.47 (br s, 2H), 3.72-3.87 (m, 2H), 3.81 (dd, 9, 7, 1H), 3.90-4.11 (m, 6H), 3.99 (s, 3H), 4.86-4.96 (m, 1H), 7.05 (br t, 6, NH), 7.04-7.16 (m, 2H), 7.19 (br d, 8, 1H), 7.28 (ddd, 7.5, 7.5, 1, 1H), 7.45 (ddd, 8, 7.5, 2, 1H), 7.51 (br d, 7.5, 1H).
EXAMPLE 918




1H-NMR (300 MHz, CDCl3) δ 3.39 (t, 5.5, 2H), 3.52 (t, 5, 2H), 3.82 (dd, 9, 7, 1H), 3.94-4.17 (m, 7H), 4.00 (s, 3H), 4.88-4.98 (m, 1H), 6.85 (ddd, 8, 8, 1, 1H), 6.88 (br t, 6, NH), 7.00 (dd, 8.5, 1, 1H), 7.06-7.18 (m, 2H), 7.38 (ddd, 8.5, 8, 2, 1H), 8.05 (dd, 8, 2, 1H), 11.24 (br s, OH);
EXAMPLE 919




1H-NMR (300 MHz, CDCl3-CD3OD (9:1)) δ 3.40 (br t, 5, 2H), 3.53 (br t, 5.5, 2H), 3.63 (dd, 14.5, 6, 1H), 3.73 (dd, 9, 6.5, 1H), 3.75 (dd, 14.5, 3.5, 1H), 4.04 (t, 5, 2H), 4.06 (dd, 9, 9, 1H), 4.13 (br t, 5.5, 2H), 4.77-4.87 (m, 1H), 5.93 (t, 54, 1H), 6.88 (ddd, 8, 8, 1, 1H), 7.00 (dd, 8, 1, 1H), 7.06-7.17 (m, 2H), 7.38 (ddd, 8, 8, 1.5, 1H), 7.99 (dd, 8, 1.5, 1H);
EXAMPLE 920




1H-NMR (300 MHz, CDCl3) δ 2.29 (s, 9H), 3.36 (br t, 4.5, 2H), 3.44-3.51 (m, 4H), 3.80 (dd, 9, 7, 1H), 3.92-4.03 (m, 3H) 3.99 (s, 3H), 4.07 (br t, 5, 2H), 4.85-4.95 (m, 1H), 7.05-7.16 (m, 2H), 7.61 (s, 2H);
EXAMPLE 921




1H-NMR (300 MHz, CDCl3) δ 0.69-0.83 (m, 2H), 0.85-1.01 (m, 2H), 1.38-1.48 (m, 1H), 3.38 (t, 5, 2H), 3.51 (br t, 5.5, 2H), 3.65-3.72 (m, 2H), 3.76 (dd, 9, 6.5, 1H), 3.98 (dd, 9, 9, 1H), 4.03 (br t, 5, 2H), 4.13 (t, 5.5, 2H), 4.74-4.83 (m, 1H), 6.53 (br t, 6, NH), 6.86 (ddd, 8, 8, 1, 1H), 7.00 (dd, 8, 1, 1H), 7.05-7.16 (m, 2H), 7.38 (ddd, 8.5, 8, 1.5, 1H), 8.04 (dd, 8, 1.5, 1H), 11.25 (br s, OH);
EXAMPLE 922




1H-NMR (300 MHz, CDCl3) δ 3.38 (t, 5.5, 2H), 3.51 (t, 5, 2H), 3.61-3.80 (m, 2H), 3.76 (dd, 9, 6.5, 1H), 4.01 (dd, 9, 9, 1H), 4.03 (br t, 5, 2H), 4.12 (br t, 5.5, 2H), 4.76-4.86 (m, 1H), 6.83 (br t, 6, NH), 6.86 (ddd, 8, 8, 1, 1H), 6.99 (dd, 8, 1, 1H), 7.04-7.14 (m, 2H), 7.37 (ddd, 8, 8, 1.5, 1H), 8.03 (dd, 8, 1.5, 1H), 8.26 (d, 2, 1H), 11.19 (br s, OH);
EXAMPLE 923




1H-NMR (300 MHz, CDCl3) δ 2.74 (d, 5, 3H), 3.38 (t, 5, 2H), 3.51 (t, 5.5, 2H), 3.55 (ddd, 15, 6, 3, 1H), 3.69 (ddd, 15, 6, 4.5, 1H), 3.87 (dd, 9, 7, 1H), 3.98 (dd, 9, 9, 1H), 4.03 (br t, 5, 2H), 4.12 (br t, 5.5, 2H), 4.73-4.82 (m, 1H), 5.22 (br q, 5, NH), 5.71 (br t, 6, NH), 6.85 (ddd, 8, 8, 1, 1H), 6.99 (dd, 8, 1, 1H), 7.04-7.15 (m, 2H), 7.37 (ddd, 8, 8, 1.5, 1H), 8.02 (dd, 8, 1.5, 1H), 11.17 (br s, OH);
EXAMPLE 924




1H-NMR (300 MHz, CDCl3) δ 2.81 (s, 6H), 3.32-3.60 (m, 6H), 3.88 (dd, 9, 6, 1H), 4.01 (dd, 9, 9, 1H), 4.13 (br t, 5.5, 2H), 4.76-4.85 (m, 1H), 5.33 (br s, NH), 6.86 (ddd, 8, 8, 1, 1H), 6.99 (dd, 8, 1, 1H), 7.07-7.17 (m, 2H), 7.38 (ddd, 8, 8, 1.5, 1H), 8.04 (dd, 8, 1.5, 1H), 11.24 (br s, OH);
EXAMPLE 925




1H-NMR (300 MHz, CDCl3) δ 3.40 (br t, 5, 2H), 3.51 (br t, 5.5, 2H), 3.57 (dd, 11, 6.5, 1H), 3.64 (dd, 11, 4, 1H), 3.84 (dd, 9, 6, 1H), 4.04 (t, 5, 2H), 4.10 (dd, 9, 9, 1H), 4.14 (t, 5.5, 2H), 4.83-4.93 (m, 1H), 6.86 (ddd, 8, 8, 1, 1H), 7.00 (dd, 8, 1, 1H), 7.10-7.21 (m, 2H), 7.36 (ddd, 8, 8, 2, 1H), 8.06 (dd, 8, 2, 1H), 11.29 (br s, OH);
EXAMPLE 926




1H-NMR (300 MHz, CDCl3) δ 3.10 (s, 3H), 3.40 (br t, 5, 2H), 3.53 (br t, 5.5, 2H), 3.89 (dd, 9, 6, 1H), 4.04 (t, 5, 2H), 4.09 (dd, 9, 9, 1H), 4.14 (t, 5.5, 2H), 4.88-4.97 (m, 1H), 4.42 (dd, 12, 3.5, 1H), 4.50 (dd, 12, 3.5, 1H), 6.86 (ddd, 8, 8, 1, 1H), 7.00 (br d, 8, 1H), 7.08-7.19 (m, 2H), 7.38 (ddd, 8, 8, 1.5, 1H), 8.01 (dd, 8, 1.5, 1H), 11.29 (br s, OH);
EXAMPLE 927




1H-NMR (300 MHz, CDCl3) δ 3.67 (br t, 4.5, 2H), 3.50 (br t, 5.5, 2H), 3.74-3.84 (m, 2H), 3.91 (ddd, 15, 6, 3.5, 1H), 4.02 (t, 5.5, 2H), 4.05 (dd, 9, 9, 1H), 4.09-4.15 (m, 2H), 4.84-4.94 (m, 1H), 6.82 (ddd, 8, 8, 1, 1H), 6.85 (ddd, 8, 8, 1, 1H), 6.96 (dd, 8, 1, 1H), 6.98 (dd, 8, 1, 1H), 7.02-7.14 (m, 2H), 7.29-7.42 (m, 2H), 7.48 (dd, 8, 1.5, 1H), 8.04 (dd, 8, 1.5, 1H), 11.23 (br, OH);
EXAMPLE 928




1H-NMR (300 MHz, CDCl3) δ 2.02 (s, 3H), 3.47 (t, 5, 2H), 3.57 (t, 6, 2H), 3.61-3.73 (m, 2H), 3.76 (dd, 9, 7, 1H), 3.93 (br s, 2H), 4.02 (dd, 9, 9, 1H), 4.16 (br s, 2H), 4.73-4.82 (m, 1H), 6.55 (br t, 6, NH), 6.92 (dd, 9, 9, 1H), 7.06 (br dd, 9, 2.5, 1H), 7.42 (dd, 15.5, 2.5, 1H);
EXAMPLE 929




1H-NMR (300 MHz, CDCl3) δ 3.37 (br t, 4.5, 2H), 3.51 (br t, 5.5, 2H), 3.80-3.98 (m, 5H), 4.08 (dd, 9, 9, 1H), 4.11 (br 7, 5.5, 2H), 4.88-4.98 (m, 1H), 7.05-7.16 (m, 2H), 7.56 (br t, 6, NH), 7.38 (dd, 8, 5, 1H), 7.40 (dd, 8, 5, 1H), 8.07 (ddd, 8, 2, 1.5, 1H), 8.14 (ddd, 8, 2, 1.5, 1H), 8.69 (dd, 5, 1.5, 1H), 8.72 (dd, 5, 1.5, 1H), 9.00 (d, 2, 1H), 9.06 (d, 2, 1H);
EXAMPLE 930




1H-NMR (300 MHz, CDCl3) δ 2.02 (s, 3H), 3.52-3.71 (m, 6H), 3.75 (dd, 9, 7, 1H), 4.00 (dd, 9, 9, 1H), 4.14 (br t, 5.5, 2H), 4.23 (t, 5, 2H), 4.72-4.82 (m, 1H), 6.47 (br t, 6, NH), 6.52 (dd, 3.5, 2, 1H), 6.91 (dd, 9, 9, 1H), 7.03 (dd, 9, 3, 1H), 7.19 (d, 3.5, 1H), 7.40 (dd, 15, 3, 1H), 7.60 (d, 2, 1H);
EXAMPLE 931




1H-NMR (300 MHz, CDCl3) δ 2.02 (s, 3H), 2.95 (s, 6H), 3.47-3.59 (m, 4H), 3.59-3.69 (m, 2H), 3.69-3.80 (m, 3H), 4.00 (dd, 9, 9, 1H), 4.10 (t, 5, 2H), 4.71-4.81 (m, 1H), 6.52 (br t, 6, NH), 6.90 (dd, 9, 9, 1H), 7.01 (br dd, 9, 2.5, 1H), 7.38 (dd, 14.5, 2.5, 1H);
EXAMPLE 932




1H-NMR (300 MHz, CDCl3) δ 3.45-3.76 (m, 4H), 3.82 (dd, 9, 6.5, 1H), 3.93 (br t, 5.5, 2H), 3.96-4.15 (m, 3H), 4.01 (s, 3H), 4.21 (t, 5, 2H), 4.88-4.98 (m, 1H), 6.71 (br, NH), 7.07-7.19 (m, 2H), 7.27 (dd, 8, 5, 1H), 8.11 (ddd, 8, 3, 1.5, 1H), 8.32 (dd, 5, 1.5, 1H), 8.54 (d, 3, 1H);
EXAMPLE 933




1H-NMR (300 MHz, CDCl3) δ 1.43 (t, 7, 3H), 3.46-3.55 (m, 4H), 3.81 (br t, 5.5, 2H), 3.95-4.15 (m, 3H), 4.01 (s, 3H), 4.28 (t, 5, 2H), 4.38 (q, 7, 2H), 4.88-4.97 (m, 1H), 6.64 (br t, 6, NH), 7.02 (ddd, 8, 8, 1, 1H), 7.06-7.17 (m, 2H), 7.52 (ddd, 8, 8, 2, 1H), 8.05 (dd, 8, 2, 1H), 8.62 (br d, 8, 1H);
EXAMPLE 934




1H-NMR (300 MHz, CDCl3) δ 2.85 (d, 5, 3H), 3.40 (br t, 5, 2H), 3.47 (br t, 5.5, 2H), 3.79 (br t, 5.5, 2H), 3.82 (dd, 9, 7, 1H), 3.93-4.15 (m, 5H), 4.00 (s, 3H), 4.88-4.98 (m, 1H), 5.84 (br q, 5, NH), 7.00 (br t, 6, NH), 7.03-7.14 (m, 2H);
EXAMPLE 935




1H-NMR (300 MHz, CDCl3) δ 2.98 (s, 6H), 3.38-3.50 (m, 4H), 3.73 (br t, 5.5, 2H), 3.82 (dd, 9, 7, 1H), 3.95-4.12 (m, 5H), 4.00 (s, 3H), 4.88-4.98 (m, 1H), 7.02-7.14 (m, 2H+NH);
EXAMPLE 936




1H-NMR (300 MHz, CDCl3) δ 2.63 (s, 6H), 3.38 (br t, 5.5, 2H), 3.46 (br t, 5, 2H), 3.78 (br t, 5.5, 2H), 3.85 (dd, 9, 6.5, 1H), 3.96-4.10 (m, 5H), 4.00 (s, 3H), 4.90-5.00 (m, 1H), 6.62 (br s, NH), 7.04-7.16 (m, 2H), 7.21 (br t, 6, NH);
EXAMPLE 937




1H-NMR (300 MHz, CDCl3) δ 2.03 (s, 3H), 3.44-3.54 (m, 4H), 3.57-3.70 (m, 2H), 3.74 (dd, 9, 6.5, 1H), 4.00 (dd, 9, 9, 1H), 4.02 (t, 5, 2H), 4.74-4.84 (m, 1H), 6.63 (br t, 6, NH), 7.05-7.17 (m, 2H), 7.27 (dd, 8, 5, 1H), 7.90 (br s, NH), 8.11 (ddd, 8, 3, 1.5, 1H), 8.30 (dd, 5, 1.5, 1H), 8.56 (d, 3, 1H);
EXAMPLE 938




1H-NMR (300 MHz, CDCl3-CD3OD (9:1)) δ 3.34-3.50 (m, 4H), 3.74-3.90 (m, 3H), 3.94-4.12 (m, 5H), 4.00 (s, 3H), 4.89-4.99 (m, 1H), 7.05-7.17 (m, 2H);
EXAMPLE 939




1H-NMR (300 MHz, CDCl3-CD3OD (9:1)) δ 3.38-3.48 (m, 4H), 3.79 (br t, 5.5, 2H), 3.84 (dd, 9, 7, 1H), 3.92-4.11 (m, 5H), 4.00 (s, 3H), 4.88-4.99 (m, 1H), 7.04-7.15 (m, 2H)
EXAMPLE 940




1H-NMR (300 MHz, CDCl3) δ 3.38-3.47 (m, 4H), 3.76-3.84 (m, 2H), 3.79 (s, 3H), 3.82 (dd, 9, 7, 1H), 3.94-4.11 (m, 5H), 4.00 (s, 3H), 4.89-4.98 (m, 1H), 7.03-7.16 (m, 2H+NH), 8.39 (br s; NH);
EXAMPLE 941




1H-NMR (300 MHz, CDCl3-CD3OD (9:1)) δ 3.38-3.48 (m, 4H), 3.81 (dd, 9, 7, 1H), 3.92 (br t, 5.5, 2H), 3.97-4.12 (m, 3H), 4.01 (s, 3H), 4.19 (br t, 5, 2H), 4.88-4.98 (m, 1H), 7.04-7.15 (m, 2H);
EXAMPLE 942




1H-NMR (300 MHz, CDCl3) δ 3.44-3.52 (m, 4H), 3.82 (dd, 9, 7, 1H), 3.92 (br t, 5.5, 2H), 3.95-4.11 (m, 3H), 3.97 (s, 3H), 4.00 (s, 3H), 4.19 (t, 5, 2H), 4.89-4.98 (m, 1H), 7.03 (br t, 6, NH), 7.05-7.16 (m, 2H), 7.47 (d, 1, 1H), 8.33 (br s, NH), 8.44 (d, 1, 1H);
EXAMPLE 943




1H-NMR (300 MHz, CDCl3) δ 3.38-3.49 (m, 4H), 3.78-3.86 (m, 3H), 3.96-4.16 (m, 5H), 4.00 (s, 3H), 4.47 (s, 2H), 4.88-3.98 (m, 1H), 6.33 (t, 6, NH), 7.03-7.14 (m, 2H), 7.27 (dd, 8, 4.5, 1H), 7.47 (br t, 6, NH), 7.69 (ddd, 8, 2, 1, 1H), 8.52 (dd, 4.5, 1, 1H), 8.57 (d, 2, 1H);
EXAMPLE 944




1H-NMR (300 MHz, CDCl3) δ 2.24 (s, 3H), 3.40 (br t, 5.5, 2H), 3.45 (br t, 5.5, 2H), 3.67-3.86 (m, 3H), 3.73 (s, 3H), 3.95-4.10 (m, 3H), 4.00 (s, 3H), 4.37 (d, 6, 2H), 4.88-3.98 (m, 1H), 5.97 (s, 1H), 6.25 (t, 6, NH), 7.02-7.14 (m, 2H), 7.24 (br t, 6, NH);
EXAMPLE 945




1H-NMR (300 MHz, CDCl3) δ 2.01 (s, 6H), 3.36-3.44 (m, 4H), 3.81 (dd, 9, 7, 1H), 3.93-4.09 (m, 5H), 4.00 (s, 3H), 4.14 (br t, 5, 2H), 4.88-4.98 (m, 1H), 7.02-7.13 (m, 2H), 7.29 (br t, 6, NH);
EXAMPLE 946




1H-NMR (300 MHz, CDCl3) δ 1.33 (t, 7, 3H), 3.38-3.48 (m, 4H), 3.79-3.91 (m, 3H), 4.00 (s, 3H), 4.07-4.11 (m, 3H), 4.15 (t, 5, 2H), 4.26 (q, 7, 2H), 4.90-5.00 (m, 1H), 7.14 (br t, 6, NH), 7.06-7.17 (m, 2H), 8.00 (br s, NH);
EXAMPLE 947




1H-NMR (300 MHz, CDCl3) δ 3.40-3.49 (m, 8H), 3.78-3.88 (m, 6H), 3.96-4.10 (m, 6H), 4.00 (s, 6H), 4.13 (t, 5, 4H), 4.89-4.99 (m, 2H), 7.01-7.14 (m, 4H+NH);
EXAMPLE 948




1H-NMR (300 MHz, CDCl3) δ 3.36-3.48 (m, 4H), 3.64 (dd, 14.5, 6, 1H), 3.70-3.83 (m, 4H), 3.90 (br t, 5, 2H), 4.07 (dd, 9, 9, 1H), 4.78-4.88 (m, 1H), 5.95 (t, 54, 1H), 7.04-7.16 (m, 2H);
EXAMPLE 949




1H-NMR (300 MHz, CDCl3) δ 2.62 (s, 6H), 3.37 (br t, 5, 2H), 3.45 (br t, 5, 2H), 3.64-3.83 (m, 5H), 4.04-4.16 (m, 3H), 4.84-4.94 (m, 1H), 5.36 (br s, NH2), 7.08-7.19 (m; 2H);
EXAMPLE 950




1H-NMR (300 MHz, CDCl3) δ 3.39-3.52 (m, 4H), 3.58 (dd, 12, 7, 1H), 3.65 (dd; 12, 4, 1H), 3.80-3.92 (m, 3H), 3.90 (br t, 5, 2H), 4.07 (dd, 9, 9, 1H), 4.78-4.88 (m, 1H), 5.95 (t, 54, 1H), 7.04-7.16 (m, 2H);
EXAMPLE 951




1H-NMR (300 MHz, CDCl3-CD3OD (9:1)) δ 3.40-3.50 (m, 4H), 3.82 (br t, 2H), 3.91 (dd, 9, 6, 1H), 4.11 (t, 5, 2H), 4.13 (dd, 9, 9, 1H), 4.44 (dd, 12, 4, 1H), 4.53 (dd, 12, 3.5, 1H), 4.96 (dddd, 9, 6, 4, 3.5, 1H), 5.65 (br s, NH), 7.09-7.20 (m, 2H);
EXAMPLE 952




1H-NMR (300 MHz, CDCl3) δ 2.03 (s, 3H), 2.94 (s, 3H), 3.55-3.78 (m, 9H), 4.01 (dd, 9, 9, 1H), 4.13 (t, 5.5, 2H), 4.72-4.82 (m, 1H), 6.21 (br t, 6, NH), 6.90 (dd, 9, 9, 1H), 7.05 (dd, 9, 2.5, 1H), 7.38 (dd, 15, 2.5, 1H);
EXAMPLE 953




1H-NMR (300 MHz, CDCl3) δ 2.03 (s, 3H), 3.04 (s, 6H), 3.44-3.54 (m, 4H), 3.59 (t, 5.5, 2H), 3.61-3.69 (m, 2H), 3.73 (dd, 9, 6.5, 1H), 3.99 (dd, 9, 9, 1H), 4.04 (t, 5.5, 2H), 4.73-4.83 (m, 1H), 6.18 (br t, 6, NH), 7.04-7.15 (m, 2H);
EXAMPLE 954




1H-NMR (300 MHz, CDCl3) δ 3.04 (s, 6H), 3.44-3.54 (m, 4H), 3.59 (t, 5.5, 2H), 3.81 (dd, 9, 7, 1H), 3.97-4.12 (m, 5H), 4.01 (s, 3H), 4.88-4.98 (m, 1H), 7.04-7.15 (m, 2H);
EXAMPLE 955




1H-NMR (300 MHz, CDCl3) δ 2.03 (s, 3H), 3.40 (br t, 6, NH), 3.37-3.49 (m, 4H), 3.58-3.70 (m, 2H), 3.74 (dd, 9, 6.5, 1H), 3.94-4.03 (m, 3H), 4.13 (t, 5, 2H), 4.74-4.83 (m, 1H), 5.78 (dd, 10.5, 2, 1H), 6.46 (dd, 17, 2, 1H), 6.80 (dd, 17, 10.5, 1H), 7.04-7.15 (m, 2H)
EXAMPLE 956




1H-NMR (300 MHz, CDCl3) δ 2.03 (s, 3H), 3.47 (t, 5.5, 2H), 3.59-3.70 (m, 4H), 3.75 (t, 5.5, 2H), 3.75 (dd, 9, 6, 1H), 4.00 (dd, 9, 9, 1H), 4.18 (t, 5, 2H), 4.74-4.84 (m, 1H), 6.41 (br s, NH), 6.91 (A2B2, J=9.5, 2H), 7.06-7.17 (m, 2H), 8.16 (A2B2, J=9.5, 2H).
TEST EXAMPLE 1
The compounds of the above Examples were tested for antimicrobial activity.
(Test Method)
Minimal inhibitory concentration (MIC: μg/ml) against different strains of bacteria was assayed according to the standard method recommended by CLSI (clinical and laboratory standards institute). Samples were prepared from test compound solution in DMSO (1280 μg/mL) by two fold (serial) dilution with DMSO. The sample was added to bacteria suspension at the concentration of 5%, and MIC was determined. Mueller Hinton Broth, which has been adjusted for cation concentration, was used for culture media in this test. The inoculation concentration was about 5×105 CFU/mL.
(Result)
The compound of the invention showed strong antimicrobial activity, which was comparable to or more (e.g., four times or more) than linezolid and vancomycin, against various strains of bacteria, such as VRE (vancomycin resistance enterococcus), VISA (vancomycin-intermediate Staphylococcus aureus). For example, the MIC value (μg/mL) of the compound of the working examples (e.g., Examples 81, 82, 83, 84, 85, 86 and 91) was equal to or less than 1, against bacteria such as S. aureus FDA 209P, S. aureus smith, S. aureus ATCC 700787, E. faecalis ATCC 29212, E. faecalis SR7914, E. faecium SR7917.
EXAMPLE 957
Synthesis of Quinolone Compound
The compound of the invention, wherein Ring B is quinolone in formula I, was prepared according to the following procedure.
7-bis(hydroxyethyl)amino Compound (62)




The difluoro complex (61) (686 mg, 2.0 mmol) is added with diethanolamine (4.20 g, 40 mmol) and heated to 60° C. with stirring. After determining the disappearance of the compound 61 by TLC, water was added to dissolve, and the solution was neutralized to pH 6-7 with diluted hydrochloric acid. The solution was extracted with chloroform, washed with water and dried. Solvent was removed to obtain a yellow solid (820 mg). The yellow solid was dissolved in chloroform, and a solution of diazo methane in ether as preliminarily prepared was added.
After determining the disappearance of the carboxylic acid by TLC, solvent was removed. The residue was purified by silica gel column chromatography (WAKO gel B0, 40 ml, chloroform to 2-5% methanol/chloroform) to afford desired 282 mg (36%) of 7-bis(hydroxyethyl)amino compound (62), and 269 mg (43%) of difluoro compound (63).
62: 1H-NMR (300 MHz, CDCl3): δ 0.93 (m, 2H), 1.18 (m, 2H), 3.43 (br t, 5.1, 4H), 3.74 (br t, 5.1, 4H), 3.89 (s, 3H), 3.92 (m, 1H), 3.92 (s, 3H), 7.95 (d, 12.3, 1H), 8.64 (s, 1H).
63: 1H-NMR (300 MHz, CDCl3): δ 1.05 (m, 2H), 1.22 (m, 2H), 3.93 (s, 3H), 3.99 (m, 1H), 4.09 (d, 1.8, 3H), 8.05 (dd, 10.2, 8.4, 1H), 8.63 (s, 1H).
EXAMPLE 958
7-bis(methanesulfonyloxyethyl)amino Compound (64)




To a solution of the amino compound (62, 282 mg, 0.7 mmol), triethylamine (0.5 ml) in acetonitrile (15 ml), and methanesulfonyl chloride (0.5 ml) were added dropwise under ice-cooling with stirring. After determining the disappearance of the starting material, the solution was poured into diluted hydrochloric acid, extracted with chloroform. After washing with water and dryness, solvent was removed. The residue was purified by silica gel column chromatography (WAKO GEL B0, 30 ml, chloroform to 2% methanol/chloroform) to afford 397 mg (quant.) of 7-bis (methanesulfonyloxyethyl)amino compound (64) as yellow oil.
64: 1H-NMR (300 MHz, CDCl3): δ 0.87 (m, 2H), 1.18 (m, 2H), 2.96 (s, 6H), 3.79 (br t, 5.1, 4H), 3.87 (s, 3H), 3.92 (m, 1H), 3.93 (s, 3H), 4.34 (br t, 5.2, 4H), 7.95 (d, 12.3, 1H), 8.65 (s, 1H).
EXAMPLE 959
7-bisBOC triazacycloheptyl Compound (65)




60% NaH (92 mg, 2.3 mmol) was washed with n-hexane and suspended in DMF (5 ml) under argon atmosphere. Under ice-cooling, bis-Boc-hydrazine (243 mg, 1.04 mmol) in DMF (5 ml) was added dropwise and stirred for 5 minute at this temperature and additional 10 minutes at room temperature. To the resultant pale-yellow solution, the mesyl compound (64, 480 mg, 0.87 mmol) in DMF (10 ml) was added dropwise under ice-cooling, stirred at room temperature for 30 minute, and followed by heating to 80-90° C. with stirring. After determining the disappearance of the starting material, solvent was removed under reduced pressure. Diluted hydrochloric acid water was added and the solution was extracted with chloroform. After washing with water and dryness, solvent was removed. The residue was purified by silica gel column chromatography (WAKO GEL B0, 40 ml, chloroform to 2% methanol/chloroform) to afford 195 mg (38%) of triazacycloheptyl compound (65) as yellow oil.
65: 1H-NMR (300 MHz, CDCl3): δ 0.94 (m, 2H), 1.15 (m, 2H), 1.48-1.49 (br s, 18H), 3.27-3.38 (m, 4H), 3.60-3.70 (m, 3H), 3.74 (s, 3H), 3.92 (s, 3H), 3.92 (m, 1H), 4.16 (m, 1H), 7.95 (d, 12.3, 1H), 8.60 (s, 1H).
EXAMPLE 960
7-bistriazacycloheptyl Compound (66)




To a solution of the bis-Boc-triazacycloheptyl compound (65, 114 mg) in methanol (10 ml), 10% aqueous potassium hydroxide solution (5 ml) was added under ice-cooling, and the solution was stirred at room temperature for 4 hours. After the reaction, pH was adjusted with diluted hydrochloric acid to 4, and the solution was extracted with chloroform. After washing with water and dryness, solvent was removed. The residue was dissolved in dichloromethane (1 ml), and TFA (1 ml) was added. The mixture was left stand overnight. Removing solvent and recrystallization from methanol-ether afforded 83 mg of the titled compound (46) as yellow needle-like crystal.
66: yellow needle-like crystal mp: 169-172° C. (MeOH-Et2O); 1H-NMR (300 MHz, DMSO): δ 1.02-1.11 (m, 4H), 3.63 (m, 4H), 3.72 (s, 3H), 4.16 (m, 1H), 7.77 (d, 12, 1H), 8.71 (s, 1H).
EXAMPLE 961
Monoacetyl Derivative of 7-bis-triaza-cycloheptyl Compound (67)




To a solution of the bis-Boc-triaza-cycloheptyl compound (65, 72 mg, 0.12 mmol) in dichloromethane (2 ml), TFA (2 ml) was added, and the mixture was left stand overnight. Sodium hydrogen carbonate solvent was added, extracted with chloroform, washed with water and dried, and solvent was removed. The residue (52 mg) was dissolved in chloroform (5 ml), added with acetic anhydride (15 μmL, 1.5 eq.) and stirred at room temperature for 10 min. Sodium hydrogen carbonate solvent was added, extracted with chloroform, washed with water, dried, and solvent was removed. The residue was purified by silica gel column chromatography (WAKO GEL B0, 30 ml, chloroform to 1-4% methanol/chloroform) to afford 34 mg (64%) of monoacyl methyl ester compound.
To a solution of the monoacyl methyl ester compound (34 mg) in methanol (2 ml), 10% aqueous potassium hydroxide solution (2 ml) was added under ice-cooling and stirred at room temperature for 30 min. After the reaction, pH was adjusted with diluted hydrochloric acid to 5-6, the solution was extracted with chloroform. After washing with water and dryness, solvent was removed. The residue was dissolved in dichloromethane (1 ml) and added with TFA (1 ml). The mixture was left stand overnight. Solvent was removed, and the residue was purified by silica gel column chromatography (WAKO GEL B0, 20 ml, chloroform to 5% methanol/chloroform) and recrystallized from methanol-hexane to afford 25 mg (76%) of the titled compound (67) as a pale-orange needle-like crystal.
67: pale-orange needle-like crystal mp: 193-196° C. (MeOH-Hexane); 1H-NMR (300 MHz, CDCl3): δ 0.94 (m, 2H), 1.15 (m, 2H), 2.13 & 2.25 (s, 3H), 3.09-3.72 (m, 7.5H), 3.73 & 3.74 (s, 3H), 3.92 (m, 1H), 4.56 (m, 0.5H), 7.92 (d, 12, 1H), 8.60 (s, 1H).
EXAMPLE 962
Monohydroxy Acetyl Derivative of 7-bis-triaza-cycloheptyl Compound (69)




To a solution of the bis-Boc-triaza-cycloheptyl compound (65, 100 mg, 0.18 mmol) in dichloromethane (2 ml), TFA (2 ml) was added and stirred for 30 min. sodium hydrogen carbonate solvent was added, extracted with chloroform, washed with water, and dried, and solvent was removed. The residue (70 mg) was dissolved in chloroform (5 ml), and added with acetoxyacetyl chloride (18 μmL, 1.5 eq.) at room temperature and stirred for 5 min. Sodium hydrogen carbonate solvent was added, extracted with chloroform, washed with water, and dried, and solvent was removed. The residue was purified by silica gel column chromatography (WAKO GEL B0, 20 ml, chloroform to 1% methanol/chloroform) to afford 19 mg (19%) of monoacetoxy acetyl methyl ester compound (68).
68: 1H-NMR (300 MHz, CDCl3): δ 0.94 (m, 2H), 1.15 (m, 2H), 2.14 (s, 3H), 3.09-3.90 (m, 8H), 3.73 & 3.76 (s, 3H), 3.92 (s, 3H), 3.92 (m, 1H), 5.00 (s, 2H), 7.93 (d, 12, 1H), 8.61 (s, 1H).
To a solution of the monoacetoxy acetyl methyl ester compound (48, 27 mg) in methanol (2 ml), 10% aqueous potassium hydroxide solution (2 ml) was added under ice-cooling, and the solution was stirred at room temperature for 10 min. After the reaction, pH was adjusted with diluted hydrochloric acid to 5-6, and the solution was extracted with chloroform. After washing with water and dryness, solvent was removed. The residue was recrystallized from ethanol-hexane to afford 10 mg (42%) of the titled compound (69) as pale-orange needle-like crystal.
69: pale-orange needle-like crystal mp: 15 7-159° C. (EtOH-Hexane); 1H-NMR (300 MHz, CDCl3): δ 1.00 (m, 2H), 1.22 (m, 2H), 3.23-3.90 (m, 8H), 3.77 (s, 3H), 4.03 (m, 1H), 7.93 (d, 12, 1H), 8.84 (s, 1H).
EXAMPLE 963
7-BOC-diazaoxy Cycloheptyl Compound (70)




60% NaH (96 mg, 2.4 mmol) was washed with n-hexane, and suspended in DMF (3 ml) under argon atmosphere. N—BOC hydroxylamine (106 mg, 0.8 mmol) in DMF (5 ml) was added dropwise and stirred at the temperature for 10 min. To the resultant pale-yellow solution, mesyl compound (64, 430 mg, 0.78 mmol) in DMF (3 ml) was added dropwise under ice-cooling, and heated to 70-80° C. with stirring for 2 hours. After determining the disappearance of the starting material, the mixture was diluted with ethyl acetate, washed with water, and dried, and solvent was removed. The residue was purified by silica gel column chromatography (WAKO GEL B0, 40 ml, chloroform to 1% methanol/chloroform) to afford 88 mg (23%) of the titled compound (70) as orange oil.
70: 1H-NMR (300 MHz, CDCl3): δ 0.94 (m, 2H), 1.15 (m, 2H), 1.48-1.49 (br s, 18H), 3.27-3.38 (m, 4H), 3.60-3.70 (m, 3H), 3.74 (s, 3H), 3.92 (s, 3H), 3.92 (m, 1H), 4.16 (m, 1H), 7.95 (d, 12.3, 1H), 8.60 (s, 1H).
EXAMPLE 964
7-diazaoxy Cycloheptyl Compound (71)




To a solution of the N—BOC-diazaoxy cycloheptyl compound (50, 88 mg) in dichloromethane (1 ml), TFA (1 ml) was added and stirred at room temperature for 10 min. Toluene was added, and solvent was removed. To a solution of the residue in methanol (2 ml), 10% aqueous potassium hydroxide solution (2 ml) was added under ice-cooling, the solution was stirred at room temperature for 10 min. After the reaction, pH was adjusted with diluted hydrochloric acid to 5-6, and the solution was extracted with chloroform. After washing with water and dryness, solvent was removed. The residue (80 mg) was recrystallized from methanol-ether to afford the titled compound (71) as orange needle-like crystal.
71: pale-orange needle-like crystal mp: 222-224° C. (MeOH-Hexane); 1H-NMR (300 MHz, CDCl3): δ=1.01 (m, 2H), 1.22 (m, 2H), 3.66 (t, J=6 Hz, 4H), 3.83 (t, J=6 Hz, 4H), 3.88 (s, 3H), 4.06 (m, 1H), 7.94 (d, J=12 Hz, 1H), 8.86 (s, 1H).
TEST EXAMPLE 2
Antimicrobial Activity of the Quinolone Compounds of the Invention
The quinolone compounds of the invention were tested for antimicrobial activity according to the procedure in Test Example 1.
(Result)
The compound of the invention showed strong antimicrobial activity, which was comparable to or more (e.g., four times or more) than commercially available newquinolone antimicrobial agents (e.g., ciprofloxacin, gatifloxacin moxifloxacin), against various strains of bacteria, such as VRE (vancomycin resistance enterococcus), MRSA (methicillin-resistant Staphylococcus aureus). For example, the MIC values (μg/mL) of Compound (66) of Examples 960, Compound (71) of Examples 964 were equal to or less than 1, against bacteria such as S. aureus FDA 209P, S. aureus SR3637, E. faecalis ATCC 29212, E. faecalis SR7914.
EXAMPLE 965
Synthesis of Compound 88




Compounds 82 and 83

To 50 cm3 egg-plant flask, charged with Compound 81 (3.1291 g, 10.38 mmol), 4-fluorobenzaldehyde (1.9321 g, 15.57 mmol) and K2CO3 (2.9080 g, 21.04 mmol), pyridine (10 cm3) was added to obtain a suspension. The suspension was heated with stirring for 88 hours. Pyridine was removed to obtain the residue, which was then added with H2O (100 cm3), extracted three times with AcOEt, washed with saturated aqueous NaCl, dried over Na2SO4, filtrated and concentrated.
The resultant residue was purified by silica gel column chromatography (BW-200, 30 g, eluent; 5%→10%→50% AcOEt/n-hexane→10% MeOH/CH2Cl2) to afford Compound 82 (0.7581 g, 1.87 mmol) and compound 83 (0.3143 g, 1.03 mmol). The respective carboxyl compounds of Compounds 82 and 83, wherein the formyl group is oxidized, were also obtained.
Yield: 18% (compound 82), 10% (compound 83), unreacted Compound 81 (65%) was recovered.
Compound 82: 1H NMR (CDCl3) δ=1.33 & 1.36 & 1.41 (18H, three singlet peaks of the conformers, t-Bu×2), 3.14-3.91 (6H, m), 4.10-4.32 (2H, m), 6.77 (2H, d, J=9.1 Hz), 7.74 (2H, d, J=9.1 Hz), and 9.75 (1H, s, CHO)
Compound 83: 1H NMR (CDCl3) δ=1.20 (9H, s, t-Bu), 3.09 (2H, t, J=5.2 Hz), 3.70 (2H, t, J=5.2 Hz), 3.70-3.86 (4H, m), 4.82 (1H, br s, NH), 6.76 (2H, d, J=8.5 Hz), 7.73 (2H, d, J=8.5 Hz), and 9.73 (1H, s, CHO).
EXAMPLE 966
Compound 84
To 100 cm3 egg-plant flask, charged with Compound 82 (1.2082 g, 2.98 mmol), pyridine (1 cm3) and MeOH (10 cm3) were added to prepare a solution. To this solution, HONH2.HCl (0.3584 g, 5.16 mmol) was added, and the mixture was stirred at room temperature for 21 hours. After removing pyridine and MeOH, H2O (50 cm3) and AcOEt (100 cm3) was added to separate the phase, and the aqueous layer was extracted once with AcOEt. The combined organic layer was washed once with H2O and once with saturated aqueous NaCl, dried over Na2SO4, filtrated, and concentrated to afford the residue (1.1838 g) containing Compound 84 as main product.
EXAMPLE 967
Compound 85
To 100 cm3 egg-plant flask, charged with the residue containing Compound 84 as main product (1.1838 g), pyridine (3 cm3) and CH2Cl2 (15 cm3) were added to dissolve. To this solution, NCS (0.5020 g, 3.76 mmol) was added at 0° C., and the mixture was stirred at this temperature for 3 hours and for additional 15 hours at room temperature. The residue was added with H2O (50 cm3) and AcOEt (100 cm3) to separate the phase, and the aqueous layer was extracted once with  AcOEt. The combined organic layer was washed once with H2O and once with saturated aqueous NaCl, dried over Na2SO4, filtrated, and concentrated to afford the residue containing Compound 85 as main product.
EXAMPLE 968
Compound 86
To 100 cm3 egg-plant flask, charged with the residue containing Compound 85 as main product (1.1838 g), Et3N (0.80 cm3, 5.69 mmol) and CH2Cl2 (20 cm3) was added to dissolve. To this solution, allyl alcohol (0.40 cm3, 5.85 mmol) was added at room temperature and stirred for 24 hours at this temperature. The residue obtained by removing the solvent was subjected to purification by silica gel column chromatography (BW-200, 30 g, eluent; AcOEt→5% MeOH/CH2Cl2), but there were fractions containing substantial by-product. Therefore, the fraction containing Compound 86 was only collected.
1H NMR (CDCl3) δ=1.34-1.42 (18H, t-Bu), 2.19 (1H, br s, OH), 3.13-3.86 (10H), 4.09-4.28 (2H), 4.74-4.86 (1H, m), 6.71 (2H, d, J=8.8 Hz), and 7.53 (2H, d, J=8.8 Hz).
EXAMPLE 969
Compound 87
The above fraction containing Compound 86 was concentrated to the residue (1.0953 g), which was then dissolved in CH2Cl2 (20 cm3) and added with Et3N (0.80 cm3, 5.69 mmol). MsCl (0.40 cm3, 5.17 mmol) in CH2Cl2 (5 cm3) was added dropwise at 0° C., and warmed to room temperature and stirred for 2.5 hours.
The reaction was quenched with saturated aqueous NaHCO3 (30 cm3), extracted four times with CH2Cl2, washed once with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated to obtain the residue (1.2848 g). The residue was dissolved in DMF (20 cm3), added with NaN3 (0.6000 g, 9.23 mmol) and stirred at 60° C. for 3 hours and at room temperature for additional 40 hours. The solution was added with H2O (50 cm3) and AcOEt (40 cm3) to separate the phase, the aqueous layer was extracted once with AcOEt. The combined organic layer was washed once with H2O and once with saturated aqueous NaCl, dried over Na2SO4, filtrated, and concentrated. The residue was purified by silica gel column chromatography (BW-200, 30 g, eluent; 50%→80% AcOEt/n-hexane) to afford 0.3171 g (0.632 mmol) of Compound 87.
Yield (from 82): 21%
1H NMR (CDCl3) δ=1.34-1.48 (18H, t-Bu), 3.06-3.86 (10H), 4.07-4.28 (2H), 4.78-4.91 (1H, m), 6.65-6.73 (2H, m), and 7.44-7.56 (2H, m).
EXAMPLE 970
Synthesis of Compound 88
To 50 cm3 egg-plant flask, charged with Compound 87 (0.3171 g, 0.632 mmol), THF (3 cm3) was added to dissolve. To this solution, Ph3P (0.2525 g, 0.963 mmol) and H2O (0.20 cm3, 11.1 mmol) were added at room temperature, and stirred at room temperature for 52 hours. The residue obtained by removing the solvent was purified by silica gel column chromatography (BW-200, 30 g, eluent; 50%→100% AcOEt/n-hexane→10% MeOH/CHCl3) to afford 0.2413 g (0.507 mmol, 80%) of amine.
The amine (0.2413 g, 0.507 mmol) was charged in 50 cm3 egg-plant flask, and pyridine (5 cm3) was added to dissolve. Ac2O (2.0 cm3) was added at room temperature and stirred at this temperature for 15 hours. Solvent was removed to obtain the residue (0.2556 g) as Compound 88.
Yield: 78%
1H NMR (CDCl3) δ=1.27-1.41 (18H, t-Bu), 1.90 (3H, s, Ac), 2.80-3.68 (10H), 4.02-4.20 (2H), 4.66-4.78 (1H, m), 6.10 (1H, t, J=6.0 Hz), 6.63 (2H, d, J=8.8 Hz), and 7.42 (2H, d, J=8.8 Hz).
EXAMPLE 971
Synthesis of Compound 94




Compound 91

NaH (60% in mineral oil; 3.4311 g, 85.8 mmol), charged in 200 cm3 egg-plant flask, was washed three times with n-hexane. Residual n-hexane was removed under reduced pressure, and DMF (150 cm3) was added. Compound 90 (10.26 g, 34.2 mmol) was added at room temperature, and the mixture was stirred at this temperature for 10 min. Compound 89 (9.8497 g, 40.7 mmol) in DMF (50 cm3) was then added dropwise to this mixture, and the mixture was stirred at this temperature for 18 hours. The mixture was poured into H2O (500 cm3), extracted three times with AcOEt, washed once with water and with saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered, and concentrated.
The resultant residue was purified by silica gel column chromatography (BW-200, 150 g, eluent; 10%→20%→30%→50% AcOEt/n-hexane) to afford 3.9235 g (8.36 mmol) of Compound 91.
Yield: 25%
1H NMR (CDCl3) δ=1.31-1.43 (9H, t-Bu), 3.08-3.74 (6H), 4.00-4.28 (2H), 4.98-5.24 (4H, m, CH2Ph), and 7.20-7.38 (10H, m).
EXAMPLE 972
Compounds 93 and 94
To 500 cm3 egg-plant flask, charged with Compound 91 (3.9235 g, 8.36 mmol) and 10% Pd/C (0.7777 g), MeOH (60 cm3) and CH2Cl2 (20 cm3) were added to obtain a suspension. The suspension was subjected to H2 substitution and stirred for 7 days. The reaction was filtered through celite Pad, the filtrate was concentrated to the crude product (92). The crude product (2.2861 g) was dissolved in MeCN (50 cm3), and K2CO3 (3.3520 g, 24.25 mmol) and 3,4-difluoro nitro benzene (3.6271 g, 22.80 mmol) were added, and the mixture was heated with stirring for 14 hours. H2O (50 cm3) was added, and the mixture was extracted five times with AcOEt, washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, filtrated and concentrated. The resultant residue was purified by silica gel column chromatography (BW-200, 60 g, eluent; 10%→20%→30%→40% AcOEt/n-hexane) to afford Compound 93 (0.5019 g, 1.47 mmol) and Compound 94 (0.4347 g, 0.91 mmol).
Yield: 18% (compound 93), 11% (compound 94).
Compound 93: 1H NMR (CDCl3) δ=1.45 (9H, s, t-Bu), 3.00-3.14 (2H), 3.36-3.74 (7H), 7.48 (1H, t=9.1 Hz), and 7.84-8.01 (2H, m).
Compound 94: 1H NMR (CDCl3) δ=1.53-1.57 (9H, t-Bu), 3.38-5.76 (8H), 6.61 (2H, t, J=8.6 Hz), and 7.84-8.01 (4H, m).
EXAMPLE 973
Synthesis of Compound 103




Compound 102

To a solution of BOC compound (101, 1.01 g) in chloroform (25 ml), trifluoroacetic acid (2 ml) was added and stirred at room temperature for 19 hours.
After the reaction, saturated aqueous NaHCO3 was added, and the mixture was extracted with chloroform-methanol (9:1). After dryness (Na2SO4), solvent was removed. The residue was purified by silica gel chromatography (hexane-ethyl acetate (1:1)) to afford 526 mg (74%) of Compound (102) as colorless syrup.
102: colorless syrup; 1H-NMR (300 MHz, CDCl3) δ 3.09 (t, 5.5, 1H), 3.14 (t, 5.5, 1H), 3.54-3.70 (m, 4H), 3.82 (t, 5.5, 1H), 3.91 (t, 5.5, 1H), 5.16 (s, 2H), 5.84 (br, NH), 7.29-7.40 (m, 5H)
EXAMPLE 974
Compound 103
To a solution of the amino compound (102, 321 mg) and 3,4,5-trifluoro nitrobenzene (487 mg) in acetonitrile (12 ml), K2CO3 (561 mg) was added, and the mixture was heated with stirring for 21 hours. After the reaction, aqueous NH4Cl was added, and the mixture was extracted with chloroform-methanol (9:1). After dryness (Na2SO4), solvent was removed. The residue was purified by silica gel chromatography (hexane-ethyl acetate (2:1)) to afford 45 mg (8%) of pale-yellow candy-like compound (103) in the first fraction, and 258 mg (80%) of the starting material was recovered in the eluted fraction with hexane-ethyl acetate (1:1).
103: pale-yellow candy-like material; 1H-NMR (300 MHz, CDCl3) δ 3.55 (br t, 5.5, 1H), 3.62 (br t, 5.5, 1H), 3.70-3.81 (m, 4H), 4.01 (t, 5.5, 1H), 4.09 (t, 5.5, 1H), 5.19 (s, 2H), 7.31-7.39 (m, 5H), 7.75-7.84 (m, 2H)
Industrial Applicability
The compound of the invention is useful as a pharmaceutical active ingredient or an intermediate in the synthesis thereof. Particularly, the compound of the invention is useful as an antimicrobial agent based on its antimicrobial activity.

## Claims

1. A compound of the formula:



or a pharmaceutically acceptable salt thereof
wherein
Y1 is NP2 or O;
P1 and P2 are independently hydrogen, a substituent selected from Substituent Group S1 or an amino protecting group, or P1 and P2 may be taken together with N atom to which they are attached to form optionally substituted heterocycle;
Substituent Group S1 consists of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted formyl, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted lower alkyloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted carbamoyl, lower alkylthio, cycloalkylthio, arylthio, optionally substituted lower alkylsulfonyl, optionally substituted phenylsulfonyl, optionally substituted aromatic heterocycle(lower)alkyl, optionally substituted aryl, and optionally substituted heterocyclic group;
Ring B is optionally substituted and optionally condensed benzene ring or optionally substituted heterocycle;
with the proviso that the compound is not the following compounds:




wherein Ph is phenyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring B is substituted with one or more substituent selected from the group consisting of halo, nitro, amino, amino protected with an amino protecting group, optionally substituted amide, formyl, carboxyl, carboxamide, optionally substituted alkyl, lower alkoxy, hydroxyimino, optionally substituted oxazolidinone, optionally substituted isoxazole, and optionally substituted heterocyclic group (preferably 5- or 6-membered).

3. The compound according to claim 1, represented by the formula:



or a pharmaceutically acceptable salt thereof
wherein
P1 and P2 are hydrogen, a substituent selected from Substituent Group S1 or an amino protecting group, or P1 and P2 may be taken together with N atom to which they are attached to form optionally substituted heterocycle;
Ring B1 is a benzene ring optionally substituted with one or more halogen atom;
R10 is —NO2 or —NHP3;
P3 is hydrogen or an amino protecting group.

4. The compound according to claim 1, represented by the formula:



or a pharmaceutically acceptable salt thereof,
wherein
P1 is hydrogen, a substituent selected from Substituent Group S1 or an amino protecting group;
Substituent Group S1 consists of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted formyl, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted lower alkyloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted carbamoyl, lower alkylthio, cycloalkylthio, arylthio, optionally substituted lower alkylsulfonyl, optionally substituted phenylsulfonyl, optionally substituted aromatic heterocycle(lower)alkyl, optionally substituted aryl, and optionally substituted heterocyclic group;
Ring B is optionally substituted and optionally condensed benzene ring or optionally substituted heterocycle.

5. The compound according to any one of claims 1, 2 or 4 wherein Ring B is a substituted quinoline ring.

6. A compound of the formula:



or a pharmaceutically acceptable salt thereof,
wherein
Y1 is NP2 or O;
P1 and P2 are independently hydrogen, a substituent selected from Substituent Group S1 or an amino protecting group, or P1 and P2 may be taken together with N atom to which they are attached to form optionally substituted heterocycle;
R10, R11, R12, R13, R14, and R15 are independently hydrogen, lower alkyl, cycloalkyl, cycloalkyl lower alkyl, halo, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, lower alkylamino, optionally substituted aryl, or optionally substituted heterocyclic group, or R12 and R13 are taken together with their neighboring atom(s) to form optionally substituted heterocycle.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R10 is hydrogen, R11 is halo, R12 is lower alkoxy, R13 is cycloalkyl, R14 is hydrogen, R15 is carboxy or lower alkoxycarbonyl.

8. A pharmaceutical composition comprising the compound according to any one of claims 1 or 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

9. An antimicrobial agent comprising the compound according to any one of claims 1 or 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.