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ZA200708970B - Polycyclic carbamoylpyridone derivative having HIV integrase inhibitory activity - Google Patents

Polycyclic carbamoylpyridone derivative having HIV integrase inhibitory activity Download PDF

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Publication number
ZA200708970B
ZA200708970B ZA200708970A ZA200708970A ZA200708970B ZA 200708970 B ZA200708970 B ZA 200708970B ZA 200708970 A ZA200708970 A ZA 200708970A ZA 200708970 A ZA200708970 A ZA 200708970A ZA 200708970 B ZA200708970 B ZA 200708970B
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South Africa
Prior art keywords
optionally substituted
hydroxy
lower alkyl
formula
methyl
Prior art date
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ZA200708970A
Inventor
Johns Brian Alvin
Kawasuji Takashi
Taishi Teruhiko
Toada Yoshiyuki
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Smithkline Beecham Corp
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Description

SPECIFICATION
Polycyclic Carbamoylpyridone Deyrivative Having HIV Integrase Inhibitory Activity [Technical Field] {oo01]
The present invention relates to novel compounds possessing an antiviral activity, in detail polycyclic carbamoylpyridone derivatives possessing an inhibitory activity against HIV integrase and a pharmaceutical composition containing the same, especially an anti-HIV agent. [Background Art] 0002]
Among viruses, human immunodeficiency virus (HIV), a kind of retrovirus, is known to cause acquired immuncdeficiency syndrome (AIDS). The therapeutic agent for AIDS is mainly selected from a group of reverse transcriptase inhibitors (e.g., AZT, 3TC) and protease inhibitors (e.g., Indinavir), but they are proved to be accompanied by side effects such as nephropathy and the emergence of resistant viruses. Thus, the development of anti-HIV agents having the other mechanism of action has been desired,
On the other hand, a combination therapy is reported to be efficient in treatment for AIDS because of the frequent emergence of the resistant mutant. Reverse transcriptase inhibitors and protease inhibitors are clinically used as an anti-HIV agent, however agents having the same mechanism of action often exhibit cross-resistance or only an additional activity. Therefore, anti-HIV agents having the other mechanism of action are desired.
Under the circumstances above, an HIV integrase ;nhibitor has been focused on as an anti-HIV agent having a novel mechanism of action (Ref: Patent Documents 1 and 2) . As an anti-HIV agent having such a mechanism of action, known are carbamoyl substituted hydroxypyrimidinone derivative (Ref: Patent Documents 3 and 4) and carbamoyl-substituted hydroxypyrrolidione derivative (Ref: Patent Document 5). Further, a patent application concerning carbamoyl-substituted hydroxypyridone derivative has been filed (Ref: Patent Document 6, Example 8) .
Other known carbamoylpyridone derivatives include 5-alkoxypyridine-3-carboxamide derivatives and 7 -pyrone-3-carboxamide derivatives, which are a plant growth inhibitor or herbicide (Ref: Patent Documents 7-9).
Other HIV integrase inhibitors include N-containing condensed cyclic compounds
(Ref: Patent Document 10). [Patent Document 11W0038/0166275 [Patent Document 2)W02004/024693 [Patent Document 3]W008/035076 [Patent Document 4JW003/036076 [Patent Document 5)W02004/004657 [Patent Document 68]JP Patent Application 2008-32772 [Patent Document 71JP Patent Publication 1990-108668 [Patent Document 8]JP Patent Publication 1990-108683 [Patent Document 9]JP Patent Publication 1990-96506 [Patent Document 101W02005/016927 [Disclosure of Invention] [Problem to be Solved by the Invention]
[0003]
The development of a novel integrase inhibitor has been desired. {Means to Solve the Problem]
[0004]
The present inventors have intensively studied to find that a novel polycyclic carbamoylpyridone derivative possesses a potent HIV integrase inhibitory activity.
Moreover, the present inventors have discovered that a compound of the present invention and a pharmaceutical composition containing the same are useful as an antiviral agent, an antiretroviral agent, an anti-HIV agent, an anti-HTLV-1 (Human
T cell leukemia virus type 1) agent, an anti-FIV (Feline immunodeficiency virus) agent or an anti-SIV (Simian immunodeficiency virus) agent, especially an anti-HIV agent or anti-AIDS agent, to accomplish the present invention shown below. (1A compound of the formula:
OH 0 © x 71
RAL NR N<_ / (1) 0] R3 (wherein,
Z! is NR+
RY is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted aryl, optionally : substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from CO, 0, S, SO, SOz NRe (Ru is hydrogen or lower alkyl), N= and =N-)), O or CHei: 72 is optionally substituted lower alkylene or optionally substituted lower alkenylene, each may be intervened by a heteroatom group selected from O, S, SO,
SO, NRS (RS is hydrogen, optionally substituted lower alky), optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted aryl, op tionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy or optionally substituted amino, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from CO, O, 5, SO, SO» NR (RS is selected independently from the same substituent group as RY), N= and =N-)), ‘N= or =N-
Rt is hydrogen or lower alkyl;
X is a single bond, a heteroatom group selected from O, S, SO, SOz2and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom;
R? is optionally substituted aryl
R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino;
RY and Z2 part taken together forms a ring, whexe the compound (I is represented by the following formula (I-1), or (I-11):
OH 0
ONY ON
A ee (1-1) lo) R® R14 RX (wherein,
A ring is optionally substituted heterocycle;
R!4 and RX are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optienally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from O, S, SO, SOz, NRS (R8 is selected independently from the same substituent group as R%), -N= and =N-), hydroxy, optionally substituted amino, optionally substituted lower alkyl carbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxy carbonyl, optionally substituted arylcarbonyl, optionally substituted aryl lower alkyl carbonyl, optionally substituted aryloxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkyl carbonyl, optionally substituted heterocycleoxy carbonyl or optionally substituted aminocarbonyli a broken line represents the presence or absence of a bond, provided that when the broken line represents the presence of a bond, RX is not present;
R! is hydrogen or lower alkyl
X is a single bond, a heteroatom group selected from O, S, SO, SOzand NH, or lower alkylene or lower alkenylene each may be intervened by the hetexoatom group:
R? is optionally substituted aryl;
RY is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkeny), optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino)
OH 0] 0) 2 1 D
RE, NR ~~ AN (1-11) . 0 RS (wherein,
D ring is optionally substituted heterocycle;
R! is hydrogen or lower alkyl;
X is a single bond, a heteroatom group selected from 0, S, SO, SOzand NUH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group;
R2 is optionally substituted aryl
R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, op tionally substituted heterocyclic group, op tionally substituted heterocycleoxy or optionally substituted amino), its pharmaceutically acceptable salt, or solvate thereof. (2) A compound according to the above (1), pharmaceutically acceptable salt, or solvate thereof, wherein R! is hydrogen. (3) A compound according to the above (1), pharmaceutically acceptable salt, or solvate thereof, wherein X is lower alkylene; R? is phenyl or phenyl substituted with at least halogen. (4) A compound according to the above (1), pharmaceutically acceptable salt, or solvate thereof, wherein R23 is hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy or optionally substituted amino. (5) A compound according to the above (1), pharmaceutically acceptable salt, ox solvate thereof, wherein R¥ is hydrogen. (6) A compound according to the above (1), pharmaceutically acceptable salt, or solvate thereof, wherein R! is hydrogen or lower alkyl; X is lower alkylene; R?is phenyl or phenyl substituted with at least halogen; R3is hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy or optionally substituted amino. (7) A compound of the formula:
OH 0] 0]
IAN
2 1 . A . : REL ~NR x Na (1-1) 0 R3 R14 RX (wherein,
A ring is optionally substituted heterocycle;
Ri and RX are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or
Jower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from O, S, SO, S02 NR® (RS is selected independently from the same substituent group 8s RY), -N= and =N-), hydroxy, optionally substituted amino, optionally substituted lower alkyl carbonyl, optionally substituted cycloalkylearbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxy carbonyl, optionally substituted arylearbonyl, optionally substituted aryl lower alkyl carbonyl, optionally substituted aryloxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkyl carbonyl, optionally substituted heterocycleoxy carbonyl or optionally substituted aminocarbonyli a broken line represents the presence or absence of a bond, provided that when the broken line represents the presence of a bond, RX is not present:
R! is hydrogen or lower alkyl:
X is a single bond, a heteroatom group selected from O, 8, SO, SOzand NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group:
R2? is optionally substituted aryl;
R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted - lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino), its pharmaceutically acceptable salt, or solvate thereof 8) A compound according to the above (7), pharmaceutically acceptable salt, or solvate thereof, wherein R! is hydrogen or lower alkyl: X is lower alkylene; R% is phenyl or phenyl substituted with at least halogen; R?¥is hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower allenyloxy or optionally substituted amino. (9) A compound according to the above (7), pharmaceutically acceptable salt, or solvate thereof, wherein a broken line represents the absence of a bond. (10) A compound according to the above (7), pharmaceutically acceptable salt, ox solvate thereof, wherein RX is hydrogen: R!4is hydrogen or optionally substituted lower alkyl.
(11) A compound according to the above (7), pharmaceutically acceptable salt, or solvate thereof, wherein A ring is an optionally substituted and optionally condensed 5° to 7- membered heterocycle containing 1 to 2 hetero atom(s). (12) A compound of the formula:
OH oO
Z NTS
(R) "3 OSC “le: ~~ Na > (1-1-1) oO R? R™* R* (wherein,
A ring is an optionally substituted and optionally condensed 5- to 7 membered heterocycle containing 1 to 2 hetero atom(s); the stereochemistry of an asymmetric carbon represented by * shows R- or S- configuration, or a mixture thereof;
R!4 and RX are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, op tionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue ox lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from O, 8, SO, SO2 NRS (Rb is selected independently from the same substituent group as R14), -N= and =N-), hydroxy, optionally substituted amino, optionally substituted lower alkyl carbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxy carbonyl, optionally substituted arylcarbonyl, optionally substituted aryl lower alkyl carbonyl, optionally substituted aryloxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkyl carbonyl, optionally substituted hetexocycleoxy carbonyl or optionally substituted aminocarbonyl;
R¢ is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy ox optionally substituted amino), its pharmaceutically acceptable salt, or
R! is hydrogen or lower alkyl;
R is independently selected from halogen and Substituent group Si;
Substituent group S1{: optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue, or lower alkyl substituted with optionally substituted phosphoric acid residue (wherein the lower alkyl may be intervened with a heteroatom group(s) selected from CO, 0, O, S, SO, S02, NR» (Rn is hydrogen or lower alkyl), -N= and =N-), lower alkoxy lower alkyl, amino lower alkyl optionally substituted with mono: ox di- lower alkyl, halogenated lower alkyl, lower alkoxy, carbamoyl optionally substituted with mono- or di- lower alkyl, optionally substituted lower alkyl sulfonyl amino, halogenated lower alkoxy, hydroxy lower alkyl) m is an integer of 0 to 3, its pharmaceutically acceptable salt, or solvate thereof. (18) A compound according to the above (12), pharmaceutically acceptable salt, or solvate thereof, wherein RX and Ri“ are independently hydrogen or optionally ” substituted lower. (14) A compound according to the above (12), pharmaceutically acceptable salt, or solvate thereof, wherein RX and R!4 are hydrogens. (15) A compound according to the above (12), pharmaceutically acceptable salt, or solvate thereof, wherein R3is hydrogen,
(16) A compound according to the above (12), pharmaceutically acceptable salt, or solvate thereof, wherein mis 0, or 1 to 3 and at least one of R is halogen. (17) A compound according to the above (7) or (12), pharmaceutically acceptable salt, or solvate thereof, wherein A ring is any one of the following:
RE er R27 RY Ree R34
PS PW ow PY a %, + Zz cas EX z R %] 2 A on
Z=0or NR¥ Z=0 or NR Z=0 or NR¥® (A- (a2) (a3) (wherein, R20 to R10 are each independently a group selected from Substituent group
S2, or any two groups of R20 to R10, which bonds to the same carbon atom, taken together with the carbon atom, may form an optionally substituted carbocyle or optionally substituted heterocycle, or each combination of (R20 and R22), (R*3 and R24), (R26 and R29), (R27 and R), (R30 and R31), (R92 and R341), (R35 and R36), (R37 and R28), and (R39andR49), taken together with the neighboring atom, may form an optionally substituted carboeyle or optionally substituted heterocycle.
Substituent group S2: hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocycle, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkylearbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted arylcarbonyl, optionally substituted aryl lower alkylearbonyl, optionally substituted aryl oxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkylcarbonyl, optionally substituted hetevocycleoxycarbonyl,
optionally substituted aminocarbonyl, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue, or lower alkyl substituted with optionally substituted phosp horic acid residue (the lower alkyl may be intervened with a heteroatom group(s) selected from CO, 0, 8, SO, SOz, NRS (Ro is independently selected from the same Substituent group as RY), -N= and =N") the stereochemistry of an asymmetric carbon represented by * shows R- or S- configuration, or a mixture thereof) (18) A compound according to the above (17), pharmaceutically acceptable salt, ox solvate thereof, wherein R20 to R40 are each indep endently hydrogen or substituted lower alkyl, or any two groups of R20 to R10, which bonds to the same carbon atom, taken together with the carbon atom, may form an optionally substituted 3- to 7 membered carbocyle or optionally substituted 3- to 7- membered heterocycle, or each combination of (R20 and R22), (R#¥ and R#4), (R25 and R26), (R27 and R#Y), (R30 and R31), (R22 and R31), (R95 and R36), (R37 and R39), and (R39andR19), taken together with the neighboring atom, may form an optionally substituted 5- to 7- membered carbocyle or optionally substituted 5- to 7 membered heterocycle. (19) A compound according to the above (17), pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-1); one of R20 to R25 is optionally substituted lower alkyl and the others are hydrogens. (20) A compound according to the above (17), pharmaceutically acceptable salt, or solvite thercof, wherein A ring is a ring represented by (A-1); one of (R20 and R22), (R23 and R24), and (R25 and R20), taken together with the neighboring atom, may form an optionally substituted 5- to 7- membered carbocyle or optionally substituted 5- to 7- membered heterocycle. (21) A compound according to the above (17), pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-1); Z=NR26, and R25 and R26 taken together with the neighboring atom may form an optionally substituted 5- to 7 membered heterocycle. (22) A compound according to the above (17), pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-2); one of R?’ to R30 is optionally substituted lower alkyl and the others are hydrogens. (23) A compound according to the above (17), pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-2); ane of (R*"and R29) and (R30 and RY), taken together with the neighboring atom, may form an optionally substituted 5° to 7- membered carboeyle or optionally substituted 5° to 7- membered heterocycle. : (24) A compound according to the above (17), pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-2); Z=NR3!, and R¥ and R3! taken together with the neighboring atom may form an optionally substituted 5- to 7- membered heterocycle. (25) A compound according to the above (17), pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-3); one of R92 to R8%is optionally substituted lower alkyl and the others are hydrogens. (26) A compound according to the above (17), pharmaceutically acceptable salt, ov solvate thereof, wherein A ring is a ving represented by (A-3); one of (R92and RM), (R#sandR3),(R47andR%),and (R%andRA40), taken together with the neighboring atom, may form an optionally substituted 6- to 7 membered carboeyle or optionally substituted 5- to 7- membered heterocycle. (27) A compound according to the above (17), pharmaceutically accoptable salt, or solvate thereof, wherein A ring is a ring represented by (A-3); Z=NR10, and R32 and R taken together with the neighboring atom may form an optionally substituted 5- to 7 membered heterocycle. (28) A compound according to the above (12), pharmaceutically acceptable salt, or solvate thereof, wherein RX is hydrogen; R!is hydrogen or optionally substituted lower; RY is hydrogen; m is 1 to 3 and at least one of Rs is halogen; A ring is a ring described in Claim 17. (29) A compound according to the above (12), pharmaceutically acceptable salt, ox solvate thereof, wherein RX is hydrogen; Ris hydrogen: R? is hydrogen; mis 0, or 1 to 3 and at least one of Rs is halogeni A ring is a ring described in Claim 17: R20 to RW are each independently hydrogen or substituted lower alkyl, or any two groups of R20 to R19, which bonds to the same carbon atom, taken together with the carbon atom, may form an optionally substituted 3- to 7- membered carbocyle or optionally substituted 8- to 7- membered heterocycle, ox each combination of (R20 and R23), (R2 and R24), (R25 and R20), (R27 and R29), (R30 and RY), (R32and R34), (R36 and R36), (R87 and R99), and (R%%andR40), taken together with the neighboring carbon atom, may form an optionally substituted 5- to 7- membered carbocyle or optionally substituted 5- to 7- membered heterocycle. (30) A compound of the formula:
OH 0] fo § N 2 1 D .
RNR x oN (1-11) o] R3 (wherein,
D ring is optionally substituted heterocycle;
R! is hydrogen or lower alkyl;
X is a single bond, a heteroatom group selected from O, 8, SO, SOz and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group:
R2 is optionally substituted aryl; :
R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino), pharmaceutically acceptable salt, or solvate thereof .
(31) A compound selected from the group consisting of: (BE, 1129) M[(2,4-DifluorophenyDmethyll-6-hydroxy-8-methyl-5,7-diox0-2,3,5.7, 11,11a -hexahydro[1,3] oxazolo(8,2-alpyrido[1,2- dlpyrazine-8-carboxamidei (4af2,132.9)- MN-[(2,4-Difluorophenyl methyl): 10-hydroxy-9,11-dioxo-2,8,4a,5,9,11, 13,18a -octa hydro: | Fr pyridol1,2- alpyrrolo(1',2/:3,limidazol1,2- dlpyrazine-8-carboxamide; (32.5, 138.9) M-[(2,4-Difluoropheny)mothyll-8-hydroxy-7,9-dioxo-1,2,3,3a,4,5,7.9, 13,18a -decahydropyrido(1',2'14,6]pyrazinol1,2- alpyrrolo(1,2- clpyrimidine: 10-carboxamide; (4a.5,18a.R)- MV [(2,4-Difluorophenyl)methyl)- 10-hydroxy-9,11-dioxo-2,3,42,5,9,11,18,138 -octahydro-1H-pyridoll,2- alpyrrolo[1',2':3,4]limidazo(1,2 dipyrazine-8-carboxamide; (40.5,13a.8)- N[(4-FluorophenyDmethyl]-10-hydroxy-9, 11-dioxo-2,3,44a,5,9,11,13,18a-o0ct ahydro- 1 &pyrido[1,2-alpyrrolo[1’,2':3,4limidazol1,2- dlpyrazine-8-carboxamide; (38, 115.8) N-[(2,4-Difinorophenyl) methyl}-6-hydroxy-5,7-dioxo-3- (phenylmethy))-2,3,5, 7,11, 11a-hexahydrol1,8loxazolol3,2- alpyridol1,2- dlpyrazine-8-carboxamide; (32.5,132.9)- M[(4-Fluorophenyl)methyll-8-hydroxy-7,9-dioxo- 1,2,3,3a,4,5,7,9,13,13a-de cahydropyxidol1',2/:4,5]pyrazinol[1,2-alpyrrolo(1,2-clpyrimidine-10-carboxamide:
(35 11a /)- MN [(2,4-DifluorophenyDmethyl)-6-hydroxy-8-[(L.S)- 1-methylpropyl)-5,7-dioxo -2,3,5,7,11,11a-hexahydrol1,3loxazolo (8,2-alpyridol1,2- dipyrazine-8-carboxamide; (38, 11aR)-N ((2,4-Difluorophenyl)methyl)-6-hydroxy-3- methyl-5,7-diox0"2,3,6,7,11, 11a -hexahydro[1,3]oxazolol3,2- alpyrido[1,2- dlpyrazine-8-carboxamide:; (35, 11aR)- M-[(4-FluorophenyDmethyll-6-hydroxy-3-methyl-6,7-diox02,3,5,7, 11,11ahe xahydro[1,8)oxazolo[3,2- alpyridol1,2- dipyrazine-8-carboxamide; (35 112 )-V [(2,4-Difluorophenylmethyl]-3-(1, 1-dimethylethyl)-6-hydroxy-6,7-dioxo-2 ,3,6,7, 11,11a-hexahydrol1,3]oxazolo(8,2- alpyrido[1,2- dlpyrazine-8-carboxamide; (3.5, 11a2)-3-(1,1-Dimethylethyl)- M [(4-fluorophenylmethyl]-6-hydroxy-5,7-dioxo"2,3,5, 7,11, 11a-hexahydro(1,3loxazolo[8,2-alpyrido[1,2-dlpyrazine-8-carboxamide; (38, 118.2) N[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-8-phenyl-2,3,5,7, 11,11a -hexahydrol1,3loxazolo[3,2- alpyrido[1,2- dlpyrazine-8-carboxamide; (3.5, 11aR)- N-[(2,4-Difluorophenyl) methyl}-6-hydroxy-3-(hydroxymethy)-5,7-dioxo-2,3, 57,11, 11a-hexahydrol1,8oxazolo[8,2- alpyrido[1,2-dlpyrazine-8-carboxamide; 25, 37)- N-[(2,4-Difluorophenyl)methyll-6-hydroxy-3-methyl-5,7-dioxo-2-phenyl-2,8,5,7 ,11,11a-hexa hydro[1,3]oxazolo[3,2- alpyrido[1,2- dlpyrazine-8-carboxamide;
(8.11129) N-[(2, 4 DifluorophenyDmethyll-6-hydroxy6,7-dioxo 3 (phenylmethyl)-2,3,5, 7,11,11a-hexahydro[1,8]oxazolo (3,2-alpyridolL,2- dipyrazine-8-carboxamide; (BR 1129) MV [(2,4-Difluoropheny)methyll-6-hydroxy-3-(2-methylpropyl)-5,7-dioxo2,3, 6.7,11,11a-hexahydrol1,3)oxazolo[3,2-alpyrido(1,2- dipyrazine-8-carboxamide; (5a. 14a7)- N-[(2,4-Difiuorophenyl)methyl)-11-hydroxy-10, 12-dioxo-1,2,3,4,5a,6,10,12, 14,14a-decahydropyridol1,2-alpyrido[1',2':3,4limidazo(1,2- dlpyrazine-9-carboxamide: (25, 3,9- M-[(2, 4-Difluorophenyl methyll-6-hydroxy-3-[(methyloxy)methyll-5,7-dioxo-2-p henyl-2,3,5,7, 11,11a-hexahydrol1,8]loxazolo(3,2- alpyrido{1,2- dlpyrazine-8-carboxamide (35,11aR)-3-(Cyclohexylmethyl)- NV* ((2,4-difluorophenyl)methyll-6-hydroxy-5,7-dioxo-2, 3,5,7,11,11a- hexahydrol1,3loxazolol3,2-alpyridol1,2- dlpyrazine-8-carboxamide; (38, 11a/)- MN(2,4-Difluorophenyl)methyl}-6-hydroxy-3-(1-methylethyl)-5,7-dioxo-2,3,5, 7.11, 11a-hexahydro(1,3loxazolo[8,2- alpyrido[1,2- dlpyxrazine-8-carboxamide; (5a. 1425) M1(2,4-Difluorophenylmethyl]-12-hydroxy- 11,13-dioxo-54,6a,7,11,13,14a- hexahydro-5Hindenol1',2'14,51(1,8loxazolol8,2- alpyrido[1,2-dlpyrazine-10-carboxamid e;

Claims (1)

  1. [Name of Document] Scope of Claims 1, A compound of the formula: OH 0]
    © x 71
    RAL ANAL ANG Na / wm Z2
    0] R3 (wherein,
    Z! is NR4;
    R4 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from CO, Q, S, SO, SO2 NR2» (Ra is hydrogen or lower alkyl), -N= and =N-)), O or CHy;
    Z?is optionally substituted lower alkylene or optionally substituted lower alkenylene, each may be intervened by a heteroatom group selected from O, S, SO, S02, NR? (Rf is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy or optionally substituted amino, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted
    "phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue ox lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from CO, O, S, SO, SO2, NR (RS is selected independently from the same substituent group as R4), ‘N= and =N-)), -N= or
    =
    R'is hydrogen or Jower alkyl;
    X is a single bond, a heteroatom group selected from O, S, SO, $02 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom;
    R? is optionally substituted aryl;
    R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino:
    R4 and Z¢ part taken together forms a ring, where the compound Dis represented by the following formula (I-1), or (I-11):
    OH O ©) x N A 600 (1-1) fe) R3 R14 Rx (wherein,
    A ring is optionally substituted heterocycle;
    R11 and R* are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from 0, S, SO, SOz, NR (R8 is selected independently from the same substituent group as R4), -N= and =N-), hydroxy, optionally substituted amino, optionally substituted lower alkyl carbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxy carbonyl, optionally substituted arylcarbonyl, optionally substituted aryl lower alkyl carbonyl, optionally substituted aryloxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkyl carbonyl, optionally substituted heterocycleoxy carbony! or optionally substituted aminocarbonyl; a broken line represents the presence or absence of a bond, provided that when the broken line represents the presence of a bond, RX is not present: R! is hydrogen or lower alkyl; X is a single bond, a heteroatom group selected from 0, 8, SO, SOzand NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group; R? is optionally substituted aryl; : R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino) OH o] Tr D yea (1-11) eo] R3 (wherein, D ring is optionally substituted heterocycle; R! is hydrogen or lower alkyl; X is a single bond, a heteroatom group selected from O, S, SO, SO2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group: R2is optionally substituted aryl; R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino); or a pharmaceutically acceptable salt, or solvate thereof,
    2. A compound according to Claim 1, pharmaceutically acceptable salt, or solvate thereof, wherein R! is hydrogen.
    3. A compound according to Claim 1, pharmaceutically acceptable salt, or solvate thereof, wherein X is lower alkylene: R? is phenyl or phenyl substituted with at least halogen.
    4. A compound according to Claim 1, pharmaceutically acceptable salt, or solvaie thereof, wherein R3is hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy or optionally substituted amino.
    5. A compound according to Claim 1, pharmaceutically acceptable salt, or solvate thereof, wherein 13 is hydrogen.
    6. A compound according to Claim 1, pharmaceutically acceptable salt, or solvate thereof, wherein RJ is hydrogen or lower alkyli X is lower alkylene; R?is phenyl or phenyl substituted with at least halogen; Rd is hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy or optionally substituted amino.
    7. A compound of the formula: ’ OH Oo o . = N 2 1 3 A RAP Se Ne (1-1) 0 R3 R14 RX (wherein, Aring is optionally substituted heterocycle; ) Rv and R¥ are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from O, S, SO, SOz, NR5 (Ro is selected independently from the same substituent group as R4), ‘N= and =N-), hydroxy, optionally substituted amino, optionally substituted lower alkyl carbonyl, optionally substituted cycloalkylearbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxy carbonyl, optionally substituted arylearbonyl, optionally substituted aryl lower alkyl carbonyl, optionally substituted aryloxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkyl carbonyl, optionally substituted heterocycleoxy carbonyl or optionally substituted aminocarbonyl; a broken line represents the presence or absence of a bond, provided that when the broken line represents the presence of a bond, RX is not present; R1is hydrogen or lower alkyl; X is a single bond, a heteroatom group selected from 0, 8, SO, SOz and NH, or lowex alkylene or lower alkenylene each may be intervened by the heteroatom group; R? is optionally substituted aryl; R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino); or a pharmaceutically acceptable salt, or solvate thereof
    8. A compound according to Claim 7, pharmaceutically acceptable salt, or solvate thercof, wherein R! is hydrogen or lower alkyl; X is lower alkylene; R2is phenyl or phenyl substituted with at least halogen; Ris hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl], lower alkoxy, lower alkenyloxy or optionally substituted amino.
    9. Acompound according to Claim 7, pharmaceutically acceptable salt, or solvate thereof, wherein a broken line represents the absence of a bond.
    10. A compound according to Claim 7, pharmaceutically acceptable salt, or solvate thereof, wherein RX is hydrogen; R!* is hydrogen or optionally substituted lower alkyl.
    11. A compound according to (Claim 7, pharmaceutically acceptable salt, or solvate thereof, wherein A ring is an optionally substituted and optionally condensed 5° to 7- membered heterocycle containing 1 to 2 hetero atom(s).
    12. A compound of the formula: OH 0
    Q. = | AN N A — RIM NRL AN ; (1-1-1) lo) Rs R14 RX (wherein, A ring is an optionally substituted and optionally condensed 5° to 7- membered heterocycle containing 1 to 2 hetero atom(s)
    the stereochemistry of an asymmetric carbon represented by * shows R- or S- configuration, or a mixture thereof;
    RI and RX are independently. hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from QO, 8, SO, SOz2, NR (RS is selected independently from the same substituent group as R41), -N= and =N-), hydroxy, optionally substituted amino, optionally substituted lower alkyl carbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxy carbonyl, optionally substituted arylcarbonyl, optionally substituted aryl lower alkyl carbonyl, optionally substituted aryloxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkyl carbonyl, optionally substituted heterocycleoxy carbonyl or optionally substituted aminocarbonyl;
    R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino), its pharmaceutically acceptable salt, or
    R'is hydrogen or lower alkyl;
    R is independently selected from halogen and Substituent group Si;
    Substituent group S1(: optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue, or lower alkyl substituted with optionally substituted phosphoric acid residue (wherein the lower alkyl may be intervened with a heteroatom group(s) selected from CO, 0, 0, S, SO, SOz, NR~ (R» is hydrogen or lower alkyl), -N= and =N-), lower alkoxy lower alkyl, amino lower alkyl optionally substituted with mono- ox di- lower alkyl, halogenated lower alkyl, lower alkoxy, carbamoyl optionally substituted with mono- or di- lower alkyl, optionally substituted lower alkyl sulfonyl amino, halogenated lower alkoxy, hydroxy lower alkyl) m is an integer of 0 to 3); or a pharmaceutically acceptable salt, or solvate thereof, ’
    13. A compound according to Claim 12, pharmaceutically acceptable salt, or solvate thereof, wherein RX and R! are independently hydrogen or optionally substituted lower alkyl.
    14. A compound according to Claim 12, pharmaceutically acceptable salt, or solvate thereof, wherein R* and R' are hydrogens.
    15. A compound according to Claim 12, pharmaceutically acceptable salt, or solvate thereof, wherein R3is hydrogen.
    16. A compound according to Claim 12, pharmaceutically acceptable salt, or solvate thereof, wherein m is 0, or 1 to 3 and at least one of R is halogen.
    17. A compound according to Claim 7 or 12, pharmaceutically acceptable salt, or solvate thereof, wherein A ring is any one of the followings: 32 RE ar R27 R R33 R34 Se RZ FS R So R35 N R N N T PG %, Ng SR YE R30 wz R37 2 - R Rds R38 Z=0 or NR? Z = 0 or NRM Z=0 or NR‘ (A-1) (A2) (A-3) (wherein, R20 to R10 aye each independently a group selected from Substituent group $2, or any two groups of R20 to R40, which bonds to the same carbon atom, taken together with the carbon atom, may form an optionally substituted carbocyle ox optionally substituted heterocycle, or each combination of (R20 and R22), (R23 and R24), (R26 and R26), (R?7 and R29), (R20 and R31), (R92 and R#4), (R96 and R36), (R37 and R38), and (R3andR"0), taken together with the neighboring atom, may form an optionally substituted carbocyle or optionally substituted heterocycle. Substituent group S2: hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocycle, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkylcarbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted arylearbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryl oxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkylcarbonyl, optionally substituted heterocycleoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue, or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened with a heteroatom group(s) selected from CO, 0, 8, SO, SOs, NR5 (Rb is independently selected from the same Substituent group as RY), N= and =N-) the stereochemistry of an asymmetric carbon represented by * shows R- or S- configuration, or a mixture thereof)
    18. A compound according to Claim 17, pharmaceutically acceptable salt, or solvate thereof, wherein R2? to R10 are each independently hydrogen or substituted lower alkyl, or any two groups of R20 to R49, which bonds to the same carbon atom, taken together with the carbon atom, may form an optionally substituted 3- to 7- membered carbocyle or optionally substituted 3: to 7- membered heterocycle, or each combination of (R20 and R22), (R23 and R24), (R20 and R26), (R27 and R29), (R30 and R31), (R32 and R34), (R85 and R36), (R87 and R38), and (R3%andR"), taken together with the neighboring atom, may form an optionally substituted 5+ to 7- membered carbocyle or optionally substituted 5- to 7- membered heterocycle.
    19. A compound according to Claim 17, pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-1)i one of R20 to R2% is optionally substituted lower alkyl and the others are hydrogens.
    20. A compound according to Claim 17, pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-1); one of (R20 and R22), (R23 and R21), and (R26 and R29), taken together with the neighboring atom, may form an optionally substituted B- to 7- membered carbocyle or optionally substituted 5- to 7: membered heterocycle.
    21. A compound according to Claim 17, pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-1); Z=NR26, and R20 and R26 taken together with the neighboring atom may form an optionally substituted 5- to 7- membered heterocycle. :
    22. A compound according to Claim 17, pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-2); one of R27 to R30 is optionally substituted lower alkyl and the others are hydrogens.
    23. A compound according to Claim 17, pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-2); one of (R27and R29) and (R%0 and R91), taken together with the neighboring atom, may form an optionally substituted 5- to 7- membered carbocyle or optionally substituted 5- to 7- membered heterocycle.
    24. A compound according to Claim 17, pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-2); Z=NR2!I, and R30 and R3! taken together with the neighboring atom may form an optionally substituted 5- to 7- membered heterocycle.
    25. A compound according to Claim 17, pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-3); one of R32 to R39 is optionally substituted lower alkyl and the others are hydrogens.
    26. A compound according to Claim 17, pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-8); one of (R#2andR3),(R35and R96), (R37and R38), and (R32andRA4Y), taken together with the neighboring atom, may form an optionally substituted 5- to 7 membered carbocyle or optionally substituted 5- to 7- membered heteroaycle.
    27. A compound according to Claim 17, pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-3); Z=NR4, and R39 and R40 taken together with the neighboring atom may form an optionally substituted 5- to 7- membered heterocycle.
    28. A compound according to Claim 12, pharmaceutically acceptable salt, or solvate thereof, wherein RX is hydrogen; R!4 is hydrogen or optionally substituted lower; R3 is hydrogen; m is 1 to 3 and at least one of Rs is halogen; A ring is a ring described in
    Claim 17.
    29. A compound according to Claim 12, pharmaceutically acceptable salt, or solvate thereof, wherein R¥ is hydrogen; R!* is hydrogen; R? is hydrogen; mis 0, or 1 to 3 and at least one of R is halogen; A ring is a ring described in Claim 17; R20 to R10 are each independently hydrogen or substituted lower alkyl, or any two groups of R20 to R79, which bonds to the same carbon atom, taken together with the carbon atom, may form an optionally substituted 3- to 7- membered carbocyle or optionally substituted 3- to 7- membered heterocycle, or each combination of (R20 and R22), (R23 and R21), (R25 and R26), (R27 and R29), (R$ and R31), (R32and Ri), (R36 and R39), (R37 and R38), and (R#andR49), taken together with the neighboring carbon atom, may form an optionally substituted 5- to 7- membered carbocyle or optionally substituted 5- to 7+ membered heterocycle.
    30. A compound of the formula: OH 0 : 0 EN N 2 1 D ) ANP x N (1-11) lo) R? (wherein, D ring is optionally substituted heterocycle; R! is hydrogen or lower alkyl; X is a single bond, a heteroatom group selected from O, 8, SO, SO2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group; RR? is optionally substituted aryl; R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino); or a pharmaceutically acceptable salt, or solvate thereof
    31. A compound selected from the group consisting of: (3,112.9 M((2,4-Difluorophenyl) methyll-6-hydroxy-3-methyl-5,7-dioxa-2,3,5,7,11,11a -hexahydro[1,3loxazolo[3,2-alpyrido[1,2- dlpyrazine-8-carboxamide;
    (4a R,1329)- M[(2,4-Difluorophenyl) methyl): 10-hydroxy-9,11-diox0-2,3,4a,5,9,11,13,13a ‘octahydro-1/Fpyrido[1,2-alpyrrolol1',2':3,4}imidazol1,2- dlpyrazine-8-carboxamide; (3a513a9)- MV [(2,4-Diftuorophenylmethyl]-8-hydroxy-7,9-dioxo-1,2,3,3a,4,5,7.9, 13,13a "decahydropyrido(1',2":4,5]pyrazinol1,2-alpyrrolol1,2- dpyrimidine- 10-carboxamide: (4a8 13a )- NV ((2,4-Difluorophenyl)methyll- 10-hydroxy-9,11-dioxo-2,3,4a,5,9, 11,13,18a "octahydro-1/ pyrido[1,2-alpyrrolo[1',2:3,4limidazol1,2- dlpyrazine-8-carboxamide;
    (4a8,13a.R)- NV [(4-Fluorophenyl) methyl) 10-hydroxy-9,11-dioxo0-2,3,44,5,9,11,13,13a-oct ahydro- 1H pyridol1,2-alpyrrolol1',2"3,4)imidazo[1,2- dlpyrazine-8-carboxamide; (35 11a) MN [(2,4-Difluorophenyl)methyll-6-hydroxy-5,7-dioxe-3-(phenylme thyl)-2,3,6, 7,11,11a-hexahydro(1,3loxazolo[8,2- alpyridol1,2- dlpyrazine-8-carboxamide; (3a5, 13a.) V-[(4-Fluorophenyl)methyl]-8-hydroxy-7,9-dioxo-1,2,3,3a,4,5,7,9, 13,13a-de cahydropyrido(1',2"4,5lpyrazino(1,2-alpyrrolo[1,2- dpyrimidine- 10-carboxamide; (85,11a R)- V-[(2,4-Difluorophenylunethyl] *6-hydroxy-3-[(1.9-1-methylpropyl}-5,7-dioxo "2,3,6,7,11,11a-hexahydro[1,8]oxazolol3,2-alpyridol1,2- dlpyrazine-8-carboxamide. 3s, 11a Rf): N[(2,4-Difluorophenyl)methyll-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7, 11,11a -hexahydro(1,3Joxazolo[3,2- alpyridol1,2- dlpyrazine-8-carboxamide; (35,1127) M4 ‘Fluorophenylmethyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7, 11,11a-he xahydro(l,3)oxazolo[8,2- alpyrido[1,2-dlpyrazine-8-carboxamide;
    (3.5,11a.R)-N-[(2,4-Difluorophenyl)methyl)-3-(1,1-dimethylethyl)-6-hydroxy-6,7-dioxo-2 ,3,5,7,11,11a-hexahydrol1,3loxazolol3,2-alpyrido[1,2- dlpyrazine-8-carboxamide; (35,11aR)-3-(1,1-Dimethylethyl)- M-[(4-fluorophenyDmethyl)-6-hydroxy-5,7-dioxo-2,3,5, 7,11,11a-hexahydrol1,3loxazolo(3,2- alpyrido[1,2-dlpyrazine-8-carboxamide; (3S, 11a) -M[(2,4-Difluorophenyl)methyll-6-hydroxy-5,7-dioxo-8-pheny!-2,3,5,7,11,11a -hexahydroll,3loxazolol3,2-alpyrido[1,2-dlpyrazine-8-carboxamide; 35, 11a) N-[(2,4-Difluorophenylmethyll-6-hydroxy-3-(hydroxymethyl)-5,7-dioxo-2,3, 5,7,11,11a-hexahydro(l,3Joxazolo(3,2- alpyrido[1,2- dlpyrazine-8-carboxamide; (28,31) N[(2,4-Diflucrophenyl)methyll-6-hydroxy-3-methyl-5,7-dioxo-2-phenyl-2,3,5,7 ,11,11a-hexahydroll,3loxazolo(3,2- alpyridol1,2- dlpyrazine-8-carboxamide; (3,112.9) N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-(phenylmethyl)-2,3,5, 7,11,11a-hexahydro[1,3loxazolo{8,2- a}pyrido(1,2-dlpyrazine-8-carboxamide; (38,1125) N-((2,4-Difluorophenyl) methyll-6-hydroxy-3-(2-methylpropyl)-5,7-dioxo°2,3, 5,7,11,11a-hexahydro(1,3]loxazolo[8,2-alpyridol1,2-dlpyrazine-8-carboxamide; (5a RB, 14a R)- N-[(2,4-Difluorophenyl)methyll-11-hydroxy-10,12-dioxo-1,2,3,4,5a,6,10,12, 14,14a-decahydropyrido[1,2-alpyrido[1',2':3,4}imidazo[1,2- dlpyrazine-9-carboxamide;
    (25,39) N-[(2,4-Difluorophenylmethyll-6-hydroxy-3-[(methyloxy)methyl]-5,7-dioxo-2-p henyl-2,8,6,7,11,11a-hexahydroll,3]loxazolo[3,2- alpyrido[1,2- dlpyrazine-8-carboxamide
    (3.5, 11a R)-3-(Cyclohexylmethyl)- MV-[(2,4-difluorophenyDmethyl]-6-hydroxy-5,7-dioxo-2, 3,5,7,11,11a-hexahydrol1,3Joxazolo(3,2- al pyrido(l,2-dlpyrazine-8-carboxamide; (85, 11a B)- M[(2,4-Difluorophenyl)mathyll-6-hydroxy-3-(1-methylethyl)-5,7-diox0-2,3,5, 7,31,11a-hexahydroll,3loxazolo{3,2-alpyridol1,2- dlpyrazine-8-carboxamide; (5aR 14a.) N-[(2,4-Difluorophenyl)methyl}l-12-hydroxy-11,13-dioxo-5a,6a,7,11,13,14a" hexahydro-6H-indenol1',2":4,51{1,3)oxazolc(3,2- alpyridol1,2- dlpyrazine-10-carboxamid ei (25,3R,11a9- M[(2,4-Difluorophenyl)methyll-6-hydroxy-5,7-dioxo-2,3-diphenyl-2,8,6,7, 11,11a-hexahydro[1,3)oxazolol[3,2-alpyrido[1,2-dlpyrazine-8-carboxamide; (283,113 RK) -N((2,4-difluorophenyl)methyl}-8-hydroxy-5,7-dioxo-2,3-diphenyl-2,3,5,7, 11,11a-hexahydro(1,3loxazolo[8,2-alpyrido(1,2-dlpyrazine-8-carboxamide;- (3Z, 11a.9)-M[(2,4-Difluorophenyl) methyll-6-hydroxy-3-(1-methylethyl)-5,7-dioxo-2,3,5, 7,11,11a-hexahydro[1,3)oxazolo[3,2- alpyrido[1,2-dlpyrazine-8-carboxamide: (38, 11a R)- N-((2,4-Difluorophenyl)methyl}-6-hydroxy- 3-[2-(inethylthio)ethyl] -5,7-dioxo- 2,3,6,7,11,11a-hexahydrol1,3}oxazolol[3,2-alpyridol1,2-dlpyrazine-8-carboxamide;
    (3.5, 11aR)- NV [(2,4-Difluorophenyl)methyl}-8-hydroxy-8-[2-(methylsulfonyDethyl]-6,7-di 0x0-2,3,5,7,11,11a-hexahydrol1,3loxazolol3,2- alpyrido{1,2- dlpyrazine-8-carboxamide; (38 11a R)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(14-indol-8-ylmethyl)-5,7-dioxo -2,8,5,7,11,11a-hexahydrol[1,3)oxazolol8,2-alpyridol1,2- dlpyrazine-8-carboxamide;
    4.R 12a) MV{{4-fluorophenyl)methyl}-7-hydroxy-4-methyl-1-(2-methylpropyl)-6,8-diox 0'1,2,3,4,6,8,12,12a-octahydropyrido(1',2:4,5]pyrazino{1,2- alpyrimidine-9-carboxamid e; (4R,12a R)- N-{(4-FluorophenyDmethyll-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-diox 0-1,2,3,4,6,8,12,12a-octahydropyrido{1',2':4,5]pyrazinol[1,2- alpyrimidine-9-carboxamid e: .
    (4.51229 -N-[(2,4-Difluorophenyl)methyl}l-7-hydroxy-4-methyl-1-(2-methylpropyl)-6,8- dioxo- 1,2,3,4,6,8,12, 12a-octahydropyrido{1',2':4,6}pyrazino[1,2-alpyrimidine-8-carboxa mide; }
    (4.5,1225)-1-(Cyclopropylmethyl)- V-[(2,4-difluorophenyD)methyll-7-hydroxy-4-methyl-6 ,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido(1',2"4,5)pyrazinol1,2-alpyrimidine-9-carbo xamide;
    (4.51205) M-[(2,4-Difluorophenyl)methyl}-1-(2-furanylmethyl)-7-hydroxy-4-methyl-6,8 -diox0-1,2,3,4,6,8,12,12a-octahydropyrido{1',2":4,6)pyrazinoll,2-alpyrimidine-9-carbox amide;
    (45,12a.8)- N-((2,4-DifluorophenyDmethyll-7-hydroxy-4-methyl-6,8-dioxo-1-(1,3-thiazol- 2-ylmethy})-1,2,3,4,6,8,12,12a-0octahydropyrido[1',2':4,5]pyrazino(1,2- alpyrimidine-9-¢ arboxamide;
    (4a R,6aR, 144.5 N-{(2,4-Difluorophenyl)methyl)- 12-hydroxy-11,13-dioxo-1,3,4,4a,5,6a, 7,11,13,14a-decahydro-2 H-pyrido[1',2':4,6]pyrazino[1,2-2][3, 1]benzoxazine- 10-carboxa mide;
    (4aR,6a2,14a8)- N[(4-FluorophenyDmethyl)-12-hydroxy-11,13-dioxo-1,3,4,4a,5,62,7,11 ,13,14a-decahydro-2.A-pyrido[l’,2':4,6]pyrazino(1,2-a](3, 1)benzoxazine- 10-carboxamide (88,4a2,6a 2,142.9) N[(2,4-Difluorophenyl)methyl}- 12-hydroxy-11,13-dioxo-3-phenyl-1 ,3,4,4a,5,6a,7,11,13,14a-decahydro-2 H-pyrido[1',2:4, 5] pyrazine{1,2-a}{3, 1lbenzoxazine -10-carboxamide; R (4a8,6aS,14a8)-N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-(2-methylpropyl)-11,13-d ioxo0-1,2,3,4,4a,5,6,6a,7,11,18,14a dodecahydropyridol1',2':4,5]pyrazino{l,2-a)quinazoli ne-10-carboxaimide; (6aR,7aS,11a8)-N-[(2,4-Difluorophenyl)methyl)-1-hydroxy-2,13-dioxo-2,6a,7,7a,8,9, 10, 11,11a,13-decahydro-6H-pyridol1',2":4,5]pyrazinol1,2-albenzimidazole-3-carboxamide; (6aS,7a8,11a8)-N-[(2,4-Difluorophenyl)methyl]-1-hydroxy-2, 13-dioxe-2,6a,7,7a,8,9,10, 11,11a,13-decahydro-6H-pyrido(1',2':4,5]pyrazinol1,2-albenzimidazole-3-carboxamide;
    (5a8,14a8) N-{(2,4-Difluorophenylmethyll- 11-hydroxy-10,12-dioxo-1,2,3,4,5a,6,10,12, 14,14a-decahydropyrido[1,2-alpyrido[1',2"8,4}imidazol1,2-d)pyrazine-9-carboxamide; (4aR,14aR)-N-[(2,4-Difluorophenyl)methyl]-9-hydroxy-8, 10-dioxo-2,3,4,4a,5,6,8,10, 1 4, 14a-decahydro- 1H pyrido[1,2-clpyridol1',2':4,5)pyrazino{1,2-alpyrimidine- 11-carboxam ides;
    (4.R,12a R)- MV [(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(3-methylbutyl)-6,8-d © iox0-1,2,8,4,6,8,12,12a octahydropyridel1',24,5)pyrazinol1,2- alpyrimidine-9-carboxa mide;
    (4.5,122.8)- M[(2,4-Difluorophenyl)methyl]l- 7-hydroxy-4-methyl 1-(1-methylethyl)-6,8-di ox0-1,2,3,4,6,8,12,12a octahydropyrido[1',2:4,6lpyrazino(1,2- alpyrimidine-9-carboxam ide;
    (4.5,12a9)- N[(2,4-Difluorophenyl) methyl) 7-hydroxy-4-methyl-1-(3-methylbutyl)-6,8-d ioxo-1,2,3,4,6,8,12,12a-0octahydropyrido[1',2':4,5]pyrazino(1,2- alpyrimidine-9-carboxa mide; (45,122.89) N[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo- 1-(3-pyridinyl methyl)-1,2,3,4,6,8,12,12a octahydropyrido{1',2":4,5lpyrazinol1,2- alpyrimidine-9-carbo xamide;
    (4.5,12a.9)- 1-Cyclopropyl- NV-[(2,4-difluorophenyDmethyl}-7-hydroxy-4-methyl-6,8-dioxo-
    1,2,3,4,6,8,12,12a-octahydropyridoll’,2"4,5]pyrazinoll,2-alpyrimidine-9-carboxamide;
    (4.51229) M[(2,4-Difluorophenyl) methyl]-7-hydroxy-4-methyl- 1-[2-(methyloxy)ethyll- 6,8-diox0-1,2,3,4,6,8,12,12a-octahydropyrido(1',2':4,5]lpyrazinol1,2- alpyrimidine-9-carb oxamide; (3a8,5a5,13a8)-N-[(2,4-Diflucrophenymethyll-11-hydroxy-5-(2-methylpropyl)- 10,12-d iox0-2,8,3a,4,6,5a,6,10,12,13a-decahydro- 1H-cyclopentalelpyridol1',2':4,6]pyrazinoll,2 -alpyrimidine-9-carboxamide; (8R,11a9-M-[(2,4-Difiuorophenyl)methyl]-3-ethyl-6-hydroxy-5,7-dioxo-2,3,6,7,11,11a-h exnhydro(l,3Joxazolo[3,2- alpyridol(1,2-dlpyrazine-8-carboxamide: (4a8,6a8,14aS)-N-{(2,4-Difluorophenyl)methyll-12-hydroxy-6-[2-(4-moxrpholinyl}ethyll- 11,13-dioxo-1,2,3,4,42,5,6,6a,7,11,13,14a-dodecahydropyrido[1',2":4,5]pyrazino[1,2-alq uinazoline-10-carboxamide; (3aR,5aR,13aS)-N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-10,12-dioxo-1,2,3,3a,4, 53, 6,10,12, 13a-decahydrocyclopentaldlpyridol1’,2"4, bipyrazinol2,1-bl[1,3loxazine-9-carbo xamide; (4a5,6a8,14aS8)-N-{(2,4-Difluorophenyl)methyl]-12-hydroxy-6-methyl-11,13-dioxo-1,2,3 ,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1',2":4,5]pyrazinoll,2-alquinazoline-10-car boxamide; (428,6a8,14a8)-N-[(2,4-Diftnorophenyl)methyl]-12-hydroxy-6-(2-(methyloxy)ethyll- 11,
    l3-diexo-1,2,3,4,4a,5,6,6a,7,11,13, 11a dodecahydropyridol1',2":4,5)pyrazinol1,2-alquin azoline-10-carboxamide; . (428,6a8,14a8)-6-[2-(Acetylamino)ethyl]-N-[(2,4-difluorophenyl)methyll- 12-hydroxy- 1 1,13-diox0-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[l',2"4,5]pyrazino(1,2-alqui nazoline*10-carboxamide; (35 11a R)- N-[(2,4-DifluorophenyDmethyl]-3-ethyl-6-hydroxy-5,7-diox0-2,3,5,7,11,11a-h exahydro(l,8Joxazolo(3,2- alpyridol1,2-dlpyrazine-8-carboxamide; (38,112 7)-3-Butyl-M((2,4-difluorophenyl)methyll-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-h -exahydroll,3]Joxazolo[3,2-alpyridol1,2-dlpyrazine-8-carboxamides; (85,112) M[(2,4-Difluorophenyl) methyll-6-hydroxy-3-[(4-hydroxyphenyl)methyll-5,7 dioxo-2,3,5,7,11,11a-hexahydroll,8loxazolol3,2- alpyridoll,2- dlpyrazine-8-carboxsamide (48,12a8)-1-Cyclobutyl-N-[(2,4-difluorophenyl)methyll-7-hydroxy-4-methyl-6,8-dioxo-1 ,2,3,4,6,8,12,12a-octahydropyrido(1',2":4,5]pyrazino(1,2-alpyrimidine-9-carboxamide;
    (4.5,12a8)- M{(2,4-Difluorophenyl)methyll-7-hydroxy-4-methyl-6,8-dioxo" 1-(tetrahydro- 2H thiopyran-4-y1)-1,2,3,4,8,8,12,12a-octahydropyrido{1',2:4,5]pyrazino[1,2- al pyrimid ine-9-carboxamide; (45,1229) N*[(2,4-Difluorophenyl)methyll-7-hydroxy- 1,4-bis(2-methylpropyl)-6,8-dioxo -1,2,3,4,6,8,12,12a-octahydropyridol1',2"4,6]pyrazinoll,2- alpyrimidine-9-carboxamide;
    (4a8,6a8,14a8)-N-[(2,4-Difluorophenyl)methyl)- 12-hydroxy-6-(2-hydroxyethyl)- 11,13-d ioxo-1,2,3,4,4a,5,6,6a,7, 11,13,14a-dodecahydropyridol1',2":4,5]pyrazinol1,2-alquinazoli ne-10-carboxamide; (4a8,6a8, 14aS)-6-Cyclopropy!-N-[(2,4-difluorophenyl)methyl)- 12-hydroxy-11,13-dioxo- 1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyridol1',2" 4,5] pyrazinol1,2-alquinazoline-1 O-carboxamide; (4a8,6a8,14a8)-N-[(2,4-Difluorophenyl)methyl]- 12-hydroxy-11, 18-dioxo-6-[2-(1-pyrroli dinyDethyl]-1,2,8,4,4a,5,6,6a,7,11,13, 14a-dodecahydropyrido[1’,2"4,5lpyrazinoll,2-alq uinazoline-10-carboxamide; (4a8,14a8)-N-1(2,4-Difluorophenyl)methyl]-9-hydroxy-8,10-dioxo-2,3,4,42,5,6,8,10, 14, 1 : 4a-decahydro-1H-pyrido[1,2-clpyrido[1',2"4,6]pyrazino(l,2-alpyrimidine- 11-carboxami de; 48, 12a8)'N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-[2-(methyloxy)ethyl} 6,8 dioxo-1,2,3,4,6,8,12,12a-octahydropyridol1',2':4,5]pyrazinoll,2-alpyrimidine-9-carboxa mide; (4S,12a8)- 1-Cyclobutyl-N-[(4-fluorophenyl)methyl)-7-hydroxy-4-methy}-6,8-dioxo-1,2,3 +4,6,8,12,12a octahydropyrido{1’,2':4,5}pyrazinol1,2-alpyrimidine-9-carboxamide;
    (48,12a8)-N-|(4-Fluorophenyl)methyl)-7-hydroxy-4-methyl-1-(2-methylpropyl)-6,8-diox 0-1,2,3,4,6,8,12,12a-octahydropyridol1',2"i4,5lpyrazinell,2-alpyrimidine-9-carboxamid
    : e; (45,12a9)-N-[(4-Fluoropheny)methyl]-7-hydroxy-1,4-dimethyl-6,8-dioxo- 1,2,3,4,6,8,12 ,12a-octahydropyrido[1',2"4,6]pyrazino{1,2-alpyrimidine-9-carboxamide;
    (48,12a.9)- M[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo- 1-(tetrahydro-2 4 -thiopyran-4-y1)-1,2,3,4,6,8,12,12a-octahydropyridol1',2":4,5)pyrazinoli,2- alpyrimidine “9-carboxamide; ’ (45,1229) M-[(2,4-DifluorophenyDmethyll-7-hydroxy- 1,4-dimethyl-6,8-dioxo-1,2,3,4,6,8 .12,12a-octahydropyrido[1',2':4,5]pyrazinoll,2- alpyrimidine-9-carboxamide; (45,1229) N[(4-Fluorophenyl)methyl}-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo -1,2,3,4,6,8,12,12a-octahydropyrido(1',2%4,5)pyrazinol1,2- alpyrimidine-9-carboxamide; (45,12a.8)- M-[(4-Fluorcphenyl)methyl}-7-hydroxy-1,4-bis(2-methylpropyl)-6,8-dioxo-1,2 ,3,1,6,8,12,12a-octahydropyrido[1',2":4,5lpyrazinol1,2- alpyrimidine-9-carboxamide; enantiomers thereof, diastereomers thereof mixtures of enantiomers thereof] mixtures of diastereomers thereof mixtures of enantiomers and diastereomers thereof; and pharmaceutically acceptable salts thereof.
    32, A compound selected from the group consisting of:
    (42.8132 R)-N[(2,4-DifluorophenyDmethyl]-10-hydroxy-9,11-dioxo-2,3,44,5,9,11,13,13a -octahydro- 1 H-pyrido[1,2-alpyrrolo[1',2':3,4)imidazo[1,2-dlpyrazine-8-carboxamide;
    (4a.5,13a 5) MV [(4-Fluorophenylmethyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13, 13a-0ct ahydro-1 H-pyrido[1,2-alpyrrolo(l',2:3,4limidazo[1,2- dlpyrazine-8-carboxamide;
    . (8.5,11aR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[(1.5)-1-methylpropyll-5,7-dioxo -2,8,5,7,11,11a-hexahydrol1,3loxazclo{3,2- alpyridol1,2-dlpyrazine-8-carboxamide; (35,11aR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a -hexahydroll,8lexazolo[8,2-alpyrido{1,2-dlpyrazine-8-carboxamide; (35,118 B)- N-[{(4-Fluorophenyl)methyll-6-hydroxy-3-methyl-5,7-diox0-2,3,5,7,11,11a he xahydro[1,3]oxazolo[3,2-alpyridol1,2-dlpyrazine-8-carboxamide; (45,1209) N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropyD-6,8- dioxo0-1,2,8,4,6,8,12,12a-octahydropyrido{1’,2":4,6)pyrazino[1,2- alpyrimidine-9-carboxa mide;
    (4.5,12a.9)-1-(Cyclopropylmethyl)- V-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6 ,8-diox0-1,2,8,4,6,8,12,12a-octahydropyrido{1’,2':4,5)pyrazino(1,2- alpyrimidine-9-carbo xamide; (4a R,6aR, 142.5) N-{(2,4-Diflnorophenyl)methyl)-12-hydroxy-11,13-dioxo"1,3,4.4a,5,64, 7,11,13,14a-decahydro-2 H-pyrido[1',2":4,5]pyrazinoll,2-al[3,11benzoxazine- 10-carboxa mide; (4a R,6a 14a.) M[(4-Fluorophenyl)methyl]-12-hydroxy-11,18-dioxo-1,3,4,4a,6,6a,7,11 113,14a-decahydro-2 HF pyrida[1',2":4,61pyrazino(1,2- a][3,1]benzoxazine-10-carboxamide h 45,9aR)-5-Hydroxy-4-methyl-6,10-dioxo-3,4,6,9,9a, 10-hexahydro-2H- 1-oxa-4a, . 8a-diaza-anthracene7-carboxylic acid 2,4,-difluoro-benylamide; 4R,9a8) 5 -Hydroxy-4-methyl-6,1Q-dioxo-8,4,6,9,9a,10-hexahydro-2H- 1-oxa-4a, 8a-dlaza-anthracene-7-carboxylic acid 2,4,-difluoro-benylamide; 2R,92S)-5-Hydroxy-2-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H- 1-oxa-4a, 8a-diaza-anthracene-7-carboxylic acid 4-fluoro-benylamide: enantiomers thercofi diastereomers thereof; mixtures of enantiomers thereof; mixtures of diastereomers thereof, mixtures of enantiomers and diastereomers thereofi and pharmaceutically acceptable salts thereof.
    33. A compound according to claims 31 or 32 wherein the pharmaceutically acceptable salt is a sodium salt.
    34. A pharmaceutical composition comprising a compound according to any one of Claims 1 to 33, or a pharmaceutically acceptable salt, or solvate thereof.
    35. A pharmaceutical composition according to Claim 34, which is an anti-HIV © agent.
    36. A process for the preparation of a compound of formula (I-20a)
    2N [e} 0] B® [o} -~ H = N [s¥Sees H © (1-20a) wherein Re is one or two halogen; Rz is Ci-salkyl, Ces-1marylCi-salkyl, Ceiaaryl, or alkoxy; and P! is Cg-14arylCi-salkyl; comprising condensing a compound of the formula - 1 P~o o H ON" 0or® . N x N A hb
    [0] CHO wherein Re is one or two halogen; R80 is Ci.salkyl; and P1 is Ce-14arylCi-salkyl; with a compound of the formula =H HN OH wherein R# is Ci-salkyl, Ce 14arylCi-salkyl, Ce14aryl, or alkoxy; to form a compound of formula (I-20a).
    37. A process for the preparation of a compound of formula (I-20b) PN Qo O R? lo] x a - NEN Neto H 0 (1-20b) wherein Re is one or two halogen; R# is Ci-salkyl, Ce-1aarylCir-salkyl, Cg-10aryl, or alkoxy: and P! is Ca1sarylCrsalkyli comprising condensing a compound of the formula r ~o Io) Cx ° D or . N x N R® h 0] CHO wherein Re is one or two halogen; R80 is Cisalkyl; and P! is Ce-1aarylCr-salkyls with a compound of the formula rR HN QOH ~ wherein Rz is Crsalkyl, Cs 14arylCrsalkyl, Cs-14aryl, or alkoxy: to form a compound of formula (I-20b),
    38. A process for the preparation of a compound of formula (1-214)
    1 . Po 0 Coo Ks R® N x Shs H © (1-218) wherein Re is one or two halogen; and P! is Ce14arylCr-salkyls comprising condensing a compound of the formula ’ 1 P~o o N x oN R® “NY lo} CHO wherein Re is one or two halogen; R50 is Cy.galkyl; and P! is Ce-1aarylCisalkyl;s with a compound of the formula EN NH, } to form a compound of formula (I-21a).
    39. A process for the preparation of a compound of formula (I-21b)
    P~o o 39 ’ > jie R® x pA Sie o (1-21b) wherein Roe is one or two halogen; and P! is Ce-14arylCi-salkyli comprising condensing a compound of the formula pl So 0 : N NN R h 0] CHO wherein Re is one or two halogen; R% is Cisalkyl; and P! is CeasarylCrsalkyls with a compound of the formula } Gy NH, to form a compound of formula (I-21b). 40, A process for the preparation of a compound of formula ([-22a) IN 0} 0} =F | Ox N o A x Ne H R 3 aN © (i-22a) wherein Re is one or two halogen; and P! is Cg-1sarylCisalkyl; comprising condensing a compound of the formula:
    "To © a IC x -N R® 3 0] CHO wherein Re is one or two halogen; R% is Ci-salkyli and P! is Cs.uaarylCisalkyli with a compound of the formula 2 © toforma compound of formula (1-22a).
    41. A process for the preparation of a compound of formula (I-22b) 1 PYo o : WOT e N x NA N R aN © (1-22b) wherein Re is one or two halogen: and P! is Ce-1aarylCr-salkyl; comprising condensing a compound of the formula 1 PNo 0 N x N R° 3 oO CHO wherein Re is one or two halogen; R30 is Ci-galkyli and P? is CgisarylCisalkyls with a compound of the formula no NH, to form a compound of formula ([-22b), 42, A process for the preparation of a compound of formula (1-232)
    , [a ~o 0 Oxy NH ° N x Nan R 3 H © (1-234) wherein Re is one or two halogen; and P! is Ce-yaarylCi.salkyl; comprising condensing a compound of the formula 1 P~o 0 H Or or® L No AN R hb) lo} CHO wherein Re is one or two halogen; R80 is Ci-salkyl; and P! is Ce11arylCi-salkyl; ‘with a compound of the formula N NH, : to form a compound of formula (1-232).
    43. A process for the preparation of a compound of formula (I-23b) PN © [o] x N RH 0) K x Net R 3 a © (1-23b) wherein Re is one or two halogen; and P! is Cs.jaarylCi-salkyl; comprising condensing a compound of the formula 1 Po 0 Ca JOE N x oN R° 3 o CHO wherein Re is one or two halogen; R80 is C-salkyl; and P! is Ce-1aary)Crsalkyl; with a compound of the formula ~
    H NH, to form a compound of formula (1-23b). 44, A process for the preparation of a compound of formula (I-24a)
    1 . P~o o B H @} EN i) o N _ Nk R 5 N H RY! © (1-242) wherein Re is one or two halogen: R#! is hydrogen, Cus-scycloalkyl, heterocycle, or Ci-salkyl optionally substituted with hydroxy, Cascycloalkyl, alkoxy, heteroeyele, heteroaryl, Cs.a4aryl, or amino, wherein said amino may be optionally substituted with —C(0O)Ci-salkyl or Ci-salkyl; and I’! is Ce-14arylCir.aalkyl; comprising condensing a compound of the formula Po 0 xn -N R® h Di [eo] CHO wherein Re is one or two halogen; R50 is Cisalkyl; and PY is CsqarylCi-salkyl; with a compound of the formula . Rr’ HN HN RY wherein R# is Ciesalkyli R# is hydrogen, Cascycloalkyl, , heterocycle, or Ci-salkyl optionally substituted with hydroxy, Ca.ecycloalkyl, alkoxy, heterocycle, heteroaryl, Cp-saryl, or amino, wherein said amino may be optionally substituted with —C(0)C)-salkyl or Ci-salkyl; to form a compound of the formula (I-24a).
    920, FY Process i0Lr vag preparaviun V1 1 Cup UL LU ULL Wid \L Ly
    PYo o =& SUBS SS = N x Neto H tg © RY (1-24b) wherein Re is one or two halogen; R#! is hydrogen, Csscycloalkyl, heterocycle, or Ci-salkyl optionally substituted_ with hydroxy, Ca-scycloalkyl, alkoxy, heterocycle, heteroaryl, Cs-1saryl, or amino, wherein said amino may be optionally substituted with —C(0)Ci-salkyl or Ci-salkyl: and P! is CgagarylCisalkyls comprising condensing a compound of the formula Po o Q 50 Ck pet R° hb) h [o} CHO . wherein Re is one or two halogen; R80 is Ci-salkyl; and P! is Ce14a1y1Ci-salkyl; with a compound of the formula Rr? wr HN RY wherein R* is Cisalkyli R*! is hydrogen, Ca-scycloalkyl, heterocycle, or Ci-salkyl optionally substituted with hydroxy, Cs-scycloalkyl, alkoxy, heterocycle, heteroaryl, Csasaryl, or amino, wherein said amino may be optionally substituted with —~C(0)C)-salkyl or Ci-salkyl; to form a compound of the formula (I-24b). 46, A process for the preparation of a racemic compound of formula (1-25) NS Oo O DA R® N x Ney 0 H Poel] (I-25)
    wherein Re is one or two halogen; R#! is hydrogen, Caucycloalkyl, heterocycle, or
    Ci.salkyl optionally substituted with hydroxy, Ca-eycloalkyl, alkoxy, heterocycle, heteroaryl, Cy-iiaryl, or amino, wherein said amino may be optionally substituted with —C(0)Ci-salkyl or Ci-salkyli and P! is Cg-1aarylCi-salkyli comprising condensing a compound of the formula 1 Po 0 0 S0 x Ck =-N R® 3 oO CHO wherein Re is one or two halogen; R50 is Ci-salkyl; and P! is CeaaarylCrsalkyls with a racemic compound of the férmula 21 wig” : wherein R#!' is hydrogen, Caccycloalkyl, heterocycle, or Ci-aalkyl opticnally substituted with hydroxy, Csscycloalkyl, alkoxy, heterocycle, heteroaryl, Ceisaryl, or amino, wherein said amino may be optionally substituted with —C(0)Ci-salkyl ox Cr-nalkyls to form a racemic compound of the formula (I-26). 47, A process for the preparation of a racemic compound of formula (I-26) . Po o lr IT ) N x -N AS le} Rr? (I-26) } wherein Re is one or two halogen: R*! is hydrogen, Cs-eeycloalkyl, heterocycle, or Ci-salkyl optionally substituted with hydroxy, Caacycloalkyl, alkoxy, heterocycle, heteroaryl, Ceisaryl, or amino, wherein said amino may be optionally substituted with —-C(0)Ci-salkyl or Cisalkyli and P! is Ce-1aarylCrsealkyli comprising condensing a compound of the formula P~o o . ~N -N ’ R® 3 0 CHO wherein Re is one or two halogen; R% is Crsalkyl; and P! is Ce-14axylCi-salkyl; with a racemic compound of the formula _R* NHN wherein R2! is hydrogen, Cs-ceycloalkyl, heterocycle, or Crsalkyl optionally substituted with hydroxy, Ca-scycloalkyl, alkoxy, heterocycle, heteroaryl, Cq-14aryl, or amino, wherein said amino may be optionally substituted with ~C(O)Ci-salkyl or Ci-salkyls } to form a racemic compound of formula (I-26).
    48. A process for the preparation of a racemic compound of formula (1-27) 1 P~o 0 N SA Pio > 1-27 wherein Re is halogen: and P! is Ce-11arylCi-salkyli comprising condensing a compound of the formula PN O 50 x Ck x-N on R® 3 o] . CHO wherein Re is one or two halogen; R% is Ci-salkyl; and P! is Cg-14arylCi-salkyls : with a racemic compound of the formula
    PCT/UCS2006/016604 NH, OH or to form a racemic compound of formula (I-27).
    49. A compound as claimed in any of claims 1 to 33 for use in medical therapy.
    50. Use of a compound as claimed in any of claims 1 to 33 in the manufacture of a medicament for the treatment or prophylaxis of an HIV infection.
    51. A compound of formula (I-20a) described in Claim 36. formula (I-20b) described in Claim 37, formula (I-21a) described in Claim 38, formula (I-21b) described in Claim 29, formula (1-22a) described in Claim 40, formula (i-22b) described in Claim 41, formula (I-23a) described in Claim 42, formula (I-23b) described in Claim 43, formula (1-242) described in Claim 44, formula (I-24b) described in Claim 45, formula (1-25) described in Claim 46, formula (1-26) described in Claim 47, or formula (I-27) described in Claim 48, ox a pharmaceutically acceptable salt thereof.
    52. A compound of formula (I-20a) described in Claim 36. formula (I-20b) described in Claim 37, formula (I-21a) described in Claim 38, formula (I-21Db) described in Claim 39, formula (1-222) described in Claim 40, formula (1-22b) described in Claim 41, formula (I-23a) described in Claim 42, formula (I-23b) described in Claim 43, formula (1-242) described in Claim 44, formula (I-24b) described in Claim 45, formula (I-25) described in Claim 46, formula (I-26) described in Claim 47, or formula (I-27) described in Claim 48, or a pharmaceutically acceptable salt thereof, wherein each P! is hydrogen.
    53. A pharmaceutical composition according to claim 34 wherein said composition comprises at least one additional therapeutic agent selected from reverse transcriptase inhibitors and protease inhibitors.
    54. Use of a compound according to any of claims 1 to 33 and another therapeutic agent, in the manufacture of a medicament for treatment of an HIV infection in a human 277 AMENDED SHEET
    PCT/US2006/016604
    55. Use according to claim 54 wherein said therapeutic agent is selected from reverse transcriptase inhibitors and protease inhibitors.
    56. A compound according to any one of claims 1 to 33, 49, 51 or 52, substantially as herein described with reference to and as illustrated in any of the examples.
    57. A composition according to any one of claims 34, 35 or 53, substantially as herein described with reference to and as illustrated in any of the examples.
    58. A process according to any one of claims 36 to 48, substantially as herein described with reference to and as illustrated in any of the examples.
    59. Use according to any one of claims 50, 54 or 55, substantially as herein described with reference to and as illustrated in any of the examples. 278 AMENDED SHEET
ZA200708970A 2005-04-28 2007-10-18 Polycyclic carbamoylpyridone derivative having HIV integrase inhibitory activity ZA200708970B (en)

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