WO2005014543A1 - Compose a cycle condense utilise comme inhibiteur de la polymerase du vhc - Google Patents
Compose a cycle condense utilise comme inhibiteur de la polymerase du vhc Download PDFInfo
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- WO2005014543A1 WO2005014543A1 PCT/JP2004/011640 JP2004011640W WO2005014543A1 WO 2005014543 A1 WO2005014543 A1 WO 2005014543A1 JP 2004011640 W JP2004011640 W JP 2004011640W WO 2005014543 A1 WO2005014543 A1 WO 2005014543A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
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- A—HUMAN NECESSITIES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
Definitions
- the present invention relates to a fused ring compound or a pharmaceutically acceptable salt thereof, which exhibits an anti-hepatitis C virus (HCV) activity, particularly an anti-HCV activity by an RNA-dependent RNA polymerase inhibitory activity.
- HCV anti-hepatitis C virus
- the present invention also relates to a hepatitis C virus polymerase inhibitor, an anti-hepatitis C virus agent and a therapeutic agent for hepatitis C, containing the fused ring compound or a pharmaceutically acceptable salt thereof.
- HCV Hepatitis C virus
- HCV infection accounts for a few percent of the world's population, and the infection is characterized by long-term chronicity.
- HCV is an RNA virus having an envelope, and its genome is a single-stranded plus-chain RNA, and is classified into the genus Hepacivirus of the Flaviviridae family (from The International Committee on Taxonomy of Viruses of the International Union of Microbiological Societies).
- HBV hepatitis B virus
- HCV often translocates to persistent infection even when it infects adults with well-developed immune mechanisms, because it evades the host's immune system for reasons that are not yet apparent.
- HCV infection is involved in skin diseases such as chronic measles, lichen planus, and cryoglobulinemia purpura (Nisshin Gakkai, 111 (7), 1075-81, 2001).
- interferon treatment is known as the only effective treatment for HCV elimination.
- interferon treatment is known as the only effective treatment for HCV elimination.
- only one-third of all patients can eliminate the virus with interferon, and it is known that the remaining individuals have no or only temporary effects.
- polyethylene glycol-modified interfaces have been put to practical use, and although their efficacy has been enhanced and side effects have been reduced, their efficiency has still been extremely low.
- anti-HCV drugs that can be used in place of interferon or in combination therewith Expectations are great.
- Ribavirin (1-) 3-D-ribofuranosyl-1H-1,2,4-triazole-13-potorupoxamide has been marketed as a therapeutic agent for hepatitis C in combination with interferon. Although the efficacy of interferon is enhanced, the efficacy is still low, and there is a need for a new therapeutic agent for hepatitis C.
- HCV itself encode proteins such as serine protease, RNA helicase, and RNA-dependent RNA polymerase, and these proteins function as specific proteins essential for the growth of HCV.
- HCV polymerase is an essential enzyme for virus growth.
- HCV gene replication with a plus-strand RNA gene involves first transforming the plus-strand RNA into type II, synthesizing complementary minus-strand RNA, and then amplifying the plus-strand RNA by transforming the minus-strand RNA into type II It is believed to be a procedure. It has been shown that the site called NS5B of the HCV-encoded protein precursor exhibits RNA-dependent RNA polymerase activity (EMB0 J., 15, 12-22, 1996). It is thought to play a central role in gene replication.
- inhibitors of HCV polymerase can be targets for the development of anti-HCV drugs, and expectations for their development are high.
- effective HCV polymerase inhibitors have not yet been developed, and there are still insufficient drugs to treat hepatitis C.
- a compound described in WO 03/010140 is known.
- indole compounds A, B, C, D, etc. are described as anti-HCV agents having polymerase inhibitory activity (Example No. 1 (page 41), 10 (page 51), 14). (Page 57), Compound No. 149 (page 79)).
- WO 03/010141 describes the above compounds and the like as synthetic intermediates of anti-HCV agents having polymerase inhibitory activity (pages 92, 101, 108, 112, 115, 116 page).
- Japanese Patent Application Laid-Open Nos. 2001-247550 (WO 01/47883, EP 1 16 2196A1, US 2003Z0050320) and WO 03/000254 (US 2003/0050320) disclose an anti-HC having a polymerase inhibitory activity.
- V agent the following indole compounds H and the like and benzoimidazole compounds I and the like are described (WOO 3Z000254, Example compound No. 502 (p. 206), 1198 (p. 315)).
- WO 03/000254 further describes the following benzoimidazole compounds KL, M, N, O, etc. (Example compound numbers 371 (page 468), 400 (page 479), 407 (page 480) ), 423, 424 (p. 485)).
- WOO 2Z04.425 describes the following benzoimidazole compound ⁇ and the like as anti-HCV agents having polymerase inhibitory activity (entry Ichiban No. 7005 (p. 228)).
- WO 03/026587 also discloses the following compounds S, T, etc. as anti-HCV agents having polymerase inhibitory activity (Example Nos. 12 (page 56), 65 (page 65)).
- Compound S (Ex.65)
- Compound T (Ex.12)
- therapeutic agents for hepatitis C having a benzimidazole skeleton include W097Z 36866, JP-A-2000-51 1899 (EP 906097), WO 9 /
- the compounds described in 51619 are also known.
- WO 03/007945 also describes benzoimidazole compounds and the like as synthetic intermediates of anti-HCV agents having polymerase inhibitory activity.
- WO 99/09007 and US Pat. No. 5,932,743 describe the following indole compounds U and the like as one chemical library compound that can be used for screening of pharmaceuticals (W099 / 09007, Example 12 (p. 25)).
- compounds with anti-HCV activity are effective in the prevention and treatment of hepatitis C, and in particular, anti-HCV agents with HCV RNA-dependent RNA polymerase inhibitory activity are It has been revealed that the agent can be an effective agent for preventing and treating hepatitis C, and an agent for preventing and treating diseases caused by hepatitis C.
- an object of the present invention is to provide a compound having an anti-HCV action, particularly a compound having an RNA-dependent RNA polymerase inhibitory action.
- the present inventors have conducted intensive studies to find compounds having an anti-HCV action, particularly an RNA-dependent RNA polymerase inhibitory action, and as a result, completed the present invention. More details are as shown in the following [1] to [54].
- G 1 is C (one R 1 ) or a nitrogen atom
- G 2 is C (one R 2 ) or a nitrogen atom
- G 3 is C (one R 3 ) or a nitrogen atom
- G 4 is C (one R 4 ) or a nitrogen atom
- G 5 , GG 8 and G g are each independently a carbon atom or a nitrogen atom, and G 7 may be substituted with C (one R 7 ), an oxygen atom, a sulfur atom, or R 8 Nitrogen atom,
- RR 2 , R 3 and R 4 are each independently:
- R 1D1 represents a hydrogen atom or a group selected from Group C below
- R 102 is a hydrogen atom, a C1-6 alkanoyl group, a C1-6 alkylsulfonyl group, or a C1-6 alkyl group which may be substituted with 1 to 3 substituents selected from Group A below) Means.
- R 1D3 means a group selected from the following group C or a glucuronic acid residue.
- R 1C! 4 and R 105 each independently represent a hydrogen atom, a hydroxyl group, a cyano group, a C1-6 alkoxy group, or a group selected from the following group F.
- R 106 represents a hydroxyl group, an amino group, a C1-6 alkyl group, or a C1-6 alkylamino group
- R 1C 8 represents a hydrogen atom, a C1-6 alkyl group, a hydroxyl group, or a C1-6 alkoxy group which may be substituted with 1 to 3 substituents selected from the following group A. . ),
- R 1M independently represents a hydrogen atom or a group selected from Group C below
- R UQ , R m and R m each independently represent a hydrogen atom or a group selected from Group C below
- R 113 represents a group selected from Group C below
- the heterocyclic group contains 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom.
- R 116 , R m and 118 each independently represent a hydrogen atom or a group selected from the following group C),
- R 119 and R 12 each independently represent a hydrogen atom or a group selected from Group C below), (23)-NR 121 S 0 2 122
- R m and R each independently represent a hydrogen atom or a group selected from Group C below
- R 124 each independently represent a hydrogen atom or a group selected from Group C below
- E 5 represents an oxygen atom, a sulfur atom, or N (-R 126 )
- R 126 represents a hydrogen atom or a C 1-6 alkyl group
- R 125 is a hydrogen atom, Or a C1-6 alkyl group.
- (2 ′ ′) a group selected from the following Darp C,
- R and 1 " 2 each independently represent a hydrogen atom or a group selected from the following group C, and R us represents a group selected from the following group C.) Yes,
- R L2 and R L3 are each independently
- (2 ′ ′) a group selected from the following group C,
- R L14 represents a group selected from the following group F: wherein ring D 1 and ring D 2 are each independently
- the heterocyclic group includes 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom.
- the heterocyclic group contains 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom.
- telo atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom
- R s and R 6 are each independently
- R 116 represents a hydrogen atom or a group selected from Group C below
- R m and R 118 each independently represent a hydrogen atom, a C 1-6 alkanol group, or a group selected from Group C below
- R xl represents a hydrogen atom or a C1-6 alkyl group
- R x2 is a C1-6 alkyl group, a C1-6 alkoxycarbonyl group, or a C1-6 alkylamino group which may be substituted with 1 to 3 substituents selected from Group A below
- 1 represents 0 or an integer of 1 to 6.
- R x3 is a hydrogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 substituents selected from Group A below, or 1 to 3 substituents selected from Group A below)
- x4 and R x5 are each independently a hydrogen atom or a group selected from Group C below
- R x6 is a hydrogen atom or a group selected from the following group C, and q means 0, 1, 2 or 3
- R x7 is a hydrogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 substituents selected from Group A below, or a C1-6 alkanoyl group,
- R x8 is a hydrogen atom or a C 1-6 alkyl group which may be substituted with 1 to 3 substituents selected from Group A below. ),
- R x9 is a hydrogen atom, a C1-6 alkyl group optionally substituted with 1 to 3 substituents selected from Group A below, or a C1-6 alkanol group,
- R xl ° is a hydrogen atom or a group selected from Group C below. ), (17) -N xll - CONR xl2 R x13
- R xll , R xl2 and R xl3 are each independently a hydrogen atom or a group selected from the following group C), or
- heterocyclic group contains 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom
- heterocyclic C 1-6 alkyl group is C 1 -substituted with “heterocyclic group optionally substituted with 1 to 5 substituents selected from group D” as defined above.
- -6 means an alkyl group.
- w is an integer of 1 to 3
- R yl1 and R yl2 each independently represent a hydrogen atom or a group selected from the following group C
- R yl3 means a group selected from the following group C
- R y2 and R y3 are each independently
- (2 ′ ′) a group selected from the following group C,
- R y4 and y5 are each independently
- R yl4 represents a hydrogen atom or a group selected from the following group C
- R yl5 represents a hydrogen atom, a C1-6 alkyl group, a C1-6 alkanol group, or a C6-14 aryl C1 -6 means an alkyloxycarbonyl group.
- ⁇ Pi R ys taken together, may form a C3- 8 consequent Roarukan together with the carbon atoms to which they are attached. ).
- T 1 and T 2 independently represent one NR one, one O— or one S—, and R ′′, R t2 and R ts each independently represent the following group A group selected from D, and k represents an integer of 1 to 4.
- i and j are each independently 0 or an integer of 1 to 4 (provided that the sum of i and j is at least 1);
- R 9 and R 1 () each independently represent a group selected from Group D below. ). ⁇ .
- R al R a2 ⁇ Pi R a4 represents a hydrogen atom, or means CI- 6 alkyl group
- R a3 is C1 - means an alkyl group
- R bl , R b2 and R b4 each independently represent a hydrogen atom or a C 1-6 alkyl group, R b3 represents a C 1-6 alkyl group, and r is 0 or an integer from 1 to 6.
- t independently represents 0 or an integer of 1 to 6
- R d2 is (1) Hydrogen atom or.
- q 0, 1, 2 or 3;
- d3 and R d4 are each independently
- R d6 and R d7 are each independently
- R d8 is a group selected from the following group F,
- R dl3 and R dl4 are each independently
- R dl5 and R dl6 are each independently
- R dl8 is a group selected from the following group F,
- R dl9 and R d2 are each independently
- R d21 , R d22 and R d23 are each independently
- p 0 or an integer of 1 to 6
- the heterocyclic group includes 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom.
- q 0, 1, 2 or 3;
- R e3 and R e4 are each independently:
- R e6 and R e7 are each independently
- R e8 is a group selected from the following group F,
- R el3 and R el4 are each independently: (1) a hydrogen atom or
- R el5 and R el6 are each independently: (1) a hydrogen atom, or
- R el8 is a group selected from the following group F: (0) —NR e19 —COOR e20 ,
- R el9 and R e2 ° are each independently
- R e21, R e22 ⁇ Pi R e23 are each independently
- the heterocyclic group includes 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom.), And.
- (t) It may be a C 1-6 alkyl group which may be substituted with 1 to 3 substituents selected from the group A.
- the heterocyclic group includes 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom.
- heterocyclic C1-6 alkyl group is a C1-6 substituted with a ⁇ heterocyclic group which may be substituted with 1 to 5 substituents selected from Group B '' as defined above. Means an alkyl group
- R 2A is a carboxyl group or a carboxylic acid equivalent, and other symbols are as described in [1].
- R 8 is a C1-6 alkyl group which may be substituted with a group represented by the formula —CONR e6 R e7 (wherein each symbol is as defined in [1]).
- R 8 is a C1-6 alkyl group which may be substituted with a group represented by the formula —CONR e6 R e7 (wherein each symbol is as defined in [1]).
- R 8 is a C 1-6 alkyl group which may be substituted with a group represented by the formula: COR e8 (wherein R e8 is as described in [1]). Or a pharmaceutically acceptable salt thereof.
- 2-oxo-1 [4- (1-pyrrolidinyl) piperidine-1 1-yl] ethyl, 2- (3,3-dihydroxypiperazine-1-11-yl) 1-2-oxoethyl, 2- (4- 1-yl-methylbiperazine) 1- 2-oxoethyl, 2— (4-methoxypiperidine) —2-oxoxethyl,
- u 1 is an integer of 1 to 6, and other symbols are as described in [1].
- R 8 has the formula - NR e9 CO- R el ° ( . Wherein each symbol is located through Ride according to [1]) may be substituted with a group represented by C1- 6
- R 2 force carboxyl group, one COOR ONHSO 2 —R m , one SO 2 NHCO—R 115 , or a heterocyclic group which may be substituted with 1 to 5 substituents selected from group B (where each symbol is as defined in [1] Or the pharmaceutically acceptable salt thereof according to [22].
- T is _ ⁇ "_, one S—, one SO—, one SO 2— , one O—, one T 1
- a heterocyclic group optionally substituted with 1 to 5 substituents selected from group D, a C1-6 alkyl optionally substituted with 1 to 3 substituents selected from group A Group,
- a pharmaceutical composition comprising the compound according to any one of [1] to [36] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- a hepatitis C virus polymerase inhibitor comprising, as an active ingredient, the compound according to any one of [1] to [36] or a pharmaceutically acceptable salt thereof.
- An anti-hepatitis C virus agent comprising as an active ingredient the compound according to any one of [1] to [36] or a pharmaceutically acceptable salt thereof.
- a therapeutic agent for hepatitis C comprising as an active ingredient the compound according to any one of [1] to [36] or a pharmaceutically acceptable salt thereof.
- a therapeutic agent for hepatitis C comprising the combination of (a) the hepatitis C virus polymerase inhibitor according to [38] and (b) interferon.
- An anti-hepatitis C virus agent comprising the combination of the anti-hepatitis C virus agent according to (a) [39] and (b) interferon.
- a pharmaceutical composition comprising at least one drug selected from the group consisting of
- a method for treating hepatitis C comprising administering to a mammal an effective amount of the compound according to any of [1] to [36] or a pharmaceutically acceptable salt thereof.
- a method for inhibiting hepatitis C virus polymerase comprising administering to a mammal an effective amount of the compound according to any of [1] to [36] or a pharmaceutically acceptable salt thereof.
- halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and is preferably a fluorine atom, a chlorine atom or a bromine atom.
- the “C1-6 alkyl group” represents a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and is preferably a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms. Specifically, methyl, ethyl, propyl, isopropyl, butyl, isoptyl, Examples thereof include sec-butinole group, tert-butinole group, pentinole group, isopentinole group, tert-pentyl group, and hexyl group.
- C 2 6 alkenyl group is a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, Bulle group, Ariru group, 1 one propenyl group, isopropenyl group, 1-pteninole group, 2-butulyl group, 1,3-ptagel group, 2-isopentyl group, 3-isohexenyl group, 4-methyl-3-pentulle group,
- C 2-6 alkynyl group is a straight-chain or branched-chain alkynyl group having 2 to 6 carbon atoms, specifically, an ethur group, a 1-propenyl group, a 2-propenyl group, a 3-butynyl group and the like. Is mentioned.
- the “halogenated C 1-6 alkyl group” is a group in which the above-defined “C 1-6 alkyl group” is substituted by the above-defined “halogen atom”, and preferably, the alkyl moiety has a carbon number of It is a halogenated alkyl group which is 1 to 4 linear or branched alkyl groups. Specific examples include a fluoromethyl group, a difluoromethyl group, a trifluoromethylinole group, a bromomethyl group, a chloromethyi / le group, a 1,2-dichloroethynole group, a 2,2-dichloromethylethyl group, a 2,2,2-trifluoroethyl group, and the like. Is mentioned.
- C 1-6 alkylene refers to straight-chain alkylene having 1 to 6 carbon atoms, and includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene, and hexamethylene.
- C 2-6 alkenylene refers to linear alkenylene having 2 to 6 carbon atoms, and examples thereof include bi-lene, propenylene, 1-ptenylene, and 1,3-ptagenylene.
- the “C 1-6 alkoxy group” is an alkyloxy group whose alkyl moiety is the “C 1-6 alkyl group” as defined above, and preferably, the alkyl moiety is a straight-chain having 1 to 4 carbon atoms. Or an alkoxy group which is a branched alkyl group. Specific examples include a methoxy group, an ethoxy group, a propoxy group, an isopropyloxy group, a butoxy group, an isobutyloxy group, a tert-butyloxy group, a pentyloxy group, and a hexyloxy group.
- C 1-6 alkoxy C 1-6 alkoxy group is defined as above wherein “C 6 alkoxy group” is substituted by “C 1-6 alkoxy group” as defined above, and is preferably Is an alkyloxyalkyloxy group whose alkyl moiety is a linear or branched alkyl group having 1 to 4 carbon atoms. Specific examples include a methoxymethoxy group, an ethoxymethoxy group, a 1- (methoxy) ethoxy group, a 2- (methoxy) ethoxy group. A methoxypropoxy group, an isopropyloxyethoxy group and the like.
- the “C 1-6 alkanoyl group” is an alkyl-carbonyl group whose alkyl moiety is the “C 1-6 alkyl group” as defined above, and preferably the alkyl moiety is a straight-chain having 1 to 4 carbon atoms. Or an alkynyl group which is a branched alkyl group. Specific examples include an acetyl group, a propionyl group, a butyryl group, an isoptyryl group, and a pipeparyl group.
- C 1-6 alkoxycarbonyl group means that the alkoxy moiety is defined as above “
- alkyloxycarbonyl group which is a “C 1-6 alkoxy group”, and preferably an alkoxycanoleponyl group in which the alkyl moiety is a linear or branched alkyl group having 1 to 4 carbon atoms.
- methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropyloxycarbonyl group, putoxycanoleponinole group, isoptinoleoxycanoleponinole group, tert-butynoleoxy force examples include a norbornyl group, a pentyloxycarbonyl group, and a hexyloxycarbonyl group.
- the “C 1-6 alkylamino group” is an alkylamino group or a dialkylamino group whose alkyl moiety is the “C 1-6 alkyl group” defined above, and preferably the alkyl moiety Is an alkylamino group or a dialkylamino group which is a linear or branched alkyl group having 1 to 4 carbon atoms.
- Examples include an N-methylamino group, an N-isobutyl-N-isopropylamino group, and the like.
- an “rC 1-6 alkanoylamino group” is an alkyl-carboyl-amino group whose alkanoyl moiety is ⁇ C 1-6 alkanoyl group as defined above, and preferably the alkyl moiety has 1 carbon atom.
- C.4 to C.4 alkyl carbamino groups which are linear or branched alkyl groups.
- acetylamino, propionyl Examples include an amino group, a petyrylamino group, an isobutyrylamino group, a piperoylamino group, and the like.
- the “C 1-6 alkylsulfonyl group” is an alkyl-sulfonyl group whose alkyl moiety is the “C 1-6 alkyl group” defined above, and preferably the alkyl moiety has 1 to 4 carbon atoms.
- An alkylsulfonyl group which is a linear or branched alkyl group.
- Specific examples include a methanesulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, a butylsulfonyl group, an isobutylsulfonyl group, a tert-butylsulfonyl group, a pentylsulfonyl group, and a hexylsulfonyl group.
- a methanesulfonyl group an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, a butylsulfonyl group, an isobutylsulfonyl group, a tert-butylsulfonyl group, a pentylsulfonyl group, and a hexylsul
- the “C 6-14 aryl group” is an aromatic hydrocarbon group having 6 to 14 carbon atoms, specifically, phenyl, naphthyl, anthryl, indul, azulenyl, fluorenyl, and phenanthryl groups. And a phenyl group.
- the “C 3-8 cycloalkyl group” is a saturated cycloalkyl group having 3 to 8, preferably 5 to 7 carbon atoms, specifically, a cyclopropyl group, a cyclobutyl group.
- the “C 3-8 cycloalkenyl group” is a cycloalkenyl group having 3 to 8, preferably 5 to 7 carbon atoms, and contains at least one, preferably one or two double bonds.
- C 6-14 aryl C 1-6 alkyloxycarbonyl group means that the alkyl part is “C 1-6 alkyl group” as defined above, and the aryl moiety is “C 6-alkyl group” as defined above. 14 aryl group, which is an aryl-alkyl-oxycarbyl group.
- the alkyl moiety is a linear alkyl group having 1 to 4 carbon atoms, and the aryl moiety is an arylalkyloxycarbonyl group which is a phenyl group.
- a benzyloxycarbonyl group a phenethyloxycarbonyl group, a 3-phenylpropyloxycarbonyl group, a 2-phenylpropyloxycarbonyl group. 4-phenylphenyloxycarbonyl And the like.
- bond means a direct connection. For example, in one O—L 1 —P h, when L 1 is “bond”, it means one O—P h.
- diarctic acid residue refers to the remaining group other than any of the hydroxyl groups of dulctic acid, and is preferably a group substituted at the 1-position of / 3-D-glucuronic acid.
- Heterocyclic group and “heterocyclic group containing 1 to 4 heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom” mean, in addition to carbon atom, Has 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms, and has 3 to 14 ring-forming atoms, and is a saturated ring, an unsaturated ring, or a monocyclic ring. And fused rings.
- the monocyclic heterocyclic group examples include a pyridyl group, a pyrazul group, a pyrimidinyl group, a pyridazinyl group, a 1,3,5-triazinyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, and a triazolyl group (1 , 2,3-triazolyl group, 1,2,4-triazolyl group), tetrazolyl group, chenyl group, furyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, oxaziazolyl group (1,2,4_oxaziazolyl group) Group, 1,3,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, thiadiazolyl group (1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,5-
- the heterocycle also includes a group represented by the following formula.
- E 1 is an oxygen atom, a sulfur atom or NH
- E 2 is an oxygen atom, CH 2 or NH
- E 3 is an oxygen atom or a sulfur atom, where f is an integer of 1 to 3
- h and h are the same or different and are each an integer of 1 to 3.
- heterocyclic group which is a condensed ring examples include a quinolyl group, an isoquinolyl group, a quinazolyl group, a quinoxalyl group, a phthalagel group, a cinnolinyl group, a naphthyridinyl group, and a 5,6,7,8-tetrahydroquinolyl group.
- the C 3-8 cycloalkane moiety is cyclopropane, cyclobutane, cyclopentane, cyclohexane , Cycloheptane and cyclootatan.
- the cycloalkane moiety is preferably cyclopropane.
- Ra al and Ra 2 each independently represent a hydrogen atom or a ⁇ C1-6 alkyl group '' as defined above, and Ra 3 represents a ⁇ Cl-6 alkyl group '' as defined above.
- Ra 3 represents a ⁇ Cl-6 alkyl group '' as defined above.
- -NR al R a2 for example, amino group, methylamino group, ethylamino group, isopyramino group, dimethylamino group, ethylamino group, diisopropylamino group, ditert-butylamino group, N-ethylamino-methylamino group, etc.
- (6) -COOR al for example, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, an isopropyloxycarbonyl group, a tert-butoxycarbonyl group, etc.
- - CONR al R a2 e.g., force Rubamoiru group, a methyl Scarpa moil group, Echiru Karupamoiru group, an isopropyl Scarpa moil group, dimethylcarbamoyl group, Jefferies Chirukarupamoiru group, diisopropyl Scarpa moil group, di-tert- Puchirukaru Bamoiru group, N —Ethyl—N-methylcarbamoyl group),
- Group B refers to the following substituent groups (1) to (21).
- R bl , R b2 and R M each independently represent a hydrogen atom or a ⁇ C1-6 alkyl group '' as defined above, and R b3 represents a ⁇ C1-6 alkyl group '' as defined above.
- r is 0 or an integer of 1 to 6.
- (16)-(CH 2 ) r -CON bl -SO 2 R b3 for example, methanesulfonylcarbamoyl group, ethylsulfurcarbamoyl group, isopropylsulfonylcarbamoyl group, tert-butylsulfonylcarbamoyl group, N-methyl-N- (methanesulfonyl) carbamoyl group, methanesulfonylcarbamoylmethyl group, 2- (ethylsulfonylcarbamoyl) ethyl group, etc.),
- N-OR bl for example, hydroxyimino group, methoxyimino group, ethoxyimino group, isopropyloxyimino group, tert-butoxyimino group, etc.
- (21)-(CH 2 ) r -SO b3 for example, methanesulfinyl group, ethylsulfinyl group, isopropylpropylsulfinyl group, tert-butylsulfinyl group, methanesulfinylmethyl group, 2- (ethylsulfinyl) ethyl Group etc.).
- C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from group A refers to “C 1-6 alkyl group” defined as above “Group A” defined above. It may be substituted by one to three selected substituents, and includes an unsubstituted alkyl group.
- 3-hydroxypropyl group 4-hydroxybutyl group, 1-hydroxy-1-methylethyl group, 1-hydroxypropane-1-yl group, 1,3-dihydroxypropyl-pan-2-yl group , 1-hydroxy-2-methylpropane-12-yl group, carboxymethyl group, ethoxycarbonylmethyl group, 2-carboxyethyl group, methoxymethyl group, methoxethyl group, methoxyethoxyl group, ethoxycarbo Nylmethyl group, 2-ethoxycarbonylethyl group, 2-dimethylaminoethyl group, rubamoylmethyl group, methylcarbamoylmethyl group, sulfomethyl group, sulfamoinolemethinole group, 2-sunolefamoineoletinole group, methinoles reference Moinolemethinole group and the like.
- C2-6 alkenyl group optionally substituted with 1 to 3 substituents selected from Group A includes “C 2-6 alkenyl group” as defined above, and “Group A” as defined above. Which may be substituted with 1 to 3 substituents selected from Contains alkenyl groups.
- C 2-6 alkyl group optionally substituted with 1 to 3 substituents selected from group A means “C 2-6 alkynyl group” as defined above.
- A may be substituted with one to three substituents selected from” A ", and includes an unsubstituted alkynyl group.
- Specific examples include an ethyl group, a 1-propynyl group, a 2-propyl group, and a 3-butyl group.
- C 6-14 aryl group which may be substituted with 1 to 5 substituents selected from group B refers to “C 6-14 aryl group” as defined above; It may be substituted with 1 to 5 selected substituents, and includes an unsubstituted aryl group.
- C 3-8 cycle optionally substituted with 1 to 5 substituents selected from group B
- ⁇ mouth alkyl group '' means a ⁇ C 3-8 cycloalkyl group '' as defined above, which may be substituted with 1 to 5 substituents selected from ⁇ group B '' as defined above, Contains cycloalkyl groups.
- C 3-8 cycloalkenyl group optionally substituted with 1 to 5 substituents selected from group B refers to “C 3-8 cycloalkenyl group” defined above. And may be substituted with 1 to 5 substituents selected from the group consisting of an unsubstituted cycloalkenyl group.
- heterocyclic group which may be substituted with 1 to 5 substituents selected from group B
- heterocyclic group as defined above
- 1 to 5 selected from “group B” as defined above may be substituted with an unsubstituted heterocyclic group.
- the preferred ⁇ heterocyclic group optionally substituted with 1 to 5 substituents selected from group B '' in ring Cy is ((a C) b
- E 4 is an oxygen atom, a sulfur atom, CH 2 or N (— R Cyl ), wherein R 1 is a hydrogen atom or a C 1-6 alkyl group, and a and b are each independently To represent an integer of 1 to 3.
- a pyrrolidur group an imidazoliduryl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a thiomorpholyl group, a tetrahydrovinylyl group, a tetrahydrodotiopyranyl group, a 1-oxotetrahydrothiopyranyl group, a 1,1 And a dioxotetrahydrothiopyrael group.
- C 6-14 aryl C 1-6 alkyl group optionally substituted with 1 to 5 substituents selected from group B refers to “C 1-6 alkyl group” defined above. It is substituted with “C 6-14 aryl group which may be substituted with 1 to 5 substituents selected from group B”.
- benzyl group 1-naphthylmethyl group, 2-naphthylmethyl group, phenyl group, 3-phenylpropyl group, 2-phenylpropyl group, 3-fluorobenzinole group, 4-fluoronorbenole group
- Benzene 3-chlorobenzene, 4,4-cyclobenzene, 3,5-cyclobenzene, pentafluorobenzene, 4-methylbenzyl Group, 4-tert-butylbenzyl group, 2-trifluoromethylbenzyl group, 4-trifluoromethylbenzyl group, 412 trobenzyl group, 4-cyanobenzyl group, 4-acetylbenzyl group, 4-hydroxybenzyl, 4-aminobenzyl, 4-aminobenzyl, 4-methylaminobenzyl, 4-acetylaminobenzyl, 4- (methylsulfonylamino) benzyl 4-Methoxybenzyl group, 3,4,5-Trimethoxy
- heterocyclic C 1-6 alkyl group optionally substituted with 1 to 5 substituents selected from group B is defined as the “C 1-6 alkyl group” defined above, And a heterocyclic group which may be substituted with 1 to 5 substituents selected from Group B.
- 3-hydroxypyrrolidinylmethyl group 2- (4-hydroxypiperidino) Tyl group, 1- (tert-butoxycarbonyl) piperidine-1-ylmethyl group, 1-acetylbiperidine-14-ylmethyl group, 1-methylsulfonylpiperidine-14-ylmethyl group, piperazinyl Examples include a methyl group, a morpholinomethyl group, a thiomorpholinylmethyl group, a 2-tetrahydropyraelmethyl group, a 2-quinolylmethyl group, and a 1-isoquinolylmethyl group.
- the ⁇ C 3-8 cycloalkyl C 1-6 alkyl group which may be substituted with 1 to 5 substituents selected from Group B '' is the above-defined ⁇ C 1-6 alkyl group '' It is a group substituted by "C 3-8 cycloalkyl group optionally substituted with 1 to 5 substituents selected from group B" in the definition.
- Pentylmethyl group of 2-methyl mouth 3-Methylcyclohexyl Methyl group, 4-methylcyclohexylmethyl group, 4,4-dimethylcyclohexylmethyl group, 3,5-dimethylcyclohexylmethyl group, 4-tert-butylcyclohexylmethyl group, 4-hydroxycyclohexylmethyl group, 4-methoxycyclohexane Xinolemethynole group and 2,3,4,5,6-pentafluoro / reolocyclohexylmethyl group.
- Group C refers to the following substituent groups (1) to (3).
- Group F refers to the following substituent groups (1) to (7).
- Group D refers to the following substituent groups (a) to (u).
- q 0, 1, 2 or 3.
- R d6 and R d7 are each independently
- R d8 is a “group selected from group F” as defined above).
- R dl2 is (1) Hydrogen atom or.
- R dl3 and R dl4 are each independently
- R dl5 and Rdl 6 are each independently
- R dl8 is a “group selected from group F” as defined above, (For example, the substitution group, trifluoroacetylsulfamoyl group, 2- (dimethylamino) ethylsulfamoyl group, benzoyls, the substitution group mentioned in “One (CH 2 ) r — SO 2 NR bl — COR b2 ” of Group B Rufamoyl group, phenylacetylsulfamoyl group, 3-morpholinopropionylsulfamoyl group, N-acetyl-1-N-benzyles / refamoinole group, etc.)
- R dl9 and R d2fl are each independently
- R d21 , R d22 and R d23 are each independently
- p means 0 or an integer of 1 to 6.
- Group E refers to the following substituent groups (a) to (t).
- ⁇ C2-6 alkynyl group optionally substituted with 1 to 3 substituents selected from group A '' as defined above, (For example, hydroxyl, methoxy, ethoxy, isopropyloxy, tert-butyloxy, trifluoromethyloxy, methoxymethoxy, phenoxy, benzyloxy, 4-pyridylmethoxy, 4- Carboxybenzyloxy, buroxy, ethuroxy, etc.)
- q 0, 1, 2 or 3.
- mercapto group methylsulfuryl group, methanesulfonyl group, ethylsulfonyl group, isopropylsulfonyl group, tert-butylsulfonyl group, methylsulfinyl group, sulfo group, trifluoromethanesulfonyl group, 2- (methylamino ) Ethylsulfonyl, 2- (dimethylamino) ethylsulfonyl, 3- (dimethylamino) propylsulfonyl, phenylsulfonyl, 4-tolylsulfonyl, benzylsulfonyl, etc.
- R e3 and R e4 are each independently:
- amino group methylamino group, ethylamino group, isopropylamino group, dimethylamino group, ethylamino group, diisopropylamino group, ditert-butylamino group, N-ethyl-1-N-methylamino group, fueramino group, benzyloxyamino group, Toximethylamino, N-ethyl-N- (carbamoylmethyl) amino, N-ethyl-N— [2- (acetylamino) ethyl] Amino, N— [2-amino-2- (dimethylcarbamoyl) ethyl] N-ethylamino group, N, N-bis (aminomethyl) amino group, etc.
- R e6 and R e7 are each independently
- R e8 is a “group selected from group F” as defined above).
- sulfamoyl group methylsulfamoyl group, ethylsulfamoyl famoyl group, diisopropylsulfamoyl group, ditert-butylsnorrefamoyl group, trifluoromethylsulfamoyl group, 2- (dimethylamino) ethylsulfamoyl Tomb, phenylsulfamoyl group, benzylsulfamoyl group, 2-morpholinoethylsulfamoyl group, etc.) (ni) —CONR e15 —SO 2 R el6 , where R el5 and R el6 are each independently ,
- R el8 is a “group selected from group F” as defined above,
- R el9 and R e2 ° are each independently
- R e21, R e22 ⁇ Pi R e23 are each independently
- ureido 3-methylureido, 3-ethylureido, 3-isopropylureido, 3,3-dimethylureido, 3,3-getylperido, 3,3-diisopropylureido, 3 , 3-ditert-butylperido group, 3-ethyl-13-methylureido group, 1,3-dimethylureido group, trimethylperido group, etc.
- a group selected from the following group F (for example, hydroxyimino group, methoxyimino group, ethoxyimino group, isopropyloxyimino group, tert-butoxyimino group, etc.).
- (t) It may be a C 1-6 alkyl group which may be substituted with 1 to 3 substituents selected from the group A.
- C 6-14 aryl group which may be substituted with 1 to 5 substituents selected from group D refers to “C 6-14 aryl group” as defined above, and “group D” as defined above. And may be substituted with 1 to 5 substituents selected from the group consisting of an unsubstituted aryl group.
- C 3-8 cycloalkyl group which may be substituted with 1 to 5 substituents selected from Group D refers to “C 3-8 cycloalkyl group” defined as above, It may be substituted with 1 to 5 substituents selected from Group D, and includes an unsubstituted cycloalkyl group.
- positions 3, 4, 5 and 6 of the 2-pyridyl group, positions 2, 4, 5 and 6 of the 3-pyridyl group, positions 2, 3, 5 and 6 of the 4-pyridyl group and positions of the 2-chelyl group Fluorine atom, chlorine atom, bromine atom, nitro group, methyl group, tert-butyl group, carboxyl group, trifluoromethyl group, hydroxy at the 2, 4 or 5 position of the 3, 4- or 5-position, 3-Chenyl group Examples thereof include those substituted with a methyl group, a methoxymethyl group, a 2-carboxyethyl group, a methoxy group, a carpamoyl group, a methylthio group, a dimethylaminocarponyl group, a methylsulfonyl group, an amino group or an acetylamino group.
- C 6-14 aryl C 1-6 alkyl group optionally substituted with 1 to 5 substituents selected from Group D means “C 1-6 alkyl group” defined above. "C 6-14 may be substituted with 1 to 5 substituents selected from Group D Reel group ".
- benzyl group 1-naphthylmethyl group, 2-naphthylmethyl group, phenethyl group, 3-phenylpropyl group, 2-phenylpropyl group, 3-fluorobenzinole group, 4-funolenobenzinole group , 3-chlorobenzene group, 4-chlorobenzene group, 4,5-dichlorobenzene group, 4-dichlorobenzene group, 4-promobenzene group, 4-nitrobenzene group Benzene group, pentaphnolenobenzinole group, 4-methylinobenzyl group, 4-tert-butylbenzyl group, 2-trifluoromethylbenzyl group, 4-trifluoromethylbenzyl group, 4- (hydroxymethyl) benzyl group 4-(Methoxymethyl) benzyl group, 4- (2-carboxyethyl) benzyl group.
- heterocyclic C 1-6 alkyl group optionally substituted with 1 to 5 substituents selected from Group D refers to the “C 1-6 alkyl group” defined above. And substituted with 1 to 5 substituents selected from group D.
- C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from group E refers to “C 1-6 alkyl group” defined as above “Group E” defined above. It may be substituted by one to three selected substituents, and includes an unsubstituted alkyl group.
- C 2-6 alkenyl group optionally substituted with 1 to 3 substituents selected from group E is defined as “C 2-6 alkenyl group” 1S as defined above. E "may be substituted with one to three substituents selected from the group consisting of unsubstituted alkenyl groups.
- C 6-14 aryl group which may be substituted with 1 to 5 substituents selected from group E refers to “C 6-14 aryl group” defined above. It may be substituted with 1 to 5 selected substituents, and includes an unsubstituted aryl group.
- C 3-8 cycloalkyl group optionally substituted with 1 to 5 substituents selected from Group E refers to “C 3-8 cycloalkyl” 1S as defined above. And may be substituted with 1 to 5 substituents selected from Includes substituted alkyl groups.
- a fluorine atom, a chlorine atom, a bromine atom, a -toro group, a methyl group, a tert-butyl group, a carboxynole group, a triflorenomethyl group, a hydroxymethyl group, a methoxymethyl group, a 2-hydroxyloxyl group are added to a cyclopentyl group or a cyclohexyl group.
- those substituted with a methoxy group, a carbamoyl group, a methylthio group, a dimethylaminocarbonyl group, a methylsulfonyl group or an acetylamino group are substituted with a methoxy group, a carbamoyl group, a methylthio group, a dimethylaminocarbonyl group, a methylsulfonyl group or an acetylamino group.
- a heterocyclic group which may be substituted with 1 to 5 substituents selected from Group E refers to "heterocyclic group” defined above. 1 to 5 selected from “Group E” defined above. And may include an unsubstituted heterocyclic group.
- Carboxylic acid equivalent means a biological equivalent here, and may be any substituent having the same polar effect as carboxylic acid.
- carboxylic acid means a biological equivalent here, and may be any substituent having the same polar effect as carboxylic acid.
- R 1Q6 represents a hydroxyl group, an amino group, or a C1-6 alkylamino group
- R 107 ′ means an amino group or a C 1-6 alkylamino group
- -P O
- OH OH
- R 1G9 represents a hydrogen atom or a substituent selected from the above group C.
- R 111 and R 112 each independently represent a hydrogen atom or a substituent selected from the above group C).
Abstract
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