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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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  • 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
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
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  • 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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  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
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  • C07K14/08—RNA viruses
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Definitions

• the present invention relates to compounds exhibiting coronavirus 3CL protease inhibitory activity and pharmaceutical compositions containing compounds exhibiting coronavirus 3CL protease inhibitory activity.
• the coronavirus which belongs to the subfamily Orthocoronavirus subfamily, Coronaviridae, order of the Nidoviridae, has a genome size of about 30 kilobases, and is the largest single-stranded + stranded RNA virus among known RNA viruses.
• Coronaviruses are classified into four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus, and there are two types of coronaviruses that infect humans: Alphacoronavirus (HCoV-229E, HCoV-229E, HCoV -NL63) and five members of the genus Betacoronavirus (HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, SARS-CoV-2).
• HCoV-229E HCoV-NL63, HCoV-HKU1, HCoV-OC43
• SARS severe acute respiratory syndrome
• MERS Middle East respiratory syndrome coronavirus
• SARS-CoV novel coronavirus
• Non-Patent Document 1 The novel coronavirus disease (COVID-19) that broke out in Wuhan, China in December 2019 spread rapidly throughout the international community, and was declared a pandemic by the WHO on March 11, 2020. As of September 6, 2022, the number of confirmed infected people reached 600 million or more, and the number of deaths reached 6.5 million or more (Non-Patent Document 1). Droplet infection, contact infection and aerosol infection have been reported as the main infection routes of SARS-CoV-2. (Non-Patent Document 2). The incubation period is about 2 to 14 days, and cold-like symptoms such as fever (87.9%), dry cough (67.7%), malaise (38.1%), and phlegm (33.4%) are typical. (Non-Patent Document 3). In severe cases, respiratory failure due to acute respiratory distress syndrome, acute lung injury, interstitial pneumonia, etc. occurs. Multiple organ failures such as renal failure and liver failure have also been reported.
• Coronaviruses synthesize two polyproteins when they infect cells. Included in these two polyproteins are the replication complexes that make up the viral genome, and two proteases. Protease plays an essential role in cleaving polyproteins synthesized from viruses and allowing each protein to function. Of the two proteases, 3CL protease (main protease) is responsible for most of the polyprotein cleavage (Non-Patent Document 4). For COVID-19 therapeutics targeting 3CL protease, in June 2021, Pfizer completed a Phase 1b trial of Lufotrelvir (PF-07304814), a prodrug of PF-00835231, at ClinicalTrials. gov (NCT04535167).
• PF-00835231 Lufotrelvir
• PF-07321332 In December 2021, PAXLOVID(TM) was granted Emergency Use Authorization in the United States, and on February 10, 2022, Paxlovid(R) pack was granted special approval in Japan.
• Non-Patent Documents 5-8 and 13-16 Although compounds with 3CL protease inhibitory activity are disclosed in Non-Patent Documents 5-8 and 13-16, none of these documents describe or suggest compounds that are relevant to the present invention.
• Patent Document 1 discloses a derivative having a ⁇ 2X3 receptor inhibitory activity, it does not describe or suggest 3CL protease inhibitory activity or antiviral effect.
• Non-Patent Document 9 and Patent Documents 2 and 5-8 describe compounds having structures similar to the compounds of the present invention, but neither describe nor suggest 3CL protease inhibitory activity and antiviral effects. do not have.
• An object of the present invention is to provide compounds having coronavirus 3CL protease inhibitory activity.
• the present invention provides a compound having an antiviral effect, particularly a coronavirus growth-inhibiting effect, and a medicament containing the compound.
• the present invention relates to the following.
• Ring A is (Wherein, carbon atom a, carbon atom b, R 3a , R 3b , R 6 , R 7 , R 7′ , R 8 , R 9 , R 9′ , s and p are the above items (1′′′) or a pharmaceutically acceptable salt thereof according to the above item (1'''), which is a ring represented by ).
• R 3a and R 3b are each independently (wherein Y is CR 10h R 10h′ or O; t is an integer from 0 to 5, Each R 10a is independently halogen, cyano, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted sulfoximino or substitute
• R 2 is a 6-membered aromatic carbocyclic group substituted with 1 halogen and further substituted with 1, 2, 3 or 4 substituents selected from Substituent Group G or a 6-membered aromatic heterocyclic group substituted with one halogen and further substituted with one or two substituents selected from the substituent group G;
• substituent group G is a group consisting of halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy and haloalkyloxy.
• R 2 is substituted with one halogen and further 1, 2, 3 or 4 substituents selected from Substituent Group G (as defined in item (4''') above)
• Items (1''') to R 1 are a substituted or unsubstituted nitrogen-containing aromatic heterocyclic group or a substituted or unsubstituted nitrogen-containing non-aromatic heterocyclic group. (5''') or a pharmaceutically acceptable salt thereof.
• Ring A is (Wherein, carbon atom a, carbon atom b, R 3b , R 6 , R 7 , R 7′ and R 8 are the same as in item (1′′′) above).
• (10''') The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1''') to (9'''), wherein m is 0 or 1.
• each R 5a is independently a hydrogen atom and each R 5b is independently a hydrogen atom; or a pharmaceutically acceptable salt thereof.
• the present invention also relates to the following.
• Ring A is (Wherein, carbon atom a, carbon atom b, R 3a , R 3b , R 6 , R 7 , R 7′ , R 8 , R 9 , R 9′ , s and p are the above item (1′′) and (same definition)), or a pharmaceutically acceptable salt thereof according to item (1'') above.
• R 3a and R 3b each independently (In the formula, t is an integer from 0 to 5, Each R 10a is independently halogen, cyano, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted sulfoximino or substituted or unsubstituted iminosulfino;
• R 2 is a 6-membered aromatic carbocyclic group substituted with one halogen and further substituted with 1, 2, 3 or 4 substituents selected from Substituent Group G; or a 6-membered aromatic heterocyclic group substituted with one halogen and further substituted with 1 or 2 substituents selected from Substituent Group G; Any of the above items (1'') to (3''), wherein the substituent group G is a group consisting of halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy and haloalkyloxy. or a pharmaceutically acceptable salt thereof.
• R 2 is substituted with one halogen and further substituted with 1, 2, 3 or 4 substituents selected from Substituent Group G (as defined in item (4'') above)
• Substituent Group G as defined in item (4'') above
• Ring A is (Wherein, carbon atom a, carbon atom b, R 3a , R 6 and R 8 are synonymous with the above item (1''); The compound according to any one of the above items (1'') to (6''), or a pharmaceutically acceptable salt.
• Ring A is (wherein carbon atom a, carbon atom b, R 3b , R 6 , R 7 , R 7′ and R 8 are the same as in item (1′′) above), the above item (1 '') to (6''), or a pharmaceutically acceptable salt thereof.
• (9'') The compound according to any one of the above items (1'') to (8''), wherein m is 0 or 1, or a pharmaceutically acceptable salt thereof.
• the present invention also relates to the following.
• Ring A is (Wherein, R 6 , R 7 , R 9 and s are synonymous with the above item (1′), R 8 is a hydrogen atom or halogen; R3 is (In the formula, t is an integer from 0 to 5, Each R 10a is independently halogen, cyano, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic carbon
• R 2 is a 6-membered aromatic carbocyclic group substituted with one halogen and further substituted with 1, 2, 3 or 4 substituents selected from Substituent Group G, or , a 6-membered aromatic heterocyclic group substituted with one halogen and further substituted with one or two substituents selected from Substituent Group G;
• substituent group G is a group consisting of halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy and haloalkyloxy; or a pharmaceutically acceptable salt thereof.
• R 2 is substituted with one halogen and further substituted with 1, 2, 3 or 4 substituents selected from Substituent Group G (as defined in item (3') above)
• R 1 is a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group A compound as described, or a pharmaceutically acceptable salt thereof.
• Ring A is (Wherein, R 6 and R 8 are synonymous with item (1′) above; R 3 is synonymous with item (2′) above; The compound according to any one of the above items (1′) to (5′), or a pharmaceutically acceptable salt thereof, wherein R 7 is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl). .
• Ring A is (Wherein, R 6 , R 7 and R 8 are synonymous with the above item (1′); The compound according to any one of the above items (1′) to (5′), or a pharmaceutically acceptable salt thereof, wherein R 3 is the ring shown in the above item (2′)).
• the present invention also relates to the following.
• Ring A is (Wherein, R 6 , R 7 , R 9 and s are synonymous with item (1) above, R 8 is a hydrogen atom or halogen; R3 is (In the formula, t is an integer from 0 to 5, Each R 10a is independently halogen, cyano, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substitute
• R 2 is a 6-membered aromatic carbocyclic group substituted with one halogen and further substituted with 1, 2, 3 or 4 substituents selected from Substituent Group G, or a 6-membered aromatic heterocyclic group substituted with one halogen and further substituted with 1 or 2 substituents selected from substituent group G;
• substituent group G is a group consisting of halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy and haloalkyloxy, or A pharmaceutically acceptable salt.
• R 2 is a 6-membered group substituted with one halogen and further substituted with 1, 2, 3 or 4 substituents selected from Substituent Group G (as defined in item (3) above)
• R 1 is a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group. , or a pharmaceutically acceptable salt thereof.
• Ring A is (Wherein, R 6 and R 8 are synonymous with item (1) above; R 3 is synonymous with item (2) above; The compound according to any one of the above items (1) to (5), or a pharmaceutically acceptable salt thereof, wherein R 7 is a ring represented by a hydrogen atom, halogen, or substituted or unsubstituted alkyl). (7) The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1) to (6), wherein m is 0 or 1. (8) the compound or a pharmaceutically acceptable compound according to any one of the above items (1) to (7), wherein each R 5a is independently a hydrogen atom and each R 5b is independently a hydrogen atom; salt.
• coronavirus growth inhibitor according to item (13) above wherein the coronavirus is an alphacoronavirus and/or a betacoronavirus.
• coronavirus growth inhibitor according to item (13) above wherein the coronavirus is SARS-CoV-2.
• the above items (1) to (10), (1′) to (11′), (1′′) to (12′′), and (1′′′) to (14′′′) A pharmaceutical composition for the prevention and/or treatment of coronavirus infection, comprising any of the compounds or pharmaceutically acceptable salts thereof.
• coronavirus is an alphacoronavirus and/or a betacoronavirus.
• the coronavirus is SARS-CoV-2.
• the coronavirus infection is novel coronavirus infection (COVID-19).
• the compound according to the present invention has inhibitory activity against coronavirus 3CL protease and is useful as a therapeutic and/or preventive agent for coronavirus infections.
• Halogen includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Fluorine and chlorine atoms are particularly preferred.
• Alkyl includes a linear or branched hydrocarbon group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, still more preferably 1 to 4 carbon atoms. do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl , isooctyl, n-nonyl, n-decyl and the like.
• alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl. More preferred embodiments include methyl, ethyl, n-propyl, isopropyl and tert-butyl.
• alkenyl refers to a group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, still more preferably 2 to 4 carbon atoms, having one or more double bonds at any position. straight or branched chain hydrocarbon groups.
• alkenyl include vinyl, allyl, propenyl, isopropenyl and butenyl. More preferred embodiments include ethenyl, n-propenyl, and the like.
• alkynyl refers to a group having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. It includes straight chain or branched hydrocarbon groups. Furthermore, it may have a double bond at any position. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like. Preferred embodiments of "alkynyl” include ethynyl, propynyl, butynyl and pentynyl. More preferred embodiments include ethynyl, propynyl and the like.
• Aromatic carbocyclic group means a monocyclic or bicyclic or more cyclic aromatic hydrocarbon group. Examples include phenyl, naphthyl, anthryl, phenanthryl and the like. Six-membered aromatic carbocyclic groups include phenyl. A preferred embodiment of the "aromatic carbocyclic group” is phenyl.
• Aromatic carbocyclic ring means a ring derived from the above “aromatic carbocyclic group”.
• a substituted or unsubstituted aromatic carbocyclic ring formed by R 3 and R 8 together with the carbon atoms to which they are attached and "R 3a and R 8 and R 3b and R
• the substituted or unsubstituted aromatic carbocyclic ring formed by 8 together with the carbon atoms to which each is attached includes, for example, the following rings.
• R 10b and R 10c , R 10c and R 10d , R 10d and R 10e , R 10f and R 10g , R 10g and R 10h , R 10h and R 10i , and R 10i and R The substituted or unsubstituted aromatic carbocyclic ring formed by each of 10j independently together with the carbon atoms to which they are attached includes, for example, the following rings.
• non-aromatic carbocyclic group means a monocyclic or bicyclic or more ring saturated cyclic hydrocarbon group or cyclic non-aromatic unsaturated hydrocarbon group.
• the "non-aromatic carbocyclic group” having two or more rings also includes a monocyclic or non-aromatic carbocyclic group having two or more rings condensed with the above “aromatic carbocyclic group”.
• the "non-aromatic carbocyclic group” also includes a group that forms a bridge or a spiro ring as shown below.
• the monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 4 to 8 carbon atoms.
• Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl and the like.
• the bicyclic or more non-aromatic carbocyclic group preferably has 8 to 20 carbon atoms, more preferably 8 to 16 carbon atoms.
• Examples include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like.
• Non-aromatic carbocyclic ring means a ring derived from the above “non-aromatic carbocyclic group”.
• R 10b and R 10b' , R 10c and R 10c' , R 10d and R 10d' , R 10e and R 10e' , R 10f and R 10f' , R 10g and R 10g' , R 10h and R 10h′ , R 10i and R 10i′ , and R 10j and R 10j′ are each independently a substituted or unsubstituted non-aromatic carbocyclic ring formed together with the carbon atoms to which they are attached. ” includes, for example, the following rings.
• R 10b and R 10c , R 10c and R 10d , R 10d and R 10e , R 10f and R 10g , R 10g and R 10h , R 10h and R 10i , and R 10i and R The substituted or unsubstituted non-aromatic carbocyclic ring formed by each of 10j independently together with the carbon atoms to which they are attached includes, for example, the following rings.
• “Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms which are the same or different and are arbitrarily selected from O, S and N in the ring. do.
• An aromatic heterocyclic group with two or more rings includes a monocyclic or an aromatic heterocyclic group with two or more rings condensed with the ring in the above "aromatic carbocyclic group", and the bond is Either ring may have it.
• the monocyclic aromatic heterocyclic group is preferably 5- to 8-membered, more preferably 5- or 6-membered.
• Five-membered aromatic heterocyclic groups include, for example, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like.
• 6-membered aromatic heterocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like.
• the bicyclic aromatic heterocyclic group is preferably 8- to 10-membered, more preferably 9- or 10-membered.
• indolyl isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl.
• Ryl benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl, etc. is mentioned.
• 9-membered aromatic heterocyclic groups include indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazo lyl, benzotriazolyl, benzofuranyl, imidazopyridyl, triazolopyridyl, oxazolopyridyl, thiazolopyridyl and the like.
• Ten-membered aromatic heterocyclic groups include quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, pyrazinopyridazinyl, and the like.
• the aromatic heterocyclic group having 3 or more rings is preferably 13- to 15-membered. Examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl and the like.
• Nonrogen-containing aromatic heterocyclic group means a monocyclic or bicyclic or more aromatic heterocyclic group having one or more nitrogen atoms in the ring.
• Aromatic heterocyclic ring means a ring derived from the above “aromatic heterocyclic group”.
• a substituted or unsubstituted aromatic heterocyclic ring formed by R 3 and R 8 together with the carbon atoms to which they are attached and "R 3a and R 8 and R 3b and R
• the substituted or unsubstituted aromatic heterocyclic ring formed by 8 together with the carbon atoms to which they are attached includes, for example, the following rings.
• the “substituted or unsubstituted aromatic heterocyclic ring formed by two R 10a bonded to adjacent carbon atoms together” includes, for example, the following rings. (Wherein, R Y is a hydrogen atom, substituted or unsubstituted alkyl, etc.)
• Non-aromatic heterocyclic group means a monocyclic or bicyclic or more non-aromatic cyclic group having one or more heteroatoms in the ring that are the same or different and arbitrarily selected from O, S and N.
• a bicyclic or more non-aromatic heterocyclic group is a monocyclic or bicyclic or more non-aromatic heterocyclic group, the above "aromatic carbocyclic group”, “non-aromatic carbocyclic group”, and / Or each ring in the "aromatic heterocyclic group” is condensed, furthermore, the ring in the above "aromatic heterocyclic group” is condensed to a monocyclic or bicyclic or more non-aromatic carbocyclic group and the bond may be in any ring.
• non-aromatic heterocyclic group also includes a group that forms a bridge or a spiro ring as shown below.
• the monocyclic non-aromatic heterocyclic group is preferably 3- to 8-membered, more preferably 5- or 6-membered.
• Three-membered non-aromatic heterocyclic groups include, for example, thiiranyl, oxiranyl, aziridinyl.
• Examples of 4-membered non-aromatic heterocyclic groups include oxetanyl and azetidinyl.
• Five-membered non-aromatic heterocyclic groups include, for example, oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, thiolanyl, and the like. mentioned.
• 6-membered non-aromatic heterocyclic groups include, for example, dioxanyl, thianyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydropyranyl, dihydrooxazinyl, tetrahydropyridazinyl hexahydropyrimidinyl, dioxazinyl, thiinyl, thiazinyl and the like.
• Seven-membered non-aromatic heterocyclic groups include, for example, hexahydroazepinyl, tetrahydrodiazepinyl, oxepanyl.
• the non-aromatic heterocyclic group having two or more rings is preferably 8- to 20-membered, more preferably 8- to 13-membered, still more preferably 8- to 10-membered. Examples include indolinyl, isoindolinyl, chromanyl, isochromanyl and the like.
• a “nitrogen-containing non-aromatic heterocyclic group” means a monocyclic or bicyclic or more non-aromatic heterocyclic group having one or more nitrogen atoms in the ring.
• a non-aromatic heterocyclic group having two or more rings is a monocyclic or nitrogen-containing non-aromatic heterocyclic group having two or more rings, and the above "aromatic carbocyclic group” and “non-aromatic carbocyclic group” and/or condensed rings in the "aromatic heterocyclic group”, and the bond may be present in any ring.
• Bicyclic or more non-aromatic heterocyclic groups include monocyclic or bicyclic or more non-aromatic carbocyclic groups in which each ring in the above "nitrogen-containing aromatic heterocyclic group” is condensed. However, the bond may be present in any ring. For example, the following groups are shown. Furthermore, the "nitrogen-containing non-aromatic heterocyclic group” also includes groups that are crosslinked or form spiro rings as described below.
• Non-aromatic heterocyclic ring means a ring derived from the above “non-aromatic heterocyclic group”.
• the “substituted or unsubstituted non-aromatic heterocyclic ring formed by two R 10a bonded to adjacent carbon atoms together” includes, for example, the following rings.
• R 10b and R 10b' , R 10c and R 10c' , R 10d and R 10d' , R 10e and R 10e' , R 10f and R 10f' , R 10g and R 10g' , R 10h and R 10h′ , R 10i and R 10i′ , and R 10j and R 10j′ are each independently a substituted or unsubstituted non-aromatic heterocyclic ring formed together with the carbon atoms to which they are attached. ” includes, for example, the following rings.
• R 10b and R 10c , R 10c and R 10d , R 10d and R 10e , R 10f and R 10g , R 10g and R 10h , R 10h and R 10i , and R 10i and R The substituted or unsubstituted non-aromatic heterocyclic ring which 10j is each independently formed together with the carbon atoms to which they are attached includes, for example, the following rings.
• the “substituted or unsubstituted non-aromatic heterocyclic ring formed by R 3b and R 7′ together with the atoms to which they are attached” includes, for example, the following rings.
• the nitrogen atom c represents the nitrogen atom to which R 7' binds in the above formula (I);
• Carbon atom d represents the carbon atom to which R 3b is bound in formula (I) above
• Trialkylsilyl means a group in which the above three “alkyl” are bonded to a silicon atom.
• the three alkyl groups may be the same or different. Examples include trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like.
• Iminosulfino means the following formula: means a group represented by One or two hydrogen atoms at any position may be substituted. Alkyl etc. are mentioned as a substituent of "substituted iminosulfino.”
• substituent group ⁇ means “optionally substituted with one or more groups selected from substituent group ⁇ ". The same applies to the substituent groups ⁇ , ⁇ and ⁇ '.
• a carbon atom at any position may be bonded to one or more groups selected from Substituent Group A below.
• Substituent group A halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, penta fluorothio, trialkylsilyl, alkyloxy optionally substituted with substituent group ⁇ , alkenyloxy optionally substituted with substituent group ⁇ , alkynyloxy optionally substituted with substituent group ⁇ , substituted with substituent group ⁇ alkylcarbonyloxy optionally substituted with substituent group ⁇ , alkenylcarbonyloxy optionally substituted with substituent group ⁇ , alky
• Substituent group ⁇ halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, and cyano.
• Substituent group ⁇ halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group ⁇ , alkenyl optionally substituted with substituent group ⁇ , optionally substituted with substituent group ⁇ alkynyl, alkylcarbonyl optionally substituted with substituent group ⁇ , alkenylcarbonyl optionally substituted with substituent group ⁇ , alkynylcarbonyl optionally substituted with substituent group ⁇ , substituted with substituent group ⁇ alkylsulfanyl optionally substituted with substituent group ⁇ , alkenylsulfanyl optionally substituted with substituent group ⁇ , alkynylsulfanyl optionally substituted with substituent group ⁇ , alkylsulfinyl optionally substituted with substituent group ⁇ , alkenylsulfinyl optionally substituted with substituent group ⁇ , alkynylsulfinyl optionally substituted with substituent group ⁇ , alken
• Substituent Group ⁇ Substituent Group ⁇ , alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl and alkynylcarbonyl.
• Substituent group ⁇ ' Substituent group ⁇ and oxo.
• Substituent group B halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, penta fluorothio, trialkylsilyl, alkyl optionally substituted with substituent group ⁇ , alkenyl optionally substituted with substituent group ⁇ , alkynyl optionally substituted with substituent group ⁇ , optionally substituted with substituent group ⁇ alkyloxy, alkenyloxy optionally substituted with substituent group ⁇ , alkynyloxy optionally substituted with substituent group ⁇ , alkylcarbon
• non-aromatic carbocycle and “non-aromatic heterocycle” are substituted with “oxo” they mean rings in which two hydrogen atoms on the carbon atoms are substituted as follows.
• Substituents of “substituted amino”, “substituted imino”, “substituted carbamoyl” and “substituted sulfamoyl” include Substituent Group D below. It may be substituted with one or two groups selected from Substituent Group D.
• Substituent group D halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group ⁇ , alkenyl optionally substituted with substituent group ⁇ , optionally substituted with substituent group ⁇ alkynyl, alkylcarbonyl optionally substituted with substituent group ⁇ , alkenylcarbonyl optionally substituted with substituent group ⁇ , alkynylcarbonyl optionally substituted with substituent group ⁇ , substituted with substituent group ⁇ alkylsulfanyl optionally substituted with substituent group ⁇ , alkenylsulfanyl optionally substituted with substituent group ⁇ , alkynylsulfanyl optionally substituted with substituent group ⁇ , alkylsulfinyl optionally substituted with substituent group ⁇ , alkenylsulfinyl optionally substituted with substituent group ⁇ , alkynylsulfinyl optionally substituted with substituent group ⁇ , alkeny
• substituents of the "substituted or unsubstituted non-aromatic heterocyclic group" and the "substituted or unsubstituted nitrogen-containing non-aromatic heterocyclic group” for R 1 include: oxo; thioxo; halogen; cyano; nitro; carboxy; substituted or unsubstituted carbamoyl; substituted or unsubstituted alkyl; substituted or unsubstituted alkyloxy; substituted or unsubstituted alkylcarbonyl; substituted or unsubstituted alkyloxycarbonyl; substituted or unsubstituted alkylsulfanyl; substituted or unsubstituted amino; substituted or unsubstituted aromatic carbocyclic groups; substituted or unsubstituted aromatic heterocyclic group; substituted or unsubstituted non-aromatic carbocyclic groups; substituted or unsubstituted non-aro
• substituents of the "substituted or unsubstituted non-aromatic heterocyclic group" and the "substituted or unsubstituted nitrogen-containing non-aromatic heterocyclic group” for R 1 include: oxo; halogen; are mentioned. It may be substituted with one or more groups selected from these.
• substituents of the "substituted or unsubstituted aromatic heterocyclic group" and the “substituted or unsubstituted nitrogen-containing aromatic heterocyclic group” for R 1 include: halogen; cyano; hydroxy; substituted or unsubstituted alkyl; substituted or unsubstituted alkyloxy; substituted or unsubstituted alkyloxycarbonyl; substituted or unsubstituted amino; substituted or unsubstituted aromatic carbocyclic groups; It may be substituted with one or more groups selected from these.
• substituents of the "substituted or unsubstituted aromatic heterocyclic group" and the “substituted or unsubstituted nitrogen-containing aromatic heterocyclic group” for R 1 include: halogen; cyano; hydroxy; substituted or unsubstituted alkyl; substituted or unsubstituted alkyloxy; It may be substituted with one or more groups selected from these.
• substituents of the "substituted or unsubstituted aromatic heterocyclic group" and the “substituted or unsubstituted nitrogen-containing aromatic heterocyclic group” for R 1 include: halogen; cyano; hydroxy; substituted alkyl (as a substituent, halogen; optionally substituted with one or more groups selected from these); unsubstituted alkyl; unsubstituted alkyloxy; It may be substituted with one or more groups selected from these.
• substituents of the "substituted or unsubstituted aromatic heterocyclic group" and the “substituted or unsubstituted nitrogen-containing aromatic heterocyclic group” for R 1 include: halogen; cyano; substituted alkyl (as a substituent, halogen; optionally substituted with one or more groups selected from these); unsubstituted alkyl; substituted alkyloxy (substituents include halogen; optionally substituted with one or more groups selected from these); unsubstituted alkyloxy; It may be substituted with one or more groups selected from these.
• substituents of the "substituted or unsubstituted carbamoyl" for R 1 include: substituted or unsubstituted alkyl; substituted or unsubstituted non-aromatic carbocyclic groups; It may be substituted with one or more groups selected from these.
• substituents of the "substituted or unsubstituted carbamoyl" for R 1 include: substituted or unsubstituted alkyl; It may be substituted with one or more groups selected from these.
• substituents of the "substituted or unsubstituted carbamoyl" for R 1 include: substituted alkyl (as substituents, halogen, non-aromatic carbocyclic group; optionally substituted with one or more groups selected from these); unsubstituted alkyl; unsubstituted non-aromatic carbocyclic groups; It may be substituted with one or more groups selected from these.
• substituents of the "substituted or unsubstituted carbamoyl" for R 1 include: Alkyl; It may be substituted with one or more groups selected from these.
• substituents of the "substituted or unsubstituted aromatic carbocyclic group" for R 2 include: halogen; cyano; substituted or unsubstituted alkyl; substituted or unsubstituted alkynyl; substituted or unsubstituted alkyloxy; is mentioned. It may be substituted with one or more groups selected from these.
• substituents of the "substituted or unsubstituted 6-membered aromatic carbocyclic group" for R 2 include: halogen; cyano; substituted or unsubstituted alkyl; substituted or unsubstituted alkyloxy; substituted or unsubstituted alkyloxycarbonyl; are mentioned. It may be substituted with one or more groups selected from these.
• substituents of the "substituted or unsubstituted 6-membered aromatic carbocyclic group" for R 2 include: halogen; cyano; substituted alkyl (as substituents, halogen, alkyloxy; optionally substituted with one or more groups selected from these); unsubstituted alkyl; substituted alkyloxy (as a substituent, an aromatic carbocyclic group; optionally substituted with one or more groups selected from these); unsubstituted alkyloxy; unsubstituted alkyloxycarbonyl; is mentioned. It may be substituted with one or more groups selected from these.
• substituents of the "substituted or unsubstituted aromatic heterocyclic group" for R 2 include: halogen; cyano; substituted or unsubstituted alkyl; substituted or unsubstituted alkynyl; substituted or unsubstituted alkyloxy; are mentioned. It may be substituted with one or more groups selected from these.
• substituents of the "substituted or unsubstituted 6-membered aromatic heterocyclic group" for R 2 include: halogen; are mentioned. It may be substituted with one or more groups selected from these.
• substituents of the "substituted or unsubstituted aromatic carbocyclic group" for R 3 , R 3a , R 3b and R 3b' include: halogen; cyano; carboxy; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl substituted or unsubstituted alkyloxy; substituted or unsubstituted alkylcarbonyl; substituted or unsubstituted alkylsulfonyl; substituted or unsubstituted carbamoyl; substituted or unsubstituted sulfamoyl; substituted or unsubstituted amino; substituted or unsubstituted imino; substituted or unsubstituted iminosulfino; substituted or unsubstituted aromatic carbocyclic groups; substituted or unsubstituted aromatic heterocyclic group; substituted or
• substituents of the "substituted or unsubstituted aromatic carbocyclic group" for R 3 , R 3a , R 3b and R 3b' include: halogen; cyano; substituted or unsubstituted alkyl; substituted or unsubstituted carbamoyl; substituted or unsubstituted imino; substituted or unsubstituted iminosulfino; is mentioned. It may be substituted with one or more groups selected from these.
• substituents of the "substituted or unsubstituted aromatic carbocyclic group" for R 3 , R 3a , R 3b and R 3b' include: halogen; cyano; hydroxy; carboxy; substituted or unsubstituted alkyl; substituted or unsubstituted alkyloxy; substituted or unsubstituted alkylcarbonyl; substituted or unsubstituted alkyloxycarbonyl; substituted or unsubstituted alkylsulfinyl; substituted or unsubstituted alkylsulfonyl; substituted or unsubstituted sulfoximino; substituted or unsubstituted iminosulfino; substituted or unsubstituted amino; substituted or unsubstituted carbamoyl; substituted or unsubstituted N-(bis(dialkylamino)methylene)carbamoyl; substituted or unsubstitute
• substituents of the "substituted or unsubstituted aromatic carbocyclic group" for R 3 , R 3a , R 3b and R 3b' include: halogen; cyano; hydroxy; carboxy; Substituted alkyl (substituents include halogen, hydroxy, carboxy, carbamoyl, dialkylcarbamoyl, alkylsulfonylalkylcarbamoyl, dialkylaminoalkylcarbamoyl, alkyl non-aromatic heterocyclic group carbamoyl, alkyloxy, alkyloxycarbonyl, dialkylsulfoxyiminyl , non-aromatic heterocyclic group, alkyl non-aromatic heterocyclic group, amino non-aromatic heterocyclic group carbonyl; optionally substituted with one or more groups selected from these); unsubstituted alkyl; substituted alkyloxy (as a substituent,
• substituents of the "substituted or unsubstituted aromatic carbocyclic group" for R 3 , R 3a , R 3b and R 3b' include: Halogen, cyano, substituted or unsubstituted alkyl (substituents include halogen, cyano, hydroxy, carboxy, carbamoyl, dialkylcarbamoyl, alkylsulfonylalkylcarbamoyl, dialkylaminoalkylcarbamoyl, (alkyl non-aromatic heterocyclic group) carbamoyl , alkyloxy, dialkylsulfoxyimino, amino non-aromatic heterocyclic group carbonyl; optionally substituted with one or more groups selected from these), unsubstituted alkyloxy, unsubstituted alkylcarbonyl, unsubstituted alkyl sulfonyl, substituted sulfoxyimino (a
• substituents of the "substituted or unsubstituted aromatic heterocyclic group" for R 3 , R 3a , R 3b and R 3b' include: halogen; cyano; carboxy; hydroxy; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl substituted or unsubstituted alkyloxy; substituted or unsubstituted alkylcarbonyl; substituted or unsubstituted alkylsulfonyl; substituted or unsubstituted carbamoyl; substituted or unsubstituted sulfamoyl; substituted or unsubstituted amino; substituted or unsubstituted imino; substituted or unsubstituted iminosulfino; substituted or unsubstituted aromatic carbocyclic groups; substituted or unsubstituted aromatic heterocyclic group; substitute
• substituents of the "substituted or unsubstituted aromatic heterocyclic group" for R 3 include: halogen; cyano; hydroxy; substituted or unsubstituted alkyl; substituted or unsubstituted carbamoyl; substituted or unsubstituted imino; substituted or unsubstituted iminosulfino; are mentioned. It may be substituted with one or more groups selected from these.
• substituents of the "substituted or unsubstituted aromatic heterocyclic group" for R 3 , R 3a , R 3b and R 3b' include: halogen; cyano; hydroxy; substituted or unsubstituted alkyl; substituted or unsubstituted alkyloxy; substituted or unsubstituted amino; substituted or unsubstituted carbamoyl; is mentioned. It may be substituted with one or more groups selected from these.
• substituents of the "substituted or unsubstituted aromatic heterocyclic group" for R 3 , R 3a , R 3b and R 3b' include: halogen; cyano; hydroxy; substituted alkyl (as substituents, halogen, hydroxy; optionally substituted with one or more groups selected from these); unsubstituted alkyl; substituted alkyloxy (as a substituent, halogen; optionally substituted with one or more groups selected from these); unsubstituted alkyloxy; substituted amino (as substituents, alkyl, carbamoyl, alkylcarbonyl, alkylsulfinyl, alkylsulfonyl; optionally substituted with one or more groups selected from these); unsubstituted amino; substituted carbamoyl (as a substituent, alkyl, unsubstituted non-aromatic heterocyclic alkyl, unsubstituted non-ar
• substituents of the "substituted or unsubstituted non-aromatic heterocyclic group" for R 3 , R 3a , R 3b and R 3b' include: halogen; carboxy; hydroxy; oxo; substituted or unsubstituted alkyl; substituted or unsubstituted alkyloxycarbonyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted alkyloxy; substituted or unsubstituted amino; substituted or unsubstituted carbamoyl; substituted or unsubstituted aromatic carbocyclic groups; substituted or unsubstituted aromatic heterocyclic group; is mentioned.
• substituents of the "substituted or unsubstituted non-aromatic heterocyclic group" for R 3 , R 3a , R 3b and R 3b' include: halogen; hydroxy; substituted or unsubstituted alkyl; substituted alkyloxy; substituted or unsubstituted amino; substituted or unsubstituted carbamoyl; are mentioned. It may be substituted with one or more groups selected from these.
• substituents of the "substituted or unsubstituted non-aromatic heterocyclic group" for R 3 , R 3a , R 3b and R 3b' include: Oxo; halogen; cyano; hydroxy; carboxy; substituted or unsubstituted alkyl; substituted or unsubstituted alkyloxy; substituted or unsubstituted alkyloxycarbonyl; substituted or unsubstituted amino; substituted or unsubstituted carbamoyl; substituted or unsubstituted alkylsulfonyl; substituted or unsubstituted aromatic heterocyclic group; substituted or unsubstituted non-aromatic heterocyclic carbonyl; is mentioned. It may be substituted with one or more groups selected from these.
• substituents of the "substituted or unsubstituted non-aromatic heterocyclic group" for R 3 , R 3a , R 3b and R 3b' include: Oxo; halogen; cyano; hydroxy; carboxy; substituted alkyl (substituents include halogen, hydroxy, carboxy, alkyloxy, amino, alkylamino, unsubstituted non-aromatic heterocyclic groups; optionally substituted with one or more groups selected from these); unsubstituted alkyl; substituted alkyloxy (as a substituent, halogen; optionally substituted with one or more groups selected from these); unsubstituted alkyloxy; unsubstituted alkyloxycarbonyl; substituted amino (as substituents, alkyl, alkylcarbonyl, alkyloxycarbonyl; optionally substituted with one or more groups selected from these); unsubstituted amino; substituted carbamoyl
• substituents of the "substituted or unsubstituted non-aromatic heterocyclic group" for R 3 , R 3a , R 3b and R 3b' include: hydrogen atom, halogen, cyano, hydroxy, carboxy, substituted or unsubstituted alkyl (as substituents, halogen, hydroxy, alkyloxy; optionally substituted with one or more groups selected from these), substituted or unsubstituted alkyloxy (as a substituent, halogen; optionally substituted with one or more groups selected from these), unsubstituted alkyloxycarbonyl, substituted or unsubstituted amino (as a substituent, alkyl , alkylcarbonyl; optionally substituted with one or more groups selected from these), substituted or unsubstituted carbamoyl (as a substituent, alkyl; substituted with one or more groups selected from may be), unsubstituted alkyls
• substituents of the “substituted or unsubstituted amino” for R 3 and the “substituted amino” for R 3a , R 3b and R 3b′ include: substituted or unsubstituted alkyl; substituted or unsubstituted alkylcarbonyl; substituted or unsubstituted alkylsulfonyl; substituted or unsubstituted aromatic carbocyclic groups; substituted or unsubstituted non-aromatic carbocyclic groups; substituted or unsubstituted non-aromatic heterocyclic groups; are mentioned. It may be substituted with one or more groups selected from these.
• substituents of the “substituted or unsubstituted amino” for R 3 and the “substituted amino” for R 3a , R 3b and R 3b′ include: substituted alkyl (as substituents, halogen, hydroxy, alkyloxy, non-aromatic carbocyclic groups; optionally substituted with one or more groups selected from these); unsubstituted alkyl; substituted alkylcarbonyl (as substituents, halogen, carbamoyl; optionally substituted with one or more groups selected from these); unsubstituted alkylcarbonyl; unsubstituted alkylsulfonyl; substituted aromatic carbocyclic group (as a substituent, haloalkyl, alkyloxy; optionally substituted with one or more groups selected from these); unsubstituted aromatic carbocyclic group; substituted non-aromatic carbocyclic group (as substituents, halogen, hydroxy
• substituents of the “substituted or unsubstituted amino” for R 3 and the “substituted amino” for R 3a , R 3b and R 3b′ include: substituted or unsubstituted alkyl; substituted or unsubstituted non-aromatic carbocyclic group; is mentioned. It may be substituted with one or more groups selected from these.
• substituents of the “substituted or unsubstituted amino” for R 3 and the “substituted amino” for R 3a , R 3b and R 3b′ include: substituted alkyl (as substituents, halogen, alkyloxy; optionally substituted with one or more groups selected from these); unsubstituted alkyl; an unsubstituted non-aromatic carbocyclic group; is mentioned. It may be substituted with one or more groups selected from these.
• substituents of "substituted or unsubstituted alkyloxy" for R 3 , R 3a , R 3b and R 3b' include: halogen; hydroxy; sulfothio; substituted or unsubstituted non-aromatic carbocyclic ring; substituted or unsubstituted non-aromatic heterocyclic groups; are mentioned. It may be substituted with one or more groups selected from these.
• substituents of "substituted or unsubstituted alkyloxy" for R 3 , R 3a , R 3b and R 3b' include: halogen; hydroxy; sulfothio; substituted non-aromatic carbocyclic ring (as a substituent, halogen; optionally substituted with one or more groups selected from these); unsubstituted non-aromatic heterocyclic group; are mentioned. It may be substituted with one or more groups selected from these.
• substituents of "substituted or unsubstituted carbamoyl” and “substituted or unsubstituted sulfamoyl" in R 3 , R 3a , R 3b and R 3b' include: substituted or unsubstituted alkyl; are mentioned. It may be substituted with one or more groups selected from these.
• substituents of "substituted or unsubstituted carbamoyl” and “substituted or unsubstituted sulfamoyl" in R 3 , R 3a , R 3b and R 3b' include: unsubstituted alkyl; are mentioned. It may be substituted with one or more groups selected from these.
• substituents of "substituted or unsubstituted non-aromatic carbocyclic oxy" in R 3 , R 3a , R 3b and R 3b' include: halogen; are mentioned. It may be substituted with one or more groups selected from these.
• Substituents of "substituted or unsubstituted alkyl" for R 3 , R 3b and R 3b' include, for example, substituted or unsubstituted aromatic carbocyclic groups; is mentioned. It may be substituted with one or more groups selected from these.
• substituents of "substituted or unsubstituted alkyl" for R 3 , R 3b and R 3b' include: substituted or unsubstituted alkyloxy; substituted or unsubstituted aromatic carbocyclic group; is mentioned. It may be substituted with one or more groups selected from these.
• substituents of "substituted or unsubstituted alkyl" for R 3 , R 3b and R 3b' include: an unsubstituted aromatic carbocyclic group; are mentioned. It may be substituted with one or more groups selected from these.
• substituents of "substituted or unsubstituted alkyl" for R 3 , R 3b and R 3b' include: unsubstituted alkyloxy; unsubstituted aromatic carbocyclic group; are mentioned. It may be substituted with one or more groups selected from these.
• substituents of "substituted or unsubstituted alkyloxy" for R 6 include: halogen; are mentioned. It may be substituted with one or more groups selected from these.
• substituents of "substituted or unsubstituted alkyl", “substituted or unsubstituted alkenyl” and “substituted or unsubstituted alkynyl” for R 7 include: halogen; hydroxy; are mentioned. It may be substituted with one or more groups selected from these.
• substituents of "substituted or unsubstituted alkyloxy" for R 7 include: halogen; cyano; substituted or unsubstituted alkyloxy; substituted or unsubstituted aromatic carbocyclic groups; are mentioned. It may be substituted with one or more groups selected from these.
• substituents of "substituted or unsubstituted alkyloxy" for R 7 include: halogen; cyano; unsubstituted alkyloxy; an unsubstituted aromatic carbocyclic group; are mentioned. It may be substituted with one or more groups selected from these.
• substituents of "substituted or unsubstituted alkylsulfoxy" for R 7 include: halogen; are mentioned. It may be substituted with one or more groups selected from these.
• substituents of the “substituted or unsubstituted carbamoyl” for R 7 include substituted or unsubstituted alkyl; is mentioned. It may be substituted with one or more groups selected from these.
• substituents of the “substituted or unsubstituted carbamoyl” for R 7 include unsubstituted alkyl; is mentioned. It may be substituted with one or more groups selected from these.
• R 1 includes a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl or a substituted or unsubstituted amino (hereinafter referred to as A- 1).
• R 1 includes a substituted or unsubstituted nitrogen-containing aromatic heterocyclic group, a substituted or unsubstituted nitrogen-containing non-aromatic heterocyclic group, or a substituted or unsubstituted carbamoyl (hereinafter referred to as A-6 ).
• R 1 includes a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted amino (hereinafter referred to as A-2).
• R 1 includes a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as A-3).
• R 1 includes a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as A-4).
• R 1 includes a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as A-5).
• R 1 includes a substituted or unsubstituted nitrogen-containing aromatic heterocyclic group or a substituted or unsubstituted nitrogen-containing non-aromatic heterocyclic group (hereinafter referred to as A-7).
• R 1 includes a substituted or unsubstituted nitrogen-containing aromatic heterocyclic group (hereinafter referred to as A-8).
• R 1 includes a substituted or unsubstituted nitrogen-containing non-aromatic heterocyclic group (hereinafter referred to as A-9).
• R 1 includes a substituted or unsubstituted 5- to 9-membered nitrogen-containing aromatic heterocyclic group or a substituted or unsubstituted 6-membered nitrogen-containing non-aromatic heterocyclic group (hereinafter referred to as A-10). .
• R 1 includes a substituted or unsubstituted 5- to 9-membered nitrogen-containing aromatic heterocyclic group (hereinafter referred to as A-11).
• R 1 includes a substituted or unsubstituted 6-membered nitrogen-containing non-aromatic heterocyclic group (hereinafter referred to as A-12).
• R 1 includes substituted or unsubstituted triazolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted dihydropyridyl or substituted or unsubstituted imidazopyridyl (hereinafter referred to as A-12).
• R 2 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group
• a cyclic group or a substituted or unsubstituted alkyl may be mentioned (hereinafter referred to as B-1).
• R 2 includes a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as B-2).
• R 2 includes a substituted or unsubstituted aromatic carbocyclic group (hereinafter referred to as B-3).
• R 2 includes a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as B-4).
• R 2 includes a substituted or unsubstituted 6-membered aromatic carbocyclic group or a substituted or unsubstituted 6-membered aromatic heterocyclic group (hereinafter referred to as B-7).
• R 2 includes a substituted or unsubstituted 6-membered aromatic carbocyclic group (hereinafter referred to as B-8).
• R 2 includes a substituted or unsubstituted 6-membered aromatic heterocyclic group (hereinafter referred to as B-9).
• R 2 is 1, 2, 3, 4 or A 6-membered aromatic carbocyclic group substituted with 5 substituents, or a 6-membered aromatic heterocyclic group substituted with 1 or 2 substituents selected from Substituent Group G can be mentioned. (hereinafter referred to as B-10).
• R 2 is substituted with one halogen and further selected from Substituent Group G (Substituent Group G: halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy and haloalkyloxy) 6-membered aromatic carbocyclic group substituted with 1, 2, 3 or 4 substituents, or substituted with 1 halogen and further 1 or 2 substituents selected from substituent group G and a 6-membered aromatic heterocyclic group substituted with a group (hereinafter referred to as B-5).
• Substituent Group G Substituent Group G: halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy and haloalkyloxy
• R 2 is substituted with one halogen and further selected from Substituent Group G (Substituent Group G: halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy and haloalkyloxy) and a 6-membered aromatic carbocyclic group substituted with 1, 2, 3 or 4 substituents (hereinafter referred to as B-6).
• Substituent Group G halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy and haloalkyloxy
• B-6 6-membered aromatic carbocyclic group substituted with 1, 2, 3 or 4 substituents
• R 3 is a hydrogen atom, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkyl oxy or substituted or unsubstituted amino (hereinafter referred to as C-1).
• R 3 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted alkyloxy or a substituted or unsubstituted amino (hereinafter referred to as C-2).
• R 3 includes a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as C-3).
• R 3 includes a substituted or unsubstituted aromatic carbocyclic group (hereinafter referred to as C-4).
• R 3 includes a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as C-5).
• R3 is (In the formula, t is an integer from 0 to 5,
• Each R 10a is independently halogen, cyano, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or
• R 3a is a hydrogen atom, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted alkyl oxy, substituted amino, halogen, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted non-aromatic carbocyclic oxy or substituted or unsubstituted non-aromatic heterocyclic oxy (hereinafter referred to as C-7).
• R 3b and R 3b' are each independently a hydrogen atom, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group group, substituted or unsubstituted alkyloxy, substituted amino, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted non-aromatic carbocyclic oxy or substituted or Examples thereof include unsubstituted non-aromatic heterocyclic oxy (hereinafter referred to as C-8).
• R 3a , R 3b and R 3b′ are each independently a hydrogen atom, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted amino, halogen, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted non-aromatic carbocyclic oxy or substituted or unsubstituted unsubstituted and aromatic heterocyclic oxy (hereinafter referred to as C-9).
• R 3a , R 3b and R 3b′ each independently include a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as C-10 ).
• R 3a , R 3b and R 3b′ each independently include a substituted or unsubstituted aromatic carbocyclic group (hereinafter referred to as C-11).
• R 3a , R 3b and R 3b′ each independently include a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as C-12).
• R 3a , R 3b and R 3b′ are each independently (In the formula, t is an integer from 0 to 5, Each R 10a is independently halogen, cyano, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted sulfoximino or substituted or unsubstituted iminos
• R 3a and R 3b are each independently (In the formula, each symbol has the same meaning as C-13 above) (hereinafter referred to as C-14).
• R 3a , R 3b and R 3b′ are each independently (In the formula, each symbol has the same meaning as C-13 above) or a substituted amino group (hereinafter referred to as C-15).
• R 3a and R 3b are each independently (In the formula, each symbol has the same meaning as C-13 above) or a substituted amino group (hereinafter referred to as C-16).
• Examples of the ring formed together with the carbon atoms to which R 3 and R 8 are attached include a substituted or unsubstituted aromatic carbocyclic ring or a substituted or unsubstituted aromatic heterocyclic ring (hereinafter referred to as C'- 1).
• Examples of the ring formed together with the carbon atoms to which R 3a and R 8 and R 3b and R 8 are respectively bonded include a substituted or unsubstituted aromatic carbocyclic ring (hereinafter referred to as C'-2).
• R 4a includes a hydrogen atom or substituted or unsubstituted alkyl (hereinafter referred to as D-1).
• R 4a includes a hydrogen atom or unsubstituted alkyl (hereinafter referred to as D-3).
• R 4a includes a hydrogen atom (hereinafter referred to as D-2).
• R 4b includes a hydrogen atom or substituted or unsubstituted alkyl (hereinafter referred to as E-1).
• R 4b includes a hydrogen atom (hereinafter referred to as E-2).
• R 5a includes a hydrogen atom or substituted or unsubstituted alkyl (hereinafter referred to as F-1).
• R 5a includes a hydrogen atom (hereinafter referred to as F-2).
• R 5b includes a hydrogen atom or substituted or unsubstituted alkyl (hereinafter referred to as G-1).
• R 5b includes a hydrogen atom (hereinafter referred to as G-2).
• R 6 includes a hydrogen atom, halogen, substituted or unsubstituted alkyloxy, hydroxy or cyano (hereinafter referred to as H-2).
• R 6 includes halogen, substituted or unsubstituted alkyloxy, hydroxy or cyano (hereinafter referred to as H-3).
• R 6 includes halogen, alkyloxy or hydroxy (hereinafter referred to as H-4).
• R 6 includes a hydrogen atom, halogen, or substituted or unsubstituted alkyloxy (hereinafter referred to as H-1).
• R7 is a hydrogen atom, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic carbocyclic ring, substituted or unsubstituted unaromatic heterocycle, substituted or unsubstituted unaromatic carbocyclic oxy, substituted or unsubstituted amino, substituted or unsubstituted alkylsulfoxy, substituted or unsubstituted carbamoyl, hydroxy, carboxy, formyl and cyano (hereinafter referred to as I-2).
• R 7 includes a hydrogen atom, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy or substituted or unsubstituted amino (hereinafter referred to as I-1).
• R 7 includes a hydrogen atom, halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy (hereinafter referred to as I-3).
• R 7' includes a hydrogen atom or substituted or unsubstituted alkyl (hereinafter referred to as I'-1).
• R 9' includes a hydrogen atom or substituted or unsubstituted alkyl (hereinafter referred to as I'-2). Examples of the ring formed together with the atoms to which R 3b and R 7′ are bonded include a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as I′′-1).
• R 8 and R 8′ each independently include a hydrogen atom, halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy (hereinafter referred to as J-2).
• R 8 and R 8′ each independently include a hydrogen atom or halogen (hereinafter referred to as J-3).
• R 8 includes a hydrogen atom or halogen (hereinafter referred to as J-1).
• R 8 includes a hydrogen atom (hereinafter referred to as J-4).
• R 8 includes halogen (hereinafter referred to as J-5).
• R 9 includes halogen, hydroxy, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy (hereinafter referred to as O-2).
• R 9 includes halogen, hydroxy or alkyl (hereinafter referred to as O-2).
• R 9 includes substituted or unsubstituted alkyl (hereinafter referred to as O-1).
• n 0, 1 or 2 (hereinafter referred to as K-1).
• m is 0 or 1 (hereinafter referred to as K-2).
• Examples of m include 0 (hereinafter referred to as K-3).
• m includes 1 (hereinafter referred to as K-4).
• n is 0, 1 or 2 (hereinafter referred to as L-1). n includes 0 or 1 (hereinafter referred to as L-2). n includes 0 (hereinafter referred to as L-4). n includes 1 (hereinafter referred to as L-3).
• p is 1, 2 or 3 (hereinafter referred to as M-1). p includes 1 (hereinafter referred to as M-2).
• s is 0, 1 or 2 (hereinafter referred to as N-1). s includes 0 or 1 (hereinafter referred to as N-3). s can be 0 (hereinafter referred to as N-2).
• R 1 includes A-1, A-2, A-3, A-4 or A-5.
• R 2 includes B-1, B-2, B-3, B-4, B-5 or B-6.
• R 3 includes C-1, C-2, C-3, C-4, C-5, C-6, or C'-1.
• R 4a includes D-1 or D-2.
• R 4b includes E-1 or E-2.
• R 5a includes F-1 or F-2.
• R 5b includes G-1 or G-2.
• R 6 includes H-1.
• R 7 includes I-1.
• R 8 includes J-1.
• m includes K-1, K-2, K-3 or K-4.
• n includes L-1, L-2 or L-3.
• R 1 includes A-6, A-7, A-8 or A-9.
• R 2 includes B-5, B-6, B-7, B-8 or B-9.
• R 3a includes C-7, C-10, C-11, C-12 or C-14.
• R 3b includes C-8, C-9, C-10, C-11, C-12 or C-14.
• R 4a includes D-2 or D-3.
• R 4b includes E-2.
• R 5a includes F-2.
• R 5b includes G-2.
• R 6 includes H-1, H-2 or H-3.
• R 7 includes I-1 or I-2.
• R 8 includes J-1 or J-2.
• m includes K-2, K-3 or K-4.
• n includes L-2, L-3 or L-4.
• Ring A is is a ring represented by; wherein R 3a and R 3b are each independently (wherein Y is CR 10h R 10h′ or O; t is an integer from 1 to 5, Each R 10a is independently halogen, cyano, substituted or unsubstituted alkyl (substituents include halogen, cyano, hydroxy, carboxy, carbamoyl, dialkylcarbamoyl, alkylsulfonylalkylcarbamoyl, dialkylaminoalkylcarbamoyl, alkyl non-aromatic heterocyclic group carbamoyl, alkyloxy, dialkylsulfoxyimino, amino non-aromatic heterocyclic group carbonyl; optionally substituted with one or more groups selected from these), unsubstituted alkyloxy, unsubstit
• R 1 The substituents on the ring of the "substituted or unsubstituted 6-membered nitrogen-containing non-aromatic heterocyclic group" for R 1 are groups selected from oxo and halogen; optionally substituted;
• R 2 is 1, 2, 3, 4 or a 6-membered aromatic carbocyclic group substituted with 5 substituents, or a 6-membered aromatic heterocyclic group substituted with 1 or 2 substituents selected from substituent group G;
• n is 0 or 1;
• R 4a and R 4b are each independently a hydrogen atom or alkyl;
• m is 0 or 1;
• R5a and R5b are each independently a hydrogen atom.
• the compounds of formula (I) are not limited to any particular isomer, but include all possible isomers (e.g. keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers , rotamers, etc.), racemates or mixtures thereof.
• One or more hydrogen, carbon and/or other atoms of the compounds of formula (I) may be substituted with isotopes of hydrogen, carbon and/or other atoms, respectively.
• isotopes include 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O , 31 P, 32 P, 35 S, 18 F, 123 I and Hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included, as is 36 Cl.
• the compounds of formula (I) also include such isotopically substituted compounds.
• the isotopically substituted compounds are also useful as pharmaceuticals and include all radiolabeled compounds of formula (I).
• a "radiolabeling method" for producing the "radiolabel” is also encompassed by the present invention, and the “radiolabel” is useful as a research and/or diagnostic tool in metabolic pharmacokinetic studies, binding assays. is.
• Radiolabeled compounds of formula (I) can be prepared by methods well known in the art.
• a tritium-labeled compound of formula (I) can be prepared by introducing tritium into a specific compound of formula (I) through a catalytic dehalogenation reaction using tritium.
• This method comprises reacting a suitably halogenated precursor of a compound of formula (I) with tritium gas in the presence or absence of a base, in the presence of a suitable catalyst such as Pd/C.
• a suitable catalyst such as Pd/C.
• 14 C-labeled compounds can be prepared by using starting materials with a 14 C carbon.
• Pharmaceutically acceptable salts of the compound represented by formula (I) include, for example, the compound represented by formula (I) and an alkali metal (e.g., lithium, sodium, potassium, etc.), alkaline earth metal (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc.) and salts with amino acids, or inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.), and organic acids (e.g., formic acid, acetic acid, propionic acid) , trifluoroacetic acid, citric acid, lactic acid, tarta
• the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form solvates (e.g., hydrates, etc.), co-crystals and/or crystal polymorphs, and the present invention also includes such various solvates, co-crystals and polymorphs.
• a "solvate” may be coordinated with any number of solvent molecules (eg, water molecules, etc.) to a compound of formula (I).
• solvent molecules eg, water molecules, etc.
• the compound represented by formula (I) or a pharmaceutically acceptable salt thereof When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb water, attach adsorbed water, or form a hydrate. Also, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be recrystallized to form polymorphs.
• “Co-crystal” means that a compound or salt of formula (I) and a counter molecule are present in the same crystal lattice, and may contain any number
• the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention also includes such various prodrugs.
• Prodrugs are derivatives of the compounds of the invention having groups which are chemically or metabolically degradable, and which, upon solvolysis or under physiological conditions, become pharmaceutically active compounds of the invention in vivo.
• a prodrug is a compound that undergoes enzymatic oxidation, reduction, hydrolysis, or the like under physiological conditions in vivo and is converted into a compound represented by formula (I), or a compound that is hydrolyzed by gastric acid or the like to form formula (I). It includes compounds that are converted to the indicated compounds, and the like. Methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". A prodrug may itself have activity.
• the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group
• a compound having a hydroxyl group and a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable Prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting with sulfonyl anhydrides and mixed anhydrides or by reacting with a condensing agent are exemplified.
• the compound according to the present invention has coronavirus 3CL protease inhibitory activity, it is useful as a therapeutic and/or prophylactic agent for diseases associated with coronavirus 3CL protease.
• the term "therapeutic agent and/or prophylactic agent” also includes symptom improving agents.
• Diseases involving coronavirus 3CL protease include viral infections, preferably coronavirus infections.
• coronaviruses include coronaviruses that infect humans. Coronaviruses that infect humans include HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and/or SARS-CoV-2.
• coronaviruses include alphacoronaviruses and/or betacoronaviruses, more preferably betacoronaviruses, and even more preferably sarvecoviruses.
• alphacoronaviruses include HCoV-229E and HCoV-NL63. Particularly preferred is HCoV-229E.
• betacoronaviruses include HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and/or SARS-CoV-2. HCoV-OC43 or SARS-CoV-2 is preferred, and SARS-CoV-2 is particularly preferred.
• the betacoronavirus includes betacoronavirus A strain ( ⁇ -coronavirus lineage A), betacoronavirus B strain ( ⁇ -coronavirus lineage B), and betacoronavirus C strain ( ⁇ -coronavirus lineage C). is mentioned. More preferred are ⁇ -coronavirus lineage A and ⁇ -coronavirus lineage B, particularly preferably ⁇ -coronavirus lineage B.
• Betacoronavirus lineage A includes, for example, HCoV-HKU1 and HCoV-OC43, preferably HCoV-OC43.
• Betacoronavirus lineage B includes, for example, SARS-CoV and SARS-CoV-2, preferably SARS-CoV-2.
• coronaviruses include HCoV-229E, HCoV-OC43 and/or SARS-CoV-2, particularly preferably SARS-CoV-2.
• Coronavirus infections include infections by HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV, MERS-CoV, and/or SARS-CoV-2.
• infections caused by HCoV-229E, HCoV-OC43 and/or SARS-CoV-2 particularly preferably infections caused by SARS-CoV-2.
• a novel coronavirus infection (COVID-19) is particularly preferred as the coronavirus infection.
• the compounds represented by formula (I) according to the present invention can be produced, for example, by the general synthetic methods shown below. Extraction, purification, and the like may be carried out as in ordinary organic chemistry experiments.
• the compounds of the present invention can be produced with reference to methods known in the art. For example, it can be manufactured with reference to WO2013/184806, US4731106, WO2013/064083, and WO2020/261114.
• Ring A is an Aromatic Carbocyclic Ring or an Aromatic Heterocyclic Ring (Wherein, Lg is a leaving group, and other symbols are as defined above.)
• HATU, WSC ⁇ HCl and a condensing agent such as HOBt or PyBOP are added to compound (A-1) in the presence of a solvent such as DMF, DMA, NMP or THF or in a mixed solvent thereof to obtain an amine corresponding to the desired product.
• (A-2) and, if necessary, tertiary amines such as triethylamine, N-methylmorpholine and N,N-diisopropylethylamine are added, and the temperature is adjusted to 0.1 at 0°C to 60°C, preferably 20°C to 40°C.
• Compound (A-3) can be obtained by reacting for hours to 24 hours, preferably 0.5 hours to 12 hours.
• Compound (A-3) is treated with triphosgene, CDI, di-tert-butyl dicarbonate in the presence of a solvent such as DMF, DMA, NMP, THF, toluene, acetonitrile, dimethylsulfoxide, dioxane, dichloromethane or a mixed solvent thereof.
• a solvent such as DMF, DMA, NMP, THF, toluene, acetonitrile, dimethylsulfoxide, dioxane, dichloromethane or a mixed solvent thereof.
• Urea, 4-nitrophenyl chloroformate, methyl chloroformate, etc. are added, and the mixture is heated at 0° C. to 140° C., preferably 20° C. to 100° C. for 0.1 hour to 24 hours, preferably 0.5 hour.
• a compound (A-4) can be obtained by reacting for up to 12 hours.
• Compound (A-4) is treated with a compound corresponding to the desired product ( A-5) is added and reacted at 0° C. to 100° C., preferably 20° C. to 60° C. for 0.1 hour to 24 hours, preferably 0.5 hour to 12 hours to produce compound (I). can do.
• Leaving groups include, for example, halogen and —OSO 2 (C t F 2t+1 ) (where t is an integer of 1 to 4).
• Preferred halogens are chlorine, iodine and bromine
• preferred —OSO 2 (C t F 2t+1 ) groups are —OTf groups (trifluoromethanesulfonate).
• Ring A is an Aromatic Carbocyclic Ring or an Aromatic Heterocyclic Ring (Wherein, Lg is a leaving group, and other symbols are as defined above.)
• Compound (B-4) is treated with a compound corresponding to the desired product ( B-5) is added and reacted at 0° C. to 100° C., preferably 20° C. to 60° C. for 0.1 hour to 24 hours, preferably 0.5 hour to 12 hours to give compound (B-6).
• Leaving groups include, for example, halogen and —OSO 2 (C t F 2t+1 ) (where t is an integer of 1 to 4).
• Preferred halogens are chlorine, iodine and bromine
• preferred —OSO 2 (C t F 2t+1 ) groups are —OTf groups (trifluoromethanesulfonate).
• Ring A is a Non-Aromatic Carbocyclic Ring or a Non-Aromatic Heterocyclic Ring (Wherein, Lg is a leaving group, and other symbols are as defined above.)
• the compound (C-4) can be produced by Alternatively, the compound (C-2) is treated with a base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride in the presence of DMF, DMSO, NMP or the like, or in a mixed solvent thereof, to obtain the desired product.
• the compound (C-3) corresponding to is added and reacted at 0 ° C. to 100 ° C., preferably 20 ° C. to 60 ° C. for 0.1 hour to 24 hours, preferably 0.5 hours to 12 hours, to obtain a compound (C-4) can be produced.
• Leaving groups include, for example, halogen and —OSO 2 (C t F 2t+1 ) (where t is an integer of 1 to 4).
• Preferred halogens are chlorine, iodine and bromine
• preferred —OSO 2 (C t F 2t+1 ) groups are —OTf groups (trifluoromethanesulfonate).
• Compound (C-4) is treated with a compound corresponding to the target product ( C-5) is added and reacted at 0° C. to 100° C., preferably 20° C. to 60° C. for 0.1 hour to 24 hours, preferably 0.5 hour to 12 hours to give compound (C-6).
• Leaving groups include, for example, halogen and —OSO 2 (C t F 2t+1 ) (where t is an integer of 1 to 4).
• Preferred halogens are chlorine, iodine and bromine
• preferred —OSO 2 (C t F 2t+1 ) groups are —OTf groups (trifluoromethanesulfonate).
• the compounds according to the present invention have coronavirus 3CL protease inhibitory activity, they are useful as therapeutic and/or prophylactic agents for viral infections. Furthermore, the compound of the present invention is useful as a medicine, and preferably has one or more of the following excellent characteristics. a) It has a weak inhibitory effect on CYP enzymes (eg, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.). b) shows good pharmacokinetics such as high bioavailability and moderate clearance; c) high metabolic stability; d) Does not exhibit irreversible inhibitory action on CYP enzymes (eg, CYP3A4) within the concentration range of the measurement conditions described herein.
• CYP enzymes eg, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.
• coronavirus growth inhibitory activity for example, it has high coronavirus growth inhibitory activity under the addition of human serum (HS) or human serum albumin (HSA).
• HS human serum
• HSA human serum albumin
• EC 50 is 10 ⁇ M or less, preferably 1 ⁇ M or less, and more preferably 100 nM or less in the CPE suppression effect confirmation test (SARS-CoV-2) described later.
• the pharmaceutical composition of the present invention can be administered orally or parenterally.
• parenteral administration methods include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ocular, ear and intravaginal administration.
• internal solid preparations e.g., tablets, powders, granules, capsules, pills, films, etc.
• internal liquid preparations e.g., suspensions, emulsions, elixirs, syrups, etc.
• Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets, and powders and granules may be dry syrups.
• the capsules may be soft capsules, microcapsules or sustained release capsules.
• injections In the case of parenteral administration, injections, drops, external preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coatings, gargles, enemas, Any commonly used dosage form such as ointments, plasters, jellies, creams, patches, poultices, powders for external use, suppositories, etc.) can be suitably administered. Injections may be emulsions such as O/W, W/O, O/W/O and W/O/W types.
• a pharmaceutical composition can be prepared by mixing an effective amount of the compound of the present invention with various pharmaceutical additives such as excipients, binders, disintegrants, and lubricants suitable for the dosage form, if necessary. Furthermore, by appropriately changing the effective amount, dosage form and/or various pharmaceutical additives of the compound of the present invention, the pharmaceutical composition can be used as a pharmaceutical composition for children, the elderly, critically ill patients, or for surgery. You can also For example, a pediatric pharmaceutical composition can be used for neonates (less than 4 weeks after birth), infants (4 weeks after birth to less than 1 year), infants (1 to less than 7 years of age), children (7 to less than 15 years of age), or 15 Patients between the ages of 18 and 18 can be administered. For example, geriatric pharmaceutical compositions may be administered to patients 65 years of age or older.
• the dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the patient's age, body weight, type and degree of disease, administration route, etc., but when administered orally, it is usually 0.05 to 200 mg / kg/day, preferably within the range of 0.1 to 100 mg/kg/day. In the case of parenteral administration, it is generally 0.005 to 200 mg/kg/day, preferably 0.01 to 100 mg/kg/day, although it varies greatly depending on the route of administration. It may be administered once to several times a day.
• the compound of the present invention is, for example, a therapeutic drug for other novel coronavirus infections (COVID-19) (the therapeutic drug is not approved It may also be used in combination with drugs received, and drugs under development or to be developed) (hereinafter referred to as concomitant drugs).
• the timing of administration of the compound of the present invention and the concomitant drug is not limited, and they may be administered to the subject at the same time or at different times.
• the compound of the present invention and the concomitant drug may be administered as two or more formulations containing each active ingredient, or may be administered as a single formulation containing those active ingredients.
• the dosage of the concomitant drug can be appropriately selected based on the clinically used dosage.
• the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination, and the like. For example, when the subject of administration is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.
• CDI carbonyldiimidazole
• DMA dimethylacetamide
• DMAP 4-dimethylaminopyridine
• DMF N,N-dimethylformamide
• ESI electrospray ionization
• FBS fetal bovine serum
• NMP N-methylpyrrolidone
• PdCl 2 (dppf) [1,1 '-Bis(diphenylphosphino)ferrocene]palladium
• II dichloride dichloromethane adduct
• PyBOP (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate
• RT retention time
• RuPhos Pd G3 (2-dicyclohexylphosphino -2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)
• Step 4 Synthesis of Compound 4 Compound 3 (50.0 mg, 0.137 mmol), DMF (1.0 ml) and potassium carbonate (37.7 g, 0.273 mmol) were mixed and stirred at room temperature for 10 minutes. 1-(Bromomethyl)-2,4,5-trifluorobenzene (32.3 mg, 0.143 mmol) was added at 0° C., warmed to room temperature and stirred for 2 hours. Water was added to the reaction solution, and the precipitated solid was dissolved in chloroform, washed with water, and dried over sodium sulfate.
• Step 5 Synthesis of compound 5 Compound 4 (48.0 mg, 0.0940 mmol), (5-carbamoyl-2-chlorophenyl)boronic acid (24.4 mg, 0.122 mmol), dioxane (0.7 ml), 2 mol/ An L potassium carbonate aqueous solution (0.0940 ml, 0.188 mmol) and PdCl 2 (dppf) (6.88 mg, 0.00941 mmol) were mixed and stirred at 90° C. for 4 hours under nitrogen atmosphere. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. After the organic layer was washed with water, it was dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
• Step 2 Synthesis of Compound 10
• Compound 11 (3.32 g, 20.9 mmol) was dissolved in acetic acid (33 ml), sodium iodide (3.76 g, 25.1 mmol), chloramine T (7.07 g, 25.1 mmol). was added and stirred at room temperature for 30 minutes.
• a 10 mol/L sodium hydroxide aqueous solution (61.2 ml, 612 mmol), ethyl acetate (30 ml), sodium thiosulfate (3.31 g, 20.9 mmol) and water (30 ml) were added to the reaction mixture to separate the layers.
• Step 4 Synthesis of Compound 12
• Compound 11 (2.86 g, 13.2 mmol) was dissolved in methanol (30 ml) and tetrahydrofuran (15 ml), and 2 mol/L sodium hydroxide aqueous solution (33.0 ml, 66.0 mmol) was added to give Stirred at 60° C. for 45 minutes. After cooling to room temperature, it was neutralized with 2 mol/L hydrochloric acid. The precipitated solid was collected by filtration and washed with water to obtain compound 12 (1.47 g, 7.28 mmol, yield 55%).
• Step 5 Synthesis of Compound 13 Compound 13 (691 mg, 2.33 mmol, yield 94%) was obtained in the same manner as Step 1 of Example 1.
• Step 7 Synthesis of Compound 15 Compound 15 (265 mg, 0.568 mmol, yield 92%) was obtained in the same manner as Step 4 of Example 1.
• Step 8 Synthesis of Compound (I-0176)
• Compound (I-0176) (126 mg, 0.222 mmol, yield 69%) was obtained in the same manner as in Step 5 of Example 1.
• Step 9 Synthesis of compound (I-0177)
• Compound 18 (111 mg, 0.195 mmol), chlorotrimethylsilane (63.7 mg, 0.586 mmol), sodium iodide (88.0 mg, 0.586 mmol), acetonitrile (1. 1 ml) were mixed and stirred at 70° C. for 30 minutes.
• the reaction solution was cooled to room temperature, saturated aqueous sodium hydrogencarbonate solution was added, and the precipitated solid was collected by filtration and washed with water to obtain compound 19 (85.7 mg, 0.155 mmol, yield 79%).
• Step 10 Synthesis of Compound (I-0169)
• Compound (I-0177) (76.4 mg, 0.138 mmol) was dissolved in DMF (1.5 ml), and cesium carbonate (225 mg, 0.690 mmol) and iodomethane (98. 0 mg, 0.690 mmol) was added and stirred at room temperature for 45 minutes.
• Water (5 ml) and ethyl acetate (5 ml) were added to the reaction mixture to separate the layers, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate.
• Step 2 Synthesis of compound 17
• Dichloromethane (2.0 ml) was added to compound 16 (200 mg, 0.392 mmol), and 1.0 mol/L boron tribromide-dichloromethane solution (0.862 ml, 0.862 mmol) was added at 0°C. The mixture was added and stirred as it was for 2 hours.
• Methanol (2.0 ml) and 2.0 mol/L sodium hydroxide aqueous solution (1.5 ml) were added to the reaction solution, and the mixture was stirred at 50° C. for 1 hour.
• the reaction solution was cooled to room temperature, and the precipitated solid was collected by filtration and washed with water to obtain compound 17 (181 mg, 0.349 mmol, yield 89%).
• Step 3 Synthesis of compound 18 Compound 17 (192 mg, 0.370 mmol) was dissolved in DMF (1.0 ml), potassium carbonate (51.1 mg, 0.370 mmol) and allyl bromide (0.0680 ml, 0.740 mmol). was added and stirred at 60° C. for 5 hours. Compound 18 (175 mg, 0.326 mmol, 88% yield) was obtained by cooling the reaction solution to room temperature, adding water, and filtering the precipitated solid.
• Step 4 Synthesis of compound 19 Compound 18 (175 mg, 0.326 mmol) was dissolved in NMP (1.3 ml) and stirred at 240°C for 1 hour. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain compound 19 (175 mg, 0.326 mmol, yield 100%).
• Step 5 Synthesis of compound 20 Compound 19 (175 mg, 0.326 mmol) was dissolved in tetrahydrofuran (1.5 ml) and water (0.5 ml), 2,6-lutidine (0.0760 ml, 0.653 mmol), periodine Sodium phosphate (209 mg, 0.979 mmol) and potassium osmate (VI) dihydrate (3.61 mg, 0.00979 mmol) were added and stirred at room temperature for 1.5 hours. Water (3 ml) and ethyl acetate (5 ml) were added to the reaction mixture to separate the layers, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate.
• Step 8 Synthesis of compound (I-0353) Using compound 22 (33.2 mg, 0.0640 mmol), compound (I-0353) (25.4 mg, 0.0420 mmol, Yield 66%) was obtained.
• Step 3 Synthesis of compound (I-0325)
• Compound 24 (55.0 mg, 0.127 mmol), chlorotrimethylsilane (41.6 mg, 0.382 mmol), sodium iodide (57.3 mg, 0.382 mmol), acetonitrile ( 2.2 ml) were mixed and stirred at 70° C. for 2 hours.
• the reaction solution was cooled to room temperature, an aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate.
• Step 2 Synthesis of Compound 26
• Compound 26 (20.0 g, 55.2 mmol, yield 77%) was obtained in the same manner as in Step 2 of Example 1.
• Step 3 Synthesis of Compound 27
• Compound 27 (19.4 g, 38.1 mmol, yield 93%) was obtained in the same manner as in Step 4 of Example 1.
• Step 2 Synthesis of Compound 30
• Compound 29 (3.04 g, 9.25 mmol) was dissolved in methanol (15 mL) and tetrahydrofuran (15 mL), 2 mol/L sodium hydroxide aqueous solution (23.1 mL, 46.2 mmol) was added, Stirred at 60° C. for 1 hour. After cooling to room temperature, it was neutralized with 2 mol/L hydrochloric acid. The precipitated solid was collected by filtration and washed with water to obtain compound 30 (2.53 g, 8.04 mmol, yield 87%).
• Step 3 Synthesis of compound 31
• Compound 30 (1.10 g, 3.50 mmol) was dissolved in DMF (11 mL), 7-fluoroimidazo[1,2-a]pyridin-3-amine (634 mg, 4.19 mmol), PyBOP (2.37 g, 4.54 mmol), diisopropylethylamine (1.53 mL, 8.74 mmol) were added and stirred at room temperature for 3 hours.
• Water (50 mL) was added to the reaction mixture to separate the layers, and the aqueous layer was extracted with ethyl acetate. After the organic layer was washed with water, it was dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
• Step 4 Synthesis of Compound (I-1065)
• Compound 31 (1.20 g, 2.68 mmol), 1,3,5-trifluoro-2-nitrobenzene (949 mg, 5.36 mmol), CDI (1.74 g, 10.6 mmol). 7 mmol) was dissolved in DMA (24 mL), 60% sodium hydride (322 mg, 8.04 mmol) was added at 0° C. and stirred at the same temperature for 30 minutes. The reaction solution was added to a mixed solution of water (50 mL) and 2 mol/L hydrochloric acid (2 mL) and extracted with ethyl acetate.
• Step 5 Synthesis of compound (I-0978)
• Compound (I-1065) (47.0 mg, 0.0990 mmol), (1S,4S)-2-oxa-5-azabicyclo[2,2,1]heptane hydrochloride ( 14.8 mg, 0.109 mmol) and diisopropylethylamine (0.0518 mL, 0.298 mmol) were dissolved in DMA (0.47 mL) and stirred at 110° C. for 2 hours. Water (20 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After the organic layer was washed with water, it was dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
• the compound represented by the formula (I) according to the present invention has a coronavirus 3CL protease inhibitory action and may inhibit coronavirus 3CL protease.
• the IC50 is preferably 50 ⁇ M or less, more preferably 1 ⁇ M or less, and even more preferably 100 nM or less.
• Test Example 1-1 Cytopathic effect (CPE) suppression effect confirmation test using human TMPRSS2-expressing Vero E6 cells (Vero E6/TMPRSS2 cells) ⁇ Operating procedure> ⁇ Dilution and dispensing of test sample Dilute the test sample with DMSO in advance to an appropriate concentration, prepare a 2- to 5-fold serial dilution series, and then dispense into a 384-well plate.
• CPE Cytopathic effect
• Test Example 1-2 Cytopathic effect (CPE) suppression effect confirmation test using human TMPRSS2 and ACE2-expressing HEK293T cells (HEK293T/ACE2-TMPRSS2 cells) ⁇ Operating procedure> ⁇ Dilution and dispensing of test sample Dilute the test sample with DMSO in advance to an appropriate concentration, prepare a 2- to 5-fold serial dilution series, and then dispense into a 384-well plate.
• CPE Cytopathic effect
• the luminescence signal (Lum) is measured with a plate reader.
• x is the logarithmic value of the compound concentration and y is % Efficacy
• the compounds of the invention were tested essentially as described above. The results are shown below.
• the EC50 value is "A” when less than 0.1 ⁇ M, "B” when 0.1 ⁇ M or more and less than 1 ⁇ M, and "C” when 1 ⁇ M or more and less than 10 ⁇ M.
• Test Example 2 SARS-CoV-2 3CL protease inhibitory activity test ⁇ Material> ⁇ Commercially available Recombinant SARS-CoV-2 3CL Protease - Commercially available substrate peptide Dabcyl-Lys-Thr-Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe-Arg-Lys-Met-Glu(Edans)-NH2 (SEQ ID NO: 1) - Internal Standard peptide Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Gln (SEQ ID NO: 2) Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Gln is described in the literature (Atherton, E.; Sheppard, R.C., "In Solid Phase Peptide Synthesis, A Practical Approach", IRL Press at Oxford University).
• an assay buffer consisting of 20 mM Tris-HCl, 1 mM EDTA, 10 mM DTT, 0.01% BSA is used.
• ⁇ Dilution and dispensing of test sample Dilute the test sample with DMSO in advance to an appropriate concentration, prepare a 2- to 5-fold serial dilution series, and then dispense into a 384-well plate. Addition of Enzyme and Substrate, Enzyme Reaction Add 8 ⁇ M substrate and 6 or 0.6 nM enzyme solution to the prepared compound plate and incubate at room temperature for 3 to 5 hours.
• reaction stop solution (0.067 ⁇ M Internal Standard, 0.1% formic acid, 10 or 25% acetonitrile) is added to stop the enzymatic reaction.
• Measurement of Reaction Products Reaction completed plates are measured using a Rapid Fire System 360 and mass spectrometer (Agilent, 6550 iFunnel Q-TOF) or a Rapid Fire System 365 and mass spectrometer (Agilent, 6495C Triple Quadrupole).
• a solution (75% isopropanol, 15% acetonitrile, 5 mM ammonium formate
• B solution 0.01% trifluoroacetic acid, 0.09% formic acid
• the reaction product detected by the mass spectrometer is calculated using RapidFire Integrator or a program capable of equivalent analysis and taken as a product area value.
• the internal standard detected at the same time is also calculated and used as the internal standard area value.
• ⁇ Calculation of each measurement item value> ⁇ P/IS is calculated by calculating the area value obtained in the item before calculating P/IS using the following formula.
• P / IS Product area value / Internal Standard area value 50% SARS-CoV-2 3CL protease inhibitory concentration (IC 50 ) calculation
• x is the logarithmic value of the compound concentration and y is % Inhibition
• y is % Inhibition
• the compounds of the invention were tested essentially as described above. Results are shown in the table below.
• the IC 50 value is "A” when less than 0.1 ⁇ M, "B” when 0.1 ⁇ M or more and less than 1 ⁇ M, and "C” when 1 ⁇ M or more and less than 10 ⁇ M. (result)
• Test Example 3 CYP Inhibition Test Using commercially available pooled human liver microsomes, O-deethylation of 7-ethoxyresorufin, which is a typical substrate metabolic reaction of major human CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4). (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), hydroxylation of terfenadine (CYP3A4), The extent to which the amount of each metabolite produced is inhibited by the compounds of the invention is assessed.
• reaction conditions are as follows: substrate, 0.5 ⁇ mol/L ethoxyresorufin (CYP1A2), 100 ⁇ mol/L tolbutamide (CYP2C9), 50 ⁇ mol/L S-mephenytoin (CYP2C19), 5 ⁇ mol/L dextromethorphan (CYP2D6), 1 ⁇ mol/L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37°C; enzyme, pooled human liver microsomes 0.2 mg protein/mL; concentration of the compound of the present invention, 1, 5, 10, 20 ⁇ mol/L (4 points) .
• resorufin CYP1A2 metabolite
• CYP1A2 metabolite resorufin in the centrifugation supernatant was quantified using a fluorescence multi-label counter or LC/MS/MS, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4'-hydroxylation. body (CYP2C19 metabolite), dextrorphan (CYP2D6 metabolite), terfenadine alcohol (CYP3A4 metabolite) are quantified by LC/MS/MS. Note that the dilution concentration and dilution solvent are changed as necessary.
• Test Example 4 CYP3A4 (MDZ) MBI Test Regarding the CYP3A4 inhibition of the compounds of the present invention, this is a test to evaluate the mechanism based inhibition (MBI) ability from the enhancement of the inhibitory action resulting from the metabolic reaction of the compounds of the present invention. CYP3A4 inhibition is evaluated using pooled human liver microsomes as an index of 1-hydroxylation of midazolam (MDZ).
• Reaction conditions were as follows: substrate, 10 ⁇ mol/L MDZ; pre-reaction time, 0 or 30 minutes; substrate metabolism reaction time, 2 minutes; reaction temperature, 37°C; 0.05 mg/mL at the time of reaction (at 10-fold dilution); point).
• a control (100%) was obtained by adding only DMSO, which is a solvent in which the compound was dissolved instead of the compound of the present invention, to the reaction solution, and the residual activity (%) was calculated when the compound of the present invention was added at each concentration, IC is calculated by inverse estimation by logistic model using concentration and inhibition rate.
• Preincubation IC of 0 min/Preincubation IC of 30 min is taken as the Shifted IC value, and if the Shifted IC is 1.5 or more, it is positive, and if the Shifted IC is 1.0 or less, it is negative.
• Administration method Oral administration is forcibly administered into the stomach using an oral probe. Intravenous administration is administered through the tail vein using a syringe with an injection needle. (6) Evaluation item: Blood is collected over time, and the concentration of the compound of the present invention in plasma is measured using LC/MS/MS. (7) Statistical analysis: Concerning the transition of the concentration of the compound of the present invention in plasma, the area under the plasma concentration-time curve (AUC) was calculated by the moment analysis method. Calculate the bioavailability (BA) of the compounds of the invention. Note that the dilution concentration and dilution solvent are changed as necessary.
• Test Example 7 Metabolic Stability Test Pooled human liver microsomes or pooled rat liver microsomes were reacted with the compound of the present invention for a certain period of time, and the residual rate was calculated by comparing the reacted and unreacted samples. Evaluate the extent to which
• the compound of the present invention in the centrifugation supernatant is quantified by LC/MS/MS or solid phase extraction (SPE)/MS, and the amount of the compound of the present invention after reaction for 0 minutes is taken as 100%. is shown as the residual rate.
• the hydrolysis reaction was carried out in the absence of NADPH, and the glucuronidation reaction was carried out in the presence of 5 mmol/L UDP-glucuronic acid instead of NADPH.
• the dilution concentration and dilution solvent are changed as necessary.
• the composition of the JP-1 liquid is as follows. Add water to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to make 1000 mL.
• the composition of the JP-2 liquid is as follows. One volume of water is added to one volume of 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate dissolved in water to make up to 1000 mL.
• the formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention in any way.
• the compounds of the invention can be administered topically by any conventional route, especially enterally, e.g. orally, e.g. in the form of tablets or capsules, or parenterally, e.g. in the form of injection solutions or suspensions.
• it can be administered as a pharmaceutical composition in the form of lotions, gels, ointments or creams, or in nasal or suppository form.
• a pharmaceutical composition comprising a compound of the invention in free form or in pharmaceutically acceptable salt form together with at least one pharmaceutically acceptable carrier or diluent can be prepared by mixing, mixing, It can be manufactured by a granulation or coating method.
• oral compositions can be tablets, granules, capsules containing excipients, disintegrants, binders, lubricants, etc. and active ingredients.
• injectable compositions may be in the form of solutions or suspensions, may be sterilized, and may contain preservatives, stabilizers, buffers and the like.
• the compound according to the present invention has an inhibitory effect on coronavirus 3CL protease, and is believed to be useful as a therapeutic and/or prophylactic agent for diseases or conditions involving coronavirus 3CL protease.

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