Pharmaceutical for preventing and treating HIV infection characterized by combining integrase inhibitor and Anti-HIV drug

Abstract

To provide pharmaceuticals useful for the prevention or treatment of HIV infection.SOLUTION: Provided is a pharmaceutical for preventing or treating HIV infection, comprising: (A) a compound represented by formula (I): (where, ring A is a non-aromatic heterocycle; ring B is a benzene ring or a pyridine ring; Q is -NHC(O)- or the like; R1 is each independently halogen or the like; R2a and R2b are each independently hydrogen or the like; R3 is alkyl or haloalkyl; R4 is hydrogen or alkyl; and n is an integer of 1 to 3), or a pharmaceutically acceptable salt thereof, in combination with (B) a compound having anti-HIV activity or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical for preventing and treating HIV infection, more specifically to a pharmaceutical for preventing and treating HIV infection, which comprises a compound having HIV-1 integrase inhibitory activity or a pharmaceutically acceptable salt thereof in combination with at least one compound having anti-HIV activity or a pharmaceutically acceptable salt thereof. [Background technology]

[0002] Among viruses, the human immunodeficiency virus (HIV), a type of retrovirus, is known to cause acquired immunodeficiency syndrome (AIDS). Reverse transcriptase inhibitors (TDF, 3TC, etc.), protease inhibitors (darunavir, etc.), and integrase inhibitors (dolutegravir, etc.) have been the mainstream treatments for AIDS. However, side effects and the emergence of resistant viruses have become apparent, and the development of anti-HIV drugs with a different mechanism of action is anticipated.

[0003] Since the development of combination antiretroviral therapy (cART) in 1996, anti-HIV efficacy and the emergence of drug-resistant viruses have dramatically improved, significantly improving the prognosis for HIV-infected patients. Currently, cART, which involves oral combinations of two to four anti-HIV drugs, has become the standard treatment for HIV / AIDS. The three anti-HIV drugs recommended for initial treatment in combination therapy are polymerase inhibitors, protease inhibitors, and integrase inhibitors. However, drugs with the same mechanism of action often exhibit cross-resistance or only additive effects. Furthermore, the emergence of common drug-resistant mutations can render other drugs in the same class ineffective. Therefore, there is a need for the development of anti-HIV drugs with distinct mechanisms of action that are effective against existing drug-resistant mutant viruses.

[0004] Bicyclic or higher carbamoylpyridone derivatives are known as anti-HIV drugs having integrase inhibitory activity (Patent Documents 1 to 29). Among these, Patent Document 3 describes a carbamoylpyridotriazine derivative. Furthermore, pyridone derivatives having a heterocyclic side chain are known as anti-HIV drugs having integrase inhibitory activity (Patent Documents 5, 8, 9, 12, 13, 19, 23, 24, 27, 30-33). Of these, Patent Document 9 describes a fused tricyclic pyridopyrazine derivative. Furthermore, Patent Document 5 describes a fused tricyclic pyridopyrazine derivative and a fused tricyclic pyridotriazine derivative. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2006 / 088173 Pamphlet [Patent Document 2] International Publication No. 2006 / 116764 Brochure [Patent Document 3] International Publication No. 2007 / 049675 Pamphlet [Patent Document 4] International Publication No. 2011 / 129095 Brochure [Patent Document 5] International Publication No. 2014 / 099586 Brochure [Patent Document 6] International Publication No. 2014 / 100323 Brochure [Patent Document 7] International Publication No. 2014 / 104279 Brochure [Patent Document 8] International Publication No. 2014 / 183532 Brochure [Patent Document 9] International Publication No. 2014 / 200880 Brochure [Patent Document 10] International Publication No. 2015 / 039348 Brochure [Patent Document 11] International Publication No. 2015 / 048363 Brochure [Patent Document 12] International Publication No. 2015 / 089847 Brochure [Patent Document 13] International Publication No. 2015 / 095258 Brochure [Patent Document 14] International Publication No. 2015 / 006731 Brochure [Patent Document 15] International Publication No. 2015 / 006733 Brochure [Patent Document 16] International Publication No. 2015 / 199167 Brochure [Patent Document 17] International Publication No. 2016 / 090545 Brochure [Patent Document 18] International Publication No. 2016 / 094198 Brochure [Patent Document 19] International Publication No. 2016 / 094197 Brochure [Patent Document 20] International Publication No. 2016 / 106237 Brochure [Patent Document 21] International Publication No. 2016 / 154527 Brochure [Patent Document 22] International Publication No. 2016 / 161382 Brochure [Patent Document 23] International Publication No. 2016 / 187788 Brochure [Patent Document 24] International Publication No. 2016 / 191239 Brochure [Patent Document 25] International Publication No. 2017 / 087256 Brochure [Patent Document 26] International Publication No. 2017 / 087257 Brochure [Patent Document 27] International Publication No. 2017 / 106071 Brochure [Patent Document 28] International Publication No. 2017 / 113288 Brochure [Patent Document 29] International Publication No. 2017 / 116928 Brochure [Patent Document 30] International Publication No. 2005 / 016927 Pamphlet [Patent Document 31] International Publication No. 2011 / 105590 Brochure [Patent Document 32] International Publication No. 2013 / 054862 Brochure [Patent Document 33] International Publication No. 2016 / 027879 Brochure Summary of the Invention [Problem to be solved by the invention]

[0006] The object of the present invention is to provide a pharmaceutical useful for the treatment or prevention of HIV infection, which has strong anti-HIV activity by using drugs with different mechanisms in combination, suppresses the emergence of drug-resistant HIV, and is effective against mutant strains and strains resistant to existing drugs. [Means for solving the problem]

[0007] The present invention provides the following inventions. [1] (A) Formula (I): [ka] (wherein ring A is any one of the following rings: [ka] X1 is a CR 9a R 9b or O; R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are each independently hydrogen, halogen, alkyl, haloalkyl, alkyloxy, alkyloxyalkyl, or a 3- to 6-membered non-aromatic carbocyclic group; R 5a and R 6a , or R 6a and R 7a may be taken together with the adjacent atom to form an aromatic carbocycle which may be substituted with halogen, a 3- to 6-membered non-aromatic carbocycle which may be substituted with halogen, or a 4- to 6-membered non-aromatic heterocycle which may be substituted with halogen (however, when forming an aromatic carbocycle, R 5b and R 6b , or R 6b and R 7b come together to form a bond); R 5b and R 6b may be taken together to form a bond; R 8a , R 8b , R 9a , R 9b , R 10a , R 10b , R 11a and R 11bare each independently hydrogen, halogen, alkyl, haloalkyl, alkyloxy, alkyloxyalkyl, or a 3- to 6-membered non-aromatic carbocyclic group; R 8a and R 10a may together form a C1-C3 bridge; R 10a and R 11a may be taken together with adjacent atoms to form a 5-membered non-aromatic carbocyclic ring; R 9a and R 9b may be taken together with adjacent atoms to form a 4-membered non-aromatic carbocyclic ring or a 5-membered non-aromatic heterocyclic ring; R 8a and R 9a may come together to form a bond; Ring B is a benzene ring or a pyridine ring; Q is -NHC(O)- or a 5-membered aromatic heterocycle; R 1 are each independently halogen, alkyl, haloalkyl, alkyloxy, cyano, or haloalkyloxy; R 2a and R 2b are each independently hydrogen, alkyl, or haloalkyl; R 3 is alkyl or haloalkyl; R 4 is hydrogen or alkyl; and n is an integer from 1 to 3. or a pharmaceutically acceptable salt thereof; (B) A compound having anti-HIV activity or a pharmaceutically acceptable salt thereof A pharmaceutical for preventing or treating HIV infection, comprising the combination of: [2]R 3 [1] The pharmaceutical agent according to [1], wherein [3]R 1 The pharmaceutical according to [1] or [2], wherein each of these is independently a halogen. [4]R 2a is hydrogen and R 2bThe medicine according to any one of [1] to [3], wherein [5] The medicine according to any one of [1] to [4], wherein Q is -NHC(O)-. [6] The medicine according to any one of [1] to [4], wherein Q is a 5-membered aromatic heterocycle. [7](A) is the compound I-3, I-7, I-11, I-16, I-23, I-24, I-32, II-1, II-4, II-5, II-13, II-14, II-16, II-19, II-21, II-23, II-26, II-31, II-34, II-3 6, II-38, II-41, II-43, II-45, II-47, II-49, II-52, II-56, II-58, II-62, II-63, II-64, II-68, II-89, II-92, II-93, II-95, II-96, II-98, The pharmaceutical composition according to [1], wherein the compound is selected from the group consisting of II-106, II-109, II-110, II-112, II-113, II-117, II-118, II-125, II-127, II-128, II-129, II-130, II-131, II-132, II-136, II-138, II-139, II-142, II-143, II-144, II-147, II-148, II-149, II-150, II-151, II-155, II-156, II-157, and pharmaceutically acceptable salts thereof. [8] The pharmaceutical according to any one of [1] to [7], wherein (B) is at least one selected from compounds having a polymerase inhibitory activity, compounds having a ribonuclease H inhibitory activity, compounds having an allosteric inhibitory activity against the HIV-1 Integrase (IN)-Lens epitherium-derived growth factor (LEDGF) complex, compounds having a protease inhibitory activity, compounds having an adsorption / entry inhibitory activity, compounds having a budding inhibitory activity, compounds having a maturation inhibitory activity, and compounds having a capsid inhibitory activity, and pharmaceutically acceptable salts thereof. [8-1] The pharmaceutical according to any one of [1] to [7], wherein (B) is at least one selected from compounds having a polymerase inhibitory activity, compounds having a ribonuclease H inhibitory activity, compounds having an allosteric inhibitory activity against the HIV-1 Integrase (IN)-Lens epitherium-derived growth factor (LEDGF) complex, compounds having a protease inhibitory activity, compounds having an adsorption / invasion inhibitory activity, compounds having a budding inhibitory activity, compounds having a maturation inhibitory activity, compounds having a capsid inhibitory activity, pharmaceutically acceptable salts thereof, and antibodies having anti-HIV activity. [9] A compound having an allosteric inhibitory activity against the HIV-1 integrase (IN)-lens epitherium-derived growth factor (LEDGF) complex is represented by the formula (I'): [ka] (In the formula, R 3A ' and R 4A' each independently represents hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, ringoxy, substituted or unsubstituted non-aromatic carbocycleoxy, substituted or unsubstituted aromatic heterocycleoxy, substituted or unsubstituted non-aromatic heterocycleoxy, substituted or unsubstituted aromatic carbocyclesulfanyl, substituted or unsubstituted non-aromatic carbocyclesulfanyl, substituted or unsubstituted aromatic heterocyclesulfanyl, substituted or unsubstituted non-aromatic heterocyclesulfanyl, substituted or unsubstituted aromatic carbocyclecarbonyl, substituted or unsubstituted non-aromatic carbocyclecarbonyl, substituted or unsubstituted aromatic heterocyclecarbonyl, substituted or unsubstituted non-aromatic heterocyclecarbonyl, substituted or unsubstituted amino, or substituted or unsubstituted carbamoyl; R 3A ' and R 4A ' may, together with adjacent atoms, form a substituted or unsubstituted monocyclic carbocyclic ring or a substituted or unsubstituted monocyclic heterocyclic ring, and the carbocyclic ring or heterocyclic ring may be further fused with a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring; R 4A 'T 1 together with the atoms on the ring arcs, may form a substituted or unsubstituted monocyclic heterocycle, which may be further fused with a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle; T 1The ring is a substituted or unsubstituted monocyclic heterocycle, (1) the heterocycle may be fused with another substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, and / or (2) two non-adjacent atoms constituting the heterocycle may be bridged by a substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene; R 1 ' is halogen, cyano, nitro or X 1 '-R 11 ' and X 1 ' represents a single bond, -O-, -S-, -NR 12 '-, -CO-, -SO-, -SO2-, -O-CO-, -CO-O-, -NR 12 '-CO-, -CO-NR 12 '-, -NR 12 '-CO-O-, -NR 12 '-CO-NR 13 '-, -NR 12 '-SO2- or SO2-NR 12 '-and R 11 ' is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; R 12 ' and R 13 each independently represents a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl; X 1 '-NR 12 '-, -CO-NR 12 '- or SO2-NR 12 '-', then R 11 ' and R 12 ' may be taken together with the adjacent nitrogen atom to form a substituted or unsubstituted non-aromatic heterocycle, X 1 '-NR 12'-CO-NR 13 '-', then R 11 ' and R 13 ' may be taken together with the adjacent nitrogen atom to form a substituted or unsubstituted non-aromatic heterocycle, R 1 'T 1 together with the carbon atoms or nitrogen atoms on the ring arcs, may form a substituted or unsubstituted monocyclic carbocycle or a substituted or unsubstituted monocyclic heterocycle, which may be further fused with a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle; R 2 each independently represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyloxy, or substituted or unsubstituted cycloalkenyloxy; n' is 1 or 2; R 3 ' means a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; R 4 ' is hydrogen or a carboxy-protecting group).

[10] (B) AZT, 3TC, didanosine, zalcitabine, sanilvudine, abacavir, tenofovir, tenofovir disoproxil, tenofovir Alafenamide, Emtricitabine, Nevirapine, Efavirenz, Capravirine, Etravirine, Delavirdine, Rilpivirine, VM-1500A, VM-1500, Doravirine, MK-8507, MK-8504, MK-8583, Compounds I'-001, I'-027, I'-043, I'-189, I'-220, I'-292, I'-304, Indinavir, Ritonavir, Saquinavir, Nelfinavir, Amprenavir, Atazanavir, Lopinavir, Fosamprenavir, Darunavir, Maraviroc, Enfuvirtide, Ibalizumab, PRO-140, Temsavir, Fostemsavir The pharmaceutical composition according to [8], which is at least one selected from tromethamine, Combinectin, BDM-2, GSK-2838232, GSK-3640254, GS-6207, MK-8527 and MK-8558, and pharmaceutically acceptable salts thereof. [10-1] (B) AZT, 3TC, didanosine, zalcitabine, sanilvudine, abacavir, tenofovir, tenofovir disoproxil, tenofovir Alafenamide, Emtricitabine, Nevirapine, Efavirenz, Capravirine, Etravirine, Delavirdine, Rilpivirine, VM-1500A, VM-1500, Doravirine, MK-8507, MK-8504, MK-8583, Compounds I'-001, I'-027, I'-043, I'-189, I'-220, I'-292, I'-304, Indinavir, Ritonavir, Saquinavir, Nelfinavir, Amprenavir, Atazanavir, Lopinavir, Fosamprenavir, Darunavir, Maraviroc, Enfuvirtide, Ibalizumab, PRO-140, Temsavir, Fostemsavir The pharmaceutical according to [8-1], which is at least one selected from tromethamine, Combinectin, BDM-2, GSK-2838232, GSK-3640254, GS-6207, MK-8527, MK-8558, pharmaceutically acceptable salts thereof, 3BNC117LS, 10-1074LS, GS-9722, GS-9723, N6LS, ARC07-523LS, and VRC01-LS.

[11] The pharmaceutical composition according to any one of [1] to

[10] , [8-1] and [10-1], wherein (A) and (B) are administered in combination.

[12] The pharmaceutical agent according to any one of [1] to

[10] , [8-1] and [10-1], which is a combination drug.

[13] An anti-HIV activity enhancer for a compound described in (B) of [1] or a pharmaceutically acceptable salt thereof, which has anti-HIV activity and contains a compound described in (A) of [1] or a pharmaceutically acceptable salt thereof.

[14] An anti-HIV activity enhancer for the compound described in (A) of [1] or a pharmaceutically acceptable salt thereof, which has anti-HIV activity and contains the compound described in (B) of [1] or a pharmaceutically acceptable salt thereof.

[15] A pharmaceutical composition comprising the compound described in (A) of [1] or a pharmaceutically acceptable salt thereof as an active ingredient, for use in combination with the compound described in (B) of [1] or a pharmaceutically acceptable salt thereof, which has anti-HIV activity.

[16] A pharmaceutical composition comprising a compound described in (B) of [1] or a pharmaceutically acceptable salt thereof as an active ingredient, for use in combination with a compound described in (A) of [1] or a pharmaceutically acceptable salt thereof, which has anti-HIV activity. [Effects of the Invention]

[0008] The medicament of the present invention is useful for treating and / or preventing HIV infection. BEST MODE FOR CARRYING OUT THE INVENTION

[0009] The meaning of each term used in this specification is explained below. Unless otherwise specified, each term has the same meaning whether used alone or in combination with other terms. The term "consisting of" means having only the constituent elements. The term "comprising" is meant to be open-ended and not to exclude unlisted elements.

[0010] The present invention provides a compound of formula (A) (I): [ka] (wherein ring A is any one of the following rings: [ka] X1 is a CR 9a R 9b or O; R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are each independently hydrogen, halogen, alkyl, haloalkyl, alkyloxy, or alkyloxyalkyl, or a 3-membered non-aromatic carbocyclic group; R 5a and R 6a , or R 6a and R 7a may be taken together with the adjacent atom to form an aromatic carbocycle which may be substituted with halogen, a 3- to 6-membered non-aromatic carbocycle which may be substituted with halogen, or a 4- to 6-membered non-aromatic heterocycle which may be substituted with halogen (however, when forming an aromatic carbocycle, R 5b and R 6b , or R 6b and R 7b come together to form a bond); R 5b and R 6b may be taken together to form a bond; R 8a , R 8b , R 9a , R 9b , R 10a , R 10b , R 11a and R 11b are each independently hydrogen, halogen, alkyl, haloalkyl, alkyloxy, alkyloxyalkyl, or a 3-membered non-aromatic carbocyclic group; R 8a and R 10a may together form a C1-C3 bridge; R 10a and R11a may be taken together with adjacent atoms to form a 5-membered non-aromatic carbocyclic ring; R 9a and R 9b may be taken together with adjacent atoms to form a 4-membered non-aromatic carbocyclic ring or a 5-membered non-aromatic heterocyclic ring; R 8a and R 9a may come together to form a bond; Ring B is a benzene ring or a pyridine ring; Q is -NHC(O)- or a 5-membered aromatic heterocycle; R 1 are each independently halogen, alkyl, haloalkyl, alkyloxy, cyano, or haloalkyloxy; R 2a and R 2b are each independently hydrogen, alkyl, or haloalkyl; R 3 is alkyl or haloalkyl; R 4 is hydrogen or alkyl; and n is an integer from 1 to 3. or a pharmaceutically acceptable salt thereof; (B) A compound having anti-HIV activity or a pharmaceutically acceptable salt thereof The pharmaceutical composition is characterized by combining the above.

[0011] The "compound having anti-HIV activity" (B) to be combined with (A) is a compound obtained by EC 50 The value is measured, and a compound having a value of less than 100 μM, preferably less than 1 μM, more preferably less than 100 nM can be used. However, the "compound having anti-HIV activity or a pharmaceutically acceptable salt thereof" used in (B) is a compound different from the compound used as (A) or a pharmaceutically acceptable salt thereof.

[0012] Examples of "compounds having anti-HIV activity" include compounds having polymerase inhibitory activity, compounds having ribonuclease H inhibitory activity, compounds having an allosteric inhibitory activity against the HIV-1 Integrase (IN)-Lens epitherium-derived growth factor (LEDGF) complex, compounds having protease inhibitory activity, compounds having adsorption / invasion inhibitory activity, compounds having budding inhibitory activity, compounds having maturation inhibitory activity, compounds having capsid inhibitory activity, and antibodies having equivalent anti-HIV activity. "Compounds having anti-HIV activity" are not limited to those that are commercially available or under development, but examples of commercially available or under development include AZT, 3TC, didanosine, zalcitabine, sanilvudine, abacavir, tenofovir, tenofovir disoproxil, tenofovir alafenamide, emtricitabine, nevirapine, efavirenz, capravirine, etravirine, delavirdine, rilpivirine, VM-1500A, VM-1500, doravirine, MK-8507, MK-8504, MK-8583, indinavir, ritonavir, saquinavir, nelfinavir, amprenavir, atazanavir, lopinavir, fosamprenavir, darunavir, maraviroc, enfuvirtide, ibalizumab, S-648414, PRO-140, temsavir, and fostemsavir. Examples include tromethamine, Combinectin, BDM-2, GSK-2838232, GSK-3640254, GS-6207, MK-8527, MK-8558, 3BNC117LS, 10-1074LS, GS-9722, GS-9723, N6LS, ARC07-523LS, and VRC01-LS. More preferred are 3TC, abacavir, tenofovir, tenofovir alafenamide, emtricitabine, rilpivirine, VM-1500A, VM-1500, doravirine, MK-8504, MK-8583, atazanavir, darunavir, maraviroc, enfuvirtide, ibalizumab, S-648414, PRO-140, fostemsavir tromethamine, Combinectin, BDM-2, GSK-2838232, GSK-3640254, GS-6207, and the like. The "compound having anti-HIV activity" preferably has a mechanism of action different from that of the compound used as (A) or a pharmaceutically acceptable salt thereof, that is, a compound other than a compound having an HIV integrase inhibitory activity. Preferred are compounds having a polymerase inhibitory activity, compounds having an allosteric inhibitory activity against the HIV-1 Integrase (IN)-Lens epitherium-derived growth factor (LEDGF) complex, and compounds having a protease inhibitory activity, and more preferred are compounds having a polymerase inhibitory activity.

[0013] The "compound having polymerase inhibitory activity" may be any compound that has polymerase inhibitory activity and falls under the above-mentioned "compound having anti-HIV activity." Prodrugs thereof are also included. Examples of "compounds having polymerase inhibitory activity" include, but are not limited to, the compounds described below. 3'-azido-3'-deoxythymidine; (-)-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-cytosine; 2',3'-dideoxyinosine; 2',3'-dideoxycytidine; (-)-2',3'-didehydro-3'-deoxythymidine; (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol; [[(R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acid; 4-amino-5-fluoro-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2(1H)-one; 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one; (-)-(S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one; 5-[(3,5-dichlorophenyl)thio]-4-isopropyl-1-(4-pyridylmethyl)imidazole-2-methanol carbamate; 4-[6-amino-5-bromo-2-(4-cyanoanilino)pyrimidin-4-yloxy]-3,5-dimethylbenzonitrile; N-(2-(4-(3-(isopropylamino)pyridin-2-yl)piperazine-1-carbonyl)-1H-indol-5-yl)methanesulfonamide; 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]pyrimidin-2-yl]amino]benzonitrile; 2-(4-bromo-3-(3-chloro-5-cyanophenoxy)-2-fluorophenyl)-N-(2-chloro-4-sulfamoylphenyl)acetamide; N-[4-[[2-[4-bromo-3-(3-chloro-5-cyanophenoxy)-2-fluorophenyl]acetyl]amino]-3-chlorophenyl]sulfonylpropanamide; 3-chloro-5-[[1-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy]benzonitrile; MK-8507; Compounds described in WO2014 / 058747; Examples of prodrugs include the compounds shown below. (R)-[[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acid bis(isopropoxycarbonyloxymethyl)este; 1-methylethyl N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinoyl]-L-alaninate; MK-8504; MK-8583

[0014] Preferred examples of the "compound having polymerase inhibitory activity, or a pharmaceutically acceptable salt thereof" include AZT, 3TC, didanosine, zalcitabine, sanilvudine, abacavir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, emtricitabine, nevirapine, efavirenz, capravirine, etravirine, delavirdine, delavirdine mesylate, rilpivirine, rilpivirine hydrochloride, VM-1500A, VM-1500, doravirine, MK-8507, MK-8504, MK-8583, and the like. More preferred examples include 3TC, abacavir, abacavir sulfate, tenofovir, tenofovir alafenamide fumarate, emtricitabine, rilpivirine, rilpivirine hydrochloride, VM-1500A, VM-1500, doravirine, MK-8504, and MK-8583.

[0015] The term "compounds having RNase H inhibitory activity" refers to any compounds that have RNase H inhibitory activity and fall under the above-mentioned "compounds having anti-HIV activity." Prodrugs thereof are also included. Examples of "compounds having RNase H inhibitory activity" include, but are not limited to, the compounds described below. Compounds described in WO2008 / 010964; Compounds described in WO2011 / 075747

[0016] The term "compounds having an allosteric inhibitory effect on the HIV-1 Integrase (IN)-Lens epitherium-derived growth factor (LEDGF) complex" refers to any compound that has an allosteric inhibitory effect on the HIV-1 Integrase (IN)-Lens epitherium-derived growth factor (LEDGF) complex and falls within the above-mentioned "compounds having anti-HIV activity." These compounds also include their prodrug forms. Examples of "compounds having an allosteric inhibitory activity against the HIV-1 Integrase (IN)-Lens epitherium-derived growth factor (LEDGF) complex" include compounds described in WO2015 / 174511, WO2016 / 194806, etc., including, but not limited to, the compounds described below. [ka] (In the formula, R 3A ' and R 4A' each independently represents hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, ringoxy, substituted or unsubstituted non-aromatic carbocycleoxy, substituted or unsubstituted aromatic heterocycleoxy, substituted or unsubstituted non-aromatic heterocycleoxy, substituted or unsubstituted aromatic carbocyclesulfanyl, substituted or unsubstituted non-aromatic carbocyclesulfanyl, substituted or unsubstituted aromatic heterocyclesulfanyl, substituted or unsubstituted non-aromatic heterocyclesulfanyl, substituted or unsubstituted aromatic carbocyclecarbonyl, substituted or unsubstituted non-aromatic carbocyclecarbonyl, substituted or unsubstituted aromatic heterocyclecarbonyl, substituted or unsubstituted non-aromatic heterocyclecarbonyl, substituted or unsubstituted amino, or substituted or unsubstituted carbamoyl; R 3A ' and R 4A ' may, together with adjacent atoms, form a substituted or unsubstituted monocyclic carbocyclic ring or a substituted or unsubstituted monocyclic heterocyclic ring, and the carbocyclic ring or heterocyclic ring may be further fused with a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring; R 4A 'T 1 together with the atoms on the ring arcs, may form a substituted or unsubstituted monocyclic heterocycle, which may be further fused with a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle; T 1The ring is a substituted or unsubstituted monocyclic heterocycle, (1) the heterocycle may be fused with another substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, and / or (2) two non-adjacent atoms constituting the heterocycle may be bridged by a substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene; R 1 ' is halogen, cyano, nitro or X 1 '-R 11 ' and X 1 ' represents a single bond, -O-, -S-, -NR 12 '-, -CO-, -SO-, -SO2-, -O-CO-, -CO-O-, -NR 12 '-CO-, -CO-NR 12 '-, -NR 12 '-CO-O-, -NR 12 '-CO-NR 13 '-, -NR 12 '-SO2- or SO2-NR 12 '-and R 11 ' is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; R 12 ' and R 13 each independently represents a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl; X 1 '-NR 12 '-, -CO-NR 12 '- or SO2-NR 12 '-', then R 11 ' and R 12 ' may be taken together with the adjacent nitrogen atom to form a substituted or unsubstituted non-aromatic heterocycle, X 1 '-NR 12'-CO-NR 13 '-', then R 11 ' and R 13 ' may be taken together with the adjacent nitrogen atom to form a substituted or unsubstituted non-aromatic heterocycle, R 1 'T 1 together with the carbon atoms or nitrogen atoms on the ring arcs, may form a substituted or unsubstituted monocyclic carbocyclic ring or a substituted or unsubstituted monocyclic heterocyclic ring, which may be further fused; R 2 each independently represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyloxy, or substituted or unsubstituted cycloalkenyloxy; n' is 1 or 2; R 3 ' means a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; R 4 ' is hydrogen or a carboxy protecting group).

[0017] Preferred examples of the "compound having an allosteric inhibitory activity against the HIV-1 Integrase (IN)-Lens epitherium-derived growth factor (LEDGF) complex, or a pharmaceutically acceptable salt thereof" include the compounds described below, or pharmaceutically acceptable salts thereof. [ka]

[0018] The "compound having protease inhibitory activity" may be any compound that has protease inhibitory activity and falls under the above-mentioned "compound having anti-HIV activity." Prodrugs thereof are also included. Examples of "compounds having protease inhibitory activity" include, but are not limited to, the compounds described below. (S)-1-((2S,4R)-4-benzyl-2-hydroxy-5-(((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)-5-oxopentyl)-N-(tert-butyl)-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide; 5-thiazolymethyl [(αS)-α-[(1S,3S)-1-hydroxy-3-[(2S)-2-[3-[(2-isopropyl-4-thiazolyl)methyl]-3-methylureido]-3-methylbutyramido]-4-phenylbutyl]phenetyl]carbamate; (-)-cis-N-tert-butyldecahydro-2-[(2R,3S)-2-hydroxy-4-phenyl-3-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(3S,4aS,8aS)-isoquinoline-3-carboxamide; (-)-(3S,4aS,8aS)-N-tert-butyl-2-[(2R,3R)-2-hydroxy-3-(3-hydroxy-2-methylbenzoylamino)-4-(phenylthio)butyl]decahydroisoquinoline-3-carboxamide; (3S)-tetrahydro-3-furyl[N-[(1S,2R)-3-(4-amino-N-isobutylbenzenesulfonamido)-1-benzyl-2-hydroxypropyl]carbamate; dimethyl (3S,8S,9S,12S)-9-benzyl-3,12-di-tert-butyl-8-hydroxy-4,11-dioxo-6-[4-(pyridin-2-yl)benzyl]-2,5,6,10,13-pentaazatetradecanedioate; (αS)-tetrahydro-N-[(αS)-α-[(2S,3S)-2-hydroxy-4-phenyl-3-[2-(2,6-xylyloxy)-acetamido]butyl]phenethyl]-α-isopropyl-2-oxo-1(2H)-pyrimidineacetamide; (S)-tetrahydrofuran-3-yl ((2S,3R)-4-((4-amino-N-isobutylphenyl)sulfonamido)-1-phenyl-3-(phosphonooxy)butan-2-yl)carbamate; (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl [(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1-benzyl-2-hydroxypropyl] carbamate

[0019] Preferred examples of the "compound having protease inhibitory activity or a pharmaceutically acceptable salt thereof" include indinavir, indinavir sulfate ethanolate, ritonavir, saquinavir, saquinavir mesylate, nelfinavir, nelfinavir mesylate, amprenavir, atazanavir, atazanavir sulfate, lopinavir, fosamprenavir, fosamprenavir calcium hydrate, darunavir, darunavir ethanolate, etc. More preferred examples include atazanavir, atazanavir sulfate, darunavir, darunavir ethanolate, etc.

[0020] The term "compounds having adsorption / penetration inhibitory activity" refers to any compound that has adsorption / penetration inhibitory activity and corresponds to the above-mentioned "compounds having anti-HIV activity." Prodrugs of these compounds are also included. Examples of "compounds having an action of inhibiting adsorption and invasion" include, but are not limited to, the compounds described below. 4,4-difluoro-N-[(1S)-3-[(1R,3S,5S)-3-[3-methyl-5-(propan-2-yl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]octan-8-yl]-1-phenylpropyl]cyclohexanecarboxamide; N-acetyl-L-tyrosyl-L-threonyl-L-seryl-L-leucyl-L-isoleucyl-L-histadyl-L-seryl-L-leucyl-L-isoleucyl-L-α-gl utamyl-L-α-glutamyl-L-seryl-L-glutaminyl-L-asparaginyl-L-glutaminyl-L-glutaminyl-L-α-glutamyl-L-lysyl-L-a sparaginyl-L-α-glutamyl-L-glutaminyl-L-α-glutamyl-L-leucyl-L-leucyl-L-α-glutamyl-L-leucyl-L-α-aspartyl-L- lysyl-L-tryptophyl-L-alanyl-L-seryl-L-leucyl-L-tryptophyl-L-asparaginyl-L-tryptophyl-L-phenylalaninamide; anti-CD4 antibody; Anti-CCR5 antibody; 1-(4-benzoylpiperazin-1-yl)-2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]ethane-1,2-dione; Combinectin Examples of prodrugs include the compounds shown below. Fostemsavir tromethamine

[0021] Preferred examples of the "compound having an adsorption / penetration inhibitory effect, or a pharmaceutically acceptable salt thereof" include maraviroc, enfuvirtide, ibalizumab, PRO-140, temsavir, fostemsavir tromethamine, and combinectin.

[0022] The "compound having budding inhibitory activity" may be any compound that has budding inhibitory activity and corresponds to the above-mentioned "compound having anti-HIV activity." Prodrugs thereof are also included.

[0023] The "compound having a maturation inhibitory effect" may be any compound that has a maturation inhibitory effect and corresponds to the above-mentioned "compound having an anti-HIV effect." Prodrugs thereof are also included. Examples of "compounds having a maturation inhibitory effect" include, but are not limited to, the compounds described below. GSK-2838232; GSK-3640254

[0024] Preferred examples of the "compound having a maturation inhibitory activity, or a pharmaceutically acceptable salt thereof" include GSK-2838232, GSK-3640254, and the like.

[0025] The term "compounds having capsid inhibitory activity" refers to any compounds that have capsid inhibitory activity and fall under the category of "compounds having anti-HIV activity" described above. Prodrugs thereof are also included. Examples of "compounds having capsid inhibitory activity" include, but are not limited to, the compounds described below. Compounds described in WO2012 / 065062; Compounds described in WO2013 / 006738; Compounds described in WO2014 / 110296; Compounds described in WO2014 / 110297; Compounds described in WO2014 / 110298; Compounds described in WO2014 / 134566; Compounds described in WO2015 / 130966; Compounds described in WO2016 / 033243; Compounds described in WO2018 / 035359; Compounds described in WO2018 / 203235; Compounds described in WO2019 / 161017; Compounds described in WO2019 / 198024; Compounds described in WO2020 / 031112; Compounds described in WO2020 / 053811; Compounds described in WO2020 / 058844; Compounds described in WO2020 / 084480; Compounds described in WO2020 / 084491; Compounds described in WO2020 / 084492; Compounds described in WO2020 / 089778; Compounds described in WO2020 / 095176; Compounds described in WO2020 / 095177; Compounds described in WO2020 / 157692

[0026] Preferred examples of the "compound having a capsid inhibitory activity or a pharmaceutically acceptable salt thereof" include GS-6207 (Lenacapavir), the compounds shown below or pharmaceutically acceptable salts thereof, and the like. [ka]

[0027] The "antibody having an anti-HIV activity equivalent thereto" may be any substance that has anti-HIV activity and falls under the above-mentioned "compound having anti-HIV activity." Examples of "antibodies having anti-HIV activity equivalent to those" include, but are not limited to, the antibodies described below. 3BNC117LS; 10-1074LS; GS-9722; GS-9723; N6LS; ARC07-523LS; VRC01-LS

[0028] The "compound having anti-HIV activity or a pharmaceutically acceptable salt thereof" may be one or more drugs, and is not limited to one drug.

[0029] The compound represented by formula (I) of (A), or a pharmaceutically acceptable salt thereof, or a solvate thereof will be explained below.

[0030] The term "halogen" includes fluorine, chlorine, bromine, and iodine atoms, with fluorine and chlorine atoms being particularly preferred.

[0031] The term "alkyl" includes straight-chain or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Examples of alkyl include 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, and n-decyl. Preferred embodiments of "alkyl" 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.

[0032] The term "alkenyl" refers to a linear or branched hydrocarbon group having one or more double bonds at any position and having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms. Examples of alkenyl include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, and pentadecenyl. Preferred embodiments of "alkenyl" include vinyl, allyl, propenyl, isopropenyl, and butenyl. More preferred embodiments include ethenyl and n-propenyl.

[0033] The term "alkynyl" refers to a linear or branched hydrocarbon group having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms, which has one or more triple bonds at any position. It may also have a double bond at any position. Examples of alkynyl include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl. Preferred embodiments of "alkynyl" include ethynyl, propynyl, butynyl, and pentynyl. More preferred embodiments include ethynyl, propynyl, and the like.

[0034] The term "alkylene" includes a straight-chain or branched divalent hydrocarbon group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, and hexamethylene.

[0035] The term "alkenylene" refers to a linear or branched divalent hydrocarbon group having one or more double bonds at any position and having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms. Examples include vinylene, propenylene, butenylene, and pentenylene.

[0036] The term "alkynylene" refers to a linear or branched divalent hydrocarbon group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms, and having one or more triple bonds at any position. These may further have a double bond at any position. Examples include ethynylene, propynylene, butynylene, pentynylene, and hexynylene.

[0037] The term "aromatic carbocyclic group" refers to a monocyclic or bicyclic or more aromatic hydrocarbon group, such as phenyl, naphthyl, anthryl, and phenanthryl. A preferred embodiment of the "aromatic carbocyclic group" is phenyl.

[0038] The term "non-aromatic carbocyclic group" refers to a monocyclic or bicyclic or multicyclic saturated or non-aromatic unsaturated hydrocarbon group. The term "non-aromatic carbocyclic group" refers to a monocyclic or bicyclic or multicyclic non-aromatic carbocyclic group in which the rings of the above-mentioned "aromatic carbocyclic group" are fused to the monocyclic or bicyclic or multicyclic non-aromatic carbocyclic group. Furthermore, "non-aromatic carbocyclic group" also includes groups that form bridged or spiro rings, such as: [ka] The monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and even more preferably 4 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl. The non-aromatic carbocyclic group having two or more rings preferably has 8 to 20 carbon atoms, more preferably 8 to 16. Examples thereof include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, and fluorenyl. The "cycloalkyl" preferably has 3 to 10 carbon atoms, more preferably 3 to 7 carbon atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like. "Cycloalkenyl" includes cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like.

[0039] The term "aromatic heterocyclic group" refers to a monocyclic or bicyclic or more aromatic cyclic group having one or more identical or different heteroatoms selected from O, S and N in the ring. The aromatic heterocyclic group having two or more rings also includes a monocyclic or two or more ring aromatic heterocyclic group fused with a ring in the above-mentioned "aromatic carbocyclic group", and the bond may be on any of the rings. The monocyclic aromatic heterocyclic group is preferably 5- to 8-membered, more preferably 5- or 6-membered. Examples of 5-membered aromatic heterocyclic groups include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, and thiadiazolyl. Examples of 6-membered aromatic heterocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. The bicyclic aromatic heterocyclic group is preferably 8- to 10-membered, more preferably 9- or 10-membered. Examples thereof include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, and thiazolopyridyl. The aromatic heterocyclic group having three or more rings is preferably 13 to 15-membered, and examples thereof include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, and dibenzofuryl.

[0040] The term "non-aromatic heterocyclic group" refers to a monocyclic or bicyclic or more non-aromatic cyclic group having one or more identical or different heteroatoms selected from O, S, and N in the ring. Bicyclic or more non-aromatic heterocyclic groups include those in which a monocyclic or bicyclic or more non-aromatic heterocyclic group is fused with each ring of the above-mentioned "aromatic carbocyclic group," "non-aromatic carbocyclic group," and / or "aromatic heterocyclic group," as well as those in which a monocyclic or bicyclic or more non-aromatic carbocyclic group is fused with a ring of the above-mentioned "aromatic heterocyclic group," and the bond may be on any ring. Furthermore, the term "non-aromatic heterocyclic group" also encompasses groups that form bridged or spiro rings, such as: [ka] The monocyclic non-aromatic heterocyclic group is preferably a 3- to 8-membered group, more preferably a 5- or 6-membered group. Examples of 3-membered non-aromatic heterocyclic groups include thiiranyl, oxiranyl, and aziridinyl. Examples of 4-membered non-aromatic heterocyclic groups include oxetanyl and azetidinyl. Examples of 5-membered non-aromatic heterocyclic groups include oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, and thiolanyl. Examples of 6-membered non-aromatic heterocyclic groups include dioxanyl, thianyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydropyranyl, dihydrooxazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxazinyl, thiinyl, thiazinyl, etc. Examples of 7-membered non-aromatic heterocyclic groups include hexahydroazepinyl, tetrahydrodiazepinyl, oxepanyl, etc. The non-aromatic heterocyclic group having two or more rings is preferably 8 to 20-membered, more preferably 8 to 10-membered, and examples thereof include indolinyl, isoindolinyl, chromanyl, and isochromanyl.

[0041] The terms "aromatic carbocycle", "non-aromatic carbocycle", "aromatic heterocycle" and "non-aromatic heterocycle" mean rings derived from the above-mentioned "aromatic carbocyclic group", "non-aromatic carbocyclic group", "aromatic heterocyclic group" and "non-aromatic heterocyclic group", respectively.

[0042] The term "carbocycle" refers to the above-mentioned "aromatic carbocycle" and "non-aromatic carbocycle". The term "heterocycle" means the above-mentioned "aromatic heterocycle" and "non-aromatic heterocycle".

[0043] Examples of the "carboxy-protecting group" include alkyl (eg, methyl, ethyl, t-butyl) and aralkyl (eg, benzyl), more preferably alkyl having 1 to 4 carbon atoms.

[0044] In this specification, the phrase "optionally substituted with substituent group α" means "optionally substituted with one or more groups selected from substituent group α." The same applies to substituent groups β, γ, γ', and E. "Optionally substituted with halogen" means "optionally substituted with one or more groups selected from halogens." Preferably, it may be substituted with 1 to 3 halogens.

[0045] Substituents for "substituted alkyl," "substituted alkenyl," "substituted alkynyl," "substituted alkylene," "substituted alkenylene," "substituted alkynylene," "substituted alkyloxy," "substituted alkenyloxy," "substituted alkynyloxy," "substituted alkylcarbonyl," "substituted alkenylcarbonyl," and "substituted alkynylcarbonyl" include the following Substituent Group A. Carbon atoms at any position may be bonded to one or more groups selected from the following Substituent Group A. Substituent group A: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl, Alkyloxy optionally substituted with substituent group α, alkenyloxy optionally substituted with substituent group α, alkynyloxy optionally substituted with substituent group α, alkylcarbonyloxy optionally substituted with substituent group α, alkenylcarbonyloxy optionally substituted with substituent group α, alkynylcarbonyloxy optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkyloxycarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α alkenyloxycarbonyl, alkynyloxycarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, sulfamoyl optionally substituted with substituent group β, Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic oxy optionally substituted with substituent group γ, non-aromatic carbocyclic oxy optionally substituted with substituent group γ', aromatic heterocyclic oxy optionally substituted with substituent group γ, non-aromatic heterocyclic oxy optionally substituted with substituent group γ', aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ, Non-aromatic carbocyclic carbonyloxy which may be substituted, aromatic heterocyclic carbonyloxy which may be substituted by substituent group γ, non-aromatic heterocyclic carbonyloxy which may be substituted by substituent group γ', aromatic carbocyclic carbonyl which may be substituted by substituent group γ, non-aromatic carbocyclic carbonyl which may be substituted by substituent group γ', aromatic heterocyclic carbonyl which may be substituted by substituent group γ, non-aromatic heterocyclic carbonyl which may be substituted by substituent group γ', aromatic carbocyclic oxycarbonyl which may be substituted by substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxy optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxy optionally substituted with substituent group γ', aromatic heterocyclic alkyloxy optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxy optionally substituted with substituent group γ', aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxycarbonyl which may be substituted, aromatic heterocyclic alkyloxycarbonyl which may be substituted with substituent group γ, non-aromatic heterocyclic alkyloxycarbonyl which may be substituted with substituent group γ', aromatic carbocyclic sulfanyl which may be substituted with substituent group γ, non-aromatic carbocyclic sulfanyl which may be substituted with substituent group γ', aromatic heterocyclic sulfanyl which may be substituted with substituent group γ, non-aromatic heterocyclic sulfanyl which may be substituted with substituent group γ', aromatic carbocyclic sulfinyl which may be substituted with substituent group γ,Non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ, and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0046] Substituent group α: halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, alkylamino, dialkylamino, alkylaminoalkyloxy, dialkylaminoalkyloxy, sulfanyl, cyano, nitro, guanidino and pentafluorothio.

[0047] Substituent group β: halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ' bonyl, aromatic heterocyclyloxycarbonyl optionally substituted by substituent group γ, aromatic carbocyclic sulfanyl optionally substituted by substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted by substituent group γ', aromatic heterocyclic sulfanyl optionally substituted by substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted by substituent group γ', aromatic carbocyclic sulfinyl optionally substituted by substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted by substituent group γ', aromatic heterocyclic sulfinyl optionally substituted by substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted by substituent group γ', aromatic carbocyclic sulfonyl optionally substituted by substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted by substituent group γ', aromatic heterocyclic sulfonyl optionally substituted by substituent group γ, and non-aromatic heterocyclic sulfonyl optionally substituted by substituent group γ'.

[0048] Substituent group γ: Substituent group α, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl.

[0049] Substituent group γ': Substituent group γ and oxo.

[0050] Substituents on the ring of an "aromatic carbocyclic group" and "aromatic heterocyclic group", such as "substituted aromatic carbocycle", "substituted aromatic heterocycle", "substituted aromatic carbocycle-oxy", "substituted aromatic heterocycle-oxy", "substituted aromatic carbocycle-carbonyl", "substituted aromatic heterocycle-carbonyl", "substituted aromatic carbocycle-sulfanyl", and "substituted aromatic heterocycle-sulfanyl", include the following substituent group B. An atom at any position on the ring may be bonded to one or more groups selected from the following substituent group B. Substituent group B: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl, Alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, alkyloxy optionally substituted with substituent group α, alkenyloxy optionally substituted with substituent group α, alkynyloxy optionally substituted with substituent group α, alkylcarbonyloxy optionally substituted with substituent group α, alkenylcarbonyloxy optionally substituted with substituent group α, alkynylcarbonyloxy optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, substituted with substituent group α alkyloxycarbonyl optionally substituted with substituent group α, alkenyloxycarbonyl optionally substituted with substituent group α, alkynyloxycarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, sulfamoyl optionally substituted with substituent group β, An aromatic carbocyclic group optionally substituted with a substituent group γ, a non-aromatic carbocyclic group optionally substituted with a substituent group γ', an aromatic heterocyclic group optionally substituted with a substituent group γ, a non-aromatic heterocyclic group optionally substituted with a substituent group γ', an aromatic carbocyclic oxy optionally substituted with a substituent group γ, a non-aromatic carbocyclic oxy optionally substituted with a substituent group γ', an aromatic heterocyclic oxy optionally substituted with a substituent group γ, a non-aromatic heterocyclic oxy optionally substituted with a substituent group γ', an "aromatic carbocyclic carbonyloxy optionally substituted with a substituent group γ" ", "non-aromatic carbocyclic carbonyloxy optionally substituted by substituent group γ'", "aromatic heterocyclic carbonyloxy optionally substituted by substituent group γ", and "non-aromatic heterocyclic carbonyloxy optionally substituted by substituent group γ'", aromatic carbocyclic carbonyl optionally substituted by substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted by substituent group γ', aromatic heterocyclic carbonyl optionally substituted by substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted by substituent group γ', aromatic carbocyclic carbonyl optionally substituted by substituent group γ heterocyclic oxycarbonyl, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxy optionally substituted with substituent group γ', non-aromatic carbocyclic alkyloxy optionally substituted with substituent group γ', aromatic heterocyclic alkyloxy optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxy optionally substituted with substituent group γ', aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ',Aromatic carbocyclic alkyloxyalkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxyalkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyloxyalkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxyalkyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ, and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'. ,

[0051] Substituents on the ring of a "non-aromatic carbocyclic group" and a "non-aromatic heterocyclic group," "substituted non-aromatic carbocycle," "substituted non-aromatic heterocycle," "substituted non-aromatic carbocycle-oxy," "substituted cycloalkyloxy," "substituted cycloalkenyloxy," "substituted non-aromatic heterocycle-oxy," "substituted non-aromatic carbocycle-carbonyl," "substituted non-aromatic heterocycle-carbonyl," "substituted non-aromatic carbocycle-sulfanyl," and "substituted non-aromatic heterocycle-sulfanyl" include the following substituent group C. An atom at any position on the ring may be bonded to one or more groups selected from the following substituent group C. Substituent group C: Substituent group B and oxo.

[0052] When a "non-aromatic carbocycle" or a "non-aromatic heterocycle" is substituted with "oxo", it means a ring in which two hydrogen atoms on a carbon atom are replaced as follows: [ka]

[0053] Substituents for the "substituted amino" and "substituted carbamoyl" include the following Substituent Group D. The "substituted amino" and "substituted carbamoyl" may be substituted with 1 or 2 groups selected from Substituent Group D. Substituent group D: halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, sulfamoyl optionally substituted with substituent group β, Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0054] Preferred embodiments of each symbol in the compound represented by formula (I) of (A) are shown below. Examples of the compound represented by formula (I) include all combinations of the specific examples shown below. The A ring is one of the following rings: [ka] Examples include: A preferred embodiment of ring A is any of the following rings: [ka] A more preferred embodiment of ring A is (a) or (b-1) above.

[0055] Examples of the ring B include a benzene ring and a pyridine ring. A preferred embodiment of ring B is a benzene ring.

[0056] R 1 Each of the groups independently includes halogen, alkyl, haloalkyl, alkyloxy, cyano, or haloalkyloxy. R 1 A preferred embodiment of is halogen, alkyl or haloalkyl. R 1 A more preferred embodiment of is halogen.

[0057] R 2a and R 2b Each independently includes hydrogen, alkyl, or haloalkyl. R 2a and R 2b One of the preferred embodiments of is hydrogen. R 2a One of the preferred embodiments of is hydrogen. R 2b In one preferred embodiment, is hydrogen or methyl, and in a more preferred embodiment, is hydrogen.

[0058] R 3 The group may be alkyl or haloalkyl. R 3 One of the preferred embodiments of is alkyl.

[0059] R 4The group may be hydrogen or alkyl. R 4 In one preferred embodiment, it is hydrogen or methyl, and in a more preferred embodiment, it is hydrogen.

[0060] R 5a , R 5b , R 6a , R 6b , R 7a and R 7b Each of the groups independently includes hydrogen, halogen, alkyl, haloalkyl, alkyloxy, alkyloxyalkyl, or a 3- to 6-membered non-aromatic carbocyclic group (eg, cyclopropyl, etc.). R 5a , R 5b , R 6a , R 6b , R 7a and R 7b In one preferred embodiment, each of the groups independently represents hydrogen, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkyloxy, or C1-3 alkyloxyC1-3 alkyl. R 5a A preferred embodiment of is hydrogen or alkyl, and a more preferred embodiment is hydrogen. R 5a Another preferred embodiment of is hydrogen or C1-3 alkyl. R 5b A preferred embodiment of is hydrogen or alkyl, and a more preferred embodiment is hydrogen. R 5b Another preferred embodiment of is hydrogen or C1-3 alkyl. R 6a A preferred embodiment of is hydrogen, alkyl, or alkyloxyalkyl, and a more preferred embodiment is hydrogen. R 6a Another preferred embodiment of is hydrogen, C1-3 alkyl or C1-3 alkyloxyC1-3 alkyl. R 6aAnother preferred embodiment of is hydrogen, halogen, alkyl, haloalkyl, alkyloxyalkyl or a 3- to 6-membered non-aromatic carbocyclic group (eg, cyclopropyl, etc.), and a further preferred embodiment is hydrogen. R 6a Another preferred embodiment of is hydrogen, halogen, C1-3 alkyl, C1-3 haloalkyl, or C1-3 alkyloxyC1-3 alkyl. R 6b One of the preferred embodiments of is hydrogen. R 7a A preferred embodiment of is hydrogen, alkyl or alkyloxyalkyl, and a more preferred embodiment is alkyloxyalkyl. R 7a Another preferred embodiment of is hydrogen, C1-3 alkyl or C1-3 alkyloxyC1-3 alkyl, and a more preferred embodiment is C1-3 alkyloxyC1-3 alkyl. R 7a Another preferred embodiment of is hydrogen, halogen, alkyl, haloalkyl, alkyloxyalkyl or a 3- to 6-membered non-aromatic carbocyclic group (eg, cyclopropyl, etc.), and a more preferred embodiment is alkyloxyalkyl. R 7b One of the preferred embodiments of is hydrogen. R 5a and R 6a , or R 6a and R 7a may be joined together with the adjacent atom to form an aromatic carbocycle (e.g., benzene, etc.) which may be substituted with halogen, a 3- to 6-membered non-aromatic carbocycle (e.g., cyclopropane, cyclopentane, etc.) which may be substituted with halogen, or a 4- to 6-membered non-aromatic heterocycle (e.g., tetrahydrofuran, etc.) which may be substituted with halogen (however, when forming an aromatic carbocycle, R 5b and R 6b , or R 6b and R 7b come together to form a bond). R 5b and R 6b may be taken together to form a bond.

[0061] R 8a , R 8b , R 9a , R 9b , R 10a , R 10b , R 11a and R 11b and each independently include hydrogen, halogen, alkyl, haloalkyl, alkyloxy, alkyloxyalkyl, or a 3-membered non-aromatic carbocyclic group (eg, cyclopropyl, etc.). R 8a , R 8b , R 9a , R 9b , R 10a , R 10b , R 11a and R 11b In one preferred embodiment, each of the groups independently represents hydrogen, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkyloxy, or C1-3 alkyloxyC1-3 alkyl. R 8a A preferred embodiment of is hydrogen or alkyl, and a more preferred embodiment is hydrogen. R 8a Another preferred embodiment of is hydrogen or C1-3 alkyl. R 8b A preferred embodiment of is hydrogen or alkyl, and a more preferred embodiment is hydrogen. R 8b Another preferred embodiment of is hydrogen or C1-3 alkyl. R 9a A preferred embodiment of is hydrogen, alkyl or alkyloxyalkyl. R 9a Another preferred embodiment of is hydrogen, C1-3 alkyl or C1-3 alkyloxyC1-3 alkyl. R 9a Another preferred embodiment of is hydrogen, halogen, alkyl, haloalkyl, alkyloxyalkyl, or a 3- to 6-membered non-aromatic carbocyclic group (eg, cyclopropyl, etc.). R 9bA preferred embodiment of is hydrogen or alkyl, and a more preferred embodiment is hydrogen. R 9b Another preferred embodiment of is hydrogen or C1-3 alkyl. R 10a A preferred embodiment of is hydrogen, alkyl, or alkyloxy, and a more preferred embodiment is hydrogen. R 10a Another preferred embodiment of is hydrogen, C1-3 alkyl or C1-3 alkyloxy. R 10a Another preferred embodiment of is hydrogen, halogen, alkyl, haloalkyl, alkyloxyalkyl, or a 3- to 6-membered non-aromatic carbocyclic group (eg, cyclopropyl, etc.). R 10b One of the preferred embodiments of is hydrogen. R 11a A preferred embodiment of is hydrogen or alkyl, and a more preferred embodiment is hydrogen. R 11a Another preferred embodiment of is hydrogen or C1-3 alkyl. R 11a Another preferred embodiment of is hydrogen, halogen, alkyl, haloalkyl, alkyloxyalkyl, or a 3- to 6-membered non-aromatic carbocyclic group (eg, cyclopropyl, etc.). R 11b One of the preferred embodiments of is hydrogen. R 8a and R 10a may together form a C1-C3 bridge, preferably a C1-C2 bridge. R 10a and R 11a may be joined with adjacent atoms to form a 5-membered non-aromatic carbocyclic ring (eg, cyclopropane, etc.). R 9a and R 9b may be combined with adjacent atoms to form a 4-membered non-aromatic carbocyclic ring (eg, cyclobutane, etc.) or a 5-membered non-aromatic heterocyclic ring (eg, 1,3-dioxolane, etc.). R 8a and R 9amay come together to form a bond.

[0062] n is an integer of 1 to 3. One of the preferred embodiments of n is an integer of 2 to 3. A more preferred embodiment of n is an integer of 1 to 2.

[0063] Q includes -NHC(O)- or a 5-membered aromatic heterocycle. A preferred embodiment of Q is -NHC(O)- (the bond on the left is CR 2a R 2b (combined with ). Another preferred embodiment of Q is a 5-membered aromatic heterocycle. Another preferred embodiment of Q is any of the following rings (the bond on the left is CR 2a R 2b Combine with); [ka] Another preferred embodiment of Q is any of the following rings (the bond on the left is CR 2a R 2b Combine with); [ka] A more preferred embodiment of Q is the ring shown in (1) above.

[0064] Preferred compounds in the compound represented by formula (I) of (A) are Example compounds I-3, I-7, I-11, I-16, I-23, I-24, I-32, II-1, II-4, II-5, II-13, II-14, II-16, II-19, II-21, II-23, II-26, II-31, II-34, II-36, II-38, II-41, II-43, II-45, II-47, II-49, II-52, II-56, II-58, II-62, II-63, II-64, II-68, II-89, II-9 2, II-93, II-95, II-96, II-98, II-106, II-109, II-110, II-112, II-113, II-117, II-118, II-125, II-127, II-128, II-129, II-130, II-131, II-132, II-136, II-138, II-139, II-142, II-143, II-144, II-147, II-148, II-149, II-150, II-151, II-155, II-156 and II-157. More preferred compounds among the compounds represented by formula (I) of (A) include Example compounds I-7, I-11, II-26, II-36, II-52, II-92, II-96, II-109, II-110, and II-158.

[0065] Preferred embodiments of the compound of formula (I') in (B) are shown below. (Embodiment 1) Formula (I') is of the following formula: [ka] (In the formula, R 1 ' is alkyl or halogen; R 2 ' is alkyloxy; R 3' is an aromatic carbocyclic group optionally substituted with halogen, alkyl and / or alkyloxy, a non-aromatic carbocyclic group optionally substituted with halogen, alkyl and / or alkyloxy, an aromatic heterocyclic group optionally substituted with halogen, alkyl and / or alkyloxy, or a non-aromatic heterocyclic group optionally substituted with halogen, alkyl and / or alkyloxy; R 4 ' is hydrogen; R 3A ' is hydrogen or halogen; R 4A ' is an alkyl, halogen, alkynyl, or non-aromatic carbocyclic group optionally substituted with cyano, halogen, hydroxy, or alkyloxy; R a ' is hydrogen, alkyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxyalkyl, alkylsulfonyl, or haloalkylsulfonyl; R b each ' is independently hydrogen, alkyl, haloalkyl, or alkyloxyalkyl; R c and each ' is independently hydrogen, alkyl, haloalkyl, or alkyloxyalkyl.

[0066] (Embodiment 2) Formula (I') is of the following formula: [ka] (In the formula, R 1 ' is alkyl or halogen; R 2 ' is alkyloxy; R 3' is an aromatic carbocyclic group optionally substituted with halogen, alkyl and / or alkyloxy, a non-aromatic carbocyclic group optionally substituted with halogen, alkyl and / or alkyloxy, an aromatic heterocyclic group optionally substituted with halogen, alkyl and / or alkyloxy, or a non-aromatic heterocyclic group optionally substituted with halogen, alkyl and / or alkyloxy; R 4 ' is hydrogen; R 3A ' is hydrogen or halogen; R 4A ' is an alkyl, halogen, alkynyl, or non-aromatic carbocyclic group optionally substituted with cyano, halogen, hydroxy, or alkyloxy; R a ' represents an aromatic heterocyclic group optionally substituted with one or more groups selected from the substituent group E or a non-aromatic heterocyclic group optionally substituted with one or more groups selected from the substituent group E; wherein the substituent group E represents alkyl, halogen, alkyloxy, dialkylaminoalkyloxy, alkylaminoalkyloxy, aminoalkyloxy, non-aromatic heterocyclylalkyloxy, non-aromatic heterocyclyloxy optionally substituted with alkyl and / or oxo, non-aromatic heterocyclic group optionally substituted with alkyl and / or oxo, dialkylaminoalkyl, alkylaminoalkyl, aminoalkyl, non-aromatic heterocyclylalkyl, and aromatic heterocyclic group optionally substituted with alkyl; R b each ' is independently hydrogen, alkyl, haloalkyl, or alkyloxyalkyl; R c and each ' is independently hydrogen, alkyl, haloalkyl, or alkyloxyalkyl.

[0067] Unless otherwise specified, the compound according to the present invention is not limited to a particular isomer, and includes all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotamers, etc.), racemates, or mixtures thereof.

[0068] Radiolabeled compounds of the present invention can be prepared by methods well known in the art. For example, tritium-labeled compounds of the present invention can be prepared by introducing tritium into a specific compound of the present invention through catalytic dehalogenation using tritium. This method involves reacting a suitable halogen-substituted precursor of the compound of the present invention with tritium gas in the presence of a suitable catalyst, such as Pd / C, with or without a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)." 14 C-labeled compounds are 14 It can be prepared by using a raw material having C carbon.

[0069] Pharmaceutically acceptable salts of the compounds according to the present invention include salts of the compounds according to the present invention with alkali metals (e.g., lithium, sodium, potassium, etc.), alkaline earth metals (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 amino acids, or salts of 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, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.). These salts can be formed by conventional methods.

[0070] The compounds according to the present invention or pharmaceutically acceptable salts thereof may form solvates (e.g., hydrates, etc.), co-crystals, and / or crystalline polymorphs, and the present invention also encompasses such various solvates, co-crystals, and crystalline polymorphs. A "solvate" may be coordinated with the compound according to the present invention with any number of solvent molecules (e.g., water molecules, etc.). When the compounds according to the present invention or pharmaceutically acceptable salts thereof are left in the atmosphere, they may absorb moisture, resulting in the adsorbed water adsorbing, or they may form hydrates. Furthermore, crystalline polymorphs may be formed by recrystallization of the compounds according to the present invention or pharmaceutically acceptable salts thereof. A "co-crystal" means that the compounds according to the present invention or salts thereof and counter molecules are present in the same crystal lattice, and may contain any number of counter molecules.

[0071] The compounds of the present invention or pharmaceutically acceptable salts thereof may form prodrugs, and the present invention also encompasses such various prodrugs. Prodrugs are derivatives of the compounds of the present invention having a chemically or metabolically decomposable group, and are compounds that become pharmaceutically active compounds of the present invention in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are converted into active compounds by enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in vivo, and compounds that are converted into active compounds by hydrolysis with gastric acid, etc. Methods for selecting and producing appropriate prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985." Prodrugs may themselves be active.

[0072] (Method for producing the compound according to the present invention) Typical methods for producing the compounds used in the present invention are exemplified below. Extraction, purification, etc. may be carried out by the same procedures as in ordinary organic chemistry experiments. The compounds used in the present invention can be synthesized by taking into consideration methods known in the art. The starting compounds may be commercially available compounds, compounds described in the present specification, compounds described in the documents cited in the present specification, or other known compounds.

[0073] When it is desired to obtain a salt of the compound according to the present invention, if the compound used in the present invention is obtained in the form of a salt, it may be purified as is, or if it is obtained in the free form, it may be dissolved or suspended in an appropriate organic solvent, and an acid or a base may be added to form a salt by a conventional method.

[0074] The compound (A) of formula (I) used in the present invention can be prepared, for example, by the method described below. (Method 1) When Q is -NHC(O)- [ka] (In the formula, P 1 is a hydroxy protecting group; P 2 is an amino protecting group; R and R' are carboxy protecting groups; Z 1 is CR 5a R 5b or CR 8a R 8b m is an integer of 2 to 3, and when m is 2, -(Z)2- is -(CR 7a R 7b -CR 6a R 6b )-, m is 3, -(Z)3- is -(CR 11a R 11b -CR 10a R 10b -CR 9a R 9b )-, or (CR 11a R 11b -CR 10a R 10b -O)-; Hal is halogen; P 1 , P 2R and R' may be groups that can be protected and / or deprotected by the methods described in Protective Groups in Organic Synthesis, Theodora W Greene (John Wiley & Sons), etc., and for example, P 1 is an aromatic carbocyclic alkyl, etc., and P 2 is alkyloxycarbonyl, etc., and R and R' are alkyl, etc.; other symbols are as defined above. Process 1 Compound a1 can be obtained by subjecting compound a, which is commercially available or can be prepared by a known method, to a general deprotection reaction of the carboxy protecting group. Process 2 Compound a3 can be obtained by adding a condensing agent such as HATU, WSC·HCl, or PyBOP to compound a1 in the presence of a solvent such as DMF, DMA, NMP, THF, chloroform, or dichloromethane, and then adding compound a2, which is commercially available or can be prepared by a known method, and a tertiary amine such as triethylamine, N-methylmorpholine, pyridine, or DIEA, and reacting the mixture at 10°C to 60°C, preferably 20°C to 40°C, for 0.1 to 24 hours, preferably 1 to 12 hours. Process 3 Compound a4 can be added to compound a3 in the presence of a solvent such as THF, methanol, ethanol, chloroform, dichloromethane, or THF, and reacted at 60°C to 120°C, preferably 80°C to 100°C, for 0.5 hours to 24 hours, preferably 1 hour to 12 hours, to obtain compound a5. Process 4 Compound a6 can be obtained by subjecting compound a5 to a general deprotection reaction of an amino protecting group. Process 5 Compound a6 can be reacted with commercially available compound a7, which can be prepared by a known method, and an acid, such as acetic acid, p-toluenesulfonic acid, or methanesulfonic acid, in the presence of a solvent, such as dichloromethane, dichloroethane, chloroform, methanol, ethanol, toluene, DMF, DMA, or THF, at 20°C to 130°C, preferably 20°C to 100°C, for 0.1 to 24 hours, preferably 1 to 12 hours, to obtain compound a8. Process 6 Compound a9 can be obtained by adding a base such as cesium carbonate or potassium carbonate and a salt such as sodium iodide or potassium iodide to compound a8 in the presence of a solvent such as DMF, DMA, NMP, or THF, and reacting the mixture at 0°C to 60°C, preferably 0°C to 40°C, for 0.1 hours to 24 hours, preferably 1 hour to 12 hours. Process 7 Compound a9 can be resolved into a10 by chiral SFC. Process 8 Compound a10 can be subjected to a general deprotection reaction of a hydroxy protecting group to give compound Ia.

[0075] (Method 2) [ka] (In the formula, each symbol has the same meaning as defined above.) Process 1 Compound a5 can be reacted with a base such as cesium carbonate, potassium carbonate, or triethylamine, or a salt such as sodium iodide or potassium iodide when Hal is chloro, in the presence of a solvent such as DMF, DMA, NMP, or THF, and then compound b1, which is commercially available or can be prepared by a known method, is added, and the reaction is carried out at 0°C to 60°C, preferably 20°C to 40°C, for 0.1 hours to 24 hours, preferably 1 hour to 12 hours, to obtain compound b2. Process 2 Compound b3 can be obtained by subjecting compound b2 to a general deprotection reaction of an acetal. Process 3 Compound a9 can be obtained by adding an acid such as acetic acid, p-toluenesulfonic acid, methanesulfonic acid, or trifluoroacetic acid to compound b3 in the presence of a solvent such as dichloromethane, dichloroethane, chloroform, acetonitrile, methanol, ethanol, toluene, DMF, DMA, or THF, and reacting the mixture at 20°C to 130°C, preferably 80°C to 120°C, for 0.1 to 24 hours, preferably 1 to 12 hours. Process 4 Compound Ia can be synthesized according to steps 7 and 8 of Preparation 1.

[0076] (Method 3) [ka] (In the formula, each symbol has the same meaning as defined above.) Process 1 Compound c1, which is commercially available or can be prepared by a known method, is added to compound a5 in the presence of a solvent such as THF or toluene, and a Mitsunobu reagent such as DEAD / PPh3, DIAD / PPh3, DMEAD / PPh3, or ADDP / n-Bu3P is added, followed by reaction at 0°C to 100°C, preferably 20°C to 80°C, for 0.1 to 24 hours, preferably 1 to 12 hours, to obtain compound c2. Process 2 Compound c2 can be subjected to a general alkene oxidative cleavage reaction to obtain compound c3, for example, using ozonolysis or K2OsO4 / NaIO4. Process 3 Compound c3 can be reacted under the same conditions as in step 3 of production method 2 to obtain compound a9. Process 4 Compound Ia can be synthesized according to steps 7 and 8 of Preparation 1.

[0077] (Method 4) [ka] (In the formula, each symbol has the same meaning as defined above.) Process 1 Compound a5 and compound d1 are reacted under the same conditions as in step 1 of production method 3 to obtain compound d2. Process 2 Compound d3 can be obtained by subjecting compound d2 to a general deprotection reaction of a hydroxy protecting group. Process 3 Compound d4 can be obtained by subjecting compound d3 to a general oxidation reaction of the hydroxyl group. Process 4 Compound d4 can be reacted under the same conditions as in step 3 of production method 2 to obtain compound a9. Process 5 Compound Ia can be synthesized according to steps 7 and 8 of Preparation 1.

[0078] (Method 5) [ka] (In the formula, each symbol has the same meaning as defined above.) Process 1 Compound a5 and compound e1 are reacted under the same conditions as in step 5 of production method 1 to obtain compound e2. Process 2 Compound e3 can be obtained by adding a base such as cesium carbonate or potassium carbonate to compound e2 in the presence of a solvent such as DMF, DMA, NMP, or THF, and reacting the mixture at 0°C to 60°C, preferably 0°C to 40°C, for 0.1 to 24 hours, preferably 1 to 12 hours. Process 3 Compound e4 can be obtained by subjecting the compound to a general deprotection reaction of a hydroxy protecting group. Process 4 Compound a9 can be obtained by adding a Mitsunobu reagent such as DEAD / PPh3, DIAD / PPh3, DMEAD / PPh3, or ADDP / n-Bu3P to compound e4 in the presence of a solvent such as THF or toluene, and reacting the mixture at 0°C to 100°C, preferably 20°C to 80°C, for 0.1 to 24 hours, preferably 1 to 12 hours. Process 5 Compound Ia can be synthesized according to steps 7 and 8 of Preparation 1.

[0079] (Production Method 6) When Q is a 5-membered aromatic heterocycle [ka] (wherein Q is a 5-membered aromatic heterocycle; the other symbols are as defined above.) Process 1 Compound f1 can be obtained by adding a condensing agent such as HATU, WSC·HCl, or PyBOP to compound f, which is commercially available or can be prepared by a known method, in the presence of a solvent such as DMF, DMA, NMP, THF, chloroform, or dichloromethane, and then adding compound a4, which is commercially available or can be prepared by a known method, and a tertiary amine such as triethylamine, N-methylmorpholine, pyridine, or diisopropylethylamine, and reacting at 10°C to 60°C, preferably 20°C to 40°C, for 0.1 to 24 hours, preferably 1 to 12 hours. Process 2 Compound f3 can be obtained by adding compound f2, which is commercially available or can be prepared by a known method, and an acid such as acetic acid, pyridinium p-toluenesulfonate, p-toluenesulfonic acid, or methanesulfonic acid to compound f1 in the presence of a solvent such as DMF, DMA, or NMP, and reacting the mixture at 20°C to 120°C, preferably 60°C to 100°C, for 0.1 to 24 hours, preferably 1 to 12 hours. Process 3 Compound f4 can be obtained by subjecting compound f3 to a known general deprotection reaction of an amino protecting group. Process 4 Compound f4 can be reacted under the same conditions as those described in Production Methods 1 to 5 to obtain compound f5. Process 5 Compound f5 can be reacted with a halogenating reagent such as bromine, NBS, NCS, or NIS in a solvent such as dichloromethane, dichloroethane, acetonitrile, or DMF at -30°C to 50°C, preferably -10°C to 20°C, for 0.1 to 10 hours, preferably 0.5 to 2 hours, to give compound f6. When Hal is chloro or iodo, compound f6 can be obtained by reacting at 10°C to 150°C, preferably 60°C to 120°C, for 0.5 to 24 hours, preferably 1 to 6 hours. Process 7 Compound f6 can be reacted in a solvent or mixed solvent such as dioxane, DMF, DME, THF, DMSO, etc. with a palladium catalyst such as Pd(PPh3)4, Pd(OAc)2, Pd(PPh3)2Cl2, Pd(dppf)2Cl2, or Pd(dtbpf), a base such as potassium acetate, sodium acetate, potassium carbonate, or potassium phosphate, and bis(pinacolato)diboron under a nitrogen atmosphere at 0°C to 150°C, preferably 60°C to 120°C, for 0.5 hours to 24 hours, preferably 1 hour to 12 hours, to obtain compound f7. Process 8 Compound f7 can be reacted in a solvent or mixed solvent such as dioxane, DMF, DME, THF, water, etc. with a palladium catalyst such as Pd(PPh3)4, Pd(OAc)2, Pd(PPh3)2Cl2, Pd(dppf)2Cl2, or Pd(dtbpf), a base such as potassium carbonate, sodium carbonate, cesium carbonate, or potassium phosphate, and a commercially available or known compound f8 prepared by a method, under a nitrogen atmosphere at 0°C to 150°C, preferably 60°C to 120°C, for 0.5 hours to 24 hours, preferably 1 hour to 12 hours, to obtain compound f9. Process 9 Compound Ib can be synthesized according to steps 7 and 8 of Preparation 1.

[0080] (Method 7) [ka] (In the formula, other symbols have the same meanings as above.) Process 1 Compound g is converted into an acid chloride by adding a base such as triethylamine or diisopropylethylamine and ethyl chloroformate to compound g in the presence of a solvent such as dichloromethane, dichloroethane, chloroform, DMF, DMA, NMP, or THF, and then compound g1, which is commercially available or can be prepared by a known method, is added and reacted at 0°C to 60°C, preferably 0°C to 20°C, for 0.1 to 24 hours, preferably 1 to 12 hours, to obtain compound g2. Process 2 Compound g2 can be reacted with an acid such as T3P, trifluoroacetic acid, phosphoric acid, hydrochloric acid, sulfuric acid, or hydrobromic acid in the presence of a solvent such as ethyl acetate, dichloromethane, dichloroethane, chloroform, dioxane, DMF, DMA, or THF at 20°C to 130°C, preferably 60°C to 100°C, for 0.1 to 24 hours, preferably 1 to 12 hours, to obtain compound g3. Process 3 Compound Ic can be synthesized according to steps 7 and 8 of Preparation 1.

[0081] The compound obtained above may be further chemically modified to synthesize another compound. If a reactive functional group (e.g., OH, COOH, NH) is present in the side chain portion during the above reaction, it may be protected before the reaction and deprotected after the reaction, if desired. Examples of protecting groups (amino-protecting groups, hydroxy-protecting groups, etc.) include ethoxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, and other protecting groups described in Protective Groups in Organic Synthesis, T.W. Greene, John Wiley & Sons Inc. (1991). The introduction and removal of protecting groups can be achieved by methods commonly used in organic synthetic chemistry (see, for example, Protective Groups in Organic Synthesis, T.W. Greene, John Wiley & Sons Inc. (1991)), or by methods similar thereto. Furthermore, the conversion of functional groups contained in each substituent can be achieved by known methods other than the above-described production methods (e.g., Comprehensive Organic Transformations, R.C. Larock (1989)), and some of the compounds of the present invention can be used as synthetic intermediates to further lead to novel derivatives. The intermediates and target compounds in each of the above production methods can be isolated and purified by purification methods commonly used in organic synthetic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, etc. Alternatively, the intermediates can be used in the next reaction without any particular purification.

[0082] The compound represented by (B) used in the present invention may be a commercially available compound, or may be prepared by the methods described in, for example, US6838464B, WO2018 / 035359, WO2015 / 174511, WO2016 / 194806, etc.

[0083] In one embodiment, the medicament of the present invention comprises: (A) Formula (I): [ka] (wherein ring A is any one of the following rings: [ka] X1 is a CR 9a R 9b or O; R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are each independently hydrogen, alkyl, alkyloxy, or alkyloxyalkyl; R 5a and R 6a , or R 6a and R 7a may be taken together with the adjacent atom to form an aromatic carbocycle which may be substituted with halogen, a 3- to 6-membered non-aromatic carbocycle which may be substituted with halogen, or a 4- to 6-membered non-aromatic heterocycle which may be substituted with halogen (however, when forming an aromatic carbocycle, R 5b and R 6b , or R 6b and R 7b come together to form a bond); R 5b and R 6b may be taken together to form a bond; R 8a , R 8b , R 9a , R 9b , R 10a , R 10b , R 11a and R 11b are each independently hydrogen, alkyl, alkyloxy, or alkyloxyalkyl; R 8a and R 10a may together form a C1-C3 bridge; R 10a and R 11a may be taken together with adjacent atoms to form a 5-membered non-aromatic carbocyclic ring; R 9a and R 9b may be taken together with adjacent atoms to form a 4-membered non-aromatic carbocyclic ring or a 5-membered non-aromatic heterocyclic ring; R 8aand R 9a may come together to form a bond; Ring B is a benzene ring or a pyridine ring; Q is -NHC(O)- or a 5-membered aromatic heterocycle; R 1 are each independently halogen, alkyl, haloalkyl, alkyloxy, cyano, or haloalkyloxy; R 2a and R 2b are each independently hydrogen, alkyl, or haloalkyl; R 3 is alkyl or haloalkyl; R 4 is hydrogen or alkyl; and n is an integer from 1 to 3. or a pharmaceutically acceptable salt thereof; (B) A compound having anti-HIV activity or a pharmaceutically acceptable salt thereof The pharmaceutical of the present invention is used for the prevention and / or treatment of HIV infection. In one embodiment, the present invention provides a pharmaceutical for the prevention or treatment of HIV infection that combines (A) and (B). In another embodiment, the present invention provides a pharmaceutical for the prevention and / or treatment of HIV infection that contains (A) and (B).

[0084] In another aspect, the present invention provides an anti-HIV activity enhancer which combines (A) and (B).

[0085] Here, the "medicament characterized by a combination" includes a pharmaceutical containing each compound, a mode in which each compound is used as a combination drug, a mode in which each compound is used as a kit, a mode in which they are administered simultaneously, a mode in which they are administered at an interval, and a mode in which a drug is used in combination with another drug, and although it is sometimes abbreviated to "combined", these have the same meaning. Preferably, it is a combination drug.

[0086] The compound represented by (A) or a pharmaceutically acceptable salt thereof can be used in combination with (B) a compound having anti-HIV activity or a pharmaceutically acceptable salt thereof, and can enhance the anti-HIV activity of (B) a compound having anti-HIV activity or a pharmaceutically acceptable salt thereof. Furthermore, (B) a compound having anti-HIV activity or a pharmaceutically acceptable salt thereof can be used in combination with (A) a compound having anti-HIV activity or a pharmaceutically acceptable salt thereof, thereby enhancing the anti-HIV activity of (A) a compound having anti-HIV activity or a pharmaceutically acceptable salt thereof.

[0087] In another embodiment, the medicament of the present invention is (A) Formula (I): [ka] (wherein ring A is any one of the following rings: [ka] X1 is a CR 9a R 9b or O; R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are each independently hydrogen, alkyl, alkyloxy, or alkyloxyalkyl; R 5a and R 6a , or R 6a and R 7a may be taken together with the adjacent atom to form an aromatic carbocycle which may be substituted with halogen, a 3- to 6-membered non-aromatic carbocycle which may be substituted with halogen, or a 4- to 6-membered non-aromatic heterocycle which may be substituted with halogen (however, when forming an aromatic carbocycle, R 5b and R 6b , or R 6b and R 7b come together to form a bond); R5b and R 6b may be taken together to form a bond; R 8a , R 8b , R 9a , R 9b , R 10a , R 10b , R 11a and R 11b are each independently hydrogen, alkyl, alkyloxy, or alkyloxyalkyl; R 8a and R 10a may together form a C1-C3 bridge; R 10a and R 11a may be taken together with adjacent atoms to form a 5-membered non-aromatic carbocyclic ring; R 9a and R 9b may be taken together with adjacent atoms to form a 4-membered non-aromatic carbocyclic ring or a 5-membered non-aromatic heterocyclic ring; R 8a and R 9a may come together to form a bond; Ring B is a benzene ring or a pyridine ring; Q is -NHC(O)- or a 5-membered aromatic heterocycle; R 1 are each independently halogen, alkyl, haloalkyl, alkyloxy, cyano, or haloalkyloxy; R 2a and R 2b are each independently hydrogen, alkyl, or haloalkyl; R 3 is alkyl or haloalkyl; R 4 is hydrogen or alkyl; and n is an integer from 1 to 3. or a pharmaceutically acceptable salt thereof; (B) A pharmaceutical characterized by combining at least one selected from compounds having polymerase inhibitory activity, compounds having ribonuclease H inhibitory activity, compounds having an allosteric inhibitory activity against the HIV-1 Integrase (IN)-Lens epitherium-derived growth factor (LEDGF) complex, compounds having protease inhibitory activity, compounds having adsorption / entry inhibitory activity, compounds having budding inhibitory activity, compounds having maturation inhibitory activity, compounds having capsid inhibitory activity, and pharmaceutically acceptable salts thereof.

[0088] In another embodiment, the medicament of the present invention is (A) Formula (I): [ka] (wherein ring A is any one of the following rings: [ka] X1 is a CR 9a R 9b or O; R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are each independently hydrogen, alkyl, alkyloxy, or alkyloxyalkyl; R 5a and R 6a , or R 6a and R 7a may be taken together with the adjacent atom to form an aromatic carbocycle which may be substituted with halogen, a 3- to 6-membered non-aromatic carbocycle which may be substituted with halogen, or a 4- to 6-membered non-aromatic heterocycle which may be substituted with halogen (however, when forming an aromatic carbocycle, R 5b and R 6b , or R 6b and R 7b come together to form a bond); R 5b and R 6b may be taken together to form a bond; R 8a , R 8b , R 9a , R 9b , R 10a , R 10b , R 11a and R 11b are each independently hydrogen, alkyl, alkyloxy, or alkyloxyalkyl; R 8a and R 10a may together form a C1-C3 bridge; R 10a and R 11a may be taken together with adjacent atoms to form a 5-membered non-aromatic carbocyclic ring; R 9a and R 9b may be taken together with adjacent atoms to form a 4-membered non-aromatic carbocyclic ring or a 5-membered non-aromatic heterocyclic ring; R 8a and R 9a may come together to form a bond; Ring B is a benzene ring or a pyridine ring; Q is -NHC(O)- or a 5-membered aromatic heterocycle; R 1 are each independently halogen, alkyl, haloalkyl, alkyloxy, cyano, or haloalkyloxy; R 2a and R 2b are each independently hydrogen, alkyl, or haloalkyl; R 3 is alkyl or haloalkyl; R 4 is hydrogen or alkyl; and n is an integer from 1 to 3. or a pharmaceutically acceptable salt thereof; (B) AZT, 3TC, didanosine, zalcitabine, sanilvudine, abacavir, tenofovir, tenofovir disoproxil, tenofovir Alafenamide, Emtricitabine, Nevirapine, Efavirenz, Capravirine, Etravirine, Delavirdine, Rilpivirine, VM-1500A, VM-1500, Doravirine, MK-8507, MK-8504, MK-8583, Compounds I'-001, I'-027, I'-043, I'-189, I'-220, I'-292, I'-304, Indinavir, Ritonavir, Saquinavir, Nelfinavir, Amprenavir, Atazanavir, Lopinavir, Fosamprenavir, Darunavir, Maraviroc, Enfuvirtide, Ibalizumab, PRO-140, Temsavir, Fostemsavir At least one selected from tromethamine, Combinectin, BDM-2, GSK-2838232, GSK-3640254, GS-6207, MK-8527, MK-8558, and pharmaceutically acceptable salts thereof. The pharmaceutical composition is characterized by combining the above.

[0089] In another embodiment, the medicament of the present invention is (A) Formula (I): [ka] (wherein ring A is any one of the following rings: [ka] X1 is a CR 9a R 9b or O; R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are each independently hydrogen, alkyl, alkyloxy, or alkyloxyalkyl; R 5a and R 6a , or R 6a and R 7amay be taken together with the adjacent atom to form an aromatic carbocycle which may be substituted with halogen, a 3- to 6-membered non-aromatic carbocycle which may be substituted with halogen, or a 4- to 6-membered non-aromatic heterocycle which may be substituted with halogen (however, when forming an aromatic carbocycle, R 5b and R 6b , or R 6b and R 7b come together to form a bond); R 5b and R 6b may be taken together to form a bond; R 8a , R 8b , R 9a , R 9b , R 10a , R 10b , R 11a and R 11b are each independently hydrogen, alkyl, alkyloxy, or alkyloxyalkyl; R 8a and R 10a may together form a C1-C3 bridge; R 10a and R 11a may be taken together with adjacent atoms to form a 5-membered non-aromatic carbocyclic ring; R 9a and R 9b may be taken together with adjacent atoms to form a 4-membered non-aromatic carbocyclic ring or a 5-membered non-aromatic heterocyclic ring; R 8a and R 9a may come together to form a bond; Ring B is a benzene ring or a pyridine ring; Q is -NHC(O)- or a 5-membered aromatic heterocycle; R 1 are each independently halogen, alkyl, haloalkyl, alkyloxy, cyano, or haloalkyloxy; R 2a and R 2b are each independently hydrogen, alkyl, or haloalkyl; R 3is alkyl or haloalkyl; R 4 is hydrogen or alkyl; and n is an integer from 1 to 3. or a pharmaceutically acceptable salt thereof; (B) the following compound: [ka] or a pharmaceutically acceptable salt thereof.

[0090] In another embodiment, the medicament of the present invention is (A) Formula (I): [ka] (wherein ring A is any one of the following rings: [ka] X1 is a CR 9a R 9b or O; R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are each independently hydrogen, alkyl, alkyloxy, or alkyloxyalkyl; R 5a and R 6a , or R 6a and R 7a may be taken together with the adjacent atom to form an aromatic carbocycle which may be substituted with halogen, a 3- to 6-membered non-aromatic carbocycle which may be substituted with halogen, or a 4- to 6-membered non-aromatic heterocycle which may be substituted with halogen (however, when forming an aromatic carbocycle, R 5b and R 6b , or R 6b and R 7b come together to form a bond); R 5b and R 6b may be taken together to form a bond; R 8a , R 8b , R 9a , R 9b , R 10a , R 10b , R 11a and R 11b are each independently hydrogen, alkyl, alkyloxy, or alkyloxyalkyl; R 8a and R 10a may together form a C1-C3 bridge; R 10a and R 11a may be taken together with adjacent atoms to form a 5-membered non-aromatic carbocyclic ring; R 9a and R 9b may be taken together with adjacent atoms to form a 4-membered non-aromatic carbocyclic ring or a 5-membered non-aromatic heterocyclic ring; R 8a and R 9a may come together to form a bond; Ring B is a benzene ring or a pyridine ring; Q is -NHC(O)- or a 5-membered aromatic heterocycle; R 1 are each independently halogen, alkyl, haloalkyl, alkyloxy, cyano, or haloalkyloxy; R 2a and R 2b are each independently hydrogen, alkyl, or haloalkyl; R 3 is alkyl or haloalkyl; R 4 is hydrogen or alkyl; and n is an integer from 1 to 3. or a pharmaceutically acceptable salt thereof; (B) A pharmaceutical characterized by combining at least one selected from 3BNC117LS, 10-1074LS, GS-9722, GS-9723, N6LS, ARC07-523LS, and VRC01-LS.

[0091] In another embodiment, the medicament of the present invention is (A) Compound I-7, I-11, II-26, II-36, II-52, II-92, II-96, II-109, II-110, II-158, or a pharmaceutically acceptable salt thereof; (B) A pharmaceutical characterized by combining at least one selected from 3TC, abacavir, tenofovir, tenofovir alafenamide, emtricitabine, rilpivirine, VM-1500A, VM-1500, doravirine, MK-8504, MK-8583, compounds I'-001, I'-027, I'-043, I'-189, I'-220, I'-292, I'-304, atazanavir, darunavir, maraviroc, enfuvirtide, ibalizumab, PRO-140, fostemsavir tromethamine, Combinectin, BDM-2, GSK-2838232, GSK-3640254, GS-6207, and pharmaceutically acceptable salts thereof.

[0092] In another embodiment, the medicament of the present invention is (A) Compound I-7, I-11, II-26, II-36, II-52, II-92, II-96, II-109, II-110, II-158, or a pharmaceutically acceptable salt thereof; (B) A pharmaceutical characterized by combining at least one selected from 3TC, abacavir, tenofovir, tenofovir alafenamide, emtricitabine, compounds I'-001, I'-027, I'-043, I'-189, I'-220, I'-292, I'-304, and pharmaceutically acceptable salts thereof.

[0093] In another embodiment, the medicament of the present invention is (A) Compound I-7, I-11, II-26, II-36, II-52, II-92, II-96, II-109, II-110, II-158, or a pharmaceutically acceptable salt thereof; (B) the following compound: [ka] or a pharmaceutically acceptable salt thereof.

[0094] In another embodiment, the medicament of the present invention is (A) Compound I-7, I-11, II-26, II-36, II-52, II-92, II-96, II-109, II-110, II-158, or a pharmaceutically acceptable salt thereof; (B) A pharmaceutical characterized by combining at least one selected from 3BNC117LS, 10-1074LS, GS-9722, GS-9723, N6LS, ARC07-523LS, and VRC01-LS.

[0095] In another embodiment, the medicament of the present invention is (A) Compound I-7, I-11, II-26, II-36, II-52, II-92, II-96, II-109, II-110, II-158, or a pharmaceutically acceptable salt thereof; (B) 3TC, abacavir, tenofovir, tenofovir alafenamide, emtricitabine, rilpivirine, VM-1500A, VM-1500, doravirine, MK-8504, MK-8583, compounds I'-001, I'-027, I'-043, I'-189, I'-220, I'-292, I'-304, atazanavir, darunavir, maraviroc, enfuvirtide, ibalizumab, PRO-140, fostemsavir tromethamine, Combinectin, BDM-2, GSK-2838232, GSK-3640254, GS-6207, and the following compounds: [ka] and pharmaceutically acceptable salts thereof, 3BNC117LS, 10-1074LS, GS-9722, GS-9723, N6LS, ARC07-523LS, and VRC01-LS.

[0096] In another embodiment, the medicament of the present invention is (A) Compound I-7, I-11, II-26, II-36, II-52, II-92, II-96, II-109, II-110, II-158, or a pharmaceutically acceptable salt thereof; (B) A pharmaceutical characterized by combining at least one selected from 3TC, rilpivirine, VM-1500A, VM-1500, I'-189, darunavir, GSK-2838232, GS-6207, and pharmaceutically acceptable salts thereof.

[0097] The pharmaceutical agent of the present invention can be administered orally or parenterally. Examples of parenteral administration include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ocular, otic, and vaginal administration.

[0098] For oral administration, the compound may be prepared and administered in any of the commonly used dosage forms, such as solid preparations for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.) and liquid preparations for internal use (e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, aromatic perfumes, extracts, decoctions, tinctures, etc.), according to conventional methods. 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; powders and granules may be dry syrups; and capsules may be soft capsules, microcapsules, or sustained-release capsules.

[0099] For parenteral administration, the compound can be suitably administered in any of the commonly used dosage forms, such as injections, infusions, and topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, infusions, liniments, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, powders for topical use, suppositories, etc.). Injections may be emulsions such as O / W, W / O, O / W / O, and W / O / W types.

[0100] Pharmaceutical compositions can be prepared by mixing an effective amount of the compound used in the medicament of the present invention with various pharmaceutical additives, such as excipients, binders, disintegrants, and lubricants, appropriate for the dosage form. Furthermore, by appropriately modifying the effective amount of the compound used in the medicament of the present invention, the dosage form, and / or various pharmaceutical additives, the pharmaceutical composition can also be prepared as a pharmaceutical composition for pediatrics, the elderly, critically ill patients, or surgical patients. For example, pediatric pharmaceutical compositions can be administered to newborns (less than 4 weeks old), infants (4 weeks old to less than 1 year old), toddlers (1 year old to less than 7 years old), children (7 years old to less than 15 years old), or patients aged 15 to 18 years. For example, pharmaceutical compositions for the elderly can be administered to patients aged 65 years or older.

[0101] The dosage of the pharmaceutical of the present invention can be appropriately selected based on the clinically used dosage. The compounding ratio of the compound represented by (A) to the concomitant drug (B) can be appropriately selected depending on the administration subject, administration route, target disease, symptoms, combination, etc. For example, when the administration subject is a human, 0.01 to 400 parts by weight of the concomitant drug (B) may be used per 1 part by weight of the compound represented by (A). [Example]

[0102] The present invention will be explained in more detail below with reference to examples and test examples of the present invention, but the present invention is not limited thereto. Furthermore, changes may be made within the scope of the present invention. The names of compounds shown in the following examples and comparative examples do not necessarily conform to the IUPAC nomenclature. The NMR analyses obtained in the examples were carried out at 300 MHz using DMSO-d6 and CDCl3.

[0103] Furthermore, when NMR data is presented, not all measured peaks may be listed. In the examples, "No." represents the compound number, "Structure" represents the chemical structure, and "MS" represents the molecular weight determined by LC / MS (liquid chromatography / mass spectrometry).

[0104] (Measurement conditions) (A) Column: ACQUITY UPLC® BEH C18 (1.7 μm id 2.1 x 50 mm) (Waters) Flow rate: 0.8 mL / min; UV detection wavelength: 254 nm; Mobile phase: [A] is an aqueous solution containing 0.1% formic acid; [B] is an acetonitrile solution containing 0.1% formic acid. A linear gradient of 5%-100% solvent [B] was performed over 3.5 minutes, followed by a 0.5 minute hold at 100% solvent [B]. (B) Column: Shim-pack XR-ODS (2.2 μm, id 50 × 3.0 mm) (Shimadzu) Flow rate: 1.6 mL / min; UV detection wavelength: 254 nm; Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 10%-100% solvent [B] was performed over 3 minutes, and then 100% solvent [B] was maintained for 0.5 minutes. (C) Column: Shim-pack XR-ODS (2.2 μm, id 50 × 3.0 mm) (Shimadzu) Flow rate: 1.6 mL / min; UV detection wavelength: 254 nm; Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 10%-100% solvent [B] was performed over 8 minutes, and then 100% solvent [B] was maintained for 0.5 minutes.

[0105] Examples relating to formula (I) of (A) are described below. Example 1 [ka] Process 1 Compound 1 (1.50 g, 3.59 mmol) was added to a 2 mol / L ethylamine methanol solution (17.9 ml, 35.9 mmol) and stirred at 100°C for 1 hour under microwave irradiation. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and then the mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was removed by evaporation. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give compound 2 (1.15 g, 74% yield). 1H-NMR(CDCl3)δ: 14.53(s, 1H), 8.64(brs, 1H), 8.46(s, 1H), 7.37(m, 5H), 6.57(brs, 1H), 5.38(s, 2H), 3.24(dt, J=14.0, 6.6Hz, 2H), 1.45(s, 9H), 1.02(t, J=7.3Hz, 4H). Process 2 Compound 2 (9.59 g, 22.2 mmol) was dissolved in dichloromethane (180 ml), and (2,4-difluorophenyl)methanamine (4.77 g, 33.3 mmol), PyBOP (13.9 g, 26.7 mmol), and DIEA (11.7 ml, 66.7 mmol) were added and stirred at room temperature for 18 hours. The reaction mixture was washed with water and saturated brine, and the organic layer was dried over sodium sulfate. The solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give compound 3 (11.5 g, 93% yield). 1H-NMR(CDCl3)δ: 10.20(t, J=5.8Hz, 1H), 8.54(brs, 1H), 8.49(s, 1H), 7.38(m, 5H), 6.87-6.79(m, 2H), 6.61(t, J=5.5Hz, 1H), 5.28(s, 2H), 4.64(d, J=5.9Hz, 2H), 3.18(ddt, J=18.8, 10.2, 3.8Hz, 3H), 1.83-1.80(m, 1H), 1.43(s, 9H), 0.99(t, J=7.3Hz, 3H). Process 3 Compound 3 (11.5 g, 9.54 mmol) was dissolved in dioxane (57.5 ml), and 4 mol / L hydrochloric acid / dioxane solution (300 ml) was added and stirred at room temperature for 4 hours. After the solvent was evaporated under reduced pressure, saturated aqueous sodium carbonate was added and the mixture was extracted with chloroform-methanol. The organic layer was dried over sodium sulfate, and the solvent was evaporated to give a crude product. The crude product was solidified with diisopropyl ether to give compound 4 (7.80 g, 83% yield). 1H-NMR(CDCl3)δ: 10.33(s, 1H), 8.60(s, 1H), 7.39(m, 5H), 6.83(m, 3H), 5.82(s, 2H), 5.26(s, 2H), 4.64(d, J=5.8Hz, 2H), 3.28-3.21(m, 2H), 1.02(t, J=7.3Hz, 3H). Process 4 Compound 4 (200 mg, 0.438 mmol) was dissolved in dichloromethane (4 ml), and compound 5 (111 mg, 0.920 mmol) and acetic acid (catalytic amount) were added and stirred at room temperature for 19 hours. The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography (chloroform-methanol) to give compound 6 (265 mg, 100% yield). MS: m / z = 559 [M+H] Process 5 Compound 6 (245 mg, 0.438 mmol) was dissolved in DMF (5 ml), and cesium carbonate (428 mg, 1.31 mmol) was added at 0°C. The mixture was stirred at room temperature for 18 hours. Dilute hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate, and the solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give a racemic mixture (139 mg, yield 60%). The resulting racemic mixture was subjected to optical resolution by SFC to give compound 7. Column: CHIRALPAK IA / SFC (5 μm, id 250 x 20 mm) Flow rate: 30 mL / min UV detection wavelength: 250 nm Separation conditions: The composition ratio of MeOH / CO2 was maintained at 45 / 55, and the solution was pumped for 21 minutes. 1H-NMR(CDCl3)δ: 10.46(s, 1H), 8.51(s, 1H), 7.58(m, 2H), 7.34(m, 4H), 6.81(m, 2H), 5.41(d, J=10.4Hz, 1H), 5.26(d, J=10.4Hz, 1H), 4.91(s, 1H), 4.64(m, 2H), 4.39(dd, J=14.3, 7.2Hz, 1H), 3.18-2.88(m, 3H), 2.24(d, J=14.7Hz, 1H), 2.00(m, 1H), 1.85(m, 2H), 1.72(d, J=13.6Hz, 1H), 1.38(m, 1H), 1.16(t, J=7.1Hz, 3H). Process 6 Compound 7 (44.0 mg, 0.0840 mmol) was dissolved in DMF (0.88 ml), lithium chloride (35.7 mg, 0.842 mmol) was added, and the mixture was stirred at 90°C for 1.5 hours. Water was added to the reaction mixture, which was then acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and the solvent was evaporated. The resulting crude product was solidified from diethyl ether to give compound I-23 (19 mg, 52% yield). 1H-NMR(CDCl3)δ: 11.98(s, 1H), 10.42(s, 1H), 8.46(s, 1H), 7.36(dd, J=15.2, 8.6Hz, 1H), 6.83-6.77(m, 2H), 5.06(s, 1H), 4.64(m, 2H), 4.35(td, J=14.2, 6.9Hz, 1H), 3.20-3.09(m, 2H), 3.00(d, J=10.8Hz, 1H), 2.31(d, J=15.4Hz, 1H), 2.06(m, 1H), 1.89(m, 2H), 1.76(m, 1H), 1.42-1.36(m, 1H), 1.24(t, J=7.1Hz, 4H).

[0106] Example 2 [ka] Process 1 Under a nitrogen atmosphere, a solution of compound 8 (1.3 mL, 11.1 mmol) in THF (7.0 mL) was added dropwise to a solution of magnesium (322 mg, 13.3 mmol) in THF (3.0 mL) and stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0°C, and copper iodide (210 mg, 1.1 mmol) was added. A solution of compound 9 (1.2 mL, 16.6 mmol) in THF (6.0 mL) was added dropwise. The mixture was warmed to room temperature and stirred for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 10 (192 mg, 11% yield). 1H-NMR(CDCl3)δ: 4.86(t, J=4.8Hz, 1H), 3.99-3.96(m, 2H), 3.90-3.79(m, 3H), 1.72-1.67(m, 2H), 1.55-1.48(m, 4H), 1.36(d, J=4.5Hz, 1H), 1.20(d, J=6.3Hz, 3H). Process 2 To a solution of compound 11 (334 mg, 0.60 mmol) in THF (2.0 mL), compound 10 (192.2 mg, 1.2 mmol), triphenylphosphine (315 mg, 1.2 mmol), and bis(2-methoxyethyl) azodicarboxylate (281 mg, 1.0 mmol) were added and stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was then evaporated. The resulting residue was crudely purified by silica gel column chromatography (hexane-ethyl acetate). MS: m / z = 699 [M+H] Process 3 To a solution of the crude product (100 mg) obtained in the second step in acetonitrile (1.0 mL) was added paratoluenesulfonic acid hydrate (45.1 mg, 0.242 mmol), and the mixture was heated to reflux for 210 minutes. The reaction mixture was allowed to cool to room temperature, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The resulting residue was dissolved in DMF (1.0 mL), and cesium carbonate (140 mg, 0.43 mmol) and benzyl bromide (34.1 μL, 0.29 mmol) were added. The mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give compound 13 (65.1 mg). MS: m / z = 537 [M+H] Process 4 The same reaction as in Step 6 of Example 1 was carried out to give compound I-31 (31 mg, yield 57%). 1H-NMR(CDCl3)δ: 11.93(s, 1H), 10.40(s, 1H), 8.39(s, 1H), 7.40-7.34(m, 1H), 6.84-6.77(m, 2H), 5.11-5.09(m, 1H), 4.64(d, J=5.8Hz, 2H), 4.40-4.31(m, 1H), 3.27-3.21(m, 1H), 3.13-3.06(m, 1H), 2.32-2.28(m, 1H), 2.12-2.04(m, 1H), 1.86-1.83(m, 1H), 1.79-1.75(m, 1H), 1.63-1,48(m, 2H), 1.21(t, J=7.2Hz, 3H), 0.89(d, J=6.3Hz, 3H).

[0107] Example 3 [ka] Process 1 To a solution of compound 11 (352 mg, 0.629 mmol) in DMF (3.5 ml), potassium carbonate (261 mg, 1.89 mmol) and 4-bromobutene (147 mg, 0.943 mmol) were added and the mixture was allowed to react at room temperature overnight. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was then evaporated. MS: m / z = 611 [M+H] Process 2 To the crude product obtained in step 1, a 4 mol / L hydrochloric acid / dioxane solution (3.15 ml) was added and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. MS: m / z = 511 [M+H] Process 3 The crude product obtained in step 2, acrolein (102 mg, 1.83 mmol), and p-toluenesulfonic acid hydrate (11.6 mg, 0.061 mmol) were dissolved in dichloroethane (9.6 mL) and stirred at 100°C for 6 hours. After the reaction mixture was allowed to cool to room temperature, water and saturated aqueous sodium bicarbonate were added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 16 (115 mg). MS: m / z = 549 [M+H] Process 4 Compound 16 (66.4 mg, 0.121 mmol) and Hoveyda-Grubbs second-generation catalyst (60 mg, 0.139 mmol) were dissolved in dichloromethane (10 mL) and heated under reflux for 6 hours. The solvent was evaporated, and the resulting residue was roughly purified by silica gel column chromatography (ethyl acetate-methanol). MS: m / z = 521 [M+H] Process 5 Compound 17 obtained in step 4 was optically resolved by SFC to give compound 18. Column: CHIRALPAK IC / SFC (5 μm, id 250 x 20 mm) Flow rate: 20 mL / min UV detection wavelength: 220 nm Separation conditions: The composition ratio of MeOH / CO2 was maintained at 70 / 30, and the solution was pumped for 21 minutes. Process 6 The same reaction as in Step 6 of Example 1 was carried out to give Compound II-65 (11 mg, yield 74%). 1H-NMR(CDCl3)δ: 11.93(s, 1H), 10.42(t, J=5.6Hz, 1H), 8.50(s, 1H), 7.40-7.33(m, 1H), 6.84-6.77(m, 2H), 6.28-6.24(m, 1H), 5.96-5.91(m, 1H), 5.32(d, J=5.2Hz, 1H), 4.68(dd, J=15.2, 6.0Hz, 1H), 4.61(dd, J=15.6, 6.0Hz, 1H), 3.83(dt, J=21.2, 7.2Hz, 1H), 3.53(dt, J=20.8, 6.8Hz, 1H), 3.39(td, J=11.2, 4.4Hz, 1H), 3.04(dd, J=10.8, 6.8Hz, 1H), 2.77-2.68(m, 1H), 2.35(dt, J=18.8, 4.8Hz, 1H), 1.23(t, J=7.2Hz, 3H).

[0108] Example 4 [ka] Process 1 To a solution of compound 11 (326 mg, 0.59 mmol), compound 19 (87 mg, 0.77 mmol), and triphenylphosphine (307 mg, 1.18 mmol) in THF (3.5 mL) was added di-2-methoxyethyl azodicarboxylate (274 mg, 1.18 mmol) at 0°C, and the mixture was allowed to stand at room temperature for 12 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 20 (293 mg, 77% yield). MS: m / z = 653 [M+H] Process 2 Compound 20 (287 mg, 0.44 mmol) was suspended in dioxane (3.4 mL) and water (2.3 mL). 2,6-lutidine (0.10 mL), sodium hydrogen periodate (282 mg, 1.32 mmol), and potassium osmate(VI) dihydrate (8.0 mg, 0.02 mmol) were added at 0°C, and the mixture was heated from 0°C to room temperature over 5 hours. The reaction mixture was filtered through Celite®, and 10% aqueous sodium thiosulfate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 21 (223 mg, 78% yield). MS: m / z = 655 [M+H] Process 3 Compound 21 (192 mg, 0.29 mmol) was dissolved in a 4 mol / L hydrochloric acid / dioxane solution (1.47 ml) and stirred at room temperature for 2 hours. The solvent was evaporated, and the resulting crude product was dissolved in toluene (2.0 ml). A catalytic amount of acetic acid was added, and the mixture was stirred at 90°C for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and then the solvent was evaporated. The resulting residue was purified by silica gel column chromatography to obtain a diastereomeric mixture. The resulting diastereomeric mixture was optically resolved by SFC to obtain compound 22 (69 mg, yield 44%). Column: Two CHIRALPAK IC / SFC (5 μm, id 250 x 20 mm) in series Flow rate: 20 mL / min UV detection wavelength: 220 nm Separation conditions: The composition ratio of MeOH / CO2 was maintained at 65 / 35, and the solution was pumped for 35 minutes. MS: m / z = 537 [M+H] Process 4 The same reaction as in Step 6 of Example 1 was carried out to give Compound II-34. MS: m / z = 447 [M+H]

[0109] Example 5 [ka] Process 1 To a solution of compound 23 (1.59 g, 12.2 mmol) in DMF (16.0 mL) was added imidazole (0.998 g, 14.66 mmol) and t-butyldimethylsilyl chloride (1.84 g, 12.21 mmol) at 0°C and stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 24 (1.39 g, 47% yield). 1H-NMR(CDCl3)δ: 3.47-3.55(m, 4H), 2.09-2.15(m, 2H), 1.88-1.95(s, 1H), 1.65-1.79(m, 2H), 1.32-1.42(m, 2H), 0.88-0.89(m, 1H), 0.85(s, 9H), 0.039(s, 6H). Process 2 To a solution of compound 24 (400 mg, 0.164 mmol), compound 11 (700 mg, 1.26 mmol), and triphenylphosphine (660 mg, 2.52 mmol) in THF (7 mL) was added di-2-methoxyethyl azodicarboxylate (589 mg, 2.52 mmol) at 0°C and the mixture was allowed to stand at room temperature for 12 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was then evaporated. The resulting residue was crudely purified by silica gel column chromatography (hexane-ethyl acetate). Process 3 A 1 mol / L TBAF / THF solution (1.63 ml, 1.63 mmol) was added to a solution of compound 25 (1.06 g, 1.35 mmol) in THF (10.0 mL) and stirred at room temperature for 12 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 26 (720 mg, 80% yield). MS: m / z = 669 [M+H] Process 4 Dess-Martin periodinane was added to a solution of compound 26 (720 mg, 1.08 mmol) in dichloromethane (8.0 mL) at 0°C, and the mixture was stirred at room temperature for 1 hour. A 10% aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium bicarbonate were added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 27 (393 mg, 55% yield). MS: m / z = 667 [M+H] Process 5 A solution of compound 27 (393 mg, 0.59 mmol) in acetonitrile (8.0 mL) was heated to 60°C and stirred for 80 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The resulting crude product was dissolved in DMF (4.0 mL), and cesium carbonate (576 mg, 1.77 mmol) and benzyl bromide (0.21 mL, 1.77 mmol) were added at 0°C. The mixture was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) and subjected to SFC optical resolution to give compound 28 (89 mg, 28% yield). Column: Two CHIRALPAK IC / SFC (5 μm, id 250 x 20 mm) in series Flow rate: 20mL / min UV detection wavelength: 220 nm Separation conditions: The composition ratio of MeOH / CO2 was maintained at 75 / 25, and the solution was pumped for 45 minutes. MS: m / z = 549 [M+H] Process 6 The same reaction as in Step 6 of Example 1 was carried out to obtain Compound II-1 (11 mg, yield 74%). MS: m / z = 459 [M+H]+

[0110] Example 6 [ka] Process 1 To a solution of compound 2 (3 g, 6.95 mmol) in DMF (60 mL), potassium carbonate (2.02 g, 14.6 mmol) and 2-(4-bromobutyl)-1,3-dioxolane (2.53 mL, 16.7 mmol) were added and the mixture was allowed to react at room temperature overnight. The reaction mixture was neutralized with 1 mol / L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated to give compound 29. MS: m / z = 688 [M+H] Process 2 To a solution of compound 29 in THF (47.8 mL), 2 mol / L aqueous sodium hydroxide solution (17.38 mL, 139 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was neutralized by adding 2 mol / L hydrochloric acid little by little and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give compound 30. MS: m / z = 560 [M+H] Process 3 To a solution of compound 30 in 1,4-dioxane (5 mL), 4 mol / L hydrogen chloride (1,4-dioxane solution, 34.8 mL, 139 mmol) was added and stirred at room temperature for 1 hour. The solvent was evaporated from the reaction solution, and toluene was added and evaporated again to obtain compound 31. MS: m / z = 416 [M+H] Process 4 A few drops of acetic acid were added to a solution of compound 31 in toluene (50 mL), and the mixture was stirred for 30 minutes at 110° C. The solvent was evaporated from the reaction mixture, and the resulting residue was solidified with ethanol / isopropyl ether to give compound 32 (2.44 g, 88% yield over four steps). 1H-NMR(CDCl3)δ:15.1(s, 1H), 8.48(s, 1H), 7.57-7.55(m, 2H), 7.36-7.29(m, 3H), 5.53(d, J=10.4Hz, 1H), 5.36(d, J=10.4Hz 1H), 4.93-4.91(m, 1H), 4.20(td, J=21.6, 7.2Hz, 1H), 3.24-3.02(m, 3H), 2.28-1.73(m, 5H), 1.41-1.31(m, 1H), 1.18(t, J=7.2Hz, 3H). Process 5 To a solution of compound 32 (300 mg, 0.755 mmol) in dichloromethane (3 mL), triethylamine (0.419 mL, 3.02 mmol) and ethyl chloroformate (90.0 mg, 0.830 mmol) were added at 0°C and stirred at room temperature for 30 minutes. Compound 33 (216 mg, 0.906 mmol) was added to the reaction solution and stirred at room temperature for 1 hour. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give compound 34 (466 mg, 100% yield). MS: m / z = 582 [M+H] Process 6 To a solution of compound 34 (439 mg, 0.755 mmol) in ethyl acetate (6 ml), a 50% T3P / ethyl acetate solution (2.25 ml, 7.55 mmol) was added and stirred at 100°C for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate, and the solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain a racemic compound. The racemic compound was optically resolved by SFC to obtain compound 35. Column: CHIRALPAK IA / SFC (5 μm, id 250 x 20 mm) Flow rate: 20mL / min UV detection wavelength: 220 nm Separation conditions: The composition ratio of MeOH / CO2 was maintained at 65 / 35, and the solution was pumped for 25 minutes. 1H-NMR(CDCl3)δ: 8.80(s, 1H), 7.60(m, 2H), 7.34-7.27(m, 4H), 6.85(t, J=8.9Hz, 2H), 5.55(d, J=10.3Hz, 1H), 5.33(d, J=10.4Hz, 1H), 4.97(m, 1H), 4.46(s, 2H), 4.40(m, 1H), 3.23(m, 1H), 3.10-3.03(m, 2H), 2.24(m, 1H), 2.02(m, 1H), 1.89(m, 2H), 1.72(m, 1H), 1.42(m, 1H), 1.17(t, J=7.2Hz, 3H). Process 7 Compound I-11 (63 mg, yield 68%) was obtained in the same manner as in Step 6 of Example 1. 1H-NMR(CDCl3)δ: 12.04(s, 1H), 8.73(s, 1H), 7.31(m, 1H), 6.84(t, J=8.6Hz, 2H), 5.14(s, 1H), 4.45(s, 2H), 4.36(m, 1H), 3.26-3.04(m, 3H), 2.33(d, J=14.9Hz, 1H), 2.08(t, J=14.7Hz, 1H), 1.91(m, 3H), 1.42(m, 1H), 1.24(t, J=7.2Hz, 3H).

[0111] Example 7 [ka] Process 1 A solution of compound 36 (1.0 g, 2.8 mmol) synthesized in the same manner as in Example 1 in dichloromethane (10 mL) was cooled to 0°C, and NBS (0.56 g, 3.1 mmol) was added and stirred overnight at room temperature. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain a racemic compound. The racemic compound was optically resolved by SFC to obtain compound 37. Column: CHIRALPAK IB / SFC (5μm, id250x20mm) Flow rate: 30 mL / min UV detection wavelength: 220 nm Separation conditions: The composition ratio of MeOH / CO2 was maintained at 35 / 65, and the solution was pumped for 21 minutes. 1H-NMR(CDCl3)δ: 7.83(s, 1H), 7.64(d, J=7.0Hz, 2H), 7.34-7.27(m, 3H), 5.48(d, J=10.3Hz, 1H), 5.26(d, J=10.3Hz, 1H), 4.92-4.90(m, 1H), 4.43-4.39(m, 1H), 3.20-3.14(m, 1H), 3.05-2.98(m, 2H), 2.26-2.22(m, 1H), 1.97-1.94(m, 1H), 1.84-1.82(m, 2H), 1.73-1.69(m, 1H), 1.41-1.39(m, 1H), 1.16(t, J=7.2Hz, 3H). Process 2 Compound 37 (250 mg, 0.58 mmol) was dissolved in toluene, and compound 38 (183 mg, 0.87 mmol), Pd(OAc) (13.0 mg, 0.06 mmol), 2-dicyclohexylphosphino-2'-(N,N-diamino)biphenyl (46 mg, 0.12 mmol), and cesium carbonate (565 mg, 1.7 mmol) were added. The mixture was sealed and stirred at 140 °C for 2 h. The mixture was allowed to cool to room temperature, insoluble materials were removed by filtration through Celite, and the solvent was evaporated. The resulting residue was crudely purified by silica gel column chromatography (hexane-ethyl acetate) and then purified by reverse phase chromatography to give compound 39 (40 mg, 12% yield). 1H-NMR(CDCl3)δ: 8.63(s, 1H), 7.64-7.61(m, 3H), 7.34-7.19(m, 4H), 6.83-6.79(m, 2H), 5.58(d, J=10.3Hz, 1H), 5.33(d, J=10.3Hz, 1H), 4.96-4.94(m, 1H), 4.44-4.40(m, 1H), 4.19(s, 2H), 3.22-3.18(m, 1H), 3.09-3.02(m, 2H), 2.27-2.23(m, 1H), 2.01-1.97(m, 1H), 1.86-1.84(m, 2H), 1.74-1.70(m, 1H), 1.43-1.40(m, 1H), 1.17(t, J=7.0Hz, 3H). Project 8 Using the same method as Process 6 of Example 1, compound I-2 (22 mg, yield 67%) was obtained. 1H-NMR(CDCl3)δ: 11.81(brs, 1H), 8.59(s, 1H), 7.54(s, 1H), 7.20-7.18(m, 1H), 6.83-6.78(m, 2H), 5.11-5.09(m, 1H), 4.40-4.31(m, 1H), 4.18(s, 2H), 3.24-3.02(m, 3H), 2.34-2.29(m, 1H), 2.09-2.01(m, 1H), 1.90-1.85(m, 2H), 1.78-1.74(m, 1H), 1.46-1.36(m, 1H), 1.23(t, J=7.0 Hz, 3H).

[0112] Example 8

change

[0113] The compounds shown below were similarly synthesized using the general synthesis method described above or the synthesis methods described in Examples 1 to 8.

[0114] [Table 1] [Table 2]

[0115] [Table 3] [Table 4]

[0116] [Table 5] [Table 6] [Table 7] [Table 8]

[0117] [Table 9] [Table 10]

[0118] [Table 11]

[0119] The physical data of each compound is shown below. [Table 12]

[0120] Examples relating to formula (I') of (B) are described below. Example 9 The following compounds were synthesized in the same manner using the synthesis methods described in WO2015 / 174511, WO2016 / 194806, etc. [ka]

[0121] The other compounds (B) were commercially available compounds or were synthesized according to known methods.

[0122] The following are examples of biological tests of the compounds according to the present invention.

[0123] Test Example 1: Anti-HIV activity A serial dilution series of the test sample was prepared in a 96-well microplate (50 μL / well). 5 MT-4 cell suspension (cells / mL) was dispensed at 100 μL per well into plates containing test samples, followed by 50 μL of HIV virus solution per well. The cells were mixed using a plate mixer and incubated in a CO2 incubator for 4 days. 30 μL of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) solution was dispensed into each well. The incubation was continued for 1 hour in a CO2 incubator. 150 μL of supernatant was removed from each well, taking care not to absorb the cells. 150 μL of cell lysis solution was added and mixed thoroughly using a plate mixer until all cells were lysed. The absorbance of the mixed plate was measured at dual wavelengths of 560 nm and 690 nm using a microplate reader. The 50% HIV inhibitory concentration (EC50) was determined from the concentration-response curve using the four-parameter logistic curve fitting model shown below. y=A+((BA) / (1+(C / x) D )) A = minimum inhibition rate (negative control, 0%) B = Maximum inhibition rate (positive control, 100%) C = compound concentration at inflection point D = slope coefficient x=compound concentration y=inhibition rate (%) (result) The results of the example compounds of formula (I) in (A) are shown below. [Table 13] The results for the example compounds of formula (I') in (B) are shown below. Compound I'-001:0.69nM Compound I'-027:9.9nM Compound I'-043: 1.4nM Compound I'-189: 1.6nM Compound I'-220: 5.9nM Compound I'-292: 2.5nM Compound I'-304:4.1nM From the above test results, it was revealed that the compounds according to the present invention exhibited high anti-HIV activity and are therefore useful as HIV drugs.

[0124] Test Example 2: Tolerance evaluation test A serial dilution series of the test sample was prepared in a 96-well microplate (50 μL / well). 5A HeLa-CD4 cell suspension containing 100 cells / mL was dispensed into a plate containing the test sample at 100 μL per well, followed by 50 μL of HIV virus solution (wild-type and mutant strains) per well. The cells were mixed using a plate mixer and incubated in a CO2 incubator for 3 days. The culture supernatant was aspirated from each well, and 100 μL of the cell lysis buffer included in the reporter assay kit was dispensed and frozen in a freezer (-80°C). The frozen plate was thawed at room temperature, mixed using a plate mixer, and centrifuged at 1,200 rpm for 5 minutes. 20 μL of the supernatant from each well was dispensed into a 96-well black microplate. 100 μL of the chemiluminescent reagent included in the reporter assay kit was dispensed into each well and incubated at room temperature for approximately 1 hour. Luminescence was measured using a MicroBeta TRILUX. The 50% HIV inhibitory concentration (EC50) was determined from the concentration-response curve using the four-parameter logistic curve fitting model shown below. y=A+((BA) / (1+(C / x) D )) A = minimum inhibition rate (negative control, 0%) B = Maximum inhibition rate (positive control, 100%) C = compound concentration at inflection point D = slope coefficient x=compound concentration y=inhibition rate (%) In addition, the resistance (fold change (FC)) of each mutant strain was calculated using the following formula. FC = EC50 of mutant strain / EC50 of wild-type strain (result) The results of the example compounds of formula (I) in (A) are shown below. The FC for mutant strain 1 (E138K / G140S / Q148H / N155H) and the FC for mutant strain 2 (E92Q / E138T / G140S / Q148H) are shown in the table. [Table 14] FC against mutant strain 3 (E92Q / E138K / G140S / Q148H) Compound I-032:7.7 Compound I-011:7.7 FC against mutant strain 4 (T97A / E138T / G140S / Q148H) Compound I-032:10 Compound I-011:3.2 The above test results show that the compound according to the present invention has a high resistance barrier and is less likely to cause HIV-resistant viruses. Therefore, the compound of formula (I) (A) exhibits high anti-HIV activity and can therefore be a useful pharmaceutical agent for treating and / or preventing HIV infection.

[0125] Test Example 3: Combined Effect Confirmation Test The two compounds whose combined effects were to be investigated were mixed in various ratios, and the anti-HIV activity (50% HIV inhibitory concentration) of each combination was determined by the method of Test Example 1. The dosewise additivity value (D value) was calculated from the obtained results according to the calculation method in Reference 1 to determine the combined effect. The calculation method of the D value is briefly described below. The 50% HIV inhibitory concentration of compound I alone is X I The concentration of compound I when a certain combination of compound I and compound J shows 50% inhibition is x I If so, FIC I is defined as follows: FIC I = x I / X I When anti-HIV activity is evaluated by combining M concentrations of compound X1 and N concentrations of compound X2, the D value is calculated by the following formula 1.

[0126]

number

[0127] Test Example 4: CYP Inhibition Test Using commercially available pooled human liver microsomes, the following typical substrate metabolic reactions of major human CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4): O-deethylation of 7-ethoxyresorufin (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4'-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4) were used as indicators to evaluate the extent to which the production of each metabolite was inhibited by the compound of the present invention.

[0128] The reaction conditions were as follows: substrates: 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time: 15 minutes; reaction temperature: 37°C; enzyme: pooled human liver microsomes, 0.2 mg protein / mL; and concentrations of the compound of the present invention: 1, 5, 10, and 20 μmol / L (4 points).

[0129] Five substrates, human liver microsomes, and the compounds of the present invention were added to a 96-well plate in 50 mmol / L Hepes buffer at the above composition, and the coenzyme NADPH was added to initiate the metabolic reaction. After 15 minutes at 37°C, the reaction was stopped by adding a 1:1 (V / V) methanol / acetonitrile solution. After 15 minutes of centrifugation at 3000 rpm, resorufin (a CYP1A2 metabolite) in the supernatant was quantified by fluorescence multilabel counter or LC / MS / MS. Hydroxylated tolbutamide (a CYP2C9 metabolite), 4'-hydroxylated mephenytoin (a CYP2C19 metabolite), dextrorphan (a CYP2D6 metabolite), and terfenadine alcohol (a CYP3A4 metabolite) were quantified by LC / MS / MS.

[0130] The control (100%) was a reaction solution containing only DMSO, the solvent in which the compound was dissolved, instead of the compound of the present invention. The remaining activity (%) was calculated, and the IC was calculated by inverse estimation using a logistic model using the concentration and inhibition rate. 50 was calculated.

[0131] Test Example 5: CYP3A4 (MDZ) MBI test This test evaluates the mechanism-based inhibition (MBI) ability of the compounds of the present invention by measuring the potentiation of the inhibitory effect due to the metabolic reaction of the compounds of the present invention. CYP3A4 inhibition was evaluated using pooled human liver microsomes and the 1-hydroxylation of midazolam (MDZ) as an index.

[0132] The reaction conditions were as follows: substrate, 10 μmol / L MDZ; pre-reaction time, 0 or 30 minutes; substrate metabolic reaction time, 2 minutes; reaction temperature, 37°C; pooled human liver microsomes, 0.5 mg / mL during pre-reaction and 0.05 mg / mL (10-fold dilution) during reaction; concentration of the compound of the present invention during pre-reaction, 1, 5, 10, 20 μmol / L (4 points) or 0.83, 5, 10, 20 μmol / L (4 points).

[0133] A 96-well plate was prepared as a pre-reaction solution by adding pooled human liver microsomes and a compound solution according to the present invention in K-Pi buffer (pH 7.4) in the above pre-reaction composition. A portion of the solution was transferred to another 96-well plate so that it was diluted 1 / 10 with K-Pi buffer containing the substrate. The coenzyme NADPH was added to initiate the reaction (no pre-reaction: preincubation 0 min). After the specified reaction time, the reaction was stopped by adding a 1 / 1 (V / V) methanol / acetonitrile solution. The remaining pre-reaction solution was also added with NADPH to initiate the pre-reaction (pre-reaction: preincubation 30 min). After the specified reaction time, a portion of the solution was transferred to another plate so that it was diluted 1 / 10 with K-Pi buffer containing the substrate, and the reaction was stopped by adding a 1 / 1 (V / V) methanol / acetonitrile solution. The plates on which each indicator reaction had been performed were centrifuged at 3000 rpm for 15 minutes, and the 1-hydroxymidazolam in the supernatant was quantified by LC / MS / MS.

[0134] The control (100%) was a reaction solution containing only DMSO, the solvent in which the compound was dissolved, instead of the compound of the present invention. The residual activity (%) was calculated when each concentration of the compound of the present invention was added, and the IC was calculated by inverse estimation using a logistic model using the concentration and inhibition rate. The shifted IC value was calculated as the IC at 0 min preincubation / IC at 30 min preincubation. A shifted IC of 1.5 or higher was considered positive (+), and a shifted IC of 1.0 or lower was considered negative (-). (result) The results for the example compounds of formula (I) in (A) are shown below. Compound I-032:(-) Compound II-058:(-) Compound II-117:(-) Compound II-130:(-)

[0135] Test Example 6: BA Test Materials and methods for oral absorption studies (1) Animals used: Rats were used. (2) Rearing conditions: Rats were allowed free access to solid food and sterilized tap water. (3) Dosage and grouping: Oral and intravenous administration was performed at the specified dose. The groups were set up as follows (dosages varied depending on the compound): Oral administration: 2-60 μmol / kg or 1-30 mg / kg (n=2-3) Intravenous administration: 1-30 μmol / kg or 0.5-10 mg / kg (n=2-3) (4) Preparation of administration solution: Oral administration was performed as a solution or suspension, and intravenous administration was performed as a solubilized solution. (5) Administration method: Oral administration was performed by forcibly administering the compound into the stomach using an oral sonde. Intravenous administration was performed by administering the compound into the tail vein using a syringe with an injection needle. (6) Evaluation item: Blood samples were collected over time, and the plasma concentration of the compound according to the present invention was measured using LC / MS / MS. (7) Statistical analysis: The area under the plasma concentration-time curve (AUC) of the compound according to the present invention was calculated by moment analysis, and the bioavailability (BA) of the compound according to the present invention was calculated from the dose ratio and AUC ratio between the oral and intravenous administration groups.

[0136] Test Example 7: Clearance evaluation test Experimental materials and methods (1) Animals used: Rats were used. (2) Rearing conditions: Rats were allowed free access to solid food and sterilized tap water. (3) Dosage and grouping: The animals were administered intravenously at a predetermined dose. The groups were set up as follows: Intravenous administration 1 μmol / kg (n=2) (4) Preparation of administration solution: The solution was solubilized using a solvent of dimethyl sulfoxide / propylene glycol = 1 / 1 and administered. (5) Administration method: The drug was administered via the tail vein using a syringe with an injection needle attached. (6) Evaluation item: Blood samples were collected over time, and the plasma concentration of the compound according to the present invention was measured using LC / MS / MS. (7) Statistical analysis: The total body clearance (CLtot) and elimination half-life (t1 / 2) of the plasma compound of the present invention were calculated by moment analysis. (result) The results for the example compounds of formula (I) in (A) are shown below. Compound I-032:0.111mL / min / kg,12.3hr Compound II-023:0.102mL / min / kg,26.7hr Compound II-104:0.0226mL / min / kg,35.4hr Compound II-110:0.0364mL / min / kg,23.6hr From the above results, the compounds according to the present invention have small clearance and long elimination half-lives, and are therefore useful as long-acting integrase inhibitors.

[0137] Test Example 8: Metabolic stability test The compound of the present invention was reacted with commercially available pooled human liver microsomes for a certain period of time, and the remaining rate was calculated by comparing the reacted sample with the unreacted sample to evaluate the extent to which the compound of the present invention was metabolized in the liver.

[0138] Human liver microsomes (0.5 mg protein / mL) were incubated in 0.2 mL of buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) in the presence of 1 mmol / L NADPH at 37°C for 0 or 30 minutes (oxidative reaction). After the reaction, 50 μL of the reaction mixture was added to 100 μL of a 1 / 1 (v / v) methanol / acetonitrile solution, mixed, and centrifuged at 3,000 rpm for 15 minutes. The compound of the present invention in the supernatant was quantified by LC / MS / MS or solid-phase extraction (SPE) / MS, and the remaining amount of the compound of the present invention after the reaction was calculated based on the amount of compound at 0 minutes of reaction (100%). (Results) The remaining rate at a compound concentration of 0.5 μmol / L is shown in the table below. The results for the example compounds of formula (I) in (A) are shown below. [Table 17]

[0139] Test Example 9: Fluctuation Ames Test The mutagenicity of the compounds of the present invention was evaluated. 20 μL of frozen Salmonella typhimurium (Salmonella typhimurium TA98 strain, TA100 strain) was inoculated into 10 mL of liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) and pre-cultured with shaking at 37°C for 10 hours. For the TA98 strain, 7.70 to 8.00 mL of the bacterial solution was centrifuged (2000 × g, 10 minutes) to remove the culture medium. The bacteria were suspended in the same volume of Micro F buffer (K2HPO4: 3.5 g / L, KH2PO4: 1 g / L, (NH4)2SO4: 1 g / L, trisodium citrate dihydrate: 0.25 g / L, MgSO4·7H2O: 0.1 g / L) as the bacterial suspension used for centrifugation, and added to 120 mL of Exposure medium (Micro F buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL). For the TA100 strain, 3.10–3.42 mL of bacterial suspension was added to 120–130 mL of Exposure medium to prepare the test bacterial suspension. DMSO solution of the compound according to the present invention (several serial dilutions of 2- to 3-fold common ratio from the maximum dose of 50 mg / mL), DMSO as a negative control, and 50 μg / mL 4-nitroquinoline-1-oxide DMSO solution for the TA98 strain and 0.25 μg / mL 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution for the TA100 strain as positive controls under non-metabolic activation conditions, 40 μg / mL 2-aminoanthracene DMSO solution for the TA98 strain and 20 μg / mL 2-aminoanthracene DMSO solution for the TA100 strain under metabolic activation conditions were mixed with 12 μL of each and 588 μL of test bacterial solution (a mixture of 498 μL of test bacterial solution and 90 μL of S9 mix under metabolic activation conditions), and cultured with shaking at 37 ° C. for 90 minutes. 460 μL of the bacterial solution exposed to the compound according to the present invention was mixed with 2300 μL of indicator medium (MicroF buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL), and 50 μL of the mixture was dispensed into 48 wells of a microplate and incubated statically at 37°C for 3 days.Wells containing bacteria that have acquired the ability to grow due to a mutation in the amino acid (histidine) synthase gene change color from purple to yellow due to a change in pH, so the number of wells that showed yellow bacterial growth out of 48 wells per dose was counted and evaluated compared with the negative control group. Negative mutagenicity is indicated as (-), and positive mutagenicity is indicated as (+).

[0140] Test Example 10: hERG test To assess the risk of electrocardiogram QT interval prolongation due to the compounds of the present invention, we used CHO cells expressing the human ether-a-go-go related gene (hERG) channel to measure the delayed rectifier K channel, which plays an important role in the ventricular repolarization process. + Current (I Kr The effect of the compound according to the present invention on the leukemia cells was investigated. Using a fully automated patch clamp system (QPatch; Sophion Bioscience A / S), the whole-cell patch clamp technique was used to measure the I induced by holding the cell at a membrane potential of -80 mV and applying a leak potential of -50 mV, followed by a depolarizing stimulus of +20 mV for 2 seconds and a repolarizing stimulus of -50 mV for 2 seconds. Kr The extracellular solution containing 0.1% dimethyl sulfoxide (NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl2: 2 mmol / L, MgCl2: 1 mmol / L, glucose: 10 mmol / L, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol / L, pH = 7.4) was used as a vehicle, and the vehicle and the extracellular solution containing the compound of the present invention dissolved at the desired concentration were applied to the cells at room temperature for 7 minutes or more. Kr The absolute value of the maximum tail current was measured using analysis software (QPatch Assay software; Sophion Bioscience A / S) based on the current value at the resting membrane potential. Furthermore, the maximum tail current after application of the compound according to the present invention relative to the maximum tail current after application of the vehicle was calculated as an inhibition rate, and the I of the compound according to the present invention was calculated. KrThe impact on

[0141] Test Example 11: Solubility test The solubility of the compounds of the present invention was determined with the addition of 1% DMSO. A 10 mmol / L compound solution was prepared in DMSO. 2 μL of the compound solution of the present invention was added to 198 μL of JP-1 solution or JP-2 solution, respectively. After shaking at room temperature for 1 hour, the mixture was filtered under suction. The filtrate was diluted 10- or 100-fold with methanol / water = 1 / 1 (V / V) or acetonitrile / methanol / water = 1 / 1 / 2 (V / V / V), and the concentration in the filtrate was measured using LC / MS or solid-phase extraction (SPE) / MS with the absolute calibration curve method.

[0142] The composition of 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 JP-2 liquid is as follows: Dissolve 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate in water to make 1000 mL, and add 1 volume of water to 1 volume of the solution.

[0143] Test Example 12: Powder solubility test An appropriate amount of the compound of the present invention was placed in an appropriate container, and 200 μL of JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid, and water added to 1000 mL), JP-2 solution (3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate dissolved in water to make 1000 mL, and then 1 volume of water was added), or 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (1.08 g of TCA and JP-2 solution added to make 100 mL) was added to each container. If the entire amount was dissolved after adding the test solution, additional compound of the present invention was added as needed. The containers were sealed and shaken at 37°C for 1 hour, then filtered. 100 μL of each filtrate was diluted 2-fold by adding 100 μL of methanol. The dilution ratio was changed as necessary. The containers were checked for the presence of bubbles and precipitates, sealed, and shaken. The compounds of the present invention were quantified using HPLC using the absolute calibration curve method.

[0144] Test Example 13: Ames test The mutagenicity of the compounds of the present invention was evaluated in an Ames test using Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 and Escherichia coli WP2uvrA as test strains. A 0.1 mL DMSO solution of the compound of the present invention was mixed with 0.5 mL of S9mix (metabolically activated conditions) or 0.5 mL of phosphate buffer (non-metabolically activated conditions) and 0.1 mL of test bacterial solution, and layered onto a minimal glucose agar plate with 2 mL of soft layer agar containing histidine and biotin or tryptophan. Simultaneously, a negative control (DMSO) and a positive control (2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide, sodium azide, 9-aminoacridine, or 2-aminoanthracene) were tested in the same manner. After 48 hours of incubation at 37°C, the number of revertant colonies that appear is counted and evaluated by comparison with the negative control. A concentration-dependent increase in the number of revertant colonies, which is at least twice the number of colonies in the negative control, is considered positive (+).

[0145] Test Example 14: Nav Test To evaluate the proarrhythmic risk of the compounds of the present invention, HEK cells expressing the voltage-gated sodium channel (Nav1.5 channel) encoded by the SCN5A gene were used to investigate the proarrhythmic risk of the Na channel, which plays an important role in the depolarization process of myocardium. + Current (I Na The effect of the compound according to the present invention on the leukemia cells was investigated. Using a fully automated patch clamp system (QPatch; Sophion Bioscience A / S), the whole-cell patch clamp technique was used to measure I induced by applying a depolarizing stimulus of -10 mV for 20 ms while the cells were held at a membrane potential of -100 mV. NaThe I was recorded. The vehicle was an extracellular solution containing 0.3% dimethyl sulfoxide (NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl2: 2 mmol / L, MgCl2: 1 mmol / L, glucose: 10 mmol / L, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol / L, TEA (Tetraethylammonium Hydroxide): 10 mmol / L, pH = 7.4). The vehicle and the extracellular solution containing the compound of the present invention dissolved at the desired concentration were applied to the cells at room temperature for 5 minutes or more. Na The absolute value of the maximum peak current was measured using analysis software (QPatch Assay software; Sophion Bioscience A / S) based on the current value at the resting membrane potential. Furthermore, the ratio of the maximum peak current when the compound of the present invention was applied to the maximum peak current when the vehicle was applied was calculated, and the I of the compound of the present invention was calculated. Na The impact on (result) The results for the example compounds of formula (I) in (A) are shown below. Compound I-007 103% Compound I-011 102% Compound I-022 97.1% Compound I-023 101% Compound I-032 92.1% Compound II-026 79% Compound II-098 96.7% Compound II-106 109% Compound II-109 93.3% Compound II-110 89.3% Compound II-117 88.8% Compound II-118 86.2% Compound II-120 78.8% Compound II-158 90.7% From the above results, no clear increase in current was observed, and there is little concern that the compounds of the present invention may cause arrhythmia due to an increase in Na current.

[0146] Test Example 15: Anti-HIV activity evaluation test using peripheral blood mononuclear cells (PBMC) from healthy individuals A serial dilution series of the test sample was prepared in a 96-well microplate (50 μL / well). 5 PBMCs stimulated with phytohemagglutinin (PHA) at 1000p / well were mixed with the required number of wells containing HIV virus solution and incubated at 37°C for 1 hour. After incubation, the cell suspension was centrifuged and the supernatant discarded. The infected cells were dispersed in culture medium at 150 μL / well for the required number of wells, and then dispensed at 150 μL / well into a 96-well microplate containing the test sample. The mixture was mixed using a plate mixer and incubated in a CO2 incubator for 4 days. Reverse transcriptase activity in the culture medium was measured. The 90% HIV inhibitory concentration (EC90) was determined from the concentration-dependence curve using the four-parameter logistic curve fitting model shown below. y=A+((BA) / (1+(C / x) D )) A = minimum inhibition rate (negative control, 0%) B = Maximum inhibition rate (positive control, 100%) C = compound concentration at inflection point D = slope coefficient x=compound concentration y=inhibition rate (%) (result) The results of the example compounds of formula (I) in (A) are shown below. Compound I-007 1.0nM Compound II-026 0.73nM Compound II-045 3.3nM Compound II-109 1.7nM

[0147] Test Example 16: Anti-HIV activity evaluation test in the presence of human serum proteins A serial dilution series of the test sample was prepared in a 96-well microplate (50 μL / well). 100 μL of human serum protein solution (50% human serum protein concentration) was dispensed into the 96-well microplate containing the test sample and allowed to stand at room temperature for 1 hour. 100 μL of culture medium was dispensed into the serum-free plate. 3.0 x 10 5 MT-4 cells (cells / well) and 3 μL / well of HIV virus solution were mixed for the required number of wells and incubated at 37°C for 1 hour. After incubation, the cell suspension was centrifuged and the supernatant discarded. The infected cells were dispersed in culture medium (50 μL / well) for the required number of wells. 50 μL / well of the cells were dispensed into a 96-well microplate containing the test sample and human serum protein (final human serum protein concentration: 25%). The mixture was mixed using a plate mixer and incubated in a CO2 incubator for 4 days. 30 μL of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) solution was dispensed into each well. The incubation was continued for 1 hour in a CO2 incubator. 150 μL of the supernatant was removed from each well, taking care not to absorb the cells. 150 μL of cell lysis solution was added and mixed thoroughly using a plate mixer until all the cells were lysed. The absorbance of the mixed plate was measured at two wavelengths, 560 nm and 690 nm, using a microplate reader. The 50% HIV inhibitory concentration (EC50) was determined from the concentration-dependence curve using the four-parameter logistic curve fitting model shown below. y=A+((BA) / (1+(C / x) D )) A = minimum inhibition rate (negative control, 0%) B = Maximum inhibition rate (positive control, 100%) C = compound concentration at inflection point D = slope coefficient x=compound concentration y=inhibition rate (%) In addition, the potency whit (PS) was calculated based on the following formula, where PS is an extrapolated value of 100% human serum protein concentration. PS = 4 x (EC50 in the presence of 25% human serum protein / EC50 in the absence of human serum protein) (result) The PS in the presence of human serum proteins is shown in the table (100% extrapolated value). The results for the example compounds of formula (I) in (A) are shown below. Compound I-007 116 Compound II-026 364 Compound II-045 236 Compound II-109 56

[0148] These test results indicate that the pharmaceutical of the present invention can be useful as a therapeutic and / or preventive agent for symptoms and / or diseases induced by HIV infection.

[0149] Formulation example 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 present invention can be administered as pharmaceutical compositions by any conventional route, in particular 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, or topically, e.g., in the form of lotions, gels, ointments, or creams, or in the form of intranasal or suppositories. Pharmaceutical compositions containing the compounds of the present invention in free form or in the form of a pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier or diluent can be prepared by conventional mixing, granulation, or coating methods. For example, oral compositions can be tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, etc., and active ingredients, etc. Injectable compositions can be solutions or suspensions, which may be sterilized and may contain preservatives, stabilizers, buffers, etc. [Industrial Applicability]

[0150] The pharmaceutical of the present invention can be useful as a therapeutic and / or preventive agent for symptoms and / or diseases induced by HIV infection.

Claims

1. (A) Formula (I): 【Chemical 1】 (Wherein, ring A is any of the following rings: 【Chemistry 2】 X1 is CR ９ａ R ９ｂ or O; R ５ａ , R ５ｂ , R ６ａ , R ６ｂ , R ７ａ and R ７ｂ are each independently hydrogen, halogen, alkyl, haloalkyl, alkyloxy, alkyloxyalkyl, or a 3-6 membered non-aromatic carbocyclic group; R ５ａ and R ６ａ , or R ６ａ and R ７ａ may be taken together with the adjacent atom to form an aromatic carbocycle which may be substituted with halogen, a 3- to 6-membered non-aromatic carbocycle which may be substituted with halogen, or a 4- to 6-membered non-aromatic heterocycle which may be substituted with halogen (however, when forming an aromatic carbocycle, R ５ｂ and R ６ｂ , or R ６ｂ and R ７ｂ together to form a bond); R ５ｂ and R ６ｂ may together form a bond; R ８ａ , R ８ｂ , R ９ａ , R ９ｂ , R １０ａ , R １０ｂ , R １１ａ and R １１ｂ are each independently hydrogen, halogen, alkyl, haloalkyl, alkyloxy, alkyloxyalkyl, or a 3-6 membered non-aromatic carbocyclic group; R ８ａ and R １０ａ may together form a C1-C3 bridge; R １０ａ and R １１ａ may be taken together with adjacent atoms to form a 5-membered non-aromatic carbocyclic ring; R ９ａ and R ９ｂ may be taken together with adjacent atoms to form a 4-membered non-aromatic carbocyclic ring or a 5-membered non-aromatic heterocyclic ring; R ８ａ and R ９ａ may together form a bond; Ring B is a benzene ring or a pyridine ring; Q is —NHC(O)— or a 5-membered aromatic heterocycle; R １ are each independently halogen, alkyl, haloalkyl, alkyloxy, cyano, or haloalkyloxy; R ２ａ and R ２ｂ are each independently hydrogen, alkyl, or haloalkyl; R ３ is alkyl or haloalkyl; R ４ is hydrogen or alkyl; and n is an integer from 1 to 3. or a pharmaceutically acceptable salt thereof; (B) A compound having an anti-HIV activity or a pharmaceutically acceptable salt thereof A pharmaceutical for preventing or treating HIV infection, characterized by combining

2. R ３ The pharmaceutical composition of claim 1, wherein is alkyl.

3. R １ The pharmaceutical composition according to claim 1 or 2, wherein each of the is independently a halogen.

4. R ２ａ is hydrogen, and R ２ｂ The pharmaceutical agent according to any one of claims 1 to 3, wherein is hydrogen or alkyl.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein Q is -NHC(O)-.

6. The pharmaceutical composition according to any one of claims 1 to 4, wherein Q is a 5-membered aromatic heterocycle.

7. (A) is the compound I-3, I-7, I-11, I-16, I-23, I-24, I-32, II-1, II-4, II-5, II-13, II-14, II-16, II-19, II-21, II-23, II-26, II-31, II-34, II-36, I I-38, II-41, II-43, II-45, II-47, II-49, II-52, II-56, II-58, II-62 , II-63, II-64, II-68, II-89, II-92, II-93, II-95, II-96, II-98, II- 106, II-109, II-110, II-112, II-113, II-117, II-118, II-125, II-127, II-128, II-129, II-130, II-131, II-132, II-136, II-138, II-139, II-142, II-143, II-144, II-147, II-148, II-149, II-150, II-151, II-155, II-156 and II-157, and pharmaceutically acceptable salts thereof.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein (B) is at least one selected from a compound having a polymerase inhibitory activity, a compound having a ribonuclease H inhibitory activity, a compound having an allosteric inhibitory activity against the HIV-1 Integrase (IN)-Lens epithelium-derived growth factor (LEDGF) complex, a compound having a protease inhibitory activity, a compound having an adsorption / invasion inhibitory activity, a compound having a budding inhibitory activity, a compound having a maturation inhibitory activity, a compound having a capsid inhibitory activity, and pharmaceutically acceptable salts thereof.

9. A compound having an allosteric inhibitory activity against the HIV-1 Integrase (IN)-Lens epithelium-derived growth factor (LEDGF) complex is represented by formula (I'): 【Chemistry 3】 (In the formula, R ３Ａ ' and R ４Ａ ' each independently represents hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, ringoxy, substituted or unsubstituted non-aromatic carbocycleoxy, substituted or unsubstituted aromatic heterocycleoxy, substituted or unsubstituted non-aromatic heterocycleoxy, substituted or unsubstituted aromatic carbocyclesulfanyl, substituted or unsubstituted non-aromatic carbocyclesulfanyl, substituted or unsubstituted aromatic heterocyclesulfanyl, substituted or unsubstituted non-aromatic heterocyclesulfanyl, substituted or unsubstituted aromatic carbocyclecarbonyl, substituted or unsubstituted non-aromatic carbocyclecarbonyl, substituted or unsubstituted aromatic heterocyclecarbonyl, substituted or unsubstituted non-aromatic heterocyclecarbonyl, substituted or unsubstituted amino, or substituted or unsubstituted carbamoyl; R ３Ａ ' and R ４Ａ ' may, together with adjacent atoms, form a substituted or unsubstituted monocyclic carbocyclic ring or a substituted or unsubstituted monocyclic heterocyclic ring, and the carbocyclic ring or heterocyclic ring may be further fused with a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring; R ４Ａ ' is T １ together with the atoms on the ring arcs, may form a substituted or unsubstituted monocyclic heterocycle, which may be further fused with a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle; T １ The ring is a substituted or unsubstituted monocyclic heterocycle, (1) the heterocycle may be fused with another substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, and / or (2) two non-adjacent atoms constituting the heterocycle may be bridged by a substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene; R １ ' is halogen, cyano, nitro or X 1 '-R １１ ' and X 1 ' represents a single bond, -O-, -S-, or -NR １２ '-, -CO-, -SO-, -SO ２ -, -O-CO-, -CO-O-, -NR １２ '-CO-, -CO-NR １２ '-, -NR １２ '-CO-O-, -NR １２ '-CO-NR １３ '-, -NR １２ '-SO ２ - or SO ２ -NR １２ '- and R １１ ' is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; R １２ ' and R １３ each independently represents a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl; X 1 ' is -NR １２ '-, -CO-NR １２ '- or SO ２ -NR １２ '-, then R １１ ' and R １２ ' may be taken together with the adjacent nitrogen atom to form a substituted or unsubstituted non-aromatic heterocycle, X 1 ' is -NR 1２ '-CO-NR 1３ '-, then R 1１ ' and R 1３ ' may be taken together with the adjacent nitrogen atom to form a substituted or unsubstituted non-aromatic heterocycle, R １ ' is T １ together with the carbon atoms or nitrogen atoms on the ring arcs, may form a substituted or unsubstituted monocyclic carbocycle or a substituted or unsubstituted monocyclic heterocycle, which may be further fused with a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle; R ２ each independently represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyloxy, or substituted or unsubstituted cycloalkenyloxy; n' is 1 or 2; R ３ ' represents a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; R ４ 9. The pharmaceutical composition according to claim 8, wherein R 1 is a compound represented by the formula (I) and R 2 is a carboxy-protecting group.

10. (B) AZT, 3TC, didanosine, zalcitabine, sanilvudine, abacavir, tenofovir, tenofovir disoproxil, tenofovir Alafenamide, emtricitabine, nevirapine, efavirenz, capravirine, etravirine, delavirdine, rilpivirine, VM-1500A, VM-1500, doravirine, MK-8507, MK-8504, MK-8583, compounds I'-001, I'-027, I'-043, I'-189, I'-220, I'-292, I'-304, indinavir, ritonavir, saquinavir, nelfinavir, amprenavir, atazanavir, lopinavir, fosamprenavir, darunavir, maraviroc, enfuvirtide, ibalizumab, PRO-140, temsavir, fostemsavir The pharmaceutical agent according to claim 8, which is at least one selected from tromethamine, Combinectin, BDM-2, GSK-2838232, GSK-3640254, GS-6207, MK-8527, and MK-8558, and pharmaceutically acceptable salts thereof.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein (A) and (B) are administered in combination.

12. The pharmaceutical agent according to any one of claims 1 to 10, which is a combination drug.

13. 10. An anti-HIV activity enhancer for a compound having anti-HIV activity described in (B) of claim 1 or a pharmaceutically acceptable salt thereof, comprising the compound described in (A) of claim 1 or a pharmaceutically acceptable salt thereof.

14. 10. An anti-HIV activity enhancer for the compound described in claim 1 (A) or a pharmaceutically acceptable salt thereof, which has anti-HIV activity, comprising the compound described in claim 1 (B) or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising the compound of claim 1 (A) or a pharmaceutically acceptable salt thereof as an active ingredient, for use in combination with the compound of claim 1 (B) having anti-HIV activity, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition for use in combination with a compound having anti-HIV activity described in (A) of claim 1 or a pharmaceutically acceptable salt thereof, comprising the compound described in (B) of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

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