Polycyclic pyridopyrazine derivatives

Abstract

The present invention provides a compound represented by formula (I). (In the formula, an A ring is a C5-C7 non-aromatic carbocycle or a 5- to 7-membered non-aromatic heterocycle; a B ring is a benzene ring or the like; Q is -NHC(O)- or a 5-membered aromatic heterocycle; R1 are each independently a halogen or the like; R2a and R2b are each independently hydrogen, alkyl, or haloalkyl; R3 is an alkyl or the like; R4 and R5 are each independently a hydrogen and the like; R6 are each independently halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, or alkyloxyalkyl; n is an integer of 1-3; and m is an integer of 0 to 3.)

Description

[Technical Field]

[0001] The present invention relates to novel compounds having antiviral activity, more particularly to polycyclic pyridopyrazine derivatives having HIV integrase inhibitory activity, and to pharmaceuticals, particularly anti-HIV drugs, containing the same. [Background technology]

[0002] Among viruses, the human immunodeficiency virus (HIV), a type of retrovirus, is known to cause acquired immunodeficiency syndrome (AIDS). Currently, various guidelines recommend combination therapies for naive patients, primarily consisting of an integrase inhibitor (e.g., dolutegravir) and two nucleoside reverse transcriptase inhibitors (NUCs) with different resistance profiles (e.g., ABC+3TC, FTC+TAF). These combinations are highly effective and safe, resulting in higher patient satisfaction compared with earlier treatments. Meanwhile, the availability of safer drugs and favorable prognosis have led to the recommendation to start treatment as soon as HIV infection is detected. Furthermore, the life expectancy of HIV-infected individuals is approaching that of healthy individuals, leading to longer drug use. Due to the side effects of long-term use and the lack of convenient treatment options once viral resistance emerges, there is a trend toward leaving NUCs unused. Therefore, there is a need for the establishment of two-drug therapy using two major drugs, and the development of a major drug that can be combined with an integrase inhibitor. Furthermore, there is a need for a treatment with longer dosing intervals, i.e., a long-acting injectable drug that can complete treatment with a single injection at intervals of one month or more, to improve patients' quality of life (QOL), such as alleviating medication fatigue caused by long-term medication and enabling them to enjoy daily life more.

[0003] To meet this demand, the integrase inhibitor cabotegravir is currently in Phase 3 development as a long-acting injectable. The non-nucleoside reverse transcriptase inhibitor rilpivirine is also being developed as a long-acting injectable, with the aim of establishing a two-drug treatment regimen. However, these drugs require injections once every one or two months, which can be painful and involves three to four injections. Therefore, to further improve patients' quality of life, the development of a drug that can be administered at a lower dose, with less pain, and that can be completed with a single injection every three months is desirable. Raltegravir and elvitegravir are first-generation oral integrase inhibitors, while dolutegravir is a second-generation inhibitor. When naive patients receive dolutegravir, resistance mutations do not emerge. However, when dolutegravir is used to treat patients infected with a virus resistant to first-generation integrase inhibitors, further resistance mutations may develop, making dolutegravir ineffective. Therefore, there is a need to develop inhibitors with a higher resistance barrier than dolutegravir.

[0004] Furthermore, bicyclic or higher carbamoylpyridone derivatives are known as anti-HIV drugs having integrase inhibitory activity (Patent Documents 1 to 29). Of these, Patent Documents 9 and 20 describe fused tricyclic carbamoylpyridopyrazine derivatives. Patent Document 22 describes fused tetracyclic carbamoylpyridopyrazine derivatives. 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 to 33). Of these, Patent Document 9 describes a fused tricyclic pyridopyrazine 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] An object of the present invention is to provide novel compounds with long-lasting integrase inhibitory activity and a high resistance barrier. [Means for solving the problem]

[0007] As a result of extensive research, the present inventors have found that novel pyridopyrazine derivatives have an integrase inhibitory effect with a high resistance barrier. Furthermore, they have found that the compounds of the present invention and pharmaceuticals containing them are useful as antiviral drugs (e.g., antiretroviral drugs, anti-HIV drugs, anti-HTLV-1 (Human T cell leukemia virus type 1) drugs, anti-FIV (Feline immunodeficiency virus) drugs, and anti-SIV (Simian immunodeficiency virus) drugs), particularly anti-HIV drugs, anti-AIDS drugs, or drugs for treating diseases related thereto, and have completed the present invention described below.

[0008] The present invention provides the following inventions. [1] Formula (I): [ka] (In the formula, Ring A is a C5-C7 non-aromatic carbocycle or a 5-7 membered non-aromatic heterocycle, and the non-aromatic carbocycle and non-aromatic heterocycle may be further condensed with a benzene ring, a 3-7 membered non-aromatic carbocycle or a 3-7 membered non-aromatic heterocycle, or may form a spiro ring of a 3-7 membered non-aromatic carbocycle and a 3-7 membered non-aromatic heterocycle; Ring B is a benzene ring or a pyridine ring; Q is -NHC(O)- (the bond on the left is CR 2a R 2b ) 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 and R 5 are each independently hydrogen or alkyl; R 6 are each independently halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, or alkyloxyalkyl; or Two Rs attached to non-adjacent atoms 6 may together form a C1-C3 bridge, which may be interrupted by a heteroatom; n is an integer from 1 to 3; and m is an integer of 0 to 3. provided that when m is 0, a) ring B is a pyridine ring, or b) ring A is a C5-C7 non-aromatic carbocycle which may be further fused with a benzene ring, a 3- to 7-membered non-aromatic carbocycle or a 3- to 7-membered non-aromatic heterocycle, or may form a spiro ring of a 3- to 7-membered non-aromatic carbocycle and a 3- to 7-membered non-aromatic heterocycle, and Q is a 5-membered aromatic heterocycle, or c) ring A is a C5-C7 non-aromatic carbocycle which may be further fused with a benzene ring, a 3- to 7-membered non-aromatic carbocycle or a 3- to 7-membered non-aromatic heterocycle, or may form a spiro ring of a 3- to 7-membered non-aromatic carbocycle and a 3- to 7-membered non-aromatic heterocycle, and Q is -NHC(O)-, [ka] The group represented by [ka] or d) ring A is a 5- to 7-membered non-aromatic heterocycle, which may be further fused with a benzene ring, a 3- to 7-membered non-aromatic carbocycle, or a 3- to 7-membered non-aromatic heterocycle, or may form a spiro ring of a 3- to 7-membered non-aromatic carbocycle and a 3- to 7-membered non-aromatic heterocycle, and Q is a 5-membered aromatic heterocycle; [ka] The group represented by [ka] (wherein the following compounds are included): [ka] ) or a pharmaceutically acceptable salt thereof. [2] Ring A is a C5-C7 non-aromatic carbocyclic ring, R 6 are each independently halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, or alkyloxyalkyl; Two Rs attached to non-adjacent atoms 6 are taken together to form a C1-C3 bridge, or a pharmaceutically acceptable salt thereof. [3]R 4 and R 5

[0022]

[0023] The compound according to [1] or [2], or a pharmaceutically acceptable salt thereof, wherein [4]R 3 The compound according to any one of [1] to [3], or a pharmaceutically acceptable salt thereof, wherein is alkyl. [5]R 1 The compound according to any one of [1] to [4], or a pharmaceutically acceptable salt thereof, wherein each of the is independently a halogen. [6]R 2a is hydrogen and R 2b

[0022] The compound according to any one of [1] to [5], or a pharmaceutically acceptable salt thereof, wherein is hydrogen or alkyl. [7] The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [6], wherein Q is -NHC(O)-. [8] Q is the following ring (the left bond is CR 2a R 2b Combine with): [ka] The compound according to any one of [1] to [6], or a pharmaceutically acceptable salt thereof, wherein [9]R 4 and R 5 The compound according to any one of [1] to [8], or a pharmaceutically acceptable salt thereof, wherein the stereochemistry of the carbon atom adjacent to [ka]

[10] Formula (IA): [ka] (In the formula, The A ring is a C5-C6 non-aromatic carbocyclic ring; Ring B is a benzene ring or a pyridine ring; Q is -NHC(O)- (the bond on the left is CR 2a R 2b ) 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 6 are each independently halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, or alkyloxyalkyl; or Two Rs attached to non-adjacent atoms 6 may together form a C1-C3 bridge; n is an integer from 1 to 3; and and m is an integer of 0 to 2.) (provided that the following compounds: [ka] ) or a pharmaceutically acceptable salt thereof.

[11] R 3

[10] The compound or a pharmaceutically acceptable salt thereof according to

[10] , wherein

[12] R 1 The compound according to either

[10] or

[11] , or a pharmaceutically acceptable salt thereof, wherein each of the groups independently represents a halogen.

[13] R 2a is hydrogen and R 2b The compound or a pharmaceutically acceptable salt thereof according to any one of

[10] to

[12] , wherein is hydrogen or alkyl.

[14] The compound or a pharmaceutically acceptable salt thereof according to any one of

[10] to

[13] , wherein Q is -NHC(O)-.

[15] Q is the following ring (the left bond is CR 2a R 2b Combine with): [ka] The compound according to any one of

[10] to

[13] , or a pharmaceutically acceptable salt thereof, wherein

[16] The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to

[15] , wherein ring B is a benzene ring.

[17] A pharmaceutical composition comprising the compound according to any one of [1] to

[16] or a pharmaceutically acceptable salt thereof.

[18] The pharmaceutical composition according to

[17] , which is an anti-HIV agent.

[19] The pharmaceutical composition according to

[17] , which is an HIV integrase inhibitor.

[20] An HIV integrase inhibitor comprising the compound according to any one of [1] to

[16] or a pharmaceutically acceptable salt thereof.

[21] A method for treating and / or preventing HIV infection, which comprises administering the compound according to any one of [1] to

[16] or a pharmaceutically acceptable salt thereof.

[22] The compound according to any one of [1] to

[16] , or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of HIV infection.

[0009] The present invention further provides a method for preventing or treating HIV infection, which comprises administering an effective amount of the above compound to a human. The present invention further provides the above compounds for use as anti-HIV drugs. [Effects of the Invention]

[0010] The compounds of the present invention have integrase inhibitory activity and / or cell proliferation inhibitory activity against viruses, particularly HIV and viruses resistant to HIV. Therefore, they are useful for the prevention or treatment of various diseases and viral infections (e.g., AIDS) in which integrase is involved. More preferably, the compounds of the present invention are useful as long-acting integrase inhibitors. Furthermore, they are also excellent in terms of their resistance profile, such as the likelihood of new HIV-resistant viruses emerging. Even more preferably, the compounds of the present invention have preventive or therapeutic effects against drug-resistant HIV viruses. Even more preferably, the compounds of the present invention are useful as pharmaceuticals that have low clearance, long in vivo half-life, excellent solubility, metabolic stability, and the like, and have little risk of cytotoxicity or side effects (e.g., CYP inhibition, mutagenicity, electrocardiogram QT interval prolongation, arrhythmia). DETAILED DESCRIPTION OF THE INVENTION

[0011] 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.

[0012] The term "halogen" includes fluorine, chlorine, bromine, and iodine atoms. Particularly, fluorine and chlorine atoms are preferred.

[0013] 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.

[0014] "Non-aromatic carbocycle" means a monocyclic saturated hydrocarbon ring. For example, cyclopentane, cyclohexane, cycloheptane, etc. may be mentioned.

[0015] The term "5-membered aromatic heterocycle" means a 5-membered aromatic ring having one or more identical or different heteroatoms selected from O, S and N within the ring. Examples of the 5-membered aromatic heterocycle include pyrrole, imidazole, pyrazole, triazole, tetrazole, furan, thiophene, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, and thiadiazole.

[0016] The term "non-aromatic heterocycle" refers to a monocyclic non-aromatic ring having one or more identical or different heteroatoms selected from O, S and N within the ring. Examples of 5-membered non-aromatic heterocycles include oxathiolane, thiazolidine, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, THF, dihydrothiazole, tetrahydrothiazole, tetrahydroisothiazole, dioxolane, dioxole, thiolane, etc. Examples of 6-membered non-aromatic heterocycles include dioxane, thiane, piperidine, piperazine, morpholine, thiomorpholine, dihydropyridine, tetrahydropyridine, tetrahydropyran, tetrahydrooxazine, tetrahydropyridazine, hexahydropyrimidine, dioxazine, thiine, thiazine, etc. Examples of 7-membered non-aromatic heterocycles include hexahydroazepine, hexahydrodiazepine, and oxepane.

[0017] The term "C1-C3 bridge optionally containing a heteroatom" refers to a C1-C3 alkylene having one or more identical or different heteroatoms selected from O, S and N within the ring.

[0018] Preferred embodiments of each symbol in the compound represented by formula (I) are shown below. Examples of the compound represented by formula (I) include all combinations of the specific examples shown below. The ring A is a C5-C7 non-aromatic carbocycle (e.g., cyclopentane, cyclohexane, cycloheptane, etc.) or a 5- to 7-membered non-aromatic heterocycle (e.g., tetrahydrofuran, tetrahydropyran, oxepane, pyrrolidine, piperidine, azepane, etc.), and the non-aromatic carbocycle and non-aromatic heterocycle may be further condensed with a benzene ring, a 3- to 7-membered non-aromatic carbocycle (e.g., cyclopropane, cyclopentane, etc.) or a 3- to 7-membered non-aromatic heterocycle (e.g., tetrahydrofuran, etc.), or may form a spiro ring of a 3- to 7-membered non-aromatic carbocycle (e.g., cyclopropane, cyclobutane, cyclopentane, etc.) and a 3- to 7-membered non-aromatic heterocycle (e.g., oxetane, tetrahydrofuran, 1,3-dioxolane, etc.). A preferred embodiment of Ring A is a C5-C7 non-aromatic carbocyclic ring (e.g., cyclopentane, cyclohexane, cycloheptane, etc.) or a 5- to 7-membered non-aromatic heterocyclic ring (e.g., tetrahydrofuran, tetrahydropyran, oxepane, pyrrolidine, piperidine, azepane, etc.). Another preferred embodiment of Ring A is a C5-C7 non-aromatic carbocyclic ring (e.g., cyclopentane, cyclohexane, cycloheptane, etc.), and a more preferred embodiment is a C5-C6 non-aromatic carbocyclic ring (e.g., cyclopentane, cyclohexane, etc.).

[0019] Ring B includes a benzene ring or a pyridine ring. A preferred embodiment of ring B is a benzene ring.

[0020] 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.

[0021] 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.

[0022] R 3 The group may be alkyl or haloalkyl. R 3 One of the preferred embodiments of is alkyl.

[0023] R 4 The 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.

[0024] R 5 The group may be hydrogen or alkyl. R 5 In one preferred embodiment, it is hydrogen.

[0025] R 6 are each independently halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, or alkyloxyalkyl, or two R 6 are taken together to form a heteroatom (NR 7 , O or S) may be interposed. R 6 In one preferred embodiment, is halogen, haloalkyl, alkyloxy, haloalkyloxy or alkyloxyalkyl, more preferably alkyloxy or alkyloxyalkyl. R 6 Another preferred embodiment of is halogen, C1-3 haloalkyl, C1-3 alkyloxy, C1-3 haloalkyloxy or C1-3 alkyloxyC1-3 alkyl, more preferably C1-3 alkyloxy or C1-3 alkyloxyC1-3 alkyl. R 6 Another preferred embodiment of the present invention is a compound having two R groups bonded to non-adjacent atoms. 6 together form a C1-C3 bridge.

[0026] R 7 may include hydrogen, alkyl, haloalkyl, alkyloxyalkyl, alkylcarbonyl, alkyloxycarbonyl, carbamoyl, alkylcarbamoyl, or alkylsulfonyl. R7 A preferred embodiment of is hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkyloxyC1-3 alkyl, C1-3 alkylcarbonyl, C1-3 alkyloxycarbonyl, carbamoyl, C1-3 alkylcarbamoyl or C1-3 alkylsulfonyl.

[0027] 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.

[0028] m is an integer of 0 to 3. In one preferred embodiment, m is an integer of 1 to 3, and more preferably an integer of 1 to 2. Another preferred embodiment of m is an integer of 0 to 2.

[0029] Q is -NHC(O)- (the bond on the left is CR 2a R 2b and a 5-membered aromatic heterocycle. A preferred embodiment of Q is -NHC(O)-. Another preferred embodiment of Q is a 5-membered aromatic heterocycle. Another preferred embodiment of Q is the following ring (the bond on the left is CR 2a R 2b Combine with); [ka] Another preferred embodiment of Q is the following ring (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.

[0030] R4 and R 5 The preferred stereochemistry of the carbon atom adjacent to is as follows: [ka]

[0031] (Embodiment 1) Formula (IA): [ka] (In the formula, The A ring is a C5-C6 non-aromatic carbocyclic ring; Ring B is a benzene ring or a pyridine ring; Q is -NHC(O)- (the bond on the left is CR 2a R 2b ) 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 6 are each independently halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, or alkyloxyalkyl; or Two Rs attached to non-adjacent atoms 6 may together form a C1-C3 bridge; n is an integer from 1 to 3; and and m is an integer of 1 to 3.) or a pharmaceutically acceptable salt thereof.

[0032] (Embodiment 2) Formula (IA): [ka] (In the formula, Ring A is a C5-C6 non-aromatic carbocyclic ring, which is further fused with a benzene ring, a 4- to 7-membered non-aromatic carbocyclic ring, or a 3- to 7-membered non-aromatic heterocyclic ring; Ring B is a benzene ring or a pyridine ring; Q is -NHC(O)- (the bond on the left is CR 2a R 2b ) 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 6 are each independently halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, or alkyloxyalkyl; or Two Rs attached to non-adjacent atoms 6 may together form a C1-C3 bridge; n is an integer from 1 to 3; and and m is an integer of 0 to 3.) or a pharmaceutically acceptable salt thereof.

[0033] (Embodiment 3) Formula (IA): [ka] (In the formula, Ring A is a C5-C6 non-aromatic carbocyclic ring, which further forms a 3-7 membered non-aromatic carbocyclic spiro ring; Ring B is a benzene ring or a pyridine ring; Q is -NHC(O)- (the bond on the left is CR 2a R 2b ) 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 6 are each independently halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, or alkyloxyalkyl; or Two Rs attached to non-adjacent atoms 6 may together form a C1-C3 bridge; n is an integer from 1 to 3; and and m is an integer of 0 to 3.) or a pharmaceutically acceptable salt thereof.

[0034] (Embodiment 4) Formula (IA): [ka] (In the formula, Ring A is a C5-C7 non-aromatic carbocycle or a 5- to 7-membered non-aromatic heterocycle, and the non-aromatic carbocycle and non-aromatic heterocycle may be further condensed with a benzene ring, a 3- to 7-membered non-aromatic carbocycle or a 3- to 7-membered non-aromatic heterocycle, or may form a spiro ring of a 3- to 7-membered non-aromatic carbocycle and a 3- to 7-membered non-aromatic heterocycle; The B ring is a pyridine ring; Q is -NHC(O)- (the bond on the left is CR 2a R 2b ) or a 5-membered aromatic heterocycle; R 1 are each independently halogen, alkyl, haloalkyl, alkyloxy, cyano, or haloalkyloxy; R 2a and R 2bare each independently hydrogen, alkyl, or haloalkyl; R 3 is alkyl, or haloalkyl; R 4 and R 5 are each independently hydrogen or alkyl; R 6 are each independently halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, or alkyloxyalkyl; or Two Rs attached to non-adjacent atoms 6 may together form a C1-C3 bridge, which may be interrupted by a heteroatom; n is an integer from 1 to 3; and and m is an integer of 0 to 3.) or a pharmaceutically acceptable salt thereof.

[0035] (Embodiment 5) Formula (IA): [ka] (In the formula, Ring A is a C5-C7 non-aromatic carbocycle or a 6- to 7-membered non-aromatic heterocycle, and the non-aromatic carbocycle and non-aromatic heterocycle may be further condensed with a benzene ring, a 3- to 7-membered non-aromatic carbocycle or a 3- to 7-membered non-aromatic heterocycle, or may form a spiro ring of a 3- to 7-membered non-aromatic carbocycle and a 3- to 7-membered non-aromatic heterocycle; Ring B is a benzene ring or a pyridine ring; Q is 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 4and R 5 are each independently hydrogen or alkyl; R 6 are each independently halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, or alkyloxyalkyl; or Two Rs attached to non-adjacent atoms 6 may together form a C1-C3 bridge, which may be interrupted by a heteroatom; n is an integer from 1 to 3; and and m is an integer of 0 to 3.) or a pharmaceutically acceptable salt thereof.

[0036] (Embodiment 6) Formula (IA): [ka] (In the formula, Ring A is a 5-6 membered non-aromatic heterocycle, which is further fused with a benzene ring, a 3-7 membered non-aromatic carbocycle, or a 3-7 membered non-aromatic heterocycle; Ring B is a benzene ring or a pyridine ring; Q is -NHC(O)- (the bond on the left is CR 2a R 2b ) 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 6 are each independently halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, or alkyloxyalkyl; or Two Rs attached to non-adjacent atoms 6may together form a C1-C3 bridge; n is an integer from 1 to 3; and and m is an integer of 0 to 3.) or a pharmaceutically acceptable salt thereof.

[0037] (Embodiment 7) Formula (IA): [ka] (In the formula, Ring A is a 5-6 membered non-aromatic heterocycle, which further forms a 3-7 membered non-aromatic carbocycle and a 3-7 membered non-aromatic heterocycle spirocycle; Ring B is a benzene ring or a pyridine ring; Q is -NHC(O)- (the bond on the left is CR 2a R 2b ) 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 6 are each independently halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, or alkyloxyalkyl; or Two Rs attached to non-adjacent atoms 6 may together form a C1-C3 bridge; n is an integer from 1 to 3; and and m is an integer of 0 to 3.) or a pharmaceutically acceptable salt thereof.

[0038] The compound of the present invention is characterized in that it has excellent resistance profile, pharmacokinetics, and safety by fixing the A ring to a specific stereostructure in formula (I).Furthermore, the compound of the present invention is characterized in that it has excellent resistance profile, pharmacokinetics, and safety by making the A ring an optically active tricyclic or higher ring pyridopyrazine derivative in formula (I).

[0039] Unless otherwise specified, the compound of 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, rotational isomers, etc.), racemates, or mixtures thereof.

[0040] Pharmaceutically acceptable salts of the compound of the present invention include salts of the compound of 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 the compound of the present invention with 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.

[0041] The compound of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (e.g., hydrate, etc.), co-crystal, and / or crystalline polymorph, and the present invention also encompasses such various solvates, co-crystals, and crystalline polymorphs. A "solvate" may be coordinated with the compound of the present invention with any number of solvent molecules (e.g., water molecules, etc.). When the compound of the present invention or a pharmaceutically acceptable salt thereof is left in the atmosphere, it may absorb moisture, and adsorbed water may adhere, or a hydrate may be formed. Furthermore, a crystalline polymorph may be formed by recrystallization of the compound of the present invention or a pharmaceutically acceptable salt thereof. A "co-crystal" means that the compound of the present invention or a salt thereof and a counter molecule are present in the same crystal lattice, and may be formed with any number of counter molecules.

[0042] The compounds of the present invention or pharmaceutically acceptable salts thereof may form prodrugs, and the present invention also encompasses various such prodrugs. Prodrugs are derivatives of the compounds of the present invention having chemically or metabolically decomposable groups, 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 to the compounds of formula (I) by enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in vivo, and compounds that are converted to the compounds of formula (I) by hydrolysis with gastric acid, etc. Methods for selecting and preparing appropriate prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985." Prodrugs may themselves be active.

[0043] When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group, examples of the prodrug include acyloxy derivatives and sulfonyloxy derivatives produced by reacting the compound having a hydroxyl group with an appropriate acyl halide, an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride, or a mixed anhydride, or by reacting the compound using a condensing agent. For example, CHCOO-, C2H5COO-, tert-BuCOO-, C 15 H 31 Examples include COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH2CH2COO-, CH3CH(NH2)COO-, CH2N(CH3)2COO-, CH3SO3-, CH3CH2SO3-, CF3SO3-, CH2FSO3-, CF3CH2SO3-, p-CH3O-PhSO3-, PhSO3-, and p-CH3PhSO3-.

[0044] (Method for producing the compound of the present invention) The compound of the present invention can be produced, for example, by the general synthesis method shown below. Extraction, purification, etc. may be carried out by treatments commonly used in organic chemistry experiments. The compounds of the present invention can be synthesized by referring to methods known in the art. (Method 1) [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; P 1 , P 2 R and R' may be groups that can be protected and / or deprotected by the methods described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons), etc., and for example, P 1 is an aromatic carbocyclic alkyl, etc., and P 2is alkyloxycarbonyl, etc., and R and R' are alkyl, etc.; other symbols are as defined above. Process 1 Compound a1, which is commercially available or can be prepared by a known method, is added to compound a, which is commercially available or can be prepared by a known method, in the presence of a solvent such as methanol, ethanol, toluene, dioxane, THF, water, or a mixed solvent thereof, in the presence or absence of a base such as sodium bicarbonate, and the reaction is carried out at 0°C to 80°C, preferably 20°C to 60°C, for 0.1 to 24 hours, preferably 1 to 12 hours. Subsequently, the reaction is subjected to a known general deprotection reaction of the amino protecting group, and then a base such as cesium carbonate, potassium carbonate, or DBU is added in the presence of a solvent such as methanol, ethanol, toluene, dioxane, or THF, and the reaction is carried out 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 a2. Process 2 Compound a3 can be obtained by adding a base such as sodium carbonate, potassium carbonate, or cesium carbonate and an alkyl halide such as iodomethane or iodoethane to compound a2 in the presence of a solvent such as DMF, DMA, NMP, DMSO, or THF, and reacting the mixture at 0°C to 80°C, preferably 20°C to 60°C, for 0.1 to 24 hours, preferably 1 to 12 hours. Process 3 Compound a4 can be obtained by subjecting compound a3 to a known general deprotection reaction of a carboxy protecting group. Process 4 Compound a6 can be obtained by adding a condensing agent such as HATU, WSC·HCl, or PyBOP to compound a4 in the presence of a solvent such as DMF, DMA, NMP, THF, chloroform, or dichloromethane, and then adding compound a5, which is commercially available or can be prepared by a known method, and a base such as triethylamine, N-methylmorpholine, pyridine, or diisopropylethylamine, 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 5 Compound a6 can be resolved into a7 and a8 by chiral SFC. Process 6 Compounds a9 and a10 can be obtained by subjecting compounds a7 and a8, respectively, to a known general deprotection reaction of a hydroxy protecting group.

[0045] (Method 2) [ka] (In the formula, each symbol has the same meaning as defined above.) Process 1 Compound a4 is converted into a mixed acid anhydride by adding a base such as triethylamine or diisopropylethylamine and ethyl chloroformate in the presence of a solvent such as dichloromethane, dichloroethane, chloroform, DMF, DMA, NMP, or THF, and then compound b1, 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 hours to 24 hours, preferably 1 hour to 12 hours, to obtain compound b2. Process 2 Compound b2 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 b3. Process 3 Compound b3 can be resolved into b4 and b5 by chiral SFC. Process 4 Compounds b6 and b7 can be obtained by subjecting compounds b4 and b5 to a known general deprotection reaction of a hydroxy protecting group, respectively.

[0046] The compound of the present invention obtained above may be further chemically modified to synthesize other compounds. In addition, 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.

[0047] The compounds of the present invention are useful as pharmaceuticals, such as antiviral drugs. The compounds of the present invention have a significant inhibitory effect on viral integrase. Therefore, the compounds of the present invention are expected to be effective in preventing or treating various diseases caused by viruses that produce at least integrase and replicate in animal cells upon infection. For example, the compounds of the present invention are useful as integrase inhibitors against retroviruses (e.g., HIV-1, HIV-2, HTLV-1, SIV, FIV, etc.), and are useful as anti-HIV drugs, etc. More preferred compounds are characterized by pharmacokinetics, such as high blood concentration, long duration of effect, and / or significant tissue distribution. Furthermore, preferred compounds are safe in terms of side effects (e.g., inhibition of CYP enzymes, mutagenicity, prolongation of the QT interval on electrocardiograms, arrhythmia).

[0048] The compounds of the present invention may also be used in combination therapy with anti-HIV drugs having different mechanisms of action, such as reverse transcriptase inhibitors, protease inhibitors and / or entry blockers. Furthermore, the above-mentioned uses include not only use as an anti-HIV combination drug, but also use as a combined drug that enhances the anti-HIV activity of other anti-HIV drugs, such as in cocktail therapy. Furthermore, in the field of gene therapy, when retroviral vectors based on HIV or MLV are used, the compound of the present invention can be used to prevent the spread of infection of the retroviral vector to tissues other than the target tissue. In particular, when cells or the like are infected with a vector in a test tube and then returned to the body, administering the compound of the present invention in advance can prevent unnecessary infection in the body.

[0049] The pharmaceutical composition of the present invention can be administered orally or parenterally, including transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ophthalmic, otic, and vaginal administration.

[0050] For oral administration, the compound may be prepared and administered in any commonly used dosage form, such as a solid preparation for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.) or a liquid preparation for internal use (e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, 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.

[0051] 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.

[0052] Pharmaceutical compositions can be prepared by mixing an effective amount of the compound of the present invention with various pharmaceutical additives, such as excipients, binders, disintegrants, and lubricants, appropriate for the dosage form. Furthermore, by appropriately adjusting the effective amount of the compound 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.

[0053] The dosage of the pharmaceutical composition of the present invention is desirably determined taking into consideration the patient's age, body weight, type and severity of the disease, route of administration, etc., but when administered orally, it is usually 0.05 to 100 mg / kg / day, preferably 0.1 to 10 mg / kg / day. When administered parenterally, it varies greatly depending on the route of administration, but is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This dosage may be administered once a day to once a month or once every three months. [Example]

[0054] An example is shown below. <Abbreviation> Bn: Benzyl DBU: Diazabicycloundecene DMA: Dimethylacetamide DMF: dimethylformamide DMSO: dimethyl sulfoxide HATU:O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate NMP: N-methylpyrrolidone PyBOP: (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate T3P: Propylphosphonic anhydride THF: tetrahydrofuran WSC·HCl: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0055] The NMR analyses obtained in each example were performed at 300 MHz or 400 MHz using DMSO-d6 and CDCl3. When presenting NMR data, 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), and the measurements were carried out under the following conditions.

[0056] Measurement conditions[1] Column: Shim-pack XR-ODS (2.2 μm, id 3.0 x 50 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. Measurement conditions [2] 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 Gradient: A linear gradient of 5%-100% solvent [B] was performed over 3.5 minutes, followed by 0.5 minutes of maintaining 100% solvent [B].

[0057] Example 1 [ka] (In the formula, Rac represents a racemic mixture.) Process 1 Compound 1 (1.11 g, 3.49 mmol) was dissolved in methanol (22.2 mL) and water (11.1 mL), and compound 2 (906 mg, 3.84 mmol) and sodium bicarbonate (586 mg, 6.97 mmol) were added and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting crude product was dissolved in dioxane (4.0 mL), and a 4 mol / L hydrochloric acid / dioxane solution (8.7 mL) was added and stirred for 40 minutes. The solvent was removed under reduced pressure, and the resulting crude product was dissolved in methanol (22.2 mL). Potassium carbonate (1.45 g, 10.5 mmol) was added and stirred at room temperature for 1 hour. Water (80.0 mL) was added to the reaction solution, and the precipitated solid was collected by filtration. The resulting solid was washed with water and air-dried to give compound 3 (1.08 g, 77% yield). LC / MS (ESI): 405.0 (m / z), retention time (min): 1.17, LC / MS conditions: [1] Process 2 Compound 3 (680 mg, 1.68 mmol) was dissolved in DMF (6.8 mL), and ethyl iodide (393 mg, 2.52 mmol) and cesium carbonate (1.10 g, 3.36 mmol) were added, followed by stirring at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate to obtain compound 4 (890 mg) as a crude product. LC / MS (ESI): 433.1 (m / z), retention time (min) 1.44:, LC / MS conditions: [1] Process 3 Compound 4 (890 mg) was dissolved in THF (14.2 mL) and water (8.4 mL). 4 mol / L aqueous lithium hydroxide solution (0.84 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Dilute hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give compound 5 (563 mg, 80% yield for two steps). LC / MS (ESI): 419.0 (m / z), retention time (min): 1.85, LC / MS conditions: [1] Process 4 Compound 5 (110 mg, 0.263 mmol) was dissolved in dichloromethane (1.1 mL), and (3-chloro-2-fluorophenyl)methanamine (62.9 mg, 0.394 mmol), HATU (150 mg, 0.394 mmol), and triethylamine (72.9 μL, 0.526 mmol) were added. The mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the organic layer was separated. The solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain a racemic mixture. LC / MS (ESI): 560.3 (m / z), retention time (min): 2.35, LC / MS conditions: [1] The resulting racemic mixture was optically resolved by SFC to give compound 6 (66.5 mg, yield 45%). Column: Two CHIRALPAK IC / SFC (5 μm, id 250 x 20 mm) in series Flow rate: 20 mL / min UV detection wavelength: 220 nm Analysis conditions: The composition ratio of MeOH / CO2 was maintained at 80 / 20, and the solution was pumped for 40 minutes. Process 5 Compound 6 (66.5 mg, 0.119 mmol) was dissolved in N,N-dimethylformamide (2.0 mL), lithium chloride (200 mg, 4.72 mmol) was added, and the mixture was stirred at 90 °C for 2.0 hours. The reaction mixture was acidified with 10% aqueous citric acid solution and extracted with chloroform. The organic layer was separated and the solvent was evaporated. The resulting residue was purified by reverse phase liquid chromatography to give compound I-1 (55.0 mg, 98% yield). LC / MS (ESI): 470 (m / z), retention time (min): 2.06, LC / MS conditions: [2] 1H-NMR (CDCl3) δ: 12.84 (s, 1H), 10.39 (t, J = 5.7 Hz, 1H), 8.37 (s, 1H), 7.33-7.24 (m, 2H), 7.07-6.99 (m, 1H), 4.77-4.64 (m, 3H), 4.39-4.32 (m, 1H), 3.91-3.79 (m, 1H), 3.58-3.45 (m, 1H), 2.90-2.56 (m, 4H), 1.29 (t, J = 7.2 Hz, 3H).

[0058] Example 2 [ka] Process 1 To a solution of compound 7 (1.11 g, 7.34 mmol) in ethanol (10 mL), sodium bicarbonate (0.93 g, 11.0 mmol) and benzyl chloroformate (1.56 mL, 11.0 mmol) were added at 0°C, and the mixture was stirred overnight at room temperature. Purified water was added to the reaction solution, which was then extracted with ethyl acetate, washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give compound 8 (2.09 g, yield 99.8%). 1 H-NMR (CDCl3) δ: 7.39-7.31 (m, 5H), 5.16-5.08 (m, 2H), 4.88 (brs, 1H), 3.79-3.69 (m, 1H), 3.64-3.52 (m, 1H), 2.76 (s, 1H), 2.24-2.13 (m, 1H), 2.10-2.01 (m, 1H), 1.77-1.58 (m, 3H), 1.43-1.32 (m, 1H). Process 2 To a solution of compound 8 (1.65 g, 5.78 mmol) in dichloromethane (20.0 mL), pyridine (0.56 mL, 6.94 mmol) and trifluoromethanesulfonic anhydride (1.17 mL, 6.94 mmol) were added at 0° C., and the mixture was stirred for 3 hours at 0° C. Purified water was added to the reaction solution, which was then extracted with dichloromethane, washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain compound 9. Process 3 Compound 9 (1.66 g, 3.97 mmol) was dissolved in NMP (15.0 mL), sodium azide (1.55 g, 23.8 mmol) was added, and the mixture was stirred at 100 °C for 1 hour. Purified water was added to the reaction solution, which was then extracted with ethyl acetate, washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel chromatography to give compound 10 (628 mg, 51% yield). 1 H-NMR (CDCl3) δ: 7.40-7.27 (m, 5H), 5.12 (s, 2H), 5.05-4.94 (m, 1H), 3.97 (t, J = 4.1 Hz, 2H), 2.04-1.85 (m, 2H), 1.77-1.63 (m, 2H), 1.57-1.32 (m, 2H). Process 4 Compound 10 (620 mg, 2.00 mmol) was dissolved in THF (6.2 mL), purified water (0.72 mL, 40.0 mmol) and triphenylphosphine (629 mg, 2.40 mmol) were added, and the reaction mixture was stirred overnight under reflux. The reaction mixture was cooled to room temperature, and di-tert-butyl dicarbonate (523 mg, 0.557 mL) was added. The mixture was stirred at room temperature for 6 hours and 45 minutes. Purified water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel chromatography to give compound 11 (572 mg, 1.49 mmol). 1 H-NMR (CDCl3) δ: 7.41-7.32 (m, 5H), 5.16-5.08 (m, 3H), 4.88 (brs, 1H), 4.28 (brs, 1H), 4.12 (q, J = 7.2 Hz, 1H), 2.13 (brs, 1H), 1.88-1.60 (m, 5H), 1.45 (s, 9H). Process 5 Compound 11 (572 mg, 1.49 mmol) was dissolved in methanol (6.0 mL), and 5% palladium carbon (15.8 mg, 0.074 mmol) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. Insoluble matter was removed by filtration through Celite (registered trademark), and the solvent was concentrated under reduced pressure to give compound 12. Process 6 Compound 12 was used in the same manner as in Example 1 to obtain compound I-7. 1 H-NMR (CDCl3) δ: 12.54 (brs, 1H), 10.48 (t, J = 5.6 Hz, 1H), 8.41 (s, 1H), 7.33-7.27 (m, 2H), 7.03 (t, J = 8.4 Hz, 1H), 4.73-4.65 (m, 2H), 4.62-4.57 (m, 1H), 4.22 (td, J = 14.3, 7.2 Hz, 1H), 3.87 (dt, J = 21.6, 2.6 Hz, 1H), 3.34 (td, J = 14.1, 7.0 Hz, 1H), 2.87 (d, J = 16.1 Hz, 1H), 2.41-2.30 (m, 1H), 2.06-1.79 (m, 4H), 1.32 (t, J = 7.2 Hz, 3H). LC / MS (ESI): 484 (m / z), retention time (min): 2.12, LC / MS conditions: [2]

[0059] Example 3 [ka] Process 1 Compound 1 (1.46 g, 4.60 mmol) was dissolved in methanol (19.4 mL), and compound 13 (970 mg, 5.06 mmol) and sodium bicarbonate (812 mg, 9.66 mmol) were added and stirred at room temperature for 3 hours. After the solvent was evaporated under reduced pressure, a 4 mol / L hydrochloric acid / dioxane solution (5.8 mL) was added and stirred at room temperature for 1 hour. Water and dichloromethane were added to the reaction solution, which was extracted with dichloromethane and dried over sodium sulfate. The solvent was evaporated. The resulting residue was suspended in a mixed solution of ethyl acetate and diisopropyl ether and filtered. The resulting solid was washed with diisopropyl ether and dried to give compound 14 (1.55 g, 74% yield). LC / MS (ESI): 456 (m / z), retention time (min): 1.79, LC / MS conditions: [2] Process 2 Compound 14 (100 mg, 0.22 mmol) was dissolved in dichloromethane (2.0 mL), triethylamine (44.4 mg, 0.44 mmol) and ethyl chloroformate (26.2 mg, 0.242 mmol) were added, and the mixture was stirred at room temperature for 1 hour. 7 mol / L ammonia / methanol solution (0.031 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for an additional 2 hours. Dichloromethane and water were added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was dried over sodium sulfate, and the solvent was evaporated to give compound 15. LC / MS (ESI): 455 (m / z), retention time (min) 1.66:, LC / MS conditions: [2] Process 3 Compound 15 was dissolved in dichloroethane (2.0 mL), and 2-trimethylsilylethanol (78.0 mg, 0.66 mmol) and iodobenzene diacetate (85.0 mg, 0.264 mmol) were added, followed by stirring for 1 hour at 80° C. After the reaction mixture was allowed to cool to room temperature, saturated aqueous sodium bicarbonate and saturated aqueous sodium thiosulfate were added, followed by extraction with dichloromethane, drying over sodium sulfate, and then the solvent was evaporated to obtain compound 16. LC / MS (ESI): 571 (m / z), retention time (min): 1.47, LC / MS conditions: [2] Process 4 Compound 16 was dissolved in THF (1.0 mL), and 1 mol / L tetrabutylammonium fluoride / THF solution (0.44 mL) was added and stirred at room temperature overnight. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give compound 17 (67 mg, yield 77%). LC / MS (ESI): 395 (m / z), retention time (min): 1.43, LC / MS conditions: [2] Process 5 Compound I-9 was synthesized in the same manner as in Example 1 using compound 17. 1 H-NMR (CDCl3) δ: 13.12 (s, 1H), 10.57 (t, J = 5.6 Hz, 1H), 8.36 (s, 1H), 7.33-7.27 (m, 2H), 7.03 (t, J = 7.9 Hz, 1H), 4.77-4.66 (m, 2H), 4.24 (d, J = 8.0 Hz, 1H), 4.03 (td, J = 14.1, 7.0 Hz, 1H), 3.78 (d, J = 7.3 Hz, 1H), 3.25 (td, J = 14.0, 7.0 Hz, 1H), 2.62 (brs, 2H), 1.83-1.13 (m, 9H). LC / MS (ESI): 460 (m / z), retention time (min): 2.05, LC / MS conditions: [2]

[0060] Example 4 [ka] Process 1 To a solution of compound 18 (2.31 g, 6.78 mmol) in dichloromethane (46 mL), sodium bicarbonate (855 mg, 10.18 mmol) and metachloroperbenzoic acid (2.21 g, 8.82 mmol) were added and stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 19 (2.41 g, 100% yield). LC / MS (ESI): 378.90 (m / z), retention time (min) 2.90: LC / MS conditions: [1] Process 2 Compound 19 (6.07 g, 17.03 mmol), ammonium chloride (0.911 g, 17.03 mmol), and sodium azide (5.54 g, 85 mmol) were dissolved in ethanol (61 mL) and water (12 mL) and heated to reflux overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 20 (2.04 g, 30% yield). LC / MS (ESI): 422.10 (m / z), retention time (min) 2.90: LC / MS conditions: [2] Process 3 To a solution of compound 20 (0.93 g, 2.33 mmol) in dichloromethane (9 mL), methanesulfonyl chloride (267 mg, 2.34 mmol) and triethylamine (0.33 mL, 2.33 mmol) were added and stirred at room temperature overnight. A 1 mol / L aqueous hydrochloric acid solution was added to the reaction solution, followed by extraction with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give compound 21 (1.11 g, 100% yield). LC / MS (ESI): 500.00 (m / z), retention time (min) 2.96: LC / MS conditions: [2] Process 4 To a solution of compound 21 (1.10 g, 2.30 mmol) in THF (11 mL), triphenylphosphine (665 mg, 2.53 mmol) was added and stirred at room temperature for 2 hours. Water (1.1 mL) and triethylamine (0.64 mL, 4.61 mmol) were added to the reaction mixture, and the mixture was further stirred overnight. 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 sodium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 22 (619 mg, 76% yield). LC / MS (ESI): 356.00 (m / z), retention time (min) 1.84: LC / MS conditions: [2] Process 5 To a solution of chlorosulfonyl isocyanate (0.17 mL, 1.94 mmol) in toluene (6 mL), t-butyl alcohol (0.184 mL, 1.94 mmol) was added dropwise under ice cooling. Pyridine (0.34 mL, 4.26 mmol) was then added dropwise to the reaction mixture, followed by stirring for 40 minutes. A solution of compound 22 (619 mg, 1.74 mmol) in THF (6 mL) was then added dropwise to the reaction mixture, followed by stirring overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 23 (0.61 g, 59% yield). LC / MS (ESI): 557.10 (m / z), retention time (min) 2.96: LC / MS conditions: [2] Process 6 Compound 23 (1.91 g, 3.57 mmol) and sodium iodide (1.93 g, 12.9 mmol) were added to DMF (19 mL) and heated with stirring at 80°C 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, dried over sodium sulfate, and the solvent was evaporated to give compound 24 (1.91 g). LC / MS (ESI): 557.10 (m / z), retention time (min) 2.99: LC / MS conditions: [2] Process 7 Compound 24 (510 mg, 0.954 mmol) was added to a mixed solution of pyridine (5 mL) and water (0.5 mL), and the mixture was heated and stirred at 80°C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was then distilled off. The resulting residue was purified by amino column chromatography (hexane-ethyl acetate) to give compound 25 (450 mg, 100% yield). LC / MS (ESI): 473.10 (m / z), retention time (min) 2.06: LC / MS conditions: [2] Process 8 Compound 1 (310 mg, 0.973 mmol) and compound 25 (460 mg, 0.973 mmol) were dissolved in methanol (5 mL) and stirred overnight at room temperature. The reaction mixture was concentrated and then dissolved in dioxane (4.6 mL). 4 mol / L hydrochloric acid / dioxane solution (3.7 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated and then THF (5 mL) and triethylamine (1.4 mL, 9.73 mmol) were added and stirred for 1 hour. The reaction mixture was concentrated, and the resulting residue was purified by reverse-phase column chromatography (water-acetonitrile) to give compound 26 (638 mg, 74% yield). LC / MS (ESI): 399.00 (m / z), retention time (min) 1.08: LC / MS conditions: [2] Process 9 Compound 26 (293 mg, 0.735 mmol) was dissolved in DMF (2.9 mL), and ethyl iodide (119 μL, 1.47 mmol) and cesium carbonate (479 mg, 1.47 mmol) were added, followed by stirring at room temperature for 1 hour. The reaction mixture was filtered through Celite (registered trademark) and concentrated. The resulting residue was purified by reverse-phase column chromatography (water-acetonitrile) to give compound 27 (157 mg, 50% yield). LC / MS (ESI): 427.10 (m / z), retention time (min) 1.45: LC / MS conditions: [2] Step 10 Compound 27 (122 mg, 0.286 mmol) was dissolved in dichloromethane (0.5 mL), and methanesulfonyl chloride (0.029 mL, 0.372 mmol) and triethylamine (0.079 mL, 0.572 mmol) were added. The mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The resulting solid was washed with ethyl acetate and dried to give compound 28 (122 mg, 85% yield). LC / MS (ESI): 505.10 (m / z), retention time (min) 1.57: LC / MS conditions: [2] Step 11 To a solution of compound 28 (122 mg, 0.242 mmol) in DMF (2.4 mL), sodium methoxide (0.1 mol / L, 725 μL, 0.725 mmol) was added, and the mixture was heated and stirred at 80°C for 30 minutes. After stirring, acetic acid (42 μL, 0.725 mmol) was added and the solvent was evaporated. The resulting residue was purified by reverse-phase column chromatography (water-acetonitrile) to give compound 29 (62 mg, 70% yield). LC / MS (ESI): 365.05 (m / z), retention time (min) 1.20: LC / MS conditions: [2] Step 12 Compound I-13 was synthesized in the same manner as in Example 1 using compound 29. LC / MS (ESI): 478.10 (m / z), retention time (min) 1.98: LC / MS conditions: [2] 1H-NMR (CDCl3) δ: 12.89 (s, 1H), 10.55 (s, 1H), 8.36 (s, 1H), 7.31-7.29 (m, 1H), 7.18-7.17 (m, 1H), 7.04-7.02 (m, 1H), 4.80-4.65 (m, 2H), 4.46 (dd, J = 8.2, 5.3 Hz, 1H), 4.25-4.15 (m, 1H), 3.83 (dq, J = 14.0, 7.0 Hz, 1H), 3.48 (dq, J = 14.0, 7.0 Hz, 1H), 3.41 (s, 3H), 3.43-3.40 (m, 2H), 2.45-2.35 (m, 1H), 2.25-2.10 (m, 1H), 2.15-1.95 (m, 2H), 1.81-1.71 (m, 1H), 1.27(t, J = 7.2 Hz, 3H).

[0061] Example 5 [ka] Process 1 Compound 5 (120 mg, 0.287 mmol) was dissolved in dichloromethane (2.4 mL), and triethylamine (159 μL, 1.15 mmol) and ethyl chloroformate (30.3 μL, 0.315 mmol) were added under ice cooling and stirred for 20 minutes. Compound 30 (82.0 mg, 0.344 mmol) was added to the reaction solution and stirred for 1.0 hour. Water was added to the reaction solution, which was extracted with chloroform. The solvent was evaporated to give compound 31 (197 mg) as a crude racemic mixture. LC / MS (ESI): 603 (m / z), retention time (min): 2.25, LC / MS conditions: [1] Process 2 Compound 31 (197 mg) was dissolved in ethyl acetate (1.2 mL), and a 50% T3P / ethyl acetate solution (1.71 mL, 2.87 mmol) was added. The mixture was heated and stirred at 80°C for 40 minutes. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain a racemic mixture. LC / MS (ESI): 585 (m / z), retention time (min): 2.30, LC / MS conditions: [1] The resulting racemic mixture was subjected to optical resolution in the same manner as in Example 1 to obtain Compound 32 (69.4 mg, yield 47%). Process 3 Compound I-16 was synthesized in the same manner as in Example 1 using compound 32. 1H-NMR (CDCl3) δ: 12.88 (s, 1H), 8.60 (s, 1H), 7.35-7.24 (m, 1H), 6.90-6.81 (m, 2H), 4.83-4.72 (m, 1H), 4.50-4.37 (m, 3H), 3.92-3.80 (m, 1H), 3.60-3.45 (m, 1H), 2.96-2.55 (m, 4H), 1.31 (t, J = 7.3 Hz, 3H). LC / MS (ESI): 495 (m / z), retention time (min): 2.01, LC / MS conditions: [1]

[0062] The compounds shown below were similarly synthesized using the general synthesis methods described above or the synthesis methods described in the Examples.

[0063] [Table 1] [Table 2]

[0064] [Table 3]

[0065] The physical data of each compound is shown below. [Table 4] [Table 5] [Table 6]

[0066] The following are examples of biological tests on the compounds of the present invention.

[0067] Test Example 1: Anti-HIV activity A serial dilution series of the test sample was prepared in a 384-well microplate using a dispenser. 4 A 20μL / mL MT-4 cell suspension was dispensed into the plate containing the test sample, followed by 20μL / well of HIV virus solution. The cells were mixed using a plate mixer and cultured in a CO2 incubator for 4 days. On the fourth day of culture, 20μL of CellTiter-Glo or CellTiter-Glo 2.0 was dispensed into each well. The reaction was carried out at room temperature for approximately 15 minutes while stirring using a plate mixer. After the reaction, the luminescence intensity of the plate was measured 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 (%) (result) [Table 7] Test Example 1B: Anti-HIV activity A serial dilution series of the test sample was prepared in a 96-well microplate (50 μL / well). 5MT-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) [Table 8] From the above test results, it was revealed that the compound of the present invention exhibited high anti-HIV activity and is therefore useful as an HIV drug.

[0068] 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 / well, followed by 50 μL / well of HIV virus solution (wild-type and mutant strains). The cells were mixed using a plate mixer and cultured in a CO2 incubator for 3 days. The culture supernatant was aspirated from each well, and 100 μL of cell lysis buffer 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. Beta-Glo Reagent was dispensed into a 384-well microplate at 20 μL / well, and 2 μL of the supernatant (diluted as necessary) was added to each well after centrifugation and incubated at room temperature for approximately 30 minutes. The luminescence intensity of the plate after the reaction was measured using a microplate reader. The 50% HIV inhibitory concentration (EC50) was determined from the concentration-response curve using a 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) FC against mutant strains (E92Q / E138T / G140S / Q148H) Compound I-005:6.7 Compound I-014:4.1 Compound I-017:6.0 Compound I-020:7.7 From the above test results, it is clear that the compound of the present invention has a high resistance barrier and is less likely to cause HIV-resistant viruses.

[0069] Test Example 3: 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.

[0070] 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), and 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).

[0071] 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.

[0072] The control (100%) was a reaction solution containing only DMSO, the solvent in which the compound was dissolved, and the remaining activity (%) was calculated. The IC was calculated by inverse estimation using a logistic model using the concentration and inhibition rate. 50 was calculated.

[0073] Test Example 4: 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.

[0074] 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).

[0075] A 96-well plate was prepared as a pre-reaction solution by adding pooled human liver microsomes and the compound of the present invention in K-Pi buffer (pH 7.4) according to the 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.

[0076] 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 the compound of the present invention was added at each concentration, 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) Compound I-022:(-)

[0077] Test example 5: 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 items: Blood samples were collected over time, and the plasma concentration of the compound of the present invention was measured using LC / MS / MS. (7) Statistical analysis: The area under the plasma concentration-time curve (AUC) of the compound of the present invention was calculated by moment analysis, and the bioavailability (BA) of the compound of the present invention was calculated from the dose ratio and AUC ratio between the oral and intravenous administration groups.

[0078] Test Example 6: 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 items: Blood samples were collected over time, and the plasma concentration of the compound of 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) Compound I-005:0.117mL / min / kg,10.9hr Compound I-017:0.0712mL / min / kg,15.3hr From the above results, the compounds of the present invention have low clearance and long elimination half-lives, and are therefore useful as long-acting integrase inhibitors.

[0079] Test Example 7: 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.

[0080] 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 3000 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 below. Compound I-003:91.7% Compound I-020:74.6%

[0081] Test Example 8: 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 of the present invention (several serial dilutions of 2- to 3-fold from the maximum dose of 50 mg / mL), DMSO as a negative control, and positive controls of 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 under non-metabolic activation conditions, 40 μg / mL 2-aminoanthracene DMSO solution for the TA98 strain under metabolic activation conditions, and 20 μg / mL 2-aminoanthracene DMSO solution for the TA100 strain under metabolic activation conditions were mixed in 12 μL each with 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 of 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 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 (+).

[0082] Test Example 9: hERG test To evaluate 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 evaluate the delayed rectifier K channel, which plays an important role in the ventricular repolarization process. + Current (I Kr The effects of the compounds of the present invention on the 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 (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) adjusted to 0.1% dimethyl sulfoxide 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 of 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 of the present invention was calculated. Kr The impact on

[0083] Test Example 10: 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 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.

[0084] 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.

[0085] Test Example 11: 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. After checking for air bubbles and precipitates, the containers were sealed and shaken. The compounds of the present invention were quantified using HPLC using the absolute calibration curve method.

[0086] Test Example 12: 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 (+).

[0087] Test Example 13: Nav Test To evaluate the proarrhythmic risk of the compounds of the present invention, we used HEK cells expressing the voltage-gated sodium channel (Nav1.5 channel) encoded by the SCN5A gene to investigate the potential role of Na, which plays an important role in the depolarization process of myocardium. + Current (I Na The effects of the compounds of the present invention on the 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 extracellular solution was adjusted to 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) as the vehicle. 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. The I obtained 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, and the charge amount when the compound of the present invention was applied to the charge amount when the vehicle was applied were calculated. Na The impact on (result) Compound I-017: Maximum current increase rate 95.6%, charge increase rate 133% Compound I-022: Maximum current increase rate 93.1%, charge increase rate 137% From the above results, no clear increase in current or charge was observed, and the compounds of the present invention are unlikely to cause arrhythmia due to an increase in Na current.

[0088] Test Example 14: 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). 5PBMCs 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 (%)

[0089] Test Example 14: Anti-HIV activity evaluation test in the presence of human serum proteins A serial dilution series of the test sample was prepared in a 384-well microplate using a dispenser. 20 μL of human serum protein solution (50% human serum protein concentration) was dispensed into the 384-well microplate containing the test sample at a rate of 20 μL / well and left to stand at room temperature for 1 hour. 20 μL of culture medium was dispensed into the serum-free plate at a rate of 3.0 x 10 6One mL of MT-4 cells (cells / mL) was mixed with 300 μL of 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 40 mL of culture medium and dispensed at 20 μL / well into a 384-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 cultured in a CO2 incubator for 4 days. On the fourth day of culture, 20 μL of CellTiter-Glo or CellTiter-Glo 2.0 was dispensed into each well. The incubation was carried out at room temperature for approximately 15 minutes while stirring using a plate mixer. After incubation, the plate was measured for luminescence intensity 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 (%) The potency shift (PS) was calculated based on the following formula: 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). Compound I-005:104 Compound I-020:29

[0090] Formulation example The compounds of the present invention can be administered as pharmaceutical compositions by any conventional route, particularly enterally, for example, orally, for example, in the form of tablets or capsules, or parenterally, for example, in the form of injection solutions or suspensions, or topically, for example, in the form of lotions, gels, ointments, or creams, or in the form of nasal 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. In addition, injectable compositions can be solutions or suspensions, which may be sterilized and may contain preservatives, stabilizers, buffers, etc. [Industrial Applicability]

[0091] The compounds of the present invention have integrase inhibitory activity and / or cell proliferation inhibitory activity against viruses, particularly HIV, and are therefore useful for the prevention or treatment of various diseases in which integrase is involved, viral infections (e.g., AIDS), and the like.

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, Ring A is a C5-C7 non-aromatic carbocycle, which may be further fused with a benzene ring, a 3- to 7-membered non-aromatic carbocycle, or a 3- to 7-membered non-aromatic heterocycle, or may form a spiro ring of a 3- to 7-membered non-aromatic carbocycle and a 3- to 7-membered non-aromatic heterocycle; Ring B is a benzene ring or a pyridine ring; Q is -NHC(O)- (the bond on the left is CR ２ａ R ２ｂ 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 and R ５ are each independently hydrogen or alkyl; R ６ are each independently halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, or alkyloxyalkyl; or Two R's attached to non-adjacent atoms ６ may together form a C1-C3 bridge, optionally interrupted by a heteroatom; n is an integer from 1 to 3; and m is an integer of 0 to 3. provided that when m is 0, a) ring B is a pyridine ring, b) Q is a 5-membered aromatic heterocycle, or c) Q is —NHC(O)—) (provided that the following compounds: 【Chemistry 2】 ) or a pharmaceutically acceptable salt thereof.

2. Ring A is a C5-C7 non-aromatic carbocyclic ring; R ６ are each independently halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, or alkyloxyalkyl; Two R's attached to non-adjacent atoms ６ and R 1 and R 2 are independently substituted or unsubstituted, and R 3 and R 4 are independently substituted or unsubstituted, and R 2 and R 3 are independently substituted or unsubstituted, and R 2 ...

3. R ４ and R ５ 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

4. R ３ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is alkyl.

5. R １ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein each of the is independently a halogen.

6. R ２ａ is hydrogen, and R ２ｂ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or alkyl.

7. 7. The compound according to claim 1, wherein Q is —NHC(O)—, or a pharmaceutically acceptable salt thereof.

8. Q is the following ring (the bond on the left is CR ２ａ R ２ｂ Combine with): 【Transformation 3】 7. The compound according to any one of claims 1 to 6, wherein:

9. Formula (IA): 【Chemistry 4】 (In the formula, Ring A is a C5-C6 non-aromatic carbocyclic ring; Ring B is a benzene ring or a pyridine ring; Q is -NHC(O)- (the bond on the left is CR ２ａ R ２ｂ 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 ６ are each independently halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, or alkyloxyalkyl; or Two R's attached to non-adjacent atoms ６ may together form a C1-C3 bridge; n is an integer from 1 to 3; and and m is an integer of 0 to 2.) (provided that the following compounds: 【Transformation 5】 ) or a pharmaceutically acceptable salt thereof.

10. R ３ 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein is alkyl.

11. R １ 11. The compound according to claim 9 or 10, or a pharmaceutically acceptable salt thereof, wherein each is independently a halogen.

12. R ２ａ is hydrogen, and R ２ｂ The compound according to any one of claims 9 to 11, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or alkyl.

13. The compound according to any one of claims 9 to 12, wherein Q is -NHC(O)-, or a pharmaceutically acceptable salt thereof.

14. Q is the following ring (the bond on the left is CR ２ａ R ２ｂ Combine with): 【Transformation 6】 13. The compound according to any one of claims 9 to 12, wherein:

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein ring B is a benzene ring.

16. A pharmaceutical composition comprising the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

17. 17. The pharmaceutical composition of claim 16, which is an anti-HIV agent.

18. 17. The pharmaceutical composition of claim 16, which is an HIV integrase inhibitor.

19. 16. An HIV integrase inhibitor comprising the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

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