Patent Application
20240400560
The present invention relates to a compound exhibiting coronavirus 3CL protease inhibitory activity and a pharmaceutical composition comprising a compound exhibiting coronavirus 3CL protease inhibitory activity.
Coronaviruses, which belong to the order Nidovirales, family Coronaviridae, and the subfamily Coronavirinae, are positive-sense single-stranded RNA viruses that have a genome size of about 30 kilobases and are the largest among the known RNA viruses. Coronaviruses are classified into four genera, namely, the genus Alphacoronavirus, the genus Betacoronavirus, Gammacoronavirus, and Deltacoronavirus, and a total of seven types of coronaviruses, including two kinds in the genus Alphacoronavirus (HCoV-229E and HCoV-NL63) and five kinds in the genus Betacoronavirus (HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and SARS-CoV-2), are known as coronaviruses that infect humans. Among these, four kinds (HCoV-229E, HCoV-NL63, HCoV-HKU1, and HCoV-OC43) are pathogens of common cold, while the other three kinds are severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV), and a novel coronavirus (SARS-CoV-2), all of which cause severe pneumonia.
Novel coronavirus infections (COVID-19) that occurred in Wuhan, China, in December 2019, rapidly spread to the international community, and the pandemic was announced by the WHO on Mar. 11, 2020. The number of infected people confirmed as of Sep. 6, 2022, reached 600 million or more, and the number of deaths reached more than 6.5 million or more (Non-patent Document 1). Droplet infection, contact infection, and aerosol infection have been reported as main routes of infection of SARS-CoV-2, and it has been confirmed that SARS-CoV-2 continues to drift in air together with aerosols and maintains infectivity for about 3 hours (Non-patent Document 2). The incubation period is about 2 to 14 days, and cold-like symptoms such as fever (87.9%), dry cough (67.7%), malaise (38.1%), and phlegm (33.4%) are typical (Non-patent Document 3). In severe cases, respiratory failure due to acute respiratory distress syndrome, acute lung injury, interstitial pneumonia, and the like occurs. Furthermore, multiple organ failure such as renal failure and hepatic failure has also been reported.
In Japan, as a result of drug repositioning of existing drugs, remdesivir, which is an antiviral drug, dexamethasone, which is an anti-inflammatory drug, and baricitinib, which is an antirheumatic drug, have been approved as therapeutic agents against COVID-19, and in January 2022, tocilizumab, which is an anti-IL-6 receptor antibody, have been received additional approval. Additionally, ronapreve (casirivimab/imdevimab), which is an antibody cocktail therapy, was approved as special case approval in July 2021, sotrovimab was approved as special case approval in September 2021, molnupiravir was approved as special case approval in December 2021, and Evusheld (tixagevimab/cilgavimab) was approved as special case approval in August 2022. However, among these drugs, there are cases where clinical use is refrained due to drug interaction, contraindications to pregnant women, and the like, and development of therapeutic drugs as new therapeutic options is awaited.
Upon infection of cells, coronaviruses synthesize two polyproteins. In these two polyproteins, replication complexes producing viral genomes, and two proteases are included. Proteases play an indispensable role for cleaving the polyproteins synthesized by viruses and causing each of the proteins to function. Between these two proteases, 3CL protease (main protease) bears most of the cleavage of the polyproteins (Non-patent Document 4).
Regarding COVID-19 therapeutic agents targeting 3CL proteases, it was published in ClinicalTrials.gov that Phase 1b trials for Lufotrelvir (PF-07304814), which is a prodrug of PF-00835231, have completed by Pfizer Inc (NCT04535167). Furthermore, in March 2021, Pfizer Inc. announced that Phase 1 trials for PF-07321332, a therapeutic agent against novel coronavirus infections, will be initiated. The structural formulae of PF-00835231, Lufotrelvir and PF-07321332 are as shown below, and these agents are different from the compound of the present invention in chemical structure (Non-patent Documents 5, 10 and 11 and Patent Documents 1 and 2).
In December 2021, PAXLOVID™ was approved for emergency use in the United States, and on Feb. 10, 2022, the PAXLOVID (registered trademark) PACK was approved as special case approval in Japan.
Furthermore, regarding COVID-19 therapeutic agents targeting 3CL proteases, the start of Phase 1 trials for PBI-0451 by Pardes Biosciences was reported in ClinicalTrials.gov on August 2021 (NCT05011812). The structural formula of PBI-0451 is as shown below, and these agents are different from the compound of the present invention in chemical structure (Non-patent Document 12).
No sufficient evidence has been obtained for mutations resistant to COVID-19 therapeutic agents targeting 3CL proteases.
Compounds having 3CL protease inhibitory activity are disclosed in Non-patent Documents 5 to 8 and 13 to 16; however, the compounds related to the present invention are neither described nor suggested in any of the documents.
Although derivatives having P2X3 receptor inhibitory activity are disclosed in Patent Document 1, 3CL protease inhibitory activity and antiviral effect have neither been described nor suggested. In addition, Non-patent Documents 9 and Patent Documents 2, and 5 to 8 describe compounds having structures similar to those of the compounds of the present invention, but none of them describes or suggests the 3CL protease inhibitory activity and the antiviral effect.
An object of the present invention is to provide a compound having coronavirus 3CL protease inhibitory activity. Preferably, the present invention provides a compound having an antiviral activity, particularly a coronavirus replication inhibitory activity, and a medicament comprising the compound.
The present invention relates to the following.
Furthermore, the present invention relates to the following.
Furthermore, the present invention relates to the following.
Furthermore, the present invention relates to the following.
The compound of the present invention has inhibitory activity against coronavirus 3CL proteases and is useful as a therapeutic (treating) agent and/or prophylactic (preventing) agent for coronavirus infections.
Hereinafter, the meaning of each term used in the present specification will be described. Unless particularly stated otherwise, each term is used in the same sense, either alone or in combination with other terms.
The term “consist of” means having only the constituent elements.
The term “comprise” means that elements are not limited to the constituent elements, and elements that are not described are not excluded.
Hereinafter, the present invention will be described while showing exemplary embodiments. Throughout the present specification, it should be understood that, unless particularly stated otherwise, an expression of a singular form also includes the concept of a plural form thereof. Therefore, it should be understood that, unless particularly stated otherwise, an article for a singular form (for example, in the case of English, “a”, “an”, “the”, or the like) also includes the concept of a plural form thereof.
Furthermore, it should be understood that, unless particularly stated otherwise, the terms used in the present specification are used in the meanings normally used in the above-described art. Accordingly, unless otherwise defined, all terminologies and scientific and technical terms used in the present specification have the same meanings as commonly understood by those having ordinary skill in the art to which the present invention belongs. In a case of contradiction, priority is given to the present specification (including definitions).
“Halogen” includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Particularly, a fluorine atom and a chlorine atom are preferred.
“Alkyl” includes linear or branched hydrocarbon groups each having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Examples include 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.
“Alkenyl” includes linear or branched hydrocarbon groups each having one or more double bonds at any position and having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms. Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, and pentadecenyl.
Preferred embodiments of “alkenyl” include vinyl, allyl, propenyl, isopropenyl, and butenyl. More preferred embodiments include ethenyl and n-propenyl.
“Alkynyl” includes linear or branched hydrocarbon groups each having one or more triple bonds at any position and having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms. Alkynyl may further have a double bond at any position. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl.
Preferred embodiments of “alkynyl” include ethynyl, propynyl, butynyl, and pentynyl. More preferred embodiments include ethynyl and propynyl.
“Aromatic carbocyclyl” means a cyclic aromatic hydrocarbon group having a single ring or two or more rings. Examples include phenyl, naphthyl, anthryl, and phenanthryl. Examples of 6-membered aromatic carbocyclyl include phenyl.
Preferred embodiments of the “aromatic carbocyclyl” include phenyl.
“Aromatic carbocycle” means a ring derived from the above-described “aromatic carbocyclyl”.
In Formula (I) above, examples of “substituted or unsubstituted aromatic carbocycle formed by R3 and R8 taken together with a carbon atom to which they are each bonded”, and the “substituted or unsubstituted aromatic carbocycles formed by R3a and R8, and R3b and R8 taken together with a carbon atom to which they are each bonded” are, for example, the following ring:
In Formula (I) above, examples of “substituted or unsubstituted aromatic carbocycle formed by R10b and R10c, R10c and R10d, R10d and R10e, R10f and R10g, R10g and R10h, R10h and R10i, and R10i and R10j each independently taken together with a carbon atom to which they are each bonded” include the following ring:
“Non-aromatic carbocyclyl” means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group, both having a single ring or two or more rings. The “non-aromatic carbocyclyl” having two or more rings also includes a non-aromatic carbocyclyl having a single ring or two or more rings, to which the ring in the “aromatic carbocyclyl” is fused.
Furthermore, the “non-aromatic carbocyclyl” also includes a bridged group or a group forming a spiro ring, such as follows.
A non-aromatic carbocyclyl having a single ring preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and even more preferably 4 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl.
A non-aromatic carbocyclyl having two or more rings preferably has 8 to 20 carbon atoms, and more preferably 8 to 16 carbon atoms. Examples include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, and fluorenyl.
“Non-aromatic carbocycle” means a ring derived from the above-described “non aromatic carbocyclyl”.
When n is 1 in Formula (I) above, examples of “substituted or unsubstituted non-aromatic carbocycle formed by R4a and R4b taken together with a carbon atom to which they are each bonded” include the following rings.
In Formula (I) above, examples of “substituted or unsubstituted non-aromatic carbocycle formed by R10b and R10b′, R10c and R10c′, R10d and R10d′, R10e and R10e′, R10f and R10f′, R10g and R10g′, R10h and R10h′, R10i and R10i′, and R10j and R10j′ each independently taken together with a carbon atom to which they are bonded” include the following rings:
In Formula (I) above, examples of “substituted or unsubstituted non-aromatic carbocycle formed by R10b and R10c, R10c and R10d, R10d and R10e, R10f and R10g, R10g and R10h, R10h and R10i, and R10i and R10j each independently taken together with a carbon atom to which they are each bonded” include the following rings:
“Aromatic heterocyclyl” means an aromatic cyclyl having a single ring or two or more rings, which has one or more identical or different heteroatoms optionally selected from O, S, and N in the ring(s).
An aromatic heterocyclyl having two or more rings also includes an aromatic heterocyclyl having a single ring or two or more rings, to which a ring in the “aromatic carbocyclyl” is fused, and the linking bond may be carried by any of the rings.
The aromatic heterocyclyl having a single ring is preferably a 5- to 8-membered ring, and more preferably a 5-membered or 6-membered ring. Examples of 5-membered aromatic heterocyclyl include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, and thiadiazolyl. Examples of 6-membered aromatic heterocyclyl include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
The aromatic heterocyclyl having two rings is preferably an 8- to 10-membered ring, and more preferably a 9-membered or 10-membered ring. Examples include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, and thiazolopyridyl. Examples of 9-membered aromatic heterocyclyl include indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzofuranyl, imidazopyridyl, triazolopyridyl, oxazolopyridyl, and thiazolopyridyl. Examples of 10-membered aromatic heterocyclyl include quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, and pyrazinopyridazinyl.
An aromatic heterocyclyl having three or more rings is preferably a 13- to 15-membered group. Examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, and dibenzofuryl.
The term “nitrogen-containing aromatic heterocyclyl” means an aromatic heterocyclyl that is monocyclic or polycyclic having two or more rings, containing one or more nitrogen atoms in the ring(s).
“Aromatic heterocycle” means a ring derived from the above-described “aromatic heterocyclyl”.
In Formula (I) above, examples of “substituted or unsubstituted aromatic heterocycle formed by R3 and R8 taken together with a carbon atom to which they are each bonded”, and the “substituted or unsubstituted aromatic heterocycle formed by R3a and R8, and R3b and R8 taken together with a carbon atom to which they are each bonded” include the following rings:
In Formula (I) above, examples of “substituted or unsubstituted aromatic heterocycle formed by two R10as bonded to an adjacent carbon atom” include the following rings.
wherein RY is a hydrogen atom, substituted or unsubstituted alkyl, or the like.
“Non-aromatic heterocyclyl” means a non-aromatic cyclyl having a single ring or two or more rings, which has one or more identical or different heteroatoms optionally selected from O, S, and N in the ring(s). A non-aromatic heterocyclyl having two or more rings also includes a non-aromatic heterocyclyl having a single ring or two or more rings, to which a ring in each of the “aromatic carbocyclyl”, “non-aromatic carbocyclyl”, and/or “aromatic heterocyclyl” is fused, as well as a non-aromatic carbocyclyl having a single ring or two or more rings, to which a ring in the “aromatic heterocyclyl” is fused, and the linking bond may be carried by any of the rings.
Furthermore, the “non-aromatic heterocyclyl” also includes a bridged group or a group forming a spiro ring, such as follows.
The non-aromatic heterocyclyl having a single ring is preferably a 3- to 8-membered ring, and more preferably a 5-membered or 6-membered ring.
Examples of 3-membered non-aromatic heterocyclyl include thiiranyl, oxiranyl, and aziridinyl. Examples of 4-membered non-aromatic heterocyclyl include oxetanyl and azetidinyl. Examples of 5-membered non-aromatic heterocyclyl include oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, and thiolanyl. Examples of 6-membered non-aromatic heterocyclyl include dioxanyl, thianyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydropyranyl, dihydroxazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxazinyl, thiinyl, and thiazinyl. Examples of 7-membered non-aromatic heterocyclyl include hexahydroazepinyl, tetrahydrodiazepinyl, and oxepanyl.
The non-aromatic heterocyclyl having two or more rings is preferably an 8- to 20-membered ring, more preferably an 8- to 13-membered ring, and even more preferably an 8- to 10-membered ring. Examples include indolinyl, isoindolinyl, chromanyl, and isochromanyl.
The term “nitrogen-containing non-aromatic heterocyclyl” means a non-aromatic heterocyclyl that is monocyclic or polycyclic having two or more rings, containing one or more nitrogen atoms in the ring(s). The non-aromatic nitrogen-containing heterocyclyl, which is polycyclic having two or more rings, includes a fused ring group wherein a nitrogen-containing non-aromatic heterocyclyl that is monocyclic or polycyclic having two or more rings is fused with a ring of the above “aromatic carbocyclyl”, “non-aromatic carbocyclyl” and/or “aromatic heterocyclyl”, and the linking bond may be held in any ring. A non-aromatic heterocyclyl having two or more rings also includes a non-aromatic carbocyclyl having a single ring or two or more rings, to which each ring in the “nitrogen-containing aromatic carbocyclyl” is fused, and the linking bond may be held in any ring.
Examples of the same include the following groups.
Furthermore, the “nitrogen-containing non-aromatic heterocyclyl” also includes a bridged group or a group forming a spiro ring, such as follows:
“Non-aromatic heterocycle” means a ring derived from the above-described “non-aromatic heterocyclyl”.
When n is 1 in Formula (I) above, examples of “substituted or unsubstituted non-aromatic heterocycle formed by R4a and R4b together with a carbon atom to which they are each bonded” include the following rings.
wherein Rx is substituted or unsubstituted alkyl, or the like.
In Formula (I) above, examples of “substituted or unsubstituted non-aromatic heterocycle formed by two R10as bonded to an adjacent carbon atom” include the following rings.
In Formula (I) above, examples of “substituted or unsubstituted non-aromatic heterocycle formed by R10b and R10b′, R10c and R10c′, R10d and R10d′, R10e and R10e′, R10f and R10f′, R10g and R10g′, R10h and R10h′, R10i and R10i′, and R10j and R10j′ each independently taken together with a carbon atom to which they are bonded” include the following rings:
In Formula (I) above, examples of “substituted or unsubstituted non-aromatic heterocycle formed by R10b and R10c, R10c and R10d, R10d and R10e, R10f and R10g, R10g and R10h, R10h and R10i, and R10i and R10j each independently taken together with a carbon atom to which they are each bonded” include the following rings:
In Formula (I) above, examples of “substituted or unsubstituted non-aromatic heterocycle formed by R3b and R7′ taken together with an atom to which they are each bonded” include the following ring.
“Trialkylsilyl” means a group in which three moieties of the above-described “alkyl” are bonded to a silicon atom. The three alkyl groups may be identical or different. Examples include trimethylsilyl, triethylsilyl, and tert-butyldimethylsilyl.
“Iminosulfino” means a group represented by the following formula:
One or two hydrogen atoms at any position may be substituted. Examples of a substituent of the “substituted iminosulfino” include alkyl, or the like.
In the present specification, the phrase “may be substituted with substituent group α” means that “may be substituted with one or more group(s) selected from substituent group α”. The same also applies to substituent groups β, γ, and γ′.
Substituent for “substituted alkyl”, “substituted alkenyl”, “substituted alkynyl”, “substituted alkyloxy”, “substituted alkenyloxy”, “substituted alkynyloxy”, “substituted alkylcarbonyloxy”, “substituted alkenylcarbonyloxy”, “substituted alkynylcarbonyloxy”, “substituted alkylcarbonyl”, “substituted alkenylcarbonyl”, “substituted alkynylcarbonyl”, “substituted alkyloxycarbonyl”, “substituted alkenyloxycarbonyl”, “substituted alkynyloxycarbonyl”, “substituted alkylsulfanyl”, “substituted alkenylsulfanyl”, “substituted alkynylsulfanyl”, “substituted alkylsulfinyl”, “substituted alkenylsulfinyl”, “substituted alkynylsulfinyl”, “substituted alkylsulfonyl”, “substituted alkenylsulfonyl” “substituted alkynylsulfonyl”, and the like include the following substituent group A. A carbon atom at any position may be bonded to one or more group(s) selected from the following substituent group A.
Substituent group A: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl, alkyloxy which may be substituted with substituent group α, alkenyloxy which may be substituted with substituent group α, alkynyloxy which may be substituted with substituent group α, alkylcarbonyloxy which may be substituted with substituent group α, alkenylcarbonyloxy which may be substituted with substituent group α, alkynylcarbonyloxy which may be substituted with substituent group α, alkylcarbonyl which may be substituted with substituent group α, alkenylcarbonyl which may be substituted with substituent group α, alkynylcarbonyl which may be substituted with substituent group α, alkyloxycarbonyl which may be substituted with substituent group α, alkenyloxycarbonyl which may be substituted with substituent group α, alkynyloxycarbonyl which may be substituted with substituent group α, alkylsulfanyl which may be substituted with substituent group α, alkenylsulfanyl which may be substituted with substituent group α, alkynylsulfanyl which may be substituted with substituent group α, alkylsulfinyl which may be substituted with substituent group α, alkenylsulfinyl which may be substituted with substituent group α, alkynylsulfinyl which may be substituted with substituent group α, alkylsulfonyl which may be substituted with substituent group α, alkenylsulfonyl which may be substituted with substituent group α, alkynylsulfonyl which may be substituted with substituent group α, amino which may be substituted with substituent group β, imino which may be substituted with substituent group β, carbamoyl which may be substituted with substituent group β, sulfamoyl which may be substituted with substituent group β, aromatic carbocyclyl which may be substituted with substituent group γ, non-aromatic carbocyclyl which may be substituted with substituent group γ′, aromatic heterocyclyl which may be substituted with substituent group γ, non-aromatic heterocyclyl which may be substituted with substituent group γ′, aromatic carbocyclyloxy which may be substituted with substituent group γ, non-aromatic carbocyclyloxy which may be substituted with substituent group γ′, aromatic heterocyclyloxy which may be substituted with substituent group γ, non-aromatic heterocyclyloxy which may be substituted with substituent group γ′, aromatic carbocyclylcarbonyloxy which may be substituted with substituent group γ, non-aromatic carbocyclylcarbonyloxy which may be substituted with substituent group γ′, aromatic heterocyclylcarbonyloxy which may be substituted with substituent group γ, non-aromatic heterocyclylcarbonyloxy which may be substituted with substituent group γ′, aromatic carbocyclylcarbonyl which may be substituted with substituent group γ, non-aromatic carbocyclylcarbonyl which may be substituted with substituent group γ′, aromatic heterocyclylcarbonyl which may be substituted with substituent group γ, non-aromatic heterocyclylcarbonyl which may be substituted with substituent group γ′, aromatic carbocyclyloxycarbonyl which may be substituted with substituent group γ, non-aromatic carbocyclyloxycarbonyl which may be substituted with substituent group γ′, aromatic heterocyclyloxycarbonyl which may be substituted with substituent group γ, non-aromatic heterocyclyloxycarbonyl which may be substituted with substituent group γ′, aromatic carbocyclylalkyloxy which may be substituted with substituent group γ, non-aromatic carbocyclylalkyloxy which may be substituted with substituent group γ′, aromatic heterocyclylalkyloxy which may be substituted with substituent group γ, non-aromatic heterocyclylalkyloxy which may be substituted with substituent group γ′, aromatic carbocyclylalkyloxycarbonyl which may be substituted with substituent group γ, non-aromatic carbocyclylalkyloxycarbonyl which may be substituted with substituent group γ′, aromatic heterocyclylalkyloxycarbonyl which may be substituted with substituent group γ, non-aromatic heterocyclylalkyloxycarbonyl which may be substituted with substituent group γ′, aromatic carbocyclylsulfanyl which may be substituted with substituent group γ, non-aromatic carbocyclylsulfanyl which may be substituted with substituent group γ′, aromatic heterocyclylsulfanyl which may be substituted with substituent group γ, non-aromatic heterocyclylsulfanyl which may be substituted with substituent group γ′, aromatic carbocyclylsulfinyl which may be substituted with substituent group γ, non-aromatic carbocyclylsulfinyl which may be substituted with substituent group γ′, aromatic heterocyclylsulfinyl which may be substituted with substituent group γ, non-aromatic heterocyclylsulfinyl which may be substituted with substituent group γ′, aromatic carbocyclylsulfonyl which may be substituted with substituent group γ, non-aromatic carbocyclylsulfonyl which may be substituted with substituent group γ′, aromatic heterocyclylsulfonyl which may be substituted with substituent group γ, and non-aromatic heterocyclylsulfonyl which may be substituted with substituent group γ′.
Substituent group α: halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, and cyano.
Substituent group β: halogen, hydroxy, carboxy, cyano, alkyl which may be substituted with substituent group α, alkenyl which may be substituted with substituent group α, alkynyl which may be substituted with substituent group α, alkylcarbonyl which may be substituted with substituent group α, alkenylcarbonyl which may be substituted with substituent group α, alkynylcarbonyl which may be substituted with substituent group α, alkylsulfanyl which may be substituted with substituent group α, alkenylsulfanyl which may be substituted with substituent group α, alkynylsulfanyl which may be substituted with substituent group α, alkylsulfinyl which may be substituted with substituent group α, alkenylsulfinyl which may be substituted with substituent group α, alkynylsulfinyl which may be substituted with substituent group α, alkylsulfonyl which may be substituted with substituent group α, alkenylsulfonyl which may be substituted with substituent group α, alkynylsulfonyl which may be substituted with substituent group α,
Substituent group γ: substituent group α, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl.
Substituent group γ′: substituent group γ and oxo.
The substituents on the rings of “aromatic carbocycle” and “aromatic heterocycle”, such as “substituted aromatic carbocyclyl”, “substituted aromatic heterocyclyl”, “substituted aromatic carbocyclyloxy”, “substituted aromatic heterocyclyloxy”, “substituted aromatic carbocyclylcarbonyloxy”, “substituted aromatic heterocyclylcarbonyloxy”, “substituted aromatic carbocyclylcarbonyl”, “substituted aromatic heterocyclylcarbonyl”, “substituted aromatic carbocyclyloxycarbonyl”, “substituted aromatic heterocyclyloxycarbonyl”, “substituted aromatic carbocyclylsulfanyl”, “substituted aromatic heterocyclylsulfanyl”, “substituted aromatic carbocyclylsulfinyl”, “substituted aromatic heterocyclylsulfinyl”, “substituted aromatic carbocyclylsulfonyl”, “substituted aromatic heterocyclylsulfonyl”, and “substituted nitrogen-containing aromatic heterocyclyl” include the following substituent group B. An atom at any position on the ring may be bonded to one or more group(s) selected from the following substituent group B.
Substituent group B: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl,
The substituents on the ring of “non-aromatic carbocycle” and “non-aromatic heterocycle” of “substituted non-aromatic carbocyclyl”, “substituted non-aromatic heterocyclyl”, “substituted non-aromatic carbocyclyloxy”, “substituted non-aromatic heterocyclyloxy”, “substituted non-aromatic carbocyclylcarbonyloxy”, “substituted non-aromatic heterocyclylcarbonyloxy”, “substituted non-aromatic carbocyclylcarbonyl”, “substituted non-aromatic heterocyclylcarbonyl”, “substituted non-aromatic carbocyclyloxycarbonyl”, “substituted non-aromatic heterocyclyloxycarbonyl”, “substituted non-aromatic carbocyclylsulfanyl”, “substituted non-aromatic heterocyclylsulfanyl”, “substituted non-aromatic carbocyclylsulfinyl”, “substituted non-aromatic heterocyclylsulfinyl”, “substituted non-aromatic carbocyclylsulfonyl”, “substituted non-aromatic heterocyclylsulfonyl”, and “substituted nitrogen-containing non-aromatic heterocyclyl” include the following substituent group C: An atom at any position on the ring may be bonded to one or more group(s) selected from the following substituent group C.
Substituent group C: substituent group B and oxo.
When the “non-aromatic carbocycle” and the “non-aromatic heterocycle” are substituted with “oxo”, this means a ring in which two hydrogen atoms on a carbon atom are substituted as follows.
The substituents for “substituted amino”, “substituted imino”, “substituted carbamoyl”, and “substituted sulfamoyl” include the following substituent group D. These moieties may be substituted with one or two group(s) selected from substituent group D.
Substituent group D: halogen, hydroxy, carboxy, cyano, alkyl which may be substituted with substituent group α, alkenyl which may be substituted with substituent group α, alkynyl which may be substituted with substituent group α, alkylcarbonyl which may be substituted with substituent group α, alkenylcarbonyl which may be substituted with substituent group α, alkynylcarbonyl which may be substituted with substituent group α, alkylsulfanyl which may be substituted with substituent group α, alkenylsulfanyl which may be substituted with substituent group α, alkynylsulfanyl which may be substituted with substituent group α, alkylsulfinyl which may be substituted with substituent group α, alkenylsulfinyl which may be substituted with substituent group α, alkynylsulfinyl which may be substituted with substituent group α, alkylsulfonyl which may be substituted with substituent group α, alkenylsulfonyl which may be substituted with substituent group α, alkynylsulfonyl which may be substituted with substituent group α,
Examples of substituents for the “substituted or unsubstituted non-aromatic heterocyclyl” and the “substituted or unsubstituted nitrogen-containing non-aromatic heterocyclyl” in R1 include:
It may be substituted with one or more group(s) selected from these.
Examples of substituents for the “substituted or unsubstituted non-aromatic heterocyclyl” and the “substituted or unsubstituted nitrogen-containing non-aromatic heterocyclyl” in R1 include:
It may be substituted with one or more group(s) selected from these.
Examples of substituents for the “substituted or unsubstituted aromatic heterocyclyl” and the “substituted or unsubstituted nitrogen-containing aromatic heterocyclyl” in R1 include:
Examples of substituents for the “substituted or unsubstituted aromatic heterocyclyl” and the “substituted or unsubstituted nitrogen-containing aromatic heterocyclyl” in R1 include:
Examples of substituents for the “substituted or unsubstituted aromatic heterocyclyl” and the “substituted or unsubstituted nitrogen-containing aromatic heterocyclyl” in R1 include:
Examples of substituents for the “substituted or unsubstituted aromatic heterocyclyl” and the “substituted or unsubstituted nitrogen-containing aromatic heterocyclyl” in R1 include:
Examples of the substituent for the “substituted or unsubstituted carbamoyl” in R1 include:
Examples of the substituent for the “substituted or unsubstituted carbamoyl” in R1 include
Examples of the substituent for the “substituted or unsubstituted carbamoyl” in R1 include
Examples of the substituent for the “substituted or unsubstituted carbamoyl” in R1 include
Examples of the substituent for the “substituted or unsubstituted aromatic carbocyclyl” in R2 include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted 6-membered aromatic carbocyclyl” in R2 include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted 6-membered aromatic carbocyclyl” in R2 include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted aromatic heterocyclyl” in R2 include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted 6-membered aromatic heterocyclyl” in R2 include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted aromatic carbocyclyl” in R3, R3a, R3b, and R3b′ include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted aromatic carbocyclyl” in R3, R3a, R3b, and R3b′ include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted aromatic carbocyclyl” in R3, R3a, R3b, and R3b′ include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted aromatic carbocyclyl” in R3, R3a, R3b, and R3b′ include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted aromatic carbocyclyl” in R3, R3a, R3b, and R3b′ include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted aromatic heterocyclyl” in R3, R3a, R3b, and R3b′ include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted aromatic heterocyclyl” in R3 include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted aromatic heterocyclyl” in R3, R3a, R3b, and R3b′ include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted aromatic heterocyclyl” in R3, R3a, R3b, and R3b′ include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted non-aromatic heterocyclyl” in R3, R3a, R3b, and R3b′ include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted non-aromatic heterocyclyl” in R3, R3a, R3b, and R3b′ include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted non-aromatic heterocyclyl” in R3, R3a, R3b, and R3b′ include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted non-aromatic heterocyclyl” in R3, R3a, R3b, and R3b′ include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted non-aromatic heterocyclyl” in R3, R3a, R3b, and R3b′ include:
Examples of the substituent for the “substituted or unsubstituted amino” in R3 and the “substituted amino” in R3a, R3b, and R3b′ include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted amino” in R3 and the “substituted amino” in R3a, R3b, and R3b′ include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted amino” in R3 and the “substituted amino” in R3a, R3b, and R3b′ include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted amino” in R3 and the “substituted amino” in R3a, R3b, and R3b′ include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted alkyloxy” in R3, R3a, R3b, and R3b′ include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted alkyloxy” in R3, R3a, R3b, and R3b′ include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted carbamoyl” and the “substituted or unsubstituted sulfamoyl” in R3, R3a, R3b, and R3b′ include substituted or unsubstituted alkyl.
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted carbamoyl” and the “substituted or unsubstituted sulfamoyl” in R3, R3a, R3b, and R3b′ include unsubstituted alkyl.
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted non-aromatic carbocyclyloxy” in R3, R3a, R3b, and R3b′ include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted alkyl” in R3, R3b, and R3b′ include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted alkyl” in R3, R3b, and R3b′ include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted alkyl” in R3, R3b, and R3b′ include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted alkyl” in R3, R3b, and R3b′ include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted alkyloxy” in R6 include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted alkyl”, the “substituted or unsubstituted alkenyl”, and “substituted or unsubstituted alkynyl” in R7 include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted alkyloxy” in R7 include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted alkyloxy” in R7 include:
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted alkylsulfoxy” in R7 include
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted carbamoyl” in R7 include
It may be substituted with one or more group(s) selected from these.
Examples of the substituent for the “substituted or unsubstituted carbamoyl” in R7 include
It may be substituted with one or more group(s) selected from these.
With regard to a compound represented by Formula (I):
wherein ring A is a ring represented by
preferred embodiments of R1, R2, R3, R4a, R4b, R5a, R5b, R6, R7, R8, R9, m, n, p, s, R3a, R3b, R3b′, R7′, R8′, R9′ are shown below. Regarding the compound represented by Formula (I), embodiments of all the combinations of specific examples shown below are mentioned as examples.
R1 may be substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted carbamoyl, or substituted or unsubstituted amino (hereinafter, referred to as A-1).
R1 may be substituted or unsubstituted nitrogen-containing aromatic heterocyclyl, substituted or unsubstituted nitrogen-containing non-aromatic heterocyclyl, or substituted or unsubstituted carbamoyl (hereinafter, referred to as A-6).
R1 may be substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, or substituted or unsubstituted amino (hereinafter, referred to as A-2).
R1 may be substituted or unsubstituted aromatic heterocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl (hereinafter, referred to as A-3).
R1 may be substituted or unsubstituted aromatic heterocyclyl (hereinafter, referred to as A-4).
R1 may be substituted or unsubstituted non-aromatic heterocyclyl (hereinafter, referred to as A-5).
R1 may be substituted or unsubstituted nitrogen-containing aromatic heterocyclyl, or substituted or unsubstituted nitrogen-containing non-aromatic heterocyclyl (hereinafter, referred to as A-7).
R1 may be substituted or unsubstituted nitrogen-containing aromatic heterocyclyl (hereinafter, referred to as A-8.
R1 may be substituted or unsubstituted nitrogen-containing non-aromatic heterocyclyl (hereinafter, referred to as A-9).
R1 may be substituted or unsubstituted 5- to 9-membered nitrogen-containing aromatic heterocyclyl, or substituted or unsubstituted 6-membered nitrogen-containing non-aromatic heterocyclyl (hereinafter, referred to as A-10).
R1 may be substituted or unsubstituted 5- to 9-membered nitrogen-containing aromatic heterocyclyl (hereinafter, referred to as A-11).
R1 may be substituted or unsubstituted 6-membered nitrogen-containing non-aromatic heterocyclyl (hereinafter, referred to as A-12).
R1 may be substituted or unsubstituted triazolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted dihydropyridyl, or substituted or unsubstituted imidazopyridyl (hereinafter, may be referred to as A-12).
R2 may be substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, or substituted or unsubstituted alkyl (hereinafter, referred to as B-1).
R2 may be substituted or unsubstituted aromatic carbocyclyl, or substituted or unsubstituted aromatic heterocyclyl (hereinafter, referred to as B-2).
R2 may be substituted or unsubstituted aromatic carbocyclyl (hereinafter, referred to as B-3).
R2 may be substituted or unsubstituted aromatic heterocyclyl (hereinafter, referred to as B-4).
R2 may be substituted or unsubstituted 6-membered aromatic carbocyclyl, or substituted or unsubstituted 6-membered aromatic heterocyclyl (hereinafter, referred to as B-7).
R2 may be substituted or unsubstituted 6-membered aromatic carbocyclyl (hereinafter, referred to as B-8).
R2 may be substituted or unsubstituted 6-membered aromatic heterocyclyl (hereinafter, referred to as B-9).
R2 may be 6-membered aromatic carbocyclyl substituted with one, two, three, four, or five substituents selected from substituent group G (substituent group G: halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, and haloalkyloxy), or 6-membered aromatic heterocyclyl substituted with one or two substituents selected from the substituent group G (hereinafter, referred to as B-10).
R2 may be 6-membered aromatic carbocyclyl which is substituted with one halogen and is further substituted with one, two, three, or four substituents selected from substituent group G (substituent group G: halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, and haloalkyloxy), or 6-membered aromatic heterocyclyl which is substituted with one halogen and is further substituted with one or two substituents selected from the substituent group G (hereinafter, referred to as B-5).
R2 may be 6-membered aromatic carbocyclyl which is substituted with one halogen and is further substituted with one, two, three, or four substituents selected from substituent group G (substituent group G: halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, and haloalkyloxy) (hereinafter, referred to as B-6).
R3 may be a hydrogen atom, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino (hereinafter, referred to as C-1).
R3 may be substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino (hereinafter, referred to as C-2).
R3 may be substituted or unsubstituted aromatic carbocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl (hereinafter, referred to as C-3).
R3 may be substituted or unsubstituted aromatic carbocyclyl (hereinafter, referred to as C-4).
R3 may be substituted or unsubstituted non-aromatic heterocyclyl (hereinafter, referred to as C-5).
R3 may be a group represented by Formula:
wherein
R3a may be a hydrogen atom, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkyloxy, substituted amino, halogen, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted non-aromatic carbocyclyloxy, or substituted or unsubstituted non-aromatic heterocyclyloxy (hereinafter, referred to as C-7).
R3b and R3b′ may be each independently a hydrogen atom, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkyloxy, substituted amino, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted non-aromatic carbocyclyloxy, or substituted or unsubstituted non-aromatic heterocyclyloxy (hereinafter, referred to as C-8).
R3a, R3b, and R3b′ may be each independently a hydrogen atom, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkyloxy, substituted amino, halogen, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted non-aromatic carbocyclyloxy, or substituted or unsubstituted non-aromatic heterocyclyloxy (hereinafter, referred to as C-9).
R3a, R3b, and R3b′ may be each independently substituted or unsubstituted aromatic carbocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl (hereinafter, referred to as C-10).
R3a, R3b, and R3b′ may be each independently substituted or unsubstituted aromatic carbocyclyl (hereinafter, referred to as C-11).
R3a, R3b, and R3b′ may be each independently substituted or unsubstituted non-aromatic heterocyclyl (hereinafter, referred to as C-12).
R3a, R3b, and R3b′ may be each independently a group represented by:
wherein
R3a and R3b may be each independently a group represented by:
wherein each symbol has the same meaning as that in the above C-13 (hereinafter, referred to as C-14).
R3a, R3b, and R3b′ may be each independently a group represented by:
R3a and R3b may be each independently a group represented by:
A ring formed by R3 and R8 taken together with a carbon atom to which they are each bonded may be a substituted or unsubstituted aromatic carbocycle, or a substituted or unsubstituted aromatic heterocycle (hereinafter, referred to as C′-1).
A ring formed by R3a and R8, and R3b and R8 taken together with a carbon atom to which they are each bonded may be a substituted or unsubstituted aromatic carbocycle (hereinafter, referred to as C-2′).
R4a may be a hydrogen atom, or substituted or unsubstituted alkyl (hereinafter, referred to as D-1).
R4a may be a hydrogen atom or unsubstituted alkyl (hereinafter, referred to as D-3).
R4a may be a hydrogen atom (hereinafter, referred to as D-2).
R4b may be a hydrogen atom, or substituted or unsubstituted alkyl (hereinafter, referred to as E-1).
R4b may be a hydrogen atom (hereinafter, referred to as E-2).
R5a may be a hydrogen atom, or substituted or unsubstituted alkyl (hereinafter, referred to as F-1).
R5a may be a hydrogen atom (hereinafter, referred to as F-2).
R5b may be a hydrogen atom, or substituted or unsubstituted alkyl (hereinafter, referred to as G-1).
R5b may be a hydrogen atom (hereinafter, referred to as G-2).
R6 may be a hydrogen atom, halogen, substituted or unsubstituted alkyloxy, hydroxy, or cyano (hereinafter, referred to as H-2).
R6 may be halogen, substituted or unsubstituted alkyloxy, hydroxy, or cyano (hereinafter, referred to as H-3).
R6 may be halogen, alkyloxy, or hydroxy (hereinafter, referred to as H-4).
R6 may be a hydrogen atom, halogen, or substituted or unsubstituted alkyloxy (hereinafter, referred to as H-1).
R7 may be a hydrogen atom, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic carbocycle, substituted or unsubstituted non-aromatic heterocycle, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted amino, substituted or unsubstituted alkylsulfoxy, substituted or unsubstituted carbamoyl, hydroxy, carboxy, formyl, or cyano (hereinafter, referred to as I-2).
R7 is a hydrogen atom, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino (hereinafter referred to as I-1).
R7 may be a hydrogen atom, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy (hereinafter, referred to as I-3).
R7′ may be a hydrogen atom, or substituted or unsubstituted alkyl (hereinafter, referred to as I′-1).
R9′ may be a hydrogen atom, or substituted or unsubstituted alkyl (hereinafter, referred to as I′-2).
A ring formed by R3b and R7′ taken together with an atom to which they are each bonded may be a substituted or unsubstituted non-aromatic heterocycle (hereinafter, referred to as I″-1).
R8 and R8′ may be each independently a hydrogen atom, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy (hereinafter, referred to as J-2).
R8 and R8′ may be each independently a hydrogen atom or halogen (hereinafter, referred to as J-3).
R8 may be a hydrogen atom or halogen (hereinafter, referred to as J-1).
R8 may be a hydrogen atom (hereinafter, also referred to as J-4).
R8 may be halogen (referred to as J-5).
R9 may be halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy (hereinafter, referred to as O-2).
R9 may be halogen, hydroxy, or alkyl (hereinafter, referred to as O-2).
R9 may be substituted or unsubstituted alkyl (hereinafter, referred to as O-1).
m may be 0, 1, or 2 (hereinafter, referred to as K-1).
m may be 0 or 1 (hereinafter, referred to as K-2).
m may be 0 (hereinafter, referred to as K-3).
m may be 1 (hereinafter, referred to as K-4).
n may be 0, 1, or 2 (hereinafter, referred to as L-1).
n may be 0 or 1 (hereinafter, referred to as L-2).
n may be 0 (hereinafter, referred to as L-4).
n may be 1 (hereinafter, referred to as L-3).
p may be 1, 2, or 3 (hereinafter, referred to as M-1).
p may be 1 (hereinafter, referred to as M-2).
s may be 0, 1, or 2 (hereinafter, referred to as N-1).
s may be 0 or 1 (hereinafter, referred to as N-3).
s may be 0 (hereinafter, referred to as N-2).
With regard to a compound represented by Formula (I):
wherein ring A is represented by:
preferred embodiments of R1, R2, R3, R4a, R4b, R5a, R5b, R6, R7, R8, m, and n are shown below. Regarding the compound represented by Formula (I), embodiments of all the combinations of specific examples shown below are mentioned as examples.
R1 may be A-1, A-2, A-3, A-4, or A-5.
R2 may be B-1, B-2, B-3, B-4, B-5, or B-6.
R3 may be C-1, C-2, C-3, C-4, C-5, C-6, or C′-1.
R4a may be D-1 or D-2.
R4b may be E-1 or E-2.
R5a may be F-1 or F-2.
R5b may be G-1 or G-2.
R6 may be H-1.
R7 may be I-1.
R8 may be J-1.
m may be K-1, K-2, K-3, or K-4.
n may be L-1, L-2, or L-3.
With regard to a compound represented by Formula (I):
wherein ring A is represented by:
preferred embodiments of R1, R2, R3a, R3b, R4a, R4b, R5a, R5b, R6, R7, R7′, R8, m, and n are shown below. Regarding the compound represented by Formula (I), embodiments of all the combinations of specific examples shown below are mentioned as examples.
R1 may be A-6, A-7, A-8, or A-9.
R2 may be B-5, B-6, B-7, B-8, or B-9.
R3a may be C-7, C-10, C-11, C-12, or C-14.
R3b may be C-8, C-9, C-10, C-11, C-12, or C-14.
R3b may be C-8, C-9, C-10, C-11, C-12, or C-14.
R4a may be D-2 or D-3.
R4b may be E-2.
R5a may be F-2.
R5b may be G-2.
R6 may be H-1, H-2, or H-3.
R7 may be I-1 or I-2.
R7′ may be I′-1, or
R3b and RV may be I″-1,
R8 may be J-1 or J-2.
m may be K-2, K-3, or K-4.
n may be L-2, L-3, or L-4.
Another exemplary embodiment of the compound represented by Formula (I) or its pharmaceutically acceptable salt are shown below.
In a compound represented by Formula (I):
The compound represented by Formula (I) is not limited to specific isomers, but includes all possible isomers (for example, keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer, rotamer, etc.), racemates, or a mixture thereof.
One or more hydrogen atom, carbon atom and/or other atom of the compound represented by Formula (I) may be substituted with an isotope of the hydrogen atom, carbon atom and/or other atom, respectively. Examples of such isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, as in the cases of 2H, 3H, 11C, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, 123I, and 36Cl, respectively. The compound represented by Formula (I) also includes a compound substituted with such an isotope. The compound substituted with the isotope is also useful as a pharmaceutical product and includes all radiolabeled forms of the compound represented by Formula (I). Furthermore, a “radiolabeling method” for producing the “radiolabeled forms” is also included in the present invention, and the “radiolabeled forms” are useful as tools for metabolic pharmacokinetics studies, studies on binding assay, and/or diagnostics.
The radiolabeled form of the compound represented by Formula (I) can be prepared by the method well known in this technical field. For example, a tritium-labeled compound represented by Formula (I) can be prepared by introducing tritium into a specific compound represented by Formula (I) by catalytic dehalogenation reaction using tritium. This method includes reacting an appropriately halogenated precursor of the compound represented by Formula (I) with tritium gas in the presence of an appropriate catalyst, such as Pd/C, and in the presence or absence of a base. Regarding other appropriate methods for preparing tritium-labeled compounds, “Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)” can be referred to. A 14C-labeled compound can be prepared by using a raw material having 14C carbon.
Examples of the pharmaceutically acceptable salt of the compound represented by Formula (I) include salts of the compound represented by Formula (I) with alkali metal (for example, lithium, sodium, potassium, etc.), alkaline earth metal (for example, calcium, barium, etc.), magnesium, transition metal (for example, zinc, iron, etc.), ammonia, organic base (for example, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc.) and amino acid or salts of the compound represented by Formula (I) with inorganic acid (for example, hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.), and organic acid (for example, formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, succinic acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, etc.). These salts can be formed according to methods that are conventionally carried out.
The compounds represented by Formula (I) or pharmaceutically acceptable salts thereof according to the present invention may form solvates (e.g., hydrates or the like), cocrystals and/or crystal polymorphs. The present invention encompasses those various solvates, cocrystals and crystal polymorphs. The “solvate” may be one wherein any number of solvent molecules (e.g., water molecules or the like) is coordinated with the compound represented by Formula (I). When the compound represented by Formula (I) or a pharmaceutically acceptable salt thereof is allowed to stand in the atmosphere, the compound may absorb water, resulting in attachment of adsorbed water or formation of a hydrate. Furthermore, crystalline polymorphs may be formed by recrystallizing the compounds represented by Formula (I) or pharmaceutically acceptable salts thereof. The term “co-crystal” means that the compound represented by Formula (I) or a salt thereof and a counter molecule are present in the same crystal lattice, and may contain any number of counter molecules.
The compounds represented by Formula (I) or pharmaceutically acceptable salts thereof may form prodrugs. The present invention also encompasses such various prodrugs. A prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound which becomes a pharmaceutically active compound of the present invention in vivo as a result of solvolysis or under physiological conditions. Prodrugs encompass compounds that are converted to the compounds represented by Formula (I) through enzymatic oxidation, reduction, hydrolysis or the like under physiological conditions and in vivo, compounds that are converted to the compounds represented by Formula (I) through hydrolysis by gastric acid etc., and the like. Methods for selecting and producing an appropriate prodrug derivative are described in, for example, “Design of Prodrugs, Elsevier, Amsterdam, 1985”. A prodrug may have activity per se.
When the compounds represented by Formula (I) or pharmaceutically acceptable salts thereof have hydroxy group(s), prodrugs include acyloxy derivatives and sulfonyloxy derivatives that are prepared by, for example, reacting compounds having hydroxy group(s) with suitable acyl halide, suitable acid anhydride, suitable sulfonyl chloride, suitable sulfonyl anhydride and mixed anhydride, or with a condensing agent. Examples include CH3COO—, C2H5COO—, tert-BuCOO—, C15H31COO—, PhCOO—, (m-NaOOCPh)COO—, NaOOCCH2CH2COO—, CH3CH(NH2)COO—, CH2N(CH3)2COO—, CH3SO3—, CH3CH2SO3—, CF3SO3—, CH2FSO3—, CF3CH2SO3—, p-CH3O-PhSO3—, PhSO3—, and p-CH3PhSO3—.
Since the compound according to the present invention has coronavirus 3CL protease inhibitory activity, the compound is useful as a therapeutic and/or prophylactic agent for a disease associated with coronavirus 3CL proteases. When the term “therapeutic agent and/or prophylactic agent” is used in the present invention, this also includes a symptom ameliorating agent. The disease associated with coronavirus 3CL proteases may be viral infections, and preferably coronavirus infections.
According to an aspect, the coronavirus may be a coronavirus that infects human beings. The coronavirus that infects human beings may be HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and/or SARS-CoV-2.
As an embodiment, as the coronavirus, Alphacoronavirus and/or Betacoronavirus, more preferably Betacoronavirus, and further preferably Sarbecovirus are exemplified.
According to an aspect, the alphacoronavirus may be HCoV-229E and HCoV-NL63. The alphacoronavirus may be particularly preferably HCoV-229E.
According to an aspect, the betacoronavirus may be HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and/or SARS-CoV-2. The betacoronavirus may be HCoV-OC43 or SARS-CoV-2, and particularly preferably SARS-CoV-2.
According to an aspect, the betacoronavirus may be betacoronavirus lineage A (β-coronavirus lineage A), betacoronavirus lineage B (β-coronavirus lineage B), and betacoronavirus lineage C (β-coronavirus lineage C). The betacoronavirus may be more preferably betacoronavirus lineage A (β-coronavirus lineage A) and betacoronavirus lineage B (β-coronavirus lineage B) and particularly preferably betacoronavirus lineage B (β-coronavirus lineage B).
Examples of the betacoronavirus lineage A (β-coronavirus lineage A) include HCoV-HKU1 and HCoV-OC43, and preferably HCoV-OC43. Examples of the betacoronavirus lineage B (β-coronavirus lineage B) include SARS-CoV and SARS-CoV-2, and preferably SARS-CoV-2. The betacoronavirus lineage C (β-coronavirus lineage C) may be MERS-CoV.
According to an aspect, the coronavirus may be HCoV-229E, HCoV-OC43, and/or SARS-CoV-2, and particularly preferably SARS-CoV-2.
The coronavirus infections may be infections caused by HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV, MERS-CoV, and/or SARS-CoV-2. Preferably, the coronavirus infections may be infections caused by HCoV-229E, HCoV-OC43, and/or SARS-CoV-2, and particularly preferably infection caused by SARS-CoV-2.
The coronavirus infections may be particularly preferably novel coronavirus infections (COVID-19).
For example, the compound represented by Formula (I) according to the present invention can be prepared by the general procedure described below. Regarding extraction, purification, and the like, the treatments carried out in ordinary experiments of organic chemistry may be carried out.
The compounds of the present invention can be produced with reference to techniques known in the art. For example, the compounds can be produced with reference to WO2013/184806, U.S. Pat. No. 4,731,106, WO2013/064083, and WO2020/261114.
(Method A) When the ring A is aromatic carbocycle or aromatic heterocycle
wherein Lg is a leaving group; and other reference symbols have the same meanings as described above.
In the presence of a solvent such as DMF, DMA, NMP, or THF, or alternatively a mixed solvent thereof, a condensing agent such as HATU, WSC·HCl and HOBt, or PyBOP is added to Compound (A-1), then, Amine (A-2) corresponding to a target, and a tertiary amine such as triethylamine, N-methylmorpholine, or N,N-diisopropylethylamine is added thereto, and the mixture is reacted at 0° C. to 60° C., or preferably 20° C. to 40° C., for 0.1 hours to 24 hours, or preferably 0.5 hours to 12 hours, whereby Compound (A-3) can be obtained.
In the presence of a solvent such as DMF, DMA, NMP, THF, toluene, acetonitrile, dimethylsulfoxide, dioxane or dichloromethane or in a mixed solvent thereof, a carbonylating agent such as triphosgene, CDI, di-tert-butyl dicarbonate, urea, 4-nitrophenyl chloroformate, or methyl chloroformate is added to Compound (A-3), and the mixture is reacted at 0° C. to 140° C., or preferably at 20° C. to 100° C., for 0.1 hours to 24 hours, or preferably 0.5 hours to 12 hours, whereby Compound (A-4) can be obtained.
In the presence of acetonitrile, acetone, DMF, DMSO, or NMP or in a mixed solvent thereof, in the presence of a base such as potassium carbonate, sodium carbonate, or cesium carbonate, Compound (A-5) corresponding to a target is added to Compound (A-4), and the mixture is reacted at 0° C. to 100° C., or preferably at 20° C. to 60° C., for 0.1 hours to 24 hours, or preferably 0.5 hours to 12 hours, whereby Compound (I) can be obtained.
Examples of the leaving group include halogen and —OSO2(CtF2t+1) (wherein t is an integer of 1 to 4). The halogen is preferably chlorine, iodine, and bromine, and the —OSO2(CtF2t+1) group is preferably an —OTf group (trifluoromethanesulfonic acid ester).
(Method B) When the ring A is aromatic carbocycle or aromatic heterocycle
wherein Lg is a leaving group; and other reference symbols have the same meanings as described above.
In the presence of a solvent such as DMF, DMA, NMP, THF, or toluene, or in a mixed solvent thereof, Compound (B-2) corresponding a target, and a tertiary amine such as triethylamine, N-methylmorpholine, or N,N-diisopropylethylamine, as well as DMAP as required, are added to Compound (B-1), and the mixture is reacted at 0° C. to 140° C., or preferably 20° C. to 100° C., for 0.1 hours to 24 hours, or preferably 0.5 hours to 12 hours, whereby Compound (B-3) can be obtained.
Examples of the leaving group include halogen and alkoxy.
An acid such as hydrochloric acid or sulfuric acid is added to Compound (B-3), and the mixture is reacted at 0° C. to 160° C., or preferably at 40° C. to 120° C., for 0.1 hours to 24 hours, or preferably 0.5 hours to 12 hours, whereby Compound (B-4) can be produced.
In the presence of acetonitrile, acetone, DMF, DMSO, or NMP or in a mixed solvent thereof, in the presence of a base such as potassium carbonate, sodium carbonate, or cesium carbonate, Compound (B-5) corresponding to a target is added to Compound (B-4), and the mixture is reacted at 0° C. to 100° C., or preferably at 20° C. to 60° C., for 0.1 hours to 24 hours, or preferably 0.5 hours to 12 hours, whereby Compound (B-6) can be obtained.
Examples of the leaving group include halogen and —OSO2(CtF2t+1) (wherein t is an integer of 1 to 4). The halogen is preferably chlorine, iodine, and bromine, and the —OSO2(CtF2t+1) group is preferably an —OTf group (trifluoromethanesulfonic acid ester).
(Method C) When the ring A is non-aromatic carbocycle or non-aromatic heterocycle
wherein Lg is a leaving group; and other reference symbols have the same meanings as described above.
In a solvent such as methanol or ethanol, urea and a base such as sodium methoxide or sodium ethoxide are added to Compound (C-1), and the mixture is reacted at 0° C. to 140° C., or preferably at 20° C. to 100° C., for 0.1 hours to 48 hours, or preferably 0.5 hours to 18 hours, whereby Compound (C-2) can be obtained.
In the presence of acetonitrile, acetone, DMF, DMSO, NMP or in a mixed solvent thereof, N,O-bis(trimethylsilyl)acetamide and a corresponding compound (C-3) and, if necessary, a quaternary ammonium salt such as tetrabutylammonium bromide are added to Compound (C-2), and the mixture is reacted at 0° C. to 140° C., or preferably at 40° C. to 100° C., for 0.1 hours to 48 hours, or preferably 0.5 hours to 18 hours, whereby Compound (C-4) can be obtained. As another method, in the presence of DMF, DMSO, or NMP or in a mixed solvent thereof, in the presence of a base such as potassium carbonate, sodium carbonate, cesium carbonate, or sodium hydride, Compound (C-3) corresponding to a target is added to Compound (C-2), and the mixture is reacted at 0° C. to 100° C., or preferably at 20° C. to 60° C., for 0.1 hours to 24 hours, or preferably 0.5 hours to 12 hours, whereby Compound (C-4) can be obtained.
Examples of the leaving group include halogen and —OSO2(CtF2t+1) (wherein t is an integer of 1 to 4). The halogen is preferably chlorine, iodine, and bromine, and the —OSO2(CtF2t+1) group is preferably an —OTf group (trifluoromethanesulfonic acid ester).
In the presence of DMF, DMSO, or NMP or in a mixed solvent thereof, in the presence of a base such as potassium carbonate, sodium carbonate, cesium carbonate, or sodium hydride, Compound (C-5) corresponding to a target is added to Compound (C-4), and the mixture is reacted at 0° C. to 100° C., or preferably at 20° C. to 60° C., for 0.1 hours to 24 hours, or preferably 0.5 hours to 12 hours, whereby Compound (C-6) can be obtained.
Examples of the leaving group include halogen and —OSO2(CtF2t+1) (wherein t is an integer of 1 to 4). The halogen is preferably chlorine, iodine, and bromine, and the —OSO2(CtF2t+1) group is preferably an —OTf group (trifluoromethanesulfonic acid ester).
Since the compound of the present invention has coronavirus 3CL protease inhibitory activity, the compound is useful as a therapeutic and/or prophylactic agent for coronavirus infections.
Furthermore, the compound of the present invention has utility as a medicine, and preferably, the compound of the present invention has any one or a plurality of the following excellent features.
Regarding the coronavirus replication inhibitor, for example, an aspect in which in the CPE effect (SARS-CoV-2) that will be described below, for example, EC50 is 10 μM or less, preferably 1 μM or less, and more preferably 100 nM or less, may be mentioned.
The pharmaceutical composition of the present invention can be administered by either an oral method or a parenteral method. Examples of a parenteral administration method include percutaneous, subcutaneous, intravenous, intra-arterial, intramuscular, intraperitoneal, transmucosal, inhalation, transnasal, ocular instillation, ear instillation, and intravaginal administration.
In the case of oral administration, the pharmaceutical composition may be prepared into any dosage form that is commonly used, such as a solid preparation for internal use (for example, a tablet, a powder preparation, a granular preparation, a capsule, a pill, or a film preparation), or a liquid preparation for internal use (for example, a suspension, an emulsion, an elixir, a syrup, a limonade, a spirit preparation, an aromatic water preparation, an extraction, a decoction, or a tincture) and administered. The tablet may be a dragee, a film-coated tablet, an enteric-coated tablet, a sustained release tablet, a troche, a sublingual tablet, a buccal tablet, a chewable tablet, or an orally disintegrating tablet; the powder preparation and granular preparation may be dry syrups; and the capsule may be a soft capsule, a microcapsule, or a sustained release capsule.
In the case of parenteral administration, the pharmaceutical composition can be suitably administered in any dosage form that is commonly used, such as an injectable preparation, an infusion, or a preparation for external use (for example, an eye drop, a nasal drop, an ear drop, an aerosol, an inhalant, a lotion, an impregnating agent, a liniment, a gargling agent, an enema, an ointment, a plaster, a jelly, a cream, a patch, a poultice, a powder preparation for external use, or a suppository). The injectable preparation may be an O/W, W/O, O/W/O, or W/O/W type emulsion, or the like.
A pharmaceutical composition can be obtained by mixing an effective amount of the compound of the present invention with various pharmaceutical additives appropriate for the dosage form, such as an excipient, a binder, a disintegrating agent, and a lubricating agent, as necessary. Furthermore, the pharmaceutical composition can be prepared into a pharmaceutical composition for use for a child, an elderly, a patient with a serious case, or a surgical operation, by appropriately changing the effective amount of the compound of the present invention, the dosage form, and/or various pharmaceutical additives. For example, a pharmaceutical composition for use for a child may be administered to a neonate (less than 4 weeks after birth), an infant (from 4 weeks after birth to less than 1 year), a preschool child (from 1 year to less than 7 years), a child (from 7 years to less than 15 years), or a patient 15 year to 18 years of age. For example, a pharmaceutical composition for an elderly may be administered to a patient 65 years of age or older.
It is desirable to set the amount of administration of the pharmaceutical composition of the present invention, after considering the age and body weight of the patient, the type and degree of the disease, the route of administration, and the like; however, in the case of oral administration, the amount of administration is usually 0.05 to 200 mg/kg/day and is preferably in the range of 0.1 to 100 mg/kg/day. In the case of parenteral administration, the amount of administration may vary greatly depending on the route of administration; however, the amount of administration is usually 0.005 to 200 mg/kg/day and is preferably in the range of 0.01 to 100 mg/kg/day. This may be administered once a day or several times a day.
The compound of the present invention may be used in combination with, for example, another therapeutic agent for novel coronavirus infections (COVID-19) (the therapeutic agent includes an approved drug and a drug that is under development or to be developed in the future) (hereinafter, referred to as concomitant drug), for the purpose of enhancing the action of the compound, reducing the amount of administration of the compound, or the like. At this time, the timing of administration for the compound of the present invention and the concomitant drug is not limited, and these may be administered simultaneously to the target of administration or may be administered with a time difference. Furthermore, the compound of the present invention and the concomitant drug may be administered as two or more kinds of preparations each including active ingredients, or may be administered as a single preparation including those active ingredients.
The amount of administration of the concomitant drug can be appropriately selected based on the clinically used dosage. Furthermore, the blending ratio of the compound of the present invention and the concomitant drug can be appropriately selected according to the target of administration, the route of administration, the target disease, symptoms, combination, and the like. For example, when the target of administration is a human being, 0.01 to 100 parts by weight of the concomitant drug may be used with respect to 1 part by weight of the compound of the present invention.
Hereinafter, the present invention will be described in more detail by way of Examples, Reference Examples, and Test Examples; however, the present invention is not intended to be limited by these.
Furthermore, abbreviations used in the present specification denote the following meanings.
The NMR analysis obtained in each Example was performed at 400 MHz, and measurement was made using DMSO-d6 and CDCl3. Furthermore, when NMR data are shown, there are occasions in which all the measured peaks are not described.
The term RT in the specification indicates retention time in an LC/MS: liquid chromatography/mass analysis, and the retention time was measured under the following conditions.
Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1×50 mm) (Waters)
Flow rate: 0.8 mL/min
UV detection wavelength: 254 nm
Mobile phase: [A] was 0.1% formic acid-containing aqueous solution, and [B] was 0.1% formic acid-containing acetonitrile solution.
Gradient: A linear gradient of 5% to 100% solvent [B] was carried out for 3.5 minutes, and then 100% solvent [B] was maintained for 0.5 minutes.
Column: Shim-pack XR-ODS (2.2 μm, i.d. 3.0×50 mm) (Shimadzu)
Flow rate: 1.6 mL/min
UV detection wavelength: 254 nm
Mobile phase: [A] was 0.1% formic acid-containing aqueous solution, and [B] was 0.1% formic acid-containing acetonitrile solution.
Gradient: A linear gradient of 10% to 100% solvent [B] was carried out for 3 minutes, and then 100% solvent [B] was maintained for 0.5 minutes.
Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1×50 mm) (Waters)
Flow rate: 0.8 mL/min
UV detection wavelength: 254 nm
Mobile phase: [A] was 10 mM ammonium carbonate in aqueous solution, and [B] was acetonitrile.
Gradient: A linear gradient of 5% to 100% solvent [B] was carried out for 3.5 minutes, and then 100% solvent [B] was maintained for 0.5 minutes.
Incidentally, in the specification, the description of MS (m/z) indicates a value observed by mass analysis.
Column: Gemini (registered trademark) 5 μm NX-C18 110 A, LC Column 100×30 mm, AXIA (trademark) Packed (Phenomenex)
Flow rate: 25 mL/min
UV detection wavelength: 254 nm
Mobile phase: [A] was 10 mmol/L ammonium carbonate aqueous solution, and [B] was acetonitrile.
Gradient: Yes
Start (0 min) [A]:[B]=40:60
End (8 min) [A]:[B]=20:80 Wash (8 to 10 min) [A]:[B]=0:100
2-Amino-4-bromo-6-fluorobenzoic acid (1.00 g, 4.27 mmol) was dissolved in dichloromethane (20 ml), PyBOP (2.67 g, 5.13 mmol) and diisopropylethylamine (2.24 ml, 12.8 mmol) were added thereto, and the mixture was stirred at room temperature for 18 hours. Water (50 ml) was added to the reaction solution, the mixture was separated, and the aqueous layer was extracted with dichloromethane. After the organic layer was washed with water, it was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give Compound 1 (1.63 g, 4.97 mmol, yield 100%).
LC/MS (ESI): m/z=328, RT=1.41 min, LC/MS measurement conditions 1
A mixture of Compound 1 (1.34 g, 4.08 mmol), THF (13 ml), and CDI (1.32 g, 8.17 mmol) was stirred at 70° C. for 4 hours. The reaction solution was cooled to room temperature, water was added thereto, and the precipitated solid was collected by filtration to give Compound 2 (906 mg, 2.56 mmol, yield 63%).
LC/MS (ESI): m/z=354, RT=1.35 min, LC/MS measurement conditions 1
Compound 2 (50.0 mg, 0.141 mmol) was dissolved in DMF (1 ml), and a 28% sodium methoxide-methanol solution (0.103 ml, 0.424 mmol) was added thereto, then the mixture was stirred at 60° C. for 1 hour. The reaction solution was cooled to room temperature, neutralized with a 10% citric acid aqueous solution, and the precipitated solid was collected by filtration to give Compound 3 (51.0 mg, 0.139 mmol, yield 99%).
LC/MS (ESI): m/z=366, RT=1.23 min, LC/MS measurement conditions 1
Compound 3 (50.0 mg, 0.137 mmol), DMF (1.0 ml), and potassium carbonate (37.7 g, 0.237 mmol) were mixed, and the mixture was stirred at room temperature for 10 minutes. To the mixture, 1-(bromomethyl)-2,4,5-trifluorobenzene (32.3 mg, 0.143 mmol) was added at 0° C., and the mixture was heated to room temperature and stirred for 2 hours. Water was added to the reaction solution, and the precipitated solid was dissolved in chloroform, washed with water, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was crystallized from ethyl acetate-diisopropyl ether to give Compound 4 (51 mg, 0.10 mmol, yield 73%).
LC/MS (ESI): m/z=510, RT=2.00 min, LC/MS measurement conditions 1
Compound 4 (48.0 mg, 0.0940 mmol), (5-carbamoyl-2-chlorophenyl)boronic acid (24.4 mg, 0.122 mmol), dioxane (0.7 ml), a 2 mol/L aqueous potassium carbonate solution (0.0940 ml, 0.188 mmol), and PdCl2 (dppf) (6.88 mg, 0.00941 mmol) were mixed, and the mixture was stirred at 90° C. for 4 hours under a nitrogen atmosphere. The reaction solution was ice-cooled, water was added thereto, and was extracted with ethyl acetate. After the organic layer was washed with water, it was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give Compound (I-0299) (22.0 mg, 0.0380 mmol, yield 40%).
LC/MS (ESI): m/z=585, RT=1.89 min, LC/MS measurement conditions 1
1H-NMR (DMSO-d6) δ: 8.34 (s, 1H), 8.09 (s, 1H), 7.91 (m, 2H), 7.66 (d, J=8.8 Hz, 1H), 7.63-7.58 (s, 1H), 7.55 (s, 1H), 7.29 (m, 1H), 6.98 (s, 1H), 6.88 (s, 1H), 5.40 (s, 2H), 5.17 (s, 2H), 3.92 (s, 3H), 3.79 (s, 3H).
2-Amino-4-bromo-6-fluorobenzoic acid (2.00 g, 8.55 mmol) was dissolved in DMA (2.0 ml), phenyl N-(5-methyl-3-pyridyl)carbamate (2.71 g, 10.3 mmol) (see WO2009127948, WO2009127949, and WO2002048152 for the synthesizing method), DMAP (0.104 g, 0.855 mmol), and triethylamine (2.84 ml, 20.5 mmol) were added thereto, and the mixture was stirred at 100° C. for 2 hours. The reaction solution was cooled to room temperature, and water (60 ml) was added thereto, then the mixture was neutralized with 2 mol/L hydrochloric acid. The precipitated solid was collected by filtration and washed with water to give Compound 5 (2.48 g, 6.74 mmol, yield 79%).
LC/MS (ESI): m/z=508, RT=2.17 min, LC/MS measurement conditions 1
Compound 5 (2.48 g, 6.74 mmol) was suspended in 2 mol/L hydrochloric acid (25 ml, 50.0 mmol), and the mixture was stirred at 100° C. for 2 hours. The reaction solution was cooled to room temperature and neutralized with saturated aqueous sodium bicarbonate solution. The precipitated solid was collected by filtration and washed with water to give Compound 6 (2.05 g, 5.85 mmol, yield 87%).
LC/MS (ESI): m/z=352, RT=1.45 min, LC/MS measurement conditions 1
Compound 7 (79.5 mg, 0.220 mmol, yield 77%) was obtained in the same manner as in Step 3 of Example 1.
LC/MS (ESI): m/z=569, RT=2.07 min, LC/MS measurement conditions 1
Compound 8 (99.5 mg, 0.197 mmol, yield 90%) was obtained in the same manner as in Step 4 of Example 1.
LC/MS (ESI): m/z=508, RT=2.17 min, LC/MS measurement conditions 1
Compound (I-0067) (24.0 mg, 0.0410 mmol, yield 42%) was obtained in the same manner as in Step 5 of Example 1.
LC/MS (ESI): m/z=581, RT=1.94 min, LC/MS measurement conditions 1
1H-NMR (DMSO-d6) δ: 8.46 (d, J=1.4 Hz, 1H), 8.42 (d, J=2.0 Hz, 1H), 8.11 (br s, 1H), 7.90 (dt, J=6.7, 2.2 Hz, 2H), 7.70 (br s, 1H), 7.67-7.65 (m, 1H), 7.57 (br s, 1H), 7.45-7.42 (m, 2H), 6.98 (s, 1H), 6.85 (s, 1H), 5.37 (br s, 2H), 3.91 (s, 3H), 2.38 (s, 3H).
Compound 9 (3.52 g, 22.2 mmol, yield 75%) was synthesized by known methods (see WO2017066742 and WO2010093849).
LC/MS (ESI): m/z=159, RT=1.19 min, LC/MS measurement conditions 1
Compound 11 (3.32 g, 20.9 mmol) was dissolved in acetic acid (33 ml), and sodium iodide (3.76 g, 25.1 mmol) and chloramine T (7.07 g, 25.1 mmol) were added thereto, then the mixture was stirred at room temperature for 30 minutes. To the reaction solution, a 10 mol/L aqueous sodium hydroxide solution (61.2 ml, 612 mmol), ethyl acetate (30 ml), sodium thiosulfate (3.31 g, 20.9 mmol), and water (30 ml) were added, and the mixture was separated. The water layer was extracted with ethyl acetate, and the organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give Compound 10 (5.01 g, 17.6 mmol, yield 84%).
LC/MS (ESI): m/z=285, RT=2.02 min, LC/MS measurement conditions 1
Compound 10 (4.62 g, 16.2 mmol), methanol (46 ml), triethylamine (4.50 ml, 32.5 mmol), and PdCl2 (dppf) (1.19 g, 1.62 mmol) were mixed, and the mixture was stirred at 60° C. for 4.5 hours under a carbon monoxide atmosphere. The reaction solution was cooled to room temperature, and the residue obtained by concentration was purified by silica gel column chromatography (hexane/ethyl acetate) to give Compound 11 (3.06 g, 14.1 mmol, yield 87%).
LC/MS (ESI): m/z=217, RT=1.76 min, LC/MS measurement conditions 1
Compound 11 (2.86 g, 13.2 mmol) was dissolved in methanol (30 ml) and tetrahydrofuran (15 ml), a 2 mol/L aqueous sodium hydroxide solution (33.0 ml, 66.0 mmol) was added thereto, and then, the mixture was stirred at 60° C. for 45 minutes. After cooled to room temperature, the mixture was neutralized with 2 mol/L hydrochloric acid. The precipitated solid was collected by filtration and washed with water to give Compound 12 (1.47 g, 7.28 mmol, yield 55%).
LC/MS (ESI): m/z=203, RT=1.49 min, LC/MS measurement conditions 1
Compound 13 (691 mg, 2.33 mmol, yield 94%) was obtained in the same manner as in Step 1 of Example 1.
LC/MS (ESI): m/z=297, RT=1.34 min, LC/MS measurement conditions 1
Compound 13 (610 mg, 2.06 mmol) was added to tetrahydrofuran (60 ml), and 60% sodium hydride (247 mg, 6.17 mmol) and CDI (667 mg, 4.11 mmol) were added at 0° C., then the mixture was stirred at room temperature for 40 minutes. Furthermore, 60% sodium hydride (247 mg, 6.17 mmol) and CDI (667 mg, 4.11 mmol) were added thereto at 0° C., and the mixture was stirred at 70° C. for 30 minutes. Water (30 ml) was added thereto, the mixture was neutralized with 2 mol/L hydrochloric acid, and the precipitated solid was collected by filtration to give Compound 14 (470 mg, 1.46 mmol, yield 71%).
LC/MS (ESI): m/z=323, RT=1.21 min, LC/MS measurement conditions 1
Compound 15 (265 mg, 0.568 mmol, yield 92%) was obtained in the same manner as Step 4 of Example 1.
LC/MS (ESI): m/z=467, RT=2.03 min, LC/MS measurement conditions 1
Compound (I-0176) (126 mg, 0.222 mmol, yield 69%) was obtained in the same manner as Step 5 in Example 1.
LC/MS (ESI): m/z=568, RT=2.24 min, LC/MS measurement conditions 1
1H-NMR (DMSO-d6) δ: 8.36 (s, 1H), 8.17 (d, J=1.9 Hz, 1H), 7.98 (dd, J=8.4, 1.9 Hz, 1H), 7.83 (d, J=8.4 Hz), 5.41 (s, 2H), 5.18 (s, 2H), 4.00 (s, 3H), 3.79 (s, 3H).
Compound 18 (111 mg, 0.195 mmol), chlorotrimethylsilane (63.7 mg, 0.586 mmol), sodium iodide (88.0 mg, 0.586 mmol), and acetonitrile (1.1 ml) were mixed, and the mixture was stirred at 70° C. for 30 minutes. The reaction solution was cooled to room temperature, a saturated aqueous sodium bicarbonate solution was added thereto, and the precipitated solid was collected by filtration and washed with water to give Compound 19 (85.7 mg, 0.155 mmol, yield 79%).
LC/MS (ESI): m/z=554, RT=1.87 min, LC/MS measurement conditions 1
1H-NMR (DMSO-d6) δ: 8.37 (s, 1H), 7.92-7.87 (m, 2H), 7.74-7.72 (m, 1H), 7.30-7.26 (m, 2H), 6.13 (br s, 1H), 5.23 (s, 2H), 5.13 (s, 2H), 3.79 (s, 3H).
Compound (I-0177) (76.4 mg, 0.138 mmol) was dissolved in DMF (1.5 ml), cesium carbonate (225 mg, 0.690 mmol) and iodomethane (98.0 mg, 0.690 mmol) were added thereto, and the mixture was stirred at room temperature for 45 minutes. Water (5 ml) and ethyl acetate (5 ml) were added to the reaction solution, the mixture was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. The residue obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform/methanol) to give Compound (I-0169) (49.0 mg, 0.0860 mmol, yield 63%).
LC/MS (ESI): m/z=568, RT=1.86 min, LC/MS measurement conditions 1
1H-NMR (DMSO-d6) δ: 8.35 (s, 1H), 8.10-8.07 (m, 2H), 7.92 (d, J=8.3 Hz, 1H), 7.27-7.23 (m, 2H), 6.44 (s, 1H), 5.37-5.23 (m, 2H), 5.12 (s, 3H), 3.79 (s, 3H), 3.08 (s, 3H).
Compound 16 (1.26 g, 2.47 mmol, yield 95%) was obtained in the same manner as Step 4 of Example 1.
LC/MS (ESI): m/z=510, RT=2.05 min, LC/MS measurement conditions 1
Dichloromethane (2.0 ml) was added to Compound 16 (200 mg, 0.392 mmol), and a 1.0 mol/L boron tribromide-dichloromethane solution (0.862 ml, 0.862 mmol) was added thereto at 0° C., then the mixture was stirred as it was for 2 hours. Methanol (2.0 ml) and a 2.0 mol/L aqueous sodium hydroxide solution (1.5 ml) were added to the reaction solution, and the mixture was stirred at 50° C. for 1 hour. The reaction solution was cooled to room temperature, and the precipitated solid was collected by filtration and washed with water to give Compound 17 (181 mg, 0.349 mmol, yield 89%).
Compound 17 (192 mg, 0.370 mmol) was dissolved in DMF (1.0 ml), and potassium carbonate (51.1 mg, 0.370 mmol) and allyl bromide (0.0680 ml, 0.740 mmol) were added thereto, then the mixture was stirred at 60° C. for 5 hours. The reaction solution was cooled to room temperature, water was added thereto, and the precipitated solid was collected by filtration to give Compound 18 (175 mg, 0.326 mmol, yield 88%).
The compound 18 (175 mg, 0.326 mmol) was dissolved in NMP (1.3 mL), and the mixture was stirred at 240° C. for 1 hour. The reaction solution was cooled to room temperature, water was added thereto, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to give Compound 19 (175 mg, 0.326 mmol, yield 100%).
LC/MS (ESI): m/z=536, RT=2.77 min, LC/MS measurement conditions 1
Compound 19 (175 mg, 0.326 mmol) was dissolved in tetrahydrofuran (1.5 ml) and water (0.5 ml), and 2,6-lutidine (0.0760 ml, 0.653 mmol), sodium periodate (209 mg, 0.979 mmol), and potassium osmate (VI) dihydrate (3.61 mg, 0.00979 mmol) were added thereto, then the mixture was stirred at room temperature for 1.5 hours. Water (3 ml) and ethyl acetate (5 ml) were added to the reaction solution, the mixture was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. The residue obtained by concentrating the solvent was purified by silica gel column chromatography (chloroform/methanol) to give Compound 20 (116 mg, 0.216 mmol, yield 66%).
LC/MS (ESI): m/z=538, RT=2.19 min, LC/MS measurement conditions 1
Compound 20 (116 mg, 0.216 mmol) was dissolved in methanol (1.2 ml), and sodium borohydride (8.15 mg, 0.216 mmol) was added thereto, then the mixture was stirred for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the precipitated solid was collected by filtration to obtain Compound 21 (85.3 mg, 0.158 mmol, yield 73%).
LC/MS (ESI): m/z=540, RT=2.41 min, LC/MS measurement conditions 1
Triphenylphosphine (49.7 mg, 0.189 mmol) and diisopropyl azodicarboxylate (47.9 mg, 0.237 mmol) were added to a tetrahydrofuran solution (1.0 ml) of Compound 21 (85.3 mg, 0.158 mmol) at 0° C., and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated, and the crude product was washed with methanol to obtain Compound 22 (33.2 mg, 0.0640 mmol, yield 40%).
LC/MS (ESI): m/z=522, RT=2.07 min, LC/MS measurement conditions 1
Compound (I-0353) (25.4 mg, 0.0420 mmol, yield 66%) was obtained in the same manner as Step 5 of Example 1, using Compound 22 (33.2 mg, 0.0640 mmol).
LC/MS (ESI): m/z=609, RT=1.83 min, LC/MS measurement conditions 1
1H-NMR (DMSO-d6) δ: 10.62 (s, 1H), 8.35 (s, 1H), 7.28 (m, 2H), 7.20 (s, 1H), 6.93 (s, 1H), 6.57 (s, 1H), 5.34 (br s, 2H), 5.17 (s, 2H), 4.70 (t, J=8.4 Hz, 2H), 3.79 (s, 3H), 3.51 (s, 2H), 2.98 (br t, J=8.4 Hz, 2H).
A mixture of 5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione (200 mg, 1.20 mmol), acetonitrile (2.0 ml) and N,O-bis(trimethylsilyl)acetamide (367 mg, 1.81 mmol) was stirred at room temperature for 40 minutes. To the reaction solution, 1-(bromomethyl)-3,4,5-trifluorobenzene (406 mg, 1.81 mmol) was added, and the mixture was stirred at 80° C. for 18 hours. Water was added to the reaction solution, the mixture was extracted with chloroform. The organic layer was washed with water and dried over sodium sulfate. The crude product obtained by concentrating the solvent was solidified with dichloromethane-diisopropyl ether to give Compound 23 (283 mg, 0.912 mmol, yield 76%).
LC/MS (ESI): m/z=311, RT=1.90 min, LC/MS measurement conditions 1
Compound 23 (50.0 mg, 0.161 mmol) was dissolved in DMF (0.75 ml), and potassium carbonate (44.5 mg, 0.322 mmol) and 3-(chloromethyl)-2-methoxypyridine (33.0 mg, 0.209 mmol) were added, then the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. The residue obtained by concentrating the solvent was purified by silica gel column chromatography (chloroform/methanol) to give Compound 24 (58.0 mg, 0.134 mmol, yield 83%).
LC/MS (ESI): m/z=432, RT=2.45 min, LC/MS measurement conditions 1
Compound 24 (55.0 mg, 0.127 mmol), chlorotrimethylsilane (41.6 mg, 0.382 mmol), sodium iodide (57.3 mg, 0.382 mmol), and acetonitrile (2.2 ml) were mixed, and the mixture was stirred at 70° C. for 2 hours. The reaction solution was cooled to room temperature, an aqueous sodium thiosulfate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the residue obtained by concentrating the solvent was purified by silica gel column chromatography (ethyl acetate/methanol) to give Compound (I-0325) (12.0 mg, 0.0290 mmol, yield 23%).
LC/MS (ESI): m/z=418, RT=1.84 min, LC/MS measurement conditions 1
1H-NMR (CDCl3) δ: 11.41 (s, 1H), 7.26-7.19 (m, 2H), 6.83 (t, J=6.9 Hz, 2H), 6.20 (t, J=6.7 Hz, 1H), 5.13 (s, 2H), 5.06 (s, 2H), 2.43 (m, 4H), 1.76 (m, 2H), 1.66 (m, 2H).
Compound 25 (24.0 g, 71.4 mmol, yield 77%) was obtained in the same manner as Step 1 of Example 1.
Compound 26 (20.0 g, 55.2 mmol, yield 77%) was obtained in the same manner as Step 2 of Example 1.
Compound 27 (19.4 g, 38.1 mmol, yield 93%) was obtained in the same manner as Step 4 of Example 1.
Compound 27 (30.0 mg, 0.0590 mmol), 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid (1R,4R)-TERT-butyl hydrochloride (24.0 mg, 0.119 mmol), DMF (0.30 ml), cesium carbonate (57.9 mg, 0.178 mmol), and RuPhos Pd G3 (4.96 mg, 0.00593 mmol) were mixed, and the mixture was stirred at 100° C. for 18 hours. The reaction solution was cooled to room temperature, chloroform and water were added, and the mixture was separated. The aqueous layer was extracted with chloroform, and the combined organic layers were concentrated. The obtained residue was purified by PLCMS to obtain Compound 28 (34.4 mg, 0.0552 mmol, yield 94%).
LC/MS (ESI): m/z=624, RT=2.79 min, LC/MS measurement conditions 1
Compound (I-0140) (8.10 mg, 0.0159 mmol, 29% yield) was obtained in the same manner as Step 3 in Example 5.
LC/MS (ESI): m/z=512, RT=1.41 min, LC/MS measurement conditions 1
1H-NMR (CDCl3) δ: 11.6 (s, 1H), 8.62 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.28 (d, J=6.4 Hz, 1H), 6.99 (d, J=4.8 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 6.16 (s, 1H), 6.10 (dd, J=6.8 Hz, 1H), 5.41-5.31 (m, 2H), 4.90 (s, 2H), 4.78 (s, 1H), 4.50 (s, 1H), 3.63 (d, J=9.2 Hz, 1H), 3.27-3.16 (m, 4H), 2.97 (d, J=10.4 Hz, 1H), 2.15 (d, J=11.2 Hz, 1H), 1.95 (d, J=10.8 Hz, 1H).
Compound 11 (5.00 g, 23.1 mmol) was dissolved in 1,4 dioxane (25 mL), and potassium phosphate (14.7 g, 69.2 mmol), 1,2-difluoro-4-iodobenzene (8.31 g, 34.6 mmol), trans-N,N-dimethylcyclohexane-1,2-diamine (1.31 g, 9.23 mmol), and copper (I) iodide (1.76 g, 9.23 mmol) were added thereto. The reaction solution was stirred at 110° C. for 7 hours under a nitrogen atmosphere. The reaction solution was cooled, diluted by adding chloroform, and then filtered through Celite (registered trademark). The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give Compound 29 (3.04 g, 9.25 mol, yield 40%).
LC/MS (ESI): m/z=329, RT=2.74 min, LC/MS measurement conditions 1
Compound 29 (3.04 g, 9.25 mmol) was dissolved in methanol (15 mL) and tetrahydrofuran (15 mL), and a 2 mol/L aqueous sodium hydroxide solution (23.1 mL, 46.2 mmol) was added, then the mixture was stirred at 60° C. for 1 hour. After cooled to room temperature, the mixture was neutralized with 2 mol/L hydrochloric acid. The precipitated solid was collected by filtration and washed with water to give Compound 30 (2.53 g, 8.04 mmol, yield 87%).
LC/MS (ESI): m/z=315, RT=2.42 min, LC/MS measurement conditions 1
Compound 30 (1.10 g, 3.50 mmol) was dissolved in DMF (11 mL), and 7-fluoroimidazo[1,2-a]pyridine-3-amine (634 mg, 4.19 mmol), PyBOP (2.37 g, 4.54 mmol), and diisopropylethylamine (1.53 mL, 8.74 mmol) were added, then the mixture was stirred at room temperature for 3 hours. Water (50 mL) was added to the reaction solution, the mixture was separated, and the aqueous layer was extracted with ethyl acetate. After the organic layer was washed with water, it was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give Compound 31 (1.20 g, 2.68 mmol, yield 77%). LC/MS (ESI): m/z=448, RT=2.23 min, LC/MS measurement conditions 1
Compound 31 (1.20 g, 2.68 mmol), 1,3,5-trifluoro-2-nitrobenzene (949 mg, 5.36 mmol), and CDI (1.74 g, 10.7 mmol) were dissolved in DMA (24 mL), and 60% sodium hydride (322 mg, 8.04 mmol) was added thereto at 0° C., then the mixture was stirred at the same temperature for 30 minutes. The reaction solution was added to a mixed liquid of water (50 mL) and 2 mol/L hydrochloric acid (2 mL), and the mixture was extracted with ethyl acetate. After the organic layer was washed with water, it was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by amino column chromatography (n-hexane/ethyl acetate) to give Compound (I-1065) (283 mg, 0.597 mmol, yield 22%).
LC/MS (ESI): m/z=474, RT=1.91 min, LC/MS measurement conditions 1
Compound (I-1065) (47.0 mg, 0.0990 mmol), (1S,4S)-2-oxa-5-azabicyclo[2,2,1]heptane hydrochloride (14.8 mg, 0.109 mmol) and diisopropylethylamine (0.0518 mL, 0.298 mmol) were dissolved in DMA (0.47 mL), and the mixture was stirred at 110° C. for 2 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. After the organic layer was washed with water, it was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give Compound (I-0978) (27.0 mg, 0.0500 mmol, yield 51%).
LC/MS (ESI): m/z=537, RT=1.75 min, LC/MS measurement conditions 1
1H-NMR (CDCl3) δ: 7.69 (m, 1H), 7.64 (d, J=2.5 Hz, 1H), 7.43-7.12 (m, 511), 6.72 (m, 1H), 4.80 (m, 1H), 4.69 (s, 1H), 4.03 (s, 311), 3.90-3.80 (m, 211), 3.28-3.04 (m, 211), 2.02-1.88 (m, 2H).
Compound (I-0957) was synthesized in the same manner as in Example 7.
LC/MS (ESI): m/z=509, RT=1.96 min, LC/MS measurement conditions 1
1H-NMR (CDCl3) δ: 8.86 (d, J=1.9 Hz, 1H), 8.77 (d, J=2.3 Hz, 1H), 7.97 (t, J=2.1 Hz, 1H), 7.46 (d, J=6.3 Hz, 1H), 7.35 (t, J=8.5 Hz, 1H), 7.26 (m, 2H), 4.84 (br s, 1H), 4.60 (br s, 1H), 4.05 (s, 3H), 3.91-3.00 (m, 4H), 2.08 (m, 2H).
The following compounds were synthesized according to the above general synthesis method and the method described in Examples. The structure and physical properties (LC/MS data) are shown in the tables below.
In the structural formula, the “wedge shape” and “dashed line” indicate the steric configuration.
Incidentally, Compounds (I-0543), (I-0544) and (I-0545) shown below are reference examples.
Biological Test Examples for the compounds of the present invention will be described below.
The compound represented by Formula (I) according to the present invention may have coronavirus 3CL protease inhibitory action and may inhibit coronavirus 3CL protease.
Specifically, in the evaluation method described below, the IC50 is preferably 50 μM or less, more preferably 1 μM or less, and even more preferably 100 nM or less.
The sample to be tested is diluted in advance to an appropriate concentration with DMSO, and a 2- to 5-fold series of serial dilutions is prepared and then dispensed into a 384-well plate.
VeroE6/TMPRSS2 cells (JCRB1819, 5×103 cells/well) and SARS-CoV-2 (100 TCID50/well) are mixed in a medium (MEM, 2% FBS, penicillin-streptomycin), the mixture is dispensed into the wells in which the sample to be tested has been introduced, and then the cells are cultured for 3 days in a CO2 incubator.
The plate that has been cultured for 3 days is returned to room temperature, subsequently CellTiter-Glo (registered trademark) 2.0 is dispensed into each well, and the plate is mixed using a plate mixer. The plate is left to stand for a certain time, and then the luminescence signals (Lum) is measured with a plate reader.
When x denotes the logarithmic value of the compound concentration and y denotes % Efficacy, the inhibition curve is approximated by the following Logistic regression equation, and the value of x when y=50(%) is inputted is calculated as EC50.
The compounds of the present invention were tested essentially as described above. The results are shown in the tables below.
Meanwhile, regarding the EC5o value, a value of less than 1 μM is denoted by “A”, and a value of 1 μM or more and less than 10 μM is denoted by “B”.
The sample to be tested is diluted in advance to an appropriate concentration with DMSO, and a 2- to 5-fold series of serial dilutions is prepared and then dispensed into a 384-well plate.
HEK293T/ACE2-TMPRSS2 cells (GCP-SL222, 5×103 cells/well) and SARS-CoV-2 (200-300 TCID50/well) are mixed in a medium (MEM, 2% FBS, penicillin-streptomycin), the mixture is dispensed into the wells in which the sample to be tested has been introduced, and then the cells are cultured for 3 days in a CO2 incubator.
The plate that has been cultured for 3 days is returned to room temperature, subsequently CellTiter-Glo (registered trademark) 2.0 is dispensed into each well, and the plate is mixed using a plate mixer. The plate is left to stand for a certain time, and then the luminescence signals (Lum) is measured with a plate reader.
When x denotes the logarithmic value of the compound concentration and y denotes % Efficacy, the inhibition curve is approximated by the following Logistic regression equation, and the value of x when y=50(%) is inputted is calculated as EC50.
The compounds of the present invention were tested essentially as described above. The results are shown in the tables below.
Meanwhile, regarding the EC5o value, a value of less than 0.1 μM is denoted by “A”, a value of 0.1 μM or more and less than 1 μM is denoted by “B”, and a value of 1 μM or more and less than 10 μM is denoted by “C”.
Dabcyl-Lys-Thr-Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe-Arg-Lys-Met-Glu(Edans)-NH2 (SEQ ID NO: 1)
Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6, 15N)-Gln (SEQ ID NO: 2)
Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6, 15N)-Gln can be synthesized with reference to documents (Atherton, E.; Sheppard, R. C., “In Solid Phase Peptide Synthesis, A Practical Approach”, IRL Press at Oxford University Pres, 1989.; Bioorg. Med. Chem., Vol. 5, No. 9, 1997, pp. 1883-1891; and the like). An example will be shown below.
H-Lys-Thr-Ser-Ala-Val-Leu(13C6, 15N)-Glu(resin)-OaOtBu (the Lys-side chain is Boc-protected, the Thr-side chain is protected with a tert-butyl group, the Ser-side chain is protected with a tert-butyl group, the C-terminal OH of Glu is protected with a tert-butyl group, and the carboxylic acid of the Glu-side chain is condensed into the resin) is synthesized by Fmoc solid-phase synthesis using a Rink amide resin. Regarding the modification of the N-terminal Dabcyl group, 4-dimethylaminoazobenzene-4′-carboxylic acid (Dabcyl-OH) is condensed on the resin using EDC/HOBT. Final deprotection and cleavage from the resin are carried out by treatment with TFA/EDT=95:5. Thereafter, purification is performed by reverse phase HPLC.
In the present test, an assay buffer composed of 20 mM Tris-HCl, 100 mM sodium chloride, 1 mM EDTA, 10 mM DTT, and 0.01% BSA is used. For a compound with an IC50 of 10 nM or less, an assay buffer composed of 20 mM Tris-HCl, 1 mM EDTA, 10 mM DTT, and 0.01% BSA is used.
The sample to be tested is diluted in advance to an appropriate concentration with DMSO, and a 2- to 5-fold series of serial dilutions is prepared and then dispensed into a 384-well plate.
To a prepared compound plate, 8 μM substrate, and a 6 or 0.6 nM enzyme solution are added, and incubation is carried out for 3 to 5 hours at room temperature. Thereafter, a reaction stopping solution (0.067 μM Internal Standard, 0.1% formic acid, and 10% or 25% acetonitrile) is added to stop the enzymatic reaction.
The plate in which the reaction has been completed is measured using Rapid Fire System 360 and a mass analyzer (Agilent, 6550 iFunnel Q-TOF), or Rapid Fire System 365 and a mass analyzer (Agilent, 6495C Triple Quadrupole). Solution A (75% isopropanol, 15% acetonitrile, 5 mM ammonium formate) and solution B (0.01% trifluoroacetic acid, 0.09% formic acid) are used as a mobile phase at the measurement.
The reaction product detected by the mass analyzer is calculated using RapidFire Integrator or an equivalent program capable of analysis and is taken as Product area value. Furthermore, the Internal Standard that has been detected at the same time is also calculated and is designated as Internal Standard area value.
The area values obtained in the previous items are calculated by the following formula, and P/IS is calculated.
P/IS=Product area value/Internal Standard area value
When x denotes the logarithmic value of the compound concentration and y denotes % Inhibition, the inhibition curve is approximated by the following Logistic regression equation, and the value of x obtainable when y=50(%) is inputted is calculated as IC50.
The compounds of the present invention were tested essentially as described above. The results are shown in the tables below.
Incidentally, regarding the IC50 value, a value of less than 0.1 μM is denoted by “A”, a value of 0.1 μM or more and less than 1 μM is denoted by “B”, and a value of 1 μM or more and less than 10 μM is denoted by “C”.
The degrees at which the amounts of respective metabolites produced are inhibited by the compound of the present invention are evaluated in commercially available pooled human liver microsomes by using the O-deethylation of 7-ethoxyresorufin (CYP1A2), the methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), the O-demethylation of dextromethorphan (CYP2D6), and the hydroxylation of terfenadine (CYP3A4), which are the typical substrate metabolism reactions of five human major CYP5 molecular species (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), as indexes.
The reaction conditions were as follows: substrate, 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; concentrations of the compound of the present invention, 1, 5, 10, and 20 μmol/L (4 points).
Each of the five substrates, the human liver microsomes, and the compound of the present invention are added according to the recipe described above into a 50 mmol/L HEPES buffer solution in a 96-well plate, and a coenzyme NADPH is added thereto to start the metabolism reactions serving as indexes. After reaction at 37° C. for 15 minutes, the reaction is terminated by the addition of a solution of methanol/acetonitrile=1/1 (V/V). After the centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant is quantified by a fluorescent multilabel counter or LC/MS/MS and hydroxytolbutamide (CYP2C9 metabolite), 4′ hydroxymephenytoin (CYP2C19 metabolite), dextromethorphan (CYP2D6 metabolite), and terfenadine alcohol metabolite (CYP3A4 metabolite) are quantified by LC/MS/MS. The dilution concentration or the dilution solvent are changed as necessary.
Only a solvent DMSO used for dissolving the compound is added to the reaction solution instead of the compound of the present invention, and the mixture is used as a control (100%). Remaining activity (%) is calculated, and IC50 is calculated by inverse estimation based on a logistic model using the concentrations and the rates of suppression.
The compounds of the present invention were tested essentially as described above.
This test as to the inhibition of CYP3A4 by the compound of the present invention is to evaluate mechanism based inhibition (MBI) ability from enhancement in inhibitory effect, caused by a metabolism reaction, of the compound of the present invention. The inhibition of CYP3A4 is evaluated in pooled human liver microsomes by using the 1-hydroxylation reaction of midazolam (MDZ) as an index.
Reaction conditions are as follows: substrate, 10 μmol/L MDZ; prereaction time, 0 or 30 minutes; substrate metabolism reaction time, 2 minutes; reaction temperature, 37° C.; pooled human liver microsomes, 0.5 mg/mL for the prereaction, and 0.05 mg/mL (10-fold dilution) for the reaction; concentrations of the compound of the present invention for the prereaction, 1, 5, 10, and 20 μmol/L (4 points) or 0.83, 5, 10, and 20 μmol/L (4 points).
The pooled human liver microsomes and a solution of the compound of the present invention are added according to the recipe of the prereaction described above into a K-Pi buffer solution (pH 7.4) as a pre-reaction solution in a 96-well plate. A portion thereof is transferred to another 96-well plate so as to be diluted by 1/10 with a K-Pi buffer solution containing the substrate. A coenzyme NADPH is added thereto to start the reaction serving as an index (0-min preincubation). After reaction for a given time, the reaction is terminated by the addition of a solution of methanol/acetonitrile=1/1 (V/V). NADPH is also added to the remaining pre-reaction solution to start prereaction (30-min preincubation). After prereaction for a given time, a portion thereof is transferred to another plate so as to be diluted by 1/10 with a K-Pi buffer solution containing the substrate, to start the reaction serving as an index. After reaction for a given time, the reaction is terminated by the addition of a solution of methanol/acetonitrile=1/1 (V/V). Each plate where the index reaction has been performed is centrifuged at 3000 rpm for 15 minutes. Then, midazolam 1-hydroxide in the centrifugation supernatants is quantified by LC/MS/MS. The dilution concentration or the dilution solvent are changed as necessary.
Only a solvent DMSO used for dissolving the compound is added to the reaction solution instead of the compound of the present invention, and the mixture is used as a control (100%). Remaining activity (%) at the time of the addition of the compound of the present invention at each concentration is calculated, and IC is calculated by inverse estimation based on a logistic model using the concentrations and the rates of suppression. Shifted IC value is calculated as “IC of preincubation at 0 min/IC of preincubation at 30 min”. When a shifted IC is 1.5 or more, this is defined as positive. When a shifted IC is 1.0 or less, this is defined as negative.
The compounds of the present invention were tested essentially as described above.
Materials and methods for experiments to evaluate oral absorption
The dilution concentration or the dilution solvent are changed as necessary.
The compounds of the present invention were tested essentially as described above.
The compounds of the present invention were tested essentially as described above.
Using pooled human liver microsomes or pooled rat liver microsomes, a compound of the present invention is reacted for a constant time, and a remaining rate is calculated by comparing a reacted sample and an unreacted sample, thereby, a degree of metabolism in liver is assessed.
A reaction is performed (oxidative reaction) at 37° C. for 0 minute or 30 minutes in the presence of 1 mmol/L NADPH in 0.2 mL of a buffer (50 mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/L magnesium chloride) containing 0.5 mg protein/mL of human or rat liver microsomes. After the reaction, 50 μL of the reaction solution is added to 100 μL of a methanol/acetonitrile=1/1 (v/v), mixed and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the centrifuged supernatant is quantified by LC/MS/MS or solid-phase extraction (SPE)/MS. The ratio of the amount of the compound after the reaction, with respect to the amount of the compound at 0 minutes of the reaction defined as 100%, is shown as the residual rate. Hydrolysis reaction is performed in the absence of NADPH, and glucuronidation reaction is performed in the presence of 5 mmol/L UDP-glucuronic acid instead of NADPH. Then, the same operation is carried out. The dilution concentration or the dilution solvent are changed as necessary.
The compounds of the present invention were tested essentially as described above.
The solubility of the compound of the present invention is determined under 1% DMSO addition conditions. 10 mmol/L solution of the compound is prepared with DMSO. 2 μL of the solution of the compound of the present invention is added to 198 μL each of a JP-1 fluid and a JP-2 fluid. The mixture is shaken for 1 hour or more at a room temperature, and the mixture is filtered. The filtrate is ten-fold diluted with methanol/water=1/1 (V/V), and the compound concentration in the filtrate is measured with LC/MS/MS or Solid-Phase Extraction (SPE)/MS by the absolute calibration method. The dilution concentration or the dilution solvent are changed as necessary.
The recipe of the JP-1 fluid is as follows.
Water is added to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to bring the amount to 1000 mL.
The recipe of the JP-2 fluid is as follows.
3.40 g of potassium dihydrogen phosphate and 3.55 g of dibasic sodium phosphate anhydrous are dissolved in water to bring the amount to 1000 mL, and to 1 volume of the resultant, 1 volume of water is added.
The compounds of the present invention were tested essentially as described above.
The preparation examples shown below are only for illustrative purposes and are by no means intended to limit the scope of the invention.
The compound of the present invention can be administered as a pharmaceutical composition by any conventional route, particularly enterally, for example, orally, for example, in the form of a tablet or a capsule; parenterally, for example, in the form of an injectable preparation or a suspension; and topically, for example, in the form of a lotion, a gel, an ointment or a cream, or as a pharmaceutical composition in a transnasal form or a suppository form. A pharmaceutical composition comprising the compound of the present invention in a free form or in the form of a pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier or diluent can be produced by a mixing, granulating, or coating method in a conventional manner. For example, the oral composition can be a tablet, a granular preparation, or a capsule, each containing an excipient, a disintegrating agent, a binder, a lubricating agent, and the like, as well as an active ingredient and the like. Furthermore, the composition for injection can be prepared as a solution or a suspension, may be sterilized, and may contain a preservative, a stabilizer, a buffering agent, and the like.
The compound according to the present invention has coronavirus 3CL protease inhibitory activity, and it is considered that the compound is useful as a therapeutic agent and/or a prophylactic agent for a disease or a condition associated with coronavirus 3CL proteases.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2021-152086 | Sep 2021 | JP | national |
| 2021-191637 | Nov 2021 | JP | national |
| 2022-093120 | Jun 2022 | JP | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/JP2022/034552 | 9/15/2022 | WO |
