JP2013107869A - Indolequinoline derivative, process for production of the same, and antimalarial agent and anticancer agent including the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound capable of becoming an effective component of an antimalarial agent with a high antimalarial activity and high safety (particularly effective also against chloroquine resistant malaria protozoa), and capable of becoming an effective component of an anticancer agent with high antitumor activity and low toxicity to normal cells.SOLUTION: There is provided an indolequinoline derivative (A) shown by formula (A) or a pharmaceutically allowable salt thereof.

Description

  The present invention relates to an indolequinoline derivative, a method for producing the derivative, and an antimalarial agent and an anticancer agent containing the derivative.

  Malaria is a contagious disease caused by infection with a protozoa belonging to the genus Plasmodium, which is transmitted through an anemone mosquito, and exhibits symptoms such as intermittent heat stroke, anemia, and splenomegaly. In recent years, malaria has begun to intensify with changes in nature and the environment. Its estimated number of infected patients is 300 to 500 million per year and the number of deaths per year is 1.5 to 3 million. It is a disease. Among the malaria parasites that infect humans, P. falciparum, distributed throughout the tropical regions of Africa, Asia, and Latin America, shows severe symptoms. It often progresses to severe malaria with symptoms such as hemorrhage, hemolytic anemia, pulmonary edema, heart failure, severe enterocolitis, etc., often showing multiple organ failure within a short period of time and causing the host to die.

  Mefloquine, chloroquine, and quinine are used for malaria treatment, but all of them may have strong side effects and should be noted. In addition, the emergence of malaria parasites that are resistant to chloroquine and other general-purpose drugs, which have been regarded as specific medicines, is a major reason for the spread of tropical malaria parasite infection, making it impossible to eradicate malaria. It's getting on. For example, chloroquine-resistant P. falciparum first appeared and expanded in Colombia and Thailand. In 1984, it expanded to 15 countries in East Asia and Oceania, 15 countries in South America, and 15 countries in sub-Saharan Africa. Mefloquine is used to prevent malaria and treat chloroquine-resistant P. falciparum malaria, but with the expansion of mefloquine-resistant malaria parasites, the effect of mefloquine has decreased (so other anti-artemisinins such as May be used in combination with malaria).

アルテミシニン等のペルオキシ環状化合物もマラリアに有効であり、特に、キク科植物から単離されるトリオキサン構造を持つアルテミシニンが治療薬として使われていた。しかしながら、アルテミシニン等に対しても耐性を示すマラリア原虫がすでに現れており、新規なマラリア剤に対して次々に耐性を有するマラリア原虫が出現し、薬剤耐性マラリア原虫の拡散が化学療法の問題となっている。薬剤耐性マラリアに唯一有効な薬剤としてキニーネが存在するが、腎不全を引き起こす可能性が極めて高く、現在の医療水準から見てリスクの高い治療薬である。

Peroxycyclic compounds such as artemisinin are also effective against malaria, and in particular, artemisinin having a trioxane structure isolated from Asteraceae has been used as a therapeutic agent. However, malaria parasites that are resistant to artemisinin and the like have already appeared, and malaria parasites that are resistant to new malaria agents appear one after another, and diffusion of drug-resistant malaria parasites becomes a problem of chemotherapy. ing. Quinine exists as the only effective drug for drug-resistant malaria, but it is extremely likely to cause renal failure and is a high-risk therapeutic agent in view of current medical standards.

その他、マラリア剤としては、例えば特許文献１に記載されたアニリン化合物、特許文献２に記載されたには置換ナフトキノン化合物や、特許文献３に記載されたクロロキンに金属錯体であるメタロセン、グルコース等の糖を共役させた化合物、特許文献４に記載された有機ペルオキシド化合物が知られている。

In addition, examples of the malaria agent include aniline compounds described in Patent Document 1, substituted naphthoquinone compounds described in Patent Document 2, metallocenes that are metal complexes with chloroquine described in Patent Document 3, glucose, and the like. A compound in which a sugar is conjugated and an organic peroxide compound described in Patent Document 4 are known.

特許文献５には、癌症状を下げる効果のある医薬品とクロロキン、キニン、メフロキンとを併用すると、これらの抗マラリア剤に対するマラリア菌の抵抗性が低下することが記載されている。

Patent Document 5 describes that when a drug having an effect of lowering cancer symptoms and chloroquine, quinine, and mefloquine are used in combination, the resistance of malaria bacteria to these antimalarial agents decreases.

  Furthermore, 5-methyl-5H-indolo [2,3-b] quinoline (neocryptolepine), an alkaloid (indolequinoline) contained in the plant Cryptolepis sanguinolenta (Lindl.) That grows naturally in West and Central Africa, It is known that it exhibits antiprotozoal activity, antibacterial / antifungal activity, antimalarial activity and the like in spite of its relatively simple structure together with -5H-indolo [3,2-b] quinolepine.

一方、癌も全世界的な疾患である。世界における癌による死亡割合は、２００８年で循環器病、感染・寄生性疾患に次いで３位であるが、２０１５年には感染・寄生性疾患を抜いて２位になると予測されている。日本においても、癌は１９８１年に死因の１位になって以来、粗死亡率は更に増加しており、近年では全死亡数の３割を超えている。がんの主な種類は、肺、胃、肝臓、大腸、乳、子宮頚がんである。

On the other hand, cancer is a worldwide disease. The death rate from cancer in the world is the third highest after cardiovascular disease and infectious / parasitic diseases in 2008, but is predicted to be second in 2015 by overtaking infectious / parasitic diseases. Even in Japan, since cancer became the leading cause of death in 1981, the crude mortality rate has further increased, and in recent years it has exceeded 30% of all deaths. The main types of cancer are lung, stomach, liver, large intestine, breast, cervical cancer.

  Cancer treatment methods include chemotherapy, surgery (surgical treatment), radiation therapy, and other cancer treatments (also there are collective treatments combining these). New drug molecules for the treatment of cancer are being developed all over the world, but despite the intensive development efforts, the threat of malignant tumors continues and exists as a disease that cannot be completely treated forever. For some types of cancer, even modern treatments are surprisingly poor. That is, a new treatment method using a novel and selective anticancer agent is strongly desired. Our anti-cancer therapy aims to inhibit the growth and lead only to cancer cells without damaging normal cells.

Many compounds having applications as anticancer agents have been proposed, but the following compounds have been proposed as compounds having a condensed ring in the molecular structure.
Patent Document 6 describes that a condensed cyclic heterocyclic derivative represented by the following formula (a derivative having a carbazole ring as a basic skeleton) has antitumor activity.

特許文献７には、下記式で表される化合物（インドリル−３−グリオキシル酸誘導体）、たとえばN-（ピリジン-４-イル）-[1-(4-フルオロベンジル)−インドールー３−イル]グリオキシルアミド（D24241）が抗腫瘍活性を有することが記載されている。

Patent Document 7 discloses a compound represented by the following formula (indolyl-3-glyoxylic acid derivative) such as N- (pyridin-4-yl)-[1- (4-fluorobenzyl) -indol-3-yl] glyoxyl. Amide (D24241) has been described to have antitumor activity.

特許文献８では、下記式（R¹またはR² = -O-(CH₂)n-O-Su, H or alkyl; Su = carbohydrate group; n = 2-6）で表される構造を有する、5,11-ジメチル-5H-インドロ[2,3-b]キノリンおよび医薬品として許容できるその塩の抗がん活性が検討されている。たとえば、R¹ = O-(CH₂)₅-O-2-deoxy-α-L-daunosaminyl, R² = Hの化合物は、子宮頸癌細胞株に対してID₅₀ = 1.46μg/mLの細胞毒性を示す。

In Patent Document 8, a compound having a structure represented by the following formula (R ¹ or R ² = -O- (CH ₂ ) nO-Su, H or alkyl; Su = carbohydrate group; n = 2-6), The anticancer activity of 11-dimethyl-5H-indolo [2,3-b] quinoline and its pharmaceutically acceptable salts has been investigated. For example, a compound with R ¹ = O- (CH ₂ ) ₅ -O-2-deoxy-α-L-daunosaminyl, R ² = H is a cell with ID ₅₀ = 1.46 μg / mL against a cervical cancer cell line Toxic.

また、非特許文献１では、6,11-ジメチル-6H-インドロ[2,3-b]キノリン骨格上の２、９位にN,N-ジアルキルアミノアルキルアミノ基を導入した化合物VIIと置換基を導入していないDiMIQ(VIII)とのヒト頸癌細胞株（KB cell）に対する抗腫瘍活性の比較が検討されている。

In Non-Patent Document 1, Compound VII in which an N, N-dialkylaminoalkylamino group is introduced at the 2nd and 9th positions on the 6,11-dimethyl-6H-indolo [2,3-b] quinoline skeleton and a substituent Comparison of anti-tumor activity against human cervical cancer cell line (KB cell) with DiMIQ (VIII) that has not been introduced is considered.

さらに、非特許文献２には、5-メチル-5H-インドロ[2,3-b]キノリン構造に関して、適当な位置にアミノ基またはアミノアルキルアミノ基を導入すると、もとのneocryptolepine自体よりも、抗マラリア活性が約１,５００倍活性化できることが示されている。

Furthermore, in Non-Patent Document 2, when an amino group or an aminoalkylamino group is introduced at an appropriate position with respect to a 5-methyl-5H-indolo [2,3-b] quinoline structure, the original neocryptolepine itself, It has been shown that antimalarial activity can be activated about 1,500 times.

  However, for this 5-methyl-5H-indolo [2,3-b] quinoline mother nucleus, a systematic assay for substituent-activity-correlation was investigated in the development of new drug molecules for cancer treatment. There are few examples. Therefore, we started to synthesize novel indolequinoline derivatives as anticancer active agents.

U.S. Pat.No. 3,761,597 U.S. Pat.No. 5,684,035 US Patent Application Publication No. 2010/0216727 US Patent Application Publication No. 2005/0131058 U.S. Pat.No. 4,897,403 Japanese Patent Laid-Open No. 9-194481 JP 2011-148809 A Polish Patent No. 202545

Godlewska, J .; Luniewski, W .; Zagrodzki, B .; Kaczmarek, L .; Bielawska-Pohl, A .; Dus, D .; Wietrzyk, J .; Opolski, A .; Siwko, M .; Jaromin, A .; Jakubiak, A .; Lozubek, A .; Peczynska-Czoch, W. Anticancer Res. 2005, 25, 2857-2868. El Sayed, I .; Van der Veken, P .; Steert, K .; Dhooghe, L .; Hostyn, S .; Van Baelen, G .; Lemiere, G .; UW Maes, B .; Cos, P .; Maes, L .; Joossens, J .; Haemers, A .; Pieters, L .; Augustyns; KJ Med. Chem., 2009, 52, 2979-2988.

  As mentioned above, the antimalarial activity is high (especially effective for chloroquine-resistant malaria parasites) and safety because of the emergence of malaria parasites that are successively resistant to conventional antimalarial agents. Development of high antimalarial agents is desired. Therefore, an object of the present invention in one aspect is to provide a compound that can be an active ingredient of such an antimalarial agent.

  In addition, development of anticancer agents having high antitumor activity and low toxicity to normal cells is also desired. Accordingly, another object of the present invention is to provide a compound that can be an active ingredient of such an anticancer agent.

  The present inventors have found that a specific derivative having an indolequinoline mother nucleus is a compound that can solve the above-mentioned problems, and have completed the present invention. That is, the present invention includes the following matters.

  [1] An indolequinoline derivative (A) represented by the following formula (A) or a pharmaceutically acceptable salt thereof:

（式（Ａ）中、
Ｒ¹はハロゲン原子、アルキル基、ヒドロキシ基、アルコキシ基、カルボキシ基、アルコキシカルボニル基またはニトロ基であり、ｎは０〜４の整数であり、
Ｒ²は下記式（Ｒ２）で表される基であり：

(In the formula (A),
R ¹ is a halogen atom, alkyl group, hydroxy group, alkoxy group, carboxy group, alkoxycarbonyl group or nitro group, n is an integer of 0 to 4,
R ² is a group represented by the following formula (R2):

式（Ｒ２）中、ｘは１または０であり、Ｚ¹、Ｚ²、およびＺ¹とＺ²の間の結合に係る一点鎖線は下記［Ｒ２−Ｉ］または［Ｒ２−ＩＩ］の通りである。

In the formula (R2), x is 1 or 0, and Z ¹ , Z ² , and an alternate long and short dash line relating to the bond between Z ¹ and Z ² are as shown in [R2-I] or [R2-II] below. is there.

[R2-I] Z ¹ and Z ² are not bonded by a one-dot chain line, Z ¹ is a hydrogen atom, Z ² has a group represented by the following formula (Z2) or a substituent. It may be an aryl group, an alkenyl group or an alkynyl group.

式（Ｚ２）中、Ｚ³は炭素原子数が１〜１２の直鎖状または分岐鎖状のアルキレン基であり、Ｚ⁴は置換基を有していてもよいアミノ基、置換基を有していてもよい含窒素ヘテロアリール基、またはヒドロキシ基である。

In formula (Z2), Z ³ is a linear or branched alkylene group having 1 to 12 carbon atoms, and Z ⁴ has an amino group which may have a substituent, or a substituent. A nitrogen-containing heteroaryl group or a hydroxy group.

[R2-II] Z ¹ and Z ² are bonded by a one-dot chain line, and together with the nitrogen atom to which they are bonded, an atomic group that forms an optionally substituted 3- to 8-membered ring structure Represents.

R ³ is a halogen atom, a carboxy group, or an alkoxycarbonyl group, m is an integer of 0 to 4,
R ⁴ , R ⁵ , broken line (i) and broken line (ii) are as defined in [R4-I] or [R4-II] below.

[R4-I] R ⁴ is absent, R ⁵ is an alkyl group, the broken line (i) is a double bond, broken line (ii) is a single bond.
[R4-II] R ⁴ is an alkyl group, R ⁵ is absent and the broken line (i) is a single bond, a broken line (ii) is a double bond.

[2] In the case where the definition of the formula (R2) is as defined in the above [R2-I], Z ⁴ in the formula (Z2) is a group represented by the following formula (Z4). Or indolequinoline derivative (A) or a pharmaceutically acceptable salt thereof.

式（Ｚ４）中、Ｚ⁵、Ｚ⁶、およびＺ⁵とＺ⁶の間の結合に係る一点鎖線は下記［Ｚ４−Ｉ］、［Ｚ４−ＩＩ］または［Ｚ４−ＩＩＩ］の通りである。

In formula (Z4), Z ⁵ , Z ⁶ , and the alternate long and short dash line relating to the bond between Z ⁵ and Z ⁶ are as shown in the following [Z4-I], [Z4-II] or [Z4-III].

[Z4-I] Z ⁵ and Z ⁶ do not have a single-dot chain bond, Z ⁵ is a hydrogen atom, Z ⁶ has an aryl group which may have a substituent, and a substituent. Or a group containing a heteroaryl group or an alkyl group.

[Z4-II] Z ⁵ and Z ⁶ are bonded by a one-dot chain line, and have an aryl group which may have a substituent together with the nitrogen atom to which they are bonded, as a substituent. The atomic group which forms a 5-membered ring structure or a 6-membered ring structure is represented.

[Z4-III] Z ⁵ and Z ⁶ do not have a single-dot bond, and Z ⁵ and Z ⁶ are alkyl groups independent of each other.
[3] The indolequinoline derivative according to [1], wherein, in the case where the definition of the formula (Z4) is as described in the above [Z4-I], the Z ⁶ is a group represented by the following formula (Z6) (A) or a pharmaceutically acceptable salt thereof.

式（Ｚ６）中、Ｚ⁷は下記式（Ｚ７１）、（Ｚ７２）、（Ｚ７３）または（Ｚ７４）で表される二価の基であり、Ｚ⁸は置換基を有していてもよいアリール基、置換基を有していてもよいヘテロアリール基、またはアルキル基である。）

In the formula (Z6), Z ⁷ is a divalent group represented by the following formula (Z71), (Z72), (Z73) or (Z74), and Z ⁸ is an aryl which may have a substituent. Group, a heteroaryl group which may have a substituent, or an alkyl group. )

〔４〕 前記Ｚ⁸が置換基を有していてもよいフェニル基、または置換基を有していてもよいピリジル基、チエニル基もしくはインドリル基である、〔３〕に記載のインドールキノリン誘導体（Ａ）またはその製薬学的に許容される塩。

[4] The indolequinoline derivative according to [3], wherein Z ⁸ is a phenyl group which may have a substituent, or a pyridyl group, a thienyl group or an indolyl group which may have a substituent ( A) or a pharmaceutically acceptable salt thereof.

  [5] In the case where the definition of the formula (Z4) is as described in the above [Z4-II], the 5-membered ring structure or the 6-membered ring structure is a group represented by the following formula (Z42). ] The indole quinoline derivative (A) or a pharmaceutically acceptable salt thereof.

式（Ｚ４２）中、Ｚ⁹は下記式（Ｚ９１）または（Ｚ９２）で表わされる二価の基であり、Ｚ¹⁰は置換基を有していてもよいアリール基である。

In formula (Z42), Z ⁹ is a divalent group represented by the following formula (Z91) or (Z92), and Z ¹⁰ is an aryl group which may have a substituent.

式（Ｚ９１）中、Ｒ⁹¹はそれぞれ独立して、水素原子、ハロゲン原子、アルキル基、アルコキシ基、カルボキシ基、またはアルコキシカルボニル基であり、ｐは１または２である。

In formula (Z91), each R ⁹¹ independently represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a carboxy group, or an alkoxycarbonyl group, and p is 1 or 2.

In the formula (Z92), R ⁹² represents a halogen atom, an alkyl group, a hydroxy group, an alkoxy group, a carboxy group, an alkoxycarbonyl group, or a nitro group, and q is an integer of 0 to 4.
[6] The indolequinoline derivative (A) or a pharmaceutically acceptable salt thereof according to [5], wherein Z ¹⁰ is a phenyl group which may have a substituent.

  [7] A method for producing an indolequinoline derivative (A) represented by the formula (A) or a pharmaceutically acceptable salt thereof, comprising the following step [1].

Process [1]
A step of reacting a compound having an indolequinoline mother nucleus structure represented by the following formula (A0) with an amine compound represented by the following formula (r2) to obtain a compound represented by the following formula (A1).

式（Ａ０）中、Ｒ¹、ｎ、Ｒ³、ｍ、Ｒ⁴、Ｒ⁵、ｉおよびｉｉは前記式（Ａ）と同義であり、Ｘはハロゲン原子または低級アシロキシ基である。

In the formula (A0), R ¹ , n, R ³ , m, R ⁴ , R ⁵ , i and ii are as defined in the formula (A), and X is a halogen atom or a lower acyloxy group.

式（ｒ２）中、Ｚ¹およびＺ²は前記式（Ｒ２）と同義である。

In formula (r2), Z ¹ and Z ² have the same meaning as in formula (R2).

式（Ａ１）中、Ｒ¹、ｎ、Ｒ³、ｍ、Ｒ⁴、Ｒ⁵、ｉおよびｉｉは前記式（Ａ０）と同義であり、Ｚ¹およびＺ²は前記式（ｒ２）と同義である。

In the formula (A1), R ¹ , n, R ³ , m, R ⁴ , R ⁵ , i and ii are as defined in the formula (A0), and Z ¹ and Z ² are as defined in the formula (r2). is there.

  [8] A method for producing an indolequinoline derivative (A) represented by the formula (A) or a pharmaceutically acceptable salt thereof, comprising the following step [1 ′].

Process [1 ']
Adding nitromethane to a compound having an indolequinoline mother nucleus structure represented by the following formula (A0) to obtain a compound represented by the following formula (A0 ′);
A step of obtaining a compound represented by the following formula (A0 ″) from the compound represented by the following formula (A0 ′) by performing Nef reaction under oxidative conditions, and represented by the following formula (A0 ″): A step of obtaining a compound represented by the following formula (A1 ′) from the compound obtained by reductive amination using an amine compound represented by the following formula (r2).

式（Ａ０）中、Ｒ¹、ｎ、Ｒ³、ｍ、Ｒ⁴、Ｒ⁵、ｉおよびｉｉは前記式（Ａ）と同義であり、Ｘはハロゲン原子または低級アシロキシ基である。

In the formula (A0), R ¹ , n, R ³ , m, R ⁴ , R ⁵ , i and ii are as defined in the formula (A), and X is a halogen atom or a lower acyloxy group.

In the formulas (A0 ′) and (A0 ″), R ¹ , n, R ³ , m, R ⁴ , R ⁵ , i and ii are as defined in the formula (A).
In formula (r2), Z ¹ and Z ² have the same meaning as in formula (R2).

In the formula (A1 ′), R ¹ , n, R ³ , m, R ⁴ , R ⁵ , i and ii have the same meaning as the formula (A0), and Z ¹ and Z ² have the same meaning as the formula (r2). It is.
[9] A production method for producing a compound represented by the following formula (A11) as the indolequinoline derivative (A),
The step [1] or [1 ′] is a step of obtaining a compound represented by the following formula (A10) by using a compound represented by the following formula (r21) as the amine compound (r2),
The manufacturing method according to [7] or [8], which includes the following step [2] after the step [1].

式（Ａ１１）中、Ｒ¹、ｎ、ｘ、Ｒ³、ｍ、Ｒ⁴、Ｒ⁵、ｉおよびｉｉは前記式（Ａ）と同義であり、Ｚ³は前記式（Ｚ２）と同義であり、Ｚ⁵およびＺ⁶は、前記［Ｚ４−ＩＩＩ］をとらないことを除き、前記式（Ｚ４）と同義である。

In formula (A11), R ¹ , n, x, R ³ , m, R ⁴ , R ⁵ , i and ii are as defined above for formula (A), and Z ³ is as defined above for formula (Z2). , Z ⁵ and Z ⁶ have the same meanings as those in the formula (Z4) except that the above [Z4-III] is not taken.

式（ｒ２１）中、Ｚ³は前記式（Ｚ２）と同義である。

In formula (r21), Z ³ has the same meaning as in formula (Z2).

式（Ａ１０）中、Ｒ¹、ｎ、ｘ、Ｒ³、ｍ、Ｒ⁴、Ｒ⁵、ｉおよびｉｉは前記式（Ａ）と同義であり、Ｚ³は前記式（Ｚ２）と同義である。

In formula (A10), R ¹ , n, x, R ³ , m, R ⁴ , R ⁵ , i and ii are as defined above for formula (A), and Z ³ is as defined above for formula (Z2). .

Process [2]
A step of obtaining the compound (A11) by reacting the compound (A10) obtained in the step [1] with a compound (z4) capable of reacting with the terminal amino group of the compound (A10).

[10] A production method for producing a compound represented by the following formula (A111) as the indolequinoline derivative (A11),
In the step [2], the step [2] is a step of obtaining the compound (A111) by using a compound represented by any of the following formulas (z611) to (z614) as the compound (z4). The manufacturing method as described.

式（Ａ１１２）中、Ｒ¹、ｘ、ｎ、Ｒ³、ｍ、Ｒ⁴、Ｒ⁵、ｉおよびｉｉは前記式（Ａ）と同義であり、Ｚ³は前記式（Ｚ２）と同義であり、Ｚ⁷およびＺ⁸は前記式（Ｚ６）と同義である。

In formula (A112), R ¹ , x, n, R ³ , m, R ⁴ , R ⁵ , i and ii are as defined above for formula (A), and Z ³ is as defined above for formula (Z2). , Z ⁷ and Z ⁸ are as defined in the above formula (Z6).

式（ｚ６１１）〜（ｚ６１４）中、Ｚ⁸は前記式（Ｚ６）と同義であり、Ｘはハロゲン原子である。

In formulas (z611) to (z614), Z ⁸ has the same meaning as in formula (Z6), and X is a halogen atom.

[11] The production method according to [10], wherein Z ⁸ is a phenyl group which may have a substituent, or a pyridyl group, a thienyl group or an indolyl group which may have a substituent.

[12] A method for producing a compound represented by the following formula (A112) as the indolequinoline derivative (A11),
The step [2] uses, as the compound (z4), a compound represented by either the following formula (z91) or (z92) and a compound represented by the following formula (z10). The production method according to [9], which is a step of obtaining the compound (A112).

式（Ａ１１２）中、Ｒ¹、ｎ、ｘ、Ｒ³、ｍ、Ｒ⁴、Ｒ⁵、ｉおよびｉｉは前記式（Ａ）と同義であり、Ｚ³は前記式（Ｚ２）と同義であり、Ｚ⁹およびＺ¹⁰は前記式（Ｚ４２）と同義である。

In formula (A112), R ¹ , n, x, R ³ , m, R ⁴ , R ⁵ , i and ii are as defined above for formula (A), and Z ³ is as defined above for formula (Z2). , Z ⁹ and Z ¹⁰ are as defined in the above formula (Z42).

式（ｚ９１）中、Ｒ⁹¹およびｐは前記式（Ｚ９１）と同義である。

In the formula (z91), R ⁹¹ and p have the same meanings as the formula (Z91).

In the formula (z92), R ⁹² and q have the same meaning as in the formula (Z92).

式（ｚ１０）中、Ｚ¹⁰は前記式（Ｚ４２）と同義である。

In formula (z10), Z ¹⁰ has the same meaning as in formula (Z42).

[13] The production method according to [12], wherein Z ¹⁰ is a phenyl group which may have a substituent.
[14] An antimalarial agent comprising the indolequinoline derivative (A) or a pharmaceutically acceptable salt thereof according to any one of [1] to [6] as an active ingredient.

  [15] An anticancer agent comprising the indolequinoline derivative (A) or a pharmaceutically acceptable salt thereof according to any one of [1] to [6] as an active ingredient.

  The indole quinoline derivative of the present invention has high antimalarial activity against chloroquine-resistant malaria parasites and high antitumor activity against multiple types of cancer cells, while being toxic to normal cells. Since it is relatively low, it is excellent in usefulness as an active ingredient of antimalarial agents and anticancer agents (low toxicity to normal cells is only when the indolequinoline derivative of the present invention is used as an active ingredient of anticancer agents. It also provides high safety when used as an active ingredient of antimalarial agents). The indole quinoline derivative of the present invention has an indole quinoline mother nucleus and thus has high chemical stability. Further, since the indole quinoline mother nucleus is derived from a natural product, it can provide medicinal information on related compounds. Also have.

  The indolequinoline derivative of the present invention is considered to inhibit the process of hemoglobin being cleaved to form hemozoin from heme, and as a result, heme is increased, toxicity to parasites is induced, and antimalarial activity is exhibited. Indolequinoline derivatives are thought to exhibit anticancer activity by intercalating with DNA because the mother nucleus is a tetracyclic planar molecule, inhibiting the function of cleaving and recombining topoisomerase II DNA. .

  On the other hand, according to the method for producing an indolequinoline derivative of the present invention, a highly pure compound can be stably supplied. Further, since this production method is carried out from the viewpoint of diversity-oriented synthesis, it is suitably used for the synthesis of highly active compounds, particularly for chemical modification for improving antimalarial activity or antitumor activity. .

In the following description, the “compound represented by the formula (...)” may be expressed as “compound (...)”.
-Indolequinoline derivative (A) and its salt-
The indolequinoline derivative (A) is a compound having an indolequinoline mother nucleus composed of a ring a, a ring b, a ring c and a ring d represented by the following formula (A).

式（Ａ）中の定義は次の通りである。

The definition in Formula (A) is as follows.

R ¹ represents a halogen atom, an alkyl group, a hydroxy group, an alkoxy group, a carboxy group, an alkoxycarbonyl group or a nitro group.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and a chlorine atom and a bromine atom are preferable.

  The alkyl group may be linear or branched and has 1 to 10 carbon atoms, such as methyl, ethyl, propyl, iso-propyl (1-methylethyl), butyl, iso -Butyl group, sec-butyl group, tert-butyl group, pentyl group, iso-pentyl group, sec-pentyl group, hexyl group, heptyl group, octyl group, 2-ethylhexyl group, nonyl group, decyl group, etc. It is done. The alkyl group may have some or all of the hydrogen atoms replaced with halogen atoms. Examples of such a halogenated alkyl group include a trifluoromethyl group, a trichloromethyl group, a chloromethyl group, a dichloromethyl group, A fluoromethyl group, a difluoromethyl group, a pentafluoroethyl group, a 2,2,2-trifluoroethyl group, a 2,2,2-trichloroethyl group, a heptafluoroisopropyl group and the like can be mentioned. Of these alkyl groups, a methyl group and a trifluoromethyl group are preferred.

Examples of the alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, and a t-butoxy group.
Examples of the alkoxy moiety of the alkoxycarbonyl group include a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, and a t-butoxy group.

n represents an integer of 0 to 4. That is, ring a does not have a group represented by R ¹ (n = 0), and a hydrogen atom may be bonded to the carbon atom at positions 1 to 4 shown in Formula (A) ( That is, it may be unsubstituted) and may have a group represented by R ¹ at any one or a plurality of carbon atoms at positions 1 to 4 (n = 1 to 4). Among these, n is preferably 0 or 1, and when n is 1, the group represented by R ¹ is preferably bonded to any one of the carbon atoms at positions 1 to 4. More preferably, it is bonded to the carbon atom at the position. When there are a plurality of groups represented by R ¹ , these groups may be the same group or different groups.

R ² represents a group represented by the following formula (R2).

式（Ｒ２）中、ｘは１または０であり、Ｚ¹、Ｚ²、およびＺ¹とＺ²の間の結合に係る一点鎖線は下記［Ｒ２−Ｉ］または［Ｒ２−ＩＩ］の通りである。

In the formula (R2), x is 1 or 0, and Z ¹ , Z ² , and an alternate long and short dash line relating to the bond between Z ¹ and Z ² are as shown in [R2-I] or [R2-II] below. is there.

[R2-I]
There is no bond by a one-dot chain line between Z ¹ and Z ² , Z ¹ is a hydrogen atom, and Z ² is a group represented by the following formula (Z2) or an aryl which may have a substituent Group, alkenyl group or alkynyl group.

式（Ｚ２）中、Ｚ³は炭素原子数が１〜１２の直鎖状または分岐鎖状のアルキレン基であり、Ｚ⁴は置換基を有していてもよいアミノ基、置換基を有していてもよい含窒素ヘテロアリール基、またはヒドロキシ基である。

In formula (Z2), Z ³ is a linear or branched alkylene group having 1 to 12 carbon atoms, and Z ⁴ has an amino group which may have a substituent, or a substituent. A nitrogen-containing heteroaryl group or a hydroxy group.

Regarding the formula (R2), examples of the aryl group which may have a substituent of Z ² include a phenyl group which may have a substituent. The aryl group may have the same substituent as R ¹ as the substituent of ring a in formula (A), that is, a halogen atom, an alkyl group, a hydroxy group, an alkoxy group. Groups, carboxy groups, alkoxycarbonyl groups and nitro groups. Specific examples of the phenyl group having a substituent include p-chlorophenyl group, methylphenyl group (tolyl group), dimethylphenyl group (xylyl group), trimethylphenyl group, ethylphenyl group, diethylphenyl group, isopropylphenyl group, tert -Butylphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 3,4,5-trimethoxyphenyl group and the like can be mentioned.

Examples of the alkenyl group for Z ² include 2-propenyl group (allyl group), 2-butenyl group, 3-butenyl group, 2-methyl-2-propenyl group, and 1-methyl-2-propenyl group.

Examples of the alkynyl group for Z ² include a 2-propynyl group (propargyl group), a 2-butynyl group, and a 3-butynyl group.
On the other hand, with respect to the formula (Z2), the linear or branched alkylene group having 1 to 12 carbon atoms in Z ³ is a linear alkylene group (normal alkylene group) having 1 to 12 carbon atoms. It may be a branched alkylene group having 1 to 12 carbon atoms in total of the main chain and side chain (for example, methyl group). For example, methylene group, ethylene group, propane-1, A 3-diyl group, a butane-1,4-diyl group, and a pentane-2,5-diyl group may be mentioned.

Examples of the nitrogen-containing heteroaryl group which may have a substituent for Z ⁴ include a pyridyl group and an indolyl group which may have a substituent. In addition, as the substituent that the nitrogen-containing heteroaryl group may have, the same substituent as R 1 as the substituent of ring a in formula (A), that is, a halogen atom, an alkyl group, a hydroxy group , An alkoxy group, a carboxy group, an alkoxycarbonyl group, and a nitro group.
The amino group which may have a substituent of Z ⁴ will be described later separately.

[R2-II]
Z < ¹ > and Z < ² > are couple | bonded by the dashed-dotted line, and represent the atomic group which forms the 3-8 membered ring structure which may be united with the nitrogen atom to which they are couple | bonded, and may be substituted.

The optionally substituted 3- to 8-membered ring structure is formed from a nitrogen-containing cyclic compound such as morpholine (6-membered ring) or diazepine (7-membered ring) which may be substituted with a carbon atom or a heteroatom. Group. Moreover, as a substituent which the said 3-8 membered ring structure may have, the substituent similar to R < ¹ > as a substituent of the ring a in Formula (A), ie, a halogen atom, an alkyl group, Examples include a hydroxy group, an alkoxy group, a carboxy group, an alkoxycarbonyl group, and a nitro group.

R ³ represents a halogen atom, a carboxy group, or an alkoxycarbonyl group. Specific examples and preferred ranges of the halogen atom and alkoxycarbonyl group for R ³ are the same as those described for R ¹ .

m represents an integer of 0 to 4. That is, ring d does not have a group represented by R ³ (m = 0), and a hydrogen atom may be bonded to the carbon atom at positions 7 to 10 shown in Formula (A) ( In other words, it may be unsubstituted) and may have a group represented by R ³ at any one or more of the carbon atoms at positions 7 to 10 (m = 1 to 4). Among these, m is preferably 0 or 1, and when m is 1, the group represented by R ³ is preferably bonded to any of carbon atoms at positions 7 to 10, More preferably, it is bonded to the carbon atom at the position. When there are a plurality of groups represented by R ³ , these groups may be the same group or different groups.

R ⁴ , R ⁵ , broken line (i) and broken line (ii) are as defined in [R4-I] or [R4-II] below.
[R4-I] R ⁴ is absent, R ⁵ is an alkyl group, the broken line (i) is a double bond, broken line (ii) is a single bond. That is, the indolequinoline derivative (A) represents 5-methyl-5H-indolo [2,3-b] quinolines.

[R4-II] R ⁴ is an alkyl group, R ⁵ is absent and the broken line (i) is a single bond, a broken line (ii) is a double bond. That is, the indole quinoline derivative (A) represents 6-methyl-6H-indolo [2,3-b] quinolines.

  The formula (A) corresponding to each of the above [R4-I] and [R4-II] is specifically shown as follows.

Ｒ⁴およびＲ⁵のアルキル基の具体例および好ましい範囲は、Ｒ¹について説明したものと同じである。

Specific examples and preferred ranges of the alkyl group for R ⁴ and R ⁵ are the same as those described for R ¹ .

The amino group which may have the substituent of Z ⁴ described above may be an unsubstituted amino group (—NH ₂ ), or a non-substituted one in which one or two hydrogen atoms of the amino group are substituted. Although it may be a cyclic amino group or an optionally substituted cyclic amino group, for example, an amino group represented by the following formula (Z4) is suitable.

式（Ｚ４）中、Ｚ⁵、Ｚ⁶、およびＺ⁵とＺ⁶の間の結合に係る一点鎖線は下記［Ｚ４−Ｉ］、［Ｚ４−ＩＩ］または［Ｚ４−ＩＩＩ］の通りである。

In formula (Z4), Z ⁵ , Z ⁶ , and the alternate long and short dash line relating to the bond between Z ⁵ and Z ⁶ are as shown in the following [Z4-I], [Z4-II] or [Z4-III].

[Z4-I]
Z ⁵ and Z ⁶ are not bonded by a one-dot chain line, Z ⁵ is a hydrogen atom, Z ⁶ is an aryl group which may have a substituent, or a heteroaryl group which may have a substituent Or it is a group containing an alkyl group.

Examples of the aryl group which may have a substituent for Z ⁶ include a phenyl group and a naphthyl group which may have a substituent.
Examples of the heteroaryl group that may have a substituent for Z ⁶ include a pyridyl group, a thienyl group, and an indolyl group that may have a substituent.

As the substituent that the aryl group and heteroaryl group may have, the same halogen atom, alkyl group, hydroxy group, alkoxy group, carboxy group, alkoxycarbonyl group as R ¹ in formula (A), and A nitro group is mentioned.

Examples of the alkyl group for Z ⁶ include the same alkyl groups as those for R ¹ in formula (A).
The aryl group which may have the above-mentioned substituent, the heteroaryl group which may have a substituent or the group containing an alkyl group may be a group consisting only of these groups, Although the group which consists of group and another structure may be sufficient, the group represented by a following formula (Z6) is suitable, for example.

式（Ｚ６）中、Ｚ⁷は下記式（Ｚ７１）、（Ｚ７２）、（Ｚ７３）または（Ｚ７４）で表される二価の基である。式（Ｚ７１）および（Ｚ７２）で表される二価の基については、＊印がＺ⁸ではなくＮに結合していることが好ましい。

In the formula (Z6), Z ⁷ is a divalent group represented by the following formula (Z71), (Z72), (Z73) or (Z74). For the divalent groups represented by the formulas (Z71) and (Z72), it is preferable that the * mark is bonded to N instead of Z ⁸ .

Ｚ⁸は、置換基を有していてもよいアリール基、置換基を有していてもよいヘテロアリール基、またはアルキル基である。Ｚ⁸の置換基を有していてもよいアリール基、置換基を有していてもよいヘテロアリール基およびアルキル基としては、それぞれ、前記Ｚ⁶と同様の置換基を有していてもよいアリール基、置換基を有していてもよいヘテロアリール基およびアルキル基が挙げられる。

Z ⁸ is an aryl group which may have a substituent, a heteroaryl group which may have a substituent, or an alkyl group. The aryl group which may have a substituent of Z ^8, the heteroaryl group which may have a substituent and the alkyl group may each have the same substituent as Z ^6. Examples include an aryl group, a heteroaryl group which may have a substituent, and an alkyl group.

[Z4-II]
Z ⁵ and Z ⁶ are bonded by a one-dot chain line, and are combined with the nitrogen atom to which they are bonded, and have a 5-membered ring structure having an aryl group which may have a substituent as a substituent, or This represents an atomic group forming a 6-membered ring structure (ring e).

  As the 5-membered ring structure or 6-membered ring structure, for example, a group represented by the following formula (Z42) is preferable.

式（Ｚ４２）中、Ｚ⁹は下記式（Ｚ９１）または（Ｚ９２）で表わされる二価の基であり、Ｚ¹⁰は置換基を有していてもよいアリール基である。

In formula (Z42), Z ⁹ is a divalent group represented by the following formula (Z91) or (Z92), and Z ¹⁰ is an aryl group which may have a substituent.

式（Ｚ９１）中、Ｒ⁹¹はそれぞれ独立して、水素原子、あるいはハロゲン原子、アルキル基、アルコキシ基、カルボキシ基、またはアルコキシカルボニル基を表す。上記各置換基の具体例および好ましい範囲は、それぞれ、式（Ａ）中のＲ¹と同様のものが挙げられる。

In formula (Z91), each R ⁹¹ independently represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a carboxy group, or an alkoxycarbonyl group. Specific examples and preferred ranges of the respective substituents are the same as those for R ¹ in the formula (A).

p is 1 or 2.
Z ⁹ is represented by the formula (Z91), and when q = 1, the ring e is a 5-membered ring, Z ⁹ is represented by the formula (Z91), and when q = 2, or Z ⁹ is represented by the formula ( When represented by Z92), ring e is a 6-membered ring.

In the formula (Z92), R ⁹² represents a halogen atom, an alkyl group, a hydroxy group, an alkoxy group, a carboxy group, an alkoxycarbonyl group, or a nitro group. Specific examples and preferred ranges of the respective substituents are the same as those described for R ^{1 in the} formula (A).

q represents an integer of 0 to 4. That is, the phenylene group represented by the formula (Z92) does not have the group represented by R ⁹² (n = 0), and a hydrogen atom is bonded to the carbon atom at positions 1 ′ to 4 ′. (That is, it may be unsubstituted) and may have a group represented by R ⁹² at any one or more of the carbon atoms at positions 1 ′ to 4 ′ (n = 1 to 1). 4).

Moreover, as an aryl group which may have a substituent as a substituent of the 5-membered ring structure or the 6-membered ring structure corresponding to Z ¹⁰ , for example, an optionally substituted phenyl Group and naphthyl group.

Examples of the substituent that the aryl group may have include a halogen atom and an optionally substituted amino group.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and a chlorine atom and a bromine atom are preferable.

Examples of the optionally substituted amino group include an unsubstituted amino group (—NH ₂ ), for example, a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group, an n-butylamino group, tert-butylamino group, n-pentylamino group, n-hexylamino group, dimethylamino group, diethylamino group, di-n-propylamino group, di-n-butylamino group, di-n-pentylamino group, di- -N-hexylamino group, N-methyl-N-ethylamino group, N-ethyl-Nn-propylamino group, N-methyl-Nn-butylamino group, N-methyl-Nn-hexyl Although substituted amino groups, such as an amino group, are mentioned, An unsubstituted amino group is preferable.

Z ¹⁰ is preferably a phenyl group having a halogen atom or an optionally substituted amino group as a substituent. In this case, the substituent is preferably present in the para position with respect to the carbon atom bonded to ring e in Z ¹⁰ .

[Z4-III]
Binding by one-dot chain line of Z ⁵ and Z ⁶ is absent, Z ⁵ and Z ⁶ independently of one another alkyl group.

Examples of the alkyl group for Z ⁵ and Z ⁶ include the same alkyl groups as those for R ¹ in formula (A). Specific examples of the amino group of [Z4-III] having such an alkyl group include dimethylamino group, diethylamino group, di-n-propylamino group, di-n-butylamino group, di-n-pentylamino. Group, di-n-hexylamino group, N-methyl-N-ethylamino group, N-ethyl-Nn-propylamino group, N-methyl-Nn-butylamino group, N-methyl-N- Examples include n-hexylamino group.

The indolequinoline derivative (A) may form a salt, particularly a pharmaceutically acceptable salt. For example, the amino group of the indolequinoline derivative (A) may form an acid addition salt with an organic acid or inorganic acid, and may form a salt with a base depending on the type of substituent. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and examples of organic acids include acetic acid, succinic acid, citric acid, lactic acid, tartaric acid, p-toluenesulfonic acid, and 10-camphorsulfonic acid. Etc.
The structure of the indolequinoline derivative (A) can be identified by NMR measurement, elemental analysis, and molecular weight measurement.

-Method for producing indolequinoline derivative (A) and salts thereof-
The production method of the indolequinoline derivative (A) and the salt thereof of the present invention basically includes the following step [1] or [1 ′], depending on the substituent represented by R ² in the compound. Accordingly, the following step [2] is further included.

Step [1]: Step of Synthesizing Compound (A1) Step [1] is a reaction between a compound having an indolequinoline mother nucleus structure represented by the following formula (A0) and an amine compound represented by the following formula (r2). And obtaining a compound represented by the following formula (A1). By the above reaction, the halogen atom of the compound (A0) is substituted with the amino group in the amine compound (r2).

式（Ａ０）中、Ｒ¹、ｎ、Ｒ³、ｍ、Ｒ⁴、Ｒ⁵、ｉおよびｉｉは前記式（Ａ）と同義である。目的とするインドールキノリン誘導体（Ａ）に対応するこれらの置換基等を有する化合物（Ａ０）を選択すればよい。

In formula (A0), R ¹ , n, R ³ , m, R ⁴ , R ⁵ , i and ii have the same meanings as in formula (A). What is necessary is just to select the compound (A0) which has these substituents etc. corresponding to the target indolequinoline derivative (A).

  X represents a halogen atom or a lower acyloxy group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and a chlorine atom and a bromine atom are preferable. Examples of the lower acyloxy group include a C1-C8 saturated or unsaturated acyloxy group which may be substituted, specifically, an acetoxy group, a trichloroacetoxy group, a trifluoroacetoxy group, a propionyloxy group, and the like. An acetoxy group is preferred.

In formula (r2), Z ¹ and Z ² have the same meaning as in formula (R2). An amine compound (r2) having Z ¹ and Z ² corresponding to R ² of the desired indolequinoline derivative (A) may be selected.

In the formula (A1), R ¹ , n, R ³ , m, R ⁴ , R ⁵ , i and ii are as defined in the formula (A0), and Z ¹ and Z ² are as defined in the formula (R2). is there. These substituents and the like in the compound (A1) correspond to those of the compound (A0) and the compound (r2) used as raw materials.

As the amine compound (r2) in the step [1], those having Z ¹ and Z ² having the same meaning as Z ¹ and Z ² in the formula (R21) representing R ² in the formula (A) are basically used. be able to. In this case, the desired indolequinoline derivative (A) is synthesized in one step as the compound represented by the formula (A1) obtained by the step [1].

However, when the target indolequinoline derivative (A) is represented by the following formula (A11), that is, the definition of the formula (R2) representing R ² in the formula (A) is described later [R2-I]. (R ² represents —NH—Z ³ —Z ⁴ ), and the definition of the formula (Z4) representing Z ⁴ is as described below [Z4-I] or [Z4-II] ( Z ⁴ represents a mono-substituted amino group or a cyclic amino group, and is not a di-substituted (dialkyl) amino group), the amine compound (r2) in step [1] is used as the desired indolequinoline derivative (A). It is preferable to use an amine compound (r21) having an unsubstituted amino group at a position corresponding to Z ⁴ instead of the amine compound having Z ² containing the same Z ⁴ as. In the step [2] to be described later, the desired indolequinoline derivative (by the predetermined reaction) is converted into an unsubstituted amino group of the intermediate (compound (A111) described later) obtained in the step [1] by a predetermined reaction. A) Z ⁴ is introduced.

In addition to the above, as the amine compound (r2) used in this step [1], an intermediate is synthesized using a compound in which Z ¹ and / or Z ² is different from the desired indolequinoline derivative (A). It is also possible to modify the functional group through one or a plurality of steps, and finally synthesize the desired indolequinoline derivative (A). For example, after using an amine compound having an alkenyl group or an alkynyl group (that is, an unsaturated bond) as Z ² , the resulting compound can be reacted with another compound having an alkenyl or alkynyl group for re-modification. .

The same applies to the case of amination through the step [1 ′] described later.
In step [1], the reaction conditions are not particularly limited as long as the halogen atom represented by X or the lower acyloxy group of compound (A0) can be substituted with an amino group in amine compound (r2), but 1 mol of compound (A0) It is preferable to use 5 to 20 moles of the amine compound (r2). In addition, the reaction between the compound (A0) and the amine compound (r2) is performed in an organic solvent such as DMF in the presence of triethylamine or the like as necessary. The reaction temperature is usually 135 to 155 ° C., and the reaction time is usually 2 to 6 hours. The completion of the reaction can be confirmed, for example, by disappearance of the spot of compound (A0) in TLC (thin layer chromatography).

The compound (A1) obtained in the step [1] can be isolated and purified from the reaction mixture by separation means such as column chromatography and recrystallization.
Here, the method for synthesizing the compound (A0) used as a raw material in the step [1] is not particularly limited, and for example, it can be synthesized as follows.

First, in the compound (A0), the definitions of the substituents R ⁴ and R ⁵ and the broken lines (i) and (ii) are the above [R4-I], and the nitrogen atom of the ring b of the indolequinoline skeleton ( The following routes (a) to (c) are exemplified as a method for synthesizing a compound in which the 5-position) is alkylated.

  (Route (a))

ルート（ａ）では、まず、化合物（１）と化合物（２）とを共アミノ化させて化合物（３）を得る。

In route (a), first, compound (1) and compound (2) are coaminated to obtain compound (3).

In the compound (1), R ¹ , R ⁵ and n are as defined in the formula (A).
In the compound (2), R ²¹ represents an alkyl group. The alkyl group is not particularly limited as long as the reaction from the compound (3) to the compound (4) occurs, but a methyl group is preferable.

  In the co-amination step, the reaction conditions are not particularly limited as long as the reaction between the compound (1) and the compound (2) proceeds and the compound (3) is obtained, but the compound (2) is added per mole of the compound (1). It is preferable to use 1.5 to 3 mol. The reaction between compound (1) and compound (2) is usually carried out in a halogenated hydrocarbon solvent such as dichloromethane or chloroform, if necessary, such as N-chlorosuccinimide, 1,4-dimethylpiperazine or trichloroacetic acid. Done below. The reaction temperature is usually 0 to 5 ° C., and the reaction time is usually 2 to 6 hours.

Next, compound (3) is intramolecularly acylated to obtain compound (4).
In the intramolecular acylation step, the reaction conditions are not particularly limited as long as the reaction proceeds and the compound (4) is obtained, but the reaction is usually refluxed in an ether such as diphenyl ether, dioxane, tetrahydrofuran, tetrahydropyran, dimethoxyethane.

Finally, compound (4) is acyloxylated by dehydroxyhalogenation or enol acetylation to obtain compound (A0).
In the dehydroxylation halogenation step, the reaction conditions are not particularly limited as long as the reaction proceeds and the compound (A0) is obtained, but usually a halogenating reagent such as POCl _{3 in} an aromatic hydrocarbon solvent such as benzene, toluene and xylene. Reflux in the presence of. In the acyloxylation step by enol acetylation, heating is performed in the presence of an acid anhydride such as acetic anhydride under the above conditions.

The completion of the reaction in each of the above steps can be confirmed by disappearance of the starting compound in TLC.
In addition, the compound obtained in each of the above steps can be isolated and purified from the reaction mixture by separation means such as column chromatography and recrystallization.

  (Route (b))

ルート（ｂ）では、ルート（ａ）で用いる化合物（１）の代わりに化合物（１'）を用いて、共アミノ化工程（化合物（３'）の製造）、分子内アシル化工程（化合物（４'）の製造）および脱ヒドロキシルハロゲン化工程またはアシロキシ化工程（化合物（Ａ０'）の製造）を行う。化合物（１'）、（３'）、（４'）および（Ａ０'）におけるＲ¹、ｎは、化合物（１）〜（Ａ０）について説明したものと同じである。化合物（２）は、ルート（ａ）で説明した化合物（２）と同じである。

In route (b), using compound (1 ′) instead of compound (1) used in route (a), a co-amination step (production of compound (3 ′)), intramolecular acylation step (compound ( 4 ′) and dehydroxylation halogenation step or acyloxylation step (production of compound (A0 ′)). R ¹ and n in the compounds (1 ′), (3 ′), (4 ′) and (A0 ′) are the same as those described for the compounds (1) to (A0). Compound (2) is the same as compound (2) described in route (a).

Finally, compound (A0 ′) is alkylated to obtain compound (A0). This compound (A0) is the same as the compound (A0) described in the route (a).
In the alkylation step, the reaction conditions are not particularly limited as long as the reaction proceeds and the compound (A0) is obtained, but the reaction is usually refluxed in an ether such as dioxane, tetrahydrofuran or dimethoxyethane using alkyl iodide or the like.

  (Route (c))

ルート（ｃ）では、ルート（ｂ）と同様に共アミノ化工程（化合物（３'）の製造）および分子内アシル化工程（化合物（４'）の製造）まで行い、ここでアルキル化工程により、化合物（４'）から化合物（４）を得る。この化合物（４）は、ルート（ａ）で説明した化合物（４）と同じである。

In the route (c), the co-amination step (production of the compound (3 ′)) and the intramolecular acylation step (production of the compound (4 ′)) are performed in the same manner as in the route (b). The compound (4) is obtained from the compound (4 ′). This compound (4) is the same as the compound (4) described in the route (a).

  In the alkylation step, the reaction conditions are not particularly limited as long as the reaction proceeds and the compound (4) is obtained, but the reaction is usually refluxed in an ether such as dioxane, tetrahydrofuran or dimethoxyethane using alkyl iodide or the like.

Subsequently, a dehydroxyl halogenation process or an acyloxylation process (production of compound (A0)) is carried out in the same manner as in route (a) to obtain compound (A0).
Among the routes (a) to (c), the routes (a) and (c) are preferable from the viewpoint of easy progress of the reaction, and the compound (a) is more preferable because a high-purity compound can be obtained at a high yield. .

On the other hand, in the compound (A0), the definitions of the substituents R ⁴ and R ⁵ and the broken lines (i) and (ii) are the above [R4-II], and the nitrogen atom of the ring c of the indolequinoline skeleton ( As a method for synthesizing a compound in which the 6-position is alkylated, the following route (d) can be mentioned.

  (Route (d))

ルート（ｄ）では、ルート（ｂ）と同様に共アミノ化工程（化合物（３'）の製造）まで行い、ここでアルキル化工程により、化合物（３'）から化合物（５）を得る。この化合物（５）は、ルート（ａ）で説明した５位がアルキル化さている化合物（３）とは異なり、６位がアルキル化されている。

In the route (d), a co-amination step (production of the compound (3 ′)) is performed in the same manner as in the route (b), and the compound (3 ′) is obtained from the compound (3 ′) by an alkylation step. This compound (5) is alkylated at the 6-position, unlike the compound (3) which is alkylated at the 5-position described in the route (a).

  In the alkylation step, the reaction conditions are not particularly limited as long as the reaction proceeds and the compound (5) is obtained, but the reaction is usually refluxed in ether such as dioxane, tetrahydrofuran, dimethoxyethane, etc. using alkyl iodide.

  Next, an intramolecular acylation step (production of compound (6)) and a dehydroxyhalogenation step or acyloxylation step (production of compound (A0)) are carried out in the same manner as in route (a) to obtain compound (A0).

Step [1 ′]: Step of Synthesizing Compound (A1 ′) Step [1 ′] is a compound represented by the following formula (A1 ′) from compound (A0) obtained in step [1], that is, compound (A1). Unlike the above, it is a process for obtaining a compound to which an amino group or the like is bonded via a methylene group, and includes, for example, the following three steps.

First step: adding nitromethane to a compound having an indolequinoline mother nucleus structure represented by the following formula (A0) to obtain a compound represented by the following formula (A0 ′);
Second Step: A step of obtaining a compound represented by the following formula (A0 ″) from the compound represented by the following formula (A0 ′) by performing Nef reaction under oxidizing conditions;
Third step: From a compound represented by the following formula (A0 ″), a compound represented by the following formula (A1 ′) is obtained by reductive amination using an amine compound represented by the following formula (r2). Step to get.

式（Ａ０）中、Ｒ¹、ｎ、Ｒ³、ｍ、Ｒ⁴、Ｒ⁵、ｉおよびｉｉは前記式（Ａ）と同義であり、Ｘはハロゲン原子または低級アシロキシ基である。目的とするインドールキノリン誘導体（Ａ）に対応するこれらの置換基等を有する化合物（Ａ０）を選択すればよい。

In the formula (A0), R ¹ , n, R ³ , m, R ⁴ , R ⁵ , i and ii are as defined in the formula (A), and X is a halogen atom or a lower acyloxy group. What is necessary is just to select the compound (A0) which has these substituents etc. corresponding to the target indolequinoline derivative (A).

In the formulas (A0 ′) and (A0 ″), R ¹ , n, R ³ , m, R ⁴ , R ⁵ , i and ii are as defined in the formula (A).
In formula (r2), Z ¹ and Z ² have the same meaning as in formula (R2). An amine compound (r2) having Z ¹ and Z ² corresponding to R ² of the desired indolequinoline derivative (A) may be selected.

In the formula (A1 ′), R ¹ , n, R ³ , m, R ⁴ , R ⁵ , i and ii have the same meaning as the formula (A0), and Z ¹ and Z ² have the same meaning as the formula (r2). It is. These substituents and the like in the compound (A1 ′) correspond to these substituents and the like of the compound (A0) and the compound (r2) used as raw materials.

Process [2]
Step [2] is a step further performed when the target indolequinoline derivative (A) cannot be obtained in one step by the above step [1] or [1 ′], and was synthesized in step [1]. This is a step for synthesizing a target indolequinoline derivative (A) or a second intermediate from a compound (intermediate) by a predetermined reaction.

  Typically, it is performed when a compound represented by the following formula (A11) is produced as the indolequinoline derivative (A). In this case, the step [1] or [1 ′] is a step of obtaining a compound represented by the following formula (A10) by using a compound represented by the following formula (r21) as the amine compound (r2). In the step [2], the compound (A10) obtained in the step [1] or [1 ′] is reacted with the compound (z4) capable of reacting with the terminal amino group of the compound (A10). And obtaining the compound (A11).

式（Ａ１１）中、Ｒ¹、ｎ、Ｒ³、ｍ、Ｒ⁴、Ｒ⁵、ｉおよびｉｉは前記式（Ａ）と同義であり、Ｚ³は前記式（Ｚ２）と同義であり、Ｚ⁵およびＺ⁶は、前記［Ｚ４−ＩＩＩ］をとらないことを除き、前記式（Ｚ４）と同義である。すなわち、前記［Ｚ４−ＩＩＩ］のようにＺ⁵およびＺ⁶が互いに独立したアルキル基である（つまりＺ⁴がジアルキルアミノ基である）インドールキノリン誘導体（Ａ）を製造する場合は、一般的にこのような工程［２］は行われず、前記工程［１］または［１’］において、末端にそのようなジアルキルアミノ基を有するアミン化合物（ｒ２）を化合物（Ａ０）と反応させればよい。

In the formula (A11), R ¹ , n, R ³ , m, R ⁴ , R ⁵ , i and ii are as defined in the formula (A), Z ³ is as defined in the formula (Z2), and Z ⁵ and Z ⁶ are synonymous with the formula (Z4) except that [Z4-III] is not taken. That is, when producing an indolequinoline derivative (A) in which Z ⁵ and Z ⁶ are independent alkyl groups (that is, Z ⁴ is a dialkylamino group) as in [Z4-III], Such a step [2] is not performed, and in the step [1] or [1 ′], the amine compound (r2) having such a dialkylamino group at the terminal may be reacted with the compound (A0).

In formula (r21), Z ³ has the same meaning as in formula (Z2).
In the formula (A10), R ¹ , n, R ³ , m, R ⁴ , R ⁵ , i and ii are as defined in the formula (A), and Z ³ is as defined in the formula (Z2).

  Specific examples of the step [2], particularly the compound (z4) used in the step, include the following two modes.

First Embodiment of Step [2] When producing a compound represented by the following formula (A111) as the indolequinoline derivative (A), that is, Z ⁵ , Z ⁶ , and Z ⁵ and Z in the formula (A11) ^{When the} dash-dot line relating to the bond between ⁶ is as described in [Z4-I] and has a group represented by the formula (Z6), the step [2] is performed as the compound (z4). By using a compound represented by any of the following formulas (z611) to (z614), this is a step of obtaining the compound (A111).

式（Ａ１１１）中、ｘ、Ｒ¹、ｎ、Ｒ³、ｍ、Ｒ⁴、Ｒ⁵、ｉおよびｉｉは前記式（Ａ）と同義であり、Ｚ³は前記式（Ｚ２）と同義であり、Ｚ⁷およびＺ⁸は前記式（Ｚ６）と同義である。

In the formula (A111), x, R ¹ , n, R ³ , m, R ⁴ , R ⁵ , i and ii have the same meaning as the formula (A), and Z ³ has the same meaning as the formula (Z2). , Z ⁷ and Z ⁸ are as defined in the above formula (Z6).

式（ｚ６１１）〜（ｚ６１４）中、Ｚ⁸は前記式（Ｚ６）と同義である。目的とする化合物（Ａ１１１）に対応したＺ⁸を有する化合物（ｚ６１１）〜（ｚ６１４）を選択すればよい。

In the formulas (z611) to (z614), Z ⁸ has the same meaning as the formula (Z6). The compounds (z611) to (z614) having Z ⁸ corresponding to the target compound (A111) may be selected.

X represents a halogen atom. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and a chlorine atom and a bromine atom are preferable.
In the first embodiment of the step [2], the reaction conditions are not particularly limited as long as —NH _{2 at} the terminal of the compound (A10) reacts with the compounds (z611) to (z614), but per 1 mole of the compound (A10) It is preferable to use 1 to 3 moles of the compounds (z611) to (z614).

  The reaction of compound (A10) with compound (z611) or (z612) is usually performed in a halogenated hydrocarbon solvent such as dichloromethane or chloroform. The reaction of compound (A1) with compound (z613) or (z614) is usually carried out in an alkylamide solvent such as dimethylformamide or dimethylacetamide, if necessary, in the presence of triethylamine or the like.

The reaction temperature is usually 0 to 5 ° C., and the reaction time is usually 2 to 6 hours. Completion of the reaction can be confirmed by disappearance of the spot of compound (A10) in TLC.
The obtained indolequinoline derivative (A111) can be isolated and purified from the reaction mixture by separation means such as column chromatography and recrystallization.

Second Embodiment of Step [2] When producing a compound represented by the following formula (A112) as the indolequinoline derivative (A), that is, Z ⁵ , Z ⁶ , and Z ⁵ and Z in the formula (A11) ^{When the} alternate long and short dash line for the bond between ⁶ is as described in [Z4-II] and has a group (ring structure) represented by the formula (Z42), step [2] By using a compound represented by either the following formula (z91) or (z92) as (z4) and a compound represented by the following formula (z10), this is a step of obtaining the compound (A112).

式（Ａ１１２）中、Ｒ¹、ｎ、ｘ、Ｒ³、ｍ、Ｒ⁴、Ｒ⁵、ｉおよびｉｉは前記式（Ａ）と同義であり、Ｚ³は前記式（Ｚ２）と同義であり、Ｚ⁹およびＺ¹⁰は前記式（Ｚ４２）と同義である。

In formula (A112), R ¹ , n, x, R ³ , m, R ⁴ , R ⁵ , i and ii are as defined above for formula (A), and Z ³ is as defined above for formula (Z2). , Z ⁹ and Z ¹⁰ are as defined in the above formula (Z42).

式（ｚ９１）中、Ｒ⁹¹およびｐは前記式（Ｚ９１）と同義である。式（ｚ９２）中、Ｒ⁹²およびｑは前記式（Ｚ９２）と同義である。目的とする化合物（Ａ１１２）に対応したＲ⁹¹およびｐを有する化合物（ｚ９１）、または目的とする化合物（Ａ１１２）に対応したＲ⁹²およびｑを有する化合物（ｚ９２）を選択すればよい。

In the formula (z91), R ⁹¹ and p have the same meanings as the formula (Z91). In the formula (z92), R ⁹² and q have the same meaning as in the formula (Z92). A compound (z91) having R ⁹¹ and p corresponding to the target compound (A112) or a compound (z92) having R ⁹² and q corresponding to the target compound (A112) may be selected.

式（ｚ１０）中、Ｚ¹⁰は前記（Ｚ４２）と同義である。目的とする化合物（Ａ１１２）に対応したＲ¹⁰を有する化合物（ｚ１０）を選択すればよい。

In the formula (z10), Z ¹⁰ has the same meaning as the above (Z42). The compound (z10) having R ¹⁰ corresponding to the target compound (A112) may be selected.

In the second embodiment of the step [2], the reaction conditions are not particularly limited as long as —NH _{2 at} the terminal of the compound (A10) reacts with the compound (z91) or (z92) and the compound (z10). It is preferable to use 1 to 5 mol of compound (z91) or (z92) and 1 to 3 mol of compound (z10) per mol of A10).

  The reaction of the compound (A10) with the compound (z91) and the compound (z10) is usually carried out in an ether such as dioxane, tetrahydrofuran, tetrahydropyran, dimethoxyethane or the like, and if necessary, a dehydrating reagent such as N, N′-dicyclohexylcarbodiimide. Done in the presence of. The reaction temperature is usually 0 to 5 ° C., and the reaction time is usually 1 to 6 hours. Completion of the reaction can be confirmed by disappearance of the spot of compound (A10) in TLC.

On the other hand, the reaction of the compound (A10) with the compound (z92) and the compound (z10) is usually carried out in an aromatic hydrocarbon solvent such as benzene, toluene, xylene or the like, if necessary, such as N, N′-dicyclohexylcarbodiimide. It is carried out in the presence of a dehydrating reagent. The reaction temperature is usually 110 to 120 ° C., and the reaction time is usually 10 to 20 hours. Completion of the reaction can be confirmed by disappearance of the spot of compound (A10) in TLC.
The obtained indolequinoline derivative (A111) can be isolated and purified from the reaction mixture by separation means such as column chromatography and recrystallization.

Process [3]
When producing a pharmaceutically acceptable salt of the indole quinoline derivative (A), the synthesized indole quinoline derivative (A) is obtained following the step [1] and the step [2] performed as necessary. The step [3] of converting to a salt is performed.

  Step [3] is usually performed by dissolving the indolequinoline derivative (A) in a suitable solvent and then adding a compound corresponding to the salt to be synthesized, for example, the inorganic acid or organic acid as described above.

-Use of indolequinoline derivative (A) and its salt-
The use of the indolequinoline derivative (A) and its (pharmaceutically acceptable) salt according to the present invention is not particularly limited, but it can be typically used as an active ingredient of a specific pharmaceutical product. it can. That is, as a first embodiment of the pharmaceutical product according to the present invention, an “antimalarial agent” comprising an indolequinoline derivative (A) or a pharmaceutically acceptable salt thereof as an active ingredient is provided. Further, as a second embodiment of the pharmaceutical product according to the present invention, an “anticancer agent” comprising an indolequinoline derivative (A) or a pharmaceutically acceptable salt thereof as an active ingredient is provided.

  In addition, as an active ingredient of the pharmaceutical of the present invention, the indolequinoline derivative (A) or a pharmaceutically acceptable salt thereof may be used alone or in combination of two or more.

  The malaria parasites to which the antimalarial agent of the present invention is applied are not limited to specific ones and are widely used for P. falciparum, T. falciparum malaria, egg-type malaria parasite, and K. fever malaria parasite. Applicable. Furthermore, it can be applied to drug-resistant malaria parasites.

  The cancers to which the anticancer agent of the present invention is applied include malignant lymphoma (Hodgkin lymphoma, non-Hodgkin lymphoma, etc.), gastric cancer, penile cancer, pharyngeal cancer (nasopharyngeal cancer, oropharyngeal cancer). , Hypopharyngeal canal, etc.), vulvar cancer, pituitary fibroma, hepatocellular carcinoma, thymoma, mycosis fungoides, cancer of unknown primary origin, myelodysplastic syndrome, uterine cancer (cervical cancer, uterine body) Cancer, uterine sarcoma), chorionic disease, esophageal cancer, renal pelvic cancer, ureteral cancer, glioma, renal cell cancer, pancreatic cancer, pancreatic endocrine tumor, testicular tumor, prostate cancer , Colon cancer (cecal cancer, colon cancer, rectal cancer, etc.), multiple myeloma, bile duct cancer, gallbladder cancer, vaginal cancer, mesothelioma, acoustic schwannoma, soft tissue sarcoma, breast cancer, brain tumor , Lung cancer, leukemia (acute myeloid leukemia, acute lymphoblastic leukemia, adult T-cell leukemia lymphoma, chronic myeloid leukemia, chronic lymph Leukemia, etc.), skin cancer (malignant melanoma, etc.), bladder cancer, chronic myeloproliferative disease, ovarian cancer, ovarian germ cell tumor, etc., but are not limited to these, indole quinoline used The anti-tumor activity of the derivative (A) can be selected as appropriate.

  The dosage form of the pharmaceutical product according to the present invention is not particularly limited, and can be prepared by selecting an appropriate dosage form according to the administration route. The pharmaceutical agent of the present invention can be administered orally or parenterally (for example, intravenously, intramuscularly, subcutaneously, intrarectally, etc.) to a human or non-human mammal. Therefore, the pharmaceutical product of the present invention may be prepared as a pharmaceutical composition for oral administration such as tablets, capsules, soft capsules, granules, powders, fine granules, syrups, solutions, suspensions and the like. Alternatively, it may be prepared as a pharmaceutical composition for parenteral administration such as injection, drip infusion, suppository for subcutaneous, intramuscular or intravenous administration. These pharmaceutical compositions may further contain various additives that are generally used in formulation according to the dosage form. Such a pharmaceutical can be produced according to a method commonly used in the art depending on the dosage form.

  For example, an injection is prepared by dissolving the above active ingredient in a diluent (for example, physiological saline, glucose injection, lactose injection, mannitol injection, etc.) available to those skilled in the art, and performing sterilization such as filtration sterilization. It is obtained by applying and filling a sealed container such as an ampoule. In addition, a lyophilized injection or a powder injection mixed with sodium chloride may be produced based on the Japanese Pharmacopoeia. Further, as additives, for example, adjuvants such as polyethylene glycol and HCO-60 (surfactant; manufactured by Nikko Chemical Co.), and carriers such as ethanol and / or liposomes and cyclodextrins may be used.

  A pharmaceutical composition suitable for oral administration or rectal administration comprises an excipient, a disintegrant, a binder, a lubricant, a suspending agent, an isotonic agent, an emulsifier and the like, and the above active ingredients according to a conventional method. It is obtained by mixing molding. Examples of excipients used include cellulose derivatives (eg, crystalline cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc.), polyvinylpyrrolidone, dextrin, starch, lactose, mannitol, sorbitol, vegetable oils (eg, corn oil, cottonseed oil, coconut) Oil, almond oil, olive oil, peanut oil, etc.), oily esters such as medium chain fatty acid glyceride oil, mineral oil, glycerin esters such as tricaprylin and triacetin, alcohols such as ethanol, physiological saline, propylene glycol, polyethylene glycol , Animal fats and oils, petrolatum and the like.

  The dose and frequency of administration of the pharmaceutical agent of the present invention are not particularly limited, and can be appropriately selected according to conditions such as the purpose of treatment or prevention, administration route, patient age, body weight, disease severity and the like. The dosage is generally 5 to 1500 mg (active ingredient weight) per day for an adult, preferably 10 to 600 mg, and is preferably administered once a day or divided into about 2 to 4 times a day.

  The pharmaceutical product of the present invention may be used in combination with other known substances (drugs and other pharmacologically active substances) effective for the same purpose, or a composition (so-called “combination”) with such active ingredients. It may be used as a mixture). For example, the antimalarial agent of the present invention may be used in combination with other antimalarial agents used for the treatment or prevention of malaria, and the anticancer agent of the present invention is used for the treatment or prevention of cancer. You may use together with other anticancer agents currently used.

  Furthermore, the indolequinoline derivative (A) of the present invention and pharmaceutically acceptable salts thereof may be used for other pharmaceuticals such as antibacterial agents, antiparasitic agents, antibacterial agents, antifungal agents, antiinfective agents, etc. May be used as an active ingredient.

-Example group I-
In the following Example Group I (Production Example 1, Examples 1-8 and evaluation test of antimalarial activity), the compound numbers correspond to those in Schemes 1 and 2.

  As shown in Scheme 1, intermediate 3 was synthesized from N-methylaniline 1 and methyl indole-3-carboxylate 2 (step i), followed by cyclization to 5-methyl-5H-indolo [2, 3-b] quinolin-11 (6H) -one 4 was obtained (step ii). This compound was dehydrated and chlorinated with phosphoryl chloride to give 11-chloro-5-methyl-5H-indolo [2,3-b] quinoline 5 (step iii). These were reacted with a series of amines to give 11-amino derivatives 6a-h (step iv).

  Furthermore, as shown in Scheme 2, the indolequinoline derivatives 9a-d, 11, 13a-b, 15, 17a-j were obtained by modifying the amino group of the side chain of the 11-amino derivative 6a-c.

[Production Example 1]
[Preparation of methyl 2- (methyl (phenyl) amino) -1H-indole-3-carboxylate (compound (3))]
A solution of methyl indole-3-carboxylate (438.0 mg, 2.5 mmol) in methylene chloride (5 mL) was flushed with argon gas, and to this solution was added N-chlorosuccinimide (367. A solution in which 1 mg, 2.75 mmol) and 1,4-dimethylpiperazine (142.7 mg, 1.25 mmol) were dissolved was added dropwise at 0 ° C. The resulting mixed solution was stirred at 0 ° C. for 2 hours, and then a solution of trichloroacetic acid (102.1 mg, 0.625 mmol) and N-methylaniline (5 mmol, 2.0 equiv.) In methylene chloride (2 mL) was dissolved. It was dripped. This mixed solution was warmed to room temperature and further reacted by stirring for 3.5 hours. The mixed solution after the reaction was washed with a saturated aqueous NaHCO ₃ solution, 1N HCl, brine and water in this order. The organic phase was dried using anhydrous MgSO ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO _2, n-hexane / ethyl acetate = 7/1) to give methyl 2- (methyl (phenyl) amino)-1H-indole-3-carboxylate (585.0Mg) Was obtained (yield 83%). The obtained solid was white and had mp = 133.6 to 135.1 ° C. and Rf (relative movement distance) = 0.40 (developing solvent ethyl acetate / hexane = 1: 5).
¹ H NMR (600 MHz, CDCl3): ppm 3.45 (s, 3 H), 3.82 (s, 3H), 6.88 (s, 1H), 6.89 (s, 1H), 6.92 (t, J = 7.20 Hz, 1H ), 7.21-7.27 (m, 5H) , 8.13 (d, J = 7.20 Hz, 1H), 8.28 (s, 1H) 13 C NMR (150.8MHz, CDCl3):. ppm 39.98, 50.82, 97.96, 110.43, 116.22 (2C), 120.58, 121.42, 121.87, 122.69, 126.67, 129.23 (2C), 131.76, 147.01, 147.78, 164.53.

[Preparation of 5-methyl-5H-indolo [2,3-b] quinolin-11 (6H) -one (compound (4))]
Methyl 2- (methyl (phenyl) amino) -1H-indole-3-carboxylate obtained in Preparation Example 1 was refluxed in diphenyl ether (8 mL) at 250 ° C. for 2 hours. The obtained solid was filtered off and washed with diethyl ether to obtain 5-methyl-5H-indolo [2,3-b] quinolin-11 (6H) -one (476.0 mg) (yield 98%). ). The resulting solid was gray and mp> 370 ° C.
¹ H NMR (600 MHz, DMSO-d ₆ ): ppm 3.96 (s, 3 H), 7.18-7.29 (m, 2 H), 7.38 (t, J = 7.20 Hz, 1H), 7.47 (d, J = 7.90 Hz 1 H), 7.71-7.78 (m, 2 H), 8.20 (d, J = 7.20 Hz, 1H), 8.39 (d, J = 7.20 Hz, 1H), 12.07 (s, 1 H). ¹³ C NMR (150.8 MHz, DMSO-d6): ppm 33.26, 102.27, 110.79, 115.21, 120.12, 121.17, 121.65, 122.79, 124.06, 124.68, 125.75, 131.16, 134.71, 139.17, 146.88, 171.52.

[Preparation of 11-chloro-5-methyl-5H-indolo [2,3-b] quinoline (compound (5))]
To a suspension obtained by adding 5-methyl-5H-indolo [2,3-b] quinolin-11 (6H) -one (1.0 equiv.) To toluene (8 mL), phosphoryl chloride (40.0 equiv.) Was added. Was added. The mixture was heated to reflux for 6 hours and then cooled in an ice bath with ice while stirring. The temperature was kept below 30 ° C. The liquid was removed and the resulting solid was washed with ether, saturated aqueous NaHCO ₃ and water in this order. The orange product was dried with P ₂ O ₅ under reduced pressure. 11-chloro-5-methyl-5H-indolo [2,3-b] quinoline (451.0 mg) was obtained (yield 94%). The resulting solid was orange and had a mp of 176.0-177.0 ° C. ¹ H NMR (600 MHz, CDCl ₃ ): ppm 4.33 (s, 3 H), 7.28 (t, J = 7.20 Hz, 1H), 7.51 (t, J = 7.20 Hz, 1H), 7.58 (t, J = 7.20 Hz, 1H), 7.72-7.74 (m, 2 H), 7.79 (t, J = 7.20 Hz, 1H), 8.43 (m, 2H). ¹³ C NMR (150.8 MHz, CDCl ₃ ): ppm 33.15, 114.23 , 117.66, 119.16, 120.23, 122.22, 123.89, 123.91, 124.98, 126.07, 129.73, 131.05, 135.85, 136.97, 155.13, 155.51.

[Example 1]
[Preparation of 11-amino-5-methyl-5H-indolo [2,3-b] quinolines (compound (6a-h))]
To the appropriate 11-chloro-5-methyl-5H-indolo [2,3-b] quinoline (compound (5)) obtained in Preparation Example 1, an excess amount of an appropriate aminoalkylamine (compound (5) 1 etc.) 10 equivalents to the amount) and added at 135 ° C. to 155 ° C. for 1 to 4 hours. The reaction was followed by TLC, and when compound (5) disappeared, the reaction was completed. After the reaction, the crude product was subjected to column chromatography (SiO ₂ ) and eluted with methanol (2N) (9: 1) containing ethyl acetate-ammonia to obtain the desired compound (compound (6a-h)).

(6a) N- (3-aminopropyl) -5-methyl-5H-indolo [2,3-b] quinolin-11-amine:
Yield: 96%, yellow solids.Mp: 69−71 ^o C; IR (KBr) 3435, 2928, 2868, 2359, 2342, 1622, 1559, 1489, 1441, 1418, 1287, 1248, 1057, 750, 669 cm ^-1 ; ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 1.80 (quint, J = 6.0 Hz, 2 H), 3.01 (t, J = 6.0 H 2 H), 4.01 (t, J = 6.0 Hz, 2 H), 4.22 (s, 3 H), 7.17 (t, J = 7.2 Hz, 1 H), 7.18 (br. S., 1 H), 7.31 (t, J = 7.2 Hz, 1 H), 7.41 ( t, J = 7.2 Hz, 1 H), 7.61 (d, J = 9.0 Hz, 1 H), 7.67 (td, J = 7.2, 1.2 Hz, 1 H), 7.76 (d, J = 7.8 Hz, 1 H ), 7.95 (d, J = 7.8 Hz, 1 H), 8.13 (d, J = 8.4 Hz, 1 H); ¹³ C NMR (150.8 MHz, CDCl ₃ ) δ ppm 32.64, 32.66, 41.26, 49.25, 105.61, 114.40, 115.86, 116.94, 118.49, 120.35, 121.37, 124.06, 124.12, 125.16, 130.08, 137.79, 148.52, 151.94, 156.55.HRMS (ESI) calcd for C ₁₉ H ₂₁ N ₄ [M + H] ⁺ Exact Mass: 305.1761 , found 305.1765.

(6b) N- (6-aminohexyl) -5-methyl-5H-indolo [2,3-b] quinolin-11-amine:
Yield: 96%, yellow solids.Mp: 54−56 ^o C; IR (KBr) 3350, 2928, 2855, 1622, 1593, 1568, 1489, 1441, 1422, 1281, 1246, 1200, 1142, 882, 752 cm ^-1 ; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.19 (m, 5 H), 1.36 (m, 1 H), 1.68 (m, 2 H), 2.38 (t, J = 6.6 Hz, 1 H), 2.95 (t, J = 6.6 Hz, 1 H), 3.83 (m, 2 H), 4.16 (s, 3 H), 6.99 (br. S., 1 H), 7.07 (t, J = 7.2 Hz, 1 H), 7.28 (t, J = 7.2 Hz, 1 H), 7.41 (t, J = 7.8 Hz, 1 H), 7.50 (d, J = 8.4 Hz, 1 H), 7.79 (t, J = 7.8 Hz, 1 H), 7.84 (d, J = 7.8 Hz, 1 H), 7.90 (d, J = 7.8 Hz, 1 H), 8.53 (d, J = 7.2 Hz, 1 H); ¹³ C NMR (150.8 MHz, DMSO-d ₆ ) δ ppm 22.58, 26.24, 26.27, 30.98, 32.66, 41.20, 48.13, 104.68, 115.41, 115.82, 116.79, 118.47, 121.12, 122.22, 124.20 (2C), 124.98, 131.13, 137.61 , 148.78, 152.10, 156.59. HRMS (ESI) calcd for C ₂₂ H ₂₇ N ₄ [M + H] ⁺ Exact Mass: 347.2230, found 347.2235.

(6c) N- (3-aminopropyl) -2-bromo-5-methyl-5H-indolo [2,3-b] quinolin-11-amine:
Yield: 94%, yellow solids.Mp: 137-139 ^o C; IR (KBr) 3229, 3152, 3067, 2940, 2909, 2857, 1622, 1589, 1557, 1505, 1487, 1441, 1418, 1389, 1281, 1238, 1209, 1109, 1057, 876, 800, 762, 743 cm ^-1 ; ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 1.82 (quint, J = 6.0 Hz, 2 H), 3.08 (t, J = 6.0 Hz, 2 H), 4.03 (m, 2 H), 4.21 (s, 3 H), 7.17 (t, J = 7.2 Hz, 1 H), 7.42 (t, J = 7.2 Hz, 1 H), 7.46 (br. s., 1 H), 7.50 (d, J = 9.0 Hz, 1 H), 7.72−7.75 (m, 2 H), 7.97 (d, J = 7.8 Hz, 1 H), 8.30 (d, J = 2.4 Hz, 1 H); ¹³ C NMR (150.8 MHz, CDCl ₃ ) δ ppm 32.23, 32.68, 41.51, 49.68, 106.28, 113.02, 116.07, 117.29, 117.52, 118.70, 121.67, 124.17, 125.56, 126.72, 132.57 , 136.66, 147.17, 152.59, 156.65. HRMS (ESI) calcd for C ₁₉ H ₁₈ BrN ₄ [M−H] ⁻ Exact Mass: 381.0720, found 381.0710.

(6d) N- (3-aminopropyl) -2-chloro-5-methyl-5H-indolo [2,3-b] quinolin-11-amine:
Yield: 92%, yellow solids.Mp: 132−134 ^o C; IR (KBr) 3420, 3264, 3050, 2934, 2870, 1618, 1587, 1559, 1491, 1443, 1418, 1341, 1290, 1279, 1248, 1217, 1115, 1065, 876, 797, 756, 731 cm ^-1 ; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.74 (quint, J = 6.6 Hz, 2 H), 2.59 (t, J = 6.6 Hz, 2 H), 3.91 (t, J = 6.6 Hz, 2 H), 4.14 (s, 3 H), 7.08 (t, J = 7.2 Hz, 1 H), 7.29 (t, J = 7.2 Hz, 1 H), 7.50 (d, J = 7.8 Hz, 1 H), 7.77−7.81 (m, 1 H), 7.85 (m, 1 H), 7.92 (d, J = 7.8 Hz, 1 H), 8.59 ( d, J = 2.4 Hz, 1 H); ¹³ C NMR (150.8 MHz, DMSO-d ₆ ) δ ppm 32.40, 33.53, 39.46, 46.75, 104.57, 116.70, 116.80, 117.11, 118.18, 122.38, 123.09, 124.11, 124.79 , 125.04, 130.24, 136.06, 147.10, 152.38, 156.34. HRMS (ESI) calcd for C ₁₉ H ₂₀ ClN ₄ [M + H] ⁺ Exact Mass: 339.1371, found 339.1382.

(6e) N- (3-aminopropyl) -2-fluoro-5-methyl-5H-indolo [2,3-b] quinolin-11-amine:
Yield: 89%, yellow solids.Mp: 87−88 ^o C; IR (KBr) 3283, 3055, 2932, 2359, 1614, 1601, 1568, 1489, 1445, 1424, 1344, 1281, 1242, 1136, 856, 795, 760, 739 cm ^-1 ; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.73 (quint, J = 6.6 Hz, 2 H), 2.60 (t, J = 6.6 Hz, 2 H), 3.92 (t, J = 6.6 Hz, 2 H), 4.16 (s, 3 H), 7.07 (t, J = 7.2 Hz, 1 H), 7.29 (t, J = 7.2 Hz, 1 H), 7.49 (d, J = 7.8 Hz, 1 H), 7.68−7.71 (m, 1 H), 7.88 (m, 1 H), 7.93 (d, J = 7.8 Hz, 1 H), 8.36 (dd, J = 11.4, 2.4 Hz , 1 H); ¹³ C NMR (150.8 MHz, DMSO-d ₆ ) δ ppm 32.48, 33.53, 39.46, 46.79, 104.78, 109.10 (d, J = 24.1 Hz), 116.31 (d, J = 7.8 Hz), 116.53 , 117.16 (d, J = 8.4 Hz), 117.97, 118.49 (d, J = 24.1 Hz), 122.35, 123.86, 124.79, 134.20, 147.32 (d, J = 3.3 Hz), 152.52, 156.46, 156.58 (d, J = 236.8 Hz); ¹⁹ F NMR (564 MHz, DMSO-d ₆ ) δ ppm −121.26. HRMS (ESI) calcd for C ₁₉ H ₂₀ FN ₄ [M + H] ⁺ Exact Mass: 323.1667, found 323.1670.

(6f) N- (3-aminopropyl) -5-methyl-2- (trifluoromethyl) -5H-indolo [2,3-b] quinolin-11-amine:
Yield: 87%, yellow solids.Mp: 64-65 ^o C; IR (KBr) 3430, 2930, 2351, 1634, 1595, 1568, 1505, 1443, 1429, 1402, 1333, 1279, 1246, 1146, 1117, 1088, 814, 762, 746 cm ^-1 ; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.76 (quint, J = 6.0 Hz, 2 H), 2.63 (t, J = 6.0 Hz, 2 H) , 3.97 (t, J = 6.6 Hz, 2 H), 4.18 (s, 3 H), 7.11 (t, J = 7.2 Hz, 1 H), 7.30 (m, 1 H), 7.53 (d, J = 7.2 Hz, 1 H), 7.96 (d, J = 7.8 Hz, 1 H), 8.00 (t, J = 6.6 Hz, 1 H), 8.04 (m, 1 H), 8.86 (s, 1 H); ¹³ C NMR (150.8 MHz, DMSO-d ₆ ) δ ppm 32.51, 33.24, 39.56, 46.98, 104.22, 115.25, 116.17, 116.93, 118.53, 123.21 (q, J = 268.1 Hz), 121.79, 124.12, 124.78, 124.89, 126.37, 139.37, 147.60, 152.10, 156.41; ¹⁹ F NMR (564 MHz, DMSO-d ₆ ) δ ppm −58.64.HRMS (ESI) calcd for C ₂₀ H ₂₀ F ₃ N ₄ [M + H] ⁺ Exact Mass: 373.1635, found 373.1646.

(6g) N- (3-aminopropyl) -2-methoxy-5-methyl-5H-indolo [2,3-b] quinolin-11-amine:
Yield: 99%, yellow solids.Mp: 105−106 ^o C; IR (KBr) 3381, 3268, 2934, 1614, 1593, 1568, 1489, 1445, 1424, 1348, 1288, 1246, 1184, 1140, 1038, 937, 810, 760 cm ^-1 ; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.72 (quint, J = 6.6 Hz, 2 H), 2.64 (t, J = 6.6 Hz, 2 H), 3.91 (s, 3 H), 3.94 (t, J = 6.6 Hz, 2 H), 4.14 (s, 3 H), 7.04 (t, J = 7.2 Hz, 1 H), 7.26 (t, J = 7.2 Hz, 1 H), 7.43-7.47 (m, 2 H), 7.79 (d, J = 9.6 Hz, 1 H), 7.92 (m, 2 H); ¹³ C NMR (150.8 MHz, DMSO-d ₆ ) δ ppm 32.23 , 33.44, 39.82, 47.18, 55.80, 104.47, 105.88, 116.18, 116.28, 116.43, 117.47, 119.52, 122.15, 123.98, 124.43, 132.18, 147.73, 152.50, 153.55, 156.26.HRMS (ESI) calcd for C ₂₀ H ₂₃ N ₄ O [M + H] ⁺ Exact Mass: 335.1866, found 335.1864.

(6h) N- (3-aminopropyl) -5-methyl-2-nitro-5H-indolo [2,3-b] quinolin-11-amine:
Yield: 83%, red solids.Mp: 159-162 ^o C; IR (KBr) 3430, 3069, 2940, 2868, 1616, 1570, 1505, 1441, 1424, 1329, 1294, 1246, 1121, 941, 826, 760, 739 cm ^-1 ; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.78 (quint, J = 6.6 Hz, 2 H), 2.67 (t, J = 6.6 Hz, 2 H), 4.00 (t , J = 6.6 Hz, 2 H), 4.20 (s, 3 H), 7.13 (t, J = 7.2 Hz, 1 H), 7.31 (t, J = 7.2 Hz, 1 H), 7.55 (d, J = 7.8 Hz, 1 H), 7.98 (t, J = 7.8 Hz, 2 H), 8.52 (m, 1 H), 9.45 (d, J = 2.4 Hz, 1 H); ¹³ C NMR (150.8 MHz, DMSO- d ₆ ) δ ppm 32.85, 32.96, 39.90, 47.21, 103.96, 115.06, 116.11, 117.26, 119.04, 121.08, 122.41, 124.21, 124.56, 124.88, 140.18, 141.06, 147.60, 151.90, 156.17.HRMS (ESI) calcd for C ₁₉ H ₁₈ N ₅ O ₂ [M−H] ⁻ Exact Mass: 348.1466, found 348.1485.

[Example 2]
[Preparation of compound (17a-j)]
11-amino-5-methyl-5H-indolo [2,3-b] quinolines (compound (6a-h), 50 mg) were dissolved in 1 mL of methylene chloride. To this solution, add a solution of phenyl isocyanate (1.1 equivalent to 1 equivalent of compound (16a-c), compound (6a-h)) in 1 mL of methylene chloride and stir for 2 to 4 hours. It was. The reaction was followed by TLC, and it was completed when the compound (6a-h) disappeared. After the reaction, the reaction solution is concentrated with an evaporator, and the crude product is eluted with methanol (2N) (9: 1) containing ethyl acetate-ammonia by column chromatography (SiO ₂ ). )

(17a) 1- (3- (5-methyl-5H-indolo [2,3-b] quinolin-11-ylamino) propyl) -3-phenylthiourea:
Yield: 99%, yellow solids.Mp: 201−203 ^o C; IR (KBr) 3335, 3208, 3055, 2938, 1622, 1595, 1568, 1539, 1512, 1485, 1441, 1422, 1406, 1310, 1277, 1242, 1190, 1142, 1103, 1072, 955, 858, 748, 733 cm ^-1 ; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.98 (quint, J = 6.6 Hz, 2 H), 3.51 ( m, 2 H), 3.89 (q, J = 6.6 Hz, 2 H), 4.16 (s, 3 H), 7.06−7.11 (m, 3 H), 7.24 (d, J = 4.2 Hz, 4 H), 7.30 (t, J = 7.2 Hz, 1 H), 7.43 (t, J = 7.8 Hz, 1 H), 7.51 (d, J = 7.8 Hz, 1 H), 7.73 (br. S., 1 H), 7.80 (t, J = 7.2 Hz, 1 H), 7.86 (d, J = 8.4 Hz, 1 H), 7.96 (d, J = 7.8 Hz, 1 H), 8.55 (d, J = 8.4 Hz, 1 H ), 9.46 (br. S., 1 H); ¹³ C NMR (150.8 MHz, DMSO-d ₆ ) δ ppm 30.36, 32.33, 41.39, 45.60, 104.58, 115.09, 115.68, 116.35, 118.22, 120.69, 122.17 (2C ), 123.16, 123.93, 124.04 (2C), 124.21, 124.69, 128.66, 130.73, 137.33, 138.87, 148.28, 151.74, 156.11, 180.24.HRMS (ESI) calcd for C ₂₆ H ₂₄ N ₅ S [M−H] ⁻ Exact Mass: 438.1758, found 438.1751.

(17b) 1-butyl-3- (3- (5-methyl-5H-indolo [2,3-b] quinolin-11-ylamino) propyl) urea:
Yield: 86%, yellow solids.Mp: 80−81 ^o C; IR (KBr) 3360, 3312, 2953, 2920, 2870, 1622, 1593, 1568, 1520, 1489, 1443, 1416, 1400, 1288, 1250, 1196, 1065, 1022, 841, 750 cm ^-1 ; ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 0.86 (t, J = 7.8 Hz, 3 H), 1.31 (sext, J = 7.8 Hz, 2 H) , 1.45 (quint, J = 7.2 Hz, 2 H), 1.68 (quint, J = 6.0 Hz, 2 H), 3.19 (q, J = 6.6 Hz, 2 H), 3.36 (q, J = 6.6 Hz, 2 H), 3.85 (q, J = 6.0 Hz, 2 H), 4.10 (s, 3 H), 5.49 (br. S., 1 H), 5.79 (br. S., 1 H), 6.92 (m, 1 H), 7.13 (t, J = 7.2 Hz, 1 H), 7.31−7.38 (m, 2 H), 7.51 (d, J = 7.8 Hz, 1 H), 7.63−7.67 (m, 2 H), 7.82 (d, J = 7.8 Hz, 1 H), 8.39 (dd, J = 9.0, 1.2 Hz, 1 H); ¹³ C NMR (150.8 MHz, CDCl ₃ ) δ ppm 13.77, 20.04, 32.33, 32.38, 33.07, 36.60, 40.19, 44.25, 105.39, 114.51, 116.07, 116.41, 119.25, 121.44, 121.83, 123.48, 124.28, 125.44, 130.64, 137.45, 149.30, 152.45, 155.40, 159.77.HRMS (ESI) calcd for C ₂₄ H _{28 5} O [M−H] ⁻ Exact Mass: 402.2299, found 402.2319.

(17c) 1- (3- (5-methyl-5H-indolo [2,3-b] quinolin-11-ylamino) propyl) -3-phenylurea:
Yield: 99%, yellow solids.Mp: 215 ^o C; IR (KBr) 3341, 3048, 3024, 2969, 2930, 1694, 1620, 1591, 1557, 1489, 1443, 1406, 1314, 1275, 1227, 1177, 1144, 891, 758, 718, 692 cm ^-1 ; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.86 (quint, J = 6.6 Hz, 2 H), 3.14 (q, J = 6.6 Hz, 2 H), 3.86 (q, J = 6.6 Hz, 2 H), 4.16 (s, 3 H), 6.18 (t, J = 6.0 Hz, 1 H), 6.87 (t, J = 7.2 Hz, 1 H), 7.06 (m, 2 H), 7.20 (t, J = 7.8 Hz, 2 H), 7.27 (t, J = 7.2 Hz, 1 H), 7.35 (d, J = 7.8 Hz, 2 H), 7.42 (t , J = 7.2 Hz, 1 H), 7.50 (d, J = 7.8 Hz, 1 H), 7.79 (t, J = 7.2 Hz, 1 H), 7.85 (d, J = 8.4 Hz, 1 H), 7.96 (d, J = 7.8 Hz, 1 H), 8.42 (s, 1 H), 8.54 (d, J = 8.4 Hz, 1 H); ¹³ C NMR (150.8 MHz, DMSO-d ₆ ) δ ppm 31.62, 32.20 , 36.48, 45.43, 105.02, 115.06, 115.62, 116.55, 117.72 (2C), 117.98, 120.55, 121.03, 122.05, 124.00, 124.07, 124.65, 128.59 (2C), 130.63, 137.40, 140.40, 148.23, 152.38, 155.52, 156.40 HRMS (ESI) calcd for C ₂₆ H ₂₄ N ₅ O [M−H] ⁻ Exact Mass: 422.1986, found 422.2003.

(17d) 1- (6- (5-methyl-5H-indolo [2,3-b] quinolin-11-ylamino) hexyl) -3-phenylurea:
Yield: 89%, yellow solids.Mp: 101-104 ^o C; IR (KBr) 3356, 3053, 2930, 2855, 1668, 1622, 1595, 1559, 1499, 1441, 1420, 1312, 1279, 1244, 1071, 750, 694 cm ^-1 ; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.19-1.25 (m, 4 H), 1.31 (quint, J = 6.6 Hz, 2 H), 1.68 (quint, J = 6.6 Hz, 2 H), 2.95 (q, J = 6.0 Hz, 2 H), 3.83 (q, J = 6.6 Hz, 2 H), 4.16 (s, 3 H), 6.03 (t, J = 6.0 Hz, 1 H), 6.86 (t, J = 7.2 Hz, 1 H), 7.01 (t, J = 5.4 Hz, 1 H), 7.08 (t, J = 7.2 Hz, 1 H), 7.19 (t, J = 7.2 Hz, 2 H), 7.28 (t, J = 7.2 Hz, 1 H), 7.34 (d, J = 7.2 Hz, 2 H), 7.42 (t, J = 7.8 Hz, 1 H), 7.50 (d, J = 7.8 Hz, 1 H), 7.78 (t, J = 7.8 Hz, 1 H), 7.84 (d, J = 7.8 Hz, 1 H), 7.91 (d, J = 7.8 Hz, 1 H), 8.34 (s , 1 H), 8.53 (d, J = 8.4 Hz, 1 H); ¹³ C NMR (150.8 MHz, DMSO-d ₆ ) δ ppm 25.90, 26.03, 29.60, 30.75, 32.22, 38.82, 48.00, 104.48, 115.06, 115.61, 116.50, 117.52 (2C), 117.96, 120.59, 120.86, 121.98, 123.98, 124.09, 124.59, 128.61 (2C), 130.66, 137.37, 140.58, 148.35, 152.10, 155.15, 156.34.HRMS (ESI) calcd for C ₂₉ H ₃₀ N ₅ O [M−H] ⁻ Exact Mass : 464.2456, found 464.2480.

(17e) 1- (3- (2-bromo-5-methyl-5H-indolo [2,3-b] quinolin-11-ylamino) propyl) -3-phenylurea:
Yield: 80%, yellow solids.Mp: 132−135 ^o C; IR (KBr) 3347, 3050, 2938, 1680, 1616, 1591, 1557, 1499, 1487, 1443, 1424, 1314, 1281, 1246, 1200, 1111, 1086, 885, 799, 760, 741, 694 cm ^-1 ; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.88 (quint, J = 6.6 Hz, 2 H), 3.14 (q, J = 6.0 Hz, 2 H), 3.84 (q, J = 6.6 Hz, 2 H), 4.13 (s, 3 H), 6.18 (t, J = 6.0 Hz, 1 H), 6.87 (t, J = 7.2 Hz, 1 H), 7.07 (t, J = 7.2 Hz, 1 H), 7.19 (t, J = 7.2 Hz, 3 H), 7.28 (t, J = 7.2 Hz, 1 H), 7.35 (d, J = 8.4 Hz, 2 H), 7.50 (d, J = 7.8 Hz, 1 H), 7.80 (m, 1 H), 7.90 (d, J = 7.2 Hz, 2 H), 8.41 (s, 1 H), 8.78 ( d, J = 1.8 Hz, 1 H); ¹³ C NMR (150.8 MHz, DMSO-d ₆ ) δ ppm 31.46, 32.37, 36.50, 45.38, 105.23, 112.92, 116.74, 117.35, 117.38, 117.70 (2C), 118.28, 121.01, 122.37, 124.02, 124.94, 125.92, 128.59 (2C), 132.94, 136.32, 140.40, 146.99, 152.49, 155.48, 156.32.HRMS (ESI) calcd for C ₂₆ H ₂₃ BrN ₅ O [M−H] ⁻ Exact Mass : 500.1091, found 500.1087.

(17f) 1- (3- (2-chloro-5-methyl-5H-indolo [2,3-b] quinolin-11-ylamino) propyl) -3-phenylurea:
Yield: 83%, yellow solids.Mp: 130 133 ^o C; IR (KBr) 3347, 3051, 2938, 1680, 1622, 1595, 1557, 1499, 1443, 1422, 1314, 1281, 1246, 1200, 1119, 991, 800, 760, 743, 694 cm ^-1 ; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.89 (quint, J = 6.6 Hz, 2 H), 3.14 (q, J = 6.0 Hz, 2 H) , 3.84 (q, J = 6.6 Hz, 2 H), 4.14 (s, 3 H), 6.17 (t, J = 6.0 Hz, 1 H), 6.87 (t, J = 7.2 Hz, 1 H), 7.07 ( t, J = 7.2 Hz, 1 H), 7.17 (m, 3 H), 7.29 (t, J = 7.2 Hz, 1 H), 7.34 (d, J = 7.8 Hz, 2 H), 7.50 (d, J = 7.8 Hz, 1 H), 7.80 (dd, J = 9.0, 2.4 Hz, 1 H), 7.86 (d, J = 9.6 Hz, 1 H), 7.91 (d, J = 7.2 Hz, 1 H), 8.40 (s, 1 H), 8.67 (d, J = 2.4 Hz, 1 H); ¹³ C NMR (150.8 MHz, DMSO-d ₆ ) δ ppm 31.45, 32.41, 36.49, 45.41, 105.32, 116.70, 116.89, 117.10, 117.69 (2C), 118.27, 121.00, 122.37, 123.02, 123.96, 124.95, 125.14, 128.57 (2C), 130.25, 136.01, 140.39, 147.06, 152.45, 155.46, 156.32.HRMS (ESI) calcd for C ₂₆ H ₂₅ ClN ₅ O [M + H] ⁺ Exact Mass: 458.1742, found 458.1747.

(17g) 1- (3- (2-fluoro-5-methyl-5H-indolo [2,3-b] quinolin-11-ylamino) propyl) -3-phenylurea:
Yield: 87%, yellow solids.Mp: 218−220 ^o C; IR (KBr) 3339, 3053, 2926, 1690, 1613, 1599, 1566, 1499, 1487, 1445, 1400, 1317, 1281, 1234, 1144, 878, 795, 760, 692 cm ^-1 ; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.84 (quint, J = 6.6 Hz, 2 H), 3.11 (q, J = 6.0 Hz, 2 H) , 3.82 (q, J = 6.6 Hz, 2 H), 4.14 (s, 3 H), 6.13 (t, J = 6.0 Hz, 1 H), 6.84 (t, J = 7.2 Hz, 1 H), 6.99 ( t, J = 6.0 Hz, 1 H), 7.04 (t, J = 7.2 Hz, 1 H), 7.16 (t, J = 7.8 Hz, 2 H), 7.26 (t, J = 7.2 Hz, 1 H), 7.31 (dd, J = 8.4, 1.2 Hz, 2 H), 7.47 (d, J = 7.8 Hz, 1 H), 7.67 (m, 1 H), 7.86 (dd, J = 9.6, 4.8 Hz, 1 H) , 7.89 (d, J = 7.8 Hz, 1 H), 8.37 (s, 1 H), 8.42 (dd, J = 10.8, 2.4 Hz, 1 H); 13C NMR (150.8 MHz, DMSO-d), 116.44 ( d, J = 7.8 Hz), 116.55, 117.16 (d, J = 8.4 Hz), 117.69 (2C), 118.08, 118.53 (d, J = 23.5 Hz), 121.00, 122.36, 123.73, 124.99, 128.57 (2C), 134.15, 140.39, 147.27 (d, J = 2.9 Hz), 152.65, 155.44, 156.45, 156.65 (d, J = 237.2 Hz); ¹⁹ F NMR (564 MHz, DMSO-d ₆ ) δ ppm −121.25.HRMS (ESI ) calcd for C ₂₆ H ₂₃ FN ₅ O [M−H] ⁻ Exact Mass: 440.1892 , found 440.1890.

(17h) 1- (3- (5-methyl-2- (trifluoromethyl) -5H-indolo [2,3-b] quinolin-11-ylamino) propyl) -3-phenylurea:
Yield: 77%, yellow solids.Mp: 204−205 ^o C; IR (KBr) 3335, 3055, 2938, 1688, 1614, 1597, 1553, 1499, 1443, 1435, 1333, 1317, 1277, 1242, 1196, 1148, 1119, 1090, 912, 816, 766, 752, 725 cm ^-1 ; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.90 (quint, J = 6.6 Hz, 2 H), 3.15 (q, J = 6.0 Hz, 2 H), 3.88 (q, J = 6.6 Hz, 2 H), 4.19 (s, 3 H), 6.17 (t, J = 6.0 Hz, 1 H), 6.87 (t, J = 7.2 Hz, 1 H), 7.10 (t, J = 7.2 Hz, 1 H), 7.19 (t, J = 7.8 Hz, 2 H), 7.29-7.34 (m, 3 H), 7.46 (t, J = 6.0 Hz , 1 H), 7.53 (d, J = 7.8 Hz, 1 H), 7.94 (d, J = 7.8 Hz, 1 H), 8.00 (d, J = 9.0 Hz, 1 H), 8.05 (dd, J = 9.0, 1.2 Hz, 1 H), 8.39 (s, 1 H), 8.94 (s, 1 H); ¹³ C NMR (150.8 MHz, DMSO-d ₆ ) δ ppm 31.47, 32.55, 36.45, 45.34, 105.04, 115.37 , 116.16, 116.97, 117.70 (2C), 118.66, 120.95, 121.03, 121.73, 121.75, 123.22 (q, J = 244.6 Hz), 123.80, 124.98, 126.38, 128.57 (2C), 139.33, 140.39, 147.61, 152.25, 155.52 , 156.46; ¹⁹ F NMR (564 MHz, DMSO-d ₆ ) δ ppm −58.57. HRMS (ESI) calcd for C ₂₇ H ₂₃ F ₃ N ₅ O [M−H] ⁻ Exact Mass: 490.1860, found 490.1 889.

(17i) 1- (3- (2-methoxy-5-methyl-5H-indolo [2,3-b] quinolin-11-ylamino) propyl) -3-phenylurea:
Yield: 98%, yellow solids.Mp: 122-124 ^o C; IR (KBr) 3383, 3050, 2936, 1682, 1614, 1597, 1568, 1532, 1499, 1445, 1314, 1288, 1246, 1142, 1036, 804, 758, 694 cm ^-1 ; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.84 (quint, J = 6.6 Hz, 2 H), 3.15 (q, J = 6.6 Hz, 2 H), 3.85 (q, J = 6.6 Hz, 2 H), 3.94 (s, 3 H), 4.15 (s, 3 H), 6.19 (t, J = 6.0 Hz, 1 H), 6.88 (t, J = 7.2 Hz, 1 H), 7.02-7.06 (m, 2 H), 7.20 (t, J = 7.8 Hz, 2 H), 7.27 (t, J = 7.2 Hz, 1 H), 7.35 (d, J = 7.2 Hz, 2 H), 7.45-7.49 (m, 2 H), 7.81 (d, J = 9.6 Hz, 1 H), 7.93 (d, J = 7.8 Hz, 1 H), 8.00 (d, J = 2.4 Hz, 1 H ), 8.43 (s, 1 H); ¹³ C NMR (150.8 MHz, DMSO-d ₆ ) δ ppm 31.74, 32.31, 36.45, 45.19, 55.87, 105.69, 105.86, 116.32, 116.35, 116.50, 117.65, 117.76 (2C) , 119.65, 121.06, 122.19, 123.81, 124.75, 128.59 (2C), 132.20, 140.38, 147.72, 152.65, 153.66, 155.60, 156.21.HRMS (ESI) calcd for C ₂₇ H ₂₆ N ₅ O ₂ [M−H] ⁻ Exact Mass: 452.2092, found 452.2102.

(17j) 1- (3- (5-methyl-2-nitro-5H-indolo [2,3-b] quinolin-11-ylamino) propyl) -3-phenylurea:
Yield: 92%, orange solids.Mp: 222−225 ^o C; IR (KBr) 3360, 2930, 1649, 1616, 1568, 1501, 1439, 1424, 1323, 1290, 1240, 1121, 1071, 814, 754, 739, 694 cm ^-1 ; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.92 (quint, J = 6.6 Hz, 2 H), 3.15 (q, J = 6.0 Hz, 2 H), 3.90 (q , J = 6.6 Hz, 2 H), 4.17 (s, 3 H), 6.15 (t, J = 6.0 Hz, 1 H), 6.87 (t, J = 7.2 Hz, 1 H), 7.12 (t, J = 7.2 Hz, 1 H), 7.18 (t, J = 7.8 Hz, 2 H), 7.30 (m, 3 H), 7.54 (d, J = 7.8 Hz, 1 H), 7.65 (t, J = 6.0 Hz, 1 H), 7.94-7.97 (m, 2 H), 8.36 (s, 1 H), 8.50 (dd, J = 9.6, 2.4 Hz, 1 H), 9.50 (d, J = 2.4 Hz, 1 H); ¹³ C NMR (150.8 MHz, DMSO-d ₆ ) δ ppm 31.31, 32.87, 36.48, 45.54, 104.83, 115.20, 116.10, 117.28, 117.66 (2C), 119.15, 121.00, 121.02, 122.41, 124.12, 124.55, 125.07, 128.56 (2C), 140.28, 140.37, 141.00, 147.68, 152.05, 155.42, 156.24. HRMS (ESI) calcd for C ₂₆ H ₂₃ N ₆ O ₃ [M−H] ⁻ Exact Mass: 467.1837, found 467.1835.

[Example 3]
[Preparation of compound (13a-b)]
11- (3-aminopropylamino) -5-methyl-5H-indolo [2,3-b] quinoline (compound (6a), 50 mg) was dissolved in 2 mL of dimethylformamide. To this solution was added a solution of sulfonyl chloride (compound (12a-b), 1.2 equivalents to 1 equivalent of compound (6a)) in 2 mL of dimethylformamide, and further triethylamine (compound (6a) 1 etc. 2 equivalents to the amount) was added and stirred at room temperature for 2-4 hours. The reaction was followed by TLC, and the reaction was completed when the compound (6a) disappeared. After the reaction, the reaction solution is concentrated with an evaporator, and the crude product is eluted with methanol (2N) (9: 1) containing ethyl acetate-ammonia by column chromatography (SiO ₂ ). ) (Yellow orange).

(13a) N- (3- (5-methyl-5H-indolo [2,3-b] quinolin-11-ylamino) propyl) benzenesulfonamide:
Yield: 68%, yellow solids.Mp: 189-192 ^o C; IR (KBr) 3389, 3055, 2932, 1626, 1568, 1489, 1445, 1420, 1308, 1281, 1246, 1153, 1092, 878, 860, 743, 691 cm ^-1 ; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.79 (quin, J = 7.2 Hz, 2 H), 2.70 (q, J = 6.6 Hz, 2 H), 3.80 (q , J = 6.6 Hz, 2 H), 4.16 (s, 3 H), 6.88 (t, J = 5.4 Hz, 1 H), 7.06 (t, J = 6.6 Hz, 1 H), 7.29 (t, J = 7.8 Hz, 1 H), 7.40 (t, J = 6.6 Hz, 1 H), 7.45 (t, J = 7.8 Hz, 2 H), 7.49 (d, J = 7.2 Hz, 1 H), 7.55 (t, J = 7.8 Hz, 1 H), 7.60 (m, 3 H), 7.80 (t, J = 7.2 Hz, 1 H), 7.85 (d, J = 9.0 Hz, 1H), 7.88 (d, J = 7.8 Hz , 1H), 8.45 (d, J = 8.4 Hz, 1H); ¹³ C NMR (150.8 MHz, DMSO-d ₆ ) δ ppm 30.80, 32.24, 40.10, 45.42, 105.16, 115.04, 115.07, 115.62, 116.48, 118.04, 120.59, 122.07, 123.97, 124.73, 126.28 (2C), 129.06 (2C), 130.64, 132.25, 137.34, 140.12, 148.08, 152.20, 156.28.HRMS (ESI) calcd for C ₂₅ H ₂₅ N ₄ O ₂ S (M + H] ⁺ Exact Mass: 445.1693, found 445.1718.

(13b) N- (3- (5-methyl-5H-indolo [2,3-b] quinolin-11-ylamino) propyl) naphthalene-2-sulfonamide:
Yield: 76%, yellow solids.Mp: 198 ^o C; IR (KBr) 3393, 3055, 2924, 2874, 2359, 1738, 1626, 1574, 1489, 1443, 1424, 1314, 1283, 1242, 1144, 1103, 1080, 878, 862, 814, 745 cm ^-1 ; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.81 (quin, J = 7.2 Hz, 2 H), 2.75 (q, J = 6.0 Hz, 2 H), 3.80 (q, J = 7.2 Hz, 2 H), 4.13 (s, 3 H), 6.86 (t, J = 6.0 Hz, 1 H), 7.03 (t, J = 7.8 Hz, 1 H), 7.27 (t, J = 7.8 Hz, 1 H), 7.33 (t, J = 7.8 Hz, 1 H), 7.48 (d, J = 7.8 Hz, 1 H), 7.62−7.71 (m, 4 H), 7.75 (t, J = 7.2 Hz, 1 H), 7.81 (d, J = 8.4 Hz, 1 H), 7.86 (d, J = 7.2 Hz, 1 H), 7.99 (d, J = 8.4 Hz, 2 H) , 8.05 (d, J = 8.4 Hz, 1 H), 8.29 (s, 1 H), 8.41 (d, J = 8.4 Hz, 1 H); ¹³ C NMR (150.8 MHz, DMSO-d ₆ ) δ ppm 30.84 , 32.19, 40.16, 45.44, 105.21, 114.98, 115.57, 116.52, 117.98, 120.48, 122.04, 122.06, 123.92, 123.98, 124.70, 127.25, 127.50, 127.79, 128.62, 129.10, 129.28, 130.58, 137.62, 134.04, 7.3 , 148.02, 152.35, 156.34. HRMS (ESI) calcd for C ₂₉ H ₂₇ N ₄ O ₂ S [M + H] ⁺ Exact Mass: 495.1849, found 495.1878.

[Example 4]
[Preparation of compound (15)]
11- (3-aminopropylamino) -5-methyl-5H-indolo [2,3-b] quinoline (compound (6a), 50 mg) was dissolved in 2 mL of dimethylformamide. To this solution was added a solution of 2-thiophenecarbonyl chloride (1.2 equivalents relative to 1 equivalent of compound (14), compound (6a)) in 2 mL of dimethylformamide, and triethylamine (compound (6a) 1 etc.). 2 equivalents to the amount) was added and stirred at room temperature for 2-4 hours. The reaction was followed by TLC, and the reaction was completed when the compound (6a) disappeared. After the reaction, the reaction solution is concentrated with an evaporator, and the crude product is eluted with methanol (2N) (9: 1) containing ethyl acetate-ammonia by column chromatography (SiO ₂ ). )

(15) N- (3- (5-methyl-5H-indolo [2,3-b] quinolin-11-ylamino) propyl) thiophene-2-carboxamide:
Yield: 95%, yellow solids.Mp: 204−205 ^o C; IR (KBr) 3424, 3333, 3059, 2930, 1732, 1622, 1593, 1566, 1545, 1499, 1439, 1418, 1358, 1294, 1248, 1204, 1144, 1071, 862, 745, 719 cm ^-1 ; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.92 (quint, J = 7.2 Hz, 2 H), 3.26 (q, J = 6.6 Hz , 2 H), 3.88 (q, J = 7.2 Hz, 2 H), 4.16 (s, 3 H), 7.02−7.07 (m, 2 H), 7.10 (dd, J = 4.8, 2.4 Hz, 1 H) , 7.27 (t, J = 7.2 Hz, 1 H), 7.41 (t, J = 7.2 Hz, 1 H), 7.49 (d, J = 7.8 Hz, 1 H), 7.64 (dd, J = 3.6, 1.2 Hz , 1 H), 7.72 (dd, J = 5.4, 1.2 Hz, 1 H), 7.79 (td, J = 7.2 1.2 Hz, 1 H), 7.85 (d, J = 7.8 Hz, 1 H), 7.94 (d , J = 7.2 Hz, 1 H), 8.52 (d, J = 6.6 Hz, 2 H); ¹³ C NMR (150.8 MHz, DMSO-d ₆ ) δ ppm 30.92, 32.22, 36.69, 45.39, 105.08, 115.06, 115.65 , 116.55, 118.00, 120.58, 122.08, 123.97, 124.02, 124.68, 127.81, 127.93, 130.64 (2C), 137.39, 139.84, 148.14, 152.38, 156.40, 161.33.HRMS (ESI) calcd for C ₂₄ H ₂₃ N ₄ OS [ M + H] ⁺ Exact Mass: 415.1587, found 415.1597.

[Example 5]
[Preparation of compound (9a-d)]
11- (3-aminopropylamino) -5-methyl-5H-indolo [2,3-b] quinoline (compound (6a), 100 mg) and aldehydes (8a-c) (compound (6a) 1 equivalent) 2 equivalents) to tetrahydrofuran (THF, 4 mL), and ω-mercaptocarboxylic acids (7a-b) (3 equivalents to 1 equivalent of compound (6a) under ice-cooling) ) Was added. After 5 minutes, N, N′-dicyclohexylcarbodiimide (1.2 equivalents to 1 equivalent of DCC, compound (6a)) was added at 0 ° C., and the mixture was stirred at room temperature for 1 to 3 hours. N, N′-dicyclohexylurea (DCU) was filtered off, the filtrate was concentrated, and the residue was extracted with chloroform. The organic phase was washed with aqueous sodium bicarbonate and brine and concentrated with an evaporator. The crude product was purified by column chromatography (SiO ₂ ) and eluted with methanol (2N) (9: 1) containing ethyl acetate-ammonia to obtain the desired compound (9a-d).

(9a) 2- (4-chlorophenyl) -3- (3- (5-methyl-5H-indolo [2,3-b] quinolin-11-ylamino) propyl) thiazolidin-4-one:
Yield: 30.4%, yellowish-orange solids.Mp: 151-154 ^o C; IR (KBr) 3368, 3057, 2930, 2864, 1668, 1616, 1593, 1489, 1462, 1408, 1316, 1261, 1217, 1088, 1013, 856, 802, 756 cm ^-1 ; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.86 (quint, J = 7.2 Hz, 2 H), 2.60 (m, 1 H), 3.37−3.46 ( m, 2 H), 3.77 (dd, J = 15.6, 1.8 Hz, 1 H), 3.82−3.92 (m, 2 H), 4.20 (s, 3 H), 5.75 (d, J = 1.2 Hz, 1 H ), 7.27 (m, 2 H), 7.34 (m, 3 H), 7.49 (t, J = 7.2 Hz, 1 H), 7.64 (m, 2 H), 7.98 (t, J = 8.4 Hz, 2 H ), 8.08 (d, J = 9.0 Hz, 1 H), 8.15 (br.s., 1 H), 8.61 (d, J = 8.4 Hz, 1 H); ¹³ C NMR (150.8 MHz, CDCl ₃ ) δ ppm 28.26, 32.97, 36.41, 40.03, 44.55, 63.37, 100.58, 113.49, 115.67, 116.45, 119.81, 121.40, 122.16, 124.17, 125.16, 126.21, 128.82 (2C), 129.45 (2C), 132.56, 135.44, 136.70, 137.22 , 137.80, 147.42, 151.77, 172.75. HRMS (ESI) calcd for C ₂₈ H ₂₄ ClN ₄ OS [M−H] ⁻ Exact Mass: 499.1365, found 499.1374.

(9b) 2- (4- (dimethylamino) phenyl) -3- (3- (5-methyl-5H-indolo [2,3-b] quinolin-11-ylamino) propyl) thiazolidin-4-one:
Yield: 65%, yellow solids.Mp: 102−104 ^o C; IR (KBr) 3356, 2928, 1661, 1614, 1593, 1564, 1524, 1493, 1441, 1418, 1352, 1281, 1246, 1184, 1167, 1063, 945, 799, 752 cm ^-1 ; ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 1.49 (m, 1 H), 1.69 (m, 1 H), 2.94 (s, 6 H), 3.15 (m , 1 H), 3.58 (m, 1 H), 3.69 (m, 1 H), 3.77−3.94 (m, 3 H), 4.28 (s, 3 H), 5.56 (s, 1 H), 6.63 (d , J = 9.0 Hz, 2 H), 6.91 (br. S., 1 H), 7.19 (m, 3 H), 7.38 (t, J = 7.2 Hz, 1 H), 7.46 (t, J = 7.2 Hz , 1 H), 7.66 (d, J = 9.0 Hz, 1 H), 7.74 (t, J = 7.8 Hz, 1 H), 7.81 (d, J = 7.8 Hz, 1 H), 7.84 (d, J = 7.8 Hz, 1 H), 8.41 (d, J = 8.4 Hz, 1 H); ¹³ C NMR (150.8 MHz, CDCl ₃ ) δ ppm 28.36, 33.19, 33.96, 39.94, 40.23 (2C), 43.71, 64.58, 105.16 , 112.13 (2C), 114.90, 116.10, 116.43, 119.80, 121.76, 121.96, 122.63, 124.01, 124.48, 125.87, 128.57 (2C), 131.01, 137.38, 147.94, 149.30, 151.15, 154.07, 172.54.HRMS (ESI) calc for C ₃₀ H ₃₀ N ₅ OS [M−H] ⁻ Exact Mass: 508.2171, found 508.2197.

(9c) 2- (4-chlorophenyl) -3- (3- (5-methyl-5H-indolo [2,3-b] quinolin-11-ylamino) propyl) -1,3-thiazinan-4-one:
Yield: 42%, yellow solids.Mp: 87−89 ^o C; IR (KBr) 3420, 2934, 1622, 1593, 1568, 1489, 1441, 1420, 1314, 1285, 1246, 1202, 1144, 1092, 1013, 829, 754 cm ^-1 ; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.95 (m, 2 H), 2.53−2.65 (m, 5 H), 3.81 (m, 1 H), 3.85−3.95 (m, 2 H), 4.18 (s, 3 H), 5.76 (s, 1 H), 7.12 (d, J = 8.4 Hz, 2 H), 7.21 (t, J = 7.2 Hz, 1 H), 7.33 −7.42 (m, 3 H), 7.51 (t, J = 7.8 Hz, 1 H), 7.57 (d, J = 7.8 Hz, 1 H), 7.62 (br. S., 1 H), 7.88 (t, J = 7.8 Hz, 1 H), 7.96 (d, J = 7.8 Hz, 2 H), 8.56 (d, J = 8.4 Hz, 1 H); ¹³ C NMR (150.8 MHz, DMSO-d ₆ ) δ ppm 20.83 , 28.50, 33.48, 33.82, 44.37, 45.45, 59.97, 114.63, 115.73, 115.93, 119.81, 122.06, 122.38, 122.55, 124.12, 125.22, 128.12 (2C), 128.33 (2C), 129.39, 131.20, 131.53, 132.21, 137.01 , 138.88, 149.75, 168.60, 171.47. HRMS (ESI) calcd for C ₂₉ H ₂₆ ClN ₄ OS [M−H] ⁻ Exact Mass: 513.1521, found 513.1535.

(9d) 2- (4-fluorophenyl) -3- (3- (5-methyl-5H-indolo [2,3-b] quinolin-11-ylamino) propyl) -1,3-thiazinan-4-one:
Yield: 29.3%, yellowish-orange solids.Mp: 92−94 ^o C; IR (KBr) 3420, 3063, 2932, 1616, 1593, 1564, 1506, 1464, 1435, 1402, 1323, 1225, 1157, 1103, 1065, 835, 754 cm ^-1 ; ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 1.85 (m, 1 H), 1.96 (m, 1 H), 2.70 (m, 1 H), 2.77−2.84 (m , 2 H), 2.91 (m, 2 H), 3.62−3.67 (m, 1 H), 4.13−4.18 (m, 1 H), 4.27 (s, 3 H), 4.29−4.35 (m, 1 H) , 5.54 (s, 1 H), 7.05 (t, J = 8.4 Hz, 2 H), 7.16−7.23 (m, 3 H), 7.33 (t, J = 7.2 Hz, 1 H), 7.42 (br. S ., 1 H), 7.51 (t, J = 7.2 Hz, 1 H), 7.64 (d, J = 8.4 Hz, 1 H), 7.77 (t, J = 7.8 Hz, 1 H), 7.83 (t, J = 9.0 Hz, 2 H), 8.48 (d, J = 8.4 Hz, 1 H); ¹³ C NMR (150.8 MHz, CDCl ₃ ) δ ppm 21.62, 28.67, 29.66, 34.22, 34.76, 44.00, 61.11, 103.37, 115.17 , 115.75 (d, J = 21.9 Hz, 2C), 116.56, 120.68, 121.74, 122.79, 124.31, 125.99, 128.16 (2C), 128.21 (2C), 131.53, 134.25, 134.27, 137.11, 150.23, 161.61, 163.26, 170.82 ¹⁹ F NMR (564 MHz, CDCl ₃ ) δ ppm −113.09. HRMS (ESI) calcd for C ₂₉ H ₂₆ FN ₄ OS [M−H] ⁻ Exact Mass: 497.1817, found 497.182 0 ..

[Example 6]
[Preparation of compound (11)]
11- (3-aminopropylamino) -5-methyl-5H-indolo [2,3-b] quinoline (compound (6a), 100 mg) and benzaldehyde (8a) (compound (6a) to 1 equivalent) 2 equivalents) is dissolved in toluene (4 mL) by heating at 70-80 ° C for 5 minutes, and thiosalicylic acid (10) (3 equivalents to 1 equivalent of compound (6a)) is added to this solution. It was. Subsequently, N, N′-dicyclohexylcarbodiimide (DCC, 1.2 equivalent to 1 equivalent of compound (6a)) was added, and the mixture was stirred for 10 to 15 hours under reflux. After cooling to room temperature, N, N′-dicyclohexylurea (DCU) was filtered off, the filtrate was concentrated, and the residue was extracted with chloroform. The organic phase was washed with aqueous sodium bicarbonate and brine and concentrated with an evaporator. The crude product was subjected to column chromatography (SiO ₂ ) and eluted with methanol (2N) (9: 1) containing ethyl acetate-ammonia to obtain the desired compound (11) (yellow orange).

(11) 2- (4-chlorophenyl) -3- (3- (5-methyl-5H-indolo [2,3-b] quinolin-11-ylamino) propyl) -2,3-dihydrobenzo [e] [1 , 3] thiazin-4-one:
Yield: 49.7%, yellow solids.Mp: 124−126 ^o C; IR (KBr) 3349, 3055, 2932, 1622, 1591, 1564, 1489, 1456, 1441, 1422, 1310, 1277, 1246, 1204, 1146, 1092, 1013, 841, 748 cm ^-1 ; ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 2.06 (m, 1 H), 2.13 (m, 1 H), 3.23 (dt, J = 15.0, 5.4 Hz, 1 H), 3.82 (m, 1 H), 4.22 (m, 1 H), 4.34 (s, 3 H), 4.51 (m, 1 H), 5.73 (s, 1 H), 7.11 (d, J = 7.8 Hz, 1 H), 7.15−7.22 (m, 5 H), 7.29 (t, J = 7.8 Hz, 1 H), 7.32−7.36 (m, 2 H), 7.58 (t, J = 7.2 Hz, 1 H), 7.68 (d, J = 9.0 Hz, 1 H), 7.70 (br. S., 1 H), 7.81 (t, J = 7.8 Hz, 1 H), 7.86 (d, J = 8.4 Hz, 1 H), 7.91 (d, J = 7.8 Hz, 1 H), 8.16 (dd, J = 7.8, 1.2 Hz, 1 H), 8.63 (d, J = 8.4 Hz, 1 H); ¹³ C NMR (150.8 MHz , CDCl ₃ ) δ ppm 29.56, 35.64, 44.08, 45.23, 61.03, 102.48, 114.67, 115.41, 116.73, 120.94, 121.41, 121.77, 123.46, 124.67, 126.25, 126.71, 127.45 (2C), 127.79, 128.49, 128.82 (2C ), 129.01, 129.95, 131.99, 132.53, 132.74, 134.51, 136.77, 136.97, 150.09, 151.09, 165.22.HRMS (ESI) calcd for C ₃₃ H ₂₆ ClN ₄ OS [M−H] ⁻ Exact Mass: 561. 1516, found 561.1517.

[Evaluation test of antimalarial activity]
The compounds synthesized as described above were evaluated in vitro for antimalarial activity.

[Activity against P. falciparum.]
In vitro activity against Plasmodium falciparum at the erythrocyte stage was measured using ³ H-hypoxanthine uptake evaluation method (by the method of Desjardins et al. 1979, Matiel and Pink. 1990 et al.) K1 protozoan strain resistant to chloroquine and pyrimethamine originating in Thailand (Thaitong et al. 1983), NF54 protozoa strain sensitive to known antimalarial agents, and chloroquine (Sigma 6666) as standard drugs Decided. Test compounds are dissolved in DMSO (dimethyl sulfoxide) at a concentration of 10 mg / mL, and in RPMI 1640 medium without hypoxanthine, HEPES (5.94 g / L), NaHCO ₃ (2.1 g / L), neomycin (100 U / mL), Albumax® (5 g / L), and 2.5% haematocrit (0.3% parasitaemia) washed parasite fungus supplemented with human red blood cells A ⁺ added.

Eleven serial dilutions of the drug in the range of 100 to 0.002 μg / mL were made. The 96-well plate was incubated at 37 ° C; 4% CO ₂ , 3% O ₂ , 93% N ₂ in a humidified atmosphere.

After 48 hours, 50 μL of ³ H-hypoxanthine (= 0.5 μCi) was added to each plate well. The plate was further cultured under the same conditions for 24 hours.
Subsequently, the plates were harvested with a Betaplate ^™ cell harvester (Wallac, Zurich, Switzerland) and the red blood cells were transferred onto glass fiber filters and further washed with distilled water. The dried filter was inserted into a plastic plate with 10 mL of scintillation liquid and the numerical reading was taken with a Betaplate ^™ liquid scintillation counter (Wallac, Zurich, Switzerland). IC ₅₀ values were obtained from sigmoid inhibition curves by linear regression (Huber 1993) using Microsoft Excel.

[In vitro cytotoxicity test using L-6 cell]
Activity testing was performed in 96-well microtiter plates. Each well is in 100 μL RPMI 1640 medium with 1% L-glutamate (200 mM), 10% fetal bovine serum and 4000 L-6 cells (primary grade taken from rat skeletal myoblasts). Cell line) supplemented.

Eleven serial dilutions of the drug in the range of 100 to 0.002 μg / mL were made. After 70 hours of incubation, the plates were checked with an inverted microscope to confirm the growth of standards and aseptic conditions. 10 μL of AlamarBlue was added to each well and a plate incubated for another 2 hours. Subsequently, the plate was read with an emission microplate fluorometer (Molecular Devices Cooperation, Sunnyvale, CA, USA) at an excitation wavelength of 536 nm and an emission wavelength of 588 nm. IC ₅₀ values were determined from sigmoid inhibition curves by linear regression (Huber 1993) SoftmaxPro software (Molecular Devices Cooperation, Sunnyvale, CA, USA).

Table 1 shows the IC ₅₀ values (μM / L), the value of the IC ₅₀ for L-6 cells ([mu] M / L), and selectivity index (SI) against chloroquine sensitive P. falciparum strain (NF54) . Selectivity index as an index of selective toxicity (SI) was determined from the value of the IC ₅₀ for the value / P. falciparum IC ₅₀ for L-6 cells.

ハロゲン原子（Br, Cl）および電子求引性基（CF₃）で置換された化合物6c, 6dおよび6fは、無置換の化合物6aに比べて、クロロキン感受性原虫株（NF54）に対する抗マラリア活性が向上した。NO₃で置換された化合物6hも顕著に活性が向上した。

Compounds 6c, 6d and 6f substituted with a halogen atom (Br, Cl) and an electron withdrawing group (CF ₃ ) have antimalarial activity against chloroquine-sensitive protozoan strain (NF54) compared to unsubstituted compound 6a. Improved. The activity of compound 6h substituted with NO ₃ was also significantly improved.

  Since the compound 6b having a long chain (6-aminohexylamino group) was slightly inferior in activity to the compound 6a having a short chain (1,3-diaminomethylene), the 3-aminopropylamino group was further modified. Aiming for high activity.

  Compounds 9a-d and 11 substituted with isothiazolin-4-one were slightly more active than compound 6a. It has been found that the presence of the non-basic side chain at the end of the 3-aminoalkylamino group increases the antimalarial activity and increases SI as compared to the case of a free amino group at the end.

Compound 13b, which is a naphthalenesulfonyl derivative, has an anti-malarial activity higher than that of compound 13a, which is a benzenesulfonyl derivative, although the SI is the same.
Compound 17a-c, a urea derivative, also shows excellent antimalarial activity, among which compound 17a has the highest anti-malaria strain (NF54) with a high SI value of 134.99 It showed malaria activity (IC ₅₀ = 9.1 nM), higher than chloroquine (IC ₅₀ = 9.4 nM). Further, the compound 17d having a long chain (6-aminohexylamino group) is slightly inferior in activity to the compound 17c having a short chain (1,3-diaminomethylene), and contrasts with the aforementioned compounds 6a and 6b. A similar trend was seen.

Comparing the compound 17c in which the C2 position is H and the compound 17e-j having a substituent at the C2 position, even when it has an electron withdrawing group (CF ₃ and NO ₂ ) as a substituent, an electron donating group (MeO) Even in the case of having an antimalarial activity, the antimalarial activity against the chloroquine sensitive protozoan strain (NF54) was clearly improved as compared with the case of having no substituent. Similarly, compounds 17e and 17f substituted with halogen atoms (Br and Cl), especially 17f substituted with chlorine atoms, have the highest SI value (1410) and chloroquine sensitive protozoan strain among all synthesized compounds IC ₅₀ (2.2 nM) against (NF54) is shown.

Table 2 shows the IC ₅₀ values (nM) for the chloroquine resistant P. falciparum strain (K1), the selectivity index (SI) for the L-6 cell, and the resistance to K1, which were further measured for some compounds. The sex index (RI) is shown (the data shown in Table 1 is also shown for reference).

表２に示す６つの化合物はすべて、クロロキンよりも、クロロキン耐性原虫株（K1）に対して顕著に高い効力を有することが確認された。

All six compounds shown in Table 2 were confirmed to have significantly higher potency against chloroquine resistant protozoan strains (K1) than chloroquine.

[Example 7]
As compound 1, a methyl indole-3-carboxylate-5-derivative having the substituent R ³ shown in Table 3 at the 5-position of the indole skeleton (corresponding to the 9-position of the indolequinoline skeleton) is used. In the same manner as in 2, compound 18a-h was synthesized. And the evaluation test of the antimalarial activity of those compounds was done like the above. The results are as shown in Table 3.

［実施例８］
下記式で表される化合物19について、前記と同様にして抗マラリア活性の評価試験を行った。結果は表４に示す通りである。なお、当該化合物は後記実施例群IIにおける化合物25jと同一であり、それと同様にして合成した。

[Example 8]
The compound 19 represented by the following formula was evaluated for antimalarial activity in the same manner as described above. The results are as shown in Table 4. The compound was the same as Compound 25j in Example Group II described later, and was synthesized in the same manner.

−実施例群II−
下記の実施例群II（実施例９〜１０および抗腫瘍活性の評価試験）では、化合物の番号はScheme 3, 4および5におけるものに対応する。

-Example group II-
In the following Example Group II (Examples 9 to 10 and anti-tumor activity evaluation test), the compound numbers correspond to those in Schemes 3, 4 and 5.

  11-Amino-5-methyl-5H-indolo [2,3-b] quinolines 11-16 are produced from substituted N-methylaniline 1 and indole-3-carboxylic acid ester 2 as shown in Scheme 3. And synthesized. First, intermediate 3 was prepared (step i), followed by cyclization to obtain 5-methyl-5H-indolo [2,3-b] quinolin-11 (6H) -one 4 (step ii). This compound was dehydrated and chlorinated with phosphoryl chloride and led to 11-chloroindolo [2,3-b] quinoline skeleton 5-10 (step iii). These were reacted with a series of amines to give 11-amino derivatives 11-16 (step iv).

なお、Scheme 3のステップi〜iiiの具体的な手順は、前記［製造例１］においてScheme 1のステップi〜iiiとして記載した手順と同様である。

In addition, the specific procedure of steps i to iii of Scheme 3 is the same as the procedure described as steps i to iii of Scheme 1 in [Preparation Example 1].

  On the other hand, 11-amino-6-methyl-6H-indolo [2,3-b] quinolines 22 were synthesized using substituted aniline 17 and indole-3-carboxylic acid ester 2 as raw materials as shown in Scheme 4. did. First, intermediate 18 was prepared (step i), and subsequently methyl iodide was allowed to act on the base and methylation occurred on N of the indole ring to obtain intermediate 19 (step v). This compound was cyclized and converted to intermediate 20 (step ii). Subsequently, dehydration and chlorination with phosphoryl chloride led to the 11-chloroindolo [2,3-b] quinoline skeleton 21 (step iii). These were reacted with a series of amines to give 11-amino derivatives 22 (step iv).

さらに、11−アミノメチル-5-メチル-5H-インドロ[2,3-b]キノリン体25は鍵化合物5から調製した。すなわち、化合物5にニトロメタンを付加させて中間体23とし、つづいてNef 反応を酸化的条件で行って11-ホルミル-5-メチル-5H-インドロ[2,3-b]キノリン体24を得た。このものに還元的アミノ化を行い、25を得た。

Furthermore, 11-aminomethyl-5-methyl-5H-indolo [2,3-b] quinoline 25 was prepared from key compound 5. That is, nitromethane was added to compound 5 to give intermediate 23, and then Nef reaction was performed under oxidative conditions to obtain 11-formyl-5-methyl-5H-indolo [2,3-b] quinoline 24. . This was reductively aminated to give 25.

Example 9 11-amino-5-methyl-5H-indolo [2,3-b] quinolines (compound (11-16)) and 11-amino-6-methyl-6H-indolo [2,3 -B] Synthesis of quinolines (compound (22)) Appropriate 11-chloro-indolo [2,3-b] quinolines (compounds (5-10, 21) were added to an excess of an appropriate amine (compound (5- 10, 21) 10 equivalents to 1 equivalent) was added, and the mixture was stirred for 1 to 8 hours at 80 ° C. to 120 ° C. The reaction was followed by TLC, and the reaction was completed when the compound (5-10, 21) disappeared. After the reaction, water was added to the reaction product, followed by extraction with ethyl acetate, and the reaction was worked up.The crude product was subjected to column chromatography (SiO ₂ ) and methanol (2N) containing ethyl acetate-ammonia (2N) ( 9: 1) to obtain the desired compound (compound (11-16, 22)).

(11a) N- (5- (Diethylamino) pentan-2-yl) -5-methyl-5H-indolo [2,3-b] quinolin-11-amine:
Yield: 98%, yellow solid, Mp: 89-91 ^o C; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 0.70 (t, J = 7.19 Hz, 6 H), 1.13-1.27 (m, 2 H), 1.44 (d, J = 6.46 Hz, 3 H), 1.57-1.65 (m, 1 H), 1.65-1.74 (m, 1 H), 2.01-2.12 (m, 2 H), 2.16 (q, J = 5.87 Hz, 4 H), 4.18 (s, 3 H), 4.29-4.39 (m, 1 H), 6.57 (d, J = 10.27 Hz, 1 H), 7.09 (m, 1 H), 7.30 ( m Hz, 1 H), 7.43 (t, J = 1.17 Hz, 1 H), 7.51 (d, J = 7.92 Hz, 1 H), 7.80 (m, 1 H), 7.86 (t, J = 6.90 Hz, 2 H), 8.58 (dd, J = 8.36, 1.03 Hz, 1 H); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ ppm 11.5, 21.6, 23.4, 32.2, 36.2, 46.0, 51.9, 52.6, 106.1 , 115.0, 116.0, 116.6, 117.9 , 120.6, 121.7, 124.1, 124.2, 124.9, 130.6, 137.4, 148.3, 152.5, 156.4;. HRMS (ESI) Calcd for C 25 H 31 N 4 [MH] - 387.2554 Found 387.2522. .

(11b) N- (2- (1H-Indol-3-yl) ethyl) -5-methyl-5H-indolo [2,3-b] quinolin-11-amine:
Yield: 90%, yellow solid, Mp: 201-203 ^o C; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 3.12 (t, J = 7.63 Hz, 2 H), 4.09-4.15 (m, 2 H), 4.16 (s, 3 H), 6.91 (ddd, J = 7.92, 7.04, 0.88 Hz, 1 H), 6.98-7.05 (m, 2 H), 7.08 (d, J = 2.35 Hz, 1 H) , 7.12 (t, J = 5.87 Hz, 1 H), 7.25-7.28 (m, 1 H), 7.28-7.31 (m, 1 H), 7.41 (ddd, J = 8.22, 7.04, 1.17 Hz, 1 H) , 7.47 (d, J = 7.92 Hz, 1 H), 7.50 (d, J = 7.92 Hz, 1 H), 7.77-7.81 (m, 1 H), 7.82-7.85 (m, 1 H), 7.87 (d , J = 7.63 Hz, 1 H), 8.54 (dd, J = 8.36, 1.03 Hz, 1 H), 10.80 (brs., 1 H); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ ppm 26.7, 32.2, 48.6, 104.7, 110.9, 111.4, 115.0, 115.6, 116.5, 117.9, 118.2, 118.3, 120.5, 121.0, 121.9, 122.9, 124.0, 124.1, 124.6, 127.0, 130.6, 136.1, 137.4, 148.1, 152.3, 156.4; _{HRMS (ESI) Calcd for C 26} H 21 N 4 [MH] -. 389.1772 Found 389.1760..

(11c) 3- (5-Methyl-5H-indolo [2,3-b] quinolin-11-ylamino) propan-1-ol:
Yield: 94%, yellow solid, Mp: 183-186 ^o C; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.85 (quin, J = 6.38 Hz, 2 H), 3.46 (t, J = 5.43 Hz, 2 H), 3.90-3.98 (m, 2 H), 4.16 (s, 3 H), 4.60 (brs., 1 H), 7.04 (t, J = 5.58 Hz, 1 H), 7.06-7.10 ( m, 1 H), 7.26-7.31 (m, 1 H), 7.41 (ddd, J = 8.14, 6.97, 1.03 Hz, 1 H), 7.50 (d, J = 7.63 Hz, 1 H), 7.76-7.81 ( m, 1 H), 7.82-7.87 (m, 1 H), 7.97 (d, J = 7.63 Hz, 1 H), 8.48 (dd, J = 8.22, 1.17 Hz, 1 H); ¹³ C NMR (150 MHz , DMSO-d ₆ ) δ ppm 32.2, 33.5, 46.0, 58.5, 104.5, 115.0, 115.5, 116.4, 117.9, 120.5, 121.9, 124.0, 124.1, 124.5, 130.6, 137.4, 148.3, 152.0, 156.2; HRMS (ESI) _{Calcd for C 19 H 18 N 3} O [MH] -. 304.1455 Found 304.1461 ..

(11d) 5-methyl-11- (4-methyl-1,4-diazepan-1-yl) -5H-indolo [2,3-b] quinoline:
Yield: 94%, orange solid, Mp: 106-107 ^o C; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.12-2.20 (m, 2 H), 2.53 (s, 3 H), 2.82-2.88 ( m, 2 H), 2.92-2.97 (t, J = 5.60 Hz, 2 H), 3.70 (t, J = 6.06 Hz, 2 H), 3.74-3.79 (m, 2 H), 4.31 (s, 3 H ), 7.21-7.27 (m, 1 H), 7.42 (ddd, J = 8.17, 5.14, 2.93 Hz, 1 H), 7.48-7.55 (m, 1 H), 7.65-7.80 (m, 3 H), 8.19 (dd, J = 7.63, 0.59 Hz, 1 H), 8.45-8.53 (d, J = 8.40 Hz, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ ppm 30.0, 32.9, 47.5, 52.0, 53.0 , 58.3, 60.9, 114.3, 117.3, 119.3, 120.8, 121.2, 122.3, 122.9, 123.8, 126.6, 128.0, 130.1, 138.2, 151.4, 154.1, 157.8.

(11e) N- (4-aminobutyl) -5-methyl-5H-indolo [2,3-b] quinolin-11-amine:
Yield: 96%, yellow solid, Mp: 69-70 ^o C; ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 1.44-1.49 (m, 2 H), 1.70 (dt, J = 14.75, 7.15 Hz, 2 H), 2.66 (t, J = 6.75 Hz, 2 H), 3.73 (t, J = 6.90 Hz, 2 H), 4.15 (s, 3 H), 5.53 (brs., 1 H), 7.15-7.19 ( m, 1 H), 7.24-7.28 (m, 1 H), 7.40-7.44 (m, 1 H), 7.53 (d, J = 8.22 Hz, 1 H), 7.61 (ddd, J = 8.44, 6.97, 1.32 Hz, 1 H), 7.76 (d, J = 7.92 Hz, 1 H), 7.83 (d, J = 7.63 Hz, 1 H), 8.04 (dd, J = 8.22, 1.17 Hz, 1 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ ppm 29.1, 30.5, 32.5, 41.4, 48.9, 107.3, 114.5, 115.6, 117.1, 118.6, 120.3, 120.8, 123.9, 124.1, 125.6, 130.1, 137.8, 148.4, 152.4, 156.4; HRMS _{(ESI) Calcd for C 20 H} 21 N 4 [MH] -. 317.1772 Found 317.1769 ..

(11f) N- (3-Aminopropyl) -5-methyl-5H-indolo [2,3-b] quinolin-11-amine:
Yield: 45%, yellow solid, Mp: 95-97 ^o C; ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 1.77-1.80 (m, 2 H), 2.97-3.01 (t, J = 6.16 Hz, 2 H), 3.99 (t, J = 6.16 Hz, 2 H), 4.20 (s, 3 H), 7.16 (td, J = 7.48, 1.17 Hz, 1 H), 7.29 (ddd, J = 8.22, 7.04, 1.17 Hz, 1 H), 7.41 (td, J = 7.48, 1.17 Hz, 1 H), 7.56-7.61 (m, 1 H), 7.65 (ddd, J = 8.51, 7.04, 1.47 Hz, 1 H), 7.75 ( d, J = 7.63 Hz, 1 H), 7.95 (d, J = 7.63 Hz, 1 H), 8.11 (dd, J = 8.36, 1.32 Hz, 1 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ ppm 32.6, 32.7, 41.3, 49.3, 105.8, 114.4, 115.9, 117.0, 118.5, 120.3, 121.4, 124.1, 124.2, 125.2, 130.1, 137.9, 148.5, 152.2, 156.7.

(11g) 5-Methyl-11-morpholino-5H-indolo [2,3-b] quinoline:
Yield: 92%, red solid, Mp: 212-215 ^o C; ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 3.50-3.55 (m, 4 H) 4.03-4.08 (m, 4 H) 4.30 (s, 3 H) 7.23-7.28 (m, 1 H) 7.43 (ddd, J = 8.16, 6.84, 1.10 Hz, 1 H) 7.52 (td, J = 7.61, 1.10 Hz, 1 H) 7.68-7.76 (m, 3 H ) 8.33 (d, J = 7.94 Hz, 1 H) 8.53 (dd, J = 8.27, 1.21 Hz, 1 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ ppm 33.0, 49.2, 67.6, 114.3, 117.5, 119.4, 120.6, 121.2, 122.7, 123.2, 124.8, 126.1, 128.3, 130.3, 137.9, 149.8, 154.5, 157.6.

(12a) 2-Chloro-N- (5- (diethylamino) pentan-2-yl) -5-methyl-5H-indolo [2,3-b] quinolin-11-amine:
Yield: 55%, brown solid, Mp: 76-78 ^o C; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 0.71 (t, J = 6.60 Hz, 6 H), 1.11-1.26 (m, 2 H), 1.44 (d, J = 6.46 Hz, 3 H), 1.55-1.64 (m, 1 H), 1.64-1.73 (m, 1 H), 2.01-2.13 (m, 2 H), 2.13-2.23 ( m, 4 H), 4.16 (s, 3 H), 4.29-4.38 (m, 1 H), 6.73 (d, J = 10.27 Hz, 1 H), 7.11 (t, J = 7.48 Hz, 1 H), 7.32 (t, J = 7.80 Hz, 1 H), 7.52 (d, J = 7.92 Hz, 1 H), 7.77-7.83 (m, 2 H), 7.88 (dd, J = 9.10, 0.88 Hz, 1 H) , 8.74 (d, J = 2.05 Hz, 1 H); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ ppm 11.4, 21.4, 23.4, 32.5, 36.1, 46.0, 51.8, 52.4, 106.5, 116.8, 117.1, 117.3, 118.2, 122.0, 123.2, 124.0, 125.2, 125.3, 130.3, 136.0, 147.1, 152.6, 156.4;. HRMS (ESI) Calcd for C 25 H 30 ClN 4 [MH] - 421.2164 Found 421.2153 ..

(12b) N- (2- (1H-Indol-3-yl) ethyl) -2-chloro-5-methyl-5H-indolo [2,3-b] quinolin-11-amine:
Yield: 67%, yellow solid, Mp: 173-175 ^o C; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.19 (t, J = 6.40 Hz, 2 H), 4.18 (t, J = 6.40 Hz, 2 H), 4.22 (s, 3H), 5.25 (brs, 3H), 7.03-7.07 (m, 2H), 7.12 (t, J = 7.20 Hz, 6 H), 7.22-7.26 (m, 2H), 7.38 -7.43 (m, 2H), 7.46 (d, J = 12.00 Hz, 1 H), 7.55-7.64 (m, 3H), 7.75 (d, J = 7.60 Hz, 1 H), 7.96 (d, J = 2.00 Hz, 1 H), 8.29 (brs, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ ppm 26.5, 32.50, 48.6, 104.9, 110.9, 111.4, 116.5, 116.9, 117.0, 118.2, 118.3, 118.3, 120.9 , 122.4, 122.9, 123.1, 123.8 , 125.0, 125.2, 127.0, 130.3, 135.9, 136.1, 147.1, 151.7, 155.9;. HRMS (ESI) Calcd for C 26 H 20 ClN 4 [MH] - 423.1382 Found 423.1393 ..

(12c) 3- (2-Chloro-5-methyl-5H-indolo [2,3-b] quinolin-11-ylamino) propan-1-ol:
Yield: 27%, yellowish green solid, Mp: 223-226 ^o C; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.87-1.89 (m, 2 H), 3.45-3.48 (q, J = 4.80 Hz, 2 H), 3.95 (q, J = 6.00 Hz, 2 H), 4.19 (s, 3 H), 4.58 (t, J = 4.80 Hz, 1 H), 7.11-7.16 (m, 2 H), 7.33 (t, J = 7.80 Hz, 1 H), 7.55 (d, J = 7.80 Hz, 1 H), 7.84-7.86 (m, 1 H), 7.92 (d, J = 9.00 Hz, 1 H), 7.97 (d, J = 7.80 Hz, 1 H), 8.66 (d, J = 2.40 Hz, 1 H); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ ppm 32.4, 33.5, 45.7, 58.3, 105.0, 116.7 , 116.8, 117.1, 118.2, 122.3 , 123.0, 124.1, 124.8, 125.0, 130.2, 136.0, 147.1, 152.4, 156.3;. HRMS (ESI) Calcd for C 19 H 18 ClN 3 O [MH] - 338.1066 Found 338.1036 ..

(12d) 2-Chloro-5-methyl-11- (4-methyl-1,4-diazepan-1-yl) -5H-indolo [2,3-b] quinoline:
Yield: 48%, orange solid, Mp: 103-105 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 2.13-2.16 (m, 2 H), 2.57 (s, 3 H), 2.89 (t, J = 5.10 Hz, 2 H), 2.95 (t, J = 5.40 Hz, 2 H), 3.69-3.77 (m, 4 H), 4.31 (s, 3 H), 7.23 (t, J = 9.90 Hz, 1 H), 7.53 (t, J = 7.20 Hz, 1 H), 7.66 (d, J = 1.20 Hz, 2 H), 7.75 (d, J = 8.10 Hz, 1 H), 8.15 (d, J = 7.20 Hz , 1 H), 8.61 (s, 1 H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 30.3, 33.2, 47.7, 52.1, 53.0, 58.6, 60.7, 115.9, 117.6, 119,8, 122,2 122.9, 123.2, 124.1, 126.1, 127.0, 128.6, 130.2, 136.8, 150.1, 154.5, 157.7.

(12e) N- (4-Aminobutyl) -2-chloro-5-methyl-5H-indolo [2,3-b] quinolin-11-amine:
Yield: 86%, yellow solid, Mp: 208-210 ^o C; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.40-1.50 (m, 2 H), 1.66 (dt, J = 14.23, 7.07 Hz, 2 H), 2.66 (t, J = 6.65 Hz, 2 H), 3.64 (t, J = 6.75 Hz, 2 H), 4.00-4.07 (s, 3 H), 5.59-5.91 (brs, 1 H), 7.09 -7.17 (m, 1 H), 7.32-7.42 (m, 2 H), 7.43-7.52 (m, 1 H), 7.68 (d, J = 7.83 Hz, 1 H), 7.76 (d, J = 7.63 Hz , 1 H), 7.99 (d, J = 2.15 Hz, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ ppm 28.9, 30.3, 32.6, 41.3, 48.8, 107.4, 115.7, 116.6, 117.1, 118.8, 121.1, 123.5, 123.8 125.6, 125.8, 129.9, 136.1, 147.2, 152.4, 156.2.

(12f) N- (3-aminopropyl) -2-chloro-5-methyl-5H-indolo [2,3-b] quinolin-11-amine:
Yield: 97%, yellow solid, Mp: 123-125 ^o C; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.73-1.77 (m, 2 H), 2.61 (t, J = 6.46 Hz, 2 H), 3.91 (t, J = 6.75 Hz, 2 H), 4.13-4.16 (s, 3 H), 7.06-7.10 (m, 1 H), 7.27-7.31 (m, 1 H), 7.50 (d, J = 7.63 Hz, 1 H), 7.78-7.82 (m, 1 H), 7.85-7.88 (m, 1 H), 7.92 (d, J = 7.92 Hz, 1 H), 8.60 (d, J = 2.35 Hz , 1 H); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ ppm 32.4, 33.1, 40.0, 46.6, 104.7, 116.7, 116.8, 117.1, 118.2, 122.4, 123.1, 124.1, 124.8, 125.0, 130.2, 136.0 , 147.0, 152.4, 156.3.

(13a) 2-Bromo-N- (5- (diethylamino) pentan-2-yl) -5-methyl-5H-indolo [2,3-b] quinolin-11-amine:
Yield: 64%, yellow solid, Mp: 77-79 ^o C; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 0.72 (t, J = 6.90 Hz, 6 H), 1.12-1.27 (m, 2 H), 1.44 (d, J = 6.46 Hz, 3 H), 1.55-1.64 (m, 1 H), 1.64-1.74 (m, 1 H), 2.08-2.19 (m, 6 H), 4.16 (s, 3 H), 4.27-4.39 (m, 1 H), 6.72-6.79 (m, 1 H), 7.11 (t, J = 7.20 Hz, 1 H), 7.32 (t, J = 7.80 Hz, 1 H), 7.52 (d, J = 7.92 Hz, 1 H), 7.79 (d, J = 7.63 Hz, 1 H), 7.82 (d, J = 9.10 Hz, 1 H), 7.92 (dd, J = 9.10, 2.05 Hz, 1 H), 8.86 (d, J = 2.35 Hz, 1 H); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ ppm 11.4, 21.4, 23.3, 32.4, 36.0, 46.0, 51.8, 52.4, 106.4, 113.1 , 116.8, 117.4, 117.8, 118.2 , 122.0, 124.0, 125.2, 126.1, 133.0, 136.3, 147.0, 152.6, 156.3;. HRMS (ESI) Calcd for C 25 H 30 BrN 4 [MH] - 465.1659 Found 465.1667 ..

(13c) 3- (2-Bromo-5-methyl-5H-indolo [2,3-b] quinolin-11-ylamino) propan-1-ol:
Yield: 70%, yellow solid, Mp: 234-236 ^o C; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.84 (s, 2 H), 3.42 (d, J = 4.99 Hz, 2 H), 3.90 (d, J = 6.16 Hz, 2 H), 4.14 (s, 3 H), 4.54 (s, 1 H), 7.05-7.10 (m, 1 H), 7.11-7.16 (m, 1 H), 7.29 (s, 1 H), 7.50 (s, 1 H), 7.80 (d, J = 9.10 Hz, 1 H), 7.88 -7.94 (m, 2 H), 8.73 (d, J = 2.05 Hz, 1 H); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ ppm 32.3, 33.5, 45.7, 58.3, 104.9, 112.8, 116.7, 117.3, 117.3, 118.2, 122.4, 124.1, 124.8, 125.9, 132.9, 136.3, 147.0, 152.4, 156.3;. HRMS (ESI) Calcd for C 19 H 17 BrN 3 O [MH] - 382.0560 Found 382.0574 ..

(13d) 2-bromo-5-methyl-11- (4-methyl-1,4-diazepan-1-yl) -5H-indolo [2,3-b] quinoline:
Yield: 82%, yellow solid, Mp: 134-137 ^o C; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.10-2.19 (m, 2 H), 2.55-2.61 (s, 3 H), 2.86- 2.92 (t, J = 4.80 Hz, 2 H), 2.93-2.99 (t, J = 5.20 Hz, 2 H), 3.70 (t, J = 5.97 Hz, 2 H), 3.73-3.78 (t, J = 4.80 Hz, 2 H), 4.29 (s, 3 H), 7.22-7.28 (m, 1 H), 7.49-7.55 (t, J = 7.20 Hz, 1 H), 7.58 (d, J = 9.00 Hz, 1 H ), 7.71-7.75 (d, J = 8.00 Hz, 1 H), 7.75-7.81 (dd, J = 8.80, 2.00 Hz, 1 H), 8.12 (d, J = 7.63 Hz, 1 H), 8.78 (d , J = 2.15 Hz, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ ppm 30.0, 33.2, 47.5, 51.9, 52.8, 58.4, 60.6, 114.4, 116.1, 117.5, 119.8, 122.5, 122.7, 122.9, 123.9, 128.5, 129.2, 132.8, 137.2, 149.9, 154.0, 157.4.

(13e) N- (4-aminobutyl) -2-bromo-5-methyl-5H-indolo [2,3-b] quinolin-11-amine:
Yield: 96%, yellow solid, Mp: 81-82 ^o C; ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 1.45-1.50 (m, 2 H), 1.65-1.69 (m, 2 H), 2.68 ( t, J = 6.60 Hz, 2 H), 3.64 (d, J = 4.11 Hz, 2 H), 4.05 (s, 3 H), 5.72 (br., 1 H), 7.17 (t, J = 7.34 Hz, 1 H), 7.29 (d, J = 8.80 Hz, 1 H), 7.39-7.44 (m, 1 H), 7.58 (dd, J = 9.10, 1.17 Hz, 1 H), 7.73 (d, J = 7.92 Hz , 1 H), 7.78 (d, J = 7.92 Hz, 1 H), 8.09 (s, 1 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ ppm 29.0, 30.5, 32.6, 41.4, 48.9, 107.6, 112.9, 116.0, 117.1, 117.3, 118.8, 121.1, 123.9, 125.9, 126.6, 132.5, 136.5, 147.0, 152.7, 156.2;. HRMS (ESI) Calcd for C 20 H 20 BrN 4 [MH] - 395.0877 Found 395.0862 ..

(13f) 2-Bromo-5-methyl-11- (4-methyl-1,4-diazepan-1-yl) -5H-indolo [2,3-b] quinoline:
Yield: 63%, yellow solid, Mp: 143-145 ^o C; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.71-1.77 (m, 2 H), 2.59 (t, J = 6.46 Hz, 2 H), 3.91 (t, J = 6.75 Hz, 2 H), 4.11-4.16 (m, 3 H), 7.08 (ddd, J = 7.92, 7.04, 0.88 Hz, 1 H), 7.29 (td, J = 7.63, 1.17 Hz, 1 H), 7.50 (dd, J = 7.92, 0.59 Hz, 1 H), 7.79 (d, J = 9.10 Hz, 1 H), 7.90 (dd, J = 9.10, 2.05 Hz, 1 H), 7.92 (d, J = 7.63 Hz, 1 H), 8.71 (d, J = 2.35 Hz, 1 H); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ ppm 32.3, 33.5, 39.5, 46.7, 104.5, 112.8, 116.7, 117.3, 117.3, 118.1, 122.4, 124.1, 124.7, 126.0, 132.9, 136.3, 147.0, 152.4, 156.3; HRMS _{(ESI) Calcd for C 19 H} 18 BrN 4 [MH] -. 381.0720 Found 381.0714 ..

(14e) N- (4-aminobutyl) -2-fluoro-5-methyl-5H-indolo [2,3-b] quinolin-11-amine:
Yield: 94%, yellow solid, Mp: 78-79 ^o C; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.47-1.53 (m, 2 H), 1.65-1.75 (m, 2 H), 2.69 ( t, J = 6.65 Hz, 2 H), 3.62-3.72 (m, 2 H), 4.12 (s, 3 H), 5.57 (brs., 1 H), 7.12-7.20 (t, J = 7.60 Hz, 1 H), 7.31-7.38 (m, 1 H), 7.39-7.50 (m, 2 H), 7.70-7.77 (m, 2 H), 7.80 (d, J = 7.83 Hz, 1 H); ¹³ C NMR ( 100 MHz, CDCl ₃ ) δ ppm 29.1, 30.5, 32.8, 41.4, 48.8, 108.2, 109.3, 109.6, 115.9, 116.0, 116.4, 116.4, 117.2, 118.0, 118.2, 118.7, 121.0, 123.6, 126.0, 134.5, 147.5, 152.8, 155.4, 156.4, 157.7; 19 F NMR (376 MHz, CDCl 3) δ ppm 121.33;. HRMS (ESI) Calcd for C 20 H 20 FN 4 [MH] - 335.1677 Found 335.1650 ..

(15c) 3- (2-methoxy-5-methyl-5H-indolo [2,3-b] quinolin-11-ylamino) propan-1-ol:
Yield: 66%, yellow solid, Mp: 206-208 ^o C; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.82 (m, 2 H), 3.42-3.47 (q, J = 4.20 Hz, 2 H), 3.89-3.91 (m, 2 H), 3.92 (s, 3 H), 4.15 (s, 3 H), 4.60 (t, J = 4.55 Hz, 1 H), 7.00 (t, J = 5.43 Hz , 1 H), 7.03-7.07 (m, 1 H), 7.28 (td, J = 7.56, 1.03 Hz, 1 H), 7.44-7.49 (m, 2 H), 7.81 (d, J = 9.10 Hz, 1 H), 7.91-7.95 (m, 2 H); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ ppm 32.3, 33.7, 45.9, 55.9, 58.6, 105.2, 106.0, 116.2, 116.3, 116.5, 117.6, 119.5 , 122.1, 123.9, 124.6, 132.2 , 147.8, 152.3, 153.6, 156.1;. HRMS (ESI) Calcd for C 20 H 20 N 3 O 2 [MH] - 334.1556 Found 334.1537 ..

(15e) N- (4-aminobutyl) -2-methoxy-5-methyl-5H-indolo [2,3-b] quinolin-11-amine:
Yield: 79%, gel; ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 1.41-1.49 (m, 2 H), 1.67-1.72 (m, 2 H), 2.62-2.67 (m, 2 H), 3.64 -3.72 (m, 2 H), 3.85 (s, 3 H), 4.11 (s, 3 H), 5.49 (brs., 1 H), 7.13 (t, J = 7.20 Hz, 1 H), 7.23 (dd , J = 6.00, 3.00 Hz, 1 H), 7.38 (t, J = 8.40 Hz, H), 7.42-7.47 (m, 2 H), 7.70 (d, J = 7.92 Hz, 1 H), 7.81 (d , J = 7.63 Hz, 1 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ ppm 29.1, 30.5, 32.6, 41.4, 48.8, 55.6, 106.4, 108.2, 115.7, 116.4, 116.8, 118.3, 118.9, 120.9, 123.7, 125.7, 132.7, 148.0, 152.6, 153.4, 156.1;. HRMS (ESI) Calcd for C 21 H 23 N 4 O [MH] - 347.1877 Found 347.1857 ..

(15f) N- (3-aminopropyl) -2-methoxy-5-methyl-5H-indolo [2,3-b] quinolin-11-amine:
Yield: 80%, yellow solid, Mp: 73-74 ^o C; ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 1.68-1.71 (m, 2 H), 2.92 (t, J = 5.87 Hz, 2 H) , 3.82 (s, 3 H), 3.90 (t, J = 5.40 Hz, 2 H), 4.12 (s, 3 H), 7.05 (brs., 1 H), 7.14 (t, J = 7.19 Hz, 1 H ), 7.21 (dd, J = 9.24, 2.79 Hz, 1 H), 7.35-7.44 (m, 3 H), 7.72 (d, J = 7.92 Hz, 1 H), 7.93 (d, J = 7.63 Hz, 1 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ ppm 32.5, 32.5, 41.4, 49.2, 55.6, 106.0, 106.4, 115.5, 116.4, 116.8 118.0, 118.8, 121.5, 124.0, 125.2, 132.6, 147.8, 152.7, 153.4, 156.6;. HRMS (ESI ) Calcd for C 20 H 21 N 4 O [MH] - 333.1721 Found 333.1684 ..

(16c) Methyl 11- (3-hydroxypropylamino) -5-methyl-5H-indolo [2,3-b] quinoline-9-carboxylate:
Yield: 89%, yellow solids. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.89 (q, J = 6.31 Hz, 9 H), 3.42-3.51 (m, 9 H), 3.86 (s, 13 H), 3.96 (q, J = 6.33 Hz, 9 H), 4.18 (s, 14 H), 4.57 (t, J = 4.70 Hz, 5 H), 7.43-7.49 (m, 9 H), 7.51 (d , J = 8.41 Hz, 4 H), 7.79-7.85 (m, 5 H), 7.86-7.93 (m, 9 H), 8.53 (d, J = 8.22 Hz, 4 H), 8.57 (d, J = 1.17 Hz, 4 H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ ppm 32.5, 33.6, 45.8, 51.6, 58.4, 103.1, 115.5, 115.6, 116.0, 118.4, 121.3, 123.6, 124.0, 124.1, 125.7, 131.2, 137.4, 149.2, 155.8, 158.3, 167.4.

(16d) Methyl 5-methyl-11- (4-methyl-1,4-diazepan-1-yl) -5H-indolo [2,3-b] quinoline-9-carboxylate:
Yield: 87%, orange solids. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.30 (brs., 2 H), 2.62 (s, 3 H), 2.99 (d, J = 3.91 Hz, 1 H), 3.14 (brs., 2 H), 3.78 (t, J = 5.97 Hz, 2 H), 3.89 (d, J = 3.52 Hz, 2 H), 3.97 (s, 3 H), 4.37 (s, 3 H) , 7.50 (ddd, J = 8.02, 5.38, 2.45 Hz, 1 H), 7.70 (d, J = 8.41 Hz, 1 H), 7.77-7.84 (m, 2 H), 8.22 (d, J = 8.41 Hz, 1 H), 8.46 (d, J = 8.22 Hz, 1 H), 8.93 (s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ ppm 29.2, 33.3, 47.2, 51.9, 52.2, 52.9, 57.9 61.3, 115.0, 116.8, 120.8, 121.0, 121.5, 122.0, 122.8, 125.7, 126.8, 129.7, 130.7, 138.5, 152.3, 157.9, 159.5, 168.1.

(16e) Methyl 11- (4-aminobutylamino) -5-methyl-5H-indolo [2,3-b] quinoline-9-carboxylate:
Yield: 94%, yellow solids. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.42-1.51 (m, 2 H), 1.75-1.84 (m, 2 H), 2.66 (t, J = 7.48 Hz , 2 H), 3.86 (s, 3 H), 3.89 (t, J = 7.04 Hz, 2 H), 4.19 (s, 3 H), 7.48 (t, J = 7.48 Hz, 1 H), 7.53 (d , J = 8.22 Hz, 1 H), 7.82-7.86 (m, 1 H), 7.89-7.93 (m, 2 H), 8.52 (s, 1 H), 8.61 (brs., 1 H); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ ppm 24.9, 27.6, 32.5, 38.7, 47.3, 51.7, 103.0, 115.5, 115.7, 116.9, 118.4, 121.4, 123.7, 124.0, 124.1, 125.8, 131.2, 137.4, 149.0, 155.9 , 158.4, 167.4.

(16f) Methyl 11- (3-aminopropylamino) -5-methyl-5H-indolo [2,3-b] quinoline-9-carboxylate:
Yield: 92%, yield solids. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.81 (q, J = 6.36 Hz, 2 H), 2.71 (t, J = 6.26 Hz, 2 H), 3.86 ( s, 3 H), 4.00 (t, J = 6.55 Hz, 2 H), 4.19 (s, 3 H), 7.46 (t, J = 7.43 Hz, 1 H), 7.52 (d, J = 8.41 Hz, 1 H), 7.79-7.86 (m, 1 H), 7.86-7.94 (m, 2 H), 8.52 (d, J = 8.22 Hz, 1 H), 8.63 (s, 1 H); ¹³ C NMR (150 MHz , DMSO-d ₆ ) δ ppm 32.5, 33.2, 40.1, 47.2, 51.6, 102.6, 115.5, 115.6, 116.0, 118.3, 121.2, 123.6, 124.1, 124.2, 125.6, 131.1, 137.5, 149.1, 155.7, 158.3, 167.4.

(16g) Methyl 5-methyl-11-morpholino-5H-indolo [2,3-b] quinoline-9-carboxylate:
Yield: 90%, orange solids. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.67-3.75 (m, 4 H), 3.98 (s, 3 H), 4.10-4.18 (m, 4 H), 4.41 ( s, 3 H), 7.52 (dt, J = 8.22, 4.11 Hz, 1 H), 7.74 (d, J = 8.41 Hz, 1 H), 7.83 (d, J = 3.91 Hz, 2 H), 8.20 (dd , J = 8.41, 1.57 Hz, 1 H), 8.50 (d, J = 8.22 Hz, 1 H), 9.01 (d, J = 0.98 Hz, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ ppm 33.7, 51.0, 52.0, 67.6, 115.1, 116.5, 120.7, 121.0, 121.1, 122.0, 122.4, 126.0, 126.5, 129.7, 131.0, 138.1, 151.3, 156.7, 158.4, 167.9.

(16h) Methyl 11- (2- (dimethylamino) ethylamino) -5-methyl-5H-indolo [2,3-b] quinoline-9-carboxylate:
Yield: 82%, yellow solids. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.26 (s, 6 H), 2.64 (t, J = 6.06 Hz, 2 H), 3.86 (s, 3 H) , 3.99 (q, J = 5.41 Hz, 2 H), 4.20 (s, 3 H), 7.25 (brs., 1 H), 7.47 (t, J = 7.53 Hz, 1 H), 7.54 (d, J = 8.22 Hz, 1 H), 7.81-7.88 (m, 1 H), 7.89-7.98 (m, 2 H), 8.53 (d, J = 8.22 Hz, 1 H), 8.69 (s, 1 H).

(16j) Methyl 11- (3- (dimethylamino) propylamino) -5-methyl-5H-indolo [2,3-b] quinoline-9-carboxylate:
Yield: 87%, yellow solids. ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 1.79-1.88 (m, 7 H), 2.39 (s, 21 H), 2.63-2.73 (m, 7 H), 3.94 ( s, 10 H), 4.15 (d, J = 4.99 Hz, 7 H), 4.23 (s, 10 H), 7.35 (t, J = 7.63 Hz, 3 H), 7.62-7.67 (m, 3 H), 7.67-7.74 (m, 7 H), 8.00 (d, J = 8.22 Hz, 3 H), 8.07 (dd, J = 8.22, 1.17 Hz, 3 H), 8.65 (s, 7 H).

(22a) 2-Chloro-N- (5- (diethylamino) pentan-2-yl) -6-methyl-6H-indolo [2,3-b] quinolin-11-amine:
Yield: 27%, brown gel; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.95 (t, J = 7.14 Hz, 6 H), 1.31 (d, J = 6.26 Hz, 3 H), 1.52-1.66 ( m, 3 H), 1.66-1.76 (m, 1 H), 2.39 (t, J = 7.34 Hz, 2 H), 2.46 (q, J = 7.11 Hz, 4 H), 3.92 (s, 3 H), 4.13 (m, 1 H), 4.52 (d, J = 10.76 Hz, 2 H), 7.30 (td, J = 7.63, 0.98 Hz, 2 H), 7.38 (d, J = 8.02 Hz, 2 H), 7.49 -7.55 (m, 2 H), 7.57 (dd, J = 9.00, 2.35 Hz, 1 H), 7.97 (d, J = 9.00 Hz, 1 H), 8.00 (d, J = 7.63 Hz, 2 H), 8.09 (d, J = 2.15 Hz, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ ppm 11.1, 22.1, 23.3, 27.6, 36.9, 46.6, 52.5, 54.1, 106.3, 108.4, 119.4, 119.8, 120.3 , 121.9, 121.9, 126.4, 126.7 , 129.3, 129.5, 141.6, 146.3, 147.4, 153.8;. HRMS (ESI) Calcd for C 25 H 30 ClN 4 [MH] - 421.2164 Found 421.2155 ..

(22b) N- (2- (1H-Indol-3-yl) ethyl) -2-chloro-6-methyl-6H-indolo [2,3-b] quinolin-11-amine:
Yield: 28%, gray solid, Mp: 207-209 ^o C; ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 3.15 (t, J = 6.46 Hz, 2 H), 3.87 (s, 3 H), 4.07 (d, J = 5.58 Hz, 2 H), 4.85 (brs., 1 H), 7.04 (s, 1 H), 7.05-7.09 (t, J = 7.80 Hz, 1 H), 7.16 (t, J = 7.48 Hz, 1 H), 7.26 (t, J = 9.60 Hz, 1 H), 7.30 (d, J = 7.92 Hz, 1 H), 7.40-7.46 (m, 2 H), 7.49-7.56 (m, 2 H), 7.65 (d, J = 7.92 Hz, 1 H), 7.94-8.00 (m, 2 H), 8.43 (brs., 1 H); 13C NMR (150 MHz, CDCl ₃ ) δ ppm 27.1, 27.7, 48.8, 104.9, 108.2, 111.4, 111.8, 118.5, 118.7, 119.7, 119.7, 120.0, 121.9, 122.0, 122.4, 122.9, 126.1, 126.4, 127.1, 129.1, 129.2, 136.5, 141.2, 146.1, 147.8, 153.7; HRMS ( _{ESI) Calcd for C 26 H 20} ClN 4 [MH] -. 423.1441 Found 423.1422 ..

(22c) 3- (2-Chloro-6-methyl-6H-indolo [2,3-b] quinolin-11-ylamino) propan-1-ol:
Yield: 74%, gray solid, Mp: 133-135 ^o C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.81 (m, 2 H), 3.39-3.49 (m, 2 H), 3.76 ( q, J = 6.52 Hz, 2 H), 3.86 (s, 3 H), 4.52 (brs., 1 H), 6.58 (brs., 1 H), 7.24-7.32 (m, 1 H), 7.49 (t , J = 8.00 Hz, 1 H), 7.57 (d, J = 8.00 Hz, 1 H), 7.64 (dd, J = 9.00, 2.15 Hz, 1 H), 7.88 (d, J = 9.00 Hz, 1 H) , 8.09 (d, J = 7.63 Hz, 1 H), 8.58 (d, J = 2.15 Hz, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ ppm (ppm) 27.6, 33.8, 46.0, 58.6, 102.7, 108.6, 118.5, 119.8, 119.9, 122.2, 122.9, 125.4, 125.8, 129.0, 140.7, 145.3, 148.2, 153.7;. HRMS (ESI) Calcd for C 19 H 17 ClN 3 O [MH] - 338.1066 Found 338.1062. .

(22d) 2-Chloro-6-methyl-11- (4-methyl-1,4-diazepan-1-yl) -6H-indolo [2,3-b] quinoline:
Yield: 35%, off white solid, Mp: 183-184 ^o C; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.21 (m, 2 H), 2.58 (s, 3 H), 2.86-2.94 (t , J = 2.40 Hz, 2 H), 3.00 (t, J = 5.20 Hz, 2 H), 3.68 (t, J = 6.06 Hz, 2 H), 3.75 (t, J = 4.80 Hz, 2 H), 3.94 (s, 3 H), 7.34 (t, J = 7.53 Hz, 1 H), 7.39 (d, J = 8.02 Hz, 1 H), 7.55-7.62 (m, 2 H), 8.02 (d, J = 9.00 Hz, 1 H), 8.38 (d, J = 7.83 Hz, 1 H), 8.43 (d, J = 2.35 Hz, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ ppm 27.7, 29.9, 47.4, 52.1, 52.9, 58.3, 61.1, 108.3, 114.9, 119.3, 120.0, 123.7, 124.0, 124.5, 127.6, 127.7, 129.1, 129.5, 142.3, 146.7, 150.6, 154.4.

(22e) N- (4-Aminobutyl) -2-chloro-6-methyl-6H-indolo [2,3-b] quinolin-11-amine:
Yield: 26%, light gray solid, Mp: 222-224 ^o C; ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 1.53 (m, 2 H), 1.77 (m, 2 H), 2.71 (t, J = 7.20 Hz, 2 H), 3.68 (t, J = 7.20 Hz, 2 H), 3.88 (s, 3 H), 4.92 (brs., 1 H), 7.25-7.29 (m, 1 H), 7.35 ( d, J = 8.40 Hz, 1 H), 7.46-7.51 (m, 1 H), 7.55 (dd, J = 8.80, 2.40 Hz, 1 H), 7.91-7.98 (m, 2 H), 8.09 (d. , J = 2.40 Hz, 1 H); 13C NMR (150 MHz, CDCl3) δ ppm 27.6, 29.3, 30.9, 41.7, 49.2, 104.6, 108.3, 118.4, 119.7, 120.2, 121.8, 121.8, 126.1, 126.4, 129.2, 129.4, 141.3, 146.3, 147.9, 153.9;. HRMS (ESI) Calcd for C 20 H 20 ClN 4 [MH] - 351.1382 Found 351.1366 ..

(22f) N- (3-Aminopropyl) -2-chloro-6-methyl-6H-indolo [2,3-b] quinolin-11-amine:
Yield: 61%, light gray solid, Mp: 78-79 ^o C; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.84-1.90 (m, 2 H), 2.99 (t, J = 6.40 Hz, 2 H ), 3.85-3.86 (m, 2 H), 3.92 (s, 3 H), 6.03 (brs., 1 H), 7.28 (t, J = 8.00 Hz, 1 H), 7.38 (d, J = 7.60 Hz , 1 H), 7.50 (t, J = 7.20 Hz, 1 H), 7.57 (dd, J = 8.80, 2.40 Hz, 1 H), 7.97 (s, J = 9.20 Hz, 1 H), 8.08 (d, J = 8.00 Hz, 1 H), 8.19 (d, J = 2.40 Hz, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ ppm 27.7, 33.7, 41.0, 48.9, 104.1, 108.2, 118.5, 119.7, 120.7, 122.1, 122.2, 126.0, 126.3, 129.2, 129.4, 141.3, 146.4, 148.2, 154.2;. HRMS (ESI) Calcd for C 19 H 18 ClN 4 [MH] - 337.122 Found 337.1205 ..

(22g) 2-Chloro-6-methyl-11-morpholino-6H-indolo [2,3-b] quinoline:
Yield: 27%, yellow solid, Mp: 245-247 ^o C; ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 3.54 (m, 4 H), 3.95 (s, 3 H), 4.09-4.14 (t, J = 4.80 Hz, 4 H), 7.36 (t, J = 7.63 Hz, 1 H), 7.41 (d, J = 8.22 Hz, 1 H), 7.58-7.63 (m, 2 H), 8.04 (d, J = 8.80 Hz, 1 H), 8.50 (d, J = 2.35 Hz, 1 H), 8.54 (d, J = 7.63 Hz, 1 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ ppm (ppm) 27.8 49.4, 67.8, 108.6, 115.6, 119.2, 20.0, 123.4, 124.0, 125.5, 127.9, 128.0, 129.4, 129.5, 142.6, 146.5, 149.1, 154.1.

(22h) 2-Chloro-N- (2- (dimethylamino) ethyl) -6-methyl-6H-indolo [2,3-b] quinolin-11-amine:
Yield: 44%, brown solid, Mp: 152-153 ^o C; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.44 (s, 6 H), 2.61 (t, J = 5.58 Hz, 2 H), 3.82 (q, J = 5.22 Hz, 2 H), 3.95 (s, 3 H), 6.19 (brs., 1 H), 7.28-7.34 (t, J = 7.20 Hz, 1 H), 7.39 (d, J = 8.02 Hz, 1 H), 7.49-7.54 (m, 1 H), 7.57 (dd, J = 9.00, 2.35 Hz, 1 H), 7.98 (d, J = 9.00 Hz, 1 H), 8.22 (d, J = 7.83 Hz, 1 H), 8.28 (d, J = 2.15 Hz, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ ppm 27.7, 44.9, 46.0, 58.9, 104.6, 108.3, 118.6, 119.9, 120.4 , 121.8, 122.8, 126.0, 126.2 , 129.2, 129.3, 141.2, 146.5, 148.5, 153.7;. HRMS (ESI) Calcd for C 20 H 20 ClN 4 [MH] - 351.1382 Found 351.1380 ..

(22i) N- (2-Aminoethyl) -2-chloro-6-methyl-6H-indolo [2,3-b] quinolin-11-amine:
Yield: 50%, light gray solid, Mp: 138-141 ^o C; ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 2.92 (t, J = 5.40 Hz, 2 H), 3.65 (q, J = 5.28 Hz , 2 H), 3.84 (s, 3 H), 5.83 (t, J = 5.28 Hz, 1 H), 7.24 (t, J = 7.48 Hz, 1 H), 7.29 (d, J = 7.92 Hz, 1 H ), 7.45 (t, J = 7.80 Hz, 1 H), 7.51 (dd, J = 9.10, 2.35 Hz, 1 H), 7.90 (d, J = 9.10 Hz, 1 H), 8.12 (d, J = 7.63 Hz, 1 H), 8.15 (d, J = 2.35 Hz, 1 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ ppm 27.5, 42.0, 50.4, 104.5, 108.0, 118.4, 119.6, 120.1, 121.8, 122.2 , 125.9, 126.0, 129.0, 129.1 , 141.0, 146.3,148.0, 153.6;. HRMS (ESI) Calcd for C 18 H 16 ClN 4 [MH] - 323.1069 Found 323.1039 ..

Example 10-1 Preparation of 2-chloro-5-methyl-11- (nitromethyl) -5H-indolo [2,3-b] quinoline 23
A solution of nitromethane (4 mmol) dissolved in DMSO (1 mL) was added with stirring to a dispersion of NaH dispersed in dry DMSO (5 mL). After the foam had subsided, compound 5 (1 mmol) dissolved in DMSO was added. The mixture was heated at 80 ^° C. for 4 hours. After cooling to room temperature, 20 mL of water was added and the mixture was washed twice with ethyl acetate to remove by-products. The aqueous phase was acidified with saturated NH ₄ Cl and the precipitate was filtered off. Filtrate 23 was washed with water and dried. Yield: 96%, brown solid; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 4.36 (s, 3 H), 6.89 (s, 2 H), 7.23 (t, J = 7.48 Hz, 1 H) , 7.54-7.59 (m, 1 H), 7.61-7.65 (m, 1 H), 7.94 (dd, J = 9.10, 2.35 Hz, 1 H), 8.11 (d, J = 9.10 Hz, 1 H), 8.18 (d, J = 7.92 Hz, 1 H), 8.60 (d, J = 2.35 Hz, 1 H); ¹³ C NMR (150 MHz, DMSO-d ₆ ) δ ppm 33.5, 72.4, 117.8, 117.8, 120.0, 120.5 , 122.6, 123.9, 124.7, 126.8 , 128.4, 129.0, 130.2, 130.7, 135.3, 154.9, 156.0;. HRMS (ESI) Calcd for C 17 H 11 ClN 3 O 2 [MH] - 324.0545 Found 324.0539 ..

[Example 10-2] Preparation of 2-chloro-5-methyl-5H-indolo [2,3-b] quinoline-11-carbaldehyde 24 Dispersion of compound 23 (0.5 mmol) in methanol (5 mL) While the solution was stirred at 0 ^° C., a freshly prepared solution of KOH (1.5 mmol) dissolved in methanol (10 mL) was added dropwise. After stirring for 30 minutes, a solution prepared by dissolving KMnO ₄ (0.335 mmol) and MgSO ₄ (1.5 mmol) in water (30 mL) was added dropwise with vigorous stirring. When the reaction was complete, the mixture was filtered through a thin layer of celite. The filtrate was extracted with CH ₂ Cl ₂ and the organic phase was dried over anhydrous MgSO ₄ . Further purification by flash chromatography on silica gel. Yield: 27%, red solid, Mp: 261-263 ^o C; ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 4.15 (s, 3 H), 7.08 (ddd, J = 7.78, 6.90, 1.17 Hz, 1 H), 7.45−7.49 (m, 2 H), 7.50−7.52 (m, 1 H), 7.57 (dd, J = 9.10, 2.35 Hz, 1 H), 7.84 (d, J = 7.63 Hz, 1 H) , 8.72 (d, J = 2.35 Hz, 1 H), 11.03 (s, 1 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ ppm 33.7, 115.4, 117.1, 118.3, 120.9, 121.9, 125.9, 126.0, 128.6, 130.1, 130.6, 131.7, 131.8, 134.6, 155.8, 156.7, 190.6.

Example 10-3 Preparation of 11-aminoalkylaminomethylated neocryptolepine derivatives 25 Aldehyde 24 (0.1 mmol) and the appropriate amine (0.5 mmol) were dissolved in MeOH. After stirring overnight at room temperature, NaBH4 (0.5 mmol) was added. The mixture was stirred for an additional 2 hours. The reaction was quenched with saturated NH ₄ Cl, extracted with CH ₂ Cl ₂ and the organic phase was dried over anhydrous MgSO ₄ . Further purification by flash chromatography on silica gel.

(25d) 2-Chloro-5-methyl-11-((4-methyl-1,4-diazepan-1-yl) methyl) -5H-indolo [2,3-b] quinoline:
Yield: 36%, orange solid, Mp: 164−166 ^o C; ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 1.83−1.90 (m, 2 H), 2.34 (s, 3 H), 2.54 (dt, J = 4.92, 2.38 Hz, 2 H), 2.63−2.72 (m, 2 H), 2.88−2.93 (m, 2 H), 2.96 (t, J = 6.16 Hz, 2 H), 4.32 (s, 3 H ), 4.49 (s, 2 H), 7.20−7.25 (m, 1 H), 7.54 (td, J = 7.63, 1.17 Hz, 1 H), 7.63−7.70 (m, 2 H), 7.72 (d, J = 7.92 Hz, 1 H), 8.28 (d, J = 7.63 Hz, 1 H), 8.60 (d, J = 2.05 Hz, 1 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ ppm 27.3, 33.2, 46.6, 54.1, 55.1, 56.3, 58.1, 115.4, 117.9, 119.9, 122.1, 124.1, 124.3, 126.9, 126.9, 128.3, 129.3, 130.1, 135.2, 139.1, 155.7, 155.9; HRMS (ESI) Calcd for C ₂₃ H _{24 ^{ClN 4 [MH] -. 391.1689}} Found 391.1750 ..

(25j) N ¹ -((2-Chloro-5-methyl-5H-indolo [2,3-b] quinolin-11-yl) methyl) -N ³ , N ³ -dimethylpropane-1,3-diamine:
Yield: 56%, red solid, Mp: 150−153 ^o C; ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 1.68−1.74 (m, 3 H), 2.15−2.19 (m, 10 H), 2.29− 2.34 (m, 4 H), 2.90 (t, J = 6.75 Hz, 3 H), 4.25 (s, 5 H), 4.53 (s, 3 H), 7.21 (td, J = 7.48, 1.17 Hz, 2 H ), 7.50−7.54 (m, 2 H), 7.57−7.60 (m, 2 H), 7.62−7.65 (m, 2 H), 7.69 (d, J = 7.92 Hz, 2 H), 8.05 (d, J = 7.63 Hz, 2 H), 8.26 (d, J = 2.05 Hz, 2 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ ppm 27.9, 33.3, 45.6, 45.7, 46.6, 49.1, 58.1, 115.8, 118.1 , 120.3, 121.6, 123.3, 123.8, 125.5, 127.3, 127.5, 129.4, 130.2, 135.4, 139.6, 155.7, 155.7.

[Anti-tumor activity evaluation test]
The compound synthesized in Example Group II was screened for antitumor activity (antiproliferative activity against cancer cells). Screening was conducted at the following institutions:
Prof. Joanna Wietrzyk and Dr. Marta −witalska
Institute of Immunology and Experimental Therapy
Polish Academy of Sciences
12, R. Weigl Street, 53-114 Wroclaw, Poland.

<Materials and methods>
(Cell line)
Established in vitro human cancer cell lines: MV4-11 (biphenotypic B myelomonocytic leukemia), A549 (non-small cell lung cancer) and HCT116 (colon cancer) and normal mice Fibroblast cell line: BALB / 3T3 was used. These cell lines are obtained from the American Type Culture Collection (Rockville, Maryland, USA) and are stored at the Immunology and Experimental Care Institute in Wroclaw, Poland.

MV4-11 cells were cultured in RPMI 1640 supplemented with 2 mM L-glutamine, 1.0 mM sodium pyruvate, and 10% fetal calf serum (all from Sigma-Aldrich, Steinheim, Germany). HCT116 and A549 cells were RPM1 1640 + OptiMEM (50:50) (Gibco, Scotland, UK) supplemented with 2 mM L-glutamate and 10% fetal calf serum (all from Sigma-Aldrich, Steinheim, Germany). Incubated in. BALB / 3T3 cells were cultured in Dulbecco medium (IIET) supplemented with 2 mM L-glutamate, 1.0 mM sodium pyruvate, and 10% fetal calf serum (all from Sigma-Aldrich, Steinheim, Germany). . All cultures were supplemented with 100 units / mL penicillin and 100 μg / mL streptomycin (both from Polfa, Tarchomin SA, Poland). All cell lines were grown in a humidified environment at 37 ° C., 5% CO ₂ .

(In vitro antiproliferative assay)
The test compound test solution 1 mg / mL was prepared by dissolving each substance in 100 μL of DMSO and filling it with 900 μL of tissue culture solution. Thereafter, the test compound was diluted with tissue culture medium so that the final concentrations were 10, 1, 0.1, 0.01, and 0.001 μg / mL.

Cells were seeded in 96-well containers (Sarstatt, Germany) at a density of 1 × 10 ⁴ cells per well 24 hours prior to the addition of the test compound.
Bioactivity testing was performed after 72 hours of exposure to different concentrations of test compound. The cytotoxic effects of test compounds in vitro used MTT (MV411) or SRB (A549, HCT116 and BALB / 3TS) assays.

The anti-proliferative property of a test compound against cancer cells was evaluated by IC ₅₀ (50% inhibitory concentration), that is, the dose of the test compound that inhibits the growth of cancer cells by 50% at a density. IC values were calculated separately for each experiment and expressed as mean ± SD. Each concentration of compound was performed three times for one experiment, which was repeated 3-5 times.

  The antiproliferative activity against normal mouse fibroblasts (BALB / 3T3) can be evaluated in the same manner as the antiproliferative activity against various cancer cell lines (MV411, A549 and HCT116). A lower activity means less cytotoxicity to normal cells (non-tumor cells).

MTT assay:
This technique is used for cytotoxicity screening against leukemia cells growing in suspension culture. The assay was performed after 72 hours of exposure to a solution of the test compound with the concentration changed from 0.001 to 10 μg / mL. During the last 3-4 hours during culture, 20 μL of MTT solution was added to each well. (MTT: 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide, reservoir: 5 mg / mL, Sigma-Aldrich, Germany). Mitochondria in living cells reduce pale yellow MTT to purple formazan. The more viable cells are present in the well, the more MTT is reduced to formazan. At the end of the incubation period, 80 μL of lysine mixture was added to each well (lysine mixture: 225 mL dimethylformamide (POCh, Gliwice, Poland), 67.5 g sodium dodecyl sulfate (Sigma-Aldrich, Germany), and 275 mL distilled water). After 24 hours, when the crystals of formazan were dissolved, the optical density of the sample was measured for absorbance at a wavelength of 570 nm with a multi-scan microplate reader (Labsystems, Helsinki, Finland). Each compound was measured three times per experiment, and this was repeated 3 to 5 times to determine the concentration (IC ₅₀ ) of the test compound that was suppressed by 50%.

SRB assay:
This technique is used for cytotoxicity screening on cells growing in adherent cultures. Details of this technique are described by Skehan. Cytotoxicity assays were performed after 72 hours of exposure to a solution of the test compound with varying concentrations from 0.01 to 10 μg / mL. Cells attached to the plastic were fixed by slowly laminating 50% TCA (trichloroacetic acid, Sigma-Aldrich, Germany) on top of the culture in each well. The test plate was incubated at 4 ° C. for 1 hour and washed 5 times with tap water. The optical density background was measured in the absence of cells in wells filled with culture medium. Cells fixed with TCA were stained with 0.4% sulforhodamine (SRB, Sigma-Aldrich, Germany) dissolved in 1% acetic acid (POCh, Gliwice, Poland) for 30 minutes. Unstained dye was removed by rinsing 4 times with 1% acetic acid. The dye bound to the protein was extracted with 10 mM unbuffered Tris base (Sigma-Aldrich, Germany) and the optical density of the sample was measured using a computer-controlled 96-well microtiter plate reader multi-scan RC photometer (Labsystems, Helsinki, (Finland) at a wavelength of 540 nm.

<Results of activity test>
The results of in vitro antiproliferative assays of 11-alkylamino- and 11-aminoalkylaminoindolo [2,3-b] quinoline derivatives are summarized in Tables 4-8.

Table 4 shows the results of an antiproliferative assay of 11-amino-5-methyl-5H-indolo [2,3-b] quinolines 11-16 (see Scheme 3) against MV4-11 (leukemia cells). All compounds tested other than 11d are cytotoxic to human leukemia cell lines (IC ₅₀ is 0.9 μM or less) and their antiproliferative properties are cisplatin (IC ₅₀ ), a well-known anticancer agent. The activity was higher than that of 2.82 μM). The most active one tested was 13f (IC ₅₀ 0.012 μM), which has an aminopropylamino group at the 11th position and a bromo group at the 2nd position in the neocryptorepine skeleton. Compounds 11c, 11e-g, 12b, 12d, 12f, 13e, 14 and 15 also showed extremely high activity (IC ₅₀ 0.06-0.45 μM). The halogen substituent at the 2-position was effective in antiproliferative properties. For example, 11-aminopropylamino-2-broindolo [2,3-b] quinoline 13f shows 4 times more activity than the corresponding non-bromo substituted 11f. A similar trend is seen in 11b and 12b. However, in the drug substituted with 3-hydroxypropylamino, when Cl and Br halogen were substituted at the 2-position, the activity was reduced by a factor of 4 compared to the non-halogen substituted product. Good antiproliferative properties were also observed when a hydroxymethyl group, which is an electron donating group, was introduced as a substituent at the 2-position.

次に、有望な活性が得られた化合物について、A549（肺がん細胞）、HCT116（結腸がん細胞）およびBALB/3T3（線維芽細胞）に対する抗増殖性をアッセイした。結果を表５に示す。検査した全ての化合物はがん細胞（A549およびHCT116）に対して細胞毒性を示し、それらのがん細胞に対する活性は標準に使ったシスプラチンの活性よりも優れていた。例えば、化合物11f, 13e, 13fおよび15fはA549およびHCT116（がん細胞）に対して高い抗増殖性を示し、細胞毒性は低いデータを示した。BALB/3T3（正常線維芽細胞）に対して、それらの抗増殖性は３〜４倍低下した。化合物12d, 12f, 14eおよび15cは主としてHCT116（結腸がん細胞）に対して選択的な抗増殖性を示したが、A549（肺がん細胞）およびBALB/3T3（正常線維芽細胞）に対して活性は４倍低下した。これらの結果より、適当なアルキルアミノ基の導入はDNAとの結合生成において活性と選択性の上昇に効果をもつことが明らかである。

Next, compounds with promising activity were assayed for antiproliferative activity against A549 (lung cancer cells), HCT116 (colon cancer cells) and BALB / 3T3 (fibroblasts). The results are shown in Table 5. All compounds tested were cytotoxic to cancer cells (A549 and HCT116), and their activity against cancer cells was superior to that of the standard cisplatin. For example, compounds 11f, 13e, 13f and 15f showed high antiproliferative activity against A549 and HCT116 (cancer cells) and data with low cytotoxicity. In contrast to BALB / 3T3 (normal fibroblasts), their antiproliferative properties were reduced 3-4 times. Compounds 12d, 12f, 14e, and 15c showed selective antiproliferative properties mainly against HCT116 (colon cancer cells) but were active against A549 (lung cancer cells) and BALB / 3T3 (normal fibroblasts) Fell 4 times. From these results, it is clear that the introduction of an appropriate alkylamino group has an effect of increasing activity and selectivity in the formation of a bond with DNA.

11-アミノ-6-メチル-6H-インドロ[2,3-b]キノリン類22（Scheme 4参照）の抗増殖性アッセイの結果を表６および７に示す。6-メチル異性体は対応する5-メチル異性体よりも低い細胞毒性を示した。ただ、22bと22gはMV4-11（白血病細胞）に対して抗増殖性が見られない。22dはHCT116（結腸がん細胞）とA549（肺ガン細胞）に効果が見られたが、BALB/3T3（繊維芽細胞）に対して細胞毒性を示さない、IC₅₀ は25 (μM以上であった。

The results of the antiproliferative assay of 11-amino-6-methyl-6H-indolo [2,3-b] quinolines 22 (see Scheme 4) are shown in Tables 6 and 7. The 6-methyl isomer showed lower cytotoxicity than the corresponding 5-methyl isomer. However, 22b and 22g do not show antiproliferative activity against MV4-11 (leukemia cells). 22d was effective against HCT116 (colon cancer cells) and A549 (lung cancer cells), but was not cytotoxic to BALB / 3T3 (fibroblasts), with an IC ₅₀ of 25 (μM or higher). It was.

11-アミノ-5-メチル-6H-インドロ[2,3-b]キノリン類25（Scheme 5参照）の抗増殖性アッセイの結果を表８に示す。11-アミノアルキルアミノネオクリプトレピン誘導体25は、MV4-11（ヒト白血病細胞）に対する一定の抗増殖性が見られたが、前述の類縁化合物と比較すると活性は著しく低下した（12d, 22d, 25d）。

The results of the antiproliferative assay of 11-amino-5-methyl-6H-indolo [2,3-b] quinolines 25 (see Scheme 5) are shown in Table 8. The 11-aminoalkylaminoneocryptrepine derivative 25 showed a certain antiproliferative activity against MV4-11 (human leukemia cells), but the activity was significantly reduced compared to the above-mentioned related compounds (12d, 22d, 25d).

Claims (15)

An indolequinoline derivative (A) or a pharmaceutically acceptable salt thereof, which is represented by the following formula (A):

(In the formula (A),
R ¹ is a halogen atom, alkyl group, hydroxy group, alkoxy group, carboxy group, alkoxycarbonyl group or nitro group, n is an integer of 0 to 4,
R ² is a group represented by the following formula (R2):

In the formula (R2), x is 1 or 0, and Z ¹ , Z ² , and an alternate long and short dash line relating to the bond between Z ¹ and Z ² are as shown in [R2-I] or [R2-II] below. is there.
[R2-I] Z ¹ and Z ² are not bonded by a one-dot chain line, Z ¹ is a hydrogen atom, Z ² has a group represented by the following formula (Z2) or a substituent. It may be an aryl group, an alkenyl group or an alkynyl group.

In formula (Z2), Z ³ is a linear or branched alkylene group having 1 to 12 carbon atoms, and Z ⁴ has an amino group which may have a substituent, or a substituent. A nitrogen-containing heteroaryl group or a hydroxy group.
[R2-II] Z ¹ and Z ² are bonded by a one-dot chain line, and together with the nitrogen atom to which they are bonded, an atomic group that forms an optionally substituted 3- to 8-membered ring structure Represents.
R ³ is a halogen atom, a carboxy group, or an alkoxycarbonyl group, m is an integer of 0 to 4,
R ⁴ , R ⁵ , broken line (i) and broken line (ii) are as defined in [R4-I] or [R4-II] below.
[R4-I] R ⁴ is absent, R ⁵ is an alkyl group, the broken line (i) is a double bond, broken line (ii) is a single bond.
[R4-II] R ⁴ is an alkyl group, R ⁵ is absent and the broken line (i) is a single bond, a broken line (ii) is a double bond. In the case where the definition of the formula (R2) is as described in the above [R2-I], Z ⁴ in the formula (Z2) is a group represented by the following formula (Z4). Indole quinoline derivative (A) or a pharmaceutically acceptable salt thereof.

In formula (Z4), Z ⁵ , Z ⁶ , and the alternate long and short dash line relating to the bond between Z ⁵ and Z ⁶ are as shown in the following [Z4-I], [Z4-II] or [Z4-III].
[Z4-I] Z ⁵ and Z ⁶ do not have a single-dot chain bond, Z ⁵ is a hydrogen atom, Z ⁶ has an aryl group which may have a substituent, and a substituent. Or a group containing a heteroaryl group or an alkyl group.
[Z4-II] Z ⁵ and Z ⁶ are bonded by a one-dot chain line, and have an aryl group which may have a substituent together with the nitrogen atom to which they are bonded, as a substituent. The atomic group which forms a 5-membered ring structure or a 6-membered ring structure is represented.
[Z4-III] Z ⁵ and Z ⁶ do not have a single-dot bond, and Z ⁵ and Z ⁶ are alkyl groups independent of each other. The indolequinoline derivative (A) according to claim 1, wherein when the definition of the formula (Z4) is as described in the above [Z4-I], the Z ⁶ is a group represented by the following formula (Z6). Or a pharmaceutically acceptable salt thereof.

In the formula (Z6), Z ⁷ is a divalent group represented by the following formula (Z71), (Z72), (Z73) or (Z74), and Z ⁸ is an aryl which may have a substituent. Group, a heteroaryl group which may have a substituent, or an alkyl group. )

The indolequinoline derivative (A) according to claim 3, wherein Z ⁸ is an optionally substituted phenyl group, or an optionally substituted pyridyl group, thienyl group or indolyl group. Its pharmaceutically acceptable salt. When the definition of the said formula (Z4) is as the said [Z4-II], the said 5-membered ring structure or a 6-membered ring structure is group represented by a following formula (Z42). Indolequinoline derivative (A) or a pharmaceutically acceptable salt thereof.

In formula (Z42), Z ⁹ is a divalent group represented by the following formula (Z91) or (Z92), and Z ¹⁰ is an aryl group which may have a substituent.

In formula (Z91), each R ⁹¹ independently represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a carboxy group, or an alkoxycarbonyl group, and p is 1 or 2.
In the formula (Z92), R ⁹² represents a halogen atom, an alkyl group, a hydroxy group, an alkoxy group, a carboxy group, an alkoxycarbonyl group, or a nitro group, and q is an integer of 0 to 4. The indolequinoline derivative (A) or a pharmaceutically acceptable salt thereof according to claim 5, wherein Z ¹⁰ is a phenyl group which may have a substituent. A method for producing an indolequinoline derivative (A) represented by the formula (A) or a pharmaceutically acceptable salt thereof, comprising the following step [1].
Process [1]
A step of reacting a compound having an indolequinoline mother nucleus structure represented by the following formula (A0) with an amine compound represented by the following formula (r2) to obtain a compound represented by the following formula (A1).

In the formula (A0), R ¹ , n, R ³ , m, R ⁴ , R ⁵ , i and ii are as defined in the formula (A), and X is a halogen atom or a lower acyloxy group.

In formula (r2), Z ¹ and Z ² have the same meaning as in formula (R2).

In the formula (A1), R ¹ , n, R ³ , m, R ⁴ , R ⁵ , i and ii are as defined in the formula (A0), and Z ¹ and Z ² are as defined in the formula (r2). is there. A method for producing the indolequinoline derivative (A) represented by the formula (A) or a pharmaceutically acceptable salt thereof, comprising the following step [1 ′].
Process [1 ']
Adding nitromethane to a compound having an indolequinoline mother nucleus structure represented by the following formula (A0) to obtain a compound represented by the following formula (A0 ′);
A step of obtaining a compound represented by the following formula (A0 ″) from the compound represented by the following formula (A0 ′) by performing Nef reaction under oxidative conditions, and represented by the following formula (A0 ″): A step of obtaining a compound represented by the following formula (A1 ′) from the compound obtained by reductive amination using an amine compound represented by the following formula (r2).

In the formula (A0), R ¹ , n, R ³ , m, R ⁴ , R ⁵ , i and ii are as defined in the formula (A), and X is a halogen atom or a lower acyloxy group.
In the formulas (A0 ′) and (A0 ″), R ¹ , n, R ³ , m, R ⁴ , R ⁵ , i and ii are as defined in the formula (A).
In formula (r2), Z ¹ and Z ² have the same meaning as in formula (R2).
In the formula (A1 ′), R ¹ , n, R ³ , m, R ⁴ , R ⁵ , i and ii have the same meaning as the formula (A0), and Z ¹ and Z ² have the same meaning as the formula (r2). It is. A production method for producing a compound represented by the following formula (A11) as the indolequinoline derivative (A),
The step [1] or [1 ′] is a step of obtaining a compound represented by the following formula (A10) by using a compound represented by the following formula (r21) as the amine compound (r2),
The manufacturing method of Claim 7 or 8 including the following process [2] after the said process [1].

In formula (A11), R ¹ , n, x, R ³ , m, R ⁴ , R ⁵ , i and ii are as defined above for formula (A), and Z ³ is as defined above for formula (Z2). , Z ⁵ and Z ⁶ have the same meanings as those in the formula (Z4) except that the above [Z4-III] is not taken.

In formula (r21), Z ³ has the same meaning as in formula (Z2).

In formula (A10), R ¹ , n, x, R ³ , m, R ⁴ , R ⁵ , i and ii are as defined above for formula (A), and Z ³ is as defined above for formula (Z2). .
Process [2]
A step of obtaining the compound (A11) by reacting the compound (A10) obtained in the step [1] with a compound (z4) capable of reacting with the terminal amino group of the compound (A10). A method for producing a compound represented by the following formula (A111) as the indolequinoline derivative (A11),
The step [2] is a step of obtaining the compound (A111) by using a compound represented by any of the following formulas (z611) to (z614) as the compound (z4). The manufacturing method as described.

In formula (A112), R ¹ , x, n, R ³ , m, R ⁴ , R ⁵ , i and ii are as defined above for formula (A), and Z ³ is as defined above for formula (Z2). , Z ⁷ and Z ⁸ are as defined in the above formula (Z6).

In formulas (z611) to (z614), Z ⁸ has the same meaning as in formula (Z6), and X is a halogen atom. The production method according to claim 10, wherein Z ⁸ is a phenyl group which may have a substituent, or a pyridyl group, a thienyl group or an indolyl group which may have a substituent. A method for producing a compound represented by the following formula (A112) as the indolequinoline derivative (A11),
The step [2] uses, as the compound (z4), a compound represented by either the following formula (z91) or (z92) and a compound represented by the following formula (z10). The manufacturing method of Claim 9 which is a process of obtaining a compound (A112).

In formula (A112), R ¹ , n, x, R ³ , m, R ⁴ , R ⁵ , i and ii are as defined above for formula (A), and Z ³ is as defined above for formula (Z2). , Z ⁹ and Z ¹⁰ are as defined in the above formula (Z42).

In the formula (z91), R ⁹¹ and p have the same meanings as the formula (Z91).
In the formula (z92), R ⁹² and q have the same meaning as in the formula (Z92).

In formula (z10), Z ¹⁰ has the same meaning as in formula (Z42). The production method according to claim 12, wherein Z ¹⁰ is an optionally substituted phenyl group.   An antimalarial agent comprising the indolequinoline derivative (A) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient.   An anticancer agent comprising the indolequinoline derivative (A) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient.